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A randomized phase III study on adjuvant treatment with radiation (RT) +/- chemotherapy (CT) in early stage high risk endometrial cancer (NSGO-EC-9501/EORTC 55991)

Reviewer: Christopher Dolinsky, MD
Abramson Cancer Center of the University of Pennsylvania
Ultima Vez Modificado: 3 de junio del 2007

Presenter: T. Hogberg
Presenter's Affiliation: Nordic Society of Gynecologic Oncology, Odense, Denmark
Type of Session: Scientific

Background

• Endometrial cancer is the most common gynecologic cancer among women in North America, affecting over 40,000 women per year.
• 75% of endometrial cancer cases present with disease confined to the uterus and surgery is the mainstay of therapy.
• Certain pathologic factors can predict for a higher likelihood of micrometastatic disease at the time of surgery.
• If a patient does in fact have micrometastatic disease, then an effective adjuvant therapy could potentially lead to a cure.
• If micrometastatic disease is confined to the pelvis, then adjuvant pelvic radiotherapy should be an effective treatment; however, if micrometastatic disease exists outside of the pelvis, then systemic therapy is required.
• The most efficacious adjuvant treatment for early stage high risk endometrial cancer remains controversial.

Materials and Methods

• Patients were enrolled in a phase III randomized trial comparing radiation therapy to chemotherapy with radiation therapy for the adjuvant treatment of endometrial cancer.
• The study's goal was to accrue 400 patients, but it was closed early secondary to poor accrual.
• Of the 382 patients evaluable, 196 were randomized to radiation therapy and 186 were randomized to chemoradiotherapy.
• Pelvic radiotherapy was given to a dose of 44 Gy; vaginal brachytherapy was optional and given at the discretion of the treating physician.
• Chemotherapy consisted of a number of different regimens depending on the center where patients were treated including: adriamycin + cisplatin, epirubicin + cisplatin, paclitaxel + carboplatin, paclitaxel + carboplatin + epirubicin.
• The primary endpoint was progression free survival.
• Patients with surgical stage I, II, IIIA and IIIC disease were eligible for this trial.
• Patients were considered high risk based on the discretion of the treating center and most patients had at least 2 of following risk factors: grade 3 disease, deep myometrial invasion, or DNA non-diploidy.
• Lymph node exploration at the time of surgery was optional.
• Patients with clear cell, serous, or anaplastic histologies were eligible regardless of risk factors.

Results

• >90 % of patients were able to complete their prescribed radiation while approximately 70% of patients were able to complete their chemotherapy.
• Vaginal brachytherapy was used in 39% of the RT patients and in 44% of the chemoRT patients.
• Median follow-up was 4.3 years.
• The estimated difference in 5 year PFS improved from 72% in the RT arm to 79% in the chemoRT arm without censoring intercurrent deaths (p=0.03).
• The RT alone patients had a higher chance of relapsing outside the pelvis (as the sole site of relapse) compared to the chemoRT arm (16% vs. 10% respectively).

Author's Conclusions

• Combined chemotherapy and radiation is superior to radiation alone as adjuvant therapy for early endometrial cancer with high risk features for metastasis.
• A new trial should compare combined chemotherapy and radiation with chemotherapy alone.

Clinical/Scientific Implications

Adjuvant radiation is the cornerstone of managing patients with high risk features after surgery for early stage endometrial cancer. This trial attempted to see if the addition of chemotherapy to radiation could improve outcomes. Unfortunately, this trial was not designed well enough to answer that question by itself. There was tremendous heterogeneity amongst the treatment regimens that were prescribed; both in terms of the chemotherapy regimen used and whether brachytherapy was employed. Also, the details regarding the prescription of brachytherapy were never reported. Patients who did not get an optional lymphadenectomy could have entered this trial with occult para-aortic disease; and if so, such patients would stand to gain more from the addition of chemotherapy than the patients that were selected for this study. This study did not report on treatment toxicity, and the statistical power of the study design was also never shown. Because these points, it is premature to conclude that chemotherapy and radiation are superior to radiation alone for the patients studied in this trial.