NCCN Categories of Evidence and Consensus
Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.
Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.
All recommendations are category 2A unless otherwise noted.
Clinical trials: NCCN believes that the best management for any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Overview
Neuroendocrine tumors account for approximately 20% of lung cancers; most (≈15%) are small cell lung cancer (SCLC).1-3 In 2012, an estimated 33,900 new cases of SCLC will occur in the United States.4 Nearly all cases of SCLC are attributable to cigarette smoking. Although the overall incidence of SCLC has been decreasing, in women it is increasing, with the male-to-female incidence ratio now 1:1.2 This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for SCLC focuses on extensive-stage SCLC because it occurs more frequently. The complete version of the NCCN Guidelines for SCLC and Lung Neuroendocrine Tumors is available at NCCN.org.
Non-small cell lung cancer (NSCLC) is the most common type of lung cancer (see the NCCN Clinical Practice Guidelines in Oncology for NSCLC at NCCN.org). When compared with NSCLC, SCLC generally has a more rapid doubling time, a higher growth fraction, and earlier development of widespread metastases. Most patients with SCLC present with hematogenous metastases (ie, extensive-stage disease), whereas only approximately one-third present with limited-stage disease confined to the chest. SCLC is highly sensitive to initial chemotherapy and radiotherapy; however, most patients eventually die of recurrent disease.5,6
In patients with extensive-stage disease, chemotherapy alone can palliate symptoms and prolong survival in most patients; in chemoresponsive patients, prophylactic cranial irradiation (PCI) can also palliate symptoms and prolong survival. However, long-term survival is rare in patients with extensive-stage disease.7,8 Clinical trials generally represent state-of-the-art treatment for patients with SCLC. Despite recent advances, the standard therapy for SCLC as outlined in these guidelines still needs to be improved. Thus, participation in clinical trials should be strongly encouraged.
Smoking cessation should be strongly promoted (1-800-QUIT-NOW is the national access number to state-based quitline services; www.smokefree.gov); former smokers should be strongly encouraged to remain abstinent. Patients who smoke have increased toxicity during treatment and shorter survival.9 Programs using behavioral counseling combined with FDA-approved medications that promote smoking cessation can be very useful (www.ahrq.gov/clinic/tobacco/tobaqrg.htm).
NCCN Clinical Practice Guidelines in Oncology: Small Cell Lung Cancer, Version 2.2013
Version 2.2013, 07-06-12 ©2013 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 11, 1; 10.6004/jnccn.2013.0011
NCCN Clinical Practice Guidelines in Oncology: Small Cell Lung Cancer, Version 2.2013
Version 2.2013, 07-06-12 ©2013 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 11, 1; 10.6004/jnccn.2013.0011
NCCN Clinical Practice Guidelines in Oncology: Small Cell Lung Cancer, Version 2.2013
Version 2.2013, 07-06-12 ©2013 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 11, 1; 10.6004/jnccn.2013.0011
NCCN Clinical Practice Guidelines in Oncology: Small Cell Lung Cancer, Version 2.2013
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Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 11, 1; 10.6004/jnccn.2013.0011
NCCN Clinical Practice Guidelines in Oncology: Small Cell Lung Cancer, Version 2.2013
Version 2.2013, 07-06-12 ©2013 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 11, 1; 10.6004/jnccn.2013.0011
NCCN Clinical Practice Guidelines in Oncology: Small Cell Lung Cancer, Version 2.2013
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Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 11, 1; 10.6004/jnccn.2013.0011
NCCN Clinical Practice Guidelines in Oncology: Small Cell Lung Cancer, Version 2.2013
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Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 11, 1; 10.6004/jnccn.2013.0011
NCCN Clinical Practice Guidelines in Oncology: Small Cell Lung Cancer, Version 2.2013
Version 2.2013, 07-06-12 ©2013 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 11, 1; 10.6004/jnccn.2013.0011
NCCN Clinical Practice Guidelines in Oncology: Small Cell Lung Cancer, Version 2.2013
Version 2.2013, 07-06-12 ©2013 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 11, 1; 10.6004/jnccn.2013.0011
NCCN Clinical Practice Guidelines in Oncology: Small Cell Lung Cancer, Version 2.2013
Version 2.2013, 07-06-12 ©2013 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 11, 1; 10.6004/jnccn.2013.0011
NCCN Clinical Practice Guidelines in Oncology: Small Cell Lung Cancer, Version 2.2013
Version 2.2013, 07-06-12 ©2013 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 11, 1; 10.6004/jnccn.2013.0011
NCCN Clinical Practice Guidelines in Oncology: Small Cell Lung Cancer, Version 2.2013
Version 2.2013, 07-06-12 ©2013 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 11, 1; 10.6004/jnccn.2013.0011
Pathology
SCLC is a malignant epithelial tumor consisting of small cells with scant cytoplasm, ill-defined cell borders, finely granular nuclear chromatin, and absent or inconspicuous nucleoli.10 The cells are round, oval, or spindle-shaped; nuclear molding is prominent. The mitotic count is high. Up to 30% of autopsies in patients with SCLC reveal areas of non-small cell carcinoma differentiation; this finding is more commonly detected in specimens from previously treated patients and suggests that pulmonary carcinogenesis occurs in a pluripotent stem cell capable of differentiation along divergent pathways.
Although 95% of small cell carcinomas originate in the lung, they can also arise from extrapulmonary sites, including the nasopharynx, gastrointestinal tract, and genitourinary tract.11-13 Both pulmonary and extrapulmonary small cell carcinomas have similar clinical and biologic behaviors, leading to high potential for widespread metastases. However, unlike SCLC, malignant cells from patients with extrapulmonary small cell carcinoma do not exhibit macromolecular 3p deletions, a finding that suggests a different pathogenesis.14
Nearly all SCLCs are immunoreactive for keratin, epithelial membrane antigen, and thyroid transcription factor-1 (TTF-1). Most SCLCs also stain positively for markers of neuroendocrine differentiation, including chromogranin A, neuron-specific enolase, neural cell adhesion molecule (NCAM; CD56), and synaptophysin. However, these markers alone cannot be used to distinguish SCLC from NSCLC, because approximately 10% of NSCLC cancers will be immunoreactive for at least 1 of these neuroendocrine markers.15
Clinical Manifestations, Staging, and Prognostic Factors
Clinical Manifestations
SCLC typically presents as a large hilar mass and bulky mediastinal lymphadenopathy that cause cough and dyspnea. Frequently, patients present with symptoms of widespread metastatic disease, such as weight loss, debility, bone pain, and neurologic compromise. It is uncommon for patients to present with a solitary peripheral nodule without central adenopathy. In this situation, fine-needle aspiration may not adequately differentiate small cell carcinoma from low-grade (typical carcinoid), intermediate-grade (atypical carcinoid), or high-grade (large-cell) neuroendocrine carcinoma (see the complete version of the NCCN Guidelines for SCLC and Lung Neuroendocrine Tumors at NCCN.org).16-18
The National Lung Screening Trial reported that screening with annual, low-dose, spiral CT scans decreased lung cancer-specific mortality and all-cause mortality in asymptomatic high-risk individuals (www.cancer.gov/newscenter/qa/2002/nlstqaQA; see the NCCN Guidelines for Lung Cancer Screening, available at NCCN.org).19 Although CT screening can detect early-stage NSCLC, it does not seem to be useful for detecting early-stage SCLC.19 This is probably because of the aggressiveness of SCLC, which results in the development of symptomatic disease between annual scans, thereby limiting the potential effect on mortality.20
Many neurologic and endocrine paraneoplastic syndromes are associated with SCLC.21-23 Neurologic syndromes include Lambert-Eaton myasthenic syndrome, encephalomyelitis, and sensory neuropathy. Patients with Lambert-Eaton syndrome present with proximal leg weakness caused by antibodies directed against the voltage-gated calcium channels.24,25 Paraneoplastic encephalomyelitis and sensory neuropathy are caused by the production of an antibody (anti-Hu) that cross-reacts with both small cell carcinoma antigens and human neuronal RNA-binding proteins, resulting in multiple neurologic deficits.26
SCLC cells sometimes produce polypeptide hormones, including vasopressin (antidiuretic hormone [ADH]) and adrenocorticotropic hormone, which cause hyponatremia of malignancy (ie, syndrome of inappropriate ADH secretion [SIADH]) and Cushing syndrome, respectively.27,28 In patients with SCLC, SIADH occurs more frequently than Cushing syndrome. Cancer treatment and/or supportive care (eg, cisplatin, opiates) may also cause hyponatremia.29,30 Treatment for SIADH includes fluid restriction (which is difficult for patients because of increased thirst), demeclocycline, or vasopressin receptor inhibitors (ie, conivaptan, tolvaptan; see page 84).29,31,32 ADH levels and hyponatremia usually improve after successful treatment of SCLC.30
Staging
The Veteran’s Administration Lung Group’s 2-stage classification scheme has been routinely used to define the extent of disease in patients with SCLC (see Table 1 in the complete version of these guidelines at NCCN.org [ST-1]): 1) extensive-stage disease is defined as disease beyond the ipsilateral hemithorax, including malignant pleural or pericardial effusion or hematogenous metastases; and 2) limited-stage disease is defined as disease confined to the ipsilateral hemithorax, which can be safely encompassed within a radiation field.33 Contralateral mediastinal and ipsilateral supraclavicular lymphadenopathy are generally classified as limited-stage disease, whereas the classification of contralateral hilar and supraclavicular lymphadenopathy is more controversial.34 Approximately two-thirds of patients present with overt hematogenous metastases, which commonly involve the contralateral lung, liver, adrenal glands, brain, bones, and/or bone marrow.
A lung cancer TNM staging system was developed by the International Association of the Study of Lung Cancer (IASLC) and adopted by the AJCC Cancer Staging Manual 7th edition (see Tables 2 and 3 in the complete version of these guidelines at NCCN.org [ST-1 and ST-2]).35-39 This staging system is applicable to both NSCLC and SCLC based on studies by the IASLC that showed the prognostic significance of the various stage designations in both diseases.35,39 Using the TNM staging system, extensive-stage SCLC is Tany,Nany,M1a/b, and T3-4 because of multiple lung nodules (see Table 1, available at NCCN.org [ST-1]).
Because most of the literature on SCLC classifies patients based on limited- or extensive-stage disease, these definitions are still most relevant for clinical decision making. For now, application of the TNM system will not change how patients are treated; however, clinical research studies should begin to use the TNM system, because it will allow for more precise assessments of prognosis and specific therapy in the future. Therefore, the SCLC algorithm was revised to include the TNM staging information (see Table 2, at NCCN.org [ST-1]).
Full staging includes a history and physical examination; CT scan (with intravenous contrast) of the chest, liver, and adrenal glands; and brain imaging using MRI (preferred) or CT scan (with intravenous contrast).34 However, once a patient has been found to have extensive-stage disease, further staging is optional, except for brain imaging. Because of the aggressive nature of SCLC, staging should not delay the onset of treatment for more than 1 week; otherwise, many patients may become more seriously ill in the interval, with a significant decline in their performance status (PS). Unilateral bone marrow aspirates and biopsies may be indicated in select patients with nucleated red blood cells on peripheral blood smear, neutropenia, or thrombocytopenia and no other evidence of metastatic disease. Bone marrow involvement as the only site of extensive-stage disease occurs in fewer than 5% of patients.
PET scans can increase staging accuracy in patients with SCLC, because SCLC is a highly metabolic disease.40-44 PET/CT is superior to PET alone.44 Approximately 19% of patients who undergo PET are upstaged from limited- to extensive-stage disease, whereas only 8% are downstaged from extensive- to limited-stage disease.34 For most metastatic sites, PET/CT is superior to standard imaging; however, PET/CT is inferior to MRI or CT for the detection of brain metastases (see the NCCN Clinical Practice Guidelines in Oncology for Central Nervous System Cancers; to view the most recent version of these guidelines, visit NCCN.org).45 Changes in management based on PET staging were reported in approximately 27% of patients, mainly because of alterations in the planned radiation field as a result of improved detection of intrathoracic sites of disease.34,41,46,47 Although PET/CT seems to improve staging accuracy in SCLC, pathologic confirmation is still required for PET/CT-detected lesions that result in upstaging.
Mediastinal staging is typically not required for patients with extensive-stage disease because they are not candidates for surgical resection, and non-surgical treatment is usually planned. Thoracentesis with cytological analysis is recommended if a pleural effusion is large enough to be safely accessed via ultrasound guidance. If thoracentesis does not show malignant cells, then thoracoscopy can be considered to document pleural involvement, which would indicate extensive-stage disease.
Staging should not focus only on sites of symptomatic disease or on sites suggested by laboratory tests. Bone scans are positive in up to 30% of patients without bone pain or an abnormal alkaline phosphatase level. Brain imaging (MRI preferred or CT scan) can identify central nervous system metastases in 10% to 15% of patients at diagnosis, of which approximately 30% are asymptomatic. Early treatment of brain metastases results in less chronic neurologic morbidity, arguing for the usefulness of early diagnosis in asymptomatic patients.
Prognostic Factors
Extensive-stage disease, poor PS (3-4), weight loss, and markers associated with excessive bulk of disease (eg, lactate dehydrogenase [LDH]) are the most important adverse prognostic factors. Younger age, good PS, normal creatinine level, normal LDH, and a single metastatic site are favorable prognostic factors in patients with extensive-stage disease.48-50
Chemotherapy
For all patients with SCLC, chemotherapy is an essential component of appropriate treatment.7 Adjuvant chemotherapy is recommended for those who have undergone surgical resection. For patients with extensive-stage disease, chemotherapy alone is the recommended treatment, although radiotherapy may be used in select patients for palliation of symptoms (see pages 81 and 85 for recommended regimens). In patients with extensive disease and brain metastases, chemotherapy can be given either before or after whole-brain radiotherapy, depending on whether the patient has neurologic symptoms (see page 81).8,51
Single-agent and combination chemotherapy regimens have been shown to be active in SCLC.52-54 Etoposide and cisplatin (EP) is the most commonly used initial combination chemotherapy regimen (see page 85).7,55,56 This combination replaced alkylator/anthracycline-based regimens based on its superiority in both efficacy and toxicity in the limited-stage setting.57
In clinical practice, carboplatin is frequently substituted for cisplatin to reduce the risk of emesis, neuropathy, and nephropathy. However, the use of carboplatin carries a greater risk of myelosuppression.58 Small randomized trials have suggested similar efficacy of cisplatin and carboplatin in patients with SCLC.59,60 A meta-analysis of 4 randomized studies compared cisplatin-based versus carboplatin-based regimens in patients with SCLC.61 Of 663 patients included in this meta-analysis, 32% had limited-stage and 68% had extensive-stage disease. No significant difference was observed in response rate (67% vs. 66%), progression-free survival (5.5 vs. 5.3 months), or overall survival (9.6 vs. 9.4 months) in patients receiving cisplatin-containing versus carboplatin-containing regimens, suggesting equivalent efficacy in patients with SCLC.
Many other combinations have been evaluated in patients with extensive-stage disease, with little consistent evidence of benefit when compared with EP. The panel recommends etoposide plus platinum as the standard regimen for patients with SCLC. Recently, the combination of irinotecan and a platinum agent has provided the greatest challenge to EP. Initially, a small phase III trial performed in Japan reported that patients with extensive-stage SCLC who were treated with irinotecan plus cisplatin experienced a median survival of 12.8 months compared with 9.4 months for patients treated with EP (P=.002).62 In addition, the 2-year survival was 19.5% in the irinotecan plus cisplatin group versus 5.2% in the EP group.62 However, 2 subsequent large phase III trials performed in the United States comparing irinotecan plus cisplatin versus EP failed to show a significant difference in response rate or overall survival between the regimens.63,64
A randomized phase II trial (n=70) comparing carboplatin and irinotecan versus carboplatin and etoposide showed a modest improvement in progression-free survival with the irinotecan combination.65 A phase III randomized trial (n=220) found that median overall survival was slightly improved with irinotecan and carboplatin compared with carboplatin and oral etoposide (8.5 vs. 7.1 months; P=.04).66 Based on these findings, the carboplatin and irinotecan regimen has been added to these guidelines as an option for patients with extensive-stage disease. A recent meta-analysis suggests an improvement in progression-free survival and overall survival with irinotecan plus platinum regimens compared with etoposide plus platinum regimens.67 However, this meta-analysis was not performed using individual patient data. In addition, the relatively small absolute survival benefit must be balanced against the toxicity profile of irinotecan-based regimens. Therefore, the panel continues to recommend etoposide plus platinum as the standard regimen for patients with SCLC.
In patients with extensive-stage disease, response rates of 60% to 70% can be achieved with combination chemotherapy alone.52 Unfortunately, median survival rates are only 9 to 11 months for patients with extensive-stage disease. After appropriate treatment, the 2-year survival rate is less than 5% in those with extensive-stage disease.68
Many strategies have been evaluated in an effort to improve on the results that have been achieved with standard treatment for extensive-stage SCLC, including the addition of a third agent to standard 2-drug regimens. In 2 trials, the addition of ifosfamide (or cyclophosphamide plus an anthracycline) to EP showed a modest survival advantage for patients with extensive disease.69,70 However, these findings have not been uniformly observed, and the addition of an alkylating agent, with or without an anthracycline, significantly increases hematologic toxicity compared with EP alone.71 Similarly, the addition of paclitaxel to either cisplatin or carboplatin plus etoposide yielded promising results in phase II trials but did not improve survival, and was associated with unacceptable toxicity in a subsequent phase III study.72 The use of maintenance or consolidation chemotherapy beyond 4 to 6 cycles of standard treatment produces a minor prolongation of duration of response without improving survival and carries a greater risk of cumulative toxicity.73
The inability to destroy residual cells, despite the initial chemosensitivity of SCLC, suggests the existence of cancer stem cells that are relatively resistant to cytotoxic therapy. To overcome drug resistance, alternating or sequential combination therapies have been designed to expose the tumor to as many active cytotoxic agents as possible during initial treatment.74 However, randomized trials have failed to show improved progression-free or overall survival with this approach.75,76
Multidrug cyclic weekly therapy was designed to increase dose intensity. Early phase II results of this approach were promising, although favorable patient selection was of some concern.77,78 Nevertheless, no survival benefits were documented in randomized trials, and excessive treatment-related mortality was noted with multidrug cyclic weekly regimens.79-82
The role of higher-dose therapy for patients with SCLC remains controversial.83 Higher complete and partial response rates, and modestly longer median survival times, have been observed in patients receiving high doses compared with those given conventional doses of the same agents.84 In general, however, randomized trials comparing conventional doses with an incrementally increased dose intensity up to 2 times the conventional dose have not consistently shown an increase in response rate or survival.85-88 In addition, a meta-analysis of trials that compared standard versus dose-intense variations of the CAV (cyclophosphamide, doxorubicin [Adriamycin], and vincristine) and EP regimens found that increased relative dose intensity resulted in only a small, clinically insignificant enhancement of median survival in patients with extensive-stage disease.89
Currently available cytokines (eg, granulocyte-macrophage colony-stimulating factor, granulocyte colony-stimulating factor) can ameliorate chemotherapy-induced myelosuppression and reduce the incidence of febrile neutropenia, but cumulative thrombocytopenia remains dose-limiting. Although trials involving patients with SCLC were instrumental in obtaining FDA approval for the clinical use of cytokines,90 little evidence suggests that maintenance of dose intensity with growth factors prolongs disease-free or overall survival, and the routine use of growth factors at the initiation of chemotherapy is not recommended.
The potential benefits of antiangiogenic therapy have begun to be evaluated in SCLC. In extensive-stage SCLC, 2 phase II trials of platinum-based chemotherapy plus bevacizumab have yielded promising response and survival data.91-93 Randomized phase III trials are ongoing to determine if the addition of bevacizumab to chemotherapy improves survival in patients with extensive-stage SCLC. Currently, the panel does not recommend use of bevacizumab in patients with SCLC.
Overall, attempts to improve long-term survival rates in patients with SCLC through the addition of more agents or the use of dose-intense chemotherapy regimens, maintenance therapy, or alternating non-cross-resistant chemotherapy regimens have failed to yield significant advantages compared with standard approaches.
Elderly Patients
The incidence of lung cancer increases with age. Although the median age at diagnosis is 70 years, elderly patients are underrepresented in clinical trials.94 Although advanced chronologic age adversely affects tolerance to treatment, an individual patient’s functional status is much more useful than age in guiding clinical decision-making (see the NCCN Clinical Practice Guidelines in Oncology for Senior Adult Oncology; to view the most recent version of these guidelines, visit NCCN.org). Older patients who are functional in terms of their ability to perform activities of daily living should be treated with standard combination chemotherapy (and radiotherapy, if indicated). However, myelosuppression, fatigue, and lower organ reserves are encountered more frequently in elderly patients; therefore, they must be watched carefully during treatment to avoid excessive risk.
Greater attention to the needs and support systems of elderly patients is recommended to provide optimal care. Overall, elderly patients have a similar prognosis as stage-matched younger patients. Randomized trials have indicated that less-intensive treatment (eg, single-agent etoposide) is inferior to combination chemotherapy (eg, platinum plus etoposide) in elderly patients with good PS (0-2).95,96 Several other strategies have been evaluated in elderly patients with SCLC.60,97-99 The use of 4 cycles of carboplatin plus etoposide seems to yield favorable results, because the area-under-the-curve (AUC) dosing of carboplatin takes into account the declining renal function of the aging patient.99 However, targeting carboplatin to an AUC of 5, rather than 6, may be more reasonable in this population.100 The usefulness of short-course, full-intensity chemotherapy has also been explored in elderly or infirm patients, and the results with only 2 cycles of chemotherapy seem to be acceptable, although this approach has not been directly compared with standard therapy.101
Second-Line (Subsequent) Therapy
Although SCLC is very responsive to initial treatment, most patients experience relapse with relatively resistant disease.102,103 These patients have a median survival of only 4 to 5 months when treated with further chemotherapy. Second-line (ie, subsequent) chemotherapy provides significant palliation in many patients, although the likelihood of response is highly dependent on the time from initial therapy to relapse. If this interval is less than 3 months (refractory or resistant disease), response to most agents or regimens is poor (≤10%). If more than 3 months have elapsed (sensitive disease), expected response rates are approximately 25%.
Subsequent chemotherapy generally involves single-agent therapy. Based on phase II trials, active subsequent agents include paclitaxel, docetaxel, topotecan, irinotecan, vinorelbine, gemcitabine, ifosfamide, temozolomide, and oral etoposide (see page 85).56,104-108 Recent data suggest that temozolomide may be useful for patients with SCLC, especially those with brain metastases and methylated methyguanine-DNA methyltransferase.104
A randomized phase III trial compared single-agent intravenous topotecan with the combination regimen CAV.109 Both arms had similar response rates and survival, but intravenous topotecan caused less toxicity. In another phase III trial, oral topotecan improved overall survival when compared with best supportive care (26 vs. 14 weeks).110 Single-agent topotecan is FDA-approved as subsequent therapy for patients with SCLC who experience initial response to chemotherapy but then experience progression after 2 to 3 months. In the algorithm, topotecan is recommended as a subsequent agent for patients with relapsed SCLC (category 1 for relapse >2-3 months up to 6 months; category 2A for relapse <2-3 months).105,109,111 Either oral or intravenous topotecan may be used, because efficacy and toxicity seem to be similar with either route.110,111
Many practicing oncologists have noted excessive toxicity with the standard regimen of 1.5 mg/m2 of intravenous topotecan for 5 days, and studies suggest that an attenuated dose may be equally efficacious with lower toxicity.112 Published studies have yielded conflicting data regarding the usefulness of weekly topotecan in patients with relapsed SCLC, and this approach remains under investigation.113,114
Recent data from phase II studies suggest that amrubicin, an investigational anthracycline, has promising activity in patients with relapsed or refractory SCLC.115-117 However, grade 3/4 toxicity, primarily neutropenia, is common.118 A randomized phase II trial suggests that amrubicin may be more effective than topotecan as second-line therapy in patients with relapsed SCLC, with response rates of 44% and 15%, respectively (P=.02).119
The optimal duration of subsequent chemotherapy has not been fully explored, although its duration is usually short and the cumulative toxicity is frequently limiting even in patients who experience response. For these reasons, subsequent chemotherapy should be given until 2 cycles beyond best response, progression of disease, or development of unacceptable toxicity.
Radiotherapy
The Principles of Radiation Therapy section in the NCCN SCLC algorithm describes the radiation doses, target volumes, and normal tissue dose volume constraints for SCLC, and includes references to support the recommendations; PCI and treatment of brain metastases are also discussed. These radiotherapy principles were updated extensively in 2012, especially for PCI (see page 86). The Principles of Radiation Therapy section in the NCCN Guidelines for NSCLC may also be useful (eg, general principles of radiotherapy, palliative radiotherapy; to view the most recent version of these guidelines, visit NCCN.org).
This section describes the studies supporting the NCCN recommendations.
Thoracic Radiotherapy
The minimum standard for thoracic irradiation is CT-planned 3D conformal radiotherapy. More advanced technologies may also be used when needed (eg, 4D CT; see page 86). The radiation target volumes can be defined on the PET/CT scan obtained at the time of radiotherapy planning using definitions in reports 50 and 62 from the International Commission on Radiation Units & Measurement. However, the pre-chemotherapy PET/CT scan should be reviewed to include the originally involved lymph node regions in the treatment fields.120,121
The normal tissue constraints used for NSCLC are appropriate when using similar radiotherapy doses (see the NCCN Guidelines for NSCLC, available at NCCN.org). When using accelerated schedules (eg, 3-5 weeks), the spinal cord constraints from the CALGB 30610/RTOG 0538 protocol can be used as a guide (see page 86).122-124 Intensity-modulated radiation therapy may be considered in select patients (see page 86 and the NCCN Guidelines for NSCLC, available at NCCN.org).125
Based on the results of a randomized trial by Jeremic et al,126 the addition of sequential thoracic radiotherapy may be considered in select patients with low-bulk metastatic disease who have a complete or near-complete response after initial chemotherapy. In this trial, patients experiencing a complete response at distant metastatic sites after 3 cycles of EP were randomized to receive either 1) further EP or 2) accelerated hyperfractionated radiotherapy (ie, 54 Gy in 36 fractions over 18 treatment days) in combination with carboplatin plus etoposide.126 The investigators found that the addition of radiotherapy resulted in improved median overall survival (17 vs. 11 months).
PCI
Intracranial metastases occur in more than 50% of patients with SCLC. Randomized studies have shown that PCI is effective in decreasing the incidence of cerebral metastases, but most individual studies did not have sufficient power to show a meaningful survival advantage.127 A meta-analysis of all randomized PCI trials (using individual patient data) reported a 25% decrease in the 3-year incidence of brain metastases, from 58.6% in the control group to 33.3% in the PCI treated group.128 Thus, PCI seems to prevent (and not simply delay) the emergence of brain metastases. This meta-analysis also reported a 5.4% increase in 3-year survival in patients treated with PCI, from 15.3% in the control group to 20.7% in the PCI group.128 Although the number of patients with extensive-stage disease was small in this meta-analysis, the observed benefit was similar in patients with limited- and extensive-stage disease.
A randomized trial from the EORTC assessed PCI versus no PCI in 286 patients with extensive-stage SCLC whose disease had responded to initial chemotherapy. PCI decreased symptomatic brain metastases (14.6% vs. 40.4%) and increased the 1-year survival rate (27.1% vs. 13.3%) compared with controls.129 Although late complications may occur with PCI (eg, neurocognitive impairment), this is less of an issue in patients with extensive-stage SCLC because long-term survival is rare.130,131
Before the decision is made to administer PCI, a balanced discussion between the patient and physician is necessary. PCI is recommended (category 1) for patients with extensive-stage disease who attain a complete or partial response.129,132 The recommended regimens for PCI include 25 Gy in 10 daily fractions (2.5 Gy/fraction), 30 Gy in 10-15 daily fractions, or 24 Gy in 8 daily fractions (see page 86).128,129,132 Higher doses (eg, 36 Gy) increased mortality and toxicity when compared with standard doses (25 Gy).132,133 PCI should not be given concurrently with systemic chemotherapy, and high total radiotherapy dose (> 30 Gy) should be avoided because of the increased risk of neurotoxicity. Fatigue, headache, and nausea/vomiting are the most common acute toxic effects after PCI.132,134
Palliative Treatment
Radiotherapy can provide excellent palliation for patients with localized symptomatic sites of disease (ie, painful bony lesions, spinal cord compression, obstructive atelectasis) or with brain metastases (see page 81 and the NCCN Guidelines for NSCLC, available at NCCN.org).135-137 Orthopedic stabilization may be useful in patients at high risk for fracture because of osseous structural impairment. Because patients with SCLC often have a short lifespan, surgery is not usually recommended for spinal cord compression. Whole-brain radiotherapy is recommended for brain metastases in patients with SCLC because of the frequent occurrence of multiple metastases (see page 86 and the NCCN Guidelines for Central Nervous System Cancers, available at NCCN.org).138 Although late complications may occur with whole-brain radiotherapy (eg, neurocognitive impairment), this is less of an issue in patients with brain metastases SCLC because long-term survival is rare.130
Surveillance
The schedule for follow-up examinations is shown in the algorithm (see page 82); the frequency of surveillance decreases during subsequent years because of the declining risk of recurrence. PET/CT or brain MRI (or CT) is not recommended for routine follow-up. If a new pulmonary nodule develops, it should prompt evaluation for a new primary lung cancer, because second primary tumors are a frequent occurrence in patients who are cured of SCLC.139,140 Smoking cessation should be encouraged for all patients with SCLC (www.ahrq.gov/clinic/tobacco/tobaqrg.htm), because second primary tumors occur less commonly in patients who quit smoking.141-143 Former smokers should be encouraged to remain abstinent.
Individual Disclosures for the NCCN Small Cell Lung Cancer Panel
References
- 1↑
Oberg K, Hellman P, Kwekkeboom D, Jelic S. Neuroendocrine bronchial and thymic tumours: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2010;21(Suppl 5):v220–222.
- 2↑
Govindan R, Page N, Morgensztern D 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;24:4539–4544.
- 3↑
Navada S, Lai P, Schwartz A, Kalemkerian G. Temporal trends in small cell lung cancer: analysis of the national Surveillance, Epidemiology, and End-Results (SEER) database [abstract]. J Clin Oncol 2006;24(Suppl 18):Abstract 7082.
- 5↑
Murray N, Turrisi AT III. A review of first-line treatment for small-cell lung cancer. J Thorac Oncol 2006;1:270–278.
- 6↑
Hann CL, Rudin CM. Management of small-cell lung cancer: incremental changes but hope for the future. Oncology (Williston Park) 2008;22:1486–1492.
- 7↑
Johnson BE, Janne PA. Basic treatment considerations using chemotherapy for patients with small cell lung cancer. Hematol Oncol Clin North Am 2004;18:309–322.
- 8↑
Demedts IK, Vermaelen KY, van Meerbeeck JP. Treatment of extensive-stage small cell lung carcinoma: current status and future prospects. Eur Respir J 2010;35:202–215.
- 9↑
Videtic GM, Stitt LW, Dar AR et al.. Continued cigarette smoking by patients receiving concurrent chemoradiotherapy for limited-stage small-cell lung cancer is associated with decreased survival. J Clin Oncol 2003;21:1544–1549.
- 11↑
Brenner B, Tang LH, Klimstra DS, Kelsen DP. Small-cell carcinomas of the gastrointestinal tract: a review. J Clin Oncol 2004;22:2730–2739.
- 12
Galanis E, Frytak S, Lloyd RV. Extrapulmonary small cell carcinoma. Cancer 1997;79:1729–1736.
- 13↑
Remick SC, Ruckdeschel JC. Extrapulmonary and pulmonary small-cell carcinoma: tumor biology, therapy, and outcome. Med Pediatr Oncol 1992;20:89–99.
- 14↑
Johnson BE, Whang-Peng J, Naylor SL et al.. Retention of chromosome 3 in extrapulmonary small cell cancer shown by molecular and cytogenetic studies. J Natl Cancer Inst 1989;81:1223–1228.
- 15↑
Guinee DG Jr, Fishback NF, Koss MN et al.. The spectrum of immunohistochemical staining of small-cell lung carcinoma in specimens from transbronchial and open-lung biopsies. Am J Clin Pathol 1994;102:406–414.
- 17
Gustafsson BI, Kidd M, Chan A et al.. Bronchopulmonary neuroendocrine tumors. Cancer 2008;113:5–21.
- 18↑
Renshaw AA, Haja J, Lozano RL, Wilbur DC. Distinguishing carcinoid tumor from small cell carcinoma of the lung: correlating cytologic features and performance in the College of American Pathologists Non-Gynecologic Cytology Program. Arch Pathol Lab Med 2005;129:614–618.
- 19↑
Aberle DR, Adams AM, Berg CD et al.. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 2011;365:395–409.
- 20↑
Cuffe S, Moua T, Summerfield R et al.. Characteristics and outcomes of small cell lung cancer patients diagnosed during two lung cancer computed tomographic screening programs in heavy smokers. J Thorac Oncol 2011;6:818–822.
- 21↑
Gandhi L, Johnson BE. Paraneoplastic syndromes associated with small cell lung cancer. J Natl Compr Canc Netw 2006;4:631–638.
- 22
Kazarian M, Laird-Offringa IA. Small-cell lung cancer-associated autoantibodies: potential applications to cancer diagnosis, early detection, and therapy. Mol Cancer 2011;10:33.
- 23↑
Marchioli CC, Graziano SL. Paraneoplastic syndromes associated with small cell lung cancer. Chest Surg Clin N Am 1997;7:65–80.
- 24↑
Titulaer MJ, Wirtz PW, Willems LN et al.. Screening for small-cell lung cancer: a follow-up study of patients with Lambert-Eaton myasthenic syndrome. J Clin Oncol 2008;26:4276–4281.
- 25↑
Meriney SD, Hulsizer SC, Lennon VA, Grinnell AD. Lambert-Eaton myasthenic syndrome immunoglobulins react with multiple types of calcium channels in small-cell lung carcinoma. Ann Neurol 1996;40:739–749.
- 26↑
Graus F, Keime-Guibert F, Rene R et al.. Anti-Hu-associated paraneoplastic encephalomyelitis: analysis of 200 patients. Brain 2001;124:1138–1148.
- 27↑
Delisle L, Boyer MJ, Warr D et al.. Ectopic corticotropin syndrome and small-cell carcinoma of the lung. Clinical features, outcome, and complications. Arch Intern Med 1993;153:746–752.
- 28↑
Johnson BE, Chute JP, Rushin J et al.. A prospective study of patients with lung cancer and hyponatremia of malignancy. Am J Respir Crit Care Med 1997;156:1669–1678.
- 29↑
Castillo JJ, Vincent M, Justice E. Diagnosis and management of hyponatremia in cancer patients. Oncologist 2012;17:756–765.
- 30↑
Pelosof LC, Gerber DE. Paraneoplastic syndromes: an approach to diagnosis and treatment. Mayo Clin Proc 2010;85:838–854.
- 31↑
Schrier RW, Gross P, Gheorghiade M et al.. Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia. N Engl J Med 2006;355:2099–2112.
- 32↑
Verbalis JG, Zeltser D, Smith N et al.. Assessment of the efficacy and safety of intravenous conivaptan in patients with euvolaemic hyponatraemia: subgroup analysis of a randomized, controlled study. Clin Endocrinol (Oxf) 2008;69:159–168.
- 33↑
Micke P, Faldum A, Metz T 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;37:271–276.
- 35↑
Shepherd FA, Crowley J, Van Houtte P et al.. The International Association for the Study of Lung Cancer lung cancer staging project: proposals regarding the clinical staging of small cell lung cancer in the forthcoming (seventh) edition of the tumor, node, metastasis classification for lung cancer. J Thorac Oncol 2007;2:1067–1077.
- 36
Ignatius Ou SH, Zell JA. The applicability of the proposed IASLC staging revisions to small cell lung cancer (SCLC) with comparison to the current UICC 6th TNM Edition. J Thorac Oncol 2009;4:300–310.
- 37
Vallieres E, Shepherd FA, Crowley J et al.. The IASLC Lung Cancer Staging Project: proposals regarding the relevance of TNM in the pathologic staging of small cell lung cancer in the forthcoming (seventh) edition of the TNM classification for lung cancer. J Thorac Oncol 2009;4:1049–1059.
- 38
Edge SB, Byrd DR, Compton CC et al.. AJCC Cancer Staging Manual, 7th ed. New York, NY: Springer; 2010.
- 39↑
Goldstraw P, Crowley J, Chansky K et al.. The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of malignant tumours. J Thorac Oncol 2007;2:706–714.
- 40↑
Podoloff DA, Ball DW, Ben-Josef E et al.. NCCN task force: clinical utility of PET in a variety of tumor types. J Natl Compr Canc Netw 2009;7(Suppl 2):S1–26.
- 41↑
Bradley JD, Dehdashti F, Mintun MA et al.. Positron emission tomography in limited-stage small-cell lung cancer: a prospective study. J Clin Oncol 2004;22:3248–3254.
- 42
Kut V, Spies W, Spies S et al.. Staging and monitoring of small cell lung cancer using [18F]fluoro-2-deoxy-D-glucose-positron emission tomography (FDG-PET). Am J Clin Oncol 2007;30:45–50.
- 43
Azad A, Chionh F, Scott AM et al.. High impact of 18F-FDG-PET on management and prognostic stratification of newly diagnosed small cell lung cancer. Mol Imaging Biol 2010;12:443–451.
- 44↑
Fischer BM, Mortensen J, Langer SW et al.. A prospective study of PET/CT in initial staging of small-cell lung cancer: comparison with CT, bone scintigraphy and bone marrow analysis. Ann Oncol 2007;18:338–345.
- 45↑
Brink I, Schumacher T, Mix M et al.. Impact of [18F]FDG-PET on the primary staging of small-cell lung cancer. Eur J Nucl Med Mol Imaging 2004;31:1614–1620.
- 46↑
Kamel EM, Zwahlen D, Wyss MT et al.. Whole-body (18)F-FDG PET improves the management of patients with small cell lung cancer. J Nucl Med 2003;44:1911–1917.
- 47↑
Vinjamuri M, Craig M, Campbell-Fontaine A et al.. Can positron emission tomography be used as a staging tool for small-cell lung cancer? Clin Lung Cancer 2008;9:30–34.
- 48↑
Foster NR, Mandrekar SJ, Schild SE et al.. Prognostic factors differ by tumor stage for small cell lung cancer: a pooled analysis of North Central Cancer Treatment Group trials. Cancer 2009;115:2721–2731.
- 49
Albain KS, Crowley JJ, LeBlanc M, Livingston RB. Determinants of improved outcome in small-cell lung cancer: an analysis of the 2,580-patient Southwest Oncology Group data base. J Clin Oncol 1990;8:1563–1574.
- 50↑
Yip D, Harper PG. Predictive and prognostic factors in small cell lung cancer: current status. Lung Cancer 2000;28:173–185.
- 51↑
Postmus PE, Haaxma-Reiche H, Gregor A et al.. Brain-only metastases of small cell lung cancer; efficacy of whole brain radiotherapy. An EORTC phase II study. Radiother Oncol 1998;46:29–32.
- 52↑
Simon M, Argiris A, Murren JR. Progress in the therapy of small cell lung cancer. Crit Rev Oncol Hematol 2004;49:119–133.
- 53
Spira A, Ettinger DS. Multidisciplinary management of lung cancer. N Engl J Med 2004;350:379–392.
- 55↑
Evans WK, Shepherd FA, Feld R et al.. VP-16 and cisplatin as first-line therapy for small-cell lung cancer. J Clin Oncol 1985;3:1471–1477.
- 57↑
Sundstrom S, Bremnes RM, Kaasa S et al.. Cisplatin and etoposide regimen is superior to cyclophosphamide, epirubicin, and vincristine regimen in small-cell lung cancer: results from a randomized phase III trial with 5 years’ follow-up. J Clin Oncol 2002;20:4665–4672.
- 58↑
Bishop JF, Raghavan D, Stuart-Harris R et al.. Carboplatin (CBDCA, JM-8) and VP-16-213 in previously untreated patients with small-cell lung cancer. J Clin Oncol 1987;5:1574–1578.
- 59↑
Skarlos DV, Samantas E, Kosmidis P et al.. Randomized comparison of etoposide-cisplatin vs. etoposide-carboplatin and irradiation in small-cell lung cancer. A Hellenic Co-operative Oncology Group study. Ann Oncol 1994;5:601–607.
- 60↑
Okamoto H, Watanabe K, Kunikane H et al.. Randomised phase III trial of carboplatin plus etoposide vs split doses of cisplatin plus etoposide in elderly or poor-risk patients with extensive disease small-cell lung cancer: JCOG 9702. Br J Cancer 2007;97:162–169.
- 61↑
Rossi A, Di Maio M, Chiodini P 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;30:1692–1698.
- 62↑
Noda K, Nishiwaki Y, Kawahara M et al.. Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer. N Engl J Med 2002;346:85–91.
- 63↑
Lara PN Jr, Natale R, Crowley J et al.. Phase III trial of irinotecan/cisplatin compared with etoposide/cisplatin in extensive-stage small-cell lung cancer: clinical and pharmacogenomic results from SWOG S0124. J Clin Oncol 2009;27:2530–2535.
- 64↑
Hanna N, Bunn PA Jr, Langer C et al.. Randomized phase III trial comparing irinotecan/cisplatin with etoposide/cisplatin in patients with previously untreated extensive-stage disease small-cell lung cancer 10.1200/JCO.2005.04.8595. J Clin Oncol 2006;24:2038–2043.
- 65↑
Schmittel A, Fischer von Weikersthal L, Sebastian M et al.. A randomized phase II trial of irinotecan plus carboplatin versus etoposide plus carboplatin treatment in patients with extended disease small-cell lung cancer. Ann Oncol 2006;17:663–667.
- 66↑
Hermes A, Bergman B, Bremnes R et al.. Irinotecan plus carboplatin versus oral etoposide plus carboplatin in extensive small-cell lung cancer: a randomized phase III trial. J Clin Oncol 2008;26:4261–4267.
- 67↑
Lima JP, dos Santos LV, Sasse EC et al.. Camptothecins compared with etoposide in combination with platinum analog in extensive stage small cell lung cancer: systematic review with meta-analysis. J Thorac Oncol 2010;5:1986–1993.
- 68↑
Chute JP, Chen T, Feigal E et al.. Twenty years of phase III trials for patients with extensive-stage small-cell lung cancer: perceptible progress. J Clin Oncol 1999;17:1794–1801.
- 69↑
Loehrer PJ Sr, Ansari R, Gonin R et al.. Cisplatin plus etoposide with and without ifosfamide in extensive small-cell lung cancer: a Hoosier Oncology Group study. J Clin Oncol 1995;13:2594–2599.
- 70↑
Pujol JL, Daures JP, Riviere A et al.. Etoposide plus cisplatin with or without the combination of 4’-epidoxorubicin plus cyclophosphamide in treatment of extensive small-cell lung cancer: a French Federation of Cancer Institutes multicenter phase III randomized study. J Natl Cancer Inst 2001;93:300–308.
- 71↑
Miyamoto H, Nakabayashi T, Isobe H et al.. A phase III comparison of etoposide/cisplatin with or without added ifosfamide in small-cell lung cancer. Oncology 1992;49:431–435.
- 72↑
Niell HB, Herndon JE II, Miller AA et al.. Randomized phase III intergroup trial of etoposide and cisplatin with or without paclitaxel and granulocyte colony-stimulating factor in patients with extensive-stage small-cell lung cancer: Cancer and Leukemia Group B trial 9732. J Clin Oncol 2005;23:3752–3759.
- 73↑
Schiller JH, Adak S, Cella D et al.. Topotecan versus observation after cisplatin plus etoposide in extensive-stage small-cell lung cancer: E7593--a phase III trial of the Eastern Cooperative Oncology Group. J Clin Oncol 2001;19:2114–2122.
- 74↑
Goldie JH, Coldman AJ. A mathematic model for relating the drug sensitivity of tumors to their spontaneous mutation rate. Cancer Treat Rep 1979;63:1727–1733.
- 75↑
Fukuoka M, Furuse K, Saijo N et al.. Randomized trial of cyclophosphamide, doxorubicin, and vincristine versus cisplatin and etoposide versus alternation of these regimens in small-cell lung cancer. J Natl Cancer Inst 1991;83:855–861.
- 76↑
Roth BJ, Johnson DH, Einhorn LH et al.. Randomized study of cyclophosphamide, doxorubicin, and vincristine versus etoposide and cisplatin versus alternation of these two regimens in extensive small-cell lung cancer: a phase III trial of the Southeastern Cancer Study Group. J Clin Oncol 1992;10:282–291.
- 77↑
Miles DW, Earl HM, Souhami RL et al.. Intensive weekly chemotherapy for good-prognosis patients with small-cell lung cancer. J Clin Oncol 1991;9:280–285.
- 78↑
Murray N, Gelmon K, Shah A. Potential for long-term survival in extensive stage small-cell lung cancer (ESCLC) with CODE chemotherapy and radiotherapy [abstract]. Lung Cancer 1994;11(Suppl 1):99. Abstract 377.
- 79↑
Sculier JP, Paesmans M, Bureau G et al.. Multiple-drug weekly chemotherapy versus standard combination regimen in small-cell lung cancer: a phase III randomized study conducted by the European Lung Cancer Working Party. J Clin Oncol 1993;11:1858–1865.
- 80
Souhami RL, Rudd R, Ruiz de Elvira MC et al.. Randomized trial comparing weekly versus 3-week chemotherapy in small-cell lung cancer: a Cancer Research Campaign trial. J Clin Oncol 1994;12:1806–1813.
- 81
Fukuoka M, Masuda N, Negoro S et al.. CODE chemotherapy with and without granulocyte colony-stimulating factor in small-cell lung cancer. Br J Cancer 1997;75:306–309.
- 82↑
Murray N, Livingston RB, Shepherd FA et al.. Randomized study of CODE versus alternating CAV/EP for extensive-stage small-cell lung cancer: an Intergroup Study of the National Cancer Institute of Canada Clinical Trials Group and the Southwest Oncology Group. J Clin Oncol 1999;17:2300–2308.
- 83↑
Teicher BA. Preclinical models for high-dose therapy. In: Armitage JO, Antman KH, eds. High-Dose Cancer Therapy: Pharmacology, Hematopoietins, Stem Cells, 2nd ed. Baltimore, MD: Williams and Wilkins; 1995:14–42.
- 84↑
Cohen MH, Creaven PJ, Fossieck BE Jr et al.. Intensive chemotherapy of small cell bronchogenic carcinoma. Cancer Treat Rep 1977;61:349–354.
- 85↑
Johnson DH, Einhorn LH, Birch R et al.. A randomized comparison of high-dose versus conventional-dose cyclophosphamide, doxorubicin, and vincristine for extensive-stage small-cell lung cancer: a phase III trial of the Southeastern Cancer Study Group. J Clin Oncol 1987;5:1731–1738.
- 86
Ihde DC, Mulshine JL, Kramer BS et al.. Prospective randomized comparison of high-dose and standard-dose etoposide and cisplatin chemotherapy in patients with extensive-stage small-cell lung cancer. J Clin Oncol 1994;12:2022–2034.
- 87
Arriagada R, Le Chevalier T, Pignon JP et al.. Initial chemotherapeutic doses and survival in patients with limited small-cell lung cancer. N Engl J Med 1993;329:1848–1852.
- 88↑
Thatcher N, Girling DJ, Hopwood P et al.. Improving survival without reducing quality of life in small-cell lung cancer patients by increasing the dose-intensity of chemotherapy with granulocyte colony-stimulating factor support: results of a British Medical Research Council Multicenter Randomized Trial. Medical Research Council Lung Cancer Working Party. J Clin Oncol 2000;18:395–404.
- 89↑
Klasa RJ, Murray N, Coldman AJ. Dose-intensity meta-analysis of chemotherapy regimens in small-cell carcinoma of the lung. J Clin Oncol 1991;9:499–508.
- 90↑
Crawford J, Ozer H, Stoller R et al.. Reduction by granulocyte colony-stimulating factor of fever and neutropenia induced by chemotherapy in patients with small-cell lung cancer. N Engl J Med 1991;325:164–170.
- 91↑
Spigel DR, Townley PM, Waterhouse DM 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;29:2215–2222.
- 92
Spigel DR, Greco FA, Zubkus JD et al.. Phase II trial of irinotecan, carboplatin, and bevacizumab in the treatment of patients with extensive-stage small-cell lung cancer. J Thorac Oncol 2009;4:1555–1560.
- 93↑
Horn L, Dahlberg SE, Sandler AB et al.. Phase II study of cisplatin plus etoposide and bevacizumab for previously untreated, extensive-stage small-cell lung cancer: Eastern Cooperative Oncology Group study E3501. J Clin Oncol 2009;27:6006–6011.
- 95↑
Girling DJ. Comparison of oral etoposide and standard intravenous multidrug chemotherapy for small-cell lung cancer: a stopped multicentre randomised trial. Medical Research Council Lung Cancer Working Party. Lancet 1996;348:563–566.
- 96↑
Souhami RL, Spiro SG, Rudd RM et al.. Five-day oral etoposide treatment for advanced small-cell lung cancer: randomized comparison with intravenous chemotherapy. J Natl Cancer Inst 1997;89:577–580.
- 97↑
Neubauer M, Schwartz J, Caracandas J et al.. Results of a phase II study of weekly paclitaxel plus carboplatin in patients with extensive small-cell lung cancer with eastern cooperative oncology group performance status of 2, or age >= 70 years. J Clin Oncol 2004;22:1872–1877.
- 98
Westeel V, Murray N, Gelmon K et al.. New combination of the old drugs for elderly patients with small-cell lung cancer: a phase II study of the PAVE regimen. J Clin Oncol 1998;16:1940–1947.
- 99↑
Okamoto H, Watanabe K, Nishiwaki Y et al.. Phase II study of area under the plasma-concentration-versus-time curve-based carboplatin plus standard-dose intravenous etoposide in elderly patients with small-cell lung cancer. J Clin Oncol 1999;17:3540–3545.
- 100↑
Matsui K, Masuda N, Yana T et al.. Carboplatin calculated with Chatelut’s formula plus etoposide for elderly patients with small-cell lung cancer. Intern Med 2001;40:603–606.
- 101↑
Murray N, Grafton C, Shah A et al.. Abbreviated treatment for elderly, infirm, or noncompliant patients with limited-stage small-cell lung cancer. J Clin Oncol 1998;16:3323–3328.
- 102↑
Hurwitz JL, McCoy F, Scullin P, Fennell DA. New advances in the second-line treatment of small cell lung cancer. Oncologist 2009;14:986–994.
- 103↑
Schneider BJ. Management of recurrent small cell lung cancer. J Natl Compr Canc Netw 2008;6:323–331.
- 104↑
Pietanza MC, Kadota K, Huberman K et al.. Phase II trial of temozolomide in patients with relapsed sensitive or refractory small cell lung cancer, with assessment of methylguanine-DNA methyltransferase as a potential biomarker. Clin Cancer Res 2012;18:1138–1145.
- 105↑
Cheng S, Evans WK, Stys-Norman D, Shepherd FA. Chemotherapy for relapsed small cell lung cancer: a systematic review and practice guideline. J Thorac Oncol 2007;2:348–354.
- 106
Ettinger DS. New drugs for chemotherapy-naive patients with extensive-disease small cell lung cancer. Semin Oncol 2001;28:27–29.
- 107
Kelly K. New chemotherapy agents for small cell lung cancer. Chest 2000;117:156S–162S.
- 108↑
Masters GA, Declerck L, Blanke C et al.. Phase II trial of gemcitabine in refractory or relapsed small-cell lung cancer: Eastern Cooperative Oncology Group trial 1597. J Clin Oncol 2003;21:1550–1555.
- 109↑
von Pawel J, Schiller JH, Shepherd FA et al.. Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer. J Clin Oncol 1999;17:658–667.
- 110↑
O’Brien ME, Ciuleanu TE, Tsekov H et al.. Phase III trial comparing supportive care alone with supportive care with oral topotecan in patients with relapsed small-cell lung cancer. J Clin Oncol 2006;24:5441–5447.
- 111↑
Eckardt JR, von Pawel J, Pujol JL et al.. Phase III study of oral compared with intravenous topotecan as second-line therapy in small-cell lung cancer. J Clin Oncol 2007;25:2086–2092.
- 112↑
Huber RM, Reck M, Gosse H et al.. Efficacy of a toxicity-adjusted topotecan therapy in recurrent small cell lung cancer. Eur Respir J 2006;27:1183–1189.
- 113↑
Shah C, Ready N, Perry M et al.. A multi-center phase II study of weekly topotecan as second-line therapy for small cell lung cancer. Lung Cancer 2007;57:84–88.
- 114↑
Shipley DL, Hainsworth JD, Spigel DR et al.. Topotecan: weekly intravenous (IV) schedule similar to standard 5-day IV schedule as second-line therapy for relapsed small cell lung cancer (SCLC)—a Minnie Pearl Cancer Research Network phase II trial [abstract]. J Clin Oncol 2006;24(Suppl 18):Abstract 7083.
- 115↑
Ettinger DS, Jotte R, Lorigan P et al.. Phase II study of amrubicin as second-line therapy in patients with platinum-refractory small-cell lung cancer. J Clin Oncol 2010;28:2598–2603.
- 116
Inoue A, Sugawara S, Yamazaki K et al.. Randomized phase II trial comparing amrubicin with topotecan in patients with previously treated small-cell lung cancer: North Japan Lung Cancer Study Group Trial 0402. J Clin Oncol 2008;26:5401–5406.
- 117↑
Onoda S, Masuda N, Seto T et al.. Phase II trial of amrubicin for treatment of refractory or relapsed small-cell lung cancer: Thoracic Oncology Research Group Study 0301. J Clin Oncol 2006;24:5448–5453.
- 118↑
Shimokawa T, Shibuya M, Kitamura K et al.. Retrospective analysis of efficacy and safety of amrubicin in refractory and relapsed small-cell lung cancer. Int J Clin Oncol 2009;14:63–69.
- 119↑
Jotte R, Conkling P, Reynolds C 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;29:287–293.
- 120↑
Bogart JA, Herndon JE II, Lyss AP et al.. 70 Gy thoracic radiotherapy is feasible concurrent with chemotherapy for limited-stage small-cell lung cancer: analysis of Cancer and Leukemia Group B study 39808. Int J Radiat Oncol Biol Phys 2004;59:460–468.
- 121↑
Liengswangwong V, Bonner JA, Shaw EG et al.. Limited-stage small-cell lung cancer: patterns of intrathoracic recurrence and the implications for thoracic radiotherapy. J Clin Oncol 1994;12:496–502.
- 122↑
Kim TH, Cho KH, Pyo HR et al.. Dose-volumetric parameters for predicting severe radiation pneumonitis after three-dimensional conformal radiation therapy for lung cancer. Radiology 2005;235:208–215.
- 123
Rose J, Rodrigues G, Yaremko B et al.. Systematic review of dose-volume parameters in the prediction of esophagitis in thoracic radiotherapy. Radiother Oncol 2009;91:282–287.
- 124↑
Kong FM, Ritter T, Quint DJ et al.. Consideration of dose limits for organs at risk of thoracic radiotherapy: atlas for lung, proximal bronchial tree, esophagus, spinal cord, ribs, and brachial plexus. Int J Radiat Oncol Biol Phys 2011;81:1442–1457.
- 125↑
Shirvani SM, Komaki R, Heymach JV et al.. Positron emission tomography/computed tomography-guided intensity-modulated radiotherapy for limited-stage small-cell lung cancer. Int J Radiat Oncol Biol Phys 2012;82:e91–97.
- 126↑
Jeremic B, Shibamoto Y, Nikolic N et al.. Role of radiation therapy in the combined-modality treatment of patients with extensive disease small-cell lung cancer: a randomized study. J Clin Oncol 1999;17:2092–2099.
- 127↑
Arriagada R, Le Chevalier T, Borie F et al.. Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. J Natl Cancer Inst 1995;87:183–190.
- 128↑
Auperin A, Arriagada R, Pignon JP et al.. Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group. N Engl J Med 1999;341:476–484.
- 129↑
Slotman B, Faivre-Finn C, Kramer G et al.. Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med 2007;357:664–672.
- 130↑
Marsh JC, Gielda BT, Herskovic AM, Abrams RA. Cognitive sparing during the administration of whole brain radiotherapy and prophylactic cranial irradiation: current concepts and approaches. J Oncol 2010;2010:198–208.
- 131↑
Slotman BJ, Senan S. Radiotherapy in small-cell lung cancer: lessons learned and future directions. Int J Radiat Oncol Biol Phys 2011;79:998–1003.
- 132↑
Le Pechoux C, Dunant A, Senan S et al.. Standard-dose versus higher-dose prophylactic cranial irradiation (PCI) in patients with limited-stage small-cell lung cancer in complete remission after chemotherapy and thoracic radiotherapy (PCI 99-01, EORTC 22003-08004, RTOG 0212, and IFCT 99-01): a randomised clinical trial. Lancet Oncol 2009;10:467–474.
- 133↑
Wolfson AH, Bae K, Komaki R et al.. Primary analysis of a phase II randomized trial Radiation Therapy Oncology Group (RTOG) 0212: impact of different total doses and schedules of prophylactic cranial irradiation on chronic neurotoxicity and quality of life for patients with limited-disease small-cell lung cancer. Int J Radiat Oncol Biol Phys 2011;81:77–84.
- 134↑
Slotman BJ, Mauer ME, Bottomley A et al.. Prophylactic cranial irradiation in extensive disease small-cell lung cancer: short-term health-related quality of life and patient reported symptoms— results of an international phase III randomized controlled trial by the EORTC radiation oncology and lung cancer groups. J Clin Oncol 2009;27:78–84.
- 135↑
Maranzano E, Trippa F, Casale M et al.. 8 Gy single-dose radiotherapy is effective in metastatic spinal cord compression: results of a phase III randomized multicentre Italian trial. Radiother Oncol 2009;93:174–179.
- 136
Lutz S, Berk L, Chang E et al.. Palliative radiotherapy for bone metastases: an ASTRO evidence-based guideline. Int J Radiat Oncol Biol Phys 2011;79:965–976.
- 137↑
Ferrell B, Koczywas M, Grannis F, Harrington A. Palliative care in lung cancer. Surg Clin North Am 2011;91:403–417.
- 138↑
Tsao MN, Lloyd N, Wong RK et al.. Whole brain radiotherapy for the treatment of newly diagnosed multiple brain metastases. Cochrane Database Syst Rev 2012;4:CD003869.
- 139↑
Johnson BE, Linnoila RI, Williams JP et al.. Risk of second aerodigestive cancers increases in patients who survive free of small-cell lung cancer for more than 2 years. J Clin Oncol 1995;13:101–111.
- 140↑
Johnson BE. Second lung cancers in patients after treatment for an initial lung cancer. J Natl Cancer Inst 1998;90:1335–1345.
- 141↑
Richardson GE, Tucker MA, Venzon DJ et al.. Smoking cessation after successful treatment of small-cell lung cancer is associated with fewer smoking-related second primary cancers. Ann Intern Med 1993;119:383–390.
- 142
Kawahara M, Ushijima S, Kamimori T et al.. Second primary tumours in more than 2-year disease-free survivors of small-cell lung cancer in Japan: the role of smoking cessation. Br J Cancer 1998;78:409–412.
- 143↑
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;340:b5569.
