Maintenance therapy with biologics

As treatments for metastatic colorectal cancer patients have improved, the average survival time has moved from approximately 12 months to as long as 36 months. For patients with unresectable disease in particular, these extended survival times also mean longer and more treatment with chemotherapies that carry their own set of toxicities. Many times within physician practice and at patient request modification of treatment regimens (maintenance therapy) or complete drug holiday is done, particularly within the first line setting. The OPTIMOX 1 and 2 studies formally assessed maintenance regimens and drug holidays with respect to effect on survival as well as toxicity. The OPTIMOX 1 study randomized 620 patients to continuous treatment with FOLFOX4 or treatment with FOLFOX7 and then maintenance therapy after 3 months of sLV5FU2. This trial showed no significant difference in PFS or OS between the two arms, and a decrease in grade 3/4 toxicity in the maintenance arm. This study lead to the OPTIMOX 2 study, where 202 patients were randomized to 3 months of mFOXFOX7 followed by maintenance sLV5FU2 versus 3 months of mFOLFOX7 followed by complete chemotherapy holiday. This study showed a nonsignificant trend towards decreased overall survival in the complete chemotherapy free interval group compared to those who had maintenance therapy (19 vs. 26 months). Based on these results it (Table presented) was determined that complete chemotherapy holidays are not preferred. As OPTIMOX 2 was ongoing, bevacizumab was approved for the treatment of metastatic colorectal cancer. Bevacizumab has since become a standard of care in most patients with first line metastatic colorectal cancer. The mechanism of action of bevacizumab, being an angiogenesis inhibitor which can decrease tumor blood vessel growth and blood flow, as well as have potential other antitumor effects such as decrease of tumor‐associated immunosuppression, makes it an attractive possible maintenance therapy agent. Bevacizumab also has less chemotherapy‐like toxicities and may be more tolerable as a long term treatment. Two studies have examined bevacizumab as a maintenance agent. The first was the MACRO trial, which randomized patients to 18 weeks of CapOx plus bevacizumab followed by either continued CapOx plus bevacizumab or bevacizumab alone. The primary endpoint of this trial was PFS, and between the two arms there was no significant difference in PFS. However, the confidence interval around the hazard ratio was large, making many feel uncomfortable saying there was no absolute non‐inferiority of the bevacizumab only maintenance arm. The next was the recently reported OPTIMOX 3/DREAM trial, which randomized patients to 3 months of first‐line chemotherapy plus bevacizumab followed by either maintenance single agent bevacizumab or bevacizumab plus erlotinib. This this did not have a continuation of chemotherapy arm. The PFS results of this trial suggested a benefit to those who received erlotinib, and the duration of PFS in both arms was along the historical PFS data for patients who continue on chemotherapy. Given the long‐term treatment of patients with first‐line metastatic colorectal cancer, the possibility of maintenance therapies is attractive to decrease side effects and improve quality of life. However, the best definitive data that exists is from the OPTIMOX 1 study, where a less intensive chemotherapy regimen may be used. The remaining data on maintenance therapies requires interpretation and assumption, but suggests that complete chemotherapy holidays are not beneficial and are possibly detrimental to patients. In addition, the role of maintenance biologic agents is not completely clear, though the PFS from single agent maintenance trials approximates that seen in continued chemotherapy trials. In practice there is continuation of biologic agents into the maintenance setting, either in combination with less intensive chemotherapy of alone. Until better data is available, the use of biologics in maintenance therapy remains the decision of the treating physician and patient.