Analysis of Radiation Facility Volume and Survival in Men With Lymph Node–Positive Prostate Cancer Treated With Radiation and Androgen Deprivation Therapy

Key Points Question Is a cancer facility’s radiation case volume associated with long-term outcomes in men with advanced prostate cancer who were treated with primary radiation therapy? Findings In this cohort study of 1899 men from a large US cancer database, men with node-positive prostate cancer undergoing curative-intent radiation therapy with concurrent androgen deprivation therapy had significantly improved median survival rates if they were treated at facilities with a high volume of such patients, independent of academic affiliation. Meaning Node-positive prostate cancer is a complex disease entity with the potential for long-term disease control with aggressive management, and these findings suggest that treatment at a high-volume radiation center is associated with improved long-term oncologic outcomes.


Introduction
Prostate cancer remains the most common malignant neoplasm in men, accounting for 20% of incident cancer cases in male US residents in 2019. 1 The decline in routine prostate-specific antigen (PSA) screening in the United States since 2012 has altered the landscape of this disease. 2 Specifically, there has been an increased incidence of advanced prostate cancer, with a concordant decrease in indolent, localized disease. 3,4 This effect has been more pronounced with the advent of more sensitive advance diagnostic imaging. 5,6 Although patients with regional (ie, nodal) or distant metastatic disease are considered stage IV by American Joint Committee on Cancer, 7 many experience long-term survival with aggressive systemic and local management. For nonmetastatic node-positive (N1) prostate cancer in particular, the National Comprehensive Cancer Network revised the historic treatment recommendation of androgen deprivation therapy (ADT) alone to now include combination external beam radiation therapy (EBRT) with concomitant ADT as the preferred treatment option. 8 Caring for patients with advanced prostate cancer, namely those with N1 prostate cancer who are eligible for curative EBRT with ADT, is complex and requires sophisticated radiation treatment planning and delivery, including dose escalation to radiographically involved lymph nodes as safely deliverable within normal tissue tolerances. Furthermore, the addition of a second-generation antiandrogen, abiraterone, has shown to improve overall survival (OS) in a post hoc analysis in men with N1 prostate cancer. 9 Although the incidence of N1 prostate cancer was historically low, the rising incidence of these advanced cases in light of reduced PSA screenings as well as the recent guideline recommendation 8 of definitive EBRT plus ADT as the preferred treatment option highlight the need to optimize management and identify factors associated with long-term outcomes in these patients.
Numerous studies have shown that patients with cancer who are treated at high-volume facilities have higher rates of long-term survival, including those who undergo primary surgery, radiation, or chemotherapy. [10][11][12][13][14][15][16][17][18][19][20] Whether radiation case volume influences long-term outcomes in men with N1 prostate cancer is unknown. Herein, we examine the association of radiation facility case volume with OS among men with N1 prostate cancer treated with EBRT and ADT. Given the complexity of management of N1 prostate cancer, we hypothesized that men treated at high-volume centers would have improved OS compared with those treated at low-volume centers.

Data Source and Study Population
The National Cancer Database (NCDB), a nationwide hospital-based cancer registry jointly sponsored by the American College of Surgeons and the American Cancer Society, collects data from more than 1400 Commission on Cancer-accredited hospitals and captures approximately 70% of incident cancer cases in the United States. The present study follows the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline. Because the study used deidentified data from the NDCB database, the requirement for formal institutional review and the need for informed consent were waived, consistent with the policies of Emory University School of Medicine.
Using the NCDB, we identified men diagnosed with T1N1M0 to T4N1M0 prostate adenocarcinoma treated with curative-intent EBRT and concomitant ADT between January 2004 and December 2016. Those who received a total radiation dose of at least 60 Gy were included in the analysis to encompass both moderately hypofractionated and standard fractionated schedules and to exclude incomplete or palliative courses of radiation. Those patients with unknown tumor stage or who underwent surgery, brachytherapy, chemotherapy, or immunotherapy were excluded. Men who initiated ADT more than 1 year before or after the start of radiation were excluded. Patients whose radiation therapy was delivered at multiple places or whose facility information was unknown were also excluded.

Defining High-vs Low-Treatment Volume Facilities
Before applying exclusion and inclusion criteria, all facilities delivering prostate radiation therapy were included in our initial analysis, and the number of prostate radiation cases for each facility per year was calculated. Given that a facility's radiation patient volume can vary from year to year, a cumulative facility volume was defined as the total number of radiation cases at an individual patient's treatment facility from 2004 until the year of that patient's diagnosis. This cumulative facility volume, specific to each patient, was then divided by the total number of years that the facility reported to the NCDB until that patient's year of diagnosis. This was subsequently defined as the average cumulative facility volume (ACFV) for that individual patient. Therefore, the ACFV was defined at the level of the patient and represents the experience level of the treating facility at the time that specific patient received treatment. It is therefore possible for patients treated at the same facility to be included as treated at either a high-ACFV center or low-ACFV center based on that individual's year of diagnosis and that particular facility's case volume per year leading up to that patient's treatment. In the final analysis data, the nonlinear association between continuous ACFV and OS was visualized in a Martingale residual plot (eFigure in the Supplement), in which the Martingale residuals were estimated from the Cox proportional hazard model and then plotted against ACFV by local linear regression curve. The optimal ACFV cutoff point that maximizes the separation between the 2 groups (high vs low ACFV) was identified via a bias adjusted log-rank test. 21 This method enabled the estimation and evaluation of the significance of the cutoff value while controlling for the bias created by the data-driven searching process.

Statistical Analysis
Descriptive statistics were used to present baseline characteristics. Covariates included facility type (academic vs nonacademic), age at diagnosis, race, primary payer, residential median income, education level, Charlson-Deyo comorbidity score, T stage, Gleason score, PSA level, total radiation dose, year of diagnosis, and distance to treatment center. Analysis of variance and χ 2 test were used to compare clinical and demographic characteristics between high-volume and low-volume facilities.
The primary end point was OS, defined as months from the date of diagnosis to the date of death or last follow-up. Kaplan-Meier curves with and without propensity score-based adjustment using inverse probability score weighting (IPSW) were used to compare OS between those treated at highvolume and low-volume facilities. All measured covariates were used to generate the propensity score. In the propensity score-weighted cohort, the balance of covariates between groups was evaluated by the standardized differences, and a value of less than 0.1 was considered a negligible imbalance. Multivariable Cox proportional hazards, which were built by backward variable selection procedure with an α Ն .05 removal criteria, were used to compare OS between those who were treated at high-volume vs low-volume facilities. Proportional hazards assumptions were tested using Kolmogorov-type supremum test and were not violated. All analyses were computed using SAS  Table 1.
Compared with low-ACFV centers, high-ACFV centers were more likely to be academic or race, Charlson-Deyo Score, year of diagnosis, and PSA did not differ between patients treated at high-and low-ACFV facilities. There was no difference between time from diagnosis to initiating ADT

JAMA Network Open | Oncology
Radiation Facility Volume and Survival in Men With Lymph Node-Positive Prostate Cancer After IPSW adjustment, all baseline characteristics were distributed evenly, with an absolute standard difference of less than 0.1 between the high-and low-ACFV centers (eAppendix in the Supplement).

Discussion
The management of N1 prostate cancer has historically been controversial, but despite lack of randomized trials investigating the role of aggressive local treatment, recent guidelines 8 have included the addition of pelvic EBRT with long-term ADT as the preferred treatment option. Several retrospective analyses have shown a significantly higher rate of failure-free survival or OS in patients who received EBRT in addition to ADT that support the recent inclusion of EBRT in the treatment algorithm. [22][23][24][25] For example, post hoc analysis of the STAMPEDE trial 22 showed that the addition of EBRT in patients with N1 prostate cancer resulted in an approximate 50% reduction in risk of failure at a median 1.5-year follow-up compared with systemic therapy alone. Population-based analyses  for advanced molecular imaging for men with N1 prostate cancer and subsequently treating elective pelvic lymph node basins with dose escalation to positron emission tomography (PET)-avid lymph nodes in addition to the prostate. 29 Nodal dose escalation is highly variable in the absence of defined clinical trial protocols, and typically it is acceptable to treat patients with as high as dose-volume histogram parameters and normal tissue tolerance (eg, bowel, bladder, and rectum) allow. With advanced treatment delivery platforms, such as volumetric arc therapy (VMAT) with image-guidance (IGRT), in conjunction with physics and dosimetry expertise, this is often accomplished via a simultaneous integrated boost to involved lymph nodes while delivering lower doses to uninvolved obturator and the internal/external iliac chain. The technique and dose is ultimately left to the discretion of the treating radiation oncologist; it is plausible that physicians at high-volume centers with VMAT and IGRT capabilities may feel more comfortable delivering higher doses to targets (ie, involved lymph nodes, prostate, seminal vesicles) despite the higher risk of complications associated with it. While the details of treatment techniques are unavailable in the NCDB, a greater percentage of men received a 74 Gy or greater boost at high-volume than low-volume centers. The NCDB does not provide details on whether the cumulative boost doses was to the prostate with or without radiographic lymph nodes; however, it is possible that dose escalation to all sites of gross disease is beneficial for long-term cancer control.
There are other aspects of care at high-volume centers, outside of radiation treatment and not quantifiable in the NCDB, that may explain the higher long-term survival rate seen in men with N1 prostate cancer. For one, high-volume facilities may harbor optimal multidisciplinary care in the same hospital and center. Treatment of patients with advanced prostate cancer requires close collaboration between urologists, radiation oncologists, medical oncologists, radiologists, and pathologists. 30 Each member of this complex team contributes to timely diagnosis, optimal staging, early initiation of therapy, and posttreatment surveillance. It is plausible that high-volume centers more often have closer collaboration and workflows between these disciplines, including the establishment of multidisciplinary clinics and tumor boards. Second, high-volume centers may more However, we believe OS is the criterion standard end point in men with N1 prostate cancer given the advanced nature of the disease with a high likelihood of distant metastatic progression and death.
Third, toxic effects and quality-of-life measurements are unavailable in the NCDB and could not be assessed; it is plausible that the improved survival at high-volume centers is associated with more aggressive therapy and subsequent worse acute toxic effects and quality of life. Fourth, some important details regarding systemic therapy are lacking in the NCDB. Specifically, duration of ADT, which could affect long-term outcomes, is unavailable and could not be accounted for. Additionally, details regarding chemotherapy use, including type of agent and number of cycles, are unavailable; therefore, we excluded patients who received any chemotherapy to avoid additional unmeasured treatment confounders, given that different chemotherapy drugs can have variable cytotoxic effects in prostate cancer. But chemotherapy may be associated with OS in this population, and studies that can include specific details regarding the chemotherapy regimen provided to men with N1 prostate cancer are warranted. Fifth, given the retrospective design using a population-based database, analyses are subject to selection biases and imbalances in unmeasured variables. While multivariate modeling and propensity score matching including all available clinical factors associated with prostate cancer outcomes were accounted for, some data unavailable in the NCDB, such as radiographic size or number of involved lymph nodes, were unable to be accounted for and could affect outcomes.

Conclusions
N1 prostate cancer is a complex disease entity with the potential for long-term disease control with aggressive management. This study found that for men with N1 prostate cancer, treatment at a facility with high radiation case volume, independent of academic affiliation, was associated with longer OS. Considering that definitive EBRT with ADT is an increasingly preferred treatment option for these men, our results are hypothesis-generating, and further studies should focus on identifying which factors unique to high-volume centers may be responsible for this benefit.