Organ Preservation Rates with Neoadjuvant Immunotherapy in dMMR/MSI-H Rectal Cancer: A Systematic Review and Meta-Analysis

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// ─── Build Document ──────────────────────────────────────────────────────────
const doc = new Document({
  creator: 'Orris AI Research Assistant',
  title: 'Meta-Analysis Protocol: Organ Preservation in dMMR/MSI-H Rectal Cancer',
  description: 'PRISMA checklist and full study protocol',
  styles: {
    default: {
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    properties: {
      page: { margin: { top: 1080, bottom: 1080, left: 1260, right: 1260 } }
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    headers: {
      default: new Header({
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          children: [new TextRun({ text: 'PROTOCOL | Organ Preservation — dMMR/MSI-H Rectal Cancer | v1.0 | June 2026', size: 16, color: '888888', font: 'Calibri' })]
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      // ── COVER ──
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        children: [new TextRun({ text: 'SYSTEMATIC REVIEW AND META-ANALYSIS', bold: true, size: 28, color: '2E4057', font: 'Calibri', allCaps: true })]
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      new Paragraph({
        alignment: AlignmentType.CENTER,
        spacing: { before: 100, after: 200 },
        children: [new TextRun({ text: 'Organ Preservation Rates with Neoadjuvant PD-1 Monotherapy\nin dMMR/MSI-H Locally Advanced Rectal Cancer:\nA Systematic Review and Meta-Analysis', bold: true, size: 30, color: '1A3A5C', font: 'Calibri' })]
      }),
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        children: [new TextRun({ text: 'PROSPERO Registration: [To be assigned upon submission]', size: 22, color: '555555', font: 'Calibri', italics: true })]
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      pageBreak(),

      // ── SECTION 1: BACKGROUND ──
      h1('1. Background and Rationale'),
      body('Locally advanced rectal cancer (LARC) — defined as clinical stage II (cT3-T4 N0) or stage III (any cT N1-N2) — has traditionally been managed with a multimodal approach comprising long-course chemoradiation (CRT) or short-course radiotherapy, followed by total mesorectal excision (TME). While this strategy achieves R0 resection in most patients, it carries substantial long-term morbidity including permanent colostomy (15–30%), anastomotic complications, low anterior resection syndrome (LARS) in up to 80% of sphincter-preserving operations, and pelvic autonomic dysfunction affecting sexual and urinary function.'),
      spacer(),
      body('Deficient mismatch repair (dMMR) or microsatellite instability-high (MSI-H) tumors represent approximately 5–10% of all rectal cancers. This biologically distinct subgroup is characterized by hypermutation, dense tumor-infiltrating lymphocyte infiltration, and marked responsiveness to immune checkpoint inhibition. In contrast, dMMR/MSI-H rectal cancers are paradoxically less responsive to standard CRT — with pathological complete response (pCR) rates reported at 5.9% compared to 8.9% in proficient MMR (pMMR) tumors — making conventional neoadjuvant treatment suboptimal for this subgroup.'),
      spacer(),
      body('The landmark phase 2 trial by Cercek et al. (NEJM 2022; extended follow-up NEJM 2025) demonstrated that neoadjuvant PD-1 blockade with dostarlimab achieved clinical complete response (cCR) in all patients (100%; n=49) with dMMR/MSI-H LARC, with 92% recurrence-free survival at 2 years and no patient requiring surgery. Parallel cohorts using sintilimab, pembrolizumab, camrelizumab, and nivolumab monotherapy have reported cCR rates of 69–100% and organ preservation in the majority of complete responders.'),
      spacer(),
      body('Despite this, no meta-analysis has been conducted that specifically designates organ preservation rate — defined as the proportion of patients who avoid radical surgery following neoadjuvant PD-1 monotherapy — as its primary endpoint. Existing systematic reviews (Petrelli et al., Crit Rev Oncol Hematol 2025; Mirza et al., J Gastrointest Cancer 2025; Cui et al. [CRD42024594173]) reported organ preservation only as a secondary finding within broader analyses of pCR, cCR, and toxicity across mixed colorectal cancer populations. None performed a pooled proportion meta-analysis restricted to rectal cancer with PD-1 monotherapy, stratified by follow-up duration, agent, and tumor stage. This evidence gap is directly relevant to clinical decision-making, as surgeons and oncologists require a precise, population-specific estimate of organ preservation probability when counseling patients.'),
      spacer(),

      h1('2. Objectives'),
      h2('2.1 Primary Objective'),
      body('To determine the pooled organ preservation rate (proportion of patients avoiding radical surgery) among adults with dMMR/MSI-H locally advanced rectal cancer treated with neoadjuvant PD-1 inhibitor monotherapy.'),
      spacer(),
      h2('2.2 Secondary Objectives'),
      bullet('To determine the pooled clinical complete response (cCR) rate following PD-1 monotherapy in this population.'),
      bullet('To determine the pooled local regrowth rate among patients managed with watch-and-wait after cCR.'),
      bullet('To determine the pooled 2-year disease-free survival (DFS) and overall survival (OS) in organ-preserved patients.'),
      bullet('To determine the pooled sphincter preservation rate among patients who did proceed to surgery.'),
      bullet('To determine the pooled rate of grade ≥3 immune-related adverse events (irAEs).'),
      bullet('To assess the durability of organ preservation by exploring follow-up duration as a moderator.'),
      bullet('To explore predictors of organ preservation through subgroup analysis and meta-regression (ICI agent, cycle number, tumor stage, tumor height, geography).'),
      spacer(),

      h1('3. PICO Framework'),
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          new TableRow({ children: [headerCell('PICO Element'), headerCell('Specification')] }),
          new TableRow({ children: [cell('Population (P)', { bold: true, shade: 'EBF5FF' }), cell('Adults (≥18 years) with histologically confirmed dMMR (IHC loss of MLH1, MSH2, MSH6, or PMS2) or MSI-H (PCR or NGS) locally advanced rectal cancer (stage II–III, cT3-T4 and/or cN+), non-metastatic', { shade: 'EBF5FF' })] }),
          new TableRow({ children: [cell('Intervention (I)', { bold: true, shade: 'E8F5E9' }), cell('Neoadjuvant PD-1 inhibitor monotherapy (any agent: dostarlimab, pembrolizumab, sintilimab, camrelizumab, nivolumab, tislelizumab, toripalimab) — no concurrent CRT or dual checkpoint blockade', { shade: 'E8F5E9' })] }),
          new TableRow({ children: [cell('Comparator (C)', { bold: true, shade: 'FFFDE7' }), cell('None required — this is a single-arm pooled proportion analysis. Where comparative data are available within a study, the monotherapy arm will be extracted.', { shade: 'FFFDE7' })] }),
          new TableRow({ children: [cell('Outcome (O)', { bold: true, shade: 'FCE4EC' }), cell('Primary: Organ preservation rate (proportion avoiding radical surgery). Secondary: cCR, local regrowth, 2-yr DFS, 2-yr OS, sphincter preservation, irAE grade ≥3, stoma-free survival', { shade: 'FCE4EC' })] }),
          new TableRow({ children: [cell('Study Design (S)', { bold: true, shade: 'F3E5F5' }), cell('Phase 1b, 2, or 3 clinical trials; prospective cohort studies; retrospective cohort studies with ≥10 patients. Minimum follow-up: 3 months after treatment completion.', { shade: 'F3E5F5' })] }),
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      }),
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      h1('4. Eligibility Criteria'),
      h2('4.1 Inclusion Criteria'),
      bullet('Human participants aged ≥18 years with a diagnosis of rectal adenocarcinoma.'),
      bullet('dMMR confirmed by IHC (loss of ≥1 MMR protein) OR MSI-H confirmed by PCR fragment analysis, next-generation sequencing, or validated assay.'),
      bullet('Locally advanced disease (cT3, cT4a, cT4b, and/or cN1-N2), non-metastatic (M0).'),
      bullet('Neoadjuvant treatment consisting of PD-1 monotherapy alone (any approved or investigational PD-1 antibody).'),
      bullet('Study reports organ preservation rate, or from which it can be calculated (number who avoided TME / total treated).'),
      bullet('Study includes ≥5 patients treated with the intervention (to avoid extreme single-case estimates distorting pooled proportion).'),
      bullet('Published in English, Chinese, or any language with available English abstract; full translation obtainable if needed.'),
      bullet('Full-text available or author-provided data sufficient for extraction.'),
      spacer(),
      h2('4.2 Exclusion Criteria'),
      bullet('pMMR/MSS patients (even if mixed cohort — only dMMR/MSI-H subgroup will be extracted if separately reported; entire study excluded if not separable).'),
      bullet('Metastatic (stage IV) disease.'),
      bullet('Colon cancer only (no rectum) — studies mixing colorectal cancer will be included only if rectal data are separately extractable.'),
      bullet('Intervention includes concurrent CRT, concurrent chemotherapy, or dual checkpoint blockade (anti-PD-1 + anti-CTLA-4 as a fixed combination) — these are separate interventions and will be excluded from the primary analysis.'),
      bullet('Studies where organ preservation was not an option offered (e.g., mandatory surgical protocols regardless of response).'),
      bullet('Case reports and case series of <5 patients.'),
      bullet('Review articles, editorials, and conference abstracts without extractable patient-level outcomes.'),
      note('Studies using PD-1 monotherapy in combination with anti-angiogenic agents (e.g., apatinib, bevacizumab) will be analyzed separately in a sensitivity analysis, not pooled in the primary analysis.'),
      spacer(),

      h1('5. Information Sources and Search Strategy'),
      h2('5.1 Databases'),
      body('The following databases will be searched from inception to the date of search (planned: July 2026):'),
      bullet('PubMed / MEDLINE'),
      bullet('Embase (via Ovid)'),
      bullet('Cochrane Central Register of Controlled Trials (CENTRAL)'),
      bullet('Web of Science Core Collection'),
      bullet('China National Knowledge Infrastructure (CNKI) — for Chinese-language studies'),
      bullet('Wanfang Data — for Chinese-language studies'),
      bullet('ClinicalTrials.gov — for unpublished or ongoing trial results'),
      bullet('WHO International Clinical Trials Registry Platform (ICTRP)'),
      bullet('ASCO Meeting Library (abstracts 2020–2026)'),
      bullet('ESMO Oncology Congress abstracts (2020–2026)'),
      spacer(),
      h2('5.2 Search Strategy (PubMed — Full String)'),
      body('The following search string will be adapted for each database with appropriate syntax:'),
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          text: '(("rectal cancer" OR "rectal neoplasm" OR "rectal carcinoma" OR "rectal adenocarcinoma" OR "rectum cancer") AND ("dMMR" OR "deficient mismatch repair" OR "mismatch repair deficient" OR "mismatch repair deficiency" OR "MSI-H" OR "microsatellite instability" OR "microsatellite instability-high" OR "MMR deficient") AND ("PD-1" OR "PD1" OR "anti-PD-1" OR "pembrolizumab" OR "dostarlimab" OR "nivolumab" OR "sintilimab" OR "camrelizumab" OR "tislelizumab" OR "toripalimab" OR "immune checkpoint inhibitor" OR "immunotherapy") AND ("neoadjuvant" OR "preoperative" OR "before surgery") AND ("organ preservation" OR "watch and wait" OR "watchful waiting" OR "nonoperative management" OR "non-operative management" OR "organ-sparing" OR "sphincter preservation" OR "stoma-free" OR "rectal preservation" OR "complete response" OR "clinical complete response" OR "cCR"))',
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      h2('5.3 Grey Literature and Hand-Searching'),
      bullet('Reference lists of all included studies and relevant systematic reviews will be manually screened.'),
      bullet('Authors of studies with insufficient outcome data will be contacted by email.'),
      bullet('ClinicalTrials.gov will be searched for completed trials without published results.'),
      spacer(),

      h1('6. Study Selection Process'),
      h2('6.1 Screening'),
      body('All search results will be imported into Covidence (or Rayyan) for duplicate removal and screening. Two independent reviewers (Reviewer A and Reviewer B) will:'),
      bullet('Screen titles and abstracts against eligibility criteria independently.'),
      bullet('Retrieve full texts of potentially eligible studies.'),
      bullet('Assess full-text articles for eligibility independently.'),
      bullet('Resolve disagreements through discussion; a third reviewer will adjudicate unresolved conflicts.'),
      body('Inter-rater agreement will be reported using Cohen\'s kappa (κ).'),
      spacer(),
      h2('6.2 PRISMA Flow Diagram'),
      body('A PRISMA 2020 flow diagram will be generated documenting: records identified, duplicates removed, records screened, full texts assessed, studies included, and reasons for exclusion at each stage.'),
      spacer(),

      h1('7. Data Extraction'),
      h2('7.1 Data Extraction Form'),
      body('A standardized data extraction form (piloted on 3 studies before formal use) will capture:'),
      spacer(),
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          new TableRow({ children: [headerCell('Category'), headerCell('Variables to Extract')] }),
          new TableRow({ children: [cell('Study Identification', { bold: true, shade: 'EBF5FF' }), cell('First author, year, country, journal, trial name/registration, study design, phase, funding source', { shade: 'EBF5FF' })] }),
          new TableRow({ children: [cell('Patient Characteristics', { bold: true, shade: 'E8F5E9' }), cell('Total n, age (mean/median), sex, ECOG PS, tumor stage (cT, cN), tumor height from anal verge, dMMR confirmation method, BRAF/KRAS status if reported', { shade: 'E8F5E9' })] }),
          new TableRow({ children: [cell('Intervention Details', { bold: true, shade: 'FFFDE7' }), cell('ICI agent name, dose, schedule, number of cycles, duration of treatment, any concomitant agents', { shade: 'FFFDE7' })] }),
          new TableRow({ children: [cell('Response Assessment', { bold: true, shade: 'FCE4EC' }), cell('Response assessment method (MRI, endoscopy, CT, PET-CT), timing of response assessment, criteria used (RECIST, mrTRG, endoscopic criteria)', { shade: 'FCE4EC' })] }),
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          new TableRow({ children: [cell('Secondary Outcomes', { bold: true, shade: 'EBF5FF' }), cell('cCR rate, pCR rate (among operated), local regrowth rate (n and %), time to regrowth, DFS (2-yr), OS (2-yr), sphincter preservation, stoma rate, irAE grade ≥3, surgical complications', { shade: 'EBF5FF' })] }),
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      }),
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      h2('7.2 Author Contact'),
      body('For studies that report cCR but do not explicitly state whether watch-and-wait was pursued, corresponding authors will be contacted via email with a standardized data request template. A minimum of two contact attempts will be made before classifying data as unavailable.'),
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      h1('8. Risk of Bias Assessment'),
      h2('8.1 Tool Selection'),
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          new TableRow({ children: [headerCell('Study Design'), headerCell('RoB Tool'), headerCell('Domains Assessed')] }),
          new TableRow({ children: [cell('Randomized phase 2/3 trials', { shade: 'EBF5FF' }), cell('Cochrane RoB 2.0', { shade: 'EBF5FF' }), cell('Randomization, deviations from intervention, missing outcome data, measurement of outcomes, selection of reported result', { shade: 'EBF5FF' })] }),
          new TableRow({ children: [cell('Non-randomized prospective cohorts', { shade: 'E8F5E9' }), cell('ROBINS-I', { shade: 'E8F5E9' }), cell('Confounding, participant selection, classification of interventions, deviations, missing data, measurement of outcomes, selection of reported result', { shade: 'E8F5E9' })] }),
          new TableRow({ children: [cell('Retrospective cohort studies', { shade: 'FFFDE7' }), cell('ROBINS-I', { shade: 'FFFDE7' }), cell('Same as above, with emphasis on selection and confounding domains', { shade: 'FFFDE7' })] }),
        ]
      }),
      body('Two independent reviewers will conduct all RoB assessments; disagreements resolved by consensus.'),
      spacer(),

      h1('9. Statistical Analysis Plan'),
      h2('9.1 Primary Analysis — Pooled Proportion Meta-Analysis'),
      body('The primary analysis will pool the organ preservation proportion across all included studies using a random-effects model. Given that proportions are expected to be near 1.0 in several studies (near-100% cCR studies), raw proportions will be stabilized using the Freeman-Tukey double arcsine transformation prior to pooling, then back-transformed for presentation.'),
      spacer(),
      bullet('Model: DerSimonian-Laird random-effects estimator (REML as sensitivity).'),
      bullet('Effect measure: Pooled proportion with 95% confidence interval.'),
      bullet('Prediction interval will be reported to convey between-study variability.'),
      bullet('Software: R (meta, metafor packages); forest plots generated with forestplot or ggplot2.'),
      spacer(),
      h2('9.2 Heterogeneity Assessment'),
      bullet('I² statistic: <25% low, 25–50% moderate, 50–75% substantial, >75% considerable heterogeneity.'),
      bullet('Cochran Q test (p<0.10 considered significant).'),
      bullet('tau² (between-study variance) reported for each meta-analytic pooling.'),
      spacer(),
      h2('9.3 Subgroup Analyses (Pre-specified)'),
      new Table({
        width: { size: 100, type: WidthType.PERCENTAGE },
        rows: [
          new TableRow({ children: [headerCell('Subgroup Variable'), headerCell('Categories'), headerCell('Rationale')] }),
          new TableRow({ children: [cell('ICI Agent', { shade: 'EBF5FF' }), cell('Dostarlimab vs. Pembrolizumab vs. Sintilimab vs. Other', { shade: 'EBF5FF' }), cell('Agent-specific binding kinetics and pharmacodynamics may affect response depth', { shade: 'EBF5FF' })] }),
          new TableRow({ children: [cell('Treatment Duration / Cycles', { shade: 'E8F5E9' }), cell('<4 cycles vs. 4–6 cycles vs. >6 cycles', { shade: 'E8F5E9' }), cell('Dose-response relationship; minimum adequate exposure not established', { shade: 'E8F5E9' })] }),
          new TableRow({ children: [cell('Tumor T-stage', { shade: 'FFFDE7' }), cell('cT2-T3 vs. cT4a/b', { shade: 'FFFDE7' }), cell('T4 tumors may be less likely to achieve complete response; surgical salvage more complex', { shade: 'FFFDE7' })] }),
          new TableRow({ children: [cell('Tumor Height', { shade: 'FCE4EC' }), cell('Low (<5 cm from AV) vs. Mid (5–10 cm) vs. Upper (>10 cm)', { shade: 'FCE4EC' }), cell('Low rectal tumors carry highest colostomy risk; greatest clinical impact if preserved', { shade: 'FCE4EC' })] }),
          new TableRow({ children: [cell('Geographic Region', { shade: 'F3E5F5' }), cell('East Asian centers vs. Western centers', { shade: 'F3E5F5' }), cell('Potential population selection, dMMR prevalence, and institutional W&W protocol differences', { shade: 'F3E5F5' })] }),
          new TableRow({ children: [cell('Study Design', { shade: 'EBF5FF' }), cell('RCT/Prospective vs. Retrospective', { shade: 'EBF5FF' }), cell('Prospective studies with pre-defined W&W protocols may achieve higher organ preservation vs. retrospective series', { shade: 'EBF5FF' })] }),
          new TableRow({ children: [cell('Follow-up Duration', { shade: 'E8F5E9' }), cell('<12 months vs. 12–24 months vs. >24 months', { shade: 'E8F5E9' }), cell('Organ preservation durability may decrease over time as late regrowth occurs', { shade: 'E8F5E9' })] }),
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      }),
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      h2('9.4 Meta-Regression'),
      body('Continuous moderators (median follow-up duration in months, mean number of cycles, median age) will be explored via univariable meta-regression using the metafor package in R to identify predictors of organ preservation rate. Results will be interpreted cautiously given expected small sample sizes per covariate.'),
      spacer(),
      h2('9.5 Sensitivity Analyses'),
      bullet('Excluding studies with high RoB on ROBINS-I (overall "serious" or "critical" rating).'),
      bullet('Excluding retrospective studies — prospective cohorts and trials only.'),
      bullet('Excluding studies with <12 months follow-up (to assess durability-focused estimate).'),
      bullet('Including studies with PD-1 + anti-angiogenic combinations (to assess sensitivity of primary exclusion criterion).'),
      bullet('Re-analysis using Bayesian random-effects model with weakly informative prior.'),
      bullet('Leave-one-out analysis (each study removed once) to assess influence of individual studies.'),
      spacer(),
      h2('9.6 Publication Bias'),
      bullet('Funnel plot (if ≥10 studies included) with visual asymmetry assessment.'),
      bullet('Egger\'s test for small-study effects (p<0.10 considered significant).'),
      bullet('Trim-and-fill method to estimate the adjusted pooled proportion if asymmetry is detected.'),
      note('Publication bias is expected to trend toward over-reporting of high response rates in small early-phase trials. The direction and magnitude of this potential bias will be explicitly discussed.'),
      spacer(),
      h2('9.7 Certainty of Evidence — GRADE'),
      body('The GRADE framework will be used to rate the certainty (quality) of evidence for each outcome. Starting certainty will be "low" for observational studies and "high" for RCTs, then downgraded for: risk of bias, inconsistency (high I²), indirectness, imprecision (wide CI), and publication bias; upgraded for large effect size (OR >5), dose-response gradient, or residual confounding favoring null. The final certainty rating (High / Moderate / Low / Very Low) will be presented in a Summary of Findings (SoF) table.'),
      spacer(),

      h1('10. Reporting'),
      body('This systematic review and meta-analysis will be reported in accordance with the PRISMA 2020 statement (Page et al., BMJ 2021). The PRISMA 2020 checklist is provided in Section 12 of this document. The MOOSE (Meta-analysis of Observational Studies in Epidemiology) checklist will be applied as a supplementary reporting guide given the expected predominance of observational studies.'),
      spacer(),

      h1('11. Protocol Amendments'),
      body('Any deviations from this pre-registered protocol will be documented prospectively in PROSPERO with a date-stamped amendment and a clear rationale. Deviations will be transparently reported and discussed in the limitations section of the final publication.'),
      spacer(),

      h1('12. Timeline'),
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          new TableRow({ children: [headerCell('Phase'), headerCell('Activity'), headerCell('Target Date')] }),
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          new TableRow({ children: [cell('2', { shade: 'E8F5E9' }), cell('Database searches; import to screening software', { shade: 'E8F5E9' }), cell('July–August 2026', { shade: 'E8F5E9' })] }),
          new TableRow({ children: [cell('3', { shade: 'FFFDE7' }), cell('Title/abstract screening; full-text retrieval', { shade: 'FFFDE7' }), cell('August 2026', { shade: 'FFFDE7' })] }),
          new TableRow({ children: [cell('4', { shade: 'FCE4EC' }), cell('Full-text eligibility assessment; author contact', { shade: 'FCE4EC' }), cell('September 2026', { shade: 'FCE4EC' })] }),
          new TableRow({ children: [cell('5', { shade: 'F3E5F5' }), cell('Data extraction; RoB assessment', { shade: 'F3E5F5' }), cell('September–October 2026', { shade: 'F3E5F5' })] }),
          new TableRow({ children: [cell('6', { shade: 'EBF5FF' }), cell('Statistical analysis; subgroup/sensitivity analyses', { shade: 'EBF5FF' }), cell('October–November 2026', { shade: 'EBF5FF' })] }),
          new TableRow({ children: [cell('7', { shade: 'E8F5E9' }), cell('Manuscript writing; internal review', { shade: 'E8F5E9' }), cell('November–December 2026', { shade: 'E8F5E9' })] }),
          new TableRow({ children: [cell('8', { shade: 'FFFDE7' }), cell('Submission to target journal', { shade: 'FFFDE7' }), cell('January 2027', { shade: 'FFFDE7' })] }),
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      h1('13. Ethical Considerations'),
      body('This study is a systematic review and meta-analysis of previously published data. No primary data collection from patients will be performed. Ethical approval and patient consent are not required. Patient data extracted from included studies will have been subject to ethical oversight by the originating institutions.'),
      spacer(),

      h1('14. Team Roles'),
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          new TableRow({ children: [headerCell('Role'), headerCell('Responsibilities'), headerCell('Assigned To')] }),
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          new TableRow({ children: [cell('Reviewer A', { shade: 'E8F5E9' }), cell('Independent screening, data extraction, RoB assessment', { shade: 'E8F5E9' }), cell('[Reviewer A Name]', { shade: 'E8F5E9' })] }),
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          new TableRow({ children: [cell('Statistician', { shade: 'FCE4EC' }), cell('Statistical analysis plan execution, R code, forest plots', { shade: 'FCE4EC' }), cell('[Statistician Name]', { shade: 'FCE4EC' })] }),
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        ]
      }),
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      pageBreak(),

      // ── SECTION: PROSPERO LANDSCAPE ──
      h1('15. PROSPERO Registration Landscape — Conflict Assessment'),
      body('A vigorous pre-registration search was conducted across PROSPERO, PubMed, Embase, and full-text databases to identify any existing registered protocol or published systematic review that would conflict with or duplicate the proposed study. The following registrations were identified and assessed:'),
      spacer(),
      new Table({
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          new TableRow({ children: [headerCell('Registration / PMID'), headerCell('Scope'), headerCell('Primary Outcome'), headerCell('Overlap with Proposed Study'), headerCell('Verdict')] }),
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            cell('CRD42024594173\n(Cui et al., Front Immunol 2025)', { shade: 'FCE4EC' }),
            cell('Non-metastatic dMMR colorectal cancer (colon + rectum mixed). ICI monotherapy AND combination strategies.', { shade: 'FCE4EC' }),
            cell('pCR and MPR rates', { shade: 'FCE4EC' }),
            cell('Partial: Includes rectum but mixed with colon. Primary outcome is pCR/MPR, not organ preservation. Does not stratify by rectal monotherapy.', { shade: 'FCE4EC' }),
            cell('NOT duplicative — different primary outcome and population scope', { bold: true, shade: 'E8F5E9', color: '2E6E4A' })
          ]}),
          new TableRow({ children: [
            cell('CRD420251174716\n(MDPI, 2025)', { shade: 'FCE4EC' }),
            cell('Non-metastatic dMMR CRC, adjuvant vs. neoadjuvant strategies comparison (ATOMIC, NICHE-2, MOSAIC).', { shade: 'FCE4EC' }),
            cell('DFS comparison across treatment paradigms', { shade: 'FCE4EC' }),
            cell('Minimal: Focused on adjuvant vs. neoadjuvant DFS comparison across all stages. Does not focus on organ preservation or rectal cancer specifically.', { shade: 'FCE4EC' }),
            cell('NOT duplicative — different research question and outcome', { bold: true, shade: 'E8F5E9', color: '2E6E4A' })
          ]}),
          new TableRow({ children: [
            cell('CRD42024619949\n(BMC Cancer, 2025)', { shade: 'FCE4EC' }),
            cell('LARC with PD-1/PD-L1 inhibitors combined with CRT. Mixed MMR status (pMMR + dMMR).', { shade: 'FCE4EC' }),
            cell('pCR and cCR rates in CRT + ICI combinations', { shade: 'FCE4EC' }),
            cell('Minimal: Focused on CRT + ICI combination regimens, not monotherapy. Mixed MMR population. Organ preservation not the primary endpoint.', { shade: 'FCE4EC' }),
            cell('NOT duplicative — different intervention (combination vs. monotherapy)', { bold: true, shade: 'E8F5E9', color: '2E6E4A' })
          ]}),
          new TableRow({ children: [
            cell('PMID 40889731\n(Petrelli et al., Crit Rev Oncol Hematol 2025)', { shade: 'FFFDE7' }),
            cell('dMMR/MSI localized rectal cancer, all ICI strategies (mono + combo). 504 patients, 19 studies.', { shade: 'FFFDE7' }),
            cell('Narrative synthesis — cCR, pCR, organ preservation, toxicity (secondary).', { shade: 'FFFDE7' }),
            cell('Partial: Covers organ preservation but as a secondary narrative finding — no pooled proportion meta-analysis performed. Includes combination strategies alongside monotherapy.', { shade: 'FFFDE7' }),
            cell('NOT duplicative — no quantitative pooling of organ preservation as primary endpoint', { bold: true, shade: 'E8F5E9', color: '2E6E4A' })
          ]}),
          new TableRow({ children: [
            cell('PMID 41343101\n(Mirza et al., J Gastrointest Cancer 2025)', { shade: 'FFFDE7' }),
            cell('Prospective trials only, dMMR/MSI-H CRC (colon + rectum), efficacy, pCR, surgical outcomes. 352 patients, 8 trials.', { shade: 'FFFDE7' }),
            cell('pCR, MPR, cCR, surgical outcomes', { shade: 'FFFDE7' }),
            cell('Partial: Surgical outcomes included but organ preservation not the primary endpoint; colon and rectum mixed; retrospective studies excluded; no subgroup/meta-regression analysis.', { shade: 'FFFDE7' }),
            cell('NOT duplicative — different primary endpoint, population, and study design eligibility', { bold: true, shade: 'E8F5E9', color: '2E6E4A' })
          ]}),
        ]
      }),
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      pageBreak(),

      // ── SECTION: PRISMA CHECKLIST ──
      h1('16. PRISMA 2020 Checklist'),
      body('Complete the following checklist when preparing the final manuscript. All items must be addressed. Items marked "NA" should include a brief justification in the manuscript.', { italic: true }),
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      spacer(),

      pageBreak(),

      // ── REFERENCES ──
      h1('17. Key References'),
      body('The following landmark references informed the design of this protocol:'),
      spacer(),
      bullet('Cercek A, et al. Nonoperative Management of Mismatch Repair-Deficient Tumors. N Engl J Med. 2025;392:2001–2013. PMID: 40293177'),
      bullet('Cercek A, et al. PD-1 blockade in mismatch repair-deficient, locally advanced rectal cancer. N Engl J Med. 2022;386:2363–2376.'),
      bullet('Petrelli F, et al. Immune checkpoint inhibitors for dMMR/MSI localized rectal cancer: A systematic review. Crit Rev Oncol Hematol. 2025. PMID: 40889731'),
      bullet('Mirza W, et al. Neoadjuvant Immune Checkpoint Inhibition in MSI-H/dMMR Colorectal Cancer: A Systematic Review. J Gastrointest Cancer. 2025. PMID: 41343101'),
      bullet('Yu J-H, et al. Long-Term Outcomes of dMMR/MSI-H Rectal Cancer Treated With Anti-PD-1-Based Immunotherapy. JNCCN. 2024. PMID: 38498975'),
      bullet('Loufopoulos P, et al. Immunotherapy-Induced Complete Response in dMMR Rectal Cancer — A Surgical Dilemma? Cancers. 2025. PMID: 41097680'),
      bullet('Page MJ, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71.'),
      bullet('Sterne JAC, et al. ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ. 2016;355:i4919.'),
      bullet('Freeman MF, Tukey JW. Transformations related to the angular and the square root. Ann Math Stat. 1950;21:607–611.'),
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// ─── PROSPERO FIELDS ────────────────────────────────────────────────────────
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        spacing: { before: 60, after: 60 },
        children: [new TextRun({ text: 'International Prospective Register of Systematic Reviews', size: 24, color: '555555', font: 'Calibri' })]
      }),
      new Paragraph({
        alignment: AlignmentType.CENTER,
        spacing: { before: 60, after: 240 },
        children: [new TextRun({ text: 'crd.york.ac.uk/prospero', size: 22, color: '1A7BC4', font: 'Calibri', underline: { type: UnderlineType.SINGLE } })]
      }),
      new Paragraph({
        alignment: AlignmentType.CENTER,
        spacing: { before: 120, after: 120 },
        children: [new TextRun({ text: 'REGISTRATION DRAFT', bold: true, size: 28, color: '2E4057', font: 'Calibri', allCaps: true })]
      }),
      new Paragraph({
        alignment: AlignmentType.CENTER,
        spacing: { before: 100, after: 280 },
        children: [new TextRun({
          text: 'Organ Preservation Rates with Neoadjuvant PD-1 Monotherapy in\ndMMR/MSI-H Locally Advanced Rectal Cancer:\nA Systematic Review and Meta-Analysis',
          bold: true, size: 30, color: '1A3A5C', font: 'Calibri'
        })]
      }),
      new Paragraph({
        alignment: AlignmentType.CENTER,
        spacing: { before: 60, after: 60 },
        children: [new TextRun({ text: 'Version 1.0  |  June 2026', size: 22, color: '666666', font: 'Calibri' })]
      }),
      new Paragraph({
        alignment: AlignmentType.CENTER,
        spacing: { before: 40, after: 40 },
        children: [new TextRun({ text: 'Pre-registration draft — all 22 PROSPERO mandatory fields completed', size: 20, color: '888888', font: 'Calibri', italics: true })]
      }),
      spacer(),
      warningBox('Register BEFORE beginning title/abstract screening. PROSPERO will flag and may reject retrospective registrations. Submit this week (before July 2026) as planned.'),
      spacer(), spacer(),
      pageBreak(),

      // ── HOW TO USE THIS DOCUMENT ─────────────────────────────────────────
      h1('How to Use This Document'),
      body('This document contains pre-drafted content for all 22 mandatory PROSPERO registration fields. To register:'),
      bullet('Go to crd.york.ac.uk/prospero → click "Register a review" → complete the eligibility screener.'),
      bullet('Log in or create a free account using your institutional email.'),
      bullet('Copy-paste each field\'s content from this document directly into the PROSPERO online form.'),
      bullet('Fields marked [REPLACE] require your personal/institutional information before submission.'),
      bullet('Fields marked [OPTIONAL — RECOMMENDED] are not mandatory but strengthen the submission.'),
      bullet('Expected time to enter all fields: 45–60 minutes.'),
      bullet('PROSPERO approval time: typically 2–5 business days; target registration by 27 June 2026.'),
      spacer(),
      greenBox('No similar registration was found on PROSPERO for organ preservation as the primary endpoint in dMMR/MSI-H rectal cancer treated with PD-1 monotherapy. This topic is clear to register.'),
      spacer(),
      pageBreak(),

      // ── SECTION A: ADMINISTRATIVE DETAILS ───────────────────────────────
      h1('SECTION A: Administrative Details'),
      spacer(),

      // Field 1
      fieldLabel(1, 'Review Title'),
      fieldBox([
        'Organ Preservation Rates with Neoadjuvant PD-1 Inhibitor Monotherapy in dMMR/MSI-H Locally Advanced Rectal Cancer: A Systematic Review and Meta-Analysis of Pooled Proportions'
      ]),
      tip('Keep the title precise and searchable. Include "systematic review and meta-analysis" so PROSPERO can index it correctly. Character limit: ~300 characters.'),
      spacer(),

      // Field 2
      fieldLabel(2, 'Original Language Title', false),
      fieldBox(['Not applicable — review will be conducted and reported in English.']),
      spacer(),

      // Field 3
      fieldLabel(3, 'Anticipated or Actual Start Date'),
      fieldBox(['01 July 2026']),
      tip('Enter the date your database searches will begin, not the date you started thinking about the review.'),
      spacer(),

      // Field 4
      fieldLabel(4, 'Anticipated Completion Date'),
      fieldBox(['28 February 2027']),
      spacer(),

      // Field 5
      fieldLabel(5, 'Stage of Review at Time of Submission'),
      fieldBox([
        'Preliminary searches: Started',
        'Screening: Not started',
        'Data extraction: Not started',
        'Risk of bias assessment: Not started',
        'Data synthesis: Not started'
      ]),
      tip('Preliminary searches = scoping searches to refine the protocol. Formal screening must NOT have started.'),
      spacer(),

      // Field 6
      fieldLabel(6, 'Named Contact'),
      fieldBox([
        '[REPLACE: First Name Last Name]',
        'Role: Principal Investigator',
        'Institution: [REPLACE: Your Institution Name]',
        'Department: [REPLACE: e.g., Department of Surgery / Colorectal Surgery / Oncology]',
        'Address: [REPLACE: Full institutional mailing address]',
        'Country: [REPLACE: e.g., Malaysia / United Kingdom / United States]',
        'Email: [REPLACE: institutional email address]',
        'ORCID: [REPLACE: 0000-0000-0000-0000] (strongly recommended)'
      ]),
      spacer(),

      // Field 7
      fieldLabel(7, 'Named Contact Email'),
      fieldBox(['[REPLACE: institutional.email@university.edu]']),
      spacer(),

      // Field 8
      fieldLabel(8, 'Organisational Affiliation'),
      fieldBox(['[REPLACE: Full name of institution, e.g., Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia]']),
      spacer(),

      // Field 9
      fieldLabel(9, 'Review Team Members'),
      fieldBox([
        'REVIEWER 1 (Named Contact / PI): [REPLACE: Name, Institution, ORCID]',
        'REVIEWER 2 (Independent Screener): [REPLACE: Name, Institution, ORCID]',
        'REVIEWER 3 / Arbitrator: [REPLACE: Name, Institution, ORCID]',
        'STATISTICIAN: [REPLACE: Name, Institution, ORCID]',
        '',
        'Note: Minimum two independent reviewers required for screening and data extraction.'
      ]),
      spacer(),

      // Field 10
      fieldLabel(10, 'Funding Sources / Sponsors', false),
      fieldBox([
        'This systematic review and meta-analysis is not funded by any external sponsor.',
        'No pharmaceutical company, device manufacturer, or commercial entity is involved in the design, conduct, or reporting of this review.',
        '[REPLACE if applicable: List any institutional grant numbers or academic funding here]'
      ]),
      spacer(),

      // Field 11
      fieldLabel(11, 'Conflicts of Interest', false),
      fieldBox([
        'All review team members declare no conflicts of interest relevant to this systematic review.',
        'No author has received honoraria, consultancy fees, or research support from manufacturers of PD-1 inhibitors (including dostarlimab [GSK/Tesaro], pembrolizumab [Merck], nivolumab [Bristol Myers Squibb], sintilimab [Innovent], or camrelizumab [Jiangsu HengRui]).',
        '[REPLACE: Update if any team member has a relevant disclosure]'
      ]),
      spacer(),
      pageBreak(),

      // ── SECTION B: REVIEW DETAILS ────────────────────────────────────────
      h1('SECTION B: Review Details'),
      spacer(),

      // Field 12
      fieldLabel(12, 'Review Question'),
      fieldBox([
        'Among adults with dMMR/MSI-H locally advanced rectal cancer (stage II–III, non-metastatic), what proportion achieve organ preservation (avoidance of radical surgery) following neoadjuvant PD-1 inhibitor monotherapy, and what patient and treatment factors predict successful organ preservation?'
      ]),
      tip('This must be a single, clear, answerable question. PROSPERO reviewers will check this against your outcomes.'),
      spacer(),

      // Field 13
      fieldLabel(13, 'Searches'),
      fieldBoxRich([
        new Paragraph({ spacing: { before: 40, after: 40 }, children: [new TextRun({ text: 'Databases to be searched:', bold: true, size: 22, font: 'Calibri' })] }),
        new Paragraph({ spacing: { before: 20, after: 20 }, children: [new TextRun({ text: '• PubMed/MEDLINE (inception to July 2026)', size: 22, font: 'Calibri' })] }),
        new Paragraph({ spacing: { before: 20, after: 20 }, children: [new TextRun({ text: '• Embase via Ovid (inception to July 2026)', size: 22, font: 'Calibri' })] }),
        new Paragraph({ spacing: { before: 20, after: 20 }, children: [new TextRun({ text: '• Cochrane Central Register of Controlled Trials (CENTRAL)', size: 22, font: 'Calibri' })] }),
        new Paragraph({ spacing: { before: 20, after: 20 }, children: [new TextRun({ text: '• Web of Science Core Collection', size: 22, font: 'Calibri' })] }),
        new Paragraph({ spacing: { before: 20, after: 20 }, children: [new TextRun({ text: '• China National Knowledge Infrastructure (CNKI)', size: 22, font: 'Calibri' })] }),
        new Paragraph({ spacing: { before: 20, after: 20 }, children: [new TextRun({ text: '• Wanfang Data (Chinese-language studies)', size: 22, font: 'Calibri' })] }),
        new Paragraph({ spacing: { before: 20, after: 20 }, children: [new TextRun({ text: '• ClinicalTrials.gov and WHO ICTRP (for trial results)', size: 22, font: 'Calibri' })] }),
        new Paragraph({ spacing: { before: 20, after: 20 }, children: [new TextRun({ text: '• ASCO and ESMO congress abstracts (2020–2026)', size: 22, font: 'Calibri' })] }),
        spacer(),
        new Paragraph({ spacing: { before: 40, after: 40 }, children: [new TextRun({ text: 'Core search terms (PubMed):', bold: true, size: 22, font: 'Calibri' })] }),
        new Paragraph({ spacing: { before: 20, after: 20 }, children: [new TextRun({ text: '("rectal cancer" OR "rectal neoplasm" OR "rectal carcinoma") AND ("dMMR" OR "deficient mismatch repair" OR "MSI-H" OR "microsatellite instability-high") AND ("PD-1" OR "pembrolizumab" OR "dostarlimab" OR "nivolumab" OR "sintilimab" OR "camrelizumab" OR "immune checkpoint inhibitor") AND ("neoadjuvant" OR "preoperative") AND ("organ preservation" OR "watch and wait" OR "nonoperative" OR "complete response")', size: 20, font: 'Courier New', color: '1A3A5C' })] }),
        spacer(),
        new Paragraph({ spacing: { before: 20, after: 20 }, children: [new TextRun({ text: 'Language: English and Chinese (no date restriction). Reference lists of included studies and recent systematic reviews will be hand-searched.', size: 22, font: 'Calibri' })] }),
      ]),
      spacer(),

      // Field 14
      fieldLabel(14, 'Condition or Domain Being Studied'),
      fieldBox([
        'Locally advanced rectal cancer (stage II–III, non-metastatic) with confirmed deficient mismatch repair (dMMR) or microsatellite instability-high (MSI-H) status.',
        '',
        'MeSH terms: Rectal Neoplasms; Microsatellite Instability; DNA Mismatch Repair; Neoadjuvant Therapy; Organ Preservation.'
      ]),
      spacer(),

      // Field 15
      fieldLabel(15, 'Participants / Population'),
      fieldBox([
        'Adults (≥18 years) with histologically confirmed rectal adenocarcinoma, stage II (cT3-T4 N0 M0) or stage III (any cT N1-N2 M0), with dMMR confirmed by immunohistochemistry (loss of MLH1, MSH2, MSH6, and/or PMS2) OR MSI-H confirmed by PCR fragment analysis, next-generation sequencing, or validated assay.',
        '',
        'Exclusion: Patients with metastatic (stage IV) disease; patients with pMMR/MSS status; paediatric patients (<18 years); colon cancer only (rectal subgroup must be separately extractable in mixed studies).'
      ]),
      spacer(),

      // Field 16
      fieldLabel(16, 'Intervention(s), Exposure(s)'),
      fieldBox([
        'Neoadjuvant PD-1 inhibitor monotherapy administered before definitive surgical or non-operative management. Eligible agents include any anti-PD-1 antibody as monotherapy: dostarlimab, pembrolizumab, nivolumab, sintilimab, camrelizumab, tislelizumab, toripalimab, or other investigational PD-1 agents.',
        '',
        'Monotherapy is defined as PD-1 inhibitor administered without concurrent chemotherapy, radiotherapy, or anti-CTLA-4 agents during the neoadjuvant phase.'
      ]),
      spacer(),

      // Field 17
      fieldLabel(17, 'Comparator(s) / Control(s)'),
      fieldBox([
        'No comparator is required for the primary analysis. This is a single-arm pooled proportion meta-analysis estimating the organ preservation rate within the intervention arm.',
        '',
        'Where studies report both a PD-1 monotherapy arm and a comparator arm (e.g., CRT control), only the PD-1 monotherapy arm will be included in the primary analysis. Comparative data will be reported descriptively.'
      ]),
      spacer(),

      // Field 18 — KEY FIELD
      fieldLabel(18, 'Types of Study to be Included'),
      fieldBox([
        'Eligible study designs: Phase 1b, 2, or 3 clinical trials (single-arm or multi-arm where monotherapy data are extractable); prospective cohort studies; retrospective cohort studies with ≥5 dMMR/MSI-H rectal cancer patients treated with PD-1 monotherapy.',
        '',
        'Minimum follow-up: 3 months after completion of neoadjuvant treatment.',
        '',
        'Exclusion: Case reports or case series of <5 patients; review articles; conference abstracts without extractable patient-level data; editorials.'
      ]),
      spacer(),
      pageBreak(),

      // ── SECTION C: OUTCOMES ──────────────────────────────────────────────
      h1('SECTION C: Outcomes'),
      spacer(),

      // Field 19 — PRIMARY
      fieldLabel(19, 'Main Outcome(s)'),
      fieldBoxRich([
        new Paragraph({ spacing: { before: 40, after: 60 }, children: [new TextRun({ text: 'PRIMARY OUTCOME:', bold: true, size: 22, font: 'Calibri', color: '1A3A5C' })] }),
        new Paragraph({ spacing: { before: 20, after: 40 }, children: [new TextRun({ text: 'Organ preservation rate — defined as the proportion of enrolled patients with dMMR/MSI-H locally advanced rectal cancer who avoided radical surgical resection (total mesorectal excision) following neoadjuvant PD-1 monotherapy. This includes patients who achieved clinical complete response (cCR) and were managed with a watch-and-wait strategy, and patients who achieved cCR and elected non-operative management. Patients who subsequently underwent salvage surgery after initial organ preservation will be classified as having initially achieved organ preservation (per intent-to-treat principle for the primary proportion estimate).', size: 22, font: 'Calibri', color: '1C1C1C' })] }),
        spacer(),
        new Paragraph({ spacing: { before: 40, after: 60 }, children: [new TextRun({ text: 'SECONDARY OUTCOMES:', bold: true, size: 22, font: 'Calibri', color: '2E4057' })] }),
        new Paragraph({ spacing: { before: 20, after: 20 }, children: [new TextRun({ text: '1. Clinical complete response (cCR) rate — proportion achieving cCR by multimodal assessment (MRI + endoscopy ± CT/PET-CT).', size: 22, font: 'Calibri' })] }),
        new Paragraph({ spacing: { before: 20, after: 20 }, children: [new TextRun({ text: '2. Pathological complete response (pCR) rate — proportion with ypT0N0 among patients who proceeded to surgery.', size: 22, font: 'Calibri' })] }),
        new Paragraph({ spacing: { before: 20, after: 20 }, children: [new TextRun({ text: '3. Local regrowth rate — proportion of watch-and-wait patients who developed endoscopic/radiologic regrowth at the primary site.', size: 22, font: 'Calibri' })] }),
        new Paragraph({ spacing: { before: 20, after: 20 }, children: [new TextRun({ text: '4. 2-year disease-free survival (DFS) — in organ-preserved patients.', size: 22, font: 'Calibri' })] }),
        new Paragraph({ spacing: { before: 20, after: 20 }, children: [new TextRun({ text: '5. 2-year overall survival (OS) — in organ-preserved patients.', size: 22, font: 'Calibri' })] }),
        new Paragraph({ spacing: { before: 20, after: 20 }, children: [new TextRun({ text: '6. Sphincter preservation rate — among patients who proceeded to surgery.', size: 22, font: 'Calibri' })] }),
        new Paragraph({ spacing: { before: 20, after: 20 }, children: [new TextRun({ text: '7. Rate of grade ≥3 immune-related adverse events (irAEs).', size: 22, font: 'Calibri' })] }),
        new Paragraph({ spacing: { before: 20, after: 20 }, children: [new TextRun({ text: '8. Stoma-free survival at 2 years.', size: 22, font: 'Calibri' })] }),
      ]),
      spacer(),
      pageBreak(),

      // ── SECTION D: DATA AND ANALYSIS ────────────────────────────────────
      h1('SECTION D: Data and Analysis'),
      spacer(),

      // Field 20
      fieldLabel(20, 'Data Extraction (Selection and Coding)'),
      fieldBox([
        'Data will be extracted independently by two reviewers using a pre-piloted standardized form. Variables extracted will include: study identification, country, year, trial name/registry number, study design, sample size, patient demographics (age, sex, ECOG PS), tumor characteristics (stage, T-category, N-category, tumor height from anal verge), dMMR/MSI-H confirmation method, ICI agent and dose, number of cycles, duration of treatment, response assessment method and timing, organ preservation outcome (n/total), cCR rate, pCR rate, local regrowth data, survival outcomes, and adverse events.',
        '',
        'Discrepancies between reviewers will be resolved by discussion; a third reviewer will adjudicate unresolved conflicts. Authors will be contacted by email for missing or ambiguous data, with a minimum of two contact attempts before classifying data as unavailable.',
        '',
        'Inter-rater agreement for study selection will be reported using Cohen\'s kappa (κ).'
      ]),
      spacer(),

      // Field 21
      fieldLabel(21, 'Risk of Bias (Quality) Assessment'),
      fieldBox([
        'Risk of bias will be independently assessed by two reviewers using validated tools:',
        '',
        '• Randomized trials: Cochrane Risk of Bias tool version 2.0 (RoB 2.0) — five domains: randomization, deviations from intervention, missing outcome data, measurement of outcomes, selection of reported result.',
        '',
        '• Non-randomized prospective and retrospective cohort studies: ROBINS-I (Risk Of Bias In Non-randomized Studies of Interventions) — seven domains: confounding, participant selection, classification of interventions, deviations from intended interventions, missing data, measurement of outcomes, selection of reported result.',
        '',
        'Overall risk of bias will be rated as: low, some concerns, high, or critical (RoB 2.0) / low, moderate, serious, or critical (ROBINS-I). Sensitivity analyses will exclude studies with high or critical risk of bias.'
      ]),
      spacer(),

      // Field 22
      fieldLabel(22, 'Strategy for Data Synthesis'),
      fieldBoxRich([
        new Paragraph({ spacing: { before: 40, after: 40 }, children: [new TextRun({ text: 'Primary analysis: Pooled proportion meta-analysis', bold: true, size: 22, font: 'Calibri' })] }),
        new Paragraph({ spacing: { before: 20, after: 40 }, children: [new TextRun({ text: 'Organ preservation proportions will be pooled across all eligible studies using a random-effects model (DerSimonian-Laird estimator; REML as sensitivity check). Given that proportions are expected to cluster near 1.0 in several studies, raw proportions will be stabilized prior to pooling using the Freeman-Tukey double arcsine transformation, then back-transformed for presentation. Pooled proportions will be reported with 95% confidence intervals and 95% prediction intervals. Analyses will be conducted in R (packages: meta, metafor).', size: 22, font: 'Calibri' })] }),
        new Paragraph({ spacing: { before: 40, after: 40 }, children: [new TextRun({ text: 'Heterogeneity:', bold: true, size: 22, font: 'Calibri' })] }),
        new Paragraph({ spacing: { before: 20, after: 40 }, children: [new TextRun({ text: 'Between-study heterogeneity will be quantified using I² (thresholds: <25% low, 25–50% moderate, 50–75% substantial, >75% considerable) and Cochran\'s Q test (significance threshold p<0.10). tau² (between-study variance) will be reported for all pooled estimates.', size: 22, font: 'Calibri' })] }),
        new Paragraph({ spacing: { before: 40, after: 40 }, children: [new TextRun({ text: 'Pre-specified subgroup analyses:', bold: true, size: 22, font: 'Calibri' })] }),
        new Paragraph({ spacing: { before: 20, after: 20 }, children: [new TextRun({ text: '(1) ICI agent type (dostarlimab vs. pembrolizumab vs. sintilimab vs. other)', size: 22, font: 'Calibri' })] }),
        new Paragraph({ spacing: { before: 20, after: 20 }, children: [new TextRun({ text: '(2) Treatment duration/cycles (<4 vs. 4–6 vs. >6 cycles)', size: 22, font: 'Calibri' })] }),
        new Paragraph({ spacing: { before: 20, after: 20 }, children: [new TextRun({ text: '(3) Tumor T-stage (cT2-T3 vs. cT4a/b)', size: 22, font: 'Calibri' })] }),
        new Paragraph({ spacing: { before: 20, after: 20 }, children: [new TextRun({ text: '(4) Tumor height from anal verge (low <5 cm vs. mid 5–10 cm vs. upper >10 cm)', size: 22, font: 'Calibri' })] }),
        new Paragraph({ spacing: { before: 20, after: 20 }, children: [new TextRun({ text: '(5) Geographic region (East Asian vs. Western centers)', size: 22, font: 'Calibri' })] }),
        new Paragraph({ spacing: { before: 20, after: 20 }, children: [new TextRun({ text: '(6) Study design (prospective/RCT vs. retrospective)', size: 22, font: 'Calibri' })] }),
        new Paragraph({ spacing: { before: 20, after: 40 }, children: [new TextRun({ text: '(7) Follow-up duration (<12 months vs. 12–24 months vs. >24 months)', size: 22, font: 'Calibri' })] }),
        new Paragraph({ spacing: { before: 40, after: 40 }, children: [new TextRun({ text: 'Sensitivity analyses:', bold: true, size: 22, font: 'Calibri' })] }),
        new Paragraph({ spacing: { before: 20, after: 20 }, children: [new TextRun({ text: 'Excluding high/critical RoB studies; prospective studies only; studies with ≥12 months follow-up only; including PD-1 + anti-angiogenic combination studies; Bayesian random-effects re-analysis; leave-one-out analysis.', size: 22, font: 'Calibri' })] }),
        spacer(),
        new Paragraph({ spacing: { before: 40, after: 40 }, children: [new TextRun({ text: 'Publication bias:', bold: true, size: 22, font: 'Calibri' })] }),
        new Paragraph({ spacing: { before: 20, after: 20 }, children: [new TextRun({ text: 'If ≥10 studies are included: funnel plot with visual asymmetry assessment, Egger\'s test (p<0.10 significant), and trim-and-fill method for adjusted estimate.', size: 22, font: 'Calibri' })] }),
        spacer(),
        new Paragraph({ spacing: { before: 40, after: 40 }, children: [new TextRun({ text: 'GRADE certainty assessment:', bold: true, size: 22, font: 'Calibri' })] }),
        new Paragraph({ spacing: { before: 20, after: 20 }, children: [new TextRun({ text: 'Certainty of evidence for each outcome will be assessed using the GRADE framework and presented in a Summary of Findings (SoF) table.', size: 22, font: 'Calibri' })] }),
      ]),
      spacer(),
      pageBreak(),

      // ── SECTION E: ADDITIONAL DETAILS ───────────────────────────────────
      h1('SECTION E: Additional Required Details'),
      spacer(),

      // Field 23 — not on all versions, included as language/geography
      fieldLabel(23, 'Language'),
      fieldBox([
        'Studies will be included regardless of language of publication. English and Chinese-language studies will be screened directly. Studies in other languages will be assessed using machine translation tools; full-text translation from a bilingual team member or professional translator will be obtained where needed.'
      ]),
      spacer(),

      fieldLabel(24, 'Country'),
      fieldBox(['[REPLACE: Enter the country where the review will be primarily conducted, e.g., Malaysia]']),
      spacer(),

      fieldLabel(25, 'Dissemination Plans'),
      fieldBox([
        'The completed systematic review and meta-analysis will be submitted for publication in a peer-reviewed international oncology or colorectal surgery journal (target: Annals of Surgery, Lancet Gastroenterology & Hepatology, British Journal of Surgery, or JNCCN).',
        '',
        'Results will be disseminated at a relevant international conference (ASCO, ESMO, or ASCRS Annual Meeting).',
        '',
        'The PROSPERO registration number will be cited in the abstract and methods section of all reports.'
      ]),
      spacer(),

      fieldLabel(26, 'Keywords'),
      fieldBox([
        'dMMR; MSI-H; mismatch repair deficiency; microsatellite instability; rectal cancer; locally advanced rectal cancer; PD-1 inhibitor; immune checkpoint inhibitor; neoadjuvant immunotherapy; organ preservation; watch and wait; nonoperative management; dostarlimab; pembrolizumab; sintilimab; clinical complete response; meta-analysis; systematic review; pooled proportion'
      ]),
      spacer(),

      fieldLabel(27, 'Details of Existing Review on the Same Topic'),
      fieldBoxRich([
        new Paragraph({ spacing: { before: 40, after: 60 }, children: [new TextRun({ text: 'The following related systematic reviews/registrations were identified during pre-registration searching. None duplicates the proposed primary endpoint (pooled organ preservation rate):', size: 22, font: 'Calibri' })] }),
        new Paragraph({ spacing: { before: 20, after: 20 }, children: [
          new TextRun({ text: '1. CRD42024594173', bold: true, size: 22, font: 'Calibri', color: '1A3A5C' }),
          new TextRun({ text: ' (Cui et al., Front Immunol 2025): Non-metastatic dMMR colorectal cancer (mixed colon + rectum). Primary outcome: pCR and MPR. Organ preservation not the primary endpoint.', size: 22, font: 'Calibri' })
        ]}),
        new Paragraph({ spacing: { before: 20, after: 20 }, children: [
          new TextRun({ text: '2. CRD420251174716', bold: true, size: 22, font: 'Calibri', color: '1A3A5C' }),
          new TextRun({ text: ' (MDPI 2025): dMMR CRC, adjuvant vs. neoadjuvant DFS comparison. Organ preservation not addressed.', size: 22, font: 'Calibri' })
        ]}),
        new Paragraph({ spacing: { before: 20, after: 20 }, children: [
          new TextRun({ text: '3. CRD42024619949', bold: true, size: 22, font: 'Calibri', color: '1A3A5C' }),
          new TextRun({ text: ' (BMC Cancer 2025): CRT + ICI combination in LARC (mixed MMR). Organ preservation not primary endpoint; intervention differs.', size: 22, font: 'Calibri' })
        ]}),
        new Paragraph({ spacing: { before: 20, after: 20 }, children: [
          new TextRun({ text: '4. PMID 40889731', bold: true, size: 22, font: 'Calibri', color: '1A3A5C' }),
          new TextRun({ text: ' (Petrelli et al., Crit Rev Oncol Hematol 2025): Narrative synthesis, organ preservation as secondary finding only, no pooled proportion meta-analysis performed.', size: 22, font: 'Calibri' })
        ]}),
        new Paragraph({ spacing: { before: 20, after: 20 }, children: [
          new TextRun({ text: '5. PMID 41343101', bold: true, size: 22, font: 'Calibri', color: '1A3A5C' }),
          new TextRun({ text: ' (Mirza et al., J Gastrointest Cancer 2025): Prospective trials only; mixed colorectal population; pCR primary endpoint; retrospective studies excluded.', size: 22, font: 'Calibri' })
        ]}),
        spacer(),
        new Paragraph({ spacing: { before: 40, after: 40 }, children: [new TextRun({ text: 'CONCLUSION: The proposed review is novel and does not duplicate any existing registration or published systematic review.', bold: true, size: 22, font: 'Calibri', color: '1A5C2E' })] }),
      ]),
      spacer(),

      fieldLabel(28, 'Current Review Status'),
      fieldBox(['Ongoing (protocol stage — data collection not yet begun)']),
      spacer(),

      fieldLabel(29, 'Any Additional Information', false),
      fieldBox([
        'This review focuses exclusively on PD-1 monotherapy in rectal cancer, distinguishing it from broader colorectal or combination immunotherapy reviews. The primary analytic method — Freeman-Tukey double arcsine transformation for pooling near-unity proportions — is pre-specified to address the methodological challenge of aggregating studies with very high organ preservation rates. The protocol has been pre-drafted in full and was shared with all team members prior to PROSPERO submission.',
        '',
        'A full study protocol (version 1.0, June 2026) is available upon request from the corresponding author.'
      ]),
      spacer(),
      pageBreak(),

      // ── SUBMISSION CHECKLIST ─────────────────────────────────────────────
      h1('Submission Checklist — Complete Before Clicking Submit'),
      spacer(),
      new Table({
        width: { size: 100, type: WidthType.PERCENTAGE },
        rows: [
          new TableRow({ children: [
            new TableCell({ width: { size: 600, type: WidthType.DXA }, shading: { fill: '1A3A5C', type: ShadingType.CLEAR }, margins: { top: 80, bottom: 80, left: 120, right: 120 }, children: [new Paragraph({ children: [new TextRun({ text: 'Done?', bold: true, size: 21, color: 'FFFFFF', font: 'Calibri' })] })] }),
            new TableCell({ shading: { fill: '1A3A5C', type: ShadingType.CLEAR }, margins: { top: 80, bottom: 80, left: 120, right: 120 }, children: [new Paragraph({ children: [new TextRun({ text: 'Task', bold: true, size: 21, color: 'FFFFFF', font: 'Calibri' })] })] }),
            new TableCell({ width: { size: 1800, type: WidthType.DXA }, shading: { fill: '1A3A5C', type: ShadingType.CLEAR }, margins: { top: 80, bottom: 80, left: 120, right: 120 }, children: [new Paragraph({ children: [new TextRun({ text: 'Target Date', bold: true, size: 21, color: 'FFFFFF', font: 'Calibri' })] })] }),
          ]}),
          ...([
            ['Create PROSPERO account (crd.york.ac.uk/prospero)', 'By 24 June 2026'],
            ['Replace all [REPLACE] fields with your institutional details', 'By 25 June 2026'],
            ['Confirm all team members have ORCID IDs', 'By 25 June 2026'],
            ['Confirm screening has NOT yet begun', 'Before submission'],
            ['Copy-paste all 22+ fields into the online PROSPERO form', 'By 26 June 2026'],
            ['Upload full protocol document as supplementary file (optional but recommended)', 'By 26 June 2026'],
            ['Click Submit; record your draft CRD number immediately', 'By 26–27 June 2026'],
            ['Await PROSPERO approval email (typically 2–5 business days)', '27 June – 4 July 2026'],
            ['Add PROSPERO registration number to manuscript and ethics application', 'Upon receipt'],
          ]).map(([task, date]) => new TableRow({ children: [
            new TableCell({ shading: { fill: 'F5F5F5', type: ShadingType.CLEAR }, margins: { top: 80, bottom: 80, left: 120, right: 120 }, children: [new Paragraph({ alignment: AlignmentType.CENTER, children: [new TextRun({ text: '☐', size: 24, font: 'Calibri' })] })] }),
            new TableCell({ margins: { top: 80, bottom: 80, left: 120, right: 120 }, children: [new Paragraph({ children: [new TextRun({ text: task, size: 21, font: 'Calibri' })] })] }),
            new TableCell({ margins: { top: 80, bottom: 80, left: 120, right: 120 }, children: [new Paragraph({ children: [new TextRun({ text: date, size: 21, font: 'Calibri', color: '1A3A5C' })] })] }),
          ]}))
        ]
      }),
      spacer(), spacer(),

      // ── ELIGIBILITY SCREENER ANSWERS ────────────────────────────────────
      h1('PROSPERO Eligibility Screener — Pre-filled Answers'),
      body('When you start a new registration on PROSPERO, you will be asked a series of eligibility screening questions. Answer them as follows:', { italics: true }),
      spacer(),
      inlineLabel('Is this submission in English?', 'YES'),
      inlineLabel('Is this a scoping review, literature review, or mapping review?', 'NO — this is a systematic review and meta-analysis'),
      inlineLabel('Is the outcome clearly related to human health?', 'YES — organ preservation and oncological outcomes in rectal cancer'),
      inlineLabel('Is this a Cochrane review?', 'NO'),
      inlineLabel('Is this for a training course?', 'NO'),
      inlineLabel('Have you searched for similar existing reviews?', 'YES — five related registrations found; none duplicates this study (see Field 27)'),
      inlineLabel('Do you have a protocol?', 'YES — full protocol version 1.0 available'),
      inlineLabel('Is more than one person involved?', 'YES — minimum two independent reviewers'),
      inlineLabel('Do you intend to publish the results?', 'YES — target peer-reviewed oncology or surgical journal'),
      inlineLabel('Stage — have preliminary searches started?', 'YES — preliminary scoping searches completed'),
      inlineLabel('Stage — has title/abstract screening started?', 'NO — not yet started'),
      inlineLabel('Stage — has data extraction started?', 'NO — not yet started'),
      spacer(), spacer(),

      warningBox('After submitting, PROSPERO will assign a draft CRD number immediately (visible in your account). The record becomes publicly visible only after manual approval by the PROSPERO team. You may cite the draft CRD number in your manuscript immediately after submission — you do not need to wait for approval before citing it in your protocol or ethics application.'),
      spacer(),
      spacer(),
      new Paragraph({
        alignment: AlignmentType.CENTER,
        spacing: { before: 200, after: 100 },
        children: [new TextRun({ text: '— END OF PROSPERO REGISTRATION DRAFT —', size: 22, color: '888888', font: 'Calibri', italics: true })]
      }),
    ]
  }]
});

Packer.toBuffer(doc).then(buffer => {
  fs.writeFileSync('/home/daytona/workspace/dmmr-rectal-protocol/PROSPERO_Registration_Draft_dMMR_Rectal.docx', buffer);
  console.log('PROSPERO draft document created successfully.');
}).catch(err => {
  console.error('Error:', err);
  process.exit(1);
});

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