Radiotherapy in Ewing's sarcoma and PNET of the chest wall: results of the trials CESS 81, CESS 86 and EICESS 92

PURPOSE: Treatment results and the pattern of relapse were evaluated in the multimodal treatment of Ewing's sarcomas of the chest wall. METHODS AND MATERIALS: In a retrospective analysis, 114 patients with non-metastatic Ewing's sarcoma of the chest wall were evaluated. They were treated in the CESS 81, CESS 86, or EICESS 92 studies between January 1981 and December 1993. The treatment consisted of polychemotherapy (VACA, VAIA, or EVAIA) and local therapy, either surgery alone (14 patients), radiotherapy alone (28 patients) or a combination of both (71 patients). The median follow-up was 46.6 months (range 5-170). A relapse analysis for all patients with local or combined relapses was performed. RESULTS: Overall survival was 60% after 5 years, event-free survival was 50%. Thirty-seven patients had a systemic relapse (32.4%), 11 patients had a local relapse alone (9.6%), and 3 patients had a combined local and systemic relapse (2.6%). The risk to relapse locally after 5 years was 0% after surgery alone, 19% after radiation alone, and 19% after postoperative irradiation. None of the 8 patients with preoperative irradiation have failed locally so far. With the introduction of central radiotherapy planning in CESS 86, local control of irradiated patients improved. Ten of 14 patients with local failure could be evaluated in the relapse analysis: 3 patients had an in-field relapse, 4 patients had a marginal relapse, 2 patients had a relapse outside the radiation fields, and 1 patient failed with pleural dissemination. Six treatment deviations were observed. CONCLUSION: Local control was best after surgery alone in a positively selected group of patients. Local control after radiation or combined radiation and surgery was good. With diligent performance of radiotherapy, it will be possible to further improve the results in the radiotherapy group.     

A 2-week pretreatment with 13-cis-retinoic acid + interferon-alpha-2a prior to definitive radiation improves tumor tissue oxygenation in cervical cancers

BACKGROUND: We have evaluated the tumor tissue pO2 in cervical cancers in patients treated with 13-cis-retinoic acid and interferon-alpha-2a prior to and during radiotherapy. PATIENTS AND METHODS: From June 1995 through April 1997, 22 patients with squamous cell carcinoma FIGO IIB/III of the cervix who were scheduled for definitive radiotherapy with curative intent received additional treatment with 13-cis-retinoic acid (cRA, isotretinoin) plus interferon-alpha-2a (IFN-alpha-2a) as part of a phase-II protocol. cRA/IFN-alpha-2a started 14 days prior to radiotherapy (1 mg per kilogramme body weight cRA orally daily plus 6 x 10(6) IU IFN-alpha-2a subcutaneously daily). After this induction period, standard radiotherapy was administered (external irradiation with 50.4 Gy in 28 fractions of 1.8 Gy plus HDR-brachytherapy). During radiotherapy, cRA/IFN-alpha-2a treatment was continued with 50% of the daily doses. Tumor tissue pO2-measurements were performed prior to and after the cRA/IFN-induction period as well as at 20 Gy and at the end of radiotherapy with an Eppendorf-pO2-histograph. RESULTS: In 11 out of the 22 patients, pO2-measurements were performed prior to the cRA/IFN-induction therapy. The median pO2 of these untreated tumors was 17.7 +/- 16.3 mm Hg. The relative frequency of hypoxic readings with pO2-values below 5 mm Hg ranged from 0% to 60.6% (mean 24.3 +/- 21.0%). After the 2-week induction period with cRA/IFN, the median pO2 had increased from 17.7 +/- 16.3 mm Hg to 27.6 +/- 19.1 mm Hg (not significant). In all 5 patients with hypoxic tumors prior to cRA/IFN (median pO2 of 10 mm Hg or less), the median pO2 was above 20 mm Hg after the 2-week cRA/IFN-induction. In this subgroup of hypoxic tumors, the median pO2 increased from 6.3 +/- 2.7 mm Hg to 27.0 +/- 5.6 mm Hg (p = 0.004, t-test for paired samples). The frequency of hypoxic readings (pO2-values < 5 mm Hg) decreased from 44.7 +/- 17.1% to 2.0 +/- 2.5% (p = 0.012, t-test for paired samples). There was, however, no obvious volume reduction after 14 weeks of cRA/IFN on clinical examination. A complete clinical remission of the local tumor was observed in 19/22 patients after radiotherapy and additional cRA/IFN-alpha-2a-treatment. In primarily hypoxic tumors (with a median pO2 below 10 mm Hg prior to treatment), 4/5 achieved complete remission. CONCLUSIONS: Pretreatment with cRA/IFN improves oxygenation of primarily hypoxic cervical cancers. The mechanisms of action remain unclear and further investigation of the combination regimen is recommended.     

Ewing's tumors with primary lung metastases: survival analysis of 114 (European Intergroup) Cooperative Ewing's Sarcoma Studies patients

PURPOSE: To analyze event-free survival (EFS) and prognostic factors in patients who present with Ewing's tumors (ET) of bone and synchronous pulmonary and/or pleural metastases (ppm). PATIENTS AND METHODS: Of 1,270 patients (pts) registered at the continental office of the German/European Intergroup Cooperative Ewing's Sarcoma Studies (CESS81, CESS86, EICESS92), 114 were diagnosed ET with ppm. Patients underwent neoadjuvant therapy and local treatment of the primary tumor. Whole-lung irradiation 15 to 18 Gy was applied to 75 ppm-pts. EFS and 95% confidence intervals (CIs) were estimated according to the Kaplan-Meier method, and prognostic factors were analyzed by log-rank tests and Cox and logistic regression procedures. RESULTS: On November 1, 1997, at a median time under study of 5.9 years, the 5-year EFS was 0.36 (95% CI, 0.26 to 0.46) and the 10-year EFS was 0.30 (95% CI, 0.19 to 0.41). Thirty-seven of 59 (63%) first relapses involved lung and/or pleura, and the lungs were the only site of relapse in 26 of 59 (44%) ppm-pts. Risk factors identified in univariate and multivariate tests were poor response of the primary tumor toward chemotherapy, metastatic lesions in both lungs, and treatment without additional lung irradiation. CONCLUSION: Chemotherapy response of the primary tumor is a prognostic factor in patients with ET with ppm. Strategies of treatment intensification warrant further evaluation.     

Can an extremely elevated radiosensitivity in patients be recognized by the in-vitro testing of lymphocytes?

BACKGROUND: We have examined the in-vitro radiosensitivity of lymphocytes in patients with extreme acute and chronic reactions after curative radiotherapy under the assumption of increased genetic radiosensitivity. PATIENTS AND METHODS: 16 patients (14 females, 2 males, age 40 to 69 years) were retrospectively examined 1 to 108 months after radiotherapy. All had undergone definitive or postoperative curative radiotherapy for cancer (12 breast cancer, 2 lung, 1 bladder, and 1 head and neck cancer). None of them had known genetic disorders with increased radiosensitivity. Four patients were considered as having probably increased radiosensitivity; they had shown poor tolerance to radiotherapy (1 severe acute reaction with cessation of radiotherapy in bladder cancer and subsequent bladder shrinkage after 45 Gy, 1 acute skin reaction well above average with subsequent fibrosis after irradiation for regional recurrence of breast cancer, 1 radiation myelitis after palliative irradiation with 5 x 5 Gy for lung cancer, 1 severe acute reaction after mediastinal irradiation for lung cancer). Twelve patients were considered as having normal tolerance to radiotherapy. They had tolerated radiotherapy well with normal acute reactions and no or minimal signs of late radiation sequelae. Lymphocyte cultures were prepared from all patients and irradiated with 0.7 and 2 Gy, respectively; 1 culture served as control (0 Gy). Chromosomes 1, 2, and 4 were stained using fluorescence in-situ hybridization (FISH) with a 3-colour-chromosome-in-situ suppression technique. Chromosomal breaks were counted in 200 to 1000 mitoses. Radiation sensitivity was expressed as radiation-induced breaks per mitoses corrected for breaks at 0 Gy. The probes were coded and the examiner did not know the clinical course. RESULTS: Significant differences in interindividual radiation sensitivity were detectable. The frequency of radiation-induced breaks/1000 mitoses ranged from 70 to 556 after 0.7 Gy and from 420 to 1210 after 2 Gy. The 4 patients with increased clinical radiation sensitivity showed also increased chromosomal radiation-induced damage as compared to the 12 patients with normal radiation tolerance (469 +/- 103 vs. 126 +/- 79 breaks/1000 mitoses induced by 0.7 Gy, p = 0.0011, and 864 +/- 258 vs. 574 +/- 119 breaks/1000 mitoses induced by 2 Gy, p = 0.019). CONCLUSIONS: Patients with increased clinical radiosensitivity exhibited increased chromosomal damage in lymphocytes in vitro measured with chromosome painting with a FISH-technique. This technique may be useful to detect patients with severely enhanced radiosensitivity. The results suggest that if radiosensitivity is abnormally elevated this may be present and detectable in different organs.     

Medical technology and advocacy in Washington

A historical perspective on advocacy groups that influence US government actions is presented. The targets of these groups in the executive branch, legislative branch, and outside agencies and advisory groups are discussed. These targets include the Department of Health and Human Services, which includes the Health Care Financing Administration and the Public Health Service; the Office of the Secretary, which encompasses the Secretary's immediate staff, the General Counsel, and the Assistant Secretary for Planning and Evaluation; and the Office of Technology Assessment, which assists the Congress by providing it with objective analysis of major policy issues related to scientific and technological change. Six major keys to achieving effective advocacy are listed     

p53 status in radiation-induced soft-tissue sarcomas

BACKGROUND: Following therapeutic irradiation after a latency period of many years radiation-induced tumors, often sarcomas, can arise. Results of radiation-induced DNA damage can be 1. p53 over-expression, inducing growth arrest or apoptosis, and 2. occurrence of mutations, frequently including the p53 gene, as one molecular promotor for carcinogenesis. We were interested whether radiation-induced sarcomas are associated with alterations of the p53 status. MATERIAL AND METHODS: Samples from 11 radiation-induced soft-tissue sarcomas (STS) were studied by a non-radioactive PCR-SSCP sequencing analysis and by immunohistochemistry with five antibodies for their p53 status. RESULTS: A tumor of one patient possessed a G->A transition in codon 280 (exon 8). Of 11 tumors, 9 showed nuclear p53 positivity, detected by monoclonal antibody DO-1. Of these 9 patients, 7 died during the observation period, whereas the 2 patients with DO-1 negative tumor samples are still alive. CONCLUSIONS: p53 over-expression and p53 mutation occur in radiation-induced STS. p53 status is expected to have prognostic impact for radiation-induced STS.     

Oxygenation status of squamous cell carcinoma of the head and neck: comparison of primary tumors, their neck node metastases and normal tissue

AIM: Investigation of the relationship between the pO2-status of primary tumors, their cervical neck node metastases and normal tissues in squamous cell carcinomas of the head and neck. PATIENTS AND METHODS: Pretreatment oxygenation of primary tumors, their neck node metastases and of the contralateral sternocleidomastoid muscle was assessed in 16 patients with histologically proven advanced squamous cell carcinomas of head and neck. Oxygenation was measured with a polarographic microelectrode system (Eppendorf-pO-Histograph). Using CT/MRT additionally the volume of the tumors was estimated. RESULTS: A highly significant correlation existed between the median pO2 of primary tumors and their neck node metastases and between the relative proportion of hypoxic values (< 5 mm Hg) of both anatomic sites (both p = 0.0001) (Figure 1). Primary tumors were not different from their neck node metastases, neither regarding the pO2 median values nor in view of the relative frequency of hypoxic values (Table 1). No correlation was found between the volume of primary tumors and the one of their neck node metastases. For volume of tumors and the oxygenation status no relationship was found as well. Significantly different was the median pO2 in the muscles from the one of the malignant tissues (p = 0.0004). CONCLUSION: The results suggest that for to estimate the oxygenation status of squanious cell carcinomas of the head and neck pO2 measurements of primary tumors and neck node metastases are equally sufficient.