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).

F1NCCN 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

F2NCCN 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

F3NCCN 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

F4NCCN 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

F5NCCN 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

F6

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

T1

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.

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    NCCN Clinical Practice Guidelines in Oncology: Small Cell Lung Cancer Version 2:2012

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    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®.

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    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®.

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    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®.

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    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®.

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    LUNG NEUROENDOCRINE TUMORS: Small Cell Lung Cancer Version 2:2012

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