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ABSTRACT & COMMENTARY
Stage ib and iia cervical cancer can be cured by radical surgery or radiation therapy. The optimal strategy is not known because randomized studies have not been done. The lack of accurate comparative data regarding efficacy and toxicity has led to the current approach of treatment selection, which essentially depends on the policy of the institution, the gynecologist or radiation oncologist involved, and the age and general health of the patient. The recent, prospective, randomized study by Landoni and colleagues was designed to provide a scientific basis for treatment selection.
Landoni et al compared external and internal radiation therapy with radical hysterectomy and node dissection in 486 patients with FIGO stage IB and IIA disease. Staging for all patients included an intravenous pyelogram (IVP), lymphangiography (LAG), cystoscopy, chest radiography, and other tests as clinically indicated before randomization to radical surgery (class III radical hysterectomy) or radical radiation therapy. The latter included external pelvic irradiation to 47 Gy over 2-3 weeks followed by one cesium-137 implant. The total dose at the point of the insert from both external and internal radiation sources ranged from 70-90 Gy (median 76 Gy). The total dose to the pelvic wall was greater than 50 Gy, and, if the LAG was positive, paraaortic nodes were treated to a dose of 45 Gy over five weeks. Adjuvant radiation therapy was administered following surgery to all patients with one or more of the following pathologic risk factors: surgical stage more than pT2a; less than 3 mm of uninvolved cervical stroma; incision of tumor (cut-through); and lymph node metastases. Adjuvant radiation therapy consisted of external beam pelvic RT to a total dose of 50.4 Gy over five weeks with 45 Gy to the paraaortic region if common iliac or paraaortic nodes were involved.
Of the 468 patients with stage IB or IIA disease, only 343 were eligible to be randomized. There were no differences between the two groups in the factors likely to affect prognosis (i.e. FIGO stage, positive LAG, and histological type). The poor risk pathologic features were found much more frequently in women who had a cervical diameter greater than 4 cm. This led to the more frequent use of adjuvant radiation therapy (84% and 54%, respectively) in these patients than in women with a cervical diameter less than 4 cm. Overall, 64% of patients in the radical surgery arm received adjuvant radiation therapy. After a median follow-up of 87 months, the overall and disease-free actuarial five-year survival for all patients was 83% and 74%, respectively. There was no difference between the two groups. Although patients with a cervical diameter greater than 4 cm did more poorly than those whose diameter was less than 4 cm, the results were not affected by the treatment employed. The results in patients with tumors of squamous histology were also unaffected by treatment modality; however, for patients with adenocarcinoma of the cervix, there was a significant advantage for surgery compared to radiation therapy in both overall (70% vs 59%; P = 0.05) and disease-free survival (66% vs 47%; P = 0.02). Overall, 25% of patients developed recurrent disease regardless of the treatment used. Sixty percent of relapses were local, and 40% were distant. Approximately 20% of the relapsed patients could be cured of their disease, usually by crossover to the other arm of the study.
A review of non-randomized studies indicates that the five-year survival rate for patients with stage IB or IIA cervical cancer is 80-85% whether initial therapy is surgery or radiation therapy. The five-year survival rate of 83%, regardless of treatment that was observed in this randomized study, confirms what has been suspected clinically for many yearsboth treatment strategies are equally efficacious. However, because 64% of the patients in the "surgery" group received postoperative radiation therapy, this trial is more a comparison of surgery plus RT vs. RT alone. Even when both modalities are used, neither the overall nor disease-free survival were improved compared to radiation therapy alone. When two treatments have been shown to be equally effective, we usually choose one regimen over the other because of toxicity profile, patient or doctor preference, and, more commonly of late, cost. There was no cost analysis in this study, but since more than half the patients undergoing surgery also received radiation therapy and the morbidity was worse in the combined treatment group, we presume the surgery arm would be more expensive.
There does not appear to be a clear advantage to either arm in terms of the toxicity experienced. There were two deaths in the surgery arm (overall mortality rate = 0.6%) and none in the radiation therapy arm. There were more short-term complications in the surgery group, which tended to be reversible, and more long-term complications in the radiation therapy group, which were more difficult to manage. The median follow-up is only seven years so other complications may yet occur. Similar problems face patients and physicians in the treatment of early-stage Hodgkin’s disease where equally effective strategies (radiation therapy with chemotherapy at relapse vs. initial chemotherapy) are selected based on toxicity. The full extent of the complications of therapy in patients with Hodgkin’s disease has yet to be appreciated 15-20 years from initial therapy. The same may be true for the women in this study.
Unfortunately, this well-done, scientific study does not directly answer the question of which therapy is best. Thus, we are still faced with selecting treatment based on soft findings. However, surgery alone appears to be superior for patients with an adenocarcinoma of the cervix and for young women who desire preservation of coital and ovarian function. Radiation therapy is probably best for our elderly patients and the remainder should be considered for treatment on an individual basis. It is our view that if at all possible, only one modality should be employed.
In addition, based on the secondary complications in patients with Hodgkin’s disease, we urge that the long-term follow-up of these patients be continued and that outcomes be reanalyzed at 10, 15, and even 20 years of follow-up. It may be that long before we have an answer.