Prognostic factors and oncologic outcome in 146 patients with colorectal peritoneal carcinomatosis treated with cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy: Italian multicenter study S.I.T.I.L.O.

AIM: The present study was specifically designed to assess the major clinical and pathological variables of patients with colorectal peritoneal carcinomatosis in order to investigate whether currently used criteria appropriately select candidates for peritonectomy procedures (cytoreductive surgery) combined with hyperthermic intraperitoneal chemotherapy (HIPEC). PATIENTS AND METHODS: Preoperative, operative and follow-up data on 146 consecutive patients presenting with peritoneal carcinomatosis of colorectal origin and treated by surgical cytoreduction combined with HIPEC in 5 Italian Hospital and University Centers were prospectively entered in a common database. Univariate and multivariate analyses were used to assess the prognostic value of clinical and pathologic factors. RESULTS: Over a minimum 24-month follow-up, the overall morbidity rate was 27.4% (mortality rate: 2.7%) and was directly related to the extent of surgery. Peritoneal cancer index (PCI), unfavorable peritoneal sites, synchronous or previously resected liver metastasis and the completeness of cytoreduction, all emerged as independent prognostic factors correlated with survival. CONCLUSIONS: Until research provides more effective criteria for selecting patients based upon the biomolecular features of carcinomatosis, patients should be selected according to the existing independent prognostic variables.

Hyperthermic isolated perfusion with tumor necrosis factor-alpha and doxorubicin for the treatment of limb-threatening soft tissue sarcoma: the experience of the Italian Society of Integrated Locoregional Treatment in Oncology (SITILO).

BACKGROUND: Tumor necrosis factor-alpha (TNFalpha)-based hyperthermic isolated limb perfusion (HILP) is routinely carried out at most oncological institutions in the treatment of locally advanced soft tissue limb sarcoma (STS), employing high TNFalpha dosages. After a phase I-II study, the SITILO (Italian Society of Integrated Locoregional Therapies in Oncology) centers began to employ the lower dose of 1 mg of TNFalpha. The aim of this paper is to report on the results obtained in 75 patients with limb-threatening STS treated with a low TNFalpha dose and doxorubicin (Dx). PATIENTS AND METHODS: HILP with TNFalpha (at a dosage of either 1 mg) and Dx was administered to 75 patients with limb-threatening STS: 37 males and 38 females; median age 50 years; tumor in the lower and upper limbs in 58 and 17 patients, respectively; primary and recurrent tumors in 45 and 30 patients, respectively. Most tumors (77%) were high grade. Tumor resection was carried out 6 to 8 weeks after HILP. RESULTS: The grade of limb toxicity was mild to moderate in the vast majority of patients (76%). Grades IV and V were observed, but only when high muscle temperatures were recorded and high TNFalpha dosages were employed. Systemic toxicity was also mild to moderate and there were no postoperative deaths. Complete and partial tumor responses were 34% and 48%, respectively, with an overall response of 82% . Limb sparing surgery was carried out in 85.3% of patients. At a median follow-up of 28 months, 16 recurrences (21.3%) were recorded, with a 5-year locoregional disease-free survival of 63% . The 5-year disease-free survival and overall survival were 36.7% and 61.6%, respectively. CONCLUSION: HILP with 1 mg of TNFalpha is an effective neoadjuvant therapy resulting in a high rate of limb sparing in limb-threatening STS, with acceptable local reactions and negligible systemic toxicity.

120 peritoneal carcinomatoses from colorectal cancer treated with peritonectomy and intra-abdominal chemohyperthermia: a S.I.T.I.L.O. multicentric study.

A multicentric study has been carried out on 120 patients affected by peritoneal carcinomatosis from colorectal cancer. Patients have been treated by cytoreductive surgery and intra-operative hyperthermic chemoperfusion (HIPEC) with cisplatin (CDDP) and mitomycin-c (MMC). A small group of patients were treated with oxaliplatin (LOHP) following the Elias et al. scheme [intravenous 5-fluorouracil (400 mg/m2) and leucovorin (20 mg/m2) followed by intraperitoneal perfusion with LOHP (460 mg/m2) in 2 l/m2, during 30 min at 43 degrees C]. CC-0 cytoreduction was achieved in 85.2% of the patients. Major morbidity and mortality was 22.5% and 3.3%, respectively. No G4 toxicity was registered. The three-year survival was 25.8%. The difference in survival evaluating complete cytoreduction (CC-0) vs. incomplete (CC1-2; residual tumor nodules greater than 2.5 mm) was statistically significant (p < 0.0001). Evaluating only the patients that could be cytoreduced to CC-0, the 3-year survival was raised to 33.5%. In our experience the peritoneal cancer index (PCI) has been demonstrated to be a weak prognostic factor reaching a statistical significance only after the exclusion of patients with resected hepatic metastases. The patients treated with oxaliplatin were alive and free-of-disease after a 16-month median follow-up.

[Peritonectomy and chemohyperthermia in the treatment of peritoneal carcinomatosis: learning curve]. / Peritonectomia e chemioipertermia nel trattamento delle carcinosi peritoneali: "learning curve".

A prospective study has been carried on 37 patients affected by peritoneal carcinomatosis from various primary. Patients have been treated by cytoreductive surgery and intraoperative hyperthermic chemoperfusion. CC 0-1 has been achieved in 81%. The temperature distribution study showed a "barrier effect" with no statistically significant correlation to the survival. Major morbidity and mortality was respectively 37.8% and 16.2%. Two-yr overall survival was 49.1% for all series. Morbidity was significantly directly correlated to the duration of the surgical treatment. A learning curve of 19 months have been observed, after that only one death out 21 procedures has been recorded. Peritoneal carcinomatosis patients, that are submitted to integrated treatment, need a peculiar management that is not comparable to any other in the oncological setting and that requires specific competence.

[Laparoscopic intraperitoneal antiblastic hyperthermic chemoperfusion in the treatment of refractory neoplastic ascites. Preliminary results]. / Chemioperfusione ipertermico antiblastica intraperitoneale laparoscopica per il trattamento delle asciti neoplastiche refrattarie. Risultati preliminari.

A method of laparoscopic continuous hyperthermic peritoneal perfusion (CHPP) is proposed for the treatment of debilitating malignant ascites. The authors report 14 cases of peritoneal malignancy, not amenable to peritonectomy due to massive infiltration of the small bowel. The ascites disappeared in all treated cases.

[Doxorubicin in antiblastic hyperthermic perfusion in the treatment of advanced soft-tissue sarcoma of the limbs]. / La doxorubicina nella perfusione ipertermico antiblastica nel trattamento dei sarcomi avanzati dei tessuti molli degli arti.

Different antineoplastic drugs have been associated to hyperthermia in the treatment of advanced soft tissue limb sarcoma with a good results in terms of conservative surgery (77%-97%), locoregional control (77%-87%) and overall survival (72%). Two different studies were performed: the first was carried out to analyze the doxorubicin-TNFalpha-hyperthermia association (three different trials) in terms of toxicity and efficacy of the treatment (tumor response, locoregional control, disease free and overall survival). The results showed that the trimodality association (doxorubicin TNFalpha and hyperthermia) is the best regimen able to obtain a 77% of objective response and 77% of limb sparing in patients candidate to amputation but may result in high local toxicity if high temperatures (>41.5 degrees C) were maintained during perfusion. The second study describes the employment of liposomal doxorubicin in hyperthermic antiblastic perfusion (HAP) in terms of tumor response, conservative surgery and toxicity; the maximum tolerable dose (MTD) of doxorubicin was 16 mg/l of perfused limb volume at the temperature of 41.5 degrees C; the conservative surgery was possible in 91% of the cases and mild (grade I and II) toxicity was observed in the perfused limb with high temperature (>41.5 degrees C).

TNFa-based isolated hyperthermic limb perfusion (HILP) in the treatment of limb recurrent melanoma: update 16 years after its first clinical application.

Hyperthermic Limb Perfusion (HILP) with Tumor Necrosis Factor alpha (TNFalpha) and interferon gamma (IFNgamma) was pioneered by Liénard and Lejeune in 1988. TNFalpha was empirically employed at a dosage of 3-4 mg that is ten times the systemic maximum tolerated dose (MTD). Sixteen years after its first clinical application more than 300 patients have been treated and some clarifications can be made regarding three major questions: the real role of IFNgamma, the TNFalpha dose and eligibility criteria for patient selection. A randomized phase II study has demonstrated that IFNgamma does not increase significantly the efficacy but does increase side-effects. Experimental and clinical results seem to indicate that patients with bulky melanoma disease can really benefit from TNFalpha HILP carried out with only 1 mg.

Liposomal doxorubicin in the perfusional treatment of advanced soft tissue limb sarcoma.

Liposome-containing doxorubicin has been employed in the treatment of advanced soft tissue limb sarcoma during hyperthermic perfusion. A phase I-II study was carried out starting with a standard dose of 10 mg//L of limb volume, the dosage was escalated with 2 mg for each triplet of patients. The maximum tolerable (MTD) dose was established as the amount able to cause a grade IV limb reaction at least in two out of three patients, the temperature level remained unchanged (41.5 degrees C). The grade of limb reaction ranged between I-II (mild edema and erythema). Only in two patients treated with 18 mg/L of limb volume was a grade IV limb reaction observed, therefore MTD at a temperature of 41.5 degrees C is 16 mg. A good tumor response was observed in 29% of the patients, partial response in 71%. The tumor shrinkage after perfusion permitted conservative surgery in 91% of the cases.

[Indications for integrated surgical treatment of peritoneal carcinomatosis of colorectal origin: experience of the Italian Society of Locoregional Integrated Therapy in Oncology]. / Indicazioni al trattamento chirurgico integrato delle carcinosi peritoneali di origine colorettale: esperienza della società Italiana di terapie integrate locoregionali in oncologia.

A multicentric prospective study has been carried on 69 patients affected by peritoneal carcinomatosis from colorectal cancer. Patients have been treated by cytoreductive surgery and intraoperative hyperthermic chemoperfusion. CC 0-1 has been achieved in 82%. Major morbidity and mortality was respectively 21.7% and 2.9%. Three years overall survival was 26.7% for all series. Difference in survival evaluating CC 0-1 vs CC 2 patients and PCI < or = 10 vs > 10 was statistically significant. Evaluating only patients CC 0-1 and PCI < or = 10 overall survival rised up to 44.7% at 4 years. A smaller subgroup of patients with a disease-free interval to peritoneal carcinomatosis > or = 2-year showed a 50% disease-free survival at 5 years. In conclusion PCI < or = 10, complete or optimal cytoreduction feasibility and disease-free interval have to be considered for the patients selection to the integrate treatment.

[Anti-blastic hyperthermic perfusion in the treatment of melanoma of the extremities in the loco-regional diffusion phase]. / La perfusione ipertermico-antiblastica nel trattamento del melanoma degli arti nella fase di diffusione loco-regionale.

Primary limb melanoma may recur in terms of satellitosis, in transit metastases and/or regional node involvement. Hyperthermic antiblastic perfusion (HAP) permits the isolation of involved extremity from the systemic circulation and to deliver high doses of antineoplastic drugs. The association of cytostatic drugs to hyperthermia (> or = 41.5 degrees C) results in a synergistic effect with an increased therapeutic effectiveness. The overall 5 and 10-year survival rates in relation to the disease stages are st. II 75% and 67%; st. IIIA 59% and 42%; st. IIIAB 36% and 30% respectively. The results confirm that HAP is considered the treatment of choice of loco-regional spreading limb melanoma. Recently, the tumor necrosis factor (TNF) has been combined with Melphalan and hyperthermia. This trimodality association seems to be superior to Melphalan and hyperthermia alone only in patient with bulky tumors (i.e., multiple nodules), as a matter of fact the complete tumor response rates observed in these patients have been 67% and 20% respectively. The greater effectiveness of trimodality association has to be confirmed by multicentric randomized trials.

An Italian Multicentric Phase II study on peritonectomy and intra peritoneal hyperthermic perfusion (IPHP) to treat patients with pseudomyxoma peritonei.

Pseudomyxoma peritonei (PMP) is a rare disease with a poor prognosis when not adequately treated. It is characterized by a complete redistribution of mucin within the peritoneal cavity. The aim of this multicentric study was to evaluate the survival, morbidity, toxicity and mortality of patients with PMP treated by cytoreductive surgery (CRS) with intraperitoneal hyperthermic perfusion (IPHP). Seventy patients with PMP (31 males and 39 females) were enrolled onto a Phase II clinical trial. One patient was operated on twice because of disease recurrence. CRS was performed with peritonectomy procedures. The closed, opened and semi-closed abdomen techniques were employed for IPHP using cisplatin plus mitomycin-C for 60 minutes under hyperthermic conditions (42.5 degrees C). Sixty two (87%) patients were optimally cytoreduced. Five-year overall survival, progression-free survival and locoregional progression-free survival were 91%, 54% and 69%, respectively. Thirteen Grade III complications occurred in 10 (14%) patients and the most frequent one was gastrointestinal fistula/perforation (11%). There was one case (1.4%) of treatment-related mortality 21 days after treatment. CRS associated with IPHP permitted complete tumour removal with an acceptable morbidity and mortality in patients with PMP. This study confirms the efficacy of the combined treatment on long-term survival and local disease control.

An Italian Multicentric Phase II study on peritonectomy and intra peritoneal hyperthermic perfusion (IPHP) to treat patients with peritoneal mesothelioma.

Peritoneal mesothelioma (PM) is a rare disease, with a poor prognosis. We decided to prospectively evaluate the prognostic impact and the morbimortality of cytoreductive surgery combined with intraperitoneal hyperthermic perfusion in the treatment of this clinical entity. Sixty one patients with PM (31 males and 30 females) were enrolled onto a Phase II multicentric clinical trial. The mean age was 51 years (range: 24-72). CRS was performed with peritonectomy procedures. The closed, opened and semi-closed abdomen techniques were employed for IPHP using cisplatin plus mitomycin-C or cisplatin and doxorubicin for 60/90 minutes under hyperthermic conditions (42.5 degrees C). One patient was operated on twice because of disease recurrence. Mean follow-up was 20 months (range: 0.1-76). Forty six (74%) patients were optimally cytoreduced. Five-year overall and 5 yr progression-free survivals were 54% and 37%, respectively. Completeness of cytoreduction was significantly associated with outcome. Twenty Grade III complications occurred in 14 (23%) patients and the most frequent one was digestive fistula/perforation (11%). No treatment-related mortality was recorded. CRS + IPHP was proven to be acceptable in terms of morbidity and mortality in patients with PM and suggest a positive impact on outcome. Further prospective controlled studies are warranted to confirm these results.

Sitilo experience on peritoneal carcinomatosis from colorectal cancer: clinical prognostic features.

UNLABELLED: A multicentric prospective study has been carried on 69 patients affected by peritoneal carcinomatosis from colorectal cancer. Patients have been treated by cytoreductive surgery and intraoperative hyperthermic chemoperfusion. CC 0-1 has been achieved in 82%. Major morbidity and mortality was 21.7% and 2.9% respectively. Three-yrs overall survival was 26.7% for all series. Difference in survival evaluating CC 0-1 vs. CC 2 pts and PCI < or = 10 vs. >10 was statistically significant. Evaluating only patients CC 0-1 and PCI < or = 10 4-yrs overall survival rised up to 44.7%. A smaller subgroup of patients with a disease-free interval to peritoneal carcinomatosis > or = 2-yrs showed a 5-yrs disease-free survival of 50%. CONCLUSIONS: PCI < or = 10, complete or optimal cytoreduction feasibility have to be considered for the patients selection to the integrate treatment. Disease-free interval seems to be a powerful prognostic indicator and deserve to be better outlined in further studies.

Doxorubicin in isolation limb perfusion in the treatment of advanced limb soft tissue sarcoma.

Hyperthermic antiblastic perfusion/HAP) has been proven to be an effective neoadjuvant treatment in the treatment of advanced soft tissue limb sarcoma. As a matter of fact high percentage of limb sparing surgery, local control and functional results have been obtained wide this technique. Many antineoplastic drugs have been associated to hyperthermia by isolation limb perfusion, the aim of this paper was to describe the results obtained with doxorubicin in association to hyperthermia with or without Tumor Necrosis Factor (TNF) alpha in order to identify the most effective regimen in the multidisciplinary treatment of soft tissue limb sarcoma. A total of 106 patients have been evaluated. Three different study were performed: the first was a phase I study carried out in order to assess the maximum tolerable dose (MTD) of doxorubicin during HAP; the second was a phase II study with doxorubicin, and the third was a phase I - II study aimed at evaluating the MTD and tumor response of TNF alpha in association to doxorubicin and hyperthermia. Grade IV limb toxicity was recorded in 11 patients ( 4 in trial A, 3 in trial B, and 4 in trial C). The grade of limb reaction was strictly related to TNF dosage (> 1 mg) and temperature level (> 41.5 degrees C), therefore the best regimen is represented by temperature level not exceeding 41.5 degrees C and 1 mg of TNFalpha. The trimodality association (TNF, doxorubicin and hyperthermia) was proven to be the best regimen able to obtain a 77% of objective response (complete response, 22%) and a 77% of limb sparing in patients candidate to amputation. The results above mentioned showed the HAP with doxorubicin and TNFalpha (1 mg) is a very effective neoadjuvant treatment in the multidisciplinary treatment of advanced soft tissue limb sarcoma.

Hyperthermic antiblastic perfusion in the treatment of locoregional spreading limb melanoma.

On the basis of personal experience and a review of the literature, the authors have evaluated the results obtained with hyperthermic antiblastic perfusion (HAP) for the treatment of stage II, III and IIIAB limb melanoma. The evaluation showed that today HAP may be considered a safe and effective treatment, with a major complication rate ranging between 1% and 4%. In terms of tumor response, locoregional control and survival, this treatment has provided better results than other regional chemotherapeutic modalities and undoubtedly better results than those obtained with conventional, even radical, surgery. The multivariate analysis showed that, of the treatment-related prognostic factors, the minimum tumor temperature influenced the percentage of complete response (CR) to the greatest extent (P<0.03), with a positive trend also with regard to the dosage of the antiblastic drug employed (P<0.08). In turn, the complete response rate was a determinant as far as locoregional control (50%; P<0.0009) and disease-free (51.4%; P=0.0009) and overall survival (63%; P<0.009) rates were concerned. Of the tumor-related prognostic factors, the number of lesions (P<0.0014), sex (P<0.04), and the number of disease recurrences (P<0.01) appear to influence overall survival.

Hyperthermic antiblastic perfusion with TNFalpha and melphalan in stage III limb melanoma patients: A phase I - II SITILO study.

Hyperthermic antiblastic perfusion (HAP) has been proven to be an effective treatment of loco-regional spreading limb melanoma. The mean complete response (CR) rate obtained is 54%, with an objective responses (OR) rate ranging between 70% and 100%. Recently, Tumor Necrosis Factor (TNFalpha) has been employed at high dosages (3-4 mg) in association to Melphalan and hyperthermia. This trimodality combination increased the percentage of CR (70%-90%), but systemic toxicity was also reported due to high TNF doses. A phase I - II study was undertaken in order to assess the MTD of TNFalpha in association to true hyperthermia (41.5 degrees C) and Melphalan. Twenty patients affected with stages IIIA (9 patients), IIIAB (10 patients), and IV (1 patient) were enrolled in this study. The trimodality treatment did not increase the local and systemic toxicity. CR was observed in 70% of the patients, PR in 20% with on OR rate of 90%. These figures are overlapping those obtained with high TNF dosages. No correlation was observed between tumor responses and TNF doses. Taking into account that 70% of our patients have been treated with TNF dosages between 0.5 mg on 1.6 mg, we conclude that 1 mg is the best dosage to be applied during HAP. Patients with bulky tumor are the best candidate to TNF perfusion, because no differences have been observed in terms of CR in patients with low tumor burden treated with TNF-Melphalan-hyperthermia or Melphalan-hyperthermia.

Peritonectomy and hyperthermic antiblastic perfusion in the treatment of peritoneal carcinomatosis.

AIMS: Some low-grade malignant tumours arising in the abdomen tend to remain loco-regionally confined to peritoneal surfaces, without systemic dissemination. In these cases complete surgical tumour cytoreduction followed by intra- or post-operative regional chemotherapy has curative potential. The aim of this study was to evaluate the outcome for patients treated in this way. METHODS: Peritonectomy was performed, involving the complete removal of all the visceral and parietal peritoneum involved by disease. After peritonectomy, hyperthermic antiblastic perfusion was carried out throughout the abdominopelvic cavity for 90 min, at a temperature of 41.5-42.5 degrees C, with mitomycin C (3.3 mg/m2/l) and cisplatin (25 mg/m2/l) (for appendicular or colorectal primaries), or cisplatin alone (for ovarian primaries). Alternatively, the immediate post-operative regional chemotherapy was performed with 5-fluorouracil (13.5 mg/kg) and Lederfolin (125 mg/m2) (for colonic or appendicular tumours) or cisplatin (25 mg/m2) (for ovarian tumours), each day for 5 days. RESULTS: Thirty-five patients affected by extensive peritoneal carcinomatosis were submitted to peritonectomy, with no residual macroscopic disease in all cases except three. Twenty-six patients were able to undergo the combined treatment involving loco-regional chemotherapy. Complications were observed in 54% of the patients and led to death in four of them. At a mean follow-up of 17 months overall 2-year survival was 55.2%, with a median survival of 26 months. CONCLUSIONS: After a learning curve of 18 months the feasibility of the integrated treatment increased to more than 90%, while mortality decreased dramatically. The curative potential of the combined therapeutic approach seems high in selected patients with peritoneal carcinomatosis not responding to systemic chemotherapy. Careful selection of patients can minimize the surgical risk, but the treatment should currently be reserved for clinical trials.

Treatment of peritoneal carcinomatosis with intent to cure.

BACKGROUND AND OBJECTIVES: Low-grade malignant tumors arise in the abdomen, do not infiltrate, and "redistribute" on the peritoneum with no extraregional spreading. In these cases, aggressive surgery combined with localized chemotherapy may provide cure. METHODS: After removing the tumor with the regional peritoneum en bloc, intraabdominal hyperthermic chemoperfusion was performed throughout the abdominopelvic cavity. Alternatively, early intraabdominal chemotherapy, starting on the first postoperative day, was administered for 5 days. RESULTS: Forty patients affected with extensive peritoneal carcinomatosis underwent peritonectomy, with no residual macroscopic disease except in four cases. Seventy-five percent of the patients underwent locoregional chemotherapy. Major complications were observed in 40% of the patients and led to death in five; there was a direct correlation to the duration of surgery (P = 0.03). At a mean follow-up of 20 months, the overall 2-year survival was 61.4%, with a median survival of 30 months. CONCLUSIONS: After a learning curve of 18 months, the feasibility of the integrated treatment increased to greater than 90%, and mortality dramatically decreased. The combined treatment resulted in a high survival rate in patients with extensive carcinomatosis who were no longer responsive to traditional therapies.

Hyperthermic antiblastic perfusion with alpha tumor necrosis factor and doxorubicin for the treatment of soft tissue limb sarcoma in candidates for amputation: results of a phase I study.

To improve the therapeutic effectiveness of hyperthermic antiblastic perfusion (HAP), the association of recombinant tumor necrosis factor alpha (rTNF alpha), doxorubicin, and true hyperthermia (41 degrees C) was employed for the treatment of soft tissue limb sarcoma. A dose-escalation study according to Fibonacci's modified scheme was conducted, starting with a rTNF alpha dose of 0.5-3.3 mg. The doxorubicin doses (0.7 and 1.4 mg for the upper and lower limbs, respectively) and temperature level (41 degrees C) remained unchanged. Eighteen patients have been treated thus far: 9 males and 9 females of a mean age of 33 years (range: 24-71 years). The tumor was located in the upper limb in one patient and in the lower limbs in seventeen. Only 16 patients were evaluable, as 2 refused further treatment after the perfusion. In terms of local toxicity, a grade I limb reaction was observed in 3 patients, a grade II or III in 10 patients, and a grade IV in 5 patients, showing a strict correlation between the TNF dose and the grade of limb reaction. In fact, a grade III-IV limb reaction was observed in 66.6% of the patients treated with > 1 mg of rTNF alpha. The maximum tolerable dose in association with doxorubicin and true hyperthermia (41 degrees C) was 2.4 mg. Eleven patients showed a good pathological response (> 75%) and five patients showed a partial response (> 25%-< 75%). In no case was stable or progressive disease observed. The postperfusional tumor shrinkage permitted limb-sparing surgery in 75% of the patients, all of whom were candidates for amputation before HAP. No recurrences have been observed thus far. Two patients developed regional disease: one presented with a skip femur metastasis that disappeared after radiotherapy and systemic chemotherapy; the second developed regional node involvement, requiring a radical node dissection. Another patient had pulmonary metastases, 2 months after the HAP, which were resected. At a median follow-up of 12 months, all the patients are living without disease. The results of this phase I study suggest that the association of rTNF alpha, doxorubicin, and true HAP (41 degrees C) by regional perfusion is feasible and safe at a maximum tolerable rTNF alpha dose of 2.4 mg. However, because no correlation was found between the amount of rTNF alpha and the tumor response, 1 mg is recommended as the dose able to provide a high tumor necrosis rate and low local and systemic toxicity. This association appears to play an important role in the neoadjuvant treatment of soft tissue limb sarcoma.