The impact of central review and central therapy planning on the treatment of children and adolescents with Hodgkin lymphoma.

PURPOSE: The multicentre response-adapted paediatric Hodgkin lymphoma trial GPOH-HD95 (1995-2001, 925 patients) was followed by the 'HD-Interval' period (2001-2002, 203 patients). During this period, treatment was recommended according to GPOH-HD95 protocol with only minor changes. Central review and treatment planning as in HD95, however, had to be omitted in the absence of funding. Results of both periods were compared to evaluate the impact of central review on staging, stratification, treatment planning and outcome. METHODS: Pre- and post-chemotherapy computed tomography and magnetic resonance imaging of HD-Interval patients were evaluated with respect to reliability of staging, response assessment and subsequent treatment stratification. RESULTS: Despite more favourable patient characteristics and treatment group stratifications, the 10-year progression-free survival (PFS) was inferior in HD-Interval patients compared to GPOH-HD95 patients with nearly identical therapy (86% versus 91%, P=0.01). Of 142 patients without guidance by the reference centre, 56 (39%) received a treatment deviating from protocol recommendations: chemotherapy doses were either lower or higher than recommended in 17% of patients, and deviations concerning radiotherapy dose and treatment volume occurred in 25% and 20%, respectively. In both periods, the 10-year PFS was lower in patients with diminished therapy compared to those with adequate treatment according to the given recommendations (HD-Interval: 72% versus 89%, P=0.02; GPOH-HD95: 80% versus 92%, P=0.04). CONCLUSIONS: Deviations from protocol treatment may influence negatively the outcome in paediatric oncology. Protocol enrolment and compliance including timely and correct treatment are crucial. Central reference and consultation centres offer quality assurance, support protocol adherence, and hence influence PFS.

Treatment of children and adolescents with Hodgkin lymphoma without radiotherapy for patients in complete remission after chemotherapy: final results of the multinational trial GPOH-HD95.

UNLABELLED: PURPOSE To minimize the risk of late effects in pediatric Hodgkin lymphoma (HL) by omitting radiotherapy (RT) in patients in complete remission (CR) after chemotherapy and reducing the standard radiation dose to 20 Gy in patients in incomplete remission. PATIENTS AND METHODS: Between 1995 and 2001, 925 patients with classical HL (cHL) were registered from seven European countries in German Society of Pediatric Oncology and Hematology Hodgkin Lymphoma Trial 95. Patients in treatment group 1 (TG1; early stages) received two cycles of vincristine, prednisone, procarbazine, and doxorubicin or vincristine, prednisone, etoposide, and doxorubicin chemotherapy; additional two or four cycles of cyclophosphamide, vincristine, prednisone, and procarbazine were added in TG2 (intermediate stages) or TG3 (advanced stages), respectively. Patients in CR (assessed by computed tomography or magnetic resonance imaging) did not undergo RT. Those with tumor volume reduction more than 75% received reduced involved-field RT with 20 Gy and an additional 10- or 15-Gy boost only for larger residuals. RESULTS: Rates of overall survival, progression-free survival (PFS), and event-free survival at 10 years were (± SE) 96.3% ± 0.6%, 88.2% ± 1.1%, and 85.4% ± 1.3%, respectively. PFS for TG1 patients without or with RT was 97.0% ± 2.1% versus 92.2% ± 1.7% (P = .214) but was unsatisfactory for nonirradiated patients in TG2 (68.5% ± 7.4% v 91.4% ± 1.9%; P < .0001), with similar but not significant results in TG3 (82.6% ± 5.4% v 88.7% ± 2.0%, P = .259). Reduction of the standard radiation dose from 25 to 20 Gy did not increase failure rate. CONCLUSION: RT can be omitted in early stage HL in so defined CR following this chemotherapy. RT with 20(-35) Gy proved to be sufficient in patients with incomplete remission following chemotherapy.

Long-term outcome after polychemotherapy and intensive local radiation therapy of high-grade osteosarcoma.

BACKGROUND: Current standard therapy for high-grade osteosarcoma is neoadjuvant chemotherapy and complete resection of the primary tumour. Irradiation can improve local control if complete tumour resection is not possible or refused, but data on long-term outcome are not available. PATIENTS AND METHODS: We report on long-term results for overall survival, occurrence of local recurrence and metastasis, joint function and side-effects in 13 patients with high-grade osteosarcoma having been treated with a combination of local irradiation and polychemotherapy (median follow-up of 13.5 years). RESULTS: Ten of the 13 patients were alive 4-23 years after diagnosis. Three patients suffered local recurrence, in 2 of them tumour control and long-term survival could be achieved by secondary salvage surgery and polychemotherapy. In 5 patients pathological fractures of the irradiated bones occurred, none of them was associated with local recurrence. In 7 of the 10 long-term survivors good or fair joint function was achieved. CONCLUSIONS: We conclude that combination of chemotherapy and intensive local irradiation can achieve long-term local control and even cure in high-grade osteosarcoma. Thus radiation therapy may represent an alternative to definite surgery in selected patients, in particular in those with good response to chemotherapy, when surgery is not feasible or refused.

Randomized study of postoperative radiotherapy and simultaneous temozolomide without adjuvant chemotherapy for glioblastoma.

PURPOSE: To evaluate the efficacy of simultaneous postoperative temozolomide radiochemotherapy in glioblastoma patients. PATIENTS AND METHODS: From February 2002 to July 2004, n = 65 patients from 11 German centers with macroscopic complete tumor resection were randomized to receive either postoperative radiotherapy alone (RT, n = 35) or postoperative radiotherapy with simultaneous temozolomide (RT + TMZ, n = 30). Patients were stratified according to age (< or =/>50 years) and WHO performance score (0-1 vs. 2). RT consisted of 60 Gy in 30 fractions. In the RT + TMZ arm, oral TMZ was administered daily at a dose of 75 mg/m(2) including weekends (40-42 doses). Adjuvant treatment was not given, but in both arms, patients with recurrent tumors and in good condition (WHO 0-2) were scheduled for salvage chemotherapy with TMZ. RESULTS: The trial was stopped early due to the results of EORTC-study 26981-22981 that showed a survival benefit for the combination of concomitant and adjuvant TMZ compared to radiotherapy alone. In total, 62/65 patients were evaluable. Stratification variables were well balanced (< or = 50 years 26% vs. 20%, WHO 0-1 91% vs. 100%). Neither overall survival (median 17 vs. 15 months) nor progression-free survival (median 7 vs. 6 months) differed significantly between the two arms. In the RT (RT + TMZ) arm, 76% (62%) of the progressing patients received salvage chemotherapy with TMZ, 36% (50%) had a second resection. There was a time-constant trend for increased general quality of life (EORTC questionnaire QLQ C30) and brain-specific quality of life (EORTC questionnaire B20) in the combined arm. Lymphopenia G3-4 was more frequent (33 vs. 6%) in the RT + TMZ arm. CONCLUSION: After early closure of this trial, a benefit for progression-free survival for simultaneous TMZ radiochemotherapy alone could not be demonstrated. In both arms, salvage therapies were frequently used and probably had a major effect on overall survival.

Salvage therapy of progressive and recurrent Hodgkin's disease: results from a multicenter study of the pediatric DAL/GPOH-HD study group.

PURPOSE: To evaluate a salvage therapy (ST-HD-86) for patients with progressive and relapsed Hodgkin's disease after primary treatment in the pediatric DAL/GPOH studies. The essential chemotherapeutic regimens were ifosfamide, etoposide, and prednisone (IEP) and doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). METHODS: One hundred seventy-six patients with progression (n = 51) or first relapse (n = 125) were enrolled by 67 centers. The median time from initial diagnosis to progression/relapse was 1.1 year (range, 0.1 to 15.3 years), and the patients' median age was 14.7 years (range, 4.3 to 24.5 years). Salvage chemotherapy consisted of two to three cycles of IEP alternating with one to two cycles of ABVD supplemented in part by one to two cycles of cyclophosphamide, vincristine, procarbazine, and prednisone or lomustine (CCNU), etoposide, and prednimustine. Radiotherapy was given to involved areas using individualized doses. In the 1990s, additional high-dose chemotherapy with autologous stem-cell transplantation (SCT) was introduced for patients with unfavorable prognosis. RESULTS: Disease-free survival (DFS) and overall survival (OS) after 10 years are 62% and 75%, respectively (SE, 4% each). Of 176 patients, 73 suffered second events. The risk-factor analysis revealed the time to progression/relapse as the strongest prognostic factor (P = .0001). Patients with progression have an inferior outcome (DFS, 41%; OS, 51%), whereas patients with late relapse (> 12 months after end of therapy) do well (DFS, 86%; OS, 90%), although none of them received SCT in second remission. CONCLUSION: The result can be considered favorable. Whereas the salvage strategy for progressive disease has to be optimized further, it is possible to reduce intensity and avoid SCT in late relapses after Hodgkin's disease in childhood/adolescence.

[Dissection or irradiation of the axilla in postmenopausal patients with breast cancer? Long-term results and long-term effects in 655 patients]. / Axilladissektion oder Axillabestrahlung bei postmenopausalen Patientinnen mit Mammakarzinom? Langzeitergebnisse und Langzeitfolgen bei 655 Patientinnen.

BACKGROUND: Until 1993 postmenopausal women with breast cancer did not receive adjuvant chemotherapy in our institution even if axillary nodes were involved. So in these patients axillary dissection had no diagnostic value for further treatment. Therefore we started a prospective study in which dissection of axillary nodes was replaced by irradiation in postmenopausal cN0 patients. PATIENTS AND METHODS: From 1986 to 1993 we irradiated 655 patients with breast cancer after breast conserving surgery (BET). In all 144 cN1- and all 209 premenopausal cN0-patients axillary dissection was recommended. Of 302 postmenopausal cN0 patients 129 had breast surgery in our institution. In a total of 129 patients axillary dissection was replaced by irradiation (AxRT-group). They were compared with all 173 patients referred from other hospitals for irradiation after both breast conserving surgery and axillary dissection (AxOP-group). Dissected patients with gross tumor involvement of the axilla or less than eight nodes removed had additional axillary irradiation. Patients age, tumor size, vessel-, muscle- or skin invasion and grading were similar in both groups (Table 1). However, in the AxRT-group there were more patients with negative hormone receptors, multifocal and medial sited tumors. Late complications after dissection and/or irradiation of the axilla were evaluated in 502 patients free of locoregional relapse and with a minimal follow up of 3 years (median 9.5 years). RESULTS: After 5, 10 and 15 years tumor free survival rates were 90%, 82% and 79% in the AxOP-group vs 91%, 82% and 80% in the AxRT-group, respectively (p = 0.95) (Figure 1). Overall survival (p = 0.98) (Figure 2), local (p = 0.47) and axillary control (p = 0.12) were equal in both groups (Figures 3 and 4). However, serious problems like lymphedema of the arm, pain, mobility impairment occurred in 26% patients following axillary dissection but only in 1% after axillary irradiation. No difference in late sequelae after axillary dissection with or without irradiation could be detected (26 vs 27%) (Table 2). CONCLUSION: In postmenopausal cN0-patients axillary dissection should be replaced by axillary irradiation, since it offers the same chance for cure with much lower morbidity.

Expression vectors for studying cytoskeletal proteins in Dictyostelium discoideum.

We generated and tested a set of cloning vectors designed to facilitate the production, purification and visualization of proteins in Dictyostelium discoideum. The vectors are derived from the Dictyostelium-E. coli shuttle vector pDXA-3H (6.1 kb), which carries the origin of replication of the Dd high-copy-number plasmid, Ddp2, a high-copy-number E. coli plasmid origin of replication, an act6 promoter driven G418 resistance cassette, the bacterial ampicillin resistance gene and an expression cassette. The new cloning vectors carry expression cassettes consisting of the strong constitutive actin-15 promoter, a translation start followed by a multiple cloning site, sequences for the addition of purification or visualization tags, and Dictyostelium polyadenylation and termination signals. Vectors designed to facilitate protein visualization in living Dictyostelium cells contain either coding sequences for the cyan (CFP) or yellow (YFP) variants of green fluorescent protein (GFP). Versions of the vectors for the production of N- and C-terminal fusions with the fluorescent proteins were generated. To facilitate protein purification, vectors for the production of glutathione-S-transferase (GST) fusion proteins and Strep- or FLAG-affinity-tagged proteins were generated. Additionally, a vector for the production of His8-tagged proteins was generated, which has the G418-resistance cassette replaced by a hygromycin resistance cassette.