Ovarian Cancer

What every physician needs to know:

While less common than cancers of the cervix and endometrium, ovarian cancer causes more deaths in the United States than the two other major female pelvic malignancies combined. Unfortunately, there are no known effective screening tests for the cancer, symptoms are non-specific, and the large majority of patients present with advanced stage (stage III or IV) disease.

Physicians need to consider the diagnosis of ovarian cancer in any woman presenting with at least moderately severe, but non-specific abdominal/pelvic pain or bloating lasting more than several weeks. It is critical to emphasize that these symptoms are absolutely not specific for ovarian cancer, but their continued presence should lead to further evaluation.

Epithelial cancers of the ovaries (including serous, mucinous, endometrioid, and clear cell adenocarcinoma) account for approximately 90% of ovarian malignancies. The remainder are stromal (e.g., granulosa and Sertoli-Leydig tumors) and germ-cell (e.g., dysgerminoma, endodermal sinus tumors, malignant teratoma, embryonal carcinoma) tumors. The principal focus of this overview is epithelial ovarian cancers.

Beware of other conditions that can mimic ovarian cancer:

Patients presenting with non-specific abdominal pain and swelling may have a primary malignant (e.g. cancer of the colon, pancreas) or non-malignant (e.g., diverticulitis, colitis) gastrointestinal process or another gynecologic malignancy (e.g., metastatic endometrial cancer).

Which individuals are most at risk for developing ovarian cancer:

The most important risk factor for the development of ovarian cancer is a family history of the malignancy, a feature present in approximately 5-10% of women with the neoplasm. The majority of women with a genetic basis for ovarian cancer are now known to have either BRCA1 or BRCA2 genetic abnormalities.

Recently reported data suggest specific groups of individuals with ovarian cancer, and unique ovarian subtypes have a particularly high likelihood of having a BRCA-related malignancy. In an analysis of over 1,000 unselected patients with epithelial ovarian cancer, BRCA mutations were found in as many as 25% of women who were under the age of 50 at diagnosis, 18% of patients with serous histologic subtype, and more than 25% of individuals with Jewish, Italian or Indo-Pakistani ethnic origin. Of interest, there were no cases of such mutations in the uncommon mucinous ovarian cancer subtype.

A personal history of infertility, breast cancer, and prolonged use of post-menopausal hormone replacement have also been suggested in some studies to increase the risk of ovarian cancer.

Conversely, multiple pregnancies, pre-menopausal use of oral contraceptives, undergoing a bilateral tubal ligation or prophylactic oophorectomies in the post-menopausal period have been shown to decrease the risk of ovarian cancer.

What laboratory and imaging studies should you order to characterize this patient's tumor (i.e., stage, grade, CT/MRI vs PET/CT, cellular and molecular markers, immunophenotyping, etc.)

How should you interpret the results and use them to establish prognosis and plan initial therapy?

The standard work-up for a woman suspected of having ovarian cancer includes the performance of a CT scan of the abdomen and pelvis to document the presence of a pelvic mass and reveal the extent of intraperitoneal and extraperitoneal tumor spread.

The serum CA-125 antigen level is also obtained, but is not specific for ovarian cancer. However, because over 90% of patients with advanced ovarian cancer will have an elevated serum level of this tumor antigen, the finding of a normal serum value would suggest the possibility of a non-ovarian site (e.g. colon, gastric, pancreatic cancer) in a patient with radiographic findings highly suggestive of malignant disease.

Staging

Table I. TNM and FIGO staging of ovarian cancer.

What should the initial definitive therapy for the cancer be?

Surgery

Complete and systematic surgical staging is essential, as incomplete staging may result in inadequate post-operative treatment and thereby compromise clinical outcomes. It has been shown that staging and cytoreduction are less likely to be adequate, and long-term survival poorer, when a gynecologic oncologist is not present at the initial operation.

Components of surgical staging for suspected early stage ovarian cancer include:

Multiple cytologic washings.
Intact tumor removal.
Complete abdominal exploration including evaluation and random biopsies of all visceral and parietal surfaces within the peritoneal cavity, including the diaphragm
Removal of internal reproductive organs (remaining ovaries, uterus, fallopian tubes), which may be preserved in selected patients with stage IA disease wishing to maintain fertility.
Omentectomy.
Aortic and pelvic lymph node sampling.
Even in the setting of regionally advanced disease, standard initial treatment for epithelial ovarian cancer includes an attempt at maximal surgical cytoreduction (if possible to zero volume residual macroscopic cancer).

Chemotherapy

Platinum-based combination chemotherapy is administered after surgical cytoreduction. While cisplatin and carboplatin appear to be therapeutically equivalent in ovarian cancer, carboplatin is generally employed due to its more favorable toxicity profile. The most commonly employed regimen is:

Carboplatin AUC 5-7.5 (6 commonly used) IV day 1.
Palitaxel 175 mg/m²; day 1 every 21 days for 6-8 cycles.

Alternative regimens include:

Carboplatin AUC 6 day 1.
Docetaxel 75 mg/m²; day 1 every 21 days for 6-8 cycles.

Carboplatin AUC 6 day 1.
Paclitaxel 70-80 mg/m²; days 1, 8, 15 every 21 days for 6-8 cycles.

Neoadjuvant (pre-operative) chemotherapy

Although still not universally accepted in the United States, a landmark phase 3 randomized trial demonstrated equivalent survival outcome (with reduced morbidity) with a strategy of neoadjuvant carboplatin-paclitaxel chemotherapy administered to patients with extensive intra-abdominal disease, a clinical/radiographic picture consistent with ovarian cancer and a histologic diagnosis of adenocarcinoma) followed by definitive surgical cytoreduction compared to the “standard approach” of primary surgery followed by chemotherapy.

Three-drug combinations

There is no evidence that adding a third cytotoxic drug to platinum/taxane combinations improves outcome (progression-free or overall survival) compared to this two drug combination. However, recently reported preliminary phase 3 trial data has demonstrated that the addition of the anti-vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab to carboplatin-paclitaxel chemotherapy prolongs progression-free survival. This occurs only if this drug is continued in a single-agent “maintenance strategy” following the completion of 6-8 cycles of combination therapy. Additional follow-up of the treated patient populations will be required to determine if this novel strategy improves overall survival in ovarian cancer.

Maintenance paclitaxel

The controversial “maintenance approach” in ovarian cancer entails the delivery of single-agent paclitaxel (delivered as a 3-hour infusion every 28 days for one year) in women with advanced disease who achieve a clinically defined complete response to primary chemotherapy. This approach was shown to significantly improve progression-free survival in one reported phase 3 trial. It remains unknown if the approach will favorably impact overall survival. An ongoing phase 3 trial is addressing this important issue.

Intraperitoneal (IP) chemotherapy

Several phase 3 randomized trials have demonstrated that the intraperitoneal administration of cisplatin as primary treatment of small volume residual advanced ovarian cancer (largest remaining residual tumor volume less than 1-2cm in maximal diameter) favorably impact overall survival in this malignancy.

A recommended IP chemotherapy regimen includes the following:

Paclitaxel 135 mg/m²; IV infusion over 24 hours day 1.
Cisplatin 75-100 mg/m²; intraperitoneal (IP) on day 2.
Paclitaxel 60 mg/m²; PI on day 8 (max BSA 2.0 m2).
Treatment administered every 21 days for 6 cycles

Unfortunately, the added toxicity (e.g. use of cisplatin rather than carboplatin; need for intraperitoneal catheter placement and associated side-effects) and additional time/effort required have reduced enthusiasm for this approach among treatment oncologists. Ongoing clinical research is attempting to reduce the side-effects associated with this strategy, with a particular focus on substituting carboplatin for cisplatin.

Chemotherapy for early-stage disease

Several randomized trials have demonstrated the favorable impact of cytotoxic chemotherapy on survival of women with early stage (e.g., high-grade stage 1 disease) ovarian cancer. As a result, only a small group of patients (e.g., adequately surgically evaluated patients with low-grade stage 1 ovarian cancer) diagnosed with this malignancy are not treated with a platinum-based chemotherapy regimen. In most circumstances adjuvant therapy will include 6 cycles of a carboplatin-paclitaxel regimen.

Treatment of recurrent disease

Platinum-sensitive disease

While the large majority (70-80%) of patients with advanced ovarian cancer will respond to platinum-based chemotherapy, recurrence of the disease process is unfortunately the rule rather than the exception.

For patients whose disease has recurred more than 6-12 months following the completion of platinum-based therapy, reintroduction of a platinum regimen is generally attempted. Exceptions to this strategy include individuals with persistent chemotherapy-induced neuropathy or those patients who have exhibited serious platinum-associated hypersensitivity.

The angiogenesis inhibitor bevacizumab, a recombinant humanized monoclonal antibody against vascular endothelial growth factor A (VEGF-A) may be used in combination with chemotherapy (either carboplatin plus paclitaxel, carboplatin alone, or gemcitabine alone) in platinum-sensitive patients, and continued as monotherapy afterward until progression or unacceptable toxicity.

Combination platinum-based regimens that may be employed in the second-line setting (based on evidence from phase 3 randomized trials) include:

Carboplatin AUC 5 IV day 1.
Pegylated liposomal doxorubicin (Doxil) 30 mg/m²; IV day 1.
Repeat cycle every 3-4 weeks.

Gemcitabine 1000 mg/m²; IV days 1 and 8.
Carboplatin AUC 4 on day 1.
Repeat cycle every 3 weeks.

Carboplatin AUC 5 IV day 1.
Paclitaxel 175 mg/m²IV day 1.
Bevacizumab 15 mg/kg day 1.
Repeat cycle every 3 weeks.

Gemcitabine 1000 mg/m²; IV days 1 and 8.
Bevacizumab 15 mg/kg day 1.
Repeat cycle every 3 weeks.

Carboplatin AUC 5 IV day 1.
Bevacizumab 15 mg/kg day 1.
Repeat cycle every 3 weeks.

Platinum-resistant disease

In patients with platinum-resistant disease (treatment-free interval < 6 months from the completion of the last platinum regimen) a large and growing number of therapeutic options are available. Of note, there is currently no evidence based on data from phase 3 trials to suggest that any single anti-neoplastic agent is superior to another in terms of therapeutic efficacy in this clinical setting, although toxicity profiles and convenience of administration schedules vary greatly.

It should also be noted that there are no phase 3 trial data to demonstrate the superiority of combination chemotherapy in the platinum-resistant setting compared to the judicious use of sequential single-agent treatments designed to favorably impact survival, patient-specific symptoms, and overall quality of life. However, the addition of the bevacizumab to single-agent chemotherapy has been demonstrated to improve progression-free but not overall survival.

There are multiple single agent regimens with documented biological activity (> 10% response rates) in platinum-resistant ovarian cancer. Bevacizumab may also be given in combination with single-agent chemotherapy. It may be added to pegylated liposomal doxorubicin, paclitaxel or topotecan chemotherapy and continued afterward as monotherapy until progression or unacceptable toxicity.

Agents commonly used in the platinum-resistant setting include:

Pegylated liposomal doxorubicin 40 mg/m²; IV every 28 days +/- bevacizumab 10 mg/kg IV every 14 days
Paclitaxel 80 mg/m² IV on days 1, 8, 15, and 22 every 28 days +/- bevacizumab 10 mg/kg IV every 14 days
Topotecan 1-1.5 mg/m²; IV days 1-5 every 21 days +/- bevacizumab 15 mg/kg IV every 21 days (alternative dosing: Topotecan 3.75-4 mg/m²; IV days 1, 8, and 15 every 28 days +/- bevacizumab 10 mg/kg IV every 14 days)
Gemcitabine 800-1000 mg/m²; IV days 1 and 8 every 21 days
Etoposide 50 mg PO twice daily days 1-14 every 21 days

Targeted Therapy

In patients harboring germline BRCA mutations, inhibition of the poly-ADP ribose polymerase (PARP) can be cytotoxic to BRCA deficient cells. The PARP1 protein is necessary for repairing single-strand DNA breaks. Inhibition of PARP1 leads to an accumulation of these single-strand breaks, which if unrepaired prior to replication, leads to double-strand breaks. Tumor cells deficient in BRCA1 or 2 activity are unable to repair these double-strand breaks efficiently, leading to cell death.

The PARP inhibitors olaparib (Lynparza) and rucaparib (Rubraca) are approved for use in patients with deleterious mutations in BRCA who have received multiple prior lines of chemotherapy (three or two respectively). Niraparib (Zejula) has been shown to extend progression-free survival when used as maintenance therapy in relapsed, platinum-sensitive disease. The effect was largest in BRCA mutant patients, although non-mutated patients still derived benefit and it is approved for both BRCA-mutant and wild-type patients in this setting.

Olaparib 400 mg PO twice daily taken until progression or unacceptable toxicity.
Rucaparib 600 mg PO twice daily taken until progression or unacceptable toxicity.
Niraparib 300 mg PO daily until progression or unacceptable toxicity, following a complete or partial response to at least two prior platinum-based chemotherapy regimens.

Radiation therapy

Currently, radiation is uncommonly used in this malignancy except to palliate specific symptoms (e.g., painful pelvic sidewall mass in a patient with platinum-resistant disease).

What other therapies are helpful for reducing complications?

Ovarian cancer patients receiving chemotherapy should receive standard supportive care medications. Radiation therapy may be employed to palliate specific symptoms.

Similarly, the role of surgery in the resistant setting is limited, but may be of great value to providing highly meaningful short-term relief of distressing symptoms (e.g., colostomy or illeoostomy for large bowel and small bowel obstruction, respectively).

What should you tell the patient and the family about prognosis?

Ovarian cancer is a highly chemotherapy-sensitive malignancy. Even patients with advanced intra-abdominal disease or spread outside the abdominal cavity can achieve major symptomic benefit and long-term disease free survival.

However, once the disease has recurred or has not achieved a clinically-defined complete response to primary chemotherapy, there is currently no evidence that any second-line strategy has legitimate curative intent (although survival can certainly be prolonged with the delivery of a variety of second-line treatment approaches).

Stage-specific 5-year survival rates for invasive epithelial ovarian cancer:

I: 89%

II: 66%

III: 34%

IV: 18%

What if scenarios.

Ovarian germ cell tumors

These tumors represent 2-3% of ovarian cancers and tend to occur in younger women (median age 30 years). Subtypes include dysgerminoma, endodermal sinus tumors, malignant teratoma, embryonal carcinoma. 50-75% of patients are diagnosed with stage I-II disease. Biomarkers that are useful in the diagnosis and surveillance of the disease include human chorionic gonadotropin (hCG) and alpha-fetoprotein (AFP). CA-125 may also be elevated.

Surgery is the initial step in therapy. For most cases, post-operative chemotherapy with three cycles of bleomycin, etoposide, cisplatin (BEP) is appropriate (four cycles if there is residual disease at time of surgery):

Bleomycin 30 units IV days 1, 8, and 15.
Etoposide 100 mg/m²; IV days 1-5.
Cisplatin 20 mg/m²; IV days 1-5.
Repeat cycle every 21 days for 3 cycles (4 cycles for residual disease).

Ovarian stromal tumors

These are rare, hormone secreting tumors that may cause precocious puberty in young girls. Subtypes include granulosa and Sertoli-Leydig tumors. Treatment includes surgery followed by chemotherapy using regimens applied to epithelial ovarian cancers.

Follow-up surveillance and therapy/management of recurrences.

In general most patients completing therapy for ovarian cancer undergo routine physical examination by their gynecologic oncologist, the frequency of which decreases as the time from completion of therapy increases. It is common practice for patients to have serum CA-125 antigen levels drawn at the time of each follow-up clinic visit to assess for the presence of recurrence of the malignant process.

This general practice has been called into question based on the results of a phase 3 randomized trial that failed to demonstrate a favorable impact on survival or quality-of-life associated with the performance of routine CA-125 surveillance in asymptomatic patients who had completed their primary chemotherapy program.

However, in the United States, despite the availability of this evidence-based data, most patients (and their oncologists) prefer to use this serum marker to assess the status of the malignancy.

Pathophysiology

The definitive pathophysiology associated with the development of ovarian cancer remains to be defined. The absence of a clearly-defined pre-malignant state, such as documented in cervix cancer, has hindered efforts in this arena.

Due to the unique process of tissue damage and repair associated with ovulation, as well as epidemiologic evidence that infertility increases the risk of ovarian cancer while multiple pregnancies and use of oral contraceptives reduce the risk, it is logical to assume that molecular pathways associated with inflammation are critical in the establishment of a malignancy in this organ.

Highly provocative data has suggested that many ovarian cancers actually originate in the fallopian tube, but more research in this arena will be required before it is possible to make a definitive statement regarding the relationship between the fallopian tube and ovarian cancer.

While specific molecular abnormalities have not been documented to define all ovarian cancers, some researchers have suggested that it may be reasonable to divide patients in two molecular categories:

One characterized by high-grade serous histology, frequent p53 molecular abnormalities (50-80% of cases) and responsiveness to platinum-based chemotherapy.
A second group of lower grade cancers, with poor response to platinum and the presence (in 20-50% of cases) of B-RAF, K-RAS and PTEN mutations.

What other additional laboratory studies may be ordered?

CT-scans of the abdomen/pelvis can be helpful in assessing the extent of disease, and the ability to optimally resect intra-abdominal cancer. The use of PET scans in ovarian cancer continues to be explored. While this test is frequently obtained to asses for the presence and extent of cancer, the clinical utility of the test compared to the less expensive CT scan and serum CA-125 antigen level remains to be more fully evaluated.

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