Intraperitoneal chemotherapy for ovarian cancer with peritoneal metastases, systematic review of the literature and focused personal experience

Introduction

Epithelial ovarian cancer (EOC) causes 60% of ovarian cancer cases and is the fourth most common cause of death from cancer in women. The most frequent histologic type (70% of cases) is high-grade serous ovarian cancer with a typical biological behavior. According to FIGO classification the stage III includes a tumor with involvement of one or both ovaries and/or the Fallopian tubes with peritoneal involvement, outside the pelvis (FIGO IIIb) and retroperitoneal lymph node involvement (FIGO IIIc) (1). Stages IIIb and IIIc comprise about 60% of EOC. The standard of care for EOC includes a surgical removal of all visible evidence of disease by extensive cytoreductive surgery (CRS). This includes hysterectomy and bilateral salpingo-oophorectomy, total omentectomy, appendectomy (in mucinous histologic types), removal of bulky pelvic and aortic lymph nodes, and removal of all macroscopic disease. The cancer resection is followed by intravenous (IV) chemotherapy (CT), including a platinum-based drug with or without a taxane (2,3).

Recurrence is a common event in high grade EOC, with 75% of women experiencing relapse within 2 years from diagnosis and subsequent treatment (4). Among patients with recurrent disease, two-third have peritoneal metastases (5). The most investigated factors predicting outcome after recurrence is the platinum-free interval following primary platinum-based chemotherapy and the presence of BRCA mutations (6). Traditionally, most patients with recurrent-EOC (rEOC) are treated with chemotherapy alone, the type of which is guided by the platinum sensitivity. Patients with recurrence more than six months after a complete response are considered “platinum-sensitive” (platinum-S) and can be re-treated with platinum-based CT. Patients with persistent disease after front-line treatment or patients who recur within 6 months are considered “platinum-resistant” (platinum-R) and are unlikely to respond to further platinum. In recent decades several studies concerning the role of intraperitoneal antibodies, immunotherapy, radiotherapy and the administration of chemotherapeutic agents directly into the peritoneal cavity before, during or after surgery, have been performed to evaluate their impact on survival.

Intraperitoneal (IP) CT has been introduced into the therapeutic algorithm of EOC with positive but not definitive results. Several methodologies for delivering IP CT have been described. The most common way to perform intraperitoneal chemotherapy is the hyperthermic intraperitoneal chemotherapy (HIPEC). Early post-operative intraperitoneal chemotherapy (EPIC) and the pressurized intraperitoneal aerosolized chemotherapy (PIPAC) have also been described and utilized with interesting results.

EOC HIPEC may be used with variable timing: Primary CRS, secondary CRS, interval debulking, CRS for progressive ovarian cancer, CRS in recurrent EOC and palliative surgery (2).

Our systematic review aims to present the different results of IP CT at different timepoints of the disease and to review the drugs administered intraperitoneally. Moreover, a personal experience describing new results obtained with combined administration of platinum and taxanes as HIPEC will be presented. We present the following article in accordance with the PRISMA 2009 Checklist (available at http://dx.doi.org/10.21037/jgo-2020-06).

Material and methods

Systematic review

A computerized search was performed in selected databanks (MEDLINE, Scopus, EMBASE). Citations were included for the period between January 1990 and January 2020 using the primary search strategy: ovarian cancer, intraperitoneal chemotherapy, HIPEC, EPIC, PIPAC, IP, drugs, pharmacokinetic, pharmacodynamic, hyperthermia, outcome, follow-up, consolidative, combined with and/or. No search restrictions were imposed. The dates were selected to allow comprehensive published abstracts of clinical trials, consensus conferences, comparative studies, congresses, guidelines, government publications, multicenter studies, systematic reviews, meta-analysis, large case series, original articles, and randomized controlled trials. Only EOC (serous, mucinous, clear cell, carcinosarcoma, endometrioid, cystadenocarcinoma, adenocarcinoma, Fallopian tube carcinoma, and primary peritoneal malignancies) were included in the study. The research strategy is summarized in Figure 1. Two reviewers (FC and PF) analyzed the literature and selected studies. Were uncertainty arises a thirs reviewer was asked to express his opinion (LA).

Figure 1 PRISMA flow chart.

Personal experience:

From our electronic database we selected patients with EOC treated with CRS combined with HIPEC at different time points of the disease (upfront CRS and HIPEC, interval CRS and HIPEC, CRS and HIPEC for recurrent EOC) from January 2011 to May 2019. A retrospective analysis of prospectively collected data was performed. All patients had an Eastern Cooperative Oncology Group (ECOG) performance status ≤2, stage IIIC and IV EOC with resectable disease, no extra-abdominal disease and no significant comorbidities which would preclude the combined treatment. Patients with histology other than EOC and without complete data concerning follow-up were excluded.

The extent of the disease after laparotomy was determined by PCI. The abdomen and pelvis were divided into 13 regions and the size of the lesion was scored as 0–3. The maximum score was 39. CRS was performed removing all peritoneum and visceral organs involved by the tumor. Omentectomy, appendectomy and cholecystectomy were routinely performed. The completeness of cytoreduction score (CC) was estimated by the surgeon at the conclusion of the procedure according to the following classification: CC0—complete cytoreduction of all visible disease; CC1—minimal residual disease with nodules less than 2.5 cm; CC2—residual disease with nodules of 2.5 mm to 2.5 cm; and CC3—residual disease with nodules greater than 2.5 cm. HIPEC was performed with the “coliseum technique”: one inflow and four outflow catheters were placed with the open abdomen that was partially closed with a surgical adhesive drape performing a “closed-HIPEC with open abdomen technique”, with a IP temperature was 42–43 °C. HIPEC regimens were: Cisplatin 100 mg/m² + paclitaxel 175 mg/m² or cisplatin 100 mg/m² + mitomycin C 16 mg/m² or cisplatin 100 mg/m² + doxorubicin 15.2 mg/L of perfusate or cisplatin 100 mg/m² alone. After HIPEC, the perfusate was drained and the reconstruction was performed.

The primary endpoints of the analysis were DFS and OS. Univariate and multivariate analysis were performed to define factors affecting OS and DFS, as secondary endpoint.

Statistical analysis

DFS and OS were calculated as the interval between the date of CRS and HIPEC and the data of the last follow-up or of the death or of the recurrence of disease. DFS and OS were calculated with Kaplan-Meier method, and survival estimates were compared using the log-rank test. Multivariate analysis was performed for OS and DFS with Cox regression. Statistical significance was defined as a P value <0.005. All analysis was performed using SPSS 20 (IBM Corp, Released 2011, IBM SPSS Statistics for Windows, Version 20.0, Armonk, NY, USA)

Systematic review results

The focus of the majority of the studies concerning advanced ovarian cancer are tumor biology and behavior of the tumor. Noteworthy, women with mutations of BRCA1 and BRCA2 genes have a higher risk (11–40%) to develop EOC. Cytoreductive surgery (CRS) has been showed as one of the most important factors influencing survival rates. The aim of CRS is to remove all visible disease, giving a demonstrated survival benefit with increasing completeness of cytoreduction. Intraperitoneal chemotherapy aims to remove residual microscopic disease with an additional positive effect of reducing systemic toxicity as compared to the intravenous CT.

In 2002, a meta-analysis by Bristow et al. analyzed 6,885 women with stage III and IV EOC. They demonstrated that if CRS removed less than 25% of the disease patients experienced a mean weighted median survival of 22.7 months. IF CRS removed more than 75% of the disease the mean weighted median survival was 33.9 months. Each 10% increase in cytoreduction rate was associated with an increase of 5.5% in median survival time (7). However, at primary surgery, in 74% and 73% respectively of women with stage III and stage IV of disease there was lymph node positivity. For this reason, IV CT remains fundamental to reduce or limit lymphatic tumor dissemination and to downstage and downsize the tumor (2,8). Despite aggressive treatment more than 60% of women had recurrence within 12–18 months. In general, recurrence is seen in 29.4% in abdominal cavity and 25.9% in the pelvis, 7.1% in retroperitoneal lymph node and 6.3% in superficial lymph nodes (9). The addition of HIPEC has many goals: To treat microscopical disease, to increase drug penetration into the tissues, to have an intrinsic antitumor effect and to increase the cytotoxicity of some CT drugs. In the open technique it can be manual and uniformly distributed (3,10).

In 2006 a National Cancer Institute (NCI) clinical announcement about EOC (FIGO III–IV) reported that adding IP CT to IV CT significantly improves survival by 12 months (range 0–16 months) if associated with optimal CRS (CC0-1). However in a recent report, Vergote et al. (8) suggested that IP CT was not a standard of care in first-line treatment for advanced EOC because of the results of the GOG 252 study.

Some reports comparing IP/IV to only IV therapy, showed a possible increasing in toxicity in IP/IV regimens; however, it is short-term and manageable (3). Certain CT agents, including cisplatin and paclitaxel, were found to have distinct pharmacokinetic advantages when administered intraperitoneally (11-13). The American Society of Peritoneal Surface Malignancies (ASPSM) suggests the use of mitomycin-C or paclitaxel especially in platinum-resistant disease (3).

Primary epithelial ovarian cancer

Few trials were published about HIPEC in primary EOC (pEOC). HIPEC for pEOC can be proposed in an upfront setting (U-HIPEC) or as an interval treatment (I-HIPEC) (14). U-HIPEC for primary CRS would be followed by platinum-based adjuvant chemotherapy. However, frequently women with pEOC cannot tolerate primary CRS due to a lack of fitness for major surgery or the extent of disease. In these cases a neoadjuvant chemotherapy followed by CRS plus I-HIPEC may be appropriate.

Three randomized controlled trials (RCT) have been conducted to evaluate HIPEC in upfront or interval setting in pEOC (Table 1). Van Driel in 2018 published the results of the OVHIPEC trial (16). 245 patients were randomized to HIPEC and CRS or CRS alone in an interval setting. In the study group a 12 months increase in overall survival (OS) and 4 months increase in progression-free survival (PFS) were demonstrated. Moreover, morbidity and quality of life were similar in the two groups. Survival in the control group (33.9 months) was very similar to the results reported by Chiva et al. in their meta-analysis concerning primary or interval CRS alone in EOC (33 months). As a comparison I-HIPEC increased median OS to 45.7 months (versus 33.9) without increasing toxicity rate and with a similar quality of life (15,19).

Table 1 Randomized controlled trials focus on intraperitoneal chemotherapy for primary EOC and recurrent EOC
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Lim et al., in their RCT in 2017, reported the randomization of 184 patients with similar result both in OS, PFS and mortality in an upfront setting. They reported an increased anemia and acute kidney injury rate in the HIPEC group. However, these authors found in neo-adjuvant chemotherapy (NACT) subgroup an improved outcome in favour of HIPEC and suggested that a longer follow-up may help in showing the real effect of HIPEC (20).

The last study from Koole et al. reported in 2019 results derived from the randomization of 246 patients managed in an interval setting. They did not find significant differences in survival, recurrence or quality of life results (15).

Observational studies reported in literature considered both primary EOC (pEOC) and recurrent EOC (rEOC).

There are three prospective studies analyzing pEOC treated with CRS + HIPEC in an upfront setting (21-23) (Table 2). In more than 94% of patients a complete cytoreduction (CC0) was achieved. No mortality was reported, and major morbidity ranged between 20% to 44%. Despite the different drug regimens (Paris et al. added adjuvant bevacizumab) the 2-year OS was 93.2% (23).

Table 2 Prospective observational studies focus on intraperitoneal chemotherapy for primary EOC
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The HYPERO study (20) reported in U-HIPEC setting a mean OS of 41.7 months, with a 2y-OS of 57% and a 5y-OS of 33.3%, and in I-HIPEC setting a mean OS of 68.6 months, with a 2y-OS of 80.4% and a 5y-OS of 50.2%.

There are four retrospective studies focused on pEOC. In these studies different HIPEC timings and CT regimens were compared (up-front, interval, or associate with dose-dense chemotherapy) (24-27) (Table 3). CC0 was achieved in more than 73% of patients. These studies reported a mortality rate lower than 3% and a morbidity rate of 13–26.5%. The reported DFS ranged between 10 and 35 months. 5-years OS ranged between 31.5 and 46.8%. Biacchi et al. (25), analyzed women with primary advanced tubo-ovarian high-grade serous cancer. They showed no difference between U- or I-HIPEC in terms of DFS and OS. U-HIPEC showed similar outcome to patients who underwent I-HIPEC with complete response after NACT. However, the small number of patients undergoing U-HIPEC and the retrospective design limited the reliability of this study. No differences in terms of complications, were reported comparing HIPEC (I- or U-) with cisplatin (75 mg/m²) or paclitaxel (60 mg/m²) (26). Rettenmaier et al. (24) suggested that dose density chemotherapy with HIPEC may offer better results in terms of OS and DFS, especially in BRCA mutated patients. In conclusion, as suggested by van Driel, the optimal timepoint may be the I-HIPEC. The NACT provides a higher rate of CC0 cytoreduction and can be advantageously associated with HIPEC. Moreover, HIPEC may have a role in reducing peritoneal recurrence in EOC, which has a greater impact on survival than lymph nodal recurrence (28). The role of bevacizumab in front-line setting combined with HIPEC remains to be explored. Lastly, more attention should be paid to the genotypes in evaluating results and approaches. Futher answers might come from from the several ongoing trials (Table 4).

Table 3 Retrospective observational studies focus on intraperitoneal chemotherapy for primary EOC
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Table 4 Ongoing randomized controlled trials about CRS and HIPEC for primary and recurrent EOC found in clinicalregister.gov at March 2020
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Recurrent epithelial ovarian cancer (rEOC)

The prognosis of rEOC treated with standard chemotherapy is poor, with a reported median survival of 12–24 months (29). In a few studies focusing on platinum-S patients, the median OS reaches 35 months, while in platinum-R patients it is about 12 months (22). The need for alternative treatment modalities has been pointed out by Stathopoulos et al., who stated that multiple chemotherapy lines do not offer a survival benefit as compared to one or two lines (2,30).

In recent years, patients with rEOC with a BRCA mutation (BRCAmut) are most likely to benefit from treatment with PARP inhibitors, after response to a platinum-based chemotherapy, with reported DFS of 11.2 months (compared to 4.3 months of the placebo group) and OS of 34.9 months (31). For patients with wild-type BRCA (BRCAwt) treated with Olaparib, the reported DFS was 7.4 (compared to 5.5 months in the placebo group) and the median OS of 24.5 months.

The role of CRS in rEOC and its role in relation with the patients’ BRCA status has recently been clarified by the AGO DESKTOP III/ENGOT ov20 trial results (32). The study showed a significant survival advantage of 7.2 months in platinum-S women with positive AGO score who underwent complete resection. They showed a DFS of 14 months without and of 19.6 months with CRS. BRCAmut patients had the best DFS regardless of having received secondary CRS or not, with a 5-year DFS of 73% in non-resected women versus 78% in resected women (P=0.558). Conversely, BRCAwt patients who underwent complete CRS had a significantly longer DFS compared with BRCAwt patients who did not receive surgery (5-year DFS of 54% vs. 42%; P=0.048).

HIPEC with recurrent epithelial ovarian cancer

Many retrospective and prospective observational studies (Tables 5-8) focused on the effects of HIPEC on patients with rEOC with heterogenous results. In these studies taken together, the reported median OS for rEOC treated with CRS and HIPEC ranges from 24.3 to 58.3 months (5y-OS: 8–79%) and the median DFS from 6 to 28 months (5y-DFS: 7–30%). In the largest study by Bakrin et al. (75), on 477 rEOC treated with CRS+HIPEC, the median OS was 45.7 months, with a OS of CC-0 patients of 52 months (compared to 33 months in not completely cytoreduced patients), without difference between platinum-S and platinum-R patients. In the study by Classe et al. (41) on 314 patients the 5y-OS was 38.0% (median OS 42 months for platinum-S and 51 months for platinum-R, P=0.38) and 5y-DFS was 14% (median DFS 13 months for platinum-S and 14 months for platinum-R, P=0.013). In the study by Bakrin et al. (36) on 246 patients the median OS was 48.9 months (48 months in platinum-R and 52 months in platinum-S) and the 5y-OS 35%; the median DFS was 12.8 months and the 5y-DFS 9%. Focusing on platinum-S patients treated with CRS+HIPEC, the reported OS ranged from 26 to 58.8 months (5y-OS: 50–79%) and the DFS from 6 to 27 (5y-DFS: 30%). The reported OS for platinum-R patients ranges from 9 to 51 months (33). Bakrin et al. (36) and Chatzigeorgiou et al. (39) compared OS of platinum-R and platinum-S patients with rEOC treated with CRS + HIPEC without showing significant difference.

Table 5 Retrospective observational studies focus on intraperitoneal chemotherapy for recurrent EOC
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Table 6 Prospective studies focus on intraperitoneal chemotherapy for recurrent EOC
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Table 7 Retrospective observational studies focus on intraperitoneal chemotherapy for primary and recurrent EOC
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Table 8 Prospective observational studies focus on intraperitoneal chemotherapy for primary and recurrent EOC
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Three case-control studies (33,56,59), all focusing on platinum-S patients, compared patients with rEOC treated with CRS+HIPEC with patients treated with traditional systemic CT. In the study by Safra et al. (59) and by Marocco et al. (56) patients treated with CRS and HIPEC showed significantly longer OS and DFS. In the study by Amira et al. (33) there was no significant difference in outcomes of the two groups. Safra et al. (59) compared BRCAmut and BRCAwt patients with rEOC treated with CRS+HIPEC or with systemic chemotherapy alone. The significant benefit in median DFS that was observed in the HIPEC group remained regardless of the patients’ BRCA status (BRCAwt: 21.8 in HIPEC group vs. 12.1 in control group, P=0.011; BRCAmut: 20.9 in HIPEC group vs. 12.6 in control group, P=0.012). The observed benefit in OS remained significant in BRCAmut patients treated with HIPEC and showed a trend toward a benefit in BRCAwt patients (BRCAwt: 61.6 in HIPEC group vs. 47.7 in control group, P=0.068; BRCAmut: 80.1 in HIPEC group vs. 71.6 in control group, P=0.036).

In eight case-control studies (35,47,55-57,60,62,77), almost all focused on platinum-S patients. They compared outcomes of patients treated with CRS + HIPEC with patients treated with CRS alone for rEOC. Most of the studies (47,55,57,62) showed a significant benefit in terms of OS and DFS in patients treated with HIPEC. Other studies showed better outcomes in HIPEC group but without statistical significance (38,56,60).

There is only one RCT that included 120 patients with rEOC (FIGO IIIC-IV) comparing CRS + HIPEC + systemic chemotherapy with CRS + systemic chemotherapy. The study showed a significant higher OS in the HIPEC group (26.9 vs. 14.2 months in stage IIIC and 26.4 vs. 11.9 months in stage IV, P=0.006). Furthermore, in the HIPEC group similar OS in platinum-S and platinum-R patients was observed while in the control group the OS of platinum-S patients was significantly longer than platinum-R ones (15.2 vs. 10.2, P=0.002). Median OS in HIPEC group was significantly higher than in CRS group both in PCI<15 (P=0.031) and in PCI>15 patients (P=0.049). This benefit remained only in CC-0 patients (30.9 vs. 16.9 months, P=0.038).

The study by Spiliotis (Table 1) was criticized by some authors (100) regarding methods and statistical analysis. The endpoints, the randomization procedure and the systemic CT regimen were not explained and DFS, morbidity and mortality were not reported. In two recent meta-analyses (101,102) including observational studies and the only RCT on rEOC, CRS + HIPEC showed a significant advantage compared to CRS alone in terms of OS and DFS (if CC-3 patients were excluded). Almost all the studies agree in affirming the completeness of the cytoreduction (CC-0) as the major prognostic factor on OS and DFS (18,34,39,42,44,52,57,69,76). The reported major morbidity and mortality for CRS + HIPEC in patients with rEOC ranges from 8.3 to 72% and from 0 to 22.2% respectively. Then, evidence to date suggests a role for HIPEC in both platinum-R and platinum-S patients and in both BRCAmut and BRCAwt patients with rEOC, but further phase III trial are needed in this setting.

Other intraperitoneal chemotherapy

A large case-control propensity-score study by Lu et al. (64) on 310 patients with rEOC compared CRS associated with platinum-based NIPEC with CRS associated with IV CT, showing significantly longer DFS in the NIPEC group, both in platinum-S and platinum-R patients (4.9 vs. 2.4 months, P<0.001, for platinum-R disease, and 9.8 vs. 6.9 months, P<0.001, for platinum-S disease). Three prospective observational studies (71-73) focusing on rEOC treated with PIPAC with cisplatin and doxorubicin showed a histologic tumor regression in 64% with median OS ranging from 13.6 to 14.7 months. The reported OS and DFS obtained with IP CT other than HIPEC in rEOC ranged from 13.6 to 25.5 months and from 2.4 to 9.8 months, respectively.

Consolidation intraperitoneal chemotherapy

Intraperitoneal chemotherapy has also been applied as consolidation treatment when patients present complete response to primary treatment (CRS and systemic chemotherapy) to reduce the chance of recurrence.

HIPEC

Several non-randomized reports (Tables 9,10) have investigated the use of second-look surgery with HIPEC as additional treatment following a complete response to frontline therapy. The median OS and DFS of patients with EOC treated with consolidation HIPEC ranges from 14 to 64.4 moths (5y-OS 70–84.21%) and from 13 to 18.5 months (5y-DFS 45–63%) respectively. Some case-control studies (105-107) compared consolidation HIPEC after CRS and post-operative systemic chemotherapy with no further therapies. In the study by Gori et al. (105) patients in the HIPEC group reached a median OS of 64.4 months (5y-OS 70%) and a 5y-DFS of 45% compared with 46.4 months (5y-OS 58%) and 0% in the control group. In the study by Kim et al. (106) patients in the HIPEC group showed significantly higher 8y-OS (84% vs. 25%, P=0.0004) and 8y-DFS (63% vs. 29%, P=0.027).

Table 9 Prospective observational studies focus on intraperitoneal chemotherapy as consolidation therapy for EOC
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Table 10 Retrospective observational studies focusing on intraperitoneal chemotherapy as consolidation therapy for EOC
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A relative advantage of HIPEC delivery at the time of consolidation is the potential for a reduction in the toxicity of associated CRS (29). The major morbidity associated with consolidation HIPEC ranges from 0% to 51% and the mortality is 0% in all studies.

Other intraperitoneal chemotherapy

The RCT by Piccart on 152 patients with stage IIB-IIC-III EOC treated with CRS and platinum-based systemic CT with evidence of complete remission at surgical second-look, compared patients treated with post-operative consolidation NIPEC cisplatin (administered through an intraperitoneal catheter) with Cisplatin with patients treated with no further therapies. In the NIPEC group, the 5y-OS and 5y-DFS were 70% and 53% respectively, compared to 60% and 52% in control group. The respective hazard ratios for DFS and OS with 95% CI: were 0.89 (0.59-1.33) and 0.82 (0.52-1.29). For the NIPEC consolidation CT (other than HIPEC) median OS ranges from 39 to 73 months (5y-OS 58-72%) and median DFS from 13 to 34 months (5y-DFS 34-52%). Suidan et al. compared survival outcomes for patients with advanced EOC who received primary systemic and IP chemotherapy to those who received systemic CT followed by consolidation IP chemotherapy. In this study primary IP chemotherapy was associated with improved OS and with the same DFS compared to systemic CT followed by consolidation IP CT in patients with optimally cytoreduced advanced EOC (median OS 78.8 vs. 57.5 months, P=0.004; median DFS 23.7 vs. 19.7 months, P=0.11).

Early postoperative intraperitoneal chemotherapy (EPIC)

Early postoperative intraperitoneal chemotherapy (EPIC) presents some potential advantages in respect to the HIPEC (84,111). In fact, it is administered immediately after the CRS and inside the abdomen when the tumor burden within the abdominal cavity is minimal. EPIC timing and way of administration may allow an effective penetration within sites of wound healing potentially reducing the possibility to have cancer cells entrapped within fibrin deposits and scars.

EPIC associated potential disadvantages are the increased rate of postoperative morbidity and infections (112-114). EPIC does not necessitate hyperthermia and may be utilized after HIPEC or CRS alone. It is usually administered within the 4^th-5^th post-operative day through the abdominal drains placed during surgery. Therapy cycles usually last for 24 hours ensuring an adequate exposure of the tumor cells to the drugs. Suggested drugs for EPIC are the cell-cycle specific such as 5-fluorouracil and taxanes (115,116).

An alternative to EPIC is the dose-dense early postoperative intraperitoneal chemotherapy (DD-EPIC) given in front-line. It seems to give good results. In fact, some data showed that DD-EPIC seems to significantly increase non-progression rate in advanced OC. A phase 2 trial where 218 patients with FIGO IIIC–IV OC were randomly allocated to receive DD-EPIC followed by intravenous (IV) chemotherapy (DD-EPIC group), or IV chemotherapy alone (IV group) reported a median OS of 67.5 and 46.3 months in the DD-EPIC and IV group, respectively. Estimated OS at 5 years was 61.0% with DD-EPIC, and 38.2% with IV. Estimated PFS at 5 years was 26.0% vs. 8.5% for DD-EPIC and intravenous, respectively (117).

Intraperitoneal drugs in ovarian cancer:

Several drugs have been utilized intraperitoneally in treating EOC. Dosages, perfusion times, and methodologies are different across the different centers. Even if supported by definitive scientific literature, most of these drugs have never been recognized as officially applicable within the peritoneal cavity. In several cases the use of IP drugs for HIPEC, EPIC or NIPEC administration is off-label under the direct responsibility of the oncologists and surgeons.

Cisplatin (cis-diamminedichloroplatinum-III, CDDP) action works through the formation of adducts to DNA causing cells apoptosis (118). CDDP can be applied in normothermia or in hyperthermia. Hyperthermia seems to augment the CDDP effect (119-121). The main concern in CDDP use is the potential nephrotoxicity (122). However, it has been questioned if the potential nephrotoxicity is mainly due to the renal excretion and the consequent potential toxicity, or to the fact that surgical physiological load of extensive CRS on already unhealthy kidneys may promote a secondary-hit related renal injury leading to renal insufficiency (123). This may necessitate, in the most severe cases, transient or definitive renal replacement therapy. The toxicity, in fact, seems to be related to the aggressive CRS and not only to drug exposure (95). Renal failure is generally relatively low and under the toxicity threshold (95). Moreover, the broad heterogeneity in the CDDP dosages throughout the different trials is not correlated to the different complication rates, further suggesting the correlation of the complications rate to the CRS procedure and not only to the CDDP administration.

Taxanes act by stabilizing the microtubule against depolymerization thereby disrupting normal microtubule dynamics and preventing the cells to perform their normal activity in a cell cycle-specific way (124). The main characteristic of paclitaxel and docetaxel is the high molecular weight that allows for a high area under the curve (AUC) ratio of 853 and 861, respectively (125). This characteristic contributes to give to these drugs a clear pharmacokinetic advantage for IP administration (126). Conflicting results exist about the possible thermal augmentation of this class of drugs (126). Taxanes have been used in a neoadjuvant intraperitoneal setting as well as EPIC or adjuvant post-operative repetitive administrations. The research interest is to increase their bioavailability.

Doxorubicin or hydroxyldaunorubicin (adriamycin) is part of the antibiotic family of chemotherapy agents and precisely an anthracycline. It acts depending on the temperature modifying the cell membrane (127,128). Doxorubicin has a favorable AUC ratio of 230 due to the high molecular weight (129-133). The toxicity encountered in intravenous administration is a dose limiting cardiotoxicity that is not present with IP delivery. A mild thermal augmentation has been demonstrated for doxorubicin (134). PEGylated liposomal doxorubicin seems to have even more favorable pharmacokinetic effect (135).

Mitomycin C acts by cross-linking DNA with the antibiotic type molecule. It needs to be activated to enter the cells and be effective (136). Its AUC is 23.5 and this quality associated with thermal enhancement give the molecule a favorable action in HIPEC administration (137).

Oxaliplatin (oxalato-1,2-diaminocyclohexane-platinum (II)) has a very low AUC and a rapid absorption into the tissues. For these reasons oxaliplatin is usually administered during HIPEC with short application times. Hyperthermia enhance its effect on tumor cells but oxaliplatin-based HIPEC increase the risk of bleedings (119,138). In general, oxaliplatin should be infused within a dextrose-based carrier because of instability in other solutions (139).

Convincing data exist concerning the synergism between heat and the activity of many antineoplastic drugs against tumor cells growing in vitro (91,119). Pharmacokinetic data provide a credible rationale for HIPEC. However more data about the different pharmacological aspects and comparative efficacy studies between the different drugs are needed (98,112,140). The pharmacokinetics of several antineoplastic drugs utilized during HIPEC have been defined (61,116) especially for cisplatin (63) and paclitaxel, which are among the most effective against EOC. Good results have been demonstrated with the administration of the two drugs together during HIPEC (28,95,96). A comparable concentration of cisplatin + paclitaxel in the peritoneal tissue and in the perfusate during HIPEC have been demonstrated, showing a good antineoplastic effect with low systemic drug absorption. This will give the maximal anticancer effect with low risk of side-effects due to systemic drug circulation (95). However, the pharmacokinetics of these molecules was investigated during and after intraperitoneal administration with hyperthermia only when infused alone and not in combination. It is not possible to exclude pharmacokinetic interaction between these two different drugs. Some studies are trying to compare the effect of the different molecules when administered intraperitoneally with hyperthermia.

A prospective cohort of 41 patients with stage IIIC or IV EOC treated with CRS and HIPEC, where analyzed according to the two combinations of drugs. Cisplatin/doxorubicin were given to 19 patients (46%) and paclitaxel to the other 22 patients (54%). No difference in morbidity and mortality rate and survival rates were demonstrated within the two groups. The 3y-OS was 66% in cisplatin + doxorubicin group and 82.9% in paclitaxel group (P=0.248) (141).

Results

Present study included 57 patients: 35 with pEOC and 22 with rEOC. Three of the 35 patients with pEOC were treated with upfront CRS+HIPEC, while 32 with interval CRS+HIPEC. Pre-operative and intra-operative data are showed in Table 11. Mean PCI was 11.93±9.18. In the 89.5% of patients CC-0 was obtained. The 84.2% of patients received Cisplatin + Taxol as HIPEC regimen. Major complication rate and mortality rate were 35.1% and 1.8% respectively. Re-operation rate was 12.3%. The mean ICU length of stay (LOS) was 4.25 days (SD 9.7, median 2, range 0–54). The mean total LOS was 27.18 days (SD 24.00, median 20, range 10-124). The 70.2% of patients received post-operative IV CT. The mean OS for pEOC was 40.2 months (SE 3.9, 95% CI: 32.5–47.9). The median OS for pEOC was not reached. The median DFS for pEOC was 13 months (SE 1.7, 95% CI: 9.7–16.3), with 2y-OS of 71% and 2y-DFS of 37%. The median OS and DFS for rEOC were 46 months (SE 0.0) and 11 months (SE 2.9, 95% CI: 5.2–16.7) respectively, with 2y-OS of 68% and 2y-DFS of 34%. There was no significant difference in OS and DFS between pEOC and rEOC (Figure 2).

Table 11 Patients’ characteristics
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Figure 2 Kaplan-Meier survival curves of primary and recurrent epithelial ovarian cancer.

No significant difference in OS and DFS was found between patients with FIGO stage IIIC and IV.

Among patients with rEOC, CC-0 patients had significantly longer median OS than CC-1,2 patients (46 vs. 4 months, P<0.001) with 2y-OS of 76% vs. 0%. Furthermore, patients with rEOC and PCI <15 had significantly longer median OS than patients with PCI>14 (46 vs. 19 months, P=0.014) with 2y-OS of 100% vs. 29%. Tables 12 reports univariate and multivariate analysis of factors influencing OS. Cisplatin + Taxol as IP CT regimen was the only significant factor improving OS at multivariate analysis (OR 6.54, 95% CI: 1.24–34.47, P=0.027). Patients treated with IP Cisplatin + Taxol showed a median OS of 46 months (SD 6.4, 95% CI: 33.4–58.6), while patients treated with other IP regimens showed a median OS of 12 months (SD 3.1, 95% CI: 6.0–18.0). The 2y-OS was 72% and 3y-OS was 68% for Cisplatin + Taxol as IP CT, while the 2y and 3y-OS was 0% for other IP CT regimen (Figure 2).

Table 12 Univariate and multivariate analysis on risk factors for OS and DFS
Full table

Patients treated with IP Cisplatin + Taxol showed a median DFS of 13 months (SD 1.6, 95% CI: 9.9–16.1), while patients treated with other IP regimens showed a median DFS of 8 months (SD 3.1, 95% CI: 1.9–14.1) (Figure 3). Only tumor grading was the significant factor affecting DFS at univariate analysis (Table 12).

Figure 3 Kaplan-Meier survival curves of HIPEC cisplatin + paclitaxel vs. other HIPEC regimens.

Conclusion

Intraperitoneal chemotherapy in ovarian cancer showed positive results that may be considered semi-definitive according to the level of evidence and should be maintained as a starting point for further investigations. At present intraperitoneal chemotherapy should be proposed to patients with advanced ovarian cancer as standard treatment at almost all disease stages. Platinum + taxane-based intraperitoneal regimens demonstrated superior results compared to other regimens.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editors (Paul H. Sugarbaker and Kurt Van der Speeten) for the focused issue “Intraperitoneal Chemotherapy for Peritoneal Metastases: HIPEC, EPIC, NIPEC, PIPAC and More” published in Journal of Gastrointestinal Oncology. This article has undergone external peer review.

Reporting Checklist: The authors have completed the PRISMA 2009 Checklist. Available at http://dx.doi.org/10.21037/jgo-2020-06

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/jgo-2020-06). The focused issue was sponsored by the Peritoneal Surface Oncology Group International (PSOGI). The authors have no other 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/.

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