Ovarian Cancer Treatment & Management

In women who present with GI carcinomatosis but without an obvious pelvic mass, an extensive search often fails to identify a primary tumor. These patients can be presumed to have ovarian carcinoma or primary peritoneal carcinoma and treated with cytoreductive surgery followed by platinum-based chemotherapy.

Surgery is the initial treatment of choice, provided patients are medically fit. Patients who are not fit for surgery may be given chemotherapy and considered for surgery later. The aim of surgery is to confirm the diagnosis, define the extent of disease, and resect all visible tumor. The role of cytoreduction was demonstrated by Griffiths in 1975 and has been confirmed by many others.

A retrospective analysis from Lin et al found that epidural anaesthesia and analgesia for ovarian serous adenocarcinoma surgery was associated with reduced mortality during the initial years of follow-up.^[35]

Appropriate surgery depends on whether or not disease is visible outside the ovaries. It is essential that where no disease is visible outside the ovaries, the patient be adequately surgically staged because the incidence of microscopic metastases is significant. Surgery for patients with stage IV disease should be individualized, particularly when disease is in the liver and above the diaphragm. Patients who are in stage IV because of small-volume disease in the liver, abdominal wall, or lung should undergo cytoreductive surgery if medically fit.

If there is no visible disease outside an ovary, aspirate ascitic fluid for cytology studies. Perform peritoneal washings for cytology if ascites is not present. Remove the ovary and ovarian tumor intact. Perform diaphragmatic scraping or biopsy for cytology studies. Obtain peritoneal biopsy specimens. Perform a subcolic omentectomy. Obtain bilateral para-aortic and pelvic node samples. Obtain biopsy samples of adhesions or other suspicious areas.

If the patient does not desire future fertility, perform a total abdominal hysterectomy and excise the opposite ovary. Remove the appendix if mucinous tumor is present.

If macroscopic disease is visible outside of the ovary, all visible tumor should be removed. This may require extensive surgery, including bowel resection, excision of peritoneal implants, liver resection, omentectomy, and splenectomy.

The extent of bowel resection should depend on the role this plays in achieving maximal cytoreduction.

The standard care for ovarian cancer includes surgical exploration for primary staging and for cytoreduction or debulking. If the disease appears to be confined to the pelvis, comprehensive surgical staging is indicated.

The incision for surgery should be midline abdominal. In young women with early-stage disease, a transverse incision may be considered. Careful inspection and/or palpation of the abdominal contents should be performed, including all peritoneal surfaces, the liver, large and small bowel and mesentery, stomach, appendix, kidneys, spleen, retroperitoneal spaces, and all pelvic structures.

The staging procedure should include the following:

• Peritoneal cytology
• Multiple peritoneal biopsies
• Omentectomy
• Pelvic and para-aortic lymph node sampling.

This should be performed by a gynecologic oncologist at the time of initial laparotomy. The volume of residual disease at the completion of surgery represents one of the most powerful prognostic factors. According to the 2011 National Comprehensive Cancer Network (NCCN) ovarian cancer guidelines, residual disease of less than 1 cm is evidence of optimal cytoreduction, although the greatest possible effort should be made to remove all obvious disease. As of this guideline, distal pancreatectomy may be considered in all stages for optimal surgical cytoreduction.^[36]

Patients with advanced ovarian cancer are classified in 3 groups as follows, based on the postoperative residual tumor:

• Good risk - Microscopic disease outside the pelvis (stage IIIa) or macroscopic disease less than 2 cm outside the pelvis (stage IIIb)
• Intermediate risk - Macroscopic disease less than 2 cm outside the pelvis only after surgery
• Poor risk - Macroscopic disease more than 2 cm after surgery or disease outside the peritoneal cavity

Interval debulking can be performed in patients who were not adequately debulked at the time of initial surgery. It should also be considered in those patients in whom an initial debulking surgery was not attempted.

Patients receive 3 cycles of postoperative chemotherapy. Approximately 60% of patients are then able to undergo optimal resection. Surgical treatment is followed by 3 more cycles of chemotherapy.

A European prospective, randomized, clinical trial demonstrated that this approach improves the outcome of patients with advanced ovarian cancer.^[37] However, this was not confirmed in a study conducted in the United States.^[38] A major difference between both studies was the extent of the initial debulking procedure. In the US study, initial optimal debulking was attempted in all patients. A meta-analysis found no conclusive evidence regarding the possible survival benefit of interval debulking but noted apparent benefit only in patients whose primary surgery was not performed by gynecologic oncologists or was less extensive.^[39]

According to guidelines developed by the American College of Obstetricians and Gynecologists, laparoscopy may be used for diagnostic purposes in a patient with low risk for ovarian cancer and to remove cystic masses. The mass must be 10 cm or smaller as viewed by a sonogram, must have a distinct border and no solid parts, and must not be associated with ascites. The serum CA125 level must be normal (< 35 U/mL), and the patient must have no family history of ovarian cancer. If a chance exists that ovarian cancer may be present, surgery is best arranged in conjunction with a specialist in gynecologic cancer surgery. The patient can then undergo all necessary surgery for her cancer under a single anesthetic, without delay.

As part of initial treatment of epithelial ovarian cancer, laparoscopic surgery may be performed for early stage disease when no disease is visible outside of the ovaries. Its use in more advanced disease, when spread is visible outside the ovaries, is more limited due to the scope of cytoreductive surgery necessary and the risk of port-site recurrence. Laparoscopy also has a role in second-look inspection and in the staging of apparently early-stage disease found by chance during another surgery.

The 2011 NCCN ovarian cancer guidelines state that minimally invasive surgery may be considered in selected patients with Stage 1 disease. This is particularly true where an incidental finding of ovarian cancer was made during prophylactic oophorectomy.^[36]

An assessment by Park et al found that secondary cytoreductive surgery is safe and effective in patients with platinum-sensitive recurrent ovarian cancer. The surgery was most beneficial in patients who had remained disease free for more than 24 months after primary treatment and in those who achieved optimal cytoreduction.^[40]

Only a small percentage of women with epithelial ovarian cancer can be treated with surgery alone. These include patients with stage IA grade 1 and stage IB grade 1 serous, mucinous, endometrioid, and Brenner tumors. Clear-cell carcinomas are associated with a significantly worse prognosis in stage I, and patients with this histologic subtype should be considered for chemotherapy at all stages.

Patients not treated with chemotherapy should be monitored closely at regular intervals with clinical examination, serum CA125 estimation, and ultrasonography if an ovary is still present. Surgery to remove the uterus and residual ovary should be considered when the patient no longer desires to remain fertile.

The 2011 NCCN ovarian cancer guidelines recommend pelvic examinations at least every 2-3 cycles in women receiving primary chemotherapy.^[36]

Higher-risk early-stage disease includes all histologic subtypes with stage IA and stage IB grade 2 and all stage I grade 3. These patients should be treated with front-line chemotherapy with a taxane/platinum combination for a minimum of 3 courses. They should consider participating in clinical trials.

All patients with stage II cancer and greater should receive front-line chemotherapy and should strongly consider participation in clinical trials.

Standard therapy for all patients with advanced disease following surgery is a taxane/platinum combination, usually carboplatin and either paclitaxel or docetaxel for a minimum of 6 courses; however, this may be changing soon. Carboplatin given at an area under the curve (AUC) of 6-7.5 mg/mL/min (using the Calvert formula for calculating total dose of carboplatin: Total dose (mg) = target AUC x (GFR + 25), where GFR = glomerular filtration rate, taken to be the creatinine clearance in mL/min and AUC in mg/mL/min.

The normal range of AUC for treatment of ovarian carcinoma varies from 5-8. Patients who have received extensive prior chemotherapy or radiation should start with an AUC of less than 5. Paclitaxel and docetaxel are usually dosed at 175 mg/m² and 60-75 mg/m² respectively. Cisplatin at 50-75 mg/m² can be substituted for carboplatin. Increasing the dose intensity of cisplatin did not improve progression-free survival or overall survival compared with standard chemotherapy.^[41] Docetaxel in combination with carboplatin has been shown to provide equivalent survival rates with less neurotoxicity but greater neutropenia.

Standard postoperative chemotherapy is combination therapy with platinum and paclitaxel. Cisplatin and paclitaxel or carboplatin and paclitaxel are accepted alternatives. Randomized studies have proven that both regimens result in equivalent survival rates. However, because of a more tolerable toxicity profile, the combination of carboplatin and paclitaxel is preferred. If patients are treated with cisplatin, paclitaxel should be administered as a 24-hour infusion to decrease the risk of neurotoxicity. Another alternative is to combine carboplatin with docetaxel.

The combination of paclitaxel and carboplatin is customarily given every 3 weeks (day 1 of a 21-d cycle). Because the addition of other drugs to this regimen has proved disappointing, Katsumata et al studied the use of a dose-dense regimen, in which paclitaxel is given on days 1, 8, and 15 and carboplatin is given on day 1.^[42] Compared with the conventional regimen, the dose-dense regimen resulted in longer median progression-free survival (28.0 mo versus 17.2 mo) and higher overall survival at 3 years (72.1% versus 65.1%). Early discontinuation was more common with the dose-dense regimen, and these patients were more likely to experience toxicity, especially neutropenia and anemia.

A study by Morgan et al found that first-cycle maximum tolerated dose of intraperitoneal carboplatin combined with intravenous paclitaxel did not predict the tolerability of the regimen over multiple cycles. An intraperitoneal dose of carboplatin at area under the curve (AUC) of 6 in combination with paclitaxel can be administered with a high rate of completion over multiple cycles. Neutropenia is a frequent dose-limiting toxicity; thus, adding hematopoietic growth factors may permit a high completion rate while maintaining this dose.^[43]

Patients receiving adjuvant intraperitoneal chemotherapy are more likely to have recurrences outside the abdominal cavity, according to a study by Tanner et al.^[44]

In a study by Kurtz et al, patients aged 70 years or older experienced more neuropathy and had a higher incidence in the carboplatin-paclitaxel group.^[45] As with all study patients, the therapeutic index was better among elderly women with platinum-sensitive recurrent ovarian cancer who received carboplatin-pegylated liposomal doxorubicin than among those who received carboplatin-paclitaxel.

The 2011 NCCN ovarian cancer guidelines panel recommends the use of dose-dense paclitaxel as the first-line treatment of stage II, III, or IV epithelial ovarian cancer. However, clinicians should inform their patients about the high toxicity of this newly added regimen so they can weigh the benefits and risks of the therapy.^[36]

Postoperative chemotherapy is indicated in all patients with ovarian cancer except those who have surgical-pathologic stage I disease with low-risk characteristics. A meta-analysis suggests that postoperative platinum-based chemotherapy prolongs both progression-free survival and overall survival in the majority of patients with early-stage ovarian cancer. However, these authors also noted strong evidence that optimal surgical staging identifies patients who are at low risk and have little or nothing to gain from adjuvant chemotherapy.^[46]

Many women experience symptoms of ovarian dysfunction (ie, amenorrhea and hot flashes) during treatment with chemotherapy. The younger the woman at the time of treatment, the more likely the return of normal ovarian function and the more tolerant the ovaries are to higher doses of alkylating agents.

An increase in congenital anomalies in babies conceived following treatment with chemotherapy does not seem to occur. The necessity for chemotherapy during a preexisting pregnancy fortunately is rare, but antifolate drugs such as methotrexate probably should be avoided during the first trimester.

Intraperitoneal chemotherapy

Use of chemotherapy agents instilled into the peritoneal cavity has the theoretical advantage that much higher concentrations can be obtained locally without the risk of adverse systemic effects; however, the agents are unable to penetrate more than a few millimeters. At least 3 randomized studies comparing chemotherapy regimens, including the intraperitoneal route with the intravenous route, have shown a survival advantage for the arms receiving intraperitoneal chemotherapy.

The most recent Gynecologic Oncology Group protocol #172 published in January 2006 showed that following optimal cytoreductive surgery women with advanced epithelial ovarian cancer randomized to receive part of their chemotherapy with cisplatin and paclitaxel intraperitoneally had a median progression-free interval and median overall survival approximately 5 months and 16 months greater than those women receiving standard intravenous chemotherapy. Thus, intraperitoneal chemotherapy should be strongly considered for the treatment of front-line disease following surgery where 5mm or less-residual disease exists and perhaps, for more advanced cancers.

This route of chemotherapy may cause more side effects for the patient and administration requires the placement of a subcutaneous tube into the peritoneal cavity (an intraperitoneal port); this is associated with a number of complications including infection, blockage, retraction out of the peritoneal cavity, and discomfort. Nevertheless, randomized studies show a survival benefit and disease-free survival benefit and the National Cancer Institute has suggested that all women with optimally cytoreduced disease should at least be offered intraperitoneal treatment.

Results from randomized clinical trials suggest that in patients with optimally debulked disease, intraperitoneal administration of chemotherapy (cisplatin) is superior to intravenous administration.^[47] Recent meta-analyses confirm that intraperitoneal administration of chemotherapy is associated with an improvement in survival.^{[48, 49]} However, this approach is also associated with more toxicity. The National Cancer Institute released a clinical announcement supporting the use of intraperitoneal chemotherapy in optimally debulked ovarian cancer.^[50]

Jaaback et al found that intraperitoneal chemotherapy increases overall survival and progression-free survival in advanced ovarian cancer; however, catheter-related complications and toxicity must be considered in the treatment decision.^[51]

Neoadjuvant chemotherapy

This is given to patients with disease that is initially considered inoperable or if the patient is unfit for surgery at the time of diagnosis. If the patient has a good response to 3 or more cycles of chemotherapy, interval debulking surgery may be performed followed by further chemotherapy. Overall, patients treated with this approach likely have an inferior outcome to patients undergoing initial maximal cytoreductive surgery followed by chemotherapy.

Patients with advanced ovarian cancer who are not candidates for surgical cytoreduction may be treated initially with 2-3 cycles of conventional chemotherapy and can then be reevaluated for surgical cytoreduction. However, optimal initial cytoreduction remains the standard of care for most patients.

A study by Joly et al found that pegylated liposomal doxorubicin with carboplatin instead of paclitaxel was associated with a low rate of hypersensitivity reaction among patients with relapsed ovarian cancer.^[52] In a separate study by Pignata et al, pegylated liposomal doxorubicin with carboplatin produced a similar response rate to carboplatin with paclitaxel; the authors conclude that it could be an alternative to standard therapy.^[53]

Neoadjuvant chemotherapy followed by interval surgery provided equivalent outcomes to standard primary surgery followed by chemotherapy in women with stage III and IV ovarian cancer.^[54]

According to the 2011 NCCN ovarian cancer guidelines, a patient should be evaluated for neoadjuvant chemotherapy by a fellowship-trained gynecologist oncologist before being considered a nonsurgical candidate.^[36]

Maintenance chemotherapy

Most patients with ovarian cancer achieve a complete clinical response after debulking surgery and platinum-based chemotherapy. However, 50% experience relapse and ultimately die of the disease. Therefore, strategies to decrease the risk of recurrence have been investigated. A phase III randomized trial exploring the impact of 12 monthly cycles of paclitaxel as maintenance chemotherapy was discontinued by the Data Safety and Monitoring Committee when a prospectively defined interim analysis revealed a highly statistically significant improvement in progression-free survival; an ongoing phase III trial is addressing the question of whether this maintenance strategy has a significant effect on overall survival.^[55]

The experimental chemotherapeutic agent olaparib has shown antitumor activity in patients with high-grade serous ovarian cancer. A phase II study was conducted in 2012 to evaluate maintenance treatment with olaparib in patients with platinum-sensitive, relapsed, high-grade serous ovarian cancer. Participants had received two or more platinum-based regimens and had experienced a partial or complete response to their most recent treatment. The study showed a progression-free advantage, but no overall survival advantage. Further studies are needed before olaparib can be recommended as a standard of care in this particular setting. It remains an option based on individual clinical situations.^[56]

A meta-analysis indicated that continuing chemotherapy improved progression-free survival and overall survival, especially if complete response was reached after primary therapy.

Second-line chemotherapy

Recurrent ovarian cancer is classified into 2 categories, depending on the length of time the patient remained disease-free after completing chemotherapy: (1) relapse that occurs more than 6 months after initial chemotherapy is considered platinum-sensitive; (2) earlier relapse is considered platinum-resistant. Patients with platinum-sensitive disease may exhibit a good response if rechallenged with a platinum-based regimen.^{[57, 58]} The probability of response increases with the duration of the disease-free interval.

Results from clinical trials suggest that combination chemotherapy offers an improvement in response rate, progression-free survival, and overall survival. Several chemotherapy agents elicit a response in patients whose disease is resistant to platinum-based therapies. These include liposomal doxorubicin, topotecan, oral etoposide, gemcitabine, docetaxel, and vinorelbine. Other agents that may be used are ifosfamide, 5-fluorouracil with leucovorin, and altretamine (Hexalen). Tamoxifen, an oral antiestrogen, exhibits modest activity but has a favorable toxicity profile.

The addition of gemcitabine to carboplatin plus paclitaxel did not improve overall survival or progression-free survival; therefore, it is not a good candidate for a third non-cross-resistant drug in the treatment of advanced ovarian cancer.^[59] In a phase 3 randomized study, topotecan and cisplatin followed by carboplatin and paclitaxel were more toxic and without improved efficacy.^[60]

A randomized multicenter phase II trial of the North-Eastern German Society of Gynecological Oncology Ovarian Cancer Study Group indicated similar effectiveness and less toxicity in platinum-resistant recurrent ovarian cancer for weekly topotecan compared to conventional 5-day schedules.^[61]

A study by Haldar et al found that epithelial growth factor inhibitors, including pertuzumab, may add activity to standard chemotherapy among women with platinum-resistant ovarian cancer.^[62]

Consolidation chemotherapy

Ovarian cancer has a very high response rate when treated front-line; despite this, most patients develop recurrent cancer. Many have shown interest in research into treatments to prevent or prolong the interval of recurrence (such as consolidation therapy). A Gynecologic Oncology Group protocol was discontinued when a statistical improvement in disease-free survival was demonstrated in patients receiving 12 months versus 3 months of additional monthly paclitaxel after initial therapy. However, questions remain about this study, which was not completed as designed. Since no consensus on management in this situation exists, patients should be encouraged to participate in clinical trials of consolidation therapy.

Hyperthermic intraperitoneal chemotherapy

The instillation into the peritoneal cavity of chemotherapeutic agents in a solution heated to between 40°C and 43°C was first introduced in an attempt to induce longer survival in patients with gastric carcinomas that had spread to the peritoneal cavity. Considerable experimental evidence shows that not only is heat alone tumoricidal, but it also increases the activity of many different chemotherapeutic agents, several of which have activity in ovarian cancer.

Ovarian cancer is a good theoretical target for surgical debulking combined with hyperthermic chemotherapy because it combines 3 separately useful modalities: surgical debulking, intraperitoneal chemotherapy, and heat. No randomized, phase III studies have been performed in ovarian cancer cases and more research is warranted.

Radiation has not been widely accepted as a routine treatment modality in the initial treatment of patients with epithelial ovarian cancer, despite reports of efficacy for higher-risk stage I and II disease and in stage III disease where small-volume residual disease is present after surgery. In selected cases, pelvic diseases may respond to palliative dosing regimens with minimal toxicity.

The safety of estrogen replacement therapy (ERT) after treatment for epithelial ovarian cancer has not been tested in a randomized trial, but current evidence suggests that the benefits of ERT outweigh the risks.

Younger women with endometrioid subtypes are of concern because these tumors theoretically are estrogen-sensitive. If estrogen is used in such patients, a progestogen probably should be given with it.

Several recent case reports have raised the possibility of the use of hormonal therapy in the management of recurrent granulose-theca cell tumors. Responses to medroxyprogesterone acetate, GnRH agonists, and megestrol (Megace)^[23] have all been reported in a small number of patients with progressive disease not responsive to chemotherapy.

Several recent reports have documented the use of the aromatase inhibitor anastrozole, which inhibits the conversion of androstenedione to estrone, in the management of patients who previously received surgery and chemotherapy.^[63] Several patients with recurrent disease demonstrated normalization of their serum inhibin, decrease in tumor size, and an increase in disease-free survival. Several authors have recommended aromatase inhibitors as a treatment strategy for recurrent and refractory disease. Currently, however, the number of cases is too small to draw any conclusions, and the use of aromatase inhibitors should be considered strictly experimental.

The OCEANS phase III study reported that when bevacizumab (Avastin) was combined with chemotherapy, a 52% risk reduction for recurrence in disease progression was observed (HR=0.48, P < .0001) compared with women who received chemotherapy alone. The study included women with recurrent, platinum-sensitive ovarian, peritoneal, or fallopian tube carcinoma, who received bevacizumab in combination with carboplatin and gemcitabine followed by continued use of bevacizumab alone until disease progression. Other results of the trial include a median progression-free survival of 12.4 months, compared with 8.4 months in women who received chemotherapy alone. Additionally, the overall response rate of tumor shrinkage was 79% in women receiving the bevacizumab-based regimen, compared with 57% in those who received chemotherapy alone.^[64]

A study by Stone et al concluded the presence of a paracrine circuit, wherein increased production of thrombopoietic cytokines in tumor and host tissues leads to a paraneoplastic thrombocytosis, which fuels tumor growth. Targeting these cytokines may have therapeutic potential.^[65]

Second-look laparotomy is a surgical procedure performed within a few weeks following initial treatment of epithelial ovarian cancer when no disease is evident on clinical examination, by CA125, or radiology. The aim is to inspect the abdominal cavity for disease and, when no macroscopic disease is found, perform peritoneal washings and extensive biopsies for pathologic assessment for microscopic disease. Some years ago this surgery went out of fashion in many centers because no effective treatment was available for those found to have disease present following front-line therapy, and, thus, the evaluation did not improve prognosis. Of those patients who had completely negative findings at second-look surgery (a complete pathologic response), 56% had recurrence by 5 years and 60% by 10 years. In the Gynecologic Oncology Group Study #172, despite the improvement in overall survival rate, 65% of these patients developed recurrence within the time period of the study.^[47]

Efforts are now underway to find effective methods of delaying or preventing recurrence following front-line therapy. The best way to determine that a woman is pathologically disease-free is a second surgery because regular clinical investigations are far from accurate. It may be possible to perform this evaluation adequately using the laparoscope in many instances.

In most patients presenting with advanced epithelial ovarian cancer, the disease recurs, and the prognosis for these patients is poor. The goal of further therapy is to achieve a response to treatment and to prolong meaningful quality survival.

Treatment of recurrent disease may involve surgery, chemotherapy, and radiation. Participation in clinical trials should be considered. If a localized mass is present, surgery may play a role prior to the initiation of further chemotherapy. Response is more likely in patients who previously had a good response to first-line therapy and who had a long interval between the completion of initial therapy and the time of recurrence.

Patients whose previous response to platinum agents was good and who have gone at least 6 months since completing initial therapy may be re-treated with a taxane together with carboplatin or cisplatin. Patients with platinum-resistant disease who respond poorly to treatment with platinum agents initially and who have a short interval to recurrence do poorly. These patients particularly should be offered participation in clinical trials, if available. Agents with some activity in this situation include topotecan, etoposide, liposomal doxorubicin, and docetaxel and altretamine. Single-agent therapy is usually given for recurrent disease, although combination therapy is becoming more popular and several combinations have been reported. Antiangiogenesis agents, such as bevacizumab, and hormonal agents, such as tamoxifen and anastrozole, may have a role to play.

The 2011 NCCN ovarian cancer guidelines encourage participation in clinical trials of bevacizumab, which is showing promising results. Increased progression-free survival has been seen in patients receiving bevacizumab as first-line therapy and as maintenance therapy, compared with standard chemotherapy alone.^[36]

A study by O’Malley et al found that a combination of paclitaxel and bevacizumab significantly increased progression-free survival, including a trend toward improved overall survival, among women previously heavily treated for recurrent epithelial ovarian cancer.^[66]

Samples of recurrent tumor or ascitic fluid can be sent to one of several laboratories for chemotherapeutic assay. This assay involves culturing tumor cells in media containing a range of chemotherapy agents. This allows chemotherapy agents to be offered to patients with the greatest potential for activity, and, conversely, this allows drugs associated with extreme resistance to be avoided.

Patients who were initially sensitive to platinum-containing chemotherapy have overall response rates of 30-60%, with an overall survival of 12-48 months, whereas patients resistant to chemotherapy have expected response rates of 12-32%, with an overall survival of 7-12 months.

The finding of elevated CA125 in the serum in the absence of clinical or radiographic disease is a relatively common situation in patients with epithelial ovarian cancer following initial treatment. Treatment of these patients is controversial.

However, the 2011 NCCN ovarian cancer guidelines panel recommends evaluation for CA125 tumor marker with each follow-up visit.^[36]

The standard treatment for ovarian cancer starts with staging and cytoreductive surgery. Based on the surgical staging, patients are classified as having limited disease (stages I and II) or advanced disease (stages III and IV).

Low risk for recurrence is indicated by the following:

• Grade 1 or 2 disease
• No tumor on external surface of the ovary
• Negative peritoneal cytology
• No ascites
• Tumor growth confined to the ovaries

High risk for recurrence is indicated by the following:

• Grade 3 disease
• Preoperative rupture of the capsule
• Tumor on the external surface of the ovary
• Positive peritoneal cytology
• Ascites
• Tumor growth outside of the ovary
• Clear cell tumors
• Surgical stage II

When potentially curative treatment options are unavailable or are ineffective, the clinical goal changes from cure to palliation.

Recurrent ovarian cancer is seldom curable. Second-line, third-line, or even fourth-line chemotherapy is often administered in a palliative fashion, both to diminish symptoms and to prolong life. When chemotherapy is considered for patients with good performance status, it is most appropriate to offer enrollment in formal clinical studies such as those coordinated by the Gynecologic Oncology Group. Recently, oral thalidomide has shown activity in heavily pretreated patients with ovarian cancer when compared with traditional intravenous chemotherapy.^[67] When chemotherapeutic options are exhausted or the adverse effects are not worth the small potential for benefit, other means of palliating symptoms of progressive ovarian cancer are necessary.

Ovarian cancer spreads regionally in the form of scattered deposits of tumor on all surfaces in the peritoneal cavity. Morbidity and mortality as a direct result of this process are far more common than symptoms related to recurrence, specifically at the primary tumor site or in distant extra-abdominal sites.

Bowel obstruction

Bowel obstruction is a common terminal effect of progressive ovarian cancer. Rectosigmoid obstruction in the face of progressive disease is best palliated with a transverse loop colostomy. Often, a small incision at the stoma site is all that is necessary to identify the dilated proximal colon and to elevate it through the anterior abdominal wall. The stoma starts to function immediately, and patients can eat and return to their baseline functional status soon. Cecostomy tube placement can be used to vent the large intestine in colonic obstruction. However, cecostomy sites are prone to recurrent obstruction from solid stool and tube placement is most appropriate in those patients with extremely short life expectancies.

Small bowel obstruction is more challenging. Multiple areas of partial small bowel obstruction are typically not amenable to surgical correction. Tumor implants on the bowel surface and mesentery cause adhesions and impede peristalsis. Infrequently, an isolated small bowel obstruction can be managed with bowel resection and reanastomosis. More commonly, palliation is achieved with a percutaneous gastrostomy tube draining by gravity or with a nasogastric tube on suction. Medical management may also be beneficial to decrease gastrointestinal secretions with somatostatin combined with erythromycin to improve motility in the management of small bowel obstruction.

Ascites

Ascites can result from widespread microscopic and macroscopic tumor infiltration over the peritoneum, preventing absorption of peritoneal fluid. This symptom can become quite troubling when progressive disease is unresponsive to chemotherapy. Patients complain of pain, early satiety, vomiting, fatigue, and shortness of breath. Diuretics are of limited efficacy in relieving malignant ascites, and relief is best obtained by repetitive paracentesis. Placement of a semipermanent drainage tube, Pleurx, has been FDA approved for symptomatic relief in patients with recurrent ascites. The eventual metabolic impact is depletion of albumin. However, the immediate temporary improvement in patient comfort usually takes precedence over long-term nutritional status for a patient who is terminally ill.

Anorexia

Anorexia seldom occurs without a component of bowel obstruction or ascites. For anorexia without associated bowel obstruction, treatment with megestrol acetate or steroids can stimulate appetite and lead to an increased sense of well-being. Parenteral nutritional support might be appropriate as a short-term measure perioperatively following relief of bowel obstruction or other intervention. However, long-term parenteral nutritional support is seldom an appropriate measure in a patient with incurable malignant impairment of bowel function.

Constipation

Constipation may be an adverse effect of narcotic analgesics or colonic dysmotility from tumor involvement. Treatment options range from behavioral changes to medicinal agents. When possible, an increase in fluid intake and exercise can be of benefit, as does close attention to bodily signals of defecation. More useful to the patient with cancer is the addition of fiber, colonic stimulants, and laxatives to their regimen.

For narcotic-induced constipation, stool softeners should be combined with stimulant laxatives such as docusate sodium tablets and senna or bisacodyl tablets. Cascara, a liquid cathartic derived from tree bark, is also useful. For patients with obstipation or for those in whom the above measures are inadequate, enemas and suppositories are helpful. Enema choices include warm tap water, phosphate/biphosphate, soapsuds, milk and molasses, and mineral oil. Bisacodyl or glycerin suppositories are also useful. Saline laxatives draw fluid into the intestine, causing distention and reflex peristalsis. Saline laxatives include magnesium sulfate, milk of magnesia, magnesium citrate, Phospho-soda, and sodium phospate. Prolonged use of these agents may cause fluid and electrolyte imbalance and should be avoided in malnourished patients.

Stimulant laxatives include senna, bisacodyl, cascara, castor oil, phenolphthalein, Miralax, and danthron. These drugs may ultimately contribute to a loss of normal bowel function and cause laxative dependence, but this issue is often unimportant in the palliative care setting. Lubricating agents include oral ingestion of mineral oil. Prolonged use of mineral oil may lead to malabsorption of fat-soluble vitamins. Lactulose draws water into the intestinal lumen, softens stools, and increases defecation frequency. Excessive use can lead to fluid and electrolyte imbalance. Polyethylene glycol electrolyte solution is useful for stimulating defecation with minimal fluid or electrolyte imbalance.

Fatigue and dyspnea

Fatigue or dyspnea secondary to anemia can be treated with blood transfusions or erythropoietin. Transfusions provide immediate improvement, whereas erythropoietin injections may take weeks to improve fatigue.

To see complete information on Palliative Care of the Patient With Advanced Gynecologic Cancer, please go to the main article by clicking here.

Most ovarian cysts are functional in nature and resolve with minimal treatment. However, ovarian cysts can herald an underlying malignant process or, possibly, distract the emergency clinician from a more dangerous condition, such as ectopic pregnancy, ovarian torsion, or appendicitis. When ovarian cysts are large, persistent, or painful, surgery may be required, sometimes resulting in removal of the ovary.

The accepted initial treatment for LMP tumors is surgical removal of the tumor and biopsies. Surgery begins with a full assessment of the pelvis and abdominal contents as for epithelial ovarian cancer and is carried out as described below.

Patients who are premenopausal and desire preservation of fertility can be treated with unilateral oophorectomy alone. In selected cases, ovarian cystectomy may be enough for stage IA serous tumors of LMP. Hysterectomy and removal of the other ovary can be performed if the patient no longer desires to remain fertile.

When complete surgical staging is performed in patients with LMP tumors, some patients with disease originally thought to be confined to the ovaries are found to have disease that has spread. However, the value of this has not been defined in early-stage disease.

In advanced disease, patients should undergo cytoreductive surgery, as for invasive epithelial ovarian cancer, to remove all visible tumor.

The postoperative management protocol is far from clear. To date, no medical therapy has been shown to clearly improve outcomes. Chemotherapy and radiation therapy are not indicated for LMP tumors following complete resection for stage I and II disease. In cases where disease has spread from the ovaries at the time of surgery, and particularly where implants are found to be invasive, chemotherapy can be considered, but data establishing its efficacy are absent.

Regular follow-up care includes clinical examination and serum CA125 estimation, especially if the original tumor was serous and/or the CA125 was elevated. If a patient retains 1 or both ovaries, annual ultrasound examination may be indicated (see Workup).

LMP tumors do not recur in most patients. When they do, initial debulking surgery usually is indicated. Chemotherapy has no proven role.

Surgery is the initial treatment for GCTs, and, in young patients, this can be conservative, with preservation of the uterus and contralateral ovary, because chemotherapy is very effective. Second-look surgery generally is not indicated following initial treatment.

For a tumor that possibly is a dysgerminoma, surgery is the initial management. Assessment of the abdominal and pelvic contents is made as for EOC.

Where no macroscopic disease exists outside the ovary, unilateral oophorectomy should be performed, excising the tumor intact and without rupture. Staging procedures include washings, omental biopsy, and sampling of paraaortic and pelvic lymph nodes. The opposite ovary should be carefully inspected, and a biopsy should be performed if necessary. However, in young patients, the uterus and opposite ovary should be left in situ.

If disease is present outside the ovary, an effort should be made to remove all visible tumor while maintaining fertility for the patient. In a young patient, debulking disease from the contralateral ovary, without performing oophorectomy, should be acceptable.

Many patients present having already undergone a unilateral oophorectomy that diagnosed the dysgerminoma. Consideration should be given to staging these patients, laparoscopically if possible, if a negative result will spare the patient from receiving chemotherapy. If chemotherapy will be given regardless, initial staging surgery is not warranted.

Adequately staged dysgerminoma patients with stage IA disease can be monitored without further therapy, whatever the size of the primary tumor. However, 15-20% of tumors recur, mostly in the first 2 years after treatment.

All dysgerminoma patients at a stage greater than IA require combination chemotherapy, with the most accepted regimen in the United States being bleomycin, etoposide, and cisplatin (BEP). In patients with advanced disease, the combination of vincristine, actinomycin D, and cyclophosphamide (VAC) has been used following BEP as consolidation therapy. Dysgerminoma is very radiosensitive, but radiation rarely is used, especially in young patients, because of its effect on future fertility. Stage IA disease is associated with a 5-year survival rate of higher than 95%, but even with advanced disease, the 5-year survival rate is good following surgery and chemotherapy.

In the premenopausal patient who has an immature teratoma, treatment should include unilateral oophorectomy and surgical staging. The contralateral ovary rarely is involved, and biopsy of the other ovary is not necessary. If a patient no longer desires to remain fertile or is postmenopausal, hysterectomy with removal of both ovaries is sensible.

Patients with stage IA grade 1 immature teratoma do not need adjuvant therapy postoperatively. The standard of care for high-grade stage I disease postoperatively has been chemotherapy with BEP. Evidence is accumulating that such patients can be treated more conservatively following surgery, provided good follow-up care is maintained. Patients with stage IA grade 2 disease can be monitored only. The conservative management of stage IA grade 3 is more controversial.

No tumor markers exist for immature teratoma, and follow-up care should include clinical examination together with ultrasound at regular intervals. Second-look laparoscopy or laparotomy may be considered, particularly in patients who had macroscopic residual disease at the end of surgery. Immature teratoma may be associated with the development of benign teratomatous masses and peritoneal glial implants that may remain for a long time. All masses at second surgery should be removed to be sure that no immature (malignant) elements are present. If such elements are present, the patient should have further chemotherapy with VAC.

The prognosis for immature teratoma depends on the extent of the tumor and the grade. Stage I grades 1 and 2 have almost 100% survival. Patients with incompletely resected tumor have a 50% chance of survival.

A study by Rungruang et al found that women upstaged to IIIC by retroperitoneal involvement had better outcomes than those with intraperitoneal tumors, suggesting a unique subset of stage III patients, according to the International Federation of Gynecology and Obstetrics ovarian cancer surgical staging system.^[68]

Endodermal sinus cell tumors secrete alpha-fetoprotein. Following standard surgery, all patients should be treated with BEP. Other chemotherapy regimens may be necessary.

Although granulosa cell tumors are malignant and Sertoli-Leydig cell tumors less so, they behave in a much less malignant fashion than epithelial ovarian cancers.

Juvenile granulosa cell tumor is usually unilateral and confined to the ovary and can be managed with surgery alone.

For Sertoli-Leydig cell tumors, the surgery is unilateral oophorectomy, and, if patients' childbearing has been completed, total hysterectomy and bilateral oophorectomy is performed. The overall 5-year survival rate is 70-90%.

Small-cell carcinoma is treated with surgery and chemotherapy, but the prognosis is poor.

Mixed mesodermal sarcoma or carcinosarcoma should be treated with surgery (see Epithelial Ovarian Cancer - Treatment), followed by platinum-containing chemotherapy. Prognosis is poor.

Treatment of metastatic tumors of the ovary relates to the primary site.

Normalization of tumor marker values may indicate cure despite radiographic evidence of persistent disease. In this situation, the residual tumor is frequently nonviable. Sometimes, tumor marker levels may rise after effective treatment (due to cell lysis), but the increase may not portend treatment failure. A consistent increase in tumor marker levels, combined with lack of clinical improvement, may indicate treatment failure. Residual elevation after definitive treatment usually indicates persistent disease.

The following tumor markers are helpful in assessing response to chemotherapy and in determining relapse when monitoring patients with complete remission. Further studies are needed to determine the role of these markers.

Squamous cell carcinoma antigen

The squamous cell carcinoma antigen level can be increased in patients with epidermoid carcinoma of the cervix, benign tumors of epithelial origin, and benign skin disorders.

Carcinoembryonic antigen

Most epithelial neoplasms of the ovary also express carcinoembryonic antigen (CEA). The neoplasms include, with decreasing intensity and frequency, Brenner, endometrioid, clear cell, and serous tumors. CEA is frequently present in patients with cancer that has metastasized to the ovary because the primary cancer is generally mammary or gastrointestinal in origin and these tumors frequently contain CEA.

Alpha-fetoprotein

Alpha-fetoprotein (AFP) is a normal fetal serum protein synthesized by the liver, yolk sac, and gastrointestinal tract that shares sequence homology with albumin. AFP is a major component of fetal plasma, reaching a peak concentration of 3 mg/mL at 12 weeks of gestation. Following birth, AFP rapidly clears from the circulation because its half-life is 3.5 days. AFP concentration in adult serum is less than 20 ng/mL.

Most endodermal sinus tumors of the ovary express AFP. AFP is present within the cytoplasm of tumor cells and in the characteristic hyalin globules observed in the endodermal sinus tumor. AFP is also expressed by ovarian embryonal cell carcinoma, immature teratomas, and polyembryomas.

Lysophosphatidic acid

Lysophosphatidic acid stimulates cancer cell proliferation, intracellular calcium release, and tyrosine phosphorylation, including mitogen-activated protein kinase activation. Lysophosphatidic acid has been shown to be a multifunctional signaling molecule in fibroblasts and other cells. It has been found in the ascitic fluid of patients with ovarian cancer and is associated with ovarian cancer cell proliferation.

MIB-1

MIB1-determined tumor growth fraction has recently been studied as an additional tool for the decision of adjuvant therapy in patients with very early stages of ovarian carcinomas. In one study, MIB1 predicted tumor recurrences in 84% of the ovarian cancers.

L1 (CAM)

According to Daponte et al, L1 (CAM) immunoreactivity correlates with stage and grade of ovarian cancer. It increases from benign tumors to early carcinomas and to advanced stage carcinomas progressively and significantly. L1 (CAM) expression represents a novel diagnostic marker in serous ovarian neoplasms that shows characteristics of tumor progression. L1 expression is associated with chemotherapy response.^[69]

Consult a gynecologic oncologist if ovarian cancer is suspected. The question of when to obtain preoperative consultation with a gynecologic oncologist can be difficult to delineate. A good rule of thumb is that all postmenopausal and premenarchal patients with adnexal masses should have the benefit of a consultation with an oncologist because the risk of malignancy is greater. In reproductive-aged patients, the vast majority of adnexal masses are benign. Patients with radiologic or sonographic findings suggestive of malignancy (solid or mixed solid and cystic tumors, ascites, etc) and patients with endocrinologic symptoms and an adnexal mass should have the benefit of a preoperative consultation with a gynecologic oncologist. Patients with a question of malignancy preoperatively can also be evaluated with serum tumor markers including CA125, CA19-9, LDH, AFP, beta-hCG, and inhibin levels. Appropriate referral should be made if any of these are significantly elevated.

Patients with primarily GI complaints may benefit from a consultation with a gastroenterologist to rule out a primary GI source prior to surgical exploration. Endoscopy can be performed during this preoperative evaluation if indicated.

The risk of developing epithelial ovarian cancer is significantly reduced by bearing children, using the combined oral contraceptive pill, undergoing tubal ligation, and undergoing bilateral oophorectomy.

Evidence suggests that taking the oral contraceptive pill for at least 5 years reduces the relative risk of developing EOC to 50% of the risk for a woman who has never taken it.

Prophylactic bilateral salpingo-oophorectomy is indicated in high-risk women.^[63] The American College of Obstetricians and Gynecologists recommends offering salpingo-oophorectomy to women with BRCA1 or BRCA2 mutations by age 40 years or when childbearing is complete (level A recommendation).^[70] Surgical prophylaxis decreases the risk by at least 90%. Not all cases of ovarian cancer are prevented, as women are still at risk for developing primary peritoneal carcinomas.

The epithelial lining of the ovaries is embryologically identical with the lining of the peritoneal cavity, and similar cancers can develop from the peritoneum. Thus, while oophorectomy prevents a pure epithelial ovarian cancer from developing, a small risk still exists for developing carcinoma of the peritoneum, a disease that behaves similarly to epithelial ovarian cancer.

BRAC1 and BRAC2 mutations are common among women with invasive ovarian cancer; thus, women diagnosed with invasive, nonmucinous ovarian cancer are candidates for genetic testing.^[71]

For patients who are known carriers of BRCA1 or BRCA2 mutations, bilateral oophorectomy may be performed as soon as childbearing is complete, and probably before the patient is aged 35 years. This reduces the chance of developing EOC, but it does not prevent carcinoma of the peritoneum.

For women with BRCA1 and BRCA2 mutations who opt to not undergo early oophorectomy, the task force of the Cancer Genetics Studies Consortium recommends transvaginal ultrasound, timed to avoid the middle of the menstrual cycle, together with serum CA125 levels performed every 6-12 months in women aged 25-35 years. Use of the oral contraceptive pill is associated with lower risk of EOC in these women.

Follow-up should occur at 2- to 3-month intervals for the first 2 years for patients not undergoing chemotherapy. Then, this can be spaced out to every 4-6 months for the next 3 years, then yearly thereafter. A history should be obtained and pelvic examination should be performed at each visit. Also, serum determination of tumor markers (ie, inhibin levels) should be performed if these were elevated preoperatively or immediately postoperatively.

If any evidence of recurrence arises during follow-up, imaging studies, usually an abdominopelvic CT scan should be performed to look for recurrent tumors. Most recurrences are confined to the abdomen and pelvis. Other imaging studies may be ordered as dictated by physical examination findings.