Support Care Cancer (2004) 12:852–858DOI 10.1007/s00520-004-0671-9 O R I G I N A L A R T I C L E

Sunil VermaDanielle Kerr-CresswellGeorge DranitsarisFlay CharbonneauMaureen TrudeauGeetha YogendranAnne-Marie CestaMark Clemons

Bisphosphonate use for the managementof breast cancer patientswith bone metastases:A survey of Canadian Medical Oncologists

Received: 3 May 2004Accepted: 8 July 2004Published online: 21 August 2004� Springer-Verlag 2004

S. Verma · D. Kerr-Cresswell ·G. Dranitsaris · F. Charbonneau ·M. Trudeau · G. Yogendran · A.-M. Cesta ·M. ClemonsToronto SunnybrookRegional Cancer Centreand Cancer Care Ontario,Toronto, Canada

M. Clemons ())Division of Medical Oncology,Toronto-SunnybrookRegional Cancer Centre,2075 Bayview Avenue,Toronto, Ontario, M4 N 3M5, Canadae-mail: mark.clemons@sw.caTel.: +1-416-4805847Fax: +1-416-2171338

Abstract Background: The use ofbisphosphonates (BP) in breast can-cer patients with bone metastases(BM) has been shown to reduce bonepain and lower the risk of skeletal-related events (SREs). Many practiceguidelines exist for the use of BPs inpatients with BM. Unfortunately,none clearly address whether thebenefits of BP use apply equally to allsubgroups of patients, the duration oftherapy, and when to discontinue BPtherapy. A questionnaire was there-fore developed and administered todetermine how medical oncologistsin Canada use BPs in clinical prac-tice. Methods: A structured mailingstrategy was adopted. The populationconsisted of 100 medical oncologistswith active breast cancer practices inCanada. All regions of Canada wererepresented. The questionnaire wasdeveloped to capture data on re-spondent demographics, BPs used,major factors influencing decisionmaking, and clinical practice in situ-ations where there is a lack of high-quality data. Results: Completedquestionnaires were returned by 76medical oncologists. All treatedbreast cancer and the majority (68%)were based at teaching hospitals.Ninety-six percent of respondentsregularly prescribed BPs, initiating

therapy at the time the patient pre-sented with BM. Although 79% ofrespondents recognized that therewas no clear data to support thecontinued use of BP after bony pro-gression, 53% stated that they rarelyor never discontinue a BP oncestarted. In situations where a BP wasdiscontinued, the majority of respon-dents report the reason for discon-tinuation was a decrease in patientperformance status. In the patientwith clearly progressive visceral me-tastases and an estimated prognosisof less than 6 months, 75% of re-spondents would still commence BPtherapy. Conclusions: This studyconfirms that most medical oncolo-gists in Canada, while acknowledginglack of evidence, maintain patients onBP therapy when patients have anexpected survival of less than 6months or even after patients pro-gress while on a BP. More research isneeded to determine the role of con-tinuing, switching, or discontinuingBP therapy in the context of diseaseprogression or shortened expectedsurvival.

Keywords Bisphosphonates ·Guidelines · Drug-use evaluation ·Breast cancer

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Introduction

The majority of women with metastatic breast cancer willeither present with or subsequently develop bone metas-tases (BM) [5, 8]. The development of BM has significantconsequences for patients in terms of both morbidity andmortality. Two-thirds of patients with BM will subse-quently develop a skeletal-related event (SRE), such asbone pain, nonvertebral and vertebral pathological frac-tures, hypercalcemia of malignancy, spinal-cord com-pression, and the need for radiation therapy [15, 16].Many of these patients will require medical, radiation,and/or surgical interventions to manage or prevent thesecomplications. Furthermore, the presence of BM-relatedcomplications has an impact on patient prognosis. Wom-en with bone-only or dominant disease typically have amedian survival of 2–3 years. However, patients withbone-related complications, such as pathological frac-tures, spinal-cord compression, or hypercalcemia of ma-lignancy have an even shorter median survival of 12, 4,and 3 months, respectively [6, 8].

Bisphosphonates (BP), such as oral clodronate, intra-venous pamidronate, and intravenous zoledronic acid arepotent inhibitors of bone resorption [14]. Randomized

controlled trials comparing a BP with either placebo or notreatment in secondary prophylaxis (i.e., in patients withbreast cancer and established BM) have shown that theuse of BPs in addition to standard treatment can signifi-cantly reduce SREs [10, 11, 12]. As a result of thesestudies, the use of bisphosphonates in patients with BMhas increased dramatically. In the province of Ontarioalone, $5.3 million or 10% of the total Cancer Care On-tario (CCO) New Drug Funding budget was spent onpamidronate in 2002–2003 [4].

BP use has also increased because of their inclusion inmany systemic treatment guidelines based on the evi-dence obtained from randomized controlled trials. Inter-national and provincial practice guidelines (Table 1) statethat BP therapy should be initiated at the time of diag-nosis of BM. However, differences between guidelinesexist not only for what BP should be used but also whe-ther or not they should be stopped after further boneprogression while on BP therapy [1, 3, 9]. These differ-ences between guidelines are important, as they lead toinconsistencies in clinical practice. They also have costimplications, as these agents are expensive, not only interms of drug cost but also in terms of nursing and patienttime.

Table 1 International and provincial guidelines for commencementand discontinuation of bisphosphonates (BP) for metastatic breastcancer. ASCO American Society of Clinical Oncology, ACB Al-berta Cancer Board, BCCA British Columbia Cancer Agency, CCM

Cancer Care Manitoba, NCTRF Newfoundland Cancer Treatmentand Research Foundation, CCNS Cancer Care Nova Scotia, CCOCancer Care Ontario, N/A not available

Guidelines Recommended BPfor prevention ofskeletal metastases

Initiation Discontinuation Funding restrictions

International ASCO IV pamidronate Diagnosis of bonemetastases

Continue BP untilevidence of substantialdecline in a patient’sgeneral performancestatus

N/A

Provincial Alberta(ACB)

Oral clodronate Diagnosis of bonemetastases

IV pamidronate onlyallowed if pt. Unableto tolerate clodronate

British Columbia(BCCA)

Oral clodronate Diagnosis of bonemetastases

Continue until death,intolerance or obviousrapid deterioration inperformance status

Po/IV clodronateIV pamidronate

Manitoba (CCM) Oral clodronate Postmenopausal breastcancer and osteolyticlesions and on chemo/hormonal therapy

N/A IV pamidronate onlyallowed if pt. Unableto tolerate clodronate

Newfoundland(NCTRF)

IV Pamidronate Diagnosis of bonemetastases

Treatment shouldcontinue indefinitely

None

Nova Scotia (CCNS) No provincialguidelines, localinstitution policy

Diagnosis of bonemetastases

N/A N/A

Ontario (CCO) Oral clodronateor IV pamidronate

Diagnosis of bonemetastases

None IV pamidronate onlyallowed if patient unableto tolerate clodronatea

Quebec IV pamidronate Diagnosis of bonemetastases

None None

a Since March 2002, guidelines allow for physicians to initiate patient on pamidronate in the first-line setting.

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To determine how BP are being used in actual clinicalpractice across Canada, a survey of Medical Oncologiststreating breast cancer patients was undertaken. Thequestions we proposed to address in this study were:

– What is the current standard clinical practice ofphysicians with respect to the use of BP in women withmetastatic breast cancer?

– What proportion of medical oncologists continue theirpatients on a BP for BM from breast cancer despiteprogression either in their bones or at any other diseasesite?

Methods

Data collection

The questionnaire was developed to capture data on respondentdemographics, BP used, major factors influencing decision making,and clinical decision making in situations where there is a lack ofhigh-quality data. This questionnaire was sent to 100 medical on-cologists with active breast cancer practices in Canada. The on-cologists were informed about the nature and the primary purposeof the study.

Study population

This was a multicenter survey involving medical oncologists fromacross Canada. The study population included a cross section ofoncologists from university-affiliated teaching hospitals, commu-nity practice, and those involved in guideline development.

Survey instrument

The questionnaire (see Appendix 1) focused on assessing the on-cologist’s clinical practice and addressing the main endpoints of thestudy. The first part of the survey addressed respondent demo-graphic data, type and setting of oncology practice, and number ofyears of experience in breast cancer. The second part of the surveyfocused on the information related to the respondent’s current ap-proach to managing breast cancer patients with metastatic bonedisease and barriers against the use of their preferred option. Thefinal section presented a series of case studies based on areas withlimited published evidence to determine how the respondent wouldmanage each patient.

Sample size and questionnaire administration

After initial pilot testing, questionnaires were faxed or e-mailed to100 medical oncologists across the country. A structured mailingstrategy was adopted.

Statistical analysis

All collected data was presented descriptively as means, medians,or proportions. Parametric and nonparametric statistical tests wasused to compare differences between regions.

Results

The questionnaires were completed and returned by 76medical oncologists for an overall response rate of 76%.Demographic data of the respondents is outlined in Ta-ble 2. Sixty-eight percent of oncologists practiced atteaching hospitals. The study group well represented theregions across the country. Ninety-six percent of thosesurveyed regularly prescribed BP, and they initiated thistreatment at the time the patient presented with BM pri-marily or developed BM during the course of their disease.

Given the clinical scenario of a patient with asymp-tomatic BM secondary to breast cancer, 75/76 (98.7%)oncologists surveyed would initiate BP therapy. Seventy-one of 76 (93.4%) would initiate treatment even if themetastases were blastic, even though the evidence fromRCTs exists only for lytic metastases. Most oncologists,54/76 (71.0%), used oral clodronate as their initial BPagent, while the remaining 22/76 (28.9%) would use IVpamidronate as their agent of choice. Fifty-seven of 76(75.0%) medical oncologists surveyed would recommendBP therapy even if the prognosis with treatment was lessthan 6 months due to the presence of progressive visceralmetastases (Table 3). When managing a patient withprogressive bony metastases already on a BP agent, 39/76(51.3%) would continue the same BP agent, 31/76 (40.8%)would switch to another BP, and 6/76 (7.9%) (Table 4)would stop BP therapy completely. In the event that apatient was to develop an SRE while on a BP agent, 35/74

Table 2 Demographics

Total number of oncologistssurveyed: 76

Number Percent

Region of practiceAtlantic 8 (11%)Quebec 11 (14%)Ontario 31 (31%)Manitoba/Saskatchewan 7 (9%)Alberta 11 (14%)British Columbia 8 (11%)

Practice settingCommunity 19 (25%)Teaching hospital 52 (68%)Other 5 (7%)

Years of experience in treating breast cancer patients<5 15 (20%)5–10 17 (22%)10–15 12 (16%)15–20 8 (11%)>20 24 (32%)

Proportion of patients in your practice who have breast cancer<25% 14 (18%)25–50% 26 (34%)50–75% 19 (25%75–99% 11 (14%)100% 6 (8%)

Use of bisphosphonate on a regular basis for breast cancer patientsYes 73 (96%)No 3 (4%)

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(47.3%) would continue them on the same BP, 36/74(48.7%) would switch to another BP, and 2/74 (2.7%)would stop BP use completely (Table 5). For those on-cologists who chose to switch to another BP, the mostcommon agent of choice was IV pamidronate. Most on-cologists, 60/76 (80%), acknowledged that there was noevidence to recommend switching BP therapy when facingprogressive visceral or bony disease.

The majority of oncologists surveyed would keep thepatients on BP therapy once initiated. The most commonreason identified for discontinuation was declining per-formance status, as stated by 52.0% of the respondents.Adverse drug reactions (ADRs) were stated as the secondmost common reason for discontinuation. Only 4/76(5.3%) oncologists identified progressive disease or anSRE as a reason for discontinuation.

Discussion

The use of BP in the management of BM from breastcancer is well established. There are, however, differ-ences in systemic treatment guidelines regarding not onlywhich BP should initially be used but also whether or notBP should be continued after disease progression. Thesedifferences have important consequences towards incon-sistencies in patient care between physicians and secondlyin terms of total drug cost. Since pamidronate is infusedover at least 2 h in the ambulatory care clinic, there areadditional costs such as nursing time, infusion apparatus,and monthly hospital visits. This study presented an op-portunity to gain practical information about how theseexpensive agents are being utilized in the medical on-cology setting across Canada.

The medical oncologists surveyed have adopted thepublished data for the use of BP in the prevention ofSREs. Seventy-five of 76 (98%) would start patients withBP in the setting of newly diagnosed bone metastases.Most favored the use of oral clodronate (71%) versus IVpamidronate (29%) as their initial BP of choice. There hasnot been a head-to-head comparison between the twoagents, and the choice of particular agent is dependentupon local practice guidelines and funding policies. How-ever, discrepancies and uncertainty in these guidelines onwhen to discontinue BP therapy has also impacted clinicalpractice in this setting. The question as to whether or notBP should be continued after progression of BM is im-portant [13]. It is clear from the data reported here that themajority of oncologists (51.3%) continue their patients onthe same BP even when they have progressive bony me-tastases. Even though this is consistent with the provincialguidelines, it is important to realize that despite the use ofBP, most patients with BM will eventually progress intheir bones. The paucity of published data supporting theefficacy of BPs after progression suggests that many pa-tients receiving these agents may not actually benefit fromthis therapy [2]. Despite citing the level of evidence as“Insufficient data”, the American Society of Clinical On-cology (ASCO) guidelines for the continuation of pami-dronate after progression suggest that intravenous BP becontinued until evidence of substantial decline in a pa-tient’s general performance status [9]. This was also theprimary reason for discontinuation of BP use cited by thesurveyed medical oncologists.

Table 5 Use of bisphosphonate (BP) if there is evidence of askeletal-related event (SRE). Same oncologists would favor tocontinue on the same BP; Switch oncologists would favor to switchto another BP

Province Regional use of BP if there is evidence of SRE

Use BP Stop BP

Same Switch

Atlantic 5/8 (63%) 3/8 (37%) 0Quebec 3/11 (27.%) 7/11 (64%) 1/11 (9%)Ontario 11/31 (35%) 19/31 (61%) 0Manitoba/Saskatchewan

5/7 (71%) 2/7 (29%) 0

Alberta 4/9 (44%) 5/9 (56%) 0British Columbia 7/8 (88%) 0 1/8 (12.5%)Total 35/74 (47%) 36/74 (49%) 2/74 (3%)

71/74 (95%)

Table 3 Regional use of bisphosphonates even if the prognosis wasless than 6 months

Province Yes (%) No (%)

Atlantic 6/8 (75%) 2/8 (25%)Quebec 7/11 (64%) 4/11 (36%)Ontario 25/31 (81%) 6/31 (19.3%)Manitoba/Saskatchewan 5/7 (71%) 2/7 (29%)Alberta 11/11 (100%) 0/11 (0%)British Columbia 6/8 (75%) 2/8 (25%)Total 57/76 (75%) 19/76 (25%)

Table 4 Use of bisphosphonate (BP) if there is evidence of pro-gressive disease in the bones or if there is evidence of a skeleatalrelated event. Same Oncologists would favor to continue on thesame BP; Switch oncologists would favor to switch to another BP

Province Regional use of BP if there is evidenceof progressive disease in the bones

Use BP Stop BP

Same Switch

Atlantic 5/8 (63%) 3/8 (37%) 0Quebec 3/11 (27.%) 7/11 (64%) 1/11 (9%)Ontario 13/31 (42%) 16/31 (52%) 2/31 (6%)Manitoba/Saskatchewan

5/7 (71%) 1/7 (14%) 1/7 (14%)

Alberta 6/11 (55%) 4/11 (36%) 1/11 (9%)British Columbia 7/8 (88%) 0 1/8 (12.5%)Total 39/76 (51%) 31/76 (41%) 6/76 (8%)

70/76 (92%)

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In order to limit the use of BPs to those patients whoare most likely to benefit, it has been proposed that wom-en with BM who endure a protracted course will have alonger survival and thus live long enough to derive ben-efit from BP therapy [6, 7]. Indeed, the large pamidronatestudies had as eligibility criteria a prognosis of at least6 months survival [10, 11, 12, 16]. In addition, a largemajority of patients in these studies had bone-only me-tastases. The overall 13% absolute reduction in SREsreported in these trials was therefore achieved in a pop-ulation with a relatively favorable prognosis. Most (75%)of the medical oncologists surveyed in our study wouldinitiate or maintain BP therapy in patients with a prog-nosis of less than 6 months. Thus, treating patients with ashort prognosis may be even less cost effective and amore efficient strategy may be to delay initiation of BP oravoid it altogether in patients with a particularly poorprognosis, i.e., those patients with rapidly progressivevisceral metastases.

In summary, the use of BP for BM has led to a majorimprovement in the management of women with meta-static breast cancer. However, a real need exists forrandomized trials looking at the continued use of BPfollowing skeletal events while on a BP and also theirrole in the management of patients with poor prognosisdisease. These studies could also incorporate quality-of-life measures, patient preference, treatment complianceand possibly correlation with bone markers to determineif the benefit is confined to subgroups with a markerresponse or at least no early increase. One possible trialcould include patients progressing while on a BP ran-domized to either placebo, continuation of the same BPor to an increased dosing intensity of the same BP, or to anewer-generation BP such as zoledronic acid. Until thesestudies are done, there will continue to be major differ-ences between medical oncologists’ choice of treatment,funding guidelines, and clinical management of thesepatients.

Appendix 1

Bisphosphonate use in patients with breast cancerwith bone metastases

Although formal guidelines exist with respect to the ini-tiation of bisphosphonates in patients with bone metas-tases from breast cancer, there are no evidence-basedguidelines to direct the timing of the initiation of bis-phosphonate therapy, the duration of bisphosphonate ther-apy, or whether or not subgroups of patients are morelikely to benefit from bisphosphonate therapy than others.The purpose of this questionnaire is to determine howphysicians currently manage their patients who developmetastatic bone disease. The results will be used to de-

termine the need for and feasibility of a clinical trial.Your answers are entirely confidential.

Please circle the response that best applies:

1) Do you practice at a:a) community-based hospitalb) teaching hospitalc) other (please specify)

2) How many years of experience do you have in treatingbreast cancer patients?

a) <5 yearsb) 5–10 yearsc) 10–15 yearsd) 15–20 yearse) >20 years

3) What proportion of your practice consists of breastcancer patients?

a) <25%b) 25–50%c) 50–75%d) 75–99%e) 100%

4) How many new breast cancer patients do you see?a) one per monthb) one per weekc) more than one per week (please indicate number:

2 3 4 >5)

5) How often do you see a patient with newly diagnosednew bone metastases?

a) one per yearb) one per monthc) one per weekd) more than one per week (please indicate how many: 2

3 4 >5)

6) Do you regularly prescribe bisphosphonates for patientswith bone metastases from breast cancer?

a) Yesb) No

If your answer is “no” please stop here and simplyreturn the questionnaire.

7) If a 50 year old patient is seen in your clinic withnewly diagnosed bone metastases in the ribs and ver-tebral bodies:

i. I would usually recommend a bisphosphonate even ifthis patient has little or no pain. Yes/No

ii. I would usually recommend a bisphosphonate even ifthe metastases were blastic. Yes/No

iii. I would usually recommend a bisphosphonate even ifthe prognosis with treatment is probably less than 6

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months due to the presence of progressive visceralmetastases. Yes/No

8) Which bisphosphonate do you use initially whentreating the patient with bone metastases?

a) Oral clodronateb) Intravenous clodronatec) Intravenous pamidronated) Etidronatee) Alendronatef) Zoledronic acidg) Other (please specify)

10) Of those patients destined to have a skeletal-relatedevent (i.e. pathological fracture, spinal cord com-pression), by what percentage do you think the bis-phosphonate reduces the risk?

a) Fewer than 25%b) 25–50%c) >50%

11) A patient has been taking the bisphosphonate that youprescribed for the past 6 months. She then experi-ences increasing bone pain associated with diseaseprogression within bone. Irrespective of her othertherapies, which statement describes your usual prac-tice with respect to bisphosphonates:

a) I would continue to prescribe the bisphosphonate asbefore

b) I would stop bisphosphonate therapyc) I would switch to another bisphosphonated) Other:

12) A patient has been taking the bisphosphonate that youprescribed for the past 6 months. She then develops askeletal-related event (i.e. pathological fracture, spi-nal cord compression). Irrespective of her other ther-apies, which statement describes your usual practicewith respect to bisphosphonates:

a) I would continue to prescribe the bisphosphonate asbefore

b) I would stop bisphosphonate therapyc) I would switch to another bisphosphonated) Other:

13) In the event that you were to switch bisphosphonates,which would you use as second line therapy in thisinstance?

a) Oral clodronateb) Intravenous clodronatec) Intravenous pamidronated) Etidronatee) Alendronatef) Zoledronic acidg) Other (please specify)

14) To your knowledge, what is the level of evidencesupporting the continued use of bisphosphonates inpatients who have had a skeletal related event (e.g.fracture, spinal cord compression etc.) despite AL-READY being on a bisphosphonate?

a) Level Ia: Randomized double blind trialb) Level Ib: Randomized non-blinded trialc) Level IIa: Population based cohort studyd) Level IIb: Case control studye) Level III: Case seriesf) Level IV: There is no evidence to continue bisphos-

phonate therapy after a skeletal related event

15) Once you have started a patient on bisphosphonatetherapy, how often do you discontinue bisphospho-nate therapy?

a) Neverb) <5%c) 5–25%d) >50%

16) What would be the most common reason you woulddiscontinue bisphosphonate therapy entirely?

a) Intolerable side effectsb) Worsening bone painc) Radiologic evidence of progressiond) Skeletal related event (pathologic fracture, spinal cord

compression)e) Progression of disease outside of bonef) Marked deterioration in performance statusg) Other (specify)

17) Would you be comfortable in entering patientswith bone metastases who have had progressionof their bone disease while on a bisphosphonateinto a clinical trial in which they would be ran-domized to one of three arms: 1) continuing withtheir bisphosphonate, 2) switching to a differentbisphosphonate, or 3) discontinuing their bisphos-phonate?

a) Yesb) No

Section II

We are pilot testing this questionnaire. We would be verygrateful if you can answer a few more questions about it.Any comments you may have are also of value.

1. Please state which question(s) are most relevant fromyour perspective as a clinician

– Why

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References

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2. Body JJ, Mancini I (2002) Bisphos-phonates for cancer patients: why, how,and when? Support Care Cancer10(5):399–407

3. Breast Cancer Disease Site Group. Useof bisphosphonates in patients withbone metastases from breast cancer.CCO Practice Guideline Initiative.Available from: URL: www.hiru.mc-master.ca/ccopgi/guidelines/bre/cpg1_11.html

4. Cancer Care Ontario (2000) New drugfunding program. Available from:URL: www.cancercare.on.ca/treatment/newdrugs.html.

5. Coleman R (1997) Skeletal complica-tions of malignancy. Cancer 80:1588–1594

6. Coleman R, Rubens R (1987) Theclinical course of bone metastases frombreast cancer. Br J Cancer 55:61–66

7. Coleman R, Smith P, Rubens R (1998)Clinical course and prognostic factorsfollowing bone recurrence from breastcancer. Br J Cancer 77:336–340

8. Hill M, Richards M, Gregory W, SmithP, Rubens R (1993) Spinal cord com-pression in breast cancer: a review of 70cases. Br J Cancer 68:969–973

9. Hillner BE, Ingle JN, Chelebowski RTet al (2003) American Society of Clin-ical Oncology 2003 Update on the roleof bisphosphonates and bone health is-sues in women with breast cancer.J Clin Oncol 21(21):4042–4057

10. Hortobagyi G, Theriault R, Lipton Aet al (1998) Long-term prevention ofskeletal complications of metastaticbreast cancer with pamidronate. J ClinOncol 16:2038–2044

11. Hortobagyi G, Theriault R, Porter L etal (1996) Efficacy of pamidronate inreducing skeletal complications in pa-tients with breast cancer and lytic bonemetastases. NEJM 335:1785–1791

12. Lipton A, Theriault RL, Hortobagyi GNet al (2000) Pamidronate preventsskeletal complications and is effectivepalliative treatment in women withbreast carcinoma and osteolytic bonemetastases: long term follow-up of tworandomized, placebo-controlled trials.Cancer 88(5):1082–1090

13. Major P, Cook R, Tozer R, Hirte H(1998) Bisphosphonates for bone me-tastases in breast cancer patients: trialdesign issues and evaluation of pub-lished studies. Current Oncology5:181–187

14. Mundy G (1997) Mechanisms of bonemetastasis. Cancer 80:1546–1556

15. Rubens R (1998) Bone metastases—theclinical problem. Eur J Cancer 34:210–213

16. Theriault RL, Lipton A, Hortobagyi GNet al (1999) for the Protocol 18 ArediaBreast Cancer Study Group. Pami-dronate reduces skeletal morbidity inwomen with advanced breast cancerand lytic bone lesions: a randomized,placebo-controlled trial. J Clin Oncol17(3):846–854

2. Please state which questions should be removed fromthe survey

– Why

3. Please state which questions should be reworded be-cause they are currently difficult to understand:

4. Are there additional questions that should be added tothe survey: Yes / No

– If yes, what are they:

Thank you for participating in this survey. Your re-sponses are very important.