Originally published 2/1/2018
There are two broad categories of metastatic prostate cancer: a) androgen deprivation therapy (ADT, often called chemical castration) is still putting the brakes on the cancer, so this is called metastatic castration-sensitive prostate cancer (mCSPC); and b) the ADT brakes can no longer control the cancer, so this is called metastatic castration-resistant prostate cancer (mCRPC). At the time we posted the blog below, radium-223 had become a standard of care for prolonging survival when a patient had mCRPC mets to the bone only. Results of numerous studies since then have continued to demonstrated improved survival as well as reduced bone pain. For example, a paper published in Jan. 2022 reported on a series of 133 patients, including low-, intermediate- and high-risk cases, whose mCRPC bone mets were treated with radium-223. Those who were low risk had an average of 23 months overall survival, compared with 8- and 5-month averages for the intermediate- and high-risk patients, respectively. The authors suggest a need to study earlier administration of the isotope.[i] Previously, Dandapani et al. (2020) pointed out that radium-223 is now being studied for administration much earlier in the timeline of the disease, when the bone mets are still castration-sensitive, but this is still investigational.[ii] Reasons for caution in earlier administration of the intravenous radiopharmaceutical may include that its impact on a patient’s immune system and the microenvironment of the bone is not yet fully understood.[iii] Nevertheless, patients with mCRPC bone mets stand to gain longer life and better quality of life from standard-of-care treatment with radium-223.
It is always thrilling when a treatment is working so well in a clinical trial that the study ends early and the FDA moves rapidly with approval. This was the case with a clinical study called ALSYMPCA (Alpharadin in Symptomatic Prostate Cancer Patients). The purpose of this Phase III trial was to compare the effectiveness of a promising radioisotope with that of a placebo in controlling prostate cancer that had spread to the bones, and to track survival.
Prostate cancer bone mets
When prostate cancer spreads to the bones, it is no longer able to be cured. Instead, therapies are aimed at controlling/reducing the bone lesions, preventing or slowing further cancer spread, strengthening bone, and managing pain. Treatments include chemotherapy, bone-strengthening drug protocols, fracture repair, and surgery or ablation (minimally invasive tumor destruction) as indicated.
Isotopes are elements that emit radiation. Certain isotopes have been used successfully with prostate cancer bone mets to control pain, improve quality of life, and to a lesser extent prolong survival. These include Strontium-89, Samarium-153, and Rhenium.
A more recent entry into the field is Radium-223 which has unique clinical properties.[iv] Because it selectively seeks bone and bone formation, it binds with prostate cancer’s tumor-forming activity. Radium-223 emits high-energy alpha-particle radiation that has a toxic effect on the DNA of tumor cells. The path of the radioactive particles (alpha particles) emitted by Radium-223 is extremely short, so there is little-to-no effect on neighboring healthy tissues.
The ALSYMPCA study
The ALSYMPCA study began enrolling patients in 2008, the goal being to enroll 900 prostate cancer patients with bone mets but no other identified metastases. The study was carried out at 136 centers in 19 countries. On a 2-to-1 ratio, participants would be randomly assigned to receive either six intravenous injections of Radium-223 (one every 4 weeks) or to receive a placebo (whatever the current standard for managing prostate cancer bone mets at each center). Ultimately, 921 men were enrolled, and of that group, 614 received Radium-223 and 307 received placebo. Each patient was scheduled to be followed for three years, meaning that the those who entered the study in 2011 would be followed until 2014.
However, a remarkable thing occurred. An analysis of 809 cases conducted while the trial was still continuing (an interim analysis) found that that the Radium-223 therapy “was associated with significantly prolonged overall survival compared with placebo…”[v] The investigators recommended closing the trial, and allowing the placebo patients to cross over and receive the Radium-223 protocol. On May 15, 2013 the U.S. Food and Drug Administration (FDA) expedited approval for Radium-223 for the treatment of prostate cancer bone mets that are causing symptoms.
A subsequent follow-up analysis confirmed that significant extension of survival for Radium-223 patients. Furthermore, there were fewer study related adverse events for Radium-223 than for the placebo treatments, and patients who received the isotope reported higher quality of life scores based on standardized questionnaires.
When the interim results were published, an accompanying editorial (Vapiwala & Gatstein, 2013) noted that the study “imparts some long-awaited momentum to research on the use of alpha emitters and shows an overall survival advantage with a compound that is safe and manageable for both patients and providers. Radium-223 will both complement and contend with existing therapies.”[vi]
Since the ALSYMPCA trial was closed, a surge of published studies and articles has occurred as Radium-223 is incorporated into treatments for prostate cancer bone mets. Since 2016 alone, 21 papers have already appeared. The ALSYMPCA study turned a dramatic page in the chapter on treating a difficult condition. Physicians and patients will undoubtedly continue to see improvements and advances based on this isotope, alone or in combination with other therapies.
NOTE: This content is solely for purposes of information and does not substitute for diagnostic or medical advice. Talk to your doctor if you are experiencing pelvic pain, or have any other health concerns or questions of a personal medical nature.
[i] Charrois-Durand C, Saad F, Barkati M, Lattouf JB, Perrotte P et al. A single-center, multidisciplinary experience with radium-223 dichloride in men with metastatic castrate-resistant prostate cancer. Can Urol Assoc J. 2022 Jan 27.
[ii] Dandapani SV, Wong J, Twardowski P. Review of Radium-223 and Metastatic Castration-Sensitive Prostate Cancer. Cancer Biother Radiopharm. 2020 Sep;35(7):490-496
[iii] Dorff TB, Stein C, Kortylewski M, Posadas E et al. Evaluating Changes in Immune Function and Bone Microenvironment During Radium-223 Treatment of Patients with Castration-Resistant Prostate Cancer. Cancer Biother Radiopharm. 2020 Sep;35(7):485-489.
[iv] Raval A, Dan TD, Williams N, Pridjian A, Den R. Radioisotopes in management of metastatic prostate cancerIndian J Urol. 2016 Oct-Dec; 32(4): 277–281.
[vi] Vapiwala N, Glatstein E. Fighting prostate cancer with Radium-223—not your madame’s isotope. N Engl J Med. 2013 July 18;369:276-78.