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Purpose: Stereotactic radiosurgery (SRS) is the current standard of care in patients with brain metastases and controlled extracranial disease. Radiation necrosis (RN) is the dose-limiting side effect of SRS, but the dose constraints especially for fractionated SRS remain poorly defined. We assessed the risk of RN after 3-fraction SRS with a goal to identify specific dose-volume constraints associated with grade 3 or higher RN (G3RN)., Methods and Materials: A single-institutional retrospective review of patients treated with 3-fraction SRS was performed. The primary endpoint was G3RN, which was defined as severe symptoms with evidence of necrosis on magnetic resonance imaging with perfusion and/or biopsy confirmation. Tissue volume around each target lesion was contoured, and volumetric doses per lesion were recorded. Logistic regression models were used to estimate the relationship between RN and each volumetric dose, and normal tissue complication probability modeling was performed using a modified Lyman-Kutcher-Burman model., Results: From 2015 to 2021, 434 patients underwent 539 courses of linear accelerator-based SRS; 2518 lesions were treated. Median SRS dose was 24 Gy. Median follow-up after SRS was 7.9 months, and the median overall survival was 9 months. A total of 93 patients (17.2%) and 123 lesions (4.9%) developed any RN. Forty-two patients (7.8%) and 57 lesions (2.3%) developed G3RN. On logistic regression, V20 and V23 were best predictors of any grade RN and G3RN, respectively, with cutoff values of 4 cc, 10 cc, and 20 cc associated with <5%, <7.5%, and <10% risk of any RN, respectively, and V23 < 15 cc associated with <5% risk of G3RN. With constrained optimization of the normal tissue complication probability Lyman-Kutcher-Burman model for G3RN, we obtained a TD50 (uniform dose resulting in a 50% complication risk) of 31.4 Gy (95% CI, 27.8-35.1 Gy)., Conclusions: In patients receiving 3-fraction SRS, G3RN was seen in 7.8% of patients, and 2.3% of the lesions were treated. V20 and V23 were the most robust dosimetric parameters associated with RN. Further studies evaluating the outcomes and RN in patients treated with fractionated SRS compared with single-fraction SRS are warranted., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: To test the hypothesis that increasing radiation therapy (RT) dose to the thoracic vertebral bodies (TVBs) contributes to the development of hematologic toxicities (HTs) in patients with lung cancer., Methods and Materials: Cases of non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) treated with definitive chemoradiation with concurrent platinum-based doublet chemotherapy at our institution from 2007 to 2016 were identified. Mean TVB dose and the volume of TVBs receiving at least 5 to 60 Gy (V 5 -V 60 ) were retrospectively recorded. Logistic regression was used to test associations between grade ≥3 HT (HT3+) and dosimetric/clinical parameters. Normal tissue complication probability was evaluated using the Lyman-Kutcher-Burman (LKB) model for HT3+, and receiver operating characteristics analysis was used to determine dosimetric cut-points., Results: We identified 201 patients, the majority having NSCLC (n=162, 81%) and stage III to IV disease (n=179, 89%). All patients received either cisplatin/etoposide (n=107, 53%) or carboplatin/paclitaxel (n=94, 47%). Median RT dose was 60 Gy (range, 60-70 Gy). The rate of HT3+ was 49% (n=99). Increasing mean TVB dose (per Gy) was associated with higher odds of developing HT3+ (odds ratio 1.041, 95% confidence interval 1.004-1.080, P=.032), as were increasing TVB V 5 to V 20 . These dosimetric correlates to HT3+ persisted on multivariate analysis. Constrained optimization of the LKB model for HT3+ yielded the parameters: n=1, m=1.79, and TD 50 =21.4 Gy. Optimal cut-points identified were V 5 =65%, V 10 =60%, V 20 =50%, and mean dose=23.5 Gy. Patients with values above these cut-points had an approximately 2-fold increased risk of HT3+., Conclusions: We found that mean TVB dose and low-dose parameters (V 5 -V 20 ) were associated with HT3+ in chemoradiation for lung cancer. Per the LKB model, bone marrow behaves like a parallel organ (n=1), implying that mean TVB dose is a useful predictor for toxicity. These data suggest that efforts to spare dose to the TVBs may reduce rates of severe HT., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: Triapine, a novel inhibitor of the M2 subunit of ribonucleotide reductase (RR), is a potent radiosensitizer. This phase 1 study, sponsored by the National Cancer Institute Cancer Therapy Evaluation Program, assessed the safety and tolerability of triapine in combination with radiation (RT) in patients with locally advanced pancreas cancer (LAPCA)., Methods and Materials: We evaluated 3 dosage levels of triapine (24 mg/m2, 48 mg/m2, 72 mg/m2) administered with 50.4 Gy of RT in 28 fractions. Patients with LAPCA received triapine thrice weekly, every other week during the course of RT. Dose-limiting toxicity (DLT) was assessed during RT and for 4 weeks after its completion. Dynamic contrast-enhanced magnetic resonance imaging and serum RR levels were evaluated as potential predictors for early response., Results: Twelve patients were treated. Four patients (1 nonevaluable) were enrolled at dosage level 1 (DL1), 3 patients at DL2, and 5 patients (2 nonevaluable) at DL3. No DLTs were observed, and the maximum tolerated dose was not reached. Two patients (17%) achieved partial response, and 6 patients (50%) had stable disease. One patient underwent R0 resection after therapy. Ninety-two percent of patients (100% at DL3) experienced freedom from local tumor progression. In 75% of patients who eventually experienced progression, metastases developed without local progression. RR levels did not seem to predict outcome. In 4 patients with available data, dynamic contrast-enhanced magnetic resonance imaging may predict early response or resistance to therapy., Conclusion: The combination of triapine at 72 mg/m2 3 times weekly every other week and standard RT is tolerable with interesting activity in patients with LAPCA., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: We report the results of a phase II study to determine the reproducibility of a submandibular salivary gland transfer (SGT) surgical technique for prevention of radiation (XRT)-induced xerostomia in a multi-institutional setting and to assess severity of xerostomia., Methods and Materials: Eligible patients had surgery for primary, neck dissection, and SGT, followed by XRT, during which the transferred salivary gland was shielded. Intensity modulated radiation therapy, amifostine, and pilocarpine were not allowed, but postoperative chemotherapy was allowed. Each operation was reviewed by 2 reviewers and radiation by 1 reviewer. If 13 or more (of 43) were "not per protocol," then the technique would be considered not reproducible as per study design. The secondary endpoint was the rate of acute xerostomia, grade 2 or higher, and a rate of ≤ 51% was acceptable., Results: Forty-four of the total 49 patients were analyzable: male (81.8%), oropharynx (63.6%), stage IV (61.4%), median age 56.5 years. SGT was "per protocol" or within acceptable variation in 34 patients (77.3%) and XRT in 79.5%. Nine patients (20.9%) developed grade 2 acute xerostomia; 2 had grade 0-1 xerostomia (4.7%) but started on amifostine/pilocarpine. Treatment for these 11 patients (25.6%) was considered a failure for the xerostomia endpoint. Thirteen patients died; median follow-up for 31 surviving patients was 2.9 years. Two-year overall and disease-free survival rates were 76.4% and 71.7%, respectively., Conclusions: The technique of submandibular SGT is reproducible in a multicenter setting. Seventy-four percent of patients were prevented from XRT-induced acute xerostomia., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: To evaluate the conventionally fractionated and hypofractionated grid therapy in debulking cervical cancers using the linear quadratic (LQ) model., Methods and Materials: A Monte Carlo technique was used to calculate the dose distribution of a commercially available grid in a 6-MV photon beam. The LQ model was used to evaluate the therapeutic outcome of both the conventionally fractionated (2 Gy/fraction) and hypofractionated (15 Gy/fraction) grid therapy regimens to debulk cervical cancers with different LQ parameters. The equivalent open-field dose (EOD) to the cancer cells and therapeutic ratio (TR) were defined by comparing grid therapy with the open debulking field. The clinical outcomes from 114 patients were used to verify our theoretical model., Results: The cervical cancer and normal tissue cell survival statistics for grid therapy in two regimens were calculated. The EODs and TRs were derived. The EOD was only a fraction of the prescribed dose. The TR was dependent on the prescribed dose and the LQ parameters of both the tumor and normal tissue cells. The grid therapy favors the acutely responding tumors inside radiosensitive normal tissues. Theoretical model predictions were consistent with the clinical outcomes., Conclusions: Grid therapy provided a pronounced therapeutic advantage in both the hypofractionated and conventionally fractionated regimens compared with that seen with single fraction, open debulking field regimens, but the true therapeutic advantage exists only in the hypofractionated grid therapy. The clinical outcomes and our study indicated that a course of open-field radiotherapy is necessary to control tumor growth fully after a grid therapy.

Purpose: Advanced and recurrent tumors of the paranasal sinuses can be difficult to irradiate to high doses with standard external beam radiotherapy (EBRT), conventional brachytherapy, or intraoperative electron beams. We, therefore, explored the role of intraoperative high-dose-rate brachytherapy (IOHDR) as a boost to EBRT in primary tumors or as sole adjuvant treatment in recurrent disease., Methods and Materials: Between 1992 and 1998, 34 patients with locally advanced tumors arising in the paranasal sinuses were treated with IOHDR after maximal surgical excision. Twenty-seven patients with new primaries underwent gross resection and 10-12.5 Gy IOHDR followed by 45-50 Gy EBRT. Seven previously irradiated (45-63 Gy) patients with recurrent disease were treated with 15-20 Gy of IOHDR alone after gross excision. Local control and overall survival were analyzed using the Kaplan-Meier method and compared using the log-rank test., Results: After a mean follow-up of 6 years (range 34-120 months), the 1-, 3-, and 5-year actuarial survival rate was 80%, 62%, and 44%, respectively. The overall local control rate at 1 and 5 years was 75% and 65%, respectively, and distant failure was documented in 44% of patients. Subgroup analysis revealed that the presence of gross disease after surgical resection was the strongest prognosticator, with a 5-year survival and local control rate of 17% and 50%, respectively, compared with 60% and 68%, respectively, for microscopic disease. The local control rates of patients with new primaries were similar to those of patients treated for recurrent disease (63% vs. 71%), probably because gross residual disease occurred only in the group of patients with new primaries. The addition of EBRT to IOHDR increased the 5-year disease-free survival rate from 27% to 44% but had no effect on local control (64% vs. 65%)., Conclusion: IOHDR can be safely used to deliver a high radiation dose to locally advanced and recurrent tumors in the paranasal sinuses. In an attempt to improve outcome, we are now adding limited-dose EBRT (20-30 Gy) after 17.5 Gy of IOHDR in previously irradiated patients and increasing the EBRT dose for both microscopic (50-54 Gy) and gross residual disease (60-65 Gy) after 15 Gy of IOHDR in previously unirradiated patients. Chemosensitization should also be considered in previously irradiated patients and in those with gross residual disease. Interstitial boosting techniques, which can deliver higher doses at depth, should also be considered in patients with gross residual disease.

Purpose: This is a retrospective review to evaluate the role of surgery and intraoperative electron beam radiotherapy (IOERT) in the treatment of patients with previously irradiated advanced head and neck cancers., Methods and Materials: Between January 1992 and March 1997, 38 patients (31 males, 7 females; median age of 62 years) with recurrent head and neck cancer were treated with maximal resection and IOERT at the Ohio State University (OSU). All had been previously treated with full-course radiotherapy (median 65.1 Gy, range 50-74.4 Gy). Twenty-nine patients (76%) had previously undergone one or more surgical procedures. After maximal surgery the tumor bed was treated with IOERT (single field in 36 patients and 2 fields in 2 patients), most commonly with 6 MeV electrons (87%). The dose administered (at 90% isodose line) was 15 Gy for close or microscopically positive margins in 34 patients and 20 Gy for gross disease in 1 patient. Further external beam radiation therapy (EBRT) was not given., Results: After a median follow-up of 30 months (range 8-39 months), 24 of the 38 patients (66%) recurred within the IOERT field. Median time to IOERT failure was 6 months (95% CI: 4.3-7.7). The 6-month, 1-, and 2-year control rates within the IOERT volume were 41%, 19%, and 13%, respectively. Thirty of the 38 patients (79%) recurred in locoregional areas. Median time to locoregional failure was 4 months (95% CI: 3.3-4.7). The 6-month, 1-, and 2-year locoregional control rates were 33%, 11%, and 4%, respectively. Distant metastases occurred in 7 patients, 5 in association with IOERT failure and 2 with locoregional failure. Median overall survival was 7 months (95% CI: 4.7-9.3). The 6-month, 1-, 2-, and 3-year actuarial survival rates were 51%, 21%, 21%, and 8%, respectively. Major treatment-related complications occurred in 6 patients (16%)., Conclusion: IOERT alone, at the dose used, is not sufficient for control of recurrent, previously irradiated head and neck cancers. Since higher IOERT doses are associated with high morbidity, we are currently evaluating the addition of limited EBRT dose and/or brachytherapy to improve the local control of these poor prognostic recurrent tumors, with acceptable morbidity.