Investigating locations of recurrences with MRI after CRS-HIPEC for colorectal peritoneal metastases.

PURPOSE: Patients with colorectal peritoneal metastases (PM) treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are at high risk of recurrent disease. Understanding where and why recurrences occur is the first step in finding solutions to reduce recurrence rates. Although diffusion-weighted (DW) MRI is not routinely used in the follow-up of CRC patients, it has a clear advantage over CT in detecting the location and spread of (recurrent) PM. This study aimed to identify common locations of recurrence in CRC patients after CRS-HIPEC with MRI. METHOD: This was a single-centre retrospective study of patients with recurrent PM after CRS-HIPEC performed between January 2016 and August 2020. Patients were eligible for inclusion if they had both an MRI preoperatively (MRI1) and at the time of recurrent disease (MRI2). Two abdominal radiologists reviewed in consensus and categorized recurrences according to their location on MRI2 and in correlation with previous disease location on prior imaging (MRI1) and the surgical report of the CRS-HIPEC. RESULTS: Thirty patients were included, with a median surgical PCI of 7 (range 3-21) at the time of primary CRS-HIPEC. In total, 68 recurrent metastases were detected on MRI2, of which 14 were extra-peritoneal. Of the remaining 54 PM, 42 (78%) occurred where the peritoneum was damaged due to earlier resections or other surgical procedures (e.g. inserted surgical abdominal drains). Most recurrent metastases were found in the mesentery, lower abdomen/pelvis and abdominal wall (87%). CONCLUSIONS: Most recurrent PMs appeared in the mesentery, lower abdomen/pelvis and abdominal wall, especially where the peritoneum was previously damaged.

Evolution of clinical nature, treatment and survival of locally recurrent rectal cancer: Comparative analysis of two national cross-sectional cohorts.

BACKGROUND: In the Netherlands, use of neoadjuvant radiotherapy for rectal cancer declined after guideline revision in 2014. This decline is thought to affect the clinical nature and treatability of locally recurrent rectal cancer (LRRC). Therefore, this study compared two national cross-sectional cohorts before and after the guideline revision with the aim to determine the changes in treatment and survival of LRRC patients over time. METHODS: Patients who underwent resection of primary rectal cancer in 2011 (n = 2094) and 2016 (n = 2855) from two nationwide cohorts with a 4-year follow up were included. Main outcomes included time to LRRC, synchronous metastases at time of LRRC diagnosis, intention of treatment and 2-year overall survival after LRRC. RESULTS: Use of neoadjuvant (chemo)radiotherapy for the primary tumour decreased from 88.5% to 60.0% from 2011 to 2016. The 3-year LRRC rate was not significantly different with 5.1% in 2011 (n = 114, median time to LRRC 16 months) and 6.3% in 2016 (n = 202, median time to LRRC 16 months). Synchronous metastasis rate did not significantly differ (27.2% vs 33.7%, p = 0.257). Treatment intent of the LRRC shifted towards more curative treatment (30.4% vs. 47.0%, p = 0.009). In the curatively treated group, two-year overall survival after LRRC diagnoses increased from 47.5% to 78.7% (p = 0.013). CONCLUSION: Primary rectal cancer patients in 2016 were treated less often with neoadjuvant (chemo)radiotherapy, while LRRC rates remained similar. Those who developed LRRC were more often candidate for curative intent treatment compared to the 2011 cohort, and survival after curative intent treatment also improved substantially.

Perioperative Systemic Therapy Versus Cytoreductive Surgery and HIPEC Alone for Resectable Colorectal Peritoneal Metastases: Patient-Reported Outcomes of a Randomized Phase II Trial.

BACKGROUND: As part of a randomized phase II trial in patients with isolated resectable colorectal peritoneal metastases (CPMs), the present study compared patient-reported outcomes (PROs) of patients treated with perioperative systemic therapy versus cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) alone. Also, PROs of patients receiving perioperative systemic therapy were explored. PATIENTS AND METHODS: Eligible patients were randomized to perioperative systemic therapy (experimental) or CRS-HIPEC alone (control). PROs were assessed using EORTC QLQ-C30, QLQ-CR29, and EQ-5D-5L questionnaires at baseline, after neoadjuvant treatment (experimental), and at 3 and 6 months postoperatively. Linear mixed modeling was used to compare five predefined PROs (visual analog scale, global health status, physical functioning, fatigue, C30 summary score) between arms and to longitudinally analyze PROs in the experimental arm. RESULTS: Of 79 analyzed patients, 37 (47%) received perioperative systemic therapy. All predefined PROs were comparable between arms at all timepoints and returned to baseline at 3 or 6 months postoperatively. The experimental arm had worsening of fatigue [mean difference (MD) + 14, p = 0.001], loss of appetite (MD + 15, p = 0.003), hair loss (MD + 18, p < 0.001), and loss of taste (MD + 27, p < 0.001) after neoadjuvant treatment. Except for loss of appetite, these PROs returned to baseline at 3 or 6 months postoperatively. CONCLUSIONS: In patients with resectable CPM randomized to perioperative systemic therapy or CRS-HIPEC alone, PROs were comparable between arms and returned to baseline postoperatively. Together with the trial's previously reported feasibility and safety data, these findings show acceptable tolerability of perioperative systemic therapy in this setting.

Neoadjuvant FOLFOXIRI prior to chemoradiotherapy for high-risk ("ugly") locally advanced rectal cancer: study protocol of a single-arm, multicentre, open-label, phase II trial (MEND-IT).

BACKGROUND: The presence of mesorectal fascia (MRF) invasion, grade 4 extramural venous invasion (EMVI), tumour deposits (TD) or extensive or bilateral extramesorectal (lateral) lymph nodes (LLN) on MRI has been suggested to identify patients with indisputable, extensive locally advanced rectal cancer (LARC), at high risk of treatment failure. The aim of this study is to evaluate whether or not intensified chemotherapy prior to neoadjuvant chemoradiotherapy improves the complete response (CR) rate in these patients. METHODS: This multicentre, single-arm, open-label, phase II trial will include 128 patients with non-metastatic high-risk LARC (hr-LARC), fit for triplet chemotherapy. To ensure a study population with indisputable, unfavourable prognostic characteristics, hr-LARC is defined as LARC with on baseline MRI at least one of the following characteristics; MRF invasion, EMVI grade 4, enlarged bilateral or extensive LLN at high risk of an incomplete resection, or TD. Exclusion criteria are the presence of a homozygous DPD deficiency, distant metastases, any chemotherapy within the past 6 months, previous radiotherapy within the pelvic area precluding standard chemoradiotherapy, and any contraindication for the planned treatment. All patients will be planned for six two-weekly cycles of FOLFOXIRI (5-fluorouracil, leucovorin, oxaliplatin and irinotecan) prior to chemoradiotherapy (25 × 2 Gy or 28 × 1.8 Gy with concomitant capecitabine). A resection will be performed following radiological confirmation of resectable disease after the completion of chemoradiotherapy. A watch and wait strategy is allowed in case of a clinical complete response. The primary endpoint is the CR rate, described as a pathological CR or a sustained clinical CR one year after chemoradiotherapy. The main secondary objectives are long-term oncological outcomes, radiological and pathological response, the number of resections with clear margins, treatment-related toxicity, perioperative complications, health-related costs, and quality of life. DISCUSSION: This trial protocol describes the MEND-IT study. The MEND-IT study aims to evaluate the CR rate after intensified chemotherapy prior to concomitant chemoradiotherapy in a homogeneous group of patients with locally advanced rectal cancer and indisputably unfavourable characteristics, defined as hr-LARC, in order to improve their prognosis. TRIAL REGISTRATION: Clinicaltrials.gov: NCT04838496 , registered on 02-04-2021 Netherlands Trial Register: NL9790. PROTOCOL VERSION: Version 3 dd 11-4-2022.

Percutaneous cryoablation: a novel treatment option in non-visceral metastases of the abdominal cavity after prior surgery.

PURPOSE: To assess the primary safety and oncological outcome of percutaneous cryoablation in patients with non-visceral metastases of the abdominal cavity after prior surgery. METHODS: All patients with non-visceral metastases after prior abdominal surgery, treated with percutaneous cryoablation, and at least one year of follow-up were retrospectively identified. Technical success was achieved if the ice-ball had a minimum margin of 10 mm in three dimensions on the per-procedural CT images. Complications were recorded using the Society of Interventional Radiology (SIR) classification system. Time until disease progression was monitored with follow-up CT and/or MRI. Local control was defined as absence of recurrence at the site of ablation. RESULTS: Eleven patients underwent cryoablation for 14 non-visceral metastases (mean diameter 20 ± 9 mm). Primary tumor origin was renal cell (n = 4), colorectal (n = 3), granulosa cell (n = 2), endometrium (n = 1) and appendix (n = 1) carcinoma. Treated metastases were localized retroperitoneal (n = 8), intraperitoneal (n = 2), or in the abdominal wall (n = 4). Technical success was achieved in all procedures. After a median follow-up of 27 months (12-38 months), all patients were alive. Local control was observed in 10/14 non-visceral metastases, and the earliest local progression was detected after ten months. No major adverse events occurred. One patient suffered a minor asymptomatic adverse event. CONCLUSION: This proof-of-concept study suggests that cryoablation can be a minimal invasive treatment option in a selected group of patients with non-visceral metastases in the abdominal cavity after prior surgery.

Metachronous peritoneal metastases in patients with pT4b colon cancer: An international multicenter analysis of intraperitoneal versus retroperitoneal tumor invasion.

BACKGROUND: It was hypothesized that colon cancer with only retroperitoneal invasion is associated with a low risk of peritoneal dissemination. This study aimed to compare the risk of metachronous peritoneal metastases (mPM) between intraperitoneal and retroperitoneal invasion. METHODS: In this international, multicenter cohort study, patients with pT4bN0-2M0 colon cancer who underwent curative surgery were categorized as having intraperitoneal invasion (e.g. bladder, small bowel, stomach, omentum, liver, abdominal wall) or retroperitoneal invasion only (e.g. ureter, pancreas, psoas muscle, Gerota's fascia). Primary outcome was 5-year mPM cumulative rate, assessed by Kaplan-Meier analysis. RESULTS: Out of 907 patients with pT4N0-2M0 colon cancer, 198 had a documented pT4b category, comprising 170 patients with intraperitoneal invasion only, 12 with combined intra- and retroperitoneal invasion, and 16 patients with retroperitoneal invasion only. At baseline, only R1 resection rate significantly differed: 4/16 for retroperitoneal invasion only versus 8/172 for intra- +/- retroperitoneal invasion (p = 0.010). Overall, 22 patients developed mPM during a median follow-up of 45 months. Two patients with only retroperitoneal invasion developed mPM, both following R1 resection. The overall 5-year mPM cumulative rate was 13% for any intraperitoneal invasion and 14% for retroperitoneal invasion only (Log Rank, p = 0.878), which was 13% and 0%, respectively, in patients who had an R0 resection (Log Rank, p = 0.235). CONCLUSION: This study suggests that pT4b colon cancer patients with only retroperitoneal invasion who undergo an R0 resection have a negligible risk of mPM, but this is difficult to prove because of its rarity. This observation might have implications regarding individualized follow-up.

Diagnostic performance of MRI for staging peritoneal metastases in patients with colorectal cancer after neoadjuvant chemotherapy.

INTRODUCTION: MRI improves the selection of patients with colorectal cancer (CRC) and peritoneal metastases (PM) for cytoreductive surgery by accurately assessing the extent of PM reflected as the peritoneal cancer index (PCI). The performance of MRI after neoadjuvant chemotherapy (NACT) for staging PM, however is unknown. The purpose of this study was to determine whether MRI could also accurately determine the PCI after NACT. MATERIALS AND METHODS: This was a single-centre, retrospective study of patients with PM from CRC or appendiceal origin who received NACT followed by diffusion-weighted (DW)-MRI and surgery from January 2016 to February 2021. Two radiologists assessed the PCI on restaging DW-MRI (mriPCI). The reference standard was the surgical PCI (sPCI). The main outcome was the diagnostic performance of restaging DW-MRI in predicting whether patients were eligible for cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), defined as a PCI < 21 with metastases on resectable locations. If CRS-HIPEC was performed, the resected peritoneal lesions were assessed and correlated with the final pathological PCI (pPCI). RESULTS: Thirty-three patients were included. Both readers correctly detected all 23 patients with resectable disease. Eight out of ten patients with unresectable disease during staging surgery were detected by both readers with MRI. The intraclass correlation (ICC) between both readers was excellent (0⋅87 (95% CI: 0⋅75 to 0⋅93)). The ICC between pPCI and mriPCI was 0⋅74 (0⋅49-0⋅88) and 0⋅82 (0⋅66-0⋅91) for the 2 readers. Surgical PCI (sPCI) had a similar correlation as mriPCI with pPCI 0⋅82 (0⋅62- 0⋅92)) and 0⋅81 (0⋅57-0⋅92)). CONCLUSION: DW-MRI is a promising tool to reassess the peritoneal cancer index after neoadjuvant chemotherapy.

Seeing the whole picture: Added value of MRI for extraperitoneal findings in CRS-HIPEC candidates.

PURPOSE: In colorectal cancer (CRC) patients the selection of suitable cytoreductive surgery and hyperthermic peritoneal chemotherapy (CRS-HIPEC) candidates is based on the location and extent of peritoneal metastases (PM) and presence of extraperitoneal metastases. MRI is increasingly being used to accurately assess the extent of PM, however, the significance of extraperitoneal findings in these scans has never been evaluated before. METHODS: CRC patients who had undergone an additional MRI scan after standard work-up with CT for preoperative staging between January 2016-January 2020 were selected. CT and MRI reports were reviewed for new abdominopelvic extra-peritoneal findings on MRI (MR-EPF) and MR-EPFs concerning lesions previously indicated as equivocal (uncertain benign/malignant) on CT. Reference standard were surgical results or follow-up imaging. RESULTS: In 158 included patients 60 MR-EPFs (in 58/158 patients) were noted: twenty-six (43%) were new findings and thirty-four (57%) were equivocal findings on CT. Of the 34 equivocal findings 27 were 'rejected/less likely malignant' and 7 'confirmed/more likely malignant' based on MRI. In 29 patients (18%) the MR-EPFs had direct influence on treatment planning. Three patients (2%), eligible for CRS-HIPEC on CT, were deemed inoperable due to MR-EPFs. CONCLUSION: MRI had an added value in more than a third of the patients due to abdominopelvic extraperitoneal findings that were undetected or indeterminate on CT and therefore influenced the treatment in a substantial part of the patients. Combined with the known accurate detection of peritoneal disease on MRI, MRI seems a logical addition to the diagnostic workup of potential CRS-HIPEC candidates.

Dedicated MRI staging versus surgical staging of peritoneal metastases in colorectal cancer patients considered for CRS-HIPEC; the DISCO randomized multicenter trial.

BACKGROUND: Selecting patients with peritoneal metastases from colorectal cancer (CRCPM) who might benefit from cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) is challenging. Computed tomography generally underestimates the peritoneal tumor load. Diagnostic laparoscopy is often used to determine whether patients are amenable for surgery. Magnetic resonance imaging (MRI) has shown to be accurate in predicting completeness of CRS. The aim of this study is to determine whether MRI can effectively reduce the need for surgical staging. METHODS: The study is designed as a multicenter randomized controlled trial (RCT) of colorectal cancer patients who are deemed eligible for CRS-HIPEC after conventional CT staging. Patients are randomly assigned to either MRI based staging (arm A) or to standard surgical staging with or without laparoscopy (arm B). In arm A, MRI assessment will determine whether patients are eligible for CRS-HIPEC. In borderline cases, an additional diagnostic laparoscopy is advised. The primary outcome is the number of unnecessary surgical procedures in both arms defined as: all surgeries in patients with definitely inoperable disease (PCI > 24) or explorative surgeries in patients with limited disease (PCI < 15). Secondary outcomes include correlations between surgical findings and MRI findings, cost-effectiveness, and quality of life (QOL) analysis. CONCLUSION: This randomized trial determines whether MRI can effectively replace surgical staging in patients with CRCPM considered for CRS-HIPEC. TRIAL REGISTRATION: Registered in the clinical trials registry of U.S. National Library of Medicine under NCT04231175 .

Health-related quality of life after interval cytoreductive surgery with or without hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with stage III ovarian cancer.

INTRODUCTION: The addition of hyperthermic intraperitoneal chemotherapy (HIPEC) to interval cytoreductive surgery (CRS) improves recurrence-free (RFS) and overall survival (OS) in patients with FIGO stage III ovarian cancer. We evaluated the effect of HIPEC on patient's health-related quality of life (HRQoL) in the OVHIPEC trial. MATERIALS AND METHODS: OVHIPEC was a multicentre, open-label, randomized phase III trial for patients with stage III ovarian cancer. Patients were randomly assigned (1:1) to receive interval CRS with or without HIPEC with cisplatin. HRQoL was assessed using the EORTC QLQ-C30, and the ovarian (QLQ-OV28) and colorectal cancer (QLQ-CR38) modules. HRQoL questionnaires were administered at baseline, after surgery, after end of treatment, and every three months thereafter. HRQoL was a secondary endpoint, with the prespecified focus on the QLQ-C30 summary score and symptom scores on fatigue, neuropathy and gastro-intestinal symptoms. HRQoL was analysed using linear and non-linear mixed effect models. RESULTS: In total, 245 patients were randomized. One-hundred-ninety-seven patients (80%) completed at least one questionnaire. No significant difference over time in the QLQ-C30 summary scores was observed between the study arms (p-values for linear and non-linear growth: p > 0.133). The pattern over time for fatigue, neuropathy and gastro-intestinal symptoms did not significantly differ between treatment arms. CONCLUSION: The addition of HIPEC to interval CRS does not negatively impact HRQoL in patients with stage III ovarian cancer who are treated with interval CRS due to the extent of disease. These HRQoL results, together with the improvement in RFS and OS, support the viability of HIPEC as an important treatment option in this patient population. CLINICALTRIALS. GOV NUMBER: NCT00426257. EUDRACT NUMBER: 2006-003466-34.

Comparison of the Peritoneal Cancer Index and Dutch region count as tools to stage patients with peritoneal metastases of colorectal cancer.

BACKGROUND: Extent of peritoneal metastases (PM) is among the most powerful prognostic factors for survival after cytoreductive surgery (CRS). This study aimed to compare the Peritoneal Cancer Index (PCI) and the Dutch region count as tools for staging PM of colorectal cancer. The Dutch region count is a simpler classification that distinguishes seven rather than 13 abdominal regions. Presence or absence of PM is recorded. METHODS: This was a retrospective cohort study in two tertiary referral centres in the Netherlands. Consecutive patients with colorectal PM who were intentionally treated with CRS and subsequent hyperthermic intraperitoneal chemotherapy in 2016 and 2017 were included. The PCI and Dutch region count were both recorded during laparotomy. Correlation between scoring tools was calculated using Spearman's rank correlation coefficient. Diagnostic values were calculated for different cut-off values of the PCI, alongside the Dutch region count. The correlation of both scores was determined for the exploration and validation cohorts separately. RESULTS: In the exploration and validation cohorts, 73 and 85 patients respectively were included. Spearman's correlation coefficients of 0·897 and 0·961 were observed for continuous scores of the Dutch region count and PCI in the exploration and validation group respectively. A cut-off value of 20 for the PCI score and 5 for the Dutch region count showed 91·9 and 94·5 per cent sensitivity, and 81·8 and 91·7 per cent specificity, respectively. CONCLUSION: The Dutch region count correlated well with the PCI score, and may help to simplify reporting of the extent of peritoneal disease.

ANTECEDENTES: La extensión de las metástasis peritoneales (peritoneal metastases, PM) es uno de los factores pronósticos más importantes para la supervivencia después de la cirugía citorreductora (cytoreductive surgery, CRS). El objetivo de este estudio fue comparar el índice de carcinomatosis peritoneal (Peritoneal Cancer Index, PCI) y el recuento holandés por regiones como herramientas para la estadificación de las PM del cáncer colorrectal. El recuento holandés por regiones es una clasificación más simple que distingue 7 regiones abdominales en lugar de 13. En dichas regiones abdominales se registró la presencia o ausencia de PM. MÉTODOS: Se llevó a cabo un estudio de cohortes retrospectivo en dos centros de referencia terciarios en los Países Bajos. Se incluyeron pacientes consecutivos con PM de origen colorrectal que fueron tratados con CRS seguida de quimioterapia intraperitoneal hipertérmica (hyperthermic intraperitoneal chemotherapy, HIPEC) en 2016 y 2017. Durante la laparotomía se recogieron datos del índice PCI y de la clasificación de las regiones abdominales. Se utilizó el coeficiente de correlación de Spearman para analizar la correlación entre estas dos herramientas de puntuación. Se calculó la precisión diagnóstica en función de diferentes umbrales del índice PCI junto con los datos del recuento por regiones. Asimismo, se calcularon las correlaciones entre ambas puntuaciones en las cohortes de exploración y validación por separado. RESULTADOS: Se incluyeron 73 pacientes en la cohorte de exploración y 85 en la de validación. Los coeficientes de correlación de Spearman eran de 0,987 para puntuaciones continuas del recuento holandés por regiones abdominales y del PCI en la cohorte de exploración y de 0,961 en la cohorte de validación. Los umbrales de corte de 20 para el índice PCI y de 5 para el recuento por regiones demostraron sensibilidades de 91,9% y 94,5%, y especificidades de 81,8% y 91,7%, respectivamente. CONCLUSIÓN: El recuento holandés por regiones abdominales se correlacionó bien con el PCI y puede ser útil para simplificar la extensión de la enfermedad peritoneal.

Treatment of PERItoneal disease in Stomach Cancer with cytOreductive surgery and hyperthermic intraPEritoneal chemotherapy: PERISCOPE I initial results.

BACKGROUND: The role of cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) in gastric cancer is unknown. This non-randomized dose-finding phase I-II study was designed to assess the safety and feasibility of HIPEC, following systemic chemotherapy, in patients with gastric cancer and limited peritoneal dissemination. The maximum tolerated dose of normothermic intraperitoneal docetaxel in combination with a fixed dose of intraperitoneal oxaliplatin was also explored. METHODS: Patients with resectable cT3-cT4a gastric adenocarcinoma with limited peritoneal metastases and/or tumour-positive peritoneal cytology were included. An open HIPEC technique was used with 460 mg/m2 hyperthermic oxaliplatin for 30 min followed by normothermic docetaxel for 90 min in escalating doses (0, 50, 75 mg/m2 ). RESULTS: Between 2014 and 2017, 37 patients were included. Of 25 patients who completed the full study protocol, four were treated at dose level 1 (0 mg/m2 docetaxel), six at dose level 2 (50 mg/m2 ) and four at dose level 3 (75 mg/m2 ). At dose level 3, two dose-limiting toxicities occurred, both associated with postoperative ileus. Thereafter, another 11 patients were treated at dose level 2, with no more dose-limiting toxicities. Based on this, the maximum tolerated dose was 50 mg/m2 intraperitoneal docetaxel. Serious adverse events were scored in 17 of 25 patients. The reoperation rate was 16 per cent (4 of 25) and the treatment-related mortality rate was 8 per cent (2 patients, both in dose level 3). CONCLUSION: Gastrectomy combined with cytoreductive surgery and HIPEC was feasible using 460 mg/m2 oxaliplatin and 50 mg/m2 normothermic docetaxel.

ANTECEDENTES: El papel de la cirugía citorreductora (cytoreductive surgery, CRS) combinado con la quimioterapia intraperitoneal hipertérmica (hyperthermic intraperitoneal chemotherapy, HIPEC) en el cáncer gástrico no está definido. Este estudio fase I-II no aleatorizado de escalado de dosis fue diseñado para evaluar la seguridad y la viabilidad de HIPEC, después de la quimioterapia sistémica, en pacientes con cáncer gástrico con diseminación peritoneal limitada. Además, se exploró la máxima dosis tolerada (maximum tolerated dose, MTD) de docetaxel intraperitoneal normotérmico en combinación con una dosis fija de oxaliplatino intraperitoneal. MÉTODOS: Se incluyeron pacientes con adenocarcinoma gástrico cT3-cT4a resecable con metástasis peritoneales limitadas y/o citología peritoneal positiva. Se utilizó una técnica HIPEC abierta con 460 mg/m2 de oxaliplatino hipertérmico (30 minutos) seguido de docetaxel normotérmico (90 minutos) en dosis crecientes (0, 50, 75 mg/m2 ). RESULTADOS: Entre 2014 y 2017, se incluyeron 37 pacientes. De los 25 pacientes que completaron la totalidad del protocolo del estudio, 4 pacientes fueron tratados en el nivel de dosis 1 (0 mg/m2 de docetaxel), 6 pacientes en el nivel de dosis 2 (50 mg/m2 ) y 4 pacientes en el nivel de dosis 3 (75 mg/m2 ). En el nivel de dosis 3, se produjeron dos casos de toxicidad limitante de dosis (dose-limiting toxicities, DLTs), ambas asociadas con un íleo postoperatorio. Posteriormente, otros 11 pacientes fueron tratados con el nivel de dosis 2, y no se produjeron más DLTs. La MTD de docetaxel intraperitoneal fue de 50 mg/m2 . Se registraron efectos adversos graves en 17 de 25 pacientes. La tasa de reoperación fue del 16% (n = 4) y la mortalidad relacionada con el tratamiento fue del 8% (n = 2; ambos en el nivel de dosis 3).

Long-term survival after hyperthermic intraperitoneal chemotherapy using mitomycin C or oxaliplatin in colorectal cancer patients with synchronous peritoneal metastases: A nationwide comparative study.

OBJECTIVES: In the Netherlands, limited variability exists in performance of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) among centers treating colorectal peritoneal metastases (PM), except for the intraperitoneal drug administration. This offers a unique opportunity to investigate any disparities in survival between the two most frequently used HIPEC regimens worldwide: mitomycin C (MMC) and oxaliplatin. METHODS: This was a comparative, population-based cohort study of all Dutch patients diagnosed with synchronous colorectal PM who underwent CRS-HIPEC between 2014 and 2017. They were retrieved from the Netherlands Cancer Registry. Main outcome was overall survival (OS). The effect of the intraperitoneal drug on OS was investigated using multivariable Cox regression analysis. RESULTS: In total, 297 patients treated between 2014 and 2017 were included. Among them, 177 (59.6%) received MMC and 120 (40.4%) received oxaliplatin. Only primary tumor location was different between the two groups: more left-sided colon in the Oxaliplatin group (47.5% vs. 33.3%, respectively, p=0.048). The 1-, 2- and 3-year OS were 84.6% vs. 85.8%, 61.6% vs. 63.9% and 44.7% vs. 53.5% in patients treated with MMC and oxaliplatin, respectively. Median OS was 30.7 months in the MMC group vs. 46.6 months in the oxaliplatin group (p=0.181). In multivariable analysis, no influence of intraperitoneal drug on survival was observed (adjusted HR 0.77 [0.53-1.13]). CONCLUSIONS: Long-term survival between patients treated with either MMC or oxaliplatin during CRS-HIPEC was not significantly different.

Diagnostic performance of imaging for the detection of peritoneal metastases: a meta-analysis.

PURPOSE: Detection of peritoneal metastases (PM) is key in the staging and management of gastrointestinal and ovarian cancer patients. The purpose of this meta-analysis was to determine the diagnostic performance of CT, PET(CT), and (DW)MRI in detecting PM. METHODS: A literature search in Pubmed, Embase (Ovid), and Scopus was performed (January 1997-May 2018) to identify studies reporting on the accuracy of imaging PM in the diagnostic workup of gastrointestinal or ovarian cancers. Inclusion criteria were region-based or patient-based studies comprising > 15 patients, surgery/histology/radiological follow-up as a reference standard, and sufficient data to construct a 2 × 2 contingency table. Two observers performed data extraction. The sensitivity, specificity, and diagnostic odds ratio (DOR) were calculated using a bivariate random-effects model and hierarchical summary operating curves (HSROC) were generated. RESULTS: Of 3457 citations retrieved, twenty-four articles met all inclusion criteria. Thirty-seven datasets could be extracted for analysis including 20 for CT, 10 for PET(CT), and 7 for (DW)MRI. The pooled sensitivity, specificity, and DOR for the detection of PM for region-based studies for CT were 68% (CI, 46-84%), 88%(CI, 81-93%), and 15.9 (CI, 4.4-58.0) respectively; 80% (CI, 57-92%), 90% (CI, 80-96%), and 36.5 (CI, 6.7-199.5) for PET(CT), respectively; 92% (CI, 84-96%), 85% (CI, 78-91%), 63.3 (CI, 31.5-127.3) for (DW)MRI. In the patient-based group, not enough studies were included to make a pooled analysis for (DW)MRI and PET(CT). CONCLUSION: (DW)MRI and PET(CT) showed comparable diagnostic performance for the detection of peritoneal metastases in ovarian and gastrointestinal cancer patients. Since MRI is more widely available than PET(CT) in clinical practice, this potentially is the imaging method of choice in most centers in the future. KEY POINTS: • Detection of peritoneal metastases plays an important role in the accurate staging of cancer patients, however, there is no accepted reference standard for the imaging of peritoneal metastases • This meta-analysis shows that (DW)MRI provided the highest sensitivity for the detection of peritoneal metastases in ovarian and gastrointestinal cancer patients • Although (DW)MRI and PET(CT) show a comparable overall diagnostic performance, (DW)MRI seems to be the imaging method of choice since it is more available in daily practice than PET(CT).

Effect of intraperitoneal chemotherapy concentration on morbidity and survival.

BACKGROUND: Selected patients with colorectal peritoneal metastases are treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). The concentration of intraperitoneal chemotherapy reflects the administered dose and perfusate volume. The aim of this study was to calculate intraperitoneal chemotherapy concentration during HIPEC and see whether this was related to clinical outcomes. METHODS: An observational multicentre study included consecutive patients with colorectal peritoneal metastases who were treated with CRS-HIPEC between 2010 and 2018 at three Dutch centres. Data were retrieved from prospectively developed databases. Chemotherapy dose and total circulating volumes of carrier solution were used to calculate chemotherapy concentrations. Postoperative complications, disease-free and overall survival were correlated with intraoperative chemotherapy concentrations. Univariable and multivariable logistic regression, Cox regression and survival analyses were performed. RESULTS: Of 320 patients, 220 received intraperitoneal mitomycin C (MMC) and 100 received oxaliplatin. Median perfusate volume for HIPEC was 5·0 (range 0·7-10·0) litres. Median intraperitoneal chemotherapy concentration was 13·3 (range 7·0-76·0) mg/l for MMC and 156·0 (91·9-377·6) mg/l in patients treated with oxaliplatin. Grade III or higher complications occurred in 75 patients (23·4 per cent). Median overall survival was 36·9 (i.q.r. 19·5-62·9) months. Intraperitoneal chemotherapy concentrations were not associated with postoperative complications or survival. CONCLUSION: CRS-HIPEC was performed with a wide variation in intraperitoneal chemotherapy concentrations that were not associated with complications or survival.

ANTECEDENTES: Ciertos pacientes seleccionados con metástasis peritoneales de cáncer colorrectal (peritoneal metastases, PM) se tratan con cirugía citorreductora (cytoreductive surgery, CRS) y quimioterapia intraperitoneal hipertérmica (hyperthermic intraperitoneal chemotherapy, HIPEC). La concentración de quimioterapia intraperitoneal refleja la dosis administrada y el volumen perfundido. El objetivo de este estudio fue calcular la concentración de quimioterapia intraperitoneal durante HIPEC y evaluar si ello se relacionaba con los resultados clínicos. MÉTODOS: Estudio observacional multicéntrico en el que se incluyeron pacientes consecutivos con PM de cáncer colorrectal que fueron tratados con CRS-HIPEC entre 2010 y 2018 en tres centros holandeses. Se obtuvieron los datos a partir de bases de datos mantenidas de forma prospectiva. La dosis de quimioterapia y los volúmenes circulantes totales de solución de perfusión se usaron para calcular las concentraciones de quimioterapia. Las complicaciones postoperatorias y las supervivencias libre de enfermedad y global se correlacionaron con las concentraciones de quimioterapia intraoperatoria. Se realizaron regresiones logísticas univariable y multivariable, regresión de Cox y análisis de supervivencia. RESULTADOS: De 320 pacientes, 220 recibieron mitomicina C intraperitoneal (MMC) y 100 oxaliplatino (OXA). El volumen medio de perfusión para HIPEC fue 5,0 L (rango 0,7-10,0). La mediana de concentración intraperitoneal del agente quimioterápico fue de 13,3 mg/L (rango 7,0-76,0) para MMC y 156,0 mg/L (rango 91,9 - 377,6) en pacientes tratados con OXA. Las complicaciones de grado 3 o mayores ocurrieron en 23,4% (n = 75). La mediana de supervivencia global fue de 36,9 meses (rango intercuartílico 19,5-62,9). Las concentraciones de quimioterapia intraperitoneal no se asociaron con las complicaciones postoperatorias ni con la supervivencia. CONCLUSIÓN: La CRS-HIPEC se realizó con una amplia variación en las concentraciones de quimioterapia intraperitoneal que no se asociaron con las complicaciones ni con la supervivencia.

Tissue diagnosis during colorectal cancer surgery using optical sensing: an in vivo study.

BACKGROUND: In colorectal cancer surgery there is a delicate balance between complete removal of the tumor and sparing as much healthy tissue as possible. Especially in rectal cancer, intraoperative tissue recognition could be of great benefit in preventing positive resection margins and sparing as much healthy tissue as possible. To better guide the surgeon, we evaluated the accuracy of diffuse reflectance spectroscopy (DRS) for tissue characterization during colorectal cancer surgery and determined the added value of DRS when compared to clinical judgement. METHODS: DRS spectra were obtained from fat, healthy colorectal wall and tumor tissue during colorectal cancer surgery and results were compared to histopathology examination of the measurement locations. All spectra were first normalized at 800 nm, thereafter two support vector machines (SVM) were trained using a tenfold cross-validation. With the first SVM fat was separated from healthy colorectal wall and tumor tissue, the second SVM distinguished healthy colorectal wall from tumor tissue. RESULTS: Patients were included based on preoperative imaging, indicating advanced local stage colorectal cancer. Based on the measurement results of 32 patients, the classification resulted in a mean accuracy for fat, healthy colorectal wall and tumor of 0.92, 0.89 and 0.95 respectively. If the classification threshold was adjusted such that no false negatives were allowed, the percentage of false positive measurement locations by DRS was 25% compared to 69% by clinical judgement. CONCLUSION: This study shows the potential of DRS for the use of tissue classification during colorectal cancer surgery. Especially the low false positive rate obtained for a false negative rate of zero shows the added value for the surgeons. Trail registration This trail was performed under approval from the internal review board committee (Dutch Trail Register NTR5315), registered on 04/13/2015, https://www.trialregister.nl/trial/5175 .

Factors influencing long-term survival after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for pseudomyxoma peritonei originating from appendiceal neoplasms.

Background: Pseudomyxoma peritonei (PMP) is a rare disease, most commonly of appendiceal origin. Treatment consists of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC). The aim of this study was to identify prognostic factors for recurrence and survival. Methods: This was an observational study using a prospectively designed database containing consecutive patients with PMP originating from the appendix, undergoing CRS-HIPEC at a tertiary referral centre between 1996 and 2015. Histopathological slides were reassessed. Cox regression was used for multivariable analyses. Results: Of 225 patients identified, 36 (16·0 per cent) were diagnosed with acellular mucin, 149 (66·2 per cent) had disseminated peritoneal adenomucinosis (DPAM) and 40 (17·8 per cent) had peritoneal mucinous carcinomatosis (PMCA). The 5-year overall survival (OS) rates were 93, 69·8 and 55 per cent respectively. Recurrence was observed in 120 patients (53·3 per cent), 39 of whom (17·3 per cent) were treated with a second CRS-HIPEC procedure. Factors independently associated with poor disease-free survival were six or seven affected regions (hazard ratio (HR) 6·01, 95 per cent c.i. 2·04 to 17·73), incomplete cytoreduction (R2a resection: HR 1·67, 1·05 to 2·65; R2b resection: HR 2·00, 1·07 to 3·73), and more than threefold raised carcinoembryonic antigen (CEA) and/or carbohydrate antigen (CA) 19-9 level (HR 2·31, 1·30 to 4·11). Factors independently associated with poorer OS were male sex (HR 1·74, 1·09 to 2·77), incomplete cytoreduction (R2a resection: HR 1·87, 1·14 to 3·08; R2b resection: HR 2·28, 1·19 to 4·34), and more than threefold raised CEA and/or CA19-9 level (HR 2·89, 1·36 to 6·16). Conclusion: CEA and CA19-9 levels raised more than threefold above the upper limit identify patients with PMP of appendiceal origin and poorer survival.

The impact of radiological retroperitoneal lymphadenopathy on survival after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for colorectal peritoneal metastases.

OBJECTIVES: To investigate the impact of retroperitoneal lymphadenopathy (RPLP) on pre-operative CT scan on overall survival (OS) and disease-free survival (DFS) after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) for peritoneal metastases (PM) of colorectal cancer. BACKGROUND: In patients with PM enlarged retroperitoneal lymph nodes (RPLP) are usually considered extra-regional lymph node metastases and therefore these patients may be excluded from CRS-HIPEC. This is a clinical dilemma since it is often hard to obtain histology from these nodes. METHODS: In this multicenter, retrospective study all consecutive patients with colorectal PM treated with CRS-HIPEC between 2004 and 2013 were included. The preoperative CT-scan was re-analyzed for the presence of RPLP based on the radiological appearance of enlarged lymph nodes. Outcomes were OS and DFS. Kaplan-Meier methods and Cox regression modeling were used to analyze the impact of RPLP on OS and DFS. RESULTS: In 25 of 401 patients (6.1%) RPLP was observed on the preoperative CT-scan. Patient, tumor and surgical characteristics did not statistically significantly differ between groups with and without RPLP. After a median follow-up of 46 months, the one-, three- and five-year survival was 80%, 59%, 38% and 90%, 50%, 36% in the group with and without RPLP respectively. Median OS (47 vs. 35 months, logrank: p = 0.70) and median DFS (14 vs. 15 months, logrank: p = 0.81) did not statistically significantly differ between groups. In multivariable analysis, RPLP did not significantly influence survival. CONCLUSION: Enlarged retroperitoneal lymph nodes on a pre-operative CT-scan should not automatically exclude patients from CRS-HIPEC.

Diffusion-weighted MRI assessment of the peritoneal cancer index before cytoreductive surgery.

BACKGROUND: Patients with limited peritoneal metastases from colorectal cancer may be candidates for an aggressive surgical approach including cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC). Selection is based on surgical inspection during laparoscopy or laparotomy. The aim of this study was to investigate whether diffusion-weighted MRI (DW-MRI) can be used to select patients for CRS-HIPEC. METHODS: This was a prospective study at a tertiary referral centre. Patients with confirmed or suspected colorectal peritoneal metastases scheduled for exploratory laparotomy or laparoscopy were eligible. Two radiologists assessed the peritoneal cancer index (PCI) on CT (CT-PCI) and DW-MRI (MRI-PCI). The reference standard was PCI at surgery. Radiologists were blinded to the surgical PCI and to each other's findings. The main outcome was the accuracy of DW-MRI in predicting whether patients had resectable disease (PCI less than 21) or not. RESULTS: Fifty-six patients were included in the study, of whom 49 could be evaluated. The mean(s.d.) PCI at surgery was 11·27(7·53). The mean MRI-PCI was 10·18(7·07) for reader 1 and 8·59(7·08) for reader 2. Readers 1 and 2 correctly staged 47 of 49 and 44 of 49 patients respectively (accuracy 96 and 90 per cent). Both readers detected all patients with resectable disease with a PCI below 21 at surgery (sensitivity 100 per cent). No patient was overstaged. The intraclass correlation (ICC) between readers was excellent (ICC 0·91, 95 per cent c.i. 0·77 to 0·96). MRI-PCI had a stronger correlation with surgical PCI (ICC 0·83-0·88) than did CT-PCI (ICC 0·39-0·44). CONCLUSION: DW-MRI is a promising non-invasive tool to guide treatment selection in patients with peritoneal metastases from colorectal cancer.

Histopathological and molecular classification of colorectal cancer and corresponding peritoneal metastases.

BACKGROUND: Patients with colorectal peritoneal carcinomatosis have a very poor prognosis. The recently developed consensus molecular subtype (CMS) classification of primary colorectal cancer categorizes tumours into four robust subtypes, which could guide subtype-targeted therapy. CMS4, also known as the mesenchymal subtype, has the greatest propensity to form distant metastases. CMS4 status and histopathological features of colorectal peritoneal carcinomatosis were investigated in this study. METHODS: Fresh-frozen tissue samples from primary colorectal cancer and paired peritoneal metastases from patients who underwent cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy were collected. Histopathological features were analysed, and a reverse transcriptase-quantitative PCR test was used to assess CMS4 status of all collected lesions. RESULTS: Colorectal peritoneal carcinomatosis was associated with adverse histopathological characteristics, including a high percentage of stroma in both primary tumours and metastases, and poor differentiation grade and high-grade tumour budding in primary tumours. Furthermore, CMS4 was significantly enriched in primary tumours with peritoneal metastases, compared with unselected stage I-IV tumours (60 per cent (12 of 20) versus 23 per cent; P = 0.002). The majority of peritoneal metastases (75 per cent, 21 of 28) were also classified as CMS4. Considerable intrapatient subtype heterogeneity was observed. Notably, 15 of 16 patients with paired tumours had at least one CMS4-positive tumour location. CONCLUSION: Significant enrichment for CMS4 was observed in colorectal peritoneal carcinomatosis. Surgical relevance Cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) improves survival of selected patients with colorectal peritoneal carcinomatosis, but recurrence is common. Histopathological and molecular analysis of colorectal peritoneal carcinomatosis could provide clues for development of novel therapies. In this study, colorectal peritoneal carcinomatosis was found to be enriched for tumours with high stromal content and CMS4-positive status. To further improve prognosis for patients with colorectal peritoneal carcinomatosis, therapies that target tumour-stroma interaction could be added to CRS-HIPEC.