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Which Patients With Microscopic Disease and Rhabdomyosarcoma Experience Relapse After Therapy? A Report From the Soft Tissue Sarcoma Committee of the Children’s Oncology Group

From the Primary Children’s Medical Center, Salt Lake City, UT; University of Nebraska Medical Center, Omaha, NE; Columbus Children’s Hospital, Columbus; Barrett Clinical Cancer Center, Cincinnati, OH; Mayo Clinic, Rochester, MN; Johns Hopkins Hospital, Baltimore, MD; University of Rochester, Rochester, NY; St Jude Children’s Research Hospital, Memphis, TN; Stanford University Medical Center, Stanford, CA; Dana-Farber Cancer Institute, Boston, MA; Children’s Hospital of Pittsburgh, Pittsburgh, PA; and M.D. Anderson Cancer Center, Houston, TX.

Address reprint requests to Lynn M. Smith, MD, Children’s Oncology Group, PO Box 60012, Arcadia, CA 91066-6012.

	ABSTRACT

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PURPOSE: To identify which patients with rhabdomyosarcoma and microscopic residual disease (group II) are likely to not respond to therapy.

PATIENTS AND METHODS: Six hundred ninety-five patients with group II tumors received chemotherapy and 90% received radiation therapy on Intergroup Rhabdomyosarcoma Study (IRS)-I to IRS-IV (1972 to 1997). Tumors were subgrouped depending on the presence of microscopic residual disease only (subgroup IIa), resected positive regional lymph nodes, (subgroup IIb), or microscopic residual disease and resected positive regional lymph nodes (subgroup IIc).

RESULTS: Overall, the 5-year failure-free survival rate (FFSR) was 73%, and patients with embryonal rhabdomyosarcoma treated on IRS-IV fared especially well (5-year FFSR, 93%; n = 90). Five-year FFSRs differed significantly by subgroup (IIa, 75% and n = 506; IIb, 74% and n = 101; IIc, 58% and n = 88; P = .0037) and treatment (IRS-I, 68%; IRS-II, 67%; IRS-III, 75%; IRS-IV, 87%; P < .001). Multivariate analysis revealed positive associations between primary site (favorable), histology (embryonal), subgroup IIa or IIb, treatment (IRS-III/IV), and better FFSRs. Patterns of treatment failure revealed local failure to be 8%, regional failure, 4%, and distant failure, 14%. The relapse pattern noted over the course of IRS-I to IRS-IV shows a decrease in the systemic relapse rates, particularly for patients with embryonal histology, suggesting that improvement in FFSRs is primarily a result of improved chemotherapy.

CONCLUSION: Group II rhabdomyosarcoma has an excellent prognosis with contemporary therapy as used in IRS-III/IV, and those less likely to respond can be identified using prognostic factors: histology, subgroup, and primary site. Patients with embryonal rhabdomyosarcoma are generally cured, although patients with alveolar rhabdomyosarcoma or undifferentiated sarcoma, particularly subgroup IIc at unfavorable sites, continue to need better therapy.

	INTRODUCTION

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THE CURE RATE for rhabdomyosarcoma has steadily improved over the past 30 years, with refinements in systemic therapy, surgical techniques, and advances in radiation therapy (RT). Extent of disease (which defines patients into groups) is one of the most important prognostic factors to predict which patients are likely to be cured.^1,2 Patients with tumors confined to the primary site of origin have a much better prognosis compared with those with regional or metastatic disease, and those with resectable disease at the time of initiation of chemotherapy have the highest cure rates.^2-7 Patients with group II rhabdomyosarcoma fit into this latter category, which includes patients with residual microscopic disease and/or resected regionally involved lymph nodes at the time of initiation of chemotherapy. The basis for the inclusion of resected regional nodes in group II assumes that microscopic residual disease remains in the regional nodal basin because a formal lymph node dissection has generally not been preformed or advocated.

Although many patients with microscopic residual disease are cured, some experience relapse despite adjuvant chemotherapy and RT. Higher-than-expected tumor burdens have been reported in specimens of group II patients who undergo elective wide re-excision to obtain clear surgical margins. Survival results improved when microscopic disease could be eliminated by complete resection.⁸ Other potential factors influencing outcome include histologic subtype (alveolar v embryonal), primary site (favorable v unfavorable), and regional node involvement.^1,9,10 When adverse prognostic factors are known, failure-free survival rates (FFSRs) can be influenced by tailoring therapy toward the risk for relapse, as seen by improved outcome on Intergroup Rhabdomyosarcoma Study (IRS)-II compared with IRS-I for localized alveolar extremity rhabdomyosarcoma.¹¹ To identify which patients with microscopic disease are likely not to respond to therapy, we reviewed the clinical characteristics, outcomes, and patterns of response of 695 patients treated on IRS-I through IRS-IV.

	PATIENTS AND METHODS

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Patients and Staging
Eligibility criteria for analysis included previously untreated patients, age less than 21 years, and a biopsy-proven diagnosis of rhabdomyosarcoma, undifferentiated sarcoma (UDS), or sarcoma not otherwise specified who were entered onto studies IRS-I through IRS-IV with group II disease. Patients were staged according to the IRS clinical grouping classification (Table 1). Surgeons on the IRS committee verified the group. Sixty-five patients were entered onto the study as group I (20 patients) or III (45 patients). However, after central surgical review, they were reclassified as group II. The majority of these patients were not reclassified in time to receive treatment intended for group II but are included in the analysis to provide outcome for all patients with group II tumors enrolled onto IRS I-IV studies. All patients registered on regimens for group II were nonrandomly assigned to receive RT as part of the treatment plan. Patients registered on regimens for group III were also scheduled to receive RT, but at higher doses. Patients registered on regimens for group I were not, by design, scheduled to receive RT.

	RESULTS

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A total of 695 eligible patients with group II rhabdomyosarcoma were enrolled onto IRS-I (1972 to 1978, n = 180), IRS-II (1978 to 1984, n = 177), IRS-III (1984 to 1991, n = 203), and IRS-IV (1991 to 1997, n = 135). Seventy-three percent of the patients had microscopic residual disease and no evidence of regional lymph node involvement (subgroup IIa), 14% of the patients had no microscopic residual disease at the primary site but had involved regional lymph nodes that were resected (subgroup IIb), and 13% of the patients had both microscopic residual disease of the primary site and involved regional lymph nodes that were resected (subgroup IIc). The patient and tumor characteristics by categories of group II tumors are listed in Table 2. Comparisons among subgroups show that patients with subgroup IIa were more likely to have parameningeal or orbit primary sites, although patients with subgroup IIb or IIc were more likely to have genitourinary, non–bladder/prostate (GU non-BP) primary sites (P < .001). Patients with subgroup IIb or IIc were more often male (P = .005), adolescents 15 years or older (P < .001), and diagnosed with larger (> 5 cm) primary tumors (P = .003). The relatively high proportion of adolescent males with paratesticular primaries accounts for these differences in subgroup IIb or IIc. Subgroup IIc is further distinguished by a greater percentage of patients with alveolar rhabdomyosarcoma (P = .02).

FFSRs and OS Rates
Follow-up for survivors ranged from 0 to 25 years (median, 8.4 years). The estimated 5-year FFSR for the entire cohort is 73% (n = 695; 95% confidence interval [CI], 69% to 76%), and the estimated 5-year OS rate is 78% (95% CI, 75% to 81%). Only nine patients experienced relapse between 5 and 10 years after treatment. Therefore, the 5-year estimates reflect stable survival rates out to 10 years.

Figure 1 shows outcome by IRS treatment. Patients treated on IRS-IV had significantly better outcomes (5-year FFSR, 87%; P < .001) when compared with earlier studies. Figure 2 shows outcome by subgroup. Patients with subgroup IIa and IIb had similar outcomes (5-year FFSR of approximately 75%), and these were significantly better compared with patients with subgroup IIc (5-year FFSR, 58%; P = .0037).

View larger version (14K): [in this window] [in a new window]   Fig 1. FFSR for group II according to IRS study.

View larger version (15K): [in this window] [in a new window]   Fig 2. FFSR for group II according to subgroup.

Table 3 shows the outcome for patients with group II tumors according to histology and primary site. Patients with embryonal rhabdomyosarcoma, subgroup IIa or IIb, and favorable site fared well, although subgroup IIc that occurred at unfavorable sites conferred a poor outcome (5-year FFSR, 88%; n = 183 v 5-year FFSR, 38%; n = 16; P < .001). Similar trends were noted for patients with alveolar rhabdomyosarcoma or UDS. However, this did not reach statistical significance (5-year FFSR, 72%; n = 58 v 5-year FFSR, 47%; n = 34; P = .15). Table 4 shows outcome according to histology, primary site, and IRS study. For patients with embryonal rhabdomyosarcoma, FFSR improved dramatically on IRS-IV (5-year FFSR, 93%) as compared with IRS-I through IRS-III (5-year FFSR of approximately 75%). For patients with alveolar rhabdomyosarcoma or UDS, the FFSR was somewhat improved for patients treated on IRS-III and IRS-IV (5-year FFSR of approximately 69%), as compared with those treated on IRS-I and IRS-II (5-year FFSR of approximately 55%). The main improvement for patients with alveolar rhabdomyosarcoma or UDS seemed to be restricted to those with primary tumors at unfavorable sites treated on IRS-III and IRS-IV (P = .01).^3-6

Regional treatment failure. Regional treatment failure was not a common pattern of treatment failure. However, as expected, the incidence of regional treatment failure was higher for patients with subgroup IIb or IIc (5% to 8%) as compared with patients with subgroup IIa (2%). Regional treatment failure was more frequent for patients with alveolar rhabdomyosarcoma or UDS (8%) compared with embryonal rhabdomyosarcoma (1%). The risk for regional treatment failure was highest for patients with alveolar rhabdomyosarcoma or UDS in subgroup IIb (13%).

Local treatment failure. Local treatment failure was similar for patients with subgroup IIa (8%), IIb (9%), and IIc (6%) and did not differ by histologic subtype.

Outcome for the Patients Not Receiving Radiation Therapy
A total of 37 patients did not receive RT, although they were entered onto regimens that specified RT. Twenty of the 37 patients did not receive RT because of concerns for late effects in young children. Of these 20 patients, the 5-year FFSR was 69% and the 5-year OS rate was 85%.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
This retrospective review of over 690 patients with rhabdomyosarcoma and microscopic residual disease has identified which patients are most likely not to respond to therapy. We showed that, with contemporary therapy, outcome is excellent for patients with group II tumors, with more than 85% surviving long term. Those patients at highest risk to not respond to therapy could be identified using prognostic factors that include alveolar/UDS histology, subgroup IIc, unfavorable primary sites, and treatment on IRS-I/II.

One of the most important predictors for outcome, regardless of extent of disease, is histologic subtype.^3-6,13 This study confirms the strong influence of histologic subtype on outcome, as more than 25% of patients with alveolar rhabdomyosarcoma or UDS and microscopic disease do not respond to therapy, although treatment failure is rare among patients with embryonal histology.

Patients with embryonal rhabdomyosarcoma have not always enjoyed excellent survival in IRS studies. Those patients with unfavorable primary sites and/or subgroup IIc who received IRS-I/II therapy had significantly higher distant treatment failure rates as compared with those with favorable primary sites or subgroup IIa or IIb. Changes in systemic therapy on IRS-III/IV led to significant decreases in distant relapse rates with improved cure rates. The most significant improvement was on the most recent IRS-IV study, in which chemotherapy for patients with embryonal histology tumors was changed from primarily two-drug therapy with VA to three-drug regimens (VAC/VA + ifosfamide/VI + etoposide) using cyclophosphamide (Cytoxan; Bristol-Myers Squibb Co, Princeton, NJ) (2.2 g/m²) or the ifosfamide equivalent. With these changes, 97% of patients are alive at 5 years, and the negative influence of subgroup IIc and unfavorable primary site in outcome has disappeared.

Of interest is a subset of patients with embryonal rhabdomyosarcoma who were identified as having a low rate of distant treatment failure and a high cure rate throughout all IRS studies (subgroup IIa or IIb, favorable primary site). These observations support separating patients with group II embryonal tumors into categories based on risk for not responding to treatment. Patients with subgroup IIa or IIb at favorable sites have a low risk for submicroscopic distant disease, and two-drug regimens (VA) should be adequate therapy, although patients with subgroup IIc or unfavorable primary sites have a higher risk for harboring submicroscopic distant disease and might benefit from more intensive therapy.

Patients with alveolar or UDS histology who are most likely to not respond to therapy include those with subgroup IIc occurring at unfavorable primary sites treated with IRS-I/II therapy. Distant relapse is the most common cause of treatment failure, and those with subgroup IIc are at the greatest risk. Subgroup IIc has been previously identified as a poor prognostic factor in earlier IRS studies.¹ Although these patients have regional node involvement, this factor alone does not explain the inferior FFSR, because patients with subgroup IIb have an outcome similar to those with node-negative tumors (subgroup IIa). By definition, patients with subgroup IIc have a greater tumor burden compared with patients with subgroup IIa or IIb. Additionally, patients with subgroup IIc are more likely to have invasive tumors. Taken together, these factors may contribute to the high risk for submicroscopic distant disease for patients with alveolar histology and subgroup IIc.

The first major improvements in outcome for patients with alveolar histology occurred on IRS-III when therapy was intensified for all patients, not just those with extremity primary sites as was delivered on IRS-II. Significant benefits associated with improved chemotherapy were apparent only in patients with unfavorable primary sites, although those with favorable primary sites showed little change in FFSR.

Changes in distant relapse rates over IRS studies highlight the inherent biologic differences between embryonal and alveolar rhabdomyosarcoma or UDS.^2,14,15 Whereas patients with embryonal histology were relatively chemosensitive, those with alveolar histology were less sensitive to the same drugs. Therapeutic agents targeted to the recently characterized translocations, found in most alveolar tumors, offer potential novel treatment strategies.

Group II includes patients with clinically involved resected regional lymph nodes because it is presumed that only microscopic disease remains in the undissected regional lymph nodes. The current IRS staging evaluation emphasizes the importance of detecting regional lymph node spread so that all disease can be therapeutically targeted. In the case of patients with subgroup IIb and IIc tumors, all clinically or pathologically involved lymph nodes should be encompassed within the radiation treatment portal. The predilection for regional nodal spread is, in part, determined by primary site, with paratesticular and extremity tumors having the highest incidence of regional spread at diagnosis. This treatment paradigm is highlighted by a recent report of adolescent boys with group II paratesticular tumors who experienced better 3-year FFSRs than those with group I tumors treated on IRS-IV.¹⁶ Although careful evaluation of regional lymph nodes is incorporated into the management guidelines of current IRS protocols, the true incidence of regional lymph node involvement may be underestimated, particularly in earlier IRS studies, in which regional lymph nodes were not as systematically evaluated. Despite this possibility, the incidence of regional lymph node treatment failure was low, particularly for subgroup IIa. As expected, regional node treatment failure was more common in patients with alveolar histology and in patients with subgroup IIb and IIc tumors. Continued improvements in regional control will be an important factor in decreasing the treatment failure rates for patients with alveolar histology.

Local treatment failure was less than 10% for all patients with group II tumors. Single-institution studies have reported similar findings. Mandell et al¹⁷ showed more than 90% local control for patients with subgroup IIa and IIc. For patients with only microscopic disease at the primary site (subgroup IIa), Regine et al¹⁸ reported 96% local tumor control with a median dose of 40 Gy, which is similar to our result of 92%.

Local treatment failure was not influenced by histologic subtype, as patients with embryonal and alveolar histology have similar rates of local treatment failure. It is of interest that, as distant relapse rates decreased for patients with embryonal histology, local treatment failure became the predominant pattern of treatment failure.

The delivery of postoperative RT using appropriate radiation doses and volumes and timing of RT are important factors influencing local treatment failure.¹⁹ A critical analysis of radiation treatment factors was not a focus of this study, and therefore we cannot comment on local treatment failure rates with respect to technical considerations. The optimal dose of radiation to control microscopic residual disease has yet to be defined. Reduction of radiation doses from 60 Gy on IRS-I to 41.40 Gy on IRS-III/IV did not compromise local control rates. Mandell et al¹⁷ have suggested that doses as low as 30 Gy may be sufficient for some patients with group II embryonal rhabdomyosarcoma. IRS-V is addressing this question by decreasing the dose of radiation for patients with subgroup IIa to 36 Gy.

To avoid late effects associated with surgery and RT, the International Society of Pediatric Oncology investigators have withheld local therapy for patients who achieve a complete response to chemotherapy. As expected, local recurrence rates are higher for patients who do not receive traditional local control measures.^20,21 When RT was withheld in the current study for concern of the deleterious effects in young patients, the risk for treatment failure increased (FFSR, 69%), although overall survival was good (OS, 85%) as a result of effective salvage therapy. If cure rates and complication rates are not compromised by the use of effective salvage therapy, a reasonable population to test the hypothesis of eliminating RT would be those patients with embryonal rhabdomyosarcoma at a favorable primary site in subgroup IIa or IIb. This subset of patients is typically younger than 5 years of age at the time of diagnosis and most susceptible to the late effects of RT or surgery.

The risk-based therapeutic strategies currently used for patients with group II tumors were supported by the major findings in this study. For patients with embryonal histology, VA or VAC and RT provides high cure rates. On IRS-V, patients with embryonal histology are now entered onto a low-risk protocol and receive VA and RT for favorable primary sites (orbit/eyelid, non–parameningeal/genitourinary, GU non-BP) and negative nodes (subgroup IIa), although all others receive VAC and RT. On the basis of excellent outcomes for patients with embryonal histology, favorable primary sites, and subgroup IIb, these patients may also be considered for VA chemotherapy in future studies. On IRS-V, VA is intensified (ie, 50% increase in the cumulative vincristine dose and 67% increase in the dactinomycin dose), but the drugs are delivered over a longer period of time (45 weeks v 32 weeks). VAC is also intensified by increasing the cumulative dose of cyclophosphamide (18% higher than on IRS-IV) delivered over 45 weeks. The therapeutic strategies for embryonal rhabdomyosarcoma on IRS-VI study will focus on defining the optimal VA/VAC doses/scheduling and radiation dose/volume to minimize acute and late toxicity of therapy.

For patients with alveolar/UDS histology, current therapeutic strategies are aimed at the improvement of systemic and regional control. On IRS-V, these patients are now entered onto an intermediate-risk protocol designed to test the efficacy of a novel therapeutic agent, topotecan, used in combination with vincristine and cyclophosphamide. This is being compared against VAC, with higher cumulative doses of vincristine, cyclophosphamide, and dactinomycin than were used on IRS-IV.

	ACKNOWLEDGMENTS

 
Supported by grant nos. CA-24507 and CA-72989 from the Department of Health and Human Services, United States Public Health Service, Washington, DC.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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Submitted January 29, 2001; accepted May 5, 2001.

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