What’s New in Maintenance, Second- and Third-Line Therapy in Colorectal Cancer Treatment

In this session, titled “What’s New in Maintenance, Second- and Third-line Therapy in Colorectal Cancer Treatment,” Aimery de Gramont, MD, PhD, of the Hôpital Saint-Antoine, Paris, France, provided an historical perspective on treating patients with metastatic colorectal cancer and the use of maintenance therapy before focusing his discussion on current recommendations and options for second- and third-line therapies.

Dr. de Gramont began by reviewing all first-line trials from 2010 to 2012, including those with irinotecan, oxaliplatin, a tyrosine kinase inhibitor (TKI), cetuximab, and panitumumab. All of the agents demonstrated a median progression-free survival (PFS) time of approximately 8 to 10 months with a total difference of 2.8 months; however, for overall survival (OS), the difference was 8.4 months.  This difference demonstrates the importance of second- and third-line agents in improving OS in these patients.

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Regarding the some of the options available for maintenance therapy, the OPTIMOX1 trial1 from 2006 showed a benefit of a biweekly regimen of leucovorin and 5-fluorouracil (LV/5FU2) as maintenance therapy and reintroduction of FOLFOX (LV and 5FU with oxaliplatin).  Maintenance therapy with 5FU was superior to completely stopping therapy as demonstrated in the OPTIMOX22 (2009) and COIN3 (2011) trials.  However, the trials found some subgroups of patients can stop maintenance chemotherapy after 3 months, for example, those with a normal carcinoembryonic antigen level (OPTIMOX 1) or a normal platelet count (COIN Trial).

The question of maintenance chemotherapy with bevacizumab alone or cetuximab alone was evaluated in the MACRO4 (2012) and NORDIC5 (2012) trials. These agents may be more active than completely stopping therapy, but less active than continuing standard chemotherapy.

Additional in-depth discussion was provided on the 2012 DREAM6 trial.  In this trial, patients received either FOLFOX7, capecitabine, or FOLFIRI, and then if complete response/partial response or stable disease were achieved, were randomly assigned to bevacizumab alone or bevacizumab plus erlotinib.  This study demonstrated a median PFS of 4.57 months versus 5.75 months (hazard ratio, 0.73; median OS not available).   Surprisingly, there was no change in results based on KRAS status.  Ongoing trials for maintenance therapy include CAIRO3, AIO KRK0207, and MARTHA SICOG; results for these trials should be available within the next few years.

For second-line therapy, current standard recommendations include switching regimens, for example, from FOLFOX to FOLFIRI or FOLFIRI to FOLFOX, or considering combination therapies such as FOLFOX plus bevacizumab, irinotecan plus cetuximab, or FOLFIRI plus panitumumab.  Aflibercept is a newer option based on the 2012 VELOUR7 trial, where patients who progressed on an oxaliplatin-based, first-line chemotherapy were randomly assigned to receive aflibercept plus FOLFIRI or placebo plus FOLFIRI.  Results of the this trial demonstrated a median OS of 13.5 months compared with 12.1 months, respectively (HR, 0.82),  and a median PFS of 6.9 months compared with  4.7 months, respectively (HR, 0.76).  Aflibercept improved the overall response rate and decreased the progressive disease rate.  There was no difference in response, PFS, or OS in patients who previously received bevacizumab.  Aflibercept did have increased gastrointestinal toxicity, particularly diarrhea and increased stomatitis.  Aflibercept has not been evaluated as a second-line therapy in conjunction with an oxaliplatin-based regimen.