Abstract
BACKGROUND:
Whole pelvic radiation therapy (WPRT) may improve outcomes compared to prostate only radiation therapy (PORT) in some subsets of men with prostate cancer, as in the POP-RT trial. However, there is concern about increased risk of adverse effects with WPRT, including the development of radiation-induced second malignancies (SM). Given the rarity of SM, little is known about relative rates of SM between WPRT and PORT.
METHODS:
A retrospective cohort analysis was performed of men with nonmetastatic, node-negative prostate cancer with at least 60 months of follow-up using a national database. SM probabilities were compared in men receiving either WPRT or PORT using multivariable logistic models adjusting for clinical and sociodemographic factors. Temporal sensitivity analyses stratified by year of diagnosis and length of follow-up were also conducted.
RESULTS:
Of 50237 patients in the study, 39338 (78.4%) received PORT, and 10899 (21.7%) received WPRT. Median follow up was 106.2 months (IQR 82.32 – 132.25). Crude probabilities of SM were 9.16% for WPRT and 8.88% for PORT. The adjusted odds ratio (AOR) for development of SM with PORT vs. WPRT was 1.046 (95%CI 0.968 – 1.130). Temporal sensitivity analyses by stratifying by year of diagnosis and follow-up length also did not demonstrate any significant difference in rates of SM between WPRT and PORT using AORs with WPRT as the referent.
CONCLUSIONS:
Retrospective analysis of over 50000 patients did not demonstrate an association between WPRT and an increased probability of SM compared to PORT. Given the findings of POP-RT, the use of WPRT may become widespread for certain subsets of men. Thus, our findings could help guide how we counsel patients deciding between WPRT and PORT, and suggests need for prospective assessment of SM risk with WPRT and PORT.
Introduction
Significant controversy surrounds the inclusion of pelvic lymph nodes in the treatment of prostate cancer(1-4). Studies comparing whole pelvis radiation therapy (WPRT) to prostate only radiation therapy (PORT) have published contradicting findings regarding the superiority of either WPRT or PORT in various patient groups, leaving the inclusion of pelvic lymph nodes to the discretion of the treating physician. The recent POP-RT trial, however, demonstrated that in patients with high-risk, non-metastatic and node-negative prostate cancer, WPRT has a significant benefit in biochemical failure-free survival (BFFS) and disease-free survival (DFS) compared to PORT (5). This carries significant implications for the treatment of select groups of men with prostate cancer.
However, the higher radiation dose and larger treatment volume used in WPRT raise concerns about the increased risk of side effects, including the development of radiation-induced second malignancies (SM), a critical but relatively uncommon sequela of radiation therapy (6-9). Compared to radical prostatectomy (RP), which is estimated to have a 15% biochemical recurrence rate (10) but no theoretical risk of radiation-induced SM, several studies have found that radiation therapies are associated with increased rates of various SMs. One such study suggests that the relative risk of developing bladder cancer after external beam radiotherapy (EBRT) and brachytherapy are 1.88 and 1.52 compared to RP (6), while another found that EBRT was associated with an increased absolute rate of bladder, lung, and rectal cancers of 3.9%, 5.2%, and 2.4% respectively (7). Of note, when analyses were limited to patients who developed SM 10+ years after radiation therapy, EBRT was associated with an increase lung cancer diagnosis rates only.
Evidence about the relative probability of SM in men receiving WPRT versus PORT is limited but may inform treatment decisions. To address this question, we compared the probability of SM among men with prostate cancer receiving WPRT versus PORT in a large national database.
Methods
Patient Population
We performed a retrospective cohort study of men with nonmetastatic, node-negative prostate cancer from the 2004-2017 National Cancer Database (NCDB), a nationwide hospital-based cancer registry sponsored by ACS and American College of Surgeons that captures 70% of new cancer diagnoses. We excluded men with <60 months of follow up from diagnosis since diagnosis (diagnosed after 2014) since they were unlikely to have developed a radiation induced SM in that timeframe. Prostate cancer risk group was categorized based on NCCN risk stratification: low risk (Gleason 6, prostate specific antigen [PSA] < 10ng/mL, and cT1-T2a), intermediate risk (Gleason 7, PSA 10-2 ng/mL, or cT2b-T2c), or high risk (Gleason 8-10, PSA > 20 ng/mL, or cT3-T4).
Definition of treatments and outcomes
All patients in this study received 75 to 90 Gy of photon-based intensity-modulated radiation therapy (IMRT) to either the whole prostate with or without seminal vesicles or to a portion of the prostate. Patients were categorized as receiving WPRT if they received a total phase I and II treatment involving 75 to 90 Gy, and phase I of their treatment involved at least 40 to 55 Gy to a treatment field including the draining lymph nodes (median 4500cGy, IQR 4500cGy – 5040cGy). Patients were categorized as receiving PORT if phase I of their treatment plan did not involve any radiation to draining lymph nodes. Patients who were treated with other treatment modalities including brachytherapy were excluded to optimize comparative study between WPRT and PORT only.
SM was defined using the variable indicating the sequence of malignancies over the lifetime of each patient, as used in previous studies (11,12). Patients coded as 0 indicated no subsequent second malignancy after first diagnosis, while 1 indicated the development of at least one additional subsequent primary, excluding cutaneous squamous and basal cell carcinomas. Other details regarding the second cancer are not available. Patients coded as 2 or greater indicated the presence of 2 or more independent malignant or in situ primaries. These patients (7.8%) were excluded from our analysis because the timing of SM relative to prostate radiation was indiscernible, thus introducing potential confounding variables.
Statistical Analysis
The means and frequencies for baseline demographic characteristics were calculated, then tabulated separately for men treated with WPRT and those treated with PORT. Baseline characteristics were compared using χ2 analysis for categorical variables and Kruskal-Wallis analysis for continuous variables. Crude rates of secondary malignancies for WPRT and PORT were calculated and compared using adjusted odds ratios (AOR) with 95% confidence intervals. AORs were defined by multivariable logistic regressions to account for potential confounding variables.
A primary multivariable logistic regression was conducted with binarized SM as the primary dependent variable of interest, adjusted for the following clinical and sociodemographic covariates provided by NCDB: Prostate cancer risk group, receipt of androgen deprivation therapy, race, ethnicity, Charlson-Deyo comorbidity score, year of diagnosis, treatment facility type, geographic region, urbanicity/rurality, distance from treatment facility, zip code-wide median household income, zip code-wide educational attainment, and insurance status. Temporal sensitivity analyses stratified by 1) year of diagnosis (2004 to 2007, 2008 to 2011, 2012 to 2014) and 2) length of follow-up (60 to <90 months, 90 to <120 months, ≥120 months) were conducted with WPRT as the referent group.
Analyses were performed with Stata/BE 17.0 (StataCorp, College Station, TX). The Dana-Farber/Harvard Cancer Center institutional review board deemed this study exempt from the need for review board approval because deidentified data were used.
Results
Of the 50237 men in our study, 79.7% were white and 16.3% Black, while 88.8% were non-Hispanic. The mean age of our sample was 68.8 years at diagnosis (SD 7.65, IQR 64.0 – 75.0). The median time of follow-up was 106.2 months (IQR 82.32 – 131.25). Overall, 39338 (78.4%) received PORT, and 10899 (21.7%) received WPRT. The characteristics of the WPRT and PORT groups are summarized in Table 1.
Table 1.
Baseline cohort characteristics based on treatment modality, whole pelvis radiation therapy (WPRT) or pelvis only radiation therapy (PORT).
| WPRT | PORT | p-value | |
|---|---|---|---|
| Total cohort | 10,899 | 39,338 | – |
| Second malignancy N (%) | 998 (9.16) | 3494 (8.88) | 0.374 |
| Median follow-up, months (IQR) | 100.01 (IQR 79.15-127.05) | 107.22 (IQR 82.83 - 131.25) | < 0.001 |
| Median age, years (IQR) | 70 (IQR 64-75) | 70 (IQR 64-74) | < 0.001 |
| Risk group | < 0.001 | ||
| Low risk | 1316 (12.07) | 11022 (28.02) | – |
| Intermediate risk | 4447 (40.80) | 19100 (48.55) | – |
| High risk | 5136 (47.12) | 9216 (23.43) | – |
| ADT | < 0.001 | ||
| No ADT | 3542 (32.50) | 21489 (54.63) | – |
| Had ADT | 7134 (65.46) | 16814 (42.75) | – |
| ADT unknown | 223 (2.05) | 1033 (2.63) | – |
| Race | < 0.001 | ||
| White | 8480 (77.81) | 31579 (80.28) | – |
| Black | 1929 (17.70) | 6266 (15.93) | – |
| Other | 490 (4.50) | 1493 (3.80) | – |
| Hispanic ethnicity | < 0.001 | ||
| Non-Hispanic | 9814 (90.04) | 34778 (88.41) | – |
| Hispanic | 407 (3.73) | 1714 (4.36) | – |
| Ethnicity unknown | 678 (6.22) | 2846 (7.23) | – |
| Charlson-Deyo comorbidity score | < 0.001 | ||
| 0 | 9298 (85.31) | 34410 (87.47) | – |
| 1 | 1317 (12.08) | 4024 (10.23) | – |
| 2 | 220 (2.02) | 695 (1.77) | – |
| ≥3 | 64 (0.59) | 209 (0.53) | – |
| Year | < 0.001 | ||
| 2004 to 2007 | 3216 (29.51) | 15136 (38.48) | – |
| 2008 to 2011 | 5469 (50.18) | 18462 (46.93) | – |
| 2012 to 2014 | 2214 (20.31) | 5740 (14.59) | – |
| Facility Type | < 0.001 | ||
| Community | 7054 (64.72) | 23276 (59.17) | – |
| Academic | 3845 (32.28) | 16.062 (40.83) | – |
| Region | < 0.001 | ||
| New England | 484 (4.44) | 3455 (8.78) | – |
| Middle Atlantic | 1894 (17.38) | 8791 (22.35) | – |
| South Atlantic | 2515 (23.08) | 8460 (21.51) | – |
| East North Central | 2703 (24.80) | 7366 (18.72) | – |
| East South Central | 541 (4.96) | 1637 (4.16) | – |
| West North Central | 794 (7.29) | 2742 (6.97) | – |
| West South Central | 459 (4.21) | 1778 (4.52) | – |
| Mountain | 292 (2.68) | 1028 (2.61) | – |
| Pacific | 1217 (11.17) | 4081 (10.37) | – |
| Urbanicity | < 0.001 | ||
| Metro | 9090 (83.40) | 33429 (84.98) | – |
| Urban | 1606 (14.74) | 5332 (13.55) | – |
| Rural | 203 (1.86) | 577 (1.47) | – |
| Distance | < 0.001 | ||
| 0 to <10mi | 6496 (59.60) | 24020 (61.06) | – |
| 10 to <20mi | 2339 (21.46) | 8369 (21.27) | – |
| 20 to <50mi | 1624 (14.90) | 5529 (14.06) | – |
| >=50mi | 440 (4.04) | 1420 (3.61) | – |
| Zip Code-Wide Median Household Income | < 0.001 | ||
| Less than $40,227 | 2227 (20.43) | 7522 (19.12) | – |
| $40,227 - $50,353 | 2489 (22.84) | 8465 (21.52) | – |
| $50,354 - $63,332 | 2554 (23.43) | 9299 (23.64) | – |
| $63,333 + | 3629 (33.30) | 14052 (35.72) | – |
| Insurance | < 0.001 | ||
| Private Insurance | 3063 (28.10) | 12204 (31.02) | – |
| Government | 7484 (68.67) | 26029 (66.17) | – |
| Uninsured | 184 (1.69) | 537 (1.37) | – |
| Unknown | 168 (1.54) | 568 (1.44) | – |
| Zip Code-Wide Percent without High School Education | < 0.001 | ||
| 17.6% or more | 2110 (19.36) | 7597 (19.31) | – |
| 10.9% to 17.5% | 3029 (27.79) | 9888 (25.14) | – |
| 6.3% to 10.8% | 3031 (27.81) | 11642 (29.59) | – |
| Less than 6.3% | 2729 (25.04) | 10211 (25.96) | – |
Crude probabilities of SM were 9.16% for WPRT and 8.88% for PORT (Figure 1). The AOR per primary multivariable logistic model for PORT was 1.046 (95%CI 0.968 – 1.130) with WPRT as the referent (Table 2). Temporal sensitivity analyses by stratifying by year of diagnosis and follow-up length also did not demonstrate any significant difference in rates of SM between WPRT and PORT using AORs with WPRT as the referent. Crude probabilities of SM between WPRT and PORT stratified by year of diagnosis and follow-up length are illustrated in Figure 2 and Figure 3 respectively. Subgroup analysis by year of diagnosis: 2004 to 2007 AOR 1.052, 95% CI 0.930 – 1.190, 2008 to 2011 AOR 1.081, 95%CI 0.966 – 1.210, 2012 to 2014 AOR 0.912, 95%CI 0.734 – 1.133 (Supplementary Table 1). Subgroup analysis by follow-up length: 60 to <90 months AOR 1.030, 95%CI 0.914 – 1.161, 90 to <120 months AOR 1.082, 95%CI CI 0.946 – 1.2369, ≥120 months AOR 1.046, 95%CI 0.893 – 1.225 (Supplementary Table 2).
Figure 1.
Second malignancies among men receiving whole prostate radiation therapy (WPRT) or pelvis only radiation therapy (PORT). The primary multivariable adjusted logistic regression model was used to predict reported probabilities; error bars represent 95% confidence intervals.
Table 2.
Adjusted odds ratios (AORs) and 95% confidence intervals (95% CI) comparing the odds of developing a second malignancy in patients treated with whole pelvic radiation therapy (WPRT) or pelvis only radiation therapy (PORT). AORs are calculated based on a multivariable logistic regression model.
| Treatment mode | AOR | 95% CI | 95% CI | P-value |
|---|---|---|---|---|
| WPRT | Ref | - | - | n/a |
| PORT | 1.046 | 0.968 | 1.130 | 0.252 |
| Year of diagnosis | ||||
| Year (continuous, 2014 ref) | 0.882 | 0.868 | 0.895 | 0.000 |
| Race | ||||
| White | Ref | - | - | n/a |
| Black | 0.854 | 0.773 | 0.943 | 0.002 |
| Other | 0.614 | 0.501 | 0.752 | 0.000 |
| Hispanic ethnicity | ||||
| Non-Hispanic | Ref | - | - | n/a |
| Hispanic | 0.704 | 0.586 | 0.846 | 0.000 |
| Ethnicity unknown | 0.579 | 0.501 | 0.670 | 0.000 |
| Insurance | ||||
| Private Insurance | Ref | - | - | n/a |
| Government | 1.134 | 1.046 | 1.229 | 0.002 |
| Uninsured | 1.146 | 0.862 | 1.524 | 0.349 |
| Unknown | 0.852 | 0.635 | 1.143 | 0.284 |
| Zip Code-Wide Percent without High School Education | ||||
| 117.6% or more | Ref | - | - | n/a |
| 10.9% to 17.5% | 0.991 | 0.895 | 1.096 | 0.857 |
| 6.3% to 10.8% | 0.980 | 0.876 | 1.096 | 0.719 |
| Less than 6.3% | 0.991 | 0.872 | 1.126 | 0.889 |
| Zip Code-Wide Median Household Income | ||||
| Less than $40,227 | Ref | - | - | n/a |
| $40,227 - $50,353 | 0.947 | 0.853 | 1.051 | 0.304 |
| $50,354 - $63,332 | 0.975 | 0.873 | 1.090 | 0.660 |
| $63,333 + | 0.917 | 0.809 | 1.039 | 0.173 |
| Charlson-Deyo comorbidity score | ||||
| 0 | Ref | - | - | n/a |
| 1 | 1.139 | 1.033 | 1.256 | 0.009 |
| 2 | 1.331 | 1.080 | 1.641 | 0.007 |
| ≥3 | 1.396 | 0.955 | 2.041 | 0.085 |
| Risk group | ||||
| Low risk | Ref | - | - | n/a |
| Intermediate risk | 1.088 | 1.002 | 1.182 | 0.045 |
| High risk | 1.022 | 0.924 | 1.129 | 0.678 |
| Facility Type | ||||
| Community | Ref | - | - | n/a |
| Academic | 0.929 | 0.869 | 0.994 | 0.033 |
| Region | ||||
| New England | Ref | - | - | n/a |
| Middle Atlantic | 0.922 | 0.811 | 1.047 | 0.210 |
| South Atlantic | 0.895 | 0.786 | 1.018 | 0.091 |
| East North Central | 1.034 | 0.909 | 1.176 | 0.613 |
| East South Central | 1.031 | 0.859 | 1.238 | 0.740 |
| West North Central | 1.099 | 0.939 | 1.286 | 0.240 |
| West South Central | 0.807 | 0.666 | 0.978 | 0.028 |
| Mountain | 0.991 | 0.796 | 1.235 | 0.938 |
| Pacific | 0.904 | 0.779 | 1.048 | 0.180 |
| Distance | ||||
| 0 to <10mi | Ref | - | - | n/a |
| 10 to <20mi | 0.950 | 0.877 | 1.029 | 0.208 |
| 20 to <50mi | 0.828 | 0.746 | 0.920 | 0.000 |
| >=50mi | 0.670 | 0.551 | 0.815 | 0.000 |
| ADT | ||||
| No ADT | Ref | - | - | n/a |
| Had ADT | 1.086 | 1.011 | 1.166 | 0.023 |
| ADT unknown | 0.866 | 0.699 | 1.073 | 0.187 |
| Age | ||||
| Age (continuous) | 1.017 | 1.012 | 1.022 | 0.000 |
| Urbanicity | ||||
| Metro | Ref | - | - | n/a |
| Urban | 1.114 | 1.003 | 1.237 | 0.043 |
| Rural | 1.637 | 1.293 | 2.073 | 0.000 |
| Follow-up time | ||||
| Months follow-up | 0.995 | 0.994 | 0.997 | 0.000 |
Figure 2.
Crude rates of secondary malignancies among men whole pelvis radiation therapy (WPRT) or pelvis only radiation therapy (PORT) upon on stratification by year of diagnosis. Error bars represent 95% confidence intervals. No significantly different adjusted odds ratio compared to WPRT.
Figure 3.
Crude rates of secondary malignancies among men whole pelvis radiation therapy (WPRT) or pelvis only radiation therapy (PORT) upon on stratification by length of follow-up. Error bars represent 95% confidence intervals. No significantly different adjusted odds ratio compared to WPRT.
Discussion
Our study fits into a wider debate about the inclusion of pelvic lymph nodes in radiation therapy of men with prostate cancer, which remains controversial: Prior studies such as GETUG-01 and RTOG 9413 showed no clear benefit to WPRT versus PORT in treatment of patients with intermediate-risk or high-risk localized prostate cancer.(2,13) However, the recent findings of POP-RT provided strong evidence for the use of WPRT in patients with high-risk, nonmetastatic and node-negative prostate cancer, demonstrating a significant increase in biochemical failure-free survival (BFFS), disease-free survival (DFS), and distant metastasis-free survival (DMFS) for men treated with WPRT compared to PORT (5).
There are ongoing trials evaluating various radiation techniques in the treatment of men with intermediate to high-risk prostate cancer, for whom inclusion of pelvic lymph nodes may be indicated. These include RTOG 0924, an open-labeled phase III trial comparing high-dose RT to the prostate and seminal vesicles (PORT) to WPRT in patients with high risk prostate cancer (4). However, if the findings of POP-RT are replicated and applied to clinical care, many more men with localized prostate cancer may be treated WPRT. Thus, it is crucial to understand the differences in potential side effects between WPRT and PORT.
That there is an increased risk of SM in patients receiving pelvic and/or prostate radiation has long been accepted (7,9,14,15). A more recent study demonstrated that the probability of SM after radiation therapy may differ by technique, including conventionally fractionated intensity-modulated radiotherapy (CF-IMRT), HF-IMRT, brachytherapy, and radiotherapy (12). This study found that HF-IMRT, CF-IMRT, and brachytherapy, but not SBRT, were associated with increased rates of SM compared to radical prostatectomy. Notably, this study did not look specifically at WPRT or PORT. Our study seeks to address this gap by demonstrating that despite the concern of increased toxicity with WPRT secondary to increased dose and field volume, the rates of SM did not significantly differ between WPRT and PORT in men with nonmetastatic, non-nodal prostate cancer.
Although a greater integral dose with WPRT may theoretically increase the risk of SM, it is possible that the relative increase from PORT to WPRT does not result in a clinically meaningful difference with regard to SM risk. RTOG 9413, a randomized study comparing PORT vs WPRT for patients with localized prostate cancer treated with non-IMRT techniques similarly found no significant difference in the risk of SM between these arms (2,16). Similar findings have been observed in the context of other cancer types. A comparison of SM rates with median follow-up of 13 years of the PORTEC-2 randomized study comparing vaginal brachytherapy versus pelvic EBRT for endometrial carcinoma identified no difference in risk of second cancer between treatments arms (17), and a large cohort analysis comparing patients who received local radiation versus locoregional radiation for breast cancer found no statistically significant increase in risk of SM with regional irradiation (18). While volume and field size effects have been demonstrated to impact SM risk for pediatric patients and young adults who receive radiotherapy such as in the context of Hodgkin’s lymphoma (19,20), it is not clear in the adult population that elective irradiation of nodal regions substantially increases this risk. Following prostate cancer treatment, the true additional risk of SM from radiation may be quite small when modern techniques are used (12), and that small risk may largely be driven by tumorigenesis in organs surrounding the high dose region near the prostate and seminal vesicles.
Of note, a recent study by D'Amico et al. found a nominally greater rate of SM in men who received RT to pelvic nodes, prostate, and seminal vesicles with ADT compared to men who underwent RT to prostate and seminal vesicles only, a finding that was not present in the cohort that received RT+ADT+docetaxel (21,22). It is possible that with more contemporary field sizes and modern radiation therapy planning techniques that there is a bigger difference between prostate only and pelvic field sizes that may contribute to RT-induced second cancer risk. Future studies will need to clarify in larger samples the association between radiation dose and treatment volumes in various cancer types and SM.
Limitations
Our study is limited by its retrospective nature, which increases risk of selection bias and confounding variables, and by the confines of the NCDB database, which does not include data on certain variables like family history, obesity, alcohol use, or smoking status, the latter of which is a known predictor of SM in men with prostate cancer treated with radiation therapy (23). Moreover, the NCDB database does not provide additional details about the site or etiology of any second malignancies (i.e., whether the tumor arises in a region that received radiation). However, the baseline demographic characteristics did not greatly differ between men treated with WPRT versus PORT, other than risk group, suggesting a similar baseline risk for radiation-induced SM, sporadic SM, and SM secondary to other unknown variables. For most patients, prostate risk group is not thought to be a risk factor for SM. Furthermore, the NCDB does not provide details about the timing of the second malignancy other than occurrence after the initial prostate cancer, obviating time-to-event analysis. Therefore, our reliance on relative odds (quantified by adjusted odds ratios) may contribute to the literature by describing relative but not absolute rates of SM for WPRT and PORT. With this limitation in mind, we excluded patients with <5 years follow-up as any SM that developed within that timeframe is not likely to be RT induced. This methodology has been used in prior studies of SM (11,12,24). Finally, a proportion of patients in the NCDB database have follow-up <10 years, limiting detection of SM, which can take 10-20+ years to develop. Sensitivity analysis by follow-up length, including >120 months, did not detect any differences in rates of SM.
Conclusion
Whole pelvis radiation therapy (WPRT) was not associated with an increased probability of second malignancies compared to pelvis only radiation therapy (PORT) in a sample of men with nonmetastatic, node-negative prostate cancer from a large national cancer database. Given the findings of POP-RT, the use of WPRT could become widespread for certain subsets of men with localized prostate cancer, especially if the findings of the ongoing RTOG 0924 trial suggest benefit with irradiation of pelvic lymph nodes. Thus, our finding that there is no significant difference in SM between WPRT and PORT could help guide how we counsel patients deciding between these radiation techniques.
Supplementary Material
Footnotes
Conflict of Interest Statement for All Authors: P.L.N. reported receiving grants and personal fees from Bayer, Janssen, and Astellas and personal fees from Boston Scientific, Dendreon, Ferring, COTA, Blue Earth Diagnostics, Myovant Sciences, and Augmenix unrelated to the submitted work. K.W.M.: research funding (Pfizer); consulting (EMD Serono/Pfizer); honoraria (UpToDate, OncLive). E.C.D. is funded in part through the Cancer Center Support Grant from the National Cancer Institute (P30 CA008748).
Availability of Data and Materials for this Work: Research data are available through the National Cancer Database at https://www.facs.org/quality-programs/cancer/ncdb.
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