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© 2000 American Society for Clinical Oncology
American Society of Clinical Oncology Guideline on the Role of Bisphosphonates in Breast Cancer
From the American Society of Clinical Oncology, Alexandria, VA. Address reprint requests to American Society of Clinical Oncology, Health Services Research Department, 225 Reinekers Lane, Suite 650, Alexandria, VA 22314; email guideline{at}asco.org ABSTRACT PURPOSE: To determine clinical practice guidelines for the use of bisphosphonates in the prevention and treatment of bone metastases in breast cancer and their role relative to other therapies for this condition. METHODS: An expert multidisciplinary panel reviewed pertinent information from the published literature and meeting abstracts through May 1999. Additional data collected as part of randomized trials and submitted to the United States Food and Drug Administration were also reviewed, and investigators were contacted for more recent information. Values for levels of evidence and grade of recommendation were assigned by expert reviewers and approved by the panel. Expert consensus was used if there were insufficient published data. The panel addressed which patients to treat and when in their course of disease, specific drug delivery issues, duration of therapy, management of bony metastases with other therapies, and the public policy implications. The guideline underwent external review by selected physicians, members of the American Society of Clinical Oncology (ASCO) Health Services Research Committee, and the ASCO Board of Directors. RESULTS: Bisphosphonates have not had an impact on the most reliable cancer end point: overall survival. The benefits have been reductions in skeletal complications, ie, pathologic fractures, surgery for fracture or impending fracture, radiation, spinal cord compression, and hypercalcemia. Intravenous (IV) pamidronate 90 mg delivered over 1 to 2 hours every 3 to 4 weeks is recommended in patients with metastatic breast cancer who have imaging evidence of lytic destruction of bone and who are concurrently receiving systemic therapy with hormonal therapy or chemotherapy. For women with only an abnormal bone scan but without bony destruction by imaging studies or localized pain, there is insufficient evidence to suggest starting bisphosphonates. Starting bisphosphonates in patients without evidence of bony metastasis, even in the presence of other extraskeletal metastases, is not recommended. Studies of bisphosphonates in the adjuvant setting have yielded inconsistent results. Starting bisphosphonates in patients at any stage of their nonosseous disease, outside of clinical trials, despite a high risk for future bone metastasis, is currently not recommended. Oral bisphosphonates are one of several options which can be used for preservation of bone density in premenopausal patients with treatment-induced menopause. The panel suggests that, once initiated, IV bisphosphonates be continued until evidence of substantial decline in a patient’s general performance status. The panel stresses that clinical judgment must guide what is a substantial decline. There is no evidence addressing the consequences of stopping bisphosphonates after one or more adverse skeletal events. Symptoms in the spine, pelvis, or femur require careful evaluation for spinal cord compression and pathologic fracture before bisphosphonate use and if symptoms recur, persist, or worsen during therapy. The panel recommends that current standards of care for cancer pain, analgesics and local radiation therapy, not be displaced by bisphosphonates. IV pamidronate is recommended in women with pain caused by osteolytic metastasis to relieve pain when used concurrently with systemic chemotherapy and/or hormonal therapy, since it was associated with a modest pain control benefit in controlled trials. CONCLUSION: Bisphosphonates provide a meaningful supportive but not life-prolonging benefit to many patients with bone metastases from cancer. Further research is warranted to identify clinical predictors of when to start and stop therapy, to integrate their use with other treatments for bone metastases, to identify their role in the adjuvant setting in preventing bone metastases, and to better determine their cost-benefit consequences. IN THE UNITED STATES, the breast is the most common site of malignancy in women. It is estimated that in 1999 30% of new cancer cases in women arose in this site, 176,300 cases were diagnosed, and almost 44,000 women died.1 Bone is the most common site of metastasis in patients with breast cancer. Fisher et al2 examined the site of first metastatic lesion in women undergoing radical mastectomy and found that bone was the initial site in 26%. However, a substantially larger proportion of patients will ultimately develop metastasis to bone. The incidence varies between series,3 but the majority of women with metastatic breast cancer eventually develop bone metastasis. Median survival with metastatic breast cancer varies widely depending on the site(s) of involvement. Women with bone-only or dominant disease have typically a median survival of 3 years. The spread of breast cancer to bone can cause significant morbidity to the patient in terms of pain and decreased activity. Pathologic fractures can be devastating, as in decreased mobility from femoral fractures or in spinal cord compromise with vertebral body collapse. Since metastatic breast cancer is essentially not curable with current treatment, emphasis must be placed on quality of life. Measures to reduce morbidity from skeletal involvement by breast cancer are important for optimizing a patient’s quality of life. Bisphosphonates are a new class of agents that have been shown in a variety of studies to reduce bony complications associated with breast cancer. In some studies, improvements were noted in quality of life end points. However, bisphosphonates have not been found to improve survival. Given the large number of women with breast cancer who theoretically could be considered candidates for this form of therapy, the American Society of Clinical Oncology (ASCO), as a service to patients, its members, and practicing physicians in general, convened an expert panel under the auspices of its Health Services Research Committee to develop recommendations regarding the use of bisphosphonates for breast cancer (Table 1) and, in a separate report, multiple myeloma. The following recommendations for use of bisphosphonates specifically exclude from consideration the use of bisphosphonates as therapy for hypercalcemia in breast cancer or other malignancies.
PRACTICE GUIDELINES The ASCO Health Services Research Committee uses the following definition for guidelines: "Practice guidelines are systematically developed statements to assist practitioner and patient decisions about health care for specific clinical circumstances."4 Attributes of good guidelines include validity, reliability, reproducibility, clinical applicability, multidisciplinary process, review of evidence, and documentation. Utilization of guidelines may improve patient outcomes, improve medical practice, minimize inappropriate practice variation, provide decision support tools for practitioners and points of reference for medical orientation and education, and may provide criteria for self-evaluation and assistance with reimbursement and coverage decisions. It is important to realize, however, that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. Accordingly, ASCO considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient’s individual circumstances. They cannot be assumed to apply to interventions performed in clinical trials, which are designed to test innovative and novel therapies in a disease for which better therapy is sorely needed. In that guideline development involves a review and synthesis of the latest literature, a practice guideline also serves to identify important questions for further research and those settings in which investigational therapy should be considered. METHODS A methodology similar to that applied in prior ASCO practice guidelines was used.
Panel Composition
Process The entire panel met twice. The first meeting was intended to identify topics to be addressed by the guideline, to develop a strategy for completion of the guideline, and to do a preliminary review of the initial literature search. A second meeting reviewed work to date and refined assignments for the guideline. Subsequently, a subgroup of the panel, including the cochairs, met primarily by conference telephone calls to review progress, identify other supporting or evolving data, and refine the initial strategies and scope of the guidelines to facilitate timely completion of the guidelines. A rating of the evidence was made by consensus of the group rather than by a specific weighting method. Table 2 lists the definitions used in determining the levels of evidence and the grades of recommendation.5,6 These definitions were the same as in prior ASCO guidelines. The guideline was circulated in draft form, and all members of the panel had an opportunity to comment on the levels of evidence as well as the systematic grading of the data supporting each recommendation. Subsequently, an external review by individuals (see Acknowledgment) not directly involved in development of the guideline assessed the clarity, utility, and completeness of the document. Final text editing was performed by B. Hillner and J. Ingle.
Guideline and Conflict of Interest The content of the guidelines and the manuscript were reviewed and approved by the ASCO Health Services Research Committee and by the ASCO Board of Directors before dissemination. All members of the expert panel complied with ASCO policy on conflict of interest, which requires disclosure of any financial or other interest that might be construed as constituting an actual, potential, or apparent conflict. Members of the expert panel completed ASCO’s disclosure form and were asked to reveal ties to companies developing products that might potentially be affected by promulgation of the guideline. Information was requested regarding employment, consultancies, stock ownership, honoraria, research funding, expert testimony, and membership on company advisory committees. No conflicts were identified that required any individual’s role to be limited.
Revision Dates
Definition of End Points In metastatic bone disease, almost all studies have found no benefit in overall survival with the use of bisphosphonates. Therefore, disease progression and quality of life are the primary end points. A variety of complications can occur and be measured as meaningful end points: fractures, spinal cord compression, hypercalcemia, and pain. For pathologic fractures, their presence or absence and site are not subject to substantial observer variation. However, measuring their functional consequence, associated pain severity, and subsequent therapeutic action (ie, surgery or radiation) can vary by the observer or caregiver. Therefore, randomized and double-blind assessments are essential. In many of the clinical reports reviewed, the panel could not discern the primary end point of the various reported end points. In cooperation with the FDA, the intravenous (IV) pamidronate trials in women with osteolytic bony metastases used an unusual, preplanned end point of total skeletal-related events (SREs). SREs were an aggregate of all sites and number of pathologic fractures, spinal cord collapse/compression, and therapeutic radiation therapy, including pain and impending fracture. This definition included an aggregate score of the occurrence of an event (surgery), need for therapeutic action(s) even if an adverse event had not occurred but was impending (radiation), and need for symptom control (pain relief without radiographic evidence of new bony lesions). A limitation with the SRE definition is that it included pathologic fractures that were asymptomatic but detected by surveillance radiographs. From a statistical perspective, the appropriate end point for determining the biologic efficacy of bisphosphonates or any other intervention in osteolytic bone disease is the time to first SRE.7 Such an analysis does not make any assumption about the distribution of SREs across a treatment arm. From a clinical perspective, an aggregate score of symptomatic SREs may be more informative. BISPHOSPHONATE BACKGROUND Bisphosphonates are analogs of endogenous pyrophosphate in which a carbon atom replaces the central atom of oxygen. This carbon substitution makes these compounds resistant to hydrolysis and allows two additional chains of variable structure. One of these side chains usually contains a hydroxyl moiety, which allows high affinity for calcium crystals and bone mineral. The differences at the other side chain produce marked differences in the antiresorptive potency of different bisphosphonates, as listed in Table 3. In fact, the newer bisphosphonates, such as ibandronate and zoledronate, show 10,000- to 100,000-fold greater potency than do the older agents, such as etidronate. The clinical approval status of these bisphosphonates is listed in Table 3.
Bisphosphonates have an affinity for bone and are preferentially delivered to sites of increased bone formation or resorption. Once deposited on the surface of bone, bisphosphonates are ingested by osteoclasts that are engaged in bone resorption.8,9 Bisphosphonates are potent inhibitors of osteoclastic bone resorption and are effective in treating cancer-induced hypercalcemia of malignancy, Paget’s disease of bone, and postmenopausal osteoporosis. Therefore, it was logical to explore different bisphosphonates to treat patients with osteolytic bone metastases from breast carcinoma. The mechanism of action and biochemistry of bisphosphonates have been reviewed recently by Fleisch.10 Although seven bisphosphonates are available worldwide for various conditions, only two agents are approved for metastatic bone disease: clodronate and pamidronate. Clodronate is available in oral and IV forms. Pamidronate is only available in IV form. WHOM TO TREAT Bone is the most common site of breast cancer metastases, and the majority of women with metastatic disease develop bone metastases. Ideally, oncologists would like to identify predictors of who will develop bone metastases and who will develop complications (fractures, intractable pain) as a consequence of their bony disease, and then to stratify women into who is or is not likely to respond to interventions intended to modify the natural history of bony complications. Such predictors, such as biochemical bone markers, are currently not validated but are under investigation. Current evidence has principally used the presence of radiographic evidence of bony metastases to stratify risk. GUIDELINES FOR THE USE OF BISPHOSPHONATES IN BREAST CANCER Bisphosphonate Use in Women With Radiographic Evidence of Bony Metastases
Lytic Disease on Plain Radiographs Level of Evidence: I Grade of Recommendation: A The recommendation for using bisphosphonates in women with radiographic evidence of osteolytic bony metastases is based on well-designed randomized controlled studies. In all instances, no survival advantage was detected. The benefits were principally seen in reductions in skeletal complications, eg, pathologic fractures, surgery for fracture or impending fracture, radiation, spinal cord compression, and hypercalcemia. Among women receiving chemotherapy, Hortobagyi et al11 randomized 382 women with at least one lytic bone lesion to receive either pamidronate 90 mg or IV placebo over 2 hours on a monthly basis for 12 months. Bony metastases were first detected on average 1.6 to 1.9 years before pamidronate was first administered in this trial. Pamidronate was superior to placebo in terms of time to occurrence of the first skeletal complication (median, 13.1 v 7.0 months, P = .005), proportion of women with any skeletal complication (43% v 56%, P = .008), change in bone pain (P = .046), and performance score (P = .027). Forty-eight percent of the women completed the first year of the trial and continued randomized assigned treatment for up to a maximum of 2 years.12 The difference in overall skeletal complications continued to favor pamidronate and remained statistically significant after 15, 18, 21, and 24 months, and the time to first skeletal complication favored the pamidronate group (median, 7.0 v 13.9 months, P < .001). The incidences of nonvertebral pathologic fractures, radiation therapy to bone, bone surgery, and hypercalcemia were all reduced by statistically significant amounts with pamidronate. Despite the improvements in control of bony metastases, pamidronate did not have a survival advantage. Importantly, long-term treatment was not found to be associated with unexpected adverse events. A similar trial was conducted in women receiving hormonal therapy. Theriault et al13 randomized 374 women to receive either pamidronate 90 mg or IV placebo over 2 hours every 4 weeks for up to 2 years. Bone was the only site of metastatic disease for about 70% of women at trial entry. The time to first skeletal complication was prolonged with pamidronate compared with placebo (median, 10.4 v 6.9 months, P = .049). In addition, the proportion of women with skeletal complications was reduced (56% v 67%, P = .027). The odds ratio of having an SRE while on placebo was 1.6 (95% confidence interval [CI], 1.1 to 2.5) compared with pamidronate. Bone pain scores improved from baseline during the first year of treatment in the pamidronate group but worsened in the placebo group (P = .002). Median survival was unchanged with pamidronate at 37 months. The recommended dosage and interval are based on those used in these trials, ie, IV pamidronate 90 mg over 1 to 2 hours every 3 or 4 weeks (depending on the systemic therapy schedule). The 1-hour infusion recommendation is based on a recent report showing no adverse effects compared with a 2-hour infusion.14 No trials are known to be in progress that further refine the dose, interval, or patient subgroups who benefit from IV pamidronate for metastatic disease. An open-label study from Conte et al15 studied 395 women randomized to receive either chemotherapy alone or chemotherapy plus pamidronate given as a 45-mg (one half the dose used by Hortobagyi et al11,12 ) IV infusion over 1 hour every 3 weeks until progressive disease was identified on radiographs or bone scan. The presence of bone metastases was first detected a median of 3 months before treatment with bisphosphonates, which was a substantially shorter time than in the Hortobagyi et al study. Considering the primary end points of the Conte et al study, women who received pamidronate had a 48% longer median time to disease progression in bone (249 v 168 days, P = .02) and a higher proportion of the previously defined marked pain relief (44% v 30%, P = .025). No differences in the number of SREs were seen between groups. Two randomized clinical trials have addressed the value of oral bisphosphonates in women with breast cancer metastatic to bone. Paterson et al16 performed a randomized, double blind, placebo-controlled trial of oral clodronate 1,600 mg/d versus placebo in women with assessable bone metastasis. There were no requirements with respect to concomitant systemic therapy. Clodronate was superior to placebo in terms of total number of hypercalcemia episodes (28 v 52, P < .01), number of terminal hypercalcemia episodes (seven v 17, P < .05), incidence of vertebral fractures (84 v 124 per 100 women-years, P < .025), rate of vertebral deformity (168 v 252 per 100 patient-years, P < .001), and combined rate of all morbid SREs (218 v 305 per 100 patient-years, P < .001). However, the time to first adverse SRE was not statistically improved with clodronate. An open-label randomized study was performed by van Holten-Verzantvoort et al17 of oral pamidronate versus control in 161 women with bone metastases. Bone metastases were first detected on average 12 to 15 months before randomization. The pamidronate dose was initially set at 600 mg/d, but this was decreased to 300 mg/d because of gastrointestinal toxicity after entry of 29 of the 81 women randomized to receive pamidronate. The pamidronate group had reductions in hypercalcemia by 65%, in severe bone pain by 30%, in symptomatic impending fractures by 50%, and in the need for other therapies, including systemic treatment and radiotherapy, by 35%. The observed benefits occurred primarily by reducing multiple complications in a small number of women. Median survival was comparable between groups at about 24 months. Recent reviews on bisphosphonates have generally supported the value of this class of agents in the management of women with metastatic breast cancer to bone.18-20 The judgment was made that the recommended agent should be pamidronate based on the availability of level I evidence with a grade A recommendation and approval by the U.S. FDA. This position was taken with knowledge of the results from studies with clodronate, which were considered to be less compelling in terms of benefit as reviewed above,15,16 and only IV pamidronate has been approved by the U.S. FDA. If a large heterogeneous cohort of women with osteolytic bone lesions were considered, the panel’s impression is that clinical judgment would suggest that highest priority be given to initiating bisphosphonates in women with multiple lytic bone metastases or disease in weight-bearing bones or vertebrae. Current studies are underpowered to determine whether the risks and benefits support such a prioritization. Clinical judgment is also required because some clinical scenarios may dictate that bisphosphonates be withheld until the clinical course is clarified, for example, a patient with extensive visceral metastasis but minimal, asymptomatic osseous metastasis. No direct comparative trials of pamidronate and clodronate, the two agents approved in Canada for lytic bone metastasis, have been reported or are in progress. No direct comparisons of any of the oral bisphosphonates, for example, clodronate to etidronate or aledronate, are known to be in progress. No trials are in progress to further refine the role of IV pamidronate in the metastatic setting. More potent bisphosphonates are being developed that may be more effective than pamidronate. The recommendation specifically indicates that the bone metastases are lytic in nature. This raises a question regarding the use of bisphosphonates in women with purely blastic metastases, which occur in a noninconsequential minority of women (eg, 13% of women in the series of Scheid et al21). There is evidence of increased osteoclastic activity in women with blastic bone metastasis22; however, there is insufficient evidence on which to make a recommendation in such women. This represents an area in need of research and reconsideration in the future.
Abnormal Radiographic Scan With Localized Pain and Normal Plain Radiographs Level of Evidence: Insufficient data. Not available (N/A) Grade of Recommendation: Panel consensus
Asymptomatic Abnormal Bone Scan With Normal Radiographs Level of Evidence: Insufficient data. N/A Grade of Recommendation: Panel consensus Biochemical Markers
Guideline:
Level of Evidence:
Grade of Recommendation: Biochemical markers could have a variety of roles in management of metastatic bone disease, eg, identification of women most at risk of bony complications, monitoring of bisphosphonate therapy, especially to identify women who are not benefiting from them, and identification of women with bone pain who will benefit from bisphosphonates compared with other treatments.23 Currently, varieties of bone resorption markers (pyridinoline, deoxypyridinoline, N- or C-telopeptide) are under investigation.24 Some have been correlated with, but not shown to be statistically significant predictors of, prognosis or response. Therefore, at this time, these markers should only be used within research protocols and have no role in routine care. Duration of Therapy
Guideline:
Level of Evidence:
Grade of Recommendation: The optimal duration of bisphosphonate use is unknown, since this issue has never been the focus of a clinical trial. In the previously described trials of pamidronate in women with osteolytic disease,11-13 pamidronate (or placebo) was given for 2 years or until patient refusal, physician- or patient-defined unacceptable toxicity, or death. In the metastatic setting, this question is not being studied. Evaluations with a primary end point of the time to first adverse bony event are optimal for establishing the biologic efficacy of the agents. However, since the total number and type of bony complications, in addition to prevention, are relevant, the lack of information on stopping rules has substantial financial and patient convenience consequences. In addition, bony complications are a rare example of how multiple adverse events (painful sites or fractures) of similar type can occur. Therefore, the occurrence of the first adverse event does not preclude a future benefit of the therapy. Role in Control of Pain Secondary to Bone Metastases
Guideline:
Level of Evidence:
Grade of Recommendation:
Guideline:
Level of Evidence:
Grade of Recommendation: In parallel with the prior discussion of bisphosphonates’ role in the primary or secondary prevention of skeletal complications, their role in pain management secondary to bony metastases must be separated into helping a patient with current bone pain versus reducing future pain. In the previously discussed trials of IV pamidronate versus placebo concurrent with systemic therapies, pamidronate was associated with a modest pain control benefit.11-13 About 85% of women at entry had some bone pain. The bone pain scores were calculated by multiplying the pain severity (0 to 3) by the pain frequency (0 to 3). In both trials, the mean pain score was improved between 1 and 1.5 units after each 3-month assessment up to 1 year. What defined a clinically relevant change in pain score cannot be ascertained from the reports. Global quality-of-life scores and Eastern Cooperative Oncology Group performance status in pamidronate-treated women were statistically better maintained in the trial using chemotherapy but not with hormonal systemic therapy. At 1 year, approximately 15% to 20% of women receiving pamidronate needed radiation therapy for bone pain; by 2 years, 20% to 25% needed radiation therapy for bone pain. For women with current bone pain, no studies have compared the efficacy of IV bisphosphonates to that of radiotherapy. Many studies of bisphosphonates as primary therapy for bony pain are of a nonrandomized, open-label design involving a mixture of cancers and have not controlled for concurrent use of systemic antineoplastic therapy. Therefore, a placebo effect is possible. These studies generally focus on establishing dose, schedule, and time to analgesic effect. In a recent review, Body et al20 summarized the available phase II trials. In these studies, only IV bisphosphonates have consistently shown an effect. In general, the onset of benefit was seen after 6 weeks (two or more treatments) with at least a 60-mg dosage per treatment of pamidronate.25,26 Bisphosphonates had a greater effect in reducing a summary pain score than in reducing the concurrent need for narcotics. Only three small studies were double-blind in design. Ernst et al27,28 performed two studies of IV clodronate. The first was a cross-over trial in 21 patients with a mixture of breast, lung, and prostate cancers who received either clodronate 600 mg IV daily for 5 days or placebo with subsequent cross-over at 1 week.27 Using a 10-cm visual analog scale, several symptoms, including pain, were evaluated. The mean difference in pain score over 7 days was 0.89 (95% CI, 1.43 to -0.35) in favor of clodronate. Ernst et al’s second study of 60 patients compared clodronate 600 mg or 1,500 mg with placebo with subsequent cross-over at 2 weeks.28 Analgesic use did decline significantly with clodronate, as did the visual analog pain scales scores, but the latter decline was not statistically significant. Coleman et al29 studied 52 women, 30 of whom had breast cancer with painful progressive bone disease, who were heavily pretreated with systemic therapies. Patients received pamidronate 120 mg or placebo every 4 weeks, and no other systemic therapy was allowed. Pain scores were derived from a weekly questionnaire. A response was defined as a reduction in pain score of 20% or more on 2 consecutive weeks. During the 4-week placebo-controlled phase, five (24%) of 21 pamidronate-treated women versus one (4%) of 25 placebo-treated women achieved a symptomatic response. The optimal combination or sequencing of radiotherapy or radiopharmaceuticals with bisphosphonates has not been studied. All these therapies are associated with substantial costs. The relative rank order of their costs will depend mostly on the dose and schedule of radiation therapy and the specific radiopharmaceutical. Given the small number of studies discussed above and the lack of direct comparisons, the panel recommends that current standards of care for cancer pain, analgesics and local radiation therapy, not be displaced by bisphosphonates. The optimal complementary role of bisphosphonates needs to be further defined. Role of Bisphosphonates If No Radiographic Evidence of Bone Metastases
Extraskeletal Metastases Without Evidence of Bony Metastases This clinical situation has not been studied using IV bisphosphonates and should be the focus of new clinical trials. Level of Evidence: II (oral) and N/A (IV) Grade of Recommendation: B/Panel consensus This recommendation is supported by evidence from two small-randomized trials of oral bisphosphonates. Kanis et al30 performed a randomized, double-blind, placebo-controlled trial of oral clodronate versus placebo in 133 women with recurrent breast cancer but no evidence of skeletal metastasis. The planned treatment duration was 3 years. The clodronate group had a significantly lower number of skeletal metastases (32 v 63, P < .005) and 26% fewer skeletal complications than did the placebo group (P < .01). However, although the number of women who developed skeletal metastasis was lower in the clodronate group (15 v 19), this difference was not statistically significant. Van Holten-Verzantvoort et al31 also performed a small trial using oral pamidronate 300 mg/d compared with placebo in 124 women with breast cancer without bone metastases but at high risk because of locally advanced or extraskeletal disease. There was no difference in the number of or time to first radiologic manifestations of bone metastases. No trials using IV bisphosphonates have been done in women without evidence of skeletal metastasis.
Bisphosphonates as Adjuvant Therapy Level of Evidence: II Grade of Recommendation: C The ultimate goal of antiosteoclastic therapy should be the primary prevention of bone metastases. There is a large body of animal and in vitro evidence that bisphosphonates reduce tumor burden in bone and possibly at extraskeletal sites.10,32 It is not known if all bisphosphonates have the same antitumor effects, which drug has the best effect, and if this effect is clinically meaningful. These preclinical observations suggest that a benefit in reduction of bone metastases and possibly other metastatic sites (with a resulting improvement in survival) may occur when these drugs are applied in the adjuvant setting. As discussed in Ongoing and Future Research (below), the relative potency of the bisphosphonate is likely to be critical to such an effect.
Three studies provide provocative data on the use of bisphosphonates to prevent the appearance of bone metastasis in women with breast cancer. Diel et al33 randomized 302 women with T1 to T4, N0 to N2 primary breast cancer and immunocytochemical evidence of cancer (positive for tumor-associated glycoprotein TAG-12) in a bone marrow aspirate to receive either clodronate 1,600 mg/d for 2 years or no bisphosphonate. The type of adjuvant systemic therapy was used in accordance with specific guidelines. With a median follow-up of 36 months, the incidence of overall metastasis (13% v 29%), bone metastasis (8% v 17%), and visceral metastasis (8% v 19%) was more than cut in half (each P Powles et al34 reported preliminary results of a double-blind trial in which 1,079 women were randomized to receive either clodronate 1,600 mg/d or placebo (starting 6 months after surgery). The arms were balanced by stage and nodal status. At 2.5 years of follow-up, definitive evidence of bone metastasis occurred in 5.2% of women receiving clodronate and in 8.1% of women receiving placebo (P = .054). In a subset analysis of postmenopausal women, the incidences were 3.5% and 7.3% (P = .041). In premenopausal women, the incidences were similar (7.1% and 9.1%, P = .41). The overall relative risk of bony metastases was 0.67 (95% CI, 0.42 to 1.06, P = .08). No effect was observed on other sites of metastases or overall survival. Saarto et al35 reported preliminary results of a double-blind trial of 299 women with node-positive breast cancer who were randomized to receive clodronate 1,600 mg/d or placebo for 3 years. All women received adjuvant therapy: premenopausal women received chemotherapy with cyclophosphamide, methotrexate, and fluorouracil and postmenopausal women received antiestrogens. After a minimum follow-up of 5 years, more, not fewer, bone metastases were detected in the clodronate group (26%) than in the control group (18%). In addition, nonskeletal metastases were more common (45% v 27%) and survival was worse (68% v 81%) in the clodronate group. All these findings were statistically significant and persisted after adjustments were made for number of lymph nodes, tumor size, and progesterone receptor status. At the two extremes, the Diel et al33 and Saarto et al35 trial findings were surprising. No one expected either such a marked benefit or associated harm from clodronate, which suggests that chance is likely to remain a major problem given their small trial size for an adjuvant therapy (few adverse events). The Powles et al34 trial is the largest, yet heterogeneous, in terms of stage and adjuvant therapy and, to date, is without multivariate analyses with other prognostic factors and interactions with standard adjuvant therapy. However, it is truer to the standard adjuvant population in that there was no selection of women by risk of metastasis. Given that the three trials are inconsistent, it remains uncertain whether bisphosphonates are beneficial and, if so, what duration of therapy is needed. At present, adjuvant clodronate cannot be recommended as a standard of care for all women about to undergo systemic adjuvant therapy, yet these trials provide provocative data worthy of establishing hypotheses for prospective studies. Osteoporosis Prevention
Guideline:
Level of Evidence:
Grade of Recommendation: Women with premature menopause related to cancer-related therapy, usually chemotherapy, are at risk of developing of osteoporosis.34,36 Recent randomized trials have addressed the value of bisphosphonates in women with chemotherapy-induced menopause. Delmas et al37 performed a randomized, double-blind, placebo-controlled trial in 53 women (36 receiving tamoxifen) who were postmenopausal for at least 6 months because of chemotherapy or radiation therapy after breast cancer surgery. Women were randomized to receive either risedronate (30 mg/d) or placebo for 2 weeks followed by 10 weeks without treatment, and this 12-week cycle was repeated 12 times. At 2 years, the mean difference in bone mineral density was 2.5% (95% CI, 0.2% to 4.9%) and 2.6% (95% CI, 0.3% to 4.8%) in the lumbar spine and femoral neck, respectively. Clodronate has been demonstrated to preserve bone density in postmenopausal women receiving tamoxifen.38 Subsequently, Powles et al34 randomized 300 postmenopausal women with operable breast cancer, of whom 74% also received tamoxifen, to receive oral clodronate (1,600 mg/d) or placebo for 2 years. After 2 years, the bone mineral density in the lumbar spine, hip, and trochanter increased at all sites between 1.7% and 2.3% (all statistically significant increases) in the clodronate-treated group compared with the placebo group. Saarto et al39 performed an open-label randomized trial comparing oral clodronate (1,600 mg/d) for 3 years to a control in 148 premenopausal women who also received six cycles of cyclophosphamide, methotrexate, and fluorouracil chemotherapy. At 2 years, the severity of bone loss was less severe with clodronate (-2.0 v -5.9% in the vertebral spine and +0.9% v -2.0% in the femoral neck; P = .0005 and P = .017, respectively). The benefit was predominantly seen in women who developed amenorrhea after chemotherapy (-5.9% v -9.5% in the vertebral spine at 2 years). On the other hand, women who preserved menstruation had only marginal changes in their bone mineral density. Tamoxifen is recognized as an effective adjuvant therapy in premenopausal women with receptor-positive cancer,40 is infrequently associated with permanent premature menopause,41 and has defined modest benefit in both bone mineral density maintenance and fracture rates.42-44 Nonetheless, the above trials support an additional benefit for bisphosphonates with respect to bone density maintenance, even in women receiving tamoxifen. It should be recognized that other options for the prevention of osteoporosis are available.45 Risedronate and clodronate in women with chemotherapy-associated premature menopause have not been compared with other FDA-approved interventions for bone density preservation (including aledronate, raloxifene, and estrogen). With respect to estrogens, although there is increasing interest in their use in breast cancer survivors, concerns related to estrogen-associated breast cancer cell stimulation have been raised.46,47 In women without a history of breast cancer, conventional osteoporosis prevention strategies used in other clinical settings commonly involve identification of high-risk subgroups, ie, women with low bone density or high rates of bone loss.45 Such an approach has not been evaluated for efficacy or relative cost in breast cancer populations, an issue especially pertinent in the adjuvant setting, given the uncertain effect of bisphosphonates on bone metastasis risk.33-35 SAFETY AND ADVERSE EFFECTS Bisphosphonates are generally well tolerated when given intravenously. In randomized controlled trials, the incidence of most adverse effects in women treated with pamidronate was similar to that observed in the placebo group. Transient myalgias, arthralgias, and flu-like symptoms with fever tend to occur more often in women treated with pamidronate.48 Mild infusion-site reactions have also been reported. Women have rarely discontinued pamidronate therapy because of adverse effects. No serious long-term adverse effects have been reported. In the long-term follow-up of multiple myeloma patients treated as part of the randomized controlled trial, new or worsening anemia occurred more often in the pamidronate-treated patients than in the placebo group (38% v 25%) during the last 12 cycles of treatment.49 Long-term results of the breast cancer chemotherapy trial also reported that anemia and thrombocytopenia occurred slightly more often in the pamidronate group than in the placebo group.11 The levels of anemia and thrombocytopenia were not sufficient to lead to differences in RBC transfusion or erythropoietin use. Uveitis and other ocular adverse effects are rare but well described.48 No increased risk of renal insufficiency or hypocalcemia has been observed in patients treated with pamidronate infusions for up to 2 years. The risk of adverse effects may be related to the length of infusion. In one uncontrolled study of 69 patients, the incidence of local reactions was reported to be higher when pamidronate (60 mg) was administered as a 1-hour infusion as compared with a 4-hour infusion.50 However, a recent series found no difference in renal or general tolerability between a 1- and 2-hour infusion.51 These data on 1-hour infusion have been published in abstract form only.51 We await a final peer-reviewed publication. INITIATION AND MANAGEMENT OF OTHER THERAPIES FOR OSTEOLYTIC BONE DISEASE In women with known metastatic breast cancer or previously treated cancer who are at high risk for bony metastases, symptoms in the spine, pelvis, or proximal femur require careful evaluation to monitor for spinal cord compression and pathologic fracture. Diagnostic assessment is recommended if symptoms are present despite current therapy or recur in a previously treated site. Symptoms in other bones important to functional integrity also warrant specific diagnostic evaluation and follow-up. A detailed discussion of the appropriateness criteria for imaging and of treatment decisions for the use of radiation therapy and surgery is beyond the scope of this bisphosphonate-focused guideline. Other sources are available for an expanded discussion of these issues.52-54 Localized treatment of bone metastases, with radiotherapy and/or surgery, is used for sites of progressive disease that compromise function.52,55 Uncontrolled localized pain, reducing the risk for pathologic fracture, and spinal cord compression are the most common indications to treat bone metastases with radiotherapy. The goal of palliative radiation is to relieve symptoms, restore function, and prevent the sequelae of disease progression in the area treated. Radiopharmaceuticals are an option in the treatment of diffuse symptomatic bone metastases or if symptoms recur in a previously irradiated site when bone marrow preservation is not an issue because it compromises systemic chemotherapy.56 Combining external-beam irradiation and radiopharmaceuticals is an increasing focus of research. Significant morbidity caused by pathologic fracture and spinal cord compression can result from untreated bone metastases. Spinal cord compression and pathologic fracture require emergent intervention regardless of other recent therapies. COMMENTARY: PUBLIC POLICY AND COST-UTILITY IMPLICATIONS The widespread use of bisphosphonates will have a major impact on drug budgets within capitation or nationalized health care systems. The costs consequences and patient expectation of benefit will vary depending on the following: the phase of breast cancer when bisphosphonate use is initiated, eg, adjuvant, asymptomatic metastatic bony disease, symptomatic bony disease; the specific bisphosphonate used; and how the bisphosphonate is delivered. The time to initiate bisphosphonates is a critical issue with an incomplete database. The available clinical trials show a clear benefit from IV bisphosphonates in women with radiographic evidence of bone metastases. This situation is estimated to be present in only 25% to 35% of all women when they are first diagnosed as having metastatic breast cancer.57 Table 4 contrasts the differences and generalizability in expected median survival, time to treatment, and sites of metastases between the women in the pamidronate trials and other women. The guideline implies that initiating bisphosphonate therapy in all women at the first detection of metastatic bone disease is beneficial, although at trial entry, the women in the IV pamidronate studies had median survival times (1.6 to 1.9 years) with their metastatic disease approximately equal to the median survival of all women with metastatic breast cancer (2.0 years).58-63
Preventing feared complications such as fracture and bone pain should lead to measurable changes in quality-of-life indicators. In the pamidronate trials,8-10 the panel recommends that current standards of care for cancer pain, analgesics and local radiation therapy not be displaced by bisphosphonates. If women had bone pain at entry, a consistent improvement in subsequent pain control was found. For many women, bisphosphonates were associated with better maintenance of Eastern Cooperative Oncology Group or World Health Organization performance status over time. However, overall survival and overall quality of life, measured with the Quality of Life Index, were not changed. Therefore, the costs and modest inconvenience of pamidronate are important concerns that must be balanced against these benefits. The lack of scientific data on stopping rules (discussed in Duration of Therapy, above) presents an uncomfortable carte blanche approach to patient care. Ideally, future randomized comparisons will address these financial issues directly. Retrospective, ad hoc cost utility analyses consistently show that pamidronate will require new expenditures; that is, the cost of adverse SREs avoided is less than the costs incurred in pamidronate delivery.64,65 Hillner et al’s analysis of the previously discussed pamidronate trials found cost-effectiveness ratios associated with adding pamidronate of $108,200 per quality-adjusted life year in women concurrently treated with chemotherapy and $305,300 per quality-adjusted life year in women initially treated with hormonal therapy. These ratios are much higher than most routinely accepted medical therapies. The costs to prevent one SRE were $9,350 in the chemotherapy cohort and $12,760 in the hormonal therapy cohort. These ratios are highly sensitive to the price of pamidronate as well as to a previously undiscussed issue, ie, the number of the adverse SREs avoided that are asymptomatic or can be treated conservatively with analgesics. At least 60% of fractures were of this type in the pamidronate trials. Dranitsaris and Hsu’s66 Canadian analysis came to different conclusions. They modeled pamidronate concurrent with chemotherapy and concluded that its incremental cost per quality-adjusted life year was $18,700 per quality-adjusted life year gained. The major differences in the results are explained in the Canadian model primarily by an approximately 50% lower pamidronate cost per treatment compared with the U.S. and by the fact that all patients with a nonvertebral fracture were assumed to be hospitalized. ONGOING AND FUTURE RESEARCH Questions of the specific drug, when to initiate drug therapy, duration of therapy, and the use of markers to select high-risk women define the direction of current clinical trials with bisphosphonates. Third-generation bisphosphonates seem to be more powerful inhibitors of osteoclasts. However, only randomized clinical trials will provide information on relative clinical efficacy. In the adjuvant setting, studies using a placebo control design should be encouraged. The panel recognized the dilemma that future clinical trials of metastatic bone disease in breast cancer are likely to consider some form of bisphosphonate the standard of care even in settings where it has not been addressed. The scientific logic or precedent for the class of agents’ effect should not be inferred, yet recruitment in comparative trials, if they include a placebo arm, is likely to be difficult. Clinical evaluation of zoledronate and ibandronate is in progress. Zoledronate can be given safely over several minutes and produces antiresorptive effects, as assessed by bone resorption marker, similar to those of 90 mg of pamidronate.32 Preliminary reports from a randomized phase II study using zoledronate have been presented.67 A total of 280 women with lytic bony metastases (including 171 women with breast cancer) were randomized to receive nine monthly treatments of either 0.4 mg, 2.0 mg, or 4.0 mg of zoledronate as a 5-minute infusion or 90 mg of pamidronate as a 2-hour infusion. The primary goal was to determine a dose(s) of zoledronate that reduced the need for radiation to less than 30% of treated women. Duration of follow-up was not reported. Total SREs in the 2-mg and 4-mg zoledronate cohorts (30% to 35%) were similar to the pamidronate cohort. This trial was not powered to show superiority of zoledronate compared with pamidronate. An ongoing, larger, phase III randomized trial is comparing a higher dose of zoledronate with 90 mg of pamidronate in the treatment of multiple myeloma or breast cancer with lytic disease. Ibandronate is another newer potent bisphosphonate. A phase III placebo-controlled trial of 462 breast cancer patients with bone metastases has been completed and preliminary results have been reported.68 The entry criteria and design were similar to those in the previous discussed IV pamidronate study. Women received either monthly 2 mg or 6 mg of ibandronate as a 1- or 2-hour infusion or placebo injections in addition to their antineoplastic therapy. The duration of follow-up was not reported. The mean number of events per patient year on treatment was reduced from 1.08 in women receiving placebo to 1.0 in women receiving 2 mg of ibandronate and to 0.56 in women receiving 6 mg of ibandronate. The difference between placebo and 6 mg of ibandronate was significant (P = .03). The event-free survival rate was also superior between the placebo group and the ibandronate 6-mg group. Other clinical trials are currently ongoing and planned in both the metastatic disease and adjuvant settings. A double-blind comparison of zoledronate to pamidronate has closed to accrual but not yet reported. In this trial, women with at least one bone metastasis, as confirmed by conventional radiograph, that was either purely lytic, mixed lytic/sclerotic, or purely sclerotic were randomized to receive either zoledronate (4 mg or 8 mg) or pamidronate (90 mg) given intravenously every 3 to 4 weeks. In the adjuvant setting, the Breast Intergroup will be conducting an open label study (S9905, coordinated by the Southwest Oncology Group) of observation versus zoledronate 8 mg IV every 4 weeks for 2 years in women with resected stage I, II, or IIIA breast cancer who are receiving standard systemic adjuvant therapy. The National Surgical Adjuvant Breast and Bowel Project is planning a double-blind (B34) trial to evaluate oral clodronate (1,600 mg daily) versus placebo for 3 years in women after treatment for stage I and II breast cancer. APPENDIX
Bisphosphonates Expert Panel
ACKNOWLEDGMENTS The expert panel expresses its gratitude to Patricia Legant, MD, William P. Vaughan, MD, Robert E. Coleman, MD, Gabriel N. Hortobagyi, MD, Janardan D. Khandekar, MD, Pierre P. Major, MD, and Trevor J. Powles, MD, for their thoughtful reviews of earlier versions of the guideline. REFERENCES 1. Landis SH, Murray T, Bolden S, et al: Cancer statistics, 1998. CA Cancer J Clin 48:6-29, 1998[Abstract] 2. Fisher B, Ravdin RG, Ausman RK, et al: Surgical adjuvant chemotherapy in cancer of the breast: Results of a decade of cooperative investigation. Ann Surg 168:337-356, 1968[Medline] 3. Galasko CSB: The anatomy and pathways of skeletal metastases, in Weiss L, Gilbert HA (eds): Bone Metastasis. Boston, MA,Hall Medical Publishers, 1981, pp 49-63 4. Canadian Medical Association: The Canadian task force on the periodic health examination. J 121:1193-1254, 1979
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.003). Particularly striking was the unanticipated finding that the clodronate group showed superiority in terms of metastasis-free survival and overall survival (96% v 85%, P = .001). 
