Population pharmacokinetics of hyperthermic intraperitoneal oxaliplatin in patients with peritoneal carcinomatosis after cytoreductive surgery

Purpose

To characterize the hyperthermic intraperitoneal oxaliplatin (HIO) pharmacokinetics in peritoneum and plasma in patients with peritoneal carcinomatosis (PC) after cytoreductive surgery (CRS).

Methods

Data from 36 patients receiving HIO diluted in isotonic 4 % icodextrin were combined with data from 13 patients receiving HIO diluted in isotonic 5 % dextrose. Total oxaliplatin in peritoneal and plasma fluids were used to characterize an open two-compartment disposition model with linear distribution and elimination and first-order absorption from peritoneum to plasma using NONMEM software. The effect of patient- and treatment-related covariates on oxaliplatin pharmacokinetic parameters was explored.

Results

The typical value (interindividual variability, %) in k _a , CL, and V _ss were 0.57 h^?1 (43 %), 1.71 L h^?1 (39 %), and 77 L (65 %), respectively. No significant effect of age, body surface area, sex, creatinine clearance, liver metastases, PC index, and complete cytoreduction on pharmacokinetic parameters was found. A 12–15 % reduction in peritoneal volume of distribution was observed in patients receiving HIO diluted in 5 % dextrose relative to those patients receiving HIO diluted in 4 % icodextrin.

Conclusions

The integration of peritoneal and plasma data demonstrated oxaliplatin linear absorption from peritoneum to plasma, non-specific distribution to a peripheral compartment, and linear elimination from the central compartment when HIO was administered with isotonic carrier solutions to PC patients who underwent CRS. Only the effect of the carrier solution had an impact in the peritoneal volume of distribution, but its clinical relevance seems to be limited, especially for short HIO infusions (<60 min).     

Quality of life in patients with peritoneal surface malignancies after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy

Background

An increasing number of patients are presenting with peritoneal carcinomatosis and more centers are performing cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). While morbidity and mortality are shown to be acceptable, quality of life after surgery should be assessed.

Methods

63 patients who had CRS and HIPEC from 2001 to 2012 and who were still alive and on follow up were included. The EORTC-QLQ-C30 was administered to the patients.

Results

Median age was 53 years (14–71). 44% had ovarian primaries, 21% had appendicael primaries and 19% had colorectal primaries. Median follow-up was 1.08 years (0.06–9.8). The median time from surgery to the questionnaire was 1.3 years (0.24–10.18). There was no statistical difference in scores when comparing by age, gender, recurrence, gender, PCI score, presence of a complication and type of primary cancer. Scores were highest less than 6 months after surgery, dropped subsequently but rose again after 2 years. Our patients had better scores compared to a control group of outpatient cancer patients at our institution as well as the reference EORTC group.

Conclusions

In keeping with previous quality of life studies done for CRS and HIPEC patients, we have shown that our patients can achieve a good quality of life after CRS and HIPEC even with recurrent disease.     

Direct surgery with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for patients with colorectal peritoneal metastases

IntroductionNeoadjuvant chemotherapy is widely used in treatment of peritoneal metastases from colorectal cancer, but there is little scientific evidence for this approach. This study aimed to study survival in patients treated with direct surgery with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC), i.e. without neoadjuvant chemotherapy.Material and methodsPatients with histopathologically confirmed peritoneal metastases from colorectal cancer that underwent first-time CRS-HIPEC with complete cytoreduction (CC0 or 1) at Karolinska University Hospital 2012–2019 were included. Patients with synchronous extraperitoneal metastases were excluded if not treated before end of follow-up. Factors associated with overall survival (OS) and disease-free survival (DFS) were evaluated using the Kaplan-Meier method and Cox regression models. The multivariable models were adjusted for sex, age, synchronous/metachronous peritoneal metastases, peritoneal carcinomatosis index (PCI), extraperitoneal metastases and the pathological tumor (T) and lymph node (N) stage of the primary tumor.ResultsIn all, 131 patients underwent complete CRS-HIPEC for peritoneal metastases without neoadjuvant chemotherapy. The median OS and DFS were 40.3 months and 12.5 months, respectively, in patients treated with direct surgery. In the multivariable model, PCI≥16 was the only variable associated with decreased OS, whereas elevated PCI, metachronous development of peritoneal metastases and synchronous extraperitoneal metastases were associated with decreased DFS. Age was not associated with an impaired prognosis.ConclusionPatients who underwent direct surgery with CRS-HIPEC had a good prognosis, with a median OS of more than 3 years. The results from this study question the need of neoadjuvant chemotherapy in all patients eligible for CRS-HIPEC.     

Long-term survival after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) for patients with peritoneal metastases of urachal cancer

IntroductionUrachal adenocarcinoma (UrAC) is a rare malignancy arising from persistent urachal remnants, which can cause peritoneal metastases (PM). Currently, patients with this stage UrAC are considered beyond cure. Our objective is to report long-term oncological outcome after cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) for patients with PM of urachal adenocarcinoma (UrAC).Materials and methodsWe identified 55 patients with UrAC treated at our hospital between 1994 and 2017. Patients were staged with CT, bone scintigraphy and/or PET/CT. From 2001 on, cN0M0 patients underwent staging laparoscopy. Ten patients had PM and were treated with CRS/HIPEC; 35 showed no metastases and underwent local treatment; 10 had distant metastases and received palliative chemotherapy.Disease-specific survival (DSS) rates were estimated using the Kaplan-Meier method and log-rank tests. Postoperative complications represent a secondary outcome.ResultsThe median follow-up was 96.8 months. Of the CRS/HIPEC patients, 5 (50%) developed a recurrence; 4 (40%) died of disease. The 2-yr and 5-yr DSS after CRS/HIPEC were 66.7% and 55.6%, respectively. DSS of the CRS/HIPEC patients did not significantly differ from DSS of patients without metastases who only underwent curative local treatment and was superior to patients with distant metastases (P = 0.012). The overall complication rate after CRS/HIPEC was 60%. Major complications (Clavien 3) constituted 20%. The study is limited by its retrospective nature and the small sample size.ConclusionCRS/HIPEC demonstrates satisfactory long-term oncological outcome for patients with PM of UrAC. It may be offered as a potentially curative treatment option for this group of patients.     

Morbidity after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy with carboplatin used for ovarian,tubal, and primary peritoneal cancer

Background and objectives: Hypertherm intraperitoneal chemotherapy (HIPEC) is increasingly used in the treatment of ovarian, tubal, and primary peritoneal cancer (OC). The aim was to evaluate short-term morbidity of cytoreductive surgery (CRS) and carboplatin HIPEC. Methods: Prospective feasibility study performed from January 2016 to December 2017. Twenty-five patients with primary OC (FIGO III-IV) received upfront or interval CRS combined with carboplatin HIPEC at dose 800 mg/m ². Primary outcome measurements: grade 3 to 5 adverse events within 30 days according to Common Terminology Criteria for Adverse Events. Secondary outcome measurements: reoperation rate, length of hospital stay, readmission rate, and time from surgery to systemic chemotherapy administration. Results: No deaths (grade 5) or grade 4 adverse events were observed. Eleven patients (44.0%) experienced at least one grade 3 adverse event, the most common being an infection (28.0%) and neutropenia (12.0%). The reoperation rate was 8.0%. The median hospital stay was 14 days (range 9-25 days), and five patients (25.0%) were readmitted within 30 days after surgery. Median time from surgery to the administration of the first dose of systemic chemotherapy was 41 days (range 24-81 days). Conclusion: Our small-scale prospective study supports that CRS and carboplatin HIPEC used for primary advanced-stage OC is feasible with acceptable morbidity.     

Indications for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in elderly patients with peritoneal malignancy

Purpose

A combination of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS + HIPEC) is effective for some peritoneal malignancies. However, the indications for elderly patients remain unclear, with substantial postoperative morbidity and mortality being problematic.

Materials

Clinical data were analyzed in 42 patients undergoing CRS + HIPEC for peritoneal malignancy. The primary tumor was located in the appendix in 32 cases and elsewhere in 10 cases. Operative results and survival data were compared between patients aged ≥70 and <70 years.

Results

Fourteen patients were older than 70 years. Elderly patients had a higher peritoneal cancer index (32.0 vs. 21.5), higher CA19-9 level (189.0 vs. 28.1), and higher frequency of grade 4–5 complications (5/9 vs. 2/26) than the younger patients. Grade 4–5 respiratory failure occurred in three elderly patients. There was a significant difference of postoperative survival between the elderly patients and younger patients, with 5-year survival rates being 41.3 and 74.2%, respectively (p = 0.0166). The poor prognosis of elderly patients was related to the higher frequency of grade 4–5 complications.

Conclusions

Elderly patients were referred for treatment with more advanced disease than younger patients. An age ≥70 years was associated with more frequent grade 4–5 complications and worse survival. Performing CRS + HIPEC in elderly patients should be considered carefully due to the risk of severe complications, especially respiratory failure.

     

Current status of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy in patients with peritoneal carcinomatosis from colorectal cancer

Peritoneal carcinomatosis (PC) arising from colorectal cancer (CRC) is generally considered a terminal condition with no treatment options. However novel treatment strategies have emerged combining cytoreductive surgery (CRS), including peritonectomy procedures, with intraperitoneal chemotherapy. The intraoperative application of cytotoxic drugs combined with hyperthermia (hyperthermic intraperitoneal chemotherapy [HIPEC]) has been considered to deliver cytotoxicity most effectively to peritoneal tumor implants. In selected groups of patients with no remaining macroscopic tumor manifestations on peritoneal surfaces after CRS and HIPEC, median survival times may reach 5 years, with a 5 year overall survival rate of 50%. HIPEC has been performed with different cytotoxic drugs, in combination with early postoperative intraperitoneal chemotherapy (EPIC), and embedded into various systemic perioperative and/or postoperative chemotherapeutic regimens. Prognosis largely depends on the intraabdominal tumor burden, which can be assessed by the peritoneal cancer index (PCI), and the completeness of cytoreduction. In this review we discuss the most relevant prognostic parameters, the outcome of patients with PC from CRC treated with CRS and HIPEC, and the impact of different chemotherapeutic variations used during HIPEC. From this analysis it can be concluded that CRS and HIPEC offers a chance for long-term survival in selected patients with PC of colorectal origin.     

新辅助化疗联合肿瘤细胞减灭术及术后腹腔热灌注化疗治疗晚期卵巢癌的疗效观察

  目的   探讨新辅助化疗联合肿瘤细胞减灭术及术后腹腔热灌注治疗晚期卵巢癌的临床疗效。   方法   分析郑州人民医院从2009年4月至2012年7月收治的60例晚期卵巢癌的患者,分为两组,研究组患者术前采取新辅助化疗联合肿瘤细胞减灭术及术后腹腔热灌注辅助化疗2次（顺铂80 mg）,术后给予TC/TP方案化疗,对照组采取常规肿瘤细胞减灭术+术后TC/TP方案化疗,比较两组患者在手术时间、出血量、腹水量、术后化疗疗程、疗效、复发与死亡、生存率等数据的差异。   结果   研究组患者在术中的各项疗效指标优于对照组,且有统计学显著性差异（P < 0.05）,临床治疗有效率高于对照组。   结论   在临床上对于晚期卵巢癌患者采取术前新辅助化疗联合肿瘤细胞减灭术术后腹腔热灌注辅助化疗,对于患者的疗效较常规的方法有较大的提高,值得在临床上进行推广。      

Long-term outcomes of elderly patients with peritoneal metastases of colorectal origin after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy

IntroductionCytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC) were reportedly safe for the elderly. However, long-term survival data in this subgroup of patients are scarce. Our aim was to evaluate the peri-operative and long-term outcomes of CRS + HIPEC in colorectal peritoneal metastases (CRC-PM) in patients ≥70 years of age.Material and methodsWe retrospectively analyzed our combined institutional databases for patients who underwent CRS + HIPEC for CRC-PM. Clinical and pathological characteristics, as well as overall survival (OS) and progression-free survival (PFS) were compared between the groups. Tumor extent was measured by the peritoneal carcinomatosis index (PCI) and completeness of cytoreduction by the CCR score. Major morbidity was defined according to Clavien-Dindo classification.ResultsThe dataset of 159 patients included 33 elderly and 126 non-elderly patients. Clinical characteristics between the groups differed only in medical comorbidities (Charlson comorbidity index 10 vs. 7, P < 0.001) and delivery of post-HIPEC adjuvant treatment (12.5% vs. 43.8%, P = 0.004). Overall PCI and CCR0 rates were similar between the groups, as were length of stay and major morbidity and mortality rates. Long-term outcomes in the elderly group were lower than those of the non-elderly (median OS: 21.8 vs. 40.5 months, P < 0.001; median PFS: 6 vs. 8 months, P = 0.02, respectively).ConclusionsCRS + HIPEC in selected elderly patients can be safe in terms of postoperative morbidity and mortality. However, despite the same surgical extents and radicality, their long-term outcomes are inferior, possibly due to under-usage of systemic chemotherapy.     

腹腔热灌注化疗联合细胞减灭术对胆囊癌腹膜转移的临床疗效研究

目的:探讨腹腔热灌注化疗(hyperthermic intraperitoneal chemtheropy,HIPEC)治疗胆囊癌伴腹膜转移患者的临床疗效研究。方法:本文回顾性分析海军军医大学东方肝胆外科医院2015年1月至2018年1月收治的84例胆囊癌合并腹膜转移患者,31例患者给予HIPEC联合细胞减灭术(cytoreductive surgery,CRS)+术后1个月全身化疗为研究组,53例给予细胞减灭术+术后1个月全身化疗为对照组,观察比较两组临床疗效及不良反应发生情况。结果:研究组中位生存时间为(21.72±2.96)个月,显著长于对照组的(14.93±2.09)个月(P<0.05)。研究组白细胞减少、血红蛋白减少、血小板减少、胃肠道反应、肝功能损伤和肾功能损伤较对照组无显著性差异(P>0.05)。结论:HIPEC治疗进展期胆囊癌临床疗效显著,可延长患者生存时间,不良反应较小,值得推广应用。     

肿瘤细胞减灭加腹腔热灌注化疗术后静脉血栓栓塞症的预防

  目的  评估行肿瘤细胞减灭术（cytoreductive surgery,CRS）加腹腔热灌注化疗（hyperthermic intraperitoneal chemotherapy,HIPEC）治疗的腹膜癌患者静脉血栓栓塞症（venous thromboembolism,VTE）发生风险,研究术后早期主/被动活动联合间歇充气加压按摩对VTE的预防效果。  方法  对2015年5月至2016年8月武汉大学中南医院肿瘤科收治的120例胃肠道及妇科肿瘤等来源的腹膜癌患者行CRS+HIPEC治疗,使用Caprini血栓风险评估模型评价VTE风险,所有患者采取早期肢体主/被动活动及间歇充气加压按摩治疗,记录分析VTE相关事件。  结果  患者中位Carprini评分为12（10~16）分,均为VTE极高危组,在3个月的随访中仅1例患者发生深静脉血栓,经药物治疗后痊愈。  结论  腹膜癌患者VTE风险极高,术后早期足背曲/跖曲及扩胸等主/被动运动联合间歇充气加压按摩,可有效预防VTE。      

Safety of intraperitoneal Mitomycin C versus intraperitoneal oxaliplatin in patients with peritoneal carcinomatosis of colorectal cancer undergoing cytoreductive surgery and HIPEC

Background

Colorectal peritoneal carcinomatosis (PC) is commonly treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). There is an ongoing international debate about which intraperitoneal chemotherapeutic agent is preferred, Mitomycin C (MMC) or oxaliplatin. We questioned whether the type of chemotherapeutic agent influenced postoperative complication rates or short-term survival.

Rate and extent of oxaliplatin absorption after hyperthermic intraperitoneal administration in peritoneal carcinomatosis patients

Purpose

To determine the rate and extent of hyperthermic intraperitoneal oxaliplatin (HIO) absorption in peritoneal carcinomatosis patients treated with cytoreductive surgery (CRS) and the effect of the isotonic carrier solution on HIO absorption parameters.

Methods

Full pharmacokinetic profiles collected in peritoneum and plasma from 57 subjects treated with CRS followed by 30 min of HIO were pooled with sparse plasma concentrations collected from 50 patients with solid tumors treated with intravenous oxaliplatin. Pharmacokinetic data were jointly analyzed with nonlinear mixed-effect model (NONMEM VII software). The effect of carrier solution (icodextrin 4 % vs. dextrose 5 %) and selected patient covariates on oxaliplatin pharmacokinetics was investigated. Model evaluation was performed using predictive checks and nonparametric bootstrap.

Results

An open linear two-compartment disposition model with linear absorption from peritoneum to plasma was used to characterize the oxaliplatin pharmacokinetics in peritoneum and plasma. No patient-related covariates were associated with oxaliplatin pharmacokinetics. The volume of distribution in the peritoneum (V _a) exponentially decreased due to the carrier solute absorption. The reduction in V _a was 1.76-fold faster when HIO was administered in dextrose 5 %, relative to icodextrin 4 %. For HIO durations of 30 min, the rate of oxaliplatin absorption ranges from 0.84 to 0.96 h^?1 for icodextrin 4 % and from 0.86 to 1.09 h^?1 for dextrose 5 %. The extent of HIO absorption was 38 %, regardless of the carrier solution.

Conclusions

Hyperthermic intraperitoneal oxaliplatin absorption is fast and incomplete. The small difference in oxaliplatin exposure between both carrier solutions evaluated is not clinically relevant for HIO durations of 30 min.     

Treatment of peritoneal carcinomatosis from colorectal cancer by cytoreductive surgery and hyperthermic perioperative intraperitoneal chemotherapy.

PURPOSE: Peritoneal carcinomatosis from colorectal cancer is resistant to standard treatments and median survival time for patients ranges between 6 and 8 months. Aggressive cytoreductive surgery with hyperthermic intraperitoneal perioperative chemotherapy may increase median survival. METHOD: Patients undergoing cytoreductive surgery and perioperative hyperthermic chemotherapy (mitomycin C, intraoperatively; 5-fluorouracil early post-operatively) for peritoneal carcinomatosis from colorectal cancer from 1996 to 2003 were evaluated retrospectively. RESULTS: From 1996 to 2003, 18 cytoreductive procedures were performed. The post-operative morbidity rate was 44.4% with no treatment related mortality. The median total operation time was 5 h 28 min (range: 3 h 20 min to 7 h 10 min). The median follow-up was 21 months. The median survival was 15 months. CONCLUSION: Surgical debulking and perioperative intraperitoneal chemotherapy improved survival with acceptable morbidity and mortality. Completeness of the resection was the most important prognostic indicator.     

Prognostic scores for colorectal cancer with peritoneal metastases treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy

Background: Selecting colorectal patients for HIPEC-surgery needs improvement. The study aim was to improve the colorectal peritoneal score (COREP) and to compare it with three other scores: peritoneal-surface disease-severity score (PSDS), colorectal-peritoneal metastases prognostic-surgical-score (COMPASS), and the CEA/PCI ratio.

Method: Twelve preoperative factors were chosen to evaluate for COREP score modification. Criteria from logistical analyses were set to qualify for the modified COREP score (mCOREP). Odds ratios were used to assign score points for the eligible factors with open/close laparotomy prediction as endpoint. mCOREP was applied internally and compared with the original COREP, PSDS, COMPASS, and CEA/PCI ratio. Odds ratios, hazard ratios, and Kaplan–Meier curves were used for comparison.

Results: Seven factors qualified for mCOREP: CEA, CA 19-9, CA-125, C-reactive protein, albumin, platelet count and signet-cell histology. mCOREP was superior to the original COREP. mCOREP and COMPASS scores were the only scores with independent prognostic value. The mCOREP had the best discriminatory ability between its prognostic groupings. mCOREP 11?+?had 9?months survival with half of patients being open/close surgery.

Conclusion: The mCOREP has successfully been simplified while still improving its prognostic ability. The mCOREP and COMPASS scores have independent prognostic value. Patients with mCOREP 11?+?may not benefit from treatment.     

完全肿瘤细胞减灭术加腹腔热灌注化疗治疗胃癌腹膜转移的病例筛选策略

目的:构建肿瘤细胞减灭程度(completeness of cytoreduction,CC)预测模型,为肿瘤细胞减灭术(cytoreductive surgery,CRS)加腹腔热灌注化疗(hyperthermic intraperitoneal chemotherapy,HIPEC)治疗胃癌腹膜转移(gastric cancer with peritoneal metastasis,GCPM)提供病例筛选方法。方法:比较完全CRS(complete CRS,CCRS)组和不完全CRS(incomplete CRS,ICRS)组患者基本临床病理特征和治疗参数,通过逻辑回归模型筛选CC独立预测因子,精准预测CCRS可能性。结果:125例患者纳入本研究,其中CC0组52例(41.6%),中位总生存期为30.0(95%CI:16.8～43.3)个月;CC1-3组73例,中位总生存期7.3(95%CI:5.7～8.8)个月,差异有统计学意义(P<0.001),而CC1、CC2和CC3组间中位总生存期差异无统计学意义(P>0.05)。因此,CC0定义为CCRS组,CC1-3定义为I...