Gy IMRT Research Articles

Progression-Free Survival in Patients with WHO-2 Meningioma Undergoing Active Surveillance Based on DOTATATE PET Evidence of Gross Total Resection: Prospective Observational Study

MRI is the standard of care for meningioma radiotherapy planning, but lacks sensitivity for postoperative small volume disease and osseous or parenchymal invasion. NRG-BN003 (NCT03180268) randomizes patients with WHO-2 meningiomas and MRI-determined gross total resection (GTR) to observation or 60 Gy IMRT to the resection bed. More sensitive and specific imaging biomarkers than MRI may improve clinical outcomes in meningioma by limiting unnecessary irradiation of normal tissues and improving radiotherapy targeting. [68Ga]-DOTATATE, a PET radiotracer targeting somatostatin receptor 2 (SSTR2) is a highly sensitive and specific meningioma biomarker. Our dedicated DOTATATE brain PET/MRI and PET/CT protocol allows meningioma differentiation from post-treatment change, using SUV analysis and Patlak modeling. Our prospective IRB-approved observational trial (NCT04081701) has imaged >100 patients with meningioma. In the sub-analysis presented here, we prospectively evaluated PFS in patients with WHO-2 tumors and postoperative GTR as determined by [68Ga]-DOTATATE brain PET/MRI or PET/CT who were managed solely with active surveillance. We hypothesized that the PFS of patients with GTR by PET managed with active surveillance would be higher than reported PFS data for patients with MRI-determined GTR, using NRG-BN003's observation arm (randomized trial comparing observation to fractionated RT) as a reference standard. From the cohort of >100 patients with SSTR2-positive brain neoplasms enrolled between 9/2019 and 10/2022 and imaged according to our previously published protocol, a sub-cohort of patients were selected with WHO-2 meningioma, postoperative findings of GTR, and postoperative active surveillance with periodic MRI every 3-6 months. Kaplan-Meier survival analysis was performed. A total of 12 patients met inclusion criteria. Mean patient age was 64 years and 5 (42%) were female. Mean follow up period was 23.4 months (range: 7-38). 83% (10/12) patients underwent postoperative PET/MRI and 17% (2/12) underwent PET/CT. 2 patients (17%) progressed, at 22 and 34 months, respectively; the remainder remain progression-free. Both patients who had progression were successfully salvaged with focal fractionated radiosurgery. Kaplan-Meier analysis demonstrated PFS at almost 3 years to be 75%, which is substantially higher than the reported 3-year PFS of 60% in the literature. Overall survival was 100%. [68Ga]-DOTATATE PET can improve the specificity of imaging-based assessment of the extent of resection of WHO-2 meningiomas, thereby improving clinical outcomes. In this cohort of patients with completely resected WHO-2 meningiomas (as assessed by postoperative gadolinium-enhanced MRI and DOTATATE PET) who are conservatively managed, recurrences have been rare and amenable to radiosurgical salvage.

HDR brachytherapy and radiotherapy as salvage treatment for macroscopic recurrence in the prostate bed after radical prostatectomy.

370 Background: To present early and late toxicity, biochemical, local, regional and distant control and survival in a prospective series of 75 patients with macroscopic local recurrence in the prostate bed after radical prostatectomy treated by salvage HDR brachytherapy. Methods: Between 12/1999 and 12/2020, 75 patients (pts) with exclusive macroscopic recurrence in the prostate bed after radical prostatectomy without nodal or distant metastases, were included in the study. Pts were prospectively treated by 46 Gy IMRT radiotherapy to the surgical bed followed by 16 Gy HDR brachytherapy in 2 implants of 8Gy each, one week apart and hormone therapy for 36 months. Rectal limitant dose was 85% and for urethra 115% of the prescribed dose. Toxicity was recorded according to the EORTC/RTOG criteria. Special attention to PSA levels, biochemical, local, nodal and distant metastases control and survival, as well as to quality of life was taken. Results: All pts completed treatment. No pts experienced grade 3 or higher rectal or urinary toxicity. odos los pacientes completaron el tratamiento. 2 pts presented G1 rectal toxicity (ocasional rectorragia) and 1 pts G2 rectitis (persistent rectorragia), that ceased with topic treatment (cortisone ointment) 1 Pts had G1 urethral toxicity (dysuria), that spontaneously disappeared qat few months no requiring any medical intervention. No patient developed stenosis, necrosis or urethral fistula during follow-up. With a median follow-up of 102 months, 13 pts had failure of the disease: 6 biochemical-only, 2 local recurrence, 2 pelvic recurrence, 1 paraaortic recurrence and 2 distant metastases. 2 patients died by the disease and 1 patient died by other cause (age related). Conclusions: IMRT plus HDR brachytherapy was a safe treatment without any early or late significant side-effect. Combined treatment by IMRT and HDR plus androgen deprivation was extraordinary effective in the control or macroscopic local recurrences in the prostatectomy bed after radical prostatectomy. Further studies are warranted.

NIMG-91. DOTATATE PET/MR-GUIDED POSTOPERATIVE MANAGEMENT IN WHO-2 MENINGIOMA: ACTIVE SURVEILLANCE BASED ON PET/MR EVIDENCE OF GROSS TOTAL RESECTION

Abstract BACKGROUND MRI, the standard of care (SOC) for meningioma radiotherapy planning, lacks sensitivity for postoperative small volume disease and osseous or parenchymal invasion. BN003 (NCT03180268) randomizes patients with WHO-2 meningiomas and MRI-determined GTR to observation or 60 Gy IMRT to the resection bed. More sensitive and specific imaging biomarkers may improve clinical outcomes in meningioma by limiting unnecessary radiation of normal tissues and improving radiation targeting. [68Ga]-DOTATATE is a PET radiotracer targeting somatostatin receptor 2 (SSTR2), a highly sensitive and specific meningioma biomarker. We developed a dedicated DOTATATE brain PET/MRI protocol allowing meningioma differentiation from post-treatment change, using SUV analysis and Patlak modeling. Our prospective observational trial (NCT04081701) has imaged over 90 patients with meningioma. This IRB-approved study evaluated PFS in patients with WHO-2 tumors and postoperative GTR by [68Ga]-DOTATATE PET/MRI who were managed solely with active surveillance. We hypothesized that the PFS of patients with GTR by PET/MRI managed with active surveillance would be higher than for patients with MRI-determined GTR, using NRG-BN003’s observation arm (randomized trial comparing observation to fractionated radiotherapy) as a reference standard. METHODS 92 patients with SSTR2-positive brain neoplasms were enrolled between 9/2019 and 5/2022 and imaged according to our previously published protocol. 8 patients met inclusion criteria (WHO-2 meningioma & postoperative PET/MR GTR) and were followed with SOC MRI. Kaplan-Meier survival analysis was performed. RESULTS 5/8 subjects (62.5%) were women; the mean age was 67 years. MRI follow-up data were available for a mean of 19.75 months (range: 7-38 months). One subject (12.5%) progressed at 21 months; the remainder remain progression-free. Kaplan-Meier analysis demonstrated 3-year PFS to be 80%, which is substantially higher than the reported 3-year PFS of 69% in the literature. CONCLUSIONS [68Ga]-DOTATATE PET can improve the specificity of imaging-based assessment of the extent of resection of WHO-2 meningiomas.

EUSOM: Phase 2 Trial of Avasopasem Manganese (GC4419) for Oral Mucositis in Patients Receiving Chemoradiotherapy for Locally Advanced, Nonmetastatic Head and Neck Cancer

<h3>Purpose/Objective(s)</h3> Severe oral mucositis (SOM; gr 3–4 on the WHO scale) occurs in about 70% of patients receiving chemoradiotherapy (CRT) for head and neck cancer (HNC). Current treatment approaches focus primarily on symptoms. (Elad 2020) Avasopasem (AVA; GC4419) is an investigational selective dismutase mimetic that rapidly converts superoxide to hydrogen peroxide, potentially interrupting SOM development. (Riley 2007, Sonis 2001) In a phase 2 study, AVA vs placebo reduced SOM duration, incidence, and severity (gr 4 incidence) in patients with locally advanced HNC undergoing CRT (Anderson 2019), prompting initiation of the phase 3 ROMAN study (NCT03689712). The objective of the phase 2 EUSOM open-label trial was to assess the feasibility (safety and efficacy) of a vasospasm in European patients receiving CRT for locally advanced squamous cell carcinoma of the head and neck. <h3>Materials/Methods</h3> In EUSOM (NCT04529850), patients with locally advanced, nonmetastatic HNC in Belgium, Czech Republic, Germany, Poland, Spain and Switzerland received AVA 90 mg IV before each daily fraction (2.0–2.2 Gy, M–F) of intensity-modulated radiation therapy (IMRT; 60–72 Gy over appx. 7 weeks), with investigator's choice of cisplatin 100 mg/m² q3wks x 3 or 40 mg/m² weekly x 6–7. WHO grade of OM was assessed twice weekly through IMRT then weekly for 4 weeks. The primary endpoint was safety. SOM incidence, severity (gr 4), and duration were secondary endpoints. <h3>Results</h3> N=38 enrolled, 37 (median age 61 [range 45–79]; 81% male) received ≥1 dose of AVA, 33 received ≥ 60 Gy IMRT and ≥ 5 wks AVA (per protocol). Primary tumor: oral (n=15), oropharyngeal (n=20), or other (n=2). AVA median duration of exposure was 6.7 weeks. Median cumulative IMRT dose was 69.3 Gy (range 14–74). Mean cumulative cisplatin dose was 245.5 mg/m² and 212.3 mg/m², respectively, for patients receiving q3w (11/37) and weekly (26/37) schedules; 91% and 58%, respectively, received ≥200 mg/m². The most frequent adverse events (AEs) were lymphopenia, nausea, leukopenia, and anemia. Hypotension occurred in 19% (n=7, 3 gr 3) and was the most frequent AVA-related AE (n=5). Serious AEs (N=18; 49%) included pneumonia (n=3), COVID-19 (n=2), and hypotension (n=2, 1 AVA-related leading to AVA discontinuation). SOM efficacy for the full and per protocol population (≥60 Gy RT and ≥25 infusion of AVA; n=33) are shown in the table. <h3>Conclusion</h3> The AE profile observed in EUSOM was comparable to published data and suggested that vasospasm was well tolerated in these patients. SOM incidence appeared lower than historic expectations. Funder Galera Therapeutics, Inc.

Association of plasma tumor tissue modified viral HPV DNA (TTMV) with tumor burden, treatment type, and outcome: A translational analysis from NRG-HN002.

6006 Background: NRG-HN002 was a phase II trial that randomized patients with p16-positive oropharynx cancer to 60 Gy IMRT with concurrent cisplatin (IMRT-C) or 60 Gy accelerated IMRT. The protocol specified plasma collection at pretreatment (t0), intratreatment (20-28 Gy, t1), and 2 weeks to 1 month posttreatment (t2); at these timepoints, TTMV was assayed. A prespecified analysis evaluated: association of t0 TTMV to gross tumor volume (GTV) of primary and lymph nodes; t0-t1 decrease in TTMV; and association of t2 TTMV to treatment and outcome. Methods: TTMV was quantified as fragments/mL of plasma. If TTMV-HPV16 was not detected (&lt;5 fragments/mL) or was a low value, the specimen was tested for TTMV-HPV18, -HPV31, -HPV33, and -HPV35. The distribution of t0 TTMV fragments was highly skewed, so these data were log-transformed; their correlation to GTV was measured by Pearson coefficient. Paired and two-sample t-tests were used to compare t0 and t1 log-transformed fragments within and between arms. Proportions of TTMV detection at t2 between arms were compared using Fisher’s exact test. Rates of undetectability and fragment clearance (≥94% reduction from t0) at t2 were estimated. The negative predictive value (NPV) was estimated for 2-year locoregional failure (LRF) and progression-free survival (PFS). Results: Of 306 eligible patients, 164 (53.6%) donated at least one specimen. The median collection time/RT dose was -2.6 days before RT (Q1-Q3, -4.0-0.0), at 24 Gy (22-28), and 25.5 days after RT end (18-31). The t0, t1, and t2 patient participation rates were 53.6%, 45.4%, and 42.5%. Zero TTMV fragments were detected in 10.4% at t0, 19.4% at t1, and 93.1% at t2. At t0, t1, and t2, 83.5%, 79.1%, and 6.2% had detectable TTMV; 78.0%, 73.4%, and 5.4% had TTMV-HPV16. In correlating GTV to t0 TTMV fragments, the Pearson coefficient was 0.30 (95% CI 0.15-0.44). In a linear model, T stage (p=0.01) and N stage (p=0.004) were positively associated with t0 TTMV fragments. On the IMRT-C arm, the t0-to-t1 mean change was -1.06 (p=0.0009), and for IMRT, it was -0.22 (p=0.35) (p=0.03 between arms). The t2 TTMV detectability rate was 3.3% for IMRT-C vs 8.7% for IMRT (p=0.28). The t2 TTMV undetectability rate was 93.8% and the fragment clearance rate was 95.4%. Two-year LRF and PFS were 6.2% and 91.4%. The NPV of t2 undetectability was 95.0% (95% CI 89.4-98.1) for 2-year LRF and 93.3% (95% CI 87.3-97.1) for 2-year PFS, and for fragment clearance was 94.3% and 92.7%. Conclusions: Feasibility of the TTMV-HPV assay in clinical trial specimens was established. About 10% of p16-positive patients had zero TTMV fragments at baseline. Among those with TTMV detectability, 6.6% had types other than TTMV-HPV16. T and N stage were positively associated with TTMV fragments. The IMRT-C arm achieved rapid TTMV undetectability unlike IMRT. The NPV of posttreatment undetectability was 93-95% for 2-year LRF and PFS.

Outcomes After Accelerated Partial Breast Irradiation in Women With Triple Negative Subtype and Other "High Risk" Variables Categorized as Cautionary in The ASTRO Guidelines.

PurposeTo report a primary objective clinical outcome of ipsilateral breast recurrence following accelerated partial breast irradiation (APBI) in women with triple negative and other high risk breast cancer (as described in 2017 ASTRO guidelines) (i.e., age 40–49, size 2.1–3.0 cm, estrogen receptor negative and invasive lobular breast cancer). Secondary objectives of axillary and regional failure as well as overall survival are also reported.Methods and MaterialPatients from two clinical trials (NCT01185145, NCT01185132) were treated with 38.5 Gy IMRT or 3D-CRT APBI w/3.85 Gy fraction/BID fractionation for 10 fractions. Triple negative and other high risk patients (n=269) were compared to a total of 478 low risk patients which ASTRO defined as “suitable” for APBI. High risk patients, for the purpose of this study, were defined as those who possess one or more high risk criteria: triple negative (n=30), tumor size >2 cm <3 cm (n=50), HER 2+ (n=54), age range 40–50 years (n=120), ER- (n=43), and ILC histology (n=52).ResultsMedian follow up was 4.0 years for all patients. No significant difference was found for this high-risk cohort at 5 years for ipsilateral breast, or regional recurrences. Axillary recurrence was significantly adversely impacted by triple negative and ER- statuses (p=0.01, p=0.04). There were significant correlations between triple negative type and axillary recurrence on multivariate analysis (p=0.03). Overall survival for all patients was unaffected by any of the high-risk categories.ConclusionThe data from this study suggests that women possessing high risk features are at no more meaningful risk for recurrence than other patients considered to be acceptable for APBI treatment. However, the finding of axillary recurrence in patients with triple negative breast cancer does warrant a degree of caution in proceeding with accelerated partial breast irradiation technique in this patient group.

Abstract P2-13-05: Outcomes after accelerated partial breast irradiation in “high risk” and women categorized as cautionary in the ASTRO guidelines

Abstract Purpose: To report a primary objective clinical outcome of ipsilateral breast recurrence following accelerated partial breast irradiation (APBI) in cautionary (as described in 2017 revised ASTRO APBI guidelines) and high-risk women (age &amp;lt;50, tumor size &amp;lt;3 cm and ≥2 cm, HER2/neu positive, combined estrogen/progesterone (ER/PR) negative, ER negative, and triple negative). Secondary objectives of axillary and regional failure as well as overall survival are also reported. Methods and Material: Between March 2004 and April 2016 patients were enrolled in two APBI breast protocols (Phase II NCT01185145 and Phase III NCT01185132). Patients were treated with 38.5 Gy IMRT or 3D-CRT APBI w/ 3.85 Gy fraction/BID fractionation for 10 fractions. Patients who were ER/PR negative, ER negative, PR negative, HER2 positive, ≥2 cm primary tumors, or triple negative were compared to a total of 543 patients who were enrolled in the Phase II and Phase III trials. High risk patients were defined as those who possess one or more high risk criteria: triple negative (n=30), ER-/PR- (n=40), tumor size ≥2 cm &amp;lt;3 cm (n=50), HER 2+ (n=54), age range 40-50 years (n=120), ER- (n=43) and ILC histology (n=52). Clinical outcomes of ipsilateral breast, axillary, combined regional recurrences (breast or axillary) (RR), and overall survival (OS) were analyzed and compared in each cohort Results: Median follow up was 4.0 years for all patients. No significant difference was found for this cautionary/high risk cohort at 5 years for ipsilateral breast, or regional recurrences. However, axillary recurrence was significantly adversely impacted by triple negative status, as well as both ER- and combined ER/PR- status (p=0.01, p=0.04, p=0.03, respectively). On multivariate analysis, the only significant correlations were between triple negative type and axillary recurrence (p=0.03). Overall survival for all patients was unaffected by any of the high-risk categories. Estimated Recurrence-free and Overall Survival at 5 years VariableIpsilateral breast recurrencepAxillary recurrencepRegional recurrencepAll Patients OSpHER-2/neupositive100%0.45100%0.64100%0.3895.3%0.88negative98%99.5%97.4%95.8%Size&amp;lt;2 cm98%0.5699.5%0.6697.7%0.7795.9%0.11≥2 cm96%100%95.8%87.4%Both ER/PR negativeyes100%0.3297.3%0.0397.3%0.9886.6%0.25no98%99.7%97.6%95.9% Triple negativeyes100%0.3496.7%0.0196.7%0.9384.3%0.16no98%99.7%97.6%95.9%HistologyIDCA98%0.4599.7%0.0797.7%0.7595.8%0.14ILCA100%97.5%97.5%88.9%Age&amp;gt; 5098%0.2899.5%0.4597.8%0.5595.2%0.10≤ 5097%100%97%96.6%ERpositive97.9%0.399.7%0.0497.6%0.9496%0.29negative100%97.5%97.5%87.5% Conclusion: There were no statistically significant differences in clinical local ipsilateral breast or regional recurrence outcomes at 5 years for patients currently considered to be cautionary/high risk. Axillary recurrence, however, was adversely impacted by triple negative, ER-, and combined negative ER/PR status. ER- and ER/PR- status similarly affected axillary recurrence. In light of these differences, however, the actual increase in axillary recurrence ranges from 2.4%-3% and are of questionable clinical significance. These data suggest that women possessing cautionary/high risk features are at no more risk for ipsilateral breast recurrence than other patients considered to be acceptable for APBI treatment. Citation Format: Anabel Goulding, Charles Leonard, Shannon Tole, Lora Barke, Jodi Widner, Lina Asmar, Yunfei Wang. Outcomes after accelerated partial breast irradiation in “high risk” and women categorized as cautionary in the ASTRO guidelines [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-13-05.

PATH-47. TTF MAY APPLY SELECTIVE PRESSURE TO GLIOBLASTOMA CLONES WITH ANEUPLOIDY: A CASE REPORT

Abstract BACKGROUND The Tumor Treating Fields (TTF) mechanism of action is hypothesized act upon mitosis by disrupting the cell spindle apparatus. However, biomarkers and human tissue correlation of the effect of the TTF device are lacking. CASE: A 41 year-old previously healthy woman was found to have a right frontoparietal glioblastoma after she developed subacute onset of left hemiparesis and headache. The tumor was IDH wild type MGMT promoter unmethylated and TERT mutated. Chromosomal Microarray (CMA) was performed and demonstrated genome wide aneuploidy primarily characterized by hyperdiploidy. She underwent a gross total resection of the enhancing portion of the tumor and subsequent standard chemoradiotherapy (60 Gy IMRT with concomitant temozolomide) followed by initiation of the TTF device and adjuvant temozolomide. Six months after diagnosis, after 72 days of using the TTF device with 75% compliance and completion of the third cycle of temozolomide the patient had radiographic recurrence. She underwent a repeat resection. Pathology demonstrated recurrent tumor. Genetic analysis no longer demonstrated chromosomal losses or gains: the tumor was diploid. DISCUSSION This case may be a demonstration of effect of the TTF device applying a selective pressure to cells with multiple chromosomal gains and losses as the efficiency of mitosis in these cells may already be severely compromised. We are currently performing CMA on all patients with available tissue treated with the TTF device at our institution, with a planned retrospective analysis to explore this hypothesis further. CONCLUSION Repeat resection with detailed genetic analysis of GBM recurrence after therapies may help generate hypotheses regarding mechanisms of resistance, and in this case, mechanisms of action of the TTF.

Predicting Late Radiation-Induced Xerostomia with Parotid PET Biomarkers and Dose Metrics

Xerostomia is a common long-term toxicity from head and neck radiotherapy that is only partially predicted by delivered dose to salivary glands. Associations between parotid gland imaging biomarkers and late radiation-induced xerostomia have recently been shown. The aim of this study was to assess predictive models for late xerostomia incorporating pre-treatment parotid PET biomarkers compared to a base model using parotid dose alone in a homogeneous group of patients treated for orophangeal cancer. 47 patients with p16+ oropharyngeal squamous cell carcinoma were treated on two prospective institutional protocols with 70 Gy IMRT and concurrent carboplatin/paclitaxel. The 90th percentile of standardized uptake value (SUV-P90) was generated from each parotid gland on pre and 3-month post-RT PET scans. Late xerostomia (12-months post-RT) was defined by the patient-reported University of Michigan Xerostomia Questionnaire (XQ), and parotid-specific salivary flow rate (SFR). XQ outcomes included both the summary score (XQ-sum12m) and the most variable eating-related item as determined by principal component analysis: frequency of sipping fluids to aid in swallowing food (XQ-sip12m). Univariate analysis was applied to dose and SUV-P90 features as predictors of late xerostomia using both continuous and discrete scales. Multivariate analysis was applied for dose only and combined dose and SUV-P90 using penalized logistic regression for feature selection and model prediction based on the LASSO technique. Mean parotid dose and SUV-P90 from both pre and post-RT PET scans were significantly associated with patient-reported xerostomia and stimulated SFR (Stim12m) but not unstimulated SFR. Associations were stronger for SUV-P90 from the contralateral parotid (SUV-P90CL) than the ipsilateral parotid, and from 3-month PET scans relative to pre-treatment scans. On multivariate analysis, the addition of pre-treatment SUV-P90CL and an interaction term for dose and SUV to the model significantly improved the prediction for late moderate or severe xerostomia compared to the base model, from AUC = 0.70 to 0.74 for XQ-sum12m and from 0.74 to 0.84 for XQ-sip12m. The improvements remained statistically significant upon cross-validation. The addition of pre-treatment parotid PET biomarkers significantly improved a predictive model for late patient-reported xerostomia over a model based on parotid dose alone. The improvement was greatest for the single eating-related item with the largest inter-patient variability (XQ-sip12m). Correlation between SUV-P90 from 3-month post-RT PET scans and late xerostomia was even higher than those from pre-treatment scans, suggesting that mid-treatment scans should be further explored for a potential role in adaptive radiotherapy.Abstract 121; Table 1SUV-P90CL (3m)Mean XQ-Sum12mMean XQ-Sip12mMean Stim12m< 1.551.37.50.171.5 - 2.029.04.40.392.0 - 2.521.92.80.48> 2.510.81.30.80 Open table in a new tab

PIK3CA mutation as a prognostic factor in HPV-associated oropharynx cancer.

6011 Background: PIK3CA is the most frequently mutated gene in HPV-associated oropharyngeal SCC (OPSCC), with a prevalence of 20-30%. While PIK3CA mutations have been associated with adverse outcomes in cervical cancer, their prognostic significance in HPV-associated OPSCC remains unknown. We sought to elucidate the significance of PIK3CA mutations in a prospective cohort of HPV-associated OPSCC patients treated with definitive chemoradiation (CRT). Methods: Seventy-eight patients with HPV-associated OPSCC were prospectively enrolled on three protocols: LCCC 1121 (NCT03161821) or two phase II clinical trials of de-intensified CRT (NCT02281955 / NCT03077243). De-intensified regimen was 60 Gy IMRT with concurrent cisplatin (30mg/m2). Next-generation sequencing of tumor samples was performed using a targeted panel-based assay (UNCSeq), including over 200 genes. We estimated disease-free survival (DFS) using the Kaplan-Meier method and compared treatment groups with two-sided log-rank test (Medcalc). Results: Sequencing was performed in 78 patients with a median follow-up of 24 months. Seventy-five patients received 60Gy; three patients received 70Gy. Ten patients had disease recurrence (2 regional only, 5 distant only, 3 regional and distant). Thirty-eight of 78 patients had at least one mutation identified (17 PIK3CA, 4 PTEN, 3 KRAS, 3 FBXW7, 3 FGFR3, 2 TP53, 2 prothrombin 20210, 1 NRAS, 1 BRCA1, 1 factor V Leiden, 1 FLT3, 1 RAD50, 1 PIK3R1). The most common site of PIK3CA mutation was the helical domain (E545K – 8/17, E542K – 2/17). Despite similar T/N staging and tobacco pack years, patients with WT-PIK3CA had significantly higher DFS (93%) compared with 65% for patients with PIK3CA mutations (p = 0.0009). Patients with mutations other than PIK3CA also had improved DFS relative to those with PIK3CA mutations (96% vs. 65%; p = 0.0147). Conclusions: PIK3CA mutation is associated with worse DFS in a prospective cohort of newly diagnosed HPV-associated OPSCC patients treated with definitive CRT. These findings suggest that patients with PIK3CA mutations may not be suitable for de-intensified therapy and investigation of novel treatment strategies may be appropriate.

Mature results of the LCCC1413 phase II trial of de-intensified chemoradiotherapy for HPV-associated oropharyngeal squamous cell carcinoma.

6022 Background: To report the mature results from a prospective phase II clinical trial of highly de-intensified chemoradiotherapy (CRT) for patients with HPV-associated oropharyngeal squamous cell carcinoma (OPSCC). Methods: The major inclusion criteria were: 1) T0-T3, N0-N2, M0, 2) p16 positive, and 3) minimal/remote smoking history. Treatment was limited to 60 Gy intensity modulated radiotherapy with concurrent weekly intravenous cisplatin 30 mg/m2(second choice was cetuximab). Patients with T0-T2 N0-1 disease did not receive chemotherapy. All patients had a 10 to 12-week post-treatment PET/CT to determine need for planned neck dissection. The primary study endpoint was 2 year progression free survival (PFS). Secondary endpoint measures include 2 year local control (LC), regional control (RC), distant metastasis free survival (DMFS), cause specific survival (CSS) and overall survival (OS), and patient reported symptoms (PRO-CTCAE) and quality of life (EORTC QLQ-C30 &amp; H&amp;N35). Results: 114 patients were enrolled (median f/u of 28.8 months, range 2.6 to 51.4) with 84 having a minimum follow-up of 2 years. Smoking status was as follows: 47% never, 33% ≤ 10 pack years, and 19% &gt; 10 pack years. Post-treatment PET/CT complete response rate was 93% at the primary site and 80% in the neck. Eleven patients had planned neck dissection with 4 having pathological residual disease. Two year LC, RC, DMFS, PFS, CSS, and OS were the following: 96%, 99%, 91%, 88%, 97%, and 95%. Neither smoking status nor receipt of cetuximab correlated with recurrence. Four patients with recurrent disease had PIK3CA mutations. Thirty four percent of patients required a feeding tube (none permanent) for a median of 10.5 weeks. Mean pre- and 2-year post-treatment EORTC QOL scores were: Global 79/83 (lower worse), Swallowing 8/9 (higher worse), Dry Mouth 14/45 (higher worse), and Sticky Saliva 9/28 (higher worse). Mean pre- and 2 year post-treatment PRO-CTCAE (0 to 4 scale, higher worse) scores were: Swallowing 0.5/0.7 and Dry mouth 0.4/1.4. There were no ≥ Grade 3 late adverse events. Conclusions: Clinical outcomes with a highly de-intensified CRT regimen of 60 Gy IMRT with concurrent low-dose cisplatin are excellent in patients with HPV-associated OPSCC. Clinical trial information: NCT02281955.

Long-term outcomes following stereotactic body radiotherapy boost for oropharyngeal squamous cell carcinoma

Background/purpose: To determine the efficacy and toxicity profile of a stereotactic body radiotherapy (SBRT) boost as a first line treatment in patients with oropharyngeal squamous cell carcinoma (OPSCC).Materials and methods: We performed a retrospective cohort study in 195 consecutive OPSCC patients with T1-small T3 disease, treated at Erasmus MC between 2009 and 2016 with a SBRT (3 × 5.5 Gy) boost after 46 Gy IMRT. Primary endpoints were disease-specific survival (DSS) and Grade ≥3 toxicity (Common Terminology Criteria). The Kaplan-Meier method and Cox regression model were applied to determine rates and risk factors.Results: The median follow-up was 4.3 years. Treatment compliance was high (100%). Rates of 5-year DSS and late grade ≥3 toxicity were 85% and 28%, respectively. Five-year overall survival was 67%. The most frequently observed toxicities were mucosal ulceration or soft tissue necrosis (n = 30, 5 year 18%), dysphagia or weight loss (n = 18, 5 year 12%) and osteoradionecrosis (n = 11, 5 year 9%). Current smoker status (hazard ratio [HR] = 2.9, p = .001) and Charlson Comorbidity Index ≥2 (HR = 1.9, p = .03) were was associated with increased toxicity risk. Tooth extraction prior to RT was associated with increased osteoradionecrosis risk (HR = 6.4, p = .006).Conclusion: We reported on outcomes in the largest patient series to date treated with a hypofractionated boost for OPSCC. Efficacy was good with survival rates comparable to conventionally fractionated (chemo)radiotherapy. Grade ≥3 toxicity profiles showed high rates of soft tissue necrosis and osteoradionecrosis. Strategies to mitigate severe toxicity risks are under investigation to improve the tolerability of the SBRT boost.

Pretreatment FDG PET-Based Metabolic Nodal Sub-Tumor Volumes Improve Node-Specific Failure-Free Survival Prediction in Low-Risk Oropharyngeal Cancer Patients Following Chemoradiation Therapy

To compare the performance of lymph-node specific and conventional total node FDG-PET metabolic tumor volume (MTV) for failure-free survival (FFS) prediction in low-risk oropharyngeal cancer patients. Pretreatment FDG-PET scans of 144 HPV-associated oropharyngeal cancer patients with ≤10 pack-year smoking history and treated with definitive chemoradiation therapy (chemo-RT) to 70 Gy IMRT were retrospectively analyzed. Patients with upfront surgical excision of the primary tumor or planned neck dissection were excluded. The primary tumor and each PET-avid lymph node (totaling 481) were contoured and labeled by a radiation oncologist. Conventional nodal MTV (MTVC) was calculated using a combined lymph node 50% maximum standardized uptake value (SUV50%) threshold. Lymph-node-specific MTV (MTVI) was calculated using SUV50% from each lymph node. Finally, modified nodal MTV (MTVM) was calculated as the sum of all MTVI for each patient. Recurrence patterns including nodal failure location and time to biopsy-proven failure were analyzed. Nodal failure was defined as positive pathology in an unplanned neck dissection. ROC analysis was performed to assess the predictive performance of MTVC and MTVM for patient-level nodal failure within one year as a binary endpoint right censored by follow-up time, distant metastasis, new primary tumor, or death within one year. ROC analysis was also used on MTVI for node-specific failure prediction. Using Kaplan-Meier analysis, Mantel-Haenszel hazard ratios (HRs) were calculated for three evenly distributed quartile cut points to compare relative risks for patient-level and node-specific FFS. Statistical significance was assessed at a confidence level of 95% using Bonferroni correction for multiplicity. Confidence intervals of the ROC area under the curve (AUC) were calculated using bootstrap resampling. Eleven nodal failures (7.6% of patients, 3.3% of lymph nodes) occurred within a median (interquartile) of 5.0 (4.0-11.2) months from chemo-RT initiation. For one-year patient-level failure, modified MTV did not improve prediction performance (MTVC-AUC = 0.758 (95% CI: 0.636-0.882), MTVM-AUC = 0.682 (95% CI: 0.517-0.847)). MTVC>11.2 cc was associated with statistically significant HR of 7.6 (95% CI: 1.76-32.8), p<0.019; however, MTVM was not statistically significant for any of the tested cut points. For node-specific failure, MTVI-AUC= 0.833 (95% CI: 0.697-0.968), and MTVI > 6.6 cc was associated with HR of 14.43 (95% CI: 3.62-57.6), p<0.001. Modified MTV using additive node-specific thresholding did not improve patient-level nodal FFS prediction, indicating that conventional nodal MTV may be adequate. However, node-specific MTV was strongly predictive of node-specific failures, which may guide differential dosing regimens for oropharyngeal RT in low-risk patients. As such, radiation dose de-intensification may not be indicated for some highly metabolic tumor sub-volumes.

SU‐F‐T‐104: Determining the NTCP Parameters of Pharyngeal Constrictors and Proximal Esophagus for Radiation Induced Swallowing Problems Recorded Six Months After Radiation Therapy for Head and Neck Tumors

Purpose:To estimate the radiobiological parameters of four NTCP models that describe the dose‐response relations of pharyngeal constrictors and proximal esophagus regarding the severity of patient reported swallowing problems 6 months post chemo‐radiotherapy. To identify the section/structure that best correlates with the manifestation of the clinical endpoints. Finally, to compare the goodness‐of‐fit of those models.Methods:Forty‐three patients were treated on a prospective multi‐institutional phase II study for oropharyngeal squamous cell carcinoma. All the patients received 60 Gy IMRT and they reported symptoms using the novel patient reported outcome version of the CTCAE. We derived the individual patient dosimetric data of superior, medium and inferior sections of pharyngeal constrictors (SPC, MPC and IPC), superior and inferior sections of esophagus (SES and IES) as separate structures as well as combinations. The Lyman‐Kutcher‐Burman (LKB), Relative Seriality (RS), Logit and Relative Logit (RL) NTCP models were used to fit the patient data. The fitting of the different models was assessed through the area under the receiver operating characteristic curve (AUC) and the Odds Ratio methods.Results:The AUC values were highest for the SPC for Grade ≥ 2 (0.719 for the RS and RL models, and 0.716 for LKB and Logit). For Grade ≥ 1, the respective values were 0.699 for RS, LKB and Logit and 0.676 for RL. For MPC the AUC values varied between 0.463–0.477, for IPC between 0.396–0.458, for SES between 0.556–0.613 and for IES between 0.410–0.519. The Odds Ratio for the SPC was 15.6 (1.7–146.4) for RS, LKB and Logit for NTCP of 55%.Conclusion:All the examined NTCP models could fit the clinical data with similar accuracy. The SPC appear to correlate best with the clinical endpoints of swallowing problems. A prospective study could establish the use of NTCP values of SPC as a constraint in treatment planning.

SU-G-BRC-15: The Potential Clinical Significance of Dose Mapping Error for Intra- Fraction Dose Mapping for Lung Cancer Patients

Purpose: To evaluate the dose-mapping error (DME) inherent to conventional dose-mapping algorithms as a function of dose-matrix resolution. Methods: As DME has been reported to be greatest where dose-gradients overlap tissue-density gradients, non-clinical 66 Gy IMRT plans were generated for 11 lung patients with the target edge defined as the maximum 3D density gradient on the 0% (end of inhale) breathing phase. Post-optimization, Beams were copied to 9 breathing phases. Monte Carlo dose computed (with 2*2*2 mm3 resolution) on all 10 breathing phases was deformably mapped to phase 0% using the Monte Carlo energy-transfer method with congruent mass-mapping (EMCM); an externally implemented tri-linear interpolation method with voxel sub-division; Pinnacle's internal (tri-linear) method; and a post-processing energy-mass voxel-warping method (dTransform). All methods used the same base displacement-vector-field (or it's pseudo-inverse as appropriate) for the dose mapping. Mapping was also performed at 4*4*4 mm3 by merging adjacent dose voxels. Results: Using EMCM as the reference standard, no clinically significant (>1 Gy) DMEs were found for the mean lung dose (MLD), lung V20Gy, or esophagus dose-volume indices, although MLD and V20Gy were statistically different (2*2*2 mm3). Pinnacle-to-EMCM target D98% DMEs of 4.4 and 1.2 Gy were observed (2*2*2 mm3). However dTransform, which like EMCM conserves integral dose, had DME >1 Gy for one case. The root mean square RMS of the DME for the tri-linear-to- EMCM methods was lower for the smaller voxel volume for the tumor 4D-D98%, lung V20Gy, and cord D1%. Conclusion: When tissue gradients overlap with dose gradients, organs-at-risk DME was statistically significant but not clinically significant. Target-D98%-DME was deemed clinically significant for 2/11 patients (2*2*2 mm3). Since tri-linear RMS-DME between EMCM and tri-linear was reduced at 2*2*2 mm3, use of this resolution is recommended for dose mapping. Interpolative dose methods are sufficiently accurate for the majority of cases. J.V. Siebers receives funding support from Varian Medical Systems.

SU‐D‐204‐05: Fitting Four NTCP Models to Treatment Outcome Data of Salivary Glands Recorded Six Months After Radiation Therapy for Head and Neck Tumors

Purpose:To estimate the radiobiological parameters of four popular NTCP models that describe the dose‐response relations of salivary glands to the severity of patient reported dry mouth 6 months post chemo‐radiotherapy. To identify the glands, which best correlate with the manifestation of those clinical endpoints. Finally, to evaluate the goodness‐of‐fit of the NTCP models.Methods:Forty‐three patients were treated on a prospective multiinstitutional phase II study for oropharyngeal squamous cell carcinoma. All the patients received 60 Gy IMRT and they reported symptoms using the novel patient reported outcome version of the CTCAE. We derived the individual patient dosimetric data of the parotid and submandibular glands (SMG) as separate structures as well as combinations. The Lyman‐Kutcher‐Burman (LKB), Relative Seriality (RS), Logit and Relative Logit (RL) NTCP models were used to fit the patients data. The fitting of the different models was assessed through the area under the receiver operating characteristic curve (AUC) and the Odds Ratio methods.Results:The AUC values were highest for the contralateral parotid for Grade ≥ 2 (0.762 for the LKB, RS, Logit and 0.753 for the RL). For the salivary glands the AUC values were: 0.725 for the LKB, RS, Logit and 0.721 for the RL. For the contralateral SMG the AUC values were: 0.721 for LKB, 0.714 for Logit and 0.712 for RS and RL. The Odds Ratio for the contralateral parotid was 5.8 (1.3–25.5) for all the four NTCP models for the radiobiological dose threshold of 21Gy.Conclusion:It was shown that all the examined NTCP models could fit the clinical data well with very similar accuracy. The contralateral parotid gland appears to correlated best with the clinical endpoints of severe/very severe dry mouth. An EQD2Gy dose of 21Gy appears to be a safe threshold to be used as a constraint in treatment planning.

Complete neoadjuvant therapy in rectal cancer (CONTRE): A Brown University Oncology Research Group phase II study.

3530 Background: After preoperative chemoradiation and surgery, many patients (pts) with clinical stage II-III rectal cancer are unable to tolerate adjuvant FOLFOX chemotherapy, which may compromise disease-free and overall survival (DFS/OS). This study was designed to assess treatment delivery, toxicity and impact on pathologic response of administering chemotherapy prior to chemoradiation and surgery. Methods: Pts with clinical T3-4 and/or N1-2 rectal cancer, staged by endorectal ultrasound (ERUS) and pelvic MRI, received modified (m) FOLFOX6 every two weeks x eight cycles, followed by 50.4 Gy IMRT with concurrent capecitabine 825mg/m2 BID, 5 days per week, followed by surgery 4-8 weeks later. Results: There were 39 pts enrolled between August 2010 and June 2012; median age was 61 (30-79); clinical stage II n=7, stage III n=32. Distance from the anal verge: 5cm n=29. There were four pts presented with lumen obstruction preventing advancement of the endoscope and 31 with rectal blee...

The Prevalence of Persistent Prostate Cancer after Radiotherapy Detected at Radical Cystoprostatectomy for Bladder Cancer

More than half of the men who receive treatment for prostate cancer elect radiotherapy. After radiotherapy recurrence is determined by an increase in prostate specific antigen and not usually by pathological confirmation. We describe the prevalence of persistent gradable prostate cancer in men treated with radiotherapy for prostate cancer at radical cystoprostatectomy for bladder cancer. A total of 78 patients underwent radiotherapy (brachytherapy and/or external beam radiation) before the development of bladder cancer requiring radical cystectomy at our institution. All tissues were evaluated by a specialized genitourinary pathologist. Median time from radiotherapy to radical cystoprostatectomy was 77 months. Gradable prostate cancer was identified in 45% of patients. Of the tumors 69% were Gleason score 7 or greater, 17% were pT3 or greater and 5% showed positive lymph nodes. Men treated more recently were less likely to have gradable prostate cancer, including 100% before 1980, 49% between 1980 and 2000 and 10% from 2000 to the present (p=0.002) as were those who received external beam radiation alone compared to brachytherapy and combined brachytherapy/external beam radiation (58% vs 27% and 14%, respectively, p=0.005). After radiotherapy 45% of men had persistent prostate cancer (37% of men with no evidence of disease). A decreased prostate cancer rate was associated with later treatment year and combined brachytherapy/external beam radiation regimens. Similar to men treated with radical cystoprostatectomy for muscle invasive bladder cancer, meticulous attention should be paid during prostate removal in men treated with radiotherapy because many may have persistent prostate cancer. In addition, markers other than prostate specific antigen should be studied in men treated with radiotherapy to better identify those with biochemical recurrence.

Intensity‐modulated radiation therapy with dose‐painting for pediatric sarcomas with pulmonary metastases

We examined patterns of failure in pediatric patients with thoracic sarcoma and pulmonary metastases treated with intensity-modulated radiation therapy with dose-painting (DP-IMRT). Eleven pediatric patients, five with Ewing sarcoma family tumors (ESFT) and six with rhabdomyosarcoma (RMS), with primary thoracic tumors and pulmonary metastases underwent DP-IMRT with chemotherapy for definitive treatment. Eight patients also underwent surgery. Median time to RT was 21 (15-31) weeks. Nine patients received 45-50.4-Gy in 1.8 Gy fractions to the primary tumor (n = 3) or post-operative tumor bed (n = 6). Two patients ≤4 years received 12 Gy intraoperative radiation therapy and 30.6-36 Gy IMRT postoperatively to the tumor bed. All patients received 14-16.8 Gy in 0.54-0.88 Gy fractions to the whole lungs (n = 6) or hemithorax (n = 5) using dose-painting technique. A representative case was re-planned with IMRT plus standard AP/PA whole lung irradiation (WLI) for dosimetric comparison. With 27-month median follow-up, 3-year pulmonary relapse-free survival in all patients was 61%: 80% for RMS and 40% for ESFT. Five patients (4 ESFT and 1 RMS) experienced pulmonary relapse at median 16 (9-41) months. There were no local failures. Our representative case demonstrated more homogeneous target volume coverage of the whole lungs and decreased mean dose to esophagus (15%), heart (31%), spinal cord (15%), and liver (19%) with DP-IMRT. The treatment of children with a primary thoracic tumor and pulmonary metastases poses a significant challenge. DP-IMRT is one solution to this technical problem. Initial data from this small series suggest DP-IMRT is feasible and produces superior sparing of critical normal tissues.

A phase II study of complete neoadjuvant therapy in rectal cancer (CONTRE): The Brown University Oncology Group.

335 Background: While preoperative chemoradiation followed by surgery is the standard approach for patients (pts) with newly diagnosed clinical stage II-III rectal cancer, many are unable to tolerate postoperative adjuvant chemotherapy which may compromise disease-free and overall survival. CONTRE is a multicenter phase II study designed to determine the feasibility of administering all chemotherapy prior to surgery and to assess its impact on pathologic complete response (pCR) and complete (R0) resection Methods: Pts with T3-4 and/or N1-2 rectal cancer, staged by endorectal ultrasound (ERUS) and pelvic MRI, receive modified (m) FOLFOX6 every 2 weeks x 8 cycles, followed by repeat MRI and proctoscopy to assess response. Pts then receive 50.4 Gy IMRT with 5-FU 225 mg/m2/day or capecitabine 825mg/m2 BID, 5 days per week during radiation, followed by surgery 4-8 weeks later. Results: Thus far, we have enrolled 36 of a planned 39 pts (median age 58, range 30-79; T2-1, T3-30, T4-2; N1-20, N2-7). 28 of the first 30 (93%) completed 8 cycles of mFOLFOX6. 26 pts have completed chemoradiation while 2 chose to proceed directly to surgery. All patients opted to receive capecitabine during radiation. Grade 3/4 toxicities during chemotherapy and chemoradiation have included diarrhea (16%) and neutropenia (12%), with grade 3 renal and cardiac toxicities reported in one patient each. A clinical complete response after chemotherapy alone was achieved in 3 of 29 (10%). Of the first 21 pts undergoing surgery, pCR has been achieved in 6 (29%) and R0 resections in 100%. Thus far, all pts have been able to undergo sphincter-sparing resections. Study accrual will be completed by the meeting. Conclusions: A larger proportion of stage II-III rectal cancer pts are able to complete mFOLFOX6 (&gt;90% in our cohort) when administered prior to chemoradiation and surgery. Complete neoadjuvant treatment may represent a well-tolerated alternative to the current standard treatment sequence and a platform for the evaluation of novel therapeutics such as targeted agents during preoperative therapy. Funded in part by LIFEcycle, Inc. Clinical trial information: NCT01363843.