GECOP-MMC: phase IV randomized clinical trial to evaluate the efficacy of hyperthermic intraperitoneal chemotherapy (HIPEC) with mytomicin-C after complete surgical cytoreduction in patients with colon cancer peritoneal metastases.

BACKGROUND: The French PRODIGE 7 trial, published on January 2021, has raised doubts about the specific survival benefit provided by HIPEC with oxaliplatin 460 mg/m2 (30 minutes) for the treatment of peritoneal metastases from colorectal cancer. However, several methodological flaws have been identified in PRODIGE 7, specially the HIPEC protocol or the choice of overall survival as the main endpoint, so its results have not been assumed as definitive, emphasizing the need for further research on HIPEC. It seems that the HIPEC protocol with high-dose mytomicin-C (35 mg/m2) is the preferred regime to evaluate in future clinical studies. METHODS: GECOP-MMC is a prospective, open-label, randomized, multicenter phase IV clinical trial that aims to evaluate the effectiveness of HIPEC with high-dose mytomicin-C in preventing the development of peritoneal recurrence in patients with limited peritoneal metastasis from colon cancer (not rectal), after complete surgical cytoreduction. This study will be performed in 31 Spanish HIPEC centres, starting in March 2022. Additional international recruiting centres are under consideration. Two hundred sixteen patients with PCI ≤ 20, in which complete cytoreduction (CCS 0) has been obtained, will be randomized intraoperatively to arm 1 (with HIPEC) or arm 2 (without HIPEC). We will stratified randomization by surgical PCI (1-10; 11-15; 16-20). Patients in both arms will be treated with personalized systemic chemotherapy. Primary endpoint is peritoneal recurrence-free survival at 3 years. An ancillary study will evaluate the correlation between surgical and pathological PCI, comparing their respective prognostic values. DISCUSSION: HIPEC with high-dose mytomicin-C, in patients with limited (PCI ≤ 20) and completely resected (CCS 0) peritoneal metastases, is assumed to reduce the expected risk of peritoneal recurrence from 50 to 30% at 3 years. TRIAL REGISTRATION: EudraCT number: 2019-004679-37; Clinicaltrials.gov: NCT05250648 (registration date 02/22/2022, ).

The American Society of Peritoneal Surface Malignancies evaluation of HIPEC with Mitomycin C versus Oxaliplatin in 539 patients with colon cancer undergoing a complete cytoreductive surgery.

BACKGROUND: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) are gaining acceptance as treatment for selected patients with colorectal cancer with peritoneal carcinomatosis (CRCPC). Tremendous variations exist in the HIPEC delivery. METHODS: The American Society of Peritoneal Surface Malignancies (ASPSM) examined the overall survival in patients with CRCPC who underwent a complete cytoreduction and HIPEC with Oxaliplatin vs. Mitomycin C (MMC), stratifying them by the Peritoneal Surface Disease Severity Score (PSDSS). RESULTS: Median overall survival (OS) of 539 patients with complete cytoreduction was 32.6 months, 32.7 months for the MMC group and 31.4 months for the Oxaliplatin group (P = 0.925). However, when stratified by PSDSS, median OS rates in PSDSS I/II patients were 54.3 months in those receiving MMC vs. 28.2 months in those receiving oxaliplatin (P = 0.012), whereas in PSDSS III/IV patients, median OS rates were 19.4 months in those receiving MMC vs. 30.4 months in those receiving Oxaliplatin (P = 0.427). CONCLUSION: These data suggest that MMC might be a better agent for HIPEC delivery than Oxaliplatin in patients with CRCPC, favorable histologies and low burden of disease (PSDSS I/II) undergoing complete cytoreduction. Prospective studies are warranted, which stratify patients by their PSDSS and randomize them to HIPEC with MMC vs. Oxaliplatin.

The American Society of Peritoneal Surface Malignancies (ASPSM) Multiinstitution Evaluation of the Peritoneal Surface Disease Severity Score (PSDSS) in 1,013 Patients with Colorectal Cancer with Peritoneal Carcinomatosis.

BACKGROUND: Extensive clinical experience suggests that hyperthermic intraperitoneal chemotherapy (HIPEC) may play an important role in the management of colorectal cancer patients with peritoneal carcinomatosis (CRCPC). However, there remains no established nonsurgical process to rationally select patients for this management, either for inclusion/stratification in clinical trials or as a component of standard of care. The Peritoneal Surface Disease Severity Score (PSDSS) was introduced as a basis to improve patient selection. METHODS: The American Society of Peritoneal Surface Malignancies conducted a retrospective review of 1,013 CRCPC patients. The PSDSS was evaluated on 3 specific criteria obtained before surgery (symptoms, extent of peritoneal dissemination, and primary tumor histology). Overall survival was analyzed according to four tiers of disease severity, and a comparison was made between patients who underwent cytoreductive surgery + HIPEC and those who did not. RESULTS: The PSDSS was calculated on 884 patients (87 %). The median survival of 275 patients not undergoing CRS/HIPEC based on their PSDSS-I (n = 8), II (n = 80), III (n = 55), and IV (n = 132)-was 45, 19, 8, and 6 months, respectively. The median survival of 609 patients who underwent CRS/HIPEC based on their PSDSS-I (n = 75), II (n = 317), III (n = 82), and IV (n = 135)-was 86, 43, 29, and 28 months, respectively. CONCLUSIONS: These data support that the PSDSS, undertaken before surgery, is capable of defining CRCPC populations who have a statistically defined high or considerably lower likelihood of long-term survival after CRS/HIPEC. The PSDSS can be quite useful in the decision to enter CRCPC patients into, and their stratification within, clinical trials.

Hyperthermic intraperitoneal chemotherapy: methodology and safety considerations.

Several methods of delivering hyperthermic intraperitoneal chemotherapy (HIPEC) during the course of cytoreductive surgery have been described, but no significant differences in treatment results have been found among them. HIPEC is a safe treatment for the patient and for healthcare workers involved in the procedure provided standard protective and environmental measures are used. This article describes the different techniques in use and the technology available for the administration of HIPEC. Also reviewed are the safety features that must be taken into consideration when performing this procedure. Recommended guidelines to prevent associated occupational hazards are provided.

Early- and long-term outcome data of patients with pseudomyxoma peritonei from appendiceal origin treated by a strategy of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

PURPOSE: Pseudomyxoma peritonei (PMP) originating from an appendiceal mucinous neoplasm remains a biologically heterogeneous disease. The purpose of our study was to evaluate outcome and long-term survival after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) consolidated through an international registry study. PATIENTS AND METHODS: A retrospective multi-institutional registry was established through collaborative efforts of participating units affiliated with the Peritoneal Surface Oncology Group International. RESULTS: Two thousand two hundred ninety-eight patients from 16 specialized units underwent CRS for PMP. Treatment-related mortality was 2% and major operative complications occurred in 24% of patients. The median survival rate was 196 months (16.3 years) and the median progression-free survival rate was 98 months (8.2 years), with 10- and 15-year survival rates of 63% and 59%, respectively. Multivariate analysis identified prior chemotherapy treatment (P < .001), peritoneal mucinous carcinomatosis (PMCA) histopathologic subtype (P < .001), major postoperative complications (P = .008), high peritoneal cancer index (P = .013), debulking surgery (completeness of cytoreduction [CCR], 2 or 3; P < .001), and not using HIPEC (P = .030) as independent predictors for a poorer progression-free survival. Older age (P = .006), major postoperative complications (P < .001), debulking surgery (CCR 2 or 3; P < .001), prior chemotherapy treatment (P = .001), and PMCA histopathologic subtype (P < .001) were independent predictors of a poorer overall survival. CONCLUSION: The combined modality strategy for PMP may be performed safely with acceptable morbidity and mortality in a specialized unit setting with 63% of patients surviving beyond 10 years. Minimizing nondefinitive operative and systemic chemotherapy treatments before definitive cytoreduction may facilitate the feasibility and improve the outcome of this therapy to achieve long-term survival. Optimal cytoreduction achieves the best outcomes.

Peritoneal carcinomatosis: cytoreductive surgery and HIPEC--overview and basics.

Tumor involvement of the peritoneum-peritoneal carcinomatosis-is a heterogeneous form of cancer that had been generally regarded as a sign of systemic tumor disease and as a terminal condition. The multimodal treatment approach for patients with peritoneal carcinomatosis, which had been conceived and developed, consists of what is known as cytoreductive surgery, followed by hyperthermic intraperitoneal chemotherapy (HIPEC). Depending on the tumor mass as assessed intraoperatively and the histopathological differentiation, patients who undergo cytoreductive surgery and HIPEC have a significant survival benefit. Mean increases in the survival period ranging from six months to up to four years have now been reported. In view of the substantial logistic effort and the extent of the surgery involved, this treatment approach represents a major challenge both for patients and for surgical oncologists, as well as for the members of the overall interdisciplinary structure required, which includes oncology, anesthesiology and intensive care, psycho-oncology, and patient management. The surgical procedures alone may take 8-14 hr. The present paper provides an overview of the basis for the approach and the use of specialized classifications and quantitative prognostic indicators.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal malignant disease.

Peritoneal Malignant Disease (PMD) is the presence of tumoral tissue on the peritoneal surface from primary tumors or tumors from other locations (e.g. digestive or gynecologic). It is a regional disease with poor prognosis when treated with repeated "debulking" and traditional systemic chemotherapy. Cytoreduction plus hyperthermic intraperitoneal chemotherapy (HIPEC) is a combined multimodal regional procedure aimed at reducing the macroscopic tumoral mass as much as possible and treating with chemotherapy the microscopic disease that is out of the scope of the surgeon. This combined treatment may change the natural history of PMD, it is translated into a higher overall survival and cancer-free survival and it offers the option of cure in selected cases. The high-complexity procedure is also associated with complications and mortality, but in similar rates as other major oncologic procedures.

Indications and patient selection for cytoreductive surgery and perioperative intraperitoneal chemotherapy.

Cytoreductive surgery combined with perioperative intraperitoneal chemotherapy has provided unprecedented results in the management of peritoneal-based neoplasms. Prognostic factors leading to a survival advantage when this treatment modality is employed have been identified. A steep learning curve has been described as well. Therefore, knowledgeable indication setting and proper selection of patients to whom this combined treatment can be offered is warranted in order to obtain the best results at the lowest possible toxicity.

Incidence, risk factors, and impact of severe neutropenia after hyperthermic intraperitoneal mitomycin C.

BACKGROUND: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are considered the standard of care for patients with peritoneal dissemination of appendiceal cancer and are increasingly being evaluated for use in patients with carcinomatosis from colon cancer. Mitomycin C (MMC) is one of the most frequently used HIPEC agents in the management of peritoneal-based gastrointestinal malignancies. This study analyzes the incidence and risk factors for developing neutropenia following MMC-HIPEC combined with CRS. METHODS: All patients undergoing CRS and MMC-HIPEC for appendiceal cancer between January 1993 and October 2006 were retrospectively reviewed. Logistic regression was used to identify risk factors for the development of neutropenia, defined as an absolute neutrophil count (ANC) <1,000/mm(3). RESULTS: One hundred and twenty MMC-HIPEC were performed in 117 patients with appendiceal cancer. The incidence of neutropenia was 39%. Neutropenia occurred in 57.6% of female and 21.3% of male patients (p < 0.0001). Female gender and MMC dose per body surface area (BSA) were independent risk factors for neutropenia on multivariable logistic regression [odds ratio (OR) of neutropenia in females = 3.58 (95% confidence interval, CI: 1.52, 8.43); OR for 5 unit (mg/m(2)) increase in MMC dose per BSA = 3.37 (95% CI: 1.72, 6.63)]. Neutropenia did not increase the risk of mortality, postoperative infection or length of hospital stay. CONCLUSION: Neutropenia is a frequent complication associated with MMC-HIPEC. Female sex and MMC dose per BSA are independent risk factors for neutropenia. These differences must be considered in the management of patients undergoing MMC-HIPEC to minimize the toxicity of the procedure.

Peritoneal Surface Oncology: A progress report.

The Fourth International Workshop on Peritoneal Surface Malignancy took place in Madrid (Spain) on December 2, 3 and 4, 2004. The meeting brought together 132 health care professionals currently working on or interested in the management of peritoneal surface malignancy, from 19 countries. The topics covered included diagnostic pathology, technology of hyperthermic peritoneal perfusion, quantitative prognostic indicators, accreditation of treatment programs, ovarian cancer, gastric cancer, peritoneal mesothelioma, appendiceal mucinous tumors, colorectal cancer, morbidity and mortality, and were presented by 25 invited speakers. This article summarizes the most significant discussion points and conclusions relative to the aforementioned topics. The following consensus points were reached: (1) cytoreductive surgery combined with perioperative intraperitoneal chemotherapy is unquestionably considered the standard of care for mucinous appendiceal tumors with peritoneal spread at the present time; (2) there is a need for standardization in the nomenclature used in this field and as a first step "HIPEC" was chosen as the recommended acronym to be used to refer to hyperthermic intraperitoneal chemotherapy in the future; (3) close international collaboration is needed to advance in the standardization of prognostic indicators, technology for HIPEC, accreditation of peritoneal surface malignancy treatment programs, anesthesia management and pathology, and ad hoc working groups were assembled for some of these issues. Future directions for clinical research in this field, especially in carcinomatosis of colorectal origin were identified and extensively discussed.