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Originally published as JCO Early Release 10.1200/JCO.2003.07.078 on October 27 2003 © 2003 American Society for Clinical Oncology
Bisphosphonates for Men With Prostate Cancer: Sifting Through the Rubble
1 Genitourinary Oncology Service, Memorial Sloan-Kettering Cancer Center, Joan and Sanford Weill Medical College of Cornell University, New York, NY WITH 28,900 projected deaths due to prostate cancer in the United States in 2003, an effective agent certainly would have the potential to affect a large number of men.1 Small et al,2 in this issue of the Journal of Clinical Oncology, add new and important information to the evolving challenge of if, how, and when to optimally use bisphosphonates in men with metastatic prostate cancer who have symptomatic progressive disease despite surgical or chemical castration. Overall, no effect on bone pain or decrease in skeletal-related events was seen when the bisphosphonate pamidronate disodium, was administered to men with castrate-resistant disease and pain from bone metastases. Previously, several randomized and nonrandomized studies indicated that bisphosphonates may be useful to alleviate bone pain from metastatic prostate cancer and decrease the incidence of skeletal-related events, such as pathologic fracture, spinal cord compression, or the need for surgery or radiotherapy.3–7 This new information from Small et al certainly complicates the interpretation of these results. So what sets this trial apart from the others? This study evaluated the utility of the second-generation bisphosphate pamidronate disodium as adjunctive therapy. Unlike many of the other trials evaluating bisphonates in this clinical state, patients had to have had bone pain secondary to osseous metastases. Moreover, standard radiation therapy to treat extraskeletal or symptomatic osseous disease was allowed, along with additional hormonal or chemotherapy after randomization. The primary aim of the study was to determine whether pamidronate disodium could significantly reduce bone pain, based on changes on the brief pain inventory scale, and decrease analgesic consumption. This is a practical and clinically relevant end point. The proportion of patients in each arm who had skeletal-related events at 9 and 27 weeks was also investigated. Three hundred fifty patients were included in the intent-to-treat analysis. However, only 301 patients were assessable for pain and analgesic evaluation at 9 weeks, and the number dropped further, to 218 patients, by the termination of the study at 27 weeks. The treatment groups were well balanced for potential confounding factors. The intent-to-treat analysis demonstrated no significant changes in baseline pain scores between the treatment groups; however, in patients who had decreasing or stable analgesic requirements, mean decrease in pain scores was significantly improved, compared with that of the placebo group. Because the observed decreases from the baseline were less than 3 points on the pain inventory scale, it raises the question of whether this has any clinical significance. The investigators performed an exploratory analysis to look for trends for the effects of pamidronate disodium in groups with varying degrees of pain at baseline. In patients starting with moderate pain, a brief improvement of pain at 9 weeks favoring the pamidronate disodium group was seen, but this difference was not apparent at week 27. The proportions of patients in the two groups who had a skeletal-related event at week 9 were similar (12% in the pamidronate disodium group v 11% in the placebo group) and at week 27 were the same (25% for both groups). The overall lack of efficacy for the addition of pamidronate disodium could be attributed to many factors, including end points insensitive to determine the clinical benefit; confounding effects of concomitant antitumor or palliative therapies; or the use of a less potent bisphosphonate. The importance of this trial is that it used a practical end point clinicians can rely on daily to evaluate the effectiveness of therapy: the authors investigated whether the drug helps reduce pain and delays the need for intervention for osseous metastatic disease. Their study also used the bisphosphonates in the real world of treating patients, which involves treating them concomitantly with steroids, chemotherapy, or radiotherapy. Perhaps a more potent third generation bisphosphonate may have had an additional effect on the clinical outcome. Saad et al7 also reported a randomized study in which the bisphosphonate zoledronic acid, given intravenously 4 mg every 3 weeks, reduced the occurrence of a composite end point cited as "skeletal-related events." So we have two large studies, one by Saad et al and the one in this issue of the Journal of Clinical Oncology, reported by Small, with findings that may appear contradictory. Besides the difference in the potency in bisphosphonates, chance, validity issues, or varying clinical states may explain some of the discrepancies noted between these two trials. Small et al argue that the patients in their study may have more advanced disease than the patients in the Saad et al study (as reflected by a higher mean baseline serum prostate-specific antigen level and the proportion of patients with significant symptomatic disease) and that this factor may modify the ability to measure a treatment effect of bisphosphonates. We would need an extremely large study to prove the complete absence of an effect of a bisphosphonate in patients with bone metastases from prostate cancer; in real life, we do not have the scientific means to exclude a very small effect. The Small et al study, being moderately sized, presents data consistent with a small effect by pamidronate disodium. Interestingly, several major events the study documented occur with virtually identical frequency in the pamidronate disodium and the placebo group. Forty-two (25%) of 169 patients had at least one skeletal event in the pamidronate disodium group, versus 46 (25%) of 181 patients in the placebo group, translating to a relative risk of 0.98 (95% CI, 0.68 to 1.40.) Thus, the 95% CI includes a reduction of the number of patients with at least one skeletal event of 32%. If we instead put the burden of proof on those claiming efficacy, we have to examine the study by Saad et al in greater detail. Concerning their main end point, a skeletal-related event, results were similar to placebo for zoledronic acid, given first at 8 mg and thereafter at 4 mg; 38% of patients given the former had a skeletal-related event, compared with 44% given placebo. For unclear reasons, a lower percentage (33%) of patients given 4 mg (but not 8 mg) of zoledronic acid from the beginning had a significant reduction in the number of skeletal-related events than did the placebo group.7 Two questions arise when one examines the Saad study: Why were the results different between the two arms receiving zoledronic acid? What impact did the large attrition rate have? After 1 year, 160 of the original 435 patients were alive in the two arms receiving zoledronic acid, compared with 69 of the original 208 patients randomly assigned to receive the placebo.7 However, even though chance and validity issues may not explain these findings, there is an effect on skeletal-related events as measured in the trial; the question as to how this translates into a clinical benefit remains. Interestingly, Saad et al noted little impact on analgesic scores and quality-of-life indices, supporting the findings by Small et al. In both the Saad et al and Small et al studies, side effects were documented. Nausea, dizziness, fever, and myalgia were seen more frequently when treated with zoledronic acid than with placebo. Fever, nausea, fatigue, and weight decrease was documented more frequently after pamidronate disodium than after placebo. These symptoms probably had an impact on patients’ sense of well-being and self-assessed quality of life. So if avoidance of skeletal-related events has a beneficial effect on sense of well-being and self-assessed quality of life, it must be weighed against the adverse effects of the treatment. If a skeletal-related event is the discovery of an asymptomatic bone lesion, bisphosphonate therapy could actually have a detrimental impact on the well-being and quality of life of the patient. Therefore, one way to move forward in establishing the role of bisphosphonate therapy may be to avoid these complicated composite end points and concentrate on direct measures of clinical benefit in the future. Though many others can find additional faults that may explain why this trial did not show more clinical benefit to patients, the end points and the patients treated represent the real world and have given some clinical insight into how to manage our patients. The cumulative data on bisphosphonates in patients with castrate metastatic prostate cancer to date have not shown substantial clinical benefit to patients, if using relevant end points that are used to assess other therapeutic agents in this disease. Until this evidence is provided, routine administration of bisphosphates in castrate metastatic prostate cancer cannot be recommended. Certainly, the Small et al report will not end the debate about the role of bisphosphonates in prostate cancer. Further studies in this and other prostate cancer clinical states to evaluate the role of the bisphosphonates are needed, using end points that translate into real patient benefits. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The authors indicated no potential conflicts of interest. REFERENCES
1. Jemal A, Murray T, Samuels A, et al: Cancer Statistics, 2003. CA Cancer J Clin 53:5–26, 2003
2. Small E, Smith M, Seaman J, et al: Combined analysis of two mutlicenter, 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 3. Carey P, Lippert M: Treatment of painful prostatic bone metastases with oral etidronate disodium. Urology 32:403–407, 1988[CrossRef][Medline] 4. Cresswell S, English P, Hall R, et al: Pain relief and quality-of-life assessment following intravenous and oral clodronate in hormone-escaped metastatic prostate cancer. Br J Urol 76:360–365, 1995[Medline] 5. Smith JA Jr: Palliation of painful bone metastases from prostate cancer using sodium etidronate: Results of a randomized, prospective, double-blind, placebo-controlled study. J Urol 141:85–87, 1989[Medline] 6. Berruti A, Dogliotti L, Tucci M, et al: Metabolic bone disease induced by prostate cancer: Rationale for the use of bisphosphonates. J Urol 166:2023–2031, 2001[CrossRef][Medline]
7. Saad F, Gleason D, Murray R, et al: A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst 94:1458–1468, 2002
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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