Cardiovasc Intervent Radiol (2023) 46:1469–1482

https://doi.org/10.1007/s00270-022-03356-z

REVIEW

Cryoablation for the Palliation of Painful Bone Metastasis:

A Systematic Review
Shaghayegh Khanmohammadi1,2 • Alireza Noroozi3 • Mir Saeed Yekaninejad4 •

Nima Rezaei1,2,5

Received: 28 October 2022 / Accepted: 28 December 2022 / Published online: 11 January 2023
 Springer Science+Business Media, LLC, part of Springer Nature and the Cardiovascular and Interventional Radiological Society of Europe
(CIRSE) 2023

Abstract
Background Cryoablation is a minimally invasive proce-
dure to treat painful bone metastases in patients with can-
cer. We designed a systematic review to understand the
safety and effects of cryoablation on the pain and quality of
life (QoL) of cancer patients.
Method We searched PubMed, ISI, Cochrane library, and
Scopus databases using the keywords ‘‘Cryoablation,’’
‘‘Pain,’’ and ‘‘Bone metastasis.’’ Inclusion criteria were: (1)
Original studies published until September 8, 2022; (2)
studies on patients over 18 years and affected by bone
metastasis; (3) bone metastasis treated with stand-alone
cryoablation; (4) studies reporting patients’ pain before and
at least one time-point following cryoablation; and (5)
English-language studies.
Results We screened 696 articles. Fifteen studies on 376
patients were included. Time points for pain assessment
ranged from 1 day to 6 months. Spine was the most fre-
quent treated location. All studies reported a significant
pain reduction between 1 day and 6 months after the
cryoablation procedure. The highest mean difference
between pre- and post-procedure scores was 5.8 (VAS
scale) after 4 weeks. The overall rate of minor and major
complications was 12.74%. Cryoablation improved the
QoL of cancer patients and decreased the need for
analgesics.
Conclusion Cryoablation is a safe and useful procedure for
palliating painful bone metastasis and increasing the QoL
of cancer patients. Future studies should adopt a stan-
dardized pain reporting scale to allow for meta-analysis.
Keywords Cryoablation
Thermal ablation
Bone
metastasis
Interventional radiology
Pain

Palliative therapy

& Mir Saeed Yekaninejad

yekaninejad@yahoo.com
& Nima Rezaei
rezaei_nima@yahoo.com Introduction
1
Research Center for Immunodeficiencies, Children’s Medical
Center, Tehran University of Medical Sciences, Qarib St., Metastasis is one of the main reasons for the failure of
Keshavarz Blvd., Tehran, Iran cancer therapy and death in patients with cancer [1]. Bone
2
Network of Immunity in Infection, Malignancy and is the third most common site for cancer metastasis. Bone
Autoimmunity (NIIMA), Universal Scientific Education and metastasis results in various complications, including sev-
Research Network (USERN), Tehran, Iran ere pain, pathologic fractures, bone marrow aplasia, spinal
3
School of Medicine, Islamic Azad University, Tehran, Iran cord compression, and hypercalcemia. Bone pain is the
4
Department of Epidemiology and Biostatistics, School of most common pain resulting from cancer, which is highly
Public Health, Tehran University of Medical Sciences, suggestive of bone metastasis [2]. Painful bone metastasis
Poursina St., Keshavarz Blvd., Tehran, Iran reduces the QoL of patients with cancer. Thus, pain man-
5
Department of Immunology, School of Medicine, Tehran agement and local tumor control are of importance in
University of Medical Sciences, Tehran, Iran

123
1470 S. Khanmohammadi et al.: Cryoablation for the Palliation of Painful Bone Metastasis…
patients with cancer in order to improve the QoL of the
patients [3].
Pain palliation methods notably include analgesics (e.g.,
opioids and non-steroidal anti-inflammatory drugs), anti-
cancerous systemic therapies (e.g., chemotherapy), and
radiotherapy, alone or in combination with other tech-
niques in patients with painful bone metastasis; however,
not all patients benefit from the aforementioned methods,
and they may show a partial response or no response [4].
Besides, surgery is of limited value as it is an aggressive
method in frail patients. Several minimally invasive inter-
ventional techniques are used to palliate pain in patients
with bone metastasis. Thermal ablation, embolization, and
cement osteoplasty are among the minimally invasive
treatments for painful bone metastasis, which have shown
promising results [5]. Thermal ablation uses extreme heat
(e.g., radiofrequency ablation [RFA]) or cold (e.g.,
cryoablation). The visibility of the ice ball, large ablations,
and less pain are the main advantages of cryoablation over
other thermal ablation modalities [6].
Previous studies have demonstrated the efficacy of
cryoablation in improving QoL and reducing pain and the
need for analgesics in patients with painful bone metastasis
[7, 8]. However, most studies on cryoablation in the setting
of painful bone metastasis have small study populations.
Therefore, we performed a systematic literature search to
understand the sole effects of percutaneous cryoablation in
terms of analgesia and safety for pain palliation in patients
with painful bone metastasis.
Methods
This review was conducted in compliance with the review
protocol registered on PROSPERO, PROSPERO 2022
CRD42022358768. This study followed the guidelines in
the Preferred Reporting Items for Systematic Reviews and
Meta-Analyses (PRISMA) Statement [9].
Literature Search
We systematically searched the electronic databases
PubMed, Web of Science (ISI), SCOPUS, and Cochrane
library for original articles from inception to September 8,
2022. We built our search strategy in PubMed and subse-
quently searched other databases through the following
medical subject headings (MeSH) terms and free key-
words: ‘‘Cryoablation,’’ ‘‘Pain,’’ ‘‘Bone metastasis,’’
‘‘Metastasis,’’ ‘‘Neoplasm,’’ and their expansions. The
search strategy is available in the Supplementary Material.
We transferred all records to EndNote software 20 and
removed the duplicates.
123
Selection Criteria
We included the studies that met all the following criteria
in the final analysis: (1) randomized controlled or non-
randomized studies with a prospective or retrospective
design; (2) studies on patients over 18 years and affected
by bone metastasis (solitary or multiple); (3) bone metas-
tasis treated with cryoablation; (4) studies reporting
patients’ pain before and at least one time-point following
cryoablation; and (5) English-language studies.
We excluded case reports, letters, editorials, book
chapters, commentary articles, review articles, and con-
ference abstracts. Papers reporting the efficacy of cryoab-
lation in combination with other therapies, notably cement
osteoplasty and radiotherapy, were also excluded.
Two reviewers screened all the titles and abstracts
independently for paper selection. After the collection of
eligible studies, a comprehensive full-text review and data
extraction were conducted by two authors independently.
The third reviewer resolved conflicts in the title/abstract
screening.
Data Extraction
The full text of all included papers was reviewed com-
prehensively by two reviewers to extract specific data in a
dedicated electronic spreadsheet (Excel 2016; Microsoft).
Conflicts were resolved through consensus. For each
included study, the following data were extracted when
available: author name, publication year, sample size by
sex, mean age (range and SD), number of lesions, lesion
location, primary tumor, follow-up period, time points for
pain assessment, previous treatment, ablation cycle, pro-
cedure time (range and SD), number of cryoprobes, guid-
ance method, pain scale, baseline pain, post-operative pain
in different time points, mean difference between pre- and
post-operative scores, pain relief (i.e., no pain), changes in
the use of pain medications, change in QoL, and
complications.
Quality Assessment
We used Study Quality Assessment Tools [10] developed
by NIH for case series and before-after studies with no
control group to assess the risk of bias in the included
studies. Each criterion was answered with ‘‘Yes,’’ ‘‘No,’’ or
‘‘Other’’ (cannot determine, not applicable, not reported).
After determining the answer to each question, each study
was scored as good, fair, or poor. Two reviewers inde-
pendently rated included articles according to the NIH
checklists. We did not perform the quality assessment to
exclude studies but to clarify the robustness of the
S. Khanmohammadi et al.: Cryoablation for the Palliation of Painful Bone Metastasis… 1471

Fig. 1 PRISMA flowchart

Identification of studies via databases and registers

Records removed before

Records identified from:
screening:

Identification
Databases (Cochrane=66
Duplicate records removed
PubMed=196
(n=232)
Scopus=438
Records marked as ineligible
ISI=228
by automation tools (n=0)
Total=928)
Records removed for other
Registers (n = 0)
reasons (n=0)

Records screened Records excluded**

(n=696) (n=661)

Reports sought for retrieval Reports not retrieved

(n=35)
Screening

(n=0)

Reports excluded:
Reports assessed for eligibility
additional procedure (n=5)
(n=35)
insufficient data (n=5)
duplicate data (n=1)
Combined data with other
methods (n=3)
Terminated RCT (n=2)
combined with non-bone
metastasis (n=4)
Included

Studies included in review

(n=15)

evidence. Discordance in ratings was resolved through
discussion between the reviewers.
Statistical Analysis
Descriptive statistics were used in Microsoft Excel 2016.
We calculated the numbers and percentages for the
tables when they were not reported. The difference
between preoperative and postoperative pain scores was
calculated if not reported.
Results
Our search identified 928 publications, including 66 arti-
cles from the Cochrane library, 228 articles from Web of
Science, 196 articles from PubMed, and 438 articles from
Scopus. After removing duplicates, 696 records were
screened through title and abstract, and 661 articles were
removed. We reviewed the full-text of 35 articles and
excluded 20 articles (Supplementary Material) due to the
following reasons: (1) additional procedures (n = 5), (2)
insufficient data (n = 5), (3) duplicate data (n = 1), (4)
combined data with other methods (n = 3), (5) terminated
RCTs (n = 2), and (6) combined with non-bone metastasis
(n = 4). Finally, 15 articles were included in our study.
Figure 1 shows a flow diagram of study selection.
The result of the study quality assessment is summarized
in Table 1. Overall, based on the NIH criteria, six studies
scored as good, six studies as fair, and three studies as poor.
The baseline characteristics of the included reports are
demonstrated in Table 2. Overall nine retrospective case
series [11–19] and six prospective studies (one prospective
case series [20] and five prospective interventional studies
[7, 8, 21–23]) were included. The total number of patients,
females, and males were 376 (the smallest sample size was
7 and the largest was 66), 159, and 187, respectively; two
studies did not determine the number of either sex [12, 14].
Two studies had the same study population, but we inclu-
ded them both since they used different pain assessment

123
1472 S. Khanmohammadi et al.: Cryoablation for the Palliation of Painful Bone Metastasis…

Table 1 Quality assessment of the included studies

ID 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Questions

Prospective interventional studies

1. Was the study question or objective clearly Yes Yes Yes Yes Yes
stated?
2. Were eligibility/selection criteria for the study Yes Yes Yes Yes Yes
population prespecified and clearly described?
3. Were the participants in the study Yes Yes Yes Yes Yes
representative of those who would be eligible
for the test/service/intervention in the general
or clinical population of interest?
4. Were all eligible participants that met the Yes Yes Yes Yes Yes
prespecified entry criteria enrolled?
5. Was the sample size sufficiently large to No Yes Yes Yes Yes
provide confidence in the findings?
6. Was the test/service/intervention clearly Yes Yes Yes Yes Yes
described and delivered consistently across the
study population?
7. Were the outcome measures prespecified, Yes No Yes Yes Yes
clearly defined, valid, reliable, and assessed
consistently across all study participants?
8. Were the people assessing the outcomes No No No No No
blinded to the participants’ exposures/
interventions?
9. Was the loss to follow-up after baseline 20% No No No Yes Yes
or less? Were those lost to follow-up
accounted for in the analysis?
10. Did the statistical methods examine changes Yes Yes No No Yes
in outcome measures from before to after the
intervention? Were statistical tests done that
provided p values for the pre-to-post changes?
11. Were outcome measures of interest taken Yes Yes Yes Yes Yes
multiple times before the intervention and
multiple times after the intervention (i.e., did
they use an interrupted time-series design)?
12. If the intervention was conducted at a group NA NA NA NA NA
level (e.g., a whole hospital, a community,
etc.) did the statistical analysis consider the use
of individual-level data to determine effects at
the group level?
Prospective/Retrospective case series
1. Was the study question or objective clearly Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes
stated?
2. Was the study population clearly and fully Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes
described, including a case definition?
3. Were the cases consecutive? No No No No Yes No No Yes Yes Yes
4. Were the subjects comparable? Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes
5. Was the intervention clearly described? Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes
6. Were the outcome measures clearly defined, Yes No Yes Yes No Yes Yes Yes Yes Yes
valid, reliable, and implemented consistently
across all study participants?
7. Was the length of follow-up adequate? No No Yes NA No Yes No No Yes No
8. Were the statistical methods well-described? Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes

123
S. Khanmohammadi et al.: Cryoablation for the Palliation of Painful Bone Metastasis…
Table 1 continued
ID 1 2 3 4
Questions
9. Were the results well-described? Yes Yes
Overall score Fair Poor Poor Fair
NA Not available
systems [22, 23]. Overall, 436 lesions were treated. The
age of the included patients ranged from 20 to 95. The
follow-up period ranged from 1 day to 44 months; how-
ever, six months was the last time point assessment for
pain. Radiotherapy, chemotherapy, hormonal therapy,
immunotherapy, and surgery were among the previous
treatments of the included patients. Lung, breast, kidney,
and colorectal cancers were the most common primary
tumor sites. Spine, pelvic bone, and ribs were the most
frequent treated location.
The cryoablation procedure length ranged from 15 to
280 min. Computed tomography (CT) scan, ultrasound
(US), and fluoroscopy were used as guidance methods, but
the common guide among the included studies was CT
scan. The number of cryoprobes ranged from 1 to 11
(Table 3).
The visual analogue scale (VAS) (n = 5), brief pain
inventory-short form (BPI-SF) (n = 4), and numeric rating
scale (NRS) (n = 6) were used to measure pain in patients
(Table 4). Mean baseline VAS, NRS, and BPI-SF across
studies ranged from 6.9 to 7.5, 3.3 to 9.2, and 4.7 to 8.2,
respectively. In nine studies, changes in pain medication
intake were evaluated; five studies [7, 16, 17, 19, 20]
reported a decrease in opioid or non-opioid drugs after the
cryoablation procedure, but the others [8, 12, 18, 21]
reported no change in analgesic use.
Among the studies using the VAS scale, mean baseline
pain ranged from 6.9 to 7.5, and the highest mean differ-
ence between pre- and post-procedure scores was 5.8 four
weeks after the procedure. The highest and lowest com-
plete response (absence of pain) rates were 41.7% (week 4)
and 14.30% (week 24), respectively. The highest and
lowest partial response rate belonged to week 24 (72.2%
and 35.7%) in two different studies. The mean baseline
pain in studies using the NRS system was between 3.3 and
9.2, and the highest mean difference between pre- and post-
procedure scores was 5.3 four weeks after the procedure.
The lowest mean difference between pre- and post-proce-
dure scores was reported one day after the procedure.
Among the studies using BPI-SF mean baseline pain ran-
ged from 4.7 to 8.2, and the highest and lowest mean dif-
ference between pre- and post-procedure scores for worst
1473
5 6 7 8 9 10 11 12 13 14 15
Yes Yes No No Yes Yes Yes Yes
Fair Good Fair Good Good Poor Fair Fair Good Good Good
pain was 5.7 (week 24) and 0.9 (week 1), respectively.
Besides, the highest and lowest mean differences between
pre- and post-procedure scores for average pain were 3.8
(week 24) and 1.2 (week 1), respectively. All the mean
differences were statistically significant across studies
except for the worst pain one week after the procedure.
Three studies compared the cryoablation procedure with
other palliation methods [16, 20, 22]. Di Staso et al.
compared the efficacy of cryoablation with radiotherapy
and radiotherapy ? cryoablation in alleviating pain in
painful bone metastasis; 11.2% of patients treated with
radiotherapy, 32% of patients treated with cryoablation,
and 72% of patients treated with cryoablation followed by
radiotherapy experienced complete response. Narcotic
medications were not required in 13%, 36%, and 76% of
patients treated with radiotherapy, cryoablation, and
cryoablation followed by radiotherapy, respectively [20].
Li et al. compared the efficacy of cryoablation with zole-
dronic acid and the combination of zoledronic acid with
cryoablation; the mean patient response for average pain
was their results demonstrated that cryoablation caused a
drop in pain in a shorter time period than zoledronic acid,
but zoledronic acid had a more durable response in the later
weeks; however, the combination of zoledronic acid with
cryoablation was more effective than the other methods
[22]. Thacker et al. [16] compared RFA with cryoablation,
and they showed that total hospital stays after cryoablation
and RFA were 1.0 ± 2.2 (1–11) and 3.5 ± 5.3 (1–26)
days, respectively; besides, the differences between anal-
gesic usage (morphine-equivalent dose) 24 h before and
24 h after cryoablation and radiotherapy were - 23.6 ±
137.0 (- 394.9 to 269.9) and 21.6 ± 124.7 (- 361.4 to
285), respectively.
All included studies, except for one study [12], reported
complications after the cryoablation procedure. Overall, in
385 cases complications were evaluated. Fever (3.90%),
fracture (2.34%), plexus injury (1.82%), nerve injury
(1.56%, e.g., dysesthesia, neuropraxia, and nerve com-
pression), pain (1.56%), thermal injury (0.52%), hyper-
calcemia (0.52%), infection (0.26%), and bleeding (0.26%)
occurred after cryoablation procedures.
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 Table 2 Basic characteristics of included studies
1474

ID References Study type Sample Mean age No. of Lesion location Primary tumor Follow-up Time Previous treatment
size (M/ (SD) lesions period point(s) for

123
F) (range) pain
assessment

1 Arrigoni Retrospective 28 (13/ 62 25 Sacroiliac region (n = 14), Breast (n = 7), kidney (n = 8), 3 months Baseline, NA
[11] case series 15) (32–83) spine (n = 5), rib (n = 2), head and neck (n = 2), GIST week 12
acetabulum (n = 4), sternum (n = 1), colorectal cancer
(n = 1), femur (n = 1), tibia (n = 5), lung (n = 2), bladder
(n = 1), ischio-pubic region (n = 2), sarcoma (n = 1)
(n = 1)
2 Callstrom Prospective 14 (8/6) 54 (16) 22 Clavicle (n = 2), ilium (n = 2), Paraganglioma (n = 2), ovary 6 months Baseline, day Chemotherapy/
[21] trial (21–74) rib (n = 7), lamina (n = 1), (n = 1), kidney (n = 1), 1, day 4, radiotherapy
acetabulum (n = 2), chest squamous cell (n = 1) lung weeks 1, 2,
wall (n = 4), scapula (n = 1), (n = 1), desmoid (n = 1), thyroid 3, 4, 6, 8,
sacrum (n = 2), femur (n = 1), adrenal (n = 1), 10, 12, 14,
(n = 1) melanoma (n = 1), rectum 16, 18, 20,
(n = 2), renum (n = 2), 22, 24
3 Callstrom Prospective 61 (39/ 61 (14) 69 Rib/chest wall (n = 33), Iliac/ Lung (n = 16), renal (n = 10), 44 months Baseline, day Chemotherapy/
[8] trial 22) (21–95) ischium/pubic bones colorectal (n = 7), prostate 1, day 4, radiotherapy
(n = 20), scapula/clavicle/ (n = 4), squamous cell (non- weeks 1, 2,
sternum (n = 7), sacrum lung) (n = 3), transitional cell 3, 4, 6, 8,
(n = 5), extremity (n = 2), (n = 2), paraganglioma (n = 2), 10, 12, 14,
vertebral body (n = 1), breast (n = 2), melanoma 16, 18, 20,
mastoid (n = 1) (n = 4), other (n = 11) 22, 24
4 Di Staso Prospective 25 (12/ 67.5 25 Pelvis (n = 8), sacrum (n = 7), Lung (n = 6), prostate (n = 8), 3 months Baseline, Chemotherapy/
[20] case series 13) (64.4– vertebrae (n = 4), humerus renal (n = 4), colorectal (n = 2), week 12 immunotherapy/
70.6) (n = 2), rib (n = 2), femur breast (n = 5) hormonal
(n = 2)
5 Gallusser Retrospective 16 62 (42– 18 Vertebrae (n = 2), femur Breast (n = 2), tonsillar spinal cell 12 (1.5–39) Chemotherapy/
[12] case series 80) (n = 5), ilium (n = 3), rib (n = 1), lung (n = 3), sarcoma months radiotherapy/
(n = 3), sacrum (n = 5) (n = 2), renal (n = 3), melanoma immunotherapy/
(n = 1), rectal (n = 1), surgery
hepatocellular (n = 2), cutaneous
spinal cell carcinoma (n = 1)
6 Hegg [13] Retrospective 7 (4/3) 59.3 (15) 7 Sternum (n = 7) Breast (n = 3), lung (n = 3), NA Baseline, Radiotherapy
case series (38–80) thyroid (n = 1), renal (n = 2) week 4
S. Khanmohammadi et al.: Cryoablation for the Palliation of Painful Bone Metastasis…
 Table 2 continued
ID References Study type Sample Mean age No. of Lesion location Primary tumor Follow- Time point(s) for pain assessment Previous treatment
size (M/ (SD) lesions up
F) (range) period

7 Jennings Prospective 66 (35/ 60.8 66 Rib (n = 16), ilium Lung (n = 19), 3 months Baseline, week 1,4,8,12,16,20,24 Chemotherapy/
[7] trial 31) (14.3) (n = 13), pelvis breast (n = 9), radiotherapy/
(32–87) (n = 8), chest wall kidney (n = 8), immunotherapy/
(n = 4), acetabulum colon (n = 5), hormonal
(n = 3), sacrum prostate (n = 4),
(n = 3), scapula sarcoma (n = 3),
(n = 3), ischium thyroid (n = 3),
(n = 3), sternum stomach (n = 2),
(n = 3), humerus other (n = 13)
(n = 2), femur (n = 1),
vertebrae (n = 1), other
(n = 6)
8,9 Li [22, 23] Prospective 28 (15/ 54.8 41 Rib (n = 14), chest wall Lung (n = 9), breast 6 months Baseline, day 4, week Radiotherapy/
trial 13) (10.52) (n = 7), vertebrae (n = 8), renal 1,2,4,6,8,10,12,14,16,18,20,22,24 chemotherapy
(37–72) (n = 10), clavicle (n = 3), prostate
(n = 3), sacrum (n = 3), colorectal
(n = 3), ilium (n = 1), (n = 2),
acetabulum (n = 2), hepatocellular
scapula (n = 1) carcinoma (n = 1),
stomach (n = 1),
nasopharynx
(n = 1)
10 Ma [14] Retrospective 14 NA 19 Total sample: extremity Lung (n = 14) 1 month Baseline, week 4 NA
case series (n = 1), humerus
S. Khanmohammadi et al.: Cryoablation for the Palliation of Painful Bone Metastasis…

(n = 2), ribs (n = 4),

spine (n = 51),
acetabulum (n = 2),
ilium (n = 11), pubis
(n = 3), ischium
(n = 1), others (n = 2)
1475

123
 Table 2 continued
1476

ID References Study type Sample Mean No. of Lesion location Primary tumor Follow-up Time Previous treatment
size (M/ age lesions period point(s) for

123
F) (SD) pain
(range) assessment

11 MacArthur Retrospective 16 (7/9) 53.2 16 Rib (n = 1), ilium (n = 7), Colorectal (n = 3), hepatocellular 436 days Baseline, Chemotherapy
[15] case series (29– acetabulum (n = 3), (n = 3), HL(n = 1), breast (n = 1), (31 days– month 3
73) calcaneus (n = 1), renal (n = 3), sarcoma (n = 1), 5.9 years)
sternum (n = 1), esophageal (n = 2), osteosarcoma
vertebrae (n = 2), sacrum (n = 1), chondrosarcoma (n = 1)
(n = 1)
12 Thacker Retrospective 36 (22/ 60 (20– 36 Chest wall (n = 8), head Colorectal (n = 6), renal (n = 7), 1 day Baseline, Radiotherapy
[16] case series 14) 78) (n = 1), extremity lung(n = 5), others (n = 18) day 1
(n = 3), pelvis (n = 21),
spine (n = 3)
13 Tomasian Retrospective 14 (5/9) 53 (20– 31 Vertebrae (n = 31) Lung (n = 4), colorectal (n = 3), breast 3 months Baseline, Radiotherapy/
[17] case series 73) (n = 2), thyroid (n = 2), head & neck week chemotherapy
(n = 1), pancreas (n = 1), 1,4,12
hemangioendothelioma (n = 1)
14 Yang [18] Retrospective 26 (15/ 67 (7.3) 36 Rib (n = 24), pelvis Lung (n = 8), colorectal (n = 6), breast 6 months Baseline, Radiotherapy/
case series 11) (54– (n = 10), vertebrae (n = 6), liver (n = 4), esophageal day 1, chemotherapy
81) (n = 2) (n = 1), stomach (n = 1) week 4,
12, 24
15 Zugaro Retrospective 25 (12/ 67.5 25 Pelvis (n = 8), sacrum Lung (n = 7), prostate (n = 3), renal 3 months Baseline, Chemotherapy/
[19] case series 13) (64.4– (n = 7), rib (n = 2), (n = 4), colorectal (n = 2), breast week 12 immunotherapy/
70.6) vertebrae (n = 4), (n = 9) hormonal
humerus (n = 2), femur
(n = 2)
HL Hodgkin lymphoma, M/F Male/female, NA Not available, SD Standard deviation
S. Khanmohammadi et al.: Cryoablation for the Palliation of Painful Bone Metastasis…
S. Khanmohammadi et al.: Cryoablation for the Palliation of Painful Bone Metastasis… 1477

Table 3 Cryoablation-related variables

ID Ablation cycle (min) goal Procedure time (min) mean (SD) (range) Number of cryoprobe mean (SD) (range) Guidance method

1 f/t/f/t 10,5,10,5 NA NA CT
2 f/t/f 10, 8, 10 139 (53) (83–280) 2.8 (1.5) (1–7) CT, US, fluoroscopy
3 f/t/f 10, 8, 10 129 (50–210) 3.4 (1.8) (1–8) CT, US
4 f/t/f/t 15,10, 15, 10 NA NA CT
5 NA NA (3–6) CT, US
6 f/t/f 11, 5, 10 NA 4 (2–11) CT, US
7 f/t/f/t 19.6, 14.7, 19.6, 14.7 100.1 (48.21) (15–227) 3 (2) (1–10) CT
8,9 f/t/f*3 20 per cycle NA NA CT
10 NA NA 2 (1–10) Fluoroscopy, CT
11 f/t/f 10,8,10 NA 1.6 (1–3) CT
12 f/t/f 10,8,10 108 (42.3) (42–238) 3 (1.7) (1.0–8.0) CT, US
13 f/t/f 10,5,10 NA NA CT
14 f/t/f/t 10–15,3–5/10–15/3–5 NA NA CT
15 f/t/f/t 15,10,15,10 NA NA CT
CT Computed tomography, f/t Freezing/thawing, NA Not available, SD Standard deviation, US Ultrasound

Eight studies evaluated the effect of cryoablation on
QoL in patients with painful bone metastasis, and QoL was
improved in all of them. Jennings et al. demonstrated that
participant-reported interference of pain on QoL reduced
from 5.5 (baseline) to 3.9 after 1 week and 2.5 after
24 weeks [7].
Discussion
This systematic review evaluated the efficacy of cryoab-
lation in palliating painful bone metastasis. All studies
reported a significant pain reduction between 1 day and
6 months after the cryoablation procedure, but only 55% of
studies reported a decrease in using pain medications.
Despite the large number of screened studies, only 15
papers were included in the final analysis. The low number
of included studies and their small sample sizes demon-
strate the lack of experience on a large scale for cryoab-
lation applied to treat painful bone metastasis. All of the
studies included in this review showed that cryoablation
could be an effective method to alleviate pain and improve
QoL in patients with bone metastasis for short- and mid-
term (up to 24 weeks). Results regarding changes in pain
medication use were controversial, and not all the studies
showed a decrease in pain medications.
The gold standard for treating bone metastases pain
since the 1990s has been radiotherapy, even though the
reported outcomes are suboptimal. Approximately 30% of
patients do not benefit from radiotherapy. Up to 50% of
patients who experience partial or complete pain relief after
radiation therapy are likely to experience recurrent pain 20
to 24 weeks after the completion of the treatment [24, 25].
Studies have shown that patients with a failure in their
radiotherapy could benefit from percutaneous treatments,
such as RFA and cryoablation [24]. Moreover, adding
percutaneous treatments to radiotherapy has shown
promising results compared to radiotherapy alone [26, 27].
For instance, patients treated with RFA ? radiotherapy
showed higher rates of complete response in terms of pain
relief than patients treated with radiotherapy alone [28]. Di
Staso et al. compared the efficacy of cryoablation with
radiotherapy alone and radiotherapy ? cryoablation; their
results showed that cryoablation is superior to radiotherapy
in palliating painful bone metastasis and reducing narcotic
use. The combination of cryoablation with radiotherapy is
more effective than cryoablation or radiotherapy alone in
alleviating pain in patients with bone metastasis [20].
Following the reports of the safety and efficacy of RFA
for the palliation of painful musculoskeletal metastatic
disease [29], cryoablation began to appear in studies with
several benefits, including direct visualization of the abla-
tion zone, reduced intra- and post-procedural pain, and the
ability to use numerous probes [29]. It is worth mentioning
that cryoablation not only palliates pain in patients with
bone metastasis but also contributes to local tumor control
in bone lesions [11, 12].
RFA and cryoablation seem to have similar efficacy in
palliating painful bone metastasis. Thacker et al. [16]
compared the reduction in analgesic dose and hospital stay
in patients treated with RFA or cryoablation, retrospec-
tively; their results showed that the group of patients
treated with cryoablation showed a greater reduction in
analgesic dose and shorter hospital stays than the group

123
 Table 4 Pain evaluation
1478

ID Pain Baseline Baseline Post- Pain type Post- Post- Difference Difference Pain Change in Change Complication
scale (n) mean operative operative operative between pre- between pre- relief medication in QoL

123
(SD) (n) mean time and post- and post- (0–100)
(SD) point of operative operative
measure score mean score p value

1 VAS 28 6.9 (1.4) 28 – 3.5 (2.6) Week 12 3.4 \ 0.0001 NA NA NA Bleeding (1/28)
2 BPI- 14 6.7 13 Worst pain 5.8 Week 1 0.9 0.236 56 No change in opioid Improved No major
SF 11 3.8 Week 4 2.9 0.003 71 and non-opioid complication
drugs
10 2.5 Week 6 4.2 0.001 87
8 3.4 Week 8 3.3 0.007 79
3 BPI- 61 7.1 57 Worst pain 5.1 Week 1 2 \ 0.0001 62 No change in opioid Improved Infection (1/61)
SF 49 4 Week 4 3.1 \ 0.0001 67
35 3.6 Week 8 3.5 \ 0.0001 80
16 1.4 Week 24 5.7 \ 0.0001 88
61 4.7 57 Average 3.5 Week 1 1.2 0.0003 –
49 pain 2.6 Week 4 2.1 \ 0.0001 –
35 2.1 Week 8 2.6 \ 0.0001 –
16 0.9 Week 24 3.8 \ 0.0001 –
4 VAS 25 7.5 25 CR (a pain 8/25 Week 12 – – – Decrease in opioid Improved Sacral plexus injury
score of 0 (32%) (7/50), transient
at treated peripheral nerve
site) injury (2/50),
25 PR (pain 9/25 Week 12 – – – humerus fracture
reduction (36%) (1/50)
of C 2
5 NRS 16 3.3 (3–4) 16 – 1.2 (0–4) Last F/U 2.1 0.0024 – No change NA NA
6 NRS 7 7 (1.9) 7 – 1.8 (1.2) Week 4 5.3 (2.3) 0.00049 – NA NA No complication
7 BPI- 66 7.3 64 Worst pain 5.2 Week 1 2.1 – – Mean total Improved 3 patients
SF 54 Worst pain 4.6 Week 4 2.7 – – morphine-
equivalent daily
50 Worst pain 4.5 Week 8 2.61 (0.43) – –
dose decreased
(95%
from 31.4 to 15.8
CI - 3.45
over 6 months
to - 1.78)
40 Worst pain 3.7 Week 12 3.6 – –
37 Worst pain 3.6 Week 16 3.7 – –
34 Worst pain 3.8 Week 20 3.5 – –
34 Worst pain 3.7 Week 24 3.6 – –
S. Khanmohammadi et al.: Cryoablation for the Palliation of Painful Bone Metastasis…
 Table 4 continued
ID Pain Baseline Baseline mean Post- Pain type Post-operative Post- Difference Difference Pain Change in Change Complication
scale (n) (SD) operative mean (SD) operative between between relief medication in QoL
(n) time pre- and pre- and (0–100)
point of post- post-
measure operative operative
score mean score
p value

8,9 BPI- 28 8.2 28 Worst pain Reported on – – – NA Improved Fracture (5/28),

SF figure (exact hypercalcemia
VRS numbers (2/28), muscle
were NA) pain (3/28),
28 7.32 28 Average pain Reported on – – – fever (15/28)
figure (exact
numbers
were NA)
28 Reported on 28 CR (the 14.30% Week 24 – – –
figure (exact absence of
numbers pain without
were NA) the need for
increasing
analgesic
relief)
28 PR (pain 35.70% Week 24 – – –
reduction
of C 2
10 NRS 14 7.9 (1.7) 14 – 4.8 (3.8) Week 4 3.1 \ 0.05 NA NA Pain (1/27),
fracture (2/27)
S. Khanmohammadi et al.: Cryoablation for the Palliation of Painful Bone Metastasis…

11 NRS 16 9. 2 (0.8) 16 – 3.4 (1.4) Week 12 5.8 – – NA Improved Neuropraxia (1)

12 NRS 36 6.5 (2.27) 36 – 3.5 (2.91) Day 1 2.0 (2.87) – – Decrease in NA Dysthesia (1),
morphine thermal injury
(1)
13 NRS 14 8 (1) 14 – 3 (1) Week 1 5 – – Decrease in Improved Radicular lower
3 (1) Week 4 5 – – morphine extremity
nerve pain (2)
3 (1) Week 12 5 – –
1479

123
 Table 4 continued
1480

ID Pain Baseline Baseline Post- Pain type Post- Post- Difference Difference between Pain Change in Change Complication
scale (n) mean operative operative operative between pre- and pre- and post- relief medication in QoL

123
(SD) (n) mean time point of post-operative operative score (0–100)
(SD) measure score mean p value

14 VAS 26 7.1 (1.1) 26 – 2.1 (1.7) Day 1 5 \ 0.0001 No change NA Skin frostbite (1),
26 – 1.3 (1.8) Week 4 5.8 \ 0.0001 – nerve
compression
26 – 1.6 (1.7) Week 12 5.5 \ 0.0001 –
(1), fracture (1)
26 – 1.8 (1.3) Week 24 5.3 \ 0.0001 –
26 CR (a pain 8/26 Day 1 – – –
score of 0 (22.2%)
26 at treated 15/26 Week 4 – – –
site) (41.7%)
26 13/26 Week 12 – – –
(36.1%)
26 8/26 Week 24 – – –
(22.2%)
26 PR (pain 25/26 Day 1 – – –
reduction (69.4%)
26 of C 2 20/26 Week 4 – – –
(55.6%)
26 20/26 Week 12 – – –
(55.6%)
26 26/26 Week 24 – – –
(72.2%)
15 VAS 25 7.5 25 CR 8/25 Week 12 – – – Decrease Improved Transient nerve
(32%) in injury (1)
opioid
25 PR 9/25 Week 12 – – –
(36%)
BPI-SF Brief pain inventory-short form, CR Complete response, NA Not available, NRS Numeric rating scale, PR Partial response, QoL Quality of life, SD Standard deviation, VAS Visual
analog scale
S. Khanmohammadi et al.: Cryoablation for the Palliation of Painful Bone Metastasis…
S. Khanmohammadi et al.: Cryoablation for the Palliation of Painful Bone Metastasis…
treated with RFA. Moreover, De Marini et al. [30] inves-
tigated the safety profile of cryoablation and RFA and
demonstrated that minor complications are more prevalent
after RFA compared to cryoablation due to more post-
procedural pain in patients treated with RFA.
Patients with painful bone metastasis could benefit from
combining cryoablation with other therapies. Li et al. [22]
showed that patients with painful bone metastasis treated
with cryoablation have a faster mean and worst pain
response than patients treated with zoledronic acid; in this
study combination of zoledronic acid and cryoablation is
more effective in palliating painful bone metastasis than
cryoablation or zoledronic acid alone. Moreover, the
combination of cryoablation with cement osteoplasty has
shown promising results in reducing pain in patients with
painful bone metastasis [31, 32]. Although some studies
with small sample sizes have shown that the combination
of cryoablation with cement osteoplasty is not superior to
cryoablation alone in terms of pain control, cement
osteoplasty in patients treated with cryoablation, especially
in weight-bearing bones may be mandatory [14, 16].
Based on our results, cryoablation has a low rate of post-
procedure complications and is a safe method to control
pain in patients with bone metastasis. Auloge et al. retro-
spectively reviewed the complications of bone tumor
cryoablation over ten years. Fractures, infection, tumor
seeding, bleeding, severe hypotension, post-procedural
pain, peripheral neuropathy, and temporary paresthesia
were among the major and minor complications after
cryoablation. The total, major, and minor complication
rates were 9.1%, 2.5%, and 4.1%, respectively. Risk factors
for complications after cryoablation were using more than
three cryoprobes, ECOG-PS [ 2, long-bone cryoablation,
and age [ 70 years [33].
To the best of our knowledge, our study is one of the
first systematic reviews on the efficacy of cryoablation in
palliating pain in patients with bone metastasis. We also
investigated the effect of cryoablation on pain medication
use and the QoL of the patients. However, our study has
several limitations. Due to the different pain measuring
systems in the included studies, we were unable to conduct
a meta-analysis. Some of the included studies had poor
quality, and we cannot ignore the probability of con-
founding bias or poor methodology. One of the main lim-
itations of our study was the small sample sizes and
retrospective studies, which could affect the results. Pre-
vious treatments of patients could also alter the results.
Besides, sex-specific investigations were impossible since
the results of the studies were not reported by sex. Thus,
conducting RCTs with large sample sizes is recommended
to better understand the effect of cryoablation on pain
palliation, QoL, and analgesic use.
1481
Conclusion
In conclusion, cryoablation is an effective and safe pro-
cedure to control pain and improve the QoL of patients
with painful bone metastasis for short- and mid-term (from
1 day to 6 months). Patients with painful bone metastasis
could benefit more from combining cryoablation with other
therapies, such as radiotherapy and bisphosphonates, than
single therapies. Further prospective randomized trials and
studies with large sample sizes are needed to investigate
the long-term efficacy of cryoablation and to find strong
evidence for the precise efficacy of cryoablation in alle-
viating pain. Studies with similar pain measuring systems
and detailed reporting of the results are required to allow
meta-analysis.
Supplementary InformationThe online version contains
supplementary material available at https://doi.org/10.1007/s00270-
022-03356-z.
Acknowledgements This study was supported by a Grant from
Tehran University of Medical Sciences (63742).
Funding This study was not supported by any funding.
Declarations
Conflict of interest The authors declare that they have no conflict of
interest.
Consent for publication For this type of study, consent for publi-
cation is not required.
Ethical approval This article does not contain any studies with
human participants or animals performed by any of the authors.
Informed consent For this type of study, informed consent is not
required.
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