D. Mullen

Intensity modulated radiation therapy for squamous cell carcinoma of the vulva: Treatment technique and outcomes

Objective The objective of this study was to present the treatment technique and evaluate clinical outcomes after intensity modulated radiation therapy (IMRT) for vulvar cancer. Methods and materials This retrospective study included 39 patients with squamous cell carcinoma of the vulva treated with IMRT from 2005 to 2015. There were 21 patients treated with postoperative IMRT, 13 with definitive IMRT, and 5 with preoperative IMRT. Tumor staging was Federation of Gynecology and Obstetrics stage I in 6, stage II in 7, stage III in 19, and stage IV in 7 patients. Concurrent chemotherapy was administered to 14 patients. Brachytherapy was delivered in 8 patients. Results The median follow-up was 34 months (range, 3.3-71). Median IMRT dose to patients receiving pre- or postoperative IMRT was 5040 cGy (range, 5040-6080). Median combined IMRT and brachytherapy dose to gross tumor was 7000 cGy (range, 5040-7520) in those treated with definitive RT. The 3-year locoregional control (LRC) and overall survival for those receiving postoperative RT were 89% and 67%, respectively. The 3-year LRC and overall survival for those receiving definitive IMRT were 42% and 49%, respectively. In patients receiving definitive or neoadjuvant IMRT, 69% had complete clinical response and 44% had complete pathologic response. The actuarial 3-year inguinal recurrence rate was 7%. There were no acute grade 3-4 hematological, gastrointestinal, or genitourinary toxicities. There were no late grade 3-4 gastrointestinal or genitourinary toxicities. Conclusions IMRT for vulvar cancer is associated with high rates of LRC in the postoperative setting and limited radiation-related toxicity. Durable LRC of disease after definitive IMRT remains challenging, and several refinements to our treatment technique are suggested.

Association of post-treatment positron emission tomography with locoregional control and survival after radiation therapy for squamous cell carcinoma of the vulva.

BACKGROUND/PURPOSE The aim of this study was to investigate the use of post-treatment F-18 fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) for vulvar cancer and compare metabolic response to clinical outcomes. MATERIALS/METHODS This retrospective study included 21 patients with vulvar squamous cell carcinoma treated with curative-intent radiation between 2007 and 2015. All patients received intensity-modulated radiation treatment (IMRT), a pre-treatment FDG/PET-CT, and a post-treatment FDG-PET/CT performed at a median time of 3months post-IMRT. RESULTS Median follow-up time was 28months. Post-treatment FDG-PET/CT demonstrated no evidence of disease (NED) in 12 patients and residual or progressive disease (PD) in 9. FDG-PET/CT response significantly correlated with biopsy-proven locoregional failure (p=0.02) and was the only significant factor associated with overall survival (OS) (p=0.049). Patients with NED on FDG-PET had a 2-year locoregional control (LRC) of 89% versus 25% for those with PD (p<0.01). Patients with NED on FDG-PET/CT had a 2-year OS of 100% versus 42% for those with PD (p=0.02). FDG-PET/CT evaluation had a sensitivity of 100% and a specificity of 71% for detecting pathologically proven residual disease in patients receiving neoadjuvant or definitive radiation. CONCLUSION In this single-institution study of women with vulvar cancer, post-treatment response on FDG-PET/CT was associated with LRC and OS.

Distant intracranial failure in melanoma brain metastases treated with stereotactic radiosurgery in the era of immunotherapy and targeted agents

Purpose Stereotactic radiosurgery (SRS) in combination with immunotherapy (IMT) or targeted therapy is increasingly being used in the setting of melanoma brain metastases (MBMs). The synergistic properties of combination therapy are not well understood. We compared the distant intracranial failure rates of intact MBMs treated with SRS, SRS + IMT, and SRS + targeted therapy. Methods and materials Combination therapy was defined as delivery of SRS within 3 months of IMT (anti-CTLA-4 /anti-PD-1 therapy) or targeted therapy (BRAF/MEK inhibitors). The primary endpoint was distant intracranial failure after SRS, which was defined as any new MBM identified on brain magnetic resonance imaging. Outcomes were evaluated using the Kaplan Meier method and Cox proportional hazards. Results A total of 72 patients with melanoma with 233 MBMs were treated between April 2006 and April 2016. The number of MBMs within each treatment group was as follows: SRS: 121; SRS + IMT: 48; and SRS + targeted therapy: 64. The median follow-up was 8.9 months. One-year distant intracranial control rates for SRS, SRS + IMT, and SRS + targeted therapy were 11.5%, 60%, and 10%, respectively (P < .001). On multivariate analysis, after adjusting for steroid use and number of MBMs, SRS + IMT remained associated with a significant reduction in distant intracranial failure compared with SRS (hazard ratio [HR], 0.48; 95% confidence interval [CI], 0.29-0.80; P = .003) and compared with SRS + targeted therapy (HR, 0.41; 95% CI, 0.25-0.68; P = .001).One-year local control for SRS, SRS + IMT, and SRS + targeted therapy was 66%, 85%, and 72%, respectively (P = .044). On multivariate analysis, after adjusting for dose, SRS + IMT remained associated with a significant reduction in local failure compared with SRS alone (HR, 0.37; 95% CI, 0.14-0.95; P = .04). Conclusions SRS with immunotherapy is associated with decreased distant and local intracranial failure compared with SRS alone. Prospective studies are warranted to validate this result.

Lymphovascular space invasion and lack of downstaging after neoadjuvant chemotherapy are strong predictors of adverse outcome in young women with locally advanced breast cancer

Younger age diagnosis of breast cancer is a predictor of adverse outcome. Here, we evaluate prognostic factors in young women with locally advanced breast cancer (LABC). We present a retrospective review of 104 patients younger than 40 years with LABC treated with surgery, radiotherapy (RT), and chemotherapy from 2003 to 2014. Patient‐, tumor‐, and treatment‐related factors important for overall survival (OS), local/regional recurrence (LRR), distant metastasis (DM), and recurrence‐free survival (RFS) were evaluated. Mean age at diagnosis was 34 years (23–39 years) with a median follow‐up of 47 months (8–138 months). Breast‐conserving surgery was performed in 27%. Axillary lymph node dissection was performed in 85%. Sixty percent of patients received neoadjuvant chemotherapy with 19% achieving pathologic complete response (pCR), and 61% downstaged. Lymph node positivity was present in 91% and lymphovascular space invasion (LVSI) in 35%. Thirty‐two percent of patients had triple negative tumors (TN, ER‐/PR‐/HER2 nonamplified). Four‐year OS and RFS was 84% and 71%, respectively. Factors associated with worse OS on multivariate analysis include TN status, LVSI, and number of positive lymph nodes. LVSI was also associated with DM and LRR, as well as worse RFS. Downstaging was associated with improved 4 year RFS in patients receiving neoadjuvant chemotherapy (74% vs. 38%, P = 0.002). With high risks of recurrence and inferior OS compared to older women, breast cancer in young women can be difficult to treat. Among additional factors, presence of LVSI and lack of downstaging portends a particularly worse prognosis.

Cardiac dose is associated with immunosuppression and poor survival in locally advanced non-small cell lung cancer

PURPOSE Studies have associated increased radiation therapy (RT) heart dose with cardiac toxicity. Others have correlated RT-related immunosuppression with worsened survival. Given the large vascular volumes irradiated during locally advanced non-small cell lung cancer (LA-NSCLC) treatment, we hypothesized an association between increased heart dose and immunosuppression. METHODS We identified 400 LA-NSCLC patients treated with definitive RT ± chemotherapy between 2001 and 2016. Absolute lymphocyte counts (ALC), absolute neutrophil counts (ANC), and neutrophil-to-lymphocyte ratio (NLR = ANC/ALC) were analyzed pre-RT, during RT, and post-RT. Multivariable analysis (MVA) was performed to correlate Clinical factors with both hematologic toxicity and overall survival. An upper tertile threshold to increase specificity of NLR was chosen to dichotomize continuous hematologic variables. RESULTS Median follow up was 17 months (range 0.2-174 months) in all patients and 46 months (range 0.2-161 months) in survivors. A total of 94% of patients had stage III disease and 77% received concurrent chemo radiation. Two-year overall survival (OS), freedom from local recurrence (FFLR), and freedom from distant metastases (FFDM) was 42%, 60% and 45%, respectively. Median survival was 18 months. On MVA for OS (n = 207), male gender (Hazard Ratio [HR] 1.7; 95% CI 1.2-2.3), RT alone (HR 2.1; 95% CI 1.9-4.0), the percentage of heart receiving ≥50 Gy (V50) (HR 1.02; 95% CI 1.01-1.03), and higher NLR at 4 months (HR 1.02, 95% CI 1.01-1.03) were associated with reduced OS. ALC nadir was not associated with treatment outcomes. NLR >10.5 was associated with decreased OS (p < 0.001) and decreased FFDM (p = 0.04). On MVA evaluating factors associated with hematological toxicity (n = 247), adjuvant chemotherapy (HR 2.6; 95% CI 1.3-5.0; p = 0.006), RT alone (HR 3.6; 95% CI 1.1-12; p = 0.04), and heart V50 >25% (HR 2.0; 95% CI 1.1-3.5; p = 0.02) were associated with a NLR >10.5 4 months post-RT. CONCLUSION RT related immunosuppression is associated with worse patient outcomes, and may represent a source of increased mortality beyond cardiac toxicity alone.

Post-operative radiation effects on lymphopenia, neutrophil to lymphocyte ratio, and clinical outcomes in palatine tonsil cancers

OBJECTIVE To evaluate radiation-induced lymphopenia associated with unilateral vs. bilateral neck radiation and to test post-treatment neutrophil to lymphocyte ratio (NLR) as a prognostic clinical biomarker. METHODS This was a single academic center retrospective review of palatine tonsil squamous cell cancer patients treated with post-operative intensity modulated radiation therapy (IMRT) from 1997 to 2013. Absolute lymphocyte count (ALC) and NLR were evaluated during and after radiation for up to a year. Correlations of lab values with loco-regional control (LRC), freedom from distant metastases (FFDM), and overall survival (OS) were assessed. RESULTS Ninety-nine patients with median follow up 5.8 years had ALC recorded at least at baseline and within one year of starting RT. Acute grade 3-4 lymphopenia (<10 weeks from RT start) occurred in 79% of bilateral neck RT patients (n = 70) and 58% of unilateral neck RT patients (n = 29), p = 0.03. There was no significant difference in late grade 3-4 (p = 0.12) lymphopenia. In a multivariable Cox regression model, acute NLR > 11.875 correlated with worse OS (HR = 4.4, 95% CI 1.2-16). Late NLR > 6.875 independently correlated with significantly worse FFDM (HR = 16, 95% CI 1.9-137) and OS (HR = 12, 95% CI 3.0-48). CONCLUSIONS Unilateral neck radiation may prevent acute iatrogenic immunosuppression. In exploratory analyses, elevated post-treatment NLR was associated with risk for distant metastases and death.

Predictors of acute throat or esophageal patient reported pain during radiation therapy for head and neck cancer

Background and purpose Acute pain during weekly radiotherapy (RT) to the head and neck is not well characterized. We studied dose-volume metrics and clinical variables that are plausibly associated with throat or esophageal pain as measured with a weekly questionnaire during RT. Materials and methods We prospectively collected weekly patient-reported outcomes from 122 head and neck cancer patients during RT. The pain score for each question consisted of a four-level scale: none (0), mild (1), moderate (2), and severe (3). Univariate and multivariate ordinal logistic regression analyses were performed to investigate associations between both esophageal and throat pain and clinical as well as dosimetric variables. Results In multivariate analysis, age was significantly associated with both types of pain, leading to odds ratio (OR) = 0.95 (p = 0.008) and OR = 0.95 (p = 0.007) for esophageal and throat pain, respectively. For throat pain, sex (OR = 4.12; p = 0.010), with females at higher risk, and fractional organ at risk (OAR) mean dose (OR = 3.30; p = 0.014) were significantly associated with throat pain. Conclusions A fractional OAR mean dose of 1.1 Gy seems a reasonable cutoff for separating no or mild pain from moderate to severe esophageal and throat pain. Younger patients who received RT experienced more esophageal and throat pain. Females experienced more throat pain, but not esophageal pain.

Magnetic Resonance Image-Guided Radiotherapy (MRIgRT): A 4.5-Year Clinical Experience

AIMS Magnetic resonance image-guided radiotherapy (MRIgRT) has been clinically implemented since 2014. This technology offers improved soft-tissue visualisation, daily imaging, and intra-fraction real-time imaging without added radiation exposure, and the opportunity for adaptive radiotherapy (ART) to adjust for anatomical changes. Here we share the longest single-institution experience with MRIgRT, focusing on trends and changes in use over the past 4.5 years. MATERIALS AND METHODS We analysed clinical information, including patient demographics, treatment dates, disease sites, dose/fractionation, and clinical trial enrolment for all patients treated at our institution using MRIgRT on a commercially available, integrated 0.35 T MRI, tri-cobalt-60 device from 2014 to 2018. For each patient, factors including disease site, clinical rationale for MRIgRT use, use of ART, and proportion of fractions adapted were summated and compared between individual years of use (2014-2018) to identify shifts in institutional practice patterns. RESULTS Six hundred and forty-two patients were treated with 666 unique treatment courses using MRIgRT at our institution between 2014 and 2018. Breast cancer was the most common disease, with use of cine MRI gating being a particularly important indication, followed by abdominal sites, where the need for cine gating and use of ART drove MRIgRT use. One hundred and ninety patients were treated using ART in 1550 fractions, 67.6% (1050) of which were adapted. ART was primarily used in cancers of the abdomen. Over time, breast and gastrointestinal cancers became increasingly dominant for MRIgRT use, hypofractionated treatment courses became more popular, and gastrointestinal cancers became the principal focus of ART. DISCUSSION MRIgRT is widely applicable within the field of radiation oncology and new clinical uses continue to emerge. At our institution to date, applications such as ART for gastrointestinal cancers and accelerated partial breast irradiation (APBI) for breast cancer have become dominant indications, although this is likely to continue to evolve.

SU-F-BRA-14: Optimization of Dosimetric Guidelines for Accelerated Partial Breast Irradiation (APBI) Using the Strut-Adjusted Volume Implant (SAVI)

Purpose: Treatment planning guidelines for accelerated partial breast irradiation (ABPI) using the strut-adjusted volume implant (SAVI) are inconsistent between the manufacturer and NSABP B-39/RTOG 0413 protocol. Furthermore neither set of guidelines accounts for different applicator sizes. The purpose of this work is to establish guidelines specific to the SAVI that are based on clinically achievable dose distributions. Methods: Sixty-two consecutive patients were implanted with a SAVI and prescribed to receive 34 Gy in 10 fractions twice daily using high dose-rate (HDR) Ir-192 brachytherapy. The target (PTV_EVAL) was defined per NSABP. The treatments were planned and evaluated using a combination of dosimetric planning goals provided by the NSABP, the manufacturer, and our prior clinical experience. Parameters evaluated included maximum doses to skin and ribs, and volumes of PTV_EVAL receiving 90%, 95%, 100%, 150%, and 200% of the prescription (V90, etc). All target parameters were evaluated for correlation with device size using the Pearson correlation coefficient. Revised dosimetric guidelines for target coverage and heterogeneity were determined from this population. Results: Revised guidelines for minimum target coverage (ideal in parentheses): V90≥95%(97%), V95≥90%(95%), V100≥88%(91%). The only dosimetric parameters that were significantly correlated (p<0.05) with device size were V150 and V200. Heterogeneity criteria were revised for the 6–1 Mini/6-1 applicators to V150≤30cc and V200≤15cc, and unchanged for the other sizes. Re-evaluation of patient plans showed 90% (56/62) met the revised minimum guidelines and 76% (47/62) met the ideal guidelines. All and 56/62 patients met our institutional guidelines for maximum skin and rib dose, respectively. Conclusions: We have optimized dosimetric guidelines for the SAVI applicators, and found that implementation of these revised guidelines for SAVI treatment planning yielded target coverage exceeding that required by existing guidelines while preserving heterogeneity constraints and minimizing dose to organs at risk.

WE‐E‐BRE‐09: Investigation of the Association Between Radiation‐Induced Pain and Radiation Dose in Head and Neck Cancer Patients

PURPOSE Patients with head and neck cancer who undergo radiotherapy often experience several undesirable side-effects, including xerostomia, trismus, and pain in the head and neck area, but little is know about the dose-volume predictors of such pain. We investigated the association between radiation dose and both throat and esophagus pain during radiotherapy. METHODS We analyzed 124 head and neck patients who received radiotherapy at the Washington University School of Medicine in Saint Louis. For these patients, weekly PROs were recorded, including 16 pain and anatomical location questions. In addition, 17 observational symptoms were recorded. Patients were asked to describe their pain at each site according to a four-level scale: none (0), mild (1), moderate (2), and severe (3). We explored the association between throat pain and the mean dose received in oral cavity and between esophageal pain and the mean dose received in the esophagus. The severity of pain was determined by the difference between the baseline (week 1) pain score and the maximum pain score during treatment. The baseline pain score was defined as the first available pain score before receiving 10 Gy because radiotherapy pain originates later during treatment. Dose-volume metrics were extracted from treatment plans using CERR. To evaluate the correlation between pain and radiation dose, Spearmans correlation coefficient (Rs) was used. RESULTS The associations between throat pain and the mean dose to the oral cavity, and between esophagus pain and the mean dose to the esophagus, were both statistically significant, with Rs=0.320 (p=0.003) and Rs=0.424 (p<0.0001), respectively. Mean dose, for each structure, was a better predictor of pain than total integral dose. CONCLUSION We demonstrated that pain during radiotherapy in head and neck patients highly correlates with the dose delivered. We will further investigate the association between other pain locations and relevant normal tissue dose characteristics.