The New Ice Age of Musculoskeletal Intervention: Role of Percutaneous Cryoablation in Bone and Soft Tissue Tumors

Round 1

Reviewer 1 Report

Very well written and comprehensive overview. 
What do you recommend as a maximum in size for both bone and soft tissue lesions? Is there a maximum in ablation volume a single electrode can achieve and can larger lesions be ablated using multiple elctrodes simultaneously?
Are there any disadvantages of cryablations compared to RFA/MWA, and can you think of indications where RFA/MWA would be a better treatment option?

Author Response

We would like to thank the Editor and the Reviewers for taking the time to review the manuscript. We sincerely appreciate all valuable comments and suggestions, which helped us to improve the quality of the manuscript. We provide one copy of the revised manuscript with the changes highlighted.

Reviewer 1:

1. 1. What do you recommend as a maximum in size for both bone and soft tissue lesions? Is there a maximum in ablation volume a single electrode can achieve and can larger lesions be ablated using multiple elctrodes simultaneously? 
2. 2. Are there any disadvantages of cryablations compared to RFA/MWA, and can you think of indications where RFA/MWA would be a better treatment option?

Response to 1 and 2: Thank you for this very pertinent comment. According to the Reviewer’s suggestion, we have clarified the concept through the text by adding the following sentences: “Regarding treatment effectiveness and safety, the visualization of the iceball offers high precision. It permits the simultaneous use of many cryoprobes, allowing for the ablation of large lesions (> 5 cm), the creation of iceballs with a diameter greater than 8 cm, and the shaping of the ablation zone to the shape of the target lesion through varied geometry of probe placement. In general, when multiple probes are used, they are placed approximately 2 cm apart within the tumor and 1 cm from the outer tumor margin. It is also less painful than RFA during ablation and after treatment, with a shorter hospital stay” in the discussion section.

Reviewer 2 Report

Thanks for submitting your manuscript. It is a very good review with good conclusions. 

However, I have a few suggestions.

1.  The first sentence of your manuscript noting 'minimally invasive procedures have become a cornerstone in the treatment of various types of tumors' is likely too broad. For most soft tissue and bone tumors, surgery which is often major or not minimally invasive is still the mainstay. I might suggest mentioning cryoablation as an exploratory although promising technique similar to your conclusions.

2.  The section on malignant bone and soft tissue tumors notes 'clinical success of this technology for the treatment of various primary bone and soft tissue tumors makes it a viable alternative for a wide range of malignancies'. I again believe this is an overstatement given the very small number of patients treated by cryoablation compared to standard treatments. Much of the current literature lacks underlying tumor grade, biology or prognosis in their reports which makes it difficult to compare outcomes. Of course, there are no randomized trials and little prospective data which the authors appropriately mention in the conclusions. I would recommend toning down the language or mentioning limitations here. I would suggest all cases should be reviewed by a multidisciplinary team (sarcoma tumor group) where cryoablation is discussed as one of the options to ensure appropriate consensus based treatment. Can the authors discuss?

3.  Cryoablative techniques are very uncommon for recurrent RPS based on the literature numbers given. It is hard to determine the goal of treatment in many studies as treating if it is there but asymptomatic may not be needed. Can the authors mention goals of treatment and limitations here? I would suggest treatment again should be in the context of a tumor board consensus.

4. For remaining sections, I would just ensure the limitations of the literature are mentioned. Again it is difficult to compare to existing treatments if the underlying tumor grade/ biology/ prognosis is uncertain or not mentioned. 

5. For benign but asymptomatic tumors (e.g. osteomas, other), can the authors mention the role of observation rather than intervention as first step similar to the recommended approach to desmoid tumors.

Overall, a good review of the technical success of cryoablation and outcomes but should be in context of current treatment paradigms.

Author Response

We would like to thank the Editor and the Reviewers for taking the time to review the manuscript. We sincerely appreciate all valuable comments and suggestions, which helped us to improve the quality of the manuscript. We provide one copy of the revised manuscript with the changes highlighted.

Reviewer 2: 

1. 1.  The first sentence of your manuscript noting 'minimally invasive procedures have become a cornerstone in the treatment of various types of tumors' is likely too broad. For most soft tissue and bone tumors, surgery which is often major or not minimally invasive is still the mainstay. I might suggest mentioning cryoablation as an exploratory although promising technique similar to your conclusions.

Response: Thank you for this very useful comment. According to the Reviewer’s suggestion, we have deleted the sentence “In the rapidly evolving world of oncology, minimally invasive procedures have become a cornerstone in the treatment of various types of tumors, including those of bone and soft tissue” and changed it with “Interventional oncology has emerged as an increasingly crucial component of the multidisciplinary team, providing innovative and minimally invasive treatment approaches for various types of musculoskeletal tumors.”

2. 2.  The section on malignant bone and soft tissue tumors notes 'clinical success of this technology for the treatment of various primary bone and soft tissue tumors makes it a viable alternative for a wide range of malignancies'. I again believe this is an overstatement given the very small number of patients treated by cryoablation compared to standard treatments. Much of the current literature lacks underlying tumor grade, biology or prognosis in their reports which makes it difficult to compare outcomes. Of course, there are no randomized trials and little prospective data which the authors appropriately mention in the conclusions. I would recommend toning down the language or mentioning limitations here. I would suggest all cases should be reviewed by a multidisciplinary team (sarcoma tumor group) where cryoablation is discussed as one of the options to ensure appropriate consensus based treatment. Can the authors discuss?

Response: According to the Reviewer’s suggestion we have changed some sentences in the Malignant Bone and Soft Tissue Tumors section:

• “Percutaneous cryoablation is increasingly used for the treatment of a variety of bone and soft tissue neoplasms.” changed it with “Percutaneous cryoablation is becoming an increasingly accepted option within the multidisciplinary sarcoma board for the treatment of primary bone and soft tissue tumors, applicable for selected cases”. 

• “Lately, minimally invasive techniques such as radiofrequency ablation, microwave ablation, or cryoablation have been proposed as potential surgical substitutes for different recurrent bone and soft tissue tumors“ changed to “Lately, minimally invasive techniques such as radiofrequency ablation, microwave ablation, or cryoablation have been proposed as potential surgical alternatives for some selected recurrent bone and soft tissue tumors”.

• “The early successful application of this technology for the treatment of diverse primary bone and soft tissue tumors presents it as a feasible alternative to surgery for a broad spectrum of cancers” changed to “Some initial studies evaluated the therapeutic effect of Cryoablation for the treatment of a variety of primary bone and soft tissue malignancies with promising results, however the scientific evidence is still limited.”

3. 3.  Cryoablative techniques are very uncommon for recurrent RPS based on the literature numbers given. It is hard to determine the goal of treatment in many studies as treating if it is there but asymptomatic may not be needed. Can the authors mention goals of treatment and limitations here? I would suggest treatment again should be in the context of a tumor board consensus.

Response: According to the Reviewer’s suggestion we have clarified this concept through the text by adding the following sentences “Some retrospective studies reported on the effectiveness and safety of percutaneous cryoablation in the treatment of recurring retroperitoneal soft tissue sarcomas” and “In some selected cases Cryoablation has proven safe and effective as a palliative treatment for RPSs and could be included in the armamentarium of the sarcoma board” in the Recurrent Retroperitoneal Soft Tissue Tumors section. 

4. For remaining sections, I would just ensure the limitations of the literature are mentioned. Again it is difficult to compare to existing treatments if the underlying tumor grade/ biology/ prognosis is uncertain or not mentioned. 

Response: According to the Reviewer’s suggestion, we have added the following sentences:

• In bone metastases section “The current body of literature is mostly exploring the palliative effect and local tumor control of cryoablation for bone metastases, that makes this technique a useful tool in the multidisciplinary management of cancer patients.”
  
  
• In the Conclusion section “being increasingly incorporated into the multidisciplinary decision-making process of tumor boards”

We would like to underline that the conclusion of the review already states “However, more research is required to fully understand the extent of cryoablation's capabilities. Future research directions should focus on establishing standardized patient selection criteria, examining the possibilities when cryoablation is paired with other localized or systemic treatments, and implementing more long-term studies and randomized controlled trials to evaluate its enduring effectiveness and safety.”

5. 5. For benign but asymptomatic tumors (e.g. osteomas, other), can the authors mention the role of observation rather than intervention as first step similar to the recommended approach to desmoid tumors.

Response: Thank you for this useful comment. We have clarified this concept through the text “For asymptomatic cyst initial wait and see is advised and intervention is recommended in case of progression or beginning of symptoms” in the aneurysmal bone cyst section.

For asymptomatic locally aggressive tumors such as desmoid tumors we have mentioned the wait-and-see strategy. All the other benign tumors (Osteoid osteoma, Osteoblastoma,  Aneurysmal Bone cyst) mentioned are highly symptomatic and the wait-and-see strategy is not described. We did not mention benign asymptomatic tumors such as simple Osteoma in this Review. 

Round 2

Reviewer 2 Report

Thank you for addressing all of my prior comments. I have no additional suggestions.