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Chemotherapy options in elderly and frail patients with metastatic colorectal cancer (MRC FOCUS2): an open-label, randomised factorial trial.
Lancet. 2011 May 21; 377(9779):1749-59
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08 Aug 2011
Clinical Trial
DOI: 10.3410/f.12444961.13652063
The FOCUS2 trial provides some of the first randomized evidence that combination chemotherapy can be given -- with appropriate caution and vigilance -- to the previously understudied group of patients in their late seventies with substantial frailty.
Patients who were deemed 'unfit' for standard doses...Continue reading
Patients who were deemed 'unfit' for standard doses...Continue reading
The FOCUS2 trial provides some of the first randomized evidence that combination chemotherapy can be given -- with appropriate caution and vigilance -- to the previously understudied group of patients in their late seventies with substantial frailty.
Patients who were deemed 'unfit' for standard doses of chemotherapy were randomized via a 2x2 design to receive one of the following treatment arms, all given at a 20% dose reduction: sLV5FU2 (leucovorin, 5-fluorouracil [5FU]), FOLFOX (oxaliplatin, 5FU, leucovorin), capecitabine, CapeOx. After 6 weeks of treatment, patients were allowed to be escalated to full-dose therapy, providing they had not experienced a grade 3 or higher toxicity and they were amenable to escalation.
A total of 459 patients were included. These patients were substantially older than the average trial population, with an overall median age of 74; 43% of patients were over the age of 75. Furthermore, 71% of patients were deemed unfit for full doses of chemotherapy on the basis of frailty by their treating oncologist.
Only 37% of patients had their dose escalated, and escalation was more common in patients treated with single-agent 5FU or capecitabine. In contrast, 49% of the study population required further dose reduction by 12 weeks for adverse effects.
In this elderly and frailer group of patients with metastatic colorectal cancer, progression-free survival (PFS, the primary endpoint) was improved by oxaliplatin, hazard ratio (HR) 0.84, 95% confidence interval (CI) 0.69-1.01. This benefit was more apparent in the FOLFOX versus 5FU comparison where median PFS was 3.5 months in 5FU patients and 5.8 months in FOLFOX patients. Capecitabine (median 5.2) and Cape/Ox (median 5.8 months) performed similarly. Of note, in the pivotal de Gramont paper comparing LV5FU2 and FOLFOX4, median PFS was 6.2 months in the 5FU group and 9 months in the FOLFOX group {1}. As expected, the response rate was higher in the oxaliplatin-treated patients. Oxaliplatin had little to no effect on overall survival in this group of patients. There was no difference in PFS or overall survival (OS) between 5FU and capecitabine. Severe (grade 3 or higher) toxicities were more common in capecitabine-treated patients.
Though there was little survival benefit to oxaliplatin, the investigators included a novel measure called the 'Overall Treatment Utility', which is a composite of efficacy, toxicity, and the patient's subjective interpretation of treatment worth and tolerance. According to this measure, oxaliplatin use was significantly associated with a better chance of having a 'good' Overall Treatment Utility. There was no difference between 5FU and capecitabine for this score.
The FOCUS2 investigators should be commended for an excellent trial design that provides us with information on how to treat the large group of frail and older patients with metastatic colorectal cancer. These data suggest it is reasonable to try FOLFOX in older and frail patients with caution. Many will be unable to tolerate it; however, a significant proportion of these older, frail patients will tolerate FOLFOX, and those patients are likely to at least have prolonged disease-free survival (DFS). FOCUS2 also confirms that capecitabine is not less toxic than 5FU/LV when given on an infusional backbone, and may be harder for this older population to manage.
Patients who were deemed 'unfit' for standard doses of chemotherapy were randomized via a 2x2 design to receive one of the following treatment arms, all given at a 20% dose reduction: sLV5FU2 (leucovorin, 5-fluorouracil [5FU]), FOLFOX (oxaliplatin, 5FU, leucovorin), capecitabine, CapeOx. After 6 weeks of treatment, patients were allowed to be escalated to full-dose therapy, providing they had not experienced a grade 3 or higher toxicity and they were amenable to escalation.
A total of 459 patients were included. These patients were substantially older than the average trial population, with an overall median age of 74; 43% of patients were over the age of 75. Furthermore, 71% of patients were deemed unfit for full doses of chemotherapy on the basis of frailty by their treating oncologist.
Only 37% of patients had their dose escalated, and escalation was more common in patients treated with single-agent 5FU or capecitabine. In contrast, 49% of the study population required further dose reduction by 12 weeks for adverse effects.
In this elderly and frailer group of patients with metastatic colorectal cancer, progression-free survival (PFS, the primary endpoint) was improved by oxaliplatin, hazard ratio (HR) 0.84, 95% confidence interval (CI) 0.69-1.01. This benefit was more apparent in the FOLFOX versus 5FU comparison where median PFS was 3.5 months in 5FU patients and 5.8 months in FOLFOX patients. Capecitabine (median 5.2) and Cape/Ox (median 5.8 months) performed similarly. Of note, in the pivotal de Gramont paper comparing LV5FU2 and FOLFOX4, median PFS was 6.2 months in the 5FU group and 9 months in the FOLFOX group {1}. As expected, the response rate was higher in the oxaliplatin-treated patients. Oxaliplatin had little to no effect on overall survival in this group of patients. There was no difference in PFS or overall survival (OS) between 5FU and capecitabine. Severe (grade 3 or higher) toxicities were more common in capecitabine-treated patients.
Though there was little survival benefit to oxaliplatin, the investigators included a novel measure called the 'Overall Treatment Utility', which is a composite of efficacy, toxicity, and the patient's subjective interpretation of treatment worth and tolerance. According to this measure, oxaliplatin use was significantly associated with a better chance of having a 'good' Overall Treatment Utility. There was no difference between 5FU and capecitabine for this score.
The FOCUS2 investigators should be commended for an excellent trial design that provides us with information on how to treat the large group of frail and older patients with metastatic colorectal cancer. These data suggest it is reasonable to try FOLFOX in older and frail patients with caution. Many will be unable to tolerate it; however, a significant proportion of these older, frail patients will tolerate FOLFOX, and those patients are likely to at least have prolonged disease-free survival (DFS). FOCUS2 also confirms that capecitabine is not less toxic than 5FU/LV when given on an infusional backbone, and may be harder for this older population to manage.
References
1.
Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer.
J Clin Oncol 2000 Aug; 16(18):2938-47
PMID: 10944126
Disclosures
None declared
Add Comment
Goldberg R and Sanoff H: F1000Prime Recommendation of [Seymour MT et al., Lancet 2011, 377(9779):1749-59]. In F1000Prime, 08 Aug 2011; DOI: 10.3410/f.12444961.13652063. F1000Prime.com/12444961#eval13652063
09 Aug 2011
Clinical Trial
DOI: 10.3410/f.12444961.13680055
This study is a must read for physicians taking care of frail older adults with metastatic colorectal cancer and for those interested in designing elderly-specific clinical trials.
This study used a 2x2 factorial design to randomize 459 'frail' older adults with metastatic colorectal cancer to one...Continue reading
This study used a 2x2 factorial design to randomize 459 'frail' older adults with metastatic colorectal cancer to one...Continue reading
This study is a must read for physicians taking care of frail older adults with metastatic colorectal cancer and for those interested in designing elderly-specific clinical trials.
This study used a 2x2 factorial design to randomize 459 'frail' older adults with metastatic colorectal cancer to one of four first-line systemic therapies. The authors were interested in investigating optimal treatment approaches for patients considered unfit for standard full-dose chemotherapy by their practitioner. The authors investigated the utility of attenuated starting doses -- 80% of standard -- as well as novel outcome measures including the evaluation of quality of life and a composite measure of overall treatment utility (OTU). OTU attempts to capture patient and physicians satisfaction with the outcome of any treatment decision.
The authors asked two primary questions: (1) does the addition of oxaliplatin in this patient population improve progression-free survival; and (2) does the substitution of capecitabine for fluorouracil improve quality of life? Patients were randomized to 5-fluorouracil (5FU) alone, capecitabine, 5FU and oxaliplatin in combination, or oxaliplatin and capecitabine in combination. The results suggested a number of interesting findings. First, there is a trend towards benefit with use of oxaliplatin although the primary outcome was not statistically significant (p=0.07). No significant increase in grade 3 toxicity was appreciated with use of oxaliplatin. Alternatively, while capecitabine was equivalent in efficacy to 5FU, there was no benefit in quality of life measured by the EORTC-QLQ-C30 questionnaire. However, there was a significant increase in toxicity associated with capecitabine vs. 5FU. Clinically, this calls into question the often held belief that capecitabine is a better alternative for older adults from the standpoint of quality of life. In addition, this study supports considering use of an oxaliplatin combination with a 20% dose reduction for older adults considered frail.
The authors note that the study accrued patients well ahead of schedule, suggesting that this was a very well-received protocol by both practitioners and patients and serves as a successful example of creative trial design asking relevant questions of an understudied population. It should be noted that the definition of frailty and 'unfit for standard chemotherapy' was not rigorously defined, which has been a consistent challenge in designing elderly-specific trials and extrapolating data to clinical practice. In addition, this study did exclude patients with an ECOG performance status greater than 2, suggesting that truly frail patients were not enrolled and these data do not necessarily apply to that population. Trial registration: ISRCTN21221452
This study used a 2x2 factorial design to randomize 459 'frail' older adults with metastatic colorectal cancer to one of four first-line systemic therapies. The authors were interested in investigating optimal treatment approaches for patients considered unfit for standard full-dose chemotherapy by their practitioner. The authors investigated the utility of attenuated starting doses -- 80% of standard -- as well as novel outcome measures including the evaluation of quality of life and a composite measure of overall treatment utility (OTU). OTU attempts to capture patient and physicians satisfaction with the outcome of any treatment decision.
The authors asked two primary questions: (1) does the addition of oxaliplatin in this patient population improve progression-free survival; and (2) does the substitution of capecitabine for fluorouracil improve quality of life? Patients were randomized to 5-fluorouracil (5FU) alone, capecitabine, 5FU and oxaliplatin in combination, or oxaliplatin and capecitabine in combination. The results suggested a number of interesting findings. First, there is a trend towards benefit with use of oxaliplatin although the primary outcome was not statistically significant (p=0.07). No significant increase in grade 3 toxicity was appreciated with use of oxaliplatin. Alternatively, while capecitabine was equivalent in efficacy to 5FU, there was no benefit in quality of life measured by the EORTC-QLQ-C30 questionnaire. However, there was a significant increase in toxicity associated with capecitabine vs. 5FU. Clinically, this calls into question the often held belief that capecitabine is a better alternative for older adults from the standpoint of quality of life. In addition, this study supports considering use of an oxaliplatin combination with a 20% dose reduction for older adults considered frail.
The authors note that the study accrued patients well ahead of schedule, suggesting that this was a very well-received protocol by both practitioners and patients and serves as a successful example of creative trial design asking relevant questions of an understudied population. It should be noted that the definition of frailty and 'unfit for standard chemotherapy' was not rigorously defined, which has been a consistent challenge in designing elderly-specific trials and extrapolating data to clinical practice. In addition, this study did exclude patients with an ECOG performance status greater than 2, suggesting that truly frail patients were not enrolled and these data do not necessarily apply to that population. Trial registration: ISRCTN21221452
Disclosures
None declared
Klepin H: F1000Prime Recommendation of [Seymour MT et al., Lancet 2011, 377(9779):1749-59]. In F1000Prime, 09 Aug 2011; DOI: 10.3410/f.12444961.13680055. F1000Prime.com/12444961#eval13680055
F1000Prime Recommendations, Dissents and Comments for [Seymour MT et al., Lancet 2011, 377(9779):1749-59]. In F1000Prime, 20 May 2013; F1000Prime.com/12444961
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BACKGROUND: Elderly and frail patients with cancer, although often treated with chemotherapy, are under-represented in clinical trials. We designed FOCUS2 to investigate reduced-dose chemotherapy options and to seek objective predictors of outcome in frail patients with advanced colorectal cancer.
METHODS: We undertook an open, 2 × 2 factorial trial in 61 UK centres for patients with previously untreated advanced colorectal cancer who were considered unfit for full-dose chemotherapy. After comprehensive health assessment (CHA), patients were randomly assigned by minimisation to: 48-h intravenous fluorouracil with levofolinate (group A); oxaliplatin and fluorouracil (group B); capecitabine (group C); or oxaliplatin and capecitabine (group D). Treatment allocation was not masked. Starting doses were 80% of standard doses, with discretionary escalation to full dose after 6 weeks. The two primary outcome measures were: addition of oxaliplatin ([A vs B] + [C vs D]), assessed with progression-free survival (PFS); and substitution of fluorouracil with capecitabine ([A vs C] + [B vs D]), assessed by change from baseline to 12 weeks in global quality of life (QoL). Analysis was by intention to treat. Baseline clinical and CHA data were modelled against outcomes with a novel composite measure, overall treatment utility (OTU). This study is registered, number ISRCTN21221452.
FINDINGS: 459 patients were randomly assigned (115 to each of groups A-C, 114 to group D). Factorial comparison of addition of oxaliplatin versus no addition suggested some improvement in PFS, but the finding was not significant (median 5·8 months [IQR 3·3-7·5] vs 4·5 months [2·8-6·4]; hazard ratio 0·84, 95% CI 0·69-1·01, p=0·07). Replacement of fluorouracil with capecitabine did not improve global QoL: 69 of 124 (56%) patients receiving fluorouracil reported improvement in global QoL compared with 69 of 123 (56%) receiving capecitabine. The risk of having any grade 3 or worse toxic effect was not significantly increased with oxaliplatin (83/219 [38%] vs 70/221 [32%]; p=0·17), but was higher with capecitabine than with fluorouracil (88/222 [40%] vs 65/218 [30%]; p=0·03). In multivariable analysis, fewer baseline symptoms (odds ratio 1·32, 95% CI 1·14-1·52), less widespread disease (1·51, 1·05-2·19), and use of oxaliplatin (0·57, 0·39-0·82) were predictive of better OTU.
INTERPRETATION: FOCUS2 shows that with an appropriate design, including reduced starting doses of chemotherapy, frail and elderly patients can participate in a randomised controlled trial. On balance, a combination including oxaliplatin was preferable to single-agent fluoropyrimidines, although the primary endpoint of PFS was not met. Capecitabine did not improve QoL compared with fluorouracil. Comprehensive baseline assessment holds promise as an objective predictor of treatment benefit.
FUNDING: Cancer Research UK and the Medical Research Council.
Copyright © 2011 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S0140-6736(11)60399-1
PMID: 21570111
