Combination versus sequential chemotherapy for advanced colorectal cancer

Now that there are several effective drugs to treat advanced colon and rectal cancer,  is it better to give several at once in combination or one after the other in sequence? 

The current issue of The Lancet has reports of two large randomized trials to compare overall survival and serious side effects of sequences of chemotherapy versus combination strategies.  The CAIRO  trial tested strategies with oral capecitabine (Xeloda®), irinotecan (Camptosar®),and oxaliplatin (Eloxatin®).  The FOCUS trial studied continuous infusion 5FU (fluorouracil), irinotecan, and oxaliplatin.

Neither trial included biologic agents bevacizumab (Avastin®), cetuximab (Erbitux®), or panitumumab (Vectibix®) which have become part of standard treatment for metastatic colorectal cancer.

A comment  in The Lancet considers whether or not this new information should prompt a change in standard chemotherapy regimens in the United States and Europe.

In the Netherlands CAIRO trial, 820 patient who had not been previously treated for metastatic colorectal cancer were randomized to receive either:

• Sequential strategy:  (First) single drug capecitabine, (Second) single drug irinotecan, (Third) combination of oxaliplatin and capecitabine (CAPOX).
• Combination strategy:  (First)combination of capecitabine and irinotecan (CAPIRI) followed by (Second) combination of capecitabine and oxaliplatin (CAPOX).

In both strategies, patients remained on each regimen until their cancer progressed and then moved to the next line of treatment.

There was no significant difference in overall survival in the CAIRO trial between the two groups.  Median overall survival for the sequential strategy was 16.3 months; for the combination strategy 17.4 months.  There was more serious hand-foot syndrome in the sequential arm (13 percent versus 7 percent for the combination arm.)

The FOCUS trial, conducted in the United Kingdom, used continuous infusion 5FU rather than oral capecitabine.  2135 patients were randomized to one of three strategies:

• A:  Continuous infusion 5FU with leucovorin followed by single agent irinotecan.
• B:  Continuous infusion 5FU followed by either 5FU plus irinotecan (FOLFIRI) or 5FU plus oxaliplatin (FOLFOX)
• C: Either FOLFIRI or FOLFOX from the beginning of treatment.

Median survival for the A strategy that used two single drugs was 13.9 months,  not as good as either B or C.  For B, median survival was 15.0 months for FOLFIRI and 15.2 months for FOLFOX.

When combinations were given from the beginning, median survival for the FOLFIRI group was 16.7 months compared to 15.4 months for FOLFOX.  Statistically, using the combination FOLFIRI strategy for first-line treatment was superior to other treatment approaches.

Writing for the CAIRO trial, lead author Miriam Koopman MD, concluded,

Our results show that, for patients with advanced colorectal cancer, combination treatment with all effective cytotoxic drugs was no better than their sequential use. Progression-free survival over all subsequent treatment lines was not significantly different between the study groups. Additionally, sequential treatment was associated with less toxicity during first-line treatment than was combination therapy.

For the FOCUS trial, Matthew T. Seymour MD and his colleagues wrote,

Our data challenge the assumption that, in this non-curative setting, maximum tolerable treatment must necessarily be used first-line. The staged approach of initial single-agent treatment upgraded to combination when required is not worse than first-line combination, and is an alternative option for discussion with patients.

Comments from Hans-Joachim Schmoll and Daniel Sargent on the meaning of these two trials and their impact on patient decision-making will be discussed in a subsequent C3 News and Events post.

SOURCE 

For CAIRO trial:  Koopman et. al.The Lancet, Volume 370, Number 9582, July 14, 2007.

For FOCUS trial:  Seymour et. al. The Lancet, Volume 370, Number 9582, July 14, 2007