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Results of Treatment for Soft Tissue Sarcoma in Childhood and Adolescence: A Final Report of the German Cooperative Soft Tissue Sarcoma Study CWS-86

From the Department of Oncology/Haematology, Olga Hospital, Stuttgart; Institute of Paidopathology, University of Kiel, Kiel; Charite-Virchow-Klinikum, Berlin; University Children's Hospital, Düsseldorf; Department of Radiology, University of Regensburg, Regensburg; Department of Oncology/Haematology, University of Tübingen, Tübingen; Department of Radiotherapy, Katharinen Hospital, Stuttgart, Germany; and St Anna Kinderspital, Vienna, Austria.

Address reprint requests to Ewa Koscielniak, MD, Department of Oncology/Haematology, Olga Hospital, Bismarckstrasse 8, D-70176 Stuttgart 1, Germany; email cws.study{at}olgahospital.s.shuttle.de

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
PURPOSE: The goal of the second German Soft Tissue Sarcoma Study CWS-86 (1985 to 1990) was to improve the prognosis in children and adolescents with soft tissue sarcoma by means of a clinical trial comprising intensive chemotherapy and risk-adapted local therapy.

PATIENTS AND METHODS: There were 372 eligible patients. A staging system based on the postsurgical extent of disease was used. Chemotherapy consisted of vincristine, dactinomycin, doxorubicin, and ifosfamide. Radiotherapy was administered early at 10 to 13 weeks simultaneously with the second chemotherapy cycle (32 Gy or 54.4 Gy). The single dose was reduced to 1.6 Gy and given twice daily (accelerated hyperfractionation).

RESULTS: The event-free survival (EFS) and overall survival rates at 5 years were 59% ± 3% and 69% ± 3%, respectively. The 5-year EFS rate according to stage was as follows: stage I, 83% ± 5%; stage II, 69% ± 6%; stage III, 57% ± 4%; and stage IV, 19% ± 6%. The outcome for patients with stage III disease who required radiotherapy was much better in the CWS-86 study compared with the CWS-81 study (5-year EFS, 60% ± 5% v 44% ± 6%; P = .053). The most common treatment failure was isolated local relapse, with 14% of patients relapsing at the primary tumor site.

CONCLUSION: The improved design of the study incorporating risk-adapted radiotherapy allowed treatment to be reduced for selected groups of patients without compromising survival.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
SOFT TISSUE SARCOMAS (STS) are very heterogeneous tumors, both pathologically and clinically, making standardization of therapy very difficult. No single institution examines an adequate number of cases of the various histologic subtypes within a short period to allow treatment comparisons. Only large multicenter studies can accumulate enough information to improve prognosis and minimize the late sequelae in children with STS.^1-5 The first multicenter German STS study (CWS-81) was conducted under the auspices of the German Society of Pediatric Oncology between 1981 and 1986. The results of this study have been reported previously.⁴ The second German STS study, CWS-86, was open for patient entry from December 1985 to December 1990. Two major innovations have been introduced into the CWS-86 therapy concept: a modified chemotherapeutic regimen and a new concept for the stratification and application of radiotherapy.

The main objective of the CWS-86 study was, as in the CWS-81 study, to use a coordinated, multidisciplinary therapeutic approach to improve the duration and quality of survival for children with STS. The study was designed to determine the validity of the following points: (1) whether adjuvant chemotherapy for primary, resectable tumors could be further reduced when ifosfamide was substituted for cyclophosphamide in the four-drug cycle; the duration of treatment was 16 weeks for stage I disease and 26 weeks for stage II disease compared with 35 weeks in the CWS-81 study; (2) whether the replacement of cyclophosphamide by ifosfamide in the four-drug cycle could improve the response in patients with macroscopic residual tumor; (3) whether the degree of tumor volume reduction after preoperative chemotherapy in patients with macroscopic residual tumor could be used as a basis for risk-adapted radiotherapy; (4) whether early (10 to 13 weeks) hyperfractionated, accelerated radiotherapy given simultaneously with chemotherapy can improve local tumor control; and (5) whether the 32-Gy dose, when accelerated and hyperfractionated, given simultaneously with chemotherapy, is adequate for local tumor control in a selected group of patients.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Definitions
The same clinical staging system as in the CWS-81 study⁴ was used, which is based on the extent of disease and surgical excision and adapted from the International Rhabdomyosarcoma Study Group (IRS).¹ Stage I indicates localized disease, completely resected without regional node involvement; stage II indicates grossly resected tumor with microscopic residual disease with (B) or without (A) evidence of regional node involvement; stage III indicates incomplete resection with macroscopic residual disease or biopsy; and stage IV indicates distant metastatic disease at diagnosis. Patients' disease was staged by the treating physician at the time of diagnosis and registration. The initial data, including radiographic examination, chemotherapy dosage, and type and extent of surgery, were reviewed by members of a multidisciplinary committee. The primary tumor sites were grouped into the seven categories defined by the International Rhabdomyosarcoma Workshop (Jerusalem 1987): orbit, head/neck nonparameningeal, parameningeal, genitourinary bladder/prostate, genitourinary non—bladder/prostate, extremity, and others. The nasopharynx—nasal cavity, middle ear—mastoid region, paranasal sinuses (maxillary, ethmoid, and sphenoid), pterygopalatine-infratemporal fossa, and the parapharyngeal region were considered as parameningeal sites. The tumor-node-metastasis criteria were used to define preoperative tumor characteristics.⁶

Before chemotherapy was started, the tumor volume was measured by computed tomography or magnetic resonance imaging scanning and/or sonography. The scanner sections were made at 1- to 2-cm intervals through the tumor. The areas of tumor in each of these cuts were outlined and then measured on the film by computer. The total tumor volume was estimated by multiplying the depth between each cut by the average of the two areas, defining each slice and then aggregating all of the slices. If, for technical reasons, it was not possible to do this, the volume was determined by means of the following formula: V = 1/6pi xyz (x = largest width; y = length; and z = height). The response to preoperative chemotherapy was assessed according to the degree of tumor regression after 7 to 9 weeks of chemotherapy (one cycle of vincristine, dactinomycin, ifosfamide, and doxorubicin [VAIA II]). A complete response was considered to be the complete disappearance of all signs of the tumor (confirmed by radiographic means). A good response was a tumor volume regression of two thirds; a poor response was defined as a regression of one third but less than two thirds; and nonresponse was a regression of less than one third. Patients with stage I or II disease were considered to be free of disease, ie, in complete remission (CR), whereas those with stages III and IV disease were considered to be in CR only after the disappearance of all signs and symptoms of disease. If there was evidence of residual tumor on computed tomography or magnetic resonance imaging scans, the patients were considered to be in CR when the findings remained unchanged over a 6-month period. ECG and echocardiograms were recommended before the start of therapy and before each additional dose of anthracycline. In the case of cardiac abnormalities, a radionuclide scan was recommended. Renal glomerular and tubular function were examined before each course of ifosfamide.

Study Design
The study design is shown in Fig 1. Table 1 lists the differences in the design and treatment schedule as compared with the CWS-81 study. All patients received a four-drug chemotherapy regimen (VAIA II). Ifosfamide was administered as a continuous infusion over 48 hours with mesna protection and hydration. The doxorubicin dose was split (2 x 20 mg/m²/d) and infused over 10 to 60 minutes. In comparison to the cycle of vincristine, dactinomycin, cyclophosphamide, and doxorubicin (VACA) in the CWS-81 study, the dose-intensity of doxorubicin was reduced to approximately 70% (10 mg/m²/wk v 15 mg/m²/wk) so that the cumulative dose for stage I was reduced by 80 mg/m² (160 mg/m² v 240 mg/m² in the CWS-81 study) and by 160 mg/m² for stage III (320 mg/m² v 480 mg/m²). The cumulative dose in patients with stage II disease remained unchanged at 240 mg/m². The dose-intensity of dactinomycin was increased by 100% (0.187 mg/m²/wk v 0.375 mg/m²/wk). However, because the duration of therapy was reduced for all stages, the cumulative dose of dactinomycin diminished (60% to 63%). Patients with stage I and II extremity tumors received four VAIA cycles (similar to stage III). This intensification of chemotherapy for extremity tumors was introduced during the CWS-81 study because of the poor results observed in this group. For patients with stage III disease whose response to preoperative chemotherapy was poor (< two-thirds one-third tumor volume reduction), the drug combination PIAV, in which the dactinomycin in the VAIA cycle was replaced by cisplatin, was used as second-line chemotherapy. Patients who did not respond (< one third) were regarded as off-study patients, and melphalan/novantrone or cisplatin/mitomycin (parameningeal) were proposed as a salvage therapy.

View larger version (29K): [in this window] [in a new window]   Fig 1. Treatment schedule according to clinical stage in the CWS-86 study.

The decision concerning the definitive local tumor control was made earlier (7 to 10 weeks) in comparison to the CWS-81 study (16 to 20 weeks). Radiotherapy was stratified according to the clinical stage of the primary tumor and the localization and degree of tumor volume reduction after the first chemotherapy cycle: 32 Gy for patients with stage III disease with good response and 54.4 Gy for those showing a poor response. Radiotherapy was administered parallel to the second chemotherapy cycle but before second-look surgery. The higher dose of 54.4 Gy was split (2 x 27.2 Gy) with an interval of 1 to 2 weeks. The single dose was reduced to 1.6 Gy and given twice daily (accelerated and hyperfractionated). Patients with stage I and II disease and those with stage III disease who achieved a clinical CR after one cycle (7 to 9 weeks) of chemotherapy did not undergo irradiation, with the exception of patients with extremity and parameningeal primary tumors, those with bone erosion at presentation, and those with synovial sarcoma, for whom radiotherapy was considered necessary regardless of primary tumor stage or response to chemotherapy. Second-look surgery was compulsory in patients with macroscopic residual tumor after two VAIA cycles and radiotherapy (16 to 20 weeks). Similarly, as in the CWS-81 study, special guidelines were followed regarding radiotherapy for patients with tumors in the parameningeal region, ie, those adjacent to the meninges and those with evidence of meningeal extension defined as cranial nerve palsy, increased intracranial pressure, positive CSF cytology, or erosion of the base of the skull. Patients with a parameningeal tumor and no evidence of meningeal involvement received radiotherapy to the primary tumor plus a 2-cm margin to the adjacent meninges. The dose was adapted according to the response to chemotherapy. Patients with evidence of meningeal involvement or intracranial extension of the tumor received whole-brain radiotherapy, or in the case of positive cytologic examination of the CSF, additional spinal radiotherapy. Children younger than 2 years did not undergo irradiation, and for those between 2 and 3 years of age, decisions were made on a case-by-case basis. The radiation schedule was either drawn up by one of the committee radiotherapists (M.H. or B.F.S.), or a previously planned schedule was reviewed with respect to the adequacy of the dose and volume applied.

Patient Population
As in the CWS-81 study, the present study enrolled untreated patients with a confirmed diagnosis of rhabdomyosarcoma (RMS), extraosseous Ewing's sarcoma (EES), peripheral neuroectodermal tumors (PNET), synovial sarcoma, and undifferentiated sarcoma. Informed consent was obtained from the parents, patients, or both. Patients with other rare STS were registered in the study with the purpose of obtaining information about the treatment and outcome of these rare sarcomas in children and adolescents in Germany. Similarly, older patients (age > 19 years) with RMS-like tumors, which are more typical in children than in adults, were included in the study registry, even if they were not treated exactly according to the concept of the protocol, and were considered as nonprotocol patients.

This report concerns the group of patients younger than 19 years whose diagnoses were either RMS, undifferentiated sarcoma, EES/PNET, or synovial sarcoma. Patients with metastatic disease were treated according to the protocol CWS-86 only until December 1989, when the European Cooperative Study for Metastatic Mesenchymal Tumors was opened. The median potential follow-up period was 58.8 months (range, 1 to 133 months),⁵ making this report a description of the final results of the study.

A total of 386 patients enrolled by 57 institutions (see Appendix 1) from December 20, 1985, to December 31, 1990, were registered, 372 of whom met all eligibility criteria for entry onto the study and were included in the analysis of outcome, consistent with the intent-to-treat principle.⁷ Patients were not eligible for analysis of outcome if they had received prior chemotherapy or radiation (n = 4) or if the information was not sufficient for assessment of the eligibility criteria (n = 6); four patients were excluded for miscellaneous reasons. Complete information to assess the treatment according to the study protocol criteria was available for 310 patients, and these patients were included in the analysis of prognosis according to response to preoperative chemotherapy and the modalities of local therapy. The median age was 6 years (range, 1 to 18) years, and the male to female ratio was 1.19:1. The median follow-up duration for survivors was 65.2 months. The percentage of patients who underwent follow-up evaluation for 5 years was 62% for all patients and 79% for survivors. The histology had to be confirmed by a panel of consultant pathologists (Appendix 2). The pathologic criteria that had to be met were published elsewhere.⁸ Patients with EES and PNET were analyzed together because no international consensus exists about the diagnostic criteria for these tumors.

Table 2 lists the characteristics of eligible patients in terms of stage, primary tumor site, histology, and TN characteristics. Sixty-two percent of the patients had primary, nonresectable tumors (stage III or IV) at the time of presentation. Patients with metastatic disease had a higher incidence of the alveolar type of RMS compared with patients with nonmetastatic disease (60% and 18%, respectively; P = .0001). Tumors of the extremity were mainly alveolar RMS or nonrhabdomyomatous STS (36% v 4%; P .0001), in contrast to tumors sited in the head/neck and genitourinary region, which were embryonal RMS (66% v 19%; P < .0001). The primary tumor sites were not evenly distributed among the different stages. The majority of patients (78%) with paratesticular localization (genitourinary non—bladder/prostate) had stage I or II disease at presentation in contrast to patients with parameningeal tumors, 95% of whom presented with stage III or IV disease. The distribution of patients by histology, stage, primary tumor site, and TN characteristic was similar to that observed in CWS-81⁴ with one exception: the male/female ratio was 1.3:1 in contrast to the CWS-81 study, where it was 2.5:1.

Statistical Methods
Prognosis was defined according to the duration of survival and event-free survival (EFS). Survival and EFS curves were estimated according to the Kaplan-Meier method.⁹ A failure was defined as relapse or death. The survival curves were calculated from the start of treatment in all stages. The duration of CR was defined as the period between the time CR was achieved until relapse or death occurred. The cutoff date for the statistical analysis was May 1998. The log-rank test (Mantel-Haenszel) was used to compare the survival curves of two groups that differ by a potential prognostic factor. A generalization of Gehan's generalized Wilcoxon test was used to compare three or more samples.^{10 2} tests were used for the comparison of frequency distribution of patients characteristics and to test differences in response and relapse numbers between groups of patients.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Pattern of Survival and Relapse
The Kaplan-Meier analysis showed 5-year overall survival and EFS rates of 69% ± 3% and 59% ± 3%, respectively, for all patients (Fig 2). The 5-year EFS rates according to disease stage were as follows: stage I, 83% ± 5%; stage II, 69% ± 6%; stage III, 57% ± 4%; and stage IV, 19% ± 6% (Fig 3). The EFS rates for the various pathologic entities differed, however, without reaching statistical significance for heterogeneity of groups: RMS, 60% ± 3%; EES/PNET, 47% ± 7%; and synovial sarcoma, 72% ± 9% (P = .09) (Fig 4). However, the difference between the two groups, ie, EES/PNET and synovial sarcoma, was significant (P = .039). The prognosis for patients with embryonal RMS was better than that for those with alveolar histology (5-year EFS rates, 67% ± 4% v 41% ± 6%, respectively; P = .01) (Fig 5). Three hundred forty-eight patients (94%) achieved a CR, and 238 patients (64%) are alive with no evidence of disease (Table 3). The proportion of patients in first CR was related to primary disease stage: 85%, 63%, 59%, and 24% for stages I, II, III, and IV, respectively (P < .000). The most common therapy failure was an isolated local relapse (LR), with 48 patients (14%) relapsing at the primary tumor site. The total local failure rate, ie, locoregional, isolated relapse, and LR combined with a systemic or lymph node relapse, was 20%. Thirty eight patients (11%) developed distant metastases as a first event.

View larger version (29K): [in this window] [in a new window]   Fig 2. Kaplan-Meier estimates of survival and EFS for all eligible patients.

View larger version (35K): [in this window] [in a new window]   Fig 3. Kaplan-Meier estimates of EFS according to stage.

View larger version (32K): [in this window] [in a new window]   Fig 4. Kaplan-Meier estimates of EFS according to histology.

View larger version (33K): [in this window] [in a new window]   Fig 5. Kaplan-Meier estimates of EFS according to subtype of RMS (eRMS, embryonal RMS; aRMS, alveolar RMS).

Outcome in Patients With Nonmetastatic STS
Of the 310 patients (97%) with nonmetastatic tumors who achieved CR, 83 (27%) relapsed (Table 4). The pattern of relapse differed between RMS and EES/PNET tumors. In RMS, isolated locoregional relapses dominated (59% of all relapses), in contrast to EES/PNET, where predominantly systemic failures were observed (isolated metastases and combined relapses, 58% of all failures; P = .04). In 26 patients with synovial sarcoma, only one LR but four isolated metastases occurred. The proportion of patients in first CR differed only slightly in patients with nonmetastatic tumors between the various histologic subtypes. The most favorable outcome was observed in synovial sarcoma (69%), followed by RMS (64%) and EES/PNET (62%). If the pattern of relapse between the two histologic subtypes of RMS (Table 5) is compared, alveolar RMS had a significantly higher overall incidence of relapse (43% v 23%; P = .003) and a higher rate of systemic (isolated and combined) failures (22% v 10%; P = .01). However, the proportion of patients in first CR did not differ significantly between histologic types (alveolar, 53% v nonalveolar, 66%) in nonmetastatic patients. Similarly, the proportion of patients surviving was not statistically different in nonalveolar versus alveolar type of RMS (75% v 64%; P = .54).

Prognosis According to Pretreatment Characteristics in Patients With Nonmetastatic RMS
Because prognosis differed between RMS, EES/PNET, and synovial sarcoma, an analysis of the relevance of pretreatment characteristics for prognosis was performed only in the group of RMS patients as the largest histologic group. The following patient- and tumor-related variables were considered: sex, age (< 5 years, 5 to 10 years, > 10 years), primary tumor site, histologic type (alveolar v nonalveolar), tumor size (< 5 cm v 5 cm), tumor invasiveness (T1 v T2), and involvement of regional lymph nodes (N0 v N1) based on clinical findings. The estimated 5-year EFS rate, analyzed according to the pretreatment characteristics of the 251 patients with nonmetastatic RMS, is listed in Table 6. Tumor invasiveness, age, and regional lymph node involvement had no impact on survival in contrast to sex, histology (alveolar RMS v nonalveolar RMS), primary tumor site, and tumor size when analyzing the whole group of patients with nonmetastatic RMS (stages I to III). Patients with a distinctly better prognosis were those with genitourinary non—bladder/prostate tumors (observed/expected failures [O/E] = 0.26), in contrast to tumors of the extremity (O/E = 1.36), head/neck nonparameningeal (O/E = 1.74), parameningeal (O/E = 1.2), and others (O/E = 1.23). However, the relation of single factors to prognosis differed according to disease stage. In stage I, only tumor size showed a correlation with survival, whereas nosignificant prognostic factors were identified instage II disease. Sex, primary tumor site, size, and histology (alveolar v nonalveolar) were relevant for prognosis in stage III disease.

Prognosis According to Pretreatment Characteristics in Patients With Metastatic STS
In 51 patients with primary metastatic tumors, the following factors were examined for their relevance to prognosis: age ( 10 years v > 10 years), histology (alveolar v nonalveolar RMS v EES/PNET), number and site of metastases (single-organ metastases v multiple-organ metastases), and bone/bone marrow metastases. In the univariate analysis (data not shown), no factor was significantly relevant for prognosis, despite a slightly better 5-year EFS rate in patients without bone/bone marrow metastases (24% ± 10% v 15% ± 7%; P = .25) and those younger than 10 years (30% ± 9% v 8% ± 5%; P = .09).

Response to Preoperative Chemotherapy and Relevance to Prognosis
The analysis of response to preoperative chemotherapy was conducted in patients who were treated according to the protocol and for whom complete data necessary for this evaluation was available. There were 147 assessable patients with macroscopic, residual tumor (stage III) who received chemotherapy before definitive local tumor control (Table 7). Thirteen percent of assessable patients were in CR, and 60% showed a good response after the first cycle of chemotherapy. The best EFS rate was observed in patients who showed a good response, but compared with patients in CR after one cycle of chemotherapy, there was no significant difference (5-year EFS rate, 67% ± 6% v 58% ± 11%). Because tumor size was found to be related to prognosis in the CWS-86 study as well as in the CWS-81 study,⁴ we analyzed survival according to tumor regression after one VAIA cycle and size of the primary tumor (Table 8). We found that one group, namely, patients with tumors less than 5 cm and with a complete or good response, had a distinctively better prognosis (77% ± 7%) than the other three groups. The chance of cure was similar for patients with large tumors (> 5 cm) who showed a good response to chemotherapy and those with small tumors (< 5 cm) with a poor response (54% ± 7% v 47% ± 13%). In contrast, the EFS rate after 5 years for patients with large tumors (> 5 cm) and a poor response was only 32% ± 12%. The degree of tumor volume regression was not analyzed in patients with stage IV disease because of inaccuracy of assessment in the case of multiple tumor manifestations, especially in patients with bone and bone marrow metastases.

Role of Salvage Chemotherapy
In the case of poor responders and nonresponders, salvage chemotherapy (see Patients and Methods) was proposed. However, compliance to this recommendation was very poor because only seven patients with a poor response (< two thirds one third) received the combination PIAV, and two patients who did not respond to the VAIA therapy received melphalan/novantrone or cisplatin/mitomycin (parameningeal). As a result, the role of salvage therapy cannot be assessed accurately.

Local Tumor Control in Nonmetastatic Patients
The analysis of the role of local therapy for prognosis was conducted in patients treated according to the protocol and for whom complete data were available. One hundred twelve patients underwent a primary resection of the tumor with (stage II) or without (stage I) positive margins (Table 9). Fourteen patients (28%) with stage I and 32 (51%) with stage II disease underwent irradiation. The total relapse rate did not differ between irradiated and nonirradiated patients with stage I disease (21% v 11%; P = .2). Similarly, the LR rate was only slightly better in irradiated patients (0% v 6%). In patients with positive margins, however, there was a statistically significant difference between irradiated and nonirradiated patients as far as the LR rate was concerned (6% v 37%; P < .0006). Fifteen patients received a dose of 32 Gy, and the LR rate was 13%.

Thirty-one patients with stage III disease did not receive radiotherapy, 16 because they were younger than 3 years. Ninety-seven percent achieved CR after chemotherapy and/or surgery. The total relapse rate was 40% in this group, with an isolated LR rate of 27% representing the major cause of treatment failure. In patients who underwent irradiation, the total relapse rate was 28% (P = .2) with an LR rate of 10% (P < .001). The median time to the beginning of radiotherapy was 94 days. Sixty-six percent of patients received preoperative radiotherapy. In 67 patients with stage III disease who received radiotherapy at a dose of 25 to 35 Gy (60 patients received 32 Gy), the LR rate was 13%; in 49 patients who received a dose greater than 35 Gy (27 patients received 54 Gy), the LR rate was 7% (nonsignificant; Table 10). Patients who received early preoperative radiotherapy after showing a good response to chemotherapy had an excellent 5-year EFS rate of 67% ± 6%.

Toxicity
There were 10 therapy-related deaths (2.7%) in patients in first CR (Table 11). Another three patients died during therapy for relapse or progression as a result of treatment-related complications (ie, intracranial bleeding, hemolytic-uremic syndrome, infection).

Nine patients (2.4%), three with stage I and six with stage III disease, developed a secondary malignancy (one malignant fibrous histiocytoma, one osteosarcoma, two astrocytoma, two acute myeloblastic leukemia, two acute lymphoblastic leukemia, and one colon carcinoma) 3 to 4 years after diagnosis of RMS, and five died as a result.

Six patients (1.6%) developed cardiac abnormalities that were defined by the treating physicians as cardiomyopathy. These patients had received a cumulative dose of doxorubicin of 240 to 320 mg/m²; one died because of cardiac insufficiency.

In 210 patients, an assessment of the glomerular, proximal, and distal renal tubular function was performed. At the time of diagnosis, all of the children had normal renal function. The cumulative dose of ifosfamide ranged from 20 to more than 100 g/m². A total of 59 patients (27%) had evidence of proximal tubular damage. Twelve children (6%) developed a Fanconi-like syndrome that required oral supplementation. These patients had received a cumulative dose of ifosfamide of more than 60 g/m², and nine of 12 were younger than 4 years. However, five patients had an intraabdominal tumor, four of whom were treated with abdominal radiotherapy. In addition, 13 patients showed evidence of glomerular damage.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Based on the results of the CWS-81 study, the CWS-86 study was designed to address a number of new issues. One of the aims was to modify the chemotherapy with respect to the length of treatment. Ifosfamide was introduced in place of cyclophosphamide based on data showing that ifosfamide seemed to be a more effective agent in the treatment of some pediatric tumors and the fact that we wanted to evaluate the role of ifosfamide in the treatment of STS.^11,12 A four-drug regimen similar to that used in the CWS-81 study was recommended for all clinical stages, but the duration of treatment was reduced. A new concept for the application and stratification of radiotherapy was developed for local tumor control. Despite the reduction of the chemotherapy, the overall results were slightly better in comparison to the CWS-81, with 5-year overall survival and EFS rates of 69% ± 3% and 59% ± 3% versus 61% ± 4% and 57% ± 4%, respectively.⁴ Similarly, the prognosis according to clinical stage did not differ in comparison to the CWS-81 study.⁴ Although the overall results of treatment in CWS-86 only improved slightly, a number of new aspects in the management of STS became evident when the different stages were analyzed separately.

The prognosis for patients with stage I disease was very good, with a 5-year EFS rate of 83% ± 5%, comparable to other published pediatric studies.^1-3For patients whose disease was totally resectable, a four-drug regimen similar to that used in the CWS-81 study was recommended. However, cyclophosphamide was replaced by ifosfamide, and the dose-intensity of doxorubicin was reduced from 15 mg/m²/wk to 10 mg/m²/wk, whereas it was increased for both dactinomycin (0.342 v 0.375 mg/m²/wk) and vincristine (0.6 v 0.9 mg/m²/wk). It is not possible to draw any conclusions about the contribution of ifosfamide to the success of treatment for patients with stage I disease. A number of clinical trials (IRS I, IRS II, and IRS III) did not include either alkylating agents or anthracyclines in the treatment of patients with stage I RMS and EES with good prognoses, but they were treated over a longer period (up to 2 years), thus resulting in a higher cumulative doses of vincristine and dactinomycin than in the CWS study.^1-3 The results for stage I disease have not been analyzed according to histology because the predominant group was embryonal RMS, and other histologic entities accounted for only a few cases. Because there was no clear evidence that ifosfamide contributed to the good prognosis of these patients, a four-drug combination with dose-intensities for vincristine, dactinomycin, and doxorubicin similar to that in the CWS-86 study, and with cyclophosphamide replacing ifosfamide (similar to the CWS-81 study), was recommended for stage I disease in the CWS-91 study, with the exception of patients with parameningeal and extremity primary tumor sites. In addition, the duration of treatment was reduced to 10 weeks. A preliminary analysis of the CWS-91 study has not demonstrated any statistically significant difference in prognosis; in particular, there was no increase in the LR rate (data not shown). The data from the Italian Cooperative Group (ICG RMS 88), which treated patients with stage I disease with a 16-week regimen of vincristine and dactinomycin, showed similar results to those in the CWS and IRS Studies (M. Carli, personal communication, October 1998). It can be concluded that for the majority of patients with stage I disease, treatment with two drugs (vincristine/dactinomycin) for approximately 20 weeks is sufficient. In the current CWS-96 study, a two-drug regimen of vincristine and dactinomycin for 20 weeks has been recommended for a group of patients with a very good prognosis with embryonal histology and stage I, pT1, the aim being to maintain the same good results but to avoid the probability of late toxicity (cardiotoxicity, tubulopathy, infertility, and second malignancies).

The 5-year EFS rate in patients with stage II disease was slightly worse in the CWS-86 study compared with the CWS-81 study (69% ± 6% v 88% ± 5%), but the difference was not significant. The chemotherapy duration was reduced to 26 weeks compared with 35 weeks in the CWS-81 study. However, the cumulative doses of vincristine, dactinomycin, and doxorubicin were almost identical in both studies. The cumulative dose of ifosfamide was 54 g/m² versus 10.8 g/m² for cyclophosphamide in the CWS-81 study; therefore, the ifosfamide/cyclophosphamide dose ratio was 5:1. Whether the use of an anthracycline improved the prognosis for stage II disease is not clear. In the IRS III study, there was a randomized comparison of vincristine and cyclophosphamide versus vincristine, cyclophosphamide, and doxorubicin for selected patients in clinical group II (almost identical to stage II in the CWS studies). There was an improvement in prognosis for patients treated with doxorubicin, but the statistical analysis was inconclusive.³ The prognosis for nonirradiated patients with stage II disease in the CWS-86 study was worse than in the CWS-81 (total relapse rate, 40% v 19%; P > .5), but the difference is not statistically significant. Both chemotherapy regimens (VACA for 35 weeks in the CWS-81 and VAIA for 26 weeks in the CWS-86) seem to be of comparable efficacy. In the CWS-86 protocol, it was stipulated that only patients with stage II disease with tumors of the extremity or with associated bone erosion should be irradiated. Thirty-two patients (51%) with stage II disease received radiotherapy. The LR rate was 6% in irradiated patients and 37% in nonirradiated patients (P < .0006). Even if the difference in total relapse rate was not significant (19% v 40%; P = .069), this is clear evidence that patients with positive margins require radiotherapy. However, it should be emphasized that there were 19 of 30 patients with stage II disease who did not undergo irradiation and remained in continuous CR. For patients who did not undergo irradiation and who relapsed locally, there was still a possibility of cure; nine of 11 have remained in second CR (data not shown). This raises the question about the best stratification criteria for radiotherapy in stage II disease. Unfortunately, neither the CWS-86 study nor other published studies have been able to answer this question clearly. In IRS studies, because all patients with stage II disease underwent irradiation,^1-3 it is not possible to define accurately a group of patients with positive margins after resection of STS who did not require radiotherapy. The median radiation dose for patients with stage II disease was 44.5 Gy in the CWS-86 study. Fifteen patients underwent irradiation at a dose of 32 Gy. Similarly, in the IRS I study, the patients with stage II disease underwent irradiation at a dose of 50 to 60 Gy, and in the IRS II study, they received 40 to 45 Gy without an increase in the relapse rate.³ It seems that the majority of patients with unclear margins can undergo irradiation with a reduced dose (32 to 40 Gy).

Stage II disease, defined as grossly resected tumor with microscopic residual disease, is a very heterogeneous group with respect to primary tumor site, which includes both paratesticular and localized parameningeal and TN characteristics. The decision to classify a tumor postoperatively as stage II is very subjective and fraught with error. Even if standard recommendations concerning primary and secondary surgical procedures had been defined in the CWS-86 study, some patients underwent surgery before entry to the protocol by surgeons without major oncologic experience, particularly with respect to pediatric tumors. After inadequate primary surgery, it is very difficult to assess the margins precisely. It is noteworthy that the majority of LRs (85%) occurred in patients with a primary tumor in the head/neck region, stressing the differences in quality of surgical/pathologic assessment of tumor control depending on site. What lesson can be learned from the CWS-86 study for patients with unclear margins after primary resection? The results achieved with the VAIA regimen for 26 weeks and a reduced dose of radiotherapy in the CWS-86 study are comparable to the previous CWS-81 study and to the IRS studies that included a much higher cumulative dose of alkylating agents and vincristine and in which a larger proportion of patients underwent irradiation to a higher dose.^1-3 The role of doxorubicin in the treatment of RMS-like tumors remains unclear. In the subsequent German study (CWS-91), the chemotherapy was further reduced to 14 weeks (VACA). The preliminary analysis showed no deterioration in the results in comparison to the CWS-86 study (internal analysis, data not shown). In the current CWS-96 study, a selected group of patients with stage II disease is treated over a longer period (25 weeks) but without doxorubicin.

Sixty percent of the localized tumors were not resectable at diagnosis. For those patients, preoperative chemotherapy was recommended, and the secondary local therapy was stratified according to tumor volume regression after one cycle of chemotherapy. The replacement of cyclophosphamide with ifosfamide in the CWS-86 study was based on preliminary data showing the efficacy of this drug in sarcomas of soft tissue and bone and the superiority of ifosfamide over its parent compound, cyclophosphamide, in vitro.^11-13 Because the degree of tumor volume reduction after one cycle has been shown in the CWS-81 study to be related to prognosis, the goal of intensifying the chemotherapy was to increase the number of patients with a complete or good response and thereby reduce the number of patients requiring radiotherapy and/or extended surgery. Because of the slower rate of initial four-carbon ring hydroxylation, the dose of ifosfamide used is higher than that of cyclophosphamide.¹⁴ Equivalent doses of ifosfamide are three or four times greater than those of cyclophosphamide as determined by measurement of alkylating activity in plasma and urine.¹⁵ However, experiments in animal models showed a comparable cytotoxic effect of ifosfamide versus cyclophosphamide with a dose ratio of 2:1.¹³ The cumulative dose of ifosfamide was 18 g/m² per cycle in comparison to 3.6 g/m² of cyclophosphamide in the CWS-81 study, ie, a dose ratio of 5:1. If we compare the efficacy of ifosfamide versus cyclophosphamide by comparing the response rates measured by tumor volume reduction in the CWS-86 versus CWS-81 studies, the "gain" was observed in a higher proportion of patients with two thirds tumor volume reduction (55% v 31%; P > .001) with a reduction in the proportion of so-called poor responders, ie, those with a tumor volume reduction of one third but less than two thirds.¹⁶

The percentage of patients with stage III disease who underwent irradiation was similar in the CWS-86 and CWS-81 studies (79% v 77%); therefore, the introduction of ifosfamide did not reduce the proportion of irradiated patients, and the prognosis for nonirradiated patients did not improve. However, the median radiotherapy dose was much lower in the CWS-86 study compared with the CWS-81 study (32 Gy v 40 Gy). The local failure rate in patients with stage III disease was lower in the CWS-86 study than in the CWS-81 study (14% v 44%; P < .001). The prognosis for patients with stage III disease analyzed according to the intent-to-treat principle did not improve in the CWS-86 study in comparison to CWS-81 study, but patients treated strictly according to the protocol who showed a good response to preoperative chemotherapy followed by radiotherapy had an excellent prognosis, with an EFS rate of 67% ± 6% (v 45% ± 11% in the CWS-81 study; data not shown). Because the prognosis for patients without radiotherapy did not improve in the CWS-86 study, one can speculate that the better prognosis in irradiated patients was a result of the better concept of definitive local therapy in the CWS-86 study. The following factors should be considered as potentially influencing the improvement of local tumor control: earlier, preoperative application of radiotherapy; acceleration and hyperfractionation; and simultaneous radiotherapy and chemotherapy. The adaptation of the cumulative dose to response to chemotherapy allowed a dose reduction with amelioration of local tumor control. In the IRS studies, early local therapy in patients with stage III disease was also found to be favorable for prognosis.³ The concept of the stratification of local therapy from the CWS-86 study was continued but with minor modifications in the subsequent CWS studies (-91 and -96).

The univariate analysis showed sex, primary tumor site, histology, and tumor size as relevant for prognosis. Similar pretreatment parameters were found by other investigators to be related to prognosis^1,17,18

A fatal outcome caused by myelosuppression and infection was a rare event (1.6%), and the overall rate of therapy-related deaths for patients in first CR was not much higher (2.7%).

Nine patients (2.4%), three with stage I and six with stage III disease, developed a secondary malignancy (malignant fibrous histiocytoma, osteosarcoma, astrocytoma, acute leukemia, and colon carcinoma) 3 to 4 years after diagnosis of RMS, and five patients died as a result. Heyn et al¹⁹ reported a 1.7% cumulative incidence of second malignant neoplasm in children treated for RMS in the IRS studies. In the majority of patients examined by Heyn et al for whom family histories were available, there was either a history of neurofibromatosis or a family history suggesting the Li-Fraumeni syndrome.

Six patients (1.6%) developed cardiac abnormalities, one of whom has died as a result. The patients had received a cumulative dose of 240 to 320 mg/m² doxorubicin. The IRS III study reported cardiac damage after doxorubicin therapy in 9% of patients, which was severe in 5%.³ Casper et al²⁰ observed cardiotoxicity in 61% of patients who received doxorubicin as a bolus after a median doxorubicin doses of 420 mg/m² and in 42% of patients who received doxorubicin as a continuous infusion with a median dose of 540 mg/m². This very high cardiotoxicity is probably related to the higher age (median, 50 years) and higher cumulative dose of doxorubicin. However, depending on the method used for defining cardiac abnormalities, a very high percentage of late, anthracycline-related cardiotoxicity was reported in survivors of childhood acute lymphoblastic leukemia.²¹

Six percent of the children developed a Fanconi-like syndrome. However, five had an abdominal tumor, and four received abdominal radiotherapy; therefore, additional factors probably contributed to the development of renal damage. The cumulative dose of ifosfamide in these patients was more than 60 g/m², and nine of 12 were younger than 4 years. It is well known that a higher cumulative dose of ifosfamide and young age is associated with an increased risk of developing renal damage. Other groups reported a similar incidence of ifosfamide-related nephrotoxicity.²² Because there was no clear evidence that the replacement of cyclophosphamide with ifosfamide in the CWS-86 study produced an improvement in results, and the incidence of nephrotoxicity was relatively high, a decision was made to reintroduce cyclophosphamide in place of ifosfamide in the CWS-91 study for better prognostic groups of patients.

In conclusion, by addressing the main objectives of the CWS-86 study, the following statements can be made:

1. Adjuvant chemotherapy for primary, resectable tumors was reduced to 16 weeks for patients with stage I disease and 26 weeks for those with stage II disease, compared with 35 weeks in the CWS-81 study, without compromising survival. It is unclear whether the replacement of cyclophosphamide with ifosfamide in the four-drug cycle played a role. The cumulative doses of cytostatic agents have been reduced, which could be important in relation to the development of late toxic effects such as second malignancies, organ damage, and infertility.

2. The replacement of cyclophosphamide by ifosfamide in the four-drug cycle (VAIA instead of VACA) improved the response in patients with macroscopic residual tumor by increasing the proportion of patients with a reduction in tumor volume two thirds.

3. Reduction in tumor volume after preoperative chemotherapy combined with tumor size in patients with residual tumor can be used as a basis for risk-adapted radiotherapy.

4. Early (10 to 13 weeks), hyperfractionated, accelerated radiotherapy given simultaneously with chemotherapy improved local tumor control in patients with a good response after preoperative chemotherapy.

5. The radiation dose of 32 Gy, when accelerated and hyperfractionated, given simultaneously with chemotherapy is adequate for local tumor control in patients who show a good response to preoperative chemotherapy. Whether the same principle can be applied to each histologic entity cannot be answered on the basis of this study.

	APPENDIX

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Institutions Participating in the German Cooperative Soft Tissue Sarcoma Study CWS-86
The following institutions participated in German Cooperative Soft Tissue Sarcoma Study CWS-86: Universitätskinderklinik, Aachen; Kinderklinik des KZVA, Augsburg; Caritaskrankenhaus, Bad Mergentheim; Städt. Krankenanstalten, Bayreuth; Universitätskinderklinik, Berlin; Universitätskinderklinik, Bonn; Städt. Kinderkrankenhaus, Braunschweig; Kinderklinik Jürgenstraße, Bremen; Allg. Krankenhaus, Celle; Vestische Kinderklinik, Datteln; Kinderklinik, Dortmund; Medizin. Univ. Klinik, Düsseldorf; Universitätskinderklinik, Düsseldorf; St Johannes-Hospital, Kinderklinik, Duisburg; St Johannes-Hospital, Medizinische Klinik, Duisburg; Universitätskinderklinik, Erlangen; Universitätskinderklinik, Essen; Universitätskinderklinik, Frankfurt; Universitätskinderklinik, Freiburg; Städt. Kinderklinik, Fulda; Universitätskinderklinik, Giessen; Universitätskinderklinik, Göttingen; Universitätskinderklinik, Hamburg; Kinderklinik St Elisabeth, Hamm; Märkische Kinderklinik, Hamm; Kinderklinik der Medizinische Hochschule Hannover, Hannover; Universitätskinderklinik, Heidelberg; Universitätskinderklinik, Homburg/Saar; Krankenhaus Bethanien, Iserlohn; Städt. Kinderklinik, Karlsruhe; Medizinische Klinik, Karlsruhe; Städt. Kinderklinik, Kassel; Universitätskinderklinik, Kiel; Städt. Krankenanstalten, Köln; Universitätskinderklinik, Köln; Städt. Krankenanstalten, Krefeld; Universitätskinderklinik, Lübeck; Kreiskrankenhaus, Lüdenscheid; Universitätskinderklinik, Mainz; Universitätskinderklinik, Mannheim; Universitätskinderklinik, Marburg; Kinderabteilung, München/Harlaching; Universitätskinderklinik, München/Schwabing; Dr. von Haunersche's Kinderspital, München; Universitätskinderpolikl, München; Universitätskinderklinik, Münster; Cnopf'sche Kinderklinik, Nürnberg; Städt. Kinderklinik, Saarbrücken; DRK-Kinderklinik, Siegen; Johanniter-Kinderklinik, St Augustin; Olgahospital, Stuttgart; Krankenhaus der Barmherzigen Brüder, Trier; Mutterhaus der Borromäerinnen, Trier; Universitätskinderklinik, Tübingen; Universitätskinderklinik, Ulm; Universitätskinderklinik, Würzburg; and Klinikum Barmen, Wuppertal, Germany.

Reference pathologists of the CWS-86 study: D. Harms, MD (Kiel) and M. Altmannsberger, MD (Göttingen).

	ACKNOWLEDGMENTS

 
Supported by grant no. 01Z80831/82 from the Federal Ministry of Research and Technology, Bonn, and grant no. M34/8 from the German Cancer Aid Foundation, Bonn, Germany.

We thank Iris Veit and Erika Halmen for excellent data management and our colleagues from participating centers.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
1. Maurer HM, Beltangady M, Gehan EA, et al: The Intergroup Rhabdomyosarcoma Study I: A final report. Cancer61:209-220, 1988[Medline]

2. Maurer HM, Gehan EA, Beltangady M, et al: The Intergroup Rhabdomyosarcoma Study II. Cancer71:1904-1922, 1993[Medline]

3. Crist W, Gehan EA, Ragab AH, et al: The third Intergroup Rhabdomyosarcoma Study. J Clin Oncol13:610-630, 1995[Abstract/Free Full Text]

4. Koscielniak E, Jürgens H, Winkler K, et al: Treatment of soft tissue sarcoma in childhood and adolescence: A report of the German Cooperative Soft Tissue Sarcoma Study. Cancer70:2557-2567, 1992[Medline]

5. Treuner J, Flamant F, Carli M: Results of treatment of rhabdomyosarcoma in the european studies, in Maurer HM, Ruymann FB, Pochedly C (eds): Rhabdomyosarcoma and Related Tumors in Children and Adolescents. Boca Raton, FL, CRC Press, 1991, pp 227-241

6. Harmer MH (ed): TNM Classification of Pediatric Tumors. Geneva, Switzerland, Union International Contre le Cancer, 1982, pp 23-28

7. Simon R, Wittes RE: Methodologic guidelines for reports of clinical trials. Cancer Treat Rep69:1-2, 1985[Medline]

8. Harms D, Schmidt D: Classification of solid tumors in children: The Kiel Pediatric Tumor Registry Falkner F Kretchmer N Rossi E(eds): Monographs in Paediatrics1-18Basel, Switzerland, S Karger, 1986

9. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc53:457-481, 1958

10. Gehan EA: A generalized Wilcoxon test for comparing arbitrarily single-censored samples. Biometrika52:203-223, 1965a[Abstract/Free Full Text]

11. De Kraker J, Voute PA: Experience with ifosfamide in paediatric tumours. Cancer Chemother Pharmacol24:28-29, 1989 (suppl) [Medline]

12. Voute PA, J de Kraker: Ifosfamide in pediatric oncology. Semin Oncol19:2-7, 1992[Medline]

13. Brock N: The oxazaphosphorines. Cancer Treat Rev10:3-12, 1983

14. Brock N: Oxazaphosporine cytostatics: Past-present-future. Cancer Res49:1-7, 1989[Abstract/Free Full Text]

15. Zalupski M, Baker LH: Ifosfamide. J Natl Cancer Inst80:556-566, 1988[Abstract/Free Full Text]

16. Carli M, Trener J, Koscielniak E, et al: Ifosfamide, more is better? 6g vs. 9 g/m² in VAIA may influence tumor response rate in childhood rhabdomyosarcoma? The experience of the German (CWS-86) and the Italian (ICS RMS 88) cooperative studies. Proc Natl Acad Sci U S A11:319, 1991 (abstr)

17. Rodary C, Gehan EA, Flamant F, et al: Prognostic factors in 951 non-metastatic rhabdomyosarcoma in children: A report from the International Rhabdomyosarcoma Workshop. Med Pediatr Oncol19:89-95, 1991[Medline]

18. Crist WM, Garnsey L, Beltangady M, et al: Prognosis in children with rhabdomyosarcoma: A report of the Intergroup Rhabdomyosarcoma Studies I and II. J Clin Oncol8:443-452, 1990[Abstract]

19. Heyn R, Haeberlen V, Newton WA, et al: Second malignant neoplasm in children treated for rhabdomyosarcoma. J Clin Oncol11:262-270, 1993[Abstract/Free Full Text]

20. Casper ES, Gaynor JJ, Hajdu SI, et al: A prospective randomised trial of adjuvant chemotherapy with bolus vs.continuous infusion of doxorubicin in patients with high-grade extremity soft tissue sarcoma and analysis of prognostic factors. Cancer68:1221-1229, 1991[Medline]

21. Sorensen K, Levitt G, Bull C, et al: Anthracycline dose in childhood acute lymphoblastic leukemia: Issues of early survival versus late cardiotoxicity. J Clin Oncol15:61-68, 1997[Abstract/Free Full Text]

22. Ho PT Zimmerman K, Wexler LH, et al: A prospective evaluation of ifosfamide-related nephrotoxicity in children and young adults. Cancer64:2557-2564, 1995

Submitted February 9, 1999; accepted July 22, 1999.

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