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© 2002 American Society for Clinical Oncology Response to Neoadjuvant Chemotherapy Combined With Regional Hyperthermia Predicts Long-Term Survival for Adult Patients With Retroperitoneal and Visceral High-Risk Soft Tissue SarcomasByFrom the Department of Internal Medicine III, Diagnostic Radiology and Institute for Biostatistics and Epidemiology, Klinikum Grosshadern Medical Center, Ludwig-Maximilians-University; and the KKG Hyperthermia/GSF-National Research Center for Environment and Health, Munich, Germany. Address reprint requests to C.-M. Wendtner, MD, Ludwig-Maximilians-Universität, Medizinische Klinik III, Klinikum Grosshadern, Marchioninistr 15, D-81377 Munich, Germany; email: Clemens.Wendtner{at}med3.med.uni-muenchen.de
PURPOSE: To determine the efficacy of neoadjuvant chemotherapy combined with regional hyperthermia (RHT) for local tumor control and overall survival (OS) in adult patients with retroperitoneal or visceral (RP/V) high-risk soft tissue sarcomas (HR-STS). PATIENTS AND METHODS: From 1991 to 1997, 58 patients with HR-STS at RP/V sites were prospectively treated with four cycles of etoposide, ifosfamide, and doxorubicin combined with RHT followed by surgery, adjuvant chemotherapy, and radiation. RESULTS: Objective response rate assessable in 40 patients was 13% (five partial responses). Including minor responses (n = 8), the radiographic response rate was 33%. The pathologic response rate assessable in 26 patients after surgical resection was 42%. Median OS was 31 months. At a median observation time of 74 months, 5-year probability of local failure-free survival (LFFS), distant metastasis-free survival, event-free survival, and OS were 25%, 51%, 20%, and 32%, respectively. Averaged minimum temperatures (Tmin) and time-averaged temperatures achieved in 50% (T50) and 90% (T90) of all measured tumor sites differed significantly between responders and nonresponders (Tmin, 39.3°C v 38.0°C; P = .002; T50, 40.9°C v 40.3°C; P = .038; T90, 40.1°C v 39.3°C; P = .017). At 5-year follow-up, probability of LFFS (59% v 0%; P < .001) and OS (60% v 10%; P < .001) was significantly in favor of patients responding to neoadjuvant thermochemotherapy. CONCLUSION: Response to neoadjuvant chemotherapy combined with RHT is predictive for an improved local tumor control resulting in a long-term survival benefit for patients with HR-STS at unfavorable RP/V sites; however, the impact of RHT has to be defined in a randomized phase III trial.
UNFAVORABLE PROGNOSIS of soft tissue sarcomas (STS) is determined by high-grade histology, large tumor size (  5 cm), and deep localization.1 Whereas median overall survival (OS) for patients with extremity lesions is 33 months, patients with high-grade tumors of the retroperitoneum were reported to have an even worse prognosis, with a median OS between 9 and 20 months despite surgical resection.2,3 Recently, it was shown that retroperitoneal or visceral (RP/V) sites are an additional poor prognosticator independent of other factors like tumor size, grade, and recurrence.4 The unfavorable outcome of these patients is often due to the fact that tumors at RP/V sites present with multiorgan involvement, thus precluding complete surgical resection. Typically the majority of patients with RP/V tumors frequently die with local disease without evidence of distant metastasis at the time of death.4 Therefore, strategies to enhance the efficacy of local therapies are needed. Local control is usually accomplished by surgical resection, although complete gross resection remains illusive in most cases.5 Five-year survival rates after radical excision of undifferentiated RP STS were reported to be as low as 16%.6 Adjuvant radiation therapy is often restricted by the adverse effects of irradiation on adjacent nontumoral tissue. Further adjuvant treatment modalities such as early postoperative intraperitoneal doxorubicin, high-dose adjuvant radiotherapy with protecting silicone implants, or intraoperative radiation therapy were explored in small patient series.7-10 In an effort to improve local tumor control, a multimodality treatment strategy including regional hyperthermia (RHT) seemed attractive to be explored in this high-risk patient population. The rationale for the combination of cytotoxic drugs with hyperthermia in the treatment of high-risk STS (HR-STS) is based on experimental evidence that heat exposure increases the killing of tumor cells by direct thermal cytotoxicity and is able to sensitize perfused tumor tissue towards chemotherapy in a synergistic manner.11 Hyperthermia combined with conventional chemotherapy has meanwhile been integrated in multimodality treatment strategies for various tumors.12 In addition, recent results indicate that heat shock proteins induced in tumor cells under hyperthermic stress are able to elicit specific T- and NK-cell immune responses.13-15 Hyperthermia in combination with radiotherapy as neoadjuvant treatment for HR-STS patients was already shown to impact positively on local tumor control, whereas it did not seem to influence the rate of distant metastases or survival.16 RHT was shown to be feasible and efficacious in former phase II studies, including patients with locally advanced STS who received ifosfamide-based chemotherapy combined with RHT.17-19 The objective of this analysis is to determine the response rate and survival parameters for patients with HR-STS of RP/V sites after neoadjuvant thermochemotherapy.
Patients Eligibility Patients were required to have histologically confirmed STS without manifestation of distant disease. Furthermore, patients had to fulfill high-risk criteria, ie, only tumors with grade 2 or 3 histology, size 5 cm, and extracompartmental and deep extension were eligible. Patients had to have a good performance status (World Health Organization grade 0 to 2) and normal organ functions. Patients with primary STS (S1 group), as well as with recurrent (S2 group) or inadequately resected tumors (S3 group), were eligible, and previous chemotherapy was an exclusion criteria. The ethical committee of the Ludwig-Maximilians-University, Munich, Germany, approved the study protocol. Written informed consent was obtained from all patients enrolled onto this study.
Staging Procedures and Treatment Program Neoadjuvant protocol treatment was composed of etoposide, ifosfamide, and doxorubicin (EIA) chemotherapy and RHT. Chemotherapy consisted of doxorubicin 50 mg/m2 day 1, etoposide 125 mg/m2 days 1 and 4, and ifosfamide 1,500 mg/m2 days 1 to 4. EIA chemotherapy was combined with RHT (days 1 and 4). Thermochemotherapy was repeated every 3 weeks, and a total of four courses of neoadjuvant treatment were given. For RHT, the BSD 2000 system was used, which is an electromagnetic deep regional-heating device (BSD Medical Corporation, Salt Lake City, UT).20 After completion of neoadjuvant therapy, patients underwent a restaging procedure with evaluation of response, and tumors were resected if possible. Patients without progressive disease after neoadjuvant therapy were eligible for postoperative treatment comprising four cycles of EI chemotherapy with RHT (RHT-91) or EIA chemotherapy without RHT (RHT-95).18,19 Patients who were not preirradiated received external-beam radiotherapy using mega-voltage equipment. Radiation was applied to treatment fields and consisted of a total dose in the range of 45 to 65 Gy in daily fractions (1.8 to 2.0 Gy).
Treatment Evaluation Feasibility of RHT was assessed by calculating time-averaged temperatures for each RHT at each monitored site. Temperatures were averaged over all RHT treatments to yield an average minimum (Tmin) and maximum (Tmax) temperature for an individual patient. Time-averaged temperatures achieved in 20% (T20), 50% (T50), and 90% (T90) of all measured tumor sites were determined during each RHT treatment and documented.17
Statistics
The RHT-91 and RHT-95 protocols were each designed as a monocentric, nonrandomized, controlled, single arm phase II study with objective response and OS as the primary end points. Sample size estimation for patients with RP/V HR-STS was performed for the improvement in median OS from 15 months to 30 months by use of the log-rank test. In case of 3.5 years recruitment period and 5-year follow-up, the required number was estimated as 36 patients for each study, resulting in a total of 72 patients (
Patient Characteristics Between February 1991 and July 1997, 58 patients with S1, S2, or S3 locally advanced sarcomas of the RP/V sites were registered. The study population consisted of 27 male and 31 female patients with a median age of 51 years (range, 19 to 70 years) and a median Karnofsky index of 80%. The majority of patients, ie, 45 of 58, entered the protocol after previous surgical and/or radiotherapeutic interventions, whereas 13 patients never had treatment for their HR-STS before (Table 1). The feasibility of an adequate R0-resection was excluded for every patient before inclusion in this study. Based on all patients (n = 58), the mean ellipsoidal tumor volume was 624 cm3 (95% CI, 280 to 967 cm3), indicating the extensive local stage of most lesions. Excluding all patients with only microscopic disease at entry of study (S3/R1 category), the mean tumor volume was calculated with 927 cm3. The most common histologic subtypes were liposarcomas (n = 17), leiomyosarcomas (n = 16), and malignant fibrous histiocytomas (n = 8). Of the 58 patients in the study, 35 showed manifestation of a moderately differentiated (grade 2) sarcoma, and 23 patients showed a poorly differentiated (grade 3) sarcoma (Table 2).
Feasibility and Toxicity Forty-eight patients (83%) received the prescribed number of preoperative EIA chemotherapy cycles combined with RHT. Three patients received one additional cycle because of a delay in the planning of surgery. The median number of EIA cycles administered was four (range, two to five cycles) combined with eight RHT treatments (range, four to 10 treatments). Postoperative chemotherapy was not given to 27 patients because of disease progression or refusal of further therapy. Of the 31 patients who were started on postoperative chemotherapy, 23 patients (77%) received the intended four cycles (Table 3).
During the neoadjuvant treatment, nonhematologic toxicity was mainly mild; very severe (grade 4) side effects were noticed in less than 9% of patients. Two patients suffered from a lethal infection (one peritonitis and one fungal infection), two patients experienced grade 4 neurotoxicity (one sensory defect and one central apnea), and one patient had acute renal failure. The most frequent side effects were alopecia, which was observed for all patients, and nausea, which was seen in the majority of patients (83%). Infections were documented for 15 patients (26%) including the two patients with lethal infections. Hematologic toxicity was significant in terms of leukopenia, which occurred in almost every patient during the treatment courses (grade 3, 57% and grade 4, 26%). Severe thrombocytopenia (grade 3) was observed only in three patients (5%) (Table 4). A severe side effect specifically associated to RHT was pain within the applicator (caused by water bolus pressure of the cooling system) in four patients (7%). Severe skin burns manifesting as blisters were only observed in two patients (3%). Otherwise, only mild erythema in the heating field was seen (Table 4).
Response to Treatment and Surgery Results Forty of 58 patients were assessable for response that was evaluated after completion of neoadjuvant thermochemotherapy. Previously R1-resected patients (S3 group) could only be evaluated in case of disease progression. The overall objective response rate was 13%, and consisted of five partial responses (PR). Including minor responses (MR; n = 8), the radiographic response rate was 33% (Table 5). Among patients with a measurable tumor volume at the start of treatment, there was no significant correlation between response and either mean or median tumor volume (  2 test, P = .268 and P = .333, respectively). Dividing the tumor volume in two classes with the median (377 cm3) or mean (927 cm3) as cut points, respectively, there was no significant correlation observed between response and tumor volume (Mann-Whitney U test, P = .791; t test, P = .088).
Thirty of the 58 patients (52%) underwent surgery after completion of neoadjuvant thermochemotherapy. In the resected tissue of 26 assessable patients, pCR was detectable in six patients (23%). The radiographic response of these patients included five PR and one MR. FHR was documented in five patients and was associated with three MR and two stable diseases as radiographic responses. In summary, 11 of 26 assessable patients showed a pathologic response in their resected tumor, resulting in a pathologic response rate of 42% (Table 6).
Among the 30 patients undergoing surgery, conservative resections were performed in 29 patients, whereas mutilative surgery (hemipelvectomy) was necessary for only one patient. For 28 patients, surgical resection was not necessary (S3/R1 category; n = 18) or possible, ie, seven patients were inoperable because of progressive disease, two patients died during the operative procedure, and one patient refused surgery. Complete tumor resection or marginal resection by nonmutilative methods was possible in eight (27%) and 10 (33%) patients, respectively. Six of the eight patients achieving a complete resection of their tumor were responders to neoadjuvant thermochemotherapy according to radiographic (four PR and two MR) and pathologic criteria (five pCR and one FHR) (Table 7).
Comparison of intratumoral temperatures for responders (PR, MR, pCR, and FHR) and nonresponders was performed for 27 assessable patients. The averaged Tmax achieved in tumors of responders and nonresponders showed no statistically significant difference (42.5°C ± 0.9°C v 42.2° ± 0.9°C; P = .43) in contrast to the Tmin (39.3°C ± 1.0°C v 38.0°C ± 1.3°C; P = .002). With regard to T20, T50, and T90 of all measured tumor sites, T50 (40.9°C ± 0.7°C v 40.3°C ± 1.1°C) and T90 (40.1°C ± 0.7°C v 39.3°C ± 1.2°C) differed significantly between responding and nonresponding patients (P = .038 and P = .017, respectively). A correlation was observed between heat induction and tumor histology; patients with leiomyosarcomas who all developed progressive disease showed significantly lower T50 (t test, P = .0001; Mann-Whitney U test, P = .0046) and T90 (t test, P = .0066; Mann-Whitney U test, P = .0094) but not T20 (Table 8). A correlation was seen between Tmin and tumor grading (grade 2, 38.3°C and grade 3, 39.5°C; t test, P = .03), whereas no association was observed between grading and response to neoadjuvant therapy ( 2 test, P = .276). To analyze the correlation between tumor volume and heat induction, we divided the tumor volume into two classes, with the median (405 cm3) as cut point. Whereas patients with a tumor volume  405 cm3 showed to have significantly higher Tmax (t test, P = .042; Mann-Whitney U test, P = .037) than patients with a tumor volume more than 405 cm3, no significant levels were achieved for the other temperature parameters. A correlation between tumor volume and response was not seen (t test, P = .86; Mann-Whitney U test, P = .98).
After completion of surgery, thirty-one patients received adjuvant chemotherapy, and 27 of them completed therapy with external-beam radiation as consolidation for local tumor control. At the end of entire protocol treatment, 25 patients (43%) were tumor-free. Persistent or progressive disease was documented in 33 patients (57%). A significant association between the remaining disease status and response to protocol treatment became apparent in these two groups of patients (P = .008).
Relapse and Survival
Distant disease was documented in 22 patients (38%). The 5-year distant metastasis-free survival rate was 51% (95% CI, 35% to 67%) (Fig 3). Forty-five patients (78%) developed local and/or distant disease recurrence during the follow-up period. The 5-year EFS rate was 20% (95% CI, 9% to 31%), and the median EFS time was 19 months (Fig 4). At present, 17 patients (29%) are alive. The 5-year estimated OS rate was 32% (95% CI, 20% to 44%), with a median OS time of 31 months (Fig 4). Probability of OS was higher for patients receiving postoperative chemotherapy (P = .018). Furthermore, OS was superior, although not statistically different, for patients being R0/R1-resected within the study protocol (n = 17) in contrast to patients entering onto the study with only microscopic tumors detectable (n = 18); the median OS time was 56 months versus 31 months, and estimated 5-year OS rate was 50% (95% CI, 25% to 75%) versus 38% (95% CI, 15% to 60%) (P = .297) (Fig 5). Survival outcome was significantly worse for patients who were only R2-resected on protocol (median OS time, 28 months; 5-year OS, 29%; 95% CI, 5% to 52%) compared with R0/R1-resected patients (P = .04) (Fig 5). Furthermore, there was no difference regarding the probability for OS (P = .965) between patients with microscopic tumor at the start of protocol treatment (S3/R1 category) and all the other patients who entered onto the study with macroscopic tumor (S1, S2, and S3/R2 groups).
To analyze the correlation between tumor volume and LFFS and OS, respectively, the tumor volume was divided either by using the median or the mean of the tumor volume as cut points. Excluding all patients with only microscopic disease at entry of the study, and based on the median tumor volume (377 cm3) as the cut point, there was no significant correlation between tumor volume and LFFS (P = .632) and OS (P = .288). However, based on the mean tumor volume (927 cm3), there was a significant correlation with respect to OS; patients with a tumor volume more than 927 cm3 showed to have an inferior OS (P = .014). Using the same statistical tests on the basis of all study patients (n = 58), a significant correlation between tumor volume and OS was only observed with the mean tumor volume (624 cm3) (P = .012) but not with the median tumor volume (139 cm3) (P = .796) as the cut point. A significant correlation was neither calculated between median tumor volume and LFFS (P = .568) nor between mean tumor volume and LFFS (P = .144). Probability of LFFS showed significant differences between responding (PR, MR, pCR, and FHR) (n = 15) and nonresponding (n = 25) patients; 5-year LFFS rate was 59% (95% CI, 34% to 84%) for responders versus 0% for nonresponders (P = .00056). Median LFFS time was 11 months for nonresponders and 67 months for responders (Fig 6). Comparison of estimated OS rates at 5-year follow-up in responding patients (60%; 95% CI, 35% to 85%) versus nonresponders (10%; 95% CI, 0% to 23%) showed a strong statistical difference with respect to a superior survival for responders (P = .00018) (Fig 7). Median OS time for nonresponders was only 25 months, whereas the median OS time has not yet been reached for patients responding to neoadjuvant treatment.
In this prospective trial, patients with HR-STS at unfavorable RP/V sites received uniformly neoadjuvant chemotherapy combined with RHT, and the treatment was well tolerated and feasible in the majority of patients. The median OS for patients within this study was 31 months and is similar to the survival time reported for patients with more favorable STS of the extremities and is much better than documented median survival times of 9 to 20 months for RP STS.1-3 We are aware that this comparison to historical series of patients being treated before 1990 is difficult and may not account for refinements in surgical selection and resection techniques that have transpired since that time. It is important to note that besides inclusion of unfavorable anatomic tumor sites and recurrent STS, the study protocol allowed for the treatment of patients who had tumors that were not adequately resectable before entering the study.26 This argues for a high burden of patients with unfavorable prognosis in our study in contrast to other neoadjuvant treatment protocols where only patients were included who were judged to have resectable tumors before the start of neoadjuvant chemotherapy.27 The fact that R0-resection was achieved in a proportion of patients after neoadjuvant treatment supports the idea of a tumor downstaging. Moreover, it was demonstrated that previously resected patients who had only a microscopic tumor left at the start of protocol treatment had a significantly higher probability of local relapse in comparison with patients whose tumor was resected after neoadjuvant thermochemotherapy. In the literature, conflicting data have been presented with regard to the role of neoadjuvant treatment for HR-STS.27-30 Our study can confirm early results by Pezzi et al27 who showed a significant benefit in survival for responders to neoadjuvant chemotherapy while these patients had exclusive STS of the extremity. Recently, it was demonstrated that patients with high-grade extremity STS who showed a pathologic response after neoadjuvant chemotherapy had less local recurrences and a favorable OS.29 We were able to demonstrate in our high-risk population of RP/V STS a significant association between response to neoadjuvant chemotherapy and superior local tumor control, which also translated in a highly significant survival benefit. Local tumor control, which is especially critical for RP/V STS patients (death often occurs because of local disease progression without distant metastases), might be partially achieved by the addition of RHT as a local treatment modality to systemic chemotherapy. Not only radiographic response but also pathologic response evaluation should be taken into account for defining patients with thermochemotherapy-sensitive STS. Radiographic techniques often underestimate the real extent of response because fibrous tissues produced after neoadjuvant chemotherapy may prevent visible shrinkage of tumor masses. Assessment of response using histologic techniques is also problematic because it is time consuming and difficult because of inherent tumor necrosis. Meanwhile, newer techniques like [F-18]fluorodeoxyglucose positron emission tomography imaging and dynamic infrared imaging are available that might be useful in early detection of patients with chemosensitive sarcomas who would probably benefit from further systemic adjuvant treatment.31,32 The role of adjuvant radiation therapy for patients with RP/V STS remains unclear.2,5,33 Radiation was often limited by tolerance of adjacent intra-abdominal or retroperitoneal tissue. Whereas the impact of adjuvant radiotherapy on local tumor control has been documented in randomized trials for extremity STS, its role is not defined for RP/V STS.34,35 Radiation therapy was shown to be the only factor significant for a reduction in the risk of local recurrence in RP sarcomas.36 But even intraoperative radiation therapy, which enables better shielding of adjacent normal tissue and therefore adequate dosing in the tumor bed, was not shown to have any significant impact on OS.37 In a former randomized trial of adjuvant radiation therapy for patients with RP/V sarcomas, a benefit of this treatment modality could not be documented.38 We could show an association between time-averaged intratumoral temperatures and response that was independent from the initial tumor burden the patients presented with. A strong correlation was found between temperatures within the tumor and response to treatment in a former study, including 40 patients with advanced sarcomas who were treated from 1986 to 1990.17 It is important to point out that in the present study, patients received RHT in combination with chemotherapy, but the design of this phase II trial did not include a control arm that involved chemotherapy alone. Therefore, it is not possible to define what the addition of RHT contributed to the survival benefit observed for patients responding to neoadjuvant treatment. Although we could show that quality of heating is associated with response to neoadjuvant therapy, the definitive role of RHT within this multimodality approach has to be defined after completion of an ongoing, randomized, multicentric phase III Intergroup study (European Organization for Research and Treatment of Cancer 62961/European Society of Hyperthermic Oncology RHT-95) that includes neoadjuvant chemotherapy combined with RHT in the experimental treatment arm compared with chemotherapy alone in the control arm.39
Supported, in part, by the Deutsche Krebshilfe (M99/94/Wi II) and the European Society of Hyperthermic Oncology. We thank the following colleagues for their contribution: W. Wilmanns, M. Reiser, G. Baretton, H.-G. Rau, G. Heiss, R. Wilkowski, H.-R. Dürr, C. Salat, M. Falk, M. Santl, A. Teuschl, and C. Adalin.
Presented, in part, at the Thirty-Seventh Annual Meeting of the American Society of Clinical Oncology, San Francisco, CA, May 12-15, 2001.
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7. Ball AB, Cassoni A, Watkins RM, et al: Silicone implant to prevent visceral damage during adjuvant radiotherapy for retroperitoneal sarcoma. Br J Radiol 63: 346-348, 1990 8. Sugarbaker PH: Early postoperative intraperitoneal Adriamycin as an adjuvant treatment for visceral and retroperitoneal sarcoma. Cancer Treat Res 81: 7-14, 1996[Medline] 9. Pisters PWT, Patel SR, Crane C, et al: Combined modality management of retroperitoneal sarcomas: Phase I trial of preoperative doxorubicin-based concurrent chemoradiation, surgical resection and intra-operative electron-beam radiation therapy (IORT). 6th Annual Meeting of the Connective Tissue Oncology Society (CTOS), Amsterdam, the Netherlands, November 2-4, 2000 10. Jpen P, Betensky RA, Choudry U, et al: Complete resection and intra-operative radiation therapy improve outcome of retroperitoneal sarcomas. 6th Annual Meeting of the Connective Tissue Oncology Society (CTOS), Amsterdam, the Netherlands, November 2-4, 2000 11. Dewey WC: Interaction of heat with radiation and chemotherapy. Cancer Res 44: 4714-4720, 1984 12. Falk MH, Issels RD: Hyperthermia in oncology. Int J Hyperthermia 17: 1-18, 2001[Medline]
13. Udono H, Srivastava PK: Heat shock protein 70-associated peptides elicit specific cancer immunity. J Exp Med 178: 1391-1396, 1993
14. Udono H, Levey DL, Srivastava PK: Cellular requirements for tumor-specific immunity elicited by heat shock proteins: Tumor rejection antigen gp96 primes CD8+ T cells in vivo. Proc Natl Acad Sci USA 91: 3077-3081, 1994
15. Multhoff G, Botzler C, Wiesnet M, et al: CD3 negative large granular lymphocytes recognize a heat inducible immunogenic determinant associated with the 72kD heat shock protein (HSP) on human sarcoma cells. Blood 86: 1374-1382, 1995 16. Prosnitz LR, Maguire P, Anderson JM, et al: The treatment of high-grade soft tissue sarcomas with preoperative thermoradiotherapy. Int J Radiat Oncol Biol Phys 45: 941-949, 1999[CrossRef][Medline] 17. Issels RD, Prenninger SW, Nagele A, et al: Ifosfamide plus etoposide combined with regional hyperthermia in patients with locally advanced sarcomas: A phase II study. J Clin Oncol 8: 1818-1829, 1990[Abstract] 18. Issels RD, Abdel-Rahman S, Wendtner C-M, et al: Neoadjuvant chemotherapy combined with regional hyperthermia for locally advanced primary or recurrent high-risk soft tissue sarcomas of adults: Follow-up report of a phase II study. Eur J Cancer 37: 1599-1608, 2001[CrossRef][Medline] 19. Wendtner C-M, Abdel-Rahman S, Baumert J, et al: Treatment of primary, recurrent or inadequately resected high-risk soft tissue sarcomas (HR-STS) of adults: Results of a phase II pilot study (RHT-95) of neoadjuvant chemotherapy combined with regional hyperthermia. Eur J Cancer 37: 1609-1616, 2001[CrossRef][Medline] 20. Van der Zee J, Gonzalez Gonzalez D, van Rhoon GC, et al: Comparison of radiotherapy alone with radiotherapy plus hyperthermia in locally advanced pelvic tumors: A prospective, randomised, multicentre trial—Dutch Deep Hyperthermia Group. Lancet 355: 1119-1125, 2000[CrossRef][Medline] 21. Trotti A, Byhardt R, Stetz J, et al: Common toxicity criteria-version 2.0: An improved reference for grading the acute effects of cancer treatment—Impact on radiotherapy. Int J Radiat Oncol Biol Phys 47: 13-47, 2000[CrossRef][Medline] 22. Mann HB, Whitney DR: On a test of whether one of 2 random variables is stochastically larger than the other. Ann Math Stat 18: 50-61, 1947[CrossRef] 23. Kaplan E, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53: 457-481, 1958[CrossRef] 24. Greenwood M: The Natural Duration of Cancer: Reports on Public Health and Medical Subjects, vol 33. London, United Kingdom, Her Majesty’s Stationary Office, 1926, pp 1-26 25. Anderson JR, Cain KC, Gelber RD: Analysis of survival by tumor response. J Clin Oncol 1: 710-719, 1983[Abstract]
26. Pisters PW, Leung DH, Woodruff J, et al: Analysis of prognostic factors in 1,041 patients with localized soft tissue sarcomas of the extremities. J Clin Oncol 14: 1679-1689, 1996 27. Pezzi CM, Pollock RE, Evans HL, et al: Preoperative chemotherapy for soft-tissue sarcomas of the extremities. Ann Surg 211: 476-481, 1990[Medline]
28. Pisters PWT, Patel SR, Varma DGK, et al: Preoperative chemotherapy for stage IIIB extremity soft tissue sarcoma: Long-term results form a single institution. J Clin Oncol 15: 3481-3487, 1997
29. Eilber FC, Rosen G, Eckardt J, et al: Treatment-induced pathologic necrosis: A predictor of local recurrence and survival in patients receiving neoadjuvant therapy for high-grade extremity soft tissue sarcomas. J Clin Oncol 19: 3203-3209, 2001 30. Casper ES, Gaynor JJ, Harrison LB, et al: Preoperative and postoperative adjuvant combination chemotherapy for adults with high grade soft tissue sarcoma. Cancer 73: 1644-1651, 1994[CrossRef][Medline] 31. Schuetze S, Conrad E, Bruckner J, et al: FDG PET response to neoadjuvant chemotherapy predicts survival in patients with soft tissue sarcoma. Proc Am Soc Clin Oncol 20: 348, 2001 (abstr 389) 32. Janicek M, Waxman A, Janicek MR, et al: Assessment of early response to therapy in sarcomas: Dynamic infrared imaging (DIRI), computed tomography (CT) and F-18 FDG positron emission tomography (PET). Proc Am Soc Clin Oncol 20: 348, 2001 (abstr 390)
33. Bevilacqua RG, Rogatko A, Hajdu SI, et al: Prognostic factors in primary retroperitoneal soft-tissue sarcomas. Arch Surg 126: 328-334, 1991
34. Pisters PWT, Harrison LB, Leung DH, et al: Long term results of a prospective randomized trial evaluating the role of adjuvant brachytherapy in soft tissue sarcoma. J Clin Oncol 14: 859-868, 1996
35. Yang JC, Chang AE, Baker AR, et al: A randomized prospective study of the benefits of adjuvant radiation therapy in the treatment of soft tissue sarcoma of the extremity. J Clin Oncol 16: 197-203, 1998 36. Heslin MJ, Lewis JJ, Nadler E, et al: Prognostic factors associated with long-term survival for retroperitoneal sarcoma: Implications for management. J Clin Oncol 15: 2832-2839, 1997[Abstract]
37. Sindelar WF, Kinsella TJ, Chen WP: Intraoperative radiotherapy in retroperitoneal sarcomas: Results of a prospective, randomized clinical trial. Arch Surg 128: 402-410, 1993 38. Rosenberg SA, Chang AE, Glatstein E: Adjuvant chemotherapy for treatment of extremity soft tissue sarcomas: Review of National Cancer Institute experience. Cancer Treat Symp 3: 83-88, 1985 39. EORTC 62961/ESHO RHT-95: Randomized study comparing neoadjuvant chemotherapy etoposide + ifosfamide + adriamycin (EIA) combined with regional hyperthermia (RHT) versus neoadjuvant chemotherapy alone in the treatment of high-risk soft tissue sarcomas in adults. http://www.med.uni-muenchen.de/tzm/eortc Submitted July 26, 2001; accepted March 29, 2002.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
= 5%; ß = 20%). 
