Download Five-yeAr experience oF McGill University`s Adolescent And yoUnG

research
Five-year experience of
McGill University’s
Adolescent and Young
Adult Oncology Program
The challenge of serving a unique population
Michael Palumbo, MD, PhD, Petr Kavan, MD, PhD, David Roberge, MD,
Thierry Muanza, MD, Sabrina R. Perri, PhD, and Gerald Batist, MD
Contributing authors
Abstract
Progress in pediatric oncology has been among the most dramatic stories
in modern medicine. In contrast, survival rates for adolescents and young
adults (AYA) with cancer plateaued in the late 1970s. Reasons for this
are not fully understood and may include differences in the biology of the
cancers, poor understanding of host and tumour physiology, poor enrollment into adult and pediatric clinical trials, and lack of AYA-specific clinical trials. Further, AYA patients suffer from frequent loss to followup,
delayed diagnosis and poor treatment compliance. To address these
issues, in 2003 McGill University created an AYA oncology program
with a corresponding patient registry. After five years in existence the
program has achieved increased enrollment into clinical trials (including
AYA-specific trials), along with reduced loss to followup. The program
has also facilitated tumour banking and the implementation of psychosocial and rehabilitation services crucial to this population. We describe
ongoing challenges that will likely affect attempts to establish similar programs elsewhere, and propose possible solutions to these challenges:
lack of awareness of the unique therapeutic, psychosocial and rehabilitation needs of this population, the paucity of available clinical trials and
the reluctance of some clinicians to refer patients to the program. As we
learned with pediatric oncology, improved outcomes in the AYA population will require centralization of AYA oncology programs, along with
interprovincial and international cooperation.
Petr Kavan MD, PhD is Director of the McGill Adolescent and Young Adult Oncology Program
and Associate Professor of Medicine at McGill University. Michael Palumbo, MD, PhD is a
Resident in Internal Medicine at McGill University and Director of Statistics for the adolescent
and Young Adult Oncology Program. David Roberge, MD and Thierry Muanza, MD are
both Assistant Directors of the AYA Program and Assistant Professors of Medicine at McGill.
Sabrina R. Perri, PhD is a Regional Medical Liaison in Oncology (Scientific Affairs) at
AMGEN Canada Inc., Medical Affairs, Amgen, Canada. Gerald Batist, MD is a Professor
and The Director of Oncology at McGill University.
Address for correspondence: Dr. Petr Kavan, MD, PhD, E-715, Segal Cancer Center, Jewish
General Hospital, 3755 Côte-Ste-Catherine, Montreal, QC, H3T 1E2; Tel: 514 340 8222
ext.4210; Fax: 514 340 8302; Email: [email protected]
Mark Karanofsky, MD
Richard Dalfen, MD
Martin Chasen, MD
Evgenia Garoufalis, MD
Marie-Christine Guiot, MD
Rolando Del Maestro, MD, PhD
Richard Leblanc, MD
Christine Leblanc, RN
Eleanor Scharf, RN, MSc
Randi Fogelbaum, MSW, PSW
Mary Ann Dalzell, MSc Pht.
The contributing authors are
from the Adolescent and
Young Adult Oncology Program,
Department of Oncology,
McGill University, Montreal,
Quebec, Canada.
Rationale
The problem
Initiatives set forth nearly half a century ago to improve outcomes in children diagnosed with a malignancy
have dramatically improved survival.
In 1971, The National Cancer Act
added adults with cancer as a priority,
and considerable advances have been
made in a number of adult malignancies. In the mid 1990s, several studies,
performed mainly by Bleyer et al,
identified a population of patients
largely between 15 to 19 years of age
who were not benefiting from the
advances in either pediatric or adult
malignancies.1-4 Recent subgroup analyses, including a Progress Review from
The National Cancer Institute (NCI),
have determined that improvement in
©2009 Parkhurst, publisher of Oncology Exchange. All rights reserved.
38
ΠVOL. 8, N0. 2, may 2009
research
cancer survival has lagged considerably
for the 15- to 39-year age group, now
referred to by NCI as adolescents and
young adults (AYA).5-10 The NCI made
several subsequent recommendations
in hopes of improving outcomes for
this population.6,9 There is no standard
international definition of “young
adult” — the Public Health Agency of
Canada has defined patients suffering
from a malignancy between the ages
of 20 to 44 years as young adults.11 In
this article, AYA denotes patients from
15 to 39 years of age.
The incidence of cancer in the North
American AYA population is approximately 60 cases per 100,000 men and
100 cases per 100,000 women.11,12 The
most common AYA malignancies are
breast cancer, lymphoma, melanoma,
female genital tract tumours, thyroid
carcinoma, soft-tissue sarcomas, testicular
cancer, colorectal carcinoma, leukemia,
brain tumours and osteosarcoma.6 In
comparison to both pediatric and
older adult patients, the AYA population tends to have a worse prognosis
— particularly when being treated for
breast cancer, colorectal cancer, softtissue sarcoma, non-Hodgkin lymphoma or leukemia.6 Suggested explanations for the inferior outcomes include
differences in the biology of the cancers, poor understanding of host and
tumour physiology, poor enrollment
into adult and pediatric clinical trials,
and lack of AYA-specific clinical trials.
There is evidence that significant
improvement in survival can be achieved
in patients 15 to 19 years of age with
acute lymphoblastic leukemia, Ewing
sarcoma, rhabdomyosarcoma, non-
Hodgkin lymphoma and primary bone
tumours when these patients are treated
according to pediatric protocols.5,13-18
Similar results may also hold true for
the entire AYA population but studies
are lacking. Other suggested explanations for poor AYA outcomes include
delayed diagnosis and poor treatment
compliance.
The NCI recently made landmark
recommendations with regards to AYA
cancer patients,6,19 among them:
• increase the number of AYA patients
in clinical trials
• increase the number of available
specimens for the study of AYA
tumour biology
• increase our understanding of host
and tumour physiology and create a
specific classification system for
these cancers, rather than using
pediatric or adult classifications
• review previously acquired clinical
trial data for AYA subset analysis
• focus initially on cancers that occur
with the highest frequency and have
the largest differential in prognosis
relative to either their adult or pediatric counterparts: sarcoma, leukemia, lymphoma, breast cancer and
colorectal cancer.
pists, occupational therapists, nutrition
specialists and a data manager. Fellows
interested in this new subdiscipline are
also involved and incorporated as team
members. The majority of team members have extensive experience in pediatric care. Entry clinics are at the
Royal Victoria Hospital (RVH), Montreal Neurological Hospital (MNH)
and Sir Mortimer B. Davis Jewish
General Hospital (JGH), and a multidisciplinary clinic is located at the
JGH Segal Cancer Centre. The referring physician has the choice of referring a patient for complex treatment
or for consultation only.
The wide variety of services offered
was intended to encompass patients’
needs and requirements during their
treatment period. Several clinical
research associates on the team, in
conjunction with the McGill Clinical
Research Program, design, implement
and accrue patients into clinical trials.
After initial assessment, all patients are
presented at the AYA tumour board
and if needed at the site-specific tumour
board. Tissue banking is also facilitated with the help of AYA-affiliated surgeons and pathologists. The group
works closely with cancer support
groups established by Hope & Cope,
Venturing Out Beyond Our Cancer
(VOBOC) and The Cedars Cancer
Institute. AYA clinics are held two specific days each week so that AYA
patients visit the clinic and infusion
room together. AYA program physicians also act as consultants by attending tumour board meetings (sarcoma,
brain and gastrointestinal), and are
involved in treatment discussions of
AYA patients still being assessed by
surgeons — critical to obtaining referrals to the AYA program.
Soon after its creation, medical and
surgical oncologists specializing in
breast, hepatic, colorectal, sarcoma
and genitourinary cancers began to
join the team and refer their patients.
This report points out some of our
successes and acknowledges some
challenges the McGill AYA program
faces — challenges that will likely be
encountered by other institutions setting up AYA programs. Some of these
include increasing the awareness of
the therapeutic, psychosocial and
rehabilitation needs of AYA patients,
McGill’s AYA oncology program
In an attempt to meet the challenges
faced by AYA patients, in 2003 McGill
University created the first AYA oncology program (AYAO) in Canada.
This program is now open to patients
diagnosed with a malignancy before
the age of 39, inclusive (the original
age range was 18 to 30, inclusive), and
older adults suffering from a pediatrictype malignancy.
The program consists of the director
(a hematologist/oncologist with pediatric oncology training), two assistant
directors (both radiation oncologists,
one of whom is also trained in pediatric
radiation oncology), medical oncologists (one with specific expertise in
rehabilitation), two general practition­
ers, psychiatrists, psychologists,
tumour site-specific surgeons, a team
of radiologists to grant patients rapid
access to imaging, pathologists, pharmacists, a “pivot” nurse who helps the
patient navigate the healthcare system
and available resources, clinical nurse
specialists, social workers, physiothera-
©2009 Parkhurst, publisher of Oncology Exchange. All rights reserved.
ΠVOL. 8, N0. 2, may 2009
39
research
Methods
We conducted a retrospective chart
review of the patients referred to the
McGill AYA program from January 2003
until March 2008 who were diagnosed
at less than 31 years of age. Most patients
were at least 18 years old, as most
younger patients are treated in children’s
hospitals, but some who were older
than 15 and had a typical adult malignancy were referred to the program.
FIGURE 1. Age at diagnosis and referral for McGill AYA patients
diagnosed with a malignancy at < 31 years of age*
40
35
30
percent
increasing the number of available
clinical trials and increasing the number of patient referrals.
25
20
15
10
5
0
10–14
15–19
20–24
25–29
Results
Patient characteristics and
referral statistics
Of 160 patients referred to the program,
64 (40%) were female and 96 (60%)
were male. Figure 1 shows the age
distributions at time of diagnosis and
referral: it represents all patients in the
program diagnosed with a malignancy
before 31 years of age. At present, the
AYA program accepts all patients diagnosed with a malignancy at less than
40 years of age, but this was a recent
change, based on NCI and Health
Canada classifications, and is not
reflected in the figure. While the number of referrals increased every year, a
review of the tumour registries at
McGill’s participating institutions
revealed an overall referral rate of 42%
at the JGH and 35% at the RVH and
MNH. Approximately 44% of patients
were referred from Quebec institutions
outside the McGill catchment area.
Tumour types, reasons for
referral and treatment statistics
A wide variety of tumour types were seen
in the AYA program. Cancer types
were 33% sarcoma, 26% brain or other
central nervous system (CNS) tumours,
13% leukemia or lymphoma, 11%
genitourinary or germ cell tumours,
8% gastrointestinal, 5% melanoma and
4% thyroid and breast cancer. Reasons
for referral were: 109 patients (71%)
for primary treatment, 29 (19%) for
second- or third-line treatment, 11
(7%) for followup and 5 patients (3%)
for second opinions. Eighty percent of
patients were seen within two weeks of
referral, with 15% seen on the same day
and 43% seen within the first week.
30–34
age
ΠVOL. 8, N0. 2, may 2009
40–44
> 45
n diagnosis
n referral
* The age range of patients was only changed to 15–44 years recently,
based on NCI and Health Canada classifications.
Figure 2 shows wait times from first
contact to first treatment: 80%
received treatment within three weeks
of first contact.
Clinical trials and outcomes
Numerous clinical trials are ongoing at
McGill. These include therapeutic,
rehabilitation and nutrition program
trials and fertility management trials.
Several recently initiated Children’s
Oncology Group (COG) trials and two
AYA-specific trials are actively recruiting patients. Between 2003 and 2007,
the overall number of patients enrolled
in clinical trials each year has ranged
between 14% and 32%, averaging about
27%; of these, 24 (50%) were in therapeutic trials, 17 (36%) were in fertility
trials and 6 (13%) were in a nutrition
and cancer rehabilitation trial. Figure 3,
page 42, shows 5-year survival curves.
Of all patients entered into the program
since 2003, 36% were in remission,
23% had stable disease (either on or
off treatment), 9% had disease progression, 23% had died and approximately 12% had been lost to followup.
Overall survival rates were 65% for
sarcomas and 88% for brain tumours,
which are both major tumour sites.
Discussion
As previously mentioned, improvement in long-term survival in AYA
patients has been minimal compared
to pediatric and older adult oncology
patients.5,6,10,19 Success in pediatric
oncology resulted from initiatives
begun several decades ago that recognized the low incidence of cancer in
this population (0.5%). Initiatives
included concentrating patients within
specialized centres, study of tumour
biology, and national and international
collaborations to design pediatric clinical trials. At 3% to 4% of all cancers,
cancer in the AYA population is more
frequent but still relatively rare.11,12
Clearly, initiatives similar to those
instituted for pediatric malignancies
are required to improve treatment
outcomes for AYA malignancies.
Treating adolescents and young
adults with cancer has many associated
complexities that AYA centres must be
prepared to tackle. From a therapeutic
perspective, evidence that pediatric
protocols may offer better long-term
survival for some AYA malignancies
calls for implementation of pediatric
protocols at adult sites. The need for
increased access to pediatric clinical
trials ultimately requires that treating
physicians have experience with pediatric protocols, be members of the
COG and that sites be recognized by
the COG. Many COG protocols,
however, have upper age limits that
restrict access of AYA patients, and
©2009 Parkhurst, publisher of Oncology Exchange. All rights reserved.
40
35–39
research
COG does not have protocols for
many adult malignancies, e.g. breast
cancer. Although this may change in
the future, AYAO sites must also be
prepared to design and implement
AYA-specific trials through an AYAO
cooperative group.
Many psychosocial challenges arise
when treating AYA patients. They often
find treatment in clinics filled with older
adults psychologically challenging. They
may feel they do not have the time to
deal with their cancer or oncology followup schedule because of school, work
and social activities. They may misunderstand the seriousness of their disease
due to the lack of public knowledge
about cancer in AYA patients, combined
with a false sense of invincibility common in AYAs. Such factors result in poor
treatment compliance and elevated rates
of loss to followup. McGill designed
its AYAO program in recognition of
these considerations. The McGill core
team members have pediatric oncology
experience and many are part of COG,
resulting in successful activation of
selected COG trials at an adult institution. Further, our clinical research team
has begun to implement AYA-specific
trials; future projects include collaborations with other AYA groups to expand
the size and number of these trials.
Successes
The number of patients included in
clinical trials in our program has been
nearly three- to four-fold greater than
that reported in the general AYA
oncology population.4,5,9 Concentrating patients together and offering
numerous services has reduced loss to
followup (12%) in comparison to published rates, which have been reported
as being up to 50% to 70% when transitions from pediatric centres to adult
care are included.20 Regarding outcomes, five-year survival rates of 50%
to 60% for sarcoma patients and of
70% to 80% for brain/CNS tumours
have been reported.5,12 Our five-year
survival for sarcoma is comparable at
53%; for brain tumours it is higher at
88%, potentially owing to McGill’s
strong neuro-oncology program.
AYA patient with a typical pediatric
malignancy like medulloblastoma or
rhadomyosarcoma, a medical oncologist specializing in the management of
breast cancer can refer a patient to the
program while remaining the treating
physician. Referral will allow for
increased access to clinical trials, psychosocial services, patient support
groups and tumour banking. Cases
can then be discussed regularly at AYA
tumour board meetings. At the very
minimum, patients should be referred
for a second opinion so they can be
placed on the AYA registry and evaluated for current or upcoming clinical
trials. If the patient does not attend
the AYA clinics, AYAO teams need the
flexibility to meet with patients at
non-AYA clinics. Regardless of the
method of referral, AYAO programs
are needed to promote patient access
to pediatric and AYA clinical trials and
to allow accumulation of tumour specimens and clinical data to help advance
the field of AYA oncology. AYAO programs have an important role in educating physicians about the unique
needs of the population and should
remain flexible to accommodate their
adult oncology colleagues.
AYAO patients diagnosed with
readily treatable malignancies such as
testicular tumours should also be
referred to the program. Not only will
they likely benefit from the psychosocial and rehabilitation programs, but
those presenting with advanced or
refractory disease should be enrolled
in clinical trials. Even those presenting
with favourable disease pathology may
benefit from being included in trials
looking at reducing the treatment
intensity and subsequent toxic side
effects. All pediatric oncology patients
should be referred, given the small yet
non-negligible increased risk of malignancy throughout life and the physical, psychosocial and fertility side
effects of therapeutic interventions, as
well as implications for future insurance coverage. Importantly, a small
subset of these cancer survivors (e.g.
hereditary retinoblastoma patients)
will be at significantly increased risk
for second malignancies and complications. Considering that the average
pediatrician or family practitioner lacks
extensive experience with rare tumours
Challenges
Despite team efforts and increasing
collaborations between hematologists
and medical/surgical oncologists, the
percentage of patients referred (42%)
is still low. This is an obstacle many
institutions will likely face when instituting an AYA program. With the
expanding definition of AYA now
encompassing patients aged anywhere
from 15 to 39 or 44, obtaining referrals
may become increasingly problematic.
Cancer specialists need to be made be
aware that referral to the program does
not necessarily change the treating
physician. While referral for treatment
by an AYA oncologist with pediatric
experience is likely appropriate for an
FIGURE 2. Wait times from first contact to first treatment
35.00
29.21
30.00
percent
25.00
20.22
20.00
16.85
15.73
15.00
10.00
5.62
5.00
3.37
5.62
1.12
2.25
≤ 49
> 49
0.00
same day
≤ 7
≤ 14
≤ 21
≤ 28
≤ 35
≤ 42
days
©2009 Parkhurst, publisher of Oncology Exchange. All rights reserved.
ΠVOL. 8, N0. 2, may 2009
41
research
Toward age-sensitive
oncology care
No matter how much attention and
specialized care AYAO patients receive,
the significance of the unique biologic
and psychosocial implications of age
cannot be overstated. In the pediatric
setting, where this concept was recognized long ago, the development of
specialized programs has had a powerful impact. Interestingly, recent experimental and clinical experience suggests
that a comparable scenario may also
be true of elderly (> 70 years) patients
with cancer.21 A potential model to
consider in a comprehensive cancer
centre is to view all patients not only
with regard to their tumour diagnosis,
but to offer additional treatment and
research designed to respond to
patients through the ages: pediatric,
adolescent and young adult, mature
adult and elderly. Such a scenario is
challenging and requires creative evaluation of current practice, but is likely
critical to optimizing cancer care. n
Œ
Disclosure
AMGEN Canada Inc. provides McGill’s AYA
program with research support. Dr. Batist reports
serving on Amgen advisory boards. Dr. Kavan
reports receiving research support from Amgen
and Hoffmann-La Roche and being on advisory
boards of Amgen, Hoffmann-la Roche, SanofiAventis and Schering-Plough. No other potential
conflicts of interest were reported.
References
1. Albritton K, Bleyer WA.The management of
cancer in the older adolescent. Eur J Cancer.
2003;39(18):2584-99.
2. Bleyer A. Older adolescents with cancer in North
America deficits in outcome and research. Pediatr
Clin North Am. 2002 Oct;49(5):1027-42.
3. Bleyer WA. Cancer in older adolescents and
young adults: epidemiology, diagnosis, treatment,
survival, and importance of clinical trials. Med
Pediatr Oncol 2002 Jan;38(1):1-10.
4. Bleyer WA, Tejeda H, Murphy SB et al. National
cancer clinical trials: children have equal
access; adolescents do not. J Adolesc Health
1997;21(6):366-73.
5. Bleyer A. Young adult oncology: the patients
and their survival challenges. CA Cancer J Clin
2007;57(4):242-55.
6. Bleyer A, Barr R, Hayes-Lattin B et al. The distinctive biology of cancer in adolescents and young
adults. Nat Rev Cancer 2008;8(4):288-98.
FIGURE 3. Five-year survival curves for McGill AYA patients
120.00
t
n
5
100.00
t
n
5
t
5
n
t
5
n
t
5
n
80.00
percent
and their therapeutic side effects,
referral to a more experienced team
for regular followup may be beneficial.
5
t
n
ΠVOL. 8, N0. 2, may 2009
5
5
t
n
n
t
60.00
n
t
40.00
20.00
0.00
0
1
3
6
12
24
36
48
60
months
n
t
5
7. Bleyer, WA, O’Leary, M, Barr, R et al. Cancer
Epidemiology in Older Adolescents and Young
Adults 15 to 29 Years of Age, Including SEER
Incidence and Survival, 1975-2000. 2006 [cited;
Available from www.seer.cancer.gov/publications/aya
8. Gibbon DG, Schaar D, Kamen B. A call to action:
Cancer in adolescents and young adults: An
unrecognized healthcare disparity. J Pediatr
Hematol Oncol 2006;28(9):549-51.
9. National Institutes of Health. Closing the gap:
Research and care imperatives for adolescents
and young adults with cancer. A report of the
Adolescent and Young Adult Oncology Progress
Review Group. 2006. Available from http://
planning.cancer.gov/disease/AYAO_PRG_
Report_2006_FINAL.pdf
10. Schmidt C. Lack of progress in teen and young
adult cancers concerns researchers, prompts
study. J Natl Cancer Inst 2006;98(24):1760-3.
11. Cancer Care Ontario. Cancer in Young Adults in
Canada. Toronto, ON, Canada, May 2006. Available at www.cancercare.on.ca/toolbox/libraries/
hcplibrary/
12. Surveillance, Epidemiology and End Results
(SEER) Program. Adolescent and Young Adult
Cancer by Site, Incidence, Survival and Mortality.
2005 [cited; Available from www.seer.cancer.gov
> Statistics > Cancer statistics review > 32. Adult
and Young Adult Cancer
13. Boissel N, Auclerc MF, Lhéritier V et al. Should
adolescents with acute lymphoblastic leukemia
be treated as old children or young adults? Comparison of the French FRALLE-93 and LALA-94
trials. J Clin Oncol 2003;21(5):774-80.
14. de Bont JM, Holt B, Dekker AW. Significant difference in outcome for adolescents with acute
lymphoblastic leukemia treated on pediatric vs
15.
16.
17.
18.
19.
20.
21.
all tumours
sarcoma
brain/CNS
adult protocols in the Netherlands. Leukemia
2004;18(12):2032-5.
Ferrari A, Dileo P, Casanova M et al. Rhabdomyosarcoma in adults. A retrospective analysis of
171 patients treated at a single institution.
Cancer 2003;98(3):571-80.
Kantarjian HM, O’Brien S, Smith TL et al. Results
of treatment with hyper-CVAD, a dose-intensive
regimen, in adult acute lymphocytic leukemia.
J Clin Oncol 2000;18(3):547-61.
Ramanujachar R, Richards S, Hann I et al. Adolescents with acute lymphoblastic leukaemia:
outcome on UK national paediatric (ALL97) and
adult (UKALLXII/E2993) trials. Pediatr Blood
Cancer 2007;48(3):254-61.
Ramanujachar R, Richards S, Hann I, Webb D.
Adolescents with acute lymphoblastic leukaemia:
emerging from the shadow of paediatric and
adult treatment protocols. Pediatr Blood Cancer
2006;47(6):748-56.
U.S. Department of Health and Human Services,
National Institutes of Health, National Cancer
Institute and the LIVESTRONG™ Young Adult
Alliance. Closing the gap: Research and care
imperatives for adolescents and young adults
with cancer. A report of the Adolescent and
Young Adult Oncology Progress Review Group.
2006. Available at http://searchosp1.nci.nih.gov/
disease/AYAO_PRG_Report_2006_FINAL.pdf
Oeffinger KC, Mertens AC, Hudson MM et al.
Health care of young adult survivors of childhood
cancer: a report from the Childhood Cancer Survivor Study. Ann Fam Med 2004;2(1):61-70.
Retornaz F, Monette J, Batist G et al. Usefulness
of frailty markers in the assessment of the health
and functional status of older cancer patients
referred for chemotherapy: a pilot study. J Gerontol
A Biol Sci Med Sci 2008;63(5):518-22.
©2009 Parkhurst, publisher of Oncology Exchange. All rights reserved.
42
5