Discrepancy between recommendations regarding hyperthermic intraperitoneal chemotherapy (HIPEC) in ovarian cancer management: a narrative review

Introduction

Background

The lifetime risk of developing ovarian cancer (OC) is 1.3%, which means that 1 in 78 women will be diagnosed with OC (1). Although the highest incidence of OC occurs in Europe and North America, those regions have decreasing trend in incidence and mortality (2,3). The opposite situation is observed in China and African countries, where the incidence of OC is increasing and it is predicted to increase continuously in the next years (4-6). Incomprehensibly, a substantial increase in incidence was observed in younger females (3). The number of asymptomatic ovarian masses has increased with the use of prenatal ultrasonography (7). However, only 5% of ovarian tumors diagnosed during pregnancy are malignant and majority of them are non-epithelial (mainly germ cell tumors and sex cord-stromal tumors) (7). Germ cell tumors differ to epithelial OCs with their earlier age of incidence, faster rate of growth, unilateral localization (95% of cases) and good prognosis (8).

Incidence rates are calculated per 100,000 people, so they do not show the actual number of new cases. Considering constantly growing population around the world, the number of new cases of OC has raised from 152,000 in 1990 to 314,000 in 2020, while the number of deaths due to OC in the same time period increased from 95,000 to 207,000 (9). Moreover, prognosis for next decades is unfavorable. In 2040, the number of new cases and deaths due to OC will be higher—among countries with low human development index (HDI) by 96% and 100%, respectively, while in countries with very high HDI by 19% and 28%, respectively (10). Although the incidence of OC is not at the top among all malignancies, it has the highest mortality rate among gynecological cancers (9). The poor prognosis of OC is confirmed by the ratio of deaths to new cases (65%), which is similar to stomach cancer (70%) and significantly higher than in breast cancer (30%), endometrial cancer (22%), and even cervical cancer (56%) (11).

According to molecular mechanism type I epithelial OCs are proposed to exhibit relatively indolent behavior and genetic stability (12). In contrast, type II epithelial OCs are suggested to be inherently aggressive tumors, which can disseminate even from small primary lesion in the ovary or fallopian tube (12). High-grade serous OC is the most common histological type and constitute approximately 75% of all epithelial OC. It was found that high-grade serous OC arise through the type II pathway and typically harbor mutations in TP53 and BRCA genes. Germline mutations in BRCA1/2 occur in up to 15% of newly diagnosed OC cases and represent the strongest risk factor for epithelial OC (13). BRCA1/2 carriers exhibit a more favorable response to platinum-based chemotherapy and poly (ADP-ribose) polymerase (PARP) inhibitors compared to non-carriers (13). This leads to improved survival, despite the OC typically being diagnosed at an advanced stage (14).

OC frequently involves the peritoneum, however in most cases, it spreads superficially and towards the peritoneal cavity without deep penetration into muscles, bowels and internal organs. The peritoneal barrier plays a role not only in development of peritoneal metastases, but also in transport of different substances, inflammatory response, antigen presentation, fibrosis and fibrinolysis and tissue repair (15). This barrier is a complex structure made up of the peritoneum, parenchymal cells, interstitial cells, interstitial matrix, pericytes, and the endothelial cells that form the microvessels (16). Intravenous (IV) chemotherapy administration could have limited penetration to peritoneal carcinomatosis, especially that tumor clusters are able to grow up to a size of 2 mm without external nutrients and capillaries (17). Therefore, intraperitoneal (IP) route could omit the peritoneal barrier and chemotherapy could directly act to the tumor. Initially, adjuvant IP chemotherapy was extensively studied. Although a Cochrane meta-analysis showed that IP chemotherapy improves survival in advanced OC (18), its use in clinical practice has been limited (19,20). It was found that 58% of patients did not completed adjuvant IP chemotherapy, mainly due to peritoneal catheter complications (21). IP chemotherapy was associated with higher serious complications rate, more intense abdominal discomfort and neurotoxicity compared to IV route (22). IP chemotherapy, as well as extensive abdominal surgery, inflammation and infection may contribute to the formation of the intraabdominal adhesions (23,24). Intraabdominal adhesions may limit distribution of chemotherapy in the peritoneal cavity (25). Finally, GOG-252 study did not confirm any survival benefit of IP chemotherapy compared to IV administration (22). Therefore, adjuvant IP chemotherapy has not been adopted in everyday clinical practice. European Society of Medical Oncology (ESMO) decline IP chemotherapy as a standard of care due to greater toxicity and complexity of its administration (26). In National Comprehensive Cancer Network (NCCN) guidelines IP regimens can be offered to selected patients in stages II and III, but it is always combined with IV chemotherapy so that systemic disease can also be treated (27).

Rationale and knowledge gap

Hyperthermic intraperitoneal chemotherapy (HIPEC) used immediately after cytoreductive surgery, omits problems related to the catheter, multiple drug administration and high rate of treatment discontinuation. An additional advantage of HIPEC compared to IP adjuvant chemotherapy is excellent exposure of the peritoneal lesions, lack of peritoneal adhesions and the possibility to reach all regions of the peritoneal cavity. The clinical significance of HIPEC in OC is currently extensively researched. Although it is not a new therapeutic method, its role in the treatment of OC has not yet been precisely defined, and recommendations for the use of HIPEC are not consistent (26-28). European Society of Gynecologic Oncology (ESGO) and ESMO do not recommend HIPEC in the treatment of primary or recurrent OC (26,28). European experts considered HIPEC to be an experimental method and should not be considered as standard therapy. As opposed to this, NCCN guidelines found that HIPEC with cisplatin (100 mg/m²) can be considered during interval cytoreduction in patients with stage III disease according to protocol used in OV-HIPEC-01 trial, i.e.: an intraabdominal temperature of 40 ℃, perfusion with cisplatin at a dose of 100 mg per square meter, flow rate of 1 liter per minute (with 50% of the dose perfused initially, 25% at 30 minutes, and 25% at 60 minutes) and 90-minute perfusion period.

Objective

Due to the opposite statement of ESGO/ESMO and NCCN regarding HIPEC in OC management, we present this narrative review to analyze the effectiveness, potential confounding factors, complications and immunological issues related to HIPEC. We present this article in accordance with the Narrative Review reporting checklist (available at https://cco.amegroups.com/article/view/10.21037/cco-23-152/rc).

Methods

PubMed was searched using “hyperthermic intraperitoneal chemotherapy”, “HIPEC”, “ovarian cancer”, “immune response” to find relevant articles to this review (Table 1). Full-text articles published in English, including basic science, observational studies, randomized trials and meta-analyses published between January 1, 2015 and August 30, 2023 were included. References from articles were screened for additional studies. There were no exclusion criteria for the literature search. The authors provide a narrative summary of the findings and implications of these studies. All authors contributed to literature search and approved the selected literature.

Efficacy of HIPEC in OC

European guidelines, that do not recommend HIPEC in OC management, were supported by a meta-analysis (29) and a randomized trial (30). Chiva et al. showed no benefit in survival with an increased risk of side effects (29). Lim et al. in OV-HIPEC-01 trial also found that addition of HIPEC to cytoreductive surgery did not improve progression-free and overall survival (OS) in patients with advanced epithelial OC. However, in a subgroup analysis, in patients with interval debulking surgery (IDS), HIPEC improved OS and progression-free survival (PFS) (30). Those results confirmed outcomes of a previously published randomized trial by van Driel et al., who found that addition of HIPEC to IDS resulted in longer recurrence-free survival and OS than surgery alone (31). Improved survival in patients undergoing IDS + HIPEC vs. IDS alone was confirmed in several recently published meta-analyses (32-35) (Table 2). The significance of HIPEC during cytoreductive surgery in recurrent disease is not clear, while results of meta-analysis were discordant (Table 2).

In a meta-analysis by Kim et al., the effectiveness of HIPEC was assessed depending on chemotherapy administration (44). It was found, that, chemotherapy given before surgery played a key role in the effectiveness of HIPEC, regardless of primary or recurrent OC. Patients who received chemotherapy up to 6 months before HIPEC had improved survival (44). Finding a group of patients who will benefit from HIPEC is crucial. Jian et al. analyzed all OC patients together, irrespective of primary and recurrent disease (45). This meta-analysis did not demonstrate any improvement in OS nor disease-free survival (45).

OC is now considered as a chronic disease with periods of remission and relapse. Reduction in the number of relapses (even without OS improvement) is important because every treatment of relapse is associated with deterioration of the quality of life, including intensification of pain, limitation of physical activity and emotional tension or anxiety (46). OC recurrence frequently is located in the peritoneal cavity. It has been shown that 50% of disease recurrences in patients undergoing HIPEC are located outside the peritoneal cavity (47). Shifting the site of recurrence outside the peritoneal cavity after HIPEC may reduce the incidence of gastrointestinal obstruction and the need for a palliative stoma, which may lead to improvement in quality of life.

Factors affecting HIPEC efficacy

Chemotherapy

Apart from proper qualification to HIPEC, there are many factors that may influence the effectiveness of the procedure (Table 3). The most frequently used cytostatic agent in advanced OC is single-drug chemotherapy using cisplatin at a dose of 75 mg/m² (50–100 mg/m²) (44). However, the choice of the optimal cytostatic agent in HIPEC procedure has not been yet determined (40). The effectiveness of HIPEC may vary depending on the chemotherapy used and its dose. The study conducted by Chambers et al. showed that the use of paclitaxel and cisplatin during HIPEC significantly improves PFS compared to the use of cisplatin alone (48). Although the OS data are not yet available, it appears that the use of multi-drug chemotherapy during HIPEC may provide better treatment outcomes than single-drug regimen. The mechanism of action of cisplatin and carboplatin is similar, but their pharmacokinetics are different and may lead to different therapeutic results. Zivanovic et al. showed that carboplatin was well tolerated but did not lead to improved oncological outcomes (49).

Although most patients initially respond to platinum-based chemotherapy delivered intravenously, resistance develops over time. Platinum resistance is associated with poor prognosis and therapeutic options are limited. However, it has been shown that the use of HIPEC may be effective in platinum-resistant patients. In gynecologic patients with platinum-resistant disease, either paclitaxel or Mitomycin C can be considered, but there is still advantage of using cisplatin. Bakrin et al. conducted a study in 246 patients with recurrent epithelial OC. It included both platinum-sensitive and platinum-resistant cases. All of them underwent optimal cytoreduction and HIPEC (50). There was no statistically significant difference in OS between platinum-sensitive and platinum-resistant patients (52 vs. 48 months, P=0.568). In addition, Spiliotis et al. demonstrated improved survival in patients undergoing HIPEC during secondary cytoreduction (51). The survival time in patients who underwent HIPEC did not differ between the platinum-resistant and platinum-sensitive groups (26.6 vs. 26.8 months), while in patients who did not undergo HIPEC it was significantly shorter in platinum-resistant patients (15.2 vs. 10.2 months). These results indicate that HIPEC can overcome platinum resistance in recurrent OC. Similar observations were presented by Costales et al., who demonstrated the effectiveness of secondary cytoreduction with HIPEC in the treatment of recurrent OC regardless of platinum sensitivity (52). The ongoing KOV-HIPEC-02 (NCT05316181) trial will provide more information regarding significance of HIPEC in platinum-resistant OC. In this two-armed, phase III trial, patients are randomized to the experimental group (cytoreductive surgery + HIPEC + physician-choice chemotherapy) or control group (physician-choice chemotherapy). HIPEC is carried out using the open or closed technique with infusing 41.5–42.0 ℃ doxorubicin 35 mg/m² and mitomycin 15 mg/m² for 90 minutes. PFS, a primary objective of the trial, is expected to be analyzed within a few years. OS, safety and quality of life are secondary endpoints and will be completed after 2029 year.

Hyperthermia

Increased temperature up to 40.5–43 ℃ enhances the cytotoxic effect of chemotherapy drugs, leading to greater destruction of cancer cells (Figure 1) (53). Improved effectiveness of chemotherapy may also result from the effect of hyperthermia on altered blood flow through the tumor tissue (54). Hyperthermia reverses hypoxic tumor environment by increasing vascular permeability, improving tissue oxygenation and normalizing pH. This promotes better distribution of the chemotherapy drug into the tumor. The molecular mechanism of synergy between hyperthermia and chemotherapy involves the induction of reactive oxygen species (ROS), which leads to increased drug uptake. ROS damage tumor cells in two ways: (I) by directly damaging DNA and (II) by increasing the synthesis of p53 protein, which results in cell cycle arrest and initiates apoptosis (55). Moreover, it has been shown that cancer cells can be selectively destroyed under the influence of hyperthermia (41–43 ℃) (56).

Figure 1 Relationship between surgery, HIPEC and immune system. HIPEC, hyperthermic intraperitoneal chemotherapy.

To assess the relationship between chemotherapy effectiveness and temperature, the thermal enhancement ratio (TER) was introduced. It is defined as the ratio of the dose necessary to induce a therapeutic effect at 37 ℃ to the dose required to achieve the same therapeutic effect at an elevated temperature (57). The effectiveness of heat enhancement chemotherapy depends not only on the type of cytostatic agent and temperature, but also on the type and origin of cancer cells (58). Platins show different TERs at higher temperatures, while mitomycin and 5-fluorouracil do not show any enhancement of the effect with increasing temperature (Table 4) (58). The high TER value for platinum derivatives is closely related to their increased uptake in hyperthermia. The degree of heat enhancement for individual cytostatics can be both linear and threshold, which further affects the effectiveness of chemotherapy.

Other factors related to HIPEC technique

Various types of substances are used as solvents for cytostatics: 0.9% NaCl, 1.5% dextrose, 5% glucose. The impact of these substances on the effectiveness of HIPEC has not been analyzed in the published literature so far. However, some of them have been found to contribute to electrolyte disturbances. It has been shown that the use of 1.5% dextrose is associated with the occurrence of hyponatremia, hypokalemia and reduced serum pH (59).

There are three methods to perform HIPEC: open, semi-open and closed techniques. No study has been published directly comparing different methods in OC. Therefore, no method can be recommended as preferred option in clinical practice (60).

BRCA status

Koole et al. performed a post hoc analysis of data retrieved from 200 (82%) patients enrolled in the OVHIPEC-1 trial to assess the predictive effect of homologous recombination deficiency and BRCA mutation status on response to HIPEC treatment (61). Patients were assigned to three subgroups depending on the tumour genomic profile: BRCA1/2 mutated, homologous recombination deficient with BRCA wild-type (HRD/BRCAwt) and homologous recombination proficient. The authors demonstrated in a multivariable analysis a significant beneficial effect on the OS for treatment with HIPEC and for having BRCA1/2 mutations. Most benefit from addition of HIPEC to cytoreductive surgery was observed in the subgroup with HRD/BRCAwt tumors.

Insights from a retrospective case-control study by Ghirardi et al. indicate that patients with BRCA wild-type tumors might benefit from addition of HIPEC after primary debulking surgery due to increase in chemosensitivity (62). Similar findings were suggested in a study by Schaaf et al. as authors stated that hyperthermia may impair the repair of DNA damage caused by chemotherapy agents resulting in an effect similar to that of PARP inhibitors in homologous recombination proficient tumors (63).

In the future, more information regarding BRCA status and HIPEC efficacy may be served by CHIPOR randomized trial (64).

Role of minimally invasive surgery (MIS)

Petrillo et al. hypothesize that MIS may enhance cisplatin uptake to the peritoneum and plasma due to integrity of the abdominal wall and higher intraabdominal pressure (65). They compared cisplatin pharmacokinetic profile in women with recurrent OC treated with MIS vs. laparotomy. It was found that cisplatin concentration in peritoneal tissue and serum was higher in patients treated with MIS (65). However, the role of MIS and HIPEC has not been established due to lack of randomized data. Feasibility of laparoscopy/robotic surgery and HIPEC was assessed in several retrospective studies (66,67). Fagotti et al. presented a case series of 10 patients with isolated platinum sensitive recurrent OC, who underwent MIS and HIPEC (66). No serious complications were found. Post-operative 18F-fludeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) scan did not reveal any residual disease and no secondary recurrence was observed. Morton et al. assessed peri-operative outcomes in primary OC after IDS with MIS or laparotomy (67). Decision regarding MIS or open technique was based on patients’ characteristics. No differences were found in adverse perioperative outcomes and rate of complete resections, while hospitalization was shorter in MIS group (67). Laparotomy remains main technique preceding HIPEC. However, MIS and HIPEC may be feasible in properly selected patients without multifocal disease or peritoneal carcinomatosis.

Immune response in HIPEC

The use of hyperthermia in cancer treatment occurs after observation of spontaneous tumor regression in patients with persistent fever. Fever has stimulating effects on the innate and adaptive immune system through multiple pathways, where interleukin-6 (IL-6) seems to play a central role (68). Hyperthermia has been reported to cause the alteration in the expression of thousands of genes which are involved in different cellular processes including protein folding, cell death and cell cycle (69). Hyperthermia activates the main regulator of the heat shock response the heat shock factor 1 (HSF1), which together with hypoxia-inducible factor 1 (HIF-1) and other partners activates the production of heat shock proteins (HSPs) (70). The HSPs belong to chaperone proteins and their function is to protect intracellular proteins from misfolding or aggregation and inhibit cell death. According to their molecular weight, HSP family consists of HSP110, HSP90, HSP70, HSP60, HSP40, and other small HSPs. In fact, the overexpression of HSPs is one of the features of many solid tumors, and is known that HSPs have a tumor protective function. Therefore, the activation of HSPs by hyperthermia and its effect on immune response can be a double blade sword. The HSPs may activate the different immune cells type including monocytes, macrophages, B cells, dendritic cells (DC) via binding the tumor antigens, which in consequence may lead to activation of cytotoxic T-cell (71), but HSF1 can also enhance the expression of programmed death-ligand 1 (PD-L1) in breast cancer cells. Moreover, the HSPs can be also released by normal cells in response to stress, transported into the extracellular compartment as extracellular HSPs (eHSPs) which may promote the remodeling of extracellular matrix, promote stromal cell activation like cancer-associated fibroblasts (CAFs), which secrete pro-tumor cytokines (72). eHSPs also can bind directly to the different receptors on the cancer cells surface where have a cancer protective function (73).

The described effects may not apply to HIPEC method where mild hyperthermia is used. The mild hyperthermia used in HIPEC increases in vascular adhesion molecules, may enhance immune cells recruitment and tumor infiltration (74). Moreover, the use of mild hyperthermia in animal models, showed the enhancement of natural killer, CD4 and CD8 T cells infiltration and activation, reduction of tumor growth and improved animal survival. Treatment of melanoma with 43 ℃ during 30 min, in mice model, resulted in activation of DCs and cytotoxic CD8 T cells in the draining lymph node. Those results clearly demonstrated the promising potential of mild, local hyperthermia in induction of immune response that may reduce the risk of recurrence and tumor metastasis (75).

Another author found that in peritoneal metastases of colorectal carcinoma in mice model, HIPEC together with mitomycin C led to increased infiltration of CD4, CD8 T cells and B cells into omental and visceral metastases. The HIPEC significantly increased the expression of HSP-90 mRNA, which strongly suggests the HSPs involvement in these processes (76). In the same cancer model, it was found that combining HIPEC with immune checkpoint inhibitor (anti-PD-1) treatment improved animals survival compared with HIPEC alone (77). In OC mice model the combined chemotherapy with hyperthermia led to the conclusion that hyperthermia increased the number of IP macrophages and DCs compared to chemotherapy group alone (78). Moreover, Huang and colleagues in OC mice model compared the effects of HIPEC and conventional IP chemotherapy on bone marrow and neutrophil recovery. They found that hyperthermia increased the neutrophil-recruiting cytokine levels in the serum and reduced the magnitude of chemotherapy-induced neutropenia. This strongly suggests that HIPEC compared with conventional IP chemotherapy improved neutrophil and bone marrow recovery (79). Zunino et al. observed that vaccine composed of CT26 cancer cells treated with HIPEC or mitomycin C, and after injected into mice may induce efficient immune response, which is mediated via HSP90 protein (80).

The effects of hyperthermia on the peritoneal immune environment have not been studied in detail, and the exact mechanism of HIPEC is still unclear and need to be further elucidated.

Complications

One of the main issues against introducing HIPEC into clinical practice was the concern regarding the potential high toxicity and increased risk of delaying adjuvant chemotherapy due to complications after HIPEC.

It was estimated that in HIPEC, serious complications occurred in 19.3–20.5% of patients, and 30-day mortality was 1.1–2.3% (81,82). Xia et al. showed that the overall number of serious complications in the case of HIPEC was not higher than in cytoreduction alone (33). HIPEC has not been found to increase the risk of intestinal anastomotic leak (83). There was no increased risk of blood transfusion, intestinal obstruction, peritoneal effusion or thromboembolic events (33). In preliminary results of CHIPOR randomized trial, it was found that addition of HIPEC was related to two fold higher serious (grades 3 and 4) complications compared to patients without HIPEC (64). There was also a higher risk of HIPEC-dependent complications, such as nausea, leukopenia, neutropenia, electrolyte disturbances and hypoalbuminemia (33). However, the risk of constipation after HIPEC was lower than after cytoreduction alone.

Acute kidney injury (AKI) is one of the most serious complications related to HIPEC with potentially increased mortality rate and risk of progression to chronic kidney disease (84). The incidence of AKI varies greatly but can be as high as 66% (85). Among the cytostatics used in HIPEC, cisplatin is characterized by the highest nephrotoxicity. The mechanism of cisplatin nephrotoxicity is diverse, and the risk of AKI may be increased by intraoperative blood loss, dehydration, or insufficient intraoperative hydration (Table 5).

Cisplatin also has a toxic effect directly on the nephron. It accumulates in epithelial cells, leading to DNA damage. Consequently, cytokines and inflammatory cells are recruited to the kidneys. The accumulation of mast cells, neutrophils, macrophages, NK cells and T lymphocytes further exacerbates kidney damage. Sodium thiosulfate as a chelating agent has been shown to have a nephroprotective effect (86). It binds to platinum and can deactivate it. This leads to a reduction in the excretion of cisplatin by the kidneys and, consequently, reduces the necrosis of renal tubular cells. In addition, sodium thiosulfate prevents cisplatin-stimulated magnesium loss.

Quality of life (QoL)

Toxicity of HIPEC may negatively impact on quality of life. Koole et al. evaluated the effect of HIPEC on patient’s health-related quality of life in the OVHIPEC trial (88). Patients filled EORTC QLQ-C30 questionnaires at baseline, after surgery, after end of treatment, and every three months thereafter. No significant difference in QoL was observed in patients with HIPEC compared to those without HIPEC (88). Similar results were seen in patients enrolled to KOV-HIPEC-01 trial (89). There were no statistically significant differences in functional scales and symptom scales between HIPEC and control group. Moreover, addition of HIPEC to cytoreductive surgery decreased postoperative pain. Patients in HIPEC group reported lower pain in early postoperative period, which led to lesser consumption of analgetics (90).

Conclusions

Survival improvement related to addition HIPEC to surgery in OC was observed in most meta-analyses. Previously published randomized trials indicated longer PFS and OS in patients undergoing HIPEC after IDS compared to those without HIPEC (30,91). Nevertheless, HIPEC is not widely accepted in clinical practice. This may be changed by the results of two ongoing randomized trials evaluating addition of HIPEC to IDS: KOV-HIPEC-04 (NCT05827523) and HOTT (NCT05659381). In those studies, patients randomized to HIPEC arm received a dose of cisplatin 75 and 100 mg/m², respectively. Apart from survival, quality of life, cost-effectiveness and effect of homologous recombination repair deficiency will be assessed. Despite this, several issues need to be explained. Future studies should focus on determining a subgroup of patients, who mostly benefit from HIPEC. At the same time, this will limit the exposure of non-responding patients to side effects related to HIPEC. This will lead to the unification of European and American recommendations.

Another issue regarding HIPEC in OC management is determining its role and place in the era of Poly (ADP-ribose) polymerase (PARP) inhibitors and other evolving treatment modalities. This applies to both first-line treatment and recurrent disease management.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://cco.amegroups.com/article/view/10.21037/cco-23-152/rc

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