Neoadjuvant, HIPEC and maintenance treatment in ovarian and peritoneal serous cancer: current status
Review Article

Neoadjuvant, HIPEC and maintenance treatment in ovarian and peritoneal serous cancer: current status

Stergios Boussios1,2, Agne Sadauskaite1, Foivos S. Kanellos3, Alexandros K. Tsiouris3, Afroditi Karathanasi1, Matin Sheriff1

1Medway NHS Foundation Trust, Gillingham, Kent, UK; 2AELIA Organization, Thessaloniki, Greece; 3Department of Biological Applications & Technology, University of Ioannina, Ioannina, Greece

Contributions: (I) Conception and design: S Boussios, M Sheriff; (II) Administrative support: All authors; (III) Provision of study materials or patients: All authors; (IV) Collection and assembly of data: All authors; (V) Data analysis and interpretation: All authors; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

Correspondence to: Dr. Stergios Boussios, MD, PhD, MRCP (London). Consultant Medical Oncologist, Medway NHS Foundation Trust, Windmill Road, ME7 5NY, Gillingham, Kent, UK. Email: stergiosboussios@gmail.com; stergios.boussios@nhs.net.

Abstract: High-grade serous epithelial ovarian cancer (EOC) is the most lethal gynecological disease due to lack of screening test sensitivity. Currently, there is no clear consensus over the regime these patients should receive. The main two options for the management of patients with advanced EOC are upfront debulking surgery (UDS) with adjuvant chemotherapy (ACT) or neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS). Optimizing patients’ selection for UDS might offer higher progression-free survival (PFS) and overall survival (OS) rates. New imaging methodologies and biomarkers can guide this process. Peritoneal metastasis from EOC is a major challenge in the clinical management. The results for the role of heated intraperitoneal chemotherapy (HIPEC) combined with aggressive cytoreductive surgery (CRS) are controversial and prospective randomized trials are warranted. The addition of bevacizumab or poly (ADP-ribose) polymerase (PARP) inhibitors as concomitant and/or maintenance therapy has shown to improve PFS in patients with platinum-sensitive recurrent EOC. Serous peritoneal papillary carcinoma (SPPC) arises in the peritoneal surface lining the abdomen and pelvis without a discriminative primary tumor site. Clinical, pathological and biological differences hint towards SPPC and primary EOC being as a spectrum of disease. Patients with SPPC are traditionally managed similarly to stage III–IV EOC. The recommended approach integrates aggressive CRS, and systemic chemotherapy to remove the macroscopic tumor, eradicate the microscopic residual disease, and control the microscopic metastasis.

Keywords: Upfront debulking surgery (UDS); interval debulking surgery (IDS); cytoreductive surgery (CRS); heated intraperitoneal chemotherapy (HIPEC); bevacizumab; poly (ADP-ribose) polymerase inhibitors (PARP inhibitors); serous peritoneal papillary carcinoma (SPPC)


Received: 07 May 2020; Accepted: 16 June 2020; Published: 25 September 2020.

doi: 10.21037/gpm-20-41


Introduction

Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer mortality among women. Patients are mostly presented with advanced disease at diagnosis, and approximately 80% relapse, with an estimated median progression-free survival (PFS) of around 12–18 months (1). Traditionally, high grade serous EOC is managed with radical surgery, followed by adjuvant chemotherapy (ACT). When upfront surgery is medically contraindicated, or complete cytoreduction not feasible, neoadjuvant chemotherapy (NACT) prior to interval debulking surgery (IDS) could be an alternative therapeutic maneuver in advanced EOC (2,3). Identification of predictive factors for optimal selection of patients for upfront debulking surgery (UDS) may improve PFS and overall survival (OS) rates. There is no consensus on the efficacy of heated intraperitoneal chemotherapy (HIPEC) combined with aggressive cytoreductive surgery (CRS). In the era of novel targeted therapies, HIPEC demands strict criteria for application. The treatment of platinum-sensitive recurrent EOC has improved by the addition to the platinum-based regimen of the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab or the poly (ADP-ribose) polymerase (PARP) inhibitors. In 2016 Food and Drug Administration (FDA) approved bevacizumab for the treatment of platinum-sensitive recurrent EOC in combination with platinum-based chemotherapy (4). Phase II–III placebo-controlled trials have evaluated PARP inhibitors as maintenance therapy following platinum-based treatment. They did demonstrate a benefit in PFS over placebo in the overall population of recurrent EOC patients, which was more significant in those with a germline or somatic mutation in the breast cancer genes 1 and 2 (BRCA1/2) (5-9). Beyond BRCA1/2 mutant cells that are highly susceptible to PARP inhibitors, deficiencies in Fanconi anemia genes (BRIP1, PALB2), the core RAD genes (RAD51C, RAD51D), and genes involved in HR pathway either directly (CHEK2, BARD1, NBN, ATM) or indirectly [cyclin-dependent kinase 12 (CDK 12)], were also displayed to confer sensitivity to these drugs (10). Identification of the optimal treatment after the first platinum-sensitive recurrence, is still an unmet need. Within this context, it is required design of trials that will directly compare the two available maintenance strategies. Patients with serous peritoneal papillary carcinoma (SPPC) have a similar clinical presentation, histological features, and pattern of spread to those with primary EOC (11). These clinical entities are commonly approached as a single disease and arriving at the correct diagnosis can be challenging. Among patients considered to have primary EOC, 15% suffer instead of SPPC (11). Much effort has been made into researching differences of the molecular mechanisms of EOC and SPPC, but far share the same therapeutic approach.


Neoadjuvant treatment vs. UDS

The majority of newly diagnosed EOC patients are treated with radical surgery, followed by adjuvant platinum-based chemotherapy (12). However, surgical treatment options are debated. In advanced EOC, the choice of upfront debulking in cases of high grade-serous EOC versus NACT followed by IDS is not always clear. Precise patient selection criteria to guide therapeutic decisions in this setting is warranted.

Complete cytoreduction represents the most important clinical endpoint, associated with improved survival in patients undergoing debulking surgery (13). Initially, the EORTC 55971 trial randomized patients with advanced/metastatic EOC to primary debulking surgery followed by ACT or to NACT, followed by IDS and ACT (NCT00003636) (2). Five years later was published the similarly designed CHORUS trial (ISRCTN74802813) (3). Both were non-inferiority studies and demonstrated equivalent OS in both treatment arms. Based on these two studies, NACT followed by IDS has been established in advanced EOC as therapeutic choice of equal efficacy, as compared to upfront debulking. Randomized phase III clinical trials comparing upfront versus IDS in advanced EOC are summarized in Table 1.

Table 1
Table 1 Phase III clinical trials on UDS followed by ACT versus IDS after NACT in stage III–IV EOC, peritoneal, or fallopian tube cancer (https://www.clinicaltrials.gov/)
Full table

Several prognostic factors should be taken into account prior to surgical decision (14,15). Mesothelin, FLT4, α-1 acid glycoprotein (AGP) and cancer antigen 125 (Ca-125) are proposed as predictive biomarkers for the incorporation of anti-angiogenic agents (bevacizumab) to the first line treatment (16). Angiogenesis and vascular remodeling are complex processes that involve regulation by the cytokines angiopoietin-1 (Ang1) and Ang2. Ang1 is a potent angiogenic growth factor signaling through Tie2, whereas Ang2 was initially identified as a vascular disruptive agent with distinct functions from VEGF and antagonistic activity through Tie2.

Genomic factors, such as cyclin E1 amplifications and loss of BRCA1/2 mutations, have also been predictive value for the decision of IDS versus upfront surgery, taken that they distinguish chemo-resistant from chemo-sensitive high grade-serous EOC (17). Gorodnova et al., reported that EOC patients with BRCA1/2 germ-line mutation show high sensitivity to platinum-based NACT (18). Equally, expression of the homologous recombination (HR) genes BRCA2, p53, and FANCB is associated with prolonged OS in EOC patients receiving NACT followed by IDS, and represents a positive predictive factor for platinum-based NACT (19).

Tumor-infiltrating lymphocytes (TILs) and tumor cell-free DNA (cfDNA) have also been proposed as predictive biomarkers; nevertheless, their use is limited and there is lack of standard methods for their isolation (20). It seems that, high levels of TILs are correlated with better response to NACT, suggesting that host immune response influences the tumor chemo-sensitivity (21-23). In a retrospective analysis of tumor tissue from 130 patients with EOC, those with higher CD3 (P=0.03), PD-L1 (P=0.007), and PD-1 (P=0.02) expression had prolonged OS (24). Analysis of cfDNA identify genomic alterations and captures the heterogeneity of the primary and metastatic tumors. cfDNA analysis can provide insight into molecular characterization, early diagnosis, monitoring of treatment response, and/or resistance, and optimal selection of patients for treatment in adjuvant setting (25).

A scoring system evaluating body mass index (BMI) of the patients, Ca-125 levels and imaging staging was conducted to predict those with potential benefit from UDS. Patients with BMI <30 kg/m2, Ca-125 <100 IU/L and absence of positron emission tomography/computed tomography (PET/CT) findings suggestive of either diaphragmatic and omental carcinomatosis, or parenchymal metastases, have better chance of complete cytoreduction, following UDS (26). Furthermore, patients older than 65 years of age, with albumin levels <25 g/L and ascites >1 L do not experience benefit from UDS.

Definitely, unresectable disease due to generalized carcinomatosis should be treated with NACT (21). From the surgical perspective, deep infiltration or diffuse metastasis within small and large bowel are correlated with high morbidity rates (16). Similarly, celiac lymph node involvement is associated with increased chance of both large bowel resection and metastasis to small bowel mesentery (27). It seems that lymph node involvement does not promote upfront CRS, whereas peritoneal carcinomatosis leads to surgical complications, within the context of upfront debulking (16,28,29). Laparoscopic index of Fagotti is a 100-point score based on objective parameters determined at pre-cytoreduction laparoscopy. Predictive parameters include elements of extraperitoneal and metastatic disease, such as peritoneal carcinomatosis, diaphragmatic and mesenteric disease, omental metastasis, bowel and stomach infiltration and liver metastases (30). Each parameter was assigned 2 points if present and 0 points otherwise. Patients are classified into three risk groups of incomplete cytoreduction. Those at high risk would be treated with NACT. For the subset of intermediate-risk patients, laparoscopy for the assessment of disease resectability is reasonable, whereas low-risk patients may undergo upfront surgery.

As far as concerned imaging techniques in high-grade serous EOC, PET/CT scan is recommended for the assessment of the extent of the disease and consequently, the decision about IDS versus upfront surgery in advanced EOC (21). Malignant pleural effusion and metastasis over diaphragm are related to lower chances of complete cytoreduction. However, further studies are required for the clarification of the predictive value of these radiological features. Additionally, PET with 2-deoxy-2-(fluorine-18)fluoro-D-glucose (18F-FDG) is proven to be adequate for estimating NACT response (21). Video-assisted thoracoscopy is recommended in patients with pleural involvement, for staging purposes, whereas real-time ultrasound elastography is limited nowadays (21). The predictive value of diffusion-weighted magnetic resonance imaging (DW-MRI) is based on the providing information about serosal intestinal, mesenteric vascular and distant site involvement (21,29).


HIPEC

Regardless that CRS and systemic chemotherapy remain the standard treatment of EOC, HIPEC becomes nowadays an option for candidate patients (31). HIPEC is the delivery of intraperitoneal chemotherapy in heated perfusate, following aggressive CRS. Intraperitoneal chemotherapy could reduce plasma toxicity compared with intravenous administration and increase the effect upon heating (32).

Several randomized phase II/III trials in different settings are summarized in Table 2. Among them, 4 enrolled patients during upfront treatment, 1 at the time of primary debulking surgery, whereas 2 at the time of interval debulking, after 3 cycles of NACT. The latest National Comprehensive Cancer Network (NCCN) guidelines support the policy of HIPEC at interval cytoreduction (33). Furthermore, 4 clinical trials recruited patients with recurrent disease, eligible for secondary CRS. It seems that the use of HIPEC in this setting has been more extensively investigated. An analysis of 16 studies, concluded that HIPEC in recurrent EOC, resulted in improved survival (34). Morbidity consistently ranged between 12% and 30%. Treatment related side effects usually were related to myelosuppression and nephrotoxicity (35). However, differentiation between surgical complications and HIPEC is challenging (35). The OS and PFS rates were compatible with those reported in the OCEANS, DESKTOP, and CALYPSO trials; nevertheless, due to the separate designs of these trials, direct head to head comparison is not feasible (34,36-38).

Table 2
Table 2 Phase II/III randomized controlled HIPEC trials (https://www.clinicaltrials.gov/)
Full table

Furthermore, the tasks of optimal drug choice, dosing, time and temperature should also be resolved. Currently, the rationale for HIPEC incorporated in a multi-model treatment in patients with advanced EOC is strong. The main concern is related to the tolerance, which maintain skepticism about the implementation of this therapeutic intervention (39). The evidence of the mortality and morbidity of HIPEC compared to CRS alone is rather inconclusive, and inconsistent (40,41). In any case, HIPEC should be offered at well-organized centers after precise patients’ selection (42). Obviously, further well-designed prospective randomized trials are warranted to clarify the role of HIPEC application in the management of primary EOC.


Maintenance treatment

Despite recent achievements in the upfront treatment, approximately 80% of EOC patients experience disease relapse within 5 years following initial diagnosis. The median OS of recurrent EOC ranges from 12 to 24 months (43). Until recently, patients with platinum-sensitive recurrent EOC were treated with re-challenging platinum-based regimens. The therapeutic outcome of this subset of patients has been improved by the addition to the platinum-based regimen of the anti-VEGF antibody bevacizumab or PARP inhibitors.

Indeed, results from three phase III trials demonstrated prolongation of the PFS with the incorporation of bevacizumab to the platinum-based chemotherapy, followed by maintenance bevacizumab, when compared to chemotherapy alone (4,38,44). This therapeutic strategy should be specifically indicated in the subset of patients with high disease burden at relapse, where a prompt tumor shrinkage could lead to better control of disease related symptoms. The FDA and the European Medicine Agency (EMA) approved bevacizumab for the treatment of platinum-sensitive recurrent EOC in combination with carboplatin and either gemcitabine or paclitaxel in 2016 and 2017, respectively. Approval was granted based on findings from OCEANS trial, which demonstrated increased objective response rate (ORR) of about 20% for the combination arm, as compared to chemotherapy alone (38). Despite this, recent evidence from the ENGOT-ov18/AGO-OVAR 2.21 trial demonstrated better efficacy of carboplatin plus pegylated liposomal doxorubicin as compared to carboplatin plus gemcitabine, either combined with bevacizumab [median PFS 13.3 vs. 11.7 months, hazard ratio (HR): 0.80; 95% confidence interval (CI): 0.68–0.96, P=0.0128] (45).

PARP inhibitors have changed management standards of patients with platinum-sensitive recurrent EOC. Olaparib, rucaparib, and niraparib have all obtained FDA and/or EMA approval in EOC in different settings. Veliparib and talazoparib are in earlier clinical development (46,47). Approved PARP inhibitors have been evaluated as maintenance therapy of recurrent EOC patients. Phase II–III placebo-controlled trials demonstrated a benefit in PFS in the overall population, specifically in those with either germline or somatic BRCA1/2 mutations (5-9). Both BRCA and HR deficiency status represent novel predictive biomarkers of response to chemotherapy and PARP inhibitors. Germline BRCA1/2 mutations enhance EOC risk and account for approximately 14% of EOC. These genes encode proteins with a crucial role in the repair of double-strand DNA breaks (DSBs) through HR deficiency. Furthermore, somatic mutations and epigenetic inactivation of BRCA1/2 have been implicated in sporadic EOC. Beyond germline pathogenic variants in BRCA1/2 genes, alterations in BRIP1, RAD51C, RAD51D, and mismatch repair genes also increase the risk of EOC (10). Furthermore, the option of PARP inhibitors combined with drugs that inhibit HR deficiency represent a novel treatment that may sensitize EOC with de novo or acquired HR proficiency to PARP inhibitors. Further research should aid identification of patients’ most likely to benefit from combined treatment (48).

Side effects represent a crucial factor for the choice of the optimal agent for the maintenance treatment. Bevacizumab has overall manageable side effects, and the specific toxicity profile is related to its mechanism of action. The most frequent adverse events include hypertension, proteinuria, hemorrhages and thromboembolic events, poor wound healing and gastrointestinal perforation. As a consequence, patients at higher risk to experience bevacizumab induced side effects should be treated with a PARP inhibitor if indicated (49). Maintenance therapy with PARP inhibitors is generally well tolerated, which affects patients’ compliance and quality of life, hugely important parameters in the maintenance setting. The most common severe toxicities attributed to these drugs include anemia and fatigue (50). Although PARP inhibitors oppose the catalytic activity of PARP in general, there are remarkable differences in their abilities to trap PARP, based on the size and structure of each separate molecule. This explains the different magnitude of cytotoxicity and their distinct safety profile (51).

The therapeutic approach of recurrent EOC is further influenced by the changing landscape of the first line treatment. The SOLO-1 trial has established a new standard of care in patients with BRCA1/2 mutations; olaparib arm achieved approximately 70% reduction in risk of disease progression compared to placebo (1). Niraparib has also been effective in the up-front setting with prolongation of PFS over placebo in a population at high-risk of recurrence. The benefit was reached in patients with BRCA1/2 mutations and in BRCA wild-type patients with a positive HR deficiency score, assessed by “myChoice HRD” commercial genomic scar assay by Myriad (9,52). Similar results have been reported by PAOLA1 GINECO/ENgOT-ov25 trial, assessed the combination of olaparib with bevacizumab (53). As more patients access to PARP inhibitors first line therapy, clinical trials for the establishment of the optimal therapeutic sequence are warranted.

Table 3 summarizes maintenance clinical trial data, following the first platinum-sensitive recurrence. It is difficult to directly compare the activity of different PARP inhibitors and bevacizumab since head-to-head studies are lacking.

Table 3
Table 3 Randomized studies of maintenance treatment in platinum sensitive (PFI ≥6 m) recurrent EOC
Full table

Future directions of immunotherapy in EOC

Despite the fact that early data from preclinical studies imply that EOC has an immunogenic microenvironment, immune checkpoint inhibitors have not yet produced favorable responses in clinical trials. When analyzed according to biomarker status, PD-L1 positivity did not predict objective response in nivolumab trial, while objective response to atezolizumab was observed in 2 out of 8 patients who had ≥5% PD-L1 expression in immune cells (54,55). In a study evaluated efficacy of avelumab, ORR in PD-L1 positive and negative cohorts were 11.8% and 7.9%, respectively, when cut-off for PD-L1 positivity was set at 1% (56). The KEYNOTE-100 trial was the largest study on single immune checkpoints inhibitors in EOC. PD-L1 expression was measured as combined positive score (CPS), defined as the ratio of PD-L1 positive cells to viable tumor cells (57). The ORR to pembrolizumab was reported as 5% for CPS <1, 10.2% for CPS ≥1 and 17.1% for CPS ≥10, respectively. Ipilimumab, a monoclonal antibody against cytotoxic T-lymphocyte associated protein 4 (CTLA-4), was administered to 9 advanced EOC patients after immunization with granulocyte-macrophage colony-stimulating factor and only one patient had a partial response (PR) (58). In a phase II trial of 40 recurrent platinum-sensitive EOC patients, treated with the monoclonal against CTLA-4 antibody ipilimumab, ORR was reached at 10.3% (59). Based on the outcome of these trials, EOC does not seem to respond well to anti PD-1/PD-L1 or anti-CTLA monotherapy. However, it should be taken into consideration that enrolled patients were heavily pretreated with chemotherapy. Furthermore, the samples of these studies were mostly small. As such, conclusions should be drawn carefully.

A reasonable strategy for increasing tumor immunogenicity and enhancing efficacy of immunotherapy is the combination with chemotherapy. The phase III JAVELIN Ovarian 200 trial, enrolled 566 platinum-resistant or platinum-refractory EOC patients who had received up to 3 lines of treatment (60). Addition of avelumab to pegylated liposomal doxorubicin did not significantly prolong PFS and OS. However, patients of PD-L1 positive subgroup (≥1% of tumor cells or ≥5% of immune cells) achieved an improved survival (HR: 0.72; P=0.11 for PFS and HR: 0.59; P=0.005 for OS). Furthermore, combination with VEGF blockade is an additional potential method to increase anti-tumor efficacy of immunotherapy. There are ongoing randomized phase III trials investigating addition of atezolizumab to chemotherapy and/or bevacizumab in different EOC settings (NCT03038100, NCT02891824, and NCT02839707) (61-63). Overall, identification of predictive biomarkers for the optimal selection of candidates for immunotherapy is crucial.


Serous primary peritoneal carcinoma

SPPC share subtle clinical features that differ from those with primary EOC. SPPC affects overweight and older patients, as well as those with high parity and later menarche. It is mostly multifocal, characterized by diffuse micronodular spread, resulting in high tumor burden in upper abdomen and diaphragmatic surfaces. Furthermore, discordant allelic losses have been observed among multiple intrapatient peritoneal deposits. The fact that different genetic events take place at different peritoneal loci, distinguishes SPPC from EOC with the unifocal nature (64,65).

In terms of the molecular biology, SPPC is more commonly characterized by immunohistochemical overexpression of human epidermal growth factor receptor 2 (HER2), and higher proliferation index Ki-67 as compared to EOC (66-68). This provided the rationale of the anaplastic nature of the SPPC, along with the common development of platinum resistance. Expression of estrogen and progesterone receptors is less frequent in SPPC, similarly to the lower incidence of loss of heterozygosity on chromosomes (66,68). Finally, there is no distinction in the protein expression patterns of p53 and BCL2, the microvessel density, and microRNA profiles (66,67,69,70). Based on this molecular evidence, SPPC and primary EOC seem to represent two clinical entities of a spectrum of disease rather than completely separate malignancies.

The recommended diagnostic work-up for patients with SPPC includes basic blood analyses and imaging with scans of chest, abdomen, and pelvis (71). The serum Ca-125 is not pathognomonic but can be monitored if the baseline level is raised (72). Overall, surgical staging remains diagnostically the gold standard, whereas endoscopies of the upper and lower gastrointestinal system and PET-CT scans may provide additional information (73).

Histologically, SPPC exhibits a complex papillary or glandular architecture, similarly to the papillary serous EOC (74). Immunohistochemically, it is typically positive for CK7, CD15, S-100, P53, WT-1, ER, and PAX-8 and negative for calretinin (75-77). SPPC should be differentiated from peritoneal mesotheliomas, which are negative for Ber-EP4 and MOC-31 and positive for calretinin and D2-40 (78).

SPPC typically metastasize to the peritoneal cavity, pelvic and para-aortic lymph nodes, which highlights the importance of aggressive local control (79). The rationale of total peritonectomy is the removal of precursor sites and microscopic residual disease (80). Impressively, residual tumors have been reported in 60% of grossly normal appearing peritoneum (81,82). Lymph nodes are in general equally involved in both clinical entities. The strong recommendation of systematic lymph node dissection in those with SPPC is related to the fact that the more frequently met postoperative adhesions as compared to EOC, limit further surgeries at recurrence (80,83). NACT is effective for achievement of optimal local control (84). Patients with complete response (CR) to NACT may not require surgery. A case series described that among 44 patients with SPPC treated with NACT, only 17 underwent CRS (85). However, the surgical subset experienced lower recurrence rates (65% vs. 93%) and significantly longer median PFS (25 vs. 9 months; P=0.001) and OS (48 vs. 18 months; P=0.0016) (85).

The treatment strategy of CRS-HIPEC in patients with primary or recurrent SPPC is still under investigation. Incorporation of HIPEC to standard multimodality therapy allows local control of peritoneal carcinomatosis (86). In two case series of 32 and 22 patients treated with CRS followed by HIPEC, the reported 5-year OS was 57.4% and 64.9%, respectively (80,87). In terms of systematic chemotherapy, the combination of platinum/taxane yielded an ORR of 53–100% and median OS of 15–42 months (88). Apart from EOC patients, clinical trials of PARP inhibitors and bevacizumab in either upfront or maintenance setting, enroll those with SPPC; nevertheless, studies has not provided outcomes of each disease separately (46,48).


Conclusions

There is a lack of consensus regarding the optimal surgical timing and patients’ selection criteria for either upfront debulking surgery, or IDS. Algorithms should be conducted, depending on evidence-based prognostic factors. Complete surgical debulking remains the most reliable clinical endpoint, associated with longer survival. There is as strong rationale for the implementation of HIPEC in EOC treatment and data from randomized clinical trial are pending. The landscape of maintenance therapy for EOC is rapidly changing. Currently, antiangiogenesis (bevacizumab), and PARP inhibitors (olaparib, niraparib and rucaparib) have been incorporated in maintenance treatment and led to prolongation of PFS in patients with platinum-sensitive recurrent EOC. However, question remains regarding the choice of the optimal agent in the absence of head-to-head clinical trials’ data. Patients with SPPC are traditionally managed similarly to patients with advanced/metastatic primary EOC. Due to lack of prospective trials, the supportive evidence is limited to single institutions retrospective series.


Acknowledgments

The authors acknowledge support from the Research and Innovation department of Medway NHS Foundation Trust.

Funding: None.


Footnote

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/gpm-20-41). SB serves as an unpaid editorial board member of Gynecology and Pelvic Medicine from May 2020 to Apr 2022. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.


References

  1. Boussios S, Moschetta M, Karihtala P, et al. Development of new poly(ADP-ribose) polymerase (PARP) inhibitors in ovarian cancer: Quo Vadis? Ann Transl Med 2020. [Crossref]
  2. Vergote I, Tropé CG, Amant F, et al. Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer. N Engl J Med 2010;363:943-53. [Crossref] [PubMed]
  3. Kehoe S, Hook J, Nankivell M, et al. Primary chemotherapy versus primary surgery for newly diagnosed advanced ovarian cancer (CHORUS): an open-label, randomised, controlled, non-inferiority trial. Lancet 2015;386:249-57. [Crossref] [PubMed]
  4. Coleman RL, Brady MF, Herzog TJ, et al. Bevacizumab and paclitaxel-carboplatin chemotherapy and secondary cytoreduction in recurrent, platinum-sensitive ovarian cancer (NRG Oncology/Gynecologic Oncology Group study GOG-0213): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 2017;18:779-91. [Crossref] [PubMed]
  5. Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med 2012;366:1382-92. [Crossref] [PubMed]
  6. Coleman RL, Oza AM, Lorusso D, et al. ARIEL3 investigators. Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2017;390:1949-61. [Crossref] [PubMed]
  7. Pujade-Lauraine E, Ledermann JA, Selle F, et al. SOLO2/ENGOT-Ov21 investigators. Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol 2017;18:1274-84. [Crossref] [PubMed]
  8. Oza AM, Cibula D, Benzaquen AO, et al. Olaparib combined with chemotherapy for recurrent platinum-sensitive ovarian cancer: a randomised phase 2 trial. Lancet Oncol 2015;16:87-97. [Crossref] [PubMed]
  9. Mirza MR, Monk BJ, Herrstedt J, et al. ENGOT-OV16/NOVA investigators. niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med 2016;375:2154-64. [Crossref] [PubMed]
  10. Boussios S, Karathanasi A, Cooke D, et al. PARP Inhibitors in ovarian cancer: the route to "Ithaca". Diagnostics (Basel) 2019;9:55. [Crossref] [PubMed]
  11. Pentheroudakis G, Pavlidis N. Serous papillary peritoneal carcinoma: unknown primary tumour, ovarian cancer counterpart or a distinct entity? A systematic review. Crit Rev Oncol Hematol 2010;75:27-42. [Crossref] [PubMed]
  12. Lheureux S, Braunstein M, Oza AM. Epithelial ovarian cancer: evolution of management in the era of precision medicine. CA Cancer J Clin 2019;69:280-304. [PubMed]
  13. du Bois A, Reuss A, Pujade-Lauraine E, et al. Role of surgical outcome as prognostic factor in advanced epithelial ovarian cancer: a combined exploratory analysis of 3 prospectively randomized phase 3 multicenter trials: by the Arbeitsgemeinschaft Gynaekologische Onkologie Studiengruppe Ovarialkarzinom (AGO-OVAR) and the Groupe d'Investigateurs Nationaux Pour les Etudes des Cancers de l'Ovaire (GINECO). Cancer 2009;115:1234-44. [Crossref] [PubMed]
  14. Clifford C, Vitkin N, Nersesian S, et al. Multi-omics in high-grade serous ovarian cancer: biomarkers from genome to the immunome. Am J Reprod Immunol 2018;80:e12975. [Crossref] [PubMed]
  15. van Zyl B, Tang D, Bowden NA. Biomarkers of platinum resistance in ovarian cancer: what can we use to improve treatment. Endocr Relat Cancer 2018;25:R303-18. [Crossref] [PubMed]
  16. Colombo N, Sessa C, du Bois A, et al. ESMO-ESGO consensus conference recommendations on ovarian cancer: pathology and molecular biology, early and advanced stages, borderline tumours and recurrent disease†. Ann Oncol 2019;30:672-705. [Crossref] [PubMed]
  17. Katchman BA, Chowell D, Wallstrom G, et al. Autoantibody biomarkers for the detection of serous ovarian cancer. Gynecol Oncol 2017;146:129-36. [Crossref] [PubMed]
  18. Gorodnova TV, Sokolenko AP, Ivantsov AO, et al. High response rates to neoadjuvant platinum-based therapy in ovarian cancer patients carrying germ-line BRCA mutation. Cancer Lett 2015;369:363-7. [Crossref] [PubMed]
  19. Kessous R, Octeau D, Klein K, et al. Distinct homologous recombination gene expression profiles after neoadjuvant chemotherapy associated with clinical outcome in patients with ovarian cancer. Gynecol Oncol 2018;148:553-8. [Crossref] [PubMed]
  20. Katopodis P, Chudasama D, Wander G, et al. Kinase Inhibitors and Ovarian Cancer. Cancers (Basel) 2019;11:1357. [Crossref] [PubMed]
  21. Cho JH, Kim S, Song YS. Neoadjuvant chemotherapy in advanced ovarian cancer: optimal patient selection and response evaluation. Chin Clin Oncol 2018;7:58. [Crossref] [PubMed]
  22. Josahkian JA, Saggioro FP, Vidotto T, et al. Increased STAT1 expression in high grade serous ovarian cancer is associated with a better outcome. Int J Gynecol Cancer 2018;28:459-65. [Crossref] [PubMed]
  23. Jin C, Xue Y, Li Y, et al. A 2-protein signature predicting clinical outcome in high-grade serous ovarian cancer. Int J Gynecol Cancer 2018;28:51-8. [Crossref] [PubMed]
  24. Martin de la Fuente L, Westbom-Fremer S, Arildsen NS, et al. PD-1/PD-L1 expression and tumor-infiltrating lymphocytes are prognostically favorable in advanced high-grade serous ovarian carcinoma. Virchows Arch 2020;477:83-91. [Crossref] [PubMed]
  25. Oliveira KCS, Ramos IB, Silva JMC, et al. Current perspectives on circulating tumor DNA, precision medicine, and personalized clinical management of cancer. Mol Cancer Res 2020;18:517-28. [Crossref] [PubMed]
  26. Chesnais M, Lecuru F, Mimouni M, et al. A pre-operative predictive score to evaluate the feasibility of complete cytoreductive surgery in patients with epithelial ovarian cancer. PLoS One 2017;12:e0187245. [Crossref] [PubMed]
  27. Angeles MA, Ferron G, Cabarrou B, et al. Prognostic impact of celiac lymph node involvement in patients after frontline treatment for advanced ovarian cancer. Eur J Surg Oncol 2019;45:1410-6. [Crossref] [PubMed]
  28. Powless CA, Aletti GD, Bakkum-Gamez JN, et al. Risk factors for lymph node metastasis in apparent early-stage epithelial ovarian cancer: implications for surgical staging. Gynecol Oncol 2011;122:536-40. [Crossref] [PubMed]
  29. McIntosh LJ, O'Neill AC, Bhanusupriya S, et al. Prognostic significance of supradiaphragmatic lymph nodes at initial presentation in patients with stage III high-grade serous ovarian cancer. Abdom Radiol (NY) 2017;42:2513-20. [Crossref] [PubMed]
  30. Makar AP, Tropé CG, Tummers P, et al. Advanced ovarian cancer: primary or interval debulking? five categories of patients in view of the results of randomized trials and tumor biology: primary debulking surgery and interval debulking surgery for advanced ovarian cancer. Oncologist 2016;21:745-54. [Crossref] [PubMed]
  31. Rufián S, Muñoz-Casares FC, Briceño J, et al. Radical surgery-peritonectomy and intraoperative intraperitoneal chemotherapy for the treatment of peritoneal carcinomatosis in recurrent or primary ovarian cancer. J Surg Oncol 2006;94:316-24. [Crossref] [PubMed]
  32. Sugarbaker PH. Surgical responsibilities in the management of peritoneal carcinomatosis. J Surg Oncol 2010;101:713-24. [Crossref] [PubMed]
  33. Armstrong DK, Alvarez RD, Bakkum-Gamez JN, et al. NCCN guidelines insights: ovarian cancer, version 1.2019. J Natl Compr Canc Netw 2019;17:896-909. [Crossref] [PubMed]
  34. Hotouras A, Desai D, Bhan C, et al. Heated intraperitoneal chemotherapy (HIPEC) for patients with recurrent ovarian cancer: a systematic literature review. Int J Gynecol Cancer 2016;26:661-70. [Crossref] [PubMed]
  35. Polom K, Roviello G, Generali D, et al. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for treatment of ovarian cancer. Int J Hyperthermia 2016;32:298-310. [Crossref] [PubMed]
  36. Wagner U, Marth C, Largillier R, et al. Final overall survival results of phase III GCIG CALYPSO trial of pegylated liposomal doxorubicin and carboplatin vs paclitaxel and carboplatin in platinum-sensitive ovarian cancer patients. Br J Cancer 2012;107:588-91. [Crossref] [PubMed]
  37. Harter P, du Bois A, Hahmann M, et al. Surgery in recurrent ovarian cancer: the Arbeitsgemeinschaft Gynaekologische Onkologie (AGO) DESKTOP OVAR trial. Ann Surg Oncol 2006;13:1702-10. [Crossref] [PubMed]
  38. Aghajanian C, Blank SV, Goff BA, et al. OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J Clin Oncol 2012;30:2039-45. [Crossref] [PubMed]
  39. Quenet F, Elias D, Roca L, et al. A UNICANCER phase III trial of hyperthermic intra-peritoneal chemotherapy (HIPEC) for colorectal peritoneal carcinomatosis (PC): PRODIGE 7. J Clin Oncol 2018;36: abstr LBA3503.
  40. Cascales Campos PA, Gil J, Munoz-Ramon P, et al. Hipec in ovarian cancer. Why is it still the ugly duckling of intraperitoneal therapy? J Cancer Sci Ther 2016;8:30.
  41. Fotopoulou C, Sehouli J, Mahner S, et al. HIPEC: HOPE or HYPE in the fight against advanced ovarian cancer? Ann Oncol 2018;29:1610-3. [Crossref] [PubMed]
  42. Riggs MJ, Pandalai PK, Kim J, et al. Hyperthermic intraperitoneal chemotherapy in ovarian cancer. Diagnostics (Basel) 2020;10:43. [Crossref] [PubMed]
  43. Ledermann JA, Raja FA, Fotopoulou C, et al. Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2018;29:iv259. [Crossref]
  44. Pignata S, Lorusso D, Joly F, et al. Chemotherapy plus or minus bevacizumab for platinum-sensitive ovarian cancer patients recurring after a bevacizumab containing first line treatment: the randomized phase 3 trial: MITO16B-MaNGO OV2B-ENGOT OV17. J Clin Oncol 2018;36:5506. [Crossref]
  45. Pfisterer J, Shannon CM, Baumann K, et al. AGO-OVAR 2.21/ENGOT-ov 18 Investigators. Bevacizumab and platinum-based combinations for recurrent ovarian cancer: a randomised, open-label, phase 3 trial. Lancet Oncol 2020;21:699-709. [Crossref] [PubMed]
  46. Boussios S, Karihtala P, Moschetta M, et al. Veliparib in ovarian cancer: a new synthetically lethal therapeutic approach. Invest New Drugs 2020;38:181-93. [Crossref] [PubMed]
  47. Boussios S, Abson C, Moschetta M, et al. Poly (ADP-Ribose) Polymerase Inhibitors: Talazoparib in Ovarian Cancer and Beyond. Drugs R D 2020;20:55-73. [Crossref] [PubMed]
  48. Boussios S, Karihtala P, Moschetta M, et al. Combined Strategies with poly (ADP-Ribose) polymerase (PARP) inhibitors for the treatment of ovarian cancer: a literature review. Diagnostics (Basel) 2019;9:87. [Crossref] [PubMed]
  49. Lorusso D, Fontanella C, Maltese G, et al. The safety of antiangiogenic agents and PARP inhibitors in platinum-sensitive recurrent ovarian cancer. Expert Opin Drug Saf 2017;16:687-96. [Crossref] [PubMed]
  50. Mullen MM, Kuroki LM, Thaker PH. Novel treatment options in platinum-sensitive recurrent ovarian cancer: a review. Gynecol Oncol 2019;152:416-25. [Crossref] [PubMed]
  51. Moore K, Colombo N, Scambia G, et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med 2018;379:2495-505. [Crossref] [PubMed]
  52. González-Martín A, Pothuri B, Vergote I, et al. Niraparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med 2019;381:2391-402. [Crossref] [PubMed]
  53. Ray-Coquard I, Pautier P, Pignata S, et al. Olaparib plus bevacizumab as first-line maintenance in ovarian cancer. N Engl J Med 2019;381:2416-28. [Crossref] [PubMed]
  54. Hamanishi J, Mandai M, Ikeda T, et al. Safety and antitumor activity of anti-PD-1 antibody, nivolumab, in patients with platinum-resistant ovarian cancer. J Clin Oncol 2015;33:4015-22. [Crossref] [PubMed]
  55. Liu JF, Gordon M, Veneris J, et al. Safety, clinical activity and biomarker assessments of atezolizumab from a phase I study in advanced/recurrent ovarian and uterine cancers. Gynecol Oncol 2019;154:314-22. [Crossref] [PubMed]
  56. Disis ML, Taylor MH, Kelly K, et al. Efficacy and safety of avelumab for patients with recurrent or refractory ovarian cancer: phase 1b results from the JAVELIN solid tumor trial. JAMA Oncol 2019;5:393-401. [Crossref] [PubMed]
  57. Matulonis UA, Shapira-Frommer R, Santin AD, et al. Antitumor activity and safety of pembrolizumab in patients with advanced recurrent ovarian cancer: results from the Phase 2 KEYNOTE-100 study. Ann Oncol 2019;30:1080-7. [Crossref] [PubMed]
  58. Hodi FS, Butler M, Oble DA, et al. Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients. Proc Natl Acad Sci USA 2008;105:3005-10. [Crossref] [PubMed]
  59. Phase II study of ipilimumab monotherapy in recurrent platinum-sensitive ovarian cancer. Available online: (Accessed on 11 June 2020).https://clinicaltrials.gov/ct2/show/results/NCT01611558
  60. Pujade-Lauraine E, Fujiwarab K, Ledermann JA, et al. Avelumab alone or in combination with pegylated liposomal doxorubicin versus pegylated liposomal doxorubicin alone in platinum-resistant or refractory epithelial ovarian cancer: Primary and biomarker analysis of the phase III JAVELIN Ovarian 200 trial. Gynecol Oncol 2019;154:21-2. [Crossref]
  61. A study of atezolizumab versus placebo in combination with paclitaxel, carboplatin, and bevacizumab in participants with newly-diagnosed stage III or stage IV ovarian, fallopian tube, or primary peritoneal cancer (IMagyn050). Available online: (Accessed on 11 June 2020).https://clinicaltrials.gov/ct2/show/NCT03038100
  62. ATALANTE: atezolizumab vs placebo phase III study in late relapse ovarian cancer treated with chemotherapy + bevacizumab (ATALANTE). Available online: (Accessed on 11 June 2020).https://clinicaltrials.gov/ct2/show/NCT02891824
  63. Pegylated liposomal doxorubicin hydrochloride with atezolizumab and/or bevacizumab in treating patients with recurrent ovarian, fallopian tube, or primary peritoneal cancer. Available online: (Accessed on 11 June 2020).https://clinicaltrials.gov/ct2/show/NCT02839707
  64. Huang LW, Garrett AP, Muto MG, et al. Identification of a novel 9 cM deletion unit on chromosome 6q23-24 in papillary serous carcinoma of the peritoneum. Hum Pathol 2000;31:367-73. [Crossref] [PubMed]
  65. Schorge JO, Muto MG, Welch WR, et al. Molecular evidence for multifocal papillary serous carcinoma of the peritoneum in patients with germline BRCA1 mutations. J Natl Cancer Inst 1998;90:841-5. [Crossref] [PubMed]
  66. Halperin R, Zehavi S, Hadas E, et al. Immunohistochemical comparison of primary peritoneal and primary ovarian serous papillary carcinoma. Int J Gynecol Pathol 2001;20:341-5. [Crossref] [PubMed]
  67. Chen LM, Yamada SD, Fu YS, et al. Molecular similarities between primary peritoneal and primary ovarian carcinomas. Int J Gynecol Cancer 2003;13:749-55. [Crossref] [PubMed]
  68. Huang LW, Garrett AP, Schorge JO, et al. Distinct allelic loss patterns in papillary serous carcinoma of the peritoneum. Am J Clin Pathol 2000;114:93-9. [Crossref] [PubMed]
  69. Terai Y, Ueda M, Kumagai K, et al. Tumor angiogenesis and thymidine phosphorylase expression in ovarian carcinomas including serous surface papillary adenocarcinoma of the peritoneum. Int J Gynecol Pathol 2000;19:354-60. [Crossref] [PubMed]
  70. Pentheroudakis G, Spector Y, Krikelis D, et al. Global microRNA profiling in favorable prognosis subgroups of cancer of unknown primary (CUP) demonstrates no significant expression differences with metastases of matched known primary tumors. Clin Exp Metastasis 2013;30:431-9. [Crossref] [PubMed]
  71. Fizazi K, Greco FA, Pavlidis N, et al. Cancers of unknown primary site: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2015;26:v133-8. [Crossref] [PubMed]
  72. Iavazzo C, Vorgias G, Katsoulis M, et al. Primary peritoneal serous papillary carcinoma: clinical and laboratory characteristics. Arch Gynecol Obstet 2008;278:53-6. [Crossref] [PubMed]
  73. Prat J. FIGO Committee on Gynecologic Oncology. Staging classification for cancer of the ovary, fallopian tube, and peritoneum. Int J Gynaecol Obstet 2014;124:1-5. [Crossref] [PubMed]
  74. Gibbs AR. Tumours of the serosal membranes. armed forces institute of pathology atlas of tumour pathology, fourth series, fascicle 3. Occup Environ Med 2007;64:288. [Crossref]
  75. Liu Q, Lin JX, Shi QL, et al. Primary peritoneal serous papillary carcinoma: a clinical and pathological study. Pathol Oncol Res 2011;17:713-9. [Crossref] [PubMed]
  76. Ozcan A, Shen SS, Hamilton C, et al. PAX 8 expression in non-neoplastic tissues, primary tumors, and metastatic tumors: a comprehensive immunohistochemical study. Mod Pathol 2011;24:751-64. [Crossref] [PubMed]
  77. Matsuo K, Sheridan TB, Mabuchi S, et al. Estrogen receptor expression and increased risk of lymphovascular space invasion in high-grade serous ovarian carcinoma. Gynecol Oncol 2014;133:473-9. [Crossref] [PubMed]
  78. Boussios S, Moschetta M, Karathanasi A, et al. Malignant peritoneal mesothelioma: clinical aspects, and therapeutic perspectives. Ann Gastroenterol 2018;31:659-69. [PubMed]
  79. Steinhagen PR, Sehouli J. The involvement of retroperitoneal lymph nodes in primary serous-papillary peritoneal carcinoma. a systematic review of the literature. Anticancer Res 2011;31:1387-94. [PubMed]
  80. Deraco M, Sinukumar S, Salcedo-Hernández RA, et al. Clinico-pathological outcomes after total parietal peritonectomy, cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in advanced serous papillary peritoneal carcinoma submitted to neoadjuvant systemic chemotherapy- largest single institute experience. Eur J Surg Oncol 2019;45:2103-8. [Crossref] [PubMed]
  81. Unal OU, Oztop I, Yazici O, et al. Treatment and prognostic factors in primary peritoneal carcinoma: a multicenter study of the Anatolian Society of Medical Oncology (ASMO). Oncol Res Treat 2014;37:332-8. [Crossref] [PubMed]
  82. Crane EK, Sun CC, Ramirez PT, et al. The role of secondary cytoreduction in low-grade serous ovarian cancer or peritoneal cancer. Gynecol Oncol 2015;136:25-9. [Crossref] [PubMed]
  83. Atallah D, Rassy EE, Chahine G. Is the LION strong enough? Future Oncol 2017;13:1835-7. [Crossref] [PubMed]
  84. Luyckx M, Leblanc E, Filleron T, et al. Maximal cytoreduction in patients with FIGO stage IIIC to stage IV ovarian, fallopian, and peritoneal cancer in day-to-day practice: a Retrospective French Multicentric Study. Int J Gynecol Cancer 2012;22:1337-43. [Crossref] [PubMed]
  85. Connolly CF, Yahya S, Chan KK, et al. Outcomes following interval debulking surgery in primary peritoneal carcinoma. Anticancer Res 2016;36:255-9. [PubMed]
  86. Yuan J, He L, Han B, et al. Long-term survival of high-grade primary peritoneal papillary serous adenocarcinoma: a case report and literature review. World J Surg Oncol 2017;15:76. [Crossref] [PubMed]
  87. Bakrin N, Gilly FN, Baratti D, et al. Primary peritoneal serous carcinoma treated by cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy. A multi-institutional study of 36 patients. Eur J Surg Oncol 2013;39:742-7. [Crossref] [PubMed]
  88. Pavlidis N, Pentheroudakis G. Cancer of unknown primary site. Lancet 2012;379:1428-35. [Crossref] [PubMed]
doi: 10.21037/gpm-20-41
Cite this article as: Boussios S, Sadauskaite A, Kanellos FS, Tsiouris AK, Karathanasi A, Sheriff M. Neoadjuvant, HIPEC and maintenance treatment in ovarian and peritoneal serous cancer: current status. Gynecol Pelvic Med 2020;3:19.