Continuing Education Activity

Ovarian cancer is one of the most common causes of cancer-related deaths in women of developed nations. They should be diagnosed early for better chances at curing it to avoid the high rates of morbidity and mortality. This article reviews the epidemiology, risk factors, pathophysiology, histopathology of ovarian cancer and also highlights the role of the interprofessional team in the management of this condition along with a discussion of few landmark trials and recent ongoing trials impacting the future treatment regimens and subsequent prognosis of patients with this disease.

Objectives:

• Describe the epidemiology of ovarian cancer.
• Review the evaluation of a patient with suspected ovarian cancer.
• Summarize the treatment options of ovarian cancer.
• Outline some interprofessional team strategies that can result in better care coordination for patients presenting with ovarian cancer.

Introduction

Ovarian cancer is the leading cause of death in women diagnosed with gynecological cancers. It is also the fifth most frequent cause of death in women, in general.[1] Most of the cases are diagnosed at an advanced stage, which leads to poor outcomes of this disease. The existing screening tests have a low predictive value contributing further to this misery. Detailed gynecological evaluation along with transvaginal ultrasound and laboratory marker like cancer antigen-125 (CA-125) assay are the key early detection strategies which have shown no significant beneficial effect in the morbidity or mortality of this cancer.[2] 

The standard line of care treatment includes surgery and platinum-based chemotherapy; however, anti-angiogenic bevacizumab and Poly(ADP-ribose) polymerase (PARP) inhibitors have gained momentum in the management of this gynecological malignancy in the past decade.[3] 

A high rate of recurrence following the initial treatment has been observed. Most of these relapsed cases are less curable and known to have an increased incidence of treatment failures. Hence, effective prevention and detection strategies and new treatment modalities based on a better understanding of molecular characterization of this cancer are the need of the hour. This article reviews the epidemiology, risk factors of ovarian cancer and also highlights the evaluation and multidisciplinary approach in the management of this condition, along with a discussion of a few of the recent ongoing trials.

Etiology

There are various risk factors associated with ovarian cancer. It mostly affects postmenopausal women, where increasing age is associated with an increased incidence, advanced stage of this disease, and lower reported survival rates. Parity poses a protective role according to a few case-control studies with higher age at childbirth linked to a decreased risk of ovarian cancer.[4] The strongest risk factor of ovarian cancer is a positive family history of breast or ovarian cancer, where a personal history of breast cancer also augments the risk.[5] Several studies have shown an increased risk of smoking, especially the risk of mucinous epithelial tumors.[4]

Epidemiology

In 2020, there are approximately 21,750 new ovarian cancer cases, which comprises 1.2% of all cancer cases. The estimated number of deaths related to it are 13,940. The 5-year relative survival rate is expected to be 48.6%. Around 15.7% of the ovarian cancer cases are diagnosed at the local stage, and about 58% at the metastasized stage, where the 5-year survival dips down to 30.2% instead of 92.6% if detected at an early stage of local spread. An average incidence rate per 100,000, age-adjusted to the 2000 US standard population is 11.1 in 2012-2016. The incidence is highest in non-Hispanic whites (11.6 per 100,000), followed by American Indians and Alaska Natives (10.3 per 100,000), Hispanics (10.1 per 00,000), non-Hispanic blacks, and Asian and Pacific Islanders. Ninety percent of ovarian cancers are epithelial, with the serous subtype being the most common. Age-adjusted rates of new ovarian cancer cases are on a reducing trend based on statistical models of analysis.[6]

Histopathology

The four most common histological types of epithelial ovarian cancer are serous, endometrioid, clear cell, and mucinous tumor.  They have further subtypes based on their peculiar biology and treatment responses. The uncommon subtypes are Brenner and seromucinous.

Ovarian cancer can be further classified into two subtypes- Type I or Type II tumors, the latter being a more fatal variant, thought to be caused by continuous ovarian cycles leading to inflammation and endometriosis. Type I tumor includes low-grade serous, endometrioid, clear-cell, and mucinous carcinomas, with the rare subtypes being seromucinous and Brenner tumors. Type I tumors mostly arise from atypical proliferative (borderline) tumors. Type II tumors include high-grade serous carcinoma, carcinosarcoma, and undifferentiated carcinoma, which mainly originate from serous tubal intraepithelial carcinoma. Type I tumors usually present at an early stage and are low grade except for clear cell, which is considered high grade. Their proliferative activity is usually low. They are diagnosed early and carry a good prognosis. In comparison, Type II tumors are high-grade tumors and almost always of advanced stage. They have high proliferative activity with rapid and aggressive progression and a high degree of chromosomal instability compared to type I with the presence of p53 mutations in most of the cases.[7]

Ovarian serous carcinoma is the most common subtype of ovarian carcinoma. It presents as low-grade (10% of all the serous subtype tumors) or high-grade carcinoma (90% of all the serous subtype tumors).  The low-grade subtype (LGSC) shows minimal nuclear atypia, rare mitosis, and lesser molecular abnormalities. In contrast, the high-grade subtype (HGSC) shows significant nuclear atypia and mitosis (>12 per 10 high-power fields) with more copies of molecular abnormalities as seen by cytogenetic analysis.[8] LGSCs are usually diagnosed at a young age and carry a better prognosis than HGSCs, which tend to present at an older age with a 10-year mortality rate of 70%.[9] Further analysis revealed that a high frequency of KRAS and BRAF mutations are found in low-grade serous carcinoma, whereas high-grade serous carcinoma shows a high frequency of p53 and BRCA 1 and 2 genes mutations with an absence of KRAS/BRAF mutation.[8] 

Ovarian endometrioid carcinomas have been postulated to be derived from endometriosis. Morphologically, their cut sections reveal cystic areas showing soft masses and bloody fluid, with less common solid areas showing extensive hemorrhage and necrosis. No major molecular markers have been studied in this subtype; however, the beta-catenin gene mutation is noted to be one of the most common molecular abnormalities. One can differentiate between the endometrioid carcinoma arising from ovaries and uterus based on the molecular studies, even though they appear quite similar morphologically. Ovarian endometrioid cancers have microsatellite instability and PTEN alterations less frequently than the ones arising from the uterine cavity.[8] Single ovarian carcinoma is found to have a less frequency of beta-catenin mutation as compared to synchronous tumors.[10] They are usually diagnosed at an earlier stage, offering a better prognosis to women with this histological subtype of ovarian cancer.

Ovarian mucinous carcinoma (MOC) is often heterogeneous, where a mixture of elements, including benign and malignant tumors, are found in a single specimen. KRAS mutations are common in these tumors. As commonly associated with metastases from the gastrointestinal tract (GI), the intestinal subtype will show the presence of glands with architectural and cytology clinical features of adenocarcinoma; however, it may lack stromal invasion.[8] It is hard to distinguish primary ovarian mucinous carcinomas from metastatic mucinous appendix tumors due to their close association, hence many gynecologic oncologists practice routine appendectomy in all these patients with MOC.[11] Evidence of micro invasions is less commonly found in intestinal subtype borderline tumors. Invasive mucinous carcinoma is uncommon, and the prognosis is found to be favorable compared to serous subtype, considering the mostly diagnosed at stage I itself, about 80%.[8] The molecular alterations responsible for malignant conversion of the benign mucinous tumor is still unknown.

Ovarian clear cell carcinomas are less prevalent and account for <5% of ovarian carcinoma. Histopathologically they show cellular clearing, cystic growth pattern, and a characteristic hobnail growth pattern. Immunohistochemically, overexpression of BAX in stage I and stage II tumors is predominant, whereas anti-apoptotic protein BCL-2 is expressed more in metastatic lesions than in primary lesions.  A lower relative BCL-2/BAX ratio is found in early-stage ovarian clear cell carcinoma tumors as compared to the higher relative ratio found in metastatic lesions.[8] They are also commonly diagnosed in earlier stages and hence carry a good prognosis, similar to endometrioid cancers.

Cytokeratin-7 (CK7) shows diffuse and strong staining in all serous ovarian tumors. It is positive in 80% to 100% of mucinous ovarian tumors, and other ovarian epithelial tumors also show positivity for CK7. About 96% of ovarian adenocarcinomas were positive for CK7 compared to metastatic colorectal, which shows about a 25% positivity.

History and Physical

Symptoms of ovarian cancer are non-specific, and hence they can be easily missed at an early stage as the symptoms can be attributed to other possible disease processes. The symptoms often become apparent in the late stage (stage III or stage IV). The presenting symptoms include a combination of abdominal fullness, bloating, nausea, abdominal distention, early satiety, fatigue, change in bowel movements, urinary symptoms, back pain, dyspareunia, and loss of weight. The symptoms occur vaguely months before the diagnosis of ovarian cancer.[12]

A thorough physical examination should be done, including rectovaginal examination on an empty bladder to look for pelvic and abdominal masses in clinical cases of high suspicion. In advanced cases, a palpable pelvic mass or ascites or diminished breath sounds due to the presence of pleural effusions can also be found. As a result of metastases to the umbilicus, a sister Mary Joseph nodule will rarely be seen. Sign of Lesar-Trélat, which refers to a sudden increase in the finding of seborrheic keratosis, also gives a clinical clue indicating the presence of occult cancer.[13]

Paraneoplastic syndromes can be infrequently associated with ovarian cancer. Subacute cerebellar degeneration due to tumor-induced autoimmune reactivity against cerebellar antigens can lead to symptoms like ataxia, dysarthria, nystagmus vertigo, and diplopia. This condition commonly precedes the occurrence of the primary ovarian tumor by months or years. Trousseau's syndrome has also been associated with ovarian cancer. Increased levels of circulating parathyroid hormone-releasing protein can lead to hypercalcemia, which can manifest as altered mental status, fatigue, constipation, abdominal pain, and increased thirst and urinary frequency. Such early warning signs of various paraneoplastic syndromes should be considered well in advance to avoid the diagnosis of ovarian cancer directly at an advanced stage where the patient may not be amenable to curative therapy.[14][13]

Evaluation

In patients with a high degree of clinical suspicion, radiological imaging including transvaginal ultrasonography (TVUS, highly sensitive and preferred) and/or abdominal and pelvic ultrasonography is done. It gives a fair idea about the size, location, and complexity of the ovarian mass. For defining tumor extension, further imaging with chest and abdomen pelvis CT scan, pelvic MRI, and/or PET scan can be done. 

Measurement of CA-125 levels is usually done in adjunction with the imaging. CA-125 is elevated in most of the epithelial ovarian cancers overall, but only half of the early stage epithelial ovarian cancers.[15] The specificity and positive predictive value is found to be higher in postmenopausal women than in premenopausal women. Increased CA-125 levels are also observed in other physiological or benign pathological conditions such as endometriosis, pregnancy, ovarian cysts, inflammatory peritoneal diseases. Hence, other biomarkers are currently being studied to improve specificity for ovarian cancer biomarkers. Human epididymis protein 4 (HE4) is a new biomarker that is currently being evaluated. It is found to be more sensitive for ovarian cancer and found in approximately 100% of serous and endometrioid subtypes. Based on recent studies, a combination of higher CA-125 and HE4 levels are thought to be predictive of malignant ovarian tumors and may serve as a useful diagnostic tool in the future.[16] CA-125 levels can also be used to calculate the risk of malignancy index (RMI), which also utilizes TVUS findings and menopausal status. RMI above 200 is associated with a high risk of malignancy, with a greater than 96 % specificity.[13]

The malignancy algorithm (ROMA) risk utilizes a mathematical formula that incorporates HE-4 and CA 125 levels adjusted for pre and post-menopausal status to determine the risk of malignancy.[17] The ROMA is a valuable screening test that takes advantage of the high specificity of HE4 and high-sensitivity of CA-125 to detect more patients of ovarian cancer overall, especially in the early stages. The risk of malignancy index (RMI) index is usual for the patient, where the score incorporates TVUS findings, menopausal status, and CA-125 levels.[13] Currently, multimarker longitudinal models are being worked on for the early detection of ovarian cancer.[18]

Optimal staging with exploratory laparotomy and close evaluation of abdominal and pelvic region for disease, including inspection of peritoneal surfaces with biopsy and/or pelvic washings, is done. It establishes the stage using the International Federation of Gynecology and Obstetrics (FIGO) staging of ovarian cancer. It is followed by total abdominal hysterectomy and bilateral salpingo-oophorectomy (BSO) with para-aortic and pelvic lymph node dissection and omentum. The tissue biopsies evaluated by a pathologist help provide the final diagnosis concerning the histological type, grade, and staging.[9]

Treatment / Management

Debulking Surgery

Treatment of ovarian cancer conventionally includes a combination of chemotherapy and surgery. In the early stage of invasive epithelial ovarian carcinoma, unilateral salpingo-oophorectomy while preserving the uterus and contralateral ovary is done, with comprehensive surgical staging where lesions show a low likelihood of progressing to malignancy. However, for advanced-stage ovarian cancer, a debulking surgery comprising hysterectomy/bilateral salpingo-oophorectomy (BSO) has shown better outcomes. It is imperative to determine whether debulking surgery would be beneficial for a patient by initially performing exploratory laparoscopic surgery. The presence of a large or residual tumor burden can block perfusion to the affected region leading to damaged tissue and increase chances of further cellular damage with multidrug chemotherapy resistance.[9] Laparoscopic surgeries are noted to be less invasive with decreased recovery time as opposed to debulking surgeries. Patients with ovarian cancer should have genetic risk evaluation and germline, somatic (BRCA 1/2) testing done if previously not tested, as the latter guides the maintenance therapy.

Primary Debulking Surgery versus Neoadjuvant Chemotherapy

A gynecologic oncologist initially evaluates patients with suspected advanced stage IIIC or IV ovarian cancer to determine if they are appropriate surgical candidates or not. Neoadjuvant chemotherapy is recommended to decompress the tumor burden for the ones deemed poor surgical candidates with a low likelihood of optimal cytoreduction.  According to the Society of Gynecologic Oncology (SGO) and American Society of clinical oncology (ASCO), clinical practice guidelines state that women with a favorable surgical profile can receive either neoadjuvant chemotherapy or undergo cytoreduction surgery. But if they have a high likelihood of attaining cytoreduction to less than 1 cm with acceptable morbidity, primary cytoreductive surgery should be preferred. Before administering neoadjuvant chemotherapy, patients should carry a histological diagnosis of invasive ovarian cancer confirmed by biopsy preferred over specimens obtained from fine-needle aspiration of paracentesis.[19]

Various clinical trials have compared neoadjuvant chemotherapy with interval cytoreduction surgery versus primary cytoreductive surgery upfront, showing equal overall median survival. Two of the phase III trials have shown non-inferiority of neoadjuvant chemotherapy compared to cytoreductive surgery followed by chemotherapy in women with stage IV disease. This proves that neoadjuvant chemotherapy can be significantly utilized in patients with advanced-stage invasive ovarian cancer patients who are poor surgical candidates with high tumor burden. The European organization for research and treatment of cancer (EORTC), phase III trial EORTC 55971 recruited women with stage IIIC-IV epithelial ovarian cancer (n=670) and CHORUS trial had a similar recruitment profile with women of stage III A-B besides (n= 550). They showed non-inferiority of median overall survival with neoadjuvant chemotherapy when compared to primary cytoreductive surgery upfront. In a pooled analysis of individual patient data from these two trials, EORTC 55971 and CHORUS trials, women with stage IV disease had better survival outcomes with neoadjuvant chemotherapy followed by cytoreductive surgery.[20] An exploratory analysis of the EORTC 55971 randomized trial found that patients with stage IIIC (<4.5 cm) and less invasive metastatic tumors had better survival outcomes with primary cytoreductive surgery. In contrast, patients with stage IV disease (>4.5cm) and more invasive metastatic tumors had better survival outcomes with neoadjuvant chemotherapy.[21]

Maximal Cytoreductive Surgery

One of the most powerful independent determinants of improved median survival among patients with stage III or IV ovarian carcinoma is to achieve maximal cytoreduction. Hence, irrespective of the surgery sequence, before or after neoadjuvant chemotherapy, optimal cytoreduction is strongly recommended to achieve ideally no residual disease. A meta-analysis of 6885 patients with stage III and IV ovarian cancer showed a 5.5% increase in overall median survival with a 10% increase in maximal cytoreduction in one of the studies. When the actuarial survival was being estimated comparing cohorts with less than or equal to 25% maximal cytoreduction and more than 75% maximal cytoreduction, there was an increase of 50% of mean weighted median survival time.  However, platinum dose intensity did not have a statistically significant relation to the log median survival time.[22] If interval cytoreduction surgery is being performed after neoadjuvant chemotherapy, it is usually done after four or fewer cycles ensuring early surgical intervention in the disease course. However, if the patient has received bevacizumab as a part of their initial neoadjuvant chemotherapy regimen, there should be a gap of at least 20 days before surgical intervention due to the risk of highly compromised postoperative healing.[23] 

Primary Chemotherapy and Neoadjuvant Therapy

• Early-stage ovarian cancer:Adjuvant chemotherapy in women with early-stage ovarian cancer has been studied extensively and based on the evidence. The final clinical decision has to be individualized for every patient. Based on four randomized control trials (ACTION 2003; Bolis 1995; ICON1 2003; trope 2000) which studied platinum-based chemotherapy, women with early-stage epithelial ovarian cancer showed better overall survival (OS) (HR 0.71; 95% CI 0.53 to 0.93) and progression-free survival (PFS) (HR 0.67; 95% CI 0.53 to 0.84) with adjuvant chemotherapy than the ones who did not receive it.  However, one of those trials, ICON1 2003, showed similar evidence in high-risk patients with adjuvant chemotherapy but not among others. Based on the pooled data in a meta-analysis, which included all the patients (total of 772) in ICON1 2003 and two-thirds of patients in ACTION 2003, evidence of overall benefit in early-stage ovarian cancer women was observed after sub-optimal staging.[24] In stage IA or 1B epithelial ovarian cancer or grade 1 endometrioid carcinomas, considering the good survival rates, surgical treatment alone is recommended over adjuvant chemotherapy with close observation.[23] Another prospective randomized phase III trial was done. Patients were randomly assigned to either adjuvant platinum-based chemotherapy or observation followed by surgery, with endpoints being overall survival and recurrence-free survival (RFS). It provided evidence that chemotherapy improves both overall and recurrence-free survival in the non-optimally staged patients (patients with residual disease); however, these findings were not observed in optimally staged patients (patients with a slight chance of residual disease). This suggests that adjuvant chemotherapy in early-stage ovarian cancer affects the micro-metastasis that goes unnoticed at the time of surgical staging.[25] A meta-analysis of all the randomized clinical trials that studied women of stages I-II epithelial ovarian cancer compared to adjuvant chemotherapy with observation showed no overall survival benefit of adjuvant chemotherapy (hazard ratio 0.91, 0.51 to 1.61).[23] Overall, the available evidence supports the use of adjuvant chemotherapy in patients with early-stage ovarian cancer with high-risk features like the stage IC and stage II disease and clear cell or high-grade histology. While the optimal regimen is unclear, most clinicians use carboplatin with paclitaxel extrapolating their evidence in the advanced stage of ovarian cancer.
• Advanced stage ovarian cancer:The standard approach in treating patients with advanced ovarian cancer uses platinum and a taxane. The option of intravenous (IV) and intraperitoneal (IP) chemotherapy depends on the optimal debulking of the tumor. A phase III trial, GOG111, showed improved overall survival in patients with a combination of cisplatin and paclitaxel when compared to the cohort receiving cisplatin and cyclophosphamide combination. The first line chemotherapeutic agent for epithelial ovarian cancer is platinum-based cisplatin or carboplatin along with a taxane family agent, paclitaxel or docetaxel. There have been many studies concluding that carboplatin is as effective as cisplatin and better tolerated. Also, weekly dose-dense chemotherapy with carboplatin and paclitaxel combination has not shown any additional benefit in PFS than standard three-weekly chemotherapy or an additional third agent or a longer period of the chemotherapy cycle.[23] Chemotherapeutic agents are administered IV or IP or a combination of both. In advanced age ovarian cancer patients, IP carboplatin chemotherapy is well-tolerated. There have been four landmark trials, namely GOG 104, GOG 114, GOG 172, and GOG 252, which have shown improved survival benefit of intraperitoneal or intravenous chemotherapy, with strong evidence supporting the same, however clinically, its use has been inconsistent.[26][27] This is mostly due to increased frequency of toxicity, especially neutropenia, thrombocytopenia, neurotoxicity, and adverse gastrointestinal symptoms affecting the quality of life of patients treated with intraperitoneal chemotherapy as well as due to the addition of bevacizumab studied in GOG 252 didn't show any advantage of IV/IP compared to IV with bevacizumab.[28] 

Chemotherapy in Elderly

Elderly patients aged over 70 years or older with comorbidities who have stage III-IV ovarian cancer were studied in a randomized control trial, which showed worse survival outcomes with carboplatin monotherapy versus carboplatin-paclitaxel three weekly/weekly.[23] But when combination therapy is being used, a modified dose-dense regimen of weekly carboplatin plus paclitaxel has shown to be better tolerated with a lower toxicity profile than the conventional dosing (three weeks schedule). Still, it did not prolong progression-free survival, as shown in a MIT07 phase III trial, which can also be used for elderly patients with comorbidities.[29][30] The frail elderly patients were found to have decreased high-grade neutropenia, febrile neutropenia, thrombocytopenia, and neuropathy.[23] An ongoing prospective trial of older women of age equal to or greater than 70 on different chemotherapy regimen combinations will help us predict chemotherapy tolerance. However, preliminary results have commented on patients with higher baseline instrumental activities of the daily living score are more likely to complete four chemotherapy cycles and less likely to experience high-grade toxicity.[31]

Maintenance Therapy

Maintenance therapy is conceptualized to ensure the effective killing of residual slowly dividing cells by decelerating the cell turnover so that the dormant population of cancer cells does not progress to grow enough to be detected by either elevation of biomarkers or clinical evidence of recurrent disease. Several randomized trials have been done to compare maintenance therapy versus observation. 

• Platinum-based agent:A phase III trial, GOG 178, randomized patients to 12 months versus 3 months of maintenance therapy with paclitaxel after complete clinical response with platinum/paclitaxel therapy in patients with stage III-IV ovarian cancer. After 50% accrual interval analysis, improved PFS was seen favoring the extended therapy cohort. However, the study closed early. A follow-up study later showed no overall survival benefit compared to the same maintenance monotherapy for 22 months versus 14 months.[32] Another trial, GOG 175, showed no significant difference in 5-year survival or recurrence-free interval (RFI) where high-risk early-stage ovarian cancer patients were randomized to observational versus weekly paclitaxel 40 mg/m²x 24 weeks after completion of 6 cycles of carboplatin and paclitaxel for 3 cycles.[33] A three-arm phase III trial following standard chemotherapy, GOG 0212, compared observation without immediate therapy to 12 months of paclitaxel or polyglutamated paclitaxel but showed disappointing results.[34] To conclude, the results of maintenance, chemotherapy trials have been discouraging.

• Anti-angiogenic inhibitor:Pazopanib, an oral multikinase inhibitor of vascular endothelial growth factor receptor (VEGFR) -1/2/3, platelet-derived growth factor (PDGFR) alpha/beta and c-kit, has also been studied as maintenance therapy in a study of 940 patients with patients of ovarian cancer stage II-IV. These patients had a complete clinical response to five cycles of platinum-taxane chemotherapy and were randomized to pazopanib versus placebo for 24 months showing a median improvement in PFS in the pazopanib arm; no benefit was seen in overall survival data. BRCA1/2 carriers were noted to have an additional significant benefit.[35] Bevacizumab is a humanized monoclonal antibody against vascular endothelial growth factor (VEGF) that has been studied in combination with chemotherapy followed by bevacizumab, single agent, maintenance therapy in two major landmark trials (ICON7 and GOG0218) of patients with advanced-stage ovarian cancer. The studies showed an improved PFS in the maintenance bevacizumab cohort when compared with surveillance only.[36] The FDA eventually approved it. Bevacizumab has also been associated with serious side effects like hemorrhage, thrombosis, hypertension, proteinuria, bowel perforation.[23] In a subset analysis of the ICON 7 trial, patients with large volume residual disease after their primary cytoreductive surgery or stage IV disease who fall into the high-risk category showed a greater median overall survival benefit. Secondary analysis of GOG0128 revealed improved overall survival in a particular subgroup of patients with ascites, who are at high risk of recurrence and mortality from stage IV disease.[36] This targeted therapy should be individualized in patients. However, it does show significant benefit in PFS when used as concurrent therapy followed by single-agent maintenance therapy but without any clear clinical benefit in overall survival.
• Poly(ADP)-ribose polymerase (PARP) inhibitors:PARP inhibitors have recently gained momentum for the maintenance treatment of ovarian cancer. Olaparib was the first FDA-approved drug in this subgroup indicated to treat advanced BRCA mutated ovarian cancer after platinum-based chemotherapy, based on SOLO-1, phase III randomized double-blind, placebo-controlled trial. It showed a reduction in disease progression or death by 70% (hazard ratio 0.30, 0.23 to 0.41; P<0.001).[37] PAOLA-1 trial, a phase III randomized controlled trial of 806 women with stage III-IV high-grade serous or endometrioid ovarian cancer, showed a PFS benefit of 4.5 months in the group that received olaparib and bevacizumab maintenance versus placebo and bevacizumab.[38] This combination of olaparib and bevacizumab achieved FDA approval as a first-line maintenance treatment for these patients with ovarian cancer after initial platinum-based chemotherapy with partial or complete response or tumors associated with homologous recombination deficiency (HRD) defined by the presence of deleterious BRCA mutation. Further noted clinical trials include the VELIA trial and PRIMA trial using Veliparib and Niraparib maintenance therapy, respectively, showing markedly improved PFS compared to the placebo group in patients with newly diagnosed advanced-stage ovarian cancer who initially responded to first-line platinum-based chemotherapy.[39][40]
• Immunotherapy:It has recently shown significant benefits in solid malignant tumors. However, published data do not show any benefit in patients with ovarian cancers so far. The resulting controversial data diverted the focus on combination strategies involving immune- checkpoint inhibitors with PARPs, chemotherapy, anti-angiogenic agents, and more. A combination of such therapies shows more significant anti-tumor activity than concentrating on a single pathway. This promising data is from initial phase trials, and further results from ongoing phase II and III trials are awaited.[41]
• Vaccines:Vaccines are currently being studied for ovarian cancer, where the basis lies in activating the immune cells to destroy the cancer cells. The potential tumor-associated antigen molecules targeted in ovarian cancer in ongoing ovarian cancer vaccine researches are CA-125, p53 protein, HER-2, and more.[41] There are currently ongoing pilot and phase I or II trials for the use of therapeutic vaccines in ovarian cancer patients by employing novel techniques. Other emerging therapies being studied in clinical trials are using adoptive T-cell transfer and chimeric antigen receptor therapy (CAR-T) as a part of future strategies to ensure reduced cancer burden and improved life expectancy in this patient population.

Recurrent Ovarian Cancer

About 80% of women with advanced-stage ovarian cancer more commonly have tumor progression or recurrence. Platinum free interval (PFI) is one of the most reliable predictors indicating the response of recurrent ovarian cancer to subsequent chemotherapy. PFI refers to the interval between the completion of the last platinum-based chemotherapy and the occurrence of relapse.[42] However, platinum sensitivity is generally used to refer to an interval of greater than 6 months between the last platinum-based chemotherapy (PBC) cycle and commencement of subsequent PBC.

The role of surgery in cases of recurrent ovarian cancer is yet quite undefined. GOG 213, a phase III multicenter randomized clinical trial enrolled patients with platinum-sensitive recurrent ovarian cancer, randomized patients to surgical cytoreductive surgery followed by adjuvant PBC or only PBC with a primary endpoint of overall survival showed no improved benefit in patients receiving secondary surgical cytoreduction followed by chemotherapy and chemotherapy alone (HR for death 1.29, 0.97 to 1.72; P=0.08).[23]  Desktop III trial, which compares surgery followed by chemotherapy versus chemotherapy only in recurrent platinum-sensitive ovarian cancer, is currently ongoing whose results are eagerly awaited.  They had announced their preliminary results in ASCO 2017 showing improvement in PFS and longer interval of the period to the start of subsequent chemotherapy in favor of surgery followed by chemotherapy. There are two other trials- Surgery for Ovarian Cancer Recurrence (SOCceR) and Surgery or Chemotherapy in Recurrent Ovarian Cancer (SOC 1) comparing surgery and chemotherapy with surgery alone in such groups of patients, with awaited results. To conclude, none of the studies have resulted in longer overall survival with second-degree surgical cytoreduction in patients with platinum-sensitive recurrent epithelial ovarian cancer diagnosed surgery.[43]

Large phase III trials have also resulted in the approval of bevacizumab, as discussed above, which was studied in combination with chemotherapy for the treatment of recurrent ovarian cancer as well as for maintenance therapy (GOG 218, or OCEANS and AURELIA trials).[42] The studies have shown an objective improvement of PFS. However, they failed to prove a benefit in overall survival. Nevertheless, antiangiogenic agents have shown activity in these platinum-sensitive recurrent ovarian cancer however further studies are needed to define their benefit clearly. Evidence shows the use of aromatase inhibitors like letrozole for the treatment of recurrent low-grade serous and endometrioid epithelial ovarian cancer based on large retrospective cohort studies.

PARP inhibitors have been under clinical development at various stages and have shown their efficacy in patients with germline BRCA mutations. They were first approved as monotherapy in ovarian cancer patients with deleterious germline or somatic BRCA mutations who have not responded to chemotherapy. Further studies showed significant PFS benefit in patients with an initial response to be BC with maintenance PARP inhibitor therapy. An overall survival benefit is yet to be proven, which requires a longer follow-up. SOLO-2 study assessed maintenance monotherapy with olaparib in patients with platinum-sensitive recurrent ovarian cancer and BRCA mutation showing significantly improved PFS for the patients receiving olaparib with no significant detrimental effect on patient's quality of life.[44] 

PAOLA-1, a phase III trial, studied olaparib with bevacizumab in platinum-sensitive recurrent ovarian cancer showing PFS benefit in the patients receiving the combination. The results were quite consistent with those observed in the SOLO 1 trial. The safety profile of olaparib was quite consistent in the trials, with a higher incidence of serious adverse events noted in the group receiving a combination of olaparib and bevacizumab than with placebo plus bevacizumab, the most common one being anemia.[38] Many phase III trials have shown PARP inhibitor maintenance therapy in patients with platinum-sensitive recurrent ovarian cancer with clinical benefits.  Recently in the 2019 SGO annual meeting, an abstract was presented which described a retrospective study of a few patients who have been previously treated with PARP inhibitor for epithelial ovarian cancer, where a second PARP inhibitor treatment was used; however, the most common reason for discontinuation of treatment was toxicity.[23] Further studies using PARP inhibitors as maintenance therapy and predicting their resistance would be areas of further research.

Platinum resistance poses a very poor prognosis, where these patients have a recurrence of the disease within 6 months of completion of cytoreductive surgery and adjuvant chemotherapy.  It is imperative to have goals of care discussion with these patients as their overall survival rates are quite grim. Focusing on newer targets like tumor vasculature, DNA repair, intracellular signaling inhibition, and other molecular targets will provide more avenues to be explored for optimizing the treatment of recurrent ovarian cancer.

To conclude, advanced-stage ovarian cancer patients are treated with primary reductive surgery, followed by platinum-based chemotherapy. But poor surgical candidates or patients who might not achieve effective cytoreductive surgery are recommended to undergo neoadjuvant chemotherapy. Optimal cytoreductive surgery is very important to achieve as it is one of the most powerful predictors of survival of these patients. There is a high rate of relapse in patients with advanced-stage whose response to subsequent platinum-based chemotherapy depends on various factors. Targeted therapies are the new emerging treatment strategies where bevacizumab and PARP inhibitors have become first-line therapies for maintenance and PARP inhibitors as the first line for recurrent cases. Genetic screening for all newly diagnosed ovarian cancer is recommended.

Differential Diagnosis

The differential diagnosis for ovarian cancer includes:

• Colon cancer
• Embryologic remnants
• Gastric adenocarcinoma
• Metastatic gastrointestinal carcinoma
• Ovarian torsion
• Peritoneal cyst
• Retroperitoneal mass
• Uterine fibroids
• Endometriosis
• Papillary adenocarcinoma
• Serous adenocarcinomas
• Undifferentiated adenocarcinomas
• Small-cell adenocarcinomas
• Brenner tumors

Radiation Oncology

Historically, whole abdomen radiation was practiced during early times; however, due to the increased frequency of toxicity and complications, its use became nonexistent. Currently, the role of radiation in ovarian cancer is limited to palliation, either for symptom control or to treat a localized spread of disease. Adjuvant radiotherapy has not even shown any survival benefit in the early stages of clear cell carcinoma, including a high-risk subset of patients.[45]

Due to the advent of advanced systemic therapies, radiation has taken a backseat in the management of ovarian cancer, offering limited use. Stereotactic body radiotherapy (SBRT) is one of the newer techniques for palliative radiation. There is still evidence of high rates of distant progression of lesions with its use, even when local control is achieved.[46]

Currently, with the emergence of new techniques like SBRT, intensity-modulated radiotherapy, and low dose hypofractionation, the role of radiation is strongly considered for local-regionally recurrent ovarian cancer, especially for chemotherapy-resistant lesions.[47][48]

Staging

Ovarian cancer is staged according to the 8th edition American Joint Committee of Cancer (AJCC), International Federation of Gynecology and Obstetrics (FIGO) staging system and corresponding Tumor, Node, Metastasis (TNM) classification.

Stage I - Tumor limited to ovaries (one or both) or fallopian tube(s)

• IA - Tumor limited to one ovary (capsule intact) or fallopian tube, no tumor on ovarian or fallopian tube surface; no malignant cells in ascites or peritoneal washings
• IB - Tumor limited to both ovaries (capsules intact) or fallopian tubes; no tumor on ovarian or fallopian tube surface; no malignant cells in ascites or peritoneal washings
• IC - Tumor limited to one or both ovaries or fallopian tubes, with any of the following:
• IC1    Surgical spill
• IC2    Capsule rupture before surgery or tumor on the ovarian or fallopian tube surface
• IC3    Malignant cells in ascites or peritoneal washings

Stage II - Tumor involves one or both ovaries or fallopian tubes with a pelvic extension below pelvic brim or primary peritoneal cancer

• IIA - Extension and/or implants on the uterus and/or fallopian tube(s) and/or ovaries
• IIB - Extension to and/or implants on other pelvic tissues

Stage III - Tumor involves one or both ovaries or fallopian tubes, or primary peritoneal cancer, with microscopically confirmed peritoneal metastasis outside the pelvis and/or metastasis to the retroperitoneal (pelvic and/or para-aortic) lymph nodes

• IIIA1 - Positive retroperitoneal lymph nodes only (histologically confirmed)
• IIIA1i  Metastasis up to and including 10 mm in greatest dimension
• IIIA1ii  Metastasis more than 10 mm in greatest dimension
• IIIA2   Microscopic extrapelvic (above the pelvic brim) peritoneal involvement with or without positive retroperitoneal lymph nodes
• IIIB - Macroscopic peritoneal metastasis beyond pelvis 2 cm or less in greatest dimension with or without metastasis to the retroperitoneal lymph nodes
• IIIC - Macroscopic peritoneal metastasis beyond the pelvis more than 2 cm in greatest dimension with or without metastasis to the retroperitoneal lymph nodes (includes an extension of tumor to the capsule  of liver and spleen without parenchymal involvement of either organ)

Stage IV - Distant metastasis, including pleural effusion with positive cytology; liver or splenic parenchymal metastasis; metastasis to extra-abdominal organs (including inguinal lymph nodes and lymph nodes outside the abdominal cavity), and transmural involvement of intestine

• IVA - Pleural effusion with positive cytology
• IVB - Liver or splenic parenchymal metastases; metastases to extra-abdominal organs (including inguinal lymph nodes and lymph nodes outside the abdominal cavity); transmural involvement of intestine

Prognosis

The prognosis of ovarian cancer is directly dependent on the disease stage at the time of diagnosis. It is also significantly associated with baseline performance status, FIGO stage, and volume of residual disease post-primary cytoreductive surgery. The median survival of ovarian cancer is approximately around 40% to 50% at 10 years, with stage-related survival for stage I between 70% to 92% compared to stage IV being less than 6%.[49] 

In women with a disease that spread to adjacent tissues, 5-year survival rates drop down to 80% and 25% for the ones with metastatic disease.[9] Patients with recurrent disease can be treated. However, they are usually incurable. Recurrent platinum-sensitive ovarian cancer median survival is approximately 3 years; however, it is about just 1 year for platinum-resistant patients.[49][50] 

Most of these patients with ovarian cancer develop malignant bowel obstruction in the late-stage, which is quite difficult to manage. Palliative symptom management is the mainstay in such patients. Debulking surgery is the strongest predictor of prognosis, where the volume of residual disease post-surgery is directly correlated to overall survival and PFS.[51]

Complications

Women who succumbed to ovarian cancer are found to have various complications in the last 6 months of life, the most common ones being:

• Fatigue or weakness (75%)
• Nausea or vomiting (71%)
• Constipation (49%)
• Pedal edema (44%)
• Anemia (34%) 

Women who could not be offered treatment are frequently found to have serious complications like ascites, bowel obstruction, pleural effusion, and bladder obstruction, apart from disorders of nutrition.[52]

Deterrence and Patient Education

The patient should be explained and counseled about all the treatment options available along with prognosis at the time of diagnosis, depending on the stage of presentation. Counseling for genetic testing should also be done, which does have an impact on treatment at times. The palliative care team and other related consultants' involvement should be sought timely regardless of cancer stage to enable comprehensive care, anticipate the disease course, and make a great impact on the quality of life of the patients. Patients should also be explained about the recent ongoing clinical trials if pertinent to their particular case.

Enhancing Healthcare Team Outcomes

Ovarian cancer remains one of the lethal malignancies in women despite the leading ongoing clinical trials and the introduction of new treatment lines in the past few decades. The poor clinical outcome is majorly due to the failure of effective strategies for the early detection of ovarian cancer.[53] There is also evidence regarding the deviation of care from the recommended guidelines, possibly due to clinical variation seen in ovarian cancer care.[54]

With the goal of ovarian cancer to be diagnosed at an earlier and more curable stage, we are still in need of the development of effective strategies. The volume of residual disease post cytoreduction surgery is one of the powerful determinants of patients' survival. Hence it should be done only by an experienced gynecologic oncologist who sees a high number of cases at a large busy hospital (>20 cases/year).[55]

Shared decision-making in terms of management of patients regarding newly available treatment strategies or clinical trials by going through benefits, safety profile, symptom control, and a discussion about the prognosis is one of the key elements. A close interprofessional team play with major roles played by medical oncologists and surgical oncologists helps in the smooth and effective management of the patients. Involvement of palliative care early helps fully optimize the treatment course and improve the quality of life.[56][57]

Patients in clinical remission should be offered affordable yet effective strategies for close surveillance follow-ups where patients should also be educated about the symptoms indicating recurrence of the disease and should be encouraged for genetic risk counseling if not done previously in the early disease course.