Case Challenges

Side effects and bone health in a 53-year-old male on ADT

The efficacy of androgen deprivation therapy for prostate adenocarcinoma has been known for more than 50 years.

Within the past 10 years, however, there has been an increasingly robust understanding of systemic side effects of such therapies. Much work has been done to find new management strategies to ameliorate these adverse effects, as well as new therapeutics to attenuate clinical complications.

Two of these — intermittent androgen deprivation therapy (ADT) and the use of denosumab (Xgeva, Amgen) — are highlighted by a recent patient case.

Amit Mehta

A 53-year-old man developed hematuria, prompting further investigation. Initial laboratory testing included a PSA, which was 5.9 ng/mL. The only other symptom he was experiencing was occasional pain in the perineal region, but he had no urinary difficulty. Biopsy revealed prostate adenocarcinoma, and subsequent radical prostatectomy documented a Gleason 4+5, T2c N0 M0 adenocarcinoma.

He had an uncomplicated postoperative course, with an undetectable PSA level 1 year later. However, at that point, the PSA began to rise to 0.18 ng/mL. He underwent salvage radiotherapy, but 9 months later, the PSA rose to 1.2 ng/mL. The only symptomatology during this time was intermittent right hip pain. Scans were negative for any suspicious lesions. He was started on androgen deprivation with leuprolide, and his PSA dropped to 0.4 ng/mL.

He sustained this response over the next year, although the PSA fluctuated between 0.3 ng/mL and 1 ng/mL.

Most disconcerting for the patient, however, was the fact he was experiencing a number of new symptoms consistent with side effects of ADT. These included fatigue, insomnia, sexual side effects (difficulty with erection) and the development of osteoporosis. The patient recently had gotten married and, hence, naturally had concerns about his quality of life on treatment.

At the time of these symptoms, the patient had a PSA value of 0.24 ng/mL and a testosterone level of less than 10 ng/dL. Given the presentation, the option of intermittent ADT was discussed with the patient, and he chose to take that approach. As such, leuprolide was held while monitoring his symptoms and lab studies.

After 4 months, the serum testosterone returned to the normal range at 396.1 ng/dL. His symptoms gradually began to improve, as well. He reported better energy and fewer sexual side effects. During the subsequent 6 months, the PSA fluctuated between 0.7 ng/mL and 1.4 ng/mL, and it most recently was recorded at 1.03 ng/mL.

Concomitantly, the patient was begun on denosumab for skeletal event prevention, as he has documented osteoporosis and continues on hormonal therapy — albeit now intermittently — for prostate cancer. He continues to do well without bone pain, and he also is on calcium and vitamin D supplementation.

Discussion

The patient shares several common predicaments that many prostate cancer patients on ADT face.

Although his PSA has been fairly well controlled, he has multiple concerning side effects affecting his quality of life, including osteoporosis in the setting of ongoing hormonal therapy. Fortunately, data have emerged within the past year to support better management options for these patients.

A large phase 3 randomized trial evaluated intermittent vs. continuous androgen suppression. The trial involved 1,386 patients who were randomly assigned between the two groups.

Results were reported at the 2011 ASCO annual meeting.

Influential studies

The primary endpoint, OS, was equivalent between the groups: 8.8 years for those in the intermittent group vs. 9.1 years for those in the continuous group (HR=1.02; 95% CI, 0.86-1.21).

Multiple quality-of-life measures were superior in the intermittent therapy group, including physical function, fatigue, desire for sexual activity and erectile function (P<.01 for all). No differences were seen in the rate of myocardial events or osteoporotic fractures.

Interestingly, the time to hormone resistance was better in the intermittent androgen suppression arm, although this was not the primary endpoint (HR=0.8; 95% CI, 0.67-0.98). Overall, 35% of patients in the intermittent therapy arm had testosterone levels return to normal range.

Bone health is another critical management issue for patients on hormonal therapy. In the aforementioned phase 3 trial, the results showed no difference in the rate of osteoporotic fractures.

Skeletal events also have been known to be a common clinical event in prostate cancer, and they have potentially serious consequences. To this end, a RANK ligand inhibitor, denosumab, was evaluated in patients with prostate cancer undergoing ADT.

In a phase 3, double blind trial, 1,468 patients who had been on ADT for at least 12 months were randomly assigned between denosumab 60 mg subcutaneously every 6 months and placebo. The primary endpoint was change in bone mineral density at the lumbar spine at 24 months.

Results showed that lumbar spine bone mineral density improved 5.6% with denosumab, whereas it fell 1% on placebo (P≤001). Significant improvements also were seen in secondary endpoints, including bone mineral density in the femoral neck and hip. In addition, there was a decreased incidence of new vertebral fractures at 36 months (1.5% in the denosumab group vs. 3.9% in the placebo group). Serious adverse events were equal between groups, and no cases of osteonecrosis of the jaw were seen in this study.

Conclusion

These are two practice-changing clinical trials, and they address important treatment-related issues that often present in prostate adenocarcinoma.

This data, along with the availability of new therapeutic agents, allows more nuanced and improved management in this large patient population.

References:

  • Crook JM. Abstract #4514. Presented at: the ASCO Annual Meeting; June 3-7, 2011; Chicago.
  • Smith MR. N Engl J Med. 2009;361:745-755.

For more information:

  • Amit Mehta, MD, is an attending physician at Regional Cancer Care in Durham, N.C. He also is a member of the HemOnc Today Editorial Board. Disclosure: Dr. Mehta reports no relevant financial disclosures.

The efficacy of androgen deprivation therapy for prostate adenocarcinoma has been known for more than 50 years.

Within the past 10 years, however, there has been an increasingly robust understanding of systemic side effects of such therapies. Much work has been done to find new management strategies to ameliorate these adverse effects, as well as new therapeutics to attenuate clinical complications.

Two of these — intermittent androgen deprivation therapy (ADT) and the use of denosumab (Xgeva, Amgen) — are highlighted by a recent patient case.

Amit Mehta

A 53-year-old man developed hematuria, prompting further investigation. Initial laboratory testing included a PSA, which was 5.9 ng/mL. The only other symptom he was experiencing was occasional pain in the perineal region, but he had no urinary difficulty. Biopsy revealed prostate adenocarcinoma, and subsequent radical prostatectomy documented a Gleason 4+5, T2c N0 M0 adenocarcinoma.

He had an uncomplicated postoperative course, with an undetectable PSA level 1 year later. However, at that point, the PSA began to rise to 0.18 ng/mL. He underwent salvage radiotherapy, but 9 months later, the PSA rose to 1.2 ng/mL. The only symptomatology during this time was intermittent right hip pain. Scans were negative for any suspicious lesions. He was started on androgen deprivation with leuprolide, and his PSA dropped to 0.4 ng/mL.

He sustained this response over the next year, although the PSA fluctuated between 0.3 ng/mL and 1 ng/mL.

Most disconcerting for the patient, however, was the fact he was experiencing a number of new symptoms consistent with side effects of ADT. These included fatigue, insomnia, sexual side effects (difficulty with erection) and the development of osteoporosis. The patient recently had gotten married and, hence, naturally had concerns about his quality of life on treatment.

At the time of these symptoms, the patient had a PSA value of 0.24 ng/mL and a testosterone level of less than 10 ng/dL. Given the presentation, the option of intermittent ADT was discussed with the patient, and he chose to take that approach. As such, leuprolide was held while monitoring his symptoms and lab studies.

After 4 months, the serum testosterone returned to the normal range at 396.1 ng/dL. His symptoms gradually began to improve, as well. He reported better energy and fewer sexual side effects. During the subsequent 6 months, the PSA fluctuated between 0.7 ng/mL and 1.4 ng/mL, and it most recently was recorded at 1.03 ng/mL.

Concomitantly, the patient was begun on denosumab for skeletal event prevention, as he has documented osteoporosis and continues on hormonal therapy — albeit now intermittently — for prostate cancer. He continues to do well without bone pain, and he also is on calcium and vitamin D supplementation.

Discussion

The patient shares several common predicaments that many prostate cancer patients on ADT face.

Although his PSA has been fairly well controlled, he has multiple concerning side effects affecting his quality of life, including osteoporosis in the setting of ongoing hormonal therapy. Fortunately, data have emerged within the past year to support better management options for these patients.

A large phase 3 randomized trial evaluated intermittent vs. continuous androgen suppression. The trial involved 1,386 patients who were randomly assigned between the two groups.

Results were reported at the 2011 ASCO annual meeting.

Influential studies

The primary endpoint, OS, was equivalent between the groups: 8.8 years for those in the intermittent group vs. 9.1 years for those in the continuous group (HR=1.02; 95% CI, 0.86-1.21).

Multiple quality-of-life measures were superior in the intermittent therapy group, including physical function, fatigue, desire for sexual activity and erectile function (P<.01 for all). No differences were seen in the rate of myocardial events or osteoporotic fractures.

Interestingly, the time to hormone resistance was better in the intermittent androgen suppression arm, although this was not the primary endpoint (HR=0.8; 95% CI, 0.67-0.98). Overall, 35% of patients in the intermittent therapy arm had testosterone levels return to normal range.

Bone health is another critical management issue for patients on hormonal therapy. In the aforementioned phase 3 trial, the results showed no difference in the rate of osteoporotic fractures.

Skeletal events also have been known to be a common clinical event in prostate cancer, and they have potentially serious consequences. To this end, a RANK ligand inhibitor, denosumab, was evaluated in patients with prostate cancer undergoing ADT.

In a phase 3, double blind trial, 1,468 patients who had been on ADT for at least 12 months were randomly assigned between denosumab 60 mg subcutaneously every 6 months and placebo. The primary endpoint was change in bone mineral density at the lumbar spine at 24 months.

Results showed that lumbar spine bone mineral density improved 5.6% with denosumab, whereas it fell 1% on placebo (P≤001). Significant improvements also were seen in secondary endpoints, including bone mineral density in the femoral neck and hip. In addition, there was a decreased incidence of new vertebral fractures at 36 months (1.5% in the denosumab group vs. 3.9% in the placebo group). Serious adverse events were equal between groups, and no cases of osteonecrosis of the jaw were seen in this study.

Conclusion

These are two practice-changing clinical trials, and they address important treatment-related issues that often present in prostate adenocarcinoma.

This data, along with the availability of new therapeutic agents, allows more nuanced and improved management in this large patient population.

References:

  • Crook JM. Abstract #4514. Presented at: the ASCO Annual Meeting; June 3-7, 2011; Chicago.
  • Smith MR. N Engl J Med. 2009;361:745-755.

For more information:

  • Amit Mehta, MD, is an attending physician at Regional Cancer Care in Durham, N.C. He also is a member of the HemOnc Today Editorial Board. Disclosure: Dr. Mehta reports no relevant financial disclosures.

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