Electrochemotherapy Is Effective in the Treatment of Bone Metastases
, Francesca De Terlizzi 2, Laura Saenz 3, Nikolin Alì 1, Giuseppe Bianchi 1 and Davide Maria Donati 1Round 1
Reviewer 1 Report
The paper presents a retrospective study of bone metastase treated with EQT. Evaluation post-treatment of clinical and radiological response at 6 moths, pain, overall performance and tumoral response.
The manuscript is important to describe criterions of EQT treatment in bones. The design of study are interesting. My concerning is about pre-operative planning and the configuration of electrodes to effective treatment.
- Electrochemotherapy is dependent of electric field distribution. Do you use some software to planning the treatments? How were these planning’s?
- Bones present great difference of electric conductivity compare with tumor and muscles, this electric property interfere with electric field distribution. It will be great if the authors introduce and discuss how bones and neighbourhood affect the electric field distribution (see recent papers about effects of numerical electrical field distribution on bones and the neighbourhood as: https://onlinelibrary.wiley.com/doi/abs/10.1111/aor.13820 and https://pubmed.ncbi.nlm.nih.gov/29759043/).
- The authors should provide inform that despite EQT produces good response in the treatment in and near bones, electric field distribution can produce blind spot (regions without treatments, see https://doi.org/10.1016/j.medengphy.2021.10.011) caused by the difference in conductivity of tissues (e.g., bones and muscle). The pre-operative planning are essential to avoid these problems.
Author Response
Rew 1
The paper presents a retrospective study of bone metastase treated with EQT. Evaluation post-treatment of clinical and radiological response at 6 moths, pain, overall performance and tumoral response.
The manuscript is important to describe criterions of EQT treatment in bones. The design of study are interesting. My concerning is about pre-operative planning and the configuration of electrodes to effective treatment.
- Electrochemotherapy is dependent of electric field distribution. Do you use some software to planning the treatments? How were these planning’s?
Added a paragraph describing the sofware used for pre-operative planning
- Bones present great difference of electric conductivity compare with tumor and muscles, this electric property interfere with electric field distribution. It will be great if the authors introduce and discuss how bones and neighbourhood affect the electric field distribution (see recent papers about effects of numerical electrical field distribution on bones and the neighbourhood as: https://onlinelibrary.wiley.com/doi/abs/10.1111/aor.13820 and https://pubmed.ncbi.nlm.nih.gov/29759043/).
Added a paragraph
- The authors should provide inform that despite EQT produces good response in the treatment in and near bones, electric field distribution can produce blind spot (regions without treatments, see https://doi.org/10.1016/j.medengphy.2021.10.011) caused by the difference in conductivity of tissues (e.g., bones and muscle). The pre-operative planning are essential to avoid these problems.
- Added a paragraph on this point: The Cliniporator calculates the most appropriate electric field to achieve electroporation in all of the treated tissues; after the delivery of the current, the Cliniporator communicates if electric field between the pairs of electrodes was effective in inducing the electroporation of the tissue crossed by the current, if not machine recalculates the parameters of the current, and the electrical supply with the new parameters is then repeated.
Author Response File: 
Author Response.docx
Reviewer 2 Report
Summary
Bone is the third most common site for cancer metastasis. When cancer metastasizes to bone, it can lead to pain, fractures, calcium imbalances, and spinal nerve compression, which significantly diminish patient quality of life. In this manuscript, Campanacci et al. investigate the effectiveness of electrochemotherapy (ECT) for the treatment of bone metastasis. ECT utilizes electrical pulses to deliver chemotherapy in a more localized fashion. An advantage to electrochemotherapy is that it is a minimally invasive way to deliver a localized concentration of drug to the tumor, thereby reducing off-target effects in other tissues. A second advantage specific to the bone is that it does not seem to damage the mineral structure of the bone. In the current study, 38 patients received ECT treatment for bone metastasis. Of the 38, 29% had objective responses to treatment, 59% had stable disease, and 16% had progressive disease by RECIST criteria. By PERCIST criteria, there was 36% OR, 15% SD, and 50% PD. Sixty-eight percent of patients showed pain reduction. This reduction is pain is comparable, or slightly less than what is reported in the discussion for radiotherapy and other ablation techniques. However, ECT may cause less damage to the nearby bone. While the current study does not include a comparison group to standard therapies, the authors do address reported reductions in pain associated with other treatment strategies in the discussion.
Major comments to authors:
The vertebrae and ribs are some of the most common sites for bone metastasis, yet only one patient with costo-vertebral lesion(s) was included in the study. Please comment on the utility of performing ECT for vertebral and rib metastases and if there are associated technical challenges/limitations to using ECT on these sites.
The authors report that 76% of the bone lesions were lytic. Please comment on whether these patients were also receiving anti-resorptive therapies in the study period and if this may be a confounding factor to interpreting the results.
Please discuss the results of the current study within the context of published studies investigating ECT for bone metastasis.
Please include a table or tables summarizing the response to treatment according to RECIST and PERCIST criteria, pain pre- and post-ECT, and radiologic responses to go along with the text in Lines 144-181.
Minor comments to the authors:
The text refers to Figure 1 (Line 181), but the figure present in the manuscript is labelled Figure 2. Is the figure mis-labelled or is there a figure missing?
Endometrial/uterine cancers don’t frequently metastasize to the bone, yet 15% of the bone metastases in the study are from patients with endometrial/uterine primary tumors, the same as breast cancer. Are there contributing factors to why endometrial/uterine cancer patients seem overrepresented in this study? Does the proportion of bone mets coming from these patients in this study reflect the proportion of bone mets coming from endometrial/uterine cancer patients in the region where the study took place?
Line 117: “’primitive” tumor should be changed to “primary” tumor
Author Response
Rew 2
omments and Suggestions for Authors
Summary
Bone is the third most common site for cancer metastasis. When cancer metastasizes to bone, it can lead to pain, fractures, calcium imbalances, and spinal nerve compression, which significantly diminish patient quality of life. In this manuscript, Campanacci et al. investigate the effectiveness of electrochemotherapy (ECT) for the treatment of bone metastasis. ECT utilizes electrical pulses to deliver chemotherapy in a more localized fashion. An advantage to electrochemotherapy is that it is a minimally invasive way to deliver a localized concentration of drug to the tumor, thereby reducing off-target effects in other tissues. A second advantage specific to the bone is that it does not seem to damage the mineral structure of the bone. In the current study, 38 patients received ECT treatment for bone metastasis. Of the 38, 29% had objective responses to treatment, 59% had stable disease, and 16% had progressive disease by RECIST criteria. By PERCIST criteria, there was 36% OR, 15% SD, and 50% PD. Sixty-eight percent of patients showed pain reduction. This reduction is pain is comparable, or slightly less than what is reported in the discussion for radiotherapy and other ablation techniques. However, ECT may cause less damage to the nearby bone. While the current study does not include a comparison group to standard therapies, the authors do address reported reductions in pain associated with other treatment strategies in the discussion.
Major comments to authors:
The vertebrae and ribs are some of the most common sites for bone metastasis, yet only one patient with costo-vertebral lesion(s) was included in the study. Please comment on the utility of performing ECT for vertebral and rib metastases and if there are associated technical challenges/limitations to using ECT on these sites. Answer: added a paragraph about this
The authors report that 76% of the bone lesions were lytic. Please comment on whether these patients were also receiving anti-resorptive therapies in the study period and if this may be a confounding factor to interpreting the results. Added a paragraph. The outcome was considered not influenced by the ani-resorbtion drugs because this therapy was taken since several months before treatment
Please discuss the results of the current study within the context of published studies investigating ECT for bone metastasis. Answer: actually we did. The literature about ECT for bone metastases is not very rich. The first two papers about pre-clinic studies (Fini et al) were cited and discussed, then we published the first clinical study on ECT for bone metastases (ESOPEII, Bianchi et al), and the multicentric study on 102 patients (Campanacci et al). I added the paper on ECT for vertebral mets (Cornelis et al).
Please include a table or tables summarizing the response to treatment according to RECIST and PERCIST criteria, pain pre- and post-ECT, and radiologic responses to go along with the text in Lines 144-181.
Added tab 3
Minor comments to the authors:
The text refers to Figure 1 (Line 181), but the figure present in the manuscript is labelled Figure 2. Is the figure mis-labelled or is there a figure missing? Was a mistake: fig 1 is correct
Endometrial/uterine cancers don’t frequently metastasize to the bone, yet 15% of the bone metastases in the study are from patients with endometrial/uterine primary tumors, the same as breast cancer. Are there contributing factors to why endometrial/uterine cancer patients seem overrepresented in this study? Does the proportion of bone mets coming from these patients in this study reflect the proportion of bone mets coming from endometrial/uterine cancer patients in the region where the study took place?
No it’s a coincidence
Line 117: “’primitive” tumor should be changed to “primary” tumor. Done
All the added paragraphs are in green
Author Response File: Author Response.docx
