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Denosumab in castration-resistant prostate cancer
Correspondence
Denosumab in castration-resistant prostate cancer Matthew Smith and colleagues (Jan 7, p 39)1 show that denosumab increases bone-metastasis-free survival in patients with castration-resistant prostate cancer. They also report that 33 patients (5%) in the experimental group developed osteonecrosis of the jaw, and another nine (1%) developed hypocalcaemia, both adverse effects being attributable to denosumab administration. Smith and colleagues report hazard ratios; however, they do not comment on numbers needed to treat (NNT). Figure 2 in the paper1 shows 72%, 54%, and 40% bonemetastases-free survival at 12, 24, and 36 months of follow-up, respectively, in the control group. By use of these proportions and the reported hazard ratio, the number of patients needed to treat to prevent one case of bone metastasis would be 27·5 (95% CI 15·0–210·7), 19·1 (10·2–149·3), and 17·0 (8·9–135·2)2 at 12, 24, and 36 months, respectively. From table 2 in the paper,1 considering osteonecrosis of the jaw alone, the number needed to harm (NNH) would be 21·5 (16·3–32·9), calculated on an intention-to-treat basis. Thus NNT for bone-metastasis-free survival and NNH for osteonecrosis of the jaw are not very dissimilar. Smith and colleagues discuss that most cases of osteonecrosis of the jaw were managed conservatively.1 However, 21 patients (64%) required debridement and curettage that necessitated expert surgeon involvement and a tertiary hospital inpatient setting.3,4 The reported mucosal healing in 13 patients (39%) was recorded in February, 2011—8 months after the analysis cutoff. Although mucosal healing is a definite marker for disease amelioration, it is not evidence of resolution, since this would also require imaging www.thelancet.com Vol 379 May 12, 2012
techniques.3,5 Even so, 20 patients (3·6%) still had the disease. Because oral risk factors were noted in 31 (94%) of patients with osteonecrosis of the jaw,1 future denosumab trials should include preventive interventions to avoid harming participants. We declare that we have no conflicts of interest.
*Athanassios Kyrgidis, Thrasivoulos-George Tzellos [email protected] Department of Oral Maxillofacial Surgery (AK) and Department of Pharmacology (AK, T-GT), Aristotle University of Thessaloniki, 54630 Thessaloniki, Greece 1
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3
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5
Smith MR, Saad F, Coleman R, et al. Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial. Lancet 2012; 379: 39–46. Altman DG, Andersen PK. Calculating the number needed to treat for trials where the outcome is time to an event. BMJ 1999; 319: 1492–95. Ruggiero SL, Dodson TB, Assael LA, Landesberg R, Marx RE, Mehrotra B. American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws—2009 update. J Oral Maxillofac Surg 2009; 67 (suppl 1): 2–12. Vahtsevanos K, Kyrgidis A, Verrou E, et al. Longitudinal cohort study of risk factors in cancer patients of bisphosphonate-related osteonecrosis of the jaw. J Clin Oncol 2009; 27: 5356–62. Kyrgidis A, Tzellos T-G, Toulis K, Antoniades K. The facial skeleton in patients with osteoporosis: a field for disease signs and treatment complications. J Osteopor 2011; published online Feb 16. DOI: 10.4061/2011/147689.
Authors’ reply We appreciate the comments from Athanassios Kyrgidis and Thrasivoulos-George Tzellos on our report of denosumab treatment in men with castration-resistant prostate cancer at high risk of developing bone metastasis. Calculations of number needed to treat (NNT) and number needed to harm (NNH) can be used to assess quantitatively the balance of benefits and risks of treatment. Kyrgidis and Tzellos calculate NNT and NNH on the basis of crude incidences. However, for long-term, event-driven trials and chronic disorders, calculations based on adjusted event rates per patient-year are more appropriate
because the benefits or harms are determined irrespective of treatment duration.1 By use of this approach, NNT for bone-metastasis-free survival (where the event is bone metastasis or death) was 21·4 (1/[(370 placebo events/1134·2 placebo patient-years)– (335 denosumab events/1198·2 denosumab patient-years)]) and NNH for osteonecrosis of the jaw was 38·0 (1/[(33/1254·7)– (0/1206·4)]). On the basis of these calculations, the NNH for osteonecrosis of the jaw is almost twice the NNT for bone-metastasisfree survival, consistent with a favourable benefit:risk profile. Additionally, NNT/NNH methods do not take into account any qualitative differences between the benefit and the harm. Bone metastases are irreversible, life-changing events that are systemic in nature, associated with progressive and significant morbidity, and trigger initiation of systemic antineoplastic treatments such as chemotherapy, immune therapy, or second-line hormonal therapy. Osteonecrosis of the jaw is a localised event, and in our study was generally mild to moderate in severity. In patients who developed osteonecrosis of the jaw, no discernible worsening in patient-reported outcomes, including pain, were noted throughout the development of the event, and, by contrast with the statements made by Kyrgidis and Tzellos, dental interventions to treat osteonecrosis of the jaw did not usually require hospital admission. At the time our trial was started, whether denosumab was associated with osteonecrosis of the jaw was not known. Comprehensive measures to detect and adjudicate osteonecrosis of the jaw were put in place, but with no specific requirement for preventive dentistry. In accordance with current guidelines for treatment with antiresorptive therapies,2 patients should have appropriate preventative dentistry before treatment initiation, and maintain good oral hygiene and
Submissions should be made via our electronic submission system at http://ees.elsevier.com/ thelancet/
e50
Denosumab in castration-resistant prostate cancer Matthew Smith and colleagues (Jan 7, p 39)1 show that denosumab increases bone-metastasis-free survival in patients with castration-resistant prostate cancer. They also report that 33 patients (5%) in the experimental group developed osteonecrosis of the jaw, and another nine (1%) developed hypocalcaemia, both adverse effects being attributable to denosumab administration. Smith and colleagues report hazard ratios; however, they do not comment on numbers needed to treat (NNT). Figure 2 in the paper1 shows 72%, 54%, and 40% bonemetastases-free survival at 12, 24, and 36 months of follow-up, respectively, in the control group. By use of these proportions and the reported hazard ratio, the number of patients needed to treat to prevent one case of bone metastasis would be 27·5 (95% CI 15·0–210·7), 19·1 (10·2–149·3), and 17·0 (8·9–135·2)2 at 12, 24, and 36 months, respectively. From table 2 in the paper,1 considering osteonecrosis of the jaw alone, the number needed to harm (NNH) would be 21·5 (16·3–32·9), calculated on an intention-to-treat basis. Thus NNT for bone-metastasis-free survival and NNH for osteonecrosis of the jaw are not very dissimilar. Smith and colleagues discuss that most cases of osteonecrosis of the jaw were managed conservatively.1 However, 21 patients (64%) required debridement and curettage that necessitated expert surgeon involvement and a tertiary hospital inpatient setting.3,4 The reported mucosal healing in 13 patients (39%) was recorded in February, 2011—8 months after the analysis cutoff. Although mucosal healing is a definite marker for disease amelioration, it is not evidence of resolution, since this would also require imaging www.thelancet.com Vol 379 May 12, 2012
techniques.3,5 Even so, 20 patients (3·6%) still had the disease. Because oral risk factors were noted in 31 (94%) of patients with osteonecrosis of the jaw,1 future denosumab trials should include preventive interventions to avoid harming participants. We declare that we have no conflicts of interest.
*Athanassios Kyrgidis, Thrasivoulos-George Tzellos [email protected] Department of Oral Maxillofacial Surgery (AK) and Department of Pharmacology (AK, T-GT), Aristotle University of Thessaloniki, 54630 Thessaloniki, Greece 1
2
3
4
5
Smith MR, Saad F, Coleman R, et al. Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial. Lancet 2012; 379: 39–46. Altman DG, Andersen PK. Calculating the number needed to treat for trials where the outcome is time to an event. BMJ 1999; 319: 1492–95. Ruggiero SL, Dodson TB, Assael LA, Landesberg R, Marx RE, Mehrotra B. American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws—2009 update. J Oral Maxillofac Surg 2009; 67 (suppl 1): 2–12. Vahtsevanos K, Kyrgidis A, Verrou E, et al. Longitudinal cohort study of risk factors in cancer patients of bisphosphonate-related osteonecrosis of the jaw. J Clin Oncol 2009; 27: 5356–62. Kyrgidis A, Tzellos T-G, Toulis K, Antoniades K. The facial skeleton in patients with osteoporosis: a field for disease signs and treatment complications. J Osteopor 2011; published online Feb 16. DOI: 10.4061/2011/147689.
Authors’ reply We appreciate the comments from Athanassios Kyrgidis and Thrasivoulos-George Tzellos on our report of denosumab treatment in men with castration-resistant prostate cancer at high risk of developing bone metastasis. Calculations of number needed to treat (NNT) and number needed to harm (NNH) can be used to assess quantitatively the balance of benefits and risks of treatment. Kyrgidis and Tzellos calculate NNT and NNH on the basis of crude incidences. However, for long-term, event-driven trials and chronic disorders, calculations based on adjusted event rates per patient-year are more appropriate
because the benefits or harms are determined irrespective of treatment duration.1 By use of this approach, NNT for bone-metastasis-free survival (where the event is bone metastasis or death) was 21·4 (1/[(370 placebo events/1134·2 placebo patient-years)– (335 denosumab events/1198·2 denosumab patient-years)]) and NNH for osteonecrosis of the jaw was 38·0 (1/[(33/1254·7)– (0/1206·4)]). On the basis of these calculations, the NNH for osteonecrosis of the jaw is almost twice the NNT for bone-metastasisfree survival, consistent with a favourable benefit:risk profile. Additionally, NNT/NNH methods do not take into account any qualitative differences between the benefit and the harm. Bone metastases are irreversible, life-changing events that are systemic in nature, associated with progressive and significant morbidity, and trigger initiation of systemic antineoplastic treatments such as chemotherapy, immune therapy, or second-line hormonal therapy. Osteonecrosis of the jaw is a localised event, and in our study was generally mild to moderate in severity. In patients who developed osteonecrosis of the jaw, no discernible worsening in patient-reported outcomes, including pain, were noted throughout the development of the event, and, by contrast with the statements made by Kyrgidis and Tzellos, dental interventions to treat osteonecrosis of the jaw did not usually require hospital admission. At the time our trial was started, whether denosumab was associated with osteonecrosis of the jaw was not known. Comprehensive measures to detect and adjudicate osteonecrosis of the jaw were put in place, but with no specific requirement for preventive dentistry. In accordance with current guidelines for treatment with antiresorptive therapies,2 patients should have appropriate preventative dentistry before treatment initiation, and maintain good oral hygiene and
Submissions should be made via our electronic submission system at http://ees.elsevier.com/ thelancet/
e50