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JOURNAL OF CLINICAL ONCOLOGY
ONCOLOGY GRAND ROUNDS
To Treat or Not to Treat, That Is the Question: The Role of Bone-Targeted Therapy in Metastatic Prostate Cancer Celestia S. Higano, University of Washington, Seattle, WA See accompanying article on page 1143 The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors’ suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice.
A 62-year-old construction site manager experienced 6 weeks of back pain that was not responsive to over-the-counter nonsteroidal anti-inflammatory medications. He visited his wife’s primary care physician for evaluation. He denied neurologic symptoms or worsening of pain while lying down. He smoked (30 pack-years, quit 4 years ago), and drinks 3 beers each evening and more on weekends (up to a six-pack). He has had two lower extremity fractures from falls at construction sites. At the time of the physical examination, he was 5 feet 11 inches tall and weighed 194 pounds. He was alert, oriented, and in mild distress. He had no percussion tenderness of his spine, and a neurologic examination was negative. A digital rectal examination revealed an enlarged prostate with an area of induration of the left, normal rectal tone, and guaiac-negative stool. Laboratory studies included normal blood counts, electrolytes, and renal and liver function tests (including lactic acid dehydrogenase and total protein). The prostatespecific antigen (PSA) was 114 ng/mL; he had no prior PSA test. A bone scan showed diffuse bony involvement including the T7 vertebral body and left pedicle, ribs, pelvis, and calvarium. Magnetic resonance imaging of his spine confirmed bone metastases but showed no evidence of extension into the epidural space or spinal cord compromise. A prostate biopsy revealed Gleason 4ⴙ4 adenocarcinoma of the prostate. Androgen deprivation therapy with leuprolide acetate was initiated, and the addition of a bone-targeted agent was considered. CHALLENGES IN DIAGNOSIS AND MANAGEMENT
Before 1986 when the US Food and Drug Administration (FDA) approved the prostate-specific antigen (PSA) blood test, 20% of all men diagnosed with prostate cancer presented with metastatic disease. In the post-PSA era, the incidence of this presentation has fallen dramatically to approximately 7% of all new diagnoses.1 However, men still present with metastatic prostate cancer without a prior diagnosis of the disease. In most cases, newly diagnosed metastatic prostate cancer is responsive to lowering testosterone to castrate levels (termed “castration sensitive”). Thus, androgen deprivation therapy (ADT) to lower testosterone levels with either orchiectomy or, more commonly, a gonadotropin-releasing hormone analog or antagonist is considered the standard of care as first-line therapy. Bone pain usually responds rapidly to ADT, and unless spinal cord compression is evident, use of external-beam radiation therapy for pain control is unnecessary. Journal of Clinical Oncology, Vol 32, No 11 (April 10), 2014: pp 1107-1111
Prostate cancer becomes castration resistant over time, despite ADT. Castration-resistant prostate cancer is defined as an increasing PSA and/or progressive disease according to imaging with castrate levels of serum testosterone (⬍ 50 ng/dL). Time to progression to castration resistance can be quite variable. The PSA response to ADT can be helpful in predicting the time to the development of castration resistance. An analysis of all patients treated with ADT during the induction phase of the SWOG 9346 study,2 a large phase III trial in men with newly diagnosed metastatic castration-sensitive disease, showed that the PSA value at 7 months in response to ADT is a powerful prognostic marker for long-term survival; men who achieved a PSA ⱕ 0.2 ng/mL after 7 months of ADT had a median survival of 6.25 years compared with those with a PSA more than 0.2 ng/mL and ⱕ 4 ng/mL and those whose PSA failed to decrease below 4 ng/mL, who had a median survival of 3.7 years and 1.1 year, respectively. Predictive factors for patients whose PSA failed to decrease below 4 ng/mL at 7 months (the group experiencing the worst © 2014 by American Society of Clinical Oncology
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Celestia S. Higano
survival) included higher initial PSA, Gleason score ⱖ 8, younger age, worse performance status, and the presence of bone pain. Thus, the absolute value of PSA after 7 months of ADT in men with metastatic castration-sensitive disease can be used to stratify patients into survival risk categories, although there are currently no data from clinical trials that inform how the clinician should respond to this information. For men whose PSA fails to decrease below 4 ng/mL and who are in the poorest risk group, I initiate discussions regarding the likelihood of needing additional therapy such as enzalutamide or abiraterone for the probable early onset of castration-resistant disease. SUMMARY OF THE RELEVANT LITERATURE
In prostate cancer, bone metastases are predominantly osteoblastic with a sclerotic appearance on plain film or computed tomography scans. Three classes of bone-targeted agents (bisphosphonates, receptor activator of nuclear factor-kappa B ligand [RANKL] inhibitor, radioisotope) have been studied in phase III trials in men with metastatic prostate cancer (Table 1).3-9 The trials involved two populations of patients: those with castration-resistant prostate cancer and those with castration-sensitive disease. Historically, most trials have been performed in the castration-resistant population, given that castrationsensitive tumors often have a prolonged natural history. Metastatic Castration-Resistant Disease: Bone-Targeted Antiresorptive Agents Bisphosphonates. Zoledronic acid is a potent aminobisphosphonate that inhibits osteoclast function and induces osteoclast apoptosis. Originally, it was hypothesized that zoledronic acid might not be as effective in treating osteoblastic compared with osteolytic bone metastases, and in fact, pamidronate, a less potent, second-generation bisphosphonate, was no better than placebo in reducing skeletal-related events (SREs) or pain in men with metastatic prostate cancer.3 In 1998, a phase III trial was launched in which men with metastatic castration-resistant prostate cancer were randomly assigned to one of two doses of zoledronic acid (4 or 8 mg) or placebo administered once every 3 weeks for 15 months. Early in the trial, the 8-mg dose level was dropped to 4 mg as a result of renal toxicity. The median time to the first SRE was not reached in the zoledronic acid arms and was deemed to be at least 420 days (or 13.8 months), because fewer than 50% of patients had experienced an SRE at that time point (v 10.5 months in the placebo arm). An extension phase of the study continued therapy for an additional 9 months (for a total of 24 months) and confirmed the efficacy of zoledronic acid versus placebo (median time to first SRE, 16.0 v 10.5 months, respectively) with a 36% reduction in SREs.4a The FDA approved zoledronic acid for treatment of men with castration-resistant prostate cancer metastatic to bone in 2002. Although zoledronic acid became the standard of care for the prevention of SREs, a retrospective observational study showed that only 40% to 50% of patients with metastatic prostate cancer were treated with zoledronic acid.10 RANKL inhibitor. Denosumab is a monoclonal antibody against RANKL, responsible for activating osteoclast differentiation and survival. Given its potency and different mechanism of action, this agent held the promise of noninferiority or possibly superiority to zoledronic acid in terms of SRE prevention. In 2006, a phase III trial compared the efficacy of denosumab 120 mg through subcutaneous 1108
© 2014 by American Society of Clinical Oncology
injection administered once every 4 weeks versus zoledronic acid 4 mg through intravenous (IV) infusion administered once every 4 weeks until the primary analysis cutoff date. The time to the first SRE was 20.7 months for densumab versus 17.1 months for zoledronic acid (hazard ratio [HR], 0.82), demonstrating that denosumab was modestly better than zoledronic acid for delaying or preventing SREs.7 In 2012, the FDA approved denosumab for the treatment of bone metastases resulting from prostate and other solid tumors (with no specification for castration resistance). Bone-targeted radioisotopes. Radium 223, an alpha-emitting radioisotope, is another bone-directed therapy that the FDA recently approved to treat metastatic castration-resistant prostate cancer. Unlike the antiresorptive agents and the other approved radioisotopes (strontium and samarium), radium 223 offers antitumor activity with a survival benefit. In a phase III trial of men with symptomatic, metastatic castration-resistant prostate cancer in whom docetaxel failed or who were deemed unfit for docetaxel treatment, patients were treated with best supportive care and either radium 223 50 kBq/kg or placebo IV administered once every 4 weeks for six doses.6 Overall survival was improved in the radium arm, with a median overall survival of 14.0 months versus 11.2 months for placebo (HR, 0.70). Median time to first symptomatic SRE was 15.6 months versus 9.8 months, respectively (HR, 0.66). In the preplanned subgroup analysis of HRs for death, patients benefited from radium 223 whether they received a bisphosphonate or not. Metastatic Castration-Sensitive Prostate Cancer In the setting of metastatic prostate cancer that is sensitive to castration, only two phase III trials have examined bone-targeted therapy, both using antiresorptive drugs (Table 1). Dearnaley et al7,8 studied a first-generation bisphosphonate: clodronate 2,080 mg administered orally daily or matching placebo for 3 years. Although the primary report found that clodronate was no better than placebo in terms of bone progression–free survival,7 longer-term follow-up demonstrated that there was a 23% reduction in death compared with placebo.8 Despite these findings, clodronate has not been approved in the United States and is not widely used. The other phase III trial in men with metastatic castrationsensitive prostate cancer is the Cancer and Leukemia Group B/Alliance trial reported by Smith et al9 in the accompanying article. This trial asked an important question about whether the use of zoledronic acid earlier in the natural history of prostate cancer metastatic to bone would be more beneficial in lowering the risk of SREs than waiting until the onset of castration-resistant disease. Men with bone metastases who had started ADT within 6 months of diagnosis were randomly assigned to receive zoledronic acid 4 mg or placebo once every 4 weeks. All patients were treated with open-label zoledronic acid at progression to castration resistance. The median time to the first SRE for the zoledronic acid and placebo arms was 31.9 and 28.8 months (HR, 0.97), respectively; median progression-free survival was 10.6 and 9.2 months (HR, 0.89), respectively; median overall survival was 37.9 and 36.0 months (HR, 0.88), respectively. These differences were not statistically significant, indicating that earlier treatment was not beneficial. Interestingly, an exploratory analysis of a subset of 82 men how experienced an SRE before study entry suggested that the median time to the first SRE was 31.9 months in the zoledronic acid arm versus 17.6 months in the placebo arm (HR, 0.56). The nature of the SREs before study entry was not described; however, it is likely that some of JOURNAL OF CLINICAL ONCOLOGY
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www.jco.org
1,904
921
Fizazi5
Parker6
645
Smith9
Extension: clodronate v placebo Zoledronic acid v placebo
Clodronate v placebo
Extension: zoledronic acid v placebo Denosumab v zoledronic acid Radium 223 v placebo
Zoledronic acid v placebo
Pamidronate v placebo
Agents
Clodronate 2,080 mg orally v placebo daily for 3 years maximum Zoledronic acid 4 mg IV once every 4 weeks
Clodronate 2,080 mg orally v placebo daily for 3 years maximum
Denosumab 120 mg SC v zoledronic acid 4 mg IV once every 4 weeks Radium 223 50 kBq/kg v placebo IV once every 4 weeks for six doses
Pamidronate 90 mg v placebo IV once every 3 weeks for 27 weeks Zoledronic acid 4 mg v 8 mg v placebo IV once every 3 weeks for 15 monthsⴱ Zoledronic acid 4 mg v placebo IV for 24 months
Dose
HR
NS
39 v 26
0.77
NT
14.9 v 11.3 0.70
NS
NS
NT
NT
Median (months)
NS
NT
13.6 v 8.4
20.7 v 17.1
16.0 v 10.5
11.9 v 10.5
NT
Median (months)
Primary end point: bone PFS, NS Median follow-up, 4.9 years
0.66
0.82
0.677
NR
HR
Time to First SRE
Median follow-up, 11.5 years Subset with prior SRE: median time to first SRE, 31.9 v 17.6 months; HR, 0.56
25% with SRE in each arm 33.2 v 44.2% with SRE
Comment
Abbreviations: HR, hazard ratio; IV, intravenous; NR, not reported; NS, not significant; NT, not tested; OS, overall survival; PFS, progression-free survival; SC, subcutaneous; SRE, skeletal-related event. ⴱ 8-mg arm reduced to 4 mg as a result of renal toxicity. †Extension of original study.
278
Dearnaley8†
311
122
Saad4a†
Metastatic castrationsensitive disease Dearnaley7
643
350
Metastatic castrationresistant disease Small3
Saad4
No. of Patients
Trial
OS
Table 1. Bone-Targeted Agents Studied in Phase III Trials in Men With Metastatic Prostate Cancer
Bone-Targeted Therapies and Metastatic Prostate Cancer
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Level 1 Evidence for Use of Disease State Antiresorptive Therapy
Other Considerations
Castration sensitive
No for Z, unknown for D
Risk for fracture (FRAX), previous SRE, bone pain
Castration resistant
Yes for Z and D, D superior to Z
Dental hygiene, renal function, IV or SC administration cost
Metastatic prostate cancer to bone
Fig 1. Approach to decision making regarding use of antiresorptive therapy for metastatic prostate cancer. D, denosumab; FRAX, fracture risk algorithm; IV, intravenous; SC, subcutaneous; SRE, skeletal-related event; Z, zoledronic acid.
these patients presented with pain and were treated with radiation therapy in addition to concurrently starting ADT. Although this subset analysis suggests that zoledronic acid may benefit a small proportion of men presenting with SREs, the overall results of this trial do not support the routine addition of zoledronic acid to the treatment of men with metastatic castration-sensitive disease. SUGGESTED APPROACHES TO MANAGEMENT
Given the results of the phase III trials discussed in the Summary of the Relevant Literature section, patients with newly diagnosed castrationsensitive metastatic disease should not routinely be treated early with zoledronic acid, whereas treatment with either denosumab or zoledronic acid should be strongly considered in those with castrationresistant disease. However, the importance of certain clinical features besides disease state when deciding whether to use antiresorptive therapy is discussed in this section and summarized in Figure 1. For men with metastatic castration-resistant disease, the clinical trial data clearly demonstrate benefit in terms of prevention and delay of SREs for both zoledronic acid and denosumab, with denosumab being superior to zoledronic acid. However, there are some patientspecific factors that should be considered before prescribing these agents. First, because of the small but real risk of osteonecrosis of the jaw, all patients should undergo a baseline dental examination and complete any invasive dental work before starting therapy.11 In patients with poor dental hygiene, the increased risk for osteonecrosis of the jaw with either agent may outweigh the benefits of using an antiresorptive agent. Another consideration is renal function. Zoledronic acid is excreted by the kidneys and can cause renal toxicity when the creatinine is increased. The dosage of zoledronic acid must be based on renal function and is contraindicated when the creatinine clearance is less than 30 mL/min, whereas denosumab is not excreted by the kidneys and can be administered even to patients on dialysis. The incidence of hypocalcemia is greater after denosumab (13%) than after zoledronic acid (6%).5 All patients treated with antirepsorptive agents should also be advised to take supplemental calcium and vitamin D. In the setting of castration-sensitive metastatic disease in a patient about to start ADT, the decision to use an antiresorptive agent has another dimension besides SREs. ADT causes loss of bone mineral density and increases the risk of fracture.11a In any patient who is about to start ADT, whether metastatic to bone or not, the underlying risk 1110
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for fracture resulting from existing osteopenia, osteoporosis or based on FRAX (a fracture risk algorithm) estimate should be determined. FRAX is an online assessment tool that incorporates age, body mass index, and other clinical risk factors to calculate the 10-year probability of a hip or major osteoporosis-related fracture. In individuals with no bone metastases but for whom there is a significant fracture risk (10-year probability of a hip fracture is ⱖ 3% or major osteorporosisrelated fracture is ⱖ 20%), the National Osteoporosis Foundation suggests consideration of pharmacologic therapy. Drugs that increase bone mineral density in men treated with ADT include zoledronic acid (5 mg once per year),12 alendronate (70 mg once per week),13 and denosumab (60 mg once every 6 months).14 However, only denosumab has been shown to decrease fracture risk.14 The osteoporosis consideration is not relevant in patients with castration-resistant disease if denosumab or zoledronic acid is going to be administered every 3 to 4 weeks for prevention or delay of SREs. The patient presented in this case study presented with several risk factors that could herald increased fracture risk even in the absence of cancer. These include his prior fractures (although traumatic), smoking history, alcohol intake, and ADT. The answer to the FRAX question regarding secondary osteoporosis should be answered yes if the patient is on or about to start ADT. For this patient, FRAX calculates a 3.1% to 4.9% (depending on how one answers the smoking question) 10-year risk of hip fracture, whereas the risk of major osteoporotic-related fracture is approximately 17%. This patient, who needs ADT, will be at increased risk for hip fracture, which can dramatically decrease life expectancy, even in a person without cancer.15,16 In this patient, the presence of metastatic disease in bone further compromises bone integrity and increases the risk for SREs. Another consideration concerns the fact that this patient has several of the clinical features—namely bone pain at presentation and a Gleason score of 8 —that could put him in the poor risk group of men with metastatic castration-sensitive disease defined by the SWOG 9346 trial.2 This raises concerns about earlier progression to castration resistance and death; perhaps, given the proximity of castration resistance, starting antiresorptive therapy earlier at a dose and schedule that is known to impact SRE might make sense. Starting ADT alone usually results in resolution of pain, but antiresorptive agents are also effective. Zoledronic acid reduced pain and analgesic scores compared with placebo4; subsequently, denosumab was shown to prevent the progression of pain more effectively than zoledronic acid in an integrated study.17 A final reason to consider the addition of antiresorptive therapy is that this patient could theoretically be in the subset of patients who benefited from early zoledronic acid in the Cancer and Leukemia Group B/Alliance trial. Although patients who present with pain usually respond to ADT alone, many are also treated concomitantly with radiation therapy. This would have constituted an SRE, and this subgroup experienced significant benefit from early zoledronic acid. For these reasons, I favor treating this patient with either denosumab or zoledronic acid, cognizant of the negative data from the prospective, randomized clinical trial reported by Smith et al.10 Because of its ability to prevent fracture (in this patient who is a risk according to FRAX) in the nonmetastatic setting, I would choose denosumab, acknowledging that this agent has not been studied in the metastatic castration-sensitive setting and that, although denosumab is superior to zoledronic acid in delaying SREs and pain progression in the castration-resistant state, the same cannot be assumed for the JOURNAL OF CLINICAL ONCOLOGY
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Bone-Targeted Therapies and Metastatic Prostate Cancer
castration-sensitive population. However, zoledronic acid would also be an acceptable alternative when cost, reimbursement, availability, or route of administration are at issue (Fig 1). Before starting therapy, I would check the patient’s vitamin D level and prescribe supplemental calcium and vitamin D. Both zoledronic acid and denosumab trials included recommendations for supplementation, and low vitamin D levels have been reported to result in profound hypocalcemia in a patient treated with zoledronic acid.18 Serum calcium, magnesium, and phosphate should all be monitored during therapy. One might wonder, “What about treating this patient with extensive bone metastases with radium 223, an agent that, unlike the antiresportives, has been shown to extend survival?” At present, no data support the use of this radioisotope in patients with castrationsensitive disease, although it is tempting to speculate that earlier use of radium 223 may be beneficial in terms of overall survival as well as SRE prevention. The trial by Smith et al10 clearly showed that earlier use of zoledronic acid did not decrease the risk of SRE or improve survival in all comers. Future studies may shed light on the early use of radium 223 in this disease state. In conclusion, individual clinical features of a patient must factor into decision making, and the resulting decision may seemingly conREFERENCES 1. National Cancer Institute: SEER cancer statistics factsheets: Prostate cancer. http://seer.cancer .gov/statfacts/html/prost.html 2. Hussain M, Tangen CM, Higano C, et al: Absolute prostate-specific antigen value after androgen deprivation is a strong independent predictor of survival in new metastatic prostate cancer: Data from Southwest Oncology Group Trial 9346 (INT0162). J Clin Oncol 24:3984-3990, 2006 3. Small EJ, Smith MR, Seaman JJ, et al: Combined analysis of two multicenter, randomized, placebo-controlled studies of pamidronate disodium for the palliation of bone pain in men with metastatic prostate cancer. J Clin Oncol 21:4277-4284, 2003 4. Saad F, Gleason DM, Murray R, et al: A randomized, placebo controlled trial of zoledronic acid in patients with hormone refractory metastatic prostate carcinoma. J Natl Cancer Inst 94:14581468, 2002 4a. Saad F, Gleason DM, Murray R, et al: Longterm efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J Natl Cancer Inst 96:879-882, 2004 5. Hagiwara M, Delea TE, Cong Z, et al: Utilization of intravenous bisphosphonates in patients with bone metastases secondary to breast, lung, or prostate cancer. Support Care Cancer 22:103-113, 2013 6. Fizazi K, Carducci M, Smith M, et al: Denosumab versus zoledronic acid for treatment of bone
tradict one based only on level-one clinical trial results. Clinical trials are conducted under well-defined circumstances and cannot be applied without considering patient-specific circumstances. Treatment algorithms must be used to guide but not dictate clinical practice. We still need thoughtful clinicians to practice the art of medicine and choose the best therapy for the individual patient. AUTHOR’S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) and/or an author’s immediate family member(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Celestia S. Higano, Amgen (C) Stock Ownership: None Honoraria: None Research Funding: None Expert Testimony: None Patents, Royalties, and Licenses: None Other Remuneration: None
metastases in men with castration-resistant prostate cancer: A randomised, double-blind study. Lancet 377:813-822, 2011 7. Parker C, Nilsson S, Heinrich D, et al: Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med 369:213-223, 2013 8. Dearnaley DP, Sydes MR, Mason MD, et al: A double-blind, placebo-controlled, randomized trial of oral sodium clodronate for metastatic prostate cancer (MRC PR05 Trial). J Natl Cancer Inst 95:13001311, 2003 9. Dearnaley DP, Mason MD, Parmar MK, et al: Adjuvant therapy with oral sodium clodronate in locally advanced and metastatic prostate cancer: Long-term overall survival results from the MRC PR04 and PR05 randomised controlled trials. Lancet Oncol 10:872-876, 2009 10. Smith MR, Halabi S, Ryan CJ, et al: Randomized controlled trial of early zoledronic acid in men with castration-sensitive prostate cancer and bone metastases: Results of CALGB 90202 (Alliance). J Clin Oncol 32:1143-1150, 2014 11. Ruggerio SL, Dodson TB, Assael LA, et al: American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaw: 2009 update. J Oral Maxillofac Surg 67:2-12, 2009 (suppl 5) 11a. Shahinian VB, Kuo Y-F, Freeman JL, et al: Risk of fracture after androgen deprivation for prostate cancer. N Engl J Med 352:154-164, 2005 12. Michaelson MD, Kaufman DS, Lee H, et al: Randomized controlled trial of annual zoledronic acid to prevent gonadotropin-releasing hormone agonist-
induced bone loss in men with prostate cancer. J Clin Oncol 25:1038-1042, 2007 13. Greenspan SL, Nelson JB, Trump DL, et al: Effect of once-weekly oral alendronate on bone loss in men receiving androgen deprivation therapy for prostate cancer: A randomized trial. Ann Intern Med 146:416-424, 2007 14. Smith MR, Egerdie B, Herna´ndez Toriz N, et al: Denosumab in men receiving androgendeprivation therapy for prostate cancer. N Engl J Med 361:745-755, 2009 15. Center JR, Nguyen TV, Schneider D, et al: Mortality after all major types of osteoporotic fracture in men and women: An observational study. Lancet 353:878-882, 1999 16. Cree M, Soskolne CL, Belseck E, et al: Mortality and institutionalization following hip fracture. J Am Geriatr Soc 48:283-288, 2000 17. von Moos R, Body JJ, Egerdie B, et al: Pain and health-related quality of life in patients with advanced solid tumours and bone metastases: Integrated results from three randomized, double-blind studies of denosumab and zoledronic acid. Support Care Cancer 21:3497-3507, 2013 18. Breen TL, Shane E: Prolonged hypocalcemia after treatment with zoledronic acid in a patient with prostate cancer and vitamin D deficiency. J Clin Oncol 22:1531-1532, 2004
DOI: 10.1200/JCO.2013.53.8900; published online ahead of print at www.jco.org on March 3, 2014
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In the last paragraph of the Discussion section, the last sentence was given as: “In conclusion, long-term follow-up of this randomized trial showed significantly better 5-year EFS and OS rates for myeloablative therapy with purged ABMT than for non–myeloablative chemotherapy, and cis-RA given after intensive therapy resulted in significant improvement in 5-year OS rates, regardless of the type of consolidation.” While it should have been:
“In conclusion, long-term follow-up of this randomized trial showed significantly better 5-year EFS rate for myeloablative therapy with purged ABMT than for nonmyeloablative chemotherapy, although there was no statistically significant improvement in OS.” The online version has been corrected in departure from the print. The authors apologize for the mistakes. DOI: 10.1200/JCO.2014.57.0382; published June 10, 2014
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The April 10, 2014, editorial by Friedlander et al, entitled “The End of the Beginning: Circulating Tumor Cells As a Biomarker in Castration Resistant Prostate Cancer” (J Clin Oncol 32:1104-1106, 2014), contained an error. The last sentence of the eighth paragraph was inadvertently given as, “Similarly, in the Trastuzumab in HER2-Negative Early Breast Cancer As Adjuvant Treatment for Circulating Tumor Cells (TREAT-CTC) study, women with detectable CTCs after neoadjuvant chemotherapy are randomly assigned to trastuzumab or a placebo to see whether vascular endothelial growth factor–directed therapy reduces relapses in women at high risk of recurrence.”
It should have been given as, “Similarly, in the Trastuzumab in HER2-Negative Early Breast Cancer As Adjuvant Treatment for Circulating Tumor Cells (TREAT-CTC) study, women with detectable CTCs after neoadjuvant chemotherapy are randomly assigned to trastuzumab or a placebo to see whether human epidermal growth factor receptor 2 – directed therapy reduces relapses in women at high risk of recurrence.” The authors apologize for the mistake. . DOI: 10.1200/JCO.2014.57.0036; published June 10, 2014
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The April 10, 2014, Oncology Grand Rounds article by C.S. Higano, entitled “To Treat or Not to Treat, That Is the Question: The Role of Bone-Targeted Therapy in Metastatic Prostate Cancer” (J Clin Oncol 32:1107-1111), contained an error. On page 1108, in the section Summary of the Relevant Literature, the last sentence of the first paragraph under the heading Met-
astatic Castration-Resistant Disease: Bone-Targeted Antiresorptive Agents, incorrectly cited reference 10. It should have cited reference 5. Journal of Clinical Oncology apologizes for the mistake. DOI: 10.1200/JCO.2014.57.0044; published June 10, 2014
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JOURNAL OF CLINICAL ONCOLOGY
ONCOLOGY GRAND ROUNDS
To Treat or Not to Treat, That Is the Question: The Role of Bone-Targeted Therapy in Metastatic Prostate Cancer Celestia S. Higano, University of Washington, Seattle, WA See accompanying article on page 1143 The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors’ suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice.
A 62-year-old construction site manager experienced 6 weeks of back pain that was not responsive to over-the-counter nonsteroidal anti-inflammatory medications. He visited his wife’s primary care physician for evaluation. He denied neurologic symptoms or worsening of pain while lying down. He smoked (30 pack-years, quit 4 years ago), and drinks 3 beers each evening and more on weekends (up to a six-pack). He has had two lower extremity fractures from falls at construction sites. At the time of the physical examination, he was 5 feet 11 inches tall and weighed 194 pounds. He was alert, oriented, and in mild distress. He had no percussion tenderness of his spine, and a neurologic examination was negative. A digital rectal examination revealed an enlarged prostate with an area of induration of the left, normal rectal tone, and guaiac-negative stool. Laboratory studies included normal blood counts, electrolytes, and renal and liver function tests (including lactic acid dehydrogenase and total protein). The prostatespecific antigen (PSA) was 114 ng/mL; he had no prior PSA test. A bone scan showed diffuse bony involvement including the T7 vertebral body and left pedicle, ribs, pelvis, and calvarium. Magnetic resonance imaging of his spine confirmed bone metastases but showed no evidence of extension into the epidural space or spinal cord compromise. A prostate biopsy revealed Gleason 4ⴙ4 adenocarcinoma of the prostate. Androgen deprivation therapy with leuprolide acetate was initiated, and the addition of a bone-targeted agent was considered. CHALLENGES IN DIAGNOSIS AND MANAGEMENT
Before 1986 when the US Food and Drug Administration (FDA) approved the prostate-specific antigen (PSA) blood test, 20% of all men diagnosed with prostate cancer presented with metastatic disease. In the post-PSA era, the incidence of this presentation has fallen dramatically to approximately 7% of all new diagnoses.1 However, men still present with metastatic prostate cancer without a prior diagnosis of the disease. In most cases, newly diagnosed metastatic prostate cancer is responsive to lowering testosterone to castrate levels (termed “castration sensitive”). Thus, androgen deprivation therapy (ADT) to lower testosterone levels with either orchiectomy or, more commonly, a gonadotropin-releasing hormone analog or antagonist is considered the standard of care as first-line therapy. Bone pain usually responds rapidly to ADT, and unless spinal cord compression is evident, use of external-beam radiation therapy for pain control is unnecessary. Journal of Clinical Oncology, Vol 32, No 11 (April 10), 2014: pp 1107-1111
Prostate cancer becomes castration resistant over time, despite ADT. Castration-resistant prostate cancer is defined as an increasing PSA and/or progressive disease according to imaging with castrate levels of serum testosterone (⬍ 50 ng/dL). Time to progression to castration resistance can be quite variable. The PSA response to ADT can be helpful in predicting the time to the development of castration resistance. An analysis of all patients treated with ADT during the induction phase of the SWOG 9346 study,2 a large phase III trial in men with newly diagnosed metastatic castration-sensitive disease, showed that the PSA value at 7 months in response to ADT is a powerful prognostic marker for long-term survival; men who achieved a PSA ⱕ 0.2 ng/mL after 7 months of ADT had a median survival of 6.25 years compared with those with a PSA more than 0.2 ng/mL and ⱕ 4 ng/mL and those whose PSA failed to decrease below 4 ng/mL, who had a median survival of 3.7 years and 1.1 year, respectively. Predictive factors for patients whose PSA failed to decrease below 4 ng/mL at 7 months (the group experiencing the worst © 2014 by American Society of Clinical Oncology
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survival) included higher initial PSA, Gleason score ⱖ 8, younger age, worse performance status, and the presence of bone pain. Thus, the absolute value of PSA after 7 months of ADT in men with metastatic castration-sensitive disease can be used to stratify patients into survival risk categories, although there are currently no data from clinical trials that inform how the clinician should respond to this information. For men whose PSA fails to decrease below 4 ng/mL and who are in the poorest risk group, I initiate discussions regarding the likelihood of needing additional therapy such as enzalutamide or abiraterone for the probable early onset of castration-resistant disease. SUMMARY OF THE RELEVANT LITERATURE
In prostate cancer, bone metastases are predominantly osteoblastic with a sclerotic appearance on plain film or computed tomography scans. Three classes of bone-targeted agents (bisphosphonates, receptor activator of nuclear factor-kappa B ligand [RANKL] inhibitor, radioisotope) have been studied in phase III trials in men with metastatic prostate cancer (Table 1).3-9 The trials involved two populations of patients: those with castration-resistant prostate cancer and those with castration-sensitive disease. Historically, most trials have been performed in the castration-resistant population, given that castrationsensitive tumors often have a prolonged natural history. Metastatic Castration-Resistant Disease: Bone-Targeted Antiresorptive Agents Bisphosphonates. Zoledronic acid is a potent aminobisphosphonate that inhibits osteoclast function and induces osteoclast apoptosis. Originally, it was hypothesized that zoledronic acid might not be as effective in treating osteoblastic compared with osteolytic bone metastases, and in fact, pamidronate, a less potent, second-generation bisphosphonate, was no better than placebo in reducing skeletal-related events (SREs) or pain in men with metastatic prostate cancer.3 In 1998, a phase III trial was launched in which men with metastatic castration-resistant prostate cancer were randomly assigned to one of two doses of zoledronic acid (4 or 8 mg) or placebo administered once every 3 weeks for 15 months. Early in the trial, the 8-mg dose level was dropped to 4 mg as a result of renal toxicity. The median time to the first SRE was not reached in the zoledronic acid arms and was deemed to be at least 420 days (or 13.8 months), because fewer than 50% of patients had experienced an SRE at that time point (v 10.5 months in the placebo arm). An extension phase of the study continued therapy for an additional 9 months (for a total of 24 months) and confirmed the efficacy of zoledronic acid versus placebo (median time to first SRE, 16.0 v 10.5 months, respectively) with a 36% reduction in SREs.4a The FDA approved zoledronic acid for treatment of men with castration-resistant prostate cancer metastatic to bone in 2002. Although zoledronic acid became the standard of care for the prevention of SREs, a retrospective observational study showed that only 40% to 50% of patients with metastatic prostate cancer were treated with zoledronic acid.10 RANKL inhibitor. Denosumab is a monoclonal antibody against RANKL, responsible for activating osteoclast differentiation and survival. Given its potency and different mechanism of action, this agent held the promise of noninferiority or possibly superiority to zoledronic acid in terms of SRE prevention. In 2006, a phase III trial compared the efficacy of denosumab 120 mg through subcutaneous 1108
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injection administered once every 4 weeks versus zoledronic acid 4 mg through intravenous (IV) infusion administered once every 4 weeks until the primary analysis cutoff date. The time to the first SRE was 20.7 months for densumab versus 17.1 months for zoledronic acid (hazard ratio [HR], 0.82), demonstrating that denosumab was modestly better than zoledronic acid for delaying or preventing SREs.7 In 2012, the FDA approved denosumab for the treatment of bone metastases resulting from prostate and other solid tumors (with no specification for castration resistance). Bone-targeted radioisotopes. Radium 223, an alpha-emitting radioisotope, is another bone-directed therapy that the FDA recently approved to treat metastatic castration-resistant prostate cancer. Unlike the antiresorptive agents and the other approved radioisotopes (strontium and samarium), radium 223 offers antitumor activity with a survival benefit. In a phase III trial of men with symptomatic, metastatic castration-resistant prostate cancer in whom docetaxel failed or who were deemed unfit for docetaxel treatment, patients were treated with best supportive care and either radium 223 50 kBq/kg or placebo IV administered once every 4 weeks for six doses.6 Overall survival was improved in the radium arm, with a median overall survival of 14.0 months versus 11.2 months for placebo (HR, 0.70). Median time to first symptomatic SRE was 15.6 months versus 9.8 months, respectively (HR, 0.66). In the preplanned subgroup analysis of HRs for death, patients benefited from radium 223 whether they received a bisphosphonate or not. Metastatic Castration-Sensitive Prostate Cancer In the setting of metastatic prostate cancer that is sensitive to castration, only two phase III trials have examined bone-targeted therapy, both using antiresorptive drugs (Table 1). Dearnaley et al7,8 studied a first-generation bisphosphonate: clodronate 2,080 mg administered orally daily or matching placebo for 3 years. Although the primary report found that clodronate was no better than placebo in terms of bone progression–free survival,7 longer-term follow-up demonstrated that there was a 23% reduction in death compared with placebo.8 Despite these findings, clodronate has not been approved in the United States and is not widely used. The other phase III trial in men with metastatic castrationsensitive prostate cancer is the Cancer and Leukemia Group B/Alliance trial reported by Smith et al9 in the accompanying article. This trial asked an important question about whether the use of zoledronic acid earlier in the natural history of prostate cancer metastatic to bone would be more beneficial in lowering the risk of SREs than waiting until the onset of castration-resistant disease. Men with bone metastases who had started ADT within 6 months of diagnosis were randomly assigned to receive zoledronic acid 4 mg or placebo once every 4 weeks. All patients were treated with open-label zoledronic acid at progression to castration resistance. The median time to the first SRE for the zoledronic acid and placebo arms was 31.9 and 28.8 months (HR, 0.97), respectively; median progression-free survival was 10.6 and 9.2 months (HR, 0.89), respectively; median overall survival was 37.9 and 36.0 months (HR, 0.88), respectively. These differences were not statistically significant, indicating that earlier treatment was not beneficial. Interestingly, an exploratory analysis of a subset of 82 men how experienced an SRE before study entry suggested that the median time to the first SRE was 31.9 months in the zoledronic acid arm versus 17.6 months in the placebo arm (HR, 0.56). The nature of the SREs before study entry was not described; however, it is likely that some of JOURNAL OF CLINICAL ONCOLOGY
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1,904
921
Fizazi5
Parker6
645
Smith9
Extension: clodronate v placebo Zoledronic acid v placebo
Clodronate v placebo
Extension: zoledronic acid v placebo Denosumab v zoledronic acid Radium 223 v placebo
Zoledronic acid v placebo
Pamidronate v placebo
Agents
Clodronate 2,080 mg orally v placebo daily for 3 years maximum Zoledronic acid 4 mg IV once every 4 weeks
Clodronate 2,080 mg orally v placebo daily for 3 years maximum
Denosumab 120 mg SC v zoledronic acid 4 mg IV once every 4 weeks Radium 223 50 kBq/kg v placebo IV once every 4 weeks for six doses
Pamidronate 90 mg v placebo IV once every 3 weeks for 27 weeks Zoledronic acid 4 mg v 8 mg v placebo IV once every 3 weeks for 15 monthsⴱ Zoledronic acid 4 mg v placebo IV for 24 months
Dose
HR
NS
39 v 26
0.77
NT
14.9 v 11.3 0.70
NS
NS
NT
NT
Median (months)
NS
NT
13.6 v 8.4
20.7 v 17.1
16.0 v 10.5
11.9 v 10.5
NT
Median (months)
Primary end point: bone PFS, NS Median follow-up, 4.9 years
0.66
0.82
0.677
NR
HR
Time to First SRE
Median follow-up, 11.5 years Subset with prior SRE: median time to first SRE, 31.9 v 17.6 months; HR, 0.56
25% with SRE in each arm 33.2 v 44.2% with SRE
Comment
Abbreviations: HR, hazard ratio; IV, intravenous; NR, not reported; NS, not significant; NT, not tested; OS, overall survival; PFS, progression-free survival; SC, subcutaneous; SRE, skeletal-related event. ⴱ 8-mg arm reduced to 4 mg as a result of renal toxicity. †Extension of original study.
278
Dearnaley8†
311
122
Saad4a†
Metastatic castrationsensitive disease Dearnaley7
643
350
Metastatic castrationresistant disease Small3
Saad4
No. of Patients
Trial
OS
Table 1. Bone-Targeted Agents Studied in Phase III Trials in Men With Metastatic Prostate Cancer
Bone-Targeted Therapies and Metastatic Prostate Cancer
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Level 1 Evidence for Use of Disease State Antiresorptive Therapy
Other Considerations
Castration sensitive
No for Z, unknown for D
Risk for fracture (FRAX), previous SRE, bone pain
Castration resistant
Yes for Z and D, D superior to Z
Dental hygiene, renal function, IV or SC administration cost
Metastatic prostate cancer to bone
Fig 1. Approach to decision making regarding use of antiresorptive therapy for metastatic prostate cancer. D, denosumab; FRAX, fracture risk algorithm; IV, intravenous; SC, subcutaneous; SRE, skeletal-related event; Z, zoledronic acid.
these patients presented with pain and were treated with radiation therapy in addition to concurrently starting ADT. Although this subset analysis suggests that zoledronic acid may benefit a small proportion of men presenting with SREs, the overall results of this trial do not support the routine addition of zoledronic acid to the treatment of men with metastatic castration-sensitive disease. SUGGESTED APPROACHES TO MANAGEMENT
Given the results of the phase III trials discussed in the Summary of the Relevant Literature section, patients with newly diagnosed castrationsensitive metastatic disease should not routinely be treated early with zoledronic acid, whereas treatment with either denosumab or zoledronic acid should be strongly considered in those with castrationresistant disease. However, the importance of certain clinical features besides disease state when deciding whether to use antiresorptive therapy is discussed in this section and summarized in Figure 1. For men with metastatic castration-resistant disease, the clinical trial data clearly demonstrate benefit in terms of prevention and delay of SREs for both zoledronic acid and denosumab, with denosumab being superior to zoledronic acid. However, there are some patientspecific factors that should be considered before prescribing these agents. First, because of the small but real risk of osteonecrosis of the jaw, all patients should undergo a baseline dental examination and complete any invasive dental work before starting therapy.11 In patients with poor dental hygiene, the increased risk for osteonecrosis of the jaw with either agent may outweigh the benefits of using an antiresorptive agent. Another consideration is renal function. Zoledronic acid is excreted by the kidneys and can cause renal toxicity when the creatinine is increased. The dosage of zoledronic acid must be based on renal function and is contraindicated when the creatinine clearance is less than 30 mL/min, whereas denosumab is not excreted by the kidneys and can be administered even to patients on dialysis. The incidence of hypocalcemia is greater after denosumab (13%) than after zoledronic acid (6%).5 All patients treated with antirepsorptive agents should also be advised to take supplemental calcium and vitamin D. In the setting of castration-sensitive metastatic disease in a patient about to start ADT, the decision to use an antiresorptive agent has another dimension besides SREs. ADT causes loss of bone mineral density and increases the risk of fracture.11a In any patient who is about to start ADT, whether metastatic to bone or not, the underlying risk 1110
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for fracture resulting from existing osteopenia, osteoporosis or based on FRAX (a fracture risk algorithm) estimate should be determined. FRAX is an online assessment tool that incorporates age, body mass index, and other clinical risk factors to calculate the 10-year probability of a hip or major osteoporosis-related fracture. In individuals with no bone metastases but for whom there is a significant fracture risk (10-year probability of a hip fracture is ⱖ 3% or major osteorporosisrelated fracture is ⱖ 20%), the National Osteoporosis Foundation suggests consideration of pharmacologic therapy. Drugs that increase bone mineral density in men treated with ADT include zoledronic acid (5 mg once per year),12 alendronate (70 mg once per week),13 and denosumab (60 mg once every 6 months).14 However, only denosumab has been shown to decrease fracture risk.14 The osteoporosis consideration is not relevant in patients with castration-resistant disease if denosumab or zoledronic acid is going to be administered every 3 to 4 weeks for prevention or delay of SREs. The patient presented in this case study presented with several risk factors that could herald increased fracture risk even in the absence of cancer. These include his prior fractures (although traumatic), smoking history, alcohol intake, and ADT. The answer to the FRAX question regarding secondary osteoporosis should be answered yes if the patient is on or about to start ADT. For this patient, FRAX calculates a 3.1% to 4.9% (depending on how one answers the smoking question) 10-year risk of hip fracture, whereas the risk of major osteoporotic-related fracture is approximately 17%. This patient, who needs ADT, will be at increased risk for hip fracture, which can dramatically decrease life expectancy, even in a person without cancer.15,16 In this patient, the presence of metastatic disease in bone further compromises bone integrity and increases the risk for SREs. Another consideration concerns the fact that this patient has several of the clinical features—namely bone pain at presentation and a Gleason score of 8 —that could put him in the poor risk group of men with metastatic castration-sensitive disease defined by the SWOG 9346 trial.2 This raises concerns about earlier progression to castration resistance and death; perhaps, given the proximity of castration resistance, starting antiresorptive therapy earlier at a dose and schedule that is known to impact SRE might make sense. Starting ADT alone usually results in resolution of pain, but antiresorptive agents are also effective. Zoledronic acid reduced pain and analgesic scores compared with placebo4; subsequently, denosumab was shown to prevent the progression of pain more effectively than zoledronic acid in an integrated study.17 A final reason to consider the addition of antiresorptive therapy is that this patient could theoretically be in the subset of patients who benefited from early zoledronic acid in the Cancer and Leukemia Group B/Alliance trial. Although patients who present with pain usually respond to ADT alone, many are also treated concomitantly with radiation therapy. This would have constituted an SRE, and this subgroup experienced significant benefit from early zoledronic acid. For these reasons, I favor treating this patient with either denosumab or zoledronic acid, cognizant of the negative data from the prospective, randomized clinical trial reported by Smith et al.10 Because of its ability to prevent fracture (in this patient who is a risk according to FRAX) in the nonmetastatic setting, I would choose denosumab, acknowledging that this agent has not been studied in the metastatic castration-sensitive setting and that, although denosumab is superior to zoledronic acid in delaying SREs and pain progression in the castration-resistant state, the same cannot be assumed for the JOURNAL OF CLINICAL ONCOLOGY
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Bone-Targeted Therapies and Metastatic Prostate Cancer
castration-sensitive population. However, zoledronic acid would also be an acceptable alternative when cost, reimbursement, availability, or route of administration are at issue (Fig 1). Before starting therapy, I would check the patient’s vitamin D level and prescribe supplemental calcium and vitamin D. Both zoledronic acid and denosumab trials included recommendations for supplementation, and low vitamin D levels have been reported to result in profound hypocalcemia in a patient treated with zoledronic acid.18 Serum calcium, magnesium, and phosphate should all be monitored during therapy. One might wonder, “What about treating this patient with extensive bone metastases with radium 223, an agent that, unlike the antiresportives, has been shown to extend survival?” At present, no data support the use of this radioisotope in patients with castrationsensitive disease, although it is tempting to speculate that earlier use of radium 223 may be beneficial in terms of overall survival as well as SRE prevention. The trial by Smith et al10 clearly showed that earlier use of zoledronic acid did not decrease the risk of SRE or improve survival in all comers. Future studies may shed light on the early use of radium 223 in this disease state. In conclusion, individual clinical features of a patient must factor into decision making, and the resulting decision may seemingly conREFERENCES 1. National Cancer Institute: SEER cancer statistics factsheets: Prostate cancer. http://seer.cancer .gov/statfacts/html/prost.html 2. Hussain M, Tangen CM, Higano C, et al: Absolute prostate-specific antigen value after androgen deprivation is a strong independent predictor of survival in new metastatic prostate cancer: Data from Southwest Oncology Group Trial 9346 (INT0162). J Clin Oncol 24:3984-3990, 2006 3. Small EJ, Smith MR, Seaman JJ, et al: Combined analysis of two multicenter, randomized, placebo-controlled studies of pamidronate disodium for the palliation of bone pain in men with metastatic prostate cancer. J Clin Oncol 21:4277-4284, 2003 4. Saad F, Gleason DM, Murray R, et al: A randomized, placebo controlled trial of zoledronic acid in patients with hormone refractory metastatic prostate carcinoma. J Natl Cancer Inst 94:14581468, 2002 4a. Saad F, Gleason DM, Murray R, et al: Longterm efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J Natl Cancer Inst 96:879-882, 2004 5. Hagiwara M, Delea TE, Cong Z, et al: Utilization of intravenous bisphosphonates in patients with bone metastases secondary to breast, lung, or prostate cancer. Support Care Cancer 22:103-113, 2013 6. Fizazi K, Carducci M, Smith M, et al: Denosumab versus zoledronic acid for treatment of bone
tradict one based only on level-one clinical trial results. Clinical trials are conducted under well-defined circumstances and cannot be applied without considering patient-specific circumstances. Treatment algorithms must be used to guide but not dictate clinical practice. We still need thoughtful clinicians to practice the art of medicine and choose the best therapy for the individual patient. AUTHOR’S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) and/or an author’s immediate family member(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Celestia S. Higano, Amgen (C) Stock Ownership: None Honoraria: None Research Funding: None Expert Testimony: None Patents, Royalties, and Licenses: None Other Remuneration: None
metastases in men with castration-resistant prostate cancer: A randomised, double-blind study. Lancet 377:813-822, 2011 7. Parker C, Nilsson S, Heinrich D, et al: Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med 369:213-223, 2013 8. Dearnaley DP, Sydes MR, Mason MD, et al: A double-blind, placebo-controlled, randomized trial of oral sodium clodronate for metastatic prostate cancer (MRC PR05 Trial). J Natl Cancer Inst 95:13001311, 2003 9. Dearnaley DP, Mason MD, Parmar MK, et al: Adjuvant therapy with oral sodium clodronate in locally advanced and metastatic prostate cancer: Long-term overall survival results from the MRC PR04 and PR05 randomised controlled trials. Lancet Oncol 10:872-876, 2009 10. Smith MR, Halabi S, Ryan CJ, et al: Randomized controlled trial of early zoledronic acid in men with castration-sensitive prostate cancer and bone metastases: Results of CALGB 90202 (Alliance). J Clin Oncol 32:1143-1150, 2014 11. Ruggerio SL, Dodson TB, Assael LA, et al: American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaw: 2009 update. J Oral Maxillofac Surg 67:2-12, 2009 (suppl 5) 11a. Shahinian VB, Kuo Y-F, Freeman JL, et al: Risk of fracture after androgen deprivation for prostate cancer. N Engl J Med 352:154-164, 2005 12. Michaelson MD, Kaufman DS, Lee H, et al: Randomized controlled trial of annual zoledronic acid to prevent gonadotropin-releasing hormone agonist-
induced bone loss in men with prostate cancer. J Clin Oncol 25:1038-1042, 2007 13. Greenspan SL, Nelson JB, Trump DL, et al: Effect of once-weekly oral alendronate on bone loss in men receiving androgen deprivation therapy for prostate cancer: A randomized trial. Ann Intern Med 146:416-424, 2007 14. Smith MR, Egerdie B, Herna´ndez Toriz N, et al: Denosumab in men receiving androgendeprivation therapy for prostate cancer. N Engl J Med 361:745-755, 2009 15. Center JR, Nguyen TV, Schneider D, et al: Mortality after all major types of osteoporotic fracture in men and women: An observational study. Lancet 353:878-882, 1999 16. Cree M, Soskolne CL, Belseck E, et al: Mortality and institutionalization following hip fracture. J Am Geriatr Soc 48:283-288, 2000 17. von Moos R, Body JJ, Egerdie B, et al: Pain and health-related quality of life in patients with advanced solid tumours and bone metastases: Integrated results from three randomized, double-blind studies of denosumab and zoledronic acid. Support Care Cancer 21:3497-3507, 2013 18. Breen TL, Shane E: Prolonged hypocalcemia after treatment with zoledronic acid in a patient with prostate cancer and vitamin D deficiency. J Clin Oncol 22:1531-1532, 2004
DOI: 10.1200/JCO.2013.53.8900; published online ahead of print at www.jco.org on March 3, 2014
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In the last paragraph of the Discussion section, the last sentence was given as: “In conclusion, long-term follow-up of this randomized trial showed significantly better 5-year EFS and OS rates for myeloablative therapy with purged ABMT than for non–myeloablative chemotherapy, and cis-RA given after intensive therapy resulted in significant improvement in 5-year OS rates, regardless of the type of consolidation.” While it should have been:
“In conclusion, long-term follow-up of this randomized trial showed significantly better 5-year EFS rate for myeloablative therapy with purged ABMT than for nonmyeloablative chemotherapy, although there was no statistically significant improvement in OS.” The online version has been corrected in departure from the print. The authors apologize for the mistakes. DOI: 10.1200/JCO.2014.57.0382; published June 10, 2014
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The April 10, 2014, editorial by Friedlander et al, entitled “The End of the Beginning: Circulating Tumor Cells As a Biomarker in Castration Resistant Prostate Cancer” (J Clin Oncol 32:1104-1106, 2014), contained an error. The last sentence of the eighth paragraph was inadvertently given as, “Similarly, in the Trastuzumab in HER2-Negative Early Breast Cancer As Adjuvant Treatment for Circulating Tumor Cells (TREAT-CTC) study, women with detectable CTCs after neoadjuvant chemotherapy are randomly assigned to trastuzumab or a placebo to see whether vascular endothelial growth factor–directed therapy reduces relapses in women at high risk of recurrence.”
It should have been given as, “Similarly, in the Trastuzumab in HER2-Negative Early Breast Cancer As Adjuvant Treatment for Circulating Tumor Cells (TREAT-CTC) study, women with detectable CTCs after neoadjuvant chemotherapy are randomly assigned to trastuzumab or a placebo to see whether human epidermal growth factor receptor 2 – directed therapy reduces relapses in women at high risk of recurrence.” The authors apologize for the mistake. . DOI: 10.1200/JCO.2014.57.0036; published June 10, 2014
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The April 10, 2014, Oncology Grand Rounds article by C.S. Higano, entitled “To Treat or Not to Treat, That Is the Question: The Role of Bone-Targeted Therapy in Metastatic Prostate Cancer” (J Clin Oncol 32:1107-1111), contained an error. On page 1108, in the section Summary of the Relevant Literature, the last sentence of the first paragraph under the heading Met-
astatic Castration-Resistant Disease: Bone-Targeted Antiresorptive Agents, incorrectly cited reference 10. It should have cited reference 5. Journal of Clinical Oncology apologizes for the mistake. DOI: 10.1200/JCO.2014.57.0044; published June 10, 2014
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