Impact of Opioid Use on Duration of Therapy and Overall Survival for Patients with Advanced Non-Small Cell Lung Cancer Treated with Immune Checkpoint Inhibitors

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The authors compare the effect of opioid doses on Non-small cell lung cancer patients with Immune checkpoint inhibitor treatments. They found high dosages of Opioids lead to poor duration of treatment and overall survival rate. All the results successfully demonstrate the conclusion. This paper may be interesting to specific researchers in the field. The manuscript can be published by revising the following minor comments.

1. line 115: typo, bone metastasis, please check all the spelling over the whole manuscript.

2. figure 1, lacking od figure legend, blue and red lines representation?

3. figure 1, what is the time frame of the No. at risk? Please clearly label, including figure 2

 

 

 

Comments on the Quality of English Language

good

Author Response

Thank you for reviewing our submission. We have included a line by line reply to your review and recommendations.

1. line 115: typo, bone metastasis, please check all the spelling over the whole manuscript.

We have fixed this typo in line 115 as well as in other places where it appeared throughout the manuscript, including Figure 3 and Table 3. These can be seen in as edits with tracked changes. 

2. figure 1, lacking od figure legend, blue and red lines representation?

This was accidentally omitted from a prior version of the image. This has been corrected, blue is no/low opioid, red is high opioid.

3. figure 1, what is the time frame of the No. at risk? Please clearly label, including figure 2

The number at risk aligns with the tick marks on the graph (thus represent the number at risk at 6 month intervals). These numbers did not align well with the tick marks in Figure 1, which has been corrected. The numbers in Figure 2 align well with the tick marks. We have also included a description of this in the Figure 1 and 2 legends to help clarify this.

Reviewer 2 Report

Comments and Suggestions for Authors

The study "Impact of Opioid Use on Overall Survival for Patients with Advanced Non-Small Cell Lung Cancer" evaluated the impact of opioid use on the efficacy of immune checkpoint inhibitors (ICIs) in 209 NSCLC patients. The main finding of the study is that high opioid use, quantified as a Morphine Equivalent Daily Dose (MEDD) greater than 50, is associated with significantly shorter duration of therapy and reduced overall survival in patients with advanced NSCLC receiving ICIs. Study design and presentation of the results are quite appropriate for the scope of the manuscript. Overall, the study is well designed and the manuscript is well organized.I would like to offer the following points for consideration by the authors towards the improvement of the manuscript:

1- Please explain why you did not investigate the relationship between opioid use and PFS, but stated that it was correlated with DOT.

2- I think it would be appropriate to add to the title that the study was conducted in patients receiving ICIs.

3- “We defined high opioid use as an MEDD > 50” and “After initial review of the planned analysis, we subsequently divided the low/no opioid group into two groups: low opioid use (5 < MEDD < 50) and 98 no/minimal opioid use (MEDD < 5)”  What is the rationale for classifying opioid use according to these values (5 and 50) ?

4- A small percentage of the references are from the last 3 years. The inclusion of more recent results would be highly appreciated by the general reader interested in this topic.

 

 

 

 

 

Comments on the Quality of English Language

Minor editing of English language required

Author Response

We thank you for your review of our manuscript and appreciate your thoughtful feedback and recommendations. We have addressed your comments below.

1- Please explain why you did not investigate the relationship between opioid use and PFS, but stated that it was correlated with DOT.

We addressed this in our manuscript (see lines 78-84), but will provide additional rationale here. We had several reasons for which we felt DOT would be a more appropriate outcome measure in our study.

1) The surveillance imaging was not always consistent for our patients and we felt that this could influence and potentially bias PFS results

2) Due to the retrospective nature of the study and different intervals of imaging obtained without routine RECIST calculation collected in real time, we used DOT as a surrogate endpoint that approximates PFS in a more real-world approximation of duration of clinical benefit from ICI. DOT may overestimate PFS in cases where the treating physician treats beyond what would have been considered RECIST progression. Use of DOT as a surrogate endpoint is also supported by the paper we cite (ref 21) which shows that DOT correlates with PFS and OS in patients with NSCLC treated with ICI. There was a small minority of patients for whom the images were not available, which wouldn't allow evaluation of progression by RECIST. We worried that this also potentially would bias results by not including data from these patients.

3) Duration of therapy would also account for treatment beyond progression, which is clinically meaningful in patients with NSCLC treated with ICI. 

2- I think it would be appropriate to add to the title that the study was conducted in patients receiving ICIs.

We agree and have edited the title as follows:

Impact of Opioid Use on Duration of Therapy and Overall Survival for Patients with Advanced Non-Small Cell Lung Cancer Treated with Immune Checkpoint Inhibitors

3- “We defined high opioid use as an MEDD > 50” and “After initial review of the planned analysis, we subsequently divided the low/no opioid group into two groups: low opioid use (5 < MEDD < 50) and 98 no/minimal opioid use (MEDD < 5)”  What is the rationale for classifying opioid use according to these values (5 and 50) ?

We defined high opioid use as an MEDD > 50. This is based on a CDC Report offering prescribing guidance for opioid use (ref 22). The CDC identifies patients with an MEDD > 50 as higher risk for opioid overdose (in non-cancer patients) and considers > 50 and >90 and moderate and high opioid use levels. An MEDD > 50 (again predominantly in non-cancer patients) is associated with increased risk of overdose but without significant improvement in pain control per this report. We felt that combining these two higher opioid use categories would be an appropriate measure to identify patients with high opioid use based on established MEDD cutoffs instead of some other arbitrary cutoff.

We explain the rationale of the including an MEDD < 5 in the no opioid group in lines 323-330. This level of opioid use has been shown to differentiate occasional/intermittent opioid use and regular/scheduled opioid use (ref 35) and in a prior retrospective review was not associated with inferior survival, whereas opioid use > 5 MEDD was (ref 28). Since the purpose of this analysis was an exploratory analysis of the interaction of opioids and immunotherapy in addition to the known effect of opioids in advanced NSCLC, we chose to evaluate patients grouped in this way given these prior studies. 

4- A small percentage of the references are from the last 3 years. The inclusion of more recent results would be highly appreciated by the general reader interested in this topic.

We updated the discussion to include a couple of additional references showing additional data to further support an association with opioid use and inferior outcomes.

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

I am satisfied that the authors have addressed all of my previous concerns about the article. It is now much improved and I feel that it is now suitable for publication.

Comments on the Quality of English Language

Minor