Intermittent vs Continuous ADT for Patients A Review of the NCCN Guidelines – Christopher Wallis and Zachary Klaassen

September 13, 2021

Christopher Wallis and Zachary Klaassen review the  NCCN clinical practice guidelines on prostate cancer. This discussion is the third part of their discussion of androgen deprivation therapy (ADT). Dr. Wallis begins this discussion with a conversation on intermittent vs continuous ADT for patients with prostate cancer. He examines the quality of life in conjunction with survival measurements. About halfway through the conversation, Dr. Klaassen takes over to discuss the risks of traditional ADT and its adverse effects. Dr. Klaassen takes a moment to discuss recent studies showing a potential associated cognitive decline with ADT. This conversation concludes with a discussion on how the panel believes that intermittent ADT should be strongly considered.

Biographies:

Christopher J.D. Wallis, MD, Ph.D., Assistant Professor in the Division of Urology at the University of Toronto

Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor Surgery/Urology at the Medical College of Georgia at Augusta University, Georgia Cancer Center


Read the Full Video Transcript

Christopher Wallis: Hello and thank you for joining us for this UroToday discussion of the NCCN Clinical Practice Guidelines in Oncology with a focus on the prostate cancer guidelines from February 2021. This is the third part of our discussion of androgen deprivation therapy. I'm Chris Wallis, an Assistant Professor in the Division of Urology at the University of Toronto. With me today is Zach Klaassen, Assistant Professor in the Division of Urology at the Medical College in Georgia. Within the NCCN prostate cancer guidelines, the chapter on ADT has six components. The first three of these were discussed in part one of our discussion. Part four was discussed in part two of our discussion and now we are going to discuss parts five and six in this third talk.

So we will first focus on the question of intermittent versus continuous ADT for patients with prostate cancer. And the rationale for intermittent ADT is based on a balance of the toxicity and oncologic benefits. And as most will know, ADT is associated with substantial side effects, and notably these increase with increasing duration of therapy. So the use of intermittent ADT in which cycles of ADT are used with re-exposure may both delay androgen independence providing an oncologic benefit, but more importantly, reduced treatment morbidity and improved quality of life. Such an approach, however, requires close monitoring of both PSA and testosterone levels and of the patient's clinical status.

So this is the PR-7 trial looking at the role of intermittent ADT in non-metastatic disease. This trial enrolled patients who had biochemical recurrence after either primary or salvage external beam radiotherapy and to be eligible for inclusions, patients had to have PSA's of at least three nanograms per milliliter. As you can see in this Kaplan-Meier curve, the hazard ratio for overall survival shows superimposition of the curves for both continuous and intermittent with a non-inferiority P-value of 0.009.

Notably, when we look at investigator-reported causes of death in the intention to treat population, there are some differences between the groups. When we look at prostate cancer-related deaths, these are somewhat less common in patients receiving continuous therapy, however other causes of death unrelated to prostate cancer are more common in those receiving continuous therapy, supporting the overall rationale that intermittent therapy may reduce morbidity and here even the mortality associated with the toxicity of ADT.

When we consider the goal of improving the quality of life, the NCCN guideline panel [inaudible 00:02:59] says, "Being modestly improved with the use of intermittent therapy, although we see statistically significant benefits in terms of hot flashes, sexual desire, and urinary symptoms with marginal improvements in fatigue." In post hoc analyses, we see that patients with high-grade disease had a suggestion of longer overall survival when receiving continuous ADT, although the guidelines panel notes that this is a hypothesis-generating rather than a conclusive finding.

When we look at the meta-analysis of these data, we see here, a meta-analysis of six randomized controlled trials. And when we are considering mortality rates, the pooled result indicates near interchangeable findings for the two approaches. And so the conclusion is that there is no difference in overall mortality or in disease progression, although when we look at toxicity, there are demonstrated improvements in quality of life, as well as lower adverse events and lower costs for patients receiving intermittent therapy.

We can then consider this approach in the metastatic setting. This is the SWOG trial led by Dr. Hussain. Hussain enrolled patients with metastatic disease and all patients received an initial seven months of induction ADT. Patients who had a PSA, which declined to at least four nanograms per milliliter or less subsequently were randomized to ongoing continuous therapy or an intermittent approach. As you can see on the right of this Kaplan-Meier curve, the curves are relatively similar for the first few years with a slight separation later. The hazard ratio here is 1.10 with a confidence interval of 0.99 to 1.23. Now the pre-specified upper boundary of the confidence interval for non-inferiority was 1.20. Thus, the interpretation of this hazard ratio is that we can neither conclude superiority nor non-inferiority. And as a result, this is a statistically inconclusive result.

The authors found, when we look at the quality of life outcomes, that there is better erectile function early on, and in fact, which then dissipated and interestingly found similar rates of endocrine, bone, and cognitive related events between the two groups with worse ischemic and thrombotic events in the intermittent arms. A post hoc stratification by disease extent showed that in patients with minimal disease, the absolute survival for patients receiving intermittent therapy is 5.4 years versus 6.9 years when receiving continuous therapy. When we look at extensive disease, these absolute differences were smaller, 4.9 in the internment arm and 4.4 in the continuous arm.

So when we look at the overall conclusion, considering additional observational data as well as meta-analysis, the panel believes that intermittent ADT should be strongly considered for patients starting on androgen deprivation. A subsequent go on is to suggest a personalized approach to this that all patients with metastatic disease should be started on ADT when clinically indicated. After six months of ADT, patients can then be stratified according to their PSA response, with a PSA less than 0.2 nanograms per milliliter, being at low risk with a relatively long projected median survival. Those with PSA's between 0.2 and four form in the intermediate-risk group. And those with PSA's greater than four comprising the high-risk group.

For those who have minimal toxicity from their ADT at seven months, there is a minimal potential to benefit from an intermittent approach, and as such continuous therapy may be advocated on the basis of the potential for oncologic benefits. However, those who have significant toxicity may actually benefit from an intermittent approach due to the quality of life gains to be offered. And this should be therefore considered in patients who have lower intermediate-risk disease, given the higher oncologic risk in patients with high-risk disease.

At this point in time, I'm now going to hand it over to Zach to walk us through the NCCN guideline panels assessment of the risks of traditional ADT and their adverse effects.

Zachary Klaassen: Thanks Chris. So as you can see on this list, ADT is associated with several adverse effects and this includes hot flashes, vasomotor instability, loss of libido, erectile dysfunction, penile testicular shrinkage, loss of muscle mass and strength, fatigue, anemia, breast enlargement, and tenderness, depression and mood swings, hair loss, osteoporosis, clinical fractures, obesity, insulin resistance, dyslipidemia, diabetes, acute kidney injury, and cardiovascular disease. Importantly, several studies recently have looked at the potential associated with cognitive decline and dementia associated with ADT.

So looking at these adverse events, intensity and spectrum do vary greatly and for men on continuous ADT, side effects increase with prolonged duration. However, the risks may also vary based on ADT formulations and for example, relugolix, which is an oral GnRH antagonist, may help with alleviating some of these adverse events. Many of these adverse events are reversible and can be avoided or mitigated and as we discuss with our patients in the clinic routinely, physical activity may counter many of the side effects of ADT.

Bone health is important during ADT as ADT is known to be associated with an increased risk of osteoporosis and fracture. In a number of population-based studies, the fracture risk may be as high as 21% to 54% with increased fracture risk associated with increasing duration of ADT, older age, and increased comorbidities. In this study published in JAMA oncology by Maxine Sun and colleagues, they looked at orchiectomy versus medical ADT and found that the fracture risk was lower among patients with surgical castration with a hazard ratio of 0.77 and a 95% confidence interval of 0.62 to 0.94. Mechanistically ADT increases the bone turnover and decreases bone mineral density with a bone mineral density decrease of 2.3% during the initial ADT therapy and continued decline over prolonged use of ADT. Additionally, ADT decreases muscle mass and leads to an increased risk of falls.

So the panel recommends, with regards to bone health and ADT, that there should be screening and treatment of osteoporosis according to the general population, which includes bone mineral density testing at baseline, calcium and vitamin D supplementation, and additional treatment if low bone mass or if there is an increased risk of fracture among these patients. So the treatment for bone health may include bisphosphonates, which increase directly bone mineral density, as well as denosumab, which is a RANK-L inhibitor, which increases bone mineral density and has been shown to decrease the risk of fractures. Additional treatments include an additional denosumab or zoledronic acid at five milligrams, IV annually, or alendronate at 70 milligrams PO weekly.

For the remaining slides, we will talk about diabetes and cardiovascular disease as they pertain to ADT. In this study from the Journal of Clinical Oncology from several years ago, they looked at the adjusted hazard ratios for diabetes, coronary artery disease, and myocardial infarction. And we can see here that when we look at diabetes with the reference arm being no treatment, we can see that GnRH agonists increased the incidence of diabetes with a hazard ratio of 1.44. Similarly, so does orchiectomy. So surgical castration also increases diabetes with a hazard ratio of 1.34. Looking at coronary artery disease, GnRH agonists increase the incidence of coronary heart disease with a hazard ratio of 1.16. However, interestingly, orchiectomy did not increase the risk of coronary artery disease. And finally looking at myocardial infarction, GnRH agonists also increased the risk of MI with a hazard ratio of 1.11, whereas orchiectomy, similar to coronary artery disease, did not increase the risk of MI.

However, data on whether these increases in cardiovascular risk factors translate to cardiovascular mortality is mixed. Data on ADT formulations are also similarly mixed where some data shows that LHRH agonists and antagonists are similar. Another study shows that LHRH antagonists are associated with a lower risk of cardiac events among those with cardiovascular risk factors.

In terms of mechanistically, ADT increases fat mass and decreases lean body mass.  GnRH agonists increased fasting insulin and decreased insulin sensitivity, and ADT increases serum cholesterol and triglycerides. So in context, we know that cardiovascular disease and diabetes are leading causes of morbidity and mortality in this population, including prostate cancer patients, and screening and interventions are recommended among those men that are treated with ADT. However, whether these should differ from the general population in terms of frequency is unclear at this point in time.

So in conclusion from this discussion of ADT in the NCCN guidelines, the panel believes that intermittent ADT should be strongly considered, as well as ADT is associated with a variety of adverse events, which patients must be counseled about in the clinic in terms of their ability to mitigate and reverse these adverse events.  And included in the discussion with each clinic visit, that physical activity may encounter many of the adverse events that we've previously discussed.

Thank you very much and we hope you enjoyed this NCCN discussion of ADT looking at intermittent versus continuous as well as side effects associated with ADT.
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