Concurrent Cisplatin-Based Radiotherapy and Chemotherapy for Locally Advanced Cervical Cancer
abstract & commentary
Synopsis: Regimens of radiotherapy and chemotherapy that contain cisplatin improve the rates of survival and progression-free survival among women with locally advanced cervical cancer.
Source: Rose PG, et al. N Engl J Med 1999;340: 1144-1153.
Rose and associates performed a randomized trial of radiotherapy in combination with three concurrent chemotherapy regimens: cisplatin alone; cisplatin, fluorouracil, and hydroxyurea; and hydroxy-urea alone in patients with locally advanced cervical cancer. Women with primary untreated invasive squamous cell carcinoma, adenosquamous carcinoma, or adenocarcinoma of the cervix of stage IIB, III, or IVA without involvement of the para-aortic lymph nodes, were enrolled. All patients received external beam radiotherapy according to a strict protocol. Patients were randomly assigned to receive one of three chemotherapy regimens: cisplatin alone on a weekly basis for six weeks; cisplatin on day 1 and 29, followed by fluorouracil for 96 hours starting on days 1 and 29, and oral hydroxyurea twice weekly for six weeks; or oral hydroxyurea twice weekly for six weeks. The study included 526 women. The median duration of follow-up was 35 months. Both groups that received cisplatin had a higher rate of progression-free survival than the group that received hydroxyurea alone (P < 0.001 for both comparisons). The relative risks of progression of disease or death were 0.57 in group 1 and 0.55 in group 2, as compared with group 3. The overall survival rate was significantly higher in groups 1 and 2 than in group 3, with relative risks of death of 0.61 and 0.58, respectively. Rose et al conclude that regimens of radiotherapy and chemotherapy that contain cisplatin improve the rates of survival and progression-free survival among women with locally advanced cervical cancer.
Comment by David M. Gershenson, MD
Approximately 14,000 new cases of invasive cervical cancer are annually diagnosed in the United States. However, cervical cancer represents one of the most common cancers among females worldwide, particularly in developing countries. In 1996, the National Institutes of Health (NIH) Consensus Conference Statement on Cervical Cancer concluded that "there is no evidence that hydroxyurea or any other concomitant agent should be incorporated into standard practice." Since 1996, information from five phase III randomized trials has become available. The totality of these data represents the most dramatic advance in the treatment of cervical cancer in the past 40 years. In fact, the emergence of this information prompted the National Cancer Institute to issue a Clinical Announcement in February 1999—two months prior to publication of three of these articles in the New England Journal of Medicine.
The RTOG study findings demonstrated that concurrent radiation and chemotherapy with cisplatin and 5FU leads to improved survival in women with stages IB or IIA (bulky or with positive pelvic lymph nodes), IIB, III, and IVA cervical cancer. This treatment was compared to extended field radiation, which covered the pelvis and para-aortic lymph nodes. In the combined therapy arm, there was a significant reduction in both distant and locoregional recurrences.
Based on early studies from Roswell Park Cancer Center showing promising results with hydroxyurea in the treatment of cervical cancer, over the past several years the Gynocologic Oncology Group (GOG) has invested a tremendous amount of resources and energy in studying the activity of this drug on cervical cancer. The GOG presented here demonstrated improved survival associated with concurrent radiation and chemotherapy with either weekly cisplatin or the combination of cisplatin and 5FU; both regimens were superior to radiation plus hydroxyurea. The results of this study have finally put hydroxyurea on the shelf.
A third article accompanied these two important studies in the April 15, 1999 issue of the New England Journal of Medicine.1 In this phase III trial, patients with bulky (greater than 4 cm) stage IB cervical cancer with negative lymph nodes were randomized to one of two arms: 1) pelvic radiation and intracavitary radiation with weekly cisplatin followed by extrafascial hysterectomy; or 2) pelvic radiation and intracavitary radiation followed by extrafascial hysterectomy. The survival rate for women who received weekly cisplatin as part of their treatment was superior—83% vs. 74%; this difference in survival was statistically significant.
Two other as yet unpublished studies were included in the National Cancer Institute (NCI) Clinical Announcement. In yet another GOG study in which patient accrual was completed in 1990, patients with locally advanced cervical cancer (stages IIB, III, and IVA without positive para-aortic nodes) were randomized to receive one of two treatments: 1) pelvic and intracavitary radiation plus chemotherapy with cisplatin and 5FU; or 2) pelvic and intracavitary radiation plus chemotherapy with hydroxyurea. Patients who received the chemotherapy combination of cisplatin and 5FU had a statistically significant improvement in survival—67% vs. 57%. In a study of the Southwest Oncology Group (SWOG), which was recently presented at the annual meeting of the Society of Gynecologic Oncologists, patients with stages IA2, IB, and IIA cervical cancer found to have metastatic disease in the pelvic lymph nodes, positive parametrial involvement, or positive surgical margins at time of radical hysterectomy and bilateral pelvic lymphadenectomy were randomized to one of two treatments: 1) pelvic radiation plus the combination of cisplatin and 5FU; or 2) radiation alone. The women who received the combination of radiation and chemotherapy had a statistically significant improvement in three-year survival—87% vs. 77%.
The findings of these studies indicate that platinum-based chemotherapy should be added to radiation for women with locally advanced cervical cancer or for women who are found to have specific unfavorable histopathological factors at the time of radical hysterectomy. Future studies will undoubtedly refine our know- ledge and attempt to define the optimal chemotherapy regimen. Every obstetrician-gynecologist should be aware of this dramatic change in the standard treatment of a large proportion of women with invasive cervical cancer.
Reference
1. Keys HM, et al. N Engl J Med 1999;340:1154-1161.
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