A Phase II Trial of Once Weekly Hypofractionated Breast Irradiation for Early Stage Breast Cancer.

PURPOSE: To report an interim analysis of a phase II trial of once weekly, hypofractionated breast irradiation (WH-WBI) following breast conserving surgery (BCS). METHODS: Patients had stage 0-II breast cancer treated with breast BCS with negative margins. WH-WBI was 28.5 or 30Gy delivered to the whole breast using tangential beams with no elective coverage of lymph nodes. The primary endpoint was ipsilateral breast tumor recurrence (IBTR). Secondary endpoints were distant disease-free survival (DDFS), recurrence free survival (RFS), overall survival (OS), adverse events and cosmesis. RESULTS: From 2011 to 2015, 158 patients received WH-WBI. Median follow up was 4.4 years (range 0.2-8.1). Stage distribution was DCIS 22%; invasive pN0 68%; invasive pN1 10%. 80 patients received 30 Gy and 78 received 28.5 Gy with median follow up times of 5.6 and 3.7 years, respectively. There were 5 IBTR events, all in the 30 Gy group. The 5- and 7- year risks of IBRT for all patients were 2.2% (95% CI 0.6-5.8) and 6.0% (95% CI 1.1-17.2), respectively. The 7-year rates of DDFS, RFS, and OS were 96.3%, 91.5% and 89.8%, respectively. Improvement in IBTR-free time was seen in DCIS, lobular histology, low grade tumors, Her2 negative tumors and 28.5 Gy dose (all p < 0.0001). CONCLUSIONS: Disease-specific outcomes after WH-WBI are favorable and parallel those seen with conventional radiation techniques for stage 0-II breast cancer.

Patterns of care and outcomes of radiotherapy or hormone therapy in patients with medically inoperable endometrial adenocarcinoma.

OBJECTIVE: The optimal treatment for medically inoperable endometrioid endometrial adenocarcinoma is unknown. The goal of this study was to evaluate the patterns of care and efficacy of radiotherapy (RT) or hormone therapy (HT) in the treatment of these patients. METHODS: We performed a query of the National Cancer Database (NCDB) of patients with medically inoperable endometrioid adenocarcinoma of the endometrium diagnosed between 2004 and 2016 and treated with either RT or HT. A multivariate Cox regression model and propensity weighted analyses were used to evaluate overall survival after controlling for confounding variables. A multinomial logistic regression model was used to assess predictors of RT or HT use. RESULTS: A total of 1036 patients were included in this cohort, and 73% (n = 759) were treated with RT alone. Patients who received definitive HT compared to RT were more likely to be older, diagnosed in the earlier years of this analysis, treated at lower-case volume centers, diagnosed with high-grade disease, or located outside of metropolitan areas. On multivariate analysis, treatment with HT alone versus RT alone was associated with significantly worse overall survival in the multivariate Cox model but not on propensity score weighted analysis. Interaction effect testing revealed that older patients and those treated at lower-volume centers had improved survival with RT compared to HT. CONCLUSIONS: We identified factors associated with the receipt of RT or HT in medically inoperable endometrial cancer patients. Treatment with RT correlated with improved survival compared to HT in older patients and those treated at lower-volume centers.

Role of adjuvant chemotherapy in patients with FIGO stage IB grade 3 endometrial endometrioid adenocarcinoma treated with surgery and post-operative radiotherapy.

BACKGROUND: The optimal treatment of patients with FIGO stage IB grade 3 endometrial endometrioid adenocarcinoma remains unknown. OBJECTIVE: To compare overall survival following treatment with a hysterectomy and adjuvant radiotherapy with or without chemotherapy in this group of patients. METHODS: Patients diagnosed between January 2004 and January 2016 with FIGO stage IB grade 3 endometrial endometrioid adenocarcinoma treated with hysterectomy and postoperative radiotherapy with or without adjuvant concurrent chemotherapy were identified in the National Cancer Database. Overall survival was assessed with Kaplan-Meier curves. A Cox model was constructed to evaluate survival after controlling for confounding variables. A logistic regression model was used to reveal predictors of chemotherapy use. RESULTS: A total of 2173 patients were included. The receipt of chemotherapy was associated with an increased 5-year overall survival from 67.6% to 75.6% (p=0.0313). This association trended toward statistical significance on multivariate analysis (adjusted HR (aHR) 0.80; 95% CI 0.63 to 1.01; p=0.0653). Other factors associated with improved survival were undergoing a lymphadenectomy, absence of lymphovascular space invasion, younger age, smaller tumor size, non-black race, and absence of comorbidities. Patients who underwent brachytherapy, had lymphovascular space invasion, were younger, were diagnosed in the more recent years, and were treated in higher volume centers were more likely to receive adjuvant chemotherapy. CONCLUSION: Adjuvant chemotherapy and radiation therapy were associated with an increase in survival in patients with FIGO stage IB grade 3 endometrial endometrioid adenocarcinoma compared with those treated with adjuvant radiotherapy alone.

Surface mould brachytherapy in oral and oropharyngeal cancers.

INTRODUCTION: There are insufficient data on surface mold brachytherapy (SMB) in treating oral cancers. We reviewed our institutional experience to investigate the efficacy and toxicity of this treatment modality. MATERIAL AND METHODS: We retrospectively reviewed all the patients treated between 1989 and 2018 with high-dose-rate iridium-192 SMB for oral and oropharyngeal squamous cell carcinomas at our institution. Surface mold brachytherapy was delivered via an acrylic surface mold with 1-5 inserted catheters spaced 1 cm apart fabricated by our dental oncologist. The Kaplan-Meier product estimator was used to assess local control (LC), locoregional control (LRC), distant metastasis-free survival (DMFS), and overall survival (OS). Cox proportional hazards regression analysis was used to assess the relationship of various variables and patient outcomes. RESULTS: Eighteen patients met the inclusion criteria and were evaluated. Indications for treatment were primary tumor (n = 13), local recurrence (2), locoregional recurrence (1), and oligometastatic disease (1). Ten patients received SMB alone and 8 received external beam radiotherapy with an SMB boost. The acute toxicity outcomes were as follows: no toxicity (n = 1), grade 1 (7), grade 2 (9), and grade 3 (1). Late effects were rare, only occurring in 3 patients. The one- and two-year LC were 81% and 68%, LRC 77% and 64%, DMFS 81% and 81%, and OS 77% and 46%. CONCLUSIONS: Surface mold brachytherapy is a viable modality as either primary or boost treatment for superficial oral cancers. In our patients, this treatment method has a low toxicity profile and resulted in reasonable LC.

Stereotactic body radiation therapy (SBRT) of adrenal gland metastases in oligometastatic and oligoprogressive disease.

BACKGROUND: Stereotactic body radiation therapy (SBRT) as a form of noninvasive treatment that is becoming increasingly used to manage cancers with adrenal gland metastases. There is a paucity of data on safety and efficacy of this modality. The aim of the study was to evaluate the safety and efficacy of adrenal gland SBRT in oligometastatic and oligoprogressive disease. MATERIALS AND METHODS: In this retrospective study, we performed a single-institution analysis of 26 adrenal lesions from 23 patients with oligometastatic or oligoprogressive disease treated from 2013 to 2019 with the goal of achieving durable local control. Palliative cases were excluded. Radiation dosimetry data was collected. Kaplan Meier product estimator and Cox proportional hazards regression analysis were used for statistical analysis. RESULTS: The median dose was 36 Gy in 3 fractions (range: 24-50 Gy and 3-6 fractions) with a median biologically effective dose (BED10) of 72 (range: 40-100). 1-year local control rate was 80% and median local control was not achieved due to a low number of failures. 1- and 2-year overall survival rates were 66% and 32%. Toxicity was mild with only one case of grade 2 nausea and no grade 3-5 toxicity. Higher neutrophil to lymphocyte ratio was associated with worse overall survival and a trend toward worse progression-free survival. In addition, worse performance status and lower BED10 were associated with worse survival. No such association could be shown for primary tumor location, histology, size or stage. CONCLUSION: Adrenal SBRT for oligometastatic or oligoprogressive disease is a safe and effective form of treatment.

Stereotactic Body Radiation Therapy (SBRT) in Pelvic Lymph Node Oligometastases.

The role of stereotactic body radiation therapy (SBRT) in achieving durable local control and palliation of pain in pelvic lymph node oligometastatic disease is not well-studied. We performed a retrospective analysis of 30 patients with 43 pelvic lymph node oligometastases from various primary cancers all but one with non-prostate primaries treated at our institution with SBRT. The median follow-up time was 21 months. The median SBRT dose was 24 Gy in four fractions. The one-, two-, and five-year local control was 74%, 71%, and 70% and one-, two-, and five-year overall survival was 70%, 47%, and 31%. Toxicities were mild with no grade 3 or higher.

Stereotactic Body Radiation Therapy in Oligometastatic Uterine Cancer: Clinical Outcomes and Toxicity.

We report on clinical outcomes in patients with oligometastatic uterine cancer treated with stereotactic body radiation therapy (SBRT). Twenty-seven patients with 61 lesions were treated with SBRT. Median follow-up was 16.9 months. Local control was achieved in 49/61 (80.3%) lesions. One-year local-progression-free survival and overall survival were 75.9% and 65.4%. Lesions with favorable response were smaller than lesions with unfavorable response (p = .007). Liver lesions were less likely to achieve favorable response (p = .0128). There were no grade 3 or 4 events. Treatment with SBRT can provide excellent local control in oligometastatic uterine cancer with minimal toxicity.

Stereotactic body radiation therapy (SBRT) in recurrent, persistent or oligometastatic gynecological cancers.

OBJECTIVE: SBRT is a well-tolerated technique and provides local-regional control in a variety of metastatic and recurrent tumor types. The role of SBRT in extracranial recurrent, persistent, or oligometastatic gynecological tumors is not well-studied. We therefore retrospectively analyzed a sizeable number of patients in this setting. METHODS: We performed a retrospective review of 86 patients with 209 tumors treated at our institution with SBRT for recurrent, persistent, or oligometastatic extracranial gynecological tumors. The median follow-up was 20 months (range 1-91). The median SBRT dose was 24 Gy (range 10-50) delivered in a median of 4 fractions (range 1-6). The Kaplan-Meier curves and log rank tests were used to assess local control (LC) and overall survival (OS). Cox proportional hazards model was used to evaluate for covariates associated with LC and OS. RESULTS: The 1- and 3-year LC were 80% and 68% respectively. The 1- and 3-year OS were 70% and 39%. 32% of the lesions demonstrated complete response, 23% partial response and 20% stable disease. SBRT achieved better local control in smaller tumors. Toxicity was typically mild with grade 1 gastrointestinal toxicity and fatigue being the most common. Only 4.3% of treatments resulted in grade 2 or greater toxicity. There was only one case of grade 3 and no grade 4 or 5 toxicities. CONCLUSIONS: SBRT offers a high rate of local control with low incidence of toxicity, mainly grade 1 GI toxicity and fatigue, and provides effective salvage therapy for oligometastatic extracranial pelvic and extra-pelvic gynecological tumors.

Verrucous carcinoma of the vulva: Patterns of care and treatment outcomes.

BACKGROUND: Verrucous vulvar carcinoma (VC) is an uncommon and distinct histologic subtype of squamous cell carcinoma (SCC). The available literature on VC is currently limited to case reports and small single institution studies. AIMS: The goals of this study were to analyze data from the National Cancer Database (NCDB) to quantitate the incidence of VC and to investigate the effects of patient demographics, tumor characteristics, and treatment regimens on overall survival (OS) in women with verrucous vulvar carcinoma. METHODS AND RESULTS: Patients diagnosed with vulvar SCC or VC between the years of 2004 and 2016 were identified in the NCDB. OS was assessed with Kaplan-Meier curves and the log-rank test. Construction of a Cox model compared survival after controlling for confounding variables. The reported incidence of SCC of the vulva has significantly increased since 2004 (p < .0001). In contrast, the incidence of VC has remained stable (p = .344) since 2004. Compared to SCC, VC was significantly more likely to be diagnosed in older women (p < .0001) and treated with surgery alone (p < .0001). However, on propensity score weighted analysis there was a trend toward improved 5-year OS in women with VC compared to those with SCC (63.4% vs. 57.7%, p = .0794). Multivariable Cox survival analysis showed an improvement in OS in VC patients treated with both primary site and regional lymph node surgery compared to primary site surgery alone (adjusted hazard ratio [aHR] 0.67, 95% confidence interval [CI] 0.46-0.97, p = .0357). CONCLUSION: Verrucous carcinoma is more likely to present in older women. Regional lymph node surgery in addition to primary site surgery significantly improves OS in VC patients.

Final Analysis of a Phase 2 Trial of Once Weekly Hypofractionated Whole Breast Irradiation for Early-Stage Breast Cancer.

PURPOSE: We hypothesize that 5-fraction once weekly hypofractionated (WH) whole breast irradiation (WBI) would be safe and effective after breast-conserving surgery for medically underserved patients with breast cancer. We report the protocol-specified primary endpoint of in-breast tumor recurrence (IBTR) at 5 years. METHODS AND MATERIALS: After provided informed consent, patients were treated with WH-WBI after breast-conserving surgery were followed prospectively on an institutional review board-approved protocol. Women included in this study had stage 0-II breast cancer treated with negative surgical margins and met prespecified criteria for being underserved. WH-WBI was 28.5 or 30 Gy delivered to the whole breast with no elective coverage of lymph nodes. The primary endpoint was IBTR at 5 years. Secondary endpoints were distant disease-free survival, recurrence-free survival, overall survival, adverse events, and cosmesis. RESULTS: One hundred fifty-eight patients received WH-WBI on protocol from 2010 to 2015. Median follow-up was 5.5 years (range, 0.2-10.0 years). Stage distribution was 22% ductal carcinoma in situ, 68% invasive pN0, and 10% invasive pN1. Twenty-eight percent of patients had grade 3 tumors, 10% were estrogen receptor negative, and 24% required adjuvant chemotherapy. There were 6 IBTR events. The 5-, 7-, and 10-year risks of IBTR for all patients were 2.7% (95% confidence interval [CI], 0.89-6.34), 4.7% (95% CI, 1.4-11.0) and 7.2% (95% CI, 2.4-15.8), respectively. The 5-, 7-, and 10-year rates of distant disease-free survival were 96.4%, 96.4%, and 86.4%; the recurrence-free survival rates were 95.8%, 93.6%, and 80.7%; and the overall survival rates were 96.7%, 88.6%, and 76.7%, respectively. Improvement in IBTR-free time was seen in ductal carcinoma in situ, lobular histology, low-grade tumors, T1 stage, Her2-negative tumors, and receipt of a radiation boost to the lumpectomy bed. CONCLUSIONS: Postoperative WH-WBI has favorable disease-specific outcomes that are comparable to those seen with conventional and moderately hypofractionated radiation techniques. WH-WBI could improve access to care for underserved patients with stage 0-II breast cancer.

The impact of brachytherapy boost and radiotherapy treatment duration on survival in patients with vaginal cancer treated with definitive chemoradiation.

PURPOSE: Vaginal cancer is a rare tumor that is optimally treated with a combination of chemotherapy (CHT) and radiation therapy. Because of the rarity of this cancer, the benefit of a brachytherapy boost (BT) and the relevance of radiotherapy time to treatment completion (TTC) are unclear. METHODS: Patients diagnosed between 2004 and 2015 with non-metastatic vaginal cancer treated with definitive CHT and external beam radiotherapy with or without BT but with no surgery were identified in the National Cancer Database. Overall survival (OS) was assessed with Kaplan-Meier curves, and differences between groups were compared with the log-rank test. A Cox model was constructed to evaluate survival after controlling for confounders. A Cox model using a penalized spline function was constructed to evaluate how the length of radiation therapy correlated with OS among patients receiving BT. RESULTS: A total of 1094 patients who met the inclusion criteria were identified. The utilization of BT was associated with improved 5-year OS (62.9% vs. 49.3%, p = 0.0126) on propensity score-weighted analyses. TTC of 63 days or less was associated with improved 5-year OS (67.8% vs. 54.5%, p = 0.0031) in patients who underwent BT. Other factors associated with improved OS in patients who received CHT, external beam radiotherapy, and BT were younger age, absent comorbidity score, and negative lymph nodes. CONCLUSIONS: A brachytherapy boost and shorter TTC were associated with a survival benefit in a cohort of patients with non-metastatic vaginal cancer treated with definitive chemoradiotherapy.

Cardiac radiation dose distribution, cardiac events and mortality in early-stage lung cancer treated with stereotactic body radiation therapy (SBRT).

BACKGROUND: The impact of radiation dose to the heart in early-stage lung cancer patients treated with definitive stereotactic body radiation therapy (SBRT) is not well known. We, therefore, analyzed whether higher radiation dose to the heart would lead to an increase in cardiac toxicity and overall mortality. METHODS: Seventy-four patients with 75 tumors treated definitively with SBRT for early-stage non-small cell lung cancer (NSCLC) and two cases of limited-stage small cell lung cancer (SCLC) with an average follow-up of 35 months (range, 1-130 months) were retrospectively analyzed. The whole heart and cardiac substructures including atria, ventricles, heart valves, atrioventricular (AV) node and four major coronary artery branches were contoured using commercial treatment planning software. For each structure, multiple dose-volume parameters were recorded. The relation between radiation doses to the heart, tumor location, and preexisting medical conditions with the development of cardiac events and mortality was assessed. RESULTS: Overall, there was large variability in dose to cardiac substructures: mean heart dose (MHD) averaged 1.90 Gy (range, 0.04-11.00 Gy) equivalent 2 Gy dose (EQD2) and average max dose to the left anterior descending artery (LAD) was 5.67 Gy (range, 0.04-48.60 Gy) EQD2. Patients with tumor location in the upper lobes received higher cardiac radiation dose compared to other lobes (P<0.0001). There was no difference in MHD between central and peripheral tumor locations. The distance between heart and tumor was negatively associated with MHD (r=-0.61, P<0.0001). Eighteen patients developed cardiac complications including the need for defibrillator placement, arrhythmia development and worsening heart failure. Preexisting cardiac disease was associated with an increased number of cardiac events after radiotherapy (P=0.039). However, neither radiation dose to the whole heart or the cardiac substructures, nor comorbidities such as diabetes, hypercholesterolemia, hypertension or COPD were associated with the number of cardiac events or overall mortality. CONCLUSIONS: Radiation doses to the heart and its substructures show large variability. Cardiac events occurred more frequently in patients with a history of heart problems. At present, the effect of radiation dose on cardiac toxicity is unclear in patients undergoing SBRT for early-stage lung cancer. Longer follow-up and a larger cohort are needed to assess for late cardiac sequelae.

Lung and Heart Dose Variability During Radiation Therapy of Non-Small Cell Lung Cancer.

PURPOSE: To investigate the hypothesis that positional and anatomic variations during radiation therapy induce changes in lung and heart volumes and associated radiation doses. METHODS AND MATERIALS: In this longitudinal investigation, variations in lung and heart volumes and standard dose parameters of mean lung dose, lung V20Gy, mean heart dose, and heart V40Gy were analyzed on weekly 4-dimensional CT scans of 15 lung cancer patients during conventionally fractionated radiochemotherapy. Tumor, individual lung lobes, and heart were delineated on the mid-ventilation phase of weekly 4-dimensional CT scans. Lung lobes and heart were also contoured on individual breathing phases of pre-, mid-, and end-of-treatment scans. Planning dose was transferred to consecutive scans via rigid registration. Volume and dose variations were assessed relative to the initial planning scan. RESULTS: Interfraction lung volume variability relative to week 0 was twice as large as tidal volume variability (8.0% ± 5.3% vs 4.0% ± 3.3%, P=.003). Interfraction lung volume variation ranged between 0.8% and 17.1% for individual patient means. Lower lung lobes had larger volume variability compared with upper lobes (13.5% ± 8.1% vs 7.0% ± 5.0%, P<.00001). Average mean lung dose variation was 0.5 Gy (range, 0.2-1.0 Gy for individual patient means) and average lung V20Gy variation 0.9% (range, 0.2%-1.6%). Average heart volume variation was 7.2% (range, 3.4%-12.6%). Average mean heart dose variation was 1.2 Gy (range, 0.1-3.0 Gy) and average heart V40Gy variation 1.4% (range, 0%-4.2%). CONCLUSIONS: Anatomic and positional variations during radiation therapy induce changes in radiation doses to lung and heart. Repeated lung and heart dose assessment will provide a better estimate of the actual delivered dose and will improve prediction models for normal tissue toxicity, if assessed in larger cohorts.

Effect of atelectasis changes on tissue mass and dose during lung radiotherapy.

PURPOSE: To characterize mass and density changes of lung parenchyma in non-small cell lung cancer (NSCLC) patients following midtreatment resolution of atelectasis and to quantify the impact this large geometric change has on normal tissue dose. METHODS: Baseline and midtreatment CT images and contours were obtained for 18 NSCLC patients with atelectasis. Patients were classified based on atelectasis volume reduction between the two scans as having either full, partial, or no resolution. Relative mass and density changes from baseline to midtreatment were calculated based on voxel intensity and volume for each lung lobe. Patients also had clinical treatment plans available which were used to assess changes in normal tissue dose constraints from baseline to midtreatment. The midtreatment image was rigidly aligned with the baseline scan in two ways: (1) bony anatomy and (2) carina. Treatment parameters (beam apertures, weights, angles, monitor units, etc.) were transferred to each image. Then, dose was recalculated. Typical IMRT dose constraints were evaluated on all images, and the changes from baseline to each midtreatment image were investigated. RESULTS: Atelectatic lobes experienced mean (stdev) mass changes of -2.8% (36.6%), -24.4% (33.0%), and -9.2% (17.5%) and density changes of -66.0% (6.4%), -25.6% (13.6%), and -17.0% (21.1%) for full, partial, and no resolution, respectively. Means (stdev) of dose changes to spinal cord Dmax, esophagus Dmean, and lungs Dmean were 0.67 (2.99), 0.99 (2.69), and 0.50 Gy (2.05 Gy), respectively, for bone alignment and 0.14 (1.80), 0.77 (2.95), and 0.06 Gy (1.71 Gy) for carina alignment. Dose increases with bone alignment up to 10.93, 7.92, and 5.69 Gy were found for maximum spinal cord, mean esophagus, and mean lung doses, respectively, with carina alignment yielding similar values. 44% and 22% of patients had at least one metric change by at least 5 Gy (dose metrics) or 5% (volume metrics) for bone and carina alignments, respectively. Investigation of GTV coverage showed mean (stdev) changes in VRx, Dmax, and Dmin of -5.5% (13.5%), 2.5% (4.2%), and 0.8% (8.9%), respectively, for bone alignment with similar results for carina alignment. CONCLUSIONS: Resolution of atelectasis caused mass and density decreases, on average, and introduced substantial changes in normal tissue dose metrics in a subset of the patient cohort.

A Preliminary Study on Racial Differences in HMOX1, NFE2L2, and TGFß1 Gene Polymorphisms and Radiation-Induced Late Normal Tissue Toxicity.

PURPOSE: This study tested whether racial differences in genetic polymorphisms of 4 genes involved in wound repair and response to radiation can be used to predict the occurrence of normal tissue late effects of radiation therapy and indicate potential therapeutic targets. METHODS AND MATERIALS: This prospective study examined genetic polymorphisms that modulate the expression of 4 genes involved in inflammation and fibrosis and response to radiation (HMOX1, NFE2L2, NOS3, and TGFß1). DNA from blood samples of 179 patients (∼ 80% breast and head and neck) collected at the time of diagnosis by their radiation oncologist as exhibiting late normal tissue toxicity was used for the analysis. Patient demographics were as follows: 56% white, 43% African American, 1% other. Allelic frequencies of the different polymorphisms of the participants were compared with those of the general American population stratified by race. Twenty-six additional patients treated with radiation, but without toxicity at 3 months or later after therapy, were also analyzed. RESULTS: Increased frequency of a long GT repeat in the HMOX1 promoter was associated with late effects in both African American and white populations. The single nucleotide polymorphisms (SNP) rs1800469 in the TGFß1 promoter and the rs6721961 SNP in the NFE2L2 promoter were also found to significantly associate with late effects in African Americans but not whites. A combined analysis of these polymorphisms revealed that >90% of African American patients with late effects had at least 1 of these minor alleles, and 58% had 2 or more. No statistical significance was found relating the studied NOS3 polymorphisms and normal tissue toxicity. CONCLUSIONS: These results support a strong association between wound repair and late toxicities of radiation. The presence of these genetic risk factors can vary significantly among different ethnic groups, as demonstrated for some of the SNPs. Future studies should account for the possibility of such ethnic heterogeneity in the late toxicities of radiation.