Promises and pitfalls in the treatment of ovarian cancer

Is it becoming an orphan disease?

James Fleck: Anticancerweb 19(08), 2021

Considering the entire malignant tumor burden in woman, ovarian cancer ranks eighth in worldwide incidence (ASR = 6.6) and mortality (ASR = 4.2), according to the Global Cancer Observatory. Among gynecological tumors, ovarian cancer moves upward to the third position in incidence and second in mortality. Cervical cancer, followed by endometrial cancer take the leading position in incidence, but the international high crude mortality rate (CMR) of ovarian cancer (CMR = 66%) compared to endometrial cancer (CMR = 23.3%) make ovarian cancer the second leading tumor in mortality among all gynecological malignancies. Data from American Cancer Society in 2021, estimates that in USA 21,410 women will have a new diagnosis of ovarian cancer, and 13,770 women will die from this disease. Unfortunately, in USA the crude mortality rate for ovarian cancer (CMR = 64.3%) is not different from the international data. Additionally, due to a lower incidence of cervical cancer in USA, when compared to the international scenario, ovarian cancer will account for more women deaths than any other cancer of the female reproductive system. Despite being a very worrying epidemiological fact, ovarian cancer is very close to being considered a rare disease. Data from American Cancer Society indicated, in 2018, the prevalence of ovarian cancer as 235,081 women living with the disease in USA. A disease is classified as rare when it affects fewer than 200,000 Americans. It's close enough! It is precisely here that the most important risks are found, jeopardizing the basic and clinical investigation in ovarian cancer. Consequently, a low rate of improvement has been observed in the early diagnosis and treatment of ovarian cancer. Rare diseases tend to be switched to orphan diseases, which tend to be neglected. The development of new diagnostic or therapeutic interventions is often not considered profitable due to the high cost of laboratory and clinical research, targeting a limited number of potential patients. The figure below, represents the timeline of relevant events contributing for ovarian cancer treatment in the last 85 years.

NCI = National Cancer Institute, CP = Cyclophosphamide, Bev = Bevacizumab, PARP = poly (ADP-ribose) polymerase

Unfortunately, there is no effective screening methods for ovarian cancer , which lead to an early-stage diagnosis in only 25% of the cases. Most patients (75%) are diagnosed as locally advanced (III) or metastatic (IV) disease. Although total hysterectomy plus bilateral salpingo-oophorectomy is the standard primary treatment for early stage ovarian cancer, the benefit of secondary cytoreduction surgery remains controversial. Adjuvant platinum-based chemotherapy (mostly used carboplatin + paclitaxel) seems to be beneficial for tumors confined to the ovary with positive peritoneal washing (stage IC), clear cell histology or high tumor grade. A recent Cochrane Database Systematic Review, exploring the best approach for advanced epithelial ovarian cancer (Stage III and IV) suggested there is little or no benefit in survival outcome comparing the primary debulking surgery + chemotherapy versus neoadjuvant chemotherapy followed by interval surgery. Decision making should be tailored by individual prognostic indices. A Dutch multicenter, open label, phase III trial accrued 245 stage III ovarian cancer patients who had at least stable disease after neoadjuvant chemotherapy to receive additional hyperthermic intraperitoneal chemotherapy (HIPEC) or interval surgery alone. The addition of HIPEC was associated with greater recurrence-free survival and overall survival. However, a disappointing median overall survival of 45.7 months is still being observed in the surgery + HIPEC group.

Almost 20 years have passed before new drugs were introduced in the treatment of advanced ovarian cancer. The identification of germline and somatic BRCA1/2 mutations observed in 15 to 20% of ovarian cancer patients supported the use of PARP inhibitors as maintenance therapy in the platinum-sensitive population. Olaparib maintenance therapy provided a median overall survival benefit of 12·9 months, compared with placebo in patients with BRCA1/2 mutated platinum-sensitive relapsed ovarian cancer. For some advanced ovarian cancer patients without BRCA1/2 mutations, maintenance with bevacizumab with or without a PARP inhibitor seems to be a reasonable alternative. Bevacizumab maintenance was associated with a higher progression-free survival. The overall survival benefit could not be demonstrated, probably due to the crossover allowed after progression in the control arms. Despite recent improvements, advanced ovarian cancer remains an incurable disease and all stakeholders should join efforts for a better future in this almost orphan disease.



1.     Meigs JV: Tumors of the Female Pelvic Organs, New York: Macmillan, 1934

2.     Griffiths CT: Surgical resection of tumor bulk in the primary treatment of ovarian carcinoma, Natl Cancer Inst Monography42:101-104, 1975 

3.     HE Lambert and RJ Berry: High dose cisplatin compared with high dose cyclophosphamide in the management of advanced epithelial ovarian cancer (FIGO stages III and IV): report from the North Thames Cooperative Group, Br Med J 290: 889 – 93, 1985

4.     A DuBois, JP Neijt and JT Thigpen: First line chemotherapy with carboplatin plus paclitaxel in advanced ovarian cancer - a new standard of care? Annals of Oncology 10 (Suppl. I): 535-S41, 1999

5.     Stewart L: Advanced Ovarian Cancer Trialists Group, Cochrane Database Syst Rev, 2000

6.     Krishnansu S. Tewari, Robert A. Burger, Danielle Enserro, et all: Final Overall Survival of a Randomized Trial of Bevacizumab for Primary Treatment of Ovarian Cancer, J Clin Oncol 37:2317-2328, 2019

7.     Moore K, Colombo N, Scambia G, et al: Maintenance Olaparib in Patients with Newly Diagnosed Advanced Ovarian Cancer, N Engl J Med 379 (26): 2495, 2018

8.     Coleridge SL, Bryant A, Kehoe S, et al: Chemotherapy versus surgery for initial treatment in advanced ovarian epithelial cancer, Cochrane Database Syst Rev, Feb 5, 2021 

9.     Van Driel WJ, Koole SN, Sikorska K, et al: Hyperthermic Intraperitoneal Chemotherapy in Ovarian Cancer, N Engl J Med 378(3): 230, 2018

10.   Poveda A, Floquet A, Ledermann JA, et al: Olaparib tablets as maintenance therapy in patients with platinum-sensitive relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a final analysis of a double-blind, randomised, placebo-controlled, phase 3 trial, Lancet Oncol 22(5):620, 2018

11.   Burger RA, Brady MF, Bookman MA, et al: Incorporation of bevacizumab in the primary treatment of ovarian cancer, N Engl J Med 365(26): 2473-83, 2011

12.   Oza AM, Cook AD, Pfisterer J: Standard chemotherapy with or without bevacizumab for women with newly diagnosed ovarian cancer (ICON7): overall survival results of a phase 3 randomised trial, Lancet Oncol, 16(8):928-36, 2015 

13.   Photo by an-vision on Unsplash