Pelvic Radiation with Concurrent Chemotherapy Compared with Pelvic and Para-Aortic Radiation for High-Risk Cervical Cancer

Authors: Morris M, Eifel P, Jiandong L, et al.
Source: N Engl J Med 1999; 340:1137-1143.

Background

• Cervical cancers that are bulky, extend to parametrial/pelvic tissues and/or involve pelvic lymph nodes benefit from external-beam plus intracavitary radiation.
• RTOG 79-20 reported improved survival in women with locally advanced cancer (bulky IB, IIA and IIB) treated with prophylactic radiation to the para-aortic nodes.
• Early studies exploring concurrent chemoradiotherapy to eradicate micrometastases and radiosensitize tumor have been criticized because of their use of deficient radiotherapy techniques as well as the lack of appropriate control groups (radiation alone).
• The randomized clinical trial discussed here, RTOG 90-01, compared the survival after pelvis and para-aortic field radiotherapy versus pelvic radiotherapy with concurrent cisplatin-based chemotherapy.

Materials and Methods

• 403 patients with SqCCa (90%), AdenoCa or AdenoSqCa of the cervix, stages IIB through IVA (IB & IIA allowed if at least 5 cm or involving pelvic LNs), were entered
• All patients had prospective assessment of PALN by lymphangiogram (75%) or surgical exploration (25%)
• Patients in the RT alone group (RT) received 45 Gy to their whole pelvic as well as para-aortic region up to the bottom of L1. This was complemented by a LDR brachytherapy boost for a total dose to point A of 86-87 Gy
• Patients in the chemoradiation group (CRT) received 45 Gy to their whole pelvis with concurrent cisplatin (75 mg/m2) and 5-FU (4g/m2 over 96 hour). This chemotherapy was repeated q 3 weeks x 3
• All external-beam radiotherapy was delivered with megavoltage equipment
• KPS had to be at least 60 (>80% had KPS =90)
• Patients were stratified by FIGO stage (IB-IIB vs. III-IVA) and method of PALN assessment
• Median follow up reported in the original article was 43 months; the quoted figures are from a recent update (ASTRO 2002) with a median follow-up of 55 months

Results

• Median duration of radiotherapy was 58 days, with a mean dose to point A of 89 Gy in each group
• Outcomes were significantly better for patients treated with chemoradiation
• OS was 73% vs. 52%
• For patients stage I-II disease, OS was 79% vs. 55%
• For patients stage III-IVA disease, OS was nearly significantly better (59% vs. 45%, p=.07)
• Local failure was 18% vs. 34%
• Development of DM was 18% vs. 31%
• PA node failure was 7% (CRT) vs. 4% (RT)
• Although grade 3-4 acute side effects occurred more frequently in the CRT group, there were no differences in major late complications (RT, 14% versus CRT, 12%)
• Most late complications were rectal or colonic in nature

Author's Conclusions

• Pelvic radiation therapy with concurrent cisplatin and 5FU chemotherapy reduces the risk of both local and distant relapses, decreasing the overall rate of recurrence by 50%
• This translated into a significant survival gain for the CRT group
• There were gains in Stage III-IVA disease, though the greatest advantage was seen in patients with Stage I-II disease
• The benefit observed was gained without an increase in toxicity

Clinical/Scientific Implications

• The radiation therapy delivered in this study was superior to previous regimens reported in that the median dose was higher and the median duration of treatment was shorter
• Also, the chemotherapy regimen employed a relatively aggressive dose of cisplatin, 75 mg/m2 per administration for three cycles (one cycle during an intracavitary procedure)
• PALN irradiation is probably necessary for patients with known para-aortic involvement, and may benefit selected patients when used in a prophylactic setting
• With several studies documenting increased efficacy of chemoradiation over radiation alone in the treatment of locally advanced cervical cancer, this has become the indisputable standard of care for these patients
• Further research is necessary to determine the best chemotherapy agents, schedule, and route of delivery.
• • This study is the only of five recent randomized trials in this area to show a decrease in local failure as well as distant failure, suggesting that the combination of cisplatin and 5FU is better than cisplatin alone
  • Weekly cisplatin can be adjusted quickly in response to toxicity