Optimizing GRID and Lattice Spatially Fractionated Radiation Therapy: Innovative Strategies for Radioresistant and Bulky Tumor Management.

Treating radioresistant and bulky tumors is challenging due to their inherent resistance to standard therapies and their large size. GRID and lattice spatially fractionated radiation therapy (simply referred to GRID RT and LRT) offer promising techniques to tackle these issues. Both approaches deliver radiation in a grid-like or lattice pattern, creating high-dose peaks surrounded by low-dose valleys. This pattern enables the destruction of significant portions of the tumor while sparing healthy tissue. GRID RT uses a 2-dimensional pattern of high-dose peaks (15-20 Gy), while LRT delivers a three-dimensional array of high-dose vertices (10-20 Gy) spaced 2-5 cm apart. These techniques are beneficial for treating a variety of cancers, including soft tissue sarcomas, osteosarcomas, renal cell carcinoma, melanoma, gastrointestinal stromal tumors (GISTs), pancreatic cancer, glioblastoma, and hepatocellular carcinoma. The specific grid and lattice patterns must be carefully tailored for each cancer type to maximize the peak-to-valley dose ratio while protecting critical organs and minimizing collateral damage. For gynecologic cancers, the treatment plan should align with the international consensus guidelines, incorporating concurrent chemotherapy for optimal outcomes. Despite the challenges of precise dosimetry and patient selection, GRID RT and LRT can be cost-effective using existing radiation equipment, including particle therapy systems, to deliver targeted high-dose radiation peaks. This phased approach of partial high-dose induction radiation therapy with standard fractionated radiation therapy maximizes immune modulation and tumor control while reducing toxicity. Comprehensive treatment plans using these advanced techniques offer a valuable framework for radiation oncologists, ensuring safe and effective delivery of therapy for radioresistant and bulky tumors. Further clinical trials data and standardized guidelines will refine these strategies, helping expand access to innovative cancer treatments.

Practice Patterns of Spatially Fractionated Radiation Therapy: A Clinical Practice Survey.

Purpose: Spatially fractionated radiation therapy (SFRT) is increasingly used for bulky advanced tumors, but specifics of clinical SFRT practice remain elusive. This study aimed to determine practice patterns of GRID and Lattice radiation therapy (LRT)-based SFRT. Methods and Materials: A survey was designed to identify radiation oncologists' practice patterns of patient selection for SFRT, dosing/planning, dosimetric parameter use, SFRT platforms/techniques, combinations of SFRT with conventional external beam radiation therapy (cERT) and multimodality therapies, and physicists' technical implementation, delivery, and quality procedures. Data were summarized using descriptive statistics. Group comparisons were analyzed with permutation tests. Results: The majority of practicing radiation oncologists (United States, 100%; global, 72.7%) considered SFRT an accepted standard-of-care radiation therapy option for bulky/advanced tumors. Treatment of metastases/recurrences and nonmetastatic primary tumors, predominantly head and neck, lung cancer and sarcoma, was commonly practiced. In palliative SFRT, regimens of 15 to 18 Gy/1 fraction predominated (51.3%), and in curative-intent treatment of nonmetastatic tumors, 15 Gy/1 fraction (28.0%) and fractionated SFRT (24.0%) were most common. SFRT was combined with cERT commonly but not always in palliative (78.6%) and curative-intent (85.7%) treatment. SFRT-cERT time sequencing and cERT dose adjustments were variable. In curative-intent treatment, concurrent chemotherapy and immunotherapy were found acceptable by 54.5% and 28.6%, respectively. Use of SFRT dosimetric parameters was highly variable and differed between GRID and LRT. SFRT heterogeneity dosimetric parameters were more commonly used (P = .008) and more commonly thought to influence local control (peak dose, P = .008) in LRT than in GRID therapy. Conclusions: SFRT has already evolved as a clinical practice pattern for advanced/bulky tumors. Major treatment approaches are consistent and follow the literature, but SFRT-cERT combination/sequencing and clinical utilization of dosimetric parameters are variable. These areas may benefit from targeted education and standardization, and knowledge gaps may be filled by incorporating identified inconsistencies into future clinical research.

An International Consensus on the Design of Prospective Clinical-Translational Trials in Spatially Fractionated Radiation Therapy for Advanced Gynecologic Cancer.

Despite the unexpectedly high tumor responses and limited treatment-related toxicities observed with SFRT, prospective multi-institutional clinical trials of SFRT are still lacking. High variability of SFRT technologies and methods, unfamiliar complex dose and prescription concepts for heterogeneous dose and uncertainty regarding systemic therapies present major obstacles towards clinical trial development. To address these challenges, the consensus guideline reported here aimed at facilitating trial development and feasibility through a priori harmonization of treatment approach and the full range of clinical trial design parameters for SFRT trials in gynecologic cancer. Gynecologic cancers were evaluated for the status of SFRT pilot experience. A multi-disciplinary SFRT expert panel for gynecologic cancer was established to develop the consensus through formal panel review/discussions, appropriateness rank voting and public comment solicitation/review. The trial design parameters included eligibility/exclusions, endpoints, SFRT technology/technique, dose/dosimetric parameters, systemic therapies, patient evaluations, and embedded translational science. Cervical cancer was determined as the most suitable gynecologic tumor for an SFRT trial. Consensus emphasized standardization of SFRT dosimetry/physics parameters, biologic dose modeling, and specimen collection for translational/biological endpoints, which may be uniquely feasible in cervical cancer. Incorporation of brachytherapy into the SFRT regimen requires additional pre-trial pilot investigations. Specific consensus recommendations are presented and discussed.

An International Consensus on the Design of Prospective Clinical-Translational Trials in Spatially Fractionated Radiation Therapy.

PURPOSE: Spatially fractionated radiation therapy (SFRT), which delivers highly nonuniform dose distributions instead of conventionally practiced homogeneous tumor dose, has shown high rates of clinical response with minimal toxicities in large-volume primary or metastatic malignancies. However, prospective multi-institutional clinical trials in SFRT are lacking, and SFRT techniques and dose parameters remain variable. Agreement on dose prescription, technical administration, and clinical and translational design parameters for SFRT trials is essential to enable broad participation and successful accrual to rigorously test the SFRT approach. We aimed to develop a consensus for the design of multi-institutional clinical trials in SFRT, tailored to specific primary tumor sites, to help facilitate development and enhance the feasibility of such trials. METHODS AND MATERIALS: Primary tumor sites with sufficient pilot experience in SFRT were identified, and fundamental trial design questions were determined. For each tumor site, a comprehensive consensus effort was established through disease-specific expert panels. Clinical trial design criteria included eligibility, SFRT technology and technique, dose and fractionation, target- and normal-tissue dose parameters, systemic therapies, clinical trial endpoints, and translational science considerations. Iterative appropriateness rank voting, expert panel consensus reviews and discussions, and public comment posting were used for consensus development. RESULTS: Clinical trial criteria were developed for head and neck cancer and soft-tissue sarcoma. Final consensus among the 22 trial design categories each (a total of 163 criteria) was high to moderate overall. Uniform patient cohorts of advanced bulky disease, standardization of SFRT technologies and dosimetry and physics parameters, and collection of translational correlates were considered essential to trial design. Final guideline recommendations and the degree of agreement are presented and discussed. CONCLUSIONS: This consensus provides design guidelines for the development of prospective multi-institutional clinical trials testing SFRT in advanced head and neck cancer and soft-tissue sarcoma through in-advance harmonization of the fundamental clinical trial design among SFRT experts, potential investigators, and the SFRT community.

Feasibility of 18-MV grid therapy from radiation protection aspects: unwanted dose and fatal cancer risk caused by photoneutrons and scattered photons.

PURPOSE: Photoneutron production is a common concern when using 18-MV photon beams in radiation therapy. In Spatially Fractionated Grid Radiation Therapy (SFGRT), the grid block in the collimation system modifies the neutron production, photon scattering, and electron contamination in and out of the radiation field. Such an effect was studied with grids made of different high-Z materials by Monte Carlo simulations. The results were also used to evaluate the lifetime risk of fatal cancers. METHODS: MCNPX® code (2.7.0 extensions) was employed to simulate an 18-MV LINAC (Varian 2100 C/D). Three types of grid made of brass, cerrobend, and lead were used to study the neutron and electron fluence. Output factors for each grid with different field sizes were calculated. A revised female MIRD phantom with an 8-cm spherical tumor inside the liver was used to estimate the dose to the tumor and the critical organs. A 20-Gy SFGRT plan with Anterior Posterior (AP) - Posterior Anterior (PA) grid beams was compared with a Conventional Fractionated Radiation Therapy (CFRT) plan which delivered 40-Gy to the tumor by AP-PA open beams. Neutron equivalent dose, photon equivalent dose, as well as lifetime risks of fatal cancer were calculated in the organs at risk. RESULTS: The grid blocks reduced the fluence of contaminant electrons inside the treatment field by more than 50%. The neutron fluences per electron-history in SFGRT plans with brass, cerrobend and lead were on average 55%, 31% and 31% less than that of the CFRT plan, respectively. However, when converting to fluences per delivered dose (Gy), the cerrobend and lead grid may incur higher neutron dose for 20 × 20 cm2 field size and above. The changes in neutron mean energy, as well as the correlated radiation weighting factors, were insignificant. The total risk due to the photoneutrons in the SFGRT plans was 87% or lower than that in the CFRT plans. In both SFGRT and CFRT plans, the contribution of the primary and scattered photons to the fatal cancer risk was 2 times or more than the photoneutrons. The total risks from photons in SFGRT with brass, cerrobend, and lead blocks were 1.733, 1.374, and 1.260%, respectively, which were less than 30% of the total photon-risk in CFRT (5.827%). CONCLUSION: In the brass, cerrobend, and lead grids, the attenuation of photoneutrons outweighs its photoneutron production in 18-MV SFGRT. The total cancer risks from photons and photoneutrons in the SFGRT plans were 30% or less of the risks in the CFRT plans (5.911%). Using 18 MV photon beams with brass, cerrobend, and lead grid blocks is still a feasible option for SFGRT.

Understanding High-Dose, Ultra-High Dose Rate, and Spatially Fractionated Radiation Therapy.

The National Cancer Institute's Radiation Research Program, in collaboration with the Radiosurgery Society, hosted a workshop called Understanding High-Dose, Ultra-High Dose Rate and Spatially Fractionated Radiotherapy on August 20 and 21, 2018 to bring together experts in experimental and clinical experience in these and related fields. Critically, the overall aims were to understand the biological underpinning of these emerging techniques and the technical/physical parameters that must be further defined to drive clinical practice through innovative biologically based clinical trials.

Early clinical results of proton spatially fractionated GRID radiation therapy (SFGRT).

OBJECTIVE: Approximately 70 patients with large and bulky tumors refractory to prior treatments were treated with photon spatially fractionated GRID radiation (SFGRT). We identified 10 additional patients who clinically needed GRID but could not be treated with photons due to adjacent critical organs. We developed a proton SFGRT technique, and we report treatment of these 10 patients. METHODS: Subject data were reviewed for clinical results and dosimetric data. 50% of the patients were metastatic at the time of treatment and five had previous photon radiation to the local site but not via GRID. They were treated with 15-20 cobalt Gray equivalent using a single proton GRID field with an average beamlet count of 22.6 (range 7-51). 80% received an average adjuvant radiation dose to the GRID region of 40.8Gy (range 13.7-63.8Gy). Four received subsequent systemic therapy. RESULTS: The median follow-up time was 5.9 months (1.1-18.9). At last follow-up, seven patients were alive and three had died. Two patients who had died from metastatic disease had local shrinkage of tumor. Of those alive, four had complete or partial response, two had partial response but later progressed, and one had no response. For all patients, the tumor regression/local symptom improvement rate was 80%. 50% had acute side-effects of grade1/2 only and all were well-tolerated. CONCLUSION: In circumstances where patients cannot receive photon GRID, proton SFGRT is clinically feasible and effective, with a similar side-effect profile. ADVANCES IN KNOWLEDGE: Proton GRID should be considered as a treatment option earlier in the disease course for patients who cannot be treated by photon GRID.

Colon cancer presenting as a testicular metastasis.

We report a case of a 43-year-old male who initially presented with intermittent testicular pain as the first sign of metastatic stage IV colon cancer. Physical examination revealed a normal penis, scrotum and testes. Magnetic resonance imaging (MRI) of pelvis showed an irregular 3 cm mass of the spermatic cord and right radical inguinal orchiectomy was performed. The pathological diagnosis was metastatic adenocarcinoma. In conclusion, even though metastases to the testes are rare, they should be considered in clinical practice especially in older men who present with a testicular mass or discomfort.

High-Dose Radiation as a Dramatic, Immunological Primer in Locally Advanced Melanoma.

A 53-year-old white male presented with a right axillary melanoma that became widely metastatic and progressive despite multiple systemic treatments. He became refractory to ipilimumab (Yervoy) and pembrolizumab (Keytruda). He presented with a very large, painful left posterior neck mass that was 18 x 15 x 8 cm in size clinically. He was treated with a single fraction of 20 Gy using parallel opposed, spatially fractionated GRID radiation therapy (SFGRT), along with concurrent pembrolizumab. He also received 50 Gy in 25 fractions of conventional radiation. After five months of concurrent treatment, the refractory neck mass had completely resolved and he had no lasting side effects. Our dramatic case confirms the synergistic effect of high-dose GRID radiation as a primer for renewed, enhanced immunological response, and we have used this approach successfully on a number of similar patients with rapid and durable results.

The international cancer expert corps: a unique approach for sustainable cancer care in low and lower-middle income countries.

The growing burden of non-communicable diseases including cancer in low- and lower-middle income countries (LMICs) and in geographic-access limited settings within resource-rich countries requires effective and sustainable solutions. The International Cancer Expert Corps (ICEC) is pioneering a novel global mentorship-partnership model to address workforce capability and capacity within cancer disparities regions built on the requirement for local investment in personnel and infrastructure. Radiation oncology will be a key component given its efficacy for cure even for the advanced stages of disease often encountered and for palliation. The goal for an ICEC Center within these health disparities settings is to develop and retain a high-quality sustainable workforce who can provide the best possible cancer care, conduct research, and become a regional center of excellence. The ICEC Center can also serve as a focal point for economic, social, and healthcare system improvement. ICEC is establishing teams of Experts with expertise to mentor in the broad range of subjects required to establish and sustain cancer care programs. The Hubs are cancer centers or other groups and professional societies in resource-rich settings that will comprise the global infrastructure coordinated by ICEC Central. A transformational tenet of ICEC is that altruistic, human-service activity should be an integral part of a healthcare career. To achieve a critical mass of mentors ICEC is working with three groups: academia, private practice, and senior mentors/retirees. While in-kind support will be important, ICEC seeks support for the career time dedicated to this activity through grants, government support, industry, and philanthropy. Providing care for people with cancer in LMICs has been a recalcitrant problem. The alarming increase in the global burden of cancer in LMICs underscores the urgency and makes this an opportune time fornovel and sustainable solutions to transform cancer care globally.

Adjuvant pelvic irradiation for cervical cancer in the setting of a transplanted pelvic kidney.

Postoperative radiation therapy is often needed following resection for gynecological cancers. A pelvic kidney, whether ectopic or transplanted, is considered an absolute contraindication for radiation if the organ is left in place. A 45-year-old, immunosuppressed patient with FIGO IB1 cervical adenocarcinoma was treated with intensity-modulated radiation therapy (IMRT) to 45 Gy to the modified whole pelvis with a boost to 59.4 Gy to high-risk areas despite having a transplanted kidney in the right iliac fossa. The irradiation prevented further local failure in the pelvis at 36-month follow-up with no decrement in renal function. Radiation to the modified pelvis using IMRT while avoiding the renal allograft is technically feasible and should be offered to more high-risk patients.

Decrease of the lumpectomy cavity volume after whole-breast irradiation affects small field boost planning.

To determine whether small field boost (SFB) replanning is necessary when the lumpectomy cavity (LPC) decreases during whole-breast irradiation (WBI) and what parameters might predict a change in the SFB plan. Forty patients had computed tomography (CT) simulation (CT1) within 60 days of surgery and were resimulated (CT2) after 37.8-41.4 Gy for SFB planning. A 3-field photon plan and a single en face electron plan were created on both CTs and compared. In the 26 patients who had a ≥5 cm(3) and a ≥25% decrease in lumpectomy cavity volume (LCV) between CT scans, the SFB plan using photons was different in terms of normal breast tissue volume irradiated (BTV) (p < 0.001), and field dimensions (p < 0.001). In 20/35 patients, the energy or field size changed for electron plans on CT2, but no tested characteristics predicted for a change. Less BTV was irradiated using electrons than photons in 29% (CT1) to 37% (CT2). SFB replanning needs to be individualized to each patient because of the variety of factors that can impact dosimetric planning. Replanning is recommended when using 3-field photons if the patient has experienced a ≥5 cm(3) and a ≥25% decrease in LCV during WBI. Some patients may benefit from electron SFB replanning but no tested characteristics reliably predict those who may benefit the most. The amount of BTV irradiated is less with electrons than in photon plans and this has the potential to improve cosmesis, a clinically important outcome in breast-conserving therapy.

High-dose spatially fractionated GRID radiation therapy (SFGRT): a comparison of treatment outcomes with Cerrobend vs. MLC SFGRT.

PURPOSE: Spatially fractionated GRID radiotherapy (SFGRT) using a customized Cerrobend block has been used to improve response rates in patients with bulky tumors. The clinical efficacy of our own multileaf collimator (MLC) technique is unknown. We undertook a retrospective analysis to compare clinical response rates attained using these two techniques. METHODS AND MATERIALS: Seventy-nine patients with bulky tumors (median diameter, 7.6 cm; range, 4-30 cm) treated with SFGRT were reviewed. Between 2003 and late 2005, the Cerrobend block technique (n = 39) was used. Between late 2005 and 2008, SFGRT was delivered using MLC-shaped fields (n = 40). Dose was prescribed to dmax (depth of maximum dose) and was typically 15 Gy. Eighty percent of patients in both groups received external beam radiotherapy in addition to SFGRT. The two-sided Fisher-Freeman-Halton test was used to compare pain and mass effect response rates between the two groups. RESULTS: Sixty-one patients (77%) were treated for palliative intent and 18 (23%) for curative intent. The majority of patients had either lung or head-and-neck primaries in both groups; the most frequent site of SFGRT application was the neck. The majority of patients complained of either pain (65%) or mass effect (58%) at intake. Overall response rates for pain and mass response were no different between the Cerrobend and MLC groups: pain, 75% and 74%, respectively (p = 0.50), and mass effect, 67% and 73%, respectively (p = 0.85). The majority of toxicities were Grade 1 or 2, and only 3 patients had late Grade 3-4 toxicities. CONCLUSIONS: MLC-based and Cerrobend-based SFGRT have comparable and encouraging response rates when used either in the palliative or curative setting. MLC-based SGFRT should allow clinics to more easily adopt this novel treatment approach for the treatment of bulky tumors.

Helical tomotherapy versus single-arc intensity-modulated arc therapy: a collaborative dosimetric comparison between two institutions.

PURPOSE: Both helical tomotherapy (HT) and single-arc intensity-modulated arc therapy (IMAT) deliver radiation using rotational beams with multileaf collimators. We report a dual-institution study comparing dosimetric aspects of these two modalities. METHODS AND MATERIALS: Eight patients each were selected from the University of Maryland (UMM) and the University of Wisconsin Cancer Center Riverview (UWR), for a total of 16 cases. Four cancer sites including brain, head and neck (HN), lung, and prostate were selected. Single-arc IMAT plans were generated at UMM using Varian RapidArc (RA), and HT plans were generated at UWR using Hi-Art II TomoTherapy. All 16 cases were planned based on the identical anatomic contours, prescriptions, and planning objectives. All plans were swapped for analysis at the same time after final approval. Dose indices for targets and critical organs were compared based on dose-volume histograms, the beam-on time, monitor units, and estimated leakage dose. After the disclosure of comparison results, replanning was done for both techniques to minimize diversity in optimization focus from different operators. RESULTS: For the 16 cases compared, the average beam-on time was 1.4 minutes for RA and 4.8 minutes for HT plans. HT provided better target dose homogeneity (7.6% for RA and 4.2% for HT) with a lower maximum dose (110% for RA and 105% for HT). Dose conformation numbers were comparable, with RA being superior to HT (0.67 vs. 0.60). The doses to normal tissues using these two techniques were comparable, with HT showing lower doses for more critical structures. After planning comparison results were exchanged, both techniques demonstrated improvements in dose distributions or treatment delivery times. CONCLUSIONS: Both techniques created highly conformal plans that met or exceeded the planning goals. The delivery time and total monitor units were lower in RA than in HT plans, whereas HT provided higher target dose uniformity.

Comparative analysis of the post-lumpectomy target volume versus the use of pre-lumpectomy tumor volume for early-stage breast cancer: implications for the future.

PURPOSE: Three-dimensional conformal accelerated partial breast irradiation (APBI-3D-CRT) is commonly associated with the treatment of large amounts of normal breast tissue. We hypothesized that a planning tumor volume (PTV) generation based on an expansion of the pre-lumpectomy (pre-LPC) intact tumor volume would result in smaller volumes of irradiated normal breast tissue compared with using a PTV based on the post-lumpectomy cavity (post-LPC). Use of PTVs based on the pre-LPC might also result in greater patient eligibility for APBI-3D-CRT. METHODS AND MATERIALS: Forty-one early-stage breast cancers were analyzed. Preoperative imaging was used to determine a pre-LPC tumor volume. PTVs were developed in the pre- and post-LPC settings as per National Surgical Breast and Bowel Project (NSABP)-B39 guidelines. The pre- and post-LPC PTV volumes were compared and eligibility for APBI-3D-CRT determined using NSABP-B39 criteria. RESULTS: The post-LPC PTV exceeded the pre-LPC PTV in all cases. The median volume for the pre- and post-LPC PTVs were 93 cm(3) (range, 24-570 cm(3)) and 250 cm(3) (range, 45-879 cm(3)), respectively, p <0.001. The difference between pre- and post-LPC PTVs represented a median of 165 cc (range, 21-482 cc) or 16% (range, 3%-42%) of the whole breast volume. Three of 41 vs. 13 of 41 cases were ineligible for APBI-3D-CRT when using the pre- and post-LPC PTVs, respectively. CONCLUSION: PTVs based on pre-LPC tumor expansion are likely associated with reduced amounts of irradiated normal breast tissue compared with post-LPC PTVs, possibly leading to greater patient eligibility for APBI-3D-CRT. These findings support future investigation as to the feasibility of neoadjuvant APBI-3D-CRT.

Comparing radiation treatments using intensity-modulated beams, multiple arcs, and single arcs.

PURPOSE: A dosimetric comparison of multiple static-field intensity-modulated radiation therapy (IMRT), multiarc intensity-modulated arc therapy (IMAT), and single-arc arc-modulated radiation therapy (AMRT) was performed to evaluate their clinical advantages and shortcomings. METHODS AND MATERIALS: Twelve cases were selected for this study, including three head-and-neck, three brain, three lung, and three prostate cases. An IMRT, IMAT, and AMRT plan was generated for each of the cases, with clinically relevant planning constraints. For a fair comparison, the same parameters were used for the IMRT, IMAT, and AMRT planning for each patient. RESULTS: Multiarc IMAT provided the best plan quality, while single-arc AMRT achieved dose distributions comparable to those of IMRT, especially in the complicated head-and-neck and brain cases. Both AMRT and IMAT showed effective normal tissue sparing without compromising target coverage and delivered a lower total dose to the surrounding normal tissues in some cases. CONCLUSIONS: IMAT provides the most uniform and conformal dose distributions, especially for the cases with large and complex targets, but with a delivery time similar to that of IMRT; whereas AMRT achieves results comparable to IMRT with significantly faster treatment delivery.

Improved survival with radiation therapy in high-grade soft tissue sarcomas of the extremities: a SEER analysis.

PURPOSE: The benefit of radiation therapy in extremity soft tissue sarcomas remains controversial. The purpose of this study was to determine the effect of radiation therapy on overall survival among patients with primary soft tissue sarcomas of the extremity who underwent limb-sparing surgery. METHODS AND MATERIALS: A retrospective study from the Surveillance, Epidemiology, and End Results (SEER) database that included data from January 1, 1988, to December 31, 2005. A total of 6,960 patients constituted the study population. Overall survival curves were constructed using the Kaplan-Meir method and for patients with low- and high-grade tumors. Hazard ratios were calculated based on multivariable Cox proportional hazards models. RESULTS: Of the cohort, 47% received radiation therapy. There was no significant difference in overall survival among patients with low-grade tumors by radiation therapy. In high-grade tumors, the 3-year overall survival was 73% in patients who received radiation therapy vs. 63% for those who did not receive radiation therapy (p < 0.001). On multivariate analysis, patients with high-grade tumors who received radiation therapy had an improved overall survival (hazard ratio 0.67, 95% confidence interval 0.57-0.79). In patients receiving radiation therapy, 13.5% received it in a neoadjuvant setting. The incidence of patients receiving neoadjuvant radiation did not change significantly between 1988 and 2005. CONCLUSIONS: To our knowledge, this is the largest population-based study reported in patients undergoing limb-sparing surgery for soft tissue sarcomas of the extremities. It reports that radiation was associated with improved survival in patients with high-grade tumors.