Perioperative chemotherapy and regional hyperthermia for high-risk adult-type soft tissue sarcomas.

A group of patients with adult-type soft tissue sarcoma is at high risk of local recurrence and distant metastases. Age, tumour site, histological subtype, tumour size and grade have been identified as the most important independent adverse prognostic factors. Macroscopically complete tumour resection is considered as the mainstay of treatment with the addition of preoperative or postoperative radiotherapy for extremity or trunk localisation. Retroperitoneal localisation requires compartmental resection and is associated with a worse prognosis. Here, radiotherapy is of no proven value. Perioperative chemotherapy is considered to treat micrometastatic disease not detectable at the time of diagnosis. The neoadjuvant application gives the risk of distant metastasis the greatest importance as therapy is carried out at the earliest possible time, whereas adjuvant chemotherapy is delayed by surgery and the necessary wound healing. With reported response rates up to 30%, both the operability may be improved and the risk of intraoperative tumour cell dissemination may be reduced, resulting also in reduced local relapse rates. However, the potential risk of early tumour progression may counteract this benefit. Optimised strategies with multimodality approaches including chemotherapy, regional hyperthermia (RHT) and immunotherapeutic agents have been shown to improve survival in high-risk patients. Here, we focus on the data from available randomised studies investigating the use of perioperative chemotherapy in patients with high-risk adult-type soft tissue sarcoma, including the use of RHT for local enhancement of chemotherapy effect and immune induction.

Safety and Efficacy of Anlotinib, a Multikinase Angiogenesis Inhibitor, in Patients with Refractory Metastatic Soft-Tissue Sarcoma.

Purpose: The prognosis for patients with refractory soft-tissue sarcoma (STS) is dismal. Anlotinib has previously shown antitumor activity on STS in preclinical and phase I studies.Patients and Methods: Patients 18 years and older, progressing after anthracycline-based chemotherapy, naïve from angiogenesis inhibitors, with at least one measurable lesion according to RECIST 1.1, were enrolled. The main subtypes eligible were undifferentiated pleomorphic sarcoma (UPS), liposarcoma (LPS), leiomyosarcoma (LMS), synovial sarcoma (SS), fibrosarcoma (FS), alveolar soft-part sarcoma (ASPS), and clear cell sarcoma (CCS). Participants were treated with anlotinib. The primary endpoint was progression-free rate at 12 weeks (PFR12 weeks).Results: A total of 166 patients were included in the final analysis. Overall, the PFR12 weeks was 68%, and objective response rate was 13% (95% confidence interval, 7.6%-18%). The median progression-free survival (PFS) and overall survival (OS) were 5.6 and 12 months, respectively. The PFR12 weeks, median PFS and OS were: 58%, 4.1 and 11 months for UPS (n = 19); 63%, 5.6 and 13 months for LPS (n = 13); 75%, 11 and 15 months for LMS (n = 26); 75%, 7.7 and 12 months for SS (n = 47); 81%, 5.6 and 12 months for FS (n = 18); 77%, 21 and not reached for ASPS (n = 13); 54%, 11 and 16 months for CCS (n = 7); and 44%, 2.8 and 8.8 months for other sarcoma (n = 23), respectively. The most common clinically significant grade 3 or higher adverse events were hypertension (4.8%), triglyceride elevation (3.6%), and pneumothorax (2.4%). No treatment-related death occurred.Conclusions: Anlotinib showed antitumor activity in several STS entities. The toxicity was manageable. Clin Cancer Res; 24(21); 5233-8. ©2018 AACR.

Effect of Neoadjuvant Chemotherapy Plus Regional Hyperthermia on Long-term Outcomes Among Patients With Localized High-Risk Soft Tissue Sarcoma: The EORTC 62961-ESHO 95 Randomized Clinical Trial.

IMPORTANCE: Patients with soft tissue sarcoma are at risk for local recurrence and distant metastases despite optimal local treatment. Preoperative anthracycline plus ifosfamide chemotherapy improves outcome in common histological subtypes. OBJECTIVE: To analyze whether the previously reported improvement in local progression-free survival by adding regional hyperthermia to neoadjuvant chemotherapy translates into improved survival. DESIGN, SETTING, AND PARTICIPANTS: Open-label, phase 3 randomized clinical trial to evaluate the efficacy and toxic effects of neoadjuvant chemotherapy plus regional hyperthermia. Adult patients (age ≥18 years) with localized soft tissue sarcoma (tumor ≥5 cm, French Federation Nationale des Centers de Lutte Contre le Cancer [FNCLCC] grade 2 or 3, deep) were accrued across 9 centers (6, Germany; 1, Norway; 1, Austria; 1, United States) from July 1997 to November 2006. Follow-up ended December 2014. INTERVENTIONS: After stratification for tumor presentation and site, patients were randomly assigned to either neoadjuvant chemotherapy consisting of doxorubicin, ifosfamide, and etoposide alone, or combined with regional hyperthermia. MAIN OUTCOMES AND MEASURES: The primary end point was local progression-free survival. Secondary end points included treatment safety and survival, with survival defined from date of randomization to death due to disease or treatment. Patients lost to follow-up were censored at the date of their last follow-up. RESULTS: A total of 341 patients were randomized, and 329 (median [range] age, 51 [18-70] years; 147 women, 182 men) were eligible for the intention-to-treat analysis. By December 2014, 220 patients (67%; 95% CI, 62%-72%) had experienced disease relapse, and 188 (57%; 95% CI, 52%-62%) had died. Median follow-up was 11.3 years. Compared with neoadjuvant chemotherapy alone, adding regional hyperthermia improved local progression-free survival (hazard ratio [HR], 0.65; 95% CI, 0.49-0.86; P = .002). Patients randomized to chemotherapy plus hyperthermia had prolonged survival rates compared with those randomized to neoadjuvant chemotherapy alone (HR, 0.73; 95% CI, 0.54-0.98; P = .04) with 5-year survival of 62.7% (95% CI, 55.2%-70.1%) vs 51.3% (95% CI, 43.7%-59.0%), respectively, and 10-year survival of 52.6% (95% CI, 44.7%-60.6%) vs 42.7% (95% CI, 35.0%-50.4%). CONCLUSIONS AND RELEVANCE: Among patients with localized high-risk soft tissue sarcoma the addition of regional hyperthermia to neoadjuvant chemotherapy resulted in increased survival, as well as local progression-free survival. For patients who are candidates for neoadjuvant treatment, adding regional hyperthermia may be warranted. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00003052.

Hyperthermic isolated limb perfusion. The switch from Steinmann pins to Omni-tract assisted isolation.

BACKGROUND: Hyperthermic isolated limb perfusion (HILP) represents an alternative to amputation for patients with either in-transit melanoma or unresectable soft tissue sarcoma, entailing delivery of high-dose chemotherapy after isolation of the extremity, under hyperthermic conditions. Stabilization of the Esmarch elastic bandage is so far performed with the use of Steinmann pins. In this study, we presented our experience with HILP and demonstrated an alternative technique for limb isolation using an Omni-tract retractor instead of the traditional Steinmann pin, while comparing the two methods. METHODS: Forty patients, 28 with recurrent in-transit melanoma and 12 with locally advanced/recurrent sarcoma of the limbs, underwent HILP in a single institution and were included in the study. The Steinmann pin was applied in the first 23 cases, whereas the Omni-tract retractor was applied in the latter 17 patients. RESULTS: The median follow-up for the whole study group was 17.5 mo, whereas the overall response rate was 92.9% for melanoma and 75% for sarcoma patients. Both overall survival and local progression-free survival differed significantly between patients with complete response and those with partial response, stable disease or progressive disease. The use of the Omni-tract retractor was advantageous in every examined field, with the overall complication rate, duration of analgesic administration, and total opioid and paracetamol dose, being significantly less in the Omni-tract patient group. CONCLUSIONS: Although this study was not a randomized trial, we consider that the noninvasive application of the Omni-tract retractor will gain significant acceptance, by contributing to the reduction of HILP complications.

A phase II trial comparing pazopanib with doxorubicin as first-line treatment in elderly patients with metastatic or advanced soft tissue sarcoma (EPAZ): study protocol for a randomized controlled trial.

BACKGROUND: Anthracycline-based treatment remains the backbone of chemotherapy for nonresectable soft tissue sarcomas (STS). More than 30 % of patients with STS are aged 60 years or older, limiting the choice of treatment to single-agent approaches for this elderly population. Hematological toxicity is frequent during doxorubicin monotherapy, grade 4 neutropenia is reported in 34 %, with a febrile neutropenia rate of 9 % in STS. We assume that comorbidities in the elderly population may limit tolerability of doxorubicin, and novel agents may improve tolerability and health-related quality of life while maintaining efficacy. We therefore investigated whether the tyrosine kinase inhibitor pazopanib exerts such a clinical benefit in elderly patients with STS (pazopanib for elderly [the EPAZ study]). METHODS/DESIGN: This study is a randomized, controlled, open-label, multicenter, phase II noninferiority trial in which pazopanib 800 mg once daily is being compared six cycles of intravenous doxorubicin 75 mg/m(2) as first-line treatment in elderly patients (≥60 years) with metastatic or advanced STS. A total of 120 patients will be randomized 1:2 to receive doxorubicin or pazopanib, stratified by Eastern Cooperative Oncology Group performance status (0-1 vs. 2) and liposarcoma histology (yes vs. no). The primary endpoint is progression-free survival based on local tumor assessment according to Response Evaluation Criteria in Solid Tumors criteria. Secondary endpoints include grade 4 neutropenia and febrile neutropenia in hierarchical order, as well as overall survival, objective response rate, health-related quality of life, and geriatric assessments. DISCUSSION: Pazopanib is associated with promising tolerability according to previous studies and may offer a significant clinical advantage in first-line treatment of STS compared with doxorubicin. The elderly population seems especially appealing for such an approach, since these patients are not suitable for aggressive combination therapy. The EPAZ study will confirm whether pazopanib may be an alternative to toxic chemotherapy for elderly patients with STS. TRIAL REGISTRATION: ClinicalTrials.gov NCT01861951 ; registered on 11 April 2013. EudraCT 2011-004168-30; registered on 4 June 2012.

Effective local control of advanced soft tissue sarcoma with neoadjuvant chemoradiotherapy and surgery: A single institutional experience.

PURPOSE: There is a sound theoretical basis but little clinical evidence substantiating the benefits of concurrent chemoradiotherapy with two-drug chemotherapy for locally advanced soft tissue sarcomas. Our five-year data on the feasibility and effectiveness of neoadjuvant chemoradiotherapy with systemically effective doses of adriamycin and ifosfamide combined is presented here. PATIENTS AND METHODS: Between 2000 and 2011, 53 patients with UICC (2010) stage I (n=1, 1.9%), II (n=12, 22.7%) or III (n=40, 75.5%) nonmetastatic soft tissue sarcoma received neoadjuvant chemoradiotherapy with ifosfamide (1.5 g/m(2)/day, d1-5, q28) and doxorubicin (50mg/m(2)/day, d3, q28) plus concurrent radiotherapy with a target dose of 50-64 Gy (median 60 Gy). The treatment of 34 patients (64.2%) was combined with hyperthermia. RESULTS: At five years, the local control rate was 89.9% (± 5.7%), distant metastasis-free survival 66.6% (± 7.6%), and survival 83.3% (± 6%). The R0 resection rate was 81.1%. Radiotherapy was completed as planned in all patients and chemotherapy in 42/53 (70.2%). Grades III (n=21, 29.6%) and IV (n=18, 34%) leukopenia was the main acute adverse event. All acute and chronic non-hematologic toxicities were moderate. CONCLUSION: Neoadjuvant chemoradiotherapy for soft tissue sarcoma is associated with good feasibility, manageable acute and late toxicities, and high local efficacy.

[Systemic therapy and hyperthermia for locally advanced soft tissue sarcoma]. / Systemische Therapie und Hyperthermie beim lokal fortgeschrittenen Weichteilsarkom.

Patients with high-risk soft tissue sarcomas (FNCLCC grades 2-3, > 5 cm and deep lying) are at a high risk of local recurrence or distant metastases despite optimal surgical tumor resection. Therefore, multimodal treatment should be considered for this difficult to treat patient group. Besides surgery, radiation therapy and chemotherapy, hyperthermia has become a valid, complementary treatment option within multimodal treatment concepts. Hyperthermia in this context means the selective heating of the tumor region to temperatures of 40-43 °C for 60 min by microwave radiation in addition to simultaneous chemotherapy or radiation therapy. A randomized phase III study demonstrated that the addition of hyperthermia to neoadjuvant chemotherapy improved tumor response and was associated with a minimal risk of early disease progression as compared to chemotherapy alone. The addition of hyperthermia to a multimodal treatment regimen for high-risk soft tissue sarcoma consisting of surgery, radiation therapy and chemotherapy, either in the neoadjuvant or adjuvant setting after incomplete or marginal tumor resection, significantly improved local progression-free and disease-free survival. Based on these results and due to the generally good tolerability of hyperthermia, this treatment method in combination with chemotherapy should be considered as a standard treatment option within multimodal treatment approaches for locally advanced high-risk soft tissue sarcoma.

Effect of concurrent chemotherapy and hyperthermia on outcome of preoperative radiotherapy of high-risk soft tissue sarcomas.

BACKGROUND AND PURPOSE: As treatment results for high-risk soft tissue sarcoma are still disappointing, treatment intensification is warranted. We performed a retrospective analysis of multimodal preoperative treatment to evaluate the additional effect of concurrent chemotherapy and/or locoregional hyperthermia in comparison to radiotherapy alone. PATIENTS AND METHODS: Between 1999 and 2011, 28 patients were treated with neoadjuvant radiotherapy to a median 45 Gy for high-risk soft tissue sarcoma. All tumors were deep-seated and grade 2 or 3, 86% (n = 24) larger than 5 cm. Multimodal treatment (n = 12) consisted of ifosfamide (n = 7), locoregional hyperthermia (n = 3), or both modalities (n = 2) concurrent to radiotherapy. RESULTS: Prognostic factors (grade, size, histology, location) were balanced in the groups with and without concurrent multimodal treatment. There was a significant improvement of disease-specific survival (100% vs. 70% at 3 years, p = 0.03) with multimodal treatment. Distant metastases-free survival was influenced, but was not statistically significant. Local control and disease-free survival did not differ in the two groups. CONCLUSION: Our data suggest that multimodal treatment with ifosfamide and/or locoregional hyperthermia in combination with neoadjuvant radiotherapy might improve outcome in high-risk soft tissue sarcomas.

[Current state of neoadjuvant therapy of soft tissue sarcoma]. / Aktueller Stand der neoadjuvanten Therapie bei Weichteilsarkomen.

The treatment of soft tissue sarcoma is clinically challenging. Referral to an experienced center with an interdisciplinary team is strongly recommended. Neoadjuvant therapy, including irradiation and chemotherapy, has been applied to improve local control rates, eradicate micrometastases and assess chemosensitivity. However, the role of neoadjuvant therapy remains controversial, especially for systemic therapy, as the only available randomized trial failed to prove a benefit for survival. Nevertheless, on the basis of the current body of literature, neoadjuvant therapy can be considered on an individual basis for patients with high-risk tumors. Whenever possible, patients should be included in a clinical trial.

Intraoperative radiotherapy (IORT) combined with external beam radiotherapy (EBRT) for soft-tissue sarcomas--a retrospective evaluation of the Homburg experience in the years 1995-2007.

PURPOSE: To retrospectively evaluate the results after a regimen of surgery, IORT (intraoperative radiotherapy), and EBRT (external beam radiotherapy) for soft-tissue sarcomas METHODS: 38 consecutive patients underwent IORT for soft-tissue sarcoma; 29 were treated for primary tumours, 9 for recurrences. There were 14 cases with liposarcomas, 8 with leiomyosarcomas, 7 with malignant fibrous histiocytomas. 27/38 tumours were located in the extremities, the remaining ones in the retroperitoneum or the chest. Radical resection was attempted in all patients; a R0-resection was achieved in 15/38 patients, R1 in 12/38 pats and R2 in 4/38 pats. IORT was performed using a J-125 source and a HDR (high dose rate) afterloading machine after suturing silicone flaps to the tumour bed. The total dose applied ranged from 8-15 Gy/0.5 cm tissue depth measured from the flap surface. After wound healing external beam radiotherapy (EBRT) was applied in 31/38 patients with total doses of 23-56 Gy dependent on resection status and wound situation. The mean duration of follow-up was 2.3 years. RESULTS: A local recurrence was found in 10/36 patients, lymph node metastases in 2/35, and distant metastases in 6/35 patients. The actuarial local control rate was 63%/5 years. The overall survival rate was 57%/5 years. There was no statistically significant difference between the results after treatment for primaries or for recurrences. Late toxicity to the skin was found in 13/31 patients, wound healing problems in 5/31 patients. A neuropathy was never seen. CONCLUSION: The combination of surgery, IORT, and EBRT yields favourable local control and survival data which are well within the range of the results reported in the literature. The complication rates, however, are considerable although the complications are not severe, they should be taken into account when therapy decisions are made.

Final analysis of a phase II trial using sorafenib for metastatic castration-resistant prostate cancer.

OBJECTIVE: To determine if sorafenib is associated with an improved 4-month probability of progression-free survival, using radiographic and clinical criteria alone, in patients with metastatic castration-resistant prostate cancer. Secondary endpoints included pharmacokinetics, toxicity analysis and overall survival. PATIENTS AND METHODS: The study was an open-label, phase II, two-stage design, focusing on the results from the second stage, as criteria for progression were modified after completing the first stage. Sorafenib was given at a dose of 400 mg orally twice daily in 28-day cycles. Clinical and laboratory assessments were done every 4 weeks, and radiographic scans were obtained every 8 weeks. RESULTS: Twenty-four patients were accrued in the second stage; the median (range) age was 66 (49-85) years, the on-study prostate-specific antigen level was 68.45 (5.8-995) ng/mL, the Gleason score 8 (6-9) and Eastern Cooperative Oncology Group status 1 (in 17 patients). Of the 24 patients, 21 had previous chemotherapy with docetaxel. All patients had bony metastases, either alone (in 11) or with soft-tissue disease (in 13). One patient had a partial response; 10 patients had stable disease (median duration 18 weeks, range 15-48). At a median potential follow-up of 27.2 months, the median progression-free survival was 3.7 months and the median overall survival was 18.0 months. For the whole trial of 46 patients the median survival was 18.3 months. Most frequent toxicities included hand-foot skin reaction (grade 2 in nine patients, grade 3 in three), rash, abnormalities in liver function tests, and fatigue. CONCLUSIONS: Sorafenib has moderate activity as a second-line treatment for metastatic castration-resistant prostate cancer.

Soft tissue sarcoma of the vulva: A clinical study.

The purpose of this study is to report clinical aspects and treatment results of patients seen at Johns Hopkins. A search of the tumor registry of the Sidney Kimmel Comprehensive Cancer Center found 453 patients with malignancies of the vulva registered between 1977 and 1997. Patient and tumor characteristics, treatment methods, and follow-up were obtained from charts. Seven patients were identified with sarcoma of the vulva. Of these, one was removed from analysis due to histology. Three patients had leiomyosarcoma, two had fibrosarcoma, and one had epithelioid sarcoma. The mean age was 41. Mean time to diagnosis was 6 months. All but one of the tumors was located on the labia majora. Median tumor size was 3.5 cm. Surgery varied from wide local excision to radical vulvectomy with inguinal lymph node dissection. Surgical margins were microscopically negative in five of the six cases. Two patients had received adjuvant external beam radiation. One of them had a tumor greater than 5 cm and close surgical margins and the other had high-grade tumor, which recurred after previous surgery. Mean follow-up was 127.8 months. There have been no recurrences to date.

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 isolated limb perfusion for extremity sarcomas.

BACKGROUND: The treatment options available for extremity sarcomas are amputation or limb-sparing surgery with radiation, which may incur significant morbidity and body disfigurement. Hyperthermic isolated limb perfusion (HILP) may be an attractive option in extremity sarcomas for unresectable lesions to preserve limb function and maintain quality of life. METHODS: We report the outcomes of 5 patients who underwent HILP for unresectable primary or recurrent extremity sarcomas from 1994 to 2000 at our institution. RESULTS: All patients had initial complete clinical responses to HILP, and the limb was salvaged in 4 of the 5 patients. Complications included chronic lymphedema, neuropathic pain, and prolonged wound healing. CONCLUSIONS: HILP with melphalan is a safe and effective treatment option for selected patients with locally advanced and unresectable extremity sarcomas. The response rates are high, with limb salvage occurring in most patients. Further studies of larger groups of patients are warranted.

[Interventional MR-guided laser induced thermotherapy in oncologic indications. Status and prospects]. / Interventionelle MR-gesteuerte laserinduzierte Thermotherapie bei onkologischen Fragestellungen. Stand und Ausblick.

MR-guided LITT (laser-induced thermotherapy) is currently being evaluated for its effectiveness in clinical oncology. MR-guided LITT is defined as a minimally invasive technology based on the effects of the applied Nd-YAG laser on tumorous tissue. Due to specific characteristics of the laser-induced coagulative effect, online monitoring via MR thermometry is possible and extremely precise. In a period of 6 years 335 patients suffering from malignant soft tissue tumors were prospectively treated via MR-guided LITT. We evaluated the local tumor control rate, the rate of complications and the survival data from the clinical and MRI follow-up. Our results prove that MR-guided LITT results in a extremely low rate of side effects and an effective tumor control rate higher than 95%, depending on the size of the lesion. It is concluded that this therapeutic concept is of clinical value for patients with primary and secondary liver cancer, malignant lymph node involvement, abdominal recurrent tumors and tumors of the head and neck.

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.

[A phase-I/II study on the local hyperthermia of cervical N2/N3 lymph node metastases]. / Phase-I/II-Studie zur lokalen Hyperthermie zervikaler N2/N3-Lymphknotenmetastasen.

BACKGROUND: Patients with advanced lymph node metastases from head and neck tumors at stage N2/N3 (i.e. UICC IV) present a difficult therapeutic problem. Despite combined radio-chemotherapy and hyperfractionated and/or accelerated fractionation regimens, local control of these tumors remains unsatisfactory. For this reason, the value of local radio wave/microwave hyperthermia was examined for this patient group in a phase I/II study.

[Results of isolated hyperthermic extremity perfusion in soft tissue sarcomas within the scope of a multimodality treatment concept]. / Ergebnisse der isolierten hyperthermen Extremitätenperfusion bei Weichteilsarkomen im Rahmen eines multimodalen Behandlungskonzeptes.

Soft-tissue sarcomas (STS) of the extremities are characterized by a high rate of local recurrences. Limb salvage approaches using multimodality therapy protocols have replaced amputation. In order to evaluate isolated hyperthermic limb perfusion (ILP) in a multimodality therapy concept, we reviewed our patients treated using this method. Between January 1982 and December 1995, 25 ILPs, using cisplatin, melphalan and adriamycin, were performed in 22 patients with STS. Forty percent were treated for local recurrences; histology was dominated by malignant fibrous histiocytoma (MFH) and synovial sarcoma. In all, 68% of the STS were classified as UICC stage IIb or IIIa/b. Most of the cases (14) underwent wide or radical resection, 4 patients received intraoperative radiotherapy, and 5 were treated with external beam radiation. Complications were recorded in 32% of the cases. With a median follow-up of 45 months (range 1-143), the 5-year overall survival rate was 81%. The median recurrence-free time was 19 months and the 5-year disease-free survival rate 34%. There were 13 local failures, and distant metastases developed in 36% of the patients. Concerning high-grade sarcomas (UICC stage IIb, IIIa/b), we found local recurrences in 75% of all cases. Five of 11 patients with local failures underwent perfusion after they refused amputation, and 7 incompletely resected STS received ILP without reoperation. All of these demonstrated local recurrence. This rate of local recurrence proved to be different from patients with tumor-free resection margins (p = 0.0001, log-rank test). The amputation rate after isolated limb perfusion was 27% (mean 11 months after treatment). Long-term results of ILP showed a considerable local recurrence rate and a low disease-free survival. Perfusion in patients without tumor-free resection margins does not prevent local recurrence. We conclude that ILP with cisplatin, melphalan and adriamycin should be considered carefully and is not an additional treatment strategy of fist choice.

[Hyperthermia and palliative radiotherapy for sarcoma]. / Ipertermia e radioterapia palliative dei sarcomi.

The current treatment of bone and soft tissue sarcomas consists of a multimodality approach based on the combination of surgery, radiotherapy and, more rarely, chemotherapy. Since local recurrence is an important cause of failure and morbidity, new treatment modalities such as hyperthermia, have been proposed to try to overcome this problem. July, 1982, to June, 1993, twelve patients (15 lesions) with recurrent or locally advanced sarcoma, were treated at the Department of Radiation Oncology, S. Chiara Hospital-Trento (Italy) with irradiation and hyperthermia. Radiation therapy was delivered with different techniques using palliative or radical doses (24-70 Gy) and different fractionation schedules. Local microwave hyperthermia was given in 2-9 sessions (mean 4.7). Eight (53.3%) complete responses and 4 (26.6%) partial responses were observed. Three lesions recurred at 11, 13, and 30 months; 5-year actuarial local control was 25.4 +/- 13.4%. Actuarial 5-year overall survival was 49.5 +/- 16.4%. Toxicity was mild: two superficial necroses, spontaneously healed after few months, were observed; local pain during hyperthermic treatment was recorded in 15% of sessions. Lesion volume and total radiation dose appeared to be correlated with the response. In our experience, the combination of radiotherapy and hyperthermia seems to be a valuable therapeutic approach in the treatment of locally advanced or recurrent sarcomas.