Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy versus cytoreductive surgery alone for colorectal peritoneal metastases (PRODIGE 7): a multicentre, randomised, open-label, phase 3 trial.

BACKGROUND: The addition of hyperthermic intraperitoneal chemotherapy (HIPEC) to cytoreductive surgery has been associated with encouraging survival results in some patients with colorectal peritoneal metastases who were eligible for complete macroscopic resection. We aimed to assess the specific benefit of adding HIPEC to cytoreductive surgery compared with receiving cytoreductive surgery alone. METHODS: We did a randomised, open-label, phase 3 trial at 17 cancer centres in France. Eligible patients were aged 18-70 years and had histologically proven colorectal cancer with peritoneal metastases, WHO performance status of 0 or 1, a Peritoneal Cancer Index of 25 or less, and were eligible to receive systemic chemotherapy for 6 months (ie, they had adequate organ function and life expectancy of at least 12 weeks). Patients in whom complete macroscopic resection or surgical resection with less than 1 mm residual tumour tissue was completed were randomly assigned (1:1) to cytoreductive surgery with or without oxaliplatin-based HIPEC. Randomisation was done centrally using minimisation, and stratified by centre, completeness of cytoreduction, number of previous systemic chemotherapy lines, and timing of protocol-mandated systemic chemotherapy. Oxaliplatin HIPEC was administered by the closed (360 mg/m2) or open (460 mg/m2) abdomen techniques, and systemic chemotherapy (400 mg/m2 fluorouracil and 20 mg/m2 folinic acid) was delivered intravenously 20 min before HIPEC. All individuals received systemic chemotherapy (of investigators' choosing) with or without targeted therapy before or after surgery, or both. The primary endpoint was overall survival, which was analysed in the intention-to-treat population. Safety was assessed in all patients who received surgery. This trial is registed with ClinicalTrials.gov, NCT00769405, and is now completed. FINDINGS: Between Feb 11, 2008, and Jan 6, 2014, 265 patients were included and randomly assigned, 133 to the cytoreductive surgery plus HIPEC group and 132 to the cytoreductive surgery alone group. After median follow-up of 63·8 months (IQR 53·0-77·1), median overall survival was 41·7 months (95% CI 36·2-53·8) in the cytoreductive surgery plus HIPEC group and 41·2 months (35·1-49·7) in the cytoreductive surgery group (hazard ratio 1·00 [95·37% CI 0·63-1·58]; stratified log-rank p=0·99). At 30 days, two (2%) treatment-related deaths had occurred in each group.. Grade 3 or worse adverse events at 30 days were similar in frequency between groups (56 [42%] of 133 patients in the cytoreductive surgery plus HIPEC group vs 42 [32%] of 132 patients in the cytoreductive surgery group; p=0·083); however, at 60 days, grade 3 or worse adverse events were more common in the cytoreductive surgery plus HIPEC group (34 [26%] of 131 vs 20 [15%] of 130; p=0·035). INTERPRETATION: Considering the absence of an overall survival benefit after adding HIPEC to cytoreductive surgery and more frequent postoperative late complications with this combination, our data suggest that cytoreductive surgery alone should be the cornerstone of therapeutic strategies with curative intent for colorectal peritoneal metastases. FUNDING: Institut National du Cancer, Programme Hospitalier de Recherche Clinique du Cancer, Ligue Contre le Cancer.

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.

Metastatic Potential and Survival of Duodenal and Pancreatic Tumors in Multiple Endocrine Neoplasia Type 1: A GTE and AFCE Cohort Study (Groupe d'étude des Tumeurs Endocrines and Association Francophone de Chirurgie Endocrinienne).

OBJECTIVE: To assess the distant metastatic potential of duodeno-pancreatic neuroendocrine tumors (DP-NETs) in patients with MEN1, according to functional status and size. SUMMARY BACKGROUND DATA: DP-NETs, with their numerous lesions and endocrine secretion-related symptoms, continue to be a medical challenge; unfortunately they can become aggressive tumors associated with distant metastasis, shortening survival. The survival of patients with large nonfunctional DP-NETs is known to be poor, but the overall contribution of DP-NETs to metastatic spread is poorly known. METHODS: The study population included patients with DP-NETs diagnosed after 1990 and followed in the MEN1 cohort of the Groupe d'étude des Tumeurs Endocrines (GTE). A multistate Markov piecewise constant intensities model was applied to separate the effects of prognostic factors on 1) metastasis, and 2) metastasis-free death or 3) death after appearance of metastases. RESULTS: Among the 603 patients included, 39 had metastasis at diagnosis of DP-NET, 50 developed metastases during follow-up, and 69 died. The Markov model showed that Zollinger-Ellison-related tumors (regardless of tumor size and thymic tumor pejorative impact), large tumors over 2 cm, and age over 40 years were independently associated with an increased risk of metastases. Men, patients over 40 years old and patients with tumors larger than 2 cm, also had an increased risk of death once metastasis appeared. CONCLUSIONS: DP-NETs of 2 cm in size or more, regardless of the associated secretion, should be removed to prevent metastasis and increase survival. Surgery for gastrinoma remains debatable.

Strategies for Managing Intraoperative Discovery of Limited Colorectal Peritoneal Metastases.

BACKGROUND: Management of limited synchronous colorectal peritoneal metastases (CRPM) is critical to outcome. Resection of the primary tumor and CRPM can be performed concurrently, followed by hyperthermic intraperitoneal chemotherapy (HIPEC) either immediately, during the same procedure (one-stage), or during a systematic second-stage procedure (two-stage). OBJECTIVE: The aim of this study was to compare these two strategies for morbidity, mortality, and survival. METHODS: All patients presenting with limited (initial Peritoneal Cancer Index [PCI] ≤ 10) synchronous CRPM who had undergone complete cytoreductive surgery plus HIPEC between 2000 and 2016 were selected from a prospectively maintained institutional database. RESULTS: Overall, 74 patients were included-31 in the one-stage group and 43 in the two-stage group. During second-stage surgery, a peritoneal recurrence was diagnosed in 37 (86%) patients, 12 of whom had a PCI > 10 (28%) and 2 of whom had unresectable disease (5%). Among the one-stage group, peritoneal recurrence occurred in 29% of patients after a median delay of 23 months. Overall survival at 1, 3, and 5 years was similar between the two groups, i.e. 96%, 59%, and 51% for the one-stage group, and 98%, 77%, and 61% for the two-stage group. A PCI > 10 at the time of HIPEC, as well as liver metastases, were independent negative prognostic factors. CONCLUSIONS: For incidental limited CRPM diagnosed during primary tumor resection, one-stage curative treatment is preferable, avoiding a supplementary surgical procedure. Given the critical issues associated with completeness of resection, patients should be referred to centers specialized in peritoneal surgery.

Is Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy Justified for Biphasic Variants of Peritoneal Mesothelioma? Outcomes from the Peritoneal Surface Oncology Group International Registry.

BACKGROUND: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) has dramatically improved the survival of patients with epithelioid peritoneal mesothelioma. It is unknown if CRS/HIPEC is indicated for the more aggressive biphasic mesothelioma variant. METHODS: A retrospective analysis of the Peritoneal Surface Oncology Group International (PSOGI) registry including data from 33 centers was performed. Survival was reviewed based on mesothelioma type, completion of cytoreduction, and volume of disease. RESULTS: Overall, 484 of 1165 (41.5%) CRS/HIPEC procedures with complete CC0 and CC1 cytoreductions were analyzed; 450 (93%) procedures were performed for epithelioid mesotheliomas, while 34 (7%) were performed for biphasic mesotheliomas. For patients with CC0 resection, 5-year survival was 64.5 and 50.2% (median 7.8 and 6.8 years; p = 0.015) for epithelioid and biphasic mesotheliomas, respectively, while inclusion of CC1 resections in the analysis resulted in inferior 5-year survival of 62.9% and 41.6% (median 7.8 and 2.8 years; p = 0.0012), respectively. Incomplete CC2 resections for biphasic primaries resulted in a median survival of 4.3 months. Univariate analysis of the biphasic cohort indicated Peritoneal Cancer Index (PCI; p = 0.015), CC status of resection (p < 0.0001), and Ki67 (p = 0.04) as predictors of survival. Systemic chemotherapy before (p = 0.55) or after (p = 0.7) CRS/HIPEC did not influence survival. In multivariate analysis, only PCI (p = 0.03) and CC (p = 0.04) remained significant. CONCLUSIONS: Long-term survival is achievable in patients with low-volume biphasic mesothelioma after complete macroscopic cytoreduction. Biphasic peritoneal mesotheliomas should not be considered as an absolute contraindication for CRS/HIPEC if there is low-volume disease and if complete cytoreduction can be achieved.

Cytoreductive Surgery Plus Hyperthermic Intraperitoneal Chemotherapy for Peritoneal Metastases From a Small Bowel Adenocarcinoma: Multi-Institutional Experience.

BACKGROUND: The multi-institutional registry in this study evaluated the outcome after cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) for patients with peritoneal metastases (PM) from small bowel adenocarcinoma (SBA). METHODS: A multi-institutional data registry including 152 patients with PM from SBA was established. The primary end point was overall survival (OS) after CRS plus HIPEC. RESULTS: Between 1989 and 2016, 152 patients from 21 institutions received a treatment of CRS plus HIPEC. The median follow-up period was 20 months (range 1-100 months). Of the 152 patients, 70 (46.1%) were women with a median age of 54 years. The median peritoneal cancer index (PCI) was 10 (mean 12; range 1-33). Completeness of cytoreduction (CCR) 0 or 1 was achieved for 134 patients (88.2%). After CRS and HIPEC, the median OS was 32 months (range 1-100 months), with survival rates of 83.2% at 1 year, 46.4% at 3 years, and 30.8% at 5 years. The median disease-free survival after CCR 0/1 was 14 months (range 1-100 months). The treatment-related mortality rate was 2%, and 29 patients (19.1%) experienced grades 3 or 4 operative complications. The period between detection of PM and CRS plus HIPEC was 6 months or less (P = 0.008), and multivariate analysis identified absence of lymph node metastasis (P = 0.037), well-differentiated tumor (P = 0.028), and PCI of 15 or lower (P = 0.003) as independently associated with improved OS. CONCLUSION: The combined treatment strategy of CRS plus HIPEC achieved prolonged survival for selected patients who had PM from SBA with acceptable morbidity and mortality.

Postoperative hepatic arterial chemotherapy in high-risk patients as adjuvant treatment after resection of colorectal liver metastases - a randomized phase II/III trial - PACHA-01 (NCT02494973).

BACKGROUND: After curative-intent surgery for colorectal liver metastases (CRLM), liver recurrence occurs in more than 60% of patients, despite the administration of perioperative or adjuvant chemotherapy. This risk is even higher after resection of more than three CRLM. As CRLM are mostly supplied by arterial blood flow, hepatic arterial infusion (HAI) of chemotherapeutic agents after resection of CRLM is an attractive approach. Oxaliplatin-based HAI chemotherapy, in association with systemic fluoropyrimidines, has been shown to be safe and highly active in patients with CRLM. In a retrospective series of 98 patients at high risk of hepatic recurrence (≥4 resected CRLM), adjuvant HAI oxaliplatin combined with systemic chemotherapy was feasible and significantly improved disease-free survival compared to adjuvant, 'modern' systemic chemotherapy alone. METHODS/DESIGN: This study is designed as a multicentre, randomized, phase II/III trial. The first step is a non-comparative randomized phase II trial (power, 95%; one-sided alpha risk, 10%). Patients will be randomly assigned in a 1:1 ratio to adjuvant systemic FOLFOX (control arm) or adjuvant HAI oxaliplatin plus systemic LV5FU2 (experimental arm). A total 114 patients will need to be included. The main objective of this trial is to evaluate the potential survival benefit of adjuvant HAI with oxaliplatin after resection of at least 4 CRLM (primary endpoint: 18-month hepatic recurrence-free survival rate). We also aim to assess the feasibility of delivering at least 4 cycles of HAI (or i.v.) oxaliplatin after surgical treatment of at least 4 CRLM, the toxicity (NCI-CTC v4.0) of adjuvant HAI plus systemic chemotherapy, including HAI catheter-related complications, compared to systemic chemotherapy alone, and the efficacy of adjuvant HAI on hepatic and extra-hepatic recurrence-free (survival and overall survival). DISCUSSION: If 18-month hepatic recurrence-free survival is greater than 50% in the experimental arm, the study will be pursued in phase III, for which the primary endpoint will be 3-year recurrence-free survival rate. Patients randomized in the phase II will be included in the phase III, with an additional number of 106 patients. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02494973 . Trial registration date: July 10, 2015.

Cytoreductive surgery and hyperthermic intraperitoneal perfusion with chemotherapy in children with peritoneal tumor spread: A French nationwide study over 14 years.

BACKGROUND: Efficacy and role of cytoreductive surgery (CRS) and hyperthermic peritoneal perfusion with chemotherapy (HIPEC) remain poorly documented in pediatric tumors. METHODS: This retrospective national study analyzed all pediatric patients with peritoneal tumor spread treated by CRS and HIPEC as part of a multimodal therapy in France from 2001 to 2015. RESULTS: Twenty-two patients (nine males and 13 females) were selected. The median age at diagnosis was 14.8 years (4.2-17.6). Seven had peritoneal mesotheliomas; seven, desmoplastic small round cells tumors (DSRCT); and eight, other histologic types. A complete macroscopic resection (CC-0, where CC is completeness of cytoreduction) was achieved in 16 (73%) cases. Incomplete resections were classified as CC-1 in four (18%) cases and CC-2 in two (9%) cases. Fourteen (64%) patients had complications within 30 days from HIPEC, requiring an urgent laparotomy in eight (36%) cases. Thirteen (59%) patients received adjuvant chemotherapy and four (18%) received total abdominal radiotherapy after surgery. Sixteen (72%) patients had relapse after a median time of 9.6 months (1.4-86.4) and nine (41%) eventually died after a median time of 5.3 months (0.1-36.1) from relapse. Six (27%) patients (four mesotheliomas, one pseudopapillary pancreatic tumor, and one DSRCT) were alive and in complete remission after a median follow-up of 25.0 months (5.3-78.2). The mean overall survival (OS) and disease-free survival (DFS) were 57.5 months (95% CI [38.59-76.32]) and 30.9 months (95% CI [14.96-46.77]). Patients with a peritoneal mesothelioma had a significantly better OS (p = 0.015) and DFS (p = 0.028) than other histologic type. CONCLUSIONS: In this national series, outcomes of HIPEC are encouraging for the treatment of peritoneal mesothelioma in children.

Conversion to Complete Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Malignant Peritoneal Mesothelioma After Bidirectional Chemotherapy.

BACKGROUND: This report aims to describe preliminary results concerning secondary resectability after bidirectional chemotherapy for initially unresectable malignant peritoneal mesothelioma (MPM). METHODS: Between January 2013 and January 2016, 20 consecutive patients treated for diffuse MPM not suitable for upfront surgery received bidirectional chemotherapy associating intraperitoneal and systemic chemotherapy. Evaluation of the response to chemotherapy was assessed clinically and by laparoscopy. RESULTS: The median peritoneal cancer index (PCI) score at staging laparoscopy was 27 (range 15-39). Altogether, 118 intraperitoneal chemotherapy cycles were administered without any specific adverse catheter-related event. Concerning tolerance, 85% of the patients experienced no pain or mild pain during chemotherapy administration. The clinical response rate was 60% after a median of three chemotherapy cycles. At laparoscopic reevaluation, the median PCI was 18 (range 0-35), and a secondary resectability was considered for 55% of the patients. Complete cytoreduction surgery followed by hyperthermic intraperitoneal chemotherapy (HIPEC) was finally achieved for 10 patients (50%), with a median intraoperative PCI score of 14 (range 6-30). After a median follow-up period of 18 months, the 2-year overall survival rate was 83.3% for the patients treated by CRS followed by HIPEC and 44% for the patients treated by bidirectional chemotherapy. CONCLUSION: Bidirectional chemotherapy is a promising, well-tolerated treatment capable of increasing the resection rate for selected patients with diffuse MPM initially considered as unresectable or borderline resectable. For patients with definitively unresectable disease, bidirectional chemotherapy achieves a higher clinical response rate.

Not All Patients with a Pancreatic Neuroendocrine Tumour Will Benefit from All Approved or Recommended Therapeutic Options: A Real-Life Retrospective Study.

BACKGROUND: At least nine therapeutic options are recommended or approved for pancreatic neuroendocrine tumour (pNET). The primary endpoint of this study was to determine the number of therapeutic lines given before death. Secondary endpoints were to determine toxic events as a function of number of therapeutic lines and of time. METHODS: Patients with pNET treated between 1998 and 2010 at our centre were characterised. All therapeutic lines were recorded as well as tumour- or toxic-related deaths. Persistent treatment-related toxicity (PTRT) was defined as: chronic kidney disease, anaemia, thrombocytopenia, neutropenia, severe liver failure, cardiac failure and recurrent sepsis, precluding at least one other therapeutic option or second cancers. RESULTS: Ninety-two patients were analysed. The median follow-up was 7 years. The 1-, 2- and 5-year overall survival rates were 90, 81 and 51%, respectively. After 3 and 5 therapeutic lines, 23 and 50% of patients had died, respectively. After 3 and 5 lines, the frequency of toxic events was 8 and 24%, respectively. Overall, 17 toxic events were observed including 6 treatment-related deaths and 11 PTRT. After 1, 2 and 5 years of treatment, the frequency of toxic events was 6, 9 and 16%, respectively. CONCLUSION: Tumour- and toxic-related deaths as well as PTRT may preclude access to all therapeutic options in patients with pNET. Optimised risk benefit sequence should be investigated.

Strategies to prevent peritoneal carcinomatosis arising from colorectal cancer.

In the last decades, cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy became a curative option for peritoneal metastases in selected patients, otherwise considered for palliative therapy alone. Better knowledge of physiopathology of peritoneal spread and identification of predictive factors for peritoneal relapse prompted specialized centers to investigate the role of a 'proactive approach' in order to early detect peritoneal metastasis. These encouraging data could justify an active attitude in selected patients at high risk of peritoneal recurrence after curative resection of primary tumor. Selection criteria and the timing of complementary hyperthermic intraperitoneal chemotherapy remain important points of discussion. In this article, we will discuss treatment principles and future perspectives to early treat and, if possible, to prevent peritoneal dissemination after curative treatment of colorectal cancer.

Ninety percent of the adverse outcomes occur in 10% of patients: can we identify the populations at high risk of developing peritoneal metastases after curative surgery for colorectal cancer?

BACKGROUND: Peritoneal metastases (PM) occur in 3.4-6.3% after curative surgery for non-metastatic colorectal cancer. Systematic "2nd look" surgery helps overcoming the diagnostic problem but can be only proposed to selected patients. The aim of this study was to update the knowledge on risk factors of developing PM after curative surgery for colorectal cancer. METHODS: A systematic review of the literature published between 2011 and 2016 was made, searching for all clinical studies reporting the incidence of recurrent PM after curative surgery for colorectal cancer and factors associated with the primary tumour that were likely to influence this recurrence rate. RESULTS: Seven new clinical studies were considered informative for risk factors and added to the 16 reviewed in 2013. Even if the level of evidence was low, data suggested rates of recurrent PM at 1 year between 54% and 71% after completely resected synchronous PM, between 62% and 71% after resection of isolated synchronous ovarian metastases, of 27% after surgery for a perforated primary tumour, of 16% after surgery for a pT4 tumour, and between 11% and 36% after surgery for a mucinous histological subtype. No new risk factor was identified. CONCLUSIONS: Evidence regarding the incidence of recurrent PM after curative surgery for colorectal cancer is poor. Situations at higher risk of recurrent PM are synchronous PM, synchronous isolated ovarian metastases, perforated primary tumour with serosa invasion and mucinous histological subtype.

Linear Relationship of Peritoneal Cancer Index and Survival in Patients with Peritoneal Metastases from Colorectal Cancer.

BACKGROUND: The peritoneal cancer index (PCI) is the main prognostic factor for establishing potentially resectable peritoneal metastases from colorectal cancer. Attempts have been made to set a PCI cutoff on which to base indications of complete cytoreductive surgery (CCRS) with hyperthermic intraperitoneal chemotherapy (HIPEC), but none have reached consensus. The aim of this study was to investigate the relation between the PCI and overall survival (OS). METHODS: We included all consecutive patients homogeneously treated with CCRS and HIPEC between 2003 and 2012. The PCI was calculated at the end of the surgical procedure. The correlation between the PCI and OS was studied using statistical modeling from the simplest to the most complex methods (including linear, quadratic, cubic, and spline cubic). These models were compared by Akaike's information criteria (AIC). RESULTS: For the 173 treated patients, 5-year OS reached 41 %. The mean PCI was 10.2 (±6.8). The linear model was the most appropriate to relate the PCI to OS as confirmed with the AIC scoring system. In multivariate analysis, the PCI was confirmed as being the most important prognostic factor (hazard ratio = 1.1 for each supplementary point, p < 0.0001). CONCLUSIONS: There is a perfect linear correlation between the PCI and OS, which precludes setting a unique PCI cutoff for CCRS + HIPEC. Overall, CCRS + HIPEC is generally indicated for PCI < 12 and contraindicated for PCI > 17. Between 12 and 17, other parameters have to be taken into account, such as the presence of extraperitoneal metastases, general performance status, and chemosensitivity.

Sarcopenia is Associated with Chemotherapy Toxicity in Patients Undergoing Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy for Peritoneal Carcinomatosis from Colorectal Cancer.

BACKGROUND: Despite the positive survival results of cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC), criticisms have been put forward regarding the safety of this treatment as a result of a high morbidity rate. Muscle depletion (sarcopenia) is associated with the occurrence of postoperative complications. The purpose of this study was to determine the association between sarcopenia and postoperative morbidity after CRS-HIPEC for peritoneal carcinomatosis from colorectal cancer by distinguishing the complications linked to CRS itself and those associated with chemotherapy (HIPEC) toxicities. METHODS: Data concerning 97 consecutive patients who had undergone CRS-HIPEC were recorded. We analyzed the events occurring within 30 days after surgery that were prospectively recorded in a database. Sarcopenia was assessed using the L3 muscle index on computed tomography performed during the 2 months preceding surgery. RESULTS: The sarcopenic patients experienced significantly more chemotherapy toxicities (57 vs. 26 %; p = 0.004) and especially neutropenia (36 vs. 17 %; p = 0.04) than their nonsarcopenic counterparts. There was no difference in complications linked to the CRS procedure between sarcopenic and nonsarcopenic patients. In the multivariate analysis, sarcopenia was the only parameter independently associated with the risk of chemotherapy toxicity (odds ratio 3.97; 95 % confidence interval 1.52-10.39; p = 0.005). CONCLUSIONS: Despite the local administration of chemotherapy, systemic toxicity was observed in sarcopenic patients after CRS-HIPEC. This relationship favors new treatment strategies with white blood cell growth factors or chemotherapy dosing based on muscle value.

Can a Benefit be Expected from Surgical Debulking of Unresectable Pseudomyxoma Peritonei?

PURPOSE: This study evaluated the role of surgical debulking in improving pseudomyxoma peritonei (PMP)-related symptoms if complete cytoreductive surgery (CCRS) of huge PMP is unachievable. METHODS: This was a retrospective analysis of a prospective database of all patients in our tertiary care center treated for PMP between 1992 and 2014. All cases of surgical debulking in patients scheduled for CCRS that proved unachievable during the operation were selected for the present study. RESULTS: Among the 338 patients operated on for PMP, 39 (11.5 %) had undergone surgical debulking because CCRS was unachievable. All of these patients were symptomatic before surgery, and the median PCI was 32 (5-39). More than 80 % of the disease burden was resected in 23 patients (59 %). Mortality and major morbidity rates were 2.5 and 23 %, respectively. After debulking surgery, symptoms gradually subsided over a median time of 23 months and 50 % of the patients no longer experienced PMP-related symptoms after a median follow-up of 24.5 months. After a median follow-up of 46.4 months (range 3-120), median overall (OS) and progression-free (PFS) survival times were 55.5 and 20 months, respectively. Five-year OS and PFS rates were 46 and 11 %, respectively. CONCLUSIONS: Aggressive debulking surgery in case of unachievable CCRS for huge PMP can offer prolonged relief of PMP-related symptoms and long-term survival, in experienced centers that are able to be sufficiently aggressive to resect the major part of the disease, and conservative enough to achieve low mortality and good quality of life.

Early Postoperative Chemotherapy After Complete Cytoreduction and Hyperthermic Intraperitoneal Chemotherapy for Isolated Peritoneal Carcinomatosis of Colon Cancer: A Multicenter Study.

PURPOSE: The prognosis of peritoneal carcinomatosis (PC) from colorectal cancer has been improved with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). However, benefits of postoperative chemotherapy (CT) are unclear. METHODS: This retrospective, multicenter study included 231 patients treated by CRS and HIPEC for isolated PC of colon cancer in four expert's centers. Overall survival (OS), progression-free survival (PFS), and peritoneal recurrence-free survival (PRFS) were compared between patients with adjuvant CT (started within 3 months after surgery) and patients with surveillance only. RESULTS: After exclusion of 10 patients for early postoperative death (4%), 221 patients were included (CT group: n = 151; surveillance group: n = 70). Main postoperative CT regimens (median of 6 cycles) were Folfox (28%), Folfiri bevacizumab (24.5%), Folfiri (16%), and Folfiri cetuximab (12.5%). The median OS after surgery was 43.3 months with no difference between CT and surveillance groups. In multivariate analysis, a low peritoneal cancer index (p < 0.0001) and a long delay between diagnosis of CP and HIPEC (p = 0.001) were associated with increased OS. The median PFS and PRFS were 12.4 and 17 months, respectively. At 1 year, more patients were without progression (p = 0.001) or PC recurrence (0.0004) in the CT group, but with prolonged follow-up this difference was no longer significant. CONCLUSIONS: Early postoperative CT does not improve OS after CRS and HIPEC for colon carcinomatosis. However, a transient effect on PFS and PRFS was observed. A subgroup of patients who may benefit more from CT remain to be defined.

Cytoreductive Surgery Combined with Hyperthermic Intraperitoneal Chemotherapy with Oxaliplatin Increases the Risk of Postoperative Hemorrhagic Complications: Analysis of Predictive Factors.

BACKGROUND: Treatment of peritoneal carcinomatosis (PC) using cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is recommended as curative treatment for selected patients. Modalities of HIPEC remain heterogeneous and HIPEC using oxaliplatin (HIPEC-Ox) appears to increase the risk of postoperative hemorrhagic complications (HCs). OBJECTIVE: The aim of this study was to assess the risk of HCs after CRS combined with HIPEC-Ox versus other drugs, and to determine predictive factors for HCs after HIPEC-Ox. METHODS: Data from 701 patients included in the National French Registry who were treated with CRS and HIPEC at 24 centers between 1998 and 2007 were used to evaluate the incidence of HCs following HIPEC with or without oxaliplatin. Overall, 771 patients treated with HIPEC-Ox at five French specialty centers were then analyzed to determine factors associated with the occurrence of HCs. RESULTS: The overall incidence of HCs was 9.8 %. When used with HIPEC, oxaliplatin significantly and independently increased the rate of HCs (15.7 vs. 2.6 % for other drugs; p = 0.004, odds ratio 32.4). Among the 771 patients who underwent HIPEC-Ox, HCs occurred in 14.3 % of patients. The only independent risk factor for HCs was an extended PC with a Peritoneal Cancer Index (PCI) >12 (p = 0.040). CONCLUSION: HIPEC-Ox increases the risk of HCs compared with HIPEC with other drugs. The potential oncologic benefit of oxaliplatin and the risk of HCs should be considered in patients with PC who have a high PCI, as well as in at-risk patients.

Recurrence of Solid Pseudopapillary Neoplasms of the Pancreas: Results of a Nationwide Study of Risk Factors and Treatment Modalities.

BACKGROUND: Solid pseudopapillary neoplasms of the pancreas (SPPN) can relapse very late, but little is known about risk factors for recurrence and optimal treatment. We aimed to identify risk factors for recurrence and to analyze treatment modalities in all French pediatric cases of SPPN over the past 20 years. MATERIAL AND METHODS: Data were collected from pediatric oncologists and surgeons, and also from adult pancreatic surgeons in order to identify late recurrences. RESULTS: Fifty-one patients (41 girls) were identified. Median age at diagnosis was 13.1 years [8.7-17.9]. Abdominal pain was the commonest presenting symptom (32/49, 65%). The tumor was located in the pancreatic head in 24 patients (47%). Preoperative biopsy or cytology was performed in 14 cases (28%). All patients were operated with a median of 23 days [0-163] after diagnosis. The rate of postoperative morbidity was 29%. With a median follow-up of 65 months [0.3-221], the overall and event-free survival was 100% and 71%, respectively. Seven patients (13.7%) relapsed with a median of 43 months [33-94] after initial surgery. Six were treated surgically, either alone (n = 3) or with perioperative chemotherapy (n = 2) or hyperthermic intraperitoneal chemotherapy (n = 1). One patient in whom further treatment was not feasible was still alive at last news. Risk factors for recurrence were positive surgical margins (P = 0.03) and age less than 13.5 years at diagnosis (P = 0.03). CONCLUSIONS: SPPN recurrence in this pediatric series was a rare and late event that did not undermine overall survival. Complete surgical removal of recurrent tumors appears to be the best option.

Prognostic similarities and differences in optimally resected liver metastases and peritoneal metastases from colorectal cancers.

PURPOSE: To analyze and compare survival in patients operated for colorectal liver metastases (LM) with that in patients optimally resected for peritoneal metastases (PM). PATIENTS AND METHODS: This study concerns 287 patients with LM and 119 patients with PM treated with surgery plus chemotherapy between 1993 and 2009, excluding patients presenting both LM and PM. RESULTS: Mortality (respectively, 2.7% and 4.2%), morbidity (respectively, 11% and 17%), and 5-year overall survival (OS) rates (respectively, 38.5% and 36.5%) were not statistically different between the LM group and the PM group. Multivariate analysis showed that the extent of the disease was the main prognostic factor, which led us to divide the population into 5 subgroups. The best 5-year OS rate (72.4%) was obtained in patients with minimal peritoneal disease [peritoneal cancer index (PCI) ≤5]. OS was similar for the patients with less than 10 LM and those with a PCI between 6 and 15 (respectively, 39.4% and 38.7%). Five-year OS was lower in patients with more than 10 LM (18.1%), and dramatically low for patients with a PCI > 15 (11.8%). CONCLUSIONS: This study underlines the prognostic impact of the tumor burden in metastatic colorectal disease. In selected patients, similar survival rates can be obtained after optimal treatment of LM and PM. As the role of optimal surgical resection of LM is widely accepted, our results confirm that an optimal attitude should also be adopted to treat PM with a PCI < 16, particularly in patients with very low PCI (<5) where survival could be better than LM.

Extent of colorectal peritoneal carcinomatosis: attempt to define a threshold above which HIPEC does not offer survival benefit: a comparative study.

BACKGROUND: The main prognostic factors after complete cytoreductive surgery (CCRS) of colorectal peritoneal carcinomatosis (PC) followed by intraperitoneal chemotherapy (IPC) are completeness of the resection and extent of the disease. This study aimed to determine a threshold value above which CCRS plus IPC may not offer survival benefit compared with systemic chemotherapy. METHODS: Between March 2000 and May 2010, 180 patients underwent surgery for PC from colorectal cancer with intended performance of CCRS plus IPC. RESULTS: Among the 180 patients, CCRS plus IPC could be performed for 139 patients (curative group, 77 %), whereas it could not be performed for 41 patients (palliative group, 23 %). The two groups were comparable in terms of age, gender, primary tumor characteristics, and pre- and postoperative systemic chemotherapy. The mean peritoneal cancer index (PCI) was lower in the curative group (11 ± 7) than in the palliative group (23 ± 7) (p < 0.0001). After a median follow-up period of 60 months (range 47-74 months), the 3-year overall survival (OS) rate was 52 % [95 % confidence interval (CI) 43-61 %] in the curative group compared with 7 % (95 % CI 2-25 %) in the palliative group. Comparison of the survivals for each PCI (ranging from 5 to 36) shows that OS did not differ significantly between the two groups of patients when the PCI was higher than 17 (hazard ratio 0.64; range 0.38-1.09). CONCLUSION: This study confirmed the major prognostic impact of PC extent. When the PCI exceeds 17 in PC of colorectal origin, CCRS plus IPC does not seem to offer any survival benefit.