Future directions in neoadjuvant therapy of rectal cancer: Maximizing pathological complete response rates

Geisinger Cancer Institute, 1000 E. Mountain Blvd., Wilkes Barre, PA 18711, USA.
Cancer Treatment Reviews (Impact Factor: 7.59). 07/2009; 35(7):547-52. DOI: 10.1016/j.ctrv.2009.05.002
Source: PubMed


Neoadjuvant therapy is widely accepted as the current standard of care for localized rectal cancer. Downstaging of disease has been significantly improved and pathological complete response rates (pCR) which were historically below 10% with preoperative radiation alone, now range from 15% to 30% with preoperative chemo-radiation. While the availability of new chemotherapeutic drugs (Irinotecan, Oxaliplatin, etc.) and molecular targeted agents (Bevacizamab, Cetuximab, etc.) hold a great deal of promise, results of recent studies indicate that the pCR rate with neoadjuvant therapy appears to have plateaued at 20-30%. The use of more intensive multidrug combinations has, however, significantly increased the toxicity of treatment. New paradigms in neoadjuvant therapy are therefore needed to further improve results of treatment. This review presents strategies for neoadjuvant therapy, with the potential to improve pCR rates and also survival of patients.

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    • "New paradigms in neoadjuvant therapy are therefore needed to further improve results of treatment. Although we have not been successful in developing new agents that are effective radiation sensitizers in rectal cancer, this is still a very worthwhile goal, and innovations in biologics and nanoparticles could be of major importance (Mohiuddin M., et al, 2009). "

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    ABSTRACT: To evaluate the feasibility and pathologic complete response rate of induction bevacizumab + modified infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX) 6 regimen followed by concurrent bevacizumab, oxaliplatin, continuous infusion 5-fluorouracil (5-FU), and radiation for patients with rectal cancer. Eligible patients received 1 month of induction bevacizumab and mFOLFOX6. Patients then received 50.4 Gy of radiation and concurrent bevacizumab (5 mg/kg on Days 1, 15, and 29), oxaliplatin (50 mg/m(2)/week for 6 weeks), and continuous infusion 5-FU (200 mg/m(2)/day). Because of gastrointestinal toxicity, the oxaliplatin dose was reduced to 40 mg/m(2)/week. Resection was performed 4-8 weeks after the completion of chemoradiation. The trial was terminated early because of toxicity after 26 eligible patients were treated. Only 1 patient had significant toxicity (arrhythmia) during induction treatment and was removed from the study. During chemoradiation, Grade 3/4 toxicity was experienced by 19 of 25 patients (76%). The most common Grade 3/4 toxicities were diarrhea, neutropenia, and pain. Five of 25 patients (20%) had a complete pathologic response. Nine of 25 patients (36%) developed postoperative complications including infection (n = 4), delayed healing (n = 3), leak/abscess (n = 2), sterile fluid collection (n = 2), ischemic colonic reservoir (n = 1), and fistula (n = 1). Concurrent oxaliplatin, bevacizumab, continuous infusion 5-FU, and radiation causes significant gastrointestinal toxicity. The pathologic complete response rate of this regimen was similar to other fluorouracil chemoradiation regimens. The high incidence of postoperative wound complications is concerning and consistent with other reports utilizing bevacizumab with chemoradiation before major surgical resections.
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