Utility of Circulating Tumor DNA Assessment in Characterizing Recurrence Sites after Optimal Resection for Metastatic Colorectal Cancer.

BACKGROUND: Plasma circulating tumor DNA (ctDNA) is a promising biomarker for metastatic colorectal cancer (mCRC); however, its role in characterizing recurrence sites after mCRC resection remains poorly understood. This single-institution study investigated the timing of ctDNA detection and its levels in the context of recurrence at different sites after mCRC resection. STUDY DESIGN: Patients who underwent optimal resection of CRC metastases involving the peritoneum, distant lymph nodes, or liver, with serial postoperative tumor-informed ctDNA assessments (Signatera) were included. Recurrence sites, as defined by surveillance imaging or laparoscopy, were categorized as peritoneal-only and other distant sites (liver, lung, lymph nodes, or body wall). RESULTS: Among the 31 included patients, ctDNA was detected in all 26 (83.4%) patients with postoperative recurrence and was persistently undetectable in 5 patients who did not experience recurrence. At 3 months postsurgery, ctDNA was detected in 2 (25%) of 8 patients with peritoneal-only recurrence and 17 (94.4%) of 18 patients with distant recurrence (p < 0.001). Beyond 3 months, ctDNA was detected in the remaining 6 patients with peritoneal-only disease and 1 patient with distant disease. ctDNA detection preceded the clinical diagnosis of recurrence by a median of 9 weeks in both groups. At recurrence, peritoneal-only recurrent cases exhibited lower ctDNA levels (median 0.4 mean tumor molecules/mL, interquartile range 0.1 to 0.8) compared with distant recurrence (median 5.5 mean tumor molecules/mL, interquartile range 0.8 to 33.3, p = 0.004). CONCLUSIONS: Peritoneal-only recurrence was associated with delayed ctDNA detection and low levels of ctDNA after optimal resection for mCRC. ctDNA testing may effectively characterize recurrence sites and may help guide subsequent treatments specific to the disease sites involved.

A Novel Assessment of Metabolic Pathways in Peritoneal Metastases from Low-Grade Appendiceal Mucinous Neoplasms.

BACKGROUND: There is a paucity of targeted therapies for patients with pseudomyxoma peritonei (PMP) secondary to low-grade appendiceal mucinous neoplasms (LAMNs). Dysregulated metabolism has emerged as a hallmark of cancer, and the relationship of metabolomics and cancer is an area of active scientific exploration. We sought to characterize phenotypic differences found in peritoneal metastases (PM) derived from LAMN versus adenocarcinoma. METHODS: Tumors were washed with phosphate-buffered saline (PBS), microdissected, then dissociated in ice-cold methanol dried and reconstituted in pyridine. Samples were derivatized in tert-butyldimethylsilyl (TBDMS) and subjected to gas chromatography-coupled mass spectrometry. Metabolites were assessed based on a standard library. RNA sequencing was performed, with pathway and network analyses on differentially expressed genes. RESULTS: Eight peritoneal tumor samples were obtained and analyzed: LAMNs (4), and moderate to poorly differentiated adenocarcinoma (colon [1], appendix [3]). Decreases in pyroglutamate, fumarate, and cysteine in PM from LAMNs were found compared with adenocarcinoma. Analyses showed the differential gene expression was dominated by the prevalence of metabolic pathways, particularly lipid metabolism. The gene retinol saturase (RETSAT), downregulated by LAMN, was involved in the multiple metabolic pathways that involve lipids. Using network mapping, we found IL1B signaling to be a potential top-level modulation candidate. CONCLUSIONS: Distinct metabolic signatures may exist for PM from LAMN versus adenocarcinoma. A multitude of genes are differentially regulated, many of which are involved in metabolic pathways. Additional research is needed to identify the significance and applicability of targeting metabolic pathways in the potential development of novel therapeutics for these challenging tumors.

Impact of cumulative complications on 1-year treatment-related healthcare costs in patients with colorectal peritoneal metastases undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy.

BACKGROUND: The aim of this study was to evaluate the impact of all minor and major complications on treatment-related healthcare costs in patients who undergo cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) for the treatment of colorectal peritoneal metastases (PMs). METHOD: Patients with histologically proven colorectal PMs who underwent CRS + HIPEC from March 2006 to October 2019 in a tertiary referral centre were retrospectively identified from a prospectively maintained database. Patients were divided into six subgroups according to the severity of the complications, which were scored using the comprehensive complication index (CCI) (CCI 0-9.9, CCI 10-19.9, CCI 20-29.9, CCI 30-39.9, CCI 40-49.9, and CCI 50 or higher). Treatment-related healthcare costs up to 1 year after CRS + HIPEC were obtained from the financial department. Differences in costs and survival outcomes were compared using the chi-squared test and Kruskal-Wallis H test. RESULTS: A total of 142 patients were included (CCI 0-9.9, 53 patients; CCI 10-19.9, 0 patients; CCI 20-29.9, 45 patients; CCI 30-39.9, 14 patients; CCI 40-49, 9 patients; and CCI 50 or higher, 21 patients). Median (interquartile range) treatment-related healthcare costs increased significantly and exponentially for the CCI 30-39, CCI 40-49, and CCI 50 or higher groups (€48 993 (€44 262-€84 805); €57 167 (€43 047-€67 591); and €82 219 (€55 487-€145 314) respectively) compared with those for the CCI 0-9.9 and CCI 20-29.9 groups (€33 856 (€24 433-€40 779) and €40 621 (€31 501-€58 761) respectively, P < 0.010). CONCLUSION: Treatment-related healthcare costs increase exponentially as more complications develop among patients who undergo CRS + HIPEC for the treatment of colorectal PMs. Anastomotic leakages after CRS + HIPEC lead to an increase of 295 per cent of treatment-related healthcare costs.

Assessment of postoperative pain after pressurized intraperitoneal aerosol chemotherapy (PIPAC) in the treatment of peritoneal metastasis.

PURPOSE: Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a new surgical technique, for the treatment of initially unresectable peritoneal metastasis (PM). Our objective was to assess postoperative pain and morbidity. METHODS: Between July 2016 and September 2020, data from 100 consecutive PIPAC procedures with oxaliplatin (PIPAC Ox) or doxorubicin-cisplatin (PIPAC C/D) in 49 patients with PM (all etiologies) were analyzed. Pain was self-assessed using a visual analog scale (VAS) of 0-10. RESULTS: The median PIPAC procedures per patient were 2 [1-3]. Patients indicated greatest pain at 4 pm on the day of the procedure (D0) and on postoperative D1 at 8 am and 4 pm. Postprocedural moderate-to-severe pain (VAS 4-10) was more frequent with PIPAC Ox than with PIPAC C/D, respectively 14 (36.8%) vs 7 (13.5%); p = 0.010. Hospitalization was longer for patients with moderate-to-severe pain than for others (median 4 days [3-7] vs 3 days [2-4], p = 0.004). Multivariate analysis identified oxaliplatin as a factor associated with greater pain (OR [95% CI], 2.95 [1.10-7.89]. Opiate administration was similar after PIPAC Ox and PIPAC C/D procedures, p = 0.477. CONCLUSION: PIPAC was well-tolerated, and pain was well-controlled in the majority of patients. Pain was greatest at 4 pm on D0 and 8 am and 4 pm on D1. PIPAC Ox is associated with greater pain than PIPAC C/D, independently of opiate treatment. Moderate-to-severe pain was associated with longer hospital stays.

Assessment of the use of computed tomography colonography in early detection of peritoneal metastasis in patients with gastric cancer: A prospective cohort study.

Peritoneal metastasis (PM) is one of the most frequent forms of gastric cancer recurrence. In this study, we aimed to use computed tomography (CT) colonography (CTC) to detect signs of PM earlier in patients in whom PM was suspected but not yet diagnosed. CTC was used to evaluate patients with clinical symptoms or general CT findings that were suspicious but not sufficient to confirm PM. In total, 18 patients with suspected PM were enrolled. Ten patients (55.6%) had PM on CTC. Abnormal colonic deformities were identified at locations other than those of the lesions detected by general CT in seven patients. The sensitivity and specificity of CTC for the detection of PM were 83.3% and 100%, respectively. The median overall survival after CTC was 201 days in the CTC-positive group, which was significantly shorter than that in the CTC-negative group (945 days, p = 0.01). In the multivariate analysis, a positive CTC finding was the only factor independently associated with survival (p = 0.005). According to our experience with 18 patients, CTC can be an alternative to conventional imaging for early detection of PM. Further prospective studies with larger sample sizes are warranted to confirm and validate these findings. University hospital Medical Information Network Clinical Trials Registry (UMIN-CTR): Registration number: UMIN000044167.

Quantitative Indocyanine Green Fluorescence Imaging Assessment for Nonmucinous Peritoneal Metastases: Preliminary Results of the ICCP Study.

BACKGROUND: In selected patients with peritoneal metastases of colorectal origin, complete cytoreduction has been the main single prognostic factor influencing long-term outcomes. In these patients, indocyanine green fluorescence imaging seems to be useful in detecting small subclinical peritoneal implants. However, quantitative fluorescence analysis has not yet been established as standard. OBJECTIVE: This study aimed to evaluate the sensitivity and specificity of quantitative indocyanine green fluorescence assessment in the detection of peritoneal metastases of nonmucinous colorectal origin. DESIGN: This is a single-center, single-arm, low-intervention prospective trial. SETTINGS: A fluorescence assessment device was used for intraoperative fluorescence quantitative assessment. PATIENTS: Consecutive patients diagnosed with peritoneal metastases of colorectal origin who met the inclusion criteria were selected for curative surgery. INTERVENTIONS: Intravenous indocyanine green was administered 12 hours before surgery. Cytoreduction was performed through nodule identification under white light and then under indocyanine green. Finally, ex vivo fluorescence was assessed. MAIN OUTCOME MEASURES: The primary outcomes measured were the sensitivity and specificity of quantitative fluorescence. RESULTS: The first 11 enrolled patients were included in this preliminary analysis. In total, 52 nodules were resected, with 37 (71.1%) being diagnosed as malignant in the histopathological analysis. Of those, 5 (13.5%) were undetectable under white light and were identified only with fluorescence. A total of 15 nonmalignant nodules were detected under white light, 8 (53.3%) of which were fluorescence negative. Fluorescence greater than 181 units might be the threshold of malignancy, with a sensitivity and specificity of 89.0% and 85.0%, whereas uptake less than 100 units appears to correlate with a benign pathology. LIMITATIONS: The limited sample size, the physiological uptake, and excretion of indocyanine green might interfere with the assessment of unnoticed implants in the bowel serosa and liver. CONCLUSIONS: Quantitative indocyanine green seems to be useful for the assessment of nonmucinous colorectal peritoneal metastases. Fluorescence uptake greater than 181 units appears to correlate with malignancy, whereas uptake less than 100 units appears to correlate with a benign pathology. See Video Abstract at http://links.lww.com/DCR/B743. EVALUACIN CUANTITATIVA DE IMGENES DE FLUORESCENCIA CON VERDE DE INDOCIANINA PARA METSTASIS PERITONEALES NO MUCINOSAS RESULTADOS PRELIMINARES DEL ESTUDIO ICCP: ANTECEDENTES:En pacientes seleccionados con metástasis peritoneales de origen colorrectal, la citorreducción com-pleta ha sido el único factor pronóstico principal que influye en el resultado a largo plazo. En estos pacientes, las imágenes de fluorescencia con verde de indocianina parecen ser útiles para detectar pequeños implantes peritoneales subclínicos. Sin embargo, el análisis cuantitativo de fluorescencia aún no se ha establecido como estándar.OBJETIVO:Evaluar la sensibilidad y especificidad de la evaluación cuantitativa de fluorescencia verde de indo-cianina, en la detección de metástasis peritoneales de origen colorrectal no mucinoso.DISEÑO:Ensayo prospectivo de intervención baja de un solo brazo y un solo centro.ENTORNO CLINICO:El dispositivo se utilizó para la evaluación cuantitativa de fluorescencia intraoperatoria.PACIENTES:Pacientes consecutivos diagnosticados con metástasis peritoneales de origen colorrectal, selecciona-dos para cirugía curativa y que cumplieron con los criterios de inclusión.INTERVENCIONES:Se administró verde de indocianina por vía intravenosa 12 h antes de la cirugía. La citorreducción se realizó mediante identificación de nódulos con luz blanca y luego con verde de indocianina. Final-mente, se evaluó la fluorescencia ex vivo.PRINCIPALES MEDIDAS DE VALORACION:Sensibilidad y especificidad cuantitativa de la fluorescencia.RESULTADOS:Los primeros 11 pacientes fueron incluidos en este análisis preliminar. En total se resecaron 52 nódu-los, siendo 37 (71,1%) diagnosticados como malignos en el análisis histopatológico. De ellos, 5 (13,5%) eran indetectables bajo luz blanca y solamente se identificaron con fluorescencia. Se detec-taron un total de 15 nódulos no malignos bajo luz blanca, de los cuales 8 (53,3%) fueron fluorescen-tes negativos. La fluorescencia superior a 181 unidades podría ser el umbral de malignidad, con una sensibilidad y especificidad del 89,0% y el 85,0% respectivamente; mientras que la captación por debajo de 100 unidades parece correlacionarse con una patología benigna.LIMITACIONES:El tamaño limitado de la muestra; la captación fisiológica y la excreción de verde de indocianina pueden interferir con la evaluación de implantes inadvertidos en la serosa intestinal y el hígado.CONCLUSIONES:La cuantificación del verde de indocianina, parece ser útil en la evaluación de metástasis peritonea-les colorrectales no mucinosas. La captación de fluorescencia por encima de 181 unidades parece correlacionarse con la malignidad, mientras que la captación por debajo de 100 unidades parece co-rrelacionarse con una patología benigna. Consulte Video Resumen en http://links.lww.com/DCR/B743. (Traducción - Dr. Fidel Ruiz Healy).

Cost-effectiveness analysis of pressurized intraperitoneal aerosol chemotherapy (PIPAC) in patients with gastric cancer and peritoneal metastasis.

OBJECTIVE: The aim of this study was to assess the cost-effectiveness of pressurized intraperitoneal aerosol chemotherapy with low-dose cisplatin and doxorubicin (PIPAC C/D) for the treatment of advanced gastric cancer. METHODS: A Partitioned Survival Model followed by state transition Markov model was developed to estimate the costs and effectiveness of the use of PIPAC C/D versus palliative chemotherapy in the UK. The intervention was assessed at two different levels of care, including upfront therapy (PIPAC C/D plus Oxaliplatin in combination with Capecitabine (XELOX) chemotherapy versus first-line chemotherapy alone) and second-line therapy (PIPAC C/D alone versus second-line chemotherapy (ramucirumab monotherapy)). Data from multiple sources, including published literature and UK-based databases, were used to inform the economic model. RESULTS: For the upfront therapy analysis, the estimated total costs in the intervention and comparator arms were £32,606 (SD: £3877) and £17,844 (SD: £920), respectively. PIPAC C/D plus XELOX led to an increase of 0.46 in quality-adjusted life-years (QALYs) gained. The incremental cost per QALY gained was £31,868. For the second-line therapy analysis, the use of PIPAC C/D led to an increase of 0.19 in QALYs and a £21,474 reduction in costs, meaning the intervention was a dominant strategy. CONCLUSIONS: The cost-effectiveness results for the upfront therapy analysis indicate that PIPAC C/D plus chemotherapy is a cost-effective strategy. Additionally, PIPAC C/D alone as a second-line therapy has the potential to reduce costs and improve clinical outcomes for patients with advanced gastric cancer with peritoneal metastasis.

Assessment of peritoneal metastases with DW-MRI, CT, and FDG PET/CT before cytoreductive surgery for advanced stage epithelial ovarian cancer.

BACKGROUND: Preoperative assessment of peritoneal metastases is an important factor for treatment planning and selection of candidates for cytoreductive surgery (CRS) in primary advanced stage (FIGO stages III-IV) epithelial ovarian cancer (EOC). The primary aim was to evaluate the efficacy of DW-MRI, CT, and FDG PET/CT used for preoperative assessment of peritoneal cancer index (PCI). MATERIAL AND METHODS: In this prospective observational cohort study, 50 advanced stage EOC patients were examined with DW-MRI and FDG PET/CT with contrast enhanced CT as part of the diagnostic program. All patients were deemed amenable for upfront CRS. Imaging PCI was determined for DW-MRI, CT, and FDG PET/CT by separate readers blinded to the surgical findings. The primary outcome was agreement between the imaging PCI and PCI determined at surgical exploration (the reference standard) evaluated with Bland-Altman statistics. RESULTS: The median surgical PCI was 18 (range: 3-32). For all three imaging modalities, the imaging PCI most often underestimated the surgical PCI. The mean differences between the surgical PCI and the imaging PCI were 4.2 (95% CI: 2.6-5.8) for CT, 4.4 (95% CI: 2.9-5.8) for DW-MRI, and 5.3 (95% CI: 3.6-7.0) for FDG PET/CT, and no overall statistically significant differences were found between the imaging modalities (DW-MRI - CT, p = 0.83; DW-MRI - FDG PET/CT, p = 0.24; CT - FDG PET/CT, p = 0.06). CONCLUSION: Neither DW-MRI nor CT nor FDG PET/CT was superior in preoperative assessment of the surgical PCI in patients scheduled for upfront CRS for advanced stage EOC.

Next-generation sequencing and histological response assessment in peritoneal metastasis from pancreatic cancer treated with PIPAC.

BACKGROUND: Peritoneal metastasis from pancreatic cancer (PM-PC) may be treated with repeated pressurised intraperitoneal aerosol chemotherapy (PIPAC). Utility of next-generation sequencing (NGS) to detect cancer-related mutations in peritoneal quadrant biopsies (QBs) and peritoneal fluid (PF) after systemic and PIPAC treatment has not been evaluated. Around 90% of pancreatic cancers (PCs) harbour a KRAS mutation, making PC ideal for the evaluation of this aspect. AIMS: Evaluation of PM-PC in terms of (1) histological response to PIPAC using Peritoneal Regression Grading Score (PRGS), (2) clinical characteristics and (3) frequency of mutations in QBs and PF before and after PIPAC. METHODS: Peritoneal QBs and PF were obtained prior to each PIPAC. NGS for 22 cancer-related genes was performed on primary tumours, QBs and PFs. Response was assessed by the four-tiered PRGS. RESULTS: Sixteen patients treated with a median of three PIPAC procedures were included. The mean PRGS was reduced from 1.91 to 1.58 (p=0.02). Fifty-seven specimens (13 primary tumours, 2 metastatic lymph nodes, 16 PFs and 26 QB sets) were analysed with NGS. KRAS mutation was found in 14/16 patients (87.50%) and in QBs, primary tumours and PF in 8/12 (66.67%), 8/13 (61.53%) and 6/9 (66.67%). The median overall survival was 9.9 months (SE 1.5, 95% CI 4.9 to 13.9). CONCLUSION: PIPAC induces histological response in the majority of patients with PM-PC. KRAS mutation can be found in PM-PC after PIPAC at a frequency similar to the primaries. NGS may be used to detect predictive mutations in PM-PC of various origins, also when only post-PIPAC QBs or PFs are available.

A decision analysis comparing three strategies for peritoneal lavage cytology testing in staging of gastric cancer in China.

BACKGROUND: Positive peritoneal cytology (PCY) indicates metastasis (M1) in gastric cancer (GC) patients; both the American and Chinese guidelines recommend laparoscopic peritoneal lavage (LPL) for cytology. However, relatively high costs impair the widespread use of LPL in some resource-limited regions in China, and the cost-effectiveness of PCY testing remains unclear. Therefore, we performed a decision analysis to evaluate the cost-effectiveness of PCY testing by comparing the guideline-recommended intraoperative LPL, a newly proposed preoperative percutaneous peritoneal lavage (PPL), and a third strategy of exploratory laparotomy with no cytology testing (ELNC) among GC patients. METHODS: We developed a decision-analytic Markov model of the aforementioned three strategies for a hypothetical cohort of GC patients with curative intent after initial imaging, from the perspective of Chinese society. We estimated costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs) as primary outcomes; we also conducted one-way and probabilistic sensitivity analyses to investigate the model's robustness. RESULTS: We found that ELNC was dominated (i.e., more expensive and less effective) by PPL and LPL. LPL was the most cost-effective method with an ICER of US$17,200/QALY compared to PPL, which was below the Chinese willingness-to-pay (WTP) threshold of US$29,313 per QALY gained. In sensitivity analyses, PPL was more likely to be cost-effective with a lower WTP threshold. CONCLUSIONS: Cytology testing through either LPL or PPL was less expensive and more effective than ELNC among GC patients. Moreover, LPL was the most cost-effective modality at the current WTP threshold, while PPL could potentially be cost-effective in lower-income areas.

Impact of extent of disease on 1-year healthcare costs in patients who undergo cytoreductive surgery with hyperthermic intraperitoneal chemotherapy for colorectal peritoneal metastases: retrospective observational cohort study.

BACKGROUND: The goal of this retrospective observational study was to determine the impact of the extent of peritoneal disease on 1-year healthcare costs in patients with colorectal peritoneal metastases (PM) who undergo cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS + HIPEC). The extent of peritoneal disease, expressed by the Peritoneal Cancer Index (PCI), directly affects the complexity of CRS + HIPEC and ultimately survival outcomes. The impact of the PCI on treatment-related healthcare costs remains unknown. METHODS: Data from patients with colorectal PM who underwent CRS + HIPEC between January 2012 and November 2017 were extracted retrospectively from an institutional database. Patients were divided into four subgroups with PCI scores ranging from 0 to 20. Treatment-related costs up to 1 year after CRS + HIPEC were obtained from the financial department. Differences in costs and survival outcomes were compared using the χ2 test and Kruskal-Wallis H test. RESULTS: Seventy-three patients were included (PCI 0-5, 22 patients; PCI 6-10, 19 patients; PCI 11-15, 17 patients; PCI 16-20, 15 patients). Median (i.q.r.) costs were significantly increased for the PCI 11-15 and PCI 16-20 groups (€51 029 (42 500-58 575) and €46 548 (35 194-60 533) respectively) compared with those for the PCI 0-5 and PCI 6-10 groups (€33 856 (25 293-42 235) and €39 013 (30 519-51 334) respectively) (P = 0·009). CONCLUSION: Treatment-related healthcare costs are significantly increased among patients with extensive tumour burden (PCI score 10 or above) who undergo CRS + HIPEC for the treatment of colorectal PM.

ANTECEDENTES: El objetivo de este estudio observacional retrospectivo fue determinar el impacto de la extensión de la enfermedad peritoneal sobre los costes de atención médica al año en pacientes con metástasis peritoneales (peritoneal metastases, PM) de origen colorrectal que se someten a cirugía citorreductora con quimioterapia intraperitoneal hipertérmica (cytoreductive surgery with hyperthermic intraperitoneal chemotherapy, CRS + HIPEC). La extensión de la enfermedad peritoneal, expresada por el índice de carcinomatosis peritoneal (peritoneal cancer index, PCI), afecta directamente a la complejidad de la CRS + HIPEC y, en última instancia, a los resultados de supervivencia. El impacto de la PCI en los costes de la atención médica relacionados con el tratamiento sigue siendo desconocido. MÉTODOS: Los datos de pacientes con PM de origen colorrectal que se sometieron a CRS + HIPEC entre enero de 2012 y noviembre de 2017 se extrajeron retrospectivamente de una base de datos institucional. Los pacientes se dividieron en cuatro subgrupos con PCI que variaron de 0 a 20. Los costes relacionados con el tratamiento hasta un año después de la CRS + HIPEC se obtuvieron del departamento financiero. Las diferencias en los costes y los resultados de supervivencia se compararon mediante los tests χ2 y de Kruskal-Wallis H. RESULTADOS: Se incluyeron 73 pacientes (PCI 0-5, 22 pacientes; PCI 6-10, 19 pacientes; PCI 11-15, 17 pacientes y PCI 16-20, 15 pacientes). Los costes medios aumentaron significativamente para los grupos PCI 11−15 y PCI 16−20 (51.029€ (rango intercuartílico, RIQ) 42.500€−58575€)) y 46.548€ (RIQ 35.194€-60.533€), respectivamente)) en comparación con los de los grupos PCI 0−5 y PCI 6-10 (33.856€ (RIQ 25.293€−42.23€) y 39.013€ (RIQ 30.519€-51.334€), respectivamente, P = 0,009). CONCLUSIÓN: Los costes de la atención médica relacionados con el tratamiento aumentan significativamente entre los pacientes con una carga tumoral extensa (es decir, PCI ≥ 10) que se someten a CRS + HIPEC para el tratamiento de PM de origen colorrectal.

Cytoreductive surgery (CRS) with hyperthermic intraoperative peritoneal chemotherapy (HIPEC) versus standard of care (SoC) in people with peritoneal metastases from colorectal, ovarian or gastric origin: protocol for a systematic review and individual participant data (IPD) meta-analyses of effectiveness and cost-effectiveness.

INTRODUCTION: There is uncertainty about whether cytoreductive surgery (CRS)+hyperthermic intraoperative peritoneal chemotherapy (HIPEC) improves survival and/or quality of life compared with standard of care (SoC) in people with peritoneal metastases who can withstand major surgery. PRIMARY OBJECTIVES: To compare the relative benefits and harms of CRS+HIPEC versus SoC in people with peritoneal metastases from colorectal, ovarian or gastric cancers eligible to undergo CRS+HIPEC by a systematic review and individual participant data (IPD) meta-analysis. SECONDARY OBJECTIVES: To compare the cost-effectiveness of CRS+HIPEC versus SoC from a National Health Service (NHS) and personal social services perspective using a model-based cost-utility analysis. METHODS AND ANALYSIS: We will perform a systematic review of literature by updating the searches from MEDLINE, Embase, Cochrane library, Science Citation Index as well as trial registers. Two members of our team will independently screen the search results and identify randomised controlled trials comparing CRS+HIPEC versus SoC for inclusion based on full texts for articles shortlisted during screening. We will assess the risk of bias in the trials and obtain data related to baseline prognostic characteristics, details of intervention and control, and outcome data related to overall survival, disease progression, health-related quality of life, treatment related complications and resource utilisation data. Using IPD, we will perform a two-step IPD, that is, calculate the adjusted effect estimate from each included study and then perform a random-effects model meta-analysis. We will perform various subgroup analyses, meta-regression and sensitivity analyses. We will also perform a model-based cost-utility analysis to assess whether CRS+HIPEC is cost-effective in the NHS setting. ETHICS AND DISSEMINATION: This project was approved by the UCL Research Ethics Committee (Ethics number: 16023/001). We aim to present the findings at appropriate international meetings and publish the review, irrespective of the findings, in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42019130504.

Radiological assessment of Peritoneal Cancer Index on preoperative CT in ovarian cancer is related to surgical outcome and survival.

PURPOSE: To evaluate whether Peritoneal Cancer Index (PCI) assessed on preoperative CT (CT-PCI) can be used as non-invasive preoperative tool to predict surgical outcome, disease-free survival (DFS) and overall survival (OS). MATERIALS AND METHODS: This is a retrospective, observational cohort study performed in a single institution. We considered all patients with diagnosis of ovarian cancer and preoperative CT, who had undergone upfront cytoreductive surgery between 2008 and 2010 and had post-operative clinical follow-up to December 2015. Two radiologists reviewed CT scans and assessed CT-PCI using Sugarbaker's diagram. We assessed the discriminatory capacity of the CT-PCI score on the surgical outcome by ROC curve analysis. DFS and OS were assessed by Kaplan-Meier nonparametric curves and by multivariable Cox-regression analysis. RESULTS: A total of 297 patients were included in the present analysis. CT-PCI was positively correlated with post-operative residual disease [odds ratio (OR) 1.04, 95% CI 1.01-1.07, p = 0.003]. ROC curve analysis returned AUC = 0.64 for the prediction of total macroscopic tumour clearance. In multivariable analysis, patients with no peritoneal disease seen on CT had a significantly longer DFS [Hazard ratio (HR) 2.28, p = 0.007]. Radiological serosal small bowel involvement was an independent predictor for shorter OS (HR 3.01, p = 0.002). CONCLUSION: Radiological PCI assessed on preoperative CT is associated with the probability of residual disease after cytoreductive surgery; however, it has low performance as a triage test to reliably identify patients who are likely to have complete cytoreductive surgery. CT-PCI is positively correlated with both DFS and OS and may be used as an independent prognostic factor, for example in patients with high FIGO stages.

Cost analysis of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy and the risk factors for their increased cost in a public insurance health care system - Single centre study.

INTRODUCTION: This study aimed to evaluate the costs of CRS and HIPEC and treatment of the related postoperative complications in the public healthcare system. We also aimed to identify the risk factors that increase the cost of CRS and HIPEC. MATERIALS AND METHODS: We retrospectively evaluated 80 patients who underwent CRS and HIPEC between February 2016 and November 2018 in the Department of Surgery, University Hospital of Olomouc, Czech Republic. Intraoperative factors and postoperative complications were assessed. The treatment cost included the surgery, hospital stay, intensive care unit (ICU) admission, pharmaceutical charges including medication, hospital supplies, pathology, imaging, and allied healthcare services. RESULTS: The postoperative morbidity rate was 50%, and the mortality rate was 2.5%. The mean length of hospitalisation and ICU admission was 15.44 ± 8.43 and 6.15 ± 4.12 for all 80 patients and 10.73 ± 2.93 and 3.73 ± 1.32, respectively, for 40 patients without complications, and 20.15 ± 13.93 and 8.58 ± 6.92, respectively, for 40 patients with complications. The total treatment cost reached €606,358, but the total reimbursement was €262,931; thus, the CRS and HIPEC profit margin was €-343,427. Multivariate analysis showed that blood loss ≥1.000 ml (p = 0.03) and grade I-V Clavien-Dindo complications (p < 0.001) were independently associated with increased costs. CONCLUSION: The Czech public health insurance system does not fully compensate for the costs of CRS and HIPEC. Hospital losses remain the main limiting factor for further improving these procedures. Furthermore, treatment costs increase with increasing severity of postoperative complications.

Assessment of the aerosol distribution pattern of a single-port device for intraperitoneal administration of therapeutic substances.

BACKGROUND: In the last 20 years, intraperitoneal chemotherapy (IPC) has been explored as a modality for the management of peritoneal metastases of gynecologic, gastrointestinal, and primary peritoneal tumors. Direct delivery of chemotherapeutic agents to the peritoneal cavity space has proved superior to systemic chemotherapy when evaluating characteristics such as drug concentration reached in the peritoneal space, penetration into peritoneal metastases, and chemotherapy-related toxicity. Traditionally, IPC is delivered by peritoneal lavage with a liquid solution. This form of delivery has limitations, including inhomogeneous intraperitoneal distribution and limited ability to penetrate tissues and metastatic nodules. An alternative mode of delivery is so-called pressurized intraperitoneal aerosol chemotherapy (PIPAC). Within this context, the present study sought to identify the pattern of spatial distribution of therapeutic solutions aerosolized into the peritoneal space using a single-port PIPAC device and ascertain whether the aerosolized method is superior to the traditional (liquid) mode of IPC delivery. METHODS: Analysis of the rate of intra-abdominal staining with aerosolized 2% silver nitrate in five porcine models. RESULTS: Assessment of differences in stain impregnation between the upper, middle, and lower abdomen did not reveal significant differences (p = 0.42). The median sum scores were 1 for the upper abdomen and 3 for the middle and lower abdomen. CONCLUSIONS: Aerosolization does not reach all regions of the abdomen homogeneously. However, adequate exposure of the upper abdomen, mid-abdomen, and lower abdomen to chemotherapeutic agents can be achieved with PIPAC.

Pathological assessment of cytoreductive surgery specimens and its unexplored prognostic potential-a prospective multi-centric study.

BACKGROUND AND AIM: The grade/histological subtype is one of the most important prognostic markers in patients undergoing cytoreductive surgery (CRS). Our aim was to study other potential prognostic information that can be derived from the pathological evaluation of CRS specimens and provide a broad outline for evaluation of these. METHODS: This prospective study (July to December 2018) included all patients undergoing cytoreductive surgery (CRS). A protocol for pathological evaluation was laid down which was based on existing practices at the participating centers and included evaluation of the pathological PCI, regional node involvement, response to chemotherapy, morphology of peritoneal metastases (PM) and distribution in the peritoneal cavity. RESULTS: In 191 patients undergoing CRS at 4 centers, the pathological and surgical PCI differed in over 75%. Nodes in relation to peritoneal disease were positive in 13.6%. Disease in normal peritoneum adjacent to tumor nodules was seen in >50% patients with ovarian cancer and mucinous apppendiceal tumors. 23.8% of evaluated colorectal PM patients had a complete response and 25.0% ovarian cancer patients had a near complete pathological response to chemotherapy. CONCLUSIONS: Pathological evaluation of extent and distribution of peritoneal disease differs from the surgical evaluation in majority of the patients. Lymph node involvement in relation of peritoneal disease is common. The morphological presentation of PM in ovarian cancer and mucinous appendiceal tumors merits evaluation of more extensive resections in these patients. Standardized methods of synoptic reporting of CRS specimens could help capture vital prognostic information that may in future influence how these patients are treated.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy versus palliative systemic chemotherapy in stomach cancer patients with peritoneal dissemination, the study protocol of a multicentre randomised controlled trial (PERISCOPE II).

BACKGROUND: At present, palliative systemic chemotherapy is the standard treatment in the Netherlands for gastric cancer patients with peritoneal dissemination. In contrast to lymphatic and haematogenous dissemination, peritoneal dissemination may be regarded as locoregional spread of disease. Administering cytotoxic drugs directly into the peritoneal cavity has an advantage over systemic chemotherapy since high concentrations can be delivered directly into the peritoneal cavity with limited systemic toxicity. The combination of a radical gastrectomy with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has shown promising results in patients with gastric cancer in Asia. However, the results obtained in Asian patients cannot be extrapolated to Western patients. The aim of this study is to compare the overall survival between patients with gastric cancer with limited peritoneal dissemination and/or tumour positive peritoneal cytology treated with palliative systemic chemotherapy, and those treated with gastrectomy, CRS and HIPEC after neoadjuvant systemic chemotherapy. METHODS: In this multicentre randomised controlled two-armed phase III trial, 106 patients will be randomised (1:1) between palliative systemic chemotherapy only (standard treatment) and gastrectomy, CRS and HIPEC (experimental treatment) after 3-4 cycles of systemic chemotherapy.Patients with gastric cancer are eligible for inclusion if (1) the primary cT3-cT4 gastric tumour including regional lymph nodes is considered to be resectable, (2) limited peritoneal dissemination (Peritoneal Cancer Index < 7) and/or tumour positive peritoneal cytology are confirmed by laparoscopy or laparotomy, and (3) systemic chemotherapy was given (prior to inclusion) without disease progression. DISCUSSION: The PERISCOPE II study will determine whether gastric cancer patients with limited peritoneal dissemination and/or tumour positive peritoneal cytology treated with systemic chemotherapy, gastrectomy, CRS and HIPEC have a survival benefit over patients treated with palliative systemic chemotherapy only. TRIAL REGISTRATION: clinicaltrials.gov NCT03348150 ; registration date November 2017; first enrolment November 2017; expected end date December 2022; trial status: Ongoing.

Can We Accurately Identify Peritoneal Metastases Based on Their Appearance? An Assessment of the Current Practice of Intraoperative Gastrointestinal Cancer Staging.

BACKGROUND: Peritoneal lesions are common findings during operative abdominal cancer staging. The decision to perform biopsy is made subjectively by the surgeon, a practice the authors hypothesized to be imprecise. This study aimed to describe optical characteristics differentiating benign peritoneal lesions from peritoneal metastases. METHODS: The study evaluated laparoscopic images of 87 consecutive peritoneal lesions biopsied during staging laparoscopies for gastrointestinal malignancies from 2014 to 2017. A blinded survey assessing these lesions was completed by 10 oncologic surgeons. Three senior investigators categorized optical features of the lesions. Computer-aided digital image processing and machine learning was used to classify the lesions. RESULTS: Of the 87 lesions, 28 (32%) were metastases. On expert survey, surgeons on the average misidentified 36 ± 19% of metastases. Multivariate analysis identified degree of nodularity, border transition, and degree of transparency as independent predictors of metastases (each p < 0.03), with an area under the receiver operating characteristics curve (AUC) of 0.82 (95% confidence interval [CI], 0.72-0.91). Image processing demonstrated no difference using image color segmentation, but showed a difference in gradient magnitude between benign and metastatic lesions (AUC, 0.66; 95% CI 0.54-0.78; p = 0.02). Machine learning using a neural network with a tenfold cross-validation obtained an AUC of only 0.47. CONCLUSIONS: To date, neither experienced oncologic surgeons nor computerized image analysis can differentiate peritoneal metastases from benign peritoneal lesions with an accuracy that is clinically acceptable. Although certain features correlate with the presence of metastases, a substantial overlap in optical appearance exists between benign and metastatic peritoneal lesions. Therefore, this study suggested the need to perform biopsy for all peritoneal lesions during operative staging, or at least to lower the threshold significantly.