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Patients with stage II colon cancer make up 26% of all patients with newly diagnosed colon cancer, and determining which ones need adjuvant chemotherapy to avert a relapse remains challenging, reported Al B. Benson III, MD, of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
“What constitutes a high-risk stage II patient?” he asked. “The short answer is, we don’t know.” Although much work has gone into identifying prognostic factors in this population, he noted, their presence is not associated with treatment outcome. “In other words, just because someone’s high risk doesn’t mean that that individual has a better chance to respond to chemotherapy,” he explained.
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| Dr. Benson |
Several clinical trials and some practice-based studies have helped to clarify the impact of adjuvant chemotherapy for patients with stage II colon cancer overall and in certain subgroups, according to Dr. Benson. The Intergroup 0089 trial compared different types of 5-fluorouracil (5-FU)–based adjuvant chemotherapy for high-risk patients with stage II and III colon cancer (T4 disease with obstruction or perforation) (Haller DG et al. J Clin Oncol 2005;23:8671–8678). Treatment regimens in the four arms of the trial were 5-FU + low-dose leucovorin (LV); 5-FU + levamisole + low-dose LV; 5-FU + high-dose LV; and 5-FU + levamisole. There was no statistical difference in the 5- or 10-year survival rates in the four treatment arms. The 5-year rate of overall survival in patients with high-risk stage II disease was about 75% to 80%—similar to that typically observed in the overall population of patients with stage II disease.
The IMPACT investigators also looked at the issue of adjuvant chemotherapy, performing a meta-analysis of trials randomizing patients with stage II or III colon cancer to receive surgery alone or with adjuvant 5-FU/LV (IMPACT investigators. Lancet 1995;345:939–944). “The benefit of adjuvant therapy was pretty much exclusively seen in the stage III patients,” Dr. Benson said.
Using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database, an analysis of outcomes associated with adjuvant chemotherapy in patients with stage II colon cancer in routine clinical practice was performed (Schrag D et al. J Clin Oncol 2002;20:3999–4005), according to Dr. Benson. This analysis found that a substantial proportion (27%) of patients with usual-risk stage II disease (T3N0 with no obstruction or perforation) received chemotherapy, but the 5-year rate of survival did not differ from that of their counterparts not given chemotherapy (78% vs 75%). The SEER-Medicare results mirrored the IMPACT results for stage II disease, indicating “that the real-world experience is fairly comparable to the clinical trial experience for this population of patients,” remarked Dr. Benson.
In terms of risk factors, Dr. Benson said, further analysis of patients with stage II disease in the SEER cohort indicated that survival was poorer for those who were older, male, and black as well as those who had more comorbidities and more urgent hospital admission; it was unaffected by adjuvant chemotherapy as well as factors such as tumor grade and socioeconomic status.
In the Intergroup 0089 trial, a multivariate analysis
conducted among the patients with high-risk stage II disease showed that the
number of lymph nodes removed significantly predicted survival, with an 8-year
rate of 79% among patients who had more than 20 nodes removed but only 59%
among those who had 10 or fewer nodes removed (Le Voyer TE et al. J Clin
-Oncol 2003;21:2912–2919). “What was striking here was the vast majority of
patients in this trial had 10 or fewer lymph nodes sampled,” he remarked.
Turning to newer regimens, Dr. Benson discussed preliminary results from the MOSAIC trial, which compared adjuvant FOLFOX4 (5-FU, LV, oxaliplatin [Eloxatin]) with a 5-FU/LV regimen (LV5FU2). Data from this trial suggest at least a disease-free survival benefit favoring FOLFOX4 in patients with stage II and III overall (de Gramont A et al. J Clin Oncol 2005;23[suppl]:246s). However, in stratified analyses, the benefit appears to be restricted to patients with stage III disease, Dr. Benson said. The data do suggest, however, that among the stage III group, disease-free survival benefit from FOLFOX4 is greater for those with N2 disease than for those with N1 disease. “The MOSAIC trial gives us a hint that maybe high-risk patients may get more benefit from combination therapy,” he observed.
“Many of us believe the old paradigm of design for clinical trials is one we need to move away from,” Dr. Benson asserted. A new approach, and one that has been advocated by the Food and Drug Administration, is a trial design that considers tumor and patient biomarkers when selecting a treatment that is most likely to benefit a specific patient. The largest trials of this kind to date have been retrospective, he noted. “The cooperative groups have this excellent database of patient characteristics, so it becomes possible to match biological factors with patient outcome.”
Giving an example, Dr. Benson discussed a retrospective study of the use of molecular markers to identify risk groups among patients given adjuvant chemotherapy for colon cancer (Watanabe M et al. N Engl J Med 2001;344:1196–1206). Results indicated that among patients with stage III disease, survival was poorer for those who had loss of heterozygosity of chromosome 18 (18q LOH) than for those who did not; furthermore, among patients with microsatellite instability, survival was poorer for those without the transforming growth factor-b1 RII mutation than for those with this mutation. “Based on this analysis, it was possible to define a high-risk and a low-risk group,” Dr. Benson observed.
Taking this approach one step further, the Intergroup designed trial ECOG 5202, which Dr. Benson described as the first of its kind, as well as the largest trial of stage II colon cancer in the United States and Canada. “This trial is now active, and we certainly encourage you all to consider this trial for your patients,” he said. In the trial, patients’ resected tumors are analyzed in real time for molecular markers, with the aim of identifying low- and high-risk groups. Patients at low risk are assigned to observation only, whereas patients at high risk are randomized to differing chemotherapy regimens.
Lending support for the ECOG 5202 trial design are the results of a recent systematic analysis of 37 randomized controlled trials undertaken by the American Society of Clinical Oncology (ASCO) and the Cancer Care Ontario Practice Guideline Initiative to address the uncertainty surrounding adjuvant chemotherapy for patients with stage II colon cancer (Benson AB III et al. J Clin Oncol 2004;22:3408–3419). A meta-analysis of 12 of the trials that had critical design elements was also performed. The results of this analysis recapitulated the findings of individual trials, showing no significant survival benefit of adjuvant chemotherapy in this group as a whole.
“Because of this, ASCO has strongly recommended that for individual patients, the physician and the patient need to cover important points of discussion,” Dr. Benson said, including whether the benefits of adjuvant chemotherapy outweigh the risks.