Neoadjuvant intraperitoneal chemotherapy followed by radical surgery and HIPEC in patients with very advanced gastric cancer and peritoneal metastases: report of an initial experience in a western single center

Patients with advanced gastric cancer present with peritoneal metastases in about 30% of cases [1] and up to 50% of those treated with curative intent will develop relapse in the peritoneum. Standard treatment for these individuals is systemic chemotherapy, but median survival in this scenario is poor, around 3 to 6 months in most studies [2], reaching a little over 1 year in a recent Eastern trial [3].

Cytoreductive surgery (CRS) followed by hyperthermic intraperitoneal chemotherapy (HIPEC) for gastric cancer patients with peritoneal metastases has been associated with improved survival in a selected group of patients both in an Eastern [2] and in a large French multicenter series [4]. The results from both studies have emphasized the importance of patient selection, as the ones with the best results were treated with preoperative systemic chemotherapy, had limited peritoneal dissemination, measured by a low peritoneal cancer index (PCI), and were treated with a complete cytoreduction [4].

The association of neoadjuvant intraperitoneal and systemic chemotherapy has been investigated recently and seems to be a very important tool for patient selection. In a large Eastern series, individuals who had negative cytology after this preoperative regimen and were treated with CRS + HIPEC had improved survival compared to those with positive cytology [5]. The addition of laparoscopic HIPEC (L-HIPEC) and more effective systemic chemotherapy to this multidisciplinary treatment, labeled as bidirectional intraperitoneal and systemic chemotherapy (BISIC), has led to more significant response rates and improved survival in this set of patients [1].

The aim of this study was to report the first four consecutive cases of gastric cancer patients who presented with advanced disease and disseminated peritoneal metastases and were treated with L-HIPEC and BISIC, followed by CRS + HIPEC.

This is a retrospective, single-center case series based on routinely collected data extracted from patients’ electronic charts. This paper was written in accordance with CARE guideline for case reports [6].

The inclusion criteria were diagnosis of synchronous metastatic gastric cancer with peritoneal dissemination as the sole site of metastatic disease and treatment with BISIC (as described below) between October 2015 and August 2017 (Table 1).

Treatment was adapted according to Yonemura’s original protocol (2006), which he later modified, adding more effective systemic chemotherapy and with a different dosage of the intraperitoneal drugs [1, 7]. As S-1 is not currently available in Brazil, Capecitabine was used instead of S-1. Briefly, during the first laparoscopy, before any treatment, extensive intraperitoneal lavage (EIPL) [8] and L-HIPEC (Cisplatin 30 mg/m2 + Docetaxel 30 mg/m2, for 1 h at 42 ^oC) were performed. At the end of the procedure, a peritoneal port-a-cath (DistricAth®, Districlass Médical, France) was placed with its tip directed toward the cul-de-sac. After a 15-day period of rest, patients initiated normothermic chemotherapy. On day 1, Cisplatin 30 mg/m2 and Docetaxel 30 mg/m2 were infused into the peritoneal cavity for 2 h after adequate pre-medication. On day 8, Cisplatin 30 mg/m2 and Docetaxel 30 mg/m2 were given intravenously in separate bags according to standard infusion protocols. Capecitabine 850 mg/m2 PO twice a day was administered from day 1 to day 14. Cycles were repeated every 21 days.

Treatment strategy consisted on repeating BISIC cycles three times, followed by CT scans, endoscopy, and a new laparoscopy. According to the surgical findings, another three cycles of BISIC was performed, or patient was taken to CRS, which included gastrectomy + D2-lymphadenectomy, resection of peritoneal lesions, and HIPEC.

During treatment, patients were followed for toxicity at least once per cycle, and response evaluation with endoscopy and CT scans were performed every three cycles. After cytoreductive surgery, CT scans were repeated every 2–3 months.

All patients signed informed consent after extensive discussion with patients and relatives regarding potential benefits and risks of the treatment. Toxicity was graded according to Common Toxicity Criteria (CTC) 4.0.

We report in this series the first four cases of gastric cancer patients with very advanced peritoneal disease who were treated with a multimodality regimen that included systemic and intraperitoneal chemotherapy in a recently nominated regimen known as BISIC [1], followed by cytoreductive surgery and HIPEC, in a single Western cancer center. The most important findings in these cases were the lack of postoperative morbidity and the significant response in peritoneal dissemination associated with treatment, which turned patients who would be candidates for palliative chemotherapy only into candidates for a more radical therapy and a chance for improved survival.

Three of the four patients reached a significant response that allowed them to be treated with a complete cytoreductive surgery and also received HIPEC with Docetaxel and Cisplatin for 60 min. The association of CRS and HIPEC has been proven superior to CRS alone in a Chinese randomized trial with 68 patients, in which the multimodality group had a median survival of 11 months compared to 6.5 months in the surgery only group. These poor numbers in both groups may be related to patient selection, as 42% of individuals in this study did not have a complete CRS with no residual macroscopic disease (CC-0) [9]. This trial confirmed the findings of a large French multicenter study that subjects who are candidates for this multimodality regimen should receive preoperative chemotherapy, should have low disease burden, expressed in PCI count, and should receive a CC-0 CRS as a mandatory step of their treatment [4].

Canbay et al. first described the use of neoadjuvant intraperitoneal chemotherapy combined with systemic chemotherapy in a large single-center series in Japan, with 194 patients. Out of these individuals, 152 (78%) were classified as responders, a classification that at the time included patients whose cytology became negative after the administration of two cycles of intraperitoneal Cisplatin and Docetaxel and six cycles of S-1. These responders were then taken to CRS and HIPEC, and the median survival of those who received CC-0 surgery was 18 months [5], which was an improvement compared to the results of chemotherapy alone, even in Eastern studies [10].

This regimen was later modified by the same group, and the concept of a laparoscopic hyperthermic intraperitoneal chemotherapy perfusion (L-HIPEC) was introduced. Its main advantage would be a minimally invasive procedure with direct vision, which would allow for a more valid assessment of the peritoneal disease extent in the peritoneal cavity. Also, a more effective systemic chemotherapy regimen was adopted, with the use of Cisplatin and Docetaxel intravenously associated with the intraperitoneal regimen (BISIC). This treatment has been described in detail in the literature [1, 11]. The most important benefit of this association seems to be a higher response rate in peritoneal disease extent. In a study of this regimen in 105 patients, the association of L-HIPEC and BISIC led to a significant change in PCI, as 44% of patients had baseline PCI under 12, compared to 67% after treatment. Also, 66% of all subjects experienced a decrease or complete disappearance in peritoneal metastases in the re-staging laparoscopy [12]. We identified this response in three of our patients, with decreases of 100, 52, and 31%, with numbers that were obtained in open surgery and that could have been undervalued in the staging laparoscopies. The less significant response and the disease progression findings were identified in the two patients who had systemic chemotherapy prior to L-HIPEC and BISIC. Although sample size was too small to draw any conclusions, it is possible that the performance of this prior treatment could have helped induce drug resistance.

Another aspect that should be highlighted is the very low morbidity associated with the procedure. In the study above, no patient developed grade IV and V toxicity and only four had grade III events after L-HIPEC and BISIC. Our cases had similar results, with no grade III, IV, or V events after chemotherapy and no postoperative complication. We certainly do not expect zero morbidity in future cases, but that resembles our previous results with adjuvant HIPEC, in which no patient developed organ insufficiency and there was no mortality [13]. Very similar results have been recently reported in an American cancer center series, with 11% morbidity and no mortality associated with the L-HIPEC [14]. That reinforces the notion that the morbidity and mortality associated with CRS and HIPEC is highly influenced by surgery extent.

This is a very small case series, and interpreting its results is somewhat limited. However, this multimodality treatment has been performed extensively in a Japanese institution and its results have shown a very acceptable toxicity and promising response rates, with long-term survival in selected patients [1]. We report here our group preliminary experience, with favorable results in subjects with very advanced gastric cancer and diffuse peritoneal metastases. A higher number of cases should confirm the validity of these results and provide more meaningful analyses.

In conclusion, the association of L-HIPEC and BISIC has led to a good response in peritoneal disease extent in our initial experience and allowed radical procedures to be performed in individuals who were otherwise candidates for palliative chemotherapy.