Palifermin Compared to Supersaturated Calcium Phosphate Rinse in Prevention of Severe Oral Mucositis after Stem Cell Transplantation in Patients Receiving Radiotherapy-Based Myeloablative Conditioning

Round 1

Reviewer 1 Report

Hadid and colleagues present comparative data on the use of Palifermin or supersaturated Calcium Phosphate rinse (SCPR) to prevent oral mucositis (OM) after hematopoietic stem cell transplantation. The design of the study is not randomized but sequential. According to their data Palifermin was superior to SCPR in preventing severe (WHO grade 3 and 4) OM. The study is sound and clean but there are some major drawbacks.

- The data is more than 10 years old. Patients were treated between 2008 and 2012. Protocols have changed substantial since then.

- Several studies showed that Palifermin reduced severe mucositis especially when used with myeloablative conditioning (MAC) including TBI. However, the FBT regimen described in the study combines full dose (4x 3,2mg/kg) Busulfan with 4 Gy TBI and therefore is extremely toxic. At least in Europe it is rarely used these days.

- The title therefore should include the information that the study only included MAC TBI conditioning. In the present form the title is too universal.

- there is no information how many of the patients treated with allogeneic HSCT received MTX as GvHD prophylaxis and if this was balanced between the groups,

- Table 1 has to be re-formatted

Author Response

Please see the attachment

Author Response File: Author Response.pdf

Reviewer 2 Report

The study is a retrospective study that aims to compare the efficacy of supersaturated calcium phosphate rinse (SCPR) and the efficacy of palifermin in the prevention of severe oral mucositis (OM) in patients who underwent conditioning regimens for hematopoietic stem cell transplantation (HSCT). The study is interesting and the manuscript is well-written. There are some issues that should be considered;

In the abstract, it is recommended to improve briefly the description of the methods of the study by adding the inclusion and exclusion criteria, the groups considered, and the evaluation methods.

In the whole manuscript and in the introduction in particular, the authors didn’t consider the discussion of the studies and the clinical guidelines proposed by the very important associations regarding this argument; which are the “Multinational Association of Supportive Care in Cancer” and the “International Society of Oral Oncology” (MASCC/ISOO). It is recommended to include their works in the introduction and the discussion section in the manuscript.

Here is one of their works; Elad S, et al. Mucositis Guidelines Leadership Group of the Multinational Association of Supportive Care in Cancer and International Society of Oral Oncology (MASCC/ISOO). MASCC/ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy. Cancer. 2020;126(19):4423-4431.

In the methods section, it is not clear how the authors compared the severity of OM between the two groups. Is the percentage of the maximum grade of OM in each group considered and compared eventually? If yes the word maximum should be added and an improvement of the description of the analysis should be performed.

An example of this confusing point can be seen obviously in figure 1, where it is not clear if the percentage of each grade in each group is the percentage of patients who experienced this maximum OM grade or not. Please a declaration of this crucial point should be addressed in the manuscript and in the figures and tables.

The authors stated that “Patients are assessed daily for the development and severity of OM by an experienced transplant physician beginning on the day of transplantation and continuing until neutrophil engraftment or resolution of OM, whichever is later.”. Based on that the duration of the overall OM and the duration of each OM grade for each group are important variables that should be considered for the comparison of the severity of OM between both groups. It is recommended to calculate in each group the duration of the overall OM and the duration of each OM grade and then compare them statistically between both considered groups.

Before undergoing the transplantation procedures, this kind of patients should be subjected to a comprehensive oral examination to treat and eliminate all the potential sources of oral infection that might compromise the transplantation procedures, and increase the risk of OM development. Is this procedure considered in the study or not? If yes please discuss that in the methods section. If not, this is a significant limitation that should be declared and discussed because it probably means that the patients are not completely equal at the baseline phase.   

In the discussion, it is recommended to compare the results of this study with other proposed prevention protocols for OM; for example Photobiomodulation (PBM) protocols, here you can find some recent studies;

- Zadik Y, et al. Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO). Systematic review of photobiomodulation for the management of oral mucositis in cancer patients and clinical practice guidelines. Support Care Cancer. 2019;27(10):3969-3983.

- Mohsen A, et al. Photo-Biomodulation as a Prevention Modality of Oral Mucositis in Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation. Applied Sciences. 2020; 10(21):7479.

Author Response

Please see the attachment

Author Response File: Author Response.pdf

Round 2

Reviewer 2 Report

The study is improved after the revision.