North of Scotland Cancer Network Clinical Management Guideline for Non Small Cell Lung Cancer

THIS DOCUMENT IS North of Scotland Cancer Network Clinical Management Guideline for Non Small Cell Lung Cancer [Based on WOSCAN NSCLC CMG with further extensive consultation within NOSCAN] UNCONTROLLED WHEN PRINTED Document Control Prepared by Approved by Dr Emma Brown + Changes informed to NMcL Issue date Review date September 2016 Version This version V2.3 (20160630) Page 1 of 10

General principles THIS DOCUMENT IS Clinical Management Guideline for Initial Diagnosis, pre-treatment Evaluation & Staging All patients (including those who decline, or are considered clinically not suitable for active treatment) should be registered with the appropriate Lung cancer MDT in order to ensure accurate data capture and an opportunity for peer review In advance of any patient being discussed at the specialist Lung Cancer MDT, it is important to have taken steps earliest to establish i) a definitive diagnosis ii) an indication of clinical staging (see page 10) All patients should be referred or made aware earliest to the service Lung Clinical Nurse Specialist for assessment and ongoing specialist advice, education, support and co-ordination of care for both the patient and their relatives throughout the treatment pathway: this is in addition to any other specialist referrals that may also be clinically required depending on individual patient circumstances. Key Points* For all patients either undergoing investigation for, or with a suspected/confirmed diagnosis of lung cancer: The informed wishes of individual patient must direct any decision making with respect to treatment choices within this Clinical Management Plan. The 7th edition of the TNM classification of lung cancer should be used for staging purposes The IASLC** international nodal map should be used in the assessment and staging of lymph node disease MRI or CT scanning of the head should be considered For all patients with a confirmed diagnosis of lung cancer and being considered potentially suitable for radical treatment: A CT scan of the chest, lower neck and upper abdomen with intravenous contrast medium administration should be arranged early in the diagnostic pathway Positron Emission Tomography (PET)-CT scanning should be made available. PET positive mediastinal nodes should be evaluated by further mediastinal sampling The presence of isolated distant metastases/synchronous tumours should be confirmed by biopsy or further imaging Radical treatment should be offered without further mediastinal lymph node sampling if there is no significant uptake in normal sized mediastinal lymph nodes on PET-CT scanning,. The adequacy of diagnostic and staging samples should be considered in the context of selection of patients for targeted therapy. Where there is negligible additional risk to the patient, ensure biopsy samples are taken in adequate numbers and size. Trans-bronchial Needle Aspiration (TBNA) and Endo-bronchial Ultrasound/Endoscopic Ultrasound (EBUS/EUS)-guided TBNA should be used as an initial diagnostic and staging procedure according to findings on CT or PET-CT scans. Confirm negative results obtained by TBNA and EBUS/EUS-guided TBNA by mediastinoscopy and lymph node biopsy where clinically appropriate. *Source: British Thoracic Society Guidelines on the radical management of patients with lung cancer, Thorax, 2010;65 (Supp111) ** IASLC International Association for the Study of Lung Cancer V2.3 (20160630) Page 2 of 10

Clinical Management Guideline for Radical Treatment - Stage I and II Disease THIS DOCUMENT IS Treatment and pathological stage Adjuvant Treatment Follow-up Initial Evaluation, Clinical Staging, Pre treatment & Evaluation; See (BTS Guideline) on Page 1 Surgical exploration and pt1 T2, N0 (Stage IA/B) pt1-2, NI (Stage IIA-B) pt1-2, N2-3 (Stage IIIA) Complete Incomplete Complete Incomplete Complete Incomplete Consider adjuvant SACT* Radiotherapy Adjuvant SACT* Adjuvant SACT* and radiotherapy Adjuvant SACT* Radiotherapy and SACT* Surveillance Unresectable Radical radiotherapy +/- SACT* For SACT (ie chemotherapy) regimens - see page 7/8 Refused to have surgery or medically inoperable Palliative Radiotherapy Radical Radiotherapy Chemo-radiotherapy Stereotatic Ablative Body Radiotherapy V2.3 (20160630) Page 3 of 10

THIS DOCUMENT IS Clinical Management Guideline for Radical Treatment - Stage IIIA Disease Initial Evaluation Clinical Stage Pre-Treatment Evaluation Mediastinal Biopsy Initial and Adjuvant Treatment Unresectable/ Medically unfit Treat according to clinical stage Follow-up N2 Node Negative Assess for thoracotomy Surgical plus Mediastinal Lymph Node dissection N0-1 N2 Complete See Page 2 Adjuvant SACT* Refer to BTS Guideline (on Page 1) T1-3, N2 (Stage IIIA) PET Scan Mediastinal nodal sampling Assess medical Fitness N2 Node Positive PS 0 and single station disease Brain imaging PS 0 1 Multistation disease Brain imaging PS 2 Concurrent or sequential chemoradiotherapy* Radical radiotherapy CHART or 55/20 Incomplete Radiotherapy and SACT* Surveillance For SACT (ie chemotherapy) regimens - see page 7/8 Large volume of disease or Poor pulmonary function or Poor PS Palliative radiotherapy +/_ SACT Metastatic disease or pleural effusion See Stage IV Protocol (Page 6) V2.3 (20160630) Page 4 of 10

THIS DOCUMENT IS Clinical Management Guideline for Radical Treatment - Stage IIIB Disease Initial Evaluation Clinical Stage Treatment Evaluation Primary Treatment Adjuvant Treatment Follow-up T1-3, N3 (Stage IIIB) Assess Volume of Disease & PS PS 0 or 1 PS2 Local symptoms Radical (chemo) radiotherapy* or SACT* +/- high dose palliative radiotherapy Palliative radiotherapy Consider SACT* Refer to BTS Guideline Page 1 Possibly resectable PS 0-1 Induction SACT* Surgical re-evaluation Surgery T4, N0 (Stage IIIB) No pleural effusion Unresectable PS 2 Radical (chemo) radiotherapy or SACT* +/- high dose palliative radiotherapy Radical Radiotherapy PS 0-1 Palliative radiotherapy for local symptoms Best Supportive Care Palliative Care Referral * For SACT (ie chemotherapy) regimens see page 7/8 Surveillance V2.3 (20160630) Page 5 of 10

THIS DOCUMENT IS Clinical Management Guideline for Initial Treatment - Stage IV Disease Initial Evaluation Clinical Stage Pre-Treatment Evaluation Primary Treatment Adjuvant Treatment Stage IIIB T4 + Pleural or pericardial effusion Pleural or pericardial drainage Cytology negative Treatment according to T and N stage Refer to BTS Guideline Page 1 Cytology positive Local therapy if necessary (e g, pleurodesis, pericardial window) + treatment as for stage IV disease. (below) Stage IV or Malignant Pleural Effusion Performance Status Symptom Evaluation Tumour pathology assessment Palliative SACT* or biological therapy (page 6) Consider 2 nd /3 rd line systemic therapy Palliative Radiotherapy For SACT (ie chemotherapy) regimens - see page 7/8 Best Supportive Care Palliative Care Referral Consider Phase 1 / 2 trials V2.3 (20160630) Page 6 of 10

Squamous Cell THIS DOCUMENT IS Clinical Management Guideline for Systemic Anti-Cancer Therapy Curative Intent Chemotherapy prior to surgical or sequential chemo-radiotherapy irrespective of EGFR Status Non- Squamous Cell Carboplatin + Gemcitabine Carboplatin [AUC* 5] IV infusion on Day 1 Gemcitabine 1250mg/m² IV infusion on Day(s) 1 & 8 Repeat every 3 weeks/21days Continue to maximum of 4 cycles Cisplatin + Docetaxel Cisplatin 75mg/m² IV infusion on Day 1 Docetaxel 75mg/m² IV infusion on Day 1 Repeat every 3 weeks Continue to a maximum of 4 cycles Concurrent Chemotherapy with radiotherapy [or SOCCAR] Cisplatin + Vinorelbine Cycles 1 (prior to commencement) & Cycle 4 (following after completion) of radiotherapy only Cisplatin 80mg/m² IV Infusion on Day 1 Vinorelbine 25mg/m² (50mg max) IV infusion on Day 1 Vinorelbine 60mg/m² (160mg max) Administered orally on Day 8 Cycle duration: 3 weeks/21days Cycles 2 & 3 (at the same time as receiving radiotherapy) Cisplatin 80mg/m 2 IV Infusion on Day(s) 1 & 8 Vinorelbine 15mg/m 2 IV Infusion on Day(s) 1 & 8 Cycle duration: 3 weeks/21days Cisplatin + Pemetrexed Cisplatin 75mg/m 2 IV infusion on Day 1 Pemetrexed 500mg/m 2 IV Infusion on Day 1 Repeat every 3 weeks Continue to maximum of 4 cycles Note: If Cisplatin contraindicated, replace with Carboplatin [AUC*5] Adjuvant Chemotherapy Cisplatin + Vinorelbine Cisplatin 80mg/m 2 IV Infusion on Day1 Vinorelbine 25mg/m 2 (50mg max) IV infusion on Day 1 Vinorelbine 60mg/m 2 (60mg max.) Administered orally on Day 8 Note: - If Cisplatin contraindicated, replace with Carboplatin [AUC*5] - Vinorelbine may be either IV infusion or Oral at the respective doses. *AUC Area under the Curve (as per Cockroft-Gault equation) SOCCAR - A randomised phase II trial comparing sequential versus concurrent chemotherapy and radical hypo-fractionated radiotherapy in patients with inoperable stage III Non-Small Cell Lung Cancer V2.3 (20160630) Page 7 of 10

Clinical Management Guideline for THIS DOCUMENT IS Patients newly diagnosed requiring palliative SACT At all stages in this flow chart consider patient performance status and participation in clinical trials. 1 st Line 2 nd Line 3 rd Line Adenocarcinoma EGFRm Erlotinib or Afatinib Cisplatin (or Carbo) Pemetrexed Docetaxel +/- nintedonib Adenocarcinoma EGFRw Non-squamous Cisplatin (or Carbo) & Pemetrexed Gemcitabine Docetaxol Progressive Disease on treatment If ALK-1 Translocation Give crizotinib Docetaxel +/- Nintedonib Trials or PAS Scheme Partial Response or Stable Disease on treatment Maintenance pemetrexed Progressive Disease Squamous, & not Otherwise specified Cisplatin (or Carbo) & Gemcitabine or Vinorelbine or Docetaxol Docetaxel No further chemotherapy Outside of trials EGFRm = Mutation EGFRw = Wild Type V2.3 (20160630) Page 8 of 10

Clinical Management Guideline for Systemic Anti-Cancer Therapy Palliative Intent Afatinib Afatinib 40mg (escalating to 50mg if tolerated) Administered Orally Continue until disease progression or unacceptable toxicity. Carboplatin + Gemcitabine Carboplatin [AUC 5]* by IV infusion on Day 1 Gemcitabine 1250mg/m² by IV infusion on Days 1 & 8 Repeat every 3 weeks/21 days Continue to a maximum of 4 cycles Cisplatin + Pemetrexed Cisplatin 75mg/m² by IV infusion on Day 1 Pemetrexed 500mg/m² by IV infusion on Day 1 Repeat every 3 weeks/21 days Continueto a maximum for 4 cycles. Note: If Cisplatin contraindicated, replace with Carboplatin [AUC*5] Cisplatin + Vinorelbine Cisplatin 80mg/m² IV Infusion on Day 1 Vinorelbine 25mg/m² (max. 50mg) IV infusion on Day 1 Vinorelbine 60mg/m² (max. 160mg) orally on Day 8 Repeat every 3 weeks/21 days Continue to a maximum of? cycles. Note: If Cisplatin contraindicated, replace with Carboplatin [AUC*5] and Vinorelbine may be either IV infusion or Oral at the respective doses. Crizotinib Crizotinib 250mg Administered orally Continue until disease progression or unacceptable toxicity Docetaxel Docetaxel 60-75mg/m² IV infusion on Day 1 Repeat every 3 weeks/21 days Continue until disease progression or unacceptable toxicity. Docetaxel + Nintedanib Docetaxel 60-75mg/m² IV infusion on Day 1 Nintedanib 200mg Administered orally from Days 2 to 21 Repeat every 3 weeks/21days Continue until disease progression or unacceptable toxicity. Erlotinib Erlotinib 150mg Administered orally Continue until disease progression or unacceptable toxicity. Maintenance Pemetrexed 500mg/m² IV infusion on Day 1 Repeated every 3 weeks/21days Continue until disease progression or unacceptable toxicity *AUC Area under the Curve (as per Cockroft-Gault equation) V2.3 (20160630) Page 9 of 10

Primary Tumour (T) Clinical Management Guideline for THIS DOCUMENT IS AJCC TNM Lung Cancer Staging 7 th Edition 2009 TX T0 Tis T1 T1a T1b T2 T2a T2b T3 T4 Primary tumour cannot be assessed, or tumour proven by the presence of malignant cells in sputum or bronchial washings but not visualized by imaging or bronchoscopy There is no evidence of primary tumour Carcinoma in situ Tumour 3 cm or less in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (for example, not in the main bronchus)¹ Tumour 2 cm or less in greatest dimension Tumour more than 2 cm but 3 cm or less in greatest dimension Tumour more than 3 cm but 7 cm or less or tumour with any of the following features (T2 tumours with these features are classified T2a if 5 cm or less): involves main bronchus, 2 cm or more distal to the carina; invades visceral pleura (PL1 or PL2); associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung Tumour more than 3 cm but 5 cm or less in greatest dimension Tumour more than 5 cm but 7 cm or less in greatest dimension Tumour 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 carina¹ 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 Tumour of any size that invades any of the following: mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, carina, separate tumour nodule(s) in a different ipsilateral lobe Distant Metastasis (M) M0 No distant metastasis M1 Distant metastasis M1a Separate tumour nodule(s) in a contralateral lobe, tumour with pleural nodules or malignant pleural (or pericardial) effusion² M1b Distant metastasis (in extrathoracic organs) Regional Lymph Nodes (N) NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastases N1 Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension N2 Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s) N3 Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s) Notes: ¹ The uncommon superficial spreading tumour 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. ² Most pleural (and pericardial) effusions with lung cancer are due to tumour. In a few patients, however, multiple cytopathologic examinations of pleural (pericardial) fluid are negative for tumour, 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 tumour, the effusion should be excluded as a staging element and the patient should be classified as M0. V2.3 (20160630) Page 10 of 10