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© 2003 American Society for Clinical Oncology Treatment of Localized Nonorbital, Nonparameningeal Head and Neck Rhabdomyosarcoma: Lessons Learned From Intergroup Rhabdomyosarcoma Studies III and IV
From the Department of Pediatrics, Hospital for Sick Children, Toronto, Ontario, Canada; the Departments of Preventive and Societal Medicine and Hematology/Oncology, University of Nebraska Medical Center, Omaha, NE; Department of Radiation Oncology, Johns Hopkins Hospital, Baltimore, MD; Department of Radiation Oncology, Stanford University Medical Center, Stanford, CA; Department of Surgery, Children’s Hospital of Pittsburgh, Pittsburgh, PA; Department of Laboratory Medicine, Children’s Hospital of Columbus, Columbus, OH; and Department of Hematology/Oncology, University of Missouri-Columbia School of Medicine, Columbia, MO. Address reprint requests to Alberto S. Pappo, MD, Children’s Oncology Group, PO Box 60012, Arcadia, CA 91066-6012, email: alberto.pappo{at}sickkids.ca.
Purpose: The characteristics and clinical outcomes of children and adolescents with localized nonorbital, nonparameningeal head and neck rhabdomyosarcoma (RMS) treated on national protocols from the Intergroup Rhabdomyosarcoma Group are reported. Patients and Methods: We conducted a retrospective review of 164 children and adolescents enrolled in the third and fourth Intergroup Rhabdomyosarcoma Studies. Variables analyzed included age, sex, primary tumor site, histologic subtype, clinical group, therapy, site and rate of treatment failure, and time to initial recurrence. Results: Localized nonorbital, nonparameningeal RMS accounted for 9% of all cases of RMS. The median age at diagnosis was 5 years; the median follow-up was 6.6 years. Estimated 5-year failure-free survival (FFS) and survival (S) rates were 76% (95% CI, 69% to 83%) and 83% (95% CI, 77% to 89%), respectively. In multivariate analysis, patients with clinically involved regional nodes (N1) had worse FFS (P = .02). For patients with embryonal tumors, FFS was significantly improved, especially among patients with Group I/II without nodal disease clinical Group I, II N0. For patients with alveolar/undifferentiated histology, FFS was significantly worse in children under the age of 1 year. Actuarial estimates of recurrences at 15 years were local (19%), regional (5%), and distant (9%). Conclusion: More than 80% of patients with RMS of the head and neck are cured of their disease using surgery and vincristine, dactinomycin ± cyclophosphamide with or without radiotherapy. Our results indicate that early, limited exposure to cyclophosphamide might reduce recurrence in low-risk embryonal patients and that reduced dosages might achieve comparable results with improved toxicity profiles. These hypotheses will be tested in the next generation of trials from the Soft Tissue Committee of the Children’s Oncology Group.
APPROXIMATELY 4% of all childhood tumors are rhabdomyosarcoma (RMS), the most common soft-tissue sarcoma in children and adolescents.1 About 35% of all RMSs arise in the head and neck region, and nearly 75% of those tumors are confined to the orbit or parameningeal area.2 The remainder arise in the oral cavity, larynx, parotid region, cheek, scalp, and soft tissues of the neck; these are commonly termed nonorbital, nonparameningeal tumors. The results of the first and second Intergroup Rhabdomyosarcoma Studies (IRS) showed that the 5-year failure-free survival (FFS) of patients with nonorbital, nonparameningeal tumors was 70%. Chemotherapy in these trials consisted of two to four drugs (ie, vincristine and dactinomycin, with or without cyclophosphamide and doxorubicin) and local control measures that included radiation therapy (RT) and multiagent chemotherapy.3–5 Since the publication of the results of these trials, the IRS has conducted two additional studies, IRS-III and IRS-IV. Patients in the IRS-III trial, excluding patients with neck primary tumor sites, were treated with only two drugs: vincristine and dactinomycin (VA). In planning for the IRS-IV trial, the committee determined that the results of IRS-III were similar to the two previous trials, and thus, the trials were deemed to be unacceptable for patients with stage 1 nonorbital tumors. Therefore, an alkylating agent was incorporated into the standard VA backbone therapy in an attempt to improve outcome in these patients. This report summarizes the outcomes of 164 children and adolescents with localized nonorbital, nonparameningeal head and neck RMS who were treated on the IRS-III and IRS-IV trials. The findings of these trials provide the rationale for risk-directed therapy for subsequent trials in these patients.
Patients The study population comprised children and adolescents with localized nonorbital, nonparameningeal head and neck RMS who were enrolled on either IRS-III or IRS-IV between 1984 and 1997. Eligible patients were less than 21 years of age, had newly diagnosed RMS or undifferentiated sarcoma, and had normal organ function (ie, creatinine < 1.2 mg/dL, bilirubin < 1.5 mg/dL, absolute neutrophil count > 1,500/µL, platelets > 150,000/µL). Treatment began within 42 days of definitive surgery (ie, biopsy or resection). The trial protocols were approved by the respective institutional review boards, and informed consent was obtained from all patients, parents, or guardians, as appropriate. Nonorbital, nonparameningeal head and neck tumors are defined as neoplasms that arise in the neck, parotid region, oropharynx, cheek and masseter muscle, scalp, oral cavity, larynx, and other nonorbital, nonparameningeal sites. Primary neck tumors are defined as those that originate in the cervical soft tissues between the mastoid area and the clavicle.
Staging
Treatment IRS-III trial. Patients with clinical group I or II embryonal tumors were treated with VA, with or without RT (Fig 1  , regimens 31 and 32). Patients with clinical group III embryonal tumors located in the head region were treated with regimen 32, whereas patients with tumors located in the neck area were treated more aggressively with one of three regimens that comprised RT and multiagent chemotherapy with three or more drugs (Fig 1, regimens 34, 35, and 36). Patients with clinical group I or II tumors with unfavorable (ie, alveolar) histologies received chemotherapy with vincristine, dactinomycin, cyclophosphamide, cisplatin, and doxorubicin for 1 year, in addition to receiving local RT.7 Drug dosages were reduced by 50% for infants younger than 1 year of age and were subsequently increased to 75% and 100% as tolerated. Patients with clinical group I alveolar tumors and all patients with clinical group II disease received local RT (dosage, 41.4 Gy). Patients with clinical group III disease received local RT at doses based on patient age and the initial tumor size (range, 41.4 to 50.4 Gy).
IRS-IV trial. In the absence of renal abnormalities, patients were randomly assigned to one of three 43-week chemotherapy regimens comprising 1) vincristine, dactinomycin, and cyclophosphamide (VAC); 2) vincristine, dactinomycin, and ifosfamide (VAI); or 3) vincristine, ifosfamide, and etoposide (VIE; Fig 2 ).8 Patients with clinical group II or III disease received local RT based on the amount of tumor remaining after initial surgery. Patients with group II disease received a total dose of 41.4 Gy by conventional fractionation, whereas patients with group III disease were randomly assigned to receive either 50.4 Gy in 1.8-Gy daily fractions (conventional) or 59.4 Gy in 1.2-Gy bid fractions at a interfraction interval of 6 hours (ie, hyperfractionated RT).9
Statistical Methods Definition of End Points FFS was defined as the time from the start of treatment to disease recurrence or death as a first event. This end point represents the percentage of patients who remained alive without progressive disease or death from any cause. Survival was defined as the time from start of treatment to death from any cause. FFS and survival for patients who never experienced the event of interest (ie, disease-recurrence or death) were censored at the time of the patient’s last contact date.
Data were analyzed on an intent-to-treat basis and included patients who did not receive their protocol-specified therapies. Variables that were analyzed included age, sex, primary tumor site, histologic subtype (eg, botryoid, embryonal, or alveolar/undifferentiated sarcoma), and clinical group (Table 1
FFS and survival curves were calculated by the method of Kaplan and Meier.10 Confidence intervals (CIs) for estimates of time-to-event distributions were calculated using Greenwood’s formula for the variance of the estimates.11 The cumulative incidence rates of local, regional, or distant recurrence were estimated using cumulative incidence curves. Differences between curves were analyzed by the log-rank test.12 Comparison of frequency distributions of patient characteristics were analyzed by Sites of First Failure Progressive disease, or failure, was defined as increased size of the primary tumor or appearance of disease at a previously uninvolved site. Failure was considered local if the tumor recurred at the site of primary disease (including recurrence with CNS extension), with or without regional or distant recurrence. Failure was considered regional if regional lymph nodes were involved, with or without local or distant recurrence. Distant recurrence was defined as any metastatic disease present at the time of recurrence. The failure site categories are, therefore, not mutually exclusive.
Patient Characteristics Between 1984 and 1997, 1,777 patients with localized (ie, clinical group I-III) RMS were treated on the IRS-III (n = 888) and IRS-IV (n = 889) studies, and 164 (9%) of those patients had primary tumors in the nonorbital, nonparameningeal head and neck area.
The median age of these patients (103 patients in IRS-III and 61 patients in IRS-IV) at diagnosis was 5 years (range, 0 to 18 years), and the median follow-up at the time of this report was 6.6 years (range, 11 months to 15 years). The clinical characteristics of these patients are summarized in Table 3
Survival and Prognostic Factors The estimated 5-year FFS and survival for all patients was 76% (95% CI, 69% to 83%) and 83% (95% CI, 77% to 89%), respectively (Fig 3 ). No significant difference in FFS or survival was observed between patients enrolled on the two trials; the estimated 5-year FFS was 74% (95% CI, 66% to 83%) for the 103 patients enrolled in IRS-III and 78% (95% CI, 67% to 89%) for the 61 patients enrolled in IRS-IV (P = .61). Similarly, the estimated 5-year survival for patients in IRS-III and IRS-IV was 83% (95% CI, 75% to 90%) and 83% (95% CI, 72% to 95%), respectively (P = .73).
In univariate analysis, female sex and absence of nodal involvement were associated with better FFS (P = .04 and .03, respectively), but only absence of nodal involvement was a prognostic factor for survival (P = .02). In multivariate analysis, patients with clinically involved regional nodes (N1) had lower FFS (P = .02) than did patients who did not have clinically involved nodes (N0). After adjusting for the effect of nodal status, no other patient characteristics were significantly associated with clinical outcome. FFS estimates stratified by category were: female, not N1 (n = 69): 89%; male, not N1 (n = 64): 70%; female, N1 (n = 18): 54%; and male, N1 (n = 13): 65% (P = .006). Unlike the results of the IRS-I trial, a primary tumor in the neck was not a prognostic factor for outcome in this series of children who were treated with modern therapies.
Clinical Outcome According to Histologic Subtype
For patients with alveolar/undifferentiated tumors (n = 58), estimated 5-year FFS and overall survival figures were similar for patients enrolled in IRS-III and IRS-IV (Table 4  ). However, FFS was significantly influenced by the age of the patient; patients under 1 year (n = 6) had significantly worse FFS (17%; 95% CI, 1% to 46%) than patients aged 1 to 9 years (69%; 95% CI, 54% to 84%) and patients aged 10 years or older (82%; 95% CI, 59% to 99%; P = .0043; Fig 5). Of the six patients with alveolar/undifferentiated histology under 1 year of age, four experienced subsequent relapse.
Patterns of Disease-Recurrence and Relapse The 15-year cumulative incidence of tumor recurrence was local in 19%, regional in 5%, and distant in 9% of the patients. Local recurrence was more prevalent in the IRS-III trial (20%) than it was in the IRS-IV trial (9%). Estimated 3-year survival after relapse was 32% (95% CI, 16% to 48%). The 3-year estimated survival after local, regional, and distant recurrences was 43% (95% CI, 20% to 67%), 14% (95% CI, 1% to 40%), and 28% (95% CI, 1% to 54%), respectively.
Our review confirms the excellent clinical outcomes of contemporary treatment regimens for patients with nonparameningeal, nonorbital RMS. More than 80% of these patients are expected to be cured from their disease using vincristine and dactinomycin ± cyclophosphamide (VAC) with or without RT. These results compare favorably with the results of previous IRS trials and with those of other large multi-institutional trials, including the Malignant Mesenchymal Study 84 of the International Society of Pediatric Oncology (SIOP) and the German Cooperative Soft Tissue Sarcoma Study (CWS) 86.13,14 The results of our series demonstrate a similar FFS for all patients with head and neck nonorbital, nonparameningeal tumors who were enrolled in the IRS I-IV trials. However, patients with embryonal tumors enrolled in IRS-IV had a higher 5-year event-free survival than patients who were enrolled in IRS I-III. Although we are aware of the difficulties of attributing causality in nonrandomized comparisons, we believe that this improvement in 5-year FFS in the IRS-IV trial is likely a result of the addition of an alkylating agent, such as cyclophosphamide, to the chemotherapy regime8 While an FFS difference was observed for patients with lymph node-negative, surgically resected (clinical Group I and II) embryonal tumors, survival of these patients was comparable in IRS-III and IRS-IV and exceeded 90%. Because long-term survival is similar, children with lymph node-negative Group I or II nonorbital, nonparameninegal head and neck tumors now receive protocol VA chemotherapy with (Group II) or without (Group I) RT. However, it is possible that the FFS benefit observed with the addition of an alkylating agent in the IRS-IV trial could be obtained with early, short-term exposure to an alkylating agent, such as cyclophosphamide. The next trial for the treatment of children with low-risk RMS will attempt to maintain or improve the current survival and FFS while reducing the late effects of therapy by adding limited-dose cyclophosphamide (maximum dose, 4 to 6 g/m2) to standard-dose VA therapy in children with low-risk disease features. We expect that this limited dose will improve the FFS rates of these patients while avoiding the adverse effects of higher-dose and longer-duration treatment. The additional toxicity associated with the addition of limited-dose cyclophosphamide to the standard VA therapy should be more than offset by avoiding the psychological effects associated with recurrence and by the more serious long-term effects of salvage therapy in the proportion of patients who experience recurrence. Although our comparisons are limited by the small numbers of patients in each subset in our review, patients with embryonal tumors and regional nodal disease and/or unresected primary tumors (N1 and Group III) in the IRS-IV trial had better FFS and survival estimates (85% and 92%, respectively) than patients in the IRS-III (67% and 78%, respectively), the IRS-II (69% and 74%, respectively) and the IRS-I (61% and 61%, respectively) trials. In IRS-III, all patients with nonparameningeal, nonorbital tumors of the head received two-drug therapy (VA) with or without RT, whereas in IRS-IV, all patients with primary tumors in the head and neck received a three-drug combination (VAC, VAI, or VIE) with or without RT. Thus, our findings support the addition of an alkylating agent, such as cyclophosphamide, to standard VA therapy for these patients, a treatment strategy currently being tested in the IRS-V study. However, the optimal dose and duration of this three-drug combination has not been well defined and, for this reason, the next trial of the Soft Tissue Sarcoma Committee of the Children’s Oncology Group will explore the effect of limiting the cumulative dose of cyclophosphamide to between 4 and 6 g/m2. The addition of an intensified regimen that incorporated alkylating agents, such as cyclophosphamide, did not, however, benefit patients with alveolar tumors, as was the case with alveolar RMS that arises in other sites.8 Patients who were less than 1 year of age and who had an alveolar tumor had a particularly high rate of treatment failure (83%), and of note, three of these children with clinical Group II (n = 2) and Group III (n = 1) disease did not receive RT. A review of 439 patients with completely resected alveolar RMS showed that irradiation produces a survival advantage for all children with unfavorable histology, including those with clinical Group I disease.15 We recognize, however, that irradiation of infants is a difficult problem. Both the IRS and the European investigators (ie, investigators from CWS and SIOP) lack sufficient data to demonstrate that withholding radiation for infants can be routinely recommended at this time. Therefore, until these issues are clarified, the current IRS-V study recommends irradiation of all children with an alveolar/undifferentiated tumor, regardless of clinical group or stage, and randomly assigns patients to chemotherapy with standard VAC or VAC alternating with topotecan and cyclophosphamide, a promising drug combination that has proven particularly effective in patients with alveolar tumors.16 Future trials will likely test novel drug combinations in an effort to decrease failure rates. The multimodal treatment approach adopted by the IRS differs from that of other multi-institutional trials in Europe. These differences may explain some of the disparities in reported FFS estimates. For example, in the SIOP 84 trial, 17 children with nonorbital, nonparameningeal RMS were treated with a primary chemotherapeutic approach using ifosfamide, vincristine, and dactinomycin.14 Although the 5-year survival estimate of 77% for the SIOP trial is comparable to the 83% survival estimate observed in our series, the failure rate in the European series was significantly higher. Only 35% of patients in the SIOP MMT84 trial were treated successfully with chemotherapy alone; the remainder required additional local therapies. The higher rate of treatment failure, coupled with a comparable survival rate, raises questions about the optimal method to achieve treatment success in RMS. Because irradiation of the head and neck in children may be associated with significant long-term sequelae, such as impaired statural growth, facial asymmetry, poor dentition, and visual problems and/or cataracts,17 future trials should examine possible ways to lessen the side-effects of irradiation in select patients, such as by reducing the dose of RT on the basis of the preoperative response to chemotherapy, an approach currently being explored in the IRS-V study. In the CWS 86 trial, patients with Group III tumors (ie, < 5 cm in size) who achieved a complete response to preoperative chemotherapy had a 5-year FFS of 77% without initial RT. The same study showed that accelerated and hyperfractionated RT (1.6 Gy twice daily) with a total dose of 32 Gy was adequate to control microscopic disease in patients who had a good but incomplete response to preoperative chemotherapy.13 In conclusion, over 80% of children with localized nonorbital, nonparameningeal RMS can be cured with chemotherapy and RT. The philosophy of the Soft Tissue Sarcoma Committee of Children’s Oncology Group continues to be to optimize tumor control while retaining form and function. Thus, the addition of low to moderate doses of alkylating agents to the standard chemotherapy regime in future trials might prove beneficial in decreasing the number of local, regional, and distant recurrences in patients with Group I and II disease. For patients with unresected and/or lymph node-positive disease, a three-drug combination that incorporates an alkylating agent plus local/regional RT seems beneficial, but the optimal dose and fractionation of RT require further evaluation within the context of a prospective, multi-institutional trial.
Supported in part by grants CA-24507 and CA-72989 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD. Membership list of the Soft Tissue Sarcoma Committee of the Children’s Oncology Group available upon request.
1. Ries LA, Smith MA, Gurney JG, et al: Cancer incidence and survival among children and adolescents: United States Surveillance, Epidemiology, and End-Results (SEER) program 1975–1995. NIH Pub No 99-4649. Bethesda, MD, 1999
2. Pappo AS, Shapiro DN, Crist WM, Maurer HM. Biology and therapy of pediatric rhabdomyosarcoma. J Clin Oncol 13:2123–2139, 1995 3. Wharam MD Jr., Foulkes MA, Lawrence W Jr., et al: Soft tissue sarcoma of the head and neck in childhood: Nonorbital and nonparameningeal sites. A report of the Intergroup Rhabdomyosarcoma Study (IRS)-I. Cancer 53:1016–1019, 1984[CrossRef][Medline] 4. Maurer HM, Gehan EA, Beltangady M, et al: The Intergroup Rhabdomyosarcoma Study-II. Cancer 71:1904–1922, 1993[CrossRef][Medline]
5. Wharam MD, Beltangady MS, Heyn RM, et al: Pediatric orofacial and laryngopharyngeal rhabdomyosarcoma. An Intergroup Rhabdomyosarcoma Study report. Arch Otolaryngol Head Neck Surg 113:1225–1227, 1987 6. Maurer HM, Beltangady M, Gehan EA, et al: The Intergroup Rhabdomyosarcoma Study-I. A final report. Cancer 61:209–220, 1988
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8. Baker KS, Anderson JR, Link MP, et al: Benefit of intensified therapy for patients with local or regional embryonal rhabdomyosarcoma: Results from the Intergroup Rhabdomyosarcoma Study IV. J Clin Oncol 18:2427–2434, 2000 9. 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] 10. Kaplan E, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457–481, 1958[CrossRef] 11. Simon R, Wittes RE: Methodologic guidelines for reports of clinical trials. Cancer Treat Rep 69:1–3, 1985[Medline] 12. Peto R, Pike MC, Armitage P, et al: Design and analysis of randomized clinical trials requiring prolonged observation of each patient: II. Analysis and examples. Br J Cancer 35:1–39, 1977[Medline]
13. 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 14. 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[CrossRef][Medline]
15. Wolden SL, Anderson JR, Crist WM, et al: Indications for radiotherapy and chemotherapy after complete resection in rhabdomyosarcoma: A report from the Intergroup Rhabdomyosarcoma Studies I to III. J Clin Oncol 17:3468–3475, 1999 16. Meyer WH, Breitfeld PP, Lyden E, et al: The drug pair, topotecan/cyclophosphamide, is active in previously untreated rhabdomyosarcoma (RMS): A report from the Intergroup Rhabdomyosarcoma Study Group (IRSG). Proc Amer Soc Clin Oncol 19:582a, 2000 (abstr 2288). 17. Raney RB, Asmar L, Vassilopoulou-Sellin R, et al: Late complications of therapy in 213 children with localized, nonorbital soft-tissue sarcoma of the head and neck: A descriptive report from the Intergroup Rhabdomyosarcoma Studies (IRS)-II and III. Med Pediatr Oncol 33:362–371, 1999[CrossRef][Medline] Submitted January 8, 2002; accepted October 8, 2002.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 tests. A P value of less than 0.05 was considered statistically significant. Analyses were based on the data available as of January 2001. 
