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The Effect of Radium-223 Therapy in Agent Orange-Related Prostate Carcinoma

Federal Practitioner. 2020 December;37(12)a:570-575 | 10.12788/fp.0062
November 6, 2020|AVAHO
Andrew Liman, MD;Rashmikant Shah, MD;Vida Passero, MD;Jocelyn Tan, MD;Hema Rai, MD;Laurie Harrold, MD;Joyce Tokarsky, CNS;Agnes Liman, MD;Vidhi Gupta, MD;Kristina Gerszten, MD
Author and Disclosure Information

Andrew Liman is Section Chief, Hematology/Oncology and Agnes Liman is a Staff Physician, Pathology and Laboratory Medicine, both at VA Central California Health Care System in Fresno. Vida Passero is Section Chief; Laurie Harrold, Jocelyn Tan, and Hema Rai are Staff Physicians; Joyce Tokarsky is a Staff Nurse Practitioner, all in the Hematology/Oncology section at VA Pittsburgh Health Care System in Pennsylvania. Rashmikant Shah, Kristina Gerszten, and Vidhi Gupta are Staff Physicians in the Radiology section at VA Pittsburgh Health Care System, Pennsylvania. at VA Central California Health Care System in Fresno. Andrew Liman is an Assistant Clinical Professor of Medicine at the University of California San Francisco at Fresno. Vida Passero, Laurie Harrold, Jocelyn Tan, and Hema Rai are Assistant Clinical Professors of Medicine at the University of Pittsburgh Cancer Institute in Pennsylvania.
Correspondence: Andrew Liman (andrew.liman@va.gov)

 

Author disclosures
A poster was presented at ESMO (European Society of Medical Oncology) meeting in Singapore, November 22-24, 2019. An abstract was published in Annals of Oncology, 30 (suppl 9), November 2019. The authors report no actual or potential conflicts of interest with regard to this article.

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The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the US Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Background: Radium-223 (Ra-223) radioisotope has been reported to increase median survival in bone metastatic prostate carcinoma. The addition of Ra-223 to abiraterone was associated with an increased risk of bone fractures. There has been no comprehensive data for using Ra-223 in veterans who were exposed to Agent Orange (AO+).

M ethods: We present a retrospective study of veterans with bone metastatic castration-resistant prostate cancer (CRPC) who received standard doses of Ra-223 and other sequential therapies at US Department of Veterans Affairs Pittsburgh Healthcare System in Pennsylvania from 2014 to 2018. Veterans were divided into 2 groups: those who were exposed to Agent Orange (AO+) and those who had no exposure (AO-). Time to study was calculated from the initiation of Ra-223. Time to skeletal-related events (SRE), progression of prostate specific antigen (PSA), bone metastasis, and alkaline phosphatase (ALP) were calculated in months using unpaired t test with 2-tailed P values. Median survival was calculated by Kaplan Meier R log-rank test.

Results: There were 34 veterans with bone metastatic CRPC: 17 veterans (50%) were AO+ and 17 veterans (50%) were AO-. The mean age of diagnosis of AO+ veterans was 62 years and 69 years ( P = .005) for AO- veterans (the mean Gleason score 8.2 and 8.0, respectively [ P = .71]). The median number of Ra-223 cycles was 6 (60%). Ten veterans received Ra-223 as first line (29%) and 24 veterans received Ra-223 later (71%). There were 12 SREs with median survival of 15 months. There was no difference in mean time to SRE between AO+ (8 veterans, 10.6 months) and AO- (4 veterans, 10.3 months) ( P = .93). The mean time to PSA progression for AO+ was 5.4 months and AO- was 6.8 months ( P = .28). Mean time to bone progression for AO+ was 7.6 months and AO- was 10.1 months ( P = .16). Mean time to ALP progression for AO+ and AO- was 6.3 months and 8.7 months, respectively ( P = .05). Twenty veterans (58%) had died. Median survival for Ra-223 first was 32 months and for Ra-223 later was 15 months ( P = .14; hazard ratio [HR] 0.48; 95% CI, 0.17- 1.3). Median survival for AO+ and AO- veterans was 12 months and 18 months, respectively ( P = .15; HR, 2.0; 95% CI, 0.77-5.0).

Conclusions: There was no statistical difference between AO+ and AO- veterans in terms of time to SRE, PSA, bone and ALP progression, even though there was a trend of shorter duration in AO+ veterans. There was no median survival difference between Ra-223 first vs Ra-223 later as well as between AO+ and AO- but there is a trend of worse survival in AO+ veterans.

Ansbaugh and colleagues reported that AO was associated with a 75% increase in the risk of Gleason ≥ 7 and a 110% increase in Gleason ≥ 8. AO+ veterans are at risk for the detection of high-grade prostate carcinoma. They also tend to have an average age of diagnosis that is 4 to 5 years younger than AO- veterans.6

Our study revealed that AO+ veterans were diagnosed at a younger age (mean 62 years) compared with that of AO- veterans (mean 69 years, P = .005). We also proved that AO veterans have a higher mean Gleason score (8.2) compared with that of AO- veterans (8.0). Veterans received therapy at the time of diagnosis of prostate carcinoma with either radical prostatectomy, radiation therapy, or ADT with leuprolide acetate. Mean PSA at the start of Ra-223 therapy for AO+ was 92.8 (range, 2-551); for AO- was 102.3 (range, 4-639), which is not statistically significant.

Ra-223, an α-emitting radiopharmaceutical, mimics calcium in forming complexes with the bone mineral hydroxyapatite, which specifically targets bone metastases. Ra-223 preferentially targets new bone growth surrounding bone metastases while emitting α particles within the tumor microenvironment. α particles have high linear energy transfer with enhanced ability to induce lethal double-stranded DNA breaks, thus eliciting greater cytotoxic effects on bone-metastatic tumor sites.7

In a phase 3, randomized, double-blind, placebo-controlled study by Parker and colleagues (ALSYMPCA study), 921 patients who had received, were not eligible to receive, or declined docetaxel, in a 2:1 ratio, were randomized to receive 6 injections of Ra-223 or matching placebo.2 Ra-223 significantly improved overall survival (OS) (median, 14.9 months vs 11.3 months) compared with that of placebo. Ra-223 also prolonged the time to the first symptomatic SRE (median, 15.6 months vs 9.8 months), the time to an increase in the total ALP level (median 7.4 months vs 3.8 months), and the time to an increase in the PSA level (median 3.6 months vs 3.4 months).2

In our study, the mean time to SRE for AO+ was 10.6 months and AO- was 10.3 months (P = .93). Mean time to PSA progression for AO+ was 5.4 months and for AO- was 6.8 months (P = .28). Mean time to bone progression for AO+ and for AO- were 7.6 months and 10.1 months respectively (P = .16). Mean time to ALP progression for AO+ and AO- were 6.3 months and 8.7 months respectively (P = .05). There is a trend of shorter PSA progression, bone progression, and ALP progression in AO+ veterans, though these were not statistically significant due to small sample population. In our study the median survival in for AO- was 18 months and for AO+ was 12 months, which is comparable with median survival of 14.9 months from the ALSYMPCA study.

There were 12 veterans who developed SREs. All received radiation therapy due to bone progression or impending fracture. AO+ veterans developed more SREs (n = 8) when compared with AO- veterans (n = 4). There were more AO- veterans alive (n = 10) than there were AO+ veterans (n = 4). The plausible explanation of this may be due to the aggressive pattern of prostate carcinoma in AO+ veterans (younger age and higher Gleason score).

VAPHS participated in the ERA trial between 2014 and 2016. The trial enrolled 806 patients who were randomly assigned to receive first-line Ra-223 or placebo in addition to abiraterone acetate plus prednisone.3 The study was unblinded prematurely after more fractures and deaths were noted in the Ra-223 and abiraterone group than there were in the placebo and abiraterone group. Median symptomatic SRE was 22.3 months in the Ra-223 group and 26.0 months in the placebo group. Fractures (any grade) occurred in 29% in the Ra-223 group and 11% in the placebo group. It was suggested that Ra-223 could contribute to the risk of osteoporotic fractures in patients with bone metastatic prostate carcinoma. Median OS was 30.7 months in the Ra-223 group and 33.3 months in the placebo group.3

We enrolled 3 veterans in the ERA clinical trial. Two AO+ veterans had SREs at 7 months and 11 months. In our study, the median OS for Ra-223 first line was 32 months, which is comparable with median survival of 30.7 months from ERA-223 study. Median survival for Ra-223 later was only 15 months. We recommend veterans with at least 2 to 3-bone metastasis receive Ra-223 in the first-line setting rather than second- or third-line setting. In this retrospective study with Ra-223 and other therapies, we proved that AO+ veterans have a worse response and OS when compared with that of AO- veterans.

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