expert roundtables

Beyond Pain Palliation: Considerations in Therapeutic Layering

by E. David Crawford, MD, Daniel J. George, MD, and Oliver Sartor, MD

Overview

Symptoms, including pain, are important indicators of disease progression in patients with metastatic castration-resistant prostate cancer (mCRPC). With scant level-1 evidence that speaks to comparative and sequential treatment concepts, panelists discuss rationales for earlier use of the various approved agents, weighing data from clinical trials showing improved outcomes such as overall survival and quality of life, in addition to pain reduction.

Q:

What are your thoughts on treatment goals for patients with advanced disease who may already be symptomatic?

Oliver Sartor, MD

C. E. and Bernadine Laborde Professor of Cancer Research
Medical Director, Tulane Cancer Center
Assistant Dean for Oncology
Tulane University School of Medicine
New Orleans, LA

If patients are having symptoms from the disease, one will assess whether or not those are focal symptoms, like bone pain, or systemic symptoms, like fatigue, malaise, dysgeusia, and weight loss. One of the things we can often do in this sort of segregation of systematic progression and focal progression is to use a little radiation to help clean up our focal problems. Sometimes that gets overlooked, and it’s quite easy. There are a lot of data now on external beam radiation therapy for bone metastases, where we can just give a single fraction and actually have substantial palliation. Now, with respect to mCRPC, what’s interesting is that, in some ways, the field is somewhat of a victim of its own success. We’ve had so much progress with abiraterone, enzalutamide, cabazitaxel, radium-223, and sipuleucel-T—and all of this occurring recently over the last decade. When we look at the level-1 evidence we have, there is a lot of it; however, we have very little in the way of comparative studies and very little in the way of sequential concepts that we’ve tested prospectively. It really is a little bit of a conundrum.

With respect to mCRPC, what’s interesting is that, in some ways, the field is somewhat of a victim of its own success.

Oliver Sartor, MD

E. David Crawford, MD

Professor of Surgery and Radiation Oncology
Head, Section of Urologic Oncology
University of Colorado
Denver School of Medicine
Denver, CO

Agreed. When somebody presents with mCRPC, it opens up the door for all these newer drugs. So, how do you layer them? Well, there are some really good data to support layering with more than just one agent. Sipuleucel-T, if you get that in early, we’ve shown that if your PSA is less than about 20 ng/mL, then you have a 13-month survival benefit. And one can add abiraterone to that; and one can add enzalutamide to that, and you can start compounding these benefits. Radium-223 is unique: it’s an alpha particle, which is very large, and it’s the only radiopharmaceutical to show an improvement in survival rate in mCRPC, and it’s not just for patients who are writhing in bone pain at the end of the line. The FDA approval for radium-223 is not simply to reduce pain, but it’s also for bone disease and improving outcomes, so it should be utilized earlier. So, there is a lot of excitement right now about these new drugs. Survival rates for advanced and castration-resistant disease are increasing significantly. I may be an optimist, but one day, with all these new drugs, maybe we would be able to convert this to a chronic disease, like diabetes and heart disease—we don’t cure it, but we treat and manage it. And I think that is something that could come to fruition in not too long a period of time. 

The FDA approval for radium-223 is not simply to reduce pain, but it’s also for bone disease and improving outcomes, so it should be utilized earlier.

E. David Crawford, MD

Daniel J. George, MD

Professor of Medicine and Surgery
Director, Genitourinary Oncology
Duke Cancer Institute Durham,
North Carolina

I think that sometimes we can get lulled into a sense of patients having stable disease because the kinetics of disease progression can be subtle, and this is true in practice and even in our clinical trial populations. It’s because of this subtlety that sometimes drugs like radium-223 or chemotherapy may in some cases be unfortunately used very late. It doesn’t dawn on the clinician that the patient is really dying from their cancer until they’re hit over the head with a 20- or 30-lb weight loss, or a need for palliative radiation to multiple sites, or for narcotics, etc. At that point, the patient generally has about 6 months to live, and there’s really not a proper opportunity in there to administer palliative chemotherapy or the full course of radium-223. 

I agree with not overscanning and the benefits of watching, but this is where the patient’s history and the doctor-patient discussion are so critical. It isn’t necessarily going to be one more spot on the bone scan that’s going to tell me the patient is progressing, but perhaps the patient’s symptoms and functional status (ie, a change in functional status or in the patient’s ability to continue to stay as active as usual). Those are the things we tend not to pick up on very well. Very few of us use that sort of serial, longitudinal, patient-reported outcomes type of tool, yet that may be a more sensitive way of picking up sudden changes that suggest the need to move on to the next therapy, or to add agents like radium-223 early enough to get through all 6 cycles of therapy. This a very critical piece, and it’s one of the areas in which we’re still coming up short in the field, and even I catch myself sometimes being late with these therapies. So, it’s hard, even for people who see a lot of prostate cancer. I can imagine for the clinician who doesn’t see the patient regularly, it’s even more difficult to know when to switch. 

I agree with not overscanning and the benefits of watching, but this is where the patient’s history and the doctor-patient discussion are so critical.

Daniel J. George, MD

References

Crawford ED, Petrylak DP, Shore N, et al. The role of therapeutic layering in optimizing treatment for patients with castration-resistant prostate cancer (prostate cancer radiographic assessments for detection of advanced recurrence II). Urology. 2017;104:150-159.

Heidenreich A, Bastian PJ, Bellmunt J, et al. EAU guidelines on prostate cancer. Part II: treatment of advanced, relapsing, and castration-resistant prostate cancer. Eur Urol. 2014;65(2):467-479.

Heinrich D, Bektic J, Bergman AM, et al. The contemporary use of radium-223 in metastatic castration-resistant prostate cancer. Clin Genitourin Cancer. 2017 Sep 6. pii: S1558-7673(17)30275-6. doi: 10.1016/j.clgc.2017.08.020. [Epub ahead of print].

Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med 2013;369(3):213-223.

Saad F, Carles J, Gillessen S, et al. Radium-223 and concomitant therapies in patients with metastatic castration-resistant prostate cancer: an international, early access, open-label, single-arm phase 3b trial. Lancet Oncol. 2016;17(9):1306-1316.

Sartor O, Coleman RE, Nilsson S, et al. An exploratory analysis of alkaline phosphatase, lactate dehydrogenase, and prostate-specific antigen dynamics in the phase 3 ALSYMPCA trial with radium-223. Ann Oncol. 2017;28(5):1090-1097.

Schellhammer PF, Chodak G, Whitmore JB, Sims R, Frohlich MW, Kantoff PW. Lower baseline prostate-specific antigen is associated with a greater overall survival benefit from sipuleucel-T in the Immunotherapy for Prostate Adenocarcinoma Treatment (IMPACT) trial. Urology. 2013;81(6):1297-1302.

Scher HI, Morris MJ, Stadler WM, et al; Prostate Cancer Clinical Trials Working Group 3. Trial design and objectives for castration-resistant prostate cancer: updated recommendations from the Prostate Cancer Clinical Trials Working Group 3. J Clin Oncol. 2016;34(12):1402-1418.

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