The Feasibility of Immunocryosurgery in the Treatment of Non-Superficial, Facial Basal Cell Carcinoma That Relapsed after Standard Surgical Excision: An Experience Report from Two Centers

Round 1

Reviewer 1 Report

I enjoyed reviewing this article entitled "The feasibility of immunocryosurgery in the treatment of non-superficial, facial basal cell carcinoma (BCC) that relapsed after standard surgical excision: A retrospective experience report". Indeed this non-ablative therapy, as an alternative to surgical treatment for BCC, seems promising. Indeed, more than half of treated patients were relapse-free with immunocryosurgery after five years of follow-up. 

However, the number of cases is not high, considering the two centers included in the study. Therefore, some points need to be clarified: 

-Were aggressive histological subtypes of BCC, such as basosquamous carcinoma, included in the study?  

-How many cases were from each center?

- How can you explain that the treatment effectiveness is not affected by the patient's age and tumour size? Please clarify this aspect.

 Although imiquimod is considered valid and substantially safe, cases of progression are possible, are there some hypotheses about the presence of some resistance mechanisms against this topical immune modifier?

Author Response

Dear Editor

The Authors wish to express their appreciation to the Reviewers of the Manuscript curroncol-1948523 entitled “The feasibility of immunocryosurgery in the treatment of relapsed basal cell carcinoma after standard surgical excision: A retrospective experience report” for the time and effort spend to improve the manuscript.

The Text and Supporting material have been adapted according to Reviewers suggestions in order to improve the readability and context of the manuscript. Point to point answers to Reviewer Comments follow.

Yours Sincerely

Georgios Gaitanis

Open Review

Comments and Suggestions for Authors

 

I enjoyed reviewing this article entitled "The feasibility of immunocryosurgery in the treatment of non-superficial, facial basal cell carcinoma (BCC) that relapsed after standard surgical excision: A retrospective experience report". Indeed, this non-ablative therapy, as an alternative to surgical treatment for BCC, seems promising. Indeed, more than half of treated patients were relapse-free with immunocryosurgery after five years of follow-up.

Authors’ response: The authors thank the Reviewer for the supporting comments. 

Reviewer’s query 1: However, the number of cases is not high, considering the two centers included in the study.

Authors’ response: Thank you for the opportunity to clarify that for patients with BCC relapse after surgery immunocryosurgery is offered as second-line treatment modality (p. 2; lines: 85-86).

Therefore, some points need to be clarified: 

Reviewer’s query 2: Were aggressive histological subtypes of BCC, such as basosquamous carcinoma, included in the study?  

Authors’ response: STable 1 has been amended to include the histological subtypes of the included tumors. A relevant sentence was added to the Results section (p. 3; lines 136-7).

Reviewer’s query 3: How many cases were from each center?

Authors’ response: Twenty-three tumors were treated in Greece and the remaining in Switzerland. A relevant sentence was added in the section ‘Results’ (p. 3; lines: 134-6).

Reviewer’s query 4: How can you explain that the treatment effectiveness is not affected by the patient's age and tumour size? Please clarify this aspect.

Authors’ response: We would like to suggest that the aggressiveness of the tumors, as indicated by the history of multiple relapses prior to immunocryosurgery, is a strong predictor that probably integrates aggressiveness contributions of different factors, including tumor size. Moreover, the dispersion of the ages of the patients and of the tumor sizes is comparatively modest. Particularly, except for 3 cases, the rest 24 tumors measured <20mm in largest diameter, tumor sizes for which we have previously shown that there is no difference in therapeutic outcomes with immunocryosurgery (see References 2 and 3 of this paper).   

Reviewer’s query 5: Although imiquimod is considered valid and substantially safe, cases of progression are possible, are there some hypotheses about the presence of some resistance mechanisms against this topical immune modifier?

Authors’ response: Thank you for this constructive comment. Indeed, imiquimod is a highly efficacious modality for BCC, especially in the framework of immunocryosurgery that ensures a brisk inflammatory response, known to be connected to higher efficacy rates. However, in cancer therapy, irrespective of applied therapeutic modality, treatment failures cannot be totally prevented: a 100% effectiveness is an unrealistic goal. Treatment failures may be linked to either pharmaco-biological or not mechanisms. Especially many self-applied non-surgical treatment modalities of skin cancer, including imiquimod, depend significantly on patients’ compliance. In addition, because of the relative higher uncertainty regarding the recognition of the borders of the primary tumor -higher risk compared to the better recognizable surgery scars-, recurrent new primaries in the vicinity of the formerly treated BCC may be erroneously diagnosed as relapses. Regarding drug resistance, there is some evidence in the literature that certain polymorphisms in the X-chromosomal TLR7 gene might cause resistance to imiquimod, mediated through reduced TNF-α levels have been proposed as a possible mechanism. As extensive analysis of these resistance mechanisms would be out of scope in this article, we only included a small comment (page 7, lines 257-261) and two additional references (Ref 29; 30) for further elaboration by interested readers.    

 

Reviewer’s query 6: On which basis did you define complete response to treatment? Did you perform a biopsy and histologic examination, or it was defined on clinical and dermoscopic grounds only? If yes, you should include this as a limitation (lack of histologic confirmation of response). 

Authors’ response: Immunocryosurgery is a minimally invasive therapeutic approach. The assessment of short-term treatment outcomes of BCC with this modality, including complete response; is accordingly based exclusively on the non-invasive evaluation of the treated site, with the same clinical criteria used to approach the diagnosis of lesions suspected of BCC. It is worth noting, that one of the main ‘end-points’ used to measure the therapeutic efficacy of any anti-neoplastic modality is the relapsing behavior of the treated cases as a function of the follow up time. The post-treatment histologic examination of the treated tumor site is, actually, a ‘proxy’ evaluation procedure that does not ‘confirm complete treatment response’. Please, note that this is in accordance with the observation of relapse events after ‘histologically verified’ surgical treatments of BCC (including Mohs’ surgery). For these reasons we do not agree that the ‘lack of histologic confirmation’ is a drawback of immunocryosurgery to be discussed as a limitation of this modality in this article.

 

Reviewer’s query 7: Please include data about the histological subtype of treated BCCs. The histological subtype of BCC must be included in the Cox model and assessed as a potential predictor.

Authors’ response: Data on histological subtypes of immunocryosurgery-treated relapses are now included in Table S1. A corresponding comment was also added in the section Results (p. 3, lines 136-8). Histology was explored -together with the 4 presently shown factors- in a 5-predictors Cox model; it did not modify the reported conclusions. Based on significance considerations and because histology is known to either remain the same (majority of cases) or become more aggressive (most of the rest) after relapse we suggested that the corresponding predictive information was already integrated in the event of the relapse prior to immunocryosurgery and was further propagated as a relapse risk after immunocryosurgery. Consequently, to guarantee the reliability of the reported Cox analysis with 27 included subjects in the present study we had to restrict the reported model to 5 variables (Vittinghoff E, McCulloch CE. Am J Epidemiol 2006; 165: 710-8), focusing consequently on the four most significant regressors. Based on above arguments we did not add any comment on the predictive impact of histology in this paper.    

 

 

 

Reviewer 2 Report

On which basis did you define complete response to treatment? Did you perform a biopsy and histologic examination, or it was defined on clinical and dermoscopic grounds only? If yes, you should include this as a limitation (lack of histologic confirmation of response). 

Please include data about the histological subtype of treated BCCs. The histological subtype of BCC must be included in the Cox model and assessed as a potential predictor. 

 

Author Response

Reviewer’s query 1. On which basis did you define complete response to treatment?

Authors’ response. Thank you for the opportunity to clarify this point. Corresponding information was added in the revised text (p. 3, lines 108-111 and 114-117). Please note also our response to the related query #6 of Reviewer 1, above.  

 

Reviewer’s query 2. Did you perform a biopsy and histologic examination, or it was defined on clinical and dermoscopic grounds only? If yes, you should include this as a limitation (lack of histologic confirmation of response). 

Authors’ response. Please refer to our response to the similar query #6 of Reviewer 1, above.

 

Reviewer’s query 3. Please include data about the histological subtype of treated BCCs. The histological subtype of BCC must be included in the Cox model and assessed as a potential predictor. 

Authors’ response. Please refer to our response to the similar query #7 of Reviewer 1, above.

Round 2

Reviewer 1 Report

I suggested the article in its present form