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Originally published as JCO Early Release 10.1200/JCO.2006.05.9212 on September 25 2006 © 2006 American Society of Clinical Oncology. Phase II Trial Evaluating the Palliative Benefit of Second-Line Zoledronic Acid in Breast Cancer Patients With Either a Skeletal-Related Event or Progressive Bone Metastases Despite First-Line Bisphosphonate Therapy
From the Division of Medical Oncology, Princess Margaret Hospital; Division of Medical Oncology; Department of Clinical Pathology, Sunnybrook and Women's College Health Sciences Centre, Toronto, Ontario, Canada Address reprint requests to Mark J. Clemons, MD, Princess Margaret Hospital (Suite 5-205), 610 University Avenue, Toronto, Ontario, Canada M5G 2M9; e-mail: Mark.Clemons{at}uhn.on.ca
PURPOSE: This study evaluated whether additional palliative benefits could be derived from the second-line use of the more potent bisphosphonate zoledronic acid in metastatic breast cancer patients with either progressive bone metastases or skeletal-related events (SRE), despite first-line therapy with either pamidronate or clodronate. PATIENTS AND METHODS: This prospective study evaluated the impact of second-line zoledronic acid on pain, quality of life, and markers of bone turnover (for example, urinary N-telopeptide [NTX]). Patients received monthly zoledronic acid (4mg) for 3 months. Study evaluations were made weekly during the first month and again at week 8. No changes in chemotherapy or endocrine therapy were allowed in the month before or after commencing study treatment. RESULTS: Thirty-one women completed this study. By week 8, patients had experienced significant improvements in pain control (P < .001). There was a downward trend in urinary NTX levels over the same time period (P = .008). Overall, there was a trend towards a positive correlation between improvement in pain control and reduction in week one urinary NTX relative to baseline (Spearman's rho r = 0.27; P = .15). CONCLUSION: This is the first study to demonstrate that patients with either progressive bone metastases or SREs while on clodronate or pamidronate can have relevant palliative benefits with a switch to the more potent bisphosphonate zoledronic acid. This is reflected by significant improvements in pain control and bone turnover markers. If confirmed in randomized trials, these findings have major implications to the use of bisphosphonates in both the metastatic and adjuvant settings.
Breast cancer is the most common malignancy in women in North America. In 2005, there were an estimated 214,620 new cases and 41,330 deaths.1 Despite adjuvant treatment, many women will ultimately develop metastatic disease. Bone remains the most common site of distant disease recurrence and is affected in an estimated 65% to 75% of women with advanced breast cancer. Of those women with bone metastases, two thirds will subsequently develop skeletal-related events (SREs) and even in their absence, nearly all patients will have progression of their bone disease.2 The effective management of bone metastases is essential for improving a patient's quality and quantity of life. The management of bone metastases from breast cancer has been revolutionized by the use of the bisphosphonates. When used in addition to chemotherapy or hormonal therapy, these inhibitors of osteoclast mediated bone resorption, have been shown in randomized trials to significantly reduce the incidence of and delay the onset of SREs. 4-8 Indeed it is now standard practice to prescribe a bisphosphonate to breast cancer patients with newly diagnosed bone metastases.9 Despite modern treatments such as bisphosphonates, chemotherapy, endocrine therapy, trastuzumab, radiation, and analgesics, patients continue to suffer the morbidity and mortality consequences of bone metastases. The development of innovative therapeutic solutions has been hampered by the lack of tools that would allow the rapid assessment of bone response.10 Randomized trials comparing bisphosphonates have used the incidence and frequency of SREs as the primary end point. In such trials, SREs are typically defined as pathologic vertebral and nonvertebral fractures, spinal cord compression, hypercalcemia and surgery, or radiation to bone.11 However, pain, immobility, analgesic use, and costs (direct and indirect) are not components of the SRE composite end point. It can be argued these end points are as important as traditional SREs in the assessment of bisphosphonates.12 Trials with SREs as primary end points also require a substantial sample size to provide adequate statistical power and can take many years to give meaningful results.11,13 As an alternative primary surrogate end point of response to bisphosphonate therapy, biomarkers of bone metabolism may allow a more rapid assessment of treatment efficacy.14 Of the potential bone markers available to date, bone remodeling N-telopeptide of type I collagen (NTX) has demonstrated the strongest correlation with the extent of bone metastases, severity of bone pain, symptomatic relief, decrease in the incidence of SREs, and improved survival.14,15 Coleman et al16 recently demonstrated that high and moderate levels of urinary NTX (uNTX; > 50 nmol/mmol creatinine) are associated with a two-fold increase in the risk of SREs and disease progression compared with patients with lower NTX levels (P = .001). Control of NTX levels can therefore be viewed as an important surrogate for evaluating new strategies for managing progressive bony disease.17 While it is standard practice to prescribe bisphosphonates to all breast cancer patients with newly diagnosed bone metastases, the management of patients who are on a bisphosphonate when either SREs occur or there is progression of bone metastases is unclear. While oncologists traditionally switch systemic anticancer therapy on progression, the impact of switching to an alternate second-line bisphosphonate in these patients remains relatively unexplored.18 In Canada, the most commonly used bisphosphonates in patients with metastatic breast cancer are intravenous pamidronate and oral clodronate.19 It is therefore worthwhile to investigate if additional palliative benefit could be derived from the second-line use of a more potent bisphosphonate. As zoledronic acid is at least equivalent and possibly superior to pamidronate in terms of reducing SREs,6 this seemed the most appropriate agent to test in this second-line setting. In this phase II study, the palliative efficacy of second-line zoledronic acid was evaluated. Biochemical markers of bone metabolism were also assessed in an exploratory analysis to identify an early predictor of patient benefit.
The primary objective of this prospective study was to measure the palliative benefit of second-line zoledronic acid in breast cancer patients with either a skeletal related event or progressive bone metastases. Palliative benefit was reflected through various measures of pain (Brief Pain Inventory) and quality of life (Functional Assessment of Cancer Therapy [FACT]).20,21 Palliative response was defined as a reduction of at least two units in the worst pain score using the Brief Pain Inventory. Markers of bone resorption (uNTX, urinary deoxypyridinoline [DPD], and formation [serum bone-specific alkaline phosphatase [BAP]) were also measured at the same fixed time points. The secondary objective consisted of measuring the strength of the correlation between pain reduction and early changes of biochemical markers of bone turnover in order to find a rapid predictor of patient benefit. Study inclusion criteria were: patients with histologically confirmed breast cancer with known bone metastases. Patients had to have either an SRE (defined as pathologic vertebral and nonvertebral fractures, spinal cord compression, hypercalcemia and surgery, or radiation to bone) or radiologic progression of bone metastases while on clodronate or pamidronate, good performance status (Karnofsky performance score, > 60) and a life expectancy of at least 3 months. Due to the potential effects of new systemic therapy on the palliative end points, new or additional systemic anticancer treatments in the month before or after commencing study treatment were not allowed. Patients previously on an oral bisphosphonate continued the oral agent until the day before starting zoledronic acid. Patients on pamidronate received their last infusion 3 weeks before commencing study. To avoid zoledronic acid induced hypocalcaemia, patients were prescribed oral supplementation of calcium and vitamin D. Patients with an acute pathologic fracture, spinal cord compression, or hypercalcemia, prior hypersensitivity to bisphosphonates, or severe renal or hepatic dysfunction were excluded from the study. The Research Ethics Board of Sunnybrook and Women's College Health Sciences Center approved the study protocol. After patients provided written informed consent to participate in the study, their current bisphosphonate (pamidronate or clodronate) was discontinued and replaced with a monthly infusion of zoledronic acid (4 mg) over 15 minutes for 3 months. Measures of pain, number of pain sites, and quality of life were conducted at baseline and on a weekly basis during the first month and then again at week 8. At these time points a second pass morning urine sample was also collected and blood drawn for laboratory tests. Apart from routine clinical monitoring, the urine sample was assayed for creatinine by a standard kinetic Jaffe method, for uNTX with the Osteomark enzyme immunoassay (EIA) kit (Wampole Laboratories, Princeton NJ) and for free DPD by the Metra EIA kit (Quidel Corporation, San Diego, CA). Serum was stored at –20C and BAP assayed on all samples in batch mode using the Metra EIA kit (Quidel Corporation). Data were presented descriptively as means, medians, or proportions. Friedman's nonparametric ANOVA for repeated measures was used to test the significance of changes in pain, quality of life scores, uNTX, DPD, and BAP relative to baseline. Spearman's rho was used to calculate the correlation between NTX change in week one and change in worst pain score from week 8, relative to baseline. The likelihood ratio test as part of an exploratory logistic regression analysis was used to determine if a decrease in uNTX at week one relative to baseline was a significant predictor of palliative response to zoledronic acid when measured at week 8. The sample size of this trial was based on the strength of correlation between changes in uNTX and changes in pain relative to baseline scores. Using a level of significance of .05, a sample size of 31 patients is required to detect a correlation coefficient between these two parameters of at least 0.30 (r = 0.3). Given the small sample size and the unknown nature of the sampling distribution, nonparametric bootstrapping was used to estimate the variance of the clinical predictors. All of the statistical analyses were performed using Stata, version 9.0 (Stata Corp, College Station, TX).
A total of 31 patients completed this study. Demographic and disease related information is presented in Table 1. Patients had a mean age of 58 years and biochemistry related parameters were within expected limits at study entry. Approximately 42% of patients had bone as their only site of metastatic disease while 48% had bone and visceral metastases. Patients had received a median of two and one regimens of prior endocrine therapy and chemotherapy, respectively, for metastatic disease. Pamidronate was the most commonly used agent with 25 (80.6%) of 31 patients having received this agent as first-line therapy while six patients were receiving oral clodronate. Median duration of prior bisphosphonate therapy was 22 months. Overall, patients had experienced a median of two SREs while on first-line bisphosphonate therapy.
With respect to study entry criteria (either progressive bone metastases or the occurrence of an SRE while on first-line bisphosphonate therapy), 15 of 31 patients had experienced an SRE. Radiation therapy to bone was the SRE event in 14 of the15 (Table 1). For the 14 patients who entered the study after radiotherapy to bone the median time from radiotherapy to study entry was 82 days, range, 2 to 1,467 days. The median time from the last change in systemic treatment (chemotherapy or hormone therapy) to entering the study in all 31 patients was 151.5 days, range, 28 to 1,222 days. As required in the study protocol, pain, quality of life, and biochemical markers of bone turnover were measured at baseline and on a weekly basis during the first month and then again at week 8. However, changes in systemic chemotherapy or endocrine therapy were permitted after week 4, which occurred in only five patients. By week 8, patients had a statistically significant reduction in their worst pain and average pain scores (P < .001) with 13 (41.9%) of 31 patients experiencing a palliative response (Figs 1 and 2). In addition, there were also statistically significant reductions in the number of pain sites relative to baseline (Fig 3). Despite the advanced state of disease, overall quality of life did not deteriorate over the 8-week study period.
With respect to the markers of bone turnover, NTX appeared to be the most sensitive to drug response with statistically significant reductions over the 8-week study period (Fig 4). In contrast, urinary DPD was less sensitive as indicated by a smaller, more variable and nonsignificant decline over time (Fig 5). Bone alkaline phosphate did not decline but rose slightly, which occurs when bone formation capability is preserved (data not shown). When expressed as percent change relative to baseline over time, uNTX demonstrated consistent reductions up to week 8 (Fig 6). Overall, there was a positive correlation between improvement in pain control and reduction in week one uNTX relative to baseline (Spearman's rho r, 0.27; P = .15; 95% CI, –0.046 to 0.58).
The final analysis performed in the current study was exploratory in nature and intended to determine if early reductions in uNTX relative to baseline could be used to predict palliative response at week 8. Given our small sample size and the limited palliative response rate (ie, 13 of 31 patients), only two binary predictor variables were evaluated in a logistic regression analysis; a week 1 fall in uNTX relative to baseline (any drop; yes v no) and duration of primary bisphosphonate therapy before study entry of more than 6 months (yes v no). These variable definitions were created based on a priori hypotheses after a review of the literature and the pathophysiology of metastatic bone disease. At week 1, 23 (76.7%) of 30 had a drop in their uNTX relative to baseline. At week 8, these 23 patients experienced a 2.4 unit decline in their worst pain score, compared with only a 0.28 unit drop in the seven patients whose week 1 uNTX increased relative to baseline (P = .11). A week 1 drop in uNTX relative to baseline was identified as an important predictor for palliative response to zoledronic acid when measured at week 8 (odds ratio, 9.4; 95% CI, 2.28 to 79.8). Similarly, patients who received first-line bisphosphonate therapy for at least 6 months were also more likely to derive a palliative response (odds ratio, 6.28; 95% CI, 1.83 to 90.0).
Bisphosphonates are an accepted standard of practice in the management of breast cancer patients with bone metastases. However, many questions about their use remain unanswered. It is important to realize that these agents are not a panacea—even with bisphosphonate use from the time of diagnosis of bone metastases, many patients will continue to have SREs and nearly all will have progression of their bone disease.3 The optimal use of these agents in all types of patients is unknown. In addition, there is no evidence supporting their continued use on bony progression and multiple SREs. As a result, patients often continue to receive the same bisphosphonate until death. In one multicenter drug use evaluation study 90% of patients received a bisphosphonate as the last intravenous drug administered before death.19 Furthermore, there are some issues with the use of SREs as the primary end point in randomized bisphosphonate trials. Pain, which is the most commonly expressed symptom by patients with bone metastases, is not quantified by the SRE end point.22 In clinical practice, most patients with bone progression and SREs are maintained on the same agent without any supportive evidence. This is the first prospective study to demonstrate that second-line bisphosphonate therapy with the more potent agent is able to provide substantial palliative benefit, as reflected by significant improvements in pain scores. In addition, uNTX was a sensitive marker for pain control with zoledronic acid as indicated by the immediate and maintained reduction in average levels relative to baseline. Our exploratory analysis also suggests that uNTX may become a rapid predictor of palliative pain response when second-line bisphosphonates are used in patients with progressive bone disease or SREs while on a first-line agent. If validated with additional prospective data, this clinical predictor could be used to identify which patients would most benefit from the second-line use of the more potent agent. In those patients who do not have a drop in their week 1 uNTX, zoledronic acid could be discontinued after a single dose allowing patients to be offered other options for pain control. Some would question why pamidronate and clodronate continue to be used in Canada. In Canada, pamidronate and clodronate are both available in generic formulations with monthly costs of less than $100 (Canadian dollars). In contrast, zoledronic acid is available at a cost of over $500 (Canadian dollars). It is recognized from the randomized bisphosphonate trials of the late 1990s, which compared bisphosphonate with placebo, that the absolute magnitude of benefit was approximately 13%.4 Therefore a substantial proportion of patients receiving bisphosphonates are unlikely to receive any absolute benefit from this treatment. While randomized trials have demonstrated a modest improvement in SRE avoidance with zoledronic acid as an alternative to pamidronate, Canadian formulary committees felt that this benefit could not justify the substantial incremental cost over pamidronate and clodronate.9,24 Given all these considerations, a cost-effective strategy may be to initiate therapy with the less expensive agent and then substitute second-line zoledronic acid in those patients who develop SREs or progressive bone metastases. Continuation of zoledronic acid would be particularly effective in those patients that have a fall in uNTX. This might also be a useful strategy given the concern over toxicities associated with prolonged bisphosphonate use.25 More definitive conclusions require a randomized trial of continued therapy with the same bisphosphonate such a pamidronate or randomizing to a second more potent agent, such as zoledronic acid or ibandronate. Our group will be undertaking such a trial. There are a number of limitations in this study. This was a small single-center, open label, phase II nonrandomized trial. It is recognized that changes in systemic therapy and/or radiotherapy before study entry might also affect urNTX values and pain scores potentially contaminating the effects of zoledronic acid. The median time from the last change in systemic treatment (chemotherapy or hormone therapy) before entering the study in all 31 patients was 151.5 days, range: 28 to 1,222 days. With respect to study entry criteria (either progressive bone metastases or the occurrence of an SRE while on first-line bisphosphonate therapy), 15 of 31 patients had experienced an SRE and of these patients radiation therapy to bone was the SRE event in 14 of 15 patients (Table 1). For these patients, the median time from radiotherapy to study entry was 82 days, range, 2 to 1,467 days. Only in 3 of 14 patients was radiotherapy given with 30 days of commencing the study (ie, days 2, 10, and 22). Given the long time intervals between a change in systemic therapy and radiotherapy to bone before commencing study medication the contaminating effects of these treatment modalities on the fall in uNTX are likely marginal. The current trial protocol allowed the treating clinician to start new systemic anticancer therapies after week 4. Even though this occurred in only five patients, such new treatments may have contaminated our measurements of pain control. A number of large randomized trials are currently exploring the role of adjuvant bisphosphonate therapy in the management of early stage breast cancer.23 The only data reported so far are for oral clodronate and intravenous pamidronate. If as expected, adjuvant bisphosphonates demonstrate improved patient outcomes, there will be an urgent need to know which agents to use in those patients who subsequently develop bone metastases despite receiving adjuvant bisphosphonate therapy. The current trial may shed some light into the design of novel and efficient randomized trials in such patients. In conclusion, this is the first prospective study to demonstrate that second-line therapy with the more potent zoledronic acid is able to provide substantial palliative benefit to patients who develop SREs or new bone metastases while on a less potent first-line agent. In addition, uNTX may allow the rapid assessment of whether or not patients in this setting will derive palliative benefits from second-line therapy. As the role of bone markers continues to evolve it is likely they will become invaluable tools to optimize bisphosphonate use.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. 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.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C)
published online ahead of print at www.jco.org on September 25, 2006. Supported in part by the Canadian Breast Cancer Foundation, Ontario Chapter. Laboratory studies (T.S., B.Y.L.W., D.E.C.C.) were supported in part by a grant from the Dairy Farmers of Canada. Presented in part in poster format at the 28th Annual San Antonio Breast Cancer Symposium, San Antonio, TX, December 8-11, 2005. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Jemal A, Murray T, Ward E, et al: Cancer statistics, 2005. CA Cancer J Clin 55:10-30, 2005 2. Plunkett TA, Smith P, Rubens RD: Risk of complications from bone metastases in breast cancer: Implications for management. Eur J Cancer 36:476-482, 2000[CrossRef][Medline] 3. Ross JR, Saunders Y, Edmonds PM, et al: Systematic review of role of bisphosphonates on skeletal morbidity in metastatic cancer. BMJ 327:469-475, 2003 4. Lipton A, Theriault R, Hortobagyi G, et al: Pamidronate prevents skeletal complications and is effective palliative treatment in women with breast carcinoma and osteolytic bone metastases: Long-term follow-up of two randomized controlled trials. Cancer 88:1082-1090, 2000[CrossRef][Medline] 5. Kristensen B, Ejlertsen B, Groenvold M, et al: Oral clodronate in breast cancer patients with bone metastases: A randomized study. J Intern Med 246:67-74, 1999[CrossRef][Medline] 6. Rosen LS, Gordon DH, Dugan W, et al: Zolendronic acid is superior to pamidronate for the treatment of bone metastases in breast carcinoma patients with at least one osteolytic lesion. Cancer 100:36-43, 2004[CrossRef][Medline] 7. Body JJ, Diel IJ, Lichinitzer M, et al: Oral ibandronate reduces the risk of skeletal complications in breast cancer patients with metastatic bone disease: Results from two randomized, placebo controlled phase III studies. Br J Cancer 90:1133-1137, 2004[CrossRef][Medline] 8. Body JJ, Diel IJ, Lichinitser MR, et al: On behalf of the MF 4625 Study Group: Intravenous ibandronate reduces the incidence of skeletal complications in patients with breast cancer and bone metastases. Ann Oncol 14:1399-1405, 2003 9. Hillner B, Ingle JN, Chlebowski RT, et al: American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer. J Clin Oncol 21:4042-4057, 2003 10. Clamp A, Danson S, Nguyen H, et al: Assessment of therapeutic response in patients with metastatic bone disease. Lancet Oncol 5:607-616, 2004[CrossRef][Medline] 11. Major P, Cook R: Efficacy of bisphosphonates in the management of skeletal complications of bone metastases and selection of clinical end-points. Am J Clin Oncol 25:s10-s18, 2002[Medline] 12. Gainford MC, Dranitsaris G, Clemons M: Recent developments in bisphosphonates for patients with metastatic breast cancer. BMJ 330:769-773, 2005 13. Anderson PK, Gill RD: Cox's regression model for counting processes: A large sample study. Ann Stat 10:1100-1120, 1982 14. Brown JE, Ellis SP, Gutcher SA, et al: Using bone turnover markers to direct bisphosphonate therapy: Is this a feasible approach? Cancer Treat Rev 31:S30, 2005 15. Ali SM, Demers LM, Leitzel K, et al: Baseline serum NTx levels are prognostic in metastatic breast cancer patients with bone-only metastases. Ann Oncol 15:455-459, 2004 16. Coleman RE, Major P, Lipton A, et al: Predictive value of bone resorption and formation markers in cancer patients with bone metastases receiving the bisphosphonate zoledronic acid. J Clin Oncol 23:4925-4935, 2005 17. Roodman GD: High bone turnover markers predict for outcome in patients with bone metastases. J Clin Oncol 23:4821-4822, 2005 18. Jagdev SP, Purohit OP, Heatley S, et al: Comparison of the effects of intravenous pamidronate and oral clodronate on symptoms and bone resorption in patients with metastatic bone disease. Ann Oncol 12:1433-1438, 2001 19. Clemons M, Enright K, Cesta A, et al: Do physicians follow systemic treatment and funding policy guidelines? Can J Clin Pharmacol 11:168-178, 2004 20. Cleeland CS, Ryan KM: Pain assessment: Global use of the Brief Pain Inventory. Ann Acad Med 23:129-138, 1994 21. Cella DF, Tulsky DS, Gray G, et al: The Functional Assessment of Cancer Therapy (FACT) scale: Development and validation of the general measure. J Clin Oncol 11:570-579, 1993 22. LoRusso P: Analysis of skeletal related events in breast cancer and response to therapy. Semin Oncol 28:22-27, 2001 (suppl 11)[Medline] 23. Clemons M, Verma S: Should oral bisphosphonates be standard of care in women with early breast cancer? Breast Cancer Res Treat 90:315-318, 2005[CrossRef][Medline] 24. Hillner BE: Pharmacoeconomic issues in bisphosphonate treatment of metastatic bone disease. Semin Oncol 28:64-68, 2001 (suppl 11)[CrossRef][Medline] 25. Bamias A, Kastritis E, Bamia E, et al: Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: incidence and risk factors. J Clin Oncol 23:8580-8587, 2005 Submitted January 26, 2006; accepted August 15, 2006. This article has been cited by other articles:
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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INTRODUCTION
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