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William H Meyer

Publications and source records attributed to William H Meyer.

At least 19 recordsLinked to original sources
PubMed2008

Comparison of results of a pilot study of alternating vincristine/doxorubicin/cyclophosphamide and etoposide/ifosfamide with IRS-IV in intermediate risk rhabdomyosarcoma: a report from the Children's Oncology Group.

BACKGROUND: Over 50% of patients with rhabdomyosarcoma (RMS) have intermediate risk disease, with a 3-year failure-free survival (FFS) of 50%-70% depending on histology. Doxorubicin is active against RMS, but its role in improving outcome remains controversial. Ifosfamide is as active as cyclophosphamide in RMS, with the Fourth Intergroup RMS Study (IRS-IV) showing equivalent outcomes for patients treated with ifosfamide for the first 28 weeks compared to cyclophosphamide. Treatment with alternating cycles of non-cross-resistant chemotherapy has been used in a number of diseases with good results. PROCEDURE: The results of a pilot study utilizing alternating courses of vincristine, doxorubicin, cyclophosphamide, and etoposide/ifosfamide (VDC/IE) were compared for outcome and patient characteristics to a group of similar matched patients treated on IRS-IV. RESULTS: The 5-year FFS for patients with parameningeal (PM) primaries on IRS-IV and the VDC/IE study were 72% and 82%, respectively (P = 0.26); for patients with non-PM primaries, the estimated risk of failure for VDC/IE study versus IRS-IV was 0.54. Combining all disease sites and performing analysis for relative risk of failure for 46 VDC/IE patients and 342 IRS-IV patients, the relative risk of failure for the VDC/IE study compared to the IRS-IV study is 0.5 (P = 0.06). CONCLUSIONS: VDC/IE is as effective therapy for intermediate risk RMS as IRS-IV therapy. It is being explored along with irinotecan in relapsed patients and newly diagnosed high-risk patients.

Adolescent↗
PubMed2006

Analysis of prognostic factors in patients with nonmetastatic rhabdomyosarcoma treated on intergroup rhabdomyosarcoma studies III and IV: the Children's Oncology Group.

PURPOSE: The outcome for localized rhabdomyosarcoma (RMS) or undifferentiated sarcoma (UDS) is affected by age, histology, primary anatomic site, extent of disease, and therapy. PATIENTS AND METHODS: We evaluated patient and disease characteristics for their ability to predict outcome for patients with nonmetastatic RMS or UDS treated on Intergroup Rhabdomyosarcoma Study (IRS) -III (1984 to 1991) or IRS-IV (1991 to 1997). RESULTS: The estimated 5-year failure-free survival (FFS) rate was 90% for patients with embryonal RMS (ERMS) stage 1, group I or IIa; stage 2, group I; or group III orbit. The estimated 5-year FFS rate was 87% for patients with ERMS stage 1, group IIb or IIc; stage 1, group III nonorbit; stage 2, group II; and stage 3, group I or II; and 73% for patients with ERMS stage 2 or 3, group III. The estimated 5-year FFS rate was poor for patients with stage 2 or 3, group III ERMS with invasive (T2) tumors who were age younger than 1 year or 10 years or older (56%) and patients with stage 2 or 3, group III extremity primary tumors (43%). Overall, outcomes for patients with alveolar RMS (ARMS) or UDS were worse than for patients with ERMS. However, the 5-year FFS rate was good for patients with ARMS/UDS at favorable sites with group I or II (80%) or group III (76%) disease. The FFS rate was poorer for patients with ARMS/UDS at unfavorable sites with group I or II (66%) or group III (45%) disease. The estimated 5-year FFS rate was 31% for patients with group III ARMS/UDS at unfavorable sites with regional lymph node disease, which is similar to metastatic RMS. CONCLUSION: Patient and disease characteristics identify distinct subsets with different outcomes, allowing the Soft Tissue Sarcoma Committee of the Children's Oncology Group to refine risk-adapted therapy assignment.

Adolescent↗
PubMed2006

Pooled analysis of phase II window studies in children with contemporary high-risk metastatic rhabdomyosarcoma: a report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group.

PURPOSE: The Soft Tissue Sarcoma Committee of the Children's Oncology Group has conducted five upfront window trials in patients with newly diagnosed metastatic rhabdomyosarcoma to identify promising new treatment agents. PATIENTS AND METHODS: This pooled analysis identified a total of 420 patients (115 from Intergroup Rhabdomyosarcoma Study III [IRS-III] and 305 from the five window trials). We assessed window therapy response rate, failure-free survival (FFS), and overall survival (OS). RESULTS: Response rates (complete + partial response) assessed at week 6 of window therapy ranged from 41% to 55% and did not predict FFS (P = .073) or OS (P = .31). FFS was influenced by trial (P = .048); patients enrolled onto IRS-III and the ifosfamide/etoposide and ifosfamide/doxorubicin trials fared best. When grouped and compared with topoisomerase I poison trials, ifosfamide/topoisomerase II inhibitor trials had superior FFS (P = .013). However, there was no difference in survival. CONCLUSION: Upfront phase II window trials can efficiently provide robust estimates of activity for new agents and combinations in newly diagnosed patients with high-risk rhabdomyosarcoma. Our data indicate that, for some phase II window trials, the risk of treatment failure may be increased but that the trend towards lower survival for some of the window trials compared with IRS-III is not statistically significant. Window nonresponders did not suffer worse FFS or OS than patients who responded to window therapy. Finally, these results provide a rationale for incorporating ifosfamide, etoposide, doxorubicin, and topoisomerase I poisons in future trials of high-risk metastatic rhabdomyosarcoma.

Adolescent↗
PubMed2006

Expression and genomic status of EGFR and ErbB-2 in alveolar and embryonal rhabdomyosarcoma.

Both epidermal growth factor receptor (EGFR) and ErbB-2 play an important role in cancer biology and constitute promising molecular targets of therapy. EGFR and ErbB-2 expression has been observed in rhabdomyosarcoma cell lines but not analyzed systematically in rhabdomyosarcoma tumors. Tissue microarray sections representing 66 rhabdomyosarcoma tumors (34 embryonal rhabdomyosarcoma, 32 alveolar rhabdomyosarcoma) were surveyed by immunohistochemistry using antibodies specific for EGFR and ErbB-2. Immunostains were assessed for intensity (0: no immunostaining; 1: weak; 2: moderate; 3: strong) and percentage of at least 500 neoplastic cells exhibiting membranous or membranous and cytoplasmic immunostaining. EGFR and ErbB-2 expression was considered positive if the product of intensity and percentage was greater than 10. Patients had a median age of 5.7 years (range 8 months-19.1 years), and of 65/66 patients, 38 were males and 27 were females. Expression of ErbB-2 was identified in 22/66 (33%) cases and tended to be more frequent in the alveolar subtype (13/32, 41%, vs 9/34, 26%, P=0.30). Expression of EGFR was identified in 31/66 (47%) cases and correlated with the embryonal subtype (26/34, 76%, vs 5/32, 16%, P<0.0001) independent of stage, age, and gender. Coexpression of EGFR and ErbB-2 was identified in eight tumors, of which six were embryonal rhabdomyosarcoma. None of the cases exhibited EGFR or ErbB-2 gene amplification, as assessed using fluorescence in situ hybridization. Furthermore, analysis of 11 additional rhabdomyosarcoma tumors (six alveolar; five embryonal) revealed no evidence of mutations in EGFR exons 18, 19, 20, and 21. In summary, expression of EGFR and/or ErbB-2 is detected in a sizeable subset of rhabdomyosarcoma tumors without evidence of EGFR or ErbB-2 amplification or mutations in the EGFR tyrosine kinase domain. Notably, expression of EGFR correlates with the embryonal subtype, which is also more likely to coexpress EGFR and ErbB-2.

Adolescent↗
PubMed2006

Metastatic osteosarcoma.

BACKGROUND: The outcome of patients with metastatic osteosarcoma treated in two consecutive trials from 1986 to 1997 was analyzed to evaluate the efficacy of carboplatin-based multiagent chemotherapy and to identify prognostic factors. The initial study (OS-86) used ifosfamide, cisplatin, doxorubicin, and high-dose methotrexate, and the subsequent study (OS-91) used the same agents at similar doses, but carboplatin was substituted for cisplatin. METHODS: Twelve patients (median age, 15.1 yrs) were treated in OS-86 for osteosarcoma metastatic to the lung only (11 patients) or bone only (1 patient), and 17 patients (median age, 15.1 yrs) were treated in OS-91 for osteosarcoma metastatic to the lung only (12 patients), bone only (2 patients), lung and bone (2 patients), or other site (1 patient). RESULTS: Patients with metastatic disease enrolled in OS-86 and those with metastatic disease enrolled in OS-91 did not differ in terms of demographic features, histologic subtype, site of primary tumor, or site of metastases. There was a difference in survival according to treatment protocol (P = 0.054). All survivors (four of whom were enrolled in OS-86 and one of whom was enrolled in OS-91) had lung metastases only. Five-year survival estimates for patients with lung metastases only were 45.5 +/- 13.7% (OS-86) and 8.3 +/- 5.6% (OS-91) (P = 0.084). Unilateral lung metastases (P = 0.006), no more than three lung nodules (P = 0.014), and surgical remission (P = 0.001) were associated with improved survival probability. CONCLUSIONS: The poor outcome of patients with metastatic osteosarcoma treated in OS-91 justifies the use of cisplatin with its associated toxicity in patients with high-risk disease.

Adolescent↗
PubMed2005

Rhabdomyosarcoma: new windows of opportunity.

Rhabdomyosarcoma is a highly malignant, small blue cell tumor characterized by muscle differentiation. With modern treatment, more than 70% of children and adolescents with this disease are cured. Adequate biopsy to obtain sufficient tissue for accurate diagnosis and molecular characterization is critical. Patients must be assessed for tumor extent; the Intergroup Rhabdomyosarcoma Study (IRS) clinical group and Staging system is universally applied in North America. Multidisciplinary therapy is necessary to maximize cure rates. Local control relies on complete surgical excision when possible; those whose tumors are not completely excised and those with alveolar histology tumors require local irradiation to maximize local control. In North America, vincristine (Oncovin); Eli Lilly and Company, Indianapolis, http://www.lilly.com), dactinomycin (Cosmegen); Merck & Co., Inc., Whitehouse Station, NJ, http://www.merck.com), and cyclophosphamide are the standard chemotherapy agents. The IRS has used therapeutic window studies to confirm the predictive nature of preclinical xenograft models and to identify several new single agents and combinations of agents with activity in high-risk patient groups. Despite these efforts, the outcome for these high-risk patients remains poor. The next generation of Children's Oncology Group studies will evaluate the efficacy of topoisomerase-I inhibitors and dose-compression therapy approaches. New advances in molecular characterization of tumors, including gene-expression analysis, may identify new therapeutic targets that can be exploited by expanded preclinical drug discovery efforts, and hold the promise of revolutionizing risk-based therapies.

Combined Modality Therapy↗
PubMed2004

Sclerosing rhabdomyosarcomas in children and adolescents: a clinicopathologic review of 13 cases from the Intergroup Rhabdomyosarcoma Study Group and Children's Oncology Group.

In recent reports, investigators have described a variant of adult sclerosing rhabdomyosarcoma (RMS) that is characterized by a hyalinizing, matrix-rich stroma. To determine whether this variant occurs in children, we investigated this phenomenon in a recent series of 1207 pediatric patients who had RMS accessioned by the Intergroup Rhabdomyosarcoma Study Group, now part of Children's Oncology Group. Thirteen patients had features of sclerosing RMS; 9 had been diagnosed with alveolar RMS (ARMS), 3 with embryonal RMS (ERMS), and 1 with a spindle cell RMS. Primary sites included head and neck (6 patients), extremities (5 patients), scrotum (1 patient), and retroperitoneum (1 patient). Patients' ages ranged from 0.3 to 16 years. All tumors showed positivity for myogenin, MyoD, and desmin, but only 2 patients demonstrated the strong myogenin staining typically seen in ARMS. Three patients diagnosed with ARMS demonstrated embryonal-appearing foci, and 3 of 4 patients who had nonalveolar tumors had ARMS-like foci. Standard reverse transcriptase-polymerase chain reaction performed on RNA isolated from frozen sections showed 1 ARMS with a positivity for PAX3-FKHR with four patients classified as having ARMS and 1 as having spindle cell RMS were negative for both ARMS fusion transcripts (PAX3- and PAX7-FKHR). Cytogenetic testing in 2 patients who had ARMS-like foci demonstrated mild hyperdiploidy in both patients and a near-tetraploid clone in 1 patient. Sclerosing RMS may arise in children, have mixed ERMS-ARMS histology, originate from the head and neck, and lack strong myogenin staining.

Adolescent↗
PubMed2004

Failure pattern and factors predictive of local failure in rhabdomyosarcoma: a report of group III patients on the third Intergroup Rhabdomyosarcoma Study.

PURPOSE: To analyze patterns of failure and factors predictive of local treatment failure in children enrolled on the third Intergroup Rhabdomyosarcoma Study who had either biopsy only or subtotal resection of their primary tumor, had no distant metastases, and received radiation therapy for local control. PATIENTS AND METHODS: Treatment failure was categorized as local, regional nodal, or distant metastatic. The 5-year cumulative risk of failure was estimated for each category and factors predictive of local failure risk were determined using the Cox model and binary recursive partitioning. RESULTS: The estimated 5-year cumulative incidence rates by failure category were: total local (with or without concurrent regional or distant failure), 19%; total regional nodal, 2%; total distant, 11%; and death from toxicity or unknown recurrence type, 4%. Lymph node involvement at diagnosis was the single factor most predictive of increased total local failure risk (5-year cumulative incidence 32%) compared with children with negative nodes or unknown node status (16%). No significant effect on local failure risk was observed by total radiotherapy dose over the prescribed range of 41.4 Gy to 50.4 Gy. For all patients (N = 405), the estimated 5-year failure-free survival and overall survival were, respectively, 70% and 78%. CONCLUSION: Local failure after radiotherapy for group III rhabdomyosarcoma patients is the predominant type of relapse. Involved lymph nodes at diagnosis predict a higher risk of local and distant treatment failure compared with patients whose lymph nodes are negative.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2004

High-dose methotrexate pharmacokinetics and outcome of children and young adults with osteosarcoma.

BACKGROUND: High-dose methotrexate (HDMTX) is used frequently in combination regimens that include nephrotoxic chemotherapy. The authors evaluated the impact of factors such as age and prior nephrotoxic agents on MTX pharmacokinetics in children and young adults with osteosarcoma and examined whether MTX pharmacokinetic parameters were associated with outcome. METHODS: The authors evaluated MTX pharmacokinetics in 140 patients who were treated with 1083 courses of HDMTX on 3 consecutive studies of multiagent chemotherapy at a single institution. The influence of MTX pharmacokinetics on the outcome of 107 patients with localized disease was examined. RESULTS: Mean peak MTX concentrations > or = 1000 microM were achieved in 135 patients (96%). MTX clearance was decreased after cisplatin therapy (P = 0.01), after cisplatin in combination with ifosfamide therapy (P < 0.0001), and after MTX therapy (P = 0.003). In patients with localized osteosarcoma, a higher mean MTX area under the curve, a higher mean peak concentration of MTX, a longer mean time above a threshold concentration (500 microM), and a lower mean MTX clearance were associated with lower probability of event-free survival (EFS). Patients who had a mean peak MTX plasma concentration > 1500 microM were found to have a worse outcome (estimated 5-year EFS, 58.5% +/- 6.7%) compared with patients who had a mean peak concentration < or = 1500 microM (estimated 5-year EFS, 75.5% +/- 6.6%; P = 0.02). CONCLUSIONS: When HDMTX (12 g/m(2)) was used with multiagent therapy for patients with osteosarcoma, very high MTX exposures were associated with poorer outcome. The prospective evaluation of MTX pharmacokinetics and their relation to outcome in a large study is warranted to further substantiate the current findings and to elucidate the causative mechanism.

Adolescent↗
PubMed2004

Efficacy of topotecan and cyclophosphamide given in a phase II window trial in children with newly diagnosed metastatic rhabdomyosarcoma: a Children's Oncology Group study.

PURPOSE: To determine the antitumor activity and toxicity of topotecan given immediately after cyclophosphamide as window therapy, then in combination with conventional agents in pediatric patients with newly diagnosed metastatic rhabdomyosarcoma (RMS). PATIENTS AND METHODS: Sixty-one patients younger than 21 years with newly diagnosed metastatic RMS or undifferentiated sarcoma were assigned window therapy (weeks 0 to 6) with topotecan (0.75 mg/m(2) daily x 5 every 21 days) immediately after cyclophosphamide (250 mg/m(2) daily x 5 every 21 days; TC). We continued to give these agents in combination with vincristine (VTC) to patients who showed objective improvement, partial response (PR), or complete response (CR) to TC and alternated courses of VTC with vincristine, dactinomycin and cyclophosphamide (VAC) during weeks 6 to 41 (VTC/VAC). Those who showed no response or progressive disease after TC received only VAC. All patients received radiotherapy to sites of unresected disease (weeks 15 to 21). RESULTS: The overall response rate (CR + PR) to TC was 47% (95% CI, 35% to 60%). Tumor size < or = 5 cm was associated with early response. Myelosuppression was the primary toxicity to TC. Overall 3-year disease-free survival and survival were estimated to be 10% (95% CI, 2% to 19%) and 20% (95% CI, 8% to 32%), respectively. Toxicity profiles for patients who received VTC/VAC or VAC alone were comparable. CONCLUSION: Topotecan after cyclophosphamide is a combination that is active against newly diagnosed RMS, with an acceptable toxicity profile. Disease-free survival and overall survival, however, remain disappointing for children with metastatic RMS at diagnosis.

Adolescent↗
PubMed2004

Results of treatment of fifty-six patients with localized retroperitoneal and pelvic rhabdomyosarcoma: a report from The Intergroup Rhabdomyosarcoma Study-IV, 1991-1997.

BACKGROUND: We reviewed 56 IRS-IV patients with localized rhabdomyosarcoma [RMS] of the retroperitoneum/pelvis to assess outcome and prognostic factors, including the value of initially excising >or=50% of the tumor (debulking) before chemotherapy. METHODS: Patients had embryonal RMS [N=38], alveolar RMS [N = 7], RMS not otherwise specified [NOS, N = 7], or undifferentiated sarcoma [N = 4]. Fifteen patients were debulked; 41 patients were biopsied. All received VAC; most received radiotherapy. RESULTS: Estimated 5-year failure-free survival [FFS] and overall survival rates were 70 and 75%, respectively. FFS rates were better for patients <10 years old and those with embryonal RMS compared to alveolar RMS/undifferentiated sarcoma. After adjusting for age and histological differences, FFS was better for patients whose tumor was debulked prior to beginning therapy [P = 0.02]. CONCLUSIONS: These results are superior to those of previous protocols for patients with RMS of the retroperitoneum/pelvis. Initial excision of >or=50% of the tumor may be associated with increased FFS.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2003

Prognostic factors and clinical outcomes in children and adolescents with metastatic rhabdomyosarcoma--a report from the Intergroup Rhabdomyosarcoma Study IV.

PURPOSE: To identify risk factors associated with outcomes in children with metastatic rhabdomyosarcoma (RMS) treated on the fourth Intergroup Rhabdomyosarcoma Study (IRS-IV). PATIENTS AND METHODS: Patients with metastatic RMS were treated with one of two regimens that incorporated a window of either ifosfamide and etoposide (IE) with vincristine, dactinomycin, and cyclophosphamide (VAC) or vincristine, melphalan (VM) and VAC. Study end points were failure-free survival (FFS) and overall survival (OS). Clinical factors including age, histology, sites of primary and metastatic disease, and number of sites of metastatic disease were correlated with those end points. RESULTS: One hundred twenty-seven patients were eligible for analysis. The estimated 3-year OS and FFS for all patients were 39% and 25%, respectively. By univariate analysis, 3-year OS was significantly influenced by histology (47% for embryonal v 34% for all others, P =.026) and increasing number of metastatic sites (P =.028). By multivariate analysis, the presence of two or fewer metastatic sites was the only significant predictor (P =.007 and.006, respectively). The combination of embryonal histology with two or fewer metastatic sites identified a subgroup with 3-year FFS of 40% and OS of 47%. CONCLUSION: Children with group IV RMS treated on the IRS-IV study had improved OS and FFS if they had two or fewer metastatic sites and embryonal histology. This favorable subset of patients has outcomes approaching those observed in selected patients with localized, nonmetastatic disease. Thus, these patients might not be appropriate candidates for regimens that include experimental agents with substantial toxicities or unproven antitumor activity.

Adolescent↗
PubMed2002

Children from ethnic minorities have benefited equally as other children from contemporary therapy for rhabdomyosarcoma: a report from the Intergroup Rhabdomyosarcoma Study Group.

PURPOSE: To define the clinical characteristics of rhabdomyosarcoma (RMS) occurring in children from ethnic minorities and determine whether these children have benefited equally from advances in therapy. PATIENTS AND METHODS: This was a retrospective cohort analysis of children treated on the Intergroup Rhabdomyosarcoma Study Group protocols between 1984 and 1997. The clinical features and outcomes of 336 African-American children and 286 children from other ethnic minorities were compared with those of white children (n = 1,721). RESULTS: African-American, other ethnic group, and white children enjoyed similar 5-year failure-free survivals (FFS) of 61%, 61%, and 66%, respectively, P =.15. Compared with white children, nonwhite patients more often had (1) invasive, T2 tumors (P =.03); (2) stage 2 or 3 tumors (P =.003); (3) large tumors (more than 5 cm, P <.006); and/or (4) tumors with positive regional nodes (ie, N1, P =.002). Using Cox proportional hazards analysis, seven patient risk categories were defined with significant differences in outcome. This model was then used to search for other factors associated with FFS after adjusting for these risk categories. Only T stage and age remained associated with FFS (P =.001 and P <.001, respectively). After adjusting for T stage, risk category, and age, we explored the relationship of ethnic group to FFS and found that, compared with whites, the relative risk of failure was 1.14 for African-American patients and 1.2 for other ethnic minority patients, values that are not significantly different. CONCLUSION: Patients from ethnic minority groups more often have larger, invasive tumors with positive lymph nodes. Nevertheless, they have benefited as equally as white children from the dramatic progress in therapy of RMS.

Black or African American↗