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 three 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".)
For most patients, EOC is treated surgically and followed by adjuvant platinum- and taxane-based chemotherapy. However, neoadjuvant chemotherapy (NACT) prior to definitive surgery is an alternative option in selected patients. This topic will review the rationale and administration of NACT for EOC. Other relevant topics in the treatment of EOC include:
OVERVIEW AND RATIONALE — NACT refers to the administration of systemic therapy before surgery. Typically, three to four cycles of NACT are administered, after which resectability is assessed by imaging (algorithm 1). For those who are candidates, interval cytoreduction is performed, followed subsequently by further cycles of chemotherapy in the adjuvant setting. For those who do not have resectable disease after the initial cycles of NACT, primary medical therapy is offered, without surgery.
The goal of NACT is to reduce perioperative morbidity and mortality and increase the likelihood of a complete resection of disease at the time of cytoreductive surgery. Despite the potentially improved surgical outcomes that result from NACT, clinical studies have shown that survival is not improved with NACT followed by surgery versus standard surgery followed by adjuvant chemotherapy [1-3].
OUTCOMES RELATIVE TO PRIMARY DEBULKING SURGERY — Available data suggest that for selected women with stage III or IV EOC, NACT and interval cytoreduction, followed by adjuvant chemotherapy are similar to primary cytoreduction and adjuvant chemotherapy, with respect to overall survival (OS) and progression-free survival (PFS), and are associated with less perioperative morbidity and mortality [4,5].
In a Cochrane review including three randomized trials enrolling 1521 women with stage III/IV ovarian cancer, those randomly assigned to NACT followed by debulking surgery experienced a similar OS as those assigned to primary debulking surgery followed by chemotherapy (hazard ratio [HR] 0.95, 95% CI 0.84-1.07) . Among four randomized trials evaluating PFS in such women, results for PFS were also similar between the groups (HR 0.97, 95% CI 0.87-1.07). NACT was, however, associated with lower postoperative mortality (relative risk 0.18, 95% CI 0.06-0.54). Rates of infection, need for stoma formation, and bowel resection were also lower in the NACT group. Similar results were seen in the phase III SCORPION trial [7,8].
NACT also permits the assessment of the effectiveness of chemotherapy prior to surgery, which may help to inform subsequent treatment. Patients who progress on NACT are unlikely to benefit from surgery because of intrinsically chemoresistant disease.
Approach — Our approach is to offer NACT to the following groups of women (algorithm 1):
●Those with advanced EOC (eg, stage IIIC or IV) with clinically apparent, unresectable disease who are unlikely to become complete or optimally cytoreduced (ie, no residual cancer or <10 mm of residual disease at the end of surgery, respectively) if taken to the operating room at the time of presentation [4,5]. (See 'Defining unresectable disease' below.)
●Those with EOC (of any stage) who are initially poor operative candidates, but who are likely to tolerate surgery after chemotherapy.
For those who are unlikely to tolerate surgery at any point due to poor functional status, we proceed with chemotherapy alone, with the goal of tumor control. (See "First-line chemotherapy for advanced (stage III or IV) epithelial ovarian, fallopian tube, and peritoneal cancer".)
Attempts to identify the subset of patients most likely to benefit from NACT are under active investigation [9,10]. For example, an exploratory analysis that included patients treated on the European Organisation and Research for the Treatment of Cancer (EORTC) 55971 trial sought to determine if baseline characteristics could identify patients most appropriate to undergo NACT rather than primary surgery . Women with stage IV disease had higher five-year overall survival rates following NACT compared with primary surgery (22 versus 5 percent, respectively). However, other markers including age, performance status, tumor grade, and histology did not suggest a benefit from NACT versus primary surgery, or vice versa. These data suggest that clinical features could help define those patients most likely to benefit from NACT. Further data are required.
Defining unresectable disease — The decision on whether to proceed with NACT is based on the clinical status of the patient and whether or not disease is resectable at the time of presentation. Therefore, all patients require clinical staging. At our institution, this requires baseline imaging (eg, computed tomography [CT] of the chest, abdomen, and pelvis) to determine if the disease is resectable or not, and possible diagnostic laparoscopy. (See 'Role of diagnostic laparoscopy' below.)
Most experts agree that criteria for unresectability include patients with the following :
●Diffuse and/or deep infiltration of the small bowel mesentery
●Diffuse carcinomatosis involving the stomach and/or large parts of the small or large bowel
●Infiltration of the duodenum and/or parts of the pancreas (not limited to the pancreatic tail)
●Involvement of the large vessels of the hepatoduodenal ligament, celiac trunk, or behind the porta hepatis
●Involvement of the liver parenchyma
●Lymph node metastases in axilla or mediastinum
Role of diagnostic laparoscopy — It is often difficult to preoperatively assess whether women with advanced EOC can be optimally cytoreduced at the time of primary surgery . Therefore, for women with stage III or IV EOC in whom it is not clear if complete cytoreduction is possible, we obtain a diagnostic laparoscopy to visually assess for resectability. If the surgeon conducting the assessment feels disease is resectable, primary surgery should be performed. If complete resectability is unlikely, NACT can be administered.
In a meta-analysis of 18 studies (including 1563 participants), including one randomized trial, laparoscopic assessment suggested that disease was suitable for optimal debulking (no macroscopic residual disease or residual disease <1 cm) in approximately 70 to 100 percent of women . In the two studies in which all women underwent surgery irrespective of laparoscopy findings, none of the women with laparoscopy suggestive of unresectable disease subsequently experienced optimal debulking (ie, there were no false-positive laparoscopies).
Guidelines to determine the accuracy of laparoscopic assessment for primary debulking have been developed . This scoring system assigned a score of 2 (positive/extensive) or 0 (absence/limited) to the following factors:
The reported accuracy of debulkability of these factors ranged from 82 (bowel infiltration) to 94 percent (omental caking). In a prospective validation of this assessment, a score of 8 or higher resulted in a zero probability of optimal resection, and such patients should be advised to proceed with NACT.
However, some women have suboptimal primary debulking surgery, despite laparoscopy predicting optimal debulking. Complete cytoreduction does not solely depend upon the patient's and tumor's characteristics, but also depends on surgical expertise and an institution's infrastructure. In multidisciplinary cancer centers with advanced expertise in gynecologic oncology, optimal debulking rates in excess of 70 percent have been reported even for patients with bulky stage IIIC disease (ie, patients with evidence of abdominal metastases ≥20 mm preoperatively) . We strongly advocate that a gynecologic oncologist be involved in surgical decision-making and treatment in these circumstances.
Despite the potential benefit of diagnostic laparoscopy, some experts prefer to proceed with neoadjuvant treatment in patients who appear to have unresectable disease based on imaging alone. In patients who do not have a laparoscopy, either a CT-guided biopsy or cytology must be obtained before beginning treatment to confirm Müllerian malignancy.
CHOICE OF REGIMEN — For women who will undergo NACT, we offer an initial three cycles of intravenous carboplatin plus paclitaxel, with the addition of bevacizumab for those with high-risk disease (eg, pleural effusion, ascites), as in the adjuvant setting. (See "First-line chemotherapy for advanced (stage III or IV) epithelial ovarian, fallopian tube, and peritoneal cancer", section on 'Angiogenesis inhibition' and "First-line chemotherapy for advanced (stage III or IV) epithelial ovarian, fallopian tube, and peritoneal cancer", section on 'Dose-dense versus conventionally dosed IV therapy'.)
The preference for this regimen is based on the activity of this combination in the adjuvant treatment of EOC, as well as its use in neoadjuvant trials .
Intraperitoneal chemotherapy is not administered prior to interval debulking. Dosing and administration of neoadjuvant treatment is similar to adjuvant treatment and is discussed separately. (See "First-line chemotherapy for advanced (stage III or IV) epithelial ovarian, fallopian tube, and peritoneal cancer", section on 'Choice of agents'.)
TREATMENT EVALUATION AND SUBSEQUENT APPROACH — Although there are no formal guidelines regarding the ideal assessment strategy for women receiving NACT, in our practice we perform serial evaluations prior to the start of each cycle, which consist of an interim history and physical examination, complete blood count, serum chemistries (including liver and renal function tests), and cancer antigen (CA) 125 measurement.
We assess for treatment response with computed tomography after three cycles of NACT, as was done in the randomized trial conducted by the European Organisation and Research for the Treatment of Cancer . All patients are also seen by an experienced gynecologic oncology surgeon in order to determine whether to proceed with surgery (algorithm 1) [11,16], based on the imaging findings and CA 125 measurement .
●We proceed with surgical cytoreduction in patients who do not progress during NACT and in whom there is a chance of resecting all residual disease or achieving an optimal cytoreduction. After surgery, another three to six more cycles of chemotherapy are administered. (See 'Adjuvant treatment in patients treated with NACT' below.)
●Patients with disease progression at any point, as well as those who have had an insufficient response after three cycles of therapy for optimal cytoreduction to be feasible, represent a group with chemoresistant disease. Subsequent surgery is likely to introduce morbidity with unclear benefit. As such, we treat these patients with medical therapy similar to the treatment of women with platinum-resistant EOC and typically do not pursue surgical options. However, we recognize that the approach in such situations is variable, and that other experts consider further rounds of neoadjuvant treatment and re-evaluation for surgery for those who have had some response to NACT [18,19]. (See "Medical treatment for relapsed epithelial ovarian, fallopian tube, or peritoneal cancer: Platinum-resistant disease".)
DEFINITIVE SURGICAL TREATMENT
Surgical approach — Definitive surgical cytoreduction after NACT is attempted if there is a reasonable chance of resecting macroscopic tumor (preferred goal) or at least of achieving an optimal cytoreduction (ie, <10 mm residual disease), preferably gauged by a surgeon with training in gynecologic oncology [11,16]. The surgical approach following NACT is similar to that for women who undergo a primary surgical procedure and is discussed separately. (See "Epithelial carcinoma of the ovary, fallopian tube, and peritoneum: Surgical staging".)
Heated intraperitoneal chemotherapy at surgery — For patients who undergo NACT and have an optimal surgical result (ie, residual disease <1 cm), we suggest heated intraperitoneal (IP) chemotherapy (HIPEC) at the time of cytoreduction, provided that technical expertise is available.
Data on HIPEC treatment following neoadjuvant chemotherapy has shown mixed results with increased toxicity. However, two recent prospective randomized trials suggest there is a benefit if the expertise to provide HIPEC is available [20,21].
●This strategy was evaluated in a 2018 randomized trial of 245 women with stage III disease who received intravenous (IV) chemotherapy, with or without HIPEC . Participants were women who received three cycles of IV carboplatin and paclitaxel as NACT, after which optimal or complete cytoreduction was considered feasible. They were assigned to surgery with HIPEC cisplatin at 100 mg/m2 or surgery alone; all women then received three additional cycles of IV carboplatin and paclitaxel. In the intention-to-treat analysis, at a median follow-up of 4.7 years, fewer patients had died in the HIPEC group (50 versus 62 percent). The HIPEC group had a longer median recurrence-free survival (14 versus 11 months; HR 0.63, 95% CI 0.48-0.83) and median overall survival (45 versus 33 months; HR 0.70, 95% CI 0.53-0.92) . The rate of grade 3 or 4 adverse events was similar in the two groups (27 and 25 percent).
●In a separate trial, among 184 patients with stage III or IV ovarian cancer who underwent primary cytoreductive surgery or interval cytoreductive surgery after NACT, with <1 cm residual tumor, HIPEC versus control resulted in similar progression-free survival (PFS; 20 versus 19 months, respectively) . Improvements in overall survival were not statistically significant (70 versus 61 months, respectively). However, in the subgroup of 77 patients who had interval cytoreductive surgery after NACT, HIPEC improved median PFS and overall survival relative to control (median PFS 30 versus 24 months, HR 0.60, 95% CI 0.37-0.99; median overall survival 62 versus 48 months, HR 0.53, 95% CI 0.29-0.96). This study had several limitations, including the small sample size, particularly in the subgroup who got interval cytoreduction after NACT; moreover, enrollment in the trial was not stratified by primary or interval cytoreductive surgery, and there may have been possible imbalance between the groups. The 2018 trial, designed specifically to evaluate HIPEC at the time of interval cytoreduction after NACT, provides stronger support for its use .
Although there are now two randomized trials showing an advantage when HIPEC is used at the time of interval cytoreduction, the technical expertise required for peritoneal stripping and subsequent HIPEC may limit its application in many centers. In addition, it is still not clear if the additional dose of chemotherapy, the IP administration, or the heating was responsible for the benefit . Despite this, for women with advanced ovarian cancer who undergo NACT, we suggest HIPEC at the time of interval cytoreduction provided the expertise is available and with careful patient selection (ie, patients with residual disease <1 cm).
ADJUVANT TREATMENT IN PATIENTS TREATED WITH NACT
Number of cycles — For women treated with NACT, there is no consensus in the best treatment approach following interval debulking surgery. We proceed with further treatment with intravenous (IV) carboplatin and paclitaxel for three to six cycles, as has been done in a randomized trial evaluating NACT (ie, some contributors offer three cycles, while others typically administer six, except in verified stage I/II disease (algorithm 1)) . (See 'Outcomes relative to primary debulking surgery' above and "First-line chemotherapy for advanced (stage III or IV) epithelial ovarian, fallopian tube, and peritoneal cancer".)
Intravenous versus intraperitoneal treatment — While we typically treat women who have received NACT with adjuvant IV therapy due to toxicity considerations, intravenous (IV)/intraperitoneal (IP) treatment may be an appropriate alternative for a select group of patients. For example, we may offer IV/IP treatment after interval cytoreduction to patients who received NACT due to a high initial preoperative risk and subsequently underwent optimal cytoreduction (eg, for a patient who presented with a large pulmonary embolism, which was subsequently treated). However, we would rarely utilize IV/IP therapy for patients who underwent neoadjuvant treatment due to extensive extra-abdominal disease.
Although several adjuvant therapy trials have suggested improvements with IV/IP chemotherapy over IV chemotherapy in patients with optimally debulked disease, data are mixed [24-27], and there are only limited data to inform the benefits and risks of adjuvant IV/IP treatment in women who received NACT prior to surgery. The phase II OV21/PETROC study evaluated IV versus IV/IP therapy, but did not show conclusive differences between the two approaches . In this study, approximately 200 women who had been treated with NACT and underwent an optimal cytoreduction were randomly assigned to a 21-day cycle regimen consisting of IV carboplatin and paclitaxel (administered on days 1 and 8) or to IP carboplatin plus IV/IP paclitaxel. There was a trend towards improved progression-free survival (PFS) at nine months among those receiving IV paclitaxel/IP carboplatin compared with those receiving IV treatment only (25 versus 39 percent), but this was not statistically significant. Although the trial was not powered to detect differences in median survival, IV paclitaxel/IP carboplatin was associated with nonsignificant trends in improved median PFS (13 versus 11 months) and overall survival (59 versus 38 months).
Thus, it remains unclear whether IV/IP therapy should be standard treatment for patients who have received neoadjuvant treatment and optimal cytoreduction, particularly given mixed results from previous studies regarding its tolerability in this subset of patients [29-31]. Furthermore, OV21/PETROC was a phase II study, and there is no planned phase III study underway, making it difficult to draw definitive conclusions regarding relative efficacy. Finally, rather than a dose-dense or every-three-week schedule of carboplatin and paclitaxel, patients assigned to IV treatment on day 1 received paclitaxel 135 mg/m2 plus IV carboplatin area under the curve (AUC) 5/6 and on day 8 received paclitaxel 60 mg/m2, possibly decreasing the efficacy of the control arm.
Overall, available data suggest that IP chemotherapy after NACT is feasible, although they are not definitive. Still, on the basis of these results, IV/IP treatment appears to be a reasonable alternative in select women who undergo optimal cytoreduction following NACT. Further discussion on the role of IP therapy for EOC among patients who did not receive neoadjuvant treatment is discussed separately. (See "Intraperitoneal chemotherapy for treatment of ovarian cancer" and "First-line chemotherapy for advanced (stage III or IV) epithelial ovarian, fallopian tube, and peritoneal cancer", section on 'Women with optimally cytoreduced disease'.)
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
●Overview and rationale – Neoadjuvant chemotherapy (NACT) refers to the administration of systemic therapy before definitive surgery. The goal of NACT is to reduce perioperative morbidity and mortality and increase the likelihood of a complete resection of disease at the time of cytoreductive surgery. (See 'Overview and rationale' above.)
●Patient selection – For patients with clinically apparent, unresectable epithelial ovarian cancer (EOC) who are unlikely to undergo optimal cytoreduction, we offer NACT (algorithm 1). We also offer NACT to patients with EOC who are poor operative candidates because of medical comorbidities or a poor performance status, but who are likely to tolerate surgery after chemotherapy (table 1). (See 'Patient selection' above.)
●Role of diagnostic laparoscopy – For women with stage III or IV EOC in whom it is not clear if complete cytoreduction is possible, we obtain a diagnostic laparoscopy to determine resectability. (See 'Role of diagnostic laparoscopy' above.)
●Choice of chemotherapy – For women who will undergo NACT, we suggest intravenous (IV) platinum-based chemotherapy rather than other regimens (Grade 2B). Our preference is to administer carboplatin plus paclitaxel, with or without bevacizumab, given the activity of this combination in the adjuvant setting. (See "First-line chemotherapy for advanced (stage III or IV) epithelial ovarian, fallopian tube, and peritoneal cancer".)
●Assessment while on NACT and next steps – Although there are no formal guidelines regarding the ideal assessment strategy for women receiving NACT, in our practice we perform serial evaluations, which consist of an interim history and physical examination, complete blood count, serum chemistries (including liver and renal function tests), and cancer antigen (CA) 125 measurement prior to the start of each cycle. (See 'Choice of regimen' above.)
•We evaluate for treatment response after three NACT cycles.
-We proceed with a surgical cytoreduction in patients in whom there is a chance of resecting all residual disease (or achieving an optimal cytoreduction). We advocate for this procedure to be performed by a fellowship trained gynecologic oncology surgeon.
-For patients who undergo NACT and subsequently have an optimal surgical result (ie, residual disease <1 cm), we suggest HIPEC at the time of cytoreduction (Grade 2B), provided that technical expertise is available. Omission of HIPEC is also acceptable, particularly in centers lacking the appropriate expertise or resources. (See 'Heated intraperitoneal chemotherapy at surgery' above.)
-For patients who experience disease progression during NACT, or continue to be unlikely to have an optimal cytoreduction after three cycles of NACT, we suggest medical therapy (Grade 2C), rather than further rounds of NACT followed by surgery. We utilize a regimen similar to the treatment of women with platinum-refractory EOC. (See "Medical treatment for relapsed epithelial ovarian, fallopian tube, or peritoneal cancer: Platinum-resistant disease".)
However, other experts consider further rounds of neoadjuvant treatment and re-evaluation for surgery for those who have had some response to NACT.
●Treatment following surgery – Following surgery, we suggest adjuvant platinum-based chemotherapy rather than no further treatment (Grade 2C). We suggest IV chemotherapy rather than a regimen that incorporates intraperitoneal therapy (Grade 2C). Our preference is to administer carboplatin and paclitaxel for three to six cycles. (See 'Adjuvant treatment in patients treated with NACT' above.)
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