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Salvage Whole-Abdominal Radiation Therapy After Second-Look Laparotomy or Secondary Debulking Surgery in Patients With Ovarian Cancer

Posted on: Friday, 5 August 2005, 09:00 CDT

Objectives

To determine the response and toxicity associated with the use of whole-abdominal radiation therapy (WART) in women with ovarian cancer.

Introduction

While significant strides have been made, the overall survival for women diagnosed with advanced epithelial ovarian cancer is poor despite aggressive cytoreductive surgery and platinum-based chemotherapy. With our current treatment regimens, the majority of women will achieve a complete clinical remission, however up to 50% of these women will have at least microscopic disease at the time of a secondary surgical assessment. Therefore, there has been considerable interest in determining the most beneficial consolidative therapy for these women as the majority will have a disease recurrence. However, to date the benefits of and the agents to be used in consolidative therapy are not clear. Chemotherapy, radiotherapy, hormones and biologic agents are all reasonable treatment modalities to be used for consolidation. Given that many of the women with a positive second-look laparotomy will have small volume disease, WART may be effective as it is able to sterilize small tumor volumes.

Methods

A retrospective review of 171 women who received WART after surgery for persistent or recurrent epithelial ovarian cancer between 1981 and 2000 was performed. Initial therapy consisted of cytoreductive surgery followed by systemic platinum-based chemotherapy in 170 of the women. The primary endpoint was progression-free survival (PFS) from the time of second look laparotomy (SLL) or secondary cytoreduction (SD). PFS was defined as the time from SLL or SD to disease progression or death without progression. secondary endpoints included overall survival (OS) defined as time from SLL or SD to death from any cause and intestinal complications from WART.

OS and PFS were estimated using the Kaplan-Meier method. The log- rank test was used to assess whether PFS or OS differed with respect to age, tumor grade, stage, amount of disease at the time of SLL or SD, amount of residual disease at the completion of surgery or radiation course. Cox modeling was performed to determine which variables were associated with PFS and OS.

Results

Patient characteristics

* 109 women with a clinical complete response (CR) and documented persistent disease at SLL who received WART and 62 women who received WART after SD for recurrent disease were included.

* The median age was 59 years and 80% had either stage III or IV disease.

* After primary surgery 59% were optimally dehulked (≤ 2 cm residual), 13% were suboptimally debulked and 29% had an uncertain status.

* At the time of SLL or SD, 24% had microscopic disease, 40% had disease < 2cm and 35% had at least 2 cm of disease. At the completion of SLL or SD, 67% had microscopic disease, 30% had disease ≤ 2 cm and 3% had disease > 2 cm.

Radiation therapy

* After SLL or SD, all the women received WART through an open- field technique. Seventy percent of the women received a pelvic boost and 12% received a para-aortic boost.

* The median dose to the whole abdomen was 25.5 Gy (range 1.0- 30.5 Gy); the median dose to the pelvis was 24.0 Gy (range 3.0-59.7 Gy); and the median boost to the para-aortic region was 15.0 Gy (range 7.5-42.0 Gy).

* One hundred and twenty-three of the 171 patients (72%) completed their planned RT. The others discontinued therapy because of toxicity (30 patients), disease progression (7 patients) or other reasons (8 patients).

* Median follow-up was 98.4 months (range 1.6-192.0 months) for those undergoing SLL and a median of 8.7 months (range 2.0-116.4 months) for those undergoing SD.

Response, progression free survival and overall survival

Second-look laparotomy

* Of the 109 women who underwent SLL followed by WART, 83 (76%) completed the planned therapy.

* Median PFS was 19.8 months with an estimated 5-year PFS rate of 24% (95% C.I., 17-34%). Median OS was 35.1 months with an estimated 5-year OS rate of 29% (95% C.I., 22-40%).

* Multivariate analysis showed that age, amount of residual disease at the completion of SLL were independently associated with OS. In addition, these three factors and amount of disease at the initiation of SLL were associated with PFS.

* Patients with microscopic disease at the completion of SLL had a 5-year PFS of 41% compared to patients with gross disease who had a PFS of 8% (P < 0.001).

Secondary debulking

* Of the 62 women who underwent SD followed by WART, 40 (65%) completed the planned therapy.

* Median PFS was 11.0 months with an estimated 5-year PFS rate of 6% (95% C.I., 2-18%). Median OS was 19.5 months with an estimated 5- year OS rate of 11% (95% C.I., 4-27%).

* Both PFS and OS were increased in those women who were able to complete prescribed WART (P < 0.001).

* Survival was not associated with the amount of residual disease at the completion of SD (P = 0.20).

Toxicity

Second-look laparotomy

* Seventeen of the 109 women (16%) had a small bowel obstruction and all but 1 woman had had a pelvic boost. Twelve women required surgery and 5 were managed expectantly. One woman died of a SBO 2.4 years after WART.

Secondary debulking

* Nine (15%) women developed a bowel obstruction, all of which had a pelvic boost. One woman was managed expectantly and the other 8 required surgery. Three of the surgically managed women died of progressive bowel obstruction within 10 months of completing WART (1 with disease, 2 no evidence of disease).

Conclusion

In women with positive SLL, WART may be considered, but only in those with microscopic residual disease. In these women, up to 15% may have a treatment related small bowel obstruction. In women with recurrent disease, regardless of the degree of secondary cytoreduction, WART may not be acceptable secondary to bowel toxicity.

Commentary

Ovarian cancer affects approximately 25,000 women every year in the United States and despite new treatment efforts it continues to represent a highly lethal malignancy. Surgical resection followed by platinum and taxane based chemotherapy is considered the mainstay of current epithelial ovarian cancer treatment. The majority of patients will achieve a complete clinical response with these measures, however many of these patients relapse with incurable disease. The poor predictive value of complete clinical response is evidenced by a 50% positive SLL rate. The absence of complete pathologic response represents the barrier to improved cure rates in ovarian cancer. Based on the high rates of subclinical disease after surgery and standard chemotherapy, some have advocated an extension of therapy or consolidation to improve survival. Continued chemotherapy, biologic agents directed at distinct cellular pathways, intraperitoneal radioactive colloids, immunotherapy, and as discussed in this paper radiation therapy have all been investigated as potential agents to assist in improving survival.

The concept of WART is appealing in ovarian cancer given its propensity to recur predominantly in the peritoneal cavity. The disadvantages associated with WART can be attributed to the associated gastrointestinal toxicity, and the inability to deliver adequate dose for macroscopic tumor. Thomas et al. [1] reviewed the role of radiation therapy for consolidation or salvage therapy in ovarian cancer. The review included 713 patients from 28 published studies. The WART results were overall disappointing with a limited benefit in either the consolidation or salvage settings. Inappropriate patient selection, toxicity, biologic factors inherent to the tumor, and a variety of treatment techniques between studies were all cited as potential reasons WART did not improve survival. Patients with negative or microscopic ( < 5 mm) disease at the time of SLL were thought to be the appropriate candidates for WART consideration. Similarly, the current report demonstrated a potential benefit for WART in women with microscopic residual disease at SLL and no benefit for macroscopic disease or in the salvage setting. These findings unfortunately raise the favorable tumor biology versus improved treatment question that is inherent to most ovarian cancer discussions. Patients who meet these criteria represent a favorable group and it is unclear whether WART offers the improved outcome or if other more tolerable treatments would offer similar results.

Dusenbery et al. [2] reviewed 5 randomized controlled trials evaluating consolidation radiation therapy compared with chemotherapy. Two favored radiation therapy, 2 found no difference and 1 favored chemotherapy. Based on these results, these authors call for a reevaluation of the role of radiation therapy in ovarian cancer. A recent randomized trial conducted by the Swedish- Norwegian Ovarian Cancer Study Group showed that in women with microscopic disease at SLL, the PFS and OS of WART and chemotherapy (cisplatin and doxorubicin or epirubicin) were similar at 5 years. However, in those women with a complete pathologie response, the 5- year PFS was 56.3% in the WART group and 36.0% and 35.5% for those treated with chemotherapy or observation, respectively (P = 0.03). There was no difference, however, in the 5-year OS. One has to also consider that this study was conducted in a cohort of wome\n who never received a taxane and whether this data would he transferable to women who have been treated with induction platinum and taxane based chemotherapy.

Given the high rates of complete clinical response with first line therapy, the role of consolidation therapy is becoming increasingly more important in ovarian cancer. It remains to be seen if radiation therapy should play a role in this phase of treatment of if consideration should be given to other less toxic regimens. The ideal consolidation regimen should offer improved overall survival with acceptable toxicity.

Further reading

Thomas G. Is there a role for consolidation or salvage radiotherapy after chemotherapy in advanced epithelial ovarian cancer? Gynecol Oncol 1993;51:97-103.

Dusenhery KE, Bellaris EE, Potish RA, Twiggs LB, Boente ND, et al. Twenty-five year outcome of sequential abdominal radiotherapy and melphalan: implications for future management of epithelial carcinoma of the ovary. Gynecol Oncol 2005;96:307-13.

Selected references

1. Fuks A, Rizel S, Brian S. Chemotherapeutic and surgical induction of pathological complete remission and whole abdominal irradiation for consolidation does not enhance the cure of stage III ovarian carcinoma. J CHn Oncol 1988;6:509-16.

2. Sorbe B, on behalf of the Swedish-Norwegian Ovarian Cancer Study Group. Consolidation treatment of advanced (FIGO stage III) ovarian carcinoma in complete surgical remission after induction chemotherapy: a randomized, controlled, clinical trial comparing whole abdominal radiotherapy, chemotherapy, and no further treatment. Int J Gynecol Cancer 2003;13:278-86.

Dowdy SC, Metzinger DS, Gebhart JB, Srivatsa P, Haddock MG, Suman VJ, Podratz KC. Gynecol Oncol 2005;96:389-94

Commentary by: Teresa L. Rutledge, MD, and Paola A. Gehrig, MD, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

Copyright CRC Press Mar 2005

Source: Women's Oncology Review

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