3D Conformal Radiotherapy Research Articles

Physician Rated Cosmesis and Patient Reported Outcomes after Concomitant Boost (CB) vs. Sequential Boost (SB) for Adjuvant Treatment of Breast Cancer: A Prospective Randomized Study

<h3>Purpose/Objective(s)</h3> The aim of the current study was to compare toxicity, cosmesis and patient reported outcomes after sequential radiation therapy boost vs. concomitant boost in the adjuvant setting of breast cancer treatment. <h3>Materials/Methods</h3> One hundred and forty-five breast cancer patients who underwent breast conserving surgery and were candidates for tumor bed boost following whole breast irradiation (WBI) were randomized to receive either concomitant boost (CB) (n=71) or sequential boost (SB) (n=74). All patients received WBI to a total dose of 40.05 Gy/15 F/3 weeks. Patients in the SB arm received 10 Gy/5 F / 1 week to the boost volume following WBI. Patients in the CB arm received 7.95 Gy/15 F/3 weeks to the boost volume concomitant with the WBI. All treatments were carried out using 3D conformal radiation therapy. Physicians rated cosmesis prior to starting radiation and at 6 and 12 months after end of treatment. All patients filled a validated quality of Life questionnaire 12 months after end of treatment. <h3>Results</h3> Median follow-up 30 months (range, 18-48). G III or higher acute skin toxicity was observed in 12 (16.4%) patients in the SB arm and in 4 (6.3%) patients in the CB arm (p 0.042). GII or higher late skin toxicity developed in 4 (5.4%) patients in the SB arm and in 1 (1.4%) patient in the CB arm (p 0.18). GII subcutaneous fibrosis was observed in 3 (4%) patients in the SB arm and in none of the patients in the CB arm. Prior to radiation treatment, 50 (67.5%) patients had Excellent/good cosmesis in the SB arm vs. 47 (66.2%) patients in the CB arm (p 0.59). At 6 months after radiation, 44 (59.4%) patients had Excellent/good cosmesis in the SB arm vs. 40 (56.3%) patients in the CB arm (p 0.83). At 12 months after radiation, 50 (67.5%) patients in the SB arm had Excellent/good cosmesis vs 42 (59.2%) patients in the CB arm (p 0.57). twelve months after radiation, 50 (78.1%) patients in the SB arm reported very satisfied/satisfied with their cosmetic outcomes compared to 44 (72.1%) patients in the CB arm (p 0.43). <h3>Conclusion</h3> Concomitant boost radiation therapy is non-inferior to sequential boost in terms of late toxicity, cosmesis and patient satisfaction with slightly more favorable outcome in the acute toxicity and shorter overall treatment time.

Extracranial Hypofractionated Radiotherapy for Advanced Melanoma in the Era of Immunotherapy

<h3>Purpose/Objective(s)</h3> The role of radiation therapy in optimizing localcontrol continues to evolve in the era of immunotherapy which has dramatically improved outcomes for select patients with advanced melanoma. We sought to evaluate the temporal relationship between hypofractionated radiation therapy and immunotherapy delivery and its impact on outcomes. <h3>Materials/Methods</h3> On an IRB approved protocol, we evaluated patients treated from 2017-2021 with 6Gyx5 fractions for extracranial disease with cutaneous melanoma at a single institution managed with intensity modulated radiation therapy, 3D conformal radiation therapy, or electron therapy. Radiosurgery patients were excluded. Patient characteristics and IO therapy delivery schedules were extracted from the medical record and Kaplan-Meier curves were generated for progression free survival (PFS) and overall survival (OS). Patients were divided into cohorts of receiving IO therapy within three weeks of radiation therapy (concurrent) vs those that did not. Treated targets were assessed using RECIST 1.1 criteria. Chi-Square was utilized to assess relationships between response rates and sequencing of IO (concurrent vs not). <h3>Results</h3> Twenty-seven lesions were treated in 25 patients and 19 patients received IO. Fourteen (56%) patients carried BRAF mutations. Median OS for the entire cohort was 36.3 months (95% CI 15-62) and median follow up was 15.2 months. There were no significant differences between patients who received dual agent IO vs single agent IO, or between IO therapy within 3 weeks of radiation vs outside of this window. In patients with gross disease, the complete response rate was 60%, partial response was 8.7% and 21% experienced stable or locally progressive disease. Response rates did not vary by radiation therapy timing when using Chi-Square (p>0.05). Therapy was tolerated well with no acute grade 4-5 toxicities. <h3>Conclusion</h3> No temporal relationship between IO therapy and hypofractionated RT was found within the cohort. Treatment was well tolerated well with 68% obtaining a complete or partial response to hypofractionated radiation therapy for gross disease with 6Gy x 5 fractions. The short treatment duration makes this treatment schedule appealing and convenient for patients with advanced disease. The complexity of therapy for advanced melanoma with multiple prior treatment lines, limited number of patients, and uncertainty of duration of activity immunotherapy limit the extent of this analysis. Larger datasets with more granular detail are necessary to identify a potential temporal relationship between concurrent immunotherapy and hypofractionated radiation therapy.

Trends and Predictors of Proton Therapy Utilization in Early-Stage Hodgkin Lymphoma: A National Cancer Database Analysis

<h3>Purpose/Objective(s)</h3> Early stage (ES) Hodgkin Lymphoma (HL) is a highly curable malignancy for which consolidative radiotherapy (RT) is often recommended. HL frequently affects young adults, who are at elevated risk of late RT toxicity. Proton therapy (PT), which can offer a more optimal integral dose distribution compared to conventional photon radiotherapy (XRT), is often pursued in this population when available. We aimed to report trends in PT utilization using the National Cancer Database (NCDB) over a period of increasing modality availability. <h3>Materials/Methods</h3> The NCDB was used to identify adult patients with stage I or II classical HL treated with multiagent chemotherapy and consolidative RT (XRT or PT) between 2004 and 2018. PT utilization was analyzed over time using Pearson's Chi-squared test, with confidence intervals (CI) around the annual percentage of patients treated with PT calculated using the Clopper-Pearson method. Predictors of PT utilization were determined using Chi-squared tests and multivariable logistic regression. <h3>Results</h3> From 2004 to 2018, 14,344 patients met inclusion criteria, of which 51.5% were male, 86.5% were white, and the median age was 36 years old (ranging from 18 to 90 with most patients (59.4%) within the category of 18 to 40 years old). Only 198 (1.4%) patients received PT. The most common histologies were nodular sclerosing (78%) and mixed cellularity (13%). Of those with adequately coded data: the most common total RT doses (cGy) were 3060 (28%), 3000 (18%), 3600 (14%), and 2000 (10%); 56% were treated with IMRT vs 3D conformal RT (44%); RT site included head and neck in 50% and thorax in 44%, and 70% had RT at nonacademic centers distributed throughout the US (south 25%, northeast 24%, midwest 34%, west 17%). From 2004 to 2018, the percentage of PT receipt increased from 1% (n=9, 95% CI 0-1%) to 4% (n=34, 95% CI 3-6%), with an inflection point at 2012. From 2004 to 2012 an average of 3.8 patients were treated with PT per year, whereas from 2013 to 2018 the average was 27.3 per year (p < 0.001). Of those receiving PT, 79% were 18-40 years ole while the oldest was 78, and 58% were female. On univariable analysis, receipt of PT was associated with younger age (p<0.001), female gender (p=0.01), private insurance (p<0.001), Medicaid (p<0.001), and above median income quartile by zip code (MIQBZ) (p=0.003). Charlson-Comorbidity Index score 0 (vs. ≥1; p=0.10) trended towards significance in predicting PT and was included in the multivariable model. Variables remaining significant for predicting PT receipt on multivariable logistic regression included age ≤ 40 (OR 2.1, CI 1.4-3.0, p<0.001), above MIQBZ (OR 1.6, CI 1.1-2.2, p=0.01), and female gender (OR 1.5, CI 1.1-2.0, p=0.01). <h3>Conclusion</h3> PT utilization in ES HL patients has gradually but significantly increased since 2004, with an inflection point at 2013. Female patients under 40 with above MIQBZ are most likely to be receiving PT.

Evaluation of Patient Reported Outcome Differences by Radiotherapy Technique for Bone Metastases in a Non-Incentivized Health Care System

<h3>Purpose/Objective(s)</h3> We previously demonstrated a low utilization, but mild increase over time, of advanced radiotherapy (RT) techniques (3D conformal RT [3DCRT], intensity modulated radiotherapy [IMRT] and stereotactic ablative radiotherapy [SABR] from 2009-2016) for bone metastases. Patient reported outcome (PRO) data was not yet available in our previous publication. This analysis therefore compares PROs by RT technique in a public, salary-funded, non-incentivized health care system, to assess if patient reported pain and impact on quality of life (QoL) is superior with advanced techniques. <h3>Materials/Methods</h3> From 2017-2021 inclusive, patients with bone metastases who completed the brief pain inventory (BPI) PRO questionnaire at one of five BC Cancer centers before and after RT were identified, and RT technique was categorized as simple (e.g., parallel opposed pair) or advanced (e.g., 3DCRT, IMRT, or SABR). Pain response was compared using chi-square tests. Patient reported interference on QoL to pain was compared with t-tests. Multivariable analyses of pain response and pain impact on QoL was compared with logistic and linear regression, respectively. <h3>Results</h3> 1712 patients completed the BPI, with an average age of 64 (SD 12.4). From 2017 – 2021 the rate of advanced RT technique use increased significantly (p<0.001; 2.4%, 2.5%, 9.6%, 4.7%, 7.9%), with most advanced techniques consisting of 3DCRT (26%) or IMRT (67%) versus SABR (7%). Comparing simple vs advanced techniques, neither the complete response (12.2% vs 11.9%; p=0.93) nor the partial response (50.1% vs 50.6%; p=0.92) were significantly different. There was no significant patient reported difference in pain interfering with general activity (p=0.70), mood (p=0.26), walking ability (p=0.89), normal work (p=0.37), relationships (p=0.63), sleep (p=0.94), or enjoyment of life (p=0.31). Controlling for age, gender, primary histology, and treatment region, there was no significant association between advanced RT (vs simple RT) and a partial (OR 1.04; 95% CI: 0.66-1.64) or complete (OR 0.97; 0.48-1.93) pain response. <h3>Conclusion</h3> In this publicly funded, non-incentivized health care system, there was no patient reported difference in pain or impact of pain on quality of life between simple vs advanced RT techniques. Given there is increasing utilization of advanced RT techniques in our cohort and other jurisdictions internationally, there is further need for randomized trials to assess the benefits of advanced techniques given their increased cost and inconvenience to patients.

Cost of Care Related to Treatment of Bone Metastases: Real World Data from a National Health Insurance Provider

<h3>Purpose/Objective(s)</h3> Bone metastases are a common occurrence in patients with advanced stage malignancy, often impacting quality of life. Radiation has been, and remains, a highly effective modality for the treatment of symptomatic bone metastases. Various radiation fractionation schemes and techniques exist and are used across the United States in these patients. The cost of care presumably varies significantly based on those factors (technique and number of fractions). We accessed payer claims data from a health insurance provider in Pennsylvania, Delaware, and West Virginia to help determine the actual cost of care for patients with bone metastases treated with radiation. <h3>Materials/Methods</h3> This study was a secondary data analysis of medical claims data using a retrospective design among insured members in Pennsylvania, Delaware, and West Virginia with an ICD-10 code of C79.51 and history of radiation therapy billed under that code from 1/1/2016 to 9/30/2021. Patients were grouped by age, sex, and geographical region. Number of claims and total cost of care were tabulated by year. We also examined which radiation technique was used (intensity modulated radiation therapy (IMRT) vs. 3D conformal radiotherapy (3D CRT) vs. complex isodose plan) based on CPT codes. Lastly, we looked at the use of image guided radiation therapy (IGRT) over that same time period, again using CPT codes. <h3>Results</h3> We identified 29,201 patients treated with radiation for diagnosis code C79.51 between 2016 and 2021. The median number of claims per year was 4,866 (2,744-6,000). Fifty-one percent of patients were male (13,676). The majority of patients (79%) resided in Pennsylvania. The median total cost of care related to ICD-10 C79.51 was $181,918,217 ($163,672,315-$183,565,407). The median number of claims for those years was 95,024 (89,870-101,449). The number of claims per patient varied from 2.3-5.0 and 3.5-10.2 for isodose complex treatment and IMRT, respectively. Most patients were treated using isodose complex technique or 3D CRT (combined 80-90%) with a relatively even split. The use of IMRT remained relatively stable over the timeframe (5-15%). The use of IGRT increased over time, with highest number of claims for IGRT being 2020 (458 claims) (median 266, range: 183-458). The median cost per year for all care related to ICD10 C79.51 was $10,887,581, $7,274,264, and $1,902,141 for patients treated with 3D CRT, IMRT, and isodose complex, respectively. <h3>Conclusion</h3> Radiation remains a widely used technique for the palliation of bone metastases. The cost of care related to its use are significant. The use of IGRT increased over time, with no obvious impact on overall cost of care. The use of IMRT remained low for bone metastases, with an associated increase in cost of care. The overall cost of care remained lowest for those patients treated with isodose complex treatment.

Trends in IMRT Utilization for Definitive Treatment of Cervical Cancer, 2004-2018

<h3>Purpose/Objective(s)</h3> Intensity-modulated radiation therapy (IMRT) is an advanced radiotherapy technique that delivers conformal radiation to desired targets while minimizing dose to surrounding organs at risk. In the post-operative setting, IMRT is associated with reduced acute and late genitourinary and gastrointestinal side effects for patients with cervical cancer. However, no prospective randomized data exist for the use of IMRT in the setting of definitive treatment of intact cervical cancer. The objective of this study was to identify trends in IMRT use for this population. <h3>Materials/Methods</h3> Patients with stage IB2-IVA cervical cancer diagnosed from 2004-2018 who were treated with curative intent chemoradiation were identified in the National Cancer Database. Patients who underwent primary surgical management, did not receive external beam radiation to the pelvis or received radiation outside the pelvis, or received an unspecified technique or target of radiation were excluded. The primary outcome of interest was utilization of IMRT vs 3D conformal radiotherapy (3D-CRT) over time. A Cochrane-Armitage test was performed to assess trends over time. T-tests, chi-square tests, and multivariable logistic regression with propensity score matching were used to identify factors associated with receipt of IMRT. <h3>Results</h3> Overall, 13,974 patients met inclusion criteria; 4,590 (33%) received IMRT, and 9,384 (67%) received 3DCRT. In this cohort, 65% were non-Hispanic White, 45% were early stage (I-II), 80% were squamous histology, 62% received brachytherapy, and 28% had lymph node involvement. The utilization of IMRT increased from 30% in 2004 to 71% in 2018 (p<0.001). After adjustment for clinical and demographic variables, factors associated with IMRT use were: Hispanic ethnicity (adjusted odds ratio [aOR] 1.2, 95% confidence interval [CI] 1.0-1.5), treatment in the Western U.S. (aOR 1.4, CI 1.2-1.7) and the Southern U.S. (aOR 1.3, CI 1.1-1.5), living more than 50 miles from the treatment facility (aOR 1.2, CI 1.0-1.5), stage III disease (aOR 1.3, CI 1.1-1.5), and lymph node involvement (aOR 1.4, CI 1.3-1.6). Compared to an academic medical center, patients receiving care at a comprehensive community cancer center were less likely to receive IMRT (aOR 0.66, CI 0.59-0.72). There were no differences in IMRT use by age, insurance, or medical comorbidities. <h3>Conclusion</h3> Despite the lack of prospective efficacy data supporting the use of IMRT in patients with intact cervical cancer, IMRT has dramatically increased over the last fifteen years especially for patients with advanced-stage disease or lymph node involvement. More data on the optimal use of IMRT, including appropriate target volume margins and on-board imaging, are needed.

Toxicity Analysis of Patients with Prostate Cancer Treated with 3D-Conformal Compared to Intensity Modulated Radiotherapy: Secondary Analysis of RTOG 0126 and RTOG 0415

<h3>Purpose/Objective(s)</h3> Patients with low- (LR) and intermediate-risk (IR) prostate cancer (PC) have excellent control rates following definitive radiation therapy (RT), but may experience treatment morbidity that impacts quality-of-life. To decrease normal tissue toxicity, modern techniques such as intensity modulated (IM) RT have largely replaced 3D-Conformal (3D-C) RT for PC. The objective of our study was to describe the comparative benefit of IMRT over 3D-CRT for patients undergoing prostate RT across different RT dosing and fractionation schemes. <h3>Materials/Methods</h3> We performed a post-hoc analysis of patients enrolled on RTOG 0126 and RTOG 0415. RTOG 0126 randomized to dose escalated (DE), conventionally fractionated (CF) RT (79.2 Gy/44 Fx) or standard dose (SD) CF RT (70.2 Gy/39 Fx). RTOG 0415 randomized to hypofractionated (HF) RT (70 Gy/28 Fx) or SD CF RT (73.8 Gy/41 Fx). Treatment with 3D-CRT and IMRT was at the discretion of the treating physician; target OAR dose constraints were the same irrespective of RT modality. We performed a logistic regression analysis of RT modality and acute and late grade 2+ gastrointestinal (GI) or genitourinary (GU) toxicity as per CTCAE criteria across the different dose regimens. <h3>Results</h3> A total of 2,590 patients treated in both studies were included in our analysis. The median patient age was 69 and median follow up was 6.9 years. On RTOG 0126, 66.3% and 33.7% were treated with 3DCRT and IMRT respectively, while 20.6% and 78.2% were treated with 3DCRT and IMRT on RTOG 0415, respectively. On both studies combined, the overall rate of acute grade 2+ GI and GU toxicity was 7.7% and 20.9%, respectively; the rate of late grade 2+ GI and GU toxicity was 18.2% and 17.5%, respectively. There was no significant difference in acute grade 2+ GI or GU toxicity between those treated with either RT modality across the different dosing regimens. For patients receiving DE CF RT, IMRT resulted in improved late grade 2+ GI toxicity compared to 3D-CRT (16.8% vs. 23.4%, OR=0.65, 95% CI 0.44-0.96, p=0.03). There was also a significant improvement in late grade 2+ GU toxicity with the use of IMRT compared to 3D-CRT (9.4% vs. 16.1%, OR=0.53, 95% CI 0.32-0.86, p=0.01). However, there was no significant difference in toxicity rates between IMRT and 3D-CRT for late GI or GU toxicity when using SD CF RT or HF RT. <h3>Conclusion</h3> Patients undergoing CF dose-escalated RT benefit from IMRT, while patients receiving CF SD (70.2Gy or 73.8 Gy) RT or HF RT did not show a difference in toxicity based on RT modality. These data provide a framework to compare the relative benefit of modern RT techniques (e.g., proton, SBRT, MR-guided RT) to IMRT in future studies.

Machine Learning to Refine Selection Criteria of Post-Operative Radiotherapy for Resectable Stage III-N2 Non-Small Cell Lung Cancer

<h3>Purpose/Objective(s)</h3> The role of post-operative radiotherapy (PORT) for completely resected N2 non-small cell lung cancer (NSCLC) is controversial, given the recently published LungART and PORT-C trials. We sought to utilize machine learning to identify a subset of patients who may still benefit from PORT based on the extent of nodal involvement. <h3>Materials/Methods</h3> Patients with completely resected N2 NSCLC were identified in the National Cancer Database diagnosed between 2004 and 2017. The query was subsequently limited to patients with pN2 disease, known pathologic T stage, and no evidence of distant metastasis. Patients were excluded if they had unknown follow-up, did not undergo surgery (lobectomy, bilobectomy, or pneumonectomy), did not undergo lymph node dissection, had positive margins, had unknown number of positive lymph nodes or total lymph nodes examined, or received neoadjuvant radiation. We trained a machine-learning based model of overall survival (OS). SHapley Additive exPlanation values (SHAP) were used to identify prognostic and predictive thresholds for the number of positive lymph nodes (LNs) involved and lymph node ratio (LNR). Multivariable (MVA) Cox proportional-hazards regression was used for confirmatory analysis. <h3>Results</h3> A total of 16,789 patients with completely resected N2 NSCLC were identified. Of the patients that met inclusion criteria, 6181 (36.8%) received PORT. When radiation treatment technique could be determined, about half received 3D conformal radiation therapy (18.7% of all patients) and about half received IMRT (19.9% of all patients). Median follow-up for the entire cohort was 32.0 months (0-183.1 months). Median OS of the whole population was 41.7 months (95%CI: 40.7-43.1). For patients who received PORT, median OS was 47.6 months (95%CI: 45.2-49.7). For patients who did not receive PORT, median OS was 38.6 months (95%CI: 37.1-39.9). Using SHAP values, we identified thresholds of 3+ positive LNs and a LNR of 0.34+. On MVA, PORT was not significantly associated with OS (HR: 0.96; 95%CI: 0.92-1.01); (p=0.111). However, a subset analysis of patients with 3+ positive LNs revealed that PORT improved OS (HR: 0.91; 95%CI: 0.86-0.97; p=0.002). Patients with 3+ positive LNs had a 5-year OS of 38% (95%CI: 36-40%) with PORT compared to 31% (95%CI: 29-32%) without PORT. Patients with 1-2 positive LNs had a 5-year OS of 49% (95%CI: 47-51%) with PORT compared to 44% (95%CI: 43-46%) without PORT. On a separate subset analysis, in patients with a LNR of 0.34+, PORT improved OS (HR: 0.90; 95%CI: 0.85-0.96; p=0.001). Patient with positive LNR of 0.34+ had a 5-year OS of 38% (95%CI: 36-40%) with PORT compared to 29% (95%CI: 28-31%) without PORT. Patients with a positive LNR of 0.00-0.33 had a 5-year OS of 47% (95%CI: 45-49%) with PORT compared to 43% (95%CI: 42-44%) without PORT. <h3>Conclusion</h3> This study suggests that patients with 3+ positive LNs or a LNR of 0.34+ may present a subpopulation of patients who could benefit from PORT. These findings warrant further investigation in a future prospective study.

Bombarding Oligoprogression: Oncologic Outcomes Following Localized Radiotherapy in Oligoprogressive Non-Small Cell Lung Cancer Patients on Maintenance Systemic Therapy

<h3>Purpose/Objective(s)</h3> The purpose of this study is to evaluate the efficacy and toxicity of focal radiotherapy (RT) to all oligoprogressive sites to prolong the durability of current systemic therapy or meaningful clinical benefit (MCB) in patients with metastatic non-small cell lung cancer (NSCLC) and one to five sites of progressive disease. The primary endpoints include progression-free survival (PFS) and MCB. Secondary endpoints include overall survival (OS), local control (LC), event free survival (EFS), and toxicities of RT. <h3>Materials/Methods</h3> Treatment records at our institution were reviewed (2018 to 2021) and included if they had metastatic NSCLC, started maintenance systemic therapy, developed oligoprogression (1-5 sites), and all oligoprogressive sites amenable to and treated with RT with the intent for MCB. Prior RT was allowed. Kaplan-Meier survival analysis and log-rank testing were performed using R-Studio software. PD-L1 status and actionable mutations were also documented. Toxicities were documented using the CTCAE v5.0. <h3>Results</h3> From our records, 23 patients were identified and met inclusion criteria. Thirteen (57%) were female and 10 were male. Twenty-one (91%) of patients had adenocarcinoma, 10 (43%) had actionable mutations, and 13 (57%) had PD-L1 expression > 1%. 13 patients (56%) were on PD1/PD-L1 checkpoint inhibition, 7 (30%) patients were on EGFR-targeted therapy, and 3 (13%) patients were receiving chemotherapy alone. A total of 41 targets were irradiated with a median of 2 per patient (range 1 to 4), with 28 (68%) targets receiving stereotactic body radiotherapy or radiosurgery, 12 (29%) receiving intensity-modulated radiotherapy, and 1 (2%) receiving 3D conformal RT. At a median follow-up of 12.6 months, there were 17 progression events; 6 patients started next-line therapy and 6 were recommended no further therapy based on declining performance status or no suitable next line systemic therapy. Four patients received additional targeted radiotherapy for oligoprogression and did not switch therapies. Median PFS, OS, and EFS were 8.4 months (IQR 4.1 – 17.5), 17.2 months (IQR 12.6 – 31.4), and 8.3 months (IQR 2.7 – 12.0), respectively. At 12 months follow-up, 6 (43%) of 14 living patients maintained their systemic therapy without initiating next-line therapy. Median time to start of next line therapy (MCB) was not reached in this analysis due to few events. There was one local failure of an irradiated site yielding an in-field failure rate of 4%. Two patients (9%) had grade 3 chronic toxicity related to RT and were medically managed. <h3>Conclusion</h3> We identified that in oligoprogressive metastatic NSCLC patients, targeted RT to all progressive sites yielded high rates of LC and favorable rates of PFS and MCB. Future prospective trials with well-selected oligoprogressive patients are warranted to further evaluate the role of focal RT to oligoprogressive sites in this patient population.

Risk for Second Primary Hematologic Malignancies by Radiotherapy Technique in Prostate Cancer Survivors

<h3>Purpose/Objective(s)</h3> Among the most serious adverse effects after radiotherapy for prostate cancer is the development of second malignant neoplasms. Recent advances in radiotherapy techniques, such as the introduction of intensity-modulated radiation therapy (IMRT) and proton beam radiotherapy (PBRT), have aimed to reduce exposure to adjacent healthy tissues but may lead to greater bone marrow exposure. Risks for developing myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) but not lymphoid malignancies after radiotherapy have been demonstrated. We quantified risks of hematologic malignancies following IMRT and PBRT compared to 3D conformal radiotherapy (CRT) in a large cohort of prostate cancer patients. <h3>Materials/Methods</h3> This retrospective cohort study used the linkage of Surveillance, Epidemiology, and End Results (SEER) cancer registry data with Medicare claims, including men who were diagnosed with first primary non-metastatic prostate cancer at ages 66-84 years from 2002-2014, received external beam radiotherapy (IMRT, PBRT, or CRT) but no chemotherapy in the first year after diagnosis, and survived ≥2 years after diagnosis without a second primary cancer. Using Cox regression, hazard ratios (HR) and corresponding 95% confidence intervals (CI) were computed to estimate risk of second primary hematologic malignancies, classified into subtypes according to the World Health Organization, after IMRT and PBRT vs CRT. Models were adjusted for age at prostate cancer diagnosis, tumor grade, race, Charlson comorbidity score, and receipt of initial prostate cancer therapy. <h3>Results</h3> The cohort (median follow-up=6.8 years) included 69,966 patients, of whom 23,806 received CRT alone, 43,901 received IMRT without PBRT, and 2,259 received PBRT. A total of 387 patients developed a myeloid malignancy, most commonly MDS/AML, N=291), and 739 developed a lymphoid malignancy, most commonly plasma cell neoplasms (N=178) and diffuse large B-cell lymphoma (N=159). Compared to patients who received CRT, neither IMRT nor PBRT was associated with risk of developing myeloid malignancies overall (IMRT: N=211, HR=0.89, 95%CI 0.70-1.13; PBRT: N=13, HR=0.97, 95%CI 0.55-1.74), with similar results for MDS/AML specifically. Similarly, neither IMRT nor PBRT was associated with risk of developing lymphoid malignancies overall (IMRT: N=390, HR=0.93, 95%CI 0.78-1.11; PBRT: N=24, HR=0.94, 95%CI 0.61-1.43) compared to CRT, with similar results for specific lymphoid malignancy subtypes. <h3>Conclusion</h3> This is among the first cohort studies analyzing risk of hematologic malignancies by subtype after prostate cancer radiotherapy. With longer follow-up and larger sample size compared to previous reports, the hypothesized change in risk for MDS/AML with IMRT/PBRT compared to CRT was not observed. As more data accumulates from patients receiving PBRT, we can gain greater insight into the technique's long-term effects.

Utilization of Advanced Radiation Techniques in Neuroendocrine Carcinoma of the Pancreas

<h3>Purpose/Objective(s)</h3> Pancreatic neuroendocrine neoplasms (PNEN) are a rare disease entity with a wide spectrum of clinical behavior. To date, surgery remains the standard of care curative option for patients with early stage PNENs. However, a subset of patients will be ineligible for surgery requiring alternative treatment approaches such as radiotherapy. We thus used the National Cancer Database to examine trends in radiation use for PNEN, focusing specifically on different radiation techniques. <h3>Materials/Methods</h3> We queried the NCDB from 2004-2015 for patients with PNEN that were treated with external beam radiation techniques including 3D conformal radiotherapy (3D-CRT), intensity modulated RT (IMRT), and stereotactic body radiation therapy (SBRT). Baseline characteristics were tabulated. Multivariable logistic regression was used to identify predictors of SBRT and IMRT use. Multivariable Cox regression was used to identify predictors of survival. Kaplan Meier curves were generated to estimate survival. <h3>Results</h3> Using the above criteria we identified 185 patients, of which 18% received SBRT and 25% received IMRT. The median age was 61 years (31-90) and the majority of patients (27%) had stage II disease. The median IMRT dose was 45 Gy (IQR: 41.6-50.4 Gy) in 25 fractions and the median SBRT dose was 30 Gy (25.5-39.8 Gy) in 5 fractions. Predictors of SBRT use included lack of chemotherapy and earlier T stage. Predictors of IMRT use were conventional fractionation and more recent treatment year. The median follow up was 21.9 months (IQR: 10.7-38.6). On Cox regression, predictors of worse survival were older age, higher comorbidity score, higher grade, and higher T stage. Kaplan Meier analysis revealed median survival of 27 months and 40 months for CFRT and SBRT, respectively (p=0.17). <h3>Conclusion</h3> This analysis shows a small but steady increase in the use of advanced radiation techniques for localized PNEN. SBRT appears to be a reasonable option in appropriately selected candidates.

A Pilot Study of CONcurrent ChEmotherapy and RadioTherapy in Adjuvant Treatment of Breast Cancer (CONCERT)

<h3>Purpose/Objective(s)</h3> The study hypothesis was that concurrent adjuvant chemoradiation (CTRT) is safe in adjuvant treatment of breast cancer. This was tested in a prospective interventional pilot study with dose-limiting toxicity as the primary endpoint. It also assesses the compliance rate, toxicity rate and short-term disease related outcomes. CTRI/2019/02/017411 <h3>Materials/Methods</h3> Stage II-III invasive breast cancer patients who were planned for adjuvant taxane-based chemotherapy and adjuvant radiotherapy were screened for the study during April 2019 to December 2020. Patients received standard 3D conformal radiotherapy (40 Gy in 15 fractions over 3 weeks ± boost in case of breast conservation) which was started with the third cycle of adjuvant taxanes in a 3-weekly schedule, or with the eighth cycle of adjuvant taxanes in weekly schedule. <h3>Results</h3> Sixty patients were analyzed. Median age of the study cohort was 46 years (28-66 years). Large majority (60%) women were pre-menopausal and had ECOG performance status 0 (95%) 32 patients (54%) had right sided tumors. Patients either underwent breast conservation surgery (48%) or modified radical mastectomy (52%) with axillary sampling in only small proportion of the patients (20%). 59 patients (98%) received all four cycles of anthracycline based chemotherapy (50 in the neoadjuvant setting) All the patients were compliant with taxane based chemotherapy with dose reduction in three patients in view of peripheral neuropathy. All patients completed adjuvant radiotherapy without any treatment interruption either for taxanes or radiotherapy. No dose-limiting toxicity was documented for any patient. Minimal chemotherapy-related toxicities have been reported in the form of 7 patients (11.6%) having Grade I-II fatigue and 8 patients (13.3%) having Grade I-II peripheral neuropathy. Radiotherapy-related toxicity was also minimal. The incidence of grade 0, 1 and 2 dermatitis were 4%, 84% and 12% respectively while grade 0, 1 and 2 dysphagia were 31%, 57 and 12% respectively. There was no difference between weekly and 3-weekly regimens with respect to compliance rate or toxicity. Dermatitis as well as dysphagia subsided completely by 4 weeks post-completion of CTRT. The median duration between first and last cycle of taxanes was 74 days (range 62 to 107) and radiotherapy start and conclusion was 23 days (range 19 to 28). Four patients had recurrence, one had local and distant recurrence and rest had distant recurrence only. At the median follow up of 23 months, median DFS of 17.5 months (9-22 months) and median OS of 26 months (11-33 months). The 3-year actuarial rate of DFS and OS was 75% and 98.3% respectively. <h3>Conclusion</h3> Concurrent taxane-based adjuvant CTRT is safe and feasible alternative to sequential chemotherapy and radiotherapy. There is minimal toxicity and excellent compliance for both 3-weekly as well as weekly schedules. Hence, it will be worthwhile to test concurrent CTRT in randomized setting with health-economics and disease-related endpoints.

Thirteen Years with Preoperative 5 × 5 Gy in Soft Tissue Sarcomas: A Pattern of Local Failure

<h3>Purpose/Objective(s)</h3> There is a growing number of phase 1 and 2 clinical trials with hypofractionated five-fraction preoperative radiotherapy (RT) in soft tissue sarcomas (STS). Those studies showed consistently safety and efficacy of such an approach. We introduced preoperative 5 × 5Gy in 2009, conducted and published results of three clinical trials. The mature results of the first trial showed 81% of 5-year local recurrence-free survival that is on the lower level of acceptable local control. The aim of this study was the analysis of the profile of patients who experienced local relapse (LR) to design a new clinical trial with the most optimal hypofractionated regimen. <h3>Materials/Methods</h3> We analyzed patients who received 5 × 5 Gy and underwent surgery for localized STS from three clinical trials, namely 5 × 5Gy and immediate surgery with or without perioperative chemotherapy, 5 × 5Gy with a prolonged gap to surgery in myxoid liposarcomas and combination of 5 × 5Gy with anthracycline-ifosfamide chemotherapy in marginally resectable tumors. Moreover, we included all patients who were treated outside the abovementioned trials with 5 × 5 Gy. We analyzed patients' characteristics, pathological diagnosis, RT technique, gap to surgery, chemotherapy regimen, date of LR, and type of LR. <h3>Results</h3> We found 173 (101 male and 73 female) patients who experienced local relapse after 5 × 5 Gy preoperative RT given between 2009 and 2021. The median age was 59 years. Eighty-three were irradiated for primary untreated disease, 91 for LR after previous surgery and six for a scar after non-oncological resection of STS. The most common pathological subtype of relapsed tumor was pleomorphic sarcoma (n=40) followed by myxofibrosarcoma (n=31), malignant peripheral nerve sheath tumor (n=31), and synovial sarcoma (n=19). The vast majority of STS were large (median 8 cm) and high grade (G3 n=105, G2 n=39) and localized on thigh (n=50). Only 13% of patients (n=22) were treated with IMRT/VMAT which was widely introduced in 2018 in our sarcoma center whereas the other received 3D-conformal RT (n=152). All but three patients received 5 × 5Gy followed by immediate surgery 3-7 days after irradiation. The majority of patients did not receive chemotherapy (n=126) which was introduced as a preferred treatment for high-risk sarcomas in 2016. 62% of patients experienced LR more than 12 months after surgery. One hundred thirteen patients were amenable to any form of curative surgery (conservative or amputation). We observed a decrease in the number of local recurrences year by year after the introduction of the 5 × 5 Gy protocols, probably due to the introduction of IMRT/VMAT and neoadjuvant chemotherapy. <h3>Conclusion</h3> This analysis showed that the profile of local relapse is similar to the general profile of STS patients. Thus, we can carefully say that 5Gy fraction dose should be increased in further trials to those used in similar studies i.e., 5 × 6Gy and 5 × 7Gy.

Disparities in Specialized Radiation Treatment Modalities for Grade Group 2, Intermediate-Risk Prostate Cancer

<h3>Purpose/Objective(s)</h3> Men with Grade Group 2 (GG2) intermediate risk (IR) prostate cancer (PCa) have multiple curative radiation (RT) options. Compared to conventional external beam photon RT (XRT), including 3D-conformal RT (3DCRT) and IMRT, highly conformal RT techniques may provide less integral RT dose to normal tissue, including brachytherapy (BT), SBRT, and proton beam radiation therapy (PBT). These treatments require either advanced equipment and/or specialized training. Here we analyzed national trends in utilization of XRT, BT monotherapy, SBRT, and PBT, and assessed potential factors associated with receiving each technique. We hypothesize that socioeconomic and/or racial disparities are associated with differences in utilization of these specialized techniques. <h3>Materials/Methods</h3> Men diagnosed with favorable IR PCa cancer, defined as Gleason 3+4 disease, PSA < 20 and clinical stage T1-T2 N0 M0, between 2004-2017 were identified in the National Cancer Database. Cohorts were defined as: XRT (3DCRT+IMRT, hypofractionated (HF) or standard fractionation (SF)), BT monotherapy (HDR, LDR), SBRT (5 fx) and PBT (HF or SF). Trends in utilization were examined. Associations between technique and patient, clinical disease, and sociodemographic characteristics were assessed by multivariable logistic regression, with <i>P</i><0.05 considered significant. <h3>Results</h3> 71,140 patients met inclusion criteria of which 72.4% received standard XRT and 27.6 % received specialized radiation modalities (18.5% brachytherapy, 6.0% SBRT, & 3.1% PBT). Utilization of XRT and BT declined from 71.0% (XRT) and 27.5% (BT) in 2004 to 69.7% (XRT) and 17.2% (BT) in 2017. Receipt of SBRT and PBT increased from 0% (SBRT) and 1.45% (PBT) in 2004 to 9.9% (SBRT) and 3.3% (PBT) in 2017, respectively. On multivariable logistic regression, Black patients were less likely to receive BT (adjusted OR 0.79; 95%CI 0.74-0.83), SBRT (adjusted OR 0.77; 95%CI 0.70-0.85), or PBT (adjusted OR 0.39; 95%CI 0.33-0.47) compared to XRT (all <i>P</i><0.0001). Socially disadvantaged seniors (SDS; age >65 years with Medicaid insurance) were less likely to receive specialized RT (adjusted OR 0.45; 95%CI 0.31-0.60; P<0.0001). Factors associated with increased likelihood of receiving BT, SBRT, or PBT included: treatment at Academic/Research center, treatment at a metropolitan facility, younger age, lower Charlson-Deyo Comorbidity Score, and lower PSA at presentation (all P < 0.01). <h3>Conclusion</h3> Trends in utilization of RT modalities have dramatically changed in recent years with a sharp decline in BT, a doubling of PBT, and rapid adoption of SBRT, as coded in the NCDB. Compared to White patients with GG2 IR PCa, there are disparities in utilization of BT, SBRT, and PBT for Black patients and for SDS. It is unclear whether similar disparities exist for other prostate cancer grade groups for which BT and SBRT are being utilized. Future efforts should address access-to-care challenges for the use of these specialized techniques as they are expanded into higher GG.

A Combined Hypofractionated Volumetric Modulated Arc Radiotherapy, Radio-Sensitising and Adjuvant Metronomic Chemotherapy Treatment for Canine Stage IV Nasal Tumours With Intracranial Extension

Radiation therapy has become the standard of care in the treatment of canine intranasal neoplasia, but because of the poor prognosis associated with stage IV nasal tumours and the proximity of the brain to the irradiation target, few data regarding the treatment of very advanced neoplasms are available. The aim of this pilot study was to evaluate the feasibility, safety and effectiveness of a combined treatment composed of definitive high-dose hypofractionated volumetric modulated arc radiotherapy on tumours with concurrent treatment of regional lymph nodes if positive or as prophylaxis, carboplatin radio-sensitising, and adjuvant metronomic chemotherapy for stage IV canine nasal tumours with intracranial extension.A pilot observational study was conducted in 7 dogs. Magnetic resonance imaging follow-up examinations revealed complete responses in 5 dogs and partial responses in 2. The median overall survival time, evaluated via Kaplan−Meier survival analysis, was 310 days with a 95% confidence interval of 210-400 days, whereas the median progression-free survival was 240 days with a 95% confidence interval of 190-290 days.Despite the proximity of highly sensitive organs at risk, no grade III or IV toxicities were observed, and volumetric modulated arc radiotherapy seemed to be a feasible treatment option for stage IV canine nasal tumours where conformal 3D radiotherapy has proven to give higher doses with severe damage to the surrounding unaffected tissues. Further studies are needed on the role of the sphenoid bone microscopic infiltration and regional lymph node involvement. The absence of severe toxicity could also lead to a dose escalation study and chemotherapy scheme.

Development of a computational pregnant female phantom and calculation of fetal dose during a photon breast radiotherapy.

The incidence of carcinoma during pregnancy is reported to be 1:1000-1:1500 pregnancies with the breast carcinoma being the most commonly diagnosed. Since the fetus is most sensitive to ionizing radiation during the first two trimesters, there are mixed clinical opinions and no uniform guidelines on the use of radiotherapy during pregnancy. Within this study the pregnant female phantom in the second trimester, that can be used for radiotherapy treatment planning (as DICOM data), Monte Carlo simulations (as voxelized geometry) and experimental dosimetry utilizing 3D printing of the molds (as .STL files), was developed. The developed phantom is based on MRI images of a female patient in her 18th week of pregnancy and CT images after childbirth. Phantom was developed in such a manner that a pregnant female was scanned "in vivo" using MRI during pregnancy and CT after childbirth. For the treatment of left breast carcinoma, 3D conformal radiotherapy was used. The voxelized geometry of the phantom was used for Monte Carlo (MC) simulations using Monte Carlo N-Particle transport codeTM 6.2 (MCNP). The modeled photon breast radiotherapy plan, applied to the phantom, indicated that the fetus dose is 59 mGy for 50 Gy prescribed to the breast. The results clearly indicate that only 9.5% of the fetal dose is caused by photons that are generated in the accelerator head through scattering and leakage, but the dominant component is scattered radiation from the patient's body.

Trends in Postoperative Intensity-Modulated Radiation Therapy Use and Its Association With Survival Among Patients With Incompletely Resected Non–Small Cell Lung Cancer

National guidelines allow consideration of postoperative radiation therapy (PORT) among patients with incompletely resected non-small cell lung cancer (NSCLC). However, there is a paucity of prospective data because recently completed trials excluded patients with positive surgical margins. In addition, unlike for locally advanced NSCLC, the role of intensity-modulated radiation therapy (IMRT) for PORT remains unclear. To evaluate trends of IMRT use for PORT in the US and the association of IMRT with survival outcomes among patients with incompletely resected NSCLC. This retrospective cohort study used data from the National Cancer Database for patients diagnosed between January 2004 and December 2019 with incompletely resected NSCLC who underwent upfront surgery with positive surgical margins followed by PORT. IMRT vs 3D conformal radiation therapy (3DCRT) for PORT. The main outcome was overall survival. Multivariable Cox proportional hazards regression assessed the association of IMRT vs 3DCRT with overall survival. Multivariable logistic regression identified variables associated with IMRT. Propensity score matching (1:1) was performed based on variables of interest. A total of 4483 patients (2439 men [54.4%]; median age, 67 years [IQR, 60-73 years]) were included in the analysis. Of those, 2116 (47.2%) underwent 3DCRT and 2367 (52.8%) underwent IMRT. Median follow-up was 48.5 months (IQR, 31.1-77.2 months). The proportion of patients who underwent IMRT increased from 14.3% (13 of 91 patients) in 2004 to 70.7% (33 of 471 patients) in 2019 (P < .001). IMRT was associated with improved overall survival compared with 3DCRT (adjusted hazard ratio, 0.84; 95% CI, 0.78-0.91; P < .001). Similar findings were observed for 1463 propensity score-matched pairs; IMRT was associated with improved 5-year overall survival compared with 3DCRT (37.3% vs 32.2%; hazard ratio, 0.88; 95% CI, 0.80-0.96; P = .003). IMRT use was associated with receipt of treatment at an academic facility (adjusted odds ratio [aOR], 1.15; 95% CI, 1.00-1.33; P = .049), having T4 stage tumors (aOR, 1.50; 95% CI, 1.13-1.99; P = .005) or N2 or N3 stage tumors (aOR, 1.25; 95% CI, 1.04-1.51; P = .02), and receipt of pneumonectomy (aOR, 1.35; 95% CI, 1.02-1.80; P = .04). This cohort study found that use of IMRT for PORT among patients with incompletely resected NSCLC increased in the US from 2004 to 2019 and was associated with improved survival compared with 3DCRT. Further studies are warranted to investigate the role of different radiation therapy techniques for PORT.

Verification of monitoring unit calculations for the 3D conformal radiotherapy treatment planning system

The present work aims to validate an Independent Calculation of Monitoring Units (ICMU) software developed to accurately calculate the number of Monitoring Units (MU) used in radiation treatment. The calculation was performed for the photon beam with a variety of nominal energies (6 MV − 18 MV) and filed size ranging from 3 × 3 cm2 to 40 × 40 cm2. Two set-up conventions of treatment techniques were tested, a constant source to surface distance (SSD) and an isocentric set-up with a constant source to axis distance (SAD). The ICMU software was written in C-sharp (C #), using the equivalent square field size concept to calculate the radiation field quantities and connects to a database containing measurements quantities such as Tissue Phantom ratio (TPR) and Output Factors (OFs). The ICMU was successfully validated by comparing it to the Treatment Planning System (TPS) or CMS Monitor Unit Calculations (CMS_MU). The required standards were satisfactorily met (5.0%).

Practice Patterns and Perspectives on Stereotactic Body Radiation Therapy for the Metastatic Spine From Lower- and Middle-Income Countries.

We wanted to understand the current practice patterns and stereotactic body radiation therapy (SBRT) utilization for spine metastases in lower- and middle-income countries (LMICs). A questionnaire was designed to identify the current practice patterns of treating spine metastases, uptake of spine SBRT in routine care, dose fractionations commonly used, and the perceived benefits and toxicities of using ablative doses. Individuals registering for a spine SBRT workshop were requested to answer the questionnaire. We received 395 responses from radiation oncologists (ROs) working in 12 different LMICs. The majority of respondents were from an academic institute (57.5%). Two hundred seventy-four respondents further identified themselves from the government/public sector (44.89%), corporate/private sector (47.89%), not-for-profit organization (5.4%), or public-private partnership (5.4%). The respondents indicated that 8.43%, 27.46%, 41.73%, and 10.04% of the spine metastases patients are treated using clinical marking, X-ray-based, 3D conformal radiation therapy, and SBRT, respectively. A third of the respondents did not have any experience of spine SBRT; those with high-volume practice were predominantly from an academic institute. The majority of respondents would use spine SBRT to reduce pain severity (71.9%) and achieve durable pain control (61.01%) in the setting of oligometastases (92.73%) and reirradiation (56.69%). Respondents preferred 3- to 5-fraction regimens (64.9%) over 1-2 fractions (33.68%). The top three reasons for not using spine SBRT were resource constraints (50%), lack of machine (37.11%), and lack of training (27.34%). There is heterogeneity in spine SBRT practice and utilization between academic and nonacademic institutes. Resource and infrastructure constraints along with lack of training are limiting the use of SBRT among ROs from LMICs. Collaborative studies from LMICs will help in resolving unique challenges posed by resource constraints.

Dosimetric comparison between intensity modulated radiotherapy and three-dimensional conformal radiotherapy in adjuvant setting after radical cystectomy in high-risk urothelial bladder cancer

Objective: To compare the 4-field 3D conformal radiotherapy technique (3DCRT) to the intensity-modulated radiotherapy (IMRT) 9-field technique for adjuvant radiotherapy post radical cystectomy in high-risk urothelial bladder cancer cases. Patients and Methods: A dosimetric analysis of 11 urothelial bladder cancer patients who underwent radical cystectomy was performed. These patients were presented to the radiotherapy department, National Cancer Institute, Cairo, between 2018 and 2020 with adjuvant radiotherapy using the IMRT technique. Two plans were designed for each patient, one using 9-field IMRT and the second using 4-field 3DCRT. The two techniques were compared, including the PTV, bowel bag, rectum, neobladder, and pelvic bone marrow. Results: Comparing different DVHs, the planning target volume (PTV) was adequately covered in both plans, while the 9-field IMRT technique delivered significantly lower doses to OARs (bowel, rectum, and pelvic bone marrow). Conclusion: The IMRT technique incredibly spared the OARs more than that obtained by the 3DCRT technique, while both techniques covered the PTV adequately. The IMRT technique, through sparing OARs, was expected to decrease early and late radiation side effects.