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2011 NCCN Small Cell Lung Cancer


NCCN Guidelines Index SCLC Table of Contents Discussion

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines?)

Small Cell Lung Cancer
Version 1.2012 NCCN.org

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NCCN Guidelines? Version 1.2012 Panel Members Small Cell Lung Cancer
* Gregory P. Kalemkerian, MD/Chair ? University of Michigan Comprehensive Cancer Center Wallace Akerley, MD ? Huntsman Cancer Institute at the University of Utah Ramaswamy Govindan, MD ? Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine John C. Grecula, MD § The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute James Hayman, MD, MBA § University of Michigan Comprehensive Cancer Center Rebecca Suk Heist, MD, MPH ? Massachusetts General Hospital Cancer Center Leora Horn, MD, MSc ? Vanderbilt-Ingram Cancer Center Thierry Jahan, MD ? ? UCSF Helen Diller Family Comprehensive Cancer Center Marianna Koczywas, MD ?? ? City of Hope Comprehensive Cancer Center Cesar A. Moran, MD ? The University of Texas MD Anderson Cancer Center

NCCN Guidelines Index SCLC Table of Contents Discussion

Harvey B. Niell, MD ? ? ? University of Tennessee Cancer Institute Janis O’Malley, MD ф University of Alabama at Birmingham Comprehensive Cancer Center Jyoti D. Patel, MD ? Robert H. Lurie Comprehensive Cancer Center of Northwestern University Neal Ready, MD, PhD ? Duke Cancer Institute Charles M. Rudin, MD, PhD ? ? The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Charles C. Williams, Jr., MD ? H. Lee Moffitt Cancer Center and Research Institute NCCN Kristina Gregory, RN, MSN, OCN Miranda Hughes, PhD

Paul Bogner, MD ? Roswell Park Cancer Institute Hossein Borghaei, DO, MS ? ? Fox Chase Cancer Center Laura Chow, MD ? Fred Hutchinson Cancer Research Center/Seattle Cancer Center Alliance
Robert J. Downey, MD ? Memorial Sloan-Kettering Cancer Center Leena Gandhi, MD, PhD ? ? Dana-Farber/Brigham and Women's Cancer Center

Apar Kishor P. Ganti, MD ? UNMC Eppley Cancer Center at the Nebraska Medical Center

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NCCN Guidelines Panel Disclosures

? Medical Oncology ? Surgery/Surgical oncology § Radiation oncology/Radiotherapy ? Hematology/hematology oncology ? Internal medicine ? Pathology ф Diagnostic/Interventional Radiology *Writing Committee Member

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NCCN Guidelines? Version 1.2012 Table of Contents Small Cell Lung Cancer
NCCN Small Cell Lung Cancer Panel Members Summary of the Guidelines Updates Small Cell Lung Cancer: · Initial Evaluation and Staging (SCL-1) · Limited Stage, Workup and Treatment (SCL-2) · Extensive Stage, Workup and Treatment (SCL-4) · Response Assessment after Initial Therapy (SCL-5) · Surveillance (SCL-5) · Subsequent Therapy and Palliative Therapy (SCL-6) · Principles of Surgical Resection (SCL-A) · Principles of Chemotherapy (SCL-B) · Principles of Radiation Therapy (SCL-C) · Principles of Supportive Care (SCL-D) Lung Neuroendocrine Tumors: · Workup and Primary Treatment (LNT-1) > High-grade neuroendocrine carcinoma (large cell neuroendocarcinoma) > Intermediate-grade neuroendocrine carcinoma (atypical carcinoid) > Low-grade neuroendocrine carcinoma (typical carcinoid) > Combined SCLC and NSCLC Staging (ST-1)

NCCN Guidelines Index SCLC Table of Contents Discussion

Clinical Trials: The NCCN believes that the best management for any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. To find clinical trials online at NCCN member institutions, click here: nccn.org/clinical_trials/physician.html
NCCN Categories of Evidence and

Consensus: All recommendations are Category 2A unless otherwise specified. See NCCN Categories of Evidence and Consensus

The NCCN Guidelines? are a statement of evidence and 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 representations or warranties of any kind regarding their content, use or application and disclaims any responsibility for their application or use in any way. The NCCN Guidelines are copyrighted by National Comprehensive Cancer Network?. All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any form without the express written permission of NCCN. ?2011.
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NCCN Guidelines? Version 1.2012 Updates Small Cell Lung Cancer
General - PET scan was changed to PET/CT scan. SCL-1 Initial Evaluation · ”Differential” was added to CBC. · Chest x-ray was removed. · Bone scan was moved from the algorithm and added as footnote “c”: “If PET/CT is not available, a bone scan may be used to identify metastases. Pathologic confirmation is recommended for lesions detected by PET/CT that alter stage.” · PET/CT was clarified by adding “if limited stage is suspected.” · Footnote “a”modified: “...further staging evaluation is optional. However, head MRI (preferred) or CT should be obtained in all patients.” Stage · Limited stage: “that do not fit in a tolerable radiation field” added. SCL-2 Additional Workup · ”If pleural effusion is seen on chest x-ray” changed to “If pleural effusion is present”. · Footnote “e”: number associated with cytological examinations removed. · Combined 3rd and 4th bullets dealing with bone mets: “Bone radiographs of areas showing abnormal uptake on PET/CT or bone scan to evaluate potential metastases; consider MRI of bony lesions if radiographs are equivocal.” SCL-4 · Bone radiographs removed as additional workup. Initial Treatment · For management of osseous structural impairment: “Consider palliative external-beam RT and orthopedic stabilization if risk of fracture” added. SCL-5 · Changed oncology follow-up visits to the following: 3-4 mo during y 1-2 and every 6 mo during y 3-5. · Added 4th bullet under surveillance “PET/CT is not recommended for routine follow-up.”

NCCN Guidelines Index SCLC Table of Contents Discussion

Summary of changes in the 1.2012 version of the NCCN Small Cell Lung Cancer Guidelines from the 2.2011 version include:
SCL-A · Last bullet added, “PCI is not recommended in patients with poor performance status or impaired mental functioning.” · References 3 and 4 are new to the page. SCL-B 1 of 2 · Limited stage: “The use of myeloid growth factors is not recommended during concurrent chemotherapy plus radiotherapy” added to chemotherapy + RT. · References added for subsequent chemotherapy options. SCL-B 2 of 2 · References added for subsequent chemotherapy options. SCL-C 1 of 2 · Limited stage: Bullet 3 modified: Radiation target volumes should be defined based on the pretreatment PET scan and CT scan obtained at the time of radiotherapy planning, following ICRU definitions (Reports 50 and 62). 8-10 Radiation doses should be calculated with inhomogeneity corrections. Bullet 4 modified: Three-dimensional conformal radiation techniques are preferred. In selected patients, IMRT may be considered (http://www.icru.org/index.php?option=com_content&task=view&id= 171). 11 Four-dimensional imaging and/or other available techniques should also be performed to assess tumor movement and motion management should be used to achieve movement of less than 1 cm or the PTV margin should be increased appropriately. 12 · Prophylactic cranial radiotherapy: “For extensive-stage patients, 20 Gy in 5 fractions may be considered” is new to the page. SCL-C 2 of 2 · References 11, 12 are new to the page. LNT-1 · Footnote “d” modified: Options include cisplatin/etoposide, temozolomide, sunitinib and everolimus. · References added for systemic chemotherapy options.

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UPDATES

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NCCN Guidelines? Version 1.2012 Small Cell Lung Cancer
DIAGNOSIS INITIAL EVALUATION a STAGE

NCCN Guidelines Index SCLC Table of Contents Discussion

Small cell or combined Small cell/non-small cell lung cancer on biopsy or cytology of primary or metastatic site

· H&P · Pathology review · CBC with differential, platelets · Electrolytes, liver function tests (LFTs), Ca, LDH · BUN, creatinine · Chest/liver/adrenal CT with IV contrast whenever possible · Head MRI (preferred) or CT b · PET/CT scan (if limited stage is suspected) a,c · Smoking cessation counseling and intervention

Limited stage d (T any, N any, M0; except T3-4 due to multiple lung nodules that do not fit in a tolerable radiation field)

See Additional Workup (SCL-2)

Extensive stage d (T any, N any, M1a/b; T3-4 due to multiple lung nodules)

See Additional Workup (SCL-4)

a If

extensive stage is established, further staging evaluation is optional. However, head MRI (preferred) or CT should be obtained in all patients. MRI is more sensitive than CT for identifying brain metastases and is preferred over CT. c If PET/CT not available, bone scan may be used to identify metastases. Pathologic confirmation is recommended for lesions detected by PET/CT that alter stage. d See Staging on page ST-1.
b Head
Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
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SCL-1

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NCCN Guidelines? Version 1.2012 Small Cell Lung Cancer
STAGE ADDITIONAL WORKUP

NCCN Guidelines Index SCLC Table of Contents Discussion

Limited stage (T any, N any, M0; except T3-4 due to multiple lung nodules that do not fit in a tolerable radiation field)

· If pleural effusion is present, thoracentesis is recommended; if thoracentesis inconclusive, consider thoracoscopy e · Pulmonary function tests (PFTs) (if clinically indicated) · Bone radiographs of areas showing abnormal uptake on PET/CT or bone scan to evaluate potential metastases; consider MRI of bony lesions if radiographs are equivocal · Unilateral marrow aspiration/biopsy in select patients f

Clinical stage T1-2, N0

PET/CT scan g

Pathologic mediastinal staging h,i

See Initial Treatment (SCL-3)

Limited stage in excess of T1-T2, N0

See Initial Treatment (SCL-3)

Bone marrow biopsy, thoracentesis, or bone studies consistent with malignancy

Follow Pathway For Extensive-Stage Disease (See SCL-4)

e Most

pleural effusions in patients with lung cancer are due to cancer; however, if the effusion is too small to allow image-guided sampling, then the effusion should not be considered in staging. If cytological examination of pleural fluid is negative for cancer, fluid is not bloody and not an exudate and clinical judgment suggests that the effusion is not directly related to the cancer, then the effusion should not be considered evidence of extensive stage disease. f Selection criteria include: nucleated RBCs on peripheral blood smear, neutropenia, or thrombocytopenia. g PET scan to identify distant disease and to guide mediastinal evaluation, if not previously done. h See Principles of Surgical Resection (SCL-A). i Mediastinal staging procedures include mediastinoscopy, mediastinotomy, endobronchial or esophageal ultrasound-guided biopsy, and video-assisted thoracoscopy. If endoscopic lymph node biopsy is positive, additional mediastinal staging is not required.
Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
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SCL-2

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NCCN Guidelines? Version 1.2012 Small Cell Lung Cancer
TESTING RESULTS Pathologic mediastinal staging h,i negative Clinical stage T1-2, N0 Pathologic mediastinal staging h,i positive or medically inoperable INITIAL TREATMENT l Lobectomy h (preferred) and mediastinal lymph node dissection or sampling Good performance status (PS 0-2) Poor PS (3-4) due to SCLC Poor PS (3-4) not due to SCLC Good PS (0-2) Limited stage in excess of T1-2, N0 Poor PS (3-4) due to SCLC Poor PS (3-4) not due to SCLC Chemotherapy j + concurrent RT k (category 1) Chemotherapy j ± RT k Individualized treatment including supportive care l N0 N+ ADJUVANT TREATMENT Chemotherapy j Concurrent chemotherapy j + mediastinal RT k Chemotherapy j + concurrent thoracic RT k (category 1) Chemotherapy j ± RT k Individualized treatment including supportive care l

NCCN Guidelines Index SCLC Table of Contents Discussion

See Response Assessment + Adjuvant Treatment (SCL-5)

See Response Assessment + Adjuvant Treatment (SCL-5)

h See

Principles of Surgical Resection (SCL-A). staging procedures include mediastinoscopy, mediastinotomy, endobronchial or esophageal ultrasound-guided biopsy, and video-assisted thoracoscopy. If endoscopic lymph node biopsy is positive, additional mediastinal staging is not required. j See Principles of Chemotherapy (SCL-B). k See Principles of Radiation Therapy (SCL-C). l See Principles of Supportive Care (SCL-D).
i Mediastinal
Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
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SCL-3

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NCCN Guidelines? Version 1.2012 Small Cell Lung Cancer
STAGE Extensive stage without localized symptomatic sites or brain metastases INITIAL TREATMENT l Combination chemotherapy j,m including supportive care l See NCCN Palliative Care Guidelines · Poor PS (3-4) · Severely debilitated Individualized therapy including supportive care l or chemotherapy See NCCN Palliative Care Guidelines Chemotherapy j ± RT k to symptomatic sites For management of osseous structural impairment, consider palliative external-beam RT k and orthopedic stabilization, if risk of fracture RT k to symptomatic sites before chemotherapy unless immediate systemic therapy is required. See NCCN Central Nervous System Cancers Guidelines May administer chemotherapy first, with whole-brain RT k after chemotherapy j Whole-brain RT k before chemotherapy, j unless immediate systemic therapy is required

NCCN Guidelines Index SCLC Table of Contents Discussion

Extensive stage (T any, N any, M1a/b; T3-4 due to multiple lung nodules)

Extensive stage + localized symptomatic sites

· SVC syndrome · Lobar obstruction · Bone metastases

See Response Assessment + Adjuvant Treatment (SCL-5)

Spinal cord compression

Asymptomatic Extensive stage with brain metastases Symptomatic

j See

Principles of Chemotherapy (SCL-B). Principles of Radiation Therapy (SCL-C). l See Principles of Supportive Care (SCL-D). m Sequential radiotherapy to thorax in selected patients with low-bulk metastatic disease and CR or near CR after systemic therapy.
k See
Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
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SCL-4

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NCCN Guidelines? Version 1.2012 Small Cell Lung Cancer
RESPONSE ASSESSMENT FOLLOWING INITIAL THERAPY ADJUVANT TREATMENT SURVEILLANCE

NCCN Guidelines Index SCLC Table of Contents Discussion

Complete response or Partial response · Chest x-ray (optional) · Chest/liver/adrenal CT with IV contrast whenever possible · Head MRI or CT, if prophylactic cranial irradiation (PCI) to be given · Other imaging studies, to assess prior sites of involvement, as clinically indicated · CBC, platelets · Electrolytes, LFTs, Ca, BUN, creatinine

Limited or extensive stage: PCI k,n (category 1)

Stable Disease

After recovery from primary therapy: · Oncology follow-up visits every 3-4 mo during y 1-2, every 6 mo during y 3-5, then annually > At every visit: H&P, chest imaging, bloodwork as clinically indicated · New pulmonary nodule should initiate workup for potential new primary · Smoking cessation intervention · PET/CT is not recommended for routine follow-up

For Relapse, see Secondline Therapy (SCL-6)

Primary progressive disease

See Subsequent Therapy/Palliation (SCL-6)

k See n Not

Principles of Radiation Therapy (SCL-C). recommended in patients with poor performance status or impaired mental function.

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
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SCL-5

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NCCN Guidelines? Version 1.2012 Small Cell Lung Cancer
PROGRESSIVE DISEASE SUBSEQUENT THERAPY/PALLIATION

NCCN Guidelines Index SCLC Table of Contents Discussion

Relapse

Subsequent chemotherapy j or Clinical trial or Palliative symptom management, including localized RTk to symptomatic sites

Continue until two cycles beyond best response or progression of disease or development of unacceptable toxicity

Clinical trial or Palliative symptom management, including localized RT k to symptomatic sites

Primary progressive disease

Palliative symptom management, including localized RTk to symptomatic sites or Clinical trial or Subsequent chemotherapy j (PS 0–2)

j See k See

Principles of Chemotherapy (SCL-B). Principles of Radiation Therapy (SCL-C).

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
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SCL-6

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NCCN Guidelines? Version 1.2012 Small Cell Lung Cancer
PRINCIPLES OF SURGICAL RESECTION

NCCN Guidelines Index SCLC Table of Contents Discussion

· Stage I SCLC is diagnosed in less than 5% of patients with SCLC. · Patients with disease in excess of T1-2, N0 do not benefit from surgery. 1 · Patients with SCLC that is clinical stage I (T1-2, N0) after standard staging evaluation (including CT of the chest and upper abdomen, brain imaging, and PET/CT imaging) may be considered for surgical resection. > Prior to resection, all patients should undergo mediastinoscopy or other surgical mediastinal staging to rule out occult nodal disease. This may also include an endoscopic staging procedure. > Patients who undergo complete resection (preferably by a lobectomy with either mediastinal nodal dissection or sampling) should be treated with postoperative chemotherapy. Patients without nodal metastases should be treated with chemotherapy alone. Patients with nodal metastases should be treated with postoperative concurrent chemotherapy and mediastinal radiation therapy. · Because prophylactic cranial irradiation (PCI) can improve both disease-free and overall survival in patients with SCLC who have complete or partial response, PCI is recommended (category 1) after adjuvant chemotherapy in patients who have undergone a complete resection. 2 PCI is not recommended in patients with poor performance status or impaired mental functioning. 3,4

1 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-3S. 2 Auperin A, Arriagada R, Pignon JP, et al. Prophylactic cranial irradiation for patients with small-cell cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group. N Engl J Med 1999;341:476-84. 3 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. 4 Le Péchoux 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. Lancet Oncol 2009;10(5):467-474.
Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
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SCL-A

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NCCN Guidelines? Version 1.2012 Small Cell Lung Cancer
PRINCIPLES OF CHEMOTHERAPY* Chemotherapy as primary therapy: · Limited stage (maximum of 4-6 cycles): > Cisplatin 60 mg/m 2 day 1 and etoposide 120 mg/m 2 days 1, 2, 3 1 > Cisplatin 80 mg/m 2 day 1 and etoposide 100 mg/m 2 days 1, 2, 3 2 > Carboplatin AUC 5-6 day 1 and etoposide 100 mg/m 2 days 1, 2, 3 3 > During chemotherapy + RT, cisplatin/etoposide is recommended (category 1). > The use of myeloid growth factors is not recommended during concurrent chemotherapy plus radiotherapy. · Extensive stage (maximum of 4-6 cycles): > Cisplatin 75 mg/m 2 day 1 and etoposide 100 mg/m 2 days 1, 2, 3 4 > Cisplatin 80 mg/m 2 day 1 and etoposide 80 mg/m 2 days 1, 2, 3 5 > Cisplatin 25 mg/m 2 days 1, 2, 3 and etoposide 100 mg/m 2 days 1, 2, 3 6 > Carboplatin AUC 5-6 day 1 and etoposide 100 mg/m 2 days 1, 2, 3 7 > Cisplatin 60 mg/m 2 day 1 and irinotecan 60 mg/m 2 days 1, 8, 15 8 > Cisplatin 30 mg/m 2 and irinotecan 65 mg/m 2 days 1, 8 every 21 days 9 > Carboplatin AUC 5 day 1 and Irinotecan 50 mg/m 2 days 1, 8, and 15 10

NCCN Guidelines Index SCLC Table of Contents Discussion

Subsequent chemotherapy: · Clinical trial preferred. · Relapse < 2-3 mo, PS 0-2: > paclitaxel 11,12 > docetaxel 13 > topotecan 14,15 > irinotecan 16 > ifosfamide 17 > gemcitabine 18,19 · Relapse > 2-3 mo up to 6 mo: > topotecan PO or IV (category 1) 14,15, 20 > paclitaxel 11,12 > docetaxel 13 > irinotecan 16 > gemcitabine 18,19 > vinorelbine 21,22 > oral etoposide 23,24 > cyclophosphamide/doxorubicin/vincristine (CAV) 14 ! Relapse > 6 mo: original regimen 25,26 Consider dose reductions versus growth factors in the poor performance status patient.

See References on SCL-B 2 of 2

*The regimens included are representative of the more commonly used regimens for Small Cell Lung Cancer. Other regimens may be acceptable.
Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
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SCL-B 1 of 2

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NCCN Guidelines? Version 1.2012 Small Cell Lung Cancer
PRINCIPLES OF CHEMOTHERAPY References
1 Turrisi AT

NCCN Guidelines Index SCLC Table of Contents Discussion

3rd, 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(4):265-271. 2 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(33): 5247-5252. 3 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(9):1231-1238. 4 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(24):4665-4672. 5 Ihde DC, Mulshine JL, Kramer BS, et al. Prospective randomized comparison of highdose and standard-dose etoposide and cisplatin chemotherapy in patients with extensive-stage small-cell lung cancer. J Clin Oncol 1994;12(10):2022-2034. 6 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(11):1471-1477. 7 Okamoto H, Watanabe K, Nishiwaki Y, et al. Phase II study of area under the plasmaconcentration-versus-time curve-based carboplatin plus standard-dose intravenous etoposide in elderly patients with small cell lung cancer. J Clin Oncol 1999;17(11):35403545. 8 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(2): 85-91. 9 Hanna N, Bunn Jr. PA, 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(13):2038-2043. 10 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. 11 Smit EF, Fokkema E, Biesma B, et al. A phase II study of paclitaxel in heavily pretreated patients with small-cell lung cancer. Br J Cancer 1998; 77:347-351. 12 Yamamoto N, Tsurutani J, Yoshimura N, et al. Phase II study of weekly paclitaxel for relapsed and refractory small cell lung cancer. Anticancer Res 2006; 26:777-781. 13 Smyth JF, Smith IE, Sessa C, et al. Activity of docetaxel (Taxotere) in small cell lung cancer. Eur J Cancer 1994; 30A:1058-1060.

14 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(2):658-667. 15 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(34):5441-5447. 16 Masuda N, Fukuoka M, Kusunoki Y, et al. CPT-11: a new derivative of camptothecin for the treatment of refractory or relapsed small-cell lung cancer. J Clin Oncol 1992; 10:1225-1229. 17 Cantwell BM, Bozzino JM, Corris P, et al. The multidrug resistant phenotype in clinical practice; evaluation of cross resistance to ifosfamide and mesna after VP16-213, doxorubicin and vincristine (VPAV) for small cell lung cancer. Eur J Cancer Clin Oncol 1988; 24:123-129. 18 Van der Lee I, Smit EF, van Putten JW, et al. Single-agent gemcitabine in patients with resistant small-cell lung cancer. An Oncol 2001; 12:557-561. 19 Masters GA, Declerck L, Blanke C, et al. Phase II trial of gemcitabine in refractory or relapsed small-cell lung cancer. J Clin Oncol 2003; 21:1550-1555. 20 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(15):2086-2092. 21 Jassem J, Karnicka-Mlodkowska H, van Pottelsberghe C, et al. Phase II study of vinorelbine (Navelbine) in previously treated small cell lung cancer patients. Eur J Cancer 1993; 29A:1720-1722. 22 Furuse K, Kuboa K, Kawahara M, et al. Phase II study of vinorelbine in heavily previously treated small cell lung cancer. Oncology 1996; 53:169-172. 23 Einhorn LH, Pennington K, McClean J. Phase II trial of daily oral VP-16 in refractory small cell lung cancer. Semin Oncol 1990; 17:32-35. 24 Johnson DH, Greco FA, Strupp J, et al. Prolonged administration of oral etoposide in patients with relapsed or refractory small-cell lung cancer: a phase II trial. J Clin Oncol 1990; 8:1613-1617. 25 Postmus PE, Berendsen HH, van Zandwijk N, et al. Retreatment with the induction regimen in small cell lung cancer relapsing after an initial response to short term chemotherapy. Eur J Cancer Clin Oncol 1987;23:1409-1411. 26 Giaccone G, Ferrati P, Donadio M, et al. Reinduction chemotherapy in small cell lung cancer. Eur J Cancer Clin Oncol 1987;23:1697-1699.

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
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SCL-B 2 of 2

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NCCN Guidelines? Version 1.2012 Small Cell Lung Cancer
PRINCIPLES OF RADIATION THERAPY

NCCN Guidelines Index SCLC Table of Contents Discussion

Limited Stage: · Radiotherapy should be delivered as either 1.5 Gy bid (twice daily) to a total dose of 45 Gy (category 1), or 2 Gy once daily to 60-70 Gy. 1-6 If bid fractionation is utilized, there should be at least a 6 hour inter-fraction interval to allow for repair of normal tissue. · Radiotherapy should start concurrent with chemotherapy, cycle 1 or 2 (category 1). 7 · Radiation target volumes should be defined based on the pretreatment PET scan and CT scan obtained at the time of radiotherapy planning, following ICRU definitions (Reports 50 and 62). 8-10 Radiation doses should be calculated with inhomogeneity corrections. · Three-dimensional conformal radiation techniques are preferred. In selected patients, IMRT may be considered (http://www.icru.org/index.php?option=com_content&task=view&id=171). 11 Four-dimensional imaging and/or other available techniques should also be performed to assess tumor movement and motion management should be used to achieve movement of less than 1 cm or the PTV margin should be increased appropriately. 12 Normal Tissue Constraints: 13,14 · Normal tissue doses will be dependent on tumor size and location. The following normal tissue constraints from CALGB 30610/ RTOG 0538 protocol should be used as a guide: > If BID accelerated hyperfractionation (i.e. 45 Gy/ 30 twice daily treatments) irradiation schema is utilized, the maximum spinal cord dose should be limited to ? 41 Gy (including scatter irradiation). If once daily dose irradiation is utilized, the maximum spinal cord dose should be limited to ? 50 Gy (including scatter irradiation). > The volume of both lungs (total lungs minus the clinical target volume) that receives > 20 Gy (V20 ) should be < 40%. Alternatively the mean dose to the total lung volume should be ? 20 Gy. > Mean dose to the esophagus should be < 34 Gy. > Heart: 60 Gy to < 1/3, 45 Gy to < 2/3, 40 Gy to < 100%. Prophylactic Cranial Radiotherapy: · Parallel opposed fields should be utilized to encompass the whole brain. The field edges should be at least 1 cm from the outer skull margin. The recommended dose is 25 Gy in 10 fractions or 30 Gy in 15 fractions. For extensive-stage patients, 20 Gy in 5 fractions may be considered. 15,16

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
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SCL-C 1 of 2

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NCCN Guidelines? Version 1.2012 Small Cell Lung Cancer
PRINCIPLES OF RADIATION THERAPY References
1 Turisi AT

NCCN Guidelines Index SCLC Table of Contents Discussion

3rd, 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(4):265-271. 2 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 smallcell lung cancer. Int J Radiat Oncol Biol Phys 2004;59(4):943-951. 3 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(2):355-359. 4 Roof KS, Fidias P, Lymch TJ, et al. Radiation dose escalation in limited-stage small cell lung cancer. Int J Radiat Oncol Biol Phys 2003;57(3):701-8. 5 Bogart JA, Herndon JE, 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(2):460-468. 6 Yuen AR, Zou G, Turrisi AT, et al. Similar Outcome of elderly patients in Intergroup Trial 0096: Cisplatin, etoposide, and thoracic radiotherapy administered once or twice daily in limited stage small cell lung carcinoma. Cancer 2000;89(9):1953-1960. 7 Takada M, Fukuoka M, Kawahara M, et al. Phase III study of concurrent versus sequential thoracic radiotherapy in combination with cisplatin and etoposide for limitedstage small-cell lung cancer: results of the Japan Clinical Oncology Group Study 9104. J Clin Oncol 2002;20(14):3054-3060. 8 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(3):496-502. 9 The International Commission on Radiation Units and Measurement (ICRU) Report #50: Prescribing, Recording, and Reporting Photon Beam Therapy: Library of Congress Cataloging-in-Publication Data. 1993. 10 The International Commission on Radiation Units and Measurements Prescribing, Recording and Reporting Photon Beam Therapy: Supplement to ICRU Report 50, Library of Congress Cataloging-in-Publication Data. 1999. 11 International Commission on Radiation Units and Measurements. Report 83: Prescribing, Recording, and Reporting Intensity-Modulated Photon-Beam Therapy (IRT). Journal of the ICRU 2010;10(1). http://www.icru.org/index.php?option=com_content&task=view&id=171 12 Keall PJ, et al. The management of respiratory motion in radiation oncology report of AAPM Task Group 76. Med Phys 2006;33:3874-3900. 13 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. 14 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:dd282-7. 15 Le Péchoux 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. Lancet Oncol 2009;10(5):467-474. 16 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.

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
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SCL-C 2 of 2

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NCCN Guidelines? Version 1.2012 Small Cell Lung Cancer
PRINCIPLES OF SUPPORTIVE CARE

NCCN Guidelines Index SCLC Table of Contents Discussion

· Smoking cessation counseling · Granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) during RT is not recommended (category 1 for GM-CSF). · Syndrome of inappropriate antidiuretic hormone > Fluid restriction > Saline infusion for symptomatic patients > Demeclocycline > Antineoplastic therapy · Cushing’s syndrome > Consider ketoconazole > Try to control before initiation of antineoplastic therapy · Leptomeningeal disease: See NCCN Carcinomatous/Lymphomatous Meningitis Guidelines · Pain Management: See NCCN Adult Cancer Pain Guidelines · Nausea/Vomiting: See NCCN Antiemesis Guidelines · Psychosocial distress: See NCCN Distress Management Guidelines · See NCCN Palliative Care Guidelines as indicated

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
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SCL-D

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NCCN Guidelines? Version 1.2012 Lung Neuroendocrine Tumors
PATHOLOGY High-grade neuroendocrine carcinoma (large-cell neuroendocrine carcinoma) Low-grade neuroendocrine carcinoma (typical carcinoid) a Biopsy Intermediategrade neuroendocrine carcinoma (atypical carcinoid) WORKUP CLINICAL STAGE/TREATMENT

NCCN Guidelines Index SCLC Table of Contents Discussion ADJUVANT TREATMENT

Treat per NCCN Non-Small Cell Lung Cancer Guidelines Stage I Surgery: c · Chest/abdominal CT · Bronchoscopy · If enlarged mediastinal nodes on CT, mediastinoscopy or other mediastinal staging · Consider octreotide scan · PET scan (optional) b Stage II Lobectomy or other anatomic resection e + mediastinal lymph node dissection or sampling Intermediate grade (atypical) II, III Stage IIIb, IV or unresectable Treat per NCCN Small Cell Lung Cancer Guidelines (see SCL-1)
d There

Low grade (typical)

I, II, III

Observe

I

Observe

Stage IIIa

Combined SCLC and NSCLC
a Management

Systemic therapy, d Consider octreotide if octreotide scan positive or symptoms of carcinoid syndrome

Cisplatin/ etoposide ± RT (category 2B)

of endocrine symptoms as indicated (See the Carcinoid Tumors section in the NCCN Neuroendocrine Tumors Guidelines). b PET scan is undergoing evaluation in clinical trials and should only be considered as a supplement and not a replacement to other studies. c For Stage III, typical: RT recommended if surgery is not feasible. For Stage III, atypical: Chemotherapy/RT is recommended if surgery is not feasible.

is no substantial evidence for a commonly used regimen. Options include cisplatin/etoposide, temozolomide, sunitinib, or everolimus. References: 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; Ekebald 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; Kulke MH, Lenz HJ, Meropol NJ, et al. Activity of sunitinib in patients with advanced neuroendocrine tumors. J Clin Oncol 2008;26:3403-3410; 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. e Wedge resection for peripheral low-grade neuroendocrine carcinoma (category 2B).

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
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LNT-1

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NCCN Guidelines? Version 1.2012 Staging Small Cell Lung Cancer

NCCN Guidelines Index SCLC Table of Contents Discussion

Table 1 - Definition of small cell lung cancer consists of two stages: (1) Limited-stage disease: disease confined to the ipsilateral hemithorax, which can be safely encompassed within a tolerable radiation field. (2) Extensive-stage disease: disease beyond ipsilateral hemithorax which may include malignant pleural or pericardial effusion or hematogenous metastases. Table 2 - Definitions of TNM T Primary Tumor TX Primary tumor cannot be assessed, or tumor proven by the presence of malignant cells in sputum or bronchial washings but not visualized by imaging or bronchoscopy T0 No evidence of primary tumor Tis Carcinoma in situ T1 Tumor 3 cm or less in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus)* T1a Tumor 2 cm or less in greatest dimension T1b Tumor more than 2 cm but 3 cm or less in greatest dimension T2 Tumor with any of the following features of size or extent: · More than 3 cm but 7 cm or less · Involves main bronchus, 2 cm or more distal to the carina · Invades the visceral pleura (PL1 or PL2) · Associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung T2a Tumor more than 3 cm but 5 cm or less in greatest dimension T2b Tumor more than 5 cm but 7 cm or less in greatest dimension T3 Tumor more than 7 cm or one that directly invades any of the following: parietal pleural (PL3) chest wall (including superior sulcus tumors), diaphragm, phrenic nerve, mediastinal pleura, parietal pericardium; or tumor in the main bronchus (less than 2 cm distal to the carina* but without involvement of the carina; or associated atelectasis or obstructive pneumonitis of the entire lung or separate tumor nodule(s) in the same lobe T4 Tumor of any size that invades any of the following: mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, carina, separate tumor nodule(s) in a different ipsilateral lobe N NX N0 N1 N2 N3 M M0 M1 Regional Lymph Nodes Regional lymph nodes cannot be assessed No regional lymph node metastasis Metastasis to ipsilateral peribronchial and/or ipsilateral hilar lymph nodes, and intrapulmonary nodes including involvement by direct extension Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s) Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s) Distant Metastasis No distant metastasis Distant metastasis M1a Separate tumor nodule(s) in a contralateral lobe tumor with pleural nodules or malignant pleural (or pericardial) effusion** M1b Distant metastasis

*The uncommon superficial spreading tumor of any size with its invasive component limited to the bronchial wall, which may extend proximally to the main bronchus, is also classified as T1a. **Most pleural (and pericardial) effusions with lung cancer are due to tumor. In a few patients, however, multiple cytopathologic examinations of pleura (pericardial) fluid are negative for tumor, and the fluid is nonbloody and is not an exudate. Where these elements and clinical judgment dictate that the effusion is not related to the tumor, the effusion should be excluded as a staging element and the patient should be classified as M0.

Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original and primary source for this information is the AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer Science and Business Media LLC (SBM). (For complete information and data supporting the staging tables, visit www.springer.com.) Any citation or quotation of this material must be credited to the AJCC as its primary source. The inclusion of this information herein does not authorize any reuse or further distribution without the expressed, written permission of Springer SBM, on behalf of the AJCC.
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ST-1

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NCCN Guidelines? Version 1.2012 Staging Small Cell Lung Cancer
Table 3 - Anatomic Stage/Prognostic Groups Occult carcinoma Stage 0 Stage IA Stage IB Stage IIA TX Tis T1 T2a T2b T1 T2a T2b T3 T1-2 T3 T4 T1-2 T3 T4 Any T Any T N0 N0 N0 N0 N0 N1 N1 N1 N0 N2 N1-2 N0-1 N3 N3 N2-3 Any N Any N M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M1a M1b

NCCN Guidelines Index SCLC Table of Contents Discussion

Stage IIB Stage IIIA

Stage IIIB

Stage IV

Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original and primary source for this information is the AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer Science and Business Media LLC (SBM). (For complete information and data supporting the staging tables, visit www.springer.com.) Any citation or quotation of this material must be credited to the AJCC as its primary source. The inclusion of this information herein does not authorize any reuse or further distribution without the expressed, written permission of Springer SBM, on behalf of the AJCC.
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ST-2

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NCCN Guidelines? Version 1.2012 Small Cell Lung Cancer
Discussion
This discussion is being updated to correspond with the newly updated algorithm. Last updated 04/11/11

NCCN Guidelines Index SCLC Table of Contents Discussion

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.

cure using chemotherapy plus thoracic radiotherapy.7 In patients with extensive-stage disease, chemotherapy alone can palliate symptoms and prolong survival in most patients, but long-term survival is rare.8, 9 Surgery is appropriate for the few patients (2%-5%) with surgically resectable stage I SCLC.10 Smoking cessation should be strongly encouraged (1-800-QUIT-NOW—the national access number to State-based quitline services) (http://www.smokefree.gov/). Patients who smoke have increased toxicity during treatment and shorter survival.11 Programs using behavioral counseling combined with Food and Drug Administration (FDA)–approved medications that promote smoking cessation can be very useful (http://www.surgeongeneral.gov/tobacco/index.html).

Pathology Overview
Small cell lung cancer (SCLC) accounts for about 15% of all lung cancers.1, 2 In 2010, it is estimated that 33,000 new cases of SCLC occurred in the United States.3, 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 1:1.1 When compared with non-small cell lung cancer (NSCLC), SCLC generally has a more rapid doubling time, a higher growth fraction, and earlier development of widespread metastases. Most patients with SCLC present with hematogenous metastases, while only about one third of patients present with limited disease confined to the chest. SCLC is highly sensitive to initial chemotherapy and radiotherapy; however, most patients eventually die from recurrent disease.5, 6 In patients with limited-stage SCLC, the goal of treatment is to achieve a 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.12 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.13-15 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 MS-1

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NCCN Guidelines? Version 1.2012 Small Cell Lung Cancer
extrapulmonary small cell carcinoma do not exhibit macromolecular 3p deletions, a finding that suggests a different pathogenesis.16 Nearly all SCLCs are immunoreactive for keratin, epithelial membrane antigen, and thyroid transcription factor 1 (TTF1). 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.17

NCCN Guidelines Index SCLC Table of Contents Discussion

voltage-gated calcium channels.20 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.21 SCLC cells also can produce numerous polypeptide hormones, including adrenocorticotropic hormone (ACTH) and vasopressin (ADH), which cause Cushing’s syndrome and hyponatremia of malignancy, respectively.22, 23 Staging The Veteran’s Administration Lung Group 2-stage classification scheme has been routinely used to define the extent of disease in patients with SCLC as shown in Table 1: (1) limited-stage disease is defined as disease confined to the ipsilateral hemithorax, which can be safely encompassed within a tolerable radiation field; and (2) extensive-stage disease is defined as disease beyond the ipsilateral hemithorax, including malignant pleural or pericardial effusion or hematogenous metastases.24 Contralateral mediastinal and ipsilateral supraclavicular lymphadenopathy are generally classified as limited-stage disease, while 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) (7th edition, 2010) (see Tables 2 and 3).25-29 This new staging system is applicable to both NSCLC and SCLC based on studies by the IASLC which demonstrated the prognostic significance of the various stage MS-2

Clinical Manifestations, Staging, and Prognostic Factors
Clinical Manifestations SCLC typically presents as a large hilar mass and bulky mediastinal lymphadenopathy that cause cough and dyspnea. Frequently, patients present with symptoms of widespread metastatic disease, such as weight loss, debility, bone pain, and neurologic compromise. It is uncommon for patients to present with a solitary peripheral nodule without central adenopathy. In this situation, fine-needle aspiration may not adequately differentiate small cell carcinoma from low-grade (typical carcinoid), intermediate-grade (atypical carcinoid), or high-grade (large-cell) neuroendocrine carcinoma (see the “Lung Neuroendocrine Tumors” page in the 2011 SCLC algorithm and the NCCN Neuroendocrine Tumors Guidelines).18 Many neurologic and endocrine paraneoplastic syndromes are associated with SCLC.19 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

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NCCN Guidelines? Version 1.2012 Small Cell Lung Cancer
designations in both diseases.25, 29 Using the new TNM staging system, limited-stage SCLC is T any, N any, M0 except T3-4 due to multiple lung nodules (see “Stage” in the NCCN 2011 SCLC algorithm). Extensive-stage SCLC is T any, N any, M1a/b, and T3-4 due to multiple lung nodules. Because most of the literature on SCLC classifies patients based on limited or extensive-stage disease, these definitions are still most relevant for clinical decision-making. For now, application of the TNM system will not change how patients are treated; however, clinical research studies should begin to utilize the TNM system, because it will allow for more precise assessments of prognosis and specific therapy in the future. Therefore, the 2011 SCLC algorithm was revised to include the TNM staging information (see Table 2). All SCLC patients, 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; computed tomography (CT) scan (with IV contrast) including the chest, liver, and adrenal glands; a magnetic resonance imaging (MRI) scan (preferred) or CT scan of the brain; and a bone scan (optional if positron emission tomography [PET]–CT scan is obtained). 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 less than 5% of patients. A PET-CT scan is optional but can be used as part of the initial evaluation in addition to the other recommended studies.

NCCN Guidelines Index SCLC Table of Contents Discussion

PET scans can increase staging accuracy in patients with SCLC.30-34 PET-CT is superior to PET alone. By PET, about 15% of patients are up-staged from limited to extensive stage while only 5% are downstaged from extensive to limited stage. For most metastatic sites, PET is superior to standard imaging; however, PET is inferior to MRI or CT for the detection of brain metastases. Changes in management based on PET staging were reported in 16%-38% of patients, mainly due to alterations in the planned radiation field due to improved detection of intrathoracic sites of disease.31, 35, 36 While PET appears to improve staging accuracy in SCLC, pathologic confirmation is still required for PET-detected lesions that result in up-staging. Similarly, pathologic mediastinal staging is required to confirm PET scan results in patients who appear to have clinical stage T1-2, N0 disease prior to surgical resection. Mediastinal staging can be done by either conventional mediastinoscopy or by minimally invasive techniques such as transesophageal endoscopic ultrasound–guided fine-needle aspiration (EUS-FNA), endobronchial ultrasound–guided transbronchial needle aspiration (EBUS-TBNA), or video-assisted thoracoscopy (VATS).37, 38 If a pleural effusion is large enough to be seen by a chest radiograph, then thoracentesis is recommended. 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) 3 cytopathologic examinations of pleural fluid are 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.

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MS-3

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NCCN Guidelines? Version 1.2012 Small Cell Lung Cancer
Staging should not be focused only to sites of symptomatic disease or sites 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 (CNS) metastases in 10% to 15% of patients at diagnosis, of which about 30% are asymptomatic. Early treatment of brain metastases results in less chronic neurologic morbidity, arguing for the utility of early diagnosis in asymptomatic patients. Due to the aggressive nature of SCLC, staging should not delay the onset of treatment 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, such as lactate dehydrogenase (LDH), are the most important adverse prognostic factors. In patients with limited-stage disease, female gender, age younger than 70 years, normal LDH, and stage I disease are associated with a more favorable prognosis. In patients with extensive-stage disease, younger age, good PS, normal creatinine level, normal LDH, and a single metastatic site are favorable prognostic factors.39-41

NCCN Guidelines Index SCLC Table of Contents Discussion

SCLC algorithm for recommended regimens). In patients with extensive disease and brain metastases, chemotherapy can be given either before or after whole-brain RT depending on whether or not the patient has neurologic symptoms (see “Initial Treatment for Extensive Stage” in the 2011 SCLC algorithm).9, 44 Single-agent and combination chemotherapy regimens have been shown to be active in SCLC.45-47 Etoposide and cisplatin (EP) is the most commonly used initial combination chemotherapy regimen (see “Principles of Chemotherapy” in the 2011 SCLC algorithm).8, 48, 49 This combination replaced alkylator/anthracycline-based regimens based on superiority in both efficacy and toxicity in the limited-stage setting.50 EP plus concurrent thoracic radiotherapy is now the recommended therapy for patients with limited-stage disease (category 1).42, 43, 51 In combination with thoracic radiotherapy, EP causes an increased risk of esophagitis, pulmonary toxicity, and hematologic toxicity.52 The hematologic toxicity is manageable with dose reductions or growth factor support, although myeloid growth factors should be used with caution during concurrent chemotherapy plus radiotherapy (see the “NCCN Myeloid Growth Factors in Cancer Treatment Guidelines”). In clinical practice, carboplatin is frequently substituted for cisplatin in order to reduce the risk of emesis, neuropathy, and nephropathy. However, the use of carboplatin carries a greater risk of myelosuppression.53 The substitution of carboplatin for cisplatin in patients with limited-stage disease has not been adequately evaluated and should only be done when cisplatin is contraindicated or poorly tolerated.54, 55 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.56

Chemotherapy
For all patients with SCLC, chemotherapy is an essential component of appropriate treatment.8 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).7, 42, 43 For patients with extensive-stage disease, chemotherapy alone is the recommended treatment (see the 2011

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Many other combinations have been evaluated in patients with extensive-stage disease with little consistent evidence of benefit when compared with EP. In recent years, 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 achieved a median survival of 12.8 months compared to 9.4 months for patients treated with EP (P=.002).57 In addition, 2-year survival was 19.5% in the irinotecan plus cisplatin group versus 5.2% in the EP group.57 However, 2 subsequent large phase III trials performed in the United States comparing irinotecan plus cisplatin to EP failed to demonstrate a significant difference in response rate or overall survival between the regimens.58, 59 A randomized phase II trial (n = 70) comparing carboplatin and irinotecan versus carboplatin and etoposide showed a modest improvement in progression-free survival with the irinotecan combination.60 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 versus 7.1 months, P=.04).61 Based on these findings, the carboplatin and irinotecan regimen has been added to the guidelines as an option for patients with extensive-stage disease. A recent meta-analysis suggests an improvement in progression-free and overall survival with irinotecan plus platinum regimens compared to etoposide plus platinum regimens.62 However, the relatively small absolute survival benefit needs to be balanced against the toxicity profile of irinotecan-based regimens. Therefore, the NCCN panel continues to consider etoposide plus platinum 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, while

NCCN Guidelines Index SCLC Table of Contents Discussion

in extensive-stage disease, response rates of 60% to 70% can be achieved with combination chemotherapy alone.45 Unfortunately, median survival rates are only 14 to 20 months and 9 to 11 months for patients with limited-stage and extensive-stage disease, respectively. After appropriate treatment, the 2-year survival rate is about 40% in patients with limited-stage disease, but less than 5% in those with extensive-stage disease.63 Thoracic radiotherapy improves local control rates by 25% in limited-stage disease patients and is associated with improved survival.42, 43 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. 64, 65 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 demonstrated a modest survival advantage for patients with extensive disease.66, 67 However, such 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.68 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.69 The use of maintenance or consolidation chemotherapy beyond 4 to 6 cycles of standard treatment produces a minor prolongation of duration of response without improving survival and carries a greater risk of cumulative toxicity.70 The inability to destroy residual cells, despite the initial chemosensitivity of SCLC, suggests the existence of cancer stem cells that are relatively MS-5

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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.71 However, randomized trials have failed to show improved progression-free or overall survival with this approach.72, 73 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.74, 75 Nevertheless, no survival benefits were documented in randomized trials and excessive treatment-related mortality was noted with multidrug cyclic weekly regimens.76-79 The role of higher-dose therapy for patients with SCLC remains controversial.80 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.81 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 rate or survival.82-85 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.86 Currently available cytokines (e.g., GM-CSF and G-CSF) can ameliorate chemotherapy-induced myelosuppression and reduce the incidence of febrile neutropenia, but cumulative thrombocytopenia remains dose limiting. Although trials involving SCLC patients were instrumental in obtaining FDA approval for the clinical use of

NCCN Guidelines Index SCLC Table of Contents Discussion

cytokines,87 there is little evidence to suggest 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 anti-angiogenic 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 RT followed by maintenance bevacizumab (phase II trial) was terminated early due to an unacceptable incidence of tracheoesophageal fistulae (http://www.fda.gov/downloads/Safety/MedWatch/SafetyInformation/Saf etyAlertsforHumanMedicalProducts/UCM153953.pdf). In extensive-stage SCLC, two phase II trials of platinum-based chemotherapy plus bevacizumab have yielded promising response and survival data.88, 89 Randomized phase III trials are ongoing to determine if the addition of bevacizumab to chemotherapy improves survival in patients with extensive-stage SCLC. At present, the NCCN panel does not recommend use of bevacizumab in patients with SCLC. Overall, attempts to improve long-term survival rates in patients with SCLC through the addition of more agents or the use of dose-intense chemotherapy regimens, maintenance therapy, or alternating non-cross-resistant chemotherapy regimens have failed to yield significant advantages 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 under-represented in clinical trials.90 While advanced chronological age does adversely affect tolerance to treatment, an individual patient’s functional status is much more useful than age in guiding clinical decision making (see the “NCCN Senior Adult Oncology Guidelines”). If an older person is MS-6

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functional in terms of the ability to perform activities of daily living, he/she 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 need to be watched carefully during treatment in order to avoid excessive risk. Greater attention to the needs and support systems of elderly patients is recommended in order to provide optimal care. Overall, elderly patients have a similar prognosis when compared to 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).91, 92 Several other strategies have been evaluated in elderly patients with SCLC.56, 93-95 The use of 4 cycles of carboplatin plus etoposide appears to yield favorable results, because the AUC (area-under-the-curve) dosing of carboplatin takes into account the declining renal function of the aging patient.95 However, targeting carboplatin to an AUC of 5, rather than 6, may be more reasonable in this population.96 The utility of short-course, full-intensity chemotherapy has also been explored in elderly or infirm patients, and the results with only 2 cycles of chemotherapy appear to be quite acceptable, though this approach has not been directly compared to standard therapy.97 Salvage (Second-Line) Therapy Although SCLC is very responsive to initial treatment, most patients relapse with relatively resistant disease.98, 99 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.

NCCN Guidelines Index SCLC Table of Contents Discussion

If this interval is less than 3 months (refractory or resistant disease), response to most agents or regimens is poor (10% or less). If more than 3 months have elapsed (sensitive disease), expected response rates are approximately 25%. In phase II trials, active subsequent agents include paclitaxel, docetaxel, oral etoposide, irinotecan, topotecan, vinorelbine, gemcitabine, and ifosfamide, (see “Principles of Chemotherapy” in the 2011 SCLC algorithm).49, 100-103 In a randomized phase III trial, single-agent IV topotecan was compared to the combination regimen CAV.104 Both arms had similar response rates and survival, but IV topotecan caused less toxicity. In another phase III trial, oral topotecan improved overall survival when compared with best supportive care (26 versus 14 weeks).105 Single-agent topotecan is approved by the U.S. FDA as subsequent therapy for patients with SCLC who initially respond to chemotherapy but then progress after 2-3 months. In the NCCN algorithm, topotecan is recommended as a subsequent agent for patients with relapsed SCLC (category 1 for relapse > 2-3 months up to 6 months).100, 104, 106 Either oral or IV topotecan may be used since efficacy and toxicity appear to be similar with either route.105, 106 Many practicing oncologists have noted excessive toxicity with the standard regimen of topotecan IV 1.5 mg/m2 × 5 days, and recent studies suggest that an attenuated dose may be equally efficacious with lower toxicity.107 Published studies have yielded conflicting data regarding the utility of weekly topotecan in patients with relapsed SCLC and this approach remains under investigation.108, 109 Recent data from phase II studies suggest that amrubicin, an investigational anthracycline, has promising activity in patients with relapsed or refractory SCLC.110-112 However, grade 3-4 toxicity, primarily neutropenia, is common.113 A randomized phase II trial MS-7

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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).114 The optimal duration of subsequent chemotherapy has not been fully explored; although even in patients who respond, the duration of response is usually short and cumulative toxicity is frequently limiting. For these reasons, subsequent chemotherapy should be given until 2 cycles beyond best response, progression of disease, or development of unacceptable toxicity. For patients with localized symptomatic sites of disease (i.e., painful bony lesions, obstructive atelectasis, or brain metastases), radiotherapy can provide excellent palliation (see “Initial Treatment for Extensive Stage” in the 2011 SCLC algorithm).

NCCN Guidelines Index SCLC Table of Contents Discussion

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 versus sequential), timing of radiotherapy (early versus late), volume of the radiation port (original tumor volume versus shrinking field as the tumor responds), dose of radiation, and fractionation of radiotherapy. Based on randomized trials, early, concurrent radiotherapy is recommended along with chemotherapy for patients with limited-stage SCLC. 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.52 Another randomized phase III trial by the National Cancer Institute of Canada—comparing radiotherapy beginning with either cycle 2 or cycle 6 of chemotherapy— demonstrated that early radiotherapy was associated with improved local and systemic control and with longer survival.116 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 when compared to late concurrent or sequential radiotherapy.117 Another meta-analysis also found that early concurrent thoracic radiation with platinum-based chemotherapy increases 2- and 5-year overall survival.118 The Eastern Cooperative Oncology Group/Radiation Therapy Oncology Group (ECOG/RTOG) compared once a day to twice a day radiotherapy with EP.119 In this trial, 412 patients with limited-stage SCLC were treated with concurrent chemoradiotherapy using a total MS-8

Radiotherapy
The “Principles of Radiation Therapy” section in the NCCN 2011 SCLC algorithm 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 for 2011. The NCCN NSCLC RT guidelines may also be useful. This Discussion 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.115 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 when compared with chemotherapy alone.42, 43 However, achieving long-term local control

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NCCN Guidelines? Version 1.2012 Small Cell Lung Cancer
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 there was a higher incidence of grade 3-4 esophagitis when compared with the once daily regimen. Median survival was 23 versus 19 months (P=.04), and 5-year survival was 26% versus 16% in the twice-daily and once-daily radiotherapy arms, respectively.119 A significant criticism of this trial is that the doses of radiation on the two arms were not biologically equivalent. In light of this, on-going trials are evaluating biologically equivalent doses of 45 Gy delivered twice daily versus 60-70 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 demonstrated no survival difference between once-a-day thoracic radiotherapy to 50.4 Gy with concurrent EP and a split-course of twice-daily thoracic radiotherapy to 48 Gy with concurrent EP.120 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-a-day radiotherapy must have an excellent PS and good baseline pulmonary function.
NCCN Guidelines

NCCN Guidelines Index SCLC Table of Contents Discussion

Three-dimensional (3D) conformal radiation techniques are preferred, if available. The radiation target volumes should be defined on the CT scan obtained at the time of radiotherapy planning using definitions in reports 50 and 62 from the International Commission on Radiation Units and Measurement (ICRU). However, the pre-chemotherapy CT scan should be reviewed to include the originally involved lymph node regions in the treatment fields.123, 126 The CALCB 30610/RTOG 0538 protocol should be used as a guide to determine the normal tissue dose volume constraints (see the NCCN 2011 SCLC algorithm).127-129 In select patients with low-bulk metastatic disease who have a complete or near complete response after initial chemotherapy, the addition of sequential thoracic radiotherapy may be considered based on the following randomized trial. Patients with a complete response at distant metastatic sites after 3 cycles of EP were randomized to receive further EP or accelerated hyperfractionated RT (i.e., 54 Gy in 36 fractions over 18 treatment days) in combination with carboplatin plus etoposide.130 In this trial, the addition of RT resulted in improved median overall survival (17 versus 11 months). Prophylactic Cranial Irradiation (PCI) Intracranial metastases occur in more than 50% of patients with SCLC. Randomized studies have shown that PCI is effective in decreasing the incidence of cerebral metastases, but most individual studies did not have sufficient power to demonstrate a meaningful survival advantage.131 Moreover, late neurologic sequelae have been attributed to radiotherapy, particularly in studies using fractions greater than 3 Gy and/or administering PCI concurrent with chemotherapy. When given after the completion of chemotherapy and at a low dose per fraction, PCI may cause less neurological toxicity. Symptomatic brain

For limited-stage disease, the NCCN guidelines recommend that RT should be used concurrently with chemotherapy and RT 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 60 to 70 Gy (see “Principles of Radiation Therapy” in the 2011 SCLC algorithm).42, 117, 119-124 Concurrent chemoradiotherapy (category 1) is preferable to sequential therapy in patients with good PS (0-2).52, 125

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metastases result in major morbidity, which frequently does not completely resolve with therapeutic cranial irradiation. A meta-analysis of all randomized PCI trials 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.132 Thus, it appears that PCI prevents and does 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.132 Although the number of patients in this meta-analysis with extensive-stage disease was small, 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 when compared to those who did not receive PCI.133 A randomized trial from the EORTC assessed PCI versus no PCI in 286 patients with extensive-stage SCLC who had responded to initial chemotherapy. PCI decreased symptomatic brain metastases (14.6% versus 40.4%) and increased the 1-year survival rate (27.1% versus 13.3%) when compared to controls.134 A balanced discussion between the patient and physician is necessary before making a decision to administer PCI. PCI is recommended (category 1) for patients with either limited- or extensive-stage disease who attain a complete or partial response.134, 135 However, PCI is not recommended for patients with poor PS (3-4) or impaired mental function. The recommended dose for PCI is 25 Gy in 10 fractions or 30 Gy in 15 fractions (see “Principles of Radiation Therapy” in the 2011 SCLC algorithm).134, 135 PCI should not be given concurrently with systemic chemotherapy because of the increased risk of neurotoxicity.

NCCN Guidelines Index SCLC Table of Contents Discussion

Fatigue, headache, and nausea/vomiting are the most common acute toxic effects after PCI.135, 136

Surgical Resection of Stage I SCLC
The “Principles of Surgical Resection” for SCLC are described in the NCCN 2011 SCLC algorithm; studies supporting these NCCN recommendations are described in this section. Briefly, the 2011 SCLC algorithm states that surgery should only be considered for patients with stage I (T1-2 N0) SCLC.137 Data show that patients with clinically staged disease in excess of T1-2, N0 do not benefit from surgery.137 Note that only 5% of patients with SCLC have true stage I SCLC.26 The Lung Cancer Study Group conducted the only prospective randomized trial evaluating the role of surgery in SCLC.137 Patients with limited-stage disease, excluding those with solitary peripheral nodules, received 5 cycles of chemotherapy with CAV; those demonstrating 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. Regarding the utility of surgery in SCLC, most of the data are from retrospective reviews.138-142 These studies report favorable 5-year survival rates of 40%-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 be considered only 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.

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NCCN Guidelines? Version 1.2012 Small Cell Lung Cancer
Recent analyses of the SEER database also suggest that surgery may be appropriate for some patients with localized disease.10, 143 However, these studies are limited by the lack of information on chemotherapy use in the SEER 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 of trials comparing surgery plus adjuvant chemotherapy to concurrent chemoradiotherapy in rigorously staged patients. Occult nodal disease should be ruled out by mediastinal staging before resection in all patients with clinical stage I (T1-2, N0) SCLC who are being considered for surgical resection.144 If resection is performed, the NCCN panel favors lobectomy and does not feel that segmental or wedge resections are appropriate for patients with SCLC. After complete resection, adjuvant chemotherapy or chemoradiation is recommended.140, 145, 146 Adjuvant chemotherapy alone is recommended for patients without nodal metastases, while concurrent chemotherapy and postoperative mediastinal RT are recommended for patients with nodal metastases (see “Initial Treatment for Clinical Stage T1-2” in the 2011 SCLC algorithm). PCI should be considered after adjuvant therapy in patients who have undergone a complete resection, because PCI can improve survival in patients with SCLC in complete remission (see previous section on “Prophylactic Cranial Irradiation” in this Discussion).132

NCCN Guidelines Index SCLC Table of Contents Discussion

Patients with limited-stage disease who are not enrolled in a clinical trial should be treated with concurrent chemotherapy (EP for 4 cycles) plus early thoracic radiotherapy (category 1). Chest radiotherapy should begin during cycle 1 or 2 of chemotherapy and should consist of either 45 Gy as 1.5 Gy twice daily (category 1) or 2.0 Gy once daily to 60-70 Gy. PCI is recommended (category 1) for patients who achieve a complete or partial response. For patients with extensive-stage disease, standard combination platinum-based chemotherapy is recommended, with subsequent PCI for responding patients.

Surveillance
Follow-up examinations are recommended every 2 to 3 months during the first year with concomitant chest imaging; the frequency of surveillance decreases during subsequent years in light of the declining risk of recurrence (see “Surveillance” in the 2011 SCLC algorithm). If a new pulmonary nodule develops, it should prompt evaluation for a new primary lung cancer since second primary tumors are a frequent occurrence in patients who are cured of SCLC.147, 148 Smoking cessation should be encouraged for all patients with SCLC, because second primary tumors occur less commonly in patients who quit smoking. 149-151

Management of Patients Not Participating in Clinical Trials
Clinical trials generally represent state-of-the-art treatment for patients with SCLC. Despite recent advances, the standard therapy for SCLC as outlined by the NCCN guidelines still results in suboptimal outcomes. Thus, participation in clinical trials should be strongly encouraged.
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References
1. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17008692. 2. 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. Available at: http://meeting.ascopubs.org/cgi/content/abstract/24/18_suppl/7082?sid =13581f84-afb5-4b4e-a899-515d9dc5517b. 3. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin 2010;60:277-300. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20610543. 4. American Cancer Society. Cancer Facts & Figures 2010. Atlanta: American Cancer Society; 2010. Available at: http://www.cancer.org/downloads/STT/Cancer_Facts_and_Figures_201 0.pdf. 5. Murray N, Turrisi AT, 3rd. A review of first-line treatment for smallcell lung cancer. J Thorac Oncol 2006;1:270-278. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17409868. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19133604.

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7. Stinchcombe TE, Gore EM. Limited-stage small cell lung cancer: current chemoradiotherapy treatment paradigms. Oncologist 2010;15:187-195. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20145192. 8. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15094173. 9. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20044461. 10. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20101146. 11. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/12697879. 12. Zakowski MF. Pathology of small cell carcinoma of the lung. Semin Oncol 2003;30:3-8. Available at: http://www.ncbi.nlm.nih.gov/pubmed/12635085. 13. Brenner B, Tang LH, Klimstra DS, Kelsen DP. Small-cell carcinomas of the gastrointestinal tract: a review. J Clin Oncol

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REF-1

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2004;22:2730-2739. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15226341. 14. Galanis E, Frytak S, Lloyd RV. Extrapulmonary small cell carcinoma. Cancer 1997;79:1729-1736. Available at: http://www.ncbi.nlm.nih.gov/pubmed/9128989. 15. Remick SC, Ruckdeschel JC. Extrapulmonary and pulmonary small-cell carcinoma: tumor biology, therapy, and outcome. Med Pediatr Oncol 1992;20:89-99. Available at: http://www.ncbi.nlm.nih.gov/pubmed/1310345. 16. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/2569043. 17. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/7524299. 18. Renshaw AA, Haja J, Lozano RL, Wilbur DC. Distinguishing carcinoid tumor from small cell carcinoma of the lung: correlating cytologic features and performance in the College of American Pathologists Non-Gynecologic Cytology Program. Arch Pathol Lab Med 2005;129:614-618. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15859631. 19. Marchioli CC, Graziano SL. Paraneoplastic syndromes associated with small cell lung cancer. Chest Surg Clin N Am 1997;7:65-80. Available at: http://www.ncbi.nlm.nih.gov/pubmed/9001756.

NCCN Guidelines Index SCLC Table of Contents Discussion

20. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/8957015. 21. Graus F, Keime-Guibert F, Rene R, et al. Anti-Hu-associated paraneoplastic encephalomyelitis: analysis of 200 patients. Brain 2001;124:1138-1148. Available at: http://www.ncbi.nlm.nih.gov/pubmed/11353730. 22. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/8383484. 23. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/9372692. 24. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/12234695. 25. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18090577. REF-2

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26. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19156001. 27. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19652623. 28. Edge SB, Byrd DR, Compton CC, et al. AJCC Cancer Staging Manual, 7th ed. New York: Springer; 2010. 29. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17762336. 30. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19555588. 31. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15310768. 32. 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

NCCN Guidelines Index SCLC Table of Contents Discussion

tomography (FDG-PET). Am J Clin Oncol 2007;30:45-50. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17278894. 33. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19921339. 34. 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;18:338345. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17060487. 35. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/14660716. 36. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18282355. 37. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19096305. 38. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19395972.

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REF-3

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39. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19402175. 40. Albain KS, Crowley JJ, LeBlanc M, Livingston RB. Determinants of improved outcome in small-cell lung cancer: an analysis of the 2,580patient Southwest Oncology Group data base. J Clin Oncol 1990;8:1563-1574. Available at: http://www.ncbi.nlm.nih.gov/pubmed/2167954. 41. Yip D, Harper PG. Predictive and prognostic factors in small cell lung cancer: current status. Lung Cancer 2000;28:173-185. Available at: http://www.ncbi.nlm.nih.gov/pubmed/10812187. 42. Pignon JP, Arriagada R, Ihde DC, et al. A meta-analysis of thoracic radiotherapy for small-cell lung cancer. N Engl J Med 1992;327:16181624. Available at: http://www.ncbi.nlm.nih.gov/pubmed/1331787. 43. Warde P, Payne D. Does thoracic irradiation improve survival and local control in limited-stage small-cell carcinoma of the lung? A metaanalysis. J Clin Oncol 1992;10:890-895. Available at: http://www.ncbi.nlm.nih.gov/pubmed/1316951. 44. 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;46:2932. Available at: http://www.ncbi.nlm.nih.gov/pubmed/9488124. 45. Simon M, Argiris A, Murren JR. Progress in the therapy of small cell lung cancer. Crit Rev Oncol Hematol 2004;49:119-133. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15012973.

NCCN Guidelines Index SCLC Table of Contents Discussion

46. Spira A, Ettinger DS. Multidisciplinary management of lung cancer. N Engl J Med 2004;350:379-392. Available at: http://www.ncbi.nlm.nih.gov/pubmed/14736930. 47. Johnson BE. Management of small cell lung cancer. Clin Chest Med 2002;23:225-239. Available at: http://www.ncbi.nlm.nih.gov/pubmed/11901913. 48. Evans WK, Shepherd FA, Feld R, et al. VP-16 and cisplatin as firstline therapy for small-cell lung cancer. J Clin Oncol 1985;3:1471-1477. Available at: http://www.ncbi.nlm.nih.gov/pubmed/2997406. 49. Jackman DM, Johnson BE. Small-cell lung cancer. Lancet 2005;366:1385-1396. Available at: http://www.ncbi.nlm.nih.gov/pubmed/16226617. 50. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/12488411. 51. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17114657. 52. 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 REF-4

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2002;20:3054-3060. Available at: http://www.ncbi.nlm.nih.gov/pubmed/12118018. 53. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/2821197. 54. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/11697833. 55. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/7993835. 56. 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 smallcell lung cancer: JCOG 9702. Br J Cancer 2007;97:162-169. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17579629. 57. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/11784874.

NCCN Guidelines Index SCLC Table of Contents Discussion

58. Lara PN, Jr., Natale R, Crowley J, et al. Phase III trial of irinotecan/cisplatin compared with etoposide/cisplatin in extensivestage small-cell lung cancer: clinical and pharmacogenomic results from SWOG S0124. J Clin Oncol 2009;27:2530-2535. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19349543. 59. Hanna N, Bunn PA, Jr, Langer C, et al. Randomized phase III trial comparing irinotecan/cisplatin with etoposide/cisplatin in patients with previously untreated extensive-stage disease small-cell lung cancer 10.1200/JCO.2005.04.8595. J Clin Oncol 2006;24:2038-2043. Available at: http://www.ncbi.nlm.nih.gov/pubmed/16648503. 60. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/16423848. 61. Hermes A, Bergman B, Bremnes R, et al. Irinotecan plus carboplatin versus oral etoposide plus carboplatin in extensive smallcell lung cancer: a randomized phase III trial. J Clin Oncol 2008;26:4261-4267. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18779613. 62. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20978445. 63. Chute JP, Chen T, Feigal E, et al. Twenty years of phase III trials for patients with extensive-stage small-cell lung cancer: perceptible REF-5

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progress. J Clin Oncol 1999;17:1794-1801. Available at: http://www.ncbi.nlm.nih.gov/pubmed/10561217. 64. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18594317. 65. 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. Available at: http://meeting.ascopubs.org/cgi/content/abstract/27/15S/7555. 66. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/7595712. 67. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/11181777. 68. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/1334539. 69. Niell HB, Herndon JE, 2nd, Miller AA, et al. Randomized phase III intergroup trial of etoposide and cisplatin with or without paclitaxel and

NCCN Guidelines Index SCLC Table of Contents Discussion

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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15923572. 70. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/11304763. 71. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/526911. 72. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/1648142. 73. 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 smallcell lung cancer: a phase III trial of the Southeastern Cancer Study Group. J Clin Oncol 1992;10:282-291. Available at: http://www.ncbi.nlm.nih.gov/pubmed/1310103. 74. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/1846406. REF-6

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75. 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. Available at: 76. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/8410110. 77. 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;12:18061813. Available at: http://www.ncbi.nlm.nih.gov/pubmed/8083704. 78. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/9010043. 79. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/10561291. 80. 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: Williams and Wilkins; 1995:14-42.

NCCN Guidelines Index SCLC Table of Contents Discussion

81. Cohen MH, Creaven PJ, Fossieck BE, Jr., et al. Intensive chemotherapy of small cell bronchogenic carcinoma. Cancer Treat Rep 1977;61:349-354. Available at: http://www.ncbi.nlm.nih.gov/pubmed/194691. 82. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/2824707. 83. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/7931470. 84. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/8247036. 85. 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 colonystimulating 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/10637255. 86. Klasa RJ, Murray N, Coldman AJ. Dose-intensity meta-analysis of chemotherapy regimens in small-cell carcinoma of the lung. J Clin REF-7

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Oncol 1991;9:499-508. Available at: http://www.ncbi.nlm.nih.gov/pubmed/1847968. 87. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/1711156. 88. 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;4:15551560. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19875975. 89. Horn L, Dahlberg SE, Sandler AB, et al. Phase II study of cisplatin plus etoposide and bevacizumab for previously untreated, extensivestage small-cell lung cancer: Eastern Cooperative Oncology Group Study E3501. J Clin Oncol 2009;27:6006-6011. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19826110. 90. Hurria A, Kris MG. Management of lung cancer in older adults. CA Cancer J Clin 2003;53:325-341. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15224973. 91. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/8774567. 92. Souhami RL, Spiro SG, Rudd RM, et al. Five-day oral etoposide treatment for advanced small-cell lung cancer: randomized comparison

NCCN Guidelines Index SCLC Table of Contents Discussion

with intravenous chemotherapy. J Natl Cancer Inst 1997;89:577-580. Available at: http://www.ncbi.nlm.nih.gov/pubmed/9106647. 93. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15143079. 94. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/9586913. 95. 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 smallcell lung cancer. J Clin Oncol 1999;17:3540-3545. Available at: http://www.ncbi.nlm.nih.gov/pubmed/10550152. 96. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/11506300. 97. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/9779708. 98. Hurwitz JL, McCoy F, Scullin P, Fennell DA. New advances in the second-line treatment of small cell lung cancer. Oncologist REF-8

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NCCN Guidelines? Version 1.2012 Small Cell Lung Cancer
2009;14:986-994. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19819917. 99. Schneider BJ. Management of recurrent small cell lung cancer. J Natl Compr Canc Netw 2008;6:323-331. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18377850. 100. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17409809. 101. Ettinger DS. New drugs for chemotherapy-naive patients with extensive-disease small cell lung cancer. Semin Oncol 2001;28:27-29. Available at: http://www.ncbi.nlm.nih.gov/pubmed/11479894. 102. Kelly K. New chemotherapy agents for small cell lung cancer. Chest 2000;117:156S-162S. Available at: http://www.ncbi.nlm.nih.gov/pubmed/10777472. 103. 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;21:15501555. Available at: http://www.ncbi.nlm.nih.gov/pubmed/12697880. 104. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/10080612. 105. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17135646.

NCCN Guidelines Index SCLC Table of Contents Discussion

106. Eckardt JR, von Pawel J, Pujol JL, et al. Phase III study of oral compared with intravenous topotecan as second-line therapy in smallcell lung cancer. J Clin Oncol 2007;25:2086-2092. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17513814. 107. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/16481389. 108. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17399850. 109. 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. Available at: http://meeting.ascopubs.org/cgi/content/abstract/24/18_suppl/7083. 110. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20385980. 111. 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 REF-9

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NCCN Guidelines? Version 1.2012 Small Cell Lung Cancer
Trial 0402. J Clin Oncol 2008;26:5401-5406. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18854562. 112. 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;24:54485453. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17135647. 113. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19225927. 114. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21135284. 115. Simon G, Ginsberg RJ, Ruckdeschel JC. Small-cell lung cancer. Chest Surg Clin N Am 2001;11:165-188, ix. Available at: http://www.ncbi.nlm.nih.gov/pubmed/11253596. 116. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/8381164. 117. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15570087.

NCCN Guidelines Index SCLC Table of Contents Discussion

118. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17513057. 119. Turrisi AT, 3rd, 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;340:265271. Available at: http://www.ncbi.nlm.nih.gov/pubmed/9920950. 120. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15234027. 121. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/12738309. 122. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/14529774. 123. Bogart JA, Herndon JE, 2nd, 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15145163. REF-10

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NCCN Guidelines? Version 1.2012 Small Cell Lung Cancer
124. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/16505424. 125. Socinski MA, Bogart JA. Limited-stage small-cell lung cancer: the current status of combined-modality therapy. J Clin Oncol 2007;25:4137-4145. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17827464. 126. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/8120547. 127. 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;235:208215. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15703313. 128. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18950881. 129. 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 2010. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20934273.

NCCN Guidelines Index SCLC Table of Contents Discussion

130. 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;17:20922099. Available at: http://www.ncbi.nlm.nih.gov/pubmed/10561263. 131. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/7707405. 132. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/10441603. 133. Patel S, Macdonald OK, Suntharalingam M. Evaluation of the use of prophylactic cranial irradiation in small cell lung cancer. Cancer 2009;115:842-850. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19117355. 134. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17699816. 135. 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 2200308004, RTOG 0212, and IFCT 99-01): a randomised clinical trial. Lancet Oncol 2009;10:467-474. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19386548. REF-11

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NCCN Guidelines? Version 1.2012 Small Cell Lung Cancer
136. 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;27:7884. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19047288. 137. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/7988254. 138. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15450573. 139. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/11093496. 140. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15632826. 141. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18978561.

NCCN Guidelines Index SCLC Table of Contents Discussion

142. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/6289013. 143. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20082453. 144. Inoue M, Nakagawa K, Fujiwara K, et al. Results of preoperative mediastinoscopy for small cell lung cancer. Ann Thorac Surg 2000;70:1620-1623. Available at: http://www.ncbi.nlm.nih.gov/pubmed/11093497. 145. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/2835443. 146. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15867769. 147. Johnson BE, Linnoila RI, Williams JP, et al. Risk of second aerodigestive cancers increases in patients who survive free of small-

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REF-12

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NCCN Guidelines? Version 1.2012 Small Cell Lung Cancer
cell lung cancer for more than 2 years. J Clin Oncol 1995;13:101-111. Available at: http://www.ncbi.nlm.nih.gov/pubmed/7799009. 148. Johnson BE. Second lung cancers in patients after treatment for an initial lung cancer. J Natl Cancer Inst 1998;90:1335-1345. Available at: http://www.ncbi.nlm.nih.gov/pubmed/9747865. 149. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/8393311. 150. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/9703291. 151. 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. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20093278.

NCCN Guidelines Index SCLC Table of Contents Discussion

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