Cynthia E. Herzog

High-Dose Melphalan, Etoposide, Total-Body Irradiation, and Autologous Stem-Cell Reconstitution as Consolidation Therapy for High-Risk Ewing’s Sarcoma Does Not Improve Prognosis

PURPOSE To determine whether consolidation therapy with high-dose melphalan, etoposide, and total-body irradiation (TBI) with autologous stem-cell support would improve the prognosis for patients with newly diagnosed metastatic Ewings sarcoma (ES). PATIENTS AND METHODS Thirty-two eligible patients with newly diagnosed ES metastatic to bone and/or bone marrow were enrolled onto this study. Treatment was initially comprised of five cycles of induction chemotherapy (cyclophosphamide, doxorubicin, and vincristine alternating with ifosfamide and etoposide) and local control. Peripheral-blood stem-cell collection was performed after the second cycle of chemotherapy, with delay if the bone marrow was persistently involved. If patients had a good response to initial therapy, they proceeded to consolidation therapy with melphalan, etoposide, TBI, and stem-cell support. RESULTS Of the 32 eligible patients, 23 proceeded to high-dose therapy consolidation. Of the nine patients who did not proceed to consolidation, four were secondary to progressive disease and two were secondary to toxicity. Three patients died from toxicity during the high-dose phase of the therapy. The majority of the patients who underwent high-dose consolidation therapy experienced relapse and died with progressive disease. Two-year event-free survival (EFS) for all eligible patients is 20%. The 2-year post-stem-cell reconstitution EFS for the subset of 23 patients who received consolidation therapy is 24%. Analysis of peripheral-blood stem-cell collections by molecular techniques for minimal residual disease showed contamination of at least some samples by tumor cells in all three patients with available data. CONCLUSION Consolidation with high-dose melphalan, etoposide, TBI, and autologous stem-cell support failed to improve the probability of EFS in this cohort of patients with newly diagnosed metastatic ES.

Outcome and Reproductive Function After Chemotherapy for Ovarian Dysgerminoma

PURPOSE To review the outcome for all patients with ovarian dysgerminoma treated at the M.D. Anderson Cancer Center who received bleomycin, etoposide, and cisplatin (BEP) and to assess the menstrual and reproductive function of those who received conservative treatment. PATIENTS AND METHODS Clinical information was abstracted from the medical record. Patients completed a detailed questionnaire about menstrual and reproductive function; those who did not return the questionnaire were interviewed by telephone. RESULTS Twenty-six patients were identified as having been treated with BEP chemotherapy for pure ovarian dysgerminoma from January 1984 to January 1998. Their median age was 19.5 years (range, 7 to 32 years). Sixteen patients underwent fertility-sparing surgery in the form of unilateral salpingo-oophorectomy. At a median follow-up time of 89 months, 25 (96%) of the 26 patients remained continuously disease-free. One patient apparently developed a second primary dysgerminoma in her remaining ovary after BEP and was clinically disease-free after further treatment. Of the 16 patients who underwent fertility-sparing surgery, one was lost to follow-up when she was pregnant, and one was still premenarchal. Of the remaining 14 patients, 10 (71%) maintained their normal menstrual function during and after chemotherapy, and 13 (93%) had returned to their prechemotherapy menstrual pattern at the time of the questionnaire. Five pregnancies have occurred thus far, and two patients have had difficulty conceiving. CONCLUSION Most patients with metastatic dysgerminoma can expect cure with maintenance of normal reproductive function when treated with conservative surgery and BEP chemotherapy.

Overview of sarcomas in the adolescent and young adult population.

Based on the data of the Surveillance, Epidemiology and End Results Section of the National Cancer Institute (SEER) program, soft tissue and bone sarcomas account for about 1% of all new malignancies diagnosed in the United States each year. However, there are numerous different histologic types, and any given type of sarcoma is extremely rare. Determining the incidence of sarcomas by age and type is difficult due to the limited data reported. The SEER program collects data regarding age but only limited data on histology, while most series reported in the literature include either adults or pediatric patients, but rarely both. In an effort to estimate the frequency and absolute numbers of different sarcomas in the adolescent and young adult population, the University of Texas M. D. Anderson Cancer Center (MDACC) tumor registry was queried for all soft tissue sarcomas from 1990 through 2003, and all bone sarcomas from 1990 through 2002. Based on this query, an overview of sarcomas that occur predominantly in the adolescent and young adult (AYA) population is presented. These sarcomas include rhabdomyosarcoma, synovial sarcoma, neurogenic sarcoma, epithelioid sarcomas, alveolar soft parts sarcoma, Ewing sarcoma, and osteosarcoma. Using the percentages for occurrence of each histologic type determined from the MDACC database, and the SEER estimate of overall sarcoma incidence, an estimate of the number of new cases in 2004 for the predominant histologic types occurring in the AYA population are presented. Also reviewed are the chromosomal translocations that occur frequently in sarcomas presenting in the AYA population.

Phase I Pharmacokinetic and Pharmacodynamic Study of 17-N-Allylamino-17-Demethoxygeldanamycin in Pediatric Patients with Recurrent or Refractory Solid Tumors: A Pediatric Oncology Experimental Therapeutics Investigators Consortium Study

Purpose: Heat shock protein 90 (Hsp90) is essential for the posttranslational control of many regulators of cell growth, differentiation, and apoptosis. 17-N-Allylamino-17-demethoxygeldanamycin (17-AAG) binds to Hsp90 and alters levels of proteins regulated by Hsp90. We conducted a phase I trial of 17-AAG in pediatric patients with recurrent or refractory neuroblastoma, Ewings sarcoma, osteosarcoma, and desmoplastic small round cell tumor to determine the maximum tolerated dose, define toxicity and pharmacokinetic profiles, and generate data about molecular target modulation. Experimental Design: Escalating doses of 17-AAG were administered i.v. over 1 to 2 h twice weekly for 2 weeks every 21 days until patients experienced disease progression or toxicity. harmacokinetic and pharmacodynamic studies were done during cycle 1. Results: Fifteen patients were enrolled onto dose levels between 150 and 360 mg/m2; 13 patients were evaluable for toxicity. The maximum tolerated dose was 270 mg/m2. DLTs were grade 3 transaminitis and hypoxia. Two patients with osteosarcoma and bulky pulmonary metastases died during cycle 1 and were not evaluable for toxicity. No objective responses were observed. 17-AAG pharmacokinetics in pediatric patients were linear; clearance and half-life were 21.6 ± 6.21 (mean ± SD) L/h/m2 and 2.6 ± 0.95 h, respectively. Posttherapy increases in levels of the inducible isoform of Hsp70, a marker of target modulation, were detected in peripheral blood mononuclear cells at all dose levels. Conclusion: 17-AAG was well tolerated at a dose of 270 mg/m2 administered twice weekly for 2 of 3 weeks. Caution should be used in treatment of patients with bulky pulmonary disease.

Novel bone cancer drugs: investigational agents and control paradigms for primary bone sarcomas (Ewing's sarcoma and osteosarcoma).

Background: New investigational agents and chemotherapy regimens including cyclophosphamide + topotecan, temozolomide + irinotecan, and anti-IGF-1R antibodies in Ewings sarcoma (ES) and liposomal muramyltripeptide phosphatidylethanolamine (L-MTP-PE), aerosol therapy, and bone-specific agents in osteosarcoma (OS) may improve survival and/or quality of life on ‘continuation’ therapy. Objective: Review of investigational approaches and control paradigms for recurrent or metastatic primary bone tumors. Methods: Analyze temozolomide + irinotecan data and review in the context of other newer approaches including antiangiogenesis, anti-IGF-1R antibodies and bisphosphonates for ES. Review some current state-of-the-art approaches for OS including L-MTP-PE, anti-IGF-1R inhibition, aerosol therapies and bone specific agents. Results/conclusion: L-MTP-PE with chemotherapy in OS has been shown to improve survival; compassionate access is available for recurrence and/or metastases. Aerosol therapy (granulocyte–macrophage colony stimulating factor, cisplatin, gemcitabine) for lung metastases is a promising approach to reduce systemic toxicity. The bone-specific agents including denosumab (anti-receptor activator of NF-κB ligand antibody) and bisphosphonates may have benefit against giant cell tumor, ES and OS. Anti-IGF-1R antibody SCH717454 has preclinical activity in OS but best effectiveness will most likely be in combination with chemotherapy earlier in therapy. Both temozolomide + irinotecan and cyclophosphamide + topotecan combinations are very active in ES and are likely to be tested with anti-IGF-1R antibodies against ES.

Early lymphocyte recovery as a prognostic indicator for high-risk Ewing sarcoma

Background Increasing evidence suggests that lymphocyte recovery plays a major part in tumor control. Facilitating immune reconstitution might be a novel direction of cancer therapy. The purpose of this study was to determine if early lymphocyte recovery is an independent prognostic indicator for high-risk Ewing sarcoma outcome. Results Data of 24 Ewing sarcoma patients were analyzed (age, 3 to 50 y; median, 16.5; male to female, 16:8). The 5-year overall survival (OS) of the total population was 47.9% [10.6 standard error (SE)]. Patients were separated into 2 groups: prolonged lymphopenia versus early lymphocyte recovery, using a threshold absolute lymphocyte count (ALC) of ≥500 cells/μL on day 15. The majority (67%; n=16) of the patients had an ALC ≥500 cells/μL, and of these 10/16 are alive with a 5-year OS of 58.7% (13.2 SE). In contrast, 33% (n=8) of patients had an ALC <500 cells/μL on day 15 and only 2/8 are alive with a 5-year OS of 25% (15.3 SE). This difference was significant (P=0.007 using the log rank test). When comparing patients with metastatic disease, patients with an ALC-15 <500 cells/μL had a median survival of 13 months, whereas patients with an ALC-15 ≥500 cells/μL had a median survival of 29.5 months. All patients had an ALC before chemotherapy of >1000 cells/μL. The difference was significant (P value=0.001 using the log rank test). Univariate analysis of platelet counts, age, sex, and absolute neutrophil count showed no statistically significant association with OS. Conclusions The data demonstrate that an ALC ≥500 cells/μL on day 15 of the first course of chemotherapy is an independent prognostic factor associated with superior OS in high-risk Ewing sarcoma.

A half century of experience with carcinoid tumors in children.

PURPOSE To investigate the frequency, presentation, clinical management, and prognosis of appendiceal carcinoid tumors in children. METHOD A review of our institutions experience over 50 years. RESULTS Twenty-two patients below the age of 20 presented with appendiceal carcinoid tumor. The mean age at presentation was 14.6 years. Twelve patients presented with symptoms of appendicitis. No tumor was > 2.0 cm in size. Only 2 patients underwent resection beyond appendectomy. No patient had recurrent or metastatic carcinoid tumor, and all but 1 patient (who died of ovarian choriocarcinoma) are alive without evidence of carcinoid tumors 1.5 to 30 years after diagnosis. CONCLUSIONS Appendiceal carcinoid tumors in children are rarely life-threatening and the incidence of large tumors (> 2.0 cm) is very low. The role of right hemicolectomy in large (> 2.0 cm) tumors is questionable in this age group.

Chemotherapy response is an important predictor of local recurrence in ewing sarcoma

Local recurrence in Ewing sarcoma is associated with a poor prognosis. The purpose of the study was to determine the factors that predict local recurrence after surgical treatment of the primary tumor.

Multimodality treatment of osteosarcoma: Radiation in a high-risk cohort

Chemotherapy during radiation and/or bone‐seeking radioisotope therapy (153‐samarium; 1 mCi/kg) during radiation may improve osteosarcoma cancer control.

Outcomes in pediatric melanoma: Comparing prepubertal to adolescent pediatric patients

Objective:The aim of this study was to determine the influence of age on outcome in pediatric melanoma patients and to identify factors associated with positive lymph node status in this population. Methods:A retrospective review of a prospective pediatric melanoma database, using sentinel lymph node biopsy (SLNB), from 1992 to 2006, identified 109 patients with the primary diagnosis of melanoma. Patient age was dichotomized as prepubescent (<10 years of age) and adolescent (≥10–18 years of age). Factors investigated included patient race, sex, and lymph node status and tumor thickness, Spitzoid or Non-Spitzoid histology, radial growth phase, and vascular invasion. The Fishers exact test was used to compare patient groups. Time-to-event analysis was performed using the Kaplan-Meier method. Results:There were 25 prepubescent and 84 adolescent patients. Prepubescent patients were more often non-White, had greater tumor thickness, more spitzoid tumors and more vascular invasion. Ten-year overall survival (OS) was 89% and 10-year event-free survival (EFS) was 73%. Among 57 patients who had an SLNB, prepubertal patients had a higher percentage of sentinel lymph node positivity. The odds having a positive SLNB decreased by 13% each year with increasing age. Patients with a tumor thickness ≥2.01 mm had higher odds of having a positive lymph node compared with those patients with a tumor thickness ⩽1.0. Conclusions:This is the largest known study of prepubertal melanoma patients. Although OS and EFS did not differ by age groups, younger ages showed increased risk of lymph node metastasis and thicker tumors. This suggests that the younger pediatric patients may have a disease that differs biologically from that of the older pediatric patients.