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Failure Pattern and Factors Predictive of Local Failure in Rhabdomyosarcoma: A Report of Group III Patients on the Third Intergroup Rhabdomyosarcoma Study

From the Children's Oncology Group, Arcadia; Stanford University School of Medicine, Stanford, CA; The Johns Hopkins School of Medicine, Baltimore, MD; University of Nebraska Medical Center, Omaha, NE; Children's Hospital Medicine Center, Cincinnati, OH; Quality Assurance Review Center, Providence, RI; Washington University School of Medicine, St Louis, MO; Children's Hospital of Pittsburgh, Pittsburgh, PA; and University of Oklahoma Health Sciences Center, Oklahoma City, OK.

Address reprint requests to Moody D. Wharam Jr, MD, FACR, Department of Radiation Oncology and Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Suite 1460, 401 N Broadway, Baltimore, MD 21231; e-mail: wharamo{at}jhmi.edu or smason{at}childrensoncologygroup.org

	ABSTRACT

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PURPOSE: To analyze patterns of failure and factors predictive of local treatment failure in children enrolled on the third Intergroup Rhabdomyosarcoma Study who had either biopsy only or subtotal resection of their primary tumor, had no distant metastases, and received radiation therapy for local control.

PATIENTS AND METHODS: Treatment failure was categorized as local, regional nodal, or distant metastatic. The 5-year cumulative risk of failure was estimated for each category and factors predictive of local failure risk were determined using the Cox model and binary recursive partitioning.

RESULTS: The estimated 5-year cumulative incidence rates by failure category were: total local (with or without concurrent regional or distant failure), 19%; total regional nodal, 2%; total distant, 11%; and death from toxicity or unknown recurrence type, 4%. Lymph node involvement at diagnosis was the single factor most predictive of increased total local failure risk (5-year cumulative incidence 32%) compared with children with negative nodes or unknown node status (16%). No significant effect on local failure risk was observed by total radiotherapy dose over the prescribed range of 41.4 Gy to 50.4 Gy. For all patients (N = 405), the estimated 5-year failure-free survival and overall survival were, respectively, 70% and 78%.

CONCLUSION: Local failure after radiotherapy for group III rhabdomyosarcoma patients is the predominant type of relapse. Involved lymph nodes at diagnosis predict a higher risk of local and distant treatment failure compared with patients whose lymph nodes are negative.

	INTRODUCTION

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Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma.¹ More than 70% of children with localized RMS are cured with combined modality treatment based on multiagent chemotherapy and local control using surgery and/or radiotherapy. Patients enrolled on the intergroup rhabdomyosarcoma protocols were classified by the extent of initial surgery. Resection with tumor-free margins was surgicopathologic group I (if they were also node-negative) and, for embryonal histology, postoperative radiotherapy was not required; resection with microscopically positive margins or involved lymph nodes was used in group II, and postoperative radiotherapy was required. Most children with localized RMS (54%), however, have subtotal resection or biopsy only of their primary tumor (group III). For these patients, radiation therapy is the definitive local control method, and its success is essential to avoid local failure and reduced survival rate. To better understand the efficacy of definitive radiation therapy, we studied the patterns of treatment failure and patient, tumor, and radiation treatment factors predictive of local treatment failure in children with group III RMS who received radiotherapy on the third Intergroup Rhabdomyosarcoma Study, on which patients were enrolled from 1984 to 1991.

	PATIENTS AND METHODS

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Patients
The study population included all eligible patients with Group III RMS who were treated on Intergroup Rhabdomyosarcoma Study III (IRS-III), and who received radiotherapy as part of their protocol treatment. The eligibility requirements for IRS-III patients have been published previously.² Briefly, patients eligible for IRS-III were untreated; younger than 21 years; and had histologically confirmed RMS, extraosseus Ewing's sarcoma, or undifferentiated sarcoma. Patients with primary brain or spinal cord disease were ineligible. Written informed consent was obtained for all patients according to US Federal guidelines and the Declaration of Helsinki. Protocol approval by institutional review boards was required. Patients were required to begin therapy within 42 days of initial biopsy and within 21 days after definitive surgery. Patient data included sex, racial or ethnic background, and age. Tumor-related data included: primary site, size, clinical assessment of lymph node status, histologic subtype, and whether the primary tumor was confined to the anatomic site of origin (T₁) or had extension or fixation to adjacent tissue (T₂). Primary site classification used standard anatomic nomenclature; however, the category "other" included various sites: intrathoracic (n = 1), perineum (n = 4), gastrointestinal (n = 5), genitourinary (not bladder or prostate) (n = 12), trunk (n = 13), retroperitoneum (n = 32), and all others (n = 10). The timing of radiation therapy and the dose-time relationship were not dependent on induction chemotherapy response, and response data were therefore not obtained. Patient characteristics are summarized in Table 1.

Treatment
Treatment and outcome for patients with group III disease treated on IRS-III have been published previously². Those with group III embryonal tumors located in the orbit or head were treated with vincristine + actinomycin-D (VA) chemotherapy. Other patients with group III disease (excluding special pelvic and selected other sites) were assigned randomly to one of three multiagent chemotherapy regimens (VA + cyclophosphamide [VAC]; VAC + cisplatin and vincristine + adriamycin + cyclophosphamide [VadrC]; or VadrC-VAC + cisplatin + etoposide). Patients with group III disease located at special pelvic sites were treated with VAdrC-VAC + cisplatin + etoposide. Drug dosages were reduced by 50% for infants younger than 1 year, and subsequently increased to 75% and then 100% as tolerated.

IRS-III guidelines required that patients with group III disease begin radiotherapy at week 7 (exception: week 1 for high-risk parameningeal primary patients) and that treatment planning be based on age and tumor size as assessed at diagnosis. The protocol specified a tumor size and age-dependent dosage to the primary tumor (Table 2). Treatment was at 1.8 Gy per fraction once per day, 5 days per week. Radiation port margins of 5 cm were recommended. Treatment of involved lymph nodes was required, whether or not resected, to be the same total dose as the primary site, with a margin of 1 to 2 cm. Volume reductions during the radiotherapy course secondary to prior chemotherapy response were not allowed but were required when necessary to avoid exceeding normal tissue tolerance recommendations as listed in the protocol.

Definition of Failure Pattern Terms
The records of all patients not in continuous complete remission status were reviewed to assess the site or sites of treatment failure, the relationship of the failure site to the radiotherapy plan, and/or cause of death. Failure patterns were classified as local, regional, or distant. Category was determined by the initial site(s) of failure only (ie, failure events that were concurrent or within 1 month). A subsequent failure site did not change the assignment of failure pattern category.

Local failure refers to failure of the primary tumor to regress, or to reappearance of tumor at the primary site either within or adjacent to the radiation treatment volume or in initially involved regional lymph nodes. Regional failure is defined as recurrence in regional lymph nodes that were not included in the original radiotherapy field. Distant failure is defined as the appearance of tumor at a site representing hematogenous dissemination; or malignant cells in pleural fluid, ascitic fluid, or CSF. Total local failure refers to patients with both local failure only and those with concurrent local and regional or distant failures. Similarly, the total distant failure group is inclusive of all patients with distant failure with or without local and/or regional failure. Therefore, the groups are not mutually exclusive.

Statistical Considerations
Failure-free survival (FFS) was defined as the time from study entry to the first occurrence of progression, relapse after response, or death from any cause. Overall survival was defined as time from study entry to death, again, from any cause. Patients not experiencing an event were censored at their date of last contact. Estimates of "time to event" distributions were calculated using the method of Kaplan and Meier,⁴ and outcome among subsets of patients were compared using the log-rank test.⁵ Because observation of one type of recurrence precluded the observation of the time to another type of recurrence, the distribution of time to a specific failure type was estimated using cumulative incidence curves.⁶ Recursive partitioning methods were used to identify subsets of patients with differing risk of failure,⁷ and the variables assessed were age, T stage, N stage, tumor size, tumor stage, primary site, and histology.

	RESULTS

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Of 1,062 eligible patients treated on IRS-III, 472 had group III disease (gross residual disease after biopsy or initial surgery and no distant metastases). Sixty-seven did not receive radiotherapy—12 because of relapse before radiotherapy was scheduled and 55 because radiotherapy was not delivered owing to patient or physician preference. The remaining 405 patients are the subjects of this report.

Patient Characteristics
Patient and tumor characteristics for the population are listed in Table 1. The median age at study entry was 5 years, two thirds of patients were male, and more than three-fourths of patients were white. Sixty-five percent had primary tumors that arose in unfavorable sites (stages 2 and 3). Three had clinical evidence of metastatic disease that was not confirmed at surgery. Half had large (> 5 cm) tumors, nearly two-thirds had evidence of tumor invasion (T₂), and 14% had evidence of regional node involvement. Seventy-two percent of patients had tumors of embryonal histology. The most common primary sites were parameningeal (28%), orbit (19%), and bladder or prostate (18%).

Survival and FFS
The median follow-up for surviving patients was 9.5 years. The estimated 5-year FFS and overall survival for the 405 patients with Group III disease who received radiotherapy was 70% (95% CI, 66% to 75%) and 78% (95% CI, 73% to 82%), respectively.

Patterns of Failure
One hundred thirty-four patients (33%) relapsed or had an event that removed them from the continuously disease-free category. Those events were distributed as follows: local failure only, 51 patients (38%); regional failure only, 4 patients (3%); distant failure only, 26 patients (19%); local plus regional and/or distant failure, 24 patients (18%); unknown site of recurrence, 10 patients (7%); and death as a first event from toxicity or second cancer, 19 patients (14%). Seventy-one percent of the 105 patients who relapsed (with known recurrence site) had local failure, and 45% had distant relapse as a component of their failure pattern. Approximately 90% of all local failures occurred by 37 months.

The failure pattern was further analyzed to assess specific 5-year cumulative incidence rates according to the sites of relapse as follows: local only, 13%; local plus concurrent regional and/or distant failures, 19%; regional (including local), 2%; distant (including local and/or regional), 11%; and death from toxicity or unknown recurrence type, 4% (Table 3).

Recursive partitioning was used to identify subsets of patients with differing risks of failure. T stage, N stage, and age defined three prognostically different patient subsets. The first subset (n = 226) comprised T₁, N₀/N_x patients (all ages), and those aged 1 to 9 years who were T₂, N₀ /N_x. Their estimated 5-year FFS was 78% (95% CI, 73% to 84%). Patients younger than 1 year or older than 10 years with T_2, N₀/N_x RMS (n = 62), had an estimated 5-year FFS of 61% (95% CI, 49% to 73%). Patients with regional nodal involvement (N₁), regardless of age or invasiveness (n = 58), had the worst outcomes, with a 5-year FFS estimate of 45% (95% CI, 32% to 58%).

Predictors of Total Local Failure and Distant Failure
In univariate analysis, factors not statistically significant for total local failure included age, sex, site, size, stage, and histology. Node status was significant, and the 5-year cumulative incidence of total local failure was estimated at 32% for patients with N₁ disease, and 16% for patients with N₀/N_x disease (P = .001). Compared with N₀ and N_x patients, children with N₁ disease were more likely to be older than 9 years, have alveolar or undifferentiated histology, have tumor size greater than 5 cm, and have less favorable primary site (extremity, head and neck, and other; P < .05). Of all N₁ patients, 33% had alveolar or undifferentiated histology. Of all alveolar or undifferentiated histology patients, 24% were N₁. Sex distribution did not differ by node status.

Recursive partitioning was used to identify patient subsets with differing risks of total local failure. The four subsets identified (5-year local failure risk) were: N_1, (32%); and N₀/N_x, embryonal, 10 years, (23%). Two subsets with similar outcome, which are separated for comparison, included: N_o/N_x, alveolar/undifferentiated/other histology, any age, (16%); and N₀/N_x, embryonal histology, and age less than 10 years, (15%; Fig 1).

View larger version (17K): [in this window] [in a new window]   Fig 1. Estimated cumulative incidence of total local failures by regression tree groups in Intergroup Rhabdomyosarcoma Study III, group III (P < .001).

Risk of Total Local Failure and Radiotherapy
We analyzed the association of risk of total local failure with various radiotherapy characteristics. Total radiotherapy dose to the primary tumor was assigned by patient age and tumor size (Table 2). There was no statistically significant difference in the estimated 5-year cumulative risk of total local failure by assigned dose: 41.4 Gy, 14%; 45 Gy, 23%; and 50.4 Gy, 16% (P = .20) There was no observed difference in local failure risk for the three assigned dose groups for the subsets of N₀/N_x and N₁ patients; however, the number of patients in these subsets is too small to provide reliable estimates of local failure risk. The estimated total local failure risk by actual (rather than assigned) total dose (n = 378) was assessed in three total dose ranges: less than 42.5 Gy (n = 97), 42.51 to 47.5 Gy (n = 154), and greater than 47.5 Gy (n = 127). The 5-year cumulative incidence rates of total local failure in each dose range were 18%, 18%, and 20%, respectively (P = .82). Patients (n = 339) were divided into four subsets by tumor size ( 5 cm and > 5 cm) and total dose ( 47.5 Gy and > 47.5 Gy). The estimated 5-year cumulative incidence of local failure was not significantly different (P = .27).

Analysis of Compliance With Radiotherapy Guidelines
An assessment of whether radiotherapy was delivered according to protocol guidelines was made by members of the radiation oncology subcommittee. Cases were judged to have been appropriate (n = 235), with minor (n = 22) or major (n = 116) deviations from treatment guidelines, or inevaluable (n = 30). Pretreatment patient and tumor characteristics were analyzed as predictors of guideline compliance. Patients were more likely to have received appropriate radiotherapy if they had stage 1 (P = .01), T₁ (P = .03), or embryonal histology tumors (P = .005), or if the primary site was extremity, bladder/prostate, head and neck, or orbit (compared with parameningeal or other sites; P = .001). The likelihood of appropriate radiotherapy guidelines compliance was not affected by patient age (P = .06), tumor size (P = .32), or node status (P = .28). The estimated 5-year risk of total local failure was lower when evaluation of radiotherapy was assessed as appropriate, compared with having major or minor deviations (15% v 24%, P = .012).

	DISCUSSION

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The Third Intergroup Rhabdomyosarcoma Study tailored therapy according to relapse risk, and was based on the extent of disease present after biopsy or surgery and the location and histologic subtype of the primary tumor. Radiotherapy was required for local control for patients with gross residual disease (group III).³ In this subset, radiotherapy provides a higher local control rate when compared with studies in which it is not given. The European study MMT 84 used a primary chemotherapy approach for all patients. Those who achieved a complete remission after chemotherapy did not receive radiotherapy, and only 34 of 186 patients were cured with chemotherapy alone. Local recurrence accounted for 85% of treatment failures.⁸ The multimodal risk–based approach used in IRS-III produced a 5-year FFS of 70% for group III patients. Despite these encouraging results, approximately 30% of our patients had treatment failure before 5 years of follow-up, and 71% of these events involved a local failure component. Risk of failure for patients with group III disease was associated with age, invasiveness, and regional node involvement. The estimated 5-year FFS for patients without regional node involvement with noninvasive (T₁) tumors or invasive (T₂) tumors and age 1 to 9 years was 78%, compared with 61% for patients without regional node involvement with T₂ tumors and age younger than 1, or older than 10 years, and only 45% for patients with regional node involvement. The failure pattern for IRS-III group III patients was similar to IRS-II, in which most failures were local, but differed from the pattern of disease recurrence observed in the first IRS trial, in which distant failures predominated.^9,10

The radiotherapy total dose guidelines for IRS-III group III patients were determined by age at diagnosis and tumor size—factors selected to tailor doses to tumor burden and reduce doses for young patients. Divisions for each category were based on median tumor size (5 cm) and age older or younger than 6 years. Historically, children older than 6 years had increased risk of local failure.¹¹ The analysis herein was done to assess the effect of patient, tumor, and treatment factors on risk of local failure. The major end point (total local failure contrasted with local failure only) was chosen to not overestimate utility of definitive radiotherapy. The estimated 5-year cumulative incidence of total local failure was 19%, which was comparable to the same end point for similar IRS-II patients (22%),¹² but higher than observed in IRS-IV (13%).¹³

Patient- and tumor-related local failure predictive factors that were analyzed included age, primary site, tumor size, extent (T₁ or T₂), histology, stage, and node status. By univariate analysis, only node status predicted increased total local failure risk. With recursive partitioning, node status, age, and histology were predictive of total local failure. Age younger than 10 years with embryonal histology and alveolar/undifferentiated/other histology were favorable when assessed by recursive partitioning (in N₀/N_x children). Analysis of patients older and younger than 6 years, combined with tumor size, was not of prognostic significance. Although constituting only 14% of all patients, children with N₁ disease accounted for approximately a quarter of all total local failures.

Lower total radiation doses (actual) were not predictive of local failure risk. Similarly, analysis of assigned radiation dose by patient age and tumor size (Table 2) was not of prognostic significance. These data cannot be interpreted to confirm whether or not there is a radiation dose-response relationship, since dose assignment is keyed to potentially prognostic (and therefore confounding) factors. Other radiation parameters not studied were delay in starting radiotherapy and protraction of overall treatment time. Delay of more than 30 days from diagnosis to starting radiotherapy was an adverse prognostic factor in an Australian study that combined patients in all surgicopathologic groups.¹⁴ Protraction of overall time has not been studied in RMS, but is associated with worse outcome in medulloblastoma.¹⁵ In addition, data were not obtained to assess whether recurrences were in-field or marginal. Those patients whose radiotherapy protocol compliance review (of total dose and volume) was without deviations had a reduced risk of local failure. The significance of this observation is confounded, however, by selection bias (ie, compliance was more likely in children with favorable tumor-related characteristics). Conversely, node status did not affect compliance with radiotherapy guidelines. Other explanations for the adverse effect of positive nodes on local failure risk are not apparent from our analysis.

Several strategies to improve local control have been studied. In IRS-IV, group III patients were prospectively randomized to compare once-a-day fractionation (total dose, 50.4 Gy) to 1.1 Gy twice per day (total dose, 59.4 Gy). The trial was designed to yield a 10% improvement in local control with hyperfractionation; however, the local failure risks were not different.¹³ At St Jude Children's Research Hospital, 28 patients were selected from a total of 79 group III patients on the basis of complete response (with or without delayed surgery) to receive reduced radiotherapy dose (median, 40 Gy). Twenty-two (79%) had local control.¹⁶ The Cooperative Soft Tissue Sarcoma Study Group CWS-86 protocol assigned radiation dose to group III patients based on response to induction chemotherapy: good response, 32 Gy; and poor response, 54.4 Gy (both hyperfractionated). The local relapse rates were 13% and 7%, respectively. Since two-thirds of the patients had subsequent surgery, the concept of planned response–based, reduced-dose radiotherapy could not be evaluated. A favorable patient subset (good response to chemotherapy and preoperative radiotherapy) had a 5-year event-free survival (67%) that is similar to that of the population reported here (70%).¹⁷

In the IRS-III trial and the subsequent IRS-IV study, local failure risk exceeded the risk of distant metastases as a first failure event.^2,18 The current IRS-V protocol explores the role of surgery after induction chemotherapy (12 weeks for most group III patients) as a strategy to reduce local failure risk. The decision for resection is determined by chemotherapy response, and whether form and function can be preserved. If such surgery is performed, postoperative radiotherapy is required, with dose determined by resection margin status: gross residual, 50.4 Gy; microscopic residual, 41.4 Gy; and clear margins, 36 Gy.

Better understanding of the molecular biology of RMS may lead to an improved cure rate. Recent clinical advances, however, may soon also contribute to a better outcome. Newer chemotherapy regimens that incorporate inhibitors of topoisomerase I are being studied in IRS-V and may lead to reduction in local and distant failures. Contemporary imaging with magnetic resonance greatly facilitates accurate assessment of primary tumor location and extent. A new development becoming more widely available in radiation oncology centers is the use of computer software to enable fusion of magnetic resonance images to the computed tomography–based imaging obtained with modern simulation equipment. The result is more accurate definition of tumor volume and the opportunity to more precisely encompass that volume with 3-dimensional or intensity-modulated radiotherapy. Future clinical trials that incorporate these and other advances should be designed to improve local control.

	Authors' Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	NOTES

 
Supported by the Department of Health and Human Services, United States Public Health Service grants No. CA-24507, CA-30138, CA-30969, CA-29139, and CA-13539.

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

 
1. Pappo AS, Shapiro DN, Crist WM, et al: Biology and therapy of pediatric rhabdomyosarcoma. J Clin Oncol 13:2123-2139, 1995[Abstract/Free Full Text]

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8. Flamant F, Rodary C, Rey A, et al: Treatment of non-metastatic rhabdomyosarcomas in childhood and adolescence: Results of the second study of the International Society of Paediatric Oncology—MMT84. Eur J Cancer 34:1050-1062, 1998

9. Maurer HM, Gehan EA, Beltangady M, et al: The Intergroup Rhabdomyosarcoma Study-II. Cancer 71:1904-1922, 1993[CrossRef][Medline]

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13. Donaldson SS, Meza J, Breneman JC, et al: Results from the IRS-IV randomized trial of hyperfractionated radiotherapy in children with rhabdomyosarcoma: A report from the IRSG. Int J Radiat Oncol Biol Phys 51:718-728, 2001[CrossRef][Medline]

14. Mameghan H, Fisher R, Tobias V, et al: Local failure in childhood rhabdomyosarcoma and undifferentiated sarcoma: Prognostic factors and implications for curative therapy. Med Pediatr Oncol 21:88-95, 1993[Medline]

15. del Charco J, Bolek T, McCollough W, et al: Medulloblastoma: Time-dose relationship based on a 30 year review. Int J Radiat Oncol Biol Phys 42:147-154, 1998[CrossRef][Medline]

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17. Koscielniak E, Harms D, Henze G, et al: Results of treatment for soft tissue sarcoma in childhood and adolescence: A final report of the German Cooperative Soft Tissue Sarcoma Study CWS-86. J Clin Oncol 17:3706-3719, 1999[Abstract/Free Full Text]

18. Crist WM, Anderson JR, Meza J, et al: Intergroup Rhabdomyosarcoma Study-IV: Results for patients with non-metastatic disease. J Clin Oncol 19:3091-3102, 2001[Abstract/Free Full Text]

Submitted August 19, 2003; accepted March 4, 2004.

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This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wharam, M. D. Articles by Meyer, W. H. Search for Related Content PubMed PubMed Citation Articles by Wharam, M. D. Articles by Meyer, W. H. Social Bookmarking                            What's this?