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Randomized Feasibility Study of De-escalated (Every 12 wk) Versus Standard (Every 3 to 4 wk) Intravenous Pamidronate

in Women With Low-risk Bone Metastases FromBreast Cancer

Eitan Amir, MB, ChB,* Orit Freedman, MD,w Lindsay Carlsson, MN,z

George Dranitsaris, MPharm,* George Tomlinson, PhD,y Andreas Laupacis, MD,8

Ian F. Tannock, MD, PhD,* and Mark Clemons, MDz

Objectives: Despite substantial variability in individual risk of skeletalcomplications, patients with metastatic bone disease are treated with

bisphosphonates at the same dose and dosing interval. This studyassessed the feasibility of conducting a randomized trial of less fre-quent bisphosphonate administration in women with breast cancer and low-risk bone metastases.

Methods: A randomized feasibility study was conducted. Patientsreceiving intravenous bisphosphonates for Z3 months and with low-risk baseline serum C-telopeptide (CTx) levels (< 600ng/L) wereassigned to pamidronate 90 mg intravenously every 3 to 4 weeks(control) or every 12 weeks (de-escalated). CTx, bone alkaline phos-

phatase, and pain scores (Brief Pain Inventory and Functional As-sessment of Cancer Therapy-Bone Pain) were collected every 12weeks for 48 weeks.

Results: Fifty-four patients were approached, 44 consented, and 38were randomized. Median age was 55 (range, 29 to 77) and median

baseline CTx was 163 ng/L (range, 10 to 526). Fourteen control group participants (73.7%) and 13 de-escalated group participants (68.4%)maintained CTx in the low-risk range ( P = 0.64). All patients changingto higher-risk range had progressive extraskeletal disease. Compared with the control group, there was a time-dependent increase in CTx inthe de-escalated group. There were no significant differences in bonealkaline phosphatase, Brief Pain Inventory, or Functional Assessmentof Cancer Therapy-Bone Pain.

Conclusions: It is feasible to conduct randomized trials of de-escalated pamidronate in low-risk women treated with Z3 months of prior bi-sphosphonate therapy. De-escalated scheduling satisfied our predefined definition of noninferiority compared with 3- to 4-weekly treatment.Larger trials should assess whether increasing CTx levels with de-escalated therapy lead to higher rates of skeletal complications.

Key Words: bone metastases, breast cancer, pamidronate, de-escala-

tion, 12-weekly

( Am J Clin Oncol 2013;36:436–442)

Bone is a common site of metastasis from breast cancer.Women with bone as the predominant or only site of metastatic spread tend to have longer survival than womenwith visceral metastases.1 Despite their relatively favorableoutcomes, these women are at risk of developing skeletal-related events (SREs), defined as the need for radiation or surgery to bone, pathologic fractures, spinal cord compression,or hypercalcemia.2 The administration of bisphosphonates incombination with systemic anticancer therapy has been shownin randomized trials to delay the onset and reduce the

frequency of SREs.3,4 The optimal dosing frequency of bi-sphosphonates is not known. Treatment is usually given every3 to 4 weeks based on data derived from the treatment of hypercalcemia of malignancy.5–7

There is substantial variation in the frequency of SREsamong patients with bone metastases from breast cancer.8

Despite this, practice guidelines recommend that bone-targeted agents be given at the same dose and frequency to all patientsirrespective of their individual risk.9 However, it is likely thatsome patients may derive similar benefit from less frequentadministration of these agents. Bisphosphonates exert a pro-longed effect on bone.10 In patients with metastatic bone dis-ease, the median duration of symptomatic benefit from a singledose of pamidronate therapy is approximately 12 weeks.11

Reducing the frequency of intravenous bisphosphonateadministration in those at low risk of skeletal complicationshas several potential advantages. It would reduce direct ex- penditure for drug costs and chair time in infusion clinics, aswell as indirect costs to patients and their family related to thetime needed to receive treatment. It could also reduce cumu-lative toxicities associated with bisphosphonates such as renalimpairment12 and osteonecrosis of the jaw.13

Assessment of the efficacy of bisphosphonate treatmentcan be difficult. Radiologic tests such as bone scintigraphy or computed tomography are unreliable, and the clinician is oftenleft basing treatment decisions on a combination of the pa-tients’ symptoms and/or development of SREs to document progression of bone disease.14 More recently, there has been

increasing interest in the use of biochemical marker of boneresorption and bone formation to help assess bone response totherapy.15

From the *Division of Medical Oncology and Hematology, University of Toronto and Princess Margaret Hospital; zAmbulatory Care, PrincessMargaret Hospital; yToronto General Research Institute, Universityof Toronto and University Health Network; 8Keenan Research Centre,Li Ka Shing Knowledge Institute of St. Michael’s Hospital, Universityof Toronto, Toronto; wDepartment of Medical Oncology, R.S.McLaughlin Durham Regional Cancer Centre, Oshawa; and zDivisionof Medical Oncology, University of Ottawa and The Ottawa HospitalCancer Centre, Ottawa, ON, Canada.

Funded by the Division of Medical Oncology at Princess Margaret Hos- pital, Toronto, Canada. No pharmaceutical company funding wasreceived.

The authors declare no conflicts of interest.Reprints: Eitan Amir, MB, ChB, Division of Medical Oncology, Princess

Margaret Hospital, 610 University Ave., Toronto ON, Canada M5G

2M9. E-mail: [email protected] r 2012 by Lippincott Williams & WilkinsISSN: 0277-3732/13/3605-0436DOI: 10.1097/COC.0b013e3182568f7a

ORIGINAL ARTICLE

436 | www.amjclinicaloncology.com American Journal of Clinical Oncology Volume 36, Number 5, October 2013

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Bone resorption can be assessed biochemically by thedetermination of bone resorption markers in serum and urine.Evidence has shown that N-terminal crosslinking telopeptideof type I collagen (NTx) is a rapid and reliable predictor of response to bisphosphonate therapy.16 Several studies havedemonstrated that urinary NTx falls in response to bi-

sphosphonate therapy in patients with bone metastases and thatthis fall is associated with improved palliation, a decreased risk of SREs, and improved survival.17,18 Data also show that anabsolute value of urinary NTx of 100 nM/mM creatinine corresponds withhigher risk.19 More recently, serum C-telopeptide (sCTX) has been begun to replace urinary NTx due to its lower coefficientof variability.20 In a large prospective cohort of women,21 itwas possible to extrapolate that the low-risk cutoff of urinary NTX (< 100 mM/mM creatinine) corresponds to a value of < 600 ng/L of sCTX (the difference between second and third tertiles).

Alkaline phosphatase is the most frequently used bio-

chemical marker of osteoblastic bone formation. However, 4different isoforms of this enzyme exist in humans and these are produced in various tissues. Therefore, assays of total alkaline phosphatase can be nonspecific. The bone-specific isoform of alkaline phosphatase (BAP) has been shown to best reflectdifferent stages of osteoblast differentiation during the ex-tracellular matrix maturation phase of osteogenesis.22

This feasibility study was designed to explore whether itis feasible to conduct a randomized trial of de-escalated pa-midronate (once every 12 wk) in women with metastatic breastcancer and low-risk bone metastases (defined as baseline sCTxlevels < 600 ng/L). Furthermore, unlike other ongoing trials23,24

in which prior treatment with 3- to 4-weekly bisphosphonateswas needed for at least 9 months, this study assessed the role

of less frequent therapy after only 3 months. It also aimed todetermine whether de-escalated scheduling is noninferior tostandard treatment.

MATERIALS AND METHODS

Study PopulationWomen with breast cancer and radiologic or biopsy con-

firmed bone metastases and sCTx levels in the low-risk range[defined as sCTx levels in the lowest tertile (< 600 ng/L)]21 wereeligible. Maximum suppression of bone resorption has beenshown to occur after 3 months of bisphosphonate therapy25;therefore, eligible patients must have received antiresorptiontherapy for at least 3 months and had no change in systemic

anticancer therapy or radiation therapy in the 28 days beforerandomization. Patients with baseline renal function above theinstitutional normal range were excluded due to the lack of datainforming the dosing of pamidronate in these patients. The studywas approved by the Research Ethics Board of Princess MargaretHospital, Toronto, Canada.

Trial DesignA randomized, noninferiority, feasibility study was con-

ducted in a single large cancer center. Study participants werestratified according to baseline serum sCTx (< 400 and 400 to600 ng/L) and duration of prior bisphosphonate use ( < 6 and > 6 mo) and were then randomly allocated to receive pamidr-onate 90 mg intravenously every 3 to 4 weeks (control group)

or every 12 weeks (de-escalated group).sCTx and BAP levels were measured every 12 weeks for

48 weeks. Patients also completed validated pain questionnaires

[Brief Pain Inventory (BPI)26 and Functional Assessment of Cancer Therapy-Bone Pain (FACT-BP)]27 and were questioned on occurrences of toxicities of bisphosphonates (if any) at thesame times. Those remaining in the low-risk sCTx group con-tinued to receive their allocated treatment. Those whose telopeptide levels rose above 600 ng/L remained on study, but

thereafter received treatment every 3 to 4 weeks. Censoring wascarried out for any patient receiving radiation therapy to bone or a change in systemic therapy. All patients received concomitantvitamin D3 (800 to 1000IU/d) and calcium (1200 to 1500 mg/d)to prevent hypocalcemia and/or secondary hyperparathyroidism.

EndpointsThe primary goal of this study was to assess feasibility of

conducting a randomized trial of de-escalated pamidronate in agroup of low-risk patients with bone metastases. Feasibilitywas defined completion of follow-up in Z90% of enrolled patients. Secondary goals were to assess the proportion of patients remaining in the low-risk sCTx range throughout the48-week study and to explore the absolute changes in sCTx,

BAP, BPI and FACT-BP pain scores, and the number of symptomatic SREs in patients in each study group. Adverseeffects were graded and recorded according to the NCI Com-mon Terminology Criteria for Adverse Events, version 3.0.

An exploratory, post hoc analysis to assess reasons for patients changing from low to high risk was also conducted. Inthis analysis, laboratory and imaging investigations that wereconducted as standard of care were assessed for evidence of bone-only progression or for progressive disease in extra-skeletal sites as well.

Biochemical AnalysesSerum samples were collected after an overnight fast, were

allowed to clot for at least 30 minutes, and then centrifuged

at 3000rpm for 10 minutes in a clinical centrifuge at roomtemperature. Samples were then analyzed immediately. sCTxwas measured with an enzyme-linked immunosorbent assay[Beta-Cross Laps/serum assay; Roche Diagnostics Canada Inc.,Laval, QC; detection limit 10 ng/L, interassay variability 5.4% to7.9%, reference range for healthy women: 50 to 900 ng/L (pre-menopausal) and 210 to 1100ng/L (postmenopausal)]. SerumBAP was measured by immunoassay using a monoclonal antibody(Metra Biosystems, San Diego, CA; detection limit 0.7 IU/L, in-terassay variability 5.2%, reference range for healthy women: 15to 43 IU/L).

Statistical AnalysisThis study used a pragmatic sample size that was con-

sidered feasible for a single-center study. Assuming that 20%of patients would have a change in their telopeptide levelsfrom low to high risk over a 48-week period and using the testof 2 proportions with a maximal allowable difference (d) be-tween arms of ± 10% (ie, between 10% and 30% of patientschanging from low to high risk), a total of 38 patients wererequired to provide 80% power with an a of 0.1. This samplesize would allow the predicted proportion of enrolled patientswho complete the study (90%) be able to be estimated 95%confidence intervals of 76.5% to 96.1%. Skewed data were logtransformed, and generalized estimating equations were used in a repeated measures analysis to compare sCTx and BAPlevels between the groups over the 48-week period after anadjustment for baseline values. Differences in BPI and FACT-

BP scores were assessed using linear least squares and ordinallogistic regression analysis with a repeated measures structure.The main analysis was performed on all observed data under a

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plausible assumption about the missing data as described byWhite et al.28 Consistent with our a of 0.1, statistical sig-nificance of all testing was based on a 2-sided test using acutoff of P = 0.10.

RESULTSPatient Enrolment

Over a period of 16 months, 54 patients were approached to enter the study and 44 provided informed consent. Of these,6 patients (13.6%) failed screening due to baseline sCTx levels> 600 ng/L. Therefore, 38 patients were eligible for random-ization to the study with 19 participants allocated to each arm.Thirty-five patients (92.1%) were followed for the entire48-week study period. One patient in the control group died of progressive breast cancer between 12 and 24 weeks and 2 patients in the de-escalated group withdrew consent (1 after 12 wk and 1 after 36 wk). One patient reported fear of de-escalated therapy as the reason for withdrawal, whereas theother transferred her care to another treatment center wherecontinued participation in the trial was not possible. Neither patient experienced increasing sCTx, BAP, pain scores, or aSRE during the study period (Fig. 1). Missing data weretherefore considered to be missing at random, and the mainanalysis was conducted using all available data without im- putation for missing values. Patient characteristics were well balanced in the 2 treatment arms (Table 1).

Biomarker ChangesFourteen control group participants (73.7%) and 13 de-

escalated group participants (68.4%) maintained sCTx in thelow-risk range (test of 2 proportions, P = 0.64). Kaplan-Meier plots showing time to change from low-risk to high-risk sCTx

levels are shown in Figure 2. An exploratory analysis showed that there was evidence of progressive extraskeletal disease inall patients not maintaining sCTx in the low-risk range(n = 11). No women with stable disease (n = 20) or progressivemetastases confined to bone (n = 7) had a change in sCTx fromthe low-risk to higher-risk group. A quantitative increase insCTx over time in women receiving de-escalated therapy metthe prespecified cutoff for clinical significance ( P = 0.096,Fig. 3A). A nonsignificant quantitative difference in sCTxover time was also apparent in the subgroup of women withstable disease and progressive metastases confined to bone

( P = 0.59, Fig. 4). There was no statistically significant dif-ference in levels of BAP over time between the 2 treatmentgroups ( P = 0.37). However, in the de-escalated arm, there wasa numerical increase in BAP levels from week 24 onward,suggesting increased bone turnover beyond this time point(Fig. 3B).

Clinical EndpointsOver the 48-week follow-up period, 2 symptomatic SREs

were observed in each treatment group. Both required radiationtherapy to control bone pain. There were a total of 3 serious

FIGURE 1. CONSORT diagram. CTx indicates C-telopeptide.

TABLE 1. Patient Characteristics

Variables

Control Group (3-4 wk)

n = 1 9

De-escalated Group

(12 wk) n = 19

Age (y)Median 50 60

Range 39-63 42-77Baseline CTx (ng/L)

Median 153 182Range 87-492 10-526

Baseline BAP (IU/L)Median 18 18Range 11-56 4-131

Prior bisphosphonate therapy (mo)Median 8 9Range 6-26 3-88

Body mass index (kg/m2)Median 25.3 28.8Range 19.2-34.7 22.2-44.4

Baseline parathyroid hormone level (pmol/L)Median 6.2 7.3

Range 2.4-26.0 1.8-14.0Baseline vitamin D level (nmol/L)Median 88 96Range 45-134 44-162

Baseline BPI score (cumulative)Median 3 16Range 0-39 0-60

Baseline FACT-BP score (cumulative)Median 7 20Range 2-36 5-27

BAP indicates bone alkaline phosphatase; BPI, Brief Pain Inventory; CTx,C-telopeptide; FACT-BP, Functional Assessment of Cancer Therapy-Bone Pain.

FIGURE 2. Kaplan-Meier plots showing time to change fromlow-risk to high-risk C-telopeptide levels.

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adverse events (2 in the control group and 1 in the de-escalated group). All events related to hospitalization for control of symptoms related to disease progression. We did not observeany bisphosphonate-specific toxicities such as renal impair-ment, osteonecrosis of the jaw, or atrial fibrillation in either arm of the study.

Pain ScoresPain scores as measured by BPI and FACT-BP remained

generally stable over time in both the control and the de-es-calated groups (Figs. 3C, D). There were no statistically sig-nificant differences between groups in cumulative pain scoresas measured by BPI ( P = 0.21) or by FACT-BP ( P = 0.59).

There was no correlation between sCTx and FACT-BP(Spearman r, 0.07; P = 0.76) or with BPI (Spearman r, 0.19; P = 0.41).

DISCUSSIONThe use of bisphosphonates provides symptomatic im-

provement to women with metastatic breast cancer but doesnot influence either progression-free or overall survival.29–31 Incontrast to other supportive care measures, there have been fewattempts to individualize the use of bisphosphonates in womenwith bone metastases from breast cancer. Indeed, currentguidelines advise a “1-size-fits-all” approach with the recom-mendation that all patients receive the same dose and frequency of bisphosphonates regardless of their underlyingrisks or needs.9

In this study, we report a feasibility study assessing lessfrequent administration of intravenous pamidronate compared

with standard 3- to 4-weekly dosing in women at low risk of skeletal events. Our results show that it is feasible to carry outa randomized trial in this setting. De-escalated therapy did not

FIGURE 3. Changes in endpoints over time. A, Serum C-telopeptide. B, Bone-specific alkaline phosphatase. C, Brief Pain Inventory. D,Functional Assessment of Cancer Therapy-Bone Pain. CI indicates confidence interval.




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seem inferior as measured by the proportion of patients re-maining at low risk of developing skeletal complications over the 48-week study period. However, this exploratory studyobserved a time-dependent increase in bone resorption bio-markers in the de-escalated arm that was not statisticallysignificant. These findings should be tested in a larger randomized trial.

There has been increasing interest in the use of bone

resorption biomarkers in the risk assessment of patients withmetastatic bone disease and for personalizing treatment inthese patients.32–34 Urinary NTx has historically been the preferred marker of bone resorption. However, data show thatsCTx is comparable with NTx21,35 and validation studies showthat CTx is robust and reliable.36 Furthermore, CTx has beenshown to be a sensitive biomarker in women with breastcancer.37 High levels of CTx have been associated with worserelapse-free survival,38 and normalization of high levels has been shown to be associated with pain relief during treatmentwith pamidronate.17

Among the 11 patients who did not maintain their CTxlevels in the prespecified low-risk range (5 in the control armand 6 in the de-escalated arm), all patients showed signs of

disease progression in extraskeletal and skeletal sites, withnone showing evidence of bone-only progression. As all pa-tients had bone metastases, these results likely reflect failure of systemic anticancer therapy rather than of bone-specifictreatment. In those with stable extraskeletal or bone-onlymetastatic disease, there were no patients who changed fromthe low-risk CTx range to higher-risk levels, although therewas an absolute increase in CTx levels in those receivingde-escalated therapy.

There were differences in biomarkers between the 2treatment arms. Patients receiving de-escalated therapyshowed a consistent and maintained increase in absolute CTxlevels compared with those receiving standard, 3- to 4-weeklytreatment. Although the absolute values remained in the low-

risk group ( < 600 ng/L) in the absence of progression in other metastatic sites, it is possible that continued de-escalated therapy beyond 48 weeks may lead to further rises in CTx and

to increased skeletal complications. BAP is a useful marker of active bone formation with only minor cross reactivity withliver-specific alkaline phosphatase.39 However, unlike CTx,BAP has a more complex association with bone turnover. BAPlevels decrease in response to initiation of antiresorptivetherapy,40 but conversely, in patients previously treated with

antiresorptive therapy, levels can rise in response to either anabolic therapy41 or second-line bisphosphonates.16 We did not observe significant changes in BAP, although there was anumerical increase in levels beyond 24 weeks in women re-ceiving de-escalated therapy. The clinical relevance of thesenonsignificant changes is unclear.

There were no differences in pain scores as measured by both BPI and FACT-BP between the 2 treatment schedules.Compared with baseline, there were trends toward increasing pain with time in both arms of the study, although these were notstatistically significant. Pain scores have been shown previouslyto correlate with bone resorption biomarkers such as CTx in patients with progressive bone metastases.16,42 In this study, wedid not observe consistent association between CTx and pain

scores. This may be explained by differences in the character-istics of patients in this study and those in previous trials. Our study enrolled patients with low risk and therefore lesssymptomatic bone metastases, and in this group, there is likely to be a poorer correlation between these biomarkers and pain.

We did not observe any occurrences of bisphosphonate-specific toxicity. Such toxicities are uncommon and occur after cumulative dosage of bisphosphonates,12,13 and it is thereforelikely that the small sample size and limited follow-up did notallow for detection of such adverse events. Nonetheless, it islikely that bisphosphonate-specific toxicity will occur lessoften in those receiving a less intensive dosing schedule.

This study has limitations. First, changes in systemictherapy and/or provision of radiation therapy might affect CTx

values and pain scores, thereby contaminating the effects of randomization. We tried to minimize such effects by excludingwomen who received radiation therapy or a change in systemictherapy in the 28 days before randomization and censoringsuch patient after randomization. Second, this was a small,single-center, unblinded, randomized feasibility study and in-termediate endpoints such as biomarkers of bone resorptionwere used to define activity of bisphosphonate therapy. Theuse of clinically relevant endpoints such as number and/or frequency of SREs would be more relevant, but this would have required a large sample size and was not feasible for thisfeasibility study. More definitive trials using endpoints thatare clinically relevant to patients are ongoing.22,23,43,44 Un- published data from 1 study23 showed that rates of SREs and

time to such events were similar between those treated withmonthly and 3-monthly zoledronic acid. However, rates of accrual in other studies have been below expectations. Clini-cian enthusiasm for our study was high, and it is hoped that theresults from our study may encourage others to accrue patientsto ongoing studies. Third, the ability of this study to determinenoninferiority may be criticized. The prespecified outcomeused to assess differences between control and de-escalated groups was the proportion of patients whose biomarkers re-mained in the low-risk range. However, the correlation be-tween low levels of serum bone resorption biomarkers and favorable outcome is derived from studies in patients who had high levels at baseline and subsequently normalized in re-sponse to treatment. Telopeptide biomarkers may therefore

have better positive predictive value for skeletal outcomesthan negative predictive value.45 It is possible that positiveoutcomes relate more to the fall of resorption biomarkers

FIGURE 4. Changes in serum C-telopeptide over time for pa-tients with metastatic disease confined to bone. CI indicatesconfidence interval.




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(suggesting response to therapy) than to the resultant lowlevels of bone resorption. In our study, all patients had low baseline levels of CTx and few women showed substantialchange in bone resoprtion. This leads to uncertainty in our definition of “low-risk” status. Finally, the increasing use of zoledronic acid or denosumab in many settings means that

pamidronate might not reflect the standard of care. However,zoledronic acid did not show superiority over pamidronate inthe only head-to-head trial,46 and it is therefore likely that our results can be applied to zoledronic acid. The different phar-macokinetic and efficacy properties of denosumab compared with bisphosphonates47 mean that these results cannot begeneralized to this agent.

In conclusion, randomized trials of de-escalated pamidr-onate in women with low-risk bone metastases are feasibleeven after limited pretreatment with monthly bisphosphonates.Twelve-weekly treatment seems noninferior to 3- to 4-weeklytreatment for patients with stable systemic disease, especiallythose with bone-only metastatic disease, although this willrequire confirmation in a larger trial. Well-powered random-

ized trials are needed to adequately advise clinicians and patients on the optimal dose of bisphosphonates in women withmetastatic breast cancer in a variety of clinical settings.Although bone resorption biomarkers may be used to selectlower-risk patients for de-escalated therapy, larger trials should use clinically relevant endpoints, as biomarker surrogates maynot accurately predict risk in all patients.

ACKNOWLEDGMENTS

The authors acknowledge the roles of Esther Lee and Tazmin Usmani in trial coordination.

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http://www.clinicaltrials.gov/ct2/show/NCT00869206http://www.clinicaltrials.gov/ct2/show/NCT00869206http://www.clinicaltrials.gov/ct2/show/NCT00458796http://www.clinicaltrials.gov/ct2/show/NCT00458796http://www.clinicaltrials.gov/ct2/show/NCT00458796http://www.clinicaltrials.gov/ct2/show/NCT00458796http://www.clinicaltrials.gov/ct2/show/NCT00869206http://www.clinicaltrials.gov/ct2/show/NCT00869206

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