Effect of Doxepin Mouthwash or Diphenhydramine-Lidocaine-Antacid Mouthwash vs Placebo on Radiotherapy-Related Oral Mucositis Pain: The Alliance A221304 Randomized Clinical Trial.

Importance: Oral mucositis causes substantial morbidity during head and neck radiotherapy. In a randomized study, doxepin mouthwash was shown to reduce oral mucositis-related pain. A common mouthwash comprising diphenhydramine-lidocaine-antacid is also widely used. Objective: To evaluate the effect of doxepin mouthwash or diphenhydramine-lidocaine-antacid mouthwash for the treatment of oral mucositis-related pain. Design, Setting, and Participants: A phase 3 randomized trial was conducted from November 1, 2014, to May 16, 2016, at 30 US institutions and included 275 patients who underwent definitive head and neck radiotherapy, had an oral mucositis pain score of 4 points or greater (scale, 0-10), and were followed up for a maximum of 28 days. Interventions: Ninety-two patients were randomized to doxepin mouthwash (25 mg/5 mL water); 91 patients to diphenhydramine-lidocaine-antacid; and 92 patients to placebo. Main Outcome and Measures: The primary end point was total oral mucositis pain reduction (defined by the area under the curve and adjusted for baseline pain score) during the 4 hours after a single dose of doxepin mouthwash or diphenhydramine-lidocaine-antacid mouthwash compared with a single dose of placebo. The minimal clinically important difference was a 3.5-point change. The secondary end points included drowsiness, unpleasant taste, and stinging or burning. All scales ranged from 0 (best) to 10 (worst). Results: Among the 275 patients randomized (median age, 61 years; 58 [21%] women), 227 (83%) completed treatment per protocol. Mucositis pain during the first 4 hours decreased by 11.6 points in the doxepin mouthwash group, by 11.7 points in the diphenhydramine-lidocaine-antacid mouthwash group, and by 8.7 points in the placebo group. The between-group difference was 2.9 points (95% CI, 0.2-6.0; P = .02) for doxepin mouthwash vs placebo and 3.0 points (95% CI, 0.1-5.9; P = .004) for diphenhydramine-lidocaine-antacid mouthwash vs placebo. More drowsiness was reported with doxepin mouthwash vs placebo (by 1.5 points [95% CI, 0-4.0]; P = .03), unpleasant taste (by 1.5 points [95% CI, 0-3.0]; P = .002), and stinging or burning (by 4.0 points [95% CI, 2.5-5.0]; P < .001). Maximum grade 3 adverse events for the doxepin mouthwash occurred in 3 patients (4%); diphenhydramine-lidocaine-antacid mouthwash, 3 (4%); and placebo, 2 (2%). Fatigue was reported by 5 patients (6%) in the doxepin mouthwash group and no patients in the diphenhydramine-lidocaine-antacid mouthwash group. Conclusions and Relevance: Among patients undergoing head and neck radiotherapy, the use of doxepin mouthwash or diphenhydramine-lidocaine-antacid mouthwash vs placebo significantly reduced oral mucositis pain during the first 4 hours after administration; however, the effect size was less than the minimal clinically important difference. Further research is needed to assess longer-term efficacy and safety for both mouthwashes. Trial Registration: ClinicalTrials.gov Identifier: NCT02229539.

Proposed prognostic scoring system evaluating risk factors for biochemical recurrence of prostate cancer after salvage radiation therapy.

OBJECTIVE: To update a previously proposed prognostic scoring system that predicts risk of biochemical recurrence (BCR) after salvage radiation therapy (SRT) for recurrent prostate cancer when using additional patients and a PSA value of 0.2 ng/mL and rising as the definition of BCR. PATIENTS AND METHODS: We included 577 patients who received SRT for a rising PSA after radical prostatectomy in this retrospective cohort study. Clinical, pathological, and SRT characteristics were evaluated for association with BCR using relative risks (RRs) from multivariable Cox regression models. RESULTS: With a median follow-up of 5.5 years after SRT, 354 patients (61%) experienced BCR. At 5 years after SRT, 40% of patients were free of BCR. Independent associations with BCR were identified for the PSA level before SRT (RR [doubling]: 1.25, P < 0.001), pathological tumour stage (RR [T3a vs T2] 1.21, P = 0.19; RR [T3b/T4 vs T2] 2.09, P < 0.001; overall P < 0.001), Gleason score (RR [7 vs <7] 1.63, P < 0.001; RR [8-10 vs <7] 2.28, P < 0.001; overall P < 0.001), and surgical margin status (RR [positive vs negative] 0.71, P = 0.003). We combined these four variables to create a prognostic scoring system that predicted BCR risk with a c-index of 0.66. Scores ranged from 0 to 7, and 5-year freedom from BCR for different levels of the score was as follows: Score = 0-1: 66%, Score = 2: 46%, Score = 3: 28%, Score = 4: 19%, and Score = 5-7: 15%. CONCLUSION: We developed a scoring system that provides an estimation of the risk of BCR after SRT. These findings will be useful for patients and physicians in decision making for radiation therapy in the salvage setting.

Negative margin technique - a novel planning strategy to improve dose conformation in SBRT using dynamic conformal arc delivery.

The purpose of this study was to introduce a planning strategy for dynamic conformal arc therapy (DCAT), named negative margin technique (NMT), and evaluate its dosimetric gain in lung stereotactic body radiation therapy (SBRT). In DCAT, the field aperture is continuously conformed to the planning target volume (PTV) with an aperture margin (AM) to compensate for the penumbra effect with gantry rotation. It is a common belief the AM should be positive (or at least 'zero'). However, the radial penumbra width becomes significantly wider because of continuously overlapped beams in arc delivery. Therefore, we hypothesize if the 'negative margin' is applied in the radial direction, it would improve the PTV dose conformation while reducing normal tissue dose. For verification, trial plans were made using the NMT and compared with 'zero margin (ZM)' plans for five lung SBRT cases representing different situations depending on the location of the PTV and organs at risk. All plans met 95% PTV coverage with the prescription dose and spared the spinal cord below the tolerance. Two conventional conformation indices (the ratio of prescription isodose volume to the PTV (CI100) and the ratio of 50% prescription isodose volume to the PTV (CI50)) and a modified conformation index were investigated. The maximum dose at 2 cm from the PTV (Dmax-2cm) and the percent of lung volume receiving 20 Gy (V20) were also evaluated. Another planning simulation was performed with a total of ten randomly selected lung SBRT cases to mimic actual practice. In this simulation, optimization with ZM was first performed and further optimization using the NMT was processed for cases that could not meet a goal of CI100 = 1.2 with the ZM optimization. In all cases, both the CI100 and CI50 values were significantly reduced (overall, 9.4% ± 4.1% and 5.9%± 3.1% for CI100 and CI50, respectively). The modified conformation index values also showed similar improvement (overall, 10.1% ± 5.7% increase). Reduction of Dmax-2cm was also observed in all cases (4.5% ± 2.2%). V20 values decreased in all cases but one (5.7% ± 3.9%, excluding the increased case). In the random group simulation, it was possible to achieve the goal with just one NMT trial for five out of six cases that did not meet the goal in the ZM optimization. Interestingly, however, one case needed as many as six iterations to get the CI100 = 1.2 goal. The NMT turned out to be an effective planning strategy that could bring significant improvement of dose conformation. The NMT can be easily implemented in most clinics with no prerequisite.

Proton Therapy With Concurrent Chemotherapy for Thoracic Esophageal Cancer: Toxicity, Disease Control, and Survival Outcomes.

Purpose: When treating esophageal cancer with radiation therapy, it is critical to limit the dose to surrounding structures, such as the lung and/or heart, as much as possible. Proton radiation therapy allows a reduced radiation dose to both the heart and lungs, potentially reducing the risk of cardiopulmonary toxicity. Here, we report disease control, survival, and toxicity outcomes among patients with esophageal cancer treated with proton radiation therapy and concurrent chemotherapy (chemoradiation therapy; CRT) with or without surgery. Materials and Methods: We enrolled 17 patients with thoracic esophageal carcinoma on a prospective registry between 2010 and 2021. Patients received proton therapy to a median dose of 50.4-GyRBE (range, 50.4-64.8) in 1.8-Gy fractions.Acute and late toxicities were graded per the Common Terminology Criteria for Adverse Events, version 4.0 (US National Cancer Institute, Bethesda, Maryland). In addition, disease control, patterns of failure, and survival outcomes were collected. Results: Nine patients received preoperative CRT, and 8 received definitive CRT. Overall, 88% of patients had adenocarcinoma, and 12% had squamous cell carcinoma. With a median follow-up of 2.1 years (range, 0.5-9.4), the 3-year local progression-free, disease-free, and overall survival rates were 85%, 66%, and 55%, respectively. Two patients (1 with adenocarcinoma and 1 with squamous cell carcinoma) recurred at the primary site after refusing surgery after a complete clinical response to CRT. The most common acute nonhematologic and hematologic toxicities, respectively, were grades 1 to 3 esophagitis and grades 1 to 4 leukopenia, both affecting 82% of patients. No acute cardiopulmonary toxicities were observed in the absence of surgical resection. Reagarding surgical complications, 3 postoperative cardiopulmonary complications occurred as follows: 1 grade 1 pleural effusion, 1 grade 3 pleural effusion, and 1 grade 2 anastomotic leak. Two severe late CRT toxicities occurred: 1 grade 5 tracheoesophageal fistula and 1 grade 3 esophageal stenosis requiring a feeding tube. Conclusion: Proton radiation therapy is a safe, effective treatment for esophageal cancer with increasing evidence supporting its role in reducing cardiopulmonary toxicity.

Evaluation of MDM2, p16, and p53 staining levels as biomarkers of biochemical recurrence following salvage radiation therapy for recurrent prostate cancer.

BACKGROUND AND PURPOSE: The selection of appropriate candidates for salvage radiation therapy (SRT) to address a rising PSA following radical prostatectomy remains challenging. Herein, we provide the first evaluation of the ability of staining levels of the tumor based biomarkers MDM2, p16, and p53 to aid in prediction of biochemical recurrence (BCR) among men undergoing SRT for recurrent prostate cancer. MATERIAL AND METHODS: We identified 152 patients who were treated with SRT between July 1987 and July 2003. Staining levels of MDM2, p16, and p53 in primary tumor samples removed during prostatectomy were detected using monoclonal antibodies and quantified by use of a computer-assisted method. Associations of staining levels with BCR were evaluated using Cox proportional hazards regression models; relative risks (RRs) and 95% confidence intervals (CIs) were estimated. RESULTS: Compared to patients with low staining (≤median) as measured by percentage of cells with nuclear staining, there was no significant difference in risk of BCR for patients with high MDM2 staining (RR: 0.90, 95% CI: 0.57-1.45, P = 0.67), high p16 staining (RR: 0.88, 95% CI: 0.54-1.44, P = 0.62), or high p53 staining (RR: 1.33, 95% CI: 0.84-2.11, P = 0.23) in multivariable analysis. These results were consistent when considering alternate percentile cutpoints and alternate quantifications of biomarker staining. CONCLUSIONS: Our results provide evidence that MDM2, p16, and p53 staining levels are not useful in the prediction of BCR after SRT. As such, these biomarkers are of little clinical use in the selection of appropriate candidates for SRT.

Impact of neoadjuvant chemoradiation on the tumor burden before liver transplantation for unresectable cholangiocarcinoma.

The very early experience with liver transplantation (LT) for cholangiocarcinoma (CC) was dismal because of the poor survival outcomes and the high recurrence rates. However, LT for CC in conjunction with neoadjuvant chemoradiation recently has shown encouraging results, although the data are extremely limited. At our institution between 2001 and 2008, 22 CC patients underwent protocol orthotopic LT at a median age of 45 years (range = 24-63 years). At a median follow-up of 601.5 days (range = 111-1388 days), the median survival time of the cohort was 3.3 years. The 1-, 2-, and 3-year Kaplan-Meier survival probabilities were 90%, 70%, and 63%, respectively, whereas the historical 5-year survival rates were 0% to 18% for intrahepatic CC and 23% to 26% for extrahepatic CC when patients underwent transplantation without neoadjuvant therapy. These encouraging survival rates for patients with this type of tumor, which is difficult to diagnose and treat, are no less significant when they are compared to the national 1- and 3-year survival rates (86% and 68%, respectively) of patients undergoing deceased donor LT for malignant neoplasms of the liver (as reported by the United Network for Organ Sharing). In our series, disease recurrence was significantly associated with a larger residual tumor [6.3 versus 2.0 cm (mean values), P = 0.008] and with a shorter waiting time for LT after the chemoradiation protocol [18 versus 56 days (mean values), P = 0.04]. Our LT protocol for CC was found to be promising for patients with truly extrahepatic CC and for patients within stages I to IIB of the American Joint Committee on Cancer Staging system (100% survival at a median follow-up of 2.2 years), but the results were notably poor for patients with stage III extrahepatic CC (median survival = 1.2 years). These observations highlight the need for accurate preoperative staging of CC for ideal LT recipient selection and the importance of a low tumor burden and a longer wait after neoadjuvant therapy. More effective chemoradiation regimens for reducing the tumor burden and the appropriate timing of LT after neoadjuvant chemoradiation require further research.

Outcomes and Patterns of Recurrence for Anaplastic Thyroid Cancer Treated With Comprehensive Chemoradiotherapy.

PURPOSE: Radiation therapy (RT) plays an important role in locoregional tumor control for anaplastic thyroid cancer (ATC). Due to its rarity, RT guidelines for ATC are lacking. We describe ATC patterns of nodal disease at presentation and progression and propose corresponding RT target volumes. METHODS AND MATERIALS: We identified all patients with ATC treated at our institution with definitive or adjuvant intensity modulated radiation therapy and concomitant chemotherapy from 2006 to 2020. We identified in-field, marginal, and out-of-field sites of locoregional recurrence and progression (LRR). RESULTS: Forty-seven patients met inclusion. Median follow-up was 6.6 months (interquartile range, 1.9-19.6). Nodal levels involved at presentation included: IB (2.1%), II (23.4%), III (21.3%), IV (21.3%), V (12.8%), VI (34%), and mediastinal (6.4%). All patients received elective nodal RT to levels II-IV and VI. RT volumes also included: IA (23.4%), IB (44.7%), V (87.2%), retropharyngeal/retrostyloid (RP/RS) (27.7%), and mediastinal 1 to 6 (53.2%). Cumulative incidence of LRR at 3- and 12-months was 26.1% (95% confidence interval, 15.9-42.8) and 35.7% (23.9-53.4). Isolated LRR risk at 3- and 12-months was 6.5% (2.2-19.8) and 8.9% (3.4-22.9). Fourteen (29.8%) patients experienced in-field LRR in the thyroid gland or postoperative tumor bed, II-IV, VI, and mediastinal 1 and 3A. Four (8.5%) patients had marginal LRRs, 3 of whom progressed in the mediastinum at 2, 3P, 4, and 6. Two (4.3%) patients experienced out-of-field LRRs. Throughout the pretreatment and follow-up period, no patients had disease at IA, and 1 (2.1%) patient each had disease at IB and RP/RS. No baseline or treatment characteristics, including RT dose (stratified by < or ≥66 Gy), were significant predictors of LRR on univariate analysis. CONCLUSIONS: Isolated LRR risk in patients with ATC treated with comprehensive RT and chemotherapy is low. Aggressive multimodality therapy should be reserved for willing, fit patients with no or limited distant disease burden. When treating comprehensively, complete inclusion of mediastinal levels 1 to 6 may be warranted to avoid marginal disease progression. Omission of levels I and RP/RS can be considered.

Carbon Ion Radiotherapy in the Management of Hepatocellular Carcinoma.

Localized hepatocellular carcinoma (HCC) that is unresectable and non-transplantable can be treated by several liver-directed therapies. External beam radiation therapy (EBRT) is an increasingly accepted and widely utilized treatment modality in this setting. Accelerated charged particles such as proton beam therapy (PBT) and carbon ion radiation therapy (CIRT) offer technological advancements over conventional photon radiotherapy. In this review, we summarize the distinct advantages of CIRT use for HCC treatment, focusing on physical and biological attributes, and outline dosimetric and treatment planning caveats. Based on these considerations, we posit that HCC may be among the best indications for use of CIRT, as it allows for maximizing tumoricidal doses to the target volume while minimizing the dose to the organs at risk.

Improving identification of candidates for lung cancer screening in a high risk population.

BACKGROUND: Low dose computerized tomography (LDCT) has been shown to reduce lung cancer specific mortality by 20 %. Despite U.S. Preventive Services Task Force (USPSTF) endorsement, screening of appropriate patients in the U.S. remains low, at 1.9 %. The goal of this study was to assess the number and type of patients that would qualify for lung cancer screening based upon recommendations by various guidelines. METHODS: We prospectively collected a patient reported questionnaire, including smoking history, family history, exposure history, and demographics, from April-October 2017 from new consults in the Department of Radiation Oncology and Otolaryngology (ORL). Patients smoking status and patient factors were collected and reported. Patients qualifying for screening by USPSTF, the National Comprehensive Cancer Network (NCCN), and Tammemagi scoring criteria were identified. Multivariate analysis assessed the factors associated with positive criteria for screening and the sensitivity of each criterion was calculated. RESULTS: There were 546 new consults during the study period and 528 successfully completed the questionnaire. A total of 104/528 (20 %) patients who completed questionnaires qualified for screening based on any guideline. After exclusion of active lung cancer (n = 19), poor prognosis (n = 24), and CT as part of surveillance (n = 16), 45 (8.5 %) patients would require LDCT. Of the entire population, 10 %, 11 % and 18 % of patients qualified based on USPSTF, NCCN, and Tammemagi, which was reduced to 4.9 %, 5.3 %, and 7.8 %, respectively after exclusions. Patients with head and neck cancer (40 %), skin cancer (27 %), and prostate cancer (11 %) accounted for the majority of patients eligible for screening after exclusions. The sensitivity of the USPSTF, NCCN, and Tammemagi criteria in patients with a diagnosis of lung cancer (n = 26) was 38.5 % (CI95 20.2 %-59.4 %), 46.2 % (CI95 26.6 %-66.6 %), and 61.5 % (CI95 40.6 %-79.8 %), respectively. CONCLUSIONS: We successfully identified 9 % of an oncology population at consultation who could benefit from lung cancer screening in survivorship. Distribution of a written or electronic questionnaire at consultation is a simple, low cost, effective method of identifying patients who would benefit from LDCT.

Treatment outcomes of squamous cell carcinoma of the oral cavity in young adults.

OBJECTIVES: The natural history of squamous cell carcinoma (SCC) of the oral cavity (OC) in young adults is unknown. We sought to provide an updated report on treatment outcomes of patients with OC SCC who were 40 years or younger. MATERIALS AND METHODS: We performed a retrospective analysis of 124 consecutive patients with primary OC SCC treated at Mayo Clinic (1980-2014). Patient and tumor characteristics and treatment approach were abstracted from patient charts. RESULTS: Median patient age was 35 years (range, 19-40 years). The most common primary site was oral tongue (107 patients; 86.3%). Most patients (101; 81.5%) underwent wide local excision. Surgery alone was curative in 77 patients (62.1%); 47 (37.9%) received radiotherapy, and 26 (21%) received chemotherapy. Five-year overall survival (OS) was 78.1%; 10-year OS was 76.9%. Five-year disease-free survival (DFS) was 66.6%; 5-year local control was 87.6%; and 5-year locoregional control was 78.5%. On multivariable analysis, factors associated with worse OS and DFS were higher pathologic T stage (P = .008), lymph node positivity (P < .001), and disease recurrence (P < .001). CONCLUSION: Young adults with primary OC SCC may be treated with a similar treatment approach as older adults.

Treatment of a glioblastoma multiforme dural metastasis with stereotactic radiosurgery: A case report and select review of the literature.

Glioblastoma multiforme (GBM) is a primary brain neoplasm accounting for approximately 75% of all high grade gliomas. It is diffusely infiltrative and exhibits rapid proliferation with a poor overall prognosis. Maximum surgical resection and postoperative radiotherapy, accompanied by concurrent and adjuvant temozolomide chemotherapy, remain the standard of care without major therapeutic advances over the past 10 years. Herein, we present the case of a 64-year-old Caucasian male with a GBM who subsequently developed a left frontal dural metastasis, subsequently treated with stereotactic radiosurgery (20 Gy in 1 fraction). With six month follow-up, the patient showed near complete resolution of his dural metastases and no overall change in neurological symptoms or side effects following radiosurgery. Due to the paucity of clinical literature regarding dural metastases from GBM, its optimal treatment remains unknown. While the role of SRS has yet to be defined in this setting, here we provide evidence suggesting its overall efficacy in the treatment of select dural GBM metastases.

Survival trends among non-small-cell lung cancer patients over a decade: impact of initial therapy at academic centers.

BACKGROUND: Treatment of non-small-cell lung cancer (NSCLC) has been rapidly advancing over the last decade. Academic centers are considered equipped with better expertise. NSCLC outcome trends in novel therapeutic era and impact of initial treatment at academic centers have not been reported. METHODS: The National Cancer Database (NCDB) was used to identify NSCLC incident cases from 2004 to 2013. Overall survival (OS) was plotted by year of diagnosis and type of initial treatment center, accounting for several factors available in NCDB. RESULTS: A total of 1 150 722 NSCLC patients were included and separated by initial treatment center type (academic: 31.5%; nonacademic: 68.5%). Median follow-up and OS for all patients were 11.8 months (range: 0-133.6 months) and 13.1 months (95% CI: 13.08-13.17), respectively. Median OS improved significantly for those diagnosed in 2010-2013 (14.8 months [95% CI: 14.7-14.9]) as compared to 2004-2009 (12.4 months [95% CI: 12.3-12.5]) (P < 0.001). Treatment at academic centers was associated with improved OS (multivariate HR for OS = 0.929 [95% CI: 0.92-0.94], P < 0.0010). Four-year OS for academic and nonacademic cohorts was 28.5%% and 22.1%, respectively (P < 0.001), and the difference was more pronounced in stage I to III NSCLC. CONCLUSION: In this largest analysis, thus far, NSCLC survival has improved over time, and type of initial treatment center significantly influences survival. Identifying and removing barriers to obtaining initial treatment of NSCLC at academic medical centers could improve OS.

Stereotactic Body Radiotherapy for Medically Inoperable Stage I-II Non-Small Cell Lung Cancer: The Mayo Clinic Experience.

OBJECTIVE: To examine disease control and survival after stereotactic body radiotherapy (SBRT) for medically inoperable, early-stage non-small cell lung cancer (NSCLC) and determine associations of pretreatment 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) maximum standardized uptake values (SUVmax), biologically effective dose, and mediastinal staging with disease control and survival outcomes. PATIENTS AND METHODS: We retrospectively reviewed the cases of consecutive patients with FDG-PET-staged, medically inoperable NSCLC treated with SBRT at our institution between January 1, 2008, and August 4, 2014. Cumulative incidences of recurrence were estimated, accounting for the competing risk of death. Associations of SUVmax, biologically effective dose, and mediastinal staging with outcomes were evaluated using Cox proportional hazards regression models. RESULTS: Among 282 patients, 2-year cumulative incidences of recurrence were 4.9% (95% CI, 2.6%-8.3%) for local, 9.8% (95% CI, 6.3%-14.2%) for nodal, 10.8% (95% CI, 7.0%-15.5%) for ipsilateral lung, 6.0% (3.3%-9.8%) for contralateral lung, 9.7% (95% CI, 6.3%-14.0%) for distant recurrence, and 26.1% (95% CI, 20.4%-32.0%) for any recurrence. The 2-year overall survival was 70.4% (95% CI, 64.5%-76.8%), and the 2-year disease-free survival was 51.2% (95% CI, 44.9%-58.5%). Risk of any recurrence was significantly higher for patients with higher SUVmax (hazard ratio [per each doubling], 1.29 [95% CI, 1.05-1.59]; P=.02). A similar association with SUVmax was observed when considering the composite outcome of any recurrence or death (hazard ratio, 1.23 [95% CI, 1.05-1.44]; P=.01). The SUVmax was not significantly associated with other outcomes (P≥0.69). Two-year cumulative incidences of local recurrence for patients receiving 48 Gy in 4 fractions, 54 Gy in 3 fractions, or 50 Gy in 5 fractions were 1.7% (95% CI, 0.3%-5.6%), 3.7% (95% CI, 0.7%-11.4%), and 15.3% (95% CI, 5.9%-28.9%), respectively (P=.02); this difference was independent of lesion size (P=.02). CONCLUSION: Disease control was excellent for patients who received SBRT for early-stage NSCLC, and this series represents the largest single-institution experience from the United States on SBRT for early-stage inoperable NSCLC. Higher pretreatment FDG-PET SUVmax was associated with increased risk of any recurrence, and the 50 Gy in 5 fractions dose prescription was associated with increased risk of local recurrence.

Outcomes and patterns of failure for sinonasal undifferentiated carcinoma (SNUC): The Mayo Clinic Experience.

BACKGROUND: Sinonasal undifferentiated carcinoma (SNUC) is a rare aggressive disease arising in the nasal cavity and paranasal sinuses with poor prognosis and unclear optimal management. METHODS: Forty patients were analyzed. Nasal cavity was the most common primary site. Most patients presented with T4 disease, received trimodality therapy, and were treated with intensity-modulated radiotherapy (IMRT). RESULTS: Median follow-up was 6.9 years. Sixteen patients (40%) experienced recurrent disease, 5 local (12.5%), 1 regional (2.5%), and 10 distant (25%). The 5-year overall survival (OS), recurrence-free survival (RFS), and locoreginal control (LRC) were 44%, 39%, and 71%, respectively. Patients treated with trimodality therapy had better outcomes compared to single modality therapy. Improved OS was noted with IMRT and with doses ≥60 Gy. The most common cause of death was distant metastasis. CONCLUSION: SNUC is an aggressive malignancy with a high tendency to metastasize. Better outcomes were obtained with a trimodality approach. Modern radiotherapy (RT) techniques and doses ≥ 60 Gy were associated with improved OS.

Patient-reported distress and survival among patients receiving definitive radiation therapy.

OBJECTIVE: Patient-reported distress (PRD) has not been well assessed in association with survival after radiation therapy (RT). The aims of this study were to evaluate the association between PRD level and survival after definitive RT and to identify the main causes of distress in definitive RT patients. METHODS AND MATERIALS: A total of 678 consecutive patients receiving definitive RT at our institution from April 2012 through May 2015 were included. All patients answered a PRD questionnaire that contained 30 items related to possible causes of distress, which could be rated from 1 (no distress) to 5 (high distress). Additionally, patients were asked to rate their overall distress level from 0 (no distress) to 10 (extreme distress). This overall distress level was our primary patient-reported distress measure and was examined as a continuous variable and as a categorical variable with 3 PRD levels (low, 0-3 [n = 295]; moderate, 4-6 [n = 222]; and high, 7-10 [n = 161]). RESULTS: As a continuous variable in multivariable Cox regression analysis, a higher overall PRD level was associated with poorer survival after RT (hazard ratio [HR], 1.39; P = .004). As a categorical variable, compared with patients with low distress, survival was poorer for patients with moderate distress (HR, 1.62; P = .038) or high distress (HR, 1.49; P = .12), but the latter difference was not significant. When the moderate and high distress levels were combined, survival was significantly poorer compared with the low distress level (HR, 1.57; P = .034). The top 5 specific causes of distress that patients mentioned were "How I feel during treatment," "Fatigue," "Out-of-pocket medical costs," "Pain that affects my daily functioning," and "Sleep difficulties." CONCLUSIONS: PRD before or during RT is a prognostic factor associated with decreased survival. Distress screening guidelines and interventions should be implemented for patients receiving definitive RT.

Outcomes of patients with loco-regionally recurrent or new primary squamous cell carcinomas of the head and neck treated with curative intent reirradiation at Mayo Clinic.

BACKGROUND: We reviewed outcomes of patients with loco-regionally recurrent (LRR) or new primary (NP) squamous cell carcinoma of the head and neck (SCCHN) treated at our institution with reirradiation (RRT). METHODS: Patients received definitive RRT (DRRT) or post-operative RRT following salvage surgery (PRRT) from 2003 to 2011. Measured survival outcomes included loco-regional relapse free survival (LRFS) and overall survival (OS). RESULTS: Among 81 patients (PRRT, 42; DRRT, 39), median PRRT and DRRT doses were 60 Gy (12-70 Gy) and 69.6 Gy (48-76.8 Gy). The majority of patients received IMRT-based RRT (n = 77, 95 %). With median follow-up of 78.1 months (95 % CI, 56-96.8 months), 2-year OS was 53 % with PRRT and 48 % with DRRT (p = 0.12); 23 % of patients were alive at last follow-up. LRFS at 2 years was 60 %, and did not differ significantly between PRRT and DRRT groups. A trend toward inferior LRFS was noted among patients receiving chemotherapy with RRT versus RRT alone (p = 0.06). Late serious toxicities were uncommon, including osteoradionecrosis (2 patients) and carotid artery bleeding (1 patient, non-fatal). CONCLUSIONS: OS of PRRT- and DRRT-treated patients in this series appears superior to the published literature. We used IMRT for the majority of patients, in contrast to several series and trials previously reported, which may account in part for this difference. Future studies should seek to improve outcomes among patients with LRR/NP SCCHN via alternative therapeutic modalities such as proton radiotherapy and by incorporating novel systemic agents.

Management of Metastatic Apocrine Hidradenocarcinoma with Chemotherapy and Radiation.

Hidradenocarcinoma is a rare aggressive form of cutaneous adnexal skin carcinoma originating from the sweat gland. Due to its low incidence, prognostic and treatment strategies are still being explored both for primary and advanced disease. This tumor most often presents as either solid or cystic appearing subcutaneous nodules, which may be associated with pruritus or ulceration. To date the mainstay of treatment for local disease has been surgical excision; however, the paucity of historical data available has shown that these tumors often behave aggressively with high rates of local recurrence, metastasis, and poor overall outcomes. There are few case reports describing the utility of radiation therapy in the treatment of hidradenocarcinoma. Herein, we present a case of metastatic apocrine hidradenocarcinoma in a 32-year-old Caucasian male. The patient initially underwent excisional biopsy which confirmed the diagnosis of poorly differentiated, highly infiltrative, apocrine hidradenocarcinoma. He received systemic chemotherapy for metastatic disease, followed by radiation therapy to areas of grossly palpable adenopathy. Prior to radiation therapy the patient had an enlarged hypermetabolic conglomerate of lymph nodes in the right axilla, and borderline enlarged low activity nodes within the left axilla. He received 3 cycles of chemotherapy followed by tamoxifen and radiation therapy (50.4 Gy in 28 fractions) to areas of progressive disease in the bilateral axilla, lower neck, and axillary skin. Following treatment, the patient had complete resolution of skin nodules and improvement of his pruritus. While the role of radiation therapy in the treatment of hidradenocarcinoma has not been well established, this case report demonstrated the potential benefit of external beam radiotherapy in the management of this rare disease.

Angiosarcoma of the scalp and face: the Mayo Clinic experience.

IMPORTANCE: The etiology and optimal treatment are unknown for angiosarcoma, an aggressive malignant tumor that affects vascular endothelial cells and can be mistaken for benign lesions such as hemangioma. OBJECTIVE: To determine the treatment outcomes of patients with angiosarcoma of the face or scalp treated with a combination of surgery, radiation therapy, and/or chemotherapy. DESIGN, SETTING, AND PARTICIPANTS: Retrospective study of 55 patients with angiosarcoma of the face or scalp treated between January 1, 1973, and December 31, 2012, at a tertiary-care academic medical institution. INTERVENTIONS: Surgery, radiation therapy, and/or chemotherapy. MAIN OUTCOMES AND MEASURES: Locoregional control (LRC), recurrence-free survival (RFS), and overall survival (OS). RESULTS: Fifty-five patients had angiosarcoma localized to the face or scalp. Forty of these patients (73%) received a combination of surgery, radiation therapy, and/or chemotherapy. Eight patients (15%) were treated with surgery alone, 1 (2%) with radiation alone, 5 (9%) with chemotherapy alone, and 1 (2%) with observation alone. Median (range) follow-up for surviving patients was 25.2 (4.7-227.1) months. Five-year LRC, RFS, and OS (95% CI) were 18% (7%-32%), 16% (6%-31%), and 38% (21%-54%), respectively. Of 36 patients with failed treatment, 34 had failure in a local and/or regional site. On univariate analysis, the use of multimodality therapy (vs no multimodality therapy) was associated with higher 5-year LRC (95% CI) (20% [3%-37%] vs 11% [0%-29%]; P = .04), higher RFS (19% [2%-36%] vs 10% [0%-27%]; P = .02), and higher OS (46% [26%-66%] vs 16% [0%-43%]; P = .04). Age 70 years or older (vs <70 years) was associated with lower 5-year LRC (95% CI) (5% [0%-14%] vs 48% [23%-74%]; P = .02) and lower RFS (5% [0%-13%] vs 49% [24%-75%]; P = .04). Radiation therapy (vs no radiation therapy) was associated with higher 5-year LRC (95% CI) (20% [3%-36%] vs 12% [0%-32%]; P = .02) and higher RFS (19% [2%-35%] vs 12% [0%-31%]; P = .004). On multivariable analysis, age younger than 70 years (vs ≥70 years) was associated with improved 5-year LRC (95% CI) (48% [23%-74%] vs 5% [0%-14%]; P = .03) and RFS (49% [24%-75%] vs 49% [24%-75%]; P = .04). CONCLUSIONS AND RELEVANCE: Multimodality therapy for angiosarcoma is associated with improved LRC, RFS, and OS. Younger patients with resectable disease undergoing multimodality therapy for angiosarcoma had the best clinical outcomes.

Image-guided intensity-modulated radiotherapy for prostate cancer: Dose constraints for the anterior rectal wall to minimize rectal toxicity.

Rectal adverse events (AEs) are a major concern with definitive radiotherapy (RT) treatment for prostate cancer. The anterior rectal wall is at the greatest risk of injury as it lies closest to the target volume and receives the highest dose of RT. This study evaluated the absolute volume of anterior rectal wall receiving a high dose to identify potential ideal dose constraints that can minimize rectal AEs. A total of 111 consecutive patients with Stage T1c to T3a N0 M0 prostate cancer who underwent image-guided intensity-modulated RT at our institution were included. AEs were graded according to the Common Terminology Criteria for Adverse Events, version 4.0. The volume of anterior rectal wall receiving 5 to 80Gy in 2.5-Gy increments was determined. Multivariable Cox regression models were used to identify cut points in these volumes that led to an increased risk of early and late rectal AEs. Early AEs occurred in most patients (88%); however, relatively few of them (13%) were grade ≥2. At 5 years, the cumulative incidence of late rectal AEs was 37%, with only 5% being grade ≥2. For almost all RT doses, we identified a threshold of irradiated absolute volume of anterior rectal wall above which there was at least a trend toward a significantly higher rate of AEs. Most strikingly, patients with more than 1.29, 0.73, or 0.45cm(3) of anterior rectal wall exposed to radiation doses of 67.5, 70, or 72.5Gy, respectively, had a significantly increased risk of late AEs (relative risks [RR]: 2.18 to 2.72; p ≤ 0.041) and of grade ≥ 2 early AEs (RR: 6.36 to 6.48; p = 0.004). Our study provides evidence that definitive image-guided intensity-modulated radiotherapy (IG-IMRT) for prostate cancer is well tolerated and also identifies dose thresholds for the absolute volume of anterior rectal wall above which patients are at greater risk of early and late complications.

Evaluation of Serum Calcium as a Predictor of Biochemical Recurrence following Salvage Radiation Therapy for Prostate Cancer.

Background. Previous reports have shown a positive association between serum calcium level and prostate cancer mortality. However, there is no data regarding whether higher serum calcium levels are associated with increased risk of biochemical recurrence (BCR) following salvage radiation therapy (SRT) for prostate cancer. Herein, we evaluate the association between pretreatment serum calcium levels and BCR in a cohort of men who underwent SRT. Methods. We evaluated 165 patients who underwent SRT at our institution. Median dose was 65.0 Gy (range: 54.0-72.4 Gy). We considered serum calcium as both a continuous variable and a 3-level categorical variable (low [≤9.0 mg/dL], moderate [>9.0 mg/dL and ≤9.35 mg/dL], and high [>9.35 mg/dL]) based on sample tertiles. Results. We observed no evidence of a linear association between serum calcium and BCR (relative risk (RR): 0.96, P = 0.76). Compared to men with low calcium, there was no significantly increased risk of BCR for men with moderate (RR: 0.94, P = 0.79) or high (RR: 1.08, P = 0.76) serum calcium levels. Adjustment for clinical, pathological, and SRT characteristics in multivariable analyses did not alter these findings. Conclusion. Our results provide evidence that pretreatment serum calcium is unlikely to be a useful tool in predicting BCR risk following SRT.