Proton Pump Inhibitors and Oncologic Treatment Efficacy: A Practical Review of the Literature for Oncologists

Round 1

Reviewer 1 Report

I read with interest the impressive overview article on PPI use and different oncologic treatments. The authors provided a thorough overview of the literature until now, so it will be a very good resource for references AND a useful document to check for the clinician. Although I know the PPI literature quite well, I am surprised they found so many studies specifically for the cancer patient. I especially like the table!

I only have some suggestions, which could make the picture more complete. I would discuss or at least mention, is the potential carcinogenic effect of PPIs per se (still a very hot debate within the gastroenterology field, with rapidly increasing evidence questioning the safety of long-term use, not only because of the reported cancer risk); and that there are also studies published which show they have a detrimental effect on overall survival, and cancer specific survival. So even if there is no evidence to date for an interaction with cancer treatment, there may be other reasons to reconsider the need for treatment with anti-acid drugs (and other drugs). It seems an individualised approach will always be warranted for each cancer patient, taking into account probability of survival and quality of survival.

What I do miss, is a short discussion on different cancer types. I am a clinical epidemiologist, and not an oncologist, so I am not that familiar with the specific drugs – but I wonder if there could be a different risk of adverse effects depending on the cancer type. I know some of the presented drugs are already cancer-type specific. It is pharmacokinetics/dynamics – so theoretically it shouldn’t matter. But if it is a gastro-intestinal cancer, PPI use can also have a “direct” effect on the gastro-intestinal mucosa and tumour, also through microbiome alterations (which could in turn affect PK/PD). But at the other hand, those are the patients with the highest clinical need for anti-acid drugs…

Author Response

Dear Reviewer,

 

Thank you so much for your inputs.

- Paragraph 3 explains in general the main mechanisms that might explain interactions between cancer drugs and PPIs. Then, for which class of drugs, we try to explain the mechanism, when there is one described. Some studies are cancer-specific, but others are not. In terms of the organization of the manuscript, we preferred to divide DDIs by classes of drugs instead of by cancer types, since data are much stronger according to classes of drugs.  

- We added a sentence to the last paragraph of the introduction: Although growing body of evidence suggests both pro- and anti-carcinogenic associated with PPIs, those associations will not be explored in thus manuscript.

Given the already extensive manuscript, we believe it would take another manuscript to discuss about that.

 

Best regards,

Reviewer 2 Report

Authors present a review entitled “Proton pump inhibitors and oncologic treatment efficacy: a practical review of the literature for oncologists” in which they summarize the state of the art of possible interactions of PPI treatment on anti cancer drugs absorbance. The topic is really relevant and the review is well conceived, even though some key points should be clarified:

• Authors should not generically talk about PPI, but specify if there are differences enlighten between the different  proton pumps inhibitors used and if so, specify those differences;
• Table 1 should be improved by adding a column indicating, if possible, which PPI was used and what type of interaction was made evident;
• Authors are suggested to add a general paragraph summarizing the main mechanism of interactions which occur in PPI administration in concomitance with anti-cancer treatment.

 

Some minor typos and formatting issues should be revised:

• superscripts e.g H^+;
• font consistency;
• paragraph 9, please space correctly;
• revise References for format and character font.

Author Response

Thank you so much for your inputs. Here are our answers:

- Most studies did not specify which PPI was used. When so, we did cite which PPI was being considered. When PPI was used, it means that studies did not specify which one was used.

- Paragraph 3 explains in general the main mechanisms that might explain interactions between cancer drugs and PPIs. Then, for which class of drugs, we try to explain the mechanism, when there is one described. Some studies are cancer-specific, but others are not.

- We could not find the error in spacing from paragraph 9.

- In terms of adding a column in Table 1 regarding which PPI and which type of interaction, we tried to consider that. However, as explained before, most studies did not specify which PPI was used. In addition, explanations regarding mechanisms of actions can be find in the main text. Another column in the Table would make the Table less friendly.

- We added a sentence in the last paragraph from the introduction section explaining that there are no data by tumor types.

Round 2

Reviewer 2 Report

The answers the authors give about the issues arouse in first round revision are satisfactory. 

I would suggest, for clarification, to specify in paragraph 3 that some studies are cancer-specific, while some aren't.

Same for Table 1, specify in capture that mechanisms have been better elucidated in the main text.

Error in spacing in paragraph 9 has been solved (title spaced from the text and in a different page).

 

Author Response

Thank you so much!

 

IWe have specified in paragraph 3 that most studies are not cancer-specific.

In Table 1, we have specified in capture that mechanisms have been better elucidated in the main text.

Author Response File: Author Response.doc