General Ovarian Cancer Information

Ovarian cancer is the top killer of women with gynecological cancers, and the fifth most common cause of death among women overall. Unfortunately, most cases are identified late, leading to a low survival rate.

Introduction

To date, screening tests have had limited success in predicting this disease. A combination of detailed gynecological evaluation, transvaginal ultrasound, and cancer antigen-125 (CA-125) assay appears to provide no real improvement in prognosis.

The standard line of care treatment includes surgery and platinum-based chemotherapy. In the past decade, Poly(ADP-ribose) polymerase (PARP) inhibitors have gained prominence in the management of this gynecological malignancy.

A high rate of recurrence after the initial treatment has been seen. Most of these cases have a low likelihood of cures and have been noticed to have an elevated occurrence of unsuccessful treatments. As a result, it is important to have effective prevention and detection policies, new treatment modalities dependent on a greater knowledge of molecular definition of this cancer, and efficient evaluation and multidisciplinary tactics in the handling of this condition. This article also looks into the epidemiology, risks factors associated with ovarian cancer as well as recent trials that are currently active.

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Causes of Ovarian Cancer / Etiology

Risk factors for ovarian cancer vary, but postmenopausal women comprise the majority of sufferers. Age-linked incidence, severity, and survival rates worsen with advancing years. Conversely, parity appears to have a protective element – the higher the age at childbirth, the lower the likelihood of ovarian cancer. The strongest risk factor is having a family history of either breast or ovarian cancer; conversely, a personal history of breast cancer increases susceptibility. Smoking has also been linked to this disease, particularly with mucinous epithelial tumors.

What Causes Ovarian Cancer – Epidemiology

In 2020, it’s estimated that there are 21,750 new cases of ovarian cancer, comprising 1.2% of all cancer cases. Additionally, the 5-year relative survival rate is predicted to be 48.6%. Out of those affected, 15.7% are diagnosed in the local stage; conversely, 58% have already progressed to metastasis – yielding a 5-year survival rate of 30.2%; this is in contrast to 92.6% if detected in the early stages of local spread. Despite an average incidence rate per 100,000 that was age-adjusted to the 2000 US standard population at 11.1 for 2012-2016; non-Hispanic whites had the highest number at 11.6 per 100,000; followed by American Indians and Alaska Natives (10.3), Hispanics (10.1) and non-Hispanic blacks and Asian and Pacific Islanders with lower rates respectively. 90% of ovarian cancers are epithelial – with serous being the most common type – however age-adjusted rates are decreasing due to statistical models that were used for analysis.

Histopathology

Serous, endometrioid, clear-cell, and mucinous tumors are the four most common histological types of epithelial ovarian cancer; Brenner and seromucinous tumors are uncommon types.

Ovarian cancer can be divided into two types: Type I and Type II, the latter being more deadly as it is thought to stem from repeated ovarian cycles, causing inflammation and endometriosis. Type I tumor consists of low-grade serous, endometrioid, clear-cell, and mucinous carcinomas, with seromucinous and Brenner tumors being rare. Most of these originate from atypical proliferative (borderline) tumors. This type of tumor generally has a good prognosis because they usually present in early stages and have low proliferative activity except for the clear-cell subtype which may be high grade. On the other hand, Type II tumors are high-grade and highly aggressive; they tend to progress fast with a high level of chromosomal instability compared to ones in Type I and are often linked to p53 mutations. These are usually present in advanced states.

Ovarian serous carcinoma is the most common type of ovarian carcinoma, with 10% occurring as low-grade tumors and 90% presenting as high-grade. Low-grade serous carcinomas typically present with minimal nuclear atypia and rare mitoses, whereas high-grade ones have prominent nuclear atypia and more than twelve mitoses in every ten HPFs. In addition, LGSCs tend to be diagnosed in younger patients and carry a better prognosis, yet HGSCs are usually seen in older patients whose ten-year mortality rate is around 70%. Analysis further found that KRAS/BRAF mutations were more common in LGSCs while p53 and BRCA 1/2 genes abnormalities were predominant among HGSCs.

Ovarian endometrioid carcinomas have been suggested to arise from endometriosis. On cut sections, one may observe cystic areas with soft masses and bloody fluid, as well as less frequent solid areas with extensive hemorrhage and necrosis. Molecular studies of this subtype are limited, although mutations of the beta-catenin gene appear to be quite common. It is possible to determine if the cancer was derived from ovaries or uterus through molecular analysis, despite their similar morphologies. Single ovarian tumors generally have a lower rate of beta-catenin mutation than synchronous tumors. Furthermore, such cancers are typically diagnosed at an earlier stage, granting a better prognosis for those affected by this histological subtype of ovarian cancer.

Ovarian mucinous carcinoma (MOC) is known for its heterogeneity, comprised of benign and malignant tumors. KRAS gene mutations are quite common in these types of neoplasms.[8] Micro invasions are rarely observed in the intestinal subtype borderline tumors. Distinguishing primary ovarian mucinous carcinomas from metastatic mucinous appendix tumors is challenging, therefore many gynecologic oncologists suggest preemptive appendectomy for these patients with MOC.[11] Compared to serous subtype MOCs, invasive mucinous carcinoma is rarer and at a more favorable stage with 80% typically being diagnosed at stage I. The molecular mechanisms resulting in the transformation from benign to malignant mucinous tumors remain unknown.

Ovarian clear cell carcinomas are much less common, making up only around 5% of all ovarian carcinoma. Histopathologically, they feature cellular clearing, a cystic growth pattern and a distinctive hobnail growth pattern. Immunohistochemically, tumors in stage I and II show predominance of BAX overexpression whereas metastatic lesions express more anti-apoptotic protein BCL-2. Early-stage ovarian clear cell carcinoma has a lower relative BCL-2/BAX ratio compared to that seen in metastases.[8] These types of cancers are usually diagnosed at an earlier stage which gives them a favorable prognosis, just like endometrioid cancers.

In all serous ovarian tumors, cytokeratin-7 (CK7) is strongly stained. Most mucinous ovarian tumors are positive for CK7, while other epithelial ovarian tumors are also positive. A total of 96% of ovarian adenocarcinomas are positive for CK7, as compared to about 25% of metastatic colorectal cancer.

History and Physical

The symptoms of ovarian cancer can be easy to miss, as they can resemble other medical issues. In the late stages (stage III or IV), a combination of abdominal fullness, nausea, bloating, early satiety, fatigue, changes in bowel movements, urinary problems, back pain, dyspareunia, and weight loss may occur. It is not uncommon for these signs to manifest months before diagnosis.

A comprehensive physical examination should be conducted, including rectovaginal assessment with an unfilled bladder to detect pelvic and abdominal masses in scenarios of intense uncertainty. In later stages, a tangible pelvic mass, ascites or impaired breath sounds caused by the existence of pleural effusions can also be seen. As metastases to the umbilicus are rare, a Sister Mary Joseph nodule may rarely be visible. Furthermore, a rapid growth in seborrheic keratosis – known as the Lesar-Trélat sign – is indicative of a concealed cancer.

Paraneoplastic syndromes are rarely linked to ovarian cancer. One of these is subacute cerebellar degeneration, which can cause ataxia, dysarthria, nystagmus, vertigo and diplopia; it typically appears before the discovery of the primary tumor, by weeks or months. Trousseau’s Syndrome can also be a forewarning of the disease: high levels of parathyroid hormone-releasing protein may lead to hypercalcemia and its symptoms such as mental confusion, fatigue, constipation, abdominal pains and increased thirst and urination. Prompt recognition of such signs can allow earlier diagnosis and treatment for ovarian cancer before it reaches an advanced stage when curative measures are not possible.

Evaluation

A high degree of clinical suspicion requires radiological imaging, including transvaginal ultrasonography (TVUS), abdominal and pelvic ultrasound, and/or CT scans. As a result, it gives a good idea of the size, location, and complexity of the ovarian mass. Further imaging can be done with chest and abdomen pelvic CT scans, pelvic MRIs, and/or PET scans to determine tumor extension.

The measurement of CA-125 levels is typically accompanied with imaging. Elevated CA-125 can generally be seen in the majority of epithelial ovarian cancers, yet only half of early-stage epithelial ovarian cancers. While the specificity and positive predictive value in premenopausal women is lower than that in postmenopausal women, increased CA-125 levels can also be observed due to other benign conditions such as endometriosis, pregnancy, ovarian cysts and inflammatory peritoneal diseases. Thus, further research has been conducted on additional biomarkers to improve specificity for Ovarian cancer detection. Human epididymis protein 4 (HE4) has emerged as a new biomarker and is being evaluated further. It is believed to provide a more sensitive detection for Ovarian cancer and is found in approximately 100 % of serous and endometrioid subtypes. To use this combination with higher CA-125 levels for an enhanced predictability of malignant Ovarian tumours, recent studies suggest that this could offer a useful diagnostic tool for the future. Another calculation based on CA-125 levels called Malignancy Risk Index (RMI), incorporating TVUS findings and menopausal status, states that RMI above 200 has 96

ROMA is a useful screening tool that combines the high specificity of HE4 and the high sensitivity of CA-125, allowing it to detect more cases of ovarian cancer, especially in its early stages. In addition, the Risk of Malignancy Index (RMI) is used to calculate the risk for a patient based on TVUS findings, age, and CA-125 levels. Researchers are currently looking into developing multimarker longitudinal models with better accuracy for the early detection of ovarian cancer.

Ideally, staging of ovarian cancer is determined using the International Federation of Gynecology and Obstetrics (FIGO) staging guidelines which involve exploratory laparotomy and careful examination of the abdominal and pelvic region. Biopsy and/or pelvic washings are conducted to inspect the peritoneal surfaces while a total abdominal hysterectomy with bilateral salpingo-oophorectomy (BSO) and removal of para-aortic and pelvic lymph nodes/omentum is also completed. This procedure aids in obtaining accurate tissue biopsies for a final diagnosis on the histological type, grade, and staging from the pathologist.

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Treatment and Management

Debulking Surgery

Treatment of ovarian cancer includes a combination of chemotherapy and surgery. For early-stage invasive epithelial ovarian carcinoma, unilateral salpingo-oophorectomy while preserving the uterus and contralateral ovary is done with surgical staging to assess the likelihood of malignancy. Advanced-stage ovarian cancer may benefit from debulking surgery comprising hysterectomy/bilateral salpingo-oophorectomy (BSO); however, exploration laparoscopic surgery can determine whether this would be beneficial for a patient. Laparoscopic surgeries are less invasive with a shorter recovery period than debulking surgeries. It is strongly recommended that patients with ovarian cancer have genetic risk evaluation and germline or somatic BRCA 1/2 testing, even if it has not been previously conducted, as this will affect their maintenance therapy.

Primary Debulking Surgery versus Neoadjuvant Chemotherapy

A gynecologic oncologist initially evaluates patients with suspected advanced stage IIIC or IV ovarian cancer to identify if they can be successfully given surgery. Neoadjuvant chemotherapy is recommended for those deemed unfit surgical candidates with a low probability of optimal cytoreduction. Both the Society of Gynecologic Oncology (SGO) and American Society of Clinical Oncology (ASCO) state that women with a positive surgical report can get either neoadjuvant chemotherapy or go through cytoreductive surgery. Nevertheless, if the chances of decreasing the tumor size to less than one cm are high, primary cytoreductive surgery should be favored over others. Before giving neoadjuvant chemotherapy, patients have to take biopsy for accurate histological diagnosis of invasive ovarian cancer; fine-needle aspiration and paracentesis specimens can also be used as supplementary tests.

Clinical trials have demonstrated that neoadjuvant chemotherapy can be used as an equal substitute to primary cytoreductive surgery upfront in women with stage IV ovarian cancer. This finding was supported by two phase III trials, the European Organization for Research and Treatment of Cancer (EORTC) trial 55971 (involving 670 patients) and CHORUS (with 550 participants). Both displayed non-inferiority of median overall survival when neoadjuvant chemotherapy was compared to direct surgery. A combined analysis of both studies also demonstrated that patients with advanced-stage invasive ovarian cancer, who are poor surgical candidates with high tumor burden, had better survival outcomes with neoadjuvant chemotherapy followed by cytoreduction. Additionally, an exploratory analysis of EORTC 55971 found that those affected by stage IIIC tumors (< 4.5 cm) or less invasive metastatic tumors fared better with primary cytoreduction; still, those diagnosed with stage IV disease (> 4.5 cm) or more invasive metastatic tumors could benefit more from neoadjuvant chemotherapy.

Maximal Cytoreductive Surgery

Maximal cytoreduction is an independent determinant of improved median survival in stage III and IV ovarian carcinoma patients. Thus, it is advisable to undergo optimal cytoreduction, either before or after neoadjuvant chemotherapy, to ideally reach no residual disease. Evidence has suggested this can increase median survival by 5.5%. Furthermore, a study showed that log median survival time can be improved by 50% by having more than 75% maximal cytoreduction than those with 25% or less. Platinum dose intensity was not related to the log median survival time. If surgery follows neoadjuvant chemotherapy, it should take place after four or fewer cycles for early intervention.

Primary Chemotherapy and Neoadjuvant Therapy

Extensive studies of adjuvant chemotherapy in women with early-stage ovarian cancer have been conducted. Four randomized control trials (ACTION 2003; Bolis 1995; ICON1 2003; trope 2000) that studied platinum-based chemotherapy showed that these women had 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). Of those trials, ICON1 2003 offered evidence of an overall benefit for high-risk patients with adjuvant chemotherapy, while a meta-analysis which included all of the 772 patients from ICON1 2003 and two-thirds of the patients from ACTION 2003 suggested a general advantage after suboptimal staging for stage IA or 1B epithelial ovarian cancer or grade 1 endometrioid carcinomas. Results from a randomized phase III trial comparing adjuvant platinum-based chemotherapy with observation followed by surgery indicated that non–optimally staged patients benefited from the former, while no gain was seen in optimally staged participants. However, a meta-analysis of all randomized clinical trials featuring stages I–II epithelial ovarian.

Maintenance Therapy

To effectively kill residual slowly dividing cancer cells in maintenance therapy, the cell turnover rate is slowed in order to prevent the dormant population of cancer cells from growing enough to be detected by elevated biomarkers or clinical evidence of recurrent disease by either elevation of biomarkers or clinical evidence. Observation versus maintenance therapy has been compared in several randomized trials.

Immunotherapy has recently indicated tremendous potential in treating solid malignant tumors. On the other hand, its efficacy in treating ovarian cancers is still unclear and consequently, debate still rages on this topic. That said, more promising results are emerging from the combining of different therapies, such as immune-checkpoint inhibitors with PARPs, chemotherapy, anti-angiogenic agents etc., which appear to produce better anti-tumor activity than a single approach. Initial phase trials have been positive so far, and anticipation is running high for the outcomes of the ongoing phase II and III trials.
The potential of vaccines to be used as a treatment for ovarian cancer is currently being explored. Various tumor-associated antigen molecules are being targeted; these include CA-125, p53 protein and HER-2. Several trials have been conducted in the process of developing novel therapeutic vaccines for ovarian cancer patients. Additionally, adoptive T-cell transfer and chimeric antigen receptor therapy (CAR-T) represent upcoming therapies which may reduce the burden of ovarian cancer and improve life expectancy amongst those affected by it.

Radiation Oncology

Early on, whole abdomen radiation was practiced; however, its use became rare due to the increased frequency of complications and toxicity. Radiation is currently used only for palliation, either to control symptoms or to treat localized spreads of ovarian cancer. In a high-risk subset of patients with clear cell carcinoma, adjuvant radiotherapy has not even been shown to improve survival.

Despite its limited use, radiation has taken a backseat in ovarian cancer management due to the advent of advanced systemic therapies. A newer palliative radiation technique is stereotactic body radiotherapy (SBRT). Even when local control is achieved, there is still evidence that lesions progress distantly.

Radiation is widely considered for local-regionally recurrent ovarian cancer, especially for chemotherapy-resistant lesions, since new techniques like SBRT, intensity-modulated radiotherapy, and low dose hypofractionation have been developed.

Staging

Currently 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 for ovarian cancer is directly affected by the stage of the disease at diagnosis. It is also significantly affected by baseline performance status, FIGO stage, and volume of residual disease after primary cytoreductive surgery. At 10 years, the median survival rate for ovarian cancer is between 40% and 50%, stage-related survival rates for stage I are between 70% and 92%, and stage IV survival rates are less than 6%.

In women with a disease that spreads to adjacent tissues, five-year survival rates drop to 80% and 25% for those with metastatic disease. Patients with recurrent disease can be treated. However, recurrent platinum-sensitive ovarian cancer usually has a median survival rate of three years, but a median survival rate of one year for platinum-resistant patients.

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

Enhancing Healthcare Outcomes

In spite of the ongoing clinical trials and introduction of new treatment lines in recent decades, ovarian cancer remains one of the most lethal cancers in women. The poor clinical outcome is primarily due to the failure of effective strategies for the early detection of ovarian cancer. The clinical variation seen in ovarian cancer care may also be contributing to deviations from the recommended guidelines.

We still need to develop effective strategies to diagnose ovarian cancer at an earlier and more curable stage. One of the major determinants of a patient’s survival is the volume of residual disease after cytoreduction surgery. Only an experienced gynecologic oncologist with a high number of cases at a busy hospital (>20 cases a year) should perform this procedure.

The management of patients and newly available treatment strategies or clinical trials should involve close collaboration between medical oncologists, surgical oncologists and palliative care professionals. Through shared decision-making by discussing the benefits, safety profile, symptom control and prognosis, it will help ensure optimal treatment and an improved quality of life.

Close surveillance follow-up strategies should be offered to patients in clinical remission. Patients should also be educated on the symptoms that indicate recurrence of the disease and encouraged to seek genetic risk counseling if not already done during the early stages of the disease.

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