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Surgical Oncology Focusing on Minimally Invasive Surgery, More Randomized Clinical Trials

Laura Newman

Surgery, the oldest treatment for cancer, is turning toward minimally invasive approaches as technology and understanding of cancer improve. Perhaps Bernard Fisher, M.D., breast cancer surgeon from the University of Pittsburgh, deserves the most credit in the United States for moving cancer surgery toward an organ-conserving approach. At the same time, he pushed cancer surgeons toward adopting a higher standard of evidence.

Fisher pressed for randomized controlled trials testing the traditional Halsted radical mastectomy against total mastectomy, and, subsequently, total mastectomy against lumpectomy with or without radiation therapy. He fought hard for those trials, meeting resistance on many fronts. Eventually, clinical trials proved Fisher right: breast-cancer mortality with lumpectomy and radiation was proven equivalent to that attained with more radical surgery. Sure enough, the standard of care for breast cancer surgery slowly moved toward adoption of lumpectomy and radiation, a procedure now well recognized to confer many other benefits.

Fisher and others in Europe, such as Umberto Veronesi, M.D., helped swing the door open, letting in the notion that minimally invasive surgery might work for other cancers. Good results with lumpectomies and improvements in technology led to many more attempts at using minimally invasive, laparoscopic and thorascopic surgery, both in general surgery and cancer surgery.

A key lesson learned was that, together with an understanding of how cancer spreads, less invasive surgery can accomplish the same goals as open procedures. Also, randomized clinical trials should be used to test even the most promising procedures. Some innovative surgical techniques were studied in prospective randomized clinical trials involving multiple institutions and surgeons, but, unfortunately, many more were not.

"Broad adoption of laparoscopic cholecystectomy—the classic case of minimally invasive surgery that was disseminated before surgeons were trained in the technique—led to an unacceptably high rate of common bile duct injuries, some of them life-threatening," said Samuel A. Wells Jr., M.D., group chair of the recently launched American College of Surgeons Oncology Group and professor of surgery at Duke University Medical Center, Durham, N.C.



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Dr. Samuel A. Wells Jr.

 
The harms became so worrisome that news accounts and peer-reviewed journal articles took up the issue, while regulators acted to preserve the public’s health. "In New York, the state issued a moratorium on the procedure until it could be shown that it could be done safely," said Heidi Nelson, M.D., colon surgeon at the Mayo Clinic, Rochester, Minn.

But today, many people would argue that the kinks have been worked out so that laparoscopic cholecystectomy can be performed safely. At cancer meetings here and abroad, laparoscopic surgeons argue that minimally invasive cancer surgery wins hands-down in terms of fewer side effects, faster recovery, less scarring, and a quicker return to work. And patient testimonials often provide strong endorsements for such an approach.

"It’s like the automobile," said Ralph V. Clayman, M.D. "Nobody is going back to the horse." Clayman, professor of urology at Washington University School of Medicine in St. Louis, pioneered the laparoscopic nephrectomy for renal cell tumors. Advantages of the laparoscopic surgery include "being able to remove the kidney intact, get patients home sooner, and use 70% to 80% less pain medication."

This month at the American Urological Association’s annual meeting, Andrew Portis, M.D., a urologic fellow who trained under Clayman and a practicing urologist in St. Louis, reported the first long-term outcomes of laparoscopic nephrectomy at three centers in the United States, Canada, and Japan.

Evaluating 64 patients who underwent laparoscopic nephrectomy and 69 who underwent an open procedure, the nonrandomized study showed similar recurrence-free survival in patients with T1 and T2 renal cell cancer (92% for the laparoscopic procedure and 91% for the open surgery). At 5 years, cancer-specific survival was 98% in the laparoscopic group versus 92% in those who underwent open surgery, and overall survival was 81% for the laparoscopic group and 89% for the open surgery group.

"This was the one major area that people had concerns about," Clayman acknowledged. That said, laparoscopic nephrectomy has long been the standard of care, although there has not been a prospective randomized trial.

Surgical oncology has made strides in embracing nonsurgical modalities. Increasingly, the biology of cancer is factored into surgical decision-making, with chemotherapy, radiation, and novel drugs being included in algorithms that used to rely predominantly on surgery alone. Several of these combinations are now being tested in clinical trials.

Clinical Trials Gain Momentum

Despite a strong tradition of apprenticeship and small case series, the field of surgical oncology is now taking part in more multicenter, randomized controlled trials. Recognition of the need to upgrade surgical oncology study design by the National Cancer Institute and the surgical oncology community has helped to build a much-needed infrastructure for mounting clinical trials, say observers.

In 1998, the American College of Surgeons Oncology Group officially began under Wells’ direction. The concept for a surgical oncology clinical trials group had been brewing for several years. NCI urged establishing the new study group, and initial surgical oncology protocols addressing the most common solid tumors were developed.

"This is a great opportunity for surgical oncologists," said Wells, who is group chair of ACOSOG. While the first trials relied on surgical investigators who had prior experience with clinical trials, semiannual meetings are open to all surgeons, and Wells hopes that the group can encourage more surgical oncologists to become clinical trials investigators.

Thoracic and breast cancer trials in ACOSOG now have broad participation, according to Wells, who estimated patient accrual in these trials at approximately 300 patients per month. Three trials are under way in breast cancer, and a fourth is slated to open soon.

ACOSOG is in the early stages of planning a major prostate cancer trial comparing radical prostatectomy with brachytherapy. Wells noted that these two treatments have never been evaluated in a head-to-head trial. Another trial in the works is addressing which operation works best for metastatic liver disease. A study of patients with advanced melanoma of an extremity will compare isolated limb perfusion with melphalan alone versus melphalan plus tumor necrosis factor.

ACOSOG is a "very important accomplishment," said John Niederhuber, M.D., director and professor of surgery at the University of Wisconsin Comprehensive Cancer Center, Madison. Modeled after the National Surgical Adjuvant Breast and Bowel Project, the new group offers surgeons a chance to participate in clinical trials. Niederhuber stressed that surgeons started with practically no infrastructure or set-up for research, data managers, and biostatisticians—all of which is a costly endeavor.



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Dr. John Niederhuber

 
Before ACOSOG was established, "surgeons never really felt welcome in the traditional cooperative groups," he said. "They were never able to get into the inner circle."

That said, efforts to increase the number of surgical oncology clinical trials are apparent through the European Organization for Research and Treatment of Cancer, the Dutch Commissie Klinisch Vegelijkend Ondoerzoek, and other international study groups around the world, as well as through long standing groups in the United States, including NSABP and the Gynecologic Oncology Group.

The NSABP is evaluating sentinel node biopsy for breast cancer, specifically studying whether sentinel node biopsy can safely replace axillary node dissection in the approximately 70% of patients with negative sentinel nodes. ACOSOG is looking at the same concern, but only in women with positive sentinel nodes.

"Sentinel node biopsy holds promise for reducing morbidity, postoperative recovery, and decreasing costs," said Ted Trimble, M.D., head of NCI’s surgery section in the Cancer Therapy Evaluation Program.

"Laparoscopic-assisted gynecologic procedures can provide a valuable second-look procedure that can help determine switches in chemotherapy." But important questions must be answered before these are used widely, he explained. "We need to figure out how to use these techniques and be certain that we minimize disparity in outcomes because not everyone gets optimal outcomes."

There is some concern that sentinel node biopsy has hit mainstream practice before these large trials have been completed. "Surgeons have voted with their feet for this procedure," reported Stephen Edge, M.D., breast surgeon at Roswell Park Cancer Center in Buffalo, N.Y., at the recent American Society of Clinical Oncology annual meeting. "Sentinel node biopsy has been rapidly adopted as the standard of care," Edge said of his study of 8 of 19 National Comprehensive Cancer Network hospitals.

Edge is supportive of the sentinel node biopsy clinical trials, but he acknowledged that by the time the trials were launched in 1999, many surgeons had converted to using sentinel node biopsy. He defended the change in practice, citing "a fair bit of market pressure to adopt these techniques" or risk losing patients.

The effectiveness of laparoscopic colectomy is the subject of another prospective clinical trial. In the trial, which will be headed by the Mayo Clinic’s Nelson, 800 patients are being randomly assigned to laparoscopic colectomy or open colectomy.

Safety and effectiveness questions that the trial will address include "to what extent a small incision translates into a less extensive resection," said Nelson. Investigators are also comparing staging evaluation techniques with the two procedures, with particular emphasis on evaluation of liver metastases and findings of carcinomatosis. An unacceptably high wound recurrence rate with laparoscopic colectomy, reported in some series, raises other concerns. Outcomes measures in the trial are overall survival, disease-free survival, types of recurrence, mortality and morbidity, patient-reported quality of life, and cost.

Nelson simply does not believe there are adequate data to back adopting the technique widely at this time. "I don’t offer it outside of a clinical trial," she said. And she is delighted that most of her colleagues are participating in the laparoscopic colectomy trial and awaiting its results, rather than adopting it early on before it is proved safe and effective. Besides the laparoscopic colectomy colon cancer trial, Nelson pointed to "seven international trials in colon cancer," with a similar rise in lung and breast cancer trials.

Looking back, Nelson recalled how far the field has come. "Surgical oncologists were not reared with a mindset for clinical trials," she said. "There was no mentality for doing them. With medical oncology, conducting a trial was relatively straightforward. There, you could design your study to compare drug A to drug B."

"This was not so in surgical oncology," she said. "The formulas for doing the trials, the machinery, did not exist."



             
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