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PHOTODYNAMIC THERAPY (PDT) IN ENT - 50 MARKS

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1. INTRODUCTION AND HISTORICAL BACKGROUND

• 1900: Von Tappeiner and Jesionek first described photosensitization
• 1972: Discovery of tumour-localizing properties of haematoporphyrins
• 1978: Dougherty introduced clinical PDT using haematoporphyrin derivatives
• 1986: FDA approved porfimer sodium (Photofrin) - first photosensitizer
• 1999: FDA approved ALA (Levulan) for actinic keratoses
• 2000s onward: Second- and third-generation photosensitizers developed

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2. DEFINITION AND BASIC CONCEPT

"PDT is a subset of photochemotherapy where, in addition to an administered drug and the application of light, oxygen is required to complete the process."

• Scott-Brown's Otorhinolaryngology Head & Neck Surgery Vol 1, p. 632

┌─────────────────────────────────────────────────┐
│                                                 │
│   PHOTOSENSITIZER + LIGHT + OXYGEN = PDT EFFECT│
│                                                 │
│   Remove ANY ONE component → No PDT effect     │
│                                                 │
└─────────────────────────────────────────────────┘

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3. MECHANISM OF ACTION (PHOTOCHEMISTRY)

Step-by-Step Mechanism

FLOWCHART 1: MECHANISM OF PDT

Photosensitizer administered (IV / topical)
            ↓
Selective accumulation in tumour tissue
(Tumour retains PS longer than normal tissue)
            ↓
Drug-light interval (3–96 hours)
            ↓
Laser/light of specific wavelength applied
            ↓
PS absorbs photons → Excited Singlet State (S1)
            ↓
Intersystem crossing → Excited Triplet State (T1)
            ↓
         ┌──────────────┤
         │              │
    TYPE I Rxn      TYPE II Rxn (dominant)
    (radical)           ↓
         │        Triplet PS + Ground state O₂
         │              ↓
         │        SINGLET OXYGEN (¹O₂)
         ↓              ↓
    Superoxide,    Oxidative damage to:
    Hydroxyl         - Cell membranes
    radicals         - Mitochondria
                     - Nuclear membranes
                          ↓
                    APOPTOSIS + NECROSIS
                    + VASCULAR COLLAPSE

Key Photochemical Reactions

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4. PDT MECHANISM DIAGRAM

• Top pathway (direct cellular injury): Topical ALA/mALA diffuses into target epithelial cells → converted to Protoporphyrin IX (PpIX) in mitochondria → photoactivation (hν) → membrane perforation → apoptosis
• Bottom pathway (vascular injury): Systemic photosensitizer arrives via bloodstream into endothelial cells → photoactivation → thrombus formation and vascular wall damage → O₂ delivery ceases → ischemic necrosis
• Net result: Both direct apoptosis and ischemic necrosis cause irreversible target cell death

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5. ALA/PpIX BIOSYNTHETIC PATHWAY

FLOWCHART 2: ALA BIOSYNTHETIC PATHWAY IN PDT

Normal pathway:
Glycine + Succinyl CoA → [δ-ALA synthase] → δ-ALA
                                ↑
                         Heme (negative feedback)

PDT intervention (exogenous ALA bypasses this):
Exogenous δ-ALA (topical/IV) → bypasses feedback →
    → Porphobilinogen
    → (multiple steps)
    → Uroporphyrinogen III
    → Coproporphyrinogen III
    → Protoporphyrin IX (PpIX) ← ACTIVE PHOTOSENSITIZER
    → Heme (if ferrochelatase adds Fe²⁺)

In tumour cells: Ferrochelatase activity is REDUCED
→ PpIX accumulates preferentially in tumour tissue
→ Selective photosensitization

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6. PHOTOSENSITIZERS

Generation Classification

FLOWCHART 3: GENERATIONS OF PHOTOSENSITIZERS

┌─────────────────────────────────────────────────────────────┐
│           PHOTOSENSITIZER GENERATIONS                       │
│                                                             │
│  1st GENERATION          2nd GENERATION    3rd GENERATION  │
│  (1970s-1980s)           (1990s-2000s)     (2000s-present) │
│                                                             │
│  • Haematoporphyrin       • mTHPC/Foscan    • Nanoparticle  │
│    derivative (HpD)       • Verteporfin       conjugates   │
│  • Porfimer sodium        • ALA/5-ALA       • Antibody-    │
│    (Photofrin)            • mALA              targeted PS  │
│  • DHE                    • Temoporfin      • EGFR-targeted │
│                           • Chlorins,       • Liposomal PS  │
│  Disadvantages:             Phthalocyanines • Photoimmuno-  │
│  - Long photosensitivity  Advantages:         therapy       │
│  - Skin reactions         - Shorter DLI                    │
│  - Mixed composition      - Better tissue                  │
│  - Short wavelength         penetration                    │
│    (630 nm)               - Less                           │
│  - Less selective           photosensitivity               │
│                           - Higher                         │
│                             selectivity                    │
└─────────────────────────────────────────────────────────────┘

Commonly Used Photosensitizers in ENT

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7. PROCEDURE / TECHNIQUE

Steps of PDT in Head and Neck

FLOWCHART 4: PROCEDURE OF PDT

STEP 1: PATIENT SELECTION & ASSESSMENT
    - Clinical staging of tumour
    - Determine curative/palliative intent
    - Assess tumour depth (PDT best for <1 cm depth)
    - Rule out contraindications (porphyria, photosensitivity disorders)
    ↓
STEP 2: PHOTOSENSITIZER ADMINISTRATION
    - For head/neck cancers: IV infusion (porfimer sodium or mTHPC)
    - For superficial lesions: topical ALA or mALA
    - Patient kept in dim light / photosensitivity precautions
    ↓
STEP 3: DRUG-LIGHT INTERVAL (DLI)
    - Allows PS to accumulate selectively in tumour
    - Duration varies: 15 min (verteporfin) to 96 hrs (mTHPC)
    - Normal tissue clears PS faster than tumour tissue
    ↓
STEP 4: LIGHT DELIVERY
    - Light source: Argon pump-dye laser, diode laser, LED
    - Wavelength: matched to PS absorption peak
    - Delivery: via rigid/flexible endoscope, optical fibres, surface illumination
    - Dose (fluence): 50–200 J/cm²
    - For hollow organs (oesophagus, larynx): cylindrical diffuser fibre
    - For surface lesions: flat/microlens fibres
    ↓
STEP 5: TISSUE RESPONSE
    - Immediate: vascular stasis, tumour oedema
    - 24–72 hrs: inflammatory response, necrosis
    - 1–4 weeks: tissue sloughing, healing
    ↓
STEP 6: POST-TREATMENT CARE
    - Photosensitivity precautions: avoid sunlight 4–6 weeks (porfimer)
                                    or 2 weeks (mTHPC/Foscan)
    - Wound care, debridement if needed
    - Endoscopic surveillance at 4–6 weeks
    - Assessment of response: complete vs. partial
    ↓
STEP 7: REPEAT IF NEEDED
    (PDT can be repeated unlike radiotherapy - major advantage)

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8. APPLICATIONS IN ENT / HEAD AND NECK SURGERY

8.1 Oral Cavity and Oropharynx

"PDT has a potential role in the treatment of widespread premalignant and superficial oral carcinoma." - Cummings Otolaryngology, p. 1675

• Premalignant lesions: Leukoplakia, erythroplakia - excellent results with ALA-PDT
• Oral cavity SCC: Best results reported in oral cavity and oropharynx
• Karakullukcu et al. (170 patients with early-stage oral cavity/oropharynx neoplasms): 90% response rate, 70% complete cure rate
• Photofrin activated by 620 nm light; produces oxidizing free radicals via vascular disruption → tumour necrosis

8.2 Laryngeal Carcinoma

• PDT particularly suitable for early laryngeal cancers (T1, T2) due to:
  • Excellent endoscopic access
  • Organ preservation (voice preservation)
  • Repeatable without radiation dose limits
• Biel treated 25 patients with early laryngeal SCC → complete response in all patients, including 17 who had previously failed radiotherapy
• Biel's meta-analysis (217 patients, multiple centres):
  • Complete response: 194 (89%)
  • Partial response: 23 (10.6%)
  • No failure to respond: 0%

8.3 Nasopharyngeal Carcinoma

• Lofgren et al.: PDT in 5 patients with circumscribed nasopharyngeal carcinoma
• Drug activated with laser light under topical anaesthesia
• After 4 years: 3/5 patients had no evidence of disease
• Particularly useful for residual/recurrent disease after radiotherapy

8.4 Recurrent Respiratory Papillomatosis (RRP / Laryngeal Papillomatosis)

"PDT is based on the transfer of energy to a photosensitive drug such as dihematoporphyrin ether (DHE), which has a tendency to concentrate within papillomas." - Cummings Otolaryngology, RRP chapter

• IV DHE: 4.25 mg/kg before photoactivation
• Argon pump-dye laser for photoactivation
• Shows small but statistically significant decrease in RRP growth rate
• Best in patients with severe disease

• Parallel-arm RCT (23 patients, aged 4–60 years)
• Improvement in laryngeal disease noted
• However: relapse occurred over 3–5 years
• Poorly tolerated by ~25% of patients
• NOT FDA-approved in the USA

8.5 Oesophageal Cancer (relevant to ENT surgeons)

• Porfimer sodium PDT vs. Nd:YAG laser ablation (Phase II RCT, 218 patients):
  • Equivalent improvement in dysphagia
  • Fewer perforations with PDT (1% vs. 7%, p<0.05)
• Overholt & Panjehpour (55 patients with Barrett's oesophagus with dysplasia):
  • Good response at 6 months
  • 43/55 patients with high-grade dysplasia/adenocarcinoma showed endoscopic ablation
  • Complication: oesophageal stricture in 53%

8.6 Sinonasal Tumours

• Inverted papilloma of the sinonasal cavity has been targeted with PDT
• Dilkes et al. used mTHPC and ALA for squamous carcinoma at multiple head and neck sites (mid-1990s)
• In nearly all cases, a visible response to PDT was identified
• Complications: local pain at photosensitizer injection site, post-treatment skin photosensitivity

8.7 Chronic Rhinosinusitis (CRS) / Biofilm

"PDT has been shown to effectively treat bacteria, fungi, and biofilms." - Cummings, CRS chapter

• Two studies examining PDT on Staphylococcus and Pseudomonas biofilms showed 99.9% reduction in bacteria after single exposure
• No human studies yet in CRS
• Currently: insufficient evidence, not recommended in routine CRS management

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9. LIGHT SOURCES USED IN PDT

• For ENT/hollow organs: light delivered via optical fibres through flexible endoscopes
• Cylindrical diffuser fibres used for tubular organs (trachea, oesophagus, larynx)
• Surface illumination for oral cavity, skin

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10. ADVANTAGES AND DISADVANTAGES

┌──────────────────────────────────┬─────────────────────────────────┐
│         ADVANTAGES               │        DISADVANTAGES            │
├──────────────────────────────────┼─────────────────────────────────┤
│ • Selective tumour destruction   │ • Prolonged skin photosensitivity│
│ • Organ/function preservation    │   (4-6 weeks with porfimer)     │
│ • Can be repeated (unlike XRT)   │ • Limited depth of penetration  │
│ • Not affected by prior XRT,     │   (<5-10 mm tissue depth)       │
│   chemotherapy, or surgery       │ • Not for bulky/deep tumours    │
│ • Minimal systemic toxicity      │ • Requires laser equipment      │
│ • Good cosmetic outcome          │ • Expensive                     │
│ • Outpatient procedure possible  │ • Stricture formation           │
│   (for topical lesions)          │   (oesophageal)                 │
│ • Multiple treatments possible   │ • Tumour not absolutely specific│
│ • Useful for field cancerization │   (normal tissue necrosis also) │
│ • Favourable functional results  │ • Limited to endoscopically     │
│ • Potential for palliation       │   accessible tumours            │
│   AND cure                       │ • Response rates ~50% for RRP   │
└──────────────────────────────────┴─────────────────────────────────┘

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11. CONTRAINDICATIONS

• Porphyria (cutanea tarda, variegate porphyria)
• Known hypersensitivity to photosensitizer
• Existing photosensitivity disorders

• Tumour invasion of major blood vessels (risk of fatal haemorrhage after necrosis)
• Tumour eroding into trachea (risk of tracheo-oesophageal fistula)
• Patients unable to protect themselves from light exposure
• Deep/bulky tumours (>1 cm depth - inadequate light penetration)

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12. COMPLICATIONS

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13. PDT vs PUVA THERAPY (Comparison Table)

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14. OVERALL MANAGEMENT FLOWCHART FOR PDT IN HEAD AND NECK

FLOWCHART 5: PATIENT SELECTION AND MANAGEMENT FOR PDT IN H&N

         Suspected Head & Neck Tumour / Premalignant Lesion
                              ↓
                Clinical Assessment + Imaging + Biopsy
                              ↓
              ┌───────────────┴──────────────────┐
              ↓                                  ↓
   Superficial / Early Stage             Advanced / Deep Tumour
   T1/T2, <5 mm depth                   T3/T4, >1 cm depth
              ↓                                  ↓
        PDT SUITABLE                    PDT NOT PRIMARY CHOICE
              ↓                         (Consider surgery/chemo-XRT)
   Select Photosensitizer:              However PDT may be used:
   - Oral/OP: Porfimer, mTHPC           - Palliatively
   - RRP: DHE, mTHPC                    - As adjuvant
   - Superficial: ALA/mALA              - For recurrence
              ↓
   Administer Photosensitizer
   (IV infusion or topical)
              ↓
   DRUG-LIGHT INTERVAL
   (48–96 hrs for systemic; 1–4 hrs for ALA)
              ↓
   Light Delivery via Endoscope/Fibre
   - Appropriate wavelength
   - Measured fluence (50–200 J/cm²)
              ↓
   ┌──────────────────────────────────┐
   │ PHOTOSENSITIVITY PRECAUTIONS     │
   │ (4–6 weeks for porfimer;         │
   │  2 weeks for mTHPC)              │
   └──────────────────────────────────┘
              ↓
   Follow-up at 4–6 weeks
              ↓
   ┌──────────────────┬───────────────────┐
   ↓                  ↓                   ↓
Complete           Partial             No Response
Response           Response                 ↓
   ↓                  ↓            Consider alternative
Surveillance     Repeat PDT          (Surgery/XRT)
                 (advantage:
                 repeatable)

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15. SPECIFIC CONSIDERATIONS BY TEXTBOOK AUTHORS

Scott-Brown's (Otorhinolaryngology H&N Surgery Vol 1, Chapter on Lasers and PDT):

• Emphasises the triad requirement: drug + light + oxygen
• The drug-light interval is 3–96 hours for head and neck PDT
• Tumour targeting arises from: (1) selective uptake by tumour due to PS structure and (2) accurate application of appropriate wavelength
• Skin phototoxicity and limited tissue penetration are the current PDT shortcomings
• Conclusion: "PDT has a significant place in the future management of head and neck cancer"
• Key trials: Karakullukcu (170 patients, 90% response), Biel (25 laryngeal, 100% response), Lofgren (5 NPC, 3/5 disease-free at 4 years)

Cummings Otolaryngology:

• Oral SCC: Photofrin + 620 nm light → oxidizing free radicals → vascular disruption → tumour necrosis
• Advantage: potential for multiple treatments with favourable functional and cosmetic results
• Disadvantage: prolonged skin photosensitivity up to 6 weeks
• Newer generation PS may be more specific and result in less photosensitization
• RRP: DHE (4.25 mg/kg) → statistically significant decrease in RRP growth, especially severe disease

Goodman & Gilman's Pharmacological Basis of Therapeutics:

• ALA and mALA are prodrugs converted to PpIX within living cells
• PpIX in presence of specific wavelengths and O₂ → reactive oxygen species → oxidize cell membranes, proteins, and mitochondrial structures → apoptosis
• Epidermis, sebaceous glands, and neoplastic cells accumulate more porphyrin → preferential targeting
• Half-life of accumulated porphyrins: ~30 hours → photosensitivity precautions for at least 48 hours after treatment

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16. RECENT ADVANCES (2021-2026)

FLOWCHART 6: EVOLUTION OF PDT - RECENT ADVANCES

Classical PDT (1st Gen PS)
    ↓
2nd Gen PS (mTHPC, ALA, Verteporfin)
    ↓
3rd Gen / Targeted PDT
    ↓
┌─────────────────────────────────────────────┐
│           RECENT ADVANCES (2021-2026)        │
├─────────────────────────────────────────────┤
│ 1. NANOPARTICLE-ENHANCED PDT                │
│    • Liposomal drug delivery (2026)         │
│    • Gold nanoparticle PS conjugates        │
│    • Polymeric nanoparticles                │
│    Advantages: deeper penetration,          │
│    improved selectivity, reduced side effects│
│                                             │
│ 2. EGFR-TARGETED PDT (Ulfo et al. 2022)    │
│    • Anti-EGFR antibody conjugated to PS    │
│    • Highly relevant in HNSCC (EGFR+)       │
│    • PMID: 35213974                         │
│                                             │
│ 3. IMMUNOTHERAPY COMBINATION                │
│    • PDT + PD-L1 checkpoint blockade        │
│    • PDT-induced immunogenic cell death     │
│    • Activates anti-tumour immunity         │
│    • Synergistic with anti-PD-1/PD-L1      │
│                                             │
│ 4. DAYLIGHT PDT (D-PDT)                    │
│    • For actinic keratoses                  │
│    • Natural daylight as light source       │
│    • Improved patient comfort vs pain       │
│                                             │
│ 5. ANTIMICROBIAL PDT (aPDT)                │
│    • Staphylococcus aureus biofilm (CRS)    │
│    • 99.9% bacterial reduction in vitro     │
│    • Pseudomonas aeruginosa biofilm         │
│    • Methylene blue as PS                   │
│                                             │
│ 6. PHOTODYNAMIC DIAGNOSIS (PDD)            │
│    • ALA-induced PpIX for tumour mapping    │
│    • "Blue light cystoscopy" model          │
│    • Application to laryngeal early lesions │
│                                             │
│ 7. MACHINE LEARNING INTEGRATION            │
│    • AI-based dosimetry optimization        │
│    • Predicting tumour response             │
│    • Personalised light dosing              │
│                                             │
│ 8. PDT + SURGERY COMBINATION for RRP       │
│    • Pan Y et al., Am J Otolaryngol 2024   │
│    • Surgery + PDT vs surgery alone        │
│    • Improved outcomes, reduced recurrence │
│    • PMID: 39142078                         │
└─────────────────────────────────────────────┘

• Kolarikova et al., Med Res Rev 2023 - "Photodynamic therapy: Innovative approaches for antibacterial and anticancer treatments" - comprehensive review of antibacterial and anticancer PDT (PMID: 36757198)
• Aebisher et al., Int J Mol Sci 2024 - "Photodynamic Therapy: Past, Current, and Future" - latest state-of-the-art review (PMID: 39457108)
• Balakirski et al., J Dtsch Dermatol 2024 - "PDT in dermatology: established and new indications" (PMID: 39226531)
• Pan Y et al., Am J Otolaryngol 2024 - Surgery + PDT for RRP - improved outcomes (PMID: 39142078)
• Nano-enhanced PDT for HNSCC: Nanoplatform-Enhanced PDT - systematic bibliometric analysis [PMC 2025]

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17. PDT IN CONTEXT OF RGUHS SYLLABUS

RGUHS Important Points to Remember:

1. Three essentials of PDT: Photosensitizer + Light + Oxygen
2. Primary mechanism: Type II photochemical reaction → Singlet oxygen (¹O₂)
3. Best results in ENT: Early laryngeal and oral cavity SCC
4. PDT for RRP: DHE (4.25 mg/kg) via argon pump-dye laser
5. Photofrin (Porfimer sodium): First approved PS, 630 nm, 4-6 weeks photosensitivity
6. mTHPC (Temoporfin/Foscan): Second generation, 652 nm, less photosensitivity
7. ALA (5-ALA): Prodrug → PpIX via heme biosynthesis; used topically
8. Biel's statistics: 89% complete response in 217 patients with H&N SCC
9. Karakullukcu: 90% response rate, 70% cure in oral/oropharynx PDT
10. Key advantage: PDT can be repeated unlike radiotherapy

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18. SUMMARY TABLE

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• Scott-Brown's Otorhinolaryngology Head & Neck Surgery Vol 1 & 2 (9781138094611, 9781138094634) - Chapters on Lasers & PDT, RRP
• Cummings Otolaryngology Head and Neck Surgery (9780323612173) - Chapters on Oral Cavity, Larynx, CRS, RRP
• Goodman & Gilman's Pharmacological Basis of Therapeutics (9781264258079) - Chapter 75
• Dermatology 2-Volume Set 5e (Griffiths, 9780702082252) - Chapter 135: PDT
• Fitzpatrick's Dermatology (9780071837781) - PDT chapters
• Kolarikova et al., Med Res Rev 2023 (PMID: 36757198)
• Aebisher et al., Int J Mol Sci 2024 (PMID: 39457108)
• Pan Y et al., Am J Otolaryngol 2024 (PMID: 39142078)