Supplementary Figure 1: Number of cancer cases and deaths across indications in 2020, Millions

Prostate cancer patients with biochemical recurrence (BCR) face a decision of whether to start salvage therapy (ST), which may reduce the probability of metastatic progression at the cost of side effects. To inform the decision to start ST at or after BCR, models that make counterfactual predictions incorporating treatment are highly desirable. However, estimation of such models using observational data requires care due to time-varying confounding by the longitudinal biomarker prostate-specific antigen (PSA). Moreover, a careful definition of the estimands of interest, referred to as "predictimands", is required due to the possibility of delayed initiation of treatment after biochemical recurrence. In this study, we utilize the framework of joint longitudinal and survival models to tackle these issues, estimating a model for pre-ST PSA trajectories and risk of metastasis that incorporates the effect of ST, from a dataset of 2075 patients with BCR. We define relevant predictimands for a new patient after BCR under three scenarios: Immediately treated, never treated, and treatment under a dynamic regime, where ST is started when PSA is observed to exceed a pre-specified threshold. We propose a Monte Carlo scheme for computing these predictimands, adapting previous work on dynamic predictions from joint models to account for treatment timing. This methodology is applied to an example patient and validated in a simulation study. This methodology could be adapted to a wide variety of applications requiring counterfactual predictions in the presence of time-varying treatments and biomarkers. Code to implement such analyses is available in the R package JMbayes2.

PURPOSE:The impact of radiation therapy (RT) dose de-escalation on organs at risk (OARs) for human papillomavirus-associated oropharyngeal cancer (OPC) is not known. This study retrospectively assessed OAR dosimetric outcomes of de-escalated RT for OPC. METHODS AND MATERIALS:We conducted a retrospective analysis of dosimetric data for patients with T1 to 4, N0 to 3 human papillomavirus-associated OPC treated with intensity modulated RT at a single academic institution between August, 2014 and January, 2023. All patients received 70 Gy to gross disease. The low-dose group received 30 Gy to the subclinical neck, and high-dose patients received 50-60 Gy. Propensity score matching was performed to balance differences in clinical staging between groups. Mean OAR doses were collected and compared between the groups. RESULTS:A total of 575 patients were included. Of these, 226 (39.3%) had bilateral nodal disease. Significant reductions in mean doses were observed across all OARs. For matched 30 Gy patients with unilateral nodal disease, the contralateral parotid gland mean dose was 833 cGy, compared with 1391 cGy (P< .001). Other mean dose reductions included ipsilateral parotid gland (1984 vs 2769 cGy; P< .001), ipsilateral submandibular gland (5709 vs 6036 cGy; P= .008), contralateral submandibular gland (2832 vs 3734 cGy; P< .001), and larynx (2119 vs 3186 cGy; P< .001). Patients with bilateral nodal disease also had lower OAR doses in the 30 Gy group, including right parotid (1661 vs 2402 cGy; P< .001), left parotid (1725 vs 2443 cGy; P< .001), right submandibular gland (5385 vs. 6001; P= .002), left submandibular gland (5283 vs 5948 cGy; P= .005), and larynx (2341 vs 3846 cGy; P< .001). CONCLUSION:Subclinical neck RT dose de-escalation can generate low OAR doses well under established dose constraints. These reductions have the potential to mitigate toxicities such as xerostomia and dysphagia, and they may improve long-term patient quality of life. Ongoing prospective research evaluating toxicities and quality of life from RT de-escalation for OPC is warranted.

Introduction:Adenoid cystic carcinoma (ACC) of the head and neck is a rare malignancy with a high risk of perineural invasion, local recurrence, and distant metastasis. Recurrent ACC poses unique challenges due to its aggressive nature, resection limited by morbidity, and prior radiation. Proton therapy, with its ability to spare normal tissues via the Bragg peak, may offer a promising and safe re-irradiation approach, especially in patients not amenable to resection requiring high definitive doses. The purpose of this study was to evaluate outcomes of patients with recurrent ACC treated with proton radiation. Methods:We reviewed the records of all patients with recurrent head and neck ACC treated with proton therapy between November 2012 and December 2023. This cohort included patients with both resected and unresected disease. Standard imaging, including MRI for perineural spread and PET for distant recurrence, was used in all cases. Descriptive statistics were used to analyze patient, tumor, and treatment characteristics, and the Kaplan-Meier method and cumulative incidence curves were utilized to estimate overall survival (OS) and loco-regional recurrence (LRR), respectively. Results:A total of 19 patients were included, with 6 (32%) receiving adjuvant re-irradiation and 13 (68%) receiving definitive proton re-irradiation. Median dose in the adjuvant group was 63.36 (59.40-70.07), and 59.20 (14.80-70.00) in the primary RT group. The median OS for all patients was 62% at 24 months and 48% at 48 months. Patients receiving adjuvant therapy had an OS of 80% at 24 and 48 months, while those not receiving surgery had an OS of 52% and 31% at 24- and 48-months. LRR at 24 months was 11% for all patients. No grade 5 toxicities were observed. Conclusion:This study demonstrates the feasibility and potential benefits of proton re-irradiation for recurrent ACC, with promising local-regional control and minimal toxicity.

Background and purpose Adaptive radiotherapy for head and neck cancer is resource-intensive, and existing geometric triggers lack a quantitative dose basis. We developed a model based on dose differences derived from cone-beam computed tomography to predict adaptive radiotherapy benefit. Materials and methods Seventy-four patients with head and neck cancer treated with sequential-phase intensity-modulated radiotherapy and offline adaptive radiotherapy were analyzed. Patients were labeled as high or low adaptive radiotherapy benefit by k-means clustering of dose features derived from the resimulation computed tomography. A multivariable logistic regression classifier was trained on percent mean dose differences measured on the week 3 cone-beam computed tomography for five normal tissues (both parotid glands, both submandibular glands, and the oral cavity) and evaluated by leave-one-out cross-validation, alongside a parallel classifier using normal tissue volume changes. Results Dose differences correlated with adaptive radiotherapy benefit for all five normal tissues (Spearman ρs = −0.76 to −0.43; all p < 0.01, Jonckheere–Terpstra trend test), whereas volume changes showed no significant association (all p > 0.10). The dose model achieved an area under the receiver operating characteristic curve of 0.78 versus 0.54 for the volume model. On univariate analysis the ipsilateral parotid gland was the strongest single-organ predictor, whereas the multivariable model assigned the largest standardized coefficient to the ipsilateral submandibular gland, reflecting collinearity between the parotid glands. Conclusions Dose differences derived from cone-beam computed tomography provide an objective, quantitative basis for predicting adaptive radiotherapy benefit in head and neck cancer, offering a practical alternative to geometric triggers and supporting selective, resource-efficient adaptation.

This retrospective study compared the efficacy and toxicity of concurrent triweekly versus weekly cisplatin in patients with previously untreated, biopsy-proven NPC who received definitive CRT followed by adjuvant chemotherapy. Patients with distant metastasis, Karnofsky Performance Status < 80, induction chemotherapy, or no adjuvant therapy were excluded. Medical records of 205 patients treated between June 2000 and June 2023 were reviewed. Patients received triweekly cisplatin (100 mg/m2 every 3 weeks [administered as 50 mg/m2 on days 1 and 2 every 21 days]) or weekly cisplatin (40 mg/m2), with radiotherapy to 70 Gy/35 fractions or 69.96 Gy/33 fractions. Treatment outcomes were analyzed using the Kaplan-Meier method and Cox proportional hazards model, while toxicity profiles were compared using the chi-square test. After a median follow-up of 76 months, the 10-year overall survival rate was 76.5%. The cumulative cisplatin dose was higher in the triweekly group (263.9 ± 50.1 vs. 247.8 ± 35.4 mg/m2, p = 0.0107), while the weekly group included more patients older than 50 years (63.2% vs. 46.6%, p = 0.0338). No significant differences were observed between the triweekly and weekly groups in overall survival (p = 0.9096) and progression-free survival (p = 0.9186). The weekly cisplatin group exhibited a higher incidence of Grade 1-2 hypomagnesemia (p = 0.0415). Other acute toxicities, including gastrointestinal, renal, hematologic, otologic, neurologic, and electrolyte toxicities, as well as 1-year post-treatment kidney injury, hearing impairment, tinnitus, and peripheral neuropathy, were comparable between groups. These findings demonstrate similar survival outcomes and toxicity profiles between concurrent triweekly and weekly cisplatin regimens in NPC treated with curative CRT followed by adjuvant chemotherapy.

Magnetic resonance imaging (MRI) guided adaptive radiotherapy for prostate cancer (PCa) allows daily treatment adaptation to the geometry of tumor and organs to deliver precise treatments while sparing organs from radiation. However, manual delineation of tumors and organs limits the adoption of this technology. Deep learning (DL) methods, though promising for in-distribution (ID) data that resembles training, deteriorate in performance when applied to out-of-distribution (OOD) datasets. Hence, we developed a novel parallel-route coherent feature mixup (PaRC-mix) training approach for single source to multi-domain generalization. PaRC-mix performs feature augmentations at multiple network layers through matching linear combinations of features extracted across training batches. PaRC-mix training was implemented in UNet++ to segment PCa from apparent diffusion coefficient images and compared to other mixup approaches. Models were trained on 2,029 samples from 3.0T GE MRI and tested on 557 PCa samples from 3 datasets used for diagnosis, treatment planning, and during radiation scans acquired using 3T Siemens, 3T Philips, and 1.5T Elekta Unity MR-Linac scanners from public and institutional datasets. PaRC-mix training led to significantly more accurate tumor detection ($\mathrm{p}<$ 0.001) and segmentation ($\mathrm{p}<0.001$) compared to other methods.

IntroductionRadiation dose de-escalation for human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) has been actively investigated to reduce long-term toxicity. Following the recent failure of randomized non-inferiority trials, the real-world adoption and outcomes of de-escalated radiation remain unclear. We evaluated contemporary patterns of dose de-escalation and associated overall survival (OS) in a national cohort.MethodsThe National Cancer Database was queried for patients diagnosed from 2018–2022 with p16-positive OPSCC meeting NRG-HN005 eligibility criteria (cT1–2N1 or cT3N0–1) treated with definitive external beam radiation therapy without primary surgery. Dose-de-escalated radiation therapy (DDRT) was defined as 50.0–65.9 Gy; standard-dose radiation therapy (SDRT) as ≥66.0 Gy. Multivariable logistic regression identified predictors of DDRT. OS was estimated using Kaplan–Meier methods with log-rank testing and 2-month landmark analysis.ResultsAmong 14,869 patients, 1,119 (7.5%) received DDRT. DDRT was more frequently delivered at academic centers (50.3% vs 40.0%, p<0.001). On multivariable analysis, academic facility type (Odds Ratio: 1.76, 95% Confidence Interval 1.31-2.43, p<0.001), more recent year of diagnosis, and geographic region were independently associated with DDRT. Three-year OS was inferior with DDRT compared with SDRT (82.1% vs 88.9%, p<0.001). Among patients receiving first-course chemotherapy, DDRT remained associated with worse OS (82.5% vs. 89.8%, p<0.001). No significant difference was observed among patients not receiving chemotherapy; however, this subgroup was small and likely underpowered to detect a meaningful difference. Landmark analysis yielded consistent findings.ConclusionRadiation dose de-escalation remains infrequent in contemporary U.S. practice but is more commonly delivered at academic centers. In this population-based analysis, de-escalation was associated with inferior overall survival, aligning with recent randomized evidence. Reduced-dose radiation should remain investigational pending biomarker-guided selection strategies.

PURPOSE:Whole gland brachytherapy is an effective treatment for radiorecurrent prostate cancer. Partial gland (focal) treatment may provide equal efficacy with an improved toxicity profile for appropriate patients. METHODS AND MATERIALS:We conducted a retrospective review of 100 patients who underwent focal HDR (19 Gy/1, HDR1; 22 Gy/2, HDR2) or LDR (Pd-103) brachytherapy between January 2017 and December 2024. All patients had prostate biopsies and the majority had MRI and/or PET imaging. ADT was used in 57 patients. Patients were followed with PSA, toxicity, and quality of life assessments. Nadir + 2 definition was used for biochemical failure (BF). Biochemical progression-free survival (bPFS), local failure-free survival (LFFS), toxicities, and quality of life were compared using Kaplan-Meier, Cox regression, and Chi-squared analyses. The median follow-up for the entire cohort was 26.5 months. RESULTS:The 3-year bPFS (95% CI) for the HDR1, HDR2, and LDR cohorts were 72.3% (60.0-87.1), 84.0% (64.9-100), and 50% (12.5-100), respectively. On multivariate analyses, the only significant predictor for bPFS was presalvage PSA (p = 0.03). Local failure was only seen in the HDR1 cohort during the follow-up period. Grade 3+ GU and GI toxicities at 2-years for the entire cohort were 4.0% (0.0-8.5) and 2.8% (0.0-6.6), respectively. CONCLUSIONS:Focal brachytherapy provides excellent early outcomes for patients with radiorecurrent prostate cancer. There was no difference in bPFS by brachytherapy type. There were no local failures in the HDR2 and LDR cohorts; however, follow up was short.

Supplementary Figure 2: Number of cancer cases and deaths across geography in 2020, Millions

Postoperative radiation therapy (PORT) is widely recommended following surgical resection of adenoid cystic carcinoma (ACC) of the major salivary glands, yet its association with overall survival in the contemporary treatment era remains incompletely characterized. Using the National Cancer Database, we identified 2,384 patients with nonmetastatic ACC of the major salivary glands who underwent definitive surgical resection between 2004 and 2021. Of these, 1,776 (74.5%) received PORT and 608 (25.5%) underwent surgery alone. Median follow-up was 75.9 months, and follow-up was censored at 100 months to account for the indolent natural history of ACC. PORT was associated with improved 8-year overall survival compared to surgery alone (76.9% vs 70.3%), which remained significant on multivariable analysis after adjustment for age, sex, comorbidity, extent of disease, margin status, and chemotherapy receipt (HR 0.76, 95% CI 0.62-0.95, p = 0.013). This benefit extended to patients with early-stage disease (pT1-2 N0/NX: HR 0.65, 95% CI 0.51-0.85, p = 0.001), large tumors without nodal involvement (pT3-4 N0/NX: HR 0.69, 95% CI 0.48-0.99, p = 0.043), and negative surgical margins (HR 0.67, 95% CI 0.51-0.89, p = 0.006). However, among patients with pT3-4 tumors and positive surgical margins, PORT was not associated with improved overall survival (HR 0.81, 95% CI 0.48-1.37, p = 0.423), a finding that was robust on adjusted analysis (HR 0.97, 95% CI 0.56-1.68, p = 0.913). This subgroup may represent a biologically distinct and more aggressive subset of ACC in whom locoregional therapy alone is insufficient to alter survival outcomes, possibly due to a higher propensity for distant metastasis driving mortality. These findings support the broad use of PORT in nonmetastatic major salivary gland ACC while identifying a high-risk subgroup warranting further investigation into the role of systemic therapy and intensified multimodality treatment.

Supplementary Table 1: Authors and affiliations

Objective: To report the prevalence of osteoradionecrosis (ORN) in oral cavity (OC) cancer patients following intensity-modulation radiation therapy (IMRT) or proton therapy (PRT). Methods: A retrospective study was conducted on consecutive cohort of OC cancer patients treated with IMRT or PRT for squamous cell carcinoma (SCC). Patient information and treatment related variables were collected from medical records. Patients who developed ORN were uniformly graded using CTCAE v5. Cox proportional hazards model was used to compare risk factors between IMRT and PRT. Kaplan-Meier method was used to estimate the cumulative incidence (CI) of ORN. Results: A total of 479 OC SCC patients (426 treated with IMRT and 53 treated with PRT) were included in this study. The median follow-up time was 35 months (IQR, 17-68 months). The prevalence of ORN was similar between groups: 11% (47/426) in the IMRT group (21 Grade 1, 13 Grade 2, 13 Grade 3) and 11.3% (6/53) in the PRT group (2 Grade 1, 3 Grade 2, 1 Grade 3). The median time to ORN development was shorter following IMRT [13 months (IQR, 9-39)] compared to PRT [28 months (IQR, 4-42)].The 3-year CI of any grade ORN was 9.6 % and 11.4 % for IMRT and PRT (log-rank P-value = 0.550), respectively. On univariable analysis, smoking history (P = 0.072), tumor stage (P = 0.011), tumor with mandibular invasion (P = 0.007), and extent of mandibular intervention (P < 0.001) was associated with ORN development. On multivariable analysis, the extent of mandibular intervention remained a significant risk factor (P < 0.001). Conclusion: In this single-institution study, we found a similar prevalence of ORN following IMRT (11%) and PRT (11.3 %) in OC cancer patients.

IMPORTANCE AND OBJECTIVE:Prostate cancer is the second most common cancer among men globally and the number of cases is expected to double from 2020 to 2040. A greater understanding of health system factors that can be leveraged to improve prostate cancer control may guide health system planning in anticipation of the growing global burden of prostate cancer. DESIGN:This ecological cross-sectional study made use of the most recent available national health system metrics for countries with prostate cancer incidence and mortality estimates available from the International Agency for Research on Cancer (IARC). IARC data represent the most updated estimates as of April 2025. MAIN OUTCOMES:National estimates of age-standardized mortality-to-incidence ratios (MIR) were derived from the GLOBOCAN 2022 database for male patients with prostate cancer of all ages. Health spending as a percent of gross domestic product, physicians per 1000 population, nurses and midwives per 1000 population, surgical workforce per 1000 population, gross domestic product (GDP) per capita, Universal Health Coverage Service Coverage Index (UHC index), availability of pathology services, human development index (HDI), gender inequality index, and number of radiotherapy centers per 1000 population were collected. The association between prostate MIR and each metric was evaluated using simple univariable linear regression models. Those with p < 0.005 (Bonferroni corrected) were included in multivariable models. Variation inflation factor analysis facilitated exclusion of variables with significant multicollinearity. R2 defined goodness of fit. RESULTS:Based on IARC estimate availability, data for 185 countries were collected; data availability ranged from 144 (77.8%, surgical workforce per 1000 population known) to 185 (100%, GDP per capita, RT centers per 1000 population). On univariable analysis, each of the 10 metrics was significantly associated with MIR of prostate cancer (< 0.001 forall). All but one (HDI, due to mutlicollinearity) were included in the multivariable model. The final multivariable model included 123 countries with complete data. Of those included in the regression with complete data, 44 of 123 (35.8%) were high-income countries; of those excluded due to incomplete data, 16 of 62 (25.8%) were high-income countries (χ² p = 0.17 comparing the proportion of high-income countries in the included and excluded groups). Therefore, the following variables were independently associated with lower (improved) MIR for prostate cancer: (1) surgical workforce per 1000 population, (2) UHC index, (3) radiotherapy centers per 1000 population, (4) GDP per capita. The final model had R2 of 0.8408. CONCLUSIONS AND RELEVANCE:Analysis of global data and health-system metrics suggest that surgical workforce, degree of UHC, availability of radiotherapy centers, and GDP per capita are independently associated with improved prostate cancer outcomes. In leveraging individual countries' health systems as data points, these findings may guide health system planning and prioritization. Efforts to strengthen access to surgery and radiotherapy in the context of broader and equitable cancer system strengthening may represent concrete points of action for public health efforts, given the growing global burden of prostate cancer.

Purpose/Objectives:Adenoid cystic carcinoma (ACC) of the head and neck is a rare malignancy with a prolonged but infiltrative course, marked by perineural invasion and high risk of local recurrence and distant metastases. The standard of care for head/neck ACC is surgery and postoperative radiation. Definitive radiation is reserved for those with definitive disease. Given the advantage of proton beam to tailor its dose around the tumor while sparing critical tissues, we sought to report our proton experience in the treatment of head/neck ACC. Materials/Methods:We retrospectively analyzed 106 patients treated with definitive or adjuvant proton therapy for ACC from 2012 to 2023. All patients were staged with computed tomography (CT), magnetic resonance imaging (MRI), and/or positron emission tomography (PET) and were evaluated by a multidisciplinary team. Radiation doses were ≥66 Gy(RBE) adjuvantly and ≥70 Gy(RBE) definitively. Patients were treated using either uniform scanning or pencil beam scanning (PBS) proton therapy. Primary endpoints included overall survival (OS), progression-free survival (PFS), and locoregional recurrence (LRR), assessed using Kaplan-Meier and cumulative incidence methods. Results:Of 106 patients, 76 were treated postoperatively and 30 definitively. The 5-year OS was 75% overall, 86% for the adjuvant group, and 45% for the definitive group. Five-year PFS was 47% overall, 54% (adjuvant) vs 29% (definitive). Locoregional control at 5 years was 89% overall, with 93% for adjuvant vs 74% for definitive treatment. Toxicities were generally mild, with acute grade ≤2 dermatitis (53%) and mucositis (33%) most common. Chronic toxicities included xerostomia (38%) and temporal lobe necrosis (4%). Conclusion:Proton therapy for ACC of the head and neck yields excellent locoregional control, particularly in the adjuvant setting, with manageable toxicity. For patients with unresectable disease or those seeking organ preservation, definitive proton therapy remains a viable, durable treatment option. These findings support proton therapy as a preferred modality in head and neck ACC.

5014 Background: Metastasis directed therapy (MDT) with stereotactic body radiotherapy (SBRT) is a standard of care in patients with oligometastatic hormone-sensitive prostate cancer (HSPC) and can delay the use of ADT. Combining SBRT with a defined period of systemic therapy may lead to durable control of oligometastatic disease and is often used in this setting, however the optimal intensity and duration of hormonal blockade with SBRT remains unclear. Methods: Metacure is a multi-center, multi-arm randomized phase 2 trial that tests novel systemic therapies in the context of a multimodality approach, including SBRT to oligometastatic sites. The B2 and B2 expansion cohorts of Metacure tested SBRT +/- salvage RT to prostate bed/nodes with time-limited ADT+ARPI hormonal blockade in patients (pts) with PSMA-PET detected metachronous oligometastatic HSPC. Eligible pts had biochemical recurrence or persistence (PSA >0.2) after prostatectomy with metastases treatable within max 3 RT plans. Cohort B2 randomized pts to metastasis-directed SBRT with either 10 months of ADT + apalutamide + abiraterone acetate plus prednisone (ADT+APA+AAP) or ADT + apalutamide (ADT+APA). In the B2 expansion cohort pts received 6 months of ADT+APA with SBRT. The primary endpoint was proportion of pts with undetectable PSA (PSA<0.1) at 12 months from treatment start in pts with recovered testosterone (T). Secondary objectives included PSA<0.1 at 24 months, time to PSA progression (PSA 0.2), time to T recovery, rPFS, and PFS (PSA, radiographic, or clinical progression or death). Results: 36 pts were treated in the combined B2 (10 pts) and B2 expansion (26 pts) cohorts. Median follow-up was 35 months for cohort B2 and 19 months for the B2 expansion. T recovery (>150ng/dl) at 12 months from treatment start occurred in 3/5 (60%) ADT+APA+AAP and 2/5 (40%) ADT+APA pts on cohort B2 and 14/26 pts (54%) on the B2 expansion (ADT+APA). Of those, 2/2 (100%) B2 ADT+APA+AAP pts, 3/3 (100%) B2 ADT+APA and 11/14 (79%) B2 expansion pts had PSA <0.1. This met the pre-specified threshold for activity for the B2 expansion of 4 pts. Median time to PSA progression and PFS was 26 months for the B2 ADT+APA+AAP arm and not reached for the B2 ADT+APA arm or B2 expansion cohort. Median rPFS was not reached in any group. At 12 months, all patients on B2 and B2 expansion were progression free. At 18 months, PFS for B2 was 100% (ADT+APA) and 60% (ADT+APA+AAP) and was 85% for the B2 expansion. At 24 months, PFS was 60% for ADT+APA and 60% for ADT+APA+AAP pts on cohort B2. Median T recovery was 3.0 and 5.5 months for the B2 and B2 expansion cohorts. Grade 3 TRAEs were seen in 0/10 B2 and 1/26 B2 expansion subjects (lymphopenia). Conclusions: SBRT with short course intensified hormonal blockade was well tolerated and led to durable disease control in pts with PSMA PET-detected metachronous oligometastatic prostate cancer. Clinical trial information: NCT03436654 .