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Internal Assessment Theory Examination - Paper II

Gynecological Oncology

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Q1. Risk Categorization in Ca Endometrium + PORTEC 4a Trial [6+4]

Part A: Risk Categorization (ESGO/ESTRO/ESP 2021 + FIGO 2023)

1. POLE exonuclease domain sequencing (exons 9, 11, 13, 14)
2. MMR IHC (MLH1, MSH2, MSH6, PMS2) or MSI-PCR
3. p53 IHC (surrogate for TP53 mutation)

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Part B: PORTEC-4a Trial (Lancet Oncol, 2026) [PMID 41449145]

PORTEC-4a Adjuvant Treatment Algorithm
━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━
 High-Intermediate Risk EC Post-Surgery
          │
          ▼
    Molecular Profile
    ┌──────┼──────────────┐
    │      │              │
Favourable  Intermediate  Unfavourable
(46%)      (40%)         (14%)
    │      │              │
POLE/NSMP  MMRd/NSMP     p53abn or
WT        CTNNB1 mut     Sub LVSI or
    │      │             L1CAM +
    ▼      ▼              │
Observation VBT          Pelvic RT
           (21Gy/3#)    (45-48.6Gy)
━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━

• 46% of patients with favourable profile safely avoided radiation (de-escalation)
• 14% with unfavourable profile received escalated pelvic RT (appropriate intensification)
• Molecular profiling enables individualized adjuvant therapy - not one-size-fits-all
• Vaginal recurrence rates remained non-inferior despite omitting RT in many patients
• Supports mandatory molecular testing in all high-intermediate risk EC

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Q2. Management of Platinum-Resistant Ovarian Carcinoma [10]

Treatment Algorithm

Platinum-Resistant Ovarian Cancer
━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━
              ▼
    Assess FRα expression
    (VENTANA FOLR1 assay)
    ┌──────────────────────┐
    │                      │
  FRα HIGH                FRα low/neg
    │                      │
    ▼                      ▼
Mirvetuximab         Single-agent chemo
Soravtansine         (preferred options):
(ELAHERE - FDA 2022) ├─ Pegylated liposomal
MIRASOL trial:       │  doxorubicin (PLD)
ORR 42%, OS benefit  ├─ Paclitaxel (weekly)
vs chemo             ├─ Gemcitabine
                     ├─ Topotecan
                     └─ Bevacizumab +
                        chemotherapy
━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━

Key Evidence

Biomarker-Directed Therapy Table

Non-Platinum Chemotherapy Doses

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Q3. WHO Analgesic Ladder + Malignant Bowel Obstruction [5+5]

Part A: WHO Analgesic Ladder - Critical Evaluation

MODIFIED WHO ANALGESIC LADDER (Updated 4-Step Model)
━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━
STEP 4: Interventional / Invasive Procedures
├─ Nerve blocks (celiac plexus, superior hypogastric)
├─ Intrathecal/epidural opioids
├─ Spinal cord stimulation
└─ Palliative sedation (refractory)

STEP 3: Strong Opioids (moderate-severe pain, NRS >6)
├─ Morphine (oral/SC/IV/continuous infusion)
├─ Oxycodone / Hydromorphone
├─ Fentanyl (TD patch / OTFC)
├─ Methadone (neuropathic component)
└─ ± Non-opioids + adjuvants

STEP 2: Weak Opioids (mild-moderate pain, NRS 4-6)
├─ Codeine, Tramadol, Low-dose strong opioids
└─ ± Non-opioids (paracetamol/NSAIDs)
   *** CONTROVERSY: Fallon et al. (Ann Oncol 2022) -
   2-step approach (skip Step 2) non-inferior, fewer
   adverse events, preferred in LMICs

STEP 1: Non-opioids (mild pain, NRS 1-3)
├─ Paracetamol (1g QID)
├─ NSAIDs (with PPI cover)
└─ Adjuvants (gabapentin, antidepressants, corticosteroids)
━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━
Direction: Bidirectional (UP for chronic pain; DOWN for acute)

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Part B: Malignant Bowel Obstruction (MBO) Management

MBO MANAGEMENT FLOWCHART
━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━
Patient presents with MBO
        │
  ┌─────┴──────┐
  │            │
Good PS     Poor PS / Diffuse peritoneal
  │           carcinomatosis
  ▼                   │
Consider surgery    Medical Management
├─ Resection/        (ESMO preferred)
│  bypass             │
├─ Stenting          ├─ IV octreotide 300-600mcg/d
└─ Ostomy            ├─ Dexamethasone 8-16mg/d
  (if single         ├─ Antiemetics (cyclizine/
   obstruction)      │  haloperidol/ondansetron)
                     ├─ Hyoscine butylbromide
                     │  (antisecretory)
                     ├─ Opioids for pain/colic
                     ├─ NGT if acute decompression
                     └─ TPN / IV fluids (palliative)
━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━

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Q4. Concurrent Chemoradiation: Rationale + Regimens + Keynote A18 [3+4+3]

Part A: Biological Rationale for Concurrent Chemotherapy with RT

MECHANISMS OF RADIO-SENSITIZATION
━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━
1. CELL CYCLE ARREST
   Cisplatin → G2/M arrest → More radiosensitive phase

2. INHIBITION OF DNA REPAIR
   RT → DSBs → Repair by homologous recombination
   Cisplatin → Inhibits NER (nucleotide excision repair)
   → Accumulation of lethal DNA damage

3. RE-OXYGENATION
   Chemo reduces tumor bulk → Less hypoxia
   Hypoxic cells are radioresistant (3x more resistant)

4. REDISTRIBUTION
   Chemo kills rapidly dividing cells in S-phase
   → Remaining cells redistribute to radiosensitive G2/M

5. APOPTOSIS SYNERGY
   Both activate p53-dependent and independent
   apoptotic pathways simultaneously

6. ANTI-ANGIOGENESIS
   Bevacizumab + RT → Vascular normalization
   → Better O2 delivery → More radiosensitization
━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━

Part B: Chemotherapy Regimens with RT in Ca Cervix

• DNA cross-linking → Enhanced DSBs with RT
• G2/M block → Increased radiosensitivity
• Inhibits VEGF-mediated repair
• Proven OS benefit in meta-analysis (5% absolute benefit)

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Part C: KEYNOTE-A18 Trial (Lancet 2024; OS update Lancet 2024)

• Arm A: Pembrolizumab 200mg q3w × 5 cycles + CCRT → Pembrolizumab 400mg q6w × 15 cycles
• Arm B: Placebo + CCRT → Placebo maintenance

• First immunotherapy to show OS benefit in LACC
• Pembrolizumab + CCRT is now emerging standard of care for high-risk LACC
• Benefit seen regardless of PD-L1 status
• Main added toxicities: immune-mediated (pneumonitis, hypothyroidism, colitis)
• NCCN Category 1 recommendation for high-risk LACC (2024)

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Q5. HRD + PARP Inhibition Mechanism + PARPi in Recurrent OC [4+6]

Part A: Homologous Recombination Deficiency (HRD) & PARP Cell Death

SYNTHETIC LETHALITY: BASIS OF PARPi ACTION
━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━
NORMAL CELL:
SSBs ──PARP─→ BER repair ──→ Cell survives
              (base excision)

BRCA1/2 WT cell + PARPi:
SSBs ──PARPi─→ SSB not repaired
──→ Replication fork stall → DSBs
──→ Repaired by Homologous Recombination (BRCA intact)
──→ Cell SURVIVES

HRD CELL (BRCA1/2 mut / HRD+) + PARPi:
SSBs ──PARPi─→ SSB not repaired (PARP trapped on DNA)
──→ Replication fork collapse → DSBs
──→ HR is DEFICIENT (no functional BRCA1/2)
──→ Cell uses error-prone NHEJ → Genomic instability
──→ CELL DEATH (Synthetic Lethality)

Two mechanisms:
1. Catalytic inhibition (PARP can't add PAR chains)
2. PARP trapping (PARP stuck on DNA = more toxic)
━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━

• Narrow: BRCA1/2 germline or somatic mutation
• Broad (HRD score): BRCA mutation + genomic instability markers (LOH, TAI, LST) - tested by Myriad myChoice CDx or FoundationOne CDx

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Part B: PARPi in Recurrent Ovarian Cancer (Evidence)

• PARPi significantly improve PFS across all subgroups in OC (PFS HR ~0.50 overall)
• Greatest benefit: gBRCA-mutated > somaticBRCA > HRD+ > HRD-negative
• OS benefit strongest in BRCA-mutated subgroups

• Anemia, thrombocytopenia, neutropenia (all; especially niraparib)
• Nausea, fatigue
• MDS/AML (1-2%, long-term use)
• Pneumonitis (olaparib, rare)

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Q6. WHO Screening Criteria + Evaluation Parameters [5+5]

Part A: WHO Criteria for Screening Program (Wilson & Jungner, 1968; updated)

• Evidence from RCTs should confirm benefit
• Benefit should outweigh harms (physical, psychological, ethical)
• Equity of access must be ensured
• Patient values and preferences considered

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Part B: Parameters for Evaluating Screening Tests

• ↑ Sensitivity → ↓ Specificity (shifting threshold down)
• Lead time bias: Apparent survival benefit due to earlier detection
• Length-time bias: Screening preferentially detects slow-growing tumors
• Overdiagnosis: Detection of disease that would never cause symptoms

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Q7. Uterine Sarcoma Classification + Embryonal RMS Management [5+5]

Part A: Classification (WHO 2020)

UTERINE MESENCHYMAL TUMORS (WHO 2020)
━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━
I. ENDOMETRIAL STROMAL TUMORS
   ├─ Endometrial stromal nodule (benign)
   ├─ Low-grade endometrial stromal sarcoma (LG-ESS)
   │   → JAZF1-SUZ12 or JAZF1-PHF1 fusion
   ├─ High-grade endometrial stromal sarcoma (HG-ESS)
   │   → YWHAE-NUTM2 or ZC3H7B-BCOR fusion
   └─ Undifferentiated uterine sarcoma (UUS)
      → Diagnosis of exclusion; very aggressive

II. SMOOTH MUSCLE TUMORS
   ├─ Leiomyoma (benign)
   ├─ STUMP (uncertain malignant potential)
   └─ Leiomyosarcoma (LMS)
      → Most common uterine sarcoma (60%)
      → Spindle cell, epithelioid, myxoid variants

III. MISCELLANEOUS UTERINE SARCOMAS
   ├─ Rhabdomyosarcoma (embryonal, alveolar, pleomorphic)
   ├─ PEComa (perivascular epithelioid cell tumor)
   │   → mTOR pathway; treat with mTOR inhibitors
   └─ Inflammatory myofibroblastic tumor (IMT)
      → ALK rearrangement; crizotinib responsive

IV. CARCINOSARCOMA
   → Treated as high-grade carcinoma (epithelial-mesenchymal)
   → NOT classified as sarcoma in WHO 2020
━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━

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Part B: Uterine Embryonal Rhabdomyosarcoma (ERMS) in an Adolescent

ADOLESCENT UTERINE ERMS MANAGEMENT
━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━
Step 1: MULTIDISCIPLINARY TEAM
├─ Pediatric oncology + gynecologic oncology
├─ STAGING: Clinical, MRI pelvis, CT chest/abdomen
│  Bone marrow biopsy, PET-CT
└─ IRS Grouping / EpSSG risk stratification

Step 2: PRIMARY SURGERY (if resectable)
├─ FERTILITY-SPARING: trachelectomy/excision if possible
├─ Complete resection preferred (Group I = best outcome)
├─ Lymph node biopsy (not formal dissection)
└─ Avoid mutilating surgery upfront

Step 3: CHEMOTHERAPY (VAC Regimen - cornerstone)
├─ Vincristine 1.5 mg/m² (d1)
├─ Actinomycin D 0.015 mg/kg (d1-d5)
├─ Cyclophosphamide 2.2 g/m² (d1)
│  (or VAI = vincristine, actinomycin, ifosfamide)
├─ IRS-V: 4 cycles neoadjuvant → response assess → surgery
└─ 12-18 cycles total (risk-adapted)

Step 4: RADIATION (site/risk dependent)
├─ Low-risk (Group I, completely resected): No RT
├─ Intermediate/High risk: RT to primary site
│  (45-50.4 Gy; brachytherapy for vaginal/cervical)
└─ Whole abdomen RT if peritoneal dissemination

Step 5: FERTILITY CONSIDERATIONS
├─ Avoid bilateral oophorectomy if possible
├─ Ovarian transposition before pelvic RT
├─ Fertility counseling + oocyte cryopreservation
└─ Conservative surgery followed by chemo/RT
━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━

• Localized disease: 5-yr OS ~80%
• Metastatic disease: 5-yr OS ~30%

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Q8. Advances in Brachytherapy + Radiation Complications [5+5]

Part A: Recent Advances in Brachytherapy

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Part B: Complications of Radiation and Management

Short-Term (Acute) Complications (<90 days)

Long-Term (Late/Chronic) Complications (>90 days)

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Q9. HIPEC Evidence in Advanced Ovarian Cancer + Peri-op Complications [5+5]

Part A: Evidence For and Against HIPEC in First-Line Advanced OC

EVIDENCE SUPPORTING HIPEC

• Direct cytotoxic effect on peritoneal micrometastases (inadequate IV drug penetration to peritoneum)
• Heat (41°C) enhances drug uptake, increases DNA cross-linking
• Cisplatin 25-fold higher intraperitoneal concentration vs IV
• Targets implants <2.5mm not amenable to surgical resection

EVIDENCE AGAINST / CONCERNS

• HIPEC at interval CRS may be offered in stage III EOC with good response to NACT at high-volume centers (Evidence Level IIA)
• Not routinely recommended outside of clinical trials for upfront primary debulking

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Part B: Peri-operative Complications of HIPEC

PERI-OPERATIVE COMPLICATIONS OF HIPEC
━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━
INTRAOPERATIVE
├─ Hypothermia (heat exposure paradox - systemic cooling)
├─ Hemodynamic instability (vasodilation, hypotension)
├─ Bowel injury during infusion
└─ Drug extravasation / spillage risk

EARLY POST-OP (within 30 days)
├─ Systemic (CHIPOR: 49% grade 3+)
│   ├─ Anaemia (23% grade 3+)
│   ├─ Electrolyte disturbance (14%)
│   ├─ Renal failure (10%)
│   └─ Hepatotoxicity (11%)
├─ GI
│   ├─ Anastomotic leak (5-15%)
│   ├─ Ileus (prolonged) - 20-30%
│   ├─ Fistula formation
│   └─ Delayed gastric emptying
├─ Infectious
│   ├─ Abdominal sepsis / peritonitis
│   ├─ Wound infection
│   └─ Pneumonia
└─ Thromboembolic
    ├─ DVT / PE (high risk: prolonged surgery)
    └─ LMWH prophylaxis mandatory

LATE COMPLICATIONS
├─ Abdominal adhesions → bowel obstruction
├─ Incisional hernia
├─ Cisplatin nephrotoxicity (cumulative)
├─ Peripheral neuropathy (cisplatin)
└─ Persistent ascites
━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━

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Q10. End of Life Care in Cancer + Bony Pain in Advanced Cervical Cancer [5+5]

Part A: End of Life Care (EOLC) in Cancer

EOLC FRAMEWORK
━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━
1. GOALS OF CARE DISCUSSION (early, documented)
   ├─ What matters most to the patient?
   ├─ Advance care planning / living will
   └─ DNAR / CPR discussion

2. SYMPTOM CONTROL (proactive)
   ├─ Pain → WHO ladder + adjuvants
   ├─ Dyspnea → low-dose opioids, fans, benzodiazepines
   ├─ Nausea → metoclopramide / haloperidol
   └─ Terminal secretions → hyoscine butylbromide

3. COMMUNICATION
   ├─ Honest, compassionate
   ├─ Involve family/caregiver
   └─ Multidisciplinary team approach

4. PLACE OF CARE
   ├─ Home (preferred by majority)
   ├─ Hospice
   └─ Hospital (if symptom burden high)

5. LAST HOURS / DAYS CARE
   ├─ Syringe driver (continuous SC infusion)
   ├─ Stop non-essential medications
   ├─ Mouth care, pressure sore prevention
   └─ Family support, bereavement care
━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━

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Part B: Managing Bony Pain in Advanced/Metastatic Cervical Cancer

BONY PAIN MANAGEMENT ALGORITHM - Advanced Cervical Ca
━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━
STEP 1: ASSESS
├─ Pain intensity (NRS 0-10)
├─ Imaging: X-ray, bone scan, MRI spine
├─ Rule out spinal cord compression (EMERGENCY)
└─ Neuropathic component? Burning, shooting → add gabapentin

STEP 2: PHARMACOLOGICAL
├─ NSAIDs (high efficacy for bone pain)
│   └─ Naproxen 500mg BD or Ibuprofen 400mg TDS + PPI
├─ Opioids (moderate-severe pain)
│   └─ Morphine SR (start 10-30mg BD; titrate)
│   └─ Fentanyl patch (TTS) for stable pain
│   └─ Immediate-release for breakthrough (1/6 daily dose)
├─ Adjuvants
│   ├─ Dexamethasone 4-16mg/d (anti-oedema, nerve compression)
│   ├─ Gabapentin 300-900mg TDS (neuropathic element)
│   └─ Amitriptyline 10-75mg nocte (neuropathic)
└─ Bone-targeted agents
    ├─ Zoledronic acid 4mg IV q4w (bisphosphonate)
    │   → Reduces SREs (pathological #, pain, hypercalcemia)
    └─ Denosumab 120mg SC q4w (RANKL inhibitor)
        → Superior for SRE prevention; no renal dose adjustment

STEP 3: RADIATION
├─ PALLIATIVE RT (MOST EFFECTIVE for localized bone pain)
│   ├─ Single fraction 8Gy (as effective as multi-fraction)
│   ├─ 20Gy/5# or 30Gy/10# (multi-fraction; re-treatment easier)
│   └─ Response rate: 60-80%; complete relief in 30-40%
├─ Reirradiation - if previous RT in field, limited re-dose
└─ Stereotactic body RT (SBRT) for spine (24Gy/2# or 24Gy/3#)

STEP 4: INTERVENTIONAL
├─ Vertebroplasty/kyphoplasty (vertebral collapse)
├─ Superior hypogastric plexus block (pelvic pain)
├─ Epidural/intrathecal analgesia (refractory pain)
└─ Orthopaedic fixation (impending/pathological fracture)

STEP 5: SPINAL CORD COMPRESSION (ONCOLOGICAL EMERGENCY)
├─ Dexamethasone 16mg STAT + 4mg q6h
├─ Emergency MRI spine
├─ Surgical decompression (if operable) OR
└─ Urgent RT (8Gy single fraction or 20Gy/5#)
━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━

• If no prior pembrolizumab/bevacizumab: KEYNOTE-826 regimen (pembrolizumab + cisplatin/paclitaxel ± bev)
• Bone-only metastases: Palliative RT most effective
• Hypercalcemia of malignancy: Zoledronic acid IV + aggressive hydration

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Reference Summary

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Quick Answer Summary