Last year, I met a patient with metastatic prostate cancer. He was in the hospital with severe bone disease, and I was working with a resident involved in his care. Before we entered the patient’s room, the resident turned to me. “Remember what you’re about to see,” she said.
And I still do. The room was dark when we entered, the patient alone. We asked if he wanted the lights on; he groaned that he did not. I remember how meager and brittle his body seemed and how he lay perfectly motionless as we spoke. When we asked to examine him, his face knotted up, as if simply the thought of changing position was too heavy a burden to bear.
When metastatic prostate cancer spreads to the bone, the effects can be devastating. Many patients, like the one I helped care for, struggle with uncontrolled, unrelenting pain. Others suffer pathologic fractures and increasing disability. And most men with such advanced disease will die from it
These profound costs underscore the need for better treatment options. They also make the findings reported in this week’s NEJM particularly exciting: treating bone metastases with radium-223 dichloride, a radioactive isotope, can significantly improve survival and quality of life for patients with metastatic castration-resistant prostate cancer.
Radium-223 is an alpha emitter; it works by emitting high-energy radiation that induces DNA breaks, killing cells in its path. It also naturally seeks out bone — specifically, areas of high bone turnover. Radium-223 treatment can be administered as a simple intravenous infusion. The combination of being toxic, targeted, and easy to use makes it an attractive candidate for treating bone metastases.
This was the basis for the Alpharadin in Symptomatic Prostate Cancer Patients (ALSYMPCA) study, a large phase III double-blind study conducted between 2008 and 2011 across nearly 20 countries. The study randomly assigned over 900 patients, in a 2:1 ratio, to receive either six injections of radium-223 or matching placebo. The primary endpoint was overall survival, while secondary endpoints included time to first symptomatic skeletal event and other indicators of disease progression.
The study found that treatment with radium-223 significantly prolonged survival. Median survival among patients in the treatment arm was 14.9 months, as compared to 11.3 months in the placebo group, representing a 30.5% reduction in the risk of death (HR 0.70, P<0.001). All secondary efficacy endpoints also pointed to the benefits of treatment with radium-223. For example, time to the first symptomatic skeletal event was significantly longer (median 15.6 months, versus 9.8 months with placebo; P<0.001).
With these functional benefits, quality of life also improved. More patients in the treatment arm had a meaningful improvement in quality of life — as measured by a Functional Assessment of Cancer Therapy-Prostate (FACT-P) total score — when compared to patients in the control group (25% versus 16%; P=0.02).
Importantly, treatment with radium-223 was not only effective but also safe. There were no clinically meaningful differences between the treatment and control groups in the frequency of adverse events. This was true for both hematologic and non-hematologic events and across all grades of event severity.
From a public safety standpoint, radium-223 offers comfort as well. Its half-life is approximately 11 days, so it decays fairly quickly into stable compounds that can be discarded like ordinary waste. This means that many of the safety concerns historically associated with radium — in particular radium-226, the isotope that Marie Curie isolated, which has a half-life of over 1600 years and decays into volatile radon gas — don’t apply to the use of radium-223.
The ALSYMPCA study was stopped early given the observed safety and efficacy of radium-223 treatment. The results are highly encouraging for clinical practice. For patients who are too frail or unwilling to undergo chemotherapy, radium-223 represents a much-needed treatment alternative that is simple and easily tolerated.
In an accompanying editorial, Drs. Neha Vapiwala and Eli Glatstein of the Department of Radiation Oncology at the University of Pennsylvania write: “Radium-223 will both complement and contend with existing therapies. While its most appropriate ‘fit’ is actively investigated, the first-line role of taxanes in metastatic castration-resistant prostate cancer may be reexamined and the viability of alpha particles in medicine may be newly explored 115 years after their discovery.”
NEJM Deputy Editor Dr. Dan Longo states: “This new radionuclide is ideal for targeting osteoblastic metastases. The radium mimics calcium and the alpha emissions act over a short distance, limiting collateral tissue damage. This is a welcome new tool in the arsenal for control of pain from prostate cancer bone lesions.”
When I think of the metastatic prostate cancer patient whose suffering I saw last year, I remember how consuming his pain was, how its presence filled the room. I also remember how defeated he seemed. By providing a better way to treat bone metastases, radium-223 may give patients like him a reason to be hopeful. The treatment cannot stop the cancer, but it makes the patient more comfortable so that his extended life has greater value.
What is your current treatment algorithm for patients with skeletal involvement of metastatic prostate cancer? How do you manage patients who cannot or elect not to receive chemotherapy? How do you anticipate your practice changing given the findings of the ALSYMPCA study?
View the NEJM Quick Take, an animated overview of the ALSYMPCA study.