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S0307 Phase III Trial of Bisphosphonates as Adjuvant Therapy for Primary Breast Cancer.

Sponsor
Southwest Oncology Group (Other)
Overall Status
Completed
CT.gov ID
NCT00127205
Collaborator
National Cancer Institute (NCI) (NIH), North Central Cancer Treatment Group (Other), Eastern Cooperative Oncology Group (Other), NSABP Foundation Inc (Other), Cancer and Leukemia Group B (Other), NCIC Clinical Trials Group (Other)
6,097
Enrollment
3
Arms
188.9
Duration (Months)

Study Details

Study Description

Brief Summary

RATIONALE: Zoledronate, clodronate, or ibandronate may delay or prevent bone metastases in patients with nonmetastatic breast cancer. It is not yet known whether zoledronate is more effective than clodronate or ibandronate in treating breast cancer.

PURPOSE: This randomized phase III trial is studying zoledronate to see how well it works compared to clodronate or ibandronate in treating women who have undergone surgery for stage I, stage II, or stage III breast cancer.

Condition or Disease Intervention/Treatment Phase
  • Drug: clodronate disodium
  • Drug: ibandronate sodium
  • Drug: zoledronic acid
 Phase 3

Detailed Description

OBJECTIVES:

  • Compare disease-free survival and overall survival of women with resected primary stage I-III adenocarcinoma of the breast treated with adjuvant zoledronate vs clodronate vs ibandronate.

  • Compare the distributions of sites of first disease recurrence in patients treated with these drugs.

  • Compare adverse events in patients treated with these drugs.

  • Correlate parathyroid hormone related protein status and N-telopeptide levels at baseline with disease-free survival and sites of first recurrence in patients treated with these drugs.

  • Investigate whether there is an association between inherited germ-line single nucleotide polymorphisms (SNP, rs2297480) in farnesyl diphosphate synthase (FDPS) and the adverse event of acute phase reactions in these patients.

OUTLINE: This is a randomized, multicenter study. Patients are randomized to 1 of 3 treatment arms.

  • Arm I: Patients receive zoledronate IV over 15 minutes once a month for 6 months and then once every 3 months for 2.5 years.

  • Arm II: Patients receive oral clodronate once daily for 35 months.

  • Arm III: Patients receive oral ibandronate once daily for 35 months. Treatment in all arms continues in the absence of disease recurrence or unacceptable toxicity.

After completion of study treatment, patients are followed every 6 months until disease recurrence and then annually for up to 10 years.

PROJECTED ACCRUAL: A total of 5,400 will be accrued for this study.

Study Design

Study Type:
Interventional
Actual Enrollment :
6097 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Phase III Trial of Bisphosphonates as Adjuvant Therapy for Primary Breast Cancer
Study Start Date :
Jul 1, 2005
Actual Primary Completion Date :
Dec 1, 2017
Actual Study Completion Date :
Mar 29, 2021

Arms and Interventions

Arm Intervention/Treatment
Experimental: Arm I

Patients receive zoledronate IV over 15 minutes once a month for 6 months and then once every 3 months for 2.5 years.

Drug: zoledronic acid
Given IV
Active Comparator: Arm II

Patients receive oral clodronate once daily for 35 months.

Drug: clodronate disodium
Given orally
Experimental: Arm III

Patients receive oral ibandronate once daily for 35 months.

Drug: ibandronate sodium
Given orally

Outcome Measures

Primary Outcome Measures

  1. Disease-free Survival [Disease assessments are completed every 6 months for 5 years then annually for 5 years or until death or recurrence]

    Time from date of registration to date of first observation of recurrence or death due to any cause. Patients last known to be alive who have not experienced recurrence of disease are censored at their last contact date. The outcome for the disease-free survival will be presented as 5 year survival rate.

Secondary Outcome Measures

  1. Overall Survival [follow up completed every 6 months for 5 years and then annually for 5 years or until death]

    Time from date of registration to date of death due to any cause. Patients last known to be alive are censored at their last contact date. The outcome for overall survival will be presented as 5 year overall survival rate.

  2. Distributions of Sites of First Recurrence on the Three Arms. [Disease assessments are completed every 6 months for 5 years then annually for 5 years or until death or recurrence]

    All sites of invasive disease documented within 30 days of first documentation of invasive recurrence.

  3. Number of Patients With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs [Toxicity assessment is repeated every 2 months for the first 6 months, then every 3 months until 3 years or end of treatment.]

    Adverse Events (AEs) are reported by CTCAE Version 4.0. Only adverse events that are possibly, probably or definitely related to study drug are reported.

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years and Older
Sexes Eligible for Study:
Female
Accepts Healthy Volunteers:
No
DISEASE CHARACTERISTICS:

  • Histologically confirmed primary adenocarcinoma of the breast

  • Stage I-III disease

  • No evidence of metastatic disease

  • Must have undergone lumpectomy or total mastectomy for primary disease within the past 12 weeks, or have completed chemotherapy within the past 8 weeks

  • Axillary evaluation per institutional standards

  • Currently receiving or planning to receive standard adjuvant systemic therapy comprising chemotherapy, hormonal therapy, or combined chemotherapy/hormonal therapy for breast cancer

  • Patients who are at low risk for disease recurrence and for whom adjuvant systemic therapy will not be prescribed are not eligible

  • Patients who receive biologic agents only or local radiotherapy only (without chemotherapy and/or hormone therapy) are not eligible

  • Additional therapies are allowed including radiotherapy and biologic agents (e.g., trastuzumab [Herceptin^®], bevacizumab, or hematopoietic growth factors)

  • Neoadjuvant therapy or hormonal therapy alone is allowed provided study entry occurs ≥ 12 weeks after completion of surgery

  • Patients with skeletal pain are eligible provided bone scan and/or roentgenological exam are negative for metastatic disease

  • Suspicious findings must be confirmed as benign by x-ray, MRI, or biopsy

  • Hormone receptor status:

  • Not specified

PATIENT CHARACTERISTICS:

Age

  • 18 and over

Sex

  • Female

Menopausal status

  • Not specified

Performance status

  • Zubrod 0-2

Life expectancy

  • Not specified

Hematopoietic

  • Not specified

Hepatic

  • Not specified

Renal

  • Creatinine ≤ 2 times upper limit of normal

  • Creatinine clearance ≥ 30 mL/min

  • No renal failure

Other

  • Not pregnant or nursing

  • Negative pregnancy test

  • Fertile patients must use effective contraception

  • No history of esophageal stricture or motility disorders

  • Gastroesophageal reflux disorder allowed

  • No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, or adequately treated stage I or II cancer in complete remission

PRIOR CONCURRENT THERAPY:

Biologic therapy

  • Prior or concurrent hematopoietic growth factors allowed

  • HER-2-targeted therapies allowed

  • Antiangiogenics allowed

Chemotherapy

  • See Disease Characteristics

Endocrine therapy

  • See Disease Characteristics

Radiotherapy

  • Concurrent radiotherapy to the breast, chest wall, or lymph node group allowed at the discretion of the treating physician

Surgery

  • See Disease Characteristics

Other

  • Prior neoadjuvant therapy allowed

  • Prior bisphosphonates for bone density allowed

  • No other concurrent bisphosphonates as adjuvant therapy or for treatment of osteoporosis

  • No concurrent enrollment in clinical trials with bone density as an endpoint

  • Concurrent enrollment on any other locoregional or systemic therapy breast cancer study (including cooperative group studies) allowed

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

  • Southwest Oncology Group
  • National Cancer Institute (NCI)
  • North Central Cancer Treatment Group
  • Eastern Cooperative Oncology Group
  • NSABP Foundation Inc
  • Cancer and Leukemia Group B
  • NCIC Clinical Trials Group

Investigators

  • Study Chair: Julie R. Gralow, MD, Seattle Cancer Care Alliance
  • Study Chair: Robert B. Livingston, MD, University of Arizona
  • Study Chair: James N. Ingle, MD, Mayo Clinic
  • Study Chair: Carla I. Falkson, MD, University of Alabama at Birmingham
  • Study Chair: Alexander H Paterson, MD, FRCP, Tom Baker Cancer Centre - Calgary
  • Study Chair: Elizabeth C. Dees, MD, UNC Lineberger Comprehensive Cancer Center
  • Study Chair: Mark J. Clemons, MD, Toronto Sunnybrook Regional Cancer Centre

Study Documents (Full-Text)

More Information

Additional Information:

Publications

None provided.
Responsible Party:
Southwest Oncology Group
ClinicalTrials.gov Identifier:
NCT00127205
Other Study ID Numbers:
  • CDR0000437061
  • S0307
First Posted:
Aug 5, 2005
Last Update Posted:
Jul 2, 2021
Last Verified:
Jun 1, 2021
Keywords provided by Southwest Oncology Group
stage I breast cancer
stage II breast cancer
stage IIIA breast cancer
stage IIIB breast cancer
stage IIIC breast cancer
Additional relevant MeSH terms:
Breast Neoplasms
Zoledronic Acid
Ibandronic Acid
Clodronic Acid

Study Results

Participant Flow

Recruitment Details
Pre-assignment Detail
Arm/Group Title Arm I Zoledronate Arm II Clodronate Arm III Ibandronate
Arm/Group Description Patients receive zoledronate IV over 15 minutes once a month for 6 months and then once every 3 months for 2.5 years. zoledronic acid: Given IV Patients receive oral clodronate once daily for 35 months. clodronate disodium: Given orally Patients receive oral ibandronate once daily for 35 months. ibandronate sodium: Given orally
Period Title: Overall Study
STARTED 2262 2268 1567
COMPLETED 1433 1295 955
NOT COMPLETED 829 973 612

Baseline Characteristics

Arm/Group Title Arm I Zoledronate Arm II Clodronate Arm III Ibandronate Total
Arm/Group Description Patients receive zoledronate IV over 15 minutes once a month for 6 months and then once every 3 months for 2.5 years. zoledronic acid: Given IV Patients receive oral clodronate once daily for 35 months. clodronate disodium: Given orally Patients receive oral ibandronate once daily for 35 months. ibandronate sodium: Given orally Total of all reporting groups
Overall Participants 2231 2235 1552 6018
Age (years) [Median (Full Range) ]
Median (Full Range) [years]
53.0
52.6
52.7
52.7
Age, Customized (Count of Participants)
Age < 55
1270
56.9%
1304
58.3%
894
57.6%
3468
57.6%
Age >= 55
961
43.1%
931
41.7%
658
42.4%
2550
42.4%
Sex: Female, Male (Count of Participants)
Female
2231
100%
2235
100%
1552
100%
6018
100%
Male
0
0%
0
0%
0
0%
0
0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native
12
0.5%
8
0.4%
4
0.3%
24
0.4%
Asian
70
3.1%
90
4%
57
3.7%
217
3.6%
Native Hawaiian or Other Pacific Islander
2
0.1%
2
0.1%
3
0.2%
7
0.1%
Black or African American
129
5.8%
118
5.3%
85
5.5%
332
5.5%
White
1975
88.5%
1976
88.4%
1374
88.5%
5325
88.5%
More than one race
12
0.5%
5
0.2%
2
0.1%
19
0.3%
Unknown or Not Reported
31
1.4%
36
1.6%
27
1.7%
94
1.6%
Nodal Status (Count of Participants)
Negative
1089
48.8%
1152
51.5%
784
50.5%
3025
50.3%
1~3
722
32.4%
685
30.6%
489
31.5%
1896
31.5%
>=4
404
18.1%
385
17.2%
267
17.2%
1056
17.5%
ER/PR (Count of Participants)
Negative (ER-, PR-)
480
21.5%
487
21.8%
319
20.6%
1286
21.4%
Positive (ER+ or PR+)
1747
78.3%
1747
78.2%
1231
79.3%
4725
78.5%
HER2 status (Count of Participants)
HER2 negative
1787
80.1%
1786
79.9%
1247
80.3%
4820
80.1%
HER2 positive/equivocal
418
18.7%
427
19.1%
288
18.6%
1133
18.8%
Breast disease subtype (Count of Participants)
ER+ or PR+, HER2-
1437
64.4%
1419
63.5%
1015
65.4%
3871
64.3%
ER+ or PR+, HER2+
292
13.1%
312
14%
205
13.2%
809
13.4%
ER/PR-, HER2- (triple neg)
350
15.7%
367
16.4%
232
14.9%
949
15.8%
ER/PR-, HER2+ (triple neg)
126
5.6%
115
5.1%
83
5.3%
324
5.4%
Stage (Count of Participants)
Stage I
721
32.3%
770
34.5%
509
32.8%
2000
33.2%
Stage II
992
44.5%
954
42.7%
694
44.7%
2640
43.9%
Stage III
472
21.2%
460
20.6%
304
19.6%
1236
20.5%
Chemotherapy (Count of Participants)
Not given or planned
446
20%
454
20.3%
319
20.6%
1219
20.3%
Given or planned
1779
79.7%
1778
79.6%
1232
79.4%
4789
79.6%
Hormonal Therapy (Count of Participants)
Not given or planned
542
24.3%
535
23.9%
367
23.6%
1444
24%
Given or planned
1670
74.9%
1686
75.4%
1170
75.4%
4526
75.2%

Outcome Measures

1. Primary Outcome
Title Disease-free Survival
Description Time from date of registration to date of first observation of recurrence or death due to any cause. Patients last known to be alive who have not experienced recurrence of disease are censored at their last contact date. The outcome for the disease-free survival will be presented as 5 year survival rate.
Time Frame Disease assessments are completed every 6 months for 5 years then annually for 5 years or until death or recurrence

Outcome Measure Data

Analysis Population Description
Only eligible patients will be included in the analysis.
Arm/Group Title Arm I Zoledronate Arm II Clodronate Arm III Ibandronate
Arm/Group Description Patients receive zoledronate IV over 15 minutes once a month for 6 months and then once every 3 months for 2.5 years. zoledronic acid: Given IV Patients receive oral clodronate once daily for 35 months. clodronate disodium: Given orally Patients receive oral ibandronate once daily for 35 months. ibandronate sodium: Given orally
Measure Participants 2231 2235 1552
Number (95% Confidence Interval) [percentage of analyzed participants]
88
3.9%
88
3.9%
87
5.6%
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Arm I Zoledronate, Arm II Clodronate, Arm III Ibandronate
Comments
Type of Statistical Test Other
Comments
Statistical Test of Hypothesis p-Value 0.49
Comments
Method Log Rank
Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Arm I Zoledronate, Arm II Clodronate
Comments
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value 0.24
Comments
Method Regression, Cox
Comments
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.09
Confidence Interval (2-Sided) 95%
0.94 to 1.26
Parameter Dispersion Type:
Value:
Estimation Comments
Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Arm I Zoledronate, Arm III Ibandronate
Comments
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value 0.50
Comments
Method Regression, Cox
Comments
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.06
Confidence Interval (2-Sided) 95%
0.90 to 1.24
Parameter Dispersion Type:
Value:
Estimation Comments
2. Secondary Outcome
Title Overall Survival
Description Time from date of registration to date of death due to any cause. Patients last known to be alive are censored at their last contact date. The outcome for overall survival will be presented as 5 year overall survival rate.
Time Frame follow up completed every 6 months for 5 years and then annually for 5 years or until death

Outcome Measure Data

Analysis Population Description
Only eligible patients will be included in the analysis.
Arm/Group Title Arm I Zoledronate Arm II Clodronate Arm III Ibandronate
Arm/Group Description Patients receive zoledronate IV over 15 minutes once a month for 6 months and then once every 3 months for 2.5 years. zoledronic acid: Given IV Patients receive oral clodronate once daily for 35 months. clodronate disodium: Given orally Patients receive oral ibandronate once daily for 35 months. ibandronate sodium: Given orally
Measure Participants 2231 2235 1552
Number (95% Confidence Interval) [percentage of analyzable patients]
93
92
93
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Arm I Zoledronate, Arm II Clodronate, Arm III Ibandronate
Comments
Type of Statistical Test Other
Comments
Statistical Test of Hypothesis p-Value 0.50
Comments
Method Log Rank
Comments
3. Secondary Outcome
Title Distributions of Sites of First Recurrence on the Three Arms.
Description All sites of invasive disease documented within 30 days of first documentation of invasive recurrence.
Time Frame Disease assessments are completed every 6 months for 5 years then annually for 5 years or until death or recurrence

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title Arm I Zoledronate Arm II Clodronate Arm III Ibandronate
Arm/Group Description Patients receive zoledronate IV over 15 minutes once a month for 6 months and then once every 3 months for 2.5 years. zoledronic acid: Given IV Patients receive oral clodronate once daily for 35 months. clodronate disodium: Given orally Patients receive oral ibandronate once daily for 35 months. ibandronate sodium: Given orally
Measure Participants 2231 2235 1552
Local/Regional only
41
1.8%
55
2.5%
36
2.3%
Contralateral only
17
0.8%
18
0.8%
17
1.1%
Distant recurrence
218
9.8%
207
9.3%
146
9.4%
Unknown location of recurrence
10
0.4%
15
0.7%
10
0.6%
Bone as 1st site of distant recurrence
110
4.9%
108
4.8%
82
5.3%
Bone only
62
2.8%
48
2.1%
44
2.8%
Bone and nodes only
2
0.1%
2
0.1%
2
0.1%
Bone and other distant sites (beside nodes)
46
2.1%
58
2.6%
36
2.3%
Liver/lung/other visceral without bone recurrence
57
2.6%
67
3%
40
2.6%
Brain/other CNS (+/- any other site)
31
1.4%
24
1.1%
22
1.4%
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Arm I Zoledronate, Arm II Clodronate, Arm III Ibandronate
Comments Statistical analysis for recurrence to bone
Type of Statistical Test Other
Comments
Statistical Test of Hypothesis p-Value 0.93
Comments
Method Log Rank
Comments
4. Secondary Outcome
Title Number of Patients With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs
Description Adverse Events (AEs) are reported by CTCAE Version 4.0. Only adverse events that are possibly, probably or definitely related to study drug are reported.
Time Frame Toxicity assessment is repeated every 2 months for the first 6 months, then every 3 months until 3 years or end of treatment.

Outcome Measure Data

Analysis Population Description
Patients who received at least one dose of protocol treatment.
Arm/Group Title Arm I Zoledronic Acid Arm II Clodronate Arm III Ibandronate
Arm/Group Description Patients receive zoledronate IV over 15 minutes once a month for 6 months and then once every 3 months for 2.5 years. zoledronic acid: Given IV Patients receive oral clodronate once daily for 35 months. clodronate disodium: Given orally Arm III Ibandronate Patients receive oral ibandronate once daily for 35 months. ibandronate sodium: Given orally
Measure Participants 2113 2169 1518
ALT, SGPT (serum glutamic pyruvic transaminase)
1
0%
3
0.1%
1
0.1%
AST, SGOT
1
0%
5
0.2%
3
0.2%
Alkaline phosphatase
0
0%
1
0%
0
0%
Allergic reaction/hypersensitivity
2
0.1%
1
0%
1
0.1%
Anorexia
0
0%
1
0%
0
0%
Arthritis (non-septic)
5
0.2%
2
0.1%
2
0.1%
Auditory/Ear-Other (Specify)
1
0%
0
0%
0
0%
Bilirubin (hyperbilirubinemia)
0
0%
1
0%
1
0.1%
Blood/Bone Marrow-Other (Specify)
0
0%
0
0%
1
0.1%
CNS cerebrovascular ischemia
0
0%
1
0%
0
0%
Calcium, serum-low (hypocalcemia)
3
0.1%
2
0.1%
1
0.1%
Cardiac General-Other (Specify)
0
0%
0
0%
1
0.1%
Confusion
0
0%
1
0%
0
0%
Constipation
0
0%
1
0%
1
0.1%
Creatinine
2
0.1%
1
0%
4
0.3%
Dehydration
1
0%
2
0.1%
0
0%
Dental: periodontal disease
2
0.1%
0
0%
0
0%
Dental: teeth
0
0%
1
0%
0
0%
Diarrhea
2
0.1%
11
0.5%
5
0.3%
Distention/bloating, abdominal
0
0%
1
0%
0
0%
Dizziness
1
0%
3
0.1%
0
0%
Dysphagia (difficulty swallowing)
0
0%
1
0%
1
0.1%
Dyspnea (shortness of breath)
3
0.1%
2
0.1%
3
0.2%
Edema: limb
1
0%
1
0%
4
0.3%
Endocrine-Other (Specify)
0
0%
1
0%
0
0%
Esophagitis
0
0%
2
0.1%
5
0.3%
Extremity-upper (function)
0
0%
0
0%
1
0.1%
Fatigue (asthenia, lethargy, malaise)
11
0.5%
10
0.4%
7
0.5%
Febrile neutropenia
1
0%
1
0%
0
0%
Fever in absence of neutropenia, ANC lt1.0x10e9/L
1
0%
1
0%
0
0%
Flu-like syndrome
3
0.1%
0
0%
0
0%
Fracture
0
0%
3
0.1%
1
0.1%
Gastritis (including bile reflux gastritis)
0
0%
1
0%
1
0.1%
Glucose, serum-high (hyperglycemia)
0
0%
2
0.1%
0
0%
Heartburn/dyspepsia
2
0.1%
22
1%
22
1.4%
Hemoglobin
3
0.1%
2
0.1%
1
0.1%
Hemorrhage, GI - Rectum
0
0%
1
0%
0
0%
Hemorrhage, GI - Stomach
0
0%
0
0%
1
0.1%
Hot flashes/flushes
3
0.1%
5
0.2%
4
0.3%
Hypertension
2
0.1%
2
0.1%
1
0.1%
Hypotension
0
0%
1
0%
0
0%
INR (of prothrombin time)
0
0%
1
0%
0
0%
Incontinence, urinary
1
0%
0
0%
0
0%
Inf (clin/microbio) w/Gr 3-4 neuts - Skin
1
0%
1
0%
0
0%
Inf (clin/microbio) w/Gr 3-4 neuts - Soft tissue
1
0%
0
0%
0
0%
Inf w/normal ANC or Gr 1-2 neutrophils - Bone
1
0%
0
0%
0
0%
Inf w/normal ANC or Gr 1-2 neutrophils - Bronchus
0
0%
1
0%
0
0%
Inf w/normal ANC or Gr 1-2 neutrophils - Dental
0
0%
1
0%
1
0.1%
Infection with unknown ANC - Appendix
0
0%
0
0%
1
0.1%
Infection with unknown ANC - Liver
1
0%
0
0%
0
0%
Infection with unknown ANC - Skin (cellulitis)
0
0%
1
0%
0
0%
Insomnia
1
0%
3
0.1%
0
0%
Irregular menses (change from baseline)
2
0.1%
0
0%
0
0%
Irritability (children lt3 years of age)
0
0%
1
0%
0
0%
Joint-function
0
0%
0
0%
1
0.1%
Left ventricular systolic dysfunction
0
0%
0
0%
1
0.1%
Leukocytes (total WBC)
2
0.1%
1
0%
0
0%
Lymphopenia
2
0.1%
3
0.1%
0
0%
Magnesium, serum-high (hypermagnesemia)
1
0%
2
0.1%
0
0%
Magnesium, serum-low (hypomagnesemia)
1
0%
0
0%
0
0%
Masculinization of female
0
0%
0
0%
1
0.1%
Memory impairment
1
0%
0
0%
0
0%
Metabolic/Laboratory-Other (Specify)
0
0%
1
0%
0
0%
Mood alteration - anxiety
0
0%
0
0%
1
0.1%
Mood alteration - depression
1
0%
1
0%
1
0.1%
Mood alteration - euphoria
0
0%
1
0%
0
0%
Mucositis/stomatitis (clinical exam) - Oral cavity
1
0%
0
0%
0
0%
Muscle weakness, not d/t neuropathy - Extrem-lower
0
0%
1
0%
0
0%
Muscle weakness, not d/t neuropathy - Extrem-upper
0
0%
1
0%
0
0%
Muscle weakness, not d/t neuropathy - body/general
0
0%
1
0%
0
0%
Nausea
3
0.1%
5
0.2%
2
0.1%
Neuropathy: motor
0
0%
0
0%
1
0.1%
Neuropathy: sensory
0
0%
6
0.3%
4
0.3%
Neutrophils/granulocytes (ANC/AGC)
6
0.3%
5
0.2%
0
0%
Obesity
1
0%
1
0%
0
0%
Opportunistic inf associated w/gt=Gr 2 lymphopenia
1
0%
0
0%
0
0%
Osteonecrosis (avascular necrosis)
6
0.3%
1
0%
3
0.2%
Pain - Abdomen NOS
0
0%
1
0%
1
0.1%
Pain - Back
3
0.1%
2
0.1%
6
0.4%
Pain - Bone
47
2.1%
19
0.9%
19
1.2%
Pain - Chest wall
0
0%
1
0%
0
0%
Pain - Chest/thorax NOS
0
0%
0
0%
2
0.1%
Pain - Extremity-limb
4
0.2%
3
0.1%
4
0.3%
Pain - Head/headache
8
0.4%
3
0.1%
1
0.1%
Pain - Joint
39
1.7%
35
1.6%
42
2.7%
Pain - Muscle
23
1%
5
0.2%
16
1%
Pain - Neck
1
0%
0
0%
1
0.1%
Pain - Neuralgia/peripheral nerve
1
0%
0
0%
0
0%
Pain - Oral cavity
0
0%
0
0%
1
0.1%
Pain - Pain NOS
1
0%
0
0%
0
0%
Pain - Stomach
1
0%
1
0%
1
0.1%
Pain - Throat/pharynx/larynx
0
0%
0
0%
1
0.1%
Pain - Vagina
0
0%
0
0%
1
0.1%
Pain-Other (Specify)
4
0.2%
4
0.2%
0
0%
Pancreatitis
0
0%
1
0%
0
0%
Perforation, GI - Duodenum
0
0%
1
0%
0
0%
Phosphate, serum-low (hypophosphatemia)
19
0.9%
6
0.3%
8
0.5%
Platelets
1
0%
0
0%
0
0%
Potassium, serum-high (hyperkalemia)
0
0%
0
0%
1
0.1%
Potassium, serum-low (hypokalemia)
1
0%
5
0.2%
1
0.1%
Proteinuria
0
0%
0
0%
1
0.1%
Pruritus/itching
0
0%
1
0%
0
0%
Rash/desquamation
0
0%
3
0.1%
2
0.1%
Renal failure
2
0.1%
2
0.1%
5
0.3%
Renal/Genitourinary-Other (Specify)
0
0%
0
0%
3
0.2%
Retinal detachment
1
0%
0
0%
0
0%
Rigors/chills
1
0%
0
0%
0
0%
Secondary Malignancy-poss rel to cancer Tx
0
0%
1
0%
0
0%
Sexual/Reproductive Function-Other (Specify)
1
0%
0
0%
1
0.1%
Sodium, serum-low (hyponatremia)
0
0%
1
0%
0
0%
Soft tissue necrosis - Head
0
0%
0
0%
1
0.1%
Syncope (fainting)
2
0.1%
0
0%
0
0%
Thrombosis/embolism (vascular access-related)
1
0%
1
0%
0
0%
Thrombosis/thrombus/embolism
0
0%
0
0%
1
0.1%
Tinnitus
1
0%
0
0%
0
0%
Urticaria (hives, welts, wheals)
1
0%
2
0.1%
1
0.1%
Vomiting
1
0%
1
0%
1
0.1%
Weight gain
0
0%
1
0%
0
0%
Weight loss
0
0%
1
0%
1
0.1%

Adverse Events

Time Frame Toxicity assessment is repeated every 2 months for the first 6 months, then every 3 months until 3 years or end of treatment.
Adverse Event Reporting Description For Adverse Event assessment, we include patients who are eligible and evaluable for adverse events (e.g., received at least one dose of protocol treatment) in the analysis. For all-cause mortality, we include all eligible patients in the analysis.
Arm/Group Title Arm I Zoledronic Acid Arm II Clodronate Arm III Ibandronate
Arm/Group Description Patients receive zoledronate IV over 15 minutes once a month for 6 months and then once every 3 months for 2.5 years. zoledronic acid: Given IV Patients receive oral clodronate once daily for 35 months. clodronate disodium: Given orally Patients receive oral ibandronate once daily for 35 months. ibandronate sodium: Given orally
All Cause Mortality
Arm I Zoledronic Acid Arm II Clodronate Arm III Ibandronate
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 238/2231 (10.7%) 263/2235 (11.8%) 182/1552 (11.7%)
Serious Adverse Events
Arm I Zoledronic Acid Arm II Clodronate Arm III Ibandronate
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 21/2125 (1%) 190/2186 (8.7%) 141/1530 (9.2%)
Blood and lymphatic system disorders
Febrile neutropenia 0/2125 (0%) 3/2186 (0.1%) 6/1530 (0.4%)
Hemoglobin 0/2125 (0%) 3/2186 (0.1%) 2/1530 (0.1%)
Cardiac disorders
Cardiac General-Other 0/2125 (0%) 2/2186 (0.1%) 2/1530 (0.1%)
Cardiac-ischemia/infarction 1/2125 (0%) 1/2186 (0%) 4/1530 (0.3%)
Conduction abnorm/AV block - Sick sinus syndrome 0/2125 (0%) 1/2186 (0%) 0/1530 (0%)
Left ventricular diastolic dysfunction 0/2125 (0%) 3/2186 (0.1%) 1/1530 (0.1%)
Left ventricular systolic dysfunction 0/2125 (0%) 1/2186 (0%) 4/1530 (0.3%)
Pain - Cardiac/heart 0/2125 (0%) 3/2186 (0.1%) 0/1530 (0%)
Palpitations 0/2125 (0%) 0/2186 (0%) 1/1530 (0.1%)
Pericardial effusion (non-malignant) 0/2125 (0%) 0/2186 (0%) 1/1530 (0.1%)
SVT and nodal arrhythmia - Atrial fibrillation 0/2125 (0%) 4/2186 (0.2%) 1/1530 (0.1%)
SVT and nodal arrhythmia - Atrial tachycardia/PAT 0/2125 (0%) 1/2186 (0%) 0/1530 (0%)
SVT and nodal arrhythmia - SVT tachycardia 0/2125 (0%) 2/2186 (0.1%) 0/1530 (0%)
SVT and nodal arrhythmia - Sinus bradycardia 0/2125 (0%) 1/2186 (0%) 1/1530 (0.1%)
SVT and nodal arrhythmia - Sinus tachycardia 0/2125 (0%) 1/2186 (0%) 0/1530 (0%)
Valvular heart disease 0/2125 (0%) 0/2186 (0%) 1/1530 (0.1%)
Ventricular arrhythmia - PVCs 0/2125 (0%) 0/2186 (0%) 1/1530 (0.1%)
Ventricular arrhythmia - Ventricular fibrillation 0/2125 (0%) 0/2186 (0%) 1/1530 (0.1%)
Endocrine disorders
Endocrine-Other 0/2125 (0%) 2/2186 (0.1%) 0/1530 (0%)
Eye disorders
Ocular/Visual-Other 0/2125 (0%) 0/2186 (0%) 1/1530 (0.1%)
Vision-blurred vision 0/2125 (0%) 1/2186 (0%) 0/1530 (0%)
Gastrointestinal disorders
Colitis 0/2125 (0%) 2/2186 (0.1%) 0/1530 (0%)
Constipation 0/2125 (0%) 0/2186 (0%) 2/1530 (0.1%)
Dental: periodontal disease 0/2125 (0%) 1/2186 (0%) 0/1530 (0%)
Diarrhea 0/2125 (0%) 4/2186 (0.2%) 2/1530 (0.1%)
Distention/bloating, abdominal 0/2125 (0%) 1/2186 (0%) 0/1530 (0%)
Esophagitis 0/2125 (0%) 1/2186 (0%) 1/1530 (0.1%)
Fistula, GI - Colon/cecum/appendix 0/2125 (0%) 1/2186 (0%) 0/1530 (0%)
Gastritis (including bile reflux gastritis) 0/2125 (0%) 1/2186 (0%) 0/1530 (0%)
Gastrointestinal-Other 0/2125 (0%) 0/2186 (0%) 1/1530 (0.1%)
Hemorrhage, GI - Cecum/appendix 0/2125 (0%) 1/2186 (0%) 0/1530 (0%)
Hemorrhage, GI - Esophagus 0/2125 (0%) 1/2186 (0%) 0/1530 (0%)
Hemorrhage, GI - Stomach 0/2125 (0%) 0/2186 (0%) 1/1530 (0.1%)
Hemorrhage, GI - Varices (rectal) 0/2125 (0%) 1/2186 (0%) 0/1530 (0%)
Nausea 0/2125 (0%) 2/2186 (0.1%) 5/1530 (0.3%)
Obstruction, GI - Cecum 0/2125 (0%) 1/2186 (0%) 0/1530 (0%)
Obstruction, GI - Small bowel NOS 0/2125 (0%) 5/2186 (0.2%) 0/1530 (0%)
Obstruction, GI - Stomach 0/2125 (0%) 0/2186 (0%) 1/1530 (0.1%)
Pain - Abdomen NOS 0/2125 (0%) 10/2186 (0.5%) 2/1530 (0.1%)
Pancreatitis 0/2125 (0%) 3/2186 (0.1%) 2/1530 (0.1%)
Perforation, GI - Duodenum 0/2125 (0%) 1/2186 (0%) 0/1530 (0%)
Ulcer, GI - Stomach 0/2125 (0%) 1/2186 (0%) 0/1530 (0%)
Vomiting 0/2125 (0%) 2/2186 (0.1%) 3/1530 (0.2%)
General disorders
Death not associated with CTCAE term - Death NOS 0/2125 (0%) 1/2186 (0%) 1/1530 (0.1%)
Edema: head and neck 0/2125 (0%) 1/2186 (0%) 0/1530 (0%)
Edema: limb 0/2125 (0%) 1/2186 (0%) 0/1530 (0%)
Fatigue (asthenia, lethargy, malaise) 0/2125 (0%) 4/2186 (0.2%) 0/1530 (0%)
Pain - Chest/thorax NOS 0/2125 (0%) 0/2186 (0%) 3/1530 (0.2%)
Pain - Pain NOS 0/2125 (0%) 1/2186 (0%) 0/1530 (0%)
Pain-Other 0/2125 (0%) 1/2186 (0%) 0/1530 (0%)
Sudden death 1/2125 (0%) 1/2186 (0%) 0/1530 (0%)
Syndromes-Other 1/2125 (0%) 1/2186 (0%) 0/1530 (0%)
Hepatobiliary disorders
Cholecystitis 0/2125 (0%) 4/2186 (0.2%) 7/1530 (0.5%)
Liver dysfunction/failure (clinical) 0/2125 (0%) 0/2186 (0%) 1/1530 (0.1%)
Pain - Liver 0/2125 (0%) 1/2186 (0%) 0/1530 (0%)
Immune system disorders
Allergic reaction/hypersensitivity 0/2125 (0%) 4/2186 (0.2%) 0/1530 (0%)
Infections and infestations
Inf (clin/microbio) w/Gr 3-4 neuts - Blood 0/2125 (0%) 3/2186 (0.1%) 1/1530 (0.1%)
Inf (clin/microbio) w/Gr 3-4 neuts - Catheter-rel 0/2125 (0%) 1/2186 (0%) 0/1530 (0%)
Inf (clin/microbio) w/Gr 3-4 neuts - Sinus 0/2125 (0%) 1/2186 (0%) 0/1530 (0%)
Inf (clin/microbio) w/Gr 3-4 neuts - Skin 1/2125 (0%) 0/2186 (0%) 0/1530 (0%)
Inf w/normal ANC or Gr 1-2 neutrophils - Blood 0/2125 (0%) 2/2186 (0.1%) 0/1530 (0%)
Inf w/normal ANC or Gr 1-2 neutrophils - Bronchus 0/2125 (0%) 1/2186 (0%) 0/1530 (0%)
Inf w/normal ANC or Gr 1-2 neutrophils - Catheter 0/2125 (0%) 2/2186 (0.1%) 0/1530 (0%)
Inf w/normal ANC or Gr 1-2 neutrophils - Colon 0/2125 (0%) 2/2186 (0.1%) 0/1530 (0%)
Inf w/normal ANC or Gr 1-2 neutrophils - Kidney 0/2125 (0%) 0/2186 (0%) 1/1530 (0.1%)
Inf w/normal ANC or Gr 1-2 neutrophils - Lung 0/2125 (0%) 4/2186 (0.2%) 3/1530 (0.2%)
Inf w/normal ANC or Gr 1-2 neutrophils - Lymphatic 0/2125 (0%) 1/2186 (0%) 0/1530 (0%)
Inf w/normal ANC or Gr 1-2 neutrophils - Skin 0/2125 (0%) 16/2186 (0.7%) 12/1530 (0.8%)
Inf w/normal ANC or Gr 1-2 neutrophils - Soft tiss 0/2125 (0%) 1/2186 (0%) 2/1530 (0.1%)
Inf w/normal ANC or Gr 1-2 neutrophils - Wound 0/2125 (0%) 2/2186 (0.1%) 0/1530 (0%)
Inf w/normal ANC or Gr 1-2 neutrophils-Foreign bod 0/2125 (0%) 0/2186 (0%) 2/1530 (0.1%)
Infection with normal ANC or Grade 1 or 2 neutroph 0/2125 (0%) 1/2186 (0%) 1/1530 (0.1%)
Infection with unknown ANC - Appendix 0/2125 (0%) 1/2186 (0%) 1/1530 (0.1%)
Infection with unknown ANC - Blood 0/2125 (0%) 0/2186 (0%) 1/1530 (0.1%)
Infection with unknown ANC - Bronchus 0/2125 (0%) 1/2186 (0%) 0/1530 (0%)
Infection with unknown ANC - Catheter-related 0/2125 (0%) 0/2186 (0%) 1/1530 (0.1%)
Infection with unknown ANC - Duodenum 0/2125 (0%) 0/2186 (0%) 1/1530 (0.1%)
Infection with unknown ANC - Foreign body (e.g., g 0/2125 (0%) 1/2186 (0%) 1/1530 (0.1%)
Infection with unknown ANC - Heart (endocarditis) 0/2125 (0%) 0/2186 (0%) 1/1530 (0.1%)
Infection with unknown ANC - Lung (pneumonia) 0/2125 (0%) 2/2186 (0.1%) 3/1530 (0.2%)
Infection with unknown ANC - Skin (cellulitis) 0/2125 (0%) 10/2186 (0.5%) 3/1530 (0.2%)
Infection with unknown ANC - Soft tissue NOS 0/2125 (0%) 2/2186 (0.1%) 0/1530 (0%)
Infection with unknown ANC - Upper airway NOS 0/2125 (0%) 0/2186 (0%) 1/1530 (0.1%)
Infection with unknown ANC - Urinary tract NOS 0/2125 (0%) 0/2186 (0%) 1/1530 (0.1%)
Infection with unknown ANC - Wound 0/2125 (0%) 7/2186 (0.3%) 1/1530 (0.1%)
Infection-Other 0/2125 (0%) 2/2186 (0.1%) 3/1530 (0.2%)
Injury, poisoning and procedural complications
Fracture 0/2125 (0%) 11/2186 (0.5%) 10/1530 (0.7%)
Intra-operative Injury-Other 0/2125 (0%) 1/2186 (0%) 0/1530 (0%)
Intra-operative injury - Ovary 0/2125 (0%) 0/2186 (0%) 1/1530 (0.1%)
Leak (including anastomotic), GI - Leak NOS 0/2125 (0%) 0/2186 (0%) 1/1530 (0.1%)
Rash: dermatitis associated w/radiation 0/2125 (0%) 0/2186 (0%) 1/1530 (0.1%)
Seroma 0/2125 (0%) 0/2186 (0%) 1/1530 (0.1%)
Thrombosis/embolism (vascular access-related) 0/2125 (0%) 1/2186 (0%) 1/1530 (0.1%)
Vessel injury-artery - Carotid 0/2125 (0%) 1/2186 (0%) 0/1530 (0%)
Wound complication, non-infectious 0/2125 (0%) 0/2186 (0%) 2/1530 (0.1%)
Investigations
ALT, SGPT (serum glutamic pyruvic transaminase) 0/2125 (0%) 5/2186 (0.2%) 1/1530 (0.1%)
AST, SGOT 0/2125 (0%) 4/2186 (0.2%) 2/1530 (0.1%)
Alkaline phosphatase 0/2125 (0%) 1/2186 (0%) 0/1530 (0%)
Bilirubin (hyperbilirubinemia) 0/2125 (0%) 1/2186 (0%) 0/1530 (0%)
Creatinine 0/2125 (0%) 1/2186 (0%) 1/1530 (0.1%)
Leukocytes (total WBC) 0/2125 (0%) 3/2186 (0.1%) 2/1530 (0.1%)
Lymphopenia 0/2125 (0%) 1/2186 (0%) 0/1530 (0%)
Neutrophils/granulocytes (ANC/AGC) 0/2125 (0%) 5/2186 (0.2%) 3/1530 (0.2%)
Metabolism and nutrition disorders
Acidosis (metabolic or respiratory) 0/2125 (0%) 1/2186 (0%) 1/1530 (0.1%)
Anorexia 0/2125 (0%) 1/2186 (0%) 0/1530 (0%)
Calcium, serum-low (hypocalcemia) 0/2125 (0%) 2/2186 (0.1%) 1/1530 (0.1%)
Dehydration 0/2125 (0%) 8/2186 (0.4%) 4/1530 (0.3%)
Glucose, serum-high (hyperglycemia) 0/2125 (0%) 2/2186 (0.1%) 0/1530 (0%)
Glucose, serum-low (hypoglycemia) 0/2125 (0%) 3/2186 (0.1%) 0/1530 (0%)
Magnesium, serum-low (hypomagnesemia) 0/2125 (0%) 1/2186 (0%) 0/1530 (0%)
Pancreatic endocrine: glucose intolerance 0/2125 (0%) 0/2186 (0%) 1/1530 (0.1%)
Phosphate, serum-low (hypophosphatemia) 0/2125 (0%) 2/2186 (0.1%) 2/1530 (0.1%)
Potassium, serum-high (hyperkalemia) 0/2125 (0%) 1/2186 (0%) 1/1530 (0.1%)
Potassium, serum-low (hypokalemia) 0/2125 (0%) 3/2186 (0.1%) 1/1530 (0.1%)
Sodium, serum-low (hyponatremia) 0/2125 (0%) 3/2186 (0.1%) 0/1530 (0%)
Musculoskeletal and connective tissue disorders
Arthritis (non-septic) 0/2125 (0%) 0/2186 (0%) 1/1530 (0.1%)
Muscle weakness, not d/t neuropathy - body/general 0/2125 (0%) 0/2186 (0%) 1/1530 (0.1%)
Musculoskeletal/Soft Tissue-Other 0/2125 (0%) 1/2186 (0%) 2/1530 (0.1%)
Osteonecrosis (avascular necrosis) 13/2125 (0.6%) 5/2186 (0.2%) 5/1530 (0.3%)
Pain - Back 0/2125 (0%) 1/2186 (0%) 3/1530 (0.2%)
Pain - Bone 0/2125 (0%) 2/2186 (0.1%) 2/1530 (0.1%)
Pain - Chest wall 0/2125 (0%) 1/2186 (0%) 0/1530 (0%)
Pain - Extremity-limb 0/2125 (0%) 1/2186 (0%) 0/1530 (0%)
Pain - Joint 0/2125 (0%) 1/2186 (0%) 0/1530 (0%)
Pain - Muscle 0/2125 (0%) 3/2186 (0.1%) 0/1530 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Death - Disease progression NOS 1/2125 (0%) 1/2186 (0%) 2/1530 (0.1%)
Pain - Tumor pain 0/2125 (0%) 1/2186 (0%) 1/1530 (0.1%)
Secondary Malignancy-poss rel to cancer Tx 2/2125 (0.1%) 1/2186 (0%) 1/1530 (0.1%)
Nervous system disorders
Ataxia (incoordination) 0/2125 (0%) 1/2186 (0%) 1/1530 (0.1%)
CNS cerebrovascular ischemia 0/2125 (0%) 4/2186 (0.2%) 4/1530 (0.3%)
Cognitive disturbance 0/2125 (0%) 1/2186 (0%) 0/1530 (0%)
Dizziness 0/2125 (0%) 5/2186 (0.2%) 1/1530 (0.1%)
Hemorrhage, CNS 0/2125 (0%) 1/2186 (0%) 0/1530 (0%)
Neurology-Other 0/2125 (0%) 1/2186 (0%) 2/1530 (0.1%)
Neuropathy: CN VII Motor-face; Sensory-taste 0/2125 (0%) 0/2186 (0%) 1/1530 (0.1%)
Neuropathy: motor 0/2125 (0%) 1/2186 (0%) 2/1530 (0.1%)
Neuropathy: sensory 0/2125 (0%) 2/2186 (0.1%) 1/1530 (0.1%)
Ocular/Visual-Other 0/2125 (0%) 0/2186 (0%) 1/1530 (0.1%)
Pain - Head/headache 0/2125 (0%) 7/2186 (0.3%) 0/1530 (0%)
Somnolence/depressed level of consciousness 0/2125 (0%) 0/2186 (0%) 1/1530 (0.1%)
Syncope (fainting) 0/2125 (0%) 3/2186 (0.1%) 5/1530 (0.3%)
Vasovagal episode 0/2125 (0%) 0/2186 (0%) 1/1530 (0.1%)
Psychiatric disorders
Confusion 0/2125 (0%) 2/2186 (0.1%) 1/1530 (0.1%)
Mood alteration - depression 0/2125 (0%) 3/2186 (0.1%) 1/1530 (0.1%)
Personality/behavioral 0/2125 (0%) 1/2186 (0%) 0/1530 (0%)
Renal and urinary disorders
Cystitis 0/2125 (0%) 0/2186 (0%) 1/1530 (0.1%)
Glomerular filtration rate 0/2125 (0%) 1/2186 (0%) 0/1530 (0%)
Hemorrhage, GU - Ureter 0/2125 (0%) 0/2186 (0%) 1/1530 (0.1%)
Hemorrhage, GU - Urinary NOS 0/2125 (0%) 0/2186 (0%) 1/1530 (0.1%)
Obstruction, GU - Ureter 0/2125 (0%) 1/2186 (0%) 1/1530 (0.1%)
Pain - Bladder 0/2125 (0%) 0/2186 (0%) 1/1530 (0.1%)
Pain - Kidney 0/2125 (0%) 0/2186 (0%) 1/1530 (0.1%)
Proteinuria 0/2125 (0%) 0/2186 (0%) 1/1530 (0.1%)
Renal failure 0/2125 (0%) 2/2186 (0.1%) 0/1530 (0%)
Renal/Genitourinary-Other 0/2125 (0%) 2/2186 (0.1%) 2/1530 (0.1%)
Reproductive system and breast disorders
Hemorrhage, GU - Uterus 0/2125 (0%) 1/2186 (0%) 0/1530 (0%)
Sexual/Reproductive Function-Other 1/2125 (0%) 0/2186 (0%) 4/1530 (0.3%)
Respiratory, thoracic and mediastinal disorders
Bronchospasm, wheezing 0/2125 (0%) 2/2186 (0.1%) 1/1530 (0.1%)
Cough 0/2125 (0%) 1/2186 (0%) 1/1530 (0.1%)
Dyspnea (shortness of breath) 0/2125 (0%) 10/2186 (0.5%) 9/1530 (0.6%)
Hemorrhage, pulmonary/upper respiratory - Larynx 0/2125 (0%) 0/2186 (0%) 1/1530 (0.1%)
Hypoxia 0/2125 (0%) 2/2186 (0.1%) 3/1530 (0.2%)
Pleural effusion (non-malignant) 0/2125 (0%) 3/2186 (0.1%) 2/1530 (0.1%)
Pneumonitis/pulmonary infiltrates 0/2125 (0%) 3/2186 (0.1%) 1/1530 (0.1%)
Pulmonary hypertension 0/2125 (0%) 0/2186 (0%) 1/1530 (0.1%)
Pulmonary/Upper Respiratory-Other 0/2125 (0%) 2/2186 (0.1%) 0/1530 (0%)
Skin and subcutaneous tissue disorders
Dermatology/Skin-Other 0/2125 (0%) 1/2186 (0%) 1/1530 (0.1%)
Pruritus/itching 0/2125 (0%) 1/2186 (0%) 1/1530 (0.1%)
Rash/desquamation 0/2125 (0%) 0/2186 (0%) 2/1530 (0.1%)
Rash: erythema multiforme 0/2125 (0%) 1/2186 (0%) 0/1530 (0%)
Rash: hand-foot skin reaction 0/2125 (0%) 1/2186 (0%) 0/1530 (0%)
Urticaria (hives, welts, wheals) 0/2125 (0%) 0/2186 (0%) 1/1530 (0.1%)
Vascular disorders
Hematoma 0/2125 (0%) 1/2186 (0%) 0/1530 (0%)
Hypertension 0/2125 (0%) 1/2186 (0%) 0/1530 (0%)
Hypotension 0/2125 (0%) 2/2186 (0.1%) 0/1530 (0%)
Phlebitis (including superficial thrombosis) 0/2125 (0%) 0/2186 (0%) 1/1530 (0.1%)
Thrombosis/thrombus/embolism 0/2125 (0%) 9/2186 (0.4%) 10/1530 (0.7%)
Other (Not Including Serious) Adverse Events
Arm I Zoledronic Acid Arm II Clodronate Arm III Ibandronate
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 1854/2125 (87.2%) 1942/2186 (88.8%) 1366/1530 (89.3%)
Blood and lymphatic system disorders
Hemoglobin 376/2125 (17.7%) 326/2186 (14.9%) 251/1530 (16.4%)
Gastrointestinal disorders
Constipation 230/2125 (10.8%) 259/2186 (11.8%) 180/1530 (11.8%)
Diarrhea 288/2125 (13.6%) 447/2186 (20.4%) 223/1530 (14.6%)
Heartburn/dyspepsia 138/2125 (6.5%) 332/2186 (15.2%) 280/1530 (18.3%)
Nausea 454/2125 (21.4%) 555/2186 (25.4%) 307/1530 (20.1%)
Pain - Abdomen NOS 133/2125 (6.3%) 146/2186 (6.7%) 100/1530 (6.5%)
Vomiting 158/2125 (7.4%) 243/2186 (11.1%) 123/1530 (8%)
General disorders
Edema: limb 243/2125 (11.4%) 212/2186 (9.7%) 163/1530 (10.7%)
Fatigue (asthenia, lethargy, malaise) 851/2125 (40%) 749/2186 (34.3%) 560/1530 (36.6%)
Fever in absence of neutropenia, ANC lt1.0x10e9/L 261/2125 (12.3%) 82/2186 (3.8%) 70/1530 (4.6%)
Flu-like syndrome 108/2125 (5.1%) 24/2186 (1.1%) 18/1530 (1.2%)
Pain-Other 185/2125 (8.7%) 149/2186 (6.8%) 122/1530 (8%)
Rigors/chills 109/2125 (5.1%) 27/2186 (1.2%) 18/1530 (1.2%)
Injury, poisoning and procedural complications
Rash: dermatitis associated w/radiation 108/2125 (5.1%) 100/2186 (4.6%) 70/1530 (4.6%)
Investigations
ALT, SGPT (serum glutamic pyruvic transaminase) 290/2125 (13.6%) 540/2186 (24.7%) 170/1530 (11.1%)
AST, SGOT 308/2125 (14.5%) 581/2186 (26.6%) 190/1530 (12.4%)
Alkaline phosphatase 114/2125 (5.4%) 166/2186 (7.6%) 77/1530 (5%)
Creatinine 205/2125 (9.6%) 230/2186 (10.5%) 127/1530 (8.3%)
Leukocytes (total WBC) 366/2125 (17.2%) 370/2186 (16.9%) 205/1530 (13.4%)
Lymphopenia 209/2125 (9.8%) 181/2186 (8.3%) 125/1530 (8.2%)
Metabolic/Laboratory-Other 120/2125 (5.6%) 132/2186 (6%) 67/1530 (4.4%)
Neutrophils/granulocytes (ANC/AGC) 160/2125 (7.5%) 213/2186 (9.7%) 100/1530 (6.5%)
Platelets 118/2125 (5.6%) 140/2186 (6.4%) 51/1530 (3.3%)
Weight gain 124/2125 (5.8%) 137/2186 (6.3%) 81/1530 (5.3%)
Metabolism and nutrition disorders
Calcium, serum-high (hypercalcemia) 109/2125 (5.1%) 97/2186 (4.4%) 61/1530 (4%)
Calcium, serum-low (hypocalcemia) 196/2125 (9.2%) 162/2186 (7.4%) 111/1530 (7.3%)
Glucose, serum-high (hyperglycemia) 484/2125 (22.8%) 429/2186 (19.6%) 283/1530 (18.5%)
Glucose, serum-low (hypoglycemia) 119/2125 (5.6%) 84/2186 (3.8%) 58/1530 (3.8%)
Magnesium, serum-low (hypomagnesemia) 120/2125 (5.6%) 88/2186 (4%) 82/1530 (5.4%)
Phosphate, serum-low (hypophosphatemia) 148/2125 (7%) 87/2186 (4%) 80/1530 (5.2%)
Potassium, serum-low (hypokalemia) 172/2125 (8.1%) 189/2186 (8.6%) 88/1530 (5.8%)
Sodium, serum-low (hyponatremia) 114/2125 (5.4%) 106/2186 (4.8%) 78/1530 (5.1%)
Musculoskeletal and connective tissue disorders
Arthritis (non-septic) 206/2125 (9.7%) 197/2186 (9%) 143/1530 (9.3%)
Pain - Back 295/2125 (13.9%) 253/2186 (11.6%) 213/1530 (13.9%)
Pain - Bone 614/2125 (28.9%) 390/2186 (17.8%) 303/1530 (19.8%)
Pain - Extremity-limb 260/2125 (12.2%) 231/2186 (10.6%) 173/1530 (11.3%)
Pain - Joint 1071/2125 (50.4%) 968/2186 (44.3%) 756/1530 (49.4%)
Pain - Muscle 488/2125 (23%) 339/2186 (15.5%) 294/1530 (19.2%)
Nervous system disorders
Dizziness 196/2125 (9.2%) 157/2186 (7.2%) 134/1530 (8.8%)
Neuropathy: sensory 464/2125 (21.8%) 447/2186 (20.4%) 311/1530 (20.3%)
Pain - Head/headache 310/2125 (14.6%) 270/2186 (12.4%) 205/1530 (13.4%)
Psychiatric disorders
Insomnia 345/2125 (16.2%) 310/2186 (14.2%) 204/1530 (13.3%)
Mood alteration - anxiety 178/2125 (8.4%) 159/2186 (7.3%) 106/1530 (6.9%)
Mood alteration - depression 236/2125 (11.1%) 227/2186 (10.4%) 151/1530 (9.9%)
Reproductive system and breast disorders
Pain - Breast 129/2125 (6.1%) 144/2186 (6.6%) 102/1530 (6.7%)
Vaginal dryness 128/2125 (6%) 137/2186 (6.3%) 90/1530 (5.9%)
Respiratory, thoracic and mediastinal disorders
Cough 216/2125 (10.2%) 216/2186 (9.9%) 143/1530 (9.3%)
Dyspnea (shortness of breath) 185/2125 (8.7%) 133/2186 (6.1%) 116/1530 (7.6%)
Skin and subcutaneous tissue disorders
Hair loss/Alopecia (scalp or body) 138/2125 (6.5%) 120/2186 (5.5%) 90/1530 (5.9%)
Rash/desquamation 306/2125 (14.4%) 307/2186 (14%) 194/1530 (12.7%)
Sweating (diaphoresis) 97/2125 (4.6%) 97/2186 (4.4%) 79/1530 (5.2%)
Vascular disorders
Hot flashes/flushes 795/2125 (37.4%) 808/2186 (37%) 579/1530 (37.8%)
Hypertension 94/2125 (4.4%) 127/2186 (5.8%) 60/1530 (3.9%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.

Results Point of Contact

Name/Title SWOG statistician
Organization SWOG Statistics & Data Management Center
Phone 2066674263
Email jmiao@fredhutch.org
Responsible Party:
Southwest Oncology Group
ClinicalTrials.gov Identifier:
NCT00127205
Other Study ID Numbers:
  • CDR0000437061
  • S0307
First Posted:
Aug 5, 2005
Last Update Posted:
Jul 2, 2021
Last Verified:
Jun 1, 2021