The Role of Chemotherapy and Biologic Therapy in the Treatment of Metastatic Colorectal Cancer
Colorectal cancer (CRC) is the third most common cancer diagnosed in men and women in the US, with an estimated annual incidence of almost 150,000 new cases. In terms of cancer-related deaths in the US, it ranks second (after lung cancer), with about 60,000 deaths yearly. Worldwide, the incidence and mortality are 800,000 and 500,000 respectively.
For initial treatment of metastatic CRC (mCRC) patients (pts), Dr. Chu stated that FOLFOX chemotherapy has become the regimen of choice in the U.S. FOLFOX is a combination of intravenous (IV) 5-FU and oxaliplatin. This regimen was designed based on the fact that oxaliplatin resulted in improved response rates (RR), time-to-progression (TTP), and overall survival (OS) when added to standard 5-FU-based treatment, and when compared to 5-FU alone. The use of oral 5-FU (capecitabine, brand name Xeloda) instead of standard IV 5-FU is increasingly accepted in clinical practice. This is based on the X-ACT trial (Cassidy et al., JCO 2004), which found a statistical trend towards better survival and a superior safetly profile with oral 5-FU compared to IV 5-FU. Taking this one step further, phase II and III trials have shown that the combination of Xeloda and oxaliplatin (Xelox) is clinically equivalent to the current first-line standard of FOLFOX.
The most exciting recent developments in mCRC have revolved around bevacizumab (brand name Avastin), a recombinant humanized monoclonal antibody to vascular endothelial growth factor (VEGF). VEGF seems to play an important role in tumor angiogenesis, and thus blocking this activity should have an anti-tumor effect. A survival benefit was seen when bevacizumab was added to FOLFOX in the second-line setting (Giantonio, et al.) In light of this, many would advocate the use of FOLFOX and Avastin as the standard of care for first-line treatment of mCRC.
One question, then, asked Dr. Chu, is whether Avastin can also be used safely and effectively with Xelox-based regimens? To help answer this question, he discussed results of a phase II trial presented at the 2005 ASCO meeting (Fernando, et al) looking at a regimen called Xelox-A (Xeloda, oxaliplatin, and Avastin), given every 2 weeks to 30 pts with untreated mCRC. Preliminary data demonstrate RR of 57% and TTP of 11.9 months, indicating that Xelox-A appears to be highly active with an impressive delay in disease progression, one of the longest reported to date for this disease. Furthermore, the combination appears to be well tolerated to date (at a Xeloda dose of 850 mg po twice daily). Enrollment in this study is ongoing, with a planned total accrual of 50 pts.
Yet another important study question is whether Xelox-A is more effective when given every 2 weeks or every 3 weeks? This is being studied in protocol ML18491, a randomized phase II trial that opened July 2005 and is currently recruiting pts.
The presenter mentioned an ongoing phase III trial that will compare Xelox +/- Avastin vs. FOLFOX4 +/- Avastin.
Dr. Chu then discussed the issue of epidermal growth factor receptor (EGFR) inhibition in mCRC, and whether the EGFR antibody cetuximab could be used with FOLFOX-based regimens? The ACROBAT study is looking at FOLFOX4 and cetuximab; preliminary data presented at ASCO 2005 (Diaz-Rubio) indicate an overall RR of 74%, a TTP of 12.3 months, and an acceptable toxicity profile. Compared to historical RR of 45-50% with FOLFOX4 alone, this is a promising gain.
Finally, Dr. Chu mentioned the ongoing CALGB/SWOG Intergroup trial investigating pts who have been treated with FOLFOX (and a much smaller percentage treated with FOLFIRI, which replaces oxaliplatin with irinotecan) and randomizing them to cetuximab, Avastin, or both (this third arm is based on the Bond-2 trial, Saltz, et al.).
In summary, Dr. Chu suggested a "pyramid" of therapeutic options: the base includes either Xeloda or infusional 5-FU, with the next layer adding oxaliplatin or irinotecan (eg: FOLFOX or FOLFIRI), followed by antibody targeted therapies (anti-VEGF or anti-EGFR agents like Avastin or cetuximab), and finally small molecule targeted agents such as erlotinib, gefitinib, PTK787.