Detailed dose reduction and delay protocols were provided see protocol. Patient symptoms were assessed by investigators throughout treatment and scored with National Cancer Institute Common Toxicity Criteria for Adverse Events version 3.
Patients completed the European Organisation for Research and Treatment of Cancer quality-of-life core questionnaire QLQ-C30 12 and five additional questions with similar structure to that used in the QLQ-C30 about trial-specific symptoms and patient views on how acceptable and worthwhile their treatment was.
Forms were scheduled to be completed at baseline before randomisation , 6 weeks, 12 weeks, and every 12 weeks thereafter before knowledge of CT scan results. The primary objective of this part of the COIN trial was to establish whether intermittent therapy was non-inferior to continuous therapy in terms of overall survival in patients with advanced colorectal cancer.
The secondary aims were to evaluate failure-free survival of the treatment strategies , response, toxic effects, quality of life, and cost-effectiveness. Results of the cost-effectiveness analysis are not yet available.
The primary quality-of-life outcome measures were palliation, toxic effects, functional scales, and global quality of life. The sample size for comparison of arm A versus C was patients per arm.
Stata version The primary question was one of non-inferiority, so both intention-to-treat ITT and per-protocol analyses of overall survival were planned. The ITT analysis included all patients randomly allocated to treatment groups, whereas the per-protocol analysis included patients who reached the point at which continuous and intermittent strategies diverged—ie, they received a full 12 weeks' treatment allowing for one missed cycle , remained on trial, and had no evidence of progressive disease at 12 weeks within 4 weeks.
Additionally, the patients included in the per-protocol analysis had to have adhered to the assigned protocol strategy at 12 weeks—ie, patients in arm A continuing treatment and those in arm C starting a chemotherapy-free interval. This population was defined to correspond to the patient cohort who, when seen at the week timepoint outside a trial context , would benefit from discussion about whether to continue treatment or begin a chemotherapy-free interval. Overall survival was calculated as time from randomisation to death from any cause.
At the time of analysis, survivors were censored at the date that they were last known to be alive. Strategy-failure-free survival was defined as the time from randomisation to failure of the COIN strategy to which a patient was randomly assigned webappendix p 3.
In the continuous treatment group, this measure equated to conventional progression-free survival. In the intermittent treatment group, a strategy-failure-free survival event occurred when a patient had progressive disease during a planned treatment period or within 8 weeks of starting a chemotherapy-free interval.
Patients were censored at the last date for which a case report form was completed. The primary analysis timepoint for quality of life was 24 weeks after randomisation, but baseline and week data were also analysed since these timepoints were milestones in the treatment strategy. Only patients in the per-protocol population with data at all three timepoints were analysed. Ordinal logistic regression was used to predict week and week scores rounded into five categories, adjusting for treatment arm and previous scores.
Prognostic and predictive modelling was done with Cox proportional hazards regression. To investigate whether these covariates modified the treatment effect, predictive models were fitted that included the covariate, treatment arm, and a treatment-predictive factor interaction term; interaction tests were done with likelihood-ratio tests of the null hypothesis that the interaction coefficient is zero.
The trial was conceived and developed by the National Cancer Research Institute advanced colorectal clinical studies group. The MRC Clinical Trials Unit was responsible for all data collection and analysis, and contributed to the writing of the report.
The corresponding author had full access to the data and had final responsibility for the decision to submit for publication. Between March 9, , and May 9, , patients were randomly allocated to treatment groups at centres in the UK and Ireland, with patients assigned to the comparison of continuous versus intermittent treatment. Table 1 shows their baseline characteristics, which were well balanced between the trial arms. Figure 2 shows the progress of patients through the stages of the trial.
No major differences were identified by choice of chemotherapy for any of the outcome measures of this comparison. Median survival in each arm is derived directly from the Kaplan-Meier curve. This is intended to give a clinical interpretation of the results as compared with the prespecified bound.
The median number of chemotherapy-free intervals was two range one to six. Protocol treatment in both treatment groups was identical up to 12 weeks the time of the first scheduled radiological disease assessment. Best overall response by RECIST criteria did not differ between treatment groups, suggesting that most patients achieve best response within the first 12 weeks of therapy. Response at 12 weeks and best response in arms A and C and response after rechallenge arm C only.
Haematological toxic effects and hand—foot syndrome were more common on continuous treatment than on intermittent treatment, whereas nausea and vomiting occurred more often in patients receiving intermittent treatment.
Grade 3 or worse peripheral neuropathy and hand—foot syndrome were more frequent during continuous treatment webappendix p 4. Less than two-thirds of patients complied with the quality-of-life component of COIN. No clear evidence of differences in baseline characteristics was identified between those patients who completed quality-of-life questionnaires and all patients randomly allocated to treatment groups, but the risk of such differences cannot be eliminated.
Odds ratios ORs are for arm C compared with arm A, and are from ordinal regression models adjusting for previous timepoints baseline, 12 weeks. ORs greater than 1 indicate worse quality of life, and ORs less than 1 indicate better quality of life. We undertook a post-hoc exploratory analysis of the effects of protocol adherence on overall survival. Clinicians were classified according to the proportion of their patients assigned to intermittent therapy in the per-protocol population who restarted treatment after a chemotherapy-free interval.
For so-called adherent clinicians, there was no survival difference between arms A and C. But for non-adherent clinicians, there was an early survival advantage for arm A. However, this difference lessens over time and the overall HR is non-significant figure 4. Effects of adherence to protocol on overall survival within the per-protocol population.
The final model contained the following previously identified prognostic variables: previous adjuvant chemotherapy or surgery; alkaline phosphatase; body surface-area; platelet count; time from diagnosis to randomisation; resection of primary tumour; mutation present in any of KRAS , NRAS, or BRAF ; and number of metastatic sites.
The 16 factors entered into the prognostic model were also explored for predictive value for overall survival in the per-protocol population figure 5. All these results were independent of known prognostic factors.
Kaplan-Meier curves of overall survival within the per-protocol population, by baseline platelet subgroup. The goal of palliative chemotherapy is to increase overall survival with improvement or minimum deficit in quality of life. This study provides a large dataset relevant to the effect of chemotherapy-free intervals on both overall survival and quality of life in advanced colorectal cancer. The trial did not meet its primary outcome objective, which was to show non-inferiority of intermittent chemotherapy versus continuous chemotherapy as first-line therapy in advanced colorectal cancer.
This policy therefore cannot be routinely recommended for all patients. However, there seems to be a large subpopulation of patients for whom intermittent therapy provides similar survival benefit and can be recommended. The COIN trial has shown that intermittent chemotherapy is associated with improved quality of life, shortened time on chemotherapy, reduced number of visits to hospital, and a minimum difference in overall survival.
Non-inferiority trials are often misconstrued as equivalence trials, which they are not. The outcomes of such trials give an indication of similarity, which should be interpreted with all relevant data in hand and not as a single endpoint. The striking outcome from the study is the significant correlation of a raised baseline platelet count as a predictive biomarker for use of a continuous or intermittent chemotherapy strategy.
By contrast, the three-quarters of patients with normal platelet counts had improved quality of life on almost all measures, with no detriment in overall survival.
Raised platelet count has previously been identified as a poor prognostic marker in advanced colorectal cancer. The shorter overall survival in this UK trial compared with some other trial settings is probably related to a combination of several factors, such as a more advanced distribution of disease at presentation, fewer available effective treatments, or different attitudes of patients and clinicians to additional therapy.
The patterns are consistent with later stage at diagnosis or differences in treatment, particularly in Denmark and the UK. Since COIN recruited widely from centres across the UK and Ireland and had broad inclusion criteria, it is likely to be representative of outcomes for advanced colorectal cancer in the UK. Failure to restart oxaliplatin-based chemotherapy after an interval has previously been identified as detrimental to survival.
The proportion of COIN patients restarting oxaliplatin and the low numbers receiving second-line chemotherapy regimens compared with some other countries reflects a less aggressive approach that is characteristic of UK oncology and could also have contributed to the lower overall survival. Additionally, the predominantly UK study setting is important in that bevacizumab was not reimbursed for first-line treatment or subsequent use in routine NHS practice during the study period, and although its availability would probably have resulted in longer overall survival, the effect of addition of this targeted agent on a chemotherapy-free interval strategy is unclear.
Three randomised trials are examining this issue, 19 , 20 , 21 but preliminary data are only available for one. The two other trials continue to recruit. In the AIO trial, 20 patients are randomly allocated to one of three arms bevacizumab plus fluoropyrimidine, bevacizumab alone, or no treatment after 24 weeks of induction oxaliplatin fluoropyrimidine and bevacizumab and complete accrual is due in In the CAIRO 3 study, 21 patients are randomly assigned to bevacizumab plus capecitabine or no treatment after 18 weeks of induction oxaliplatin, capecitabine, and bevacizumab.
EGFR-targeted monoclonal antibodies cetuximab and panitumumab have also been recently licensed in the first-line advanced colorectal cancer setting and cetuximab has been explored in an intermittent strategy in the Nordic VII 22 and COIN-B trials.
Consequently, our findings should be interpreted cautiously for health-care environments in which bevacizumab, cetuximab, and panitumumab are widely available.
However, our message that omission of chemotherapy for long periods in selected patients without overall survival deficit could be even more relevant in such contexts. Potential benefits from the continuation of such targeted agents with or without the addition of a fluoropyrimidine, when oxaliplatin is temporarily discontinued, have yet to be shown in terms of progression-free or strategy-failure-free survival or more importantly in terms of overall survival in any completed randomised controlled trials; such data are eagerly awaited.
Standard UK practice is to image patients at week intervals. International trials, especially commercially sponsored studies evaluating the effects of novel agents, now often use assessments every 6—8 weeks. Although COIN only required imaging every 12 weeks, clinical assessment was done every 6 weeks, during which clinical or biochemical progression would have been identified.
During treatment breaks, patients in arm C attended hospital as outpatients or day cases on an average of two occasions every 12—24 weeks, whereas those in arm A would have been seen on at least eight occasions and possibly 12 depending on the chemotherapy regimen. This more frequent clinical review could have led to earlier identification of disease progression.
The secondary and subgroup analyses of the trial are intended to offer some guidance to practising clinicians, patients, and patient advocates. There is also evidence of reduced cumulative toxicities of neuropathy and hand—foot syndrome.
The overall effect on quality of life with time off treatment in arm C, as assessed at the specific timepoints of 12 and 24 weeks, suggest an improvement in fatigue, nausea and vomiting, anorexia or loss of appetite, constipation, diarrhoea, dry or sore mouth, and difficulty handling objects.
However, pain seems to be slightly but consistently more frequent in those receiving the intermittent strategy, which could be accounted for by the increased likelihood of tumour progression or activity during a chemotherapy-free interval. By contrast, emotional functioning appeared worse in the intermittent group at the end of the first week treatment period when all patients had received equivalent therapy.
This result might reflect anxiety induced by the idea of treatment being stopped temporarily. Yet this finding disappears at 24 weeks, when those on continuous therapy may be uncertain about continuing effectiveness or tolerability of ongoing treatment. In advanced colorectal cancer, for patients treated with palliative intent, as in most other malignancies, time off chemotherapy remains a treatment option. This study has shown and quantified the benefits of a chemotherapy-free interval in terms of reduced time on chemotherapy, reduced cumulative toxic effects, and improved quality of life after an initial week period of induction chemotherapy.
In the whole population, there was a small reduction in overall survival with intermittent compared with continuous chemotherapy, exceeding our predefined non-inferiority bound. However, the identification of raised platelet count as a potential biomarker separating patient subsets who do better from those who do not is very important.
Thrombocytosis could identify a patient subgroup in whom cytokine activation is driving a more aggressive disease course, but which is sensitive to therapeutic intervention. By contrast, the three-quarters of patients in COIN with normal platelet counts at randomisation suffered no loss in overall survival and could reap potentially important benefits of chemotherapy-free intervals.
Conventional palliative chemotherapy for treatment of advanced colorectal cancer is given continuously until progressive disease or cumulative toxic effects occur, or the patient chooses to discontinue.
In a previous Medical Research Council study, CR06B, 5 a shortened course of chemotherapy with reuse of the same treatment on progression showed an improvement in quality of life with no loss of survival. Similar findings have been reported in other cancer types, generally showing that short-course treatment is as effective as long-course.
One consistent finding is that patients receiving short-course therapy can have a reduced time to disease progression, but several investigators have reported that at the time of progression patients can be successfully rechallenged with the same regimen. Searches of Medline and Cancerlit for publications and PDQ Physicians Data Query and the UKCCCR trial register for any additional open or closed trials in advanced colorectal cancer found no trials comparing these approaches when this trial was started.
Survival in COIN is shorter than for many international trials in advanced colorectal cancer, which probably reflects a more advanced stage of disease at presentation in the UK.
Additionally, the lack of routine availability of biological agents in the UK National Health Service might contribute to shortened survival and therefore restrict direct application of the COIN data in the most resource-rich health-care settings.
The finding that intermittent chemotherapy is inferior in patients with raised platelet counts is novel and needs confirmation, but supports the conventional practice of continuous chemotherapy for this cohort. Conversely, for most patients with normal platelet counts at baseline, this study suggests that chemotherapy-free intervals are associated with improved quality of life and no loss of overall survival and is therefore an option that clinicians should discuss with such patients.
We thank the patients and their families who participated in COIN. Additional support in the form of discounted products was provided by Sanofi, Wyeth, and Baxter. A list of clinical investigators can be found in the webappendix pp 1—2. RAA was the trial fellow, member of trial management group, reviewed all safety events, and co-wrote the report.
EH was the trial pharmacist and PR the trial research nurse; both were members of the trial management group. HW was one of the highest recruiters and a member of the trial management group.
TSM was chief investigator of the trial, co-wrote the protocol, chaired the trial management group, and co-wrote the report. All authors reviewed all the data and commented on the report. MTS has received travel expenses and an educational grant from Roche. Study Description. Evaluation of feasibility of adding aflibercept to an oxaliplatin-based regimen rather than a continuous administration of chemotherapy until progression, in order to decrease the risk of severe toxicities.
Detailed Description:. FDA Resources. Arms and Interventions. Outcome Measures. Primary Outcome Measures : Progression free survival at 6 months [ Time Frame: time interval from inclusion to the date of first documented disease progression or death from any cause, whichever occurs first. Assessed at 6 months. Secondary Outcome Measures : Median Progression Free Survival [ Time Frame: time interval from inclusion to the date of first documented disease progression or death from any cause, whichever occurs first.
Assessed up to 3 years after the beginning of the study ] DDC excludes: Intervals between disease progression and re-initiation of treatment, PFS of inactive treatment if PD occurs at first evaluation after treatment re-initiation. The number of patient with R0 and R1 curative salvage surgery will be assessed globally and per sequence of therapy. Eligibility Criteria. Females are neither pregnant nor in breastfeeding. Male patients with a partner of childbearing potential must agree to use effective contraception in addition to the contraceptive method used by their partner during the trial and until at least six months after the end of study treatment.
Registration in a national health care system CMU included for France. Exclusion Criteria: History or evidence upon physical examination of CNS metastasis unless adequately treated e.
Contacts and Locations. Information from the National Library of Medicine To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor. Please refer to this study by its ClinicalTrials. More Information. National Library of Medicine U. National Institutes of Health U. Department of Health and Human Services. The safety and scientific validity of this study is the responsibility of the study sponsor and investigators.
Unresectable Metastatic Colorectal Cancer. Biological: aflibercept.
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