femoral neck, although to a smaller extent; and the radius.

Transcription

1 Hi, my name is Farshid Dayyani. I m [an] assistant professor in Genitourinary Medical Oncology at The University of Texas MD Anderson Cancer Center. This is a talk on prostate cancer survivorship, examining the role of chemotherapy and androgendeprivation in prostate cancer. This is a two-part talk and that would be Part 2. One of the most important side effects associated with long-term androgen-deprivation and castration is the induction of bone loss. As we know from conditions such as osteoporosis in elderly, bone loss ree --- leads to an increased risk of fractures. And androgen-deprivation does reduce the bone marrow density, which corresponds to increased fracture risk. Serologic markers show that there is increase in bone turnover and we know that the duration of castration correlates with the actual fracture risk. But bone changes are observed as early as six months after initiation of androgendeprivation. And without treatment, one in five men on androgen-deprivation will have fractures because of secondary osteoporosis. The etiology of androgen-deprivation-induced bone loss is multifactorial. The major cause obviously is the primary purpose of androgen-deprivation and this is suppression of testosterone and hypogonadism. But contributing factors are tobacco abuse, ethanol abuse. Many of our patients with prostate cancer do receive glucocorticoids, specifically prednisone, for various reasons, such as pain palliation, but they also have a low dietary intake of calcium and vitamin D. And correlating with the fatigue that comes with ADT and other factors, they have a sedentary lifestyle which contributes to osteoporosis. Physicians treating patients with ADT should establish a pre-treatment bone mineral density, usually done by a DEXA scan, and then repeat as appropriate in regular intervals, which is usually done on an annual basis. The best treatment is prevention. And that affects lifestyle modifications that refer to the risk factors I mentioned before. Patients should be advised to do regular es --- exercise weight-bearing four to five times a week. If they are smoking, we should help them with smoking cessation programs. We should encourage them to reduce their ethanol and caffeine consumption and prescribe supplements for calcium and vitamin D to increase the dietary intake. In terms of pharmacologic treatment for ADT-induced osteoporosis, we have two classes of drugs available. Both of them inhibit osteoclasts. The more traditional one and longer available is treatment with bisphosphonates which go to the bone, bind to the --- certain residues in the bone, and inhibit osteoclasts from binding to the bone and resorbing it. Osteoclasts are the cells in the bone that do affect the degra --- degradation of bone. There have been several classes of bisphosphonates, PO and IV formats, and many of them have shown activity in men undergoing ADT in terms of preventing or even reversing bone loss. I will just quickly go through some of the more common ones. The oldest one, pamidronate, was compared with placebo in men who underwent LHRH agonist-

2 induced androgen sep --- supple --- suppression. Pamidronate was given every three months as a standard dose of 60 [mg], which is lower than we use for metastatic patients. Annual evaluation with DEXA scans and CTs and we saw 8.5% decrease in men who received androgen-deprivation alone. But there was no significant bone loss with pamidronate; therefore, actually preventing 8.5% decrease in bone loss. A more modern bisphosphonate that is more commonly used is zoledronic acid. This was given every three months at 4 mg, which is the standard dose, for up to a year. And with zoledronic acid, the bone marrow density actually increased by 5.6% in the treatment group. But as expected, with ADT alone, the bone marrow density decreased. Similar results, but with a less frequent regimen, which might be important because of toxicities of bisphosphonates, in --- in --- in --- in the first trial, Zo --- Zometa, or zoledronic acid, was given as a single dose to men with high-risk prostate cancer and a T score of less than 2.5. Those are the men at high --- highest risk for fractures. And after a year, intere --- int --- interestingly enough, the bone marrow density in those who were treated with Zometa, or zoledronic acid, had gone up by 4% but, again, as expected, decreased by 3.1% in the ADT alone group. For patients who do not like IV drugs, there is alendronate which is a pill that patients take once a week. And again, there is a randomized trial where alendronate was given on a weekly basis at the standard dose of 70 mg with ADT, compared to placebo. And we did saw [speaker intended to say see ] a modest but significant increase in bone marrow density in those patients who did receive alendronate, with a slight, but still sta --- statistically significant decrease in bone marrow density with androgen-deprivation. So these four trials taken together, various regimens, various doses, various frequencies, but altogether we can see that bisphosphonates at least prevent and in many cases increase bone marrow density when combine with androgen-deprivation. Important to know are the side effects and the adverse events of bisphosphonates. One of the very important ones, although not very common, is the osteonecrosis of the jaw. This is defined as open bone in the --- in the jaw that is healing very slowly. It s associated with dental procedures and has mainly been observed in patients who had tooth extractions while being treated with bob --- bisphosphonates. Therefore, dental health care is very important. And any major invasive procedures should be taken care of before the patients are initiated on bisphosphonates. Nephrotoxicity is well described, is dose-dependent, but also rate-dependent, meaning faster infusions of higher likelihood of inducing nephrotoxicity. And higher doses induce higher rates. For bisphosphonates, such aszole --- zoledronic acid, with good activity against ADTinduced bone loss, there are guidelines to adjust the dose based on the creatinine clearance and renal function so more patients are able to receive treatment. Based on the mechanism of action which is reducing bone resorption, the major reservoir for calcium in the body, one can easily see that one of the side effects of bisphosphonates is hypocalcemia, reduction in calcium ser --- serum calcium levels. So this should be followed very closely and repleted as needed. Sometimes with zoledronic acid, during the first 24 hours, the patient will have acute phase reactions that manifest with fever, chills, flu like symptoms. Those should be recognized and can be treated with symptomatically acetaminophen or NSAIDS.

3 Less or far less common toxicities that still should be recognized because they might be urgent are ocular toxicities such as conjunctivitis. The physician should be aware that the patient received bisphosphonates and needs to urgently refer him to Ophthalmology for treatment. Musculoskeletal pain delay --- is delayed, occurs later than the acute phase reactions and might go on and persist even after therapy is stopped. Treatment is symptomatically. Cardiovascular toxicities have been reported, such as atrial fibrillation. But given the rare occurrence as well as patients comorbidities, it is controversial whether they are actually induced by bisphosphonates. Denosumab is a newer agent, a newer class of agent that was introduced in the pre --- prevention of bone loss in men undergoing ADT. It is a humanized monoclonal antibody. And it principally binds to what is called a RANK ligand, the receptor activator of nuclear factor kappa B ligand. RANK ligand is one of the major regulators of osteoclast function and formation. As opposed to the bisphosphonates, denosumab was actually approved by the European Commission as well as the FDA to prevent bone loss in men with prostate cancer at risk for fractures. And this specifically means those undergoing androgen-deprivation therapy. Here, a cartoon to illustrate the mechanism of action. The bone-forming cells in the body, the osteoblasts, have a close interaction with the bone-resorbing cells, the osteoclasts, and this interaction is mainly mediated by RANK ligand that we already touched upon. RANK ligand goes and binds to receptors on the osteoclasts and induces their maturation and function. So denosumab, the way it works is binds these ligands here and prevents them from binding here to osteoclasts and activating them. There is a large published trial in non-metastatic prostate cancer in patients who were treated on --- with androgen-deprivation or orchiectomy. Patients were enrolled when they had a T-score of less than 1 which puts them at a higher risk for fractures. Denosumab was given at the lower dose of 60 mg every six months. Obviously, no bisphosphonates were allowed su --- such that there was no interference. And the primary endpoint was bone marrow density in the lumbar spine. This was clearly met in this trial. The treatment group with denosumab have a 5.6% increase in bone marrow density at year 1, whereas the placebo-treated patients had a decrease of minus 1%. More clinically important endpoint than --- than a bone marrow density loss is the actual occurrence of vertebral fractures. And those were also significantly less common in patients treated with denosumab, rather than the placebo. As a matter of fact, there was more than a two-fold increase in the placebo arm at year 3 in terms of cumulative incidence of vertebral fractures. I will illustrate that in --- in a few slides here. The primary endpoint shown here, the loss of bone marrow density seen with the control group over time in the lumbar spine, whereas we see a early and sustained benefit with denosumab up to three years follow-up. Other parameters such as total hip also showed the benefit femoral neck, although to a smaller extent; and the radius.

4 This graph shows that the endpoint of new vertebral fractures was significant over time with an early onset. Already at one year, we had an increase of about 2% in --- in the placebo-treated patients that went up to almost 4%. And the benefit was sustained over time with denosumab. The toxicities of denosumab are partially similar to those seen with bisphosphonates. Importantly, osteonecrosis of the jaw has been reported with the use of denosumab. Its occurrence is rare when given at the doses used to prevent bone loss, which is 60 mg every six months as SubQ injection. But at higher doses, when we use it for metastatic prostate cancer, which is 120 mg every four weeks, and especially in the head-to-head comparison with zoledronic acid, the occurrence was at least as high or maybe a little bit higher, around 1.5 to 2%. We will not discuss this further here because it s not part of the topic. Based on the pathology and the pathophysiology and the mechanism of action, we know osteoclast inhibition induces hypocalcemia. And therefore, treatment with denosumab also is associated with hypogly --- hypocalcemia. Calcium levels should be checked before treatment starts and regularly afterwards and corrected as needed. There is possibly an increase in the rate of infections because the RANK receptor is not only expressed on the osteoblast, but, also on a subset of immune cells such as B cells, T cells, and antigen-presenting dendritic cells. In the FREEDOM trial, which evaluated denosumab in postmenopausal women, there was about a four-fold increase in serious skin infections with denosumab, compared to placebo. Although as you can see, the absolute rates were fairly low at 0.4%. The larger already presented HALT trial in men of non-metastatic prostate cancer, the difference was not statistically significant. But numerically, there were more serious infections and urinary tract infections in those men treated with denosumab. One have to --- One has to realize that since the occurrence is so rare, it will be difficult to show statistical significance. But one should be at least aware of the increased risk possibility. The comparison of infection risk with bisphosphonates is inconclusive because of conflicting data and at this point we cannot make any definitive statements. Other possible concerns with antibody treatment would be neutralizing antibodies which would diminish the efficacy of the drug, but this risk is fairly low with denosumab since it is a humanized antibody. And in the large published trials that we already went over, there were no significant increases or detectable rates of neutralizing antibodies. As opposed to bisphosphonates, there is no contraindication for denosumab to be given in patients with impaired renal function. But the clinician should be aware that in patients with impaired renal function, the rate of hypocalcemia is higher, so there should be special attention given to calcium levels during the course of treatment. Less dangerous but more potentially aggravating side effects of androgen-deprivation are of endocrine nature. Vasomotor symptoms, such as hot flashes, they are defined as sudden onset of any of these or the combination of any of these symptoms, such as subjective increase in the body temperature, reddening of the skin, sweating, chills. It is

5 thought that interference with the hypothalamic thermoregulation leads to these changes in the body temperature. They can occur spontaneously or induced by specific triggers, for example, a cup of coffee or change in the environmental temperature. Up to 80% of the men are affected. But it is important to know that there is a wide range of severity and, therefore, the degree to which the quality of life is impaired is very varied between the men. Some --- Some men report that they cannot sleep and they are suffering from it and while others report only once a week. For those who have more significant impairment in their quality of life, one can discuss pharmacologic treatment. And the recommendations are mainly based on those that are derived from treatment of hot flashes in menopausal women. Effective drugs include progesterone with 80 to 90% reduction in the frequency of hot flashes. And cyproterone, 95% has been reported in reduction of hot flashes. The problem with these agents is, as you can see, weight gain, which is already associated with androgen-deprivation, but more importantly, cardiovascular events and clots that are seen with cyproterone. So these medications have potentially clinically dangerous side effects that has to be com --- outweighed against the benefit of reducing hot flashes. More commonly prescribed, better tolerated SSRIs such as venlafaxine, very prevalent side effects of dry mouth and some nausea. Gabapentin is used for various conditions including neuropathies, might cause dizziness, but is associated with about half of --- of the patients re --- with improving their hot flashes. Estrogens are also effective. Up to 83% have been reported improvement. The problem is breast swelling, nipple tenderness, and especially with patients who are on anti-androgens might have worsening of the symptoms. Other agents used commonly but without evidence are clonidine, that have not been shown to be effective in randomized trials. Acupuncture has some activity in the small Phase 2 trials and could be tried. Many natural products, soy products, vitamins, herbal remedies have been suggested, but there is no well-designed prospective trial to demonstrate the efficacy. And at this point, they cannot be recommended. In summary, taking together how to treat hot flashes which might be very important for patients undergoing androgen-deprivation, we have, as I showed you, we have to balance the severity of the symptoms against the potential serious side effects, such as strokes and clots of the therapy. As a general rule, one might start with the better tolerated SSRIs, such as venlafaxine. And in more refractory cases that are severe, move to an agent such as progesterone. Fatigue is a very important and prevalent side effect of androgen-deprivation. It s a subjective decrease in the energy and is a very significant adverse event with ADT in these men. It can appear as early as three months after starting the treatment and has been shown to be independent of other co-factors such as anemia or neuropsychiatric issues such as depression. Even when we account for those co-factors, there is still a significant increase in fatigue in patients treated with ADT. Regular moderate exercise has been shown to be beneficial, as I already mentioned for other side effects such as muscle loss.

6 A few --- couple of slides just to show you the data. We know that continuous hormone treatment increases the rate of chronic fatigue and total fatigue score. And down here, we see this is also time-dependent, meaning the longer the duration, the higher the percentage of patients who are reporting chronic fatigue. Body image changes, again, less dangerous, but possibly very aggravating the quality of life and might lead to emotional distress. They should also be discussed with the patient prior to starting androgen-deprivation. Gynecomastia is caused by relative abundance of estrogen that is not counterbalanced with testosterone anymore. As mentioned before, it is more commonly seen with antiandrogens alone, associated with breast tenderness, and depending on how severe the condition is, treatment with radiation, cytoreductive surgery, but for --- also pharmacologically with serotonin with SERMs, such as tamoxifen or AIs might be considered, and these are drugs that we usually use in me --- in women. Other body image changes that are possibly interfering with the patient s quality of life are thinning of the body hair, mainly in the face and the body, but the scalp hair might actually regrow. And for men, very disturbing sometimes is the decrease in the size of genitalia that is commonly observed after long-term treatment with androgendeprivation. Neuropsychiatric changes have been described. Decrease in testosterone levels are associated with cognitive decline in older men and the cognitive pe --- performance has been shown to be associated with androgen-deprivation but only after long-term treatment. Probably --- Possibly less than two mon --- two years will not affect the cognition. The problem is that these are elderly patients and underlying comorbidities and age are likely contributing factors to these neuropsychological changes. And once we actually do account for those, then ADT alone does not seem to actually increase the risk for conditions, such as depression in our patients. I mentioned the anemia when I was talking about fatigue before. Anemia is seen in about 90% of the men at some point during the treatment with androgen-deprivation. In most cases, it is mild to moderate and does not require any treatment such as transfusions or gra --- growth factors. As I already told you, it is not correlated with fatigue, even normalizing for anemia and degree of it. The patient will have independently loss of energy. On the laboratory finding, we see a normochromic, normocytic anemia. So if we do see other forms of anemia, that should warrant further work-up to look for the cause. In summary, over the pa --- past two talks, we talked about the role of cytotoxic chemotherapy which is very well established in metastatic prostate cancer but so far, unfortunately, has not shown any survival benefit in localized prostate cancer. Clinical trials are ongoing. We concluded that androgen-deprivation therapy is the main therapeutic approach with men with prostate cancer and is widely used if --- with --- in men with localized prostate cancer, especially in the setting of external beam radiation.

7 We have to be aware of the risk and benefits of androgen-deprivation in non-metastatic prostate cancer. And those have to be discussed with the patients prior to initiation of therapy to avoid surprises. Although not li --- life-threatening, some of the side effects of androgen-deprivation might severely impact the quality of life of the patients, and these include erectile dysfunction, muscle loss, increase in adipose tissue, decreased energy and fatigue, neuropsychiatric issues such as a decline in cognition --- cognition, gynecomastia, decreased genitalia size, body hair thinning, and anemia. But we should also be aware of the potentially serious side effects and early treat them, and those include osteoporosis and vertebral fractures. And we should have our patients on vitamin D and calcium supplementation. We should encourage lifestyle changes, such as regular exercise, tobacco cessation, reduce ethanol consume and such. And think about pharmacologic treatment of bone loss on --- for men on ADT, and we know --- we concluded that denosumab is actually FDA-approved for the osteoporosis prevention. And we also know that several bisphosphonates, such as zoledronic acid have been shown to be effective, although not FDA-approved for this indication. Cardiovascular disease, although very significant and clinically relevant, has not been conclusively shown to be associated with androgen-deprivation. And at this point, the relative benefits probably outweigh the risk of androgen-deprivation with respect to cardiovascular death. Finally, diabetes, insulin resistance, and metabolic changes such as h --- hyperlipidemia have been associated with ADT and should be closely monitored and treated. This concludes the talk for --- here. I thank you for your attention and welcome all your feedback.