Body surface area-based versus concentration-based intraperitoneal perioperative chemotherapy in a rat model of colorectal peritoneal surface malignancy: pharmacologic guidance towards standardization.
ABSTRACT: Worldwide, cytoreductive surgery (CRS) and hyperthermic intraperitoneal perioperative chemotherapy (HIPEC) are used in current clinical practice for colorectal peritoneal surface malignancy (PSM) treatment. Although, there is an acknowledged standardization regarding the CRS, we are still lacking a much-needed standardization amongst the various intraperitoneal (IP) chemotherapy protocols, including the HIPEC dosing regimen. We should rely on pharmacologic evidence building towards such a standardization. The current IP chemotherapy dosing regimens can be divided into body surface area (BSA)-based and concentration-based protocols. A preclinical animal study was designed to evaluate pharmacologic advantage (PA), efficacy and survival. WAG/Rij rats were IP injected with the rat colonic carcinoma cell line CC-531. Animals were randomized into three groups: CRS alone or CRS combined with oxaliplatin-based HIPEC (either BSA- or concentration-based). There was no difference in PA between the two groups (p=0.283). Platinum concentration in the tumor nodule was significantly higher in the concentration-based group (p<0.001). Median survival did not differ between the treatment groups (p<0.250). This preclinical study, in contrast to previous thinking, clearly demonstrates that the PA does not provide any information about the true efficacy of the drug and emphasizes the importance of the tumor nodule as pharmacologic endpoint.
Project description:Peritoneal surface malignancy (PSM) is a common manifestation of digestive and gynecologic malignancies alike. At present, patients with isolated PSM are treated with a combination therapy of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). The combination of CRS and intraperitoneal (IP) chemotherapy should now be considered standard of care for PSM from appendiceal epithelial cancers, colorectal cancer and peritoneal mesothelioma. Although there is a near universal standardization regarding the CRS, we are still lacking a much-needed standardization among the various IP chemotherapy treatment modalities used today in clinical practice. Pharmacologic evidence should be generated to answer important questions raised by the myriad of variables associated with IP chemotherapy.
Project description:Peritoneal metastasis (PM) frequently occurs in patients with gastric cancer (GC) and confers a dismal prognosis despite advances in systemic chemotherapy. While systemic chemotherapy has poor peritoneal penetration, intraperitoneal (IP) chemotherapy remains sequestered, resulting in high peritoneal drug concentrations with less systemic side-effects. The first application of IP treatment was hyperthermic intraperitoneal chemotherapy (HIPEC) with cytoreductive surgery (CRS) for gastric cancer peritoneal metastasis (GCPM); but was associated with an increased morbidity and mortality rate without significantly improving overall survival (OS). While CRS confers limited benefit, the potential role of prophylactic HIPEC and laparoscopic neoadjuvant HIPEC are currently being evaluated. Combination systemic and IP chemotherapy (SIPC) gained popularity in the 1990s, since it provided the benefits of IP treatment while reducing surgical morbidity, demonstrating promising early results in multiple Phase II trials. Unfortunately, these findings were not confirmed in the recent PHOENIX-GC randomized controlled trial; therefore, the appropriate treatment for GCPM remains controversial. Small observational studies from Japan and Singapore have reported successful downstaging of PM in GC patients receiving SIPC who subsequently underwent conversion gastrectomy with a median OS of 21.6-34.6 months. Recently, the most significant development in IP-directed therapy is pressurized IP aerosol chemotherapy (PIPAC). Given that aerosol chemotherapy achieves a wider distribution and deeper penetration, the outcomes of multiple ongoing trials assessing its efficacy are eagerly awaited. Indeed, IP-directed therapy has evolved rapidly in the last 3 decades, with an encouraging trend toward improved outcomes in GCPM, and may offer some hope for an otherwise fatal disease.
Project description: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.
Project description:Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) provide an effective treatment option for selected patients with colorectal peritoneal metastasis with encouraging survival results. Many different drug combinations and HIPEC regimens including bidirectional, i.e. synchronous intravenous and intraperitoneal, drug application have been used. However, there is still no standardization of the HIPEC regimen.Between 05/2007 and 04/2010 190 patients underwent CRS and HIPEC at the University Hospital Regensburg. Thirty-two patients with peritoneal metastasis arising from colorectal or appendiceal cancer underwent complete macroscopic cytoreduction (CC-0/1) and bidirectional HIPEC and completed at least 3-year follow-up. Twenty patients received oxaliplatin-based (OX) and twelve patients received irinotecan-based HIPEC (IRI). Group-specific perioperative morbidity and 3-year survival has been determined.The grade 3/4 morbidity rate according to CTCAE v4 was 35.0% in the OX group vs. 33.3% in the IRI group (p = 1.000). There was no perioperative mortality in both groups. Median survival was 26.8 months (95% CI 15.7-33.1 months) in the IRI group and has not yet been reached in the OX group during a median follow-up of 39.4 months. Three-year survival rates were 65.0% in the OX group vs. 41.7% in the IRI group (p = 0.295).The morbidity and toxicity rates of bidirectional irinotecan-based and oxaliplatin-based HIPEC are comparable. Nevertheless, in the absence of contraindications oxaliplatin-based HIPEC might be preferred due to the positive trend regarding 3-year and median survival.
Project description:BACKGROUND:This randomized phase III study was to evaluate the efficacy and safety of cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) for the treatment of peritoneal carcinomatosis (PC) from gastric cancer. METHODS:Sixty-eight gastric PC patients were randomized into CRS alone (n = 34) or CRS + HIPEC (n = 34) receiving cisplatin 120 mg and mitomycin C 30 mg each in 6000 ml of normal saline at 43 ± 0.5°C for 60-90 min. The primary end point was overall survival, and the secondary end points were safety profiles. RESULTS:Major clinicopathological characteristics were balanced between the 2 groups. The PC index was 2-36 (median 15) in the CRS + HIPEC and 3-23 (median 15) in the CRS groups (P = 0.489). The completeness of CRS score (CC 0-1) was 58.8% (20 of 34) in the CRS and 58.8% (20 of 34) in the CRS + HIPEC groups (P = 1.000). At a median follow-up of 32 months (7.5-83.5 months), death occurred in 33 of 34 (97.1%) cases in the CRS group and 29 of 34 (85.3%) cases of the CRS + HIPEC group. The median survival was 6.5 months (95% confidence interval 4.8-8.2 months) in CRS and 11.0 months (95% confidence interval 10.0-11.9 months) in the CRS + HIPEC groups (P = 0.046). Four patients (11.7%) in the CRS group and 5 (14.7%) patients in the CRS + HIPEC group developed serious adverse events (P = 0.839). Multivariate analysis found CRS + HIPEC, synchronous PC, CC 0-1, systemic chemotherapy ? 6 cycles, and no serious adverse events were independent predictors for better survival. CONCLUSIONS:For synchronous gastric PC, CRS + HIPEC with mitomycin C 30 mg and cisplatin 120 mg may improve survival with acceptable morbidity.
Project description:Although cytoreductive surgery (CRS) and hyperthermic perioperative chemotherapy (HIPEC) have not been shown to be effective by themselves, as a combined treatment they are now standard of care for peritoneal metastases from appendiceal cancer and from colorectal cancer as well as peritoneal mesothelioma. The timing of the HIPEC in relation to the CRS is crucial in that the HIPEC is to destroy minimal residual disease that remains following the CRS and prevent microscopic tumor emboli within the abdomen and pelvis from implanting within the resection site, within fibrinous clot, or within blood clot. Proper selection of chemotherapy agents is crucial to the long-term benefit of CRS and HIPEC. One must consider the response expected with the cancer chemotherapy agent, its area under the curve (AUC) ratio indicating the amount of dose intensity within the peritoneal space, and the drug retention within the peritoneal space for a prolonged exposure. Hyperthermia will augment the cytotoxicity of the cancer chemotherapy agents and improve drug penetration. Irrigation techniques should not be overlooked as an important means of reducing the cancer cell burden within the abdomen and pelvis. Multiple technologies for HIPEC exist and these have advantages and disadvantages. The techniques vary from a totally open technique with a vapor barrier over the open abdominal space to a totally closed technique whereby the HIPEC is administered at the completion of the surgical procedure. The open techniques depend on a table-mounted retractor for suspension of the skin edges allowing a reservoir to occur within the abdomen and pelvis. There are nearly a dozen commercially available hyperthermia pumps, all of which seem to perform adequately for HIPEC although there is a variable degree of convenience and documentation of the HIPEC procedure. As the management of peritoneal metastases has progressed over three decades, early cases are now seen in which a laparoscopic CRS and HIPEC may be appropriate. Also, prophylactic use of laparoscopic HIPEC with perforated appendiceal malignancies and T4 colon cancers may be appropriate.
Project description:Peritoneal metastasis (PM) originating from gastrointestinal and gynecological malignancies are associated with a poor prognosis and rapid disease progression. Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) is an effective treatment option with curative intent. Hyperthermia enhances the cytotoxicity of chemotherapeutic drugs, thereby killing microscopic tumors and reducing the risk of tumor recurrence. Eight parameters potentially have an impact on the efficacy of HIPEC: the type of drug, drug concentrations, carrier solution, volume of the perfusate, temperature of the perfusate, duration of the treatment, the technique of delivery, and patient selection. In this review, a literature search was performed on PubMed, and a total of 564 articles were screened of which 168 articles were included. Although HIPEC is a successful treatment, there is no standardized method for delivering HIPEC: the choice of parameters is presently largely determined by institutional preferences. We discuss the current choice of the parameters and hypothesize about improvements toward uniform standardization. Quantifying the effect of each parameter separately is necessary to determine the optimal way to perform HIPEC procedures. In vivo, in vitro, in silico, and other experimental studies should shed light on the role of each of the eight parameters.
Project description:Peritoneal carcinomatosis (PC) was previously considered an incurable disease with a poor survival outcome. As our understanding of its biology evolved, the paradigm of the management of PC from colorectal cancer (CRC) has changed, including the combination of macroscopic disease control, cytoreductive surgery (CRS), maximal regional chemotherapy to treat residual microscopic disease, and hyperthermic intraperitoneal chemotherapy (HIPEC). As with many surgical innovations, CRS with HIPEC has evolved faster than data to support it, leaving many skeptics and critics. This review highlights the recent evidence of current practice and outcome of CRS with HIPEC. Furthermore, it also summarizes the ongoing clinical trials and potential future progress of this treatment modality.
Project description:BACKGROUND:The field of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has suffered from a lack of clinical trials to validate its expanding use. OBJECTIVE:To evaluate published and ongoing clinical trials seeking to better define role of CRS/HIPEC in the treatment of peritoneal surface malignancies. METHODS:Systematic review by PubMed search was performed using terms "Clinical trial," "intraperitoneal chemotherapy," and "HIPEC." ClinicalTrials.gov and EudraCT registries were searched for active clinical trials. Eligibility included CRS/HIPEC trials investigating adult patient populations from published clinical reports and/or trials currently accruing or at completion. RESULTS:Thirteen published trials and 57 active clinical trials were included for review. CONCLUSIONS:Published and ongoing U.S. and international clinical trials for CRS and HIPEC are defining important parameters that include improving patient selection, strategic sequences of treatment, cytoreductive strategies, chemotherapeutics, optimal hyperthermic temperature and timing, and toxicity profiles. Main barriers or limitations to trial development remain patient enrollment, trial design, and oncologic community collaboration. Overall progress is positive with increasing number of clinical trials throughout the world. Collaboration between surgeons and the wider oncologic community will be crucial to validate this important treatment strategy.
Project description:Colorectal cancer peritoneal metastasis (CPM) confers an exceptionally poor prognosis, and traditional treatment involving systemic chemotherapy (SC) is largely ineffective. Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) is increasingly advocated for selected patients with CPM; however, opinions are divided because of the perceived lack of evidence, high morbidity, mortality, and associated costs for this approach. As there is no clear consensus, the aim of this study was to compare outcomes following CRS+HIPEC vs SC alone for CPM using meta-analytical methodology, focusing on survival outcomes. Secondary outcomes assessed included morbidity, mortality, quality of life (QOL), and health economics (HE).An electronic literature search was conducted to identify studies comparing survival following CRS+HIPEC vs SC for CPM. The odds ratio (OR) was calculated using the Mantel-Haenszel method with corresponding 95% confidence intervals (CI) and P-values. Heterogeneity was examined using the Q-statistic and quantified with I(2). The fixed-effect model (FEM) was used in the absence of significant heterogeneity. For included studies, 2- and 5-year survival was compared for CRS+HIPEC vs SC alone.Four studies (three case-control, one RCT) provided comparative survival data for patients undergoing CRS+HIPEC (n=187) vs SC (n=155) for CPM. Pooled analysis demonstrated superior 2-year (OR 2.78; 95% CI 1.72-4.51; P=0.001) and 5-year (OR 4.07; 95% CI 2.17-7.64; P=0.001) survival with CRS+HIPEC compared with SC. Mortality ranged from 0 to 8%. No data were available for the assessment of QOL or HE.Although limited by between-study heterogeneity, the data support the assertion that in carefully selected patients, multimodal treatment of CPM with CRS+HIPEC has a highly positive prognostic impact on medium- and long-term survival compared with SC alone. There is a paucity of comparative data available on morbidity, QOL, and HE.