The Role of Second-Line Chemotherapy in Colorectal Cancer

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Abstract
Only a few years ago it was still a debate, whether patients with advanced colorectal cancer should be treated by a palliative chemotherapy at all. After the demonstration of a palliative benefit of these patients in terms of prolongation of time to progression, survival and improvement of quality of life by first-line chemotherapy, now also several second-line chemotherapy options are available. However, due to the nature of early phase II studies and in the absence of prospective randomized trials comparing the different available salvage treatment options, a clear definition of the optimal salvage treatment strategy and sequence is very difficult. The evaluation of currently available data of controlled clinical trials allows at least a suggestion what should be done in case of progression under or after a bolus 5-FU/Folinic Acid (FA) protocol. The following recommendations should help to define the suitable protocol for every patient although it should be mandatory to treat patients within ongoing comparative clinical trials: In case of progression after a treatment-free intervall of 3 months from the end of the first-line (or prior) 5FU +/- FA-based chemotherapy and prior response (partial response or minor response), the patient should be retreated with the same regimen. -In case of progression under retreatment or shortly after a first-line 5-FU/FA treatment, the further treatment options depend on the prior treatment: in case of 5-FU given as a bolus or short infusion while prior treatment the salvage protocol should use any type of protracted 5-FU-infusion +/- FA, e.g., 5-FU daily continuously until progression or weekly 24-hours infusion of 5-FU/FA. An alternative is CPT-11 (Irinotecan) as single agent, which is more easy to apply but more toxic (particularly bone marrow toxicity, diarrhea and alopecia) -in case of pretreatment with 5-FU given as prolonged high-dose infusion, one could proceed with the same infusional 5-FU regimen including the addition of Oxaliplatin; this protocol could be given weekly or biweekly (FOLFOX-2 protocol) or for 5 days with chronomodulation of 5-FU every 3 weeks. The alternative would be CPT-11 as single agent every 3 weeks; this protocol avoids the neurotoxicity which appears after higher cumulative dose of Oxaliplatin, but is associated with bone marrow toxicity, diarrhea and alopecia. In case of progression after infusional high-dose 5-FU/FA plus Oxaliplatin and no prior exposure to CPT-11, this agent is the last available option; however, it is not clear whether CPT-11 has relevant efficacy in patients refractory to infusional 5-FU plus Oxaliplatin.If the bulk of the disease is located in the liver, besides all the above mentioned options one should always consider locoregional treatment via hepatic artery (by femoral catheterization).

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