This document describes the OH (CCO)-Lung Cancer Disease Site Group endorsement of the recommendations for the treatment of patients with clinical stage III N2 non-small cell lung cancer from  NICE  Lung cancer: diagnosis and management. The original publication is available at www.nice.org.uk/guidance/ng122. The recommendations were also endorsed for patients with non-operable stage III non-small cell lung cancer from Brahmer JR, et al. The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of non-small cell lung cancer (NSCLC).# Table of Contents 
. Recommendation 3 is reprinted with the permission of NICE. 2 The endorsement of these guidelines does not imply whether chemotherapy/radiation/surgery OR chemotherapy/radiation/immunotherapy OR a combination of all four (quad-therapy) are preferred options in patients with N2 disease. It should be noted that the NICE recommendations for surgery after chemoradiation are for patients with potentially resectable stage III N2 NSCLC, while the SITC recommendations are for inoperable patients only. A formal literature search comparing these strategies was not performed and is beyond the scope of these endorsements.

# RECOMMENDATIONS Recommendation 1
Concurrent chemoradiation should be used for curative-intent treatment of patients with unresectable, lymph node-positive (N2 or N3) stage III NSCLC.
- There is insufficient evidence to recommend a specific concurrent chemotherapy regimen. Reasonable treatment options include cisplatin combined with one of etoposide, vinorelbine, vinblastine, or pemetrexed and carboplatin combined with paclitaxel. Chemotherapy regimens should be similar to those given in randomized clinical trial protocols. - A standard dose fractionation of 60 to 66 Gy given in fractions of 2 Gy once per day over six weeks is recommended. Dose escalation beyond 66 Gy with conventional fractionation is not recommended.
- Hyperfractionated radiotherapy regimens that do not result in acceleration of the treatment course, even though the total nominal radiotherapy dose may be modestly increased, are not recommended. - Routine use of induction chemotherapy prior to concurrent chemoradiotherapy is not recommended; however, this treatment paradigm can be considered for the management of bulky tumours to allow for radical planning after chemotherapy response.
Qualifying Statements for Recommendation 1
- Parameters to determine suitability for chemoradiation or other treatment options include but are not limited to performance status, weight loss, and comorbidities. - Increased toxicity, particularly esophagitis and hematologic events, is associated with the addition of chemotherapy to radiotherapy. - Although the impact of increasing the predicted biologic equivalent dose via accelerated radiotherapy regimens is unclear, further study of accelerated hypofractionated regimens is of interest to optimize the therapeutic ratio of treatment, particularly in the context of advanced imaging, radiotherapy planning, and treatment delivery. - Depending on a patient's response to chemoradiation, surgery as salvage or completion of definitive treatment (preferably by lobectomy) may be an option in a subset of patients and should be discussed at a multidisciplinary case conference. Factors to consider include whether the cancer is potentially technically resectable, patient performance status, and patient preferences.

# Recommendation 2
Durvalumab should be used in patients with stage III NSCLC who have not progressed postchemoradiation and have no contraindications to an immune checkpoint inhibitor.

# Qualifying Statements for Recommendation 2
- This was based on evidence from patients with stage III NCSLC using the 7th edition staging system. Durvalumab may be considered for patients who have stage migrated to stage III NSCLC using the 8th edition staging system. - Patients should have received a volume of lung receiving 20 Gy dose (V20) of less than 35% of the total lung volume, and should have all toxicities resolved to grade 1 or less. - Patients with any pneumonitis history or interstitial lung disease history, or evidence of radiation pneumonitis of grade 2 or above, or with V20s of greater than 35% should be considered at a higher risk of toxicity and generally counseled on the uncertainty and potentially excluded. - At this time, it is inappropriate to exclude patients from therapy based solely on a biomarker such as epidermal growth factor receptor or programmed death-ligand 1 status. 1 The Creative Common License for this document can be found here: Creative Commons Attribution 4. - Durvalumab can be given at a dose of 10 mg per kilogram of body weight intravenously within one to 42 days after chemoradiotherapy and continued for a duration of 12 months.

# Recommendation 3
For patients with operable, single-station, stage IIIA/B-N2 NSCLC who can have surgery and are well enough for multimodality therapy, consider chemoradiotherapy with surgery.
Qualifying Statements for Recommendation 3
- Discuss the benefits and risks with the person before starting chemoradiotherapy with surgery, including that: o chemoradiotherapy with surgery improves progression-free survival o chemoradiotherapy with surgery may improve overall survival. - For patients with stage IIIA/B-N2 NSCLC who are having chemoradiotherapy and surgery, ensure that their surgery is scheduled for three to five weeks after the chemoradiotherapy. - Multidisciplinary teams that provide chemoradiotherapy with surgery should have expertise in the combined therapy and in all of the individual components.

# Recommendation 4
For patients with unresectable, stage III (N2 or N3) NSCLC who cannot tolerate concurrent chemoradiation, one of the following options is recommended after a full discussion of the benefits, limitations, and toxicities of therapy:
- Sequential chemotherapy followed by radical radiation o Increasing the biologic equivalent dose using accelerated hyperfractionated radiotherapy following induction chemotherapy may be considered.
- Radical radiotherapy alone o A minimum dose of 60 Gy is recommended. o Options for altered fractionation schedules may include hyperfractionation (lower dose per fraction over the standard treatment duration), accelerated fractionation (conventional fraction size and same total dose, given in a shorter period of time), accelerated hyperfractionation (combination of these two), and hypofractionation (higher dose per fraction and fewer fractions

# BACKGROUND FOR GUIDELINE
Stage III NSCLC occurs in a heterogeneous group of patients and treatment varies considerably largely because of patient-related issues that impact application of guideline recommended treatment. Survival varies considerably. New evidence suggests that immunotherapy may be important in improving survival in these patients. The goal of this guideline was to update the 2017 OH (CCO) guideline (7-3 version 3) recommendations to include new evidence on immunotherapy. In turn, this has implications for funding of new therapies. A second goal of this project was to update and consolidate information in two OH (CCO) guidelines (7-3 version 3 and 7-4 version 2) into one document on the management of stage III NSCLC. The 7-3 version 3 guideline focused on patients with unresectable stage III NSCLC, whereas the 7-4 version 2 guideline focused on patients with potentially resectable stage III NSCLC. This current 7-3 version 4 guideline combines these two guidelines into one guideline for patients with stage III NSCLC.

# GUIDELINE ENDORSEMENT DEVELOPERS
This endorsement project was developed by the Treatment of Stage III NSCLC Guideline Development Group (GDG) (Appendix 1), which was convened at the request of the OH (CCO)'s Lung Cancer DSG and the Thoracic Cancers Advisory Committee. The project was led by a small Working Group of the Treatment of Stage III NSCLC GDG, which was responsible for reviewing the evidence base and recommendations in the National Institute for Health and Care Excellence (NICE) 2019 Lung cancer: diagnosis and management guideline  and the Society for Immunotherapy of Cancer (SITC) 2018 consensus statement on immunotherapy for the treatment of NSCLC  in detail and making an initial determination as to any necessary changes, drafting the first version of the endorsement document, and responding to comments received during the document review process. The Working Group members had expertise in radiation oncology, medical oncology, and health research methodology and included three patient representatives. Other members of the Treatment of Stage III NSCLC GDG served as the Expert Panel and were responsible for the review and approval of the draft document produced by the Working Group. Conflict of interest declarations for all GDG members are summarized in Appendix 1, and were managed in accordance with the PEBC Conflict of Interest Policy.

# PATIENT CONSULTATION PANEL
Three patient representatives participated as Consultation Panel members for the Treatment of Stage III NSCLC Working Group. They reviewed copies of the project plan and provided feedback on their comprehensibility, appropriateness, and feasibility to the Working Group's Health Research Methodologist. The Health Research Methodologist relayed the feedback to the Working Group for consideration.

# ENDORSEMENT METHODS
The PEBC endorses guidelines using the process outlined in OH (CCO)'s Guideline Endorsement Protocol. This process includes selection of a guideline, assessment of the recommendations, drafting the endorsement document by the Working Group members, internal review by content and methodology experts, and external review by Ontario clinicians and other stakeholders.
The PEBC assesses the quality of guidelines using the AGREE II tool. AGREE II is a 23item validated tool that is designed to assess the methodological rigour and transparency of guideline development and to improve the completeness and transparency of reporting in practice guidelines.
Implementation considerations such as costs, human resources, and unique requirements for special or disadvantaged populations may be provided along with the recommendations for information purposes.

# Selection of Guidelines
As a first step in developing this document, a search for recent guidelines that addressed the research questions was conducted. Research questions for tri-modality therapy and consolidation immunotherapy were developed to update the 7-3 version 3 and the 7-4 version 2 guidelines. Guidelines older than two years (published before 2017) were excluded. Evidencebased guidelines with systematic reviews that addressed the following research questions were included:
1 . The NICE 2019 guideline  addressed research questions 1 and 2 and the SITC 2018 guideline  addressed research question 3.

# Assessment of Guidelines
Guidelines were considered for endorsement if the Working Group answered yes to the following questions:
- Do you agree with the recommendations and think that no new evidence would change the recommendations? 2. Do you think the recommendations would be acceptable in Ontario? Both guidelines met the criteria for endorsement. The overall quality of both guidelines was assessed using the AGREE II tool  (Table 2-1). The pre-planned threshold for a high-quality guideline was a rigour of development score above 70% based on the AGREE II tool. Both guidelines met this criterion (Table 2-1).

# DESCRIPTION OF ENDORSED GUIDELINES
The NICE 2019 guideline covered a broad topic on the diagnosis and management of lung cancer and included recommendations on the treatment of patients with stage III NSCLC. These recommendations were based on a systematic review that included a network metaanalysis of six randomized controlled trials (RCTs) comparing chemoradiotherapy and surgery versus chemoradiotherapy alone versus chemotherapy and surgery. Therefore, their network meta-analysis addressed research questions 1 and 2 mentioned above. NICE's 2019 guideline was reviewed by stakeholders and their Guideline Executive.
The SITC 2018 document also covered a broad topic on immunotherapy in NSCLC and included recommendations on the treatment of patients with stage III NSCLC. This guidance document was based on a systematic review that addressed research question 3 mentioned above and included a large phase III RCT for durvalumab. The recommendations were reviewed by the SITC membership during an open comment period.

# ENDORSEMENT PROCESS
The recently completed 7-3 version 3 PEBC guideline included recommendations for patients with unresectable, stage III (N2 or N3) NSCLC who can or cannot tolerate chemoradiation. The Working Group members decided to endorse these recent recommendations and the justifications for these recommendations is described further below. The Working Group developed new research questions for tri-modality therapy and consolidation immunotherapy to update the 7-3 version 3 and 7-4 version 2 PEBC guidelines. The NICE and SITC guidelines addressed these research questions. The Working Group held two meetings to review the recommendations from NICE and SITC to assess whether they agreed with the interpretation of the evidence with respect to the magnitude of the desirable and undesirable effects of treatment and took into account the certainty of the evidence, the values of key stakeholders (e.g., patients, clinicians, policy makers, etc.), and the potential impact on equity, acceptability and feasibility of implementation according to GRADE's evidence-to-decision framework. The evidence from NICE and SITC for each comparison was summarized within this GRADE framework to help the Working Group members consider the evidence used by the NICE and SITC groups and to then make a judgement as to whether they agreed with the way NICE and SITC interpreted and used the evidence. The evidence from NICE and SITC and the judgements of the Working Group can be found in Appendices 3 and 4.
Taking into consideration all of these factors within the GRADE framework, the Working Group members decided to endorse the NICE recommendations, but clarified that the recommendations applied to patients with single-station N2 disease and also applied to patients with stage IIIB NSCLC. The Working Group members also endorsed NICE's recommendation to schedule surgery three to five weeks after chemoradiotherapy because this was the schedule used in the studies.
The Working Group members endorsed SITC's recommendation for durvalumab in patients with stage III NSCLC who have not progressed post-chemoradiation. The Working Group decided to clarify that these patients should have no contraindications to an immune checkpoint inhibitor. Also, the Working Group members added four qualifying statements to further clarify the patient population. These clarifications were based on the inclusion and exclusion criteria of the durvalumab trial. Furthermore, the Working Group decided to replace SITC's recommendation about the duration of durvalumab, "Limited data is available concerning durvalumab duration, and this recommendation will be reassessed as more results become available" with a qualifying statement that indicates the dose, schedule, and duration of durvalumab that was used in the trial.
The recommendation for concurrent chemoradiation for curative-intent treatment of patients with unresectable, lymph node-positive (N2 or N3) stage III NSCLC was endorsed from the 2017 7-3 version 3 PEBC guideline. In this prior version, the recommendation was adapted from the PEBC 2005, the American College of Chest Physicians 2013, the American Society of Radiation Oncology (ASTRO) 2015, and the American Society of Clinical Oncology (ASCO) 2015 guidelines. Concurrent chemoradiation has been recommended in all of these guidelines. Carboplatin and paclitaxel have been added to the options of chemotherapy regimens since the PEBC 2005 guideline. This is consistent with the ASTRO 2015 and ASCO 2015 guidelines. Also, cisplatin and pemetrexed have been added to options of chemotherapy regimens since the PEBC 2005 guideline. This is based on the PROCLAIM trial. Standard dosefractionation of 60 to 66 Gy was consistent across the guidelines. The dose per fraction has been altered to 2 Gy per fraction to be consistent with current standards recommended by the ASTRO 2015 and ASCO 2015 guidelines. The recommendation against the routine use of induction chemotherapy was consistent across these guidelines.
The recommendations for patients with unresectable, stage III (N2 or N3) NSCLC who cannot tolerate concurrent chemoradiation were also endorsed from the 2017 7-3 version 3 PEBC guideline. In this third version, the recommendations for sequential chemotherapy followed by radical radiation or radical therapy alone were endorsed from the ASTRO 2015 guideline. Also, the recommendation for radiation for symptom palliation was endorsed from the ASTRO 2011 guideline.

# ENDORSEMENT REVIEW AND APPROVAL

# Internal Review
For the endorsement document to be approved, 75% of the content experts who comprise the GDG Expert Panel must cast a vote indicating whether or not they approve the document, or abstain from voting for a specified reason, and of those that vote, 75% must approve the document. In addition, the PEBC Report Approval Panel (RAP) with methodology expertise must unanimously approve the document. The Expert Panel and RAP may specify that approval is conditional, and that changes to the document are required. Results of this review are reported in Section 3.

# External Review
Feedback on the approved draft endorsement document is obtained from content experts through Professional Consultation. Relevant care providers and other potential users of the endorsement document are contacted and asked to provide feedback on the recommendations through a brief online survey. This consultation is intended to facilitate the dissemination of the final guidance report to Ontario practitioners. Results of this review are reported in Section 3.
The endorsement document will be published on the OH (CCO) website. The Professional Consultation of the External Review is intended to facilitate the dissemination of the endorsement document to Ontario practitioners. OH (CCO)-PEBC guidelines are routinely included in several international guideline databases including the Canadian Partnership Against Cancer database, the Canadian Medical Association Infobase, NICE Evidence Search, and the Guidelines International Network Library.

# UPDATING THE ENDORSEMENT
The Lung Cancer DSG will review the endorsement on an annual basis to ensure that it remains relevant and appropriate for use in Ontario.
The Treatment of Stage III NSCLC GDG would like to thank the following individuals for their assistance in developing this report:
- Fulvia Baldassarre and Nadia Coakley for completing the AGREE II assessments - Xiaomei Yao for reviewing draft versions of this endorsement - Sara Miller for copyediting

# Recommendations for the Treatment of Patients with Clinical Stage III Non-Small Cell Lung Cancer: Endorsement of the 2019 National Institute for Health and Care Excellence Guidance and the 2018 Society for Immunotherapy of Cancer Guidance
Section 3: Internal and External Review

# INTERNAL REVIEW
The endorsement was evaluated by the GDG Expert Panel and the PEBC RAP (Appendix 1). The results of these evaluations and the Working Group's responses are described below.

# Expert Panel Review and Approval
Of the 24 members of the GDG Expert Panel, 22 members voted, for a total of 92% response in January 2020. Of those who voted, 22 approved the document (100%). The main comment from the Expert Panel and the Working Group's response is summarized in Table 3-1.

# Table 3-1. Summary of the Working Group's response to a comment from the Expert Panel.
Comments Responses 1. I suggest in Recommendation 2 that if we are going to include the current dose of durvalumab, we should also include the current schedule (since it may subsequently change, along with the dose).
The schedule for durvalumab was added to the qualifying statement for Recommendation 2.

# RAP Review and Approval
Two RAP members reviewed this document in January and February 2020. The RAP approved the document on February 3, 2020.

# EXTERNAL REVIEW Professional Consultation
Feedback was obtained through a brief online survey of healthcare professionals and other stakeholders who are the intended users of the endorsement document. Ninety-two health care professionals in Ontario with an interest in lung cancer taken from the PEBC database were contacted by email to inform them of the survey. Eight (9%) responses were received. One oncologist stated that they were unavailable to review this endorsement document at the time. The results of the feedback survey from seven people are summarized in Table 3  Another year of durvalumab after chemoradiation may be difficult for patients unless they are initially primed to the idea of continued treatments.
The final endorsed recommendations contained in Section 1 reflect the integration of feedback obtained through the external review processes with the document as drafted by the GDG Working Group and approved by the GDG Expert Panel.

# Susanna Cheng Medical Oncologist Lung Cancer Disease Site Group
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The committee noted that only one of the RCTs found a statistically significant difference in PFS but that it was also the case that the direction of effect for this outcome in each of the studies was positive for chemoradiotherapy and surgery. The committee was aware that PFS is a less reliable outcome than overall survival and discussed the potential for radiotherapy scarring to affect reliability. They did not think that there would be systematic overdiagnosis of disease progression in the non-surgical arms of the RCTs and thereby overestimation of the PFS benefit associated with surgery. Indeed, they noted that it is possible that subtle changes in disease status are missed in patients undergoing chemoradiotherapy because of radiotherapy scarring. They therefore felt that if bias towards incorrect recording of progression exists, it could work in either direction. 
  Large   Moderate   Don't know  Varies   Small   Trivial
The adverse event profile of the different interventions is uncertain but pairwise and network meta-analyses estimates conducted for the health economic model favoured chemoradiotherapy and surgery.
The committee discussed the evidence from a network meta-analysis conducted for the economic model which showed the odds ratio of death before progression was higher in the surgical interventions. They felt that this outcome was unsurprising in interventions that are more invasive in nature and noted that the other network meta-analyses had already accounted for this. Additionally, death before progression occurred in relatively few patients in any arm of any included study. They felt that discussing the risks and benefits of any surgery with patients is common practice.
The undesirable effects vary in the context of the type of surgery being performed. For example, right-sided pneumonectomy may be associated with increased mortality compared with left-sided pneumonectomy or lobectomy.

# Certainty of evidence
1c. What is the overall certainty of this evidence?
  Very low  Low   No included studies  Moderate   High
The committee agreed that the six trials most relevant to current practice were The committee agreed that the outcome that matters the most is mortality. This is because the purpose of chemotherapy, radiotherapy and surgery is to reduce mortality as much as possible. Secondary outcomes were PFS, severe adverse events and quality of life. Based on the network meta-analyses, the committee agreed that it is likely that (particularly) PFS and overall survival are better for chemoradiotherapy and surgery than the other two options if patients are well enough for it. The network meta-analysis found that chemoradiotherapy and surgery was associated with a 4 month (0.32 year) improvement in PFS versus chemoradiotherapy. The adverse event profile of the different interventions is uncertain but pairwise and network meta-analyses estimates conducted for the health economic model favoured chemoradiotherapy and surgery. The committee was unsure about the clinical plausibility of this, given that chemoradiotherapy and surgery is the most intensive intervention but agreed that there was no evidence that it was more harmful than the other two interventions. The committee agreed it was likely that there would be some quality of life loss in the months following the interventions as patients recovered. This was expected to be particularly true of the interventions including surgery. They decided that a 'consider' recommendation in favour of chemoradiotherapy and surgery was justified by the evidence. This is because there were a number of key uncertainties in the clinical data. Specifically, that none of the RCTs included in the network metaanalysis found any difference in overall survival, which was the most important outcome. Also, the 3-to 5-week wait for surgery is recommended to give people time to recover from the chemoradiotherapy.
The Working Group believed that the benefits would outweigh the harms, but that the values of the patients would need to be taken into consideration. A discussion about the effects of chemoradiotherapy and surgery on PFS and overall survival with the patient would need to occur. 

#   Yes
The committee thought that chemoradiotherapy and surgery is likely to be the most cost-effective intervention and that chemoradiotherapy was unlikely to be cost-effective compared to the other two interventions.
The committee thought that only a small number of stage IIIA-N2 patients are currently treated with chemoradiotherapy and surgery and that these recommendations therefore represent an increase in resource use, which will depend on the extent of take-up. Chemoradiotherapy with surgery is not often offered in current practice. In addition, there are specific factors to take into account when offering all these treatments together. Therefore, multidisciplinary teams providing it should have expertise both in the combined therapy, and in all the individual components. 

# Appendix 1: Affiliations and Conflict of Interest Declarations
In accordance with the PEBC Conflict of Interest Policy, the Members of the Treatment of Stage III NSCLC GDG Working Group, Expert Panel, Report Approval Panel, and Patient Consultation Panel were asked to disclose potential conflicts of interest.