Christopher G. Willett, MD

As we look forward, we suggest that the priority should be to further our understanding of the tumor’s interactions with its microenvironment and with the immune system. We think that such an understanding will be critical for advances in locally advanced rectal cancer therapy.

Historically, the treatment of squamous cell carcinoma of the anal canal has been an abdominoperineal resection (APR), resulting in loss of the anus and rectum with need for a permanent colostomy.

Radiation therapy (RT) and immunotherapy of cancer both date back more than 100 years, and yet, because radiation was often considered immunosuppressive, there had been little enthusiasm for combining them until recently. Immunotherapy has an established role in the treatment of some cancers-superficial bladder cancer treated with bacillus Calmette-Guérin (BCG), renal cell carcinoma and melanoma treated with interferon and interluekin (IL)-2 (Proleukin), and breast cancer and lymphoma treated with monoclonal antibodies such as trastuzumab (Herceptin) and rituximab (Rituxan), which partly function through antibody-dependent cellular cytotoxicity.

Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) are often overexpressed in colorectal cancer and are associated with inferior outcomes. Based on successful randomized phase III trials, anti-EGFR and anti-VEGF therapeutics have entered clinical practice. Cetuximab (Erbitux), an EGFR-specific antibody, is currently approved in the United States in combination with irinotecan (Camptosar) for patients with metastatic colorectal cancer refractory to irinotecan or as a single agent for patients unable to tolerate irinotecan-based therapy. In retrospective analyses, patients with EGFR-expressing rectal cancer undergoing neoadjuvant radiation therapy had a significantly inferior disease-free survival and lower rates of achieving pathologic complete response. Based on the positive data in metastatic colorectal cancer and synergy with radiation therapy seen in preclinical models, there is a strong rationale to combine cetuximab with neoadjuvant radiation therapy and chemotherapy in rectal cancer. Bevacizumab (Avastin), a VEGF-specific antibody, was the first antiangiogenic agent to be approved in the United States for use in combination with standard chemotherapy in the first- and second-line of treatment in metastatic colorectal cancer. VEGF-targeted therapy may lead to indirect killing of cancer cells by damaging tumor blood vessels, and may increase the radiosensitivity of tumor-associated endothelial cells. VEGF blockade can also "normalize" tumor vasculature, thereby leading to greater tumor oxygenation and drug penetration. This review will address completed and ongoing trials that have established and continue to clarify the effects of these agents in rectal cancer.

Cancer of the pancreas remains a formidable challenge in oncology.This malignancy ranks as the fourth leading cause of cancer deathin the United States in 2003, with an estimated 30,700 new cases to bediagnosed and 30,000 deaths. Although gains have been achieved inthe clinical management of these patients, this malignancy is rarelycurable. Long-term survival is limited to patients undergoing resection.For patients with localized but unresectable malignancy, radiationtherapy combined with fluorouracil, gemcitabine (Gemzar), orpaclitaxel has shown modest improvements in survival and symptompalliation. However, there has been significant progress in the diagnosticevaluation of pancreatic cancer patients, which has aided cliniciansin caring for these patients and in selecting therapies. The use ofcomputed tomography, endoscopic ultrasonography, and laparoscopytechniques will be discussed. Newer techniques of radiation therapy,such as intraoperative electron-beam radiation therapy and threedimensionalconformal radiation therapy, with the integration of newbiologically targeted agents may provide new avenues of research andprogress in this disease.

This year, approximately 40% of the 28,300 patients diagnosed with pancreatic carcinoma in the United States will present with locally advanced disease. Radiotherapeutic approaches are often employed, as these patients