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.
References:
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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
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13. Photo by an-vision on Unsplash
Despite recent progress, it is visible that there are still several gaps in knowledge about this cancer, which must be overcome so that more effective therapies can be offered. The classification of an illness as "orphan" obeys an arbitrarily decided criterion, and reducing the efforts invested based on this does not really seem to be fair conduct. As said, joining efforts, we will be able to offer more optimistic perspectives for these patients in the future.
This text makes clear the difficult reality of neglect. Despite having the second highest mortality in gynecological cancers, the evolution of knowledge about ovarian cancer is slow and often left out. In a context in which the most prevalent and, consequently, the most commented neoplasms, such as breast cancer, are targets of several advances in early diagnosis and treatment, ovarian cancer has a different reality. Although the most studied neoplasms generally have a greater impact on society, ovarian cancer has an impact that should not be overlooked, because there are still a lot of people suffering from it.
Reading the text leads us to reflect that, despite the chance that it will soon be considered an "orphan" disease, ovarian cancer is the second leading cause of death among all gynecological malignancies. Thus, the treatment of the same cannot and should not have reduced efforts and investments.
I believe that when a disease is determined as an orphan, the resources and efforts to face it are reduced, causing it to permeate the population in a latent and underdiagnosed way, causing the aggravation of deaths. This situation leads to reflection on the need to maintain research and resources to obtain treatment options even in the scenario of rare diseases, for better control and even cure, when these diseases occur.
It’s actually quite shocking to know that the tumor ranked second in mortality among all gynecological malignancies is deemed an “orphan” disease with such huge gaps in screening and new treatment options.
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