Ductal Carcinoma in Situ, Estrogen Receptor-positive Breast Cancer, Progesterone Receptor-positive Breast Cancer, Stage I Breast Cancer, Stage II Breast Cancer, Stage IIIA Breast Cancer, Stage IIIB Breast Cancer, Stage IIIC Breast Cancer
Conditions
Brief summary
RATIONALE: Zoledronic acid may prevent bone loss and help prevent or lessen musculoskeletal symptoms in women receiving hormone therapy for breast cancer. PURPOSE: This phase II trial is studying how well zoledronic acid works in preventing musculoskeletal symptoms in post-menopausal women with stage I, stage II, or stage III breast cancer receiving letrozole.
Detailed description
PRIMARY OBJECTIVES: I. Percentage of women experiencing aromatase inhibitor associated musculoskeletal symptoms (AIMSS) at 1, 3, 6, and 12 months after bisphosphonate therapy, as compared to historical controls. II. Change in Health Assessment Questionnaire Disability Index (HAQ-DI) score and 1, 3, 6 and 12 months, from baseline, among those receiving bisphosphonate, as compared to historical controls. SECONDARY OBJECTIVES: I. Change in pain scores on visual analog scale (VAS) at 1, 3, 6 and 12 months, from baseline, compared to historical controls. II. Change in amount and/or frequency of oral analgesic use at 1, 3, 6 and 12 months from baseline among those receiving bisphosphonate therapy, as compared to historical controls. III. Number of patients who discontinue or change aromatase inhibitor (AI) therapy. IV. Change in menopausal symptoms (NSABP-revised), hot flash frequency (HFRDIS),sleep quality (PSQI), depression score (CESD) and overall quality of life (EuroQOL) in patients at 1, 3, 6 and 12 months from baseline, among those receiving bisphosphonate therapy, as compared to historical controls. V. Changes in plasma estrogen concentrations at 1, 3, 6 and 12 months from baseline, among those receiving bisphosphonate therapy, as compared to historical controls. VI. Change in bone mineral density (DEXA scan) at 12 months from baseline, among those receiving bisphosphonate therapy, as compared to historical controls. VII. Change in bone turn over markers (serum-C telopeptide, bone-specific alkaline phosphatase, osteocalcin and urinary N-telopeptide) at 1, 3, 6 and 12 months from baseline, among those receiving bisphosphonate therapy, as compared to historical controls. VIII. Change in inflammatory markers (ESR, CRP, IL-1, IL-6, IL-8) at 1, 3, 6 and 12 months from baseline, among those receiving bisphosphonate therapy, as compared to historical controls. OUTLINE: Patients receive zoledronic acid intravenously (IV) at months 1 and 6. Beginning 14 days after first zoledronic acid infusion, patients receive oral letrozole once daily for 12 months in the absence of disease progression or unacceptable toxicity.
Interventions
DRUGletrozole
Given orally
DRUGzoledronic acid
Given IV
Sponsors
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
SUPPORTIVE_CARE
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients with histologically proven DCIS or stage I-III invasive carcinoma of the breast that is estrogen and/or progesterone receptor positive by immunohistochemical staining who are considering aromatase inhibitor therapy; women may receive the AI on this study as initial adjuvant hormonal treatment or following tamoxifen; patients must have completed any adjuvant chemotherapy; patients may have received preoperative chemotherapy * Postmenopausal status, defined as: \>= 60 years of age; or \< 60 years of age and amenorrheic for \>= 12 months prior to day 1 if intact uterus/ovaries; or \< 60 years of age, and the last menstrual period 6-12 months prior to day 1, if intact uterus/ovaries and meets biochemical criteria for menopause (FSH and estradiol within institutional standards for postmenopausal status); or \< 60 years of age, without a uterus, and meets biochemical criteria for menopause (FSH and estradiol within institutional standards for postmenopausal status); or \< 60 years of age and history of bilateral oophorectomy; or prior radiation castration with amenorrhea for at least 6 months; \< 60 years of age and taking medication designed to suppress ovarian function and meets biochemical criteria for menopause (estradiol levels within institutional standards for postmenopausal status; women would have had to be taking the drug for at least 30 days prior to day 1) * ECOG performance status 0-2 * Patient is aware of the nature of her diagnosis, understands the study regimen, its requirements, risks, and discomforts, and is able and willing to sign an informed consent form
Exclusion criteria
* Concurrent use of hormone replacement therapy * Concurrent use of tamoxifen; patients taking tamoxifen must discontinue the drug prior to first dose of zoledronic acid * Concurrent use of other selective estrogen receptor modulator (SERM) such as raloxifene * Concurrent consumption of soy supplements; routine dietary consumption of soy containing foods will be permitted * Prior use of an aromatase inhibitor in any setting * Current bisphosphonate use (oral or intravenous); prior bisphosphonate users would be eligible as long as the use was \> 1 month ago for oral bisphosphonates and/or \> 12 months ago for intravenous bisphosphonates, prior to starting study treatment * Moderate to severe renal impairment (serum creatinine greater than 2 mg/dL or creatinine clearance less than 50 mL/min) * Hypersensitivity to letrozole or zoledronic acid or any of its excipients * Concomitant treatment with oral or intravenous corticosteroids * Current active dental problems including infection or the teeth or jawbone (maxilla or mandibular); dental or fixture trauma, or a current or prior diagnosis of osteonecrosis of the jaw (ONJ), of exposed bone in the mouth, or of slow healing after dental procedures * Recent (within 6 weeks) or planned dental or jaw surgery (e.g. extraction, implants)
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Number of Participants With Aromatase Inhibitor Associated Musculoskeletal Symptoms (AIMSS) | 12 months |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| AIMSS as Determined by Health Assessment Questionnaire Disability Index (HAQ-DI) Score | Baseline, 1 month, 3 months, 6 months, 12 months | The HAQ-DI score ranges from 0-3 with a higher score reflective of greater disability or increased incidence of AIMSS. |
| AIMSS as Determined by Visual Analog Scale (VAS) Score | Baseline, 1 month, 3 months, 6 months, 12 months | VAS is a visual measurement tool to assess AIMSS. It is a visual scale that ranges from 0 centimeters (cm) to 10cm. The VAS score ranges from zero (0cm) to 10 (10cm), with a higher score reflecting a greater frequency of AIMSS. |
| Number of Participants Who Discontinue or Change Aromatase Inhibitor (AI) Therapy | 12 months | — |
Countries
United States
Participant flow
Recruitment details
From February 2011 to January 2013, 59 women signed consent, met eligibility criteria, and received study intervention on this clinical trial at the Sidney Kimmel Comprehensive Cancer Center (SKCCC) at Johns Hopkins.
Pre-assignment details
3 participants were screen failures and 1 participant withdrew consent prior to assignment to treatment.
Participants by arm
| Arm | Count |
|---|---|
| Arm I Patients receive zoledronic acid IV at months 1 and 6. Beginning 14 days after first zoledronic acid infusion, patients receive oral letrozole once daily for 12 months in the absence of disease progression or unacceptable toxicity.
letrozole: Given orally
zoledronic acid: Given IV
laboratory biomarker analysis: Correlative studies
enzyme-linked immunosorbent assay: Correlative studies
mass spectrometry: Correlative studies
bone scan: Correlative studies
quality-of-life assessment: Ancillary studies
questionnaire administration: Ancillary studies
pharmacogenomic studies: Correlative studies
high performance liquid chromatography: Correlative studies | 59 |
| Total | 59 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| 6-months (2nd Dose) | Change in therapy | 4 |
| Baseline (First Dose) | Adverse Event | 1 |
| Baseline (First Dose) | Change in therapy | 1 |
| Baseline (First Dose) | Lack of Efficacy | 1 |
| Baseline (First Dose) | Reason not specified | 4 |
Baseline characteristics
| Characteristic | Arm I |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 13 Participants |
| Age, Categorical Between 18 and 65 years | 46 Participants |
| Region of Enrollment United States | 59 participants |
| Sex: Female, Male Female | 59 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 59 |
| other Total, other adverse events | 53 / 59 |
| serious Total, serious adverse events | 0 / 59 |
Outcome results
Primary
Number of Participants With Aromatase Inhibitor Associated Musculoskeletal Symptoms (AIMSS)
Time frame: 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I | Number of Participants With Aromatase Inhibitor Associated Musculoskeletal Symptoms (AIMSS) | 22 Participants |
Comparison: The primary hypothesis of the study is that administration of zoledronic acid with letrozole would result in a significant decline in the percentage of women experiencing AIMSS compared to letrozole treatment alone (historical control).p-value: <0.001Bonferonni
Secondary
AIMSS as Determined by Health Assessment Questionnaire Disability Index (HAQ-DI) Score
The HAQ-DI score ranges from 0-3 with a higher score reflective of greater disability or increased incidence of AIMSS.
Time frame: Baseline, 1 month, 3 months, 6 months, 12 months
Population: Data was only collected in 58 participants at baseline, 52 participants at 1 month, 56 participants at 3 months, 51 participants at 6 months, and 45 participants at 12 months
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Arm I | AIMSS as Determined by Health Assessment Questionnaire Disability Index (HAQ-DI) Score | Baseline | 0.2 score on a scale |
| Arm I | AIMSS as Determined by Health Assessment Questionnaire Disability Index (HAQ-DI) Score | 1 month | 0.2 score on a scale |
| Arm I | AIMSS as Determined by Health Assessment Questionnaire Disability Index (HAQ-DI) Score | 3 months | 0.1 score on a scale |
| Arm I | AIMSS as Determined by Health Assessment Questionnaire Disability Index (HAQ-DI) Score | 6 months | 0.2 score on a scale |
| Arm I | AIMSS as Determined by Health Assessment Questionnaire Disability Index (HAQ-DI) Score | 12 months | 0.4 score on a scale |
Secondary
AIMSS as Determined by Visual Analog Scale (VAS) Score
VAS is a visual measurement tool to assess AIMSS. It is a visual scale that ranges from 0 centimeters (cm) to 10cm. The VAS score ranges from zero (0cm) to 10 (10cm), with a higher score reflecting a greater frequency of AIMSS.
Time frame: Baseline, 1 month, 3 months, 6 months, 12 months
Population: Data was only collected for 58 participants at baseline, 52 participants at 1 month, 55 participants at 3 months, 50 participants at 6 months, and 45 participants at 12 months
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Arm I | AIMSS as Determined by Visual Analog Scale (VAS) Score | Baseline | 0.8 score on a scale |
| Arm I | AIMSS as Determined by Visual Analog Scale (VAS) Score | 1 month | 1 score on a scale |
| Arm I | AIMSS as Determined by Visual Analog Scale (VAS) Score | 3 months | 1.4 score on a scale |
| Arm I | AIMSS as Determined by Visual Analog Scale (VAS) Score | 6 months | 1.2 score on a scale |
| Arm I | AIMSS as Determined by Visual Analog Scale (VAS) Score | 12 months | 1.9 score on a scale |
Secondary
Number of Participants Who Discontinue or Change Aromatase Inhibitor (AI) Therapy
Time frame: 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I | Number of Participants Who Discontinue or Change Aromatase Inhibitor (AI) Therapy | 5 Participants |