Sections

Treatment

Approach Considerations

Small cell lung cancer (SCLC) is characterized by rapid growth and early dissemination. Prompt initiation of treatment is important.

Patients with clinical stage Ia (T1N0) after standard staging evaluation may be considered for surgical resection, but combined treatment with chemotherapy and radiation therapy is the standard of care. Radiation therapy is often added at the second cycle of chemotherapy.

For patients with a good performance status and nonbulky disease, intensive radiation therapy early in the course of treatment is indicated. However, radiation therapy can often be delayed for patients with either a poor performance status or very bulky disease. Delaying the initiation of radiation therapy until the third cycle of chemotherapy does have the advantage of avoiding the significant myelosuppression seen with full-dose chemotherapy and large-volume radiation therapy .

For the approximately 30% of patients with SCLC who have limited-stage disease at the time of diagnosis (ie, tumors confined to the hemithorax of origin, the mediastinum, or the supraclavicular lymph nodes), management typically involves combination platinum-based chemotherapy and thoracic radiation therapy given with curative intent. Patients who achieve a complete or partial response should be offered prophylactic cranial irradiation (PCI).^{[13, 17]}

Although many patients with limited-stage SCLC have comorbidity, a Norwegian study found that patients with comorbidity complete and tolerate chemo-radiotherapy as well as other patients. No significant differences in response rates, progression-free survival, or overall survival were identified.^[38]

Extensive-stage SCLC (ie, SCLC that has spread beyond the supraclavicular areas, or with distant metastases) remains incurable with current management options, and patients are treated with combination chemotherapy. Several chemotherapy combinations are active in SCLC, but usually a platinum-containing regimen is chosen.

American College of Chest Physicians (CHEST) and the National Comprehensive Cancer Network (NCCN) guidelines recommend following treatment recommendations for SCLC in patients who have mixed histologic features of SCLC and non–small-cell lung cancer (NSCLC).^{[28, 29]}

Elderly patients with SCLC who have a good performance status (PS) (ie, Eastern Cooperative Oncology Group [ECOG] PS 0 or 1) and intact organ function should receive standard carboplatin-based chemotherapy. However, even those who have poor prognostic factors (eg, poor PS, medically significant concomitant conditions) may still be considered for chemotherapy if appropriate precautions are taken to avoid excessive toxicity and further decline in PS.^[29]

In contrast with NSCLC, for which identification of molecular targets and targeted therapies has proceeded at a brisk pace, SCLC has not been shown to respond well to most targeted therapies.^[29]Studies of vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) inhibitors have yielded disappointing results: bevacizumab,^[39]aflibercept, and vandetanib have failed to demonstrate significant improvements in survival.^[40]

Consequently, there has been little change in survival over the past 2 decades for limited- or extensive-stage SCLC.^{[41, 40]}In 2018, however, the IMpower133 study may have inaugurated a new standard of care for first-line treatment of extensive-stage SCLC, by demonstrating a significant improvement in survival with the addition of atezolizumab—a humanized monoclonal anti–programmed death ligand 1 (PD-L1) antibody—to chemotherapy with carboplatin and etoposide.^{[42, 43]} In 2019, the US Food and Drug Administration (FDA) approved atezolizumab in combination with carboplatin and etoposide for first-line treatment of adult patients with extensive-stage SCLC. In 2020, the FDA approved another PD-L1 inhibitor, durvalumab, in combination with etoposide and either carboplatin or cisplatin, for the same indication.

Various potential therapeutic strategies are also being studied. These include aurora kinase A inhibitors, polyadenosine diphosphate-ribose polymerase (PARP) inhibitors, ataxia telangiectasia and Rad3-related inhibitors, cyclin-dependent kinase 7 inhibitors, delta-like protein 3 agents, antiganglioside agents, CD47 inhibitors, and lysine-specific histone demethylase 1a inhibitors.^[44]

See Small Cell Lung Cancer Treatment Protocols for summarized information.

Combination Chemotherapy

A number of randomized trials have tried to answer questions concerning the superiority of combination over single-agent chemotherapy, the number of drugs to be used in combination, and dose intensity. Nonrandomized trials of combination chemotherapy have shown superior response rates and survival compared with single-agent chemotherapy. Common combinations include cisplatin/etoposide (PE), cisplatin/irinotecan (IP), carboplatin/etoposide, and carboplatin/irinotecan. The current standard of care for extensive metastatic small cell cancer is combination chemotherapy (cisplatin/ etoposide) with immunotherapy as discussed in detail on section on extensive stage small cell cancer.

Several platinum-based and non–platinum-based chemotherapy regimens have been used in the treatment of small cell lung cancer (SCLC) with varying results.

In a systematic review that compared the effectiveness of these regimens, Amarasena et al concluded that platinum-based chemotherapy regimens did not provide a statistically significant benefit over non–platinum-based agents in survival or overall tumor response. However, platinum-based agents did result in higher complete response rates, albeit with an associated higher incidence of nausea, vomiting, anemia, and thrombocytopenia. The investigators suggested that non–platinum-based chemotherapy regimens may have a better risk-benefit profile.^[45]

Cisplatin plus etoposide or irinotecan

Cisplatin and etoposide (PE) is currently the most widely used regimen in both limited- and extensive-stage SCLC. The combination of cyclophosphamide, doxorubicin (Adriamycin), and vincristine (CAV) has been compared with PE in at least 2 randomized trials of previously untreated extensive-stage SCLC and has shown similar survival outcomes. The PE combination is associated with less myelosuppression, whereas CAV has the convenience of administration in a single day (PE requires a 3-day program).^[45]

The PE combination has also been compared with other platinum-based regimens (eg, cisplatin and irinotecan [IP]) and has been found to be effective for metastatic SCLC. A large Japanese study that compared PE with IP in patients with extensive-stage disease showed a 3-month-longer survival period with the IP combination (12.8 mo) relative to the PE combination (9.4 mo).^[46]

Nonetheless, a more recent meta-analysis of 12 randomized, controlled trials found that, although the IP regimen significantly reduced mortality risk compared with the PE regimen, it also produced more hematologic toxicities in patients with extensive-stage SCLC.^[47]In addition, the overall response rate between PE and IP treatment groups did not differ.One of the trials in this meta-analysis suggested overall survival may be prolonged with a PCDE (etoposide, cisplatin, epirubicin, cyclophosphamide) regimen.

Several subsequent trials comparing the same combinations did not show a survival advantage with the IP combination, including a US trial that demonstrated an overall median survival time of 9.3 months for those in the IP group versus 10.2 months for those in the PE group.^[48]Therefore, the PE combination remains the first-line combination chemotherapy choice for most physicians.

Several platinum-based and non–platinum-based chemotherapy regimens have been used in the treatment of small cell lung cancer (SCLC) with varying results.

Cisplatin and etoposide

PE is currently the most widely used regimen in both limited- and extensive-stage SCLC. The combination of cyclophosphamide, doxorubicin (Adriamycin), and vincristine (CAV) has been compared with PE in at least 2 randomized trials of previously untreated extensive-stage SCLC and showed similar survival outcomes. The PE combination is associated with less myelosuppression, whereas CAV has the convenience of administration in a single day (PE requires a 3-day program).^[45]

Cisplatin and irinotecan

The PE combination has also been compared with other platinum-based regimens (eg, IP) and has been found to be effective for metastatic SCLC. A large Japanese study that compared PE with IP in patients with extensive-stage disease showed a 3-month-longer survival period with the IP combination (12.8 mo) relative to the PE combination (9.4 mo).^[46]

Nonetheless, a more recent meta-analysis of 12 randomized, controlled trials found that, although the IP regimen significantly reduced mortality risk compared with the PE regimen, it also produced more hematologic toxicities in patients with extensive-stage SCLC.^[47]In addition, the overall response rate between PE and IP treatment groups did not differ.^[47]One of the trials in this meta-analysis suggested overall survival may be prolonged with a PCDE (etoposide, cisplatin, epirubicin, cyclophosphamide) regimen.

Cisplatin-based versus carboplatin-based chemotherapy

The combination of carboplatin and etoposide has been used in patients with compromised kidney function. A study by Schmittel et al found that the combination of carboplatin/irinotecan was not superior to that of carboplatin/etoposide.^[50]

A systematic review of randomized trials comparing cisplatin- to carboplatin-based chemotherapy as the first-line treatment for SCLC found no significant difference in efficacy between the 2 treatments. This meta-analysis included 4 trials with a total of 663 patients (328 treated with cisplatin; 335 treated with carboplatin).^[51]

In the study, median overall survival was 9.6 months among cisplatin-treated patients and 9.4 months among carboplatin-treated patients. Median progression-free survival was 5.5 months among cisplatin-treated patients and 5.3 months among carboplatin-treated patients. The objective response rate was 67.1% and 66.0%, respectively. However, hematologic toxicity was higher with carboplatin, whereas nonhematologic toxicity was higher with cisplatin.^[51]

Chemotherapy Dose Intensity and Density

Patients with extensive-stage SCLC should receive 4-6 cycles (but not > 6 cycles) of cisplatin- or carboplatin-based combination chemotherapy (eg, cisplatin plus etoposide or irinotecan).^{[28, 29, 14]}Several trials have tested the use of higher doses of standard chemotherapeutic regimens in previously untreated SCLC. Despite early enthusiasm brought on by higher initial response rates, most of these trials have failed to demonstrate improved survival.^[52]

A trial by Arriagada et al comparing standard and higher doses of cyclophosphamide and cisplatin in the first cycle of chemotherapy yielded a superior survival rate only in patients receiving higher-dose chemotherapy.^[53]Higher-dose regimens, however, may cause life-threatening myelosuppression and, in the absence of survival advantage, should not be used outside of a clinical trial.

Another approach to increase the intensity of chemotherapy is to shorten the interval between cycles (increased dose density). Again, although phase II trials suggested the superiority of such an approach, randomized trials failed to show an advantage to the use of intensive weekly chemotherapy over standard regimens. One of the problems has been myelosuppression with weekly programs, such that the planned dose intensity has not been reached. Growth factor support may overcome this, but until randomized trials are reported to show clear superiority of such an approach, it remains investigational.

High-dose chemotherapy with bone marrow or stem cell transplantation

The available data do not support the use of high-dose chemotherapy with bone marrow or stem cell transplantation, because no randomized trials have evaluated this approach to assess whether it will produce better survival rates than standard management and whether it is associated with greater immediate and delayed toxicity.

Limited-Stage SCLC - Standard Management

Standard management of patients with limited-stage SCLC involves combination chemotherapy and concurrent thoracic radiotherapy. Therefore, it is necessary to refer patients to a radiation oncologist, as well as a medical oncologist. For combination chemotherapy, the American College of Chest Physicians (CHEST) recommends four cycles of a platinum agent and etoposide.^[29]

For patients receiving chemotherapy and radiotherapy, National Comprehensive Cancer Network (NCCN) guidelines recommend a maximum of four to six cycles of cisplatin and etoposide.^[28]Continuing chemotherapy beyond four to six cycles has not been shown to significantly improve overall survival in most randomized controlled trials, and has been associated with considerable risk of increased toxicity; indeed, many oncologists now stop after four cycles of therapy.^{[28, 29, 14]}

Patients who experience a complete or partial response to initial therapy and those who have undergone resection followed by adjuvant chemotherapy should be offered prophylactic cranial irradiation (PCI).

Radiotherapy

Patients with limited-stage SCLC typically receive concurrent chemotherapy and thoracic radiotherapy, which should begin as early as possible, preferably within 30 days of the start of chemotherapy.^{[29, 14]}For patients who are eligible for early concurrent chemoradiotherapy, CHEST recommends concurrent accelerated hyperfractionated radiotherapy (twice-daily treatment) with platinum-based chemotherapy.^[29]

In a randomized trial by Takada and colleagues in which treatment using cisplatin plus etoposide (PE) with concurrent thoracic radiotherapy was compared with treatment using PE with sequential thoracic radiotherapy, the investigators reported superior 2- and 5-year survival rates (2-y survival, 35.1% vs 54.4%, respectively; 5-y survival, 18.3% vs 23.7%, respectively) with the concurrent approach.^[54]However, hematologic toxicity was greater in the concurrent arm.

In another randomized trial, Turrisi and colleagues demonstrated superiority of concurrent hyperfractionated radiotherapy administered with 4 cycles of PE in limited-stage SCLC relative to once-daily radiotherapy and concurrent PE.^[55]The 10% survival improvement reported in this trial is the largest survival improvement ever noted in SCLC. In addition, 5-year survival rates were 26% versus 16%, respectively, in favor of hyperfractionated radiotherapy. However, a major flaw in this trial was that the biologic equivalent dose of radiotherapy was not equivalent between the 2 treatment arms.

The European Society for Medical Oncology (ESMO) notes that twice-daily radiotherapy is inconvenient and is associated with a significantly elevated rate of transient grade 3 esophagitis.Nevertheless, ESMO guidelines recommend considering twice-daily 1.5 Gy in a 30-fraction regimen in clinical practice, for fit patients who are willing to accept temporarily increased toxicity.^[14]

Prophylactic cranial irradiation

CHEST and NCCN guidelines recommend PCI in patients with limited-stage disease who have achieved a complete remission or in those with stage I disease who have undergone resection.^{[28, 29]}The use of PCI was initially considered controversial.^[56]Several randomized trials showed a decrease in central nervous system (CNS) relapse rate with PCI but no survival advantage. Additionally, patients receiving PCI had a higher incidence of neuropsychiatric dysfunction than did those who did not receive PCI.^[56]

Arriagada et al performed a meta-analysis of randomized trials of PCI in limited-stage SCLC and showed a 5% overall survival advantage in patients who received PCI.^[53]Although such an analysis has inherent limitations, PCI is currently offered to patients with limited-stage SCLC who have achieved a complete or partial response after having completed initial chemoradiotherapy.

In a pooled analysis that evaluated outcomes of PCI in 739 SCLC patients with stable disease or better after treatment with chemotherapy with or without thoracic radiation therapy, Schild et al found that PCI resulted in a significant survival benefit in patients with either limited or extensive SCLC. Dose fractionation appeared to be important, and PCI was associated with an increase in specific and overall grade 3+ adverse events.^[57]

Extensive-Stage SCLC - Standard Management

For decades, no better option than chemotherapy with cisplatin and etoposide was available for extensive-stage small cell lung cancer (ES-SCLC). More recently, however, the combination of chemotherapy with immunotherapy in the first-line setting has resulted in improved survival.

The combination of chemotherapy with atezolizumab—a humanized monoclonal anti–programmed death ligand 1 (PD-L1) antibody—is the new standard of care. In 2019, the FDA approved atezolizumab in combination with carboplatin and etoposide for first-line treatment of adult patients with extensive-stage SCLC, based on results of the IMpower133 trial.^{[42, 43]}

In IMpower133, median overall survival in patients who received atezolizumab plus chemotherapy (n=201) was 12.3 months, compared with 10.3 months in patients who received chemotherapy only (n=202; hazard ratio for death, 0.70; 95% confidence interval [CI], 0.54 to 0.91; P=0.007). Median progression-free survival was 5.2 months for the atezolizumab group compared with 4.3 months for the placebo group (hazard ratio for disease progression or death, 0.77; 95% CI, 0.62 to 0.96; P=0.02). The 1-year overall survival rate was 51.7% in the atezolizumab group and 38.2% in the placebo group.^[42]

In 2020, the FDA approved another PD-L1 inhibitor, durvalumab, in combination with etoposide and either carboplatin or cisplatin as first-line treatment for extensive-stage SCLC. Approval was based from the CASPIAN trial, a randomized, multicenter, open-label phase II study (n=268), in which durvalumab in combination with platinum, etoposide, and/or the cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) inhibitor tremelimumab, was associated with a significant improvement in overall survival, with a hazard ratio of 0.73; median overall survival was 13 months in the durvalumab- platinum-etoposide group compared with 10.3 months in the platinum-etoposide group, with 34% versus 25% of patients alive at 18 months.^[58]

The American College of Chest Physicians (CHEST), the National Comprehensive Cancer Network (NCCN), and the European Society for Medical Oncology (ESMO) guidelines recommend that patients with extensive-stage disease receive 4-6 cycles (but not more than 6 cycles) of cisplatin- or carboplatin-based combination chemotherapy (eg, cisplatin plus etoposide or irinotecan).^{[28, 29, 14]}

Although cisplatin/etoposide (PE) remains the most widely used combination, a randomized trial that compared the combination of cisplatin with either etoposide or irinotecan in extensive-stage disease demonstrated that the combination of cisplatin and irinotecan (IP) was superior to that of PE. The median survival was 12.8 months with IP, versus 9.4 months with the PE combination. The 2-year survival rate was also superior at 19.5% for IP, versus 5.2% for PE.^[46]

However, a confirmatory study in the United States failed to show the superiority of either regimen.^[59]

A German clinical trial reported that topotecan/cisplatin had a similar overall response rate to PE in extensive SCLC but a better time to progression and objective response rate than did PE.^[60]

Maintenance immunotherapy after first line platinum doublet

Most cases of ES-SCLC progress after completion of first-line chemotherapy and immunotherapy. Use of anti-PD-L1 therapy with atezolizumab or durvalumab as maintenace has led to improved progression-free and overall survival. In SCLC there is currently no biomarker for selection of treatment.

Radiotherapy

In general, radiotherapy is used only to palliate symptoms, if required (eg, for painful bone metastases) in extensive-stage SCLC. Response rates are excellent, but patients invariably relapse. CHEST indicates that consolidative thoracic radiotherapy is a treatment option for patients who achieve a complete response (CR) outside the chest and complete or partial (PR) response in the chest.^[29]

In a phase III randomized controlled trial, Slotman et al showed that patients with extensive-stage SCLC who had responded to chemotherapy may benefit from thoracic radiotherapy (30 Gy in 10 fractions). Although overall survival at 1 year was not significantly different in the patients who received thoracic radiotherapy, 2-year overall survival was 13% with radiotherapy versus 3% without (P=0.004). At 6 months, progression-free survival was 24% with radiotherapy versus 7% without (P=0.001). No severe toxic effects from radiotherapy were noted.^[61]

Prophylactic cranial irradiation

As with limited-stage disease, offer prophylactic cranial irradiation (PCI) to all responding patients with extensive-stage SCLC^{[28, 29, 14]}; this treatment should be considered standard therapy for this stage of the disease in these patients. Brain metastases at the time of initial diagnosis in extensive SCLC are present in about 18% of patients and increase to about 80% at 2 years.

A randomized study of PCI by the European Organization for Research and Treatment of Cancer (EORTC) in patients responding to systemic chemotherapy found that the 1-year survival rate for patients who received PCI was 27.1%, compared with 13.3% for patients who did not receive PCI.^[56]In the study, PCI not only reduced the incidence of brain metastases but also improved disease-free and overall survival rates.

However, ESMO practice guidelines note that safety data on PCI administered concurrently with chemotherapy are lacking; therefore, this combination is not recommended outside of a clinical trial.^[14]

In a phase III Japanese trial conducted in patients with extensive-stage SCLC, PCI did not result in longer overall survival compared with observation; on final analysis, median overall survival was 11.6 months in the PCI group (n=113) and 13.7 months in the observation group (n=111). These authors concluded that PCI is not essential for patients with extensive-stage SCLC who have had any response to initial chemotherapy and in whom periodic follow-up MRI scans confirm the absence of brain metastases.^[62]

Gamma knife stereotactic radiosurgery is a salvage option for patients with brain metastases for whom previous whole-brain irradiation has failed.^[63]

Management of Relapsed SCLC

Patients with relapsed small cell lung cancer (SCLC) have an extremely poor prognosis. Individuals whose disease does not respond to or that progresses on initial treatment (ie, patients with refractory disease) or those whose SCLC relapses within 6 months after completion of therapy have little chance of responding to additional chemotherapy.

In general, the administration of cisplatin and etoposide (PE) after cyclophosphamide-doxorubicin (Adriamycin)-vincristine (CAV) failure produces better response rates than does CAV given after PE.

Topotecan has FDA approval for use in chemotherapy-sensitive disease after failure of front-line chemotherapy. Because of the lack of long-term benefit of this therapy, however, patients with relapsed or refractory SCLC should be encouraged to enroll in clinical trials, if their condition permits.^[64]

The American College of Chest Physicians (CHEST) recommends offering second-line, single-agent chemotherapy to patients with relapsed or refractory SLCL. Single agents with demonstrated activity in second-line SCLC therapy include topotecan, irinotecan, paclitaxel, docetaxel, vinorelbine, oral etoposide, and gemcitabine. CHEST notes that "although response rates are generally higher with combination therapy, overall survival does not appear to be improved and the toxicity of combination regimens is frequently problematic." For patients whose SCLC relapses more than 6 months after completion of initial chemotherapy, CHEST guidelines recommend reusing the previously administered first-line chemotherapy regimen. Enrollment in a clinical trial is encouraged.^[29]

In contrast, on the basis of a phase III trial in 180 patients, Goto et al concluded that combination chemotherapy with cisplatin, etoposide, and irinotecan could be considered the standard second-line chemotherapy for selected patients with sensitive relapsed SLCL. In their study, overall survival (OS) with combination chemotherapy was 18.2 months (95% confidence index [CI] 15.7-20.6), versus 12.5 months (95% CI, 10.8-14.9) in patients with topotecan monotherapy (hazard ratio 0.67, 90% CI 0.51-0.88; P=0.0079). Patients in the combination chemotherapy arm did experience higher rates of toxicity, however.^[65]

In 2020, the FDA granted accelerated approval to the alkylating drug lurbinectedin (Zepzelca) for adults with metastatic SCLC with disease progression on or after platinum-based chemotherapy. Approval was based on the results from the PM1183-B-005-14 trial, a multicenter open-label, multi-cohort study in 105 patients with metastatic SCLC in which the overall response rate (ORR) was 35% (95% CI: 26-45%), with a median response duration of 5.3 months (95% CI: 4.1-6.4). The ORR as per independent review committee was 30% (95% CI: 22-40%) with a median response duration of 5.1 months (95% CI: 4.9-6.4).^[66]

Immune checkpoint modulation

In 2018, the FDA granted accelerated approval of nivolumab, a monoclonal antibody to programmed cell death–1 protein (PD-1), for metastatic SCLC in patients with progression after platinum-based chemotherapy and at least 1 other line of therapy. In 2020, the FDA granted accelerated approval to the PD-1 inhibitor pembrolizmab for the same indication. However, in 2021, this indication was voluntarily withdrawn from the US market for both nivolumab and pembrolizumab (including nivolumab-ipilimumab combination therapy), after further study failed to confirm significant improvement in OS. There is currently no third-line option available.^{[67, 68]}

Temozolomide and PARP inhibitors

Temozolomide (TMZ) is an oral alkylating agent previously known to have single-agent activity in SCLC. TMZ has also been studied in combination with poly (ADP-ribose) polymerase (PARP) inhibitors, which appear to have minimal single-agent activity in SCLC.^[69]A randomized trial by Pietanza et al of TMZ plus the PARP inhibitor veliparib or placebo reported no difference in progression-free survival (PFS) or OS in the study population as a whole, but PFS and OS were significantly improved in patients with SLFN11-positive tumors treated with TMZ/veliparib (PFS, 5.7 vs 3.6 months, respectively; OS, 12.2 vs 7.5 months; P= 0.014 for OS). In the trial, TMZ was given in a dosage of 150-200 mg/m²/day on days 1-5 of every 28- day cycle, and veliparib was given in a dosage of 40 mg twice daily on days 1-7.^[70]

In a study by Farago et al, the combination of TMZ with the PARP inhibitor olaparib demonstrated substantial clinical activity against relapsed SCLC. Dosages used in this study were TMZ 75 mg/m² daily, and olaparib 200 mg orally twice daily, both on days 1 to 7 of a 21-day cycle.^[69]

Brain metastases

Management of symptomatic brain metastases includes high-dose corticosteroids (eg, intravenous [IV] dexamethasone 10 mg initially, followed by an IV or oral [PO] dose of 4-6 mg q6h) and immediate whole brain radiation therapy.

For patients with asymptomatic brain metastases, systemic chemotherapy may be initiated, with plans for close surveillance of the central nervous system (CNS) metastases and initiation of brain radiation after completion of systemic treatment.

In patients with SCLC, brain metastases usually respond to systemic chemotherapy, but radiation can be sandwiched between cycles of chemotherapy if there is any clinical or radiographic evidence of progression of CNS disease.

Spinal cord compression

Spinal cord compression is an oncologic emergency, because patients rarely regain neurologic function once it has been lost. New onset of back pain in patients known to have malignant disease should raise the suspicion of cord compression.

A thorough neurologic examination and radiologic evaluation of the spine are indicated with any suspicion of spinal cord compression. The goal is to prevent the development of neurologic deficit, since such a deficit, once present, can progress within hours to cause complete paraplegia. Any delay in instituting appropriate therapy may result in permanent neurologic deficit.

Patients in whom spinal cord compression is suspected should receive IV corticosteroids even before being sent for magnetic resonance imaging (MRI). The typical dose is 10 mg of dexamethasone IV, followed by 4-6 mg IV/PO every 6 hours.

If spinal cord compression occurs in a patient with known SCLC, definitive management consists of radiation therapy and/or neurosurgical decompression, which should be undertaken without delay.

Surgical Resection

Historically, patients undergoing surgery for SCLC had a dismal prognosis. However, more recent data suggest that patients with true stage I SCLC may benefit from surgical resection. The American College of Chest physicians (CHEST) recommends that patients being considered for resection undergo invasive mediastinal staging and extrathoracic imaging, such as cranial computed tomography (CT) scanning or magnetic resonance imaging (MRI), abdominal CT scanning, and bone scanning.^[29]

Fewer than 5% of patients with SCLC present with such early-stage disease, but those who are found to have clinical stage T1/T2 N0 disease after initial staging work-up should undergo invasive mediastinal lymph node evaluation via mediastinoscopy, mediastinotomy, or endobronchial ultrasound-guided biopsy.^{[71, 14]}If no evidence of mediastinal lymph node involvement is found, then surgical exploration with resection of the primary tumor and mediastinal lymph node sampling is a reasonable treatment option.

In a study of 196 patients undergoing surgical resection of SCLC, the 5-year overall survival in patients with no pathologic evidence of lymph node involvement (pN0) was 65.5%, versus 35.1% for those with pN1-2. In pN0 patients, no statistical difference in survival was observed among patients with different pathologic T stages^[72]

Due to the systemic nature of SCLC, all patients should receive adjuvant platinum-based chemotherapy and prophylactic cranial irradiation (PCI) after successful resection.^[29]

A review by Anraku and Waddel indicated that surgical resection combined with chemotherapy for T1-2, N0, M0 SCLC may offer better local control of the disease than does chemotherapy alone.^[73]In addition, curative resection following induction chemoradiotherapy has shown a control of local relapse in almost 100% of patients. Likewise, 5- and 10-year survival rates were 39% and 35%, respectively, for all included patients, resected or not, and they were 44% and 41%, respectively, for patients with stage IIB to IIIA disease treated with a trimodality approach that included adjuvant surgery.^[73]

Management of Complications

Physicians should be aware of potential complications in patients with SCLC, including tumor lysis syndrome and electrolyte abnormalities.

Tumor lysis syndrome

Tumor lysis can occur rapidly in patients with SCLC on institution of chemotherapy, especially in cases of extensive-stage disease. The laboratory features of tumor lysis syndrome are hyperuricemia, hyperphosphatemia, hypocalcemia, and hyperkalemia. Patients should be well hydrated and, preferably, premedicated with allopurinol. The management of established tumor lysis syndrome is urinary alkalinization, correction of electrolyte abnormalities, and dialysis, if necessary.

Electrolyte abnormalities

SCLC is associated with a number of electrolyte abnormalities because of frequent production of peptide hormones. The most common abnormality is hyponatremia, which, if severe, may cause neurologic symptoms and signs, including seizures, coma, and death. Prompt recognition of hyponatremia and its severity is important.

Evidence that supports the prognostic value of this abnormality was shown in a retrospective study of 395 SCLC patients with limited and extensive disease in which patients with hyponatremia had a significantly shorter median survival time than did patients without hyponatremia.^[21]

Hyponatremia results from inappropriate secretion of antidiuretic hormone (ADH), which results in the inability of the kidneys to excrete free water. Syndrome of inappropriate ADH (SIADH) is reported in 5-10% of patients with SCLC. The serum sodium level is usually less than 130 mEq/L. Other causes of hyponatremia (ie, volume depletion, abnormal renal function) must be excluded.

Fluid restriction and pharmacologic therapy in the form of demeclocycline (a tetracycline antibiotic that decreases the sensitivity of renal tubules to the action of ADH) are the usual forms of management.

Consultations

Patients in whom lung cancer is suspected may require consultation with a pulmonologist to establish a diagnosis. Once a diagnosis has been made, medical and radiation oncologists should be consulted to complete the staging workup and devise a management plan. In addition, owing to the importance of weight loss as an indicator of poor prognosis in persons with small cell lung cancer (SCLC), obtain a dietary consultation for patients with persistent weight loss.

Long-Term Monitoring

Patients with small cell lung cancer (SCLC) require close monitoring for adverse effects and response to therapy. Blood work, including a complete blood count (CBC) with differential, is needed before each cycle of chemotherapy to ensure marrow recovery before the next dose of chemotherapy is administered. Renal function should be monitored because of nephrotoxicity from cisplatin.

Serum lactate dehydrogenase (LDH), if elevated before the start of therapy, is a good marker for response and should be monitored. In addition, computed tomography (CT) scans should be obtained after 2 cycles of therapy to assess response before chemotherapy is continued. In general, patients who are asymptomatic require follow-up only as clinically needed.^[14]

Patients who smoke cigarettes should be encouraged to quit. A meta-analysis by Parsons et al suggested that smoking cessation after diagnosis of early stage lung cancer may improve prognosis, probably by reducing cancer progression. Evaluation of data from 9 studies showed that the estimated 5-year survival rate in limited-stage SCLC was 63% in patients who quit smoking, versus 29% in those who continued to smoke.^[9]

Guidelines

Basumallik N, Agarwal M. Small Cell Lung Cancer. J Thorac Oncol. 2023 Jan. 14 (2):237-244. [QxMD MEDLINE Link]. [Full Text].
Malhotra J, Boffetta P, Mucci L. Cancer of the lung, larynx, and pleura. Adami H, Hunter D, Laglou P, Mucci L, eds. Textbook of Cancer Epidemiology. 3rd ed. New York, NY: Oxford University Press; 2018. 327-54.
Pietanza MC, Krug LM, Wu AJ, Kris MG, Rudin CM, Travis WD. Small Cell and Neuroendocrine Tumors of the lung. DeVita VT Jr, Lawrence TS, Rosenberg SA, eds. DeVita, Hellman, and Rosenberg's Cancer: Principles & Practice of Oncology. 10th ed. Philadelphia, Pa: Wolters Kluwer Health; 2015. 536-59.
Cascone T, Gold KA, Glisson BS. Small Cell Carcinoma of the Lung. Kantarjian H, Wolff R, eds. The MD Anderson Manual of Medical Oncology. 3rd ed. New York, NY: McGraw-Hill Education; 2016. 323-42.
Kalemkerian GP, Schneider BJ. Advances in Small Cell Lung Cancer. Hematol Oncol Clin North Am. 2017 Feb. 31 (1):143-156. [QxMD MEDLINE Link].
Gay CM, Stewart CA, Park EM, et al. Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities. Cancer Cell. 2021 Mar 8. 39 (3):346-360.e7. [QxMD MEDLINE Link]. [Full Text].
Wynder EL, Graham EA. Tobacco smoking as a possible etiologic factor in bronchiogenic carcinoma; a study of 684 proved cases. J Am Med Assoc. 1950 May 27. 143(4):329-36. [QxMD MEDLINE Link].
Pesch B, Kendzia B, Gustavsson P, Jockel KH, Johnen G,et al. Cigarette smoking and lung cancer--relative risk estimates for the major histological types from a pooled analysis of case-control studies. Int J Cancer. 2012 Sep 1. 131(5):1210-9. [QxMD MEDLINE Link]. [Full Text].
Parsons A, Daley A, Begh R, Aveyard P. Influence of smoking cessation after diagnosis of early stage lung cancer on prognosis: systematic review of observational studies with meta-analysis. BMJ. 2010 Jan 21. 340:b5569. [QxMD MEDLINE Link]. [Full Text].
Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA Cancer J Clin. 2023 Jan. 73 (1):17-48. [QxMD MEDLINE Link]. [Full Text].
Govindan R, Page N, Morgensztern D, Read W, Tierney R, Vlahiotis A, et al. Changing epidemiology of small-cell lung cancer in the United States over the last 30 years: analysis of the surveillance, epidemiologic, and end results database. J Clin Oncol. 2006 Oct 1. 24(28):4539-44. [QxMD MEDLINE Link].
American Cancer Society. Cancer Facts & Figures 2023. Available at https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2021/cancer-facts-and-figures-2021.pdf. Accessed: April 10, 2023.
Small Cell Lung Cancer Treatment (PDQ®): Health Professional Version. National Cancer Institute. Available at http://www.ncbi.nlm.nih.gov/books/NBK65909/#CDR0000062945__1. March 2, 2023; Accessed: April 10, 2023.
[Guideline] Dingemans AC, Früh M, Ardizzoni A, Besse B, Faivre-Finn C, Hendriks LE, et al. Small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up^†. Ann Oncol. 2021 Apr 9. 24 Suppl 6:vi99-105. [QxMD MEDLINE Link]. [Full Text].
Cancer fact sheet. World Health Organization. Available at http://www.who.int/mediacentre/factsheets/fs297/en/. 3 February 2022; Accessed: April 10, 2023.
Jemal A, Miller KD, Ma J, Siegel RL, Fedewa SA, Islami F, et al. Higher Lung Cancer Incidence in Young Women Than Young Men in the United States. N Engl J Med. 2018 May 24. 378 (21):1999-2009. [QxMD MEDLINE Link].
Jackman DM, Johnson BE. Small-cell lung cancer. Lancet. 2005 Oct 15-21. 366(9494):1385-96. [QxMD MEDLINE Link].
Janne PA, Freidlin B, Saxman S, Johnson DH, Livingston RB, Shepherd FA, et al. Twenty-five years of clinical research for patients with limited-stage small cell lung carcinoma in North America. Cancer. 2002 Oct 1. 95(7):1528-38. [QxMD MEDLINE Link].
Wu C, Xu B, Yuan P, Miao X, Liu Y, Guan Y, et al. Genome-wide interrogation identifies YAP1 variants associated with survival of small-cell lung cancer patients. Cancer Res. 2010 Dec 1. 70(23):9721-9. [QxMD MEDLINE Link].
Xun WW, Brennan P, Tjonneland A, Vogel U, Overvad K, el at. Single-nucleotide polymorphisms (5p15.33, 15q25.1, 6p22.1, 6q27 and 7p15.3) and lung cancer survival in the European Prospective Investigation into Cancer and Nutrition (EPIC). Mutagenesis. 2011 Sep. 26(5):657-66. [QxMD MEDLINE Link].
Hermes A, Waschki B, Reck M. Hyponatremia as prognostic factor in small cell lung cancer--a retrospective single institution analysis. Respir Med. 2012 Jun. 106(6):900-4. [QxMD MEDLINE Link].
Campling BG, Sarda IR, Baer KA, Pang SC, Baker HM, Lofters WS, et al. Secretion of atrial natriuretic peptide and vasopressin by small cell lung cancer. Cancer. 1995 May 15. 75(10):2442-51. [QxMD MEDLINE Link].
Shepherd FA, Laskey J, Evans WK, Goss PE, Johansen E, Khamsi F. Cushing's syndrome associated with ectopic corticotropin production and small-cell lung cancer. J Clin Oncol. 1992 Jan. 10(1):21-7. [QxMD MEDLINE Link].
Sher E, Gotti C, Canal N, Scoppetta C, Piccolo G, Evoli A, et al. Specificity of calcium channel autoantibodies in Lambert-Eaton myasthenic syndrome. Lancet. 1989 Sep 16. 2(8664):640-3. [QxMD MEDLINE Link].
[Guideline] Wender R, Fontham ET, Barrera E Jr, Colditz GA, Church TR, Ettinger DS, et al. American Cancer Society lung cancer screening guidelines. CA Cancer J Clin. 2013 Mar-Apr. 63 (2):107-17. [QxMD MEDLINE Link]. [Full Text].
[Guideline] Lung Cancer: Screening. U.S. Preventive Services Task Force. Available at http://www.uspreventiveservicestaskforce.org/Page/Document/UpdateSummaryFinal/lung-cancer-screening. March 9, 2021; Accessed: April 10, 2023.
Katki HA, Kovalchik SA, Petito LC, Cheung LC, Jacobs E, Jemal A, et al. Implications of Nine Risk Prediction Models for Selecting Ever-Smokers for Computed Tomography Lung Cancer Screening. Ann Intern Med. 15 May 2018. [Full Text].
[Guideline] NCCN Clinical Practice Guidelines in Oncology: Small Cell Lung Cancer. National Comprehensive Cancer Network. Available at http://www.nccn.org/professionals/physician_gls/pdf/sclc.pdf. Version 3.2023 — December 21, 2022; Accessed: April 10, 2023.
[Guideline] Detterbeck FC, Lewis SZ, Diekemper R, Addrizzo-Harris D, Alberts WM. Executive Summary: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013 May. 143 (5 Suppl):7S-37S. [QxMD MEDLINE Link]. [Full Text].
[Guideline] Ung YC, Maziak DE, Vanderveen JA, Smith CA, Gulenchyn K, Evans WK, for the Lung Cancer Disease Site Group. 18-fluorodeoxyglucose positron emission tomography in the diagnosis and staging of lung cancer: a clinical practice guideline. Toronto, Ontario: Cancer Care Ontario; 2007. [Full Text].
Thomson D, Hulse P, Lorigan P, Faivre-Finn C. The role of positron emission tomography in management of small cell lung cancer. Lung Cancer. 2011 Aug. 73(2):121-6. [QxMD MEDLINE Link].
American Joint Committee on Cancer. Lung. AJCC Cancer Staging Manual Amin MB, Edge S, Greene F, Byrd DR, Brookland RK, et al, eds. AJCC Cancer Staging Manual. 8th edition. New York, NY: Springer; 2016.
Dresler CM, Olak J, Herndon JE 2nd, Richards WG, el at. Phase III intergroup study of talc poudrage vs talc slurry sclerosis for malignant pleural effusion. Chest. 2005 Mar. 127(3):909-15. [QxMD MEDLINE Link].
Zakowski MF. Pathology of small cell carcinoma of the lung. Semin Oncol. 2003 Feb. 30(1):3-8. [QxMD MEDLINE Link].
Small Cell Lung Cancer Stages. American Cancer Society. Available at http://www.cancer.org/cancer/lungcancer-smallcell/detailedguide/small-cell-lung-cancer-staging. October 1, 2019; Accessed: April 3, 2020.
Micke P, Faldum A, Metz T, Beeh KM, Bittinger F, Hengstler JG, et al. Staging small cell lung cancer: Veterans Administration Lung Study Group versus International Association for the Study of Lung Cancer--what limits limited disease?. Lung Cancer. 2002 Sep. 37(3):271-6. [QxMD MEDLINE Link].
[Guideline] National Collaborating Centre for Cancer. Lung cancer. The diagnosis and treatment of lung cancer. Publication no. 121. London, UK: National Institute for Health and Clinical Excellence; 2011. [Full Text].
Halvorsen TO, Sundstrøm S, Fløtten Ø, Brustugun OT, Brunsvig P, Aasebø U, et al. Comorbidity and outcomes of concurrent chemo- and radiotherapy in limited disease small cell lung cancer. Acta Oncol. 2016 Aug 23. 1-9. [QxMD MEDLINE Link].
Spigel DR, Townley PM, Waterhouse DM, Fang L, Adiguzel I, et al. Randomized phase II study of bevacizumab in combination with chemotherapy in previously untreated extensive-stage small-cell lung cancer: results from the SALUTE trial. J Clin Oncol. 2011 Jun 1. 29(16):2215-22. [QxMD MEDLINE Link].
Lally BE, Urbanic JJ, Blackstock AW, Miller AA, Perry MC. Small cell lung cancer: have we made any progress over the last 25 years?. Oncologist. 2007 Sep. 12(9):1096-104. [QxMD MEDLINE Link].
Hanna NH, Einhorn LH. Small-cell lung cancer: state of the art. Clin Lung Cancer. 2002 Sep. 4(2):87-94. [QxMD MEDLINE Link].
Horn L, Mansfield AS, Szczęsna A, Havel L, Krzakowski M, Hochmair MJ, et al. First-Line Atezolizumab plus Chemotherapy in Extensive-Stage Small-Cell Lung Cancer. N Engl J Med. 2018 Dec 6. 379 (23):2220-2229. [QxMD MEDLINE Link]. [Full Text].
Harrison P. After Decades, New Standard of Care in Small Cell Lung Cancer. Medscape Medical News. Available at https://www.medscape.com/viewarticle/902700. September 28, 2018; Accessed: October 10, 2018.
Petty WJ, Paz-Ares L. Emerging Strategies for the Treatment of Small Cell Lung Cancer: A Review. JAMA Oncol. 2023 Mar 1. 9 (3):419-429. [QxMD MEDLINE Link].
Amarasena IU, Walters JA, Wood-Baker R, Fong K. Platinum versus non-platinum chemotherapy regimens for small cell lung cancer. Cochrane Database Syst Rev. 2008 Oct 8. CD006849. [QxMD MEDLINE Link].
Noda K, Nishiwaki Y, Kawahara M, Negoro S, Sugiura T, Yokoyama A, et al. Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer. N Engl J Med. 2002 Jan 10. 346(2):85-91. [QxMD MEDLINE Link].
Jiang L, Yang KH, Guan QL, Mi DH, Wang J. Cisplatin plus etoposide versus other platin-based regimens for patients with extensive small-cell lung cancer: a systematic review and meta-analysis of randomised, controlled trials. Intern Med J. 2012 Dec. 42(12):1297-309. [QxMD MEDLINE Link].
Hanna N, Bunn PA Jr, Langer C, Einhorn L, Guthrie T Jr, Beck T, et al. Randomized phase III trial comparing irinotecan/cisplatin with etoposide/cisplatin in patients with previously untreated extensive-stage disease small-cell lung cancer. J Clin Oncol. 2006 May 1. 24(13):2038-43. [QxMD MEDLINE Link].
Ready NE, Pang HH, Gu L, Otterson GA, Thomas SP, Miller AA, et al. Chemotherapy With or Without Maintenance Sunitinib for Untreated Extensive-Stage Small-Cell Lung Cancer: A Randomized, Double-Blind, Placebo-Controlled Phase II Study-CALGB 30504 (Alliance). J Clin Oncol. 2015 May 20. 33 (15):1660-5. [QxMD MEDLINE Link].
Schmittel A, Sebastian M, Fischer von Weikersthal L, et al. A German multicenter, randomized phase III trial comparing irinotecan-carboplatin with etoposide-carboplatin as first-line therapy for extensive-disease small-cell lung cancer. Ann Oncol. 2011 Aug. 22(8):1798-804. [QxMD MEDLINE Link].
Rossi A, Di Maio M, Chiodini P, Rudd RM, Okamoto H, Skarlos DV, et al. Carboplatin- or cisplatin-based chemotherapy in first-line treatment of small-cell lung cancer: the COCIS meta-analysis of individual patient data. J Clin Oncol. 2012 May 10. 30(14):1692-8. [QxMD MEDLINE Link].
Klasa RJ, Murray N, Coldman AJ. Dose-intensity meta-analysis of chemotherapy regimens in small-cell carcinoma of the lung. J Clin Oncol. 1991 Mar. 9(3):499-508. [QxMD MEDLINE Link].
Arriagada R, Le Chevalier T, Pignon JP, Riviere A, Monnet I, Chomy P, et al. Initial chemotherapeutic doses and survival in patients with limited small-cell lung cancer. N Engl J Med. 1993 Dec 16. 329(25):1848-52. [QxMD MEDLINE Link].
Takada M, Fukuoka M, Kawahara M, Sugiura T, Yokoyama A, Yokota S, et al. Phase III study of concurrent versus sequential thoracic radiotherapy in combination with cisplatin and etoposide for limited-stage small-cell lung cancer: results of the Japan Clinical Oncology Group Study 9104. J Clin Oncol. 2002 Jul 15. 20(14):3054-60. [QxMD MEDLINE Link].
Turrisi AT 3rd, Kim K, Blum R, Sause WT, Livingston RB, Komaki R, et al. Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med. 1999 Jan 28. 340(4):265-71. [QxMD MEDLINE Link].
Slotman B, Faivre-Finn C, Kramer G, Rankin E, Snee M, Hatton M, et al. Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med. 2007 Aug 16. 357(7):664-72. [QxMD MEDLINE Link].
Schild SE, Foster NR, Meyers JP, Ross HJ, Stella PJ, et al. Prophylactic cranial irradiation in small-cell lung cancer: findings from a North Central Cancer Treatment Group Pooled Analysis. Ann Oncol. 2012 Nov. 23(11):2919-24. [QxMD MEDLINE Link].
Paz-Ares L, Dvorkin M, Chen Y, et al. Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial. Lancet. 2019 Nov 23. 394 (10212):1929-1939. [QxMD MEDLINE Link].
Natale R, Lara P, Chansky K, et al. A randomized phase III trial comparing irinotecan/cisplatin (IP) with etoposide/cisplatin (EP) in patients (pts) with previously untreated extensive stage small cell lung cancer (E-SCLC). J Clin Oncol. 2008;26 (suppl):400s.
Heigener D, Freitag L, Eschbach C et al. Topotecan/cisplatin (TP) compared to cisplatin/etoposide (PE) for patients with extensive disease-small cell lung cancer (ED-SCLC): final results of a randomised phase III trial. J Clin Oncol. 2008;26 (suppl):400s.
Slotman BJ, van Tinteren H, Praag JO, Knegjens JL, El Sharouni SY, Hatton M, et al. Use of thoracic radiotherapy for extensive stage small-cell lung cancer: a phase 3 randomised controlled trial. Lancet. 2015 Jan 3. 385 (9962):36-42. [QxMD MEDLINE Link]. [Full Text].
Takahashi T, Yamanaka T, Seto T, Harada H, Nokihara H, Saka H, et al. Prophylactic cranial irradiation versus observation in patients with extensive-disease small-cell lung cancer: a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2017 May. 18 (5):663-671. [QxMD MEDLINE Link].
Harris S, Chan MD, Lovato JF, Ellis TL, Tatter SB, Bourland JD, et al. Gamma knife stereotactic radiosurgery as salvage therapy after failure of whole-brain radiotherapy in patients with small-cell lung cancer. Int J Radiat Oncol Biol Phys. 2012 May 1. 83(1):e53-9. [QxMD MEDLINE Link].
Jotte R, Conkling P, Reynolds C, Galsky MD, Klein L, Fitzgibbons JF, et al. Randomized phase II trial of single-agent amrubicin or topotecan as second-line treatment in patients with small-cell lung cancer sensitive to first-line platinum-based chemotherapy. J Clin Oncol. 2011 Jan 20. 29(3):287-93. [QxMD MEDLINE Link].
Goto K, Ohe Y, Shibata T, Seto T, Takahashi T, Nakagawa K, et al. Combined chemotherapy with cisplatin, etoposide, and irinotecan versus topotecan alone as second-line treatment for patients with sensitive relapsed small-cell lung cancer (JCOG0605): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2016 Aug. 17 (8):1147-1157. [QxMD MEDLINE Link].
Zepzelca (lurbinectedin) [package insert]. Palo Alto, CA: Jazz Pharmaceuticals, Inc. June 2020. Available at [Full Text].
Nivolumab Indication in Small Cell Lung Cancer Withdrawn in U.S. Market. The ASCO Post. Available at https://ascopost.com/issues/january-25-2021/nivolumab-indication-in-small-cell-lung-cancer-withdrawn-in-us-market/. January 25, 2021; Accessed: March 23, 2021.
Merck Provides Update on KEYTRUDA® (pembrolizumab) Indication in Metastatic Small Cell Lung Cancer in the US. Merck. Available at https://www.merck.com/news/merck-provides-update-on-keytruda-pembrolizumab-indication-in-metastatic-small-cell-lung-cancer-in-the-us/. March 1, 2021; Accessed: March 23, 2021.
Farago AF, Yeap BY, Stanzione M, et al. Combination Olaparib and Temozolomide in Relapsed Small-Cell Lung Cancer. Cancer Discov. 2019 Oct. 9 (10):1372-1387. [QxMD MEDLINE Link]. [Full Text].
Pietanza MC, Waqar SN, Krug LM, Dowlati A, Hann CL, Chiappori A, et al. Randomized, Double-Blind, Phase II Study of Temozolomide in Combination With Either Veliparib or Placebo in Patients With Relapsed-Sensitive or Refractory Small-Cell Lung Cancer. J Clin Oncol. 2018 Aug 10. 36 (23):2386-2394. [QxMD MEDLINE Link]. [Full Text].
Schreiber D, Rineer J, Vongtama D, et al. Surgery for limited-stage small cell lung cancer, should the paradigm shift? A SEER-based analysis. J Clin Oncol (Suppl). 2008. 26:403s.
Fu Z, Li D, Deng C, Zhang J, Bai J, Li Y, et al. Excellent survival of pathological N0 small cell lung cancer patients following surgery. Eur J Med Res. 2023 Feb 21. 28 (1):91. [QxMD MEDLINE Link]. [Full Text].
Anraku M, Waddell TK. Surgery for small-cell lung cancer. Semin Thorac Cardiovasc Surg. 2006 Fall. 18(3):211-6. [QxMD MEDLINE Link].
Mazzone PJ, Silvestri GA, Patel S, Kanne JP, Kinsinger LS, Wiener RS, et al. Screening for Lung Cancer: CHEST Guideline and Expert Panel Report. Chest. 2018 Apr. 153 (4):954-985. [QxMD MEDLINE Link]. [Full Text].
[Guideline] Jaklitsch MT, Jacobson FL, Austin JH, Field JK, Jett JR, Keshavjee S, et al. The American Association for Thoracic Surgery guidelines for lung cancer screening using low-dose computed tomography scans for lung cancer survivors and other high-risk groups. J Thorac Cardiovasc Surg. 2012 Jul. 144 (1):33-8. [QxMD MEDLINE Link].
[Guideline] Rivera MP, Mehta AC, Wahidi MM. Establishing the diagnosis of lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013 May. 143 (5 Suppl):e142S-65S. [QxMD MEDLINE Link]. [Full Text].
[Guideline] Rudin CM, Ismaila N, Hann CL, Malhotra N, Movsas B, Norris K, et al. Treatment of Small-Cell Lung Cancer: American Society of Clinical Oncology Endorsement of the American College of Chest Physicians Guideline. J Clin Oncol. 2015 Dec 1. 33 (34):4106-11. [QxMD MEDLINE Link]. [Full Text].
Moffat GT, Wang T, Robinson AG. Small Cell Lung Cancer in Light/Never Smokers - A Role for Molecular Testing?. J Natl Compr Canc Netw. 2023 Feb 15. 21 (4):336-339. [QxMD MEDLINE Link].

Media Gallery

High-power photomicrograph of small cell carcinoma on the left side of the image with normal ciliated respiratory epithelium on the right side of the image.
This coronal positron emission tomogram shows a large, focal, hypermetabolic area on the right that is consistent with a large mass in the central portion of the right upper pulmonary lobe. Multiple other smaller hypermetabolic areas suggest lymph-node metastatic disease in the chest, abdomen, and right supraclavicular region.

of 2

Table 1. Paraneoplastic Syndromes Affecting Endocrine and Neurologic Function in SCLC

Organ System	Syndrome	Mechanism	Frequency
Endocrine	SIADH	Antidiuretic hormone	15%^[22]
	Ectopic secretion of ACTH	ACTH	2-5%^[23]

Neurologic	Eaton-Lambert reverse myasthenic syndrome		3%^[24]
	Subacute cerebellar degeneration
	Subacute sensory neuropathy
	Limbic encephalopathy	Anti-Hu, anti-Yo antibodies
ACTH = adrenocorticotropic hormone; SCLC = small cell lung cancer; SIADH = syndrome of inappropriate antidiuretic hormone. Sources: (1) Campling BG, Sarda IR, Baer KA, et al. Secretion of atrial natriuretic peptide and vasopressin by small cell lung cancer. Cancer. May 15, 1995;75(10):2442-51^[22]; (2) Shepherd FA, Laskey J, Evans WK, et al. Cushing's syndrome associated with ectopic corticotropin production and small-cell lung cancer. J Clin Oncol. Jan 1992;10(1):21-7^[23]; (3) Sher E, Gotti C, Canal N, et al. Specificity of calcium channel autoantibodies in Lambert-Eaton myasthenic syndrome. Lancet. Sep 16, 1989;2(8664):640-3.^[24]

Table 2. AJCC TNM Categories for Lung Cancer

Primary Tumor (T)		Tumor Size	Location of Involvement
TX		Primary tumor can’t be assessed, or sputum cytology reveals tumor cells but the tumor is not seen on radiologic or bronchoscopic evaluation
T0		No evidence of a primary tumor
Tis		Carcinoma in situ
T1		≤3 cm in greatest dimension	Surrounded by lung or visceral pleura; no invasion more proximal than lobar bronchus
	T1a	≤1 cm in greatest dimension
	T1b	>1 cm but ≤2 cm in greatest dimension
	T1c	>2 cm but ≤3 cm in greatest dimension
T2		>3 cm but ≤5 cm in greatest dimension, or (see right column)	Main bronchus, ≥2 cm distal to carina, or Visceral pleura, or Hilar region, but not entire lung, associated with atelectasis/obstructive pneumonitis
	T2a	>3 cm but ≤4 cm in greatest dimension
	T2b	>5 cm but ≤7 cm in greatest dimension
T3		>5 cm but ≤7 cm in greatest dimension, or (see right column)	Direct invasion of: Parietal pleural chest wall, diaphragm, phrenic nerve, mediastinal pleura, parietal pericardium, or Main bronchus < 2 cm distal to carina (but not carina itself), or Entire lung with associated atelectasis/obstructive pneumonitis, or Same lobe, separate tumor nodule(s)
T4		>7 cm or (see right column)	Invasion of: Mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, or carina Different ipsilateral lobe, separate tumor nodule(s)
Node (N)		Location of Regional Metastatic Involvement
NX		Regional lymph nodes cannot be assessed
N0		No regional lymph node metastasis
N1		Ipsilateral peribronchial and/or ipsilateral hilar lymph nodes, and Intrapulmonary nodes, including direct extension
N2		Ipsilateral mediastinal and/or subcarinal lymph node(s)
N3		Contralateral mediastinal, contralateral hilar, ipsilateral/contralateral scalene, or supraclavicular lymph node(s)
Metastasis (M)		Location of Distant Metastatic Involvement
M0		No distant metastasis
M1		Distant metastasis
	M1a	Contralateral lobe tumor with separate tumor nodule(s), or Tumor with pleural nodules or malignant pleural or pericardial effusion
	M1b	Single extrathoracic metastasis in a single organ and involvement of a single distant (nonregional) node
	M1c	Multiple extrathoracic metastases in one or more organs
AJCC = American Joint Committee on Cancer. Adapted from: (1) Edge SB, Byrd DR, Compton CC, et al, eds. AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer; 2010:299-330^[32]; (2) National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology:Small Cell Lung Cancer [serial online]. 2018;v.2. Available at: http://www.nccn.org/professionals/physician_gls/pdf/sclc.pdf.^[32]

Table 3. AJCC Stage Groupings for Lung Cancer

		Primary Tumor (T)	Regional Node (N)	Metastasis (M)
Occult Cancer		TX	N0	M0
Stage 0		Tis	N0	M0
Stage IA	IA1	T1a	N0	M0
	IA2	T1b	N0	M0
	IA3	T1c	N0	M0
Stage IIA		T2b	N0	M0
Stage IIB		T1a,b,c	N1	M0
		T2a,b	N1	M0
		T3	N0	M0
Stage IIIA		T1a,b,c	N2	M0
		T2a,b	N2	M0
		T3	N1-2	M0
		T4	N0-1	M0
Stage IIIB		T1a,b,c	N3	M0
		T2a,b	N3	M0
		T3	N2	M0
		T4	N2	M0
Stage IIIC		T3-4	N3	M0
Stage IVA		Any T	Any N	M1a,b
Stage IVB		Any T	Any N	M1c
AJCC = American Joint Committee on Cancer. Adapted from: (1) Edge SB, Byrd DR, Compton CC, et al, eds. AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2016^[37]; (2) National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology:Small Cell Lung Cancer [serial online]. 2018;v.2. Available at: http://www.nccn.org/professionals/physician_gls/pdf/sclc.pdf.^[32]

Back to List

Small Cell Lung Cancer (SCLC) Treatment & Management

Approach Considerations