Tumor-Selective Immune-Active Mild Hyperthermia Associated with Chemotherapy in Colon Peritoneal Metastasis by Photoactivation of Fluorouracil-Gold Nanoparticle Complexes.

Peritoneal metastasis (PM) is considered as the terminal stage of metastatic colon cancer, with still poor median survival rate even with the best recent chemotherapy treatment. The current PM treatment combines cytoreductive surgery, which consists of resecting all macroscopic tumors, with hyperthermic intraperitoneal chemotherapy (HIPEC), which uses mild hyperthermia to boost the diffusion and cytotoxic effect of chemotherapeutic drugs. As HIPEC is performed via a closed circulation of a hot liquid containing chemotherapy, it induces uncontrolled heating and drug distribution in the whole peritoneal cavity with important off-site toxicity and a high level of morbidity. Here, we propose a safer precision strategy using near-infrared (NIR) photoactivated gold nanoparticles (AuNPs) coupled to the chemotherapeutic drug 5-fluorouracil (5-FU) to enable a spatial and temporal control of mild chemo-hyperthermia targeted to the tumor nodules within the peritoneal cavity. Both the 16 nm AuNPs and the corresponding complex with 5-FU (AuNP-5-FU) were shown as efficient NIR photothermal agents in the microenvironment of subcutaneous colon tumors as well as PM in syngeneic mice. Noteworthy, NIR photothermia provided additional antitumor effects to 5-FU treatment. A single intraperitoneal administration of AuNP-5-FU resulted in their preferential accumulation in tumor nodules and peritoneal macrophages, allowing light-induced selective hyperthermia, extended tumor necrosis, and activation of a pro-inflammatory immune response while leaving healthy tissues without any damage. From a translational standpoint, the combined and tumor-targeted photothermal and chemotherapy mediated by the AuNP-drug complex has the potential to overcome the current off-target toxicity of HIPEC in clinical practice.

Immune Reprogramming Precision Photodynamic Therapy of Peritoneal Metastasis by Scalable Stem-Cell-Derived Extracellular Vesicles.

The dissemination of tumor metastasis in the peritoneal cavity, also called peritoneal metastasis (PM) or carcinomatosis, represents a late stage of gastrointestinal and gynecological cancer with very poor prognosis, even when cytoreductive surgery is effective, due to residual microscopic disease. Photodynamic therapy (PDT) in the management of peritoneal metastasis has been clinically limited by the low tumor selectivity of photosensitizers (PS) and important adverse effects. Here, we propose extracellular nanovesicles (EVs) derived from mesenchymal stem/stromal cells (MSCs) as the fourth generation of immune active PS vectors that are able to target peritoneal metastasis with superior selectivity, potentiate PDT cytotoxicity at the tumor site without affecting healthy tissues, modulate the tumor microenvironment of immunocompetent colorectal and ovarian carcinomatosis models, and promote an antitumor immune response. A pioneering strategy was developed for high yield, large-scale production of MSC-EVs encapsulating the drug meta(tetrahydroxyphenyl)chlorin (mTHPC) (EVs-mTHPC) that is compatible with requirements of clinical translation and also preserves the topology and integrity of naturally produced EVs. Intraperitoneal injection of EVs-mTHPC showed an impressive enhancement of tumoral selectivity in comparison to the free drug and to the liposomal formulation Foslip (mean ratio of PS in tumors/organs of 40 for EVs-mTHPC versus 1.5 for the free PS and 5.5 for Foslip). PDT mediated by EVs-mTHPC permitted an important tumoral necrosis (55% of necrotic tumoral nodules versus 18% for Foslip (p < 0.0001)) and promoted antitumor immune cell infiltration, mainly proinflammatory M1-like CD80+ and CD8+ T cell effector. Intratumor proliferation was significantly decreased after PDT with EVs-mTHPC. Overall EVs vectorization of mTHPC afforded important tumoral selectivity while overcoming the PDT toxicity of the free drug and prolonged mice survival in the colorectal carcinomatosis model. MSC-EVs produced by our scalable manufacturing method appears like the clinically relevant fourth-generation PDT vehicle to overcome current limitations of PDT in the treatment of peritoneal metastasis and promote a hot tumor immune environment in PM.

Second-look surgery plus hyperthermic intraperitoneal chemotherapy versus surveillance in patients at high risk of developing colorectal peritoneal metastases (PROPHYLOCHIP-PRODIGE 15): a randomised, phase 3 study.

BACKGROUND: Diagnosis and treatment of colorectal peritoneal metastases at an early stage, before the onset of signs, could improve patient survival. We aimed to compare the survival benefit of systematic second-look surgery plus hyperthermic intraperitoneal chemotherapy (HIPEC), with surveillance, in patients at high risk of developing colorectal peritoneal metastases. METHODS: We did an open-label, randomised, phase 3 study in 23 hospitals in France. Eligible patients were aged 18-70 years and had a primary colorectal cancer with synchronous and localised colorectal peritoneal metastases removed during tumour resection, resected ovarian metastases, or a perforated tumour. Patients were randomly assigned (1:1) to surveillance or second-look surgery plus oxaliplatin-HIPEC (oxaliplatin 460 mg/m2, or oxaliplatin 300 mg/m2 plus irinotecan 200 mg/m2, plus intravenous fluorouracil 400 mg/m2), or mitomycin-HIPEC (mitomycin 35 mg/m2) alone in case of neuropathy, after 6 months of adjuvant systemic chemotherapy with no signs of disease recurrence. Randomisation was done via a web-based system, with stratification by treatment centre, nodal status, and risk factors for colorectal peritoneal metastases. Second-look surgery consisted of a complete exploration of the abdominal cavity via xyphopubic incision, and resection of all peritoneal implants if resectable. Surveillance after resection of colorectal cancer was done according to the French Guidelines. The primary outcome was 3-year disease-free survival, defined as the time from randomisation to peritoneal or distant disease recurrence, or death from any cause, whichever occurred first, analysed by intention to treat. Surgical complications were assessed in the second-look surgery group only. This study was registered at ClinicalTrials.gov, NCT01226394. FINDINGS: Between June 11, 2010, and March 31, 2015, 150 patients were recruited and randomly assigned to a treatment group (75 per group). After a median follow-up of 50·8 months (IQR 47·0-54·8), 3-year disease-free survival was 53% (95% CI 41-64) in the surveillance group versus 44% (33-56) in the second-look surgery group (hazard ratio 0·97, 95% CI 0·61-1·56). No treatment-related deaths were reported. 29 (41%) of 71 patients in the second-look surgery group had grade 3-4 complications. The most common grade 3-4 complications were intra-abdominal adverse events (haemorrhage, digestive leakage) in 12 (23%) of 71 patients and haematological adverse events in 13 (18%) of 71 patients. INTERPRETATION: Systematic second-look surgery plus oxaliplatin-HIPEC did not improve disease-free survival compared with standard surveillance. Currently, essential surveillance of patients at high risk of developing colorectal peritoneal metastases appears to be adequate and effective in terms of survival outcomes. FUNDING: French National Cancer Institute.

Hyperthermic intraperitoneal chemotherapy with cisplatin and mitomycin C for colorectal cancer peritoneal metastases: A systematic review of the literature.

BACKGROUND: The randomized trial PRODIGE 7 failed to show the benefit of oxaliplatin hyperthermic intraperitoneal chemotherapy (HIPEC) in colorectal peritoneal metastasis treatment (CR PM). This systematic review focuses on the association of cisplatin (CDDP) with mitomycin C (MMC) in HIPEC in CR PM. CONTENT: Experimental studies demonstrated that hyperthermia, in addition to CDDP ± MMC treatment, gradually improved the cytotoxic effect by increasing early apoptosis, eATP interaction, intracellular CDDP concentration (by 20%) and p73 expression. Recent studies with highly selected patients reported unusual prolonged survival with a median overall survival (OS) of approximately 60 months, with a HIPEC combination of CDDP (25 mg/m2/L) plus MMC (3.3 mg/m2/L) at a temperature of 41.5-42.5 °C for 60-90 min. Major complications occurred in less than 30% of patients with limited hematological toxicity (less than 15%). In addition, in a phase 2 trial, an adjuvant HIPEC benefit was demonstrated in colorectal cancer patients with high risk for peritoneal failure (5-year OS: 81.3% vs. 70% for the HIPEC group vs. the control group, respectively, p=0.047). After a recurrence, an iterative procedure permitted similar recurrence-free disease (13 vs. 13.7 months) with an acceptable morbidity (18.7% of severe complications). SUMMARY AND OUTLOOK: The combination of CDDP and MMC seems to be an interesting protocol as an alternative to high-dose and short-term oxaliplatin.

Synchronous liver metastases and peritoneal carcinomatosis from colorectal cancer: different strategies for curative treatment?

BACKGROUND: Management of patients with resectable hepatic metastases (HMs) and colorectal peritoneal carcinomatosis (CRPC) is not currently standardised. OBJECTIVE: The aims of this study were to evaluate the safety of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) and hepatic surgery for patients with CRPC with synchronous hepatic metastases (HM), and its impact on survival rates. METHODS: A retrospective analysis was performed, including patients undergoing CRS/HIPEC for CRPC from 2007 to September 2016 in two groups, with (HM+) and without (HM-) synchronous hepatic metastases. Patients with extra-abdominal metastases were excluded. The hepatic strategy was described. Morbimortality and survival were compared between the two groups. RESULTS: One hundred nine patients underwent CRS/HIPEC for CRPC with or without hepatic surgery with curative intent: 33 patients with (HM+) and 76 patients without (HM-) synchronous HM. The median follow-up was 30 months. All patients with HM (HM+) received neoadjuvant chemotherapy vs. 88.1% in the HM- group (p = 0.04) associated with monoclonal antibody in 66.6% of cases in the HM+ group vs. 57% in the HM- group (p = 0.01). In the HM+ group, two steps were implemented to treat peritoneal and hepatic metastases in 15 patients (45%). In this group, planned hepatic resection in two procedures was performed for eight patients, all presenting bilobar HM. Postoperative morbidity did not differ between the two groups. No deaths occurred. Median overall survival (OS) and recurrence-free survival (RFS) were 31 and 65 months (p = 0.188), versus 21 and 24 months (p = 0.119), respectively, in the HM+ versus HM- groups. In multivariate analysis, the peritoneal cancer index (PCI) was the only significant prognostic factor whereas synchronous HM was not a significant prognostic factor. CONCLUSION: Curative surgical treatment for CRPC with synchronous HM seems to be feasible and safe, and could facilitate long survival rates, compared to patients without HM. The hepatic strategy is not standardised. However, a "two-step" surgical strategy could be proposed in order to reduce postoperative morbidity rates.

Photodynamic therapy and photothermal therapy for the treatment of peritoneal metastasis: a systematic review.

BACKGROUND: The aim of this review was to analyze preclinical studies and clinical trials evaluating photodynamic therapy (PDT), and photothermal therapy (PTT) in peritoneal metastasis (PM) treatment. CONTENT: Systematic review according PRISMA guidelines. Electronic searches using PubMed and Clinical Trials. SUMMARY: A total of 19 preclinical studies analyzing PDT in PM treatment were included. Each new generations of photosensitizers (PS) permitted to improve tumoral targeting. Phase III preclinical studies showed an important tumoral biodistribution (ratio 9.6 vs normal tissue) and significant survival advantage (35.5 vs 52.5 days for cytoreductive surgery vs cytoreductive surgery+PDT, p<0.005). Height clinical trials showed important side effects (capillary leak syndrome and bowel perforation), mainly explained by low tumor-selectivity of the PS used (first generation mainly).Peritoneal mesothelioma apparition with carbon nanotubes first limited the development of PTT. But gold nanoparticles, with a good tolerance, permitted a limitation of tumoral growth (reduction of bioluminescence to 37 % 20 days after PTT), and survival benefit (35, 32, and 26 days for PTT with cisplatine, PTT alone and laser alone, respectively). OUTLOOK: Recent improvement in tumor-selectivity and light delivery systems is promising but further development would be necessary before PDT and PTT routinely applied for peritoneal carcinomatosis.

Update on clinical trials in colorectal cancer peritoneal metastasis.

BACKGROUND/PURPOSE: Peritoneal metastases (PM) arising from colorectal cancer (CRC) can be treated using cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) in select patients. OBJECTIVE: To review clinical trials that were reported during the 10th International Congress on Peritoneal Surface Malignancies and dedicated to the treatment of CRC-PM. METHODS: Ten clinical trials were presented at the 10th Peritoneal Surface Oncology Group International (PSOGI) meeting in November 2016 in Washington DC. The flow charts of the studies were identified on ClinicalTrials.gov. Additional data were collected regarding the author's presentations during the meeting. RESULTS: Four trials (Dutch, French, Italian and Spanish) focussed on a preventive strategy to decrease the rate of CRC-PM. Inclusions were closed for the French study - ProphyloCHIP. Two trials were specific, with one American study dedicated to appendix cancer and one French study testing phase 1 intraperitoneal oxaliplatin drug administration. CRS and HIPEC for PM were compared in others trials with different intraperitoneal treatments without hyperthermia or with no intraperitoneal treatment or with intravenous chemotherapy. Inclusions were closed for the French study - PRODIGE 7. CONCLUSION: The number of recruiting trials evaluating CRS and HIPEC in the prevention or therapy of CRC PM is increasing, and these have been activated in the US and different European countries. It could be postulated that in less than a decade, clinical results will change the common practice and validate the impact of PSOGI on cancer treatment.