Allogeneic and autologous stem-cell transplantation in advanced Ewing tumors

Background:An update of results from the High Risk Protocol ofthe Meta-EICESS Study, conducted at the Pediatric Stem-Cell Transplant Centersof Düsseldorf and Vienna. In order to evaluate a possible therapeuticbenefit after allogeneic SCT in patients with advanced Ewing tumors (AET), wecompared outcome after autologous and allogeneic stem-cell transplantation(SCT). Patients and methods:We analyzed 36 patients treated with themyeloablative Hyper-ME protocol (hyperfractionated total body irradiation,melphalan, etoposide ± carboplatin) between November 1986 and December1994. Minimal follow-up for all patients was five years. All patientsunderwent remission induction chemotherapy and local treatment beforemyeloablative therapy. Seventeen of thirty-six patients had multifocal primaryEwing's tumor, eighteen of thirty-six had early, multiple or multifocalrelapse, one of thirty-six patients had unifocal late relapse. Twenty-six ofthirty-six were treated with autologous and ten of thirty-six with allogeneichematopoetic stem cells. We analyzed the following risk factors, that couldpossibly influence the event-free survival (EFS): number of involved bones,degree of remission at time of SCT, type of graft, indication for SCT, bonemarrow infiltration, bone with concomitant lung disease, age at time ofdiagnosis, pelvic involvement, involved compartment radiation,histopathological diagnosis. Results:EFS for the 36 patients was 0.24 (0.21) ± 0.07.Eighteen of thirty-six patients suffered relapse or died of disease, nine ofthirty-six died of treatment related toxicity (DOC). Nine of thirty-sixpatients are alive in CR. Age 17 years at initial diagnosis (P< 0.005) significantly deteriorated outcome. According to the type ofgraft, EFS was 0.25 ± 0.08 after autologous and 0.20 ± 0.13after allogeneic SCT. Incidence of DOC was more than twice as high afterallogeneic (40%) compared to autologous (19%) SCT, even thoughthe difference did not reach significance (P = 0.08, Fisher's exacttest). Conclusions:Because of the rather short observation period,secondary malignant neoplasm (SMN) may complicate the future clinical courseof some of our patients who are currently viewed as event-free survivors. EFSin AET is not improved by allogeneic SCT due to a higher complication rate.The patient group was to small to analyze for a possiblegraft-versus-tumor effect.     

Disseminated tumor cells in the bone marrow - chances and consequences of microscopical detection methods

The detection of disseminated tumor cells (DTCs) in the hematopoetic system is important for various reasons. It is essential for tumor staging. According to the International Neuroblastoma Staging System (INSS) only the cytomorphological examination of bone marrow smears is accepted despite the fact that an infiltrate below 0.1%, can hardly be detected and even infiltrates of more than 10% are sometimes overlooked. Another important aspect is the monitoring of the disease response to cytotoxic drugs by quantifying DTCs. Moreover, bone marrow aspirates represent an ideal source to determine the genetic and biological make up of DTCs at diagnosis and during follow up. Key issues that can be tested on DTCs are: determination of the proliferation capacity, the apoptotic rate, the drug sensitivity etc. The prerequisite for such a bone-marrow diagnosis, however, is the unequivocal identification of disseminated tumor cells. Thus, in order to avoid false positive and false negative results, which are a risk in bone-marrow diagnostics, a system was developed to distinguish tumor cells from non-neoplastic cells and to facilitate the gain of insights into the biological make-up of tumor cells more easily.     

Neuroblastoma mass screening in late infancy: insights into the biology of neuroblastic tumors.

PURPOSE: Neuroblastoma screening in early infancy has detected predominantly "favorable" tumors. We postponed screening to an age between 7 and 12 months to test whether this shift of screening age might influence the detection rate of genetically/clinically unfavorable tumors. PATIENTS AND METHODS: In a 10-year period, 313,860 infants were screened by analysis of urine catecholamines. When a neuroblastoma was diagnosed, at least two different areas from every tumor were analyzed for genetic features (MYCN amplification, 1p status, ploidy). Furthermore, neuroblastoma incidence and mortality of the screened group and the cohort of 572,483 children not participating in the screening program were compared. RESULTS: Forty-six neuroblastomas were detected by mass screening. In 17 tumors (37%) at least one of the biologic features was "unfavorable." In 10 of 17 patients, one or more of these alterations were only focally present (tumor heterogeneity). In the screened cohort, neuroblastoma incidence was significantly higher when compared with unscreened children (18.2 v 11.2/100,000 births), while there was a trend towards lower incidence of stage 4 over 1 year (2.2 v 3.8). Mortality was not significantly different (0.96 v 1.57). CONCLUSION: In contrast to other neuroblastoma screening programs, more than one-third of patients were found with unfavorable genetic markers in our study. The high proportion of focal alterations suggests that biologically young neuroblastomas may consist of genetically favorable and unfavorable parts/areas/clones. We conclude that at least one-third of neuroblastomas detected by screening in late infancy are anticipated cases. This, however, does not result in significantly reduced mortality.     

High-dosage chemotherapy in primary metastasized and relapsed Ewing's sarcoma. (EI)CESS]

BACKGROUND: Patients (pts) with primary metastatic Ewing tumours (ET) have a poor prognosis for event free survival (EFS) compared to pts with localised disease. Following relapse the prognosis is extremely poor. Therefore these primary metastatic and relapsed pts were piloted for high dose therapy (HDT) for the last years. PATIENTS AND METHODS: Between April 1984 and May 1997, 131 ET pts who underwent HDT were registered in the German CESS/EICESS office: 79 pts with primary metastases and 52 pts with relapsed tumours. After induction therapy, consisting of chemotherapy and local therapy, pts received high dose regimens, mainly based on melphalan and/or etoposide (92%). Stem cell rescue was applied from allogeneic bone marrow (n = 13), autologous bone marrow (n = 17), or peripheral blood stem cells (n = 95). The date of analysis was September 1st, 1998. Outcome was calculated by Kaplan-Meier-analyses. RESULTS: The median time under study since high dose therapy was 3.7 years. 35/131 pts (26.7%) were in continuous complete remission, 80/131 pts (61.1%) had relapsed or progressed, 11/131 pts (8.4%) died of complications and 5/131 pts (3.8%) presented with secondary malignancies. For the total group of primary metastatic pts, EFS five years after diagnosis was 19% for pts with HDT and 27% for those without (p = 0.9209). The subgroup of pts with primary lung and bone metastases seemed to benefit from HDT (EFS five years after diagnosis: 34% versus 5%, p = 0.0001). Outcome of pts with an early ET relapse (< 2 years) was also improved by HDT (EFS four years after relapse: 17% versus 2%, p = 0.0001). CONCLUSIONS: The total group of primary metastatic ET pts showed no obvious benefit from HDT, based on melphalan and/or etoposide. Pts with metastases to multiple organ systems, and early relapse seemed to benefit from HDT. The value of HDT should be assessed in prospective clinical trials.     

Organ toxicity and quality of life after allogeneic bone marrow transplantation in pediatric patients: a single centre retrospective analysis.

One hundred and fifty five pediatric patients underwent allogeneic bone marrow transplantation between 1980 and 1996 in the St Anna Children's Hospital in Vienna with an overall survival of 52.3% (81 patients). Seventy-three patients with a minimum observation time of 1 year (1-13 years, median: 4.6) were analyzed retrospectively for chronic GVHD, organ toxicity (WHO score), growth and pubertal development. Chronic GVHD was diagnosed in 20 patients (27.3%), being extensive in 17 cases. Maximum organ toxicity was WHO III in two patients (3%) and WHO II in 11 patients (15%) 1 year after BMT and WHO III in one patient (2%) and WHO II in five patients (11%) 3 years after BMT. Impaired growth and pubertal development were detected in more than 30% 3 years after BMT. As all patients presented with a Karnofsky or Lansky score of more than 80%, they were asked to complete a questionnaire comprising 12 questions concerning physical state of health and psychosocial state of health. Restricted contacts were classified as imposing a severe handicap by six patients (8%), restriction in mobility and 'normal life activities' by three patients (4%) and two patients classified themselves as severely physically handicapped. Most patients (75%) reported no physical or psychical impairment.