Approach

Treatment regimens vary depending on stage of cancer.​[5][31]​​

  • Limited stage: disease confined to the ipsilateral hemithorax, which can be safely encompassed within a tolerable radiation field.

  • Extensive stage: all other disease, including metastatic disease and malignant pleural/pericardial effusions.

There are many variations and combinations of factors involved in the assessment of each patient. Care of patients with lung cancer should be undertaken by a multidisciplinary team in a specialized oncology center.

Limited disease

Patients with limited-stage SCLC are treated with concurrent chemotherapy and radiation therapy (RT).[50][51]​​​ Chemotherapy typically consists of cisplatin and etoposide, although carboplatin is frequently substituted for cisplatin.[5][31]​​​ Concurrent RT is recommended.[50][51]​​​ Early RT (given with cycle 1 or 2 of chemotherapy) is preferred to RT administered later in the chemotherapy course.[51][52]​​​ Twice-daily radiation dosing (45 Gy in 1.5-Gy fractions) is preferred though once-daily dosing (approximately 60-70 Gy in 2-Gy fractions) may be acceptable if twice-daily dosing is not feasible.[53][54][55]

Surgical intervention has limited use in SCLC because most patients present with advanced disease. For the rare patient with a solitary pulmonary mass without radiographic evidence of lymphadenopathy, it is recommended that preoperative mediastinoscopy be performed to confirm N0 status. For these patients, surgical resection, typically a lobectomy, is reasonable. Postoperative chemotherapy should then be administered. Patients with resected limited-stage SCLC with N2 status should receive mediastinal radiation in addition to chemotherapy; postoperative radiation may be considered in patients with N1 status.[5][31]​​

Lobectomy involves division of the lobar pulmonary arteries, pulmonary veins, the associated bronchus, and hilar lymph nodes, and removal en bloc. Access to the chest is usually via a thoracotomy, although minimally invasive techniques (i.e., video-assisted thorascopic surgery) are gaining favor due to shorter hospitalizations and less postoperative pain. Sampling or dissection of mediastinal lymph nodes is recommended.

US guidelines recommend preoperative exercise for people undergoing surgery for lung cancer, as it can lead to shorter hospital stay and reduced risk of postoperative complications.​[56]​ Aerobic and resistance exercise during treatment with curative intent is recommended to reduce the adverse effects of treatment.[56]​​

See Non-small cell lung cancer for further surgical details.

Extensive disease

Patients with extensive-stage SCLC typically receive chemotherapy plus immunotherapy for 4 to 6 cycles followed by maintenance immunotherapy until disease progression or unacceptable toxicities.[5]​​[57][58][31]​​​ Commonly used regimens include cisplatin plus etoposide plus durvalumab, or carboplatin plus etoposide plus either atezolizumab or durvalumab. Atezolizumab or durvalumab (immune checkpoint inhibitors) can be omitted if there are contraindications to immune checkpoint inhibitors. Cisplatin or carboplatin plus irinotecan is an additional option.[5][31]​​

Immune checkpoint inhibitors can cause unique immune-mediated adverse events that are not seen with traditional cytotoxic chemotherapy, such as pneumonitis, colitis, dermatitis, myositis, and hypothyroidism, among others. Awareness of the array of possible immune-mediated adverse events by both provider and patient is critical for early recognition and mitigation of drug to drug interactions.[59][60] Immune checkpoint inhibitors should not be used in patients who have previously received tyrosine kinase inhibitors (TKIs); toxicity has been reported with both concurrent and sequential administration of immunotherapy and TKI in nonsmall cell lung cancer trials.[5][61]​​​​

Of note, maintenance treatment with combination immunotherapy (nivolumab plus ipilimumab) did not improve overall survival compared with single-agent immunotherapy and therefore is not recommended in the first-line setting.[62]

RT can be used to palliate symptomatic sites including the lung, bone, and brain. Patients with limited sites of metastatic disease who achieve a complete extrathoracic response and at least a partial intrathoracic response to initial chemotherapy can be considered for thoracic RT to delay or prevent recurrent symptomatic disease.[51][63][64]

Prophylactic cranial irradiation (PCI)

Patients with SCLC are at high risk of developing brain metastases. Randomized trials have demonstrated a survival benefit for PCI in patients who respond to initial therapy. The data are stronger in limited-stage disease than in extensive-stage disease.[49][51][65]

Studies have tried to clarify the potential benefit of PCI in extensive-stage SCLC. One randomized trial comparing PCI to observation was performed in extensive-stage SCLC patients and showed a lower incidence of symptomatic brain metastases and increased disease-free survival and overall survival in the PCI group; however, this study has been criticized as patients were not required to have a brain magnetic resonance imaging (MRI) scan at screening, and therefore it is unclear whether patients were receiving PCI or therapeutic radiation.[66] One randomized study comparing PCI with observation (MRI surveillance) in extensive-stage disease was stopped early for futility, and while there was a decrease in incidence of brain metastases, overall survival was worse, although not statistically significant, with PCI.[65]

Among patients receiving PCI, the recommended dose is 25 Gy in 2.5-Gy fractions. One randomized trial found no difference in 2-year incidence of brain metastasis between 25-Gy and 36-Gy regimens, but there was increased toxicity with the higher dose.[67][68] PCI is not recommended in patients with poor performance status or impaired mental function. Depending on patient- and disease-specific characteristics, routine surveillance with MRI brain may be an alternative to PCI.[51]

Relapse

US guidelines recommend the original or a similar platinum-based regimen as subsequent systemic therapy for patients with treatment-free interval >6 months.[5] One meta-analysis of observational and randomized study data found that platinum-doublet chemotherapy was associated with a significantly higher objective response rate and disease control rate in patients with relapsed SCLC compared with non-platinum-based regimens.[69]

Consideration may be given to the original, or a similar, platinum-based regimen for patients with early relapse (treatment-free interval of at least 3 to 6 months).[5][31]​

Single-agent nivolumab or pembrolizumab (immune checkpoint inhibitors) are listed as subsequent treatment options for relapsed SCLC.[5][31] Nivolumab, however, did not improve survival versus chemotherapy in a randomized open-label phase III trial of relapsed SCLC.[70]​ The use of nivolumab or pembrolizumab in patients with disease progression while receiving maintenance atezolizumab or durvalumab is discouraged.[5] The response of patients with resistant or refractory disease (treatment-free interval <3 months or ≤6 months for European and US guidance, respectively) to subsequent therapies is poor and a clinical trial may be the preferred option.[5][31]​​

For patients with symptomatic intrathoracic disease or with distant metastases causing distressing symptoms, palliative radiation therapy should be considered.

The choice between the many regimens is complex and needs to be managed in a specialized oncology center. There are numerous chemotherapy drugs and combinations that may be used if a clinical trial is not feasible, although response rates are low. All have the potential to cause bone marrow suppression, nausea/vomiting, alopecia, and fatigue. Other adverse effects are specific to the particular agent.

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