Proton Therapy for HPV-Associated Oropharyngeal Cancers of the Head and Neck: a De-Intensification Strategy.

OPINION STATEMENT: The rise in the incidence of human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPC), the relatively young age at which it is diagnosed, and its favorable prognosis necessitate the use of treatment techniques that reduce the likelihood of side effects during and after curative treatment. Intensity-modulated proton therapy (IMPT) is a form of radiotherapy that de-intensifies treatment through dose de-escalation to normal tissues without compromising dose to the primary tumor and involved, regional lymph nodes. Preclinical studies have demonstrated that HPV-positive squamous cell carcinoma is more sensitive to proton radiation than is HPV-negative squamous cell carcinoma. Retrospective studies comparing intensity-modulated photon (X-ray) radiotherapy to IMPT for OPC suggest comparable rates of disease control and lower rates of pain, xerostomia, dysphagia, dysgeusia, gastrostomy tube dependence, and osteoradionecrosis with IMPT-all of which meaningfully affect the quality of life of patients treated for HPV-associated OPC. Two phase III trials currently underway-the "Randomized Trial of IMPT versus IMRT for the Treatment of Oropharyngeal Cancer of the Head and Neck" and the "TOxicity Reduction using Proton bEam therapy for Oropharyngeal cancer (TORPEdO)" trial-are expected to provide prospective, level I evidence regarding the effectiveness of IMPT for such patients.

Defining the dose-volume criteria for laryngeal sparing in locally advanced oropharyngeal cancer utilizing split-field IMRT, whole-field IMRT and VMAT.

PURPOSE: To determine the optimal dose-volume constraint for laryngeal sparing using three commonly employed intensity modulated radiation therapy (IMRT) approaches in patients with oropharyngeal cancer treated to the bilateral neck. MATERIALS AND METHODS: Thirty patients with stage II-IVA oropharynx cancers received definitive radiotherapy with split-field IMRT (SF-IMRT) to the bilateral neck between 2008 and 2013. Each case was re-planned using whole-field IMRT (WF-IMRT) and volumetric modulated arc therapy (VMAT) and plan quality metrics and dose to laryngeal structures was evaluated. Two larynx volumes were defined and compared on the current study: the Radiation Therapy Oncology Group (RTOG) larynx as defined per the RTOG 1016 protocol and the MDACC larynx defined as the components of the larynx bounded by the superior and inferior extent of the thyroid cartilage. RESULTS: Target coverage, conformity, and heterogeneity indices were similar in all techniques. The RTOG larynx mean dose was lower with WF-IMRT than SF-IMRT (22.1 vs 25.8 Gy; P < 0.01). The MDACC larynx mean dose was 17.5 Gy ± 5.4 Gy with no differences between the 3 techniques. WF-IMRT and VMAT plans were associated with lower mean doses to the supraglottic larynx (42.1 vs 41.2 vs 54.8 Gy; P < 0.01) and esophagus (18.1 vs 18.2 vs 36 Gy; P < 0.01). CONCLUSIONS: Modern whole field techniques can provide effective laryngeal sparing in patients receiving radiotherapy to the bilateral neck for advanced oropharyngeal cancers. SUMMARY: We evaluated laryngeal dose in patients with locally advanced oropharyngeal cancer treated to the bilateral neck using split-field IMRT (SF-IMRT), whole-field IMRT (WF-IMRT) and volumetric arc therapy (VMAT). All three techniques provided good sparing of laryngeal structures and were able to achieve a mean larynx dose < 33 Gy. There were no significant differences in dose to target structures or non-laryngeal organs at risk among techniques.

Reclassifying patients with early-stage Hodgkin lymphoma based on functional radiographic markers at presentation.

The presence of bulky disease in Hodgkin lymphoma (HL), traditionally defined with a 1-dimensional measurement, can change a patient's risk grouping and thus the treatment approach. We hypothesized that 3-dimensional measurements of disease burden obtained from baseline 18F-fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT) scans, such as metabolic tumor volume (MTV) and total lesion glycolysis (TLG), would more accurately risk-stratify patients. To test this hypothesis, we reviewed pretreatment PET-CT scans of patients with stage I-II HL treated at our institution between 2003 and 2013. Disease was delineated on prechemotherapy PET-CT scans by 2 methods: (1) manual contouring and (2) subthresholding of these contours to give the tumor volume with standardized uptake value ≥2.5. MTV and TLG were extracted from the threshold volumes (MTVt, TLGt) and from the manually contoured soft-tissue volumes. At a median follow-up of 4.96 years for the 267 patients evaluated, 27 patients were diagnosed with relapsed or refractory disease and 12 died. Both MTVt and TLGt were highly correlated with freedom from progression and were dichotomized with 80th percentile cutoff values of 268 and 1703, respectively. Consideration of MTV and TLG enabled restratification of early unfavorable HL patients as having low- and high-risk disease. We conclude that MTV and TLG provide a potential measure of tumor burden to aid in risk stratification of early unfavorable HL patients.

Radiographic retropharyngeal lymph node involvement in HPV-associated oropharyngeal carcinoma: Patterns of involvement and impact on patient outcomes.

BACKGROUND: The objective of the current study was to characterize the incidence, pattern, and impact on oncologic outcomes of retropharyngeal lymph node (RPLN) involvement in HPV-associated oropharyngeal cancer (OPC). METHODS: Data regarding patients with HPV-associated OPC who were treated at The University of Texas MD Anderson Cancer Center with intensity-modulated radiotherapy from 2004 through 2013 were analyzed retrospectively. RPLN status was determined by reviewing pretreatment imaging and/or reports. Outcomes analysis was restricted to patients with lymph node-positive (+) disease. Kaplan-Meier survival estimates were generated and survival curves were compared using the log-rank test. Bayesian information criterion assessed model performance changes with the addition of RPLN status to current American Joint Committee on Cancer staging. Competing risk analysis compared modes of disease recurrence. RESULTS: The incidence of radiographic RPLN involvement was 9% (73 of 796 patients) and was found to vary by primary tumor site. The 5-year rates of freedom from distant metastases (FDM) and overall survival were lower in patients with RPLN(+) status compared with those with RPLN-negative (-) status (84% vs 93% [P = .0327] and 74% vs 87% [P = .0078], respectively). RPLN(+) status was not found to be associated with outcomes on multivariate analysis. Bayesian information criterion analysis demonstrated that current American Joint Committee on Cancer staging was not improved with the inclusion of RPLN. Locoregional and distant disease recurrence probabilities for those patients with RPLN(+) status were 8% and 13%, respectively, compared with 10% and 6%, respectively, for those with RPLN(-) status. RPLN(+) status portended worse 5-year FDM in the low-risk subgroup (smoking history of <10 pack-years) and among patients who received concurrent chemotherapy but not induction chemotherapy. CONCLUSIONS: RPLN(+) status was associated with worse overall survival and FDM on univariate but not multivariate analysis. In subgroup analyses, RPLN(+) status was associated with poorer FDM in both patients with a smoking history of <10 pack-years and those who received concurrent chemotherapy, suggesting that RPLN(+) status could be considered an exclusion criteria in treatment deintensification efforts seeking to omit chemotherapy.

Pre-treatment neutrophil/lymphocyte ratio and platelet/lymphocyte ratio are prognostic of progression in early stage classical Hodgkin lymphoma.

To determine whether pre-treatment neutrophil/lymphocyte (NLR) or platelet/lymphocyte ratios (PLR) are predictive for progression in early-stage classical Hodgkin lymphoma (cHL), we derived NLR and PLR values for 338 stage I/II cHL patients and appropriate cut-off point values to define progression. Two-year freedom from progression (FFP) for patients with NLR ≥6·4 was 82·2% vs. 95·7% with NLR <6·4 (P < 0·001). Similarly, 2-year FFP was 84·3% for patients with PLR ≥266·2 vs. 96·1% with PLR <266·2 (P = 0·003). On univariate analysis, both NLR and PLR were significantly associated with worse FFP (P = 0·001). On multivariate analysis, PLR remained a significant, independent prognostic factor (P < 0·001).

Mammary stem cell and macrophage markers are enriched in normal tissue adjacent to inflammatory breast cancer.

INTRODUCTION: We hypothesized that breast tissue not involved by tumor in inflammatory breast cancer (IBC) patients contains intrinsic differences, including increased mammary stem cells and macrophage infiltration, which may promote the IBC phenotype. MATERIALS AND METHODS: Normal breast parenchyma ≥ 5 cm away from primary tumors was obtained from mastectomy specimens. This included an initial cohort of 8 IBC patients and 60 non-IBC patients followed by a validation cohort of 19 IBC patients and 25 non-IBC patients. Samples were immunostained for either CD44+CD49f+CD133/2+ mammary stem cell markers or the CD68 macrophage marker and correlated with IBC status. Quantitation of positive cells was determined using inForm software from PerkinElmer. We also examined the association between IBC status and previously published tumorigenic stem cell and IBC tumor signatures in the validation cohort samples. RESULTS: 8 of 8 IBC samples expressed isolated CD44+CD49f+CD133/2+ stem cell marked cells in the initial cohort as opposed to 0/60 non-IBC samples (p = 0.001). Similarly, the median number of CD44+CD49f+CD133/2+ cells was significantly higher in the IBC validation cohort as opposed to the non-IBC validation cohort (25.7 vs. 14.2, p = 0.007). 7 of 8 IBC samples expressed CD68 + histologically confirmed macrophages in initial cohort as opposed to 12/48 non-IBC samples (p = 0.001). In the validation cohort, the median number of CD68 + cells in IBC was 3.7 versus 1.0 in the non-IBC cohort (p = 0.06). IBC normal tissue was positively associated with a tumorigenic stem cell signature (p = 0.02) and with a 79-gene IBC signature (p < 0.001). CONCLUSIONS: Normal tissue from IBC patients is enriched for both mammary stem cells and macrophages and has higher association with both a tumorigenic stem cell signature and IBC-specific tumor signature. Collectively, these data suggest that IBC normal tissue differs from non-IBC tissue. Whether these changes occur before the tumor develops or is induced by tumor warrants further investigation.

Early-stage Hodgkin lymphoma outcomes after combined modality therapy according to the post-chemotherapy 5-point score: can residual pet-positive disease be cured with radiotherapy alone?

Early-stage classical Hodgkin lymphoma (HL) patients are evaluated by an end-of-chemotherapy positron emission tomography-computed tomography (eoc-PET-CT) after doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) and before radiation therapy (RT). We determined freedom from progression (FFP) in patients treated with ABVD and RT according to the eoc-PET-CT 5-point score (5PS). Secondarily, we assessed whether patients with a positive eoc-PET-CT (5PS of 4-5) can be cured with RT alone. The cohort comprised 174 patients treated for stage I-II HL with ABVD and RT alone. ABVD was given with a median of four cycles and RT with a median dose of 30·6 Gy. Five-year FFP was 97%. Five-year FFP was 100% (0 relapses/98 patients) for patients with a 5PS of 1-2, 97% (2/65) for a 5PS of 3, 83% (1/8) for a 5PS of 4, and 67% (1/3) for a 5PS of 5 (P < 0·001). Patients with positive eoc-PET-CT scans who were selected for salvage RT alone had experienced a very good partial response to ABVD. Risk factors for recurrence in this subgroup included a small reduction in tumour size and a 'bounce' in ≥1 PET-CT parameter (reduction then rise from interim to final scan). Thus, a positive eoc-PET-CT is associated with inferior FFP; however, appropriately selected patients can be cured with RT alone.

Factors associated with regional recurrence after lymph node dissection for penile squamous cell carcinoma.

OBJECTIVE: To identify factors associated with regional recurrence after lymph node dissection (LND) for squamous cell carcinoma (SCC) to determine which patients might benefit from adjuvant therapy. PATIENTS AND METHODS: Men who underwent LND for penile SCC from 1977 to 2014 were identified from an institutional database. Kaplan-Meier curves estimated recurrence-free survival (RFS) calculated from the date of LND. Cox regression models evaluated the association between RFS and patient and tumour characteristics. RESULTS: In all, 182 men who underwent LND for penile SCC were identified. The median patient age was 62 years and the median follow-up was 4.2 years. After LND 34 men had regional recurrence, of which 24 developed isolated regional recurrences without distant metastasis. The median RFS was 5.7 months, and the 3-year RFS rate was 70%. On univariate analysis, lymphovascular invasion, clinical and pathological nodal stage, pathological inguinal laterality, pelvic nodal involvement, lymph node density ≥5.2%, ≥3 pathologically involved lymph nodes, and extranodal extension (ENE) were associated with worse RFS (all P < 0.05). On multivariate analysis, clinical N3 disease [adjusted hazard ratio (AHR)] 3.53, 95% confidence interval (CI) 1.68-7.45; P = 0.001), ≥3 pathologically involved lymph nodes (AHR 3.78, 95% CI 2.12-6.65; P < 0.001), and ENE (AHR 3.32, 95% CI 1.93-5.76; P < 0.001) were associated with worse RFS. The 3-year RFS for patients with cN0, cN1, cN2, and cN3 disease was 91.7%, 64.5%, 54.7%, and 38.3%, respectively. For men with ≥3 involved nodes, the 3-year RFS was 17% vs 82.4% in men with <3 involved nodes. The 3-year RFS was 29.7% in men with ENE and 85.7% in men without ENE. CONCLUSION: The presence of clinical N3 disease, ≥3 pathologically involved lymph nodes, and ENE was associated with worse RFS. As regional recurrence portends a dismal prognosis with few salvage options, adjuvant therapies should be developed for men with the aforementioned adverse factors.

A Visualization and Radiation Treatment Plan Quality Scoring Method for Triage in a Population-Based Context.

Purpose: Our purpose was to develop a clinically intuitive and easily understandable scoring method using statistical metrics to visually determine the quality of a radiation treatment plan. Methods and Materials: Data from 111 patients with head and neck cancer were used to establish a percentile-based scoring system for treatment plan quality evaluation on both a plan-by-plan and objective-by-objective basis. The percentile scores for each clinical objective and the overall treatment plan score were then visualized using a daisy plot. To validate our scoring method, 6 physicians were recruited to assess 60 plans, each using a scoring table consisting of a 5-point Likert scale (with scores ≥3 considered passing). Spearman correlation analysis was conducted to assess the association between increasing treatment plan percentile rank and physician rating, with Likert scores of 1 and 2 representing clinically unacceptable plans, scores of 3 and 4 representing plans needing minor edits, and a score of 5 representing clinically acceptable plans. Receiver operating characteristic curve analysis was used to assess the scoring system's ability to quantify plan quality. Results: Of the 60 plans scored by the physicians, 8 were deemed as clinically acceptable; these plans had an 89.0th ± 14.5 percentile value using our scoring system. The plans needing minor edits or deemed unacceptable had more variation, with scores falling in the 62.6nd ± 25.1 percentile and 35.6th ± 25.7 percentile, respectively. The estimated Spearman correlation coefficient between the physician score and treatment plan percentile was 0.53 (P < .001), indicating a moderate but statistically significant correlation. Receiver operating characteristic curve analysis demonstrated discernment between acceptable and unacceptable plan quality, with an area under the curve of 0.76. Conclusions: Our scoring system correlates with physician ratings while providing intuitive visual feedback for identifying good treatment plan quality, thereby indicating its utility in the quality assurance process.

MR-guided stereotactic radiation therapy for head and neck cancers.

Purpose: MR-guided radiotherapy (MRgRT) has the advantage of utilizing high soft tissue contrast imaging to track daily changes in target and critical organs throughout the entire radiation treatment course. Head and neck (HN) stereotactic body radiation therapy (SBRT) has been increasingly used to treat localized lesions within a shorter timeframe. The purpose of this study is to examine the dosimetric difference between the step-and-shot intensity modulated radiation therapy (IMRT) plans on Elekta Unity and our clinical volumetric modulated arc therapy (VMAT) plans on Varian TrueBeam for HN SBRT. Method: Fourteen patients treated on TrueBeam sTx with VMAT treatment plans were re-planned in the Monaco treatment planning system for Elekta Unity MR-Linac (MRL). The plan qualities, including target coverage, conformity, homogeneity, nearby critical organ doses, gradient index and low dose bath volume, were compared between VMAT and Monaco IMRT plans. Additionally, we evaluated the Unity adaptive plans of adapt-to-position (ATP) and adapt-to-shape (ATS) workflows using simulated setup errors for five patients and assessed the outcomes of our treated patients. Results: Monaco IMRT plans achieved comparable results to VMAT plans in terms of target coverage, uniformity and homogeneity, with slightly higher target maximum and mean doses. The critical organ doses in Monaco IMRT plans all met clinical goals; however, the mean doses and low dose bath volumes were higher than in VMAT plans. The adaptive plans demonstrated that the ATP workflow may result in degraded target coverage and OAR doses for HN SBRT, while the ATS workflow can maintain the plan quality. Conclusion: The use of Monaco treatment planning and online adaptation can achieve dosimetric results comparable to VMAT plans, with the additional benefits of real-time tracking of target volume and nearby critical structures. This offers the potential to treat aggressive and variable tumors in HN SBRT and improve local control and treatment toxicity.

Outcomes and Pattern of Care for Spinal Myxopapillary Ependymoma in the Modern Era-A Population-Based Observational Study.

(1) Background: Myxopapillary ependymoma (MPE) is a rare tumor of the spine, typically slow-growing and low-grade. Optimal management strategies remain unclear due to limited evidence given the low incidence of the disease. (2) Methods: We analyzed data from 1197 patients with spinal MPE from the Surveillance, Epidemiology, and End Results (SEER) database (2000-2020). Patient demographics, treatment modalities, and survival outcomes were examined using statistical analyses. (3) Results: Most patients were White (89.9%) with a median age at diagnosis of 42 years. Surgical resection was performed in 95% of cases. The estimated 10-year overall survival was 91.4%. Younger age (hazard ratio (HR) = 1.09, p < 0.001) and receipt of surgery (HR = 0.43, p = 0.007) were associated with improved survival. Surprisingly, male sex was associated with worse survival (HR = 1.86, p = 0.008) and a younger age at diagnosis compared to females. (4) Conclusions: This study, the largest of its kind, underscores the importance of surgical resection in managing spinal MPE. The unexpected association between male sex and worse survival warrants further investigation into potential sex-specific pathophysiological factors influencing prognosis. Despite limitations, our findings contribute valuable insights for guiding clinical management strategies for spinal MPE.

Development and clinical implementation of a digital workflow utilizing 3D-printed oral stents for patients with head and neck cancer receiving radiotherapy.

OBJECTIVES: We describe the development of 3D-printed stents using our digital workflow and their effects on patients enrolled in the lead-in phase of a multi-center, randomized Phase-II trial. MATERIALS AND METHODS: Digital dental models were created for patients using intraoral scanning. Digital processes were implemented to develop the mouth-opening, tongue-depressing, and tongue-lateralizing stents using stereolithography. Time spent and material 3D-printing costs were measured. Physicians assessed mucositis using the Oral Mucositis Assessment Scale (OMAS) and collected MD Anderson Symptom Inventory (MDASI) reports and adverse events (AEs) from patients at various time points (TPs). OMAS and MDASI results were evaluated using paired t-test analysis. RESULTS: 18 patients enrolled into the lead-in phase across 6 independent clinical sites in the USA. 15 patients received stents (average design and fabrication time, 8 h; average material 3D-printing cost, 11 USD). 10 eligible patients with complete OMAS and MDASI reports across all TPs were assessed. OMAS increased significantly from baseline to week 3 of treatment (mean difference = 0.34; 95 % CI, 0.09-0.60; p = 0.01). MDASI increased significantly from baseline to week 3 of treatment (mean difference = 1.02; 95 % CI, 0.40-1.70; p = 0.005), and week 3 of treatment to end of treatment (mean difference = 1.90; 95 % CI, 0.90-2.92; p = 0.002). AEs (grades 1-3) were reported by patients across TPs. Mucositis and radiation dermatitis were primarily attributed to chemoradiation. CONCLUSIONS: 3D-printed stents were successfully fabricated and well tolerated by patients. As patients enroll in the randomized phase of this trial, data herein will establish a baseline for comparative analysis.

PRECISE: Preoperative Radiotherapy to Elicit Critical Immune Stimulating Effects - A Phase II Clinical Trial.

PURPOSE: Radiotherapy is an under-investigated tool for priming the immune system in intact human breast cancers. We sought here to investigate if a preoperative radiotherapy boost delivered was associated with a significant change in tumor infiltrating lymphocytes in the tumor in estrogen receptor positive, HER2Neu non-amplified breast cancers. METHODS AND MATERIALS: 20 patients were enrolled in a phase II clinical trial and received either 7.5Gy x 1 fraction or 2Gy x 5 fractions, completed 6-8 days prior to surgery. Percent stromal tumor infiltrating lymphocytes (TIL) were evaluated on hematoxylin and eosin-stained samples. Short-term safety was assessed based on time to surgery, toxicities, and cosmesis up to 6 months following boost. RESULTS: Stromal TIL increased 6-8 days following completion of boost radiotherapy (median 3.0 (IQR 1.0-6.5) prior to radiotherapy vs. median 5.0 (IQR 1.5-8.0) post radiotherapy, p=0.0037. Zero grade ≥ 3 toxicities up to 6 months following boost were experienced. 94% (16/17) patients with 6 month follow-up cosmetic assessment following breast conservation had good-excellent cosmesis by physician assessment. CONCLUSION: In this phase II trial, preoperative radiotherapy boost resulted in a short-term increase in stromal TIL with minimal toxicities. Preoperative breast radiotherapy appears to be safe and may be a feasible means for priming the tumor microenvironment.

Defining the ATM-mediated barrier to tumorigenesis in somatic mammary cells following ErbB2 activation.

p53, apoptosis, and senescence are frequently activated in preneoplastic lesions and are barriers to progression to malignancy. These barriers have been suggested to result from an ATM-mediated DNA damage response (DDR), which may follow oncogene-induced hyperproliferation and ensuing DNA replication stress. To elucidate the currently untested role of DDR in breast cancer initiation, we examined the effect of oncogene expression in several murine models of breast cancer. We did not observe a detectable DDR in early hyperplastic lesions arising in transgenic mice expressing several different oncogenes. However, DDR signaling was strongly induced in preneoplastic lesions arising from individual mammary cells transduced in vivo by retroviruses expressing either PyMT or ErbB2. Thus, activation of an oncogene after normal tissue development causes a DDR. Furthermore, in this somatic ErbB2 tumor model, ATM, and thus DDR, is required for p53 stabilization, apoptosis, and senescence. In palpable tumors in this model, p53 stabilization and apoptosis are lost, but unexpectedly senescence remains in many tumor cells. Thus, this murine model fully recapitulates early DDR signaling; the eventual suppression of its endpoints in tumorigenesis provides compelling evidence that ErbB2-induced aberrant mammary cell proliferation leads to an ATM-mediated DDR that activates apoptosis and senescence, and at least the former must be overcome to progress to malignancy. This in vivo study also uncovers an unexpected effect of ErbB2 activation previously known for its prosurvival roles, and suggests that protection of the ATM-mediated DDR-p53 signaling pathway may be important in breast cancer prevention.

Optimizing Preventive Adjuvant Linac-Based (OPAL) Radiation: A Phase 2 Trial of Daily Partial Breast Irradiation.

PURPOSE: Evidence supports use of partial-breast irradiation (PBI) in the management of early breast cancer, but the optimal dose-fractionation remains unsettled. METHODS AND MATERIALS: We conducted a phase 2 clinical trial (OPAL trial) to evaluate a novel PBI dosing schedule of 35 Gy in 10 daily fractions. Patients with close (<2 mm) margins also received a boost of 9 Gy in 3 fractions. Eligible patients underwent margin-negative lumpectomy for ductal carcinoma in situ or estrogen receptor-positive invasive breast cancer, up to 3 cm, pTis-T2 N0. The primary outcome was any grade ≥2 toxic effect occurring from the start of radiation through 6 months of follow-up. Secondary outcomes included patient-reported cosmesis, breast pain, and functional status, measured using the Breast Cancer Treatment Outcomes Scale, and physician-reported cosmesis, measured using the Radiation Therapy and Oncology Group scale. The Cochran-Armitage trend test and multivariable mixed-effects longitudinal growth curve models compared outcomes for the OPAL study population with those for a control group of similar patients treated with whole-breast irradiation (WBI) plus boost. RESULTS: All 149 patients enrolled on the OPAL trial received the prescribed dose, and 17.4% received boost. The median age was 64 years; 83.2% were White, and 73.8% were overweight or obese. With median follow-up of 2.0 years, 1 patient (0.7%) experienced in-breast recurrence. Prevalence of the primary toxicity outcome was 17.4% (26 of 149 patients) in the OPAL trial compared with 72.7% (128 of 176 patients) in the control WBI-plus-boost cohort (P < .001). In longitudinal multivariable analysis, treatment on the OPAL trial was associated with improved patient-reported cosmesis (P < .001), functional status (P = .004), breast pain (P = .004), and physician-reported cosmesis (P < .001). CONCLUSIONS: Treatment with daily PBI was associated with substantial reduction in early toxicity and improved patient- and physician-reported outcomes compared with WBI plus boost. Daily external-beam partial-breast irradiation with 13 or fewer fractions merits further prospective evaluation.

Addition of Metastasis-Directed Therapy to Intermittent Hormone Therapy for Oligometastatic Prostate Cancer: The EXTEND Phase 2 Randomized Clinical Trial.

Importance: Despite evidence demonstrating an overall survival benefit with up-front hormone therapy in addition to established synergy between hormone therapy and radiation, the addition of metastasis-directed therapy (MDT) to hormone therapy for oligometastatic prostate cancer, to date, has not been evaluated in a randomized clinical trial. Objective: To determine in men with oligometastatic prostate cancer whether the addition of MDT to intermittent hormone therapy improves oncologic outcomes and preserves time with eugonadal testosterone compared with intermittent hormone therapy alone. Design, Setting, Participants: The External Beam Radiation to Eliminate Nominal Metastatic Disease (EXTEND) trial is a phase 2, basket randomized clinical trial for multiple solid tumors testing the addition of MDT to standard-of-care systemic therapy. Men aged 18 years or older with oligometastatic prostate cancer who had 5 or fewer metastases and were treated with hormone therapy for 2 or more months were enrolled to the prostate intermittent hormone therapy basket at multicenter tertiary cancer centers from September 2018 to November 2020. The cutoff date for the primary analysis was January 7, 2022. Interventions: Patients were randomized 1:1 to MDT, consisting of definitive radiation therapy to all sites of disease and intermittent hormone therapy (combined therapy arm; n = 43) or to hormone therapy only (n = 44). A planned break in hormone therapy occurred 6 months after enrollment, after which hormone therapy was withheld until progression. Main Outcomes and Measures: The primary end point was disease progression, defined as death or radiographic, clinical, or biochemical progression. A key predefined secondary end point was eugonadal progression-free survival (PFS), defined as the time from achieving a eugonadal testosterone level (≥150 ng/dL; to convert to nanomoles per liter, multiply by 0.0347) until progression. Exploratory measures included quality of life and systemic immune evaluation using flow cytometry and T-cell receptor sequencing. Results: The study included 87 men (median age, 67 years [IQR, 63-72 years]). Median follow-up was 22.0 months (range, 11.6-39.2 months). Progression-free survival was improved in the combined therapy arm (median not reached) compared with the hormone therapy only arm (median, 15.8 months; 95% CI, 13.6-21.2 months) (hazard ratio, 0.25; 95% CI, 0.12-0.55; P < .001). Eugonadal PFS was also improved with MDT (median not reached) compared with the hormone therapy only (6.1 months; 95% CI, 3.7 months to not estimable) (hazard ratio, 0.32; 95% CI, 0.11-0.91; P = .03). Flow cytometry and T-cell receptor sequencing demonstrated increased markers of T-cell activation, proliferation, and clonal expansion limited to the combined therapy arm. Conclusions and Relevance: In this randomized clinical trial, PFS and eugonadal PFS were significantly improved with combination treatment compared with hormone treatment only in men with oligometastatic prostate cancer. Combination of MDT with intermittent hormone therapy may allow for excellent disease control while facilitating prolonged eugonadal testosterone intervals. Trial Registration: ClinicalTrials.gov Identifier: NCT03599765.

Temporal characterization of acute pain and toxicity kinetics during radiation therapy for head and neck cancer. A retrospective study.

Objectives: Pain during Radiation Therapy (RT) for oral cavity/oropharyngeal cancer (OC/OPC) is a clinical challenge due to its multifactorial etiology and variable management. The objective of this study was to define complex pain profiles through temporal characterization of pain descriptors, physiologic state, and RT-induced toxicities for pain trajectories understanding. Materials and methods: Using an electronic health record registry, 351 OC/OPC patients treated with RT from 2013 to 2021 were included. Weekly numeric scale pain scores, pain descriptors, vital signs, physician-reported toxicities, and analgesics were analyzed using linear mixed effect models and Spearman's correlation. Area under the pain curve (AUCpain) was calculated to measure pain burden over time. Results: Median pain scores increased from 0 during the weekly visit (WSV)-1 to 5 during WSV-7. By WSV-7, 60% and 74% of patients reported mouth and throat pain, respectively, with a median pain score of 5. Soreness and burning pain peaked during WSV-6/7 (51%). Median AUCpain was 16% (IQR (9.3-23)), and AUCpain significantly varied based on gender, tumor site, surgery, drug use history, and pre-RT pain. A temporal increase in mucositis and dermatitis, declining mean bodyweight (-7.1%; P < 0.001) and mean arterial pressure (MAP) 6.8 mmHg; P < 0.001 were detected. Pulse rate was positively associated while weight and MAP were negatively associated with pain over time (P < 0.001). Conclusion: This study provides insight on in-depth characterization and associations between dynamic pain, physiologic, and toxicity kinetics. Our findings support further needs of optimized pain control through temporal data-driven clinical decision support systems for acute pain management.

Oncogene-induced senescence and its role in tumor suppression.

While senescence has been known for some time as an inevitable result of repeated DNA replication, oncogene-induced senescence (OIS) represents a relatively new phenomenon. OIS, like apoptosis, has emerged to represent a putative barrier to tumorigenesis in many tissues, including the breast. Here we discuss signals that initiate OIS, evidence for its role in tumor suppression, and mechanisms for its evasion in tumorigenesis.

Adhering to Eat and Exercise Status During Radiotherapy for Oropharyngeal Cancer for Prevention and Mitigation of Radiotherapy-Associated Dysphagia.

Importance: Previously published work reported independent benefit of maintenance of oral intake (eat) and swallowing exercise adherence (exercise) during radiotherapy (RT) on diet and functional outcomes. The current study seeks to validate the authors' previously published findings in a large contemporary cohort of patients with oropharynx cancer (OPC) and address limitations of the prior retrospective study using prospective, validated outcome measures. Objective: To examine the longitudinal association of oral intake and swallowing exercise using validated, clinician-graded and patient-reported outcomes. Design, Setting, and Participants: Secondary analysis of a prospective OPC registry including patients who underwent primary RT/chemoradiotherapy (CRT) or primary transoral robotic surgery plus RT/CRT for OPC at a single-institution comprehensive cancer center. Exposures: Adherence to speech pathology swallowing intervention during RT coded as (1) eat: oral intake at end of RT (nothing by mouth [NPO]; partial oral intake [PO], with feeding tube [FT] supplement; full PO); and (2) exercise: swallowing exercise adherence (nonadherent vs partial/full adherence). Main Outcomes and Measures: Feeding tube and diet (Performance Status Scale for Head and Neck Cancer) patient-reported swallowing-related quality of life (MD Anderson Dysphagia Inventory; MDADI) and clinician-graded dysphagia severity grade (videofluoroscopic Dynamic Imaging Grade of Swallowing Toxicity; DIGEST) were collected at baseline, 3 to 6 months, and 18 to 24 months post-RT. Results: A total of 595 patients (mean [SD] age, 65 [10] years; 532 [89%] male) who underwent primary RT (111 of 595 [19%]), CRT (434 of 595 [73%]), or primary transoral robotic surgery plus RT/CRT (50 of 595 [8%]) were included in this cohort study. At the end of RT, 55 (9%) patients were NPO, 115 (19%) were partial PO, 425 (71%) were full PO, and 340 (57%) reported exercise adherence. After multivariate adjustment, subacute return to solid diet and FT were independently associated with oral intake (odds ratio [OR], 2.0; 95% CI, 1.0-4.1; OR, 0.1; 95% CI, 0.0-0.2, respectively) and exercise (OR, 2.9; 95% CI, 1.9-4.5; OR, 0.3; 95% CI, 0.1-0.5, respectively). Subacute MDADI (ß = 6.5; 95% CI, 1.8-11.2), FT duration (days; ß = -123.4; 95% CI, -148.5 to -98.4), and less severe dysphagia per DIGEST (OR, 0.6; 95% CI, 0.3-1.0) were independently associated with oral intake, while exercise was independently associated with less severe laryngeal penetration/aspiration per DIGEST-safety (OR, 0.7; 95% CI, 0.4-1.0). DIGEST grade associations with oral intake were not preserved long-term; however, exercise was associated with a higher likelihood of solid diet intake and better swallow safety per DIGEST. Conclusions and Relevance: The findings of this cohort study extend the authors' previously published findings that oral intake and swallowing exercise during RT are associated with favorable functional outcomes, now demonstrated with broader domains of function using validated measures. Patterns of benefit differed in this study. Specifically, better subacute recovery of swallow-related quality of life and less severe dysphagia were found among patients who maintained oral intake independent of exercise adherence, and shorter FT utilization and better long-term diet and swallowing safety were found among those who exercised independent of oral intake.

Unilateral Radiation Therapy for Tonsillar Cancer: Treatment Outcomes in the Era of Human Papillomavirus, Positron-Emission Tomography, and Intensity Modulated Radiation Therapy.

PURPOSE: The goal of this study was to evaluate disease, survival, and toxic effects after unilateral radiation therapy treatment for tonsillar cancer. METHODS AND MATERIALS: A retrospective study was performed of patients treated at our institution within the period from 2000 to 2018. Summary statistics were used to assess the cohort by patient characteristics and treatments delivered. The Kaplan-Meier method was used to determine survival outcomes. RESULTS: The cohort comprised 403 patients, including 343 (85%) with clinical and/or radiographic evidence of ipsilateral cervical nodal disease and 181 (45%) with multiple involved nodes. Human papillomavirus was detected in 294 (73%) tumors. Median follow-up time was 5.8 years. Disease relapse was infrequent with local recurrence in 9 (2%) patients, neck recurrence in 13 (3%) patients, and recurrence in the unirradiated contralateral neck in 9 (2%) patients. Five- and 10-year overall survival rates were 94% and 89%, respectively. Gastrostomy tubes were needed in 32 (9%) patients, and no patient had a feeding tube 6 months after therapy. CONCLUSIONS: For patients with well-lateralized tonsillar tumors and no clinically evident adenopathy of the contralateral neck, unilateral radiation therapy offers favorable rates of disease outcomes and a relatively low toxicity profile.