Complications of cryoprobe cryoablation as a surgical adjuvant for the treatment of metastatic carcinoma to bone, benign bone tumors, and soft tissue tumors: A series of 148 patients

This study describes the complication profile of modern cryoablation utilizing probes as an adjuvant during open surgical treatment of orthopedic tumors.

2][3][4] However, these excision strategies can result in the potential for recurrence due to residual disease. 5To address the concern for local recurrence, surgeons may incorporate adjuvant treatments, such as cryoablation, at the time of surgery to extend the surgical margins.Although there is limited literature investigating cryoablation probes for the treatment of orthopedic tumors, literature in other specialties, such as interventional radiology, indicates that ablation techniques may be useful in addressing residual tumors while minimizing complications.
Cryosurgery was pioneered by Marcove, who utilized liquid nitrogen to ablate tumors.Subsequently, liquid nitrogen poured or sprayed into a lesion became a viable surgical adjuvant used for benign-aggressive bone tumors and metastatic carcinoma.This process reduces the temperature of the treated tissue to at or below −21°C, which results in necrosis of the tissue. 1,6However, pouring or spraying liquid nitrogen can be difficult to control depending upon the area of interest, and the inability to accurately assess the volume of nitrogen needed.][9][10] Therefore, systems were developed using probes to deliver subcooled nitrogen. 11This targeted approach creates a more precise ablation zone, providing protection to surrounding structures and potentially decreasing the risk of complications. 12,13[14][15][16] However, to our knowledge, no study to date has assessed the use of cryoprobes as an adjuvant treatment during open resection of benign bone, soft tissue, and metastatic neoplasms to bone by orthopedic surgeons.Therefore, we sought to assess the complications associated with the utilization of the cryoprobe as an adjuvant in a large patient cohort with metastatic carcinoma to bone, benign bone tumors, and soft tissue tumors.

| Study design
All patients who underwent cryoablation procedures performed by a tumor fellowship-trained orthopedic surgeon (Lawrence R. Menendez) from January 1, 2014 to November 30, 2022 were included in the preliminary cohort.Cases were excluded if they (1)   did not have complete clinical records, (2) were performed by alternative surgeons, or (3) were not performed in the setting of metastatic carcinoma to bone, a benign bone tumor, or a soft tissue sarcoma.
All eligible patients underwent the following adjuvant cryoablation technique.First, the patient was prepared and draped in a sterile fashion.Subsequently, an incision was made providing direct access to the tumor site.The surrounding soft tissue and neurovascular structures were protected using lap pads and gel foam.Next, the tumor was curetted and the defects were filled with saline or K-Y jelly.Saline was used primarily to fill cavitary defects as it freezes and thaws faster; however, K-Y jelly was utilized for cases where the inclination of the defect impacted cavitary filling.Then, a variable quantity of 3, 8, or 10 mm cryoprobes were inserted based on the volume of the tumor to obtain appropriate margins.Next, one to two complete freeze-thaw cycles were performed based on size and the surgeon's discretion. 17,18 and follow-up).Follow-up was collected at 2 weeks, 6 weeks, and 3-month time intervals.Fracture was defined as any bony fracture, treated operatively or non-operatively, occurring in the region of the probe placement during or following the procedure.Nerve palsy was defined as any nerve-related complaint (i.e., neuropathy, neuromuscular weakness or paralysis, spasticity) in a neurologic distribution related to the region of probe placement.Wound complications included noninfectious inflammation, seromas, failure to heal, skin necrosis, or additional procedures to aid in wound healing.Infection was defined by patients who presented postoperatively with physical signs of infection (e.g., erythema or draining sinus) at the site of the cryoablation procedure and were either placed on antibiotics or had an incision and drainage procedure performed.Complications following cryoablation were reviewed and evaluated by a tumorfellowship-trained surgeon (Alexander B. Christ).
The primary outcomes of interest were the rate of fracture, nerve palsy, wound complications, infection, and aggregate complications following the procedure.Secondary outcomes included evaluating correlations between the number of probes utilized or the number of cryoablation cycles performed and the various complications.
The present study was conducted as approved by the Institutional Review Board (IRB HS-22-00553).

| Cohort characteristics
In total, 148 patients with bone or soft tissue tumors were identified who received cryoprobe cryoablation.Of those, 67.6% had metastatic carcinoma to bone, 27.7% had a benign bone tumor, had an average BMI of 27.8 ± 6.6 kg/m 2 , while metastatic bone patients had an average BMI of 27.8 ± 7.0 kg/mm 2 , benign bone patients had an average BMI of 28.7 ± 5.9 kg/m 2 , and patients with soft tissue tumors had an average BMI of 25.3 ± 18.9 kg/m 2 .ASA scores were 2.7 ± 0.6 in the overall cohort, 2.9 ± 0.5 in the metastatic bone cohort, 2.2 ± 0.8 in the benign bone cohort, and 2.4 ± 0.5 in the soft tissue cohort.Of note, only one patient in the soft tissue tumor cohort had the presence of metastatic disease at the time of operation (Table 1).
An increasing number of probes used was significantly correlated with the incidence of aggregate complications in the metastatic bone cohort (Pearson = 0.222, p = 0.027).No similarly significant associations were seen between increasing probe numbers and complications within the other cohorts, although aggregate complications for the overall cohort did trend near significance (p = 0.075).The number of cycles was significantly correlated with the incidence of aggregate complications in the overall cohort (Pearson = 0.162, p = 0.049).Finally, no correlations were seen between the number of cycles and any complications in any of the individual cohorts (p > 0.05) (Table 3).

| DISCUSSION
Here, we present the largest series to date describing the use of cryoprobe cryoablation by a highly experienced surgeon at a highvolume, tertiary academic center for the treatment of metastatic bone lesions, soft tissue tumors, and benign-aggressive bone tumors.This series defines complication rates for both bone and soft tissue tumors.Additionally, we demonstrated an association between the number of probes utilized and aggregate complications in metastatic bone tumors, as well as the number of cycles performed and aggregate complications in all patients assessed in this case series.
These data can help orthopedic oncologists anticipate potential complication profiles of cryoprobe cryoablation procedures, and assist in pre-procedure planning and patient counseling. 1,2,10r complication rates for those with metastatic and benignaggressive bone tumors are similar to those previously reported in the literature.0][21] Our 2.7% rate of neurologic complications is similar to many studies in the literature.However, the only series with a comparable cohort size reported a <1% rate in 232 patients who received poured liquid nitrogen as an adjuvant in the treatment of benign bone tumors. 7,19,20,[22][23][24] 20,23,24 However, our rate of wound complications is marginally higher than what has been described in the literature.
Chen reported 2% wound complications, as did Marcove in a series of 51 patients.Malawar reported a 3% rate in 102 patients as well. 7,25,26l three of these studies assessed the pouring of liquid nitrogen in benign bone tumors, most commonly giant cell tumors.Although our wound complication rates in bone tumors are slightly higher than previously reported, our cohort includes patients with metastatic T A B L E 1 The cohort descriptives including sex, age, body mass index (BMI), race or ethnicity, preoperative American Surgical Association (ASA) score, and follow-up.Marcove reported a 39% fracture rate following the treatment of chondrosarcoma in 18 patients and a 25% rate in 52 patients with giant cell tumors. 1,2,18Two studies reporting a lower postoperative fracture rate were Chen et al., which was <1% in their retrospective, benign bone disease case series, as well as an 80-patient series by Peeters et al., in which 1% in patients with aneurysmal bone cysts developed a postprocedure fracture. 7,22All five of these studies utilized the pouring of liquid nitrogen as an adjuvant when treating the respective lesions (Table 4).
Of note, there is a paucity of literature regarding complications following cryoprobe cryoablation for soft tissue tumors in the orthopedic setting.A 12-patient case series studying this treatment modality was performed by the senior author of this study (Lawrence R. Menendez) in 2000. 9That case series, compared to this study, reported higher rates of aggregate complications at 50%, a higher rate of nerve palsy and wound complications at 25%, and a lower infection rate at 0%.Rates of postoperative fracture were not reported in that study. 9 the present study, we evaluated novel associations between the number of probes and cycles utilized and postoperative complications.Our results indicate that in the overall cohort, the risk of aggregate complications trended toward significance, and individuals with metastatic disease to the bone have a higher risk for aggregate complications when more probes are used.We posit that The operative characteristics including the number of probes utilized, the number of cryoablation cycles performed, and postprocedure complications.patients requiring more probes are likely sicker individuals with a higher tumor burden at the time of operation, potentially contributing to the higher aggregate complication risk.Also, increasing cryoablation cycles conferred a greater risk of aggregate complications in the overall cohort.We theorize that a greater number of cycles results in greater tissue damage and therefore greater potential for postoperative complications.To reduce complications, surgeons should be judicious in both the number of probes used and freeze-thaw cycles performed on a patient-by-patient basis when utilizing this surgical technique. 27r institutional series is inclusive of a tertiary referral center that addresses late-stage, severe or rare, and complex diseases.The significantly higher tumor burden in these patients often requires multiple probes or multiple cycles to adequately address the tumors potentially contributing to a higher complication rate than series' studying only benign tumor types.Despite this, our rates remained comparable to previously reported studies that assessed localized, benign tumor types, demonstrating the improved safety of cryoprobe techniques, even in more complex pathology.
There are several notable strengths and limitations in the present study.Patients were provided by a single surgeon, which although providing limited external validity, confers a high degree of consistency in technique and approach between patients.
Although all operations were performed by one surgeon, there were no defined criteria regarding the number of freeze-thaw cycles or probes used.Furthermore, no control group was included in this study.Additionally, as with all case series, this was a retrospective evaluation that is subject to limitations in the accuracy of documentation.Nevertheless, we present the largest to-date sample size evaluating orthopedic surgical cases and cryoprobe cryoablation techniques, in addition to novel reporting on correlations between complications and the number of probes or freeze-thaw cycles and postoperative complications.We present a sample size with a high rate of metastatic disease and a heterogeneous range of tumors treated, including metastatic renal cell carcinoma, metastatic breast cancer, giant cell tumor, chondrosarcoma, and others.This more accurately represents a wide diversity of cases treated, making this data broadly applicable.
Lastly, we provide recent data spanning 10 years of procedures, and have midterm postprocedure follow-up, providing additional validity to the presented findings.

| CONCLUSION
This study describes the complication rates of musculoskeletal tumor surgeries involving cryoablation probes used as an adjuvant during the open treatment of primary benign bone lesions, metastatic disease to bone, and soft tissue tumors.Greater probe number usage correlated with increased aggregate complications in the metastatic disease to bone; meanwhile, more treatment cycles were associated with increased aggregate complications in the overall cohort.
In conclusion, these data can be beneficial for physicians during pre-procedure planning and counseling patients on the postprocedure risks of cryoprobe cryoablation.
Statistical analyses were performed using SPSS version 28.0 (IBM, Armonk).Patient demographics, descriptive variables, and complications are presented as means or percentages with standard deviations or ranges where appropriate.Correlations were assessed using Pearson Correlation Coefficients with statistical significance at p < 0.05.

and 4 .
7% had a soft tissue tumor.The average age of the overall cohort was 57.3 ± 14.8 years.The average age of the respective groups was 62.0 ± 11.0 years for the metastatic bone cohort, 45.2 ± 16.0 years for the benign bone cohort, and 61.4 ± 17.8 years for the soft tissue cohort.The follow-up duration for the overall cohort was 15.0 ± 18.4 months.The metastatic bone cohort had the shortest follow-up duration of 12.6 ± 16.2 months with the benign bone cohort and the soft tissue cohort being 21.0 ± 21.8 months and 25.3 ± 18.9 months, respectively.Patients in the overall cohort Correlation between the number of probes and the number of cycles and postprocedure complications for the various tumor types.Postprocedure complications from various case series' found throughout the literature.