Hypoxia-Directed Treatment of Human Papillomavirus-Related Oropharyngeal Carcinoma.

PURPOSE: Standard curative-intent chemoradiotherapy for human papillomavirus (HPV)-related oropharyngeal carcinoma results in significant toxicity. Since hypoxic tumors are radioresistant, we posited that the aerobic state of a tumor could identify patients eligible for de-escalation of chemoradiotherapy while maintaining treatment efficacy. METHODS: We enrolled patients with HPV-related oropharyngeal carcinoma to receive de-escalated definitive chemoradiotherapy in a phase II study (ClinicalTrials.gov identifier: NCT03323463). Patients first underwent surgical removal of disease at their primary site, but not of gross disease in the neck. A baseline 18F-fluoromisonidazole positron emission tomography scan was used to measure tumor hypoxia and was repeated 1-2 weeks intratreatment. Patients with nonhypoxic tumors received 30 Gy (3 weeks) with chemotherapy, whereas those with hypoxic tumors received standard chemoradiotherapy to 70 Gy (7 weeks). The primary objective was achieving a 2-year locoregional control (LRC) of 95% with a 7% noninferiority margin. RESULTS: One hundred fifty-eight patients with T0-2/N1-N2c were enrolled, of which 152 patients were eligible for analyses. Of these, 128 patients met criteria for 30 Gy and 24 patients received 70 Gy. The 2-year LRC was 94.7% (95% CI, 89.8 to 97.7), meeting our primary objective. With a median follow-up time of 38.3 (range, 22.1-58.4) months, the 2-year progression-free survival (PFS) and overall survival (OS) rates were 94% and 100%, respectively, for the 30-Gy cohort. The 70-Gy cohort had similar 2-year PFS and OS rates at 96% and 96%, respectively. Acute grade 3-4 adverse events were more common in 70 Gy versus 30 Gy (58.3% v 32%; P = .02). Late grade 3-4 adverse events only occurred in the 70-Gy cohort, in which 4.5% complained of late dysphagia. CONCLUSION: Tumor hypoxia is a promising approach to direct dosing of curative-intent chemoradiotherapy for HPV-related carcinomas with preserved efficacy and substantially reduced toxicity that requires further investigation.

Long-term Outcomes from a Phase 1 Dose Escalation Study Using Stereotactic Body Radiotherapy for Patients with Low- or Intermediate-risk Prostate Cancer.

BACKGROUND: Ultrahypofractionated stereotactic body radiation therapy (SBRT) has become a standard treatment intervention for localized prostate cancer. OBJECTIVE: To report final long-term tumor control outcomes and late gastrointestinal (GI) and genitourinary (GU) toxicities from a single-center phase 1 dose escalation study using SBRT for patients with low- or intermediate-risk prostate cancer. DESIGN, SETTING AND PARTICIPANTS: Between 2009 and 2012, 136 patients were enrolled and treated. The initial dose level was 32.5 Gy in five fractions. Doses were then sequentially escalated to 35 Gy, 37.5 Gy, and 40 Gy in five fractions delivered every other day. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was late treatment-related toxicity. Secondary endpoints included prostate-specific antigen (PSA) failure. RESULTS AND LIMITATIONS: The median follow-up was 10.5 yr for the 32.5-Gy group, 9.9 yr for the 35-Gy group, 8.2 yr for the 37.5-Gy group, and 7.3 yr for the 40-Gy group. The 8-yr cumulative incidence of PSA failure was 26% for 32.5 Gy, 15% for 35 Gy, 3.4% for 37.5 Gy, and 6.6% for 40 Gy. Higher radiation dose (37.5-40 Gy) and favorable intermediate risk (vs unfavorable intermediate risk) were associated with better PSA recurrence rates (p = 0.011 and 0.002, respectively). The 8-yr actuarial probability rates for survival free from late grade ≥2 toxicity were 94% for GI toxicity and 86% for GU toxicity. No grade 4 events were recorded. Higher dose levels were not associated with higher rates of late grade ≥2 GI (p = 0.2) or GU (p > 0.9) toxicity. CONCLUSIONS: SBRT doses ranging from 32.5 to 40 Gy were associated with low incidence of moderate or severe toxicities. Higher doses resulted in superior disease control outcomes 8 yr after treatment. PATIENT SUMMARY: We investigated the association between the radiotherapy dose used and the rate of control of prostate cancer. We found that higher doses resulted in more favorable outcomes without excess toxicity. This trial is registered on ClinicalTrials.gov as NCT00911118.

Differential use of postoperative psychosocial and physical services among older adults with head and neck cancer.

INTRODUCTION: Older adults undergoing head and neck cancer (HNC) surgery often have significant functional and mental health impairments. We examined use of postoperative physical, nutritional, and psychosocial services among a cohort of older adults with HNC comanaged by geriatricians and surgeons. MATERIALS AND METHODS: Our sample consisted of older adults who were referred to the Geriatrics Service at Memorial Sloan Kettering Cancer Center between 2015 and 2019 and took a geriatric assessment (GA) prior to undergoing HNC surgery. Physical, nutritional, and psychosocial service utilization was assessed. Physical services included a physical, occupational, or rehabilitation consult during the patient's stay. Nutritional services consisted of speech and swallow or nutritional consult. Psychosocial services consisted of psychiatry, psychology, or a social work consult. Relationships between each service use, geriatric deficits, demographic, and surgical characteristics were assessed using Wilcoxon rank-sum test or Chi-square test. RESULTS: In total, 157 patients were included, with median age of 80 and length of stay of six days. The most common GA impairments were major distress (61%), depression (59%), social activity limitation (SAL) (54%), and deficits in activities of daily living (ADL) (44%). Nutritional and physical services were used much more frequently than psychosocial services (80% and 85% vs 31%, respectively). Receipt of services was associated with longer median length of hospital stay, operation time, and greater deficits in ADLs. SAL was associated with physical and psychosocial consult and lower Timed Up and Go (TUG) score; instrumental ADL (iADL) deficits were associated with physical services; and depression and distress were associated with psychosocial services. DISCUSSION: The burden of psychosocial deficits is high among older adults with HNC. Future work is needed to understand the limited utilization of psychosocial services in this population as well as whether referral to psychosocial services can reduce the burden of these deficits.

Concurrent carboplatin and paclitaxel definitive radiation therapy for locally advanced head and neck cancer.

BACKGROUND: We report the outcomes of cisplatin-ineligible HNSCC patients treated with definitive chemoradiation and concurrent carboplatin and paclitaxel. MATERIALS AND METHODS: We included consecutive HNSCC patients treated from 2013 to 2021 that received definitive chemoradiation with carboplatin and paclitaxel. Locoregional recurrences (LRR) and distant metastases (DM) were estimated using cumulative incidence functions. Progression free survival (PFS) and overall survival (OS) were estimated using Kaplan-Meier methods. RESULTS: Sixty-five patients were identified with median age of 71 years (range 44-85). Median radiation dose was 70 Gy and the median doses of carboplatin and paclitaxel were AUC 1 and 40 mg/m2 , respectively. At a median follow-up of 29 (range 5-91) months, the 2-year rates of LRR, DM, PFS, and OS were 8.8%, 9.4%, 72.2%, and 88.7%, respectively. In total, there were 5 LRR, 7 DM, and 12 deaths. CONCLUSIONS: Chemoradiation with carboplatin and paclitaxel is an excellent option for cisplatin-ineligible HNSCC patients.

Dosimetric Comparison of Intensity-Modulated Radiation Therapy (IMRT) and Intensity-Modulated Proton Therapy (IMPT) for a Novel Oral Tongue Avoidance Concept in Low-Risk Squamous Cell Carcinoma of the Oral Tongue.

Purpose: After adequate surgical resection, early-stage oral tongue cancer patients can harbor a low risk of local recurrence but remain at risk of regional recurrence. Oral tongue avoidance during adjuvant radiation therapy is an attractive potential treatment strategy to mitigate treatment toxicity. We sought to quantify the dosimetric advantages of this approach and hypothesized that intensity-modulated proton therapy (IMPT) may further reduce organs at risk doses compared with intensity-modulated radiation therapy (IMRT). Materials and Methods: Five patients with oral tongue cancer treated with postoperative radiation therapy from August 2020 to September 2021 were retrospectively reviewed. Novel clinical target volume contours, excluding the oral tongue, were generated while maintaining coverage of bilateral at-risk lymph nodes. Comparison IMRT (X) and IMPT (PBT) plans were generated using standard treatment volumes (control) and avoidance volumes (study) (n = 4 plans/patient). Dosimetric variables for organs at risk were compared using the paired t test. Results: The prescribed dose was 60 Gy in 30 fractions. D95% clinical target volume coverage was similar between X and PBT plans for both control and study clinical target volumes. Comparing control with study plans, both X (58.9 Gy vs 38.3 Gy, P = .007) and PBT (60.2 Gy vs 26.1 Gy, P < .001) decreased the oral cavity dosemean. The pharyngeal constrictor dosemean was also reduced (P < .003). There was no difference between control and study plans for larynx (P = .19), parotid (P = .11), or mandible dose (P = .59). For study plans, PBT significantly reduced oral cavity dosemean (38.3 Gy vs 26.1 Gy, P = .007) and parotid dosemean (23.3 Gy vs 19.3 Gy, P = .03) compared with X. For control plans, there was no difference in oral cavity dosemean using PBT compared with X, but PBT did improve the parotid dosemean (26.6 Gy vs 19.7 Gy, P = .02). Conclusion: This study quantifies the feasibility and dosimetric advantages of oral tongue avoidance while still treating the at-risk lymph nodes for oral tongue cancer. The dosimetric difference between PBT and X was most prominent with an oral tongue-avoidance strategy.

Quality Metric to Assess Adequacy of Hydrogel Rectal Spacer Placement for Prostate Radiation Therapy and Association of Metric Score With Rectal Toxicity Outcomes.

Purpose: Although hydrogel spacer placement (HSP) minimizes rectal dose during prostate cancer radiation therapy, its potential benefit for modulating rectal toxicity could depend on the achieved prostate-rectal separation. We therefore developed a quality metric associated with rectal dose reduction and late rectal toxicity among patients treated with prostate stereotactic body radiation therapy (SBRT). Methods and Materials: A quality metric consisting of prostate-rectal interspace measurements from axial T2-weighted magnetic resonance imaging simulation images was applied to 42 men enrolled in a multi-institutional phase 2 study using HSP with prostate SBRT (45 Gy in 5 fractions). A score of 0, 1, or 2 was assigned to a prostate-rectal interspace measurement of <0.3 cm, 0.3 to 0.9 cm, or ≥1 cm, respectively. An overall spacer quality score (SQS) was computed from individual scores at rectal midline and ±1 cm laterally, located at the prostate base, midgland, and apex. Associations of SQS with rectal dosimetry and late toxicity were evaluated. Results: The majority of the analyzed cohort had an SQS of 1 (n = 17; 41%) or 2 (n = 18; 43%). SQS was associated with maximum rectal point dose (rectal Dmax; P = .002), maximum dose to 1 cc of rectum (D1cc; P = .004), and volume of rectum receiving ≥100% of prescription dose (V45; P = .046) and ≥40 Gy (V40; P = .005). SQS was also associated with a higher incidence of (P = .01) and highest-graded late rectal toxicity (P = .01). Among the 20 men who developed late grade ≥1 rectal toxicity, 57%, 71%, and 22% had an SQS of 0, 1, and 2, respectively. Men with an SQS of 0 or 1 compared with 2 had 4.67-fold (95% CI, 0.72-30.11) or 8.40-fold (95% CI, 1.83-38.57) greater odds, respectively, of developing late rectal toxicity. Conclusions: We developed a reliable and informative metric for assessing HSP, which appears to be associated with rectal dosimetry and late rectal toxicity after prostate SBRT.

Evaluation of Proton Therapy Reirradiation for Patients With Recurrent Head and Neck Squamous Cell Carcinoma.

Importance: Use of proton therapy reirradiation (PT-ReRT) for head and neck cancer is increasing; however, reports are heterogenous and outcomes can be difficult to interpret. Objective: To evaluate outcomes and toxic effects following PT-ReRT in a uniform and consecutive cohort of patients with head and neck squamous cell carcinoma. Design, Setting, and Participants: This retrospective cohort study included patients with recurrent primary head and neck squamous cell carcinoma who were treated with PT-ReRT from January 1, 2013, to December 31, 2020, at a single institution. Patient, clinical, and treatment characteristics were obtained, and multidisciplinary review was performed to record and grade early and late toxic effects. Exposures: Proton therapy reirradiation. Main Outcomes and Measures: Follow-up was defined from the start of PT-ReRT. The Kaplan-Meier method was used for outcomes of interest, including local control (LC), locoregional control, distant metastatic control, progression-free survival, and overall survival (OS). Cox proportional hazards regression modeling was used to assess associations of covariates with OS. Results: A total of 242 patients (median [range] age, 63 [21-96] years; 183 [75.6%] male) were included. Of these patients, 231 (95.9%) had a Karnofsky performance status score of 70 or higher, and 145 (59.9%) had at least a 10-pack-year smoking history. Median (range) follow-up was 12.0 (5.8-26.0) months for all patients and 24.5 (13.8-37.8) months for living patients. A total of 206 patients (85.1%) had recurrent disease vs second primary or residual disease. The median (range) interval between radiation courses was 22 (1-669) months. Median PT-ReRT dose was 70 cobalt gray equivalents (CGE) for the fractionated cohort and 44.4 CGE for the quad shot cohort. For the fractionated cohort, the 1-year LC was 71.8% (95% CI, 62.8%-79.0%) and the 1-year OS was 66.6% (95% CI, 58.1%-73.8%). For the quad shot cohort, the 1-year LC was 61.6% (95% CI, 46.4%-73.6%) and the 1-year OS was 28.5% (95% CI, 19.4%-38.3%). Higher Karnofsky performance status scores (hazard ratio [HR], 0.50; 95% CI, 0.25-0.99; P = .046) and receipt of salvage surgery prior to PT-ReRT (HR, 0.57; 95% CI, 0.39-0.84; P = .005) were associated with improved OS, whereas receipt of quad shot (HR, 1.97; 95% CI, 1.36-2.86; P < .001) was associated with worse OS. There were a total of 73 grade 3 and 6 grade 4 early toxic effects. There were 79 potential grade 3, 4 grade 4, and 5 grade 5 late toxic effects. Conclusions and Relevance: The findings of this cohort study suggest that, compared with previous reports with photon-based reirradiation, patients are living longer with aggressive PT-ReRT; however, surviving patients remain at risk of early and late complications.

Correlation of an Electronic Geriatric Assessment With Receipt of Adjuvant Radiation and Chemotherapy in Older Adults With Head and Neck Cancer.

Purpose: Treatment patterns for head and neck squamous cell carcinoma (HNSCC) vary among older adults because of concerns about their health status. Geriatric assessment may guide treatment for older adults with HNSCC by assessing their health status. Methods and Materials: We conducted a retrospective review of adjuvant treatment received by older patients with HNSCC who completed a novel geriatric assessment, the electronic Rapid Fitness Assessment, before treatment. The electronic Rapid Fitness Assessment yields an accumulated geriatric deficits (AGD) score. Higher AGD score indicates greater frailty. Comparators were age and performance status. The Wilcoxon rank sum test compared differences between those who did and did not receive adjuvant radiation therapy and chemotherapy. Results: The cohort included 73 patients, of whom 56 (77%) had oral cavity cancer. The most common geriatric deficits were major distress, social activity limitation, depression, and impaired activities of daily living. AGD score, age, and performance status were not associated with receipt of adjuvant radiation. Patients who received adjuvant chemotherapy had a significantly lower median AGD score than those who did not (3 vs 6; P = .044), but there was no association with age and performance status. Of the 17 patients with newly diagnosed disease and either positive margins or extranodal extension, only 9 received adjuvant radiation and only 3 received systemic therapy. Most often, systemic therapy was omitted because of patient preference or comorbidities and poor performance status. There was a nonstatistically significant lower AGD score between patients who did and did not receive standard fractionated radiation therapy (median, 4 vs 6.5; P = .13). Conclusions: Receipt of adjuvant chemotherapy was associated with frailty. Rates of chemotherapy utilization were very low, indicating the need for novel strategies to mitigate the toxicity burden in this patient population. Receipt of adjuvant radiation therapy was not associated with frailty; however, there was a trend toward lower frailty among those who did receive radiation therapy.

Toxicity Profiles and Survival Outcomes Among Patients With Nonmetastatic Oropharyngeal Carcinoma Treated With Intensity-Modulated Proton Therapy vs Intensity-Modulated Radiation Therapy.

Importance: Patients with oropharyngeal carcinoma (OPC) treated with radiotherapy often experience substantial toxic effects, even with modern techniques such as intensity-modulated radiation therapy (IMRT). Intensity-modulated proton therapy (IMPT) has a potential advantage over IMRT due to reduced dose to the surrounding organs at risk; however, data are scarce given the limited availability and use of IMPT. Objective: To compare toxic effects and oncologic outcomes among patients with newly diagnosed nonmetastatic OPC treated with IMPT vs IMRT with or without chemotherapy. Design, Setting, and Participants: This retrospective cohort study included patients aged 18 years or older with newly diagnosed nonmetastatic OPC who received curative-intent radiotherapy with IMPT or IMRT at a single-institution tertiary academic cancer center from January 1, 2018, to December 31, 2021, with follow-up through December 31, 2021. Exposures: IMPT or IMRT with or without chemotherapy. Main Outcomes and Measures: The main outcomes were the incidence of acute and chronic (present after ≥6 months) treatment-related adverse events (AEs) and oncologic outcomes, including locoregional recurrence (LRR), progression-free survival (PFS), and overall survival (OS). Fisher exact tests and χ2 tests were used to evaluate associations between toxic effects and treatment modality (IMPT vs IMRT), and the Kaplan-Meier method was used to compare LRR, PFS, and OS between the 2 groups. Results: The study included 292 patients with OPC (272 [93%] with human papillomavirus [HPV]-p16-positive tumors); 254 (87%) were men, 38 (13%) were women, and the median age was 64 years (IQR, 58-71 years). Fifty-eight patients (20%) were treated with IMPT, and 234 (80%) were treated with IMRT. Median follow-up was 26 months (IQR, 17-36 months). Most patients (283 [97%]) received a dose to the primary tumor of 70 Gy. Fifty-seven of the patients treated with IMPT (98%) and 215 of those treated with IMRT (92%) had HPV-p16-positive disease. There were no significant differences in 3-year OS (97% IMPT vs 91% IMRT; P = .18), PFS (82% IMPT vs 85% IMRT; P = .62), or LRR (5% IMPT vs 4% IMRT; P = .59). The incidence of acute toxic effects was significantly higher for IMRT compared with IMPT for oral pain of grade 2 or greater (42 [72%] IMPT vs 217 [93%] IMRT; P < .001), xerostomia of grade 2 or greater (12 [21%] IMPT vs 68 [29%] IMRT; P < .001), dysgeusia of grade 2 or greater (16 [28%] IMPT vs 134 [57%] IMRT; P < .001), grade 3 dysphagia (4 [7%] IMPT vs 29 [12%] IMRT; P < .001), mucositis of grade 3 or greater (10 [53%] IMPT vs 13 [70%] IMRT; P = .003), nausea of grade 2 or greater (0 [0%] IMPT vs 18 [8%] IMRT; P = .04), and weight loss of grade 2 or greater (22 [37%] IMPT vs 138 [59%] IMRT; P < .001). There were no significant differences in chronic toxic effects of grade 3 or greater, although there was a significant difference for chronic xerostomia of grade 2 or greater (6 IMPT [11%] vs 22 IMRT [10%]; P < .001). Four patients receiving IMRT (2%) vs 0 receiving IMPT had a percutaneous endoscopic gastrostomy tube for longer than 6 months. Conclusions and Relevance: In this study, curative-intent radiotherapy with IMPT for nonmetastatic OPC was associated with a significantly reduced acute toxicity burden compared with IMRT, with few chronic toxic effects and favorable oncologic outcomes, including locoregional recurrence of only 5% at 2 years. Prospective randomized clinical trials comparing these 2 technologies and of patient-reported outcomes are warranted.

Failure Patterns by PSMA PET for Recurrent Prostate Cancer after Prostatectomy and Salvage Radiation.

OBJECTIVE: To characterize patterns of failure using prostate-specific membrane antigen positron emission tomography (PSMA PET) after radical prostatectomy (RP) and salvage radiotherapy (SRT). METHODS: Patients with rising PSA post-RP+SRT underwent 68Ga-HBED-iPSMA PET/CT on a single-arm, prospective imaging trial (NCT03204123). Scans were centrally reviewed with pattern-of-failure analysis by involved site. Positive scans were classified using 3 failure categories: pelvic nodal, extra-pelvic nodal or distant non-nodal. Associations with failure categories were analyzed using cumulative incidence and generalized logits regression. RESULTS: We included 133 men who received SRT a median of 20 months post-RP; 56% received SRT to the prostatic fossa alone, while 44% received pelvic SRT. PSMA PET/CT was performed a median of 48 months post-SRT. Overall, 31% of PSMA PET/CT scans were negative, 2% equivocal and 67% had at least 1 positive site. Scan detection was significantly associated with PSA level prior to PSMA PET/CT. Analysis of 89 positive scans demonstrated pelvic nodal (53%) was the most common relapse and fossa relapse was low (9%). Overall, positive scans were pelvic (n = 35, 26%), extra-pelvic nodal (n = 26, 20%) or distant non-nodal failure (n = 28, 21%), and 70% of positive scans were oligorecurrent. We observed similar cumulative incidence for all failure categories and relatively few clinicodemographic associations. Men treated with pelvic SRT had reduced odds of pelvic failure versus exclusive fossa treatment. CONCLUSION: Pelvic, extra-pelvic nodal, and distant non-nodal failures occur with similar incidence post-SRT. Regional nodal relapse is relatively common, especially with fossa-only SRT. A high oligorecurrence rate suggests a potentially important role for PSMA-guided focal therapies.

Peer Review of Head and Neck Cancer Planning Target Volumes in Radiation Oncology.

Purpose: Radiation treatment plans undergo peer review during chart rounds, but changes to treatment volumes would require replanning. Our group implemented weekly head and neck cancer "volume rounds" to peer review all target volumes for head and neck cancer before radiation therapy (RT) planning and chart rounds. Methods and Materials: We analyzed modifications made to planning target volumes (PTVs) at volume rounds for consecutive nonproton head and neck cancer cases from May 2020 to May 2021. Nine head and neck radiation oncologists participated in weekly volume rounds during this time. Recommendations were categorized as no changes, minor changes, major changes, additional workup (eg, biopsy or imaging), and consultation or tumor board discussion needed before the start of RT. Minor changes to PTVs generally did not require a second review before treatment planning while major changes did. Results: PTVs for 511 cases involving 432 patients underwent peer review and 298 (58.3%) of these cases did not require any modifications before treatment planning. Minor and major changes were recommended in 75 (14.7%) and 86 (16.8%) cases, respectively. Forty-five (8.8%) cases were recommended to have additional workup and 23 (4.5%) required additional consultation with nonradiation surgeons or medical oncologists. Of the 45 cases that were recommended for additional workup, 40 underwent biopsy or imaging. Positive findings on imaging or biopsy occurred in 13 patients, leading to a significant change in management, including 4 patients who underwent additional surgery after positive findings before the start of RT. Conclusions: Prospective peer review during head and neck cancer volume rounds led to frequent minor and major alterations to PTVs. Significant changes in the overall treatment plan, such as additional surgery before start of RT, occurred in a minority of patients.

Clinically Localized Prostate Cancer: AUA/ASTRO Guideline. Part III: Principles of Radiation and Future Directions.

PURPOSE: The summary presented herein represents Part III of the three-part series dedicated to Clinically Localized Prostate Cancer: AUA/ASTRO Guideline, discussing principles of radiation and offering several future directions of further relevant study in patients diagnosed with clinically localized prostate cancer. Please refer to Parts I and II for discussion of risk assessment, staging, and risk-based management (Part I), and principles of active surveillance and surgery and follow-up (Part II). MATERIALS AND METHODS: The systematic review utilized to inform this guideline was conducted by an independent methodological consultant. A research librarian conducted searches in Ovid MEDLINE, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews. The methodology team supplemented searches of electronic databases with the studies included in the prior AUA review and by reviewing reference lists of relevant articles. RESULTS: The Clinically Localized Prostate Cancer Panel created evidence- and consensus-based guideline statements to aid clinicians in the management of patients with clinically localized prostate cancer. Statements regarding management of patients using radiation therapy as well as important future directions of research are detailed herein. CONCLUSIONS: This guideline aims to inform clinicians treating patients with clinically localized prostate cancer. Continued research and publication of high-quality evidence from future trials will be essential to further improve care for these men.

Clinically Localized Prostate Cancer: AUA/ASTRO Guideline, Part I: Introduction, Risk Assessment, Staging, and Risk-Based Management.

PURPOSE: The summary presented herein represents Part I of the three-part series dedicated to Clinically Localized Prostate Cancer: AUA/ASTRO Guideline, discussing risk assessment, staging, and risk-based management in patients diagnosed with clinically localized prostate cancer. Please refer to Parts II and III for discussion of principles of active surveillance, surgery and follow-up (Part II), and principles of radiation and future directions (Part III). MATERIALS AND METHODS: The systematic review utilized to inform this guideline was conducted by an independent methodological consultant. A research librarian conducted searches in Ovid MEDLINE, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews. The methodology team supplemented searches of electronic databases with the studies included in the prior AUA review and by reviewing reference lists of relevant articles. RESULTS: The Clinically Localized Prostate Cancer Panel created evidence- and consensus-based guideline statements to aid clinicians in the management of patients with clinically localized prostate cancer. Statements regarding risk assessment, staging, and risk-based management are detailed herein. CONCLUSIONS: This guideline aims to inform clinicians treating patients with clinically localized prostate cancer. Continued research and publication of high-quality evidence from future trials will be essential to further improve care for these men.

Clinically Localized Prostate Cancer: AUA/ASTRO Guideline, Part II: Principles of Active Surveillance, Principles of Surgery, and Follow-Up.

PURPOSE: The summary presented herein represents Part II of the three-part series dedicated to Clinically Localized Prostate Cancer: AUA/ASTRO Guideline, discussing principles of active surveillance and surgery as well as follow-up for patients after primary treatment. Please refer to Parts I and III for discussion of risk assessment, staging, and risk-based management (Part I), and principles of radiation and future directions (Part III). MATERIALS AND METHODS: The systematic review utilized to inform this guideline was conducted by an independent methodological consultant. A research librarian conducted searches in Ovid MEDLINE, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews. The methodology team supplemented searches of electronic databases with the studies included in the prior AUA review and by reviewing reference lists of relevant articles. RESULTS: The Clinically Localized Prostate Cancer Panel created evidence- and consensus-based guideline statements to aid clinicians in the management of patients with clinically localized prostate cancer. Statements regarding active surveillance, surgical management, and patient follow-up are detailed. CONCLUSION: This guideline aims to inform clinicians treating patients with clinically localized prostate cancer. Continued research and publication of high-quality evidence from future trials will be essential to further improve care for these men.

A Patient-Level Data Meta-analysis of the Abscopal Effect.

Purpose: The abscopal effect is defined when a form of local therapy causes tumor regression of both the target lesion and any untreated tumors. Herein cases of the abscopal effect were systematically reviewed and a patient-level data analysis was performed for clinical predictors of both duration of response and survival. Methods and Materials: The Population, Intervention, Control, Outcome, Study (PICOS) design approach, Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) literature selection process, and Meta-analysis of Observational Studies in Epidemiology (MOOSE) were used to find articles published before September 2019 in MEDLINE/PubMed and Google Scholar. Inclusion criteria were (1) population: patients with reported abscopal response; (2) intervention: documented treatment(s); (3) control: none; (4) outcomes: overall and progression-free survival; and (5) setting: retrospective case reports. Time from treatment until abscopal response and time from abscopal response until progression/death were calculated. Univariate and multivariate analyses were conducted for survival outcomes. Results: Fifty studies (n = 55 patients) were included. Median age was 65 years (interquartile range [IQR], 58-70) and 62% were male. Fifty-four (98%) patients received radiation therapy, 34 (62%) received radiation therapy alone, 5 (9.1%) underwent surgery, 4 (7.3%) received chemotherapy, and 11 (20%) received immunotherapy. Median total dose was 32 Gy (IQR, 25.5-48 Gy) and median dose per fraction was 3 Gy (IQR, 2-7.2). Median time until abscopal response was 4 months (IQR, 1-5; min 0.5, max 24). At 5 years, overall survival was 63% and distant progression-free survival was 45%. No variables had statistical significance in predicting duration of response or survival. Conclusions: Almost all reported cases of the abscopal response are after radiation therapy; however, there are no known predictors of duration of response or survival in this population.

Evaluation of Substantial Reduction in Elective Radiotherapy Dose and Field in Patients With Human Papillomavirus-Associated Oropharyngeal Carcinoma Treated With Definitive Chemoradiotherapy.

IMPORTANCE: Several de-escalation strategies for human papillomavirus (HPV)-associated oropharyngeal carcinoma (OPC) have focused on deintensifying gross disease treatment. Reduction of radiotherapy dose and target volume to subclinical regions may achieve good clinical outcomes with favorable patient quality of life (QOL). OBJECTIVE: To determine outcomes from a systematic approach of reducing radiotherapy dose and target volume to the elective treatment regions in patients with HPV-associated OPC undergoing concurrent chemoradiotherapy (CCRT). DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study included 276 consecutive patients with HPV-positive OPC receiving CCRT from March 1, 2017, to July 31, 2019. Data were analyzed from February 23 to September 13, 2021. INTERVENTIONS: Elective nodal and subclinical regions received 30 Gy of radiotherapy in 15 fractions, followed by a cone down of 40 Gy in 20 fractions to gross disease for a total dose of 70 Gy. The high retropharyngeal nodal basins in the node-negative neck and bilateral levels IB and V basins were omitted. MAIN OUTCOMES AND MEASURES: Patients were followed up to evaluate locoregional control as the primary outcome and distant metastasis-free survival, progression-free survival, and overall survival as secondary outcomes. Quality-of-life data were obtained at each visit when feasible. RESULTS: Among the 276 patients included in the analysis, the median age was 61 (range, 36-87) years; 247 (89.5%) were men; and 183 (66.3%) had less than 10 pack-years of smoking history. Most patients (251 [90.9%]) were White. Overall, 87 (31.5%) had cT3-cT4 disease and 65 (23.5%) had cN2-cN3 disease per the 8th edition of the American Joint Committee on Cancer Staging Manual. One hundred seventy-two patients (62.3%) completed 300-mg/m2 high-dose cisplatin therapy. During a median follow-up of 26 (range, 21-32) months, 8 patients developed locoregional recurrence, including 7 at the primary site or gross nodes that received a total dose of 70 Gy and 1 with a persistent node not previously identified as gross disease that received a total dose of only 30 Gy. The 24-month locoregional control was 97.0%; progression-free survival, 88.0%; distant metastasis-free survival, 95.2%; and overall survival, 95.1%. During treatment, 17 patients (6.2%) required a feeding tube. At 24 months, most of the QOL composite scores (jaw-related problems, pain, social contact, eating, speech, and swallow) were comparable or superior to baseline measures except for senses, dry mouth, muscular tension, and cognitive functioning, which improved over time but remained marginally worse than baseline. CONCLUSIONS AND RELEVANCE: This cohort study found that the evaluated de-escalation strategy for elective regions showed favorable clinical outcomes and QOL profiles. Long-term follow-up data will help affirm the efficacy of this strategy as a care option for treating HPV-associated OPC with primary CCRT.

Dermatological Adverse Events in Prostate Cancer Patients Treated with the Androgen Receptor Inhibitor Apalutamide.

PURPOSE: Patients with prostate cancer (PCa) treated with apalutamide frequently develop rash. We aim to characterize apalutamide-related dermatological adverse events (dAEs) and management. MATERIALS AND METHODS: We assessed 303 patients with PCa treated with apalutamide. DAE frequency and time to onset were calculated and clinicopathological features and management described. Associations between dAE occurrence and clinical trial participation, as well as abiraterone/prednisone exposure were detected using logistic regression models. RESULTS: Seventy-one (23.4%) patients had all-grade dAE occurring at a median of 77 (IQR: 30-135) days post-exposure. Twenty (6.6%) dAE-related therapy interruptions included: 8 (2.6%) with dose maintained on rechallenge, 7 (2.3%) with dose reduction and 5 (1.7%) with discontinuation. Common dAEs were maculopapular rashes (33.8%) and xerosis (32.4%). Seven (77.8%) of 9 histological analyses of skin biopsies supported a drug reaction. No significant differences in laboratory hematological, hepatic and renal function were detected between dAE and no dAE cohorts. Most treated grade 1/2 dAEs (29, 40.8%) required topical steroids (14, 19.7%); few required oral steroids (3, 4.2%) ± oral antihistamines. Most grade 3 dAEs (8, 11.3%) required oral/topical steroids (5, 7.0%); few required topical steroids (3, 4.2%) ± oral antihistamines. Clinical trial patients (180, 59.4%) were more likely to report dAEs than those in the off-trial setting (OR=5.1 [95% CI 2.55-10.12]; p <0.001). Of clinical trial patients, concomitant abiraterone/prednisone recipients (109 of 180, 60.6%) were more likely to report dAEs (OR=3.1 [95% CI 1.53-6.17]; p=0.002). CONCLUSIONS: Apalutamide-related dAEs are frequent and can be managed with topical ± oral steroids. With expanded approval of apalutamide, dAE identification and management are essential.

Differences in Prostate Cancer Genomes by Self-reported Race: Contributions of Genetic Ancestry, Modifiable Cancer Risk Factors, and Clinical Factors.

PURPOSE: Black men die from prostate cancer twice as often as White men, a disparity likely due to inherited genetics, modifiable cancer risk factors, and healthcare access. It is incompletely understood how and why tumor genomes differ by self-reported race and genetic ancestry. EXPERIMENTAL DESIGN: Among 2,069 men with prostate cancer (1,841 self-reported White, 63 Asian, 165 Black) with access to clinical-grade sequencing at the same cancer center, prevalence of tumor and germline alterations was assessed in cancer driver genes reported to have different alteration prevalence by race. RESULTS: Clinical characteristics such as prostate-specific antigen and age at diagnosis as well as cancer stage at sample procurement differed by self-reported race. However, most genomic differences persisted when adjusting for clinical characteristics. Tumors from Black men harbored fewer PTEN mutations and more AR alterations than those from White men. Tumors from Asian men had more FOXA1 mutations and more ZFHX3 alterations than White men. Despite fewer TP53 mutations, tumors from Black men had more aneuploidy, particularly chromosome arm 8q gains, an adverse prognostic factor. Genetic ancestry was associated with similar tumor alterations as self-reported race, but also with modifiable cancer risk factors. Community-level average income was associated with chr8q gains after adjusting for race and ancestry. CONCLUSIONS: Tumor genomics differed by race even after accounting for clinical characteristics. Equalizing access to care may not fully eliminate such differences. Therapies for alterations more common in racial minorities are needed. Tumor genomic differences should not be assumed to be entirely due to germline genetics.

Outcomes following head and neck cancer surgery among older adults as determined by an electronic geriatric assessment.

PURPOSE: Older adults with head and neck cancer have increased postoperative complications, longer hospital stays, and higher rates of mortality. Geriatric assessment (GA) provides a measure of overall health status and is preferable to using age alone for assessing fitness for surgery. We sought to determine whether a patient's frailty as determined by a novel electronic GA is associated with outcomes after head and neck cancer (HNC) surgery. METHODS: We conducted a retrospective review of 159 patients aged 75 and older referred to the Geriatrics Service at Memorial Sloan Kettering Cancer Center for pre-operative evaluation prior to undergoing HNC surgery. All patients completed the electronic Rapid Fitness Assessment (eRFA) within 60 days prior to surgery. The accumulated geriatric deficit (AGD) score includes twelve domains from the eRFA with a point assigned for each domain in which there is a deficit and a final point related to comorbidities. Three other metrics were individually assessed: age, Karnofsky Performance Scale (KPS), and number of comorbidities. We utilized multivariable linear regression and t-tests to determine whether frailty is associated with longer length of hospital stay, 30-day intensive care unit (ICU) admission, and 30-day and 90-day postoperative mortality. RESULTS: Patients with a higher AGD score spent more time in the hospital post-operatively (1.0 day increase per unit increase in AGD; 95% CI: 0.21-1.9; p = 0.015). Lower KPS was also associated with statistically significant longer length of stay (-2.70 day change per increasing index KPS; 95% CI: -4.30 - -1.00; days; p = 0.002), while age and comorbidity were not found to be statistically associated with length of stay. Higher AGD score remained significantly associated with longer length of stay on multivariable analysis (0.93 day increase per unit increase in AGD; 95% CI 0.15-1.71; p = 0.019). AGD was the only metric associated with increased risk of ICU admission (6.6 vs 5.0 geriatric deficits for those admitted vs not admitted to ICU; p = 0.024). CONCLUSIONS: Frailty is associated with increased length of hospital stay and ICU admission in older adults with HNC undergoing surgery. GA can be used to counsel patients on the expected postoperative course.

The effect of short radiation treatment breaks on chemo-radiotherapy for oropharyngeal cancers.

BACKGROUND: Numerous studies and guidelines suggest an outcome detriment from radiation treatment breaks (rTBs) and the need for compensatory dosing in patients with head and neck cancer. METHODS: In a consecutive cohort of 521 patients with oropharyngeal squamous cell carcinoma (OPSCC), we investigated the impact of rTBs and prolongation of overall treatment time (OTT) on OS, DFS, LRC, and cancer recurrence using competing risk and multivariate analyses. RESULTS: Neither OTT prolongation by ≤2 days nor rTBs of ≤3 days were associated with detriments to clinical outcomes. Consecutive breaks of ≥3 days were also not significantly associated with detriment to clinical outcomes. There was significantly increased competing mortality in those with longer breaks. CONCLUSIONS: In OPSCC patients treated with definitive concurrent chemoradiotherapy, there is no significant association between disease failure and total rTBs of ≤3 consecutive or scattered days. Further investigation is needed for longer breaks.