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Lessons learned from the maturation of a cancer drug: oxaliplatin in colorectal cancer

The addition of oxaliplatin to a fluoropyrimidine is reference treatment after colon cancer surgery in patients with stage III and in stage II if at least one high-risk criterium for recurrence is present [1–3]. Even if guidelines open for using a fluoropyrimidine alone, there is a tendency to add oxaliplatin whenever adjuvant chemotherapy is indicated, at least in stage III. Three randomized trials comparing adjuvant therapy for six months using a fluoropyrimidine with or without oxaliplatin showed that the combination improved disease-free survival (DFS) by approximately 20% (hazard ratios, HRs 0.80–0.82) [4–6]. Overall survival was also slightly improved (HRs 0.84–0.88). An average risk of recurrence of 30% after fluoropyrimidine treatment alone, typical for many stage III patients, means that six additional patients per 100 treated will not experience any recurrence if oxaliplatin was added. If the recurrence risk is higher, more treated patients are gained, but for many stage III patients, including most patients with stage II and high-risk criteria, the recurrence risk is less, and the gain from adding oxaliplatin is only a few percent. All treated patients are at risk of toxicity, including the oxaliplatin-induced chronic and often disabling neurotoxicity. The oxaliplatin-induced peripheral neuropathy (OIPN) was considered along with the gains in recurrence risk and survival when different scientific and clinical organizations such as ASCO and NCCN in the US and ESMO in Europe and national groups recommended an oxaliplatin combination for all stage III colon cancers and for stage II cancers with high-risk factors. The extent of the adverse effects, i.e. the downside of adding oxaliplatin was known from the clinical trials where the treating physicians graded the neurotoxicity according to one of a few recommended scales. Typically, acute peripheral neurotoxicity of grade 2 or higher was recorded in 30-50% of the patients and although chronic OIPN was seen, it was not considered extensive [4–6]. In the MOSAIC trial, grade 2 and 3 chronic neuropathy were seen in 4.8 and 1.3%, respectively, after 12 months and in 3.4 and 0.7%, respectively, after 4 years [4].