Intraperitoneal paclitaxel for gastric cancer with peritoneal metastasis

IP paclitaxel for peritoneal dissemination

Peritoneal-plasma barrier is a 90-μm thick barrier between the peritoneum and plasma area that is composed of a monolayer of mesothelial tissue. This retards the clearance of high-molecular-weight chemotherapeutic agents from the peritoneum and prevents the exposure of small cancer nodules on the surfaces of the abdomen and pelvis. Therefore, systemic chemotherapy can pose challenges, necessitating the direct administration of chemotherapeutic drugs into the peritoneal cavity (Fig. 2) [12].

Fig. 2
Peritoneal-plasma barrier.
Anatomy of the peritoneal membrane (upper) and intraperitoneal drug transport between the tumor tissue in the peritoneum and blood vessels (lower).

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IP paclitaxel is macromolecular fat-soluble, can be absorbed slowly from the peritoneal cavity, and is preserved at high concentrations in the peritoneal cavity, with minimal toxicity. Additionally, it is antiproliferative; therefore, the IP administration of chemotherapeutic drugs can be repeated without adhesions [13]. Compared to those of other known effective drugs for GC, including cisplatin, oxaliplatin, and 5-fluorouracil, paclitaxel has a higher molecular weight and area under the curve ratio, enabling it to penetrate more than 80 cell layers [14, 15, 16]. However, it has limitations regarding its ability to infiltrate tumors deeply and cover a restricted delivery area in the peritoneal cavity. Thus, we should combine it with systemic chemotherapy. Therefore, the IP administration of paclitaxel is considered a promising treatment for eliminating PM in GC because it penetrates directly into disseminated tumors (Fig. 3) [14, 15].

Fig. 3
Characteristics of intraperitoneal paclitaxel.

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Role of laparoscopy in IP chemotherapy

For peritoneal carcinomatosis, preoperative computed tomography and positron emission tomography underestimate the tumor burden because metastatic peritoneal implants <8 mm cannot be accurately assessed. Therefore, laparoscopy can be an alternative for the assessment of the peritoneal cancer index (PCI) and histological diagnosis, making it a highly accurate diagnostic modality for peritoneal carcinomatosis [16, 17]. For the laparoscopic evaluation of peritoneal carcinomatosis, the PCI score was proposed by Sugarbaker for the laparoscopic evaluation of peritoneal carcinomatosis. This is a quantitative assessment of cancer distribution and implant size, measured by the greatest diameter (Fig. 4) [18].

Fig. 4
PCI score.
The PCI score was proposed by Jacquet and Sugarbaker [18] for the laparoscopic evaluation of peritoneal carcinomatosis. This is a quantitative assessment of cancer distribution and implant size, measured by the greatest diameter.

PCI = peritoneal cancer index.

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Recently, Yonemura et al. [19, 20] proposed the significance of a comprehensive treatment for gastric peritoneal carcinomatosis in Japan that evolved with laparoscopic surgery. First, laparoscopic hyperthermic IP chemotherapy has the advantage of greater depth of drug penetration from the peritoneal surface compared to that associated with open hyperthermic IP chemotherapy. Bidirectional IP, systemic induction chemotherapy, and extensive peritoneal lavage can be administered [19]. Therefore, the authors reported the results of neoadjuvant laparoscopic hyperthermic IP chemotherapy and neoadjuvant IP/systemic chemotherapy. In this study, neoadjuvant IP and systemic chemotherapy reduced the PCI scores by approximately 50% before cytoreductive surgery [20].

Although laparoscopy is a useful tool for PM, the PCI score cannot be calculated in 70% of cases because of the incomplete visualization of the abdominal cavity and multiple tumor manifestations. The extent of tumor involvement in the small intestine appears to be more relevant than the calculation of the PCI score [21].

Recent results of IP paclitaxel chemotherapy

A meta-analysis comparing intravenous (IV) plus IP chemotherapy with IV chemotherapy alone included 5 randomized controlled trials (RCTs) and 1,072 patients. In the present study, the IP group showed better overall survival rates and the prevention of distant PM [22].

In several phase I and II trials, the clinical outcomes of IP chemotherapy with paclitaxel and systemic chemotherapy indicated an increase in the median survival time of up to 2 years, with an overall survival rate >70%. Furthermore, the overall response rate has been reported to be 40%–70% (Table 1) [23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34].

Table 1
Studies of intraperitoneal paclitaxel with systemic chemotherapy for gastric cancer with peritoneal metastasis

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Prof. Ishigami at Tokyo University in Japan proposed a phase III study of IP paclitaxel plus systemic S-1 and paclitaxel compared with systemic S-1 and cisplatin (SP), namely, the PHEONIX-GC trial. In the 2018, the results of the PHEONIX-GC trial were reported. Especially, the median survival times for the IP and SP arms were approximately 18 and 15 months, respectively, and the 3-year overall survival rates were approximately 22% and 6% in the IP and SP arms, respectively. Therefore, despite a trend toward survival benefits, this trial did not demonstrate the statistical superiority of IP paclitaxel plus systemic chemotherapy. However, in a subgroup analysis of overall survival, they detected a significant interaction between the treatment effect and the amount of ascites. Analysis of the ascites volume revealed that the IP group had a more favorable response. Thus, this trial suggests possible clinical benefits of IP paclitaxel therapy [35].

In 2017, Korean gastrointestinal surgeons planned to establish a multicenter trial that included a Perioperative Intraperitoneal and Systemic Chemotherapy for Gastric Cancer (PIPS-GC) trial. First, they gathered and reported multicenter retrospective data on IP and systemic chemotherapy with paclitaxel. Eighty-two patients from 2015 to 2018 were included in the analysis. The mean number of IP chemotherapy cycles was 6.6. Regarding the type of palliative surgery, 51 cases were synchronous and the mean PCI was 22. Postoperative complications were reported in 24 patients, and IP catheter-related and port-related complications were observed in 15 patients [36].

Two recent clinical trials on IP chemotherapy have been conducted in South Korea. Paclitaxel was used in both trials as an IP chemotherapy regimen. The PIPS-GC trial is a multicenter study that primarily included phase I and II trials. Twelve hospitals participated in that study [27]. However, the IPLUS study was a single-center trial involving a surgeon, oncologist, pathologist, and radiologist participating in this study. The IPLUS study group reported the results of a phase I study. Two cases of dose-limiting toxicity occurred with 80 mg; therefore, they decided to administer 60 mg, which is the recommended phase II dose. Of the 6 patients, 3 showed a partial response, 2 showed stable disease, and 1 showed progression. Conversion surgery was possible in three patients. The median overall survival period was 16.6 months and progression free survival was 9.6 months [32].

Nakashima et al. [37] reported the results of a retrospective study comparing IP paclitaxel with non-IP systemic chemotherapy and showed better survival outcomes in the IP paclitaxel group.

Conversion surgery for peritoneal dissemination

Conversion therapy for stage IV GC has recently attracted considerable attention. It is defined as a surgical treatment with no residual curative resection after chemotherapy for tumors that were originally unresectable or marginally resectable for technical and/or oncological reasons [38]. In 2016, Yoshida et al. [39] proposed a classification system for stage IV GC based on resectability and curability. This system is largely determined by macroscopic peritoneal dissemination. Therefore, the efficacy of IP and systemic chemotherapy in cases of macroscopic peritoneal dissemination suggests that achieving complete disappearance of lesions through IP chemotherapy might enable the prospect of R0 surgery, even in patients diagnosed with PM.

Ishigami et al. [40] reported the results of IP paclitaxel chemotherapy. In 2017, the authors reported conversion surgery after IP and systemic chemotherapy for PM. In total, 100 patients were enrolled, 64 of whom underwent conversion gastrectomy. The median survival time was 30 months, and better survival was noted in the surgical cases, especially in R0 cases.

In 2017, Yonemura et al. [20] proposed neoadjuvant laparoscopic hyperthermic intraperitoneal chemoperfusion (NLHIPEC) and neoadjuvant intraperitoneal and systemic chemotherapy (NIPS). In this study, NLHIPEC and NIPS reduced the PCI score in approximately 50% of the patients before cytoreductive surgery.

Recently, Kim et al. [41] reported the results of minimally invasive surgery combined with IP and systemic chemotherapy for with GC patients with PM in Korea. In total, 26 patients were enrolled, and five of them underwent conversion surgery, including laparoscopic gastrectomy.

Other modalities of IP chemotherapy

Pressurized intraperitoneal aerosol chemotherapy (PIPAC) has emerged as an alternative treatment for peritoneal carcinomatosis. Fig. 5 illustrates the PIPAC procedure using a laparoscopic CO₂ insufflator and a high-pressure injector [42].

Fig. 5
Pressurized intraperitoneal aerosol chemotherapy systm.

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In 2016, Nadiradze and colleagues [43] published the first report of PIPAC for gastric peritoneal carcinomatosis. Sixty PIPAC procedures were performed in 24 patients and tumor responses were observed in 50% of them. Subsequently, several studies have reported the application of PIPAC in GC-associated PM. Two studies focused exclusively on GC patients, whereas the others included heterogeneous populations [43, 44]. A single study emphasized the role of PIPAC in the neoadjuvant setting [45]. All studies revealed that PIPAC is feasible and has minimal perioperative morbidity even after repeated applications [46].

Thereafter, early clinical trials of PIPAC therapy using albumin-bound paclitaxel have been reported, which may result in superior efficacy in the treatment of PM compared to that associated with standard IP paclitaxel chemotherapy [47, 48]. Additionally, the retrospective results of PIPAC with taxanes have been reported by an Indian group. Thus, the role of PIPAC in combination with docetaxel and paclitaxel, either alone or in combination with other drugs, should be investigated in future prospective studies [49].

Nab-paclitaxel is an albumin-bound nanoparticle formulation of paclitaxel specifically designed to overcome the limitations of conventional paclitaxel formulations, including barriers to effective drug delivery of highly lipophilic agents [50]. Nab-paclitaxel has fewer side effects, increased tumor cell cytotoxicity, and higher overall response rates than those associated with equal doses of solvent-based paclitaxel for many solid malignancies [51]. Recently, a phase I study protocol for IP cisplatin and nab-paclitaxel administered via the PIPAC for the treatment of gastric peritoneal carcinomatosis was published [52].