---

Pain Management of Spinal Metastatic Lesions from Ovarian Clear Cell Carcinoma

---

1. Pharmacological Management (WHO Analgesic Ladder)

Step 1 — Mild Pain

• Paracetamol (acetaminophen) 500–1000 mg q6h (max 4 g/day)
• NSAIDs (e.g., ibuprofen, naproxen, ketorolac) — particularly useful for bone pain due to their anti-prostaglandin activity
  • Use with a PPI for GI protection; monitor renal function
  • NSAIDs may have additive benefit with opioids for osteolytic metastatic pain

Step 2 — Moderate Pain

• Weak opioids: codeine, tramadol, low-dose oxycodone
• ESMO alternative: Low-dose strong opioids (e.g., morphine 5–10 mg orally q4h) can be used instead of weak opioids to avoid the "ceiling effect"

Step 3 — Severe Pain

• Prescribe a regular (around-the-clock) dose plus breakthrough doses (10–15% of total daily opioid dose, available q1–2h PRN)
• Titrate every 24–48 hours as needed
• Always co-prescribe a bowel regimen (e.g., senna + macrogol); antiemetics PRN

Adjuvant Analgesics (Co-analgesics)

---

2. Radiation Therapy (RT)

Fractionation Schedules

Special consideration for OCCC: Clear cell carcinoma is considered relatively radioresistant compared to high-grade serous carcinoma. Stereotactic radiosurgery (SRS/SBRT) delivers ablative doses with high precision and is preferred when technically feasible, particularly for intact vertebral body lesions without significant epidural disease.

---

3. Interventional & Surgical Approaches

Minimally Invasive Procedures

Surgical Intervention

• Spinal cord compression or instability (Spinal Instability Neoplastic Score [SINS] ≥ 13)
• Neurological deterioration
• Failure of radiotherapy
• Need for tissue diagnosis

Epidural/Intrathecal Analgesia

• Epidural steroid injections for localized radicular pain
• Intrathecal drug delivery systems (IDDS): morphine ± ziconotide via implanted pump — highly effective for refractory cancer pain, reduces systemic opioid burden and side effects

---

4. Systemic Oncological Therapy

Chemotherapy

• First-line: Carboplatin + paclitaxel (standard; limited efficacy for clear cell)
• Second-line/recurrent: Gemcitabine, irinotecan, oxaliplatin, or clinical trials

Targeted/Immunotherapy

• mTOR inhibitors (everolimus, temsirolimus) — have activity in PIK3CA-mutated OCCC
• Immune checkpoint inhibitors (pembrolizumab, nivolumab) — OCCC has higher mutational burden than serous subtype; responses reported, especially in MSI-H tumors
• HER2-targeted therapy — small subset of OCCC overexpresses HER2
• PARP inhibitors — limited role unless BRCA-mutated
• Molecular tumor board referral is strongly encouraged

---

5. Non-Pharmacological & Supportive Measures

• Spinal orthosis/bracing: Cervicothoracic or thoracolumbar orthoses to reduce mechanical pain during mobilization
• Physiotherapy: Careful weight-bearing advice, gait aids, fall prevention
• Transcutaneous Electrical Nerve Stimulation (TENS): Adjunct for localized pain
• Psychological support: CBT, mindfulness for chronic cancer pain; address pain catastrophizing
• Palliative care integration: Early palliative care referral improves pain control, QoL, and potentially survival

---

6. Emergency: Metastatic Spinal Cord Compression (MSCC)

1. Dexamethasone 16 mg IV/PO STAT, then 4 mg q6h
2. Urgent MRI whole spine (within 24 hours, or immediately if neurological signs)
3. Neurosurgical/radiation oncology referral within 24 hours
4. DVT prophylaxis if immobile

---

Summary Algorithm

Spinal Metastatic Pain (OCCC)
         │
         ├─ Mild → Paracetamol ± NSAID + adjuvants
         ├─ Moderate → Weak opioid or low-dose strong opioid + adjuvants
         └─ Severe → Strong opioid (titrate) + dexamethasone + adjuvants
                          │
                          ├─ Radiation: EBRT or SBRT (preferred for OCCC)
                          ├─ Interventional: vertebroplasty/kyphoplasty/RFA
                          ├─ Surgical: if MSCC, instability, or cord compression
                          ├─ Intrathecal pump: if refractory systemic opioids
                          └─ Systemic therapy: PIK3CA-mTOR, ICI, clinical trial

---

• Cancer Pain Management in Adults — ESMO/WHO Guidelines, p. 13
• External Beam Radiation Therapy for Palliation of Symptomatic Bone Metastases — Clinical Practice Guideline, p. 9
• ESMO Clinical Practice Guidelines: Metastatic Bone Disease
• NCCN Guidelines: Adult Cancer Pain, Ovarian Cancer (Clear Cell Histology)

Hoarseness of Voice in Metastatic Ovarian Clear Cell Carcinoma

---

Primary Mechanism: Recurrent Laryngeal Nerve Palsy

Anatomy — Why the RLN is Vulnerable

• Arises from the left vagus nerve (CN X) at the level of the aortic arch
• Loops under the arch of the aorta (around the ligamentum arteriosum)
• Ascends in the tracheo-oesophageal groove to reach the larynx and supply all intrinsic laryngeal muscles except the cricothyroid
• Any mass in the left mediastinum, aortopulmonary window, or left paratracheal region can compress or invade it

Clinical Features of RLN Palsy

Compensation: Symptoms may partially resolve within weeks as the contralateral vocal fold adducts across the midline to meet the paralysed cord.

---

How Metastatic OCCC Causes RLN Palsy

1. Mediastinal Lymph Node Metastases

• OCCC can spread via lymphatics to para-aortic → retrocural → posterior mediastinal → paratracheal lymph nodes
• Enlarged nodes in the aortopulmonary window or left paratracheal chain compress the left RLN
• This is the most common mechanism in gynaecological cancers causing hoarseness

2. Pulmonary / Pleural Metastases

• OCCC metastasises to the lungs; hilar or mediastinal involvement from pulmonary metastases can entrap the RLN
• Malignant pleural effusion with mediastinal shift can stretch the nerve

3. Direct Mediastinal Invasion

• Advanced or recurrent OCCC with direct transdiaphragmatic extension into the posterior mediastinum
• Rare but described in peritoneal carcinomatosis with cephalad spread

4. Spinal Metastases (Relevant to This Case)

• Cervicothoracic vertebral metastases (C5–T4 level) with epidural or paravertebral mass extension can compress the vagus nerve trunk or the RLN at its origin
• Given the prior context of spinal metastases in this patient, paravertebral soft-tissue extension at a cervicothoracic level compressing the vagus/RLN is a direct consideration

---

Other Causes of Hoarseness to Consider

---

Diagnostic Approach

1. Laryngoscopy (flexible nasopharyngoscopy): Confirms vocal cord mobility — unilateral cord paralysis in paramedian position is diagnostic of RLN palsy
2. CT chest + neck with contrast: Identifies mediastinal lymphadenopathy, paravertebral masses, pulmonary metastases, or direct nerve compression
3. MRI cervicothoracic spine: If spinal metastases are present, assess for paravertebral soft-tissue component at C5–T4 levels
4. PET-CT: Maps full extent of metastatic disease including mediastinal nodes

---

Summary

---

Management of Delirium in Cancer — Ovarian Clear Cell Carcinoma with Liver, Skeletal Metastases & Vertebral Fractures

---

1. Understanding Delirium in This Patient

---

2. Causes Specific to This Patient

A. Liver Metastases

• Hepatic encephalopathy: liver metastatic replacement → reduced hepatic reserve → ammonia accumulation → cerebral dysfunction
• Impaired metabolism of opioids, benzodiazepines, and other medications → drug accumulation
• Obstructive jaundice (if biliary compression) contributing to metabolic derangement

B. Skeletal Metastases / Vertebral Fractures

• Hypercalcaemia of malignancy: osteolytic metastases release calcium → hypercalcaemia is a direct, reversible cause of delirium
• Pain: uncontrolled pain from vertebral fractures drives agitation and confusion
• Opioid toxicity: high-dose opioids required for bone pain accumulate (especially with hepatic dysfunction) → opioid-induced delirium with myoclonus
• Immobility from vertebral fractures → deconditioning, constipation, urinary retention — all precipitate delirium

C. Spinal Cord/Cauda Equina Compression

• Epidural extension from vertebral metastases → urinary retention, constipation, pain escalation → delirium precipitants

D. General Oncological Causes (Harrison's 22E, p. 129)

---

3. Assessment

Delirium Subtypes — Critical to Recognise

Hypoactive delirium is the most commonly missed subtype. The central distinguishing feature from depression/dementia is altered level of consciousness. (Harrison's 22E, p. 129)

Validated Assessment Tools (Kaplan & Sadock's, p. 7031)

---

4. Initial Workup — Identify Reversible Causes

In terminal patients, investigations should be proportionate to prognosis and goals of care. Unpleasant or burdensome diagnostics should be avoided if no actionable treatment will follow. (Kaplan & Sadock's, p. 7032)

---

5. Management

Step 1 — Treat Reversible Causes

---

Step 2 — Non-Pharmacological Management (Goldman-Cecil, p. 3751; Kaplan & Sadock's, p. 7033)

• Reorientation: clocks, calendars, familiar objects, verbal reorientation by staff and family
• Environment: quiet, well-lit room; low-level lighting at night; minimise room/staff changes
• Family presence: familiar faces reduce fear and agitation
• Sensory aids: ensure hearing aids and glasses are in use
• Sleep-wake cycle: schedule vitals and medication administration to allow uninterrupted night sleep; avoid daytime sedation
• Early mobilisation: where safe (with vertebral fractures — bracing, physio involvement)
• Communication: simple instructions, frequent eye contact, allow patient involvement in decisions
• Avoid restraints: physical restraints increase agitation — use only if patient is a danger to themselves
• Music/massage/relaxation: effective non-pharmacological adjuncts

---

Step 3 — Pharmacological Management

First-Line: Haloperidol (Harrison's 22E, p. 129; Goldman-Cecil, p. 3750; Kaplan & Sadock's, p. 7033)

QTc monitoring is mandatory with IV haloperidol. (Kaplan & Sadock's, p. 7033)

Second-Line: Atypical Antipsychotics

Note on hepatic metastases: Olanzapine is the preferred atypical because it is metabolised via multiple pathways (CYP1A2, glucuronidation) and is safer in hepatic dysfunction compared to risperidone or quetiapine.

Adjunct: Benzodiazepines

Refractory/Terminal Delirium — Palliative Sedation (Harrison's 22E, p. 129)

• Midazolam: 1–5 mg/h continuous SC or IV infusion
• Propofol: 0.3–2.0 mg/kg/h IV continuous infusion — in monitored settings only
• Up to 25% of patients with terminal delirium with myoclonus or convulsions require sedation
• Goals of care, patient/family wishes, and advance directives must guide this decision

---

6. Specific Pharmacological Considerations for This Patient

---

7. Family Communication and Goals of Care

• Inform family that delirium, especially terminal delirium, is a normal part of the dying process in up to 85% of cancer patients
• Explain that treatment aims to maintain dignity and minimise distress — not necessarily to maintain full alertness at the cost of agitation
• Clarify advance directives regarding resuscitation, sedation, and hospitalisation
• Delirium in the final hours is a sign that "it is time to ensure everything important has been said" (Harrison's 22E)

---

Summary Table — Drug Choices in This Patient

---

• Harrison's Principles of Internal Medicine 22E — pp. 129 (Table 13-7)
• Goldman-Cecil Medicine — p. 3750–3751 (End-of-Life Care; Delirium Management)
• Kaplan & Sadock's Comprehensive Textbook of Psychiatry — pp. 7031–7033 (Delirium in Cancer/Palliative Care)