Treatment intensification strategies for men undergoing definitive radiotherapy for high-risk prostate cancer.

PURPOSE: Treatment intensification of external beam radiotherapy (EBRT) plays a crucial role in the treatment of high-risk prostate cancer. METHODS: We performed a critical narrative review of the relevant literature and present new developments in evidence-based treatment intensification strategies. RESULTS: For men with high-risk prostate cancer, there is strong evidence to support prolonging androgen deprivation therapy (ADT) to 18-36 months and escalating the dose to the prostate using a brachytherapy boost. A potentially less toxic alternative to a brachytherapy boost is delivering a focal boost to dominant intraprostatic lesions using EBRT. In patients who meet STAMPEDE high-risk criteria, there is evidence to support adding a second-generation anti-androgen agent, such as abiraterone acetate, to long-term ADT. Elective pelvic lymph node irradiation may be beneficial in select patients, though more prospective data is needed to elucidate the group of patients who may benefit the most. Tumor genomic classifier (GC) testing and advanced molecular imaging will likely play a role in improving patient selection for treatment intensification as well as contribute to the evolution of treatment intensification strategies for future patients. CONCLUSION: Treatment intensification using a combination of EBRT, advanced hormonal therapies, and brachytherapy may improve patient outcomes and survival in men with high-risk prostate cancer. Shared decision-making between patients and multidisciplinary teams of radiation oncologists, urologists, and medical oncologists is essential for personalizing care in this setting and deciding which strategies make sense for individual patients.

Selecting the optimal radiation modality in prostate cancer.

There are numerous radiation modalities for the definitive treatment of localized prostate cancer. Classic clinical trials have established the basic tenets of treatment approaches, and emerging data have generated new potential avenues of treatment that optimize the therapeutic ratio by increasing prostate cancer tumor control while minimizing treatment-related toxicity. In the definitive setting, the selection of the optimal radiation therapy approach depends largely on the appropriate up-front risk stratification of men with prostate cancer, with greater intensification of treatment and greater integration of multimodality therapies for men with higher-risk disease. Hormonal therapy should be selectively deployed based on prognostic information derived from the National Comprehensive Cancer Network risk group and biologic tumor aggressiveness informed by genomic classifiers. Moreover, treatment intensification and target volume delineation are increasingly informed by molecular imaging and multiparametric magnetic resonance imaging. Herein, we perform a critical appraisal of the literature focusing on the optimal selection of radiation therapy modality for localized prostate cancer. Collaboration among medical oncologists, surgeons, and radiation oncologists will be critical for coordinating evidence-based radiation therapies when clearly indicated and for supporting shared decision-making when the evidence is incomplete.

New themes in the biological functions of 5-methylcytosine and 5-hydroxymethylcytosine.

5-methylcytosine (5-mC) and 5-hydroxymethylcytosine (5-hmC) play a critical role in development and normal physiology. Alterations in 5-mC and 5-hmC patterns are common events in hematopoietic neoplasms. In this review, we begin by emphasizing the importance of 5-mC, 5-hmC, and their enzymatic modifiers in hematological malignancies. Then, we discuss the functions of 5-mC and 5-hmC at distinct genic contexts, including promoter regions, gene bodies, intron-exon boundaries, alternative promoters, and intragenic microRNAs. Recent advances in technology have allowed for the study of 5-mC and 5-hmC independently and specifically permitting distinction between the bases that show them to have transcriptional effects that vary by their location relative to gene structure. We extend these observations to their functions at enhancers and transcription factor binding sites. We discuss dietary influences on 5-mC and 5-hmC levels and summarize the literature on the effects of folate and vitamin C on 5-mC and 5-hmC, respectively. Finally, we discuss how these new themes in the functions of 5-mC and 5-hmC will likely influence the broader research field of epigenetics.

Systemic and Tumor-directed Therapy for Oligorecurrent Metastatic Prostate Cancer (SATURN): Primary Endpoint Results from a Phase 2 Clinical Trial.

Nearly all men with metastatic hormone-sensitive prostate cancer treated with intermittent androgen deprivation therapy (ADT) experience recurrence within 6 mo of testosterone recovery. We conducted a single-arm phase 2 trial to evaluate whether addition of dual androgen receptor pathway inhibitors (ARPIs) and metastasis-directed stereotactic body radiotherapy (SBRT) to intermittent ADT improves recurrence rates for men with between one and five nonvisceral, extrapelvic metastases on prostate-specific membrane antigen positron emission tomography/computed tomography after prior radical prostatectomy. Patients received 6 mo of androgen annihilation therapy (AAT; leuprolide, abiraterone acetate plus prednisone, and apalutamide) and metastasis-directed SBRT. The primary endpoint was the percentage of patients with prostate-specific antigen (PSA) <0.05 ng/ml 6 mo after testosterone recovery (≥150 ng/dl), with the study powered to detect an improvement from 1% to 12%. We enrolled 28 men between March 2021 and June 2022. Median follow-up was 20 mo (interquartile range 16-22). Twenty-six patients (93%) completed SBRT with 6 mo of hormone therapy, of whom six discontinued at least one ARPI; two patients withdrew prematurely. At 6 mo after testosterone recovery, PSA was maintained at <0.05 ng/ml in 13/26 patients (50%, 95% confidence interval 32-67%). Rates of grade 2 and 3 AAT toxicity were 21% and 21%. The results confirm that addition of metastasis-directed SBRT to highly potent systemic therapy can maintain low PSA after testosterone recovery, although further studies are needed to clarify the optimal systemic therapy regimen. PATIENT SUMMARY: We tested a combination of intensified hormone therapy (called androgen annihilation therapy) and radiotherapy targeted at metastases in men with recurrence of metastatic prostate cancer. We found that half of patients were recurrence-free 6 months after their testosterone level recovered, and that less than a quarter of patients experienced a severe drug-related side effect. Overall, this appears to be an effective therapy with acceptable side effects. This trial is registered on ClinicalTrials.gov as NCT03902951.

Randomized Trial of Prostate-Specific Membrane Antigen PET/CT Before Definitive Radiotherapy for Unfavorable Intermediate- and High-Risk Prostate Cancer (PSMA-dRT Trial).

This multicenter randomized phase III trial (NCT04457245) evaluated the effect of performing prostate-specific membrane antigen (PSMA) PET/CT before definitive radiotherapy. Methods: Men with unfavorable intermediate- or high-risk prostate cancer were randomized 1.08:1 between receiving and not receiving a PSMA PET/CT scan before definitive radiotherapy. All other imaging modalities were allowed in the control arm. The primary endpoint was 5-y progression-free survival. Results: Fifty-four men were randomized between November 2020 and December 2021 (PSMA PET/CT, n = 25; control, n = 29). The trial closed early after approval and insurance coverage of PSMA PET/CT. In the PSMA PET/CT arm, 14 patients had localized disease (miT2b-cN0M0), 6 had locally advanced disease (miT3a-bN0M0), 3 had regional metastasis (miN1M0), and 1 had distant metastasis (miM1b). Four patients were upstaged. Conclusion: PSMA PET/CT upstaged 17% of patients, which allowed for more accurate radiotherapy planning. Unfortunately, this trial closed early before completion of target enrollment (54/316, 17%) and was underpowered to assess the effect of PSMA PET/CT on progression-free survival.

Prostate-Specific Antigen Response to Androgen Deprivation Therapy in the Neoadjuvant Setting for High-Risk Prostate Adenocarcinoma (PIRANHA): Pooled Analysis of Two Randomized Clinical Trials.

PURPOSE: A suboptimal prostate-specific antigen (PSA) response to neoadjuvant androgen deprivation therapy (ADT) among men who go on to receive definitive radiation therapy for prostate cancer might suggest the existence of castration-resistant disease or altered androgen receptor signaling. This in turn may portend worse long-term clinical outcomes, especially in men with high-risk disease. We set out to evaluate the prognostic impact of poor PSA response to neoadjuvant ADT in men with high-risk prostate cancer. METHODS AND MATERIALS: This was a post hoc analysis of the multicenter TROG 03.04 RADAR and PCS IV randomized clinical trials. Inclusion criteria for this analysis were patients with high-risk prostate cancer (defined as Gleason score ≥8, initial PSA ≥20 ng/mL, or cT3a disease or higher) who received definitive radiation therapy, at least 18 months of ADT, and had a preradiation therapy PSA level drawn after at least 3 months of neoadjuvant ADT. Poor PSA response was defined as PSA >0.5 ng/mL. Cox regression and Fine-Gray models were used to test whether poor PSA response was associated with metastasis-free survival, biochemical recurrence, prostate-cancer specific mortality, and overall survival. RESULTS: Nine hundred thirty men met inclusion criteria for this analysis. Median follow-up was 130 months (interquartile range [IQR], 89-154 months). After a median of 3 months (IQR, 3-4.2 months) of neoadjuvant ADT, the median PSA was 0.60 ng/mL (IQR, 0.29-1.59). Overall, 535 men (57%) had a PSA >0.5 ng/mL. Poor PSA response was associated with significantly worse metastasis-free survival (hazard ratio [HR], 3.93; P = .02), worse biochemical recurrence (subdistribution HR, 2.39; P = .003), worse prostate-cancer specific mortality (subdistribution HR, 1.50; P = .005), and worse overall survival (HR, 4.51; P = .05). CONCLUSIONS: Patients with PSA >0.5 mg/mL after at least 3 months of neoadjuvant ADT had worse long-term clinical outcomes and should be considered for treatment intensification.

Early Safety and Efficacy Profile of Homogeneously Dosed Salvage Stereotactic Body Radiotherapy (SBRT) for Intraprostatic Recurrences After Low Dose Rate (LDR) Brachytherapy.

INTRODUCTION: We set out to evaluate the safety and efficacy of homogeneously dosed salvage stereotactic body radiation therapy (SBRT) for intraprostatic recurrences following low dose rate (LDR) brachytherapy. PATIENTS AND METHODS: An institutional prostate SBRT database was interrogated for patients treated between January 2018 and December 2021 with salvage SBRT for intraprostatic recurrences who were previously treated with LDR brachytherapy. Patients received 30 to 34 Gy in 5 fractions to the prostate with a simultaneous integrated boost of 34 to 37.5 Gy to gross disease. The maximum urethral dose allowed was 34 Gy. Toxicities were graded using Common Terminology Criteria for Adverse Events, version 5.0. RESULTS: Eleven patients met our study's inclusion criteria with a median follow-up time of 37.9 months (range, 24.3-51.8 months). Median time between LDR brachytherapy and salvage SBRT was 7 years (range, 2-11 years) with a median PSA of 3.15 ng/mL (range, 0.90-9.83) at the time of salvage radiation. All 11 patients were alive at the time of last follow-up. Our 3-year Kaplan-Meier progression-free survival rate was 70.1%. Median time to recurrence was 24.1 months (range, 18.7-29.7 months). Late (≥3 months) grade 1, 2, and 3 urinary toxicity rates were 27.3%, 36.4%, and 9.1%, respectively. Late (≥3 months) grade 1, 2, and 3 gastrointestinal toxicity rates were 18.2%, 0%, and 9.1%, respectively. CONCLUSION: Homogeneous salvage SBRT to the prostate with urethral dose minimization has a favorable safety and efficacy profile for treating intra-prostatic recurrences following LDR brachytherapy. This may represent an ideal form of salvage SBRT for re-irradiation.

The role of adaptive planning in margin-reduced, MRI-guided stereotactic body radiotherapy to the prostate bed following radical prostatectomy: Post-hoc analysis of a phase II clinical trial.

BACKGROUND AND PURPOSE: We examined the interfractional variations of clinical target volumes (CTVs), planning target volumes (PTVs), and organs-at-risk (OARs) in patients receiving MRI-guided stereotactic body radiotherapy (SBRT) to the prostate bed and evaluated the potential role of adaptive planning. MATERIALS AND METHODS: 31 patients received 30-34 Gy in five fractions to the prostate bed on a phase II clinical trial. OARs, CTVs, and PTVs were retrospectively contoured on daily pretreatment MRIs (n = 155). Geometric comparisons were made between initial planning contours and daily pretreatment contours. Predicted treatment plans for each fraction were evaluated using the following constraints: CTV V95%>93%, PTV V95%>90%, bladder Dmax < 36.7 Gy, bladder V32.5 Gy < 35%, rectum Dmax < 36.7 Gy, rectum V27.5 Gy < 45%, rectum 32.5 Gy < 30%, and rectal wall V24Gy < 50%. Adaptive planning was simulated for all fractions that failed to meet these criteria. Plans were then re-evaluated. RESULTS: Median change in volume was 0.48% for CTV, -24.5% for bladder, and 6.95% for rectum. Median DSC was 0.89 for CTV, 0.79 for bladder, and 0.76 for rectum. 145/155 fractions (93.5%) met CTV V95%>93%. 75/155 fractions (48.4%) failed at least one OAR dose constraint. Overall, 83/155 fractions (53.5%) met criteria for adapting planning. This affected 24/31 patients (77.4%). Following adaptive planning, all fractions met CTV V95%>93% and PTV V95%>90% and 120/155 fractions (77.4%) met all OAR constraints. CONCLUSION: Due to significant interfractional variations in anatomy, a majority of fractions failed to meet both target volume and OAR constraints. However, adaptive planning was effective in overcoming these anatomic changes. Adaptive planning should be routinely considered in prostate bed SBRT.

Long-Term Quality-of-Life Outcomes After Prostate Radiation Therapy With or Without High-Dose-Rate Brachytherapy Boost: Post Hoc Analysis of TROG 03.04 RADAR.

PURPOSE: Adding high-dose-rate brachytherapy (BT) boost to external beam radiation therapy (EBRT) improves biochemical control but may affect patient-reported quality of life (QOL). We sought to determine long-term QOL outcomes for EBRT+BT versus EBRT alone. METHODS AND MATERIALS: This was a post hoc analysis of the Trans-Tasman Radiation Oncology Group 03.04 Randomized Androgen Deprivation and Radiotherapy (TROG 03.04 RADAR) trial. Only patients who received 74 Gy conventionally fractionated EBRT (n = 260) or 46 Gy conventionally fractionated EBRT plus 19.5 Gy in 3 fractions high-dose-rate BT boost (n = 237) were included in this analysis. The primary endpoint was patient-reported QOL measured using the European Organisation for Research and Treatment of Cancer QOL (EORTC QLQ-C30) and prostate-specific QOL module (EORTC QLQ-PR25) questionnaires. We evaluated temporal changes in QOL scores, rates of symptom resolution, and the proportion of men who had decrements from baseline of >2 × the threshold for minimal clinically important change (2 × MCIC) for each domain. RESULTS: At 5, 17, and 29 months after radiation therapy, the EBRT+BT group had 2.5 times (95% confidence interval [CI], 1.4-4.2; P < .001), 2.9 times (95% CI, 1.7-4.9; P < .001), and 2.6 times (95% CI, 1.4-4.6; P = .002) greater odds of reporting 2 × MCIC in urinary QOL score compared with EBRT. There were no differences beyond 29 months. EBRT+BT led to a slower rate of urinary QOL symptom score resolution up to 17 months after radiation therapy compared with EBRT (P < .001) but not at later intervals. In contrast, at the end of the radiation therapy period and at 53 months after radiation therapy, the EBRT+BT group had 0.65 times (95% CI, 0.44-0.96; P = .03) and 0.51 times (95% CI, 0.32-0.79; P = .003) the odds of reporting 2 × MCIC in bowel QOL symptom scores compared with EBRT. There were no significant differences in the rate of bowel QOL score resolution. There were no significant differences in global health status or sexual activity scores between the 2 groups. CONCLUSIONS: There were no persistent differences in patient-reported QOL measures between EBRT alone and EBRT+BT. BT boost does not appear to negatively affect long-term, patient-reported QOL.

Impact of invasive nodal staging on regional and distant recurrence rates after SBRT for inoperable stage I NSCLC.

PURPOSE/OBJECTIVES: Before definitive stereotactic body radiation therapy (SBRT) for presumably node-negative, early-stage NSCLC, many patients are staged with PET/CT alone. In patients undergoing PET/CT prior to SBRT, the role of invasive nodal staging (INS) with endobronchial ultrasound (EBUS) or mediastinoscopy is uncertain. We sought to characterize the impact of nodal staging modality on outcomes. MATERIALS/METHODS: Patients receiving definitive SBRT for T1-2N0 NSCLC deemed node-negative by either PET/CT plus INS (EBUS or mediastinoscopy) or PET/CT alone were identified. Patients with initially equivocal or positive nodes on PET/CT were excluded from this analysis. All patients received 3-5 fraction SBRT according to institutional guidelines. Control was assessed by at least one follow-up CT in all patients. Multivariable logistic regression (MVA) was performed to identify variables independently associated with use of INS. RESULTS: We identified 651 eligible patients at our institution from 2005-2016. INS was performed in 15.2% of patients (n = 99) with EBUS (n = 78) or mediastinoscopy (n = 21). Median follow-up was 19.4 months (0.2-135.1). Median survival was 28.5 months (0.6-140). Factors predictive of increased likelihood of INS after negative PET/CT on MVA were age (OR for decreasing age 1.033; 95% CI 1.058-1.010), Caucasian race (OR vs. non-white 1.852; 1.044-3.289), male sex (1.629; 1.031-2.575), central location (1.978; 1.218-3.211) and squamous histology (2.564; 1.243-5.287). Nodal and/or distant control at 2 years was similar between PET/CT alone (78%, 95% CI 74-82%) and INS + PET/CT (75%, 95% CI 65-85%) (p = 0.877) as well as on MVA. Overall survival did not differ based on staging modality. CONCLUSIONS: In patients with early-stage NSCLC deemed node-negative by PET/CT, addition of INS did not appreciably alter patterns of failure or survival after definitive SBRT. This study does not question the established value of INS for equivocal or suspicious nodes.

Treatment of oligometastatic lung cancer with brain metastases using stereotactic radiosurgery (SRS) and stereotactic body radiation therapy (SBRT).

BACKGROUND: There is increasing interest in treating oligometastatic non-small cell lung cancer (NSCLC) patients with stereotactic radiation. We aimed to address whether patients definitively treated with synchronous thoracic stereotactic body radiation therapy (SBRT) and brain stereotactic radiosurgery (SRS) had favorable outcomes with local therapy. MATERIALS AND METHODS: We reviewed a database of patients receiving lung SBRT as well as a database for brain metastasis patients treated with SRS between June 2004 and January 2016. We selected for cT1-2aN0M1 NSCLC patients with brain metastases and calculated their overall survival (OS), freedom from progression (FFP), and local control (LC) rates. RESULTS: Six patients had oligometastatic NSCLC with 1-3 synchronous brain metastases treated with lung SBRT and brain SRS. No patients received immunotherapy and two-thirds did not receive systemic therapy. Median follow-up was 9 months for the entire cohort (range, 2-95 months) and 95 months for the surviving patient. Median OS was 12.4 months (95% confidence interval [CI], 7-18 months). At 1 year, patients had 67% OS (95% CI, 29-100%), 17% FFP (95% CI, 0-46%), and 100% LC. Their brain disease had 80% 1-year LC (95% CI, 45-100%) and 53% 1-year FFP (95% CI, 5-100%). Two patients had no distant progression, two had brain progression, one had adrenal gland progression, and one had bone and liver progression. CONCLUSION: In patients presenting with oligometastatic lung cancer limited to the brain, treatment with both lung SBRT and brain SRS achieves good LC of all sites with encouraging OS.

Repeat stereotactic body radiation therapy (SBRT) for salvage of isolated local recurrence after definitive lung SBRT.

PURPOSE: Optimal management of isolated local recurrences after stereotactic body radiation therapy (SBRT) for early non-small cell lung cancer (NSCLC) is unknown and literature describing repeat SBRT for in-field recurrences after initial SBRT are sparse. We investigate the safety and efficacy of salvage SBRT for isolated local failures after initial SBRT for NSCLC. METHODS/MATERIALS: Patients receiving SBRT for isolated local recurrence after initial SBRT for early NSCLC were identified using a prospective registry. Both courses were 3-5 fractions with a biologically effective dose (BED10) of ≥100 Gy. Local failure was defined as within 1 cm of the initial planning target volume (PTV) or an overlap of the ≥25% isodose lines of the first and second treatments. Failures >1 cm beyond the PTV and without ≥25% overlap, or with additional recurrence sites were excluded. Kaplan-Meier analysis was used to estimate survival. RESULTS: A total 21 patients receiving salvage SBRT from 2008 to 2017 were identified. Median interval from initial SBRT to salvage SBRT was 23 months (7-52). Six patients (29%) had central tumors. Median follow-up time from salvage SBRT was 24 months (3-60). Median overall survival after salvage was 39 months. After reirradiation, two-year primary tumor control was 81%, regional nodal control was 89%, distant control was 75% and overall survival was 68%. Grade 2 pneumonitis occurred in 2 patients (10%) and grade 2 chest wall toxicity in 4 patients (19%). No grade 3+ toxicity was observed. CONCLUSIONS: Salvage SBRT for isolated local failures after initial SBRT appears safe, with low treatment-related toxicity and encouraging rates of tumor control.

Stereotactic Body Radiotherapy for Early-Stage Multiple Primary Lung Cancers.

BACKGROUND: Patients with multiple primary lung cancers increasingly receive multiple courses of stereotactic body radiotherapy (SBRT). We aimed to clarify the efficacy and safety of such treatments. PATIENTS AND METHODS: We reviewed a prospective lung SBRT database of patients treated for stage I non-small-cell lung cancer between June 2004 and December 2015. RESULTS: A total of 374 patients received a single course of SBRT, 14 received synchronous SBRT, 48 received metachronous SBRT alone, and 108 received surgery and metachronous SBRT. Median follow-up was 37.0 months for survivors. Patients who received a single course had a 3-year overall survival (OS) of 54.2% (95% confidence interval [CI], 48.8-59.3), 3-year freedom from progression (FFP) of 67.3% (95% CI, 60.9-72.9), and grade 3 or higher toxicity of 3.5%. Compared to single-course patients, patients receiving metachronous SBRT alone and patients receiving surgery and metachronous SBRT had improved OS (79.7% [95% CI, 64.4-88.9%], P < .0001 and 95.4% [95% CI, 89.2-98.0%], P < .0001, respectively) and FFP (85.8% [95% CI, 70.7-93.5], P = .03 and 95.4% [95% CI, 89.2-98.0%], P < .0001, respectively). Patients receiving synchronous SBRT had similar OS (46.4% [95% CI, 19.3-69.9%], P = .75) and similar FFP (57.5% [95% CI, 25.3-80.0%], P = .17) as single-course patients. There were no significant differences in rates of grade 3 or higher toxicity or of grade 1 or higher toxicity between single-course patients and the other groups. CONCLUSION: Patients who received either synchronous or metachronous SBRT had no significant detriment in OS or toxicity compared to single-course patients. This supports the use of SBRT in patients with multiple primary lung cancers.

Treatment of T3N0 non-small cell lung cancer with chest wall invasion using stereotactic body radiotherapy.

OBJECTIVES: Chest wall invasion (CWI) is observed in 5% of localized non-small cell lung cancer (NSCLC). The role of stereotactic body radiotherapy (SBRT) in these patients is unknown. We investigate the safety and efficacy of SBRT in patients with T3N0 NSCLC due to CWI. METHODS: Patients with T3N0 NSCLC due to CWI were identified using a prospective registry. CWI was defined as radiographic evidence of soft tissue invasion or bony destruction. We excluded patients with recurrent or metastatic disease. All patients were treated with definitive SBRT. Prescribed dose was 50 Gy in 5 fractions for most patients. Kaplan-Meier analysis was used to estimate survival outcomes. RESULTS: We identified 12 patients treated between 2006 and 2017. Median age was 70 (range, 58-85). Median tumor diameter was 3.0 cm (range, 0.9-7.2). Median survival was 12.0 months (range, 2.4-63). At a median follow-up of 8.9 months (range, 2.1-63), 1-year primary tumor control was 89%, involved lobar control was 89%, local-regional control was 82%, distant control was 91%, and survival was 63%. Of the 4 patients with pre-treatment chest wall pain, 3 reported improvement after SBRT. Two patients reported new grade 1-2 chest wall pain. No grade 3+ toxicity was reported, with 1 patient experiencing grade 1 skin toxicity and 3 patients experiencing grade 1-2 radiation pneumonitis. CONCLUSIONS: SBRT for CWI NSCLC is safe, with high early tumor control and low treatment-related toxicity. Most patients with pre-treatment chest wall pain experienced relief after SBRT, with no grade 3+ toxicity observed.

Defining Optimal Comorbidity Measures for Patients With Early-Stage Non-small cell lung cancer Treated With Stereotactic Body Radiation Therapy.

PURPOSE: Comparison of overall survival (OS) between stereotactic body radiation therapy (SBRT) and other treatments for early-stage non-small cell lung cancer is confounded by differences in age, performance status, and medical comorbidity. We sought to define the most robust measurement for this population among 5 indices: age, Eastern Cooperative Oncology Group performance status, Adult Comorbidity Evaluation 27, Charlson Comorbidity Index (CCI), and age-adjusted CCI (CCIa). METHODS AND MATERIALS: A total of 548 patients with stage I non-small cell lung cancer treated with SBRT were analyzed. Patients were divided into high- and low-risk groups for OS for each index using the log-rank test. Continuous and dichotomized models were compared via Akaike information criterion and the Vuong test. Multivariate Cox regression modeling was used with demographic information to determine the independent prognostic value of the continuous and dichotomized versions of the indices. The best was used to stratify the patients into as many significantly different cohorts as possible. RESULTS: Optimal cut-points between high-risk and low-risk OS groups for age, Eastern Cooperative Oncology Group status, Adult Comorbidity Evaluation 27, CCI, and CCIa were ≥75 years, ≥1, ≥3, ≥3, and ≥6 with hazard ratios for death of 1.23 (95% confidence interval, 1.00-1.50), 1.66 (1.28-2.15), 1.37 (1.12-1.67), 1.43 (1.17-1.76), and 1.47 (1.20-1.80), respectively. Dichotomizing did not result in a significant loss of prognostic power. Although there was no significant difference in prognostic power among the indices, CCIa best predicted OS. CCIa divided the patients into 3 cohorts with median OS of 42 months, 33 months, and 23 months for scores of ≤5, 6 to 7, and ≥8, respectively. CONCLUSIONS: CCIa was the best indicator of OS in every model employed with no loss of prognostic power with dichotomization. Dichotomization of CCIa (≥6) could be implemented in future comparisons of SBRT with OS. No cohort could be identified with a median survival of less than a year, for which treatment could be deemed futile.