Theoretical and Practical Implications of Treating Cachexia in Advanced Lung Cancer Patients
Round 1
Reviewer 1 Report
Dear Authors,
Thank you for your revised manuscript. I think that all the comments are responded and properly reflected to the revised manuscript. Although there is some limitations, all biases and limitations were discussed in the manuscript. I think this manuscript is now acceptable. Thank you for your all efforts.
Reviewer 2 Report
I accept the revised manuscript in its present form.
This manuscript is a resubmission of an earlier submission. The following is a list of the peer review reports and author responses from that submission.
Round 1
Reviewer 1 Report
This is a well written manuscript which accomplishes its mandate in reviewing theoretical and practical implications of treating cachexia. A brief formal description of cachexia as defined by Fearon et al. (international consensus) would be helpful. Review of the preclinical data available was helpful.
One query to the authors. I was unable to locate the Proctor et al. manuscript for review, but would the NLR be valid in a brain tumor patient on decadron (leukemoid inducing), receiving temozolomide (lymphocyte depleting)? Food for thought.
A few minor text-related notes:
22 - Provided the 46 - (6-9) 58 - strategies ( 73 - factor 15 (GDF 15) 127 - survival (17) 145 - (31) 211 - cancer (39) 318 - 319 - space 343 - scores in 344 - Eur J Cancer
Author Response
Responses to Reviewer 1:
1. In line 62, we state that the definition of cachexia was established at the International Cachexia Consensus Conference in 2011.
2. The abbreviation for the European Journal of Cancer is incorrect(Europ J Cancer). We have made the correction in the bibliography reference 41 - (Eur J cancer).
3. In lines 322-323, we respond to and agree with the reviewer’s comment that neutrophil/lymphocyte ratios might not have prognostic value in patients receiving corticosteroids.
Reviewer 2 Report
Authors reported the theoretical review of pharmacological treatments for cancer cachexia with a special focus on the combination of anticachectic and anti-PD-1/PD-L1 treatment in patients with lung cancer. Selection of themes was appropriate and cited references were properly updated. However, there is an imbalance between clinical and experimental evidences in each section. Accordingly, I think this manuscript needs following revisions.
Major comments
1) In the 2nd section (Page 2, Line 61), most of discussion was based on the experimental studies in animal model. To realize the clinical implication of author's discussion about overall survival, we need data about previous clinical trials for cancer cachexia which aimed to improve overall survival in human. It would tell us the difficulties in reproducing positive outcomes of animal experiments in clinical trials in human. For example, authors introduced the positive effect of ActRIIB inhibitor on survival of mice. However, a recent phase 2 trial of antimyostatin antibody (LY2495655) in patients with pancreatic cancer failed to improve overall survival that was a primary endpoint of this trial.
2) In the 3nd section (Page 2, Line 86), most of the discussion was based on the observational study and clinical trials. To realize the clinical implication of author's discussion about toxicity, we need discussion on possible reasons for that such as PK/PD of anticancer agents in cachectic human or animal model.
3) In the 4th section (Page 3, Line 118), most of the discussion was based on the observational study and clinical trials. We need plausible explanations based on the experimental studies for association between presence of cachexia and efficacy of immunotherapy. For example, there was several experimental studies which suggested the immunomodulating effects of leptin, IL-6, or corticosteroid in cachectic patients which may explain the association.
4) A lack of agreement regarding endpoints is very important issue in this area, as discussed in the 5th section (Page 4, Line 146). However, most of the discussion on endpoint in this report was based on the recent clinical trials for several emerging anticachectic medications and a multimodal study. To discuss endpoints systematically in this area, we need more broad aspect based on a large amount of historical studies tesing a variety of anticachectic interventions including nutrition, exercise, ONS, EPA, thalidomide, anticytokines, progestins, or NSAIDs.
Minor comments
5) Please show the reason for describing "nutritional status is the most difficult parameter"(Page 4, Line 187). Nutritional status was usually assessed by PG-SGA, MNA, MUST, or NRI in the previous clinical trials or guidelines for cancer patients (e.g. ESPEN guideline).
6) Please show the trial registration No. of the trial. (Page 4, Line 195)
7) I think that most of discussion in this report was not specific for lung cancer. I think it better to generalize the authors' hypothesis to other types of cancers associated with cachexia in the Summery section (Line 216, Page 5).
Author Response
Responses to Reviewer 2:
1. As recommended, we have classified preclinical and clinical studies. In the heading for section 3(line 74), we have stated - " preclinical and clinical" studies. In lines 74 through 134, we have introduced and discussed results from three new references describing survival results in cachexia studies: 1. Natoi(ref 38) -a review of randomized interventional cachexia trials which included a section describing overall survival results in 32% of these randomized studies. New text in lines 96 to 106 summarizes results of this review. 2. We included the trial which reported results for overall survival in cachectic pancreatic cancer patients treated with an antimyostatin antibody versus placebo(Golan T, ref 30). New text regarding this trial has been added lines 110 to 117. 3. We also described survival results of a relatively large cachexia trial in colorectal cancer patients testing creatine vs placebo (Jatoi A Ref 29). New text added in lines 107 to 110. Discussion regarding the need for carefully designed trials to evaluate the potential relationship between overall survival and cachexia treatment was also included at the end of the section in lines 118 to 133.
2. We agree the reviewer that PK/PD studies might provide an explanation for increased toxicity which has been associated with cancer treatments. However, we are not aware of studies which have evaluated these parameters in cachectic versus non-cachectic cancer patients. Our response is stated in new text - lines 158 to 167 in section 3. Two possible explanations for increased toxicity related to cancer treatments in cachectic patients are included in the new text.
3. We agree that increased understanding of the relationships between molecular and cellular interactions involved in immune response in cachectic cancer patients is needed. However, while these studies are being done, we believe that preliminary observations support looking for a signal in a small clinical trial. Additional comments addressing the reviewer’s concern have been added in the last paragraph of the 4th section. Our response is discussed in new text – lines 215 to 226.
4. We did not plan to provide a comprehensive discussion of endpoints from previous clinical trials. We believe that the endpoints in the recently completed and current phase III lung cancer cachexia trials are pertinent because they are considered to indicate clinical benefit. Our response is contained in new text – lines 232 to 234.
5. We agree that the statement describes " nutritional status is the most difficult parameter" is inappropriate. We have revised the section. We believe that a validated patient reported outcome instrument is a reasonable way to assess symptoms which impact nutrition. Our response is stated in new text in lines 285 to 291.
6. The NCT numbers for the trials are included in lines 260 & 262.
7. In our summary, we have stated that results from lung cancer trials could have implications for patients with other types of malignancies – lines 341 – 342.
Reviewer 3 Report
GENERAL COMMENTS
This is a review article in which the implications of treating cachexia syndrome in patients with advanced lung cancer has been extensively reviewed. In general, the manuscript is very well written and focused. I only have a few concerns that are specified below.
SPECIFIC MAJOR COMMENTS
1) The manuscript should be divided according to studies published in humans and those based on the use of animal models. In each section, please make the difference between animal-based and patient-based studies.
2) Something on the geographical distribution and the prevalence of cachexia in advanced lung cancer patients should be described as lung cancer is progressively being diagnosed at earlier stages in certain countries and regions. This may question the prevalence of cachexia in this type of cancer patients. This should be at least acknowledged in the review.
3) A table in which the different ongoing trials/studies should be listed and described would be welcome in the review.
4) Consider adding a figure in which the relationships between lung cancer, cachexia and the different therapies should be described.
5) Differences between therapies exclusively targeted to treat cachexia per se and those aimed to treat the tumors, which nevertheless may also attenuate cachexia in the patients should be clearly made in the review. A figure/table summarizing those differences should also be included in the review.
Author Response
Responses to Reviewer 3:
Reviewer 2 also asked that we clarify preclinical versus clinical studies. We have addressed this recommendation in our first response to reviewer 2 in lines 74 – 134.We agree that there is likely to be a paradigm shift in lung cancer stage as result of chest CT screening initiatives, and we have discussed this possibility in the introduction(Lines 33- 40). We have also stated that cachexia is more common in patients with higher stages of cancer( lines 33/34, Ref 1). National databases do not include cachexia data(Ref 1), and we are not aware of publications comparing the frequency of cachexia based in different regions of the world. Therefore, we did not include a statement regarding prevalence of cancer cachexia in different geographic regions.
We have included new text in lines 265-268 and added Table 1 which lists ongoing interventional cachexia trials. These lines also reference a recent review which has a table that lists some recently completed interventional cachexia trials.(1)
Comprehensive reviews including reference 1 have discussed mechanisms involved in cachexia. We believe that this figure is not warranted.
We agree that cancer specific therapy can be associated with weight gain probably as a result on tumor regression and inhibition of mechanisms involved in cachexia. However, there is relatively little information regarding body weight changes during lung cancer treatment. We believe that reference 35 is the first report describing weight change during first-line platinum based chemotherapy in stage IV non-small cell lung cancer patients. This study was a post-hoc analysis that included 2300 non-small cell lung cancer patients who participated in three randomized trials. There are also three reports of weight change during treatment with chemotherapy/radiation therapy in stage III non-small cell lung. We did not include these reports because they are small retrospective studies. Discussion related to these points has been added as new text in lines 215 – 226.
In addition, to our responses listed above we have modified the bibliography.
References 2 and 28 – 30 are new. Previous references 28 & 29 have been deleted because they were already included as references 16 & 17.
