Logoregional Treatment Hipec in the Management of Peritoneal Metastasis from Ovarian Cancer

Spiliotis John MD, PhD, FASPM¹*, Spiliotis Nikolaos-Jason MD ²

1. European Interbalkan Medical Center, Thessaloniki Greece.

2. University of Patra’s, Medical School, Patra Greece.

Corresponding Author: Spiliotis John MD, PhD, FASPM, European Interbalkan Medical Center, Thessaloniki Greece..

Copy Right: © 2023 Spiliotis John, This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Received Date: February 13, 2023

Published Date: March 01, 2023

Abstract

The standard of care in epithelial ovarian cancer is complete surgical cytoteduction followed by systemic chemotherapy.

The 30 % of patients even after this treatment are relapsed. The 2^nd line treatment includes logo regional management with intraperitoneal chemotherapy.

The aim of this article is to focuses in IP treatments with HIPEC.

Introduction

Epithelial ovarian cancer (EOC) is the deadliest gynecologic malignancy [1]. The majority of women are diagnosed at advanced stage with widely metastatic peritoneal disease. Standard of care involves a combination of surgery and chemotherapy. The ability to surgically resect tumors with optimal cytoreduction surgery (CRS), ideally to no gross residual disease (R0), is an important positive prognostic factor [2]. Despite the improvements seen in median survival time with the current standard of radical tumor CRS and IV carboplatin and paclitaxel, long term survival rates for patients with advanced epithelial ovarian carcinoma remain disappointing and efforts continue to develop more effective primary therapy.

One of the reasons that Intraperitoneal (IP) chemotherapy has been proposed for advanced ovarian cancer is that ovarian cancer typically spreads intraperitoneally. However, retroperitoneal disease and, according to newer imaging techniques, extra-abdominal disease are present in the majority of patients with International Federation of Gynecology and Obstetrics (FIGO) stage III or IV disease. In addition, adhesions, which are frequently observed after debulking surgery, prevent the spread of the drugs in the abdominal cavity. Furthermore, a higher drug concentration going directly to the tumor has been used as an argument for ip chemotherapy. However, the depth of drug penetration has been shown to be restricted to a limited number of cell layers.

For most patients with EOC, the majority of disease burden is in the peritoneal cavity and can be quantified by the peritoneal cancer index (PCI) [3]. The PCI is a measure of the extent of disease burden in the peritoneal cavity. Due to this location, normothermic IP chemotherapy has been studied in prospective clinical trials in the post-operative treatment of primary EOC, and NCCN has noted the combined IV/IP regimen as preferred regimen for optimally cytoreduced Stage III EOC. In the setting of recurrence, treatment guidelines are determined by the time to recurrence and location of metastatic disease.

HIPEC during CRS for EOC has been gaining more attention in the treatment of metastatic peritoneal disease. Specifically, HIPEC has more frequently been utilized in the recurrent setting with secondary CRS, but recent studies have evaluated its role in primary management of ovarian cancer.

The aim of this article is to review previous and ongoing studies regarding the use of HIPEC in context of the overall use of IP chemotherapy for the treatment of EOC.

Intraperitoneal chemotherapy (normothermic)

In normothermic IP chemotherapy, cisplatin and paclitaxel are injected into the patient’s peritoneal cavity through an intraabdominal port. IP chemotherapy is administered in the post-operative period over a course of up to six cycles. Three large prospective randomized studies support the use of IP chemotherapy in the primary treatment of EOC. In the Gynecologic Oncology Group (GOG) 104 study, patients were randomized to two arms: the control arm of cisplatin and cyclophosphamide IV and the experimental arm of cisplatin IP and cyclophosphamide IV. While there was a statistically significant overall survival (OS) benefit to the IP regimen of 49 months in comparison to 41 months for the IV regimen, consensus was the benefits of IP chemo are not greater than the benefits of new agent paclitaxel [4]. In GOG 114, patients in the control arm received six cycles of cisplatin and paclitaxel IV with an OS of 52.5 months and the experimental arm received two cycles of carboplatin IV, followed by six cycles of cisplatin and paclitaxel IP with an OS of 63.2 months. Progression free survival (PFS) and OS were statistically significant, but were partially attributed to the addition of two extra cycles of chemotherapy in the IP arm [5].

GOG 172 influenced practice patterns in the United States. The IV/IP regimen of IP cisplatin and paclitaxel, plus IV paclitaxel demonstrated the longest median OS compared to IV carboplatin and paclitaxel in patients with optimally cytoreduced stage III ovarian cancer. The median PFS for the IV alone and IV/IP regimens was 18.3 and 23.8 months, respectively. The median OS for the IV and the IP regimens was 49.7 and 66.9 months, respectively. Due to chemotherapy-associated toxicities, only 42% of women on the IP regimen actually received six cycles of therapy, and 49% received three or fewer IP cycles [6]. Because the OS benefit outweighed the toxicity of the regimen, the NCI Clinical Announcement recognized the superiority of IP chemotherapy in the optimal disease setting [7].

In a follow up analysis of the mature data of GOG 114 and GOG 172 combined, an OS benefit remains significant for IP regimens after 10 years of follow up. This benefit in OS was most pronounced in patients who underwent optimal CRS to R0 treated with the IP regimen. Specifically, in GOG 172, the OS was 127 months in this subset of patients [8]. There was also a correlation noted between survival and the number of IP cycles completed in a separate follow up analysis [9]. A more recent large prospective trial, GOG 252, compared weekly IV chemotherapy regimens to varying dose reduced IP regimens. All arms of the trial had bevacizumab added during treatment and as maintenance. No significant differences in PFS were observed between the three arms. In comparison to GOG 172, more patients were able to complete the IP regimens, but all arms had excessive toxicity. One concern in interpreting the data from GOG 252 is the addition of bevacizumab to all arms could have influenced the results and analysis [10]. With the inability to replicate the results from GOG 172 and the limitation to access IP chemotherapy outside of the tertiary setting, there has been increased interest in HIPEC as a treatment alternative in the primary and recurrent ovarian cancer setting.

HIPEC

In HIPEC, heated intraabdominal chemotherapy is administered at the end of CRS. HIPEC has several potential benefits. High-dose chemotherapy can be used because the plasma-peritoneal barrier results in little absorption into the blood stream [11,12]. In addition, there is higher peritoneal penetration in comparison to IV regimen, and HIPEC does not have the limitation of traditional IP regimen of post-operative adhesions [13,14].  Hyperthermia itself has cytotoxic effects and can increase the depth of tumor penetration by the chemotherapeutic agent up to 3 mm and moreover can potentiate its antineoplastic effects [15–18].

A major limitation to HIPEC is the previously reported morbidity and mortality and thus its use was often discouraged [19]. To proceed with HIPEC, CRS to R0, CC0 (non-visible disease remaining) or CC1 (less than 2.5 mm visible disease remaining) is required and involves radical and complex surgeries that are associated with higher complication rates. Currently, particularly in high-volume centers with HIPEC specialists, morbidity and mortality has drastically improved [20,21].

One large retrospective review of 694 patients, treated between 2005 and 2011, utilizing the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQUIP) database, demonstrated a complication rate of 33% and 30-day mortality of 2.3%, both rates consistent with outcomes for other major complex abdominal operations [21].

In 2015, Chiva et al reported a systematic review of HIPEC in ovarian cancer. Twenty-two publications with 1450 patients were used for the analyses [22]. In 493 patients, HIPEC was used in the first-line setting, and in 957 patients, it was used at the time of secondary debulking surgery. The authors concluded that their systematic review had failed to show a survival benefit that justified the use of HIPEC as a standard daily practice.

HIPEC as upfront treatment of ovarian cancer

The largest prospective randomized clinical trial demonstrated a survival advantage for patients who received HIPEC, compared to standard IV chemotherapy, for the treatment of primary EOC. (Table 1) All patients received neoadjuvant chemotherapy after determining they were not eligible for primary CRS and had to have at least stable disease after receiving up-front IV chemotherapy. The control arm received standard IV chemotherapy before and after CRS (PFS = 10.7 months, OS = 33.9 months). The experimental arm received the same standard IV chemotherapy but also received HIPEC with cisplatin during CRS (PFS = 14.2 months (p = 0.01), OS = 45.7 months (p = 0.02)). Over 90% of patients completed full six cycles of IV chemotherapy in both arms [23].

While the PFS and OS in this trial are shorter than the previous mentioned normothermic IP trials, it should be noted that this is a different patient population. The PFS and OS survival in the control arm of this trial are similar to established data in patients receiving NACT and interval CRS [24].

Similarly, a large retrospective study from Italy showed improved outcomes in patients who underwent HIPEC after having a complete or partial response to neoadjuvant IV chemotherapy in comparison to HIPEC at primary CRS. [25,26]  In addition to standardizing the HIPEC procedure, the time of administration of HIPEC is another important factor.

A retrospective cohort study from France looked at 92 patients receiving HIPEC for primary EOC treatment. The majority (60.8%) received consolidation HIPEC treatment after receiving 6–9 cycles of IV carboplatin and paclitaxel. The rest received HIPEC at primary CRS (13%) and at interval CRS (26.1%.) The majority of patients received cisplatin HIPEC (80.4%,) but 35.9% did receive a second agent with HIPEC, either doxorubicin (19.6%) or mitomycin (18.5%). Signi?cant to survival were timing of HIPEC, peritoneal cancer index (PCI), and R0 CRS. Longest median OS was seen in the primary CRS group at 52.7 months, followed by interval CRS at 36.5 months and then consolidation HIPEC at 33.4 months (p = 0.03.) Of all primary HIPEC patients, those able to be optimally cytoreduced to less than 2.5 millimeters (mm) had a median survival of 41.5 months compared to 21.2 months with residual disease greater than 2.5 mm (p < 0.01) [27]. Again, this is a different patient population than was evaluated in previous normothermic IP trials; therefore we cannot make direct comparisons.

HIPEC in the Treatment of Recurrent Ovarian Cancer

Substantially more studies have been published regarding the use of HIPEC in the management of recurrent ovarian cancer.

Although, a signi?cant amount are retrospective, evaluating a small series of patients or inconsistent with patient parameters and HIPEC dosing. Platinum agents are one of the most commonly used during HIPEC for ovarian cancer, but the dose varies in trials.

A phase I trial was published regarding the maximum tolerated dose of (MTD) of cisplatin for HIPEC at time of ?rst recurrence (Table 2).

The Mitomycin dose MTD established were 100 mg/m2 with 25% of patients experiencing Gr 3–4 toxicity. Notably no severe hematologic toxicity at this dose, and over 90% of patients completed all 6 cycles of adjuvant IV chemotherapy. The median PFS of 13.6 months was comparable to previously published PFS in recurrent ovarian patients treated with IV chemotherapy alone. Peritoneal platinum concentration was signi?cantly elevated in comparison to plasma levels, and platinum DNA adducts were found in tumor biopsies after HIPEC con?rming cytotoxic activity immediately after a single dose of cisplatin. A Phase II trial is currently open to further evaluate the ef?cacy of this dose and regimen [28].

A prospective trial from Greece evaluated the role of HIPEC at ?rst recurrence. Sixty patients were randomized to each arm; CRS followed by IV chemotherapy versus CRS with HIPEC followed by IV chemotherapy. The trial included both chemo-sensitive and chemo-resistant patients. The HIPEC chemo-sensitive patients were treated with cisplatin and paclitaxel during CRS and the chemo-resistant were treated with doxorubicin and paclitaxel or mitomycin. Mean OS was 26.7 months in the HIPEC group versus 13.4 months in the control group (p < 0.01.) The OS was similar in both the HIPEC chemo-sensitive (26.8 months) and chemo-resistant (26.6 months) subgroups. In comparison, the OS was signi?cantly different in the control arm chemo-sensitive (15.2 months) and chemo-resistant (10.2months) subgroups (p<0.01.) Both arms achieved similar rates of CCο CRS. However, the overall survival in the HIPEC CC0 group was signi?cantly higher (30.9 months) than the control CCο group (16.9 months) [29].

A similar patient population was studied in Italy. A case control study with 37 patient controls receiving either CRS and IV chemotherapy (13 patients) or IV chemotherapy alone (24 patients) versus 30 patients undergoing CRS and HIPEC. All patients were experiencing a ?rst recurrence, and the initial PFS was similar in both the control and case arms. The only signi?cant difference between the arms was pattern of recurrence. The control arm had signi?cantly more patients with single nodule or localized recurrence. All control patients achieved CC0 CRS, and 96.7% of HIPEC patients achieved CC0 CRS. PFS was 15 months in the control arm and 26 months in the HIPEC arm. Interestingly, over half of the HIPEC patients had a longer secondary PFS after HIPEC than the primary PFS after Cancers 2018, 10, 296 6 of 10 initial treatment. The HIPEC patients had signi?cantly longer OS, secondary PFS, and deaths than the control group [30].

Discussion

Ovarian cancer is the deadliest gynecologic malignancy in the United States. Normothermic IP chemotherapy for primary EOC has a known bene?t in the optimal CRS setting. Unfortunately, widespread use has not occurred due to concern for toxicity and patient access to tertiary care centers. Due to these concerns, there is interest in HIPEC therapy for the management of primary and recurrent EOC. The largest HIPEC study published to date was in the setting of primary EOC. A survival bene?t in patients undergoing interval CRS was found with the addition of HIPEC, and there was no difference in toxicity between the control and HIPEC arms [22]. A critique of the study is that it did not have an IP chemotherapy arm for comparison. The role of normothermic IP chemotherapy is unclear in the interval CRS patient population. A phase II randomized trial, OV21/PETROC, was completed and the IP regimen was found to be well tolerated with reasonable toxicity and no reduction in QOL. Therewas a noted decrease in progression of disease at nine months in the IP group, however, as the study was underpowered, there was no difference found in PFS and OS between the IV and IP arms [31].

In conclusion, there is now high quality prospective data suggesting a survival bene?t to HIPEC therapy for patients undergoing primary treatment of EOC after receipt of neoadjuvant chemotherapy and optimal cytoreduction. Poorer quality data exists supporting its use in other clinical contexts such as recurrent disease. This treatment has not been studied in multiple clinical contexts, the regimen and toxicity management has not been standardized and HIPEC has not yet been compared to other standard treatments such as normothermic IP chemotherapy. Therefore, the treatment of EOC with HIPEC outside of clinical trial would not be recommended.

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