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Journal of Clinical Oncology, Vol 22, No 1 (January 1), 2004: pp. 143-149 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.04.180 Group II Rhabdomyosarcoma and Rhabdomyosarcomalike Tumors: Is Radiotherapy Necessary?From the Department of Radiotherapy, University Hospital Muenster, Muenster; Department of Pediatric Oncology/Hematology, Olgahospital Stuttgart; Department of Radiotherapy, Katharinenhospital Stuttgart, Stuttgart; and Department of Pathology, University of Kiel, Kiel, Germany. Address reprint requests to Andreas Schuck, MD, Radiotherapy Department, University Hospital, A. Schweitzer Str 33, D-48129 Muenster, Germany; e-mail: schuck{at}uni-muenster.de
PURPOSE: In the prospective Cooperative Soft Tissue Sarcoma Study Group (CWS) 81, 86, 91, and 96 trials, radiotherapy was omitted in some patients with rhabdomyosarcoma and rhabdomyosarcoma-like tumors within Intergroup Rhabdomyosarcoma Study (IRS) group II. This analysis evaluates whether subgroups can be defined for which radiotherapy is not necessary. PATIENTS AND METHODS: Two hundred three patients who were registered between January 1981 and December 1998 were eligible for evaluation. Radiotherapy was given depending on tumor location, histology, and whether a secondary complete resection could be performed. The recommended radiation doses ranged from 32 to 54 Gy. RESULTS: One hundred ten patients did receive and 93 patients did not receive radiotherapy. The calculated local control after 5 years was 83% with and 65% without radiotherapy (P < .004). Event-free survival (EFS) at 5 years was 76% and 58%, respectively (P < .005). Overall survival (OS) at 5 years was 84% and 77% (P = not significant). The differences in local control were significant for the subgroups of irradiated patients with favorable histology, favorable site, and initial tumor size of less than 5 cm. A trend for improved local control with irradiation was observed for patients with unfavorable site, unfavorable histology, and large primary tumors. EFS was significantly improved for irradiated patients who had unfavorable histology, both favorable and unfavorable tumor sites, and small initial tumors. OS was significantly improved for patients with unfavorable histology through radiation. CONCLUSION: Local control and EFS in group II patients are improved with radiotherapy. No subgroup could be defined for which the omission of radiotherapy produced outcome equivalent to that of patients who were irradiated.
For the treatment of rhabdomyosarcomas (RMS) and RMS-like tumors, a multimodal approach is used that consists of systemic and local therapy [1-3]. The preferred local therapy approach, if possible, is a complete resection without loss of form and function and irradiation in selected cases. The grouping of the resection refers to the surgical margins. Complete resections are classified as group I, microscopically positive margins are classified as group IIa, and macroscopically residual tumor is classified as group III. Furthermore, patients with resected positive regional lymph nodes are classified as group IIb and IIc patients [1,4]. In the Cooperative Soft Tissue Sarcoma Study Group (CWS) 81, 86, 91, and 96 trials, radiotherapy was omitted in subgroups of patients with group II tumors to avoid radiation-associated toxicity [2,5]. We present here the analysis of the CWS data, which evaluates whether radiotherapy improves prognosis in group II patients and whether subgroups can be defined for which radiotherapy can be omitted without compromising the prognosis.
In the analysis, patients with group II RMS, extraosseous Ewing's sarcoma, primitive neuroectodermal tumors, and undifferentiated sarcoma treated in the CWS 81, CWS 86, CWS 91, and CWS 96 trials between 1981 and 1998 are included. Exclusion criteria were included age greater than 21 years, relapse at registration, or secondary malignancy. Favorable histology included embryonal RMS and RMS not otherwise specified (or unclassified); the latter are tumors that can be classified as rhabdomyosarcoma, but further differentiation is not possible as a result of poor differentiation or because of other factors such as small biopsy. Unfavorable histology included alveolar RMS, undifferentiated sarcoma, extraosseous Ewing's sarcoma, and primitive neuroectodermal tumors. Favorable sites were defined as tumors of the orbit, urogenital tumors excluding the bladder and prostatic sites, and head and neck tumors excluding parameningeal sites. All others were classified as unfavorable sites. The trials were approved by the institutional review boards, and the patients or parents gave informed consent to participation in the trial. All patients with Intergroup Rhabdomyosarcoma Study (IRS) group II tumors underwent tumor resection at the beginning of treatment. This was followed by chemotherapy and, in a subgroup of patients, radiotherapy. The schedule of systemic therapy for IRS group II patients for each trial is shown in Table 1.
Radiotherapy modalities for these patients in the different trials are summarized in Table 2. In all trials, the planning target volume was defined as the initial tumor extension on computed tomography or magnetic resonance imaging scan plus a margin of at least 2 cm.
Between 1981 and 1998, 203 patients with RMS and RMS-like tumors within IRS group II were treated in the CWS 81, 86, 91, and 96 trials. Of these, 172 patients were classified as group IIa, 26 patients were classified as group IIb, and one patient was classified as group IIc. Four group II patients were not further differentiated. The mean age of all patients was 7.0 years (range, 0 to 20 years). There were 142 protocol patients and 61 follow-up patients. Patients were classified as follow-up patients when the interval between diagnosis and start of therapy was greater than 8 weeks, when primary surgery was mutilating, when the time between primary surgery and potential primary reresection was greater than 4 weeks, when the cumulative dose of chemotherapy or radiotherapy differed from protocol guidelines by greater than 20%, or when the total treatment time was delayed by greater than 20% than anticipated in the protocol. One hundred ten of the patients received external-beam radiotherapy, whereas the remaining 93 patients did not. The distribution of tumor characteristics for patients with or without radiotherapy is summarized in Table 3. The reasons why radiotherapy was not applied in 93 patients are summarized in Table 4. The groups of patients who did or did not receive radiotherapy were not evenly distributed with respect to histology, tumor site, and age. The group that received radiotherapy included significantly more patients with unfavorable histology and unfavorable sites and fewer patients younger than 1 year. The median radiation dose for patients who received irradiation was 45 Gy. Seven patients received less than 32 Gy, and six patients received more than 54 Gy (range, 23 to 64 Gy).
Overall survival (OS), event-free survival (EFS), and calculated local control were estimated using the Kaplan-Meier method. For OS, only death was classified as an event. For EFS, progression during therapy, local relapse, metastases, and death resulting from tumor were classified as events when occurring as first events. For calculated local control, local and combined local/systemic relapses were events when occurring as first events, and all other first events were censored. Locoregional lymph node relapses were counted as local relapses. Statistical significance was calculated with the log-rank test. The distribution of clinical factors at diagnosis and treatment characteristics were compared using the  2 test. Minimum follow-up was 3 years, and the median follow-up was 66 months.
After 5 years, the calculated local control was 83% for patients who did receive and 65% for those who did not receive radiotherapy (P < .004; Fig 1). The corresponding calculated local control at 5 years according to risk factors and radiotherapy is shown in Table 5. The favorable local control with irradiation was statistically significant in patients with favorable histology and favorable site and with initial tumor size of less than 5 cm. The difference in local control using radiotherapy was also significant for patients who had both small initial tumor size and favorable histology. For patients with unfavorable histology, unfavorable site, or tumors greater than 5 cm, there was a trend for improved local control with radiotherapy that did not reach statistical significance. However, this may be due to the few patients under observation in these subgroups.
Reasons why radiotherapy was not applied were frequently young age, secondary complete resections, or negative biopsies at second-look surgery. In patients 3 years of age or younger, 18 patients did receive and 29 patients did not receive radiotherapy. There was one local relapse in the radiotherapy group (5.6%) and 10 local relapses (34.5%) in the no-radiotherapy group. Furthermore, there were 40 patients with complete second surgery or negative biopsies at second-look surgery who did not receive radiotherapy and 14 patients with these characteristics who did receive radiotherapy. Second surgery refers to a re-operation that is performed after undergoing initial chemotherapy. There were 11 local relapses in the first group (27.5%) and three local relapses in the latter group (21.4%). In the CWS 86 trial, radiotherapy was recommended for patients with bone erosions and extremity sites. Because there were only six patients classified with bone erosion and 19 patients with extremity sites in this trial, the effect of radiotherapy in these patients cannot be sufficiently evaluated. There was no difference in EFS among the four analyzed trials. EFS after 5 years was 76% and 58% with and without irradiation, respectively (P < .005; Fig 2), and OS was 84% and 77%, respectively (P = not significant; Fig 3). EFS and OS after 5 years according to risk factors are shown in Table 5. EFS with radiotherapy was significantly improved for patients with unfavorable histology, favorable or unfavorable site, or initial tumor size less than 5 cm and patients with combined favorable histology and tumors less than 5 cm. OS with radiotherapy was significantly improved for patients with unfavorable histology.
EFS and OS were significantly better in protocol patients compared with follow-up patients. EFS and OS were 74% and 88%, respectively, for protocol patients after 5 years and 51% and 63%, respectively, for follow-up patients (EFS, P < .002; OS, P < .001). EFS after 5 years for protocol patients with and without radiotherapy was 81% and 65%, respectively (P < .02). In follow-up patients, the corresponding EFS rates are 61% and 45%, respectively (P = not significant; Fig 4). OS for protocol patients with and without radiotherapy after 5 years is 88% and 87%, respectively, whereas OS for follow-up patients is 69% and 58%, respectively (P = not significant). When each of the four single CWS studies were analyzed separately, there was no statistical significance in EFS for protocol patients who received or who did not receive radiotherapy. The patient numbers for these four analyses, however, are small.
Of the 42 patients who experienced a local relapse alone, 13 experienced relapse with and 29 without previous irradiation. OS after local relapse was 51% and 48% after 5 years with and without previous radiotherapy, respectively.
In the CWS trials, radiotherapy was part of the protocol for some of the patients with group II soft tissue sarcomas after initial surgery [2,5]. Therapy guidelines varied among the protocols according to the histology of the tumor, the tumor site, and whether a secondary complete resection could be performed. Table 2 lists the indications for radiotherapy in the four trials. It is noteworthy that, although the indications for radiotherapy changed, patients who did not undergo irradiation always represented a more favorable subgroup. The difference in tumor sites and histology for patients who did receive versus those who did not receive radiotherapy is statistically significant (Table 3), with unfavorable sites and histology occurring mainly in the group of patients who received radiotherapy. As a result of this distribution of risk factors, more local relapses and worse EFS and OS might have been anticipated in the groups that received radiation as reported by the Intergroup Rhabdomyosarcoma Study [6]. Yet the calculated local control after 5 years with radiotherapy was 83%, compared with 65% without radiotherapy (P < .004; Fig 1). The corresponding EFS was 76% and 58%, respectively (P < .005; Fig 2), and OS was 84% and 77%, respectively (P = not significant; Fig 3). There was a statistically significant difference in OS and EFS between protocol patients and follow-up patients. The latter did not fulfill all formal criteria of protocol patients (ie, an interval between diagnosis and start of therapy of > 8 weeks) or had treatment deviations. The improvement of EFS with radiotherapy was significant for protocol patients and did not quite reach statistical significance for follow-up patients. However, this may be due to the small number of patients under observation in the latter subgroup (Fig 4). When the protocol patients of the four single studies were evaluated separately, there was no statistically significant difference between patients who did or did not receive radiotherapy. This can again be explained by the small numbers of patients in the subgroups.
The analysis of subgroups of patients according to tumor characteristics showed that local control, EFS, and OS were better in all evaluated subgroups of patients who received radiotherapy (Table 5). The difference in local control was statistically significant for patients with favorable site, favorable histology, and small primary tumors less than 5 cm in size. Even for the combination of the factors of favorable histology and small primary tumors, local control was significantly improved with radiotherapy (P < .01). Furthermore, the omission of radiotherapy in patients In the IRS I to IV trials, patients with group II tumors usually received radiotherapy [1,4,6-9]. In a report from the International Society of Pediatric Oncology, there were 38 girls with genitourinary RMS treated in the Malignant Mesenchymal Tumors Study (MMT) 84 and MMT 89 trials, including 10 girls with group II disease. Patients only received radiotherapy if there was no complete remission after chemotherapy. The OS after 5 years for all patients was good (91%). The results for group II patients according to whether radiotherapy was given were not specified [10]. In a further report from the MMT 84 trial, there were 16 patients within IRS group II who were in complete remission without radiotherapy; however, the total number of IRS group II patients who did not receive radiotherapy was not mentioned [11]. Our results and the reports from the literature demonstrate that it is possible to cure some patients with microscopically incomplete resection without additional radiotherapy. However, to date, it has not been possible to clearly define a subset of group II patients in whom radiation may be spared. The benefits of radiation in our data are apparent: patients who received radiotherapy in the CWS trials have significantly improved local control and EFS, even though they had unfavorable selection characteristics. We are not able to define patient or tumor characteristics among patients who did not receive radiotherapy that showed equivalent control rates and EFS to those of the corresponding irradiated group. Although the decision to irradiate group II patients represents a balance between improved tumor control and adverse side effects, all group II patient subgroups have improved local control and EFS with the use of radiotherapy. A difference in OS is only significant for patients with unfavorable histology because there is only a poor chance of cure after a relapse. In patients with favorable histology, the difference in OS was small but in favor of the irradiated group. In our opinion, radiotherapy is therefore generally recommended in IRS group II patients. Because there is no statistically significant difference in OS, an omission of radiotherapy in the primary treatment can be justified in patients with favorable histology where the side effects from radiotherapy would be severe, such as in extremely young patients and in those presenting with tumors in particularly sensitive sites.
The authors indicated no potential conflicts of interest.
Supported by the Deutsche Krebshilfe, project No. 70-02158. Authors' disclosures of potential conflicts of interest are found at the end of this article.
1. Crist W, Gehan E, Ragab A, et al: The Third Intergroup Rhabdomyosarcoma Study. J Clin Oncol 13:610-630, 1995 2. Koscielniak E, Juergens H, Winkler K, et al: Treatment of soft tissue sarcoma in childhood and adolescence. Cancer 70:2557-2567, 1992[CrossRef][Medline] 3. Rousseau P, Flamant F, Quintana E, et al: Primary chemotherapy in rhabdomyosarcomas and other malignant mesenchymal tumors of the orbit: Results of the International Society of Pediatric Oncology MMT 84 Study. J Clin Oncol 12:516-521, 1994[Abstract] 4. Maurer H, Beltangady M, Gehan E, et al: The Intergroup Rhabdomyosarcoma Study-I. Cancer 61:209-220, 1988[CrossRef][Medline]
5. Koscielniak E, Harms D, Henze G, et al: Results of treatment for soft tissue sarcoma in childhood and adolescence: A final report of the German Cooperative Soft tissue sarcoma Study CWS-86. J Clin Oncol 17:3706-3719, 1999
6. Smith L, Anderson J, Qualman S, et al: Which patients with microscopic disease and rhabdomyosarcoma experience relapse after treatment? A report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group. J Clin Oncol 19:4058-4064, 2001
7. Crist W, Anderson J, Meza J, et al: Intergroup Rhabdomyosarcoma Study-IV: Results of patients with nonmetastatic disease. J Clin Oncol 19:3091-3102, 2001 8. Maurer H, Gehan E, Beltangady M, et al: The Intergroup Rhabdomyosarcoma Study-II. Cancer 71:1904-1922, 1993[CrossRef][Medline] 9. Andrassy R, Hays D, Raney B, et al: Conservative surgical management of vaginal and vulvar pediatric rhabdomyosarcoma: A report from the Intergroup Rhabdomyosarcoma Study III. J Pediatr Surg 30:1034-1037, 1995[CrossRef][Medline]
10. Martelli H, Oberlin O, Rey A, et al: Conservative treatment for girls with nonmetastatic rhabdomyosarcoma of the genital tract: A report from the study committee of the International Society of Pediatric Oncology. J Clin Oncol 17:2117-2122, 1999 11. Flamant F, Rodary C, Rey A, et al: Treatment of non-metastatic rhabdomyosarcomas in childhood and adolescence: Results of the second study of the International Society of Paediatric Oncology MMT 84. Eur J Cancer 34:1050-1062, 1998 Submitted April 26, 2002; accepted October 21, 2003.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
), local relapse; (+), censored.
), censored.
3 years of age resulted in increased local relapses. After secondary complete resection or negative biopsy at second-look surgery, 11 (27.5%) of the 40 patients who did not receive radiotherapy had a local relapse. This relapse rate is comparable to the results of the no-radiotherapy group in the whole study population. Therefore, radiotherapy is likely to improve the results in this patient subgroup. The numbers in the group of patients with this outcome of second surgery who did receive radiotherapy are too low to allow a comparison (14 patients). EFS was significantly improved with radiotherapy for patients with unfavorable histology, both favorable and unfavorable tumor sites, and initial tumor size of less than 5 cm. There is little debate that patients with group II tumors and unfavorable tumor characteristics should receive irradiation. Our data show that even for patients with favorable tumor characteristics, local control and EFS decrease considerably when radiation is omitted. The results of salvage therapy of local relapses were not compromised as a result of previous radiation. Survival after local relapse with or without previous radiotherapy after 5 years was 51% and 48%, respectively. In terms of OS, there was a statistically significant difference for the subgroup of patients with unfavorable histology only. For these patients, OS after 5 years was 80% in patients with irradiation, compared with 56% in patients without irradiation. For the other subgroups, the difference in OS after 5 years ranged between 4% and 11% (
