As the subtleties of metastatic prostate cancer become increasingly recognized, treatment should evolve accordingly, said Jessica M. Clement, MD, Assistant Professor of Medicine at the University of Connecticut Health System and Neag Cancer Center, Farmington. Of particular interest to Dr. Clement is oligometastatic hormone-sensitive prostate cancer, which was the topic of her recent article in the Journal of Oncology Practice (JOP).1 The ASCO Post explored the topic further in an interview with Dr. Clement.
Focus on Earlier-Stage Disease
Why were you interested in writing about oligometastatic hormone-sensitive prostate cancer?
The reason we are thinking more about the optimal treatment of hormone-sensitive prostate cancer stems from the findings by Sweeney et al, where the early addition of docetaxel for patients with high-volume disease resulted in a big difference in overall survival.2 We’re now starting to look more carefully at how we treat all patients with prostate cancer. So far, the focus has been on castrate-resistant disease, but perhaps we should be turning our attention to an earlier clinical state of hormone-sensitive disease.
Ongoing studies are evaluating combination therapy to help elucidate the role of each separately and together, to determine the optimal interventions in this population.— Jessica M. Clement, MD
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The big question we want to answer for our patients with oligometastatic hormone-sensitive disease is whether by being more aggressive up front, we can improve outcomes. Improving survival is the number one goal in cancer care, but the other thing we could improve upon is quality of life for these men. Perhaps with targeted therapy for oligometastatic lesions, we could reduce the use, or delay the time to initiation, of androgen-deprivation therapy. Occasionally, we need to think outside the box, and ask whether there’s another way to care for this subset of patients.
How do you define “oligometastasis”?
In 1995, Hellman and Weichselbaum postulated that oligometastatic disease was a disease state that possibly reflects a time point in the malignant process that may be amenable to local therapies3; this intervention could potentially allow for patients to achieve a durable response or possible cure, despite having advanced disease. Presently, there are variable definitions of oligometastatic disease, with some proposing up to three lesions and others proposing up to five lesions.4,5 Most agree, however, that the definition requires the lesions be amenable to therapy directed at the metastases. This would be with either stereotactic body radiation therapy or surgical resection.
Overtreatment or Undertreatment?
Have we been overtreating these patients?
The truth is that we don’t know. We are always concerned about overtreatment in prostate cancer (ie, prostatectomies), especially in early-stage localized disease, low-volume disease, and disease with low Gleason scores. When we look at patients with oligometastatic disease, it’s unclear. There’s the possibility we are overtreating a lot of people, but there’s also the possibility we are undertreating a group of men and therefore missing the opportunity to provide durable responses by more aggressive upfront treatment.
As with most cancers, the optimal treatment of prostate cancer relies on multimodal therapy. This approach is becoming increasingly clear for those with oligometastatic disease, with emerging data suggesting benefit from local ablative therapies to the lesions combined with androgen-deprivation therapy. But the optimal approach is still under investigation.
Understanding -Disease Biology
You mentioned in your article in JOP that the biology of oligometastatic disease may be unique. Can you elaborate?
All metastatic disease may not be the same, and this is something we have to sort out. There has been a premise that patients with low-volume or oligometastatic disease often have a longer natural history as a result of less aggressive biology, and this results in an improved clinical course as compared with men with more extensive metastases with or without aggressive treatment. But we have historically treated all metastatic patients the same—with hormonal therapy, across the board. Now, we also give chemotherapy for high-volume disease and have impacted outcomes positively; perhaps if we tackle low-volume disease more aggressively, we may be able to interrupt the progression of disease and improve outcomes as well.
What’s the optimal means of identifying oligometastatic disease?
The identification of oligometastatic hormone-sensitive prostate cancer should be based on standard, validated imaging modalities. Presently, they include nuclear bone scan and computed tomography (CT) of the abdomen and pelvis. Magnetic resonance imaging (MRI) may also be used. Although not considered standards of care, choline-11 positron-emission tomography (PET), prostate-specific membrane antigen PET, and sodium fluoride PET are used in some instances and are clearly more effective than conventional imaging. The use of newer modalities might help us more accurately identify these patients.
To help guide treatment decisions, we also look at PSA [prostate specific antigen] doubling time, number of metastatic lesions, and presence or absence of visceral disease. We think patients with fewer metastatic lesions, and metastases limited to lymph node or bone, may be the patients to evaluate for ablative therapies.
Evaluating New Approaches
What is your own approach to optimal approach to oligometastatic disease?
My approach is rooted in the current standard of care: androgen-deprivation therapy. Based on the retrospective data for treating oligometastatic disease that I’ve described in the JOP article, in select cases, after discussing these data with patients who wished to be aggressive with treatment in the setting of oligometastatic disease, we have done radiation therapy for isolated bone metastases in conjunction with androgen-deprivation therapy. My preference is to refer to clinical trials in this situation if at all possible.
But we need prospective clinical trials to evaluate new treatment approaches, and they are being conducted (see Table 1 in JOP article1). Meanwhile, using standard imaging modalities, we can identify men with what we define as low-volume or oligometastatic disease. They have fewer lesions, and we can target them by radiotherapy or surgery. This is the discussion I have with my patients—whether to add these local therapies to systemic therapy and possibly delay disease progression and improve outcomes.
I think these local approaches will have an impact, but we will need to rely on clinical trials to determine this. Ongoing studies are evaluating combination therapy to help elucidate the role of each separately and together, to determine the optimal interventions in this population.
I would like to highlight two important phase II trials. One is the randomized STOMP trial, which is evaluating the role of metastasis-directed therapy with either surgery or stereotactic body radiation therapy in oligometastatic recurrence after local therapy, compared with active surveillance (ClinicalTrials.gov Identifier NCT01558427). The other study, which is assessing the best systemic therapy with or without radiation therapy or surgery in patients with metastatic prostate cancer (ClinicalTrials.gov Identifier NCT01751438), is recruiting patients. I encourage clinicians to enroll patients on these trials.
Any final thoughts?
I would tell clinicians to stay tuned for the results of clinical trials. The treatment of metastatic prostate cancer in the hormone-sensitive setting was stagnant until the recent addition of docetaxel for patients with high-volume disease. That changed how we treat these patients, but now we need to look further at this other population with low-volume disease and reevaluate how we treat them. We need results of these prospective phase II studies, and we have to remain open-minded. Clinical trials will provide some answers. ■
Disclosure: Dr. Clement reported no conflicts of interest.
4. Ost P, Jereczek-Fossa BA, As NV, et al: Progression-free survival following stereotactic body radiotherapy for oligometastatic prostate cancer treatment-naive recurrence: A multi-institutional analysis. Eur Urol 69:9-12, 2016.