Citations

In this study, we investigated whether radiomics features from pre-treatment positron emission tomography (PET) images could be used to predict disease progression in patients with HPV-positive oropharyngeal cancer treated with definitive proton or x-ray radiotherapy. Machine learning models were built using a dataset from Mayo Clinic, Rochester, Minnesota (n = 72) and tested on a dataset from Mayo Clinic, Phoenix, Arizona (n = 22). A total of 71 clinical and radiomics features were considered. The Mann–Whitney U test was used to identify the top 2 clinical and top 20 radiomics features that were significantly different between progression and progression-free patients. Two dimensionality reduction methods were used to define two feature sets (manually filtered or machine-driven). A forward feature selection scheme was conducted on each feature set to build models of increased complexity (number of input features from 1 to 6) and evaluate model robustness and overfitting. The machine-driven features had superior performance and were less prone to overfitting compared to the manually filtered features. The four-variable Gaussian Naïve Bayes model using the ‘Radiation Type’ clinical feature and three machine-driven features achieved a training accuracy of 79% and testing accuracy of 77%. These results demonstrate that radiomics features can provide risk stratification beyond HPV-status to formulate individualized treatment and follow-up strategies.

AbstractBackgroundDeep learning auto‐segmentation (DLAS) models have been adopted in the clinic; however, they suffer from performance deterioration owing to the clinical practice variability. Some commercial DLAS software provide an incremental retraining function that enables users to train a custom model using their institutional data to account for clinical practice variability.PurposeThis study was performed to evaluate and implement the commercial DLAS software with the incremental retraining function for definitive treatment of patients with prostate cancer in a multi‐user environment.MethodsCT‐based target organs and organs‐at‐risk (OAR) delineation of 215 prostate cancer patients were utilized. The performance of three commercial DLAS software built‐in models was validated with 20 patients. A retrained custom model was developed using 100 patients and evaluated on the remaining data (n = 115). Dice similarity coefficient (DSC), Hausdorff distance (HD), mean surface distance (MSD), and surface DSC (SDSC) were utilized for quantitative evaluation. A multi‐rater qualitative evaluation was blindly performed with a five‐level scale. Visual inspection was performed in consensus and non‐consensus unacceptable cases to identify the failure modes.ResultsThree commercial DLAS vendor built‐in models achieved sub‐optimal performance in 20 patients. The retrained custom model had a mean DSC of 0.82 for prostate, 0.48 for seminal vesicles (SV), and 0.92 for rectum, respectively. This represents a significant improvement over the built‐in model with DSC of 0.73, 0.37, and 0.81 for the corresponding structures. Compared to the acceptance rate of 96.5% and consensus unacceptable rate (i.e., both reviewers rated as unacceptable) of 3.5% achieved by manual contours, the custom model achieved a 91.3% acceptance rate and 8.7% consensus unacceptable rate. The failure modes of retrained custom model were attributed to the following: cystogram (n = 2), hip prosthesis (n = 2), low dose rate brachytherapy seeds (n = 2), air in endorectal balloon(n = 1), non‐iodinated spacer (n = 2), and giant bladder(n = 1).ConclusionThe commercial DLAS software with the incremental retraining function was validated and clinically adopted for prostate patients in a multi‐user environment. AI‐based auto‐delineation of the prostate and OARs is shown to achieve improved physician acceptance, overall clinical utility, and accuracy.

Purpose: Planning target volume (PTV) expansion for post-prostatectomy radiotherapy is typically ≥5 mm. Recent clinical trials have proved the feasibility of a reduced margin of 2–3 mm for treatments on MRI-linac. We aim to study the minimum PTV margin needed using iterative cone-beam CT (iCBCT) as image guidance on conventional linacs. Materials/Methods: Fourteen patients who received post-prostatectomy irradiation (8 with an endorectal balloon and 6 without a balloon) were included in this study. Treatment was delivered with volumetric modulated radiation therapy (VMAT). Fractional dose delivery was evaluated in 165 treatment fractions. The bladder, rectal wall, femoral heads, and prostate bed clinical tumor volume (CTV) were contoured and verified on daily iCBCT. PTV margins (0 mm, 2 mm, and 4 mm) were evaluated on daily iCBCT. CTV coverage and OAR dose parameters were assessed with each PTV margin. Results: CTV D100% was underdosed with a 0 mm margin in 32% of fractions in comparison with 2 mm (6%) and 4 mm (6%) PTV margin (p ≤ 0.001). CTV D95% > 95% was met in 93–94% fractions for all PTV expansions. CTV D95% > 95% was achieved in more patients with an endorectal balloon than those without: 0 mm—90/91 (99%) vs. 63/74 (85%); 2 mm—90/91 (99%) vs. 65/75 (87%); 4 mm—90/90 (100%) vs. 63/73 (86%). There was no difference in absolute median change in CTV D95% (0.32%) for 0-, 2-, and 4 mm margins. The maximum dose remained under 108% for 100% (0 mm), 97% (2 mm), and 98% (4 mm) of images. Rectal wall maximum dose remained under 108% for 100% (0 mm), 100% (2 mm), and 98% (4 mm) of images. Conclusions: With high-quality iCBCT image guidance, PTV margin accounting for inter-fractional uncertainties can be safely reduced for post-prostatectomy radiotherapy. For fractionated radiotherapy, an isotropic expansion of 2 mm and 4 mm may be considered for margin expansion with and without the endorectal balloon. Future application for margin reduction needs to be further evaluated and considered with the advent of shorter post-prostatectomy radiation courses.

Purpose: Post-operative prostate cancer patients are treated with full bladder instruction and the use of an endorectal balloon (ERB). We reassessed the efficacy of this practice based on daily image guidance and dose delivery using high-quality iterative reconstructed cone-beam CT (iCBCT). Methods: Fractional dose delivery was calculated on daily iCBCT for 314 fractions from 14 post-operative prostate patients (8 with and 6 without ERB) treated with volumetric modulated radiotherapy (VMAT). All patients were positioned using novel iCBCT during image guidance. The bladder, rectal wall, femoral heads, and prostate bed clinical tumor volume (CTV) were contoured and verified on daily iCBCT. The dose-volume parameters of the contoured organs at risk (OAR) and CTV coverage were assessed for the clinical impact of daily bladder volume variations and the use of ERB. Minimum bladder volume was studied, and a straightforward bladder instruction was explored for easy clinical adoption. Results: A “minimum bladder” contour, the overlap between the original bladder contour and a 15 mm anterior and superior expansion from prostate bed PTV, was confirmed to be effective in identifying cases that might fail a bladder constraint of V65% <60%. The average difference between the maximum and minimum bladder volumes for each patient was 277.1 mL. The daily bladder volumes varied from 62.4 to 590.7 mL and ranged from 29 to 286% of the corresponding planning bladder volume. The bladder constraint of V65% <60% was met in almost all fractions (98%). CTVs (D90%, D95%, and D98%) remained well-covered regardless of the absolute bladder volume daily variation or the presence of the endorectal balloon. Patients with an endorectal balloon showed smaller variation but a higher average maximum rectal wall dose (D0.03mL: 104.3% of the prescription) compared to patients without (103.3%). Conclusions: A “minimum bladder” contour was determined that can be easily generated and followed to ensure sufficient bladder sparing. Further analysis and validation are needed to confirm the utility of the minimal bladder contour. Accurate dose delivery can be achieved for prostate bed target coverage and OAR sparing with or without the use of ERB.

AbstractBackgroundIn patients with extremity soft tissue sarcoma (eSTS), we describe outcomes of preoperative external beam radiation therapy (EBRT), limb‐sparing surgery (LSS), and intraoperative electron radiation therapy (IOERT).MethodsOne hundred and eighteen patients with eSTS treated between October 17, 2002 and July 28, 2021 were identified. EBRT was delivered preoperatively followed by LSS and IOERT.ResultsThe median follow‐up was 24.9 months. The presentation was primary in 102 (94%) patients and recurrent in 6 (6%) patients. Tumor location was lower extremity in 82 (76%) patients and upper extremity in 26 (24%) patients. Stage distribution was as follows: 3 (3%) IA, 24 (22%) IB, 31 (29%) II, 24 (22%) IIIA, and 25 (23%) IIIB. Final surgical margins were negative in 96 (89%) patients. The 5‐year local control, failure‐free survival, and overall survival were 94%, 75%, and 64%, respectively. Univariate analysis identified age >50, lower extremity, and higher grade as significant negative prognostic factors for overall survival. Grade 3 fracture or osteoradionecrosis requiring surgical fixation, neuropathy, and lymphedema occurred in 7 (6%), 1 (1%), and 0 patients, respectively.ConclusionsThis study represents one of the largest series using preoperative EBRT, LSS, and IOERT for eSTS, with high local control and a low rate of late severe toxicity.

AbstractPurpose/ObjectivesHolmium laser enucleation of the prostate (HoLEP) is commonly performed in patients with significant bladder outlet obstruction. However, there are few reports on the toxicity of external beam irradiation (RT) for prostate cancer in patients after prior HoLEP. In this study, we evaluate the side effects and treatment outcomes of RT after HoLEP.Materials/MethodsEighteen patients who had HoLEP and subsequently received RT for prostate cancer were included. Data collected included patient and disease characteristics, urinary function, and radiation dose. Acute and late urinary (GU) and gastrointestinal (GI) side effects were evaluated. Disease control and survival rates were calculated using Kaplan–Meier method.ResultsMedian follow‐up was 18 months (range: 4–46 months). Median prostate volume was 107 ml before HoLEP and 24 ml after HoLEP. Median International Prostate Symptom Score (IPSS) was 17 (range: 5–32) before HoLEP. Median decline in IPSS score after HoLEP was 7 (range: −2–21). On uroflow study, peak flow rate, and post‐void residual were significantly improved after HoLEP. After radiation, peak flow rate and average flow rate showed a decline but remained significantly improved compared to pre‐HoLEP measurements. Maximum acute Common Terminology Criteria for Adverse Events (CTCAE) adverse events were 12 grade 1 and 3 grade 2 for GU, and 3 grade 1 for GI, respectively. Maximum late adverse events were 13 grade 1 and 2 grade 2 for GU, and all grade 0 for GI, respectively. At last follow‐up, there were 8 grade 1 and 1 grade 2 late GU, and 3 grade 1 late GI adverse events, respectively. There was no significant increase in urinary incontinence after RT compared to before RT. The 18‐month biochemical control, local control, distant control rates were 78%, 94%, and 80%, respectively.ConclusionsPatients who received RT as definitive treatment for prostate cancer after prior HoLEP had low risk of serious acute and late side effects. HoLEP can be safely performed and should be considered in patients with significant bladder outlet obstruction and large prostate volume before RT.

494 Background: Our aim was to compare survival between patients receiving neoadjuvant chemoradiation and orthotopic liver transplantation (OLT group) versus definitive chemoradiation (CRT group) for extrahepatic or hilar cholangiocarcinoma. Methods: 49 patients (20 in OLT group vs. 29 in CRT group) with unresectable hilar/extrahepatic cholangiocarcinoma were treated at Mayo Clinic Arizona between Feb. 1998–Sep. 2019. Treatment included external beam radiation therapy (median 4500cGy) and boost (median 900cGy) with either continuous 5-flurouracil (dose range 180–225 mg/m2) or capecitabine (dose range 825–1000 mg/m2 BID) prior to or without OLT. Radiation boosts were delivered with EBRT or bile duct brachytherapy. Patients were between 27.9–84.3 years (median 64.3) at diagnosis. 18 patients had previous diagnosis of PSC. Results: Between Feb. 1998–Sep. 2019, 31(63%) of 49 patients died by the end of follow-up. Of patients treated with neoadjuvant therapy and OLT, 7(35%) of 20 patients died. 24(86%) of 28 patients treated with definitive therapy died. The OLT cohort were younger (mean age 56.5 vs. 69.0 years), more likely to have PSC and UC (65% vs. 17%), and had a lower CA 19-9 (median 43 vs. 535)(P < 0.003). From the end date of radiation, median overall survival was 76.8 months vs. 15.6 months for the OLT and CRT groups, respectively. Survival rates at 3 and 5 years were 78% and 69% in the OLT group compared to 19% and 6% in the CRT group (HR 7.73; 3.04-19.65:(P < 0.0001)). Progression-free survival (89% vs. 30% at 3 years), and distant metastasis-free survival (88% vs. 66% at 3 years) favored OLT versus CRT alone (HR 5.74;1.12-29.34:(P < 0.02)). Univariate analysis demonstrated that the method of treatment (OLT vs. CRT) was the only variable associated with better clinical outcomes. Conclusions: In patients with unresectable extrahepatic/hilar cholangiocarcinoma, survival was higher in those who underwent chemoradiation and OLT. Patients who received definitive chemoradiation in the absence of OLT were expected to have worse overall, progression-free, and metastasis-free survival.

Abstract Background: Breast tumors exhibit intratumor heterogeneity resulting in targeted therapy resistance and other challenges in disease management. To address the sources of heterogeneity, we performed a unique, in-depth analysis of clonal architecture in primary chemoradiation-naïve breast cancers. We combined DNA content-based flow cytometry and ploidy analysis with aCGH and whole exome next-generation sequencing (NGS) in multiple biopsies from the tumors and involved lymph nodes (LNs). Material and methods: We sorted nuclei from distinct populations of diploid, tetraploid, and aneuploid cells in surgical tumor samples from three chemoradiation-naïve patients. Each sorted tumor cell population was interrogated with aCGH and whole exome NGS. In Patient #1, we sorted and interrogated the genomes of tumor populations from 12 fresh frozen sections morphologically mapped from within a HER2+, ER+, PR- primary invasive ductal carcinoma (IDC) of histological grade 3 with LN involvement and 2-3 sections from 2 out of 5 LNs. In Patient #2, 11 morphologically mapped fresh frozen sections were analyzed from a grade 2, ER+, PR+, HER2+, BRCA2 mutant LN- IDC. In parallel, matching samples were processed for IHC assays. In Patient #3 biopsies from a grade 2 ER+, PR+ primary tumor were profiled. Results: The 18 primary and LN biopsies from Patient #1 fell into 6 distinct ploidy groups albeit with aberrant but homogenous aCGH profiles, characterized by SARC amplification and homozygous deletions in ROBO1 and ROBO2. In contrast a dominant ploidy was identified throughout 10 biopsies in Patient #2 but with heterogeneous aCGH profiles. Patient #3 had a clonal homozygous deletion in Numb in each of 4 tumor biopsies. Mutation profiles obtained through exome sequencing further confirmed that ploidy was the main driver in Patient #1 whereas copy number aberrations played the key role in Patient #2 with the BRCA2 mutation (R3129X). A dendrogram based on exome variant calls of the aneuploid populations in Patient #1 strongly correlated with ploidy group and further revealed the specific clonal population characterized by a 5N ploidy and homozygous mutations in TP53 and PIK3CA as the progenitor to the ploidies present in the distant LNs. Strikingly, patients #1 and #2 were HER2 wild type across their clonal populations, contradicting IHC staining in a single core biopsy. Conclusions:Rather than inferring the presence of distinct tumor cell populations, our flow-sorting based approach of first identifying clonal populations and then interrogating their genomes, provides an objective method of exploring the sources and clinical significance of tumor heterogeneity. Our approach of clonal analysis has broad implications in the study of tumor heterogeneity and the identification of drivers in breast and other solid tumors that can advance more effective treatment and clinical management of patients with this disease. Citation Format: MARIACARLA ANDREOZZI, Princy Francis, Elizabeth Lenkiewicz, Mia Champion, Brady Laughlin, Karen Anderson, Heather Cunliffe, Ann E. McCullough, Michael T. Barrett, Barbara Pockaj. Deep clonal profiling identifies distinct mechanisms of heterogeneity and evolution in breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-175. doi:10.1158/1538-7445.AM2015-LB-175