March 08, 2017
5 min read

Adjuvant and systemic therapy ‘rapidly evolving’ for rare ovarian tumors

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Editor’s Note: This column is a three-part series intended to offer oncologists practical advice on the treatment of rare gynecologic malignancies. Part 2, published here, addresses adjuvant therapy for rare ovarian tumors. Part 1, published in the Feb. 25 issue, outlined advances in surgical management. Part 3, which will address rare diseases of the uterus and cervix, will be published in a subsequent issue.

Gynecologic cancers accounted for an estimated 105,890 new cancer diagnoses and 30,890 deaths in 2016. An estimated 107,470 new gynecologic cancers will be diagnosed in 2017, and approximately 31,600 women will die of these malignancies this year. Rare gynecologic cancers represent the histologies responsible for less than 5% to 10% of cancers in a given anatomic site.

Jubilee Brown, MD
Jubilee Brown
Erin K. Crane, MD
Erin K. Crane
R. Wendel Naumann, MD
R. Wendel Naumann

The first installment in this series presented advances in surgical management of rare gynecologic tumors. Here, we present an update on adjuvant and systemic therapy in the management of uncommon ovarian malignancies, with supporting science and practical applications.

Endometriosis-associated tumors

Although endometriosis is not uncommon, cancers arising in endometriosis are. Malignancies develop in 0.3% to 3% of endometriosis cases — a rate that is higher than the risk in the general population of one in 70 patients. Clear cell and endometrioid ovarian carcinomas and extrauterine endometrial stromal sarcomas tend to be the predominant malignant pathologies identified in patients with endometriosis. Mutations in ARID1A have been detected in clear cell carcinomas, as well as in adjacent areas of benign and atypical endometriosis. Although treatment generally follows guidelines for the incident pathology, patients with clear cell carcinomas arising from endometriosis may present at an earlier stage and have an improved OS.

Malignant germ cell tumors of the ovary

The combination of bleomycin, etoposide and cisplatin (BEP) has been curative for most patients with malignant ovarian germ cell tumors since its inception in the 1980s. Current progress centers on limiting the number of patients who require chemotherapy, as over half of patients with stage I disease will be cured without chemotherapy, and patients with early-stage disease who recur are almost universally salvaged with BEP chemotherapy.

An Intergroup National Clinical Trials Network trial is investigating this approach and is also comparing carboplatin vs. cisplatin in pediatric patients. Patients with refractory disease should be treated with TIP (paclitaxel, ifosfamide, cisplatin) or VeIP (vinblastine, ifosfamide, platinum) and, if a response is seen, they may be considered for high-dose carboplatin and etoposide chemotherapy with stem cell rescue. The cyclin-dependent kinase (CDK) inhibitors are a promising new class of targeted agents; a clinical trial with 29 patients with recurrent germ cell tumors treated with the CDK4/6 inhibitor palbociclib (Ibrance, Pfizer) demonstrated a 6-month PFS rate of 28%.

Sex cord–stromal tumors of the ovary

Patients with advanced-stage or recurrent chemotherapy-naive sex cord–stromal tumors of the ovary have historically been treated with BEP chemotherapy, but the combination of paclitaxel and carboplatin has shown comparable activity and less morbidity in retrospective analyses; this is under investigation in a cooperative group phase 3 trial. Single-agent bevacizumab (Avastin, Genentech) has also demonstrated activity in the recurrent setting and is under investigation in combination with paclitaxel.

Mutations in the FOXL2 gene appear to be the driver mutation for patients with adult granulosa cell tumors, a finding that could yield a future therapeutic strategy. Additionally, DICER1 mutations appear in patients with Sertoli–Leydig cell tumors and are linked in some cases to the rare pleuropulmonary blastoma syndrome (PPB), which is fatal when detected at an advanced stage but curable when identified in infants. Testing of family members with the DICER1 mutation can lead to screening and early identification of ovarian malignancies and PPB. The International Ovarian and Testicular Stromal Tumor Registry is collecting and analyzing DICER1 mutations in patients with gonadal stromal tumor.


Clear cell carcinoma of the ovary

The choice of adjuvant therapy for early-stage clear cell carcinoma of the ovary remains three to six cycles of IV paclitaxel and carboplatin; however, there are no relevant data to suggest that three vs. six cycles is superior to the other. In addition, irinotecan plus cisplatin compared with standard therapy showed no advantage but increased toxicity. Advanced-stage disease should be treated with six cycles of IV paclitaxel and carboplatin; no advantage to dose-dense chemotherapy, intraperitoneal chemotherapy, or irinotecan plus cisplatin has been demonstrated. Sunitinib (Sutent, Pfizer) and temsirolimus (Torisel, Pfizer) failed to show activity in recurrent disease. Ongoing trials are evaluating nintedanib (Ofev, Boehringer Ingelheim), and nivolumab (Opdivo, Bristol-Myers Squibb) has shown activity in a phase 1 trial, so it has the potential for future investigation. Other interesting therapeutic targets include PIK3CA, ARID1A, mTOR and HNF1-alpha.

Mucinous carcinoma of the ovary

Advanced-stage mucinous carcinomas of the ovary have a worse prognosis than the more common serous ovarian carcinomas, and standard paclitaxel and carboplatin chemotherapy yields poor results. Many clinicians have opted for a gastrointestinal-type regimen consisting of IV oxaliplatin and 5-FU or capecitabine with or without bevacizumab in patients with stage IB to IV disease. A cooperative group trial designed to investigate this regimen was suspended due to low accrual and a high rate of misdiagnosed gastrointestinal primary enrollment on the trial.

Low-grade serous carcinoma of the ovary

This entity is distinct from high-grade serous ovarian cancer, and is chemotherapy resistant. Patients with stage Ic disease or greater should be treated with surgery followed by adjuvant therapy. However, treatment with inhibitors of MEK, AKT or vascular endothelial growth factor, or with hormonal therapies (aromatase inhibitors, tamoxifen) may be preferred in both upfront and recurrent settings to paclitaxel and platinum therapy. Multiple trials are investigating MEK inhibitors in the recurrent setting.


The optimal treatment of patients with rare ovarian cancer is rapidly evolving, with targeted therapies under investigation and clinical trials underway. Patient outcomes depend on this, and multiple researchers have demonstrated superior results when patients undergo treatment in a high-volume center. When possible, these patients should be referred to high-volume centers of excellence and specialists with expertise in the field of these rare cancers, and they should be considered for clinical trials when available.


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The following were presented at: ASCO Annual Meeting; June 3-7, 2016; Chicago:

Farley JH, et al. Abstract 5531o.

Gershenson DM, et al. Abstract 5502.

For more information:

Jubilee Brown, MD, is professor and associate director in the division of gynecologic oncology at Levine Cancer Institute at Carolinas HealthCare System. She can be reached at 1021 Morehead Medical Drive, Suite 2100, Charlotte, NC 28204; email:

Erin K. Crane, MD, is a gynecologic oncologist at Levine Cancer Institute at Carolinas HealthCare System. She can be reached at

R. Wendel Naumann, MD, is a gynecologic oncologist at Levine Cancer Institute at Carolinas HealthCare System. He can be reached at

Disclosure: Brown, Crane and Naumann report no relevant financial disclosures.