Ovarian cancer is any cancer that affects the ovaries. It occurs mostly in post-menopausal women, but can occur at any age.¹ About 1.1% of women will be diagnosed with ovarian cancer in their lifetime.² It is the fifth-most-common cause of cancer death in women.³

Women with ovarian cancer that is discovered early have a high likelihood of survival. Unfortunately, due to its vague symptoms and difficulty to detect at early stages, approximately 60% of ovarian cancer patients are diagnosed with the cancer that has spread and the prognosis is poorer.⁴

There are several types of ovarian cancer. High-grade serous ovarian carcinoma (HGSOC) is the most common. It comprises about 50–60% of all ovarian cancers.⁵ This Protocol focuses on the treatment of HGSOC.

This Protocol will provide information that women with ovarian cancer and their loved ones need to be informed and active in decisions related to their cancer treatment. You will learn about current treatment options for ovarian cancer at all stages of the disease. This protocol also includes details on many promising new treatments being developed and how to participate in a clinical trial, as well as dietary and lifestyle changes and targeted nutrient supplementation that may complement conventional therapy.

This Protocol provides an overview of the treatment of HGSOC. For a more detailed summary of different aspects of cancer treatment, review Life Extension’s other relevant Protocols:

• Cancer Surgery
• Chemotherapy
• Cancer Immunotherapy
• Drug Repurposing in Cancer
• Cancer Radiation Therapy
• Cancer Treatment: The Critical Factors
• Cancer Adjuvant Therapy

There are three main types of ovarian cancer based on the tissue and cells from which they arise:

Germ cell tumors come from the reproductive cells (eggs) in the ovaries. Cancerous forms of these are rare and often affect younger women.

Stromal tumors come from the tissue that surrounds the ovaries. These are also rare tumors.

Epithelial ovarian cancers make up approximately 90% of all ovarian cancers.^4,6 They arise from the lining of the surface of the ovary or fallopian tubes. There are several subtypes, including the following⁶:

• Serous ovarian cancer is the most common subtype of epithelial ovarian cancer.
• High-grade serous ovarian cancer (HGSOC) is characterized by tumor cells with highly cancerous appearance and accounts for about 90% of serous ovarian cancers. (In general, the information in this Protocol applies to HGSOC.)
• Low-grade serous ovarian cancer is marked by tumor cells that have fewer cancerous features and accounts for approximately 10% of serous ovarian cancers.

• Endometrioid ovarian cancer is often associated with endometriosis and usually diagnosed early, resulting in a better prognosis.
• Mucinous cancer arising in an ovary is uncommon. It is often diagnosed early and typically has a favorable prognosis. Some mucinous cancers found in the ovaries may be metastases from the gastrointestinal tract.
• Clear cell ovarian cancer is uncommon, accounting for up to 5% of all ovarian carcinomas. It is often diagnosed in early stages and has a poor prognosis in advanced stages.

For HGSOC specifically, there are five overlappingsubtypes⁷:

• immunoreactive
• differentiated
• proliferative
• mesenchymal
• anti-mesenchymal

Prognosis differs by HGSOC subtype: the mesenchymal and proliferative subtypes have the poorest prognoses; immunoreactive subtype and anti-mesenchymal have the best prognoses; and prognosis of the differentiated type lies in between.⁷ While these associations with prognosis exist, they are primarily used for analysis of research outcomes and not tested for nor used in the current clinical setting.

The first step after being diagnosed with ovarian cancer is to determine the extent and amount of cancer present in the body. This is called cancer staging and usually involves taking tissue samples from the pelvis and abdomen (belly) to see if the cancer has spread. Imaging tests will likely also be used during initial assessment, including ultrasound, CT scans, X-rays, PET scans, and/or MRIs.^8,9

Cancer staging provides some of the most important information to help determine the level of the disease, guide treatment, and forecast prognosis.¹⁰

Ovarian cancer has four stages. In general, the lower the stage number, the less advanced the cancer and the better the prognosis. However, each person’s cancer is unique and may behave differently than other cancers of the same type and stage. The stages of ovarian cancer are^4,9:

The prognosis of ovarian cancer is directly dependent on the stage of the disease at diagnosis. Unfortunately, about most new cases of ovarian cancer are diagnosed at stage 3 or 4, when it has already spread beyond the pelvis.^12,13

The characteristics of the tumor tissue as examined under a microscope (histology) also affect prognosis. Another factor is the post-surgery tumor size: Surgery is undertaken to remove the bulk of the tumor(s) (“debulking” surgery), but if the whole tumor cannot be removed, the amount of cancer remaining after this initial surgery helps predict outcomes. Specifically, a smaller tumor volume after debulking surgery is correlated with better outcomes.¹⁴ By convention, if no remaining tumor diameter is 1 cm or more, this is considered “optimal.” However, prognosis is even better with no gross residual (also called microscopic-only residual) disease remaining.

Approximately 90% of patients with early-stage disease are recurrence-free at five years.¹⁵ However, cancer returns (relapses) in most patients with advanced-stage ovarian cancer.^15-17 Ovarian cancer eventually recurs in almost 25% of those with early-stage disease and about 70–80% of those with advanced disease.^18,19 The first relapse can occur within a few months or up to several years after initial treatment, with the median time to recurrence being 18–24 months.²⁰

The approximate predicted five-year survival rates by stage for epithelial ovarian and fallopian tube carcinomas are^11,15:

Stage 1 – 90%

Stage 2 – 60-70%

Stage 3 – 25-40%

Stage 4 – 15-20%

The 10-year survival of patients diagnosed with early-stage high-grade epithelial ovarian cancer is 55%, compared with about 15% for those whose cancer is diagnosed at an advanced stage.⁷

Other Prognostic Factors

Platinum sensitivity. Platinum-based chemotherapy drugs, such as cisplatin (Platinol) and carboplatin (Paraplatin), are commonly used as first-line treatment for ovarian cancer. Sensitivity to platinum-based chemotherapy influences survival for patients with recurrent ovarian cancer. A patient is considered platinum sensitive if her cancer initially responds to platinum-based chemotherapy. Ovarian cancer is also considered platinum sensitive if disease that recurs after initial chemotherapy responds to platinum-based agents and occurs at least six months after completion of platinum-based chemotherapy. On the other hand, if the cancer does not initially respond to platinum-based therapy, or if recurrent cancer that responded at first to platinum-based therapy no longer responds or comes back within six months of platinum-based chemotherapy, the cancer is considered platinum resistant. The median survival for women with recurrent platinum-sensitive ovarian cancer is about three years, whereas for those whose cancer is platinum-resistant it is about one year.⁴

Most patients who receive and initially respond to chemotherapy later develop chemotherapy resistance. This means that, although chemotherapy is initially effective at stopping cancer growth, it often stops working and the cancer progresses or recurs. About 20% of patients after initial treatment develop disease that is non-responsive to platinum chemotherapy, defined as progression occurring within six months after completing treatment.²¹

Body composition. There are some studies that suggest body-mass index (BMI) at either extreme (ie, being underweight or obese) is a predictor for ovarian cancer outcomes. In some studies, a low BMI was found to be associated with shorter survival; other studies found a similar association between obesity and shorter survival.23 ^22-25

In a comprehensive review and meta-analysis, muscle mass and muscle density were found to have more prognostic value than BMI in patients with ovarian cancer: BMI at diagnosis was not associated with survival outcomes, whereas higher muscle mass was associated with better progression-free survival (meaning the cancer is present but not getting worse) and muscle density was associated with better overall survival. These findings suggest body composition may be more important than body weight and BMI when predicting cancer outcomes.²²

Cachexia. The unintentional loss of more than 5% of body weight is an indicator of possible cancer cachexia. Cachexia is severe unintentional loss of skeletal muscle mass, with or without loss of body fat, together with increased protein breakdown and increased inflammation in the body. Cachexia is associated with up to 30% of cancer deaths, often because of heart or respiratory failure due to muscle loss.^26,27

It is crucial to follow a continuous targeted nutritional intervention, including dietary practices and supplements, to help counteract and reverse cachexia. Nutritional therapies for cachexia include omega-3 fatty acids, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and/or oral fish oil supplementation at high doses. Ensuring adequate intake of calories and protein is essential as well. Drugs and supplements that improve appetite and have muscle-building effects may also have a role, and incorporating exercise may help stave off muscle loss. Furthermore, a comprehensive cachexia treatment program may include psychological counseling.²⁶

For further information, refer to Life Extension’s Cachexia Protocol.

Genomic profiles and biomarkers. During the initial stages of treatment planning, your oncology team will perform tests to determine what kind of genetic changes are influencing your cancer. Understanding the types of genetic changes your cancer has will help your doctors figure out how best to treat your cancer. This section will explain the most common genetic changes encountered in HGSOC and what they might mean for your cancer treatment plan.

It is important to speak with your oncologist about genomic profiling upon diagnosis and prior to or during any treatment decisions, as well as in the case of cancer recurrence or when considering clinical trial participation. Genomic profiling and biomarker testing provide a detailed map of your tumor’s unique gene mutation landscape that helps inform treatment decisions at diagnosis and may determine eligibility for participation in a clinical trial with an experimental drug. This is because some treatments require the presence of specific tumor mutations to be effective.

Your oncology team will take blood samples and tumor samples during your initial assessment at diagnosis. Tumor genomic profiling and biomarker testing is then performed on the samples and must be interpreted by a specialist with a high level of expertise. Currently, tumor sample testing for ovarian cancer involves testing for BRCA1/2 mutations and homologous recombination deficiency (HRD) status (details below), which predict the response to platinum agents. In addition, a type of drug called a poly (ADP-ribose) polymerase (PARP) inhibitor may be helpful as part of maintenance therapy in patients whose tumor genomic profiles indicate the presence of BRCA mutations.²⁸

• BRCA. Ovarian cancer can have a hereditary component. Some women diagnosed with ovarian cancer may have family members who have had ovarian or breast cancer. At diagnosis, your tumor and blood will be tested for inherited (or hereditary) mutations in genes called breast cancer 1 and breast cancer 2 genes (BRCA1 and BRCA2). BRCA proteins, which are synthesized according to the instructions in the BRCA genes, are involved in repairing DNA damage, and therefore these mutations can affect how well your body repairs DNA. Testing for these mutations occurs routinely at the time of ovarian cancer diagnosis even if no other family members have cancer; if these mutations are present, drugs called PARP inhibitors may be used in maintenance treatment, as these drugs are effective in BRCA-positive tumors.²⁸

BRCA1 and BRCA2 gene mutations can be present in the blood (hereditary or germline mutations) or in your tumor (somatic mutations). If the blood sample tests negative for BRCA mutations, the tumor sample should still be tested to see if BRCA mutations are present in the tumor.^29,30 Identifying BRCA mutations and treating accordingly can favorably influence ovarian cancer survival.

Blood and tumor cell tests for BRCA 1 and BRCA2 mutations have been approved by the US Food and Drug Administration (FDA) as companion diagnostic tests for ovarian cancer assessment and are used to select patients with advanced cancers for targeted therapy.³¹ Work with your oncology care team to determine which test(s) are appropriate in your situation.

Women with BRCA mutations receive the most treatment benefit from PARP inhibitors and also initially respond better to platinum‐based chemotherapy (eg, carboplatin). Hereditary tumors are more chemosensitive than other tumors, thus patients with BRCA mutations have a better 5-year survival rate than those without BRCA mutations.³² This survival advantage diminishes over time in BRCA1 -positive patients, but is more persistent in BRCA2-positive patients. The Cancer Genome Atlas (TCGA) project found that BRCA1 and BRCA2 mutations occur in approximately 12.5% and 11.5% of ovarian cancer patients, respectively.⁷

On the other hand, the presence of BRCA1 and BRCA2 mutations does not appear to influence the effectiveness of surgery.³³ (See “Surgery” section below for details.)

Importantly, because BRCA mutations can run in families, children and siblings of women with these genetic markers may want to consult with a genetic counselor about screening.

• HRD. Homologous recombination deficiency (HRD) is a genetically determined tumor characteristic that results in deficient DNA repair. HRD in tumors causes genomic instability as a result of poor DNA repair and predicts a better response to platinum-based drugs and PARP inhibitors.³⁴

HRD is a fairly broad category that can be affected by various genetic mutations that affect DNA repair, including BRCA. Women whose tumors are HRD-positive benefit more from PARP inhibitors than women who are HRD-negative. Tumors can have a dysfunctional BRCA (ie, due to a mutation) and thus defective BRCA protein; or the BRCA gene can be functioning (and not mutated), but the BRCA protein still malfunctions. In both cases, DNA damage repair problems exist. Other genes and proteins involved in DNA repair and HRD include ATM, BARD1, RAD51C, RAD51D, and others.³⁵ DNA repair pathways are defective in approximately 50% of ovarian cancer patients.⁷

• CA125. Cancer antigen 125 (CA125; sometimes written as CA-125) is a tumor biomarker that can be measured using a blood test. CA125 is elevated in 50% of patients with early-stage ovarian cancer tumors and 92% of those with advanced-stage tumors; however, it can also be elevated in non-cancerous or benign conditions. Normal levels of CA125 range from 0–35 U/mL, but can rise to 500–1,000 U/mL in cases of advanced ovarian cancer.^36,37

The effectiveness of chemotherapy may be assessed by measuring the serum CA125 level: if the chemotherapy is working, CA125 levels generally drop. Normalization of CA125 early during treatment is associated with better survival in high-risk early-stage epithelial ovarian cancer patients.³⁶

• TP53. Tumor suppressor gene 53 (TP53) is a gene that makes a tumor suppressing protein called tumor protein p53 (p53). TP53 mutations are present in nearly all (96%) primary HGSOC ovarian tumor cells and are thought to be a suitable biomarker for disease monitoring. TP53mutations, depending on the type and location of the mutation, can provide information about the amount of tumor present, likely time to progression, and presence of a recurrence.^7,38 Assessment of TP53 mutations is primarily utilized in the research setting as of early 2023. As research progresses, these analyses may become more common in routine clinical care of women with ovarian cancer.^38,39

Nutritional status. Cancer-associated malnutrition can lead to several detrimental effects and is a common reason for treatments not being completed. Malnutrition results in a poorer response to anti-cancer drugs, increased chemotherapy side-effects, poor prognosis, and reduced survival. Therefore, it is critical that cancer patients prevent and/or counteract malnutrition when signs or symptoms first appear.⁴⁰ Maintaining good nutritional status during cancer treatment improves outcomes and possibly survival. Muscle wasting and malnutrition often begin during initial chemotherapy and progress, leading to frailty, decreased quality of life, and fatigue.⁴¹

A systematic review found eight studies that assessed several early feeding interventions after surgery. These studies showed a reduction in the length of hospital stay and improvement in intestinal recovery after surgery as a result of various nutritional approaches such as chewing gum, drinking coffee, eating a ketogenic diet, and supplementing with a fruit and vegetable juice concentrate.⁴²

In a retrospective study of 98 ovarian cancer patients, those who were “well-nourished” at baseline had a median survival of 20.3 months, while those who were malnourished had a median survival of only 9.8 months. Those whose nutritional status improved after three months had significantly better survival compared with those whose nutrition deteriorated, independent of age, prior treatment history, and stage at diagnosis.⁴³ One parameter used to measure malnutrition is decreased albumin levels, which have been associated with increased complications after surgery and poorer survival. Low numbers of lymphocytes (a type of immune cell) have also been associated with poor outcomes in some studies.⁴⁴

The Prognostic Nutritional Index (PNI) is calculated using blood albumin and total lymphocyte count, and PNI has been associated with ovarian cancer outcomes. In a study of over 2,000 patients, low preoperative PNI was associated with shorter overall survival and progression-free survival compared with high PNI.⁴⁵

Screening for malnutrition risk can be done quickly and easily and can be performed at every visit to help identify early malnutrition. Because malnutrition is associated with increased risk of cancer death, it is of the utmost importance to perform a screening to evaluate nutritional status and malnutrition risk for all ovarian cancer patients at time of cancer diagnosis and regularly throughout treatment. Patients at high risk for malnutrition should be referred to a registered dietitian nutritionist for a full nutritional assessment, as well as nutrient deficiency diagnosis and treatment if needed.⁴¹

Other prognostic biomarkers and tools. Potential biomarkers for predicting the chemoresistance of epithelial ovarian cancer patients are currently under investigation, including transthyretin, apolipoprotein E, haptoglobin, clusterin, alpha-1-antitrypsin, and carbonic anhydrase 1. Blood levels of these proteins have been observed to differ in chemo-sensitive versus chemo-resistant patients.⁴⁹

Other potentially useful biomarkers include ceruloplasmin, D-dimer, neutrophil-to-lymphocyte ratio, and C-reactive protein (CRP).^50-52

• Ceruloplasmin. Ceruloplasmin levels may be associated with epithelial ovarian cancer patients’ responsiveness to chemotherapy. Ceruloplasmin levels in ascites fluid (fluid that accumulates in the abdomen) has been found to be higher in chemo-resistant serous epithelial ovarian cancer patients compared with chemo-sensitive patients.⁵³
• D-dimer levels. D-dimer is a protein created during the breakdown of blood clots, and levels are measured by a simple blood test. An increased D-dimer level before surgery has been found to be associated with chemoresistance and poor outcomes in serous epithelial ovarian cancer patients. Elevated plasma D-dimer levels were associated with more advanced tumor stage, larger tumor size, increased presence of cancerous ascites, and higher serum CA125 level. Patients with elevated plasma D-dimer levels had significantly higher chemoresistance rates compared to those with normal plasma D-dimer levels.⁵⁴
• Complete blood count: neutrophil to lymphocyte ratio. Neutrophil and lymphocyte (white blood cells) levels can be measured in a blood test called a complete blood count (CBC). Pre-surgery neutrophil-to-lymphocyte ratio is a potential biomarker of responsiveness to first-line platinum-based chemotherapy and prognosis in serous ovarian cancer. A higher pre-surgery neutrophil-to-lymphocyte ratio was associated with more advanced tumor stage and grade, increased serum CA125 level, and cancer spread to lymph nodes, and was correlated with worse outcomes in serous ovarian cancer patients.⁵⁵
• CRP. C-reactive protein (CRP) is a widely studied marker of inflammation. High CRP levels in the blood are associated with lower survival rates in patients with gynecologic cancers, including ovarian cancer.⁵⁶ In one study, very high CRP levels were used to evaluate excessive muscle breakdown. A statistically significant relationship was found between quality of life and excessive breakdown of muscle, as measured by CRP.⁵⁷

Receiving a cancer diagnosis can be an overwhelming experience. Things move quickly and can be confusing. Treatment often begins very rapidly. In this section, we will help you understand generally what to expect during treatment.

Treatment of ovarian cancer is based on the tumor type, stage of the cancer, genomic mutations found in the tumor, and your needs and desires as a patient.

Most ovarian cancer patients are initially treated with surgery and then chemotherapy.⁷⁰

The goal of initial surgery is to remove as much of the cancer as possible. This is called “upfront surgery” or primary debulking surgery. Complete tumor removal during the primary surgery is the most important factor that influences prognosis for ovarian cancer patients. If initial surgery is not possible or cannot remove all the cancer, neoadjuvant chemotherapy may be recommended as the first treatment to shrink the tumor prior to surgery.

Surgery is followed by chemotherapy. Generally, chemotherapy drugs work by inhibiting the division of cancer cells, leading to cell death. The chemotherapy drugs most commonly given are a platinum-based drug (usually carboplatin [Platinol]), a taxane drug (usually paclitaxel [Taxol]), and sometimes a drug that prevents new tumor blood vessel growth (bevacizumab [Avastin]).⁷¹ This is the standard treatment for ovarian cancer.

After all chemotherapy is completed, ongoing bevacizumab therapy may be a good treatment option for those responding well to it. In addition, PARP inhibitors may be prescribed as maintenance treatment to help prevent the cancer from recurring, but whether they are used depends on the characteristics of your cancer. Your oncology care team will help you decide if maintenance therapy is needed in your case.⁷²

Surgery is usually the first step in ovarian cancer diagnosis and treatment. The goal of surgery is to diagnose or confirm the presence of cancer, determine the stage of the cancer, and remove as much of the tumor(s) as possible. The amount of tumor remaining after the initial surgery is prognostic and may help determine the choice of chemotherapy and other treatment regimens that will be advised by your oncologist.⁷⁶

Primary debulking surgery is performed prior to any other treatment, but in some cases, interval debulking surgery is preferable. In interval debulking, chemotherapy is started first, followed by surgery, and then completion of chemotherapy.⁷⁷ The usefulness of interval debulking has been shown after three, and possibly four, cycles of chemotherapy; however, it may diminish after that.

Surgery for ovarian cancer is usually performed via a large incision in the belly, called a laparotomy. In early-stage ovarian cancer, a less invasive technique involving small incisions, called laparoscopic surgery, may be feasible and appears to result in similar cancer outcomes.⁷⁸

Early-Stage Cancer

A patient with early-stage disease involving only one ovary and/or fallopian tube on the same side may opt for fertility-sparing surgery. This involves the removal of the affected ovary and perhaps fallopian tube, and is often followed by no chemotherapy. However, most women with epithelial ovarian cancer require surgery involving removal of the uterus, both fallopian tubes, and both ovaries (ie, total hysterectomy with bilateral salpingo-oophorectomy). Although the evidence is not conclusive, this more thorough surgical approach may be associated with a lower recurrence rate than fertility-sparing surgery.^73,79 Other samples may be taken to rule out advanced stage disease, such as lymph nodes and normal appearing tissues.

Advanced-Stage Cancer

In ovarian cancer that has progressed to stage 3 or 4, chemotherapy may be given to shrink the tumor prior to surgery. This is called neoadjuvant chemotherapy. After tumor shrinkage, surgery can be carried out to remove as much of the remaining tumor(s) as possible. The ovaries, fallopian tubes, and uterus are usually removed.¹¹ Depending on whether the cancer has spread, all or parts of other nearby organs may be removed as well, including the spleen, liver, gallbladder, pancreas, intestines, appendix, and bladder. Importantly, a healthy nutritional status prior to surgery has been linked to better surgical outcomes.⁸⁰

Because advanced-stage ovarian cancer is not usually cured by surgery, most advanced ovarian cancer patients undergo platinum-based chemotherapy with or without targeted treatments after surgery. Cancer recurs, even after surgery and chemotherapy, in most people with stage 3 or 4 disease. Additional surgery may be an option if cancer recurs six months or longer after chemotherapy has ended.¹¹ The option of pursuing palliative care, with the goal of improving quality of life, is an important consideration for women with advanced ovarian cancer, and should be discussed early in the course of treatment.^16,72,81

Some women with early-stage ovarian cancer are treated only with surgery, but many receive chemotherapy as well. Standard treatment for advanced-stage ovarian cancer includes chemotherapy plus surgery. Chemotherapy is usually started after surgery but may be given before surgery as well, which is called neoadjuvant chemotherapy. Generally, chemotherapy is given in cycles, with sessions weekly or every three weeks for a period of several months.⁸²

Typically, ovarian cancer is initially sensitive to chemotherapy. Systemic (whole body) chemotherapy is considered essential for most patients with ovarian cancer and generally consists of intravenous platinum-based chemotherapy. Alternative regimens, such as intraperitoneal (abdominal) chemotherapy or hormone therapy, are sometimes recommended as options, depending on cancer stage, subtype, and completeness of the initial surgery.⁸³

Toxic effects of chemotherapy include, but are not limited to, fatigue, mouth sores, appetite changes, nausea, vomiting, hair loss, kidney toxicity, nerve toxicity, and ear/hearing toxicity, anemia, and bone marrow suppression (myelosuppression).⁸⁴

Please refer to Life Extension’s "Chemotherapy" Protocol for further information about mitigating chemotherapy side effects and supporting efficacy.

Neoadjuvant Chemotherapy

Neoadjuvant chemotherapy is used to shrink the tumor before surgery. It generally consists of carboplatin and paclitaxel for three cycles followed by surgical tumor removal in intervals (between chemotherapy sessions) and additional chemotherapy after surgery for a total of six cycles or more of chemotherapy. Neoadjuvant chemotherapy is an alternative to primary debulking surgery (done before chemotherapy), especially if there is too much cancer present to allow complete removal by surgery.⁷³

Intraperitoneal Chemotherapy

Delivery of chemotherapy directly into the abdominal cavity, called intraperitoneal chemotherapy, is sometimes used to treat ovarian cancer but typically only if the cancer meets certain criteria. For select advanced-stage epithelial cancers, intraperitoneal chemotherapy may be an option, but only if there is less than one centimeter (<1 cm) of tumor remaining after surgical removal.⁸³

Intraperitoneal chemotherapy appears to be most effective in women whose cancer has been optimally surgically debulked with no or minimal residual disease. This is because intraperitoneal chemotherapy can only penetrate and kill small tumors on the peritoneal (inner abdominal lining) surface. In women who have larger tumors remaining after surgery, intravenous chemotherapy is the better option.⁸⁵

Heated intraperitoneal chemotherapy, also known as HIPEC, is a special form of chemotherapy given after patients have had standard neoadjuvant chemotherapy. It is administered into the abdomen at the time of an optimal debulking surgery. HIPEC was associated with longer survival in one study, but for a number of reasons it remains very controversial and studies are ongoing to determine its role in modern practice.⁸⁶

Chemotherapy for Early-Stage Ovarian Cancer

Many patients with stage I cancer are not treated with adjuvant (post-surgery) chemotherapy, and surgery is simply followed by observation. However, those with HGSOC usually receive adjuvant platinum-based chemotherapy. Platinum-based chemotherapy (eg, carboplatin or cisplatin) with a taxane (eg, paclitaxel and/or docetaxel) is the standard chemotherapy used.⁷³

Chemotherapy for Advanced-Stage Ovarian Cancer

Standard treatment for patients with advanced ovarian cancer is adjuvant chemotherapy using platinum-based drugs and taxanes. Whether chemotherapy can be administered via intravenous or intraperitoneal methods depends on the outcome of debulking surgery and other factors that affect prognosis.²⁸ Your oncology care team will help you select the best treatment regimen.

Depending on BRCA and HRD status, some ovarian cancer patients are candidates for ongoing maintenance therapy after initial surgery and chemotherapy. Maintenance therapy is intended to reduce the likelihood that cancer will recur or prolong the time until it gets worse. Generally, patients with advanced-stage ovarian cancer who have responded well to initial treatment may receive maintenance therapy.⁸⁷

Maintenance therapy may include PARP inhibitors (olaparib [Lynparza] or niraparib [Zejula]) and/or the anti-angiogenic agent bevacizumab.

PARP Inhibitors

Poly Adenosine Diphosphate (ADP)-ribose polymerase (PARP) inhibitors are generally used in patients who carry BRCA1 or BRCA2 mutations or have HRD-positive cancers. PARP inhibitors are approved as maintenance therapy after platinum-based chemotherapy in patients who have a complete or partial response to chemotherapy. Talk with your oncology care team to determine if a PARP inhibitor is a good option in your case, as researchers are still investigating in which ovarian cancer patients these drugs are most effective.⁸⁷

PARP inhibitors provide a different anticancer mechanism than standard platinum chemotherapy, which works by damaging DNA in cancer cells. PARP inhibitors instead prevent tumor cells from repairing DNA damage, and are particularly effective in those with HRD or BRCA1/2 mutations. Women with epithelial ovarian cancer are advised to have testing for BRCA1/2 mutations, which are inherited, or germline, mutations. In addition, somatic tumor DNA testing can detect mutations that are not inherited, such as those associated with HRD. The presence or absence of these mutations will help determine whether treatment with a PARP inhibitor is likely to be beneficial.²⁹

In women with newly diagnosed and recurrent platinum‐sensitive ovarian cancer, and those on maintenance therapy, PARP inhibitor use has been found to improve progression-free survival. However, the benefit may be small, and there is a potential for adverse effects.⁸⁸ There is an uncommon but potential risk of developing secondary blood cancers, such as acute myelogenous leukemia or myelodysplastic syndromes.

Nevertheless, a 7-year clinical trial in patients with newly diagnosed advanced ovarian cancer and a BRCA1/2 mutation found a clinically meaningful improvement in overall survival (albeit not statistically significant) with maintenance olaparib. These findings suggest the use of maintenance olaparib may help prolong remission and may also increase the potential for cure.⁸⁹

A meta-analysis published in 2022 found that, in women with newly diagnosed ovarian cancer who had BRCA or HRD mutations, PARP inhibitors might be more beneficial than bevacizumab when used with chemotherapy and/or as maintenance therapy.⁹⁰

Bevacizumab

Bevacizumab is a monoclonal antibody that targets human vascular endothelial growth factor A (VEGF-A), a protein needed for tumor blood vessel growth.⁹¹ It is used along with chemotherapy and/or as maintenance treatment for some patients with advanced or recurrent ovarian cancer. Bevacizumab is approved as maintenance therapy after carboplatin plus paclitaxel.

Bevacizumab has been found to lengthen progression-free survival in ovarian cancer patients. Its benefits have been observed with 15 months of use, but not with longer maintenance therapy.⁹² In a randomized placebo-controlled trial in 1,873 women with newly diagnosed stage 3 or 4 ovarian cancer, the average time from treatment to progression was 14.1 months for those receiving bevacizumab during and after chemotherapy and 10.3 months for those receiving chemotherapy alone; however, there was no improvement in quality of life scores and the overall survival time was similar in the two groups.⁹³ In certain patients undergoing initial treatment, such as those with stage 4 disease or suboptimal surgery, survival may be improved.⁹⁴ Also, a survival benefit may be seen in patients with platinum-sensitive recurrent disease.⁹⁵

Bevacizumab is not affected by resistance mechanisms to chemotherapy drugs or PARP inhibitors.⁹² Thus, in women with platinum-resistant recurrent ovarian cancer, bevacizumab can provide some benefit.⁷² In fact, it can significantly improve both the response rate and time before cancer progression in patients when added to chemotherapy.⁹⁶

The treatment of recurrent ovarian cancer is determined based on platinum sensitivity and the progression-free interval.

If there is a response to platinum-based chemotherapy (meaning the cancer is killed by the chemotherapy) and no cancer progression for over six months, then the cancer is platinum-sensitive.²⁸ A carboplatin-based combination is generally used for platinum-sensitive ovarian cancer; the add-on options include paclitaxel, doxorubicin, and gemcitabine (Gemzar), with or without bevacizumab, and possibly with PARP inhibitor maintenance.

Conversely, if the progression-free interval is less than six months, the cancer is considered platinum-resistant, and if it recurs during or immediately after platinum, it is refractory. Patients with platinum-resistant or refractory tumors may receive non-platinum-based chemotherapy, with or without bevacizumab, for a period of time, which could lead to a better response to platinum chemotherapy at a later point.²⁸

Radiation Therapy

Radiation therapy is a palliative treatment for metastatic, persistent, or recurrent ovarian cancer that may help relieve symptoms by temporarily shrinking tumors.^87,97 Radiation therapy has been shown to reduce symptoms such as pain, bowel or urinary tract obstruction, bleeding, and neurological problems related to metastases to the brain. Symptom relief through palliative treatment with radiation therapy may diminish the need for aggressive treatment and improve quality of life at the end of life.⁹⁷ In addition, evidence from trials in patients with other types of cancer have indicated radiation therapy targeting small metastatic tumors may lengthen survival in certain clinical scenarios.^98,99

Dealing with an ovarian cancer diagnosis can harm a woman’s emotional well-being, body image, and sexuality, often causing distress to the woman, her family, and other loved ones. Women with advanced-stage ovarian cancer will need to consider the likelihood of mortality and will want to make fully informed decisions that fit their personal wishes around end-of-life care.

Palliative care is a specialized medical approach that focuses on patient comfort, autonomy, emotional and spiritual support, and quality of life, rather than disease management alone.¹⁰⁰ Palliative therapies may include surgery, chemotherapy, and radiation therapy, but the emphasis is on treatments that specifically target relief of burdensome symptoms such as pain, bowel obstruction, ascites (fluid build-up in the abdomen), respiratory problems, blood clots, fatigue, difficulty sleeping, and stress.^101,102

Palliative care is an inevitability for most patients with advanced, progressive, or recurrent ovarian cancer, but the best time to stop symptom-inducing therapies (like chemotherapy) and shift to a palliative approach depends on the individual and should be a patient-centered decision considered early in the course of treatment.⁸¹ Ovarian cancer patients who have open and frank discussions about palliative cancer care with their team of providers are more likely to receive care that is aligned with their values and goals and report having a higher quality of life and better emotional well-being.^81,100,103 Other end-of-life considerations may include hospice care and medical assistance in dying.¹⁰⁴

The nutrients described in this section are limited to those for which human studies involving participants with ovarian cancer have been published. They are listed alphabetically. In most cases, the studies described below are preclinical (before human testing), observational in nature, or are too small in size to allow definitive conclusions.

There are many other nutrients that have been studied in the context of cancer surgery, chemotherapy, or radiation therapy more generally that may also be of interest to those with ovarian cancer. These additional potentially supportive nutrients are discussed in Life Extension’s Protocols on Chemotherapy, Cancer Surgery, Radiation Therapy, and Cancer Adjuvant Therapy. Readers of this Protocol are encouraged to also review these other Protocols and discuss with their oncology care team whether the interventions described therein may be helpful for their situation.

Agaricus blazei Murill (Sun Mushroom)

Agaricus blazei Murill, also known as “sun mushroom,” is a species of medicinal and culinary mushroom that grows in Brazil, Japan, and China. Preclinical research has shown that A. blazei possesses several anticancer and immune-modulating properties.¹⁰⁵

A study conducted in South Korea investigated the effects of consuming an extract of Agaricus blazei Murill Kyowa (ABMK) on immune status and quality of life in gynecological cancer patients undergoing chemotherapy. The study included 100 cervical, ovarian, and endometrial cancer patients who were treated with either carboplatin and etoposide (Vepesid) or carboplatin and paclitaxel, with or without oral consumption of ABMK. The results showed that natural killer cell (a type of immune cell) activity was significantly higher in the ABMK-treated group compared with the placebo group. The study also found that ABMK treatment improved some chemotherapy-associated side effects such as appetite, alopecia, emotional stability, and general weakness.¹⁰⁶

Curcumin

Many lines of preclinical evidence suggest curcumin exerts several effects that could be beneficial in the context of ovarian cancer.¹⁰⁷ Clinical trials in ovarian cancer patients found those treated with curcumin oil plus chemotherapy had improved quality of life and lower incidence of adverse effects such as gastrointestinal reactions, allergic reactions, bone marrow suppression, and neurotoxicity than those treated with chemotherapy alone.¹⁰⁸ In one trial, 60 women with ovarian cancer were divided into two groups: one group underwent chemotherapy and received injections (site unspecified) of 400 mg curcumin oil per day for three months, while the other group underwent chemotherapy alone. Participants in the curcumin group had fewer adverse reactions (eg, gastrointestinal problems, allergic reactions, bone marrow suppression, and neurotoxicity) and reported better quality of life.^108,109 In a separate trial including 62 women with ovarian cancer given injections (site unspecified) of 400 mg curcumin oil per day or placebo for 63 days in addition to chemotherapy treatment, those who received curcumin oil had fewer adverse reactions to chemotherapy treatment compared with placebo.^108,110 (Note that in the two preceding studies, the authors also reported that curcumin increased “treatment effectiveness,” but details are lacking as to how “treatment effectiveness” was measured.)

Ginseng

Ginseng (Panax ginseng) is known for enhancing immunity, and preclinical studies suggest it can kill ovarian cancer cells directly, as well as sensitize resistant ovarian cancer cells to cisplatin and paclitaxel chemotherapy.^111,112 Ginseng, as part of a traditional Chinese medicine preparation, may also improve the outcome of chemotherapy by reducing toxicity to healthy tissues, as shown in clinical trials of advanced lung cancer patients.¹¹³

A randomized controlled clinical trial in 30 epithelial ovarian cancer patients found the use of red ginseng (Panax ginseng Meyer), at a dose of 3,000 mg/day, for three months after adjuvant chemotherapy improved mood and reduced symptoms of fatigue, nausea, vomiting, anxiety, and shortness of breath.¹¹⁴

Magnesium

Low magnesium levels are a common side effect of platinum-based chemotherapy, in particular cisplatin, and are commonly seen in patients. Most patients have a mild drop in magnesium levels, but some suffer severe loss of magnesium. Those at high risk for low magnesium levels include patients with vomiting and diarrhea.¹¹⁵ Some patients may require regular testing for magnesium levels and intravenous magnesium replacement prior to each cycle of chemotherapy.

An observational study of 229 patients with advanced ovarian cancer who had undergone surgery and carboplatin-based chemotherapy examined whether magnesium levels were related to survival. This study revealed that experiencing frequent episodes of low magnesium levels during treatment was associated with shorter survival in patients with advanced ovarian cancer.¹¹⁶

Strategies to effectively counteract low magnesium levels include magnesium supplementation, more frequent magnesium tests, prevention and early treatment of vomiting and diarrhea, and timely magnesium replacement.¹¹⁶

Melatonin

Melatonin is a hormone produced mainly by a small region in the center of the brain called the pineal gland. It helps regulate circadian cycles and possesses a number of properties that may be beneficial in the context of cancer, such as modulating cell division and reducing oxidative stress and inflammation.¹¹⁷ In one study, blood melatonin levels in 96 women with ovarian cancer and 40 healthy women were compared. The cancer patients were found to have lower melatonin levels.¹¹⁸

In preclinical studies, adding melatonin to cisplatin therapy improved treatment efficacy, reduced toxic side effects, and prevented ovarian cancer cell growth in a synergistic manner, suggesting melatonin may be useful as a co-treatment for ovarian cancer with cisplatin, particularly as melatonin was reported to protect normal healthy ovarian cells from cisplatin-mediated cytotoxicity in the laboratory.^119,120 Lab studies also indicate melatonin may help prevent ovarian cancer cells from spreading.¹²¹

Selenium

A study involving 31 women undergoing chemotherapy for ovarian cancer evaluated whether selenium supplementation could counter some of the side effects of chemotherapy. A daily dose of 200 mcg selenium for three months was associated with a significant increase in white blood (immune) cell counts and a decrease in hair loss, abdominal pain, flatulence, weakness, malaise, and loss of appetite compared with control. Moreover, at the two- and three-month analyses, participants taking the selenium had increased levels of the antioxidant enzyme glutathione peroxidase in their red blood cells.¹²²

Vitamin D

Vitamin D deficiency is more common in ovarian cancer patients than those with benign ovarian conditions, and in women with recurrent ovarian cancer than those with stable ovarian cancer. In one study, vitamin D insufficiency was found in 73% of women with recurrent ovarian cancer versus 47% of women with stable ovarian cancer.¹²³

A systematic review of observational evidence reported higher vitamin D levels have been associated with a reduced risk of ovarian cancer. Some observational research has further suggested that sunlight may be a protective factor against ovarian cancer-associated death and that higher vitamin D levels are associated with improved outcomes.¹²⁴ In an Australian study, a significant correlation between higher vitamin D serum levels at diagnosis and longer survival was observed in those with invasive ovarian cancer. Average circulating vitamin D levels were about 18 ng/mL, and each 4 ng/mL increase reduced the risk of death by 7%.¹²⁵

Interestingly, vitamin D biosynthesis in the ovarian and fallopian tube epithelium seems to be impaired in healthy women with theBRCA1 mutation.¹²⁶

Vitamin E

A clinical trial found 20 women with ovarian and endometrial cancers had elevated levels of malondialdehyde (ie, a marker of oxidative damage) compared with healthy women. Surgical removal of the tumors led to an additional increase in malondialdehyde. The researchers randomized the 20 women to receive either a single dose of 1,200 mg vitamin E (form not specified) or no treatment 18 hours before surgery. Plasma levels of malondialdehyde were significantly lower one hour and 24 hours after surgery in the women who received vitamin E than in those who did not. The researchers suggest that the surgery-induced increase in oxidative damage to cells can be mitigated by giving patients a single dose of vitamin E prior to surgery.¹²⁷

Adhering to a healthy diet is crucial for women with ovarian cancer. Studies have shown that consuming a healthy diet during treatment improves overall nutritional status, which has been associated with improved quality of life and better outcomes.^57,132-135

In an analysis of data from the large Women’s Health Initiative (WHI) study, the dietary habits of women who were diagnosed with ovarian cancer during the study period were associated with survival. The WHI study began enrolling women in 1995, with follow-up through late 2012. The women whose food frequency questionnaires placed them in the top one-third of participants in terms of diet quality (according to Healthy Eating Index scores) were 27% less likely to die of any cause during the follow-up period than women with diet quality scores in the bottom one-third.¹³⁵ Adequate intake of total fruit (including 100% juice), whole fruit, total vegetables, dark green vegetables, legumes, whole grains, milk products (including fortified soy milk), total protein, seafood and plant protein, and mono- and polyunsaturated oils, as well as limited intake of saturated fats, added sugars, sodium, refined grains, and alcohol are components of a higher Healthy Eating Index score.¹³⁶ Interestingly, no association was found between death rates and individual dietary components, suggesting that overall dietary pattern was the main factor affecting survival.¹³⁵

Anti-inflammatory Diet

Chronic inflammation has been implicated as an underlying mechanism contributing to ovarian cancer development. Scores on the Dietary Inflammatory Index (DII) and Empirical Dietary Inflammatory Pattern (EDIP) assessment tools have been correlated with inflammatory biomarkers such as C-reactive protein (CRP) and interleukin-6 (IL-6).¹³⁷ Higher DII and EDIP scores, as well as high CRP levels, are associated with an increased risk of developing ovarian cancer.¹³⁸

In two observational studies involving 1,003 ovarian cancer survivors, dietary patterns before and after their cancer diagnosis, including changes in diet from before to after diagnosis, were examined. Results showed that consuming a diet with a high EDIP score after being diagnosed with ovarian cancer, regardless of pre-diagnosis EDIP score, was associated with an increased chance of death due to ovarian cancer and death from any cause compared with eating a diet with a low EDIP score before and after the cancer diagnosis. Among non-high-grade serous ovarian cancer patients, a more inflammatory diet after diagnosis was associated with increased risk of death from any cause.¹³⁹ A highly inflammatory diet was also found to be associated with all-cause mortality in a study in 490 Black women with high-grade serous ovarian carcinoma, and specifically among those who had ever smoked.¹⁴⁰

A pro-inflammatory diet was found to be one that is high in saturated fat and carbohydrates, and low in poly-unsaturated fatty acids, fiber, flavonoids, and other dietary components, such as vitamins and minerals. Thus, pro-inflammatory foods that should be avoided include those high in saturated fat and refined carbohydrates.^141,142 Eliminating inflammatory foods from the diet and/or consuming an anti-inflammatory diet after being diagnosed with ovarian cancer could increase longevity.¹⁴² Instead, consume fresh fruit and vegetables, which are rich in anti-inflammatory components, such as fiber, isoflavones, niacin, folate, and vitamins C and E.¹⁴³

A randomized controlled trial in 51 women with stages 2–4 ovarian cancer who had completed chemotherapy at least six months prior to enrollment compared a low-fat, high-fiber diet to a modified and supplemented National Cancer Institute diet. The National Cancer Institute-recommended diet (the “5-A-Day” diet) consisted of five or more servings of fruits and vegetables and 25 grams or more of fiber per day, with 20% or fewer calories from fat, and was supplemented with four fruit and vegetable juice concentrate capsules and 33 grams of soy-based beverage powder, which included 5 grams of fiber, daily. After six months, participants in the low-fat/high-fiber group had improved calorie intake and participants in both groups had increased phytonutrient levels. Importantly, blood levels of albumin (a measure of protein status) were significantly increased in the supplemented 5-A-Day diet group, as were levels of vitamin A and the carotenoids lutein and zeaxanthin.¹⁴⁴

Dairy

A very large meta-analysis of 34 observational studies with a total of 3,171,186 participants examined the relationship between various kinds of dairy products and cancer outcomes. Fermented milk consumption, which includes yogurt and soured milk, was associated with a 15% lower cancer-related death rate in women; specifically, increasing consumption by 200 grams daily was associated with a 10% decrease in total cancer mortality. However, high milk consumption was linked to an increased risk of ovarian cancer mortality in women, particularly for high- and whole-fat milk.¹⁴⁵ A study published in 2021 by researchers in China assessed the association between pre-diagnosis dairy consumption and mortality among 853 women with ovarian cancer. The study found that women with the highest dairy product intake had over twice the risk of dying from ovarian cancer compared to those with the lowest intake.¹⁴⁶ Additional studies are needed to carefully evaluate the relationship between dietary factors and ovarian cancer risk.¹⁴⁷

Smoking Status

Although smoking has not been found to be a risk factor for developing ovarian cancer overall, it has been correlated with increased likelihood of mucinous ovarian cancer.¹⁴⁹ Evidence also suggests smoking may increase serous ovarian cancer risk specifically in African American women.¹⁵⁰ Furthermore, smoking has been found to increase the risk of death in ovarian cancer patients, and quitting smoking could help women with ovarian cancer live longer.^151,152 A study that followed 519 ovarian cancer patients found being a current smoker increased the odds of dying for any reason by 70%. In women with a recurrence of ovarian cancer, being a smoker was even more dangerous: compared with past or never-smokers, current smokers were almost three times as likely to die.¹⁵³ Another study that analyzed data from 1,279 participants in the Nurses’ Health Study and Nurses’ Health Study II who were diagnosed with stage 1–3 ovarian cancer found both former and current smokers had an increased risk of death relative to never-smokers, and longer duration of smoking and higher pack-years (cigarettes per day multiplied by years of smoking) exacerbated the increased risk. Furthermore, women who continued to smoke after their cancer diagnosis had a 40% higher mortality rate compared with never-smokers, while women who quit smoking after their diagnosis had a mortality rate that was similar to that of never-smokers.¹⁵²

Physical Activity

Increasing physical activity is associated with improved survival in ovarian cancer patients. A review of 12 studies that looked at the effect of recreational physical activity on survival rates in a total of 6,806 women diagnosed with ovarian cancer found that physically active women had better outcomes than women who were more sedentary.¹⁵⁴ A study that analyzed data from 1,461 women with ovarian cancer found those who exercised regularly after their cancer diagnosis were less likely to die from their cancer. Importantly, women who reduced their activity level after being diagnosed with ovarian cancer had a higher risk of dying than women whose physical activity level was the same before and after their cancer diagnosis.¹⁵⁵

Physical activity is an important modifiable lifestyle factor that affects quality of life during chemotherapy for ovarian cancer. In a systematic review and meta-analysis, physical activity was found to improve quality of life-related factors, such as fatigue, in ovarian cancer survivors.¹⁵⁶ A randomized controlled trial showed that, for patients with ovarian cancer undergoing chemotherapy, a home-based exercise intervention, along with a cognitive behavioral therapy program, resulted in reduced cancer-related fatigue and depression and improved quality of sleep.¹⁵⁷

High-Dose Intravenous Vitamin C

Vitamin C (ascorbate) has been shown to be safe in nearly all patient populations, both alone and in combination with chemotherapies.^158,159

In one unblinded clinical trial, 25 patients with stage 3 or 4 ovarian cancer receiving carboplatin and paclitaxel were randomized to either chemotherapy plus 75–100 grams of intravenous ascorbate twice weekly for 12 months or chemotherapy alone. The ascorbate group was observed to have fewer side effects compared to the group that received only chemotherapy, and median time for disease progression was 25.5 months in the ascorbate group versus 16.75 in the chemotherapy group. This trial also showed intravenous ascorbate therapy is safe in ovarian cancer patients¹⁵⁹ Ascorbate's ability to decrease chemotherapy-induced adverse effects makes it a potentially valuable addition to chemotherapy regimens because reducing chemotherapy side-effects (toxicity) could allow patients to better tolerate chemotherapy and finish treatment. Because of its many potential benefits and minimal toxicity, examination of intravenous ascorbate in combination with standard chemotherapy in large clinical trials is warranted. It is important to note that due to limited absorption in the digestive tract, oral supplementation with vitamin C does not raise blood concentrations sufficiently for the same effects as intravenous administration.¹⁵⁸

Mistletoe Extract

A meta-analysis of findings from 41 clinical trials found that Iscador, a fermented extract of mistletoe (Viscum album), may improve cancer patients’ chance of survival, including those with ovarian cancer.¹⁶⁰ A report on four long-term observational studies indicated ovarian cancer patients whose treatment included mistletoe extract had better outcomes as well as improved emotional regulation.¹⁶¹ In an open clinical trial that included 71 ovarian cancer patients and 162 patients with other solid tumors, the inclusion of mistletoe extract therapy was found to reduce chemotherapy side effects and improve quality of life.¹⁶²

In a case report, a woman with high-grade stage 4 serous ovarian carcinoma had improvement after mistletoe therapy. The patient, whose cancer was metastatic and recurrent, had undergone two courses of ineffective chemotherapy (platinum and paclitaxel followed by doxorubicin and bevacizumab) before initiating treatment with 100–500 mg/mL of mistletoe extract, administered intraperitoneally, three times weekly for three months. The cancer then stabilized and the CA125 (CA-125) level normalized. She then received subcutaneous injections of mistletoe extract in increasing doses of 1 to 20 mg/mL for nearly 21 months, during which time her condition remained stable.¹⁶³

Another case report described the use of mistletoe extract in a patient with advanced stage 4 high-grade serous epithelial ovarian carcinoma with widespread metastases that were surgically removed. After treatment with adjuvant chemotherapy and a stem cell transplant, the patient opted for continuous treatment with mistletoe extract. The patient remained tumor-free in follow-up examinations for at least 20 years.¹⁶⁴

Mistletoe extracts like Iscador are generally administered by subcutaneous injection two to three times a week.¹⁶¹

Antibody-Drug Conjugates

Antibody-drug conjugates are newer tools in oncology. They consist of an antibody bound to a cell-killing cancer drug. The antibody helps facilitate delivery of the cell-killing drug to cancer cells.¹⁶⁵

One antibody-drug conjugate has been approved for ovarian cancer: mirvetuximab soravtansine (Elahere). This drug is indicated for patients with platinum-resistant ovarian cancer expressing folate receptor alpha.¹⁶⁶ In late-stage trials, it demonstrated a response rate of 32% and some antitumor activity,¹⁶⁷ but did not improve progression-free survival compared with chemotherapy.¹⁶⁸

Research is ongoing to refine the use of antibody-drug conjugates in ovarian cancer.¹⁶⁶

Drug repurposing refers to the use of existing drugs to treat conditions for which they are not typically indicated. Generally, drug repurposing focuses on older drugs with established safety records. Studies have shown that several well-established drugs may have benefit in reducing ovarian cancer disease burden and helping improve patient outcomes.^169,170 Note, however, that in most cases evidence relating to the use of repurposed drugs in cancer is preliminary. Rigorous, multi-center clinical trials are needed before potential benefit can be more fully understood. Patients interested in whether a repurposed drug may be worth considering in their situation should consult with their oncology team.

Metformin

The diabetes drug metformin (Glucophage) has been associated with improved survival in women with ovarian cancer in some observational studies. A meta-analysis of five studies with a total of 3,582 ovarian cancer patients found consistent evidence for improved overall survival in ovarian cancer patients with type 2 diabetes using metformin after their cancer diagnosis and improved progression-free survival in those without diabetes.¹⁷¹ Another meta-analysis of nine studies including over 10,000 women with ovarian cancer found that metformin use was associated with a 28% reduced risk of overall mortality.¹⁷² However, two other meta-analyses found no correlation between metformin use and ovarian cancer outcomes.^173,174 Findings from early clinical trials in ovarian cancer patients without diabetes have had mixed results, with one reporting no improvement in progression-free survival ¹⁷⁵ and another reporting better than expected overall survival with the addition of metformin to chemotherapy.¹⁷⁶

One clinical trial is investigating the use of metformin (850 mg twice daily orally), aspirin (160 mg once daily), letrozole (Femara) (2.5 mg once daily orally), or olaparib (300 mg twice daily orally) 10–14 days prior to surgery in patients with stage 3 or 4 high grade serous ovarian carcinoma who are going through a diagnostic laparoscopy. For more information, please refer to: https://clinicaltrials.gov/ct2/show/NCT03378297

Caution: Long-term metformin use in diabetics can lower serum levels of total vitamin B12. Therefore, vitamin B12levels should be monitored and B12 replacement therapy initiated when needed.¹⁷⁷

Statins

Ovarian cancer patients taking statins, a group of commonly prescribed cholesterol-lowering drugs, appear to have better outcomes than those not taking statins. In a meta-analysis of 12 studies, statin use was associated with improved overall survival.¹⁷³ Another meta-analysis of 16 studies, with a combined total of 37,660 ovarian cancer patients, noted markedly longer survival in those with serous or endometrioid ovarian cancer (but not mucinous or clear cell ovarian cancer) who used statins, particularly those who started statin therapy after their cancer diagnosis. The analysis also examined whether the two types of statin had different effects on survival, and found hydrophilic statins (pravastatin [Pravachol] and rosuvastatin [Crestor]) and lipophilic statins (simvastatin [Zocor], lovastatin [Mevacor], fluvastatin [Lescol], or atorvastatin [Lipitor]) had similar positive effects.¹⁷⁸

Aspirin

A few studies have examined the relationship between aspirin use and survival in ovarian cancer patients. In a small study that tracked outcomes in 77 women with clear cell ovarian cancer (an uncommon and typically aggressive form of ovarian cancer), documented long-term aspirin use was found to be associated with improved disease-free and overall survival.^179,180 An analysis of data from the Nurses’ Health Study and the Nurses’ Health Study II found that post-diagnosis use of aspirin was associated with improved ovarian cancer-specific survival.¹⁸¹ In contrast, a meta-analysis of six studies observed no association between aspirin use and mortality risk in patients with ovarian cancer.¹⁸²

Aspirin use may reduce the risk of ovarian cancer. A meta-analysis of 17 observational studies, that included over 8,000 total participants, found aspirin use six or more times per week was associated with a 13% reduction in ovarian cancer risk.¹⁸³

Beta-blockers

Beta-blockers are a class of adrenaline-inhibiting medications usually used to treat high blood pressure and other cardiovascular disorders. Selective beta-blockers target mainly heart tissue while non-selective beta-blockers can have effects throughout the body.¹⁸⁴ There are mixed findings in studies on beta-blocker use in ovarian cancer patients. In an observational study that followed 3,844 Australian women with ovarian cancer and a history of cardiovascular conditions, those who received non-selective beta-blockers for their cardiovascular issues around the time of surgery were more likely to survive their cancer at two years post-surgery than women who did not receive non-selective beta-blockers; however, women who received selective beta-blockers did not experience a survival benefit.¹⁸⁵ In a multicenter review of 1,425 women with ovarian cancer, those using non-selective beta-blockers during chemotherapy had a median overall survival of 94.9 months, while those receiving selective agents had a median survival of 38 months.¹⁸⁶

Another study involving ovarian cancer patients found certain factors were associated with a benefit from beta-blocker use. Specifically, beta-blockers were linked to increased survival during at least three years of monitoring in those over 60 years old, those with existing cardiovascular or other chronic disease, and those who used beta-blockers for one year or longer.¹⁸⁷

Itraconazole

Itraconazole (Sporanox) is an antifungal medication that has demonstrated potential anticancer effects in preclinical research.^188,189 Small observational studies in women with ovarian cancer indicate itraconazole may lengthen survival time when used alongside chemotherapy. One study examined outcomes in 19 treatment-refractory ovarian cancer patients treated with chemotherapy plus itraconazole and 36 similar patients treated with chemotherapy alone. The study found itraconazole use was associated with a 503-day (more than 16 months) increase in median overall survival.¹⁹⁰ A report on nine cases by the same researchers indicated that including itraconazole in therapy may lead to improved outcomes in patients with ovarian clear cell carcinoma, a rare and often refractory type of ovarian cancer.¹⁹¹

Bisphosphonates

Bisphosphonates, such as alendronate (Fosamax) and zoledronic acid (Reclast), are a class of drugs that interfere with bone breakdown and are used to treat osteoporosis. Laboratory and animal studies have indicated bisphosphonates, when combined with chemotherapy, may slow ovarian cancer cell proliferation, inhibit metastasis, and delay recurrence.¹⁹² In addition, some observational studies have noted a relationship between bisphosphonate use and lower risk of ovarian cancer,^193,194 while others have not.^195,196