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Medical treatment for relapsed epithelial ovarian, fallopian tubal, or peritoneal cancer: Platinum-sensitive disease
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Medical treatment for relapsed epithelial ovarian, fallopian tubal, or peritoneal cancer: Platinum-sensitive disease
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Literature review current through: Sep 2017. | This topic last updated: Sep 14, 2017.

INTRODUCTION — Epithelial cancers of ovarian, fallopian tubal, and peritoneal origin exhibit similar clinical characteristics, behavior, and in many cases, share basic biology. As such, these are often considered collectively and define epithelial ovarian cancer (EOC) in clinical trials and clinical practice. This topic will consider all three primary sites under the heading EOC.

Despite initial therapy (usually consisting of surgical cytoreduction and platinum-taxane combination therapy), the majority of women with advanced-stage ovarian cancer will relapse and require additional treatment. The likelihood for recurrence depends on many factors, including distribution of disease at initial presentation, success of initial surgical cytoreduction (ie, the presence of any residual disease), rapidity of cancer antigen 125 (CA 125) resolution, and treatment response after primary therapy. However, a predictive marker for recurrence has not been prospectively verified.

The management of patients with platinum-sensitive recurrent ovarian cancer (ie, those with a platinum-free interval of six months or longer) is discussed here. (See 'Relevance of the platinum-free interval' below.)

The management of patients with platinum-resistant disease (those with a platinum-free interval of less than six months), as well as the initial diagnosis and management of EOC, and the surgical treatment of recurrent EOC are covered separately. (See "Medical treatment for relapsed epithelial ovarian, fallopian tubal, or peritoneal cancer: Platinum-resistant disease" and "Overview of epithelial carcinoma of the ovary, fallopian tube, and peritoneum" and "Cancer of the ovary, fallopian tube, and peritoneum: Surgery for recurrent cancer" and "First-line chemotherapy for advanced (stage III or IV) epithelial ovarian, fallopian tubal, and peritoneal cancer" and "Epithelial carcinoma of the ovary, fallopian tube, and peritoneum: Clinical features and diagnosis".)

RELEVANCE OF THE PLATINUM-FREE INTERVAL — The management of relapsed disease is frequently 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). This is because the PFI correlates with progression-free survival (PFS), overall survival (OS), and response to subsequent treatment (both with platinum and nonplatinum agents as well as cytoreduction):

Patients with a PFI of six months or longer are considered to have chemotherapy-sensitive disease (often also termed "platinum-sensitive").

Patients with a PFI of less than six months are considered to have chemotherapy-resistant disease (often also termed "platinum-resistant"). Of this group, those patients who progress while on platinum-based therapy are often referred to as having "platinum-refractory" disease. The management of these patients is discussed separately. (See "Medical treatment for relapsed epithelial ovarian, fallopian tubal, or peritoneal cancer: Platinum-resistant disease".)

Although a longer PFI has been associated with better outcomes, the strategy of artificially extending the PFI with a nonplatinum regimen does not appear to improve survival outcomes compared with the use of platinum. In the MITO8 trial, 215 patients with progression 6 to 12 months after platinum-based chemotherapy were randomly assigned to nonplatinum-based chemotherapy followed at progression by platinum-based chemotherapy, or the reverse treatment sequence [1]. The nonplatinum-based therapy consisted of pegylated liposomal doxorubicin, topotecan, or gemcitabine, and the platinum-based therapy was carboplatin with either paclitaxel or gemcitabine. Although median PFS was increased (9.0 versus 5.0 months), the median OS was not improved with initial nonplatinum-based chemotherapy (21.8 versus 24.5 months; hazard ratio [HR] for death 1.38, 95% CI 0.99-1.94). It should be noted, however, that this study was terminated before meeting its primary accrual target.

TREATMENT — Women with platinum-sensitive recurrent EOC should be considered for both secondary cytoreduction and second-line chemotherapy, with or without bevacizumab. The use of second-line chemotherapy is discussed in the following sections. Secondary cytoreduction is discussed in more detail separately. (See "Cancer of the ovary, fallopian tube, and peritoneum: Surgery for recurrent cancer".)

Selection of regimen

General principles — Patients who relapse six months or longer after receiving initial therapy with a platinum-based treatment are more likely to respond to retreatment with a chemotherapy regimen that contains a platinum agent (eg, carboplatin, cisplatin). In general, combination chemotherapy is preferred to single-agent chemotherapy because in most cases, it is associated with superior objective response and progression-free survival (PFS) [2-10].

In addition, several trials suggest that women with platinum-sensitive disease achieve better response rates and PFS using maintenance treatment. This may consist of bevacizumab, olaparib, or niraparib (all of which have been approved by the US Food and Drug Administration). Although all of these agents have demonstrated improvements in PFS when used as maintenance, only bevacizumab has shown an overall survival (OS) benefit. However, single-agent therapy may be appropriate for medically frail patients or those with lingering toxicities from prior therapy.

While the ideal platinum-based combination therapy is not known, options include:

Carboplatin (area under the curve [AUC] 5) plus paclitaxel (175 mg/m2) IV (table 1), with or without bevacizumab (15 mg/kg), every three weeks [11].

Carboplatin (AUC 4) plus gemcitabine (1000 mg/m2 on days 1 and 8) IV, with or without bevacizumab, every three weeks [12].

If bevacizumab is used for either of the above regimens, it should be continued without chemotherapy as maintenance treatment. (See 'Bevacizumab' below.)

Carboplatin (AUC 5) and pegylated liposomal doxorubicin ([PLD], 30 mg/m2) IV every four weeks [13].

While paclitaxel is the only agent that has shown an OS benefit when combined with platinum-based chemotherapy in a clinical trial, these data are limited. (See 'Combination therapy' below.)

Ultimately, decisions should be individualized based on clinician and patient preferences, considering the side effect profile of each agent.

For example, for women with residual neuropathy or those who express a strong preference not to lose their hair, gemcitabine or PLD may be the preferred partner with carboplatin, rather than paclitaxel. For women who travel from a far distance, PLD may be the preferred option since it is administered on an every-four-week schedule in combination with carboplatin. Another consideration is that if bevacizumab is planned in the platinum-sensitive setting, current approvals allow combinations with carboplatin and either gemcitabine or paclitaxel only (not PLD). (See "The approach to ovarian cancer in older women", section on 'Treatment of recurrent disease' and "Cutaneous side effects of conventional chemotherapy agents", section on 'Acral erythema (hand-foot syndrome)'.)

In addition to the regimens listed above, several other choices are used in clinical practice such as:

The substitution of docetaxel for paclitaxel [14].

Administration of weekly paclitaxel in combination with platinum [15].

The combination of gemcitabine (800 to 1000 mg/m2) plus cisplatin (30 to 40 mg/m2) – Although this has been administered predominately in patients with platinum-resistant disease [16], in our experience, it is an effective alternative to carboplatin plus gemcitabine when patients experience repeat delays due to myelosuppression (although myelosuppression may also be mitigated by dose reduction of gemcitabine).

Both high-dose chemotherapy with autologous hematopoietic cell transplantation and the use of intraperitoneal chemotherapy have been evaluated in women with recurrent EOC. However, there is no evidence that either of these approaches improves survival outcomes compared with standard IV chemotherapy. These approaches are investigational and should not be considered standard of care options.

Combination therapy — Combination chemotherapy in the treatment of women with platinum-sensitive EOC was evaluated in multiple phase III studies. In general, platinum-based combination therapy demonstrates consistent improvements in response and PFS with overall response rates (complete plus partial response rates, [ORR]) from 50 to 60 percent, with additional benefit from the addition of bevacizumab. Multiple combinations are acceptable; however, the ideal platinum-based combination is not known.

Selection of regimen, as well as rationale for inclusion of bevacizumab, is discussed separately. (See 'General principles' above and 'Bevacizumab' below.)

Supporting data describing each regimen are discussed here.

Carboplatin plus paclitaxel – In parallel phase III trials conducted by the International Collaboration on Ovarian Neoplasms (ICON-4) and the Arbeitsgemeinschaft Gynaekologische Onkologie Studiengruppe Ovarialkarzinom (AGO-OVAR-2.2), 802 women were treated with conventional platinum-based chemotherapy (eg, carboplatin alone; or cisplatin, doxorubicin and cyclophosphamide [CAP]) with or without paclitaxel [11]. With a median follow-up of 42 months, those receiving platinum-based chemotherapy with paclitaxel experienced improved survival (29 versus 24 months; hazard ratio [HR] 0.82, 95% CI 0.69-0.97). There was also a higher incidence of grade 2 to 4 neurologic effects (20 versus 1 percent) and alopecia (86 versus 25 percent) for those receiving paclitaxel, though rates of myelosuppression were lower.

This is only one of two studies to date that has documented an improvement in OS; however, it has been criticized due to the high proportion of taxane-naïve patients entering into the trial (nearly 30 percent of patients in the control arm were never treated with a taxane as part of initial or subsequent therapy).

Carboplatin plus gemcitabine – A phase III study conducted by the Gynecologic Cancer Intergroup (GCIG) enrolled 356 women and randomly assigned therapy with 21-day cycles of carboplatin alone or carboplatin plus gemcitabine [12]. Compared with single-agent carboplatin, combined therapy resulted in an improved objective response rate (47 versus 31 percent) and median PFS (8.6 versus 5.8 months), although OS was not improved (18 versus 17.3 months, respectively). Patients receiving gemcitabine experienced an increase in serious (grade 3/4) hematologic toxicity, including neutropenia (71 versus 12 percent) and thrombocytopenia (35 versus 11 percent), and required granulocyte colony stimulating factors (G-CSF) more frequently (24 versus 10 percent).

Carboplatin plus PLD – The combination of carboplatin and PLD is an effective combination for platinum-sensitive EOC [17-20]. The efficacy of this combination was best shown in the phase III Caelyx in platinum-sensitive EOC (CALYPSO) trial, which was the largest phase III trial in the recurrent setting to be completed [17,18]. This study enrolled 976 women and randomly assigned them to treatment with carboplatin and either paclitaxel or PLD. With a median follow-up of 22 months, compared with carboplatin plus paclitaxel, PLD plus carboplatin resulted in improvement in median PFS (11.3 versus 9.4 months), although OS was equivalent (30.7 with carboplatin plus PLD versus 33.0 months with carboplatin plus paclitaxel [HR 0.99, 95% CI 0.85-1.16]) [18,19]. There were also fewer cases of severe (grade 3/4) neutropenia (35 versus 46 percent), lesser-grade neuropathy (5 versus 27 percent), and carboplatin hypersensitivity reactions (16 versus 33 percent). However, there were more cases of severe (grade 3/4) thrombocytopenia (16 versus 6 percent) among those receiving PLD.

Taken together, these data support the superiority of a platinum-based combination compared with single-agent platinum for initial treatment of relapsed disease. When platinum cannot be given to patients with platinum-sensitive disease (due to previous hypersensitivity or other comorbidities), single nonplatinum agents are often used. (See 'Single-agent therapy' below.)

Several studies have proposed doublets of nonplatinum agents, but no clear consensus exists as to whether they are superior to single agents in this setting [21-23]. As an example, PLD has been combined with trabectedin, a novel marine-derived alkaloid that kills cells by poisoning the DNA nucleotide excision repair machinery. In the OVA-301 study, approximately 700 women were randomly assigned to treatment with PLD (50 mg/m2 every four weeks) or PLD (30 mg/m2) plus trabectedin (1.1 mg/m2 over three hours) [24]. Compared with single-agent PLD, the combination of trabectedin plus PLD resulted in improved PFS for those with platinum-sensitive disease (median, 9.2 versus 7.5 months; HR 0.73, 95% CI 0.56-0.95), but not those with platinum-resistant disease (4 months in both arms) [22,25]. Median OS was equivalent between arms in both the platinum-sensitive and platinum-resistant cohorts. Overall, treatment was well-tolerated; neutropenia and grade 3 or 4 transaminase elevation were more common in the trabectedin group, while hand-foot syndrome and mucositis were less common. Based on these results, trabectedin is approved for use in ovarian cancer in Europe and other countries, but not in the United States (US).

Single-agent therapy — Platinum-based combination chemotherapy is the preferred treatment for most patients with platinum-sensitive relapsed EOC. A subset of women may not be candidates for retreatment with platinum agents (eg, carboplatin, cisplatin) either due to a history of a hypersensitivity reaction or persistent toxicities from first-line therapy. Such patients may be candidates for single-agent therapy with other drugs. The following agents are among the most active agents for women with platinum-sensitive recurrent EOC. A choice among them should take into account patient preferences and toxicity profile:

Etoposide – A Gynecologic Oncology Group (GOG) study involved 82 patients who were treated with etoposide (50 mg/m2 given orally for 21 days of a 28-day cycle). Among the group with platinum-sensitive EOC (n = 41), the ORR was 34 percent [26]. Serious toxicities (grade 3/4) are predominantly hematologic (neutropenia, thrombocytopenia, and leukopenia). There is also a 2 percent risk of secondary leukemia.

Topotecan – In a phase III study that included 474 women with recurrent EOC, all patients were randomly assigned to PLD or topotecan (1.5 mg/m2/day for five days every 21 days) [27]. Among platinum-sensitive patients treated with topotecan, the ORR was 29 percent. An alternative weekly schedule (4 mg/m2 weekly) was evaluated in a cohort of 43 patients and resulted in a 24 percent ORR [28]. Serious toxicity is predominantly hematologic. Several studies have suggested lower starting doses (ie, 1 to 1.25 mg/m2 for five days every 21 days) to ameliorate hematologic toxicity [29,30].

Pegylated liposomal doxorubicin – In the randomized trial of PLD versus topotecan discussed above, PLD (50 mg/m2 every 28 days) resulted in an ORR of 28 percent among platinum-sensitive patients [27]. It should be noted that while the US Food and Drug Administration (FDA)-approved dose is 50 mg/m2, most clinicians start at a lower dose (40 mg/m2) to reduce the risk of skin toxicity while maintaining the activity of this agent (versus 30 mg/m2 when given in combination with carboplatin).

Gemcitabine – In a phase III trial that included 153 patients randomly assigned treatment with PLD or gemcitabine (1000 mg/m2 on days 1, 8, and 15 of a 28-day cycle) [31], treatment with gemcitabine resulted in an ORR of 29 percent. Neutropenia is a common toxicity of this agent.

Nanoparticle albumin-bound paclitaxel (nabpaclitaxel) – Nabpaclitaxel (260 mg/m2 on day 1 every three weeks or 100 mg/m2 on days 1, 8, and 15 on a 28-day schedule) was evaluated in a cohort of 47 women with recurrent EOC and resulted in an ORR of 64 percent [32]. Nabpaclitaxel may also be given weekly (80 to 100 mg/m2 on days 1, 8, and 15 on a 28-day schedule), as has been studied in the platinum-resistant setting [33]. The most common toxicities are neutropenia and neuropathy.

Trabectedin – Although it is not available in the US, trabectedin is approved in both Europe and Canada for treatment of relapsed EOC. Trabectedin has activity in women previously treated with platinum and taxanes, but has shown most of its activity in women who relapse with platinum-sensitive disease, as demonstrated in two phase II trials:

In a multi-institutional European study, 59 women received trabectedin (1300 mcg/m2 over three hours every three weeks) [34]. Among 29 women with platinum-sensitive disease, the ORR was 43 percent; in the 30 women with platinum-resistant disease, only two responses were recorded (7 percent).

In a separate study, 141 women (62 platinum-sensitive, 79 platinum-resistant) were treated with trabectedin on a four-week cycle (580 mcg/m2 over three hours weekly for three weeks followed by one week off) [35]. Among women with platinum-sensitive disease, the ORR was 29 percent with a median PFS of five months. Among those with platinum-resistant disease, the ORR was 6 percent with a median PFS of two months.

Bevacizumab – As mentioned previously, this agent is frequently administered in the context of chemotherapy; however, several phase II trials evaluating its activity as a single agent have included patients with platinum-sensitive disease.

In the GOG trial 170-D, 11 responses (44 percent) were seen among 25 patients (41 percent of the total population) with potentially platinum-sensitive recurrent disease, including two complete responses [36].

In another phase II trial in which bevacizumab was given in combination with metronomically administered cyclophosphamide, 42 patients (60 percent of the total population) had potentially platinum-sensitive disease, among whom 14 (33 percent) had an objective partial response. The median time to progression (TTP) was approximately eight months and was significantly longer than the platinum-resistant subgroup [37].

Maintenance therapy

Choice of therapy — Our typical approach for women with platinum-sensitive recurrent EOC is to treat with the combination of carboplatin and either paclitaxel or gemcitabine, plus bevacizumab, followed by bevacizumab alone as maintenance therapy. Alternative agents that can be chosen for maintenance are poly-ADP ribose polymerase (PARP) inhibitors, and both niraparib and rucaparib are approved in this setting [38,39]. However, the two agents have not been compared directly as options for maintenance and OS data for niraparib are still pending.

Angiogenesis inhibitors — Angiogenesis plays a fundamental role in normal ovarian physiology and in the pathogenesis of EOC, progression through ascites formation, and metastatic spread. Angiogenesis inhibitors appear to be active agents in the treatment of EOC. Among them, the agent that has been most extensively evaluated in the treatment of platinum-sensitive EOC is bevacizumab. However, other angiogenesis inhibitors, such as cediranib and trebananib, are in various stages of development.

While PFS has been the subject of most clinical trials, only GOG-213, evaluating bevacizumab, was powered to address OS.

Bevacizumab — We suggest the use of bevacizumab with combination platinum-based chemotherapy and then as single-agent maintenance treatment for women with platinum-sensitive recurrent EOC. The data regarding bevacizumab specifically for women with platinum-sensitive recurrent EOC come from two seminal randomized trials:

OCEANS trial – In the phase III study of carboplatin and gemcitabine plus bevacizumab in EOC (also referred to as the OCEANS study), 484 women with platinum-sensitive EOC were randomly assigned to carboplatin (AUC 4 on day 1) and gemcitabine (1000 mg/m2 on days 1 and 8) with cycles repeated every 21 days with or without bevacizumab (15 mg/kg on day 1 every three weeks concurrent with chemotherapy for 10 cycles maximum, followed by bevacizumab alone until disease progression or toxicity) [40-42].

Bevacizumab with chemotherapy resulted in the following when compared with chemotherapy plus placebo:

An improvement in PFS (12 versus 8 months; HR 0.48, 95% CI 0.39-0.61). However, OS was not different between the two arms (34 versus 33 months).

A higher objective response rate (79 versus 57 percent).

A higher rate of treatment discontinuation for adverse events (23 versus 5 percent), including higher rates of serious hypertension (17 versus <1 percent), proteinuria >grade 3 (9 versus 1 percent), and noncentral nervous system bleeding (6 versus 1 percent). Of note, there were no cases of gastrointestinal perforation reported.

GOG 213 – In the GOG 213 trial, women with platinum-sensitive recurrent EOC were randomly assigned to surgical treatment (secondary cytoreduction versus no secondary cytoreduction) and separately, to chemotherapy (carboplatin and paclitaxel) with or without bevacizumab [43]. For those patients treated with bevacizumab, it was administered with chemotherapy and then continued as a single agent until disease progression.

The results of the medical treatment randomization, which included almost 700 women, were presented at the 2015 Annual Meeting for Women’s Cancers [43]. Compared with treatment with chemotherapy alone, the administration of bevacizumab resulted in:

An improvement in PFS (14 versus 10 months, respectively; HR 0.61, 95% CI 0.52-0.72).

A trend towards improved OS, which was significant upon reanalysis using corrected data obtained from electronic case report forms (43 versus 37 months, respectively; HR 0.82, 95% CI 0.68-0.996) [44].

Higher rates of serious (grade 3/4) gastrointestinal complications, such as perforation, necrosis, or fistula (6 versus 3 percent), and infections (13 versus 6 percent). In addition, combination treatment resulted in more reports of joint pain (15 versus 5 percent) and proteinuria (8 versus 0 percent).

The data consistently demonstrate that incorporating bevacizumab can improve PFS for women with a platinum-sensitive recurrent EOC and may also improve OS. Clinicians should discuss the potential benefits to those with platinum-sensitive disease in the context of patient preferences. For example, women with severe hypertension may opt against the use of bevacizumab.

The addition of bevacizumab may play a more important role for those with platinum-resistant relapsed EOC. This is discussed separately. (See "Medical treatment for relapsed epithelial ovarian, fallopian tubal, or peritoneal cancer: Platinum-resistant disease", section on 'Single-agent chemotherapy plus bevacizumab'.)

Cediranib — Cediranib is an investigational oral inhibitor of the vascular endothelial growth factor receptors (VEGFR1, 2, and 3).

In the International Collaborative Ovarian Neoplasms trial (ICON6), over 450 patients were treated with platinum-based chemotherapy alone (reference arm); or with concurrent cediranib (concurrent arm); or with concurrent and maintenance cediranib for 18 months (maintenance arm) [45]. Due to drug shortages after the manufacturer discontinued production, the trial was redesigned to evaluate the reference and concurrent arms only, using PFS rather than OS as the primary outcome measure [45,46]. At a median follow-up of 19.5 months, maintenance cediranib treatment improved PFS (11.0 versus 8.7 months; HR 0.56, 95% CI 0.44-0.72) [45]. While there was also a trend towards improved OS (median, 26.3 months versus 21.0 months; HR 0.77, 95% CI 0.55-1.07), data were immature given that approximately 50 percent of patients were still living at the time of data collection. Toxicity led to treatment discontinuation for 12 percent of patients on the reference arm and 39 percent of patients on the maintenance cediranib arm. Diarrhea, neutropenia, hypertension, voice changes, and hypothyroidism were more common with cediranib treatment.

Given that the reported survival advantage required that maintenance therapy continue for an additional 18 months, the benefit of treatment is not entirely clear, especially given the toxicities associated with this drug.

PARP inhibition — For patients with platinum-sensitive relapsed ovarian cancer with a partial or complete response to platinum-based chemotherapy, the PARP inhibitors niraparib and olaparib are approved by the FDA for maintenance therapy [47,48]. Rucaparib has also shown promising results but does not yet have approval from the FDA as maintenance therapy. While PFS outcomes are improved with these agents regardless of BRCA mutation status, data on OS outcomes are pending. Our approach is to use PARP inhibition for women in whom a maintenance strategy is desired but bevacizumab is considered inappropriate or is not tolerated.

Niraparib — Niraparib has shown efficacy as maintenance therapy in platinum-sensitive, relapsed disease, which appears independent of the presence of either BRCA mutation or homologous recombination deficiency (HRD). In the phase III NOVA study, 553 patients with platinum-sensitive, recurrent ovarian cancer were randomly assigned after completion of platinum-based chemotherapy in a 2:1 ratio to niraparib maintenance or placebo [49]. All patients were stratified according to presence or absence of a germline BRCA mutation (gBRCA cohort or non-gBRCA cohort); those in the non-gBRCA cohort were further classified by whether homologous recombination deficiency (HRD, using a central laboratory DNA-based test) was observed. Patients with a somatic mutation (sBRCA) were included in the non-gBRCA HRD cohort. Compared with placebo, niraparib increased PFS in all cohorts: in the gBRCA group, 21.0 versus 5.5 months (HR 0.27, 95% CI 0.17-0.41); in the overall non-gBRCA cohort, 9.3 versus 3.9 months (HR 0.45, 95% CI 0.34-0.61); and in the HRD-positive subgroup of the non-gBRCA cohort, 12.9 versus 3.8 months (HR 0.38, 95% CI 0.24-0.59). The most common grade 3 or 4 toxicities associated with niraparib were hematologic: thrombocytopenia (34 percent), anemia (25 percent), and neutropenia (20 percent). Myelodysplastic syndrome occurred in 5 of 367 patients (1.4 percent) who received niraparib. Treatment discontinuation due to toxicity occurred in 15 percent of patients receiving niraparib and in 2 percent of those receiving placebo. OS results from this study have not been reported.

Although PARP inhibitors may be expected to be less active in patients with intact DNA repair mechanisms (such as HRD-negative tumors), an exploratory analysis of HRD-negative patients still demonstrated a difference in the median PFS in this group favoring niraparib (PFS of 6.9 versus 3.8 months, respectively, HR 0.58, 95% CI 0.08-0.90). This suggests that all patients with platinum-sensitive recurrent ovarian cancer may benefit from maintenance therapy with this agent.

Olaparib — Olaparib has also been studied as maintenance therapy for those with platinum-sensitive relapsed disease in both women regardless of a BRCA mutation (Study 19) and specifically, in those with a BRCA mutation (SOLO2). Specifically, Study 19 was a randomized trial that included almost 300 women with platinum-sensitive high-grade recurrent EOC (with or without BRCA mutations) who achieved a response to their most recent treatment. These patients were randomly assigned to maintenance treatment with olaparib (400 mg orally twice a day) or placebo [50]. Compared with placebo, olaparib was associated with:

An improvement in progression-free survival (PFS) compared with placebo (eight versus five months; hazard ratio [HR] for progression or death 0.35, 95% CI 0.25-0.49), although interim analysis found no OS benefit (30 months in both; HR 0.94, 95% CI 0.63-1.39).

A low rate of serious (grade 3/4) toxicity. Adverse events (any grade) more commonly reported in the olaparib group than in the placebo group included nausea (68 versus 35 percent), fatigue (49 versus 38 percent), vomiting (32 versus 14 percent), and anemia (17 versus 5 percent).

Further results of Study 19, and of SOLO2, which enrolled women with a known germline mutation of BRCA, are discussed below. (See 'PARP inhibition in BRCA carriers' below.)

Rucaparib — Rucaparib has shown efficacy both as maintenance therapy as well as monotherapy for recurrent, platinum-sensitive, high-grade ovarian carcinoma. Data for rucaparib as subsequent-line monotherapy for those with BRCA-mutated cancers are discussed elsewhere. (See 'PARP inhibition in BRCA carriers' below.)

In the phase III ARIEL3 trial, 564 patients with relapsed high-grade serous or endometrioid ovarian carcinoma, all of whom had received ≥2 previous platinum-based therapies and achieved a complete or partial response to their most recent platinum-based treatment, were randomly assigned in a 2:1 ratio to maintenance therapy with rucaparib or to placebo [51]. In contrast to other studies of PARP inhibitors, women were permitted to enroll in this study even if they had residual bulky disease (≥2 cm).

Rucaparib improved PFS in the intention-to-treat population (10.8 versus 5.4 months; HR 0.36, 95% CI 0.30-0.45) as well as among those with a known genomic or somatic BRCA mutation (16.6 versus 5.4 months; HR 0.23, 95% CI 0.16-0.34) and those with homologous recombination deficiencies (13.6 versus 5.4 months; HR 0.32, 95% CI 0.24-0.42). Among the 37 percent of patients with measurable disease at study entry, rucaparib led to responses in 20 percent [52]. These data demonstrate efficacy of rucaparib as maintenance therapy in platinum-sensitive, relapsed ovarian cancer.

PROGNOSIS — The treatment for recurrent EOC is not curative. However, for women who achieve a response or remission to platinum-based retreatment, the durability of the second remission is an important question.

Although the data on prognosis are limited, in a study of 125 women who achieved a response to second-line platinum-based therapy, only 3 percent experienced a duration that was longer than the initial platinum-free interval (PFI) [53]. In this series, treatment was often discontinued after six cycles in responding patients, raising the question of whether a maintenance treatment would help improve the duration of second (or later) response. (See 'Maintenance therapy' above.)

SPECIAL CONSIDERATIONS

PARP inhibition in BRCA carriers — Multiple poly-ADP ribose polymerase (PARP) inhibitors have achieved approval for use in women with a BRCA mutation:

Olaparib (capsule formulation) has US Food and Drug Administration (FDA) approval for use in women with recurrent ovarian cancer associated with a germline BRCA mutation as single-agent therapy after three or more prior lines of treatment.

Rucaparib is indicated for use in women with recurrent ovarian cancer and a known BRCA mutation (either germline or somatic) after at least two prior lines of treatment.

Single-agent (maintenance) niraparib and olaparib (tablet formulation) are both approved for use in women with recurrent ovarian cancer after achievement of a response to platinum-based retreatment (regardless of BRCA mutation status). (See 'PARP inhibition' above.)

Olaparib – A subanalysis of Study 19, which enrolled those with platinum-sensitive high-grade recurrent EOC, evaluated the outcomes of maintenance therapy of olaparib specifically in patients with a known BRCA mutation (either germline or somatic) and suggested that the clinical benefit was greatest among these patients [54]. Patients with a BRCA mutation had a benefit in progression-free survival (PFS) with olaparib compared with placebo (median, 11 versus 4 months; hazard ratio [HR] 0.18, 95% CI 0.10-0.31), with a trend towards improved overall survival (OS; HR 0.73, 95% CI 0.45-1.17), which became more pronounced at longer follow-up (>5 years) [55]. By contrast, women without a BRCA mutation had a smaller PFS benefit (median, 7 versus 5.5 months; HR 0.54, 95% CI 0.34-0.85), but no benefit in OS (HR 0.99, 95% CI 0.63-1.55). A post-hoc analysis of patients with BRCA mutations that excluded those from sites where any crossover occurred demonstrated an improved OS with olaparib (HR 0.52, 95% CI 0.28-0.970). This implies that later treatment with olaparib may have confounded the OS endpoint from the primary trial [56]. Further data from Study 19 are discussed above. (See 'Olaparib' above.)

Similar results were observed in the phase III SOLO2/ENGOT-Ov21 trial, in which 295 patients with relapsed, platinum-sensitive, germline BRCA-associated high-grade serous ovarian cancer or high-grade endometrioid cancer who had received at least two lines of previous chemotherapy were randomly assigned in a 2:1 ratio to olaparib maintenance or placebo [57]. Those receiving olaparib experienced improved PFS (19.1 versus 5.5 months; HR 0.30, 95% CI 0.22-0.41). Grade 3 or higher adverse events occurred in 18 percent of those receiving olaparib versus 8 percent of those receiving placebo.

Data in support of olaparib for BRCA-associated platinum-resistant disease are discussed elsewhere. (See "Medical treatment for relapsed epithelial ovarian, fallopian tubal, or peritoneal cancer: Platinum-resistant disease", section on 'Patients with a BRCA mutation'.)

Rucaparib In a phase II, open-label study of 204 patients with recurrent, platinum-sensitive, high-grade ovarian carcinoma, those with BRCA mutations or high loss of heterozygosity (LOH) experienced longer PFS with rucaparib relative to those with low LOH [58]. In this study, patients were divided into three groups: those with BRCA mutations (germline or somatic), those who were BRCA wild-type with high LOH (≥14 percent genomic), and those who were BRCA wild-type with low LOH (<14 percent genomic). PFS was longer for patients with BRCA mutations (12.8 months, HR 0.27, 95% CI 0.16-0.44) and/or high LOH (5.7 months; HR 0.62, 95% CI 0.42-0.90) subgroups relative to those with LOH (5.2 months). The most common grade 3 or worse toxicities were anemia (22 percent) and transaminitis (25 percent). Serious adverse events included small intestinal obstruction in 5 percent of patients.

Rucaparib has also shown efficacy as maintenance therapy, both among those with BRCA-associated and nonBRCA-associated cancers. (See 'Rucaparib' above.)

Further data from studies including patients with platinum-resistant relapsed disease are discussed elsewhere. (See "Medical treatment for relapsed epithelial ovarian, fallopian tubal, or peritoneal cancer: Platinum-resistant disease", section on 'Patients with a BRCA mutation'.)

Other PARP inhibitors – Another PARP inhibitor, veliparib, was evaluated in a phase II trial in the Gynecologic Oncology Group (GOG) with encouraging results [59]. In this study, 50 women with a known BRCA mutation were treated with veliparib monotherapy (400 mg twice a day). Treatment resulted in a 26 percent overall response rate, with a 35 percent response rate among those with platinum-sensitive disease. In the overall group, the median PFS and OS were 8 and 20 months, respectively. The agent is under active investigation in combination with chemotherapy in the frontline and maintenance settings in GOG-3005.

Recurrence based on CA 125 only — Patients with ovarian cancer may be followed serially with the serum tumor marker cancer antigen 125 (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 such patients, we offer surveillance rather than chemotherapy, given results of one randomized trial that showed no benefit in OS with early versus delayed treatment (ie, treatment initiated based on objective evidence of disease progression). This trial is discussed in detail separately. (See "Overview of epithelial carcinoma of the ovary, fallopian tube, and peritoneum", section on 'CA 125 surveillance'.)

For those with relapse by CA 125 only who prefer systemic treatment over surveillance, we suggest the administration of endocrine therapy because it appears to have some activity and is less toxic than chemotherapy.

The activity of tamoxifen was demonstrated in the GOG 198 trial, which enrolled 139 patients and randomly assigned them to treatment with tamoxifen (20 mg twice daily) or thalidomide (100 mg daily with weekly dose escalation to a maximum dose of 400 mg daily). Tamoxifen resulted in a median PFS of three months and a median OS of 33 months [60]. Of note, thalidomide resulted in a 4.5- and 24-month median PFS and OS, respectively.

In a separate study of patients with estrogen receptor-positive ovarian cancer, 11 of 42 patients (26 percent) treated with letrozole (2.5 mg daily) had a PFS of six months or longer [61].

Retreatment with carboplatin and risk of hypersensitivity reactions — Women receiving carboplatin (as a single agent or in combination) as a second- or greater-line treatment are at risk for a hypersensitivity reaction. However, this does not necessarily exclude them as candidates for retreatment. Several protocols for carboplatin desensitization are available to help guide the treatment of women at risk for or who have had a platinum allergic reaction [62-64]. This topic is covered in detail elsewhere. (See "Infusion reactions to systemic chemotherapy", section on 'Platinum drugs'.)

INVESTIGATIVE APPROACHES

Combined molecular therapy — Although it remains investigational, one trial suggests that there may be a benefit to combination molecularly targeted therapy for women with platinum-sensitive EOC, particularly for those patients lacking a known BRCA mutation.

This was shown in a randomized, phase 2 trial that included 90 women with platinum-sensitive recurrent EOC who were randomly assigned to olaparib with or without cediranib [65]. With a median follow-up of 17 months, the addition of cediranib improved progression-free survival (PFS, 17 versus 9 months, respectively; hazard ratio [HR] 0.42, 95% CI 0.23-0.76), although there were also greater frequencies of serious (grade 3/4) toxicity, including fatigue, diarrhea, and hypertension.

A post-hoc analysis of this trial, which stratified patients by whether or not they carried a BRCA mutation (n = 47; including if it was not known, n = 43), suggested that the combination was associated with better outcomes in women who were not known to have a BRCA mutation. Compared with olaparib alone, the median PFS was prolonged in such women with combination treatment (17 versus 6 months; HR 0.32, 95% CI 0.14-0.74). By contrast, there was no difference in PFS in those with a BRCA mutation (median PFS, 19 versus 17 months; HR 0.55, 95% CI 0.24-1.27). Based on these results, a confirmatory phase III trial is being planned.

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, including the Foundation One, Caris Target Now, and SNaPshot technology [66,67]. 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 of chemosensitivity or resistance have been developed as a method to select the optimal chemotherapy regimen (sensitivity assays) or identify those agents least likely to be effective (resistance assays) [68,69]. In our view, utility and cost benefits of in vitro chemosensitivity and chemoresistance assays have not been clearly demonstrated, and prospective validation is required prior to routine clinical adoption. However, others disagree and use these assays to help in the selection of chemotherapy in patients with relapsed EOC. The role of these assays in EOC is covered separately. (See "First-line chemotherapy for advanced (stage III or IV) epithelial ovarian, fallopian tubal, and peritoneal cancer", section on 'In vitro chemosensitivity and resistance assays'.)

Heated intraperitoneal chemotherapy — The administration of heated intraperitoneal chemotherapy (HIPEC) is indicated for mucinous carcinomas such as appendiceal carcinoma and pseudomyxoma peritonei. Given the tendency of recurrent ovarian cancer to present as abdominal disease, there is growing interest in the use of HIPEC for women with recurrent EOC following surgical cytoreduction. However, we consider HIPEC an investigational modality for the treatment of patients with platinum-sensitive recurrent EOC.

The largest series evaluating HIPEC for recurrent EOC involved 246 patients (184 with platinum-sensitive recurrent EOC), 92 percent of whom underwent an optimal surgical cytoreduction [70]. HIPEC treatment resulted in a median overall survival (OS) of 49 months; for platinum-sensitive patients, it was 52 months. The median five-year OS rate for the entire cohort was 35 percent. There was a 12 percent incidence of serious (grade 3/4) complications, including leukopenia (3 percent), intra-abdominal hemorrhage (2 percent), and postoperative complications (5 percent), including one postoperative death due to an anastomotic leak resulting in peritonitis and acute renal failure.

These data illustrate the risks and the potential benefits associated with HIPEC for recurrent EOC. A randomized trial of HIPEC in recurrent EOC is underway. Until more data are available, we do not administer HIPEC treatment for recurrent EOC outside of a clinical trial. The administration of HIPEC in the treatment of appendiceal carcinoma and pseudomyxoma peritonei is discussed separately. (See "Cancer of the appendix and pseudomyxoma peritonei".)

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Beyond the Basics topics (see "Patient education: First-line medical treatment of epithelial ovarian cancer (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Despite initial therapy (usually consisting of surgical cytoreduction and platinum-taxane combination therapy), the majority of women with advanced-stage ovarian cancer will relapse and require additional treatment. (See 'Introduction' above.)

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). The PFI correlates with progression-free (PFS), overall survival (OS) and response to subsequent treatment (see 'Relevance of the platinum-free interval' above):

Patients with a PFI of six months or longer are considered to have platinum-sensitive disease.

Patients with a PFI of less than six months are considered to have platinum-resistant disease. (See "Medical treatment for relapsed epithelial ovarian, fallopian tubal, or peritoneal cancer: Platinum-resistant disease".)

Patients with platinum-sensitive recurrent EOC have a high probability of responding again to platinum-based treatment at the time of relapse and should be offered both secondary cytoreduction and second-line systemic therapy. (See 'Treatment' above.)

For women with platinum-sensitive ovarian cancer, we recommend treatment with a platinum-based regimen rather than a nonplatinum regimen (Grade 1B). Given improvements in progression-free and overall survival, we also suggest addition of bevacizumab (Grade 2B), although some women may opt to avoid it given the potential for added toxicity. We proceed with chemotherapy to best response or until unacceptable toxicity intervenes.

-Our preferred choice of platinum regimen is carboplatin plus paclitaxel, although carboplatin with gemcitabine may also be used. Additionally, for those who will not be treated with bevacizumab, carboplatin plus liposomal doxorubicin is an additional alternative, with lesser degrees of neuropathy and alopecia than carboplatin and paclitaxel.

For those receiving bevacizumab as part of their initial treatment, we suggest continuation of bevacizumab as maintenance treatment following best response to chemotherapy, rather than observation (Grade 2B).

For women in whom bevacizumab is not considered appropriate or was poorly tolerated, we proceed with chemotherapy alone. Following achievement of a response (either complete or partial), we suggest discontinuation of chemotherapy and the initiation of a poly-ADP ribose polymerase (PARP) inhibitor as maintenance therapy rather than observation (Grade 2B), although some patients may choose to avoid this treatment given its associated toxicities and the fact that survival data are still immature.

For women who are not candidates for treatment with carboplatin-based combinations, carboplatin as a single agent or one of the agents discussed above is reasonable. (See 'Single-agent therapy' above.)

For women with a known BRCA mutation who have progressed on multiple previous lines of chemotherapy, we suggest treatment with a poly-ADP ribose polymerase (PARP) inhibitor (Grade 2B). Both olaparib and rucaparib are approved for use in the United States in this setting, and the choice between them should be based on local availability.

For women who relapse solely by cancer antigen 125 (CA 125, with no evidence of disease on imaging and who are asymptomatic), we recommend surveillance (Grade 1B). For those who are not comfortable with surveillance, we suggest endocrine therapy rather than chemotherapy (Grade 2C). We reserve chemotherapy or other treatments for women who develop signs or symptoms related to recurrent EOC, or for those with significant growth on radiographic imaging in anticipation of preventing the onset of imminent symptoms. (See 'Recurrence based on CA 125 only' above and "First-line chemotherapy for advanced (stage III or IV) epithelial ovarian, fallopian tubal, and peritoneal cancer", section on 'Posttreatment surveillance'.)

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