Download Section 8 - Central Cancer Network

Section 8. Reducing the Incidence and Impact of
Cancer
Expert Comment:
Professor William Denny (ONZM, PhD, DSc, FRSNZ), Director,
Auckland Cancer Society Research Centre and Principal
Investigator, Maurice Wilkins Centre for Molecular
Biodiscovery
“
Drug Development
Globally, the R&D effort into new cancer therapies has never
been higher. In 2007, oncology drugs became the biggest-selling
category of drug within the WHO disease classification, and
more than 500 new cancer drug trials are registered with the
USFDA.
Much research continues into improved “classical” cytotoxic
drugs that disrupt DNA function. However, the major effort
(both small molecules and antibodies) is now focused on
“targeted” therapies aimed at up-regulated or mutant enzymes,
primarily kinases in the signal transduction and gene surveillance
networks, although additional targets do exist (e.g., DNA
methylases and histone deacetylases). A third area of growing
importance is tumour-selective prodrugs. This includes drugs
that exploit physiological differences (e.g., hypoxia, pH and
redox) between tumour and normal cells to become selectively
activated in tumours. Another class exploits the ability of
antibodies to accumulate on/in tumour cells by antigen binding
(often followed by internalisation) to deliver/release attached
toxins selectively.
An area of growing research focus for all of these classes is noninvasive diagnostic methods to verify both the presence in
tumours of the targeted enzyme (defining appropriate patients),
and its blockade by the treatment (early evidence of efficacy).
Research capacity/capability in NZ in these areas is remarkably
good, with public-good/charity-supported basic research being
complemented with commercial collaborations.
Professor Denny co-authored 11 of the publications included in this
section, in the area of drug development or oncogenesis.
”
112 Cancer
Expert Comment:
Dr Bridget Robinson, Medical Oncologist, Christchurch DHB and
Associate Professor of Medicine, University of Otago,
Christchurch
“
Cancer Control
Research into cancer control has addressed issues relevant to
New Zealand. Disparities have been addressed to a much greater
degree than before, with studies of the detection, presentation,
characteristics (including genetics) and management of cancer in
our variety of ethnic and socioeconomic settings. The specific
attention paid to cancer in Māori and Pacific people is starting to
yield results that have the potential to improve outcomes.
Modelling projects will help plan future services. New studies
focus on lifestyle factors including nutrition, obesity and physical
activity. A number of internationally recognised research groups
have contributed to the explosion of knowledge in the genetics
and molecular biology of cancer.
Some New Zealand
researchers, such those working in the areas of stomach cancer
and Wilm’s tumour, continue to lead the world in their fields of
investigation. These fundamental studies will eventually lead to
advances in management, whether by better diagnosis, prediction
or a targeted therapy. Clinical trials remain very important in
establishing best care, and now include translational molecular
studies to stratify tumours and/or patients and predict outcome.
Researchers have undertaken systematic Cochrane-type reviews
to help guide cancer management by analysis of existing data and
trials, whether or not they were published. The research has
covered the full spectrum of cancer control, and has relevance for
New Zealand and beyond.
”
Dr Robinson co-authored four of the publications featured in this
section, in the area of breast cancer or cancer disparities.
Current Research Supported or Administered by the HRC
District Health Board Research Fund (DHBRF)
Improving Detection and Management Services in Primary Care for
People with Cancer
The Cancer Steering Committee for the DHBRF has developed a Request for
Proposals (RFP) with the aim of improving the quality of primary care services for
people with cancer. The research project should identify and describe ‘best
practice’ solutions which can inform future development of service delivery
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113
models for the detection of cancer (excluding formal screening) and those which
are designed to provide effective and efficient subsequent management (including
palliative care) for people in primary care.
The research project should include recommendations for service delivery models,
which can be practically and successfully implemented by any DHB in order to
achieve the best outcomes. The Cancer Steering Committee is particularly
interested in recommendations that identify barriers to best practice and
recommendations leading to the implementation of service delivery models to
improve health outcomes and reduce inequalities.
Those service models
demonstrating best practice should also have accompanying economic
evaluations.
The research will include an investigation of the interface between the primary,
secondary and, tertiary health service providers, (including the interface with the
NGO voluntary sector). This approach should demonstrate ways of improving
population health including, primary and secondary clinical outcomes through
examples of ‘best practice’ service delivery as well as providing opportunities for
translational research.
The RFP was released in July 2008.
HRC Partnership Programme Initiatives
Cancer Control RFPs
The Ministry of Health and the HRC aim to support the New Zealand Cancer
Control Strategy through the coordination of a Primary Prevention of Cancer and
Other Chronic Diseases research programme that will provide the evidence base
required to reduce the incidence of cancer. This research venture also presents an
important opportunity to contribute to the Government’s priority area of reducing
the burden of chronic disease as the risk factors and opportunities for primary
prevention of cancer are the same as those for other chronic diseases such as
cardiovascular disease and diabetes.
For the first three years, research in this programme will be focused on two
distinct research areas: tobacco control, and nutrition, physical activity and
obesity. In June 2008, the second RFP in each of these areas was released. One
RFP is focused on establishing ways to improve delivery of nutrition and physical
activity interventions for Māori and Pacific peoples by the Healthy Eating Healthy
Action (HEHA) workforce. The other RFP is focused on motivations to quit
smoking and stay quit for Māori, Pacific and low-income New Zealanders. It is
expected that research providers for these RFPs will be contracted in November
2008.
Research providers have been confirmed for the initial RFPs that were released in
February 2007, and details of the funded projects in each of the two research areas
are listed below. Two research teams, led by Dr Cliona Ni Mhurchu and Mr
Charles Waldegrave were contracted to complete work on complementary aspects of
the nutrition, physical activity and obesity RFP.
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Enhancing food security and physical activity for Māori, Pacific and low income
whanau/families
Principal investigator: Dr Cliona Ni Mhurchu
Email address:
[email protected]
Host institution:
Auckland UniServices Ltd
Approved budget:
$599,000
End date:
31/07/2009
HRC Ref:
08/002
Aims: (1) To clarify the interaction and contribution of environmental factors to
food security and physical activity for Māori, Pacific and low-income
whanau/families; (2) To identify how these factors might be modified to improve
food security and physical activity.
Methods: (1) A systematic literature review will be undertaken and will be
supplemented by an analysis of relevant ongoing New Zealand research; (2) Focus
groups will be conducted with urban and rural Māori, Pacific and low income
New Zealanders (3) The ANGELO framework will be used to identify and
prioritise key environmental factors; (4) Individual interviews will be conducted
with 2,500 participants from the 2008 Adult National Nutrition Survey; (5) Key
informant interviews will be conducted with representatives of Māori, Pacific and
low income communities; (6) Findings from all sources will be triangulated to
identify factors with most influence on food security and physical activity and
how they could be targeted for intervention.
Outcomes: This research will provide essential information on the association of
key environmental factors with food security and physical activity amongst
Māori, Pacific and low-income whanau/familites in New Zealand.
Enhancing food security and physical activity for Māori, Pacific and low income
whanau/families
Principal investigator: Mr Charles Waldegrave
Email address:
[email protected]
Host institution:
The Family Centre
Approved budget:
$291,107
End date:
30/06/2009
HRC Ref:
08/572
This proposed research will complement a larger study of food security and
physical activity for Māori, Pacific and low-income whanau/families. Together,
the two studies will contribute to the Primary Prevention of Cancer and other
Chronic Diseases Research Strategy.
The research will involve a detailed qualitative study of the socioeconomic factors
associated with food security and physical activity for Māori and Pacific people.
The study will apply a theoretical framework using Bourdieu's concept of habitus
and insights obtained from previous applications of Bourdieu's ideas to studying
social aspects of food and the body.
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The research will be informed by the three tikanga (Māori, Pacific and
Pakeha/European) model of research and practice developed by the Family
Centre Social Policy Research Unit and benefit from the Specialist Public and
Māori Health research expertise of the Massey University Research Centre for
Māori Health and Development, and the University of Otago Department of
Human Nutrition.
Developing strategies to reduce smoking uptake and SHS exposure of NZ
children
Principal investigator: Dr Richard Edwards
Email address:
[email protected]
Host institution:
University of Otago
Approved budget:
$599,000
End date:
31/01/2010
HRC Ref:
08/003
Phase one will involve a systematic review of local and international research, and
targeted additional analyses of local datasets and original research which will be
used in building explanatory models of the influences on smoking initiation and
children's secondhand smoke (SHS) exposure in New Zealand. The models will
focus on Māori communities and the role of parents/care-givers. We will carry
out a preliminary investigation of how household smoking policies affect air
quality and children's SHS exposure.
In phase two, we will use the explanatory models to identify possible strategies to
change parental/care-giver behaviours in Māori communities, while addressing
likely barriers and constraints. We will then develop suggested community-based
interventions. We will present these to members of potential target communities,
implementation teams and other key stakeholders to assess their feasibility and
appropriateness. The final intervention strategies will inform future public health
practice to reduce smoking initiation and children's SHS exposure.
Workplace Exposure to Carcinogens RFP
In 2004, the HRC and the Department of Labour established the Occupational
Health Research Strategy: a joint research initiative with both partners providing
funding for strategic research projects. The Strategy aims to provide knowledge
on current and emerging health issues in the workplace and help to build
capability in the occupational health research area. In 2007, a RFP was released to
purchase a research project that addresses workplace exposure to carcinogens.
The following research provider has been confirmed:
Workplace exposure to carcinogens in New Zealand
Principal investigator: Dr Andrea t'Mannetje
Email address:
[email protected]
Host institution:
Massey University
Approved budget:
$399,531
End date:
31/10/2010
HRC Ref:
08/569
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This project involves an assessment of exposure to workplace carcinogens in New
Zealand, and the identification of strategies for the reduction of workplace
exposures in key industries (including the agricultural and wood conversion
sectors).
It will involve:
(i) a literature review of the occupational causes of cancer and the known
solutions for reducing and/or preventing exposures;
(ii) the development of a New Zealand specific Information System on
Occupational Exposure to Carcinogens (NZ-CAREX);
(iii) the development of a New Zealand specific Agricultural Chemicals Exposure
Matrix (NZ-ACEM);
(iv) a survey in key New Zealand industries, evaluating the work practices
regarding occupational carcinogens currently in place, the knowledge and
attitudes of employers, employees and health and safety personnel about
workplace carcinogens and possible intervention strategies.
This study will provide estimates of the number of workers exposed to
carcinogens, and determine which interventions would result in marked
reductions in occupational cancer.
HRC International Investment Opportunities Fund (IIOF)
IIOF Objective One RFP
Inferring Genetic Pathways in Melanoma cells
Principal investigator: Associate Professor Cristin Print
Email address:
[email protected]
Host institution:
The University of Auckland
Approved budget:
$567,000
End date:
31/12/2008
HRC Ref:
06/581
Melanoma is a devastating form of cancer which is especially common in New
Zealand and which is incompletely understood. Gene network analysis produces
circuit diagrams of the molecular signals that operate within cells. These diagrams
will eb based on large amounts of experimental data collected from human
melanoma calles after the disruption of over one hundred specific genes. The
predictions made by this research teams’ gene networks will be rigourously tested in
melanoma cells isolated from patients, and new mathematical methods for gene
network construction will be developed.
This work will be performed in close collaboration with the Japanese Drug
Development company GNI ltd, further developing international collaborative
links with the mushrooming Asian biotechnology industry. It will also develop an
important emerging technology in New Zealand, which will provide a strong
component of an overall strategy to improve melanoma treatment in this
country.
Phase II trial of selenomethionine with chemoradiation in head and neck cancer
Principal investigator: Dr Michael Jameson
Cancer
Email address:
Host institution:
Approved budget:
End date:
HRC Ref:
117
[email protected]
Waikato District Health Board
$80,431
31/01/2010
08/028
We are collaborating with researchers in New York State who have shown in the
laboratory that large doses of selenium (a trace mineral) can improve the side
effects of chemotherapy and radiotherapy while helping them to work more
effectively. We want to see if this works in people with head and neck cancers by
giving 80 patients in NZ and the US either selenium or placebo capsules
throughout their treatment. We will examine the impact of selenium on side
effects as well as the response of their cancer. If the results are encouraging then
we will develop much larger international trials to prove the effectiveness of
selenium when used like this. Cancers of the head and neck require aggressive
chemotherapy and radiotherapy, which causes severe side effects. If selenium can
reduce these without reducing the effectiveness of treatment then this would be a
major advance for these patients.
Ongoing research funded through the HRC’s
Round, awards and scholarships
Annual Funding
Physiological targeting in cancer therapy
Principal investigator: Professor William Wilson
Email address:
[email protected]
Host institution:
The University of Auckland
Approved budget:
$3,270,316
End date:
30/06/2011
HRC Ref:
08/103
The dominant paradigm in anticancer drug discovery is to target specific genetic
changes in cancer cells, but such agents are compromised by the enormous genetic
variability within and between tumours. This programme takes a different
approach by targeting higher-order (physiological) features of tumours such as
hypoxia. It builds on our recent success in bringing a new hypoxia-activated
prodrug, PR-104, to clinical trial, and will address gaps in knowledge to maximise
its benefit in cancer treatment and to extend this approach. One project will
determine whether the monotherapy activity of PR-104 is due to a bystander
effect, a second will identify the activating enzymes, a third will combine it with
clinical agents that enhance tumour hypoxia, and a fourth will target activation of
prodrugs to tumours using an adenovirus that replicates in cells with
retinoblastoma pathway defects. The programme represents a well-established
multidisciplinary collaboration, but also incorporates emerging investigators.
Therapeutics and diagnostic markers of cancer: From bench to clinic
Principal investigator: Professor Michael Eccles
Email address:
[email protected]
Host institution:
University of Otago
118 Cancer
Approved budget:
End date:
HRC Ref:
$2,640,067
31/07/2009
07/284
The projects comprising this programme focus on issues directly relevant to the
clinic. All projects are aimed at developing cancer diagnostics or therapeutics.
They overlap in their biology and technology and all include the p53 tumour
suppressor. Project A focuses on how the protein YB1 translocates to the nucleus,
where it contributes to drug resistance and appears to be a determinant of cancer
progression. Project B will identify the cancer phenotype that can be selectively
killed by a specific adenoviral therapy. Project C investigates the effectiveness of
silencing PAX genes as a means of killing cancer, as well as a novel gene therapy
system. These will be tested for their ability to treat ovarian cancer and
melanomas. Project D investigates the mechanism by which PAX gene expression
promotes cell survival in normal and cancer cells.
Genetics and Epigenetics of Cancer
Principal investigator: Professor Anthony Reeve
Email address:
[email protected]
Host institution:
University of Otago
Approved budget:
$3,065,659
End date:
30/06/2009
HRC Ref:
03/265
This programme will integrate the core science of the investigators in the Cancer
Genetics Laboratory. The first project (activated July 2002) headed by A. Reeve
uses microarray technology to identify patterns of gene expression which will
predict the aggressiveness/outcome of patients with colorectal cancer. The
second project (activated July 2002) headed by P Guilford will expand our
understanding of an inherited stomach cancer syndrome which is particularly
prevalent in Māori. Triggers that may initiate the disease will be sought, and
improved procedures for clinical management of the disease will be developed.
The third project (funding sought this round) headed by I Morison seeks to
identify very early genetic and epigenetics events during embryogenesis which
predispose to childhood acute lymphoblastic leukemia. The fourth project
(funding sought this round) headed by A. Reeve will investigate the hypothesis
that epigenetic events programmed in utero determine ethnic variations in the
incidence of Wilms tumour.
Glycolipid adjuvants for anti-cancer immunotherapy
Principal investigator: Dr Mattie Timmer
Email address:
[email protected]
Host institution:
Malaghan Institute of Medical Research
Approved budget:
$149,981
End date:
31/12/2010
HRC Ref:
08/427
Immunotherapy holds promise as a new treatment for cancer. It is based on the
concept that a person's immune system can be stimulated to selectively recognize
and eliminate malignant tumour cells. Cells that react to glycolipid molecules,
called iNKT cells, have been shown to have significant regulatory influence
over
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the quality of immune responses, including anti-tumour immune responses. It is
now clear that the structure of glycolipids recognised by iNKT cells can, in turn,
influence the regulatory function of these cells. We propose that immunotherapy
can be improved by selecting appropriate glycolipids to "fine tune" iNKT cell
activity in vivo. We aim to synthesise a variety of novel glycolipids with the
objective of promoting iNKT cell activities that favour immune responses to
tumours.
Stomach cancer in Māori
Principal investigator: Dr Lis Ellison-Loschmann
Email address:
[email protected]
Host institution:
Massey University
Approved budget:
$951,382
End date:
30/06/2013
HRC Ref:
08/258
Stomach cancer has one of the largest ethnic inequalities of any cancer site in the
New Zealand population with Māori rates being up to five times those of nonMāori in the late 1990s. Stomach cancer also shows a strong deprivation gradient
for both incidence and mortality. Lifestyle factors, physiological factors, genetic
factors and gene-environment interactions have all been identified as potential
risk factors for the development of stomach cancer, but the relative contributions
of these risk factors to stomach cancer in Māori are not well understood. We
propose to conduct a case-control study of risk factors for stomach cancer in
Māori, in order to identify the major risk factors and the priorities for
interventions.
Understanding the determinants of inequalities in breast cancer survival
Principal investigator: Dr Lis Ellison-Loschmann
Email address:
[email protected]
Host institution:
Massey University
Approved budget:
$1,004,153
End date:
30/06/2011
HRC Ref:
08/251R
We have demonstrated that Māori and Pacific people experience lower survival
from breast cancer than non-Māori/non-Pacific people in New Zealand, as do
people living in more deprived areas. There is no data on whether there are
urban/rural differences in cancer survival. This study will investigate possible
reasons for the inequalities in breast cancer survival, focussing on the role of
access to primary care and pathways through care from diagnosis to treatment.
We will recruit 2,100 women newly-diagnosed with breast cancer, identified
through the Cancer Registry. Information on socio-demographic factors and
facilitators/barriers to diagnostic and optimum cancer treatment services will be
collected in a face-to-face interview. Over subsequent years, linkage with death
records will be performed. We will conduct survival analyses to investigate which
factors may explain the observed inequalities. This study will provide information to
inform evidence-based practice recommendations to contribute to reducing
inequalities in survival from breast cancer.
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Wähine Hauora-Inequalities in uterine cancer: exploring the pre-diagnosis gap
Principal investigator: Dr Beverley Lawton
Email address:
[email protected]
Host institution:
University of Otago
Approved budget:
$707,474
End date:
31/01/2011
HRC Ref:
08/216
Mäori women are more likely to get uterine (womb) cancer than non-Mäori, and
are more likely to die from it. Uterine cancer can be treated if detected early
enough or if caught in the pre-cancerous phase. Post-menopausal vaginal
bleeding is the most common symptom of uterine cancer, and women with this
symptom should be referred for specialist assessment urgently. Recent evidence
suggests that Mäori women with gynaecological cancers gain access to specialist
assessment later in the disease continuum than non-Mäori. This study aims to
investigate the experience of Mäori women prior to reaching their first specialist
assessment to find out what factors contribute to delays in access. The project will
include the collection of quantitative and qualitative data that will help identify
factors contributing to disparities in uterine cancer and inform strategies to reduce
disability and death in the future.
Phase 3 trial studying optimal radiotherapy timing after radical prostatectomy
Principal investigator: Dr Maria Pearse
Email address:
[email protected]
Host institution:
Auckland District Health Board
Approved budget:
$1,169,103
End date:
30/09/2013
HRC Ref:
08/209R
Radical prostatectomy is the most common curative approach offered to men with
newly diagnosed prostate cancer. Unfortunately, up to half of these patients will
have factors placing them at high risk of their cancer recurring. Having
radiotherapy after an operation is known to improve cure rates, but what is not
known is whether it should be given straight after the operation or only when
there is a rising PSA after surgery indicating active cancer. Immediate RT may
not benefit all men and can cause serious side effects such as bladder problems
and impotence. International lack of consensus on the optimal timing of RT has
resulted in varied clinical practice. This phase 3 trial will compare the two
approaches. If RT at recurrence results in equivalent outcomes and improved
quality of life, it would become the standard treatment. A total of 470 men from
New Zealand and Australia will participate.
Free Radical Studies and Disease
Principal investigator: Associate Professor Robert Anderson
Email address:
[email protected]
Host institution:
The University of Auckland
Approved budget:
$1,405,446
End date:
30/06/2010
HRC Ref:
07/243
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121
Free radical reactions play important roles in the initiation and development of
many disease states. Free radical reactions are extremely short-lived events, which
require very fast techniques for their investigation in real time. The pulse
radiolysis facility at the University of Auckland, developed with the help of HRC
funding, is critical for several multi-disciplinary research projects being carried
out in New Zealand. These include the development of new classes of anticancer
drugs that act by a radical mechanism or are activated through one-electron
processes. The technique is also being used to understand the mechanism of
action of new TB drugs, prevention of damage by oxygen radicals and radiation,
and to explore fundamental electron transport pathways in cells. The overall aim
of this multi-faceted research application is to better understand the molecular
mechanisms of such processes, and through this rationally contribute to improved
treatments for a variety of different diseases.
Colorectal cancer control in New Zealand
Principal investigator: Professor Ann Richardson
Email address:
[email protected]
Host institution:
University of Otago
Approved budget:
$1,397,630
End date:
31/07/2010
HRC Ref:
07/124
Research objectives
To provide essential information to reduce the impact of colorectal cancer (CRC) in
NZ.
Principal methodologies
A computer model will be developed.
This model, combined with
epidemiological, clinical, economic and qualitative data, will estimate the future
services and costs required for appropriate treatment and follow-up for people
with CRC, surveillance for those at increased risk, and CRC screening in NZ.
Potential health outcomes
NZ health services cannot provide timely investigation and treatment for people
with CRC, or provide surveillance for individuals at increased risk of CRC, let
alone offer CRC screening. This research will provide information that is essential
for health service planning. It will also produce a powerful research tool for NZ,
because the approach can be adapted to other diseases to determine the
requirements of new interventions. The approach is being applied to CRC in NZ
initially, because information in this area is urgently needed.
Dual activation of anticancer prodrugs by hypoxia and reductase-armed
adenovirus
Principal investigator: Professor William Denny
Email address:
[email protected]
Host institution:
The University of Auckland
Approved budget:
$1,150,070
End date:
30/06/2010
HRC Ref:
07/079C
Cancer mortality rates are still high despite more than 50 years of drug discovery;
innovative approaches are required to make significant impacts on patient
survival. Virotherapy is a novel concept where viruses are engineered to infect
122 Cancer
and spread in tumours, destroying cancer cells as they migrate. These viruses can
also be 'armed' to express enzymes that make cancer cells sensitive to deactivated
chemotherapy agents (prodrugs). We have developed an armed replicating
adenovirus which can activate a prodrug (PR-104) that we have recently brought
to clinical trial. We will test this combination in human tumour models to
determine its antitumour potential and thus suitability for clinical evaluation. To
assist the safe development of the virus/prodrug couple we will harness the
prodrug activating enzyme to visualise the virus using non-invasive probes. This
will allow clinicians to monitor the virus using whole-body scanning. We will also
design 2nd generation prodrugs optimised for virotherapy.
Pharmacokinetics and pharmacodynamics of the hypoxia-activated prodrug PR104
Principal investigator: Professor William Wilson
Email address:
[email protected]
Host institution:
The University of Auckland
Approved budget:
$1,157,615
End date:
30/06/2010
HRC Ref:
07/079A
Tumours contain regions of hypoxia, which result from an inefficient blood
supply. Hypoxic cells in tumours are a major problem because of their resistance
to radiotherapy and chemotherapy, but at the same time represent a unique target
that can potentially be exploited to activate prodrugs selectively in tumours. We
have discovered such a compound (PR-104), with funding from a current HRC
contract. PR-104 is currently in clinical trial in NZ and elsewhere as an anticancer
agent. A surprising aspect of the drug in preclinical models is its efficacy against
aerobic as well as hypoxic cells in tumours. The proposed study will test the
hypothesis that this activity results from formation of active metabolites in
hypoxic regions which then diffuse to (and kill) adjoining aerobic tumour cells
(i.e. a "bystander effect"). The outcome of this research will impact directly on
strategies for identifying patients most likely to benefit from PR-104.
Fat and prostate cancer in the European Prospective Investigation into Cancer
and Nutrition
Principal investigator: Miss Francesca Crowe
Email address:
[email protected]
Host institution:
Oxford University (Girdlers Award)
Approved budget:
$180,000
End date:
31/01/2009
HRC Ref:
07/064
In many countries worldwide, the most common cancer in men is prostate cancer
and therefore, identifying modifiable risk factors is an important element for
reducing the population risk. There is evidence to suggest that dietary fat intake
may have an important role in the aetiology of prostate cancer through the
endogenous metabolism of hormones such as androgens and insulin-like growth
factors. Therefore, the objective is to determine the association between dietary fat
intake and the risk of prostate cancer in the entire cohort of men in the European
Prospective Investigation into Cancer and Nutrition study. Furthermore, to
determine in cross-sectional analyses, whether there are associations between fatty
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123
acids, dietary fat and hormonal biomarkers of prostate cancer risk such as
insulinlike growth factor and androgens in the controls from the nested-case
control analysis of men in the Oxford cohort.
Increasing the potency of dendritic cell based vaccines for treatment of cancer
Principal investigator: Dr Ian Hermans
Email address:
[email protected]
Host institution:
Malaghan Institute of Medical Research
Approved budget:
$562,623
End date:
30/06/2009
HRC Ref:
06/316
Cancer patients are currently being treated with a trial vaccine that involves
injecting specialised immune-stimulating cells called dendritic cells (DC) that
have been "loaded" with tumour tissue in vitro. The injected DC have the unique
ability to programme cells of the immune system to recognize and kill cancerous
tissue.
We propose to improve this vaccination strategy by first exposing the DC to a
series of compounds that simulate microbial structures, thereby provoking the
potent DC activity typically observed during infection. In addition, the DC will be
loaded with a specific lipid to encourage interactions with lipid-reactive immune
cells within the host that are also known to enhance DC activity. Antitumour
activity will be assessed in a murine model of melanoma.
These modifications should be applicable to current DC vaccination protocols in
the clinic, potentially providing stronger anti-tumour responses in cancer patients.
Cancer trends: Ethnic and socio-economic trends in cancer incidence and
survival
Principal investigator: Professor Tony Blakely
Email address:
[email protected]
Host institution:
University of Otago
Approved budget:
$924,356
End date:
31/01/2010
HRC Ref:
06/256
CANCERTRENDS will determine ethnic and socio-economic trends in cancer
incidence and survival in NZ, and examine in depth research questions on
colorectal, breast and testicular cancers and the contribution of active and passive
smoking.
CANCERTRENDS involves the linkage of census and cancer registration data
from 1981-2004 to form cohort studies of the NZ population, with the additional
linkage of mortality data to allow survival analyses.
CANCERTRENDS will accurately determine trends from 1981-2004 in cancer
incidence and survival by ethnicity and socio-economic position (income and
education) for the first time in NZ. Such information is important, yet currently
not available, for planning and prioritising within the Cancer Control Strategy.
The inclusion of smoking in the 1981 and 1996 censuses will allow a determination
of both the associations of a range of cancers with smoking, and the contribution
of smoking to differential trends in cancer incidence by ethnicity and socioeconomic position.
124 Cancer
PI3K inhibitors as targeted anticancer drugs
Principal investigator: Dr Gordon Rewcastle
Email address:
[email protected]
Host institution:
The University of Auckland
Approved budget:
$1,324,194
End date:
30/09/2009
HRC Ref:
06/062A
Human cancers each have key individual characteristics, in many cases involving
a change to a single enzyme, which are vital for their survival. Targeted anticancer
therapy involves identifying such target enzymes, generally present in only a
proportion of cancers, and designing specific drugs to inhibit them. A good
example for such an approach involves enzymes called phosphoinositide-3kinases, which play many important roles in the behaviour of the normal tissues
of our body. Recent results show that one member of this family, called p110alpha, is mutated in certain cancers and sustains their survival and resistance to
therapy. Our challenge is to develop new highly specific inhibitors of this enzyme
that do not affect other family members and thus have minimal side effects. We
have assembled a team of medicinal chemists, cell biologists and molecular
biologists in an integrated approach to develop one or more new candidate drugs
for clinical trial.
Identification of new targets for anti-vascular therapies for cancer
Principal investigator: Associate Professor Lai-Ming Ching
Email address:
[email protected]
Host institution:
The University of Auckland
Approved budget:
$1,054,162
End date:
30/09/2008
HRC Ref:
05/237R
Cancer is the leading cause of death in New Zealand, and amongst the elderly, it
is responsible for more deaths than heart disease, accidents and stroke combined.
Developing effective therapies for cancer must therefore remain a foremost
priority. Our work aims to develop treatments that activate cells within a tumour
to release proteins that damage its blood vessels, thereby starving the tumour.
This approach is radically different from, and offers a number of advantages over
conventional chemotherapies. A prototype of our anti-vascular approach,
DMXAA, is currently in clinical trials. In this project, we will capitalise on our
extensive experience with DMXAA to identify, using state of the art proteomic
technologies, the molecular targets and activation pathways that can be exploited
to cause vascular-damaging responses in tumours. This research will uncover new
targets for the design of innovative therapies urgently needed for the successful
treatment of human cancers.
Functional analysis
Principal investigator:
Email address:
Host institution:
Approved budget:
End date:
HRC Ref:
of ERp29, a protein-folding assistant up-regulated in cancer
Dr Elizabeth Ledgerwood
[email protected]
University of Otago
$912,452
31/12/2008
05/176
Cancer
125
ERp29 is a new type of human protein that was discovered at the University of
Otago. ERp29 is associated with many human diseases. Improved understanding
of its biological function will assist in the development of new diagnostic and
therapeutic opportunities. Our initial investigations suggest ERp29 may be
important for the correct production of proteins needed for cell growth. In
keeping with this, we have found that many types of cancer cells contain
increased amounts of ERp29. This suggests ERp29 may be necessary for tumour
development. In this study we will make mutant lung cancer cells that lack ERp29
and test how this change affects the ability of the cells to make proteins, and to
grow as tumours. As well as defining the role of ERp29 in cancer, determining
how ERp29 helps make proteins will benefit diseases that are caused by problems
with protein folding, such as cystic fibrosis.
Prospective, randomised, clinical study comparing laparoscopic & open surgery
for colon cancer
Principal investigator: Professor Philip Bagshaw
Email address:
[email protected]
Host institution:
University of Otago
Approved budget:
$347,100
End date:
30/06/2009
HRC Ref:
04/102
The proposal is to complete a multi-centre, prospective, randomised, clinical
study (ALCCaS) comparing traditional open and new laparoscopic (keyhole)
surgery for bowel cancer. New Zealand has among the world's highest incidences
of bowel cancer.
As our population ages, more bowel cancers are being
diagnosed. Laparoscopic surgery may offer equal treatment of cancer and be less
traumatic for patients.
This study compares the open operation with the
laparoscopic operation in a number of ways, including cancer clearance, pain, rate
of recovery and cost. Already 445 of the required 600 patients have been
recruited, randomized to have either open or laparoscopic surgery and are being
followed for 5 years. Recruitment to this study began in 1998 and is scheduled for
completion at the end of 2004. Published cancer outcomes from this research will
be significant in determining the most effective, evidence based operation overall
for the treatment of bowel cancer.
A Brief Summary of Published Abstracts - New Zealand
Research (1 June 2007 and 31 May 2008)
The information below is produced from a review of abstracts only. Those
wishing to draw conclusions from the research included should access the full
papers, for which references are provided. References to additional, relevant
publications are provided where these have not been included in the review.
A total of 328 New Zealand research publications from the last 12 months were
identified, of which 184 were deemed to be directly relevant to this objective. This
is one research area in which there is a great deal of research underway, across all
disciplines. Those publications classified as ‘reviews’ included articles from a
126 Cancer
biomedical, clinical and public health perspective, as well as literature reviews on
specific drugs (usually published by ADIS). The literature also covered a wide
range of topics, although half the publications focused on drug development,
breast, colorectal or reproductive cancers. There is a strong body of research on
drug development, with a number of promising new agents being identified and
new approaches taken to targeting existing cytotoxic drugs exclusively at cancer
cells.
A breakdown of journal articles published over the previous 12 months by
research discipline and topic.
A. Research Discipline
B. Topic of Research
100%
Chemotherapy
Other 8 (4%) 14 (8%)
21%
80%
Skin 9 (5%)
Diet & Nutrition
2 (1%)
Disparities 2 (1%)
Reproductive 17 (9%)
Drug development
29 (16%)
Occupational 2 (1%)
22%
60%
Lung 6 (3%)
Lymphomas 2 (1%)
Liver 2 (1%)
40%
Haematological
8 (4%)
Gastrointestinal
5 (3%)
Colorectal 18 (10%)
20%
28%
Cardiovascular
1 (1%)
0%
Biomedical
Oncogenesis 8 (4%)
Head & neck 9 (5%)
22%
Risk factors 3 (2%)
Urinary tract 12 (7%)
Brain & neurological
4 (2%)
Breast 23 (13%)
Disc 1 ipline
Clinical
Public Health
Review
Brain and Neurological Cancers
Irwin et al.1 have looked at the effect of delays in radiotherapy treatment induced
by resource constraints on the survival prospects of patients with high grade
glioma. In a retrospective analysis of 172 patients with a histological diagnosis of
WHO Grade 3 or 4 Astrocytoma who had undergone surgery at Wellington
Hospital between 1993 and 2003, and who subsequently underwent radiotherapy,
they found that time to radiotherapy from day of surgery was independently
related to survival. Time to radiotherapy after surgery varied from 7 days to over
16 weeks. Every additional week of delay until the start of radiotherapy increased
the risk of death (hazard ratio) by 8.9% (95%CI 2.0%-16.1%). A 6-week delay in
starting radiotherapy (from 2 weeks post-op to 8 weeks) reduced median survival
by 11 weeks for a typical patient. Multiple Cox regression analysis showed that
age, performance status, tumour grade, extent of surgical resection and
radiotherapy dose were also independently related to survival.
The
authors
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127
conclude that delay in radiotherapy results in a clinically significant reduction in
survival.
A team from the Department of Psychiatry, Middlemore Hospital (Auckland)2 has
highlighted the link between cancer and limbic encephalitis (LE). The case report
of a 55-year-old Niuean, male school teacher with an acute onset of confusion and
personality change is presented. The clinical data was obtained from various
sources including the emergency room, medical ward, psychiatric ward as well as
from discussions with other physicians involved in the management of this case.
Family members and friends were also contacted to obtain corroborative historical
information. LE was diagnosed in this case based on clinical presentation with
psychiatric symptoms, ruling out delirium due to infections, metabolic and other
toxins, as well as magnetic resonance imaging findings confirming temporal lobe
changes. LE is a known paraneoplastic syndrome that may precede the diagnosis
of an underlying malignancy. Recent advances in laboratory technology now
allow for antibodies to be identified in specific malignancies. This behooves the
clinicians to maintain a high level of diagnostic suspicion so that timely
interventions with oncology can follow. The authors go on to say that liaison
between psychiatry and other disciplines is important in managing this
condition.
Lum et al.3 present the case of a 5-year old boy with an ill-defined cortical tumour
diagnosed as pilocytic astrocytoma on biopsy, and treated with radiotherapy.
Nine years later, resection of the essentially unaltered tumour was performed for
treatment of intractable seizures. Histologically, the tumour had some areas with
the typical appearance of ependymoma as well as other areas which contained
piloid cells. There was also evidence of focal infiltrative growth. These findings
bore resemblance to a recently described entity ‘monomorphous angiocentric
glioma/angiocentric neuroepithelial tumour, which combines features of
ependymoma with pilocytic and diffuse astrocytomas. Both cortical
ependymomas and angiocentric monomorphous glioma/angiocentric
neuroepithelial tumour appear to be low-grade tumours, although their rarity
makes accurate prognosis problematic. As this case has features of both entities, it
suggests that they may be closely related.
A review by Danesh-Meyer (Department of Ophthalmology, University of
Auckland) stresses the devastating consequences of radiation-induced optic
neuropathy (RION), a complication of radiotherapy to the anterior visual
pathway, resulting in profound, irreversible visual loss4. Because of the poor
prognosis associated with RION, the risk of its potential development should be
factored into the decision to irradiate the brain. RION occurs commonly between
10-20 months, with an average of 18 months after treatment; but the onset may
range from three months to 9 years. Cumulative doses of radiation that exceed 50
Gy or single doses to the anterior visual pathway of greater than 10 Gy are usually
required for RION to develop.
Treatment with systemic corticosteroids,
anticoagulation and hyperbaric oxygen has been generally unsuccessful and
disappointing. If visual dysfunction is detected early, hyperbaric oxygen might be
beneficial, if treatment is initiated within 72 hours of visual loss.
Additional Publications
Lallu S, Naran S, Palmer D, Bethwaite P. Cyst fluid cytology of cerebellar
hemangioblastoma: A case report. Diagn Cytopathol 2008;36(5):341-3. Contact: The
128 Cancer
Cytology Unit, Department of Laboratory Services, Capital and Coast District Health
Board, Wellington, New Zealand.
Breast Cancer
Aetiology
A review by scientists at the Liggins Institute, University of Auckland5 highlights
recent evidence linking growth hormone (GH) and breast cancer. The article also
provides discussion of GH antagonism as a potential therapeutic approach for
treatment. Accumulating literature implicates GH-mediated signal transduction
in the development and progression of a wide range of malignancies, including
breast cancer.
Researchers from the Angiogenesis Research Group (Christchurch School of
Medicine) have been studying thymidine phophorylase (TP) (an enzyme which is
involved in promoting the formation of blood vessels) in breast cancer tissues6.
TP is up-regulated in abnormal cell growth and this is associated with advanced
tumour stage, microvessel density and prognosis in several tumour types. The
team has published data confirming a role for TP in vascular remodelling
involving several classes of genes, including the cell adhesion molecule, P-selectin.
The authors say that confirmation of the role of TP-mediated cell adhesion
molecule (CAM) induction is required; but this pathway may provide an
attractive therapeutic target, since it is likely to affect several important tumour
processes, including angiogenesis and metastasis.
Histology
The Cancer Genetics Research Group (University of Otago) has published a paper
on determining subtypes of invasive ductal carcinoma (IDC) of the breast7. Most
IDC are regarded as a single diagnostic entity, IDC of no special type (IDC-NST),
which is subdivided further only by grading. However, recent research suggests
that there is high clinical relevance in differentiating IDC subtypes. The Group
used immunohistochemistry techniques to identify two main sub-types of IDC in
their pilot cohort, and found that cytokeratin KRT8/18 expression differentiates
distinct subtypes of grade 3 IDC of the breast.
Additional Publications
Walker LC, Harris GC, Wells JE, Robinson BA, Morris CM. Association of
chromosome band 8q22 copy number gain with high grade invasive breast
carcinomas by assessment of core needle biopsies. Genes Chromosomes Cancer
2008;47(5):405-17. Contact: Cancer Genetics Research Group, Department of Pathology,
Christchurch School of Medicine and Health Sciences, University of Otago, Christchurch,
New Zealand.
Screening
As the pain of mammography is recognised as a significant deterrent for women
considering this examination, and may affect participation in breast screening,
researchers from the Dunedin School of Medicine have reviewed interventions
to
Cancer
129
address this8. Seven RCTs, involving 1671 women were identified for inclusion.
The review found that giving women information about the procedure prior to
the mammogram may reduce pain and discomfort. Increasing women's control
over breast compression could reduce pain experienced during the procedure,
though mammogram image quality was only maintained if the technologist
controlled the first compression. If the technologist reduced compression force of
the mammogram, discomfort experienced was unchanged. The use of breast
cushions reduced pain of mammography; however, image quality was impaired
in 2% of women in the intervention group. Acetoaminophen as a premedication
did not affect discomfort of mammography. Differences in interventions, and
inconsistency in measures, validation of pain scales, and in assessment of
mammogram quality, mean that results of these studies cannot be combined. All
results are based on single studies. The authors surmise that, currently, there are
very few proven interventions to reduce pain and discomfort of screening
mammography, especially procedures that can be readily introduced to screening
programmes. With mammography continuing as the preferred method for breast
screening, more research on such interventions is needed.
Chung et al. address the issue of difficulties in interpreting mammogram images9.
Because X-ray images are 2D projections of a 3D object, it is not trivial to localise
features identified in mammogram pairs within the breast volume. Furthermore,
mammograms represent highly deformed configurations of the breast under
compression, thus the tumour localisation process relies on the clinician's
experience. Biomechanical models of the breast undergoing mammographic
compressions have been developed to overcome this limitation. This team from
the Bioengineering Institute (University of Auckland) present the development of
a modelling framework that may be useful for tracking breast tumours between
clinical images.
Additional Publications
Jeffreys M, Warren R, Highnam R, Davey Smith G. Breast cancer risk factors and a
novel measure of volumetric breast density: cross-sectional study. Br J Cancer
2008;98(1):210-6. Contact: Centre for Public Health Research, Massey University Wellington
Campus, Private
Box
756,
Wellington,
New Zealand.
[email protected].
Highnam R, Jeffreys M, McCormack V, Warren R, Davey Smith G, Brady M.
Comparing measurements of breast density. Phys Med Biol 2007;52(19):5881-95.
Contact: Highnam Associates Limited, Wellington, New Zealand. [email protected].
McCormack VA, Highnam R, Perry N, dos Santos Silva I. Comparison of a new
and existing method of mammographic density measurement: intramethod
reliability and associations with known risk factors. Cancer Epidemiol Biomarkers
Prev 2007;16(6):1148-54. Contact: Department of Epidemiology and Population Health,
London School of Hygiene & Tropical Medicine, Wellington, New Zealand.
[email protected].
130 Cancer
Treatment
A review of the current literature by Poole and Paridaens10 looks at whether a 5year course of tamoxifen is still the optimal, standard adjuvant therapy for
patients with hormone-dependent breast cancer. Recently, data from large
randomised clinical trials have indicated that the third-generation aromatase
inhibitors (letrozole, anastrozole and exemestane) are more effective than
tamoxifen as adjuvant therapy in postmenopausal women with operable breast
cancer when given either initially, or sequentially following initial tamoxifen
therapy, within the first five years post-operatively. One large randomised trial
demonstrated that administration of letrozole to high-risk (node-positive)
postmenopausal patients who have completed 5 years' adjuvant tamoxifen further
prevents late recurrences and contralateral breast cancer, contrary to the lack of
obvious benefit of extending tamoxifen treatment to 10 years found in another
large randomised study. Aromatase inhibitors and tamoxifen should not be
administered concomitantly as this does not provide additional benefit, and a
large, randomised study demonstrated reduced disease-free survival with the
combination of anastrozole plus tamoxifen compared with anastrozole alone.
Poole and Paridaens say that further studies are required to establish whether the
third-generation aromatase inhibitors prolong overall survival compared with
tamoxifen, to evaluate their long-term efficacy and tolerability profiles, and to
determine the optimal treatment duration with these agents.
Findlay et al. have published a review on oral chemotherapy for breast cancer11.
Traditionally, anticancer therapy has been dominated by intravenous drug
therapy. However, oral agents provide an attractive approach to chemotherapy
and use of oral treatments is increasing. After reviewing a large amount of data
the team concludes that the wealth of data available and the increasing use of oral
agents in breast cancer suggest that many of the concerns and perceptions about
oral therapy, including efficacy and bioavailability, have been overcome, and that
oral therapy will play a major role in breast cancer management in the future in
both the metastatic and adjuvant settings.
Cheema et al. have done a systematic review of 10 clinical trials on progressive
resistance training (PRT) in breast cancer12. PRT was prescribed with aerobic
training in 8/10 trials reviewed, and in isolation in 2/10 trials reviewed. Upper
body PRT was prescribed in 7/10 trials, including 4/5 RCTs. No exacerbation of
objectively measured or subjectively reported lymphoedema symptoms was
reported in any of these trials. Adverse events were rare, generally
musculoskeletal in nature, and were managed effectively by conservative means.
Overall, the studies reviewed suggest that women surgically treated for breast
cancer can derive health-related and clinical benefits by performing PRT after
breast cancer surgery. They conclude that further research may be required to
stimulate greater advocacy for PRT among oncologists, and in community care
settings.
Farquhar et al. from the University of Auckland have undertaken a systematic
review and meta-analysis of high-dose chemotherapy for poor prognosis breast
cancer13. Thirteen trials with 5064 women were included. There was a significant
benefit in event-free survival for the high-dose group at three years (RR 1.19 (95%
CI 1.06, 1.19)) and four years (RR 1.24 (95% CI 1.03, 1.50)) and at five years this
Cancer
131
benefit approached statistical significance (RR 1.06 (95% CI 1.00, 1.13)). Overall
survival rates were not significantly different at any stage of follow up. There
were significantly more treatment-related deaths on the high-dose arm (RR 8.58
(95% CI 4.13, 17.80)). Morbidity was higher in the high-dose group but there was
no significant difference in the incidence of second cancers. The high-dose group
reported significantly worse quality of life immediately after treatment, but there
were few differences by one year. The research team says that there is insufficient
evidence supporting routine use of high-dose chemotherapy with autograft for
treating early, poor-prognosis breast cancer.
Herceptin
PHARMAC has published a review of the evidence underpinning funding
decisions Herceptin in the New Zealand Medical Journal14. A 9-week regimen of
trastuzumab (Herceptin) given concurrently with a taxane will be funded for
HER2-positive early breast cancer patients in New Zealand. Five randomised,
controlled trials have been reported but uncertainty persists about optimal
regimen duration, dose and sequencing, how to minimise cardiotoxicity, and
long-term clinical outcomes. However, the evidence for the 9-week concurrent
regimen was sufficient to justify funding. This regimen has shown results
comparable to longer duration treatments; allows more patients to be treated; is
relatively cost-effective; and DHBs have indicated they can provide sufficient
ancillary support services. Longer duration regimens remain unfunded because
of uncertainty surrounding long-term clinical benefits and risks; the high cost;
effects on DHB services; and their consequential unfavourable relative cost
effectiveness. New data has cast further doubt on the extent and durability of the
treatment effect for the sequential 12-month regimen. The sequential treatment
arm of trial N9831 showed benefits that were small and statistically nonsignificant, and the HERA trial 23-month follow-up suggested a waning in
efficacy with time. The authors stress that PHARMAC are supporting on-going
research in the area and remain open to new evidence on efficacy or improved
cost-effectiveness.
Additional Publications
Isaacs RJ, Frampton CM, Kuper-Hommel MJ. PHARMAC's funding of 9 weeks
Herceptin: many assumptions in a high-risk decision. N Z Med J
2007;120(1259):U2676.
Orman JS, Perry CM. Trastuzumab : in HER2 and hormone receptor co-positive
metastatic breast cancer. Drugs 2007;67(18):2781-9. Contact: Wolters Kluwer Health |
Adis, Auckland, New Zealand.
Scott LJ. Bevacizumab: in first-line treatment of metastatic breast cancer. Drugs
2007;67(12):1793-9. Contact: Wolters Kluwer Health | Adis, Auckland, New Zealand, an
editorial office of Wolters Kluwer Health, Conshohocken, Pennsylvania, USA.
[email protected].
Sekar R, Stone PR. Trastuzumab use for metastatic breast cancer in pregnancy.
Obstet Gynecol 2007;110(2 Pt 2):507-10. Contact: Department of Obstetrics and
Gynecology, Faculty of Medical and Health Science, University of Auckland, Auckland,
New Zealand. [email protected].
132 Cancer
Stuart EC, Larsen L, Rosengren RJ. Potential mechanisms for the synergistic
cytotoxicity elicited by 4-hydroxytamoxifen and epigallocatechin gallate in
2007;30(6):1407-12. Contact: Department of
MDAMB-231 cells. Int J Oncol
Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand.
Stuart EC, Rosengren RJ. The combination of raloxifene and epigallocatechin
gallate suppresses growth and induces apoptosis in MDA-MB-231 cells. Life Sci
2008;82(17-18):943-8. Contact: Department of Pharmacology & Toxicology, University of
Otago, Dunedin, New Zealand.
Ethnicity
University of Auckland researchers based in the Department of Surgery at
Middlemore Hospital (Weston et al.) have published a study on how the biological
characteristics of breast cancer differ between ethnic groups in Auckland15. The
prospective cohort study involved 1,577 people diagnosed with breast cancer in
the greater Auckland area between 2000 and 2005, who agreed to participate. The
results showed that New Zealand Māori and Pacific Island participants had larger
tumours (P < 0.0001) and higher grade tumours (P < 0.0001), with more involved
lymph nodes (P < 0.0001). When allowing for size, there was still an indication
that Māori people had higher grade tumours (P = 0.03). There was no difference
in oestrogen receptor, progesterone receptor or lymphovascular invasion between
ethnic groups. The authors suggest that there are differences in tumour biology
related to ethnicity in the Auckland population and this has implications for
breast cancer screening and management.
A team from Auckland University have looked the reasons that may explain
differences in breast cancer survival based on race or ethnicity in older American
women16. They used data from 41,020 women aged > or =68 years with incident
breast cancer between 1994-1999 including African American (2479), Hispanic
(1172), Asian/Pacific Island (1086), and white women (35,878). They found that
African American woman had poorer survival rates than white women, although
adjustment for predictor variables reduced this difference when the data from
individuals at all cancer stages (0/I, II/III, and IV) at diagnosis were combined
(Hazard Ratio(HR): 1.08; 95%CI 0.97-1.20). Screening mammography, tumour
characteristics at diagnosis, biologic markers, and treatment each produced a
similar reduction in HRs for women with stage II/III cancers (HR: 1.30; 95% CI:
1.10-1.54). Asian and Pacific Island women better survival than white women in
the all-stage (HR: 0.88; 95% CI: 0.75-1.04) and stage II/III analysis (HR: 0.88; 95%
CI: 0.75-1.04), although these findings did not reach statistical significance. There
was no significant difference in survival by race or ethnicity noted among women
diagnosed with stage IV disease. In summation, the authors say that predictor
variables contribute to, but do not fully explain, racial or ethnic differences in
breast cancer survival for elderly American women. Future analyses should
further investigate the role of biology, demographics, and disparities in quality of
care.
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133
Risk Factors
Geographic location (urban versus rural) did not affect breast cancer outcomes in a
study conducted by the Australasian Faculty of Public Health Medicine in
Hamilton17. Data from women listed on the NZCR between 1998 and 2002 was
used in a survival analysis that controlled for age, ethnicity, deprivation, and
cancer stage. Domicile was used to classify the women according to urban or
rural status. This was not found to affect diagnosis or the effectiveness of
treatment.
McKenzie and colleagues18 have undertaken a study of all 21,586 breast cancer
cases on the New Zealand Cancer Registry (July 1994-June 2004) and shown that
Māori, Pacific and women in low socioeconomic brackets have a poorer prognosis
for breast tumours on presentation. Women were categorised according to
ethnicity on the Registry. Deprivation was analysed as quintiles of the New
Zealand Deprivation Index 2001. The study found that Māori and Pacific women
were more likely to have non-local stage, less well differentiated cancer, larger
tumours and positive human epidermal growth factor receptor-type 2 (HER-2)
status than non-Māori or non-Pacific women. Māori were less likely and Pacific
women more likely than non-Māori or non-Pacific women to have negative
oestrogen (ER) and progesterone receptor (PR) status. Adjusting for deprivation
did not materially alter the results. Women living in more deprived areas had a
higher risk of non-local stage and larger tumours. These associations were only
partially explained by ethnicity. There was no relationship between tumour
grade, ER, PR or HER-2 status and deprivation.
Weighing Benefits versus Harm
A ‘citizens’ jury’ approach has been advocated as a viable way to determine how
complex benefits and harms are weighed by affected populations, particularly
where experts and advocacy groups disagree19. Researchers at the Department of
Preventive and Social Medicine, University of Otago, recruited eleven women
aged 40-49 years (randomly selected from the electoral roll) and asked them to
consider whether the New Zealand government should offer free mammography
screening to all women aged 40-49 years. Participants met over a day and a half to
hear evidence from expert witnesses with differing views and to deliberate the
verdict. All but one woman changed their minds during the jury process, and
voted against government provision of mammography screening in this age
group. The main reasons reported were the inaccuracy of the test and the potential
for harm, and the lack of firm evidence of saving lives in this age group.
Cardiovascular Cancers
The case of a 73-year-old man with a pulmonary artery sarcoma successfully
treated as a result of an international surgical collaboration has been reported20.
The tumour was initially deemed to be unresectable due to a lack of local
expertise managing cardiac malignancies. Since the patient was unable to travel
to a specialist centre in the United States, he was initially offered only palliative
therapy. However, two surgeons with experience of treating malignant cardiac
tumours travelled to New Zealand specifically to perform a potentially curative
resection of his tumour. The authors say that there should be an emphasis placed
134 Cancer
on the development of internationally acceptable protocols for the treatment of
rare conditions and improved local access to overseas surgical expertise.
Chemotherapy
An evidence-based review by Bhana (ADIS, New Zealand) focuses on
chemotherapy-induced neutropenia and primary prophylaxis21. Neutropenia is a
frequent complication of chemotherapy associated with life-threatening infections,
hospitalisation, and chemotherapy dose reductions and delays.
Primary
prophylaxis with granulocyte colony-stimulating factors has been shown to
reduce the incidence and duration of neutropenia, febrile neutropenia, infections,
hospitalisation and antibiotic use. Recent randomised clinical trials of filgrastim,
lenograstim and pegfilgrastim showed variable results across patient groups at
different risks of febrile neutropenia. Bhanu surmises that pegfilgrastim is at least
as effective as filgrastim in the prophylaxis of chemotherapy-induced neutropenia
and has improved pharmacokinetics requiring reduced administration.
Murdoch and Sager (ADIS, New Zealand) have looked at whether targeted
therapy has held its promise in an evidence-based review22. Many of the
significant advances in cancer management in recent years have centred on the
development and introduction of molecularly targeted therapies, such as
monoclonal antibodies and tyrosine kinase inhibitors. Despite targeted therapy
that has clearly benefited and even cured certain patients (eg, imatinib,
trastuzumab), the ultimate goal of curing cancer, and the more immediate goal of
replacing non-targeted chemotherapies with less toxic, targeted agents has yet to
be achieved for most cancer patients. The paper goes on to present data based on
a systematic review of RCTs that show significant benefits in selected cancers:
Non-Hodgkin's lymphoma (rituximab plus chemotherapy has a major survival
advantage over chemotherapy alone); Renal cell carcinoma (temsirolimus or
sunitinib has a significant survival benefit relative to interferon-alpha, and
sorafenib carries such a benefit in patients resistant to standard therapy);
colorectal cancer (bevacizumab plus 5-fluorouracil/leucovorin possesses a
significant survival advantage over 5-fluorouracil/leucovorin and irinotecan/5fluorouracil/leucovorin). Non-small-cell lung cancer (erlotinib significantly
prolongs survival, particularly in nonsmokers, and gefitinib may have some
utility in patients of Asian ethnicity); head and neck squamous-cell carcinoma
(cetuximab plus radiotherapy - versus radiotherapy alone - significantly improves
locoregional control and survival, without worsening radiotherapy-related
toxicity).
DNA topoisomerase IIalpha is an essential enzyme for chromosome segregation
during mitosis. Williams et al. report that this enzyme has been shown to be
down-regulated in doxorubicin-resistant cell lines23. The paper presents data on
specificity proteins (Sp 1 and Sp 3), which have been implicated in the regulation
of topoisomerase II alpha transcription, and provides a mechanistic explanation
for this effect.
Additional Publications
Carter NJ, Keam SJ. Trabectedin : a review of its use in the management of soft
tissue sarcoma and ovarian cancer. Drugs 2007;67(15):2257-76. Contact: Wolters
Kluwer Health | Adis, Auckland, New Zealand. [email protected].
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135
Dhillon S, Lyseng-Williamson KA. Zoledronic acid: a review of its use in the
management of bone metastases of malignancy. Drugs 2008;68(4):507-34. Contact:
Wolters Kluwer Health Adis, Auckland, New Zealand. [email protected].
Dhillon S, Wagstaff AJ. Lapatinib. Drugs 2007;67(14):2101-8; discussion 2109-10.
Contact: Wolters Kluwer Health | Adis, 41 Centorian Drive, Mairangi Bay, North Shore
074, Auckland, New Zealand. [email protected].
Jamieson SM, Liu JJ, Connor B, Dragunow M, McKeage MJ. Nucleolar
enlargement, nuclear eccentricity and altered cell body immunostaining
characteristics of large-sized sensory neurons following treatment of rats with
paclitaxel. Neurotoxicology 2007;28(6):1092-8. Contact: Department of Pharmacology
and Clinical Pharmacology, The University of Auckland, New Zealand.
Keam SJ. Dasatinib: in chronic myeloid leukemia and Philadelphia
chromosomepositive acute lymphoblastic leukemia. BioDrugs 2008;22(1):59-69.
Contact: Wolters Kluwer Health | Adis, Auckland, New Zealand. [email protected].
McKeage K, Plosker GL. Zoledronic acid: a pharmacoeconomic review of its use in
the management of bone metastases. Pharmacoeconomics 2008;26(3):251-68. Contact:
Wolters Kluwer Health | Adis, Auckland, New Zealand. [email protected].
McKeage MJ. Satraplatin in hormone-refractory prostate cancer and other tumour
types: pharmacological properties and clinical evaluation. Drugs 2007;67(6):859-69.
Contact: Department of Pharmacology and Clinical Pharmacology, University of
Auckland, Auckland, New Zealand. [email protected].
Colorectal Cancers
Screening
In 2005, a Colorectal Screening Advisory Group was appointed to provide
independent, strategic advice and recommendations on population screening for
colorectal cancer (CRC) in New Zealand. The group were appointed by the
National Screening Unit of the Ministry of Health. Parry et al. have now
published their advice24. After undertaking an evidence-based review of relevant
literature and assessment of CRC screening using the New Zealand Criteria to
Assess Screening Programmes, they have recommended that an immunochemical
faeces-for-occult-blood test (FOBTi) has a higher analytical sensitivity than other
laboratory tests available and would be assumed to achieve greater mortality
reduction. The authors state that currently, public hospitals cannot deliver timely
diagnostic or surveillance colonoscopy. The Advisory Group recommends that a
feasibility study of CRC screening using FOBTi be undertaken. This would help
determine the performance of the FOBTi in the New Zealand population and
whether the New Zealand health system could support an acceptable, effective
and economically efficient CRC screening programme. Furthermore, the Group
suggests that to optimise the diagnosis and treatment of colorectal cancer, there is
an immediate need to expand colonoscopy services and to ensure that the
treatment outcomes for CRC, both surgical and oncological, meet international
standards throughout New Zealand.
Kerr et al. have undertaken a Systematic review of the effectiveness of population
screening for colorectal cancer25. The aim of the study was to estimate the
136 Cancer
effectiveness of colorectal cancer screening with faecal occult blood testing
(FOBT), flexible sigmoidoscopy (FS), and combinations of FOBT and FS in
preventing colorectal cancer (CRC) deaths. METHOD: A systematic review was
conducted examining randomised controlled trials (RCTs) published between
1997 and 2004 inclusive. Four RCTs were identified that examined FOBT
screening. The three trials that investigated guaiac-based FOBT found CRC
mortality was reduced in the screening group. In the two population-based trials,
the pooled relative risk was 0.86 (95%CI 0.79-0.93). A fourth RCT was identified,
with shorter term follow-up, which considered FOBT screening combined with FS
compared with FOBT alone. No significant reduction in CRC mortality was
reported in this trial. There authors found that there is high-quality evidence
showing that guaiac-based FOBT screening reduces mortality from CRC. No such
evidence exists for screening with FS either alone, or in combination with FOBT,
but this should be re-evaluated once data become available from four large
ongoing trials.
Yeoman et al.26 have published the findings of a National Screening Unit
commissioned survey aimed to determine the current level of colonoscopy
provision in New Zealand's public hospitals, the gap in demand and provision for
diagnostic and surveillance procedures, and factors limiting colonoscopy capacity.
The researchers posted a survey, based on the United States SECAP study, to all
public endoscopy units within New Zealand in April 2005. The overall survey
response rate was 86% (24/28). Only 3 of 7 large centres, and 11 of 17 small
centres, were able to offer a diagnostic colonoscopy to patients with symptoms
suggestive of colorectal cancer (CRC) within 3 months of referral - and at the time
of the survey, 828 patients had been waiting for longer than 6 months. The
majority (85%) of public hospitals offer surveillance colonoscopy for most
indications, and at the time of the survey, 2550 patients had been waiting greater
than 6 months. Availability of endoscopy nurses and endoscopists were the main
factors limiting colonoscopy provision. The authors conclude that a significant
gap exists between colonoscopy demand and provision in New Zealand's public
hospitals. Population screening for CRC would require a significant increase in
colonoscopy capacity to ensure waiting times for symptomatic patients do not
increase.
Diagnosis
A team at Middlemore hospital27 have identified criteria for prioritizing access to
colonoscopy for suspected colon cancer. In a pilot study of 105 patients, they
showed that patients over the age of 67 years who present with rectal bleeding, or
have a family history of colorectal cancer or neoplasia, are at higher risk and
should receive a colonoscopy prior to specialist assessment.
Metastases
Lin et al. (Cancer Genetics Laboratory, Department of Biochemistry,University of
Otago) have identified genes associated with colorectal liver metastasis28. Tumour
cells have to undergo gene expression changes in order to metastasise and adapt
to a new site. The researchers investigated these changes in liver metastases of
colorectal cancer by using genome-wide microarray analysis to profile the
expression of 48 primary tumours and 28 liver metastases. Analyses revealed that
genes associated with tissue remodelling and immune response were upregulated
Cancer
137
in metastases relative to primary tumours, whereas genes associated with
proliferation and oxidative phosphorylation were downregulated. The
upregulation of genes associated with tissue remodelling and immune response
are likely to be involved in metastatic invasion and colonisation of the new site
because these genes can promote tumour progression. However, downregulation
of genes associated with proliferation suggests that proliferation in metastases
was reduced relative to primary tumours.
Surgery
Abbas and Merrie29, from Auckland City Hospital, demonstrated that removal of
peritoneal metastases in patients with malignant small bowel obstruction offers a
reasonable survival benefit in patients with resectable disease - outweighing the
attendant risks.
Hayes and Hansen30 have demonstrated that laparoscopic-assisted colectomy
(LAC) for cancer may be cost-effective over open colectomy (OC). LAC entails
greater operating time and the use of more disposable equipment costing, on
average, $1257 more than an OC. However, two separate studies have estimated
the gain in recovery time as being 12 and 33 days, respectively. Depending on the
estimates taken, LAC may prove to be a cost-effective option, with further
improvements expected as operating times and post-operative stays reduce with
time.
Wakeman et al.31 report that survival rates are considerably poorer in patients in
which iatrogenic damage to the spleen requires splenectomy during resection of
colorectal tumours. Fifty-five patients were identified who had an iatrogenic
splenectomy and matched with control cases. In the group without splenectomy,
cancer-specific survival at five years was 70 vs. 47 percent in those with a
splenectomy and at ten years survival rates were 55 vs. 38 percent in the two
groups.
Randomised controlled trials have shown a benefit for epidurals on postoperative
pain relief and ileus, and possibly respiratory, complications. There is no proven
benefit with regard to length of stay. These are the findings from a review by
Gendall et al. (Department of Surgery, Christchurch Hospital)32. They report that
the majority of data demonstrate a superior effect of epidural analgesia on pain
control after colorectal surgery. Well designed randomised controlled trials have
also shown that epidural analgesia reduces the duration of ileus after colorectal
surgery. Limited data suggest the additional benefit may be minimal after
laparoscopic surgery or when epidural analgesia is used as part of a multimodal
regime. Data does not convincingly show either a clear harmful or beneficial
effect of epidural analgesia on rates of anastomotic leakage. Epidural analgesia
may have beneficial effects on postoperative lung function but, due to low
numbers, the effects on cardiovascular and thromboembolic complications are
indeterminate.
Specialist Colorectal Units
At a time when specialist colorectal units are becoming increasingly common in
tertiary centres, Clinicians from the Department of Surgery at Nelson hospital
have published a review of colorectal cancer surgery conducted by one surgeon
in
138 Cancer
a provincial setting, from January 2000 to December 200433. The study illustrates
that high-volume colorectal surgery is possible even in a smaller New Zealand
province. Surgical practice and outcomes withstood comparison to published
results - a broad general surgical case mix and low-volume hospital environment
were not significant barriers to quality of colorectal care. The authors conclude
that provincial colorectal cancer management remains an important resource for
patients living outside major New Zealand centres. A further study conducted in
Southland on colorectal cancer surgery conducted between June 1997 and May
2000 has produced similar results and the investigators emphasize the importance
of retaining colorectal cancer services in non-specialised units 34.
Chemotherapy and Radiotherapy
A questionnaire-based survey involving 22 medical oncologists to document
variations in chemotherapy prescription patterns has been conducted by
investigators at the Department of Oncology, Waikato Hospital 35. The survey
indicates that chemotherapy prescriptions for patients with colon cancer in New
Zealand, although not uniform, are mostly in line with international
recommendations.
Abbas and Hill present the case of a 75-year-old farmer who was treated for rectal
cancer with preoperative 45 Gy of radiotherapy and abdominoperineal resection
and presented with radiation-induced sarcoma four years later36.
He was
diagnosed after he developed symptoms of bladder outlet obstruction and acute
urinary retention. He underwent a transurethral resection of the prostate and
histological examination and immunohistochemistry revealed it to be a poorly
differentiated sarcoma. The authors say that the relationship between radiation
exposure for treatment of cancer and occurrence of a second primary cancer at the
irradiated site is well known. However, this phenomenon is rare in prostate
cancer and they believe this to be the first reported case of radiation-induced
sarcoma following radiotherapy treatment for rectal cancer. Since radiotherapy
plays a pivotal role in the contemporary treatment of rectal adenocarcinoma, it is
relevant to be aware of the potential long-term carcinogenic complications of
radiotherapy of the pelvis.
Additional Publications
Hoy SM, Wagstaff AJ. Panitumumab in the treatment of metastatic colorectal
cancer: profile report. BioDrugs 2007;21(2):135-7. Contact: Wolters Kluwer
Health/Adis, Auckland, New Zealand.
McCormack PL, Keam SJ. Bevacizumab: a review of its use in metastatic colorectal
cancer. Drugs 2008;68(4):487-506. Contact: Wolters Kluwer Health Adis, Auckland,
New Zealand. [email protected].
Follow-up
Jeffery et al. say that is common clinical practice to follow patients with colorectal
cancer (CRC) for several years following their definitive surgery and/or adjuvant
therapy37. Despite this widespread practice, there is considerable controversy
about how often patients should be seen, what tests should be performed and
whether these varying strategies have any significant impact on patient outcomes.
To address this, they have undertaken a review of the available evidence
concerning the benefits of intensive follow up of colorectal cancer patients with
Cancer
139
respect to survival. Only randomised controlled trials comparing different followup strategies for patients with non-metastatic CRC treated with curative intent
were included, a total of eight studies. There was evidence that an overall
survival benefit at five years exists for patients undergoing more intensive follow
up OR was 0.73 (95% CI 0.59 to 0.91); and RD -0.06 (95% CI -0.11 to -0.02). The
absolute number of recurrences was similar. Analyses demonstrated a mortality
benefit for performing more tests versus fewer tests: OR was 0.64 (95% CI 0.49 to
0.85); and liver imaging versus no liver imaging: OR was 0.64 (95% CI 0.49 to
0.85). There were significantly more curative surgical procedures attempted in the
intensively followed arm: OR 2.41(95% CI 1.63 to 3.54). No useful data on quality
of life, harms or cost-effectiveness were available for further analysis. The results
of the review suggest that there is an overall survival benefit for intensifying the
follow up of patients after curative surgery for colorectal cancer.
Additional Publications
Frizelle FA. Colorectal cancer in New Zealand. N Z Med J 2007;120(1258):U2628.
Yeoman A, Young J, Arnold J, Jass J, Parry S. Hyperplastic polyposis in the New
Zealand population: a condition associated with increased colorectal cancer risk
and European ancestry. N Z Med J 2007;120(1266):U2827. Contact: Department of
Gastroenterology and Hepatology, Middlemore Hospital, Otahuhu, Auckland, New
Zealand.
Culturally Sensitive Services
The Northern Regional Genetic Service (Auckland District Health Board) have
published a report on their efforts to provide a process that is culturally sensitive
to Māori38. They report that in familial cancer and other late-onset disorders, there
is now the possibility of 'prediction' where a high risk conferred by family history
can be confirmed or negated by genetic testing. The authors contend that current
methods for providing information on mutational analysis are based on a
Eurocentric model of individual autonomy that is not culturally appropriate for
Māori.
Diet and Nutrition
Ferguson and Philpott39 have published a review on cancer prevention by dietary
bioactive components that target the immune response. They say that dietary
bioactive food components that interact with the immune response have
considerable potential to reduce the risk of cancer.
Reduction of chronic
inflammation or its downstream consequences may represent a key mechanism
that can be reduced through targeting signal transduction or through antioxidant
effects. Major classes of macronutrients provide numerous examples, including
amino acids (such as glutamine or arginine); lipids (such as the omega-3
polyunsaturated fatty acids); DHA or EPA; or novel carbohydrates such as
various sources of beta-glucans. Vitamins such as C and E are commonly used as
antioxidants, while zinc and selenium are minerals with a wide spectrum of
impacts on the immune system. Some of the most potent immunomodulators are
phytochemicals such as the polyphenols, epigallocatechin gallate (EGCG) or
curcumin, or isothiocyanates such as PEITC. There is accumulating evidence for
140 Cancer
cancer prevention by probiotics and prebiotics, and these may also affect the
immune response. They go on to say that genomic approaches are becoming
increasingly important in characterising potential mechanisms of cancer
prevention, optimising the rational selection of dietary bioactive food
components, or identifying humans with differing nutrient requirements for
cancer protection.
See also the study on folate supplementation under ‘Haematological Cancers - Risk
Factors’.
Disparities
Blakey et al.40 used 1981, 1986, 1991, 1996, and 2001 censuses linked to mortality
data to determine whether major structural economic reforms impacted on
disparities between income and mortality. The study covered the entire New
Zealand population aged 1-74 years. They found that although all-cause mortality
declined over the 25-year period, relative inequalities in mortality increased from
1981-4 to 1996-9. While cardiovascular disease was the major contributor to the
observed disparities between income and mortality, it decreased in importance
from 45% in 1981-4 to 33% in 2001-4 for males and from 50% to 29% for females.
However, the corresponding contribution of cancer increased from 16% to 22% for
males and from 12% to 25% for females. Although the authors could not
confidently draw a causal link between these disparities and structural reform,
they call for a review of health priorities based on the difference in the impact of
mortality causes over time.
Dachs et al41 have published a review describing patterns of cancer incidence,
mortality, and survival in indigenous populations compared with populations of
European origin in Polynesia. They highlight the dearth of data for Pacific
populations and report risk factors that differ between ethnicities, including
smoking, viral infections, and obesity.
See also the study by Mckenzie and colleagues and Weston et al. under ‘Breast Cancer’,
the study undertaken at the Hugh Adamson Cancer Epidemiology Unit under ‘Prostate
Cancer’ and the work of Stevens et al. under ‘Lung Cancer’.
Drug Development
Herst et al. from the Malaghan Institute of Medical Research have published a
paper elucidating the primary molecular target for a new drug for drug-resistant
ovarian cancer, currently in clinical trials42. Phenoxodiol, a synthetic isoflavene, is
also in early stage clinical trials for prostate and cervical cancer. Phenoxodiol
inhibits proliferation of many cancer cell lines and induces apoptosis
(programmed cell death). In addition, phenoxodiol sensitises drug-resistant
tumour cells to anticancer drugs including paclitaxel, carboplatin and
gemcitabine. The investigators studied the effects of phenoxodiol on plasma
membrane electron transport (PMET) and cell proliferation in human leukaemic
HL60 cells and mitochondrial gene knockout HL60rho(o) cells that exhibit
elevated PMET. They found that PMET may be a primary target for phenoxodiol
in tumour cells and in activated T cells.
Cancer
141
Kanwar et al. (LactoPharma Consortium, University of Auckland) have
investigated 'Iron-saturated' lactoferrin is a potent natural adjuvant for
augmenting cancer chemotherapy43. Bovine lactoferrin (bLf), an iron-containing
natural defence protein found in bodily secretions, has been reported to inhibit
carcinogenesis and the growth of tumours. The study was designed to establish
whether natural bLf and iron-saturated forms of bLf differ in their ability to
augment cancer chemotherapy. Mice were fed bLf (with varying degrees of iron
enrichment), subsequently challenged subcutaneously with tumour cells and
treated with chemotherapy they found. They found that mice fed iron-saturated
bLf bearing either EL-4, Lewis lung carcinoma or B16 melanoma tumours
completely rejected their tumours within 3 weeks following a single injection of
either paclitaxel, doxorubicin, epirubicin or fluorouracil, whereas mice fed the
control diet were resistant to chemotherapy. The BLf had to be iron saturated and
had to be fed to mice for more than 2 weeks prior to chemotherapy to be wholly
effective in eradicating tumours from all mice, suggesting that it acts as a
competence factor. It significantly reduced tumour vascularity and blood flow,
and increased antitumour cytotoxicity, tumour apoptosis and the infiltration of
tumours by leukocytes. Importantly, iron-saturated bLf restored both red and
white peripheral blood cell numbers depleted by chemotherapy, potentially
fortifying the mice against cancer. In summary, the authors conclude that bLf is a
potent natural adjuvant and fortifying agent for augmenting cancer
chemotherapy, but needs to be saturated with iron to be effective.
A review by McKeage (University of Auckland) focuses on the potential of
DMXAA in combination with docetaxel in advanced prostate cancer44. DMXAA
(5,6-Dimethylxanthenone-4-acetic acid) is a vascular disrupting agent developed
by researchers at the University of Auckland’s Cancer Society Research Centre. It
has demonstrated efficacy in combination with taxane-based chemotherapy in
patients with advanced cancer. Complementary modes of action, a lack of
pharmacokinetic interaction and distinct adverse effect profiles provide a strong
rationale for combining these anticancer agents. In a Phase II trial in men with
hormone refractory prostate cancer, DMXAA (ASA404) in combination with
docetaxel achieved a prostate-specific antigen response in more patients than
docetaxel therapy alone, and was generally well tolerated. Further clinical
evaluation of this combination in this patient population is warranted.
A team at the University of Otago’s Department of Pharmacology and Toxicology
have investigated the efficacy of two naturally derived polyphenolic compounds
in suppressing breast cancer cell growth45.
Polyphenols are a class of
phytochemicals found in plants, with known antioxidant properties.
Both
epigallocatechin gallate (EGCG, a catechin found in green tea) and curcumin (the
principal curcuminoid found in tumeric) have shown efficacy in various in vivo
and in vitro models of cancer. The research team tested their efficacy in killing
cancer cells in vitro and in vivo, when given in combination. They found that the
combination was synergistically cytotoxic both in vitro and in vivo (in mice).
Tumour volume in the treated mice decreased 49% in comparison to the control
mice.
Thotathil and Jameson have provided an overview of early early experience with
novel immunomodulators for cancer treatment46. Immunotherapy involves the
142 Cancer
treatment of cancer by modification of the host-tumour relationship. It is now
known that this relationship is quite complex and only some of the interactions
have been elucidated. Early attempts at immunotherapy, such as Coley's toxins,
were undertaken without an understanding of the processes mediating the effects.
With a better understanding of the immunology of this anticancer response, recent
trials have focussed on certain aspects of the process to stimulate an antitumour
response. In this review, the authors discuss a number of novel biological
response modifiers that work as general stimulants of the immune system,
through varied mechanisms including induction of stimulatory cytokines (such as
IFN-alpha, TNF-alpha and IL-12) and activation of T cells and the antigenpresenting dendritic cells. These compounds include Toll-like receptor agonists,
several of which are in clinical trials at present. In addition to
immunomodulatory activity, some compounds such as 5,6-dimethylxanthenone4-acetic acid (DMXAA) and thalidomide and its analogues also target existing or
developing tumour vasculature. Some of these compounds have single-agent
activity in clinical trials, while others such as DMXAA have shown promise in
combination with chemotherapy without increasing toxicity.
Lactoferrin is
another compound that has shown clinical activity with low toxicity. At present,
accepted indications for immunotherapy are limited to a few cancers such as renal
cell carcinoma and melanoma. Thotathil and Jameson look at some of the reasons
for the limited impact of immunotherapy so far and suggest possible avenues for
further research with a greater likelihood of success.
A review by a team based at the National School of Pharmacy, University of
Otago, provides the latest information on peptides and small molecules targeting
the plasminogen-activation system (PAS), which are under consideration as antimetastasis drugs for breast cancer47.
Breast cancer is the most common
malignancy afflicting Western women today and is responsible for many deaths
due to metastatic disease. Upregulation of the plasminogen-activation system
(PAS) has been shown to correlate with poor prognosis in metastatic breast cancer
and targeting this system represents an attractive strategy for the development of
anti-metastasis prophylactic drugs. Two promising classes of PAS-targeting
agents are inhibitors of the serine protease activity of urokinase plasminogen
activator (uPA) and antagonists of the interaction of uPA with its cell surface
receptor (uPAR). The review begins with a brief overview of the role of PAS in
cancer metastasis before describing in detail a subset of the small molecules and
peptides from the patent literature that target either uPA activity or uPA/uPAR
interactions for use as anti-metastasis drugs.
Additional Publications
Basse B, Ubezio P. A generalised age- and phase-structured model of human
tumour cell populations both unperturbed and exposed to a range of cancer
therapies. Bull Math Biol 2007;69(5):1673-90. Contact: Auckland Cancer Society
Research Centre, Faculty of Medical and Health Sciences, University of Auckland,
Auckland, New Zealand. [email protected].
Bridewell DJ, Porter AC, Finlay GJ, Baguley BC. The role of topoisomerases and
RNA transcription in the action of the antitumour benzonaphthyridine derivative
SN 28049. Cancer Chemother Pharmacol 2008. Contact: Auckland Cancer Society
Cancer
143
Research Centre, Faculty of Medical and Health Sciences, University of Auckland, Private
Bag 92019, Auckland, New Zealand, [email protected].
Chung F, Liu J, Ching LM, Baguley BC. Consequences of increased vascular
permeability induced by treatment of mice with 5,6-dimethylxanthenone-4-acetic
acid (DMXAA) and thalidomide. Cancer Chemother Pharmacol 2008;61(3):497-502.
Contact: Auckland Cancer Society Research Centre, Faculty of Medical and Health
Sciences, The University of Auckland, Private Bag 92019, Auckland, New Zealand.
Frederick R, Denny WA. Phosphoinositide-3-kinases (PI3Ks): combined
comparative modeling and 3D-QSAR to rationalize the inhibition of p110alpha. J
Chem Inf Model 2008;48(3):629-38. Contact: Auckland Cancer Society Research Centre
(ACSRC), School of Medical and Health Sciences, The University of Auckland, Private
Bag 92019, Auckland 1020, New Zealand. [email protected].
Guise CP, Wang AT, Theil A, Bridewell DJ, Wilson WR, Patterson AV.
Identification of human reductases that activate the dinitrobenzamide mustard
prodrug PR-104A: a role for NADPH:cytochrome P450 oxidoreductase under
hypoxia. Biochem Pharmacol 2007;74(6):810-20. Contact: Auckland Cancer Society
Research Centre, The University of Auckland, Private Bag 92019, Auckland, New
Zealand.
Hay MP, Hicks KO, Pruijn FB, et al. Pharmacokinetic/pharmacodynamic modelguided identification of hypoxia-selective 1,2,4-benzotriazine 1,4-dioxides with
antitumour activity: the role of extravascular transport. J Med Chem
2007;50(25):6392-404. Contact: Auckland Cancer Society Research Centre, Faculty of
Medical and Health Sciences, The University of Auckland, Auckland 1003, New
Zealand.
[email protected].
Hay MP, Pchalek K, Pruijn FB, et al. Hypoxia-selective 3-alkyl 1,2,4-benzotriazine
1,4-dioxides: the influence of hydrogen bond donors on extravascular transport
and antitumour activity. J Med Chem 2007;50(26):6654-64. Contact: Auckland Cancer
Society Research Centre, Faculty of Medical and Health Sciences, The University of
Auckland, New Zealand. [email protected].
Helsby NA, Goldthorpe MA, Tang MH, et al. Influence of mustard group
structure on pathways of in vitro metabolism of anticancer N-(2-hydroxyethyl)3,5-dinitrobenzamide 2-mustard prodrugs. Drug Metab Dispos 2008;36(2):353-60.
Contact: Department of Molecular Medicine and Pathology, Faculty of Medical and
Health
Sciences, University of
Auckland, Auckland,
New Zealand.
[email protected].
Herst PM, Hesketh EL, Ritchie DS, Berridge MV. Glycolytic metabolism confers
resistance to combined all-trans retinoic acid and arsenic trioxide-induced
apoptosis in HL60rho0 cells. Leuk Res 2008;32(2):327-33. Contact: Malaghan Institute
of Medical Research, P.O. Box 7060, Wellington, New Zealand. [email protected].
Hicks KO, Myint H, Patterson AV, et al. Oxygen dependence and extravascular
transport of hypoxia-activated prodrugs: comparison of the dinitrobenzamide
mustard PR-104A and tirapazamine. Int J Radiat Oncol Biol Phys 2007;69(2):560-71.
Contact: Auckland Cancer Society Research Centre, University of Auckland School of
Medical Sciences, Auckland, New Zealand. [email protected].
Huck SP, Tang SC, Andrew KA, Yang J, Harper JL, Ronchese F. Activation and
route of administration both determine the ability of bone marrow-derived
dendritic cells to accumulate in secondary lymphoid organs and prime CD8+ T
144 Cancer
cells against tumours. Cancer Immunol Immunother 2008;57(1):63-71. Contact:
Malaghan Institute of Medical Research, PO Box 7060, Wellington South, New Zealand.
Kendall JD, Rewcastle GW, Frederick R, et al. Synthesis, biological evaluation and
molecular modelling of sulfonohydrazides as selective PI3K p110alpha inhibitors.
Bioorg Med Chem 2007;15(24):7677-87. Contact: Auckland Cancer Society Research
Centre, School of Medical and Health Sciences, The University of Auckland, Private Bag
92019, Auckland 1020, New Zealand.
Liu JJ, Galettis P, Farr A, et al. In vitro antitumour and hepatotoxicity profiles of
Au(I) and Ag(I) bidentate pyridyl phosphine complexes and relationships to
cellular uptake. J Inorg Biochem 2008;102(2):303-10. Contact: Department of
Pharmacology and Clinical Pharmacology, The University of Auckland, Auckland 1142,
New Zealand.
Nelson SM, Ferguson LR, Denny WA. Non-covalent ligand/DNA interactions:
minor groove binding agents. Mutat Res 2007;623(1-2):24-40. Contact: Auckland
Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University
of Auckland, Private Bag
92019, Auckland 10000, New Zealand.
[email protected].
Palmer BD, Henare K, Woon ST, et al. Synthesis and biological activity of azido
analogues of 5,6-dimethylxanthenone-4-acetic acid for use in photoaffinity
labeling. J Med Chem 2007;50(16):3757-64. Contact: Auckland Cancer Society Research
Centre, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New
Zealand.
Patel K, Lewiston D, Gu Y, Hicks KO, Wilson WR. Analysis of the
hypoxiaactivated dinitrobenzamide mustard phosphate pre-prodrug PR-104
and
its alcohol metabolite PR-104A in plasma and tissues by liquid
chromatography-mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci
2007;856(1-2):302-11. Contact: Auckland Cancer Society Research Centre, University of
Auckland, Private Bag 92019, Auckland, New Zealand.
Patterson AV, Ferry DM, Edmunds SJ, et al. Mechanism of action and preclinical
antitumour activity of the novel hypoxia-activated DNA cross-linking agent PR104. Clin Cancer Res 2007;13(13):3922-32. Contact: Auckland Cancer Society Research
Centre, School of Medical Sciences, The University of Auckland, Auckland, New Zealand.
Singleton DC, Li D, Bai SY, et al. The nitroreductase prodrug SN 28343 enhances
the potency of systemically administered armed oncolytic adenovirus
ONYX411 (NTR). Cancer Gene Ther 2007;14(12):953-67. Contact: Auckland Cancer
Society Research Centre, Faculty of Medical and Health Sciences, The University of
Auckland, Auckland, New Zealand.
Smaill JB, Baker EN, Booth RJ, et al. Synthesis and structure-activity relationships
of N-6 substituted analogues of 9-hydroxy-4-phenylpyrrolo[3,4-c]carbazole1,3 (2H,6H)-diones as inhibitors of Wee1 and Chk1 checkpoint kinases. Eur J Med
Chem 2007. Contact: Auckland Cancer Society Research Centre, School of Medical
Sciences, The University of Auckland, Private Bag 92019, Auckland 1020, New Zealand.
Smaill JB, Lee HH, Palmer BD, et al. Synthesis and structure-activity relationships
of soluble 8-substituted 4-(2-chlorophenyl)-9-hydroxypyrrolo[3,4-c]carbazole1,3 (2H,6H)-diones as inhibitors of the Wee1 and Chk1 checkpoint kinases. Bioorg
Med Chem Lett 2008;18(3):929-33. Contact: Auckland Cancer Society Research Centre,
Cancer
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School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland
1142, New Zealand.
Spicer JA, Rewcastle GW, Kaufman MD, et al. 4-anilino-5-carboxamido-2pyridone derivatives as noncompetitive inhibitors of mitogen-activated protein
kinase kinase. J Med Chem 2007;50(21):5090-102. Contact: Auckland Cancer Society
Research Centre, Faculty of Medical and Health Sciences, The University of Auckland,
Private Bag 92019, Auckland 1142, New Zealand. [email protected].
Tang MH, Helsby NA, Goldthorpe MA, Thompson KM, Al-Ali S, Tingle MD.
Hepatic nitroreduction, toxicity and toxicokinetics of the anti-tumour prodrug CB
1954 in mouse and rat. Toxicology 2007;240(1-2):70-85. Contact: Department of
Pharmacology and Clinical Pharmacology, University of Auckland, Private Bag 92019,
Auckland, New Zealand. [email protected].
Wilson WR, Hicks KO, Pullen SM, Ferry DM, Helsby NA, Patterson AV.
Bystander effects of bioreductive drugs: potential for exploiting pathological
tumour hypoxia with dinitrobenzamide mustards. Radiat Res 2007;167(6):625-36.
Contact: Auckland Cancer Society Research Centre, The University of Auckland,
Auckland, New Zealand. [email protected].
Zhao L, Marshall ES, Kelland LR, Baguley BC. Evidence for the involvement of
p38 MAP kinase in the action of the vascular disrupting agent 5,6dimethylxanthenone-4-acetic acid (DMXAA). Invest New Drugs 2007;25(3):271-6.
Contact: Auckland Cancer Society Research Centre, Faculty of Medical and Health
Sciences, University of Auckland, Auckland, New Zealand.
Gastrointestinal Cancers
Humar and Guilford of the Cancer Genetics Laboratory (University of Otago)
have presented a theory on the development of hereditary diffuse gastric cancer
and lost cell polarity, as a short path to cancer48. They say that the mechanisms
that underlie the initiation of human cancer are poorly understood. In this paper
they describe the development of hereditary diffuse gastric cancer and argue that
it arises from the disruption of the regenerative processes that are inherent to all
epithelial tissues. This model supports the cancer stem cell hypothesis, in which
tumours contain a sub-population of cells with the key stem cell characteristics of
capacity for self renewal, differentiation and limitless replication. They argue that
epigenetic modifications induced by common environmental and physiological
pressures are able to initiate this disruption. The carcinogenic effects of these
modifications are potentially reversible through the use of epigenetic therapies
such as DNA demethylating agents and histone deacetylation inhibitors.
A retrospective analysis of 13 years of surveillance data of Barrett’s oesophagus in
212 patients has highlighted that 88% of all adenocarcinoma occurred in a subset
of only 11% patients49. All patients who developed cancer were male and all but
one patient had dysplasia or ulcerations on index endoscopy. The authors
conclude that to stratify surveillance for Barrett's esophagus, programmes could
focus on male patients with dysplasia or ulcerations on index endoscopy.
However, the cost-effectiveness of this approach remains unproven.
146 Cancer
Additional Publications
Deeks ED, Scott LJ. Docetaxel: in gastric cancer. Drugs 2007;67(13):1893-901.
Contact: Wolters Kluwer Health | Adis, Auckland, New Zealand.
[email protected].
Dhillon S, Scott LJ. Capecitabine: in advanced gastric or oesophagogastric cancer.
Drugs 2007;67(4):601-10. Contact: Wolters Kluwer Health | Adis, Auckland, New
Zealand, an editorial office of Wolters Kluwer Health, Conshohocken,
Pennsylvania, USA. [email protected].
Siddiqui MA, Scott LJ. Imatinib: a review of its use in the management of
gastrointestinal stromal tumours. Drugs 2007;67(5):805-20. Contact: Wolters
Kluwer Health/ Adis, Auckland, New Zealand. [email protected].
Haematological Cancers
Treatment
Hoy et al. (ADIS, New Zealand) report on the introduction of an intravenous
formulation of busulfan, developed to replace the oral preparation as a
conditioning treatment prior to haematopoietic stem cell transplantation (HSCT)
in paediatric patients50. Busulfan is a cytotoxic bifunctional alkylating agent.
Intravenous busulfan was considered to be well tolerated, in the particular context
of HSCT, and no failure of HSCT due to organ toxicity was reported.
Nonhaematologic adverse events commonly associated with busulfan
conditioning regimens were frequent, but generally of mild to moderate severity.
The intravenous busulfan regimen was frequently associated with elevated liver
enzymes, but hepatic veno-occlusive disease (HVOD) was infrequent, of mild to
moderate severity, and resolved within 10 days of diagnosis. Unlike oral
busulfan, intravenous busulfan does not appear to be associated with severe
HVOD or death due to organ toxicity.
ScottEconomics has undertaken an economic evaluation of third-line treatment
with alemtuzumab for chronic lymphocytic leukaemia51. Alemtuzumab was
compared with fludarabine, cyclophosphamide and rituximab (FCR). Average
costs and outcomes and incremental cost per patient treated, per survival month
and per QALY gained, were calculated. All costs were presented in 2006 New
Zealand dollars. Base-case direct medical costs for alemtuzumab per treatment
regimen per patient were $NZ15,303 lower than those for FCR. The average direct
medical cost per survival month gained for alemtuzumab was $NZ3,144 and for
FCR was $NZ4,101, and the average direct medical cost per QALY gained was
$NZ46,016 and for FCR was $NZ60,012.
Additional Publications
Cross SA, Lyseng-Williamson KA. Imatinib: in relapsed or refractory Philadelphia
chromosome-positive acute lymphoblastic leukaemia. Drugs 2007;67(17):2645-54.
Contact: Wolters Kluwer Health | Adis, Auckland, New Zealand, an editorial office of
Wolters Kluwer Health, Conshohocken, Pennsylvania, USA. [email protected].
Ganta S, Paxton JW, Baguley BC, Garg S. Development and validation of
bioanalytical method for the determination of asulacrine in plasma by liquid
chromatography. J Pharm Biomed Anal 2008;46(2):386-90. Contact: School of
Cancer
147
Pharmacy, Faculty of Medical and Health Sciences, The University of Auckland, Private
Bag 92019, Auckland, New Zealand.
Moen MD, McKeage K, Plosker GL, Siddiqui MA. Imatinib: a review of its use in
chronic myeloid leukaemia. Drugs 2007;67(2):299-320. Contact: Wolters Kluwer
Health, Adis, Auckland, New Zealand.
Plosker GL, Robinson DM. Nilotinib. Drugs 2008;68(4):449-59. Contact: Wolters
Kluwer Health Adis, Auckland, New Zealand. [email protected].
Sanford M, Lyseng-Williamson KA. Nelarabine. Drugs 2008;68(4):439-47. Contact:
Wolters Kluwer Health Adis, Auckland, New Zealand. [email protected].
Risk Factors
Researchers from the University of Otago52 have found no protective effect of
folate supplementation in pregnancy on the development of acute lymphoblastic
leukaemia (ALL) in childhood. In a national case-control study, the mothers of 97
children with ALL and 303 control children were interviewed about their intake of
supplements during pregnancy. No association with folate intake was found,
even when data from New Zealand were combined in a meta-analysis with data
from a similar study in Australia (which reported a small protective effect) and a
study in Quebec.
Head and Neck Cancers
Ewing’s Sarcoma
A case report of a 22-year-old male with Extra-skeletal Ewing's sarcoma (EES) of
the submandibular gland has been published by a team at the Head and Neck and
Skull Base Surgery/Oncology Programme (Hutt Hospital)53. The team believes
that this has not been described previously. Extra-skeletal Ewing's sarcoma (EES)
is an uncommon malignancy, especially in the head and neck region, that may
arise in various extra-osseous tissues. The patient, who underwent combined
treatment with surgical resection and chemo-irradiation, was disease free for 22
months but succumbed to multi-organ metastases 14 months later. The case
highlights the combined diagnostic role of immunohistochemical, cytogenetic and
radiological evaluation of EES.
EES is an aggressive cancer that requires
multidisciplinary management with wide surgical excision and adjunctive chemoirradiation for the best outcome.
Risk Factors
Cannabis use does not increase the risk of head and neck cancer, according to the
findings of a case control study published by the Medical Research Institute of
New Zealand (Wellington)54. Researchers analysed data from 75 cases and 319
controls. An increased risk of cancer was found with increasing tobacco use,
alcohol consumption, and decreased income but not increasing cannabis use. The
highest tertile of cannabis use (>8.3 joint years) was associated with a nonsignificant increased risk of cancer (relative risk = 1.6; 95% confidence interval:
0.5-5.2) after adjustment for confounding variables. However, the research team
cautions that, given the limited power of the study to detect a statistically
significant effect and the duration of use studied, a small or longer-term effect
cannot be excluded.
148 Cancer
Thyroid Cancers
Lallu et al. highlight two cases in which bland cytologic features seen following
fine needle aspiration cytology could have led to misdiagnosis of metastatic
thyroid carcinoma of the Hurthle cell type, had immunohistochemical stains not
been carried out55. They stress that immunohistochemistry aids the definitive
diagnosis of metastatic Hurthle cell carcinoma of thyroid, especially when the
presence of a previous thyroid lesion is not communicated to the laboratory.
Additional Publications
Blick SK, Scott LJ. Cetuximab: a review of its use in squamous cell carcinoma of
the head and neck and metastatic colorectal cancer. Drugs 2007;67(17):2585-607.
Contact: Wolters Kluwer Health | Adis, Auckland, New Zealand, an editorial office of
Wolters Kluwer Health, Conshohocken, Pennsylvania, USA. [email protected].
Ch'ng S, Low I, Ng D, et al. Epidermal growth factor receptor: a novel biomarker
for aggressive head and neck cutaneous squamous cell carcinoma. Hum Pathol
2008;39(3):344-9. Contact: Department of Medicine, Wellington School of Medicine &
Health Sciences, Wellington, 6021 New Zealand.
Gunawardena I, Kenwright D, Steventon N, Ferguson C. Primitive
neuroectodermal tumour of the tongue. J Laryngol Otol 2008;122(4):416-8. Contact:
Department of Otolaryngology, Head and Neck Surgery, Wellington Hospital,
Wellington, New Zealand. [email protected].
Lin E, Hwang TZ, Hornibrook J, Ormond T. Voice of postradiotherapy
nasopharyngeal carcinoma patients: evidence of vocal tract effect. J Voice
2008;22(3):351-64. Contact: University of Canterbury, Communication Disorders,
Christchurch, New Zealand.
Liver Cancer
A team at the New Zealand Transplant Unit of Auckland City Hospital56
presented data suggesting that careful patient selection for liver resection for
hepatocellular carcinoma can achieve good long-term patient survival and
acceptable levels of risk.
Multivariate analysis showed that only tumour
recurrence and presence of cirrhosis were significant determinants of the risk of
tumour-related death.
Sorafenib was recently approved in the US and the EU for treatment of patients
with hepatocellular carcinoma, and has been shown to significantly improved
survival in patients with advanced disease, as detailed in a recent review57.
Monotherapy with oral sorafenib 400 mg twice daily was generally well tolerated
in patients with advanced hepatocellular carcinoma, with a manageable adverse
event profile.
Cancer
149
Lung Cancer
Disparities
Stevens et al. 58 propose that low anti-cancer treatment rates may contribute to
poorer survival outcomes of patients with lung cancer in New Zealand. Survival
rates compare unfavourably with those from Australia and the United States. To
ascertain whether these poorer outcomes were related to secondary care
management or to other factors, the team documented stage of disease,
comorbidities, and initial secondary care management for patients diagnosed with
lung cancer in 2004, in Auckland and Northland (New Zealand). These data were
compared with international data. Cases were identified from regional databases
and the New Zealand Cancer Registry. Five hundred sixty-five eligible cases were
identified. Overall, 70% of cases were referred to an anticancer service, and 50%
received initial anticancer treatment. Potentially curative treatment was received
by 20% of cases. The authors say that this cohort was characterised by high comorbidity and advanced disease. Although similar to the United Kingdom, initial
treatment rates were low in comparison with Australia and the United States,
despite similar stage distributions. Overall, 50% of patients, including 30% with
early-stage disease, did not receive initial anticancer treatment.
As individuals with early-stage, non-small-cell lung cancers (NSCLC) generally
have a better of survival than those with other forms of the disease, Stevens et al.59
suggest that survival outcomes in these patients will be disproportionately
affected by appropriate or inappropriate treatment. Using the same data as in the
previous study, the team looked at management of stage I/II NSCLC, whether
management differed from international practice, and factors influencing curative
management. Of the 142 cases with stage I or II NSCLC, 79 patients (56%) were
treated with curative intent and 61 (44%) were managed palliatively. Of those
treated curatively, 69 underwent surgical resection, 9 received definitive radiation
therapy and a single patient received concurrent chemo-irradiation. Of those
managed palliatively, 21 received anti-cancer treatment and 40 received
supportive care.
Increasing age and co-morbidity reduced the chances of
receiving curative treatment (P < 0.001, P = 0.004, respectively). However,
discussion at a multidisciplinary meeting was associated with increased
likelihood of curative management (P < 0.001). The investigators observed that
disparity between New Zealand and overseas practice increased with increasing
age and co-morbidity in the patients. They found that only half of those managed
curatively commenced treatment within internationally recommended time
frames. The authors postulate that these factors may contribute to the poorer
survival rate in New Zealand and suggest that, as the management differences
increased with increasing age and co-morbidity, more nihilistic attitudes may
prevail in New Zealand.
In a further study using the same data60, Stevens et al. found that Māori were 2.5
times more likely to have locally advanced disease than localised disease
compared with Europeans (p < 0.01), and four times less likely to receive curative
rather than palliative anti-cancer treatment compared with Europeans (p < 0.01).
Māori had longer transit times from diagnosis to treatment (p < 0.001). Maori
were more likely to decline treatment and miss appointments than Europeans,
although this only partially explained management differences. The authors
say
150 Cancer
that multiple factors are potentially responsible for the higher case-fatality ratio in
Māori. Such factors include presentation with more advanced disease, lower rates
of curative treatment for non-metastatic disease, and longer transit times from
diagnosis to treatment. The investigators also say that socioeconomic deprivation,
co-morbidity levels, and failure to accept treatment did not fully explain ethnic
differences in management and call for further assessment of the underlying
issues by prospective evaluation.
Risk Factors
Aldington et al.61 from the Medical Research Institute of New Zealand
(Wellington) have shown that long-term cannabis use increases the risk of lung
cancer in young adults, with an increased relative risk of 5.7 (95% confidence
intervals: 1.5-21.6) in the highest tertile of cannabis use. They identified patients
up to 55 years of age from the New Zealand Cancer Registry (NZCR) and hospital
databases and adjusted for confounding variables, such as cigarette smoking. A
total of 79 cases of lung cancer were studied and 324 controls, in a study involving
eight District Health Boards.
Young et al. (Department of Medicine, University of Auckland) call for forced
expiratory volume in one second (FEV(1)) to be considered a marker that
identifies smokers at greatest need of medical intervention62. The authors say that
FEV(1) is more than a measure of airflow limitation, but a marker of premature
death with broad utility in assessing baseline risk of chronic obstructive
pulmonary disease, lung cancer, coronary artery disease and stroke, collectively
accounting for 70-80% of premature death in smokers. They propose that
spirometry has broad utility in identifying smokers who are at greatest risk of
cardiorespiratory complications and greatest benefit from targeted preventive
strategies, such as smoking cessation, prioritised screening and effective
pharmacotherapy.
Additional Publications
Wilson K, Widdowson M, Swanney M, Meyer R, Singh H, Beckert L. Chronic
dyspnea and wheezing in a 46-year-old nonsmoker. Chest 2008;133(4):1034-7.
Contact: Respiratory Physiology Laboratory, Department of Respiratory Medicine,
Christchurch Hospital, Christchurch, New Zealand. [email protected].
Lymphatic Cancer
A review of the literature on the use of fludarabine in non-hodgkin’s lymphoma
concludes that it is as effective as several other standard treatment regimens in
treatment-naïve patients and is also effective in patients with recurrent or
refractory disease63. The efficacy of fludarabine therapy is improved with the use
of rituximab, as part of the initial therapeutic regimen or as maintenance therapy,
and deserves consideration. Fludarabine has generally acceptable tolerability;
however, it is associated with haematological adverse events, including
myelosuppression. In closing, the authors say that fludarabine, provides a highly
effective first- or second-line option in the treatment of non-Hodgkin's lymphoma.
Macann et al. (Department of Radiation Oncology, Auckland Regional Cancer and
Blood Service and the German Hodgkin’s Lymphoma Study Group) have
Cancer
151
published a study undertaken to assess whether radiotherapy influenced the
severe pulmonary toxicity observed with concurrent administration of
gemcitabine and bleomycin in patients with advanced-stage Hodgkin’s
lymphoma64. Severe pulmonary toxicity was observed in the pilot study of
BAGCOPP
(bleomycin,
doxorubicin,
cyclophosphamide,
vincristine,
procarbazine, prednisone, and gemcitabine) for advanced-stage Hodgkin's
lymphoma.
Twenty-seven patients were enrolled on the study before its
premature closure as a result of the development of serious pulmonary toxicity in
8 patients. The pulmonary toxicity occurred either during or immediately after
the BAGCOPP chemotherapy course. Pulmonary toxicity contributed to one early
fatality but resolved in the other 7 patients after cessation of gemcitabine and
bleomycin, allowing continuation of therapy. Fifteen patients received
consolidative radiotherapy, including 4 who previously had pulmonary toxicity.
There were no reported cases of radiation pneumonitis and no exacerbation of
pulmonary symptoms in the 4 patients who had had previous pulmonary toxicity.
Gemcitabine (when administered without bleomycin) remains of interest in
Hodgkin's lymphoma and is being incorporated into a new German Hodgkin's
Lymphoma Study Group protocol that also includes consolidative radiotherapy.
This study supports the concept of the integration of radiotherapy in gemcitabinecontaining regimens in Hodgkin's lymphoma if there is an interval of at least 4
weeks between the two modalities and with a schedule whereby radiotherapy
follows the chemotherapy.
Occupational Health
A nationwide study of bladder cancer in adults65 has confirmed that hairdressers
(odds ratio (OR): 9.15; 95% confidence interval (95%CI): 1.60-62.22), and sewing
machinists (OR: 3.07; 95%CI: 1.35-6.96) appear to be at the high risk. The team
from the Centre of Public Health Research at Massey University (Wellington)
looked at 273 cases of bladder cancer and 471 controls. They also identified
occupations that may confer elevated risk levels and deserved further study.
These were: tailors and dressmakers, rubber and plastics-products machine
operators, building workers, and female market farmers and crop growers.
Firth and colleagues66 at the Otago University have undertaken a study of cancer
mortality risk in New Zealand women in the six most common occupation
groups: clerical workers, health professionals, teachers, farmers, cleaners and
textile workers. In the group aged over 20 years (7236), leukaemia was
significantly increased in health professionals (proportional mortality ratio (PMR)
was 1.52; 95% CI: 1.08-2.09, n=38). In nurses alone, the PMR for leukaemia was
1.42; 95% CI: 0.96-2.01, n=31).
Investigators at the Centre for Public Health Research (Massey University) have
looked at occupational risk factors for non-Hodgkin's lymphoma (NHL) in New
Zealand67. In a nationwide case-control study a total of 291 incident cases of NHL
(age 25-70 years) notified to the New Zealand Cancer Registry during 2003 and
2004, and 471 population controls, were interviewed face-to-face. The
questionnaire collected demographic information and a full occupational history.
The relative risk for NHL associated with ever being employed in particular
occupations and industries was calculated by unconditional logistic
regression
152 Cancer
adjusting for age, sex, smoking, ethnicity and socioeconomic status. An elevated
NHL risk was observed for field crop and vegetable growers (OR: 2.74; 95% CI:
1.04-7.25) and horticulture and fruit growing (OR: 2.28; 95% CI: 1.37-3.79),
particularly for women (OR: 3.44; 95% CI: 0.62-18.9; OR: 3.15; 95% CI: 1.50-6.61).
Sheep and dairy farming was not associated with an increased risk of NHL. Meat
processors had an elevated risk (OR: 1.97; 95% CI: 0.97-3.97), as did heavy truck
drivers (OR: 1.98; 95% CI: 0.92-4.24), workers employed in metal product
manufacturing (OR: 1.92; 95% CI: 1.12-3.28) and cleaners (OR: 2.11; 95% CI:
1.21-3.65). After semi-Bayes adjustment for the number of occupations examined
the elevated risks for horticulture and fruit growing, metal product
manufacturing and cleaners remained statistically significant, representing the
most robust findings of this study. The study confirms previous research findings
that crop farmers and meat workers are high-risk occupations for NHL in New
Zealand, and authors identify several other occupations and industries of high
NHL risk that merit further study.
Olfactory Cancer
Capelle and Krawitz report on a case of Esthesioneuroblastoma, a rare malignancy
arising from the olfactory epithelium68. A 75-year-old man presented with a
Kadish stage C esthesioneuroblastoma and underwent craniofacial surgery and
adjuvant radiotherapy. Two years later he was found to have diffuse subdural
deposits with distant bone and nodal metastases, treated with further
radiotherapy. The patient's condition subsequently deteriorated and he died.
Given this unusual pattern of failure, the authors review the recent published
studies regarding the natural history, treatment and outcome for this tumour.
Oncogenesis
A team from the Children's Cancer and Developmental Genetics Research Group
(Christchurch School of Medicine and Health Sciences) have published a review
on the role of a gene with activity in fetal development and oncogenesis69. The
authors say that embryonic and fetal development is a highly complex process
choreographed by several families of genes that regulate early development of the
embryo. Disruption in the structure and/or function of developmental genes
produces morphogenic errors of development. (Morphogenesis is the
differentiation and growth of organs or tissues during development.) One such
family is the Hedgehog (Hh) signalling pathway, which plays an important role in
the embryonal development of both invertebrates and vertebrates, including
normal development of the brain, eye, limbs, foregut and its derivatives.
Disruption of the Sonic hedgehog expression during critical periods of
development is associated with developmental disorders of the brain, namely,
holoprosencephaly, and the VATER association. Inappropriate activation of the
pathway in post-embryonic development has been demonstrated in several
human malignancies, including those of the brain and skin, both in children and
adults. Specific inhibition of Hh signalling in these tumours inhibits growth of a
wide range of malignancies. This demonstrates a requirement for Hh signalling in
these tumours. These observations suggest that a better understanding of the
genetic control of morphogenesis can ultimately provide us with greater
knowledge of how congenital structural abnormalities occur, as well as
the
Cancer
153
processes that lead to several childhood and other tumours. The authors surmise
that there may be a closer relationship between embryogenesis and oncogenesis
than previously realised.
Cox and Hampton of the Free Radical Research Group (University of Otago) have
published findings suggesting that the anti-apoptotic oncogene Bcl-2 may
promote tumourigenesis by preventing the removal of oxidatively damaged cells,
rather than protecting cells from oxidative stress - as has previously been
proposed70. The team looked at Jurkat T lymphoma cells exposed to hydrogen
peroxide at doses that induced apoptosis (programmed cell death) or necrosis. At
apoptotic doses, over-expression of Bcl-2 did block cell death. However, these
cells still showed the same signs of oxidative damage, suggesting that the
antiapoptotic activity is not associated with general antioxidant
properties. Assessment of micronuclei formation in cells over-expressing Bcl-2
showed evidence of increased genomic instability, consistent with the
impairment of apoptosis in damaged cells.
Recently published data suggests that the increased levels of autocrine human
growth hormone observed in endometriosis and endometrial adenocarcinoma
stimulates oncogenicity of endometrial carcinoma cells. Researchers from the
Liggins Institute and National Research Centre for Growth and Development, and
Department of Molecular Medicine and Pathology (University of Auckland) have
conducted studies to demonstrate this effect71. These studies demonstrate a
pivotal role for autocrine human growth factor in the development and
progression of endometrial carcinoma and indicate the potential therapeutic
relevance of human growth factor antagonism in the treatment of endometrial
carcinoma.
A review summarising the current evidence for involvement of trefoil factors
(TFFs) in human cancer has been published by researchers at the Liggins Institute
(University of Auckland)72. TFFs are oestrogen-regulated genes, which are also
regulated by other substances, including growth hormone, insulin-like growth
factor-1 and epidermal growth factor, as well as oncogenic stimuli. They are
secreted proteins present in serum and can act as growth factors promoting cell
survival, anchorage-independent growth and motility.
Recent compelling
evidence has emerged from experimental and clinical studies to indicate a pivotal
role of TFFs in oncogenic transformation, growth and metastatic extension of
common human solid tumours.
Additional Publications
Ferguson LR, Denny WA. Genotoxicity of non-covalent interactions: DNA
intercalators. Mutat Res 2007;623(1-2):14-23. Contact: Auckland Cancer Society
Research Centre, Faculty of Medical & Health Science, The University of
Auckland, New Zealand. [email protected].
Liu DX, Lobie PE. Transcriptional activation of p53 by Pitx1. Cell Death Differ
2007;14(11):1893-907. Contact: Liggins Institute and National Research Centre for
Growth and Development, University of Auckland, Auckland, New Zealand.
Mohankumar KM, Xu XQ, Zhu T, et al. HOXA1-stimulated oncogenicity is
mediated by selective upregulation of components of the p44/42 MAP kinase
pathway in human mammary carcinoma cells. Oncogene 2007;26(27):3998-4008.
154 Cancer
Contact: The Liggins Institute and National Research Centre for Growth and
Development, University of Auckland, Auckland, New Zealand.
Shafiei F, Rahnama F, Pawella L, Mitchell MD, Gluckman PD, Lobie PE. DNMT3A
and DNMT3B mediate autocrine hGH repression of plakoglobin gene
transcription and consequent phenotypic conversion of mammary carcinoma
cells. Oncogene 2008;27(18):2602-12. Contact: National Research Centre for
Growth and Development and the Liggins Institute, University of Auckland,
Auckland, New Zealand.
Orthopaedic Oncology
Clinicians from the Orthopaedic Oncology Unit, Middlemore Hospital (Auckland)
have published a review of their experience with 2-stage revision of uncemented
Kotz Modular Femoral and Tibial Replacement System prostheses, over the last 15
years73. They describe the outcomes for the eleven patients that underwent
second-stage revision and conclude that this procedure with retention of a wellingrown stem can be associated with successful eradication of infection.
Palliative Care
Researchers at the Department of General Practice of Dunedin Medical School
have undertaken a qualitative study of seven women dying from cancer in a
Dunedin hospice74. The key theme that came through from the questionnaires
was uncertainty, throughout the diagnosis and treatment process and in living
with disease (such as knowing whether they could manage an outing or be pain
free). All felt that their bodies had let them down and that they were unable to
fulfil the goal of “living until they die”. None were afraid of dying but all were
affected by increased social isolation as they withdrew from employment and
other activities. The authors conclude that having a ‘good death’ is affected not
just by management and treatment by health professionals but by the perceptions
of the individual held by others and themselves.
The Hospice and Palliative Care Service, Nurse Maude Association (Christchurch)
has undertaken an audit of the management of nausea, vomiting and bowel
obstruction in metastatic ovarian cancer75. They included a focus on
pharmacological and non-pharmacological interventions (e.g. dietary advice and
relaxation strategies). The audit involved a retrospective chart review of 17
patients and identified the current clinical management of these symptoms in
comparison with best practice guidelines. The results indicated many areas of
symptom management were in line with current evidence-based practise.
However, the use of non-pharmaceutical interventions was limited. There were
several implications for clinical practice, specifically supporting the use of
electronic integrated patient management systems and a greater use of
nonpharmaceutical (complementary) interventions.
William and Mcleod of the North Shore Hospice (Auckland) have published a
review on the management of breakthrough pain (BTP) in patients with cancer76.
They say that there is no consensus definition for BTP in patients with cancer,
meaning that it is often inadequately diagnosed and assessed, therefore making
it
Cancer
155
more challenging to manage. Cancer pain is generally moderate to severe in
intensity and persistent in nature. As most breakthrough analgesia fails to be
effective in the time required for BTP, no useful analgesia is provided but drug
adverse effects escalate. The frequency of BTP and its inadequate management
means that it has significant adverse effects on patients, their families and those
involved in their care. The article outlines a systematic, clinical and evidencebased approach to managing BTP in patients with cancer that emphasises a
holistic approach and an understanding of multi-dimensional 'total pain'.
Guidelines for managing BTP are presented and areas of developing research are
identified.
Post-Treatment Immunisation in Children
An Australasian study77 of involving 45 paediatric oncologists (37 responded) has
found that the majority of respondents (94%) would recommend commencing
booster vaccinations 6 months post treatment, in keeping with current guidelines.
Intensity of chemotherapy was seen to be an important factor, with 97% of
respondents recommending re-immunisation after intensive chemotherapy and
only 48% after a lower intensity regimen. Sixty-nine percent would recommend
yearly influenza vaccinations for their patients. The authors highlighted the
variability in the findings and called for a review of the evidence-base and
guidelines on this important variable for cancer survival.
Pancreatic Cancer
A review has been published that provides practical advice for the clinician when
confronted with questions about the risk of pancreatic cancer in relatives, and the
role of genetic testing and screening in high-risk individuals78. The author says
that there is now a sufficient body of evidence to inform relatives of their relative
risk of developing the disease.
Additional Publications
Connor S. Branch-type intraductal papillary mucinous neoplasms. World J Surg
2008;32(2):279-80. Contact: Department of Surgery, Christchurch Hospital, Private
Bag, 4710, Christchurch, New Zealand, [email protected].
Primary Care
The education and training of primary care professionals in relation to cancer and
primary care has been undertaken by a team from the Community and Home
Detox Service (Auckland Community Alchohol and Drug Service)79. A semis
structured telephone questionnaire was administered to 210 organisations in a
national audit. The team found evidence of good adult education practice, and
95% of organisations ran accredited programmes. Although pharmaceutical
industry support was not favoured, the majority (78%) described this as their
main source of funding. They conclude that there is optimism and strong
commitment among primary care cancer education and training providers.
156 Cancer
Additional Publications
McAvoy BR. General practitioners and cancer control. Med J Aust 2007;187(2):1157. Contact: Community and Home Detox Service, Auckland Community Alcohol
and
Drug
Service,
Auckland,
New
Zealand.
[email protected].
Reproductive Cancers
Cervical Cancer
Prevention
Jones et al. (Gynaecological Oncology Service, National Women's Hospital) call the
introduction of the human papilloma virus (HPV) vaccine the single most
important advance in the prevention of cervical cancer since the introduction of
cervical cytology half a century ago80. Vaccination should ideally occur prior to a
female's first sexual experience. The authors go on to suggest that the HPV
vaccine should be publicly funded in New Zealand.
Screening
Lovell et al.81 explored why a country such as New Zealand, which has elevated
awareness of cervical screening due to media coverage of adverse events, should
still experience poor rates of uptake for the free screening programme.
Qualitative interviews were conducted with 17 women who were overdue for a
smear test in 2001-2002. Nine service providers were also interviewed. The
authors conclude that, concurrent with socioeconomic limitations, concerns about
exposing the body were key in the decision to delay screening. Māori and Pacific
women in particular expressed embarrassment about exposing their bodies and
concerns over violating cultural beliefs about sacredness.
An in-depth study of 6 women (predominantly Māori) at least 6 months overdue
for a cervical smear examined their reasons for not persisting with the screening
programme. It found that the smear process could “violate women’s positive
aloneness with their bodies” and suggested that primary care services should find a
way of addressing this82.
Disease Progression and Invasive Potential
Researchers at the Department of Preventive and Social Medicine, University of
Otago (Dunedin)83 have published a study on the invasive potential of cervical
cancer at ‘stage 0’ of the disease. The unethical treatment of women diagnosed
with stage 0 cervical cancer at the National Women’s Hospital between 1955 and
1976, for whom treatment was with-held as part of a clinical study, resulted in a
judicial review. The research team accessed the records from the review and were
able to make a study of outcomes for 1229 (86%) of the 1229 women who were
diagnosed with stage 0 cervical carcinoma at the hospital during that time period.
They found that 143 women were managed only by punch or wedge biopsy and
that their cumulative incidence of invasive cancer of the cervix or vaginal vault
was 31.3% (95% CI: 22.7-42.3) at 30 years, and 50.3% (95% CI: 37.3-64.9) in the
subset of 92 such women who had persistent disease within 24 months. However,
cancer risk at 30 years was only 0.7% (95% CI: 0.3-1.9) in 593 women whose initial
Cancer
157
treatment was deemed adequate or probably adequate, and whose treatment for
recurrent disease was conventional. The study shows the importance of prompt,
conventional treatment for stage 0 carcinoma of the cervix and the low risk of
progression if this is carried out appropriately.
Surgery
A review by researchers at the National Women’s Hospital (Auckland) discusses
the literature on the association between cervical treatment and preterm birth, and
the clinical implications of these findings84. Excision of a portion of the cervix for
treatment of cervical intraepithelial neoplasia may have an adverse effect on
pregnancy outcome. The methodology and findings of the published literature on
the association between cervical treatment and preterm birth, and the clinical
implications of these findings are discussed.
Additional Publications
Gray B, Lewis H, Casey D. New Zealand's cervical screening legislation-and
response. N Z Med J 2008;121(1268):U2910. Contact:
Keam SJ, Harper DM. Human papillomavirus types 16 and 18 vaccine
(recombinant, AS04 adjuvanted, adsorbed) [Cervarix]. Drugs 2008;68(3):359-72.
Contact: Wolters Kluwer Health | Adis, Auckland, New Zealand. demail.adis.co.nz.
Schiffman M, Rodriguez AC. Heterogeneity in CIN3 diagnosis. Lancet Oncol
2008;9(5):404-6.
Endometrial Cancer
An evidence-based review of local therapy in endometrial cancer has been
published by Deeks (ADIS, New Zealand)85. Surgery is the standard primary
treatment for early stage endometrial cancer, with local adjuvant therapies such as
pelvic radiotherapy and vaginal brachytherapy most often used in patients with
high risk of recurrence. There are currently very few well designed studies
evaluating local therapies in endometrial cancer. To date, the available evidence
suggests that adjuvant external beam radiotherapy reduces locoregional
recurrence in stage I disease but not the risk of death. Considering the high
survival rate and low recurrence risk of patients with early stage disease,
postoperative adjuvant radiotherapy should perhaps be limited to patients with
high risk of recurrence, particularly since such radiotherapy is associated with
increased long-term complications and toxicity. Adjunctive chemotherapy has so
far failed to demonstrate any improvement over radiotherapy in terms of overall
survival in patients with intermediate and high-risk endometrial cancer. Deeks
says that further well controlled studies are required in order to confidently
establish the optimal use of local treatments and other therapies in endometrial
cancer.
Ovarian Cancer
Researchers from the Hospice and Palliative Care Service, Nurse Maude
Association (Christchurch) have undertaken an audit of the management of
nausea, vomiting and bowel obstruction in metastatic ovarian cancer75. Women
living with metastatic ovarian cancer experience many distressing symptoms,
such as vomiting and bowel obstruction, which challenge the expertise of nurses
158 Cancer
working in Palliative Care to promote quality of life. The audit involved a
retrospective chart review of 17 patients and identified the current clinical
management of these symptoms in comparison with best practice guidelines. The
results indicated many areas of symptom management were in line with current
evidence-based practice. However, the use of non-pharmaceutical interventions
was limited. There were several implications for clinical practice, specifically
supporting the use of electronic, integrated patient-management systems and a
greater use of non-pharmaceutical (complementary) interventions. The audit
process provided useful data for the authors to analyse current practice and
promote more effective management of these distressing symptoms.
Prostate Cancer
Aetiology
Nicholson and Whittington (Department of Anatomy and Structural Biology,
University of Otago) have published a review on the possible role oxytocin in
prostate disease86. Oxytocin is a peptide hormone produced by the posterior lobe
of the pituitary. The authors say that the discovery that the peptide is produced
locally within the male and female reproductive tracts has raised the possibility
that oxytocin may have paracrine and autocrine actions outside of the nervous
system. Oxytocin and its receptor have been identified in the human prostate.
Oxytocin has been shown to modulate contractility of prostate tissue and also to
regulate local concentrations of the biologically active androgens. Oxytocin has
also been shown to regulate cell growth. Prostate disease is common and results
from abnormal growth of the gland. Oxytocin concentrations are altered in both
benign and malignant prostate diseases and in vitro studies suggest that the
peptide may be involved in the pathophysiology of these diseases.
Screening
A team from the Department of Pathology and Molecular Medicine, (Wellington
School of Medicine and Health Sciences, Otago University) and the Department of
Radiation Oncology (Wellington Hospital) has published a review of the new
evidence base for diagnosis and treatment of prostate cancer87. Although prostate
cancer (PC) has a significant mortality, there is debate regarding the utility of PC
screening and major studies investigating the value of population-based screening
have yet to be concluded. There is increasing evidence from preliminary reports
relating to outcome prediction for PC, that early detection leads to improved
outcomes and a decrease in the burden of metastatic disease on our healthcare
system. PC is rarely symptomatic until it has metastasised to bone and because of
this prostate specific antigen (PSA)-based screening remains the only widely
available and reliable method of diagnosis for organ-confined disease. There is
now compelling evidence to show the following. 1. Cancers diagnosed by
screening are more likely to be early stage, when most can be cured by a number
of different treatment options. 2. The maximum benefits of screening are for men
aged 50-70 years. Older men have a greater chance of a clinically insignificant
cancer being diagnosed for which treatment is not necessary. 3. The familial risks
of PC are well recognised. In particular, men with one or more first-degree
relatives already diagnosed with the disease should be actively encouraged to
undergo screening. 4. Modern histopathological assessment of fine core needle
biopsies of the prostate allows for the likely behaviour of cancer present to be
accurately predicted.
Changes that mimic those of malignancy can be
confidently
Cancer
159
identified, so these cases are no longer incorrectly diagnosed. In conclusion, the
team says that these improvements mean that now most men aged 50-70 years
diagnosed with PC will have clinically significant cancers that require treatment.
Diagnosis
Mitchell et al. report the case of a 55-year-old man whose diagnosis of prostate
cancer was made following investigation of multiple cranial nerve palsies88.
Cranial nerve palsies have previously been reported in metastatic prostate
carcinoma, usually occurring late in the course of the disease.
Disparities
Researchers from the Hugh Adam Cancer Epidemiology Unit (University of
Otago) have examined ethnic differences in prostate cancer survival in New
Zealand through a national study89. Analyses were based on the 7,733 men with
histologically confirmed prostate cancer diagnosed from the start of 1996 to the
end of 1999 in New Zealand. Five-year adjusted prostate-specific mortality rates
and hazard ratios were calculated for Māori, Pacific, and European men. In
univariate analyses, Māori and Pacific men had higher mortality, particularly in
the first year after a diagnosis of prostate cancer, than did European men. The
strongest prognostic factors for prostate cancer were Gleason score and age.
When survival analyses by ethnic group were adjusted for age and Gleason score
the disparities in survival for Māori men and Pacific men with low-grade prostate
cancers remained, with European men having the best survival. Several possible
explanations have been proposed to explain the survival disparities by ethnicity in
New Zealand. Differentials in Gleason grade of disease by ethnic group explain a
lot of these disparities. The authors say that further data on stage of disease at
diagnosis, co-morbidity, treatment, access to health services, and behavioural and
environmental factors are needed to resolve these issues.
Additional Publications
Gilling PJ. Prostate Cancer Following BPH Treatments: What the Patient Should
Know. Eur Urol 2008;53(6):1109-10. Contact: PO Box 56, Tauranga, New Zealand.
Keam SJ, Scott LJ. Dutasteride: a review of its use in the management of prostate
disorders. Drugs 2008;68(4):463-85. Contact: Wolters Kluwer Health Adis, Auckland,
New Zealand. [email protected].
Wellington K, Keam SJ. Spotlight on bicalutamide 150mg in the treatment of
locally advanced prostate cancer. Drugs Aging 2007;24(2):169-71. Contact: Wolters
Kluwer Health | Adis, Auckland, New Zealand.
Risk Factors
Travier et al. have explored a possible link between HbA(1c) levels and cancer risk
90.
HbA(1c) measurements were made on blood samples of participants in a
hepatitis B (HB) screening program (1999-2001). Cancer incidence was
determined by linkage to cancer registrations and hospitalization records to the
end of 2004. Participants previously diagnosed with diabetes or cancer were
excluded. Hazard ratios (HR) and 95% confidence intervals (CIs) were estimated
using Cox regression. Among the 46,575 participants (70% Māori, 12% Pacific, 5%
Asian and 12% Other), 634 cancer cases were observed. For all cancers combined,
160 Cancer
a significant increased risk was found in persons with moderately elevated
HbA(1c) levels (6%-6.9%) (HR: 1.40; 95% CI: 1.11-1.76), with a smaller increased
risk in persons with highly elevated levels of ≥ 7% (HR: 1.09; 95% CI: 0.80-1.48) as
compared with persons having low HbA(1c) levels (<6%). The HRs for
respiratory cancers were 2.27 (95% CI: 1.34-3.86) for the moderate HbA(1c)
category and 1.58 (95% CI: 0.77-3.26) for the upper HbA(1c) category. For
endometrial cancers, the HRs were 4.05 (95% CI: 1.10-14.88) and 5.07 (95% CI:
1.20-21.31), respectively. For other cancer sites, no significantly increased risks
were found. The authors suggest that these findings are consistent with other
evidence that abnormal glucose metabolism may be associated with an increased
risk of some cancers.
Researchers at the Department of Psychological Medicine (University of Otago)
have studied peoples perceptions of modifiable cancer risk factors in New
Zealand91. An anonymous telephone questionnaire was administered 438
respondents (68% participation) 20 years and older, randomly selected from
telephone directory listings. Nearly 90% considered that there were things which
people could do to reduce cancer risk.
Unprompted, almost two-thirds
mentioned nutrition, and more than half suggested “not smoking”. Other
suggestions included being physically active, and protection from excessive sun
exposure. Two-thirds believed they could reduce their own risk, and by interview
end this increased significantly to 72%. Half named items which people could
consume to reduce risk: more vegetables, fruit or water; less alcohol, fatty foods,
and meat. Greatest awareness was of risks from sunburn, secondhand tobacco
smoke, sunlamps, eating animal fat, and being overweight, and of the protective
effects of eating grains, fruit, and vegetables. Many considered stress, cellular
phones, and genetically modified foods as risks, and vitamin and mineral
supplements as protective. Few indicated awareness of risks from hepatitis B or
alcohol. The investigators believe that greater public awareness about avoiding
tobacco smoking and excessive sun exposure suggests gains from past efforts.
They go on to say that to achieve similar awareness for other cancer prevention
strategies, and to correct misconceptions, comparable resources and efforts are
likely to be required.
Laugesen has published a review entitled “Snuffing out cigarette sales and the
smoking deaths epidemic”92, in which it is pointed out that low-nitrosamine
tobacco snuff is 20 times less dangerous than cigarette smoking. It is further
contended that oral snuff has helped to reduce smoking to unusually low levels in
Swedish men, is much less dangerous than smoking, and does not cause lung or
mouth cancer. Moreover, smokeless tobacco (which includes snuff) could reduce
smoking-caused health inequity for Māori. Snuff can improve population health,
and more so if more smokers switch to it. Continued bans on snuff are now
regarded by some experts as unsound public policy.
See also the work of Aldington et al on cannabis use, under ‘Lung Cancer’.
Skin Cancer
A team from the Department of Dermatology at Waikato Hospital have
investigated the relatively high rates of melanoma skin cancers found in
people
Cancer
161
from the Tauranga area93. Data were obtained from retrospective review of
histology reports from the public and private health systems in greater Tauranga
(Tauranga and Western Bay of Plenty Districts). Primary cutaneous melanomas
(including both invasive and in situ melanomas) reported during 2003 were
included. Age-standardized melanoma rates were calculated for the entire
population as well as for the non-Maori population of the region, identified from
the 2001 New Zealand Census. The age-standardized incidence of invasive
melanoma in the non-Maori population of the greater Tauranga region was
79/100,000. The age-standardized rate for the entire population was 70/100,000.
The rate of in situ disease was 78/100,000 for non-Maori and 72/100,000 for the
entire population. The authors conclude that the Tauranga region of New Zealand
has an exceptionally high incidence of invasive and in situ melanomas. This is
likely related to environmental, geographical and societal factors, including
relatively high levels of UV exacerbated in recent times by ozone depletion,
relatively cool summer temperatures which encourage outdoor exposure, and
relatively fair skin colouring.
Wright et al. looked at the ultraviolet radiation (UVR) exposures of 345 primary
schoolchildren at 23 schools around New Zealand, using electronic UVR monitors
for 1-week periods over 12 weeks in 2004 and 200594. Children completed activity
diaries during the period UVR measurements were made and provided
information on their indoor and outdoor status and clothing and sun protection
worn. Mean total UVR exposure was approximately 5% of the ambient UVR on a
horizontal surface, on average. Mean time spent outdoors was 2.3 h per day.
Differences in children's UVR exposure could be explained, in part, by activity where outdoor passive pursuits were associated with higher UVR exposure rates
than outdoor active and outdoor travel pursuits. Compared with older children,
the activities of younger children, although labelled the same, resulted in different
UVR exposures, either as a result of reporting differences or a real difference in
UVR exposure patterns. UVR exposure rates were generally higher on weekdays
compared with the weekend, confirming the important role of school sun
protection and skin cancer prevention programmes.
High UVR exposure
activities included physical education, athletics and lunch break.
Reynolds et al. have developed ‘heat maps’ that can be used as a new tool to
predict risk of melanoma spreading to the lymph nodes95. They report that
lymphoscintigraphy accurately maps lymphatic drainage from sites of cutaneous
melanoma to the draining sentinel lymph nodes. The Sydney Melanoma Unit has
accumulated lymphoscintigraphy data from over 5000 patients with cutaneous
melanoma over more than 15 years, collectively revealing patterns of skin
lymphatic drainage.
The investigators mapped these data onto a threedimensional computer model to provide improved visualisation and analysis of
lymphatic drainage from sites of cutaneous melanoma. They created threedimensional, colour-coded heat maps that showed the drainage patterns from
melanoma sites below the neck to individual lymph-node fields and to many
lymph-node fields. These maps highlight the inter-patient variability in skin
lymphatic drainage, and show the skin regions in which highly variable drainage
can occur. To enable interactive and dynamic analysis of these data, they also
developed software to predict lymphatic drainage patterns from melanoma skin
sites to sentinel lymph-node fields. The heat maps confirmed that the commonly
used Sappey's lines are not effective in predicting lymphatic drainage. The heat
162 Cancer
maps and the interactive software could be a new resource for clinicians to use in
preoperative discussions with patients with melanoma and other skin cancers that
can metastasise to the lymph nodes, and could be used in the identification of
sentinel lymph-node fields during follow-up of such patients.
Additional Publications
Henness S, Vereecken P. Management of Merkel tumours: an evidence-based
review. Curr Opin Oncol 2008;20(3):280-6. Contact: Wolters Kluwer Health | Adis,
Auckland, New Zealand.
Hill SE, Mortimer NJ, Hitchcock B, Salmon PJ. Parotid fistula complicating
surgical excision of a basal cell carcinoma: successful treatment with botulinum
toxin type A. Dermatol Surg 2007;33(11):1365-7. Contact: Department of Dermatology,
Waikato Hospital, Hamilton, New Zealand.
Reynolds HM, Dunbar PR, Uren RF, Thompson JF, Smith NP. Mapping
melanoma lymphoscintigraphy data onto a 3D anatomically based model. Ann
Biomed Eng 2007;35(8):1444-57. Contact: The Bioengineering Institute, University of
Auckland, Private Bag 92019, Auckland, New Zealand. [email protected].
Stoitzner P, Green LK, Jung JY, et al. Inefficient presentation of tumour-derived
antigen by tumour-infiltrating dendritic cells. Cancer Immunol Immunother 2008.
Contact: Malaghan Institute of Medical Research, Wellington, New Zealand,
[email protected].
Stoitzner P, Green LK, Jung JY, et al. Tumour immunotherapy by epicutaneous
immunization requires langerhans cells. J Immunol 2008;180(3):1991-8. Contact:
Malaghan Institute of Medical Research, Wellington, New Zealand. [email protected].
Wagstaff AJ, Perry CM. Topical imiquimod: a review of its use in the management
of anogenital warts, actinic keratoses, basal cell carcinoma and other skin lesions.
Drugs 2007;67(15):2187-210. Contact: Wolters Kluwer Health | Adis, Auckland, New
Zealand. [email protected].
Urinary Tract Cancers
Prevention
AgResearch (Hamilton) has reported the findings of a study designed to establish
whether dietary administration of broccoli sprouts extract to rats inhibits the
formation of bladder cancer induced by nitrosamine96. The incidence,
multiplicity, size, and progression of bladder cancer were all inhibited by the
extract, while the extract itself caused no histologic changes in the bladder.
Isothiocyanates are a well-known class of cancer chemopreventive agents, and
broccoli sprouts are a rich source of several isothiocyanates. The team found that
the concentrations of isothiocyanate equivalents in the urine of treated rats were 2
to 3 orders of magnitude higher than those in plasma, indicating that the bladder
epithelium, the major site of bladder cancer development, is most exposed to oral
doses of isothiocyanate. Indeed, tissue levels of isothiocyanate equivalents in the
bladder were significantly higher than in the liver. They conclude that broccoli
sprout extract is a highly promising substance for bladder cancer prevention and
Cancer
163
the isothiocyanates in the extract are selectively delivered to the bladder
epithelium through urinary excretion.
Additional Publications
See also the study by Dryson et al. under Occupational Health.
Dryson E, t Mannetje A, Walls C, et al. Case-control study of high risk occupations
for bladder cancer in New Zealand. Int J Cancer 2008;122(6):1340-6. Contact: Centre
for Public Health Research, Massey University, Wellington, New Zealand.
Pathology
A series of studies looking at prognostic and diagnostic factors in renal cell
carcinoma have been published by Delahunt and colleagues of the Department of
Pathology and Molecular Medicine, Wellington School of Medicine and Health
Sciences. The first concerns the classification of sarcomatoid renal cell carcinoma
(SRC) versus clear cell renal carcinoma97. Sarcomatoid renal cell carcinoma is
recognized as an extreme form of dedifferentiation in renal cell carcinoma and is
associated with a poor prognosis. The team investigated collagen expression
using immunohistochemistry in these 2 tumour types. They found a number of
differences in collagen expression between the tumour types, including the fact
that that only SRC showed cytoplasmic expression of collagen types I and II. The
study provides validating evidence that these 2 morphotypes should not be
considered together for classification purposes.
The second article is a review of prognostic factors for renal tumours, according to
histological subtype98. A wide variety of parameters have been investigated for
their prognostic significance in mixed series of renal cell carcinoma (RCC). The
classification of RCC into separate types with differing morphology, genotype and
probable clinical outcome has led to a re-evaluation of many prognostic
parameters with studies confined to a single RCC morphotype. Tumour stage
remains the most important predictor of RCC outcome and recent investigations
have focused upon tumour diameter and the prognostic significance of stromal,
vascular and lymphatic invasion within the renal sinus. In large tumour series,
morphotype has been correlated with patient survival, with clear cell RCC being
associated with a less favourable outcome than chromophobe RCC and to a lesser
extent papillary RCC, for organ confined tumours. The prognostic significance of
nuclear grading remains controversial. Fuhrman grading has been shown to have
prognostic utility for clear cell RCC in some series. The evidence for utility of
other markers is also discussed. The third study was undertaken to assess the
prognostic effectiveness of Fuhrman nuclear grading and the individual
components of this grading system, in a series of chromophobe RCCs99. The
authors conclude that neither Fuhrman grading, nor any of the components of the
Fuhrman grading system, is useful as prognostic indicators for this tumour type.
Additional Publications
Holyoake A, O'Sullivan P, Pollock R, et al. Development of a multiplex RNA urine
test for the detection and stratification of transitional cell carcinoma of the
bladder. Clin Cancer Res 2008;14(3):742-9. Contact: Pacific Edge Biotechnology Ltd.,
Centre for Innovation, University of Otago, Dunedin, New Zealand.
164 Cancer
Wilms’ Tumour
Nephrogenic rests are clusters of developmentally immature cells and dysplastic
(abnormal) cellular arrangements. In a review of the molecular pathology and
epidemiology of nephrogenic rests and Wilms’ tumours, Fukuzawa et al. provide
an explanation for the interethnic variations in the incidence100. Perilobar (PLNR)
and intralobar nephrogenic rests (ILNR) are distinct precursor lesions of Wilms’
tumours that have different structural, clinical, genetic, and epidemiologic
features. Wilms’ tumours in East-Asian children have unique epidemiologic
features in that the incidence is about half that of white children, an early age at
diagnosis, a male predominance, and an association with ILNR. Loss of IGF2
imprinting is associated with PLNR more commonly seen in Wilms’ tumours
from white children than tumours from children of Asian descent. Therefore, this
epigenetic difference and the higher frequency of PLNR provide an explanation
for the interethnic variations in the incidence of Wilms’ tumour. The
histopathologic, clinical, and genetic differences between ILNR and PLNR are
described in this review, followed by a description of an epigenetic mechanism
that underlies PLNR formation and the unique epidemiologic feature of Wilms’
tumours.
Additional Publications (Wilms’ tumour)
Fukuzawa R, Anaka M, Heathcott R, et al. Wilms tumour histology is determined
by distinct types of precursor lesions and not epigenetic changes. J Pathol 2008.
Contact: Cancer Genetics Laboratory, Department of Biochemistry, University of Otago,
PO Box 56, Dunedin, New Zealand.
Fukuzawa R, Heathcott RW, More HE, Reeve AE. Sequential WT1 and CTNNB1
mutations and alterations of beta-catenin localisation in intralobar nephrogenic
rests and associated Wilms’ tumours: two case studies. J Clin Pathol
2007;60(9):1013-6. Contact: Cancer Genetics Laboratory, Department of Biochemistry,
University of Otago, Dunedin, New Zealand. [email protected].
Additional Publications
Frampton JE, Keating GM. Bevacizumab: in first-line treatment of advanced
and/or metastatic renal cell carcinoma. BioDrugs 2008;22(2):113-20. Contact:
Wolters Kluwer Health | Adis, Auckland, New Zealand. [email protected].
McKeage K, Wagstaff AJ. Sorafenib: in advanced renal cancer. Drugs
2007;67(3):475-83; discussion 484-5. Contact: Wolters Kluwer Health, Adis, Auckland,
New Zealand. [email protected].
Simpson D, Curran MP. Temsirolimus : in advanced renal cell carcinoma. Drugs
2008;68(5):631-8. Contact: Wolters Kluwer Health | Adis, Auckland, New Zealand, an
editorial office of Wolters Kluwer Health, Conshohocken, Pennsylvania, USA.
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Contact: Department of Cardiothoracic Surgery, Christchurch Public Hospital,
Christchurch.
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21. Bhana N. Granulocyte colony-stimulating factors in the management of
chemotherapy-induced neutropenia: evidence based review. Curr Opin Oncol
2007;19(4):328-35. Contact: Wolters Kluwer Health Adis, Auckland, New Zealand.
22. Murdoch D, Sager J. Will targeted therapy hold its promise? An evidencebased review. Curr Opin Oncol 2008;20(1):104-11. Contact: Wolters Kluwer Health
Adis, Auckland, New Zealand.
23. Williams AO, Isaacs RJ, Stowell KM. Down-regulation of human
topoisomerase IIalpha expression correlates with relative amounts of
specificity factors Sp1 and Sp3 bound at proximal and distal promoter regions.
BMC Mol Biol 2007;8:36. Contact: Institute of Molecular Biosciences, Massey
University, Palmerston North, New Zealand. [email protected]
<[email protected]>.
24. Parry S, Richardson A, Green T, et al. Prospects for population colorectal
cancer screening in New Zealand. N Z Med J 2007;120(1258):U2633. Contact:
Middlemore Hospital, Otahuhu, Auckland. [email protected].
25. Kerr J, Day P, Broadstock M, Weir R, Bidwell S. Systematic review of the
effectiveness of population screening for colorectal cancer. N Z Med J
2007;120(1258):U2629. Contact: New Zealand Health Technology Assessment,
Department of Public Health and General Practice, University of Otago,
Christchurch.
26. Yeoman A, Parry S. A survey of colonoscopy capacity in New Zealand's public
hospitals. N Z Med J 2007;120(1258):U2632. Contact: Department of
Gastroenterology, Morriston Hospital, Morriston, Swansea, Wales, United Kingdom.
27. Bhargava A, Aldameh A, Stewart J, Hill AG. Prioritization of patients with
rectal bleeding for urgent outpatient colonoscopy--a pilot study. N Z Med J
2007;120(1258):U2637. Contact: Department of Surgery, University of Auckland,
Middlemore Hospital, Otahuhu, Auckland.
28. Lin HM, Chatterjee A, Lin YH, et al. Genome wide expression profiling
identifies genes associated with colorectal liver metastasis. Oncol Rep
2007;17(6):1541-9. Contact: Cancer Genetics Laboratory, Department of
Biochemistry, Otago School of Medical Sciences, University of Otago, Dunedin, New
Zealand.
29. Abbas SM, Merrie AE. Resection of peritoneal metastases causing malignant
small bowel obstruction. World J Surg Oncol 2007;5:122. Contact: Colorectal Unit,
Auckland City Hospital, Private Bag 92024, Auckland, New Zealand.
[email protected].
30. Hayes JL, Hansen P. Is laparoscopic colectomy for cancer cost-effective relative
to open colectomy? ANZ J Surg 2007;77(9):782-6. Contact: Department of
Surgery, Dunedin Hospital and Dunedin School of Medicine, Dunedin, New Zealand.
[email protected].
168 Cancer
31. Wakeman CJ, Dobbs BR, Frizelle FA, et al. The impact of splenectomy on
outcome after resection for colorectal cancer: a multicenter, nested, paired
cohort study. Dis Colon Rectum 2008;51(2):213-7. Contact: Department of Surgery,
Christchurch Hospital, Christchurch, New Zealand.
32. Gendall KA, Kennedy RR, Watson AJ, Frizelle FA. The effect of epidural
analgesia on postoperative outcome after colorectal surgery. Colorectal Dis
2007;9(7):584-98; discussion 598-600. Contact: Department of Surgery,
Christchurch Hospital, Christchurch, New Zealand.
33. O'Grady G, Secker A. Colorectal cancer management in the provincial New
Zealand setting of Nelson. ANZ J Surg 2007;77(11):1004-8. Contact: Department
of General Surgery, Nelson Hospital, Nelson, New Zealand. [email protected].
34. Samson PB, Ngaei G. Colorectal resection in peripheral New Zealand:
workload, outcomes and its future. ANZ J Surg 2007;77(11):999-1003. Contact:
Department of General Surgery, Southland Hospital, Invercargill, New Zealand.
[email protected].
35. Thotathil ZS, Long JE, Kennedy I, Jameson MB, Adams J, Kuper M.
Chemotherapy prescription patterns in colon cancer: a patterns-of-care survey
in New Zealand. N Z Med J 2007;120(1258):U2636. Contact: Department of
Oncology, Waikato Hospital, Hamilton. [email protected].
36. Abbas SM, Hill AG. Prostatic sarcoma after treatment of rectal cancer. World J
Surg Oncol 2007;5:82. Contact: Department of Surgery, Middlemore Hospital,
University of Auckland, New Zealand. [email protected].
37. Jeffery M, Hickey BE, Hider PN. Follow-up strategies for patients treated for
non-metastatic colorectal cancer. Cochrane Database Syst Rev 2007(1):CD002200.
Contact: Christchurch Hospital, Oncology Service, Private Bag 4710, Christchurch,
New Zealand. [email protected].
38. Port RV, Arnold J, Kerr D, Gravish N, Winship I. Cultural enhancement of a
clinical service to meet the needs of indigenous people; genetic service
development in response to issues for New Zealand Maori. Clin Genet
2008;73(2):132-8. Contact: Northern Regional Genetic Service, Auckland District
Health Board, Auckland, New Zealand.
39. Ferguson LR, Philpott M. Cancer prevention by dietary bioactive components
that target the immune response. Curr Cancer Drug Targets 2007;7(5):459-64.
Contact: Discipline of Nutrition, Faculty of Medical and Health Sciences, The
University of Auckland, Auckland, New Zealand. [email protected].
40. Blakely T, Tobias M, Atkinson J. Inequalities in mortality during and after
restructuring of the New Zealand economy: repeated cohort studies. Bmj
2008;336(7640):371-5. Contact: Health Inequalities Research Programme, University
of Otago, Wellington, PO Box 7343, Wellington, New [email protected].
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41. Dachs GU, Currie MJ, McKenzie F, et al. Cancer disparities in indigenous
Polynesian populations: Maori, Native Hawaiians, and Pacific people. Lancet
Oncol 2008;9(5):473-84. Contact: Angiogenesis Research Group, Department of
Pathology, University of Otago, Christchurch, New Zealand.
42. Herst PM, Petersen T, Jerram P, Baty J, Berridge MV. The antiproliferative
effects of phenoxodiol are associated with inhibition of plasma membrane
electron transport in tumour cell lines and primary immune cells. Biochem
Pharmacol 2007;74(11):1587-95. Contact: Malaghan Institute of Medical
Research, P.O. Box 7060, Wellington 6005, New Zealand.
43. Kanwar JR, Palmano KP, Sun X, et al. 'Iron-saturated' lactoferrin is a potent
natural adjuvant for augmenting cancer chemotherapy. Immunol Cell Biol
2008;86(3):277-88. Contact: LactoPharma Consortium, University of Auckland,
Auckland, New Zealand.
44. McKeage MJ. The potential of DMXAA (ASA404) in combination with
docetaxel in advanced prostate cancer. Expert Opin Investig Drugs
2008;17(1):23-9. Contact: The University of Auckland, School of Medical Sciences,
Department of Pharmacology and Clinical Pharmacology, Private Bag 92019,
Auckland, New Zealand. [email protected].
45. Somers-Edgar TJ, Scandlyn MJ, Stuart EC, Le Nedelec MJ, Valentine SP,
Rosengren RJ. The combination of epigallocatechin gallate and curcumin
suppresses ER alpha-breast cancer cell growth in vitro and in vivo. Int J Cancer
2008;122(9):1966-71. Contact: Department of Pharmacology and Toxicology,
University of Otago, Dunedin, New Zealand.
46. Thotathil Z, Jameson MB. Early experience with novel immunomodulators for
cancer treatment. Expert Opin Investig Drugs 2007;16(9):1391-403. Contact:
Waikato Hospital, Department of Oncology, Hamilton, New Zealand.
47. Tyndall JD, Kelso MJ, Clingan P, Ranson M. Peptides and small molecules
targeting the plasminogen activation system: towards prophylactic antimetastasis drugs for breast cancer. Recent Patents Anticancer Drug Discov
2008;3(1):1-13. Contact: National School of Pharmacy, University of Otago,
Dunedin, New Zealand. [email protected].
48. Humar B, Guilford P. Hereditary diffuse gastric cancer and lost cell polarity: a
short path to cancer. Future Oncol 2008;4(2):229-39. Contact: University of Otago,
Cancer Genetics Laboratory, Department of Biochemistry, Dunedin, New Zealand.
[email protected].
49. Switzer-Taylor V, Schlup M, Lubcke R, Livingstone V, Schultz M. Barrett's
esophagus: A retrospective analysis of 13 years surveillance. J Gastroenterol
Hepatol 2008. Contact: Department of Medical and Surgical Sciences, Medicine
Section, University of Otago Medical School, Dunedin, New Zealand.
170 Cancer
50. Hoy SM, Lyseng-Williamson KA. Intravenous busulfan: in the conditioning
treatment of pediatric patients prior to hematopoietic stem cell
transplantation. Paediatr Drugs 2007;9(4):271-8. Contact: Wolters Kluwer Health |
Adis, Auckland, New Zealand. [email protected].
51. Scott WG, Scott HM. Economic evaluation of third-line treatment with
alemtuzumab for chronic lymphocytic leukaemia. Clin Drug Investig
2007;27(11):755-64. Contact: ScottEconomics, Wellington, New Zealand.
[email protected].
52. Dockerty JD, Herbison P, Skegg DC, Elwood M. Vitamin and mineral
supplements in pregnancy and the risk of childhood acute lymphoblastic
leukaemia: a case-control study. BMC Public Health 2007;7(147):136. Contact:
Department of Preventive and Social Medicine, University of Otago, Dunedin, New
Zealand. [email protected].
53. Agir H, Brasch HD, Tan ST. Extra-skeletal Ewing's sarcoma of the
submandibular gland. J Plast Reconstr Aesthet Surg 2007;60(12):1345-8. Contact:
Head and Neck and Skull Base Surgery/Oncology Programme, Wellington Regional
Plastic, Maxillofacial and Burns Unit, Hutt Hospital, Private Bag 31907, High
Street, Lower Hutt, New Zealand.
54. Aldington S, Harwood M, Cox B, et al. Cannabis use and cancer of the head
and neck: case-control study. Otolaryngol Head Neck Surg 2008;138(3):374-80.
Contact: Medical Research Institute of New Zealand, Wellington, New Zealand.
55. Lallu S, Naran S, Bethwaite P. Fine needle aspiration cytology of unsuspected
metastatic hurthle cell carcinoma of the thyroid and its pitfalls: a report of two
cases. Diagn Cytopathol 2007;35(7):439-43. Contact: Department of Cytology,
Anatomic Pathology, Capital and Coast Wellington Hospital, Wellington, New
Zealand.
56. Bartlett AS, McCall JL, Koea JB, et al. Liver resection for hepatocellular
carcinoma in a hepatitis B endemic area. World J Surg 2007;31(9):1775-81.
Contact: Department of Hepatobiliary and Transplant Surgery, New Zealand Liver
Transplant Unit, Level 15, Support Building, Auckland City Hospital, Park Road,
Grafton, Auckland, New Zealand.
57. Simpson D, Keating GM. Sorafenib: in hepatocellular carcinoma. Drugs
2008;68(2):251-8. Contact: Wolters Kluwer Health | Adis, Auckland, New Zealand.
58. Stevens W, Stevens G, Kolbe J, Cox B. Lung cancer in New Zealand: patterns
of secondary care and implications for survival. J Thorac Oncol 2007;2(6):48193. Contact: Discipline of Oncology, University of Auckland, Auckland, New
Zealand. [email protected].
59. Stevens W, Stevens G, Kolbe J, Cox B. Management of stages I and II nonsmall-cell lung cancer in a New Zealand study: divergence from international
practice and recommendations. Intern Med J 2008. Contact: Department of
Oncology, Auckland Hospital, Auckland, New Zealand.
Cancer
171
60. Stevens W, Stevens G, Kolbe J, Cox B. Ethnic differences in the management of
lung cancer in New Zealand. J Thorac Oncol 2008;3(3):237-44. Contact: Discipline
of
Oncology, University
of
Auckland, Auckland, New Zealand.
[email protected].
61. Aldington S, Harwood M, Cox B, et al. Cannabis use and risk of lung cancer: a
case-control study. Eur Respir J 2008;31(2):280-6. Contact: Medical Research
Institute of New Zealand, Wellington, New Zealand.
62. Young RP, Hopkins R, Eaton TE. Forced expiratory volume in one second: not
just a lung function test but a marker of premature death from all causes. Eur
Respir J 2007;30(4):616-22. Contact: Department of Medicine, Auckland Hospital,
Private Bag 92019, Auckland, New Zealand. [email protected].
63. Anderson VR, Perry CM. Fludarabine: a review of its use in non-Hodgkin's
lymphoma. Drugs 2007;67(11):1633-55. Contact: Wolters Kluwer Health, Adis,
Auckland, New Zealand.
64. Macann A, Bredenfeld H, Muller RP, Diehl V, Engert A, Eich HT.
Radiotherapy does not influence the severe pulmonary toxicity observed with
the administration of gemcitabine and bleomycin in patients with advancedstage Hodgkin's lymphoma treated with the BAGCOPP regimen: a report by
the German Hodgkin's Lymphoma Study Group. Int J Radiat Oncol Biol Phys
2008;70(1):161-5. Contact: Department of Radiation Oncology, Auckland Regional
Cancer and Blood Service, Auckland, New Zealand.
65. Dryson E, t Mannetje A, Walls C, et al. Case-control study of high risk
occupations for bladder cancer in New Zealand. Int J Cancer 2008;122(6):13406. Contact: Centre for Public Health Research, Massey University, Wellington, New
Zealand.
66. Firth H, Gray A, Carpenter LM, Cox B. Cancer mortality by occupation among
New Zealand women: 1988-1997. N Z Med J 2007;120(1266):U2833. Contact:
Department of Preventive and Social Medicine, Dunedin School of Medicine, Otago
Medical School, Dunedin. [email protected].
67. t Mannetje A, Dryson E, Walls C, et al. High risk occupations for nonHodgkin's lymphoma in New Zealand: case-control study. Occup Environ Med
2008;65(5):354-63. Contact: Centre for Public Health Research, Massey University
Wellington Campus, Private Box 756, Wellington, New Zealand.
[email protected].
68. Capelle L, Krawitz H. Esthesioneuroblastoma: a case report of diffuse
subdural recurrence and review of recently published studies. J Med Imaging
Radiat Oncol 2008;52(1):85-90. Contact: Department of Radiation Oncology,
Auckland City Hospital, Auckland, New Zealand. [email protected].
69. Arsic D, Beasley SW, Sullivan MJ. Switched-on Sonic hedgehog: a gene whose
activity extends beyond fetal development--to oncogenesis. J Paediatr Child
Health 2007;43(6):421-3. Contact: Children's Cancer and Developmental Genetics
172 Cancer
Research Group, Department of Paediatrics, Christchurch School of Medicine and
Health Sciences, Christchurch, New Zealand.
70. Cox AG, Hampton MB. Bcl-2 over-expression promotes genomic instability by
inhibiting apoptosis of cells exposed to hydrogen peroxide. Carcinogenesis
2007;28(10):2166-71. Contact: Free Radical Research Group, Department of
Pathology, Christchurch School of Medicine & Health Sciences, University of Otago,
PO Box 4345, Christchurch, New Zealand.
71. Pandey V, Perry JK, Mohankumar KM, et al. Autocrine Human Growth
Hormone Stimulates Oncogenicity of Endometrial Carcinoma Cells.
Endocrinology 2008. Contact: Liggins Institute and National Research Centre for
Growth and Development, and Department of Molecular Medicine and Pathology,
Faculty of Medical and Health Sciences, University of Auckland, Private Bag 92019,
Auckland 1142, New Zealand; Hefei National Laboratory for Physical Sciences at
Microscale and School of Life Sciences, University of Science and Technology of
China, Hefei, Anhui 230027, P.R. China; Department of Pathology, Anhui Medical
University, Hefei, Anhui 230032, P.R. China.
72. Perry JK, Kannan N, Grandison PM, Mitchell MD, Lobie PE. Are trefoil factors
oncogenic? Trends Endocrinol Metab 2008;19(2):74-81. Contact: Liggins Institute,
Faculty of Medical and Health Sciences, University of Auckland, Auckland, New
Zealand.
73. Flint MN, Griffin AM, Bell RS, Wunder JS, Ferguson PC. Two-stage revision of
infected uncemented lower extremity tumor endoprostheses. J Arthroplasty
2007;22(6):859-65. Contact: Orthopaedic Oncology Unit, Middlemore Hospital,
Auckland, New Zealand.
74. McKechnie R, MacLeod R, Keeling S. Facing uncertainty: the lived experience
of palliative care. Palliat Support Care 2007;5(4):367-76. Contact: Department of
General Practice, Dunedin School of Medicine, University of Otago, Dunedin, New
Zealand. [email protected].
75. Walker J, Lane P. Challenges and choices: an audit of the management of
nausea, vomiting and bowel obstruction in metastatic ovarian cancer. Contemp
Nurse 2007;27(1):39-46. Contact: Hospice and Palliative Care Service, Nurse Maude
Association, Christchurch, New Zealand.
76. William L, Macleod R. Management of breakthrough pain in patients with
cancer. Drugs 2008;68(7):913-24. Contact: North Shore Hospice, Takapuna,
Auckland, New Zealand.
77. Crawford NW, Heath JA, Buttery JP. Immunisation practices of paediatric
oncologists: an Australasian survey. J Paediatr Child Health 2007;43(9):593-6.
Contact: NHMRC Centre for Clinical Research Excellence in Child and Adolescent
Immunisation; Murdoch Children's Research Institute, Royal Children's Hospital,
Melbourne, Victoria, Australia. [email protected].
Cancer
173
78. Windsor JA. An update on familial pancreatic cancer and the management of
asymptomatic relatives. HPB (Oxford) 2007;9(1):4-7. Contact: Faculty of Medical
and Health Sciences, University of Auckland Auckland New Zealand.
79. McAvoy BR, Fletcher JM, Elwood M. Cancer education and training in
primary health care--a national audit of training providers. Aust Fam Physician
2007;36(11):973-6. Contact: Community and Home Detox Service, Auckland
Community Alcohol and Drug Service, Auckland, New Zealand.
[email protected].
80. Jones RW, Coughlan EP, Reid JS, Sykes P, Watson PD, Cook C. Human
papilloma virus vaccines and their role in cancer prevention. N Z Med J
2007;120(1266):U2829. Contact: Gynaecological Oncology Service, National
Women's Hospital, Private Bag 92 189, Auckland. [email protected].
81. Lovell S, Kearns RA, Friesen W. Sociocultural barriers to cervical screening in
South Auckland, New Zealand. Soc Sci Med 2007;65(1):138-50. Contact:
Department of Geography, Queens University, Kingston, Ont., Canada.
[email protected].
82. Buetow S, Janes R, Steed R, Ihimaera L, Elley CR. Why don't some women
return for cervical smears? A hermeneutic phenomenological investigation.
Health Care Women Int 2007;28(9):843-52. Contact: Department of General Practice
and Primary Health Care, University of Auckland, Auckland, New Zealand.
[email protected].
83. McCredie MR, Sharples KJ, Paul C, et al. Natural history of cervical neoplasia
and risk of invasive cancer in women with cervical intraepithelial neoplasia 3:
a retrospective cohort study. Lancet Oncol 2008;9(5):425-34. Contact: Department
of Preventive and Social Medicine, University of Otago, Dunedin, New Zealand.
[email protected].
84. Sadler L, Saftlas A. Cervical surgery and preterm birth. J Perinat Med
2007;35(1):5-9. Contact: National Women's Health, Auckland District Health Board,
Department of Epidemiology and Biostatistics, School of Population Health, Faculty of
Medicine and Health Sciences, University of Auckland, Auckland, New Zealand.
[email protected].
85. Deeks E. Local therapy in endometrial cancer: evidence based review. Curr
Opin Oncol 2007;19(5):512-5. Contact: Wolters Kluwer Health, Adis, Auckland, New
Zealand.
86. Nicholson HD, Whittington K. Oxytocin and the human prostate in health and
disease. Int Rev Cytol 2007;263:253-86. Contact: Department of Anatomy and
Structural Biology, University of Otago, New Zealand.
87. Lamb DS, Slaney D, Smart R, et al. Prostate cancer: the new evidence base for
diagnosis and treatment. Pathology 2007;39(6):537-44. Contact: Department of
Pathology and Molecular Medicine, Wellington School of Medicine and Health
Sciences, and Department of Radiation Oncology, Wellington Hospital, New Zealand.
174 Cancer
88. Mitchell DM, Wynne CJ, Cowan I. Multiple cranial nerve palsies as the
presenting features of prostate carcinoma. J Med Imaging Radiat Oncol
2008;52(2):194-6. Contact: Department of Radiation Oncology, Christchurch
Hospital, Christchurch, New Zealand. [email protected].
89. Sneyd MJ. Ethnic differences in prostate cancer survival in New Zealand: a
national study. Cancer Causes Control 2008. Contact: Hugh Adam Cancer
Epidemiology Unit, Department of Preventive and Social Medicine, Dunedin School of
Medicine, University of Otago, PO Box 913, Dunedin, New Zealand,
[email protected].
90. Travier N, Jeffreys M, Brewer N, et al. Association between glycosylated
hemoglobin and cancer risk: a New Zealand linkage study. Ann Oncol
2007;18(8):1414-9. Contact: Centre for Public Health Research, Massey University,
Wellington, New Zealand. [email protected].
91. Trevena J, Reeder A. Perceptions of New Zealand adults about reducing their
risk of getting cancer. N Z Med J 2007;120(1258):U2630. Contact: Department of
Psychological Medicine, Dunedin School of Medicine, University of Otago, Dunedin.
[email protected].
92. Laugesen M. Snuffing out cigarette sales and the smoking deaths epidemic. N
Z Med J 2007;120(1256):U2587. Contact: SmokeLess New Zealand Trust, Lyttelton,
Christchurch. [email protected].
93. Salmon PJ, Chan WC, Griffin J, McKenzie R, Rademaker M. Extremely high
levels of melanoma in Tauranga, New Zealand: possible causes and
comparisons with Australia and the northern hemisphere. Australas J Dermatol
2007;48(4):208-16. Contact: Department of Dermatology, Waikato Hospital,
Tuaranga, New Zealand. [email protected].
94. Wright CY, Reeder AI, Bodeker GE, Gray A, Cox B. Solar UVR exposure,
concurrent activities and sun-protective practices among primary
schoolchildren. Photochem Photobiol 2007;83(3):749-58. Contact: Social &
Behavioural Research in Cancer Group, Department of Preventive and Social
Medicine, University of Otago, Dunedin, New Zealand.
95. Reynolds HM, Dunbar PR, Uren RF, Blackett SA, Thompson JF, Smith NP.
Three-dimensional visualisation of lymphatic drainage patterns in patients
with cutaneous melanoma. Lancet Oncol 2007;8(9):806-12. Contact:
Bioengineering Institute, University of Auckland, Auckland, New Zealand.
[email protected].
96. Munday R, Mhawech-Fauceglia P, Munday CM, et al. Inhibition of urinary
bladder carcinogenesis by broccoli sprouts. Cancer Res 2008;68(5):1593-600.
Contact: AgResearch Limited, Ruakura Agricultural Research Center, Hamilton, New
Zealand.
97. Delahunt B, Bethwaite PB, McCredie MR, Nacey JN. The evolution of collagen
expression in sarcomatoid renal cell carcinoma. Hum Pathol 2007;38(9):1372-7.
Contact: Department of Pathology and Molecular Medicine, Wellington School of
Medicine and Health Sciences, PO Box 7343, Wellington South, New Zealand.
[email protected].
98. Delahunt B, Bethwaite PB, Nacey JN. Outcome prediction for renal cell
carcinoma: evaluation of prognostic factors for tumours divided according to
histological subtype. Pathology 2007;39(5):459-65. Contact: Department of
Pathology and Molecular Medicine, Wellington School of Medicine and Health
Sciences, Wellington South, New Zealand. [email protected].
99. Delahunt B, Sika-Paotonu D, Bethwaite PB, et al. Fuhrman grading is not
appropriate for chromophobe renal cell carcinoma. Am J Surg Pathol
2007;31(6):957-60. Contact: Department of Pathology and Molecular Medicine,
Wellington School of Medicine and Health Sciences, New Zealand. [email protected].
100. Fukuzawa R, Reeve AE. Molecular pathology and epidemiology of
nephrogenic rests and Wilms tumors. J Pediatr Hematol Oncol 2007;29(9):589-94.
Contact: Cancer Genetics Laboratory, Department of Biochemistry, University of
Otago, PO Box 56, Dunedin, New Zealand.