Metastatic Colorectal Cancer Treated with Combined Liver Resection, Cytoreductive Surgery, and Hyperthermic Intraperitoneal Chemotherapy (HIPEC): Predictive Factors for Early Recurrence.

BACKGROUND: Selection of colorectal cancer patients with concomitant peritoneal (PM) and liver metastases (LM) for radical treatment with cytoreductive surgery (CRS), including liver resection and hyperthermic intraperitoneal chemotherapy (HIPEC), needs improvement. This retrospective, monocentric study was designed to evaluate the predictive factors for early recurrence, disease-free survival (DFS), and overall survival (OS) in such patients treated in a referral center. METHODS: Consecutive colorectal cancer patients with concomitant LM and PM treated with curative intent with perioperative systemic chemotherapy, simultaneous complete CRS, liver resection, and HIPEC in 2011-2022 were included. Clinical, radiological (before and after preoperative chemotherapy), surgical, and pathological data were investigated, along with long-term oncologic outcomes. A multivariate analysis was performed to identify predictive factors associated with early recurrence (diagnosed <6 months after surgery), DFS, and OS. RESULTS: Of more than 61 patients included, 31 (47.1%) had pT4 and 27 (40.9%) had pN2 primary tumors. Before preoperative chemotherapy, the median number of LM was 2 (1-4). The median surgical PCI (peritoneal carcinomatosis index) was 3 (5-8.5). The median DFS and OS were 8.15 (95% confidence interval [CI] 5.5-10.1) and 34.1 months (95% CI 28.1-53.5), respectively. In multivariate analysis, pT4 (odds ratio [OR] = 4.14 [1.2-16.78], p = 0.032]) and pN2 (OR = 3.7 [1.08-13.86], p = 0.042) status were independently associated with an early recurrence, whereas retroperitoneal lymph node metastasis (hazard ratio [HR] = 39 [8.67-175.44], p < 0.001) was independently associated with poor OS. CONCLUSIONS: In colorectal cancer patients with concomitant PM and LM, an advanced primary tumor (pT4 and/or pN2) was associated with a higher risk of early recurrence following a radical multimodal treatment, whereas RLN metastases was strongly detrimental for OS.

A PK-PD model linking biomarker dynamics to progression-free survival in patients treated with everolimus and sorafenib combination therapy, EVESOR phase I trial.

PURPOSE: The objective was to develop a pharmacokinetic-pharmacodynamic (PK-PD) model linking everolimus and sorafenib exposure with biomarker dynamics and progression-free survival (PFS) based on data from EVESOR trial in patients with solid tumors treated with everolimus and sorafenib combination therapy and to simulate alternative dosing schedules for sorafenib. PATIENTS AND METHODS: Everolimus (5-10 mg once daily, qd) and sorafenib (200-400 mg twice daily, bid) were administered according to four different dosing schedules in 43 solid tumor patients. Rich PK and PD sampling for serum angiogenesis biomarkers was performed. Baseline activation of RAS/RAF/ERK (MAPK) pathway was assessed by quantification of mRNA specific gene panel in tumor biopsies. The PK-PD modeling was performed using NONMEM® software. RESULTS: An indirect response PK-PD model linking sorafenib plasma exposure with soluble vascular endothelial growth factor receptor 2 (sVEGFR2) dynamics was developed. Progression-free survival (PFS) was described by a parametric time-to-event model. Higher decreases in sVEGFR2 at day 21 and higher baseline activation of MAPK pathway were associated with longer PFS (p = 0.002 and p = 0.007, respectively). The simulated schedule sorafenib 200 mg bid 5 days-on/2 days-off + continuous everolimus 5 mg qd was associated with median PFS of 4.3 months (95% CI 1.6-14.4), whereas the median PFS in the EVESOR trial was 3.6 months (95% CI 2.7-4.2, n = 43). CONCLUSION: Sorafenib 200 mg bid 5 days-on/2 days-off + everolimus 5 mg qd continuous was selected for an additional arm of EVESOR trial to evaluate whether this simulated schedule is associated with higher clinical benefit. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01932177.

Influence of Extraperitoneal Metastases on the Curative-Intent Management of Colorectal Peritoneal Metastases.

BACKGROUND: Selected patients with colorectal cancer peritoneal metastasis (CRPM) and extraperitoneal disease could be treated radically with a multimodal approach combining complete cytoreductive surgery, thermoablation, radiotherapy, and systemic and intraperitoneal chemotherapy. The impact of extraperitoneal metastatic sites (EPMS) in this setting remains unclear. PATIENTS AND METHODS: Patients with CRPM undergoing complete cytoreduction in 2005-2018 were grouped in: peritoneal disease only (PDO), one EPMS (1 + EPMS), two or more EPMS (2 + EPMS). A retrospective analysis compared overall survival (OS) and postoperative outcomes. RESULTS: Of 433 patients, 109 had 1 + EPMS and 31 had 2 + EPMS. Overall, 101 patients had liver metastasis, 19 lung metastasis, and 30 retroperitoneal lymph node (RLN) invasion. The median OS was 56.9 months. There was no significant OS difference between PDO and 1 + EPMS groups (64.6 and 57.9 months, respectively), whereas OS was lower in the 2 + EPMS group (29.4 months, p = 0.005). In multivariate analysis, 2 + EPMS [hazard ratio (HR) 2.86, 95% confidence interval (CI) 1.33-6.12, p = 0.007], Sugarbaker's Peritoneal Carcinomatosis Index (PCI) > 15 (HR 3.86, 95% CI 2.04-7.32, p < 0.001), poorly differentiated tumors (HR 2.62, 95% CI 1.21-5.66, p = 0.015), and BRAF mutation (HR 2.10, 95% CI 1.11-3.99, p = 0.024) were independent poor prognostic factors, while adjuvant chemotherapy was beneficial (HR 0.33, 95% CI 0.20-0.56, p < 0.001). Patients with liver resection did not show higher severe complication rates. CONCLUSION: In patients with CRPM selected for a radical surgical approach, limited extraperitoneal disease involving one site, notably the liver, does not seem to significantly impair postoperative results. RLN invasion appeared as a poor prognostic factor in this population.

Comparison of Neoadjuvant Systemic Chemotherapy Protocols for the Curative-Intent Management of Peritoneal Metastases from Colorectal Cancer, Regarding Morphological Response, Pathological Response, and Long-Term Outcomes: A Retrospective Study.

BACKGROUND: Selected patients with colorectal cancer peritoneal metastases (CRPM) could be offered a curative-intent strategy based on complete cytoreductive surgery (CRS), potentially combined with hyperthermic intraperitoneal chemotherapy (HIPEC) and perioperative systemic chemotherapy. The impact of different neoadjuvant systemic chemotherapy (NACT) regimens remains unclear due to a lack of comparative data. METHODS: Consecutive CRPM patients from a monocentric database who were treated with complete CRS after single-line NACT were included in this study. Chemotherapy regimens were tailored as a doublet drug (FOLFOX/FOLFIRI) with/without targeted therapy (anti-epidermal growth factor receptor/bevacizumab) and triplet-drug combination (FOLFIRINOX). Morphological response (MR) was assessed using the Response Evaluation Criteria in Solid Tumors criteria, and pathological response (PR) was assessed using the Peritoneal Regression Grading Score (PRGS). Long-term oncologic outcomes were compared. RESULTS: The cohort comprised 388 patients, including 127, 202, and 59 patients in the doublet, doublet + targeted, and triplet groups, respectively. MR rates were higher in the triplet (68.0%) and doublet + targeted groups (64.2%) when compared with the doublet group (42.4%, p = 0.003). Complete and major PRs were observed in 13.6% and 32.0% of patients, respectively. Higher MR rates were observed after doublet + targeted or triplet regimens, while no difference was observed for PR rates. In multivariate analysis, FOLFIRINOX was independently associated with better overall survival (hazard ratio 0.49, 95% confidence interval 0.25-0.96; p = 0.037). FOLFIRINOX also resulted in a higher rate of severe postoperative complications. CONCLUSIONS: In this retrospective study, a FOLFIRINOX regimen as NACT seemed to result in better long-term outcomes for CRPM patients after complete CRS/HIPEC, although with higher morbidity. Prospective studies are needed, including groups without NACT and those with FOLFIRINOX + bevacizumab.

Study of Thoracic CT in COVID-19: The STOIC Project.

Background There are conflicting data regarding the diagnostic performance of chest CT for COVID-19 pneumonia. Disease extent at CT has been reported to influence prognosis. Purpose To create a large publicly available data set and assess the diagnostic and prognostic value of CT in COVID-19 pneumonia. Materials and Methods This multicenter, observational, retrospective cohort study involved 20 French university hospitals. Eligible patients presented at the emergency departments of the hospitals involved between March 1 and April 30th, 2020, and underwent both thoracic CT and reverse transcription-polymerase chain reaction (RT-PCR) testing for suspected COVID-19 pneumonia. CT images were read blinded to initial reports, RT-PCR, demographic characteristics, clinical symptoms, and outcome. Readers classified CT scans as either positive or negative for COVID-19 based on criteria published by the French Society of Radiology. Multivariable logistic regression was used to develop a model predicting severe outcome (intubation or death) at 1-month follow-up in patients positive for both RT-PCR and CT, using clinical and radiologic features. Results Among 10 930 patients screened for eligibility, 10 735 (median age, 65 years; interquartile range, 51-77 years; 6147 men) were included and 6448 (60%) had a positive RT-PCR result. With RT-PCR as reference, the sensitivity and specificity of CT were 80.2% (95% CI: 79.3, 81.2) and 79.7% (95% CI: 78.5, 80.9), respectively, with strong agreement between junior and senior radiologists (Gwet AC1 coefficient, 0.79). Of all the variables analyzed, the extent of pneumonia at CT (odds ratio, 3.25; 95% CI: 2.71, 3.89) was the best predictor of severe outcome at 1 month. A score based solely on clinical variables predicted a severe outcome with an area under the curve of 0.64 (95% CI: 0.62, 0.66), improving to 0.69 (95% CI: 0.6, 0.71) when it also included the extent of pneumonia and coronary calcium score at CT. Conclusion Using predefined criteria, CT reading is not influenced by reader's experience and helps predict the outcome at 1 month. ClinicalTrials.gov identifier: NCT04355507 Published under a CC BY 4.0 license. Online supplemental material is available for this article. See also the editorial by Rubin in this issue.

Multicystic peritoneal mesothelioma treated with cytoreductive surgery followed or not by hyperthermic intraperitoneal chemotherapy: results from a large multicentric cohort.

BACKGROUND: Multicystic peritoneal mesothelioma (MCPM) is a rare, slowly growing, condition prone to recur after surgery. The role of hyperthermic intraperitoneal chemotherapy (HIPEC) added to complete cytoreductive surgery (CRS) remains controversial and difficult to assess. As patients are mostly reproductive age women, surgical approach, and fertility considerations are important aspects of the management. This observational retrospective review aimed to accurate treatment strategy reflections. METHODS: The RENAPE database (French expert centers network) was analyzed over a 1999-2019 period. MCPM patients treated with CRS were included. A special focus on HIPEC, mini-invasive approach, and fertility considerations was performed. RESULTS: Overall 60 patients (50 women) were included with a median PCI of 10 (4-14) allowing 97% of complete surgery, followed by HIPEC in 82% of patients. A quarter of patients had a laparoscopic approach. Twelve patients (20%) recurred with a 3-year recurrence free survival of 84.2% (95% confidence interval 74.7-95.0). The hazard of recurrence was numerically reduced among patients receiving HIPEC, however, not statistically significant (hazard ratio 0.41, 0.12-1.42, p = 0.200). A severe post-operative adverse event occurred in 22% of patients with five patients submitted to a subsequent reoperation. Among four patients with a childbearing desire, three were successful (two had a laparoscopic-CRS-HIPEC and one a conventional CRS without HIPEC). CONCLUSION: MCPM patients treatment should aim at a complete CRS. The intraoperative treatment options as laparoscopic approach, fertility function sparing and HIPEC should be discussed in expert centers to propose the most appropriate strategy.

Clinical and Radiologic Predictors of a Pathologic Complete Response to Neoadjuvant Chemotherapy (NACT) in Patients Undergoing Cytoreductive Surgery for Colorectal Peritoneal Metastases: Results of a Prospective Multi-center Study.

BACKGROUND: Patients undergoing cytoreductive surgery for colorectal peritoneal metastases who have a pathologic complete response (pCR) to neoadjuvant chemotherapy experience a significantly longer survival than those with residual disease. This response is known only after surgery. This study aimed to examine clinical and radiologic predictors of a pCR. METHODS: From July 2018 to December 2019, the study prospectively enrolled 120 patients. The clinical and radiologic findings were compared between patients with and without a pCR. A protocol for pathologic evaluation was followed. RESULTS: A pCR was observed in 34 patients (28.3%). Receiver operating characteristic (ROC) curves showed that patients with a surgical Peritoneal Cancer Index (sPCI) of 3 or lower had an 80% probability of experiencing a pCR, and that patients with a radiologic PCI (rPCI) of 2 or lower had a 70% probability of experiencing a pCR. A pCR was correctly predicted for 47% of the patients by imaging and for 44.4% of the patients by surgical evaluation. The site of primary tumor, the timing of peritoneal metastasis (PM), histology, tumor marker positivity, and mutations in known poor prognostic genes (KRAS) did not differ between the patients with and those without pCR. The primary tumor showed residual disease in 23.5% and regional nodes in 26.4% of the patients with pCR. CONCLUSIONS: The rPCI and sPCI concurred with a pCR in less than 50% of the patients. The patients with a lower PCI had greater concordance. An sPCI of 3 or lower was predictive of a pCR in 80% of the patients. The impact of KRAS mutations on pCR should be evaluated in a larger series. The predictors of pCR and response to systemic chemotherapy should be incorporated in prognostic scores used to select patients for surgery.

Preoperative assessment of splenic involvement in patients with peritoneal carcinomatosis with CT and MR imaging.

PURPOSE: To estimate the performances of computed tomography (CT) and magnetic resonance imaging (MRI) and those of the combination of CT with MRI in the identification of splenic involvement in patients with peritoneal carcinomatosis (PC). MATERIAL AND METHOD: CT and MRI examinations of 26 patients with PC with splenic involvement and 26 patients with PC and no splenic involvement treated by total cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) were reviewed. There were 32 women and 20 men with a mean age of 53.44 ± 12.22 (SD) years (range: 20-73 years). Imaging examinations were reviewed separately as three independent imaging sets (CT only, MRI only and CT with MRI) by two independent readers. A consensus was reached during a joint reading session and these results were used for determining the performances of the three imaging sets in the diagnosis of splenic involvement using surgical and histopathological findings as standard of reference. RESULTS: Splenic involvement was histologically proven in 26/52 patients (50%). There were no significant differences in sensitivity, specificity and accuracy for the diagnosis of splenic involvement between CT, MRI and CT + MRI, with respectively 84.62%, 96.15% and 90.00% for CT, 84.62%, 84.62% and 85.00% for MRI and 92.31%, 92.31% and 92.00% for CT + MRI. CONCLUSION: CT and MRI have similar sensitivities, specificites and accuracies for the diagnosis of splenic involvement in patients with PC. The combination of CT and MRI does not significantly improve the preoperative diagnosis of splenic involvement in patients with PC compared to CT only.

Overall survival of pseudomyxoma peritonei and peritoneal mesothelioma patients after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy can be predicted by computed tomography quantified sarcopenia.

BACKGROUND: Malnutrition is associated with increased postoperative morbidity in abdominal surgery. This study aimed to determine if sarcopenia and/or abdominal fat composition could predict postoperative outcomes for patients undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) for pseudomyxoma peritonei (PMP) and peritoneal mesothelioma (PM). METHODS: All patients who underwent a complete CRS-HIPEC for PMP and PM, between January 2009 and September 2017, were retrospectively studied. Preoperative computed tomography (CT) was used to measure the cross-sectional surface of skeletal muscle mass and adipose tissue (visceral and subcutaneous), at the level of the third lumbar vertebrae, to assess for sarcopenia and abdominal fat composition. RESULTS: Among 115 patients, 82 were treated for PMP and 33 for PM. 64 patients (55.7%) were sarcopenic on the preoperative imagery. Major postoperative complications occurred in 63 patients (54.8%), without observable difference between sarcopenic and non-sarcopenic patients (56.2% vs. 52.9%; p = 0.723). The median overall survival (OS) was 73.3 for the patients with a normal muscle mass and 57.2 months for the sarcopenic patients (p = 0.05). CONCLUSION: CT measured sarcopenia is an independent predictive factor for overall survival in patients treated for PMP and PM with CRS-HIPEC, but cannot predict postoperative morbidity.

Prediction of Resectability in Pseudomyxoma Peritonei with a New CT Score.

BACKGROUND: Curative treatment of pseudomyxoma peritonei (PMP) is complete cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC). OBJECTIVE: The aim of this study was to build and evaluate a preoperative imaging score to predict resectability. PATIENTS AND METHODS: Between 2007 and 2014, all PMP patients in two tertiary reference centers who underwent laparotomy with intent to undergo CRS and HIPEC were included in this study retrospectively. Thickness of tumor burden was measured on preoperative multidetector-row computed tomography (MDCT) by two radiologists blinded to surgical results in five predetermined areas. Patients were divided into two cohorts with the same resectability rate (building and validation). The performances of the scores were assessed using receiver operating characteristic (ROC) curve analyses. RESULTS: Overall, 126 patients were included, with compete CRS being achieved in 91/126 patients (72.2%). Two cohorts of 63 patients matched by age, sex, burden of disease, resectability rate, and pathological grade were constituted. The MDCT score was the sum of the five measures, and was higher in unresectable disease [median 46.2 mm (range 27.9-74.6) vs. 0.0 mm (range 0.0-14.0), p < 0.001]. Area under the ROC curve was 0.863 (range 0.727-0.968) and 0.801 (range 0.676-0.914) in the building and validation cohorts, respectively. A threshold of 28 mm yielded a sensitivity, specificity, positive predictive and negative predictive value of 94, 81, 81 and 94% in the building cohort, and 80, 68, 59 and 85% in the validation cohort, respectively. Using our score, overall and disease-free survival were increased in the group classified as resectable. CONCLUSION: A simple preoperative MDCT score measuring tumor burden in the perihepatic region is able to predict resectability and survival of PMP patients.

Preoperative nutritional risk assessment in patients undergoing cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy for colorectal carcinomatosis.

BACKGROUND: Malnutrition is associated with increased postoperative morbidity in colorectal surgery. This study aimed to determine if preoperative nutritional markers could predict postoperative outcomes for patients undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) for peritoneal metastasis (PM) of colorectal origin. METHODS: All patients who underwent a complete CRS-HIPEC for colorectal PM between January 2009 and December 2014 were evaluated. Preoperative clinical and biological nutritional factors, including Body Mass Index (BMI), preoperative albumin and prealbumin levels were analysed. Preoperative computed tomography was used to measure the cross-sectional surface of the visceral and subcutaneous adipose tissue, at the third lumbar vertebrae, to assess the abdominal fat composition. Skeletal muscle mass was measured to assess for sarcopenia. RESULTS: Among 214 patients, 14 (6.5%) had a BMI ≥ 35 kg/m2, 90 (42%) were sarcopenic, 19 (9%) presented albumin <35 g/L and 2 (1%) had pre-albumin <20 mg/dL. Median values for visceral and subcutaneous fat surfaces were 99.2 cm2 and 198 cm2, respectively. Hypoalbuminemia was associated with worse overall survival (23 vs. 59 months, p = 0.015). The other nutritional factors did not impact overall or progression free survival after CRS-HIPEC for colorectal PM. In multivariate analysis, major post-operative complication and hypoalbuminemia were independently associated with decreased overall survival. CONCLUSIONS: Hypoalbuminemia appears as a strong predictive factor for decreased overall survival in patients presenting PM of colorectal origin undergoing CRS-HIPEC.

Total Mesenteric Peritonectomy for Peritoneal Metastases (with video).

BACKGROUND: Complete cytoreductive surgery (CRS), combining organ resection and peritonectomy, is the only potentially curative treatment for patients with peritoneal metastases (PM).1 , 2 Diffuse mesenteric PM usually represents a contraindication for CRS.3 This report presents a standardized total mesenteric peritonectomy, which provides a therapeutic option of complete CRS for patients with diffuse mesenteric PM. PATIENT: A 73-year-old man had a diagnosis of PM caused by an urachal adenocarcinoma (signet cell type). Initial assessment found a 60-mm urachal tumor above the dome of the urinary bladder. Dedicated magnetic resonance imaging (MRI)4 and explorative laparoscopy confirmed the presence of diffuse mucinous PM suspected of pseudomyxoma peritonei arising from urachus. The patient was treated by a systemic induction chemotherapy including cisplatin, fluorouracil, and docetaxel, with an almost full regression of the PM shown on control MRI. The man then was treated with CRS and hyperthermic intraperitoneal chemotherapy.5 TECHNIQUE: Exploration found persistent diffuse macro-nodular PM with a good response to chemotherapy, a 16/39 peritoneal cancer index,6 and no digestive tract or other organ involvement. The CRS procedure included complete urachus resection, together with appendicectomy, cholecystectomy, omentectomy, and a total parietal and mesenteric peritonectomy, with a completeness of cytoreduction score6 of 1, as illustrated in the video. At this writing, after 6 months of follow-up evaluation, the patient remains free of symptomatic peritoneal disease or local recurrence. CONCLUSION: Total mesenteric peritonectomy can be safely performed with the reported technique irrespective of how widespread PM is along the mesentery as long as few small bowel serous membranes are involved.

Splenectomy Increases Postoperative Complications Following Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy.

BACKGROUND: Complete cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS + HIPEC) is increasingly performed on patients with peritoneal carcinomatosis of various origins. Splenectomy often is required in these patients to achieve complete tumor removal. Although splenectomy has been associated with increased morbidity in many major abdominal surgeries, its effect in patients undergoing CRS + HIPEC is unknown. The purpose of this study was to evaluate the impact of splenectomy during CRS + HIPEC on postoperative outcomes. METHODS: We retrospectively identified 39 patients who underwent CRS + HIPEC with splenectomy during a 3-year study period from a prospective database. We compared them to case controls (CRS + HIPEC without splenectomy) that were matched for the complexity of the procedure. We evaluated the complication rate and outcomes of patients in each group. RESULTS: During the study period, splenectomy was performed in 32 % of patients undergoing CRS + HIPEC procedure. Patients in the splenectomy group experienced more grade 3-4 complications than patients in the control group (59 vs. 35.9 %, p = 0.041) as well as more pulmonary complications (41 vs. 7.7 %, p = 0.0006). Multivariate analysis identified splenectomy as the only predictor of overall major complications (odds ratio = 2.57, 95 % confidence interval = 1.03-6.40). Mortality was similar in both groups. CONCLUSIONS: Splenectomy increases major complication rate in patients undergoing CRS + HIPEC and efforts should be made to preserve the spleen during the surgery.