Title: Caspofungin Use in Daily Clinical Practice for Treatment of Invasive Aspergillosis: Results of a Prospective Observational Registry

Transcription

1 Author's response to reviews Title: Caspofungin Use in Daily Clinical Practice for Treatment of Invasive Aspergillosis: Results of a Prospective Observational Registry Authors: Johan Maertens (johan.maertens@uz.kuleuven.ac.be) Gerlinde Egerer (Gerlinde.Egerer@med.uni-heidelberg.de) Wan Shik Shin (fire@catholic.ac.kr) Dietmar Reichert (drreichert@online.de) Michael Stek (infdiseas@aol.com) Sheenu Chandwani (chandwsh@umdnj.edu) Malathi Shivaprakash (malathi_shivaprakash@merck.com) Claudio Viscoli (viscolic@unige.it) Version: 3 Date: 9 April 2010 Author's response to reviews: see over

2 COVER LETTER Dr. Melissa Norton Editor in Chief BMI Infectious Diseases April 9, 2010 Dear Dr. Melissa Norton, I would like to thank you for the second round of comments provided on our manuscript entitled "Caspofungin Use in Daily Clinical Practice for Treatment of Invasive Aspergillosis: Results of a Prospective Observational Registry". Enclosed please find attached the revised version of the manuscript. A response to each comment received from the reviewers and a description of the changes made in the manuscript have been included within this letter. We would kindly ask you to consider this paper for publication in BMI Infectious Diseases. The paper represents original work. It has not been published, and is not under consideration for publication, elsewhere. This study represents real world experience of a diverse patient population with Invasive Aspergillosis that can contribute to the increased understanding of the disease area. Partial content was presented at the 18 th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID) meeting in Barcelona, Spain, from April 19-22, All authors have reviewed the manuscript and concur with its submission. We look forward to hearing from you soon. Thank you very much for your time and consideration. Sincerely, Malathi Shivaprakash, MS [Corresponding author on behalf of all authors] Global Human Health Merck & Co., Inc. One Merck Drive P.O. Box 100, WS 2C-45 Whitehouse Station, NJ malathi_shivaprakash@merck.com Phone: Fax:

3 REVIEWER S REPORT I would like to thank the authors for modifying parts of the article as per my original recommendations. Major compulsory revisions: However, I feel that all the necessary changes required for publication have not been made. In particular the discussion section is too short and does not discuss features of the methods and the results that should be discussed. Below are some the analyses and discussion points that need to be performed and elaborated on in the results and discussion sections, respectively before this paper can be published. 1. Most importantly, the authors have not included in the discussion section any comment on the methods of classification of the certainty of diagnosis of IA used in the study and their impact on the response rate. The authors allowed local investigators decide based on clinical judgment and local practices as to whether the cases included fulfilled their local criteria for proven or probable IA and the reference standard (i.e. EORTC/MSG criteria) was given only as a guide. It was not compulsory to use the reference standard to classify cases. Failure to use the reference standard is likely to have resulted in misclassification of cases, make diagnostic criteria over-sensitive and hence introduce bias. Furthermore, cases with changes highly suggestive of IA on radiology were eligible for inclusion in this study as probable IA. According to EORTC/MSG criteria these cases would be classified as possible IA. It is likely that the investigators overcalled the certainty of diagnosis of IA and possible cases were included as probable cases. There are studies that report that the certainty of diagnosis of IA is proportional to the outcome or response rate (i.e. proven cases have poorer outcomes than possible cases - Furst et al Blood 2003; 102: Abstract 5534). Given the authors have not collected data on how precisely local investigators determined the certainty of diagnosis of IA they cannot determine the response rates for proven vs. probable vs. possible and cannot determine if there is a significant difference in responses according to certainty of diagnosis (i.e. if there is a significant difference in response rates for proven cases vs. possible cases). Thus, to say that there response rates were impressive without elaborating in the discussion section of this paper as to the above bias is to provide an unbalanced view of the efficacy of caspofungin to the reader. In order for the paper to be viewed as scientifically valid the bias of including possible cases as probable cases needs to be discussed extensively in the discussion section. You alluded to it in the last paragraph of the discussion in the sentence starting All sites were not mandated but did not discuss in the detail that it merits.

4 Please add a paragraph on the bias of the diagnostic criteria used and its impact on the response rates (potentially over calling efficacy) in the discussion section of the article. Response: Detail has been added to the discussion section regarding the possibility of having this type of misclassification of cases and its potential impact on the response: Diagnosis of proven and probable IA was based on investigators clinical judgment and local practice standards using the EORTC/MSG criteria as a guide. All sites were not mandated to provide comprehensive diagnostic information and treatment practices for IA, which may have varied between countries and regions. This could have resulted in misclassification of disease. Cases with changes highly suggestive of IA on radiology were eligible for study inclusion as probable IA, whereas EORTC/MSG criteria would categorize these cases as possible IA. Therefore, possible cases could have been included as probable cases resulting in a bias away from null and hence, an overestimation of response rates. 2. Fungaemia In my clinical practice (where I see up to 30 patients post stem cell transplantation or undergoing chemotherapy for haematological malignancies per week) I have only seen 1 case of Aspergillus fungemia in the last 5 years. In addition, on review of Girmenia s paper (Br. J of Haematol 2001; 114: 93-98) while the rate of fungaemia is 10.1% it is also noted that this amounts to 9 cases over 17 years. This equates to a case every 2 years. Yet in your study 8 cases were seen in 18 months. Even taking into consideration my concerns about pseudo-fungaemia and given the above I still think that the opinion that the rate of fungaemia in your study is unusually high, is still valid and a paragraph commenting on the high rate along with the reasons as to why (as given in your response to my first review) is necessary in the discussion section of your article. Response: Reason for a comparatively higher rate of fungemia has been added to the discussion section as follows: As an observational study, reports of fungemia were accepted as recorded by investigators and all patients with proven or probable IA were included. Many patients with A. fungemia have a low performance score and exhibit co-morbidities which excludes them from clinical studies, but not from registries; therefore, the number of fungemia cases in our study may have been greater than expected. 3. Survival in those on monotherapy is higher that for those who received combination therapy. This is not explored nor are any reasons given. Please explore the reasons in the discussion section. In your responses you commented Only 18 patients received combination therapy and this small sample size means that it may be a trend but no definitive conclusions can be made. I agree that with this number that no definitive conclusions are likely to be made. However, despite requesting that this is analysed in your review you have not done so. You have only made a conjecture. In addition, even if no significant differences were

5 seen no comment as to why monotherapy would produce higher survival rates than combination therapy has been made. Survival is likely to be worse for those on combination therapy because those patients selected out for combination therapy are likely to be sicker, with a greater burned of disease. This finding is worthy of comment in the discussion. Response: Following has been added to the discussion: It is also worth noting that survival was lower for patients who received combination therapy as this group was likely composed of a sicker population with a greater disease burden in comparison to those selected for monotherapy. 4. The reasons why this study needed to be done when we have the published results on the efficacy and safety of caspofungin in the non-trial setting from Glasmacher et al. JAC 2006; 57: are not clearly stated. What does this study add to that of Glasmacher et al? You still have not stated in the introduction as to why we need to publish this paper when we have the data of Glasmacher et al (as referenced above). Please add a sentence for the readers as to what this study adds to the current body of literature. Why should they read this paper? What does it add to their clinical practice? Response: Changes have been made in the Background section to address this comment as follows: Caspofungin is the first echinocandin approved for use in the treatment of IA in patients who are refractory to or intolerant of other agents. In this setting, caspofungin monotherapy has an overall success rate of 45% to 60% in the context of clinical trials [6-8] and outside clinical trials in an open case setting.[9] However, there is a need for continuing studies of caspofungin efficacy and tolerability because the efficacy of these agents may change over time and is likely to vary in different real-world practices compared with clinical trials. This article describes a prospective observational registry developed to assess daily clinical practice with caspofungin when used as monotherapy or in combination therapy for initial or salvage treatment of proven or probable IA.