Adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with colon cancer at high risk of peritoneal carcinomatosis; the COLOPEC randomized multicentre trial

Background: The peritoneum is the second most common site of recurrence in colorectal cancer. Early detection of peritoneal carcinomatosis (PC) by imaging is difficult. Patients eventually presenting with clinically apparent PC have a poor prognosis. Median survival is only about five months if untreated and the benefit of palliative systemic chemotherapy is limited. Only a quarter of patients are eligible for curative treatment, consisting of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CR/HIPEC). However, the effectiveness depends highly on the extent of disease and the treatment is associated with a considerable complication rate. Methods/Design: The aim of this study is to determine the effectiveness of adjuvant HIPEC in preventing the development of PC in patients with colon cancer at high risk of peritoneal recurrence. This study will be performed in the nine Dutch HIPEC centres, starting in April 2015. Eligible for inclusion are patients who underwent curative resection for T4 or intra-abdominally perforated cM0 stage colon cancer. After resection of the primary tumour, 176 patients will be randomized to adjuvant HIPEC followed by routine adjuvant systemic chemotherapy in the experimental arm, or to systemic chemotherapy only in the control arm. Adjuvant HIPEC will be performed simultaneously or shortly after the primary resection. Oxaliplatin will be used as chemotherapeutic agent, for 30 min at 42-43 °C. Just before HIPEC, 5-fluorouracil and leucovorin will be administered intravenously. Primary endpoint is peritoneal disease-free survival at 18 months. Diagnostic laparoscopy will be performed routinely after 18 months postoperatively in both arms of the study in patients without evidence of disease based on routine follow-up using CT imaging and CEA. Discussion: Adjuvant HIPEC is assumed to reduce the expected 25 % absolute risk of PC in patients with T4 or perforated colon cancer to a risk of 10 %. This reduction is likely to translate into a prolonged overall survival. Trial registration number: NCT02231086 (Clinicaltrials.gov)

Imagine a world without cancer

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.Abstract Background Since the War on Cancer was declared in 1971, the United States alone has expended some $300 billion on research, with a heavy focus on the role of genomics in anticancer therapy. Voluminous data have been collected and analyzed. However, in hindsight, any achievements made have not been realized in clinical practice in terms of overall survival or quality of life extended. This might be justified because cancer is not one disease but a conglomeration of multiple diseases, with widespread heterogeneity even within a single tumor type. Discussion Only a few types of cancer have been described that are associated with one major signaling pathway. This enabled the initial successful deployment of targeted therapy for such cancers. However, soon after this targeted approach was initiated, it was subverted as cancer cells learned and reacted to the initial treatments, oftentimes rendering the treatment less effective or even completely ineffective. During the past 30 plus years, the cancer classification used had, as its primary aim, the facilitation of communication and the exchange of information amongst those caring for cancer patients with the end goal of establishing a standardized approach for the diagnosis and treatment of cancers. This approach should be modified based on the recent research to affect a change from a service-based to an outcome-based approach. The vision of achieving long-term control and/or eradicating or curing cancer is far from being realized, but not impossible. In order to meet the challenges in getting there, any newly proposed anticancer strategy must integrate a personalized treatment outcome approach. This concept is predicated on tumor- and patient-associated variables, combined with an individualized response assessment strategy for therapy modification as suggested by the patients own results. As combined strategies may be outcome-orientated and integrate tumor-, patient- as well as cancer-preventive variables, this approach is likely to result in an optimized anticancer strategy. Summary Herein, we introduce such an anticancer strategy for all cancer patients, experts, and organizations: Imagine a World without Cancer

Short-term outcome in patients treated with cytoreduction and HIPEC compared to conventional colon cancer surgery

textabstractCytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is an extensive procedure with considerable morbidity. Since only few hospitals perform CRS + HIPEC, this might lead to confounded outcomes between hospitals when audited. This study aims to compare outcomes between peritoneally metastasized (PM) colon cancer patients treated with CRS + HIPEC and patients undergoing conventional colon surgery. Furthermore, the impact of CRS + HIPEC on the risk of postoperative complications will be assessed, probably leading to better insight into how to report on postoperative outcomes in this distinct group of patients undergoing extensive colon surgery.All patients with primary colon cancer who underwent segmental colon resection in a tertiary referral hospital between 2011 and 2014 were included in this prospective cohort study. Outcome after surgery was compared between patients who underwent additional CRS + HIPEC treatment or conventional surgery.Consequently, 371 patients underwent surgery, of which 43 (12%) underwent CRS + HIPEC. These patients were younger and healthier than patients undergoing conventional

Short-term outcome in patients treated with cytoreduction and HIPEC compared to conventional colon cancer surgery

Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is an extensive procedure with considerable morbidity. Since only few hospitals perform CRS?+?HIPEC, this might lead to confounded outcomes between hospitals when audited. This study aims to compare outcomes between peritoneally metastasized (PM) colon cancer patients treated with CRS?+?HIPEC and patients undergoing conventional colon surgery. Furthermore, the impact of CRS?+?HIPEC on the risk of postoperative complications will be assessed, probably leading to better insight into how to report on postoperative outcomes in this distinct group of patients undergoing extensive colon surgery.All patients with primary colon cancer who underwent segmental colon resection in a tertiary referral hospital between 2011 and 2014 were included in this prospective cohort study. Outcome after surgery was compared between patients who underwent additional CRS?+?HIPEC treatment or conventional surgery.Consequently, 371 patients underwent surgery, of which 43 (12%) underwent CRS?+?HIPEC. These patients were younger and healthier than patients undergoing conventional surgery. Tumor characteristics were less favorable and surgery was more extensive in CRS?+?HIPEC patients. The morbidity rate was also higher in CRS?+?HIPEC patients (70% vs 41%; P

Survival Analysis of Pseudomyxoma Peritonei Patients Treated by Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy

OBJECTIVE: To evaluate the survival of patients with pseudomyxoma peritonei (PMP) treated by cytoreductive surgery and intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC), and to identify factors with prognostic value. SUMMARY BACKGROUND DATA: PMP is a clinical syndrome characterized by progressive intraperitoneal accumulation of mucous and mucinous implants, usually derived from a ruptured mucinous neoplasm of the appendix. Survival is dominated by pathology. METHODS: A total of 103 patients (34 men and 69 women) treated at The Netherlands Cancer Institute between 1996 and 2004 were identified. Survival was calculated from date of initial treatment and corrected for a second procedure. PMP was pathologically categorized into disseminated peritoneal adenomucinosis (DPAM), peritoneal mucinous carcinomatosis (PMCA), and an intermediate subtype (PMCA-I). Clinical and pathologic factors were analyzed to identify their prognostic value for survival. RESULTS: Median follow-up was 51.5 months (range, 0.1–99.5 months). Recurrence developed in 44%. A second procedure for recurrence was performed in 11 patients. The median disease-free interval was 25.6 months (95% confidence interval [CI], 14.8–43.6 months). The 3-year and 5-year disease-free survival probability was 43.6% (95% CI, 34.4%–55.2%) and 37.4% (95% CI, 28.2%–49.5%), respectively. The disease-specific 3-year and 5-year survival probability was 70.9% (95% CI, 62.0%–81.2%) and 59.5% (95% CI 48.7%–72.5%), respectively. Factors associated with survival were pathological subtype, completeness of cytoreduction, and degree and location of tumor load (P < 0.05). The main prognostic factor, independently associated with survival, was the pathologic subtype (P < 0.01). CONCLUSION: Cytoreductive surgery in combination with intraoperative HIPEC is a feasible treatment strategy for PMP in terms of survival. The pathologic subtype remains the dominant factor in survival. Patients should be centralized to improve survival by a combination of surgical experience and adequate patient selection

Population pharmacokinetics and pharmacodynamics of mitomycin during intraoperative hyperthermic intraperitoneal chemotherapy

During recent years, cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) with mitomycin has been used for various malignancies. To characterise the population pharmacokinetics and pharmacodynamics of mitomycin during HIPEC. Forty-seven patients received mitomycin 35 mg/m2 intraperitoneally as a perfusion over 90 minutes. Mitomycin concentrations were determined in both the peritoneal perfusate and plasma. The observed concentration-time profiles were used to develop a population pharmacokinetic model using nonlinear mixed-effect modelling (NONMEM). The area under the plasma concentration-time curve (AUC) was related to the haematological toxicity. Concentration-time profiles of mitomycin in perfusate and plasma were adequately described with one- and two-compartment models, respectively. The average volume of distribution of the perfusate compartment (V1) and rate constant from the perfusate to the systemic circulation (k12) were 4.5 +/- 1.1L and 0.014 +/- 0.003 min(-1), respectively (mean +/- SD, n = 47). The average volume of distribution of the central plasma compartment (V2), clearance from the central compartment (CL) and volume of distribution of the peripheral plasma compartment (V3) were 28 +/- 16L, 0.55 +/- 0.18 L/min and 36 +/- 8L, respectively. The relationship between the AUC in plasma and degree of leucopenia was described with a sigmoidal maximum-effect (Emax) model. The pharmacokinetics of mitomycin during HIPEC could be fitted successfully to a multicompartment model. Relationships between plasma exposure and haematological toxicity were quantified. The developed pharmacokinetic-pharmacodynamic model can be used to simulate different dosage schemes in order to optimise mitomycin administration during HIPE