TREATMENTS FOR OVARIAN CANCER EXPLAINED

Ovarian cancer represents a complex and challenging group of malignancies arising from the ovaries. Often diagnosed at advanced stages due to its insidious onset and non-specific symptoms, it remains a significant cause of gynecological cancer-related mortality. Understanding the various types, risk factors, clinical presentation, diagnostic approach, prognostic indicators, and management strategies is crucial for effective clinical care and patient outcomes.

Major Types of Ovarian Cancer

Ovarian cancers are not a single disease but a heterogeneous group classified based on the cell type from which they originate. The three main categories are:

• • • Epithelial Ovarian Cancer (EOC): This is the most common type, accounting for approximately 90% of cases. EOC originates from the cells on the surface of the ovary or, increasingly, from the fallopian tube fimbriae (for high-grade serous types). Subtypes are determined by their microscopic appearance:
      • High-Grade Serous Carcinoma (HGSC): The most frequent epithelial subtype (about 70%), often aggressive and diagnosed at advanced stages. Increasingly thought to arise from the fallopian tube fimbriae (carcinoma in situ) and implant on the ovary.
      • Low-Grade Serous Carcinoma (LGSC): Rarer and less aggressive than HGSC, typically diagnosed at earlier stages. Progresses slowly and often less responsive to chemotherapy.
      • Mucinous Carcinoma: Accounts for about 5-10% of EOCs. More often diagnosed at Stage I. If advanced, it can be challenging to treat. It’s important to distinguish primary ovarian mucinous carcinoma from metastasis to the ovary (e.g., from the gastrointestinal tract), which is much more common.
      • Endometrioid Carcinoma: Represents 5-10% of EOCs. Often associated with endometriosis and/or synchronous endometrial cancer. Usually diagnosed at earlier stages.
      • Clear Cell Carcinoma: Accounts for about 5-10% of EOCs. Also strongly associated with endometriosis. Can be aggressive, even at early stages, and may have different treatment responses compared to serous types.
      • Transitional Cell Carcinoma (Brenner Tumor Malignant): A rare subtype.
    • Germ Cell Tumors: These tumors arise from the primitive germ cells within the ovary, which are destined to become eggs. They are much less common than EOC (less than 5% of cases) and typically affect younger women and adolescents. They are often highly curable, even at advanced stages, due to their sensitivity to chemotherapy. Types include:
      • Dysgerminoma (most common subtype)
      • Teratoma (mature or immature)
      • Endodermal Sinus Tumor (Yolk Sac Tumor)
      • Choriocarcinoma
      • Embryonal Carcinoma
      • Mixed Germ Cell Tumors
    • Stromal Tumors: These tumors originate from the structural connective tissue cells of the ovary that produce hormones. They are the rarest type (less than 5% of cases) and can occur at any age. Some stromal tumors produce hormones (like estrogen or testosterone), which can cause specific symptoms. Types include:
      • Granulosa-Stromal Cell Tumors (e.g., Granulosa cell tumor)
      • Sertoli-Leydig Cell Tumors

Risk Factors

While the exact cause of ovarian cancer is not fully understood, several factors are associated with an increased risk, particularly for epithelial types:

• • • Genetic Predisposition:
      • BRCA1 and BRCA2 Mutations: These are the most significant genetic risk factors, accounting for a substantial portion of hereditary ovarian cancers. A woman with a BRCA1 mutation has up to a 44% lifetime risk, and with a BRCA2 mutation up to a 17% lifetime risk (compared to about 1.2% in the general population).
      • Lynch Syndrome (Hereditary Non-Polyposis Colorectal Cancer – HNPCC): Mutations in mismatch repair genes (MLH1, MSH2, MSH6, PMS2) increase the risk of various cancers, including ovarian (particularly endometrioid and clear cell subtypes).
      • Other Gene Mutations: Less common mutations in genes like RAD51C, RAD51D, BRIP1, PALB2, and PTEN (Cowden syndrome) are also associated with increased risk.
      • Family History: Having one or more first-degree relatives (mother, daughter, sister) with ovarian or breast cancer, even without a known genetic mutation, increases risk.
    • Reproductive History:
      • Nulliparity (Never Having Given Birth): Women who have not had children are at slightly increased risk.
      • Infertility or Use of Fertility Treatments: Studies are complex and sometimes conflicting, but some evidence suggests a possible association.
      • Early Menarche (Starting Periods Before Age 12) and Late Menopause (After Age 52): Prolonged exposure to estrogen over a lifetime is thought to play a role.
    • Personal History:
      • Endometriosis: Particularly associated with increased risk of clear cell and endometrioid ovarian cancers.
      • Breast Cancer History: A personal history of breast cancer is linked to an increased risk of ovarian cancer, partly due to shared genetic risk factors (like BRCA mutations).
    • Age: The risk of epithelial ovarian cancer increases with age, with most cases occurring after menopause (typically over age 50). Germ cell and stromal tumors can occur at younger ages.
    • Obesity: Some studies suggest a link between obesity and increased risk, though the association may be stronger for specific subtypes or less pronounced than for other gynecological cancers.
    • Hormone Replacement Therapy (HRT): Long-term use of estrogen-only HRT may slightly increase risk, though combined estrogen-progestin HRT data is less clear or shows a smaller effect, and the overall risk increase is generally considered small for the average woman.
    • Talc Powder: Some studies suggest a possible link between perineal use of talc and ovarian cancer, but the evidence is not conclusive and remains controversial.
    • Protective Factors: Factors that decrease risk include having multiple full-term pregnancies, breastfeeding, use of oral contraceptives (a significant protective factor, especially with longer duration of use), tubal ligation, and hysterectomy.

Clinical Manifestations

Ovarian cancer is often called a “silent killer” because its symptoms are typically vague, non-specific, and commonly attributed to less serious conditions like digestive issues or menstrual irregularities. This frequently leads to diagnosis at advanced stages. Key symptoms, particularly if new, persistent (lasting more than a few weeks), and occurring daily or almost daily, include:

• • • Pelvic or Abdominal Pain: Persistent discomfort, cramping, or aching in the lower abdomen or pelvis.
    • Bloating: Persistent abdominal swelling or fullness, distinct from typical transient bloating.
    • Difficulty Eating or Feeling Full Quickly: Feeling satiated after eating only a small amount of food.
    • Urinary Symptoms: Increased urgency or frequency of urination.
    • Changes in Bowel Habits: Constipation or diarrhea.
    • Fatigue: Persistent tiredness or low energy levels.
    • Unexplained Weight Change: Either weight loss or, less commonly, weight gain (often due to fluid build-up or the tumor itself).
    • Abdominal Swelling (Ascites): Accumulation of fluid in the abdomen, often causing distension.
    • Painful Intercourse: Dyspareunia.
    • Abnormal (Postmenopausal) Vaginal Bleeding: Less common in ovarian cancer than in uterine or cervical cancers, but can occur, particularly with stromal tumors or metastatic disease.

It is crucial to emphasize that these symptoms are common and usually not caused by cancer. However, the persistence and new onset of a combination of these symptoms, especially in women over 50 or those with known risk factors, warrant prompt medical investigation.

Appropriate Approach for Patient with Suspected Ovarian Cancer

When ovarian cancer is suspected based on persistent symptoms, physical examination findings, or family history, a systematic diagnostic approach is necessary:

• • 1. Clinical Evaluation:
       • Detailed History: Elicit information about the nature, duration, and frequency of symptoms, family history of cancer, reproductive history, and other risk factors.
       • Physical Examination: Includes a general physical examination to assess for signs of ascites, abdominal mass, or weight loss. A thorough pelvic examination, including rectovaginal exam, is essential to palpate for ovarian masses, uterine enlargement, or cul-de-sac nodularity.
    2. Initial Investigations:
       • Imaging:
         • Transvaginal (and/or Abdominal) Ultrasound: This is typically the first-line imaging modality to visualize the ovaries and assess for any masses, their size, characteristics (cystic vs. solid, septations, vascularity), and presence of ascites. Benign masses often have distinct ultrasound features compared to suspicious ones.
         • CT Scan (Computed Tomography) of the Abdomen and Pelvis (and Chest): If a suspicious mass is identified on ultrasound, or if there is a high clinical suspicion, a CT scan is performed for comprehensive assessment. It helps determine the extent of disease (staging), evaluate lymph nodes, and identify potential sites of metastasis (e.g., omentum, peritoneal surfaces, liver, lungs). Chest CT is part of standard staging for advanced disease.
         • MRI (Magnetic Resonance Imaging) or PET (Positron Emission Tomography): These may be used in specific situations, such as further characterization of a complex mass, evaluating distant metastasis, or assessing recurrence.
       • Blood Tests:
         • CA-125: This is the most widely used tumor marker for epithelial ovarian cancer. Elevated levels (generally >35 U/mL) are found in approximately 80% of women with advanced EOC. However, its use for screening in the general population is not recommended due to poor sensitivity (it can be normal in early-stage disease) and poor specificity (it can be elevated in many non-cancerous conditions like endometriosis, fibroids, pelvic inflammatory disease, pregnancy, and benign ovarian cysts, as well as other cancers). CA-125 is most useful in the workup of a suspected pelvic mass and for monitoring treatment response and detecting recurrence in diagnosed EOC.
         • Other Tumor Markers: Alpha-fetoprotein (AFP), human chorionic gonadotropin (hCG), lactate dehydrogenase (LDH), and Inhibin A/B may be measured if a germ cell or stromal tumor is suspected, as these markers are often elevated in those specific tumor types.
         • Full Blood Count and Biochemistry: To assess general health, kidney function, and liver function before potential surgery or chemotherapy.
    3. Referral and Management:
       • Referral to Gynecologic Oncologist: Patients with a suspicious ovarian mass or symptoms highly suggestive of ovarian cancer should be referred to a gynecologic oncologist, a surgeon specializing in gynecologic cancers. Studies consistently show better outcomes when ovarian cancer surgery is performed by a gynecologic oncologist.
       • Definitive Diagnosis: The definitive diagnosis of ovarian cancer and determination of its specific type (histology) usually requires a biopsy, often obtained during surgery (exploratory laparotomy or laparoscopy). Fine-needle aspiration (FNA) of a suspected ovarian mass is generally discouraged due to the risk of spilling tumor cells and spreading the cancer, which can negatively impact staging and prognosis.
       • Multidisciplinary Team (MDT) Discussion: Cases should ideally be discussed in an MDT meeting involving gynecologic oncologists, medical oncologists, radiation oncologists, pathologists, radiologists, and specialist nurses to formulate the optimal management plan.

Poor Prognostic Factors

Several factors influence the prognosis (likelihood of recovery or survival) for patients with ovarian cancer. Poor prognostic factors are associated with a less favorable outcome:

• • • Stage at Diagnosis: The most significant prognostic factor. Patients diagnosed at late stages (Stage III or IV, where cancer has spread beyond the pelvis) have a significantly worse prognosis than those diagnosed at early stages (Stage I or II, confined to the ovary or pelvis).
    • Tumor Grade: High-grade tumors (poorly differentiated cells that look very abnormal under the microscope and tend to grow and spread quickly) have a worse prognosis than low-grade tumors (well-differentiated cells that resemble normal tissue and grow slowly).
    • Tumor Histology: Certain subtypes, such as clear cell and mucinous carcinomas, may be associated with a less favorable prognosis, especially at advanced stages, due to potential differences in chemotherapy sensitivity compared to high-grade serous carcinoma.
    • Amount of Residual Disease After Surgery: The single most important predictor of survival after initial treatment for advanced EOC is the amount of visible tumor left after surgical debulking (cytoreduction). Optimal debulking (leaving no visible disease or residual nodules less than 1 cm in diameter) is strongly associated with improved survival compared to suboptimal debulking.
    • Performance Status: The patient’s overall health and functional capacity (ability to perform daily activities) significantly impact their ability to tolerate treatment and are important prognostic indicators.
    • Response to Chemotherapy: Failure to respond adequately to platinum-based chemotherapy (platinum resistance) is a major indicator of poor prognosis and limits future treatment options.
    • Tumor Biology: Specific molecular features of the tumor, such as high tumor burden or certain genetic alterations beyond BRCA, can influence prognosis.
    • CA-125 Response to Treatment: Failure of CA-125 levels to normalize or significantly decline after initial treatment is often indicative of residual disease and a less favorable prognosis.

Comprehensive overview of Management Options for Ovarian Cancer

The standard management of epithelial ovarian cancer, which accounts for the majority of cases, typically involves a combination of surgery and chemotherapy. Other modalities like targeted therapy, immunotherapy, and radiation therapy play roles in specific situations or subtypes. The following outline details the key components of ovarian cancer management:

1. Diagnosis and Staging

• Importance: Accurate diagnosis and staging are fundamental prerequisites to planning appropriate treatment. Ovarian cancer is surgically staged according to the International Federation of Gynecology and Obstetrics (FIGO) system, based on the findings during surgical exploration.
• Diagnostic Procedures:
  • Physical Examination: Including pelvic examination and rectovaginal examination.
  • Imaging: Ultrasound (transvaginal and abdominal), CT scans of the abdomen and pelvis, MRI, and sometimes PET-CT are used to assess the extent of disease, identify potential sites of metastasis, and guide biopsy.
  • Tumor Markers: Serum CA-125 levels are often elevated in epithelial ovarian cancer, although they are not specific and can be elevated in benign conditions. Other markers (e.g., HE4, CA 19-9, CEA) may be used, sometimes in combination (e.g., RMI, ROMA index) to help assess the risk of malignancy in adnexal masses.
  • Biopsy/Cytology: Definitive diagnosis often requires histological examination of tissue obtained via paracentesis (for ascites), image-guided biopsy, or exploratory laparoscopy/laparotomy.
  • Genetic Testing: Testing for germline mutations (especially BRCA1/BRCA2) is crucial for patients and their families, impacting risk assessment for relatives and informing treatment options (e.g., eligibility for PARP inhibitors). Somatic tumor testing for genetic alterations (including BRCA and HRD – Homologous Recombination Deficiency) is also increasingly important for treatment decisions.

2. Surgical Management

• Primary Role: Surgery is the cornerstone of treatment for most ovarian cancers, serving both diagnostic and therapeutic purposes. The primary goal of surgery for advanced-stage disease is optimal cytoreduction (debulking), which means removing as much of the visible tumor as possible. Optimal cytoreduction is strongly correlated with improved prognosis and response to subsequent chemotherapy.
• Types of Surgery:
  • Primary Cytoreductive Surgery (PCRS): Performed as the initial treatment. An exploratory laparotomy is typically performed to assess the extent of disease spread. The surgery involves a total abdominal hysterectomy (removal of the uterus), bilateral salpingo-oophorectomy (removal of both fallopian tubes and ovaries), omentectomy (removal of the fatty tissue covering the abdominal organs), and multiple biopsies of peritoneal surfaces. Depending on the extent of disease, additional procedures may be necessary, such as:
    • Pelvic and para-aortic lymphadenectomy (removal of lymph nodes).
    • Bowel resection or repair.
    • Diaphragmatic stripping or resection.
    • Splenectomy or partial pancreatectomy.
    • Resection of disease deposits from the liver surface or other organs.
  • Optimal vs. Suboptimal Cytoreduction: Optimal cytoreduction is generally defined as leaving no residual tumor nodules larger than a specific size (historically >1 cm, more recently aiming for <1 cm or ideally no macroscopic disease). Achieving optimal cytoreduction significantly improves survival outcomes.
  • Neoadjuvant Chemotherapy (NACT) followed by Interval Cytoreductive Surgery (ICS): For patients with extensive advanced disease where primary optimal debulking is deemed unlikely, or for those who are not medically fit for a major upfront surgery, NACT (usually 3-4 cycles) may be given first. The goal is to shrink the tumors, potentially making surgery more feasible and improving the chances of achieving optimal cytoreduction during ICS. ICS is then performed, followed by further cycles of chemotherapy.
  • Surgery for Early-Stage Disease: For apparent early-stage disease confined to the ovaries, surgery may be less extensive but must still include comprehensive staging procedures (peritoneal washings, biopsies of suspicious areas, omentectomy, lymph node assessment) to accurately determine the stage and guide the need for adjuvant treatment. Fertility-sparing surgery may be considered in carefully selected young women with certain early-stage, low-grade tumors.
  • Secondary Cytoreductive Surgery: May be considered in select patients with recurrent disease, particularly if the recurrence is localized, the patient has a good performance status, and a long interval has passed since prior platinum-based chemotherapy (indicating platinum sensitivity).

3. Chemotherapy

• Primary Role: Chemotherapy is the primary systemic treatment for ovarian cancer, used to kill cancer cells throughout the body. It is almost universally indicated for advanced-stage epithelial ovarian cancer and for many early-stage cases depending on the stage and tumor characteristics.
• Standard Regimens: The standard first-line chemotherapy for epithelial ovarian cancer is a combination of a platinum agent (most commonly carboplatin, sometimes cisplatin) and a taxane (most commonly paclitaxel, sometimes docetaxel). These drugs are typically given intravenously every 3 weeks for 6 cycles.
• Neoadjuvant Chemotherapy: As mentioned above, used before surgery in select patients with advanced disease.
• Adjuvant Chemotherapy: Given after primary surgery, typically 6 cycles, to eradicate any remaining microscopic disease and reduce the risk of recurrence.
• Intraperitoneal (IP) Chemotherapy: In carefully selected patients with optimally debulked (residual disease <1 cm) Stage III ovarian cancer, a combination of intravenous and intraperitoneal chemotherapy may be considered. IP chemotherapy delivers chemotherapy directly into the abdominal cavity, achieving higher drug concentrations at the site of peritoneal disease. However, it is associated with increased toxicity and is not suitable for all patients or centers.
• Chemotherapy for Recurrent Disease: Treatment for recurrent ovarian cancer depends heavily on the interval since the completion of the last platinum-based chemotherapy (the “platinum-free interval”).
  • Platinum-Sensitive Recurrence: Recurrence > 6 months after completing platinum-based therapy. Re-treatment with platinum-based combinations (e.g., carboplatin with paclitaxel, gemcitabine, or PLD – pegylated liposomal doxorubicin) is often effective.
  • Platinum-Resistant Recurrence: Recurrence < 6 months after completing platinum-based therapy, or progression during treatment. Treatment involves non-platinum single agents or combinations (e.g., PLD, topotecan, gemcitabine, weekly paclitaxel). Response rates are generally lower, and treatment focuses more on disease control and symptom management.

4. Targeted Therapies

• Role: Targeted therapies are drugs that interfere with specific molecular pathways involved in cancer growth and survival. Their use is becoming increasingly integrated into ovarian cancer management.
• PARP Inhibitors: Poly (ADP-ribose) polymerase inhibitors (e.g., olaparib, niraparib, rucaparib) are a class of targeted agents that work by interfering with DNA repair mechanisms, particularly in cells with deficiencies in homologous recombination repair (HRR), such as those with BRCA mutations.
  • Approved Uses: Used as maintenance therapy after a response to platinum-based chemotherapy (both in the upfront setting for patients with BRCA mutations or HRD, and in the recurrent platinum-sensitive setting). Also approved for treating recurrent, advanced BRCA-mutated ovarian cancer after prior lines of chemotherapy.
• Anti-Angiogenic Agents: These drugs target the formation of new blood vessels that tumors need to grow.
  • Bevacizumab: A monoclonal antibody that targets vascular endothelial growth factor (VEGF). Approved for use in combination with chemotherapy (both in the upfront setting for certain stages and in the recurrent setting) and as maintenance therapy after completing chemotherapy. It helps control ascites and can delay progression.

5. Immunotherapy

• Role: Immunotherapy aims to stimulate the patient’s own immune system to recognize and kill cancer cells. While highly effective in some cancers, the role of immunotherapy as a standalone treatment for epithelial ovarian cancer has been more limited to date.
• Checkpoint Inhibitors: Drugs like pembrolizumab and nivolumab block immune checkpoints (e.g., PD-1, PD-L1), releasing the brakes on the immune system’s attack on cancer cells.
  • Current Status: Ongoing research is exploring the use of checkpoint inhibitors in ovarian cancer, particularly in combination with chemotherapy, targeted therapies, or other immunotherapies, and in specific subtypes or patient populations (e.g., those with high tumor mutational burden or specific immune profiles). Their use as standard treatment is less established compared to other solid tumors, often confined to clinical trials or specific recurrent settings based on evolving evidence.

6. Radiation Therapy

• Role: Radiation therapy uses high-energy beams to destroy cancer cells. Its role in the management of epithelial ovarian cancer is relatively limited compared to surgery and chemotherapy.
• Primary Use: Radiation is primarily used for palliative purposes to manage symptoms caused by localized recurrence, such as pain from bone metastases or bleeding from pelvic masses.
• Other Uses: Rarely used as consolidation therapy in specific, limited situations or for treating brain metastases originating from ovarian cancer.

7. Maintenance Therapy

• Purpose: Given after completion of initial therapy (surgery and chemotherapy) when there is no evidence of disease or only minimal residual disease. The goal is to suppress remaining microscopic cancer cells, extend the time until recurrence (progression-free survival), and potentially improve overall survival.
• Agents Used:
  • PARP inhibitors (for patients meeting specific criteria, often related to BRCA mutation or HRD status).
  • Bevacizumab (often continued for a period after combination therapy).
• Duration: Maintenance therapy is typically given for a defined period (e.g., 1-2 years or until progression), depending on the agent and clinical context.

8. Management of Recurrent Disease

• Complexity: Managing recurrent ovarian cancer is challenging and aims to prolong survival while maintaining quality of life. Treatment decisions are based on the platinum-free interval, extent and location of recurrence, prior treatments, patient’s performance status, and symptoms.
• Treatment Modalities: May include chemotherapy (often re-challenging with platinum if platinum-sensitive, or using non-platinum agents), targeted therapies (especially PARP inhibitors if applicable), secondary cytoreductive surgery (in select cases), and palliative radiation therapy.
• Focus: Treatment for platinum-resistant or heavily pre-treated recurrence often shifts towards symptom control and maximizing quality of life.

9. Palliative and Supportive Care

• Importance: Palliative care is an essential component of comprehensive cancer management, provided alongside active treatment from the time of diagnosis. It focuses on preventing and relieving suffering and improving quality of life for both the patient and their family.
• Services: Includes management of physical symptoms (pain, nausea, vomiting, fatigue, bowel obstruction, ascites), psychological and emotional support, social support, and spiritual care. Discussions about goals of care are integral.
• Ascites Management: Frequent issue in advanced/recurrent disease. Managed with diuretics, paracentesis (draining fluid), or surgically placed drains. Bevacizumab may help reduce ascites formation.

10. Surveillance and Follow-up

• Purpose: Regular follow-up visits are necessary after completion of primary treatment to monitor for recurrence, manage long-term side effects of treatment, and provide ongoing support.
• Schedule: Typically involves physical examinations (including pelvic examination), symptom review, and blood tests (often including CA-125) every few months initially, with intervals increasing over time if the patient remains in remission.
• Imaging: Imaging scans (CT, PET-CT) are performed as clinically indicated based on symptoms or rising tumor markers, rather than on a fixed schedule in asymptomatic patients.

11. Clinical Trials

• Role: Participation in clinical trials is a critical option for patients at various stages of their disease, offering access to novel therapies and contributing to the advancement of knowledge in ovarian cancer treatment. Patients should discuss clinical trial options with their care team.

Conclusion

The management of ovarian cancer is multifaceted and continues to evolve with ongoing research. While surgery and chemotherapy remain central to initial treatment, the integration of targeted therapies, the exploration of immunotherapy, and the emphasis on personalized medicine based on genetic characteristics and tumor biology are transforming the landscape. Effective management requires a collaborative multidisciplinary team approach, careful consideration of individualized treatment plans, and comprehensive supportive care to optimize outcomes and quality of life for patients.