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Background: Psychiatric symptoms are commonly comorbid in childhood. The ability to disentangle unique and shared correlates of comorbid symptoms facilitates personalized medicine. Cognitive control is implicated broadly in psychopathology, including in pediatric disorders characterized by anxiety and irritability. To disentangle cognitive control correlates of anxiety versus irritability, the current study leveraged both cross-sectional and longitudinal data from early childhood into adolescence., Methods: For this study, 89 participants were recruited from a large longitudinal research study on early-life temperament to investigate associations of developmental trajectories of anxiety and irritability symptoms (from ages 2 to 15) as well as associations of anxiety and irritability symptoms measured cross-sectionally at age 15 with neural substrates of conflict and error processing assessed at age 15 using the flanker task., Results: Results of whole-brain multivariate linear models revealed that anxiety at age 15 was uniquely associated with decreased neural response to conflict across multiple regions implicated in attentional control and conflict adaptation. Conversely, irritability at age 15 was uniquely associated with increased neural response to conflict in regions implicated in response inhibition. Developmental trajectories of anxiety and irritability interacted in relation to neural responses to both error and conflict., Conclusions: Our findings suggest that neural correlates of conflict processing may relate uniquely to anxiety and irritability. Continued cross-symptom research on the neural correlates of cognitive control could stimulate advances in individualized treatment for anxiety and irritability during child and adolescent development., (Published by Elsevier Inc.)

Purpose: To calculate treatment plans and compare the dose distributions and dose-volume histograms (DVHs) for photon three-dimensional conformal radiation therapy (3D-CRT), electron therapy, intensity-modulated radiation therapy (IMRT), and standard (nonintensity modulated) proton therapy in three pediatric disease sites., Methods and Materials: The tumor volumes from 8 patients (3 retinoblastomas, 2 medulloblastomas, and 3 pelvic sarcomas) were studied retrospectively to compare DVHs from proton therapy with 3D-CRT, electron therapy, and IMRT. In retinoblastoma, several planning techniques were analyzed: A single electron appositional beam was compared with a single 3D-CRT lateral beam, a 3D-CRT anterior beam paired with a lateral beam, IMRT, and protons. In medulloblastoma, three posterior fossa irradiation techniques were analyzed: 3D-CRT, IMRT, and protons. Craniospinal irradiation (which consisted of composite plans of both the posterior fossa and craniospinal components) was also evaluated, primarily comparing spinal irradiation using 3D-CRT electrons, 3D-CRT photons, and protons. Lastly, in pelvic sarcoma, 3D-CRT, IMRT, and proton plans were assessed., Results: In retinoblastoma, protons resulted in the best target coverage combined with the most orbital bone sparing (10% was the mean orbital bone volume irradiated at > or =5 Gy for protons vs. 25% for 3D-CRT electrons, 69% for IMRT, 41% for a single 3D lateral beam, 51% for a 3D anterolateral beam with a lens block, and 65% for a 3D anterolateral beam without a lens block). A single appositional electron field was the next best technique followed by other planning approaches. In medulloblastoma, for posterior fossa and craniospinal irradiation, protons resulted in the least dose to the cochlea (for only posterior fossa irradiation at > or =20 Gy, 34% was the mean cochlear volume irradiated for protons, 87% for IMRT, 89% for 3D-CRT) and hypothalamus-pituitary axis (for only posterior fossa irradiation at > or =10 Gy, 21% was the mean hypothalamus-pituitary volume irradiated for protons, 81% for IMRT, 91% for 3D-CRT); additional dose reductions to the optic chiasm, eyes, vertebrae, mandible, thyroid, lung, kidneys, heart, and liver were seen. Intensity-modulated radiotherapy appeared to be the second best technique for posterior fossa irradiation. For spinal irradiation 3D-CRT electrons were better than 3D-CRT photons in sparing dose to the thyroid, heart, lung, kidney, and liver. With pelvic sarcoma, protons were superior in eliminating any dose to the ovaries (0% of mean ovarian volume was irradiated at > or =2 Gy with protons) and to some extent, the pelvic bones and vertebrae. Intensity-modulated radiotherapy did show more bladder dose reduction than the other techniques in pelvic sarcoma irradiation., Conclusions: In the diseases studied, using various techniques of 3D-CRT, electrons, IMRT, and protons, protons are most optimal in treating retinoblastomas, medulloblastomas (posterior fossa and craniospinal), and pelvic sarcomas. Protons delivered superior target dose coverage and sparing of normal structures. As dose-volume parameters are expected to correlate with acute and late toxicity, proton therapy should receive serious consideration as the preferred technique for the treatment of pediatric tumors.

Purpose: To study the optimization of proton beam arrangements for various intraocular tumor locations; and to correlate isodose distributions with various target and nontarget structures., Methods and Materials: We considered posterior-central, nasal, and temporal tumor locations, with straight, intrarotated, or extrarotated eye positions. Doses of 46 cobalt grey equivalent (CGE) to gross tumor volume (GTV) and 40 CGE to clinical target volume (CTV) (2 CGE per fraction) were assumed. Using three-dimensional planning, we compared isodose distributions for lateral, anterolateral oblique, and anteromedial oblique beams and dose-volume histograms of CTVs, GTVs, lens, lacrimal gland, bony orbit, and soft tissues., Results: All beam arrangements fully covered GTVs and CTVs with optimal lens sparing. Only 15% of orbital bone received doses > or =20 CGE with a lateral beam, with 20-26 CGE delivered to two of three growth centers. The anterolateral oblique approach with an intrarotated eye resulted in additional reduction of bony volume and exposure of only one growth center. No appreciable dose was delivered to the contralateral eye, brain tissue, or pituitary gland., Conclusions: Proton therapy achieved homogeneous target coverage with true lens sparing. Doses to orbit structures, including bony growth centers, were minimized with different beam arrangements and eye positions. Proton therapy could reduce the risks of second malignancy and cosmetic and functional sequelae.

Purpose: To determine the temporal lobe (TL) damage rate in 96 patients treated with high-dose proton and photon irradiation for chordomas and chondrosarcomas of the base of the skull., Methods and Materials: The records of 96 consecutive patients treated at Massachusetts General Hospital (MGH) and Harvard Cyclotron Laboratory (HCL) between June 1984 and 1993, for chordomas and chondrosarcomas of the base of the skull were reviewed. All the patients had undergone some degree of resection of the tumor prior to radiation therapy. Seventy-five patients were classified as "primary tumors" and 21 as recurrent or regrowing tumors after one or more surgical procedures. All the patients were randomized to receive 66.6 or 72 cobalt Gray equivalent (CGE) on a prospective dose-searching study by proton and photon irradiation (Radiation Therapy Oncology Group #85-26) with conventional fractionation (1.8 CGE/day, 5 fractions/week). All treatments were planned using the three-dimensional (3D) planning system developed at the Massachusetts General Hospital, and the dose was delivered using opposed lateral fields for the photon component and a noncoplanar isocentric technique for the proton component. Clinical symptoms of TL damage were classified into 4 grades. Computerized tomography (CT) and magnetic resonance imaging (MRI) scans were evaluated for white matter changes. Abnormalities associated with persistent or recurrent tumor were distinguished from radiation-induced changes. TLs were delineated on the original scans of the 10 patients with damage and those of a group of 33 patients with no clinical or MRI evidence of injury. Dose distributions were calculated and dose-volume histograms were obtained for these patients., Results: Of the patients, 10 developed TL damage, with bilateral injury in 2 and unilateral injury in 8. The cumulative TL damage incidence at 2 and 5 years was 7.6 and 13.2%, respectively. The MRI areas suggestive of TL damage were always separated from the tumor bed. Symptoms were severe to moderate in 8 patients. Several baseline factors, tumor- or host-related, were analyzed to evaluate their predictivity for TL damage: age, gender, tumor site, histology, type of presentation, type and number of surgical procedures, primary tumor volume, prescribed dose, normal tissue involvement, and volume of TL receiving doses ranging between 10 and 50 CGE or more. Only gender, in a univariate analysis (log rank) was a significant predictor of damage (0.0155), with male patients being at significantly higher risk of TL injury. In a stepwise Cox regression that included gender as a variable, no other baseline variable improved the prediction of damage., Conclusions: The 2- and 5-year cumulative TL damage rates were 7.6 and 13.2%, respectively. Despite the different TL damage rates related to age, tumor volume, number of surgical procedures prior to radiation therapy, and prescribed doses to the tumor, only gender was a significant predictor of damage (p = 0.0155) using a univariate (log rank) test. Chordomas and chondrosarcomas of the base of the skull may represent an interesting model to evaluate the TL damage rates because of their extradural origin, displacing the white matter instead of infiltrating it as gliomas do, because of their longer local recurrence-free survival other than gliomas and other brain tumors and because of the high doses of irradiation delivered to the target volume to obtain local control.

Purpose: To conduct a study of the process of treatment planning and treatment of adenocarcinoma of the rectum and sigmoid in the United States, and to compare survey results to consensus guidelines., Methods and Materials: A consensus committee developed guidelines for the radiotherapeutic management of adenocarcinoma of the rectum and sigmoid, and also developed a survey form that was used to gather data to evaluate the practice patterns for patients treated in 1989 and 1990 against the consensus guidelines. Seventy-three facilities were randomly selected for site visits from the 1321 radiation therapy facilities in the US: 21 academic, 26 hospital based, and 26 free standing. During the site visits, the radiotherapy records were examined by the surveyor physicist and radiation oncologist to extract and record the required data. Data collected included items related to treatment specific parameters, including treatment planning considerations. Analyses included stratification as to the types of institutions, academic, hospital based, or free standing., Results: For many treatment parameters there are discrepancies between the patterns of practice determined by the surveys and the consensus guidelines for radiotherapy treatment of adenocarcinoma of the rectum and sigmoid. Significant differences in practice among the stratified institution types were found in only a few parameters.

Purpose: The 1989 Patterns of Care Study included treatment planning for early breast cancer. A Consensus Committee of radiation physicists and oncologists determined current guidelines and developed questionnaires to determine treatment planning and delivery processes used by the participating institutions (e.g., use of portal films). This article presents and analyzes the results of that survey., Methods and Materials: The survey included 449 respondents, distributed as follows: 136 (30%) from Strata I (academic facilities); 169 (38%) from Strata II (hospital based facilities); and 144 (32%) from Strata III (freestanding facilities). The treatment planning procedures surveyed included: whether individualized tissue compensators are used, whether inhomogeneity corrections are used in dose calculations, the use of computerized tomography, whether isodose distributions for external beam tangents and interstitial implants are generated, the use of lymphoscintigraphy, immobilization devices, simulations, portal films, etc., Results: The survey results demonstrated that out of 305 patients from Strata I and II institutions, 237 (78%) had simulated tangential fields. Consistent with this finding is that 76% of patients from Strata I and II institutions were immobilized, while only 51% of Strata III patients were. Moreover, only 18 out of the 449 (4%) of cases did not have any type of external beam dose distribution calculated--presumably, in these cases missing tissue compensation would be unlikely. On the other hand, 41% of the Strata II, 27% of Strata III, but only 19% of Strata I (p < 0.0002) cases received CT. Surprisingly, 19% of the Strata I, 35% of the Strata II, and 25% of the Strata III (p = 0.0011) patients received lymphoscintigraphy, perhaps reflecting the use of wide tangents to encompass the internal mammary nodes in these patients. In terms of optimizing treatments, 74% of Strata I, 70% of Strata II, and 78% of Strata III patients had wedges used on both tangential fields, although in 5, 12, and 14%, respectively, no beam modification of any sort was used. Furthermore, it should be noted that in 7% of the Strata I, 23% of Strata II, and 37% of Strata III cases there was no attempt to reduce the divergence of the tangential fields into the lung. On the other hand, if one considers the 135 (of 449) patients where matching of the tangential and supraclavicular fields was applicable, 41% of Strata I, 22% of Strata II and 46% of Strata III patients had those fields matched in a vertical plane, which would involve sophisticated alignment procedures. Quality control of treatment delivery was high: 97% of all surveyed received portal films at least once. The use of thermoluminescent dosimetry (TLD) to measure the dose to the contralateral breast was of little interest: only 4 of the 305 Strata I and II patients received in vivo measurements., Conclusions: This national survey has established the patterns of treatment planning for early breast cancer. It shows a generally consistent approach-although a number of statistically significant variations have been identified.

Purpose: The Patterns of Care Study (PCS) of patients treated in 1988-89 included "patterns of treatment planning" for radiotherapy of carcinoma of the uterine cervix. A Consensus Committee of radiation physicists and oncologists established current guidelines and developed questionnaires to assess the treatment planning process (i.e., the general structure, methodology, and tools) of institutions involved in the Patterns of Care Study. This paper reports the findings of the assessment., Methods and Materials: The PCS surveyed 73 radiotherapy facilities, of which 21 are academic institutions (AC), 26 hospital-based facilities (HB), and 26 free-standing centers (FS). In total, 242 cases were assessed with 39% from academic centers, 33% from hospital-based centers, and 28% from free-standing centers. The survey collected treatment planning information such as the use of computed tomography (CT), simulation procedure, contouring of patient outline, tumor or target delineation, identification of critical structures, method of dose prescription (point or isodose), etc. Data was also obtained concerning implant boosts, e.g., radioisotope used, use of midline block for external beam treatment, availability of remote afterloader, practice of interstitial implants, combination with hyperthermia, etc., Results: There is a high degree of compliance relative to the basic treatment planning standards. For example, 171 cases (out of 173) from AC and HB institutions included simulation and 169 used port film; for cases from FS centers, 61 out of 69 involved simulation and 66 out of 69 included port film. Most institutions used linacs (231 out of 242); in five cases, Co-60 units and in six cases betatron was used. In terms of treatment planning, 53% used skin contours, but only 14% had target volume delineation, with AC and HB being slightly more conscientious in these efforts. Critical organs did not appear to be explicitly considered in external beam treatment planning, with only 3% outlining the bladder, 5% the rectum, and less than 1% the small bowel. Only 11% of the centers used CT in treatment planning, and none reported the use of magnetic resonance imaging (MRI). For patients receiving implants, about 40% had midline blocking during external beam treatment, of which one out of three were shielded by standard blocks and two out of three with customized ones. About 11% of the patients receiving implants were treated with remote afterloading devices, 5% received interstitial implants, and none were treated in combination with hyperthermia., Conclusion: The treatment planning aspects of radiotherapy of carcinoma of the cervix have been established by this Patterns of Care Study Survey. There is a high level of uniformity in the approach. Some variations exist among centers in the different strata.

Purpose: Treatment planning has been defined differently at various institutions to encompass tasks ranging from the initial evaluation of the patient to the delivery of the treatment as well as a more narrow view, focused primarily on isodose computation. To evaluate the impact of much of the new treatment-planning technology that has become available, it is necessary to define and develop recommended guidelines for the treatment-planning process., Methods and Materials: The 1989 Patterns of Care Study (PCS) included questionnaires to access treatment planning practices currently in use for the entire census of oncology facilities in the United States. These questionnaires were developed by a consensus committee consisting of both physicists and radiation oncologists whose charge was to formulate a description of current treatment-planning practices. The description was based on the committee's experience and knowledge of the treatment-planning process considered to be widely available and in general use, as well as a review of the literature. From the description of the treatment-planning process, a set of guidelines for treatment planning was developed for prostate as well as each of the other disease sites included in the PCS. Data from the study defined the general structure, methodology, process, and tools used by each institution involved in the Patterns of Care Survey Study. National averages for all of the variables were calculated with weighted averages, with the weights reflecting the sample design and number of patients in the different types of facilities. The data were stratified according to academic, hospital, or free-standing facility and were compared with the Consensus Guidelines for Treatment Planning of the Prostate., Discussion: Based on the consensus statement, the treatment-planning process was separated into the following categories: (a) Treatment-Planning Workup, (b) Treatment Plan Implementation, (c) Treatment Delivery, (d) Treatment Verification, and (e) Quality Assurance. The results from the survey were summarized for each category and compared with the consensus statement., Conclusions: Although there is an increasing trend toward using computed tomography (CT) information to acquire individualized patient data, volume definition and localization are often completed in the simulator without the direct use of CT information (47%). As more sophisticated beam arrangements and blocking are used, one needs to look at the full three-dimensional (3D) volume to ensure that there are no marginal misses due to blocking and beam arrangement. Improved and more widespread use of immobilization devices is also required with conformal treatments and reduced margins. The results of the survey helped to identify and establish the standard of practice for treatment planning of the prostate as well as to provide documentation for better defining a complete description of the treatment planning process. Well-documented guidelines will provide more consistent treatment of patients, which should have an impact on outcome.

Purpose: To conduct a survey of the process of treatment planning for the radiation treatment of Hodgkin's Disease in the United States, and to compare survey results with consensus guidelines as determined by recognized experts., Methods and Materials: A consensus committee developed guidelines for the radiotherapeutic management of Hodgkin's Disease. A series of survey forms were designed to evaluate the standards of practice and compare these with the consensus guidelines. A total of 61 facilities divided evenly into the strata of academic, hospital based, and free standing had eligible Hodgkin's Disease cases. There were 275 eligible cases of Hodgkin's Disease evaluated. Data collected from the radiation oncology records included treatment-specific parameters such as energy, dose, blocking, and calculations, as well as treatment planning practices. Statistical analysis was performed on each data element and for all institution strata., Results: For a number of treatment parameters, there were some discrepancies note between the current United States practice and the consensus guidelines. Some significant differences were found in practice between the stratified institution types. A representative sample of results are: the majority of Hodgkin's Disease patients are treated with x-ray energies in the recommended range, between 4 and 10 MV. Standard mantle (for upper extended field treatment) and modified spade (for lower extended field treatments) are the fields of choice for all types of facilities. The consensus guidelines recommended that dose calculations at multiple points be obtained; however, 15% of patients in the survey received only a single point calculation. Current irregular field dosimetry calculation software does not take account of inhomogeneities. Thirty percent of Hodgkin's Disease patients do not receive a gap calculation for the abutment of upper and lower extended fields. In 70% of treatment fields, no compensation is used. Very few patients receive any kind of in vivo dosimetry check., Conclusion: The survey served to verify that, in general, Hodgkin's Disease treatment planning at all strata of institution has kept pace with recommended practice as delineated in current literature and texts. Small pockets of practice still need improvement in technique and equipment. Changes in practice were identified that can contribute to improved dose uniformity and accuracy.

Purpose: To conduct a study of the structure and process of treatment planning in the United States., Methods and Materials: A Patterns of Care treatment planning consensus committee developed a survey form that was used to gather data for 106 items relating to the structure and process of treatment planning. These questions were general in nature and not specific to any particular disease site. Seventy-three facilities were randomly selected for site visits from the 1321 radiation therapy facilities in the United States: 21 academic, 26 hospital, and 26 free-standing. During the site visit the facility physicist, assisted by the site-visit physicist, completed the form., Results: Twenty-nine percent of facilities have cobalt-60 machines; 25% have 4 MV linacs; 75% have photon energies in the range of 5-8 MV; and less than 10% have energies greater than 20 MV. Academic facilities led hospital and free-standing facilities by about 30 percentage points in the availability of all electron energies (88 vs. 58%, approximately, in the range 4-13 MeV and scaling downward to about 60 vs. 30% at the highest energies). The national averages for the availability of Cs-137, Ir-192, and I-125 were 87, 73, and 44%, respectively. Computerized tomography (CT) scanning is not available or not used in 15% of hospital and free-standing facilities. Ninety-six percent of facilities have treatment planning computers; at 10% of facilities physicians do not participate in treatment planning. The estimated national averages of facilities having formal quality assurance (QA) programs for treatment planning systems, simulators, film processors, and blocking systems are 44, 79, 62, and 55%, respectively. Sixty-three percent of facilities obtain independent machine calibrations., Conclusion: This is the first patterns of treatment planning study carried out in the United States and the results reported here will establish a baseline for future studies. The present study has identified some elements that were unexpected, such as the percentage of facilities lacking formal QA programs for treatment planning systems; however, it has not established any impact of such findings. It is recommended that future studies include the availability of new technologies such as multileaf collimation, dynamic wedges, digital portal imaging, and CT simulation. With the increasing nationwide concern with the cost of health care, we must continue to monitor the implementation, use, and impact on treatment outcome of new and expensive technologies.

Commissioning measurements for a multi-leaf collimator installed on a dual energy accelerator with 6 and 15 MV photons are described. Detailed dosimetric characterization of the multi-leaf collimator is a requirement for modeling the collimator with treatment planning software. Measurements include a determination of the penumbra width, leaf transmission, between-leaf leakage, and localization of the leaf ends and sides. Standard radiographic film was used for the penumbra measurements, and separate experiments using radiochromic film and thermoluminescent dosimeters were performed to verify that distortions of the dose distribution at an edge due to changing energy sensitivity of silver bromide film are negligible. Films were analyzed with a scanning laser densitometer with a 210 micron spot. Little change in the penumbra edge distribution was noted for different positions of a leaf in the field. Experiments localizing the physical end of the leaves showed less than 1 mm deviation from the 50% decrement line. This small difference is attributed to the shaped end on the leaves. One side of a single leaf corresponded to the 50% decrement line, but the opposite face was aligned with a lower value. This difference is due to the tongue and groove used to decrease between-leaf leakage. For both energies, approximately 2% of photons incident on the multi-leaf collimator are transmitted and an additional 0.5% leakage occurs between the leaves. Alignment of the leaves to form a straight edge results in a penumbra profile which compares favorably with the standard technique of using alloy blocks. When the edge is stepped, the isodose lines follow the leaf pattern and the boundary is poorly defined compared to divergent blocks.

Clinical studies have been initiated in conformal radiotherapy using a computer controlled multi-leaf collimator. Quantitative dosimetry and treatment planning studies comparing field shaping by lead alloy blocks and the multi-leaf collimator demonstrate the clinical acceptability of the multi-leaf collimator. Sixteen patients with tumors in multiple sites have received some part of their treatments with both blocking systems. Studies of dosimetry and field shaping show that the multi-leaf collimator produces clinically acceptable blocking for most field shapes and disease sites. The 80-20% penumbra was characterized for a wide range of shaped beams. For straight edges perpendicular to the leaf travel, the penumbra of measured dose distributions from the multi-leaf collimator is equal to conventional divergent blocking. When the multi-leaf collimator leaves approach a contour at an angle, the penumbra increases. At forty-five degrees, the maximum angle of approach, the penumbra is approximately 4 mm wider than that for divergent blocks. Three-dimensional treatment planning demonstrates that equivalent dose distributions can be obtained from the two field shaping systems. The multi-leaf collimator can be used effectively and efficiently to treat a variety of disease sites. Its optimal utility may be in treating complex fields--five or more shaped coplanar or non-coplanar beams. It is well suited for conformal therapy applications.

Various aspects of multileaf collimator (MLC) design are examined relative to clinical requirements. The characteristics studied included: (a) irregular field edge definition or "effective" penumbra, (b) optimum field coverage for the multileaf portion of the field, and (c) leaf velocity. A film dosimetry technique was developed to measure the rapid 2-dimensional change in dose at an edge defined by a multileaf collimator with the segments staggered. The method applies a correction factor which allows for the changing ratio of scattered to primary photons at the field edge so that the energy dependence of the film is corrected. Stepped lead alloy blocks were irradiated with 6 MV photons to obtain films simulating a double-focused multileaf collimator, and the results were compared to films of fields shaped with standard divergent blocks. The effect of the shape of the leaf face (the end of the leaf) on penumbra was also studied. Proper shaping of the leaf ends may eliminate the need to exactly match beam divergence so that the mechanical of the collimator system is simplified. Leaves having several different end shapes and moving horizontally to intercept a vertical beam were compared to the divergent design where a straight face moves along an arc. The measurements showed that the "effective" penumbra (measured as the distance from the 80 to 20% isodose lines) for the multileaf collimator is a function of the angle between the direction of leaf motion and the edge defined by the leaves. In addition, all leaf end shapes showed some increase in penumbra compared to standard divergent blocking and also had increasing penumbra width as they moved over or back from the field center line. A total of 459 treatment fields and six disease sites were examined to determine the percentage of fields potentially shaped by multileaf segments of specified length. This study showed 93% of the fields had lengths of 30 cm or less and 99% had widths of 25 cm or less. A study conducted to determine the required leaf velocity to shape various target volume configurations during complete rotation (at 1 RPM) showed that a leaf speed of at least 1.5 cm/sec at isocenter is needed for dynamic conformal treatment.

Variability in patient positioning was determined by analyzing simulation and portal film measurements for 318 portals in 51 patients treated with external beam radiotherapy to the head and neck. Several indicators of error in patient positioning were examined: random error, a measure of the deviation of all portal films from the average portal film position, systematic error, a measure of the difference between the average portal film and the simulation film, and total uncertainty, a measure of the overall deviation, including both random and systematic uncertainties. The median differences noted were 0.4 cm, 0.6 cm, and 0.7 cm, for Random Error, Systematic Error, and Total Uncertainty, respectively. The treatment fields analyzed in this study show a substantial treatment-to-treatment and simulation-to-treatment variability in patient positioning. The methods described provide an improved means for the systematic analysis of variability in patient positioning.

Procedures and techniques developed for the negative pi-meson (pion) radiotherapy program at the Los Alamos Meson Physics Facility, Los Alamos, NM, are reviewed and described. A particular pion patient is followed through the entire planning and treatment sequence to describe CT scanning procedures, bolus and collimator and treatment techniques developed to minimize positioning errors (less than 5 mm). Comparison of 2-D and 3-D isodose calculations developed at Los Alamos showed differences of less than 10% attributable to multiple scattering effects and the computational models used. Treatment verification methods using in vivo ion chamber dosimetry generally confirmed the prescribed dose delivery within 10% and using TLD within 18%.

Early and late delayed effects of up to 20 fractions of pions and X rays were investigated in the mouse lung. The whole thorax of female CD-1 mice was irradiated under Ethrane/O2 anesthesia. Respiration rate was measured by whole body plethysmography at biweekly to monthly intervals. With signs of irreversible respiratory distress, animals were sacrificed and their lungs evaluated histologically. In addition to the effect of fractionation, the influence of dose-rate and anesthesia was studied as well. The degree of injury for the most predominant lesions (macrophage accumulation, fibrosis, vascular congestion) was scored, and the correlation with the relative change in respiratory rate and survival was analyzed. This analysis showed the primary lesion to be radiation pneumonitis at a median survival time of approximately 100 days. Focal fibrosis was observed to occur soon thereafter, and no evidence was obtained for an independent second wave of fibrotic injury. Fibrosis seemed primarily the result of pathological organization in areas with heavy concentration of macrophages. It was observed that the mice were unusually sensitive, with a single dose X ray ED50/180 of 8.8 Gy. A similar value was found for unanesthetized mice. This might have been the result of performing these studies at an altitude of 2100 m. The fractionation effect also seemed more pronounced, with alpha/beta values of 0.6 Gy for X rays and 4 Gy for pions, which is significantly lower compared to reported values. At the pion dose-rate of 0.25 Gy.min-1, RBE values for single doses were 0.9 when compared to high dose-rate X rays, and 1.36 at equivalent dose rates. This clearly shows that significant repair occurs during the relatively low dose-rate pion irradiations. With smaller doses per fraction, the dose-rate effect became less dominant, and for 20 fractions of pions the RBE was 1.4 compared to fractionated high dose-rate X rays. These RBE's are similar to values reported for acute effects in skin.

The results of cell killing by pion beams of different peak widths, ranges and sizes used in therapy are reported. Cultured hamster cells (V79) suspended in gelatin were used. The results indicate that: 1) there are no significant differences in cell-killing between pion beams of different ranges but of the same peak width; 2) there is a slight decrease in biological effectiveness with increasing peak width; and 3) the range-modulation functions used to produce uniform cell-killing are satisfactory for intermediate-range pion beams, but slight corrections may be required for shorter- and longer-range pion beams.

Two hundred twenty-eight patients were treated at the Los Alamos Meson Physics Facility (LAMPF) with negative pi-mesons (pions) between 1974 and 1981. Of these, 19 patients with metastatic disease were treated in pilot studies. Following the clinical determination of relative biological effectiveness (RBE) of pions, 209 patients were treated in site and dose searching studies beginning in 1977. Advanced but regionally localized cancers that were considered poorly responsive to conventional therapy were selected for treatment. A wide range of treatment fractions (22 to 45) and of total dose (1800 to 4200 cGy at the 80% isodose level) to the prescribed target volumes was explored. A follow-up observation period of between 4.5 and 9 years has been completed. The analysis focuses on 129 patients receiving pion therapy alone. Thirty-six (28%) had persisting local tumor control of which 12 (9%) suffered complications of treatment. The results varied among treatment sites, for example: prostate cancer, 18/21 (86%) locally controlled, 6/21 (29%) complications; head and neck, 8/31 (26%) locally controlled, 1/31 (3%) complications; and pancreas, none controlled and no complications. Analysis of dose-fraction response suggests a steep rising curve of complications beyond the dose level of 3750 cGy minimum, 4700 cGy maximum, in 38 fractions. The tumor control response has a broader and ill-defined curve possibly due to the heterogeneity of tumor types. The RBE for late effects in normal tissues appeared to be higher than that for acute effects although the mixture of tumor types, sites, dose, and fractionation made this estimate highly uncertain. No late secondary neoplastic changes in pion irradiated tissues were seen. It is concluded that pions can locally ablate some advanced cancers, often without significant sequelae, but that the optimum therapeutic range is critical. The Los Alamos data may be of use to ongoing pion studies in Canada and Switzerland.

Clinical investigations of pi meson radiotherapy were conducted by the Cancer Research and Treatment Center of the University of New Mexico and the Los Alamos National Laboratory from 1974 until 1982. Two hundred and thirty patients have been treated for a variety of locally advanced primary and metastatic neoplasms. One hundred and ninety-six patients have been followed for a minimum of 18 months. Crude survival data range from 11% for unresectable pancreatic carcinoma to 82% for Stages C and D1 adenocarcinoma of the prostate. Acute tolerance of normal tissues is approximately 4500 pion rad in 36 fractions over 7 weeks. Severe chronic reactions have appeared with increasing frequency after doses in excess of 4000 pion rad.