Pharmacologic rationale for treatments of peritoneal surface malignancy from colorectal cancer

The peritoneal surfaces of the abdomen and pelvis are important sites for the dissemination of gastrointestinal and gynecologic malignancy. Transcoelomic dissemination of cancer cells gives rise to carcinomatosis, which, without special treatment, is a fatal manifestation of these diseases. To treat peritoneal carcinomatosis, cytoreductive surgery removes gross disease plus perioperative intraperitoneal and perioperative intravenous chemotherapy eradicates microscopic residual disease and chemical compatibilities. Chemotherapy agents are administered either by the intraperitoneal or intravenous route, based on their pharmacologic properties. A peritoneal-plasma barrier, which retards the clearance of high molecular weight chemotherapy from the peritoneal cavity, results in a large exposure of small cancer nodules on abdominal and pelvic surfaces. Tissue penetration of the intraperitoneal chemotherapy is facilitated by moderate hyperthermia (41-42°C). Targeting of intravenous chemotherapy to the peritoneal surface is facilitated by the intraperitoneal heat. A constant dose of chemotherapy agent and volume of carrier solution, based on body surface area, allows prediction of systemic drug exposure and systemic toxicity. Timing of the hyperthermic chemotherapy as a scheduled part of the surgical procedure to uniformly expose all peritoneal surfaces is crucial to success.     

Hyperthermic intraperitoneal doxorubicin: pharmacokinetics, metabolism, and tissue distribution in a rat model

Background: The cytotoxic effect of several anticancer agents, including doxorubicin, can be enhanced by hyperthermia. The purpose of this study was to evaluate the effect of hyperthermia on the pharmacokinetics, metabolism, and tissue distribution of intraperitoneal (i.p.) doxorubicin in a rodent model. Methods: Doxorubicin was given i.p. to 20 Sprague-Dawley rats at a dose of 2 mg/kg over 60 min. Rats were randomized into two groups according to the temperature of the peritoneal perfusate: group NT received normothermic (37 °C) i.p. doxorubicin; group HT received hyperthermic (43 °C) i.p. doxorubicin. During the course of i.p. chemotherapy, peritoneal fluid and blood were sampled every 10 min. At the end of the procedure, rats were sacrificed and tissue samples (liver, spleen, small bowel, omentum, bladder, diaphragm, abdominal wall, heart) were collected. Concentrations of doxorubicin and its aglycone metabolites were determined in peritoneal fluid, plasma, and tissues by HPLC. Results: No significant differences in areas under the curve (AUC) of peritoneal fluid doxorubicin and plasma doxorubicin were found between group NT and group HT. AUC ratios (AUC peritoneal fluid/AUC blood) were 87.9 for group NT and 82.9 for group HT. Group HT exhibited increased doxorubicin concentrations for all intraabdominal tissues. These differences were significant for spleen (P = 0.03), small bowel (P = 0.03), and omentum (P = 0.03). Doxorubicin aglycone was detected in plasma of both groups within the first 10 min of the procedure. There was a significant (P < 0.001) increase in plasma aglycone AUC for group HT when compared with group NT. Group HT exhibited increased aglycone concentration for all tissues. This difference was significant for liver (P < 0.001) and bladder (P < 0.001). Conclusion: Hyperthermia did not affect significantly the pharmacokinetics of i.p. doxorubicin. Tissue concentrations of doxorubicin in small bowel, omentum, and spleen were significantly increased when the drug was administered by hyperthermic i.p. perfusion. Hyperthermia increased significantly the doxorubicin aglycone concentrations in plasma, liver, and bladder. Received: 14 August 1996 / Accepted: 12 May 1997     

Cytoreductive surgery and intraperitoneal chemotherapy for peritoneal mesothelioma

Aims

Peritoneal mesothelioma is a rare disease and traditionally has been associated with a gloomy prognosis. The present study aimed to report the outcomes following surgery and intraperitoneal chemotherapy in selected patients with peritoneal mesothelioma.

Methods

Clinicopathological features, operative procedures, early outcomes and survival were analysed for 17 consecutive patients who underwent surgery for peritoneal mesothelioma between 1998 and 2007. Seventeen consecutive patients who underwent surgery for peritoneal mesothelioma between 1998 and 2007 were analysed for clinicopathological features, operative procedures, early outcomes and survival.

Results

Seventeen patients underwent 18 laparotomies. Most presented with abdominal distension (71%) and abdominal pain or discomfort (53%). Complete cytoreduction was achieved in 8 patients, major debulking in 8, and 1 patient had an exploratory laparotomy only due to extensive disease. One patient died on day 30 postoperatively due to a chest infection and pulmonary embolism. The median survival for 8 patients who underwent complete cytoreduction was 3.7 years (range, 0.7–6.9), whereas that for 8 patients with palliative debulking was 1.0 years year (range, 0.3–5.7). Among the 12 patients who had significant ascites as a presenting symptom, 10 reported good palliation of ascites.

Conclusions

Cytoreductive surgery combined with intraperitoneal chemotherapy appears to be the optimal treatment for selected patients with peritoneal mesothelioma. Increased familiarity with this condition's presentation and natural history, and knowledge of available treatment options, will hopefully facilitate treatment of these patients and expedite speedy referral to appropriate treatment centres.     

Intraperitoneal chemotherapy against peritoneal carcinomatosis: Current status and future perspective

Peritoneal carcinomatosis (PC), caused by advanced abdominal malignancies, such as those of the ovarian and gastrointestinal tracts, has an extremely poor prognosis. Intraperitoneal (IP) chemotherapy has been clinically applied for several decades, but its clinical efficacy has not been fully determined. An accumulating body of evidence suggests that cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) is the optimal treatment for selected patients with ovarian and colorectal cancers with PC. Recent studies suggest that IP administration of taxane with systemic chemotherapy in a neoadjuvant setting improves patient survival in gastric cancer with PC. The pharmacokinetics of IP-administered drugs should be primarily considered in order to optimize IP chemotherapy. Therefore, the development of specific IP drugs using newly emerging molecular targeted reagents or new drug delivery systems, such as nanomedicine or controlled absorption/release methods, is essential to improve the efficacy of IP chemotherapy.     

Pharmacokinetic and phase II study of heated intraoperative intraperitoneal melphalan

Background: Peritoneal surface malignancy resulting from local dissemination is a common manifestation of treatment failure of gastrointestinal cancers. Although the management of carcinomatosis has been improved with an aggressive surgical approach of extensive cytoreduction followed by heated intraoperative intraperitoneal chemotherapy, no patients are cured when there is residual disease after surgery. Melphalan (l-phenylalanine mustard) is a well-known antineoplastic alkylating agent which has markedly increased pharmacological activity with heat. The use of heated intraoperative intraperitoneal melphalan may provide a pharmacokinetic and clinical advantage in this group of gastrointestinal cancer patients who cannot be made cancer-free with cytoreductive surgery. Methods: Thirteen patients with residual disease following cytoreductive surgery for peritoneal carcinomatosis were included in this study. After surgical resection and prior to anastomotic reconstruction, patients received intraperitoneal melphalan (70 mg/m²) in 3 l of 1.5% dextrose peritoneal dialysis solution at 41–42°C for 90 min. Concentrations of melphalan were assessed in the peritoneal fluid, blood, urine and tumor nodules using high-performance liquid chromatography. Results: During the 90 min of treatment 87.2±4.3% of the drug was absorbed from the perfusate/peritoneal fluid and 11.9±2.1% was excreted in the urine. The area-under-the-curve ratio of peritoneal fluid to plasma was 33.3±11.8 with an average peak plasma concentration of 0.82±0.24 μg/ml occurring at 28.5±13.1 min. Concentrations of melphalan in tumor nodules on the peritoneal surface were approximately ten times higher than in plasma with an average peak concentration of 7.2±4.2 μg/gm. The grade III/IV morbidity was 38%; there was no mortality. Conclusion: Approximately 90% of the drug was absorbed during the 90-minute procedure with a 30 times greater exposure of drug at the peritoneal surfaces than in the blood. Concentrations of the drug in peritoneal surface tumor nodules were approximately ten times greater than concentrations in the blood. These data demonstrate that heated intraoperative intraperitoneal melphalan could have a significant impact on the treatment of peritoneal surface malignancies.     

CA 19-9 to peritoneal carcinomatosis index (PCI) ratio is prognostic in patients with epithelial appendiceal mucinous neoplasms and peritoneal dissemination undergoing cytoreduction surgery and intraperitoneal chemotherapy: A retrospective cohort study

Background

Serum tumour levels have been shown to be prognostic in patients with epithelial appendiceal mucinous neoplasms with peritoneal dissemination (pseudomyxoma peritonei (PMP)). A singular index which incorporates both tumour activity (as depicted by serum tumour marker levels) and tumour volume (as depicted by peritoneal carcinomatosis index (PCI)), may give a more precise surrogate of tumour biological behaviour. The prognostic implication of this index has not yet been reported.

Cytoreductive surgery and intraperitoneal chemotherapy versus systemic chemotherapy for colorectal peritoneal metastases: A randomised trial

BackgroundFirst-line treatment of isolated resectable colorectal peritoneal metastases remains unclear. This study (the Swedish peritoneal study) compares cytoreductive surgery and intraperitoneal chemotherapy (surgery arm) with systemic chemotherapy (chemotherapy arm).MethodsPatients deemed resectable preoperatively were randomised to surgery and intraperitoneal 5-fluorouracil 550 mg/m²/d for 6 d with repeated courses every month or to systemic oxaliplatin and 5-fluorouracil regimen every second week. Both treatments continued for 6 months. Primary end-point was overall survival (OS) and secondary end-points were progression-free survival (PFS), and morbidity.ResultsThe study terminated prematurely when 48 eligible patients (24/arm) were included due to recruitment difficulties. Two-year OS was 54% in the surgery arm and 38% in the chemotherapy arm (p = 0.04). After 5 years, 8 versus 1 patient were alive, respectively (p = 0.02). Median OS was 25 months versus 18 months, respectively, hazard ratio 0.51 (95% confidence interval: 0.27–0.96, p = 0.04). PFS in the surgery arm was 12 months versus 11 months in the chemotherapy arm (p = 0.16) with 17% versus 0% 5-year PFS. Grade III–IV morbidity was seen in 42% and 50% of the patients, respectively. No mortalities.ConclusionsCytoreductive surgery with intraperitoneal chemotherapy may be superior to systemic oxaliplatin-based treatment of colorectal cancer with resectable isolated peritoneal metastases.(ClinicalTrials.gov nr:NCT01524094).     

进展期胃癌术中腹腔内及门静脉灌注化疗的临床价值

目的探讨进展期胃癌术中行腹腔内注入药物及门静脉灌注化疗防治腹膜腔种植转移和肝转移的临床作用.方法对280例进展期胃癌患者中147例行开腹后腹膜腔内注入化疗药物丝裂霉素(MMC)20 mg,使整个手术操作在腹腔内有化疗药物的条件下进行,并术中经横结肠系膜静脉插管行门静脉灌注MMC 20 mg,防治肝转移;另133例不行以上药物腹腔注入和门静脉灌注,进行对照观察.结果两组3年生存率分别为54.4%和40.6%(P=0.034),腹膜腔内种植转移、转移复发发生率分别为5.4%和13.5%(P=0.017),肝转移发生率分别为4.1%和12.7%(P=0.009).结论进展期胃癌术中行腹腔内化疗药物灌注,使整个手术在抗癌药物浸泡的腹腔内完成,是防止癌腹膜腔复发、种植转移的有效方法.门静脉灌注化疗防治肝转移是积极、有效的措施.     

A pharmacological review on intraperitoneal chemotherapy for peritoneal malignancy

Perioperative intraperitoneal chemotherapy in combination with cytoreductive surgery has been shown to be of benefit for treating selected patients with peritoneal surface malignancy. It has become a new standard of care in the management of diffuse malignant peritoneal mesothelioma and peritoneal dissemination of appendiceal malignancy. Numerous recent publications on carcinomatosis from colorectal cancer and gastric cancer identify groups of patients that would benefit from this local-regional approach for prevention and treatment of carcinomatosis. This review focuses on pharmacological information regarding intraperitoneal chemotherapeutic agents commonly used in gastrointestinal oncology.     

国产长春瑞滨联合阿霉素治疗转移性乳腺癌的临床观察

目的：观察国产长春瑞滨（盖诺）联合阿霉素方案治疗转移性乳腺癌的临床疗效。方法：运用国产长春瑞滨（25mg/m^2 iv dl,5)加阿霉素（40mg/m^2iv dl)治疗转移性乳腺癌28例,结果：取得CR4例,PR13例,总有效率（CR＋PR）达60．7％;主要毒副反应为白细胞减少,发生率为92．8％,其中Ⅲ-Ⅳ度骨髓抑制占64．2％,结论：国产长春瑞滨加阿霉素方案对转移性乳腺癌疗效明确,血骨髓抑制明显。     

高剂量大容积5－Fu腹腔化疗药代动力学和疗效实验观察

高剂量大容积５－Ｆｕ腹腔给药后２４０分钟内腹腔液浓度是股静脉血浓度的２８８倍，门静脉血浓度是股静脉血浓度的１３．８倍，肝静脉血浓度是股静脉血浓度的３．７倍，组织中肝浓度最高，胃、结肠次之，肺、肾最低。经腹腔化疗后的腹腔荷人结肠癌移植瘤裸鼠对照组全部产生腹腔移植瘤，５－Ｆｕ１０和２０ｍｇ／ｋｇ组均有２／５产生腹腔移植瘤，３０ｍｇ／ｋｇ组无腹腔移植瘤产生。结果表明高剂量大容积５－Ｆｕ腹腔化疗有利于胃肠恶性肿瘤术后腹腔复发和肝转移的防治。     

胃癌术中低渗温热腹腔化疗联合术后早期腹腔化疗的疗效观察

背景与目的:胃癌脱落细胞引起的腹腔内肿瘤复发是中晚期胃癌患者治疗失败的重要原因,腹腔内化疗可以有效地杀灭腹腔脱落细胞。本研究拟探讨术中即时低渗温热腹腔化疗联合术后早期腹腔化疗的应用价值。方法:156例胃癌患者随机分为术中即时低渗温热腹腔化疗联合术后早期腹腔化疗组(治疗1组)、单纯术中即时低渗温热腹腔化疗组(治疗2组)和未行腹腔化疗组(对照组)。结果:治疗1组的2年生存率为84.4%,对照组为65.2%,差异有显著性(P<0.05);治疗1组的3年生存率为71.1%,明显高于治疗2组(50.0%)和对照组(45.6%)(P<0.05)。治疗1组肝转移的发生率为7.7%,明显低于对照组(27.3%)(P<0.01);治疗2组肝转移的发生率为10.2%,明显低于对照组(27.3%)(P<0.05)。结论:术中即时低渗温热腹腔化疗联合术后早期腹腔化疗对胃癌有确实的疗效,腹腔化疗对胃癌术后肝转移有确实的预防效果。     

Oxaliplatin use in pressurized intraperitoneal aerosol chemotherapy (PIPAC) is safe and effective: A multicenter study

IntroductionPressurized intraperitoneal aerosol chemotherapy (PIPAC) is a new drug delivery method used in patients with peritoneal cancer (PC) of primary or secondary origin. Intraperitoneal use of oxaliplatin raises concerns about toxicity, especially abdominal pain. The objective of this study was to assess the tolerance of PIPAC with oxaliplatin (PIPAC-Ox) in a large cohort of patients and to identify the risk factors for high grade toxicity, discontinuation of treatment and impaired survival.Material and methodsThis retrospective cohort study included all consecutive patients treated with PIPAC-Ox (92 mg/m²) in five centers specialized in the treatment of PC. The procedure was repeated every 6 weeks. Outcomes of interest were Common Terminology Criteria for Adverse Events (CTCAE), symptoms and survival (Kaplan-Meier). Univariate risk factors were included in a multinominal regression model to control for bias.ResultsOverall, 251 PIPAC-Ox treatments were performed in 101 patients (45 female) having unresectable PC of various origins: 66 colorectal, 15 gastric, 5 ovarian, 3 mesothelioma, 2 pseudomyxoma, 10 other malignancies (biliary, pancreatic, endocrine) respectively. The median PCI was 19 (IQR: 10–28). Postoperative abdominal pain was present in 23 patients. Out of the 9 patients with grade 3 abdominal pain, only 3 needed a change of PIPAC drug. CTCAE 4.0 toxicity grade 4 or higher was encountered in 16(15.9%) patients. The patients had a mean of 2.5 procedures/patient (SD = 1.5). 50 subjects presented with symptom improvement.ConclusionsOxaliplatin-based PIPAC appears to be a safe treatment that offers good symptom control and promising survival for patients with advanced peritoneal disease.     

Curative cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy in patients with peritoneal carcinomatosis and synchronous resectable liver metastases arising from colorectal cancer

Objectives

This study describes the outcomes of patients with colorectal peritoneal carcinomatosis (PC) with or without liver metastases (LMs) after curative surgery combined with hyperthermic intraperitoneal chemotherapy, in order to assess prognostic factors.

Systemic chemotherapy before cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) in patients with high-grade mucinous carcinoma peritonei of appendiceal origin

BackgroundThe role of systemic chemotherapy (SC) before cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) in appendiceal high-grade mucinous carcinoma peritonei (HGMCP) is controversial. We analyzed the effect of SC prior to CRS/HIPEC in HGMCP.MethodsA prospective database of CRS/HIPEC procedures for HGMCP without signet ring cells and with signet ring cells (HGMCP-S) from 1998 to 2017 was reviewed. Exclusion criteria was prior surgery >5 regions or >2 regimens of prior SC. Perioperative variables were analyzed.ResultsThere were 140 HGMCP/HGMCP-S identified: 64 with prior SC (preSC) and 76 without (noSC). Groups were balanced for lymph node status, complete cytoreduction rate, disease burden, complications, and postoperative SC. PreSC had more HGMCP-S, moderately/poorly differentiated histology, and longer time-to-surgery (median: 6 vs 2 months, p < 0.001). Median overall survival (mOS) was 40 vs 86 and median progression-free survival (mPFS) was 19 vs 43 months for preSC vs noSC, respectively (p = 0.006 and p = 0.007). In HGMCP-S subanalysis, mOS was 25 vs 39 and mPFS 16 vs 29 months for preSC vs noSC, respectively (p = 0.188 and p = 0.063). In moderately/poorly differentiated histology subanalysis, mOS was 38 vs 56 and mPFS 18 vs 29 months in preSC vs noSC, respectively (p = 0.199 and 0.082). Prior SC was not linked to improved OS or PFS in non-signet ring HGMCP or well-differentiated histology subanalysis.ConclusionPrior SC was not associated with less disease burden, better cytoreduction rates, or improved clinical outcomes in HGMCP, regardless of histopathologic subtype. Traditional SC agents may not be effective in HGMCP in the neoadjuvant setting.     

经腹腔和静脉双途径应用紫杉醇化疗治疗晚期卵巢癌

目的：观察并评价紫杉醇(泰素)加顺铂经腹腔和静脉化疗治疗晚期卵巢癌的近期疗效及其毒副反应。方法：8例Ⅲ或Ⅳ期卵巢癌患接受泰素40mg／m^2 顺铂20～40mg／m^2腹腔注入,泰素40mg／m^2静脉滴注,每周1次,连用3周为一疗程,2个疗程后进行评价。结果：全组8例患中获得PR4例,总有效率50％;控制腹水的有效率达100％。结论：泰素和顺铂经腹腔和静脉化疗治疗晚期卵巢癌疗效肯定,毒副反应轻,值得临床进一步研究和应用。     

Outcomes of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy for peritoneal mesothelioma and predictors of survival

Background: Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) benefits selected patients with peritoneal mesothelioma. We present the outcomes of this treatment strategy in a UK peritoneal malignancy national referral centre.

Methods: Observational retrospective analysis of data prospectively collected in a dedicated peritoneal malignancy database between March 1998 and January 2016.

Results: Of 1586 patients treated for peritoneal malignancy, 76 (4.8%) underwent surgery for peritoneal mesothelioma. Median age was 49?years (range 21–73?years). 34 patients (45%) were female. Of the 76 patients, 39 (51%) had low grade histological subtypes (mostly multicystic mesothelioma), and 37 (49%) had diffuse malignant peritoneal mesothelioma (DMPM; mostly epithelioid mesothelioma). Complete cytoreduction was achieved in 52 patients (68%) and maximal tumour debulking (MTD) was performed in 20 patients (26%); the remaining 4 patients (5%) underwent a laparotomy with biopsy only. HIPEC was administered in 67 patients (88%). Median overall (OS) and disease-free survival (DFS) after CRS was 97.8 (80.2–115.4) and 58.8 (47.4–70.3) months, respectively. After complete cytoreduction, 100% overall survival was observed amongst patients with low-grade disease. Ki-67 proliferation index was significantly associated with survival outcomes after complete cytoreduction for DMPM and was an independent predictor of decreased survival.

Conclusion: With adequate patient selection (guided by histological classification and Ki-67 proliferation index) and complete cytoreduction with HIPEC, satisfactory outcomes can be achieved in selected patients with peritoneal mesothelioma.     

Impact of surgical and clinical factors on the pharmacology of intraperitoneal doxorubicin in 145 patients with peritoneal carcinomatosis

Background

Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are a combined treatment modality considered for selected patients with peritoneal carcinomatosis from colorectal and appendiceal cancer. Doxorubicin is a drug consistently used by our group in this clinical setting. The surgical and clinical factors that modify the pharmacokinetics of HIPEC may be important for the design of future perioperative chemotherapy regimens.

Materials and methods

The patients included were 145 who had colorectal or appendiceal carcinomatosis resected using CRS prior to treatment with HIPEC with doxorubicin as part of a multidrug regimen. The effect of clinical and surgical factors on drug distribution after a single intraperitoneal bolus administration with doxorubicin was determined.

Results

The pharmacokinetics of 145 patients treated with intraperitoneal doxorubicin showed a 78 times greater exposure to peritoneal surfaces as compared to plasma. At 90 min 12% of the drug remained in the chemotherapy solution and 88% was retained in the body. The extent of visceral resection and peritonectomy increased the clearance of doxorubicin from the peritoneal space. A major resection of visceral peritoneal surface, a contracted peritoneal space, and an incomplete cytoreduction reduced drug clearance.

Conclusions

Surgical and clinical factors may require modifications of chemotherapy administration. A large visceral resection and a contracted peritoneal space caused a reduced doxorubicin clearance. Total diffusion surface is an important determinant of doxorubicin pharmacokinetics.     

Results of chemotherapy using ifosfamide with doxorubicin in advanced breast cancer

Summary Ifosfamide has single agent activity in advanced breast cancer and may potentiate the activity of doxorubicin. The combination of ifosfamide 5 g/m² and doxorubicin 40 mg/m² every 3 weeks for 4 cycles was used to treat 77 patients with advanced breast cancer. Fifty three patients had not received prior chemotherapy. All patients had one or more poor prognostic features, including tumor expression of epidermal growth factor receptor in 11/12 tested. The overall response rate was 74% (95% confidence intervals 62%-83%). The median survival was 9.4 months. The principal toxicities were febrile neutropenia and ifosfamide encephalopathy each in 6% of patients. A high percentage of the projected dose intensity was administered. This is a highly active combination with acceptable toxicity in advanced breast cancer, although the long term survival remains poor. Further exploration of ifosfamide in combination chemotherapy for advanced breast cancer is warranted.