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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.
Feb. 2018 | Issels, Rolf D; Lindner, Lars H; Verweij, Jaap; Wessalowski, Rüdiger; Reichardt, Peter; Wust, Peter; Ghadjar, Pirus; Hohenberger, Peter; Angele, Martin; Salat, Christoph; Vujaskovic, Zeljko; Daugaard, Soeren; Mella, Olav; Mansmann, Ulrich; Dürr, Hans Roland; Knösel, Thomas; Abdel-Rahman, Sultan; Schmidt, Michael; Hiddemann, Wolfgang; Jauch, Karl-Walter; Belka, Claus; Gronchi, Alessandro; ,
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. PMID 29450452

Concomitant trimodality therapy of re-irradiation, chemotherapy and regional hyperthermia for a pretreated inoperable sarcoma recurrence.
Juli 2015 | LI, Minglun; Andrä, Claudia; Niyazi, Maximilian; Issels, Rolf D; Abdel-Rahman, Sultan; Oskan, Feras; Manapov, Farkhad
We hereby present a case of pre-treated unresectable sarcoma recurrence of the trunk which showed an excellent response to concomitant tri-modal therapy, consisting of re-irradiation, chemotherapy and regional hyperthermia even with a strong compromised re-irradiation dose. No significant toxicity of the combined therapy and fast achievement of the pain and neurological symptoms relief are reported. The case shows that concurrent tri-modality treatment can be considered as a therapeutic option for the management of pre-treated unresectable recurrence even in there-irradiation setting. PMID 25838253

PET response criteria in solid tumors predicts progression-free survival and time to local or distant progression after chemotherapy with regional hyperthermia for soft-tissue sarcoma.
Apr. 2015 | Fendler, Wolfgang P; Lehmann, Mona; Todica, Andrei; Herrmann, Ken; Knösel, Thomas; Angele, Martin K; Dürr, Hans Roland; Rauch, Josefine; Bartenstein, Peter; Cyran, Clemens C; Hacker, Marcus; Lindner, Lars H
We evaluated the prognostic accuracy of established PET and CT response criteria in patients with soft-tissue sarcoma (STS) after combined chemotherapy plus regional hyperthermia (RHT). PMID 25722445

Reirradiation and hyperthermia for radiation-associated sarcoma.
Jan. 2012 | de Jong, Marianne A A; Oldenborg, Sabine; Bing Oei, S; Griesdoorn, Vanessa; Kolff, M Willemijn; Koning, Caro C E; van Tienhoven, Geertjan
The objective of this study was to evaluate the role of reirradiation and hyperthermia in the treatment of radiation-associated sarcoma (RAS) in the thoracic region, which is an increasing, yet extremely rare condition with a poor prognosis. PMID 21713762

Palliation of recurrent myxofibrosarcoma with radiotherapy and hyperthermia.
Dez. 2010 | Ichinohe, K; Kobayakawa, M
Soft tissue sarcomas are rare biologically and histologically heterogeneous neoplasms that may arise throughout the body. The preferred treatment is total resection with a sufficient margin. Radiotherapy with or without chemotherapy offers another treatment option, but its effectiveness is limited. Hyperthermia, a treatment method that heats tumour tissue by exposing the target tissues to conductive heat sources or non-ionising radiation, is known to enhance the effect of radiotherapy. We report a case of an elderly man with a second recurrent myxofibrosarcoma in the left groin, who responded well to radiotherapy in combination with hyperthermia. This combination treatment was effective in maintaining the patient's quality of life during his remaining years. PMID 21140105

Neo-adjuvant chemotherapy alone or with regional hyperthermia for localised high-risk soft-tissue sarcoma: a randomised phase 3 multicentre study.
Juni 2010 | Issels, Rolf D; Lindner, Lars H; Verweij, Jaap; Wust, Peter; Reichardt, Peter; Schem, Baard-Christian; Abdel-Rahman, Sultan; Daugaard, Soeren; Salat, Christoph; Wendtner, Clemens-Martin; Vujaskovic, Zeljko; Wessalowski, Rüdiger; Jauch, Karl-Walter; Dürr, Hans Roland; Ploner, Ferdinand; Baur-Melnyk, Andrea; Mansmann, Ulrich; Hiddemann, Wolfgang; Blay, Jean-Yves; Hohenberger, Peter; , ; ,
The optimum treatment for high-risk soft-tissue sarcoma (STS) in adults is unclear. Regional hyperthermia concentrates the action of chemotherapy within the heated tumour region. Phase 2 studies have shown that chemotherapy with regional hyperthermia improves local control compared with chemotherapy alone. We designed a parallel-group randomised controlled trial to assess the safety and efficacy of regional hyperthermia with chemotherapy. PMID 20434400

Dendritic cell-based immunotherapy induces transient clinical response in advanced rat fibrosarcoma - comparison with preventive anti-tumour vaccination.
Aug. 2009 | Kucera, A; Pýcha, K; Pajer, P; Spísek, R; Skába, R
In this study we present the models of preventive and therapeutic vaccination of sarcoma-bearing rats with dendritic cells that present tumour antigens from killed tumour cells. We present the characteristics of dendritic cell-based vaccine and its capacity to induce anti-tumour immune response both in vitro and in vivo. We show that preventive vaccination efficiently prevents tumour growth. On the other hand, vaccination of rats with established tumours did not lead to eradication of the tumours. Despite the induction of a vigorous immune response after administration of dendritic cell-based vaccine and transient decrease in tumour progression, tumours eventually resumed their growth and animals vaccinated with dendritic cells succumbed to cancer. In both settings, preventive and therapeutic, dendritic cell-based vaccination induced a vigorous tumour-specific T-cell response. These results argue for the timing of cancer immunotherapy to the stages of low tumour load. Immunotherapy initiated at the stage of minimal residual disease, after reduction of tumour load by other modalities, will have much better chance to offer a clinical benefit to cancer patients than the immunotherapy at the stage of metastatic disease. PMID 19691918

Therapeutic potential of dendritic cell vaccines in sarcoma of the extremities.
Aug. 2009 | Yu, Zhe; Ren, Pengcheng; Zhang, Xudong; Zhang, Ting; Ma, Bao'an
Sarcomas of the extremities are challenging to treat. They are divided into soft-tissue and bone sarcomas in general, which also have many subtypes, based on their different mesenchymal origins and anatomical locations, respectively. Each of these sarcomas present in different ways, exhibit different behaviors and prognoses, and present unique therapeutic challenges. Dendritic cells (DCs) are the best professional antigen-presenting cells that can induce both the generation and proliferation of specific cytotoxic T lymphocytes and helper T lymphocytes through antigen presentation by MHC class I and class II molecules, respectively. In this review, a series of recently conducted immunotherapy for extremital sarcomas based on DCs are summarized and the potential for therapeutic DC vaccination targeted against these tumors is assessed. PMID 19671026

Current concepts in the management of retroperitoneal soft tissue sarcoma.
Feb. 2009 | Schwarzbach, Matthias H M; Hohenberger, Peter
Soft tissue sarcomas (STS) in the retroperitoneum are usually diagnosed at the late stages. Surgery is the mainstay of treatment. The technique of resection is standardized. After dissection of the retroperitoneal blood vessel, a retroperitoneal plane of dissection adjacent to the spinal foramina is established in between the layers of the abdominal wall. Complete resection with tumor-free resection margins is the primary goal in retroperitoneal sarcoma surgery. Preoperative assessment of pathoanatomical growth patterns with respect to retroperitoneal vascular structures--as well as to visceral and retroperitoneal organs--influences surgical strategies and thus the surgical outcome. Blood vessel replacement and a multivisceral en bloc approach improve the quality of resection. Blood vessel involvement is stratified in type I (arterial and venous involvement), type II (arterial involvement), type III(venous involvement), and type IV (no vascular involvement). Adjuvant and neoadjuvant treatment options (chemotherapy, targeted therapy, and radiation therapy) are currently being investigated. A prospective randomized phase III trial has shown a positive effect of neoadjuvant chemotherapy combined with regional hyperthermia in disease-free survival, response rate, and local control. Subsets of liposarcomas (myxoid and round cell type) are selectively responsive to novel drugs, such as trabectedin, a DNA-binding agent. Radiotherapy is applied in higher-grade locally advanced retroperitoneal STS. The optimal technique of delivering radiotherapy remains to be determined. The restricted number of patients with retroperitoneal STS and unsatisfying results in local tumor control and long-term survival indicate the need for multi-institutional cooperative studies. An international effort is required to improve the evidence level on multimodal treatment algorithms. PMID 19230548

Hyperthermia as an adjunctive treatment for soft-tissue sarcoma.
Feb. 2009 | Pennacchioli, Elisabetta; Fiore, Marco; Gronchi, Alessandro
The treatment for high-risk soft-tissue sarcomas (STSs) in adults remains a challenge for the multidisciplinary approach. Despite aggressive local treatment, high-risk STSs have a tendency for hematogenous spread, which is related, for each histologically distinct sarcoma, to risk factors, such as pathologic grade, size and location. The multimodality approach focuses on the combination of radiochemotherapy in a neoadjuvant or adjuvant setting, surgery being considered the mainstay of local treatment. Therefore, current clinical research aims include preoperative treatment to control systemic microscopic disease and to downsize the primary tumor mass. Within the past 20 years, the application of hyperthermia has been integrated in multimodal treatment strategies in several forms of advanced malignant tumors, as well as in STSs. Hyperthermia is of clinical interest in the temperature range of 40-43 degrees C. Higher temperatures of 44-46 degrees C are not clinically realistic. The rationale for the combination of cytotoxic drugs with regional hyperthermia in the treatment of STS is based upon experimental and clinical evidence that heat increases the killing of tumor cells by direct thermal toxicity and enhances the efficacy of some drugs, such as alkylating agents and platinum analogs. Moreover, recent results show that hyperthermia may be able to modulate the immune system by inducing the expression of heat-shock proteins. The approach of multimodality treatment in STS has used regional hyperthermia with systemic chemotherapy within a preoperative and postoperative strategy. The synergistic effect of hyperthermia with chemotherapy is also used in locoregional treatments, such as isolated limb perfusion and intraperitoneal chemotherapy. PMID 19192958

A pilot study of consolidative immunotherapy in patients with high-risk pediatric sarcomas.
Aug. 2008 | Mackall, Crystal L; Rhee, Eunice H; Read, Elizabeth J; Khuu, Hanh M; Leitman, Susan F; Bernstein, Donna; Tesso, Merertu; Long, Lauren M; Grindler, David; Merino, Margret; Kopp, William; Tsokos, Maria; Berzofsky, Jay A; Helman, Lee J
Patients with metastatic or recurrent Ewing's sarcoma family of tumors and alveolar rhabdomyosarcoma have <25% 5-year survival in most studies. This study administered a novel immunotherapy regimen aimed at consolidating remission in these patients. PMID 18676758

Regional hyperthermia in high-risk soft tissue sarcomas.
Juni 2008 | Issels, Rolf D
On the basis of the definition of high-risk soft tissue sarcomas and prognostic factors, the most recent developments of preoperative treatment strategies with special emphasis on regional hyperthermia combined chemotherapy are reviewed. PMID 18525341

Neoadjuvant treatment of locally advanced soft tissue sarcoma of the limbs: which treatment to choose?
Feb. 2008 | Hohenberger, Peter; Wysocki, Wojciech M
Soft tissue sarcomas (STSs) form a heterogeneous group of malignant neoplasms arising in the mesenchymal connective tissues. They can develop at any anatomic site but 60% occur in the extremities. Initially, treatment of STS relied solely on excision. In the 1970s, Enneking et al. developed the concept of compartmental resection to reduce the local failure rate. Later, Rosenberg et al. demonstrated, in a randomized study, that there was no difference in local tumor control and disease-free survival (DFS) in patients treated with amputation versus limb-saving surgery followed by 50-70 Gy external-beam radiotherapy (EBRT). A considerable proportion of patients present with locally advanced tumors as a primary or recurrent disease and cannot be resected with adequate clearance margins. These patients are threatened with amputation for complete tumor removal. Improvements in surgical techniques, such as microvascular muscle flaps, allow for the avoidance of limb loss in the majority of cases. However, the use of frozen sections to determine intraoperatively whether clear margins have been achieved is limited by the multiplanarity of resection specimens. Thus, local failure rates are 15%-25%, and preoperative measures to sterilize the invasive margin of sarcomas have been explored. High-dose preoperative EBRT for high-grade STS was developed, and its combination with intra-arterial or i.v. chemotherapy was reported to be effective. Recently, systemic chemotherapy combined with deep wave hyperthermia was shown to result in a longer DFS time in a large, randomized, phase III study. Treatment concepts differ significantly among centers and are influenced more by availability of technical equipment than by data. It is the aim of this review to elucidate the rationale of different regimens and analyze their potentials as well as weaknesses. PMID 18305063

The role of hyperthermia in combined treatment in the management of soft tissue sarcoma.
Jan. 2007 | Issels, Rolf D; Schlemmer, Marcus; Lindner, Lars H
For high-risk soft tissue sarcomas (HR-STS) of adults, new treatment strategies are needed to improve outcome with regard to local control and overall survival. Systemic chemotherapy has been integrated either after (adjuvant) or before (neoadjuvant) optimal local treatment by surgery and radiotherapy in HR-STS. This short overview summarizes the results of the combination with regional hyperthermia as a new treatment strategy to open a new therapeutic window. PMID 17254531

Noninvasive magnetic resonance thermography of soft tissue sarcomas during regional hyperthermia: correlation with response and direct thermometry.
Sep. 2006 | Gellermann, Johanna; Hildebrandt, Bert; Issels, Rolf; Ganter, Hildegard; Wlodarczyk, Waldemar; Budach, Volker; Felix, Roland; Tunn, Per-Ulf; Reichardt, Peter; Wust, Peter
The objective of this study was to evaluate noninvasive magnetic resonance (MR) thermography for the monitoring of regional hyperthermia (RHT) in patients with soft tissue sarcomas of the lower extremities and pelvis. PMID 16902986

High-risk soft tissue sarcoma: clinical trial and hyperthermia combined chemotherapy.
Juni 2006 | Issels, Rolf D
For high-risk soft tissue sarcomas (HR-STS) of adults, new treatment strategies are needed to improve outcome with regard to local control and overall survival. Systemic chemotherapy has been integrated either after (adjuvant) or before (neoadjuvant) optimal local treatment by surgery and radiotherapy in HR-STS. This short overview summarizes the results of the combination with regional hyperthermia as a new treatment strategy to open a new therapeutic window. PMID 16754344

Characterization of CD34+ progenitor-derived dendritic cells pulsed with tumor cell lysate for a vaccination strategy in children with malignant solid tumors and a poor prognosis.
Juni 2004 | Ackermann, B; Tröger, A; Glouchkova, L; Körholz, D; Göbel, U; Dilloo, D
Children and adolescents with primary multifocal, refractory or relapsed malignant extracranial solid tumors still have a poor prognosis inspite of intensive standard radio-/chemotherapy. Here complementary immunomodulatory treatment modalities may prove beneficial as consolidation therapy following cytoreduction. Neuroblastoma, Ewing tumor and soft tissue sarcoma cells have principally been shown to be susceptible towards both cytotoxic and humoral effector mechanisms. Yet in vivo they are not capable of inducing an effective antitumor response which has been attributed to low level MHC expression and lack of costimulatory surface molecules. Professional antigen - presenting cells such as dendritic cells (DCs) in contrast are capable of activating unprimed T cells and are therefore ideal tools for vaccine generation. PMID 15175963

An approach for cure: PEI-chemotherapy and regional deep hyperthermia in children and adolescents with unresectable malignant tumors.
Dez. 2003 | Wessalowski, R; Schneider, D T; Mils, O; Hannen, M; Calaminus, G; Engelbrecht, V; Pape, H; Willers, R; Engert, J; Harms, D; Göbel, U
Elevated temperatures of 40 - 44 degrees C increase the actions of various anticancer drugs including N-lost derivatives, cytotoxic antibiotics and platinum analoga. In clinical usage thermochemotherapy (TCH) should facilitate surgical resection and ameliorate local tumor control. PMID 14677093

Ifosfamide with regional hyperthermia in soft-tissue sarcomas.
Okt. 2003 | Schlemmer, M; Wendtner, C M; Issels, R D
For high-risk soft tissue sarcomas (HR-STS) of adults, new treatment strategies are needed to improve outcome with regard to local control and overall survival. Therefore, systemic chemotherapy has been integrated either after (adjuvant) or before (neoadjuvant) optimal local treatment by surgery and radiotherapy in HR-STS. The combination with regional hyperthermia as a new treatment strategy seems to open a new therapeutic window. PMID 14586154

A Systemic Hyperthermia Oncologic Working Group trial. Ifosfamide, carboplatin, and etoposide combined with 41.8 degrees C whole-body hyperthermia for metastatic soft tissue sarcoma.
Mai 2003 | Westermann, A M; Wiedemann, G J; Jager, E; Jager, D; Katschinski, D M; Knuth, A; Vörde Sive Vörding, P Z; Van Dijk, J D P; Finet, J; Neumann, A; Longo, W; Bakhshandeh, A; Tiggelaar, C L; Gillis, W; Bailey, H; Peters, S O; Robins, H I; ,
Based on earlier clinical and preclinical studies, we conducted a phase II trial in metastatic sarcoma patients of the combination of 41.8 degrees C (x60 min) radiant heat (Aquatherm) whole-body hyperthermia (WBH) with 'ICE' chemotherapy. The ICE regimen consists of ifosfamide (5 g/m(2)), carboplatin (300 mg/m(2)) and etoposide (100 mg/m(2)), concurrent with WBH, with etoposide also on days 2 and 3 post-WBH. PMID 12759526

Vaccination of pediatric solid tumor patients with tumor lysate-pulsed dendritic cells can expand specific T cells and mediate tumor regression.
Dez. 2001 | Geiger, J D; Hutchinson, R J; Hohenkirk, L F; McKenna, E A; Yanik, G A; Levine, J E; Chang, A E; Braun, T M; Mulé, J J
Dendritic cells (DCs) have been shown to be a promising adjuvant for inducing immunity to cancer. We evaluated tumor lysate-pulsed DC in a Phase I trial of pediatric patients with solid tumors. Children with relapsed solid malignancies who had failed standard therapies were eligible. The vaccine used immature DC (CD14-, CD80+, CD86+, CD83-, and HLA-DR+) generated from peripheral blood monocytes in the presence of granulocyte/monocyte colony-stimulating factor and interleukin-4. These DC were then pulsed separately with tumor cell lysates and the immunogenic protein keyhole limpet hemocyanin (KLH) for 24 h and then combined. A total of 1 x 10(6) to 1 x 10(7) DC are administered intradermally every 2 weeks for a total of three vaccinations. Fifteen patients (ages 3-17 years) were enrolled with 10 patients completing all vaccinations. Leukapheresis yields averaged 2.8 x 10(8) peripheral blood mononuclear cells (PBMC)/kg, and DC yields averaged 10.9% of starting PBMC. Patients with neuroblastoma, sarcoma, and renal malignancies were treated without obvious toxicity. Delayed-type hypersensitivity (DTH) response was detected in 7 of 10 patients for KLH and 3 of 6 patients for tumor lysates. Priming of T cells to KLH was seen in 6 of 10 patients and to tumor in 3 of 7 patients as demonstrated by specific IFN-gamma-secreting T cells in unstimulated PBMCs. Significant regression of multiple metastatic sites was seen in 1 patient. Five patients showed stable disease, including 3 who had minimal disease at time of vaccine therapy and remain free of tumor with 16-30 months follow-up. Our results demonstrate that it is feasible to generate large numbers of functional DC from pediatric patients even in those highly pretreated and with a large tumor burden. The DC can be administered in an outpatient setting without any observable toxicity. Most importantly, we have demonstrated the ability of the tumor lysate/KLH-pulsed DC to generate specific T-cell responses and to elicit regression of metastatic disease. PMID 11731436

Effect of whole body hyperthermia on radiation therapy of transplanted fibrosarcoma in Swiss mice.
Okt. 2001 | Zaidi, A K; Patil, M S; Bhatt, M B; Bagewadikar, R S; Subramanian, M; Rajan, R; Kaklij, G S; Singh, B B
The exposure of normal mice to whole body hyperthermia (1 h WBH at 39 or 40 degrees C), 20 or 48 h prior to total body irradiation (TBI) with lethal doses of gamma-rays affords significant protection as assessed by survival. The radioprotective effect of WBH, as observed in normal mice, diminished in tumour bearing mice depending upon the size of tumour. Treatment of tumour bearing mice with mild WBH, 20 h prior to local irrradiation (LIR), did not protect the transplanted tumour against radiotherapy with a single dose of 20 Gy or fractionated dose (in five fractions) of 7.5 Gy on alternate days. In fact, mild WBH treatment enhanced the tumour regression and increased the mean survival time after fractionated dose therapy. However, the prior mild WBH was found to be ineffective in protecting normal tissue, as assessed by skin contraction after local irradiation (50 Gy). This indicates that mild WBH treatment given 20 h prior to local radiotherapy enhances fibrosarcoma tumour regression but cannot protect skin (normal tissue) against local irradiation. It appears that radioprotection of animals by WBH may be the consequence of its radioprotective effect on haemopoietic tissues mediated through certain cytokines. Perhaps WBH may not have a radioprotective effect on other tissues, as evident from skin contraction studies. PMID 11587080

Neoadjuvant chemotherapy combined with regional hyperthermia (RHT) for locally advanced primary or recurrent high-risk adult soft-tissue sarcomas (STS) of adults: long-term results of a phase II study.
Aug. 2001 | Issels, R D; Abdel-Rahman, S; Wendtner, C; Falk, M H; Kurze, V; Sauer, H; Aydemir, U; Hiddemann, W
In this phase II study, activity and safety of neoadjuvant regional hyperthermia (RHT) combined with chemotherapy was investigated in 59 patients with primary advanced or recurrent high-risk soft-tissue sarcoma (STS). Patients received four EIA cycles consisting of etoposide, ifosfamide and doxorubicin combined with RHT followed by surgical resection and adjuvant treatment. The overall objective response (OR) rate was 17%, with one complete (2%) and eight partial (15%) responses. In addition, 13 minor responses (25%) were seen. At time of surgery, complete necrosis (pCR) occurred in 6 patients and >75% necrosis (favourable histological response (FHR)) in 12 patients. At the completion of protocol treatment, 36 patients were rendered disease-free which was significantly associated with the initial radiographic and/or pathological tumour response (P=0.004). Treatment-related toxicity was acceptable overall. At a medium follow-up of 82 months, local treatment failure occurred in 33 patients, median overall survival (OS) was 52 months, and the 5-year survival rate was 49% (95% confidence interval (CI): 36-61%). OS which did not differ for extremity versus non-extremity STS (P=0.21) was better for patients responding to EIA combined with RHT (P<0.01). PMID 11527684

Temperature-dependent changes in physiologic parameters of spontaneous canine soft tissue sarcomas after combined radiotherapy and hyperthermia treatment.
Feb. 2000 | Vujaskovic, Z; Poulson, J M; Gaskin, A A; Thrall, D E; Page, R L; Charles, H C; MacFall, J R; Brizel, D M; Meyer, R E; Prescott, D M; Samulski, T V; Dewhirst, M W
The objectives of this study were to evaluate effects of hyperthermia on tumor oxygenation, extracellular pH (pHe), and blood flow in 13 dogs with spontaneous soft tissue sarcomas prior to and after local hyperthermia. PMID 10656391

Pulsing of dendritic cells with cell lysates from either B16 melanoma or MCA-106 fibrosarcoma yields equally effective vaccines against B16 tumors in mice.
Juni 1998 | DeMatos, P; Abdel-Wahab, Z; Vervaert, C; Hester, D; Seigler, H
Dendritic cells (DC) pulsed in vitro with a variety of antigens have proved effective in producing specific antitumor effects in vivo. Experimental evidence from other laboratories has confirmed that shared antigens can be encountered in histologically distinct tumors. In our experiments, we set out to evaluate the immunotherapeutic potential of vaccines consisting of DC pulsed with MCA-106 fibrosarcoma or B16 melanoma cell lysates and to determine whether a cross-reactivity exists between the two tumors. PMID 9624036

Systemic hyperthermia and ICE chemotherapy for sarcoma patients: rationale and clinical status.
Okt. 1997 | Wiedemann, G J; Robins, H I; Katschinski, D M; Mentzel, M; D'Oleire, F; Kutz, M; Wagner, T
Preclinical studies are consistent with the concept that 41.8 degrees C whole body hyperthermia (WBH) can enhance the therapeutic index of specific chemotherapeutic agents. These laboratory investigations resulted in 2 phase I clinical studies, which also support this hypothesis. These trials were extended to 2 sequential phase II investigations of WBH plus ifosfamide, carboplatin and etoposide (ICE) for refractory sarcoma patients. The first study (involving 12 patients) using extra-corporeal WBH was prematurely closed to adopt a less toxic WBH technology, i.e., the radiant heat Aquatherm. To date, 12 patients have been accrued to the Aquatherm trial. Projections regarding reduced morbidity were correct. The response rate for ICE/WBH is currently 63%. The review to follow will summarize the results of these trials, as well as the laboratory and clinical data which serve to explicate the dramatic clinical results observed to date. PMID 9329558

Complete regression of human fibrosarcoma xenografts after local Newcastle disease virus therapy.
Dez. 1994 | Lorence, R M; Katubig, B B; Reichard, K W; Reyes, H M; Phuangsab, A; Sassetti, M D; Walter, R J; Peeples, M E
We have recently demonstrated that a single local injection of the avian pathogen Newcastle disease virus (NDV; strain 73-T) causes complete regression of human neuroblastoma xenografts in athymic mice (R. M. Lorence, K. W. Reichard, B. B. Katubig, H. M. Reyes, A. Phuangsab, B. R. Mitchell, C. J. Cascino, R. J. Walter, and M. E. Peeples. J. Natl. Cancer Inst., 86: 1228-1233, 1994). In this report, we tried to determine if this in vivo antineoplastic effect of NDV extends to human sarcomas. Athymic mice with s.c. HT1080 fibrosarcoma xenografts (7-14 mm) were randomly divided into two groups and treated i.t. with a single injection of either 10(7) plaque-forming units of NDV or phosphate-buffered saline. Complete tumor regression occurred in 8 of 10 mice treated with NDV while unabated tumor growth occurred in all 9 mice treated with phosphate-buffered saline (P < 0.001). To determine if complete tumor regression was long lasting, the 8 mice were monitored for 1 year, during which time no tumor recurred. To test the antitumor effects of NDV on tumors derived from a fresh human sarcoma, a similar experiment was performed in athymic mice using TH15145 synovial sarcoma xenografts at their first and second passages. Of 9 mice with TH15145 xenografts, a single i.t. injection of NDV (10(7) plaque-forming units) caused complete regression of 3 tumors and > 80% regression in 3 more tumors. In contrast, tumors in all 5 mice treated with phosphate-buffered saline exhibited unabated growth (P < 0.03 for > 80% tumor regression). Since HT1080 fibrosarcoma cells express the N-ras oncogene, we explored the effects that transfection of this oncogene has on the sensitivity to NDV. Cultured human fibroblasts that were made tumorigenic following N-ras-transfection were found to be 1000-fold more sensitive to NDV than normal fibroblasts in a cytotoxicity assay. Oncogene expression by the HT1080 fibrosarcoma may therefore contribute to the long-lasting complete regression of this sarcoma following a single local injection of NDV. PMID 7954437

Doxorubicin, cyclophosphamide, and whole body hyperthermia for treatment of advanced soft tissue sarcoma.
Juli 1984 | Gerad, H; van Echo, D A; Whitacre, M; Ashman, M; Helrich, M; Foy, J; Ostrow, S; Wiernik, P H; Aisner, J
Eleven patients with advanced soft tissue sarcoma were treated with whole body hyperthermia (41.8 degrees C-43.0 degrees C) for 2 hours, doxorubicin (45 mg/m2) at the beginning of peak temperature and cyclophosphamide (1000 mg/m2) 6 hours after doxorubicin. Warming was accomplished with a nylon and vinyl mesh water perfused suit and heating blankets under barbiturate anesthesia. Thirty-five thermochemotherapy treatments were administered after an initial baseline euthermic course. There were two complete and two partial responses including three of three liposarcomas and one of two leiomyosarcomas, and there were two disease stabilizations . Morbidity included anasarca, nausea and vomiting, diarrhea, myalgias, mild surface burns, perioral herpes simplex, reversible neuropathy, hypotension, and cardiac arrythmias . Hyperglycemia and hypophosphatemia were found during heating, and normalized at 24 hours. Liver enzyme elevations occurred 24 hours after heating and normalized within 1 week. A uniform platelet decrease (mean, 107,000/microliter) was found at 24 hours. Thermochemotherapy was found to be a feasible approach for selected patients with advanced soft tissue sarcoma for the subset of liposarcomas and leiomyosarcomas. PMID 6722720