Treatment Of Colorectal Peritoneal Metastases Research Articles

Exploiting a subtype-specific mitochondrial vulnerability for successful treatment of colorectal peritoneal metastases

Peritoneal metastases (PMs) from colorectal cancer (CRC) respond poorly to treatment and are associated with unfavorable prognosis. For example, the addition of hyperthermic intraperitoneal chemotherapy (HIPEC) to cytoreductive surgery in resectable patients shows limited benefit, and novel treatments are urgently needed. The majority of CRC-PMs represent the CMS4 molecular subtype of CRC, and here we queried the vulnerabilities of this subtype in pharmacogenomic databases to identify novel therapies. This reveals the copper ionophore elesclomol (ES) as highly effective against CRC-PMs. ES exhibits rapid cytotoxicity against CMS4 cells by targeting mitochondria. We find that a markedly reduced mitochondrial content in CMS4 cells explains their vulnerability to ES. ES demonstrates efficacy in preclinical models of PMs, including CRC-PMs and ovarian cancer organoids, mouse models, and a HIPEC rat model of PMs. The above proposes ES as a promising candidate for the local treatment of CRC-PMs, with broader implications for other PM-prone cancers.

In vitro 3D microfluidic peritoneal metastatic colorectal cancer model for testing different oxaliplatin-based HIPEC regimens.

Treatment of colorectal peritoneal metastases with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) is still evolving. Conducting a randomized trial is challenging due to the high heterogeneity in the presentation of peritoneal disease and various surgical approaches. Biological research may facilitate more rapid translation of information into clinical practice. There is an emerging need for a preclinical model to improve HIPEC treatment protocols in terms of drug doses and treatment durations. The aim of the study is to design a tool that serves as an invitro three-dimensional (3D) microfluidic peritoneal metastatic colorectal cancer model to test the efficacy of different HIPEC treatments. We determined the effects of current therapy options using a 3D static disease model on human colon carcinoma cell lines (HCT 116) and transforming growth factor-β1 induced epithelial-to-mesenchymal transition (EMT) HCT 116 lines at 37 °C and 42 °C for 30, 60, and 120 min. We determined oxaliplatin's half maximal inhibitory concentrations in a 3D static culture by using viability assay. Clinical practices of HIPEC were applied in the developed model. EMT-induced HCT 116 cells were less sensitive to oxaliplatin treatment compared to non-induced cells. We observed increased cytotoxicity when increasing the temperature from 37 °C to 42 °C and extending the treatment duration from 30 to 120 min. We found that 200 mg/m2 oxaliplatin administered for 120 min is the most effective HIPEC treatment option within the framework of clinic applications. The tool map provide insights into creating more realistic pre-clinical tools that could be used for a patient-based drug screening.

Metal-enriched HSP90 nanoinhibitor overcomes heat resistance in hyperthermic intraperitoneal chemotherapy used for peritoneal metastases

Clinical hyperthermic intraperitoneal chemotherapy (HIPEC) is regarded as a potential treatment that can prolong survival of patients with peritoneal metastases after cytoreductive surgery. However, treated tumor cells are prone to becoming heat resistant to HIPEC therapy through high expression of heat shock proteins (HSPs). Here, a carrier-free bifunctional nanoinhibitor was developed for HIPEC therapy in the management of peritoneal metastases. Self-assembly of the nanoinhibitor was formed by mixing Mn ion and epigallocatechin gallate (EGCG) in a controllable manner. Such nanoinhibitor directly inhibited HSP90 and impaired the HSP90 chaperone cycle by reduced intracellular ATP level. Additionally, heat and Mn ion synergistically induced oxidative stress and expression of caspase 1, which activated GSDMD by proteolysis and caused pyroptosis in tumor cells, triggering immunogenic inflammatory cell death and induced maturation of dendritic cells through the release of tumor antigens. This strategy to inhibit heat resistance in HIPEC presented an unprecedented paradigm for converting “cold” tumors into “hot” ones, thus significantly eradicating disseminated tumors located deep in the abdominal cavity and stimulating immune response in peritoneal metastases of a mouse model. Collectively, the nanoinhibitor effectively induced pyroptosis of colon tumor cells under heat conditions by inhibiting heat stress resistance and increasing oxidative stress, which may provide a new strategy for treatment of colorectal peritoneal metastases.

Patterns and Timing of Recurrence following CRS and HIPEC in Colorectal Cancer Peritoneal Metastasis.

Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy (CRS/HIPEC) is an established treatment of Colorectal Peritoneal Metastases (CRPM). This study aims to determine the timing and patterns of recurrent disease on imaging following complete CRS/HIPEC. Retrospective analysis of a national peritoneal tumour service database identified CRPM patients with complete CRS/HIPEC(CC0) from 2005 to-2018. Patients with<2 years follow-up or and those where post-operative histology from the CRS/HIPEC procedure did not confirm CRPM from their original colorectal cancer were excluded. Time to recurrence was measured from surgery to first radiologically illustrated recurrence. CT was the primary modality used, supplemented by PET-CT or MRI if required. Outcomes of interest were survival data (including overall survival (OS), disease-free survival (DFS) and peritoneal-recurrence free survival (PRFS)), timing and patterns of recurrent disease. 146 of the 176 patients identified were eligible for inclusion. Median OS for all study patients was 45.2 months (95% CI 38-53 months), median DFS was 11.7 months (95% CI 9-14 months), and median PRFS was 25.2 months (95% CI 14.7-30 months). Recurrent disease was seen in 112 cases (77%), radiologically classified as intraperitoneal in 50 patients (44%), single site systemic in 21 patients (19%) and multi-site in 41 patients (37%). CT detection rate for disease recurrence was 88%. Subgroup analyses showed that PCI ≥12, positive nodal primary disease and synchronous peritoneal disease were associated with worse outcomes. Patients selected for CRS/HIPEC for CRPM have an OS>45 months, with the majority recurring systemically within a year. Peritoneal recurrence is a later event after several years. Surveillance programs in this group should be most intensive in the first 2 years after surgery, using CT with oral and intravenous contrast.

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

BackgroundThe 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).MethodPatients 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.ResultsA 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).ConclusionTreatment-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.

Abstract 272: Effective treatment of colorectal peritoneal metastases by exploiting a molecular subtype specific vulnerability

Abstract In colorectal cancer, peritoneal metastases (PMs) associate with severe morbidity and dismal prognosis. Given the incidence of this disease and the lack of adequate treatments currently available, PMs pose a large unmet clinical need. Although PMs can be accompanied by more widespread metastatic disease, it often occurs as the only sign of dissemination. This implies that the route of metastatic spread to the peritoneum differs from that to distant organs. PMs are thought to result from cancer cells that spill into the abdominal cavity, and are able to attach to the peritoneal lining and form tumor deposits. This cascade places specific demands on the cancer cells. Here, we report that colorectal cancers that present with PMs almost universally classify as consensus molecular subtype 4 (CMS4). This previously recognized disease entity is characterized by mesenchymal features, poor prognosis, and resistance to therapies currently used against peritoneal metastases, which explains their limited efficacy. By leveraging disease models that capture CMS4-specific features, including the ability to form PMs in vivo, we identified elesclomol as a highly effective agent. Elesclomol kills cancer cells in a copper-dependent fashion by targeting the oxidative phosphorylation machinery, which we found to be a specific vulnerability of CMS4 cancers. Elesclomol-Cu2+ was effective following only minutes of exposure to CMS4 cell lines and organoids, supporting its use in intra-abdominal treatment procedures. It is therefore a promising candidate for the local treatment of peritoneal metastases of colorectal cancer. Citation Format: Sanne Bootsma, Mark P. Dings, Leandro Ferreira Moreno, Kristiaan J. Lenos, Louis Vermeulen, Maarten F. Bijlsma. Effective treatment of colorectal peritoneal metastases by exploiting a molecular subtype specific vulnerability [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 272.

Perioperative Systemic Therapy vs Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy Alone for Resectable Colorectal Peritoneal Metastases

To date, no randomized clinical trials have investigated perioperative systemic therapy relative to cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) alone for resectable colorectal peritoneal metastases (CPM). To assess the feasibility and safety of perioperative systemic therapy in patients with resectable CPM and the response of CPM to neoadjuvant treatment. An open-label, parallel-group phase 2 randomized clinical trial in all 9 Dutch tertiary centers for the surgical treatment of CPM enrolled participants between June 15, 2017, and January 9, 2019. Participants were patients with pathologically proven isolated resectable CPM who did not receive systemic therapy within 6 months before enrollment. Randomization to perioperative systemic therapy or CRS-HIPEC alone. Perioperative systemic therapy comprised either four 3-week neoadjuvant and adjuvant cycles of CAPOX (capecitabine and oxaliplatin), six 2-week neoadjuvant and adjuvant cycles of FOLFOX (fluorouracil, leucovorin, and oxaliplatin), or six 2-week neoadjuvant cycles of FOLFIRI (fluorouracil, leucovorin, and irinotecan) and either four 3-week adjuvant cycles of capecitabine or six 2-week adjuvant cycles of fluorouracil with leucovorin. Bevacizumab was added to the first 3 (CAPOX) or 4 (FOLFOX/FOLFIRI) neoadjuvant cycles. Proportions of macroscopic complete CRS-HIPEC and Clavien-Dindo grade 3 or higher postoperative morbidity. Key secondary outcomes were centrally assessed rates of objective radiologic and major pathologic response of CPM to neoadjuvant treatment. Analyses were done modified intention-to-treat in patients starting neoadjuvant treatment (experimental arm) or undergoing upfront surgery (control arm). In 79 patients included in the analysis (43 [54%] men; mean [SD] age, 62 [10] years), experimental (n = 37) and control (n = 42) arms did not differ significantly regarding the proportions of macroscopic complete CRS-HIPEC (33 of 37 [89%] vs 36 of 42 [86%] patients; risk ratio, 1.04; 95% CI, 0.88-1.23; P = .74) and Clavien-Dindo grade 3 or higher postoperative morbidity (8 of 37 [22%] vs 14 of 42 [33%] patients; risk ratio, 0.65; 95% CI, 0.31-1.37; P = .25). No treatment-related deaths occurred. Objective radiologic and major pathologic response rates of CPM to neoadjuvant treatment were 28% (9 of 32 evaluable patients) and 38% (13 of 34 evaluable patients), respectively. In this randomized phase 2 trial in patients diagnosed with resectable CPM, perioperative systemic therapy seemed feasible, safe, and able to induce response of CPM, justifying a phase 3 trial. ClinicalTrials.gov Identifier: NCT02758951.

Systemic therapy in addition to cytoreduction and hyperthermic intraperitoneal chemotherapy for colorectal peritoneal metastases: recent insights from clinical studies and translational research.

There is a lack of randomized or high-quality intention-to-treat cohort studies addressing the role of systemic therapy in addition to cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) as part of the treatment of colorectal peritoneal metastases (PM). Therefore, the choice whether or not to treat patients with systemic therapy is currently mainly based on expert opinion. As a result, treatment with neoadjuvant and/or adjuvant systemic therapy is implemented in various ways around the world. The aim of this review was to provide an overview of recent insights with regard to the systemic treatment of PM of colorectal origin obtained from clinical studies and translational research.

Implications of Pathologic Findings in Cytoreductive Surgery Specimens on Treatment of Colorectal Peritoneal Metastases: Results of a Prospective Multicentric Study.

A surgical peritoneal cancer index of >20 is often used to exclude patients from cytoreductive surgery for colorectal peritoneal metastases. The pathologic peritoneal cancer index in these patients may be <20. The purpose of this study was to compare the pathologic and surgical findings and to look at potential pathologic prognostic factors. This is a prospective observational study including patients undergoing cytoreductive surgery. The study was carried out at 3 peritoneal surface malignancy centers, 1 in France and 2 in India. One-hundred patients were included from July 1, 2018, to June 30, 2019. The pathologic peritoneal cancer index, peritoneal disease distribution, pathologic response to chemotherapy, factors affecting them and their relation with surgical findings, and potential prognostic value were explored. Ninety percent had colonic primaries. Fifty-one percent had left-sided tumors. The median surgical peritoneal cancer index was 4 (range, 0-35). Upper regions were involved in 32% and small bowel regions in 26%, and their involvement increased with a higher peritoneal cancer index (p < 0.001). The median pathologic peritoneal cancer index was 2 (range, 0-27) and was less than the surgical peritoneal cancer index in 57%. A pathologic complete response was obtained in 25%. Patients with pathologic complete response received more antiepidermal growth factor receptor therapy (p = 0.008); more leucovorin, 5-fluorouracil, and oxaliplatin; and folinic acid, fluorouracilirin, irinotecan hydrochloride, and oxaliplatin (p < 0.001). In 7 patients with a surgical peritoneal cancer index of >20, pathologic peritoneal cancer index was <20 in 4 patients. Disease in the primary tumor/anastomotic site was found in ≈80%. Survival outcomes are not available. Surgical peritoneal cancer index of >20 should not be the sole factor to exclude patients from surgery, especially in responders to systemic therapies. The pathologic peritoneal cancer index, pathologic response to systemic chemotherapy, and disease distribution in the peritoneal cavity should be meticulously documented. Correlation with survival will define their future prognostic value. The primary anastomotic site is a common site for peritoneal disease and should be carefully evaluated in all patients. See Video Abstract at http://links.lww.com/DCR/B490. IMPLICACIONES DE LOS HALLAZGOS PATOLÓGICOS EN MUESTRAS DE CIRUGÍA CITORREDUCTORA EN EL TRATAMIENTO DE METÁSTASIS PERITONEALES COLORRECTALES: RESULTADOS DE UN ESTUDIO PROSPECTIVO MULTICÉNTRICO: Una ICP quirúrgica de >20 se utiliza a menudo para excluir a los pacientes de la cirugía citorreductora por metástasis peritoneales colorrectales. La PCI patológica en estos pacientes puede ser <20.Comparar los hallazgos patológicos y quirúrgicos y observar los posibles factores pronósticos patológicos.Se trata de un estudio observacional prospectivo que incluye a pacientes sometidos a cirugía citorreductora.El estudio se llevó a cabo en tres centros de malignidad de la superficie peritoneal, 1 en Francia y 2 en India.Se incluyeron 100 pacientes desde el 1 de julio de 2018 al 30 de junio de 2019.No hubo intervención terapéutica.Se exploró la ICP patológica, la distribución de la enfermedad peritoneal, la respuesta patológica a la quimioterapia, los factores que la afectan y su relación con los hallazgos quirúrgicos y el valor pronóstico potencial.El noventa por ciento tenía lesiones primarias colónicas. El 51% tenía tumores del lado izquierdo. La mediana de la ICP quirúrgica 4 [0-35]. Las regiones superiores estuvieron involucradas en el 32% y las regiones del intestino delgado en un 26% y su participación aumentó con una ICP más alta (p <0,001). La mediana de la ICP patológica fue 2 [0-27] y fue menor que la ICP quirúrgica en el 57%. Se obtuvo respuesta patológica completa en el 25%. Los pacientes con respuesta patológica completa recibieron más terapia anti-EGFR (p = 0,008) y más FOLFOX y FOLFIRINOX (p <0,001). En 7 pacientes con una ICP quirúrgica de> 20, la ICP patológica fue menor de 20 en 4 pacientes. Se encontró enfermedad en el tumor primario/anastomósis en casi el 80%.Los resultados de supervivencia no están disponibles.La ICP quirúrgica de> 20 no debería ser el único factor para excluir a los pacientes de la cirugía, especialmente en los que responden a las terapias sistémicas. La PCI patológica, la respuesta patológica a la quimioterapia sistémica y la distribución de la enfermedad en la cavidad peritoneal deben documentarse meticulosamente. La correlación con la supervivencia definirá su valor pronóstico futuro. El sitio anastomótico primario es un sitio común de enfermedad peritoneal y debe evaluarse cuidadosamente en todos los pacientes. Consulte Video Resumen en http://links.lww.com/DCR/Bxxx. (Traducción-Dr. Gonzalo Hagerman).

Intraperitoneal collagenase as a novel therapeutic approach in an experimental model of colorectal peritoneal carcinomatosis

The usefulness of local collagenase in therapeutic approaches to solid tumors has been tested recently. In this study, we evaluate the safety and efficacy of intraperitoneal collagenase associated or not to mitomycin for treatment of colorectal peritoneal metastases in an experimental rat model. Using a fixed-dose procedure, we found that a dose of collagenase of 37 IU/mL administered for 15 min with a hyperthermia pump at 37.5 °C, both in isolation or associated to sequential treatment with intraperitoneal mitomycin, led to a macroscopic decrease in tumor volume as evaluated by the modified peritoneal cancer index (mPCI). Concerning the safety of the procedure, the animals showed no physiological or behavioral disorders during 8 weeks of follow-up. Local treatment for peritoneal metastases of colorectal origin with intraperitoneal collagenase has proved safe and effective in an experimental murine model. Therefore, the stroma-first approach by enzymatic breakdown of collagen from the tumor's extracellular matrix provides a new therapeutic target for colorectal peritoneal metastases.

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.

BackgroundThe 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.MethodsData 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 χ 2 test and Kruskal−Wallis H test.ResultsSeventy‐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).ConclusionTreatment‐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.

P-275 Quality of life and symptoms in patients undergoing CRS-HIPEC with or without perioperative systemic treatment for colorectal peritoneal metastases: Results from the randomised CAIRO6 trial

To investigate the effect of perioperative systemic therapy in addition to cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) on quality of life (QoL) and symptoms during and after treatment for colorectal peritoneal metastases.

Repetitive electrostatic pressurised intraperitoneal aerosol chemotherapy (ePIPAC) with oxaliplatin as a palliative monotherapy for isolated unresectable colorectal peritoneal metastases: protocol of a Dutch, multicentre, open-label, single-arm, phase II study (CRC-PIPAC)

IntroductionRepetitive electrostatic pressurised intraperitoneal aerosol chemotherapy with oxaliplatin (ePIPAC-OX) is offered as a palliative treatment option for patients with isolated unresectable colorectal peritoneal metastases (PM) in several centres worldwide. However,...

PIPAC for the Treatment of Colorectal Peritoneal Metastases

PIPAC for the Treatment of Colorectal Peritoneal Metastases

The Role of Neoadjuvant and Adjuvant Systemic Chemotherapy with Cytoreductive Surgery and Heated Intraperitoneal Chemotherapy for Colorectal Peritoneal Metastases: A Systematic Review

Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is an effective treatment for colorectal peritoneal metastases (CPM), increasing overall survival in selected patients. The aim of this systematic review was to assess the effect of neoadjuvant and adjuvant systemic chemotherapy on overall survival in patients with CPM undergoing CRS and HIPEC, compared with those who receive CRS and HIPEC alone. A systematic literature review was performed using the PubMed database, and the preferred reporting items for systematic reviews and meta-analyses guidelines formed the structure of the review. Data regarding publication details, study design, patient pathology, treatments received, follow-up periods, overall survival and safety were collected and tabulated, and study quality was assessed using the MINORS score for non-randomized studies. Sixteen of 288 studies met the inclusion criteria. Seven publications related to the role of neoadjuvant chemotherapy, and there was no strong evidence for the efficacy of neoadjuvant chemotherapy. Of note, one study observed worse survival outcomes when neoadjuvant therapy was used. Fourteen studies investigated the role of adjuvant chemotherapy and there was limited evidence that adjuvant systemic chemotherapy improves survival following CRS and HIPEC. Systemic adjuvant chemotherapy may be associated with improved overall survival, but the role of systemic neoadjuvant chemotherapy cannot be determined by the currently available evidence. The delivery of a combination of the two modes of systemic chemotherapy has not been investigated in a randomized controlled trial to date. Further research designed to investigate the role of these modalities in the patient's treatment is required.

Treatment of colorectal peritoneal metastases requires multidisciplinary efforts

Treatment of colorectal peritoneal metastases requires multidisciplinary efforts

Multidisciplinary Treatment for Colorectal Peritoneal Metastases: Review of the Literature

Peritoneum is one of the common sites of metastasis in advanced stage colorectal cancer patients. Colorectal cancer patients with peritoneal metastases (PM) are traditionally believed to have poor prognosis, which indicates it is of no value to adopt surgical treatment. With the advancement of surgical techniques, hyperthermic intraperitoneal chemotherapy (HIPEC), and multidisciplinary treatment in recent years, the cognition and treatment strategies of colorectal peritoneal metastases (CPM) have changed dramatically. In terms of prognosis, CPM under the palliative systemic treatment shows an inferior outcome compared with nonperitoneal metastasis. Nevertheless, some CPM patients amenable to the complete peritoneal cytoreductive surgery (CRS) combined with HIPEC may achieve long-term survival. The prognostic factors of CPM comprise peritoneal carcinomatosis index (PCI), completeness of cytoreduction score (CC score), the presence of extraperitoneal metastasis (liver, etc.), Peritoneal Surface Disease Severity Score (PSDSS), Japanese peritoneal staging, and so forth. Taken together, literature data suggest that a multimodality approach combining complete peritoneal CRS plus HIPEC, systemic chemotherapy, and targeted therapy may be the best treatment option for PM from colorectal cancer.

Cytoreductive surgery of colorectal peritoneal metastases: outcomes after complete cytoreductive surgery and systemic chemotherapy only.

BackgroundCytoreductive peritoneal surgery (CRS) associated with hyperthermic peritoneal chemotherapy (HIPEC) has long been considered the standard treatment for colorectal peritoneal metastases (CPM). However, although efficacy of surgery has been demonstrated, evidence supporting HIPEC’s role is less certain.MethodOverall survival (OS), progression-free survival (PFS) and morbidity were analysed retrospectively for fifty consecutively included patients treated for colorectal CPM with complete CRS and systemic chemotherapy only.ResultsMedian peritoneal cancer index (PCI) was 8 (range 1-24). 23 patients had liver or lung metastases (LLM). 22 patients had synchronous CPM. 27 complications occurred (12 Grade 1/2, 14 Grade 3, 1 Grade 4a, 0 Grade 5). Median follow-up was 62.5 months (95 %CI 45.4-81.3), median survival 32.4 months (21.5-41.7). Three- and 5-year OS were 45.5% (0.31-0.59) and 29.64% (0.17-0.44) respectively. Presence of LLMs associated with peritoneal carcinomatosis was significantly associated with poorer prognosis, with survival at 5 years of 13.95% (95 %CI 2.9-33.6) vs. 43.87% (22.2-63.7) when no metastases were present (P= 0.018). Median PFS was 9.5 months (95 %CI 6.2-11.1).ConclusionWith an equivalent PCI range and despite one of the highest rates of LLM in the literature, our survival data of CRS + systemic chemotherapy only compare well with results reported after additional HIPEC. Tolerance was better with acceptable morbidity without any mortality. Extra-hepatic metastasis (LLM) is a strong factor of poor prognosis. Awaiting the results of the randomized PRODIGE trial, these results indicate that CRS + systemic chemotherapy only is a robust hypothesis to treat colorectal CPM.

Cytoreductive surgery and intraperitoneal chemotherapy for colorectal peritoneal metastases.

To systematically review the available evidence regarding cytoreductive surgery (CRS) and intraperitoneal chemotherapy (IPC) for colorectal peritoneal metastases (CPM). An electronic literature search was carried out to identify publications reporting oncological outcome data (overall survival and/or disease free survival and/or recurrence rates) following CRS and IPC for treatment of CPM. Studies reporting outcomes following CRS and IPC for cancer subtypes other than colorectal were only included if data were reported independently for colorectal cancer-associated cases; in addition studies reporting outcomes for peritoneal carcinomatosis of appendiceal origin were excluded. Twenty seven studies, published between 1999 and 2013 with a combined population of 2838 patients met the predefined inclusion criteria. Included studies comprised 21 case series, 5 case-control studies and 1 randomised controlled trial. Four studies provided comparative oncological outcome data for patients undergoing CRS in combination with IPC vs systemic chemotherapy alone. The primary indication for treatment was CPM in 96% of cases (2714/2838) and recurrent CPM (rCPM) in the remaining 4% (124/2838). In the majority of included studies (20/27) CRS was combined with hyperthermic intraperitoneal chemotherapy (HIPEC). In 3 studies HIPEC was used in combination with early post-operative intraperitoneal chemotherapy (EPIC), and 2 studies used EPIC only, following CRS. Two studies evaluated comparative outcomes with CRS + HIPEC vs CRS + EPIC for treatment of CPM. The delivery of IPC was performed using an "open" or "closed" abdomen approach in the included studies. The available evidence presented in this review indicates that enhanced survival times can be achieved for CPM after combined treatment with CRS and IPC.

Cytoreductive surgery and intraperitoneal chemotherapy for colorectal peritoneal and hepatic metastases: a case-control study.

Concomitant treatment of colorectal peritoneal metastases (PM) and hepatic metastases (HM) remains controversial. This study compares the cytoreductive surgery (CRS) and intraperitoneal chemotherapy (IPC) treatment of colorectal peritoneal metastases (PM) with the CRS/IPC/hepatic resection treatment of colorectal PM and HM. All patients from a prospective PM registry at the Uppsala institution treated concomitantly for PM/HM with CRS/IPC/hepatic resections were included in a PM/HM-group, n=11. They were matched 1(:)2 with patients from the registry being treated only for PM with CRS/IPC, n=22. Overall survival (OS), disease-free survival (DFS), morbidity, mortality, and recurrences were compared. The PM/HM-group had median OS of 15 months (95% CI: 6-46 months) and the PM-group had a median OS of 34 months (95% CI: 19-37 months), P=0.2. The DFS was 10 months (95% CI: 3-14 months) and 24 months (95% CI: 10-32 months) respectively, P=0.1. Morbidity was 27% in both groups and one postoperative death in the PM/HM-group. Currently, 1/10 (10%) patients with an R1 resection are disease-free in the PM/HM group while 9/20 (45%) are disease-free in the PM group (P=0.05). Concomitant treatment of PM and HM with CRS/IPC/hepatic resections is feasible with no significant increase in morbidity compared to CRS/IPC. The risk of recurrences is higher in the PM/HM group with a tendency towards worse DFS.