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).^{[11, 15]}

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.^[37]

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.

The American College of Chest Physicians (ACCP) 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–SCLC.^{[27, 28]}

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.^[28]

In contrast with non-SCLC, 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.^[28]Studies of vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) inhibitors have yielded disappointing results: bevacizumab,^[38]aflibercept, and vandetanib have failed to demonstrate significant improvements in survival.^[39]

Consequently, there has been little change in survival over the past 2 decades for limited- or extensive-stage SCLC.^{[40, 39]}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.^{[41, 42]} In March 2019, the FDA approved atezolizumab in combination with carboplatin and etoposide for first-line treatment of adult patients with extensive-stage SCLC.

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.^[43]

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).^[43]

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).^[44]

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.^[45]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.^[46]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).^[43]

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).^[44]

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.^[45]In addition, the overall response rate between PE and IP treatment groups did not differ.^[45]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 renal function. A study by Schmittel et al found that the combination of carboplatin/irinotecan was not superior to that of carboplatin/etoposide.^[48]

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).^[49]

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.^[49]

Chemotherapy Dose Intensity and Density

Patients with extensive-stage small cell lung cancer (SCLC) should receive 4-6 cycles (but not > 6 cycles) of cisplatin- or carboplatin-based combination chemotherapy (eg, cisplatin plus etoposide or irinotecan).^{[27, 28, 12]}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.^[50]

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.^[51]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 small cell lung cancer (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 (ACCP) recommends four cycles of a platinum agent and etoposide.^[28]

For patients receiving chemotherapy and radiotherapy, National Comprehensive Cancer Network guidelines recommend a maximum of four to six cycles of cisplatin and etoposide.^[27]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.^{[27, 28, 12]}

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.^{[28, 12]}For patients who are eligible for early concurrent chemoradiotherapy, the American College of Chest Physicians (ACCP) recommends concurrent accelerated hyperfractionated radiotherapy (twice-daily treatment) with platinum-based chemotherapy.^[28]

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.^[52]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.^[53]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.^[12]

Prophylactic cranial irradiation

The ACCP and the National Comprehensive Cancer Network (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.^{[27, 28]}

The use of PCI was initially considered controversial.^[54]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.^[54]

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.^[51]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.^[55]

Extensive-Stage SCLC - Standard Management

Patients with extensive-stage small cell lung cancer (ES-SCLC) are treated with combination chemotherapy alone. The administration of carboplatin or cisplatin plus etoposide has been the standard of care in North America for ES-SCLC.

However, the combination of chemotherapy with atezolizumab—a humanized monoclonal anti–programmed death ligand 1 (PD-L1) antibody is the new standard of care. The IMpower133 demonstrated a significant improvement in survival with the addition of atezolizumab to carboplatin and etoposide.^{[41, 42]} In March 2019, the FDA approved atezolizumab in combination with carboplatin and etoposide for first-line treatment of adult patients with ES-SCLC.

In IMpower133, at a median follow-up of 13.9 months, the 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.^[41]

In March 2020, the FDA approved another PD-L1 inhibitor, durvalumab, in combination with etoposide and either carboplatin or cisplatin as first-line treatment for ES-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 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 plus platinum-etoposide group compared with 10.3 months in the platinum-etoposide group, with 34% versus 25% of patients alive at 18 months.^[56]

The American College of Chest Physicians (ACCP), 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 > 6 cycles) of cisplatin- or carboplatin-based combination chemotherapy (eg, cisplatin plus etoposide or irinotecan).^{[27, 28, 12]}

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.^[44]

However, a confirmatory study in the United States failed to show the superiority of either regimen.^[57]

Possible reasons for these contrasting results may have to do with differences in doses and schedules of the chemotherapeutic agents, as well as with genetic changes within different study populations. Although PE and IP had comparable overall response rates and survival outcomes, the IP combination had more gastrointestinal (GI) toxicity.^[57]

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.^[58]

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. The ACCP indicates that consolidative thoracic radiotherapy to the chest is a treatment option for patients who achieve a complete response (CR) outside the chest and complete or partial (PR) response in the chest.^[28]

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.^[59]

Prophylactic cranial irradiation

As with limited-stage disease, offer prophylactic cranial irradiation (PCI) to all responding patients with extensive stage SCLC^{[27, 28, 12]}; 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 study by the European Organization for Research and Treatment of Cancer (EORTC) that randomized patients responding to systemic chemotherapy into 2 groups, those who received PCI and those who did not, found that the 1-year survival rate for the PCI-treated group was 27.1%, compared with 13.3% for patients who did not receive PCI.^[54]In the study, PCI not only reduced the incidence of brain metastases but also improved disease-free and overall survival rates.

However, the 2010 European Society for Medical Oncology (ESMO) practice guidelines noted that safety data on PCI administered concurrently with chemotherapy are lacking; therefore, this combination is not recommended outside of a clinical trial.^[12]

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.^[60]

Gamma knife stereotactic radiosurgery

Gamma knife stereotactic radiosurgery is a salvage option for patients with brain metastases for whom previous whole-brain irradiation has failed.^[61]

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 of completion of therapy have little chance of responding to additional chemotherapy.

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

Topotecan received US Food and Drug Administration (FDA) approval in 2007 for use in chemotherapy-sensitive disease after failure of front-line chemotherapy.^[62]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.^[63]

The American College of Chest Physicians (ACCP) 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. The ACCP 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 who relapse more than 6 months after completion of initial chemotherapy, the ACCP recommends reusing the previously administered first-line chemotherapy regimen. Enrollment in a clinical trial is encouraged.^[28]

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 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.^[64]

In June 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 who had disease progression on or after platinum-based chemotherapy. 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).^[65]

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 overall survival.^{[66, 67]}

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 small cell lung cancer (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 small cell lung cancer (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 (ACCP) 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.^[28]

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.^{[68, 12]}If there is no evidence of mediastinal lymph node involvement, then surgical exploration with resection of the primary tumor and mediastinal lymph node sampling is a reasonable treatment option.

Due to the systemic nature of SCLC, all patients should receive adjuvant platinum-based chemotherapy and prophylactic cranial irradiation (PCI) after successful resection.^[28]

In a review by Anraku and Waddel, the investigators 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.^[69]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.^[69]

Management of Complications

Physicians should be aware of potential complications in patients with small cell lung cancer (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.^[19]

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.^[12]

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.^[7]

Guidelines

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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.

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

Organ System	Syndrome	Mechanism	Frequency
Endocrine	SIADH	Antidiuretic hormone	15%^[20]
	Ectopic secretion of ACTH	ACTH	2-5%^[21]

Neurologic	Eaton-Lambert reverse myasthenic syndrome		3%^[22]
	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^[20]; (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^[21]; (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.^[22]

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^[31]; (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.^[31]

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^[36]; (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.^[31]

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Small Cell Lung Cancer (SCLC) Treatment & Management

Approach Considerations