NCCN Clinical Practice Guidelines in Oncology for Small Cell Lung Cancer
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), which are treated using the NCCN Guidelines for SCLC.1-3 In 2011, an estimated 33,000 new cases of SCLC will occur in the United States.4 Nearly all cases of SCLC are attributable to cigarette smoking. Although the incidence of SCLC has been decreasing, the incidence in women is increasing and the male-to-female incidence ratio is now 1:1.2 Other lung neuroendocrine tumors (LNTs) are treated according to the LNT algorithm on page 1098 (see also the discussion section on page 1107).
Although non-small cell lung cancer (NSCLC) is the most common type of lung cancer (see the NCCN Clinical Practice Guidelines in Oncology [NCCN Guidelines] for Non-Small Cell Lung Cancer; to view the most recent version of these guidelines, visit the NCCN Web site at www.NCCN.org), 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, whereas only approximately one-third present with limited 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 limited-stage SCLC, the goal of treatment is cure using chemotherapy plus thoracic radiotherapy.7,8 In patients with extensive-stage disease, chemotherapy alone can palliate symptoms and prolong survival in most patients; however, long-term survival is rare.9,10 Surgery is only appropriate for the few patients (2%-5%) with surgically resectable stage I SCLC.11 Clinical trials generally represent state-of-the-art treatment for patients with SCLC. Despite recent advances, the standard therapy for SCLC as outlined by these NCCN Guidelines still needs to be improved. Thus, participation in clinical trials should be strongly encouraged.
Smoking cessation should be strongly promoted (national access to state-based quit-line services is available at 1-800-QUIT-NOW or www.smokefree.gov/). Patients who smoke have increased toxicity during treatment and shorter survival.12 Programs using behavioral counseling combined with FDA-approved medications that promote smoking cessation can be very useful (www.surgeongeneral.gov/tobacco/index.html).
NCCN Clinical Practice Guidelines in Oncology: Small Cell Lung Cancer Version 2:2012
Version 2.2012, 06-23-11 ©2011 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 9, 10; 10.6004/jnccn.2011.0092
NCCN Clinical Practice Guidelines in Oncology: Small Cell Lung Cancer Version 2:2012
Version 2.2012, 06-23-11 ©2011 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 9, 10; 10.6004/jnccn.2011.0092
NCCN Clinical Practice Guidelines in Oncology: Small Cell Lung Cancer Version 2:2012
Version 2.2012, 06-23-11 ©2011 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 9, 10; 10.6004/jnccn.2011.0092
NCCN Clinical Practice Guidelines in Oncology: Small Cell Lung Cancer Version 2:2012
Version 2.2012, 06-23-11 ©2011 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 9, 10; 10.6004/jnccn.2011.0092
NCCN Clinical Practice Guidelines in Oncology: Small Cell Lung Cancer Version 2:2012
Version 2.2012, 06-23-11 ©2011 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 9, 10; 10.6004/jnccn.2011.0092
LUNG NEUROENDOCRINE TUMORS: Small Cell Lung Cancer Version 2:2012
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 9, 10; 10.6004/jnccn.2011.0092
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.13 The cells are round, oval, or spindle-shaped, and 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.14-16 Both pulmonary and extrapulmonary small cell carcinomas have a similar clinical and biologic behavior, leading to a 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.17
Nearly all SCLCs are immunoreactive for keratin, epithelial membrane antigen, and thyroid transcription factor-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 one of these neuroendocrine markers.18
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. Uncommonly, patients present with a solitary peripheral nodule without central adenopathy. In this situation, fine-needle aspiration (FNA) may not adequately differentiate small cell carcinoma from low-grade (typical carcinoid), intermediate-grade (atypical carcinoid), or high-grade (large-cell) neuroendocrine carcinoma (see page 1098 and the NCCN Clinical Practice Guidelines in Oncology [NCCN Guidelines] for Neuroendocrine Tumors; to view the most recent version of these guidelines, visit the NCCN Web site at www.NCCN.org).19,20
Preliminary reports from the National Lung Screening Trial (NLST) suggest that screening with annual, low-dose, spiral CT scans can improve lung cancer-specific and overall mortality in asymptomatic high-risk individuals.21 Although CT screening can detect early-stage NSCLC, it does not seem to be useful for detecting SCLC. 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.22
Many neurologic and endocrine paraneoplastic syndromes are associated with SCLC.23,24 Neurologic syndromes include Lambert-Eaton myasthenic syndrome, encephalomyelitis, and sensory neuropathy. Patients with the Lambert-Eaton syndrome present with proximal leg weakness that is caused by antibodies directed against the voltage-gated calcium channels.25,26 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.27 SCLC cells also can produce numerous polypeptide hormones, including adrenocorticotropic hormone (ACTH) and vasopressin (ADH), which cause Cushing syndrome and hyponatremia of malignancy, respectively.28,29
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: 1) limited-stage disease is defined as disease confined to the ipsilateral hemithorax, which can be safely encompassed within a radiation field, and 2) extensive-stage disease is defined as disease beyond the ipsilateral hemithorax, including malignant pleural or pericardial effusion or hematogenous metastases.30 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. 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 new lung cancer TNM staging system was developed by the International Association of the Study of Lung Cancer (IASLC) and adopted by the American Joint Commission for Cancer (AJCC) (see Definitions of TNM and Anatomic Stage/Prognostic Groups, available online, in these guidelines, at www.NCCN.org [ST-1 and ST-2]).31-35 This new 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.31,35 Using the new TNM staging system, limited-stage SCLC is Tany,Nany,M0 except T3-4 because of multiple lung nodules that do not fit in a tolerable radiation field. Extensive-stage SCLC is Tany,Nany,M1a/b, and T3-4 because of multiple lung nodules.
Because most of the literature on SCLC classifies patients based on limited-stage 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 in 2011 to include the TNM staging information.
All patients with SCLC, even those with radiographically limited-stage disease, require systemic chemotherapy. Therefore, staging provides a therapeutic guideline for thoracic radiotherapy, which is indicated primarily for patients with limited-stage disease. Full staging includes a history and physical examination; CT scan (with intravenous contrast) of the chest, liver, and adrenal glands; and an MRI scan (preferred) or a CT scan of the brain. However, once a patient has been found to have extensive-stage disease, further staging is optional, except for brain imaging. 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. If limited-stage disease is suspected, a PET/CT scan can be performed to assess for distant metastases. A bone scan can be performed if PET/CT is not available.
PET scans can increase staging accuracy in patients with SCLC.36-40 PET/CT is superior to PET alone.40 Approximately 15% of patients who undergo PET are upstaged from limited- to extensive-stage, whereas only 5% are downstaged from extensive- to limited-stage. For most metastatic sites, PET/CT is superior to standard imaging; however, PET/CT is inferior to MRI or CT for detecting brain metastases.41 Changes in management based on PET staging were reported in 16% to 38% of patients, mainly because of alterations in the planned radiation field as a result of improved detection of intrathoracic sites of disease.37,42,43 Although PET/CT seems to improve staging accuracy in SCLC, pathologic confirmation is still required for PET/CT-detected lesions that result in upstaging. Before surgical resection, pathologic mediastinal staging is required to confirm PET/CT scan results in patients who seem to have clinical stage T1-2,N0 disease.
Mediastinal staging can be performed through either conventional mediastinoscopy or minimally invasive techniques such as transesophageal endoscopic ultrasound-guided FNA, endobronchial ultrasound-guided transbronchial needle aspiration, or video-assisted thoracoscopy.44,45
Thoracentesis with cytologic 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. A patient should be considered to have limited-stage disease if the effusion is too small to allow image-guided sampling or if 1) cytopathologic examination of pleural fluid is negative for cancer, 2) the fluid is not bloody and not an exudate, and 3) clinical judgment suggests that the effusion is not directly related to the cancer.
Staging should not be focused only to sites of symptomatic disease or those suggested by laboratory tests. Bone scans are positive in up to 30% of patients without bone pain or an abnormal alkaline phosphatase level. A brain MRI 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. 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).
Prognostic Factors
Poor PS (3-4), extensive-stage disease, weight loss, and markers associated with excessive bulk of disease (e.g., lactate dehydrogenase [LDH]) are the most important adverse prognostic factors. Female gender, age younger than 70 years, normal LDH, and stage I disease are associated with a more favorable prognosis in patients with limited-stage disease. Younger age, good PS, normal creatinine level, normal LDH, and a single metastatic site are favorable prognostic factors in patients with extensive-stage disease.46-48
Chemotherapy
For all patients with SCLC, chemotherapy is an essential component of appropriate treatment.9 Adjuvant chemotherapy is recommended for those who have undergone surgical resection. For patients with limited-stage SCLC and good PS (0-2), recommended treatment consists of chemotherapy with concurrent thoracic radiotherapy (category 1).8,49,50 For patients with extensive-stage disease, chemotherapy alone is the recommended treatment (see page 1095 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 1091).10,51
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 1095).9,55,56 This combination replaced alkylator/anthracycline-based regimens based on its superiority in both efficacy and toxicity in the limited-stage setting.57 EP plus concurrent thoracic radiotherapy is now the recommended therapy for patients with limited-stage disease (category 1).49,50,58
In combination with thoracic radiotherapy, EP causes an increased risk of esophagitis, pulmonary toxicity, and hematologic toxicity.59 The use of myeloid growth factors is not recommended in patients undergoing concurrent chemoradiation.60 In clinical practice, carboplatin is frequently substituted for cisplatin to reduce the risk of emesis, neuropathy, and nephropathy. However, the use of carboplatin is associated with a greater risk of myelosuppression.61 The substitution of carboplatin for cisplatin in patients with limited-stage disease has not been adequately evaluated and should only occur when cisplatin is contraindicated or poorly tolerated.62,63 The substitution of carboplatin for cisplatin is more acceptable in patients with extensive-stage disease, because data show these drugs are equivalent in this setting.64
Many other combinations have been evaluated in patients with extensive-stage disease, with little consistent evidence of benefit when compared with EP. 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).65 In addition, the 2-year survival was 19.5% in the irinotecan plus cisplatin group versus 5.2% in the EP group.65 However, 2 subsequent large phase III trials performed in the United States comparing irinotecan plus cisplatin with EP failed to show a significant difference in response rate or overall survival between the regimens.66,67
A randomized phase II trial (n = 70) comparing carboplatin and irinotecan versus carboplatin and etoposide showed a modest improvement in progression-free survival (PFS) with the irinotecan combination.68 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).69 Based on these findings, the carboplatin and irinotecan regimen has been added to the NCCN Guidelines as an option for patients with extensive-stage disease. A recent metaanalysis suggests an improvement in PFS and overall survival with irinotecan plus platinum regimens compared with etoposide plus platinum regimens.70 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 consider etoposide plus platinum as the standard regimen for patients with SCLC.
In patients with limited-stage disease, response rates of 70% to 90% are expected after treatment with EP plus thoracic radiotherapy, whereas in extensive-stage disease, response rates of 60% to 70% can be achieved with combination chemotherapy alone.52 Unfortunately, median survival rates are only 14 to 20 months and 9 to 11 months for patients with limited- and extensive-stage disease, respectively. After appropriate treatment, the 2-year survival rate is approximately 40% in patients with limited-stage disease, but less than 5% in those with extensive-stage disease.71 Thoracic radiotherapy improves local control rates by 25% in patients with limited-stage disease and is associated with improved survival.49,50 Recent data suggest that chemoradiotherapy may be indicated for patients with limited-stage disease who have cytologically negative or indeterminate pleural effusions, but not for those with pericardial effusions.72,73
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.74,75 However, these findings have not been uniformly observed, and the addition of an alkylating agent with or without an anthracycline significantly increases hematologic toxicity when compared to EP alone.76 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.77 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 is associated with a greater risk of cumulative toxicity.78
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.79 However, randomized trials have failed to show improved PFS or overall survival with this approach.80,81
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.82,83 Nevertheless, no survival benefits were documented in randomized trials, and excessive treatment-related mortality was noted with multidrug cyclic weekly regimens.84-87
The role of higher-dose therapy for patients with SCLC remains controversial.88 Higher complete and partial response rates, and modestly longer median survival times, have been observed in patients receiving high doses when compared with those given conventional doses of the same agents.89 In general, however, randomized trials comparing conventional doses to an incrementally increased dose intensity up to 2 times the conventional dose have not consistently shown an increase in response rates or survival.90-93 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.94
Currently available cytokines (e.g., 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,95 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 patients with limited-stage SCLC, a phase II study of irinotecan, carboplatin, and bevacizumab with concurrent radiotherapy followed by maintenance bevacizumab (phase II trial) was terminated early because of an unacceptable incidence of tracheoesophageal fistulae.96 In extensive-stage SCLC, 2 phase II trials of platinum-based chemotherapy plus bevacizumab have yielded promising response and survival data.97-99 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 the 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 when compared to 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.100 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 NCCN Clinical Practice Guidelines in Oncology [NCCN Guidelines] for Senior Adult Oncology; to view the most recent version of these guidelines, visit the NCCN Web site at www.NCCN.org). Older patients who are functional in terms of the 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 (e.g., single-agent etoposide) is inferior to combination chemotherapy (e.g., platinum plus etoposide) in elderly patients with good PS (0-2).101,102 Several other strategies have been evaluated in elderly patients with SCLC.64,103-105 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.105 However, targeting carboplatin to an AUC of 5, rather than 6, may be more reasonable in this population.106 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.107
Second-Line (Subsequent) Therapy
Although SCLC is very responsive to initial treatment, most patients experience relapse with relatively resistant disease.108,109 These patients have a median survival of only 4 to 5 months when treated with further chemotherapy. Second-line (i.e., 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. In phase II trials, active subsequent agents include paclitaxel, docetaxel, topotecan, irinotecan, vinorelbine, gemcitabine, ifosfamide, and oral etoposide (see page 1095).56,110-113 A randomized phase III trial compared single-agent intravenous topotecan with the combination regimen CAV.114 Both arms had similar response rates and survival, but intravenous topotecan caused less toxicity. In another phase III trial, oral topotecan improved overall survival compared with best supportive care (26 vs. 14 weeks).115 Single-agent topotecan is approved by the FDA 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).110,114,116 Either oral or intravenous topotecan may be used, because efficacy and toxicity seem to be similar with either route.115,116
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.117 Published studies have yielded conflicting data regarding the usefulness of weekly topotecan in patients with relapsed SCLC, and this approach remains under investigation.118,119
Recent data from phase II studies suggest that amrubicin, an investigational anthracycline, has promising activity in patients with relapsed or refractory SCLC.120-122 However, grade 3/4 toxicity, primarily neutropenia, is common.123 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).124
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 on page 1096 describes the radiation doses, target volumes, and normal tissue dose volume constraints for limited-stage SCLC, and includes references to support the recommendations; these principles were updated extensively in 2011. The Principles of Radiation Therapy section in the NCCN Guidelines for Non-Small Cell Lung Cancer may also be useful (to view the most recent version of these guidelines, visit the NCCN Web site at www.NCCN.org [NSCL-C]).
This section describes the studies supporting the NCCN recommendations.
Thoracic Radiotherapy
Trial Data: The addition of thoracic radiotherapy has improved survival for patients with limited-stage disease.125 Meta-analyses that included more than 2000 patients show that thoracic radiation for limited-stage disease yields a 25% to 30% reduction in local failure, and a corresponding 5% to 7% improvement in 2-year survival compared with chemotherapy alone.49,50 However, achieving long-term local control using conventional chemoradiotherapy for patients with limited-stage SCLC remains a challenge.
The administration of thoracic radiotherapy requires the assessment of several factors, including the timing of chemotherapy and radiotherapy (concurrent vs. sequential), timing of radiotherapy (early vs. late), volume of the radiation port (original tumor volume vs. shrinking field as the tumor responds), dose of radiation, and fractionation of radiotherapy. Early concurrent chemoradiotherapy is recommended for patients with limited-stage SCLC based on randomized trials.
A randomized trial by the Japanese Cooperative Oncology Group assessed sequential versus concurrent thoracic radiotherapy combined with EP for patients with limited-stage disease. They reported that patients treated with concurrent radiotherapy lived longer than those treated with sequential radiotherapy.59 Another randomized phase III trial (by the National Cancer Institute of Canada) comparing radiotherapy beginning with either cycle 2 or cycle 6 of chemotherapy showed that early radiotherapy was associated with improved local and systemic control and longer survival.126 A systematic review on the timing of thoracic radiotherapy in limited-stage SCLC determined that early concurrent radiotherapy results in a small but significant improvement in overall survival compared with late concurrent or sequential radiotherapy.127 Another meta-analysis also found that early concurrent thoracic radiation with platinum-based chemotherapy increases 2- and 5-year overall survival.128
The ECOG/Radiation Therapy Oncology Group compared once-daily to twice-daily radiotherapy with EP.129 In this trial, 412 patients with limited-stage SCLC were treated with concurrent chemoradiotherapy using a total dose of 45 Gy delivered either twice a day over 3 weeks or once a day over 5 weeks. The twice-daily schedule produced a survival advantage, but a higher incidence of grade 3/4 esophagitis was seen compared with the once-daily regimen. Median survivals were 23 versus 19 months (P = .04), and 5-year survival rates were 26% versus 16% in the twice-daily and once-daily radiotherapy arms, respectively.129 A significant criticism of this trial is that the doses of radiation in the 2 arms were not biologically equivalent. In light of this, ongoing trials are evaluating biologically equivalent doses of 45 Gy delivered twice daily versus 60 to 70 Gy delivered once daily. Another concern regarding hyperfractionation is that twice-daily thoracic radiation is technically challenging for patients with bilateral mediastinal adenopathy.
Another randomized phase III trial showed no survival difference between once-daily thoracic radiotherapy to 50.4 Gy with concurrent EP and a split-course of twice-daily thoracic radiotherapy to 48 Gy with concurrent EP.130 However, split-course radiotherapy may be less efficacious because of interval tumor regrowth between courses. Overall, patients selected for combined modality treatment that incorporates twice-daily radiotherapy must have an excellent PS and good baseline pulmonary function.
NCCN Guidelines: For limited-stage disease, the NCCN Guidelines recommend that radiotherapy should be used concurrently with chemotherapy and that radiotherapy should start with the first or second cycle (category 1) at a dose of either 1.5 Gy twice daily to a total dose of 45 Gy (category 1), or 2.0 Gy once daily to a total dose of 60 to 70 Gy (see page 1096).49,127,129-134 Concurrent chemoradiotherapy (category 1) is preferable to sequential therapy in patients with good PS (0-2).59,135
Three-dimensional (3-D) conformal radiation techniques are preferred, if available. The radiation target volumes should be defined on the PET/CT scan obtained at radiotherapy planning using definitions in reports 50 and 62 from the International Commission on Radiation Units & Measurements. However, the prechemotherapy PET/CT scan should be reviewed to include the originally involved lymph node regions in the treatment fields.133,136 The CALGB 30610/RTOG 0538 protocol should be used as a guide to determine the normal tissue dose-volume constraints (see page 1096).137-139 Intensity-modulated RT (IMRT) may be considered in select patients.140,141
Based on the results of a randomized trial by Jeremic et al.,142 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. The investigators randomized patients experiencing a complete response at distant metastatic sites after 3 cycles of EP to receive either further EP or accelerated hyperfractionated radiotherapy (i.e., 54 Gy in 36 fractions over 18 treatment days) in combination with carboplatin plus etoposide,142 and found that the addition of radiotherapy resulted in improved median overall survival (17 vs. 11 months).
Prophylactic Cranial Irradiation
Intracranial metastases occur in more than 50% of patients with SCLC. Randomized studies have shown that prophylactic cranial irradiation (PCI) is effective in decreasing the incidence of cerebral metastases, but most individual studies did not have sufficient power to demonstrate a meaningful survival advantage.143 Moreover, late neurologic sequelae have been attributed to PCI, particularly in studies using fractions greater than 3 Gy and/or administering PCI concurrent with chemotherapy. Thus, PCI is not recommended for patients with poor PS (3-4) or impaired mental function.
When given after the completion of chemotherapy and at a low dose per fraction, PCI may cause less neurologic toxicity. Symptomatic brain metastases result in major morbidity, which frequently does not completely resolve with therapeutic cranial irradiation.
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.144 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.144 Although the number of patients with extensive-stage disease was small in this metaanalysis, the observed benefit was similar in both limited- and extensive-stage patients. A recent retrospective study of patients with limited-stage disease also found that PCI increased survival at 2, 5, and 10 years compared with those who did not receive PCI.145
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.146
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 either limited- or extensive-stage disease who attain a complete or partial response.146,147 The recommended dose for PCI is a total dose of 25 Gy in 10 fractions (using 2.5 Gy/fraction) or a total dose of 30 Gy in 15 fractions (see page 1096).146,147 However, a total dose of 20 Gy in 5 fractions may be considered for patients with extensive-stage SCLC.146 PCI should not be given concurrently with systemic chemotherapy because of the increased risk of neurotoxicity. Fatigue, headache, and nausea/vomiting are the most common acute toxic effects after PCI.147,148
Palliative Treatment
For patients with localized symptomatic sites of disease (e.g., painful bony lesions, obstructive atelectasis, brain metastases), radiotherapy can provide excellent palliation (see page 1091).149,150 Orthopedic stabilization may be useful in patients at high risk for fracture.
Surgical Resection of Stage I SCLC
The Principles of Surgical Resection for SCLC are described on page 1094. Studies supporting these recommendations are described in this section. Briefly, the algorithm states that surgery should only be considered for patients with stage I (T1-2,N0) SCLC in whom biopsy has confirmed that mediastinal lymph nodes are not involved.151 Data show that patients with clinically staged disease in excess of T1-2,N0 do not benefit from surgery.151 Note that only 5% of patients with SCLC have true stage I SCLC.32
The Lung Cancer Study Group conducted the only prospective randomized trial evaluating the role of surgery in SCLC.151 Patients with limited-stage disease, excluding those with solitary peripheral nodules, were treated with 5 cycles of chemotherapy with CAV; those showing a response to chemotherapy were randomly assigned to undergo resection plus thoracic radiotherapy or thoracic radiotherapy alone. The overall survival of patients on the 2 arms was equivalent, suggesting no benefit to surgery in this setting. However, only 19% of patients enrolled had clinical stage I (T1-2,N0,M0) disease.
Most data regarding the benefit of surgery are from retrospective reviews.152-156 These studies report favorable 5-year survival rates of 40% to 60% in patients with stage I disease. In most series, survival rates decline significantly in patients with more advanced disease, leading to the general recommendation that surgery should only be considered in those with stage I disease. Interpretation of these results is limited by the selection bias inherent in retrospective reviews and by the variable use of chemotherapy and radiotherapy in these studies.
Recent analyses of the SEER database also suggest that surgery may be appropriate for some patients with localized disease.11,157 However, these studies are limited by the lack of information on chemotherapy use in the database. In addition, comparison of the survival of surgical patients to all those who did not undergo surgery is inherently flawed by selection bias. Ultimately, the role of surgery in SCLC will not be fully defined until results are available from trials comparing surgery plus adjuvant chemotherapy versus concurrent chemoradiotherapy in rigorously staged patients.
In all patients with clinical stage I (T1-2,N0) SCLC who are being considered for surgical resection, occult nodal disease should be ruled out through mediastinal staging before resection.158 If resection is performed, the panel favors lobectomy and does not believe that segmental or wedge resections are appropriate for patients with SCLC. After complete resection, adjuvant chemotherapy or chemoradiation is recommended.154,159,160 Adjuvant chemotherapy alone is recommended for patients without nodal metastases, whereas concurrent chemotherapy and postoperative mediastinal radiotherapy are recommended for patients with nodal metastases (see page 1090). PCI should be considered after adjuvant therapy because it can improve survival (see Prophylactic Cranial Irradiation, page 1105).144
Surveillance
Follow-up examinations are recommended every 3 to 4 months during years 1 and 2, with concomitant chest imaging (with CT but not PET/CT); the frequency of surveillance decreases during subsequent years in light of the declining risk of recurrence (see page 1092). 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 their initial SCLC.161,162 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 those who quit smoking.163-165
Lung Neuroendocrine Carcinomas
Using the 2004 WHO criteria, lung neuroendocrine carcinomas are characterized as: 1) high-grade neuroendocrine carcinomas (SCLC and large-cell neuroendocrine carcinoma [LCNEC]); 2) intermediate-grade neuroendocrine carcinomas (atypical carcinoids); or 3) low-grade neuroendocrine carcinomas (typical carcinoids).166,167
Most lung neuroendocrine carcinomas are SCLC, which are treated using these guidelines,1 whereas LCNEC is treated using the NCCN Guidelines for Non-Small Cell Lung Cancer (to view the most recent version of these guidelines, visit the NCCN Web site at www.NCCN.org).168 Low- and intermediate-grade lung neuroendocrine carcinomas account for 1% to 2% of lung cancers and are treated using the LNT guideline. Both histologic and cytologic features can be useful for distinguishing lung neuroendocrine carcinoma from SCLC and LCNEC, although diagnosis can be difficult (see also the NCCN Guidelines for Non-Small Cell Lung Cancer, available at www.NCCN.org).The proliferative marker Ki-67 may also be useful.19,20
Lung neuroendocrine carcinomas are staged using the 7th edition of the AJCC staging system for lung tumors (see Definitions of TNM and Anatomic Stage/Prognostic Groups, available online, in these guidelines, at www.NCCN.org [ST-1 and ST-2]).34,169 Both low- and intermediate-grade LNTs are usually stage I at diagnosis, although lymph node metastases (stages II-III) are more commonly seen in intermediate-grade tumors. Compared with other lung carcinomas, the prognosis is excellent for many patients with low- and intermediate-grade LNTs.
Surgery is recommended for patients with stage I, II, or IIIA low- or intermediate-grade LNTs (see page 1098). After surgical resection, 5- and 10-year survival rates are more than 90% for patients with typical carcinoid, whereas survival rates are 70% and 50% to 60% for patients with atypical carcinoid.170-172 Lymph node involvement decreases long-term survival in both typical and atypical carcinoid.170-172
Systemic therapy (e.g., cisplatin/etoposide, temozolomide, sunitinib, or everolimus) is recommended for patients with unresectable or advanced disease, although response rates are modest.1,173-177 Octreotide may be considered for select patients with positive octreotide scans or symptoms of carcinoid syndrome.
Individual Disclosures of the NCCN Guidelines Panel for Small Cell Lung Cancer
Please Note
The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines™) are a statement of consensus of the authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult the NCCN Guidelines™ is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient's care or treatment. The National Comprehensive Cancer Network® (NCCN®) makes no representation or warranties of any kind regarding their content, use, or application and disclaims any responsibility for their applications or use in any way.
© National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any form without the express written permission of NCCN.
Disclosures for the NCCN Guidelines Panel for Small Cell Lung Cancer
At the beginning of each NCCN Guidelines panel meeting, panel members disclosed any financial support they have received from industry. Through 2008, this information was published in an aggregate statement in JNCCN and online. Furthering NCCN's commitment to public transparency, this disclosure process has now been expanded by listing all potential conflicts of interest respective to each individual expert panel member.
Individual disclosures for the NCCN Guidelines for Small Cell Lung Cancer panel members can be found on page 1113. (The most recent version of these guidelines and accompanying disclosures, including levels of compensation, are available on the NCCN Web site at www.NCCN.org.)
These guidelines are also available on the Internet. For the latest update, visit www.NCCN.org.
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.
- 4↑
Siegel R, Ward E, Brawley O, Jemal A. Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin 2011;61:212-236.
- 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↑
Kalemkerian GP. Advances in the treatment of small-cell lung cancer. Semin Respir Crit Care Med 2011;32:94-101.
- 8↑
Stinchcombe TE, Gore EM. Limited-stage small cell lung cancer: current chemoradiotherapy treatment paradigms. Oncologist 2010;15:187-195.
- 9↑
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.
- 10↑
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.
- 11↑
Yu JB, Decker RH, Detterbeck FC, Wilson LD. Surveillance Epidemiology and End Results evaluation of the role of surgery for stage I small cell lung cancer. J Thorac Oncol 2010;5:215-219.
- 12↑
Videtic GMM, 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.
- 14↑
Brenner B, Tang LH, Klimstra DS, Kelsen DP. Small-cell carcinomas of the gastrointestinal tract: a review. J Clin Oncol 2004;22:2730-2739.
- 15
Galanis E, Frytak S, Lloyd RV. Extrapulmonary small cell carcinoma. Cancer 1997;79:1729-1736.
- 16↑
Remick SC, Ruckdeschel JC. Extrapulmonary and pulmonary small-cell carcinoma: tumor biology, therapy, and outcome. Med Pediatr Oncol 1992;20:89-99.
- 17↑
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.
- 18↑
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.
- 19↑
Gustafsson BI, Kidd M, Chan A et al.. Bronchopulmonary neuroendocrine tumors. Cancer 2008;113:5-21.
- 20↑
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.
- 21↑
Lung cancer trial results show mortality benefit with low-dose CT. National Cancer Institute Web site. Available at: http://www.cancer.gov/newscenter/pressreleases/2010/NLSTresultsRelease. Accessed September 1, 2011.
- 22↑
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.
- 23↑
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.
- 24↑
Marchioli CC, Graziano SL. Paraneoplastic syndromes associated with small cell lung cancer. Chest Surg Clin N Am 1997;7:65-80.
- 25↑
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.
- 26↑
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.
- 27↑
Graus F, Keime-Guibert F, Rene R et al.. Anti-Hu-associated paraneoplastic encephalomyelitis: analysis of 200 patients. Brain 2001;124:1138-1148.
- 28↑
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.
- 29↑
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.
- 30↑
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.
- 31↑
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.
- 32↑
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.
- 33
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.
- 34↑
Edge SB, Byrd DR, Compton CC et al.. AJCC Cancer Staging Manual, 7th ed. New York, NY: Springer; 2010.
- 35↑
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.
- 36↑
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.
- 37↑
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.
- 38
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.
- 39
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.
- 40↑
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.
- 41↑
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.
- 42↑
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.
- 43↑
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.
- 44↑
Rintoul RC, Tournoy KG, El Daly H et al.. EBUS-TBNA for the clarification of PET positive intra-thoracic lymph nodes- an international multi-centre experience. J Thorac Oncol 2009;4:44-48.
- 45↑
Medford AR, Bennett JA, Free CM, Agrawal S. Mediastinal staging procedures in lung cancer: EBUS, TBNA and mediastinoscopy. Curr Opin Pulm Med 2009;15:334-342.
- 46↑
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.
- 47
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.
- 48↑
Yip D, Harper PG. Predictive and prognostic factors in small cell lung cancer: current status. Lung Cancer 2000;28:173-185.
- 49↑
Pignon JP, Arriagada R, Ihde DC et al.. A meta-analysis of thoracic radiotherapy for small-cell lung cancer. N Engl J Med 1992;327:1618-1624.
- 50↑
Warde P, Payne D. Does thoracic irradiation improve survival and local control in limited-stage small-cell carcinoma of the lung? A meta-analysis. J Clin Oncol 1992;10:890-895.
- 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↑
Saito H, Takada Y, Ichinose Y et al.. Phase II study of etoposide and cisplatin with concurrent twice-daily thoracic radiotherapy followed by irinotecan and cisplatin in patients with limited-disease small-cell lung cancer: West Japan Thoracic Oncology Group 9902. J Clin Oncol 2006;24:5247-5252.
- 59↑
Takada M, Fukuoka M, Kawahara M et al.. Phase III study of concurrent versus sequential thoracic radiotherapy in combination with cisplatin and etoposide for limited-stage small-cell lung cancer: results of the Japan Clinical Oncology Group Study 9104. J Clin Oncol 2002;20:3054-3060.
- 60↑
Bunn PA Jr, Crowley J, Kelly K et al.. Chemoradiotherapy with or without granulocyte-macrophage colony-stimulating factor in the treatment of limited-stage small-cell lung cancer: a prospective phase III randomized study of the Southwest Oncology Group. J Clin Oncol 1995;13:1632-1641.
- 61↑
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.
- 62↑
Skarlos DV, Samantas E, Briassoulis E et al.. Randomized comparison of early versus late hyperfractionated thoracic irradiation concurrently with chemotherapy in limited disease small-cell lung cancer: a randomized phase II study of the Hellenic Cooperative Oncology Group (HeCOG). Ann Oncol 2001;12:1231-1238.
- 63↑
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.
- 64↑
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.
- 65↑
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.
- 66↑
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.
- 67↑
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. J Clin Oncol 2006;24:2038-2043.
- 68↑
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.
- 69↑
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.
- 70↑
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.
- 71↑
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.
- 72↑
Niho S, Kubota K, Yoh K et al.. Clinical outcome of chemoradiation therapy in patients with limited-disease small cell lung cancer with ipsilateral pleural effusion. J Thorac Oncol 2008;3:723-727.
- 73↑
Niho S, Kubota K, Yoh K et al.. Chemoradiation therapy in patients (pts) with small cell lung cancer (SCLC) with pericardial effusion but no distant metastasis [abstract]. J Clin Oncol 2009;27(Suppl 15):Abstract 7555.
- 74↑
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.
- 75↑
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.
- 76↑
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.
- 77↑
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.
- 78↑
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.
- 79↑
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.
- 80↑
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.
- 81↑
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.
- 82↑
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.
- 83.↑
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.
- 84↑
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.
- 85
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.
- 86
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.
- 87↑
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.
- 88↑
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.
- 89↑
Cohen MH, Creaven PJ, Fossieck BE Jr et al.. Intensive chemotherapy of small cell bronchogenic carcinoma. Cancer Treat Rep 1977;61:349-354.
- 90↑
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.
- 91
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.
- 92
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.
- 93↑
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.
- 94↑
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.
- 95↑
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.
- 96↑
Genetech. Important drug warning regarding Avastin (bevacuizumab). Available at: http://www.fda.gov/downloads/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/UCM153953.pdf. Accessed September 1, 2011.
- 97↑
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.
- 98
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.
- 99↑
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.
- 100↑
Hurria A, Kris MG. Management of lung cancer in older adults. CA Cancer J Clin 2003;53:325-341.
- 101↑
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.
- 102↑
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.
- 103↑
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.
- 104
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.
- 105↑
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.
- 106↑
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.
- 107↑
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.
- 108↑
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.
- 109↑
Schneider BJ. Management of recurrent small cell lung cancer. J Natl Compr Canc Netw 2008;6:323-331.
- 110↑
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.
- 111
Ettinger DS. New drugs for chemotherapy-naive patients with extensive-disease small cell lung cancer. Semin Oncol 2001;28:27-29.
- 112
Kelly K. New chemotherapy agents for small cell lung cancer. Chest 2000;117:156S-162S.
- 113↑
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.
- 114↑
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.
- 115↑
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.
- 116↑
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.
- 117↑
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.
- 118↑
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.
- 119↑
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.
- 120↑
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.
- 121
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.
- 122↑
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.
- 123↑
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.
- 124↑
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.
- 125↑
Simon G, Ginsberg RJ, Ruckdeschel JC. Small-cell lung cancer. Chest Surg Clin N Am 2001;11:165-188, ix.
- 126↑
Murray N, Coy P, Pater JL et al.. Importance of timing for thoracic irradiation in the combined modality treatment of limited-stage small-cell lung cancer. The National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 1993;11:336-344.
- 127↑
Fried DB, Morris DE, Poole C et al.. Systematic review evaluating the timing of thoracic radiation therapy in combined modality therapy for limited-stage small-cell lung cancer. J Clin Oncol 2004;22:4837-4845.
- 128↑
Pijls-Johannesma M, De Ruysscher D, Vansteenkiste J et al.. Timing of chest radiotherapy in patients with limited stage small cell lung cancer: a systematic review and meta-analysis of randomised controlled trials. Cancer Treat Rev 2007;33:461-473.
- 129↑
Turrisi AT III, Kim K, Blum R et al.. Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med 1999;340:265-271.
- 130↑
Schild SE, Bonner JA, Shanahan TG et al.. Long-term results of a phase III trial comparing once-daily radiotherapy with twice-daily radiotherapy in limited-stage small-cell lung cancer. Int J Radiat Oncol Biol Phys 2004;59:943-951.
- 131
Miller KL, Marks LB, Sibley GS et al.. Routine use of approximately 60 Gy once-daily thoracic irradiation for patients with limited-stage small-cell lung cancer. Int J Radiat Oncol Biol Phys 2003;56:355-359.
- 132
Roof KS, Fidias P, Lynch TJ et al.. Radiation dose escalation in limited-stage small-cell lung cancer. Int J Radiat Oncol Biol Phys 2003;57:701-708.
- 133↑
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.
- 134↑
De Ruysscher D, Pijls-Johannesma M, Bentzen SM et al.. Time between the first day of chemotherapy and the last day of chest radiation is the most important predictor of survival in limited-disease small-cell lung cancer. J Clin Oncol 2006;24:1057-1063.
- 135↑
Socinski MA, Bogart JA. Limited-stage small-cell lung cancer: the current status of combined-modality therapy. J Clin Oncol 2007;25:4137-4145.
- 136↑
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.
- 137↑
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.
- 138
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.
- 139↑
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, in press.
- 140↑
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, in press.
- 141↑
Prescribing, recording, and reporting intensity-modulated photon-beam therapy (IMRT)(ICRU report 83). International Commission on Radiation Units & Measurements, Inc. Available at: http://www.icru.org/index.php?option=com_content&task=view&id=171. Accessed September 1, 2011.
- 142↑
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.
- 143↑
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.
- 144↑
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.
- 145↑
Patel S, Macdonald OK, Suntharalingam M. Evaluation of the use of prophylactic cranial irradiation in small cell lung cancer. Cancer 2009;115:842-850.
- 146↑
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.
- 147↑
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.
- 148↑
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.
- 149↑
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.
- 150↑
Palliative thoracic radiotherapy in lung cancer: an American Society for Radiation Onology evidence-based clinical practice guideline. Practice Radiation Oncology Web site. Available at: http://www.practicalradonc.org/article/S18798500(11)000919/abstract. Accessed September 1, 2011.
- 151↑
Lad T, Piantadosi S, Thomas P et al.. A prospective randomized trial to determine the benefit of surgical resection of residual disease following response of small cell lung cancer to combination chemotherapy. Chest 1994;106:320S-323S.
- 152↑
Rostad H, Naalsund A, Jacobsen R et al.. Small cell lung cancer in Norway. Should more patients have been offered surgical therapy? Eur J Cardiothorac Surg 2004;26:782-786.
- 153
Inoue M, Miyoshi S, Yasumitsu T et al.. Surgical results for small cell lung cancer based on the new TNM staging system. Thoracic Surgery Study Group of Osaka University, Osaka, Japan. Ann Thorac Surg 2000;70:1615-1619.
- 154↑
Brock MV, Hooker CM, Syphard JE et al.. Surgical resection of limited disease small cell lung cancer in the new era of platinum chemotherapy: its time has come. J Thorac Cardiovasc Surg 2005;129:64-72.
- 155
Lim E, Belcher E, Yap YK et al.. The role of surgery in the treatment of limited disease small cell lung cancer: time to reevaluate. J Thorac Oncol 2008;3:1267-1271.
- 156↑
Shields TW, Higgins GA Jr, Matthews MJ, Keehn RJ. Surgical resection in the management of small cell carcinoma of the lung. J Thorac Cardiovasc Surg 1982;84:481-488.
- 157↑
Schreiber D, Rineer J, Weedon J et al.. Survival outcomes with the use of surgery in limited-stage small cell lung cancer: should its role be re-evaluated? Cancer 2010;116:1350-1357.
- 158↑
Inoue M, Nakagawa K, Fujiwara K et al.. Results of preoperative mediastinoscopy for small cell lung cancer. Ann Thorac Surg 2000;70:1620-1623.
- 159↑
Shepherd FA, Evans WK, Feld R et al.. Adjuvant chemotherapy following surgical resection for small-cell carcinoma of the lung. J Clin Oncol 1988;6:832-838.
- 160↑
Tsuchiya R, Suzuki K, Ichinose Y et al.. Phase II trial of postoperative adjuvant cisplatin and etoposide in patients with completely resected stage I-IIIa small cell lung cancer: the Japan Clinical Oncology Lung Cancer Study Group Trial (JCOG9101). J Thorac Cardiovasc Surg 2005;129:977-983.
- 161↑
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.
- 162↑
Johnson BE. Second lung cancers in patients after treatment for an initial lung cancer. J Natl Cancer Inst 1998;90:1335-1345.
- 163↑
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.
- 164
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.
- 165↑
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.
- 166↑
Travis WD, Brambilla E, Muller-Hermelink HK, Harris CC, eds. World Health Organization classification of tumors: pathology & genetics of tumors of the lung, pleura, thymus, and heart. World Health Organization Web site. Available at: http://www.iarc.fr/en/publications/pdfs-online/pat-gen/bb10/index.php. Accessed September 1, 2011.
- 167↑
Bajetta E, Catena L, Procopio G et al.. Is the new WHO classification of neuroendocrine tumours useful for selecting an appropriate treatment? Ann Oncol 2005;16:1374-1380.
- 168↑
Varlotto JM, Medford-Davis LN, Recht A et al.. Should large cell neuroendocrine lung carcinoma be classified and treated as a small cell lung cancer or with other large cell carcinomas? J Thorac Oncol 2011;6:1050-1058.
- 169↑
Travis WD, Giroux DJ, Chansky K et al.. The IASLC Lung Cancer Staging Project: proposals for the inclusion of bronchopulmonary carcinoid tumors in the forthcoming (seventh) edition of the TNM Classification for Lung Cancer. J Thorac Oncol 2008;3:1213-1223.
- 171
Rea F, Rizzardi G, Zuin A et al.. Outcome and surgical strategy in bronchial carcinoid tumors: single institution experience with 252 patients. Eur J Cardiothorac Surg 2007;31:186-191.
- 172↑
Cardillo G, Sera F, Di Martino M et al.. Bronchial carcinoid tumors: nodal status and long-term survival after resection. Ann Thorac Surg 2004;77:1781-1785.
- 173↑
Moertel CG, Kvols LK, O'Connell MJ, Rubin J. Treatment of neuroendocrine carcinomas with combined etoposide and cisplatin. Evidence of major therapeutic activity in the anaplastic variants of these neoplasms. Cancer 1991;68:227-232.
- 174
Ekeblad S, Sundin A, Janson ET et al.. Temozolomide as monotherapy is effective in treatment of advanced malignant neuroendocrine tumors. Clin Cancer Res 2007;13:2986-2991.
- 175
Kulke MH, Hornick JL, Frauenhoffer C et al.. O6-methylguanine DNA methyltransferase deficiency and response to temozolomide-based therapy in patients with neuroendocrine tumors. Clin Cancer Res 2009;15:338-345.
- 176
Kulke MH, Lenz HJ, Meropol NJ et al.. Activity of sunitinib in patients with advanced neuroendocrine tumors. J Clin Oncol 2008;26:3403-3410.
- 177↑
Yao JC, Phan AT, Chang DZ et al.. Efficacy of RAD001 (everolimus) and octreotide LAR in advanced low- to intermediate-grade neuroendocrine tumors: results of a phase II study. J Clin Oncol 2008;26:4311-4318.
