522 lines
19 KiB
Markdown
522 lines
19 KiB
Markdown
# Treatment Recommendations Guide
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## Overview
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Evidence-based treatment recommendations provide clinicians with systematic guidance for therapeutic decision-making. This guide covers the development, grading, and presentation of clinical recommendations in pharmaceutical and healthcare settings.
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## Evidence Grading Systems
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### GRADE (Grading of Recommendations Assessment, Development and Evaluation)
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**Quality of Evidence Levels**
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**High Quality (⊕⊕⊕⊕)**
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- Further research very unlikely to change confidence in estimate
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- Criteria: Well-designed RCTs with consistent results, no serious limitations
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- Example: Multiple large RCTs showing similar treatment effects
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**Moderate Quality (⊕⊕⊕○)**
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- Further research likely to have important impact on confidence
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- Criteria: RCTs with limitations OR very strong evidence from observational studies
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- Example: Single RCT or multiple RCTs with some inconsistency
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**Low Quality (⊕⊕○○)**
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- Further research very likely to have important impact on confidence
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- Criteria: Observational studies OR RCTs with serious limitations
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- Example: Case-control studies, cohort studies with confounding
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**Very Low Quality (⊕○○○)**
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- Estimate of effect very uncertain
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- Criteria: Case series, expert opinion, or very serious limitations
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- Example: Mechanistic reasoning, unsystematic clinical observations
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**Strength of Recommendation**
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**Strong Recommendation (Grade 1)**
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- Benefits clearly outweigh risks and burdens (or vice versa)
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- Wording: "We recommend..."
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- Implications: Most patients should receive recommended course
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- Symbol: ↑↑ (strong for) or ↓↓ (strong against)
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**Conditional/Weak Recommendation (Grade 2)**
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- Trade-offs exist; benefits and risks closely balanced
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- Wording: "We suggest..."
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- Implications: Different choices for different patients; shared decision-making
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- Symbol: ↑ (weak for) or ↓ (weak against)
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**GRADE Notation Examples**
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- **1A**: Strong recommendation, high-quality evidence
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- **1B**: Strong recommendation, moderate-quality evidence
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- **2A**: Weak recommendation, high-quality evidence
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- **2B**: Weak recommendation, moderate-quality evidence
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- **2C**: Weak recommendation, low- or very low-quality evidence
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### Oxford Centre for Evidence-Based Medicine (CEBM) Levels
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**Level 1: Systematic Review/Meta-Analysis**
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- 1a: SR of RCTs
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- 1b: Individual RCT with narrow confidence interval
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- 1c: All-or-none studies (all patients died before treatment, some survive after)
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**Level 2: Cohort Studies**
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- 2a: SR of cohort studies
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- 2b: Individual cohort study (including low-quality RCT)
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- 2c: Outcomes research, ecological studies
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**Level 3: Case-Control Studies**
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- 3a: SR of case-control studies
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- 3b: Individual case-control study
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**Level 4: Case Series**
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- Case series, poor-quality cohort, or case-control studies
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**Level 5: Expert Opinion**
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- Mechanism-based reasoning, expert opinion without critical appraisal
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**Grades of Recommendation**
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- **Grade A**: Consistent level 1 studies
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- **Grade B**: Consistent level 2 or 3 studies, or extrapolations from level 1
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- **Grade C**: Level 4 studies or extrapolations from level 2 or 3
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- **Grade D**: Level 5 evidence or inconsistent/inconclusive studies
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## Treatment Sequencing and Line-of-Therapy
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### First-Line Therapy
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**Selection Criteria**
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- **Standard of Care**: Guideline-recommended based on phase 3 trials
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- **Patient Factors**: Performance status, comorbidities, organ function
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- **Disease Factors**: Stage, molecular profile, aggressiveness
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- **Goals**: Cure (adjuvant/neoadjuvant), prolonged remission, symptom control
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**First-Line Options Documentation**
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```
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First-Line Treatment Options:
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Option 1: Regimen A (NCCN Category 1, ESMO I-A)
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- Evidence: Phase 3 RCT (n=1000), median PFS 12 months vs 8 months (HR 0.6, p<0.001)
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- Population: PD-L1 ≥50%, EGFR/ALK negative
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- Toxicity Profile: Immune-related AEs (15% grade 3-4)
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- Recommendation Strength: 1A (strong, high-quality evidence)
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Option 2: Regimen B (NCCN Category 1, ESMO I-A)
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- Evidence: Phase 3 RCT (n=800), median PFS 10 months vs 8 months (HR 0.7, p=0.003)
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- Population: All patients, no biomarker selection
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- Toxicity Profile: Hematologic toxicity (25% grade 3-4)
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- Recommendation Strength: 1A (strong, high-quality evidence)
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```
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### Second-Line and Beyond
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**Second-Line Selection**
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- **Prior Response**: Duration of response to first-line
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- **Progression Pattern**: Oligoprogression vs widespread progression
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- **Residual Toxicity**: Recovery from first-line toxicities
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- **Biomarker Evolution**: Acquired resistance mechanisms
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- **Clinical Trial Availability**: Novel agents in development
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**Treatment History Documentation**
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```
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Prior Therapies:
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1. First-Line: Pembrolizumab (12 cycles)
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- Best Response: Partial response (-45% tumor burden)
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- PFS: 14 months
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- Discontinuation Reason: Progressive disease
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- Residual Toxicity: Grade 1 hypothyroidism (on levothyroxine)
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2. Second-Line: Docetaxel + ramucirumab (6 cycles)
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- Best Response: Stable disease
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- PFS: 5 months
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- Discontinuation Reason: Progressive disease
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- Residual Toxicity: Grade 2 peripheral neuropathy
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Current Consideration: Third-Line Options
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- Clinical trial vs platinum-based chemotherapy
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```
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### Maintenance Therapy
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**Indications**
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- Consolidation after response to induction therapy
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- Prevention of progression without continuous cytotoxic treatment
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- Bridging to definitive therapy (e.g., transplant)
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**Evidence Requirements**
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- PFS benefit demonstrated in randomized trials
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- Tolerable long-term toxicity profile
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- Quality of life preserved or improved
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## Biomarker-Guided Therapy Selection
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### Companion Diagnostics
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**FDA-Approved Biomarker-Drug Pairs**
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**Required Testing (Treatment-Specific)**
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- **ALK rearrangement → Alectinib, Brigatinib, Lorlatinib** (NSCLC)
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- **EGFR exon 19 del/L858R → Osimertinib** (NSCLC)
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- **BRAF V600E → Dabrafenib + Trametinib** (Melanoma, NSCLC, CRC)
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- **HER2 amplification/3+ → Trastuzumab, Pertuzumab** (Breast, Gastric)
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- **PD-L1 ≥50% → Pembrolizumab monotherapy** (NSCLC first-line)
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**Complementary Diagnostics (Informative but not Required)**
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- **PD-L1 1-49%**: Combination immunotherapy preferred
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- **TMB-high**: May predict immunotherapy benefit (investigational)
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- **MSI-H/dMMR**: Pembrolizumab approved across tumor types
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### Biomarker Testing Algorithms
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**NSCLC Biomarker Panel**
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```
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Reflex Testing at Diagnosis:
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✓ EGFR mutations (exons 18, 19, 20, 21)
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✓ ALK rearrangement (IHC or FISH)
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✓ ROS1 rearrangement (FISH or NGS)
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✓ BRAF V600E mutation
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✓ PD-L1 IHC (22C3 or SP263)
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✓ Consider: Comprehensive NGS panel
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If EGFR+ on Osimertinib progression:
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✓ Liquid biopsy for T790M (if first/second-gen TKI)
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✓ Tissue biopsy for resistance mechanisms
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✓ MET amplification, HER2 amplification, SCLC transformation
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```
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**Breast Cancer Biomarker Algorithm**
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```
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Initial Diagnosis:
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✓ ER/PR IHC
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✓ HER2 IHC and FISH (if 2+)
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✓ Ki-67 proliferation index
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If Metastatic ER+/HER2-:
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✓ ESR1 mutations (liquid biopsy after progression on AI)
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✓ PIK3CA mutations (for alpelisib eligibility)
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✓ BRCA1/2 germline testing (for PARP inhibitor eligibility)
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✓ PD-L1 testing (if considering immunotherapy combinations)
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```
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### Actionable Alterations
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**Tier I: FDA-Approved Targeted Therapy**
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- Strong evidence from prospective trials
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- Guideline-recommended
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- Examples: EGFR exon 19 deletion, HER2 amplification, ALK fusion
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**Tier II: Clinical Trial or Off-Label Use**
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- Emerging evidence, clinical trial preferred
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- Examples: NTRK fusion (larotrectinib), RET fusion (selpercatinib)
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**Tier III: Biological Plausibility**
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- Preclinical evidence only
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- Clinical trial enrollment strongly recommended
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- Examples: Novel kinase fusions, rare resistance mutations
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## Combination Therapy Protocols
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### Rationale for Combinations
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**Mechanisms**
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- **Non-Overlapping Toxicity**: Maximize dose intensity of each agent
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- **Synergistic Activity**: Enhanced efficacy beyond additive effects
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- **Complementary Mechanisms**: Target multiple pathways simultaneously
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- **Prevent Resistance**: Decrease selection pressure for resistant clones
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**Combination Design Principles**
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- **Sequential**: Induction then consolidation (different regimens)
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- **Concurrent**: Administered together for synergy
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- **Alternating**: Rotate regimens to minimize resistance
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- **Intermittent**: Pulse dosing vs continuous exposure
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### Drug Interaction Assessment
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**Pharmacokinetic Interactions**
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- **CYP450 Induction/Inhibition**: Check for drug-drug interactions
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- **Transporter Interactions**: P-gp, BCRP, OATP substrates/inhibitors
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- **Protein Binding**: Highly protein-bound drugs (warfarin caution)
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- **Renal/Hepatic Clearance**: Avoid multiple renally cleared agents
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**Pharmacodynamic Interactions**
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- **Additive Toxicity**: Avoid overlapping adverse events (e.g., QTc prolongation)
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- **Antagonism**: Ensure mechanisms are complementary, not opposing
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- **Dose Modifications**: Pre-defined dose reduction schedules for combinations
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### Combination Documentation
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```
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Combination Regimen: Drug A + Drug B
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Rationale:
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- Phase 3 RCT demonstrated PFS benefit (16 vs 11 months, HR 0.62, p<0.001)
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- Complementary mechanisms: Drug A (VEGF inhibitor) + Drug B (immune checkpoint inhibitor)
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- Non-overlapping toxicity profiles
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Dosing:
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- Drug A: 10 mg/kg IV every 3 weeks
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- Drug B: 1200 mg IV every 3 weeks
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- Continue until progression or unacceptable toxicity
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Key Toxicities:
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- Hypertension (Drug A): 30% grade 3-4, manage with antihypertensives
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- Immune-related AEs (Drug B): 15% grade 3-4, corticosteroid management
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- No significant pharmacokinetic interactions observed
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Monitoring:
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- Blood pressure: Daily for first month, then weekly
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- Thyroid function: Every 6 weeks
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- Liver enzymes: Before each cycle
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- Imaging: Every 6 weeks (RECIST v1.1)
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```
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## Monitoring and Follow-up Schedules
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### On-Treatment Monitoring
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**Laboratory Monitoring**
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```
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Test Baseline Cycle 1 Cycle 2+ Rationale
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CBC with differential ✓ Weekly Day 1 Myelosuppression risk
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Comprehensive panel ✓ Day 1 Day 1 Electrolytes, renal, hepatic
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Thyroid function ✓ - Q6 weeks Immunotherapy
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Lipase/amylase ✓ - As needed Pancreatitis risk
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Troponin/BNP ✓* - As needed Cardiotoxicity risk
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(*if cardiotoxic agent)
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```
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**Imaging Assessment**
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```
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Modality Baseline Follow-up Criteria
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CT chest/abd/pelvis ✓ Every 6-9 weeks RECIST v1.1
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Brain MRI ✓* Every 12 weeks If CNS metastases
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Bone scan ✓** Every 12-24 weeks If bone metastases
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PET/CT ✓*** Response assessment Lymphoma (Lugano criteria)
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(*if CNS mets, **if bone mets, ***if PET-avid tumor)
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```
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**Clinical Assessment**
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```
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Assessment Frequency Notes
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ECOG performance status Every visit Decline may warrant dose modification
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Vital signs Every visit Blood pressure for anti-VEGF agents
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Weight Every visit Cachexia, fluid retention
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Symptom assessment Every visit PRO-CTCAE questionnaire
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Physical exam Every visit Target lesions, new symptoms
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```
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### Dose Modification Guidelines
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**Hematologic Toxicity**
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```
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ANC and Platelet Counts Action
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ANC ≥1.5 AND platelets ≥100k Treat at full dose
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ANC 1.0-1.5 OR platelets 75-100k Delay 1 week, recheck
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ANC 0.5-1.0 OR platelets 50-75k Delay treatment, G-CSF support, reduce dose 20%
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ANC <0.5 OR platelets <50k Hold treatment, G-CSF, transfusion PRN, reduce 40%
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Febrile Neutropenia Hold treatment, hospitalize, antibiotics, G-CSF
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Reduce dose 20-40% on recovery, consider prophylactic G-CSF
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```
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**Non-Hematologic Toxicity**
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```
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Adverse Event Grade 1 Grade 2 Grade 3 Grade 4
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Diarrhea Continue Continue with Hold until ≤G1, Hold, hospitalize
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loperamide reduce 20% Consider discontinuation
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Rash Continue Continue with Hold until ≤G1, Discontinue
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topical Rx reduce 20%
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Hepatotoxicity Continue Repeat in 1 wk, Hold until ≤G1, Discontinue permanently
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hold if worsening reduce 20-40%
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Pneumonitis Continue Hold, consider Hold, corticosteroids, Discontinue, high-dose
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corticosteroids discontinue if no improvement steroids
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```
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### Post-Treatment Surveillance
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**Disease Monitoring**
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```
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Time After Treatment Imaging Frequency Labs Clinical
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Year 1 Every 3 months Every 3 months Every 3 months
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Year 2 Every 3-4 months Every 3-4 months Every 3-4 months
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Years 3-5 Every 6 months Every 6 months Every 6 months
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Year 5+ Annually Annually Annually
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Earlier imaging if symptoms suggest recurrence
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```
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**Survivorship Care**
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```
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Surveillance Frequency Duration
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Disease monitoring Per schedule above Lifelong or until recurrence
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Late toxicity screening Annually Lifelong
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- Cardiac function Every 1-2 years If anthracycline/trastuzumab
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- Pulmonary function As clinically indicated If bleomycin/radiation
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- Neuropathy Symptom-based Peripheral neuropathy history
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- Secondary malignancy Age-appropriate screening Lifelong (increased risk)
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Genetic counseling One time If hereditary cancer syndrome
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Psychosocial support As needed Depression, anxiety, PTSD screening
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```
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## Special Populations
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### Elderly Patients (≥65-70 years)
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**Considerations**
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- **Reduced organ function**: Adjust for renal/hepatic impairment
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- **Polypharmacy**: Drug-drug interaction risk
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- **Frailty**: Geriatric assessment (G8, VES-13, CARG score)
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- **Goals of care**: Quality of life vs survival, functional independence
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**Modifications**
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- Dose reductions: 20-25% reduction for frail patients
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- Longer intervals: Every 4 weeks instead of every 3 weeks
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- Less aggressive regimens: Single-agent vs combination therapy
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- Supportive care: Increased monitoring, G-CSF prophylaxis
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### Renal Impairment
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**Dose Adjustments by eGFR**
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```
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eGFR (mL/min/1.73m²) Category Action
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≥90 Normal Standard dosing
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60-89 Mild Standard dosing (most agents)
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30-59 Moderate Dose reduce renally cleared drugs 25-50%
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15-29 Severe Dose reduce 50-75%, avoid nephrotoxic agents
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<15 (dialysis) ESRD Avoid most agents, case-by-case decisions
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```
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**Renally Cleared Agents Requiring Adjustment**
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- Carboplatin (Calvert formula: AUC × [GFR + 25])
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- Methotrexate (reduce dose 50-75% if CrCl <60)
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- Capecitabine (reduce dose 25-50% if CrCl 30-50)
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### Hepatic Impairment
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**Dose Adjustments by Bili and AST/ALT**
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```
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Category Bilirubin AST/ALT Action
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Normal ≤ULN ≤ULN Standard dosing
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Mild (Child A) 1-1.5× ULN Any Reduce dose 25% for hepatically metabolized
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Moderate (Child B) 1.5-3× ULN Any Reduce dose 50%, consider alternative
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Severe (Child C) >3× ULN Any Avoid most agents, case-by-case
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```
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**Hepatically Metabolized Agents Requiring Adjustment**
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- Docetaxel (reduce 25-50% if bilirubin elevated)
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- Irinotecan (reduce 50% if bilirubin 1.5-3× ULN)
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- Tyrosine kinase inhibitors (most metabolized by CYP3A4, reduce by 50%)
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### Pregnancy and Fertility
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**Contraception Requirements**
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- Effective contraception required during treatment and 6-12 months after
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- Two methods recommended for highly teratogenic agents
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- Male patients: Contraception if partner of childbearing potential
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**Fertility Preservation**
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- Oocyte/embryo cryopreservation (females, before gonadotoxic therapy)
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- Sperm banking (males, before alkylating agents, platinum)
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- GnRH agonists (ovarian suppression, controversial efficacy)
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- Referral to reproductive endocrinology before treatment
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**Pregnancy Management**
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- Avoid chemotherapy in first trimester (organogenesis)
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- Selective agents safe in second/third trimester (case-by-case)
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- Multidisciplinary team: oncology, maternal-fetal medicine, neonatology
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## Clinical Trial Considerations
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### When to Recommend Clinical Trials
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**Ideal Scenarios**
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- No standard therapy available (rare diseases, refractory settings)
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- Multiple equivalent standard options (patient preference for novel agent)
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- Standard therapy failed (second-line and beyond)
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- High-risk disease (adjuvant trials for improved outcomes)
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**Trial Selection Criteria**
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- **Phase**: Phase 1 (dose-finding, safety), Phase 2 (efficacy signal), Phase 3 (comparative effectiveness)
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- **Eligibility**: Match patient to inclusion/exclusion criteria
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- **Mechanism**: Novel vs established mechanism, biological rationale
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- **Sponsor**: Academic vs industry, trial design quality
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- **Logistics**: Distance to trial site, visit frequency, out-of-pocket costs
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### Shared Decision-Making
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**Informing Patients**
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- Natural history without treatment
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- Standard treatment options with evidence, benefits, risks
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- Clinical trial options (if available)
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- Goals of care alignment
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- Patient values and preferences
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**Decision Aids**
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- Visual representations of benefit (icon arrays)
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- Number needed to treat calculations
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- Quality of life trade-offs
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- Decisional conflict scales
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## Documentation Standards
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### Treatment Plan Documentation
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```
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TREATMENT PLAN
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Diagnosis: [Disease, stage, molecular profile]
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Goals of Therapy:
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☐ Curative intent
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☐ Prolonged disease control
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☑ Palliation and quality of life
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Recommended Regimen: [Name] (NCCN Category 1, GRADE 1A)
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Evidence Basis:
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- Primary study: [Citation], Phase 3 RCT, n=XXX
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- Primary endpoint: PFS 12 months vs 8 months (HR 0.6, 95% CI 0.45-0.80, p<0.001)
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- Secondary endpoints: OS 24 vs 20 months (HR 0.75, p=0.02), ORR 60% vs 40%
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- Safety: Grade 3-4 AEs 35%, discontinuation rate 12%
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Dosing Schedule:
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- Drug A: XX mg IV day 1
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- Drug B: XX mg PO days 1-21
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- Cycle length: 21 days
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- Planned cycles: Until progression or unacceptable toxicity
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Premedications:
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- Dexamethasone 8 mg IV (anti-emetic)
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- Ondansetron 16 mg IV (anti-emetic)
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- Diphenhydramine 25 mg IV (hypersensitivity prophylaxis)
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Monitoring Plan: [See schedule above]
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Dose Modification Plan: [See guidelines above]
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Alternative Options Discussed:
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- Option 2: [Alternative regimen], GRADE 1B
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- Clinical trial: [Trial name/number], Phase 2, novel agent
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- Best supportive care
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Patient Decision: Proceed with recommended regimen
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Informed Consent: Obtained for chemotherapy, risks/benefits discussed
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Date: [Date]
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Provider: [Name, credentials]
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```
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## Quality Metrics
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### Treatment Recommendation Quality Indicators
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- Evidence grading provided for all recommendations
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- Multiple options presented when equivalent evidence exists
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- Toxicity profiles clearly described
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- Monitoring plans specified
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- Dose modification guidelines included
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- Special populations addressed (elderly, renal/hepatic impairment)
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- Clinical trial options mentioned when appropriate
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- Shared decision-making documented
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- Goals of care aligned with treatment intensity
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