Zoledronate, Vitamin D, and Calcium With or Without Strontium 89 or Samarium 153 in Preventing or Delaying Bone Problems in Patients With Bone Metastases From Prostate Cancer, Lung Cancer, or Breast Cancer

• Sponsor: Radiation Therapy Oncology Group (Other)
• Overall Status: Completed
• CT.gov ID: NCT00365105
• Collaborator: National Cancer Institute (NCI) (NIH), NRG Oncology (Other)
• Enrollment: 261
• Locations: 147
• Arms: 2
• Actual Duration (Months): 127.6
• Patients Per Site: 1.8
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

RATIONALE: Zoledronate, vitamin D and calcium may prevent or delay bone pain and other symptoms caused by bone metastases. It is not yet known whether giving zoledronate together with vitamin D and calcium is more effective with or without strontium 89 or samarium 153 in treating patients with bone metastases from prostate cancer, lung cancer, or breast cancer.

PURPOSE: This randomized phase III trial is studying zoledronate, vitamin D, and calcium to see how well they work compared to zoledronate, vitamin D, calcium, and either strontium 89 or samarium 153 in preventing or delaying bone problems in patients with bone metastases from prostate cancer, lung cancer, or breast cancer.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer; Lung Cancer; Metastatic Cancer; Pain; Prostate Cancer	Dietary Supplement: Calcium; Dietary Supplement: Vitamin D; Drug: zoledronic acid; Drug: Sm-153; Radiation: Sr-89	Phase 3

Detailed Description

OBJECTIVES:

Primary

• Compare the efficacy of zoledronate, vitamin D, and calcium with or without strontium chloride Sr 89 or samarium Sm 153 lexidronam pentasodium, in terms of preventing or delaying the time to development of malignant skeletal-related events (SREs) (defined as a pathological bone fracture, spinal cord compression, surgery to bone, or radiation to bone) in patients with bone metastases secondary to prostate, lung, or breast cancer.

Secondary

• Compare the rate of SREs at 1 year in patients treated with these regimens.

• Compare overall survival of patients treated with these regimens.

• Compare quality of life of patients treated with these regimens.

• Compare the effect of these regimens on pain control in these patients.

• Evaluate resource utilization and cost effectiveness of these regimens.

OUTLINE: This is a randomized, open-label, multicenter study. Patients are stratified according to primary disease site (prostate vs breast vs lung) and number of bone metastases (≤ 2 vs > 2). Patients are randomized to 1 of 2 treatment arms.

Quality of life and pain are assessed at baseline and then at 1, 3, 6, and 12 months from start of protocol treatment.

After completion of study treatment, patients are followed every 6 months.

Study Design

• Study Type: Interventional
• Actual Enrollment: 261 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Supportive Care
• Official Title: Randomized Phase III Trial to Evaluate Radiopharmaceuticals and Zoledronic Acid in the Palliation of Osteoblastic Metastases From Lung, Breast, and Prostate Cancer
• Actual Study Start Date: Jul 11, 2006
• Actual Primary Completion Date: Jan 1, 2012
• Actual Study Completion Date: Feb 27, 2017

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Zoledronic acid Zoledronic acid, vitamin D and calcium supplements.	Dietary Supplement: Calcium; At least 500 mg of calcium (1 pill) by mouth daily until the study doctor thinks it is in their best interest to stop.; Dietary Supplement: Vitamin D; 400 IU of vitamin D (1 pill) by mouth daily until the study doctor thinks it is in their best interest to stop.; Drug: zoledronic acid; 4 mg of Zoledronic acid intravenously once a month until the study doctor thinks it is in their best interest to stop.; Other Names: Zometa
Experimental: Zoledronic acid + Radiopharmaceuticals Zoledronic acid, vitamin D and calcium supplements, plus Sr-89 or Sm-153.	Dietary Supplement: Calcium; At least 500 mg of calcium (1 pill) by mouth daily until the study doctor thinks it is in their best interest to stop.; Drug: zoledronic acid; 4 mg of Zoledronic acid intravenously once a month until the study doctor thinks it is in their best interest to stop.; Other Names: Zometa ; Drug: Sm-153; Single dose intravenously 1 mCi/kg body weight.; Other Names: Samarium-153 ; Radiation: Sr-89; Single dose intravenously 4 mCi.; Other Names: Strontium-89

Outcome Measures

Primary Outcome Measures

1. Time to Development of a Malignant Skeletal-related Events (SRE) [From randomization to last follow-up. Maximum follow-up at time of analysis was 80.1 months.]

   Median time to development of a malignant skeletal related event (SRE), which is defined as a pathological bone fracture, spinal cord compression, surgery to bone or radiation to bone is estimated using Kaplan-Meier method. The time of failure was measured from date of randomization to the date of a documented SRE. The analysis was planned to occur after 257 SRE have been observed, unless the criteria for early stopping are met.

Secondary Outcome Measures

1. Number of Patients Experiencing a Skeletal-related Event (SRE) Within One Year [From randomization to 1 year]

   Skeletal-related events are defined as a pathological bone fracture, spinal cord compression, surgery to bone or radiation to bone.

2. Overall Survival [From randomization to last follow-up. Maximum follow-up at time of analysis was 101.7 months.]

   Overall survival time is defined as time from randomization to the date of death from any cause. Overall survival rates are estimated by the Kaplan-Meier method. Patients last known to be alive are censored at the date of last contact.

3. Change in Functional Assessment of Cancer Therapy - General (FACT-G) at One Year [Baseline and 1 year]

   The FACT-G is a validated 27-item measure in which a higher score represents higher quality of life (QOL). Physical, functional, social and emotional well-being subscale scores are added together to form the FACT-G total score. Responses range from 0=Not a lot to 4=Very much. Certain items must be reversed before being added, by subtracting the response from 4. Subscale items are added together, multiplied by the number of items in the subscale, then divided by the number of items answered to obtain subscale totals. Total score ranges from 0-108; physical, social and functional subscales from 0-28; emotional subscale from 0-24. Each subscale requires at least 50% of the items to be completed while the overall response rate must be greater than 80%. If items are missing the subscale scores can be prorated. Change score at one year is calculated as one year score - baseline score with a positive change score indicating improvement in QOL.

4. Change in Brief Pain Inventory (BPI) at One Year [Baseline and 1 year]

   The Brief Pain Inventory (BPI) is a measurement tool for assessing clinical pain. The BPI assesses severity (pain at its "worst," "least," "average," and "now"), and interference (how much pain has interfered with seven daily activities, including general activity, walking, work, mood, enjoyment of life, relations with others, and sleep). Patients rate the severity of their pain and the degree to which their pain interferes with common dimensions of feeling and function on a scale of 0 to 10, with 0=no pain/interference and 10=interferes completely/worst pain imaginable.

5. Change in EuroQol-5 Dimension 3-level (EQ-5D-3L) at One Year [Baseline and 1 year]

   The EQ-5D-3L is a 2-part self-assessment questionnaire. First part is 5 items (mobility, self care, usual activities, pain/discomfort, anxiety/depression) each with 3 problem levels (1-none, 2-moderate, 3-extreme). The 5-item index score is transformed into a utility score between 0 (worst health state) and 1 (best health state). The 2nd part is a visual analogue scale (VAS) valuing current health state, measured on a 20-cm 10-point interval scale. Worst imaginable health state is scored as 0 at the bottom of the scale, and best imaginable health state is scored as 100 at the top. Change at one year is calculated as one-year score - baseline score with positive change indicating improved quality of life.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Histologically or cytologically proven diagnosis of solid tumor malignancy of lung, breast, or prostate prior to registration;

2. Appropriate diagnosis for protocol entry, based upon the following minimum diagnostic workup:

2.1 History/physical examination within 8 weeks prior to registration; 2.2 Bone scan within 4 weeks prior to registration; bone metastases must be visible on the scan. Other scanning modalities, such as magnetic resonance imaging (MRI), positron emission tomography (PET) 2.3 Dental evaluation according to the dental exam checklist (carried out by the investigator, the investigator's designee, or by a qualified dental professional [dental hygienist or dentist]), including history of dental surgery (e.g., extraction or implant) within 8 weeks prior to registration and recorded on the dental exam checklist; Note: If the patient has received prior oral bisphosphonate therapy and has had a prior dental evaluation within 8 weeks of registration, the evaluation should not be repeated.

2.4 Complete blood count (CBC)/differential within 2 weeks prior to registration, with adequate bone marrow function defined as follows:

• White blood cell count (WBC) ≥ 2400 cells/mm^3;

• Absolute neutrophil count (ANC) ≥ 1,800 cells/mm3;

• Platelets ≥ 60,000 cells/mm3;

• Hemoglobin ≥ 8.0 g/dl (Note: The use of transfusion or other intervention to achieve the required hemoglobin is permitted).

2.5 Serum creatinine < 3 mg/dL (265 μmol/L) within 2 weeks prior to registration; 2.6 Total bilirubin < 2.5 mg/dL (43 μmol/L) within 2 weeks prior to registration; 2.7 Pregnancy test (urine dipstick or serum) for women of childbearing potential within 2 weeks prior to registration;

1. ≥ 18 years of age;

2. Zubrod performance status 0-2 for patients with breast or prostate primaries; Zubrod performance status 0-1 for patients with lung primaries;

3. Patients receiving systemic chemotherapy or hormonal therapy are eligible for this study. See Sections 6.0 and 7.0 for further details. Note: All patients must complete external beam radiation therapy ≥ 14 days prior to registration. If patients have undergone CyberKnife treatment, treatment must be completed ≥ 14 days prior to registration.

4. Patients may have received prior oral bisphosphonate therapy, such as Fosamax® or similar medications. Duration of bisphosphonate treatment prior to study entry must be documented, and all bisphosphonates other than the study drug must be discontinued prior to registration.

5. Women of childbearing potential and male participants must agree to practice an adequate means of birth control throughout their participation in the study.

6. Patient must sign study specific informed consent prior to study entry.

Exclusion Criteria

1. Patients with brain metastases and/or spinal cord compression are excluded. Note: Patients with no evidence of disease in the brain after treatment for brain metastases are eligible.

2. Patients with painful bone metastases are not permitted until these bone metastases are successfully treated (for example by external beam irradiation) prior to registration, and the patient has stable pain for at least 2 weeks after that treatment (Stable pain is defined for this study as a patient response of 1, 2, or 3 on Questions 4 and 5 of The Brief Pain Inventory (BPI).

3. Prior treatment with Strontium-89 or Samarium-153 for bone metastases.

4. Treatment for more than 6 months with IV bisphosphonates prior to study entry;

5. Treatment with calcitonin, mithramycin, or gallium nitrate within 2 weeks prior to registration

6. Severe, active co-morbidity, defined as follows:

6.1 Evidence in the six months prior to study entry of uncontrolled congestive heart failure, hypertension refractory to treatment, or symptomatic coronary artery disease; 6.2 Current, active dental problems within 4 weeks of registration, including infection of the teeth or jawbone (maxilla or mandible); dental or fixture trauma; current or prior diagnosis of osteonecrosis of the jaw (ONJ); exposed bone in the mouth; or slow healing after dental procedures; 6.3 Dental surgery (e.g., extractions, implants) within 6 weeks of study entry and while receiving study treatment; for patients who require dental surgery, there are no data to suggest whether discontinuation of bisphosphonate treatment reduces the risk of osteonecrosis of the jaw (ONJ) [see Section 7.2.4].

6.4 Acquired Immune Deficiency Syndrome (AIDS) based upon current Center for Disease Control (CDC) definition; note, however, that HIV testing is not required for entry into this protocol. The need to exclude patients with AIDS from this protocol is necessary because the treatments involved in this protocol may be significantly immunosuppressive. Protocol-specific requirements may also exclude immuno-compromised patients.

1. Pregnant or lactating patients are excluded, as treatment may be harmful to embryos and/or nursing infants.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Providence Cancer Center at Providence Hospital	Mobile	Alabama	United States	36608
2	Roy and Patricia Disney Family Cancer Center at Providence Saint Joseph Medical Center	Burbank	California	United States	91505
3	Mercy Cancer Center at Mercy San Juan Medical Center	Carmichael	California	United States	95608
4	USC/Norris Comprehensive Cancer Center and Hospital	Los Angeles	California	United States	90089-9181
5	Robert and Beverly Lewis Family Cancer Care Center at Pomona Valley Hospital Medical Center	Pomona	California	United States	91767
6	Radiation Oncology Center - Roseville	Roseville	California	United States	95661
7	Radiological Associates of Sacramento Medical Group, Incorporated	Sacramento	California	United States	95815
8	General Robert Huyser Cancer Center at David Grant Medical Center	Travis Air Force Base	California	United States	94535-1800
9	Michael and Dianne Bienes Comprehensive Cancer Center at Holy Cross Hospital	Fort Lauderdale	Florida	United States	33308
10	Integrated Community Oncology Network	Jacksonville Beach	Florida	United States	32250
11	Baptist Cancer Institute - Jacksonville	Jacksonville	Florida	United States	32207
12	Integrated Community Oncology Network at Southside Cancer Center	Jacksonville	Florida	United States	32207
13	Baptist Medical Center South	Jacksonville	Florida	United States	32258
14	CCOP - Mount Sinai Medical Center	Miami Beach	Florida	United States	33140
15	Miami Cancer Center at Mercy Hospital	Miami	Florida	United States	33133
16	Integrated Community Oncology Network - Orange Park	Orange Park	Florida	United States	32073
17	Florida Cancer Center - Palatka	Palatka	Florida	United States	32177
18	Bay Medical	Panama City	Florida	United States	32401
19	Flagler Cancer Center	Saint Augustine	Florida	United States	32086
20	H. Lee Moffitt Cancer Center and Research Institute at University of South Florida	Tampa	Florida	United States	33612-9497
21	John B. Amos Cancer Center	Columbus	Georgia	United States	31904
22	Northeast Georgia Medical Center	Gainesville	Georgia	United States	30501
23	Northwest Community Hospital	Arlington Heights	Illinois	United States	60005
24	Good Samaritan Cancer Care Center at Advocate Good Samaritan Hospital	Downers Grove	Illinois	United States	60515-1500
25	Ingalls Cancer Care Center at Ingalls Memorial Hospital	Harvey	Illinois	United States	60426
26	Veterans Affairs Medical Center - Hines	Hines	Illinois	United States	60141
27	Advocate Christ Medical Center	Oak Lawn	Illinois	United States	60453-2699
28	Advocate Lutheran General Cancer Care Center	Park Ridge	Illinois	United States	60068-1174
29	Oncology Hematology Associates of Central Illinois, PC - Peoria	Peoria	Illinois	United States	61615
30	Cancer Institute at St. John's Hospital	Springfield	Illinois	United States	62702
31	CCOP - Carle Cancer Center	Urbana	Illinois	United States	61801
32	Center for Cancer Care at Goshen General Hospital	Goshen	Indiana	United States	46526
33	Cancer Center at Ball Memorial Hospital	Muncie	Indiana	United States	47303-3499
34	CCOP - Northern Indiana CR Consortium	South Bend	Indiana	United States	46601
35	McFarland Clinic, PC	Ames	Iowa	United States	50010
36	CCOP - Iowa Oncology Research Association	Des Moines	Iowa	United States	50309
37	John Stoddard Cancer Center at Iowa Methodist Medical Center	Des Moines	Iowa	United States	50309
38	Medical Oncology and Hematology Associates at John Stoddard Cancer Center	Des Moines	Iowa	United States	50309
39	Medical Oncology and Hematology Associates at Mercy Cancer Center	Des Moines	Iowa	United States	50314
40	Mercy Cancer Center at Mercy Medical Center - Des Moines	Des Moines	Iowa	United States	50314
41	Siouxland Hematology-Oncology Associates, LLP	Sioux City	Iowa	United States	51101
42	Lawrence Memorial Hospital	Lawrence	Kansas	United States	66044
43	CCOP - Wichita	Wichita	Kansas	United States	67214
44	Central Baptist Hospital	Lexington	Kentucky	United States	40503-9985
45	Tulane Cancer Center Office of Clinical Research	Alexandria	Louisiana	United States	71315-3198
46	Central Maine Comprehensive Cancer Center at Central Maine Medical Center	Lewiston	Maine	United States	04240
47	St. Agnes Hospital Cancer Center	Baltimore	Maryland	United States	21229
48	Hudner Oncology Center at Saint Anne's Hospital - Fall River	Fall River	Massachusetts	United States	02721
49	Cape Cod Hospital	Hyannis	Massachusetts	United States	02601
50	Saint Joseph Mercy Cancer Center	Ann Arbor	Michigan	United States	48106-0995
51	Oakwood Cancer Center at Oakwood Hospital and Medical Center	Dearborn	Michigan	United States	48123-2500
52	Josephine Ford Cancer Center at Henry Ford Hospital	Detroit	Michigan	United States	48202
53	Genesys Hurley Cancer Institute	Flint	Michigan	United States	48503
54	Hurley Medical Center	Flint	Michigan	United States	48503
55	Van Elslander Cancer Center at St. John Hospital and Medical Center	Grosse Pointe Woods	Michigan	United States	48236
56	Dickinson County Healthcare System	Iron Mountain	Michigan	United States	49801
57	West Michigan Cancer Center	Kalamazoo	Michigan	United States	49007-3731
58	Bronson Methodist Hospital	Kalamazoo	Michigan	United States	49007
59	Sparrow Regional Cancer Center	Lansing	Michigan	United States	48912-1811
60	St. John Macomb Hospital	Warren	Michigan	United States	48093
61	CentraCare Clinic - River Campus	Saint Cloud	Minnesota	United States	56303
62	Regional Cancer Center at Singing River Hospital	Pascagoula	Mississippi	United States	39581
63	Truman Medical Center - Hospital Hill	Kansas City	Missouri	United States	64108
64	CCOP - Kansas City	Kansas City	Missouri	United States	64131
65	St. John's Regional Health Center	Springfield	Missouri	United States	65804
66	Hulston Cancer Center at Cox Medical Center South	Springfield	Missouri	United States	65807
67	CCOP - Montana Cancer Consortium	Billings	Montana	United States	59101
68	Northern Rockies Radiation Oncology Center	Billings	Montana	United States	59101
69	Billings Clinic - Downtown	Billings	Montana	United States	59107-7000
70	Great Falls Clinic - Main Facility	Great Falls	Montana	United States	59405
71	Good Samaritan Cancer Center at Good Samaritan Hospital	Kearney	Nebraska	United States	68848-1990
72	Princeton Radiation Oncology Center	Jamesburg	New Jersey	United States	08831
73	Fox Chase Virtua Health Cancer Program at Virtua Memorial Hospital Marlton	Marlton	New Jersey	United States	08053
74	University Medical Center at Princeton	Princeton	New Jersey	United States	08540-3298
75	Franklin & Edith Scarpa Regional Cancer Center at South Jersey Healthcare	Vineland	New Jersey	United States	08360
76	Cancer Institute of New Jersey at Cooper - Voorhees	Voorhees	New Jersey	United States	08043
77	New Mexico Cancer Center	Albuquerque	New Mexico	United States	87109
78	New York Methodist Hospital	Brooklyn	New York	United States	11215
79	Sands Cancer Center	Canandaigua	New York	United States	14424
80	Fitzpatrick Cancer Center at Champlain Valley Physicians Hospital Medical Center	Plattsburgh	New York	United States	12901
81	Highland Hospital of Rochester	Rochester	New York	United States	14620
82	Lipson Cancer and Blood Center at Rochester General Hospital	Rochester	New York	United States	14621
83	University Radiation Oncology at Parkridge Hospital	Rochester	New York	United States	14626
84	James P. Wilmot Cancer Center at University of Rochester Medical Center	Rochester	New York	United States	14642
85	Mission Hospitals - Memorial Campus	Asheville	North Carolina	United States	28801
86	Presbyterian Cancer Center at Presbyterian Hospital	Charlotte	North Carolina	United States	28233-3549
87	Wayne Radiation Oncology	Goldsboro	North Carolina	United States	27534
88	Trinity CancerCare Center	Minot	North Dakota	United States	58701
89	McDowell Cancer Center at Akron General Medical Center	Akron	Ohio	United States	44307
90	Summa Center for Cancer Care at Akron City Hospital	Akron	Ohio	United States	44309-2090
91	Radiation Oncology Center	Alliance	Ohio	United States	44601
92	Barberton Citizens Hospital	Barberton	Ohio	United States	44203
93	Mercy Cancer Center at Mercy Medical Center	Canton	Ohio	United States	44708
94	Adena Regional Medical Center	Chillicothe	Ohio	United States	45601
95	CCOP - Columbus	Columbus	Ohio	United States	43215
96	Grandview Hospital	Dayton	Ohio	United States	45405
97	Good Samaritan Hospital	Dayton	Ohio	United States	45406
98	David L. Rike Cancer Center at Miami Valley Hospital	Dayton	Ohio	United States	45409
99	Samaritan North Cancer Care Center	Dayton	Ohio	United States	45415
100	CCOP - Dayton	Dayton	Ohio	United States	45420
101	Middletown Regional Hospital	Franklin	Ohio	United States	45005-1066
102	Charles F. Kettering Memorial Hospital	Kettering	Ohio	United States	45429
103	MedCentral - Mansfield Hospital	Mansfield	Ohio	United States	44903
104	Cancer Care Center, Incorporated	Salem	Ohio	United States	44460
105	UVMC Cancer Care Center at Upper Valley Medical Center	Troy	Ohio	United States	45373-1300
106	Cancer Treatment Center	Wooster	Ohio	United States	44691
107	United States Air Force Medical Center - Wright-Patterson	Wright-Patterson Air Force Base	Ohio	United States	45433-5529
108	Ruth G. McMillan Cancer Center at Greene Memorial Hospital	Xenia	Ohio	United States	45385
109	Natalie Warren Bryant Cancer Center at St. Francis Hospital	Tulsa	Oklahoma	United States	74136
110	Rosenfeld Cancer Center at Abington Memorial Hospital	Abington	Pennsylvania	United States	19001
111	UPMC Cancer Center at Beaver Medical Center	Beaver	Pennsylvania	United States	15009
112	UPMC Cancer Center at Jefferson Regional Medical Center	Clairton	Pennsylvania	United States	15025
113	Northeast Radiation Oncology Center	Dunmore	Pennsylvania	United States	18512
114	UPMC Cancer Center - Arnold Palmer Pavilion	Greensburg	Pennsylvania	United States	15601
115	UPMC Cancer Center at the John P. Murtha Pavilion	Johnstown	Pennsylvania	United States	15901
116	UPMC Cancer Center at UPMC McKeesport	McKeesport	Pennsylvania	United States	15132
117	UPMC - Moon	Moon	Pennsylvania	United States	15108
118	UPMC Cancer Center - Natrona Heights	Natrona Heights	Pennsylvania	United States	15065
119	Jameson Memorial Hospital - North Campus	New Castle	Pennsylvania	United States	16105
120	UPMC - Shadyside	Pittsburgh	Pennsylvania	United States	15213-2582
121	UPMC Cancer Center at Magee-Womens Hospital	Pittsburgh	Pennsylvania	United States	15213
122	UPMC Cancer Center at UPMC Presbyterian	Pittsburgh	Pennsylvania	United States	15213
123	UPMC Cancer Center at UPMC St. Margaret	Pittsburgh	Pennsylvania	United States	15215
124	UPMC Cancer Center at UPMC Passavant	Pittsburgh	Pennsylvania	United States	15237
125	UPMC Cancer Center - Upper St. Clair	Pittsburgh	Pennsylvania	United States	15243
126	UPMC Cancer Center at UPMC Northwest	Seneca	Pennsylvania	United States	16346
127	Mount Nittany Medical Center	State College	Pennsylvania	United States	16803
128	UPMC Cancer Center - Uniontown	Uniontown	Pennsylvania	United States	15401
129	Washington Hospital Cancer Center	Washington	Pennsylvania	United States	15301
130	York Cancer Center at Apple Hill Medical Center	York	Pennsylvania	United States	17405
131	Hollings Cancer Center at Medical University of South Carolina	Charleston	South Carolina	United States	29425
132	CCOP - Greenville	Greenville	South Carolina	United States	29615
133	Jon and Karen Huntsman Cancer Center at Intermountain Medical Center	Murray	Utah	United States	84157
134	Dixie Regional Medical Center - East Campus	Saint George	Utah	United States	84770
135	Utah Cancer Specialists at UCS Cancer Center	Salt Lake City	Utah	United States	84106
136	LDS Hospital	Salt Lake City	Utah	United States	84143
137	St. Francis Hospital	Federal Way	Washington	United States	98003
138	Good Samaritan Cancer Center	Puyallup	Washington	United States	98372
139	CCOP - Virginia Mason Research Center	Seattle	Washington	United States	98101
140	Franciscan Cancer Center at St. Joseph Medical Center	Tacoma	Washington	United States	98405-3004
141	CCOP - Northwest	Tacoma	Washington	United States	98405
142	MultiCare Regional Cancer Center at Tacoma General Hospital	Tacoma	Washington	United States	98405
143	North Star Lodge Cancer Center at Yakima Valley Memorial Hospital	Yakima	Washington	United States	98902
144	Theda Care Cancer Institute	Appleton	Wisconsin	United States	54911
145	Bellin Memorial Hospital	Green Bay	Wisconsin	United States	54301
146	Riverview UW Cancer Center at Riverview Hospital	Wisconsin Rapids	Wisconsin	United States	54494
147	Welch Cancer Center at Sheridan Memorial Hospital	Sheridan	Wyoming	United States	82801

Sponsors and Collaborators

• Radiation Therapy Oncology Group
• National Cancer Institute (NCI)
• NRG Oncology

Investigators

• Study Chair: Michael J. Seider, MD, PhD, FACR, Summa Center for Cancer Care at Akron City Hospital

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Radiation Therapy Oncology Group
• ClinicalTrials.gov Identifier: NCT00365105
• Other Study ID Numbers: RTOG 0517; CDR0000491233; NCI-2009-00727
• First Posted: Aug 17, 2006
• Last Update Posted: Jun 14, 2019
• Last Verified: May 1, 2019

• Keywords provided by Radiation Therapy Oncology Group: pain; bone metastases; extensive stage small cell lung cancer; recurrent breast cancer; stage IV breast cancer; recurrent non-small cell lung cancer; stage IV non-small cell lung cancer; recurrent prostate cancer; stage IV prostate cancer
• Additional relevant MeSH terms: Breast Neoplasms; Lung Neoplasms; Prostatic Neoplasms; Neoplasm Metastasis; Vitamin D; Zoledronic Acid; Calcium

Study Results

Participant Flow

Arm/Group Title	Zoledronic Acid	Zoledronic Acid + Radiopharmaceuticals
Arm/Group Description	Zoledronic acid, vitamin D and calcium supplements.	Zoledronic acid, vitamin D and calcium supplements, plus Sr-89 or Sm-153.
Period Title: Overall Study
STARTED	129	132
Eligible	124	124
Eligible With Adverse Event Data	123	124
COMPLETED	124	124
NOT COMPLETED	5	8

Baseline Characteristics

Arm/Group Title	Zoledronic Acid	Zoledronic Acid + Radiopharmaceuticals	Total
Arm/Group Description	Zoledronic acid, vitamin D and calcium supplements.	Zoledronic acid, vitamin D and calcium supplements, plus Sr-89 or Sm-153.	Total of all reporting groups
Overall Participants	124	124	248
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	68	68	68
Sex: Female, Male (Count of Participants)
Female	47 37.9%	48 38.7%	95 38.3%
Male	77 62.1%	76 61.3%	153 61.7%

Outcome Measures

1. Primary Outcome

Title	Time to Development of a Malignant Skeletal-related Events (SRE)
Description	Median time to development of a malignant skeletal related event (SRE), which is defined as a pathological bone fracture, spinal cord compression, surgery to bone or radiation to bone is estimated using Kaplan-Meier method. The time of failure was measured from date of randomization to the date of a documented SRE. The analysis was planned to occur after 257 SRE have been observed, unless the criteria for early stopping are met.
Time Frame	From randomization to last follow-up. Maximum follow-up at time of analysis was 80.1 months.

Outcome Measure Data

Analysis Population Description

Eligible patients

Arm/Group Title	Zoledronic Acid	Zoledronic Acid + Radiopharmaceuticals
Arm/Group Description	Zoledronic acid, vitamin D and calcium supplements.	Zoledronic acid, vitamin D and calcium supplements, plus Sr-89 or Sm-153.
Measure Participants	124	124
Median (95% Confidence Interval) [months]	29.9	27.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Zoledronic Acid, Zoledronic Acid + Radiopharmaceuticals
	Comments	Assuming an exponential distribution, the weighted yearly SRE hazard rate for patients treated with bisphosphonates only is 0.7991 which translates to a median time to SRE of 10.4 months. The study was designed to show a 33% relative reduction in the yearly SRE hazard rate, i.e. 15.6 months median time to SRE. Using a two-sided log-rank test assuming a type I error of 0.05, one planned interim analysis with 90% statistical power, 257 SREs are required with a total of 316 patients.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.844
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.04
	Confidence Interval	(2-Sided) 95%; 0.70 to 1.54
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Number of Patients Experiencing a Skeletal-related Event (SRE) Within One Year
Description	Skeletal-related events are defined as a pathological bone fracture, spinal cord compression, surgery to bone or radiation to bone.
Time Frame	From randomization to 1 year

Outcome Measure Data

Analysis Population Description

Eligible patients

Arm/Group Title	Zoledronic Acid	Zoledronic Acid + Radiopharmaceuticals
Arm/Group Description	Zoledronic acid, vitamin D and calcium supplements.	Zoledronic acid, vitamin D and calcium supplements, plus Sr-89 or Sm-153.
Measure Participants	124	124
Count of Participants [Participants]	28 22.6%	20 16.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Zoledronic Acid, Zoledronic Acid + Radiopharmaceuticals
	Comments
	Type of Statistical Test	Superiority
	Comments	The power of detecting an improvement from 55% in the control arm to 41% in the experimental arm with a two-sided Fisher's exact test at alpha 0.05 is 66%.
Statistical Test of Hypothesis	p-Value	0.26
	Comments
	Method	Fisher Exact
	Comments

3. Secondary Outcome

Title	Overall Survival
Description	Overall survival time is defined as time from randomization to the date of death from any cause. Overall survival rates are estimated by the Kaplan-Meier method. Patients last known to be alive are censored at the date of last contact.
Time Frame	From randomization to last follow-up. Maximum follow-up at time of analysis was 101.7 months.

Outcome Measure Data

Analysis Population Description

Eligible patients

Arm/Group Title	Zoledronic Acid	Zoledronic Acid + Radiopharmaceuticals
Arm/Group Description	Zoledronic acid, vitamin D and calcium supplements.	Zoledronic acid, vitamin D and calcium supplements, plus Sr-89 or Sm-153.
Measure Participants	124	124
Median (95% Confidence Interval) [months]	32.1	26.9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Zoledronic Acid, Zoledronic Acid + Radiopharmaceuticals
	Comments	Assuming the disease site distribution is 40%, 40%, and 20% from prostate, breast, and lung cancer populations, respectively, the weighted yearly death rate for patients treated with bisphosphonates only is 0.4390, translating to a median overall survival time of 18.9 months assuming an exponential distribution. Statistical power to detect a relative difference of 33% in the yearly death rate is 70% using a two-sided log-rank test at a 0.05 significance level and 87% to detect 50% difference.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.37
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.14
	Confidence Interval	(2-Sided) 95%; 0.86 to 1.52
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Change in Functional Assessment of Cancer Therapy - General (FACT-G) at One Year
Description	The FACT-G is a validated 27-item measure in which a higher score represents higher quality of life (QOL). Physical, functional, social and emotional well-being subscale scores are added together to form the FACT-G total score. Responses range from 0=Not a lot to 4=Very much. Certain items must be reversed before being added, by subtracting the response from 4. Subscale items are added together, multiplied by the number of items in the subscale, then divided by the number of items answered to obtain subscale totals. Total score ranges from 0-108; physical, social and functional subscales from 0-28; emotional subscale from 0-24. Each subscale requires at least 50% of the items to be completed while the overall response rate must be greater than 80%. If items are missing the subscale scores can be prorated. Change score at one year is calculated as one year score - baseline score with a positive change score indicating improvement in QOL.
Time Frame	Baseline and 1 year

Outcome Measure Data

Analysis Population Description

Eligible patients with FACT-G scores at baseline and one year

Arm/Group Title	Zoledronic Acid	Zoledronic Acid + Radiopharmaceuticals
Arm/Group Description	Zoledronic acid, vitamin D and calcium supplements.	Zoledronic acid, vitamin D and calcium supplements, plus Sr-89 or Sm-153.
Measure Participants	62	59
FACT-G Total	-1	-2
Physical Well-Being	-1	-1
Social/Family Well-Being	0	0
Emotional Well-Being	0	0
Functional Well-Being	0	0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Zoledronic Acid, Zoledronic Acid + Radiopharmaceuticals
	Comments	FACT-G Total
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.96
	Comments	Two-sided significance level of 0.01
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Zoledronic Acid, Zoledronic Acid + Radiopharmaceuticals
	Comments	Physical Well-Being
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.97
	Comments	Two-sided significance level of 0.01
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Zoledronic Acid, Zoledronic Acid + Radiopharmaceuticals
	Comments	Social/Family Well-Being
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.57
	Comments	Two-sided significance level of 0.01
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Zoledronic Acid, Zoledronic Acid + Radiopharmaceuticals
	Comments	Emotional Well-Being
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.70
	Comments	Two-sided significance level of 0.01
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Zoledronic Acid, Zoledronic Acid + Radiopharmaceuticals
	Comments	Functional Well-Being
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.46
	Comments	Two-sided significance level of 0.01
	Method	Wilcoxon (Mann-Whitney)
	Comments

5. Secondary Outcome

Title	Change in Brief Pain Inventory (BPI) at One Year
Description	The Brief Pain Inventory (BPI) is a measurement tool for assessing clinical pain. The BPI assesses severity (pain at its "worst," "least," "average," and "now"), and interference (how much pain has interfered with seven daily activities, including general activity, walking, work, mood, enjoyment of life, relations with others, and sleep). Patients rate the severity of their pain and the degree to which their pain interferes with common dimensions of feeling and function on a scale of 0 to 10, with 0=no pain/interference and 10=interferes completely/worst pain imaginable.
Time Frame	Baseline and 1 year

Outcome Measure Data

Analysis Population Description

Eligible patients with baseline and one-year BPI score

Arm/Group Title	Zoledronic Acid	Zoledronic Acid + Radiopharmaceuticals
Arm/Group Description	Zoledronic acid, vitamin D and calcium supplements.	Zoledronic acid, vitamin D and calcium supplements, plus Sr-89 or Sm-153.
Measure Participants	54	51
Median (Inter-Quartile Range) [units on a scale]	1	0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Zoledronic Acid, Zoledronic Acid + Radiopharmaceuticals
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.99
	Comments	2-sided significance level of 0.05
	Method	Wilcoxon (Mann-Whitney)
	Comments

6. Secondary Outcome

Title	Change in EuroQol-5 Dimension 3-level (EQ-5D-3L) at One Year
Description	The EQ-5D-3L is a 2-part self-assessment questionnaire. First part is 5 items (mobility, self care, usual activities, pain/discomfort, anxiety/depression) each with 3 problem levels (1-none, 2-moderate, 3-extreme). The 5-item index score is transformed into a utility score between 0 (worst health state) and 1 (best health state). The 2nd part is a visual analogue scale (VAS) valuing current health state, measured on a 20-cm 10-point interval scale. Worst imaginable health state is scored as 0 at the bottom of the scale, and best imaginable health state is scored as 100 at the top. Change at one year is calculated as one-year score - baseline score with positive change indicating improved quality of life.
Time Frame	Baseline and 1 year

Outcome Measure Data

Analysis Population Description

Eligible patients with EQ-5D-3L scores at baseline and one year

Arm/Group Title	Zoledronic Acid	Zoledronic Acid + Radiopharmaceuticals
Arm/Group Description	Zoledronic acid, vitamin D and calcium supplements.	Zoledronic acid, vitamin D and calcium supplements, plus Sr-89 or Sm-153.
Measure Participants	53	51
Index Score	-0.04 (0.14)	-0.06 (0.15)
VAS Score	-1.20 (20.43)	-6.70 (15.70)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Zoledronic Acid, Zoledronic Acid + Radiopharmaceuticals
	Comments	Index Score
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.43
	Comments	Significance level of 0.05
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Zoledronic Acid, Zoledronic Acid + Radiopharmaceuticals
	Comments	VAS Score
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.15
	Comments	Significance level of 0.05
	Method	t-test, 2 sided
	Comments

Adverse Events

Adverse Event Reporting Description	Eligible patients with adverse event data. Patients experiencing more than one of a given adverse event are counted only once for that adverse event.
Arm/Group Title	Zoledronic Acid		Zoledronic Acid + Radiopharmaceuticals
Arm/Group Description	Zoledronic acid, vitamin D and calcium supplements.		Zoledronic acid, vitamin D and calcium supplements, plus Sr-89 or Sm-153.
All Cause Mortality
	Zoledronic Acid		Zoledronic Acid + Radiopharmaceuticals
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Zoledronic Acid		Zoledronic Acid + Radiopharmaceuticals
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	31/123 (25.2%)		37/124 (29.8%)
Blood and lymphatic system disorders
Blood/bone marrow - Other:	0/123 (0%)		1/124 (0.8%)
Febrile neutropenia	0/123 (0%)		1/124 (0.8%)
Hemoglobin	6/123 (4.9%)		10/124 (8.1%)
Cardiac disorders
Atrial fibrillation	1/123 (0.8%)		2/124 (1.6%)
Cardiac General - Other:	0/123 (0%)		1/124 (0.8%)
Myocardial ischaemia	0/123 (0%)		1/124 (0.8%)
Pericardial effusion	1/123 (0.8%)		0/124 (0%)
Sick Sinus Syndrome	1/123 (0.8%)		0/124 (0%)
Sinus bradycardia	0/123 (0%)		2/124 (1.6%)
Supraventricular tachycardia	0/123 (0%)		1/124 (0.8%)
Eye disorders
Diplopia	1/123 (0.8%)		0/124 (0%)
Gastrointestinal disorders
Abdominal pain NOS	2/123 (1.6%)		1/124 (0.8%)
Colonic obstruction	0/123 (0%)		1/124 (0.8%)
Colonic perforation	1/123 (0.8%)		0/124 (0%)
Constipation	0/123 (0%)		1/124 (0.8%)
Diarrhoea NOS	0/123 (0%)		1/124 (0.8%)
Duodenal ulcer	0/123 (0%)		1/124 (0.8%)
Gastric haemorrhage	0/123 (0%)		1/124 (0.8%)
Gastrointestinal - Other:	0/123 (0%)		1/124 (0.8%)
Ileal haemorrhage	1/123 (0.8%)		0/124 (0%)
Lower gastrointestinal hemorrhage	1/123 (0.8%)		0/124 (0%)
Nausea	2/123 (1.6%)		1/124 (0.8%)
Rectal hemorrhage	0/123 (0%)		1/124 (0.8%)
Small intestinal stricture NOS	0/123 (0%)		1/124 (0.8%)
Vomiting NOS	2/123 (1.6%)		2/124 (1.6%)
General disorders
Chest pain	2/123 (1.6%)		0/124 (0%)
Death NOS	1/123 (0.8%)		1/124 (0.8%)
Disease progression NOS	3/123 (2.4%)		2/124 (1.6%)
Edema: limb:	1/123 (0.8%)		0/124 (0%)
Fatigue	4/123 (3.3%)		0/124 (0%)
Gait abnormal NOS	1/123 (0.8%)		0/124 (0%)
Pain NOS	1/123 (0.8%)		0/124 (0%)
Infections and infestations
Abdominal infection	1/123 (0.8%)		0/124 (0%)
Bladder infection NOS	1/123 (0.8%)		1/124 (0.8%)
Bone infection NOS	1/123 (0.8%)		0/124 (0%)
Bronchitis NOS	1/123 (0.8%)		0/124 (0%)
Infection - Other:	0/123 (0%)		1/124 (0.8%)
Infection with Grade 3 or 4 neutrophils (ANC <1.0 x 10e9/L): Bladder (urinary)	0/123 (0%)		1/124 (0.8%)
Infection with Grade 3 or 4 neutrophils (ANC <1.0 x 10e9/L): Catheter-related	1/123 (0.8%)		0/124 (0%)
Infection with Grade 3 or 4 neutrophils (ANC <1.0 x 10e9/L): Lung (pneumonia)	1/123 (0.8%)		1/124 (0.8%)
Infection with Grade 3 or 4 neutrophils (ANC <1.0 x 10e9/L): Pleura (empyema)	0/123 (0%)		1/124 (0.8%)
Infection with unknown ANC: Urinary tract NOS	1/123 (0.8%)		1/124 (0.8%)
Pneumonia NOS	2/123 (1.6%)		2/124 (1.6%)
Sepsis NOS	1/123 (0.8%)		1/124 (0.8%)
Skin infection	1/123 (0.8%)		0/124 (0%)
Wound infection	1/123 (0.8%)		0/124 (0%)
Injury, poisoning and procedural complications
Fracture NOS	2/123 (1.6%)		3/124 (2.4%)
Investigations
Activated partial thromboplastin time prolonged	0/123 (0%)		1/124 (0.8%)
Blood alkaline phosphatase increased	1/123 (0.8%)		1/124 (0.8%)
Blood creatinine increased	4/123 (3.3%)		3/124 (2.4%)
Leukopenia NOS	2/123 (1.6%)		1/124 (0.8%)
Lymphopenia	0/123 (0%)		1/124 (0.8%)
Metabolic/laboratory - Other:	1/123 (0.8%)		0/124 (0%)
Neutrophil count	2/123 (1.6%)		2/124 (1.6%)
Platelet count decreased	1/123 (0.8%)		7/124 (5.6%)
Prothrombin time prolonged	1/123 (0.8%)		1/124 (0.8%)
Troponin T increased	1/123 (0.8%)		0/124 (0%)
Metabolism and nutrition disorders
Anorexia	1/123 (0.8%)		0/124 (0%)
Dehydration	4/123 (3.3%)		4/124 (3.2%)
Hypercalcaemia	0/123 (0%)		1/124 (0.8%)
Hyperglycaemia NOS	1/123 (0.8%)		1/124 (0.8%)
Hyperkalaemia	0/123 (0%)		2/124 (1.6%)
Hypoalbuminemia	2/123 (1.6%)		2/124 (1.6%)
Hypocalcemia	2/123 (1.6%)		1/124 (0.8%)
Hypokalemia	2/123 (1.6%)		0/124 (0%)
Hyponatremia	2/123 (1.6%)		0/124 (0%)
Musculoskeletal and connective tissue disorders
Bone pain	2/123 (1.6%)		1/124 (0.8%)
Chest wall pain	1/123 (0.8%)		0/124 (0%)
Muscle weakness NOS	2/123 (1.6%)		1/124 (0.8%)
Osteonecrosis	1/123 (0.8%)		2/124 (1.6%)
Osteoporosis NOS	0/123 (0%)		1/124 (0.8%)
Pain in extremity	1/123 (0.8%)		0/124 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain	2/123 (1.6%)		1/124 (0.8%)
Nervous system disorders
Ataxia	2/123 (1.6%)		1/124 (0.8%)
Cerebral ischaemia	1/123 (0.8%)		2/124 (1.6%)
Depressed level of consciousness	0/123 (0%)		1/124 (0.8%)
Dizziness	3/123 (2.4%)		0/124 (0%)
Headache	1/123 (0.8%)		0/124 (0%)
Neurology - Other:	1/123 (0.8%)		0/124 (0%)
Peripheral motor neuropathy	2/123 (1.6%)		0/124 (0%)
Peripheral sensory neuropathy	3/123 (2.4%)		0/124 (0%)
Syncope vasovagal	0/123 (0%)		1/124 (0.8%)
Psychiatric disorders
Confusional state	1/123 (0.8%)		1/124 (0.8%)
Renal and urinary disorders
Bladder obstruction	0/123 (0%)		1/124 (0.8%)
Renal failure NOS	2/123 (1.6%)		1/124 (0.8%)
Renal/genitourinary - Other:	1/123 (0.8%)		1/124 (0.8%)
Urethral obstruction	0/123 (0%)		1/124 (0.8%)
Urinary incontinence	0/123 (0%)		1/124 (0.8%)
Urinary retention	0/123 (0%)		1/124 (0.8%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome	0/123 (0%)		1/124 (0.8%)
Cough	2/123 (1.6%)		0/124 (0%)
Dyspnoea	5/123 (4.1%)		3/124 (2.4%)
Hypoxia	3/123 (2.4%)		1/124 (0.8%)
Pleural effusion	0/123 (0%)		2/124 (1.6%)
Pneumonitis NOS	5/123 (4.1%)		2/124 (1.6%)
Pulmonary/upper respiratory - Other:	0/123 (0%)		2/124 (1.6%)
Skin and subcutaneous tissue disorders
Ulceration:	1/123 (0.8%)		0/124 (0%)
Vascular disorders
Hypotension NOS	5/123 (4.1%)		2/124 (1.6%)
Thrombosis	0/123 (0%)		2/124 (1.6%)
Other (Not Including Serious) Adverse Events
	Zoledronic Acid		Zoledronic Acid + Radiopharmaceuticals
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	102/123 (82.9%)		108/124 (87.1%)
Blood and lymphatic system disorders
Hemoglobin	56/123 (45.5%)		73/124 (58.9%)
Eye disorders
Ocular/visual - Other:	6/123 (4.9%)		3/124 (2.4%)
Gastrointestinal disorders
Abdominal pain NOS	8/123 (6.5%)		9/124 (7.3%)
Constipation	29/123 (23.6%)		26/124 (21%)
Diarrhoea NOS	19/123 (15.4%)		18/124 (14.5%)
Dry mouth	2/123 (1.6%)		6/124 (4.8%)
Dyspepsia	7/123 (5.7%)		3/124 (2.4%)
Nausea	30/123 (24.4%)		31/124 (25%)
Stomatitis	7/123 (5.7%)		9/124 (7.3%)
Vomiting NOS	12/123 (9.8%)		19/124 (15.3%)
General disorders
Chest pain	11/123 (8.9%)		2/124 (1.6%)
Disease progression NOS	4/123 (3.3%)		6/124 (4.8%)
Edema: limb:	28/123 (22.8%)		25/124 (20.2%)
Fatigue	68/123 (55.3%)		77/124 (62.1%)
Pain - Other:	13/123 (10.6%)		8/124 (6.5%)
Pain NOS	10/123 (8.1%)		4/124 (3.2%)
Pyrexia	5/123 (4.1%)		7/124 (5.6%)
Infections and infestations
Pneumonia NOS	1/123 (0.8%)		6/124 (4.8%)
Respiratory tract infection NOS	1/123 (0.8%)		6/124 (4.8%)
Injury, poisoning and procedural complications
Ecchymosis	2/123 (1.6%)		7/124 (5.6%)
Fracture NOS	6/123 (4.9%)		4/124 (3.2%)
Investigations
Alanine aminotransferase increased	12/123 (9.8%)		14/124 (11.3%)
Aspartate aminotransferase increased	23/123 (18.7%)		21/124 (16.9%)
Blood alkaline phosphatase increased	31/123 (25.2%)		27/124 (21.8%)
Blood bilirubin increased	7/123 (5.7%)		5/124 (4%)
Blood creatinine increased	31/123 (25.2%)		28/124 (22.6%)
Leukopenia NOS	26/123 (21.1%)		42/124 (33.9%)
Lymphopenia	13/123 (10.6%)		13/124 (10.5%)
Neutrophil count	15/123 (12.2%)		32/124 (25.8%)
Platelet count decreased	19/123 (15.4%)		52/124 (41.9%)
Weight decreased	16/123 (13%)		22/124 (17.7%)
Weight increased	2/123 (1.6%)		8/124 (6.5%)
Metabolism and nutrition disorders
Anorexia	23/123 (18.7%)		29/124 (23.4%)
Dehydration	8/123 (6.5%)		5/124 (4%)
Hypercalcaemia	10/123 (8.1%)		4/124 (3.2%)
Hyperglycaemia NOS	38/123 (30.9%)		32/124 (25.8%)
Hyperkalaemia	10/123 (8.1%)		9/124 (7.3%)
Hypoalbuminemia	26/123 (21.1%)		20/124 (16.1%)
Hypocalcemia	17/123 (13.8%)		26/124 (21%)
Hypokalemia	8/123 (6.5%)		13/124 (10.5%)
Hyponatremia	16/123 (13%)		16/124 (12.9%)
Musculoskeletal and connective tissue disorders
Arthralgia	25/123 (20.3%)		29/124 (23.4%)
Arthritis NOS	6/123 (4.9%)		6/124 (4.8%)
Back pain	39/123 (31.7%)		37/124 (29.8%)
Bone pain	40/123 (32.5%)		46/124 (37.1%)
Muscle weakness NOS	9/123 (7.3%)		10/124 (8.1%)
Muscle weakness, generalized or specific area (not due to neuropathy): Extremity-lower	6/123 (4.9%)		7/124 (5.6%)
Musculoskeletal/soft tissue - Other:	3/123 (2.4%)		8/124 (6.5%)
Myalgia	12/123 (9.8%)		12/124 (9.7%)
Neck pain	9/123 (7.3%)		8/124 (6.5%)
Pain in extremity	18/123 (14.6%)		20/124 (16.1%)
Nervous system disorders
Dizziness	21/123 (17.1%)		18/124 (14.5%)
Dysgeusia	8/123 (6.5%)		3/124 (2.4%)
Headache	15/123 (12.2%)		14/124 (11.3%)
Peripheral motor neuropathy	7/123 (5.7%)		2/124 (1.6%)
Peripheral sensory neuropathy	23/123 (18.7%)		18/124 (14.5%)
Psychiatric disorders
Anxiety	6/123 (4.9%)		9/124 (7.3%)
Depression	11/123 (8.9%)		12/124 (9.7%)
Insomnia	12/123 (9.8%)		19/124 (15.3%)
Renal and urinary disorders
Pollakiuria	9/123 (7.3%)		14/124 (11.3%)
Renal/genitourinary - Other:	4/123 (3.3%)		6/124 (4.8%)
Urinary incontinence	8/123 (6.5%)		6/124 (4.8%)
Urinary retention	5/123 (4.1%)		7/124 (5.6%)
Reproductive system and breast disorders
Pelvic pain NOS	8/123 (6.5%)		5/124 (4%)
Respiratory, thoracic and mediastinal disorders
Cough	17/123 (13.8%)		13/124 (10.5%)
Dyspnoea	26/123 (21.1%)		32/124 (25.8%)
Pulmonary/upper respiratory - Other:	4/123 (3.3%)		8/124 (6.5%)
Skin and subcutaneous tissue disorders
Alopecia	8/123 (6.5%)		12/124 (9.7%)
Dermatitis exfoliative NOS	7/123 (5.7%)		2/124 (1.6%)
Dermatology/skin - Other:	9/123 (7.3%)		6/124 (4.8%)
Localised exfoliation	4/123 (3.3%)		6/124 (4.8%)
Vascular disorders
Hot flushes NOS	16/123 (13%)		17/124 (13.7%)
Hypertension NOS	6/123 (4.9%)		4/124 (3.2%)
Hypotension NOS	4/123 (3.3%)		7/124 (5.6%)

Limitations/Caveats

This study stopped accrual early with 261 accrued out of 352 planned, due to a lower than expected rate of skeletal related events in the control arm.

More Information

Certain Agreements

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

PI's are required to abide by the sponsor's publication guidelines which require review by coauthors and subsequent review and approval by the sponsor.