Katja M. J. Thijssens

Isolated limb perfusion with tumor necrosis factor α and melphalan for locally advanced soft tissue sarcoma : The value of adjuvant radiotherapy

BackgroundThe aim was to investigate the value of adjuvant radiotherapy for locally advanced soft tissue sarcoma after hyperthermic isolated limb perfusion (ILP) with tumor necrosis factor α and melphalan followed by limb-saving surgery.MethodsFrom 1991 to 2003, 73 patients (median age, 54 years; range, 14–80 years) underwent 77 ILPs, followed by resection in 68 patients (93%). Radiotherapy was administered in case of marginally or microscopically positive resection margins. Local recurrences were scored and calculated according to the Kaplan-Meier method and log-rank test.ResultsAfter residual tumor mass resection, 58% received radiotherapy (external beam radiotherapy [EBRT]+ group), and 42% did not (EBRT− group). The median follow-up was 28 months (range, 2–159 months). A significantly better local control rate was observed in the EBRT+ compared with the EBRT− group (P < .0001). When only R0 resections in patients without metastasis were considered, the significance remained between groups (P = .0003). In the EBRT− group, an R1 or R2 resection resulted in earlier relapse of local disease compared with R0 resections (P = .0475).ConclusionsAdjuvant EBRT reduces the risk for local recurrence after delayed resection in soft tissue sarcoma patients treated with ILP and tumor necrosis factor and is indicated when resection margins are close or microscopically positive. It also seems beneficial after an R0 resection.

Quality of Life After Hyperthermic Isolated Limb Perfusion for Locally Advanced Extremity Soft Tissue Sarcoma

BackgroundQuality of life (QoL) and posttraumatic stress symptoms (PTSS) were studied in patients with soft tissue sarcoma (STS) of the extremities treated with isolated limb perfusion and delayed resection, with or without adjuvant irradiation.MethodsForty-one patients received a questionnaire that included the RAND-36 and Impact of Event Scale.ResultsThirty-nine STS survivors (16 [41%] male and 23 [59%] female; median age, 59 years; range, 15–78 years) participated in the questionnaire survey (response rate, 95%). The median age at perfusion was 49 years (range, 14–72 years). No significant differences were found in mean scores between STS survivors and the reference group with the exception of a worse physical functioning. Patients with amputations showed significantly worse physical and social functioning and more role limitations than patients whose limbs were saved. Eleven patients (28%) had a PTSS score of 0, and eight patients (20.5%) had a score ≥ 26, which suggested the need for psychological counseling. None of these eight patients had lost a limb. Patients who indicated that the choice of treatment was made by the surgeon rather than collaboratively showed significantly decreased social functioning, more role limitations, and intrusion. Greater treatment satisfaction was significantly related to better social functioning, more vitality, better general health perception, less intrusion, avoidance, and total Impact of Event Scale scores.ConclusionsEven though STS survivors’ QoL was different from that of a reference group only in physical functioning, one fifth of the patients had PTSS. An amputation, the physician’s decision rather than the patient’s decision for the perfusion treatment and a low satisfaction with the performed treatment negatively influenced QoL.

Hyperthermic isolated limb perfusion with TNF and Melphalan for primarily irresectable soft tissue sarcoma; Three time periods at risk for amputation

S: PLENARY and PARALLEL SESSIONS F i g ~ 1. S ~ v i v a l b y P E T treatment iaterLt post CRT 14 Molecular Profiling Predicts Colon Cancer Survival Better Than Dukes Staging I. Yang, 2 S. Eschrich, l G. Bloom, l J. Quackenbush, 2 T.J. Yeatman.l* 1. Surgery and Interdisciplinary Oncology, H Lee Moff i t t Cancer Center, Tampa, FL; 2. The Institute for Genomic Research, Gaithersburg, MD. Introduction: Dukes staging has been the gold standard for colon cancer staging since its inception in 1932. Recently, gene expression profiles have shown promise in discriminating tumors of varying degrees of risk. We report the first prognostic classifier based on an analysis of 20 genes capable of determining survival that is significantly more accurate than Dukes staging. Methods: Seventy-two patients were selected from the Moffitt Cancer Center Tumor Bank and Registry who had been followed for > 24 months. Gene expression profiles were created using a 32,000 cDNA microarray and then subjected to Significance Analysis of Microarray (SAM) analysis to identify large sets of discriminating genes. Construction of a Support Vector Machine was then undertaken to develop a classifier capable of predicting outcome. The accuracy of this classifier was assessed by leave one out cross validation and compared to that of standard Dukes staging. Results: Hierarchical clustering and PCA identified two populations of genes distinguishing the majority of patients that had survived > 24 mo versus those that did not. These observations strongly suggested the potential for underlying gene expression information to drive a prognostic classifier. SVM analysis identified a set of approximately 20 genes whose expression discriminated good from bad survival with better accuracy than Dukes staging at a minimum of 24 mo of follow-up (82% vs 77%). Interestingly, one of the 20 genes identified by the SVM as important in survival prediction was osteopontin, a gene we previously reported to be the gene most strongly correlated with advancing tumor stage in colorectal cancer. Conclusion: We have produced the first molecular classifier capable of predicting outcome for colon cancer that exceeds the accuracy of Dukes staging, particularly in stages B and C where discrimination is critical. This classifier is based on a 20 gene set of which osteopontin, a known gene associated with colon cancer progression, plays a prominent role. 15 Hyperthermic isolated limb perfusion with TNF and Melphalan for primarily irresectable soft tissue sarcoma; three time periods at 1 , l 2 risk for amputation R. Van Ginkel, K. Thijssens, E. Pras, W. De Graaf, 2 A. Suurmeyer, 2 H. Hoekstra.I 1. Surgical Oncology, University Hospital Groningen, Groningen, Netherlands; 2. University Hospital Groningen, Groningen, Netherlands. Introduction Hyperthemic isolated limb perfusion (HILP) with tumor necrosis factor (TNF) and Melphalan is an established treatment strategy for limb saving surgery for primarily irresectable soft tissue sarcoma (STS). The aim of this study was to investigate the long term limb salvage rate and overall survival of HILP. Patients and Methods From 1992-2003, 70 patients with biopsy proven STS of variable histologic subtypes underwent 74 perfusions. HILP was performed with 4 or 3 mg TNF and 10 or 13 mg/L extremity volume for lower respectively upper extremity. Limb salvage curves and overall survival was calculated using the Kaplan-Meier method. Results A total of 17 amputations (24 %) were performed. Overall 1, 5 and 10 years limb salvage was 81.5-4.7%, 74.9_+6.8% and 65.5_+ 10.3% respectively (Fig 1). Three time episodes of amputation were observed. The first occured within the first year after perfusion due to a postperfusion reaction with massive necrosis of the tumor or renewed tumor growth after an initial good response to perfusion. Thirteen amputations were performed in this time period (1 wk-8 months). The second time period was within 5 years with 2 amputations performed for late local recurrent disease (37 and 58 months). The third episode occurred ten years after perfusion. Amputation was performed for ischemic arterial complications (110 and 125 months). No recurrent disease was found on pathological examination of the amputated specimen. Another two patients developed a pathological fracture of the femur due to osteoporosis (78 and 129 months after perfusion). All these 4 patients received post-perfusion radiotherapy. Overall 1, 5 and 10 years survival was 81.5_+5.0%, 55.3-+6.8% and 36.3-+10.3% respectively (Fig 2). Conclusions In 4 out of 5 patients with primarily irresectable STS, TNF Melphalan HILP is able to preserve the affected extremity and the development of distant metastasis is the main reason for mortality. However, we observed late morbidity with 2 pathological fractures and 2 amputations performed for ischemic arterial complications without evidence of recurrent disease. Fi ju re 1 L i m b sa l vage Figure 2 Patient survival 80 . . . . . . . ~ 80