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Pelvic Irradiation With Concurrent Chemotherapy Versus Pelvic and Para-Aortic Irradiation for High-Risk Cervical Cancer: an Update of the Radiation Therapy Oncology Group Trial (RTOG) 90-01

Posted on: Friday, 22 October 2004, 03:00 CDT

Objective:

To report mature results of a randomized trial that compared extended-field radiotherapy (EFRT) versus pelvic radiotherapy with concomitant fluorouracil and cisplatin (CTRT) in women with loco- regionally advanced carcinomas of the uterine cervix.

Methods:

Four hundred and three women with cervical cancer were randomly assigned to receive either EFRT or CTRT. Patients were eligible if they had stage UB to IVA disease, stage IB to IIA disease with a tumor diameter greater than 5 cm, or positive pelvic lymph nodes. Patients were stratified by stage and by method of lymph node evaluation.

Results:

* Two hundred and twenty-eight surviving patients were followed for a median of 6.6 years.

* Overall survival rate at 8 years for patients treated with CTRT was 67% compared to 41% for those patients treated with EFRT (p > 0.0001).

* Risk of recurrence was also significantly lower for CTRT (36%) compared to EFRT (66%) resulting in a HR (recurrence) of: 0.49 (95 % CI: 0.36-0.66, p > 0.0001).

* Patients with stage IB to IIB disease who received CTRT had better overall and disease-free survival than those treated with EFRT (p > 0.0001).

* One hundred and sixteen patients with stage III to IVA disease had better disease-free survival (p > 0.05) and a trend toward better overall survival (p = 0.07) if they were randomly assigned to CTRT.

* The rate of serious late complications of treatment was similar for the two treatment arms.

Conclusion:

Mature analysis confirms that the addition of fluorouracil and cisplatin to radiotherapy significantly improved the survival rate of women with locally advanced cervical cancer, without increasing the rate of late treatment-related side effects.

Selected references:

Morris M, Eifel PJ, Lu J, et ai. Pelvic radiation with concurrent chemotherapy compared with pelvic and paraaortic radiation for high- risk cervical cancer. N Engl J Med 1999;340:1137-43

Pearcey R, Brundage M, Drouin P, et ai. Phase Hl trial comparing radical radiotherapy with and without cisplatin chemotherapy in patients with advanced squamous cell cancer of the cervix. J Gun Oncol 2002;20:966-72

Rose PG, Blessing JA, Gershenson DM, et of. Paclitaxel and cisplatin as Arst-line therapy in recurrent or advanced squamous cell carcinoma of the cervix: a gynecologic oncology group study. J Clin Oncol 1999;17:2676-80

Commentary:

In 1999, the National Institute of Health issued a clinical alert regarding the treatment of advanced carcinoma of the cervix, hased on the results from five prospective randomized trials comparing standard radiotherapy to cisplatin-based chemoradiation. The remarkably consistent outcome data demonstrated clear progression- free and overall survival benefits in those patients treated with various cisplatin-based chemotherapy regimens concomitantly with radiation, compared with radiation alone. Since the greatest effect was on local-regional control, its mechanism of action appears to be employed through radiosensitization - that is, enhancing the tumorocidal effects of ionizing radiation. It was hoped that since the chemotherapy was administered systemically, an additional effect on recurrence from control of micrometastatic disease would manifest by a concomitant decrease in distant disease failure. In the current trial, distant failure was significantly reduced in the experimental arm. However, this effect has not been consistent throughout the trials, and careful analysis of the current trial suggests that these distant failures may more likely reflect metastases from poor local-regional control. Isolated para-aortic failure, for instance, was not reduced by use of chemoradiation (7% vs. 9%). Although the randomized studies addressed slightly different cohorts and clinical scenarios, the data clearly shaped clinical opinion, resulting in a change to the standard of care for these women. What was missing was maturity of the data to evaluate the important treatment-related toxicities and the import of recurrence on future survival. The current manuscript addresses these issues with the longest reported follow-up series of any reported randomized trial. Though, their conclusion that the survival characteristics come without much of a price may be slightly overstated. The 'control' treatment used in this trial, namely extended field radiation, is not routinely used in clinical practice without provocation (such as mefastatic disease), precisely because of treatment-related toxicity to the intestine. This may have created opportunity for a type-II error through higher background toxicity estimates. It is also important to note that while these US-conducted randomized trials prompted the NIH to issue its statement, they represent only a subset of the reported randomized trials to date, including one recently reported trial by Pearcey et al., which failed to demonstrate any advantage to the use of chemoradiation in patients with advanced stage cervix cancer. That trial, conducted by the National Cancer Institute of Canada (NCIC) randomized 253 women to either weekly cisplatin with standard pelvic radiation and brachytherapy, or standard pelvic radiation therapy with brachytherapy. While this is a regimen more in line with standard clinical practice in the US, methodology (radiation treatment delivery), patient selection (hemoglobin levels) and pure statistical chance have all been forwarded as explanations for this studies' variance with other reported trials. In either event, women with advanced disease represent a difficult clinical challenge and a fertile area for additional research, which should be aggressively pursued.

Eifel PJ, Winter K, Morris M, Levenback C, Grigsby PW, Cooper J, Rotman M, Gershenson D, Mutch DG. J Clin Oncol 2004;22:872-8

Further reading:

Green JA, Kirwan JM, Tierney JF, Symonds P, et al. Survival and recurrence after concomitant chemotherapy and radiotherapy for cancer of the uterine cervix: a systematic review and meta- analysis. Lancet 2001 ;358:781-6

Kirwan JM, Symonds P, Green JA, Tierney J, et al. A systematic review of acute and late toxicity of concomitant chemoradiation for cervical cancer. Radiother Oncol 2003;68:217-26

Commentary by: Robert L. Coleman, MD, University of Texas, Southwestern, Dallas, TX

Copyright CRC Press Jun 2004

Source: Women's Oncology Review

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