Hyperthermic intraperitoneal chemotherapy: Rationale and technique

The combination of complete cytoreductive surgery and perioperative intraperitoneal chemotherapy provides the only chance for long-term survival for selected patients diagnosed with a variety of peritoneal neoplasms, either primary or secondary to digestive or gynecologic malignancy. Hyperthermic intraperitoneal chemotherapy (HIPEC) delivered in the operating room once the cytoreductive surgical procedure is finalized, constitutes the most common form of administration of perioperative intraperitoneal chemotherapy. This may be complemented in some instances with early postoperative intraperitoneal chemotherapy (EPIC). HIPEC combines the pharmacokinetic advantage inherent to the intracavitary delivery of certain cytotoxic drugs, which results in regional dose intensification, with the direct cytotoxic effect of hyperthermia. Hyperthermia exhibits a selective cell-killing effect in malignant cells by itself, potentiates the cytotoxic effect of certain chemotherapy agents and enhances the tissue penetration of the administered drug. The chemotherapeutic agents employed in HIPEC need to have a cell cycle nonspecific mechanism of action and should ideally show a heat-synergistic cytotoxic effect. Delivery of HIPEC requires an apparatus that heats and circulates the chemotherapeutic solution so that a stable temperature is maintained in the peritoneal cavity during the procedure. An open abdomen (Coliseum) or closed abdomen technique may be used, with no significant differences in efficacy proven to date. Specific technical training and a solid knowledge of regional chemotherapy management are required. Concerns about safety of the procedure for operating room personnel are expected but are manageable if universal precautions and standard chemotherapy handling procedures are used. Different HIPEC drug regimens and dosages are currently in use. A tendency for concurrent intravenous chemotherapy administration (bidirectional chemotherapy, so-called "HIPEC plus") has been observed in recent years, with the aim to further enhance the cytotoxic potential of HIPEC. Future trials to ascertain the ideal HIPEC regimen in different diseases and to evaluate the efficacy of new drugs or drug combinations in this context are warranted.     

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.     

Phase II studies: International registry of colorectal carcinomatosis.

Peritoneal carcinomatosis (PC) is a common manifestation of colorectal cancer and has traditionally been regarded as a terminal disease with a short median survival. Over the last decade, a new local-regional therapeutic approach combining cytoreductive surgery with perioperative intraperitoneal chemotherapy has evolved and promising survival results were reported in large phase II studies. A retrospective multicentric study of 506 patients from 28 institutions was performed to evaluate the international experience with this combined treatment and to identify the principal prognostic indicators. All patients had cytoreductive surgery and perioperative intraperitoneal chemotherapy (intraperitoneal chemohyperthermia and/or immediate postoperative intraperitoneal chemotherapy) within the 7 days following surgery. The morbidity and mortality rates were 22.9% and 4%, respectively. Patients in whom cytoreductive surgery was complete had a median survival of 32.4 months compared to 8.4 months for patients in whom complete cytoreductive surgery was not possible (p < 0.001). Positive independent prognostic indicators by multivariate analysis were complete cytoreduction, treatment by a second procedure, limited extent of PC, age less than 65 years, and use of adjuvant chemotherapy. The use of neoadjuvant chemotherapy, lymph node involvement, presence of liver metastasis and poor histological differentiation were negative independent prognostic indicators. The therapeutic approach combining cytoreductive surgery with perioperative intraperitoneal chemotherapy achieved long-term survival in carefully selected group of patients with PC from colorectal origin and offer a chance for cure or palliation in this condition. Further collaboration between peritoneal surface malignancy treatment centres are needed in order to standardize indications, intraperitoneal chemotherapy and peritonectomy techniques.     

Comprehensive approach to advanced primary and recurrent ovarian cancer: a personal experience

Despite improvements in chemotherapy agents and schedules and new drug combinations, epithelial ovarian cancer remains a leading cause of gynecologic cancer death in Western countries. It is usually diagnosed at late stages of the disease, which makes complete surgical resection technically more difficult. The targeted comprehensive approach described in this review includes cytoreductive surgery and perioperative intraperitoneal chemotherapy. The goal of this aggressive therapy is to remove all the macroscopic disease with the use of peritonectomy procedures and visceral resections, and also to eradicate microscopic disease using heated intraoperative intraperitoneal chemotherapy and early postoperative intraperitoneal chemotherapy. Patients that received a complete cytoreduction followed by perioperative intraperitoneal chemotherapy had an improved survival, with reasonable morbidity and mortality, as compared with those who received incomplete cytoreduction.     

Comprehensive approach to advanced primary and recurrent ovarian cancer: a personal experience

Despite improvements in chemotherapy agents and schedules and new drug combinations, epithelial ovarian cancer remains a leading cause of gynecologic cancer death in Western countries. It is usually diagnosed at late stages of the disease, which makes complete surgical resection technically more difficult. The targeted comprehensive approach described in this review includes cytoreductive surgery and perioperative intraperitoneal chemotherapy. The goal of this aggressive therapy is to remove all the macroscopic disease with the use of peritonectomy procedures and visceral resections, and also to eradicate microscopic disease using heated intraoperative intraperitoneal chemotherapy and early postoperative intraperitoneal chemotherapy. Patients that received a complete cytoreduction followed by perioperative intraperitoneal chemotherapy had an improved survival, with reasonable morbidity and mortality, as compared with those who received incomplete cytoreduction.     

Treatment and prevention of peritoneal carcinomatosis from gastric cancer by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: Overview and rationale

Peritoneal carcinomatosis (PC) from gastric cancer is a condition with a very bleak prognosis. Most authors consider it to be a terminal disease and recommend palliative therapy only. Multimodal therapeutic approaches to PC have emerged in the last decades, combining cytoreductive surgery (CRS) and peritonectomy procedures with perioperative intraperitoneal chemotherapy (IPEC), including hyperthermic intraperitoneal chemotherapy (HIPEC) and/or early postoperative intraperitoneal chemotherapy (EPIC).     

Cytoreductive surgery combined with perioperative intraperitoneal chemotherapy for the management of peritoneal carcinomatosis from colorectal cancer: a multi-institutional study.

PURPOSE: The three principal studies dedicated to the natural history of peritoneal carcinomatosis (PC) from colorectal cancer consistently showed median survival ranging between 6 and 8 months. New approaches combining cytoreductive surgery and perioperative intraperitoneal chemotherapy suggest improved survival. PATIENTS AND METHODS: A retrospective multicenter study was performed to evaluate the international experience with this combined treatment and to identify the principal prognostic indicators. All patients had cytoreductive surgery and perioperative intraperitoneal chemotherapy (intraperitoneal chemohyperthermia and/or immediate postoperative intraperitoneal chemotherapy). PC from appendiceal origin was excluded. RESULTS: The study included 506 patients from 28 institutions operated between May 1987 and December 2002. Their median age was 51 years. The median follow-up was 53 months. The morbidity and mortality rates were 22.9% and 4%, respectively. The overall median survival was 19.2 months. Patients in whom cytoreductive surgery was complete had a median survival of 32.4 months, compared with 8.4 months for patients in whom complete cytoreductive surgery was not possible (P <.001). Positive independent prognostic indicators by multivariate analysis were complete cytoreduction, treatment by a second procedure, limited extent of PC, age less than 65 years, and use of adjuvant chemotherapy. The use of neoadjuvant chemotherapy, lymph node involvement, presence of liver metastasis, and poor histologic differentiation were negative independent prognostic indicators. CONCLUSION: The therapeutic approach combining cytoreductive surgery with perioperative intraperitoneal chemotherapy achieved long-term survival in a selected group of patients with PC from colorectal origin with acceptable morbidity and mortality. The complete cytoreductive surgery was the most important prognostic indicator.     

Intraperitoneal chemotherapy for colorectal cancer.

The peritoneal surface remains an important failure site for patients with colorectal cancer. Peritoneal metastases of colorectal cancer are at present considered equal to distant metastatic disease. Consequently, peritoneal carcinomatosis is treated with systemic chemotherapy and surgery only to palliate complications such as obstruction. Despite the development of new chemotherapeutic agents and combinations, the results remain disappointing with a limited impact on survival. Colorectal carcinoma cells are relatively resistant to chemotherapy. Intraperitoneal chemotherapy seems to be an attractive approach in the treatment of high-risk colorectal cancer and peritoneal carcinomatosis from colorectal origin providing high local drug concentration with limited systemic side effects. Adjuvant early postoperative intraperitoneal chemotherapy is worthwhile for consideration as treatment option after resection of high-risk colorectal cancer. In the treatment of peritoneal carcinomatosis postoperative intraperitoneal chemotherapy leads to inadequate exposure of the peritoneal surface. Only an intraoperative intraperitoneal chemotherapy performed with direct cytotoxic drugs such as MMC and cisplatin overcome this problem. The limited drug penetration in tissue implies the need for extensive cytoreductive surgery. The results of phase II studies suggest that an increased median survival can be achieved with this approach. The natural history of this disease and the heterogeneity of the patients are such that only a randomized trial design will adequately answer the question whether regional treatment of patients with peritoneal dissemination of colorectal cancer actually prolongs survival. The results of such a study are to be expected in approximately 2 years time.     

Peritoneal mesothelioma

Opinion statement Peritoneal mesothelioma is usually a rapidly fatal primary peritoneal surface malignancy with a median survival time of less than 1 year, mainly because of lack of effective treatment. The incidence is approximately one per 1,000,000; approximately one fifth to one third of all mesotheliomas are peritoneal. Because of its unusual nature, the disease has not been clearly defined in terms of its natural history, diagnosis, or management. Treatment options with intravenous chemotherapy are far from satisfactory. However, because malignant peritoneal mesothelioma usually remains confined to the peritoneal cavity for most of its natural history, regional chemotherapy is an attractive option. From a theoretic perspective, the treatments are most likely to succeed in selected patients with small-volume residual disease after cytoreductive surgery. Advantages of intraperitoneal chemotherapy include greatly enhanced drug concentrations in the peritoneal cavity and decreased systemic toxicity. In designing an intraperitoneal treatment strategy for the management of peritoneal mesothelioma, the limited number of active cytotoxic drugs and the timing of drug delivery pose problems. Prognosis as determined by clinical presentation, the completeness of cytoreduction, and gender (female patients survive longer than male patients) appears to be improved by the use of intraperitoneal chemotherapy. Over the past decade, the management of these patients has evolved similarly to ovarian cancer treatment and now involves cytoreductive surgery, heated intraoperative intraperitoneal chemotherapy with cisplatin and doxorubicin, and early postoperative intraperitoneal paclitaxel. These perioperative treatments are followed by adjuvant intraperitoneal paclitaxel and second-look cytoreduction. Prolonged disease-free survival and reduced adverse symptoms with the current management strategy are documented by a high complete response rate as assessed by a negative second look. This multimodality treatment approach with debulking surgery and intraperitoneal chemotherapy has resulted in a median survival of 50 to 60 months. Peritoneal mesothelioma is an orphan disease that is treatable, with expectations for “potential” cure in a small number of patients diagnosed and treated early with definitive local/regional treatments. A prolonged high quality of life is possible in the majority of patients.     

细胞减灭术联合腹腔热灌注化疗治疗腹膜癌的围术期规范化护理

目的：探讨如何对细胞减灭术联合腹腔热灌注化疗治疗后的腹膜癌患者进行规范围术期护理。方法对33例腹膜癌患者的围术期护理进行回顾性分析,对护理的具体内容、围术期的不良事件进行总结规范。结果规范的护理减少了围术期不良事件的发生,促进了腹腔化疗管路的改进。结论针对细胞减灭术联合腹腔热灌注化疗治疗腹膜癌的患者进行规范的围术期护理,能够减少围术期不良事件的发生。     

Clinical perspective on desmoplastic small round-cell tumor

Rare diseases are often associated with uninformed medical decisions and poorly executed treatments because of inexperience of the physicians. Desmoplastic small round-cell tumor is a rare disease that is a form of peritoneal surface malignancy usually affecting young males, with a mean survival of 29 months. In order to begin to build a more knowledgeable clinical pathway all 7 patients treated at the Washington Hospital Center were studied and compared to patients described in the medical literature. Clinical and pathological data, tumor distribution, cytoreductive surgery, completeness of cytoreduction and survival were recorded and analyzed. The first most common symptoms were pain, increased abdominal girth and palpable abdominal mass in our patients and in the literature review. The overall survival did not improve with cytoreductive surgery plus intraperitoneal chemotherapy (mean survival 32 months); however, 2 long-term survivors who responded to systemic chemotherapy of 55 and 101 months were recorded. The latter may be the longest survivor reported in the literature. No consistent response to chemotherapy was observed in our patients or in any literature review. Complete surgical removal of this malignancy did not correlate with survival in our patients. The absence of improved survival of our aggressively treated patients as compared to the literature was thought to be a consequence of an advanced stage of the disease. A new comprehensive approach that uses complete clearing of cancer by surgery and perioperative systemic and perioperative intraperitoneal chemotherapy as early as is possible in the natural history of the disease emerged as goals for future management.     

Inguinal canal as an anatomic sanctuary site of relapse in peritoneal carcinomatosis previously treated with intraperitoneal chemotherapy

Early postoperative intraperitoneal chemotherapy (EPIC) and intraoperative peritoneal hypertermic chemotherapy (IPHC) are used in addition with cytoreductive surgery to treat with curative intent peritoneal carcinomatosis arising from colorectal adenocarcinomas. Three patients with such a disease were treated with perioperative intraperitoneal chemotherapy in addition to cytoreductive surgery and presented isolated local recurrence located in the inguinal canal (round ligament in two and spermatic cord in one). All these patients were treated by local surgical excision. No patient showed evidence of intra-abdominal recurrence at the last follow-up, but one developed pulmonary metastasis. When communicating with the peritoneal cavity, the inguinal canal may act as a sanctuary site for peritoneal carcinomatosis, since it is not totally soaked by the intraperitoneal chemotherapy solution. A local recurrence is thus possible. New clinical presentations such as this one have first to be described in order to improve patient follow-up.     

Management of peritoneal surface malignancy with cytoreductive surgery and perioperative intraperitoneal chemotherapy.

AIMS: A new treatment strategy combining maximal cytoreductive surgery for treatment of macroscopic disease and maximal perioperative intraperitoneal chemotherapy for residual microscopic disease, suggests that in a selected group of patients benefit is possible. The purpose of this study was to report our experience with this combined treatment and to identify the principal prognostic factors. METHODS: The study included 266 patients from 9 institutions operated on between July 1990 and July 2004. The median age was 55 years. RESULTS: The mortality rate was 7.8% and the morbidity rate 37.5%. The overall median survival was 13.7 months. Positive independent prognostic factors by multivariate analysis were gender, perioperative intraperitoneal chemotherapy and treatment by the second-look procedure. CONCLUSIONS: The therapeutic approach combining cytoreductive surgery with perioperative intraperitoneal chemotherapy achieved long-term survival in a selected group of patients with an acceptable morbidity and mortality.     

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.     

Diagnosis and treatment of peritoneal mesothelioma: The Washington Cancer Institute experience

Peritoneal mesothelioma is a rare disease, but increasing in frequency. The incidence is approximately one per 1,000,000 and about one fifth to one third of all mesotheliomas are peritoneal. Because of its unusual nature, the disease has not been clearly defined either in terms of its natural history, diagnosis, or management. This article reviews a single institution's experience with 51 patients prospectively treated over the past decade with increasingly aggressive local/regional protocols. Peritoneal mesothelioma patients generally present with two types of symptoms and signs; those with abdominal pain, usually localized and related to a dominant tumor mass with little or no ascites and those without abdominal pain, but with ascites and abdominal distention. Pathologically, a positive immunostain for calretinin has markedly increased the accuracy of diagnosis. Prognosis as determined by clinical presentation, the completeness of cytoreduction, and gender (females survive longer than males) appears to be improved by the use of intraperitoneal chemotherapy. Over the past decade, the management of these patients has evolved similarly to ovarian cancer treatment and now involves cytoreductive surgery, heated intraoperative intraperitoneal chemotherapy (HIIC) with cisplatin and doxorubicin, and early postoperative intraperitoneal paclitaxel. These perioperative treatments are followed by adjuvant intraperitoneal paclitaxel and second-look cytoreduction. Prolonged disease-free survival and reduced adverse symptoms with the current management strategy are documented by a high complete response rate as assessed by a negative second-look. This multimodality treatment approach with cytoreductive surgery and intraperitoneal chemotherapy has resulted in a median survival of 50 to 60 months. Peritoneal mesothelioma is an orphan disease that is treatable with expectations for "potential" cure in a small number of patients if diagnosed and treated early with definitive local/regional treatments. A prolonged high quality of life is possible in the majority of patients.     

A review of peritoneal mesothelioma at the Washington Cancer Institute

This article reviews a single institution's experience with 68 patients (21 females, 47 males) prospectively treated over the last 2 decades with an aggressive local-regional approach, combining maximal cytoreductive surgery with heated intraoperative intraperitoneal chemotherapy and early postoperative intraperitoneal chemotherapy. This multimodality treatment has resulted in a median survival of 67 months. Female patients had a significantly better prognosis than males. The other significant predictive factors of survival were: age, diagnosis by incidental findings, tumor extent, pathology, and completeness of cytoreduction.     

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.     

Laboratory and clinical basis for hyperthermia as a component of intracavitary chemotherapy.

Intraoperative chemotherapy with heat has been identified as a treatment option for patients with cancer spread to peritoneal surfaces. This treatment modality is viewed as a supplement to several other treatments for this group of patients including cytoreductive surgery, systemic chemotherapy, early postoperative intraperitoneal chemotherapy, and long-term bidirectional chemotherapy. The pharmacologic basis for using heat to supplement chemotherapy effects are related to the increased penetration of chemotherapy into tumor with hyperthermia, the delayed clearance of chemotherapy from the peritoneal cavity after direct instillation, and an increased cytotoxicity that has been documented with selected chemotherapy agents. Data to support the use of perioperative hyperthermic intraperitoneal chemotherapy with mucinous appendiceal carcinomatosis comes from a large number of single institution phase II studies. Also, peritoneal and pleural mesothelioma are benefited. In colon cancer carcinomatosis, large phase II multi-institutional trials and a single phase III trial documented an increased median survival of these patients from approximately 1 year to over 2 years. Prophylaxis against peritoneal carcinomatosis in gastric cancer has been demonstrated in phase III trials. In ovarian cancer the rationale for this treatment remains large but its current application is limited. Much work needs to be done to identify a proper clinical perspective on hyperthermia used with chemotherapy in patients with peritoneal surface malignancy.     

Laboratory and clinical basis for hyperthermia as a component of intracavitary chemotherapy

Intraoperative chemotherapy with heat has been identified as a treatment option for patients with cancer spread to peritoneal surfaces. This treatment modality is viewed as a supplement to several other treatments for this group of patients including cytoreductive surgery, systemic chemotherapy, early postoperative intraperitoneal chemotherapy, and long-term bidirectional chemotherapy. The pharmacologic basis for using heat to supplement chemotherapy effects are related to the increased penetration of chemotherapy into tumor with hyperthermia, the delayed clearance of chemotherapy from the peritoneal cavity after direct instillation, and an increased cytotoxicity that has been documented with selected chemotherapy agents. Data to support the use of perioperative hyperthermic intraperitoneal chemotherapy with mucinous appendiceal carcinomatosis comes from a large number of single institution phase II studies. Also, peritoneal and pleural mesothelioma are benefited. In colon cancer carcinomatosis, large phase II multi-institutional trials and a single phase III trial documented an increased median survival of these patients from approximately 1 year to over 2 years. Prophylaxis against peritoneal carcinomatosis in gastric cancer has been demonstrated in phase III trials. In ovarian cancer the rationale for this treatment remains large but its current application is limited. Much work needs to be done to identify a proper clinical perspective on hyperthermia used with chemotherapy in patients with peritoneal surface malignancy.