Download A multicentre randomized trial of intensive versus minimalist strategy

GILDA
Gruppo Italiano di Lavoro per la Diagnosi Anticipata
A multicentre randomized trial
of intensive versus minimalist
strategy in the follow-up
of patients with resected
Dukes B-C colorectal carcinoma
Draft date: May 1998
This document is an English short version of the GILDA protocol and
is intended only to provide information about the trial.
Clinicians interested in this protocol are advised to contact
the Coordinating Centre at the Mario Negri Institute, Milan, Italy.
GILDA study -Follow-up: Protocol
SCIENTIFIC COMMITTEE
Bruno Andreoni - Istituto Europeo di Oncologia, Milano
Giovanni Apolone - Istituto Mario Negri, Milano
Sandro Barni - Ospedale San Gerardo, Monza
Francesco Di Costanzo - Ospedale Santa Maria, Terni
Roberto Doci - Istituto Clinico Humanitas Milano
Roldano Fossati - Istituto Mario Negri, Milano
Massimo Gion - Ospedale Civile, Venezia
Frank E. Johnson - Saint Louis University, MO USA
Roberto Labianca - Ospedali Riuniti, Bergamo
Alessandro Liberati - Istituto Mario Negri, Milano
Silvia Marsoni - Istituto Mario Negri, Milano
Giancarlo Martignoni - Ospedale San Carlo, Milano
Paola Mosconi - Istituto Mario Negri, Milano
Maurizio Ponz de Leon - Ospedale Policlinico, Modena
Giovanni Samori - Ospedale di Circolo, Saronno
Paolo Setti Carraro - Ospedale Policlinico, Milano
Valter Torri - Istituto Mario Negri, Milano
Katherine S.Virgo - Saint Louis University, MO USA
Alberto Zaniboni - Casa di Cura Poliambulanza, Brescia
INDIPENDENT DATA MONITORING COMMITTEE
Valerio Di Carlo - Surgeon, Ospedale San Raffaele, Milano
Marco Rosselli del Turco - Oncologist, Centro Studio e Prevenzione Oncologica, Firenze
Maria Grazia Valsecchi - Biostatistician, Università degli Studi, Milano
COORDINATING CENTRE
Roldano Fossati - Principal Investigator, Istituto Mario Negri, Milano
Paola Mosconi - Responsible for Quality of Life Project, Istituto Mario Negri, Milano
Massimo Gion - Responsible for Biomarkers Project, Ospedale Civile, Venezia
Franco Rossi - Responsible for Economical Evaluation, Istituto Economia San., Milano
Valter Torri - Biostatistician, Istituto Mario Negri, Milano
Carlo Confalonieri - Consultant Oncologist,, Istituto Mario Negri, Milano
Bruno Andreoni - Consultant Surgeon, Istituto Europeo di Oncologia, Milano
Monica Flann - Trial Coordinator, Istituto Mario Negri, Milano
Angelo Tinazzi - Computer Scientist, Istituto Mario Negri, Milano
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GILDA study -Follow-up: Protocol
Monica Rita Santillo - Secretary, Istituto Mario Negri, Milano
Istituto di Ricerche Farmacologiche Mario Negri
Via Eritrea, 62 - 20157 Milano
Tel. 02/39014-503-521 - Fax. 02/33200231
e-mail: [email protected]
SUMMARY
BACKGROUND
OBJECTIVES
TRIAL DESIGN
ELIGIBILITY CRITERIA
DESCRIPTION OF FOLLOW-UP PROGRAMS
colon
rectum
STATISTICAL CONSIDERATIONS
ORGANIZATIONAL ASPECTS
PUBLICATION POLICY
TRIAL COSTS
ETHICAL APPROVAL
QUALITY OF LIFE PROJECT
INFORMATIVE LEAFLET FOR THE PATIENTS
COST ANALYSIS PROJECT
REFERENCES
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GILDA study -Follow-up: Protocol
BACKGROUND
Colorectal cancer is one of the most common cause of death due to cancer in Western
civilization with approximately 30,000 new cases registrated in Italy every year.
Although over 60% of cases are elegible for potentially curative surgery, mortality ranks
high and about 17,000 deaths are predicted this year in Italy 1.
The natural history of colorectal cancer is well known. The incidence of recurrences is
higher over the first 24 months after surgery, then it rapidly decreases and patients who
are disease free at 5 years can be reasonably considered cured. The most common site of
metastasis is the liver but even bone and lung metastases are rather frequent and locoregional relapses occur in over 19% of patients. Disease's stage is one of the most
important prognostic factor whilst the site of the primary (colon vs rectum) is a
prognosticator of tumor's way of spread. Knowledge of the most common patterns of
tumor spread lead to the use of organ-specific diagnostic strategies such as colonoscopy,
chest roentgenography, bone scan, liver echography. Current practices for following up
colorectal cancer can vary widely, ranging from a simple clinical surveillance to "secondlook" laparotomy.
Even though many editorials and reviews have been published on this topic, clinical
research in this area is sistematically neglected since oncologic research has always been
polarized toward the development of new treatment approaches. Complex health care
interventions such as post operative follow-up are aimed at improving patients' wellbeing like any other treatment strategy and in the same way, their effectiveness should
be assessed and ameliorated through the most reliable methodologic research tools.
Follow up for cancer patients after therapy given with curative intent can be considered
a particular form of screening for early detection of recurrences. The intuive belief is that
treating metastases at the earliest stage possible will translate into better patient
outcome.
It is especially difficult to evaluate the efficacy of such screening programs with
retrospective studies, because survival of asymptomatic patients who have relapses
detected at screening can only be compared with survival of symptomatic patients who
have relapses. This kind of comparison can be severely biased by •lead time (earlier
diagnosis resulting in a longer duration of recognised disease without any delay in the
time of death from colorectal cancer) and •length time (cases with a long preclinical
phase and, presumably less aggressive are more likely to be detected by a screening
program). A randomized design is thus the only valid way to get an unconfounded
estimate of the effect of follow-up.
Short of the ideal, well designed, large randomize clinical trial that critically examines
different follow-up programs in colorectal cancer we report a brief review of the
available leterature.
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GILDA study -Follow-up: Protocol
Osaka et al. have assessed the efficay of two postoperative surveillance plans to detect
potentially curable recurrences. While the incidence of metastases and the number of
surgical procedures with curative intent were higher in the intensive program this was
not associated with an improvement in survival2.
Further data are available from Beart et al. 's prospective analysis of 149 patients
undergoing physical examination, chest x-ray, chemistry studies, CEA, endoscopy and
barium enema. In this series no curative operation for recurrence was performed3.
Nava and Pagana4 analyzed the follow-up records of 240 patients and suggested
colonoscopy alone as the primary method of postoperative surveillance.
Sugarbaker5 et al. have proposed a follow-up program based on CEA assessed monthly
for three years and quaterly for the succeeding two years along with routine visits every
four months for three years and every six months for the succeding two years. Such
recommendations were derived from the prospective observation of a cohort of patients
with large bowel carcinoma followed-up with a standardized protocol. Kievit and Van
de Velde relied on a mathematical model to assess the cost/effectiveness profile of
routine measurement of CEA and concluded that this ratio was low because the test was
marred by a too high false-positive rate and the diagnostic anticipation was clinically
negligible 6. Similar conclusions were drawn by Moertel et al. who, adopting a
cost/effectiveness approach, underscored the poor prformance of CEA testing especially
in the diagnosis of metachronous disease7.
A rather comprehensive systematic review of non-randomized trials was conducted by
Bruinvel et al.8 This meta-analysis is based on seven published reports which included
follow-up data on 3,283 patients. The study found that 5-year survival did not depend
on the intensity of follow-up although a subgroup analysis showed a survival advantage
when CEA measurement was part of the follow-up protocol.
All these evidences come from non-randomized and often ill-conceived trials and,
therefore, are liable to the methodologic constrains mentioned above. Moreover, these
trials did not distinguish between colon and rectal cancer. Our knowledge of follow-up
impact resulting from randomized trials is rather scanty. In the trial of Tornqvist et al.9
one group had routine physical examination, rectoscopy, chest roentgenography,
double contrast barium enema and blood cell count whereas the comparison group
underwent similar diagnostic procedures but at longer interval. The most clinically
relevant outcome measured in this trial was the rate of curative reoperations that was
not different in the two arms. Unfortunately, the sample size was too small to guarantee
an adequate power to this study. Makela et al. reported preliminary results of another
randomized trial enrolling 106 patients onto either conventional or intensified follow-up
program10. Due to the small sample size, this study has, so far, predictably failed to
show any statistically significant difference in the rate of recurrences. More recently,
Schoemaker et al randomized 325 patients to either intensive or standard follow-up
(intensive: yearly colonoscopy, CT of the liver, chest radiography and clinical review
and simple screening tests; standard: clinical review and simple screening tests)11.
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GILDA study -Follow-up: Protocol
Authors found not significant difference in survival between the two groups but the
hazard ratio of mortality (estimated by the p value and the total number of events)
showed a 23% reduction of the risk of dying for patients randomized to the intensive
regime. The size of this benefit is comparable with the mortality reduction due to
adjuvant therapies in colorectal cancer.
On the whole, these studies have not yet had any meaningfull impact on clinical
practice.
The lack of cogency in the results of published studies has lead to a broad spectrum of
practice patterns in colorectal cancer patients follow-up. This is best shown by two
surveys promoted by The American Society of Colon and Rectal Surgeons and by The
Society of Surgical Oncology12,13. Vernava et al. report that routine clinic visits and CEA
assays were the most frequently performed items followed by colonoscopy, barium
enema, liver echography and chest x-ray. Computerized tomographic scan, bone scan
and NMR were not routinely requested at any time in asymptomatic patients. Foster et
al. reported on the current follow-up patterns of British surgeons in Wales and
Southwest England in 198714. At that time 6% of British surgeons carried out no routine
follo-up, and among the remaining 94% there was great variation in the methods used
and the frequency of their use.
A recent survey of Italian medical and surgical oncologists in charge for following-up
colorectal patients revealed that there is a wide discrepancy among the practice patterns
of clinicians in this country too.
In summary, the dearth in the literature of large, well conducted randomized trials is
striking and the age is now ripe for oncologists and surgeons to promote and run new
studies aimed at assessing which follow-up of patients who have been diagnosed with
colorectal cancer works better.
Follow-up after potentially curative treatment of colorectal cancer constitutes a
significant part of the workload of surgical and oncologic departments. Implementing
routinely an intensive or a minimalist protocol can produce dramatically different
effects on the resources expended and the patient-doctor relationships.
A comparative trial that is able to reliably detect even minimal differences between two
different follow-up regimens needs a very large sample size.
To optimize the cost-effectiveness ratio of such a trial the study protocol:
• should foster semplicity in every aspect of the experimental design (regimens
adopted, elegibility criteria, study management, flow sheets etc.);
• should tailor, as much as possible, the experimental contrast to the prevailing
follow-up attitudes. This is meant to protect the compliance to the study protocol
from the contamination of other diagnostic testing prescribed by physicians not
directly involved in the trial (e.g. GPs). This is why tests of doubtful usefulness in
the early diagnosis of recurrences or metachronous cancer but so deeply rooted in
clinical practice like the CEA will be proposed even in the minimalist plan;
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GILDA study -Follow-up: Protocol
•
•
should focus on more advanced disease (Dukes B and C) where adverse events are
frequent;
should answer clinically relevant problems while maintaing flexible enough to
allow parallel sub-projects to be tacked on.
OBJECTIVES
This study has the following 3 primary objectives:
• To compare 5 year overall survival in patients with stage Dukes B-C colorectal
cancer when randomized to intensive vs control follow-up;
• To compare 5 year mortality for colorectal cancer;
• To assess health related quality of life.
The secondary study objectives include the following analyses:
• To quantify the lead time, if any, due to the intensive program;
• To compare the incidence of recurrences, methacronous carcinoma and other
conditions liable to "curative" resection in the two arms;
• To compare the sensitivity of the two follow-up plans, meant as the capability to
diagnose metastases in still asymptomatic patients;
• To describe physicians' compliance with the follow-up programs.
There are also specific sub-projects (not included in this translation) aimed at
• Formally evaluating the cost-effectiveness of the two follow-ups.
• Setting different strategies to interpret CEA measurements.
DESIGN
This will be an open, randomized multicentre trial with two parallel groups. Patients
will be stratified by the following pre-treatment factors: trial site, disease stage (Dukes B
vs C) and anatomical site (Colon vs Rectum).
Since rigorous rules to distinguish between "Rectum" and "Colon" are lacking we
suggest the following criteria: a) endoscopic distance from the anal verge of 12 cm; b)
evidence, from the operation description, of "intra" or "extra" peritoneal location of the
tumor or evidence of underperitoneal site of the anastomosis.
Randomization will be performed centrally via telephone, within 2 months from the end
of any adjuvant treatment or within 6 months from surgery if this is the only therapeutic
procedure.
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GILDA study -Follow-up: Protocol
ELIGIBILITY CRITERIA
Inclusion criteria
• Histopathologic diagnosis of adenocarcinoma of the colon or rectum, Dukes AstlerColler modification stage B2-C, treated with curative intent (radical excision ±
adjuvant radio/chemotherapy)
• The patient must be free of known cancer prior to study entry. This should be
attested by negative results of endoscopy, echography, chest roentgenography and
CEA
Exclusion criteria
• Inability to undergo testing (disabiliy, allergy to contrast agents, etc.) and patients
geographically not amenable to full follow-up.
• Patients enrolled onto any other research protocol that requires strict adherence to
any specific follow-up practice. With regard to this, the GILDA protocol could really
be an ideal framework to test, for example, any new adjuvant therapy, simply
resorting to a double randomization. It is, infact, extremely unlikely that an
interaction between follow-up practice and treatment could bias the results.
• A history of any previous malignancy in the last 10 years (other than carcinoma in
situ of the cervix or non-melanoma skin cancer).
• No informed consent to partecipate in the trial according to local regulatory
guidelines.
DESCRIPTION OF FOLLOW-UP PROGRAMS
The two follow-up programs (minimalist and intensive) take into account the following
factors :
• Some procedures (e.g. CEA) are so deeply rooted in clinical practice that their
exclusion from a postoperative routine program was deemed unfeasible. In any case,
the dilution effect due to the prescription of these exams from other physicians not
directly involved in the research (General Practitioners etc.) would be very high.
• The experimental contrast was instead construed to assess the potential of other
diagnostic testing such as endoscopy, chest x-ray, CT, liver echography aiming to
detect distant metastases and local relapses. All the patients in this study will have
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GILDA study -Follow-up: Protocol
routine physical assessment (history and physical examination) and CEA
measurements.
• The surveillance plans will not be tailored to disease's stage but specific procedures
will be implemented to detect local recurrences in rectal cancer patients.
• The procedures timing was chosen by keeping in due consideration the suggestions
of Italian Scientific Associations and Societes and the organizational characteristics of
most of the Italian hospitals.
Follow-up programs are illustrated in the following pages; the following remarks
should improve their interpretation:
• The commencement of follow-up coincides with randomization which, in turn, must
be carried out at the end of the treatment with curative intent (radical surgery ±
adjuvant radio-chemotherapy). At randomization, patients must be free of residual
or metastatic tumor and of colorectal adenomatous polips; this should be
documented by the negative results of the following tests: chest roentgenography,
liver echography, colonoscopy and CEA. If a colonoscopy was performed before the
surgical procedure that would be enough.
• Regular office visits in rectal patients should include digital rectal examination.
• The only chemistry to be obtained in minimalist arm is CEA.
• Hematology and chemistry groups to be obtained in the intensive protocol are: CBC,
LDH, AST, ALT, Alkaline Phosphatase, gGT and CEA.
• Double-contrast barium enema can be an alternative to the few patients who refuse
colonoscopy or are technically difficult to colonoscope. In rectal patients the
endoscopy at 4 month is meant to detect an eventual anastomotic recurrence; a
rectoscopy, thus, would be sufficient.
• When prompted by signs/symtopms at physical examination or doubtful results of
blood tests, the clinician can prescribe any further diagnostic test deemed useful.
These data are to be collected on flow sheets.
• When patient's CEA level increases for the first time the treating clinician should
confirm this evidence after a month before the patient is acted upon.
• If adenomatous polyps are identified the implementation of follow-up surveillance
programs depends on the number and size of adenomas:
1) if 4 or less adenomas or 1 small (<2 cm) adenomas: no change in either intensive or
minimalist schedules;
2) if 5 or more adenomas or 1 large (_2 cm) adenomas: a colonoscopy performed 1
year after colonoscopic removal of adenomatous polyps. Afterward patients are
followed-up according to assigned follow-up regimens.
• In this protocol there are no surgical, radiotherapic or chemotherapic guidelines to
be adhered to. All data pertaining the given treatment schemes will be carefully
recorded on flow sheets.
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GILDA study -Follow-up: Protocol
COLON
Minimalist Program
4
8
Months from randomization
12 16 20 24 30 36 42
Office visit
#
#
#
#
#
#
#
#
#
#
#
CEA
#
#
#
#
#
#
#
#
#
#
#
PROCEDURE
Colonoscopy
Liver echography
#
48
60
#
#
#
Abdominal-pelvic C.T.*
Intensive Program
4
8
Months from randomization
12 16 20 24 30 36 42
Office visit
#
#
#
#
#
#
#
#
#
#
#
CBC
#
#
#
#
#
#
#
#
#
#
#
CEA + CA 19-9
#
#
#
#
#
#
#
#
#
#
#
PROCEDURE
48
60
Colonoscopy
#
#
#
#
#
Chest X-ray
#
#
#
#
#
#
#
#
#
Liver echography
#
#
#
#
Abdominal-pelvic C.T.*
* Abdominal-pelvis C.T. in colon carcinoma, as alternative to echography, should be a 2° level exam only
(doubtful result of physical examination or echography; increasing levels of CEA; predictable poor
sensitivity of echography due to obesity or other anatomic-clinical conditions)
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GILDA study -Follow-up: Protocol
RECTUM
Minimalist program
PROCEDURE
4
8
Months from randomization
12 16 20 24 30 36 42
Office visit+digital rectal
examination
3
#
#
#
#
#
#
#
#
#
#
CEA
#
#
#
#
#
#
#
#
#
#
#
Rectoscopy
#
Colonoscopy
#
Chest X-ray
#
Liver echography
#
48
60
#
#
Abdominal-pelvic C.T.*
Intensive program
PROCEDURE
4
8
Months from randomization
12 16 20 24 30 36 42
Office visit+digital rectal
examination
#
#
#
#
#
#
#
#
#
#
#
CBC
#
#
#
#
#
#
#
#
#
#
#
CEA + CA 19-9
#
#
#
#
#
#
#
#
#
#
#
Rectoscopy
#
#
48
60
Colonoscopy
#
#
#
#
#
Chest X-ray
#
#
#
#
#
#
#
#
#
Liver echography
#
Abdominal-pelvic C.T.
#
#
#
#
#
#
#
* See previous foot-note. A single abdominal-pelvic C.T. is allowed in the minimalist program of rectal
patients if it is suggested by the radiotherapist as a control after adjuvant treatment.
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GILDA study -Follow-up: Protocol
STATISTICAL CONSIDERATIONS
End points and final analysis strategy
Principal endpoints are overall survival and tumor specific mortality
Overall survival will be calculated by constructing a Kaplan-Meier survival curve and
the two regimens will be compared using the log rank test. Survival analysis will be
performed according to the intention-to-treat principle.
The odds ratio and its 95% confidence intervals will be used as a quantitative estimate of
the survival difference between the two follow-up plans.
Cancer specific mortality will be explored by an evaluation of event-specific cumulative
rates through a competing risk analysis
The four secondary endpoints will be evaluated as follows:
• Lead time. The mean relative diagnostic anticipation attributable to the intensive
follow-up regimen will be estimated by measuring total areas and their SDs under the
curves of Disease Free Survival (DFS) in the intensive and minimalist groups. For
calculating the DFS, local relapses, metastases and metachronous colorectal tumors will
be considered as failures while non-cancer-related deaths and secondary malignant
neoplasia will be censored.
• Treatment of recurrences with curative intent. It will be compared the rate of curative
reoperation between patients followed with the intensive follow-up strategy and lessintensive strategy.
• Sensitivity of follow-up regims. It will be analyzed the rate of patients already
symptomatic at diagnosis and the rate of symptomatic patients between routine visits.
• Compliance. Physicians' compliance with randomly assigned follow-up plans will be
closely monitored. Compliance in the two groups will be defined as the ratio between
the procedures actually performed and the procedures expected according to protocol
recommendations. The average frequence of execution of procedures and tests will be
also calculated by dividing the sum of all event-free intervals into the total number of
procedures performed before the occurrence of any event.
Assumptions used for the calculation of sample size
The original objective was to detect difference in the hazard ratio for overall survival between
follow-up regimens of at least 20% (i.e. an absolute difference at 5 years of approximately 5 - 6
percentage points) with an a error set at 5% and the power set at 95%; this should have required
the analysis of about 1300 events and has proved unattainable. A preliminary meta-analysis
published in the correspondence section of Lancet, March 2000 and the Cochrane systematic
overview recently published (Jeffrey GM, Hickey BE, Hider P. Follow-up strategies for patients
treated for non-metastatic colorectal cancer (Cochrane review) In: The Cochrane Library, Issue
1,2002. Oxford: Update Software) showed a survival benefit of intensive follow-ups with an
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GILDA study -Follow-up: Protocol
overall mortality Odds Ratio equivalent to 0.76 and 0.73, respectively. If we set as a new target
the detection of a difference in the hazard ratio of at least 24% with the same a error but with the
usual statistical power of 80% then we need about 1500 patients. The five randomised clinical
trials included in Cochrane systematic overview globally enrolled almost 1400 patients;
summing up these figures with the 1500 further patients of GILDA trial we will have the
statistical power to detect differences in overall survival similar to those observed in randomised
trials comparing adjuvant chemotherapy with placebo.
Analyses planning and study monitoring
Notice of accrual course state will be given to participating centres every 6 months.
Interim analyses of diagnostic anticipation (i.e. evaluation of the disease free survival)
and overall survival will be planned yearly, commencing two years after the study
beginning
Owing to the problem of multiple comparisons, interim results will be assessed by
conservative tests (threshold value <0.001) The analysis of diagnostic anticipation will be
used as an early marker of study appropriateness. In fact, intensive regimen will not
yield any survival gain if it is unable to anticipate the diagnosis of recurrence first. Based
on previous experiences in oncologic follow up programs, DFS curves should start
diverging at 2 years from randomisation, and the differences between the two follow up
programs should stabilize thereafter, till the end of the study. In fact, if the intensive
programme does not generate false positive cases the DFS curves will join together at
the end of the 5 year duration of the study when follow up programs return identical.
This is because the same number of recurrences is expected in the two study arms,
although the time pattern of their diagnosis could be different. If interim analyses show
that the chance to catch a clinical significant diagnostic anticipation (= 4 months) is less
than 0.01, then it will be reasonable to contemplate stopping study recruitment and the
quality of life analysis in recurred patients.
ORGANIZATIONAL ASPECTS
The management of this trial is based on a Scientific Committee (SC), a Coordinating
Center (CC), and an Independent Data Monitoring Committee (IDMC).
The Scientific Committee consists of surgeons, medical oncologists, epidemiologists and
statisticians representative of the Promoting Committee of the study and of participating
hospitals. The SC is the final arbitrator in all trial decisions. Specifically the SC is
responsible for monitoring accrual, deciding on possible amendments to the protocol,
over viewing the final analysis, deciding about publications
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GILDA study -Follow-up: Protocol
The Coordinating Center consists of sub-projects managers, a statistician, a consultant
oncologist, a consultant surgeon, a trial coordinator, an informatics manager and
secretarial staff.
Specifically, the CC is responsible for randomization, performing data collection,
cleaning, querying and input of clinical research forms, performing final analyses to
submit to the Scientific Committee.
At each participating center a data monitoring responsible will be nominated to
guarantee quality control of data, and to answer the CC queries.
The Independent Data Monitoring Committee (IDMC) consists of members external to
the study and will meet to review data from interim analysis. They will be responsible
for suggesting to modify, interrupt or continuing the study to the SC. The IDMC can
also ask to analyse data even outside scheduled interim analyses.
PUBLICATION POLICY
The SC shall retain ownership of all case report forms, data analyses and reports which
result from this study. The responsibility for drafting the manuscript describing the
results of the GILDA trial will lie with the Scientific Committee. Representatives of each
participating hospital will be among the co-authors provided that at least 5 cases/year
have been randomised from the respective center and all clinical research routine forms
have been adequately completed and returned to the CC.
TRIAL COSTS
This is an independent trial. It is coordinated at the Mario Negri Institute and it is aimed
at formally assessing the efficacy of diagnostic programs already widely implemented in
clinical practice. Therefore, no additional costs will be induced by the trial, and the
minimalist follow up regimen could even a cost reduction. Clinical form will be
furnished by the Coordinating Center.
ETHICAL APPROVAL
Before entering patients into the trial, clinicians must ensure that the protocol has
received clearance from their local ethics committee. The patient’s consent to participate
in the trial should be obtained after a full explanation has been given of the follow up
options and the manner of follow up allocation.
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GILDA study -Follow-up: Protocol
The right of the patient to withdraw from the trial at any time, without giving reasons,
must be respected.
After the patient has entered the trial the clinician must be free to give an alternative
follow up to that specified in the protocol at any stage if it is felt to be in the patient’s
best interests.
Similarly, the patient must remain free to withdraw at any time from the protocol
specified follow up, or from completion of the quality of life questionnaires, without
giving reasons or prejudicing her further treatment/follow up but should if possible,
continue to be followed up anyway.
QUALITY OF LIFE PROJECT
Data on the impact of follow-up intensity on psychosocial outcomes and health-related
quality of life in colorectal patients are absent. The real issue this project is meant to
clarify, as it was in our previous study in breast cancer patients, whether an intensive
surveillance protocol reassures patients or frequent testing just increases stress and
anxiety. Moreover, if intensive follow-up programs do anticipate metastases detection,
does this lead to a better control of symptoms and thus to a better health related quality
of life?
A standardized assessment of HR-QoL will be performed in all patients free of disease.
It is important to underline that what is currently defined as “Quality of Life” in biomedical research actually corresponds to what in literature is know as “Health Related
Quality of Life” (HR-QoL). HR-QoL encompasses those qualitative aspects of life that
are correlated and pertinent to disease and health domains. It is, therefore, a much less
broad concept of what is generally meant as “Quality of Life” that even if correlated to
health it is different from it.
The rationale of this study is based on the following considerations:
• there are evidences that patients, after potentially curative treatment, want to be
seen frequently by a physician and undergo diagnostic tests even if free of symptoms.
The results of the study on breast cancer follow up highlighted that is critically
important for the patients the presence of a clinician or a very well structured medical
team who, over the time, could become a landmark figure. This is a key aspect to be
considered when constructing a follow up program.
• post operative surveillance is rarely just a succession of office visits because it often
includes serial diagnostic procedures too. The psychological outcomes of these
integrated programs can be positive or negative. Positive outcomes include
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GILDA study -Follow-up: Protocol
reassurance and support. The negative outcomes include false reassurance, distress
caused by false-positive results and increased overall anxiety.
• as for any other health care interventions, patient’s degree of satisfaction about
information and care received must be duly considered.
This Quality of Life study is aimed at answering the following research questions:
• 1. which is the impact of two different follow up regimens on patients’ health status,
provided overall survival is the same across the two regimens?
• 2. which is the impact of the two follow up regimens on patients’ emotion well being?
• 3. what is patients’ satisfaction regarding the two follow up regimens?
• 4. what is the balance between survival quantity and quality since disease recurrence
and what is the impact of diagnostic anticipation of metastases on quality of life?
Two specific questionnaires have been developed to deal with these research issues, one
to be delivered to disease free patients (questions 1-3) and one to patients whose
colorectal disease has recurred (question 4).
Questionnaires
Over the last two decades a limited number of instruments for evaluating HR-QoL
have been subjected to rigorous psychometric evaluation for validity and reliability.
Such instruments can be divided into generic, disease specific or symptom oriented
questionnaires. Current trend is to use an instrument composed of a generic
questionnaire combined with a specific-disease module focussing on the domains most
relevant to the disease.
DISEASE FREE PATIENTS
HR-QoL in GILDA trial will be assessed with a modular instrument assembling different
questionnaires whose psychometric properties are well known. This instrument had
been developed over 1997, through a complex iterative process that, exploiting literature
suggestions, previous experiences of our research group and focus-group meetings with
patients, ultimately leaded to a draft version which was tested in a sample of 100 cases.
Table 1 shows the final version of the questionnaire’s structure
The underlying hypothesis is that the execution of follow up diagnostic procedures can
modify the patient’s health perception and that such perception can be evaluated, even
though indirectly, through a range of items, each of them measuring a specific domain
of health.
Such items are then grouped to reflect homogeneous areas and generate overall
numerical scores.
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GILDA study -Follow-up: Protocol
Table 1 – Questionnaire structure
______________________________________________________________________________
SCALES
HEALTH AND QUALITY OF LIFE
Overall health status(SF-12)
N° Items
INDEX
Physical functioning
Role functioning (physical)
Bodily pain
Health status perception
Vitality
Social functioning
Role functioning (emotional)
Mental health
2
2
1
1
1
1
2
2
2
Anxiety
Depression
Well being
Self-control
General health
Vitality
5
3
4
3
3
4
1
Psycho-emotional well being (PGWB)
FOLLOW -UP IMPACT (GIVIO)
Overall impact of procedures
6
1
Satisfaction health care
7
1
Impact of single procedures
24
8
______________________________________________________________________________
SF-12=Short Form Health Status Survey, 12 items; PGWB=Psychological General Well-Being;
GIVIO=Gruppo Interdisciplinare Valutazione Interventi in Oncologia
As illustrated in figure 1, the questionnaire was devised to detect differences due to
follow up strategies in terms of
-
psychological, physical and social problems (central areas) arisen during the time
the examinations are performed;
impact on patient’s perception of her/his psycho-emotional well being
(intermediate area);
finally, a repercussion in general health status (peripheral areas).
Health and quality of life
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GILDA study -Follow-up: Protocol
• The SF-36 generic questionnaire was designed in USA and it is currently one of the
most widely used instrument to test the impact of treatments on health status. It
describes two major health concepts (physical and mental) through eight multi-items
scales. SF-36 has been object of a formal translation and adjustment to Italian culture
and data from a representative sample of Italian population (5000 Italian applications,
1800 of which oncological patients) are available. SF-36 is also available as a shorter
edition of 12 items, which will be used in this study
• PGWB questionnaire explores patient’s psychological status through six different
scales: anxiety, depression, well-being, self-control, overall health status, vitality. This
questionnaire was developed to measure affective and emotional issues that reflect a
condition of well-being or distress.
Figure 1 – Theoretical impact of follow-up regimens on health status
18
GILDA study -Follow-up: Protocol
Immediate stress and
symptoms
Well-being general aspects
General health status
Quality of life
Follow-up impact
This second part is being explored through three sets of questions: 1)the impact in
terms of fear, physical signs and interference with common indoor and outdoor
activities of each single procedure, 2)the overall impact of a follow up session and 3)
the degree of satisfaction of received health care.
.
These sets of questions are adapted from the GIVIO-CNR-ACRO questionnaire, a
cancer specific questionnaire designed and validated in the framework of the GIVIO
study.
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GILDA study -Follow-up: Protocol
PATIENTS WITH RECURRED DISEASE
Patients with recurred disease will be evaluated since the diagnosis of recurrence with a
battery of six brief diary-questionnaires aimed at assessing the impact of the disease on
physical functioning, pain and symptoms. The instrument chosen for this phase of the
study is the EORTC QLQ-C30, a cancer specific questionnaire whose 30-items can be
grouped in 5 multi-item functional scales, 3 multi-item symptoms scales and 9 singleitem symptoms scales. The Italian version of this questionnaire has recently been tested
in sample of 1500 Italian oncologic patients.
Study methodology
Compliance to quality of life assessment, defined as the number of forms received out of
the number expected, depends on the level of clinicians and patients collaboration. A
high compliance, as shown by previous experiences, strictly depends on a genuine
interest by oncologists in QoL and the way clinicians motivate their patients. In GILDA
informed consent form, patients are asked to actively participate to the “quality of life”
assessment study and they are told that this is a very important aspect of the overall
research project.
Patients’ related compliance also depends on education, familiar milieu and disease
status. In previous studies the response rate to the questionnaires was high –70-80%
received of expected forms- and the quality of collected data was satisfactory. To
minimize missing QoL data we will regularly send follow up postal questionnaires to
non respondents and we will try to collect auxiliary outcome information such as QoL
rated by the general practitioner (advanced disease phase only) or patient’s relatives
(disease free and/or advanced disease phase)
These are the organizational details of QoL project:
AT RANDOMIZATION
• after follow up allocation, the patient’s code number is reported on the form and the
clinician hands the questionnaire to the patient. The patient completes the
questionnaire and then seals the stamped and addressed envelope; the sealed
envelope is collected by the clinician and posted to the Coordinating Center.
DURING FOLLOW-UP
• The questionnaire must be given to the patient at the end of the office visit (at
randomization and at 12, 24, 36, 48, e 60 months thereafter). The completed
questionnaire is returned in its sealed envelope to the clinician who is in charge to
send it to the Coordinating Center
20
GILDA study -Follow-up: Protocol
•
if after 45 days the Coordinating Center has not received the questionnaire yet, the CC
will send an exactly alike follow up questionnaire with an instruction letter
AFTER DISEASE RECURRENCE
The Coordinating Center Disease should be timely notified of any disease recurrence
(via fax or telephone notification). The CC will send a set of 6 questionnaires to the
patients, to be completed every 2 months. These questionnaire may also be completed
by a “proxy”, the trusty person indicated by the patient himself at the moment of the
informed consent signature. The identity of the compiler will be reported in the forms.
Hypotheses for data analysis
QoL data will not be analysed as single items but single items will generate scales or
overall indexes. Differences in HR-QoL data will be explored using analysis of variance.
Mean scores for each scale will be compared cross-sectionally between the intensive
group and the minimalist group at 0, 12, 24, 36, 48 and 60 months.
Longitudinal analyses will be explored with more sophisticated techniques such as
repeated measures variance analysis.
GILDA sample size should be large enough to allow to detect with a repeated measures
analysis of variance a difference of 5 points or less in the 8 scales (assuming a = 0.05 with
a power=80%).
INFORMATIVE LEAFLET FOR THE PATIENTS
A leaflet with the office visits and procedures calendar and general information about
the GILDA study will be given to the patients at the moment of study enter.
COST ANALYSIS PROJECT
The purpose of the Cost Analysis Project is to compare the costs induced by the two post
operative follow up regimens. An attempt will be made to estimate both direct costs,
such as the costs of any single procedure, and indirect costs, such as time lost from work
by the patient and his/her possible companion.
These evaluations will be conducted in disease free patients and in recurred patients
since it is anticipated that the follow up regimens could generate different time patterns
in the diagnosis of recurrences and hence possible different disease management
approaches. Both patients and clinicians will furnish useful information for costs
analysis: data on adherence to protocol follow up schedules will give the framework to
21
GILDA study -Follow-up: Protocol
estimate direct costs whilst patients will give information about indirect costs by
answering the specific questions in the quality of life forms as follows:
DISEASE FREE PATIENTS
The quality of life questionnaires will include three items aimed at documenting the
time spent for visits or diagnostic procedures and recording if the patient has applied to
other clinicians or non-scheduled examinations.
PATIENTS WITH RECURRENT DISEASE
The quality of life questionnaires will include three items aimed at assessing financial
burden to the Health Service in terms of hospital costs, drugs and out patient care.
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GILDA study -Follow-up: Protocol
23
1
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