Complete Guide: Systematic Review & Meta-Analysis

Efficacy of Cardioprotective Therapies in Preventing Trastuzumab-Related Cardiotoxicity in HER2-Positive Breast Cancer

PART 1: WHAT IS A META-ANALYSIS? (Start Here)

1. Find all existing studies on your topic
2. Pool their data mathematically
3. Calculate one combined, more powerful answer

PART 2: STEP-BY-STEP WORKFLOW (From Zero to Published)

STEP 1 → Register your protocol (PROSPERO)
STEP 2 → Develop your PICO question
STEP 3 → Write search strings & search databases
STEP 4 → Import results → Remove duplicates
STEP 5 → Title & Abstract screening
STEP 6 → Full-text screening
STEP 7 → Data extraction
STEP 8 → Quality/Risk of Bias assessment
STEP 9 → Statistical meta-analysis
STEP 10 → Write PRISMA flow diagram
STEP 11 → Write & submit the paper

STEP 1 — REGISTER ON PROSPERO (Do This FIRST, Before Searching)

• Website: prospero.york.ac.uk
• Free registration, takes ~1–2 hours
• You submit your protocol (what you plan to do) BEFORE doing it
• This prevents publication bias and gives your study a registration number (e.g., CRD42024XXXXXXX)
• Why it matters: Most journals now REQUIRE a PROSPERO number

• Title, team members, PICO, databases to be searched, inclusion/exclusion criteria, outcomes, statistical methods

STEP 2 — YOUR PICO FRAMEWORK

STEP 3 — SEARCH STRINGS & DATABASES

Databases to Search (All Free or Institutional Access):

Tip for your team: Divide databases — Person A: PubMed + Cochrane, Person B: Embase + Scopus, You: Web of Science + ClinicalTrials.gov

Your PubMed Search String (Copy-Paste Ready):

("trastuzumab"[MeSH Terms] OR "trastuzumab"[tiab] OR "Herceptin"[tiab])
AND
("HER2"[tiab] OR "HER-2"[tiab] OR "ErbB2"[tiab] OR "HER2-positive"[tiab])
AND
("breast cancer"[MeSH Terms] OR "breast neoplasms"[MeSH Terms] OR "breast cancer"[tiab])
AND
("cardiotoxicity"[tiab] OR "cardioprotection"[tiab] OR "cardiac toxicity"[tiab]
OR "left ventricular dysfunction"[tiab] OR "LVEF decline"[tiab]
OR "heart failure"[MeSH Terms] OR "cardiomyopathy"[tiab])
AND
("beta-blocker"[tiab] OR "beta blocker"[tiab] OR "carvedilol"[tiab]
OR "metoprolol"[tiab] OR "ACE inhibitor"[tiab] OR "ACE-inhibitor"[tiab]
OR "angiotensin converting enzyme inhibitor"[tiab] OR "enalapril"[tiab]
OR "lisinopril"[tiab] OR "ARB"[tiab] OR "angiotensin receptor blocker"[tiab]
OR "candesartan"[tiab] OR "statin"[tiab] OR "dexrazoxane"[tiab]
OR "cardioprotective"[tiab] OR "cardioprotection"[tiab])

Embase Search String:

('trastuzumab'/exp OR trastuzumab:ti,ab)
AND ('HER2'/exp OR 'HER2 positive breast cancer'/exp OR her2:ti,ab)
AND ('breast cancer'/exp OR 'breast neoplasm'/exp)
AND ('cardiotoxicity'/exp OR cardiotoxicity:ti,ab OR 'cardiac toxicity':ti,ab)
AND ('cardioprotection'/exp OR 'beta blocker'/exp OR 'ACE inhibitor'/exp
OR carvedilol:ti,ab OR metoprolol:ti,ab OR enalapril:ti,ab
OR candesartan:ti,ab OR statin:ti,ab OR dexrazoxane:ti,ab)

STEP 4 — IMPORT & DEDUPLICATE

1. Export all search results as .ris or .nbib files from each database
2. Import all files into Rayyan
3. Rayyan auto-detects duplicates — you review and confirm
4. Assign your two team members as reviewers in Rayyan
5. Enable blinding (reviewers screen independently — they can't see each other's decisions)

PART 3: THE MASTER TEMPLATE

📋 PROTOCOL TEMPLATE — COMPLETE

═══════════════════════════════════════════════════════════════════
SYSTEMATIC REVIEW & META-ANALYSIS PROTOCOL
═══════════════════════════════════════════════════════════════════

TITLE:
Efficacy of Cardioprotective Therapies in Preventing
Trastuzumab-Related Cardiotoxicity in HER2-Positive Breast Cancer:
A Systematic Review and Meta-Analysis

TYPE OF STUDY: Systematic Review and Meta-Analysis

PROSPERO REGISTRATION NO.: [To be filled after registration]
Registration Date: [Date]

DATE OF PROTOCOL: [Date]
Last Updated: [Date]

───────────────────────────────────────────────────────────────────
TEAM MEMBERS
───────────────────────────────────────────────────────────────────
Lead Author (Principal Investigator): [Your Name]
  Role: Protocol development, search strategy, data extraction,
        statistical analysis, manuscript writing

Co-Author 2: [Name]
  Role: Independent title/abstract screening, full-text screening,
        data extraction, quality assessment

Co-Author 3: [Name]
  Role: Independent title/abstract screening, full-text screening,
        data extraction, quality assessment

Conflict Arbiter (for disagreements): [Your Name as Lead]

───────────────────────────────────────────────────────────────────
PICO FRAMEWORK
───────────────────────────────────────────────────────────────────
P (Population):
  - Adult patients (age ≥18 years)
  - Diagnosed with HER2-positive breast cancer
  - Receiving trastuzumab-based therapy (any line)

I (Intervention):
  - Cardioprotective pharmacological therapies including:
    · Beta-blockers (carvedilol, metoprolol, bisoprolol, nebivolol)
    · ACE Inhibitors (enalapril, lisinopril, ramipril)
    · Angiotensin Receptor Blockers/ARBs (candesartan, valsartan)
    · Statins (atorvastatin, rosuvastatin)
    · Dexrazoxane
    · Combination therapy

C (Comparator):
  - Placebo
  - No cardioprotective therapy
  - Standard care alone

O (Outcomes):
  PRIMARY:
    1. Incidence of cardiotoxicity defined as:
       - LVEF (Left Ventricular Ejection Fraction) decline ≥10%
         from baseline to <53% (ESMO criteria)
       - OR LVEF decline ≥5% to <55% with symptoms
    2. Rate of trastuzumab discontinuation due to cardiac reasons

  SECONDARY:
    1. Change in LVEF (%) from baseline — continuous outcome
    2. Incidence of clinical heart failure (HF)
    3. Troponin elevation (as marker of subclinical damage)
    4. NT-proBNP changes
    5. All-cause mortality
    6. Cardiac-related hospitalizations

───────────────────────────────────────────────────────────────────
SEARCH STRATEGY
───────────────────────────────────────────────────────────────────
Databases:
  1. PubMed/MEDLINE
  2. Embase
  3. Cochrane Central Register of Controlled Trials (CENTRAL)
  4. Scopus
  5. Web of Science
  6. ClinicalTrials.gov (grey literature)

Date Range: January 2000 – Present
  (Trastuzumab FDA approval was 1998; 2000 allows landmark trials)

Language: English (primary); include non-English with translation
           if resources allow

[Insert full search strings for each database above]

───────────────────────────────────────────────────────────────────
INCLUSION CRITERIA
───────────────────────────────────────────────────────────────────
✓ Randomized Controlled Trials (RCTs) — PRIMARY focus
✓ Prospective cohort studies (if RCT data insufficient)
✓ HER2-positive breast cancer patients
✓ Trastuzumab used as part of therapy (adjuvant or metastatic)
✓ At least one cardioprotective therapy used as intervention
✓ Cardiac outcome data reported (LVEF or clinical cardiac events)
✓ Minimum follow-up: 3 months
✓ Sample size: ≥20 patients per group

───────────────────────────────────────────────────────────────────
EXCLUSION CRITERIA
───────────────────────────────────────────────────────────────────
✗ Case reports, case series (<20 patients)
✗ Review articles, editorials, letters, commentaries
✗ Animal studies / in-vitro / preclinical studies
✗ Studies without a control/comparator group
✗ Studies not reporting any cardiac outcome
✗ Patients receiving pertuzumab or TDM-1 without trastuzumab
✗ Duplicate publications (keep the most complete dataset)
✗ Conference abstracts with insufficient data

───────────────────────────────────────────────────────────────────
SCREENING PROCESS (PRISMA-Based)
───────────────────────────────────────────────────────────────────

PHASE 1 — IDENTIFICATION
  Action: Run all search strings across all 6 databases
  Expected yield: 800–2000 records (varies widely)
  Tool: Export as .ris/.nbib files

PHASE 2 — DEDUPLICATION
  Action: Import all into Rayyan; remove duplicates
  Expected: Remove ~20–35% as duplicates
  Record: Total unique records after deduplication

PHASE 3 — TITLE & ABSTRACT SCREENING
  Who: ALL THREE team members screen INDEPENDENTLY (blinded)
  Tool: Rayyan (blinding mode ON)
  Decision: Include / Exclude / Maybe
  Conflict resolution: Discuss; if unresolved → third-party

  Screened by reading ONLY the title and abstract.
  Apply inclusion/exclusion criteria.
  When in doubt → INCLUDE (err on side of caution)

PHASE 4 — FULL-TEXT SCREENING
  Who: All three team members (independently, then compare)
  Action: Retrieve full PDFs and apply strict criteria
  Exclusion at this stage must be DOCUMENTED with reason

PHASE 5 — FINAL INCLUDED STUDIES
  These are the studies that enter data extraction

Kappa Agreement: Calculate Cohen's Kappa (κ) after each phase
  κ > 0.80 = excellent agreement ✓

───────────────────────────────────────────────────────────────────
EXPECTED PRISMA NUMBERS (Template — Fill In As You Go)
───────────────────────────────────────────────────────────────────

  Records identified via database searching:     ____
    PubMed:              ____
    Embase:              ____
    Cochrane:            ____
    Scopus:              ____
    Web of Science:      ____
    ClinicalTrials.gov:  ____

  Additional records from other sources
  (manual reference searching):                  ____

  TOTAL RECORDS IDENTIFIED:                      ____

  ↓
  Duplicates removed:                            ____

  RECORDS AFTER DEDUPLICATION:                   ____

  ↓
  Title & Abstract Screened:                     ____
  Excluded at T&A stage (with reason):           ____

  FULL-TEXTS ASSESSED FOR ELIGIBILITY:           ____
  Full-texts excluded (with reasons):            ____
    - Not HER2-positive:           ____
    - No cardioprotective therapy: ____
    - No cardiac outcome:          ____
    - Wrong study design:          ____
    - Insufficient data:           ____
    - Duplicate dataset:           ____

  STUDIES INCLUDED IN META-ANALYSIS:             ____

───────────────────────────────────────────────────────────────────
DATA EXTRACTION FORM (Per Study)
───────────────────────────────────────────────────────────────────
Extract independently by 2 reviewers; resolve discrepancies by
discussion or lead author decision.

STUDY IDENTIFICATION
  First Author:
  Year of Publication:
  Country:
  Funding Source:
  Trial Registration Number:
  Study Design (RCT/Cohort):
  Follow-up Duration (months):

POPULATION
  Total Sample Size (N):
  Intervention Group (n):
  Control Group (n):
  Mean Age (years):
  % Female:
  Stage of Breast Cancer:
  HER2 confirmation method (IHC/FISH):
  Prior anthracycline use (Yes/No/%):
  Baseline LVEF (%):

INTERVENTION
  Cardioprotective drug used:
  Dose:
  Duration of therapy:
  Started: Before trastuzumab / During / After
  Concurrent anthracycline use: Yes/No

CONTROL
  Placebo / No therapy / Other:

PRIMARY OUTCOMES
  Cardiotoxicity incidence:
    Intervention group: n/N (%)
    Control group: n/N (%)
    Relative Risk or Odds Ratio (if reported):
    p-value:
    95% CI:
  Trastuzumab discontinuation (cardiac):
    Intervention: n/N (%)
    Control: n/N (%)

SECONDARY OUTCOMES
  Mean LVEF at baseline — Intervention: ___  Control: ___
  Mean LVEF at follow-up — Intervention: ___  Control: ___
  Mean LVEF change (ΔEF) — Intervention: ___  Control: ___
  SD of LVEF change — Intervention: ___  Control: ___
  Heart failure events: n (%)
  Troponin elevation: n (%)
  Hospitalizations: n (%)

NOTES / SPECIAL CONSIDERATIONS:

───────────────────────────────────────────────────────────────────
RISK OF BIAS ASSESSMENT
───────────────────────────────────────────────────────────────────
For RCTs → Use: Cochrane RoB 2.0 Tool
For Cohort Studies → Use: Newcastle-Ottawa Scale (NOS)

RoB 2.0 Domains:
  D1. Randomization process
  D2. Deviations from intended interventions
  D3. Missing outcome data
  D4. Measurement of the outcome
  D5. Selection of reported result
  Overall: Low / Some concerns / High

Assessed by: 2 reviewers independently
Tool: RoB 2.0 Excel template (available from Cochrane)

───────────────────────────────────────────────────────────────────
STATISTICAL ANALYSIS PLAN
───────────────────────────────────────────────────────────────────
Software: RevMan 5.4 (free, from Cochrane) — RECOMMENDED FOR BEGINNERS
           OR: R (meta package) / STATA (metaan)

Effect Measures:
  - Dichotomous outcomes (cardiotoxicity incidence, HF events):
    → Risk Ratio (RR) with 95% CI
  - Continuous outcomes (LVEF change):
    → Mean Difference (MD) or Standardized MD with 95% CI

Heterogeneity:
  - Assessed using Cochran's Q test and I² statistic
  - I² interpretation:
      0–25%   = Low heterogeneity → Fixed-effects model
      26–50%  = Moderate → Random-effects model
      51–75%  = Substantial → Random-effects + subgroup analysis
      >75%    = Considerable → Report with caution; focus on subgroups

Model:
  → Random-effects model (DerSimonian-Laird) recommended as default
    given expected clinical heterogeneity

Subgroup Analyses:
  1. By drug class (beta-blocker vs ACE-I vs ARB vs statin)
  2. By concurrent anthracycline use (yes vs no)
  3. By baseline LVEF (preserved vs borderline)
  4. By cancer stage (early vs metastatic)
  5. By follow-up duration (<6 months vs ≥6 months)

Sensitivity Analysis:
  - Exclude high RoB studies → check if results change
  - Exclude small studies (n<50)
  - One study leave-out analysis

Publication Bias:
  - Funnel plot (requires ≥10 studies)
  - Egger's test / Begg's test

GRADE Assessment:
  Rate overall certainty of evidence as:
  High / Moderate / Low / Very Low
  Using: GRADEpro GDT (free online tool)

───────────────────────────────────────────────────────────────────
REPORTING
───────────────────────────────────────────────────────────────────
Follow: PRISMA 2020 Checklist (27 items)
         Available at: prisma-statement.org

Target Journals (Suggested):
  High Impact: JACC, European Heart Journal, JCO
  Mid-tier: Cardio-Oncology, Breast Cancer Research & Treatment,
            PLOS ONE, Frontiers in Oncology

───────────────────────────────────────────────────────────────────
TIMELINE (Suggested — 6 Month Plan)
───────────────────────────────────────────────────────────────────
Month 1: PROSPERO registration + Search execution + Deduplication
Month 2: Title/Abstract screening (all 3 members)
Month 3: Full-text screening + Retrieval of PDFs
Month 4: Data extraction + Risk of Bias assessment
Month 5: Statistical analysis + Figures (forest plots, funnel plots)
Month 6: Manuscript writing + Internal review + Journal submission

═══════════════════════════════════════════════════════════════════

PART 4: YOUR PRISMA FLOW DIAGRAM (Explained)

┌─────────────────────────────────────────┐
│  IDENTIFICATION                          │
│  Records from databases (n = ____)       │
│  Records from other sources (n = ____)  │
└──────────────────┬──────────────────────┘
                   ↓
┌─────────────────────────────────────────┐
│  After duplicates removed (n = ____)    │
└──────────────────┬──────────────────────┘
                   ↓
┌─────────────────────────────────────────┐  ──→  Excluded (n = ____)
│  SCREENING                               │       Reasons:
│  Titles & Abstracts screened (n = ____) │       - Not relevant: ____
└──────────────────┬──────────────────────┘       - Wrong population: ____
                   ↓
┌─────────────────────────────────────────┐  ──→  Excluded with reasons
│  ELIGIBILITY                             │       (n = ____)
│  Full-texts assessed (n = ____)         │
└──────────────────┬──────────────────────┘
                   ↓
┌─────────────────────────────────────────┐
│  INCLUDED                                │
│  Studies in meta-analysis (n = ____)    │
└─────────────────────────────────────────┘

PART 5: TOOLS SUMMARY — ALL FREE

PART 6: KEY BACKGROUND KNOWLEDGE FOR YOUR PAPER

• Trastuzumab cardiotoxicity occurs in 3–7% of patients (up to 27% with concurrent anthracyclines). It manifests as Type II cardiotoxicity — typically reversible LVEF decline, unlike anthracycline-induced Type I (irreversible).
• Landmark trials to know: MANTICORE trial (carvedilol/perindopril), CECCY trial (carvedilol), PRADA trial (candesartan + metoprolol)
• Definition of cardiotoxicity varies between studies — this will be a key source of heterogeneity in your meta-analysis. Document which definition each study used.
• Cardioprotective efficacy: Current evidence is mixed — ACE inhibitors and beta-blockers show modest benefit, particularly when anthracyclines are co-administered

QUICK START CHECKLIST FOR WEEK 1

• Register on PROSPERO and submit protocol
• Create shared folder (Google Drive/OneDrive) with all three team members
• Create Rayyan account → invite both co-authors
• Download RevMan 5.4
• Run search strings on all databases → export .ris files
• Import into Rayyan → remove duplicates
• Begin title/abstract screening (independently, blinded)

Yes — This is a Strong, Feasible Topic. Here's Why.

The Study Landscape (What Exists)

But Here is the Honest Reality Check

• Frame your study as an updated meta-analysis (search up to 2024–2025)
• Include newer trials that previous meta-analyses missed
• Possibly narrow your focus slightly (e.g., "only RCTs" or "specific drug class" or "concurrent anthracycline use") to add novelty

How to Make Your Paper Stand Out

Bottom Line

What the Template Contains (12 Sections):

How to Share It

1. Copy the content into Google Docs → share the link with your two team members with edit access — everyone can fill it simultaneously
2. Or paste into Microsoft Word → convert the tables to Word tables → share via email
3. The Data Extraction Form (Section 8) — make a separate Google Sheet for this so all three of you can extract data in parallel without overwriting each other

Option 1 — Google Docs (Best for sharing with your team)

1. Open Google Docs → File → New Document
2. Copy everything from the text box below and paste it in
3. Click Share → add your two team members' emails
4. Everyone can edit simultaneously in real time

Option 2 — Microsoft Word

1. Open Word → New blank document
2. Paste the content in
3. Save as .docx → share via WhatsApp, email, or Drive

Option 3 — WhatsApp / Email

• Just copy the plain text directly and send it — it is readable as-is since it uses simple lines and spaces, no special formatting needed

================================================================
     SYSTEMATIC REVIEW & META-ANALYSIS — STUDY PROTOCOL
================================================================

SECTION 1 — STUDY IDENTIFICATION

Title       : Efficacy of Cardioprotective Therapies in
              Preventing Trastuzumab-Related Cardiotoxicity
              in HER2-Positive Breast Cancer:
              A Systematic Review and Meta-Analysis
Type        : Systematic Review and Meta-Analysis
PROSPERO No.: _______________________________
Reg. Date   : _______________________________
Version     : 1.0
Date        : _______________________________

================================================================
SECTION 2 — TEAM MEMBERS
================================================================

Lead / Principal Investigator
  Name : _______________________________
  Role : Protocol, search, analysis, writing

Co-Investigator 2
  Name : _______________________________
  Role : Independent screening, data extraction

Co-Investigator 3
  Name : _______________________________
  Role : Independent screening, data extraction

Conflict Arbiter: Lead Author

================================================================
SECTION 3 — PICO
================================================================

P — Population  : Adults (>=18 yrs), HER2-positive breast
                  cancer, receiving trastuzumab

I — Intervention: Cardioprotective therapy
                  (beta-blockers, ACE inhibitors, ARBs,
                  statins, dexrazoxane)

C — Comparator  : Placebo / No cardioprotective therapy /
                  Standard care

O — Outcomes    : Cardiotoxicity (LVEF decline, heart failure,
                  troponin rise, drug discontinuation)

================================================================
SECTION 4 — OUTCOMES
================================================================

PRIMARY
  1. Cardiotoxicity incidence
     (LVEF decline >=10% to <53% OR >=5% to <55% + symptoms)
  2. Trastuzumab discontinuation due to cardiac reasons

SECONDARY
  1. Mean change in LVEF (%) from baseline
  2. Incidence of clinical heart failure
  3. Troponin elevation
  4. NT-proBNP changes
  5. Cardiac-related hospitalizations
  6. All-cause mortality

================================================================
SECTION 5 — SEARCH STRATEGY
================================================================

Date Range : January 2000 – December 2024
Language   : English (primary)

DATABASE          DATE SEARCHED     RECORDS FOUND
PubMed            _____________     _____________
Embase            _____________     _____________
Cochrane CENTRAL  _____________     _____________
Scopus            _____________     _____________
Web of Science    _____________     _____________
ClinicalTrials    _____________     _____________
TOTAL                               _____________

PUBMED SEARCH STRING:

("trastuzumab"[MeSH Terms] OR "trastuzumab"[tiab]
OR "Herceptin"[tiab])
AND ("HER2"[tiab] OR "HER-2"[tiab]
OR "HER2-positive"[tiab])
AND ("breast cancer"[MeSH Terms]
OR "breast neoplasms"[MeSH Terms])
AND ("cardiotoxicity"[tiab] OR "cardiac toxicity"[tiab]
OR "LVEF decline"[tiab] OR "heart failure"[MeSH Terms]
OR "cardiomyopathy"[tiab])
AND ("beta-blocker"[tiab] OR "carvedilol"[tiab]
OR "metoprolol"[tiab] OR "ACE inhibitor"[tiab]
OR "enalapril"[tiab] OR "lisinopril"[tiab]
OR "candesartan"[tiab] OR "ARB"[tiab]
OR "statin"[tiab] OR "dexrazoxane"[tiab]
OR "cardioprotect*"[tiab])

================================================================
SECTION 6 — INCLUSION & EXCLUSION CRITERIA
================================================================

INCLUDE:
  1. RCTs (prospective cohorts if RCT data insufficient)
  2. HER2-positive breast cancer patients
  3. Trastuzumab as part of treatment
  4. At least one cardioprotective drug as intervention
  5. Cardiac outcome data reported (LVEF or cardiac events)
  6. Follow-up duration >= 3 months
  7. Sample size >= 20 patients per arm

EXCLUDE:
  1. Case reports / series (n <20)
  2. Reviews, editorials, letters, commentaries
  3. Animal / in-vitro / preclinical studies
  4. No comparator/control group
  5. No cardiac outcome reported
  6. Conference abstracts with no extractable data
  7. Duplicate publications (keep most complete dataset)

================================================================
SECTION 7 — PRISMA SCREENING LOG
================================================================

Screening Tool: Rayyan (rayyan.ai)

STAGE                                    COUNT
Total records (all databases)            _______
Duplicates removed                       _______
After deduplication                      _______
Excluded at title/abstract screening     _______
Full-texts assessed                      _______
Full-texts excluded — TOTAL              _______
  > Not HER2-positive                    _______
  > No cardioprotective therapy          _______
  > No cardiac outcome                   _______
  > Wrong study design                   _______
  > Insufficient data                    _______
  > Duplicate dataset                    _______
FINAL STUDIES INCLUDED                   _______

Cohen's Kappa after T&A screening : k = _______ (target >0.80)
Cohen's Kappa after full-text      : k = _______ (target >0.80)

================================================================
SECTION 8 — DATA EXTRACTION (One block per study)
================================================================

STUDY No.: ____
First Author                         : ____________________
Year                                 : ____________________
Country                              : ____________________
Study Design (RCT/Cohort)            : ____________________
Trial Registration No.               : ____________________
Funding Source                       : ____________________
Follow-up (months)                   : ____________________

POPULATION
  Total N                            : ____________________
  Intervention n                     : ____________________
  Control n                          : ____________________
  Mean Age (yrs)                     : ____________________
  % Female                           : ____________________
  Cancer Stage                       : ____________________
  HER2 Confirmation (IHC/FISH)       : ____________________
  Prior Anthracycline (Yes/No)       : ____________________
  Baseline LVEF (%)                  : ____________________

INTERVENTION
  Drug Used                          : ____________________
  Dose                               : ____________________
  Duration                           : ____________________
  Timing (before/during trastuzumab) : ____________________
  Concurrent Anthracycline (Yes/No)  : ____________________

CONTROL TYPE (placebo/none/other)    : ____________________

PRIMARY OUTCOMES
  Cardiotoxicity — Intervention      : ___/___  ( ____ %)
  Cardiotoxicity — Control           : ___/___  ( ____ %)
  RR / OR (95% CI)                   : ____________________
  p-value                            : ____________________
  Trastuzumab Stop — Intervention    : ___/___  ( ____ %)
  Trastuzumab Stop — Control         : ___/___  ( ____ %)

SECONDARY OUTCOMES
  LVEF Change — Intervention         : ______ % (SD: _____)
  LVEF Change — Control              : ______ % (SD: _____)
  HF Events — Intervention           : ______  ( ____ %)
  HF Events — Control                : ______  ( ____ %)
  Troponin Elevation                 : ____________________
  Hospitalizations                   : ____________________

Risk of Bias (RoB 2.0)               : Low / Some Concerns / High
Notes                                : ____________________

--- COPY ABOVE BLOCK FOR EACH ADDITIONAL STUDY ---

================================================================
SECTION 9 — RISK OF BIAS TABLE (Cochrane RoB 2.0)
================================================================
L = Low   H = High   ? = Some Concerns

STUDY      D1    D2    D3    D4    D5    OVERALL
________   ___   ___   ___   ___   ___   _______
________   ___   ___   ___   ___   ___   _______
________   ___   ___   ___   ___   ___   _______
________   ___   ___   ___   ___   ___   _______
________   ___   ___   ___   ___   ___   _______

D1=Randomization  D2=Deviations  D3=Missing Data
D4=Outcome Measurement  D5=Reported Results

================================================================
SECTION 10 — STATISTICAL ANALYSIS PLAN
================================================================

Software           : RevMan 5.4 (free — training.cochrane.org)
Dichotomous data   : Risk Ratio (RR) with 95% CI
Continuous data    : Mean Difference (MD) with 95% CI
Model              : Random-effects (DerSimonian-Laird)
Heterogeneity      : Cochran Q + I-squared (I2)
  I2 0-25%   = Low heterogeneity
  I2 26-50%  = Moderate
  I2 51-75%  = Substantial — do subgroup analysis
  I2 >75%    = Considerable — interpret with caution
Publication Bias   : Funnel plot + Egger's test (if >=10 studies)
Evidence Certainty : GRADE (gradepro.org)

SUBGROUP ANALYSES
  1. By drug class (beta-blocker/ACE-I/ARB/statin)
  2. By concurrent anthracycline use (yes/no)
  3. By baseline LVEF (preserved/borderline)
  4. By cancer stage (early/metastatic)
  5. By follow-up (<6 months / >=6 months)

SENSITIVITY ANALYSES
  1. Exclude high risk-of-bias studies
  2. Exclude studies with n <50 per arm
  3. Leave-one-out analysis

================================================================
SECTION 11 — TIMELINE
================================================================

MONTH   TASK                                      WHO
  1     PROSPERO + search + Rayyan import         All
  2     Title & abstract screening (blinded)      All
  3     Full-text screening + PDFs                All
  4     Data extraction + Risk of Bias            All
  5     Statistical analysis + forest plots       Lead
  6     Manuscript writing + submission           All

Target Submission Date : _______________________________
Target Journal         : _______________________________

================================================================
SECTION 12 — TOOLS
================================================================

PROSPERO        : prospero.york.ac.uk
Rayyan          : rayyan.ai
RevMan 5.4      : training.cochrane.org
RoB 2.0         : riskofbias.info
GRADEpro        : gradepro.org
PRISMA diagram  : prisma.thetacollaborative.ca
References      : zotero.org

================================================================
Protocol v1.0  |  Lead: _______________  |  Date: ___________
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To use this right now:

1. Select all the text above from the first === line to the last one
2. Copy it (Ctrl+C or long-press → Copy)
3. Open Google Docs or Microsoft Word → paste it in
4. Save and share the link with your team

PUBMED — Broad Search String

(trastuzumab OR Herceptin OR "anti-HER2") 
AND 
("breast cancer" OR "breast neoplasm" OR "breast carcinoma") 
AND 
(cardiotoxicity OR "cardiac toxicity" OR "cardio toxicity" 
OR "heart failure" OR cardiomyopathy OR "LVEF" 
OR "left ventricular" OR "ejection fraction" 
OR "cardiac dysfunction" OR "cardiac events")

This alone should give you 300–800+ results on PubMed. Do NOT add the drug names yet — that was the mistake before. You screen those papers manually.

IF YOU WANT EVEN MORE — Add This Variation:

(trastuzumab OR Herceptin) 
AND 
(cardiotoxicity OR cardioprotection OR "cardiac toxicity" 
OR "heart failure" OR "left ventricular dysfunction" 
OR "LVEF decline" OR cardiomyopathy OR "cardiac function")

OTHER DATABASES — Search Strings

COCHRANE LIBRARY

trastuzumab AND (cardiotoxicity OR "cardiac toxicity" 
OR "heart failure" OR "left ventricular")

Expected: 50–150 results (Cochrane is smaller but very high quality — mostly RCTs)

EMBASE

'trastuzumab' AND ('cardiotoxicity' OR 'cardiac toxicity' 
OR 'heart failure' OR 'left ventricular dysfunction' 
OR 'cardiomyopathy') AND 'breast cancer'

Expected: 200–500 results

SCOPUS

TITLE-ABS-KEY ( trastuzumab  AND  
( cardiotoxicity  OR  "cardiac toxicity"  
OR  "heart failure"  OR  "left ventricular"  
OR  "ejection fraction" )  
AND  "breast cancer" )

Expected: 150–400 results

WEB OF SCIENCE

TS = (trastuzumab AND ("breast cancer" OR "breast neoplasm") 
AND (cardiotoxicity OR "cardiac toxicity" OR "heart failure" 
OR "left ventricular" OR cardiomyopathy))

Expected: 150–350 results

CLINICALTRIALS.GOV

This gives you registered trials — important for finding unpublished or ongoing studies. Note down their NCT numbers.

GOOGLE SCHOLAR (Bonus — catches things others miss)

trastuzumab cardiotoxicity "breast cancer" 
cardioprotection OR "beta blocker" OR "ACE inhibitor" 
OR carvedilol OR candesartan

Pick the first 3–4 pages of results only. Export using Zotero browser plugin.

Summary Table

The Key Rule Here

Cast wide now, screen strictly later.

What To Do Right Now — Step by Step

1. Go to PubMed → paste the first broad string → click Search
2. On results page → click Save → select All results → Format: PubMed → Download as .nbib file
3. Repeat for each database → download as .ris or .csv
4. Go to rayyan.ai → create new review → upload all files
5. Rayyan auto-removes duplicates
6. Start screening