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© 2001 American Society for Clinical Oncology Intergroup Rhabdomyosarcoma Study-IV: Results for Patients With Nonmetastatic DiseaseFrom the Intergroup Rhabdomyosarcoma Study Group (IRSG) representing the Children’s Cancer Group, the Pediatric Oncology Group, and the Intergroup Rhabdomyosarcoma Statistical Office, and the Quality Assurance Review Center, Arcadia, CA. Address reprint requests to IRSG Operations Office, Children’s Oncology Group, 440 East Huntington Dr, #300, PO Box 60012, Arcadia, CA 91066-6012; email: jleeson{at}nccf.org
PURPOSE: The study goal was to improve outcome in children with rhabdomyosarcoma by comparing risk-based regimens of surgery, radiotherapy (RT) and chemotherapy. PATIENTS AND METHODS: Eight hundred eighty-three previously untreated eligible patients with nonmetastatic rhabdomyosarcoma entered the Intergroup Rhabdomyosarcoma Study-IV (IRS-IV) (1991 to 1997) after surgery and were randomized treatment by primary tumor site, group (1 to 3), and stage (I to III). Failure-free survival (FFS) rates and survival were the end points used in comparisons between randomized groups and between patient subgroups treated on IRS-III and IRS-IV. Most patients were randomized to receive vincristine and dactinomycin (VA) and cyclophosphamide (VAC, n = 235), or VA and ifosfamide (VAI, n = 222), or vincristine, ifosfamide, and etoposide (VIE, n = 236). Patients with group 3 tumors were randomized to receive conventional RT (C-RT) versus hyperfractionated RT (HF-RT). RESULTS: Overall 3-year FFS and survival were 77% and 86%, respectively. Three-year FFS rates with VAC, VAI, and VIE were 75%, 77%, and 77%, respectively (P = .42). No significant difference in outcome was noted with HF-RT versus C-RT (P = .85 and P = .90, respectively). Overall, patients with embryonal tumors benefited from intensive three-drug chemotherapy in IRS-IV (3-year FFS, 83%). The improvement was seen for patients with stage I or stage II/III, group 1/2 disease, many of whom received VA chemotherapy on IRS-III. Patients with stage 2/3, group 3 disease had similar outcomes on IRS-III and IRS-IV. Three-year FFS for the nonrandomized patient subsets was 75% with renal abnormalities; 81% for paratesticular, group 1 cases; and 91% for group 1/2 orbit or eyelid tumors. Patients with paratesticular primaries had poorer outcomes if they were more than 10 years old (3-year FFS, 63% v 90%). Myelosuppression occurred in most patients, but toxic deaths occurred in less than 1%. CONCLUSION: VAC and VAI or VIE with surgery (with or without RT), are equally effective for patients with local or regional rhabdomyosarcoma and are more effective for embryonal tumors than therapies used previously. Younger patients with group 1 paratesticular embryonal tumors and all patients with group 1/2 orbit or eyelid tumors can usually be cured with VA chemotherapy along with postoperative RT for group 2 disease.
RHABDOMYOSARCOMA, the most common soft tissue sarcoma of childhood, has become increasingly curable over the past quarter century (25% in 1970 v 70% in 1991).1,2 Single antineoplastic drugs, including vincristine (VCR), dactinomycin (AMD), and cyclophosphamide (CYP) were shown to be active against this tumor in the 1960s. Combination chemotherapy (ie, vincristine, dactinomycin, and cyclophosphamide [VAC]), used with radiation therapy (RT), was shown to increase the complete response rate among newly diagnosed patients in the 1970s, a necessary first step toward improving the cure rate overall.3,4 The results of cooperative group trials also indicated the efficacy of multimodality therapy.5 However, the relative rarity of rhabdomyosarcoma, as well as its marked clinical and biologic heterogeneity (eg, numerous primary sites, varied extent of disease at presentation, and multiple histiotypes), made the interpretation of results of relatively small studies problematic. Thus, in 1972, three pediatric cooperative cancer study groups formed the Intergroup Rhabdomyosarcoma Study (IRS) Committee (later Group [IRSG]) to combine their patients and investigative resources. Since that time, the IRSG has designed, conducted, and analyzed four consecutive trials (IRS-I, 1972 to 78; IRS-II, 1978 to 84; IRS-III, 1984 to 91; IRS-IV, 1991 to 97). Overall results of the first three studies have been reported.6-8 The fourth study, reported here, evaluated a new and promising drug pair (ie, ifosfamide [IFOS] + etoposide) and the relative efficacy of IFOS, a CYP analog, compared to CYP when both were given in combination with AMD and VCR at maximal-tolerated doses. Also, hyperfractionated radiation (HF-RT) was compared with conventional fractionated radiation therapy (C-RT) for patients with group 3 disease. The hypothesis was that a higher dose of radiation given as HF-RT would improve local tumor control without an increase in late effects.9
Study Design As in IRS-III, the IRS-IV study enrolled untreated patients younger than 21 years of age with a confirmed diagnosis of rhabdomyosarcoma or undifferentiated sarcoma, type indeterminate.10 Patients with soft tissue Ewing’s sarcoma were excluded, as were patients with primary brain or spinal cord rhabdomyosarcoma or embryonal sarcoma of the liver. Informed consent was obtained from the patients’ parents, the patients, or both, according to the guidelines of the National Cancer Institute. Patients were required to begin therapy within 42 days after the initial biopsy and within 21 days after a definitive surgical procedure. Imaging studies and surgical findings determined the extent of disease. Patients were assigned to a group following surgery based on clinically and pathologically determined extent of disease and degree of surgical resection by each participating institution, according to criteria of the IRS Post Surgical Grouping Classification (Table 1).6 If primary re-excision of tumor was the definitive operation, patients were classified according to their group after this operation, provided the surgery was done within 42 days of the initial procedure and before the start of any protocol-specified chemotherapy. Patients also were assigned a presurgery stage based on tumor site, size, presence or absence of clinically determined lymph node (LN) involvement (ie, increased LN size or positive imaging studies), and/or metastatic disease (Table 2).11
Patients with metastatic disease comprised approximately 15% of the patients who entered onto studies of the IRSG during the time period covered by this report. Because the start and ending dates for these studies were not concurrent with the remainder of the IRS-IV study, these patients are reported separately. Patients with nonmetastatic rhabdomyosarcoma were either assigned a treatment (VA for those with group 1 paratesticular tumors or those with group 1/2 orbit or eyelid tumors and VAC for those with pre-existing renal abnormalities predisposing to nephrotoxicity) or randomized to receive one of three chemotherapy regimens (VAC; vincristine, dactinomycin, and ifosfamide [VAI]; or vincristine, ifosfamide, and etoposide [VIE]; Fig 1). The doses of cyclophosphamide and IFOS were 2.2 g/m2 for 1 day per cycle and 1.8 g/m2/d for 5 days, respectively, both given with mesna (Fig 1). The doses of dactinomycin were 0.015 mg/kg/d x 5 IV; top dose, 0.5 mg and vincristine (V; 1.5 mg2 IV; top dose, 2 mg). Eight-week courses of AMD and VCR were given twice, starting on weeks 12 and 24. Patients were evaluated for response at weeks 11 to 12, 23 to 23, and 35 to 36. Patients with pre-existing hydronephrosis, single kidney, or above normal serum creatinine for age were nonrandomly assigned to VAC plus conventional RT. For patients with PM primaries receiving RT starting day 0, dactinomycin and etoposide scheduled for weeks 3 and 6 were omitted and given as added therapy during weeks 9 and 12. Granulocyte colony-stimulating factor was given to ameliorate dose-limiting hematopoietic toxicity (5 µg/kg/d SC). All other patients received pulsed VAC, VAI, or VIE therapy and VA doses through week 23. Etoposide was given at a dose of 100 mg/m2/d x 5 in the VIE regimen. Drug doses were reduced by 50% for infants less than 1 year of age to avoid excessive toxicity. Subsequent doses were increased to 75% and then to 100%, if tolerated. Patients randomized to VAC therapy who experienced severe toxicity attributed to VAC (eg, veno-occlusive disease of the liver) were switched to VIE therapy. In a few cases, physicians changed therapy from VAC to VAI because of toxicity thought to be associated with CYP.
Patients received RT according to their group. Those patients with stage I or stage II disease (Table 2) whose tumors were completely resected (group 1) received no RT. Patients with stage III, group 1 disease and all patients with residual microscopic disease (group 2) received 41.4 Gy by conventional fractionation to the tumor bed. Initially, those patients with group 3 tumors who had preexisting renal abnormalities were assigned to receive VAC and C-RT (50.4 Gy), whereas other patients with group 3 tumors (randomized to VAC, VAI, or VIE) were also randomized to receive either C-RT or HF-RT (50.4 Gy or 59.4 Gy, respectively). On February 17, 1995, the protocol was amended so that patients with group 3 tumors who had pre-existing renal abnormalities were also randomized to C-RT or HF-RT. RT was delivered using megavoltage photon or electron beam. Brachytherapy was permitted for selected patients but was not to be used for patients randomized to C-RT versus HF-RT. The volume to be irradiated was the presurgical and prechemotherapy tumor volume plus 2 cm. RT was interrupted for patients with absolute neutrophil counts less than 750/µL or platelet counts less than 75,000/µL and was resumed when these counts improved. AMD and etoposide were withheld during RT. RT commenced at week 9 (day 62) for most patients, except those requiring emergency RT at day 0 for spinal cord compression and those who had high-risk parameningeal features (direct intracranial extension, base of skull erosion, or cranial nerve palsy) or group 2 tumors of the orbit or eyelid. For these patients, RT commenced on week 1. Patients with primary tumors originating in any of the cranial-parameningeal sites (nasopharynx-nasal cavity, middle ear-mastoid region, paranasal sinuses [maxillary, ethmoid, sphenoid], or pterygopalatine-infratemporal fossa) were examined for evidence of meningeal impingement by routine roentgenograms and computed tomography or magnetic resonance imaging, were tested for cranial nerve function, and underwent cytologic examination of CSF. Patients who had cranial parameningeal sarcoma without evidence of meningeal impingement received RT to the primary tumor plus a 2-cm margin of adjacent meninges commencing at week 9. Patients with high-risk parameningeal tumors began RT on day 0 to the primary tumor plus a 2-cm margin, in addition to systemic chemotherapy. The prescribed dose was 50.4 Gy (C-RT) or 59.4 Gy (HF-RT) for group 3 tumors, given as described above. Patients with tumor cells in the CSF were declared group 4 and were managed on a separate protocol that included intrathecal chemotherapy. They are excluded from this report.
Definition of End Points
Statistical Methods and Strategy A recurrence was defined as local if the tumor recurred only at the site of primary disease; as regional if regional lymph nodes were involved, with or without local recurrence; and as distant if any metastatic disease was present at recurrence. The rates of local, regional, and distant failure were estimated using cumulative incidence curves.
Patient Population A total of 989 patients were enrolled by 115 institutions onto regimens for patients without metastatic disease from October 14, 1991, to December 31, 1997. One hundred six (11%) were found to be ineligible for study entry. Fifty-three patients did not have tumors with a qualifying histiotype after central pathology review, and 10 did not have rhabdomyosarcoma on reassessment by the treating institution. Thirteen patients were found to have metastatic disease at central surgical review, one patient refused the assigned therapy and did not receive protocol therapy, and an additional 29 patients were excluded because they did not meet other eligibility criteria. Hence, a total of 883 patients met all eligibility criteria for entry onto study and are included in this analyses. The distribution of the number of patients eligible for the various treatment regimens is given in Table 3.
Patient or Tumor Characteristics The distribution of patients by presenting characteristics, after stratification by group, site, and histology, is listed in Table 4. The percentages of patients in groups 1, 2, and 3 (23%, 15%, and 62%, respectively) differed significantly (P = .001) from findings in IRS-III (23%, 22%, and 55%, respectively). This difference reflected the enrollment of patients with advanced disease in pilot studies for IRS-V. Adjustments were made for these differences in comparisons between IRS-III and IV.
Seventy-two percent of the eligible patients were less than 10 years of age at time of diagnosis, and 5% were less than 1 year old. The median age was 5 years (range, 0 to 20 years). The male:female ratio was 1.6:1, similar to that of IRS-III. Ethnic distribution was as follows: white, 70%; black, 16%; Hispanic, 10%; other, 4%. The most common primary sites were the extremities (13%, n = 113), parameningeal sites (25%, n = 222), and genitourinary tract (31%, n = 271). Seven percent of the tumors arose in the head and neck (n = 64), 9% in the orbit (n = 81), 5% in the trunk (n = 41), 7% in the retroperitoneum (n = 64), and 3% in other sites (n = 27). Tumor size was more than 5 cm in 51% of cases. Fifty-one percent of tumors were invasive (T2). On clinical evaluation, 80% of cases lacked LN involvement, 15% had positive LNs, and in 5%, the LN status was unknown. The histopathologic classification of tumors, as specified by the IRS Pathology Review Committee (if available), was used to determine eligibility of patients for the analysis of clinical outcome. A total of 87% of the cases were reviewed by this committee. The agreement rates of the institutional diagnosis with the final review committee diagnosis for the alveolar and embryonal (including botryoid and spindle cell variants) subtypes were 70% and 91%, respectively. Frequencies of the various tumor subtypes were embryonal/botryoid/spindle cell, 70% (n = 614); alveolar, 20% (n = 184); undifferentiated sarcoma, 4% (n = 34); and other, 6% (n = 51), classified as sarcoma, not otherwise specified because of inadequate tissue or poor tissue fixation. This histologic distribution is similar to that observed in IRS-III. In the assignment of patients to groups, the participating institution agreed with the final Surgical Review Committee Group assignment in 96% of the cases reviewed (83% of all patients). The agreement rates for groups 1, 2, and 3 were 96%, 89%, and 98%, respectively.
Chemotherapy Doses Administered
Treatment Outcome Outcome of patients with stage 1 to 3 tumors with pre-existing renal abnormalities. Fifty-six patients with pre-existing renal abnormalities were assigned to receive VAC chemotherapy. For 83% of these patients, hydronephrosis was the abnormality; other abnormalities included single kidney (5%), high serum creatinine for age (8%), or obstructive uropathy (4%). The majority of these patients had group 3 tumors arising from the bladder, prostate, or retroperitoneal site. At a median follow-up of 4.0 years, the 3-year FFS rate for these patients is estimated to be 75% (95% confidence interval [CI], 63% to 87%). Three-year survival is estimated to be 80% (95% CI, 69% to 91%).
Outcome of patients with group 1 paratesticular primaries.
One hundred twelve patients with group 1 paratesticular tumors were assigned to treatment with VA. With a median of 4.0 years of follow-up, FFS was estimated to be 81% at 3 years (95% CI, 74% to 89%) and survival 90% (95% CI, 84% to 96%). Nineteen failures (four local, nine regional, and six distant) have been observed among these 112 patients with paratesticular primaries. All four local failures were within the scrotum and associated with tumor spillage or the need for hemiscrotectomy due to local tumor infiltration. The site(s) of failure among the six patients with a distant failure were as follows: abdomen and lung (n = 1), liver, paraspinal, and bone marrow (n = 1), pleura (n = 1), retroperitoneum (n = 2), or other (n = 1). Adolescent age (ie, Outcome for patients with groups 1 and 2 orbit or eyelid tumors. Two patients with group 1 and 20 patients with group 2 orbital or eyelid tumors were treated with VA, with RT added for those patients with group 2 disease. With a median follow-up of 4.3 years, the 3-year FFS rate and survival estimates for these patients are 89% (95% CI, 78% to 99%) and 100%. These results are similar to those for comparable patients treated on IRS-III (n = 25) (3-year FFS, 92%; 3-year survival rate, 100%). Outcome for patients randomized to VAC, VAI, or VIE. The distribution of patient characteristics according to the randomized treatments is listed in Table 4. There were no significant differences in the distributions of patient characteristics among treatment regimens. FFS rates among the three treatment regimens were not significantly different (Fig 2, P = .42). At a median follow-up of 3.9 years, 3-year FFS rate estimates by chemotherapy regimen were as follows: VAC, 75%; VAI, 77%; and VIE, 77%. The 3-year survival rate was also similar among the randomized chemotherapy regimens (P = .63); estimates of 3-year survival rates were VAC, 84%; VAI, 84%; VIE, 88%. No differences in FFS rates were seen by chemotherapy treatment regimen when the comparisons were restricted to patients with embryonal rhabdomyosarcoma (P = .41) or with alveolar or undifferentiated rhabdomyosarcoma (P = .86).
Outcome for patients with group 3 tumors, eligible for randomization to C-RT or HF-RT. A total of 490 eligible patients with group 3 tumors were randomized to receive either C-RT (n = 251) or HF-RT (n = 239), along with chemotherapy. The distribution of patient characteristics according to the randomized treatments is listed in Table 4. There were no significant differences in the distributions of patient characteristics between patient groups on either of the RT regimens (Table 4). Analysis of FFS and survival by the intent to treat as randomized method revealed no significant difference between the two fractionation regimens (3-year FFS and survival estimates by RT regimen are: C-RT, 73% and 83%, respectively; and HF-RT, 72% and 81%, respectively; P = .85 and .90, respectively). Results of analyses of the RT data by treatment actually received, histology, and results of local and regional disease control rates by RT treatment delivered are the subject of a separate report.9
Prognostic Factors Associated With FFS
Patients assigned to chemotherapy treatment with VAC, VAI, or VIE could be classified into prognostic subsets, based on histologic subtype of the tumor, stage, and group. Low-risk patients were defined as those who were stage I (all groups) or stage II/III, group 1/2. All other patients with locoregional disease (stage II/III, group 3) were defined as intermediate-risk patients. However, when histiotype is also considered with risk group, the estimated 3-year FFS rates were as follows: embryonal, low-risk, 93%; intermediate-risk, 76%; alveolar/undifferentiated sarcoma, low-risk, 72%; and intermediate-risk, 55%.
Comparison of Outcomes on IRS-IV to IRS-III
Sites of Treatment Failure
Toxicity
Deaths caused by toxicity occurred in eight patients. The highest fatality rate was associated with VAC for patients with pre-existing renal abnormalities (three [5%] of 56 patients); rates for other regimens were 1% or less. Six of the fatalities were secondary to septicemia that developed during a period of neutropenia. The other deaths were caused by metabolic complications (n = 1) and another cause (n = 1).
Survival After Relapse
The goal of the IRS-IV protocol, to improve overall treatment outcome for children with rhabdomyosarcoma, was not achieved despite use of intensive, multimodal therapy. The 3-year FFS estimates remain unchanged from that of IRS-III (about 76% in both studies). However, a major finding in this study is that patients with local or regional tumors with embryonal histology fared significantly better on VAC, VAI, or VIE plus surgery and RT than did similar patients treated on IRS-III (3-year FFS rates, 83% v 74%). This improvement seemed to be restricted to those patients with stage I and stage II, group 1/2 disease, many of whom received VA chemotherapy on IRS-III. Patients with stage II/III, group 3 disease had similar outcome on IRS-III and IRS-IV. The majority of the improvement is probably attributable to the addition of alkylating agent to the therapy received by patients treated on IRS-IV, although changes in RT, surgery, and/or supportive care may have played a role.15 Because none of the regimens compared was superior to any other, we concluded that VAC, with or without RT, remains the gold standard for treatment of this relatively large patient subset. However, this therapeutic gain was negatively offset by a slightly worse outcome for similar patients with alveolar or undifferentiated tumors. Clearly, a new approach to therapy is needed for these patients, because maximum-tolerated doses of front-line drugs were used in IRS-IV. In the successor study, IRS-V, patients with alveolar and undifferentiated rhabdomyosarcoma are being randomized to standard VAC or VAC alternating with VCR, topotecan, and CYP. Topotecan is an agent that has been shown to be especially active for patients with alveolar disease.16,17 In addition, all patients with alveolar and undifferentiated rhabdomyosarcoma underwent routine, planned RT. When this study was designed, many but not all, investigators believed that IFOS might be more effective than CYP for a number of pediatric tumors.18,19 Thus, we asked a question regarding effectiveness of these agents by randomizing patients to regimens with each of these drugs given at their maximum-tolerated doses. This study showed convincingly that ifosfamide and CYP are of equal effectiveness in the treatment of rhabdomyosarcoma, when used as a part of multiagent, multimodal therapy. We also directly compared the activity of a new drug pair, IFOS plus etoposide, used with vincristine (VIE), surgery, and RT, with the gold standard therapy of VAC, surgery, and RT. The drug pair, IFOS plus etoposide, was shown to be highly active against rhabdomyosarcoma, even for patients who had relapsed on a combination chemotherapy regimen, including CYP.20 We found that both three-drug combinations (ie, VAC and VIE) were equally effective for patients with nonmetastatic tumors. Finally, because we found no advantage to the use of HF-RT, we continue to recommend use of C-RT. Thus, VAC + surgery + C-RT remains the gold standard therapy for most patients with nonmetastatic embryonal rhabdomyosarcoma. Patients with group 1 to 3 tumors with renal abnormalities received VAC and fared about the same as similar patients without such abnormalities. A relatively small subset of patients with orbit or eyelid primary tumors that were completely resected (group 1, n = 2) or with microscopic residual disease only (group 2, n = 20) were treated with VA alone (group 1) or VA plus RT (group 2) after surgery. They fared well (3-year FFS rate, 91%; 3-year survival, 100%), as in IRS-III (3-year FFS rate, 92%; 3-year survival, 100%),8 confirming the efficacy of this approach. In IRS-V we are continuing to treat these patients similarly. However, for patients with embryonal histology, the RT dose is being decreased to 36 Gy for group 2 and 45 Gy for group 3 in an attempt to reduce potential late effects but still maintaining the outstanding cure rate. A recent report for a small subset of similar patients indicates that chemotherapy may not be needed after surgery and RT.21 However, VA therapy, as delivered on IRS-IV, is relatively nontoxic, and orbital exenteration with intensive re-treatment is often required at relapse. A goal of the IRSG studies is to avoid deformity and/or loss of organ function. Fifty-nine additional patients with group 3 orbital tumors were treated with VAC (n = 21), VAI (n = 20), or VIE (n = 18) with C-RT (n = 28), or HF-RT (n = 31). The FFS rate at 3 years overall is 94%, compared with 80% in IRS-III, which used cyclic VA therapy. However, overall survival was not improved (98% v 100%) because of the relatively high salvage rate for these patients. Follow-up remains relatively short for patients treated in IRS-IV. This result poses a therapeutic dilemma. Does one expose all patients with orbital, group 3 tumors to alkylating agents to benefit a few? In IRS-V we are using intensified AMD with VCR and RT given at a lower dose for patients with orbital embryonal, group 2 or 3 tumors and no RT for those with orbital embryonal group 1 tumors. Eligible patients with group 1 paratesticular rhabdomyosarcoma (n = 112) were treated with surgery followed by VA only, similar to the treatment used in IRS-III. However, it was surprising that their response to treatment was less than that achieved in IRS-III. Nineteen treatment failures have been observed thus far (four local, nine regional, and six distant). The three-year FFS rate was only 81% on IRS-IV compared with 95% on IRS-III. The explanation of this finding is likely the downstaging that occurred in IRS-IV, because surgical sampling of ipsilateral draining lymph nodes was not required as it was in IRS-III. The result was failure to identify retroperitoneal LNs with tumor by computed tomography imaging only and thus downgrouping of patients on IRS-IV that resulted in less intense therapy (eg, no RT to the retroperitoneal LNs for patients considered to have group 1 tumors by computer tomography in IRS-IV). Three-year survival is not yet adversely effected (96% in IRS-III and 92% in IRS-IV). Age was prognostically significant, in that adolescent boys 10 years of age or older fared worse (3-year FFS rates, 63% v 90% for patients aged < 10 years). More concerning still is the finding that both FFS and survival are significantly worse for adolescents with embryonal group 1 tumors in IRS-IV.14 This finding has prompted us to recommend surgical sampling of retroperitoneal LNs in IRS-V for all adolescent boys with paratesticular rhabdomyosarcoma. Therapy for those with group 2 tumors with positive retroperitoneal LNs includes RT to the retroperitoneal LNs and VAC chemotherapy for 1 year. Patients with parameningeal tumors enjoyed a favorable outcome in IRS-IV, with a 3-year FFS rate of 72%. Patients with evidence of intracranial extension had a somewhat worse 3-year FFS rate (70%) than those patients without extension (3-year FFS rate, 78%), although the difference seen on IRS-IV is now not as large as that seen in previous IRSG studies. Outcome for this patient subset was similar to that observed in IRS-III (3-year FFS, 75%).8 Patients with tumors of the bladder or prostate fared equally well on IRS-IV (3-year FFS rate, 79%) compared with IRS-III (75%) with similar local/regional treatment. The results of IRS-IV compare favorably with those of other large international studies. In the MMT89 trial in Western Europe, for example, 625 patients were treated with IFOS, VCR, and AMD, with or without cisplatin, epirubicin, and doxorubicin and with or without RT and surgery. Five-year overall and event-free survival rates for patients with nonmetastatic disease were 73% and 57%, respectively. Patients with metastatic disease were treated differently and experienced a 5-year overall survival rate of 26%. A primary chemotherapy approach was used for patients with stage II or III disease.22 The CWS86 study used VAI plus doxorubicin with or without RT in 131 patients with local/regional rhabdomyosarcoma.18 Five-year disease-free survival was 69%. Disease-free survival rates in the European studies are known to be somewhat lower than reported by the IRSG for similar patient subsets because the European approach is to use primary chemotherapy without local therapy for those patients who achieve complete response. This approach is associated with a higher local relapse rate, but survival is not adversely affected for some patient subsets, due to effective salvage therapy. The potential advantage of the European approach is that it may reduce late effects in those patients not requiring local therapy. However, the price of the additional therapy required for patients who relapse often proves to be even higher. It is difficult to weigh the overall balance of patient benefit associated with these differing approaches. Most patients eventually require local therapy with either approach, but a minority do not and thus are overtreated with the IRSG approach. Conversely, the relapse rate is much higher with the International Society of Pediatric Oncology approach, and secondary treatment is expensive, toxic, and not always successful. Serious toxicity associated with the intensified therapy used in IRS-IV included severe bone marrow suppression with subsequent episodes of septicemia and death in approximately 1% of children. There also have been cases of secondary acute myeloid leukemias (n = 5) and other secondary malignancies (n = 5), most likely related to the use of alkylating agents, anthracycline, and/or etoposide and RT, given either as part of primary therapy or at relapse.23-25 Granulocyte colony-stimulating factor was routinely used in an attempt to avoid the prolonged severe neutropenia potentially associated with IRS-IV therapy. The toxic death rate fell from approximately 5% for the IRS-IV pilot regimens to approximately 1% in IRS-IV.26,27 It is too early to determine potential late effects of therapy. Group and primary site were again shown to be of prognostic importance in the IRS-IV study.28 However, patients with group 2 tumors fared better than group 1 patients. This may be related to the routine use of RT for patients with group 2 tumors, which is not used for those with group 1 tumors (Fig 4). This is the first IRSG study to prospectively use tumor stage to classify all patients and thus combine a presurgical classification with postsurgical group, using both to determine therapy. The recent addition of molecular genetic studies of the tumor tissue to aid in risk assessment should improve our ability to accurately predict relapse in newly diagnosed patients with rhabdomyosarcoma and thus lead to more judicious use of risk-directed therapy in the near future. For example, recent studies have suggested that clinical features, natural history of disease, and response to therapy differ in subgroups of patients with alveolar rhabdomyosarcoma, defined by the presence of the t(2;13), t(1;13), or neither translocation.29 The t(2;13) translocation characterizes cases of alveolar rhabdomyosarcoma with a poor prognosis, whereas presence of the t(1;13) seems to confer a better outcome.29 Confirmatory studies to further test the clinical utility of these observations are ongoing in IRS-V. The results of IRS-IV emphasize that therapy for children with rhabdomyosarcoma should be risk directed and based primarily on tumor site, tumor history, and extent of disease. Younger patients (< 10 years old) with embryonal, group 1 tumors arising in the parapestis fared well with surgery and VA chemotherapy, whereas similar adolescents require more accurate staging with retroperitoneal LN dissection, followed by RT and VAC chemotherapy for those with group 2 tumors (Table 6). Patients with group 2/3 orbit or eyelid tumors generally fare well with surgery + VA chemotherapy (group 1) or surgery + RT + VA chemotherapy (group 2). Most other patients appear to require more intensive multimodality therapy, and the relatively poor outcome for some patient subsets indicates that new therapeutic approaches, including effective new agents, are required. Topotecan is the most promising new agent for rhabdomyosarcoma. Xenograft and clinical studies indicate topotecan’s high level of activity against human rhabdomyosarcoma, especially alveolar tumors.16,17 Also, a Pediatric Oncology Group Phase II study has demonstrated substantial activity for the drug pair topotecan plus CYP for both alveolar and embryonal tumors (Pediatric Oncology Group, personal communication, September 2000). Thus, for all patients with nonmetastatic alveolar rhabdomyosarcoma or undifferentiated sarcoma and patients with stage II/III, group 3 embryonal rhabdomyosarcoma, IRS-V will test the potential therapeutic value of VAC alternating with VCR, topotecan and CYP, comparing it with the gold standard therapy for these patients (VAC as used in IRS-IV plus RT, surgery, and hematopoietic growth factors for all patients). Infants and adolescents have worse outcome than do children with rhabdomyosarcoma, perhaps due in part to their higher frequency of undifferentiated or alveolar histiotypes and thus may especially benefit from this new approach.
The following institutions and members participated in the trial: Intergroup Rhabdomyosarcoma Study Group (IRSG) representing the Children’s Cancer Group, the Pediatric Oncology Group, and the Intergroup Rhabdomyosarcoma Statistical Office, and the Quality Assurance Review Center including Richard J. Andrassy, MD; Carola Arndt, MD; Scott Baker, MD; Frederic G. Barr, MD; W. Archie Bleyer, MD; Philip Breitfeld, MD; Julia Bridge, MD; Holcombe E. Grier, MD; Douglas Hawkins, MD; Peter J. Houghton, PhD; Michael Link, MD; Fran Laurie; William H. Meyer, MD; Jeff Michalski, MD; Sharon Murphy, MD; Charles N. Paidas, MD; Alberto S. Pappo, MD; David M. Parham, MD; Leslie Robison, PhD; Eric Sandler, MD; Lynn Smith, MD; Poul H.B. Sorensen, MD, PhD; Lisa Teot, MD; Timothy Triche, MD, PhD; Teresa J. Vietti, MD; David Walterhouse, MD; Suzanne Wolden, MD; and Richard Womer, MD.
Supported by Department of Health and Human Services (Washington, DC), United States Public Health Service grants no. CA-24507, CA-30138, CA-30969, CA-29139, and CA-13539. We acknowledge the assistance of Jodi L. Neyens with preparation of the manuscript.
See Appendix for additional members of the Intergroup Rhabdomyosarcoma Study Group.
1. Pappo AS, Shapiro DN, Crist WM, et al: Biology and therapy of pediatric rhabdomyosarcoma. J Clin Oncol 13: 2123-2139, 1995 2. Crist W, Kun L: Common solid tumors of childhood. N Engl J Med 324: 461-471, 1991[Medline]
3.
Pratt CB, Hustu HO, Fleming ID, et al: Coordinated treatment of childhood rhabdomyosarcoma with surgery, radiotherapy, and combination chemotherapy. Cancer Res 32: 606-610, 1972 4. Wilbur JR: Combination chemotherapy for embryonal rhabdomyosarcoma. Cancer Chemother Rep 58: 281-284, 1974[Medline] 5. Heyn R, Holland R, Newton WJ, et al: The role of combined chemotherapy in the treatment of rhabdomyosarcoma in children. Cancer 34: 2128-2142, 1974[Medline] 6. Maurer H, Beltangady M, Gehan E, et al: The Intergroup Rhabdomyosarcoma Study-I: A final report. Cancer 61: 209-220, 1988[Medline] 7. Maurer H, Gehan E, Beltangady M, et al: The Intergroup Rhabdomyosarcoma Study-II. Cancer 71: 1904-1922, 1993[Medline]
8.
Crist W, Gehan EA, Ragab AH, et al: The third Intergroup Rhabdomyosarcoma Study. J Clin Oncol 13: 610-630, 1995 9. Donaldson SS, Meza JL, Breneman J, et al: Results from the IRS-IV randomized trial of hyperfractionated radiation in children with rhabdomyosarcoma. Int J Radiat Oncol Biol Phys (in press) 10. Newton WA Jr., Gehan EA, Webber BL, et al: Classification of rhabdomyosarcomas and related sarcomas, pathologic aspects and proposal for a new classification: An Intergroup Rhabdomyosarcoma Study. Cancer 76: 1073-1085, 1995[Medline] 11. Lawrence W Jr, Gehan EA, Hays DM, et al: Prognostic significance of staging factors of the UICC staging system in childhood rhabdomyosarcoma: A report from the Intergroup Rhabdomyosarcoma Study (IRS-II). J Clin Oncol 5: 46-54, 1987[Abstract] 12. Kaplan E, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53: 457-481, 1958 13. 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 35-39, 1977 14. Weiner ES, Anderson JR, Ojimba JI, et al: What is optimal management for children or adolescents with localized paratesticular rhabdomyosarcoma? Results of IRS-III and IRS-IV. J Pediatr Surg (in press)
15.
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 16. Houghton P, Horton J, Houghton J: Drug sensitivity and resistance in the xenograft model, in Maurer H, Ruymann R, Pochedly C (eds): Rhabdomyosarcoma and Related Tumors in Children. Boca Raton, FL: CRC, 1991, pp 187-204
17.
Pappo AS, Lyden E, Breneman J, et al: Up-front window trial of topotecan in previously untreated children and adolescents with metastatic rhabdomyosarcoma: an intergroup rhabdomyosarcoma study. J Clin Oncol 19: 213-219, 2001
18.
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
19.
Kamen BA, Frenkel E, Colvin OM: Ifosfamide: Should the honeymoon be over? J Clin Oncol 13: 307-309, 1995
20.
Miser JS, Kinsella TJ, Triche TJ, et al: Ifosfamide with mesna uroprotection and etoposide: An effective regimen in the treatment of recurrent sarcomas and other tumors of children and young adults. J Clin Oncol 5: 1191-1198, 1987 21. Notis C, Abramson D, Sagerman R, et al: Orbital rhabdomyosarcoma: Treatment or overtreatment? Ophthalmic Genet 16: 159-162, 1995[Medline] 22. Stevens MCG, Oberlin O, Rey A, et al: On behalf of the SIOP MMT Committee: Progress in the treatment of nonmetastatic rhabdomyosarcoma (RMS)—A report from the SIOP MMT 89 and 95 studies. Med Ped Oncol 33: 177, 1999 (abstr 142)
23.
Heyn R, Haeberlen V, Newton W, et al: Second malignant neoplasms in children treated for rhabdomyosarcoma. J Clin Oncol 11: 262-270, 1993 24. Heyn R, Khan F, Ensign L, et al: Acute myeloid leukemia in patients treated for rhabdomyosarcoma with cyclophosphamide and low-dose etoposide on Intergroup Rhabdomyosarcoma Study-III. Med Pediatr Oncol 23: 99-106, 1994[Medline] 25. Mike V, Meadows A, D’Angio G: Incidence of second malignant neoplasms in children: Results of an international study. Lancet 2: 1326-1331, 1982[Medline] 26. Ortega J, Ragab A, Gehan E, et al: A feasibility, toxicity, and efficacy study of ifosfamide, actinomycin D, and vincristine for the treatment of childhood rhabdomyosarcoma: A report of the Intergroup Rhabdomyosarcoma Study-IV Pilot Study. Am J Pediatr Hematol Oncol 15: S15–S20, 1993 (suppl) 27. Ruymann FB, Vietti T, Gehan E, et al: Cyclophosphamide dose escalation in combination with Vincristine and Actinomycin-D (VAC) in gross residual sarcoma: A pilot study without hematopoietic growth factor support evaluating toxicity and response. J Pediatr Hematol Oncol 17: 331-337, 1995[Medline] 28. Crist W, Beltangady M, Gehan E, et al: Prognosis in children with rhabdomyosarcoma: A report of the Intergroup Rhabdomyosarcoma Studies I and II. J Clin Oncol 8: 443-452, 1990[Abstract]
29.
Kelly KM, Womer RB, Sorensen PH, et al: Common and variant gene fusions predict distinct clinical phenotypes in rhabdomyosarcoma. J Clin Oncol 15: 1831-1836, 1997 Submitted August 17, 2000; accepted April 3, 2001.
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 tests were used to compare the frequency distributions of patient characteristics. Analyses were based on data available as of Spring 2000. 
10 but < 21 years old) was associated with a significantly poorer FFS rate. The estimated 3-year FFS rate is 90% for the 77 patients less than 10 years of age but only 63% for the 35 patients aged 10 and older (P < .001). A more detailed analysis of outcome for this patient subset has been published.
