Biomedical subjects

N Willich

Publications and source records attributed to N Willich.

At least 19 recordsLinked to original sources

PubMed2005

[Plantar fasciitis and radiotherapy. Clinical and radiobiological treatment results].

Patients with plantar fasciitis and pain refractory to conventional therapy are treated with low-dose radiotherapy (RT), but no conclusive evidence-based and radiobiological studies had been performed. In 2001 the German Cooperative Group on Radiotherapy for Benign Diseases (GCG-BD) carried out a study by mailing a standardized questionnaire. A total of 136 institutions treated 3621 patients/year with chronic or refractory pain. The median total dose was 6 Gy (median single dose: 1 Gy); 76 institutions reported data of their clinical evaluation of a total of 7947 patients. Pain relief lasting for at least 3 months was reported in 70% and persistent pain relief in 65%. There were no acute or chronic radiogenic side effects observed. The radiobiological studies showed a significant increase of granulocyte function at 1.5 Gy and a significant decrease at 3.5 and 4.0 Gy. These results may provide a possible explanation for a local anti-inflammatory effect of low-dose RT. RT may be an excellent alternative for patients with contraindications to long-term treatment with steroids or NSAID.

Adolescent↗

PubMed2005

Heterogeneity of radiation induced apoptosis in Ewing Tumor cell lines characterized on a single cell level.

The objective of this study was to investigate heterogeneity of radiation induced apoptosis on a single cell level. Two Ewing tumor cell lines were characterized in vitro before and 24 and 72 h after radiation with 5 Gy by multiparametric flow cytometry. Annexin V, 7-AAD and fluorescence conjugated antibodies that were directed against HLA-ABC, CD11a and CD62L were used. Based on these markers radiation induced apoptosis was quantified, multiple apoptotic subpopulations were identified and a characteristic individual apoptotic profile was characterized. The characterization of HLA-ABC, CD11a and CD62L was informative to detect subpopulations of apoptotic cells. The observed heterogeneity and the identification of multiple apoptotic subpopulations reflect the complexity and diversity of biology of radiation induced cell death. This might be an indication for co-existing apoptotic pathways or it might represent sequential steps of the apoptotic cascade.

Apoptosis↗

PubMed2005

Guidelines on radioiodine therapy for differentiated thyroid carcinoma: impact on clinical practice.

AIM: For the examination of the impact on clinical practice of the guidelines for differentiated thyroid carcinoma (DTC), treatment data from the ongoing Multicenter Study Differentiated Thyroid Carcinoma (MSDS) were analyzed. PATIENTS, METHODS: Patients were randomized to adjuvant external beam radiotherapy (RTx) or no RTx in addition to standard therapy in TNM stages pT4 pN0/1/x M0/x (UICC, 5th ed. 1997). All patients were to receive the same treatment regimen consisting of thyroidectomy, ablative radioiodine therapy (RIT), and a diagnostic 131I whole-body scintigraphy (WBS) 3-4 months after RIT. RESULTS: Of 339 eligible patients enrolled between January 2000 and March 2004, 273 could be analyzed. Guideline recommendations by the German Society for Nuclear Medicine from 1999 and 1992 were complied with within 28% and 82% with regard to the interval between surgery and RIT (4 vs. 4-6 weeks), in 33% and 84% with regard to 131I activity for RIT (1-3 vs. 1-4 GBq; +/- 10%), and in 16% and 60% with regard to 131I activity for WBS (100-300 vs. 100-400 MBq; +/- 10%). CONCLUSIONS: The 1999 guideline revision appears to have had little impact on clinical practice. Further follow-up will reveal if guideline compliance had an effect on outcomes.

Combined Modality Therapy↗

PubMed2004

[PET/CT in radiotherapy].

Combining positron emission tomography (PET) and X-ray computed tomography (CT) with simultaneous acquisition may improve diagnostic accuracy in oncology. Moreover this combination holds considerable promise in radiotherapy. Metabolic information may be used in decision making in radiotherapy and in planning target volumes. Furthermore early evaluation of treatment efficacy becomes possible. New tracers for the assessment of tumour hypoxia or apoptosis in clinical routine are currently being developed. These tracers may yield high relevance in radiotherapy. Hybrid scanners facilitate patient handling and shorten the duration of acquisition. Furthermore fusion accuracy is optimal. Prospective studies have to be conducted to show that the new technology improves patient care in terms of efficiency and quality.

Blood Glucose↗

PubMed2004

Late urologic effects after adjuvant irradiation in stage I endometrial carcinoma.

OBJECTIVES: To evaluate the incidence and type of incontinence after external beam radiotherapy (RT) and brachytherapy. Distinct late effects on the urinary bladder can occur and are frequently mild after adjuvant RT for Stage I endometrial carcinoma. Not all side effects that impair quality of life (eg, urinary incontinence) are classified in the commonly used grading system. METHODS: Forty-one patients were evaluated for newly occurred urinary incontinence after adjuvant RT. The mean follow-up was 64.8 months, and the mean age was 62.1 years. The validated incontinence score from Gaudenz was used. Additionally, quality-of-life questions were asked. RESULTS: Overall, 22 (53.7%) of 41 patients complained of urinary incontinence. Urge incontinence was classified in 45.5% (10 of 22 patients) and stress urinary incontinence in 54.5% (12 of 22 patients). CONCLUSIONS: The onset of stress urinary incontinence after brachytherapy can be explained by anatomic findings, such as adverse affects to the nerve supply of the rhabdosphincter. According to our results, the exposure to additional external beam RT can cause urge incontinence. Patients and doctors must be aware that urinary incontinence, with an occurrence rate of more than 50%, represents the most common side effect after surgery and RT for Stage I endometrial carcinoma. We conclude that, depending on the type of RT, a stress incontinence rate of 24.4% and an urge incontinence rate of 29.2% is possible.

Adenocarcinoma↗

PubMed2004

Treatment of advanced Hodgkin's disease with COPP/ABV/IMEP versus COPP/ABVD and consolidating radiotherapy: final results of the German Hodgkin's Lymphoma Study Group HD6 trial.

BACKGROUND: The purpose of this study was to compare the efficacy of the hybrid chemotherapeutic regimen COPP/ABV/IMEP (cyclophosphamide-vincristine-procarbazine-prednisone-doxorubicin-bleomycin-vinblastine-ifosfamide-methotrexate-etoposide) (CAI) with that of the standard regimen COPP/ABVD (COPP/ABV, dacarbacine) (CA) in the treatment of advanced-stage Hodgkin's disease (HD). PATIENTS AND METHODS: Between January 1988 and January 1993, 588 eligible patients with HD in stages IIIB and IV were randomly assigned to a treatment or control group. The treatment group received four cycles of CAI over a complete cycle duration of 43 days. The control group received four cycles of CA over 57 days. Both groups then received consolidating radiotherapy. RESULTS: Five hundred and eighty-four patients were suitable for arm comparison. Patients in each group were similar in age, sex, histological subtype and clinical risk factors. Complete remission rates, overall survival and freedom from treatment failure at 7 years were similar for the two groups: 77% versus 78%, 73% versus 73% and 54% versus 56% for CAI and CA, respectively. Differences in acute chemotherapy-related toxicity were significant, however. Prognostic factor analysis confirmed the relevance of the International Prognostic Index and revealed that stage IVB, low hemoglobin, low lymphocyte count, high age and male gender were associated with a poor prognosis CONCLUSION: The rapidly alternating hybrid CAI did not give superior results when compared with the standard regimen CA in advanced-stage HD.

Adolescent↗

PubMed2003

Time- and dose-dependent changes of intracellular cytokine and cytokine receptor profile of Ewing tumour subpopulations under the influence of ionizing radiation.

PURPOSE: Cytokines and their corresponding cell surface receptors are involved in intercellular signalling pathways and in the radioresistance of normal and malignant cells. The aim was the characterization of the expression of intracellular cytokines, their receptors and apoptosis-associated markers under the influence of radiation. MATERIAL AND METHODS: Two Ewing tumours were characterized in vitro before and 4, 24 and 72 h after radiation with 5 and 10 Gy, and in vivo 4, 6 and 15 days after radiation with 5 and 30 Gy by five parameter flow cytometry. Direct fluorescence-conjugated antibodies directed against intracellular cytokines (interferon-gamma, tumour necrosis factor [TNF]-alpha, interleukin 1) and their receptors (CD119, CD120a, CD121a) were used. Annexin V and 7-amino-actinomycin D were used to identify radiation-induced apoptosis. RESULTS: Inter- and intra-individual heterogeneities were identified by the expression of cytokine receptors and the intracellular cytokine profile before radiation. Time- and dose-dependent up-regulation of the cytokines TNF-alpha and interleukin 1 were found in vitro. In vivo, an up-regulation of CD120a and CD121a was detectable on tumour cell subpopulations. For interferon-gamma and CD119, no changes were seen. CONCLUSIONS: The observed radiation-induced changes of cytokine and receptor profile are an indication for complex intercellular interactions in view of radioresistance-associated mechanisms between cell populations within one individual tumour. The observed heterogeneous response on radiation might have therapeutic implications for an individualized therapy based on combined radiation and cytokine modulation, defined by flow cytometric characterization of markers potentially informative for radioresistance.

Animals↗

PubMed2003

Multicenter study differentiated thyroid carcinoma (MSDS). Diminished acceptance of adjuvant external beam radiotherapy.

AIM: The Multicenter Study Differentiated Thyroid Carcinoma (MSDS) is an ongoing study in Germany, Austria, and Switzerland on the clinical benefit of adjuvant external beam radiotherapy (RTx) for locally invasive differentiated thyroid carcinoma (DTC) in TNM stages pT4 pN0/1/x M0/x (5th ed. 1997). METHODS: MSDS was designed as a prospective randomized trial. Patients receive thyroidectomy, radioiodine therapy (RIT) to ablate the thyroid remnant, and TSH-suppressive L-thyroxine therapy with or without RTx after documented elimination of cervical iodine-131 uptake (http://msds-studie.uni-muenster.de). RESULTS: 311 patients were enrolled between January 2000 and March 2003. 279 patients met the trial's inclusion criteria. 45 consented to randomization, of whom 17 were randomized into treatment arm A (RTx) and 18 into arm B (no RTx). Advised by the trial's independent Data Monitoring and Safety Committee, the MSDS steering committee decided to terminate randomization in April 2003 and continue MSDS as a prospective cohort study. 23 of the 234 patients in the observation arm of the trial were prescribed RTx by their physicians. Thus, 14% of the trial cohort were randomized or assigned to receive RTx (in-tention-to-treat analysis). In contrast, at least 44% of all patients with pT4 papillary DTC in Germany in the nation-wide PCES study underwent RTx in 1996 (p <0.001, chi(2)-test). CONCLUSIONS: Acceptance of external beam RTx as a treatment modality for DTC has receded to a degree that accrual of a sufficient number of patients for a randomized trial has been impossible. Observation of the trial cohort is continued in order to assess clinical event rates with and without RTx and chronic RTx toxicity.

Combined Modality Therapy↗

PubMed2002

Case report: Kasabach-Merritt syndrome: a review of the therapeutic options and a case report of successful treatment with radiotherapy and interferon alpha.

We describe the successful treatment of a neonate with Kasabach-Merritt syndrome who received local irradiation and interferon alpha therapy after failure of corticosteroid treatment. A male neonate, born after an uneventful pregnancy, had a huge haemangioma involving the upper right cervical region as well as severe thrombocytopenia. He was treated with corticosteroids, interferon alpha and radiotherapy. Prednisolone therapy (5 mg kg(-1) day(-1)) was started at 41 days of age. No therapeutic effect was observed after 2 weeks. At this time the tumour size had increased dramatically, platelet counts had decreased progressively and coagulation abnormalities had developed. Because corticosteroid therapy had been ineffective and the child was in a life-threatening condition, irradiation was delivered up to a total dose of 9.5 Gy in five fractions. Simultaneously, prednisolone therapy was slowly decreased and interferon alpha therapy (3 million U m(-2) day(-1)) was started and continued for 6 weeks. After irradiation with 9.5 Gy and beginning interferon alpha therapy, the tumour decreased in size and coagulation parameters normalized within 4 weeks. 6 months later, platelet counts and coagulation parameters were still normal. The tumour had further decreased in size. No acute severe side effects were observed. Radiation therapy combined with interferon alpha treatment is an alternative treatment modality when high dose corticoid steroid therapy has been ineffective in patients with Kasabach-Merritt syndrome, despite the risks of growth delay and secondary malignancy. In children showing no response to corticosteroids, radiotherapy and/or interferon alpha should be considered in Kasabach-Merritt syndrome.

Antineoplastic Agents↗

PubMed2002

Radiotherapy in the treatment of locoregional relapses of breast cancer.

Locoregional recurrences of breast cancer are associated with considerable morbidity and frequently present with concurrent metastatic disease. Yet patients without systemic spread can be treated with curative intent. In a retrospective analysis, the results of treatment of these patients have been evaluated at our institution. Between 1987 and 1996, 113 patients with locoregional breast cancer relapse, without systemic manifestation, received irradiation after local tumour excision. 13 patients (11.5%) had already received radiotherapy as part of their primary treatment. In these cases, only the area involved was treated. In all other patients, the chest wall and the ipsilateral lymph nodes were irradiated. Median dose was 50 Gy (range 20-65 Gy). Median follow-up was 4.4 years. 76 patients (67.3%) presented with chest wall recurrence only, 25 patients (22.1%) with nodal relapse only and 12 patients (10.6%) with combined relapses. 93% of patients had local control of disease after treatment. Local control rate after 5 years was 59%. 63 patients (55.8%) died within the follow-up interval, 45 patients (39.8%) owing to metastases, 4 patients (3.5%) owing to local failure and 8 patients (7%) owing to causes unrelated to tumour. Overall survival after 5 years was 43%. In multivariate analysis, positive hormone receptor status, small tumours on relapse and chest wall relapses alone were associated with improved survival. Radical local therapy is necessary in order to achieve and maintain local control and to prevent secondary dissemination in patients with only local recurrence of breast cancer.

Breast Neoplasms↗

PubMed2002

Lymphangiolipoma of the lower extremity: 5-year radiological follow-up after radiotherapy treatment.

This report describes a lymphangiolipoma located in the extremity in a young woman. Radiotherapy effectively controlled recurrent lymphangiolipoma of the left upper leg that had been judged inoperable by limb-sparing surgical resection. In the case presented here, a dose of 50 Gy in 25 fractions over 5 weeks was employed without long-term complications after 5-year follow-up.

Adolescent↗

PubMed2001

Low-dose radiation is sufficient for the noninvolved extended-field treatment in favorable early-stage Hodgkin's disease: long-term results of a randomized trial of radiotherapy alone.

PURPOSE: To show that radiotherapy (RT) dose to the noninvolved extended field (EF) can be reduced without loss of efficacy in patients with early-stage Hodgkin's disease (HD). PATIENTS AND METHODS: During 1988 to 1994, pathologically staged patients with stage I or II disease who were without risk factors (large mediastinal mass, extranodal lesions, massive splenic disease, elevated erythrocyte sedimentation rate, or three or more involved areas) were recruited from various centers. All patients received 40 Gy total fractionated dose to the involved field areas but were randomly assigned to receive either 40 Gy (arm A) or 30 Gy (arm B) total fractionated dose for the clinically noninvolved EF. No chemotherapy was given. RT films were prospectively reviewed for protocol violations and recurrences retrospectively related to the applied RT. RESULTS: Of 382 recruited patients, 376 were eligible for randomized comparison, 190 in arm A and 186 in arm B. Complete remission was attained in 98% of patients in each arm. With a median follow-up of 86 months, 7-year relapse-free survival (RFS) rates were 78% (arm A) and 83% (arm B) (P =.093). The upper 95% confidence limit for the possible inferiority of arm B in RFS was 4%. Corresponding overall survival rates were 91% (arm A) and 96% (arm B) (P =.16). The most common causes of death (n = 27) were cardiorespiratory disease/pulmonary embolisms (seven), second malignancy (six), and HD (five). Protocol violation was associated with significantly poorer RFS. Nonirradiated nodes were involved in 42 of 52 reviewed relapses, infield areas in 18, marginal areas in 17, and extranodal sites in 16. CONCLUSION: EF-RT alone attains good survival rates in favorable early-stage HD. The 30-Gy dose is adequate for clinically noninvolved areas. Protocol violation worsens the subsequent prognosis. Relapse patterns suggest that systemic therapy can reduce the 20% long-term relapse rate.

Adolescent↗

PubMed2001

CT simulation in nodal positive breast cancer.

BACKGROUND: A variety of solutions are used to match tangential fields and opposed lymph node fields in irradiation of nodal positive breast cancer. The choice is depending on the technical equipment which is available and the clinical situation. The CT simulation of a non-monoisocentric technique was evaluated in terms of accuracy and reproducibility. PATIENTS, MATERIAL AND METHODS: The field match parameters were adjusted virtually at CT simulation and were compared with parameters derived mathematically. The coordinate transfer from the CT simulator to the conventional simulator was analyzed in 25 consecutive patients. RESULTS: The angles adjusted virtually for a geometrically exact coplanar field match corresponded with the angles calculated for each set-up. The mean isocenter displacement was 5.7 mm and the total uncertainty of the coordinate transfer was 6.7 mm (1 SD). Limitations in the patient set-up became obvious because of the steep arm abduction necessary to fit the 70 cm CT gantry aperture. Required modifications of the arm position and coordinate transfer errors led to a significant shift of the marked matchline of > 1.0 cm in eight of 25 patients (32%). CONCLUSION: The virtual CT simulation allows a precise and graphic definition of the field match parameters. However, modifications of the virtual set-up basically due to technical limitations were required in a total of 32% of cases, so that a hybrid technique was adapted at present that combines virtual adjustment of the ideal field alignment parameters with conventional simulation.

Breast Neoplasms↗

PubMed2001

[Chronic radiation effects on dental hard tissue (radiation caries). Classification and therapeutic strategies].

OBJECTIVES: Since the first description of rapid destruction of dental hard tissues following head and neck radiotherapy 80 years ago, "radiation caries" is an established clinical finding. The internationally accepted clinical evaluation score RTOG/EORTC however is lacking a classification of this frequent radiogenic alteration. MATERIAL AND METHODS: Medical records, data and images of radiation effects on the teeth of more than 1,500 patients, who underwent periradiotherapeutic care, were analyzed. Macroscopic alterations regarding the grade of late lesions of tooth crowns were used for a classification into 4 grades according to the RTOG/EORTC guidelines. RESULTS: No early radiation effects were found by macroscopic inspection. In the first 90 days following radiotherapy 1/3 of the patients complained of reversible hypersensitivity, which may be related to a temporary hyperemia of the pulp. It was possible to classify radiation caries as a late radiation effect on a graded scale as known from RTOG/EORTC for other organ systems. This is a prerequisite for the integration of radiation caries into the international nomenclature of the RTOG/EORTC classification. CONCLUSIONS: The documentation of early radiation effects on dental hard tissues seems to be neglectable. On the other hand the documentation of Late radiation effects has a high clinical impact. The identification of an initial lesion at the high-risk areas of the neck and incisal part of the tooth can lead to a successful therapy as a major prerequisite for orofacial rehabilitation. An internationally standardized documentation is a basis for the evaluation of the side effects of radiooncotic therapy as well as the effectiveness of protective and supportive procedures.

Adult↗

PubMed2000

Cell heterogeneity and subpopulations in solid tumors characterized by simultaneous immunophenotyping and DNA content analysis.

BACKGROUND: Heterogeneity in human malignant tumors is a well-described phenomenon and of interest with regard to subpopulations with differences in clonality, metastatic potential, and response to therapy under different treatment regimes. The aim of this study was the simultaneous characterization of surface markers and DNA content of solid tumors to identify tumor cell subpopulations and to study the association between the expression of antigens and DNA content. METHODS: In the present study, six different malignant tumors grown as xenografts in nude mice were characterized by five-parameter flow cytometry. Immunophenotyping was performed using a variety of direct fluorescence-conjugated antibodies. In all cases, simultaneous detection of DNA content was done after staining with 7-aminoactinomycin D. RESULTS: Tumor cells were characterized by light scatter properties, antigen expression, and DNA content. Tumor cell heterogeneity, subpopulations, and DNA content-dependent antigen expression were identified. CONCLUSIONS: This method offers the possibility of characterizing solid tumors according to their immunophenotype and DNA content. The results obtained can be used to identify changes in immunophenotypic and DNA profiles of tumor cell populations before and after therapy and might be useful to define parameters predictive for response to therapy.

Animals↗

PubMed2000

Dose-dependent induction of transforming growth factor beta (TGF-beta) in the lung tissue of fibrosis-prone mice after thoracic irradiation.

PURPOSE: The lung is the major dose-limiting organ for radiotherapy of cancer in the thoracic region. The pathogenesis of radiation-induced lung injury at the molecular level is still unclear. Immediate cellular damage after irradiation is supposed to result in cytokine-mediated multicellular interactions with induction and progression of fibrotic tissue reactions. The purpose of this investigation was to evaluate the acute and long-term effects of radiation on the gene expression of transforming growth factor beta (TGF-beta) in a model of lung injury using fibrosis-sensitive C57BL/6 mice. METHODS AND MATERIALS: The thoraces of C57BL/6 mice were irradiated with 6 and 12 Gy, respectively. Treated and sham-irradiated control mice were sacrificed at times corresponding to the latent period (1, 3, 6, 12, 24, 48, 72 hours and 1 week postirradiation), the pneumonic phase (2, 4, 8, and 16 weeks postirradiation), and the beginning of the fibrotic phase (24 weeks postirradiation). The lung tissue from three different mice per dosage and time point was analyzed by a combination of polymerase chain reaction (PCR), immunohistochemistry, and light microscopy. The mRNA expression of TGF-beta was quantified by competitive reverse transcriptase/polymerase chain reaction (RT-PCR); the cellular origin of the TGF-beta protein was identified by immunohistochemical staining (alkaline phosphatase-anti-alkaline phosphatase [APAAP]). The cytokine expression on mRNA and protein level was correlated with the histopathological alterations. RESULTS: Following thoracic irradiation with a single dose of 12 Gy, radiation-induced TGF-beta release in lung tissue was appreciable already within the first hours (1, 3, and 6 hours postirradiation) and reached a significant increase after 12 hours; subsequently (48 hours, 72 hours, and 1 week postirradiation) the TGF-beta expression declined to basal levels. At the beginning of the pneumonic phase, irradiation-mediated stimulation of TGF-beta release reached maximal values at 2 and 4 weeks. The elevated levels of TGF-beta mRNA during the latent phase have been found to correlate with immunohistochemical staining of alveolar macrophages. The most striking increase in TGF-beta immunoreactivity was seen during the acute phase of pneumonitis. Throughout this observation period, type II pneumocytes and fibroblasts (apart from inflammatory cells) served as important sources of TGF-beta expression. Increased TGF-beta expression was detected prominently in regions of histopathologic radiation injury. After exposure to a single radiation dose of 6 Gy, the lung tissue revealed only a minor radiation-mediated TGF-beta mRNA response. The modest upregulation ranged from 6 hours to 48 hours after irradiation. Corresponding to the only minor histopathologic changes after thoracic irradiation with 6 Gy, measurement of TGF-beta mRNA levels during the later time points revealed no significant alterations in comparison to untreated control mice. CONCLUSIONS: This study demonstrates an acute and long-lasting increase in the expression of TGF-beta in lung tissue following thoracic irradiation with 12 Gy. The predominant localization of TGF-beta in areas of inflammatory cell infiltrates and fibrosis suggests involvement of this cytokine in the pathogenesis of radiation-induced pulmonal fibrosis. Further studies should be performed to explore the role of other cytokines in the development of radiation injury. An improved understanding of the underlying mechanisms of pulmonary fibrosis may eventually lead to modulatory intervention at the molecular level to modify the fibrotic process.

Animals↗

PubMed2000

Effect of distortions and asymmetry in MR images on radiotherapeutic treatment planning.

Before using MR-images for radiotherapeutic treatment planning, it is necessary to check whether geometrical distortions influence the calculated dose distribution. In this study, 27 MRI units from different manufacturers and with different magnetic field strengths were investigated. First, all geometrical distortions and asymmetry were determined by specially defined parameters. Virtual planning target volume and organ of risk were drawn into MR images from different units and optimized dose distributions were calculated. The resulting field parameters were then transferred to the reference geometry. Geometric distortions caused small variations of the dose maximum (+/-0.5%). Twenty-five percent of the investigated calculated dose distributions showed an increase of the 95% isodose volume, 60% a decrease. The dose deviations in the organ of risk were comparable with the dose deviations in the planning target volume (PTV). This study has shown that measurements of geometrical distortions and asymmetry are necessary for MR-assisted treatment planning. For evaluation, we recommend dose calculations with hypothetical PTV's and organs of risk. Int. J. Cancer (Radiat. Oncol. Invest.) 90, 46-50 (2000).

Electromagnetic Fields↗

PubMed2000

Postoperative neoadjuvant chemotherapy before radiotherapy as compared to immediate radiotherapy followed by maintenance chemotherapy in the treatment of medulloblastoma in childhood: results of the German prospective randomized trial HIT '91.

PURPOSE: The German Society of Pediatric Hematology and Oncology (GPOH) conducted a randomized, prospective, multicenter trial (HIT '91) in order to improve the survival of children with medulloblastoma by using postoperative neoadjuvant chemotherapy before radiation therapy as opposed to maintenance chemotherapy after immediate postoperative radiotherapy. METHODS AND MATERIALS: Between 1991 and 1997, 158 patients were enrolled and 137 patients randomized. Seventy-two patients were allocated to receive neoadjuvant chemotherapy before radiotherapy (arm I, investigational). Chemotherapy consisted of ifosfamide, etoposide, intravenous high-dose methotrexate, cisplatin, and cytarabine given in two cycles. In arm II (standard arm), 65 patients were assigned to receive immediate postoperative radiotherapy, with concomitant vincristine followed by 8 cycles of maintenance chemotherapy consisting of cisplatin, CCNU, and vincristine ("Philadelphia protocol"). All patients received radiotherapy to the craniospinal axis (35.2 Gy total dose, 1.6 Gy fractionated dose / 5 times per week followed by a boost to posterior fossa with 20 Gy, 2.0 Gy fractionated dose). RESULTS: During chemotherapy Grade III/IV infections were predominant in arm I (40%). Peripheral neuropathy and ototoxicity were prevailing in arm II (37% and 34%, respectively). Dose modification was necessary in particular in arm II (63%). During radiotherapy acute toxicity was mild in the majority of patients and equally distributed in both arms. Myelosuppression led to a mean prolongation of treatment time of 11.5 days in arm I and 7.5 days in arm II, and interruptions in 35% of patients in arm I. Quality control of radiotherapy revealed correct treatment in more than 88% for dose prescription, more than 88% for coverage of target volume, and 98% for field matching. At a median follow-up of 30 months (range 1.4-62 months), the Kaplan-Meier estimates for relapse-free survival at 3 years for all randomized patients were 0.70+/-0.08; for patients with residual disease: 0.72+/-0.06; without residual disease: 0.68+/-0.09; M0: 0.72+/-0.04; M1: 0.65+/-0.12; and M2/3: 0.30+/-0.15. For all randomized patients without M2/3 disease: 0.65+/-0.05 (arm I) and 0.78+/-0.06 (arm II) (p < 0.03); patients between 3 and 5.9 years: 0.60+/-0.13 and 0.64+/-0.14, respectively, but patients between 6 and 18 years: 0.62+/-0.09 and 0.84+/-0.08, respectively (p < 0.03). In a univariate analysis the only negative prognostic factors were M2/3 disease (p < 0.002) and an age of less than 8 years (p < 0.03). CONCLUSIONS: Maintenance chemotherapy would seem to be more effective in low-risk medulloblastoma, especially in patients older than 6 years of age. Neoadjuvant chemotherapy was accompanied by increased myelotoxicity of the subsequent radiotherapy, causing a higher rate of interruptions and an extended overall treatment time. Delayed and/or protracted radiotherapy may therefore have a negative impact on outcome. M2/3 disease was associated with a poor survival in both arms, suggesting the need for a more intensive treatment. Young age and M2/3 stage were negative prognostic factors in medulloblastoma, but residual or M1 disease was not, suggesting a new stratification system for risk subgroups. High quality of radiotherapy may be a major contributing factor for the overall outcome.

Adolescent↗