Nearly all patients with SCLC present with symptomatic disease, and less than 10% of lung cancer patients will be diagnosed prior to clinical presentation of symptoms.¹ More effective screening, including use of chest x-rays, and more recently, low-dose spiral computed tomography (CT) scanning, as well as more sensitive molecular or genomic techniques may allow for improvement in the ability to diagnose this disease at an earlier stage,² but SCLC will likely be the more difficult histologic subtype to find early because of its proclivity for early dissemination. Lung cancer also tends to affect the elderly population, and nearly half of all patients presenting with SCLC will be older than the age of 60 years.³

A thorough understanding of the symptoms associated with SCLC can help in the appropriate diagnostic workup and, ultimately, in more effective control of these symptoms in these patients. Clinical reports have identified the most common symptoms at the time of presentation.⁴ Table 24.1⁵ delineates the frequency of these various signs and symptoms.⁶ These can be classified as localized symptoms from the primary tumor, regional spread of disease, and distant effects from metastatic disease, as well as general symptoms, which may be attributed to a paraneoplastic effect. Presenting symptoms can also help predict prognosis in this disease.⁷ It has been shown that early presentation of lung cancer is often associated with a specific pattern of symptoms.⁸ Limited versus extensive disease stage, the fewer sites of metastatic involvement, good performance status, and absence of weight loss are all consistently found to correlate with survival in this disease.⁹

General Systemic SymptomsMost patients with lung cancer, and particularly SCLC, present with symptoms from their disease. Generalized systemic symptoms can include fatigue, anorexia, weight loss, and depression. These symptoms occur to a greater degree than would be expected for the extent of tumor spread.

Attempts have been made to investigate the etiology for the anorexia/cachexia syndrome associated with malignant disease, including lung cancer. This syndrome has been described as the most common cause of death in cancer patients.¹⁰ Cachexia comes from Greek meaning “bad condition” and causes significant morbidity in lung cancer patients. No definite etiology has been determined, but loss of appetite and weight loss are commonly attributed to circulating cytokines.¹¹ Up to 40% of patients may experience anorexia and cachexia,¹² often requiring interventions to improve appetite and weight gain.

Fatigue is another presenting symptom commonly associated with lung cancer.¹³ Commonly found at presentation, fatigue can be exacerbated by antineoplastic therapy including surgery, radiation, chemotherapy, and biologics. Evaluation for contributing secondary causes of fatigue, including anemia, endocrine dysfunction, and depression can identify readily treatable and reversible causes. Treatment of the primary tumor may be the most effective way to manage this symptom.

Depression can be another symptom in lung cancer patients.¹⁴ With such a poor prognosis, reactive depression is a common initial reaction to a lung cancer diagnosis. Other factors may be involved in the development of depression in patients with lung cancer. Recent clinical trials have demonstrated that quality of life can be severely impacted by a diagnosis of lung cancer. Contributing to the depression are the specific symptoms from the disease as well as the psychosocial adjustment necessary with this diagnosis and its associated
treatments.¹⁵ Further refinement of quality of life analysis in lung cancer patients is being attempted by several groups.¹⁶

Paraneoplastic symptoms associated with SCLC will be discussed later in this chapter. These symptoms are characterized by a systemic manifestation of disease not explained by local tumor effects.

Local SymptomsSCLC frequently presents as a large central tumor, often with symptoms of bronchial obstruction. Therefore, many patients present with local symptoms at the time of diagnosis of lung cancer.¹⁷ Most commonly observed are chest pain, cough, and shortness of breath.¹⁸ Cough occurs in lung cancer patients when the tumor irritates bronchial nerve fibers or leads to increased sputum production or atelectasis. Obstruction of the airway may lead to postobstructive atelectasis and/or pneumonia. These symptoms are present in at least 50% of patients at the time of diagnosis and develop in many of the remaining patients.¹⁹ Chest x-ray can identify sites of disease and evidence for postobstructive changes. A CT scan and possibly fiberoptic bronchoscopy are necessary to identify the exact location of the tumor and to help determine appropriate ways to manage respiratory symptoms.

Central tumors can erode into blood vessels, and cough can be associated with bleeding. Hemoptysis has been noted to occur in up to 35% of patients presenting with lung cancer.²⁰ Hemoptysis does not necessarily imply more advanced disease but can be associated with cavitation or local extension into blood vessels. In fact, hemoptysis does not in and of itself imply malignancy.²¹ Hemoptysis at times can be mild or can lead to fatal hemorrhage in lung cancer patients. Therefore, management of hemoptysis depends on the severity and specific etiology of the process. Various techniques from surgical resection, to external beam radiation, to bronchoscopic techniques including laser treatment, brachytherapy, cryotherapy, or photodynamic therapy can control symptoms effectively.²²

Chest pain is another common symptom in SCLC, occurring in up to 49% of patients who present with primary lung cancer.²³ Pain is generally not caused by a primary tumor in the lung parenchyma, but it can be associated with chest wall involvement or local extension of disease affecting adjacent nerve fibers. Chest pain can also be attributed to unrelated causes, such as cardiac disease, esophageal disease, or vascular disease such as aortic dissection. Thus, careful evaluation of lung cancer patients with chest pain is crucial. Alternatively, lung cancer can be diagnosed serendipitously in patients presenting with acute chest pain of unrelated etiology when the chest radiograph or CT identifies a pulmonary nodule or mass.

Dyspnea or shortness of breath is also common in patients with SCLC.²⁴ Primary tumors are unlikely to directly result in true hypoxia. However, more advanced disease, such as obstructing tumors, lymphangitic cancer spread, or central lesions that produce significant sputum can be a cause of dyspnea in these patients. Evaluation of the differential diagnosis of shortness of breath is important to determine the underlying etiology, even in patients with malignancy. Patients may have underlying pulmonary pathology resulting from chronic obstructive pulmonary disease (COPD), and acute events such as pulmonary embolism, congestive heart failure, pneumonia, pneumothorax, and cardiac ischemia are also possibilities. In addition, regional extension and pleural effusion with compression of the remaining lung can lead to shortness of breath in this population. A thorough workup for other causes of dyspnea is necessary in lung cancer patients with worsening shortness of breath.

Lung cancer patients also present with wheezing, which can be wrongly attributed to reactive airway disease such as asthma or COPD. Obstructing pulmonary lesions can lead to wheezing in SCLC patients and should be thoroughly evaluated. Primary treatment techniques such as radiation and chemotherapy may be useful in controlling this symptom, as can standard medical therapy such as bronchodilators or corticosteroids.

Involvement of the heart or pericardium can result in tachyarrhythmias. These can present with palpitations or lightheadedness. Unexplained tachycardia in lung cancer patients should be evaluated with an electrocardiogram and/or echocardiogram whenever pericardial involvement is suspected. Pericardial metastasis or effusion may be the offending etiology, and urgent attention may benefit this population.

Locally advanced SCLC can produce esophageal compression from the primary tumor or mediastinal lymphadenopathy. Patients may have dysphagia or odynophagia, and should be evaluated endoscopically or with upper gastrointestinal imaging to evaluate the etiology of the dysphagia. Local radiation provides appropriate palliation but occasionally stenting can be helpful.²⁵ Particularly in SCLC, chemotherapy may provide adequate tumor shrinkage for symptom relief.

Multimodality management of SCLC patients with significant pulmonary symptoms including a thoracic surgeon, pulmonologist, primary care physician, radiation oncologist,
radiologist, and medical oncologist leads to the most effective management of these local symptoms from lung cancer.

Regional MetastasisSCLC is notorious for its regional symptoms from locally advanced disease. Growth to adjacent structures near the lung as well as involvement of regional lymph nodes lead to these symptoms in patients with locally advanced disease. Patients with right-sided tumors can develop superior vena cava (SVC) obstruction as a result of the primary cancer or involvement of lymph nodes in the right paratracheal area. This can lead to the clinical manifestation, SVC syndrome. This is typically characterized by swelling of the arms, neck, face, and head. This syndrome can also be associated with shortness of breath, cyanosis, headaches, nausea, blurred vision, and more serious neurological sequelae.²⁶ This syndrome can also be associated with distention or dilatation of the neck and chest wall veins because of collateral blood flow. SVC syndrome can appear indolently, delaying diagnosis because of the slow changes that occur. More rapidly growing tumors or thrombosis associated with SVC syndrome can lead to a more acute presentation with rapidly developing symptoms.

In SCLC, SVC syndrome occurs in 10% to 15% of patients, more commonly than in non-small cell carcinoma.²⁷ A careful differential diagnosis is important in patients with SVC syndrome. Other malignancies including breast cancer and lymphoma, as well as other mediastinal tumors and occasionally benign disease such as tuberculosis or other infections can cause SVC syndrome and need to be considered in the differential diagnosis.

For patients presenting with SCLC and SVC syndrome, chemotherapy is generally the standard treatment approach, and radiotherapy is used only when chemotherapy has failed or there is a need for more rapid tumor cell kill. More aggressive interventions may become necessary, including vascular stenting of the SVC, therapeutic anticoagulation, or corticosteroids to decrease vascular inflammation and obstruction and alleviate clinical symptoms. Invasive procedures may be more hazardous because of the extensive collateral vascularity commonly observed with this syndrome.

Hoarseness is another regional symptom associated with SCLC. This is most commonly attributed to mediastinal lymph node involvement and compression of the left recurrent laryngeal nerve. This is nearly always associated with pathologic involvement of the levels 4 and 5 left-sided mediastinal lymph nodes. Evaluation with laryngoscopy can help confirm the diagnosis of vocal cord paralysis. CT scanning of the neck and chest with intravenous contrast can help document involved nodes in this region. Occasionally, local treatment may be necessary to improve symptoms resulting from vocal cord paralysis from recurrent nerve involvement.²⁸ Hoarseness may improve with treatment of the underlying cancer, but this symptom is commonly irreversible because of permanent nerve injury or progressive cancer in this region.

Stridor can also develop because of tracheal compression with involvement of the upper airways or bilateral recurrent laryngeal nerve involvement. This may be a result of local tumor involvement or extrinsic compression from lymphadenopathy. This can be a life-threatening emergency in patients with malignancies of the lung and/or head and neck and requires urgent airway management, usually tracheostomy. Laryngoscopic therapy can be useful in controlling upper airway tumors, but more aggressive intervention is often required, including radiation, chemotherapy, or rarely in SCLC, surgical therapy.²⁹

Patients with SCLC can present with malignant effusions in the pleural or pericardial space. These effusions are most commonly directly related to tumor involvement, either with direct invasion of the pleura or with hematologic spread to the pleura, but can also be a result of lymphatic obstruction from adenopathy or the primary tumor. Effusions can also be caused by late effects of prior therapy including surgery or radiation. Prompt management of pericardial effusions can prevent life-threatening consequences, including cardiac tamponade. Pericardial effusions, which become clinically symptomatic resulting from pressure on the ventricles, may require surgical intervention with a pericardial window or pericardial stripping, or can be managed less invasively with percutaneous catheter drainage.³⁰

Malignant pleural effusions occur in up to 20% of patients with lung cancer³¹ and may be the initial presenting sign of malignant disease.³² Lung cancer is the most common cause of malignant pleural effusion.³³ The incidence of malignant effusions in SCLC is comparable to that of non-small cell lung cancers (NSCLC) in general but less than for the adenocarcinoma histologic subtype. Some authors have argued that patients with small cell with an isolated malignant effusion as the only site of metastatic disease may have a comparable outcome to patients with limited stage disease and should therefore be treated as such.³⁴ Nonetheless, this strategy has not gained widespread acceptance. Initial evaluation should be with diagnostic and therapeutic thoracentesis. Exudative effusions should be assumed to be malignant, unless a satisfactory benign etiology can be assigned.³⁵ These effusions may require chest tube drainage and pleurodesis for optimal management, although SCLC patients may be appropriately treated with chemotherapy alone. Less invasive options are becoming available in the management of malignant pleural effusions, such as smaller catheters and home drainage.

Horner syndrome can be observed in lung cancer patients with apical lung carcinoma in the superior sulcus because of involvement of the sympathetic chain of nerves. This syndrome, more commonly associated with NSCLC, is often associated with Pancoast syndrome. SCLC more commonly is a central mass with bulky mediastinal lymphadenopathy, and therefore is not commonly involving the lung apex.³⁶ Horner syndrome is characterized by ptosis, myosis, and anhydrosis of the affected side most commonly from apical lung tumors. Pancoast syndrome is characterized by Horner syndrome plus the additional local-regional effects of involvement of the brachial plexus, chest wall, ribs, and thoracic spine.³⁷ Again,
chemotherapy often provides rapid symptomatic relief from this syndrome in SCLC, and the cancer is managed according to clinical stage.

Systemic MetastasisSCLC can spread at a rapid rate, and early diagnosis before regional or metastatic spread is rare. Nearly two thirds of patients with small cell present with systemic disease at the time of initial diagnosis. Involved sites affected by metastatic disease can cause significant symptoms. The most commonly involved sites with metastatic lung cancer include the brain, contralateral lung, liver, adrenals, and bones.³⁸ Other less common sites can also be affected, including visceral organs, skin and subcutaneous tissues, kidneys, pancreas, and spinal cord and meninges. Specific symptoms related to each of these sites of disease can appear at the time of initial diagnosis or may develop as the disease progresses. Symptomatic patients should be further evaluated with the appropriate diagnostic test (CT, magnetic resonance imaging [MRI], or radionuclide scan) to exclude additional sites of disease. Asymptomatic patients, however, may not need full evaluation for metastatic disease in the absence of clinical findings.³⁹

Optimal evaluation of patients with SCLC for evidence of metastasis generally includes a CT scan of the chest to include adrenals and liver, and consideration of brain imaging with CT or MRI, bone scanning, and possibly bone marrow biopsy. This procedure became part of standard staging of SCLC because of the frequent involvement of bone marrow by metastatic disease. More recent evidence suggests that having marrow involvement as the sole site of metastasis occurs in less than 5% of patients and may not have the prognostic significance previously thought.⁴⁰ In fact, these patients were found to have no difference in overall survival compared with patients with extensive disease without marrow involvement. Newer imaging techniques including positron emission tomography (PET) are still being evaluated in SCLC, but may play a role in defining disease stage in some patients.⁴¹

Brain metastasis is common in SCLC, occurring in 50% of patients in one autopsy series.⁴² Symptomatic patients presenting with brain metastasis from SCLC may develop headaches, nausea, fatigue, weakness, seizures, visual change, or ataxia. These symptoms can often be the presenting symptoms of the cancer and are generally controlled with treatment. Patients may also harbor metastatic disease to the brain in the absence of symptoms. Some have debated the roll of screening asymptomatic patients with brain scanning. One study found that 63% of SCLC patients with any neurologic symptoms had brain metastases on CT scan, whereas only 18% of patients with no neurologic symptoms had evidence for brain metastasis.⁴³ The more sensitive technique of MRI scanning may have picked up additional patients with small volume metastases, but the clinical implications of this are unclear, especially given the chemosensitivity of this tumor.

Options for treatment of brain metastasis include surgery, radiation, chemotherapy, or some combination. More recent data suggests that some patients with SCLC may have control of central nervous system (CNS) disease with chemotherapy alone.⁴⁴ Leptomeningeal metastasis carries a particularly grave prognosis⁴⁵ and may produce the similar neurological symptoms, changes in mental status, or the signs of meningeal irritation including stiff neck and photophobia.

Bony metastasis is another common site of metastasis and can lead to significant problems with pain. Aggressive management of symptomatic bone metastasis is necessary in this disease. Patients who present with bony pain should be evaluated with whole body bone scanning, and specific sites of involvement can be further evaluated with plain x-rays and CT or MRI scanning. Sites of symptomatic metastasis should be considered for palliative radiotherapy. Weightbearing regions in the hip, epidural spinal cord compression, or proximal humerus lesions should also be considered for surgical evaluation and possible prophylactic fixation. However, the role of aggressive local therapy for metastatic disease must be weighed carefully with the need for systemic therapy in this aggressive neoplasm. Data has emerged suggesting that bisphosphonates may be effective in reducing bony complications and discomfort caused by metastatic tumor to bone.⁴⁶ Definitive clinical trials are not yet available in SCLC patients.