Study reference

Study characteristics

Patient characteristics ²

Intervention (I)

Comparison / control (C) ³

Follow-up

Outcome measures and effect size ⁴

Comments

Bilen, 2015

Type of study:

Multicenter randomized phase II study (Strontium)

Setting and country:

Advanced castrate-sensitive prostate cancer

USA

Funding and conflicts of interest:

This study was conducted as a collaborative trial of the MD Anderson Cancer Center Community Clinical Oncology Program Research Base and MD Anderson Cancer Center. The study was supported in part by NCI grant U10 CA045809. MD Anderson is supported in part by the National Institutes of Health through Cancer Center Support Grant, CA016672

The authors made no disclosures.

Inclusion criteria:

• Castrate-sensitive prostate cancer metastatic to bone;
• ECOG performance status ≤ 3 (Karnofsky ≥40%); initiation of hormonal ablative therapy within 3 months of registration;
• Any previous neoadjuvant, concurrent, or intermittent hormonal ablative therapy to have been less than 3 years’ duration and completed at least 3 years prior to entry into this study;
• Normal organ and marrow function as defined by laboratory values.

Exclusion criteria:

• More than one prior chemotherapy regimen;
• Prior radioisotope treatment with Sr-89 or samarium-153, zoledronic acid treatment of more than 3 months’ duration prior to registration;
• Corrected serum calcium levels <8 mg/dL
• Receiving any other investigational agents at the time of enrolment;
• Known brain metastases;
• Predominantly visceral metastasis;
• Small-cell carcinoma;
• Serious illness or major dysfunction;
• HIV-positive patients receiving combination anti-retroviral therapy.

N total at baseline:

Intervention: 39

Control: 40

Important prognostic factors²:

Age, range (median):

I: 46-77 (62)

C:46-82 (63)

Groups comparable at baseline?

Yes

Standard therapy:
Androgen deprivation therapy, doxorubicin, and zoledronic acid.

+

1 dose of Sr-89 (4 mCi total dose) administered intravenously on the first day of treatment

Standard therapy:
Androgen deprivation therapy, doxorubicin, and zoledronic acid.

+

no Sr-89

Length of follow-up:

Median follow-up for the patients alive at the last follow-up: 76.9 (range: 0.07 – 103.4 months)

Loss-to-follow-up:

Intervention:

2 (5.1%)

Reason: not described

Control:

1 (2.5%)

Reason: not described

Incomplete outcome data:

Intervention:

None

Control:

4 (10%)

Reasons:
Withdrew consent prior to treatment (n=3)

Myelosuppression prior to treatment (n=1)

Outcome measures and effect size (include 95%CI and p-value if available):

Pain

Not reported

Treatment-related toxicity (Grade 3 or 4)

C: 3 (7.5%)

I:  3 (7.6%)

Quality of life

Not reported

Agarwal, 2015

Type of study:

Randomized phase II study

Setting and country:

Palliation of pain from bone metastases in patients with prostate and breast cancer

India (Mumbai)

Funding and conflicts of interest:

No funding received from any organization for this study.

The authors declare no conflict of interest.

Inclusion criteria:

• Patients suffering from multifocal pain and two or more sites of painful bone metastases corresponding to positive sites on recent 99mTc-methylene diphosphonate skeletal scintigraphy (within 4 weeks or less)
• Local external-beam radiation and previous treatment with bisphosphonates was permitted provided the time to 177Lu-EDTMP treatment was at least 4 weeks.

Exclusion criteria:

• Patients with leucocyte and thrombocyte counts below 4.0× 109 /L and 100×109 /L, respectively, or with impaired renal function (creatinine >1.5 mg/dL)
• Pain caused by pathological fracture, infiltration of a nerve plexus, or peripheral nerves

N total at baseline:

Intervention: 22

Control: 22

Important prognostic factors²:

Age, mean (SD):

I: 61 (14)

C:60 (13)

Primary (prostate/breast), n

I: 17/5

C: 15/7

Groups comparable at baseline?

Yes

Group A received a low dose (1,295 MBq).

Group B received a high dose (2,590 MBq)

Length of follow-up:

16 weeks

Loss-to-follow-up:

Not reported

Incomplete outcome data:

Not reported

Outcome measures and effect size (include 95%CI and p-value if available):

Pain

VAS decrease* (mean, SD)

I:

Baseline: 6.5 (1.6)

16 weeks: 3.8 (2.1)

P<0.001

C:

Baseline:: 7.0 (1.3)

16 weeks:3.3 (1.2)

P<0.001

No group differences (p value not reported)

Quality of life

Karnofsky performance score (mean, SD)

I:

Baseline: 56.5 (5)

16 weeks: 73 (9)

P<0.001

C:

Baseline: 57 (5)

16 weeks: 76 (5)

P<0.001

No group differences (p=0.498)

Pain relief was assessed in terms of changes in the average baseline VAS in comparison with the average VAS at 1, 2, 4, 6, 8, 12 and 16 weeks after injection.

*The VAS in 32 prostate cancer patients decreased from 6.9±1.5 to 3.4±1.8. Similarly, the VAS in 12 breast cancer patients decreased from 6.5±1.1 to 3.7±1.3.

Heery, 2018

Type of study:

Randomized phase III study

Setting and country:

Palliation of osteoblastic metastases from lung, breast, and prostate cancer

USA

Funding and conflicts of interest:

This project was supported by RTOG grant U10 CA21661 and CCOP grant U10 CA37422 from the National Cancer Institute (NCI). Additional support was provided by Novartis.

Conflicts of interest not reported. 

Inclusion criteria:

• histologically proven cancer of the prostate, breast or lung with confirmed osteoblastic bone metastases;
• No current symptoms or stable pain from their bone disease;
• A positive bone scan obtained four weeks prior to study entry; 
• Adequate bone marrow function to permit radioisotope administration and adequate renal function to permit zoledronic acid (ZA) infusion.
• Dental evaluation and clearance;
• ECOG performance status had to be 2 or better for prostate and breast cancer patients but limited to 0 or 1 for lung cancer patients

Exclusion criteria:

• Subjects with a history of prior allergy or severe reaction to vaccinia-based vaccination or an open skin wound

N total at baseline:

Intervention: 22

Control: 22 

Important prognostic factors²:

Age, mean (range):

I: 69.2 (52-86)

C:64.5 (50-80)

Groups comparable at baseline?

Yes

Sm-153-EDTMP plus vaccine

Sm-153-EDTMP

Length of follow-up:

Not reported

Loss-to-follow-up:

Not reported

Incomplete outcome data:

Intervention:

1 (4.%)

Reasons:

Did not progress, refused further treatment on day 70 due to toxicity (n=1)

Control:

4 (18.2%)

Reasons:

Refused treatment after randomization (n=3)

Did not progress,, refused further treatment on day 70 due to toxicity (n=1)

Outcome measures and effect size (include 95%CI and p-value if available):

Pain

Subjects requiring narcotic pain:

I: 8/22 (36%)

C: 11/19 (58%)

P=0.22

Quality of life

Not reported

Although the trial was designed to enroll 68 patients, the study was ended early due to poor accrual.

Seider, 2018

Type of study:

Randomized phase III study

Setting and country:

Metastatic castration-resistant prostate cancer

USA

Funding and conflicts of interest:

Funding for this study was provided through the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health, and the Cancer Therapy Evaluation Program (CTEP), National Cancer Institute, National Institutes of Health.

The authors declare no conflict of interest.

Inclusion criteria:

• mCRPC with bone metastases as determined by CT and/or bone scan;
• No visceral metastases were allowed, but small, asymptomatic lymph nodes were allowed;
• Previous treatment with docetaxel was required, and there were no limits on the number of prior chemotherapy or hormonal therapy regimens allowed for enrolment;
• Prior treatment with Sm-153-EDTMP was not allowed;
• Required to remain on testosterone-suppressing therapy unless they were surgically rendered castrate;
• ≥ 18 years of age;
• Acceptable hematologic parameters and organ function;
• ECOG performance status of ≤ 2;
• No other malignancies within 12 months, or significant medical illnesses or autoimmune diseases;
• No systemic steroid use within 2 weeks of enrollment

Exclusion criteria:

• Not specified

N total at baseline:

Intervention: 132

Control: 129

Important prognostic factors²:

Age, median (range):

I: 68 (32-90)

C:67.5 (25-88)

Primary disease:

Breast/Lung/Prostate

I: 44/12/68

C: 42/14/68

Groups comparable at baseline?

Yes

Standard therapy: Patients received ZA 4 mg IV monthly

+ a single injection of either 4 mCi Sr-89 or 1 mg/kg body weight of Sm-153 and zoledronic acid

Standard therapy:
Patients received ZA 4 mg IV monthly

+ zoledronic acid

Length of follow-up:

Not reported

Loss-to-follow-up:

Not reported

Incomplete outcome data:

Intervention:

8 (6.1%)

Reasons:

Invalid bone scan date (n=3)

Unstable bone metastases (n=2)

Dental disease (n=1)

Institution registration error (n=1)

Radiation out of time frame (n=1)

Control:

5 (3.9%)

Reasons:

Invalid bone scan date (n=2)

ANC levels (n=2)

Unstable bone metastases (n=1)

Outcome measures and effect size (include 95%CI and p-value if available):

Pain & Quality of life*

No quantitative data was presented

Description of the author:

“The addition of radiopharmaceuticals to ZA led to a significant reduction in pain at one month based on BPI* worst score (p=0.02). No other group differences were noted for QOL or toxicity.”

*Brief Pain Inventory

*Differences in QOL and pain control between treatment arms were examined using the mean FACT-G scores (total score as well as the four subscale scores) and mean BPI score from baseline to each follow-up assessment time.

Sharma, 2017

Type of study:

Randomized study

Setting and country:

Pain palliation in patients with skeletal metastases (breast/prostate cancer)

India

Funding and conflicts of interest:

Funding not reported

The authors declare no conflict of interest.

Inclusion criteria:

• Positive 99mTc-MDP bone scanning;
• Not having received chemotherapy or external beam therapy during the last 4-12 weeks;
• Normal hematological/renal parameters

Exclusion criteria:

• Absolute contraindications for pregnancy/ lactation;
• Pre-existing cytopenia;
• Super “bone scan appearance”;
• Any previous documented history of hypersensitivity or reaction to radionuclide/radiopharmaceutical administration

N total at baseline:

Intervention: 20

Control: 10

Important prognostic factors²:

Demographic characteristics were not reported/stratified for both groups.

Thirty patients (25 M:5 F, mean age: 66.0 ± 14.7 years) of breast/ prostate cancer with documented skeletal metastases were recruited.

Primary disease was not stratified for both groups.

Groups comparable at baseline?

Unable to make a judgement.

¹⁵³Sm-EDTMP

Radiopharmaceuticals were given at a dose of 37.0 MBq / kg body weight in both groups

¹⁷⁷Lu-EDTMP

Radiopharmaceuticals were given at a dose of 37.0 MBq / kg body weight in both groups

Length of follow-up:

8 weeks

Loss-to-follow-up:

Not reported

Incomplete outcome data:

Not reported

Outcome measures and effect size (include 95%CI and p-value if available):

Pain*

Responders

I: 16/20 (80%)

C: 8/10 (80%)

Pain change

(8 weeks from baseline)

I: 1.31 ± 0.48

C: 1.63 ± 0.52

Quality of life

Not reported

*The therapeutic efficacy of each of the two radionuclides at post-therapy periods of 1, 3, 6, and 8 weeks was evaluated by using WHO-standard pain scoring assessment criteria. Based upon this assessment, the response was labelled as (a) complete response when the pain score was <3.0, (b) partial response when the pain score ranged between 4 and 8, and (c) no response when the pain score was >8.0 and had no change from baseline score.

Van Dodewaard-de Jong , 2018

Type of study:

Randomized phase II study

Setting and country:

Castration-resistant prostate cancer (CRPC) metastatic to bone

The Netherlands

Funding and conflicts of interest:

Funding for this study was provided by KWF kankerbestrijding with. The authors transparently provided their conflict of interests. 

Inclusion criteria:

• Histologically documented prostate carcinoma and evidence of disease progression (either biochemical or radiological) desspite castration-levels of testosterone;
• Previous exposure to docetaxel or rhenium-188-HEDP was not allowed;
• Bone metastases showing uptake at bone scintigraphy;
• PSA progression was defined as a minimum increase of PSA of 25% over a reference value, provided that the increase was at least 2 ng/mL;
• Anti-androgens needed to be discontinued before starting therapy at least 4 weeks before enrolment for patients with prior history of response to anti-androgens;
• Age ≥18 years;
• World Health Organization performance score 0 or 1;
• Life expectancy of at least 3 months;
• Absolute neutrophil count ≥1.5 × 109 /L, platelet count ≥100 × 109 /L, adequate renal function

Exclusion criteria:

• Not specified

N total at baseline:

Intervention: 46

Control: 42

Important prognostic factors²:

Age, median (range):

I: 70.5 (54.1-84.9)

C:71.4 (64.1-84.9)

Groups comparable at baseline?

Yes

Docetaxel and rhenium-188-HED

Docetaxel

Length of follow-up:

Median follow-up 18.4 months

Loss-to-follow-up:

Not reported

Incomplete outcome data:

Eight patients in the experimental group did not receive rhenium-188-HEDP at all, whereas in the standard group three patients dropped out before the fourth cycle of docetaxel.

.

Outcome measures and effect size (include 95%CI and p-value if available):

Pain & Quality of life*

Data was visualised with box plots

 “At baseline, VAS-scores for pain assessment were available for 83 patients. After five cycles data on pain were available for 64 patients (31 in the control group and 34 in the experimental group) and after 10 cycles only for 43 patients (20 in the control group and 23 in the experimental group). In both groups median VAS-scores were already low”

“There was no significant change in global quality of life during the whole treatment period.”

*Patients completed a visual analogue scale (VAS) pain assessment and the EORTC-Quality of Life Questionnaire-30 before each treatment cycle until disease progression

Van Winter, 2022

Type of study:

Randomized phase IB and IIA study

Setting and country:

Breast cancer patients with bone metastases

UK

Funding and conflicts of interest:

The study was funded by Bayer Healthcare, supported by Yorkshire Cancer Research (YCR) through the YCR Centre for Early Phase Clinical Trials, and sponsored by the University of Sheffield. Additional support was also provided by the National Institute for Health Research (NIHR) through the use of the Clinical Research Network (CRN).

The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report

The authors transparently provided their conflict of interests. 

Inclusion criteria:

• Histological evidence of primary breast cancer with imaging evidence of bone metastases, with or without soft tissue or visceral metastases;
• Systemic chemotherapy with capecitabine had to be considered appropriate;
• Not have received more than two lines of chemotherapy in the metastatic setting;
• Prior cytotoxic therapy should have been completed 28 days or more prior to initiation of study treatment;
• Currently on a bisphosphonate/

denosumab for ≥ 6 weeks;

• ECOG-performance status of 0–2;
• Adequate haematological and biochemical parameters prior to commencing treatment.

Exclusion criteria:

• Severe and unexpected reaction to previous fluoropyrimidine therapy;
• Diagnosed with dihydropyrimidine dehydrogenase deficiency;
• Received external beam radiotherapy or an investigational drug within four weeks prior to the first study treatment;
• Imminent or established spinal cord compression based on clinical findings and/or MRI;
• Any other serious illness or medical condition thought likely to compromise safe study participation

N total at baseline:

Intervention: 25

Control: 6

Important prognostic factors²:

Age, median (range):

I: 58 (34-75)

C:55 (45-85)

Groups comparable at baseline?

Yes

Capecitabine + Ra²²³

Capecitabine

Length of follow-up:

Median follow-up, months

I:  11.5 (3.4-23.3)

C: 13.5 (3.4-21.1)

Loss-to-follow-up & incompete outcome data:

I: 15/23 (65.2%)

Reasons:

Disease progression (n=13)

Intolerability due to toxicities (n=2)

C: -

Outcome measures and effect size (include 95%CI and p-value if available):

Pain

Quality of life

QLQ-C30 at end of cyclus 6*

I: 82.1 (79.2-85.1)

C: 67.6 (55.6-79.7)

“The mean QLQ-C30 global health status was similar between the arms at baseline and end of study visit, but slightly increased in the capecitabine alone arm at cycle 6 (mean [95% CI]: 67.6 [55.6–79.7] combination arm and 82.1 [79.2–85.1] capecitabine alone arm), although numbers are small (combination = 17 capecitabine alone = 7).”

*Baseline QLQ-C30 global health status was not reported.

Study reference

(first author, publication year)

Was the allocation sequence adequately generated?

Definitely yes

Probably yes

Probably no

Definitely no

Was the allocation adequately concealed?

Definitely yes

Probably yes

Probably no

Definitely no

Blinding: Was knowledge of the allocated

interventions adequately prevented?

Were patients blinded?

Were healthcare providers blinded?

Were data collectors blinded?

Were outcome assessors blinded?

Were data analysts blinded?

Definitely yes

Probably yes

Probably no

Definitely no

Was loss to follow-up (missing outcome data) infrequent?

Definitely yes

Probably yes

Probably no

Definitely no

Are reports of the study free of selective outcome reporting?

Definitely yes

Probably yes

Probably no

Definitely no

Was the study apparently free of other problems that could put it at a risk of bias?

Definitely yes

Probably yes

Probably no

Definitely no

Overall risk of bias

If applicable/necessary, per outcome measure

LOW

Some concerns

HIGH

Bilen, 2015

Probably no;

Reason: Study-eligible patients were randomized immediately upon entry to the trial

Probably no;

Reason: Study-eligible patients were randomized immediately upon entry to the trial to receive either (sequentially numbered)

Definitely no;

Reason: Open-label trial

Probably yes;

Reason: Loss to follow-up was infrequent in intervention and control group.

Definitely yes;

Reason: All relevant outcomes were reported

Definitely yes;

Reason: No other problems noted

Some concerns

Agarwal, 2014

Probably no;

Reason: Patients were randomly assigned to two groups based on administered radioactivity.

Probably no;

Reason: Patients were randomly assigned to two groups based on administered radioactivity (sequentially numbered).

Definitely no;

Reason: Open-label trial.

Probably yes;

Reason: Loss to follow-up was not reported.

Definitely yes;

Reason: All relevant outcomes were reported.

Definitely yes;

Reason: No other problems noted.

Some concerns

Heery, 2016

Definitely yes;

Reason: Patients were randomized centrally, without stratification, using a locally-written SAS software program to generate a random 1:1 sequence of assignments to treatment, using variable block sizes (2 or 4).

Probably yes

Reason: Central allocation.

Definitely no;

Reason: Open-label trial.

Probably no

Reason: Loss to follow-up was higher in the control group.

Definitely yes;

Reason: All relevant outcomes were reported.

Definitely no;

Reason:

Although the trial was designed to enroll 68 patients, the study was ended early due to poor accrual.

HIGH

Seider, 2018

Definitely yes;

Reason: Patients were stratified by site of primary cancer (lung vs. breast, vs. prostate) and number of bone mets (≤2 vs. > 2) and randomized 1:1 using a treatment allocation scheme. 

Probably yes

Reason: Central allocation.

Definitely no;

Reason: Open-label trial.

Probably no;

Reason: Loss to follow-up was not reported

Probably yes;

Reason: All relevant outcomes were reported.

Probably yes;

Reason: The patient population in this study was somewhat different from previous trials in that blastic metastases from three different primary disease sites (prostate, breast and lung) were included.

The secondary outcomes were not quantitively reported.

HIGH

Sharma, 2017

Definitely no;

Reason: Randomization method not described.

Definitely  no:

Reason: Allocation was based on open random allocation schedule. 

Probably no;

Reason: Only patients were blinded to treatment.

Probably no;

Reason: Loss to follow-up was not reported.

Definitely yes;

Reason: All relevant outcomes were reported.

Probably no;

Reason: Demographics were not reported, funding was not reported.

HIGH

van Dodewaard-de Jong, 2018

Definitely no;

Reason: Randomization method not described.

Definitely  no:

Reason: Patients were centrally randomly assigned. 

Definitely no;

Reason: Open-label trial.

Probably no;

Reason: Loss to follow-up was infrequent. A high percentage in the experimental group did not receive the treatment at all.

Definitely yes;

Reason: All relevant outcomes were reported.

Probably no;

Reason: The outcomes pain and quality of life were not reported quantitively.

HIGH

Winter, 2022

Probably yes;

Reason: Participants were randomised 2:1 to the combination and single agent capecitabine using the CTRU 9-to-5 randomisation service, via permuted blocks.

Definitely  no:

Reason: Patients were allocated via permuted blocks.

Definitely no;

Reason: Open-label trial.

Definitely no;

Reason: A high percentage in the experimental group were lost-to-follow up due to disease progression or toxicities. 

Probably yes;

Reason: All relevant outcomes were reported, but no baseline values of quality of life were reported.

Probably no;

Reason: The baseline values of quality of life were not reported quantitively.

HIGH