Biomedical subjects

J M Slater

Publications and source records attributed to J M Slater.

At least 37 records · Page 2Linked to original sources

PubMed1999

Stereotactic radiosurgery--the role of charged particles.

Stereotactic radiosurgery using charged-particle beams has been the subject of biomedical research and clinical development for more than 50 years. Charged particles of proton mass or greater manifest unique physical properties that can be used to place a high dose of radiation preferentially within the boundaries of a deeply located intracranial target volume. Since 1954, nearly 10000 patients have been treated using this technique. Treated disorders include pituitary tumors, vascular malformations, primary and metastatic brain tumors, and subfoveal neovascularization. Charged-particle radiosurgery is particularly advantageous for the conformal treatment of large and/or irregularly shaped lesions, or for the treatment of lesions located in front of or adjacent to sensitive brain structures.

Brain Neoplasms↗

PubMed1999

Dosimetry techniques for narrow proton beam radiosurgery.

Characterization of narrow beams used in proton stereotactic radiosurgery (PSRS) requires special efforts, since the use of finite size detectors can lead to distortion of the measured dose distributions. Central axis depth doses, lateral profiles and field size dependence factors are the most important beam characteristics to be determined prior to dosimetry calculations and beam modelling for PSRS. In this paper we report recommendations for practical dosimetry techniques which were developed from a comparison of beam characteristics determined with a variety of radiation detectors for 126 and 155 MeV narrow proton beams shaped with 2-30 mm circular brass collimators. These detectors included small-volume ionization chambers, a diamond detector, an Hi-p Si diode, TLD cubes, radiographic and radiochromic films. We found that both types of film are suitable for profile measurements in narrow beams. Good agreement between depth dose distributions measured with ionization chambers, diamond and diode detectors was demonstrated in beams with diameters of 20-30 mm. The diode detector can be used in smaller beams, down to 5 mm diameter. For beams with diameters less than 5 mm, reliable depth dose data may be obtained only with radiochromic film. The tested ionization chambers are appropriate for calibration of beams with diameters of 20-30 mm. TLD cubes and diamond detectors are useful to determine relative dose in beams with diameters of 10-20 mm. Field size factors for smaller beams should be obtained with diode and radiochromic film. We conclude that dosimetry characterization of proton beams down to several millimetres in diameter can be performed using the described procedures.

Calibration↗

PubMed1999

Treatment of macular degeneration with proton beams.

Subfoveal neovascular membranes (SNVMs) are a leading cause of severe visual loss in the elderly in the United States. Previously, the only treatment that could halt progression of this disease was laser photocoagulation, which was, however, accompanied by immediate reduction in visual acuity. A single narrow proton beam was used to irradiate 45 patients to either 8 or 14 Cobalt Gray Equivalent. The alignment technique and dosimetry of these treatments are described. The proton beam direction, range, and modulation were planned with the assistance of an eye-specific planning program. A single anterior beam was used, with patients looking nasally toward a blinking fixation light at an angle of 30 degrees. Patients were aligned using a light field projected through a slit collimator. Patients' positions were monitored during treatment with a short-focal-length camera. Depth dose in a flat phantom was measured with a small-diameter parallel plate ionization chamber. Lateral profiles were measured at several depths with silver halide film. Each treatment session lasted 15 min, of which 1 min consisted of beam delivery. The proton beam stopped in the orbital cavity, delivering no primary proton dose to the brain. Dose to the center of the lens of the involved eye was less than 0.5% of the dose delivered to the macula. Treatments of SNVMs with proton beams require only a short visit to the hospital, little immobilization effort, and a minimal amount of treatment room and beam time. Compared to previous treatment trials using x-ray beams, the dose to nonocular tissues is reduced significantly.

Dose-Response Relationship, Radiation↗

PubMed1999

Nasopharyngeal carcinoma: repeat treatment with conformal proton therapy--dose-volume histogram analysis.

PURPOSE: To analyze control, survival, and complication rates of conformal proton radiation for recurrent nasopharyngeal carcinoma. MATERIALS AND METHODS: Sixteen patients with nasopharyngeal carcinoma initially treated with 50.0-88.2 Gy photons were re-treated with protons to additional doses of 59.4-70.2 CGE. Local-regional control and survival were correlated with extent of relapse, recurrence versus persistence, and prescribed dose and were subjected to dose-volume histogram analysis. Mean follow-up was 23.7 months (range, 4-47 months). RESULTS: Twenty-four-month actuarial overall and local-regional progression-free survival rates were both 50%. The 24-month actuarial overall survival rates for patients with "optimal" dose-volume histogram coverage versus "suboptimal" coverage were 83% and 17%, respectively (P = .006). Doses to critical structures were low (0-22.0 Gy); no central nervous system side effects supervened. CONCLUSION: Adequate tumor coverage, as evaluated by using dose-volume histogram analysis, was found to be the most important variable influencing local-regional control and survival. No central nervous system complications were observed; increases in the dose to adjacent critical structures are being evaluated.

Adult↗

PubMed1999

Proton-beam radiotherapy for early-stage lung cancer.

STUDY OBJECTIVE: A prospective study was undertaken to assess the efficacy and toxicity of conformal proton-beam radiotherapy for early-stage, medically inoperable non-small cell lung cancer. DESIGN: Eligible patients had clinical stage I to IIIa non-small cell lung cancer and were not candidates for surgical resection for medical reasons or because of patient refusal. Patients with adequate cardiopulmonary function received 45 Gy to the mediastinum and gross tumor volume with photons with a concurrent proton boost to the gross tumor volume of an additional 28.8 cobalt gray equivalents (CGE). Total tumor dose was 73.8 CGE given over 5 weeks. Patients with poor cardiopulmonary function received proton-beam radiotherapy to the gross tumor volume only, with 51 CGE given in 10 fractions over a 2-week period. RESULTS: Thirty-seven patients were treated in the study from July 1994 to March 1998. Clinical staging of patients was as follows: stage I, 27 patients; stage II, 2 patients; and stage IIIa, 8 patients. Eighteen patients received a combination of protons and x rays, while 19 patients received proton-beam radiation only. Follow-up of evaluable patients ranged from 3 to 45 months, with a median of 14 months. Two patients in the proton and photon arm developed pneumonitis that resolved with oral steroids; otherwise, no significant toxicities were encountered. The actuarial disease-free survival at 2 years for the entire group was 63%; for stage I patients, disease-free survival at 2 years was 86%. Local disease control was 87%. CONCLUSION: Preliminary results from this study indicate that proton-beam radiotherapy can be used safely in this group of patients. Disease-free survival and local control appear to be good and compare favorably with published reports utilizing conventional photon irradiation.

Aged↗

PubMed1999

Pulmonary injury from proton and conventional radiotherapy as revealed by CT.

OBJECTIVE: Although radiation therapy is used in early-stage inoperable lung cancer, it often results in injury to functional lung tissue. A study was undertaken to determine the frequency and severity of pulmonary injury revealed by CT in patients who had undergone conformal proton (to a limited volume) radiation therapy. We compared these findings with those from a group of patients who had undergone a combination of photon and conformal proton (to a larger volume) radiation therapy. CONCLUSION: Proton radiation therapy was associated with a lower frequency of pulmonary injury than the combined regimen. Injury correlated well with the volume of normal lung that was irradiated. Conformal proton radiation therapy appears to be able to reduce the incidence and severity of pulmonary injury revealed by CT.

Aged↗

PubMed1999

Proton radiation therapy for chordomas and chondrosarcomas of the skull base.

OBJECT: Local tumor control, patient survival, and treatment failure outcomes were analyzed to assess treatment efficacy in 58 patients in whom fractionated proton radiation therapy (RT) was administered for skull base chordomas and chondrosarcomas. METHODS: Between March 1992 and January 1998, a total of 58 patients who could be evaluated were treated for skull base tumors, 33 for chordoma and 25 for chondrosarcoma. Following various surgical procedures, residual tumor was detected in 91% of patients; 59% demonstrated brainstem involvement. Target dosages ranged from 64.8 and 79.2 (mean 70.7) Co Gy equivalent. The range of follow up was 7 to 75 months (mean 33 months). In 10 patients (17%) the treatment failed locally, resulting in local control rates of 92% (23 of 25 patients) for chondrosarcomas and 76% (25 of 33 patients) for chordomas. Tumor volume and brainstem involvement influenced control rates. All tumors with volumes of 25 ml or less remained locally controlled, compared with 56% of tumors larger than 25 ml (p = 0.02); 94% of patients without brainstem involvement did not experience recurrence; in patients with brainstem involvement (and dose reduction because of brainstem tolerance constraints) the authors achieved a tumor control rate of 53% (p = 0.04). Three patients died of their disease, and one died of intercurrent disease. Actuarial 5-year survival rates were 100% for patients with chondrosarcoma and 79% for patients with chordoma. Grade 3 and 4 late toxicities were observed in four patients (7%) and were symptomatic in three (5%). CONCLUSIONS: High-dose proton RT offers excellent chances of lasting tumor control and survival, with acceptable risks. In this series all small- and medium-sized tumors with no demonstrable brainstem involvement have been controlled; all such patients are alive. Surgical debulking enhanced delivery of full tumoricidal doses, but even patients with large tumors and disease abutting crucial normal structures benefited.

Actuarial Analysis↗

PubMed1998

Conformal proton therapy for prostate carcinoma.

BACKGROUND: The role and optimum dose of radiation to eradicate prostate cancer continues to be evaluated. Protons offer an opportunity to increase the radiation dose to the prostate while minimizing treatment toxicity. METHODS: Six hundred forty-three patients with localized prostate cancer were treated with protons, with or without photons. Treatments were planned with a 3D planning system; patients received 74-75 CGE (Cobalt Gray Equivalent) at 1.8-2.0 CGE per fraction. Patients were evaluated for response to therapy and treatment-related toxicity. RESULTS: The overall clinical disease-free survival rate was 89% at 5 years. When post-treatment prostate-specific antigen (PSA) was used as an endpoint for disease control, the 4.5-year disease-free survival rate was 100% for patients with an initial PSA of < 4.0 ng/ml, and 89%, 72%, and 53% for patients with initial PSA levels of 4.1-10.0, 10.1-20.0, and > 20.0, respectively. Patients in whom the post-treatment PSA nadir was below 0.5 ng/ml did significantly better than those whose nadir values were between 0.51-1.0 or > 1.0 ng/ml: the corresponding 5-year disease-free survival rates were 91%, 79%, and 40%, respectively. Minimal radiation proctitis was seen in 21% of patients; toxicity of greater severity was seen in less than 1%. CONCLUSION: Proton therapy to 74-75 CGE produced minimal treatment-related toxicity and excellent PSA normalization and disease-free survival in patients with low initial PSA levels. A prospective randomized dose-escalation trial is now underway to help define the optimum dose of radiation for patients with early stage prostate cancer.

Analysis of Variance↗

PubMed1998

What is the role of radiation in the treatment of subfoveal membranes: review of radiobiologic, pathologic, and other considerations to initiate a multimodality discussion.

BACKGROUND: Single-dose-fraction conformal proton beam and multiple-fraction X ray dose schedules have been used to treat subfoveal neovascular membranes. All schedules successfully controlled membrane progression, stabilized vision in most patients, and increased visual acuity in some. Conformal protons also decreased the radiation dose to healthy tissues outside the designated volume (16 mm in diameter). It appears that radiation therapy could be useful and cost-effective, but neither the optimal time-dose schedule single or multiple dose fractions nor the type of radiation proton conformal beam or x-ray therapy are defined. METHODS: By means of an extensive literature survey, we reviewed the rationale for using radiation to treat subfoveal neovascularization, examined a paradigm of radiation interaction with tissue, reviewed the histopathology of neovascular membranes, and documented the role of growth factors in the pathophysiology of the disease. Accepting that the eye is an extracranial brain extension, and that its microvasculature has properties similar to brain microvessels, we reviewed the radiobiologic response of brain microvessels. We also revisited the controversy concerning the efficacy of single-dose-fraction vs. multifraction schedules. RESULTS: This paper outlines parameters within which radiation therapy's role might be defined, and proposes a clinical radiation-biology scoring program to evaluate radiation effects, based on the SOMA concept. CONCLUSION: A prospective, controlled clinical trial is feasible and is indicated to determine radiation therapy's role in managing the proliferative component of age-related macular degeneration.

Aged↗

PubMed1998

Particle beam radiation therapy in prostate cancer: is there an advantage?

Hadron therapy uses heavy particles to deliver therapeutic ionizing energy. Each particle's inherent attributes determine the pattern of energy deposited by its beam, expressed in macro (conformability to a three-dimensional target volume) and micro (radiobiologic properties) distributions. Mass and charge regulate the inherent properties; beam energy provides a controllable, variable characteristic. Generally, heavy charged particles provide superior macrodosimetric properties; heavy particles (charged or not) have microdosimetric characteristics that produce high linear energy transfer (LET). Neutron macrodosimetry is similar to that of photons. Protons and helium ions possess superior macrodosimetric properties, plus microdosimetric characteristics resulting in low LET, yielding beam characteristics that approach the ideal for clinical radiotherapy. Hadron therapy for prostate cancer has been limited by the availability of appropriate treatment facilities. Nonetheless, encouraging results have been obtained. Neutron therapy demonstrated improved overall survival in a multi-institutional randomized trial, and improved local disease control in a subsequent trial. Proton radiation forms the boost component of several conformal dose-escalation studies. A Loma Linda University study demonstrated low treatment-related morbidity despite a prostate dose of 75 CGE; late-morbidity data were superior to published reports from multi-field, conformal photon therapy. A Phase III dose-escalation study of protons for early prostate cancer is proceeding.

Dose-Response Relationship, Radiation↗

PubMed1998

Pilot evaluation of cytokine levels in patients undergoing radiotherapy for brain tumor.

This study was undertaken to evaluate plasma levels of interleukin-1 beta (IL-1 beta), tumor necrosis factor-alpha (TNF-alpha) transforming growth factor-beta (TGF-beta), basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), and vascular endothelial growth factor (VEGF) in 3 pediatric and 14 adult patients receiving radiotherapy for brain tumor. Patients with glioblastoma, astrocytoma, chondrosarcoma, meningioma, schwannoma, and lung adenocarcinoma that had metastasized to the brain were included. Peripheral blood samples were collected before and after treatment with conventional photon and/or proton radiation; samples from healthy volunteers served as controls. Enzyme-linked immunosorbent assays were performed to quantitate the cytokines. Before irradiation, most patients had greater amounts of one or more of the cytokines compared with the mean obtained for control plasma. This was especially striking in patients with chondrosarcoma; the mean values for TGF-beta 1, TNF-alpha, bFGF, and EGF were 1458, 1289, 332, and 92% higher than in healthy subjects, respectively. After irradiation, bFGF and total TGF-beta 1 decreased in the majority of tested subjects. In contrast, IL-1 beta was detected only in pediatric patients (all with astrocytoma) and its levels after radiation were 33 to 67% higher than at pretreatment. EGF was found in four patients; post-treatment values were 125 to 608% higher in three of the individuals. These data show that cytokines are present at elevated concentrations in the blood circulation of patients with certain types of brain tumors and that changes in their levels can be detected after radiotherapy. Further investigations are warranted to determine whether these findings contribute to morbidity or therapeutic outcome.

Adult↗

PubMed1997

Proton therapy for pediatric cranial tumors: preliminary report on treatment and disease-related morbidities.

PURPOSE: Accelerated protons were used in an attempt to limit treatment-related morbidity in children with tumors in or near the developing brain, by reducing the integral dose to adjacent normal tissues. METHODS AND MATERIALS: Children treated with protons at Loma Linda University Medical Center between August 1991 and December 1994 were analyzed retrospectively. Twenty-eight children, aged 1 to 18 years, were identified as at risk for brain injury from treatment. Medical records, physical examinations, and correspondence with patients, their parents, and referring physicians were analyzed. The investigators tabulated post-treatment changes in pre-treatment signs and symptoms and made judgments as to whether improvement, no change, or worsening related to disease or treatment had supervened. Magnetic resonance images were correlated with clinical findings and radiographic impressions were tabulated. RESULTS: Follow-up ranged from 7 to 49 months (median 25 months). Four instances of treatment-related morbidity were identified. Forty-one instances of site-specific, disease-related morbidity were identified: 15 improved or resolved and 26 remained unchanged after treatment. Four patients had radiographic evidence of local failure. Three of these patients, including two with high-grade glioma, have died. CONCLUSION: Early treatment-related morbidity associated with proton therapy is low. Tumor progression remains a problem when treating certain histologies such as high-grade glioma. Escalating the dose delivered to target volumes may benefit children with tumors associated with poor rates of local control. Long-term follow-up, including neurocognitive testing, is in progress to assess integral-dose effects on cognitive, behavioral and developmental outcomes in children with cranial tumors.

Adolescent↗

PubMed1997

Combined proton and photon conformal radiation therapy for locally advanced carcinoma of the prostate: preliminary results of a phase I/II study.

PURPOSE: A study was developed to evaluate the use of combined photons and protons for the treatment of locally advanced carcinoma of the prostate. This report is a preliminary assessment of treatment-related morbidity and tumor response. METHODS AND MATERIALS: One hundred and six patients in stages T2b (B2), T2c (B2), and T3 (C) were treated with 45 Gy photon-beam irradiation to the pelvis and an additional 30 Cobalt Gray Equivalent (CGE) to the prostate with 250-MeV protons, yielding a total prostate dose of 75 CGE in 40 fractions. Median follow-up time was 20.2 months (range: 10-30 months). Toxicity was scored according to the Radiation Therapy Oncology Group (RTOG) grading system; local control was evaluated by serial digital rectal examination (DRE) and prostate specific antigen (PSA) measurements. RESULTS: Morbidity evaluation was available on 104 patients. The actuarial 2-year rate of Grade 1 or 2 late morbidity was 12% (8% rectal, 4% urinary). No patients demonstrated Grade 3 or 4 late morbidity. Treatment response was evaluated on 100 patients with elevated pretreatment serum PSA levels. The actuarial 2-year rate of PSA normalization was 96%, 97%, and 63% for pretreatment PSAs of > 4-10, > 10-20, and > 20, respectively. The 13 patients with rising PSA demonstrated local recurrence (3 patients), distant metastasis (8 patients), or no evidence of disease except increasing PSA (2 patients). CONCLUSIONS: The low incidence of side effects, despite the tumor dose of 75 CGE, demonstrates that conformal protons can deliver higher doses of radiation to target tissues without increasing complications to surrounding normal tissues. The initial tumor response, as assessed by the high actuarial rate of normalization with pretreatment PSA < or = 20, and the low rate of recurrences within the treatment field (2.8%), are encouraging.

Adenocarcinoma↗

PubMed1997

Tumor necrosis factor-alpha enhances antitumor effects of radiation against glioma xenografts.

Long-term control of high-grade brain tumors is rarely achieved with current therapeutic regimens. The aim of this study was to determine if low doses of tumor necrosis factor-alpha (TNF-alpha) could augment the effects of radiation in a glioma xenograft model and to evaluate hematological and other parameters that might indicate treatment-related toxicity. Nude mice were injected subcutaneously with C6 rat glioma cells and randomized into groups. Two different time-dose protocols were employed using intravenous human recombinant TNF-alpha and radiation beginning within 24 h after tumor cell implantation. The administration of radiation as a single agent slowed tumor progression, whereas TNF-alpha alone had no effect. However, TNF-alpha, especially when given twice per week before radiation for a total of four doses each, significantly increased the efficacy of the radiation. Low leukocyte counts were associated with combination treatment, whereas transforming growth factor-beta 1 levels were depressed in all treated groups. TNF-alpha did not modulate radiation-induced inhibition of C6 cell proliferation in vitro. The data show that TNF-alpha at relatively nontoxic doses can significantly enhance the antitumor effects of radiation against a rapidly growing glioma. This effect was more than additive, because TNF-alpha alone did not slow tumor progression.

Animals↗

PubMed1996

Phase I/II study of proton beam irradiation for the treatment of subfoveal choroidal neovascularization in age-related macular degeneration: treatment techniques and preliminary results.

PURPOSE: Age-related macular degeneration is the prevalent etiology of subfoveal choroidal neovascularization (CNV). The only effective treatment is laser photocoagulation, which is associated with decreased visual acuity following treatment in most patients. This study assessed both the response of subfoveal CNV to proton beam irradiation and treatment-related morbidity. We evaluated preliminary results in patients treated with an initial dose of 8 Cobalt Gray Equivalents (CGE) using a relative biological effectiveness (RBE) of 1.1. METHODS AND MATERIALS: Twenty-one patients with subfoveal CNV received proton irradiation to the central macula with a single fraction of 8 CGE; 19 were eligible for evaluation. Treatment-related morbidity was based on Radiation Therapy Oncology Group (RTOG) criteria; response was evaluated by Macular Photocoagulation Study (MPS) guidelines. Fluorescein angiography was performed; visual acuity, contrast sensitivity, and reading speed were measured at study entry and at 3-month intervals after treatment. Follow-up ranged from 6 to 15 months. RESULTS: No measurable treatment-related morbidity was seen during or after treatment. Of 19 patients evaluated at 6 months, fluorescein angiography demonstrated treatment response in 10 (53%); 14 (74%) patients had improved or stable visual acuity. With a mean follow-up of 11.6 months, 11 (58%) patients have demonstrated improved or stable visual acuity. CONCLUSION: A macular dose of 8 CGE yielded no measurable treatment morbidity in patients studied. Fluorescein angiography demonstrated that regressed or stabilized lesions were associated with improved visual acuity as compared with MPS results. In the next phase, a dose of 14 CGE in a single fraction will be used to further define the optimal dose fractionation schedule.

Aged↗

PubMed1996

Computed tomography slice-by-slice target-volume delineation for stereotactic proton irradiation of large intracranial arteriovenous malformations: an iterative approach using angiography, computed tomography, and magnetic resonance imaging.

PURPOSE: Target-volume delineation for stereotactic irradiation is problematic for large and irregularly shaped arteriovenous malformations (AVMs). The purpose of this report is to quantify modifications in the target volume that result from iterative treatment planning that incorporates multimodality imaging data. METHODS AND MATERIALS: Stereotactic neuroimaging procedures were performed for 20 consecutive patients with AVM volumes > 10 cm3. Angiographically defined extrema were transformed into computed tomography (CT) space. The resulting target contours were then modified by a multidisciplinary treatment planning team after iterative review of angiographic, CT, and magnetic resonance imaging (MRI) data. Volumes of interest and dose-volume histograms for proton irradiation were calculated before and after iterative target delineation. RESULTS: Initial (angiographically defined) target volumes ranged from 15.3 to 96.1 cm3 (mean, 43.6 cm3). Final (iteratively defined) target volumes ranged from 10.7 to 114.0 cm3 (mean, 38.4 cm3). The volume of presumed normal tissue excluded by iterative planning ranged from 2.6 to 47.0 cm3 (mean, 15.5 cm3). Initially untargeted AVM, most commonly obscured by embolization material, was identified in all cases (range, 0.3 to 57.8 cm3; mean, 10.3 cm3). Corresponding dose-volume histograms demonstrated marked differences regarding lesion coverage and sparing of normal tissue structures. CONCLUSIONS: Iterative target-volume delineation resulted in significant modifications from initial, angiographically defined target volumes. Substantial amounts of apparently normal tissue were excluded from the final target, and additional abnormal vascular structures were identified for incorporation. We conclude that an iterative multimodality approach to target-volume delineation may improve the overall results for stereotactic irradiation of large and complex AVMs.

Humans↗

PubMed1996

Relationship between ZCE 025 blood clearance and liver accumulation in patients with colorectal cancer.

Clinical interest in radiolabelled monoclonal antibodies (mAbs) derives from their ability to target tissues and deliver radioisotopes thereto. Diagnostic and therapeutic trials suggest that the potential of mAbs would be optimized with better understanding of factors which influence blood clearance. This study sought to advance that understanding. Nine colon cancer patients were injected with 20 mg 111In radiolabelled ZCE 025 mAb, then laser-positioned and imaged daily for one week via nuclear medicine views. Laser-positioned CT images were also obtained, enabling image registration. Blood samples were taken at 30, 60, and 90 min and at every imaging time point. Sample activity was plotted to estimate the elimination half-life (t1/2 beta). Liver radiation dose was calculated from the images and evaluated for total organ (mCi-h) and region of interest (microCi-h/g). Laboratory values and patients' physical parameters were also studied to determine their impact on liver uptake and mAb blood clearance. Liver radiation dose, as measured in this study, correlated with terminal half-life of the mAb in blood; patients' liver enzymes and physical parameters did not. Radioactivity in a 48-h or 72-h blood sample correlates with t1/2 beta and liver radiation dose, suggesting that a single 72-h sample can predict both.

Aged↗

PubMed1996

Evaluation of TNF-alpha effects on radiation efficacy in a human lung adenocarcinoma model.

This study sought to determine if pretreatment with low-dose tumor necrosis factor-alpha (TNF-alpha) can enhance the effects of radiation in an NCI-H441 human lung tumor xenograft model. In vitro assays were performed on spleen cells, blood leukocytes, and plasma from the animals, as well as on cultured tumor cells. Tumors in animals given only TNF-alpha grew as well as, or better than, tumors in their untreated counterparts at all time-dose regimens employed. In contrast, early treatment with a total radiation dose of 16 Gy resulted in complete tumor inhibition, whereas 8 Gy modestly (but significantly, P < 0.05) slowed tumor progression. However, the administration of TNF-alpha (4 x 10(4) total units/mouse) 16-18 h prior to irradiation (8 Gy total dose) enhanced the antitumor effects of radiation when treatment was initiated early (P < 0.05). Oxygen radical production and response to mitogenic stimulation by splenocytes were greatest in untreated tumor-bearing animals. Total leukocyte counts in mice given radiation or TNF-alpha + radiation were low, and treatment-related changes were found in percentages of neutrophils and lymphocytes. In vitro assays of tumor cells showed that TNF-alpha + radiation resulted in greater suppression of clonogenic survival and incorporation of [3H]TdR and [3H]UdR incorporation than either agent alone. These results suggest that the use of low-dose TNF-alpha together with radiation may be beneficial in the clinical setting and so warrant further investigation.

Animals↗