Small Cell Lung Cancer (SCLC)

Small cell lung cancer (SCLC)

• Historically referred to as "oat cell carcinoma"
• A malignant epithelial tumour originating from the pulmonary neuroendocrine cells lining the lower respiratory tract. 
• These cells are part of the diffuse neuroendocrine system and are capable of secreting polypeptide hormones.

Classification

• The 2021 WHO classification categorises SCLC as a high-grade neuroendocrine carcinoma, distinct from other neuroendocrine neoplasms like typical carcinoid (low-grade), atypical carcinoid (intermediate-grade), and large cell neuroendocrine carcinoma (LCNEC, also high-grade).

Clinical significance

• The diagnosis of SCLC implies a distinct clinical course from non-small cell lung cancer (NSCLC). 
• It guides staging (often by the VALSG two-stage system or TNM), prognosis, and therapeutic approach, which includes early systemic chemotherapy and radiotherapy rather than surgery in most cases

Cigarette Smoking

• Tobacco smoking is the predominant and most well-established cause of SCLC.
• Approximately 98% of patients diagnosed with SCLC have a documented history of smoking.
• The risk of developing SCLC increases proportionally with the intensity and duration of tobacco exposure.
• Both active and passive exposure to tobacco smoke elevate cancer risk significantly.
• Tobacco smoke contains a range of carcinogens, including polynuclear aromatic hydrocarbons, N-nitrosamines, aromatic amines, and other organic and inorganic substances.
• These compounds contribute to oncogenesis through DNA damage, mutagenesis, and interference with cellular repair mechanisms.

Cessation and Prognosis

• While nearly all SCLC cases are linked to tobacco use, smoking cessation remains crucial even after diagnosis.
• Cessation has been shown to improve treatment response and survival, and reduce the risk of treatment complications or secondary malignancies.

Radon Gas Exposure

• SCLC has also been associated with environmental exposure to radon, a radioactive inert gas resulting from the natural decay of uranium.
• Radon can accumulate in enclosed environments such as homes, particularly in areas with high uranium content in the soil.
• Although radon itself is not chemically reactive, its decay products emit alpha-particles capable of inducing DNA damage and promoting carcinogenesis within pulmonary epithelial cells.

Occupational Exposure – Uranium Mining

• Occupational settings such as uranium mining present a significant risk factor.
• All histological types of lung cancer occur with increased frequency among uranium miners, but SCLC shows the strongest association.
• The risk is compounded in miners who also smoke tobacco.
• The synergistic interaction between inhaled radon progeny and tobacco carcinogens likely amplifies the mutagenic burden, accelerating oncogenic transformation.

Tumour Origin and Behaviour

• SCLC arises from peribronchial neuroendocrine cells and infiltrates the bronchial submucosa.
• Tumours typically present as central masses, exhibit rapid proliferation, and show extensive necrosis and high mitotic activity.
• Early metastasis is common, with preferential spread to liver, bone, adrenal glands, brain, and mediastinal lymph nodes.
• Approximately two-thirds of patients present with extensive-stage disease at diagnosis.

Neuroendocrine Features and Classification

• SCLC is categorised as a high-grade neuroendocrine carcinoma, along with large cell neuroendocrine carcinoma (LCNEC).
• Microscopy reveals small cells with scant cytoplasm, finely granular chromatin, absent nucleoli, frequent mitoses, and nuclear moulding.
• In contrast, LCNEC displays prominent nucleoli, coarser chromatin, and more cytoplasm.
• A subset of SCLC termed "combined SCLC" features additional non-small cell carcinoma components such as squamous cell carcinoma or adenocarcinoma.
• These tumours often derive from pluripotent stem cells, as evidenced by observed transdifferentiation in cases of EGFR-mutant NSCLC acquiring SCLC features after treatment resistance.

Paraneoplastic Syndromes

• SCLC commonly produces peptide hormones such as ACTH and vasopressin, resulting in endocrine syndromes like ectopic Cushing’s syndrome and syndrome of inappropriate antidiuretic hormone secretion (SIADH).
• Neurologic paraneoplastic syndromes may occur due to autoantibody production, including Lambert-Eaton myasthenic syndrome and cerebellar degeneration.
• These phenomena reflect the tumour's neuroendocrine nature and systemic biological activity.

Transcriptional Subtypes and Treatment Implications

• SCLC can be subdivided into four molecular subtypes based on transcription factor expression:
  • SCLC-A: High ASCL1
  • SCLC-N: High NEUROD1
  • SCLC-P: High POU2F3
  • SCLC-I: Low ASCL1/NEUROD1/POU2F3, but enriched in immune-related and mesenchymal features
• SCLC-I subtype appears to be most responsive to immune checkpoint inhibitors.
• Subtype plasticity has been observed, with transitions from SCLC-A to SCLC-I following cisplatin exposure, which may underpin acquired chemotherapy resistance.

Genetic Alterations

• Nearly all SCLC cases harbour inactivating mutations in TP53 and RB1.
• MYC, MYCL1, and MYCN amplifications are found in around 20% of cases, often correlating with more aggressive phenotypes and sensitivity to aurora kinase inhibitors.
• Other common alterations include PTEN, CREBBP, KMT2D, and NOTCH genes, while chromosomal 3p deletions result in haploinsufficiency of multiple tumour suppressors.
• A rare “atypical” SCLC subtype retains wild-type TP53 and RB1, shows extensive chromothripsis, and is enriched in CCND1, CDK4, and MDM2 amplification. These tumours are more likely to arise in light or never smokers.

Tumour Markers and Diagnostic Features

• SCLC cells typically express cytokeratins and epithelial membrane antigen.
• TTF-1 is positive in the majority of cases and assists in distinguishing pulmonary origin from other neuroendocrine tumours.
• Neuroendocrine markers such as CD56, chromogranin, and synaptophysin are commonly expressed, though their presence is not mandatory for diagnosis.
• Additional markers may include NSE, calcitonin, dopa decarboxylase, GRP, and IGF-1.

Proteomic and Targeted Insights

• Proteomic profiling identifies elevated levels of DNA repair proteins like PARP1, CHEK1, ATR, and EZH2 in SCLC.
• SLFN11 has emerged as a predictive biomarker for response to PARP inhibitors (e.g. olaparib and veliparib), particularly in relapsed or refractory cases.
• Subtype SCLC-I is enriched for inflammatory markers and derives particular benefit from immune checkpoint blockade, supported by retrospective analyses of major clinical trials.
• Several surface antigens are under exploration as immunotherapeutic targets, including:
  • DLL3 (targeted by agents like tarlatamab)
  • SEZ6, B7-H3, and TROP-2, under investigation in antibody-drug conjugates and CAR-T therapies
• Although testing for these markers is underway, they are not yet part of standard care protocols.

Global and Regional Occurrence

• Lung cancer is one of the most frequently diagnosed cancers worldwide, with approximately 2.21 million new cases and 1.8 million deaths globally in 2020.
• It is the most common malignancy among men globally and ranks fifth among women, although regional variation exists.
• In the United Kingdom, recent data show an average of 48,500 new lung cancer cases and 34,800 lung cancer deaths annually.
• In the United States, lung cancer remains the leading cause of cancer mortality, accounting for an estimated 234,580 new cases and 125,070 deaths in 2024.

Proportion of SCLC

• SCLC comprises approximately 13–15% of all lung cancer diagnoses.
• Historically, it accounted for 20–25% of lung cancers, but its incidence has declined in parallel with reductions in smoking prevalence.
• Separate global figures for SCLC incidence are not routinely available.

Demographic Patterns

• SCLC occurs almost exclusively in smokers and is especially associated with heavy smoking history.
• It is exceedingly rare in never-smokers, comprising only around 2% of cases in published series.
• The median age at diagnosis is between 60 and 80 years.
• The sex distribution is roughly equal, with females now representing 50% of SCLC diagnoses in some regions.

Trends Over Time

• Lung cancer incidence in men began to decline in the early 1980s, following earlier reductions in smoking rates.
• In women, incidence rates rose until the mid-2000s before beginning to decline.
• The overall decline in lung cancer incidence—around 2% annually in the US since the mid-2000s—reflects public health measures and decreased tobacco use.
• A global age-standardised decline of 6.5% in lung cancer incidence occurred between 2010 and 2019.

Sex Differences in Incidence Trends

• Over the past two decades, lung cancer incidence has decreased among both men and women aged 30–54, with a steeper decline in men.
• Among younger adults, the incidence rate in women has overtaken that in men in some ethnic groups. For example, in non-Hispanic whites and Hispanics aged 44–49 years, the female-to-male incidence ratio rose from 0.88 in 1995–1999 to 1.17 in 2010–2014.
• While increased smoking among women born after 1965 explains some of this trend, biological susceptibility to tobacco carcinogens may also play a role.

Duration and Pattern of Symptoms

• The majority of patients present with symptoms of short duration—typically 8 to 12 weeks before diagnosis.
• Fewer than 5% are asymptomatic at presentation.
• Symptoms may result from local tumour growth, regional spread within the thorax, distant metastases, or paraneoplastic syndromes.

Symptoms from Local Tumour Growth

• Cough is a frequent presenting complaint, occurring in more than 50% of cases and is often new or persistent.
• Dyspnoea may result from airway obstruction, associated chronic obstructive pulmonary disease (COPD), pneumonia, phrenic nerve involvement, or pleural effusion.
• Haemoptysis occurs in approximately 25% of patients, although massive haemoptysis is rare.
• Chest discomfort or pain may affect up to one-third of patients and is generally due to pleural or chest wall invasion, as the lung parenchyma lacks pain fibres.
• Postobstructive pneumonitis or fever can develop due to rapid growth and endobronchial obstruction.

Symptoms from Intrathoracic Spread

• Mediastinal invasion may cause:
  • Hoarseness (compression of the recurrent laryngeal nerve)
  • Dysphagia (oesophageal compression)
  • Stridor or wheezing (airway compression)
  • Facial swelling, dilated neck veins, and collateral chest wall veins (superior vena cava syndrome)
  • Hemi-diaphragm elevation and dyspnoea (phrenic nerve involvement)
• These features may be more frequent in SCLC than in other lung cancer subtypes due to its rapid growth and early nodal spread.

Symptoms from Distant Metastases

• The most common sites of haematogenous spread are brain, bone, liver, adrenal glands, and bone marrow.
• Neurological signs from brain metastases include:
  • Headache (often worse in the morning)
  • Confusion, personality changes
  • Nausea, vomiting, blurred vision, photophobia
  • Focal deficits such as limb weakness, slurred speech, or seizures
• Spinal metastases may cause back pain and can rapidly progress to paraplegia or quadriplegia due to spinal cord compression—an oncological emergency.
• Bone metastases often lead to localised pain or pathological fractures, particularly in the axial skeleton and proximal long bones.
• Liver metastases may cause jaundice, right upper quadrant abdominal pain, or hepatomegaly.

Paraneoplastic Syndromes

• Paraneoplastic syndromes are systemic effects triggered by ectopic hormone production or autoimmune responses.
• Common endocrine syndromes include:
  • Syndrome of inappropriate antidiuretic hormone secretion (SIADH): 15%
  • Ectopic ACTH secretion (causing Cushing's syndrome): 2–5%
• Neurological syndromes may include:
  • Lambert-Eaton myasthenic syndrome (3%)
  • Subacute cerebellar degeneration
  • Subacute sensory neuropathy
  • Limbic encephalitis, often associated with anti-Hu or anti-Yo antibodies

Demographic and Risk Factor Clues from History

• The median age at diagnosis is between 65 and 74 years.
• More common in men, though the sex gap has narrowed.
• A history of heavy smoking is nearly universal; passive smoke exposure, radon gas, and asbestos are additional risk factors.
• The presence of underlying COPD may increase susceptibility.

Respiratory System

• Patients often present with signs of respiratory distress, including use of accessory muscles (scalene and intercostal muscles) and nasal flaring.
• Central tumours may lead to atelectasis or postobstructive pneumonia, with examination findings of reduced breath sounds and dullness to percussion.
• Pleural effusion is common in advanced disease and presents with decreased or absent breath sounds, stony dullness on percussion, and reduced tactile fremitus on the affected side.
• Wheezing, rales, or bronchial breath sounds may also be noted due to airway obstruction.

Cardiovascular System

• Pericardial effusion may occur, manifesting with distant or muffled heart sounds, raised jugular venous pressure, and hypotension if tamponade develops.
• Pulsus paradoxus (an exaggerated fall in systolic blood pressure during inspiration) is a classic sign of cardiac tamponade and should prompt urgent echocardiographic evaluation.
• In superior vena cava (SVC) obstruction, physical signs may include facial plethora, cyanosis, oedema of the head, neck, and upper limbs, and distended veins over the chest wall.

Central Nervous System

• Brain metastases may lead to signs of raised intracranial pressure including papilloedema on funduscopy, altered mental status, and gait or coordination abnormalities.
• Focal neurological deficits depend on lesion location and may include weakness, sensory loss, ataxia, or cranial nerve abnormalities.
• Cerebellar metastases or paraneoplastic cerebellar degeneration can present with dysarthria, nystagmus, or limb ataxia.
• Spinal cord compression should be suspected in patients with back pain and motor or sensory deficits; progression may be rapid and irreversible without prompt intervention.

Gastrointestinal System

• Hepatomegaly and/or jaundice may be present due to liver metastases or biliary obstruction.
• Although most patients are asymptomatic from gastrointestinal involvement, elevated liver enzymes are frequently found in metastatic cases.
• Ascites and right upper quadrant tenderness may occasionally be observed in extensive hepatic disease.

Lymphatic System

• Lymphadenopathy may be present, particularly in the supraclavicular and cervical chains.
• Palpable supraclavicular lymph nodes (especially ipsilateral to the primary lesion) are compatible with limited-stage disease.
• Enlarged axillary or contralateral supraclavicular nodes are suggestive of extensive-stage disease.
• Mediastinal lymphadenopathy may not be clinically palpable but should be suspected with signs of airway compression or SVC syndrome.

Extremities and Peripheral Signs

• Clubbing is uncommon in SCLC, occurring in only around 4% of cases (compared to ~35% in non-small cell lung cancer).
• Cyanosis may be observed in advanced disease or SVC obstruction.
• Oedema of the upper extremities may result from venous compression.
• Hypertrophic osteoarthropathy, though rare in SCLC, presents with joint pain, swelling, and periosteal new bone formation affecting distal limbs.

Chest X-ray (CXR)

• Standard posteroanterior and lateral CXR is a widely accessible and low-cost initial investigation for patients presenting with symptoms such as cough, haemoptysis, or chest pain.
• Typical findings include central or peripheral pulmonary masses, hilar lymphadenopathy, superior mediastinal widening, or pleural effusion.

Computed Tomography (CT) of the Chest, Liver, and Adrenal Glands

• All abnormalities on CXR or concerning clinical features warrant evaluation with a contrast-enhanced CT scan.
• CT delineates tumour size, lymph node involvement, and potential metastatic spread, particularly to liver and adrenal glands.
• It also distinguishes vascular structures from lymph nodes and can help stage the disease as either limited (confined to ipsilateral hemithorax) or extensive.
• Post-treatment, CT imaging is used to assess response and detect recurrence.

Tissue Diagnosis and Sampling Procedures

Bronchoscopy

• Performed when centrally located masses or mediastinal lymphadenopathy are accessible.
• Allows direct visualisation, biopsy of endobronchial lesions, bronchoalveolar lavage, brushings, and needle aspiration.
• Diagnostic yield is highest for central tumours and can be further improved by adjunct use of endobronchial ultrasound (EBUS) for peripheral lesions <2 cm.

Percutaneous Needle Biopsy

• CT-guided core or fine-needle aspiration is preferred for peripheral lesions or metastatic sites not accessible by bronchoscopy.
• Cytological findings consistent with SCLC include high nuclear-to-cytoplasmic ratio and nuclear moulding.

Thoracentesis

• Used to analyse pleural fluid when pleural effusion is present.
• Malignant cells within the effusion can aid diagnosis and staging.
• Ultrasound guidance improves safety and diagnostic yield, especially for small effusions.

Thoracoscopy

• Considered when thoracentesis is inconclusive and pleural involvement needs confirmation for staging.

Advanced Imaging and Staging

MRI or CT Brain Scan

• Recommended for all patients due to high risk of brain metastases, regardless of neurological symptoms.
• MRI is preferred due to superior sensitivity; findings may include enhancing masses with perilesional oedema.

FDG-PET/CT Scan

• Offers superior evaluation of intrathoracic and extrathoracic disease extent.
• Helps detect occult metastases and guides biopsy of the most accessible lesion for staging and diagnosis.

Bone Scan

• Used when PET/CT is unavailable to detect skeletal metastases.
• Especially indicated in patients with bone pain or elevated alkaline phosphatase.

Mediastinoscopy

• Performed in patients with solitary pulmonary nodules without apparent lymphadenopathy.
• Confirms nodal status before potential surgical resection.

Bone Marrow Aspiration and Biopsy

• Indicated in cases of unexplained anaemia, thrombocytopenia, or presence of nucleated red blood cells on peripheral smear.
• Detects marrow infiltration by tumour cells.

Laboratory and Functional Assessments

Full Blood Count (FBC)

• Baseline assessment is essential prior to initiating treatment.
• May reveal anaemia or cytopenias and monitors myelosuppressive effects of chemotherapy and radiotherapy.

Liver Function Tests (LFTs)

• Abnormalities, particularly elevated alkaline phosphatase, may suggest liver or bone metastases.

Serum Sodium

• Hyponatraemia can be a clue to syndrome of inappropriate antidiuretic hormone secretion (SIADH), a common paraneoplastic manifestation.

Renal Function Tests

• Necessary to evaluate baseline renal status before using nephrotoxic agents such as cisplatin.
• Electrolyte disturbances may occur with chemotherapy.

Pulmonary Function Tests (PFTs)

• Includes FEV₁ and DLCO, required before thoracic radiotherapy or surgery.
• Assesses baseline lung function and helps determine treatment tolerability.

Staging-Based Approach

• Limited-stage disease (LD-SCLC) refers to tumour burden confined to the ipsilateral hemithorax, mediastinum, or supraclavicular lymph nodes and potentially curable within a single tolerable radiotherapy (RT) field.
• Extensive-stage disease (ES-SCLC) involves contralateral thoracic or distant metastases and includes malignant pleural or pericardial effusions.
• A multidisciplinary team in a specialised oncology centre should coordinate care.

Limited-Stage Disease

Concurrent Chemoradiotherapy

• Standard treatment involves platinum-based chemotherapy (cisplatin or carboplatin plus etoposide) combined with thoracic RT.
• RT should commence early, preferably with cycle 1 or 2 of chemotherapy.
• Twice-daily hyperfractionated RT (45 Gy in 1.5-Gy fractions) is preferred but once-daily regimens (60–70 Gy in 2-Gy fractions) are acceptable when BID is not feasible.
• Patients with N2 involvement after surgical resection should receive postoperative mediastinal radiation.

Consolidation Immunotherapy

• Durvalumab is approved as consolidation therapy for up to 2 years in patients without disease progression following chemoradiotherapy.
• Prophylactic cranial irradiation (PCI) should be administered prior to initiating durvalumab.

Surgical Management

• Surgery is reserved for highly selected patients with stage I (T1–2, N0) disease confirmed by invasive mediastinal staging.
• Lobectomy with mediastinal lymph node dissection is preferred; postoperative chemotherapy is mandatory.
• Adjuvant RT is recommended for patients with nodal involvement.

Extensive-Stage Disease

First-Line Therapy

• Standard treatment includes 4–6 cycles of platinum-based chemotherapy (cisplatin or carboplatin) with etoposide, combined with immunotherapy (atezolizumab or durvalumab).
• Maintenance with the same immune checkpoint inhibitor continues until progression or unacceptable toxicity.
• Alternative options include cisplatin or carboplatin plus irinotecan.

Immunotherapy Considerations

• Immune-related adverse effects (e.g., pneumonitis, colitis, endocrinopathies) require prompt recognition.
• Immunotherapy is contraindicated in patients currently or previously treated with tyrosine kinase inhibitors.
• Combination immune therapy (nivolumab + ipilimumab) has not shown survival benefit in the first-line setting and is not recommended.

Radiotherapy and PCI

• Thoracic RT may be offered to patients with a complete extrathoracic and partial intrathoracic response.
• PCI reduces the incidence of brain metastases and improves survival in responders, though the benefit in ES-SCLC remains debated.
• PCI dosing: 25 Gy in 2.5-Gy fractions. MRI surveillance may be an alternative in select patients.

Relapsed SCLC

Platinum-Sensitive Relapse (>6 months)

• Re-treatment with the original platinum-based regimen is recommended.
• Platinum doublets show higher response rates than non-platinum agents.

Platinum-Resistant Relapse (≤6 months)

• Agents such as topotecan, irinotecan, paclitaxel, docetaxel, vinorelbine, or gemcitabine may be used.
• Immunotherapy options (e.g., nivolumab, pembrolizumab) have been withdrawn due to lack of survival benefit in third-line settings.
• Clinical trial enrolment is encouraged due to limited response with standard options.

Novel and Targeted Therapies

Tarlatamab

• A bispecific T-cell engager targeting DLL3 recently received FDA approval for ES-SCLC after platinum failure.
• Response rate: 40% with median duration of 9.7 months.
• Major adverse events include cytokine release syndrome and neurological toxicity.

Lurbinectedin

• An alkylating agent approved for SCLC after platinum-based therapy.
• Objective response rate: 35% with median response duration of 5.3 months.

Temozolomide + PARP Inhibitors

• Combination with veliparib or olaparib shows promise, especially in SLFN11-positive tumours.
• Ongoing trials are evaluating their role in relapsed disease.

Radiotherapy

Thoracic Radiotherapy

• Recommended early and concurrently in LD-SCLC.
• In ES-SCLC, thoracic RT may prolong progression-free survival in patients with partial or complete response to chemotherapy.

Brain Metastases

• Whole-brain radiotherapy is standard for symptomatic metastases.
• Asymptomatic cases may defer RT during initial chemotherapy with MRI surveillance.

Spinal Cord Compression

• Immediate high-dose corticosteroids followed by urgent MRI.
• Definitive treatment includes RT and/or neurosurgical decompression.

Supportive and Complication Management

Hyponatraemia and SIADH

• Occurs in 5–10% of SCLC due to ectopic ADH production.
• Management includes fluid restriction and demeclocycline in severe cases.

Tumour Lysis Syndrome

• May occur rapidly after treatment initiation.
• Prevention includes hydration and allopurinol; management may require dialysis.

Nutritional Support

• Weight loss is a poor prognostic factor; dietician consultation is advised.

Monitoring and Long-Term Follow-Up

• Blood counts, renal function, and LDH levels should be monitored throughout treatment.
• CT imaging after two chemotherapy cycles is essential to assess response.
• Smoking cessation significantly improves survival outcomes.

Survival Outcomes by Stage

• Prognosis in SCLC is primarily determined by stage at diagnosis.
• Limited-stage disease (LD-SCLC), when treated with combined chemotherapy and thoracic radiotherapy, has reported complete response rates of up to 80%, with median survival around 17 months.
• Historically, 5-year survival for LD-SCLC ranges from 12–15%, though more recent estimates suggest improvement to approximately 30–35% with the integration of immunotherapy.
• Extensive-stage disease (ES-SCLC) is associated with a poorer prognosis and is generally considered incurable.
• Combination chemotherapy alone yields complete responses in over 20% of patients, but median survival is typically 7–13 months, with 5-year survival remaining below 5%.

Impact of Immunotherapy

• Recent randomised trials have shown survival benefit with the incorporation of immune checkpoint inhibitors.
• In the ADRIATIC trial, the addition of durvalumab as consolidation therapy after chemoradiotherapy in LD-SCLC improved median overall survival to 55.9 months, compared with 33.4 months in the control arm.
• For ES-SCLC, the IMpower133 and CASPIAN trials demonstrated improved survival with atezolizumab or durvalumab added to platinum-etoposide chemotherapy, achieving median overall survival in the range of 12–13 months.
• These immuno-oncology advances mark a meaningful shift from two decades of stagnant survival outcomes.

Relapsed Disease

• Recurrent SCLC, particularly within six months of initial therapy, confers a dismal prognosis.
• The duration of response to initial therapy is a key determinant of outcome in relapse.
• Response rates and survival decline significantly in platinum-resistant or refractory cases, reinforcing the need for clinical trial enrolment in this setting.

Molecular Predictors and Emerging Biomarkers

• Genome-wide association studies have identified polymorphisms—such as in the promoter region of the YAP1 gene on chromosome 11q22—that may influence prognosis in SCLC.
• Expression of SLFN11 has emerged as a potential predictive biomarker for benefit from DNA-damaging agents and PARP inhibitors, though not yet adopted into routine prognostic stratification.
• Ongoing studies are evaluating newer biomarkers and targets including DLL3 to guide treatment and prognostication.

Prognostic Factors

• Beyond staging, several clinical features are associated with worse outcomes:
  • Poor performance status (ECOG ≥2)
  • Significant weight loss (>10% of baseline body weight)
  • Hyponatraemia, often a manifestation of SIADH, is linked to shortened survival
  • Relapsed or refractory disease
  • Continued tobacco use following diagnosis, which promotes resistance to chemotherapy and decreases survival

Treatment-Related Complications

Haematological Toxicity

• Chemotherapy commonly results in cytopenias including anaemia, neutropenia, and thrombocytopenia.
• Consequences include febrile neutropenia, bleeding, and the need for transfusions or hospitalisation.
• Myelosuppression is more frequent with concurrent chemoradiotherapy.
• In extensive-stage SCLC, agents like granulocyte-colony stimulating factor (G-CSF) or trilaciclib may be used to mitigate myelosuppression risk.
• G-CSF is not advised during concurrent chemoradiotherapy due to increased toxicity risk.

Immune-Related Adverse Events (irAEs)

• Immune checkpoint inhibitors can trigger a spectrum of toxicities not typically seen with cytotoxic agents.
• Common irAEs include pneumonitis, colitis, hepatitis, endocrinopathies (e.g., hypothyroidism), and myositis.
• High-grade toxicities require cessation of immunotherapy and treatment with corticosteroids (prednisolone 40–60 mg/day tapered over 4–6 weeks).
• Additional immunosuppressants like infliximab may be necessary in steroid-refractory cases.
• Endocrine toxicities manageable with hormone replacement may allow continuation of therapy.

Radiotherapy-Induced Oesophageal Injury

• Acute oesophagitis often develops 3–4 weeks after initiation of thoracic radiotherapy and may persist post-treatment.
• Symptoms include odynophagia and dysphagia; in severe cases, hospitalisation or PEG tube placement may be required.
• Late complications include oesophageal stricture or rare tracheo-oesophageal fistula.
• Endoscopic dilation is used for stricture management.

Radiation-Induced Lung Injury

• Radiation pneumonitis typically presents 1–6 months post-therapy with dry cough, dyspnoea, or fever.
• Diagnosis is clinical and made by excluding infection; imaging is often unremarkable.
• Treated with corticosteroids (e.g., oral prednisolone, tapered gradually).
• Chronic fibrosis may develop and, although often asymptomatic, can be debilitating in patients with compromised baseline lung function.

Disease-Related Complications

Post-Obstructive Pneumonia and Hypoxia

• Tumour-induced bronchial obstruction can lead to distal atelectasis and secondary infection.
• Symptoms may be atypical and chest radiographs may be inconclusive due to underlying malignancy.
• Prompt antibiotics are essential, and relieving the obstruction may involve:
  • Endobronchial stenting
  • Photodynamic therapy
  • Laser resection
  • External beam or brachytherapy
  • Surgical resection

Superior Vena Cava Syndrome (SVCS)

• Caused by external compression of the SVC by a tumour or mediastinal lymphadenopathy.
• Symptoms include facial swelling, upper extremity oedema, dyspnoea, and venous distension.
• Supportive measures include oxygen and head elevation.
• Definite treatment includes chemotherapy, radiotherapy, or endovascular stenting depending on urgency and disease burden.
• Surgical intervention is rarely required.

Massive Haemoptysis

• Infrequent but potentially life-threatening complication of centrally located or eroding tumours.
• Defined as expectoration of >30 mL of blood within 24 hours.
• Requires urgent assessment with bronchoscopy to identify source.
• Palliative radiotherapy or endobronchial intervention may be used for haemostasis.
• Prophylactic radiation is not routinely employed for this purpose.

Paraneoplastic and Endocrine Syndromes

Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)

• Occurs in 5–10% of patients with SCLC due to ectopic production of ADH.
• Hyponatraemia may present with lethargy, confusion, or seizures in severe cases.
• Diagnosis is supported by low serum sodium and exclusion of other causes.
• Treated with fluid restriction and demeclocycline or vasopressin receptor antagonists in refractory cases.

Ectopic ACTH Production

• Leads to Cushing’s syndrome with associated hyperglycaemia, hypokalaemia, and muscle weakness.
• Management focuses on tumour-directed therapy and supportive endocrine treatment.

Neurological Paraneoplastic Syndromes

• Conditions such as Lambert-Eaton myasthenic syndrome, cerebellar degeneration, or limbic encephalitis may occur.
• Response to tumour therapy varies; immunosuppressants may be required in some cases.

1. American Cancer Society. Cancer Facts & Figures 2024. ACS.
2. Arriagada R, Le Chevalier T, Borie F, et al. Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. N Engl J Med. 1995;332(20):1295–1300.
3. Arriagada R, Pignon JP, et al. Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. N Engl J Med. 1999;341(7):476–484.
4. Borromeo MD, Savage TK, Kollipara RK, et al. ASCL1 and NEUROD1 Reveal Heterogeneity in Pulmonary Neuroendocrine Tumors. Cell Rep. 2016;16:1259–1272.
5. Campling BG, Sarda IR, Baer KA, et al. Secretion of atrial natriuretic peptide and vasopressin by small cell lung cancer. Cancer. 1995;75(10):2442–2451.
6. Carney DN, Gazdar AF, Nau MM, Minna JD. Characterization of variant subclasses of cell lines derived from small cell lung cancer. Cancer Res. 1985;45:2924–2930.
7. D'Amico D, Carbone D, Mitsudomi T, et al. High frequency of somatically acquired p53 mutations in small-cell lung cancer cell lines and tumors. Oncogene. 1992.
8. Ettinger DS, Aisner J. Changing face of small-cell lung cancer: real and artifact. J Clin Oncol. 2006;24(28):4526–4532.
9. Farago AF, Yeap BY, et al. Combination Olaparib and Temozolomide in Relapsed SCLC. Cancer Discov. 2019;9(10):1372–1387.
10. Field RW, Krewski D, Lubin JH, et al. An overview of the North American and European residential radon lung cancer epidemiologic pooling studies. J Toxicol Environ Health A. 2006;69(7-8):599–631.
11. Gazdar AF, Bunn PA, Minna JD. Small-cell lung cancer: what we know, what we need to know and the path forward. Nat Rev Cancer. 2017;17(12):725–737.
12. Gay CM, Stewart CA, Park EM, et al. Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with therapeutic implications. Cancer Cell. 2021;39(3):346–360.
13. Govindan R, Page N, Morgensztern D, et al. Changing epidemiology of small-cell lung cancer in the United States over the last 30 years. Cancer. 2006;107(3):823–829.
14. Guinee DG Jr, Fishback NF, Koss MN, et al. The spectrum of immunohistochemical staining of small-cell lung carcinoma. Am J Clin Pathol. 1994;102(4):406–414.
15. Goto K, Sekine I, et al. Phase III study of combination chemotherapy in sensitive relapsed SCLC. Lancet Oncol. 2016;17(8):1147–1157.
16. Gay CM, Stewart CA, Park EM, et al. Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC. Cancer Cell. 2021;39:346–360.
17. Horn L, Mansfield AS, Szczęsna A, et al. First-Line Atezolizumab plus Chemotherapy in Extensive-Stage SCLC. N Engl J Med. 2018;379(23):2220–2229.
18. Jemal A, Miller KD, Ma J, Siegel RL. Higher lung cancer incidence in young women than young men in the United States. NEJM. 2018;378(21):1999–2009.
19. Jemal A, Thun MJ, Ries LA, et al. Annual report to the nation on the status of cancer, 1975–2005. JNCI. 2008;100(3):167–180.
20. Marcoux N, Gettinger SN, O'Kane G, et al. EGFR-mutant adenocarcinomas that transform to small-cell carcinoma. J Clin Oncol. 2019;37:278–285.
21. Maione P, Rossi A, Sacco PC, et al. Treatment of small cell lung cancer. Curr Treat Options Oncol. 2011;12(4):327–343.
22. Møller J, Hellmund V, Hilberg O, Løkke A. Sarcoidosis. Ugeskr Laeger. 2018;180(34).
23. Paz-Ares L, Dvorkin M, Chen Y, et al. Durvalumab plus platinum–etoposide in first-line treatment of extensive-stage SCLC (CASPIAN): a phase 3 trial. Lancet. 2019;394(10212):1929–1939.
24. Parsons A, Daley A, Begh R, et al. Influence of smoking cessation after diagnosis on prognosis of early stage lung cancer. BMJ. 2010;340:b5569.
25. Pietanza MC, Waqar SN, Krug LM, et al. Randomized study of TMZ plus veliparib or placebo in relapsed SCLC. J Clin Oncol. 2018;36(23):2386–2394.
26. Rekhtman N, Tischfield SE, Febres-Aldana CA, et al. Chromothripsis-Mediated Small Cell Lung Carcinoma. Cancer Discov. 2025;15:83–98.
27. Sequist LV, Waltman BA, Dias-Santagata D, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med. 2011;3(75):75ra26.
28. Sher E, Gotti C, Canal N, et al. Specificity of calcium channel autoantibodies in Lambert-Eaton myasthenic syndrome. Lancet. 1989;2(8664):640–643.
29. Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA Cancer J Clin. 2023;73(1):17–48.
30. Slotman BJ, Faivre-Finn C, et al. Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med. 2007;357:664–672.
31. Spigel DR, Faivre-Finn C, Gray JE, et al. Durvalumab after chemoradiotherapy in limited-stage small-cell lung cancer. N Engl J Med. 2024;390:421–432.
32. Subramanian J, Govindan R. Lung cancer in never smokers: a review. J Clin Oncol. 2007;25(5):561–570.
33. Tlemsani C, Takahashi N, Pongor L, et al. Whole-exome sequencing reveals germline-mutated SCLC subtype responsive to DNA repair-targeted therapies. Sci Transl Med. 2021;13:eabc7488.
34. Thun MJ, Carter BD, Feskanich D, et al. 50-year trends in smoking-related mortality in the United States. NEJM. 2013;368(4):351–364.
35. Travis WD, Brambilla E, Nicholson AG, et al. The 2015 World Health Organization Classification of Lung Tumors. J Thorac Oncol. 2015;10(9):1243–1260.
36. Wang Q, Gümüş ZH, Colarossi C, et al. SCLC: Epidemiology, Risk Factors, Genetic Susceptibility, Molecular Pathology, Screening, and Early Detection. J Thorac Oncol. 2023;18(1):31–44.
37. Wang Q, Gümüş ZH, Colarossi C, et al. SCLC: Epidemiology, Risk Factors, Genetic Susceptibility, Molecular Pathology, Screening, and Early Detection. J Thorac Oncol. 2023;18(1):31–44.
38. Wistuba II, Behrens C, Virmani AK, et al. High resolution chromosome 3p allelotyping in human lung cancer. Cancer Res. 2000;60:1949–1958.
39. Wang Q, Gümüş ZH, Colarossi C, et al. SCLC: Epidemiology, Risk Factors, Genetic Susceptibility, Molecular Pathology, Screening, and Early Detection. J Thorac Oncol. 2023;18(1):31–44.