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Treatment of Metastatic Non-Small Cell Lung Cancer Evidence-based Synthesis Program

Appendix A. Search Strategy for Systematic

Reviews and Cost-Effectiveness Analyses

(Search #1)

TREATMENT OF METASTATIC NON-SMALL-CELL LUNG CANCER

SEARCH METHODOLOGY

SEARCH STRATEGY #1 (SYSTEMATIC REVIEWS):

DATABASE SEARCHED & TIME PERIOD COVERED:

 PubMed – 1966-3/16/2012

 Cochrane Database of Systematic Reviews – All years

SEARCH STRATEGY (PUBMED):

lung neoplasms OR lung cancer

AND

non-small-cell OR non-small cell OR “non small cell”

AND

metastatic* OR metastasi* OR advanced

AND

Systematic[sb]

NUMBER OF RESULTS: 436

SEARCH STRATEGY (COCHRANE):

(Lung neoplasm* OR lung cancer):ti,ab,kw

AND

(Non-small cell OR “non small cell” OR non-small-cell):ti,ab,kw

NUMBER OF RESULTS:13

===============================================================

SEARCH STRATEGY #2 (COST-EFFECTIVENESS):

DATABASE SEARCHED & TIME PERIOD COVERED:

 PubMed – 1966-3/16/2012

 Cochrane Economic Evaluations – All years

PUBMED:

lung neoplasms OR lung cancer

AND

non-small-cell OR non-small cell OR “non small cell”

AND

metastatic* OR metastasi* OR advanced

AND
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Treatment of Metastatic Non-Small Cell Lung Cancer Evidence-based Synthesis Program

cost OR costs OR cost-effective* OR cost-benefit OR cost utility OR cost-utilities OR cost 

analysis OR cost analyses OR economic OR economics

NOT

Results of Search #1

NUMBER OF RESULTS: 347

COCHRANE

(Lung neoplasm* OR lung cancer):ti,ab,kw

AND

(Non-small cell OR “non small cell” OR non-small-cell):ti,ab,kw

NUMBER OF RESULTS: 30
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Treatment of Metastatic Non-Small Cell Lung Cancer Evidence-based Synthesis Program

Appendix B. Search Strategy for Trials

(Search #2)

NON-SMALL CELL LUNG CANCER – RCTS

SEARCH METHODOLOGY

DATABASE SEARCHED & TIME PERIOD COVERED:

 Medline on OVID – 2007-5/8/2012

LANGUAGE:

English

SEARCH STRATEGY:

(systematic review? or systematic overview?).tw. OR meta-analysis/ OR meta analysis.pt. OR 

metaanalys$.tw. OR meta analys$.tw. OR meta-analys$.tw. OR randomized controlled trials/ or 

randomized controlled trial.pt. OR random allocation/OR (random$ and (trial* or stud$)).ti,ab

AND

carcinoma, non-small-cell lung/ or nscls.ti,ab.OR (lung and (cancer$ or neoplasm$ or carcinom$ 

or malignan$ or tumo?r$)).ti,ab.

AND

(paclitaxel or taxol or docetaxel or taxotere or gemcitabine or gemzar or vinorelbine or navelbine 

or irinotecan or campto or camptosar or CPT-11 or pemetrexed or alimta or erlotinib or tarceva 

or gefitinib or iressa or bevacizumab or avastin or cetuximab or crizotinib).ti,ab. 

NUMBER OF RESULTS: 772

=====================================================================

DATABASE SEARCHED & TIME PERIOD COVERED:

Embase – 2007-5/8/2012

LANGUAGE:

English

SEARCH STRATEGY:

paclitaxel:ti OR taxol:ti OR docetaxel:ti OR taxotere:ti OR gemcitabine:ti OR gemzar:ti OR 

vinorelbine:ti OR navelbine:ti OR irinotecan:ti OR campto:ti OR camptosar:ti OR ‘cpt 11’:ti 

OR pemetrexed:ti OR alimta:ti OR erlotinib:ti OR tarceva:ti OR gefitinib:ti OR iressa:ti OR 

bevacizumab:ti OR avastin:ti OR cetuximab:ti OR crizotinib:ti OR paclitaxel:ab OR taxol:ab 

OR docetaxel:ab OR taxotere:ab OR gemcitabine:ab OR gemzar:ab OR vinorelbine:ab 

OR navelbine:ab OR irinotecan:ab OR campto:ab OR camptosar:ab OR ‘cpt 11’:ab OR 

pemetrexed:ab OR alimta:ab OR erlotinib:ab OR tarceva:ab OR gefitinib:ab OR iressa:ab OR 

bevacizumab:ab OR avastin:ab OR cetuximab:ab OR crizotinib:ab OR ‘paclitaxel’/exp OR 

paclitaxel

AND
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Treatment of Metastatic Non-Small Cell Lung Cancer Evidence-based Synthesis Program

((‘lung’/exp AND (cancer* OR neoplasm* OR carcinoma* OR malignan* OR tumor* OR 

tumour*) AND non:ti OR non:ab)) OR ‘lung non small cell cancer’/exp OR nsclc:ti OR nsclc:ab

AND

(randomized AND controlled AND trial*) OR (random AND allocation) OR (random* AND 

(trial* OR stud*))

AND

HUMAN

AND

‘article’/it OR ‘article in press’/it

NUMBER OF RESULTS: 659

=====================================================================

DATABASE SEARCHED & TIME PERIOD COVERED:

 Cochrane Register of Controlled Trials: 2007-5/8/2012

SEARCH STRATEGY:

“paclitaxel or taxol or docetaxel or taxotere or gemcitabine or gemzar or vinorelbine or navelbine 

or irinotecan or campto or camptosar or CPT-11 or pemetrexed or alimta or erlotinib or tarceva 

or gefitinib or iressa or bevacizumab or avastin or cetuximab or crizotinib in Title, Abstract or 

Keywords

AND

non-small cell lung OR nonsmall cell lung OR nsclc in Title, Abstract or Keywords

NUMBER OF RESULTS: 516

=====================================================================

TOTAL NUMBER OF RESULTS AFTER REMOVAL OF DUPLICATES & NONRELEVANT MATERIAL (INCLUDING PHASE II TRIALS); 820
Treatment of Metastatic Non-Small Cell Lung Cancer Evidence-based Synthesis Program

75

Appendix C. Screener Forms Used for Systematic

Reviews and Cost-Effectiveness Analyses

KEEP FOR BACKGROUND o

ID: 

Author:

1. Is it a cost-effectiveness analysis?

Yes...........................................................o

No .................................................. oSTOP

2. Does it present data on metastatic 

non-small cell lung cancer?

Yes...........................................................o

No .................................................. oSTOP

Stage I............................................ oSTOP

Stage II .......................................... oSTOP

Stage III...................................................o

Stage IV...................................................o

“Advanced” .............................................o

3. Which kind of therapy is assessed?

(Check all that apply)

First line...................................................o

Second line ..............................................o

Maintenance ............................................o

Not Stated................................................o

4. Which treatments is assessed? 

________________________________

5. Where are the data from? 

Multiple studies.......................................o

Single study .............................................o

 Name: ________________________

6. What perspective is the analysis? 

US payer..................................................o

Non-US payer..........................................o

Societal ....................................................o

________________.................................o

7. What outcome is used?

QALYs.....................................................o

Life expectancy .......................................o

________________.................................o

8. Conclusions per abstract:

Notes
Treatment of Metastatic Non-Small Cell Lung Cancer Evidence-based Synthesis Program

76

DRAFT – 04/16/2012 Lung Cancer Screener 

KEEP FOR BACKGROUND 

 

6. Which databases were searched? 

1. Is it a systematic review? Pubmed/Medline � Embase � 

 Yes ................................................  Cochrane � Other � 

 No ....................................... STOP 7. How many studies were included? 

 _______________________

2. Does it present data on metastatic 

 non-small cell lung cancer? 8. What outcomes were reported? 

 Yes ................................................  Overall survival ............................... 

 No ....................................... STOP Progression free survival ................. 

Stage I ................................. STOP Overall response rate ....................... 

 Stage II ............................... STOP Adverse events ................................. 

Stage III ........................................  ______________________________

Stage IV ........................................  ______________________________ 

“Advanced” ..................................  ______________________________

3. Which kind of therapy is assessed? 9. Conclusions per abstract: 

 (Check all that apply) ______________________________ 

 First line ........................................  ______________________________ 

 Second line ...................................  ______________________________ 

 Maintenance .................................  ______________________________ 

 Not Stated .....................................  ______________________________ 

 ______________________________ 

4. Which treatments are captured? None below: STOP Bevacizumab Cetuximab Platinum agent/therapy Gemcitabine+taxol Gemcitabine+platinum Pemetrexed Erlotinib 

Crizotinib Endostar Docetaxel Ciefitinib Vandetanib Placebo Immunotherapy Paclitaxel Gifitinib Various 

Bevacizumab 

Cetuximab 

Platinum agent/therapy 

Gemcitabine+taxol 

Gemcitabine+platinum 

Pemetrexed 

Erlotinib 

Crizotinib 

Endostar 

Docetaxel 

Ciefitinib 

Vandetanib 

Placebo 

Immunotherapy 

Paclitaxel 

Gifitinib 

5. What was the end date of the search? 

January .....................

February ...................

March .......................

April .........................

May ..........................

June ..........................  

July ........................... 

August ...................... 

September ................ 

October .................... 

November ................ 

December ................. 

NS ...........................  

2008 ......................... 

2009 ......................... 

2010 ......................... 

2011 ......................... 

NS .......................... 

ID: 

Author: 

NOTES: 
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Treatment of Metastatic Non-Small Cell Lung Cancer Evidence-based Synthesis Program

Appendix D. Peer Reviewer Comments and

Responses

Comment Response

Pre-Results

I note that the attribution to the 1st line guideline is Goffin et 

al. Similar to this VA project, I led what was a group effort. At 

some (or all) points, it would be appropriate to indicate that the 

guideline was the work of the Cancer Care Ontario Program in 

Evidence-Based Care (CCO PEBC or CCO)

We have updated the report to include 

the CCO

In the search methods, there is no indication of searching 

conference abstracts? Was this done. 

We did not search conference 

abstracts

P.10 “(the exception being the same of the never...orally)”: 

This wording in the parentheses makes no sense. What does 

“the exception being the same of” mean? I think you mean 

‘newer” targeted therapies, not ‘never’

This typo has been corrected.

Key Question #1

There is very little mention of the importance of molecular 

markers in the management of advanced NSCLC

Molecular markers are mentioned in 

the targeted therapy section. We did 

not identify studies using molecular 

markers to guide therapy outside of 

this area. We did identify studies that 

used molecular markers as a means 

for assessing overall prognosis, but 

that was not one of our key questions. 

p.16 “The five additional trials...docetaxel plus cisplatin.” : 

This is incorrect according to your table and the reference. 

Docetaxel plus cisplatin had superior survival over vindesine 

plus cisplatin.

This typo has been corrected.

Page 17. Summary 1.1. Given that survival is arguably the 

most important endpoint, QoL perhaps second, and others of 

lesser importance, I recommend specifying the “outcome” 

being considered as much as possible. Here it is survival.

We have specified that this is survival.

Page 18. Summary 1.2 As per 1.1, does one trial indicating 

a trend toward improvement with doublet negate the 

meta-analysis indicating survival improvement. Thus, the 

recommendations might continue to support a ‘survival’ 

improvement rather than just a response improvement.

We have added survival to this 

conclusion.

Page 18- first paragraph- New study presented at ASCO2012 

by Lilenbaum, et al showed that 2 agents were better than 

1 in PS 2 patients. This study has not been included in the 

discussion.

This study has now been included

P. 19 “There was no difference... grade 3/4 toxicities”: Should 

be 8.6 months, not 86

This typo has been corrected.

Last paragraph of page 22- It is important to point out that in 

the meta-analyses by Ardizonni, et al the benefit with cisplatin 

compared to carboplatin was more pronounced in nonsquamous patients and when combined with newer agents.

We added the data about non 

squamous histology.
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Treatment of Metastatic Non-Small Cell Lung Cancer Evidence-based Synthesis Program

Comment Response

Page 24. Summary 1.5. Is it worth mentioning the differences 

in toxicity profiles between cisplatin and carboplatin in this 

palliative setting?

We have added this.

P27. Additional relevant papers for 1.7.1: Mitsudomi et al 

Lancet Oncol. 2010 Feb;11(2):121-8. 

This study has now been included

P27. Additional relevant papers for 1.7.1: Han, JCO, 2012, 

30(10):2233-28

This study has now been included

P27. Additional relevant papers for 1.7.1: Rosell et al, 

EURTAC, Lancet Onc 13:239-46, 2012 ß this last trial is 

relevant in extending the several Asian studies to a Caucasian 

population. 

This study has now been included

Table F5 needs to be updated. There are now more studies. This has been updated

Page 27, Summary 1.7. is confusing, as it seems to suggest an 

OS advantage to EGFR TKI, where this has not technically 

been shown. I would be clear the ‘outcome’ is PFS. Also, 

bevacizumab may or may not improvement survival in the 

general population. Is it specific to carboplatin and paclitaxel, 

and is it better in the Asian population?

We have clarified the outcome as 

progression-free survival and the 

qualifier about the Asian subgroup.

P. 27: Add “;” to “other outcomes progression-free survival of 

10.1..”

This typo has been corrected.

It may also be worth specifying that in the absence of a 

mutation, first line tki is associated with a worse survival 

and should be avoided, as seen in the TORCH study. See 

URL: http://jco.ascopubs.org/content/early/2012/07/09/

JCO.2011.41.2056.full.pdf#page=1&view=FitH

This study has now been included

Page 29, New Lit. I would rewrite this for clarity as it jumps 

around a bit. Opening para could indicate “2 studies found 

assessing cytotoxics specifically in the elderly, and 2 studies 

examining first line egfr tki’s assessed subsets of elderly.” 

Second para could discuss the cytotoxic studies, third the 

TKI’s.

We have re-arranged this section.

Unsure why reference 113 Georgoulias is included in this 

elderly section. Median age 63 is a ‘young’ lung cancer 

population, and no subset is specified. Would remove.

We left this article in at the request of 

another technical expert, but added 

the additional qualifier about the age.

Page 30. Summary 1.12. I dispute the “Grade=low” for survival 

benefit. The benefit may be very modest (which is common to 

most NSCLC trials) but data quality is not. Looking at the 70-

80 population, I highly doubt we will see a new trial indicating 

that a doublet is bad. Caveats about the 80+ population might 

be reasonable.

We agree our initial GRADE was too 

conservative and have reclassified 

to moderate based on RCT data that 

are sparse (only 6 trials and all of 

different regimens, 4 of which found 

a benefit for doublet therapy and 2 of 

which did not).

P.30 1.12 summary: You should mention here that the data for 

monotherapy is from subgroup analyses

This caveat has been added.

On page 30 summary of key sub-question 1.12- Please mention 

that the only study evaluating a platinum based combination 

showed a survival advantage in elderly patients compared to 

single agent therapy.

This addition has been made.
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Treatment of Metastatic Non-Small Cell Lung Cancer Evidence-based Synthesis Program

Comment Response

Key Question #2

Page 32. First sentence of the page repeats itself between its 

first and second clause.

This typo has been corrected.

Page 32. Existing Systemic Reviews. Re Qi review 2012: The 

approval or non-approval of a drug seems irrelevant to the 

notion efficacy. More important might be the heterogeneity of 

the drugs in question and the phase II nature of some of the 

references.

To be relevant to VA, a drug has to 

be FDA approved for use in the US, 

although not necessarily approved 

for the particular use in question. We 

revised and increased the discussion 

of bortezomib and vandetanib. 

P.32: Only bortezomib and vandetanib are FDA approved, but 

not for NSCLC; the other two agents are not approved

This has been corrected.

P.32, Table on p. 34: This is misspelled here and in the Table on 

Page 34=bortezomib not bortezonib;

This typo has been corrected.

P. 32, p. 37, p. 38: Vandetanib is FDA approved, but not for 

NSCLC (also see the same statement on pages 37 and 38)

This has been corrected.

On page 32 the authors have missed the study by von Pawel, 

et al presented at ASCO 2011. Also please include the metaanalyses by Di Maio M, J Clin Oncol 2007.

This study has now been included

Page 32, 33 please include the TAILOR study presented at 

ASCO 2012 by Garassino, et al, comparing docetaxel and 

erlotinib

This study has now been included

Page 33. Para “The fifth system review...” appears to be a 

combination of first and second line studies. Also, the ‘overall’ 

survival was for which comparison? It would be useful to 

specify.

This has been clarified; the overall 

survival result comes from the BR.21 

study.

Para “The conclusions...” Third bullet. Might be pointed out 

this was a phase II study only.

This has been added.

Page 37. Does it add value to singly review the studies 

which were already included in the systemic reviews already 

mentioned (assuming those reviews were of sufficient quality). 

Or does this just add document length?

We agree and have deleted the text 

about trials contained in existing 

systematic reviews that we discuss in 

detail in the prior section. However, 

we retained the description of trials 

that were otherwise only included in 

the reviews by Qi and colleagues as 

we did not discuss these reviews in 

detail.

Page 38. Para “The last of the trials...” The paragraph suggests 

“no significant difference” between vandetanib and erlotinib. 

It should then specify whether a test for non-inferiority was 

achieved. Otherwise they sound truly equivalent.

This was a superiority trial, which 

failed. Then a test for non-inferiority 

was done with non-inferiority defined 

as “at least 50% of the efficacy” of 

erlotinib. We have added this to the 

description.

Page 39. “New Agents” . For these studies, it is likely useful 

to specify whether these were ‘all comers’ or ‘mutation only’ 

patients as the distinction has become relevant. Readers should 

know there is utility for the mutation negative population, as 

not all will be aware.

This has been added.
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Treatment of Metastatic Non-Small Cell Lung Cancer Evidence-based Synthesis Program

Comment Response

Page 40 Para “Sekine and colleagues....” I would addend this 

to the preceding paragraph as the QoL component as it seems 

like a completely different study until the last sentence and 

adds undue length. 

This change has been made.

Page 40. “Kim and colleagues....” Specifying non-inferiority 

vs. failed superiority will aid the audience in understanding 

how to use these drugs. If it is a failed superiority study only, 

it should not become part of the armamentarium. Similarly for 

other studies in this section.

We have now indicated that the 

primary analysis in this study was a 

superiority analysis, which was not 

statistically significant.

Page 40. Last sentence just before “Pemetrexed” section. Much 

higher? 13 vs. 6%.

This has been revised.

THOUGHT: for Table S2, alter the columns such that there is 

only one column indicating the Systemic Review Y/N: this can 

either be “Di Maio” “Qi 2012” etc, or “No”. The other columns 

are freed for other items, possibly: “n” “non-inferiority 

comparison Y/N or p= “, “HR for OS”, etc. More data, less 

wasted space.

This table has been revised to include 

only the studies in existing systematic 

reviews. Some of the other suggested 

columns are already included in Table 

S3, to which we have added histology 

and EGFR mutation status.

Page 45. Having a summary of the “trials not in reviews” in 

isolation is not helpful. The whole section appears to read as 

an unordered catalogue. A net synthesis seems is required. In 

fact, at the end of the second line section, a reader new to the 

topic will have little idea has to how they should practice. One 

might consider ordering it as the data built up historically: 1) 

it was found that docetaxel was better than best supportive 

care; 2) Pemetrexed was compared to docetaxel and found to 

be essentially equivalent but more friendly and thus caught 

on; 3) The EGFR TKI’s were new and are even more friendly, 

and were thus studied. Importantly, they were studied as 

2nd/3rd line vs. BSC, and thus may be kept in reserve after 

another second-line therapy. In any case, there is data they 

are equivalent to docetaxel in second line, and thus serve 

as an option; and 4) LUMP: other studies have been done, 

which have not added much to the second line notion: more 

ain’t better; other sexy drugs haven’t yet added much. Then 

one could give corresponding recommendations. This section 

could also be arranged by approved agents, citing the trials 

supporting the use of each, comparisons, etc, then going on to 

the ‘other’ agents.

We have reorganized this section 

following this suggestion.

NOTE that treatment by histology has had no mention 

here (it only seems to come up under cost-effectiveness). 

Histology now plays an important role in chemotherapy 

choice, particularly in 2nd/maintenance lines. The survival 

differences between docetaxel and pemetrexed by histology are 

at least as large/important as comparisons such as doublets vs. 

single agents. Although a portion of this data is from subsets, 

a document aiming to encompass 1st line, 2nd line, and 

maintenance is obligated to cover histology.

We have added a conclusion about 

pemetrexed and histology.
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Treatment of Metastatic Non-Small Cell Lung Cancer Evidence-based Synthesis Program

Comment Response

Similar reference to histology for first line seems appropriate. The issue of histology and pemetrexed 

use in first-line therapy is presented in 

the discussion of the prior reviews by 

Goffin and colleagues.

P. 47 “The erlotinib group had an overall survival... 1.09)”: 

This should be HR=0.9, not 0.90 months; also you should 

include a p value of 0.2686

This has been corrected.

Key Question #3

Table M1. 1st box under ‘what was compared’ gefitinib is 

spelled incorrectly with all i’s.

This typo has been corrected.

Page 48. Just before reference 158. Cisplati is missing an ‘n’. This typo has been corrected.

P.50: I question how you rated maintenance therapy improving 

OS as High based on the data. For the continuous therapy there 

was only a trend towards benefit in OS. For the switch trials, 

the upper bound of the HR in all but one of the trials crossed 1

The GRADE of strong is based on 

the meta-analytic pooling of the trials 

in the Zhang meta-analysis. While 

each individual trial may have not 

yielded a statistically significant 

favorable result, combining them 

statistically did yield a statistically 

significant benefit for the switch 

strategy (HR=0.85, 95% CI: 0.79-

0.92) and for continuous therapy the 

pooled result was a similar hazard 

ratio of 0.88, with a 95% CI that just 

crossed the null value (0.74-1.04). 

With the interaction being completely 

nonsignificant (p=0.78), the most 

likely explanation for the difference 

in the upper bound crossing the null 

value is fewer studies contributing to 

the continuous pooled analysis (n=3) 

than the switch pooled analysis (n=6).

P. 50 Switch therapy finding: However, there is only a trend of 

benefit in continuous therapy but there are two drugs approved 

for use for switch therapy. I think this needs to be better 

addressed in this entire section.

We have made this point.

Key Question #4

Page 56. Would change “unclear whether or not EGFR 

receptor status” to “...not EGFR mutation status” at end of first 

paragraph.

This change was made.

Page 56. 2nd paragraph. The notations “(ref 498, 449)” are 

probably leftovers. 

This typo has been corrected.

Page 59. Key sub-question 1.12. missing an ‘r’ in elotinib. This typo has been corrected.

Page 61. Table comparison with NCCN. Although commonly 

referenced, I don’t believe the NCCN ‘guidelines’ meet 

criteria for guideline quality and are more akin to consensus 

documents. Would a comparison with the ASCO guidelines be 

better? 

Perhaps this would be better, but our 

key questions specifically mentioned 

the “NCCN guidelines” and that 

is why these are included here and 

referred to as “guidelines.”
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Treatment of Metastatic Non-Small Cell Lung Cancer Evidence-based Synthesis Program

Comment Response

General

I find the answers or summaries of the Key Questions to 

be rather broad and lacking specific direction, making 

implementation difficult or impossible, therefore they are 

no better than the NCCN guidelines. While I appreciate the 

need for numerous subquestions for Key Question 1, it would 

be helpful for implementation to summarize the overall 

subquestion findings for Key Question 1 : doublets better than 

single, cisplatin over carbo if tolerated, pemetrexed for nonsquamous histology, erlotinib for EGFR mutation, etc. I feel 

the summary of the maintenance therapy question needs major 

overhauling to make sense of the data and provide direction 

based on the available data.

With the exception of the “pemetrexed 

for nonsquamous histology,” these 

conclusions are all currently in the 

report. In second-line therapy we have 

a conclusion that pemetrexed is more 

effective in nonsquamous histology. 

With respect to the maintenance 

therapy conclusions, these were 

formulated from the data. The peer 

reviewer seems to be asking for 

recommendations similar to those one 

might find in a guideline, which is not 

within the scope of this review.

There is very little mention of the importance of molecular 

markers in the management of advanced NSCLC

This has been added.

The results of the PARAMOUNT study were updated at 

ASCO2012. These updated results are relevant in many 

portions of this report.

This has been added.