Impact of adjuvant therapy in lymph-node positive vulvar cancer: The AGO CARE 1 study
Reporter: Gita Suneja, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: June 2, 2012
Presenter: Sven Mahner Affiliation: University Medical Center Hamburg-Eppendorf, Department of Gynecology, Hamburg, Germany
The incidence of vulvar cancer is rising, with an increasing number of patients being diagnosed at younger ages.
While the majority of patients with vulvar cancer can be cured by surgery alone, women with lymph node metastases often have unfavorable outcomes.
Lymph node metastases are the primary predictor of treatment failure and death, so management of the lymph nodes is of critical importance.
At present, there is no international consensus regarding indications for adjuvant radiation therapy in node-positive patients.
Furthermore, existing guidelines are based on studies with small and heterogeneous cohorts.
The primary objective of this study was to determine the benefit of adjuvant therapy in lymph-node positive women with vulvar cancer in a large, retrospective, population-based cohort.
The study sample included 1,637 patients with primary squamous cell carcinoma of the vulva included in a centralized database.
Patients were treated at one of 29 gynecologic cancer centers in Germany between 1998 and 2008.
Patients had FIGO stage IB and higher vulvar cancer.
Median follow up was 121 months.
An overall survival analysis was conducted controlling for number of lymph node metastases and administration of adjuvant therapy.
Multivariate analysis was performed to identify predictors of improved overall survival.
Of the 1,637 patients, 597 (36.5%) were T1, 816 (49.8%) were T2, 160 (9.8%) were T3 and 31 (1.9%) were T4. Thirty-three patients (2.0%) had missing stage.
910 patients were node negative (LN-), and 497 patients had lymph node metastasis to the groin (LN+).
As a group, the LN+ women were older, had higher tumor stage, larger tumor diameter, greater depth of invasion, and higher tumor grade.
214 LN+ patients (43.6%) developed recurrent disease within a median of 21.4 months.
Of the 190 LN+ patients (38.7%) who died, median overall survival was 43.4 months, compared to 212 months for LN- patients.
An increasing number of lymph nodes was associated with shorter overall survival as is detailed below:
Number LN mets
% of LN+ Pts
240 LN+ patients were treated with adjuvant radiotherapy (85.8%) or chemoradiation (14.2%).
No significant differences in patient characteristics were observed between the LN+ treated with adjuvant therapy and LN+ not treated with adjuvant therapy.
The median cumulative dose of radiation therapy was 50.4 Gy.
Median overall survival in patients treated with adjuvant therapy (either chemo or chemoRT) was significantly longer compared to LN+ patients without adjuvant treatment (66.9 vs 35.7 months, hazard ratio 0.72; 95 % CI: 0.53 - 0.97 p = 0.029).
The overall survival benefit for adjuvant treatment was observed in multivariate analysis adjusted for age, ECOG performance status, stage, grading, invasion depth and number of positive nodes. Benefit for adjuvant therapy was demonstrated irrespective of the number of involved nodes.
Older age, poor performance status, and increased number of LN involved were associated with decreased overall survival.
These findings strongly suggest that the unfavorable prognosis of patients with LN+ vulvar cancer can be improved by adjuvant therapy, irrespective of the number of affected nodes.
Because adjuvant chemoradiation has been shown to be superior to radiotherapy alone in other squamous cell carcinomas, the authors are planning a prospective phase III trial of chemoradiation in node-positive vulvar cancer (AGO-CaRE 2 trial).
This impressive study represents the largest study to date of vulvar cancer patients.
Interestingly, the study question is similar to a 25 year-old phase III trial, GOG 37 (Homesley, 1986), which sought to determine whether adjuvant radiation therapy following pelvic lymph node dissection conferred a benefit to women with vulvar cancer. The study closed prematurely when an interim analysis showed a benefit to radiation therapy. The paper was published with 3 years of follow-up demonstrating a decreased inguinal recurrence rate and an increase in overall survival when adjuvant radiation was compared to observation. Adjuvant radiation for node positive vulvar cancer was adopted as the standard of care.
Subsequent studies have debated the value of adjuvant radiation for patients with only 1-2 positive lymph nodes.
A mature analysis of the GOG 37 data published in 2009 (Kunos, 2009) showed decreased cancer related deaths in the adjuvant radiotherapy arm, but no survival benefit; however, the study was small, had incomplete follow-up, and utilized older radiation therapy techniques.
While this retrospective study demonstrates a benefit to adjuvant therapy (either radiation therapy or chemoradiation), nearly 50% of patients with positive lymph nodes were not treated with radiation. This suggests that in Germany, there has been incomplete adoption of the GOG 37 data. The reasons for this are not entirely clear from the information provided by the authors.
Nonetheless, this study adds additional evidence that adjuvant radiation therapy is of value in vulvar cancer patients with lymph node involvement.
It is possible that the therapeutic ratio can be improved even further with the addition of chemotherapy to radiation therapy, particularly for cases with extranodal extension or a large number of involved lymph nodes.
The authors' proposed phase III study is intended to address the question of adjuvant chemoradiation for lymph node positive vulvar cancer, and its results will undoubtedly prove to be interesting and important. Hopefully, the planned study will incorporate modern radiation techniques, which may differ significantly from those employed in GOG 37. Investigation of the role of both chemotherapy and modern radiation in treatment of node positive vulvar cancer is certainly warranted.
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