Comprehensive Treatment Algorithms of the Swiss Peritoneal Cancer Group for Peritoneal Cancer of Gastrointestinal Origin

Citation: Adamina, M.; Warlaumont, M.; Berger, M.D.; Daster, S.; Delaloye, R.; Digklia, A.; Gloor, B.; Fritsch, R.; Koeberle, D.; Koessler, T.; et al. Comprehensive Treatment

# Introduction
Peritoneal cancer (PC) comprises a heterogeneous group of primary peritoneal tumors and metastatic disease from various origins. Common characteristics are late diagnosis, a limited response to systemic therapy, and hence, a dismal prognosis [bib_ref] Treatment of colorectal peritoneal carcinomatosis with systemic chemotherapy: A pooled analysis of..., Franko [/bib_ref] [bib_ref] Predictors and survival of synchronous peritoneal carcinomatosis of colorectal origin: A population-based..., Lemmens [/bib_ref]. New treatment modalities and multimodal strategies have improved prognosis considerably over the last decade and a cure has become possible for selected patients. Complete cytoreductive surgery (CRS) with or without heated intraperitoneal chemotherapy (HIPEC) provides the best outcomes for most entities but entails risks for postoperative complications and a long recovery period [bib_ref] Cytoreduction (Peritonectomy Procedures) Combined with Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in Advanced Ovarian..., Giorgio [/bib_ref] [bib_ref] Toward curative treatment of peritoneal carcinomatosis from nonovarian origin by cytoreductive surgery..., Glehen [/bib_ref] [bib_ref] Peritoneal carcinomatosis from gastric cancer: A multi-institutional study of 159 patients treated..., Glehen [/bib_ref] [bib_ref] Association Francaise de Chirurgie. Pseudomyxoma peritonei: A French multicentric study of 301..., Elias [/bib_ref]. While the intent of CRS is to remove all visible disease, intraperitoneal (ip) chemotherapy addresses microscopic residual disease, so as to maximize the benefit of an extensive surgical resection. PC occurs frequently in colorectal and gastric cancers. Indeed, up to 25% of relapsing colorectal cancer patients develop metastatic disease restricted to the peritoneum, while around 8% of patients present with isolated PC at primary resection [bib_ref] Peritoneal carcinomatosis from non-gynecologic malignancies: Results of the EVOCAPE 1 multicentric prospective..., Sadeghi [/bib_ref] [bib_ref] Incidence, prevalence and risk factors for peritoneal carcinomatosis from colorectal cancer, Segelman [/bib_ref]. In gastric cancer, isolated PC is found in 5-20% of patients who undergo surgical exploration for potentially curative resection [bib_ref] Peritoneal carcinomatosis from gastric cancer: A multi-institutional study of 159 patients treated..., Glehen [/bib_ref]. In infrequent cancers such as pseudomyxoma peritonei and peritoneal mesothelioma, CRS HIPEC is a standard of care, whenever a patient is fit for major surgery [bib_ref] Toward curative treatment of peritoneal carcinomatosis from nonovarian origin by cytoreductive surgery..., Glehen [/bib_ref] [bib_ref] Association Francaise de Chirurgie. Pseudomyxoma peritonei: A French multicentric study of 301..., Elias [/bib_ref] [bib_ref] Early-and long-term outcome data of patients with pseudomyxoma peritonei from appendiceal origin..., Chua [/bib_ref] [bib_ref] Appendiceal tumours and pseudomyxoma peritonei: Literature review with PSOGI/EURACAN clinical practice guidelines..., Govaerts [/bib_ref] [bib_ref] Peritoneal mesothelioma: PSOGI/EURACAN clinical practice guidelines for diagnosis, treatment and follow-up, Kusamura [/bib_ref] [bib_ref] Multicystic peritoneal mesothelioma treated with cytoreductive surgery followed or not by hyperthermic..., Kepenekian [/bib_ref] [bib_ref] Ten-year experience with peritoneal mesothelioma, Kyziridis [/bib_ref]. Thus, in expert centers providing CRS HIPEC, cure rates above 80% are reported for pseudomyxoma peritonei [bib_ref] Association Francaise de Chirurgie. Pseudomyxoma peritonei: A French multicentric study of 301..., Elias [/bib_ref] [bib_ref] Early-and long-term outcome data of patients with pseudomyxoma peritonei from appendiceal origin..., Chua [/bib_ref] [bib_ref] American Society of Peritoneal Surface Malignancies opinion statement on defining expectations from..., Esquivel [/bib_ref] [bib_ref] Intraperitoneal chemotherapy for peritoneal surface malignancy: Experience with 1,000 patients, Levine [/bib_ref] [bib_ref] The Role of Hyperthermic Intraperitoneal Chemotherapy in Pseudomyxoma Peritonei After Cytoreductive Surgery, Kusamura [/bib_ref].
Conversely, the debate is ongoing for colorectal and gastric cancers that represent the vast majority of patients affected by PC, who are largely treated with palliative systemic therapy. Indeed, it is estimated that more than 90% of these patients only receive a systemic chemotherapy combined with a biological agent, whereas about 5% may be treated in a multimodal approach, including CRS HIPEC [bib_ref] Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for colorectal cancer: Survival outcomes and..., Esquivel [/bib_ref]. This is unfortunate and unfair to our patients as the evidence in favor of cytoreductive surgery is strong, with a controversy limited to the additional value of HIPEC in addition to a complete cytoreduction. Several international registries as well as phase 2 and phase 3 randomized controlled trials have underlined the benefit of a curative approach taking advantage of CRS HIPEC in PC of gastric and colorectal origin [bib_ref] 8-year follow-up of randomized trial: Cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic..., Verwaal [/bib_ref] [bib_ref] Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy versus cytoreductive surgery alone for colorectal..., Quenet [/bib_ref] [bib_ref] Peritoneal surface disease from colorectal cancer: Comparison with the hepatic metastases surgical..., Shen [/bib_ref] [bib_ref] Complete cytoreductive surgery plus intraperitoneal chemohyperthermia with oxaliplatin for peritoneal carcinomatosis of..., Elias [/bib_ref] [bib_ref] Cytoreductive surgery combined with perioperative intraperitoneal chemotherapy for the management of peritoneal..., Glehen [/bib_ref] [bib_ref] Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Gastric Cancer with Synchronous Peritoneal..., Marano [/bib_ref] [bib_ref] Prognostic impact of cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) in..., Granieri [/bib_ref] , with a single, although most recent, randomized controlled trial not concluding in favor of HIPEC in colorectal cancer [bib_ref] Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy versus cytoreductive surgery alone for colorectal..., Quenet [/bib_ref]. Beyond PC originating from gastrointestinal cancers, another large European multicentric randomized controlled trial demonstrated a remarkable overall survival benefit of one year in women with stage III ovarian cancer who benefited from HIPEC in addition to CRS [bib_ref] Hyperthermic Intraperitoneal Chemotherapy in Ovarian Cancer, Van Driel [/bib_ref]. Nonetheless, morbidity and resource utilization remain of concern when considering the true value of CRS HIPEC. Indeed, the nationwide Dutch CRS HIPEC prospective registry reported a mortality rate of 3% for a major morbidity of 34% and a length of stay of 16 days, which is similar to the clinical outcomes of most major oncological procedures. Importantly, numerous studies have reported that a maximal treatment including the addition of HIPEC to CRS was worth the trouble in the patients' perspective, with acceptable to high quality of life related within a few months after CRS HIPEC [bib_ref] Effect of Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy on Quality of Life..., Ali [/bib_ref] [bib_ref] Quality of life in patients after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy:..., Tsilimparis [/bib_ref] [bib_ref] Quality of life after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: An Asian..., Tan [/bib_ref] [bib_ref] Quality of Life After Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy: Early Results..., Steffens [/bib_ref] [bib_ref] Health-related quality of life after interval cytoreductive surgery with or without hyperthermic..., Koole [/bib_ref] [bib_ref] Qualityof-Life Evaluation After Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy, Dodson [/bib_ref] [bib_ref] Health-Related Quality of Life After Cytoreductive Surgery/HIPEC for Mucinous Appendiceal Cancer: Results..., Moaven [/bib_ref].
Recently, the surgical administration of intraperitoneal chemotherapy evolved further to include pressurized intraperitoneal aerosol chemotherapy (PIPAC) administered laparoscopically [bib_ref] Systematic review of pressurized intraperitoneal aerosol chemotherapy for the treatment of advanced..., Grass [/bib_ref]. Phase I and II studies have reported safety and efficacy of PIPAC for a variety of cancers [bib_ref] Pressurized intraperitoneal aerosol chemotherapy in women with recurrent ovarian cancer: A phase..., Tempfer [/bib_ref] [bib_ref] Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) with Low-Dose Cisplatin and Doxorubicin in Gastric..., Nadiradze [/bib_ref] [bib_ref] Pressurized intraperitoneal aerosol chemotherapy with oxaliplatin in colorectal peritoneal metastasis, Demtroder [/bib_ref] , including low morbidity and preservation or improvement of quality of life [bib_ref] Quality of life of patients with end-stage peritoneal metastasis treated with Pressurized..., Odendahl [/bib_ref] [bib_ref] Feasibility and Safety of Pressurized Intraperitoneal Aerosol Chemotherapy for Peritoneal Carcinomatosis: A..., Hubner [/bib_ref] [bib_ref] Impact of Pressurized Intraperitoneal Aerosol Chemotherapy on Quality of Life and Symptoms..., Teixeira Farinha [/bib_ref] [bib_ref] Pressurized Intraperitoneal Aerosol Chemotherapy, a Palliative Treatment Approach for Patients with Peritoneal..., Winkler [/bib_ref]. Moreover, iterative laparoscopy when performing PIPAC allows for repeat biopsy and objective assessment of tumor regression with a validated grading system to guide multimodal treatment [bib_ref] Reproducibility of the peritoneal regression grading score for assessment of response to..., Solass [/bib_ref]. Hence, both CRS HIPEC and PIPAC now belong to the advanced armentarium of an efficient multimodal approach to peritoneal cancer.
Today, clinicians and tumor boards that advise treatment for patients with PC are confronted with a large and dynamic body of literature in a rapidly evolving, highly specialized clinical context. Yet, RCT or prospective comparative studies are rare for most clinical situations. The aim of the present comprehensive treatment algorithms by the Swiss Peritoneal Cancer Group (SPCG) is therefore to propose a standardized and pragmatic approach for multimodal treatment of PC of gastrointestinal origin.

# Materials and methods
The SPCG was founded in 2012 as a working group within the society of Swiss Visceral Surgeons. Since inception, a medical oncologist with an academic practice has been a member of its executive board and instrumental in securing a true interdisciplinary vision. This practice consensus was elaborated along a modified Delphi process as follows:

## Review of the literature and drafting of comprehensive treatment algorithms
Pertinent literature and current guidelines on the treatment of PC of gastrointestinal origin were scrutinized by two authors from the core team from Lausanne. The literature search focused on pseudomyxoma peritonei, peritoneal mesothelioma, and PC of gastric and colorectal origin. Empirical studies including patients undergoing CRS with or without ip chemotherapy (HIPEC, PIPAC) and published in English, German, or French were included. References of the included studies were checked for additional missed articles. The best available evidence was collated giving priority to RCTs, comparative prospective studies, large-scale retrospective studies, and clinical registry data. Well-performed systematic reviews and meta-analyses were considered and searched for further references. Opinion statements, editorials, grey literature, and expert opinion were not considered in agreement with current recommendations [bib_ref] Systematic review finds that study data not published in full text articles..., Schmucker [/bib_ref]. Four working algorithms with accompanying text were drafted.

## Internal validation of the lake geneva algorithms
The 4 treatment algorithms and their accompanying text were submitted for internal review to surgical and medical oncologists involved in the treatment of PC patients at the university hospitals of Lausanne and Geneva. Substantial modifications of the algorithms were discussed and implemented during a 4-month working period including 3 face to face Delphi rounds.

## External validation of the spcg algorithms
The Lake Geneva algorithms were presented to the board of the SPCG and revised. The literature was cross-checked and updated, and the algorithms were thoroughly discussed until a consensus was reached in a further Delphi round. The SPCG algorithms were complemented by in-depth discussion and alignment to nationwide clinical practice in Swiss expert centers until a final consensus was reached and unanimously endorsed by the board of the SPCG and the lead PC clinician of 7 surgical oncology and 7 medical oncology departments. The SPCG comprehensive treatment algorithms for PC of gastrointestinal origin were presented to the international audience and faculty of the SPCG symposium and validated during the general assembly of the SPCG on 3 September 2021.
The SPCG treatment algorithms are endorsed by all Swiss institutions routinely offering extensive cytoreductive surgery with multivisceral resection and HIPEC or PIPAC, including 7 surgical oncology and 7 medical oncology departments. They are intended as representative guidance for interdisciplinary tumor boards and clinicians taking care of patients with PC and not as formal guidelines. This practice consensus intends to standardize multimodal care of patients with PC in Switzerland and promote nationwide inclusion in the prospective SPCG registry.
PC of gynecologic origin is not covered in the present treatment algorithms, yet a similar approach is currently underway by the respective working group of the SPCG.

# Results

## Pseudomyxoma peritonei
Pseudomyxoma peritonei is a rare cancer originating from a ruptured low grade mucinous neoplasia of the appendix (LAMN) with an estimated incidence of 2 to 4 per million [bib_ref] Pseudomyxoma peritonei: Natural history and treatment, Mittal [/bib_ref] [bib_ref] Consensuses and controversies on pseudomyxoma peritonei: A review of the published consensus..., Lin [/bib_ref] [bib_ref] Appendiceal neoplasms and pseudomyxoma peritonei: A population based study, Smeenk [/bib_ref]. Rarely, it may also arise from the colon, the pancreas, or the ovary [bib_ref] Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for pseudomyxoma peritonei of appendicular and..., Delhorme [/bib_ref]. It is often an incidental finding either upon radiologic examination or when performing an abdominal procedure, including appendectomy for suspected appendicitis. Left untreated, mucinous tumor cells accumulate by gravity at the sites of peritoneal fluid uptake, in the pelvis, along the rima coli and the greater and lesser omentum, and under the diaphragm. Deep infiltration of organs is not happening in the early course of the disease and the small bowel tends to be spared. Accumulation of mucus causes slowly progressive abdominal distension and organ dysfunction, including intestinal obstruction, cachexia, and ultimately, death. Metastatic disease outside the abdomen is uncommon.
Surgical treatment is the only curative option, yet the cure necessitates a complete cytoreduction. Cytoreduction typically includes a right colectomy, radical omentectomy, cholecystectomy, pelvic peritonectomy, bilateral parietal, and diaphragmatic peritonectomy, and in women, hysterectomy with salpingo-oophorectomy. Additional peritonectomy (liver capsule, mesentery), splenectomy, and bowel resection are performed when infiltration is suspected. Complete cytoreduction is essential and it proceeds irrespective of the peritoneal cancer index, with the remaining small bowel length and preservation of vital organ function being the only technical limitation. Extensive surgery is challenging for the patient and the surgeon alike, frequently lasting 6 to 12 h. Yet, when supplemented with HIPEC, a long-term cure rate above 80% can be achieved [bib_ref] Association Francaise de Chirurgie. Pseudomyxoma peritonei: A French multicentric study of 301..., Elias [/bib_ref] [bib_ref] Early-and long-term outcome data of patients with pseudomyxoma peritonei from appendiceal origin..., Chua [/bib_ref] [bib_ref] American Society of Peritoneal Surface Malignancies opinion statement on defining expectations from..., Esquivel [/bib_ref] [bib_ref] Intraperitoneal chemotherapy for peritoneal surface malignancy: Experience with 1,000 patients, Levine [/bib_ref] [bib_ref] The Role of Hyperthermic Intraperitoneal Chemotherapy in Pseudomyxoma Peritonei After Cytoreductive Surgery, Kusamura [/bib_ref] [bib_ref] Recurrence of pseudomyxoma peritonei after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy, Mercier [/bib_ref].
Neoadjuvant treatment is not generally recommended, owing to a poor response rate. Adjuvant chemotherapy is, however, advisable in selected cases with high recurrence risk, e.g., incomplete resection, high grade pseudomyxoma, and increasing peritoneal cancer index [bib_ref] Appendiceal pseudomyxoma peritonei: Predictors of recurrence and iterative surgery, Kong [/bib_ref]. Measurement of the tumor markers CEA, CA 19-9, and CA 125 is often elevated and if so, it may prove useful in the follow-up.
About a quarter of the patients treated with optimal CRS HIPEC recur [bib_ref] Appendiceal pseudomyxoma peritonei: Predictors of recurrence and iterative surgery, Kong [/bib_ref] [bib_ref] Recurrence and outcome after complete tumour removal and hyperthermic intraperitoneal chemotherapy in..., Lord [/bib_ref]. Of those qualifying for a repeat CRS HIPEC, long-term survival and morbidity is similar to the figures observed in primary CRS HIPEC patients [bib_ref] Appendiceal pseudomyxoma peritonei: Predictors of recurrence and iterative surgery, Kong [/bib_ref] [bib_ref] Recurrence and outcome after complete tumour removal and hyperthermic intraperitoneal chemotherapy in..., Lord [/bib_ref] [bib_ref] Repeated cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with..., Vassos [/bib_ref]. A large registry study totalizing 1924 patients with pseudomyxoma peritonei treated until December 2017 compared patients treated with cytoreductive surgery alone to the conventional CRS HIPEC regimen: it showed better overall survival and reasonable morbidity in patients treated with CRS HIPEC. Hence, the SPCG recommends CRS HIPEC for patients deemed fit for extensive surgery who present with a pseudomyxoma peritonei. The treatment algorithm proposed by the SPCG is illustrated in [fig_ref] Figure 1: Treatment algorithm for pseudomyxoma peritonei [/fig_ref]. These recommendations are consistent with the current guidelines of the Peritoneal Surface Oncology Group International (PSOGI) and with most national guidelines.
Performing a staging laparoscopy allows one to individualize treatment according to the extent and histology at hand [bib_ref] A Consensus for Classification and Pathologic Reporting of Pseudomyxoma Peritonei and Associated..., Carr [/bib_ref] : in the presence of localized mucin without epithelial cells, simple laparoscopic follow-up without CRS HIPEC may be offered; conversely, high-grade with signet-ring histology tumors may receive neoadjuvant systemic treatment, followed by CRS HIPEC. Notably, there is no threshold peritoneal cancer index for pseudomyxoma peritonei other than technical resectability and fitness of the patient for a major resection.
Pressurized intraperitoneal aerosol chemotherapy [bib_ref] Oxaliplatin use in pressurized intraperitoneal aerosol chemotherapy (PIPAC) is safe and effective:..., Sgarbura [/bib_ref] [bib_ref] Safety, and Efficacy of Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) for Peritoneal Metastasis:..., Kurtz [/bib_ref] is the latest addition to the interdisciplinary armentarium for the treatment of PC. PIPAC may also be considered in patients with pseudomyxoma peritonei, in particular, for unresectable cases [bib_ref] Oxaliplatin use in pressurized intraperitoneal aerosol chemotherapy (PIPAC) is safe and effective:..., Sgarbura [/bib_ref]. However, clinical experience in this context is still limited and no firm recommendation for PIPAC can be made at present.

## Peritoneal mesothelioma
Malignant mesothelioma is affecting the serosal membranes of the pleura, peritoneum, pericardium, or tunica vaginalis testis. The peritoneum is the second most frequent site following the pleura. It is a rare and highly lethal cancer with an incidence of about 0.7 to 3 per million people [bib_ref] Epidemiology of malignant peritoneal mesothelioma: A population-based study, Salo [/bib_ref] [bib_ref] Epidemiology of peritoneal mesothelioma: A review, Boffetta [/bib_ref]. It has been linked to asbestos exposure, yet the association is weaker than with pleural mesothelioma and no sex predominance exists. Patients present with abdominal distension/pain, weight loss/anorexia, while bowel obstruction is a manifestation of advanced disease. Diagnosis relies on percutaneous core needle biopsy or explorative laparoscopy with biopsy, rather than on cytological examination of serosal effusion or fine needle biopsy [bib_ref] Peritoneal mesothelioma: PSOGI/EURACAN clinical practice guidelines for diagnosis, treatment and follow-up, Kusamura [/bib_ref]. It is advisable to place all laparoscopic trocars along the midline, so as to allow for a straightforward resection at laparotomy and minimize port site metastasis.
The conventional classification distinguishes two main forms: diffuse malignant peritoneal mesothelioma (DMPM) and borderline forms, which include multicystic peritoneal mesothelioma (MCPM) and well-differentiated papillary peritoneal mesothelioma (WDPPM). DMPM itself comprises three histological subtypes (epithelioid, sarcomatoid, or biphasic) [bib_ref] Peritoneal mesothelioma: PSOGI/EURACAN clinical practice guidelines for diagnosis, treatment and follow-up, Kusamura [/bib_ref]. Expert pathology review is recommended to differentiate histological subtypes and estimate clinical course. Measurement of the tumor marker CA 125 is advised in addition to cross-sectional imaging and laparoscopy [bib_ref] Peritoneal mesothelioma: PSOGI/EURACAN clinical practice guidelines for diagnosis, treatment and follow-up, Kusamura [/bib_ref].
The two main forms show different behavior: the rarer well-differentiated papillary mesothelioma progresses slowly and metastasizes late; the more frequent diffuse malignant peritoneal mesothelioma shows an aggressive behavior and responds poorly to chemotherapy [bib_ref] Efficacy of second-line treatment and prognostic factors in patients with advanced malignant..., Kitadai [/bib_ref]. In patients of both subtypes fit for surgery, CRS HIPEC is a curative approach with no exclusion per se because of a high peritoneal cancer index. Watchful waiting is an alternative approach in the frail patient with a well-differentiated papillary peritoneal mesothelioma with treatment escalation when progressive disease is detected. In the presence of an epithelioid subtype, exploratory laparoscopy is advised to assess the true extent of disease, as no imaging modality is able to reliably assess resectability of PC of any origin. Some centers advise one to take advantage of exploratory laparoscopy to initiate intraperitoneal chemotherapy with administration of a first PIPAC. Indeed, neoadjuvant PIPAC has been shown to be effective and of low morbidity, in particular, when performed ahead of any major surgery or associated with neoadjuvant systemic chemotherapy [bib_ref] Pressurized intraperitoneal aerosol chemotherapy (PIPAC) as a neoadjuvant therapy before cytoreductive surgery..., Girshally [/bib_ref] [bib_ref] Safety and feasibility of pressurized intraperitoneal aerosol chemotherapy (PIPAC) associated with systemic..., Robella [/bib_ref]. Neoadjuvant therapy is offered whenever initial evaluation reveals a high risk peritoneal mesothelioma (peritoneal cancer index > 17, Ki-67 > 9%, sarcomatoid histology, nodal positive status, incomplete resection CC score >1), and/or borderline resectability. Following neoadjuvant systemic chemotherapy, re-evaluation is performed, including another explorative laparoscopy-which again may be supplemented by a PIPAC with the purpose to improve resectability [bib_ref] Unresectable peritoneal metastasis treated by pressurized intraperitoneal aerosol chemotherapy (PIPAC) leading to..., Alyami [/bib_ref]. Once a patient is deemed resectable and fit for surgery, CRS HIPEC is offered.
In recurrent peritoneal mesothelioma following curative CRS HIPEC, another CRS HIPEC is rarely offered but palliative systemic chemotherapy, which again may be supplemented by palliative PIPAC. Similarly, non-resectable mesothelioma is treated by systemic chemotherapy and/or PIPAC [bib_ref] Oxaliplatin use in pressurized intraperitoneal aerosol chemotherapy (PIPAC) is safe and effective:..., Sgarbura [/bib_ref] [bib_ref] Efficacy of second-line treatment and prognostic factors in patients with advanced malignant..., Kitadai [/bib_ref] [bib_ref] Multicentric initial experience with the use of the pressurized intraperitoneal aerosol chemotherapy..., Alyami [/bib_ref] [bib_ref] Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) for the treatment of malignant mesothelioma, Giger-Pabst [/bib_ref]. Of note, new data regarding the use of immune checkpoint inhibitors in the palliative setting have to be taken into consideration, especially regarding the sarcomatoid histology, but are not yet mature enough to be integrated in this algorithm. The treatment algorithm proposed by the SPCG is illustrated in [fig_ref] Figure 2: Treatment algorithm for peritoneal mesothelioma [/fig_ref]. These recommendations are consistent with the 2021 published guidelines of the Peritoneal Surface Oncology Group International [bib_ref] Peritoneal mesothelioma: PSOGI/EURACAN clinical practice guidelines for diagnosis, treatment and follow-up, Kusamura [/bib_ref] and with the Chicago consensus on peritoneal surface malignancies.

## Gastric cancer
In Western countries, gastric cancer often presents in symptomatic, late stages of disease and it is hence often incurable. It is, however, a common cancer ranking 13 th , with an incidence of 8.1 per 100,000 people in Europe (5.1/100,000 in Switzerland) and a cure rate of 37.5% [bib_ref] Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for..., Sung [/bib_ref].
The European Society of Medical Oncology recommends multimodal treatment for patients with stage  IB resectable gastric and gastroesophageal junction cancers, includ-ing laparoscopic staging, neoadjuvant chemotherapy, surgery, and adjuvant chemotherapy [bib_ref] Gastric cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up, Smyth [/bib_ref] [bib_ref] Recent eUpdates to the ESMO Clinical Practice Guidelines on hepatocellular carcinoma, cancer..., Pentheroudakis [/bib_ref]. Tumor staging includes computed tomography (CT) and frequently endoscopic ultrasound, which may provide more accurate locoregional staging than CT, as well as biopsy. Laparoscopy completes tumor staging and provides direct visualization of peritoneal surfaces and local lymph nodes, as well as biopsy of any suspicious lesions. Often, PC is diagnosed during laparoscopic staging and/or peritoneal washing. Again, no diagnostic imaging can rule out PC so that laparoscopic staging is advised in most curative situations. Indeed, PC is detected in 15-53% of gastric cancers treated with curative intent [bib_ref] The treatment of peritoneal carcinomatosis in advanced gastric cancer: State of the..., Montori [/bib_ref] [bib_ref] Incidence, time course and independent risk factors for metachronous peritoneal carcinomatosis of..., Seyfried [/bib_ref]. Measurement of the tumor markers CA 19-9 and CEA have a prognostic value and can be used in the follow-up, while HER2 and microsatellite status can be sought after as a biomarker with therapeutic implications. Last, multiplex profiling has shown that CDH1 and TAF1 mutations, 6q loss and chr19 gain were seen more frequently in PC of gastric origin, while more aggressive PC phenotypes were emerging with increased mutations in TP53, CDH1, TAF1, KMT2C, and chromosomal instability [bib_ref] Multiplex profiling of peritoneal metastases from gastric adenocarcinoma identified novel targets and..., Wang [/bib_ref]. However, the impact of molecular screening has not yet translated into clinical care.
In the presence of PC, whenever the patient is deemed resectable and presents a peritoneal cancer index not greater than 6, we advise for standard neoadjuvant chemotherapy, which may be supplemented by 2 concomitant PIPAC to optimize resectability and cure rate. Indeed, PIPAC performed in the context of unresectable GC achieved a pathologic response in more than 60% and allowed conversion to resectability in up to 14% of the patients [bib_ref] Pressurized intraperitoneal aerosol chemotherapy (PIPAC) as a neoadjuvant therapy before cytoreductive surgery..., Girshally [/bib_ref] [bib_ref] Unresectable peritoneal metastasis treated by pressurized intraperitoneal aerosol chemotherapy (PIPAC) leading to..., Alyami [/bib_ref] [bib_ref] Gastric Cancer with Peritoneal Metastasis-A Comprehensive Review of Current Intraperitoneal Treatment Modalities, Prabhu [/bib_ref] [bib_ref] Systemic chemotherapy and pressurized intraperitoneal aerosol chemotherapy (PIPAC): A bidirectional approach for..., Giorgio [/bib_ref]. The addition of PIPAC to systemic neoadjuvant chemotherapy further allows for a dynamic laparoscopic response evaluation, including iterative biopsies and tumor regression grading to inform oncologic treatment and resectability of the primary cancer and PC. CRS and HIPEC, including D2 lymphadenectomy and peritonectomy then follow, completed by adjuvant chemotherapy as mentioned in European guidelines [bib_ref] Gastric cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up, Smyth [/bib_ref] [bib_ref] Recent eUpdates to the ESMO Clinical Practice Guidelines on hepatocellular carcinoma, cancer..., Pentheroudakis [/bib_ref]. Prospective cohort series and randomized trials in Asian patients have shown a survival advantage for CRS HIPEC in gastric cancer patients presenting with PC [bib_ref] Successful intraperitoneal hyperthermic chemoperfusion for the prevention of postoperative peritoneal recurrence in..., Fujimoto [/bib_ref] [bib_ref] Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy improves survival of patients with peritoneal..., Yang [/bib_ref]. An updated large multicentric French cohort study included 277 patients and reported a consistent benefit of CRS HIPEC over CRS alone in multivariable analysis, irrespective of histology. Median OS was of 16.7 vs. 11.3 months (poorly cohesive carcinoma), respectively, 34.5 vs. 14.3 months (non-poorly cohesive carcinoma). Peritoneal cancer index below 7 (poorly cohesive carcinoma), respectively, 13 (non-poorly cohesive carcinoma) were predictive of OS [bib_ref] Peritoneal carcinomatosis from gastric cancer: A multi-institutional study of 159 patients treated..., Glehen [/bib_ref] [bib_ref] Prognosis of poorly cohesive gastric cancer after complete cytoreductive surgery with or..., Bonnot [/bib_ref]. Similar results were reported from multicentric Italian and German cohort studies [bib_ref] Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Gastric Cancer with Synchronous Peritoneal..., Marano [/bib_ref] [bib_ref] Peritoneal metastasis in gastric cancer: Results from the German database, Rau [/bib_ref]. The results of the German GASTRIPEC RCT are expected to be published shortly following presentation at ESMO 2021. The trial was powered to detect a benefit in overall survival in 180 patients. It was stopped after 105 patients or less than 60% of its planned accrual due to slow recruitment and 55 patients who stopped treatment before CRS (disease progression or death). Similar morbidity and overall survival were reported, together with a clinically and statistically significant benefit in progression-free (3.5 months) and distant metastasis-free survival [bib_ref] 1376O The effect of hyperthermic intraperitoneal chemotherapy (HIPEC) upon cytoreductive surgery (CRS)..., Rau [/bib_ref].
Conversely, when a patient is deemed unresectable or progresses during neoadjuvant chemotherapy, palliative second line treatment is offered, which can also be supplemented with PIPAC for optimal response and quality of life with conversion to resectability reported in few cases [bib_ref] Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) with Low-Dose Cisplatin and Doxorubicin in Gastric..., Nadiradze [/bib_ref] [bib_ref] Pressurized intraperitoneal aerosol chemotherapy (PIPAC) for unresectable peritoneal metastasis from gastric cancer, Alyami [/bib_ref]. PIPAC is also a valuable option for control of ascites and other symptoms in patients refractory to systemic treatment [bib_ref] Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) with Low-Dose Cisplatin and Doxorubicin in Gastric..., Nadiradze [/bib_ref] [bib_ref] Quality of life of patients with end-stage peritoneal metastasis treated with Pressurized..., Odendahl [/bib_ref] [bib_ref] Safety, and Efficacy of Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) for Peritoneal Metastasis:..., Kurtz [/bib_ref] [bib_ref] Multicentric initial experience with the use of the pressurized intraperitoneal aerosol chemotherapy..., Alyami [/bib_ref] [bib_ref] Pressurized intraperitoneal aerosol chemotherapy (PIPAC) for unresectable peritoneal metastasis from gastric cancer, Alyami [/bib_ref]. Of note, the role of immune checkpoint inhibitors as a new standard of care for gastric cancer [bib_ref] First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction,..., Janjigian [/bib_ref] in the metastatic setting has yet to be defined in the context of cytoreductive surgery.
The treatment algorithm proposed by the SPCG is illustrated in [fig_ref] Figure 3: Treatment algorithm for gastric cancer [/fig_ref]. It is important to note that supplementing perioperative chemotherapy and surgery with CRS HIPEC allows for a 5-year overall survival of up to 27% in metastatic patients who would most likely have died earlier otherwise [bib_ref] Peritoneal carcinomatosis from gastric cancer: A multi-institutional study of 159 patients treated..., Glehen [/bib_ref] [bib_ref] Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Gastric Cancer with Synchronous Peritoneal..., Marano [/bib_ref] [bib_ref] Prognostic impact of cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) in..., Granieri [/bib_ref] [bib_ref] Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy improves survival of patients with peritoneal..., Yang [/bib_ref] [bib_ref] Patients with Peritoneal Carcinomatosis from Gastric Cancer Treated with Cytoreductive Surgery and..., Chia [/bib_ref] [bib_ref] Survival advantage of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) for advanced..., Rosa [/bib_ref] [bib_ref] A Phase II Trial of Cytoreduction, Gastrectomy, and Hyperthermic Intraperitoneal Perfusion with..., Badgwell [/bib_ref] [bib_ref] Cytoreductive Surgery with or without Hyperthermic Intraperitoneal Chemotherapy for Gastric Cancer With..., Bonnot [/bib_ref]. In addition, neoadjuvant PIPAC has been successfully assessed in many specialized centers [bib_ref] Pressurized intraperitoneal aerosol chemotherapy (PIPAC) as a neoadjuvant therapy before cytoreductive surgery..., Girshally [/bib_ref] [bib_ref] Safety and feasibility of pressurized intraperitoneal aerosol chemotherapy (PIPAC) associated with systemic..., Robella [/bib_ref] [bib_ref] Pressurized Intraperitoneal Aerosol Chemotherapy-Related Clinical Trials in the Treatment of Peritoneal Metastases, Ukegjini [/bib_ref] and it is currently investigated in a dedicated trial [bib_ref] PIPAC EstoK 01: Pressurized IntraPeritoneal Aerosol Chemotherapy with cisplatin and doxorubicin (PIPAC..., Eveno [/bib_ref].

## Colorectal cancer
Colorectal cancer is the third most common cancer with an incidence of 30.4 per 100,000 people in Europe (22.3/100,000 in Switzerland) and a cure rate of 59.5%% [bib_ref] Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for..., Sung [/bib_ref]. At the time of diagnosis, up to 10% of patients with colorectal cancer have synchronous PC and more than half of the patients with recurrent disease will present with metachronous PC [bib_ref] Colorectal cancer: Prevention and management of metastatic disease, Sugarbaker [/bib_ref] [bib_ref] Peritoneal carcinomatosis of colorectal cancer: Novel clinical and molecular outcomes, Massalou [/bib_ref] [bib_ref] Epidemiology, Management, and Survival of Peritoneal Carcinomatosis from Colorectal Cancer: A Population-Based..., Quere [/bib_ref]. Of the 3 histological subtypes of colorectal cancer (adenocarcinoma (85-90%), mucinous adenocarcinoma (10-15%), signet ring cell carcinoma (1%)), PC occurs predominantly in mucinous and signet ring histologies [bib_ref] Metastatic pattern in colorectal cancer is strongly influenced by histological subtype, Hugen [/bib_ref] , while adenocarcinoma preferably metastasize to the liver. When PC is left to conventional palliative chemotherapy, median overall survival does not exceed 16 months [bib_ref] Prognosis of patients with peritoneal metastatic colorectal cancer given systemic therapy: An..., Franko [/bib_ref]. Recent developments in the management of advanced colorectal cancer include total neoadjuvant chemotherapy, targeted therapies, and refinements in the indication and practice of CRS HIPEC. Yet, the fate of patients with PC from colorectal cancer is grim, as no systemic chemotherapy including biologic agents can offer any prospect of a cure [bib_ref] Treatment of colorectal peritoneal carcinomatosis with systemic chemotherapy: A pooled analysis of..., Franko [/bib_ref] [bib_ref] Prognosis of patients with peritoneal metastatic colorectal cancer given systemic therapy: An..., Franko [/bib_ref] [bib_ref] Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer, Tol [/bib_ref] , as opposed to complete cytoreductive surgery-possibly supplemented with intraperitoneal chemotherapy. A large body of literature, including multicentric prospective clinical registries, suggests a survival benefit when complete cytoreductive surgery is achieved and HIPEC is performed [bib_ref] Toward curative treatment of peritoneal carcinomatosis from nonovarian origin by cytoreductive surgery..., Glehen [/bib_ref] [bib_ref] Intraperitoneal chemotherapy for peritoneal surface malignancy: Experience with 1,000 patients, Levine [/bib_ref] [bib_ref] Complete cytoreductive surgery plus intraperitoneal chemohyperthermia with oxaliplatin for peritoneal carcinomatosis of..., Elias [/bib_ref] [bib_ref] Peritoneal colorectal carcinomatosis treated with surgery and perioperative intraperitoneal chemotherapy: Retrospective analysis..., Elias [/bib_ref] [bib_ref] Peritoneal metastases of colorectal origin treated by cytoreduction and HIPEC: An overview, Arjona-Sanchez [/bib_ref] [bib_ref] Cytoreductive surgery in combination with hyperthermic intraperitoneal chemotherapy improves survival in patients..., Mirnezami [/bib_ref] , which has led to inclusion of CRS HIPEC in several national guidelines. As conventional imaging performs poorly for the early detection of PC, diagnostic laparoscopy may be offered in colorectal cancer patients at high recurrence risk within 6-12 months of the primary bowel resection or when the tumor marker CEA rises during follow-up with no obvious metastatic disease in radiological staging.
Two randomized controlled trials have assessed CRS HIPEC in PC of colorectal origin. The first and smaller Dutch trial (n = 105) compared standard oncologic resection and adjuvant systemic chemotherapy to CRS HIPEC and adjuvant systemic chemotherapy.
It showed a 5-month progression-free survival benefit for CRS HIPEC performed with Mitomycin C and a significant improvement in disease-free survival from 12.6 months to 22.2 months in the CRS HIPEC group. Median survival was 48 months with a 5-year survival rate of 45% in patients who achieved a complete cytoreduction supplemented by HIPEC [bib_ref] 8-year follow-up of randomized trial: Cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic..., Verwaal [/bib_ref]. The second, larger (n = 265) and recent French trial (PRODIGE-7) randomized patients peroperitavely who had just undergone complete cytoreduction and had neoadjuvant systemic chemotherapy to receive HIPEC or no further treatment. It found no survival benefit for CRS HIPEC performed with high-dose oxaliplatin ip and 5-FU/leucovorin iv, except for patients with a peritoneal cancer index of 11-15 in a post-hoc analysis [bib_ref] Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy versus cytoreductive surgery alone for colorectal..., Quenet [/bib_ref]. The latter point is consistent with a prior finding suggesting that patients with a peritoneal cancer index of up to 16 and/or limited small bowel involvement benefit most from CRS HIPEC [bib_ref] Modified selection criteria for complete cytoreductive surgery plus HIPEC based on peritoneal..., Elias [/bib_ref] [bib_ref] Direct surgery with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for patients with..., Ljunggren [/bib_ref] [bib_ref] Extent of colorectal peritoneal carcinomatosis: Attempt to define a threshold above which..., Goere [/bib_ref] [bib_ref] Is there a possibility of a cure in patients with colorectal peritoneal..., Goere [/bib_ref]. Much has been written on the strength and weakness of the PRODIGE-7 trial, which was first presented in June 2018 at the American Society of Clinical Oncology meeting and included contemporary systemic chemotherapy and targeted therapy. Complete cytoreduction was confirmed as the cornerstone of a curative approach in PC with an overall survival of 41.7 months for CRS HIPEC and of 41.2 months for CRS alone, and a recurrence-free survival of 13.1 vs. 11.1 months, respectively. While survival and 30-day morbidity did not differ significantly, 60-day morbidity was significantly higher in the CRS HIPEC arm compared to CRS alone (24.1% vs. 13.6%). Potential causes for the late morbidity were heavily preoperative systemic treatment for 6 months and an aggressive course of ip/iv intraoperative chemotherapy with maximal dosage of ip oxaliplatin (460 mg/m 2 ) and hyperthermia (43 - C) that may ultimately have made CRS HIPEC patients more vulnerable to late medical complications [bib_ref] Limitations of the PRODIGE 7 trial-Authors' reply, Quenet [/bib_ref]. Indeed, routine preoperative administration of a 6-month course of oxaliplatin-based systemic chemotherapy is not common practice across countries, nor is the aggressive HIPEC regimen of PRODIGE-7. A Dutch randomized trial (CAIRO6) currently near completion may shed light soon on the benefit of perioperative systemic chemotherapy in patients who undergo CRS HIPEC.
Signet ring cell histology is an independent unfavorable prognostic factor, regardless of the treatment approach. Data from the nationwide Dutch cancer registry have shown that the relative survival gain of CRS HIPEC is comparable for adenocarcinoma, mucinous adenocarcinoma, and signet ring histology, while systemic therapy improved survival in all histological subtypes [bib_ref] Histological subtype and systemic metastases strongly influence treatment and survival in patients..., Simkens [/bib_ref]. Since patients with signet ring histology are often younger, CRS HIPEC may thus be offered in highly selected patients with an absolute survival gain of up to 10.9 months when compared to systemic therapy, respectively 18 months when compared to supportive care only [bib_ref] Histological subtype and systemic metastases strongly influence treatment and survival in patients..., Simkens [/bib_ref].
From a molecular standpoint, BRAF mutation is overrepresented and found in up to 26% of patients with colorectal PC [bib_ref] BRAF mutation predicts for poor outcomes after metastasectomy in patients with metastatic..., Yaeger [/bib_ref] , while KRAS and BRAF mutations negatively impact survival independently of the use of current targeted therapy [bib_ref] Cytoreductive surgery in combination with hyperthermic intraperitoneal chemotherapy improves survival in patients..., Mirnezami [/bib_ref]. However, a national prospective cohort of Norvegian patients treated with CRS HIPEC between 2005 and 2015 did not see any differences in survival according to KRAS of BRAF mutations. Interestingly, patients who presented with a BRAF mutation and microsatellite instability had significantly better survival [bib_ref] Impact of KRAS, BRAF and microsatellite instability status after cytoreductive surgery and..., Larsen [/bib_ref]. In a further analysis of 505 patients who underwent CRS HIPEC at 4 European centres, KRAS mutations and to a lesser extent positive nodal stage were independent predictors of peritoneal recurrence following CRS HIPEC [bib_ref] Site of Recurrence and Survival after Surgery for Colorectal Peritoneal Metastasis, Breuer [/bib_ref].
The Biological score of peritoneal metastasis (BIOSCOPE) was recently proposed to help patient assessment and selection. It takes into account peritoneal cancer index, nodal status, differentiation grading, and KRAS/BRAF mutations and allows categorization of patients into 4 survival groups with a prediction performance of 0.70 (development/validation area under the curve). It underlined that RAS/RAF mutations impair survival after CRS HIPEC, independently of the use of current targeted therapy [bib_ref] Mutations of RAS/RAF Proto-oncogenes Impair Survival After Cytoreductive Surgery and HIPEC for..., Schneider [/bib_ref]. Tumor biology is a key element to factor in when choosing intensity and sequence of therapies.
As of Summer 2021, German, French (https://www.snfge.org/content/4-cancercolorectal-metastatique (accessed on 18 July 2022)), British, American, and Canadian [bib_ref] Canadian guidelines on the management of colorectal peritoneal metastases, Brind&apos;amour [/bib_ref] practice guidelines stated that CRS HIPEC can be considered in experi-enced centers for selected patients. Selection amounts to fitness for major surgery and completeness of cytoreduction, both of which are mandatory. In addition, the extension of PC of colorectal origin matters beyond mere resectability with a threshold peritoneal cancer index of 20 and below most commonly reported. Indeed, many expert centers today set the bar for CRS HIPEC at a peritoneal cancer index of 16 [bib_ref] Modified selection criteria for complete cytoreductive surgery plus HIPEC based on peritoneal..., Elias [/bib_ref] [bib_ref] Direct surgery with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for patients with..., Ljunggren [/bib_ref] [bib_ref] Extent of colorectal peritoneal carcinomatosis: Attempt to define a threshold above which..., Goere [/bib_ref] [bib_ref] Is there a possibility of a cure in patients with colorectal peritoneal..., Goere [/bib_ref] [bib_ref] The Characteristics of 206 Long-Term Survivors with Peritoneal Metastases from Colorectal Cancer..., Kamada [/bib_ref] [bib_ref] Patient Selection for Hyperthermic Intraperitoneal Chemotherapy in Patients with Colorectal Cancer: Consensus..., Steffen [/bib_ref] to maximize cure, while avoiding large resection of small bowel to prevent a short bowel syndrome. Peritoneal recurrence after CRS HIPEC is common with a median time to recurrence of 33 months [bib_ref] Results of two bi-institutional prospective studies using intraperitoneal oxaliplatin with or without..., Quenet [/bib_ref] [bib_ref] Recurrences after peritoneal carcinomatosis of colorectal origin treated by cytoreduction and hyperthermic..., Verwaal [/bib_ref] [bib_ref] Incidence and treatment of recurrent disease after cytoreductive surgery and intraperitoneal chemotherapy..., Van Oudheusden [/bib_ref]. Repeat CRS HIPEC can be offered in highly selected patients with similar results as for a primary procedure, once extraperitoneal metastases have been excluded [bib_ref] Repeated cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with..., Vassos [/bib_ref] [bib_ref] Iterative cytoreductive surgery with or without hyperthermic intraperitoneal chemotherapy for colorectal peritoneal..., Alzahrani [/bib_ref].
The treatment algorithm proposed by the SPCG is illustrated in [fig_ref] Figure 4: Treatment algorithm for colorectal cancer [/fig_ref]. Upfront diagnostic laparoscopy is recommended to assess the diagnosis of PC and resectability, thus overcoming the limitations and low reliability of PC imaging [bib_ref] Value of laparoscopy before cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal..., Iversen [/bib_ref]. It may include a first PIPAC to initiate treatment of PC [bib_ref] Pressurized intraperitoneal aerosol chemotherapy (PIPAC) as a neoadjuvant therapy before cytoreductive surgery..., Girshally [/bib_ref]. In the presence of resectable PC, systemic chemotherapy is performed, followed by repeat staging and CRS HIPEC, pending objective response being confirmed. Additional systemic chemotherapy follows CRS HIPEC, whenever a full regimen has not been given prior to CRS HIPEC. When, however, diagnostic laparoscopy reveals a borderline resectable situation, in particular, a peritoneal cancer index greater than 15 in a patient otherwise fit for surgery [bib_ref] Diagnostic Nodes of Patient Selection for Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy..., Steffen [/bib_ref] , a maximal approach includes neoadjuvant systemic therapy combined with 2 further PIPAC. Indeed, a published prospective series and clinical experience of Swiss centers speak for the safety and effectiveness of joint systemic and PIPAC chemotherapy as a means to optimize a response and select the patient with a chance for a cure [bib_ref] Pressurized intraperitoneal aerosol chemotherapy (PIPAC) as a neoadjuvant therapy before cytoreductive surgery..., Girshally [/bib_ref] [bib_ref] Unresectable peritoneal metastasis treated by pressurized intraperitoneal aerosol chemotherapy (PIPAC) leading to..., Alyami [/bib_ref]. Repeat staging follows, and final selection either for a curative approach including CRS HIPEC as above or for a palliative approach is done. The SPCG has drafted a Swiss multicentric randomized controlled trial to quantify the effect of PIPAC when added to standard second line systemic therapy in colorectal PC and currently is seeking funding for it.
Lastly, when a patient is deemed unresectable, palliative systemic chemotherapy may be enhanced by iterative PIPAC, including ascites control and relief. The development of extraperitoneal metastatic disease or tumor progression during neoadjuvant systemic chemotherapy is further grounds to opt for a palliative approach.

# Discussion
Peritoneal carcinomatosis affects a significant number of patients with cancers of gastrointestinal origin. Treatment options are evolving rapidly, and the prospect of a cure is realistic for selected patients who are willing and able to undergo a demanding multimodal treatment in specialized cancer centers. CRS HIPEC is a key element in this context and a complete cytoreduction is the cornerstone of every curative approach. The addition of intraperitoneal chemotherapy to complete cytoreduction is a logical step, as peritoneal relapses are frequent and driven by non-visible/non-resectable PC against which chemotherapy is best active when administered in situ. Repeat ip chemotherapy has been tested and deemed effective, yet it encompassed prolonged intraabdominal tubing (in-and effluent of chemotherapy) or repeat laparotomies, both of which are prone to morbidity. Iterative PIPAC combines the ease of a minimally invasive approach, including repeat biopsy to objectively monitor tumor response, and the advantage of repeat ip administration of chemotherapy. More than 215 publications document the effectiveness of PIPAC in the treatment of PC and multiple clinical trials include PIPAC in the multimodal approach to PC [bib_ref] First-line palliative systemic therapy alternated with electrostatic pressurised intraperitoneal aerosol chemotherapy (oxaliplatin)..., Lurvink [/bib_ref]. The combination of systemic chemotherapy and PIPAC is a further evolution in the treatment of PC [bib_ref] Pressurised intraperitoneal aerosol chemotherapy: Rationale, evidence, and potential indications, Alyami [/bib_ref] and an integral part of the present SPCG comprehensive treatment algorithms that builds up on multiple current oncologic guidelines. The present SPCG treatment algorithms are endorsed by 7 surgical oncology and 7 medical oncology departments; they reflect the forefront thinking and practice of specialized Swiss centers. They complement existing recommendations by including PIPAC in their standard of care, which is a reimbursed procedure in Switzerland since 2016 [bib_ref] Diagnostic Nodes of Patient Selection for Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy..., Steffen [/bib_ref]. They are intended as an outline for interdisciplinary discussion at tumorboards.
Providing contemporary treatment of advanced malignancies requires specialized knowledge of all involved caregivers, including medical and surgical oncologists, nutritional support, and intensive care physicians. Best practice for perioperative management of patients with CRS HIPEC has been established [bib_ref] Best practice for perioperative management of patients with cytoreductive surgery and HIPEC, Raspe [/bib_ref]. Patient care is at its best when clinicians monitor their own outcomes prospectively and participate in translational and clinical research. Hence, the SPCG has initiated in 2021 a dedicated, nationwide prospective clinical registry for all patients considered for CRS HIPEC and/or PIPAC. The SPCG registry allows clinical research and facilitates participation to clinical trials. All Swiss institutions providing CRS HIPEC and PIPAC services are either board members of the SPCG or have confirmed their participation to the SPCG registry, so that a nationwide coverage is warranted. Beyond morbidity, mortality, length of hospital stay, recurrence-free and overall survival, the SPCG registry monitors the rate of complete cytoreduction, the multimodal treatment protocol followed, and the case load of each institution. The Dutch and the British have reported their nationwide experience in standardization and specialization of care in dedicated centers for the treatment of peritoneal surface malignancies, while a minimal case load of 10 CRS HIPEC per surgeon/institution and year has been proposed as a threshold to maintain proficiency [bib_ref] Association Francaise de Chirurgie. Pseudomyxoma peritonei: A French multicentric study of 301..., Elias [/bib_ref] [bib_ref] Cytoreduction and hyperthermic intraperitoneal chemotherapy: The learning curve reassessed, Kuijpers [/bib_ref] [bib_ref] Implementation of a standardized HIPEC protocol improves outcome for peritoneal malignancy, Kuijpers [/bib_ref]. In our experience, meeting such a threshold requires a catchment area of half a million, whereas a larger referral zone of one million and an institutional volume of 20 CRS HIPEC are advisable. Looking at three metrics from the nationwide Dutch experience (960 CRS HIPEC patients) allows for performance benchmarking: the reported rate of complete cytoreduction was 80% for a median hospital stay of 16 days and a mortality rate of 3%. In terms of survival, median overall survival was 33 months (95% CI 28-38 months) for colorectal cancer and 130 months (95% CI 98-162 months) for pseudomyxoma patients [bib_ref] Implementation of a standardized HIPEC protocol improves outcome for peritoneal malignancy, Kuijpers [/bib_ref] [bib_ref] Cytoreduction and HIPEC in the Netherlands: Nationwide long-term outcome following the Dutch..., Kuijpers [/bib_ref]. Current nationwide Norwegian data report a median survival of 49 months from the time of CRS HIPEC and a 5-year overall survival of 40.1% for colorectal cancer [bib_ref] Impact of KRAS, BRAF and microsatellite instability status after cytoreductive surgery and..., Larsen [/bib_ref] , in concordance with results from British and French tertiary referral centers [bib_ref] Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy versus cytoreductive surgery alone for colorectal..., Quenet [/bib_ref] [bib_ref] Cytoreductive surgery in combination with hyperthermic intraperitoneal chemotherapy improves survival in patients..., Mirnezami [/bib_ref]. These outcomes are realistic figures that have been met and exceeded by specialized Swiss centers [bib_ref] Site of Recurrence and Survival after Surgery for Colorectal Peritoneal Metastasis, Breuer [/bib_ref] [bib_ref] Mutations of RAS/RAF Proto-oncogenes Impair Survival After Cytoreductive Surgery and HIPEC for..., Schneider [/bib_ref].

# Conclusions
The cornerstone of a curative approach in the treatment of PC is completeness of cytoreduction, which requires a high surgical expertise and routine in the care of multivisceral resections. The addition of ip chemotherapy supports completeness of cytoreduction by eliminating unseen tumor clusters prone to relapse. PIPAC is a much needed and validated addition to the treatment of PC: its inclusion to the present recommendations supports a quest for excellence by repeat delivering chemotherapy in situ and providing an objective response grading to guide multimodal treatment. The inclusion of all patients treated with CRS HIPEC and PIPAC in Switzerland in the prospective SPCG registry allows for performance benchmarking and supports clinical research. It is hoped that the present comprehensive treatment algorithms will provide guidance for interdisciplinary discussion at tumorboard and help for optimal and tailored care for patients with PC of gastrointestinal origin. Acknowledgments: We express our gratitude to patients and clinicians, staff and relatives who are instrumental in the success of a multimodal approach to PC. We also want to thank the faculty and audience of the 2021 SPCG symposium for their input and comments on the present comprehensive algorithms. Lastly, we are grateful to our family and friends for their invaluable support in a professional life devoted to the care of patients with complex needs.

## Conflicts of interest:
The authors declare that there are no conflicts of interest regarding the content of this paper.
[fig] Figure 1: Treatment algorithm for pseudomyxoma peritonei [/fig]
[fig] Figure 2: Treatment algorithm for peritoneal mesothelioma [/fig]
[fig] Figure 3: Treatment algorithm for gastric cancer [/fig]
[fig] Figure 4: Treatment algorithm for colorectal cancer [/fig]
[fig] Author: Contributions: Conceptualization, M.A., T.K., F.R. and M.H.; Formal analysis, M.A., M.W., M.D.B., S.D., R.D., A.D., B.G., R.F., D.K., T.K., K.L., P.M., R.P., F.R., T.S., C.S.W. and M.H.; Writingoriginal draft, M.A., M.W. and M.H.; Writing-review & editing, M.A., M.W., M.D.B., S.D., R.D., A.D., B.G., R.F., D.K., T.K., K.L., P.M., R.P., F.R., T.S., C.S.W. and M.H. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. [/fig]