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This retrospective preliminary review evaluated the efficacy and toxicity of fractionated proton radiotherapy in the management of pediatric craniopharyngioma. METHODS: Sixteen patients, aged 7-34 years, were treated with proton-beam radiation. All had undergone at least one tumor resection. Seven patients underwent repeat resection for recurrence; one had previous x-ray radiotherapy. A daily dose of 1.8 cobalt gray equivalent was used to give a total dose in the range of 50.4-59.4 cobalt gray equivalent. RESULTS: Local control was achieved in 14 of 15 patients. Twelve of 15 patients survived. There were few acute side effects. Long-term complications included newly diagnosed panhypopituitarism, a cerebrovascular accident from which the patient fully recovered, and an out-of-proton-field meningioma in the single patient who received previous radiotherapy. DISCUSSION: Fractionated proton radiotherapy is an effective treatment for children with craniopharyngioma. Longer follow-up is needed to evaluate late complications. [ABSTRACT FROM AUTHOR]

Radiation proctitis, an inflammation and damage to the lower part of colon, is a common adverse event of the radiotherapy of tumors in the abdominal and pelvic region (colon, prostate, cervical). Several Mn(III) porphyrin-based superoxide dismutase mimics have been synthesized and successfully evaluated in preclinical models as radioprotectants. Here we report for the first time the remarkable rectal radioprotection of frequently explored Mn(III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin, MnTE-2-PyP(5+). A batch prepared in compliance with good manufacturing practice (GMP), which has good safety/toxicity profile, was used for this study. MnTE-2-PyP(5+) was given subcutaneously at 5 mg/kg, either 1 h before or 1 h after irradiation, with additional drug administered at weekly intervals thereafter. MnTE-2-PyP(5+) ameliorated both acute and chronic radiation proctitis in male Sprague-Dawley rats irradiated with 20-30 Gy protons delivered to 2.5 cm span of rectum using spread-out Bragg peak of a proton treatment beam. Focal irradiation of the rectum produced acute proctitis, which healed, followed by chronic rectal dilation and symptomatic proctitis. MnTE-2-PyP(5+) protected rectal mucosa from radiation-induced crypt loss measured 10 days post-irradiation. Significant effects were observed with both pre- and post-treatment regimens. However, only MnTE-2-PyP(5+) pre-treatment, but not post-treatment, prevented the development of rectal dilation, indicating that proper dosing regimen is critical for radioprotection. The pre-treatment also prevented or delayed the development of chronic proctitis depending on the radiation dose. Further work aimed at developing MnTE-2-PyP(5+) and similar drugs as adjunctive agents for radiotherapy of pelvic tumors is warranted. The present study substantiates the prospects of employing this and similar analogs in preserving normal tissue during cancer radiation as well as any other radiation exposure.

Clinicians involved in conventional radiation therapy are very concerned about the dose-response relationships of normal tissues. Before proceeding to new clinical protocols, radiation biologists involved with conformal proton therapy believe it is necessary to quantify the dose response and tolerance of the organs and tissues that will be irradiated. An important focus is on the vasculature. This presentation reviews the methodology and format of using confocal microscopy and stereological methods to quantify tissue parameters, cell number, tissue volume and surface area, and vessel length using the microvasculature as a model tissue. Stereological methods and their concepts are illustrated using an ongoing study of the dose response of the microvessels in proton-irradiated hemibrain. Methods for estimating the volume of the brain and the brain cortex, the total number of endothelial cells in cortical microvessels, the length of cortical microvessels, and the total surface area of cortical microvessel walls are presented step by step in a way understandable for readers with little mathematical background. It is shown that stereological techniques, based on a sound theoretical basis, are powerful and reliable and have been used successfully.

This study quantified architectural and population changes in the rat retinal vasculature after proton irradiation using stereology. A 100 MeV conformal proton beam delivered 8, 14, 20 and 28 Gy as single and split doses to the whole eye. The vascular networks were prepared from retinal digests. Stereological methods were used to obtain the area of the retina and unbiased estimates of microvessel/artery/vein endothelial, pericyte and smooth muscle population, and vessel length. The retinal area increased progressively in the unirradiated, age-matched controls and in the retinas irradiated with 8 and 14 Gy, indicating uniform progressive retinal growth. No growth occurred after 20 and 28 Gy. Regression analysis of total endothelial cell number in all vessels (arteries, veins and capillaries) after irradiation documented a progressive time- and dose-dependent cell loss occurring over 15 to 24 months. The difference from controls was significant (P<0.01) after 28 Gy given in single and split doses and after 20 Gy given as a split dose (P<0.05). Total vessel length in microvessel was significantly shortened at 20 and 28 Gy compared to that of controls (P<0.05). No evident dose recovery was observed in the endothelial populations after split doses. At 10 Gy, the rate of endothelial cell loss, a dose parameter used to characterize the time- and dose-dependent loss of the endothelial population, was doubled.

A paper by Kubinova et al. (Radiat. Res. 000, 000-000, 2003) introduced to radiation biology the techniques of stereology required to quantify the dose response of irradiated brain populations. A paper by Mao et al. (Radiat. Res. 000, 000-000, 2003) and earlier papers by Archambeau et al. applied these techniques to quantify the population changes in the vasculature of the retina. This presentation reviews in broad terms the evolution of the need to quantify population and kinetic techniques and how the need has been met. The in vitro and in vivo descriptive and clonogenic techniques used regularly in radiation biology and in clinical therapy will not be replaced by stereology. While stereology is applicable to all tissue, it proves to be an important technique that allows the investigator to quantify cell population parameters in late-responding and non-proliferative populations.

Background: To evaluate the safety and efficacy of proton radiation therapy (PRT) for intracranial low-grade astrocytomas, the authors analyzed the first 27 pediatric patients treated at Loma Linda University Medical Center (LLUMC)., Patients and Method: Between September 1991 and August 1997, 27 patients (13 female, 14 male) underwent fractionated proton radiation therapy for progressive or recurrent low-grade astrocytoma. Age at time of treatment ranged from 2 to 18 years (mean: 8.7 years). Tumors were located centrally (diencephalic) in 15 patients, in the cerebral and cerebellar hemispheres in seven patients, and in the brainstem in five patients. 25/27 patients (92%) were treated for progressive, unresectable, or residual disease following subtotal resection. Tissue diagnosis was available in 23/27 patients (85%). Four patients with optic pathway tumors were treated without histologic confirmation. Target doses between 50.4 and 63.0 CGE (Cobalt Gray Equivalent, mean: 55.2 CGE) were prescribed at 1.8 CGE per fraction, five treatments per week., Results: At a mean follow-up period of 3.3 years (0.6-6.8 years), 6/27 patients experienced local failure (all located within the irradiated field), and 4/27 patients had died. By anatomic site these data translated into rates of local control and survival of 87% (13/15 patients) and 93% (14/15 patients) for central tumors, 71% (5/7 patients) and 86% (6/7 patients) for hemispheric tumors, and 60% (3/5 patients) and 60% (3/5 patients) for tumors located in the brainstem. Proton radiation therapy was generally well tolerated. All children with local control maintained their performance status. One child with associated neurofibromatosis, Type 1, developed Moyamoya disease. All six patients with optic pathway tumors and useful vision maintained or improved their visual status., Conclusions: This report on pediatric low-grade astrocytomas confirms proton radiation therapy as a safe and efficacious 3-D conformal treatment modality. Results are encouraging for central tumors as well as large optic pathway tumors, where dose conformity is of particular importance; yet it is difficult to achieve. Longer follow-up time is needed to fully evaluate the benefits of normal tissue sparing.

The Loma Linda University (LLU) Radiobiology Program coordinates basic research and proton beam service activities for the university and extramural communities. The current focus of the program is on the biological and physical properties of protons and the operation of radiobiology facilities for NASA-sponsored projects. The current accelerator, supporting facilities and operations are described along with a brief review of extramural research projects supported by the program. These include space craft electronic parts and shielding testing as well as tumorigenesis and animal behavior experiments. An overview of research projects currently underway at LLU is also described. These include: 1) acute responses of the C57Bl/6 mouse immune system, 2) modulation of gene expression in the nematode C. elegans and rat thyroid cells, 3) quantitation of dose tolerance in rat CNS microvasculature, 4) behavioral screening of whole body proton and iron ion-irradiated C57Bl/6 mice, and 5) investigation of the role of cell integration into epithelial structures on responses to radiation.

Calculation of normal tissue complication probabilities (NTCP) for proton radiation therapy (PRT) and two photon radiation therapy techniques for cranial irradiation of childhood optic nerve gliomas was made. Evaluation of usefulness of calculated NTCP values for comparison of treatment plans and clinical appropriateness of computed data was used. Three radiation plans were calculated on datasets of children treated previously for optic nerve gliomas with PRT. Dose-volume histograms (DVH) were computed and used to calculate NTCP. Evaluated complication endpoints were necrosis, blindness, and cognitive impairment. Calculated NTCP depended strongly on tumor volume and the normal tissue volume exposed to high radiation doses. Dose conformity and steeper dose-gradient correlated with reduced NTCP. Regarding the chosen complication endpoints, PRT was superior to 3D photons; conventional photons were calculated to have the highest NTCPs. Differences might reach clinical significance for cognitive impairment, a frequently observed toxicity. Calculated NTCP values were highly dependent on implemented clinical data. Calculation of NTCP can be used for ranking of treatment plans and modalities. Highly dependent on implemented clinical data, the calculated percentage of NTCP might be more of a figure of merit than a real predictive value and requires comparison to clinical experience. Int. J. Cancer (Radiat. Oncol. Invest.) 90, 351-358 (2000)., (Copyright 2000 Wiley-Liss, Inc.)

Purpose: This preclinical rat pilot study quantifies retinal microvessel, endothelial, and pericyte population changes produced by proton irradiation, Methods and Materials: The left eyes of rats were irradiated with single doses of 8, 14, 20, and 28 Gy protons; right eyes, with two fractions. Animals were euthanized, and eyes were removed; elastase digests were prepared, and cell populations were counted in sample fields. Results were compared with unirradiated controls., Results: Progressive time- and dose-dependent endothelial cell loss occurred following all schedules. Cell loss was significantly different from control values (p < 0.001) following 28 Gy and following 20 Gy (p < 0.05) in a single dose. Endothelial cell loss was the same for single- and split-dose schedules. Progressive endothelial cell loss produced vessel collapse and acellular vessel strands. Endothelial cells were in the G(0) phase of the mitotic cycle. 28 Gy produced photoreceptor cell loss., Conclusion: The retinal digest is an elegant bioassay to quantify the microvessel population response. Single- and split-dose schedules appear to yield similar outcomes, in terms of endothelial cell density.

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., (Copyright 1998 W.B. Saunders Company.)

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.

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.

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.

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.

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.

The purpose of the present study was to evaluate the therapeutic efficacy of locally administered low-dose interleukin-2 (IL-2) and a polysaccharopeptide (PSP) derived from Cariolous versicolor in a herpes virus Type 2-transformed murine tumor (H238) model and to determine possible mechanisms of action. BALB/c mice were inoculated subcutaneously (s.c.) with H238 tumor cells and randomized into groups: a) no tumor and no treatment control, b) tumor and no treatment control, c) tumor + IL-2 at 0 to 4 days, d) tumor + PSP at 0 to 10 days, e) tumor + IL-2 at 0 to 4 days + PSP at 0 to 10 days, and f) tumor + IL-2 at 15 to 19 days + PSP at 15 to 25 days. The IL-2 was administered s.c. at 2 x 10(4) i.u./mouse/injection; PSP was given s.c. at 2 mg/mouse/injection. No obvious toxicity was noted during the treatments. IL-2 and, to a lesser extent, PSP significantly slowed (p < 0.05) tumor progression when given alone immediately after tumor cell injection. The combination of the two modalities did not significantly enhance the antitumor effect of IL-2 alone. However, mice receiving both agents had IL-2 in the plasma, their tumors expressed low levels of transforming growth factor-beta, and their splenocyte response to mitogenic stimulation was significantly higher than in untreated controls. Changes in blood leukocyte populations and splenic oxidative burst capacity were associated with tumor presence, but not with the type of treatment. In vitro assays showed that both IL-2 and PSP can suppress the uptake of 3H-thymidine by tumor cells and that the effect is more pronounced whent the agents are used in combination. These results indicate that IL-2 and PSP can slow progression of H238 tumors and that the mechanisms of action may be related to their direct cytotoxic effects, as well to their immunomodulatory properties.

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.

Background: External beam radiotherapy in advanced neuroblastoma is limited by the volume of normal radiosensitive tissues included in the radiation field. Limitations to external radiation are the late effects to these tissues. Intraoperative radiotherapy (IORT) delivers a single high-radiation dose to a tumor while displacing normal tissues that would have been included in an external field. Standard external radiotherapy can still be done after "boost" IORT., Methods: Eight advanced-stage neuroblastoma patients who received IORT as part of their multimodality therapy were reviewed to identify the impact of IORT on operative time, complications, and tumor control in the treatment field. The IORT was accomplished by patient transport from the OR to the radiation therapy suite; these were separated by three floors., Results: IORT added 30-75 min to the operative procedure. Tumors in the resection/IORT fields showed no evidence of disease (one), stable tumor size (six), and tumor recurrence (one). Two complications were identified: a urinary fistula and CO2 retention, which was detected and corrected before the IORT. Neither of these complications was related to the IORT. Two patients who had subsequent tumor resection after IORT demonstrated tumor differentiation to ganglioneuromatous tissue., Conclusions: IORT usually can be completed in less than an hour. No IORT-associated complications were identified. IORT along with maximal tumor resection, external radiation, and chemotherapy enhances local tumor control.

Rationale and Objectives: Optimal dose schedules and total dose of ionizing radiation for human central nervous system malignancy are not known. An animal model has been developed for the investigation of rat central nervous system response to proton irradiation using magnetic resonance imaging (MRI). A clinical MRI device was used to monitor the response of the rat brain after irradiation as a possible indicator for histologic injury as a function of time and dose., Methods: Single-dose fractions of protons were delivered to the left brain of 25 adult Sprague-Dawley rats. T1- and T2-weighted images were obtained using a 1.5-T MRI device via a 12-cm diameter coil at 4- to 6-week intervals after irradiation. Coronal images were evaluated by visual inspection and relaxation maps comparing the control and irradiated hemispheres. Histologic review was conducted on all rats' brains after death., Results: Proton irradiation was delivered successfully to only the left brain of the animals. Histologic review confirms the location and extent of tissue damage demonstrated on MRIs obtained in vivo. Statistically significant differences were seen in the T2-weighted relaxation times in the irradiated cerebral hemisphere compared with the unirradiated hemisphere., Conclusion: The proton hemibrain rat model can be used to test treatment schedules of irradiation for central nervous system response using MRI to noninvasively document early and late effects within the same animal.

The evolution, time course, and dose response of gross and histologic changes associated with the acute and late changes of the skin are noted and a composite pathophysiologic operational model given. This model focuses the selection of the observations to be "scored" to assess the tolerance and cosmetic response of the skin and breast to different dose and combined therapy studies. Skin scoring, Late effects skin, Late effects breast, Skin irradiation response, Breast radiation response, Pathophysiology of irradiated skin, Dose tolerance of skin, Dose tolerance of breast, Skin functional unit, Microvessel response to irradiation.

Proton irradiation and other charged-particle modalities have demonstrated effectiveness in controlling cranial base tumors and other lesions. The combination of capabilities available with heavy charged particles makes for a desirable therapeutic option that offers the opportunity for tumor ablation while preserving normal tissue function, with obvious implications for quality of life.

We have studied radiation effects utilizing the new 250 MeV Synchrotron at Loma Linda University Medical Center. In this paper we present the data collected for the survival of Chinese hamster lung (V79) cells, that were irradiated with a beam of mixed energy protons up to 200 MeV. The RBE for protons, when compared to 60Co gamma rays, ranged from a low of 1.2 at the high energy portion of the field to 1.3+ at the low energy portion of the field. These results are consistent with the measured lineal energy (microdosimetric) spectra.

An investigation of treatment results in tonsillar region carcinomas was conducted, with particular attention to local control and morbidity from current therapy. The purpose of the investigation was to identify problems that might be resolvable with a superior treatment modality. A search was made of the National Library of Medicine's MEDLINE database, covering local control, survival, and morbidity from current therapies; dose-response relationships; and prognostic indicators. Three-dimensional radiotherapy plans were developed for representative cases, comparing photon-beam plans with proton-beam plans. Locoregional control is a major problem, and morbidity from standard therapy is high. Comparative treatment plans reveal that proton beams can deliver higher doses to the tumor volume, with significantly reduced radiation to salivary glands and mandible, than can photon-beam irradiation. The absorption and distribution characteristics of protons provide the radiation oncologist with a superior tool for treating patients with tonsillar region carcinomas. The therapeutic advantage accrues from these superior characteristics, not from an inherent biologic advantage.

The ability to vary the proton energy (depth of beam penetration) and modulate the dose distribution at the end of range permits delivery of an increased dose to the designated cancer-containing volume with a reduced dose to overlying normal brain tissue. The evolution of childhood CNS malignancy following therapy is reviewed to identify radiation response variables indicating where the proton dose distribution will improve the therapeutic ratio. The review documents that of the 1262 children expected to develop CNS malignancy in 1989, only 43% will survive 5 years. About 75% of those with medulloblastoma and over 90% with astrocytoma die from persistent (in-field) disease. When the patient has been treated with radiation, it is accepted that disease persistence indicates the cancer dose was insufficient. Potentially 536 children could show an improved incidence of local control and improved survival from an increased cancer dose available from proton irradiation. As the total dose and volume of brain irradiated is increased about 1800 cGy, brain dysfunction increases, producing a spectrum of functional and intellectual deficits which are age and volume related. About 900 irradiated patients would have fewer in-field histologic and functional changes if the dose to normal brain, or the volume of brain irradiated, is reduced by an improved dose distribution. A proton beam treatment plan, delivering a cancer dose of 7400 cGy, is simulated for a thalamic astrocytoma. The dose distribution of this plan is compared with an x-ray plan used to treat a patient, in which a dose of 5400 cGy was delivered to the astrocytoma. Comparative isodose distributions and dose-volume histograms indicate a decreased integral dose to normal brain and a decreased volume of normal brain irradiated, even as the cancer dose is boosted 2000 cGy with protons.

Proton radiation, a continuation of radiation oncology's historic search for an optimum dose distribution, offers superior characteristics for clinical radiation therapy. A complete facility for clinical proton radiation therapy has been designed for and constructed at Loma Linda University Medical Center. To bring about this achievement, a consortium of engineers, physicists, and physicians interested in the clinical applications of protons was necessary. The accelerator, the beam transport and delivery systems, the building, and the personnel who operate the system were all brought together to fully exploit the properties of protons for patient treatments, which are now underway.

Heavy charged particle beams can be widely used for cancer therapy if control in heterogeneous tissue is proved practical. A beam of protons at 200 million electron volts has been visualized in plastic and in a living animal by using an on-line positron camera. The fraction of the activity retained in the radiation site was found to be at least 70 percent of that produced in a dead animal. The sensitivity of the technique was established for a typical geometry.

The development of metastatic chest wall growths from a primary nasopharyngeal carcinoma is described. The growths developed only in areas previously irradiated prophylactically and sharply outlined the treatment portals. The adjacent skin appeared completely normal. The possible mechanisms underlying this phenomenon are reviewed.

Four patients with metastases to the brain were treated by high-dose fractionated radiation therapy. In all four cases, a complete response and prolonged disease-free survival could be documented. Unlike the standard therapy for such patients (i.e., craniotomy and postoperative irradiation), high-dose fractionated radiation therapy carries no operative risk and can encompass multiple brain metastases and metastases in deep or critical intracranial sites.

An acute single X-ray exposure of 2300 R produces in swine skin a moist reaction (ulceration) that appears at 17 days, heals by 32 days, and may break down again between 42 and 70 days. Initial studies quantified the epidermal population density changes during this 70-day period. This study was designed to quantify the density changes occurring in the endothelial cell population of the dermal microvasculature. While the basal population decreases to a nadir of 10% control by 24 days, the endothelial population remains at control levels. Beyond 24 days, the endothelial cell density decreases abruptly to 50% as the epidermal cell density returns to control levels and overshoots by 20% at 32 days. Subsequently, both populations decrease to zero by 57 days. Endothelial cell loss parallels a similar decrease in vascular lumen density. These findings indicate that the initial moist reaction results from a radiation-induced loss of epidermal cells, while the second reaction results from the loss of dermal microvasculature.

Accurate bolus is needed for extension of Bragg-peak therapy. Proton beam-stopping profiles in a lucite-styrofoam-tissue phantom and in a Rando phantom were recorded photographically. Air volumes caused the largest distortions. Lucite bolus was cut to achieve desired beam-stopping profiles. Verification of bolus effect in situ will be important to control beam penetration within 5 mm.

Breast Retraction Assessment (BRA) is an objective evaluation of the amount of cosmetic retraction of the treated breast in comparison to the untreated breast in patients who receive conservative treatment for breast cancer. A clear acrylic sheet supported vertically and marked as a grid at 1 cm intervals is employed to perform the measurements. Average BRA value (+/- standard deviation) in 29 control patients without breast cancer was 1.2 cm (+/- 0.7 cm). Average BRA value in 27 patients treated conservatively for clinical Stage I or II unilateral breast cancer was 3.7 cm (+/- 2.1 cm). BRA values in breast cancer patients ranged from 0.0 to 8.5 cm. Statistical analysis revealed that tumor size, employment of adjuvant chemotherapy and use of separate radiation lymph node fields were not factors in breast retraction. Patients who received a local radiation boost to the primary tumor bed site had statistically significantly less retraction than those who did not receive a boost. Patients who had an extensive primary tumor resection had statistically significantly more retraction than those who underwent a more limited resection. In comparison to qualitative forms of cosmetic analysis, BRA is an objective test that can quantitatively evaluate factors which may be related to cosmetic retraction in patients treated conservatively for breast cancer.

At Loma Linda University Medical Center, intraoperative radiation therapy (IORT) is used in selected cases, on an on-demand basis, in a cost-effective manner. Certain procedures and modifications are described which have enabled use of IORT on this basis.

Radiation oncologists recognize a continuing need to improve the radiation dose distribution between a cancer and the surrounding normal tissue. A most promising method of accomplishing this goal is the use of charged particle beam irradiation, the clinical use of which has been investigated for the past 40 years. Since the first clinical studies began at the Lawrence Berkeley Laboratory in 1954, more than 5,000 patients have been treated with protons, using accelerators designed for physics laboratories. Superior results are reported for the control of selected diseases by the ten facilities which are currently investigating proton radiation therapy. The findings have resulted in expansion plans in several of these facilities, and in the formulation of plans for two new facilities. We report on the planned development of a new facility at Loma Linda University, which has contracted with Fermi National Accelerator Laboratory for the design and fabrication of a 250 MeV synchrotron and its beam transport and delivery systems. This facility will be the first in the world to employ a proton accelerator dedicated to medical service and research. As such, it will be available as an international resource to develop and improve the modality.

A Phase I Pilot Study combining interstitial or intracavitary irradiation using 192Ir or 137Cs and interstitial hyperthermia in advanced or recurrent tumors is underway at the City of Hope National Medical Center. Hyperthermia is performed using 0.5 megahertz RF (500 kilohertz) radiofrequency localized current fields. In the implanted volume, a temperature of 41 degrees to 45 degrees C is maintained for 30 to 40 minutes. Hyperthermia is performed prior to irradiation in all patients. All patients had either failed previous conventional treatments, including surgery, chemotherapy and/or radiation therapy, or had advanced malignant tumors which were not felt to be controllable by conventional means. Sixteen lesions were implanted in 15 patients. Of the 16 lesions, 11/16 (68%) achieved complete response, and three had no response or recurred locally. The six patients (100%) receiving interstitial implant and hyperthermia as the primary therapy achieved complete response. Normal tissue complications were minimal. Range of response was three to 13 months. Interstitial thermoradiotherapy appears to be a safe and promising mode of therapy in advanced or recurrent accessible malignant tumors.

Organ tissue populations exist in different spatial configurations. There are the idealized "volume" configuration (bone marrow), the "monolayer" (skin basal cell or large vessel endothelial populations), the "linear" (microvascular endothelial populations) and the "isolated unit" (capillaries, intestinal crypt). This defines the size of the irradiated population (No) and influences the absolute number of cells (N) that survive per unit of tissue dimension to permit repopulation. A proliferative cell that survives irradiation replaces cells lost from distant locations according to its spatial dimension. However, in the isolated unit configuration, a proliferative cell can replace those cells lost from the unit, but an anatomical barrier prevents cell replacement extending to adjacent units. Recovery of a tissue following irradiation depends not only on the number of surviving proliferative cells, but also on the organization of those cells into sub-populations. A regenerative unit is a subpopulation capable of being regenerated from the survival of a single cell. A tissue "functional unit" is a subcomponent of the tissue which contributes independently to overall tissue function, and whose loss results in an irreversible incremental loss of function. Survival of the functional unit depends critically on the degree of interdependence among component regenerative units, and such interdependence is strongly influenced by the tissue's spatial organization. Using these concepts, a mathematical formulation expresses a tissue's functional response to irradiation in terms of cell survival parameters, the spatially-related parameters of regenerative unit size, and the number of interdependent regenerative units comprising a functional unit. It is argued that this provides a more realistic approach toward simulating the radiation response of an organ than one based on tissue bulk cell survival parameters alone.

Nutritional intake or absorption may be compromised by radiation therapy (RT) when large portions of the gastrointestinal tract are treated. Dietary counseling, oral supplements, tube feedings and intravenous hyperalimentation (IVH) have been employed to limit weight loss and lessen intestinal RT side effects. Unfortunately, no prospective study reviewed has shown improved tumor control or patient survival. Special diets and IVH have also been employed in select patients to relieve chronic malabsorption from severe radiation enteritis.

The gross changes of erythema and desquamation produced by irradiation indicate population and functional variations occurring in the epidermis, microvasculature, and dermis. However, the parameters do not distinguish the individual population kinetics. This study determines multiple histologic and cell kinetic parameters of unirradiated swine skin. The prickle cell layer exists as a shell three to six cells thick. The proliferative basal layer exists as a confluent monolayer with 2031 +/- 48 cells/cm; it has a growth fraction of 1, an average cell generation time of 12.3 +/- 2.4 days, a TS of 9.4 +/- 2.9 hr, and a TS + T1/2M of 17 to 19 hr. The labeling index is 3.9 +/- 0.1% with a diurnal variation having a 5% peak at 1800 hr and a 2.5% nadir at 0900-1100 hr. The mitotic index varies from 1.7 to 3.2% and has no clear-cut diurnal variation. These values are similar to those available for man. These data and those published previously are utilized to define a histologic model of the irradiated epidermal cell renewal system. These measured values are compared with those derived from analysis of available time-dose isoeffect data using a single-hit multitarget and a linear-quadratic model. The derived dose-survival curve is steeper with a D0 between 97 and 255 rad compared to the measured value of 337 rad.

The relationship between basal cell survival and gross response in irradiated swine skin was tested by comparing dose survival curves derived from time-dose isoeffect data with curves obtained directly from basal cell counts in histological sections. Assuming equal effect per exposure and constant cell survival at isoeffect, best-fitting single-hit multi-target and linear-quadratic response curves were determined for time-dose schedules resulting in non-healing of 50% of irradiated fields. Basal cell survivals for single doses of 970, 1649, 2231, and 2619 rad were estimated 1) by counting regenerating islands and 2) by monitoring total basal cell counts through time. The dose survival curve derived from the isoeffect data was steeper than the curve obtained from direct basal cell counts. Furthermore, the direct basal cell survival curve extrapolates to less than 100% at zero dose, indicating the presence of a resistant basal cell subpopulation. The data show that the isoeffect in this case is not strongly coupled to basal cell survival. Rather, the probability of healing of an irradiated field is more sensitive to the dose per fraction than is basal cell survival, implying a contribution to non-healing from damage to stromal elements such as the capillary endothelium.

Four sets of data from the literature were analyzed to assess the effects of field size on dose tolerance and dose fraction size dependence in irradiated skin. The data consisted of combinations of total dose and dose per exposure (or number of fractions) required to yield a given degree of visible damage to the skin, for fields of different sizes. Putative cell survival curves were constructed, under the assumptions that the isoeffect represents a fixed cell survival, and that each exposure during a course of fractionated irradiation has equal effect on cell survival. The analysis showed that overall sensitivity to radiation, and dependence on dose per exposure, both increase with field size. To account for these results we describe a model that can be qualitatively related to the geometric properties of the dermal vascular network. First, vascular function after irradiation should depend on the length of the vessels exposed to the radiation. This directly predicts an increasing sensitivity in large irradiated fields. Furthermore, if vascular function determines radiation response, the shape of the shoulder (low-dose) region of the effective survival curve will depend on the average number of vessels nourishing each cell, with a more pronounced shoulder for a high multiplicity of vessels. The model predicts a greater fractionation sensitivity in large than in small fields, in agreement with our analysis of the isoeffect data. It is therefore possible that the advantages of hyperfractionation in reducing late effects in normal tissues may be related to vascular architecture, and not to inherent differences between late and acutely responding cell populations.

A retrospective study evaluated the role of tube feeding enteral nutritional support in patients receiving radiation therapy (RT) for Stage III and IV squamous cell carcinoma of the head and neck. Tube feeding (TF) by either nasogastric, cervical esophagostomy, or gastrostomy route was based on individual physician preference and patient acceptance. TF feeding starting before and continuing through RT (planned TF) was completed in 17 patients, whereas 9 patients did not receive TF until they lost weight during RT (interventional TF). No tube feeding was performed in 63 patients. By the end of RT, the planned TF group lost an average of 4.8% of initial body weight, compared to 7.1% in the no TF group and 9.4% in the interventional TF group. At the end of RT, only 6% of the planned TF group had lost over 10% of initial body weight, compared to 24% of the no TF group and 44% of the interventional group. Excluding patients who continued to lose weight after the end of RT due to rapidly recurrent tumor, 49% of the no TF group had a post-RT nadir weight loss over 10% of initial body weight, compared to 0% of the planned RT group. However, failure to receive the full RT dose and/or lengthy rest periods during RT were just as likely to occur in the planned TF group as in the no TF group. This retrospective review also could not demonstrate improved survival in the planned TF group. Complications, including peptic ulcer disease, aspiration pneumonia, cervical stoma abscess, and hepatic encephalopathy, occurred in 7 of the 26 patients (27%) receiving either planned or interventional TF. We conclude that TF will help minimize weight loss due to side effects of RT for head and neck cancer, particularly when TF is instituted before the onset of significant weight loss due to RT side effects. Survival differences, however, were not apparent.