Proton beams in radiation therapy.

The rationale for study of proton radiation therapy is that, for some anatomic sites and tumors, the treatment volume is smaller; i.e., there is less irradiation of nontarget tissue while the target is included in three dimensions at each treatment session. As a result, the dose to the target can be raised. The consequence is that the tumor control probability improves and the frequency and severity of treatment-related morbidity decrease. These results come about from the physical fact that the proton range in tissue is finite; in comparison, absorption of photons is an exponential function and, hence, some dose is received for the full-beam path through the body. Accordingly, the dose deep to the target for proton treatments can be zero for each beam path. This situation provides a virtually certain means of improving the treatment outcome for selected categories of patients. Experience to date with proton radiation therapy has been quite limited. As of June 1991, the total number of proton radiation-treated patients was 11,763 from the various centers. Of that number, approximately 46% and 32% have been treated for small benign intracranial lesions (principally pituitary adenomas and arteriovenous malformations) and for tumors of the eye, respectively. Thus, only some 2500 patients have been treated for all other tumor types. The results from three centers and approximately 2800 patients with uveal melanoma are that the local control rate was 96% (for failures in-field, marginal, and in other parts of the eye). The local control results for chondrosarcomas and chordomas of the skull base are 91% and 65%, respectively. These percentages compare with some 35% achieved with conventional treatment. Experience with arteriovenous malformations indicates that control of bleeding and disappearance of the lesion are comparable to those achieved by other procedures. The developments from the proton therapy programs have contributed greatly to radiation treatment planning, e.g., the first three-dimensional treatment planning system put into regular clinical use (uveal melanoma), beam's eye view, digital-reconstructed radiograph, dose-volume histograms, and definitions of the uncertainty in dose around any defined point. The potential for clinical gains is high. In May 1991, the Proton Radiation Oncology Group was formed to design, supervise, and coordinate clinical trials and to assist in data analysis. The efficacy of proton radiation therapy will be compared with that of photon therapy of the very highest technology.

Potential improvement of three dimension treatment planning and proton beams in fractionated radiotherapy of large cerebral arteriovenous malformations.

The treatment of large cerebral arteriovenous malformations is a surgical challenge, especially for deep seated brain locations. Furthermore, these lesions are unfit for radiosurgical approaches due to a high risk of complications secondary to high radiation doses to large brain volumes. Fractionated precision radiotherapy can potentially deliver high, uniform, target-contoured dose distributions optimizing the dose reduction to the critical surrounding brain. The results of a study are presented in such a way that dose distributions achievable with proton beams are compared to those with 10 MV x-rays; and the potential improvements with protons evaluated, relying heavily on dose-volume histograms to examine the coverage of the lesion as well as the dose to the normal brain, brain-stem, and optic chiasm.

Importance of precise positioning for proton beam therapy in the base of skull and cervical spine.

Using proton beam therapy, high doses have been delivered to chordomas and chondrosarcomas of the base of skull and cervical spine. Dose inhomogeneity to the tumors has been accepted in order to maintain normal tissue tolerances, and detailed attention to patient immobilization and to precise positioning has minimized the margins necessary to ensure these dose constraints. This study examined the contribution of precise positioning to the better dose localization achieved in these treatments. Three patients whose tumors represented different anatomic geometries were studied. Treatment plans were developed which treated as much of the tumor as possible to 74 Cobalt-Gray-Equivalent (CGE) while maintaining the central brain stem and central spinal cord at less than or equal to 48 CGE, the surface of the brain stem, surface of the spinal cord, and optic structures at less than or equal to 60 CGE, and the temporal lobes at less than or equal to 5% likelihood of complication using a biophysical model of normal tissue complication probability. Two positioning accuracies were assumed: 3 mm and 10 mm. Both proton beam plans and 10 MV X ray beam plans were developed with these assumptions and dose constraints. In all cases with the same positioning uncertainties, the proton beam plans delivered more dose to a larger percentage of the tumor volume and the estimated tumor control probability was higher than with the X ray plans. However, without precise positioning both the proton plans and the X ray plans deteriorated, with a 12% to 25% decrease in estimated tumor control probability. In all but one case, the difference between protons with good positioning and poor positioning was greater than the difference between protons and X rays, both with good positioning. Hence in treating these tumors, which are in close proximity to critical normal tissues, attention to immobilization and precise positioning is essential. With good positioning, proton beam therapy permits higher doses to significantly more of the tumor in these sites than do X rays.

Optimization of 3D radiation therapy with both physical and biological end points and constraints.

A new optimization model is described and its clinical usefulness is demonstrated. The optimization technique was developed to allow computer optimization of 3-dimensional radiation therapy plans with biological models of tumor and normal tissue response to radiation as well as with scores based on physical dose. The emphasis was placed on the optimization model, which should describe, as closely as possible, the goal of the radiation treatment, which is eradication of the tumor while sparing normal tissues. Since the statement of the goals may vary from case to case, a technique that allows a variety of objective functions and types of constraints was developed. The optimization algorithm is capable of handling nonlinear and even discrete score (objective) functions and constraints and effectively explores the vast space of feasible solutions in a relatively short time (minutes of MicroVax 3200 CPU time). An example of computer optimization of radiation therapy of a chordoma of the sphenoid bone using x-ray and proton beams is shown and compared with the best plans achieved by an experienced planner. Directions for future development of the algorithm, allowing optimization of beam orientation, are presented.

Comparative treatment planning: proton vs. x-ray beams against glioblastoma multiforme.

The survival of patients with glioblastoma multiforme is extremely poor, the 5-year survival rate being almost zero. The cause of failure is almost exclusively local progression of tumor, the remainder is due to complications of treatment. Although this tumor is clearly radiation resistant, there is evidence of a dose response relationship. Using a thin slice CT scan of the entire head of a patient with glioblastoma multiforme, 3-dimensional radiation treatment plans were developed for treatment to a dose of 90 cobalt-Gray-equivalent (CGE). Dose distributions using protons were compared to those using x-rays. The results showed advantages for the proton beam technique. Namely the proton plan irradiated less non-target brain than the x-ray plan; this was especially so in the decrease of coverage of deep-seated structures. The volume of non-target brain that received more than 70 CGE was 175 ml for the x-ray plan and 94 ml for the proton plan. This study indicates that for a subpopulation of patients with glioblastoma multiforme, at least 90 CGE could be delivered with proton beam techniques to the target with only small volumes of normal brain structures receiving more than 70 CGE.

3-D comparative study of proton vs. x-ray radiation therapy for rectal cancer.

To assess the usefulness of proton beams for treatment of patients with rectal cancer, we have performed comparative 3D treatment planning for proton beam and x-ray beam therapy. Three common x-ray techniques (AP-PA, 3-field, and 4-field box), a proton beam only plan, and a proton boost plan were compared. The plan which would have been treated without the aid of the 3D planning system was also simulated. Dose distributions were analyzed and dose-volume histograms computed for the target volumes and critical normal tissues. Analyses of these plans demonstrate that the proton beam techniques reduce the volume of small bowel irradiated. This may allow higher doses to be delivered to the tumor, with a probable increase in local control, or a reduction in normal tissue complications probability. All the plans developed with the 3D planning system treated significantly less bowel than the one planned without it.

Probable causes of recurrence in patients with chordoma and chondrosarcoma of the base of skull and cervical spine.

PURPOSE: 141 patients with chordoma and chondrosarcoma of the base of skull and cervical spine were treated with proton and photon irradiation between 1980 and 1989. The local disease was controlled in 111 of these patients. This study reviews the 26 patients who have had their disease recur, and who have evaluable diagnostic studies to examine for probable causes of recurrence. METHODS AND MATERIALS: The histologies of the recurrent tumors were 21 non-chondroid chordomas, two chondroid chordomas, and three chondrosarcomas. The prescribed doses ranged from 67 Cobalt-Gray-Equivalent (CGE) to 72 CGE (average of 69 CGE). Doses to small regions of the tumor were deliberately reduced where they abutted certain normal tissues (brain stem, spinal cord, optic chiasm, and optic nerves) in order to keep these structures at acceptance dose levels. The first study, CT or MR scan, on which there was evidence of increase in tumor was carefully evaluated and that volume transferred to the CT scan on which the treatment plan had been developed. The 3D dose distribution in the region of recurrence was carefully analyzed and a judgement made as to the most probable cause of recurrence. RESULTS: Approximately one quarter (6 of 26) of the cases failed in the prescribed dose region. More than half (15 of 26) failed in regions where tumor dose was limited by normal tissue constraints. Approximately 10% of the patients recurred in the surgical pathway and 10% were judged to be marginal misses. CONCLUSIONS: Overall, 75% of the patients failed in regions receiving less than the prescribed dose. All tumors which failed in the high dose region had volume greater than 75 cc. Patients with cervical spine disease had a higher rate of recurrence (10 or 26) and larger tumors (average volume of 102 cc) than those with base of skull disease (16 of 115) with an average volume of 63 cc.

Proton therapy for carcinoma of the nasopharynx: a study in comparative treatment planning.

Radiation therapy for nasopharyngeal carcinoma is technically difficult because of the complexity of the regional anatomy and the natural history of the disease. The results of a study are presented showing how detailed diagnostic information available from MRI is helpful in defining the target volume to be irradiated and the critical normal structures. By using 3-dimensional planning techniques, an assessment was made of the relative merits of proton beam therapy and of X ray treatment for patients with early stage and locally advanced carcinoma of the nasopharynx. For both types of patient, the study suggests that the use of protons for the major part of treatment results in a more even distribution of dose to the tumor and an increase of approximately 5 Gy in median tumor dose with substantial reductions in doses to adjacent normal tissues. The superior dose distributions possible with protons should translate into improved local control and reduced morbidity. The difficulties of proton treatment planning for this site are addressed.

Intensity modulation for breast treatment using static multi-leaf collimators.

PURPOSE: To achieve more uniform dose distributions in breast cancer treatment using multiple sets of multi-leaf collimator (MLC) defined fields. Dose uniformity for many breast cancer patients can be significantly improved by using two or more sets of portals and the "hot" regions of a traditional treatment can be significantly reduced. METHODS AND MATERIALS: Patients for breast cancer treatment are immobilized with alpha cradle in the traditional arm-up position and have a CT scan in the treatment position. The target volume is delineated on the 5-mm thick CT slices that are obtained from the lower neck to well below the breast target volume. Medial and lateral tangential fields at conventional gantry angles are designed with the aid of digitally reconstructed radiographs (DRRs). The MLC, without collimator rotation, is used to shape the field to spare as much lung as possible. The wedges and relative weights of the beams are optimized to provide the best dose uniformity. For the patients with large dose inhomogeneity, a second set of fields is designed. The weight of the original set of fields is reduced (usually to approximately 90%) so that the "original hot" regions receive the prescription dose; the second set of fields delivers a supplemental dose to the "cold" region, typically approximately 10% of the total dose. The second set of fields has the same beam parameters but "treat" only the part of breast tissue that is "cool." Presently, the design of the reduced field is an iterative process. The process can be extended to more than two sets of portals to obtain the desired dose uniformity. RESULTS: With 3D planning and multiple MLC fields, dose uniformity in the treatment of breast patients was improved from 7%-22% to approximately 7%-15%. The volume receiving these high doses decreased significantly and shifted from the lung to the target. By keeping the gantry angles and wedges the same for the multiple fields, treatments can be delivered quickly and reliably. The internal mammary nodes (IM) can also be treated without including significant amount of lung or heart in the field. CONCLUSION: Dose uniformity can be significantly improved by using this intensity modulation technique to treat certain breast patients. With these static MLC fields creating the intensity modulation, the dose uniformity to the breast can be significantly improved and the hot region in lung reduced. There is no increase in setup complexity. The small increase in treatment time is insignificant.

Dose-volume histograms.

A plot of a cumulative dose-volume frequency distribution, commonly known as a dose-volume histogram (DVH), graphically summarizes the simulated radiation distribution within a volume of interest of a patient which would result from a proposed radiation treatment plan. DVHs show promise as tools for comparing rival treatment plans for a specific patient by clearly presenting the uniformity of dose in the target volume and any hot spots in adjacent normal organs or tissues. However, because of the loss of positional information in the volume(s) under consideration, it should not be the sole criterion for plan evaluation. DVHs can also be used as input data to estimate tumor control probability (TCP) and normal tissue complication probability (NTCP). The sensitivity of TCP and NTCP calculations to small changes in the DVH shape points to the need for an accurate method for computing DVHs. We present a discussion of the methodology for generating and plotting the DVHs, some caveats, limitations on their use and the general experience of four hospitals using DVHs.

Neuropsychological function in adults after high dose fractionated radiation therapy of skull base tumors.

PURPOSE: To evaluate the long term effects of high dose fractionated radiation therapy on brain functioning prospectively in adults without primary brain tumors. METHODS AND MATERIALS: Seventeen patients with histologically confirmed chordomas and low grade chondrosarcomas of the skull base were evaluated with neuropsychological measures of intelligence, language, memory, attention, motor function and mood following surgical resection/biopsy of the tumor prior to irradiation, and then at about 6 months, 2 years and 4 years following completion of treatment. None received chemotherapy. RESULTS: In the patients without tumor recurrence or radiation necrosis, there were no indications of adverse effects on cognitive functioning in the post-acute through the late stages after brain irradiation. Even in patients who received doses of radiation up to 66 Cobalt Gy equivalent through nondiseased (temporal lobe) brain tissue, memory and cognitive functioning remained stable for up to 5 years after treatment. A mild decline in psychomotor speed was seen in more than half of the patients, and motor slowing was related to higher radiation doses in midline and temporal lobe brain structures. CONCLUSION: Results suggest that in adults, tolerance for focused radiation is relatively high in cortical brain structures.

Conformal irradiation of the prostate: estimating long-term rectal bleeding risk using dose-volume histograms.

PURPOSE: Dose-volume histograms (DVHs) may be very useful tools for estimating probability of normal tissue complications (NTCP), but there is not yet an agreed upon method for their analysis. This study introduces a statistical method of aggregating and analyzing primary data from DVHs and associated outcomes. It explores the dose-volume relationship for NTCP of the rectum, using long-term data on rectal wall bleeding following prostatic irradiation. METHODS AND MATERIALS: Previously published data were reviewed and updated on 41 patients with Stages T3 and T4 prostatic carcinoma treated with photons followed by perineal proton boost, including dose-volume histograms (DVHs) of each patient's anterior rectal wall and data on the occurrence of postirradiation rectal bleeding (minimum FU > 4 years). Logistic regression was used to test whether some individual combination of dose and volume irradiated might best separate the DVHs into categories of high or low risk for rectal bleeding. Further analysis explored whether a group of such dose-volume combinations might be superior in predicting complication risk. These results were compared with results of the "critical volume model," a mathematical model based on assumptions of underlying radiobiological interactions. RESULTS: Ten of the 128 tested dose-volume combinations proved to be "statistically significant combinations" (SSCs) distinguishing between bleeders (14 out of 41) and nonbleeders (27 out of 41), ranging contiguously between 60 CGE (Cobalt Gray Equivalent) to 70% of the anterior rectal wall and 75 CGE to 30%. Calculated odds ratios for each SSC were not significantly different across the individual SSCs; however, analysis combining SSCs allowed segregation of DVHs into three risk groups: low, moderate, and high. Estimates of probabilities of normal tissue complications (NTCPs) based on these risk groups correlated strongly with observed data (p = 0.003) and with biomathematical model-generated NTCPs. CONCLUSIONS: There is a dose-volume relationship for rectal mucosal bleeding in the region between 60 and 75 CGE; therefore, efforts to spare rectal wall volume using improved treatment planning and delivery techniques are important. Stratifying dose-volume histograms (DVHs) into risk groups, as done in this study, represents a useful means of analyzing empirical data as a function of hetereogeneous dose distributions. Modeling efforts may extend these results to more heterogeneous treatment techniques. Such analysis of DVH data may allow practicing clinicians to better assess the risk of various treatments, fields, or doses, when caring for an individual patient.

Large scale optimization of beam weights under dose-volume restrictions.

The problem of choosing weights for beams in a multifield plan which maximizes tumor dose under conditions that recognize the volume dependence of organ tolerance to radiation is considered, and its solution described. Structures are modelled as collections of discrete points, and the weighting problem described as a combinatorial linear program (LP). The combinatorial LP is solved as a mixed 0/1 integer program with appropriate restrictions on normal tissue dose. The method is illustrated through the assignment of weights to a set of 10 beams incident on a pelvic target. Dose-volume restrictions are placed on surrounding bowel, bladder, and rectum, and a limit placed on tumor dose inhomogeneity. Different tolerance restrictions are examined, so that the sensitivity of the target dose to changes in the normal tissue constraints may be explored. It is shown that the distributions obtained satisfy the posed constraints. The technique permits formal solution of the optimization problem, in a time short enough to meet the needs of treatment planners.

The role of uncertainty analysis in treatment planning.

The role of uncertainty analysis in 3-D treatment planning systems was addressed by four institutions which contracted with NCI to evaluate high energy photon external beam treatment planning. Treatment plans were developed at eight disease sites and the effects of uncertainties assessed in a number of experiments. Uncertainties which are patient-site specific included variations in the delineation of target volumes and normal tissues and the effects of positional uncertainties due to physiological motion and setup nonreproducibility. These were found to have a potentially major impact on the doses to the target volumes and to critical normal tissues which could result in significantly altered probabilities of tumor control and normal tissue complications. Other uncertainties, such as the conversion of CT data to electron densities, heterogeneities and dose calculation algorithms' weaknesses, are related to physical processes. The latter was noted to have the greatest potential contribution to uncertainty in some sites. A third category of uncertainty related to the treatment machine, the consequences of compensator misregistration, are exclusive to the site and the treatment portal. Because conventional treatment planning systems have not incorporated uncertainty analysis, tools and techniques had to be devised for this work; further development in this area is needed. Many of the analyses could not have been done without full 3-D capabilities of the planning systems, and it can be anticipated that the availability of uncertainty analysis in these systems which allow nontraditional beam arrangements will be of great value.

Three-dimensional photon treatment planning for Hodgkin's disease.

A multi-institutional study was undertaken using computerized planning systems to develop three-dimensional (3-D) radiotherapy plans for Hodgkin's disease (H.D.). Two patients, the first afflicted with bulky stage II disease and another one with early stage I H.D., were studied. Three main categories of plan were produced for each patient: a) a traditional plan which modelled a conventional mantle treatment on the 3-D system, b) a 3-D standard plan where anterior and posterior fields were designed to cover 3-D target volumes, and c) a 3-D unconstrained plan where innovational techniques were employed. Three-dimensional planning provides information about the dose distribution throughout the large volume irradiated in patients with H.D. that is not available with conventional mantle planning. The use of 3-D techniques resulted in improved tumor coverage, but by allowing for uncertainties such as motion, the doses to normal tissues tended to be higher. The use of unorthodox beam arrangements introduced added complexities, and further increased the lung doses. The most even dose distributions were obtained by incorporating compensating filters into anterior fields. Clinicians showed wide variations in their assessment of the plans, possible reasons for which are addressed in this paper. In addition, calculated probabilities from models of tumor control and normal tissue damage are also presented.

Late rectal bleeding following combined X-ray and proton high dose irradiation for patients with stages T3-T4 prostate carcinoma.

PURPOSE: Dose escalation for prostate cancer by external beam irradiation is feasible by a 160 MeV perineal proton beam that reduces the volume of rectum irradiated. We correlated the total doses received to portions of the anterior rectum to study the possible relationship of the volume irradiated to the incidence of late rectal toxicity. METHODS: We have randomized 191 patients with stages T3 and T4 prostatic carcinoma to one of two treatment dose arms. These were: 1) 75.6 Cobalt-Gy-equivalent (CGE), 50.4 Gy delivered by 107-25 MV photons followed by 25.2 CGE delivered perineally by protons (Arm 1) or 2) 67.2 CGE delivered by 10-25 MV photons (Arm 2). RESULTS: With a median follow-up of 3.7 years, post-irradiation rectal bleeding (grades 1 and 2 only, none requiring surgery or hospitalization) from telangiectatic rectal mucosal vessels has occurred in 34% of 99 Arm-1 patients and 16% of 92 Arm-2 patients (p = 0.013). Dose-volume histograms (DVHs) for the anterior rectal wall, the posterior rectal wall and the total rectum in 41 patients treated on Arm 1 were calculated from the three dimensional dose distributions. Rectal bleeding has occurred in 14 or 34% of the 41 DVH-analyzed subset of Arm-1 patients. Both the fractional volume of the anterior rectum and the total dose received by fractional volumes of the anterior rectum significantly correlate with the actuarial probability of bleeding. CONCLUSIONS: Clinicians planning dose escalation to men with localized prostate cancer should approve with caution treatment plans raising more than 40% of the anterior rectum to more than 75 CGE without additional effort to protect the rectal mucosa because this late sequela data indicate that more than half of these men will otherwise have rectal bleeding.

Endocrine function following high dose proton therapy for tumors of the upper clivus.

The endocrine status of patients receiving proton radiation for tumors of the upper clivus was reviewed to evaluate the effect of high dose treatment on the pituitary gland. The fourteen patients had chordomas or low grade chondrosarcomas and were all treated by the same techniques. The median tumor dose was 69.7 Cobalt Gray Equivalent (CGE) with a range from 66.6 to 74.4 CGE. (CGE is used because modulated protons have an RBE of 1.1 compared to 60Co). The daily fraction size was 1.8-2.1 CGE. The median follow-up time is 48 months, ranging from 30 to 68 months. All treatments were planned using a computerized multi-dimensional system with the position of the pituitary outlined on the planning CT scan. Review of the dose distribution indicated that the dose to the pituitary ranged from 60.5 to 72.3 CGE, with a median of 67.6 CGE. One female patient had decreased thyroid and gonadotropin function at the time of diagnosis and has been on hormone replacement since that time. The other three females were all pre-menopausal at the time of radiotherapy. At this time four patients (3 males and 1 female) have developed endocrine abnormalities 14 to 45 months after irradiation. All four had evidence of hypothyroidism and two have also developed corticotropin deficiency. The three males had decreased testosterone levels; the female patient developed amenorrhea and hyperprolactinemia. All four are asymptomatic with ongoing hormone replacement.

Neurovisual outcome following proton radiation therapy.

From February 1981 to January 1984, 20 patients with a tumor of the upper clivus received proton irradiation at the Harvard Cyclotron Laboratory. For 15 patients with known neurovisual status (including visual acuity, color vision, visual field, and fundus examinations) we obtained a cumulative dose-volume histogram (DVH) of the optic nerves (ON) and the optic chiasm. The prescribed tumor doses ranged from 66.6 to 74.4 Cobalt Gray Equivalent (CGE) with a daily fraction size of 1.8 to 2.1 CGE. CGE is used because modulated protons have an RBE of 1.1 compared to 60Co. The follow-up ranged from 30 to 68 months (median 52). Two patients developed, 10 and 36 months post irradiation, a progressive visual deterioration affecting both eyes. This was attributed to an ON and a chiasm injury in one patient and to bilateral ON injury in the other patient. In the first patient, the dose-volume analysis indicated that approximately half of the ON and of the chiasm had received 65 CGE and 55 CGE, respectively. In the second patient, it indicated that a quarter of the left ON (LON) had received 55 CGE whereas the dose to the right ON (RON) was significantly less. This patient had diabetes mellitus which may be a predisposing factor. From this study, a complication rate of 20% (1/5) is observed when a substantial portion of the ON is taken to 65 CGE, while it doesn't exceed 12.5% (2/16) and 7.5% (1/13) at 55 CGE for the ON and for the chiasm, respectively. This suggests a tolerance dose implying a 10% rate of major complications close to 55 CGE. When a tumor requires a high radiation-dose, the exclusion of these structures at 55 to 60 Gy is recommended.

Conservative treatment of uveal melanoma: local recurrence after proton beam therapy.

Twenty-three of 1006 (2.3%) uveal melanoma patients treated with proton beam therapy at the Harvard Cyclotron Laboratory between July 1975 and December 31, 1986 received additional treatment for documented (15 patients) or suspected (eight patients) tumor growth in the irradiated eye. Growth within the initially irradiated volume was documented at Massachusetts Eye and Ear Infirmary in 12 patients. Documented growth occurred in nine of 665 (1.4%) patients with small and intermediate size tumors, at times after treatment ranging from 6 to 48 months (median 16 months), and in three of 341 (.9%) patients with large tumors at 7, 11, and 12 months after treatment. Melanoma growing totally outside the treated volume was also documented in three additional patients at 7, 9, and 45 months; two of these were thought to be "ring melanomas". Eight patients had the treated eye removed elsewhere for suspected tumor growth. The additional treatment in these 23 patients was conservative in nine patients (repeat proton irradiation in five and laser photocoagulation in four). Thirteen underwent immediate enucleation and one had orbital exenteration. Ultimately, 17 of the 23 eyes (74%) were removed. Estimated probability of local control of the melanoma within the irradiated eye at 60 months was 96.3 +/- 1.5%. Dose distributions to the 12 patients with documented local failure within the irradiated volume were analyzed. Ten tumors recurred marginally in an area receiving less than the prescribed dose of 70 CGE (CGE = Cobalt Gray Equivalents = proton Gy X RBE 1.1), whereas only two recurred in the volume receiving full dose. Based on these data, it appears that a dose of 70 CGE in five fractions is associated with very high rates of local control in human uveal melanoma. It is reasonable to consider initiating studies using a lower total dose or a more protracted course, to determine if some of the observed complications are dose-related.

A dose response analysis of injury to cranial nerves and/or nuclei following proton beam radiation therapy.

The low tolerance of the central nervous system (CNS) limits the radiation dose which can be delivered in the treatment of many patients with brain and head and neck tumors. Although there are many reports concerning the tolerance of the CNS, few have examined individual substructures of the brain and fewer still have had detailed dose information. This study has both. A three dimensional planning system was used to develop the combined proton beam/photon beam treatments for 27 patients with skull-base tumors. The cranial nerves and their related nuclei were delineated on the planning CT scans and the radiation dose to each was determined from three dimensional dose distributions. In the 594 CNS structures (22 structures/patient in 27 patients), there have been 17 structures (in 5 patients) with clinically manifest radiation injury, after a mean follow-up time of 74 months (range 40-110 months). From statistical analyses, dose is found to be a significant predictor of injury. Using logistic regression analysis, we find that, for each cranial nerve, at 60 Cobalt Gray Equivalent (CGE) the complication rate is 1% (0.5-3% with 95% confidence) and that the 5% complication rate occurs at 70 CGE (64-81 CGE with 95% confidence). The slope of the dose response curve (at 50%) is 3.2 (2.2-5.4 with 95% confidence). No significant relationship between dose and latency period for nerve injury was found.