Modernization of safety environment for a dedicated beamline for proton ocular therapy.

BACKGROUND: Proton therapy is an effective treatment for ocular melanoma, and other tumors of the eye. The fixed horizontal beamline dedicated to ocular treatments at Massachusetts General Hospital was originally commissioned in 2002, with much of the equipment, safety features, and practices dating back to an earlier implementation at Harvard Cyclotron in the 1970s. PURPOSE: To describe the experience of reevaluation and enhancement of the safety environment for one of the longest continuously operating proton therapy programs. METHODS: Several enhancements in quality control had been introduced throughout the years of operation, as described in this manuscript, to better align the practice with the evolving standards of proton therapy and the demands of a modern hospital. We spotlight the design and results of the failure mode and effect analysis (FMEA), and subsequent actions introduced to mitigate the modes associated with elevated risk. The findings of the FMEA informed the specifications for the new software application, which facilitated the improved management of the treatment workflow and the image-guidance aspects of ocular treatments. RESULTS: Eleven failure modes identified as having the highest risk are described. Six of these were mitigated with the clinical roll-out of a new application for image-guided radiation therapy (IGRT). Others were addressed through task automation, the broader introduction of checklists, and enhancements in pre-treatment staff-led time-out. CONCLUSIONS: Throughout the task of modernizing the safety system of our dedicated ocular beamline, FMEA proved to be an effective instrument in soliciting inputs from the staff about safety and workflow concerns, helping to identify steps associated with elevated failure risks. Risks were reduced with the clinical introduction of a new IGRT application, which integrates quality management tools widely recognized for their role in risk mitigation: automation of the data transfer and workflow steps, and with the introduction of checklists and redundancy cross-checks.

A Systematic Comparison of Dose Distributions Delivered in 125I Plaque Brachytherapy and Proton Radiation Therapy for Ocular Melanoma.

PURPOSE: To characterize dose distributions with 125I plaque brachytherapy compared with proton radiation therapy for ocular melanoma for relevant clinical scenarios, based on tumor base diameter (d), apical height (h), and location. METHODS AND MATERIALS: Plaque and proton treatment plans were created for 4 groups of cases: (1) REF: 39 instances of reference midsize circular-base tumor (d = 12 mm, h = 5 mm), in locations varying by retinal clock hours and distance to fovea, optic disc, and corneal limbus; (2) SUP: 25 superiorly located; (3) TEMP: 25 temporal; and (4) NAS: 25 nasally located tumors that were a fixed distance from the fovea but varying in d (6-18 mm) and h (3-11 mm). For both modalities, 111 unique scenarios were characterized in terms of the distance to points of interest, doses delivered to fovea, optic disc, optic nerve at 3 mm posterior to the disc (ON@3mm), lens, and retina. Comparative statistical evaluation was performed with the Mann-Whitney U test. RESULTS: Superior dose distributions favored plaque for sparing of (1) fovea in large (d + h ≥ 21 mm) NAS tumors; (2) ON@3mm in REF cases located ≤4 disc diameters from disc, and in NAS overall. Protons achieved superior dose sparing of (1) fovea and optic disc in REF, SUP, and TEMP; (2) ON@3mm in REF >4 disc diameters from disc, and in SUP and TEMP; and (3) the lens center overall and lens periphery in REF ≤6 mm from the corneal limbus, and in TEMP with h = 3 mm. Although protons could completely spare sections of the retina, plaque dose was more target conformal in the high-dose range (50% and 90% of prescription dose). CONCLUSIONS: Although comparison between plaque and proton therapy is not straightforward because of the disparity in dose rate, prescriptions, applicators, and delivery techniques, it is possible to identify distinctions between dose distributions, which could help inform decisions by providers and patients.

A Comparison of Treatment Outcomes after Standard Dose (70 Gy) versus Reduced Dose (50 Gy) Proton Radiation in Patients with Uveal Melanoma.

OBJECTIVE: To compare outcomes in a large patient cohort with small-medium tumors located within 1 disc diameter (DD) of the optic nerve and/or fovea treated with 50 Gy or 70 Gy proton therapy. DESIGN: Retrospective cohort study. SUBJECTS: A total of 1120 patients with uveal melanomas ≤ 15 mm in largest basal diameter, ≤ 5 mm in height, located within 1 DD of the optic nerve and/or fovea, who received primary treatment with protons between 1975 and 2016 at Massachusetts Eye and Ear/Massachusetts General Hospital. METHODS: The rates of outcomes were estimated using the Kaplan-Meier method. Differences between the radiation dose groups were tested using the log-rank test. MAIN OUTCOME MEASURES: Local tumor recurrence, melanoma-related mortality, and visual acuity preservation (≥ 20/200, ≥ 20/40). RESULTS: Local tumor recurrence was observed in 1.8% of the 50 Gy group and 1.5% of the 70 Gy group. The median time to recurrence was 30.7 months for patients treated with 50 Gy and 32.0 months for those treated with 70 Gy (P = 0.28). Five-year rates of vision retention (≥20/40, ≥ 20/200) were 19.4% and 49.3% for patients treated with 50 Gy and 16.4% and 40.7% in those treated with 70 Gy. Ten-year rates of melanoma-related mortality were 8.4% in the 50 Gy group and 8.9% in the 70 Gy group (P = 0.47). CONCLUSIONS: Comparable rates of local control are achieved treating small-medium tumors near the optic nerve and/or fovea with 50 Gy or 70 Gy proton therapy, supporting the use of the lower dose in patients with these tumor characteristics.

Proton beam irradiation of uveal melanoma involving the iris, ciliary body and anterior choroid without surgical localisation (light field).

AIMS: To assess treatment outcomes after proton beam irradiation (PBI) without surgical localisation of uveal melanomas involving the iris, ciliary body and anterior choroid. METHODS: Retrospective chart review of 125 patients evaluated at Massachusetts Eye and Ear and treated with PBI using a light field set-up without localisation surgery between November 1975 and April 2017. The tumours were characterised as follows: iris (n=18, 14.4%), ciliary body (n=12, 9.6%), iridociliary (n=58, 46.4%), ciliochoroidal (n=24, 19.2%) and iridociliochoroidal (n=13, 10.4%). The tumours were measured by transillumination and ultrasonography before treatment. Tumours with posterior margin located less than two disc diameters from the ora serrata were treated using the light field technique. Patient outcomes after PBI were evaluated. RESULTS: Most patients had good vision at the time of tumour diagnosis (69.6% had baseline visual acuity (VA) of ≥20/40). Median VA at last follow-up (median follow-up: 72.1 months) was 20/63. Recurrences occurred in 12 patients (9.6%) at a median time of 4.0 years post-treatment. Recurrences were treated by repeat PBI (n=5) or enucleation (n=7). Secondary enucleation was performed in 18 patients (14.4%), and 61.1% of these were due to complications. Neovascular glaucoma (NVG) developed in 21 patients (16.8%). Of seven patients who developed NVG after anti-vascular endothelial growth factor (anti-VEGF) therapies became available, five were treated with intravitreal Avastin injections (23.8% of patients with NVG). Of 69 patients diagnosed with cataract after treatment, 51 (73.9%) were characterised as radiation-related. Death from metastatic uveal melanoma occurred in 20.8% of the cohort, with a median follow-up of 10.1 years. CONCLUSIONS: Patients treated with PBI using a light field set-up technique experience good outcomes after irradiation. Eye preservation and retention of good VA are seen in the majority of cases, and tumour recurrence is low.

Characterization of an Iodinated Rectal Spacer for Prostate Photon and Proton Radiation Therapy.

PURPOSE: Conventional rectal spacers (nonI-SPs) are low-contrast on computed tomography (CT), often necessitating magnetic resonance imaging for accurate delineation. A new formulation of spacers (I-SPs) incorporates iodine to improve radiopacity and CT visualization. We characterized placement, stability, and plan quality of I-SPs compared to nonI-SPs. METHODS AND MATERIALS: Patients with intact prostate cancer (n = 50) treated with I-SPs and photons were compared to randomly selected patients (n = 50) with nonI-SPs (photon or proton therapy). The I-SP was contoured on the planning CT and cone beam CTs at 3 timepoints: first, middle, and final treatment (n = 200 scans). I-SPs Hounsfield units (HU), volume, surface area (SA), centroid position relative to prostate centroid, and distance between prostate/rectum centroids were compared on the planning CTs between each cohort. I-SP changes were evaluated on cone beam CTs over courses of treatment. Dosimetric evaluations of plan quality and robustness were performed. I-SP was tested in a phantom to characterize its relative linear stopping power for protons. RESULTS: I-SPs yielded a distinct visible contrast on planning CTs compared to nonI-SPs (HU 138 vs 12, P < .001), allowing delineation on CT alone. The delineated volume and SA of I-SPs were smaller than nonI-SPs (volume 8.9 vs 10.6 mL, P < .001; SA 28 vs 35 cm2, P < .001), yet relative spacer position and prostate-rectal separation were similar (P = .79). No significant change in HU, volume, SA, or relative position of the I-SPs hydrogel occurred over courses of treatment (all P > .1). Dosimetric analysis concluded there were no significant changes in plan quality or robustness for I-SPs compared to nonI-SPs. The I-SP relative linear stopping power was 1.018, necessitating HU override for proton planning. CONCLUSIONS: I-SPs provide a manifest CT contrast, allowing for delineation on planning CT alone with no magnetic resonance imaging necessary. I-SPs radiopacity, size, and relative position remained stable over courses of treatment from 28 to 44 fractions. No changes in plan quality or robustness were seen comparing I-SPs and nonI-SPs.

Predicting Patient-specific Dosimetric Benefits of Proton Therapy for Skull-base Tumors Using a Geometric Knowledge-based Method.

PURPOSE: To predict the organ at risk (OAR) dose levels achievable with proton beam therapy (PBT), solely based on the geometric arrangement of the target volume in relation to the OARs. A comparison with an alternative therapy yields a prediction of the patient-specific benefits offered by PBT. This could enable physicians at hospitals without proton capabilities to make a better-informed referral decision or aid patient selection in model-based clinical trials. METHODS AND MATERIALS: Skull-base tumors were chosen to test the method, owing to their geometric complexity and multitude of nearby OARs. By exploiting the correlations between the dose and distance-to-target in existing PBT plans, the models were independently trained for 6 types of OARs: brainstem, cochlea, optic chiasm, optic nerve, parotid gland, and spinal cord. Once trained, the models could estimate the feasible dose-volume histogram and generalized equivalent uniform dose (gEUD) for OAR structures of new patients. The models were trained using 20 patients and validated using an additional 21 patients. Validation was achieved by comparing the predicted gEUD to that of the actual PBT plan. RESULTS: The predicted and planned gEUD were in good agreement. Considering all OARs, the prediction error was +1.4 ± 5.1 Gy (mean ± standard deviation), and Pearson's correlation coefficient was 93%. By comparing with an intensity modulated photon treatment plan, the model could classify whether an OAR structure would experience a gain, with a sensitivity of 93% (95% confidence interval: 87%-97%) and specificity of 63% (95% confidence interval: 38%-84%). CONCLUSIONS: We trained and validated models that could quickly and accurately predict the patient-specific benefits of PBT for skull-base tumors. Similar models could be developed for other tumor sites. Such models will be useful when an estimation of the feasible benefits of PBT is desired but the experience and/or resources required for treatment planning are unavailable.

Practice Patterns Analysis of Ocular Proton Therapy Centers: The International OPTIC Survey.

PURPOSE: To assess the planning, treatment, and follow-up strategies worldwide in dedicated proton therapy ocular programs. METHODS AND MATERIALS: Ten centers from 7 countries completed a questionnaire survey with 109 queries on the eye treatment planning system (TPS), hardware/software equipment, image acquisition/registration, patient positioning, eye surveillance, beam delivery, quality assurance (QA), clinical management, and workflow. RESULTS: Worldwide, 28,891 eye patients were treated with protons at the 10 centers as of the end of 2014. Most centers treated a vast number of ocular patients (1729 to 6369). Three centers treated fewer than 200 ocular patients. Most commonly, the centers treated uveal melanoma (UM) and other primary ocular malignancies, benign ocular tumors, conjunctival lesions, choroidal metastases, and retinoblastomas. The UM dose fractionation was generally within a standard range, whereas dosing for other ocular conditions was not standardized. The majority (80%) of centers used in common a specific ocular TPS. Variability existed in imaging registration, with magnetic resonance imaging (MRI) rarely being used in routine planning (20%). Increased patient to full-time equivalent ratios were observed by higher accruing centers (P=.0161). Generally, ophthalmologists followed up the post-radiation therapy patients, though in 40% of centers radiation oncologists also followed up the patients. Seven centers had a prospective outcomes database. All centers used a cyclotron to accelerate protons with dedicated horizontal beam lines only. QA checks (range, modulation) varied substantially across centers. CONCLUSIONS: The first worldwide multi-institutional ophthalmic proton therapy survey of the clinical and technical approach shows areas of substantial overlap and areas of progress needed to achieve sustainable and systematic management. Future international efforts include research and development for imaging and planning software upgrades, increased use of MRI, development of clinical protocols, systematic patient-centered data acquisition, and publishing guidelines on QA, staffing, treatment, and follow-up parameters by dedicated ocular programs to ensure the highest level of care for ocular patients.

Visual Outcomes after Proton Beam Irradiation for Choroidal Melanomas Involving the Fovea.

PURPOSE: To report visual outcomes in patients undergoing proton beam irradiation of tumors located within 1 disc diameter of the fovea. DESIGN: Retrospective review. PARTICIPANTS: Patients with choroidal melanoma involving the fovea treated with proton beam therapy between 1975 and 2009. METHODS: Three hundred fifty-one patients with choroidal melanomas located 1 disc diameter (DD) or less from the fovea and more than 1 DD away from the optic nerve were included in this study. In a subgroup of 203 of the patients with small and medium choroidal melanomas, the effect of a reduced dose of radiation, 50 Gy (relative biological effectiveness [RBE]) versus 70 Gy (RBE), on visual outcomes was analyzed. The Kaplan-Meier method and Cox regression analysis were performed to calculate cumulative rates of vision loss and to assess risk factors for vision loss, respectively. MAIN OUTCOME MEASURES: Visual acuity and radiation complications, which included radiation maculopathy, papillopathy, retinal detachment, and rubeosis, were assessed. RESULTS: Three hundred fifty-one patients were included in this study with a mean follow-up time of 68.7 months. More than one-third of patients (35.5%) retained 20/200 or better vision 5 years after proton beam irradiation. For those patients with a baseline visual acuity of 20/40 or better, 16.2% of patients retained this level of vision 5 years after proton beam irradiation. Tumor height less than 5 mm and baseline visual acuity 20/40 or better were associated significantly with a better visual outcome (P < 0.001). More than two-thirds (70.4%) of patients receiving 50 Gy (RBE) and nearly half (45.1%) of patients receiving 70 Gy (RBE) retained 20/200 or better vision 5 years after treatment, but this difference was not significant. Approximately 20% of patients with these smaller macular tumors retained 20/40 vision or better 5 years after irradiation. CONCLUSIONS: The results of this retrospective analysis demonstrate that despite receiving a full dose of radiation to the fovea, many patients with choroidal melanoma with foveal involvement maintain useful vision. A radiation dose reduction from 70 to 50 Gy (RBE) did not seem to increase the proportion of patients who retain usable vision.

[18F]-Fluoromisonidazole positron emission tomography/computed tomography visualization of tumor hypoxia in patients with chordoma of the mobile and sacrococcygeal spine.

PURPOSE: To investigate [18F]-fluoromisonidazole positron emission tomography/computed tomography (FMISO-PET/CT) detection of targetable hypoxic subvolumes (HSVs) in chordoma of the mobile or sacrococcygeal spine. METHODS AND MATERIALS: A prospective, pilot study of 20 patients with primary or locally recurrent chordoma of the mobile or sacrococcygeal spine treated with proton or combined proton/photon radiation therapy (RT) with or without surgery was completed. The FMISO-PET/CT was performed before RT and after 19.8-34.2 GyRBE (relative biologic effectiveness). Gross tumor volumes were delineated and HSVs defined including voxels with standardized uptake values ≥1.4 times the muscle mean. Clinical characteristics and treatments received were compared between patients with and without HSVs. RESULTS: The FMISO-PET/CT detected HSVs in 12 of 20 patients (60%). Baseline and interval HSV spatial concordance varied (0%-94%). Eight HSVs were sufficiently large (≥5 cm(3)) to potentially allow an intensity modulated proton therapy boost. Patients with HSVs had significantly larger gross tumor volumes (median 410.0 cm(3) vs 63.4 cm(3); P=.02) and were significantly more likely to have stage T2 tumors (5 of 12 vs 0 of 8; P=.04). After a median follow-up of 1.8 years (range, 0.2-4.4 years), a local recurrence has yet to be observed. Three patients developed metastatic disease, 2 with HSVs. CONCLUSIONS: Detection of targetable HSVs by FMISO-PET/CT within patients undergoing RT with or without surgery for treatment of chordoma of the mobile and sacrococcygeal spine is feasible. The study's inability to attribute interval HSV changes to treatment, rapidly changing hypoxic physiology, or imaging inconsistencies is a limitation. Further study of double-baseline FMISO-PET/CT and hypoxia-directed RT dose escalation, particularly in patients at high risk for local recurrence, is warranted.

Evaluation of the dosimetric impact of interfractional anatomical variations on prostate proton therapy using daily in-room CT images.

PURPOSE: To quantify interfractional anatomical variations and their dosimetric impact during the course of fractionated proton therapy (PT) of prostate cancer and to assess the robustness of the current treatment planning techniques. METHODS: Simulation and daily in-room CT scans from ten prostate carcinoma patients were analyzed. PT treatment plans (78 Gy in 39 fractions of 2 Gy) were created on the simulation CT, delivering 25 fractions to PTV1 (expanded from prostate and seminal vesicles), followed by 14 boost fractions to PTV2 (expanded from prostate). Plans were subsequently applied to daily CT, with beams aligned to the prostate center in the sagittal plane. For five patients having a sufficiently large daily imaging volume, structure contours were manually drawn, and plans were evaluated for all CT sets. For the other five patients, the plans were evaluated for six selected fractions. The daily CT was matched to the simulation CT through deformable registration. The registration accuracy was validated for each fraction, and the three patients with a large number of accurately registered fractions were used for dose accumulation. RESULTS: In individual fractions, the coverage of the prostate, seminal vesicles, and PTV1 was generally maintained at the corresponding prescription dose. For PTV2, the volume covered by the fractional prescription dose of 2 Gy (i.e., V2) was, on average, reduced by less than 3% compared to the simulation plan. Among the 225 (39 x 5 + 6 x 5) fractions examined, 15 showed a V2 reduction larger than 5%, of which ten were caused by a large variation in rectal gas, and five were due to a prostate shift in the craniocaudal direction. The fractional dose to the anterior rectal wall was found to increase for one patient who had large rectal gas volume in 25 of the 39 fractions, and another who experienced significant prostate volume reduction during the treatment. The fractional bladder dose generally increased with decreasing fullness. In the total accumulated dose for the three patients after excluding a few fractions with inaccurate registration due to a large amount of rectal gas (a condition inconsistent with RTOG protocol), 98.5%, 96.6%, and 98.2% of the PTV2 received the prescription dose of 78 Gy. The V75 and V70 of the anterior rectal wall and bladder both remained within tolerance. CONCLUSIONS: The results confirm that the PT planning techniques and dose constraints used at our institution ensure that target coverage to the prescription dose is maintained in the presence of interfractional anatomical variations. Dose coverage in individual fractions can be compromised, and normal tissue dose increased, due to deviations in the bladder and rectal volume compared to the simulation plans or progressive changes in the prostate volume during the treatment. Deviations from the plan can be reduced with efforts aimed at maintaining consistent daily patient anatomy.

A case study in proton pencil-beam scanning delivery.

PURPOSE: We completed an implementation of pencil-beam scanning (PBS), a technology whereby a focused beam of protons, of variable intensity and energy, is scanned over a plane perpendicular to the beam axis and in depth. The aim of radiotherapy is to improve the target to healthy tissue dose differential. We illustrate how PBS achieves this aim in a patient with a bulky tumor. METHODS AND MATERIALS: Our first deployment of PBS uses "broad" pencil-beams ranging from 20 to 35 mm (full-width-half-maximum) over the range interval from 32 to 7 g/cm(2). Such beam-brushes offer a unique opportunity for treating bulky tumors. We present a case study of a large (4,295 cc clinical target volume) retroperitoneal sarcoma treated to 50.4 Gy relative biological effectiveness (RBE) (presurgery) using a course of photons and protons to the clinical target volume and a course of protons to the gross target volume. RESULTS: We describe our system and present the dosimetry for all courses and provide an interdosimetric comparison. DISCUSSION: The use of PBS for bulky targets reduces the complexity of treatment planning and delivery compared with collimated proton fields. In addition, PBS obviates, especially for cases as presented here, the significant cost incurred in the construction of field-specific hardware. PBS offers improved dose distributions, reduced treatment time, and reduced cost of treatment.

Monte Carlo calculation of imaging doses from diagnostic multidetector CT and kilovoltage cone-beam CT as part of prostate cancer treatment plans.

PURPOSE: To calculate imaging doses to the rectum, bladder, and femoral heads as part of a prostate cancer treatment plans, assuming an image guided radiation therapy (IGRT) procedure involving either the multidetector CT (MDCT) or kilovoltage cone-beam CT (kV CBCT). METHODS: This study considered an IGRT treatment plan for a prostate carcinoma patient involving 50.4 Gy from 28 initial fractions and a boost of 28.8 Gy from 16 fractions. A total of 45 CT imaging procedures, each involving a MDCT or a kV CBCT scan procedure, were carefully modeled using the MCNPX code version 2.5.0. The MDCT scanner model is based on the GE LightSpeed 16-MDCT scanner and the kV CBCT scanner model is based on the Varian On-Board Imager using parameters reported by the CT manufacturers and literatures. A patient-specific treatment planning CT data set was used to construct the phantom for the dose calculation. The target, organs-at-risk (OARs), and background voxels in the CT data set were categorized into six tissue types according to CT numbers for Monte Carlo calculations. RESULTS: For a total of 45 imaging procedures, it was found that the rectum received 78.4 and 76.7 cGy from MDCT and kV CBCT, respectively. The bladder received slightly greater doses of 82.4 and 77.9 cGy, while the femoral heads received much higher doses of 182.3 and 141.3 cGy from MDCT and kV CBCT, respectively. To investigate the impact of these imaging doses on treatment planning, OAR doses from MDCT or kV CBCT imaging procedures were added to the corresponding dose matrix reported by the original treatment plans to construct dose volume histograms. It was found that after the imaging dose is added, the rectum volumes irradiated to 75 and 70 Gy increased from 13.9% and 21.2%, respectively, in the original plan to 14.8% and 21.8%. The bladder volumes receiving 80 Gy increased to 4.6% from 4.1% in the original plan and the volume receiving 75 Gy increased to 7.9% from 7.5%. All values remained within the tolerance levels: V70<25%, V75 <15% for rectum and V75 < 25%, V80 < 15% for bladder. The irradiation of femoral heads was also acceptable with no volume receiving >45 Gy. CONCLUSIONS: IGRT procedures can irradiate the OARs to an imaging dose level that is great enough to require careful evaluation and perhaps even adjustment of original treatment planning in order to still satisfy the dose constraints. This study only considered one patient CT because the CT x rays cover a relatively larger volume of the body and the dose distribution is considerably more uniform than those associated with the therapeutic beams. As a result, the dose to an organ from CT imaging doses does not vary much from one patient to the other for the same CT settings. One factor that would potentially affect such CT dose level is the size of the patient body. More studies are needed to develop accurate and convenient methods of accounting for the imaging doses as part of treatment planning.

Life, liberty, and the pursuit of protons: an evidence-based review of the role of particle therapy in the treatment of prostate cancer.

Proton beam therapy (PBT) has been in use for a number of decades, though interest in PBT for localized prostate cancer has grown substantially in recent years. Protons offer the theoretical potential of achieving dose escalation and decreasing toxicity by capitalizing on unique physical dose deposition characteristics to avoid normal tissue. Although it has proven effective in a number of malignancies including as a means for dose escalation in prostate cancer, there is little published clinical data to support its comparative superiority over alternative forms of conformal radiation for prostate cancer. This review article explores the current evidence and clinical experience supporting PBT for prostate cancer, the uncertainties and controversies associated with this innovative technology, its potential economic implications, and future promise.

Advanced-technology radiation therapy in the management of bone and soft tissue sarcomas.

BACKGROUND: For patients with sarcomas, radiotherapy can be used as neoadjuvant, adjuvant, or primary local therapy, depending on the site and type of sarcoma, the surgical approach, and the efficacy of chemotherapy. METHODS: The authors review the current status of advanced technology radiation therapy in the management of bone and soft tissue sarcoma. RESULTS: Advances in radiotherapy have resulted in improved treatment for bone and soft tissue sarcomas. Intensity-modulated radiation therapy (IMRT) uses modifications in the intensity of the photon-beam from a linear accelerator across the irradiated fields to enhance dose conformation in three dimensions. For proton-beam radiation therapy, the nuclei of hydrogen atoms are accelerated in cyclotrons or synchrotrons, extracted, and transported to treatment rooms where the proton beam undergoes a series of modifications that conform the dose in a particular patient to the tumor target. Brachytherapy and intraoperative radiation therapy have generally been used to treat microscopic residual disease in patients with sarcomas. These technologies deliver dose to tumor cells with irradiation of limited volumes of normal tissue. Patients who may benefit from technically advanced radiotherapy include those with skull base and spine/paraspinal sarcomas, Ewing's sarcoma, and retroperitoneal/extremity sarcomas. CONCLUSIONS: Advances in radiation therapy technology, particularly IMRT, proton-beam or other charged-particle radiation therapy, brachytherapy, and intraoperative radiation therapy, have led to improved treatment for patients with bone and soft tissue sarcomas.

A treatment planning comparison of intensity modulated photon and proton therapy for paraspinal sarcomas.

PURPOSE: A comparative treatment planning study has been undertaken between intensity modulated (IM) photon therapy and IM proton therapy (IMPT) in paraspinal sarcomas, so as to assess the potential benefits and limitations of these treatment modalities. In the case of IM proton therapy, plans were compared also for two different sizes of the pencil beam. Finally, a 10% and 20% dose escalation with IM protons was planned, and the consequential organ at risk (OAR) irradiation was evaluated. METHODS AND MATERIALS: Plans for 5 patients were computed for IM photons (7 coplanar fields) and protons (3 coplanar beams), using the KonRad inverse treatment planning system (developed at the German Cancer Research Center). IMPT planning was performed assuming 2 different sizes of the pencil beam: IMPT with a beam of full width at half-maximum of 20 mm, and IMPT with a "mini-beam" (IMPT(M), full width at half-maximum = 12 mm). Prescribed dose was 77.4 Gy or cobalt Gray equivalent (CGE) for protons to the gross tumor volume (GTV). Surface and center spinal cord dose constraint for all techniques was 64 and 53 Gy/CGE, respectively. Tumor and OAR dose-volume histograms were calculated. Results were analyzed using dose-volume histogram parameters, inhomogeneity coefficient, and conformity index. RESULTS: Gross tumor volume coverage was optimal and equally homogeneous with both IM photon and IM proton plans. Compared to the IM photon plans, the use of IM proton beam therapy leads to a substantial reduction of the OAR total integral dose in the low-level to mid-dose level. Median heart, lung, kidney, stomach, and liver mean dose and dose at the 50% volume level were consistently reduced by a factor of 1.3 to 25. Tumor dose homogeneity in IMPT(M) plans was always better than with IMPT planning (median inhomogeneity coefficient, 0.19 vs. 0.25). IMPT dose escalation (to 92.9 CGE to the GTV) was possible in all patients without exceeding the normal-tissue dose limits. CONCLUSIONS: These results suggest that the use of IM photon therapy, when compared to IM protons, can result in similar levels of tumor conformation. IM proton therapy, however, reduces the OAR integral dose substantially, compared to IM photon radiation therapy. As a result, tumor dose escalation was always possible with IM proton planning, within the maximal OAR dose constraints. In IM proton planning, reducing the size of the proton pencil beam (using the "mini-beam") improved the dose homogeneity, but it did not have a significant effect on the dose conformity.

Viscosity as an experimental tool in studying the mechanism of stereoselective and product-selective chemical transformations through frictional impositions.

In the present Account, we examine the viscosity dependence as a function of temperature, pressure, and solvent polarity for the double inversion in the photolytic azoalkane denitrogenation, the thermal isomerization of housanes, and stereochemical memory versus Curtin-Hammett behavior in radical-cation rearrangements. The analysis of these stereoselective and product-selective viscosity studies in terms of the simple free-volume model demonstrates the utility of frictional effects for the elucidation of complex reaction mechanisms in molecular transformations.

Viscosity-dependent diastereoselectivity and product selectivity in the photodenitrogenation of a spirocyclopropane-substituted, DBH-type azoalkane.

In the photodenitrogenation of the spirocyclopropane-substituted azoalkane 1 in alcoholic solvents of various viscosity (from 0.6 to 89.2 cP) to the diastereomeric housanes 2 (major product) and bicyclo[3.2.0]heptenes 3 (minor product), the same (within experimental error) viscosity dependence is observed in the diastereoselectivity of the housane 2 formation as well as in the product selectivity (2/3). These viscosity effects corroborate the intermediacy of the diazenyl diradical 1DZ as a common branching point for the housane 2 and bicycloheptene 3 formation. In contrast, the diastereoselectivity of the bicycloheptene 3 generation is independent of viscosity, which implies that a nitrogen-free, symmetrical 1,4 diradical serves as precursor to the rearrangement products. The free-volume model of viscosity is employed to rationalize the product selectivity as well as the diastereoselectivity.

Stereochemical memory versus Curtin-Hammett behavior in the rearrangement of 1,3-cyclopentanediyl radical cations derived from housanes through structural effects on conformational control.

The electron-transfer-catalyzed rearrangement of the housanes 1 affords regioselectively the two cyclopentenes 2 and 3 by 1,2-migration of a group at the methano bridge. Appropriate ring annelation in the intermediary cyclopentane-1,3-diyl radical cation 1(*+) changes the stereochemical course of the rearrangement from complete stereoselectivity (stereochemical memory) for the structurally simple housane 1b to partial loss of stereoselectivity through competing conformational interconversion for the tricyclic housane 1c. Additional cyclohexane annelation, as in the tetracyclic housane 1a, results in complete loss of stereocontrol through Curtin-Hammett behavior, as substantiated by the viscosity dependence on the product ratio of the rearrangement. Whereas in the radical cations 1b(*+) and 1c(*+) the 1,2-shifts (k(2) and k(3)) are faster than the conformational anti <==> syn change (k(1), k(-1)), the reverse applies for the radical cation 1a(*+). Such structural manipulation of conformational effects in radical cation rearrangements has hitherto not been documented.

Viscosity dependence of the denitrogenation quantum yield in azoalkane photolysis: experimental evidence for reversible formation of the diazenyl diradical.

[reaction: see text] Experimental evidence is reported for the reversible formation of the singlet diazenyl diradical ((1)DZ), photolytically generated from the structurally elaborate DBH-type azoalkane. Reversiblity of the (1)DZ formation manifests itself through the decrease of the photodenitrogenation quantum yield over a ca. 40-fold viscosity variation (from 0.5 to 19.3 cP). This viscosity behavior is interpreted in terms of frictional effects on the competitive reaction modes of the diazenyl diradical.