Concurrent ifosfamide-based chemotherapy and irradiation. Analysis of treatment-related toxicity in 43 patients with sarcoma.

BACKGROUND: The current study was performed to evaluate the toxicity profile of therapeutic doses of ifosfamide (IFX) given concurrently with full-dose external beam radiotherapy (EBRT) in patients with soft tissue and bone sarcomas. METHODS: The medical records of 43 consecutive patients with soft tissue or bone sarcomas who were treated with concurrent IFX and EBRT were reviewed. RESULTS: The median patient age was 20 years. Histologies were rhabdomyosarcoma (n = 16 patients), Ewing sarcoma (n = 10 patients), malignant fibrous histiocytoma (n = 9 patients), and other soft tissue sarcomas (n = 8 patients). Thirty-one patients (72%) had localized disease, and 12 patients (28%) had synchronous local and distant disease. Treatment consisted of EBRT (median dose, 50.4 gray [Gy]) with concomitant IFX (median dose per cycle, 10.2 g/m(2)). All patients with Ewing sarcoma or rhabdomyosarcoma received additional concurrent chemotherapy. Twenty-six patients (60%) received two or more cycles of IFX, and 17 patients (40%) were treated with one cycle of IFX and EBRT. The incidences of World Health Organization Grade 3 and Grade 4 toxicities were 29% (21 of 73 cycles) and 22% (16 of 73 cycles), respectively. Grade 4 systemic toxicities included leukopenia (n = 14 patients), neurotoxicity (suicidal ideation; n = 1 patient), and diarrhea (n = 1 patient). Confluent moist desquamation (Grade 3) occurred in nine patients in the treatment field; no patient experienced Grade 4 local toxicity. Among 14 patients who were treated preoperatively, 2 patients (14%) had a pathologic complete response, and 6 patients (43%) had a pathologic near-complete response (> or = 90% necrosis). CONCLUSIONS: Local and systemic toxicities after the administration of therapeutic doses of IFX with concomitant EBRT appear comparable to those observed with either treatment alone. These results support the design of prospective studies evaluating concurrent ifosfamide and radiation therapy for patients with sarcomas.

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.

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.

Synovial sarcoma in children and adolescents: thirty three years of experience with multimodal therapy.

BACKGROUND: Synovial sarcoma (SS) is the most common type of non-rhabdomyosarcoma soft tissue sarcoma in childhood, with controversies about its prognosis and treatment. PROCEDURE: We reviewed medical records of 42 children and adolescents with SS treated at our institution between 1966 and 1999 to determine treatment results and assess prognostic factors. RESULTS: With a median follow-up duration of 7.8 years (range 0.2-22.4 years), 5-year progression free survival (PFS) and overall survival (OS) rates were 75.6% (95% Confidence Interval [CI] 62-89.2%) and 87.7% (95% CI 77.3-98.1%) respectively. Eleven patients were dead and four others had progressed but were alive without evidence of disease after further therapy. IRS grouping and tumor invasiveness were found to be significant prognostic indicators (P < 0.01 and = 0.02, respectively). Patients with initial gross total resection (IRS I and II) and non-invasive tumors (T1) were most likely to have prolonged PFS and OS. Patients with small tumors (< 5 cm) (P = 0.09) or with monophasic histology (P = 0.14) had better PFS and OS. CONCLUSIONS: Achieving a complete resection or gross total resection with microscopic residual disease is vital for survival of patients with localized SS. Patients with localized disease who received radiotherapy had improved local control. Chemotherapy did not seem to impact PFS or OS. Future large multi-institutional trials are needed to address whether post-operative chemotherapy is necessary for patients with localized, surgically removed tumors, whether radiotherapy is necessary for patients with completely resected tumors, and to ascertain the order of importance of all the candidate prognostic markers. Med Pediatr Oncol 2001;37:90-96.

Controversies in the management of paratesticular rhabdomyosarcoma: is staging retroperitoneal lymph node dissection necessary for adolescents with resected paratesticular rhabdomyosarcoma?

PURPOSE: Use of retroperitoneal lymph node dissection (RPLND) in paratesticular rhabdomyosarcoma (PTRMS) is controversial and has changed over the past 2 decades. The Intergroup Rhabdomyosarcoma Study Group (IRSG) required ipsilateral RPLND (IRPLND) for all patients with PTRMS treated on IRS-III (1984-91), but changed to clinical evaluation of RPLNs using computerized tomography (CT) in IRS-IV (1991 through 1997). In IRS-IV, only those patients with identified lymph node involvement on CT required surgical evaluation of the RPLNs. Nodal radiation therapy was administered only to patients with RPLNs recognized as positive; such patients received more intensive chemotherapy as well. Thus, they compared the incidence of recognized RPLN involvement using these 2 different approaches. They then analyzed patient outcome to determine whether this change in management affected outcome. METHODS: Eligible patients with group I or II PTRMS who were treated on IRS III (n = 100) or IRS IV (n = 134) were analyzed. Failure-free survival (FFS) and survival (S) rates were estimated using the Kaplan-Meier method and compared using the log-rank test. RESULTS: There was a significant change in the distribution of patients with group I versus II tumors from IRS-III to IRS-IV (group I, 68% in IRS-III versus 82% in IRS-IV). This was the result of decreased node recognition when CT was used to stage RPLNs in IRS-IV and was most notable for adolescents (>10 years of age). Overall, 3-year FFS was 92% for patients treated on IRS-III and 86% for those treated on IRS-IV (P =.10), whereas survival estimates were 96% and 92%, respectively (P =.30). Adolescents were at higher risk of RPLN relapse than were children (<10 years of age) and their FFS and survival were worse, regardless of IRS protocol. Furthermore, adolescents with recognized group II tumors experienced better 3-year FFS than those with group I tumors on IRS-IV (100% versus 68%, P =.06), most likely as a result of receiving radiotherapy and intensified chemotherapy. CONCLUSIONS: Use of only CT scan evaluation of RPLN in IRS-IV led to a decrease in identification of RPLN involvement in boys who present with localized PTRMS, and a higher rate of regional relapse as compared with IRS-III. Adolescents had much higher likelihood of RPLN disease, and they fared significantly worse than did younger children on both studies. Furthermore, adolescent boys with group I tumors experienced worse FFS than those with Group II tumors on IRS-IV, probably because some patients with group II tumors were not identified by CT imaging and thus received less effective therapy. These data suggest that adolescents should have ipsilateral RPLN dissection as part of their routine staging, and those with positive lymph nodes require intensified chemotherapy as well as nodal irradiation.

What constitutes optimal therapy for patients with rhabdomyosarcoma of the female genital tract?

BACKGROUND: Factors affecting outcome for rhabdomyosarcoma (RMS) of the female genital tract in patients treated on Intergroup Rhabdomyosarcoma Study Group (IRSG) protocols I-IV were evaluated to define optimal therapy. METHODS: Records of 151 patients with tumors of the female genital tract who were treated on IRSG protocols I-IV were reviewed for details regarding chemotherapy, surgery, radiotherapy (RT), and outcome. RESULTS: The overall 5-year survival was 82%, (87% for patients with locoregional tumors). Chemotherapy was primarily vincristine, actinomycin-D, and cyclophosphamide (VAC) based. Local therapy was surgery alone in 42% of patients, surgery plus RT in 19% of patients, biopsy plus RT in 12% of patients, and biopsy without RT in 21% of patients. The rate of hysterectomy decreased from 48% in IRS-I/II to 22% in IRS-III/IV with an increase in the use of RT from 23% in IRS-II to 45% in IRS-IV and continued excellent survival. Many patients with vaginal primary tumors received delayed RT or had it omitted on later studies with excellent outcome. For patients with localized embryonal/botryoid tumors, there were no significant differences in 5-year survival among patients with tumors at different sites or among patients treated on IRS-I-IV. In patients with Group I-III tumors, 43% of deaths were from toxicity. Analysis of prognostic factors, with toxic deaths censored, revealed that an age of 1-9 years at the time of diagnosis, noninvasive tumors, and the use of IRS-II or IRS-IV treatments were associated significantly with better outcome. Patients ages 1-9 years fared best (5-year survival of 98%) and patients outside of this age range especially benefited from the intensified therapy used in IRS-III or IRS-IV (5-year survival of 67% on the IRS-I/II vs. 90% in IRS-III/IV). CONCLUSIONS: Localized female genital RMS usually is curable with combination chemotherapy, a conservative surgical approach, and the use of RT for selected patients.

Intergroup rhabdomyosarcoma study-IV: results for patients with nonmetastatic disease.

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.

Synovial sarcoma in children: surgical lessons from a single institution and review of the literature.

BACKGROUND: Synovial sarcomas are malignant high-grade, soft-tissue neoplasms that account for 7% to 8% of all malignant soft-tissue tumors and are the most common nonrhabdomyosarcoma soft-tissue sarcomas in pediatric patients. STUDY DESIGN: A retrospective review of the records of children younger than 17 years with synovial sarcoma treated at the University of Texas MD Anderson Cancer Center from 1966 until 1999 was undertaken. Primary site, tumor size, tumor margins, surgical treatment, adjuvant therapy, local and distant recurrence, and survival were recorded for 42 patients. Overall survival (OS) and progression-free survival (PFS) rates were calculated by the Kaplan-Meier method. The PFS and OS comparisons were performed using the log-rank test. RESULTS: Forty-four patients were identified, but two patients were excluded because of incomplete records. The median followup duration for the 42 patients was 8.8 years (range 0.2 to 22.4 years). The 5-year progression-free survival and overall survival rates were 75.6% and 87.7%, respectively. Eleven patients were dead and four others had progressed but were alive without evidence of disease after further therapy. Intergroup Rhabdomyosarcoma Study (IRS) grouping and tumor invasiveness were found to be significant prognostic indicators (p < 0.01 and p = 0.02, respectively). Patients with initial gross total resection (IRS Groups I and II) and noninvasive tumors (T1) were most likely to have prolonged PFS and OS. Patients with small tumors (<5 cm) (p = 0.09) had better PFS and OS. Adjuvant radiation therapy appeared to be of benefit, and chemotherapy did not seem to impact PFS or OS. Tumors > or = 5 cm are associated with increased risk of local recurrence and distant metastases. CONCLUSIONS: Complete resection with clear, yet not necessarily large, margins remains the treatment of choice for synovial sarcoma in children. Adjuvant radiation therapy should possibly be considered in patients with clear margins (IRS Group I) and in patients with microscopic residual tumor (IRS Group II). Chemotherapy did not seem to impact PFS or OS. Lymph nodes should be evaluated for local regional disease.

Treatment of orbital rhabdomyosarcoma: survival and late effects of treatment--results of an international workshop.

PURPOSE: Orbital rhabdomyosarcoma (RMS) historically has been associated with an excellent survival rate. The majority of patients are cured with the use of both chemotherapy and radiation therapy, but a significant number experience important late sequelae of treatment. In an attempt to determine optimal therapy in relation both to cure and to sequelae, the experience of the four international collaborative groups (Intergroup Rhabdomyosarcoma Study Group [IRSG], International Society of Paediatric Oncology [SIOP] Sarcoma Committee, German Collaborative Soft Tissue Sarcoma Group [CWS], and Italian Cooperative Soft Tissue Sarcoma Group [ICG] studies) was shared at an international workshop. PATIENTS AND METHODS: A total of 306 eligible patients were identified from group records (186 from IRS, 43 from SIOP MMT, 40 from CWS, and 37 from ICG). Median age was 6.8 years, and median follow-up was 6.5 years. Eighty percent of patients received radiation therapy (RT) as part of primary therapy, but there were significant differences in the use of RT between the individual groups (93% in IRSG, 76% in ICG, and 70% in CWS, but only 37% in the SIOP MMT group). RESULTS: At 10 years, event-free and overall survival for the whole cohort were 77% (range, 71% to 81%) and 87% (range, 82% to 92%), respectively. There was no difference in overall survival between the collaborative groups regardless of differences in the use of initial RT. In total, 34 (12%) of 273 survivors had not received RT, although this varied between the different groups (41% in the SIOP MMT group, 20% in CWS, 7% in ICG, and 6% in IRSG). There was no difference in overall survival for the whole cohort regardless of whether radiotherapy was used as part of initial therapy (86% at 10 years for both). CONCLUSION: These data suggest that a subset of patients with orbital RMS can be cured without systematic local therapy, although the total burden of treatment (primary therapy and treatment for relapse) must be taken into account when assessing the implications for late sequelae.

The Intergroup Rhabdomyosarcoma Study Group (IRSG): Major Lessons From the IRS-I Through IRS-IV Studies as Background for the Current IRS-V Treatment Protocols.

Purpose. To enumerate lessons from studying 4292 patients with rhabdomyosarcoma (RMS) in the Intergroup Rhabdomyosarcoma Study Group (IRSG, 1972-1997).Patients. Untreated patients < 21 years of age at diagnosis received systemic chemotherapy, with or without irradiation (XRT) and/or surgical removal of the tumor.Methods. Pathologic materials and treatment were reviewed to ascertain compliance and to confirm response and relapse status.Results. Survival at 5 years increased from 55 to 71% over the period. Important lessons include the fact that extent of disease at diagnosis affects prognosis. Re-excising an incompletely removed tumor is worthwhile if acceptable form and function can be preserved. The eye, vagina, and bladder can usually be saved. XRT is not necessary for children with localized, completely excised embryonal RMS. Hyperfractionated XRT has thus far not produced superior local control rates compared with conventional, once-daily XRT. Patients with non-metastatic cranial parameningeal sarcoma can usually be cured with localized XRT and systemic chemotherapy, without whole-brain XRT and intrathecal drugs. Adding doxorubicin, cisplatin, etoposide, and ifosfamide has not significantly improved survival of patients with gross residual or metastatic disease beyond that achieved with VAC (vincristine, actinomycin D, cyclophosphamide) and XRT. Most patients with alveolar RMS have a tumor-specific translocation. Mature rhabdomyoblasts after treatment of patients with bladder rhabdomyosarcoma are not necessarily malignant, provided that the tumor has shrunk and malignant cells have disappeared.Discussion. Current IRSG-V protocols, summarized herein, incorporate recommendations for risk-based management. Two new agents, topotecan and irinotecan, are under investigation for patients who have an intermediate or high risk of recurrence.

Rhabdomyosarcoma and undifferentiated sarcoma in the first two decades of life: a selective review of intergroup rhabdomyosarcoma study group experience and rationale for Intergroup Rhabdomyosarcoma Study V.

PURPOSE: To review the importance of prognostic factors in developing new protocols for children with rhabdomyosarcoma (RMS). PATIENTS AND METHODS: Four studies conducted by the Intergroup Rhabdomyosarcoma Study (IRS) Group from 1972 through 1991. RESULTS: Favorable prognostic factors are: (1) undetectable distant metastases at diagnosis; (2) primary sites in the orbit and nonparameningeal head/neck and genitourinary nonbladder/prostate regions; (3) grossly complete surgical removal of localized tumor at the time of diagnosis; (4) embryonal/botryoid histology; (5) tumor size < or = 5 cm; and (6) age younger than 10 years at diagnosis. The IRS-V protocols are risk-based and refine therapy by reducing exposure to cyclophosphamide and radiation therapy (XRT) in patients at low risk while adding new, active agents such as topotecan or irinotecan to the standard therapy of vincristine, actinomycin D, and cyclophosphamide (VAC) plus XRT for patients with unfavorable histology or advanced disease. Collection of biologic specimens from patients with newly diagnosed disease continues to identify other factors that may distinguish patients with favorable features from those who need more intensive therapy. A new protocol that takes into account their previous treatment is needed for patients with recurrent disease. This program (being planned) does not include bone marrow/stem cell reconstitution because this strategy has thus far failed to improve survival rates of patients with metastases at diagnosis. CONCLUSION: Better understanding of biologic differences and new, active agents are needed to improve outcome of patients with unfavorable features at presentation.

Ifosfamide and etoposide are superior to vincristine and melphalan for pediatric metastatic rhabdomyosarcoma when administered with irradiation and combination chemotherapy: a report from the Intergroup Rhabdomyosarcoma Study Group.

PURPOSE: This study was designed to estimate the partial and complete response rates (CR and PR) of two novel drug pairs (vincristine and melphalan vs. ifosfamide and etoposide) and to improve overall survival of previously untreated patients with metastatic rhabdomyosarcoma. PATIENTS AND METHODS: One hundred twenty-eight patients were randomly assigned to phase II window therapy consisting of vincristine and melphalan (VM-containing regimen) or ifosfamide and etoposide (IE-containing regimen). Brief window therapy (12 wks) was immediately followed-up by vincristine, dactinomycin, and cyclophosphamide (VAC), chemotherapy, surgery, and irradiation, with continuation of either VM or IE in patients with initial response. Major endpoints were initial CR and PR rates after the phase II window phase of therapy, failure-free survival (FFS), and survival. RESULTS: Patients who received the VM-containing regimen experienced significantly more anemia, neutropenia, thrombocytopenia, and had more cyclophosphamide dose reductions. The initial PR and CR rates were not significantly different for patients treated with either regimen (VM, 74%; IE, 79%; P = 0.428). However, FFS and overall survival (OS) at 3 years were significantly better with the IE-containing regimen (FFS: 33% vs. 19%; P = 0.043; OS: 55% vs. 27%; P = 0.012). CONCLUSIONS: Although the VM-containing regimen produced a high response rate, inclusion of melphalan appeared to limit the cyclophosphamide dose that could be administered, and ultimately, this regimen was associated with a significantly worse outcome than was the IE-containing regimen. Also, the IE-containing regimen was associated with a gratifyingly high survival rate at 3 years (55%), which is significantly higher than has been observed on any previous Intergroup Rhabdomyosarcoma Study Group regimen for similar patients. We believe that this promising outcome indicates that this drug pair merits further randomized testing in metastatic rhabdomyosarcoma.

Multidisciplinary management of pediatric soft-tissue sarcoma.

The management of pediatric soft-tissue sarcomas has improved drastically through the use of multimodal therapy. These tumors include rhabdomyosarcomas and nonrhabdomyosarcomas. Both are staged using physical, radiographic, and histologic evaluation, and both have intricate staging and grouping systems that correlate closely with prognosis. However, approaches to therapy for the two tumor types remain somewhat different. Rhabdomyosarcomas are treated primarily with chemotherapy. Surgical intervention is limited to initial biopsy, wide local excision when clear margins are feasible, and resection of residual disease. Radiation therapy is reserved for patients with persistent or recurrent disease and may be delivered by external beam or brachytherapy. Nonrhabdomyosarcomas are best treated primarily by surgical resection, although radiation and chemotherapy are now being used with some success. Another major difference concerns evaluation of lymphatics. Nonrhabdomyosarcomas in children frequently behave similarly to adult sarcomas, and less commonly involve regional lymph nodes, whereas pediatric patients with rhabdomyosarcomas often have nodal involvement necessitating surgical evaluation of regional lymph nodes as part of the staging protocol. Multimodal therapy has led to improved survival as well as better functional and cosmetic results. With further clinical trials and improved techniques such as brachytherapy and lymphatic mapping with sentinel node biopsy, we expect to continue to optimize therapy for pediatric patients with soft-tissue sarcomas.

Soft-tissue sarcomas of the diaphragm: a report from the Intergroup Rhabdomyosarcoma Study Group from 1972 to 1997.

PURPOSE: To describe clinical details and outcome of children and adolescents with primary sarcomas of the diaphragm treated on Intergroup Rhabdomyosarcoma Studies (IRS) I through IV. PATIENTS AND METHODS: We reviewed the records of 15 patients with sarcoma of the diaphragm who were entered on IRS Group protocols between 1972 and 1997. Patient ages at diagnosis ranged from 0.5 to 20 years (median, 13 yrs), and 10 were girls. Patients had chest pain, dyspnea, and/or coughing, decreased breath sounds, and occasionally hepatomegaly. RESULTS: Localized, gross residual disease after initial surgery was present in 10 patients, and five had metastases at diagnosis (pleura, 3; pericardium, 1; lungs and bones, 1). Tumor subtypes were alveolar rhabdomyosarcoma (RMS) in five cases, embryonal RMS in three, undifferentiated sarcoma in three, extraosseous Ewing sarcoma in three, and unclassified sarcoma in one. Treatment consisted of radiation therapy to the primary tumor and metastases when feasible, and combination chemotherapy with vincristine, actinomycin D, and cyclophosphamide with or without doxorubicin, ifosfamide, cisplatin, and etoposide. Ten patients achieved complete remission (67%), four obtained a partial remission, and one was improved. Five patients (33%) are continuously failure-free and alive at a median of 8.8 years from diagnosis (range, 1.1-15 yrs). However, the other 10 patients experienced relapse at 0.3 to 2 years from start of therapy (median, 1 yr). Sites of relapse were local in five, distant in three, and combined in two. Death after relapse occurred at 0.39 to 2.6 years (median, 1.6 yrs) from diagnosis. CONCLUSIONS: Sarcomas of the diaphragm are generally deemed unresectable at diagnosis and/or are metastatic. Most of them are not embryonal rhabdomyosarcomas. Treatment with more effective primary chemotherapy to shrink the tumor, followed-up by surgical resection and radiation therapy, should improve the prognosis for patients with sarcomas arising in the diaphragm, especially for the majority who have localized tumors.

Late effects of therapy in 94 patients with localized rhabdomyosarcoma of the orbit: Report from the Intergroup Rhabdomyosarcoma Study (IRS)-III, 1984-1991.

BACKGROUND: We reviewed the late complications of therapy in 94 patients with localized, primary rhabdomyosarcoma of the orbit treated on the Intergroup Rhabdomyosarcoma Study (IRS)-III protocol (1984-1991). PROCEDURE: A questionnaire was sent to the institutions that had registered 106 patients with orbital RMS on the IRS-III protocol, seeking information about vision, periocular structures, and growth and development of the 102 survivors. RESULTS: Ninety-four questionnaires were returned. The median follow-up interval was 7.6 years. The affected eye was removed from 13 patients because of local recurrence (N = 10) or other causes (N = 3). Seventy-nine of the eighty-one remaining patients had received radiation therapy. Sixty-five of these seventy-nine patients (82%) developed a cataract, and 43 of them (66%) underwent cataract surgery. Fifty-five patients (70%) had decreased visual acuity. Twenty-four patients had a dry eye, and 22 had chronic keratitis, conjunctivitis, or corneal changes. Strabismus, diplopia, retinopathy, and uveitis were uncommon. The orbit was hypoplastic in 48 of 82 patients assessed (59%). Ptosis and enophthalmos were reported in 22 patients. Decreased statural growth was noted in 13 of the 53 irradiated patients aged 3-14 years at diagnosis with sufficient data (24%). CONCLUSIONS: The overall survival rate was 96% (102/106). The eye was preserved in 86% of the patients, but vision was impaired in 70% of them. Other frequent complications were cataract, orbital hypoplasia, keratoconjunctivitis, and ptosis/enophthalmos. The current IRS-V study recommends decreasing the dose of irradiation and using conformal techniques in an attempt to minimize these complications.

Imaging and clinical spectrum of rhabdomyosarcoma in children.

We retrospectively analyzed the MRI findings of rhabdomyosarcoma (RMSA) in 23 patients to evaluate its role in staging and management. Heterogeneous signal abnormalities were noted in the sarcoma lesions with significant contrast enhancement. Seven head and neck cases showed direct bone invasion and destruction; only one had distant bony metastasis. Metastasis was noted in the lymph nodes, lung, bone, abdominoperitoneum, and head and neck soft tissue. MRI findings of RMSA are most helpful in staging and assessing therapeutic response.

Survival after relapse in children and adolescents with rhabdomyosarcoma: A report from the Intergroup Rhabdomyosarcoma Study Group.

BACKGROUND: Despite advances in therapy, nearly 30% of children with rhabdomyosarcoma experience progressive or relapsed disease, which is often fatal. PATIENTS AND METHODS: To facilitate the development of a retrieval therapy protocol, we studied potential risk factors that were predictive of survival after first relapse in 605 children who were enrolled onto three consecutive Intergroup Rhabdomyosarcoma Study Group protocols. RESULTS: The median survival time from first recurrence was 0.8 years; the estimated percentage of patients who survived 5 years from first recurrence was 17% +/- 2% (mean +/- SD). Univariate analysis showed that tumor histology was an important predictor of 5-year survival (P <.001): the 5-year survival rate was 64% for patients with botryoid tumors (n = 19), 26% for patients with embryonal tumors (n = 313), and 5% for patients with alveolar or undifferentiated sarcoma (n = 273). Further analysis identified prognostic factors within histologic subtypes (P <.001). For patients with embryonal tumors, the estimated 5-year survival rate was 52% for patients who initially presented with stage 1 or group I disease, 20% for those with stage 2/3 or group II/III disease, and 12% for those with group IV disease. For patients with stage 1/group I disease, estimated 5-year survival rates were higher for patients with local (72%) or regional (50%) recurrence than for those with distant (30%) recurrence. Among patients with alveolar or undifferentiated sarcoma, only the disease group predicted outcome: the 5-year survival estimate was 40% for group I versus 3% for groups II through IV. We identified a "favorable risk" group (approximately 20% of patients) whose 5-year estimated survival rate was near 50%; for all other patients, the estimated survival was near 10%. CONCLUSION: This analysis demonstrates that the probability of 5-year survival after relapse for rhabdomyosarcoma is dependent on several factors at the time of initial diagnosis, including histologic subtype, disease group, and stage. These findings will form the basis of a multi-institutional risk-adapted relapse protocol for childhood rhabdomyosarcoma.

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. IRS Group of the Children's Cancer Group and the Pediatric Oncology Group.

BACKGROUND: This review of children and adolescents with nonorbital soft-tissue sarcoma of the head and neck was undertaken to describe late sequelae of treatment, as manifested primarily by problems with statural growth, facial and nuchal symmetry, dentition, vision and hearing, and school performance. PROCEDURE: Four hundred sixty-nine patients entered the IRS-II and -III protocols with localized, nonorbital soft-tissue sarcomas of the head and neck from 1978 through 1987. Their overall survival rate was 53% (250/469) at 5 years. Two hundred thirteen patients were surviving relapse-free 5 or more years after diagnosis, for whom there were serial height measurements at 2 or more years after initiation of therapy. Their median age at diagnosis was 5 years; the median length of follow-up was 7 years. All received multiple-agent chemotherapy, and all but 3 received irradiation to the primary tumor volume. Sixty-eight percent of the tumors arose in cranial parameningeal sites, 22% in nonparameningeal sites, and 10% in the neck. We reviewed flow sheets submitted to the IRS Group Statistical Office to ascertain which late sequelae were recorded. RESULTS: One hundred sixty-four patients (77%) had one or more problems recorded. One hundred ninety of the two hundred thirteen patients (89%) were under 15 years of age at study entry, and at follow-up 92 (48%) had failed to maintain their initial height velocity, which had decreased by more than 25 percentile points from the original value. Thirty-six of the one hundred ninety patients (19%) were receiving growth hormone injections. Hypoplasia or asymmetry of tissues in the primary tumor site was reported in 74 patients, and 13 underwent reconstructive surgery. Poor dentition or malformed teeth were noted in 61 patients. Impaired vision developed in 37 patients, owing primarily to cataracts, corneal changes, and optic atrophy. Thirty-six patients had decreased hearing acuity, and 9 were fitted with hearing aids; 5 of these 9 had received cisplatin. Thirty-five patients were noted to have problems learning in school. Four patients developed a second malignancy (two sarcomas, one carcinoma, one leukemia). CONCLUSIONS: Late sequelae affected the majority of these patients treated for soft-tissue sarcoma of the head and neck on IRS-II and -III. The potential impact of certain sequelae could be reduced by specific measures, such as surgical reconstruction and hormonal therapy. Late sequelae must be taken into account in designing future curative treatments.

Progress in the surgical management of vaginal rhabdomyosarcoma: a 25-year review from the Intergroup Rhabdomyosarcoma Study Group.

BACKGROUND/PURPOSE: During its 25 years of experience, the Intergroup Rhabdomyosarcoma Study Group (IRSG) has completed four sequential prospective clinical trials to improve survival and decrease morbidity rates in childhood rhabdomyosarcoma (RMS). Surgical management of vaginal RMS has changed dramatically. METHODS: The records of 72 patients with localized vaginal RMS were reviewed to assess surgical therapy, chemotherapy, and radiotherapy and their relation to outcome. RESULTS: Each successive IRSG trial resulted in decreased need for surgical resection (IRS-I, 100%; IRS-II, 70%; IRS-III, 30%; IRS-IV, 13%) and excellent disease-free survival using increasingly effective multiagent chemotherapy. CONCLUSIONS: Primary chemotherapy after initial biopsy provides excellent tumor control. Local resection may be appropriate, but removal of organs (ie, complete vaginectomy/hysterectomy) has no role except in persistent or recurrent disease. Mature, residual rhabdomyoblasts may be evidence of a chemotherapy response, and further surveillance and biopsy without surgical resection is adequate treatment.

Thoracic sarcomas in children.

OBJECTIVE: This study reviews the experience of the Intergroup Rhabdomyosarcoma Studies (IRS) II and III with thoracic sarcomas. SUMMARY BACKGROUND DATA: Thoracic sarcomas in children present special problems with histologic diagnosis, total resection of tumor, and local control. Previous studies have shown high rates of local and distant relapse. METHODS: Data from evaluable patients enrolled in IRS II and IRS III were reviewed. Progression-free and overall survival were estimated by the Kaplan-Meier method and statistical differences were calculated by the log-rank test. The multivariate regression analysis of data was performed using the Cox proportional hazards model. RESULTS: A total of 84 patients presented with thoracic sarcomas during IRS II (51 patients) and IRS III (33 patients). Of these, 76 were chest wall tumors, 3 were lung tumors, 4 were pleural tumors, and 1 arose from the heart. The average age at diagnosis was 8.5 years (range, 1 month-20.5 years). Thirty-three patients had alveolar histology, 17 had embryonal histology, and 12 had extraosseous Ewing's sarcoma, with indeterminate, undifferentiated, and pleomorphic histologies in the remaining 22 patients. Thirteen patients presented as group I (localized disease completely resected), 18 as group II (microscopic residual or nodal disease), 31 as group III (gross residual disease or biopsy only), and 22 as group IV (distant metastatic disease). Sixty patients (71%) achieved a complete response. Thirty-nine patients had a local relapse, and 22 had a distant relapse. Thirty-five patients (42%) survived with a mean follow-up of 1.8 years (range 0.7-11.7 years); 49 (58%) have died with an average survival of 1.1 years (range 0.3-11.7 years). Four patients (5%) died of infection or treatment complications. Progression-free survival was not significantly associated with histology, site, clinical group, or IRS study. Overall survival was significantly associated with clinical group, size, and local or distant recurrence, but not with histology or IRS study by univariate analysis. In a multivariate analysis, only clinical group and local and distant recurrence showed statistical significance (p < 0.002, < 0.006, and < 0.001, respectively). CONCLUSIONS: As expected, outcome was better for patients with totally resected or microscopically residual tumor after resection. A higher rate of recurrence in group I versus group II,although not statistically significant, suggests that identification of margin status may be difficult, and these patients may require more intensive efforts for local control. These patients continued to have a high rate of local and distant relapse, and new strategies for preventing these are under development.