Medical treatment for relapsed epithelial ovarian, fallopian tube, or peritoneal cancer: Platinum-resistant disease

INTRODUCTION — Epithelial cancers of ovarian, fallopian tube, and peritoneal origin in women exhibit similar clinical characteristics and behavior. As such, these are often combined and define epithelial ovarian cancer (EOC) in clinical trials and clinical practice. This topic will consider all three tumors under the heading EOC, and specifically will address those cancers that relapse within six months of completion of platinum-based treatment (platinum-resistant disease).

The initial diagnosis and management of EOC, the surgical treatment of recurrent EOC, and an overview of angiogenesis inhibitors in EOC are covered separately. (See "Overview of epithelial carcinoma of the ovary, fallopian tube, and peritoneum" and "Cancer of the ovary, fallopian tube, and peritoneum: Surgical options for recurrent cancer" and "First-line chemotherapy for advanced (stage III or IV) epithelial ovarian, fallopian tube, and peritoneal cancer" and "Epithelial carcinoma of the ovary, fallopian tube, and peritoneum: Clinical features and diagnosis".)

OVERVIEW OF THE TREATMENT APPROACH

Response to platinum — Despite initial therapy, the majority of women will relapse and require retreatment. The management of relapsed disease is stratified based upon the amount of time that has elapsed between the completion of platinum-based treatment and the detection of relapse, known as the platinum-free interval (PFI) (see "First-line chemotherapy for advanced (stage III or IV) epithelial ovarian, fallopian tube, and peritoneal cancer", section on 'Treatment of recurrent disease'):

●Patients with a PFI of six months or longer are considered to have "platinum-sensitive" disease. The management of these patients is discussed separately. (See "Medical treatment for relapsed epithelial ovarian, fallopian tube, or peritoneal cancer: Platinum-sensitive disease".)

●Patients with a PFI of less than six months are considered to have "platinum-resistant" disease. This includes women who experience disease progression during first-line platinum-based therapy, often referred to as having "platinum-refractory" disease, although some have challenged the relevance of this designation in favor of time as a continuous variable for recurrent disease [1]. The management of these patients (collectively referred to as having platinum-resistant EOC) is discussed here.

There are a number of active treatment options available for women with platinum-resistant EOC, and the ideal treatment is not known. We prefer sequential single-agent treatment rather than combination therapy. Therefore, our preferred option is single-agent paclitaxel as the first-line treatment for these patients, especially in those patients who have not previously been treated with paclitaxel for recurrent EOC.

First-line treatment — For patients who have not previously been treated specifically for platinum-resistant disease (ie, first-line therapy), our approach is as follows:

●We use immunohistochemistry to identify cancers with folate receptor (FR)-alpha overexpression. The US Food and Drug Administration has approved a companion diagnostic test to identify patients with epithelial ovarian cancer who are eligible for treatment with mirvetuximab soravtansine [2]. (See 'For folate receptor-alpha positive disease' below.)

●For most patients whose tumors lack FR-alpha overexpression, we utilize single-agent chemotherapy rather than combination chemotherapy. (See 'For other cancers' below.)

•For patients receiving first-line treatment for platinum-resistant recurrent disease, we administer weekly paclitaxel. However, we acknowledge that among patients who were treated with paclitaxel previously, prior toxicities may prohibit its repeated use (eg, persistent neuropathy or prior history of prolonged myelosuppression). (See 'Paclitaxel' below.)

•For patients who progressed on or are not candidates for single-agent paclitaxel in this setting, we administer pegylated liposomal doxorubicin (PLD) because of its schedule (ie, every-four-week administration) and lack of typical side effects associated with chemotherapy (eg, little risk of myelosuppression, no risk of alopecia). (See 'Pegylated liposomal doxorubicin' below.)

●For appropriately selected women with platinum-resistant recurrent disease, we administer single-agent chemotherapy plus bevacizumab. Ideal patients for chemotherapy plus bevacizumab include those patients who have received less than two prior regimens, have not received bevacizumab previously, and have no history of a bowel obstruction within six months. (See 'Addition of bevacizumab' below.)

Second- or later-line treatment — For patients who relapse after first-line or subsequent treatment and desire further therapy, limited data suggest that continuing therapy appears to be beneficial. In an analysis of 1620 patients who had originally participated in a first-line clinical trial, subsequent treatment for recurrent disease resulted in a significant improvement in median overall survival (OS) in the second-line (14 versus 4 months, hazard ratio [HR] 0.38, 95% CI 0.32-0.46), third-line (11 versus 3 months, HR 0.35, 95% CI 0.28-0.45), and fourth-line setting (8 versus 3 months, HR 0.53, 95% CI 0.37-0.74) [3].

Women diagnosed with clear cell, endometrioid, or mucinous ovarian cancer should be offered somatic tumor testing for DNA mismatch-repair deficiency [4]; as such, patients may be appropriate candidates for immune checkpoint inhibition, in the event of refractory disease. (See "Management of ovarian cancer associated with BRCA and other genetic mutations", section on 'Mismatch repair deficiency/high microsatellite instability'.)

SINGLE-AGENT THERAPY — There are multiple agents with activity in platinum-resistant EOC, but there is not one universally preferred agent for use in the first- or subsequent-line treatment. A Cochrane systematic review of trials (n = 1323) with platinum-resistant EOC concluded that topotecan, paclitaxel, and pegylated liposomal doxorubicin (PLD) have similar efficacy, but different patterns of side effects [5]. A choice among these agents depends upon the clinician's experience, the side effect profile, and prior therapy. In general, we prefer single-agent treatment with PLD because of its schedule (ie, every-four-week administration) and lack of typical side effects associated with chemotherapy (eg, little risk of myelosuppression, no risk of alopecia).

For folate receptor-alpha positive disease

Mirvetuximab soravtansine — For folate receptor (FR)-alpha positive, platinum-resistant ovarian cancer, we suggest mirvetuximab soravtansine (MIRV) as next line treatment, rather than other systemic agents. MIRV is a FR-alpha directed antibody and microtubule inhibitor conjugate that has regulatory approval in the United States for FR-alpha positive, platinum-resistant EOC that has been treated with one to three prior systemic treatment regimens [2]. Upon progression on MIRV, we proceed with next line chemotherapy, as for other cancers. (See 'For other cancers' below.)

Supporting data are as follows:

●In a randomized trial, among 453 patients with platinum-resistant, FR-alpha positive ovarian cancer, MIRV improved overall survival (OS) over chemotherapy (16.5 versus 12.8 months; hazard ratio [HR] for death 0.67, 95% CI 0.50-0.89), as well as progression-free survival (PFS; 5.6 versus 4.0 months) and objective response rates (42 versus 16 percent) [6]. Grade ≥3 adverse events occurred in 42 percent in the MIRV group and in 54 percent in the chemotherapy group.

●In a previous randomized trial, among 366 patients with platinum resistant EOC, MIRV resulted in a similar PFS compared with investigator's choice chemotherapy in the overall population (HR 0.98), with a trend towards improved PFS in those with FR-alpha high tumors that did not reach statistical significance (HR 0.69) [7]. However, MIRV was better than chemotherapy in the folate receptor alpha high population in regards to objective response rate (24 versus 10 percent) and patient-reported outcomes (27 versus 13 percent). Fewer treatment-related grade 3 or higher adverse events (25 versus 44) were seen with MIRV compared with chemotherapy.

For other cancers

Paclitaxel — Paclitaxel has been shown to be one of the most active agents in EOC, particularly in paclitaxel-naïve, platinum-resistant EOC in which response rates range between 13 and 50 percent [8-11]. Among patients with platinum-resistant disease, a prospective trial that evaluated paclitaxel administered on a weekly schedule reported a 21 percent response rate in a cohort of 48 women with platinum-resistant disease [12]. Stable disease was seen in 46 percent. The major toxicity was mild neuropathy (grade 2), which occurred in 21 percent. Severe (grade 3) neuropathy was seen in 4 percent.

Pegylated liposomal doxorubicin — In one of the largest randomized studies performed in this population, PLD (50 mg/m² every four weeks) was compared with topotecan (1.5 mg/m² daily for five days, every three weeks) in 237 women who relapsed after receiving one platinum-containing regimen, of whom 117 were platinum-refractory [13,14]. Compared with topotecan, treatment with PLD resulted in:

●A similar overall response rate (ORR; 20 versus 17 percent).

●A similar time to progression (22 versus 20 weeks).

●A similar median overall survival (66 versus 56 weeks).

●Less serious (grade 3/4) myelotoxicity, including neutropenia (12 versus 71 percent) and thrombocytopenia (1 versus 35 percent).

●More episodes of hand-foot syndrome and stomatitis. However, subsequent studies show that this can be minimized by initiating PLD at a lower dose (eg, 40 mg/m² every four weeks), with similar antitumor efficacy [15-17]. (See "Toxic erythema of chemotherapy (hand-foot syndrome)", section on 'Hand-foot syndrome'.)

Bevacizumab — Monotherapy using the antiangiogenesis inhibitor, bevacizumab, is also an option for patients with platinum-resistant EOC. The benefits of treatment were shown in several studies, including:

●Gynecologic Oncology Group (GOG) 170D – In this trial, 62 women with persistent or recurrent disease (36 of whom had platinum-resistant disease) were treated with bevacizumab (15 mg/kg every three weeks) [18]. Thirteen patients (21 percent) had a clinical response (two complete, 11 partial). Median PFS and OS were 4.7 and 17 months, respectively. There was no association of prior platinum sensitivity with the hazard of progression or death. None of the patients experienced a gastrointestinal perforation.

●In an industry-sponsored study, 44 patients who had progressed within three months of either topotecan or PLD were treated with bevacizumab (but all patients were allowed up to three prior regimens only) [19]. The ORR was 16 percent (all partial responses) and an additional 27 patients (61 percent) had stable disease. However, unlike in GOG 170D, the gastrointestinal perforation rate was 11 percent.

Gemcitabine — Gemcitabine is a commonly used agent in recurrent ovarian cancer and appears to have equivalent activity to PLD. This was shown in a trial that included 195 women with platinum-resistant EOC, all of whom were randomly assigned to treatment with gemcitabine (1000 mg/m² on days 1 and 8 of a 21-day cycle) or PLD (50 mg/m² on day 1 of a 28-day cycle) [20]. Compared with PLD, treatment with gemcitabine resulted in:

●A similar ORR (9 versus 11 percent).

●A higher proportion of stable disease (55 versus 39 percent).

●Similar median PFS (four versus three months).

●Similar median OS (13 versus 14 months).

●Toxicity associated with gemcitabine included severe (grade 3/4) fatigue (11 percent), nausea/vomiting (13 percent), and neutropenia (38 percent).

Topotecan — Topotecan is a commonly used agent in recurrent ovarian cancer. Although it is historically administered as a once-daily infusion for five days of a 28-day cycle, it is more commonly used today on a weekly schedule because at least one randomized trial showed there was no difference in survival outcomes or quality of life between the two regimens.

This was shown in the North Eastern German Society of Gynecologic Oncology randomized trial of 194 women with platinum-resistant disease who received either daily times-five treatment (1.25 mg/m²/day on days 1 through 5 of a 21-day cycle) or weekly topotecan (4 mg/m² on days 1, 8, and 15 of a 28-day cycle) [21]. Compared with weekly dosing, the daily times-five regimen produced:

●A significantly higher ORR (19 versus 9 percent).

●Similar rate of stable disease (approximately 40 percent in both groups).

●No difference in median PFS (three versus four months) or median OS (nine months in each).

●No difference in quality of life was seen between the treatment groups, per European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire.

●However, weekly dosing was associated with a 62 percent relative risk (RR) reduction in the occurrence of severe (grade 3/4) neutropenia.

Etoposide — Oral etoposide (50 mg/m² daily for 21 days every four weeks) was given to 41 women with an ORR of 27 percent [22]. Serious (grade 3/4) toxicity consisted of neutropenia (45 percent) and leukopenia (41 percent). In this trial, two deaths were associated with neutropenic sepsis, and one patient died of bleeding associated with thrombocytopenia.

Other agents — There are other agents known to be active for recurrent ovarian cancer, which are discussed briefly below:

●Docetaxel – Docetaxel (75 to 100 mg/m² given every 21 days) was evaluated in a cohort of 32 women with an ORR of 23 percent [23]. Stable disease was achieved by 28 percent. Predominant toxicity was hematologic, with serious (grade 4) thrombocytopenia in 50 percent, febrile neutropenia in 33 percent, and grade 4 neutropenia in 72 percent. Nonhematologic toxicities included mild (grade 1/2) fatigue, nausea, vomiting, and diarrhea.

●Paclitaxel (nanoparticle albumin-bound) – Nabpaclitaxel (100 mg/m² given weekly for three weeks on/one week off) was administered to 51 women in a GOG study [24]. The ORR was 23 percent, with stable disease in 36 percent. Moderate (grade 3) neutropenia was seen in 12 percent of women with mild-moderate neuropathy (grade 2/3). Otherwise, there was no significant toxicity.

●Pemetrexed – Pemetrexed (900 mg/m² every 21 days) was given to 51 patients on a GOG study [25]. The ORR was 21 percent, with an additional 35 percent experiencing stable disease. Serious toxicities (grade 3/4) included neutropenia (42 percent) and constitutional deterioration (15 percent). A European study randomized 102 women to treatment using the standard dose used above or a lower dose (500 mg/m² every 21 days) [26]. The ORR with either dose was lower than that seen in the GOG experience (9 and 10 percent for the standard and lower doses, respectively). The lower dose resulted in fewer side effects (17 versus 28 percent, respectively).

Given that there are a number of options available, the order of agents should be individualized based upon patient preference. Often the better choice is to offer a patient a well-designed, scientifically valid, peer-reviewed clinical trial. In the United States, additional information and instructions for referring a patient to an appropriate research center can be obtained at the National Institutes of Health (NIH) clinical trials website.

Addition of bevacizumab — For appropriately selected patients with platinum-resistant EOC, combining single-agent chemotherapy with the vascular endothelial growth factor receptor (VEGFR) antibody, bevacizumab, is indicated. In our practice, we administer this combination to patients who meet the criteria for the AURELIA study, with the following caveats: that there is no history of bowel obstruction in the past six months or evidence of malignant bowel involvement.

This recommendation is based on the AURELIA study, which included 361 patients with platinum-resistant ovarian cancer (defined as progression ≤6 months after ≥4 platinum-based cycles) who were randomly assigned treatment with chemotherapy plus or minus bevacizumab (15 mg/kg every three weeks or 10 mg/kg every two weeks, depending on the concomitant chemotherapy schedule) [27]. All patients met specific eligibility criteria, including:

●No evidence of disease progression during platinum-based chemotherapy (ie, chemorefractory disease)

●No more than two prior lines of chemotherapy

●No prior treatment with bevacizumab

●No history of bowel obstruction (although as stated above, we administer the combination to patients with no history of bowel obstruction in the past six months or evidence of malignant bowel involvement)

Chemotherapy options were based on the investigator's choice of one of the following [27]:

●Paclitaxel 80 mg/m² on days 1, 8, 15, and 22 every four weeks (n = 115)

●Topotecan 4 mg/m² on days 1, 8, and 15 every four weeks (or 1.25 mg/m² on days 1 through 5 every three weeks) (n = 120)

●Pegylated liposomal doxorubicin (PLD) 40 mg/m² on day 1 every four weeks (n = 126)

Of note, patients who received chemotherapy alone were allowed to cross over to single-agent bevacizumab at the time of disease progression. With a median follow-up of 13.5 months, compared with chemotherapy alone, chemotherapy plus bevacizumab resulted in [27]:

●A statistically significant improvement in the overall response rate (ORR, 31 versus 13 percent, respectively).

●A reduction in the risk of disease progression (hazard ratio [HR] 0.48, 95% CI 0.38-0.60; median duration 6.7 versus 3.4 months), but no statistically significant improvement in overall survival (OS, HR 0.85, 95% CI 0.66-1.08; median 16.6 versus 13.3 months).

●An increase in the rate of grade 2 or greater adverse events, including hypertension (20 versus 7 percent) and proteinuria (11 versus 0.6 percent). In addition, four patients (2.2 percent) treated with bevacizumab experienced a gastrointestinal perforation.

The results of a planned subset analysis of the AURELIA study evaluated the outcomes associated with the individual regimens [28]. The addition of bevacizumab to chemotherapy consistently resulted in better outcomes compared with treatment with chemotherapy alone:

●Among those who received paclitaxel, the ORR was 53 versus 30 percent with or without bevacizumab, respectively; median progression-free survival (PFS) was 10 versus 4 months (HR 0.46, 95% CI 0.30-0.71).

●Among those who received topotecan, the ORR was 17 versus 0 percent; median PFS was 6 versus 2 months (HR 0.32, 95% CI 0.21-0.49).

●Among those who received PLD, the ORR was 14 versus 8 percent; median PFS was 5 versus 4 months (HR 0.57, 95% CI 0.39-0.83).

The improvements in both ORR and PFS when bevacizumab is combined with chemotherapy represent clinically important outcomes for patients with platinum-resistant EOC. The lack of an OS advantage with combined therapy was likely impacted by the allowed cross-over for those patients who were treated with chemotherapy alone; at the time of data cut-off, 40 percent of those who experienced disease progression on chemotherapy alone had received single-agent bevacizumab. Therefore, these results support the use of chemotherapy plus bevacizumab in the treatment of appropriately selected women with platinum-resistant ovarian cancer. However, in November 2014, bevacizumab plus chemotherapy was approved for this specific indication by the US Food and Drug Administration [29].

Bevacizumab is available in Europe for EOC regardless of disease state (ie, for first-line treatment and treatment for platinum-sensitive and platinum-recurrent EOC). In addition, bevacizumab is also available in Japan for EOC regardless of disease state, if it is combined with chemotherapy followed by maintenance administration.

ALTERNATIVE OPTIONS — Patients with platinum-resistant EOC are not curable. Hence, treatments should aim to maximize quality of life while attempting to control disease. The preferred strategy to treat these patients is discussed above. (See 'Single-agent therapy' above and 'Addition of bevacizumab' above.)

Some data regarding the use of other strategies are available, discussed below.

Combination therapy — While there are a number of active treatment options available for women with platinum-resistant EOC (ie, relapse less than six months from previous treatment), we prefer sequential single-agent treatment rather than combination therapy. Combination therapy is not recommended in this population due to the additive toxicity risks and lack of high-quality evidence that it improves survival outcomes. This is illustrated in the following examples:

●Weekly paclitaxel versus a carboplatin combination – A phase III trial by the Group d'Investigateurs Nationaux pour l'Etude des Cancers Ovariens (GINECO) group enrolled 165 women with platinum-resistant cancer and randomly assigned treatment using weekly paclitaxel (80 mg/m²/week) alone, in combination with carboplatin (area under the curve [AUC] 5), or in combination with topotecan (3 mg/m²/week) on a 28-day cycle, with the following results [30]:

•A higher rate of serious (grade 3/4) neutropenia (13, 54, and 42 percent, with single-agent paclitaxel, paclitaxel plus carboplatin, or paclitaxel plus topotecan, respectively)

•A higher incidence of febrile neutropenia (0, 4, and 5 percent, respectively)

•No difference in overall response rate (ORR; 37, 39, and 35 percent, respectively)

•No difference in progression-free survival (PFS) among the treatment arms (hazard ratio for recurrence [HR] 0.92, 95% CI 0.77-1.11) or between single-agent and combination chemotherapy (HR for recurrence 0.95, 95% CI 0.69-1.32)

●Cisplatin and gemcitabine – The combination of cisplatin (30 mg/m² on days 1 and 8) and gemcitabine (600 mg/m² on days 1 and 8) was administered on 28-day cycles to 57 women in a Gynecologic Oncology Group (GOG) phase II study [31,32]. The ORR was 16 percent, with stable disease achieved in 54 percent. The median time to progression was five months. Toxicity (grade 3/4 adverse events) was substantial with this regimen; neutropenia occurred in 67 percent and gastrointestinal toxicity occurred in 12 percent. The low response rate, short PFS, and significant toxicity argue against its routine use in this population.

●Alternating doublets – In a phase II study, 45 patients were treated with three carboplatin-containing doublets administered sequentially every three weeks for a total of nine cycles [33]. The chemotherapy administered each cycle consisted of one of three doublets, in the following order: carboplatin (AUC 5) plus gemcitabine (800 mg/m² on days 1 and 8); carboplatin plus pegylated liposomal doxorubicin (PLD, 30 mg/m²); and carboplatin plus cyclophosphamide (600 mg/m²). The ORR was 39 percent, with median PFS and overall survival (OS) of 7 and 19 months, respectively. The rates of serious (grade 3/4) neutropenia and thrombocytopenia were 40 and 20 percent, respectively.

Endocrine therapy — For women with radiologic evidence of disease progression but with little or no symptoms associated with recurrent EOC, endocrine therapy can be a reasonable option. These studies illustrate the potential role for endocrine agents:

●Tamoxifen – The efficacy of tamoxifen was explored in a Cochrane review that included 623 women with recurrent EOC who participated in 1 of 14 studies [34]. Overall, 60 women (10 percent) achieved an objective response to tamoxifen alone, although the range within individual studies was 0 to 56 percent. An additional 32 percent achieved stable disease for periods of longer than four weeks.

In a randomized trial of 138 patients with platinum-resistant ovarian cancer randomly assigned in a 2:1 ratio to chemotherapy (paclitaxel or pegylated liposomal doxorubicin) versus tamoxifen, those receiving tamoxifen experienced a shorter median PFS (8.3 versus 12.7 weeks; HR 1.54, 95% CI 1.16-2.05) [35]. However, overall survival and control of gastrointestinal symptoms were similar between the two groups. Both hematologic and nonhematologic side effects as well as worsened social functioning were more frequent with chemotherapy.

●Letrozole – In a phase II trial of letrozole in 42 women with estrogen receptor-positive recurrent EOC based on cancer antigen (CA) 125 values, a serologic decrease in CA 125 >50 percent was seen in 17 percent [36]. Radiologic response was noted in 3 of 33 women (9 percent).

●Fulvestrant – In a phase II trial, the selective estrogen receptor down-regulator, fulvestrant (500 mg IM on day 1 then 250 mg on days 15, 29, and then every 28 days), was administered to 26 women with estrogen receptor-positive recurrent EOC [37]. While there were no objective responses, 50 percent had stable disease and one patient normalized a previously elevated serum CA 125. The median time to disease progression was 60 days, and treatment was well-tolerated.

Although the studies with letrozole and fulvestrant selected patients with estrogen receptor-positive disease, we do not routinely perform estrogen receptor testing in women with recurrent EOC. We reserve the use of endocrine therapy for women with asymptomatic recurrent disease. In addition, we prefer observation to endocrine therapy in the setting of CA 125 relapse, given the results of a randomized trial showing no benefit to initiation of treatment solely defined by CA 125. These results are discussed elsewhere. (See "Approach to survivors of epithelial ovarian, fallopian tube, or peritoneal carcinoma", section on 'Role of CA 125 surveillance'.)

Investigational options — Investigational approaches, including combination of the WEE1 inhibitor adavosertib with chemotherapy [38,39], antibody-drug conjugates [40], immune checkpoint inhibitors [41,42], and inhibitors of the tyrosine kinase TIE [43], are being evaluated. Further studies are required.

PROLONGING THE PLATINUM-FREE INTERVAL — For women with platinum-resistant EOC, we do not retreat with platinum, although some experts would consider platinum retreatment in select patients. The strategy of prolonging the platinum-free interval by treatment with nonplatinum agents has not been shown to improve survival and is discussed elsewhere. (See "Medical treatment for relapsed epithelial ovarian, fallopian tube, or peritoneal cancer: Platinum-sensitive disease", section on 'Relevance of the platinum-free interval'.)

SPECIAL CONSIDERATIONS

Patients with a BRCA mutation — For patients with recurrent EOC and a known germline mutation involving the breast cancer susceptibility genes (BRCA) and who have progressed on multiple prior lines of therapy, we administer a poly(ADP-ribose) polymerase (PARP) inhibitor. These data are discussed in detail elsewhere. (See "Management of ovarian cancer associated with BRCA and other genetic mutations", section on 'Recurrent BRCA-associated ovarian cancers'.)

Mismatch repair-deficient/microsatellite instability-high tumors — For women with DNA mismatch repair-deficient or microsatellite-instable ovarian cancer who have progressed on chemotherapy, use of the immune checkpoint inhibitor pembrolizumab is discussed elsewhere. (See "Management of ovarian cancer associated with BRCA and other genetic mutations", section on 'Mismatch repair deficiency/high microsatellite instability' and "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors".)

Recurrence based on CA 125 only — Patients with ovarian cancer may be followed serially with the serum tumor marker, cancer antigen (CA) 125. In some cases, patients with an elevated CA 125 may be defined as having disease progression (sometimes referred to as serologic progression), even in the absence of clinical symptoms or radiologic findings. For patients who experience a rising CA 125 within six months of completion of prior treatment, we recommend surveillance rather than chemotherapy because a randomized trial showed no survival benefit to early compared with delayed treatment (ie, treatment initiated based on objective evidence of disease progression). This trial is discussed in detail separately. (See "Approach to survivors of epithelial ovarian, fallopian tube, or peritoneal carcinoma", section on 'Role of CA 125 surveillance'.)

For asymptomatic patients with relapse by CA 125 alone who prefer systemic therapy over active surveillance, we offer endocrine therapy as a less toxic alternative to chemotherapy, as there are limited data that it can keep disease from progressing. (See "Medical treatment for relapsed epithelial ovarian, fallopian tube, or peritoneal cancer: Platinum-sensitive disease", section on 'Recurrence based on CA 125 only'.)

Malignant bowel obstruction — One of the most common problems faced by women with recurrent advanced EOC is bowel obstruction, which for the majority of women heralds a terminal event [44,45]. Options for treatment must focus on comfort and palliation (eg, placement of a percutaneous endoscopic gastrotomy tube to prevent vomiting), as both chemotherapy and surgical options have very limited utility. While some clinicians offer chemotherapy in hopes of bowel recovery, the limited data available suggest chemotherapy is not an effective treatment to restore bowel function [46]. For women who develop a malignant bowel obstruction, careful consideration of treatment (chemotherapy or surgery) should take into account the individual patient's clinical situation, performance status, preferences of treatment, and overall prognosis. (See "Cancer of the ovary, fallopian tube, and peritoneum: Surgical options for recurrent cancer", section on 'Relief of bowel obstruction'.)

Recurrent ascites — A large proportion of women with platinum-resistant EOC develop ascites, which is frequently resistant to systemic chemotherapy [47]. Therapeutic paracentesis provides relief, although it is usually temporary, with repeat abdominal paracentesis needed frequently to control symptoms (distention or shortness of breath). A PleurX catheter can be inserted by interventional radiology so that patients can remove ascites and control symptoms at home. (See "Malignancy-related ascites".)

Although the evidence is limited, angiogenesis inhibitors (eg, bevacizumab, aflibercept) have been used to manage refractory ascites and provide symptomatic relief [48-51]. As an example, in a single-institution report, four women with end-stage EOC and symptomatic ascites received bevacizumab (15 mg/kg every three weeks) in an attempt to palliate symptoms and reduce need for repeat paracentesis [48]. All patients reported subjective relief, with none requiring repeat paracentesis after treatment was started (range in duration of treatment was 12 to 24 weeks). None experienced a gastrointestinal perforation, but two patients developed mild to moderate (grade 1/2) hypertension.

For women with platinum-resistant, end-stage EOC who develop recurrent ascites, chemotherapy may be of limited use. We suggest management with paracentesis for symptomatic relief. The use of angiogenesis inhibitors such as bevacizumab is reasonable, particularly for women requiring frequent paracentesis for control of ascites. The risk of toxicity, including gastrointestinal perforation, should be considered on an individual basis. A broader discussion on the diagnosis and treatment of malignant ascites is covered separately. (See "Malignancy-related ascites".)

Genome-wide tumor analysis — Individualized molecular tumor profiling holds the promise of enabling personalized selection of molecularly-targeted treatment based on the specific genotype identified. Several platforms are available [52-54]. However, these assays require further evaluation to determine the appropriate use of genome-wide analysis in routine clinical practice.

In vitro chemosensitivity and resistance assays — In vitro assays that aim to help select the optimal chemotherapy regimen (sensitivity assays) or identify those agents least likely to be effective (resistance assays) have been developed. These assays are covered separately, but for women with platinum-resistant disease, we agree with guidelines from the American Society of Clinical Oncology and do not recommend their use in selection of therapy. (See "First-line chemotherapy for advanced (stage III or IV) epithelial ovarian, fallopian tube, and peritoneal cancer", section on 'In vitro chemosensitivity and resistance assays'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Ovarian, fallopian tube, and peritoneal cancer".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Beyond the Basics topics (see "Patient education: Treatment of ovarian cancer (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Terminology – For women who experience a recurrence, the selection of therapy is commonly based upon whether women are "sensitive" or "resistant" to platinum-based treatment. Patients who respond to initial platinum-based therapy and have a significant relapse-free interval (more than six months) have a high probability of responding again to platinum-based treatment at the time of relapse. These patients are termed "platinum-sensitive." Women who progress on or relapse within six months of completion of prior platinum-based therapy are considered "platinum-resistant." (See "First-line chemotherapy for advanced (stage III or IV) epithelial ovarian, fallopian tube, and peritoneal cancer", section on 'Treatment of recurrent disease'.)

●When to start treatment – Given the incurable nature of recurrent epithelial ovarian cancer (EOC), we recommend delay of treatment for women who relapse solely by cancer antigen 125. We reserve chemotherapy or other treatments for women who develop or are about to develop signs or symptoms related to recurrent EOC. For women with asymptomatic disease, endocrine therapy is a reasonable option. (See 'Endocrine therapy' above and "First-line chemotherapy for advanced (stage III or IV) epithelial ovarian, fallopian tube, and peritoneal cancer", section on 'Post-treatment surveillance'.)

●Choice of treatment – For most patients, we suggest single-agent chemotherapy rather than combination chemotherapy (Grade 2B):

•For patients receiving first-line treatment for platinum-resistant recurrent disease,

-If folate receptor (FR)-alpha overexpression, we suggest mirvetuximab soravtansine as next line treatment, rather than other systemic agents (Grade 2B). Upon progression, we treat as for other cancers. (See 'For folate receptor-alpha positive disease' above.)

-If not overexpressing FR-alpha, we suggest weekly paclitaxel (Grade 2C). However, we acknowledge that among patients who were treated with paclitaxel previously, prior toxicities may prohibit its repeated use (eg, persistent neuropathy or prior history of prolonged myelosuppression). For those who have received less than two prior regimens in the past and were not previously treated with bevacizumab, we suggest the addition of bevacizumab to chemotherapy (Grade 2B), provided they have no history of a bowel obstruction in the past six months (or no evidence of malignant bowel involvement). (See 'For other cancers' above and 'Addition of bevacizumab' above.)

For patients who progress on single-agent paclitaxel in this setting, we suggest pegylated liposomal doxorubicin (PLD) (Grade 2C). This is partly supported because of the schedule of administration of PLD (ie, every-four-week administration) and lack of typical side effects associated with chemotherapy (eg, little risk of myelosuppression, no risk of alopecia). (See 'Pegylated liposomal doxorubicin' above.)

•We do not retreat with platinum following intervening nonplatinum treatment because there are few data to support this strategy. However, some clinicians would consider platinum retreatment in select patients. (See 'Prolonging the platinum-free interval' above.)

●Special considerations

•Malignant bowel obstruction – For women who develop a malignant bowel obstruction, options for treatment must focus on comfort and palliation as both chemotherapy and surgical options have very limited utility. An individualized approach to the use of chemotherapy in this situation should take into account the individual patient's clinical situation, performance status, preferences of treatment, and overall prognosis. (See 'Malignant bowel obstruction' above.)

•Recurrent ascites – For women with platinum-resistant, end-stage EOC who develop recurrent ascites, chemotherapy may be of limited use. Patients are candidates for paracentesis for symptomatic relief. Alternatively, treatment with bevacizumab is also reasonable, but the risk of toxicity, including gastrointestinal perforation, should be considered on an individual basis. (See 'Recurrent ascites' above.)