I. What every physician needs to know.

Small-cell lung cancer (SCLC) is a malignant epithelial tumor of the lung/bronchus with neuroendocrine properties which morphologically appears as small, round or oval cells with scant cytoplasm and inconspicuous nucleoli. These features were the basis for 1967 WHO classification of oat cell carcinoma, which later was revised to small-cell carcinoma.

Lung tumorigenesis is hypothesized to arise from cancer stem cells capable of differentiation. A causal relationship between tobacco smoking and development of SCLC is well established. SCLC accounts for about 15% of all lung cancers and is distinguished from non-small-cell lung cancer by its rapid tumor cell doubling time and earlier development of widespread metastases. These tumors tend to be highly responsive to chemotherapy and radiotherapy.

II. Diagnostic Confirmation: Are you sure your patient has small-cell lung cancer?

In patients suspected of having small cell lung cancer based on radiographic or clinical findings, the diagnosis should be confirmed by the least invasive and safest method. Cytology examination of sputum, bronchial brushing or washing specimen(s), or pleural fluid may be adequate to establish a definitive diagnosis. If not, tissue usually can be obtained by endobronchial biopsy, transbronchial biopsy, percutaneous needle core biopsy or mediastinoscopy. The majority of SCLCs are immunoreactive for cytokeratin and TTF-1. Most are immunopositive for the neuroendocrine markers chromogranin A, neuron-specific endolase and synaptophysin. The Ki-67 labeling index is usually high.

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A. History Part I: Pattern Recognition:

SCLC arises in the central airways and often presents as a large central mass involving the mediastinum. It is rarely diagnosed in an asymptomatic patient. Frequent symptoms at the time of presentation include fatigue, cough, dyspnea, weight loss, chest pain, and hemoptysis. Superior vena cava (SVC) syndrome is more common in SCLC than in non-small-cell lung cancer.

Typical signs/symptoms of SVC syndrome include dyspnea, chest pain, hoarseness, wheezing, stridor, prominence of neck or chest wall vasculature, facial plethora and facial and periorbital edema, cyanosis, and alteration of mental status.

Most patients have distant tumor spread at diagnosis. Metastases to the brain, liver, bone, or bone marrow often results in organ-specific symptomatology or laboratory abnormalities. Adrenal gland metastases is typically asymptomatic. SCLC can metastasize to virtually any organ.

Paraneoplastic syndromes are associated with SCLC. Cushing syndrome caused by ectopic adrenocorticotropic hormone production is the most common. Hyponatremia, which can be severe, may result from inappropriate anti-diuretic hormone production or ectopic production of atrial natriuretic factor. Neurologic paraneoplastic manifestations include subacute peripheral neuropathy associated with anti-Hu antibody, Lambert-Eaton myasthenic syndrome, multifocal encephalomyelitis, retinopathy and cerebellar degeneration. Hypercalcemia is rare in SCLC.

A typical patient story for SCLC is a 71-year old man with a 75 pack a year history of tobacco smoking, who has new onset of a cough and progressive dyspnea over the prior 3 months and now exhibits weight loss, decreased appetite and fatigue. A chest X-ray obtained at the time of initial presentation may show a large hilar mass with bulky mediastinal adenopathy.

B. History Part 2: Prevalence:

SCLC comprises about 15% of all lung cancers. Lung cancer incidence rates began decreasing in the mid-1980s in men and in the mid-2000s in women as a result of decline in smoking prevalence over the previous decades.

Tobacco smoking is linked to SCLC in about 95% of cases. It is suggested that the risk of developing lung cancer in former smokers will approximate but not equal the risk in a never-smoker. Second-hand exposure increases the risk of lung cancer by 20–30% when compared to the general population. There is evidence that the combined effect of radon exposure and tobacco smoke is multiplicative.

Asbestos and tobacco smoke act synergistically to increase the risk of lung cancer. Other risk factors for development of lung cancer include chloromethyl ether, polycyclic aromatic hydrocarbons, silica, chromium, nickel, arsenic, and ionizing radiation therapy.

C. History Part 3: Competing diagnoses that can mimic small-cell lung cancer.

Non-small-cell lung cancer, carcinoid tumor, large cell neuroendocrine tumor, lymphoma, extragonadal germ-cell tumor, sarcoma, and metastatic tumor spread to the lung from another primary location, such as colon/rectum, head/neck, and kidney can mimic SCLC. The differential diagnosis also includes pulmonary infection and inflammation.

D. Physical Examination Findings.

The extent of disease and location of the tumor determine the physical findings.

The physical examination findings in localized early disease may be normal or non-specific. Intra thoracic tumor can cause dyspnea, wheeze, stridor, diminished breath sounds or rales or rhonchi, dullness to percussion of the lungs, tracheal deviation, upper body edema, Horner’s syndrome, brachial plexopathy, or spinal cord impingement manifest by sensory or motor neurologic deficits.

Patients with local regional disease can develop palpable, abnormally enlarged peripheral lymphadenopathy, especially in the supraclavicular region.

The physical examination findings in patients with distant metastases is organ-specific. Patients may also exhibit generalized weakness, weight loss or cachexia.

E. What diagnostic tests should be performed?

The diagnosis of SCLC should be confirmed by the least invasive and safest method. Cytology examination of sputum, bronchial brushing or washing specimen(s), or pleural fluid may be adequate. If not, tissue usually can be obtained by endobronchial biopsy, transbronchial biopsy, percutaneous needle core biopsy, or mediastinoscopy.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

The initial evaluation for SCLC should include a complete blood count and platelet count, serum electrolytes, serum calcium, blood urea nitrogen (BUN), serum creatinine, total bilirubin, liver transaminases, serum albumin, and serum lactate dehydrogenase, which is a prognostic indicator.

There is no specific tumor marker for SCLC.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology Small Cell Lung Cancer Version 1.2016 recommendations include:

  • Computed tomography (CT) chest/thorax/liver/adrenals with IV contrast enhancement, whenever possible.

  • Magnetic resonance imaging (MRI) brain with contrast enhancement (preferred) or CT head/brain with IV contrast enhancement.

  • PET-CT scan when limited stage is suspected. Bone radiographs or MRI as appropriate if PET-CT is equivocal. If PET-CT is not available, bone scan may be used to identify osseous metastasis. Pathologic confirmation is recommended for hypermetabolic lesions evident on PET-CT that could alter stage.

  • Unilateral bone marrow aspiration/biopsy in select patients with limited stage disease confined to the thorax who have nucleated red blood cells present on peripheral smear, neutropenia or thrombocytopenia suggestive of bone marrow infiltration.

  • If pleural effusion is present in select patients with limited stage disease, thoracentesis is recommended; if thoracentesis is inconclusive, consider thoracoscopy.

III. Default Management.

A. Immediate management.

Small cell lung cancer is a biologically aggressive malignancy which requires immediate diagnosis and therapeutic intervention. The staging work-up should not delay initiation of treatment by more than one week.

Alteration of mental status, focal neurologic deficit or seizure warrants urgent evaluation with MRI of the brain. Immediate initiation of dexamethasone is indicated in symptomatic brain metastases and prompt evaluation by a neurosurgeon and radiation oncologist is advised.

A delay in evaluation and treatment of spinal cord compression (SCC) can result in permanent bowel/bladder dysfunction or paralysis. Approximately 70% of SCC occur in the thoracic region. Symptoms progress from dull, aching, constant, and worsening back pain to paresthesia of extremities, then motor weakness, ataxia and autonomic dysfunction. A clinical suspicion of SCC should trigger initiation of therapy with dexamethasone. MRI of the entire spine with contrast enhancement is the preferred study for imaging of the central nervous system in cancer patients suspected to have SCC.

Superior vena cava syndrome can result in life-threatening increase in intracranial pressure or airway compromise. Clinical signs/symptoms may develop suddenly. Emergency treatment with radiation therapy is indicated in the setting of respiratory compromise or development of neurologic symptomatology.

B. Physical Examination Tips to Guide Management.

Monitor for:

  • Alteration of mental status

  • Hemodynamic instability

  • Tachypnea

  • Fever

  • Weight loss

  • Pallor

  • Hearing impairment

  • Distension of neck veins

  • Presence of rales

  • Rhonchi, wheezes or dullness to percussion on lung examination

  • New heart murmur

  • Development of a friction rub

  • Peripheral edema

  • Presence of jaundice

  • Ascites

  • Hepatomegaly

  • Splenomegaly

  • Peripheral sensory loss or focal motor weakness

  • Muscle atrophy

  • Ataxia

  • Loss of coordination

  • Gait disturbance

  • Skin or nail changes

  • Bone/vertebrae tenderness

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

A CBC with differential cell count, complete metabolic panel including LDH and serum magnesium should be obtained before initiation of chemotherapy and prior to administration of subsequent cycles. Dose modification may be recommended for renal or hepatic impairment or severe hematologic or non-hematologic toxicity. Adjustment in management may be indicated if the patient develops progression of tumor or inability to tolerate treatment.

Patients admitted to the hospital with complications of chemotherapy may require daily laboratory monitoring.

D. Long-term management.

Long-term management depends on the initial response to chemotherapy. For patients with limited stage or extensive stage SCLC who achieve a complete or partial response to initial therapy and have absence of brain metastasis on recent MRI, prophylactic cranial irradiation (PCI) may prolong overall survival. In patients not receiving PCI, surveillance brain imaging should be considered. PCI is not recommended for patients with poor performance status. Consolidative thoracic radiotherapy is beneficial for select patients with low-bulk metastatic disease and complete response or near complete response after initial systemic therapy. The National Comprehensive Cancer Network Guidelines for Small Cell Lung Cancer Version 1.2016 recommends surveillance with oncology follow-up visits every 3–4 months during the first two years, every 6 months during years 3–5, then annually. At each visit, a detailed history and physical examination should be done, and chest imaging and bloodwork obtained, as clinically indicated. A new pulmonary nodule should initiate work-up for potential new primary malignancy. Smoking cessation intervention should be strongly urged. PET-CT is not recommended for routine monitoring.

For patients with progressive disease after initial therapy and good performance status, subsequent chemotherapy with topotecan can be considered. Eligible patients may be offered participation in a clinical trial, if available. Alternatively, palliative best supportive care management alone can be considered.

E. Common Pitfalls and Side-Effects of Management

Surgical resection is appropriate only for select patients who have node negative stage I SCLC. Prior to surgical resection, all patients should undergo mediastinal staging to exclude nodal disease. Patients who undergo complete surgical resection should receive adjuvant systemic treatment with chemotherapy.

Elderly patients who are functional in terms of performance of usual activities of daily living should be offered standard treatment. However, older patients have lower organ reserve and must be closely monitored during treatment.

The list of potential side effects related to chemotherapeutic agents used to treat SCLC is extensive. Patients who receive chemotherapy may experience asthenia, fatigue, appetite loss, dehydration, alteration of taste, mucositis, myelosuppression, anemia, thrombocytopenia, immunosuppression and increased risk of serious infection, nausea, vomiting, diarrhea, constipation, renal toxicity, hepatic toxicity, electrolyte imbalance, peripheral sensory or motor neuropathy, autonomic dysfunction, amenorrhea, azoospermia, sterility, impotence, alopecia, immediate hypersensitivity reaction, skin and nail changes, secondary malignancy, secondary myelodysplasia or acute leukemia. Adverse effects of thoracic radiotherapy include but are not limited to radiation pneumonitis, radiation esophagitis, and skin changes.

IV. Management with Co-Morbidities

A. Renal Insufficiency.

  • For cisplatin, a 50% dose reduction is recommended if the serum creatinine clearance is 30–60 ml/min. Omit cisplatin if the serum creatinine clearance is less than 30 ml/min.

  • No dose reduction for carboplatin is recommended if the serum creatinine clearance is greater than 60 ml/min.

  • For etoposide, a 25% dose reduction is recommended if the serum creatinine clearance is 10–50 ml/min, and a 50% dose reduction is recommended if the serum creatinine clearance is less than 10 ml/min.

  • No dose reduction is necessary for irinotecan.

  • Cisplatin, carboplatin, and etoposide can be used to treat hemodialysis patients.

B. Liver Insufficiency.

  • For etoposide, a 50% dose reduction is recommended if the serum total bilirubin level is between 1.5–3.0 mg/dl or SGOT is between 60–180 mg/dl. Use of etoposide is not recommended if the bilirubin is greater than 3.0 mg/dl or SGOT larger than 180 mg/dl.

  • There is no formal recommendation for dose reduction of irinotecan in the presence of liver insufficiency, but dose reduction may be necessary.

  • No dose modification is necessary for cisplatin or carboplatin.

C. Systolic and Diastolic Heart Failure

  • Chemotherapy is not recommended for use in patients with decompensated heart failure. The chemotherapeutic agents used to treat SCLC are administered intravenously. Cisplatin requires pre- and post-hydration administered at a vigorous rate of infusion.

  • Neither cisplatin nor carboplatin require dose modification in asymptomatic heart failure.

D. Coronary Artery Disease or Peripheral Vascular Disease

  • Chemotherapy is contraindicated for use in patients with active, symptomatic vascular disease.

  • Stabilization of the patient is required before initiation of chemotherapy. No dose adjustment is necessary.

E. Diabetes or other Endocrine issues

  • No dose adjustment is required.

  • The decision to treat with chemotherapy should be individualized.

F. Malignancy

  • History of malignancy is not a contraindication to treatment.

  • Prior radiotherapy or chemotherapy must be taken into consideration.

  • Patients with history of malignancy might not meet eligibility criteria for participation in a clinical trial.

G. Immunosuppression (HIV, chronic steroids, etc).

  • There is no absolute contraindication for the use chemotherapy.

  • HAART therapy should be optimized in patients with HIV.

  • Patients with chronic immunosuppression from comorbidities are at increased risk to develop bacterial, viral, fungal, or atypical infections during chemotherapy.

  • Prophylactic antifungal, antiviral, and/or antimicrobial therapy should be used as indicated.

H. Primary Lung Disease (COPD, Asthma, ILD)

  • There is no absolute contraindication for the use of chemotherapy.

  • Patients with acute exacerbation should be stabilized prior to the initiation of chemotherapy.

I. Gastrointestinal or Nutrition Issues

  • There is no absolute contraindication for the use of chemotherapy.

  • Anorexia, nausea, vomiting, and diarrhea are common chemotherapy side effects.

  • Maintenance of adequate hydration and avoidance of dehydration, electrolyte imbalance, and weight loss during treatment is especially important.

  • Patients with limited stage disease undergoing concomitant chemoradiation are at increased risk to develop radiation esophagitis and impaired ability to maintain adequate oral intake. Nutritional supplementation may be necessary.

J. Hematologic or Coagulation Issues

  • Chemotherapy should not be given to patients with active, uncontrolled bleeding.

  • Treat acute thromboembolic events according to standard guidelines.

  • Warfarin has a potential drug-drug interaction with many chemotherapy agents.

  • Dose modification or drug discontinuation may be recommended for severe hematologic toxicity or prolonged hematologic recovery delay.

K. Dementia or Psychiatric Illness/Treatment

  • There is no absolute contraindication to the use of chemotherapy.

  • Patients must be competent to give informed consent for treatment or have assigned power of attorney.

V. Transitions of Care

A. Sign-out Considerations While Hospitalized.

The on-call oncologist should be immediately contacted if a patient receiving chemotherapy exhibits adverse reaction to treatment.

B. Anticipated Length of Stay.

The anticipated length of stay is dependent upon the admission diagnosis, therapeutic intervention received, and hospital course.

C. When is the Patient Ready for Discharge.

Discharge is dependent upon the admission diagnosis, therapeutic intervention received, and hospital course.

D. Arranging for Clinic Follow-up

1. When should clinic follow up be arranged and with whom

Outpatient follow-up with the patient’s oncologist should be arranged within 1–2 weeks after hospital discharge.

2. What tests should be conducted prior to discharge to enable best clinic first visit.

The patient’s oncologist should be contacted prior to discharge to provide guidance with post-discharge arrangements.

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.

The patient’s oncologist should be contacted prior to discharge to provide guidance with post-discharge arrangements.

E. Placement Considerations.

Certain patients with advanced malignancy who are not candidates for disease-specific therapy or who elect best supportive care management alone instead of disease-specific treatment may be considered for hospice placement.

F. Prognosis and Patient Counseling.

In addition to staging, weight loss and performance status are important prognostic indicators. Chronologic age by itself has not been identified as an independent prognostic factor. Female gender and very limited pulmonary parenchymal tumor involvement have been associated with better outcome in limited stage SCLC. Mediastinal tumor involvement and ipsilateral supraclavicular adenopathy have been associated with worse outcome in patients with limited stage small-cell lung cancer.

In extensive stage SCLC, the site and number of metastases correlate with worse prognosis. An elevated serum lactate dehydrogenase level is associated with more extensive tumor burden and worse outcome.

VI. Patient Safety and Quality Measures

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

Patients undergoing chemotherapy should be closely monitored in the outpatient setting to avoid excessive risk of treatment. Prophylactic use of growth factor support, if appropriate, may prevent recurrent severe neutropenia which increases risk for infection and readmission.

Patients with psychosocial issues may benefit from counseling by a trained clinical psychologist. Assessment to identify and eliminate barriers to health care can result in better patient outcomes. Early introduction of palliative care management improves patient quality of life and reduces need for repeat hospitalization.

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