Vic J. Verwaal

Randomized Trial of Cytoreduction and Hyperthermic Intraperitoneal Chemotherapy Versus Systemic Chemotherapy and Palliative Surgery in Patients With Peritoneal Carcinomatosis of Colorectal Cancer

PURPOSE To confirm the findings from uncontrolled studies that aggressive cytoreduction in combination with hyperthermic intraperitoneal chemotherapy (HIPEC) is superior to standard treatment in patients with peritoneal carcinomatosis of colorectal cancer origin. PATIENTS AND METHODS Between February 1998 and August 2001, 105 patients were randomly assigned to receive either standard treatment consisting of systemic chemotherapy (fluorouracil-leucovorin) with or without palliative surgery, or experimental therapy consisting of aggressive cytoreduction with HIPEC, followed by the same systemic chemotherapy regime. The primary end point was survival. RESULTS After a median follow-up period of 21.6 months, the median survival was 12.6 months in the standard therapy arm and 22.3 months in the experimental therapy arm (log-rank test, P =.032). The treatment-related mortality in the aggressive therapy group was 8%. Most complications from HIPEC were related to bowel leakage. Subgroup analysis of the HIPEC group showed that patients with 0 to 5 of the 7 regions of the abdominal cavity involved by tumor at the time of the cytoreduction had a significantly better survival than patients with 6 or 7 affected regions (log-rank test, P <.0001). If the cytoreduction was macroscopically complete (R-1), the median survival was also significantly better than in patients with limited (R-2a), or extensive residual disease (R-2b; log-rank test, P <.0001). CONCLUSION Cytoreduction followed by HIPEC improves survival in patients with peritoneal carcinomatosis of colorectal origin. However, patients with involvement of six or more regions of the abdominal cavity, or grossly incomplete cytoreduction, had still a grave prognosis.

Long-term survival of peritoneal carcinomatosis of colorectal origin

AbstractBackgroundPeritoneal carcinomatosis of colorectal cancer is probably best treated by cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC). In The Netherlands Cancer Institute, this treatment has been performed since 1995. The long tradition of this treatment enabled us to study long-term survival in detail.Methods Between 1995 and 2003, 117 patients were treated by cytoreduction and HIPEC. The aim of the cytoreduction was to remove all visible tumor. After the cytoreduction, the abdomen was perfused with mitomycin C (35 mg/m2) at 40°C to 41°C for 90 minutes. Survival was calculated by the Kaplan-Meier method. Survival was also analyzed for the following subgroups: no residual tumor, residual tumor ≤2.5 mm, and more residual tumor. Hazard ratios for each of the seven abdominal regions were calculated to determine the influence on survival.ResultsThe median survival was 21.8 months. The 1-, 3-, and 5-year survival rates were 75%, 28%, and 19%, respectively. The Kaplan-Meier curve reached a plateau of 18% at 54 months. In 59 patients a complete cytoreduction was achieved, and in 41 patients there was minimal residual disease. The median survival of these patient groups was 42.9 and 17.4 months, respectively. When gross macroscopic tumor was left behind, as was the case in 17 patients, the median survival was 5 months. Involvement of the small bowel before cytoreduction was associated with poorer outcome.Conclusions Cytoreduction followed by HIPEC showed a median survival of 21 months. From 3 years on, a consistent group of 18% of patients stayed alive.

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.

Predictors and survival of synchronous peritoneal carcinomatosis of colorectal origin: A population‐based study

The aim of our study was to provide population‐based data on incidence and prognosis of synchronous peritoneal carcinomatosis and to evaluate predictors for its development. Diagnosed in 1995–2008, 18,738 cases of primary colorectal cancer were included. Predictors of peritoneal carcinomatosis were analysed by multivariable logistic regression analysis. Median survival in months was calculated by site of metastasis. In the study period, 904 patients were diagnosed with synchronous peritoneal carcinomatosis (4.8% of total, constituting 24% of patients presenting with M1 disease). The risk of peritoneal carcinomatosis was increased in case of advanced T stage [T4 vs. T1,2: odds ratio (OR) 4.7, confidence limits 4.0–5.6), advanced N stage [N0 vs. N1,2: OR 0.2 (0.1–0.2)], poor differentiation grade [OR 2.1 (1.8–2.5)], younger age [<60 years vs. 70–79 years: OR 1.4 (1.1–1.7)], mucinous adenocarcinoma [OR 2.0 (1.6–2.4)] and right‐sided localisation of primary tumour [left vs. right: OR 0.6 (0.5–0.7)]. Median survival of patients with peritoneum as single site of metastasis remained dismal [1995–2001: 7 (6–9) months; 2002–2008: 8 (6–11) months], contrasting the improvement among patients with liver metastases [1995–2001: 8 (7–9) months; 2002–2008: 12 (11–14) months]. To conclude, synchronous peritoneal metastases from colorectal cancer are more frequent among younger patients and among patients with advanced T stage, mucinous adenocarcinoma, right‐sided tumours and tumours that are poorly differentiated. The prognosis of synchronous peritoneal carcinomatosis remains poor with a median survival of 8 months and even worse if concomitant metastases in other organs are present.

Recurrences after Peritoneal Carcinomatosis of Colorectal Origin Treated by Cytoreduction and Hyperthermic Intraperitoneal Chemotherapy: Location, Treatment, and Outcome

Background: After treatment of peritoneal carcinomatosis of colorectal cancer origin by cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC), recurrences develop in approximately 80% of patients. This study evaluates the outcome of such recurrences after initial treatment by cytoreduction and HIPEC.Methods: Between November 1995 and May 2003, 106 patients underwent cytoreduction and HIPEC. The progression-free interval, the location of the recurrence, and its treatment were recorded. Factors potentially related to survival after recurrences were studied.Results: Sixty-nine patients had a recurrence within the study period. For patients who had undergone a gross incomplete initial cytoreduction, the median duration of survival after recurrence was 3.7 months (standard error of the mean [SE], .3). If a complete cytoreduction had been accomplished initially, the median duration of survival after the recurrence was 11.1 months (SE, .9). A shorter interval between HIPEC and recurrence was associated with shorter survival after treatment of recurrence (hazard ratio, .94; SE, .02). After effective initial treatment, a second surgical debulking for recurrent disease resulted in a median survival duration of 10.3 months (SE, 1.9), and after treatment with chemotherapy it was 8.5 months (SE, 1.6). The survival was 11.2 months (SE, .5) for patients who received radiotherapy for recurrent disease. Patients who did not receive further treatment survived 1.9 months (SE, .3).Conclusions: Treatment of recurrence after cytoreduction and HIPEC is often feasible and seems worthwhile in selected patients. Selection should be based mainly on the completeness of initial cytoreduction and the interval between HIPEC and recurrence.

Population Pharmacokinetics and Pharmacodynamics of Mitomycin During Intraoperative Hyperthermic Intraperitoneal Chemotherapy

AbstractBackground: During recent years, cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) with mitomycin has been used for various malignancies. Objective: To characterise the population pharmacokinetics and pharmacodynamics of mitomycin during HIPEC. Methods: 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. Results: 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. Conclusion: 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 HIPEC.

The eligibility for local-regional treatment of peritoneal surface malignancy

At the Fifth International Workshop on Peritoneal Surface Malignancy, held in Milan, the consensus on technical aspects of cytoreductive surgery (CRS) for peritoneal surface malignancy was obtained through the Delphi process. General conflicting points concerning the eligibility to the local‐regional therapy were discussed and voted. J. Surg. Oncol. 2008;98:220–223.

American Society of peritoneal surface malignancies opinion statement on defining expectations from cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in patients with colorectal cancer

JESUS ESQUIVEL, MD,* POMPILIU PISO, MD, VIC VERWAAL, MD, THOMAS BACHLEITNER-HOFMANN, MD, OLIVIER GLEHEN, MD, SANTIAGO GONZÁLEZ-MORENO, MD, MARCELLO DERACO, MD, JOERG PELZ, MD, RICHARD ALEXANDER, MD, AND GABRIEL GLOCKZIN, MD Department of Surgical Oncology, Cancer Treatment Centers of America, Philadelphia, Pennsylvania Division of Surgical Oncology, Hospital Barmherzige, Regensburg, Germany National Cancer Institute, Amsterdam, The Netherlands Vienna University Hospital, Vienna, Australia Department of Surgical Oncology, Centre Hospitalier Lyon-Sud, Pierre-Benite, France Department of Surgical Oncology, MD Anderson Cancer Center, Madrid, Spain Department of Surgery, National Cancer Institute, Milan, Italy Department of Surgery, University of Wuerzburg, Wuerzburg, Germany Department of Surgical Oncology, University of Maryland, Baltimore, Maryland Department of Surgical Oncology, Regensburg University Hospital, Regensburg, Germany

Stability of oxaliplatin in chloride-containing carrier solutions used in hyperthermic intraperitoneal chemotherapy

PURPOSE Oxaliplatin is increasingly becoming the chemotherapeutic drug of choice for the treatment of peritoneal malignancies using cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC). Oxaliplatin is unstable in chloride-containing media, resulting in the use of 5% dextrose as the carrier solution in these procedures. Exposure of the peritoneum to 5% dextrose during perfusion times varying from 30 min to 90 min is associated with serious hyperglycemias and electrolyte disturbances. This can result in significant postoperative morbidity and mortality. In order to find out whether safer, chloride-containing carrier solutions can be used, we report the results of in-vitro analysis of oxaliplatin stability in both chloride-containing and choride-deficient carrier solutions and discuss the implications for oxaliplatin-based CRS-HIPEC procedures. METHODS 5 mg of oxaliplatin was added to 50 mL of various carrier solutions at 42 °C: 5% dextrose, 0.9% sodium chloride, Ringer lactate, Dianeal(®) PD4 glucose 1.36% solution for peritoneal dialysis and 0.14 M sterile phosphate buffer pH 7.4. Samples were collected at standardized intervals and oxaliplatin concentration was determined using a stability indicating high-performance liquid chromatographic method, coupled to an UV detector (HPLC-UV); oxaliplatin degradation products were identified using HPLC-mass spectometry. RESULTS In 5% dextrose, oxaliplatin concentration remained stable over a 2-hour period. Increasing chloride concentrations were associated with increasing degradation rates; however, this degradation was limited to <10% degradation after 30 min (the standard peritoneal perfusion time in most clinical CRS-HIPEC protocols) and <20% degradation after 120 min at 42 °C. In addition, oxaliplatin degradation was associated with the formation of its active drug form [Pt(dach)Cl2]. CONCLUSIONS The use of chloride-containing carrier solutions for oxaliplatin does not relevantly affect its concentrations under the tested in-vitro conditions. Chloride seems to promote formation of the active cytotoxic drug form of oxaliplatin and therefore could enhance its cytotoxic effect. These data show that more physiological, chloride-containing carrier solutions can be used safely and effectively as a medium for oxaliplatin in CRS-HIPEC procedures.

Peritoneal metastases from small bowel cancer: Results of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in The Netherlands

INTRODUCTION Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS + HIPEC) is currently considered the standard of care for pseudomyxoma peritonei, mesothelioma and peritoneal metastases (PM) from colorectal cancer. CRS + HIPEC has also been suggested as a potential treatment option in PM of the much rarer small bowel cancer. Therefore, the current study was undertaken to investigate the results of CRS + HIPEC in all HIPEC centers in The Netherlands. METHODS From the 4 tertiary referral centers for peritoneal surface malignancies in The Netherlands, data from all patients with peritoneally metastasized small bowel carcinoma intended to undergo CRS and HIPEC were collected between January 2005 and July 2014. Primary tumor characteristics, operative details, and survival outcomes were collected. RESULTS Sixteen of 19 patients (84.2%) who underwent explorative laparotomy underwent CRS + HIPEC. Of these patients, 81.3% were female, and primary tumors were mainly located in the ileum (50%). A complete macroscopic resection was achieved in 93.8%. Serious adverse events requiring re-intervention occurred in 25%, and no in-hospital mortality was observed. Recurrent disease was observed in 50% of patients and median survival after CRS and HIPEC was 31 months. CONCLUSION In a select group of patients in whom a complete macroscopic resection can be achieved, survival rates comparable with those in colorectal PM are attainable with acceptable morbidity. The role of adjuvant chemotherapy needs further research.