Experts Debate Value of Whole Abdominal Radiation (WAR) Therapy in Ovarian Ca

PARIS, France--Postoperative whole abdominal radiation (WAR) therapyhas no place in the management of ovarian cancer, David Gershenson,MD, of the University of Texas M.D. Anderson Cancer Center, saidin a debate at the American Radium Society meeting.

However, this perspective was refuted by Gillian Thomas, MD, whosegroup in Toronto has been one of the most consistent championsof WAR therapy.

Dr. Gershenson spotlighted a panoply of problems in the olderstudies comparing WAR with chemotherapy, including a lack of adequatesurgical staging in the Princess Margaret Hospital, Toronto, series,the absence of stratification prior to randomization in the M.D.Anderson study, and the use of ill-defined or inadequate radiotherapeutictechniques in the Canadian NCI and Danish studies.

"Therefore," he argued, "none of these studiesresolved the most relevant question--how does WAR compare withcontemporary platinum-based combination chemotherapy?"

Likewise, he continued, of five studies that supported the superiorityof radiation over chemotherapy, four were retrospective, coveringa long period of time, and shared several common flaws.

He said that these studies were flawed because (1) they includedpatients with early-stage disease, (2) had small numbers of patientswith stage III disease, (3) used chemotherapy after radiotherapyin some patients, (4) had inadequate pathology review, (5) includedpatients with borderline tumors, and (6) failed to employ aggressivecytoreductive surgery, resulting in a possible selection biastoward a preponderance of patients with stage IIIA or IIIB disease.

"Yet another concern is compromise of bone marrow toleranceto chemotherapy in patients who fail to respond to postoperativeradiation," Dr. Gershenson said. He also warned of increasedcomplication rates in ovarian cancer patients who require laparotomyfor intestinal obstruction or other problems after receiving radiationtherapy.

According to Dr. Gershenson, the only stage III patients for whomthe Toronto team recommended WAR were those with grade 1 tumorswith no gross residual disease or with 2 cm or less residual diseaseconfined to the pelvis (see table).

"But if one reviews the literature," he said, "onefinds that only 3% to 24% of patients with advanced-stage epithelialovarian cancer have grade 1 disease, and only 17% to 49% haveresidual disease of 2 cm or less."

Dr. Gershenson acknowledged that WAR therapy very likely is curativein a small subset of patients with stage III epithelial ovariancancer, but he does not recommend further study of this modalityfor a number of reasons:

• Technical expertise in radiotherapeutic techniques variesgreatly.
• WAR is applicable to only a very small subset of stage IIIpatients, and this subset may be difficult to define.
• The results appear to be influenced by selection bias.
• Subsequent chemotherapy or surgery may be significantly compromisedafter failure of postoperative radiation therapy.
• Physician bias is probably too great to allow the kind ofprospective, randomized studies that would resolve this issue.

Rebuttal From Toronto Physician

Calling this criticism "throwing the baby out with the bathwater," Dr. Thomas challenged Dr. Gershenson to show anydata proving that platinum-based chemotherapy yields disease-freesurvival rates even comparable to those achieved with WAR in patientswith optimal stage I, II, or III disease.

Dr. Thomas pointed out that WAR therapy fell into disrepute inNorth America because of an M.D. Anderson study published 20 yearsago, which showed that melphalan (Alkeran), although no betterthan radiation, was less expensive and easier to administer inthe short run.

However, she noted, the WAR therapy used in that study came uponly to the xiphoid process and missed the domes of the diaphragm.In addition, she pointed to a preponderance of more advanced diseasein the M.D. Anderson patients who received radiation.

Studies performed at Princess Mar-garet Hospital in the 1970sand early 1980s identified two distinct patient groups with disparatesurvival rates: a poor prognosis group with stage III or IV cancerand gross residual disease, and a good prognosis group with stageI, II , or III cancer and little or no residual disease.

"Clearly, there was no role for immediate postoperative radiationin poor prognosis patients," she said. The challenge layin determining which of the other patients were the best candidatesfor radiation. "The message here," she stressed, "isthat we have many modalities to use, but it is important to directthose modalities at the patients most likely to benefit."

The Toronto investigators next proceeded to randomize women withstage I or II or asymptomatic stage III disease to treatment withWAR or pelvic irradiation plus chlorambucil (Leukeran). The long-termsurvival advantage afforded by WAR, Dr. Thomas said, was particularlyevident in those women who had undergone bilateral salpingo-oophorectomyand hysterectomy, and were thus unlikely to have gross residualdisease.

Most important, she emphasized, multivariate analysis of the resultsof radiation therapy in 472 patients defined an intermediate-riskgroup in whom WAR yielded 10-year survival rates of up to 67%(see figure).

She contrasted these results with the 40% 10- to 15-year survivalrates achieved with the combination of cisplatin (Platinol) andcyclophosphamide (Cytoxan, Neosar) in women with stage II disease,and with the 20% to 25% long-term survival afforded by platinumin women with optimal stage III disease.

"It is clear that a significant proportion of patients arecured with the use of WAR," Dr. Thomas said, noting thatthe intermediate-risk group represents 30% of ovarian cancer patients.Even in high-risk stage III patients treated with chemotherapyprior to radiation, long-term survival is on the order of 30%,she said.

"I would submit to you that there is a very strong case forusing WAR in selected patients with stages I, II, and III diseasewith no macroscopic residual disease or with residual diseaseless than 2 cm confined to the pelvis," she said.

Other Study Results Cited

Dr. Thomas also cited studies from Stanford, Salt Lake City, WalterReed, and Yale indicating 10- to 15-year relapse-free survivalrates in the neighborhood of 50% for women with residual diseaseless than 2 cm who had been treated with postoperative radiation.

She said that radiotherapy is highly tolerable and less toxicthan many chemotherapy regimens currently used. In 10 studiesencompassing more than 1,000 patients treated with WAR, the incidenceof bowel obstruction requiring surgery was only 5.6%, she said.

"If you use doses less than 2,500 cGy to the whole abdomenin the fraction sizes we have recommended, and limit the pelvicdoses to 45 or 50 Gy, serious complication rates are entirelyacceptable at 1.4%," she said.

"We don't just measure the efficacy of radiation therpy withresponse rates that don't translate into cure," Dr. Thomassaid. "We measure it with long-term survival."

She concluded that it is "now time for us to integrate theavailable treatment modalities and try to use radiation therapywhere it may be effective and chemotherapy where it may be effectiveto produce the greatest long-term survival."