Impact of extent of disease on 1-year healthcare costs in patients who undergo cytoreductive surgery with hyperthermic intraperitoneal chemotherapy for colorectal peritoneal metastases: retrospective observational cohort study.

BACKGROUND: The goal of this retrospective observational study was to determine the impact of the extent of peritoneal disease on 1-year healthcare costs in patients with colorectal peritoneal metastases (PM) who undergo cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS + HIPEC). The extent of peritoneal disease, expressed by the Peritoneal Cancer Index (PCI), directly affects the complexity of CRS + HIPEC and ultimately survival outcomes. The impact of the PCI on treatment-related healthcare costs remains unknown. METHODS: Data from patients with colorectal PM who underwent CRS + HIPEC between January 2012 and November 2017 were extracted retrospectively from an institutional database. Patients were divided into four subgroups with PCI scores ranging from 0 to 20. Treatment-related costs up to 1 year after CRS + HIPEC were obtained from the financial department. Differences in costs and survival outcomes were compared using the χ2 test and Kruskal-Wallis H test. RESULTS: Seventy-three patients were included (PCI 0-5, 22 patients; PCI 6-10, 19 patients; PCI 11-15, 17 patients; PCI 16-20, 15 patients). Median (i.q.r.) costs were significantly increased for the PCI 11-15 and PCI 16-20 groups (€51 029 (42 500-58 575) and €46 548 (35 194-60 533) respectively) compared with those for the PCI 0-5 and PCI 6-10 groups (€33 856 (25 293-42 235) and €39 013 (30 519-51 334) respectively) (P = 0·009). CONCLUSION: Treatment-related healthcare costs are significantly increased among patients with extensive tumour burden (PCI score 10 or above) who undergo CRS + HIPEC for the treatment of colorectal PM.

ANTECEDENTES: El objetivo de este estudio observacional retrospectivo fue determinar el impacto de la extensión de la enfermedad peritoneal sobre los costes de atención médica al año en pacientes con metástasis peritoneales (peritoneal metastases, PM) de origen colorrectal que se someten a cirugía citorreductora con quimioterapia intraperitoneal hipertérmica (cytoreductive surgery with hyperthermic intraperitoneal chemotherapy, CRS + HIPEC). La extensión de la enfermedad peritoneal, expresada por el índice de carcinomatosis peritoneal (peritoneal cancer index, PCI), afecta directamente a la complejidad de la CRS + HIPEC y, en última instancia, a los resultados de supervivencia. El impacto de la PCI en los costes de la atención médica relacionados con el tratamiento sigue siendo desconocido. MÉTODOS: Los datos de pacientes con PM de origen colorrectal que se sometieron a CRS + HIPEC entre enero de 2012 y noviembre de 2017 se extrajeron retrospectivamente de una base de datos institucional. Los pacientes se dividieron en cuatro subgrupos con PCI que variaron de 0 a 20. Los costes relacionados con el tratamiento hasta un año después de la CRS + HIPEC se obtuvieron del departamento financiero. Las diferencias en los costes y los resultados de supervivencia se compararon mediante los tests χ2 y de Kruskal-Wallis H. RESULTADOS: Se incluyeron 73 pacientes (PCI 0-5, 22 pacientes; PCI 6-10, 19 pacientes; PCI 11-15, 17 pacientes y PCI 16-20, 15 pacientes). Los costes medios aumentaron significativamente para los grupos PCI 11−15 y PCI 16−20 (51.029€ (rango intercuartílico, RIQ) 42.500€−58575€)) y 46.548€ (RIQ 35.194€-60.533€), respectivamente)) en comparación con los de los grupos PCI 0−5 y PCI 6-10 (33.856€ (RIQ 25.293€−42.23€) y 39.013€ (RIQ 30.519€-51.334€), respectivamente, P = 0,009). CONCLUSIÓN: Los costes de la atención médica relacionados con el tratamiento aumentan significativamente entre los pacientes con una carga tumoral extensa (es decir, PCI ≥ 10) que se someten a CRS + HIPEC para el tratamiento de PM de origen colorrectal.

Role of diagnostic laparoscopy in patients with suspicion of colorectal peritoneal metastases to evaluate suitability for cytoreductive surgery with hyperthermic intraperitoneal chemotherapy.

Background: The aim of the present study was to determine the feasibility and safety of performing diagnostic laparoscopy (DLS) routinely in patients with suspicion of colorectal peritoneal metastases (PM) to evaluate suitability for cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS + HIPEC). Methods: Data for consecutive patients who underwent DLS between 2012 and 2018 were extracted retrospectively from an institutional database. The primary outcome was the degree of visibility of the abdominal cavity during DLS. Good laparoscopic evaluation of the abdominal cavity was defined as visibility of at least the regions of the diaphragm, pelvis and small bowel. Secondary outcomes were reasons for perioperative exclusion for CRS + HIPEC, major postoperative complications (Clavien-Dindo grade III or above) and difference in overall survival (OS) between patients deemed suitable or unsuitable for CRS + HIPEC. Kaplan-Meier analyses were performed. Results: Some 184 patients were analysed. Good laparoscopic evaluation was possible in 138 patients (75·0 per cent), and 24 (13·0 per cent) had conversion to an open procedure. Ninety-three patients (50·5 per cent) were excluded for CRS + HIPEC, most commonly because of absence of colorectal PM (34 patients, 37 per cent) or extensive disease (Peritoneal Cancer Index 20 or above) (33 patients, 35 per cent). Major complications occurred in five patients (2·7 per cent), with no postoperative deaths. Median OS was significantly decreased in patients who were excluded due to extensive disease (14 (95 per cent c.i. 10 to 18) months) compared with patients suitable for CRS + HIPEC (36 (27 to 45) months) (P < 0·001). Conclusion: Routinely performing DLS in patients with suspicion of colorectal PM to evaluate suitability for CRS + HIPEC is feasible and safe, avoiding the morbidity of an unnecessary laparotomy in patients with extensive disease.

Antecedentes: El objetivo del presente estudio fue determinar la viabilidad y seguridad de realizar una laparoscopia diagnóstica (diagnostic laparoscopy, DLS) de rutina en pacientes con sospecha de metástasis peritoneal (peritoneal metastasis, PM) de origen colorrectal para evaluar la idoneidad para la cirugía citorreductora con quimioterapia intraperitoneal hipertérmica (cytoreductive surgery + hyperthermic intraperitoneal chemotherapy, CRS+HIPEC). Métodos: Los datos de los pacientes consecutivos que fueron sometidos a DLS entre 2012 y 2018 se obtuvieron retrospectivamente de una base de datos institucional. La visualización de al menos las regiones de los diafragmas, pelvis e intestino delgado se definió como una correcta evaluación laparoscópica de la cavidad abdominal. Los resultados secundarios fueron las complicaciones postoperatorias mayores (Clavien­Dindo grado ≥ III), razones para la exclusión perioperatoria para CRS+HIPEC y diferencia en supervivencia global (overall survival, OS) entre pacientes que se consideraron apropiados y no apropiados para CRS+HIPEC. Se realizaron análisis de Kaplan­Meier y análisis de riesgos proporcionales. Resultados: Se analizaron 181 pacientes. En 138 pacientes (75,0%) fue posible una adecuada evaluación laparoscópica, mientras que 24 casos (13%) fueron convertidos a un procedimiento abierto. Se excluyeron 93 (50,5%) pacientes para CRS+HIPEC, más comúnmente por la ausencia de PM colorrectales (36,6%) o enfermedad extensa (37,6%). En cinco pacientes aparecieron complicaciones mayores (2,7%), sin mortalidad postoperatoria. La mediana de la OS disminuyó de forma significativa en pacientes que fueron excluidos debido a enfermedad extensa (14 meses, i.c. del 95% 10­18) en comparación con pacientes idóneos para CRS+HIPEC (35 meses, i.c. del 95% 30­40, P < 0,0001). Conclusión: La realización rutinaria de DLS en pacientes con sospecha de PM de origen colorrectal para evaluar la idoneidad de la CRS+HIPEC es viable y segura. La morbilidad de una laparotomía innecesaria puede prevenirse en pacientes con enfermedad extensa o ausencia de PM colorrectales.

Neoadjuvant chemotherapy followed by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for colorectal cancer: a feasibility and safety study.

BACKGROUND: Standard treatment for colorectal peritoneal carcinomatosis typically involves cytoreductive surgery, hyperthermic intraperitoneal chemotherapy (HIPEC), and if possible, postoperative adjuvant chemotherapy. However, a substantial percentage of patients never receive adjuvant chemotherapy because of postoperative complications. Neoadjuvant chemotherapy could be beneficial in this setting, so we assessed its feasibility and safety when used before cytoreductive surgery and HIPEC. METHODS: In this non-randomized, single-center, observational feasibility study, patients were scheduled to receive six cycles of capecitabine and oxaliplatin before cytoreductive surgery and HIPEC. Computed tomography was performed after the third and sixth chemotherapy cycles to evaluate tumor response, and patients underwent cytoreductive surgery and HIPEC if there were no pulmonary and/or hepatic metastases. Postoperative complications, graded according to the Clavien-Dindo classification, were compared with those of a historic control group that received postoperative adjuvant chemotherapy. RESULTS: Of the 14 patients included in the study, 4 and 3 had to terminate neoadjuvant chemotherapy early because of toxicity and tumor progression, respectively. Cytoreductive surgery and HIPEC were performed in eight patients, and the timing and severity of complications were comparable to those of patients in the historic control group treated without neoadjuvant chemotherapy. CONCLUSION: Patients with peritoneal metastases due to colorectal carcinoma can be treated safely with neoadjuvant chemotherapy before definitive therapy with cytoreductive surgery and HIPEC. TRIAL REGISTRATION NUMBER: NTR 3905, registered on 20th march, 2013, http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=3905.

Cytoreduction and hyperthermic intraperitoneal chemotherapy: The learning curve reassessed.

BACKGROUND: CytoReductive Surgery and Hyperthermic IntraPEritoneal Chemotherapy (CRS-HIPEC) is now the preferred treatment of many peritoneal surface malignancies. In this retrospective study we aimed to analyze how several performance indicators changed during the first 100 CRS-HIPEC procedures in hospitals which recently introduced this treatment, and compare those with an experienced institution. METHODS: The first consecutive 100 CRS-HIPEC procedures of three institutions were compared to those of the pioneer hospital. The training provided by the pioneer hospital consisted of hands-on training during the first ten procedures; hereafter guidance was available on consult basis. Operation characteristics, morbidity and completeness of cytoreduction were evaluated by case sequence. Locally-estimated-scatter-plot smoothing was used to evaluate the learning curve. RESULTS: From four institutions 372 cases were included. A macroscopic complete cytoreduction was reached in 66% of the cases in the pioneer hospital and in 86% in the new hospitals (p < 0.001). Complete cytoreduction rates were higher at start off in the new institutions compared with the experienced institution and increased significantly in the first 100 procedures. The new hospitals started with lower morbidity than the experienced hospital, which did not significantly decrease during the study period. CONCLUSION: New institutions that were trained and mentored by an experienced CRS-HIPEC hospital performed better from the beginning with regard to complete cytoreduction and morbidity rate with than the experienced center. An improvement in complete cytoreduction rate during the first 100 procedures was observed in the new institutions.

S-100B concentrations predict disease-free survival in stage III melanoma patients.

BACKGROUND: Elevation of the tumor marker S-100B in melanoma patients is a highly specific indicator of recurrence. MATERIALS AND METHODS: The role of S-100B in disease-free survival (DFS) was evaluated in stage III melanoma patients (staged with fluorodeoxyglucose positron emission tomography [FDG-PET] and computed tomography [CT]) with palpable lymph node metastases who underwent therapeutic lymph node dissection. S-100B and LDH were measured on the day before surgery (d = -1) and on days 1, 2, and 7 postoperatively. Multivariate logistic regression was used to study factors associated with preoperative elevation of S-100B. Univariate (log-rank test) and multivariate (Cox regression) survival analyses were performed to identify factors associated with DFS. RESULTS: Between 2004 and 2008, 56 patients (median age 57, range 24-93) years, 27 males (48%) and 29 females (52%) entered the study. Preoperative S-100B elevation was found in 27 patients (48%) and elevated LDH in 20 patients (36%). No association was found between these two markers at any time. Multivariate analysis showed that elevated S-100B preoperatively (hazard ratio [HR] 2.7, P = .03) was associated with DFS. S-100B elevation was associated with increased tumor size (odds ratio [OR] 3.40; P = .03). CONCLUSION: Elevated S-100B preoperatively in patients with optimally staged clinical stage III melanoma is associated with decreased disease-free survival. S100-B could be used as a prognostic marker in the stratification of new adjuvant trials to select stage III melanoma patients for adjuvant systematic treatment.

Hyperthermic isolated limb perfusion in the management of extremity sarcoma.

High local drug concentrations can be achieved in a limb with minimal systemic toxicity with the technique of hyperthermic isolated limb perfusion (HILP). The currently most successful drugs are still Tumor Necrosis Factor alpha (TNFalpha) and melphalan. With HILP, as an induction chemotherapy treatment of locally advanced primarily irresectable soft tissue sarcomas of a limb, a limb salvage rate of 71% can be achieved, with a minimal treatment related morbidity. For the HILP is no upper age limit. Systemic inflammatory response syndrome is currently seldom seen. The exact working mechanisms of TNFalpha are still unknown. Experimental work is now directed to the development of drugs sensitizing the tumor vasculature to the effects of TNFalpha. In the clinical HILP setting are currently lower doses of TNFalpha in combination with melphalan investigated. Although multidrug resistance (MDR) is a major issue in effectiveness of chemotherapy in human cancer treatment, HILPs with TNFalpha and melphalan did not induce MDR in sarcomas. The future research in HILP with TNFalpha is directed in increasing tumor sensitivity for TNF with lowering the dosage without decreasing tumor response.

Hyperthermic isolated limb perfusion with tumour necrosis factor-alpha and melphalan as palliative limb-saving treatment in patients with locally advanced soft-tissue sarcomas of the extremities with regional or distant metastases. Is it worthwhile?

The management of locally advanced soft-tissue sarcomas (STS) of the extremities in patients who present with regional and/or distant metastases at the time of diagnosis remains an unsolved problem. The recently introduced hyperthermic isolated limb perfusion (HILP) with tumour necrosis factor (TNF)-alpha and melphalan has been shown to be an effective limb-saving treatment modality, but is it feasible to use this approach with palliative intent? Nine patients, five men and four women, mean age 41 (range 21-75) years with locally advanced extremity STS and regional (n = 3) or distant (n = 6) metastases at the time of diagnosis, underwent a palliative HILP with TNF-alpha and melphalan. Resection of the residual tumour mass was performed, if possible, 6-8 weeks after HILP. Treatment-related morbidity, local recurrences and the limb salvage rate were scored during follow-up. The median follow-up period was 9 (range 3-39) months (seven deaths, but six were due to metastatic disease). Treatment-related morbidity was seen after 3 of the 10 perfusions performed (30%) and consisted of superficial wound infections (n = 2), blow out of the external iliac artery followed by an iliac thrombosis (n = 1). Two patients showed local recurrences after HILP followed by resection of the residual tumour mass, and one patient showed local progression after two perfusions without resection. Limb salvage was achieved in 8 patients (89%). Therefore, HILP with TNF-alpha and melphalan for locally advanced extremity STS in patients with disseminated disease is feasible. The local management of locally advanced extremity STS should be the same whether the intent is curative or palliative, as the local control improves the quality of life.

Feasibility and efficacy of external beam radiotherapy after hyperthermic isolated limb perfusion with TNF-alpha and melphalan for limb-saving treatment in locally advanced extremity soft-tissue sarcoma.

PURPOSE: Hyperthermic isolated limb perfusion (HILP) with tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), and melphalan is associated with a dramatic antitumor effect in locally advanced extremity soft-tissue sarcomas (STS). The aim of this study was to demonstrate the feasibility and efficacy of adjuvant radiotherapy after HILP with TNF-alpha, IFN-gamma, and melphalan and delayed surgical resection. METHODS AND MATERIALS: Between 1991 and 1995, 34 patients--16 males and 18 females, median age 50 (range 18-80) years--underwent HILP for locally advanced extremity STS. Resection of the residual tumor mass was performed in most patients after 6-8 weeks. Fifteen patients with histopathological viable tumor after resection received adjuvant 60-70 Gy external beam radiotherapy (EBRT) (44%, HILP + EBRT group). Nineteen patients received HILP without adjuvant EBRT (56%, HILP-only group). Five patients in the HILP-only group had also distant metastases (15%) and received HILP as a palliative treatment. Treatment morbidity, local recurrences, and regional and distant metastases were scored. RESULTS: During a median follow-up of 34 months (range 8-54), limb salvage was achieved in 29 patients (85%): 14 patients after HILP + EBRT and 15 patients after HILP only. None of the patients from the HILP + EBRT group developed local recurrences; however, five patients from the HILP-only did (26%) (p < 0.05). Regional metastases were observed in one patient from the HILP + EBRT group (7%) and in two patients from the HILP-only group who were treated with curative intent (14%). Distant metastases occurred in four patients after HILP + EBRT (27%) and in four patients after HILP only with curative intent (29%). The mean morbidity (subjective, objective, medical management, and analytical evaluation) score in both groups was, respectively, 0.33 for skin and subcutaneous tissue and for muscle and soft tissue, 0.34 (HILP + EBRT group) and 0.33 (HILP-only group). CONCLUSION: Adjuvant EBRT after HILP with TNF-alpha, IFN-gamma, and melphalan and delayed tumor resection of locally advanced extremity STS is feasible and may increase local tumor control without increasing treatment morbidity.

Effects of hyperthermic isolated limb perfusion with tumor necrosis factor-alpha and melphalan on pulmonary function assessments.

High doses of tumor necrosis factor-alpha (TNF) seem to be effective in the treatment of solid tumors in the extremities. By applying current intensive care technology, systemic administration of high doses of TNF levels might be feasible for the treatment of cancer in other localizations. To establish the early and late effects of high systemic TNF levels on the lungs, we determined lung function parameters in 12 patients before and after hyperthermic isolated limb perfusion (HILP) with TNF and melphalan. Because of leakage during perfusion, mean maximum systemic TNF levels of 60.0 ng/ml (range, 0.3-356 ng/ml) were obtained. Significant alterations in the vital capacity (VC), the capillary blood volume (Vc), the diffusing capacity of the alveolocapillary membrane (Dm), and the transfer capacity of the lungs for carbon monoxide per unit alveolar volume (KCO) were observed 1 week after HILP. Eight weeks after HILP, they returned to pretreatment value. Alterations in lung functions were not related to the maximum systemic TNF level. In conclusion, disturbances in pulmonary functions are observed in patients after HILP with TNF and melphalan. These disturbances, which are probably partly caused by high systemic TNF levels, are reversible and would not preclude administration of systemic TNF in high doses.

Angiographic response of locally advanced soft-tissue sarcoma following hyperthermic isolated limb perfusion with tumor necrosis factor.

BACKGROUND: Hyperthermic isolated limb perfusion (HILP) with tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), and melphalan is associated with a dramatic anti-tumor effect in which the neo-vascularization of the tumor is supposed to be the major target. The aim of the present study was to correlate the angiographic findings with the pathological response in patients undergoing HILP for locally advanced soft-tissue sarcoma. PATIENTS AND METHODS: Twenty-five patients, 14 male and 11 female, mean age 47 years (range 18-80) were studied. Angiographies were performed before and a median period of 7 weeks (range 4-14 weeks) after HILP. Eight weeks after perfusion, the residual tumor mass was resected and pathologically examined. The changes in tumor vascularization after treatment were scored and compared with the pathological response. RESULTS: All baseline angiograms showed a hypervascular tumor. After HILP, a normal angiography result (NA) was observed in 18 patients (72%) and an abnormal angiography result (AA) was observed in seven patients (28%). All patients with an NA showed a pathologically complete response (pCR) or a pathological partial response with > 90% necrosis of the tumor. Of seven patients with an AA, pathological examination showed a pCR in one patient, 10-50% viable tumor volume in four patients, and no pathological response after perfusion in two patients. A good correlation was seen between angiographic and pathological classification (p < 0.001). CONCLUSION: An angiography performed after hyperthermic isolated limb perfusion with TNF-alpha and melphalan provides a good indication, regardless of whether a good pathological response is expected.

Hyperthermic isolated limb perfusion with cisplatin in four patients with sarcomas of soft tissue and bone.

The value of hyperthermic isolated limb perfusion (HILP) with cisplatin in the management of locally advanced soft tissue sarcomas or metastatic bone sarcoma was studied. Four patients were treated with HILP under mild hyperthermia (39-40 degrees C) with 20-30 mg cisplatin/l perfused limb volume. Toxicity in the perfused limbs was moderate, and the erythema and oedema that occurred resolved spontaneously within 7-14 days as did the slight motor and sensory neuropathy over a longer period of time. Clinically, a reduction of pain was observed in all patients. Two weeks after perfusion, tumour biopsies were taken to evaluate tumour response. Two patients showed a pathological complete response, one patient showed >90% necrosis and one patient showed no response. Currently patients are treated with tumour necrosis factor and melphalan as perfusion agents. The above-mentioned results make the combination of tumour necrosis factor with cisplatin in the isolated limb perfusion setting an interesting option.

Effects of hyperthermic isolated limb perfusion with recombinant tumor necrosis factor alpha and melphalan on the human fibrinolytic system.

This study was undertaken to determine the effects on systemic fibrinolysis of hyperthermic isolated limb perfusion with recombinant tumor necrosis factor alpha (r-TNF-alpha) and melphalan, with or without pretreatment with recombinant IFN-gamma (r-IFN-gamma). Twenty patients were treated with r-TNF-alpha and melphalan; four patients, treated with melphalan only, served as controls. Of the twenty patients treated with both r-TNF-alpha and melphalan, eight received r-IFN-gamma for two days before the perfusion and as a bolus into the perfusion circuit. A significant leak of r-TNF-alpha from the perfusion circuit to the systemic circulation was observed in all r-TNF-alpha-treated patients (mean maximum TNF-alpha, 87,227 ng/liter versus 31 ng/liter in controls; P < 0.002). In these patients, but not in controls, there was an almost instantaneous rise in systemic tissue plasminogen activator activity (from 0.26 to 5.28 IU/ml in 90 min), causing activation of fibrinolysis. After a delay of 90 min, plasminogen activator inhibitor-1 (PAI-1) antigen rose to high levels in the r-TNF-alpha-treated group (mean maximum PAI-1, 1652 ng/ml versus 211 ng/ml in controls; P < 0.02), associated with a sharp decrease of tissue plasminogen activator activity and a slower decrease of plasminogen-antiplasminogen complexes (from 5.28 to 0.02 IU/ml in 2 h and from 1573 to 347 micrograms/liter in 22 h, respectively). No additional effect of IFN-gamma pretreatment on fibrinolysis could be demonstrated. These results suggest that in isolated limb perfusion with r-TNF-alpha and melphalan an initial activation of systemic fibrinolysis, induced by leakage of r-TNF-alpha from the perfusion circuit, is set off by a subsequent inhibition of the fibrinolytic system by PAI-1. This large increase in PAI-1 could place the patient at risk for deposition of microthrombi in the systemic circulation.

FDG-PET to evaluate response to hyperthermic isolated limb perfusion for locally advanced soft-tissue sarcoma.

UNLABELLED: We investigated FDG-PET in patients undergoing hyperthermic isolated limb perfusion (HILP) with rTNF-alpha, rIFN-gamma and melphalan for locally advanced soft-tissue sarcoma of the extremities. METHODS: Twenty patients (11 women, 9 men; aged 18-80 yr, mean age 49 yr) were studied. FDG-PET studies were performed before, 2 and 8 wk after HILP. After the final PET study, the tumor was resected and pathologically graded. Patients with pathologically complete response (pCR) showed no viable tumor after treatment. Those with pathologically partial response (pPR) showed various amounts of viable tumor in the resected specimens. RESULTS: Seven patients showed a pCR (35%) and 12 patients showed a pPR (60%). In one patient, pathological examination was not performed (5%). The pre-perfusion glucose consumption in the pCR group was significantly higher than in the pPR group (p<0.05). Visual analysis of the PET images after perfusion showed a rim of increased FDG uptake around the core of absent FDG uptake in 12 patients. The rim signal contained a fibrous pseudocapsule with inflammatory tissue in the pCR group, viable tumor was seen in the pPR group. The glucose consumption in the pCR group at 2 and 8 wk after perfusion had decreased significantly (p<0.05) in comparison to the glucose consumption in the pPR. CONCLUSION: Based on the pretreatment glucose consumption in soft-tissue sarcomas, one could predict the probability of a patient achieving complete pathological response after HILP. FDG-PET indicated the pathological tumor response to HILP, although the lack of specificity of FDG, in terms of differentiation between an inflammatory response and viable tumor tissue, hampered the discrimination between pCR and pPR.

High plasma tumor necrosis factor (TNF)-alpha concentrations and a sepsis-like syndrome in patients undergoing hyperthermic isolated limb perfusion with recombinant TNF-alpha, interferon-gamma, and melphalan.

OBJECTIVES: To describe the postoperative course of patients who underwent hyperthermic isolated limb perfusion with recombinant tumor necrosis factor (TNF)-alpha and melphalan after pretreatment with recombinant interferon-gamma as treatment for recurrent melanoma, primary nonresectable soft-tissue tumors, planocellular carcinoma, or metastatic carcinoma. To measure systemic TNF-alpha concentrations and relate these values with indices of disease severity. SETTING: A 12-bed surgical intensive care unit (ICU) in a university referral hospital. DESIGN: Prospective, descriptive study. PATIENTS: Consecutive patients (n=25) treated with hyperthermic isolated limb perfusion. INTERVENTIONS: Blood samples were taken at regular intervals to determine TNF-alpha concentrations during and after hyperthermic isolated limb perfusion with recombinant TNF-alpha. Hemodynamic variables were obtained with a Swan-Ganz pulmonary artery catheter. MEASUREMENTS AND MAIN RESULTS: All patients developed features of sepsis syndrome and required intensive care treatment. Most patients recovered quickly, with a median ICU stay of 2 days (range 1 to 25). Maximum systemic TNF-alpha concentrations ranged from 2284 to 83,000 ng/L (median 25,409) and returned to baseline values within 8 hrs. Despite these high concentrations of TNF-alpha, no patient died in the ICU, although the patient with the highest TNF-alpha concentration developed multiple organ failure and required continuous venovenous hemofiltration for 16 days. Linear regression analysis showed positive correlations between maximum TNF-alpha concentrations and systemic vascular resistance (p < .01), cardiac index (p < .02), Lung Injury Score (p < .02), prothrombin time (p < .02), and activated partial thromboplastin time (p < .05). CONCLUSIONS: Hyperthermic isolated limb perfusion with recombinant TNF-alpha leads to high systemic concentrations of TNF-alpha, probably due to leakage of recombinant TNF-alpha from the perfusion circuit, mainly through collateral blood flow. A sepsis-like syndrome is seen in all patients. Despite high concentrations of systemic TNF-alpha, this sepsis syndrome is short-lived and recovery is rapid and complete in most patients.

Hyperthermic isolated regional perfusion with cisplatin in the local treatment of spontaneous canine osteosarcoma: assessment of short-term effects.

To increase the effect of cisplatin on locoregional osteosarcoma, the short-term effect of hyperthermic isolated regional perfusion (HIRP) with cisplatin (30 mg/L extremity volume) was studied in 28 dogs with spontaneous osteogenic sarcoma, using clinical, radiological, and histological parameters. Thirty days postoperatively, mortality was 14.3%. Total platinum levels at the start of perfusion were 28.2 +/- 14.3 mg/L. A significant improvement (P < 0.001) in clinical score was observed in the overall group at 6 and 12 weeks after perfusion. The radiological parameter showed a stationary X-ray 2 weeks after perfusion and an improved X-ray 6 weeks after perfusion. Overall histological scores showed a moderate effect according to the Huvos classification. No additional therapeutic effect, according to the three parameters, could be demonstrated by increasing the perfusate temperature by 1 degrees C. HIRP with cisplatin is feasible in the local treatment of spontaneous osteosarcoma in dogs with acceptable locoregional toxicity. However, the histological results were modest, with none of the dogs showing a complete response 6 weeks after perfusion. Therefore, the search for the ideal perfusion agent with substantial contribution to the limb-sparing treatment in human osteosarcoma continues.