expert roundtables

Monitoring Progression and Response to Prostate Cancer Therapy: A Composite Model

by Glen Gejerman, MD, Daniel J. George, MD, William K. Oh, MD, and Oliver Sartor, MD MD, FACS

Overview

The availability of new therapeutic options for the treatment of advanced prostate cancer has underscored the importance of dedicated monitoring and assessment of individual treatment responses. Accordingly, there is an unmet clinical need for reliable biomarkers and other tools that can be used to guide therapeutic decision making. Experts discuss some of the challenges associated with monitoring a patient’s response to treatment, also describing 3 distinct windows of observation in a composite model of patient evaluation.

Q:

What issues are in play regarding the monitoring of clinical response/disease progression in patients with advanced prostate cancer?

Expert Commentary

Oliver Sartor, MD

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

The patient’s pace and the volume of the disease will dictate in part how we monitor him. I explain to patients that there are 3 key things I’m paying attention to when I see patients with prostate cancer: the patients, the scans, and the biochemical markers. First, the individual patients: how do they feel, and how are they functioning? Are they having side effects from the drugs? This is very important to assess in addition to the disease. If patients are having symptoms from the disease, is it a focal symptom, a systemic symptom (something more like fatigue, malaise, dysgeusia, or weight loss), or is something like a focal bone pain? One of the things we can often do in this sort of segregation of systematic progression and focal progression is use a little radiation to help clean up 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. The patient is really the most important issue. Then there are the scans and chemical markers. For biochemical markers, everyone knows about prostate-specific antigen (PSA), but there are other parameters that are very important. I look at the lactate dehydrogenase (LDH), alkaline phosphatase (ALP), and certainly hemoglobin (HGB). If we’re giving therapies that may alter the hematologic profile, we have to follow the complete blood count (CBC). There is a whole series of laboratory tests that I request, along with the scans. Bone scans and computed tomography (CT) scans are sort of the stock in trade, if you will, with additional specialized scans if there’s a particular need. It is important to assess these patients over time from a clinical, biochemical, and radiographic perspective. That’s how I do it, but there’s a lot of individualization and a context as well depending on the type of drug being used at any given time.

"It is important to assess patients over time from a clinical, biochemical, and radiographic perspective."

Oliver Sartor, MD, Medical Oncology

Glen Gejerman, MD

Co-Director, Urologic Oncology
Medical Director, TomoTherapy
John Theurer Cancer Center
Hackensack, NJ

I agree with that. We’re seeing a paradigm shift now, and we’re probably ahead of ourselves in terms of level 1 evidence. For example, a lot of the trials looking at adjuvant or salvage radiotherapy from the Eastern Cooperative Oncology Group and Southwest Oncology Group use standard forms of PSA, not ultrasensitive PSA. When we see patients who come in with very, very low but rising levels of PSA, the question is, do we consider that a time to intervene with pelvic radiotherapy? We’re going to have to wait for the long-term results of the RADICALS (Radiotherapy and Androgen Deprivation in Combination After Local Surgery) trial to answer that question, but that’s something that clinicians struggle with today. For metastatic prostate cancer, the newer scans are changing how we look at the disease process, whether it’s sodium fluoride (NaF) positron emission tomography (PET)/CT or C11-choline or C11-acetate scans, which are not that widely available. At centers that are using it, it’s really forcing clinicians to ask questions about how some of the original studies were performed. For example, I see many patients after a prostatectomy. I’ll get a C11 study and see some uptake in the lymph nodes. The question is, when we’re treating with pelvic radiotherapy, do we want to cover the total nodal bed, even if patients had very good lymph node dissection? These are questions we have to struggle with now. We can also use these newer studies where we have castrate resistance in early intervention. We talked about radium-223. Do we want to start looking at NaF scans that will pick up bone disease earlier, disease that might be missed on standard bone scan? Would we have a greater impact on the patient’s overall disease-free survival and then palliation? That’s a question that still has to be answered, but some of the smaller studies are showing the utility of NaF PET in that scenario.

“When we see patients who come in with very, very low but rising levels of PSA, the question is, do we consider that a time to intervene with pelvic radiotherapy?”

Glen Gejerman, MD, Radiation Oncology

Daniel J. George, MD

Professor of Medicine and Surgery
Divisions of Medical Oncology and Urology
Director, Genitourinary Oncology
Duke Cancer Institute
Duke University Medical Center
Durham, NC

I want to be a little bit careful about the new agents. They’re very much unproven. Early recurrence after localized disease is a different clinical setting, but when we get into advanced castrate-resistant disease, it’s a tremendously heterogeneous biology. It’s probably going to be difficult for a single study, particularly a molecular imaging study, to characterize the full extent of the disease burden. I favor the paradigm that Dr Sartor has suggested: a multifactorial paradigm looking at clinical biomarkers, as well as potentially investigational markers and imaging. It will have to be some mix to characterize that late-stage burden of disease, and this is where we’ve made probably the least amount of progress in the last 10 years. If we look at our prostate cancer working group, 1, 2, and 3 renditions, they’re not that different. In the Prostate Cancer Clinical Trials Working Group 3 (PCWG3) paper that just came out, the big change was the term “no longer clinically benefitting.” That’s where we are. How humbling is it that the term we use now for when it’s time to change therapy is when there is “no longer clinical benefit seen”? It’s that vague, and it’s going to be difficult to construct any one study covering that. But I do think this sort of composite model is where we have to go.

"I favor the paradigm that Dr Sartor has suggested: a multifactorial paradigm looking at clinical biomarkers, as well as potentially investigational markers and imaging.”

Daniel J. George, MD, Medical Oncology

William K. Oh, MD

Chief Medical Science Officer, Sema4
Clinical Professor of Medicine
Division of Hematology and Medical Oncology
Icahn School of Medicine at Mount Sinai
New York, NY

In many ways, this has set the field back. For the average oncologists who are seeing these patients, we do not have a good way of conveying to them how to assess the value or effectiveness of a treatment. So we have to do what Dr Sartor does. All clinicians in this field use a combination of factors, including PSA (even though we try to get away from PSA), imaging (which has been really flawed, particularly bone scans, in that it’s very hard to monitor these patients with some of the traditional available imaging), and also, obviously, symptoms. But symptoms can be very tricky. For instance, if the patient’s feeling more tired on primary androgen-deprivation therapy, is that more progression or is that just the side effect of the treatment itself? We struggled after our original efforts to better characterize how patients are progressing in clinical trials to translate that into what a doctor does, facing a patient in any given moment. For instance, his PSA is rising really slowly on a drug like abiraterone, he’s feeling fatigued, and his scans look about the same: should he continue on abiraterone or not? Those are extremely difficult questions to answer. Even though we all make choices, they’re not always based on the best level of evidence. What we really want to do, and I think we all struggle with this, is to get the greatest value out of each treatment to maximize both survival benefit and quality of life. In the end, we wind up individualizing therapy. We’re looking for better imaging tests and better biomarkers. We’re trying not to rely only on PSA, and we’re trying to give patients the benefits suggested by the studies that we do have, with certain drugs such as sipuleucel-T or radium-223 that improve overall survival. But benefits may not be visible to the patient in terms of PSA while we’re actually giving him the treatment. His PSA may be going up, and he may still have some symptoms from the cancer. Yet, what we’re trying to do is give him the maximal benefit, let’s say with radium, finishing the course so that, as the studies suggest, he will live longer. So, it would really be good for us if we had simpler biomarkers. Right now, we’re still basically “stuck” with our clinical judgment, based on the factors that Dr Sartor brought up at the beginning of this conversation.

“If the patient’s feeling more tired on primary androgen-deprivation therapy, is that more progression or is that just the side effect of the treatment itself?”

William K. Oh, MD, Medical Oncology

One thing that people have been wondering about is the use of androgen receptor (AR) splice variant, AR-V7. This came out in a paper in The New England Journal of Medicine a couple of years ago. There was quite a lot of momentum around the possibility that we could select our patients who express this variant AR and best decide whether they should or should not receive a drug like abiraterone or enzalutamide. Unfortunately, the science behind the AR-V7 story has been a little bit confusing. We saw a recent abstract at the American Society of Clinical Oncology Genitourinary Cancers Symposium that suggested that not just AR-V7 but actually full-length AR in the circulating tumor cells (CTCs) also predicted a short response to AR-targeted therapies. In fact, the more full-length AR in the CTCs, the less likely they were to respond. It’s a bit of a confusing story. Not only that, but the ability of an average oncologist to actually access this test has been quite limited. Unfortunately, I think we’ve moved a little bit past that particular test. In case some people are wondering, there will be a commercial test available sometime later this year from Epic Biosciences, but I believe most of us have actually just gone to trying these drugs empirically. Sometimes the biomarkers have to be available right when we need them.

References

Radiation and androgen deprivation in combination after local surgery (RADICALS). http://www.radicals-trial.org. Accessed June 3, 2017.

Scher HI, Morris MJ, Stadler WM, et al. 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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