About half of patients with solid tumors are cured by surgery alone. And yet randomized clinical trials in surgical oncology remain scarce.
Surgical oncologists offer various explanations: the difficulty of ensuring uniformity in surgical practice; the lack of funding by the pharmaceutical industry; and in the United States, the absence, until recently, of a surgically oriented cooperative clinical trials group.
Elma K. Kranenbarg, and Cornelis J. H. van de Velde, M.D., Ph.D., of the University of Leiden in the Netherlands published an editorial in a recent Japanese Journal of Clinical Oncology on the importance of surgical trials in oncology. They make a plea for greater participation of surgeons in clinical trials, and for closer attention to surgical variables in all cancer trials.
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A unique feature of surgical trials, they note, is the intrinsic variability in surgical treatment due to human factors.
"Randomization of patients to evaluate surgical procedures involves problems in addition to those associated with medical experimentation," they write. "Surgery, unlike a pill, is not a standardized, reproducible entity, but rather a unique product whose details are defined by variables which include, for example, the skill of the surgeon."
Peter G. Rose, M.D., a surgeon at University Hospital in Cleveland, agreed. "It's harder to standardize surgery," he said. "With chemotherapy, it's not up to the investigator to modify the doses; they are strictly written into the protocol. So it's easier to get more uniform data. In surgery, the type and the extent how radical or conservative will vary, so it's harder to quantify and compare."
A trial of lymph node dissection in gastric cancer illustrates the problem. Van de Velde and colleagues in the Dutch Gastric Cancer Group tried to determine whether the extended dissection technique practiced by Japanese surgeons improves survival and reduces recurrence. The question is important particularly so in Japan, where gastric cancer is six times more common than in the United States because complications are worse and more frequent with the extended procedure.
In the Netherlands, however, gastric cancer is relatively uncommon, so that 80 hospitals were included to get enough patients 711 over 4 years. Because the technique was unfamiliar and each surgeon operated on only a few patients, the investigators instituted a strict quality control program, including videotapes and instruction by experienced Japanese surgeons.
But as Murray F. Brennan, M.D., of Memorial Sloan-Kettering Cancer Center in New York noted in an editorial in the March 25 New England Journal of Medicine, "Unfortunately, this approach, though a laudable example of how large multi-institutional trials can be carried out, failed . . . despite serious attempts at standardization, deviations from the protocol were numerous, thereby blurring the distinction between the two procedures."
For example, in 51% of patients randomized to the extended dissection, no lymph nodes were taken from at least two "stations" that were supposed to be dissected. The authors and Brennan agree that as practiced by surgeons in the West, extended dissection does appear more likely to harm than to help patients.
Surgery as a Constant
Bernard Fisher, M.D., scientific director of the National Surgical Adjuvant Breast and Bowel Project, noted, however, that for most trials, standardization need not mean that every surgeon does an operation that is exactly the same in all technical details. It is misguided to believe that "you can't do trials because you can't guarantee that surgeons will all do precisely identical operations. You can establish boundaries that are doable by most people."
When Fisher's landmark NSABP trial of lumpectomy versus mastectomy began, "very few people in the United States were doing lumpectomies. It was an oddity. So we established a set of guidelines, and everyone cooperated and followed them, so it can be done."
In the National Cancer Institute's PDQ database, 87 of about 1,600 trials appear in a search for trials of "conventional surgery." But a quick reading of the protocols reveals that most of these trials are not evaluating a surgical intervention, but rather have surgery as a constant while other treatments are varied.
"Most trials have not evaluated surgery in terms of treatment efficacy," Rose said. One obstacle is that the surgeon's knife is often probing terra incognita meaning that before the initial surgery "we don't have a diagnosis or a stage" to assign patients to the appropriate therapy.
Money is another problem, according to Kranenbarg and van de Velde. In an interview, van de Velde said that in both Europe and the United States, "trials of systemic treatments are pushed by industry. They have a lot of money to test new drugs, whereas surgical trials are usually not supported by industry. Also, support from granting bodies is usually not so good, because surgeons are poorly represented in these bodies."
Samuel A. Wells, Jr., M.D, of the American College of Surgeons in Chicago, believes the scarcity of surgical randomized trials reflects not so much any inherent difficulty in performing trials in surgery, but simply the absence of a cooperative group dedicated to organizing such trials. Surgically oriented groups that focused on lung, gastrointestinal, and brain tumors once existed, but these were unsuccessful and were eventually dissolved, so that until recently there were no cooperative groups dedicated exclusively to surgery.
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One of these, which NSABP is also testing, is whether sentinel node biopsy in breast cancer is as effective as the more extensive standard axillary node dissection. "There's data to show that if there's no tumor in the sentinel node, there's a very high probability that there's no tumor in any other nodes in that node bed," Wells said.
"We want to start with fairly simple trials that practicing surgeons can do, because we're very eager to attract large numbers of surgeons to participate," Wells said. To ensure that participating surgeons' technique is up to standard, ACoSOG trials have a skills verification requirement in which operative notes and pathology reports are scrutinized. If a procedure is new, surgeons may attend a special clinic to learn it.
Surgery as a Variable
In one of the few U.S. trials with surgery as a variable, Rose and collaborators in the Gynecologic Oncology Group are conducting a trial of secondary debulking surgery in stage III ovarian cancer patients with residual tumors larger than 1 cm. All patients get six cycles of paclitaxel and cisplatin after initial surgery, and half are randomized to get the additional surgery.
Many important surgical questions remain unresolved because it is difficult to recruit patients to trials. One in prostate cancer which Wells hopes ACoSOG will address is the effectiveness of brachytherapy (local radiation via iridium implants) versus radical prostatectomy in patients with early stage carcinoma of the prostate. This highly important trial poses an interesting randomization, Wells said, comparing an operative to a non-operative therapy.
Fisher stressed that both physicians and patients must be educated about the importance of answering questions regarding treatment and encouraged to participate in trials to answer them. While in the past, he said, surgeons were generally more reluctant than medical oncologists to enter their patients on trial, that is no longer true.
Another open question is radical nephrectomy versus more limited surgery for renal cell cancer. The European Organization for Research and Treatment of Cancer is conducting a trial on this issue, and ACoSOG may join it, Wells said. A question in gynecologic oncology that deserves a randomized trial, Rose said, is the comparison of chemoradiation followed by hysterectomy versus chemoradiation alone.
In rectal cancer, a newly completed study of 1,400 patients in 84 hospitals in the Netherlands, showed that among those treated with standardized total mesorectal excision "the recurrence rate has gone dramatically down," compared with the standard treatment of less extensive surgery plus radiation, van de Velde said.
Even in clinical trials testing adjuvant treatments, the quality of surgery "makes an enormous difference," van de Velde said. "The surgical factor is an underestimated variable in a lot of solid tumor treatment. It has an impact not only on local control, but also on survival. Differences in the degree of local control achieved through surgery may obscure the effect of systemic treatments."
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