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The role of bisphosphonates in metastatic breast cancer
The Role of Bisphosphonates in Metastatic Breast Cancer Bruce E. Hillner The American Society of Clinical Oncology has recently developed guidelines for the use of bisphosphonates in breast cancer. Highlights of these guidelines are reviewed. Specific issues addressed included when in the course of disease should treatment be started, the duration of therapy, the role of bisphosphonates in pain control, their safety, and current estimates of their cost
effectiveness. Although intravenous bisphosphonates, primarily pamidronate, have been shown to reduce the frequency of skeletal-related complications in women with known lytic bone metastases from breast cancer, numerous major areas of clinical importance related to their use have not been studied and are highlighted. Copyright 9 2000 by W.B. Saunders Company
n the United States, breast cancer is the most common nonskin malignancy in women. In 1999, it is estimated that 30% of new cancer cases in women will arise in this site, 176,300 will be diagnosed, and almost 44,000 women will die. 1Bone is the most common site of metastasis in patients with breast cancer. Bone is the site of first metastatic lesion in approximately one quarter of women and, eventually, the majority of women develop bone metastasis. The median survival rate with metastatic breast cancer varies widely depending on the sites of involvement. W o m e n with bone only or dominant disease typically have a median survival rate of 3 years. The morbidity associated with bone metastases is well known to radiation oncologists. Although many lesions are initially asymptomatic, pain is the most c o m m o n symptom. Other complications include pathological fractures that can be devastating, such as decreased mobility from femoral fi'actures or in spinal cord compromise with vertebral body collapse. Because 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 ag~ents that have been shown to reduce bony complications associated with breast cancer in a variety of studies. In this article, the available evidence that was used in the recently developed American Society of Clinical On-
cology (ASCO) Clinical Practice Guidelines for the use of bisphosphonates in breast cancer are reviewed. 2
I
From the Depariment of Internal Medicine, Virginia Commonwealth University, and the Masaey Cancer Center,Richmond, VA. Address reprint requests to Bruce E. Hillner, ViNinia Commonwealth University, Box 980170, Richmond, VA 23298-0170. E-maih [email protected] Copyright 9 2000 by W.B. Saunders Company 1053-4296/00/1003-0008510.00/0 doi:l O.1053/srao.2000.6595
250
W h o Should Be Treated? 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 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 is limited to women with radiographic evidence of bony lytic metastases already identifiable on plain radiographs and to women concurrently receiving systemic anticancer therapy.
H o w to Treat? A benefit has only been consistently seen from intravenous bisphosphonates predominantly using at least 90 mg ofpamidronate.3,4A benefit from intravenous pamidronate was seen in two well-designed randomized controlled studies in which a reduction in skeletal complications such as pathological fractures, surgery for fracture or impending fracture, radiation, spinal cord compression, and hypercalcemia, was seen. Specifically, 382 women receiving chemotherapy with at least 1 lytic bone lesion were randomized to either 90 mg pamidronate or placebo intravenously 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. 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),
Seminars" in Radiation Oncology, Vo110, No 3 (July), 2000: pp 250-253
Bisphosphonates in Metastatic Breast Cancer
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 women completed the first year of the trial and continued randomized assigned treatment up to a maximum of 2 years. The difference in overall skeletal complications continued to favor pamidronate and remained statistically significant through 24 months and the time to first skeletal complication favored the pamidronate group (median, 7.0 v 13.9 months; P < .001). Despite the improvements in control of bony metastases, patients treated with pamidronate did not have a survival rate advantage. Importantly, long-term treatment was not associated with unexpected adverse events. A similar trial was conducted in 374 women receiving hormonal therapy wire were randomized to 90 mg pamidronate or placebo intravenously over 2 hours every 4 weeks for up to 2 years) Bone was the only site of metastatic disease for about 70% of women a t 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 a skeletal-related event on placebo was 1.6 (95% confidence interval, 1.1 to 2.5) compared with pamidronate. Bone pain scores improved fi-om 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.
Should All Women With Evidence of Lytic Lesions Be Treated? The ASCO expert panel recognized that if a~large heterogeneous cohort of women with osteolytic bone lesions were considered, 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 if 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, in a patient with extensive visceral metastasis but minimal asymptomatic osseous metastasis.
251
Abnormal Scans But Normal Plain Radiographs This unusual situation was answered only by expert opinion because no data are available to guide care. The ASCO panel recommended using pain as the primary guide for treatment and, therefore, to begin administering bisphosphonates if pain is present and to withhold it if pain is not present.
Extraskeletal Metastases Without Evidence of Bony Metastases Although this group would logically be expected to be at high risk of developing bony metastases, the efficacy of bisphosphonates in reducing this risk has not been shown in two small trials using oral bisphosphonates. No trials using intravenous bisphosphonates have been performed or are known to be in progress.
Duration of Therapy The optimal duration of bisphosphonate use is unknown because this issue has never been the focus of a clinical trial. In the two trials discussed earlier, 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 currently not being studied. Therefore, the expert panel suggested that, once initiated, intravenous bisphosphonates be continued until there is evidence of a substantial decline in a patient's general performance status, and stressed that only clinical judgment can guide how long bisphosphonates should be given, or define what constitutes a substantial decline in clinical status. The lack of information on rules regarding stopping has substantial financial consequences. There is no evidence addressing the consequences of stopping bisphosphonates after 1 or more adverse events. Studies specifically focusing on this issue are needed.
Role of Bisphosphonates in Pain Control This question was stratified into the role of bisphosphonates in women with metastatic breast cancer who are and are not receiving systemic anticancer therapy. The panel recommended that current standards of care for cancer pain, analgesics, and local radiation therapy should not be displaced by bisphos-
252
Bruce E. Hillner
phonates because bisphosphonate therapy with chemotherapy and/or hormonal therapy was associated with only a modest pain control benefit in controlled trials. There is insufficient evidence to support a role for intravenous bisphosphonates as an adjunctive therapy to radiation therapy among women with painful metastatic bone disease when systemic chemotherapy and/or hormonal therapy is not being used. The role ofbisphosphonates as the sole therapy in this setting has not been determined. In women already treated with local radiotherapy who have persistent or recurrent pain, bisphosphonates are an attractive, but little studied, salvage therapy. These recommendations were based primarily on small phase II comparisons. These showed an onset of pain relief benefit from bisphosphonates of 6 weeks, a requirement of at least 60 mg pamidronate, and a greater benefit in reducing summary pain scores than in reducing narcotic use. 5 The optimal combination or sequencing of bisphosphonates with radiotherapy or radiopharmaceuticals has not been studied. Given that all these therapies are expensive, investigation into different strategies of dose, duration, and sequencing should be explored.
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 of the placebo group. Women have rarely discontinued pamidronate therapy because of adverse effects. Transient myalgias, arthralgias, and flu-like symptoms with fever tend to occur more often in women treated with pamidronate. 6 A recent case series found no difference in renal or general tolerability between a 1- and 2-hour infusion of pamidronate. 7
Ongoing Research Questions of the specific drug, when to initiate, duration of therapy, and the use of markers to select women at high risk define the direction of current clinical trialswith bisphosphonates. The major thrust of attention is to their use in the adjuvant setting and to investigating newer, third-generation bisphosphonates that appear to be more powerful inhibitors of osteoclasts. However, only randomized clinical trials will p/covide information on relative clinical efficacy. In the adjuvant setting, studies using a placebocontrol design should be encouraged. The dilemma
facing investigators planning clinical trials of metastatic bone disease in breast cancer is that some form of bisphosphonate are likely to be considered the standard of care even in settings in which it has not been studied.
Cost-Effectiveness Implications In recent years, a variety of other supportive agents such as the selective 5-hydroxytyrptamine-3 receptor antiemetics, hematopoietic growth factors, recombinant erythropoietin, and low molecular weight heparin have transformed cancer care. Each of these is used to reduce cancer-specific symptoms or treatment-associated complications. However, establishing their financial value is a recurring challenge because these agents generally do not improve survival rates. For bisphosphonates in advanced breast cancer two retrospective cost-utility analyses appear, at first glance, to come to different conclusions. Both agree that pamidronate will require new expenditures; that is, the cost of avoiding adverse skeletal events must be less than the costs incurred in the administration of bisphosphonates. 8,9 The analysis by Hillner et al 8 of the previously discussed pamidronate trials found cost-effectiveness ratios associated with adding pamidronate of $t08,200 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 skeletalrelated event were $9,350 in the chemotherapy and $12,760 in the hormonal therapy cohorts. These high costs of preventing skeletal-related events are directly related to the cost ofpamidronate and the fact that few patients overall develop skeletal-related events. Bone metastases represent a'wide spectrum of disease. Although one site may cause symptoms, the other sites of bone metastases maybe asymptomatic. Many bone metastases can be effectively managed with therapies that are less expensive than pamidronate, such as localized radiation and analgesics. Furthermore, 60% of the pathologic fractures occurred in the pamidronate group. However, the analysis by Dranitsaris and Hsu 9 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 primarily explained in the
Bi~phosphonates in Metastatic Breast Cancer
C a n a d i a n m o d e l by an a p p r o x i m a t e l y 50% lower p a m i d r o n a t e cost p e r t r e a t m e n t c o m p a r e d with t h e U n i t e d States and t h a t all patients with a n o n v e r t e bral f r a c t u r e w e r e a s s u m e d to be hospitalized.
Conclusion In the U n i t e d States, intravenous p a m i d r o n a t e is t h e only c u r r e n t l y approved bisphosphonate for use in breast c a n c e r patients w h o have s y m p t o m s f r o m radiographically evident lytic b o n e m e t a s t a s e s and who are receiving systemic a n t i c a n c e r therapy. C u r r e n t standards of care for cancer pain, analgesics, and local radiation t h e r a p y should not be displaced by bisphosphonates. T h e optimal c o m b i n a t i o n or seq u e n c i n g of bisphosphonates w i t h r a d i o t h e r a p y or r a d i o p h a r m a c e u t i c a l s is sorely in n e e d of study.
References 1. Landis SH, Murray T, Bolden S, et al: Cancer statistics, 1999. CA CancerJ Clin 49:8-31, 1999 2. Hillner BE, BerensonJR, IngleJN, et al: ASCO guideline on the role ofbisphosphonates in breast cancer.J Clin Onco118:72-79, 2000
253
3. Hortobagyi GN, Theriault RL, Lipton A, et al: Long-term prevention of skeletal complications of metastatic breast cancerwith pamidronate. Protocol 19 Media Breast Cancer Study Group.J Clin OncoI 16:2038-2044, 1998 4. Theriault RL, Lipton A, Hortobagyi GN, et al: Pamidronate reduces skeletal morbidity in women with advanced breast cancer and lyric bone lesions: A randomized, placebo-controlled trial. Protocol 18 Pa'edia Breast Cancer Study Group. J Ciin Oncol l 7:846-854, 1999 5. BodyJJ, Bartl R, Burckhardt P, et al: Current use ofbisphosphonates in oncology.International Bone and Cancer Study Group. J Clin Onco116:3890-3899, 1998 6. CoukelI AJ, Markham A: Pamidronate. A review of its use in the management of osteolytic bone metastases, tumour-induced hypercaicaemia and Paget's disease of bone. Drugs Aging I2:149-168, 1998 7. Thuerlimann B, Morant R, Jung WF, et ah Renal safety and tolerability of 90 mg Aredia (Pamidronate) administered as an intravenous 1 hours infusion: preliminary results. Proc Am Soc Clin Oncot 19:2223A, 1999 8. Hillner BE, Weeks JC, Desch CE, eta[: Pamidronate in prevention of bone complications in metastatic breast cancer: A cost-effectiveness analysis.J Clin Oncol 18:72-79, 2000 9. Dranitsaris G, Hsu T: Cost utility analysis of prophylactic pamidronate for the prevention of skeletal related events in patients with advanced breast cancer. Support Care Cancer 7:271-279, 1999
effectiveness. Although intravenous bisphosphonates, primarily pamidronate, have been shown to reduce the frequency of skeletal-related complications in women with known lytic bone metastases from breast cancer, numerous major areas of clinical importance related to their use have not been studied and are highlighted. Copyright 9 2000 by W.B. Saunders Company
n the United States, breast cancer is the most common nonskin malignancy in women. In 1999, it is estimated that 30% of new cancer cases in women will arise in this site, 176,300 will be diagnosed, and almost 44,000 women will die. 1Bone is the most common site of metastasis in patients with breast cancer. Bone is the site of first metastatic lesion in approximately one quarter of women and, eventually, the majority of women develop bone metastasis. The median survival rate with metastatic breast cancer varies widely depending on the sites of involvement. W o m e n with bone only or dominant disease typically have a median survival rate of 3 years. The morbidity associated with bone metastases is well known to radiation oncologists. Although many lesions are initially asymptomatic, pain is the most c o m m o n symptom. Other complications include pathological fractures that can be devastating, such as decreased mobility from femoral fi'actures or in spinal cord compromise with vertebral body collapse. Because 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 ag~ents that have been shown to reduce bony complications associated with breast cancer in a variety of studies. In this article, the available evidence that was used in the recently developed American Society of Clinical On-
cology (ASCO) Clinical Practice Guidelines for the use of bisphosphonates in breast cancer are reviewed. 2
I
From the Depariment of Internal Medicine, Virginia Commonwealth University, and the Masaey Cancer Center,Richmond, VA. Address reprint requests to Bruce E. Hillner, ViNinia Commonwealth University, Box 980170, Richmond, VA 23298-0170. E-maih [email protected] Copyright 9 2000 by W.B. Saunders Company 1053-4296/00/1003-0008510.00/0 doi:l O.1053/srao.2000.6595
250
W h o Should Be Treated? 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 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 is limited to women with radiographic evidence of bony lytic metastases already identifiable on plain radiographs and to women concurrently receiving systemic anticancer therapy.
H o w to Treat? A benefit has only been consistently seen from intravenous bisphosphonates predominantly using at least 90 mg ofpamidronate.3,4A benefit from intravenous pamidronate was seen in two well-designed randomized controlled studies in which a reduction in skeletal complications such as pathological fractures, surgery for fracture or impending fracture, radiation, spinal cord compression, and hypercalcemia, was seen. Specifically, 382 women receiving chemotherapy with at least 1 lytic bone lesion were randomized to either 90 mg pamidronate or placebo intravenously 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. 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),
Seminars" in Radiation Oncology, Vo110, No 3 (July), 2000: pp 250-253
Bisphosphonates in Metastatic Breast Cancer
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 women completed the first year of the trial and continued randomized assigned treatment up to a maximum of 2 years. The difference in overall skeletal complications continued to favor pamidronate and remained statistically significant through 24 months and the time to first skeletal complication favored the pamidronate group (median, 7.0 v 13.9 months; P < .001). Despite the improvements in control of bony metastases, patients treated with pamidronate did not have a survival rate advantage. Importantly, long-term treatment was not associated with unexpected adverse events. A similar trial was conducted in 374 women receiving hormonal therapy wire were randomized to 90 mg pamidronate or placebo intravenously over 2 hours every 4 weeks for up to 2 years) Bone was the only site of metastatic disease for about 70% of women a t 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 a skeletal-related event on placebo was 1.6 (95% confidence interval, 1.1 to 2.5) compared with pamidronate. Bone pain scores improved fi-om 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.
Should All Women With Evidence of Lytic Lesions Be Treated? The ASCO expert panel recognized that if a~large heterogeneous cohort of women with osteolytic bone lesions were considered, 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 if 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, in a patient with extensive visceral metastasis but minimal asymptomatic osseous metastasis.
251
Abnormal Scans But Normal Plain Radiographs This unusual situation was answered only by expert opinion because no data are available to guide care. The ASCO panel recommended using pain as the primary guide for treatment and, therefore, to begin administering bisphosphonates if pain is present and to withhold it if pain is not present.
Extraskeletal Metastases Without Evidence of Bony Metastases Although this group would logically be expected to be at high risk of developing bony metastases, the efficacy of bisphosphonates in reducing this risk has not been shown in two small trials using oral bisphosphonates. No trials using intravenous bisphosphonates have been performed or are known to be in progress.
Duration of Therapy The optimal duration of bisphosphonate use is unknown because this issue has never been the focus of a clinical trial. In the two trials discussed earlier, 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 currently not being studied. Therefore, the expert panel suggested that, once initiated, intravenous bisphosphonates be continued until there is evidence of a substantial decline in a patient's general performance status, and stressed that only clinical judgment can guide how long bisphosphonates should be given, or define what constitutes a substantial decline in clinical status. The lack of information on rules regarding stopping has substantial financial consequences. There is no evidence addressing the consequences of stopping bisphosphonates after 1 or more adverse events. Studies specifically focusing on this issue are needed.
Role of Bisphosphonates in Pain Control This question was stratified into the role of bisphosphonates in women with metastatic breast cancer who are and are not receiving systemic anticancer therapy. The panel recommended that current standards of care for cancer pain, analgesics, and local radiation therapy should not be displaced by bisphos-
252
Bruce E. Hillner
phonates because bisphosphonate therapy with chemotherapy and/or hormonal therapy was associated with only a modest pain control benefit in controlled trials. There is insufficient evidence to support a role for intravenous bisphosphonates as an adjunctive therapy to radiation therapy among women with painful metastatic bone disease when systemic chemotherapy and/or hormonal therapy is not being used. The role ofbisphosphonates as the sole therapy in this setting has not been determined. In women already treated with local radiotherapy who have persistent or recurrent pain, bisphosphonates are an attractive, but little studied, salvage therapy. These recommendations were based primarily on small phase II comparisons. These showed an onset of pain relief benefit from bisphosphonates of 6 weeks, a requirement of at least 60 mg pamidronate, and a greater benefit in reducing summary pain scores than in reducing narcotic use. 5 The optimal combination or sequencing of bisphosphonates with radiotherapy or radiopharmaceuticals has not been studied. Given that all these therapies are expensive, investigation into different strategies of dose, duration, and sequencing should be explored.
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 of the placebo group. Women have rarely discontinued pamidronate therapy because of adverse effects. Transient myalgias, arthralgias, and flu-like symptoms with fever tend to occur more often in women treated with pamidronate. 6 A recent case series found no difference in renal or general tolerability between a 1- and 2-hour infusion of pamidronate. 7
Ongoing Research Questions of the specific drug, when to initiate, duration of therapy, and the use of markers to select women at high risk define the direction of current clinical trialswith bisphosphonates. The major thrust of attention is to their use in the adjuvant setting and to investigating newer, third-generation bisphosphonates that appear to be more powerful inhibitors of osteoclasts. However, only randomized clinical trials will p/covide information on relative clinical efficacy. In the adjuvant setting, studies using a placebocontrol design should be encouraged. The dilemma
facing investigators planning clinical trials of metastatic bone disease in breast cancer is that some form of bisphosphonate are likely to be considered the standard of care even in settings in which it has not been studied.
Cost-Effectiveness Implications In recent years, a variety of other supportive agents such as the selective 5-hydroxytyrptamine-3 receptor antiemetics, hematopoietic growth factors, recombinant erythropoietin, and low molecular weight heparin have transformed cancer care. Each of these is used to reduce cancer-specific symptoms or treatment-associated complications. However, establishing their financial value is a recurring challenge because these agents generally do not improve survival rates. For bisphosphonates in advanced breast cancer two retrospective cost-utility analyses appear, at first glance, to come to different conclusions. Both agree that pamidronate will require new expenditures; that is, the cost of avoiding adverse skeletal events must be less than the costs incurred in the administration of bisphosphonates. 8,9 The analysis by Hillner et al 8 of the previously discussed pamidronate trials found cost-effectiveness ratios associated with adding pamidronate of $t08,200 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 skeletalrelated event were $9,350 in the chemotherapy and $12,760 in the hormonal therapy cohorts. These high costs of preventing skeletal-related events are directly related to the cost ofpamidronate and the fact that few patients overall develop skeletal-related events. Bone metastases represent a'wide spectrum of disease. Although one site may cause symptoms, the other sites of bone metastases maybe asymptomatic. Many bone metastases can be effectively managed with therapies that are less expensive than pamidronate, such as localized radiation and analgesics. Furthermore, 60% of the pathologic fractures occurred in the pamidronate group. However, the analysis by Dranitsaris and Hsu 9 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 primarily explained in the
Bi~phosphonates in Metastatic Breast Cancer
C a n a d i a n m o d e l by an a p p r o x i m a t e l y 50% lower p a m i d r o n a t e cost p e r t r e a t m e n t c o m p a r e d with t h e U n i t e d States and t h a t all patients with a n o n v e r t e bral f r a c t u r e w e r e a s s u m e d to be hospitalized.
Conclusion In the U n i t e d States, intravenous p a m i d r o n a t e is t h e only c u r r e n t l y approved bisphosphonate for use in breast c a n c e r patients w h o have s y m p t o m s f r o m radiographically evident lytic b o n e m e t a s t a s e s and who are receiving systemic a n t i c a n c e r therapy. C u r r e n t standards of care for cancer pain, analgesics, and local radiation t h e r a p y should not be displaced by bisphosphonates. T h e optimal c o m b i n a t i o n or seq u e n c i n g of bisphosphonates w i t h r a d i o t h e r a p y or r a d i o p h a r m a c e u t i c a l s is sorely in n e e d of study.
References 1. Landis SH, Murray T, Bolden S, et al: Cancer statistics, 1999. CA CancerJ Clin 49:8-31, 1999 2. Hillner BE, BerensonJR, IngleJN, et al: ASCO guideline on the role ofbisphosphonates in breast cancer.J Clin Onco118:72-79, 2000
253
3. Hortobagyi GN, Theriault RL, Lipton A, et al: Long-term prevention of skeletal complications of metastatic breast cancerwith pamidronate. Protocol 19 Media Breast Cancer Study Group.J Clin OncoI 16:2038-2044, 1998 4. Theriault RL, Lipton A, Hortobagyi GN, et al: Pamidronate reduces skeletal morbidity in women with advanced breast cancer and lyric bone lesions: A randomized, placebo-controlled trial. Protocol 18 Pa'edia Breast Cancer Study Group. J Ciin Oncol l 7:846-854, 1999 5. BodyJJ, Bartl R, Burckhardt P, et al: Current use ofbisphosphonates in oncology.International Bone and Cancer Study Group. J Clin Onco116:3890-3899, 1998 6. CoukelI AJ, Markham A: Pamidronate. A review of its use in the management of osteolytic bone metastases, tumour-induced hypercaicaemia and Paget's disease of bone. Drugs Aging I2:149-168, 1998 7. Thuerlimann B, Morant R, Jung WF, et ah Renal safety and tolerability of 90 mg Aredia (Pamidronate) administered as an intravenous 1 hours infusion: preliminary results. Proc Am Soc Clin Oncot 19:2223A, 1999 8. Hillner BE, Weeks JC, Desch CE, eta[: Pamidronate in prevention of bone complications in metastatic breast cancer: A cost-effectiveness analysis.J Clin Oncol 18:72-79, 2000 9. Dranitsaris G, Hsu T: Cost utility analysis of prophylactic pamidronate for the prevention of skeletal related events in patients with advanced breast cancer. Support Care Cancer 7:271-279, 1999