Visualization and Transport of Positron Emission from Proton Activation in vivo.

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.

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.

Tissue population configuration as a modifier of organ dose response.

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.

Pathophysiology of irradiated skin and breast.

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.

Correlation of the dermal microvasculature morphology with the epidermal and the endothelial population changes produced by single X ray fractions of 1649, 2231 and 2619 rad in swine.

The role of the dermal microvasculature in the production of skin changes has not been specified. The healing moist reaction observed between 21 and 36 days following X ray exposures of 1649, 2231, and 2619 rad results from the loss and repopulation of the epidermal basal cells. The second breakdown occurring between 36 and 70 days results from the loss of endothelial cells in vessels of the papillary plexus. The epidermal population in swine skin decreases linearly to a nadir at 23 days and returns to control levels (and beyond) exponentially at 28-32 days. During this period, the endothelial cell density remains at control levels. At 28-36 days there is an abrupt decrease to 50% of control levels following administration of 1649 rad and a further decrease to 0 after 2231 and 2619 rad by 70 days. The qualitative morphology of the microvasculature remains unchanged until 32-36 days following irradiation. At that time there is increased endothelial cell pyknosis and loss of endothelial cells. A decrease in the vascular lumen cross-section profile density occurs by 43-49 days. This is accompanied by a progressive vascular dilatation. Interstitial edema becomes marked, with an inflammatory infiltrate of varying amount. Micro thrombi are found after 2619 rad, but are nearly absent after 1649 rad.

Swine basal cell proliferation during a course of daily irradiation, five days a week for six weeks (6000 rad).

In swine skin irradiated with 200 rad per day, 5 days per week for 6 weeks, basal cell density remained at control levels for the first 2 weeks and then decreased to a nadir of 50% at 38 days. Thereafter it began increasing and returned to near control levels within 1 day after the end of irradiation on day forty-three. The mitotic index increased progressively to a maximum value three times the controls at day forty-two and then decreased as the cell density returned to control levels. The pattern strongly suggests that cell proliferation occurred during the period of irradiation. The cell density changes are simulated by a model in which doubling time switches from 12 days to 2.5 days at the 50% cell density level.

Role for proton beam irradiation in treatment of pediatric CNS malignancies.

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.

Carcinoma of the tonsillar region: potential for use of proton beam therapy.

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.

Field size dependence of radiation sensitivity and dose fractionation response in skin.

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.

Development of a hospital-based proton beam treatment center.

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.

Cost-effective, available-on-demand intraoperative radiation therapy.

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.

Lack of correlation between basal cell survival and gross response in irradiated swine skin.

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.

Acute normal tissue tolerance to 7 day per week accelerated fractionation.

Fifty-six sites in 49 patients were irradiated by a 7 day/week accelerated fractionation schedule to conventional tumor doses. Daily doses were 180 to 200 rad in 85% of sites. Patients were analyzed for normal tissue tolerance. A 7 day/week accelerated fractionation appears clinically tolerable at 180 rad per fraction.

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.

Breast retraction assessment: an objective evaluation of cosmetic results of patients treated conservatively for breast cancer.

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.

Tube feeding enteral nutritional support in patients receiving radiation therapy for advanced head and neck cancer.

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.

The proton treatment center at Loma Linda University Medical Center: rationale for and description of its development.

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.

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.

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.

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.