NCCN Guidelines Insights: Small Cell Lung Cancer, Version 2.2018

The NCCN Guidelines for Small Cell Lung Cancer (SCLC) address all aspects of disease management. These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines for SCLC regarding immunotherapy, systemic therapy, and radiation therapy. For the 2018 update, new sections were added on “Signs and Symptoms of SCLC” and “Principles of Pathologic Review.”

Abstract

The NCCN Guidelines for Small Cell Lung Cancer (SCLC) address all aspects of disease management. These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines for SCLC regarding immunotherapy, systemic therapy, and radiation therapy. For the 2018 update, new sections were added on “Signs and Symptoms of SCLC” and “Principles of Pathologic Review.”

NCCN: Continuing Education

Target Audience: This activity is designed to meet the educational needs of physicians, nurses, and pharmacists involved in the management of patients with cancer.

Accreditation Statement NCCN

Physicians: National Comprehensive Cancer Network is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

NCCN designates this journal-based CE activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Nurses: National Comprehensive Cancer Network is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center‘s Commission on Accreditation.

NCCN designates this educational activity for a maximum of 1.0 contact hour.

Pharmacists: National Comprehensive Cancer Network is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.

NCCN designates this knowledge-based continuing education activity for 1.0 contact hour (0.1 CEUs) of continuing education credit. UAN: 0836-0000-18-010-H01-P

All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: 1) review the educational content; 2) take the posttest with a 66% minimum passing score and complete the evaluation at http://education.nccn.org/node/84150; and 3) view/print certificate.

Pharmacists: You must complete the posttest and evaluation within 30 days of the activity. Continuing pharmacy education credit is reported to the CPE Monitor once you have completed the posttest and evaluation and claimed your credits. Before completing these requirements, be sure your NCCN profile has been updated with your NAPB e-profile ID and date of birth. Your credit cannot be reported without this information. If you have any questions, please e-mail education@nccn.org.

Release date: October 10, 2018; Expiration date: October 10, 2019

Learning Objectives:

Upon completion of this activity, participants will be able to:

  • Integrate into professional practice the updates to the NCCN Guidelines for Small Cell Lung Cancer

  • Describe the rationale behind the decision-making process for developing the NCCN Guidelines for Small Cell Lung Cancer

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NCCN Guidelines Insights: Small Cell Lung Cancer, Version 2.2018

Version 2.2018 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 16, 10; 10.6004/jnccn.2018.0079

Disclosure of Relevant Financial Relationships

The NCCN staff listed below discloses no relevant financial relationships:

Kerrin M. Rosenthal, MA; Kimberly Callan, MS; Genevieve Emberger Hartzman, MA; Erin Hesler; Kristina M. Gregory, RN, MSN, OCN; Rashmi Kumar, PhD; Karen Kanefield; and Kathy Smith.

Individuals Who Provided Content Development and/or Authorship Assistance:

Gregory P. Kalemkerian, MD, Panel Chair, has disclosed that he receives grant/research support from AbbVie, Inc.; GlaxoSmithKline; Merck & Co., Inc.; and Takeda Pharmaceuticals North America, Inc. He also serves as a scientific advisor for Takeda Pharmaceuticals North America, Inc., and has received consulting fees/honoraria from BioMed Valley Discoveries, Inc. and Unum Therapeutics.

Billy W. Loo Jr, MD, PhD, Panel Vice Chair, has disclosed that he receives grant/research support from RaySearch Laboratories and Varian Medical Systems, Inc, and that he is an Officer/Director/other fiduciary role at TibaRay, Inc.

Karin G. Hoffmann, RN, CCM, Guidelines Coordinator, NCCN, has disclosed that she has no relevant financial relationships [employed by NCCN until 6/1/18].

Miranda Hughes, PhD, Oncology Scientist/Senior Medical Writer, NCCN, has disclosed that she has no relevant financial relationships.

This activity is supported by educational grants from AstraZeneca, Celldex Therapeutics, Celgene Corporation, Genentech, Jazz Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation, and Seattle Genetics, Inc. This activity is supported by independent educational grants from AbbVie, Merck & Co., Inc. and NOVOCURE.

Overview

Neuroendocrine tumors account for approximately 20% of lung cancers; most (14%) are small cell lung cancer (SCLC).1,2 In 2018, an estimated 29,501 new cases of SCLC will occur in the United States.1,3 Nearly all cases of SCLC are attributable to cigarette smoking.4 Smoking cessation should be strongly promoted in patients with SCLC (see NCCN Clinical Practice Guidelines in Oncology [NCCN Guidelines] for Smoking Cessation, available at NCCN.org).5 SCLC is characterized by a rapid doubling time, high growth fraction, and early development of widespread metastases. These NCCN Guidelines Insights focus on recent updates in immunotherapy, systemic therapy, and radiation therapy (RT) for patients with SCLC. For a full list of the 2018 updates, see the complete version of the NCCN Guidelines (available at NCCN.org). The NCCN Guidelines for SCLC address all aspects of disease management.

NCCN Categories of Evidence and Consensus

Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.

Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.

All recommendations are category 2A unless otherwise noted.

Clinical trials: NCCN believes that the best management for any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

Patients with SCLC typically present with a large hilar mass and bulky mediastinal lymphadenopathy

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NCCN Guidelines Insights: Small Cell Lung Cancer, Version 2.2018

Version 2.2018 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 16, 10; 10.6004/jnccn.2018.0079

that cause cough and dyspnea.6 They also frequently present with symptoms of widespread metastatic disease, such as weight loss, debility, bone pain, and neurologic compromise. For the 2018 update, the NCCN panel added a new section describing signs and symptoms of SCLC based on the tumor location and type of metastases (see SCL-A, pages 1174 and 1175). Most patients with SCLC present with extensive-stage disease with hematogenous metastases; approximately one-third present with limited disease confined to the chest. SCLC is highly sensitive to initial chemotherapy and RT; however, most patients eventually die of treatment-resistant recurrent disease.7 Surgery is only appropriate for the few patients (2%–5%) with surgically resectable stage I SCLC.8 Adjuvant chemotherapy is recommended for all patients after resection. In patients with limited-stage SCLC, the goal of treatment is cure using chemotherapy plus thoracic RT and prophylactic cranial irradiation (PCI), when appropriate.9,10 In most patients with extensive-stage disease, chemotherapy alone can palliate symptoms and prolong survival; however, long-term survival is rare.11

For the 2018 update, the NCCN panel added a new section on pathology to the Guidelines (see SCL-B 1 of 2, page 1176). The WHO classification system is currently used to classify lung tumors.1214 SCLC is a poorly differentiated tumor that is categorized as a high-grade neuroendocrine carcinoma. 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.15,16 The cells are round, oval, or spindle-shaped, and nuclear molding is prominent.17 The classic and distinctive histology on hematoxylin and eosin may be sufficient for identifying SCLC in good-quality histologic samples.15

Editor's Note: Additional updates were made to the NCCN Guidelines for SCLC (Version 1.2019) after the final review/approval of these NCCN

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NCCN Guidelines Insights: Small Cell Lung Cancer, Version 2.2018

Version 2.2018 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 16, 10; 10.6004/jnccn.2018.0079

Guidelines Insights; readers should refer to the latest version of the NCCN Guidelines for SCLC for the most current recommendations, including new regimens (available at NCCN.org).

Radiation Therapy

Thoracic RT

The addition of thoracic RT to chemotherapy has improved survival for patients with limited-stage SCLC. A meta-analysis of >2,000 patients (individual data) showed that chemotherapy/RT for limited-stage SCLC yields a 14% reduction in the mortality rate (relative risk of death, 0.86; 95% CI, 0.78–0.94; P=.001) and a corresponding absolute difference of 5.4% (±1.4%) in the 3-year survival rate compared with chemotherapy alone.18 The 3-year survival rates were 14.3% (±1.1%) for chemotherapy/RT versus 8.9% (±0.9%) for chemotherapy alone. Another meta-analysis in >1,900 patients with limited-stage SCLC showed an absolute difference of 5.4% (95% CI, 1.1%–9.7%) in the 2-year survival rate for chemotherapy/RT versus chemotherapy alone.19 Local control improved by 25.3% (95% CI, 16.5%–34.1%) for chemotherapy/RT versus chemotherapy alone. However, achieving long-term local control using conventional chemoradiotherapy for patients with limited-stage SCLC remains a challenge.

ECOG/RTOG compared once-daily versus twice-daily RT with etoposide and cisplatin.20 In this trial, 412 patients with limited-stage SCLC were treated with concurrent chemoradiotherapy using a total thoracic RT dose of 45 Gy delivered either twice daily for 3 weeks or once daily for 5 weeks. The 3-week regimen produced a survival advantage, but a higher incidence of grade 3 to 4 esophagitis was observed compared with the 5-week regimen. Median overall survival (OS) rates were 23 versus 19 months (P=.04), and 5-year OS rates were 26% versus 16% in the 3-week and 5-week RT arms, respectively, thus demonstrating the higher biological

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NCCN Guidelines Insights: Small Cell Lung Cancer, Version 2.2018

Version 2.2018 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 16, 10; 10.6004/jnccn.2018.0079

effectiveness of accelerated RT.20 However, the radiation doses in the 2 arms were not biologically equivalent. Patients in the 5-week arm received a radiation dose less than the current standard of care, whereas those in the 3-week arm received a biologically higher dose due to the shorter time frame for complete delivery of RT.

A randomized phase III trial (CONVERT) assessed once versus twice daily thoracic RT at doses that were biologically similar, 45 Gy twice daily for 3 weeks versus 66 Gy once daily for 6.5 weeks, in patients with limited-stage SCLC.21 Median OS was similar between the 2 arms (30 vs 25 months; hazard ratio [HR] for death in the once-daily group, 1.18; 95% CI, 0.95–1.45; P=.14). Although toxicity was generally similar between the arms, patients receiving 45 Gy of accelerated RT had more grade 4 neutropenia than those receiving 66 Gy of conventional RT (49% [129/266] vs 38% [101/263]; P=.05). Based on data from randomized trials, the optimal dose and fractionation of thoracic RT for SCLC remain unresolved. The NCCN panel recommends 2 options depending on individual patient characteristics: (1) 45 Gy with twice-daily fractionation for 3 weeks, or (2) 60 to 70 Gy with once-daily fractionation for 6 to 7 weeks (see SCL-F 1 of 3, page 1178). Twice-daily thoracic RT is technically challenging for patients with bilateral mediastinal adenopathy and logistically challenging for many patients and RT centers.

Prophylactic Cranial Irradiation

Intracranial metastases occur in >50% of patients with SCLC. Randomized studies have shown that PCI is effective in decreasing the incidence of cerebral metastases, but most individual studies did not have sufficient power to show a meaningful survival advantage.22 A 1999 meta-analysis of 7 randomized PCI trials (using data from individual patients) reported an absolute 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.23 This

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NCCN Guidelines Insights: Small Cell Lung Cancer, Version 2.2018

Version 2.2018 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 16, 10; 10.6004/jnccn.2018.0079

meta-analysis also reported a 5.4% increase in 3-year OS in patients treated with PCI, from 15.3% in the control group to 20.7% in the PCI group. Although the number of patients with extensive-stage disease was small (14%), the observed benefit was similar in patients with both limited-stage and extensive-stage disease. Because patients with limited-stage disease have potential for cure, PCI remains a recommendation for those without high-risk factors for developing cognitive dysfunction.

In a randomized EORTC trial that assessed PCI versus observation in 286 patients with extensive-stage SCLC whose disease had responded to initial chemotherapy, use of PCI decreased symptomatic brain metastases (14.6% vs 40.4%) and increased the 1-year OS rate (27.1% vs 13.3%) compared with observation.24 However, the trial did not require brain imaging prior to PCI or at follow-up and allowed several PCI doses and fractionation schemes. The survival advantage of PCI was recently challenged by a randomized phase III Japanese trial of 224 patients with extensive-stage SCLC.25 Patients were required to have an MRI before PCI to confirm the absence of brain metastases and to undergo surveillance MRI every 3 months during year 1 and every 6 months during year 2 to allow for early treatment of asymptomatic metastases. In addition, this trial used a single PCI regimen of 25 Gy in 10 fractions. Median OS was not improved in patients receiving PCI (11.6 months; 95% CI, 9.5–13.3) versus observation (13.7 months; 95% CI, 10.2–16.4) (HR, 1.27; 95% CI, 0.96–1.68; P=.094).25

Synthesizing these trial results, for the 2018 update the panel softened the recommendation for PCI in patients with extensive-stage disease to consider PCI. The panel also added detailed imaging recommendations for patients who do not undergo PCI (see SCL-5, page 1173). For patients with extensive-stage SCLC and good response to initial chemotherapy, reasonable options (depending on individual patient factors) include either PCI or close surveillance of the brain with MRI (preferred)

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NCCN Guidelines Insights: Small Cell Lung Cancer, Version 2.2018

Version 2.2018 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 16, 10; 10.6004/jnccn.2018.0079

or CT with contrast (in those unable to undergo MRI).

Second-Line and Beyond (Subsequent) Systemic Therapy

Although SCLC is very responsive to initial treatment, most patients experience relapse with relatively resistant disease.2628 Randomized phase III trials have demonstrated the benefit of single-agent topotecan orally or intravenously in patients with recurrent SCLC.2931 Based on phase II trials, a number of other agents have been recommended as options for subsequent systemic therapy in patients with relapsed disease, including irinotecan, paclitaxel, docetaxel, temozolomide, nivolumab ± ipilimumab, vinorelbine, oral etoposide, gemcitabine, cyclophosphamide/doxorubicin/vincristine (CAV), and bendamustine (category 2A for all agents except bendamustine, which is category 2B) (see SCL-E 1 of 3, page 1177).3241 These agents are listed in order of preference in the NCCN Guidelines. Data suggest that temozolomide may be useful for patients with SCLC, especially those with brain metastases and methylated O6-methylguanine-DNA methyltransferase (MGMT).4244 Bendamustine has modest activity based on 2 small phase II trials (response rate of 17% for chemoresistant disease and 33% for chemosensitive disease).45,46 Therefore, bendamustine has a category 2B recommendation in the NCCN Guidelines. Ifosfamide was recently deleted from the NCCN Guidelines because panel members no longer use this agent. A phase III trial (JCOG0605) in Japanese patients with sensitive relapsed SCLC reported that the combination of cisplatin, etoposide, and irinotecan improved survival (median, 18.2 months; 95% CI, 15.7–20.6) compared with topotecan (12.5 months; 95% CI, 10.8–14.9) (HR, 0.67; 90% CI, 0.51–0.88; P=.0079). However, this combination regimen had significant toxicity, and is not recommended as subsequent therapy in the NCCN Guidelines.47

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NCCN Guidelines Insights: Small Cell Lung Cancer, Version 2.2018

Version 2.2018 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 16, 10; 10.6004/jnccn.2018.0079

Nivolumab, ipilimumab, and pembrolizumab are immune checkpoint inhibitors that stimulate the immune system and thus have different mechanisms of action than standard cytotoxic chemotherapy.48 The NCCN panel recently added recommendations for nivolumab and nivolumab + ipilimumab (both are category 2A) as subsequent therapy options for patients who have experienced disease relapse ≤6 months after primary therapy.49 These recommendations are based on a phase I/II trial of patients who received either nivolumab alone or various doses of nivolumab + ipilimumab for relapsed SCLC.50 Response rates were 10% (10/98) for nivolumab at 3 mg/kg; 23% (14/61) for nivolumab at 1 mg/kg + ipilimumab at 3 mg/kg; and 19% (10/54) for nivolumab at 3 mg/kg + ipilimumab at 1 mg/kg. Responses did not correlate with PD-L1 expression; SCLC has a lower rate of PD-L1 expression than non–small cell lung cancer.50 Diarrhea was the most common grade 3 or 4 treatment-related adverse event (AE). Overall frequency of grade 3 or 4 AEs was approximately 20%, and <10% of patients discontinued treatment due to treatment-related AEs. Updated preliminary data from an expansion cohort of this trial reported a 1-year OS rate of 42% in patients receiving nivolumab + ipilimumab and 30% in those receiving nivolumab alone.51 Preliminary data showed a 2-year survival rate of 26% with nivolumab + ipilimumab and 14% with nivolumab alone.51,52 Recent data suggest that high tumor mutational burden (TMB) correlates with efficacy of nivolumab ± ipilimumab in SCLC.52 In patients with high TMB, the 1-year OS rate was 62% for nivolumab + ipilimumab and 35% for nivolumab alone. A phase IB study assessed pembrolizumab in 24 patients with pretreated, PD-L1–expressing (≥1%), extensive-stage SCLC.53 The overall response rate (ORR) was 33% (95% CI, 16%–55%). A broader phase II study evaluated pembrolizumab in 107 patients with relapsed SCLC regardless of PD-L1 expression and reported an ORR of 18.7% (35.7% in patients with PD-L1–positive tumors and 6% in those with PD-L1–negative tumors).54 Note that pembrolizumab is not currently recommended in the NCCN Guidelines (see SCL-E 1 of 3, page 1177).

Immune checkpoint inhibitors (ie, nivolumab, ipilimumab, and pembrolizumab) are associated with unique immune-mediated AEs not seen with traditional cytotoxic chemotherapy; therefore, healthcare providers need to be aware of the spectrum of potential immune-mediated AEs, know how to manage them, and educate their patients about possible AEs (see the NCCN Guidelines for Management of Immunotherapy-Related Toxicities, available at NCCN.org).55,56 For patients with immune-mediated AEs, high-dose corticosteroids are generally recommended based on the severity of the reaction. Nivolumab, ipilimumab, and pembrolizumab should be withheld or discontinued for severe or life-threatening immune-mediated AEs when indicated (see prescribing information).

Rovalpituzumab tesirine is a novel antibody-drug conjugate that targets delta-like protein 3 (DLL3) tumor expression, expressed in >80% of SCLCs. A phase I study of rovalpituzumab tesirine (74 patients with recurrent SCLC) showed an objective response rate of 18%.57 Recent data are available from a phase II study (TRINITY) of rovalpituzumab tesirine as third-line or higher treatment in patients with DLL3-expressing recurrent SCLC (N=177). The objective response rate was 18% and median OS was 6.7 months.58 Phase III trials are ongoing for treatment with rovalpituzumab tesirine in the first- and second-line setting. Note that rovalpituzumab tesirine is not currently available outside of a clinical trial and is not recommended in the NCCN Guidelines (see SCL-E 1 of 3, page 1177).

Summary

These NCCN Guidelines Insights focus on recent updates to immunotherapy, systemic therapy, and RT in the 2018 NCCN Guidelines for SCLC; major revisions are shown in the algorithm (see blue font). For patients with limited-stage SCLC, the optimal RT dose and schedule have not been established. However, a recent trial (CONVERT) reported that OS and toxicity are comparable when using either 45 Gy twice daily or 66 Gy once daily.21 Based on results of a recent Japanese trial, NCCN panel softened the recommendation for adjuvant PCI in patients with extensive-stage disease to consider PCI.25 For patients with extensive-stage disease who have not undergone adjuvant PCI, the NCCN panel added detailed brain imaging recommendations for surveillance based on this trial.

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    Version 2.2018 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

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    NCCN Guidelines Insights: Small Cell Lung Cancer, Version 2.2018

    Version 2.2018 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

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    NCCN Guidelines Insights: Small Cell Lung Cancer, Version 2.2018

    Version 2.2018 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

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    NCCN Guidelines Insights: Small Cell Lung Cancer, Version 2.2018

    Version 2.2018 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

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    NCCN Guidelines Insights: Small Cell Lung Cancer, Version 2.2018

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