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European Intergroup Studies (MMT4-89 and MMT4-91) on Childhood Metastatic Rhabdomyosarcoma: Final Results and Analysis of Prognostic Factors

From the University of Padova, Padova; Institut "G. Gaslini," Genova, Italy; Institut Gustave Roussy, Villejuif, France; Olgahospital, Stuttgart, Germany; Mater Hospitals, Brisbane, Australia; and University of Bristol, United Kingdom

Address reprint requests to M. Carli, MD, Department of Pediatrics, University Hospital of Padova, Hematology-Oncology Division, Via Giustiniani 3, 35128 Padova, Italy; e-mail: modesto.carli{at}unipd.it

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
PURPOSE: Final results are presented from two consecutive European studies for patients with metastatic rhabdomyosarcoma (RMS) to identify prognostic variables and determine the value of high-dose chemotherapy (HDCT) in complete remission.

PATIENTS AND METHODS: A total of 174 patients aged 3 months to 18 years participated. From 1989 to 1991, patients received four cycles of intensive multiagent chemotherapy. From 1991 to 1995, patients achieving complete remission received consolidation with HDCT. All received local therapy (surgery, radiation therapy) according to response.

RESULTS: At a median follow-up of 8 years, 5-year overall survival (OS) and event-free survival (EFS) for the whole group were 24% and 20%, respectively. No statistical difference was found between HDCT and standard chemotherapy (5-year OS, 36% v 27%; EFS 29% v 23%). Univariate analysis identified primary tumor in parameningeal, extremity, or other sites; age younger than 1 year and older than 10 years; bone or bone marrow metastases; multiple metastases; and multiple sites of metastases as unfavorable prognostic factors for OS and EFS. Multivariate analysis identified unfavorable site, bone or bone marrow involvement, and unfavorable age as independently unfavorable factors. Two subgroups were identified. Those with fewer than two unfavorable factors had 5-year EFS and OS of 40% and 47%, respectively. Patients with two unfavorable factors had 5-year EFS and OS of 7.5% and 9%, respectively.

CONCLUSION: A minority of patients with metastatic RMS have better survival than overall results for this population suggest. Those in the highest risk group have such poor survival that they are candidates for first-line novel therapies. There is no evidence that consolidation with HDCT improves outcome.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in childhood, accounting for approximately 6% of pediatric tumors.¹ During the last 30 years, the use of a multimodal approach to diagnosis and treatment has resulted in a significant improvement in survival, with a cure rate of approximately 70% for patients with localized disease.^2–6 Unfortunately, the prognosis for patients presenting with metastatic disease at diagnosis remains poor, with a 5-year progression-free survival of less than 30%.^6,7 These disappointing results, as well as the limited enrollment of patients with metastatic disease onto each individual European Study (International Society of Pediatric Oncology, German and Italian studies) prompted a combined European study on metastatic soft tissue sarcoma. From May 1989 to August 1995, two consecutive cooperative studies were conducted in Europe: MMT4-89 and MMT4-91. The results of some components of these studies—the value of high-dose melphalan as consolidation therapy for patients in complete remission (CR)⁸ and the effectiveness of the combination carboplatin, epirubicin, and vincristine (CEV) used as window therapy⁹—have been reported. Here we report the final results and detailed analysis of prognostic factors.

	PATIENTS AND METHODS

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Study Design
The study enrolled untreated patients aged from 3 months to 18 years, with a pathologically confirmed diagnosis of RMS and evidence of metastatic disease. Patients were required to begin therapy within 42 days from diagnosis.

The extent of disease was evaluated by imaging studies, technetium bone scan, and examination of the bone marrow, which included two aspirates and two trephine biopsies. Patients were considered to have distant metastases at diagnosis when the tumor was detected clinically or radiographically at one or more sites distant from the primary site and outside the regional lymph nodes. Patients with malignant cells in pleural fluid (associated with tumors arising in the chest or chest wall) or peritoneal fluid (from tumor in the abdominal wall, genitourinary tract, peritoneum, or pelvis) were not considered to have distant metastases on this basis alone, nor was positive CSF cytology accepted as evidence of metastatic disease in patients with primary parameningeal disease in the absence of other distant disease. Tumor-node-metastasis system staging was used to describe the tumor. Surgical biopsy, rather than extensive resection, was encouraged at diagnosis.

In the first study, MMT4-89, the treatment plan included four identical 9-week cycles. Each cycle consisted of three courses of combinations of the following drugs, administered every 21 days: course 1 was intravenous (IV) epirubicin 150 mg/m² day 1, IV carboplatin 500 mg/m² day 1, and IV vincristine 1.5 mg/m² days 1 and 8. Course 2 was IV ifosfamide 3 mg/m² days 1 to 3, IV dactinomycin 1.5 mg/m² day 1, and IV vincristine 1.5/m² days 1 and 8. Course 3 was IV ifosfamide 3 mg/m² days 1 to 3, IV etoposide 200 mg/m² days 1 to 3, and IV vincristine 1.5 mg/m² days 1 and 8.

In the second study, MMT4-91, the fourth cycle was replaced with high-dose IV melphalan 200 mg/m² with autologous bone marrow or peripheral-blood stem cell rescue. Bone marrow collection or peripheral-blood stem cell rescue collection to obtain a minimum of 2.5 x 10⁸/kg total nucleated cells or 2 x 10⁶/kg CD34, respectively, was performed after the second or third cycle.

Drug doses were started at 50% of the square-meter dose for infants younger than 1 year to avoid excessive toxicity, and subsequently increased if tolerated.

Tumor response was assessed on the basis of clinical and radiologic findings after the first and second cycles (weeks 9 and 18). Second-look operation (SLO) was planned, if feasible, after the second cycle to confirm a clinical CR by multiple biopsies or to obtain CR by removing residual tumor.

Radiation therapy (RT) was recommended for patients with microscopic or macroscopic residue after chemotherapy and/or surgery, and was delivered, where possible, both to primary tumor and metastases.

A hyperfractionated accelerated RT strategy was adopted when feasible in each center and two daily fractions of 1.6 Gy were delivered to a total dose of 40 Gy, concurrently with the third cycle of chemotherapy. Macroscopic residual disease was boosted to a total dose of 54.4 Gy. Irradiation of parameningeal tumors was recommended earlier, during the second cycle of chemotherapy. Patients with poor response at week 9 were considered off study and a phase II study with single-agent high-dose chemotherapy was recommended.

Clinical CR was defined as the disappearance of all signs of tumor based on clinical and imaging evidence. Histologic CR was defined as histologically confirmed absence of disease. Partial remission (PR) was defined as a 50% decrease in the sum of the products of the maximum perpendicular diameters of all measurable lesions. Objective response was defined as 25% to less than 50% decrease in the sum of the products of the maximum perpendicular diameters of all measurable lesions, no evidence of progression in any lesions, and no new lesions. No response indicated less than 25% decrease in the sum of the products of the maximum perpendicular diameters of all measurable lesions, no evidence of progression in any lesion, and no new lesions. Progressive disease was defined as a 25% increase in the sum of the products of the maximum perpendicular diameters of measurable lesions at any involved site and/or the appearance of new lesions.

Informed parental and/or patient consent was obtained according to local institution ethical committee requirements before beginning therapy.

Statistical Methods
Survival curves were calculated according to the Kaplan-Meier method.¹⁰ Overall survival (OS) was calculated from the time interval between the date of diagnosis and the date of last follow-up or death. Event-free survival (EFS) was calculated from the interval between diagnosis and the date of first progression, relapse, or death as a result of any cause. Analyses were based on data available as of June 30, 2003. The 95% CIs for specific estimates of time-to-event distributions were calculated using Greenwood's formula for the variance of estimates. The log-rank test was adopted to assess differences in univariate analysis. A P value less than .05 was considered statistically significant. However a P value less than .2 was needed for a variable to be included in the multivariate assessment of OS and EFS performed by Cox's regression model.¹¹ Variables that were not significantly associated with OS or with EFS were removed by stepwise modeling.

The ² test was used to compare different clinical characteristics or treatment modalities between subsets of patients.¹²

	RESULTS

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Patient Population
From May 1989 to August 1995, 207 patients were registered and enrolled onto the two studies: 174 met the eligibility criteria and were included in the analyses. Reasons for exclusion were age younger than 3 months (four patients), prior treatment (15 patients), incorrect staging (three patients), lost to follow-up after registration (five patients), and other reasons (five patients). The characteristics and clinical stage of the combined study population as well as of patients accrued and eligible for MMT4-89 and MMT4-91 studies are shown in Table 1. The male-to-female ratio was 1.2:1, median age was 8.6 years (range, 3.2 months to 18.8 years), and the most common site of primary tumor was the extremities (36%). In 90% of the patients, histology was centrally reviewed by the pathology panel of each cooperative group. The agreement rates of the institutional diagnosis with the final review committee diagnosis for the alveolar and embryonal subtype were 80% and 78%, respectively. For the remaining patients, the diagnosis reached at the treatment center was accepted. Histology was embryonal in 48%, alveolar in 42%, but not specified in 10% of patients. Tumors were predominantly large (> 5 cm in 78%) and locally invasive (T2 in 66%). Locoregional lymph node involvement was identified in 55% of patients. Multiple metastases were evident in 80% of patients and involved more than one organ in 55% of patients. The most frequent metastatic site was the lung (45%), followed by lymph nodes (41%), bone marrow (36%), and bone (32%).

Treatment Results
Chemotherapy. Response to chemotherapy at weeks 9 and 18 was assessable in 167 (96%) and 155 (89%) patients, respectively. There was an increase of the response rate (CR + PR) from 83% after the first cycle of chemotherapy to 92% after the second, as listed in Table 2. The CR rate increased from 17% to 35% between week 9 and 18 mostly due to patients who improved from PR to CR after the second cycle. Three patients who initially showed a response developed progressive disease after the second cycle. Five more patients achieved a late CR with the third or fourth cycle, yielding a total of 46% for those obtaining CR with chemotherapy alone.

RT. RT was administered to 64 patients (37%); 12 with primary parameningeal RMS. Information regarding RT was missing for seven patients. The RT target was the primary tumor (T) in 34 patients, T and regional lymph nodes (N) in 10 patients, T and metastatic sites (M) in nine patients, M alone in seven patients, and TNM in four patients. Twenty-eight patients received the protocol-recommended doses, whereas the remaining patients received dosages ranging from 16 to 56 Gy. Three patients achieved CR with RT after initial chemotherapy.

Megatherapy. High-dose chemotherapy was delivered to 53 patients as consolidation in CR. As described,⁸ the decision whether or not to use megatherapy in MMT4-91 was largely center based and did not depend on presenting features or response to initial chemotherapy in individual patients.

Relapse. Overall, 127 of 174 (73%) patients achieved CR during treatment but 86 subsequently experienced disease relapse: 30 patients locally, 52 in initial or new metastatic sites, and four in nonspecified sites. Median time to recurrence was 9 months (range, 1 to 47 months).

Outcome. At a median follow-up for surviving patients of 8 years, the estimated 5-year OS and EFS for eligible patients were 24% (95% CI, 18 to 30) and 20% (95% CI, 14 to 26), respectively (Fig 1). To evaluate the relevance of response status on survival at week 18, OS and EFS were compared between the patients in CR at week 18 and the patients who were alive but not in CR at that point. The 96 patients in CR at week 18 had a better outcome compared with the 69 patients not in CR at this point: 5-year EFS was 26% (95% CI, 17% to 35%) v 13% (95% CI, 5% to 21%; P = .0045) and 5-year OS was 32% (95% CI, 23% to 42%) v 14.5% (95% CI, 6% to 23%; P = .0041). A significantly better outcome was also evident in the 59 patients who achieved CR after the excision of residual disease with or without RT compared with the 59 patients who were in CR after chemotherapy alone: 5-year EFS was 39% (95% CI, 26% to 52%) v 20% (95% CI, 10% to 30%; P = .0012) and 5-year OS was 44% (95% CI, 31% to 57%) v 25% (95% CI, 14% to 35%; P = .0008). No difference was observed between patients who received megatherapy after achieving CR compared with those who continued with standard intensive chemotherapy: the 5-year EFS and OS rates were 29% (95% CI, 16% to 41%) and 36% (95% CI, 23% to 49%) v 23% (95% CI, 11% to 36%) and 27% (95% CI, 14% to 41%), respectively.

View larger version (15K): [in this window] [in a new window]   Fig 1. Overall survival (OS) and event-free survival (EFS) of 174 patients (PTS) with metastatic rhabdomyosarcoma at diagnosis. YR, year.

Prognostic Factors
The following pretreatment clinical characteristics were considered as potential prognostic factors: sex, age (< 1, 1 to 9, 10 years), primary tumor extension (T1 v T2), tumor size (> 5 cm and 5 cm), locoregional lymph node involvement (N0 v N1), histology (alveolar v nonalveolar), presence or absence of bone or bone marrow metastases, lung metastases, lymph node metastases, number of metastases and metastatic sites (single v multiple metastases; single v multiple organ involvement), and primary tumor site (head and neck, genitourinary, parameningeal, extremities, or other sites). Given that the presence of bone metastases was highly related to bone marrow involvement (P = .002), these two metastatic areas were combined in a single category for prognostic analysis.

Univariate analysis for EFS indicated the following unfavorable prognostic factors: primary tumor localized in parameningeal, extremities, or other sites (P = .0002), age older than 10 years and less than 1 year (P < .0001), bone or bone marrow involvement (P < .0001), presence of multiple metastases (P = .003), and multiple metastatic sites (P = .009). Univariate analysis for OS confirmed the same prognostic factors, with similar log-rank values.

After multivariate analysis, the factors that independently and significantly correlated with improved EFS and OS were favorable tumor sites (genitourinary, nonbladder or nonprostate, and head and neck), absence of bone or bone marrow metastases, and age between 1 and 9 years (Table 3).

View larger version (25K): [in this window] [in a new window]   Fig 2. (A) Overall survival (OS) and (B) event-free survival (EFS) of patients (PTS) with metastatic rhabdomyosarcoma at diagnosis according to the number of unfavorable risk factors. YR, year.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

In this study, an intensive, six-drug, multiagent regimen, including most of the drugs thought to be active against RMS, was used at close to the maximum-tolerated doses when given in combination. Surgery and/or RT were used to improve local control. As a result, 73% of patients achieved CR, 46% of these with chemotherapy alone. The overall CR rate achieved in this trial compares favorably with the CR rate reported by other studies of metastatic RMS,^6,13,15 but despite this, 5-year OS and EFS have not improved. The achievement of CR is an important step but does not prevent local or metastatic relapse, and effective local treatment should be considered whenever possible. A lower relapse rate was observed in patients who achieved CR with delayed surgery (SLO) and/or RT compared with those who obtained CR with chemotherapy alone, even when this was confirmed with biopsy. This difference is statistically significant and confirms previous reports indicating that delayed resection improves the probability of survival in extraosseous soft tissue, Ewing's sarcoma, and RMS, and is the most effective manner to remove residual, potentially chemotherapy-resistant tumor.^6,15–17 RT was recommended only for patients with residual disease after chemotherapy or SLO. However, RT was not widely used in our study and, to some extent, this omission may explain the high relapse rate.

In the second phase of this study, the MMT4-91 protocol evaluated the potential role of high-dose melphalan as consolidation chemotherapy for patients in first CR. High-dose chemotherapy followed by hematopoietic stem-cell rescue has been considered an attractive strategy to eliminate microscopic residual disease in patients in clinical CR after intensive conventional chemotherapy. However, despite longer follow-up, we failed to show that this resulted in any improvement in the OS for these patients.⁸ Similarly disappointing results have been obtained by other investigators who used intensive myeloablative regimens such as rapid vincristine/actinomycin/cyclophosphamide and melphalan¹⁸ or combinations of melphalan, carboplatin, and etoposide^19,20; thiotepa, cyclophosphamide, and carboplatin²¹; or melphalan and etoposide.²² In all of these studies, the 2- or 3-year EFS ranged from 19% to 44%.

In this study, age older than 1 year and younger than 10 years, the absence of bone or bone marrow metastases, and primary tumor in head and neck or genitourinary sites were found to be independently favorable factors for both OS and EFS. Histology was not an independent prognostic factor but because alveolar histology was closely associated with the presence of bone marrow metastases (P = .001) and with unfavorable tumor site (extremity and other primary sites, P < .001), it is possible that this obscured its prognostic value.

Prognostic factors determining clinical outcome have been identified previously for localized RMS^3,6,23 and metastatic RMS. A retrospective study of children with metastatic soft tissue sarcoma registered in the major European soft tissue sarcoma studies found that patients with genitourinary nonbladder and nonprostate primary sites and those with metastases limited to one organ or site had a higher probability of cure.⁷ In the IRS-I report,²⁴ patients with tumors originating in the genitourinary tract and those with limited metastases also had a higher chance of cure. Genitourinary primary sites and age younger than 11 years were also identified as clinical characteristics linked with improved survival by Crist et al³ in a review of prognostic factors of children treated on IRS-I and IRS-II studies. Anderson et al,²⁵ in a preliminary analysis of children with metastatic RMS treated on IRS-III and IRS-IV pilot studies, found that children aged 1 to 9 years old who had embryonal RMS fared better than infants and adolescents. In our study population, the 55 patients with embryonal tumors aged 1 to 9 years had a 5-year EFS and OS of 34.6% and 41.7%, respectively, although 71% of these patients were included in the group with fewer than two unfavorable prognostic factors. The prognostic importance of age was subsequently confirmed by Sandler et al¹³ and Joshi et al,²⁶ although the definitive report by Breneman et al¹⁴ on prognostic factors of children and adolescents with metastatic RMS treated on IRS-IV did not confirm age as a significant factor, and identified the presence of two or fewer metastatic sites and embryonal histology as the principal favorable prognostic factors. The reason for the discrepancy in comparison with their previous findings was not clear. However, when favorable prognostic criteria were applied retrospectively to patients treated on IRS studies III, IV pilot, and IV, a population with metastatic disease was identified that had a 5-year failure-free survival of 44% and a 5-year OS of 46%. These data indicated that clinical outcomes for children with metastatic RMS might not be uniformly poor, and suggested that subgroups of patients with favorable clinical characteristics could have a better outcome. The improved survival rates obtained in these favorable subgroups of metastatic patients, of course, cannot be considered satisfactory, but they may indicate the need to re-evaluate criteria for selecting patient for entry onto clinical trials that use highly experimental approaches to treatment. The analysis of survival for children treated on the MMT4-89 and MMT4-91 studies confirms our preliminary results²⁷ but shows that not all children with metastatic disease have poor prognosis.

In conclusion, the identification of prognostic factors allows patient stratification into distinct risk groups. In this large series of uniformly treated patients, we have identified a small subgroup of patients (4%) without unfavorable risk factors and good outcome (5-year OS, 78%), and another subgroup (35%) with one risk factor and an intermediate outcome (5-year OS, 40%). Unfortunately the majority of patients (56%) have more than one risk factor and a poor outcome (5-year OS, 8%). For the first group of patients, the treatment currently used produces a good outcome and this group should not need more aggressive chemotherapy or experimental therapy, whereas for the other two groups, new treatment strategies must be considered. Those with the worst outcome would be eligible for first-line studies of new agents.

	Authors' Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
The authors indicated no potential conflicts of interest.

	NOTES

 
Supported in part by the Fondazione "Città della Speranza" and MURST.

The study was presented in part at the Annual Meeting of the International Society of Pediatric Oncology (SIOP XXIX Meeting), September 23–27, 1997, Istanbul, Turkey.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
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Submitted April 16, 2004; accepted September 17, 2004.

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