Cooperative Trial CWS-91 for Localized Soft Tissue Sarcoma in Children, Adolescents, and Young Adults

  1. Ewa Koscielniak
  1. From the Olgahospital, Pediatrics 5 (Oncology, Hematology, and Immunology), and Katharinenhospital, Department of Radiotherapy, Klinikum Stuttgart; Department of Plastic Surgery and Hand Surgery, Marienhospital, Stuttgart; Institute of Pediatric Pathology, University of Kiel, Kiel; Department of Radiotherapy, University of Regensburg, Regensburg; Department of Pediatric Hematology and Oncology, University Children's Hospital Muenster, Muenster; Department of Pediatric Oncology, University of Tuebingen, Tuebingen; Department of Pediatric Oncology, University of Frankfurt (Main), Frankfurt; Asklepios Kinderklinik, St Augustin; Department of Maxillofacial Surgery, University of Hamburg, Hamburg, Germany; St Anna Kinderspital, Vienna, Austria; Ostschweizer Kinderspital, St Gallen, Switzerland; and the Queen Silvia Children's Hospital, Goeteborg, Sweden.
  1. Corresponding author: Tobias M. Dantonello, MD, Olgahospital, Pediatrics 5 (Oncology, Hematology, and Immunology), Klinikum Stuttgart, Bismarckstrasse 8, D-70176 Stuttgart, Germany; e-mail: tobias.dantonello{at}olgahospital-stuttgart.de.

  1. Presented in part at the 38th Congress of the International Society of Pediatric Oncology, September 17-21, 2006, Geneva, Switzerland.

 
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Abstract

Purpose To improve risk-adapted therapy for localized childhood soft tissue sarcoma within an international multicenter setting.

Patients and Methods Four hundred forty-one patients younger than 21 years with localized rhabdomyosarcoma and rhabdomyosarcoma-like tumors (ie, extraosseous tumors of the Ewing family, synovial sarcoma, and undifferentiated sarcoma) were eligible. Therapy was stratified according to postsurgical stage, histology, and tumor site. In unresectable tumors, treatment was further adapted depending on response to induction chemotherapy, TN classification, tumor size and second-look surgery. A novel five-drug combination of etoposide, vincristine, dactinomycin, ifosfamide, and doxorubicin (EVAIA) was evaluated for high-risk patients, but cumulative chemotherapy dosage and treatment duration were reduced for the remaining individuals as compared with that of the previous trial CWS-86. Hyperfractionated accelerated radiotherapy (HART) was recommended at doses of either 32 or 48 Gy.

Results At a median follow-up of 8 years, 5-year event-free survival (EFS) and overall (OS) survival for the entire cohort was 63% ± 4% and 73% ± 4%, respectively (all survival rates in this abstract are calculated and displayed with ±95% CI). EFS/OS rates by histology were 60% ± 5%/72% ± 5% in rhabdomyosarcoma, 62% ± 10%/69% ± 10% for Ewing tumors of soft tissues, 84% ± 12%/90% ± 10% for synovial sarcoma, and 67% ± 38%/83% ± 30% for undifferentiated sarcoma, respectively. Response to one cycle of the five-drug combination EVAIA was similar to that of the four-drug combination VAIA used in CWS-86. Two hundred twelve patients with rhabdomyosarcoma underwent radiation (EFS, 66% ± 6%); 53 of those patients had a favorable risk profile and received 32 Gy of HART (EFS, 73% ± 12%). TN classification, tumor site, tumor size, histology, and age were prognostic in univariate analysis.

Conclusion Improved risk stratification enabled decreased therapy intensity for selected patients without compromising survival. Intensified chemotherapy with EVAIA did not improve outcome of localized high-risk rhabdomyosarcoma.

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INTRODUCTION

Approximately 7% of childhood cancers are soft tissue sarcomas (STS).1 Rhabdomyosarcoma (RMS) constitutes the majority, being the fourth most common solid malignancy and predominantly affecting children younger than 5 years of age.2 Multimodal therapy and supportive care administered in the framework of cooperative clinical trials3–7 has improved survival rates from 25% in 1970 to 70% within 20 years.8

Although cure rates have increased, the price of survival has become an increasing matter of concern. Approximately half of adult sarcoma survivors have at least one major adverse outcome on their health status and are predisposed to late morbidity/early mortality.9–11 Therefore, the challenge is to develop more effective and less toxic treatment. Finding the optimal middle way between effectiveness and tolerability is a difficult balancing act, because adjustment requires consideration of young age, histologic heterogeneity, treatment multimodality, and late sequelae.

The goal of the third consecutive international Cooperative Weichteilsarkom (CWS) trial was therefore to improve survival as well as long-term quality of life. CWS-91 introduced a novel stratification system for primary and secondary treatment-to-prognosis tailoring: patients were grouped into risk groups not only according to postsurgical group (as in CWS-865) but also according to localization and histology. In primary unresected tumors, treatment was adjusted after induction chemotherapy depending on response, TN classification, tumor size, and second-look surgery.

CWS-91 aimed to evaluate whether the outcome of patients with a favorable risk profile can be maintained despite reduced chemotherapy dosage, therapy duration, and substitution of ifosfamide with cyclophosphamide; whether addition of etoposide improves response to induction chemotherapy and outcome in high-risk patients; whether patients with primary unresectable tumors benefit from improved secondary stratification after induction chemotherapy; whether risk-adapted radiotherapy with a reduced dose of 48 Gy hyperfractionated accelerated radiotherapy (HART) can maintain local control in high-risk patients compared with 54.4 Gy in CWS-86; and whether 32 Gy of HART can maintain similar local control in favorable subsets of patients.

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PATIENTS AND METHODS

Patients

Eligibility criteria were age younger than 21 years, no prior therapy or previous malignancy, localized disease, and diagnosis confirmed by pathologic review according to published criteria.12 CWS-91 was approved by the appropriate ethics and review committees. Informed consent was obtained from all patients, guardians, and/or parents.

Definitions and Risk Stratification

Patient data included age and sex. Tumor-related information comprised histology, tumor size, and site (orbit [ORB], head/neck nonparameningeal [HN-nPM] and parameningeal [HN-PM], genitourinary bladder–prostate [GU-BP] and nonbladder–prostate [GU-nBP], extremities [EXT], and others [OTH]). The staging system was adapted from the Intergroup Rhabdomyosarcoma Study (IRS) Group (IRSG) and the International Union Against Cancer TN classification.3,13 At diagnosis, patients were grouped into three risk groups (A, B, and C) according to tumor localization and IRSG. In IRSG-III patients, tumor volume was measured initially and after the first cycle of chemotherapy by local institutions without central review: volume regression was coded as ≥ 66% versus less than 66%; less than 33% regression was defined as nonresponse. If nonmutilating second-look surgery was possible, it was recommended after the first cycle. The postsurgical stage after second-look surgery was coded according to IRSG (ps). After response assessment, patients were reclassified in advantageous, disadvantageous, and nonresponder subgroups with respect to response, tumor size, and TN classification (Appendix Table A1, online only; Fig 1).

Fig 1.
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Fig 1.

Treatment stratification of CWS-91 (nonresponders not displayed). Risk Group A included all patients in Intergroup Rhabdomyosarcoma Study Grouping (IRSG) I, apart those with from extremities (EXT) and head/neck parameningeal (HN-PM) tumors. Chemotherapy was as follows: one cycle of vincristine, dactinomycin, cyclophosphamide, and doxorubicin (VACA-II; cumulative chemotherapy dosage: cyclophosphamide 4.8 g, doxorubicin 120 mg, dactinomycin 3 mg, vincristine 6 mg; duration of therapy: 10 weeks. In comparison with IRSG-I in CWS-86: 25% to 60% reduction of chemotherapy, 38% reduction of treatment duration [Appendix Table A1, online only]). Radiotherapy was as follows: IRSG-I patients did not undergo radiation, apart from those with tumors with unfavorable histology (alveolar rhabdomyosarcoma [RMA], synovial sarcoma [SySa], and extraosseous Ewing tumors [EES/pPNET]) and EXT tumors, who received 48 Gy of hyperfractionated accelerated radiotherapy (HART). Radiotherapy was also compulsory for patients with HN-PM tumors; the dosage depended on patient age, presence of intracranial tumor extension (ICE), and involvement of CSF: the tumor was irradiated with 48 Gy. A total of 32 Gy were administered to the skull base (CSF- and ICE-negative), skull (CSF-negative, ICE), and neuraxis (CSF-positive). Children younger than 1 year did not undergo radiation, and patients younger than 3 years received 24 Gy. Risk Group B included IRSG-I patients with EXT and HN-PM tumors, all IRSG-II, and IRSG-III patients with orbit (ORB; since March 1994, patients with ORB tumors received etoposide, vincristine, dactinomycin, ifosfamide, and doxorubicin [EVAIA] initially) and genitourinary nonbladder–prostate (GU-nBP) tumors. Chemotherapy was as follows: IRSG-I, IRGS-II, and advantageous (IRSG-III T1aN0 tumors with any response to induction chemotherapy and T1bN0 and T2aN0 tumors with good response [≥ 66% tumor volume reduction]) IRSG-III patients: two cycles of VACA-II (cumulative chemotherapy dosage: cyclophosphamide 9.6 g, doxorubicin 240 mg, dactinomycin 6 mg, and vincristine 12 mg; duration of therapy: 23 weeks). Disadvantageous (IRSG-III T1bN0 and T2aN0 tumors with poor response [< 66% volume reduction], T2bN0 tumors with any response, and all N1 tumors) IRSG-III: one cycle of VACA-II and two cycles of EVAIA (cumulative chemotherapy dosage: cyclophosphamide 4.8 g, doxorubicin 360 mg, dactinomycin 9 mg, ifosfamide 48 g, vincristine 18 mg, and etoposide 3.6 g; duration of therapy: 35 weeks). In comparison of IRSG-II in CWS-91 with IRSG-II in CWS-86: 0% to 47% reduction of chemotherapy, 12% reduction of treatment duration (Appendix Table A1). In comparison of advantageous IRSG-III in risk group B with IRSG-III in CWS-86: 25% to 60% reduction of chemotherapy, 36% reduction of treatment duration (Appendix Table A1). In comparison of disadvantageous IRSG-III in risk group B with IRSG-III in CWS-86: chemotherapy dose alterations ranging between 40% reduction, 13% increase, and addition of etoposide, 3% reduction of treatment duration (Appendix Table A1). Radiotherapy was as follows: radiation with 48 Gy of HART was compulsory for patients having tumors with unfavorable histology (RMA, SySa, EES/pPNET) and EXT tumors. Radiation for patients with HN-PM tumors was also compulsory, depending on a site-specific guideline (see above). IRSG-II patients did not undergo radiation if the tumor was completely resected at second-look surgery (IRSG-Ips). A total of 32 Gy of HART was prescribed for IRSG-II patients without second-look surgery or in case of secondary microscopic residual disease (IRSG-IIps). IRSG-III of the advantageous subgroup (ie, IRSG-III T1aN0-tumors with any response to induction chemotherapy and T1bN0/T2aN0 tumors with ≥ 66% tumor volume reduction) received 32 Gy if no second-look surgery was performed or in case of residual disease after second-look surgery (IRSG-IIps and IRSG-IIIps). IRSG-III patients of the disadvantageous subgroup (ie, IRSG-III T1bN0/T2aN0 tumors with < 66% volume reduction, T2bN0 tumors with any response, and all N1 tumors) received 48 Gy of radiation. Risk Group C included IRSG-III patients, apart from those with ORB and GU-nBP sites. Chemotherapy was as follows: advantageous IRSG-III (ie, IRSG-III T1aN0 tumors with any response to induction chemotherapy, T1bN0/T2aN0 tumors with ≥ 66% tumor volume reduction): one cycle of EVAIA and one cycle of VACA-II (cumulative chemotherapy dosage: cyclophosphamide 4.8 g, doxorubicin 240 mg, dactinomycin 6 mg, ifosfamide 24 g, vincristine 12 mg, and etoposide 1.8 g; duration of therapy: 23 weeks. In comparison with IRSG-III in CWS-86: 25% to 60% reduction of chemotherapy and addition of etoposide, 36% reduction of treatment duration). Disadvantageous IRSG-III: three cycles of EVAIA (etoposide 5.4 g, doxorubicin 360 mg, vincristine 18 mg, ifosfamide 72 g, and dactinomycin 9 mg; duration of therapy: 35 weeks). In comparison with IRSG-III in CWS-86: chemotherapy dosage alterations ranging between 40% reduction, 13% increase, and addition of etoposide, 3% reduction of treatment duration (Appendix Table A1). Radiotherapy: radiation with 48 Gy of HART was compulsory for tumors with unfavorable histology (RMA, SySa, EES/pPNET) and EXT tumors. The radiotherapy dosage for HN-PM tumors did depend on a site-specific guideline (see above). IRSG-III patients did not undergo radiation if the tumor was completely resected at second-look surgery (IRSG-Ips). IRSG-III of the advantageous subgroup received 32 Gy if no second-look surgery was performed or in case of residual disease remaining after second-look surgery (IRSG-IIps and IRSG-IIIps). IRSG-III patients of the disadvantageous subgroup received 48 Gy of radation. T1, tumor confined to organ or tissue of origin (T1a, tumor ≤ 5 cm in greatest dimension; T1b, tumor > 5 cm). T2, tumor not confined to organ or tissue of origin (T2a, tumor ≤ 5 cm in greatest dimension; T2b, tumor > 5 cm in greatest dimension).

Treatment

Systemic treatment depended on risk group assignment and included either four (vincristine, dactinomycin, cyclophosphamide, and doxorubicin [VACA-II]) or five drugs (etoposide, vincristine, dactinomycin, ifosfamide, and doxorubicin [EVAIA]) or a combination of both regimens:

Risk group A included all patients with completely resected tumors (IRSG-I) except for the unfavorable sites EXT and HN-PM. These patients received one cycle of VACA-II for 10 weeks.

Risk group B included IRSG-I patients with EXT and HN-PM tumors, all IRSG-II patients, and IRSG-III patients with tumors in the favorable sites ORB and GU-nBP. IRSG-I, IRSG-II, and IRSG-III patients classified as part of the advantageous group after response evaluation received two cycles of VACA-II for 23 weeks. IRSG-III patients classified as disadvantageous received one cycle of VACA-II as induction and two cycles of EVAIA afterwards. Nonresponders were treated with etoposide/ifosfamide.

Risk group C consisted of IRSG-III patients, apart from those with ORB and GU-nBP tumors. Induction chemotherapy was one cycle of EVAIA for all patients. The advantageous subgroup received one cycle of VACA-II afterwards, the disadvantageous subgroup received two more cycles of EVAIA, and nonresponders received carboplatin/dacarbazine.

The risk stratification for radiotherapy differed from risk grouping of systemic treatment (Fig 1): it was based on histology, IRSG, site, second-look surgery, response, TN classification, and tumor size. HART (2 × 1.6 Gy/d) was prescribed as in CWS-86. A dose of 48 Gy was mandatory for all patients with extremity tumors and unfavorable histologies (alveolar rhabdomyosarcoma [RMA], synovial sarcoma [SySa], and extraosseous Ewing or peripheral primitive neuroectodermal tumors [EES/pPNET]). Irradiation was also compulsory for patients with HN-PM, but was dependent on a site-specific guideline. Apart from the exceptions listed above, IRSG-I patients did not undergo radiation. IRSG-II- and IRSG-III patients did not undergo radiation if complete secondary resection could be achieved (IRSG-Ips). IRSG-II and IRSG-III patients of the advantageous subgroup received 32 Gy of HART if no second-look surgery was performed or if residual disease remained after second-look surgery (IRSG-IIps or IRSG-IIIps). All IRSG-III patients of the disadvantageous subgroup received radiation with 48 Gy.

Remission, Relapse, and Late Effects

Complete remission (CR) was defined as no detectable tumor on imaging, any residual structure remaining unchanged for 6 months, or histologically confirmed CR. Chemotherapy-related late effects at last follow-up of survivors without relapse/second malignancy were classified according to Common Terminology Criteria of Adverse Events (CTCAE), version 3.

Definition of Control Groups

Results were compared with CWS-86, the equivalence trial. Because IRSG was used for stratification in both trials, comparisons were based on it.

Statistical Methods

This analysis is based on data as of February 2007. Overall survival (OS) and event-free survival (EFS) were calculated using the Kaplan-Meier method.14 For OS, the time from diagnosis to death from any cause or last follow-up was calculated. For EFS, the time from diagnosis to first relapse or progression, death, or last follow-up was calculated. The local control rate is the proportion of patients without local failures (ie, locoregional/combined relapses, progressions of residuals after completed treatment, and death during therapy) against all patients. Confidence intervals (stated at the 95% level) for the Kaplan-Meier estimator were computed using Greenwood's Formula.15 For comparison of EFS and OS, the log-rank test was used. Differences between risk factor distribution were calculated with the χ2 test. Risk ratios in terms of survival were computed as the ratio between hazard rates. Adjustments for multiple testing were not applied. Multivariate analysis was carried out using the Cox proportional hazards model. A stepwise forward procedure was used to identify independent prognostic variables. Recruitment of approximately 500 patients was expected during 5 years. There were no formal interim analyses, but descriptive reports were presented at annual study committee meetings. The committee determined whether protocol amendments or discontinuation of the trial were necessary.

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RESULTS

Clinical Characteristics

Four hundred forty-one patients from 99 institutions in Austria, Germany, Hungary, Sweden, and Switzerland were enrolled October 1990 through November 1995. Three hundred twenty-six patients had RMS, 115 patients had RMS-like STS (EES/pPNET, n = 77; SySa, n = 32; and undifferentiated sarcoma [UDS], n = 6). The median age was 6 years (range, birth to 20 years), and the median follow-up duration was 8.3 years (range, 0.1 to 14.6 years; Table 1). Eighty-two patients with rare nonrhabdomyosarcomatous STS, for whom protocol therapy was optional, are not considered in this article.

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Table 1.

Clinical Characteristics of All Eligible Patients (n = 441)

Overall Outcome

The 5-year EFS and OS rates of all 441 patients were 63% ± 4% and 73% ± 4%, respectively (all survival rates are calculated and displayed with ±95% CI). Because prognosis differs between RMS and RMS-like STS5 and most patients had RMS, both groups were analyzed separately, focusing on RMS.

RMS: Overall Outcome

The characteristics and outcomes of patients with RMS by IRSG in comparison with the respective CWS-86 control groups are listed in Table 2 and Appendix Table A2 (online only). Although the characteristics of IRSG-I and IRSG-II patients did not differ, IRSG-III patients of CWS-91 incorporated more unfavorable factors.

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Table 2.

Characteristics and Event-Free Survival of Patients With Localized Rhabdomyosarcoma in CWS-91 in Comparison With the Control Groups of CWS-86(5)

The 5-year EFS and OS rates of the 326 RMS patients were 60% ± 5% and 72% ± 5%, respectively (5-year EFS/OS risk group A, 73% ± 15%/81% ± 12%; risk group B, 59% ± 11%/78% ± 9%; risk group C, 59% ± 6%/67% ± 6%). A total of 296 patients (91%) achieved a CR at the end of therapy, and 25 individuals were lost during follow-up. Ninety-one patients (30%) experienced (mainly locoregional) relapses. Seventy-four percent of the recurrences occurred in the 2 years after diagnosis. OS since relapse was 23% ± 8%. If CR was not achieved, median survival was 11 months.

RMS: Outcome by IRSG

IRSG-I RMS.

Five-year EFS of patients treated in risk group A with one cycle of VACA-II for 10 weeks was similar in comparison with that of the CWS-865 control group, which received 16 weeks of vincristine, dactinomycin, ifosfamide, and doxorubicin ([VAIA]; 73% ± 15% v 83% ± 12%). But outcome of IRSG-I allocated to risk group B was worse (40% ± 28%; seven of the 12 risk group B patients had extremity RMA). All 13 individuals with IRSG-I RMA had an inferior outcome compared with CWS-86 (37% ± 27% v 70% ± 32%). These 13 patients accounted for 4% of all patients with RMS.

IRSG-II RMS.

IRSG-II patients in CWS-91 and CWS-86 had similar 5-year EFS rates (62% ± 13% v 67% ± 14%). Thus two cycles of VACA-II with reduced drug doses and substitution of ifosfamide by cyclophosphamide results in similar outcome compared with VAIA.

IRSG-III RMS.

The different risk profiles of IRSG-III patients in CWS-91 and CWS-86 were exaggerated by the risk stratification, which triaged them to different subgroups. Thus patients in the largest subgroup (ie, risk group C, disadvantageous), which encompassed 75% of all IRSG-III patients, had an even more unfavorable risk profile than all IRSG-III patients with RMS.

RMS: Response to Preoperative Chemotherapy

In the 150 IRSG-III patients with clearly assessable response, the proportion of ≥ 66% responders was comparable with that of CWS-86 (65% v 75%). In CWS-91, there was no major difference between the ≥ 66% response rates to EVAIA (79 [76%] of 104 patients) and VACA-II (eight [62%] of 13 patients), but the risk profiles of both groups differed. The prognosis of ≥ 66% responders was significantly better compared with less than 66% responders (Table 3). The subgroup of RMS with ≥ 66% response and tumors ≤ 5 cm had a similarly good EFS as in CWS-86 (68% ± 18% v 77% ± 7%). If the latter analysis was restricted to embryonal rhabdomyosarcoma (RME), the outcome was even better (80% ± 18%).

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Table 3.

Comparison of 5-Year Event-Free Survival of IRSG-III Patients With Rhabdomyosarcoma and Clear Tumor Size in CWS-91 in Comparison With CWS-865 Depending on Response to Induction Chemotherapy

RMS: Outcome by IRSG-III Subgroup

Outcome (EFS/OS) by IRSG-III subgroup is as follows: risk group B (advantageous) subgroup: 64% ± 28%/91% ± 17%; risk group B (disadvantageous): 47% ± 37%/75% ± 30%; risk group C (advantageous): 52% ± 20%/65% ± 19%; risk group C (disadvantageous): 64% ± 6%/70% ± 8%. The 5-year EFS of patients treated with intensified chemotherapy (ie, three courses of EVAIA) was similar in comparison with IRSG-III patients with RMS treated with VAIA in CWS-86 (64% ± 8% v 62% ± 8%), but pretreatment characteristics differed. The small patient numbers in the remaining three subgroups (n = 42) limits the statistical power for comparison with CWS-86. However, a distinctively poorer outcome could only be observed for the six patients with RMA who did not benefit from secondary response-based treatment reductions.

RMS: Radiotherapy

Radiation was correlated with better local control rate and EFS, but OS was similar in patients who did and did not undergo radiation (Table 4). The risk profile of the 212 patients who underwent radiation after a median of 18 weeks, however, incorporated significantly more unfavorable factors. Radiation was withheld from 114 patients mainly because of young age (43% were ≤ 3 years of age) or tumors in favorable sites. Fifty patients were in IRSG-III (56% ≤ 3 years of age, 72% with tumors in favorable sites, and 25% achieved a CR with induction).

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Table 4.

Distribution and Outcome of Patients Receiving and Not Receiving Radiation With Rhabdomyosarcoma (n = 326) and RMS-Like Tumors (n = 115)

Fifty-three patients were stratified to receive 32 Gy of HART. The risk profile of this group was more favorable compared with patients who underwent radiation at higher doses. Local control rates were, however, similar (79% v 72%). Patients who underwent radiation with 32 Gy of HART had an OS rate of 88% ± 8%.

RMS: Outcome by Prognostic Factors

In univariate analysis histology, TN classification, localization, tumor size, age (and risk group) were significant (Table 5). Age (P = .05), histology (P < .0001), and T classification (P < .0001) were prognostic factors in multivariate analysis.

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Table 5.

Outcome and Univariate Analysis of Prognostic Factors in Patients With Rhabdomyosarcoma (n = 326)

RMS-Like STS

Patients with EES/pPNET had 5-year EFS and OS rates of 62% ± 10% and 69% ± 10%, respectively. EFS and OS rates for patients with SySa were 84% ± 12% and 90% ± 10%, respectively, and for patients with UDS, rates were 67% ± 38% and 83% ± 30%, respectively.

Toxicities and Secondary Malignancies

Six of 441 patients died during treatment because of therapy-related reasons (infection/sepsis, n = 5; unknown, n = 1). Six secondary malignancies occurred (five in risk group C; four cases of acute myeloid leukemia and two brain tumors in the radiation field). At last follow-up, there were no occurrences of anthracycline-related cardiotoxicity worse than CTCAE grade 1, but ifosfamide-related tubulopathy worse than CTCAE grade 2 occurred in five patients.

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DISCUSSION

CWS-91 aimed to encompass diametrically opposing goals with regard to the poor prognosis of patients with localized high-risk STS as well as treatment toxicity and its disturbing impact on quality of life.3,5,7,9–11,16 Treatment was therefore intensified for patients with high-risk disease, but reduced for patients with a favorable risk profile. Because the previous trials showed that postsurgical group (IRSG) alone is not sufficient for adequate therapy stratification, CWS-91 considered additional risk factors with the aim to find the optimal middle way between effectiveness and tolerability. Because survival per se is not the sole parameter to determine treatment success and it will require (further) decades to thoroughly investigate the burden of therapy,17,18 this analysis is mainly limited to sheer survival.

The first aim of CWS-91, to determine whether reduced treatment can maintain high cure rates in patients with RMS with favorable risk profile, was achieved for RME, but not for RMA. IRSG-I patients of risk group A (mainly RME) treated with one cycle of VACA-II had no inferior prognosis compared with CWS-86 despite reduced chemotherapy doses and treatment duration, but the statistical power of this comparison is limited. Other study groups achieved similar results without anthracyclines (and alkylating agents), but treatment was also longer and/or only patients with a more favorable risk profile received these regimens (ie, only pT1 IRSG-I).3,7,19 CWS-91 IRSG-I patients with RMA had an inferior outcome owing to inadequate chemotherapy stratification. Because of the higher treatment-intensity in CWS-86, the alveolar histotype was relevant for prognosis only in IRSG-III.5 The histologic subtype was therefore not considered for stratification of systemic treatment in CWS-91. Therapy was not changed during the trial because the significance of interim evaluations was limited as a result of the small patient number in this subset.

Cure rates for IRSG-II patients with RMS were unchanged compared with the CWS-86 control group, despite substantial shortening of treatment intensity. It is likely, although yet unproven, that these reductions will result in fewer late effects. These results suggest that ifosfamide can be substituted with cyclophosphamide in combination with dactinomycin, doxorubicin, and vincristine in correspondence with the findings of IRS-IV,4 although the sample size was relatively small. Which alkylator may be chosen for IRSG-II RMS depends on the yet unsettled toxicity profiles, weighing, for example, ifosfamide nephrotoxicity against cyclophosphamide gonadal toxicity.11,18

For the majority of IRSG-III patients with RMS, CWS-91 sought to improve prognosis by intensifying chemotherapy: ifosfamide was used instead of cyclophosphamide because of evidence supporting its superior effectiveness, and etoposide was added to VAIA.20,21 But neither survival nor the proportion of ≥ 66% responders was improved with EVAIA. The unfavorable pretreatment characteristics, which were additionally enhanced by the risk stratification, however, caused a bias that makes comparison with the control groups difficult. It is a matter of speculation whether similar response and survival of CWS-91 IRSG-III patients, despite their disadvantageous pretreatment characteristics, means that addition of etoposide to VAIA may have improved survival in comparison groups with similar risk profiles. The most likely explanation is that EVAIA did not improve outcome. The randomized IRS-IV trial did not add etoposide, but compared vincristine, dactinomycin, and cyclophosphamide with vincristine, etoposide, and ifosfamide. Survival was similar in both groups.4

Response, especially in combination with tumor size, was a predictor of outcome in CWS-81 and CWS-86.5,6 Therefore, CWS-91 assessed whether IRSG-III patients benefit from secondary response-based treatment stratification. Although patients with smaller tumors and ≥ 66% response received reduced postinduction chemotherapy and radiotherapy, they still had a distinctively better prognosis compared with those with larger tumors and poor response to treatment. Because response was confirmed as a prognostic factor in a cumulative CWS analysis just in RME (not RMA),22 and tumor size was identified as a predictor for recurrence just in RME (not RMA),23 we analyzed RME separately and could show that patients with RME ≤ 5 cm and ≥ 66% response had an especially good outcome.

Despite the unfavorable risk profile of the CWS-91 trial population, outcome of patients with RMS compared favorably with the cure rates achieved in the IRS-III trial,3 apart from the poorer prognosis of IRSG-I patients and those with extremity tumors. Although overall outcome was similar compared with MMT-89,7 OS according to site and histology was never worse, but much better, for example, in RMA (Appendix Table A3, online only).

In RMS with a favorable risk profile, radiation with 32 Gy of HART yielded a local control rate similar to that achieved with radiation with higher doses, and these patients had an excellent OS of 88%.5 Therefore, it is possible to reduce radiation doses in selected patients with maintained local control, which shields them from radiation-associated late effects. In contrast, the randomized trial IRS-IV aimed to improve local control and compared 59.4 Gy of hyperfractionated, but not accelerated, radiation with conventional fractionated 50.4 Gy in IRSG-III RMS. Local control or survival, however, could not be improved.4,24 In CWS-91, EFS and local control were lower in patients who did not undergo radiation, but the protocol avoided radiation in very young children and those individuals whose salvage options were good enough to achieve similar OS as the irradiated group. 48 Gy of HART resulted in similar outcome compared with the dose of 54.4 Gy prescribed in CWS-86.5 The evaluation of the possible benefit of HART compared with conventional radiotherapy with regard to improved tolerability or fewer late sequelae (eg, fibrosis) requires longer follow-up.5,17,25

Outcome of RMS-like STS in CWS-91 was good: in synovial sarcoma, it compared favorably with published data.5,26,27 Because synovial sarcomas are rather slow-growing tumors with a propensity to develop late (pulmonary) relapses, a long time to relapse and extended postrelapse survival can be expected. High OS rates have been reported for young patients with superficial/small tumors treated with or without chemotherapy in mainly retrospective analyses from single centers, but prolonged EFS rates were rarely published. The 5-year EFS rate of 84%, which was achieved in an unselected population of uniformly treated patients, is among the best results reported from a prospective multicenter trial. Outcome of nonmetastatic extraosseous Ewing's sarcoma also compared favorably with previous CWS and other trials in an early comparative analysis.28,29 This is in correspondence with the findings of other investigators that these tumors seem to benefit from etoposide in combination with ifosfamide and/or anthracyclines.30,31

In contrast with other trials that have revealed similar prognostic factors, all currently known risk factors, apart from age, have already been considered for treatment stratification in CWS-91.3,4,19 As a consequence of the insufficient stratification for unfavorable histologies (ie, RMA), chemotherapy in the high-risk group was prescribed for all these patients in subsequent CWS trials. The IRS used histologic subtype for chemotherapy stratification since its first trial, but the impact of histology on prognosis was still debated when CWS-91 was designed.3,5,32 Because age was identified as a new prognostic factor,4,33,34 it was considered for RME together with tumor size6,23 in the risk stratification of the current trial CWS-2002-P. Maintenance chemotherapy was also introduced because the majority of relapses in CWS-91 occurred soon after treatment stopped.23 To avoid biased control groups and to clarify whether therapy intensification can improve outcome in high-risk patients, the subsequent randomized trial CWS/ICG-96 evaluated whether the six-drug combination of carboplatin, epirubicin, vincristine, dactinomycin, ifosfamide, and etoposide (CEVAIE) is superior compared with VAIA. Preliminary analyses showed similar results,35 which supports the hypothesis that it is not intensification, but rather new agents/chemotherapy scheduling,36,37 that are the key to improving outcome of childhood STS.

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AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

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AUTHOR CONTRIBUTIONS

Conception and design: Bernhard F. Schmidt, Heribert Juergens, Thomas Klingebiel, Helmut Gadner, Joern Treuner, Ewa Koscielniak

Administrative support: Stefan S. Bielack, Sylvia Kirsch, Joern Treuner

Provision of study materials or patients: Dieter Harms, Ivo Leuschner, Manfred Herbst, Heribert Juergens, Hans-Gerhard Scheel-Walter, Stefan S. Bielack, Thomas Klingebiel, Roswitha Dickerhoff, Rainer Schmelzle, Michael Greulich, Helmut Gadner, Jeanette Greiner, Ildiko Marky, Joern Treuner, Ewa Koscielniak

Collection and assembly of data: Tobias M. Dantonello, Dieter Harms, Manfred Herbst, Sylvia Kirsch, Ines Brecht, Helmut Gadner, Ildiko Marky, Joern Treuner, Ewa Koscielniak

Data analysis and interpretation: Tobias M. Dantonello, Christoph Int-Veen, Ivo Leuschner, Ewa Koscielniak

Manuscript writing: Tobias M. Dantonello, Stefan S. Bielack, Ewa Koscielniak

Final approval of manuscript: Tobias M. Dantonello, Christoph Int-Veen, Dieter Harms, Ivo Leuschner, Heribert Juergens, Stefan S. Bielack, Thomas Klingebiel, Sylvia Kirsch, Helmut Gadner, Jeanette Greiner, Ildiko Marky, Ewa Koscielniak

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Acknowledgment

We thank all participating institutions for their support, Erika Hallmen and Iris Veit-Friedrich for excellent data management and dedicated work, and Lynn Hazlewood for review of the manuscript. Last, but not least, we thank all participating patients/parents/guardians.

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Appendix

Study committee members are as follows: Oncology: J. Treuner and E. Koscielniak, Stuttgart, Germany; H. Jürgens, Muenster, Germany; D. Niethammer, Tuebingen, Germany; H. Reddermann, Greifswald, Germany; K. Winkler, Hamburg, Germany; J.H. Hartlapp, Bonn, Germany; H. Gadner, Vienna, Austria; G. Kardos, Budapest, Hungary; I. Marky, Goeteborg, Sweden; T. Wiebe, Lund, Sweden. Radiotherapy: M. Herbst, Regensburg, Germany; B.F. Schmidt, Stuttgart, Germany; R. Hawlieczek, Vienna, Austria; E. Cavallin-Stahl, Lund, Sweden; C. Mercke, Goeteborg, Sweden; W. Alberti, Hamburg, Germany. Reference pathology: D. Harms and D. Schmidt, Kiel, Germany; D. Katenkamp, Jena, Germany; M. Altmannsberger, Giessen, Germany; P. Meister, Muenchen, Germany; R. Krepler, Vienna, Austria. Surgery: D. Bürger, Hannover, Germany; R. Schmelzle, Hamburg, Germany; P. Schweizer, Tuebingen, Germany.

Participating institutions are as follows (for institutions outside Germany, the respective country is provided in brackets): Universitätskinderklinik, Aachen; Kinderklinik, Augsburg; Kinderspital, Basel (Switzerland); Kinderklinik, Bayreuth; Kinderklinik der Freien Universität, Charité, Berlin; Kinderklinik des Helios-Klinikums, Berlin; Robert-Rössle-Klinik, Charité, Berlin; Bundeswehrkrankenhaus, Berlin; Gilead Krankenanstalten, Bielefeld; Universitätskinderklinik, Bonn; Städtische Kinderklinik, Braunschweig; Prof.-Hess-Kinderklinik, Bremen; Madarász Children's Hospital, Budapest (Hungary); Kinderklinik, Chemnitz; Kinderklinik, Coburg; Carl-Thiem-Klinikum, Cottbus; Vestische Kinderklinik, Datteln; Gyermekklinika, Debrecen (Hungary); Klinikum Dortmund; Universitätskinderklinik, Dresden; Städt. Krankenhauses, Dresden-Neustadt; Kinderklinik, Duisburg; Universitätskinderklinik, Düsseldorf; Kinderklinik, Erfurt; Universitätskinderklinik, Erlangen; Universitätskinderklinik, Essen; Universitätskinderklinik, Frankfurt; Universitätskinderklinik, Freiburg; Universitätskinderklinik, Giessen; Klinikum am Eichert, Göppingen; Drottning Silvias barnsjukhus, Sahlgrenska universitetssjukhus, Göteborg (Sweden); Universitätskinderklinik/Tumorzentrum, Göttingen; Universitätskinderklinik, Graz (Austria); Universitätskinderklinik, Greifswald; Universitätskinderklinik, Halle; Universitätskinderklinik, Hamburg; Altonaer Kinderkrankenhaus, Hamburg; Universitätskinderklinik, Hannover; Krankenhaus auf der Bult, Hannover; Universitätskinderklinik, Heidelberg; Gemeinschaftskrankenhaus, Herdecke; Städt. Krankenhaus, Hildesheim; Universitätskinderklinik, Homburg/Saar; Landeskrankenhaus, Hochzirl (Austria); Universitätskinderklinik, Jena; Städt. Klinikum und St. Vicentius Krankenhaus, Karlsruhe; Städt. Kliniken, Kassel; Universitätskinderklinik, Kiel; Landeskrankenhauses, Klagenfurt (Austria); Klinikum Kemperhof, Koblenz; Städt. Kinderkrankenhaus, Köln; Universitätskinderklinik, Köln; Kinderklinik, Krefeld; Rehabilitationskrankenhaus, Karlsbad-Langensteinbach; Universitätskinderklinik, Leipzig; Landeskrankenhaus, Leoben (Austria); Klinikum Lippe-Detmold, Detmold; Kinderklinik, Linz (Austria), Universitätskinderklinik, Lübeck; Universitetssjukhus, Lund (Sweden); Universitätskinderklinik, Magdeburg; Universitätskinderklinik, Mainz; Universitätskinderklinik, Mannheim; Universitätskinderklinik, Marburg; Kinderklinik, Minden; Dr. von Haunersches Kinderspital, München; Kinderklinik, München-Harlaching; Universitätskinderklinik, München-Schwabing; Universitätskinderpoliklinik, München; Universitätskinderklinik, Münster; Dietrich-Bonhoeffer-Klinikum, Neubrandenburg; Cnopf'sche Kinderklinik/Klinikum Süd, Nürnberg; Kinderkrankenhaus, Oldenburg; Marienhospital/Klinikum, Osnabrück; Klinikum Oberschwaben, Ravensburg; Kinderklinik St. Hedwig, Regensburg; Universitätskinderklinik, Rostock; Kinderklinik, Saarbrücken; Landeskrankenanstalten, Salzburg (Austria); Leopoldinakrankenhaus, Schweinfurt; Kinderklinik, Schwerin; DRK-Kinderklinik, Siegen; Kinderklinik, St. Augustin; Ostschweizer Kinderspital, St. Gallen (Switzerland); Olgahospital, Stuttgart; Mutterhaus der Borromäerinnen, Trier; Universitätskinderklinik/medizinische Klinik, Tübingen; Universitätskinderklinik/Bundeswehrkrankenhaus, Ulm; St. Anna Kinderspital, Vienna (Austria); Kinderklinik, Wolfsburg; Universitätskinderklinik, Würzburg; Kinderklinik, Wuppertal.

Fig A1.
View larger version:
Fig A1.

(A) Outcome of all 441 patients (5-year event-free survival [EFS]) by risk group. (B) Outcome of all patients with rhabdomyosarcoma (RMS; 5-year EFS) by Intergroup Rhabdomyosarcoma Study Grouping (IRSG). (C) Outcome of all patients with RMS (5-year EFS) by risk group.

⇓⇓⇓

View this table:
Table A1.

Evolution of Therapy Concepts in CWS-81, CWS-86, and CWS-91

View this table:
Table A2.

Characteristics and Event-Free Survival of IRSG-III Patients With Rhabdomyosarcoma According to Advantageous/Disadvantageous Subgroups and Risk Group Compared With CWS-86 IRSG-III Rhabdomyosarcoma(5)

View this table:
Table A3.

Characteristics and Outcome of Patients With Nonmetastatic Rhabdomyosarcoma in CWS-91 in Comparison With Published Data of Patients Treated in CWS-86,5 IRS-III,3 and MMT-897

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Footnotes

  • Supported by Grant No. M76/91/Tr2, Project-No. 70456, from the Deutsche Krebshilfe (German Cancer Aid), Bonn and by the Foerderkreis Krebskranke Kinder e.V., Stuttgart, Germany.

  • For a complete list of contributing centers, see the Appendix (online only).

  • Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

  • Received November 5, 2007.
  • Accepted September 30, 2008.
Previous Section
 

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  1. Published online before print February 17, 2009, doi: 10.1200/JCO.2007.15.0466 JCO vol. 27 no. 9 1446-1455
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