Lynn M. Smith

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.

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.

Breast cancer after mantle irradiation for Hodgkin's disease : Correlation of clinical, pathologic, and molecular features including loss of heterozygosity at BRCA1 and BRCA2

PURPOSE Hodgkins disease patients who receive mantle irradiation have an age-dependent increased risk of developing breast cancer. To determine if genetic factors predispose these patients to develop breast cancer, we evaluated breast cancer specimens for loss of heterozygosity (LOH) at regions where BRCA1 and BRCA2, two breast cancer tumor suppressor genes, are located. We also evaluated whether breast cancers in patients who were previously treated with radiation have a more aggressive phenotype, and whether the clinical course differed from a sporadic group of breast cancer patients. METHODS AND MATERIALS All females with Hodgkins disease who were subsequently diagnosed with breast cancer and for whom tissue blocks were available were included. Using a case-control design, case patients (previously treated with radiation therapy) were matched with sporadic control breast cancer patients for age, breast cancer stage, and date of breast cancer diagnosis. After microdissection of tumor and normal tissue from paraffin-embedded tissue blocks, DNA was extracted and samples were examined for LOH at chromosomal segments encompassing BRCA1 and BRCA2. Breast cancer specimens were also evaluated in a blinded fashion for tumor grade and immunoreactivity to estrogen and progesterone receptors, p53, her2-neu, and topoisomerase II alpha. Comparisons were made between the case and control populations using chi2 analysis, and a paired Students t test. Survival differences were evaluated using a log-rank test. RESULTS From January 1960 to December 1983, 917 patients were diagnosed with Hodgkins disease. Twelve patients were subsequently diagnosed with breast cancer and tissue blocks were available on 10 cases. No statistical difference was observed between the case and control populations for LOH at BRCA1 or BRCA2. In the Hodgkins disease group, LOH was observed in 30% of tumors at BRCA1 and 10% of tumors at BRCA2 vs. 10% and 0% of tumors in the control group at BRCA1 and BRCA2, respectively. Breast tumors from patients who received radiation therapy for Hodgkins disease displayed greater nuclear pleomorphism (p < 0.02), and an increase in topoisomerase II alpha expression (p < 0.05) vs. the control population. Five of 10 patients were pregnant at the time of their Hodgkins treatment, and those patients had a shorter time interval to the development of breast cancer compared with the patients who were not pregnant (12.4 years compared with 18.6 years). There was no significant difference in disease-free survival; however, overall survival was inferior in the population previously treated with radiation therapy for Hodgkins disease (p = 0.01). 80% of patients with a previous Hodgkins diagnosis died of breast cancer or treatment related effects vs. 30% in the control group. CONCLUSION We were unable to find statistical evidence for LOH at BRCA1 and BRCA2 in breast cancers from patients previously irradiated for Hodgkins disease. Breast cancer diagnosed after mantle irradiation may be more biologically aggressive based on the greater nuclear pleomorphism and increase in topoisomerase II alpha staining. This did not translate into a statistical difference in breast cancer disease-free survival; however, overall survival was significantly inferior in the Hodgkins disease patients.

Distinguishing undifferentiated embryonal sarcoma of the liver from biliary tract rhabdomyosarcoma: A children's oncology group study

Morphologically, the distinction between undifferentiated embryonal sarcoma of the liver (UESL) and biliary tract rhabdomyosarcoma (RMS) can be uncertain because of some shared pathologic similarities. Patients with UESL have been consistently but erroneously enrolled in Childrens Oncology Group (COG) treatment protocols because UESL was equated with RMS, despite the differing primary treatment modalities of these entities. Review of COG pathology files yielded 20 cases of UESL that were compared to 25 cases of biliary tract RMS. Clinicopathologic features including immunohistochemical staining were examined. In the UESL cases, the male:female ratio was 1:1 and the median age was 10.5 years. Histologically, hyaline globules and diffuse anaplasia were consistently present. The cases of RMS had a male:female ratio of 1.8:1 with a median age of 3.4 years and routinely lacked diffuse anaplasia and hyaline globules. Polyclonal desmin and muscle-specific actin were variably immunoreactive in UESL and RMS; however, myogenin and myogenic regulatory protein D1 (MyoD1) were uniformly negative in UESL and routinely positive in the majority of biliary tract RMS. Myogenin, in particular, was highly significant (P = 0.0003) in distinguishing RMS from UESL. With a median follow-up of 8 months, 11 of 18 patients with UESL were still alive. The estimated 5-year survival for biliary tract RMS was 66%. Establishing the correct diagnosis of these distinct clinical and pathologic entities is important, as surgery alone may be curative in UESL, whereas initial chemotherapy is often recommended for the treatment of biliary tract RMS.

Peripheral primitive neuroectodermal tumor presenting with diffuse cutaneous involvement and 7;22 translocation

We report an unusual case of peripheral primitive neuroectodermal tumor (pPNET) in an infant presenting with congenital cutaneous nodules and a t(7;22)(p21;q11.2). The biologic behavior of the tumor diverged over time from a slowly growing tumor with multiple cutaneous nodules to a more aggressive neoplasm characterized by pulmonary metastases and a soft tissue mass showing additional cytogenetic alterations.

Electron arc irradiation of the postmastectomy chest wall with CT treatment planning: 20-year experience

PURPOSE Since 1980, electron arc irradiation of the postmastectomy chest wall has been the preferred radiotherapy technique at the University of Utah for patients with advanced breast cancer. We report the results of this technique in 156 consecutive Stage IIA-IIIB patients treated from 1980 to 1998. METHODS CT treatment planning was used in all patients to identify chest wall thickness and internal mammary lymph node depth. Computerized dosimetry was used to deliver total doses of 50 Gy in 5-1/2 weeks to the chest wall and the internal mammary lymph nodes with electron arc therapy. Patients were assessed for local, regional, and distant control of disease and for survival. Univariate and multivariate proportional hazards were modeled using a hierarchical nonproportional semiparametric model testing the following prognostic factors: age, stage, tumor size, number of positive lymph nodes, estrogen receptor status, and dose. End points evaluated included disease-free survival, cause-specific survival, and overall survival. RESULTS Eighty-one percent of patients were at high risk for local-regional failure because of > T2 primary tumor or > 3 positive axillary lymph nodes. The median number of positive lymph nodes was 5, and the median tumor size was 3.5 cm. Actuarial 10-year local-regional control and overall survival were 95% and 52%, respectively. In multivariate analysis, the only factor prognostic for disease-free survival, cause-specific survival, and overall survival was the number of positive lymph nodes (p < 0.001). The 10-year rates of local-regional control for patients with 0, 1-3, 4-9, and > or = 10 involved lymph nodes were 100%, 98%, 93%, and 89%, respectively. The only rates of acute and chronic radiotherapy toxicity > or = 2 by RTOG/EORTC criteria were skin related and observed in 44% and 10% for acute and late reactions, respectively. CONCLUSION These data demonstrate excellent local-regional control rates with electron arc therapy of the postmastectomy chest wall in patients with advanced breast cancer. Our 20-year experience with electron arc radiotherapy has demonstrated the safety and efficacy of this technique. The advantage of this technique is that the internal mammary lymph node chain can be easily encompassed while the dose to heart and lung is minimized; it also obviates match lines in areas of high risk.

Therapy associated changes in childhood tumors.

Summary: Contemporary treatment regimens for the common solid tumors of childhood have led to increased numbers of post‐treatment pathologic specimens from survivors. Current therapeutic strategies for childhood cancers in North America require an accurate pathologic diagnosis and stratify patients based on combinations of clinical, biological, and pathologic features. In several tumor systems, the pathologic response to therapy also modifies the treatment regimen. Accurate pathologic interpretation of such specimens is critical in providing useful prognostic information for therapeutic decisions. Standardized handling of post‐therapy pathologic specimens, appropriate use of molecular and genetic studies, consideration of the differential diagnoses, and assessment of the potential biologic significance of therapy‐induced pathologic changes are, therefore, critical for patient management and determination of treatment protocols.

Cytogenetic-clinicopathologic correlations in rhabdomyosarcoma: a report of five cases

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children younger than the age of 15 years. Histologically, RMS can be subdivided into two major subtypes; embryonal (E-RMS) and alveolar (A-RMS) rhabdomyosarcoma, with E-RMS being the more common. Although cytogenetic and molecular genetic findings have been reported extensively for RMS, clinicopathologic-genetic correlations among these tumors have not been reported in detail. In this report, we correlate the cytogenetic findings, including fluorescence in situ hybridization and spectral karyotyping, with pathologic findings and outcome for five RMS, including two A-RMS, one E-RMS, one botryoid RMS, and one anaplastic nonclassified RMS (N-RMS). The findings in A-RMS and E-RMS generally were consistent with previous reports; however, gain of chromosome 7 in A-RMS and gain of chromosome 9 segments in E-RMS observed here have seldom been reported in the literature. Importantly, the botryoid RMS had a cytogenetic profile similar to other types of E-RMS. An add(11)(q21) observed in this tumor, together with a t(8;11)(q12 approximately 13;q21) reported previously, indicates that 11q21 rearrangements may be nonrandomly related to botryoid RMS. In addition, the N-RMS expressed a cytogenetic pattern similar to that observed in E-RMS, thus providing genetic evidence that anaplastic N-RMS is a variant of E-RMS. Finally, these cases provide cogent evidence for the diagnostic and prognostic significance of the pathologic-genetic classification of RMS.

The application of electron beam delivery using dose rate variation and dynamic couch motion in conformal treatment of the cranial-spinal axis

Radiation therapy to the cranial-spinal axis is typically targeted to the spinal cord and to the cerebrospinal fluid (CSF) in the subarachnoid space adjacent to the spinal cord and brain. Standard techniques employed in the treatment of the whole central nervous system do little to compensate for the varying depths of spinal cord along the length of the spinal field. Lateral simulation films, sagittal magnetic resonance imaging (MRI), or computerized tomography (CT) are used to estimate an average prescription depth for treatment along the spine field. However, due to the varying depth of the target along the spinal axis, even with the use of physical compensators, there can be considerable dose inhomogeneity along the spine field. With the advent of treatment machines that have full dynamic capabilities, a technique has been devised that will allow for more conformal dose distribution along the full length of the spinal field. This project simulates this technique utilizing computer-controlled couch motion to deliver multiple small electron beams of differing energies and intensities. CT planning determines target depth along the entire spine volume. The ability to conform dose along the complete length of the treatment field is investigated through the application of superpositioning of the fields as energies and intensities change. The positioning of each beam is registered with the treatment couch dynamic motion. This allows for I setup in the treatment room rather than multiple setups for each treatment position, which would have been previously required. Dose-volume histograms are utilized to evaluate the dose delivered to structures in the beam exit region. This technique will allow for precise localization and delivery of a homogeneous dose to the entire CSF space.