Our results suggest that patients with primary and unifocal STS of the extremity, in whom R0 resection is achieved after successful ILP (induction of >50% necrosis), may not benefit from adjuvant RTx. In these patients, the recurrence rate was 0%. Patients treated for recurrence of STS (n = 7), who had R0 resection and >50% tumor necrosis, showed local recurrence in one case.
The overall local recurrence rate in our series was 21%, which is in accordance with several other studies describing ILP as a limb-saving strategy for STS (11–34%), while reported recurrence rates for primarily resectable STS range from 10 to 27%.5,7,10–18
A CR rate of 4% seems low compared with the rate of 28% in the multicenter trial published by Eggermont et al. or in comparison with the latest studies of Bonvalot at al. (30%; n = 100), Grabellus et al. (15%; n = 47), and Pennachioli et al. (41%; n = 88).7,14–16 The discordance is due to selection bias, since we only included patients with limb-sparing surgery after ILP. The vast majorities of patients with MRI-proven CR were not considered for resection and had clinical follow-up for 10 years. Another bias was the exclusion of multifocal tumors in general (Lev–Chelouche, CR = 38, n = 53) or Stewart–Treves lymphangiosarcoma (Lans et al., CR = 56%; n = 16), which are known to respond well to ILP.19,20 With the introduction of the use of TNF-α in ILP there was a substantial improvement in treatment for nonresectable extremity STS.4,5,12,21,22 Nowadays ILP with delayed resection is an established strategy for limb salvage in Europe. Median time span between resection and ILP was 84 days, which was within the range of previous reports (42–117 days).22,23 Completeness of resection is an important prognostic factor for local recurrence.14,17,18,24–26 After R0 or R1 resection in patients with over 50% tumor necrosis, a local recurrence rate of only 7% was observed. Of patients with ≤50% necrosis in resection specimen, 33% had recurrence. This highly significant difference suggests that the degree of ILP-mediated tumor necrosis might be an even stronger prognostic factor for local recurrence and supports the findings of Grabellus et al.14 that improved margin status is achieved after ILP. In patients with R1 resection with >50% necrosis, 19% local recurrence was observed. This is a notable improvement in comparison with the large analysis (n = 1,041) of Pisters et al. who reported a local recurrence rate of 40% for R1 resection of extremity STS without ILP.18 Considering the larger proportion of large tumors (>10 cm; 25 vs. 56%) in our series, this result is more remarkable.
It could be argued that determining the degree of necrosis may not necessarily reflect a therapy effect but may be inherent tumor necrosis. Furthermore, macroscopic evaluation is a subjective and therefore imprecise factor. Considering the fact that tumor necrosis in untreated STS is an independent unfavorable prognostic factor, it may be assumed that the necrosis observed in ILP-treated sarcomas is indeed therapy related and prognostically relevant. Second, considering the broad categories defined for tumor necrosis in grading systems (0, <50, and >50%) it is highly unlikely that the degree of necrosis in single cases falls near the cutoff point. Furthermore, in our experience the pattern of necrosis in ILP-treated sarcomas, consisting of large confluent areas of necrosis, is different from the patch pattern of necrosis seen as spontaneous necrosis in untreated sarcomas. Finally, the MRIs that were performed before ILP showed central necrosis in only 7 (12%) of 59 cases with >50% ILP-induced necrosis.
The value of adjuvant RTx after ILP and resection is still unclear. The beneficial effect of irradiation in limb-saving surgery for STS was first demonstrated by Rosenberg et al.2 Despite reporting a significant decrease in STS local recurrence after irradiation therapy, Yang et al.27 concluded that, in selected patients with low risk for recurrence, irradiation should not be considered because of important lifetime risk for complications. Other studies claimed that adjuvant RTx in all cases had a significant positive influence in obtaining local control.10,23
Complications of RTx should not be underestimated. Hoven-Gonderie et al.28 reported that two-thirds of all patients experienced serious late toxic problems after combined treatment for STS. Major problems with wound healing and continuous wound infections (8–14%) are described in literature.29,30 Vascular damage (4–14%) is a common long-term complication of RTx.6,30,31 Kalman et al.32 described four cases of long-term vascular side-effects in the axillary artery after mastectomy with adjuvant RTx, 10–27 years after treatment. RTx may cause neuropathy, especially when a boost is given.28,33
Although radiation is effective in improving local control, several studies suggest that, after margin-free resection, a subset of patients do not benefit from RTx.14,34,35 In a prospective study, Pisters et al.9 reported that patients with T1, R0-resected STS have acceptable long-term local control and may be spared the short- and long-term toxicity of RTx.
In our series, patients were not randomized for adjuvant RTx, so the conclusions based on our findings have to be read with caution. Furthermore, with 36 patients in 18 years, the defined group that can be spared RTx is relatively small. Further studies should be performed to confirm these findings. Nevertheless, our results suggest that patients with R0 resection combined with >50% ILP-induced necrosis may be spared adjuvant RTx. The benefit of adjuvant RTx after ILP followed by limb-sparing surgery for this subset of patients seems limited. The added morbidity, the lack of survival benefit, and the limited effect on local recurrence should be discussed with these patients.