Adjuvant Radiotherapy for Cervical Cancer

Introduction

Equivalent cure rates for early stage cervical cancer (stage IB1) can be achieved with either surgery or radiotherapy. The decision to choose one treatment over the other is complex and based upon a variety of factors, including patient age, comorbid medical factors, patient preference, and the potential complications of treatment. Although a concerted effort should be made to minimize the need for combined-modality therapy because of the increased risk for toxicity, clinical situations arise where postoperative radiation radiotherapy may be indicated. Two randomized trials recently have been reported which have clarified the indications for postoperative radiotherapy.

In considering the role of postoperative radiotherapy, it is important to define the lymph node status (involved vs uninvolved), as well as the presence of high-risk central disease. The risk for recurrence and related benefit of postoperative radiotherapy for both groups of patients has been summarized by Thomas et al.

High-risk Central Features With Negative Lymph Nodes

The therapeutic benefit of adjuvant radiotherapy for patients with uninvolved nodes but high-risk features in the cervix was recently reported by Sedlis  Patients with a high (30%) risk of recurrence after surgery were identified based upon the Gynecologic Oncolgy Group (GOG) study 49.  These high-risk patients had at least two of the following risk factors: capillary-like space involvement, greater than one-third cervical stromal invasion, and a large clinical tumor diameter. Patients were randomized to treatment with surgery alone or surgery followed by irradiation. Those treated with adjuvant radiotherapy received either 46 Gy in 23 fractions or 50.4 Gy in 28 fractions. No patients received a brachytherapy boost.

At 2 years, 21% of the patients treated with surgery alone had failed to survive compared to only 12% of those who received postoperative irradiation. The survival rates at 2 years were 79% in the surgery arm and 87% for combined-modality therapy (not significant). Pelvic recurrences were identified in 21% of patients after surgery alone and in 13% of patients who received postoperative irradiation. Significant complications (grade 3/4) were encountered in 2% of patients after surgery and in 6% after combined-modality therapy.

Of note, about 7% of patients randomized to combined-modality therapy refused to undergo the radiation therapy portion of the treatment, 11% were non-compliant and received less than 85% of the prescribed dose, and 20% had treatment times in excess of the planned treatment time. Thus, about 18% of patients received either clearly suboptimal radiation therapy or no radiation therapy whatsoever. In addition, the radiation fields missed the actual target volume in some cases. Members of the GOG Cervix Committee are currently reviewing port films to assess the frequency of this problem. Finally, the study design omitted the use of vaginal brachytherapy. These deficiencies may help explain the disappointing pelvic control rates (87%) after combined surgery and radiation.

For patients who have high-risk central features but negative lymph nodes, adjuvant radiotherapy may confer a survival benefit. Central failure is the greater risk, compared to the risk of metastatic disease that is present for patients with involved nodes.   Since the central tumor volume is a common site of failure in this setting, there may be a rationale to incorporate a brachytherapy boost in addition to the external beam pelvic irradiation. External-beam radiation alone to 45 Gy to 50 Gy may not be adequate to eradicate tumor clonogens at the vagina apex where hypoxic cells are more likely to exist. Therefore, many institutions incorporate a brachytherapy boost in conjunction with external-beam radiotherapy. Typical low-dose-rate (LDR) insertions deliver 20 Gy to 30 Gy at 1.0 Gy/h to the upper one third of the vaginal mucosa. With high-dose-rate (HDR) brachytherapy, this can be accomplished in as few as 3 fractions, or even in 2 fractions. The table lists the values to deliver a 20 Gy or 30 Gy LDR-equivalent at the vaginal surface in 2 HDR fractions to 4 HDR fractions. Patients seem to tolerate the brachytherapy boost better during the first half of external-beam radiation, with lower rates of mucositis. 

Positive Lymph Nodes and High-risk Central Features

Cervical cancer patients with positive pelvic lymph nodes traditionally have received adjuvant radiotherapy. Peters et al recently published the results of an intergroup trial that randomized patients to surgery and postoperative radiation or surgery followed by concurrent chemoradiotherapy if they met the following criteria: positive pelvic lymph nodes, positive margins, or parametrial involvement. Pelvic radiotherapy was administered to a dose of 49.3 Gy in 1.7 Gy fractions. If the high common iliac lymph nodes were positive, 45 Gy was administered to both the pelvic and para-aortic regions. No brachytherapy was permitted. Two cycles of cisplatin and fluorouracil (5-FU) were delivered concurrently with the radiation therapy, and an additional 2 cycles were delivered subsequently.

At 4 years, compared to postoperative radiation alone, concurrent therapy improved the progression-free survival from 63% to 80%, and the overall survival from 71% versus 81%. As anticipated, more grade 3 and 4 hematologic and gastrointestinal toxicities were encountered in the combined chemoradiation group.

Russell presented the results of their study of 42 patients with node-positive cervical cancer who underwent a radical hysterectomy. Patients received 45 Gy in 25 fractions plus a boost of 20 Gy (LDR) or 15 Gy (HDR) in combination with 2 cycles of 5-FU (4 g/m²/96 h) and bolus cisplatin (100 mg/m²) given during the first and fifth weeks of radiation. This regimen produced a 5-year recurrence-free survival rate of 84%, among the best results reported to date.

What is the take-home message from these studies? It appears that patients with negative pelvic lymph nodes and high-risk cervical features, as defined in GOG study 92, should receive adjuvant pelvic radiotherapy, while patients with positive pelvic lymph nodes should receive concurrent chemoradiotherapy. Interestingly, 64% of patients entered on the GOG trial had tumors greater than 4 cm. A randomized trial from Italy demonstrated similar survival and relapse-free survival rates when comparing surgery (most had postoperative radiotherapy because of large tumor size) to primary radiotherapy. Unfortunately, 28% of the patients who received postoperative radiotherapy suffered serious late complications compared to 12% of those who were treated with radiation therapy alone. These complications observed for dual-therapy were much higher, and possibly more realistic, than those reported in the Sedlis et al² trial, which had a relatively short follow-up of only 2 years.

What is the role for a brachytherapy boost? I personally think a brachytherapy boost should be strongly considered for the GOG study 92 population, and for those with positive margins and/or parametrial involvement. Reasons to consider a boost include the fact that a significant portion of failures occur at the vaginal apex, and little additional toxicity is encountered by the treatment. However, until the failure patterns of both studies are further investigated, the role of a brachytherapy boost will most likely be linked to institutional preference. It is possible that the excellent results reported by Russell et al⁶ may in part be due to the brachytherapy boost.

It is of interest that only 2 years ago many patients with stage IB cervical cancer were being managed very effectively with radiotherapy alone. Now, many will receive triple-modality therapy. Although some patients have adverse pathologic factors that require postoperative radiation and chemotherapy, other patients could be spared surgery or triple-modality therapy and enjoy a similar outcome with less toxicity. For example, should a woman with a 4 cm, poorly differentiated tumor undergo surgery? Also, should the surgeon proceed with a radical hysterectomy when positive lymph nodes are discovered? Hopefully, some attempt will be made to limit therapy while maximizing cure rates-both in practice and in future clinical trials.

Published November 2000