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First-line chemotherapy for advanced (stage III or IV) epithelial ovarian, fallopian tube, and peritoneal cancer

First-line chemotherapy for advanced (stage III or IV) epithelial ovarian, fallopian tube, and peritoneal cancer
Literature review current through: May 2024.
This topic last updated: Jul 27, 2023.

INTRODUCTION — Epithelial cancers of ovarian, fallopian tube, and peritoneal origin exhibit similar clinical characteristics and behavior. As such, these are often combined together and define epithelial ovarian cancer (EOC) in clinical trials and clinical practice. This topic will consider all histologies under the heading EOC. EOC is the most common cause of death among women with gynecologic malignancies and the fifth leading cause of cancer death in women in the United States. Approximately 75 percent of women have stage III (disease that has spread throughout the peritoneal cavity or that involves lymph nodes) or stage IV (disease spread to more distant sites) disease at diagnosis. (See "Epithelial carcinoma of the ovary, fallopian tube, and peritoneum: Clinical features and diagnosis".)

Historically, the Gynecologic Oncology Group (GOG) has performed separate clinical trials for women with early (stages I and II disease) versus advanced (stages III and IV) disease. However, this separation of patient populations has not been consistent. Studies done in Canada, Europe, and elsewhere have defined patients with stage II disease or any patients requiring systemic therapy (regardless of stage) as having advanced EOC. More GOG trials included women with stage II disease as having advanced EOC. (See "Overview of epithelial carcinoma of the ovary, fallopian tube, and peritoneum", section on 'Prognosis'.)

Primary surgical cytoreduction followed by systemic chemotherapy is the preferred initial management for women with stage III or IV EOC. Patients who are not good candidates for surgery due to the location and volume of disease involvement or medical comorbidities at the time of diagnosis may be considered for neoadjuvant chemotherapy. (See "Epithelial carcinoma of the ovary, fallopian tube, and peritoneum: Surgical staging" and 'Neoadjuvant chemotherapy' below.)

First-line systemic chemotherapy for women with advanced EOC involving the abdomen (stage III) or extra-abdominal sites (eg, parenchymal liver or lung, stage IV) and post-treatment surveillance of EOC will be reviewed here. Initial surgical management, first-line therapy for women with early-stage (stage I or II) disease, and the treatment of patients with relapsed or refractory EOC are discussed separately.

(See "Overview of epithelial carcinoma of the ovary, fallopian tube, and peritoneum".)

(See "Epithelial carcinoma of the ovary, fallopian tube, and peritoneum: Surgical staging".)

(See "Adjuvant therapy of early-stage (stage I and II) epithelial ovarian, fallopian tube, or peritoneal cancer".)

(See "Medical treatment for relapsed epithelial ovarian, fallopian tube, or peritoneal cancer: Platinum-sensitive disease".)

(See "Medical treatment for relapsed epithelial ovarian, fallopian tube, or peritoneal cancer: Platinum-resistant disease".)

TIMING OF TREATMENT INITIATION — In general, we prefer to begin treatment as soon as feasible, usually within two to four weeks from surgery. While there are no high-quality data to inform the optimal timing for the initiation of first-line chemotherapy, limited data suggest that a delay of greater than approximately one month in instituting chemotherapy may be associated with a poorer outcome [1-3]. However, it is not clear whether it is the delay itself, or the clinical factors that are frequently associated with delay (such as medical comorbidities, surgical complications, delayed healing, malnourishment) that are responsible for the worse outcome.

TREATMENT SELECTION AND METHOD OF ADMINISTRATION

General principles — The standard approach to treatment for women requiring first-line chemotherapy for EOC is to use a platinum agent with a taxane. For women with optimally reduced disease (<1 cm of residual disease), there are two options: intravenous (IV) chemotherapy alone or a combination of IV and intraperitoneal (IP) chemotherapy (IV/IP therapy). Women with suboptimally reduced disease (≥1 centimeter of residual disease) are not candidates for IP therapy due to limited penetration into larger tumors. These women should therefore receive IV treatment. Further details regarding the modalities of treatment and specific regimens are found in the relevant sections below. (See 'Women with suboptimally cytoreduced disease' below and 'Choice of agents' below.)

The importance of platinum salts and taxanes was highlighted in a 2006 multiple-treatment meta-analysis that included 60 trials in women (n = 15,609) with EOC, which showed that a platinum-taxane combination improved survival when compared with [4]:

Platinum monotherapy (hazard ratio [HR] for mortality 1.16 favoring the combination, 95% CI 0.86-1.58)

A platinum plus non-taxane combination (HR for mortality 1.28 favoring platinum plus taxane, 95% CI 1.07-1.53)

For patients with a known mutation in breast cancer susceptibility gene 1 (BRCA1) or breast cancer susceptibility gene 2 (BRCA2) (BRCA carriers) who have responded to platinum-based chemotherapy (either complete or partial response), we suggest maintenance olaparib.

Additionally, expert guidelines suggest tumor testing for somatic BRCA mutations, as patients with these tumors may also derive greater benefit from certain therapies (eg, poly[ADP-ribose] polymerase [PARP] inhibitors) [5]. (See 'PARP inhibitors' below.)

Moreover, women diagnosed with clear cell, endometrioid, or mucinous ovarian cancer should be offered somatic tumor testing for mismatch-repair deficiency [5], 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'.)

Women with optimally cytoreduced disease

IV/IP therapy versus IV therapy alone

Comparative data — For women with optimally cytoreduced disease (no residual or less than 1 cm of residual disease) who have not received neoadjuvant treatment, IV/IP therapy is an appropriate option [6-9]. Some UpToDate experts prefer IV/IP treatment for optimally cytoreduced disease, while others prefer IV therapy, particularly given that other treatment options including bevacizumab and maintenance therapy with PARP inhibitors are also often included. (See 'Incorporation of angiogenesis inhibitors' below and 'Maintenance therapy' below.)

Support for intravenous/intraperitoneal (IV/IP) chemotherapy comes from randomized data comparing standard (rather than dose-dense) IV therapy with IV/IP treatment following primary cytoreductive surgery [6-9]. As examples:

In GOG 172, IV paclitaxel plus cisplatin was compared with IV paclitaxel/IP cisplatin and IP paclitaxel in 415 patients with stage III ovarian cancer and no residual mass greater than 1 cm [10]. Although only 42 percent of the patients in the IP group completed six cycles of the assigned therapy, those in the IV/IP group experienced better PFS than those in the IV group (24 versus 18 months, respectively). The median overall survival (OS) was also better in the IV/IP group (66 versus 50 months, respectively). Quality of life (QOL) was worse in the IP therapy group during and soon after treatment, but not one year after treatment.

A subsequent trial (iPocc) demonstrated a modest PFS benefit among patients receiving dose-dense IV paclitaxel and IP carboplatin versus dose-dense paclitaxel and carboplatin (23.5 versus 20.7 months; HR 0.83, 95% CI 0.69-0.99) [11]. IP catheter-related adverse events were reported in 10 percent of the IV/IP group.

However, in GOG 252, 1560 women with optimally cytoreduced stage II to III ovarian cancer were randomly assigned to one of several treatment arms with bevacizumab, including a dose-dense IV therapy arm (in which paclitaxel was administered weekly and carboplatin every three weeks, "IV therapy"); an IV/IP arm with paclitaxel IV and carboplatin IP ("IP carboplatin"); and an IV/IP arm with paclitaxel IV and cisplatin/paclitaxel IP ("IP cisplatin") [12]. Those receiving IV therapy experienced similar PFS (25 months) compared with either of the IV/IP therapy arms (PFS, 27 months for those assigned to IP carboplatin; PFS, 26 months for those assigned to IP cisplatin) [12]. Median OS for all enrolled was 76, 79, and 73 months, respectively, and median OS for stage II/III with no gross residual disease was 99 months, 105 months, and not reached (IV carboplatin, IP carboplatin, IP cisplatin, respectively). Neurotoxicity, abdominal discomfort, and reported QOL were all worse among patients receiving IV/IP therapy with cisplatin.

Differences in GOG 252 in comparison with GOG 172 and iPocc included that all treatment arms in GOG 252 also received bevacizumab [10]. Additionally, for the arm receiving cisplatin in GOG 252, it was dosed at 75 mg/m2 versus 100 mg/m2. Furthermore, paclitaxel was infused over 3 hours instead of 24 hours. Interpretation of GOG 252 is limited by several factors. Firstly, 28 percent of patients crossed over from the IV/IP paclitaxel and cisplatin arm to the dose-dense IV therapy arm, which may have diluted any potential PFS benefit with IV/IP treatment. Secondly, the effect of the addition of bevacizumab to all arms is unknown.

Preferred IV/IP therapy regimen — The most commonly used intravenous/intraperitoneal (IV/IP) regimen comes from GOG 172 and consists of six cycles of [10] (see "Treatment protocols for gynecologic malignancies", section on 'Gynecologic Oncology Group (GOG) 172 regimen (intravenous [IV] paclitaxel followed by intraperitoneal [IP] cisplatin and IP paclitaxel)'):

IV paclitaxel (135 mg/m2 over 24 hours) on day 1

IP cisplatin (100 mg/m2 in a liter of normal saline) on day 2

IP paclitaxel (60 mg/m2) on day 8

We typically use the above regimen, with the exception of reducing cisplatin to 75 mg/m2, which was the regimen used in GOG 252 [12,13], discussed in further detail below. (See 'IV/IP therapy versus IV therapy alone' above.)

The administration of further treatment for patients who respond (or do not progress) after six cycles of first-line therapy (ie, maintenance therapy) is covered below. (See 'Maintenance therapy' below.)

The GOG explored a modification to this schedule in a phase I feasibility trial (GOG 9921) [14]. Twenty women with newly diagnosed EOC were treated with paclitaxel (135 mg/m2 over three hours on day 1) immediately followed by cisplatin (75 mg/m2 IP on day 1) and paclitaxel (60 mg/m2 IP on day 8). As reported, 19 patients (95 percent) completed all six planned cycles. The dose-limiting toxicities consisted of a urinary tract infection with normal neutrophil count, grade 4 abdominal pain, and grade 3 hyperglycemia. The authors concluded that this modification represented a feasible alternative to GOG 172. As with other phase 1 trials, efficacy cannot be directly compared with other regimens, including GOG 172. Technical aspects in the placement of an IP port are covered separately. (See "Intraperitoneal chemotherapy for treatment of ovarian cancer".)

The feasibility of IP carboplatin has also been evaluated in early clinical trials [15-19], and data from GOG 252 suggest that IP therapy using carboplatin may be a possible alternative to IP cisplatin, with similar PFS and patient-reported outcomes [12]. This trial is discussed in further detail above. (See 'IV/IP therapy versus IV therapy alone' above.)

Preferred IV therapy regimen — For patients with optimally cytoreduced disease in whom intravenous (IV) therapy will be administered, choice of agents and scheduling is the same as for those with suboptimally cytoreduced disease, and is discussed below. (See 'Choice of agents' below and 'Dose-dense versus conventionally dosed IV therapy' below and 'Incorporation of angiogenesis inhibitors' below.)

Further details of IV regimens for ovarian cancer are discussed elsewhere. (See "Treatment protocols for gynecologic malignancies", section on 'Regimens for ovarian cancer'.)

Incorporation of HIPEC — For patients who undergo neoadjuvant chemotherapy and have an optimal surgical result (ie, residual disease <1 cm), incorporation of HIPEC is discussed separately. (See "Patient selection and approach to neoadjuvant chemotherapy for newly diagnosed advanced ovarian cancer", section on 'Heated intraperitoneal chemotherapy at surgery'.)

Women with suboptimally cytoreduced disease — For patients with suboptimally cytoreduced EOC, we suggest IV treatment rather than IV/IP therapy. (See 'Dose-dense versus conventionally dosed IV therapy' below.)

Choice of agents — For women requiring first-line chemotherapy for EOC, the standard IV regimen utilizes platinum and taxane agents. For select patients at higher risk of recurrence (eg, those with pleural effusions or ascites who lack a BRCA mutation), we suggest the addition of bevacizumab, which is administered with chemotherapy and continued as maintenance therapy. (See 'Incorporation of angiogenesis inhibitors' below.)

Although cisplatin [20] and/or docetaxel [21] are sometimes used in this setting, we prefer carboplatin plus paclitaxel. Our rationale is based on the following:

We prefer carboplatin rather than cisplatin because multiple trials have consistently demonstrated that carboplatin produces equivalent response rates and survival outcomes to cisplatin, but is associated with less toxicity [22-27].

Although both paclitaxel and docetaxel (the most commonly used taxanes for EOC) can be administered along with carboplatin in this setting, we prefer paclitaxel because it is less myelosuppressive than docetaxel. However, a consideration between these two taxanes can be individualized based on their differing toxicities [21]. For paclitaxel, these include a higher risk of neuropathy, myalgias, and weakness compared with docetaxel; for docetaxel, these include a higher risk of neutropenia, hypersensitivity reactions, and nausea and vomiting.

We prefer to treat for a maximum of six cycles rather than more because there are no data that treatment beyond six cycles improves outcomes, although further treatment increases the risk of treatment-related toxicities [28-30]. The administration of further treatment for patients who respond (or do not progress) after six cycles of first-line therapy (ie, maintenance therapy) is covered below. (See 'Maintenance therapy' below.)

A 2013 meta-analysis suggested that carboplatin plus pegylated liposomal doxorubicin would be a reasonable alternative to carboplatin plus paclitaxel [31]. However, the data consisted of two trials and only 820 women. Given the limited data available in this meta-analysis compared with the 2006 meta-analysis above, we advocate continued use of carboplatin plus paclitaxel in this setting unless paclitaxel is contraindicated. (See 'Treatment selection and method of administration' above.)

In addition, attempts to incorporate additional chemotherapy agents into first-line treatment of EOC have not been successful. Multiple phase III trials have not shown a survival benefit with the addition of a third agent (including doxorubicin, epirubicin, topotecan, interferon gamma) to the carboplatin plus paclitaxel backbone [32-38]. Trials evaluating more intensive regimens, including high-dose chemotherapy and hematopoietic cell transplantation, have not shown a survival advantage in clinical trials. As an example, a phase III trial of 149 patients with untreated EOC randomly assigned treatment following surgery to standard combination therapy or high-dose treatment with two cycles of cyclophosphamide and paclitaxel followed by three cycles of high-dose carboplatin and paclitaxel with autologous hematopoietic cell transplantation (HCT) [39]. For example, although median PFS was prolonged with high-dose chemotherapy in one trial compared with standard therapy (30 versus 21 months, respectively), this did not translate into an improvement in OS (median, 54 versus 63 months).

Dose-dense versus conventionally dosed IV therapy — Dose-dense intravenous (IV) therapy refers to administering chemotherapy with less time between treatments, which typically in ovarian cancer refers to use of a weekly schedule. It typically refers to one of two regimens:

Carboplatin administered every three weeks with paclitaxel administered weekly [40-43]

Both carboplatin and paclitaxel administered weekly [43,44]

For most patients, we suggest conventional dosing. (When bevacizumab is administered, it is administered with a conventionally dosed regimen.) An exception is for medically frail patients. Given overall better tolerability with the modified dose-dense regimen used in MITO-7 (ie, a lower dose of weekly paclitaxel than in other dose-dense regimens) [44], we consider this regimen for medically frail patients. (See 'Incorporation of angiogenesis inhibitors' below.)

There is no consensus on the role of dose-dense versus conventionally dosed therapy; although in one trial largely in Japanese patients, dose-dense therapy improved PFS relative to conventional therapy, in more recent studies in patients outside of Japan, efficacy is not improved with dose-dense treatment, and toxicity is often greater.

The randomized trials evaluating conventional versus dose-dense IV therapy are reviewed below. These studies included women with both suboptimally and optimally reduced disease. Comparison of dose-dense IV therapy versus IV/IP therapy for patients with optimally reduced disease only is discussed elsewhere. (See 'IV/IP therapy versus IV therapy alone' above.)

ICON8 – ICON8 randomized almost 1600 patients to treatment with six cycles of either the standard every-three-week dosing regimen (carboplatin at area under the curve [AUC] 5/6 plus paclitaxel at 175 mg/m2, arm 1), or with one of two different regimens including once weekly carboplatin and dose-dense paclitaxel (carboplatin at AUC 5/6 plus paclitaxel at 80 mg/m2 weekly, arm 2; and carboplatin at AUC 2 plus paclitaxel at 80 mg/m2 both weekly, arm 3) [45].

PFS was similar across all treatment arms (24.9 and 25.3 months in arms 2 and 3, respectively, versus 24.4 months in arm 1).

The rate of severe toxicity was higher with the dose-dense arms (62 and 53 percent for arms 2 and 3, respectively, versus 42 percent for arm 1). Patients receiving weekly treatment also reported lower mean QOL across the nine-month period after randomization [46].

These results are in contrast with Japanese Gynecologic Oncology Group (JGOG) 3016, discussed below, which may be due to pharmacogenomic differences between ethnic groups, given that ICON8 enrolled primarily European patients and JGOG 3016 enrolled mostly Japanese patients.

JGOG 3016 trial – In JGOG 3016, 631 women, approximately half of whom had optimal cytoreduction, were randomly assigned to treatment with carboplatin and paclitaxel (every three weeks) or to carboplatin (every three weeks) with weekly paclitaxel. In both arms, the regimen was repeated every three weeks for up to nine cycles [40,41]. With a median follow-up of 77 months, dose-dense therapy resulted in [41]:

A significant improvement in PFS (median, 28 versus 17.5 months, respectively; HR 0.76, 95% CI 0.62-0.91) and OS (median, 100.5 versus 62 months; HR 0.79, 95% CI 0.63-0.99) compared with conventional treatment.

Women with at least 1 cm of residual disease following surgical cytoreduction appeared to benefit the most from dose-dense therapy. Compared with conventional treatment every three weeks, dose-dense treatment resulted in an improvement in PFS (median, 17.6 versus 12 months; HR 0.71, 95% CI 0.56-0.89) and OS (median, 51 versus 33 months; HR 0.75, 95% CI 0.57-0.97). There was no significant advantage to dose-dense treatment for patients with optimally cytoreduced disease.

Subgroup analysis showed that the schedule of treatment did not influence survival outcomes for patients with clear-cell or mucinous cancers [41]. However, for women with serous and other histologic types, dose-dense therapy improved both PFS (median, 28.7 versus 17.5 months; HR 0.70, 95% CI 0.57-0.86) and OS (median, 100.5 versus 61.2 months; HR 0.76, 95% CI 0.59-0.97) compared with conventional therapy.

Despite these survival outcomes, treatment with the dose-dense schedule resulted in [40]:

A higher rate of treatment discontinuation for toxicity (52 versus 37 percent) and higher proportion of patients who had at least one treatment cycle delayed because of toxicity (76 versus 67 percent).

A similar frequency of severe (grade 3 or 4) non-hematologic toxicity (including neurotoxicity), although there was no difference in the rate of febrile neutropenia (9 percent in both groups).

GOG 262 – In GOG 262, women with stage II to IV EOC who had either optimal or suboptimally cytoreduced disease were randomly assigned to conventionally dosed carboplatin and paclitaxel or to dose-dense therapy (carboplatin every three weeks plus weekly paclitaxel) [42]. Bevacizumab administration was optional in both arms and was administered to 84 percent of patients. The majority of patients had stage III or IV disease (67 and 30 percent, respectively). At enrollment, residual disease was grossly present in 63 percent, microscopic in 24 percent, and not assessed in 13 percent of patients.

At a median follow-up of 28 months, there was no difference in PFS between the dose-dense and the conventionally dosed treatment groups (15 versus 14 months, respectively; HR for disease progression or death 0.89, 95% CI 0.74-1.06).

While the study was negative overall, subset analysis suggested a treatment difference based on whether or not bevacizumab was administered:

Among patients treated with chemotherapy only (n = 112), dose-dense treatment prolonged PFS compared with conventional dosing (median, 14 versus 10 months; HR 0.62, 95% CI 0.40-0.95).

Among patients treated with chemotherapy and bevacizumab (n = 580), PFS was similar among those treated with dose-dense versus conventionally dosed treatment (median, 15 months in both arms; HR 0.99, 95% CI 0.83-1.20).

MITO-7 trial – In the MITO-7 randomized trial, over 800 women with stage IC to IV EOC were treated with a total of six cycles using carboplatin (AUC 6 mg/mL per min) and paclitaxel (175 mg/m2) on either a standard (every three weeks) schedule versus a modified dose-dense regimen, with both agents delivered on a weekly schedule (carboplatin AUC 2 mg/mL and paclitaxel 60 mg/m2 on days 1, 8, and 15 every 21 days). This dose of paclitaxel is 20 percent less than in other studies [44]. Compared with standard treatment, weekly treatment resulted in:

Similar PFS (18 versus 17 months; HR 0.96, 95% CI 0.80-1.16) at a median follow-up of 22 months

No difference in the estimated probability of survival at 24 months (77 versus 79 percent; HR 1.20, 95% CI 0.90-1.61)

QOL scores were worse after every chemotherapy cycle in the every-three-week arm. By contrast, while there was a transient worsening in QOL after the first treatment in those undergoing weekly therapy, scores subsequently remained stable. In addition, weekly treatment was associated with lower rates of serious (grade 3/4) neutropenia (42 versus 50 percent), febrile neutropenia (0.5 versus 3 percent), thrombocytopenia (1 versus 7 percent), and neuropathy (6 versus 17 percent).

Incorporation of angiogenesis inhibitors — The incorporation of angiogenesis inhibitors with chemotherapy and subsequently as maintenance therapy in select women is discussed below. (See 'Angiogenesis inhibition' below.)

SPECIAL CONSIDERATIONS

Neoadjuvant chemotherapy — For women with advanced EOC who are poor candidates to withstand an aggressive initial surgical cytoreduction or for those with extensive disease that will preclude up-front optimal cytoreduction (to <1 cm of residual disease), we suggest neoadjuvant chemotherapy, in accordance with existing guidelines [47]. Examples of disease that may be best managed with neoadjuvant therapy due to inability to obtain optimal cytoreduction include tumor that involves the porta hepatis, has metastasized to the liver or lungs, or that causes massive ascites. The role of neoadjuvant chemotherapy for EOC is discussed separately. (See "Patient selection and approach to neoadjuvant chemotherapy for newly diagnosed advanced ovarian cancer".)

Neoadjuvant chemotherapy followed by heated intraperitoneal (IP) therapy (HIPEC) at the time of interval debulking surgery is discussed elsewhere. (See "Patient selection and approach to neoadjuvant chemotherapy for newly diagnosed advanced ovarian cancer", section on 'Heated intraperitoneal chemotherapy at surgery'.)

In vitro chemosensitivity and resistance assays — In vitro assays of chemosensitivity or resistance, such as the Chemo-FX assay or the extreme drug resistance (EDR) assay [48,49], are laboratory tests that 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). However, the utility of these assays has not been prospectively validated, and cost benefits have not been clearly demonstrated. We agree with the American Society of Clinical Oncology that concluded that the evidence is insufficient to justify the routine use of any of these assays outside of the clinical trial setting and that oncologists should make chemotherapy treatment recommendations on the basis of published clinical trial reports while taking into account an individual patient’s treatment preferences [50].

EVALUATION AFTER ADJUVANT CHEMOTHERAPY — Evaluation of women after adjuvant chemotherapy varies depending upon clinician preference. At the completion of treatment, we perform a history and physical (including pelvic) examination and cancer antigen (CA) 125. Imaging such as computed tomography (CT) of the chest, abdomen, and pelvis may be utilized as well, especially in those who do not have an informative biomarker (eg, CA 125). Although second-look laparotomy has been used in the past to define pathologic response, results of second-look laparotomy are not associated with prognosis. We recommend against a second-look operation at the end of first-line chemotherapy.

If the results of the post-treatment evaluation are normal, then a patient is considered to have a clinical complete response. However, if there is evidence of residual cancer by exam or CT, or if the CA 125 does not return to normal levels, women are considered to have platinum-resistant disease (sometimes referred to as primary refractory epithelial ovarian cancer [EOC]). Treatment of women with platinum-resistant disease is discussed separately. (See "Medical treatment for relapsed epithelial ovarian, fallopian tube, or peritoneal cancer: Platinum-resistant disease".)

MAINTENANCE THERAPY

BRCA-associated and other homologous recombination-deficient cancers — The use of maintenance therapy in patients with breast cancer susceptibility gene (BRCA)-associated cancers, or other homologous repair-deficient (HRD) cancers, is discussed elsewhere. (See "Management of ovarian cancer associated with BRCA and other genetic mutations", section on 'PARP inhibitor maintenance therapy' and "Management of ovarian cancer associated with BRCA and other genetic mutations", section on 'Other homologous recombination deficiencies'.)

BRCA-wildtype cancers that are homologous recombination proficient

Approach — For women with a serous or high-grade, endometrioid ovarian cancer completing first-line chemotherapy with a complete or partial response, we suggest the poly(ADP-ribose) polymerase (PARP) inhibitor niraparib following chemotherapy, in accordance with guidelines from the American Society of Clinical Oncology [51], although observation only or bevacizumab maintenance are reasonable alternatives. This is based on clinical trials showing that use of a PARP inhibitor as maintenance therapy affords a progression-free survival (PFS) advantage [52-55], even to women without a breast cancer susceptibility gene 1/2 (BRCA1/2) mutation. Whether it affords an overall survival (OS) advantage has not been reported, as data are immature. The largest benefit in the absence of a BRCA1/2 mutation has been seen in women who had evidence of HRD, although women without HRD still derived a modest benefit. Data in the subset of patients with a BRCA1/2 mutation or HRD are discussed elsewhere. (See "Management of ovarian cancer associated with BRCA and other genetic mutations", section on 'Other homologous recombination deficiencies'.)

As mentioned above, another option for maintenance in front-line ovarian cancer is to add a PARP inhibitor to bevacizumab, which we offer to a select group of women with high-risk cancers. Data regarding angiogenesis inhibition are discussed below. (See 'Angiogenesis inhibition' below.)

When using PARP inhibitors, we typically initiate as maintenance following chemotherapy, as data have not suggested improvements over chemotherapy alone when PARP inhibition is added to initial treatment with chemotherapy [52]. (See 'PARP inhibitors' below.)

PARP inhibitors

Efficacy — Examples of trials evaluating maintenance poly(ADP-ribose) polymerase (PARP) inhibition are summarized below [52-55], according to agent. The optimal agent in this setting is not clear, as no comparative efficacy trials have been completed. Although niraparib was the first PARP inhibitor to show benefits regardless of HRD status, subsequent data have revealed similar improvements with rucaparib; however, rucaparib does not have regulatory approval in the frontline setting. Olaparib has not shown PFS benefits in those with tumors lacking HRD in the frontline setting, nor does it have regulatory approval for this indication.

Niraparib – PFS benefits have been observed in a trial evaluating maintenance with the PARP inhibitor niraparib (PRIMA) [53]. Among 733 patients with newly diagnosed, advanced ovarian cancer and a response to platinum-based chemotherapy, PFS for those randomly assigned 2:1 to maintenance niraparib was 13.8 versus 8.2 months in the placebo group (hazard ratio [HR] 0.62, 95% CI 0.50-0.76). The primary endpoint for the study was from those patients who were HRD positive, which is discussed in detail elsewhere. (See "Management of ovarian cancer associated with BRCA and other genetic mutations", section on 'Other homologous recombination deficiencies'.)

Among 249 patients whose tumors lacked both a BRCA mutation and HRD, PFS was also improved with niraparib. However, improvement occurred to a lesser extent than in the overall study population (8.1 versus 5.4 months, HR 0.68, 95% CI 0.49-0.94).

Niraparib was associated with more frequent ≥grade 3 adverse events (AEs), including anemia (31 percent), thrombocytopenia (29 percent), and neutropenia (13 percent), all of which occurred in fewer than 2 percent of patients assigned to placebo. Individualized dosing based on pretherapy weight and platelet counts was introduced approximately two-thirds through the trial and decreased hematologic toxicity [56]. Discontinuation rate due to AEs was 12 percent.

Rucaparib – In a randomized trial (ATHENA) in 538 women with newly diagnosed stage III to IV, high-grade ovarian cancer undergoing surgical cytoreduction and responding to first-line platinum-doublet chemotherapy, those assigned to maintenance with rucaparib experienced improvement in PFS relative to the placebo group (20 versus 9.2 months, HR 0.52, 95% CI 0.40-0.68) [57]. Benefits were observed both in those with HRD tumors (29 versus 11 months, HR 0.47, 95% CI 0.31-0.72) as well as those lacking HRD, although benefits were lesser in this group (12 versus 9.1 months, HR 0.65, 95% CI 0.45-0.95). The second objective of the ATHENA trial, to test the value of adding nivolumab to PARP inhibitors, will be reported after further data maturation.

The most common grade ≥3 treatment-emergent adverse events were anemia (29 versus 0 percent) and neutropenia (15 versus 0.9 percent).

Olaparib – Although maintenance olaparib has been studied in patients with BRCA-associated ovarian cancer after a response to first-line platinum-based chemotherapy and as combination therapy with bevacizumab in patients completing first-line chemotherapy plus bevacizumab, there are no data to determine its effectiveness as a single agent in people whose tumors lack HRD.

In a randomized trial (PAOLA-1) of 806 women with newly diagnosed stage III to IV, high grade, serous or endometrioid EOC who had experienced a response to platinum-based chemotherapy plus bevacizumab, patients were randomly assigned 2:1 to olaparib and bevacizumab maintenance versus placebo and bevacizumab maintenance. Those assigned to olaparib and bevacizumab had improved median PFS (22.1 versus 16.6 months; HR 0.59, 95% CI 0.49-0.72) [54], with a trend towards improvement in median OS (57 versus 52 months; HR 0.92, 95% CI 0.76-1.12) [58]. Among patients with BRCA wildtype tumors with HRD, there was a benefit, as discussed elsewhere. (See "Management of ovarian cancer associated with BRCA and other genetic mutations", section on 'PARP inhibitor maintenance therapy'.)

However, among patients with negative or unknown HRD status, there was no benefit with the addition of olaparib to bevacizumab (median PFS was 16.9 versus 16 months with and without olaparib, respectively; HR 0.92, 95% CI 0.72-1.17).

Grade ≥3 AEs occurred in 57 percent of those receiving olaparib-bevacizumab and 51 percent of those receiving bevacizumab alone, with the most frequent ones being hypertension (19 versus 30 percent) and anemia (17 versus <1 percent). Discontinuation rate for AEs was 20 versus 6 percent, respectively.

Veliparib, another PARP inhibitor, has also been evaluated [52], but is not clinically available.

Adverse effects — In general, PARP inhibitors are well tolerated, but are associated with nausea, fatigue, and hematologic abnormalities, including anemia and thrombocytopenia, as described in the trials above. These adverse effects are typically mild. However, an association with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) has also been observed. We counsel patients about these risks prior to initiation of treatment and monitor complete blood count routinely during treatment.

Trials of PARP inhibitors as maintenance treatment in ovarian cancer have shown rates of MDS/AML ranging from approximately 1 percent in some trials [54] to as high as 8 percent in SOLO2 (versus 4 percent in the placebo group) (table 1) [59]. Meta-analyses of randomized trials in patients receiving PARP inhibitors for a variety of cancers have also shown an association [60,61].

The sum of data suggests that PARP inhibitors result in a small absolute increase in MDS/AML; therefore, hematologic monitoring is necessary.

Angiogenesis inhibition — While several trials suggest that maintenance angiogenesis inhibition after the completion of chemotherapy improves PFS compared with surveillance only, there has been no demonstrable improvement in OS. Therefore, we do not administer angiogenesis inhibitors routinely in this context. However, we do suggest their use with chemotherapy and as maintenance for select patients with a high risk of recurrence (eg, ascites, pleural effusion). Bevacizumab in combination with PARP inhibition as maintenance is discussed above. (See 'BRCA-wildtype cancers that are homologous recombination proficient' above.)

Bevacizumab — While only modest benefits have been demonstrated in randomized, first-line trials for bevacizumab, it is approved by the US Food and Drug Administration in front-line treatment. We suggest its use, in addition to conventionally dosed IV chemotherapy and as maintenance, in select patients without a known mutation in BRCA1 or BRCA2 who have a high risk of recurrence (eg, those with pleural effusions or ascites). Although a risk score has been devised to identify patients with chemoresistant tumors, who may therefore benefit from bevacizumab, it requires prospective validation prior to routine clinical use [62]. The management of those who carry a mutation in BRCA1 or BRCA2 is discussed elsewhere. (See 'PARP inhibitors' above.)

The activity of angiogenesis inhibitors and other vascular endothelial growth factor (VEGF)-targeting agents in the treatment of recurrent EOC is discussed separately. (See "Medical treatment for relapsed epithelial ovarian, fallopian tube, or peritoneal cancer: Platinum-resistant disease", section on 'Addition of bevacizumab' and "Medical treatment for relapsed epithelial ovarian, fallopian tube, or peritoneal cancer: Platinum-sensitive disease", section on 'Angiogenesis inhibitors'.)

The incorporation of bevacizumab as part of a first-line treatment program for women with newly diagnosed EOC was evaluated in two trials conducted by Gynecologic Oncology Group (GOG) 218 and ICON 7:

GOG 218 – GOG 218 was a randomized, placebo-controlled study involving almost 1900 women with stage III or IV EOC who had undergone surgical cytoreduction [63]. Women were randomly assigned to standard IV chemotherapy, bevacizumab concurrently with standard chemotherapy, or bevacizumab concurrently with standard chemotherapy and continuing as monotherapy until month 15. Standard chemotherapy consisted of six cycles of paclitaxel and carboplatin. Due to progressive disease, only 19 percent of patients completed all planned treatment.

At a median follow-up of 17 months, compared with standard chemotherapy, there was no difference in PFS with the addition of concurrent bevacizumab (11 versus 10 months). However, PFS was longer among patients receiving bevacizumab both concurrently and after chemotherapy (14 months). This translated into a significant reduction in the risk of disease progression or death (HR 0.72, 95% CI 0.63-0.82). At a median follow-up of 103 months, there was no improvement in OS with bevacizumab in either arm receiving the drug; median OS across all arms was approximately 41 months [64]. Subsequent subgroup analyses demonstrated, however, that concurrent maintenance treatment with bevacizumab improved PFS and OS specifically in women with ascites [65], and those with stage IV disease (43 versus 33 months; HR 0.75, 95% CI 0.59-0.95) [64], but not in women with stage III disease.

Although actual cost data were not collected in GOG 218, a subsequent modeled cost-effectiveness analysis using the available data on PFS and OS concluded that the cost-effectiveness ratio for the addition of bevacizumab to standard chemotherapy was unfavorable [66].

ICON7 – ICON7 randomly assigned 1528 previously untreated women with high-risk, early-stage (I or IIA clear cell or grade 3) or advanced EOC to standard IV chemotherapy (carboplatin area under the curve [AUC] 5 or 6 and paclitaxel 175 mg/m2) for six cycles with or without bevacizumab (7.5 mg/kg) during chemotherapy and then as maintenance treatment for 12 additional cycles [67,68]. Unlike GOG 218, over 90 percent of patients completed assigned treatment. Of those assigned to treatment with bevacizumab, 62 percent completed the maintenance phase.

Compared with standard chemotherapy, the incorporation of bevacizumab resulted in an increase in the overall response rate (67 versus 48 percent), a longer median PFS at 42-months follow-up (24 versus 22 months), and more serious (grade 3/4) AEs (66 versus 56 percent), including a higher rate of mild to serious (grade 2 or higher) hypertension (18 versus 2 percent) [68]. There was no difference in OS or global quality of life.

For women at high risk for progression (stage III with >1.0 cm residual disease at the end of surgery, inoperable stage III, or stage IV), bevacizumab was associated with improvement in PFS (16 versus 10.5 months, respectively) and OS (39.3 versus 34.5 months) [67]. However, this analysis was a post-hoc subgroup analysis and requires prospective validation before being accepted as a definitive result.

A more specific discussion on the toxicities of these agents in general is covered separately. (See "Cardiovascular toxicities of molecularly targeted antiangiogenic agents" and "Non-cardiovascular toxicities of molecularly targeted antiangiogenic agents".)

Others

PazopanibPazopanib is an orally administered tyrosine kinase inhibitor against the VEGF, platelet-derived growth factor (PDGF), and c-kit receptors. Its role in maintenance treatment was evaluated in a trial conducted by the Arbeitsgemeinschaft Gynaekologische Onkologie Studiengruppe Ovarialkarzinom group (AGO-OVAR 16) that included over 900 women who had surgery for EOC and subsequently completed standard first-line chemotherapy without evidence of disease progression [69]. Patients were randomly assigned to pazopanib (800 mg daily) for up to 24 months or placebo. Compared with placebo, maintenance treatment with pazopanib resulted in a significant improvement in PFS (18 versus 12 months, respectively; HR 0.766, 0.64-0.91). However, there was no corresponding improvement in OS [70]. Treatment with pazopanib was associated with significant grade 2 or greater hypertension (52 versus 17 percent), grade 3 or 4 diarrhea (8 versus 1 percent), and grade 3 or 4 hepatotoxicities (9 versus <1 percent).

Unlike the bevacizumab trials, the AGO-OVAR 16 was the only prospective trial to evaluate maintenance angiogenesis inhibition as a single agent at the completion of first-line chemotherapy. However, it provides more evidence that maintenance therapy using an angiogenesis inhibitor can prolong PFS. However, until this is shown to also improve OS, we do not administer angiogenesis inhibitors in this context as part of standard clinical practice.

NintedanibNintedanib is an orally administered tyrosine kinase inhibitor against the VEGF, fibroblast growth factor (FGF), and PDGF receptors. In a study performed by the AGO, over 1300 patients received standard front-line chemotherapy with carboplatin plus paclitaxel and were randomly assigned to treatment with nintedanib or placebo [71]. Compared with placebo, the incorporation of nintedanib modestly improved PFS (median, 17.3 versus 16.6 months; HR 0.84, 95% CI 0.72-0.98). Further follow-up is ongoing for its impact on OS. Serious (grade 3 to 5) toxicities more common among patients treated with nintedanib included:

Thrombocytopenia (18 versus 6 percent with placebo)

Anemia (14 versus 7 percent)

Neutropenia (42 versus 36 percent)

Diarrhea (22 versus 2 percent)

Fatigue (7 versus 3 percent)

Hypertension (5 versus 0.4 percent)

Hepatic transaminitis (16 versus 3 percent)

No role for maintenance chemotherapy — The majority of patients with EOC achieve a complete clinical remission with first-line chemotherapy, but the majority will recur. This has led to trials of maintenance or consolidation therapy to improve the percentage of women who remain relapse free. These efforts have focused on therapeutic vaccines; the continuation of chemotherapy beyond the standard six cycles (maintenance chemotherapy); and short-term, high-dose strategies (ie, intraperitoneal [IP] therapy, both alone and in combination with intravenous [IV] therapy). However, the data suggest that maintenance chemotherapy does not improve survival outcomes following completion of first-line therapy [72,73].

This was shown in a meta-analysis of six randomized trials (n = 902) that concluded there was no significant improvement in five-year OS to justify the administration of maintenance chemotherapy (relative risk 1.07, 95% CI 0.91-1.27) [72]. In addition, randomized trials evaluating therapeutic vaccines as a maintenance strategy have shown no benefit in either relapse-free survival or OS compared with placebo preparations [74,75].

POST-TREATMENT SURVEILLANCE — Post-treatment surveillance, including the role of cancer antigen (CA) 125 measurements, for women who have completed treatment for ovarian cancer is discussed separately. (See "Overview of epithelial carcinoma of the ovary, fallopian tube, and peritoneum", section on 'Posttreatment surveillance'.)

TREATMENT OF RECURRENT DISEASE — The overall likelihood of relapse after initial therapy for all stages of disease for women with EOC is 62 percent; it is 80 to 85 percent for women who present with stage III or IV disease.

Recurrence can be detected either serologically using tumor markers (eg, cancer antigen [CA] 125) and/or by the development of clinical or radiologic signs of progression. Based on the results of the MRC 05 study, we recommend retreatment based on signs and/or symptoms of relapsed EOC and not treating a rising CA 125 alone. (See "Overview of epithelial carcinoma of the ovary, fallopian tube, and peritoneum", section on 'CA 125 surveillance'.)

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):

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

The PFI as a predictor of outcome was illustrated in a report on 72 patients with measurable disease recurrence who had received at least two cisplatin- or carboplatin-based regimens and who had a PFI of at least four months [76]. For those with a PFI between 5 and 12 months, the overall response rate and complete response rate was 27 and 5 percent, respectively; for women with a PFI 13 to 24 months, it was 33 and 11 percent, respectively; and for those with a PFI >24 months, it was 59 and 22 percent, respectively. Although this study suggests that a 12-month cutoff may be used for the PFI, international consensus and other studies have moved towards using a cutoff of six months instead. Other factors have emerged as determinants of outcome and therapy choice in recurrent ovarian cancer such as breast cancer susceptibility gene (BRCA) mutational status, histology, and other genetic features [77].

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 5th to 6th 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 10th to 12th 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: Ovarian cancer diagnosis and staging (Beyond the Basics)" and "Patient education: Treatment of ovarian cancer (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Introduction

Epithelial cancers of ovarian, fallopian tube, and peritoneal origin exhibit similar clinical characteristics and behavior and are referred to as epithelial ovarian cancer (EOC). EOC is the most common cause of death among women with gynecologic malignancies and the fifth leading cause of cancer death in women in the United States. Approximately 75 percent of cases are stage III (spread throughout the peritoneal cavity or involving lymph nodes) or stage IV (spread to more distant sites). (See 'Introduction' above.)

Advanced-stage EOC is initially treated with surgical cytoreduction followed by first-line therapy. A choice among first-line treatments is made based upon the amount of disease remaining after surgery. Patients with <1 cm of disease in any one location are considered to have optimally cytoreduced EOC. All other patients have suboptimally cytoreduced disease. (See 'Introduction' above.)

Administration of chemotherapy

Choice of agent

-For all patients with advanced EOC, we recommend a platinum-plus-taxane combination rather than alternative regimens in the first-line setting (Grade 1B). (See 'Choice of agents' above.)

-For patients at higher risk of recurrence (eg, those with pleural effusions or ascites) we also suggest the addition of bevacizumab (Grade 2C), which is administered with a conventionally dosed IV chemotherapy regimen, followed by maintenance administration. However, given an unclear effect on overall survival advantage, even in this high-risk subset, and the relative contribution in the setting of combined treatment with a PARP inhibitor, some patients may reasonably opt to avoid bevacizumab. (See 'Angiogenesis inhibition' above.)

Route of administration – For women with optimally cytoreduced EOC, either intravenous/intraperitoneal (IV/IP) or IV only chemotherapy are appropriate options. (See 'Women with optimally cytoreduced disease' above.)

Women with suboptimally cytoreduced EOC are not appropriate candidates for IP treatment because IP administration of chemotherapy results in limited penetration into larger tumors and reduced effectiveness of treatment. Therefore, IV therapy is administered for most such women in this subgroup.

Dosing considerations – For most patients, we suggest conventional rather than dose-dense treatment (Grade 2C), although for frail patients, a modified dose-dense schedule may be preferable, as per the MITO-7 protocol. (See 'Dose-dense versus conventionally dosed IV therapy' above.)

Neoadjuvant administration for select patients – For women with advanced EOC who are not good surgical candidates, or in women who appear unlikely to have tumor that will be optimally cytoreduced, we administer neoadjuvant chemotherapy. (See 'Neoadjuvant chemotherapy' above.)

Maintenance therapy – After a response to initial treatment with chemotherapy:

For women with advanced ovarian cancer associated with a mutation in breast cancer susceptibility gene 1 (BRCA1) or breast cancer susceptibility gene 2 (BRCA2), or with homologous recombination deficiency (HRD), maintenance therapy with an inhibitor of poly(ADP-ribose) polymerase (PARP) is discussed elsewhere. (See "Management of ovarian cancer associated with BRCA and other genetic mutations", section on 'PARP inhibitor maintenance therapy'.).

For other women with advanced ovarian cancer, we also suggest maintenance treatment with the PARP inhibitor niraparib rather than no maintenance treatment (Grade 2C). However, reasonable alternatives include other PARP inhibitors, observation, or use of bevacizumab maintenance. Our recommendation is based on the observation that use of a PARP inhibitor as maintenance therapy has demonstrated a progression-free survival advantage, even to women without a BRCA1/2 mutation, in some (but not all) trials. While the largest benefit in the absence of a BRCA1/2 mutation has been seen in women who had evidence of HRD, women without HRD also appear to derive some benefit, albeit modest. Data in the subset of patients with HRD are discussed elsewhere. (See 'PARP inhibitors' above and "Management of ovarian cancer associated with BRCA and other genetic mutations", section on 'Other homologous recombination deficiencies'.)

Post-treatment evaluation and surveillance – Following the completion of treatment, we perform a post-treatment evaluation with a history, physical (including pelvic) exam, and cancer antigen (CA) 125. Imaging such as CT of the chest, abdomen, and pelvis may be utilized as needed, especially in those with a non-informative CA 125 marker. Following the documentation of a response, patients are monitored serially with physical examination and tumor marker studies. (See 'Evaluation after adjuvant chemotherapy' above and 'Post-treatment surveillance' above.)

Recurrence can be detected either serologically using tumor markers (eg, CA 125) and/or by the development of clinical or radiologic signs of progression. For women who have completed initial chemotherapy, we recommend retreatment based on signs and/or symptoms of relapsed EOC, not based on a rising CA 125 alone (Grade 1B). (See "Overview of epithelial carcinoma of the ovary, fallopian tube, and peritoneum", section on 'CA 125 surveillance'.)

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Topic 3239 Version 105.0

References

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