Title: Additional parenteral nutrition support for patients with pancreatic cancer. Results of a phase II study.

Transcription

1 Author's response to reviews Title: Additional parenteral nutrition support for patients with pancreatic cancer. Results of a phase II study. Authors: Uwe Pelzer (uwe.pelzer@charite.de) Mehmet Goevercin (mehmet.goevercin@charite.de) Jens Stieler (jens.stieler@charite.de) Dirk Arnold (dirk.arnold@medizin.uni-halle.de) Bernd Doerken (bernd.doerken@charite.de) Hanno Riess (hanno.riess@charite.de) Helmut Oettle (helmut.oettle@charite.de) Version: 7 Date: 2 March 2010 Author's response to reviews: see over

2 Charité Campus Virchow-Klinikum Berlin Charité Department of Hematology/ Oncology Director: Prof. Dr. Dörken CONKO study group Dr. med. U.Pelzer Prof. Dr Hanno Riess/ PD Dr. H. Oettle Tel Fax Dear Editor, many thanks for your comments to our paperwork. We revised the paper according the terms and conditions of the reviewers point by point. Thus we think the paper is more appropriate for your journal. The paper was checked again by a commercial copy editing service. Sincerely yours Uwe Pelzer MD and Helmut Oettle PHD Attachment: - point by point revision

3 Dear reviewers, thanks for the comments. We revised the paper according your terms. - Referee #1 Comment 1. Background, page 5, last paragraph: here the BIA parameter index of extracellar mass to body cell mass is mentioned as one of the parameters of investigation. However, only the phase angle is introduced in the text above. Please also introduce the ECM to BCM index in the background section. Action 1: Agreed, ECM/ BCM index was introduced. Comment 2. Methods, page 6, 1st paragraph: it is stated that the patients were prospectively evaluated. It is not clear what is meant by this. Please clarify and include this in the methods section. Action 2: Phrase changed at page 6, 1st paragraph. We wanted to point out the prospective character of this assessment. Comment 3. In the discussion session it what stated that patients were treated with APN until patients or the physician did not see further benefit from APN. Was this the

4 only reason to quit APN support? Or where there other reasons as well. If so, please include this information in the results section. Action 3: There were no other criteria or severe side effects in treated patients. Comment was added in the results section. Comment 4. The increase in phase angle is 10%. Is this a clinically relevant change? Please elaborate more on this. Action 4: Our study design did not allow us to draw conclusions as to the clinical relevance (eg.: overall survival, quality of life) of our findings. Comment was added. Comment 5. Where there complications developed due to the treatment with APN (such as infection or mechanical problems)? This could also be a reason to quit treatment with APN. If so, please include this information in the results section. Discussion (page 8-10) Action 5: There were no other relevant reasons to stop the APN in these pts.. Comment was added. Comment 6. In this trial, no control group was used (= people not receiving APN), everyone got treated with APN. This would of course, not be ethical in this case. But please, give some attention to this in the discussion session what this would

5 mean for the results found in the current study. Action 6: Well, discussion was extended. Comment 7. Page 8, 1st paragraph: the main conclusion is that you observed an improvement of nutritional status for the majority of patients, in particularly in phase angle. I disagree with this conclusion, since the same number of patients improve according to BMI and ECM/BCM index (n = 16 and 15, respectively) compared to phase angle (n=15). I would like to suggest to you to change your conclusion in your article and abstract. Action 7: Phase angle was the main target for this study, so we highlighted this fact. The direct correlation between phase angle and overall survival was published by Gupta, thus we wanted to influence particularly the phase angle by APN. But agree with your opinion, we generalised our conclusion. Comment 8. What do you mean with the sentence (on page 8, 1st paragraph): We also had to recognize that there is no benefit from parenteral intervention in cancer patients in general? On what do you base this, since in the sentence before this one, you conclude that you observed an improvement of nutritional status (of 84% measured by at least one parameter)? How is then the nutritional status improved if it s not due to APN? Please clarify.

6 Action 8: We wanted remark, that the APN is not an imperativ intervention for all cancer patients. We deleted this phrase because this fact is generally accepted and we do not have to point out this here. Comment 9. Page 8, 2nd paragraph: the parameters and values as starting point for APN comes a little out of the blue. This was not one of your research questions. This could, in fact, be a whole new paper. Please elaborate more on this topic (how did you come to these recommendations) and it may be better to speak of a suggested recommendation by you, the authors of this paper. Or maybe just leave it out. Action 9:Thanks, you right. That is to overgrowth. We deleted this passage. Comment 10. In addition, the nutritional status of the patients under investigation in the current paper, did improve, but not enough according to your recommended starting point for APN. In fact, doctors and patients quitted the treatment with APN, while according to your suggested recommendations, they should continue treatment. Could you please try to clarify/elaborate more on this? Action 10: See action 9, we deleted the passage. The results of the study displayed the best response during intervention. Longer treatment did not lead to higher response. We added a comment.

7 Comment 11. Page 9, 2nd paragraph: you mention that phase angle is a superior predictor of survival compared to e.g., albumin etc. Gupta et al, 2004 has concluded this from their study. Are there other studies that concluded the same? If so, please include these references here. Or otherwise, tone this statement a little bit down. Now it is presented as a fact, which is not the case if only one study has concluded this from their study. Action 11: Right, we disarmed the phrase. There were no other studies support these findings by pts. with APC. Comment 12. Page 10, 2nd paragraph: you stated that difficulties in the analysis process were also based on the indivudidually tailored therapy. How did you try to counter these problems? I can t find anything in the current paper how you ve tried to deal with this? Please include this information in the current paper. Action 12: Phrase were changed into: Difficulties in the analysis process were caused by the individually tailored chemotherapy, supportive drugs, patient opinion, course of disease and complicated assessment of remaining enteral nutrition. Due to the small size of the study we were not able to exclude these influencing variables or arrange them in subgroups. Patients were treated with APN until they or their physicians did not see further benefits from it.

8 Tables and figures: Comment 13. The titles of the figures and tables are too short. It is impossible to understand what the figures/tables describe, without reading the text of the paper. Tables and figures, however, should stand on its own. And Table 1 presents only the characteristics at start of the APN. Please mention this in the title of the table. Action 13: Titles were amended. Minor essential revisions Abstract (page 2-3): Comment 14. Background abstract (page 2): the information described here is nowhere to be found in the background of the article itself. Please either include this information in the article or rewrite this part of the abstract. Action 14: The background parts were revised. Background (page 4-6): Comment 15. Background, page 5, 1st paragraph: there is no introduction sentence that states that BIA would be a better parameter to measure nutritional status. Please include that in this paragraph. Now it is not clear why BIA is measured in this study.

9 Action 15: Statement was included. Methods (page 6-7): Comment 16. Include how many patients are evaluated, only the 32 patients included in the trial, or more patients? Action 16: We added more information to the results section: Sixty five ambulant pts with histologically proven APC had been screened between January 2002 and January 2004 in our university outpatient clinic in Berlin/ Germany. 32 of them suffered from marked progressive cachexia and were willing to receive APN. Comment 17. Could you please include in this section how the pancreatic cancer patients are diagnosed? And how many have histologically confirmed pancreatic cancer? Action 17: All pts. had a histologically proven pancreatic adenocarcinoma. Comment 18. Also, please include in which hospital/area/country the patients were recruited. Action 18: Well, included in the results section.

10 Results (page 7-8): Comment 19. Were all patients still alive at the end of the intervention? Or were some of the patients deceased? Please add this information to the results section. Action 19: Information included at page 8. Discussion (page 8-10) Comment 20. Page 8, 2nd paragraph: should phase angle below 5% not be 5? Action 20: Discussion was revised. Comment 21. Page 9, last paragraph: include a reference after the first sentence. Action 21: Reference was included. Tables and figures: Comment 22. Include in the figures and tables the units used, such as nr of patients, %, kg/m2 etc. Also include in table 1 whether these are median values or mean values. Action 22: Requirements were supplemented.

11 Discretionary revisions Background Comment 23. Page 4: I should not abbreviate the word patients. Action 23: Well, changed. Results (page 7-8): Comment 24. Maybe it would also be informative to include in the results section how the distribution of the duration of treatment with APN is among the patients. For example: nr of patients who received <10, 10-20, 20-30, >30 weeks of APN treatment. Action 24: Additional pts characteristics were included in table 1. Further details are not worth mentioning because the small data do not support more conclusions(e.g.: correlation between duration of treatment and benefit, more benefit for pts with lower BMI at start of intervention, gender/ age - benefit correlation...). Use of English language

12 Comment 25. Background article, page 4, 3rd paragraph: Even though English is not my native language, I believe that to achieving is not correct. I believe this should be to achieve. Action 25: Well, corrected. Comment 26. Discussion, page 9, 2nd paragraph: Phase angle is a superior prediction of survival than I believe the word than can not be used in this context. Action 26: Well, corrected in conclusion with comment 11. Comment 27. Discussion, page 9, 2nd paragraph: Bedside BMI ; should this not be Besides BMI? The rest of the sentence also does not sound right, I think it should be: Besides BMI or specific weight loss the ECM/BCM index is also a know tool for nutritional assessment. Action 27: Well, revised. - Referee # 2 Comment 1.) Some of the manuscript would still be improved with grammatical changes. Specifically sentence structure & tense of verbs. For example, in the abstract background

13 section, second sentence, needs to be clear that referring to patients or people with APC that are suffering from malnutrition. Could be changed to most of "these patients are" suffering from malnutrition. In the abstract conclusion sentence, need to add that you "are" currently investigating the impact of APN "on" survival. When refer to NCI guidelines, should be NCI's guidelines in background section. Also in background section, remove the ly after examiner-dependently. Last 2 sentences in background section need work. Investigated APN "on" nutritional status of pts would improve readability. In discussion, refers to phase angle in percent. Remove percent. Would recommend proofing paper again for abbreviations, sentence structure, & tense of verbs to improve readability. Small, similar changes as mentioned throughout paper would improve readability. Action 1: Well, thanks for your details. Phrases were checked and revised. We think that NCI guidelines are generally accepted in the comprehensive cancer care and there is no need for special reference. Comment 2. In the discussion section, in what appears to be the second paragraph, there is reference to bedside BMI, which I think should be bedside BIA or sentence needs to be changed to Besides BMI. It is not clear what is being conveyed here - is it bedside BIA or besides BMI or clinically significant weight loss, the ECM/BCM index is a known tool... Clarify this change so reader knows if referring to BMI or BIA & add commas for better reading.

14 Action 2: Sorry for that inaccuracy, correct phrases should be Besides BMI. Comment 3. In discussion section, under limitations, may want to reference the limitations you mention. This sounds identical to writing in Gupta et. al., particulary as it relates to how some limitations were controlled for. Would suggest adding reference. Action 3: As mentioned in the methods section we used the same procedure like other research groups (e.g. Gupta et al). So we had to deal with the same limitations. We also included the reference from Gupta et al in this section. Comment 4. All other previous recommendations appear to be addressed.