Ovarian Cancer Treatment & Management

Updated: Apr 03, 2017
  • Author: Andrew E Green, MD; Chief Editor: from Memorial Sloan-Kettering - Yukio Sonoda, MD  more...
  • Print
Treatment

Approach Considerations

Surgery is often the initial treatment of choice for ovarian cancer, provided patients are medically fit. Patients who are not candidates for optimal debulking should be considered for neoadjuvant chemotherapy followed by interval debulking surgery and further chemotherapy.  Patients who are not fit for surgery may be given chemotherapy and considered for surgery later, or treated primarily with chemotherapy.

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.

Surgery should be used in conjunction with chemotherapy with a taxane and a platinum compound (eg, paclitaxel plus carboplatin). For more information on chemotherapy regimens, see Ovarian Cancer Treatment Protocols.

In women who present with peritoneal 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 and platinum-based chemotherapy.

For more information on screening, prevention, diagnosis, and treatment, see Guidelines.

Next:

Choosing Appropriate Surgery

The appropriate surgical approach varies, depending on whether disease is visible outside the ovaries. For patients with no disease visible outside the ovaries, adequate surgical staging is essential 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 thorax can be considered for cytoreductive surgery if medically fit.

If the patient does not desire future fertility, perform a total abdominal hysterectomy and excise the opposite ovary. Appendectomy can be performed if a 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.

Previous
Next:

Surgical Staging

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 surgical approach should be individualized and may involve laparotomy or use of a minimally invasive approach. Regardless of approach, staging requires several key components. 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.
Previous
Next:

Cytoreductive Surgery

Cytoreductive surgery 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 National Comprehensive Cancer Network (NCCN) ovarian cancer guidelines, in newly diagnosed invasive epithelial ovarian cancer that involves the pelvis and upper abdomen, 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. [37] The NCCN notes that one or more of the following procedures may be considered for optimal surgical cytoreduction:

  • Bowel resection and/or appendectomy
  • Stripping of the diaphragm or other peritoneal surfaces
  • Splenectomy
  • Partial cystectomy and/or ureteroneocystotomy
  • Partial hepatectomy
  • Partial gastrectomy
  • Cholecystectomy
  • Distal pancreatectomy

Patients with advanced ovarian cancer are classified in three 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
Previous
Next:

Interval Debulking

Interval debulking can be performed in patients whose cancer was 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 three cycles of postoperative chemotherapy. Approximately 60% of patients are then able to undergo optimal resection. Surgical treatment is followed by three more cycles of chemotherapy.

A prospective, randomized, clinical trial conducted in Europe demonstrated that this approach improves the outcome of patients with advanced ovarian cancer. [51] However, this was not confirmed in a study conducted in the United States. [52] 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. [53]

Previous
Next:

Laparoscopic Surgery

According to guidelines developed by the American College of Obstetricians and Gynecologists, laparoscopy may be used for diagnostic purposes in a patient at low risk for ovarian cancer and to remove cystic masses, provided that all the following criteria are met [31] :

  • The mass is 10 cm or smaller as viewed by a sonogram
  • The mass has a distinct border and no solid parts
  • No associated ascites is present
  • The serum CA125 level is normal (<35 U/mL)
  • The patient has 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 during a single anesthetic session, 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 NCCN ovarian cancer guidelines state that minimally invasive surgery may be used by an experienced surgeon in selected patients to achieve surgical staging and debulking. In addition, the NCCN considers that minimally invasive surgery may be useful when evaluating whether maximum cytoreduction can be achieved in patients with newly diagnosed or recurrent ovarian cancer. [37]

Previous
Next:

Secondary Surgery

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. [54]

Previous
Next:

Chemotherapy Regimens

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, and endometrioid 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.

Higher-risk early-stage disease includes all histologic subtypes with stage IA and stage IB grade 3 or IC any grade These patients are usually treated with front-line chemotherapy with a taxane/platinum combination for a minimum of three courses. They should consider participating in clinical trials. Patients with IA and IB, grade 2 disease may also be candidates for chemotherapy. All patients with stage II cancer and greater should receive front-line chemotherapy or consider participation in clinical trials.

The NCCN recommends three to six cycles of intravenous taxane/carboplatin adjuvant chemotherapy for high-risk stage IA, IB, or IC epithelial ovarian cancer. [37] For stage II-IV disease, the recommended options include intraperitoneal chemotherapy, in patients with <1 cm optimally debulked stage II and III disease; or intravenous taxane/carboplatin for six cycles. In addition, completion surgery, as indicated by tumor response and potential resectability, may be used in selected patients. [37]

Carboplatin is 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. In patients who have received extensive prior chemotherapy or radiation, treatment should start at 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. [55] Docetaxel in combination with carboplatin has been shown to provide equivalent survival rates with less neurotoxicity but greater neutropenia.

Either cisplatin or carboplatin may be combined with paclitaxel. 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 adding other drugs to this regimen has proved disappointing, investigators have studied the use of a dose-dense regimen, in which paclitaxel is given on days 1, 8, and 15 and carboplatin on day 1. [56, 57] The dose-dense regimen has resulted in longer median progression-free survival and higher overall survival. Early discontinuance may be more common with the dose-dense regimen, and increased toxicity has been reported.

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 an 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. [58]

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. [59] 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.

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. [60]

Monitoring during chemotherapy

The NCCN recommends the following for monitoring during primary chemotherapy [37] :

  • Pelvic exams at least every two to three cycles
  • Interim complete blood cell count as indicated
  • Chemistry profiles if indicated
  • CA125 or other tumor markers as clinically indicated, before each cycle
  • Radiographic imaging if indicated

Ovarian function and future pregnancy

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.

Pazopanib

Adding pazopanib, a kinase inhibitor, to the standard postsurgical chemotherapy regimen has shown promise for progression-free survival in advanced ovarian cancer. In a study of 940 women with advanced ovarian cancer (epithelial ovarian, fallopian tube, or primary peritoneal cancers) who had not shown evidence of postsurgical progression after five or more cycles of platinum-taxane chemotherapy, progression-free survival in these patients was increased with the addition of pazopanib to standard treatment. [61, 62]

Most of the women in the study had stage III/IV disease (91%) at initial diagnosis and no residual disease after surgery (58%). [61, 62] At a median follow-up of 24 months, patients treated with 800 mg of pazopanib once daily had a prolonged progression-free survival, as compared with those receiving placebo. However, the pazopanib group also had a higher incidence of adverse events and serious adverse events, of which the most common were hypertension, diarrhea, nausea, headache, fatigue, and neutropenia. [61, 62] Four fatal adverse events occurred, three in the pazopanib group and one in the placebo group.

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. Results from randomized clinical trials suggest that in patients with optimally debulked disease, intraperitoneal administration of chemotherapy (cisplatin) is superior to intravenous administration. [63, 64] Meta-analyses have confirmed that intraperitoneal chemotherapy is associated with improved survival, but also with more toxicity. [65, 66]

A retrospective analysis of Gynecologic Oncology Group protocols 114 and 172 found that in patients with advanced ovarian cancer, median survival with intraperitoneal therapy was 61.8 months, compared with 51.4 months for intravenous therapy. Intraperitoneal therapy was associated with a 23% decreased risk of death, and with improved survival in patients with gross residual (≤1 cm) disease. Risk of death decreased by 12% for each cycle of intraperitoneal chemotherapy completed. [63] Thus, intraperitoneal chemotherapy should be strongly considered for the treatment of front-line disease following surgery where 5 mm or less of residual disease exists, and perhaps for more advanced cancers.

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. [67] Patients receiving adjuvant intraperitoneal chemotherapy are more likely to have recurrences outside the abdominal cavity, according to a study by Tanner et al. [68]

Intraperitoneal chemotherapy may cause more adverse 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. Modifications to improve the tolerability of intraperitoneal chemotherapy that are being examined include reduction of the total 3-hour amount of cisplatin given. [69]

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 three 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 two to three cycles of conventional chemotherapy and can then be reevaluated for surgical cytoreduction. However, optimal primary 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. [70] 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. [71]

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. [72]

The NCCN ovarian cancer guidelines note that upfront debulking surgery remains the treatment of choice in the United States. Neoadjuvant chemotherapy remains controversial, but may be considered for patients with bulky stage III-IV disease who are not candidates for surgery; however, the NCCN recommends that the assessment of such patients be performed by a gynecologic oncologist. [37]

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. [73]

A meta-analysis indicated that continuing chemotherapy improved progression-free survival and overall survival, especially if complete response was reached after primary therapy. [74]

Niraparib (Zejula) is a poly (adenosine diphosphate [ADP]–ribose) polymerase (PARP) enzyme inhibitor that was approved by the FDA in March 2017 for maintenance treatment for recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in women who are in complete or partial response to platinum-based chemotherapy. Niraparib is active both in patients with and those without BRCA mutations. See Management of Recurrent Disease, below.

Second-line chemotherapy

Recurrent ovarian cancer is classified into two 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. [75, 76] 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. [77] In a phase III randomized study, topotecan and cisplatin followed by carboplatin and paclitaxel were more toxic and without improved efficacy. [74]

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. [78]

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. [79]

In November 2014, the FDA approved bevacizumab (Avastin) for platinum-resistant, recurrent, epithelial ovarian cancer in patients who received no more than two prior chemotherapy regimens. It is indicated for use in combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan. [80]  In December 2016, bevacizumab’s indication was expanded to include women with platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer either in combination with carboplatin and paclitaxel or in combination with carboplatin and gemcitabine chemotherapy, followed by bevacizumab alone. [81, 82]

Bevacizumab approval was based on results from the phase III AURELIA study, which showed that adding bevacizumab to chemotherapy significantly improved progressive-free survival (PFS) and overall response rate (ORR). Median PFS was 3.4 months with chemotherapy alone versus 6.7 months with bevacizumab-containing therapy. ORR was 11.8% versus 27.3%, respectively (P = 0.001). The addition of bevicizumab showed a slight trend toward improving overall survival (OS) compared with chemotherapy alone, but it was not significant. The OS hazard ratio was 0.85 (P < 0.174; median OS, 16.6 versus 13.3 months, respectively). [83]

In the OCEANS phase III study, women who received the combination of bevacizumab with chemotherapy had a 52% risk reduction for recurrence in disease progression (hazard ratio 0.48, P <0.0001) 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. [84]

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. [84] However, on final analysis, median overall survival was not significantly different in patients who received bevacizumab and those who received placebo (33.6 versus 32.9 months, respectively; hazard ratio=0.95; log-rank p=0.65). [81]

A second phase III trial found adding bevacizumab to chemotherapy showed an overall survival difference of 5 months compared to paclitaxel plus carboplatin chemotherapy alone (median OS: 42.6 months vs. 37.3 months; Hazard Ratio (HR)=0.84, 95% CI: 0.69-1.01 and HR=0.82, 95% CI: 0.68-0.996). The GOG-0213 study showed that women lived a median of 3.4 months longer without disease progression with the addition of bevacizumab to chemotherapy compared to chemotherapy alone (median PFS: 13.8 months vs. 10.4 months; HR=0.61, 95% CI: 0.51-0.72). [82]

Consolidation chemotherapy

Ovarian cancer has a very high response rate to front-line treatment; despite this, most patients develop recurrent cancer. Many groups 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. [73] 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 plus hyperthermic chemotherapy, which combines three separately useful modalities: surgical debulking, intraperitoneal chemotherapy, and heat. See the videos below.

Dr. Oliver Zivanovic, MD, PhD, discusses the role of hyperthermic intraperitoneal chemotherapy in ovarian cancer. Courtesy of Memorial Sloan-Kettering Cancer Center.
Dr. Oliver Zivanovic, MD, PhD, demonstrates hyperthermic intraperitoneal chemotherapy for ovarian cancer. Courtesy of Memorial Sloan-Kettering Cancer Center.
Previous
Next:

Radiation Therapy

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.

Previous
Next:

Estrogen Replacement Therapy

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.

In younger women with endometrioid subtypes, ERT is a concern because these tumors theoretically are estrogen sensitive. If estrogen is used in such patients, a progestin should also be considered.

Previous
Next:

Experimental Medications

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, gonadotropin-releasing hormone (GnRH) agonists, and megestrol (Megace) [8] 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. [85] 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.

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. [86]

Previous
Next:

Second-Look Laparotomy

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 patients found to have disease after 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 during the study. [64]

Efforts are now under way 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. In many instances it may be possible to perform this evaluation adequately using the laparoscope.

Previous
Next:

Management of Recurrent Disease

In most patients who present 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 responded 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.

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 an elevated serum CA125 level 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.

PARP inhibitors

Poly (adenosine diphosphate [ADP]–ribose) polymerase (PARP) enzymes are involved in normal cellular homeostasis (eg, DNA transcription, cell cycle regulation, DNA repair). PARP enzyme inhibitors result in disruption of cellular homeostasis and cell death. The following PARP inhibitors are approved by the US Food and Drug Administration (FDA) for use in ovarian cancer:

  • Olaparib (Lynparza)
  • Rucaparib (Rubraca)
  • Niraparib (Zejula)

Olaparib

Olaparib is an inhibitor of PARP1, PARP2, and PARP3. Olaparib is approved as monotherapy for deleterious or suspected deleterious germline BRCA-mutated advanced ovarian cancer in patients who have been treated with three or more prior lines of chemotherapy.

Olaparib has shown antitumor activity in patients with high-grade serous ovarian cancer in several phase II studies. Lederman et al reported progression-free advantage, but no overall survival advantage, with maintenance treatment with olaparib in patients with platinum-sensitive, relapsed, high-grade serous ovarian cancer. Study participants had received two or more platinum-based regimens and had experienced a partial or complete response to their most recent treatment. [87]

Another phase II clinical trial involved patients with ovarian cancer associated with germline BRCA1/2 mutations, all of whom received olaparib (n=298). The overall response rate was 31.1% and stabilization of disease >8 weeks was seen in 40% of patients. [88]

Olaparib 400 mg PO BID continuously was compared with pegylated liposomal doxorubicin (PLD) 50 mg/m2 IV every 4 weeks. Median progression-free survival was 8.8 months for olaparib compared with 7.1 months for PLD. ORR was 31% for olaparib and 18% for PLD. [89]

Rucaparib

The PARP inhibitor rucaparib gained accelerated approval by the FDA in December 2016. It is indicated for monotherapy of women with deleterious BRCA mutations (germline and/or somatic) associated with advanced ovarian cancer who have been treated with ≥2 prior lines of chemotherapy.

Approval was based results from 106 women enrolled in 2 single-arm clinical trials, Study 10 and ARIEL2 (Assessment of Rucaparib In Ovarian CancEr TriaL2). Patients in these trials had an overall response rate of 54% (complete, 9%; partial, 45%) and a median duration of response of 9.2 months, according to the FDA press materials. The drug's prescribing information also indicates that the overall response rate as assessed by an independent radiology review was 42%, with a median duration of response of 6.7 months, while the investigator-assessed response rate was 66%. [90, 91, 92]

Continued approval of rucaparib for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. The ARIEL3 maintenance confirmatory study has completed enrollment and the ARIEL4 treatment confirmatory study is open for enrollment at the time of this update.

Niraparib

Niraparib was approved by the FDA in March 2017 for maintenance treatment for recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in women who are in complete or partial response to platinum-based chemotherapy. Unlike other PARP inhibitors (eg, olaparib, rucaparib), niraparib is active both in patients with and those without BRCA mutations

.Approval of niraparib was based on results from the placebo-controlled NOVA phase 3 trial (n=553), which showed a significant improvement in progression-free survival (PFS) with niraparib. In the germline BRCA mutation (gBRCA) cohort, PFS with niraparib versus placebo was 21.0 vs 5.5 months, respectively. PFS was 12.9  vs 3.8 months in the non-gBRCA patients who had tumors with homologous recombination deficiency (HRD), and 9.3  vs 3.9 months in the overall non-gBRCA cohort (P<0.001 for all 3 comparisons). [93]

Previous
Next:

Palliative Care

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. 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. A somatostatin analog to decrease gastrointestinal secretions can be 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 complication 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, in patients undergoing surgical relief of bowel obstruction or other intervention. However, long-term parenteral nutritional support is seldom appropriate 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 phosphate. 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.

Previous
Next:

Management of Ovarian Cysts

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.

Previous
Next:

Management of Tumors of Low Malignant Potential (Borderline Tumors)

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 sufficient 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 one 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.

Previous
Next:

Treatment of Malignant Germ Cell Tumors

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. [94]

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

Previous
Next:

Treatment of Sex-Cord Stromal Tumors

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%.

Previous
Next:

Treatment of Rare Tumors

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.

Previous
Next:

Assessment of Response to Therapy and Relapse

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 express 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 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. [95]

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. [96]

Previous
Next:

Consultations

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 (eg, solid or mixed solid and cystic tumors, ascites) 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, lactate dehydrogenase (LDH), AFP, beta-hCG, and inhibin levels. Appropriate referral should be made if any of these are significantly elevated.

Patients with primarily gastrointestinal (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.

Previous
Next:

Deterrence and Prevention

The risk of developing epithelial ovarian cancer (EOC) is significantly reduced by the following:

  • Bearing children
  • Using the combined oral contraceptive pill
  • Undergoing tubal ligation
  • Undergoing bilateral oophorectomy

Evidence suggests that taking oral contraception 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. [85] The American College of Obstetricians and Gynecologists recommends offering bilateral salpingo-oophorectomy to women with BRCA1 or BRCA2 mutations after completion of childbearing (level B recommendation). [97]  On the basis of their study in 5,783 women with a BRCA1 or BRCA2 mutation, Kinch et al concluded that in BRCA1 mutation carriers, oophorectomy at age 35 years can be recommended. [98]

Surgical prophylaxis decreases the risk by at least 80%. [98] Salpingo-oophorectomy does not prevent all cases of related cancer, 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 EOC from developing, a small risk still exists for developing carcinoma of the peritoneum, a disease that behaves similarly to EOC.

BRCA1 and BRCA2 mutations are common among women with invasive ovarian cancer; thus, women diagnosed with invasive, nonmucinous ovarian cancer are candidates for genetic testing. [99]

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. [100]

Previous
Next:

Long-term Monitoring

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, determination of tumor markers in serum (ie, inhibin) should be performed if levels 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.

Previous