Small Cell Lung Carcinoma

Small cell lung carcinoma is a high-grade neuroendocrine carcinoma that makes up 13 to 15% of lung cancers. It is almost always caused by smoking (over 95%), with a peak at 60 to 70 years. The tumor has universal loss of RB1 and TP53, a doubling time of under 30 days, a very high proliferation index (Ki-67 over 50 to 60%), early widespread metastasis and strong initial sensitivity to chemotherapy and radiotherapy.

Staging: limited stage (disease within a tolerable radiotherapy field, about 30% of patients) and extensive stage (about 70%, with metastases to liver, adrenal, bone, bone marrow and brain). Brain metastases are present in 10 to 15% at diagnosis and arise in up to 50% during the illness. Median survival is 15 to 25 months for limited disease and 10 to 13 months for extensive disease with immunotherapy.

Paraneoplastic syndromes: syndrome of inappropriate antidiuretic hormone secretion (10 to 15%), ectopic ACTH, Lambert-Eaton myasthenic syndrome and paraneoplastic neuropathy or encephalitis. Complications: superior vena cava syndrome, airway obstruction, tumor lysis, spinal cord compression and relapse in most patients.

• Cough, dyspnea, hemoptysis, chest pain and rapid weight loss over weeks
• Hoarseness, superior vena cava syndrome and pleural effusion
• Hyponatremia, confusion and seizures from syndrome of inappropriate antidiuretic hormone secretion
• Proximal weakness and autonomic dryness (Lambert-Eaton)
• Headache, neurological deficit and bone pain from metastases
• Red flags: facial swelling, stridor, cord compression signs, severe hyponatremia, and confusion

1. Chest radiograph and CT of chest and upper abdomen with contrast: a central hilar mass with mediastinal nodes, and liver and adrenal metastases.
2. Tissue diagnosis: bronchoscopic biopsy, EBUS-guided node biopsy, or core biopsy of a metastasis. Histology: small cells with scant cytoplasm, nuclear molding, crush artifact and high mitotic rate. Immunohistochemistry: chromogranin, synaptophysin, CD56 and INSM1 positive, TTF-1 positive in most.
3. Staging: MRI brain with contrast, fluorodeoxyglucose PET-CT (or CT abdomen and bone scan).
4. Laboratory tests: sodium, calcium, creatinine, liver tests, LDH, alkaline phosphatase, blood count, and cortisol or ACTH when Cushing features are present.
5. Baseline fitness assessment: performance status, pulmonary function tests and, for cisplatin, audiology and creatinine clearance.

Differentials: non-small cell carcinoma, lymphoma, large cell neuroendocrine carcinoma, atypical carcinoid, thymic or Merkel cell carcinoma metastasis.

Start treatment promptly, since delay costs survival.

1. Limited stage:
   • Concurrent chemoradiotherapy: cisplatin 75 mg/m2 IV on day 1 with etoposide 100 mg/m2 IV on days 1 to 3, every 21 days for 4 cycles. Replace cisplatin with carboplatin AUC 5 when cisplatin is unsuitable.
   • Thoracic radiotherapy starting with the first or second cycle: 45 Gy in 30 twice-daily fractions of 1.5 Gy over 3 weeks, or 60 to 70 Gy in once-daily fractions.
   • After chemoradiotherapy without progression: durvalumab 10 mg/kg IV every 2 weeks for up to 24 months.
   • Prophylactic cranial irradiation 25 Gy in 10 fractions for responders, or surveillance with brain MRI every 3 months.
   • Surgical resection (lobectomy with nodal dissection and adjuvant chemotherapy) only for rare stage I disease.
2. Extensive stage: carboplatin AUC 5 IV on day 1 with etoposide 100 mg/m2 IV on days 1 to 3 and atezolizumab 1200 mg IV on day 1 (or durvalumab 1500 mg IV), every 21 days for 4 cycles, then maintenance atezolizumab 1200 mg IV every 3 weeks (or durvalumab 1500 mg every 4 weeks) until progression. Add consolidative thoracic radiotherapy 30 Gy in 10 fractions for residual chest disease in responders.
3. Supportive care in each cycle: ondansetron 8 mg orally or IV with dexamethasone 8 mg, aprepitant 125 mg orally on day 1 then 80 mg on days 2 and 3 for cisplatin, hydration and magnesium for cisplatin, and filgrastim 5 micrograms/kg SC daily after chemotherapy when neutropenic fever risk is over 20%. Monitor thyroid function, liver tests and glucose every 4 to 6 weeks on immunotherapy.
4. Relapse: chemotherapy again if relapse is over 3 months after finishing platinum (carboplatin plus etoposide). Otherwise topotecan 1.5 mg/m2 IV on days 1 to 5 every 21 days, or lurbinectedin 3.2 mg/m2 IV every 21 days.
5. Complications:
   • Superior vena cava syndrome: stenting and radiotherapy with dexamethasone 8 mg IV twice daily.
   • Syndrome of inappropriate antidiuretic hormone secretion: fluid restriction to 800 mL daily, with tolvaptan 15 mg orally daily if sodium is under 125 mmol/L (limit the rate of correction to 8 mmol/L in 24 hours).
   • Brain metastases: whole brain radiotherapy 30 Gy in 10 fractions or stereotactic radiosurgery.
   • Cord compression: dexamethasone 16 mg IV then 4 mg every 6 hours, and urgent radiotherapy.
6. Smoking cessation: varenicline 0.5 mg orally daily for 3 days, 0.5 mg twice daily for 4 days, then 1 mg twice daily for 12 weeks.

Follow-up: CT every 2 to 3 cycles, then every 3 months for 2 years, and brain MRI at least every 3 months for 2 years. Counsel on prognosis and early palliative care involvement.