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For other articles and previous issues click here. January 31, 2005 Cancer
Coalition Examining the alliance among radiation, chemotherapy, and surgery Progress in medicine is rarely linear. While new tools and therapies sometimes replace older ones, most medical innovation is cumulative. New knowledge adds to the range of therapeutic options, which may be applied singly or in various combinations. These options can be daunting for both physicians and patients, particularly when dealing with a high-stakes disease such as cancer. Treatment modalities for cancer include surgery, radiation, chemotherapy, and a number of other lesser-used therapies. While these therapies have been in use for many years, clinicians disagree as to which combination of modalities is most effective for specific cancers. This was the question confronted during a presentation at the 2003 American Society for Therapeutic Radiology and Oncology conference in Salt Lake City, where presenters discussed the role of adjuvant multimodality therapy for esophageal, rectal, gastric, and pancreatic cancer. Esophageal Cancer Studies comparing neoadjuvant therapy for esophageal cancer with surgery alone have shown conflicting results. According to David H. Harpole, Jr, MD, chief of thoracic surgery at Duke University Medical Center, Durham, N.C., the conflicting study results are probably due to a combination of factors. First, Harpole points to a lack of consistent pretreatment staging (no computed tomography or endoesophageal ultrasound requirements). He also cites inadequate treatment dose and the use of agents that are relatively limited in their effectiveness upon esophageal cancer. While one published study shows neoadjuvant therapy for esophageal cancer to be more effective than surgery alone, Harpole questions those findings because of serious flaws in the study. He acknowledges recent improvements in chemotherapy and radiotherapy but characterizes those improvements as “slight.” Gastric Cancer In Japan, surgeons advocate an aggressive method of surgery known as extended regional node dissection, or extended lymphadenectomy, because it is said to improve local control and survival. But, according to Leonard L. Gunderson, MD, MS, Getz Family professor and chair of radiation oncology at Mayo Clinic in Scottsdale, Ariz., those benefits have been demonstrated only in nonrandomized series and are therefore questionable. Gunderson points to randomized trials in Britain and the Netherlands that fail to demonstrate any increased survival benefit for extended lymphadenectomy. “The extended node dissection is recommended, but with reservations,” says Gunderson. “It has too many side effects, too much morbidity and mortality.” Recently, multimodality therapy became the standard of care for gastric cancer in the United States. Gunderson refers to “encouraging results” with preoperative chemoradiation for locally advanced gastric cancer as the impetus behind the randomized phase 2 trial that evaluated different kinds of preoperative and postoperative chemoradiation and postoperative chemotherapy in combination with surgery. The hope was that some of these new regimens might have a better effect on systemic failure rates than previous combinations. The Gastrointestinal Intergroup coordinated the trial. “It was amazing to be able to accrue close to 600 patients for a study that established preoperative chemoradiation as the standard of care for gastric cancer,” Gunderson says. Rectal Cancer Preoperative combined modality therapy is commonly used prior to surgery on patients with ultrasound T3 or clinical TA (Takayasu’s Arteritis) disease; surgery is then followed by postoperative chemotherapy. For patients with T3 and/or N1-2 tumors, surgery is followed by postoperative multimodality therapy. Because it improves survival rates, reduces toxicity, and enhances sphincter preservation, preoperative combined modality therapy has gained acceptance as a standard adjuvant therapy for rectal cancer in the U.S. medical community. While preoperative combined modality therapy for rectal cancer is commonly practiced in the United States, some European centers advocate a short course of intensive radiation followed one week later by surgery. According to Bruce D. Minsky, MD, department of radiation oncology at Memorial Sloan-Kettering Cancer Center, New York City, there are mixed reports about this European approach. Minsky points out that only one trial, the Swedish Rectal Cancer Trial, shows advantages to the European approach. Another trial in the Netherlands and two meta-analyses showed conflicting results. Minsky believes that it’s impossible to compare results of the European short-course radiation method with the conventional American preoperative combined modality therapy because preoperative combined modality therapy is limited to patients with clinical T3 disease, while short-course radiation is typically limited to patients with clinical T1 or T2 disease. Because of its high toxicity and lack of sphincter preservation, intensive short-course radiation therapy is not used in the United States. However, radiation therapy remains a vital part of adjuvant therapy for rectal cancer. The National Institutes of Health (NIH) Consensus Development Conference of 1990 recommends external beam radiation therapy and 5-FU–based chemotherapy as standard postoperative treatment for patients with stage 2 or 3 rectal cancer. The NIH decision was based on reports showing that postoperative multimodality therapy increased survival and decreased local recurrence far better than surgery, radiation, or chemotherapy alone. Despite these apparent successes, the necessity of radiation therapy is being challenged by a European surgical technique known as total mesorectal excision (TME). European practitioners of TME report local recurrence rates under 8%. TME also reportedly preserves anal and sphincter function, as well as bladder and sexual function. Considering the impressive results of surgery alone with TME, U.S. surgeons are beginning to reexamine the need for chemoradiation. The question is: Which tumors respond best to TME alone and which might require radiation? According to David A. Rothenberger, MD, professor of surgery at the University of Minnesota, surgery alone may be most effective in treating T3NO cancers in the upper one-third or one-half of the rectum with depth of penetration of the cancer clearly confined within the mesorectum. Surgeons may select these tumors by preoperative magnetic resonance staging or ultrasound. Rothenberger points to the need for a clinical trial to test the results of TME surgery alone compared with chemoradiation and TME surgery combined. Pancreatic Cancer Because of the ineffectiveness of other modalities, surgery is considered the only cure for pancreatic cancer. Still, Willet says that adjuvant radiation therapy combined with 5-FU–based chemotherapy has been advised to improve long-term and median survival rates after surgery. The results of this effort, according to Willet, are controversial, with phase 3 trials showing conflicting results. To improve the effectiveness of combined modality therapy for pancreatic cancer, new clinical trials are testing different combinations of novel cytotoxic agents applied both alone and in combination with radiation therapy. Researchers are also developing better delivery methods for radiation dose and improved selection criteria for patients. Different Countries, Different
Standards of Care While Gunderson is pleased about recent clinical results that helped establish multimodality therapy as the standard of care for gastric cancer in the United States, he is aware of the mild xenophobic quality of decisions made by many in the medical community. “Physicians tend not to believe the results of studies that are conducted in countries other than their own,” Gunderson says. — David Surface is a freelance writer and editor based in Brooklyn, N.Y. |
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