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To adopt Monte Carlo (MC) simulations as an independent dose calculation method for proton pencil beam radiotherapy, an interface that converts the plan information in DICOM format into MC components such as geometries and beam source is a crucial element. For this purpose, a DICOM-RT Ion interface (https://github.com/topasmc/dicom-interface) has been developed and integrated into the TOPAS MC code to perform such conversions on-the-fly. DICOM-RT objects utilized in this interface include Ion Plan (RTIP), Ion Beams Treatment Record (RTIBTR), CT image, and Dose. Beamline geometries, gantry and patient coordinate systems, and fluence maps are determined from RTIP and/or RTIBTR. In this interface, DICOM information is processed and delivered to a MC engine in two steps. A MC model, which consists of beamline geometries and beam source, to represent a treatment machine is created by a DICOM parser of the interface. The complexities from different DICOM types, various beamline configurations and source models are handled in this step. Next, geometry information and beam source are transferred to TOPAS on-the-fly via the developed TOPAS extensions. This interface with two treatment machines was successfully deployed into our automated MC workflow which provides simulated dose and LET distributions in a patient or a water phantom automatically when a new plan is identified. The developed interface provides novel features such as handling multiple treatment systems based on different DICOM types, DICOM conversions on-the-fly, and flexible sampling methods that significantly reduce the burden of handling DICOM based plan or treatment record information for MC simulations.

Purpose Treatment planning for proton therapy requires the relative proton stopping power ratio (RSP) information of the patient for accurate dose calculations. RSP are conventionally obtained after mapping of the Hounsfield units (HU) from a calibrated patient computed tomography (CT). One or multiple CT are needed for a given treatment which represents additional, undesired dose to the patient. For prostate cancer, magnetic resonance imaging (MRI) scans are the gold standard for segmentation while offering dose-less imaging. We here quantify the clinical applicability of converted MR images as a substitute for intensity modulated proton therapy (IMPT) treatment of the prostate. Methods MRCAT (Magnetic Resonance for Calculating ATtenuation) is a Philips-developed technology which produces a synthetic CT image consisting of five HU from a specific set of MRI acquisitions. MRCAT and original planning CT data sets were obtained for ten patients. An IMPT plan was generated on the MRCAT for each patient. Plans were produced such that they fulfill the prostate protocol in use at Massachusetts General Hospital (MGH). The plans were then recomputed onto the nominal planning CT for each patient. Robustness analyses (±5 mm setup shifts and ±3.5 % range uncertainties) were also performed. Results Comparison of MRCAT plans and their recomputation onto the planning CT plan showed excellent agreement. Likewise, dose perturbations due to setup shifts and range uncertainties were well within clinical acceptance demonstrating the clinical viability of the approach. Conclusions This work demonstrate the clinical acceptability of substituting MR converted RSP images instead of CT for IMPT planning of prostate cancer. This further translates into higher contouring accuracy along with lesser imaging dose.

Purpose/objective(s) Patients with node-positive (LN+) uterine or cervical cancer often require adjuvant radiation to the pelvis and para-aortics, resulting in significant acute and late gastrointestinal (GI) and genitourinary (GU) toxicity. Proton therapy allows for more conformal delivery of radiation dose. The objective was to prospectively evaluate the safety and efficacy of proton beam radiation therapy (RT) for patients with LN+ uterine or cervical cancer requiring RT. Materials/methods Patients with IIIC uterine and pT1,2N1M0 cervical cancer status post hysterectomy and lymphadenectomy were eligible. Sequential (uterine) and concurrent (cervical) chemotherapy were allowed. Exclusion criteria included life expectancy Results 21 patients completed RT between 10/2013 and 10/2018. Median follow-up is 52.3 months (range, 11.2-63.4). Median age was 59.7 years (range, 31.5-79.2). 15 patients had IIIC uterine cancer (13 endometrioid) and 6 patients had cervical cancer. 52% received sequential and 29% received concurrent chemotherapy. Median dose was 45.0 Gy (RBE). 20 (95%) received VB boost. 4 received PRT and 17 EFRT. Acute grade 2 and 3 GI toxicity was 24% and 14%, respectively. Acute grade 2 and 3 GU toxicity was 10% and 0%, respectively. Acute grade 2 and 3 hematologic toxicity was 24% and 0%, respectively. To date, there have been no late toxicities > grade 3. The 2-year PFS was 81% (95% CI, 56%-92%). Of the 5 patients that recurred, 4 were peritoneal and 1 was abdominal wall and lung; no recurrences were in-field. The 2-year OS was 86% (95% CI, 62%-95%). Conclusion Scanned proton beam RT appears effective in preventing local-regional recurrence in LN+ patients with uterine and cervical cancer undergoing adjuvant radiation. Acute toxicity is low and severe late effects have not been observed but await longer follow-up. Author disclosure A.L. Russo: None. K.D. Bernstein: None. S.P. Nisbet: None. N. Horick: None. N. Depauw: None. B.Y. Yeap: None. H.M. Kooy: None. T.F. DeLaney: None. A.H. Russell: None.

Purpose Proton therapy can allow for superior avoidance of normal tissues. A widespread consensus has been reached that proton therapy should be used for patients with curable pediatric brain tumor to avoid critical central nervous system structures. Brainstem necrosis is a potentially devastating, but rare, complication of radiation. Recent reports of brainstem necrosis after proton therapy have raised concerns over the potential biological differences among radiation modalities. We have summarized findings from the National Cancer Institute Workshop on Proton Therapy for Children convened in May 2016 to examine brainstem injury. Methods and Materials Twenty-seven physicians, physicists, and researchers from 17 institutions with expertise met to discuss this issue. The definition of brainstem injury, imaging of this entity, clinical experience with photons and photons, and potential biological differences among these radiation modalities were thoroughly discussed and reviewed. The 3 largest US pediatric proton therapy centers collectively summarized the incidence of symptomatic brainstem injury and physics details (planning, dosimetry, delivery) for 671 children with focal posterior fossa tumors treated with protons from 2006 to 2016. Results The average rate of symptomatic brainstem toxicity from the 3 largest US pediatric proton centers was 2.38%. The actuarial rate of grade ≥2 brainstem toxicity was successfully reduced from 12.7% to 0% at 1 center after adopting modified radiation guidelines. Guidelines for treatment planning and current consensus brainstem constraints for proton therapy are presented. The current knowledge regarding linear energy transfer (LET) and its relationship to relative biological effectiveness (RBE) are defined. We review the current state of LET-based planning. Conclusions Brainstem injury is a rare complication of radiation therapy for both photons and protons. Substantial dosimetric data have been collected for brainstem injury after proton therapy, and established guidelines to allow for safe delivery of proton radiation have been defined. Increased capability exists to incorporate LET optimization; however, further research is needed to fully explore the capabilities of LET- and RBE-based planning.

Purpose/Objective(s) Our institution developed proton stereotactic radiosurgery (PSRS) techniques and treated patients since 1961. A recent upgrade from passive scattering (PS) delivery to pencil beam scanning (PBS) required validation of this modality for small fields. We describe the adaptation of an existing clinical PSRS service to PBS. We outline potential advantages and disadvantages the modality has to offer. Materials/Methods Patient alignment is determined from 2D/3D x-ray corrections of surgically implanted fiducials. End-to-end tests using a skull phantom were performed to validate a change of treatment planning system (TPS). PSRS PS fields from prior years established applicable parameters for dose, range, modulation, field size and aspect ratio for PBS validation. 18 fields were created to verify agreement with the TPS. A diamond detector was used to measure SOBP doses and film to measure profiles. A QA phantom enabled simultaneous measurement with film and diamond detector. X-rays were used to verify detector alignment prior to measurements. A hybrid 2D/3D γ-analysis was used to assess lateral profiles. Plans were generated for previously treated patients and used to perform end-to-end tests. These included 6 AVM, 3 pituitaries and 1 cavernous sinus lesion. Clinical directives were obtained from the original plans. Results End-to-end phantom tests conformed sub-mm alignment. Distal and proximal depth agreement were 0.10 ± 0.66% and 0.74 ± 0.48 mm. Isocenter and shallow depth dose agreement was -1.7 ± 2.9% and 2.5 ± 5.1%, respectively. Global 2%/1mm/10% γ-analysis resulted in pass rates of 97.2 ± 4.8%. 24 clinical fields were delivered. Dose agreement was -2.8 ± 2.7%. Global 3%/1mm/10% γ- analysis PASS rates were 99.5 ± 1.4%. Conclusion We have revalidated SRS appropriate fiducial-based alignment and defined a small-field QA process using a diamond detector & film to demonstrate PSRS performed with PBS delivery is accurate. Proton delivery systems and TPS modeling can differ significantly. Therefore, validation and plan quality results should not be generalized to all systems. Proton range uncertainties play an important role in determining the appropriateness of PSRS. PBS does not offer distal benefits for small targets compared to passive scattering using range compensators. Larger SRS targets with irregular shapes may benefit from intensity variations and variable modulation offered by PBS. VMAT generally provides slightly superior target coverage for small pituitary lesion, but target coverage for larger pituitary lesions not abutting the optic structures and prescribed to lower doses are more comparable for VMAT and PBS while lowering integral dose. Our validation effort enabled the transition of an active PSRS program from PS to PBS. Author Disclosure M. Bussiere: None. J. Daartz: None. J. Verburg: Employee; Massachusetts General Hospital. Research Grant; National Cancer Institute. N. Depauw: None. H.M. Kooy: None. J.S. Loeffler: Employee; Massachusetts General Hospital. Advisory Board; Mevion. P.H. Chapman: None. H.A. Shih: Employee; Dartmouth Hitchcock. Research Grant; AbbVie, NIH. Honoraria; UpToDate. Consultant; Cleveland Clinic. Speaker's Bureau; prIME Oncology. advisory; The Radiosurgery Society. director of clinical operations; Massachusetts General Hospital. clinical operational leader; Massachusetts General Hospital.

Purpose At present, proton craniospinal irradiation (CSI) for growing children is delivered to the whole vertebral body (WVB) to avoid asymmetric growth. We aimed to demonstrate the feasibility and potential clinical benefit of delivering vertebral body sparing (VBS) versus WVB CSI with passively scattered (PS) and intensity modulated proton therapy (IMPT) in growing children treated for medulloblastoma. Methods and Materials Five plans were generated for medulloblastoma patients, who had been previously treated with CSI PS proton radiation therapy: ( 1 ) single posteroanterior (PA) PS field covering the WVB (PS-PA-WVB); ( 2 ) single PA PS field that included only the thecal sac in the target volume (PS-PA-VBS); ( 3 ) single PA IMPT field covering the WVB (IMPT-PA-WVB); ( 4 ) single PA IMPT field, target volume including thecal sac only (IMPT-PA-VBS); and ( 5 ) 2 posterior-oblique (−35°, +35°) IMPT fields, with the target volume including the thecal sac only (IMPT2F-VBS). For all cases, 23.4 Gy (relative biologic effectiveness [RBE]) was prescribed to 95% of the spinal canal. The dose, linear energy transfer, and variable-RBE-weighted dose distributions were calculated for all plans using the tool for particle simulation, version 2, Monte Carlo system. Results IMPT VBS techniques efficiently spared the anterior vertebral bodies (AVBs), even when accounting for potential higher variable RBE predicted by linear energy transfer distributions. Assuming an RBE of 1.1, the V10 Gy(RBE) decreased from 100% for the WVB techniques to 59.5% to 76.8% for the cervical, 29.9% to 34.6% for the thoracic, and 20.6% to 25.1% for the lumbar AVBs, and the V20 Gy(RBE) decreased from 99.0% to 17.8% to 20.0% for the cervical, 7.2% to 7.6% for the thoracic, and 4.0% to 4.6% for the lumbar AVBs when IMPT VBS techniques were applied. The corresponding percentages for the PS VBS technique were higher. Conclusions Advanced proton techniques can sufficiently reduce the dose to the vertebral body and allow for vertebral column growth for children with central nervous system tumors requiring CSI. This was true even when considering variable RBE values. A clinical trial is planned for VBS to the thoracic and lumbosacral spine in growing children.

Setup and range uncertainties compromise radiotherapy plan robustness. We introduce a method to evaluate the clinical effect of these uncertainties on the population using tumor control probability (TCP) and normal tissue complication probability (NTCP) models. Eighteen oropharyngeal cancer patients treated with curative intent were retrospectively included. Both photon (VMAT) and proton (IMPT) plans were created using a planning target volume as planning objective. Plans were recalculated for uncertainty scenarios: two for range over/undershoot (IMPT) or CT-density scaling (VMAT), six for shifts. An average shift scenario ([Formula: see text]) was calculated to assess random errors. Dose differences between nominal and scenarios were translated to TCP (2 models) and NTCP (15 models). A weighted average (W_Avg) of the TCP\NTCP based on Gaussian distribution over the variance scenarios was calculated to assess the clinical effect of systematic errors on the population. TCP/NTCP uncertainties were larger in IMPT compared to VMAT. Although individual perturbations showed risks of plan deterioration, the [Formula: see text] scenario did not show a substantial decrease in any of the TCP endpoints suggesting evaluated plans in this cohort were robust for random errors. Evaluation of the W_Avg scenario to assess systematic errors showed in VMAT no substantial decrease in TCP endpoints and in IMPT a limited decrease. In IMPT, the W_Avg scenario had a mean TCP loss of 0%-2% depending on plan type and primary or nodal control. The W_Avg for NTCP endpoints was around 0%, except for mandible necrosis in IMPT (W_Avg: 3%). The estimated population impact of setup and range uncertainties on TCP/NTCP following VMAT or IMPT of oropharyngeal cancer patients was small for both treatment modalities. The use of TCP/NTCP models allows for clinical interpretation of the population effect and could be considered for incorporation in robust evaluation methods. Highlights: - TCP/NTCP models allow for a clinical evaluation of uncertainty scenarios. - For this cohort, in silico-PTV based IMPT plans and VMAT plans were robust for random setup errors. - Effect of systematic errors on the population was limited: mean TCP loss was 0%-2%.

Purpose This study aimed to assess the clinical impact of spot size and the addition of apertures and range compensators on the treatment quality of pencil beam scanning (PBS) proton therapy and to define when PBS could improve on passive scattering proton therapy (PSPT). Methods and Materials The patient cohort included 14 pediatric patients treated with PSPT. Six PBS plans were created and optimized for each patient using 3 spot sizes (∼12-, 5.4-, and 2.5-mm median sigma at isocenter for 90- to 230-MeV range) and adding apertures and compensators to plans with the 2 larger spots. Conformity and homogeneity indices, dose-volume histogram parameters, equivalent uniform dose (EUD), normal tissue complication probability (NTCP), and integral dose were quantified and compared with the respective PSPT plans. Results The results clearly indicated that PBS with the largest spots does not necessarily offer a dosimetric or clinical advantage over PSPT. With comparable target coverage, the mean dose (D mean ) to healthy organs was on average 6.3% larger than PSPT when using this spot size. However, adding apertures to plans with large spots improved the treatment quality by decreasing the average D mean and EUD by up to 8.6% and 3.2% of the prescribed dose, respectively. Decreasing the spot size further improved all plans, lowering the average D mean and EUD by up to 11.6% and 10.9% compared with PSPT, respectively, and eliminated the need for beam-shaping devices. The NTCP decreased with spot size and addition of apertures, with maximum reduction of 5.4% relative to PSPT. Conclusions The added benefit of using PBS strongly depends on the delivery configurations. Facilities limited to large spot sizes (>∼8 mm median sigma at isocenter) are recommended to use apertures to reduce treatment-related toxicities, at least for complex and/or small tumors.

Background In scanned proton beam therapy systematic deviations in spot size at iso-center can occur as a result of changes in the beam-line optics. There is currently no general guideline of the spot size accuracy required clinically. In this work we quantify treatment plan robustness to systematic spot size variations as a function of spot size and spot spacing, and we suggest guidelines for tolerance levels for spot size variations. Methods Through perturbation of spot size in treatment plans for 7 patients and a phantom, we evaluated the dose impact of systematic spot size variations of 5% up to 50%. We investigated the dependence on nominal spot size by studying scenarios with small, medium and large spot sizes for various inter-spot spacings. To come to tolerance levels, we used the Γ passing rate and dose-volume-histograms. Results Limits on spot size accuracy were extracted for 8 sites, 3 different spot sizes and 3 different inter-spot spacings. While the allowable spot size variation strongly depends on the spot size, the inter-spot spacing turned out to be only of limited influence. Conclusions Plan robustness to spot size variations strongly depend on spot size, with small spot plans being much more robust than larger spots plans. Inter-spot spacing did not influence plan robustness. Combining our results with existing literature, we propose limits of ±25%, ±20% and ±10% of the spot width σ , for spots with σ of 2.5, 5.0 and 10 mm in proton therapy spot scanning facilities, respectively.

Purpose: To shorten delivery times of intensity modulated proton therapy by reducing the number of energy layers in the treatment plan. Methods and Materials: We have developed an energy layer reduction method, which was implemented into our in-house-developed multicriteria treatment planning system "Erasmus-iCycle." The method consisted of 2 components: (1) minimizing the logarithm of the total spot weight per energy layer; and (2) iteratively excluding low-weighted energy layers. The method was benchmarked by comparing a robust "time-efficient plan" (with energy layer reduction) with a robust "standard clinical plan" (without energy layer reduction) for 5 oropharyngeal cases and 5 prostate cases. Both plans of each patient had equal robust plan quality, because the worst-case dose parameters of the standard clinical plan were used as dose constraints for the time-efficient plan. Worst-case robust optimization was performed, accounting for setup errors of 3 mm and range errors of 3% + 1 mm. We evaluated the number of energy layers and the expected delivery time per fraction, assuming 30 seconds per beam direction, 10 ms per spot, and 400 Giga-protons per minute. The energy switching time was varied from 0.1 to 5 seconds. Results: The number of energy layers was on average reduced by 45% (range, 30%-56%) for the oropharyngeal cases and by 28% (range, 25%-32%) for the prostate cases. When assuming 1, 2, or 5 seconds energy switching time, the average delivery time was shortened from 3.9 to 3.0 minutes (25%), 6.0 to 4.2 minutes (32%), or 12.3 to 7.7 minutes (38%) for the oropharyngeal cases, and from 3.4 to 2.9 minutes (16%), 5.2 to 4.2 minutes (20%), or 10.6 to 8.0 minutes (24%) for the prostate cases. Conclusions: Delivery times of intensity modulated proton therapy can be reduced substantially without compromising robust plan quality. Shorter delivery times are likely to reduce treatment uncertainties and costs. (C) 2015 Elsevier Inc. All rights reserved.

Purpose Proton radiation therapy is commonly used in young children with brain tumors for its potential to reduce late effects. However, some proton series report higher rates of brainstem injury (0%-16%) than most photon series (2.2%-8.6%). We report the incidence of brainstem injury and a risk factor analysis in pediatric patients with posterior fossa primary tumors treated with proton radiation therapy at our institution. Methods and Materials The study included 216 consecutive patients treated between 2000 and 2015. Dosimetry was available for all but 4 patients. Grade 2 to 5 late brainstem toxicity was assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Results The histologies include medulloblastoma (n=154, 71.3%), ependymoma (n=56, 25.9%), and atypical teratoid rhabdoid tumor (n=6, 2.8%). The median age at irradiation was 6.6 years (range, 0.5-23.1 years); median dose, 54 gray relative biological effectiveness (Gy RBE) (range, 46.8-59.4 Gy RBE); and median follow-up period, 4.2 years (range, 0.1-15.3 years) among 198 survivors. Of the patients, 83.3% received chemotherapy; 70.4% achieved gross total resection. The crude rate of injury was 2.3% in all patients, 1.9% in those with medulloblastoma, 3.6% in those with ependymoma, and 0% in those with atypical teratoid rhabdoid tumor. The 5-year cumulative incidence of injury was 2.0% (95% confidence interval, 0.7%-4.8%). The median brainstem dose (minimum dose received by 50% of brainstem) in the whole cohort was 53.6 Gy RBE (range, 16.5-56.8 Gy RBE); maximum point dose within the brainstem (Dmax), 55.2 Gy RBE (range, 48.4-60.5 Gy RBE); and mean dose, 50.4 Gy RBE (range, 21.1-56.7 Gy RBE). In the 5 patients with injury, the median minimum dose received by 50% of the brainstem was 54.6 Gy RBE (range, 50.2-55.1 Gy RBE); Dmax, 56.2 Gy RBE (range, 55.0-57.1 Gy RBE); mean dose, 51.3 Gy RBE (range, 45.4-54.4 Gy RBE); and median volume of the brainstem receiving ≥55 Gy RBE (V55), 27.4% (range, 0%-59.4%). Of the 5 patients with injury, 4 had a brainstem Dmax in the highest quartile (≥55.8 Gy RBE, P = .016) and a V55 in the highest tertile (>6.0%) of the cohort distribution (P = .047). Of the 5 patients with injury, 3 were aged >6 years (age range, 4.1-22.8 years), and 4 of 5 patients received chemotherapy and achieved gross total resection. Conclusions The incidence of injury in pediatric patients with posterior fossa tumors is consistent with previous reports in the photon setting. Our data suggest that when Dmax and V55 are kept

Purpose Setup, range, and anatomical uncertainties influence the dose delivered with intensity modulated proton therapy (IMPT), but clinical quantification of these errors for oropharyngeal cancer is lacking. We quantified these factors and investigated treatment fidelity, that is, robustness, as influenced by adaptive planning and by applying more beam directions. Methods and Materials We used an in-house treatment planning system with multicriteria optimization of pencil beam energies, directions, and weights to create treatment plans for 3-, 5-, and 7-beam directions for 10 oropharyngeal cancer patients. The dose prescription was a simultaneously integrated boost scheme, prescribing 66 Gy to primary tumor and positive neck levels (clinical target volume-66 Gy; CTV-66 Gy) and 54 Gy to elective neck levels (CTV-54 Gy). Doses were recalculated in 3700 simulations of setup, range, and anatomical uncertainties. Repeat computed tomography (CT) scans were used to evaluate an adaptive planning strategy using nonrigid registration for dose accumulation. Results For the recalculated 3-beam plans including all treatment uncertainty sources, only 69% (CTV-66 Gy) and 88% (CTV-54 Gy) of the simulations had a dose received by 98% of the target volume (D98%) >95% of the prescription dose. Doses to organs at risk (OARs) showed considerable spread around planned values. Causes for major deviations were mixed. Adaptive planning based on repeat imaging positively affected dose delivery accuracy: in the presence of the other errors, percentages of treatments with D98% >95% increased to 96% (CTV-66 Gy) and 100% (CTV-54 Gy). Plans with more beam directions were not more robust. Conclusions For oropharyngeal cancer patients, treatment uncertainties can result in significant differences between planned and delivered IMPT doses. Given the mixed causes for major deviations, we advise repeat diagnostic CT scans during treatment, recalculation of the dose, and if required, adaptive planning to improve adequate IMPT dose delivery.

Purpose To describe, in a setting of non-small cell lung cancer (NSCLC), the theoretical dosimetric advantages of proton arc stereotactic body radiation therapy (SBRT) in which the beam penumbra of a rotating beam is used to reduce the impact of range uncertainties. Methods and Materials Thirteen patients with early-stage NSCLC treated with proton SBRT underwent repeat planning with photon volumetric modulated arc therapy (Photon-VMAT) and an in-house-developed arc planning approach for both proton passive scattering (Passive-Arc) and intensity modulated proton therapy (IMPT-Arc). An arc was mimicked with a series of beams placed at 10° increments. Tumor and organ at risk doses were compared in the context of high- and low-dose regions, represented by volumes receiving >50% and Results In the high-dose region, conformality index values are 2.56, 1.91, 1.31, and 1.74, and homogeneity index values are 1.29, 1.22, 1.52, and 1.18, respectively, for 3 proton passive scattered beams, Passive-Arc, IMPT-Arc, and Photon-VMAT. Therefore, proton arc leads to a 30% reduction in the 95% isodose line volume to 3-beam proton plan, sparing surrounding organs, such as lung and chest wall. For chest wall, V30 is reduced from 21 cm 3 (3 proton beams) to 11.5 cm 3 , 12.9 cm 3 , and 8.63 cm 3 ( P =.005) for Passive-Arc, IMPT-Arc, and Photon-VMAT, respectively. In the low-dose region, the mean lung dose and V20 of the ipsilateral lung are 5.01 Gy(relative biological effectiveness [RBE]), 4.38 Gy(RBE), 4.91 Gy(RBE), and 5.99 Gy(RBE) and 9.5%, 7.5%, 9.0%, and 10.0%, respectively, for 3-beam, Passive-Arc, IMPT-Arc, and Photon-VMAT, respectively. Conclusions Stereotactic body radiation therapy with proton arc and Photon-VMAT generate significantly more conformal high-dose volumes than standard proton SBRT, without loss of coverage of the tumor and with significant sparing of nearby organs, such as chest wall. In addition, both proton arc approaches spare the healthy lung from low-dose radiation relative to photon VMAT. Our data suggest that IMPT-Arc should be developed for clinical use.

Purpose Dosimetric planning studies have described potential benefits for the use of proton radiation therapy (RT) for locally advanced breast cancer. We report acute toxicities and feasibility of proton delivery for 12 women treated with postmastectomy proton radiation with or without reconstruction. Methods and Materials Twelve patients were enrolled in an institutional review board-approved prospective clinical trial. The patients were assessed for skin toxicity, fatigue, and radiation pneumonitis during treatment and at 4 and 8 weeks after the completion of therapy. All patients consented to have photographs taken for documentation of skin toxicity. Results Eleven of 12 patients had left-sided breast cancer. One patient was treated for right-sided breast cancer with bilateral implants. Five women had permanent implants at the time of RT, and 7 did not have immediate reconstruction. All patients completed proton RT to a dose of 50.4 Gy (relative biological effectiveness [RBE]) to the chest wall and 45 to 50.4 Gy (RBE) to the regional lymphatics. No photon or electron component was used. The maximum skin toxicity during radiation was grade 2, according to the Common Terminology Criteria for Adverse Events (CTCAE). The maximum CTCAE fatigue was grade 3. There have been no cases of RT pneumonitis to date. Conclusions Proton RT for postmastectomy RT is feasible and well tolerated. This treatment may be warranted for selected patients with unfavorable cardiac anatomy, immediate reconstruction, or both that otherwise limits optimal RT delivery using standard methods.

Background and purpose Delivery of post-mastectomy radiation (PMRT) in women with bilateral implants represents a technical challenge, particularly when attempting to cover regional lymph nodes. Intensity modulated proton therapy (IMPT) holds the potential to improve dose delivery and spare non-target tissues. The purpose of this study was to compare IMPT to three-dimensional (3D) conformal radiation following bilateral mastectomy and reconstruction. Materials and methods Ten IMPT, 3D conformal photon/electron (P/E), and 3D photon (wide tangent) plans were created for 5 patients with breast cancer, all of whom had bilateral breast implants. Using RTOG guidelines, a physician delineated contours for both target volumes and organs-at-risk. Plans were designed to achieve 95% coverage of all targets (chest wall, IMN, SCV, axilla) to a dose of 50.4 Gy or Gy (RBE) while maximally sparing organs-at-risk. Results IMPT plans conferred similar target volume coverage with enhanced homogeneity. Both mean heart and lung doses using IMPT were significantly decreased compared to both P/E and wide tangent planning. Conclusions IMPT provides improved homogeneity to the chest wall and regional lymphatics in the post-mastectomy setting with improved sparing of surrounding normal structures for woman with reconstructed breasts. IMPT may enable women with mastectomy to undergo radiation therapy without the need for delay in breast reconstruction.

This study investigates whether 'pencil beam resampling', i.e. iterative selection and weight optimization of randomly placed pencil beams (PBs), reduces optimization time and improves plan quality for multi-criteria optimization in intensity-modulated proton therapy, compared with traditional modes in which PBs are distributed over a regular grid. Resampling consisted of repeatedly performing: (1) random selection of candidate PBs from a very fine grid, (2) inverse multi-criteria optimization, and (3) exclusion of low-weight PBs. The newly selected candidate PBs were added to the PBs in the existing solution, causing the solution to improve with each iteration. Resampling and traditional regular grid planning were implemented into our in-house developed multi-criteria treatment planning system 'Erasmus iCycle'. The system optimizes objectives successively according to their priorities as defined in the so-called 'wish-list'. For five head-and-neck cancer patients and two PB widths (3 and 6 mm sigma at 230 MeV), treatment plans were generated using: (1) resampling, (2) anisotropic regular grids and (3) isotropic regular grids, while using varying sample sizes (resampling) or grid spacings (regular grid). We assessed differences in optimization time (for comparable plan quality) and in plan quality parameters (for comparable optimization time). Resampling reduced optimization time by a factor of 2.8 and 5.6 on average (7.8 and 17.0 at maximum) compared with the use of anisotropic and isotropic grids, respectively. Doses to organs-at-risk were generally reduced when using resampling, with median dose reductions ranging from 0.0 to 3.0 Gy (maximum: 14.3 Gy, relative: 0%-42%) compared with anisotropic grids and from -0.3 to 2.6 Gy (maximum: 11.4 Gy, relative: -4%-19%) compared with isotropic grids. Resampling was especially effective when using thin PBs (3 mm sigma). Resampling plans contained on average fewer PBs, energy layers and protons than anisotropic grid plans and more energy layers and protons than isotropic grid plans. In conclusion, resampling resulted in improved plan quality and in considerable optimization time reduction compared with traditional regular grid planning.

The relative biological effectiveness (RBE) of passive scattered (PS) and pencil beam scanned (PBS) proton beam delivery techniques for uniform beam configurations was determined by clonogenic survival. The radiobiological impact of modulated beam configurations on cell survival occurring in- or out-of-field for both delivery techniques was determined with intercellular communication intact or physically inhibited. Cell survival responses were compared to those observed using a 6 MV photon beam produced with a linear accelerator. DU-145 cells showed no significant difference in survival response to proton beams delivered by PS and PBS or 6 MV photons taking into account a RBE of 1.1 for protons at the centre of the spread out Bragg peak. Significant out-of-field effects similar to those observed for 6 MV photons were observed for both PS and PBS proton deliveries with cell survival decreasing to 50-60% survival for scattered doses of 0.05 and 0.03 Gy for passive scattered and pencil beam scanned beams respectively. The observed out-of-field responses were shown to be dependent on intercellular communication between the in- and out-of-field cell populations. These data demonstrate, for the first time, a similar RBE between passive and actively scanned proton beams and confirm that out-of-field effects may be important determinants of cell survival following exposure to modulated photon and proton fields.

Purpose To report the early outcomes for children with high-risk neuroblastoma treated with proton radiotherapy (RT) and to compare the dose distributions for intensity-modulated photon RT (IMRT), three-dimensional conformal proton RT (3D-CPT), and intensity-modulated proton RT to the postoperative tumor bed. Methods and Materials All patients with high-risk (International Neuroblastoma Staging System Stage III or IV) neuroblastoma treated between 2005 and 2010 at our institution were included. All patients received induction chemotherapy, surgical resection of residual disease, high-dose chemotherapy with stem cell rescue, and adjuvant 3D-CPT to the primary tumor sites. The patients were followed with clinical examinations, imaging, and laboratory testing every 6 months to monitor disease control and side effects. IMRT, 3D-CPT, and intensity-modulated proton RT plans were generated and compared for a representative case of adjuvant RT to the primary tumor bed followed by a boost. Results Nine patients were treated with 3D-CPT. The median age at diagnosis was 2 years (range 10 months to 4 years), and all patients had Stage IV disease. All patients had unfavorable histologic characteristics (poorly differentiated histologic features in 8, N-Myc amplification in 6, and 1p/11q chromosomal abnormalities in 4). The median tumor size at diagnosis was 11.4 cm (range 7–16) in maximal dimension. At a median follow-up of 38 months (range 11–70), there were no local failures. Four patients developed distant failure, and, of these, two died of disease. Acute side effects included Grade 1 skin erythema in 5 patients and Grade 2 anorexia in 2 patients. Although comparable target coverage was achieved with all three modalities, proton therapy achieved substantial normal tissue sparing compared with IMRT. Intensity-modulated proton RT allowed additional sparing of the kidneys, lungs, and heart. Conclusions Preliminary outcomes reveal excellent local control with proton therapy for high-risk neuroblastoma, although distant failures continu to occur. Dosimetric comparisons demonstrate the advantage of proton RT compared with IMRT in this setting, allowing more conformal treatment and better normal tissue sparing.

This study is aimed at identifying the potential benefits of using a patient-specific aperture in proton beam scanning. For this purpose, an accurate Monte Carlo model of the pencil beam scanning (PBS) proton therapy (PT) treatment head at Massachusetts General Hospital (MGH) was developed based on an existing model of the passive double-scattering (DS) system. The Monte Carlo code specifies the treatment head at MGH with sub-millimeter accuracy. The code was configured based on the results of experimental measurements performed at MGH. This model was then used to compare out-of-field doses in simulated DS treatments and PBS treatments. For the conditions explored, the penumbra in PBS is wider than in DS, leading to higher absorbed doses and equivalent doses adjacent to the primary field edge. For lateral distances greater than 10 cm from the field edge, the doses in PBS appear to be lower than those observed for DS. We found that placing a patient-specific aperture at nozzle exit during PBS treatments can potentially reduce doses lateral to the primary radiation field by over an order of magnitude. In conclusion, using a patient-specific aperture has the potential to further improve the normal tissue sparing capabilities of PBS.

Proton, as well as other ion, beams applied by electro-magnetic deflection in pencil-beam scanning (PBS) are minimally perturbed and thus can be quantified a priori by their fundamental interactions in a medium. This a priori quantification permits an optimal reduction of characterizing measurements on a particular PBS delivery system. The combination of a priori quantification and measurements will then suffice to fully describe the physical interactions necessary for treatment planning purposes. We consider, for proton beams, these interactions and derive a 'Golden' beam data set. The Golden beam data set quantifies the pristine Bragg peak depth-dose distribution in terms of primary, multiple Coulomb scatter, and secondary, nuclear scatter, components. The set reduces the required measurements on a PBS delivery system to the measurement of energy spread and initial phase space as a function of energy. The depth doses are described in absolute units of Gy(RBE) mm² Gp⁻¹, where Gp equals 10⁹ (giga) protons, thus providing a direct mapping from treatment planning parameters to integrated beam current. We used these Golden beam data on our PBS delivery systems and demonstrated that they yield absolute dosimetry well within clinical tolerance.

Delivery of pencil beam scanning (PBS) requires the on-line measurement of several beam parameters. If the measurement is outside of specified tolerances and a binary threshold algorithm is used, the beam will be paused. Given instrumentation and statistical noise such a system can lead to many pauses which could increase the treatment time. Statistical quality control methods are typically used on manufacturing lines to monitor a process and give early detection of a gradual problem and stop the process if a deviation is statistically significant. These methods can be used to develop a more intuitive algorithm for (PBS) delivery systems that is robust and safe and leads to decreased treatment times. The Exponentially Weighted Moving Average (EWMA) control scheme monitors deviations in beam properties which are averaged over a specified number of measurements with greater weight applied to the more recent ones. Simulation of an EWMA-style algorithm safely detected shifts in random and systematic delivery errors without false alarms. Binary and EWMA methods can be combined for improved reliability without sacrificing patient safety. In the EWMA method, the mean of a beam property can be related to systematic uncertainties and the standard deviation can be related to random uncertainties. This method allows one to have separate interlock levels for each type of uncertainty and to detect systematic trends.

Pencil beam scanning (PBS) periodic quality assurance (QA) programs ensure the beam delivered to patients is within technical specifications. Two critical specifications for PBS delivery are the beam width and position. The aim of this study is to investigate whether a 2D ionization chamber array, such as the MatriXX detector (IBA Dosimetry, Schwarzenbruck, Germany), can be used to characterize submillimeter-sized PBS beam properties. The motivation is to use standard equipment, which may have pixel spacing coarser than the pencil beam size, and simplify QA workflow. The MatriXX pixels are cylindrical in shape with 4.5 mm diameter and are spaced 7.62 mm from center to center. Two major effects limit the ability of using the MatriXX to measure the spot position and width accurately. The first effect is that too few pixels sample the Gaussian shaped pencil beam profile and the second effect is volume averaging of the Gaussian profile over the pixel sensitive volumes. We designed a method that overcomes both limitations and hence enables the use of the MatriXX to characterize sub-millimeter-sized PBS beam properties. This method uses a cross-like irradiation pattern that is designed to increase the number of sampling data points and a modified Gaussian fitting technique to correct for volume averaging effects. Detector signals were calculated in this study and random noise and setup errors were added to simulate measured data. With the techniques developed in this work, the MatriXX detector can be used to characterize the position and width of sub-millimeter, σ = 0.7 mm, sized pencil beams with uncertainty better than 3% relative to σ. With the irradiation only covering 60% of the MatriXX, the position and width of σ = 0.9 mm sized pencil beams can be determined with uncertainty better than 3% relative to σ. If one were to not use a cross-like irradiation pattern, then the position and width of σ = 3.6 mm sized pencil beams can be determined with uncertainty better than 3% relative to σ. If one were to not use a cross-like pattern nor volume averaging corrections, then the position and width of σ = 5.0 mm sized pencil beams can be determined with uncertainty better than 3% relative to σ. This work helps to simplify periodic QA in proton therapy because more routinely used ionization chamber arrays can be used to characterize narrow pencil beam properties.

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.

Purpose Microdosimetric measurements were performed at Massachusetts General Hospital, Boston, MA, to assess the dose equivalent external to passively delivered proton fields for various clinical treatment scenarios. Methods and Materials Treatment fields evaluated included a prostate cancer field, cranial and spinal medulloblastoma fields, ocular melanoma field, and a field for an intracranial stereotactic treatment. Measurements were completed with patient-specific configurations of clinically relevant treatment settings using a silicon-on-insulator microdosimeter placed on the surface of and at various depths within a homogeneous Lucite phantom. The dose equivalent and average quality factor were assessed as a function of both lateral displacement from the treatment field edge and distance downstream of the beam's distal edge. Results Dose-equivalent value range was 8.3–0.3 mSv/Gy (2.5–60-cm lateral displacement) for a typical prostate cancer field, 10.8–0.58 mSv/Gy (2.5–40-cm lateral displacement) for the cranial medulloblastoma field, 2.5–0.58 mSv/Gy (5–20-cm lateral displacement) for the spinal medulloblastoma field, and 0.5–0.08 mSv/Gy (2.5–10-cm lateral displacement) for the ocular melanoma field. Measurements of external field dose equivalent for the stereotactic field case showed differences as high as 50% depending on the modality of beam collimation. Average quality factors derived from this work ranged from 2–7, with the value dependent on the position within the phantom in relation to the primary beam. Conclusions This work provides a valuable and clinically relevant comparison of the external field dose equivalents for various passively scattered proton treatment fields.

Purpose Evaluate the rationale for the proposals that prior to a wider use of proton radiation therapy there must be supporting data from phase III clinical trials. That is, would less dose to normal tissues be an advantage to the patient? Methods Assess the basis for the assertion that proton dose distributions are superior to those of photons for most situations. Consider the requirements for determining the risks of normal tissue injury, acute and remote, in the examination of the data from a trial. Analyze the probable cost differential between high technology photon and proton therapy. Evaluate the rationale for phase III clinical trials of proton vs photon radiation therapy when the only difference in dose delivered is a difference in distribution of low LET radiation. Results The distributions of biological effective dose by protons are superior to those by X-rays for most clinical situations, viz. for a defined dose and dose distribution to the target by protons there is a lower dose to non-target tissues. This superiority is due to these physical properties of protons: (1) protons have a finite range and that range is exclusively dependent on the initial energy and the density distribution along the beam path; (2) the Bragg peak; (3) the proton energy distribution may be designed to provide a spread out Bragg peak that yields a uniform dose across the target volume and virtually zero dose deep to the target. Importantly, proton and photon treatment plans can employ beams in the same number and directions (coplanar, non-co-planar), utilize intensity modulation and employ 4D image guided techniques. Thus, the only difference between protons and photons is the distribution of biologically effective dose and this difference can be readily evaluated and quantified. Additionally, this dose distribution advantage should increase the tolerance of certain chemotherapeutic agents and thus permit higher drug doses. The cost of service (not developmental) proton therapy performed in 3–5 gantry centers operating 14–16h/day and 6 days/week is likely to be equal to or less than twice that of high technology X-ray therapy. Conclusions Proton therapy provides superior distributions of low LET radiation dose relative to that by photon therapy for treatment of a large proportion of tumor/normal tissue situations. Our assessment is that there is no medical rationale for clinical trials of protons as they deliver lower biologically effective doses to non-target tissue than do photons for a specified dose and dose distribution to the target. Based on present knowledge, there will be some gain for patients treated by proton beam techniques. This is so even though quantitation of the clinical gain is less secure than the quantitation of reduction in physical dose. Were proton therapy less expensive than X-ray therapy, there would be no interest in conducting phase III trails. The talent, effort and funds required to conduct phase III clinical trials of protons vs photons would surely be more productive in the advancement of radiation oncology if employed to investigate real problems, e.g. the most effective total dose, dose fractionation, definition of CTV and GTV, means for reduction of PTV and the gains and risks of combined modality therapy.

Intensity modulated proton therapy (IMPT) implies the electromagnetic spatial control of well-circumscribed "pencil beams" of protons of variable energy and intensity. Proton pencil beams take advantage of the charged-particle Bragg peak-the characteristic peak of dose at the end of range-combined with the modulation of pencil beam variables to create target-local modulations in dose that achieves the dose objectives. IMPT improves on X-ray intensity modulated beams (intensity modulated radiotherapy or volumetric modulated arc therapy) with dose modulation along the beam axis as well as lateral, in-field, dose modulation. The clinical practice of IMPT further improves the healthy tissue vs target dose differential in comparison with X-rays and thus allows increased target dose with dose reduction elsewhere. In addition, heavy-charged-particle beams allow for the modulation of biological effects, which is of active interest in combination with dose "painting" within a target. The clinical utilization of IMPT is actively pursued but technical, physical and clinical questions remain. Technical questions pertain to control processes for manipulating pencil beams from the creation of the proton beam to delivery within the patient within the accuracy requirement. Physical questions pertain to the interplay between the proton penetration and variations between planned and actual patient anatomical representation and the intrinsic uncertainty in tissue stopping powers (the measure of energy loss per unit distance). Clinical questions remain concerning the impact and management of the technical and physical questions within the context of the daily treatment delivery, the clinical benefit of IMPT and the biological response differential compared with X-rays against which clinical benefit will be judged. It is expected that IMPT will replace other modes of proton field delivery. Proton radiotherapy, since its first practice 50 years ago, always required the highest level of accuracy and pioneered volumetric treatment planning and imaging at a level of quality now standard in X-ray therapy. IMPT requires not only the highest precision tools but also the highest level of system integration of the services required to deliver high-precision radiotherapy.

Purpose To compare treatment plans from standard photon therapy to intensity modulated X-rays (IMRT) and protons for craniospinal axis irradiation and posterior fossa boost in a patient with medulloblastoma. Methods Proton planning was accomplished using an in-house 3D planning system. IMRT plans were developed using the KonRad treatment planning system with 6-MV photons. Results Substantial normal-tissue dose sparing was realized with IMRT and proton treatment of the posterior fossa and spinal column. For example, the dose to 90% of the cochlea was reduced from 101.2% of the prescribed posterior fossa boost dose from conventional X-rays to 33.4% and 2.4% from IMRT and protons, respectively. Dose to 50% of the heart volume was reduced from 72.2% for conventional X-rays to 29.5% for IMRT and 0.5% for protons. Long-term toxicity with emphasis on hearing and endocrine and cardiac function should be substantially improved secondary to nontarget tissue sparing achieved with protons. Conclusion The present study clearly demonstrates the advantage of conformal radiation methods for the treatment of posterior fossa and spinal column in children with medulloblastoma, when compared to conventional X-rays. Of the two conformal treatment methods evaluated, protons were found to be superior to IMRT.

We derive, from first principles, a model to predict the output factors for spread-out Bragg peak proton fields (SOBP). The model is based on the simple observation that the output factor is the ratio of SOBP plateau dose to the dose measured in the ionization reference chamber. The latter, in turn, equates to the entrance dose of the SOBP corrected for inverse square. We use a theoretical derivation of this ratio to establish the relationship between the output factor and the distal range and modulation width of the SOBP. In addition, the theoretical derivation reduces the dependence on the distal range and modulation width into a single factor r = (R - M)/M. We compare the theoretical derivation against measurements obtained at the Northeast Proton Therapy Facility for output factors for clinical fields. The agreement between measurements and prediction is 2.9%.

Using multiple computed tomography (CT) scans, 50 patients undergoing prostate radiotherapy were tested for clinically significant time trends in the target and surrounding critical structures. Significant trends were observed toward increasing bladder volume and increasing bowel-to-planning target volume separation; however, no trends were observed in the prostate, seminal vesicles, or rectum. The subset of patients undergoing hormone therapy was also tested and did not independently exhibit any significant time trends.

Purpose Postmastectomy radiation therapy (PMRT), currently offered at Massachusetts General Hospital, uses proton pencil beam scanning (PBS) with intensity modulation, achieving complete target coverage of the chest wall and all nodal regions and reduced dose to the cardiac structures. This work presents the current methodology for such treatment and the ongoing effort for its improvements. Methods and Materials A single PBS field is optimized to ensure appropriate target coverage and heart/lung sparing, using an in–house-developed proton planning system with the capability of multicriteria optimization. The dose to the chest wall skin is controlled as a separate objective in the optimization. Surface imaging is used for setup because it is a suitable surrogate for superficial target volumes. In order to minimize the effect of beam range uncertainties, the relative proton stopping power ratio of the material in breast implants was determined through separate measurements. Phantom measurements were also made to validate the accuracy of skin dose calculation in the treatment planning system. Additionally, the treatment planning robustness was evaluated relative to setup perturbations and patient breathing motion. Results PBS PMRT planning resulted in appropriate target coverage and organ sparing, comparable to treatments by passive scattering (PS) beams but much improved in nodal coverage and cardiac sparing compared to conventional treatments by photon/electron beams. The overall treatment time was much shorter than PS and also shorter than conventional photon/electron treatment. The accuracy of the skin dose calculation by the planning system was within ±2%. The treatment was shown to be adequately robust relative to both setup uncertainties and patient breathing motion, resulting in clinically satisfying dose distributions. Conclusions More than 25 PMRT patients have been successfully treated at Massachusetts General Hospital by using single-PBS fields. The methodology and robustness of both the setup and the treatment have been discussed.

To determine the extent and predictors for prostatic motion in a large number of patients evaluated with multiple CT scans during radiotherapy, and evaluate the implications of these data on the design of appropriate treatment margins for patients receiving high-dose three-dimensional conformal radiotherapy.Fifty patients underwent four serial computerized tomography (CT) scans, consisting of an initial planning scan and subsequent scans at the beginning, middle, and end of the treatment course. Each scan was performed with the patient in the prone treatment position within an immobilization device used during therapy. Contours of the prostate and seminal vesicles were drawn on the axial CT slices of each scan, and the scans were matched by alignment of the pelvic bones with a chamfer matching algorithm. Using the contour information, distributions of the displacement of the organ center of mass and organ border from the planning position were determined separately for the prostate and seminal vesicles in each of the three principle directions: anterior-posterior (AP), superior-inferior (SI) and left-right (LR). Each distribution was fitted to a normal (Gaussian) distribution to determine confidence limits in the center of mass and border displacements and thereby evaluate for the optimal margins needed to contain target motion.The most common directions of displacement of the prostate center of mass (COM) were in the AP and SI directions and were significantly larger than any LR movement. The mean prostate COM displacement (+/- 1 standard deviation, SD) for the entire population was -1.2 +/- 2.9 mm, -0.5 +/- 3.3 mm and -0.6 +/- 0.8 mm in the, AP and SI and LR directions respectively (negative values indicate posterior, inferior or left displacement). The mean (+/- 1 SD) seminal vesicle COM displacement for the entire population was - 1.4 +/- 4.9 mm, 1.3 +/- 5.5 mm and -0.8 +/- 3.1 mm in the AP and SI and LR directions, respectively. The data indicate a tendency for the population towards posterior displacements of the prostate from the planning position and both posterior and superior displacements of the seminal vesicles. AP movement of both the prostate and seminal vesicles were correlated with changes in rectal volume (P = 0.0014 and0.0001, respectively) more than with changes in bladder volume (P = 0.030 for seminal vesicles and 0.19 for prostate). A logistic regression analysis identified the combination of rectal volume60 cm3 and bladder volumes40 cm3 as the only predictor of large (3 mm) systematic deviations for the prostate and seminal vesicles (P = 0.05) defined for each patient as the difference between organ position in the planning scan and mean position as calculated from the three subsequent scans.Prostatic displacement during a course of radiotherapy is more pronounced among patients with initial planning scans with large rectal and bladder volumes. Such patients may require more generous margins around the CTV to assure its enclosure within the prescription dose region. Identification and correction of patients with large systematic errors will minimize the extent of the margin required and decrease the volume of normal tissue exposed to higher radiation doses.

Purpose: This study was performed to establish the dose-localization capability and acute toxicity of a real-time intraoperative magnetic resonance (MR) image-guided approach to prostate brachytherapy in select patients with clinically localized prostate cancer. Methods and Materials: Nine patients with 1997 American Joint Commission on Cancer (AJCC) clinical stage T1cNxM0 prostate cancer, prostate-specific antigen (PSA) < 10 ng/ml, biopsy Gleason score not exceeding 3 + 4, and endorectal coil MR stage T2 disease were enrolled into this study. The prescribed minimum peripheral dose was 160 Gy to the clinical target volume (CTV), which was the MR-defined peripheral zone (PZ) of the prostate gland. Using a real-time 0.5 Tesla intraoperative MR imaging unit, 5-mm image planes were obtained throughout the prostate gland. The PZ of the prostate gland, anterior rectal wall, and prostatic urethra were identified on the T2 weighted axial images by an MR radiologist. An optimized treatment plan for catheter insertion was generated intraoperatively. Each catheter containing the 125Iodine sources was placed under real-time MR guidance to ensure that its position in the coronal, sagittal, and axial planes was in agreement with the planned trajectory. Real-time dose– volume histogram analyses were used intraoperatively to optimize the dosimetry. Results: For the 9 study patients, 89–99% (median 94%) of the CTV received a minimum peripheral dose of 160 Gy and ≥ 95% of the volume of the prostatic urethra and 42–89% (median 70%) of the volume of the anterior rectal wall received doses that were below the reported tolerance. All patients voided spontaneously within 3 h after discontinuation of the Foley catheter and no patient required more than a limited course (≤ 3 weeks) of oral α-1 blockers for postimplant urethritis. Conclusions: Real-time MR-guided interstitial radiation therapy provided the ability to achieve the planned optimized dose–volume histogram profiles to the CTV and healthy juxtaposed structures intraoperatively, with minimal acute morbidity.

The Joint Center for Radiation Therapy (JCRT) has treated intra-cranial lesions with high-dose single fraction stereotactic radiosurgery (SRS) since 1986 and with multi-fraction stereotactic radiotherapy (SRT) since 1992. This paper describes the JCRT techniques for treatment planning and delivery for SRS, and to a limited extent for SRT. LINAC quality assurance, treatment delivery, and patient management for stereotactic radiosurgery and stereotactic radiotherapy technique are closely related at the JCRT, although differences exist. An historical retrospective of our experience with stereotactic techniques including imaging modalities, treatment planning techniques, optimization methods, and treatment delivery is presented. Three treatment planning approaches, single isocenter, multiple isocenter, and micro-jaw field shaping are used to demonstrate the capabilities and technical dosimetric features of each approach. The major planning differences and clinical of each technique are described. From our experience, lesions less than 3.0 cm in maximum extent are well treated with circular fields using either a single or multiple isocenter configuration. Lesions greater than 3.0 cm in maximum extent usually benefit from field shaping using the micro-jaws. For these large lesions, the shaped field approach typically improves the dose homogeneity as well as reduces the amount of healthy brain irradiated. Our physicians choose between the three techniques to meet the desired clinical outcome the patient's situation requires.

Purpose: The patient population treated with fractionated stereotactic radiotherapy (SRT) is significantly different than that treated with stereotactic radiosurgery (SRS). Generally, lesions treated with SRT are larger, less spherical, and located within critical regions of the central nervous system; hence, they offer new challenges to the treatment planner. Here a simple, cost effective, beam shaping system has been evaluated relative to both circular collimators and an ideal dynamically conforming system for effectiveness in providing conformal therapy for these lesions. Methods and Materials: We have modeled a simple system for conformal arc therapy using four independent jaws. The jaw positions and collimator angle are changed between arcs but held fixed for the duration of each arc. Eleven previously treated SRT cases have been replanned using this system. The rectangular jaw plans were then compared to the original treatment plans which used circular collimators. The plans were evaluated with respect to tissue sparing at 100%, 80%, 50%, and 20% of the prescriptioni dose. A plan was also done for each tumor in which the beam aperture was continuously conformed to the beams eye view projection of the tumor. This was used as an ideal standard for conformal therapy in the absence of fluence modulation. Results: For tumors with a maximum extent of over 3.5 cm the rectangular jaw plans reduced the mean volume of healthy tissue involved at the prescription dose by 57% relative to the circular collimator plans. The ideal conformal plans offered no significant further improvement at the prescription dose. The relative advantage of the rectangular jaw plans decreased at lower isodoses so that at 20% of the prescriptioni dose tissue involvement for the rectangular jaw plans was equivalent to that for the circular collimator plans. At these isodoses the ideal conformal plans gave substantially better tissue sparing. Conclusion : A simple and economical field shaping device has been shown to provide all of the beam shaping advantage of a hypothetical ideal dynamically conforming system at the prescription level. This system may be immediately implemented in the clinic. It offers a substantial advantage over the currently used circular collimators in the high dose region with equivalent performance in the low dose region.

Purpose: A prototype Miniature Multi-Leaf Collimator (MMLC) designed specifically for radiosurgery and small field radiotherapy has been fabricated and evaluated at the University of Texas M. D. Anderson Cancer Center (UTMDACC). This work demonstrates the advantages of a computer-controlled MMLC vs. conventional circular collimation for the treatment of an irregularly shaped target volume in the brain. Methods and Materials: Two patients treatments were selected for this comparison from 38 intracranial tumors treated with radiosurgery at UTMDACC from 8/6/91 to 5/10/94. Target contours and critical structures defined for one of the patients was used to create a simulated target volume and critical structures in a spherical head phantom. Computer simulations were performed using traditional single isocenter treatment with a circular collimator for a set of six arcs. The same arc paths were used to compute the dose distribution for the MMLC and conformed beam geometries were defined using a three-dimensional (3D) treatment planning system with beam's eye view capabilities. Then, the calculated dose distribution for a single isocente, conformal treatment was delivered to the spherical head phantom under static conditions by shaping the MMLC to conform the target volume shape projected as a function of couch rotation and gantry angle. Planar dose distributions through the target volume were measured using therapy verification film located in the phantom. The measurements were used to verify that the 3D treatment planning system was capable of simulating the MMLC technique. For the second patient with a peanut-shaped tumor, the 3D treatment planning calculations were used to compare dose distributions for the MMLC and for traditional single and multiple isocenter treatments using circular collimators. The resulting integral dose-volume histograms (DVHs) for the target volume, normal brain, and critical structures for the three treatment techniques were compared. Results: (a) Analysis of the film dosimetry data exemplified the degree of conformation of the high-dose region to the target shape that is possible with a computer-controlled MMLC. (b) Comparison of measured and calculated dose distributions indicates that the 3D treatment planning system can simulate the MMLC treatment. (c) Comparison of DVHs from the single isocenter MMLC and circular collimator treatments shows similar coverage of the target volume with increased dose to the brain for circular collimation (4). Comparison of DVHs from the single isocenter MMLC with the multiple isocenter circular collimator treatment approach shows a more inhomogeneous dose distribution through the target volume and increased dose to the brain for the latter. Conclusion: Dosimetry data for single isocenter treatments using computer-controlled field shaping with a MMLC demonstrate the ability to conform the dose distribution to an irregularly shaped target volume. DVHs validated that the single isocenter MMLC treatment is preferable to both single and multiple isocenter, circular collimator treatment because it provides a more uniform dose distribution to an irregularly shaped target volume and reduces the dose to surrounding brain tissue for the example cases.

Purpose: In radiotherapy planning, the clinical target volume (CTV) is typically enlarged to create a planning target volume (PTV) that accounts for uncertainties due to internal organ and patient motion as well as setup error. Margin size clearly determines the volume of normal tissue irradiated, yet in practice it is often given a set value in accordance with a clinical precedent from which variations are rare. The (CTV/PTV) formalism does not account for critical structure dose. We present a numerical simulation to assess (CTV) coverage and critical organ dose as a function of treatment margins in the presence of organ motion and physical setup errors. An application of the model to the treatment of prostate cancer is presented, but the method is applicable to any site where normal tissue tolerance is a dose-limiting factor. Methods and Materials: A Monte Carlo approach was used to simulate the cumulative effect of variation in overall tumor position, for individual treatment fractions, relative to a fixed distribution of dose. Distributions of potential dose-volume histograms (DVHs), for both tumor and normal tissues, are determined that fully quantify the stochastic nature of radiotherapy delivery. We introduce the concept of Probability of Prescription Dose (PoPD) isosurfaces as a tool for treatment plan optimization. Outcomes resulting from current treatment planning methods are compared with proposed techniques for treatment optimization. The standard planning technique of relatively large uniform margins applied to the CTV, in the beam's eye view (BEV), was compared with three other treatment strategies: (a) reduced uniform margins, (b) nonuniform margins adjusted to maximize normal tissue sparing, and (c) a reduced margin plan in which nonuniform fluence profiles were introduced to compensate for potential areas of reduced dose. Results: Results based on 100 simulated full course treatments indicate that a 10 mm CTV to PTV margin, combined with an additional 5 mm dosimetric margin, provides adequate CTV coverage in the presence of known treatment uncertainties. Nonuniform margins can be employed to reduce dose delivered to normal tissues while preserving CTV coverage. Nonuniform fluence profiles can also be used to further reduce dose delivered to normal tissues, though this strategy does result in higher dose levels delivered to a small volume of the CTV and normal tissues. Conclusions: Monte Carlo-based treatment simulation is an effective means of assessing the impact of organ motion and daily setup error on dose delivery via external beam radiation therpay. Probability of Prescription Dose (PoPD) isosurfaces are a useful tool for the determination of nonuniform beam margins that reduce dose delivered to critical organs while preserving (CTV) dose coverage. Nonuniform fluenc profiles can further alter critical organ dose with potential therapeutic benefits. Clinical consequences of this latter approach can only be assessed via clinical trials.

The accuracy of intensity modulated proton therapy (IMPT) is sensitive to range uncertainties. Geometric margins, as dosimetric surrogates, are ineffective and robust optimization strategies are needed. These, however, lead to increased normal tissue dose. We explore here how this dose increase can be reduced by increasing the maximum tumor dose instead. We focus on range uncertainties, modeled by scaling the stopping powers 5% up (undershoot) or down (overshoot) compared to the nominal scenario. Robust optimization optimizes for target dose conformity in the most likely scenario, not the worst, while constraining target coverage for the worst-case scenario. Non-robust plans are also generated. Different maximum target doses are applied (105% versus 120% versus 140%) to investigate the effect on normal tissue dose reduction. The method is tested on a homogeneous and a lung phantom and on a liver patient. Target D99 of the robust plans equals the prescription dose of 60 GyE(4) for all scenarios, but decreases to 36 GyE for the non-robust plans. The mean normal tissue dose in a 2 cm ring around the target is 11% to 31% higher for the robust plans. This increase can be reduced to -8% and 3% (compared to the non-robust plan) by allowing a maximum tumor dose of 120% instead of 105%. Thus robustness leads to more normal tissue dose, but it can be compensated by allowing a higher maximum tumor dose.

Radiosurgery was historically designed as a technology to be used for the treatment of functional disorders, benign tumors, and vascular malformations. In the last 5 years, malignant lesions have become an increasingly common target for the radiosurgeon. In fact, by 1994 the most common disease treated with radiosurgery in the United States was metastatic disease. Published data suggest that radiosurgery offers excellent local control for intracranial metastatic lesions regardless of location or histology with the majority of patienss demonstrating an improved quality of life. Recent information from the Joint Center for Radiation Therapy suggests that radiosurgery compares favorably with interstitial brachy-therapy for both recurrent as well in newly diagnosed patients with malignant gliomas in terms of improved survival and the need of surgery and steroid support for symptomatic radiation changes. Prospective studies (Phase I through III) are ongoing to determine the ultimate role of radiosurgery in the management of patients with newly diagnosed and recurrent malignant gliomas, recurrent pediatric brain tumors disease, and patients with single or multiple intracranial metastases.

Treatment planning databases for pencil beam scanning PBS can be large, difficult to manage, and problematic for quality assurance when they contain tabulated Bragg peaks at small range resolution. Smaller range resolution, in the absence of an accurate interpolation method, improves the accuracy in dose calculations. In this work, we derive an approximate scaling function to interpolate between tabulated Bragg peaks, determine the accuracy of this interpolation technique, and determine the minimum number of tabulated peaks in a treatment planning database. With the new interpolation technique, three tabulated mono-energetic Bragg peaks (N =3) is a suitable lower limit for N to achieve interpolation accuracy better than ±1% of the maximum dose in pristine and spread out Bragg peaks for ranges between 6.8 and 32.1 cm of water.

The γ-index is used routinely to establish correspondence between two dose distributions. The definition of the γ-index can be written with a single equation but solving this equation at millions of points is computationally expensive, especially in three dimensions. Our goal is to extend the vector–equation method in Bakai et al (2003 Phys. Med. Biol.48 3543–53) to higher order for better accuracy and, as important, to determine the magnitude of accuracy in a higher order solution. We construct a numerical framework for calculating the γ-index in two and three dimensions and present an efficient method for calculating the γ-index with zeroth-, first- and second-order methods using tricubic spline interpolation. For an intensity-modulated radiation therapy example with 1.78 × 106 voxels, the zeroth-order, first-order, first-order iterations and semi-second-order methods calculate the three-dimensional γ-index in 1.5, 4.7, 34.7 and 35.6 s with 36.7%, 1.1%, 0.2% and 0.8% accuracy, respectively. The accuracy of linear interpolation with this example is 1.0%. We present efficient numerical methods for calculating the three-dimensional γ-index with tricubic spline interpolation. The first-order method with iterations is the most accurate and fastest choice of the numerical methods if the dose distributions may have large second-order gradients. Furthermore, the difference between iterations can be used to determine the accuracy of the method.

We present a method to include robustness into a multi-criteria optimization (MCO) framework for intensity-modulated proton therapy (IMPT). The approach allows one to simultaneously explore the trade-off between different objectives as well as the trade-off between robustness and nominal plan quality. In MCO, a database of plans each emphasizing different treatment planning objectives, is pre-computed to approximate the Pareto surface. An IMPT treatment plan that strikes the best balance between the different objectives can be selected by navigating on the Pareto surface. In our approach, robustness is integrated into MCO by adding robustified objectives and constraints to the MCO problem. Uncertainties of the robust problem are modeled by pre-calculated dose-influence matrices for a nominal scenario and a number of pre-defined error scenarios. A robustified objective represents the worst objective function value that can be realized for any of the error scenarios. The optimization method is based on a linear projection solver and is capable of handling large problem sizes resulting from a fine dose grid resolution, many scenarios, and a large number of proton pencil beams. A base-of-skull case is used to demonstrate the robust optimization method. It is demonstrated that the robust optimizationmethod reduces the sensitivity of the treatment plan to setup and range errors to a degree that is not achieved by a safety margin approach. A chordoma case is analyzed in more detail to demonstrate the involved tradeoffs between target underdose and brainstem sparing as well as robustness and nominal plan quality. The latter illustrates the advantage of MCO in the context of robust planning. For all cases examined, the robust optimization for each Pareto optimal plan takes less than 5 min on a standard computer, making a computationally friendly interface possible to the planner., Comment: 19 pages, 6 figures, to appear on Physics in medicine and biology

Stereotactic radiotherapy is a new modality that combines the accurate focal dose delivery of stereotactic radiosurgery with the biological advantages of conventional radiotherapy (1.8-2.0 Gy/day using 25-30 fractions). The modality requires sophisticated treatment planning, dedicated high-energy linear accelerator, and relocatable immobilization devices. We report here our early experience using stereotactic radiotherapy for intracranial neoplasms.Between June 1992 and September 1993, we treated 82 patients with central nervous system lesions using stereotactic radiotherapy, delivered from a dedicated 6 MV stereotactic linear accelerator. A head fixation frame provided daily relocatable setup using a dental plate for all patients over 8 years of age. A modified head frame, which does not require a mouthpiece, was used for children requiring anesthesia. The patients ranged in age from 9 months to 76 years. Thirty-three patients were children less than 21 years of age. Selection criteria for the protocol included: (a) focal, small (5 cm) radiographically distinct lesions known to be radiocurable (pituitary adenoma, craniopharyngioma, meningioma, acoustic neuroma, pilocytic astrocytoma, retinoblastoma), and (b) lesions located in regions not amenable to surgery or radiosurgery such as the brain stem or chiasm. Standard fractionation and conventional doses were delivered. Patients with low-grade astrocytoma, oligodendroglioma, or ependymoma were treated using a dose escalation regime consisting of conventional doses plus a 10% increase.Although follow-up is 16 months (range 3-16 months), posttreatment radiographic studies in 77 patients have been consistent with changes similar to those found after conventional radiation therapy. To date, reduction of up to 50% of the original volume has been noted in 19 out of 77 patients, and 4 patients had a complete response, 2 with dysgerminoma, and 1 each with astrocytoma and retinoblastoma. In 56 patients disease was either stable or the follow-up was too short for evaluation. While the follow-up is relatively short, there have been no in-field or marginal recurrences. The only unexpected radiographic findings were in three patients with pilocytic astrocytomas, who developed asymptomatic edema in the treatment volume. Accuracy in daily fractionation was excellent. In over 2000 patient setups with 41,000 scalp measurements, reproducibility was found to be within 0.41 mm (median) of baseline readings, allowing for precise immobilization throughout the treatment course. The treatment in all cases was well tolerated with minimal acute effects. Our stereotactic radiotherapy facility can provide fractionated therapy for 10-12 patients a day efficiently and accurately.The treatment and relocatable stereotactic head frames were well tolerated with minimal acute effects. No long-term sequelae have been noted, although the observation period is short. To fully define the role of stereotactic radiotherapy, we are conducting prospective studies to evaluate neurocognitive and neuroendocrine effects. We expect that this innovative approach will make a significant impact on the treatment of intracranial neoplasms, particularly in children.

Purpose : We describe an image fusion application that addresses two basic problems that previously limited the use of magnetic resonance imaging (MRI) for geometric localization in stereotactic radiosurgery (SRS) and stereotactic radiotherapy (SRT). The first limitation is imposed by the use of a relocatable, MRI-incompatible, stereotactic frame for stereotactic radiotherapy. The second limitation is an inherent lack of geometric fidelity in current MRI scanners that invalidates the use of MRI for stereotactic localization. Methods and Materials : We recently developed and implemented a novel automated method for fusing computerized tomography (CT) and MRI volumetric image studies. The method is based on a chamfer matching algorithm, and provides a quality assurance procedure to verify the accuracy of the fused image set. The image fusion protocol removes the need for stereotactic fixation of the patient for the MRI study. Results : The image fusion protocol significantly improves on the spatial accuracy of the MRI study. We demonstrate the effect of distortion and the effectiveness of the fusion with a phantom study. We present two case studies, an acoustic neurinoma treated with SRS. and a pilocytic astrocytoma treated with SRT. Conclusion : The image fusion protocol significantly improves our logistical management of treating patients with radiosurgery and makes conformal therapy practical for treating patients with SRT. The image fusion protocol demonstrates both the superior diagnostic quality and the poor geometric fidelity of MRI. MRI is a required imaging modality in stereotactic therapy. Image fusion combines the superior MRI diagnostic quality with the superior CT geometric definition, and makes the use of MRI in stereotactic therapy possible and practical.

Purpose: Stereotactic radiosurgery is becoming a more accepted treatment option for benign, deep seated intracranial lesions. However, little is known about the effects of large single fractions of radiation on cranial nerves. This study was undertaken to assess the effect of radiosurgery on the cranial nerves of the cavernous sinus. Methods and Materials: We examined the tolerance of cranial nerves (II–VI) following radiosurgery for 62 patients (4262 with meningiomas) treated for lesions within or near the cavernous sinus. Twenty-nine patients were treated with a modified 6 MV linear accelerator (Joint Center for Radiation Therapy) and 33 were treated with the Gamma Knife (University of Pittsburgh). Three-dimensional treatment plans were retrospectively reviewed and maximum doses were calculated for the cavernous sinus and the optic nerve and chiasm. Results: Median follow-up was 19 months (range 3–49). New cranial neuropathies developed in 12 patients from 3–41 months following radiosurgery. Four of these complications involved injury to the optic system and 8 (38 transient) were the result of injury to the sensory or motor nerves of the cavernous sinus. There was no clear relationship between the maximum dose to the cavernous sinus and the development of complications for cranial nerves III–VI over the dose range used (1000–4000 cGy). For the optic apparatus, there was a significantly increased incidence of complications with dose. Four of 17 patients (24°10) receiving greater than 800 cGy to any part of the optic apparatus developed visual complications compared with 035 who received less than 800 cGy ( P = 0.009). Conclusion: Radiosurgery using tumor-controlling doses of up to 4000 cGy appears to be a relatively safe technique in treating lesions within or near the sensory and motor nerves (III–VI) of the cavernous sinus. The dose to the optic apparatus should be limited to under 800 cGy.

Between 5/21/86 and 11/1/89, we treated 64 recurrent or inoperable intracranial tumors in 60 patients (40 primary, 24 metastatic) with stereotactic radiosurgery using a modified 6 MeV linear accelerator at the Joint Center for Radiation Therapy. Patients were followed until death or 1/1/90. The median follow-up was 8 months (2-43 months). Fourteen patients experienced complications from 12 hours to 7 months (median 3 months, but only two patients more than 4 months) following radiosurgery. To determine variables related to complication, we calculated integral dose-volume histograms for 61/64 lesions and the surrounding CT-defined normal tissue. We excluded 16 lesions in 15 patients for follow-up less than 4 months (12 patients) or insufficient treatment information (3 patients). The variables for which higher values were associated with significantly more toxicity in a univariate score test were: a) tumor dose inhomogeneity (p less than 0.00001), b) maximum tumor dose (p = 0.00002), c) number of isocenters (p = 0.00002), d) maximum normal tissue dose (p = 0.00005) and e) tumor volume (p = 0.0001). These variables were all highly correlated with tumor dose inhomogeneity (coefficients of rank correlation 0.75-0.81). Tumor dose inhomogeneity had a much higher loglikelihood in a logistic model than any other single variable and a higher loglikelihood than any other two variables combined. None of the 21 patients with metastatic lesions experienced a complication. When we excluded the metastatic lesions, the above five variables remained significant in univariate tests. The mean tumor dose, number of treatment arcs, total degrees of arc, tumor location, previous radiotherapy, tumor geometry, pretreatment performance status, collimator size, and age were not significantly associated with toxicity. We conclude that radiosurgery of intracranial tumors is associated with a low risk of complications for lesions less than 10cc treated with a single isocenter to maximum tumor doses less than 25 Gy with tumor dose inhomogeneity less than 10 Gy, but that treatment of larger lesions will require new treatment strategies which reduce the tumor dose inhomogeneity associated with multiple isocenter treatments.

The identification of factors associated with breast recurrence following conservative surgery (CS) and radiation therapy (RT) is of potential use in refining patient selection criteria and treatment technique. In an attempt to define such factors we examined the relationship between various clinical, pathologic and treatment characteristics and the likelihood of breast recurrence in 783 patients with clinical stage I or II breast cancer treated between July 1968 and December 1982. Treatment consisted of complete gross excision of the primary tumor and RT to a total dose of at least 60 Gy to the primary site. During this period, pre-treatment mammograms and detailed histologic assessment of the margins of resection were not routinely performed. Median follow-up for surviving patients was 80 months. Thirteen patients (1.6%) were lost to follow-up. Ninety-one patients (12%) have developed a breast recurrence, corresponding to 5- and 10-year actuarial rates of 10 and 18%, respectively. The major feature associated with breast recurrence was the presence of an "extensive intraductal component" (EIC+). An EIC+ tumor was seen in 28% of evaluable cases with infiltrating ductal carcinoma and accounted for 60% of breast recurrences. Forty-three of 166 patients (26%) with EIC+ tumors developed a breast recurrence compared with 29 of 418 patients (7%) without an EIC (EIC-) (p = 0.0001). The 5-year actuarial rates of breast relapse were 24 and 6%, respectively (p = 0.0001). Very young age (defined as 34 years of age or younger) was also a significant factor associated with the risk of breast recurrence. Very young patients comprised 8% of the patient population and accounted for 16% of breast recurrences. Fifteen of 61 very young patients (25%) developed a breast recurrence compared with 76 of 722 older patients (11%) (p = 0.001). The corresponding 5-year actuarial rates of breast recurrence were 21 and 9% (p = 0.005). None of the other clinical or pathological factors examined by univariate analysis were significantly correlated with recurrence in the breast. A multivariate model of site of first failure (polychotomous logistic regression) also showed that EIC+ tumors and very young age were the main factors associated with a high relative risk of breast recurrence. We conclude that EIC+ tumors and very young age are associated with a high risk of breast recurrence for patients treated with limited excision prior to RT.