Too Much, Too Little, Too Late to Start Again? Assessing the Efficacy of Bisphosphonates in Patients with Bone Metastases from Breast Cancer

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1 This material is protected by U.S. Copyright law. Unauthorized reproduction is prohibited. For reprints contact: Breast Cancer Too Much, Too Little, Too Late to Start Again? Assessing the Efficacy of Bisphosphonates in Patients with Bone Metastases from Breast Cancer Mark Clemons, a George Dranitsaris, b David Cole, c Mary C. Gainford a a Division of Medical Oncology and c Department of Clinical Pathology, Sunnybrook and Women s College Health Sciences Centre, Toronto, Canada; b Cancer Care Ontario, Toronto, Canada Key Words. Bisphosphonates Bone metastases Breast cancer Bone pain Efficacy Skeletal-related events Learning Objectives After completing this course, the reader will be able to: 1. Articulate the natural history of bone metastasis in the setting of advanced breast cancer. 2. Describe the role of bisphosphonates in managing bone metastases in the setting of breast cancer. 3. Discuss clinical end points used to determine whether bisphosphonates are useful in this setting. CME Access and take the CME test online and receive 1 AMA PRA category 1 credit at CME.TheOncologist.com Abstract The diagnosis of bone metastases can be a devastating occurrence for any woman with breast cancer. In this setting, bone metastases can result in skeletal-related events (SREs) such as pathologic fracture, spinal cord compression, and hypercalcemia. Several trials have confirmed the ability of bisphosphonates to reduce or delay these skeletal complications, and they should now be considered standard care for these women. The analysis of SREs is the typical primary end point in bisphosphonate studies. While not undermining their importance, the definition of SREs does not include complications important to patients, such as pain and immobility. It is these symptoms that are most frequently reported by patients, and bone pain and quality of life (QoL) are often measured as secondary end points in these trials. Bone pain and QoL measures are not standardized and are difficult to compare among patient populations. We do not yet know the true efficacy of bisphosphonates as analgesics or how they impact QoL. This paper reviews the current efficacy measures used in recent bisphosphonate trials and discusses their benefits and limitations. It also explores the role of bone biomarkers and their potential use in monitoring treatment response. The Oncologist 2006;11: Introduction The occurrence of metastatic bone disease is not only devastating to breast cancer patients but also leads to adverse outcomes in terms of greater morbidity and mortality. An estimated 70% of women with advanced breast cancer develop bone metastases. If they remain untreated, half of Correspondence: Mark Clemons, M.B., B.S., M.D., M.R.C.P., Division of Medical Oncology, Sunnybrook and Women s College Health Sciences Centre, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada. Telephone: ; Fax: ; mark. clemons@sw.ca Received November 29, 2005; accepted for publication January 17, AlphaMed Press /2006/$20.00/0 The Oncologist 2006;11:

2 228 Efficacy of Bisphosphonates in Metastatic Breast Cancer these patients will subsequently develop a skeletal-related event (SRE). SREs are generally defined as including one or more of the following: pathologic fracture, radiotherapy for bone complications (uncontrolled bone pain/impending fracture), surgery for bone complications (fractures or impending fractures), or spinal cord compression. It has been estimated that up to 40% of breast cancer patients with bone metastases will suffer a pathologic fracture, 18% will require radiation to bone, and 1% will require surgery, while <10% will develop spinal cord compression [1, 2]. However, pain is the most common symptom of bone metastases in actual practice, occurring in 50% 90% of patients [1, 3]. The treatment of breast cancer patients with bone metastases requires a multidisciplinary approach. Systemic treatment options include analgesics, hormonal therapy, chemotherapy, and biological agents such as trastuzumab and bisphosphonates [4]. Bisphosphonates such as clodronate, ibandronate, pamidronate, and zoledronic acid are now standard care for metastatic bone disease with proven ability to reduce the risk for predefined SREs [5]. A systematic review of five trials among patients with breast cancer confirms the beneficial effects of bisphosphonates over placebo. Treatment significantly reduced the odds ratio for nonvertebral fractures (0.8; 95% confidence interval [CI], ), combined fractures (0.75; 95% CI, ), radiotherapy (0.65; 95% CI, ), orthopedic surgery (0.59; 95% CI, ), and hypercalcemia (0.43; 95% CI, ) [6]. The role of bisphosphonates in the treatment of metastatic bone pain is not as clearly defined. In a randomized crossover trial of i.v. clodronate in patients with pain from bone metastases, Ernst et al. [7] reported a significant difference in daily morphine dose scores (p =.03) but no significant difference in scores from visual analogue scales (p =.51) between the placebo and clodronate groups. In a combined analysis of two studies of pamidronate, the mean pain scores at last visit increased in both the placebo and treatment groups. However, they increased significantly less in the treatment group (p <.001), with fewer patients experiencing an overall increase in pain (40% vs. 52%; p =.003) [8]. A review of phase III trials of ibandronate demonstrated that both the oral and i.v. formulations reduced bone pain to below baseline levels over 2 years (p.001 vs. placebo) [9]. In a phase III study of zoledronic acid versus placebo, while pain scores in the treatment group were consistently lower, they were not significantly different [2]. Guidelines from the American Society of Clinical Oncology (ASCO) suggest that i.v. pamidronate or zoledronic acid may be useful in the treatment of pain caused by bone metastases when used with concurrent systemic chemotherapy and/or hormonal therapy. However, there is insufficient evidence to support a role as adjunctive therapy to radiation therapy when no other systemic treatment is being used [10]. A systematic review by Wong and Wiffen [11] concluded that, although evidence supported their effectiveness in providing some pain relief for bone metastases, there were insufficient data to recommend bisphosphonates as first-line therapy, to define the most effective bisphosphonate, or to define the relative effectiveness of one agent or another against various different primaries. A recent survey reported that 31% of physicians in Europe and Canada consider bisphosphonates (on their own or in combination with other therapies) to be ineffective in controlling pain [12]. Furthermore, although patients seek rapid pain relief, the reality is that the onset of the analgesic effect is slow with standard doses of bisphosphonates. Despite the uncertainty regarding analgesic benefit, there has been a trend toward initiating bisphosphonates before delivery of palliative radiation therapy. A study by Enright et al. [13] reported that, before 1998, 42.9% of patients received palliative radiation treatment as initial therapy for bone metastases, whereas in 2001, only 27.8% of patients received palliative radiation treatment upfront. Clinicians need better methods of evaluating the effect of bisphosphonates on bone metastases in order to estimate their true efficacy and palliative value. Most studies depend on the number and timing of SREs to compare the treatment and placebo arms. The definition of an SRE does not include end points that are important to patients: pain, immobility, analgesic use, and nonhospital costs such as those of physiotherapy [5]. In addition, many studies use serial plain radiographs in the form of skeletal surveys to detect asymptomatic fractures, thereby detecting SREs but ignoring pain. Pain scores, analgesic consumption, and quality of life (QoL) scores are all subject to observer bias and are difficult to compare among different patient populations. To allow true estimation of analgesic and palliative benefits of bisphosphonates, we need a standardized pain measurement and QoL instrument that includes domains that are important to the patient. This paper reviews the current efficacy measures used in bisphosphonate trials and discusses their limitations. End Points in Bisphosphonate Trials The U.S. Food and Drug Administration s regular approval is based on end points that demonstrate that a drug provides a longer or better life or that it has a favorable effect on an established surrogate [14]. Regulatory approvals for currently available bisphosphonates were based on various clinical efficacy end points used to assess the occurrence of SREs. The Oncologist

3 Clemons, Dranitsaris, Cole et al. 229 SRE Measures Although SREs are the most frequently used primary end points in bisphosphonate trials (Table 1) [2, 8, 15 27], many different SRE scores are available, making comparisons among trials difficult. First-event analyses consider information for first SREs only. This type of analysis has been used as the primary end point in various zoledronic acid and pamidronate studies and includes the proportion of patients with at least one SRE along with the time to first event assessed by Kaplan-Meier techniques. Since bisphosphonates reduce the occurrence of subsequent SREs, first-event analysis can oversimplify the clinical picture and may not reflect the true benefit(s) of treatment [28]. Moreover, first-event analyses provide conservative estimates of palliative benefits by ignoring subsequent events over the long term. Typically, a patient s risk of experiencing an SRE increases with time as metastatic disease progresses. For this reason, the impact of treatment on skeletal morbidity is best captured by methods that measure multiple events over time. The mean skeletal morbidity rate (SMR) can be defined as the number of SREs per patient divided by the patient s time on study (in years) and has been reported and analyzed in trials of zoledronic acid and pamidronate. However, patients with bone metastases exhibit considerable variation in frequency and timing of SREs since some patients experience isolated events while others experience them in clusters [28]. When skeletal complications are temporally clustered, they are more likely related, but this clustering is not expressed in the SMR because it assumes that all SREs are independent of one another. An alternative measure is the skeletal morbidity period rate (SMPR), which also has been reported in phase III trials of i.v. and oral ibandronate. The SMPR accounts for the interdependence of events by counting events only once within a given time period and is defined as the number of periods with new events divided by the total number of periods on study per patient. The time periods chosen are typically on Table 1. Primary end points of placebo-controlled studies Bisphosphonate Dose Study SRE end points Zoledronic acid (i.v.) 4 mg every 3 4 wks Kohno et al. [2] SRE rate ratio: total number of SREs divided by total years on study Zoledronic acid (i.v.) 4 mg vs. 90 mg every 3 4 Rosen et al. [22, 23] Proportion of patients with at least one SRE vs. pamidronate (i.v.) wks Ibandronate (po) 50 mg/day Body et al. [16] SMPR: number of 12-wk periods with new skeletal complications divided by number of periods on study Ibandronate (po) 20 mg/day and 50 mg/day Tripathy et al. [25] SMPR Ibandronate (i.v.) 2 and 6 mg Body et al. [15] SMPR every 3 4 wks Pamidronate (i.v.) 90 mg every 4 wks Lipton et al. [8] SMR: number of skeletal complications divided by time on trial Pamidronate (i.v.) 60 mg every 4 wks Hultborn et al. [19] Total number of events, including disease progression, HCM, fractures, SCC, requirement for radiation, surgery, and change in systemic therapy Pamidronate (i.v.) 90 mg q 4 wks Theriault et al. [24] SMR Pamidronate (i.v.) 90 mg every 4 wks Hortobagyi et al. [18] Proportion of patients with at least one SRE Pamidronate (i.v.) 45 mg every 3 wks Conte et al. [17] Disease progression Pamidronate (po) 300 mg/day van Holten-Verzantvoort et al. [27] Total number of events, including requirement for radiation or surgery, fracture, and HCM Clodronate (po) 1,600 mg/day Tubiana-Hulin et al. [26] Time to new bone event (days) Clodronate (po) 1,600 mg/day Kristensen et al. [20] Total number of events, including HCM, fracture, and requirement for radiation Clodronate (po) 1,600 mg/day Paterson et al. [21] Total number of events, including HCM, fracture, and requirement for radiation Abbreviations: HCM, hypercalcemia of malignancy; po, orally; SCC, spinal cord compression; SMPR, skeletal morbidity period rate; SMR, skeletal morbidity rate; SRE, skeletal-related event.

4 230 Efficacy of Bisphosphonates in Metastatic Breast Cancer the order of 12 weeks. Because the SMPR accounts for the interdependence of skeletal events, it is increasingly being used in place of the SMR to report the findings of clinical trials. One important practical limitation of both the SMR and SMPR statistics is the difficulty in transforming these end points into a form that patients can understand when confronted with a decision to initiate a bisphosphonate. Multiple event analysis, such as the Andersen-Gill method [29], has been used to analyze SREs as secondary end points in clinical trials of zoledronic acid and ibandronate. The method examines all SREs and their timing throughout the course of the disease, taking variability in event rates among patients into account (including clustering), and allowing rates to vary over time [28]. It is a statistically robust method that accounts for all skeletal events and for the timing of events throughout the course of the disease. However, it does not fully account for between-group differences of patients time on study. For example, it is difficult to distinguish between groups in terms of patients who die or withdraw from the study for other reasons and are still at risk for an SRE. Cook and Lawless [30] have developed a multiple-event method that takes mortality into account, while Ghosh and Lin [31] have described another method that is useful in analyzing the cumulative number of events. Bone Pain Measures As with SREs, many different methods have been used to assess metastatic bone pain in bisphosphonate trials, and there is no universally accepted or validated instrument. Most trials use a combination of bone pain and analgesic count. Early trials did not make a formal assessment of bone pain because of the inadequacy of pain assessment methodology for patients with bone metastases. Instead, it was indirectly assessed by estimating the radiation requirement for pain, and radiation therapy was undertaken as clinically required [21]. The requirement for radiotherapy to the bone is considered an SRE in the composite end points of bisphosphonate trials. This requirement represents a significant part of the SRE end point. Therefore, in a roundabout way, SRE outcomes in these trials do incorporate some measure of pain relief. However, there is a need for a more direct assessment of metastatic bone pain relief. Randomized, placebo-controlled studies of pamidronate used a scoring system that measured both the severity (graded 0 3) and frequency (graded 0 3) of pain [8, 24]. The final bone pain score was equal to the product of the two individual scores. A score of 0 indicated no pain, while a score of 9 indicated severe, constant pain. Analgesic use was also estimated using a composite score. A final score was obtained by multiplying a score for the type of medication by a score for the frequency at which it was administered. Phase III trials of i.v. and oral ibandronate used a simple, five-point scale 0 (no pain), 1 (mild pain), 2 (moderate pain), 3 (severe pain), and 4 (intolerable pain) that patients were asked to complete every 3 4 weeks, during each study visit, to evaluate bone pain over the previous week [15, 16, 25, 32, 33]. Analgesic use was scored on a seven-point scale: 0 (none), 1 (mild analgesia; e.g., paracetamol or nonsteroidal anti-inflammatory drugs [NSAIDs]), 2 (mild analgesia and NSAIDs), 3 (moderate analgesia; e.g., codeine), 4 (opiates, morphine equivalent of <40 mg daily), 5 (opiates, 40 mg but <100 mg morphine equivalent daily), and 6 ( 100 mg morphine equivalent daily). The Brief Pain Inventory comprises a composite of four pain scores (worst, least, and average pain over the last week and current pain) and is validated for cancer pain rather than metastatic bone pain [34]. This was used in the placebo-controlled trial of zoledronic acid and a randomized comparative study of zoledronic acid versus pamidronate [2]. A five-point scale was used to measure analgesic use, ranging from 0 (no analgesic use) to 4 (strong narcotics). A range of other scales for both bone pain and analgesic use has been used by other studies. These include a visual analogue scale [19], variants of pain point scales [17], and analgesic use on a four- or five-point scale [19, 20]. While all these instruments represent an improvement in pain relief by a decrease in pain score, scale variations make it difficult for clinicians to estimate if the effect on pain relief differs among drugs. The Oncologist QoL Measures QoL measurements are subjective, multidimensional constructs reflecting functional status, psychosocial wellbeing, health perceptions, and disease- and treatmentrelated symptoms from the patient s perspective. They incorporate expectation, satisfaction, a value system, and many other aspects of a patient s life. In general, QoL has been poorly estimated in bisphosphonate studies. Pamidronate studies have used the Spitzer QoL instrument [35], which is intended to be completed by a health care professional and consists of only five items; activity, daily living, health, support, and outlook. This instrument was designed to assess the relative benefits and risks of various treatments for serious illness and of supportive programs, such as palliative care or hospice care. It is not suitable for measuring the QoL in ostensibly healthy people. Studies of clodronate [20] and ibandronate [32, 33] used the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQ-C30) [36]. This instrument is composed of modules that assess QoL for specific cancers in clinical trials. The current instrument con-

5 Clemons, Dranitsaris, Cole et al. 231 sists of 30 items with five functional scales: physical function, role function, cognitive function, emotional function, and social function. However, neither the Spitzer nor the European instrument addresses in depth the QoL issues related to the complications of bone metastases, such as mobility, functional impairment, and the side effects of bony progression, (such as pathological fractures, hypercalcemia, and spinal cord compression). There is an urgent need to develop a QoL instrument specific to bone metastases that addresses these issues. A Canadian-led group proposes to develop a specific module for patients with bone metastases that will be administered concurrently with the EORTC QLQ-C30 core questionnaire (Edward Chow, personal communication). When developed and used in future clinical trials, it will allow for more accurate self-assessment of the palliative benefits of bisphosphonate treatments. Bone Markers Markers of bone turnover (Table 2) are now frequently measured as secondary end points in bisphosphonate studies. Such markers seem to hold the most promise in identifying patients likely to respond to and benefit from bisphosphonate treatment [37]. Among them, urinary N-terminal cross-linked type 1 collagen telopeptide (untx) and C-terminal cross-linked type 1 collagen telopeptide (CTX) are the most widely used [38]. Elevated NTx levels predict subsequent SREs, and conversely, normalization of excretion rates is associated with a reduction in SREs and improvement of symptoms. A prospective study of 121 patients with solid tumors receiving bisphosphonates examined the relationship between the rate of bone resorption, measured by untx Table 2. Bone formation and resorption markers used for assessing response in metastatic bone disease from breast cancer Bone formation markers Bone-specific alkaline phosphatase Osteocalcin PINP, PICP Bone resorption markers Urinary calcium excretion Urinary hydroxyproline Collagen pyridine cross-links (PYD, DPD) Protein-bound cross-links (NTx, CTX/ICTP) Abbreviations: CTX/ICTP, C-terminal cross-linked type I collagen telopeptide; DPD, deoxypyridinoline; NTx, N- terminal cross-linked type I collagen telopeptide; PICP, C- terminal propeptide of procollagen type I; PINP, N-terminal propeptide of procollagen type I; PYD, pyridinoline. excretion, and a range of SREs, including radiotherapy to bone, hypercalcemia, spinal cord or nerve root compression, symptomatic, radiographically confirmed pathological fracture, orthopedic surgery to bone, hospital admission for control of bone pain, and death resulting from metastatic bone disease [39]. NTx was highly predictive of SREs and was significantly correlated with the number of SREs over the first and second 3-month periods studied (r = 0.62, p <.001 for 0 3 months; r = 0.46, p <.001 for 4 6 months). A recent analysis of bone biomarkers in participants of three large trials of zoledronic acid also supports this finding. Patients with high and moderate levels of NTx excretion had a twofold greater risk for skeletal complications and disease progression than patients with low levels (p <.001 for all) [40]. Lipton et al. [41] reported a link between SREs and bone markers in breast cancer patients treated with pamidronate for 6 months. NTx excretion was significantly reduced (p =.002) in patients receiving pamidronate compared with those randomized to placebo. In the pamidronate group, normalized NTx levels were associated with a lower but nonsignificant, incidence of fractures than seen in patients with NTx levels that remained elevated (42% vs. 89%). In a phase II randomized trial involving patients with breast cancer or multiple myeloma treated with different bisphosphonate regimens, greater reductions in NTx levels were obtained following treatment with the two highest dose levels of zoledronic acid and the single dose level of pamidronate than with the lowest dose of zoledronic acid, and the reductions correlated with a lower incidence of SREs [42]. Evidence for a relationship between bone markers and metastatic bone pain is limited. In a randomized trial of pamidronate for treating bone pain related to metastatic bone disease from breast or prostate cancer, symptomatic response was observed during the first 4 weeks of treatment with pamidronate but not with placebo (p <.05) [43]. Among the 52 patients treated with pamidronate, clinical response (defined as a >20% decrease in pain score on at least two consecutive measurements) was closely correlated with the rate of bone resorption assessed by a bone biomarker. Jagdev and colleagues [44] compared the effects of pamidronate and oral clodronate on pain symptoms and bone resorption in patients with metastatic bone disease from breast, prostate, renal, lung, thyroid, or other solid tumors. Pain scores in the pamidronate group improved significantly compared with those in the clodronate group after 3 months of treatment (p <.01) and at the last assessment (4 months; p <.05). Changes in levels of bone markers were correlated with changes in pain scores (p =.01).

6 232 Efficacy of Bisphosphonates in Metastatic Breast Cancer These results suggest that bone turnover is correlated with SREs in patients with metastatic bone disease and that bone markers appear to serve as adequate surrogates for the anti-sre efficacy of bisphosphonates. Because of the lack of sufficient, rigorous, prospective phase III data, current ASCO guidelines for bisphosphonates in breast cancer advise against using biochemical markers to monitor treatment routinely [10]. Despite these reservations, the potential benefits of using bone markers in managing patients with metastatic bone disease is not inconsiderable. Indeed, the ASCO guidelines acknowledge the potential clinical value of bone markers as prognostic or predictive factors of bisphosphonate response. It has been recommended that the prognostic value of bone markers be confirmed by prospective clinical trials involving comprehensive bone tumor assessments with a combination of bone imaging and bone turnover measurements [45]. Conclusion Bisphosphonates are now the treatment of choice for patients with bone metastases from breast cancer because they can delay or prevent SREs. In breast cancer patients, bisphosphonates reduce the risk for developing a skeletal event by 17% (RR 0.83; 95% CI, ) [46]. But this is not enough. At the clinical level, we need to understand what impact they have on each individual patient on a daily basis. It has been estimated that 90% of patients continue on bisphosphonates until death [47]. This can have serious financial and emotional implications. Moreover, they must return to the cancer center for treatment when terminally ill, and we do not currently assess the impact this has on them or their families. The true efficacy of bisphosphonates as analgesics and their impact on QoL are not really known. Most bisphosphonate clinical trials focus on end points such as SREs and not so much on bone pain. SRE scores do not include QoL issues important to patients. Different scores for SREs are available, making comparisons among different trials and different bisphosphonates difficult. Still, there is increasing evidence that sensitive biochemical measures of bone turnover can act as surrogate measures for treatment response in metastatic bone disease. However, the correlation between bone markers and response to treatment is only now being defined and needs further assessment in a randomized trial setting. Finally, bone pain measures are frequently not standardized and are subject to observer bias. As pain is the most frequently reported symptom from patients with metastatic bone disease, effective and rapid pain management is essential to improving levels of functioning and QoL. Pain and QoL instruments designed specifically for patients with bone metastases are urgently needed to assess the true efficacy of treatment. Recent studies have shown that rapid relief of bone pain may be achieved with loading doses of i.v. ibandronate [48]. Phase III studies are under way that will further investigate this treatment protocol in comparison with standard doses of i.v. zoledronic acid. In order to optimize patient care, we need to correlate QoL scores specific to bone metastases with information obtained from conventional trial end points. Pinpointing the nature of the correlation among traditional end points, bone markers, bone pain measures, and QoL will help guide optimal, individualized treatment strategies for patients. Disclosures of Potential Conflicts of Interest Mark Clemons and George Dranitsaris have acted as consultants for Novartis within the past 2 years. References 1 Diel IJ. Bisphosphonates in the prevention of bone metastases: current evidence. 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