Adjuvant colon cancer chemotherapy: Is there an Indian standard of care?

Colorectal cancer is one of the leading causes of cancer mortality world-wide. Patients have a 40-50% chance of disease relapse after complete surgical resection.[1]

Multiple clinical trials have established that adjuvant 5-fluorouracil (5-FU)-based chemotherapy is standard of care for Stage III disease. A relative risk reduction in mortality of 30-35% in favor of chemotherapy versus surgery alone translates into 10% absolute survival improvement at 5 years.[2345678]

The benefit for patients with a node negative (Stage II) disease is less clear. Two meta-analyses found no definitive benefit of chemotherapy in Stage II patients;[910] However, the QUASAR study showed a statistical improvement in the risk of recurrence (22.2% vs. 26.2%) and survival (80.3% vs. 77.4%) with adjuvant therapy.[11] A post-hoc subgroup analysis of patients with Stage II disease in the MOSAIC study showed an improvement trend in 3-year disease free survival (DFS) in the high-risk subgroup (T4 disease, perforation, obstruction, <10 nodes examined, poorly differentiated histology or extramural vascular invasion) of patients; 84.9% with FOLFOX and 79.8% with 5-FU-leucovorin (LV) (hazard ratio 0.72, confidence interval 0.48-1.08).[12] This evidence suggests a small survival benefit for adjuvant therapy in selected cases of Stage II disease. The MOSAIC data may translate into an absolute gain of about 8% with oxaliplatin-based regimens when compared to no treatment, particularly in patients with high-risk features.

The X-ACT study compared capecitabine and iv 5-FU/LV Mayo clinic regimen in patients with resected Stage III disease, and showed a trend towards superiority of capecitabine in both DFS (HR 0.87, CI 0.75-1.0) and overall survival (HR 0.84, CI 0.69-1.01).[13]

Oxaliplatin, irinotecan, and biological agents have shown benefit in the metastatic setting and were thus studied in the adjuvant setting. The MOSAIC trial showed an increase in 3-year DFS in the oxaliplatin/LV5FU2 combination arm (78.2% vs. 72.9%) compared with LV5FU2 alone.[12] Neutropenia, diarrhea, vomiting, and peripheral neuropathy were more common in the oxaliplatin/LV5FU2 arm; however, the rate of febrile neutropenia was 1.8% and rate of death during the treatment was similar in both groups at 0.5%. The NSABP C-07 study using the FLOX regimen versus 5-FU/LV showed a 3-year DFS of 76.5% and 71.6% respectively, with a HR of 0.79 (95% CI 0.67-0.93) in favor of FLOX.[14] The CALGB 89803 and PETACC 3 studies using irinotecan in combination with 5-FU failed to show a benefit for irinotecan in the adjuvant setting.[1516] The NSABP-C08 and AVANT trials did not show any benefit of adding bevacizumab to adjuvant FOLFOX/CAPOX. These studies have established oxaliplatin/5FU as the standard of care for Stage III disease.

The newer treatment regimens are subject to discussion with regard to toxicity and costs. The intergroup trial N9741 found that 62% of patients withdrew from treatment with FOLFOX for reasons other than disease progression (23% due to myelosuppression and 23% due to neurotoxicity.[17]

The estimated cost of 8 weeks of treatment for metastatic disease with the Mayo clinic regime of 5-FU is US$ 63, with FOLFOX is US$ 11,889 and for FOLFOX plus bevacizumab is US$ 21,033.[18] These costs are only for medications and not the cost of administration, supportive medications or treating complications. The MOSAIC trial extrapolated within-trial data to estimate a benefit in overall life expectancy. This was estimated to be 1.17 years benefit in the oxaliplatin/LV5FU2 arm compared with LV5FU2 alone. The cost per life year gained was estimated to be US$ 27,300.[19]

Ahmad, et al. should be appreciated for doing a study to look at the Indian scenario with regard to bowel cancer. Bowel cancer does not seem to be the biggest cancer issue for doctors in India; however, the landscape is changing and this would be a major problem soon. It is important to do more studies to highlight local issues with regard to finances, ease of transportation for patients and toxicities involved.

The patient numbers in this study (Stages 2 and 3) are too small to make any definitive recommendations or suggest a change in practice guidelines. The authors must collaborate with other cancer centers across the state/country and generate more data, which could be subjected to pre-defined rigorous statistical analysis. The massive numbers of patients in the Indian scenario are not truly reflected in the number and quality of research papers presented or published across the world.

It should be standard practice to discuss the option of chemotherapy with patients, whilst outlining the potential toxicities. Analysis of the cost-effectiveness of treatments also including financial and physical costs of toxicities is becoming increasingly important and strategies to optimize the same are vital.

We need to balance efficacy of treatment, costs involved with the short- and long-terms toxicities to create a truly Indian standard of care for adjuvant colon cancer.