Biomedical subjects

H Schmidberger

Publications and source records attributed to H Schmidberger.

At least 37 records · Page 2Linked to original sources

PubMed2001

In vitro response of human dermal fibroblasts to X-irradiation: relationship between radiation-induced clonogenic cell death, chromosome aberrations and markers of proliferative senescence or differentiation.

PURPOSE: To analyse the relationship between radiation-induced clonogenic cell death, chromosome aberrations and markers of proliferative senescence or differentiation. MATERIALS AND METHODS: Plateau-phase human dermal fibroblasts from 18 donors were irradiated with graded doses of 1-6 Gy 200kV X-rays. Cell survival was determined by a colony-forming assay. Markers of differentiation or senescence were: spontaneous and radiation-induced clonal differentiation, which was determined morphologically and by the cellular potential to proliferate in clonal culture, also single-cell beta-galactosidase (beta-gal) staining at pH 6.0; and the secretion of transforming growth factor-beta (TGF-beta1) into the culture medium. Chromosome aberrations were determined as genomic yields of dicentric chromosomes and the excess acentric fragments, scored in Giemsa-stained metaphases, and as partial yields of reciprocal translocations for chromosomes 4, 7 and 9 using the FISH method. RESULTS: A broad spread was found in the shapes of the survival curves, with SF2 ranging from 0.041+/-0.015 to 0.63+/-0.05. Radiation-induced clonal differentiation as well as the secretion of TGF-beta1 was elevated in radiosensitive samples. With respect to chromosome aberrations, a significant correlation was found between clonogenic survival and radiation-induced excess acentric fragments. CONCLUSIONS: In the fibroblast cell system, in vitro radiosensitivity is determined not only by processes directly involved in DNA-damage recognition and repair, but also by intracellular signalling cascades, which will lead to differentiation processes.

Cell Death↗

PubMed2000

[Interdisciplinary consensus on diagnosis and therapy of testicular tumors. Results of an update conference based on evidence-based medicine. German Testicular Cancer study Group (GTCSG)].

BACKGROUND: An "Interdisciplinary Consensus Statement on the Diagnosis and Therapy of Testicular Tumors" was prepared in 1996 by the "Interdisciplinary Testicular Tumor Working Group" (IAH) with input from representatives from diagnostic and therapeutic disciplines of various working groups of the German Cancer Society (Strahlenther Onkol 1997;173:397-406). In 1998 the IAH met again together with the "Testicular Tumor Working Party" of the Urooncology Working Group (AUO) and formed the "German Testicular Cancer Study Group" (GTCSG). Defined and accepted interdisciplinary standards from the initial meeting were revised based on current scientific developments and clinical results. This cooperating effort increased the quality of the initial recommendations and helped to put the recommendations for diagnosing and treating testicular tumor on a broader scientific basis. METHODS: According to the principles of "evidence-based medicine" (EBM), the Consensus from 1996 was modified, based on the current level of evidence from the published literature. The methodological process and evaluation criteria used were that of the "Cochrane Collaboration". RESULTS: An "Interdisciplinary Update Consensus Statement" summarizes and defines the diagnostic and therapeutic standards according to the current scientific practices in testicular cancer. For 21 separate areas scientifically based decision criteria are suggested. For treatment areas where more than one option exist without a consensus being reached for a preferred strategy, such as in seminoma in clinical Stage I or in non-seminoma Stages CS I or CS IIA/B, all acceptable alternative strategies with their respective advantages and disadvantages are presented. This "Interdisciplinary Update Consensus" was presented at the 24th National Congress of the German Cancer Society on March 21st and subsequently evaluated and approved by the various German scientific medical societies.

Evidence-Based Medicine↗

PubMed2000

Cranial irradiation of female rats causes dose-dependent and age-dependent activation or inhibition of pubertal development.

Cranial irradiation in prepubertal children with leukemia or brain tumors can lead to precocious or in high doses to late puberty. To unravel the underlying mechanisms, we developed a rat model with selective cranial Co60-irradiation technique. Infantile (12-16 d old) or juvenile (21-23 d old) female Sprague-Dawley rats received a single dose of 4, 5, 6, 9 or 2 x 9 Gy (at days 21 and 23). Each group consisted of 7-20 animals. High radiation doses (9 Gy and more) caused retardation of sexual development, whereas low radiation doses (5 or 6 Gy) led to accelerated onset of puberty in 20% of infantile irradiated rats animals as determined by vaginal opening. Interestingly, at peripubertal age (postnatal day 32-34), 5 or 6 Gy infantile irradiated rats had significantly higher serum LH levels stimulated by GnRH and estradiol levels (p < 0.05). 2 x 9 Gy irradiated rats had at the age of 3 mo a marked growth retardation and significantly lower GH levels than the controls (p < 0.05) whereas prolactin, FSH, TSH, T4, and corticosterone levels were comparable with controls. These studies demonstrate that the GnRH-pulse generator is very radiosensitive as precocious activation occurred after low dose irradiation (5 or 6 Gy) of infantile rats without any other endocrine disorder. High radiation doses (9 or 2 x 9 Gy) induced retardation of sexual maturation and later on growth hormone deficiency. Moreover this model of cranial irradiation seems to be suitable to study the molecular mechanisms of radiation induced pubertal changes.

Age Factors↗

PubMed1999

Radiotherapy for stages I and IIA/B testicular seminoma.

Radiotherapy is generally accepted as a standard treatment for early-stage testicular seminoma. Relapse rates of 2% to 5% in clinical stage I and 10% to 20% in stage IIA/B (according to the Royal Marsden classification) can be achieved. Disease-specific survival reaches 100%. With such excellent cure rates, treatment-related side effects gain particular importance. Therefore, a prospective multicenter trial was initiated for radiotherapy of testicular seminoma with limited treatment portals and low total doses of irradiation. In clinical stage I, 483 patients were treated with 26 Gy to the para-aortic region only. In stage IIA, 42 patients and, in stage IIB, 18 patients received irradiation to the para-aortic and high iliac lymph nodes with 30 and 36 Gy, respectively. With a median time to follow-up of 55 months for stage I and 55.5 months for stage IIA/B, there were 18 (3.7%) and 4 (6.7%) cases of relapse in both treatment groups. Disease-specific survival was 99.6% in stage I and 100% in stage IIA/B. Acute toxicity was dominated by moderate gastro-intestinal side effects. No major late toxicity has been observed to date. Limited volume pure para-aortic treatment for stage I and para-aortic/high iliac irradiation for stage IIA/B with 26, 30 and 36 Gy, respectively, yields excellent cure rates with only moderate acute toxicity and is therefore recommended as standard treatment.

Adolescent↗

PubMed1999

The combined effect of interferon beta and radiation on five human tumor cell lines and embryonal lung fibroblasts.

PURPOSE: The combined effect of natural Interferon-beta (n-IFN-beta) and ionizing radiation was tested in vitro on 5 different tumor cell lines and 1 embryonal lung fibroblast cell line. MATERIALS AND METHODS: The following cell lines were used: A549 (lung cancer), MCF-7 (breast cancer), CaSki (cervical cancer), WiDr (colon cancer), ZMK-1 (head and neck cancer), and MRC-5 (embryonal lung fibroblast line). Cells were incubated with n-IFN-beta (30 I.U./ml to 3000 I.U./ml) 24 h before irradiation. Irradiation was given as single dose between 1 and 6 Gy. Cell survival was evaluated using a standard colony-forming assay. RESULTS: Incubation with n-IFN-beta enhanced the effect of radiation in all tumor cell lines tested. The maximum sensitizing enhancement ratios (SER) at the 37% survival level were: 1.66 for A549 cells, 1.47 for CaSki cells, 1.56 for MCF-7 cells, 1.40 for WiDr cells, and 1.57 for ZMK-1 cells. In the nonneoplastic MRC-5 cell line, no radiosensitizing effect of n-IFN-beta could be demonstrated. The linear quadratic fit of the survival curves showed an increase of the alpha-component for all tumor cell lines treated with n-IFN-beta. CONCLUSIONS: IFN-beta enhanced the effect of radiation in the tumor cell lines, but not in the nonmalignant lung fibroblasts. The increase of the alpha component in the survival curves indicates that impaired radiation repair or the accumulation of sublethal damage might play a role for the radiosensitizing effect of n-IFN-beta.

Humans↗

PubMed1999

Unusual chondrosarcoma of the larynx: CT findings.

A case of a large low-grade mixed clear-cell and conventional chondrosarcoma of the larynx is reported involving the paraglottic space, the cricoid and thyroid cartilage and characterized by an unusual long clinical course over 22 years, although multiple recurrences occurred without developing metastases. Computed tomography suggests diagnosis by detecting calcifications and adequately demonstrates the extension of the tumor. Innersurface and surface-rendering images document the airway stenosis in all directions. The unusual feature of this case consists in the peculiar histopathological differentiation of the observed chondrosarcoma showing a large clear-cell component.

Chondrosarcoma↗

PubMed1999

Effects of paclitaxel in combination with radiation on human head and neck cancer cells (ZMK-1), cervical squamous cell carcinoma (CaSki), and breast adenocarcinoma cells (MCF-7).

BACKGROUND AND PURPOSE: The anticancer drug paclitaxel, a natural product from Taxus brevifolia, is a microtubule-stabilising agent, which has been shown to block different cells in the G2/M phase of the cell cycle and so modulate their radioresponsiveness. We investigated the radiosensitizing potential of paclitaxel in human head and neck cancer cells (ZMK-1), in cervical squamous cell carcinoma cells (CaSki) and in breast adenocarcinoma cells (MCF-7). METHODS: ZMK-1 cells were incubated with paclitaxel for 3, 9, or 24 h before irradiation. ZMK-1-, CaSki- and MCF-7 cells were incubated with paclitaxel for 24 h after irradiation. The paclitaxel concentration (70 nM, 7 nM, 0.7 nM) was chosen to obtain equivalent toxicity at the different incubation times (3 h, 9 h, 24 h respectively). Radiation doses were from 0 to 8 Gy. Cell survival was measured by a standard clonogenic assay after a 9-day incubation. Flow cytometry was used to measure the capacity of paclitaxel to cause accumulation of cells in the G2/M phase of the cell cycle. RESULTS: Paclitaxel alone was cytotoxic in a time- and concentration-dependent manner. Up to 36% of the ZMK-1 cells accumulated in G2/M after treatment for 24-36 h. If the cells were incubated with paclitaxel before irradiation the isoeffect enhancement ratios for ZMK-1 cells, determined at the 37% survival level, were 0.81, 1.48 and 1.15 for 3-h, 9-h, and 24-h pre-incubations respectively. For a paclitaxel incubation of 24 h after irradiation, the isoeffect enhancement ratios, determined at the 37% survival level, were 0.72, 0.76 and 1.2 for the ZMK-1. CaSki, and MCF-7 cells respectively. CONCLUSION: In the three cell lines no radiosensitizing effect of paclitaxel could be demonstrated unambiguously. The use of asynchronized cells or the support of cellular repair mechanisms while the cells are blocked in G2/M could partly explain the results.

Adenocarcinoma↗

PubMed1999

Radiosensitizing effect of natural and recombinant beta-interferons in a human lung carcinoma in vitro.

PURPOSE: The enhancing effect of natural interferon-beta (n-IFN-beta) or recombinant interferon-beta (r-IFN-beta) on radiation damage in tumor cells has been evaluated in several sudies. It is not clear whether the different forms of IFN-beta available today are equally efficient in modulating the intrinsic radiosensitivity of tumor cells. The purpose of this study was to compare the radiosensitizing effect of n-IFN-beta, r-IFN-beta1a, and r-IFN-beta1b in one cancer cell line. METHODS: The A549 lung-cancer cell line was grown as a monolayer culture and incubated for 24 h with n-IFN-beta (Fiblaferon), r-IFN-beta1a (Betaserin), or r-IFN-beta1b (Betaferon). Thereafter, the cultures were irradiated with single graded doses of 0, 1, 2, 4, and 6 Gy. Cellular survival was counted in a colony-forming assay at 10 days after treatment. Survival curves were established using the linear quadratic model. Statistical comparison of the survival data was performed using Student's t-test for each dose point. Interactions of IFN-beta and radiation were evaluated using isobologram analysis. RESULTS: All three types of IFN-beta enhanced the radiation sensitivity of A549 cells in a similar way as shown in the alteration of the survival curves and the isobologram analysis. The isoeffective concentration of r-IFN-beta1b was 2.7-fold higher than that of r-IFN-beta1a or n-IFN-beta. All three interferons increased the alpha-component of the survival curves in a concentration-dependent way, suggesting an influence on repair of radiation damage. The maximal sensitizing enhancement ratio (SER) obtained with n-IFN-beta or r-IFN-beta1a at 3000 IU/ml was 1.66 and 1.51, respectively. The highest SER, obtained with r-IFN-beta1b, at 8000 IU/ml was 1.93. CONCLUSIONS: All three interferons tested can equally modify the intrinsic radiosensitivity of A549 cells. The isoeffective concentration of r-IFN-beta1b is 2.7-fold that of n-IFN-beta or r-IFN-beta1a.

Cell Division↗

PubMed1999

Accuracy of alignment in breast irradiation: a retrospective analysis of clinical practice.

The objective of the study was to determine the accuracy of patient positioning in radiotherapy for breast cancer. Portal images were obtained using a fast electronic megavoltage radiotherapy imaging system in 30 cases of breast cancer. Quantitative analysis of 530 megavolt portal images and comparison with 30 digitized simulation films were performed. Five linear measurements were taken for each simulation and verification film. Central lung distance (CLD) is the distance from the dorsomedial beam edge to the inner thoracic wall in the central plane of the beam. Cranial lung distance (CrLD) is the distance from the dorsomedial beam edge to the inner thoracic wall in the plane of the beam at 4 cm from the central plane. Central beam edge to skin distance (CBESD) is the distance from the skin to the ventrolateral beam edge in the central plane of the beam. The central irradiated width (CIW) is defined as the distance from the dorsomedial beam edge to the skin. The craniocaudal distance (CCD) is defined as the distance from a particular landmark to the caudal field border. Concerning patient position in the field, mean standard deviations of the difference between simulation and treatment images were 3.9 mm for the CLD, 3.2 mm at +4 cm, 3.6 mm for the CIW, 3.3 mm for the CBESD, 3.8 mm for the CCD. In 90% of all set-up for treatment, errors were less than 1 cm. The variation of the CLD was the largest set-up error. This parameter is clinically the most significant. Future treatment delivery should be improved by introducing patient positioning devices such as thermoplastic shells. The electronic portal imaging device (EPID) appears to be an adequate tool to study the accuracy of treatment set-ups like this.

Breast Neoplasms↗

PubMed1998

Experimental studies on the role of antibody fragments in cancer radio-immunotherapy: Influence of radiation dose and dose rate on toxicity and anti-tumor efficacy.

Whereas bivalent fragments have been widely used for radio-immunotherapy, no systematic study has been published on the therapeutic performance of monovalent conjugates in vivo. The aim of our study was, therefore, to determine the therapeutic performance of (131)I-labeled Fab as compared to bivalent conjugates and to analyze factors that influence dose-limiting organ toxicity and anti-tumor efficacy. The maximum tolerated doses (MTDs) and dose-limiting organ toxicities of the (131)I-labeled anti-CEA antibody MN-14 [IgG, F(ab')2 and Fab] were determined in nude mice bearing s.c. human colon cancer xenografts. Mice were treated with or without bone marrow transplantation (BMT) or inhibition of the renal accretion of antibody fragments by D-lysine or combinations thereof. Toxicity and tumor growth were monitored. Radiation dosimetry was calculated from biodistribution data. With all 3 (131)I-labeled immunoconjugates [IgG, F(ab')2 and Fab], the red marrow was the only dose-limiting organ; MTDs were 260 microCi for IgG, 1,200 microCi for F(ab')2 and 3 mCi for Fab, corresponding to blood doses of 17 Gy, 9 Gy and 4 Gy, respectively. However, initial dose rates were 10 times higher with Fab as compared to IgG and 3 times higher as compared to F(ab')2. The MTD of all 3 immunoconjugates was increased by BMT by approximately 30%. In accordance with renal doses below 10 Gy, no signs of nephrotoxicity were observed. Despite lower absorbed tumor doses, at equitoxic dosing, Fab fragments were more effective at controlling tumor growth than the respective bivalent fragment or IgG, probably due to higher intratumoral dose rates. Our data indicate that the improved anti-tumor effectiveness of antibody fragments as compared to IgG and the higher myelotoxicity at comparably lower red marrow doses are most likely due to the higher initial dose rates observed with antibody fragments.

Animals↗

PubMed1998

Therapeutic efficacy and dose-limiting toxicity of Auger-electron vs. beta emitters in radioimmunotherapy with internalizing antibodies: evaluation of 125I- vs. 131I-labeled CO17-1A in a human colorectal cancer model.

Recent clinical results suggest that higher anti-tumor efficacy may be achieved with internalizing monoclonal antibodies (MAbs) at lower toxicity when labeled with Auger-electron, as compared to conventional beta-emitters. The aim of our study was to compare the toxicity and anti-tumor efficacy of the 125I-labeled internalizing MAb, CO17-1A, with its 131I-labeled form in a human colon cancer model in nude mice. Biodistribution studies were performed in nude mice bearing s.c. human colon cancer xenografts. For therapy, the mice were injected either with unlabeled 125I- or 131I-labeled C017-1A at equitoxic doses. Control groups were left untreated, were given a radiolabeled isotype-matched irrelevant antibody or a tumor-specific, but noninternalizing antibody. The maximum tolerated activities (MTD) of 131I-and 125I-CO17-1A without artificial support were 300 microCi and 3 mCi, respectively. Myelotoxicity was dose-limiting; bone marrow transplantation allowed for an increase of the MTD to 400 microCi of 131I-17-1A, whereas the MTD of 125I-17-1A with bone marrow support had not been reached at 5 mCi. Whereas no significant therapeutic effects were seen with unlabeled C017-1A, tumor growth was retarded with 131I-CO17-1A. With the 125I-label, however, therapeutic results were clearly superior. In contrast, no significant difference was observed in the therapeutic efficacy of the 131I- vs. 125I-labeled, noninternalizing antibodies. Our data indicate a superiority of Auger-electron emitters, such as 125I, as compared to therapy with conventional beta-emitters with internalizing antibodies. The lower toxicity of Auger emitters may be due to the short path length of their low-energy electrons, which can reach the nuclear DNA only if the antibody is internalized (as is the case in antigen-expressing tumor tissue, but not in the stem cells of the red marrow).

Animals↗

PubMed1998

Radiation rendered more cytotoxic by fludarabine monophosphate in a human oropharynx carcinoma cell-line than in fetal lung fibroblasts.

PURPOSE: Fludarabine monophosphate (fludarabine-P) is a relatively new drug in the treatment of different haematological diseases. The mechanism of action also implies a possible role of this drug as a radiosensitizer. Up to now no in vitro investigations dealing with radiosensitizing effects of fludarabine-P in carcinoma cell lines and fibroblasts have been published. The aim of our studies was to analyse the cytotoxic and radiosensitizing effects of different dosages and application schedules of fludarabine-P in a human squamous carcinoma cell line of the oropharynx (ZMK-1) and of fetal lung fibroblasts (MRC-5) in vitro. Possible mechanisms of interaction of fludarabine-P and radiation were investigated. METHODS: ZMK-1 and MRC-5 cells were cultured under standard conditions with different concentrations of fludarabine-P in combination with escalating doses of radiation. Cytotoxic effects were measured by colony-forming assays. Induction and rejoining of radiation-induced DNA double-strand breaks after incubation with fludarabine-P were measured using constant-field gel electrophoresis. Incubation times for rejoining varied from 0 h to 24 h. RESULTS: Fludarabine-P showed a radiosensitizing activity in ZMK-1 tumour cells and MRC-5 fibroblasts. The observed effects depended on the concentration and the incubation time. The largest effect was demonstrable for an incubation of 5 days, which started shortly before irradiation, whereas an incubation solely before irradiation did not have a clear effect on the cellular survival. The sensitizer enhancement ratio, at the 10% survival level, in the ZMK-1 cells was 2.2 in comparison to 1.6 in MRC-5 cells. The analysis of the interaction of fludarabine-P and ionising radiation by means of the isobologram approach, revealed an overadditive effect in the tumour cell line and an additive effect in the lung fibroblasts. Fludarabine-P did not modify the rejoining of radiation-induced DNA double-strand breaks in either cell line. CONCLUSIONS: We conclude that fludarabine-P in clinically attainable doses is a strong radiosensitizer in ZMK-1 cells and has a lower activity in the MRC-5 fibroblasts in vitro. The radiosensitization of fludarabine-P seems to be over additive in the malignant cells and additive in normal fetal fibroblasts. This would indicate that fludarabine-P might enhance the therapeutic ratio of radiation. Further investigations are warranted to identify the potential of this drug as a radiosensitizer in vivo and to elucidate the mechanism of interaction of the drug and radiation.

Carcinoma, Squamous Cell↗

PubMed1998

Intrathecal therapy of leptomeningeal CEM T-cell lymphoma in nude rats with anti-CD7 ricin toxin A chain immunotoxin.

We have established a new xenogeneic animal model of leptomeningeal metastasis (LM) by intracisternal inoculation of human CEM T-cell lymphoma into nude rats, and used it to evaluate the anti-lymphoma efficacy of an anti-CD7 ricin A chain immunotoxin (DA7). In vitro incubation with 2 microg/ml DA7 for 72 h inhibited CEM cells by 90% in a trypan blue exclusion assay. To establish its anti-lymphoma activity, one and four days after cisternal inoculation of 10(6) CEM cells, eight animals each were treated cisternally with 10 microg DA7 in 50 microl PBS or sham-treated with 50 microl PBS. Histopathologically, all eight sham-treated and five of eight DA7 treated animals showed typical features of LM with multilayers of tumor cells along the whole subarachnoid space and the ventricular walls, as well as subependymal and diffuse parenchymal tumor cell infiltration. Three DA7 treated animals were free of tumor. Two of these animals were asymptomatic long-term survivors (> 90 days). The third tumor-free animal suddenly died on day 51. Histology revealed viral myocarditis. Median symptom-free survival was 51 days (range 29-90+ days) in DA7 treated and 34 days (range 29-87 days) in sham-treated animals (p = 0.12, log-rank test). Histologically, no signs of neurotoxicity or systemic toxicity was found. However, DA7 treated animals showed a tendency to a slower weight increase on days 6-28 after tumor cell inoculation. Our results indicate that this model is useful in studying leptomeningeal seeding and intracisternal treatment of lymphoma. The demonstrated anti-tumor effect of DA7 treatment deserves further evaluation especially regarding the application of DA7 in early stages of LM from T-cell lymphoma.

Animals↗

PubMed1998

Induction combination chemotherapy with docetaxel and carboplatin in advanced non-small-cell lung cancer.

BACKGROUND: Results in the therapy of locally advanced non-small-cell lung cancer (NSCLC) by operation and/or irradiation only are poor. To improve the long-term prognosis a systemic induction chemotherapy may be successful in reducing local tumor burden and eliminating micrometastases. The efficacy of preoperative docetaxel-carboplatin combination chemotherapy was studied in a phase-II study for NSCLC stage IIIB. METHODS: 15 patients with functionally operable stage IIIB NSCLC (10 squamous-cell, 4 adeno, 1 large-cell) were enrolled to receive 4 cycles of docetaxel (100 mg/m2, day 1) and carboplatin (AUC 7.5, day 2) on an outpatient basis with G-CSF support after cycle 1 and were subsequently evaluated for surgery. Postoperatively the patients were irradiated with 50 Gy (R0-resection) or 60 Gy (R1-resection). RESULTS: Acceptable hematologic and non-hematologic toxicity was observed. On an intent-to-treat basis, 14 patients were evaluable for radiological response after 4 cycles of chemotherapy (1 patient still on therapy): 11/14 patients had radiological response of > or = 50%, 1/14 progressive disease, 2 exclusions because of toxic death (1 patient) and capillary leak (1 patient). Of 11 patients evaluated for surgery, 9 patients were resected, 1 patient is awaiting operation, 1 patient received radiotherapy because of an esophageal fistula. By histological findings a downstaging was achieved in 6/9 resected patients: histological complete response (CR) in 4 patients, partial response (PR) in 2, and no response in 3. With a mean follow-up of 8.1 months (excluding 1 patient in early postop course), 5/5 R0 and histological responders are alive and disease-free. Of the 3 histological non-responders, 1 patient (R1/2 resection) died of respiratory failure, 2 patients (1 R1 and 1 R0) of distant metastases. CONCLUSION: Outpatient therapy with docetaxel/carboplatin chemotherapy is effective in downstaging patients with NSCLC, toxicity is acceptable. Histological response may be the most important prognostic factor. The early results of this phase II study encourage evaluation of the long-term benefit within a prospective randomized phase III study.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1997

Improved treatment of medullary thyroid cancer in a nude mouse model by combined radioimmunochemotherapy: doxorubicin potentiates the therapeutic efficacy of radiolabeled antibodies in a radioresistant tumor type.

Whereas in advanced metastatic medullary thyroid cancer (MTC), a variety of chemotherapeutic regimens have achieved only limited success clinically, more recently, radioimmunotherapy (RIT) with 131I-labeled anti-carcinoembryonic antigen (CEA) monoclonal antibodies (MAbs) has shown promising results. The aims of this study were to compare, in an animal model, the therapeutic efficacy of RIT to clinically used "standard" chemotherapeutic regimens and to evaluate whether combination strategies of both modalities may be feasible and may help to improve therapeutic results in this rather radioresistant tumor type. Nude mice, bearing s.c. xenografts of the human MTC cell line, TT, were treated either with the 131I-labeled anti-CEA MAb, F023C5 IgG, or were administered chemotherapeutic regimens that had shown promising results in patients with metastatic MTC (doxorubicin and cisplatinum monotherapy, combinations of both agents, and a 5-fluorouracil/dacarbazine/streptozotocin scheme). Control groups were left untreated or were injected with an irrelevant radiolabeled antibody at equitoxic dose levels. The maximum tolerated dose (MTD) of each agent was determined. Combinations of chemotherapy and RIT were evaluated as well. Toxicity and tumor growth were monitored at weekly intervals. From the chemotherapeutic agents and schemes tested, doxorubicin monotherapy was the most effective; combination therapies did not result in an increased antitumor efficacy, but they did result in more severe toxicity. At equitoxic doses, no significant difference was found between the therapeutic efficacy of doxorubicin and that of RIT. Myelotoxicity was dose limiting with radiolabeled MAbs (MTD, 600 microCi), as well as with chemotherapeutic regimens containing alkylating agents (cisplatinum, dacarbazine, or streptozotocin). At its MTD (200 microg), doxorubicin caused only mild myelotoxicity, and despite signs of cardiac toxicity, gastrointestinal side effects were dose limiting. Accordingly, bone marrow transplantation (BMT) enabled dose intensification with RIT (MTD with BMT, 1100 microCi), which led to further increased antitumor efficacy, whereas BMT was unable to increase the MTD of doxorubicin. Due to the complementarity of toxic side effects but an anticipated synergism of antitumor efficacy, combinations of RIT with doxorubicin were tested. Administrations of 500 microCi of 131I-labeled anti-CEA and, 48 h later, 200 microg of doxorubicin (i.e., 83 and 100% of the respective single-agent MTDs), were the highest doses that did not result in an increased lethality; with bone marrow support, 1000 microCi of 131I-labeled anti-CEA could be combined with 200 microg of doxorubicin (i.e., 90 and 100% of the individual MTDs). Therapeutic results of this combined radioimmunochemotherapy were superior to equitoxic monotherapy with either agent, and indication for synergistic antitumor effects is given. At its respective MTD, radioimmunochemotherapy led to a 36% cure rate if it was given without bone marrow support and to a 85% permanent cure rate if it was given with bone marrow support. The animal model, as presented in this study, seems to be useful for the preclinical testing of therapeutic agents for the systemic treatment of MTC. At equitoxic doses, RIT with radiolabeled anti-CEA antibodies seems to be equally as effective as chemotherapy with doxorubicin. Combination of RIT and doxorubicin chemotherapy seems to have synergistic therapeutic efficacy, which may be due to a radiosensitizing effect of doxorubicin.

Animals↗

PubMed1997

Radiotherapy in stage IIA and IIB testicular seminoma with reduced portals: a prospective multicenter study.

PURPOSE: A prospective multicenter study was carried out to estimate the treatment outcome of radiotherapy in Stage II seminoma after the application of modern staging and radiotherapy techniques. The lower margin of the iliac field was positioned on the upper rim of the acetabulum to reduce the amount of scattered irradiation to the remaining testicle. METHODS AND MATERIALS: The study was carried out in 25 centers in Germany. Patients with pure seminoma, negative AFP-values, and retroperitoneal lymph node metastases of less than 5 cm in diameter were entered into the study. All patients received a ventrodorsal opposed field irradiation of the para-aortic and the ipsilateral iliac lymph nodes. The fields extended from the top of the 11th thoracic vertebra to the top of the acetabulum. Patients in Stage IIA (lymph nodes <2 cm ) received 30 Gy, and patients with Stage IIB (lymph nodes between 2 and 5 cm) 36 Gy total dose. RESULTS: 39 patients in Stage IIA and 19 patients in Stage IIB were evaluated. After a median observation time of 37 months all patients are alive and disease free. Recurrence free survival in stage IIA was 100%. Two patients in Stage IIB experienced a recurrence 10 and 17 months after the end of radiotherapy. The actuarial recurrence free survival estimate in Stage IIB was 94.1% for 1 year and 87.4% for 2 years. One recurrence in Stage IIB occurred in the mediastinum, one in the mediastinum, and one the lung. Both patients could be salvaged by chemotherapy. There were no pelvic recurrences. The treatment was well tolerated, with nausea being the most common side effect (56.9% Grade 1, 15.5% Grade 2, and 8.6% Grade 3). Diarrhea occurred in 15.5% (Grade 1), 15.5% (Grade 2), and 5.2% (Grade 3) of the patients. CONCLUSIONS: The outcome of para-aortic and ipsilateral iliac irradiation in Stage IIA/B testicular seminoma is excellent with the currently available staging methods and treatment facilities. The treatment is well tolerated. The lower margin of the iliacal field can be placed at the acetabulum.

Adult↗

PubMed1997

Radiotherapy and concomitant weekly 1-hour infusion of paclitaxel in the treatment of head and neck cancer--results from a Phase I trial.

PURPOSE: To define the maximum tolerated dose (MTD) by describing the dose-limiting toxicity (DLT) of weekly paclitaxel (PAC) given as a 1-h I.V. infusion in patients with head and neck cancer concomitant to irradiation. METHODS AND MATERIALS: Patients with unresectable or incompletely resected head and neck cancer were enrolled into a prospective, dose-escalating Phase I study. Toxicity was graded according to the WHO toxicity score. MTD dose was defined when two out of six patients developed DLT. The starting dose of PAC was 20 mg/m2 once weekly I.V. over 60 min, with a subsequent dose escalation of 10 mg/m2 in cohorts of three new patients. Radiation therapy was administered in three field technique over 6-7 weeks in 2.0 Gy/daily fractions for 5 consecutive days/week up to total doses of 60-70 Gy. RESULTS: From 1994-1996, 18 patients completing three dose levels were included into the study. Altogether, 101 courses of chemotherapy were evaluable for toxicity. On the second dose level (30 mg/m2) one of three patients experienced DLT with Grade IV mucositis. On the next dose level with 40 mg/m2 PAC weekly one patient experienced DLT being prolonged Grade III mucositis. From the following three patients required, two patients showed no DLT. The third patient showed mucositis of WHO Grade 4 and died from hemorrhage caused by a rupture of the a pharyngeal wall. Dose level 2 (30 mg/m2) was repeated and one of the three newly treated patients again suffered from mucositis WHO Grade 4. CONCLUSION: When PAC is given weekly as a 1-h infusion concomitant to radiotherapy, MTD is 30 mg/m2 with mucositis being DLT; hematological and further nonhematological toxicity is mild.

Adult↗

PubMed1997

Paclitaxel in simultaneous radiochemotherapy of head and neck cancer: preclinical and clinical results.

Several studies have presented evidence that paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) displays a radiation-sensitizing effect. We therefore analyzed the influence of paclitaxel and concomitant radiation on the proliferation kinetics of head and neck tumor cells and normal fibroblasts. Our data clearly support the notion that paclitaxel given with radiation exerts an additive effect on the clonogenic survival of squamous cell carcinoma cells and normal fibroblasts. Since concomitant radiochemotherapy has proven to be beneficial for the treatment of locally advanced head and neck cancer, we are testing the feasibility of simultaneous paclitaxel plus radiotherapy. Paclitaxel is given on a one-time weekly basis. Up to now, 13 evaluable patients have been treated, and the maximum tolerable dose has not been reached at 40 mg/m2. Mucositis is expected to be the dose-limiting toxicity.

Adult↗