Isolated limb perfusion for soft tissue sarcoma: Current practices and future directions. A survey of experts and a review of literature.

Soft tissue sarcomas constitute 1% of adult malignant tumors. They are a heterogeneous group of more than 50 different histologic types. Isolated limb perfusion is an established treatment strategy for locally advanced sarcomas. Since its adoption for sarcomas in 1992, after the addition of TNFα, few modifications have been done and although indications for the procedure are essentially the same across centers, technical details vary widely. The procedures mainly involves a 60 min perfusion with melphalan and TNFα under mild hyperthermia, achieving a limb preservation rate of 72-96%; with an overall response rates from 72 to 82.5% and an acceptable toxicity according to the Wieberdink scale. The local failure rate is 27% after a median follow up of 14-31 months compared to 40% of distant recurrences after a follow up of 12-22 months. Currently there is no consensus regarding the benefit of ILP per histotype, and the value of addition of radiotherapy or systemic treatment. Further developments towards individualized treatments will provide a better understanding of the population that can derive maximum benefit of ILP with the least morbidity.

Pseudomyxoma peritonei treated by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: results from a single centre

BACKGROUND: Pseudomyxoma peritonei (PMP) is a rare, slowly progressive disease whose prognosis depends primarily on the completeness of cytoreduction. The value of intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC) and of additional factors predicting long-term outcome and disease-free survival (DFS) remains poorly understood. This study aims to analyse survival rates and prognostic factors in patients undergoing maximal cytoreduction and HIPEC. METHODS: Thirty patients were selected from a prospective database of records for patients undergoing cytoreduction and HIPEC with mitomycin C or paclitaxel. Overall survival (OS), DFS, and the prognostic factors influencing them, were examined using multivariate analysis. RESULTS: Median follow-up was 44 months (range, 8-144). Histological classification of PMPs was DPAM in 6/30 of cases, PMCA-I in 10/30 and PMCA in 14/30. Complete cytoreduction (CC-0 and CC-1) was achieved in 28/30 of patients and CC-2 in 2/30. Median OS was 111 months (range 0-230) and five-year OS rate was 67%. Median DFS was 53.5 months (range 0-120) and 5-year DFS rate was 44%. Incomplete cytoreduction, lymph node involvement and PCI>20 were associated with poor prognosis for OS, while lymph node involvement, elevated CA-125 levels, unfavourable histology and previous chemotherapy were associated with poor outcomes for DFS. There was morbidity of Grade 3 or higher in 9/30. Post-operative mortality occurred in 1 case. CONCLUSION: Cytoreduction plus peritonectomy procedures combined with HIPEC is a safe treatment and could improve survival rates. Since the optimal cytoreduction is the primary prognostic factor, patients should be centralised under the care of experienced teams (AU)

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal malignant disease

Peritoneal Malignant Disease (PMD) is the presence of tumoral tissue on the peritoneal surface from primary tumors or tumors from other locations (e.g. digestive or gynecologic). It is a regional disease with poor prognosis when treated with repeated "debulking" and traditional systemic chemotherapy. Cytoreduction plus hyperthermic intraperitoneal chemotherapy (HIPEC) is a combined multimodal regional procedure aimed at reducing the macroscopic tumoral mass as much as possible and treating with chemotherapy the microscopic disease that is out of the scope of the surgeon. This combined treatment may change the natural history of PMD, it is translated into a higher overall survival and cancer-free survival and it offers the option of cure in selected cases. The high-complexity procedure is also associated with complications and mortality, but in similar rates as other major oncologic procedures (AU)

Intraperitoneal hyperthermic chemotherapy: an evolving paradigm for the treatment of peritoneal surface malignancies.

Unfortunately, advanced colorectal cancer is often present at the time the disease is diagnosed. Many intra-abdominal malignancies spread throughout the peritoneal cavity, which is known as carcinomatosis. Peritoneal carcinomatosis is uniformly a terminal disease with a median survival of 6 months. Systemic chemotherapy is palliative and generally provides limited improvement in survival. Conventional surgery has typically been limited to ileostomy, colostomy or intestinal bypass procedures. Cytoreductive surgery alone has long been used to treat macroscopic disease, with limited success. However, cytoreductive surgery combined with intraperitoneal hyperthermic chemotherapy (IPHC) has evolved into a novel approach for peritoneal surface malignancy. IPHC was initially described in a canine model by Spratt. Although the first clinical series of peritoneal perfusion were small, Japanese trials, which utilized IPHC for prophylaxis in patients with gastric adenocarcinoma, Fujimoto was the first to report an improvement in survival for established gastric cracinomatosis. This early work provided the proof-of-principle for what has evolved into current management with aggressive cytoreduction and IPHC. The present review will outline the rationale, current practice and future directions of IPHC in the management of peritoneal surface malignancies.

Current clinical and research approaches to optimizing regional chemotherapy: novel strategies generated through a better understanding of drug pharmacokinetics, drug resistance, and the development of clinically relevant animal models.

A common treatment modality for in transit melanoma of the extremity has been hyperthermic isolated limb perfusion (HILP) with melphalan and more recently, isolated limb infusion (ILI) with melphalan with or without dactinomycin. Research in the area has primarily focused on maximizing drug delivery through a better understanding of pharmacokinetics while maintaining acceptable levels of toxicity. Although other agents continue to be explored as regional chemotherapy agents, melphalan is currently the drug of choice, although temozolomide has demonstrated promising preclinical results. Resistance mechanisms to melphalan and melphalan pharmacokinetics are studied using animal models of HILP and ILI. The addition of modulators to overcome resistance to the traditional chemotherapy regimen may ultimately improve the clinical response in patients with in-transit melanoma of the extremity.

Future directions in regional treatment strategies for melanoma and sarcoma.

Hyperthermic isolated limb perfusion (HILP) with melphalan and more recently isolated limb infusion (ILI) with melphalan +/- dactinomycin are common treatment modalities for both in-transit melanoma of the extremity and advanced extremity sarcoma. In order to further optimize treatment, future research should focus on selection of appropriate patients, verification of a technique that produces consistent results while maintaining acceptable toxicity, and development of novel strategies and agents. Development of these novel agents and strategies has potential to not only improve the efficacy of regional chemotherapy but may also help guide future strategies for systemic treatment.

Selected hypoxic stop-flow perfusions: indication and limits.

AIMS AND BACKGROUND: The treatment of unresectable cancers is still one of the main medical challenges. Stop-flow perfusion has been used as locoregional chemotherapy based on blood supply blockage of the tumor-bearing area. The aim of the present paper is to report our personal experience in the clinical use of hypoxic stop-flow perfusion and discuss future prospects for research. METHODS AND STUDY DESIGN: Since December 1997 more than 500 stop-flow perfusions have been performed at the University of L'Aquila. Hypoxic perfusion was adopted for the following indications: recurrent rectal cancer, advanced pancreatic cancer, recurrent pelvic and limb melanoma, and recurrent limb melanoma. RESULTS: For recurrent rectal cancer median survival was 12.2 months, for advanced pancreatic cancer 9.6 months, for recurrent pelvic and limb melanoma 34.4 months, and for recurrent limb melanoma 23.8 months. CONCLUSIONS: Based on these encouraging results, stop-flow perfusion should be considered an effective treatment. Future fields of research include tailored chemotherapy and hyperthermia.

Recent trends and future perspectives in isolated hepatic perfusion in the treatment of liver tumors.

Isolated hepatic perfusion (IHP) involves a method of complete vascular isolation of the liver to enable treatment of liver tumors with high drug doses without systemic toxicity. Recent clinical studies have mainly employed IHP with melphalan with or without tumor necrosis factor-alpha and mild hyperthermia. The results of these studies demonstrate that high response and survival rates can be achieved with IHP. The current status, recent developments and future perspectives of IHP are discussed in this review.

Loco-regional perfusions (stop-flow techniques): state of art and future.

The treatment of primary advanced or unresectable recurrent cancers is still one of the main medical challenges. The Stop-flow perfusion has been used as loco-regional chemotherapy based on blood supply blockage of the tumour-bearing area. The aim of the present paper is to report the personal experience in the clinical use of stop-flow perfusions and discuss about future perspectives of research. Since December 1997 more than 400 Stop-flow perfusions have been performed at University of L'Aquila. The following types of indication have been selected: recurrent unresectable rectal cancer, advanced pancreatic cancer, thoracic lymphomas, recurrent non-small cell lung cancer, recurrent pelvic and limb melanoma, and recurrent limb melanoma. In this paper results are presented in terms of median survival. For recurrent rectal cancer median survival was 12.2 months, for advanced pancreatic cancer 9.6 months, for thoracic lymphomas 16 months, for recurrent non-small cell lung cancer 21 months, for recurrent pelvic and limb melanoma 34.4 months, for recurrent limb melanoma 23.8 months. Based on these encouraging results, Stop-flow perfusion should be considered an effective approach to locally advanced cancers. Future fields of research include personalized chemotherapy and perfusion under hyperthermic conditions.

Isolation limb perfusion for melanoma: current trends and future directions.

The current review summarizes briefly the reported limitations of the literature on isolation limb perfusion for melanoma, as well as current clinical research in the use of this modality. The most intriguing advance has been the combination of the cytokine tumour necrosis factor with melphalan; this has yielded a consistent complete response rate of 90%. Not all responses remain durable, and the impact of this very effective combination but potentially toxic regimen on patient survival remains to be shown. Future challenges in the field are proposed.

Extracorporeal support with a cadaver liver as a bridge to transplantation.

Extracorporeal liver perfusion (ECLP) has been used for detoxifying blood in patients in class IV hepatic encephalopathy. Palliation of the moribund patient utilizing extracorporeal devices with cross-circulation of a cadaver liver has been documented for over three decades. Common problems associated with this procedure which appear in the literature include cadaver liver distention, increased resistance to blood flow, and limited time of extracorporeal support due to cadaver liver failure. This report summarizes the experiences of the perfusion team in utilizing an extracorporeal circuit with an otherwise nontransplantable cadaveric liver, to support the decompensating hepatic patient as a bridge to transplantation. Between January and July 1992, three patients were supported for hepatic failure with ECLP. Two patients were placed on ECLP with a modified circuit containing two positive displacement pumps and one centrifugal pump. The third patient was placed on ECLP with a circuit that contained two centrifugal pumps and one positive displacement pump. Patient age ranged from 6 to 38 years and length of support ranged from 24 to 72 hours. In all three patients, a centrifugal pump was placed in the suprahepatic inferior vena cava line to facilitate cadaver liver drainage and decompression. Intensive monitoring of both patient and cadaver liver hemodynamics, hepatic function, and hematological status was performed. All three patients were successfully weaned from ECLP. Two patients received successful orthotopic liver transplantation. The third died of complications unrelated to ECLP after support was discontinued.(ABSTRACT TRUNCATED AT 250 WORDS)

The surgeon and chemotherapy: twenty five years personal experience.

The realm of cancer chemotherapy is complex and often conflicting. The massive use of cytotoxic agents during the past 25 years has now reached a point where major decisions have to be made. The respective roles of regional techniques, systemic therapy for metastatic disease and adjuvant cytotoxic chemotherapy, all need the most careful re-appraisal. It is important that surgical opinion continues to be expressed and that surgeons continue to participate in the study and practice of cancer chemotherapy.