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Study protocol: systematic review and meta-analysis of randomized controlled trials in first-line treatment of squamous non-small cell lung cancer

  • Amy M DeLozier1,
  • Jacqueline Brown2,
  • Fanni Natanegara1,
  • Luping Zhao1,
  • Zhanglin Lin Cui1,
  • Stephen L Able1,
  • Lee Bowman1,
  • Joseph Treat1 and
  • Lisa M Hess1Email author
Systematic Reviews20143:102

DOI: 10.1186/2046-4053-3-102

Received: 23 April 2014

Accepted: 4 September 2014

Published: 16 September 2014

Abstract

Background

There is a high unmet need for effective treatments for patients with squamous non-small cell lung cancer (NSCLC). Eli Lilly and Company is conducting a phase III, randomized, multicenter, open-label study of gemcitabine plus cisplatin plus necitumumab (GC + N) versus gemcitabine plus cisplatin (GC) for the first-line treatment of patients with stage IV squamous NSCLC. Given GC is not the only treatment commonly used for the treatment of squamous NSCLC, this study was designed to compare the survival, toxicity, and quality of life outcomes of current treatment strategies for squamous NSCLC in the first-line setting.

Methods/Design

A systematic review and meta-analysis (including indirect comparisons) of treatments used in squamous NSCLC will be conducted to assess the clinical efficacy (overall and progression-free survival), health-related quality of life (HRQoL), and safety (grade 3–4 toxicity) of GC + N compared to other treatments used in squamous NSCLC. PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines will be followed for all aspects of this study. A systematic literature review will be conducted to identify randomized controlled trials evaluating chemotherapy treatment in first-line NSCLC. Eligible articles will be restricted to randomized controlled trials (RCTs) among chemotherapy-naïve advanced NSCLC cancer patients that report outcome data (survival, toxicity, or quality of life) for patients with squamous histology. Following data extraction and validation, data consistency and study heterogeneity will be assessed. A network meta-analysis will be conducted based on the available hazard ratios for overall and progression-free survival, odds ratios for published toxicity data, and mean difference of HRQoL scales. Sensitivity analyses will be conducted.

Discussion

This is a presentation of the study protocol only. Results and conclusions are pending completion of this study.

Systematic review registration

PROSPEROCRD42014008968

Keywords

Non-small cell lung cancer Chemotherapy Non-squamous Cancer Meta-analysis Network meta-analysis

Background

Lung cancer is the leading cause of cancer-related deaths worldwide, accounting for 1.3 million deaths annually[1]. It is defined as cancer that forms in the tissues of the lung, usually in the cells lining air passages, and is divided into two main subtypes: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). NSCLC is the predominant subtype form and accounts for about 85% of all lung cancers[2]; it is further divided by cell histology into adenocarcinoma, squamous cell carcinoma, and large-cell carcinoma, with adenocarcinoma the currently predominant histology. Although the overall age-adjusted incidence rates for lung cancer are declining in many developed nations, lung cancer remains the leading cause of cancer-related deaths worldwide with an overall 5-year survival rate of about 15%[3], resulting in a significant disease burden worldwide.

The treatment of lung cancer is based on the type and stage of tumor, as well as the patient’s general medical condition. For patients diagnosed with early stage disease (i.e., stages I and II), surgery offers the best option for survival and cure. Adjuvant chemotherapy is increasingly used in those with stage II disease and occasionally for those with stage IB, depending on the size of the tumor. For those with stage III lung cancer, chemoradiotherapy alone or in addition to surgery is used to treat patients; however, while treatment is administered with a curative intent, the 5-year survival for patients with regional disease is approximately 26%, which decreases to 3.9% for patients with metastatic disease[3]. Treatment for patients with advanced disease tends to be palliative, although extension in survival may be achieved. The standard first-line drug treatments for advanced NSCLC, neoadjuvant, adjuvant, or chemoradiotherapy, are generally based on the combination of a second- or third-generation cytotoxic drug with a platinum agent (cisplatin or carboplatin).

There are many drug therapies available for treatment of NSCLC; however, not all current therapies are suitable for use in tumors of all histologies. The results of clinical trials have indicated that drugs such as pemetrexed have greater efficacy among patients with adenocarcinoma than those with other NSCLC histologies (e.g., squamous cell carcinoma)[4]. Other newer agents, such as bevacizumab, are indicated for adenocarcinoma because of higher toxicities observed in patients with squamous histology[5]. Drugs such as erlotinib and gefitinib are not restricted by histology, but have greater efficacy among patients with epidermal growth factor receptor (EGFR) mutations[6, 7]. The frequency of EGFR mutations in patients with squamous cell carcinoma, as opposed to those with adenocarcinoma, is very low[8]. Therefore, histology-specific treatment options are limited for patients with squamous cell carcinoma, which accounts for about 25% of all non-small cell lung cancers[9].

There is thus a high unmet need for effective treatments for patients with squamous NSCLC, as disease burden is large and there is currently a lack of targeted drug therapies for NSCLC squamous cell tumors. Eli Lilly and Company is currently developing necitumumab as a first-line treatment in patients with stage IV squamous NSCLC. The current phase III study (ClinicalTrials.gov identifier: NCT00981058) is a randomized, multicenter, open-label study of gemcitabine-cisplatin chemotherapy plus necitumumab (GC + N) versus gemcitabine-cisplatin (GC) chemotherapy alone in first-line treatment of patients with stage IV squamous NSCLC. The target patient population for this trial is comprised of male and female patients with histologically or cytologically confirmed, advanced squamous NSCLC, previously untreated for metastatic disease.

The purpose of this systematic literature review and meta-analysis is to compare survival, toxicity, and quality of life outcomes of current treatment strategies with necitumumab among patients with squamous NSCLC.

Methods/Design

This systematic literature review and meta-analysis (including indirect comparisons) will be conducted of treatments used in squamous NSCLC to assess the clinical efficacy, quality of life, and safety of GC + N compared to other treatments used in squamous NSCLC. To complete this objective, the following specific aims will be pursued:
  1. 1.

    To conduct a systematic literature review of randomized trials of all relevant treatments used for the first-line treatment of advanced squamous NSCLC;

     
  2. 2.

    To extract relevant data from the relevant published literature;

     
  3. 3.
    To perform indirect and direct comparisons of GC + N to all identified comparators for the following outcomes:
    1. 3.1

      Overall survival;

       
    2. 3.2

      Progression-free survival;

       
    3. 3.3

      Toxicity; and

       
    4. 3.4

      Quality of life

       
     

Search strategy

Searches will be conducted in PubMed, Ovid/MEDLINE, and Embase using free text and controlled vocabulary terms (MeSH). Studies published prior to 1995 will be excluded as NSCLC histology was not clearly differentiated at that time. Studies not published in English will be excluded. Comparisons will be made across all regimens and not just limited to "add-on" therapies. Tables 1,2, and3 detail the specific search strategies for PubMed, Ovid, and Embase, respectively.
Table 1

PubMed search strategy

PubMed search

Category

Search

Query

Items found

Disease terms

#1

"carcinoma, non small cell lung/drug therapy" [MeSH Terms]

11,135

Design terms

#2

Randomized Controlled Trials as Topic [MeSH Major Topic]

12,361

 

#3

"randomized controlled trials as topic" [MeSH Terms]

85,095

 

#4

Random Allocation [MeSH Terms]

76,843

 

#5

double blind method [MeSH Terms]

118,616

 

#6

"controlled clinical trial" [Publication Type]

85,642

 

#7

"randomized controlled trial" [Publication Type]

344,749

 

#8

"clinical trials as topic" [MeSH Terms]

263,513

 

#9

"clinical trial" [Publication Type]

709,361

 

#10

((#2 or #3 or (#4 and (#5 or #8 or #9)) or #6 or #7))

509,729

 

#11

((randomization and control and clinical and trial))

10,468

 

#12

(((randomised and control and clinical and trial) or (randomized and control and clinical and trial)))

108,134

 

#13

((((double or single or triple or treble) and (blind* or mask*) and (random*))))

136,554

 

#14

(((random and allocat*) and control* and trial))

4,775

 

#15

(#12 or #13 or #14)

214,899

 

#16

(#10 or #15)

527,440

 

#17

(#1 AND #16)

2,065

Exclusion terms

#18

Case report [Title/Abstract]

195,029

 

#19

Review [Publication Type]

1,765,829

 

#20

Letter [Publication Type]

794,012

 

#21

"systematic review" [Title/Abstract]

39,341

 

#22

"clinical review" [Title/Abstract]

3,144

 

#23

(#18 OR #19 OR #20 OR #21 OR #22)

2,734,788

 

#24

(#17 NOT #23)

1,579

Year and language terms

#25

((#24) AND ("1995" [Date - Publication]: "2013" [Date - Publication])) AND English [Language]

1,217

Table 2

Embase search strategy

Embase search

Category

Search

Query

Hits

Design terms

#1

"randomized controlled trial (topic)"/exp

37,931

 

#2

"randomized controlled trial"/exp

337,523

 

#3

"randomization"/exp

61,698

 

#4

"double blind procedure"/exp

115,032

 

#5

[controlled clinical trial]/lim

511,199

 

#6

[randomized controlled trial]/lim

337,523

 

#7

"clinical trial"/exp

961,450

 

#8

"clinical trial (topic)"/exp

73,222

 

#9

#1 OR #2 OR #3 OR #4 OR #5 OR #6

1,088,520

 

#10

singl*: ab,ti OR doubl*: ab,ti OR treb*: ab,ti OR tripl*: ab,ti AND (blind*: ab,ti OR mask*: ab,ti)

174,394

 

#11

"placebo"/exp

236,244

 

#12

random* AND (clinical OR control*) AND trial OR (placebo* AND ("randomly allocated" OR (allocated AND random*)))

504,649

 

#13

(#7 OR #8) AND (#10 OR #11 OR #12)

513,722

 

#14

#9 OR #13

705,098

Exclusion terms

#15

[conference review]/lim

3,863

 

#16

"case report":ab,ti

256,868

 

#17

[review]/lim

2,026,389

 

#18

[letter]/lim

827,115

 

#19

"phase 1 clinical trial"/exp

24,619

 

#20

[short survey]/lim OR "historical article": ab,ti

514,714

 

#21

"systematic review": ab,ti

78,920

 

#22

"clinical review": ab,ti

3,904

 

#23

#15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22

3,628,070

 

#24

#14 NOT #23

424,301

Rx terms

#25

"drug therapy"/exp/mj

574,153

 

#26

"treatment response"/exp/mj

2,763

 

#27

"treatment outcome"/exp/mj

28,936

 

#28

"drug efficacy"/exp/mj

153,753

 

#29

"outcome assessment"/exp/mj

9,603

 

#30

chemothera* OR ("drug"/exp/mj AND thera*) OR antineoplastic* OR palliat* OR standar* NEAR/2 care OR support* NEAR/2 care OR "best supportive care" OR best?support* NEXT/2 care

1,895,030

 

#31

"radiotherapy"/exp

367,367

 

#32

#25 OR #26 OR #27 OR #28 OR #29 OR #30 OR #31

2,609,134

 

#33

#23 AND #31

88,937

Disease terms

#34

((lung$ OR pulmon$) NEAR/5 (adenocarcinom$ OR squamous OR "large cell" OR "non-small cell")): ab,ti

44,817

 

#35

"lung non small cell cancer"/exp

52,027

 

#36

metastatic: ab,ti

181,820

 

#37

advanced: ab,ti

320,393

 

#38

stage 3: ab,ti

61

 

#39

"Stage 3": ab,ti

8,708

 

#40

stage 4: ab,ti

32

 

#41

"stage 4": ab,ti

5,270

 

#42

stage iii: ab,ti

30

 

#43

"stage iii": ab,ti

31,468

 

#44

stage iv: ab,ti

41

 

#45

"stage iv": ab,ti

20,205

 

#46

"stage iii/iv": ab,ti

6

 

#47

"stage iii/iv": ab,ti

4,552

 

#48

"stage iiib/iv": ab,ti

2

 

#49

"stage iii/iva": ab,ti

1

 

#50

stage* iii: ab,ti

32

 

#51

stage* iii*: ab,ti

49

 

#52

stage* iv: ab,ti

41

 

#53

stage* iv*: ab,ti

52

 

#54

stage iii*: ab,ti

47

 

#55

stage iv*: ab,ti

46

 

#56

inoperable: ab,ti

12,989

 

#57

in* operable: ab,ti

13,465

 

#58

unresectable: ab,ti

15,735

 

#59

non* resectable: ab,ti

1,208

 

#60

late* stage: ab,ti

84

 

#61

late: ab,ti AND stage: ab,ti

41,346

 

#62

metast*: ab,ti OR advance*: ab,ti

900,959

 

#63

relaps* OR recurr* OR unresect* OR non?resect* OR in?operable OR non?operable OR un?operable OR advanc* OR metasta* OR late NEAR/2 stage

1,895,338

 

#64

#34 OR #35

61,621

 

#65

#36 OR #37 OR #38 OR #39 OR #40 OR #41 OR #42 OR #43 OR #44 OR #45 OR #46 OR #47 OR #48 OR #49 OR #50 OR #51 OR #52 OR #53 OR #54 OR #55 OR #56 OR #57 OR #58 OR #59 OR #60 OR #61 OR #62 OR #63

1,943,775

 

#66

#64 AND #65

33,907

 

#67

#33 AND #66

2,689

Language and year

#68

[1995–2013]/py AND [english]/lim

12,998,680

Final

#69

#67 AND #68

2,901

Table 3

Ovid/MEDLINE search strategy

Ovid/MEDLINE search

Category

Search

Query

Hits

Design terms

#1

Randomized Controlled Trials as Topic/

100,690

 

#2

Randomized Controlled Trial/

382,290

 

#3

Random Allocation/

80,788

 

#4

Double Blind Method/

129,303

 

#5

controlled clinical trial.pt.

88,866

 

#6

randomized controlled trial.pt.

382,290

 

#7

Clinical Trial/

499,767

 

#8

clinical trial.pt.

499,767

 

#9

Clinical Trials as Topic/

173,590

 

#10

1 or 2 or 3 or 4 or 5 or 6

631,570

 

#11

7 or 8 or 9

602,541

 

#12

((singl* or doubl* or treb* or tripl*) and (blind* or mask*)).ab,ti.

145,496

 

#13

Placebos/

33,372

 

#14

((random* and (clinical or control*) and trial) or (placebo* and ("randomly allocated" or (allocated and random*)))).mp. [mp = title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier]

457,488

 

#15

12 or 13 or 14

513,100

 

#16

11 and 15

264,991

 

#17

10 or 16

645,804

Disease terms

#18

((lung* or pulmon*) and (adenocarcinom* or squamous or "large cell" or "non-small cell")).ab,ti.

59,093

 

#19

Carcinoma, Non-Small-Cell Lung/

34,861

 

#20

(metastatic or advanced or stage or "stage 3" or stage4 or "stage 4" or stageIII or "stage III" or StageIV or "Stage IV" or Stage?III or "Stage ?III" or Stage?IV or "Stage ?IV" or "StageIII/IV" or "Stage III/IV" or "StageIII?/IV?" or "Stage III?/IV?" or "StageIII/StageIV" or "Stage III/Stage IV" or "StageIII?/StageIV?" or "Stage III?/Stage IV?" or inoperable or in?operable or unresectable or non?resectable or "late?stage" or (metast* or advance*)).ab,ti.

1,177,250

 

#21

18 or 19

66,533

 

#22

20 and 21

34,403

 

#23

17 and 22

3,600

Exclusion terms

#24

case report.ab,ti.

201,610

 

#25

review.pt.

1,893,388

 

#26

letter.pt.

817,960

 

#27

Clinical Trial, Phase I.pt.

15,867

 

#28

Historical Article/

298,058

 

#29

systematic review.ab,ti.

44,587

 

#30

clinical review.ab,ti.

3,354

 

#31

24 or 25 or 26 or 27 or 28 or 29 or 30

3,184,956

 

#32

23 not 31

2,702

Rx terms

#33

drug therapy/ or treatment outcome/ or ("treatment" and "response").ab,ti. or ("drug" and "efficacy").ab,ti. or outcome assessment/

1,014,086

 

#34

32 and 33

1,611

Final

#35

limit 34 to yr = "1995 -Current"

1,464

The following is a list of the conference databases that will be searched:

  •  American Association for Cancer Research, AACR

  •  American College of Radiation Oncology

  •  American Society for Radiation Oncology, ASTRO

  •  American Society of Clinical Oncology, ASCO

  •  Asia Pacific Lung Cancer Conference, APLCC

  •  Asia Pacific Oncology Summit, APOS

  •  Asian Oncology Summit, AOS

  •  Atualizacoes em Oncologia

  •  Australian Lung Cancer Conference, ALCC

  •  Austrian Society of Haematology and Oncology, ASHO

  •  The Association for Cancer Surgery, BASO

  •  Biennial Congress of the European Association for Cancer Research, EACR

  •  British Thoracic Oncology Group Conference, BTOG

  •  Clinical Oncology Society of Australia, COSA

  •  Cancer Symposium of the Society of Surgical Oncology, CSSSO

  •  Chicago Supportive Oncology Conference, CSOC

  •  Clinical Interventional Oncology, CIO

  •  Congres National de la Societe Francaise de Radiotherapie Oncologique, SFRO

  •  Congress of the European Society for Medical Oncology, ESMO

  •  Congress of the European Society of Surgical Oncology, ESSO

  •  Congress of the International Society of Oncology and Biomarkers, ISOBM

  •  Educational Cancer Convention Lugano of the European School of Oncology, ECCLU

  •  European Lung Cancer Conference, ELCC

  •  European Multidisciplinary Cancer Congress

  •  European Multidisciplinary Conference in Thoracic Oncology, EMCTO

  •  Hematology Oncology Pharmacy Association Annual Meeting, HOPA

  •  International Conference and Exhibition on Cancer Science and Therapy, IMPAKT

  •  International Conference of the Society for Integrative Oncology

  •  International Lung Cancer Congress

  •  International Symposium on Targeted Anticancer Therapies, TAT

  •  Italian Society of Surgical Oncology Conference

  •  Medical Oncology Group of Australia, MOGA

  •  Oncology Platform and Poster Presentation, CSM 2009

  •  Scientific Association of Swiss Radiation Oncology, SASRO

  •  Scientific Meeting of the International Society for Biological Therapy of Cancer

  •  Scientific Meeting of the Society for Immunotherapy of Cancer, SITC

  •  Symposium of the International Society of Oncology Pharmacy Practitioners

  •  UK Radiation Oncology Conference

  •  World Conference on Interventional Oncology, WCIO

  •  World Congress on Cancer Science and Therapy

Eligibility assessment

To be eligible, published studies must meet the criteria outlined in Table 4. Briefly, eligible articles must report at least one of the following outcomes (overall survival, progression-free survival, quality of life, or toxicity) for patients with squamous NSCLC. Eligible articles must report data from randomized controlled trials published since 1995. Abstracts of all potentially eligible citations will be reviewed and excluded if it can be definitively stated that no eligibility criterion is met. All other publications will be considered potentially eligible. Full-text articles of all potentially eligible citations will be obtained and reviewed to determine final eligibility. The eligibility of both the abstracts and full-text articles will be assessed independently by two reviewers using the criteria and screening matrix presented in Table 4. If the two reviewers do not agree on the eligibility of an article, a third reviewer will serve as the tie breaker. Systematic reviews and other review articles will be scanned to ensure no eligible randomized controlled trials (RCTs) are missed.
Table 4

Eligibility criteria and screening matrix

Eligibility criteria

Patients

Male or female patients with histologically or cytologicallyconfirmed squamous NSCLC

 

Study participants must have not received chemotherapy treatment prior to first-line chemotherapy for NSCLC at the time of randomization in the study

Interventions

The study assesses a chemotherapy treatment in each of the study arms

 

No limits are placed on the type of chemotherapy used

Outcomes

One or more of the following outcomes must be quantitatively reported in the publication: overall survival, progression-free survival, toxicity, or quality of life

 

At least one of the required outcome variables must be reported separately for patients with advanced or metastatic (stage III/IV) NSCLC that is of squamous histology

Study design

RCTs

Time frame

1995 to present

Ineligibility criteria

Interventions

Not first-line treatment with first-line defined as patients with no prior exposure to chemotherapy

 

Radiation therapy in the absence of concurrent chemotherapy in any treatment group

Study design

Review articles, news, editorials, commentaries

Time frame

Publication date prior to 1995

Matrix for patients with "squamous histology"

Squamous inclusion obvious in abstract?

Squamous results obvious in abstract?

Inclusion

Comments

Yes

Yes

Yes

 

No

Yes

Yes

 

Yes

No

Yes/No

Need full text to determine the inclusion

No

No

Yes/No

Need full text to determine the inclusion

Only non-squamous inclusion obvious in abstract?

Squamous results obvious in abstract?

Inclusion

Comments

Yes

Yes

Not possible case

 

No

Yes

Yes

 

Yes

No

No

 

No

No

Yes/No

Need full text to determine the inclusion

Abstract mentions just NSCLC as inclusion?

Squamous results obvious in abstract?

Inclusion

Comments

Yes

Yes

Yes

 

No

Yes

Yes/No

This may be multisite cancer study, need full text to determine the inclusion

Yes

No

Yes/No

Need full text to determine the inclusion

No

No

Noise in the search

Need full text to determine the inclusion

Multiple cancers

If mentions lung cancer

Yes/No

Need full text to determine the inclusion

 

If does not mention any specific tumor types

Yes/No

Need full text to determine the inclusion

 

If only mentions breast cancer or other types and does not mention lung cancer

Noise in the search

 

Matrix for "not first-line treatment"

Condition

Line of treatment to be considered

Inclusion

Comments

Naïve NSCLC patients

1st

Yes

 

First- or front-line treatment

1st

Yes

 

Untreated NSCLC patients

1st

Yes

 

Metastatic chemo-naïve NSCLC patients

1st

Yes

 

Chemo-naïve NSCLC patients

1st

Yes

 

Second-line treatment

2nd

No

 

(Rx)-resistant NSCLC patients

2nd

No

 

Recurrent or progressive disease

2nd

No

 

(Rx)-responder/non-responder patients

2nd

No

 

If no clear information on line of treatment

NA

Yes/No

Need full text to determine the inclusion

Data extraction and verification

In a process similar to that used for assessing eligibility, two reviewers will independently extract the data elements listed in Table 5 from each eligible article. These data are extensive and it is not expected, nor is it required, that all studies will report all data fields included. However, attempts to collect as extensive of data as possible will be made to increase the potential range of sensitivity and descriptive analyses. In addition to the data extraction, two reviewers will also assess bias using the Cochrane Risk of Bias Tool and will measure study quality using the Physiotherapy Evidence Database (PEDro) scale (see the "Assessment of bias and study quality" section). Data from both reviewers will be compared. If any data element does not match, the reviewers will meet and attempt to resolve the discrepancies. In cases of non-resolution, a third reviewer will be consulted. All rules and decision criteria used in the data resolution process will be recorded for quality assurance and methodological consistency purposes. To further ensure the accuracy of the extracted data, a subset of 10% of all extracted articles will be verified by an individual not involved in the data extraction process. In cases of error detection, the full database will be reviewed to ensure accuracy.
Table 5

Variables for data extraction

Arm-phase-period information by study arm and overall

Arm

Unique arm number. Unique number for the treatment arm is a grouping variable that is used to highlight which outcome is in the same group of subjects

Integer, in case of sub-analysis arm use A.a format. Placebo = 0, for sub-arm 0.1

Number of study arms

 

1, 2, 3

Open label versus blinded

  

Phase of study

 

1, 2, 3, or unknown

Objectives

 

OS, PFS, RR, TPD, etc.

Patients randomized

Number of patients randomized to the arm

Number value

Arm description

Description of the treatment arm usually includes the drug name, dose, and frequency

e.g., methotrexate 10 mg QW (once a week)

Sub arm analysis

Indicates if the analysis is in a subset of study arm

Yes, NA. Use all in case of AE or dropout data is reported for the randomized trial population

Arm comment

Comment referring to the arm

Comment in relevance to the understating of arm or NA

Study phase

Description of the specific phase within the overall study from which the data is derived

Lead-in, active, follow-up

Study phase description

Qualifies the "Study Phase" field with any additional information deemed necessary or helpful for that arm

e.g., open-label follow-up

Phase duration

Length of time of the study phase from which the data is derived for the arm

Time

Phase duration unit

Time unit for phase duration for the arm

Units

Phase comment

Comment concerning the study phase

Any comment that is relevant to the understanding of the phase or NA

Period

Used if necessary to separate crossover periods within a crossover trial

If the phase has multiple periods, the number of the period. Integer in sequence, or NA

Period description

Used to qualify the "Period" field with any additional information deemed necessary or helpful

e.g., treatment A, titration, maintenance, NA

Period duration

Length of time of the period in a study phase from which the data is derived

Time, NA

Period duration unit

Time unit for period duration

Units, NA

Period comment

Comment concerning the period

Any comment that is relevant to the understanding of the period or NA

Repository

Description

Data entry standards

Demographics and medical history information at baseline by study arm and overall—adjusted and unadjusted

Age

Mean (or median) age in years of patient population or treatment arm population

Age in years or NR if not mentioned specifically or clearly in the trial

Percent female

Percent of females in the patient population or treatment arm population

Percent or NR if not mentioned specifically or clearly in the trial

Weight

Mean body weight of the patient or treatment arm population

Weight in kg, normalize if needed or NR if not mentioned specifically or clearly in the trial

Height

Mean height of the patient or treatment arm population

Height in cm, normalize if needed or NR if not reported

BMI

Mean body mass index of the treatment arm population

BMI in kg/m2, normalize if needed or NR if not reported in the trial

DBP

Mean (or median) diastolic blood pressure

mmHg

SBP

Mean (or median) systolic blood pressure

mmHg

Inclusion

Description of treatment arm or sub-arm inclusion criteria under the trial protocol

e.g., for sub-group females only, or NR if not mentioned specifically or clearly in the trial

Exclusion

Description of treatment arm or sub-arm exclusion criteria under the trial protocol

e.g., for sub-group exclusion of females with child-bearing potential, or NR if not mentioned specifically or clearly in the trial

Ethnic white

Percent of the ethnic population who are whites or Caucasian in the trial

Percent or NR if not mentioned specifically or clearly in the trial

Ethnic black

Percent of the ethnic population who are black in the trial

Percent or NR if not mentioned specifically or clearly in the trial

Ethnic Hispanic

Percent of the ethnic population who are Hispanic in the trial

Percent or NR if not mentioned specifically or clearly in the trial

Ethnic Asian

Percent of the ethnic population who are Asian in the trial

Percent or NR if not mentioned specifically or clearly in the trial

Ethnic other

Percent of the ethnic population who are other in the trial

Percent or NR if not mentioned specifically or clearly in the trial

Primary disease

Primary disease being studied

 

Percent current smokers

Percent of the population who are current smokers

Percent or NR if not mentioned specifically or clearly in the trial

Percent previous smokers

Percent of the population who are previous smokers

Percent or NR if not mentioned specifically or clearly in the trial

Percent adenocarcinoma type

Percent subjects with NSCLC adenocarcinoma type

Percent or NR if not mentioned specifically or clearly in the trial

Percent squamous cell carcinoma type

Percent subjects with NSCLC squamous cell carcinoma type

Percent or NR if not mentioned specifically or clearly in the trial

Percent non-squamous

  

Percent NSCLC stage 0/ I/ II

Percent subjects with NSCLC stage 0 or I or II

Percent or NR if not mentioned specifically or clearly in the trial

Percent NSCLC stage III

Percent subjects with NSCLC stage III

Percent or NR if not mentioned specifically or clearly in the trial

Percent NSCLC stage IV

Percent subjects with NSCLC stage IV

Percent or NR if not mentioned specifically or clearly in the trial

Percent NSCLC stage III/IV total

Total percent of subjects with NSCLC stages III or IV

Percent or NR if not mentioned specifically or clearly in the trial

Percent ECOG status 0

Percent subjects with Eastern Cooperative Oncology Group performance status scale 0

Percent or NR if not mentioned specifically or clearly in the trial

Percent ECOG status 1

Percent subjects with Eastern Cooperative Oncology Group performance status scale 1

Percent or NR if not mentioned specifically or clearly in the trial

Percent ECOG status 0/1 total

Percent subjects with Eastern Cooperative Oncology Group performance status scales 0 or 1

Percent or NR if not mentioned specifically or clearly in the trial

Percent Karnofsky status ≥80

Percent subjects with Karnofsky’s index of performance status >80%

Percent or NR if not mentioned specifically or clearly in the trial

Percent WHO performance status 0/1

Percent subjects with WHO performance status scale 0 or 1

Percent or NR if not mentioned specifically or clearly in the trial

Num of metastatic lymph nodes

Mean or median number of metastatic lymph nodes

NR if not mentioned specifically or clearly in the trial

Percent metastatic L-node positive

Percent subjects who are lymph node positive or with metastatic lymph nodes

Percent or NR if not mentioned specifically or clearly in the trial

Percent bone metastasis

Percent subjects with bone metastasis

Percent or NR if not mentioned specifically or clearly in the trial

Percent brain metastasis

Percent subjects with brain metastasis

Percent or NR if not mentioned specifically or clearly in the trial

Percent liver metastasis

Percent subjects with lung metastasis

Percent or NR if not mentioned specifically or clearly in the trial

Percent other metastasis

Percent subjects with other metastatic organs

Percent or NR if not mentioned specifically or clearly in the trial

Percent metastatic organ sites 1

Percent subjects with one metastatic organ or site involved

Percent or NR if not mentioned specifically or clearly in the trial

Percent metastatic organ sites 2

Percent subjects with two metastatic organs or sites involved

Percent or NR if not mentioned specifically or clearly in the trial

Percent metastatic organ sites >3

Percent subjects with three or more metastatic organs or sites involved

Percent or NR if not mentioned specifically or clearly in the trial

Percent hemoglobin <11.5 g/dl

Percent subjects with baseline hemoglobin levels <11.5 g/dl

Percent or NR if not mentioned specifically or clearly in the trial

Patient demographic comments

Any pertinent demographic comments that are not dealt by other variables

Any comment that may be relevant to the understanding of the demographic characteristics of the patient population

Percent previous surgery

Subjects with previous treatment for NSCLC as complete or partial surgery. Procedures include wedge resection (removal of part of a lobe), segmentectomy (removal of an anatomic division of a particular lobe of the lung), lobectomy (one lobe), bilobectomy (two lobes), or pneumonectomy (whole lung)

Percent or NR if not mentioned specifically or clearly in the trial

Percent previous radiotherapy

Percent subjects with previous radiotherapy as treatment for NSCLC

Percent or NR if not mentioned specifically or clearly in the trial

Percent previous chemotherapy

Percent subjects with previous chemotherapy as treatment for NSCLC

Percent or NR if not mentioned specifically or clearly in the trial

Comorbidities

 

At baseline and by treatment arm

Percent comorbidities

 

At baseline and by treatment arm;% or NR

Percent previous platinum

  

Percent no previous treatment

Percent subjects with no treatment for NSCLC

Percent or NR if not mentioned specifically or clearly in the trial

Previous treatment comments

Comments regarding the previous treatment

Any comment that may be relevant to the understanding of the previous NSCLC treatment in this record, NA if no comments

Pharmacological therapy information

Repository

Description

Data entry standards

Primary NSCLC therapy

Name of primary drug therapy used in this arm at that time point

NSCLC drug, e.g., cisplatin, docetaxel

Primary NSCLC dose

Randomized daily dose at time of outcome. Please note that this is the dose the patients were receiving when the observation is made (not the first randomized dose). If the treatment is switched at the time of observation, record the prior treatment the patients were getting just before the observation was made

Total daily dose at the time of observation

Primary NSCLC dose achieved

Average daily dose during assessment period or for the total treatment period

Average daily dose achieved. Specifically useful for dose titration and crossover trials, NA for the fixed dose trials as both dose achieved and total daily dose do not vary

Primary NSCLC dose unit

Unit of total daily or average dose achieved

Unit, NR if not reported

Primary NSCLC dose freq/cycle

  

Primary Rx days of administration

 

e.g., d1, d8

Primary therapy duration and route of administration

 

e.g., 10 min i.v. infusion

Primary NSCLC Rx cycle duration

  

Primary NSCLC Rx number of cycles

  

Primary NSCLC formulation

Special treatment formulation

Only specialized formulations like IR, CR, SR

Primary NSCLC therapy status

Indicates whether the observation refers to the first, continuing or last dose of the therapy

Start = first dose starts on at this time, continuing = treatment is continuing at this time, end = treatment has been discontinued at this time (last dose)

Primary NSCLC dose comments

Comment regarding the dosing of primary NSCLC treatment

Any comment that may be relevant to the understanding the dosing of the primary treatment in this record, NA if no comments

Combo NSCLC therapy

Name of secondary NSCLC therapy used in this arm in addition to the primary treatment at that time point

NSCLC drug, e.g., PTH NA if no secondary NSCLC therapy

Combo NSCLC dose

Randomized daily dose of the secondary NSCLC therapy at time of outcome. Refer to the dose description of primary NSCLC dose

Total daily dose at the time of observation, NR if not reported and NA if no secondary NSCLC therapy

Combination NSCLC dose achieved

Average daily dose of the secondary NSCLC therapy during assessment period or for the total treatment period

Average daily dose achieved. Specifically useful for dose titration and crossover trials, NA for the fixed dose trials as both dose achieved and total daily dose do not vary

Combination NSCLC dose unit

Unit of total daily or average dose achieved for the secondary NSCLC therapy

Unit, NR if not reported or NA if no secondary NSCLC therapy

Combination NSCLC dose reg

Frequency of secondary NSCLC therapy being administered

QD, BID, etc., NA if no secondary NSCLC therapy

Combination NSCLC dose freq/cycle

  

Combination Rx days of administration

 

e.g., d1, d8

Combination Rx duration and route of administration

 

e.g., 10 min i.v. infusion

Combination NSCLC Rx cycle duration

  

Combination NSCLC Rx number of cycles

  

Combination NSCLC dose comment

Comment regarding the dosing of secondary NSCLC therapy

Any comment that may be relevant to the understanding the dosing of the secondary treatment in this record, NA if no comments or no secondary NSCLC therapy

Concomitant medications

 

Baseline or by treatment arm

Radiation therapy information

Repository

Description

Data entry standards

Radiation therapy type

  

Radiation therapy comments

  

Assessment characterization

Repository

Description

Data entry standards

Assessment

Common name for assessment that this record refers to, e.g., PANSS

As in the assessments and conventions sheet

Assessment short form

Code for the assessment

As in the assessments and conventions sheet

Assessment comment

Any comment that describes the nature of the assessment

e.g., plasma glucose level, NA if no comments

Assessment location

Location from where the assessment value is taken or extracted from the manuscript

Table number, figure number, page number

Assessment category

Describes what the assessment value represented is, whether it is absolute, change from baseline (CFB), percent change from baseline (PCFB), or fraction of randomized patients with the event, count in case of tender or swollen joint counts

Absolute, CFB, PCFB, Frac, or Count

Assessment Stat parameter

The summary parameter of the assessment value

Mean, median, percent, NR if not reported

Stat population

Statistical population for which the efficacy/safety analyses were done and value reported

ITT, OC, completers, randomized, PPP (per protocol population: define), NR if not reported

Missing data treatment

Method used for handling with missing observations in computing the summary parameter

LOCF (last observation carried forward), none, NR if not reported and NA in case of completers

Scale lower limit

Scale lower limit

The lower limit of the scale for the assessment, NA if not applicable

Scale upper limit

Scale upper limit

The upper limit of the scale for the assessment, NA if not applicable

Assessment categories or words

Scale category description

Category that is associated with each point of the scale

Total levels

Total categories/points in the scale

The total number of categories associated with each point of the scale, e.g., 0 to 4 point scale

Total symptoms

Total symptoms in the scale

The total number of symptoms associated with the respective assessment, NA if not applicable

Total score lower limit

Lower limit of the scale, this is calculated as the number of levels multiplied with the lowest possible scale

Integer value, NA if not applicable

Total score upper limit

Upper limit of the scale, this is calculated as the number of levels multiplied with the highest possible scale

Integer value, NA if not applicable

Assessment level

For ordered categorical data "scales." Indicates which level in the categorical scale the assessment is referring to

Integer level from 1 to number of levels, if fractional responder type, enter responder threshold value, eg., ≥5% weight loss from baseline for total body weight assessment, etc., NA if not applicable

PROs

Scale, mean value, SD by group, time point

 

Time, assessment, and baseline value information

Repository

Description

Data entry standards

Assessment visit

Clinical visit at which the assessment is done

Visit 1 (usually baseline) is the first visit in the active phase. Lead in visits start at -1 and count backwards, NR if not reported

Assessment time reported

Time at which the assessment is done during the study and as reported in the manuscript

Visit 1 = baseline = time 0 and the lead in assessment time starts at -1 and count backwards

Assessment time unit reported

Unit for reported assessment time

Time unit as reported

Assessment time range reported

In case if the assessment values are average over a time interval

e.g., weeks 2 through 28 enter 2–28

Assessment time normalized

Normalized time in days at which the assessment is done during the study and as reported in the manuscript

The normalized time value using the normalized unit as days, e.g., 4 weeks = 28 days

Assessment time unit normalized

Unit for standard assessment time

Days is the standard unit

Assessment value

Assessment value reported at that time point

Assessment value as reported

Assessment unit

Assessment unit as reported

Assessment unit as reported, NA if not applicable

Assessment SE

SE of reported assessment value

SE as reported, NR if not reported

Assessment SD

SD of reported assessment value

SD as reported, NR if not reported

Assessment CI type

  

Assessment lower CI

  

Assessment upper CI

  

Assessment value normalized

Assessment value converted into normalized assessment units

Still insert value here, report if normalized units are the same as the reported units

Assessment value unit norm

Normalized assessment value units

See assessments and conventions sheet for normalized assessment standard

Assessment SE normalized

Standard error of normalized assessment value

SE in the same units as normalized assessment, may need to be calculated from SD and N; if not provided, NA

Assessment SD normalized

Standard deviation of normalized assessment value

SD in the same units as normalized assessment, may need to be calculated from SE and N; if not provided, NA

Assessment CI type normalized

  

Assessment lower CI normalized

  

Assessment upper CI normalized

  

Assessment number

Number of patients assessed at that time point and the value derived

Integer value, but for responders and dropouts, this value is calculated from the percentages reported in the trial

Assessment value comment

Comment pertaining to the assessment value that cannot be dealt by other variables

e.g., the assessment value is the mean of last 7 days of before each clinical visit, etc.

Hazard ratio

95% confidence intervals, progression-free survival, and overall survival—adjusted and unadjusted

 

Baseline visit

Clinical visit at which the baseline assessment is done

Visit 1 = baseline = time 0, NR if not reported

Baseline time

Time at which the baseline assessment is done

Visit 1 = baseline = time 0

Baseline time unit

Unit for reported baseline time

Time unit as reported

Baseline time normalized

Normalized time in days at which the baseline is done during the study and as reported in the manuscript

The normalized time value using the normalized unit as days, e.g., -4 weeks = -28 days

Baseline time unit normalized

Unit for standard baseline time

Days is the standard unit

Baseline value

Absolute baseline value for that assessment

Absolute baseline value

Baseline value unit

Assessment unit as reported

Assessment unit as reported, NA if not applicable

Baseline SE

SE of the absolute baseline value

SE as reported, NR if not reported

Baseline SD

SD of the absolute baseline value

SD as reported, NR if not reported

Baseline CI type

  

Baseline lower CI

  

Baseline upper CI

  

Baseline value normalized

Baseline value converted into normalized baseline units

Still insert value here report if normalized units are the same as the reported units

Baseline value unit normalized

Normalized baseline value units

See assessments and conventions sheet for normalized assessment standard

Baseline SE normalized

Standard error of normalized baseline value

SE in the same units as normalized baseline, may need to be calculated from SD and N; if not provided, NA

Baseline SD normalized

Standard deviation of normalized baseline value

SD in the same units as normalized baseline, may need to be calculated from SE and N; if not provided, NA

Baseline CI type normalized

  

Baseline lower CI normalized

  

Baseline upper CI normalized

  

Baseline N

Number of patients from which the baseline value is derived

Integer

Baseline value comment

Comment pertaining to the baseline value that cannot be dealt by other variables

e.g., the baseline value is the mean of last 7 days of the run in period

Reference specifications

  

Repository

Description

Data entry standards

Ref code

Numerical code assigned for the literature citation. Maps the record to the assessment details

Integer

Protocol or trial number

Protocol ID or the number of the trial report

As reported, NA if not applicable

Date modified

Date of initial entry or subsequent modification of the data point

mmddyy format

Modified by

Initials of curator

 

Modification comment

Any comment that is relevant to modification by the curator

Initial entry if new record, brief statement of change(s)

Copyright status

Provided by the client or procured by the service provider

Client provided or yes in case the manuscript is procured by the service provider

Author

Authors of publication

As reported

Journal

Journal name

Standard abbreviated forms can be used, generally as in the PubMed

Publication year

Year of the publication

Integer

Title

Title of the study

 

Volume

Volume number of the publication

e.g., 180

Pages

Page numbers of the publication

e.g., 1–24

Trial name alias

Trial name that trial is commonly referred to

NR if not reported

Inclusion description

Provide description of inclusion criteria

Can be cut and paste from PDF, can be placed in an attached note

Exclusion description

Provide description of exclusion criteria

Can be cut and paste from PDF, can be placed in an attached note

Study design

Brief description of the study design

Parallel-fixed arm, dose escalation, effect titration, crossover, etc.

Location of the trial

Geographical location where the study is conducted

Primary nationalities list

Number of countries

Number of countries the study is conducted

Integer

Number of centers

Number of centers the study is conducted

Integer

Trial start date

Date when the trial started

mmddyy format

Trial end date

Date when the trial completed

mmddyy format

Placebo-controlled or active comparator

Was there a control group and was it placebo

PBO control/active comparator

Active comparator therapy

If this was an active comparator trial what was the comparator therapy

e.g., PTH

Percent randomized to placebo

Percent of subjects in the trial who are randomized to placebo

Integer

Add-on/washout study

Was the study drug added on to standardized background Rx, was background Rx washed out prior to starting primary Rx, or was standardized background therapy withdrawn once primary RX started

Add-On, Washout, Replacement, None

Study blind

Was the trial blinded for the treatment phase

Yes, double blind

Number of arms

Number of treatment arms the patients are randomized to

Integer

Arm description

Codes and description for arms

0 = placebo and others in sequence

Dose descriptions

Brief descriptions of the treatment drugs and the respective doses along with regimens received

0 = placebo, 1 = metformin 10 mg QW…

Dose ranging within study

Does the trial contain at least two primary treatment arms where different dose strengths were administered

Yes, No. Placebo does not count as a dose strength

Primary longitudinal data

Were multiple time values reported for the primary assessment endpoint

Yes, No.

Active phase trial duration

What was the duration of the active phase of the trial

Time, units, i.e., 3 weeks

Steady state effect achieved?

Does it appear that effect stabilized over time for primary endpoints

Yes, No. Not clear

Was there a lead-in phase?

Was there a standardized lead-in phase in the study other than a simple screening visit

Yes, No

Lead-in phase duration

If so, what was the duration

If yes, time, units, i.e., 6 months. If no, 0

Was there a follow-up phase?

Was there a standardized follow-up phase that at least some patients were enrolled in after the active phase ended

Yes, No

Duration of follow-up phase

If so, what was the duration

If yes, time, units, i.e., 6 months. If no, 0

Primary endpoint

What is the primary outcome or assessment reported in the trial

e.g., HBA1C

Secondary endpoints

  

Other efficacy endpoints available

List of the other secondary efficacy or biomarker outcomes reported in the trial

e.g., HOMA

Most frequent AEs (incidence)

List the most frequently reported AE’s

e.g., vomiting, nausea, headache, dizziness

Adverse events

Grade,%, n by group, treatments for AEs, hospitalizations secondary to AEs and overall, ICU admissions secondary to AEs and overall

 

Median and mean if reported

Progression-free survival and overall survival in months (TTPD, TTTF)

 

Survival rates

Percent alive at X months

 

Response rates

At what time?

 

Toxicity

Number of individuals experiencing toxicity/treatment group

 

Analysis plan

A PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) diagram will be developed based on the search strategy and eligibility assessment to show the flow of included and excluded studies. The descriptive statistics from each trial of patients with squamous cell carcinoma will be included and described. These variables will include treatment group, number of patients, mean age (standard deviation), number and percent male, number and percent with stage IV disease, overall survival, progression-free survival, toxicity, and quality of life.

A network diagram visually describing existing treatments for squamous NSCLC will be created after all eligible studies have been identified. However, some publications may not present data in a format that allows them to be included in the study despite otherwise meeting eligibility criteria (e.g., mixed populations not reported separately, mixed histologies not reported separately, mixed lines of therapy not reported separately). In the case of a disconnected network resulting from the absence of data for the appropriate patient population, authors of such articles will be contacted and asked to provide the needed data from their publications that would enable connection to the studied network.

The primary purpose of this study is to perform indirect and direct comparisons of GC + N versus all identified comparators for overall survival (OS) and progression-free survival (PFS). Individual hazard ratios (HR) or median time-to-event (median time) and 95% confidence intervals (90% or 99% confidence intervals will be converted to 95%) for overall survival will be included in the network meta-analysis using a Bayesian approach that ensures the preservation of randomization in the network[10]. The HR will be used as the primary unit of analyses to evaluate differences in effect size between treatment groups. Data for analysis will be extracted directly from the text of each eligible article, calculated from data included in the text, or extrapolated from the Kaplan-Meier plot according to the method of Parmar and colleagues[11]. Graphs and figures will be digitized using TechDig software and/or xyscan tool (Debian, Inc) if necessary, and digitized values will be extracted.

Heterogeneity will be explored by comparing the fixed and random effects models to ensure that the network has good properties. Additionally, heterogeneity will be explored by visual inspection of forest plots. The consistency assumption will be tested by examining network diagrams to identify any closed "loops" where inconsistencies can occur. When the network is complex with multiarm trials, the "node-splitting" approach defined by Dias and colleagues[12] will be used to identify inconsistencies. Density plots of the posterior samples from models based on direct, indirect, and mixed evidence will be compared. In addition, the heterogeneity parameters (variance and standard deviation) and goodness of model fit measures (residual deviance and deviance information criterion (DIC), a Bayesian criterion for model comparison) between the direct and indirect models will be compared.

OS and PFS data will be analyzed using a log transformation of the HR and treating this as a continuous outcome. For studies with median time information, we will also use log transformation of the median time and treat this as a continuous outcome in sensitivity analyses. HRs are preferred summary statistics to median time per Michiels and colleagues[13], and hence, the analysis will utilize HR data for the primary outcome measure.

Ideally, the literature will provide values for log (HR) and the standard error (SE) for log (HR). If the SE for log (HR) is not available, an attempt will be made to estimate the missing value from the SE for median time, assuming an exponential distribution of survival time and log (HR) = -log (median time ratio). Alternatively, an estimate of the SE for log (HR) will be made on the basis of the number of subjects with events as specified below:
  1. 1.

    "MedianTime" will be converted into log (median time);

     
  2. 2.

    The SE for log (median time) is estimated as (log(upper confidence limit) - log (lower confidence limit))/2/quantile (confidence level) if a treatment arm has non-missing value for all three variables;

     
  3. 3.

    If confidence limit is missing, then the number of subjects with events can be used to estimate the standard error for log (median time) as 1/sqrt(n) for a treatment arm.

     

Individual odds ratios and/or toxicity rates for each grade 3–4 toxicity from each study will be included, respectively, in an NMA using a Bayesian approach that ensures the preservation of randomization in the network. Odds ratios will be calculated for studies reporting toxicity rates. Prior to creating the odds ratios, we will ensure that similar versions of toxicity scaling criteria have been used. Data for analysis will be directly extracted from the text of the article or calculated from data in the text.

A network meta-analysis of GC + N to all identified comparators will be conducted for health-related quality of life (HRQoL) measures (including EQ-5D and the Lung Cancer Symptom Scale (LCSS)) during and following therapy. The most common quality of life instruments as reported across studies will be analyzed. Initial analyses will be limited to those quality of life outcomes for which GC + N data are available. For each identified measure, a standardized mean difference in quality of life outcomes from each study will be included. First, the number of trials per HRQoL instrument will be determined. If the number of trials per HRQoL instrument is 2 or more, then these data will be analyzed. For each instrument, data will be assessed according to the guidelines for that particular instrument and then pooled across studies to determine the standardized mean difference.

A meta-regression will be conducted using the key covariates of patient age and stage of disease (percent of patients with stage IV), as these variables have prognostic value in squamous NSCLC. Additional covariates may be identified following the literature review and will be considered for inclusion in post hoc analyses to control for potential bias.

Sensitivity analyses

We anticipate that some studies will not report all relevant data. In order that such studies can still be included in the analysis, we may consider imputing missing data using established methods as appropriate[14]. If imputation is made, the Bayesian model as described above will be used as the primary analysis and will be compared with analyses including the imputed values. Sensitivity analyses may be conducted to examine the effect of this method using an approach proposed by Carpenter and colleagues[15], which entails imputing missing data under a missing at random assumption, and then reweighting the imputed data to allow for non-random selection. Sensitivity analyses as outlined for OS and PFS will also be conducted for HRQoL; however, the use of disparate HRQoL instruments or assessment time points may result in an inability to evaluate the study endpoint. Sensitivity analyses will be performed to assess the robustness of the findings. At a minimum, the following analyses will be conducted if there are at least three studies available for analysis:
  1. 1.

    Repeat the meta-analysis using a frequentist approach;

     
  2. 2.

    HR only (primary aim) versus HR or median time;

     
  3. 3.
    By geographical site of study enrollment;
    1. a.

      e.g., Western versus Eastern hemispheres

       
    2. b.

      e.g., Americas versus Europe versus Asia

       
     
  4. 4.

    Limit to patients with stage IV disease;

     
  5. 5.

    Direct comparisons only;

     
  6. 6.

    By excluding phase II trials;

     
  7. 7.

    By age—studies with a mean age over the age of 70;

     
  8. 8.

    Limiting the analysis to high-quality studies (≥6) as determined by the PEDro scale;

     
  9. 9.

    Removing studies considered to be biased according to the Cochrane Risk of Bias Tool.

     

Assessment of bias and study quality

The risk of bias will be appraised using the Cochrane Risk of Bias Tool (http://www.cochrane-handbook.org). This tool was developed specifically to assess the internal validity of RCTs. It consists of the following seven criteria: 1) randomization generation, 2) allocation concealment, 3) blinding of outcome assessors, 4) blinding patients and personnel, 5) incomplete outcome data (i.e., withdrawals), 6) selective outcome reporting, and 7) other risks of bias. The final item will include fraudulent results, other methodological flaws in the RCTs, and the potential for bias.

To assess publication bias, the fail-safe N will be calculated. If the number of unpublished trials that may invalidate the findings is less than five, it will be noted in the conclusions as a potential limitation of the findings. If the number of unpublished trials to invalidate the findings is five or greater, it will be noted in the results. Furthermore, funnel plot analyses will also be conducted to provide a visual representation demonstrating where unpublished data may exist. This is planned to help guide the interpretation of the study findings and the direction of bias.

Quality of selected trials for inclusion in the review will be assessed. The PEDro quality scale, an 11-item scale designed for rating the methodological quality of randomized controlled trials[16], will be used to evaluate the quality of selected trials. Here the two reviewers will independently assess studies for methodological validity prior to inclusion. Identified studies that meet the inclusion criteria will then be grouped according to the class of statin used in the trial. High quality scores will be defined as a PEDro score ≥6 and low quality scores will be defined as a PEDro score <6.

Missing data are expected in the majority of data fields collected in this meta-analysis. In cases of missing data, heterogeneity will be tested on all outcome variables to ensure that studies are comparable. Forest plots will be created for OS, PFS, toxicity, and quality of life endpoints. In the case of non-overlapping confidence intervals, the research team will discuss the need for post hoc subgroup analyses.

Discussion

The study design for this systematic review and meta-analysis is presented here to follow PRISMA standards. Industry-sponsored or industry-led studies are increasingly under scrutiny regarding transparency and risk of bias[17]. This study protocol has been designed prior to any knowledge of the study data or outcomes from existing published literature and is being disseminated in an attempt to provide the scientific community with the ability to evaluate the methods and plans of our study before it is conducted. The study protocol has been designed to meet PRISMA standards[18, 19] and is being disclosed so that our methods can be retrieved and evaluated against the final analyses and interpretation of findings.

While it is almost impossible to fully anticipate the limitations of the data once they are obtained, this study has been designed in an attempt to pre-specify all primary analyses and sensitivity analyses to demonstrate the stability in results that may be discovered. However, it is possible that there will not be sufficient data to achieve all the pre-specified study aims or to complete all planned analyses. There are also possible limitations in the network connections. Unlike patients diagnosed with lung cancers of non-squamous histology, those with squamous NSCLC have not benefited from the same depth and breadth of research conducted to identify optimal treatment strategies. Therefore, via our search criteria, we are casting a wide net in the hopes of finding studies that not only investigate, but also report, outcomes for this histological subgroup.

Our ultimate goal is to provide reliable and trustworthy data regarding the comparative efficacy of necitumumab against other possible options for care so that decision makers can come to their own conclusions regarding the value of this molecule currently in development.

Declarations

Acknowledgements

This study was funded by Eli Lilly and Company.

Authors’ Affiliations

(1)
Eli Lilly and Company
(2)
Eli Lilly and Company, Erl Wood Manor

References

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© DeLozier et al.; licensee BioMed Central Ltd. 2014

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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