In what order should chemotherapies be delivered?

This review discussed the use of second-line chemotherapy (therapy after disease progression despite initial treatment) in colorectal cancer.

Patients with advanced (spread to lymph nodes and beyond) colorectal cancer often require a second round of chemotherapy following their first treatments. The use of multiple chemotherapy agents has been associated with increased overall survival (time from treatment until death from any cause). Newer treatments that directly target the underlying causes of colorectal cancer (such as genetic abnormalities) have also increased treatment options.

For the most part, the choice of a second-line treatment is determined by which drugs were used as first-line treatment. However, the optimal sequence of treatments is not clear. Following first-line treatment, there is a question as to whether single therapies given one after the other are more effective than a combination of agents.

Many patients are given a single chemotherapy agent as a first-line treatment, often 5-fluorouracil (5-FU, Efudex). Second-line agents often include irinotecan (Camptosar) and oxaliplatin (Eloxatin), alone or in combination with other therapies. Irinotecan was found to increase overall survival, with one study showing a 36.1% 1-year survival rate. This in comparison to 13.8% in patients not treated with irinotecan. Oxaliplatin, however, was more effective when used as part of a combination (with 5–FU and leucovorin, known as FOLFOX4). Oxaliplatin treatment alone had a 0% response rate.

Because combination therapy can lead to more serious side effects, the use of sequential single agents has been examined. Single agents used one after the other have been found to lead to similar response rates as combination therapy.

Treatments that block the epidermal growth factor receptor (EGFR), such as cetuximab, improve progression-free survival time (time from treatment until disease progression). One study compared a combination of cetuximab and irinotecan to irinotecan alone. There was a significant increase in progression-free survival with the combination (4 months) compared to irinotecan alone (2.6 months). The addition of panitumumab (Vectibix) to FOLFIRI (5-FU, leucovorin, and irinotecan) also improved progression-free survival (5.9 months) compared to FOLFIRI alone (3.9 months).

Bevacizumab (Avastin) blocks the creation of new blood vessels needed for tumor growth. It significantly improved overall survival when used in combination with FOLFOX4 (12.9 months) compared to FOLFOX4 alone (10.8 months). Progression-free survival was also improved. Bevacizumab was associated with an increase in negative side effects, including high blood pressure, vomiting, and nerve damage. Bevacizumab can be used as both a first and second-line treatment. Survival rates were 52% higher in patients who continued bevacizumab following disease progression.

The review concluded that the optimal second-line treatment depends on the patient and which agents they received as first-line treatments. This study also suggested that each patient should have a planned sequence of treatments prior to the start of any therapy.