This study investigated the addition of cisplatin-based chemotherapy to standard postoperative radiation therapy in the treatment of women at high risk of recurrence after radical hysterectomy for cervical cancer. Two hundred forty-three patients with stage IA, IB, or IIA carcinoma of the cervix who had pelvic lymph node metastases, parametrial tumor infiltration, or a positive surgical margin at the time of radical hysterectomy were randomly assigned to receive pelvic radiation therapy (N = 116) or pelvic radiation therapy plus four cycles of chemotherapy (N = 127) after type 3 radical hysterectomy with pelvic lymphadenectomy. Radiation therapy in both groups consisted of 49.3 Gy in 29 factions delivered to a standard pelvic field over 6 weeks. Adjunctive chemotherapy was started on day 1 of radiation treatment. Cisplatin was administered intravenously over 2 hours at a dose of 70 mg/m2 on day 1, followed by 4 days of continuous infusion of 100 mg/m2 5-fluorouracil. The two treatment groups were similar in clinical and demographic characteristics.
In each treatment group, approximately 10 percent of patients received <45 Gy radiation. For those who received at least 45 GY, the median time to completion of radiation therapy was 41 days for the radiation-only group and 43 days for the radiation plus chemotherapy group. Seventy-one percent of the women receiving chemotherapy completed at least three cycles of treatment.
After a median follow up of 42 months, the patients who received both radiation and chemotherapy had an estimated 4-year progression-free survival rate of 80 percent, compared with 63 percent in women treated with radiation alone (P = .003). The estimated 4-year overall survival rates for these two groups were 81 and 71 percent, respectively (P = .007). Multivariate analysis found only lesion size to be a significant predictor of progression-free survival or overall survival (P = .05 and .03, respectively). Although patients in the chemotherapy group had fewer recurrences, the pattern of recurrence was similar in both groups.
Patients with adenocarcinoma or adenosquamous carcinoma who were treated with radiation alone had a worse survival rate than those with squamous tumors treated with radiation alone. However, there was no difference in survival rates among cell types in the group treated with radiation plus chemotherapy. An analysis of the women receiving chemotherapy found that higher numbers of completed chemotherapy cycles were associated with greater progression-free survival and overall survival rates (P = .03 for both). Twenty-one women in the chemotherapy group developed grade 4 toxicity that was associated with treatment. Most episodes were hematologic. Four patients in the radiation alone group experienced grade 4 toxicity.
J Clin Oncol 2000;18:1606-1613
(There has been a significant change in the approach to radiation therapy for cervical cancer in the past several years. In a prospective, randomized Gynecologic Oncology Group study, Rose et al. demonstrated significant improvement in survival and disease-free survival in patients with locally advanced cervical cancer treated with concomitant chemotherapy and radiation therapy (N Engl J Med 1999;340:144). Patients who were treated with weekly cisplatin or a combination of cisplatin, 5-fluoruracil, and hydroxyurea during radiation therapy had a 50 percent improvement in survival compared with the group who received adjuvant hydroxyurea alone. Other studies have confirmed the benefits of combined platin chemotherapy plus radiation in a variety of cervical cancers. In the study abstracted above, four cycles of chemotherapy with cisplatin and 5-fluorouracil given during and after pelvic radiation therapy improved disease-free 4-year survival to 80 percent from 63 percent with radiation alone.
Patients included in this study were women who had undergone radical hysterectomy and, on the basis of the surgical-pathologic findings, were though to be a high risk for tumor recurrence. Women with lymph node metastases, parametrial infiltration, and/or positive surgical margins were candidates for inclusion in this study. Other factors, including tumor size, depth of invasion, involvement of lymph-vascular spaces, age, and histologic findings (adenocarcinoma or adenosquamous carcinoma), have also been found to be prognostic in some studies but were not included here. These high-risk findings tend to reduce the expected 5-year survival in women with stage IB cervical cancer from about 85 percent to 50 to 60 percent. Although a variety of postoperative therapies have been evaluated in these high-risk patients, none has been conclusively proven to be of benefit.
Recently, a large, prospective, randomized Gynecologic Oncology Group study compared 137 postoperative patients at moderate risk (no lymph node metastases) treated with adjunctive pelvic radiation with a similar group of 140 women who received no postoperative therapy (Sedlis et al., Gynecol Oncol 1999;73:177). There was a significantly reduced risk of recurrence in the patients who underwent radiation therapy (15.3 percent vs. 27.9 percent), but follow-up has been too short to evaluate survival. Another prospective, randomized trial from the Austrian Gynecologic Oncology Group compared no postoperative treatment with pelvic radiation and with carboplatin/bleomycin chemotherapy in a group of high-risk patients (95 percent had positive nodes) after radical hysterectomy and pelvic lymphadenectomy (Lahousen et al., Gynecol Oncol 1999;73:196). After a median follow-up period of 4 years, each treatment group had similar rates of recurrence and survival.
The significant improvement in survival reported above was not without cost due to toxicity. Significant side effects, largely bone marrow suppression and resultant complications, occurred in 22 percent of patients treated with combined radiation and chemotherapy, whereas only 2.5 percent of women who received radiation alone suffered grade 4 toxicity. The addition of bone marrow-stimulating factors may reduce toxicity and improve tolerance and adherence to the treatment protocols. Although these results need to be confirmed by other studies, the data are promising and in agreement with data from parallel studies. Combined radiation and platin chemotherapy for most cervical cancers is now considered state of the art.-HWJ III)