Summary of recommendations

Guidelines commissioned by

 

Summary of recommendations

For explanation of levels of evidence and grades for recommendations, see Levels of evidence and grades for recommendations below. You may also like to refer to the Appendix - Guideline development process

Non-small cell lung cancer

Stage I operable

Surgery

Does complete mediastinal lymph node dissection improve overall survival compared to mediastinal lymph node staging in stage I NSCLC?

Recommendation	Grade
Systematic lymph node sampling is recommended to rule out occult nodal disease in clinical stage I patients. There is no apparent additional survival benefit of complete mediastinal node dissection in this group of patients. Last reviewed November 2015	C

Point(s)
For accurate staging according to AJCC TNM Pathological Staging, it is advisable to sample at least three lymph nodes from different stations. This is also required for prognostic purposes and for appropriate referral for adjuvant chemotherapy. Last reviewed November 2015

Is minimally invasive lobectomy as effective as open lobectomy for treatment of operable stage I NSCLC?

Recommendation	Grade
Minimally invasive lobectomy is at least as effective as open lobectomy with respect to long term survival and reported post-operative complication rates. Last reviewed December 2015	B

Radiotherapy

What is the role of radiotherapy in the treatment of operable stage I NSCLC?

Recommendation	Grade
In patients with operable stage I NSCLC, surgery is recommended over conventional radiotherapy, but SABR may be a reasonable option for patients refusing an operation, or who are high risk for a lobectomy. Last reviewed December 2015	D

Point(s)

Radiotherapy is an alternative treatment option for patients with stage I NSCLC who refuse surgery or are not fit for a standard lobectomy. There is insufficient evidence to recommend which method of radiotherapy (conventional or SABR) is preferable. In patients with peripherally situated tumours five cm or less in diameter, SABR is a reasonable treatment option. For larger tumours or those in less favourable anatomical sites near organs at risk, it may be reasonable, for patient convenience, to moderately accelerate treatment e.g. 50-55Gy in 20 fractions (extrapolating from Price et al 2012). Last reviewed December 2015

What is the role of radiotherapy after surgery in the treatment of operable stage I NSCLC?

Recommendation	Grade
In patients who have had complete resection of stage I NSCLC, postoperative radiotherapy is not recommended. Last reviewed December 2015	A
I-125 seed brachytherapy to the tumour bed is not recommended after sublobar resection for stage I NSCLC. Last reviewed December 2015	B

Point(s)
In the absence of any evidence regarding the treatment of incompletely resected stage I disease (positive margins) unsuitable for further surgery, expert consensus opinion recommends that radiotherapy be given to the site of residual disease using the same dose and technique as if no resection had been performed. Last reviewed December 2015

Chemotherapy

What is the role of chemotherapy before surgery in the treatment of operable stage I NSCLC?

Recommendation	Grade
Neoadjuvant chemotherapy is not considered standard therapy for stage IA NSCLC. Last reviewed December 2015	B
Neoadjuvant chemotherapy is not considered standard therapy for stage IB NSCLC. Last reviewed December 2015	B

What is the role of chemotherapy after surgery in the treatment of operable stage I NSCLC?

Recommendation	Grade
Post-operative adjuvant chemotherapy is not recommended for stage IA NSCLC. Last reviewed December 2015	B
Platinum-based adjuvant chemotherapy is recommended for all patients with stage IB NSCLC. Last reviewed December 2015	B

Stage I inoperable

Radiotherapy

What is the best practice radiotherapy approach in patients with stage I inoperable NSCLC?

Recommendation	Grade
In patients with inoperable stage I NSCLC and good performance status, high dose radiotherapy is an appropriate treatment option. Last reviewed November 2015	C
In patients with inoperable stage I NSCLC, high dose radiotherapy to a total of 60 Gy in 30 fractions over six weeks is a reasonable option. CHART may be used as an alternative to radical conventionally fractionated RT, provided the appropriate resources are available. Last reviewed November 2015	B

Point(s)
In patients with peripherally situated stage I NSCLC five cm or less in diameter, SABR is a reasonable treatment option. For larger tumours or those in less favourable anatomical sites close to organs at risk, it may be reasonable, for patient convenience, to moderately accelerate treatment e.g. 50-55Gy in 20 fractions (extrapolating from Price et al 2012). Last reviewed November 2015

What is the role of radiofrequency ablation in stage I inoperable NSCLC?

Point(s)
Further studies are required to define the efficacy and toxicities of radiofrequency ablation in the treatment of stage I NSCLC before its routine use can be recommended. Last reviewed December 2015
There are several techniques available for thermal ablation of tumours of which RFA is one. The others are microwave and cryo-ablation. Last reviewed December 2015

Chemotherapy

What is the role of chemotherapy when added to radiotherapy in the treatment of inoperable stage I NSCLC?

Point(s)
Insufficient evidence exists to recommend routine use of chemotherapy along with radiation for the treatment of patients with inoperable stage I NSCLC. Last reviewed December 2015

Stage II operable

Surgery

Does complete mediastinal lymph node dissection improve overall survival compared to mediastinal lymph node staging in stage II NSCLC?

Recommendation	Grade
A complete mediastinal lymph node dissection of at least Stations 2R, 4R, 7 and 8 (right side) or Stations 5, 6, 7 and 8 (left side) is recommended for surgically resected pathologically confirmed (node positive) stage II NSCLC. Last reviewed November 2015	B

Radiotherapy

What is the role of radiotherapy after surgery in the treatment of operable stage II NSCLC?

Recommendation	Grade
In patients who have had complete resection of stage II NSCLC, postoperative radiotherapy is not recommended. Last reviewed December 2015	A

Chemotherapy

What is the role of chemotherapy before surgery in the treatment of operable stage II NSCLC?

Recommendation	Grade
Chemotherapy before surgery may be considered as an option for patients with operable stage II NSCLC. Last reviewed December 2015	B
Chemotherapy before surgery in operable stage II disease, with 3-4 cycles of platinum-based regimes, may be considered in select patients, who are unlikely to receive it as adjuvant therapy. Last reviewed December 2015	B

Point(s)
No benefit in improved operability rates has been demonstrated in using chemotherapy before surgery. Survival benefit of chemotherapy seem to be similar when given either before or after surgery. Chemotherapy before surgery may be considered for those patient who are expected to have prolonged delay in surgery. Last reviewed December 2015

What is the role of chemotherapy after surgery in the treatment of operable stage II NSCLC?

Recommendation	Grade
Patients with completely resected stage II NSCLC should be offered 3-4 cycles of adjuvant cisplatin based chemotherapy. Last reviewed December 2015	A

Point(s)
The chemotherapy combination of cisplatin and vinorelbine was the most widely studied regimen which showed benefit. Last reviewed December 2015
There is insufficient evidence to support adjuvant chemotherapy for patients with ECOG performance status of ≥ 2. Last reviewed December 2015
No recommendation can be made for patients who have had less than a lobectomy. Last reviewed December 2015
Based on the 7th edition of TNM classification tumour size of >5cm would fall under stage IIA. These patients may be considered for adjuvant chemotherapy. Last reviewed December 2015
Chemotherapy benefit is seen even in patients who have received radiotherapy as part of loco-regional therapy in addition to surgery. Last reviewed December 2015
Potential long term side effects need to be considered while deciding on chemotherapy after surgery. Last reviewed December 2015

Stage II inoperable

Radiotherapy

What is the best practice radiotherapy approach in patients with stage II inoperable NSCLC?

Point(s)
Patients with inoperable stage II disease could be offered radiotherapy with curative intent with or without concomitant chemotherapy. Last reviewed November 2015

Chemotherapy

What is the role of chemotherapy when added to radiotherapy in the treatment of inoperable stage II NSCLC?

Recommendation	Grade
Insufficient evidence exists to recommend routine use of chemotherapy along with radiation for the treatment of patients with inoperable stage II NSCLC. Last reviewed August 2015	C

Point(s)

Patients with inoperable stage II disease could be offered radiotherapy with curative intent. Patients with good performance status and organ function may be considered for definitive concurrent chemo-radiation with a platin-based regime. This has to be balanced with an increased risk of toxicity. This is based on data extrapolated from studies mainly including inoperable stage III disease. Last reviewed August 2015

Stage III operable

Radiotherapy

What is the role of postoperative radiotherapy (PORT) in resected stage III NSCLC?

Recommendation	Grade
Post-operative radiation therapy in patients with pN2 disease is not recommended for routine use because of the lack of prospective randomised clinical trial data demonstrating an improvement in survival. The use of PORT could be considered in selected patients with pN2 disease. Last reviewed December 2015	C

Point(s)
Post-operative radiation therapy may be considered in the setting of a positive margin. Last reviewed December 2015

Surgery

What is the clinical benefit of mediastinal lymph node dissection in stage IIIA operable NSCLC?

Recommendation	Grade
A complete mediastinal lymph node dissection of at least Stations 2R, 4R, 7 and 8 (right side) or Stations 5, 6, 7 and 8 (left side) is recommended for surgically resected pathologically confirmed (mediastinal node positive) stage IIIA NSCLC. Last reviewed November 2015	B

What is the clinical benefit of the addition of surgery to definitive chemoradiotherapy in stage IIIA (N2) NSCLC?

Recommendation	Grade
Unselected patients with biopsy confirmed stage IIIA (N2) disease are best treated with chemoradiotherapy alone. Last reviewed December 2015	B

Point(s)
Induction chemoradiotherapy followed by surgery in selected patients with cIIIA (N2) disease is feasible and improves progression-free survival. Provided the patient does not require a pneumonectomy, the addition of surgery may improve overall survival. Last reviewed December 2015

Chemotherapy

What is the clinical benefit of adjuvant chemotherapy for patients with stage III operable NSCLC?

Recommendation	Grade
Patients who have a good performance status (WHO 1, 2) and completely resected stage III non-small cell lung cancer should be offered adjuvant cisplatin-based chemotherapy. Last reviewed December 2015	A
Patients with superior sulcus NSCLC may be considered for induction chemoradiotherapy. Last reviewed December 2015	C

Point(s)
Caution is advised in recommending adjuvant cisplatin-based chemotherapy to good performance status patients who are 70 years of age or older and/or who have clinically significant cardio-respiratory or renal co-morbidities. Last reviewed December 2015
Patients with resectable stage III non-small cell lung cancer, who are being considered for preoperative chemotherapy and surgery or surgery and postoperative chemotherapy, should have their treatment plan reviewed in a lung cancer-specific multidisciplinary meeting. The recommended treatment plan may need to be individualized to take account of such patient-specific factors as treatment preference, availability and timing of surgery, and geographically remote location. Last reviewed December 2015

What is the clinical benefit of neoadjuvant chemotherapy for patients with stage III operable NSCLC?

Recommendation	Grade
It is recommended to consider pre-operative administration of 2-3 cycles of platinum doublet-based, third-generation chemotherapy as a treatment option in good performance status patients with operable clinical stage IIIA non-small cell lung cancer. Last reviewed December 2015	A

Point(s)
Patients whose tumours respond to preoperative chemotherapy may derive additional survival benefit from postoperative chemotherapy. Last reviewed December 2015
Patients with resectable stage III non-small cell lung cancer, who are being considered for preoperative chemotherapy and surgery or surgery and postoperative chemotherapy, should have their treatment plan reviewed in a lung cancer-specific multidisciplinary meeting. The recommended treatment plan may need to be individualized to take account of such patient-specific factors as treatment preference, availability and timing of surgery, and geographically remote location. Last reviewed December 2015

What is the clinical benefit of the addition of neoadjuvant radiotherapy to neoadjuvant chemotherapy in stage IIIA (N2) NSCLC?

Recommendation	Grade
In selected patients (excellent performance status and cardio respiratory reserve) with stage cIIIA (N2) NSCLC, planned for surgery that will entail less than pneumonectomy, it is reasonable to offer neoadjuvant chemoradiotherapy. Last reviewed December 2015	C

Point(s)
Surgery alone is not advised in cIIIA (N2) disease. Last reviewed December 2015

Stage III inoperable

Radiotherapy

What is the recommended treatment approach for the definitive management of patients with good performance status and inoperable stage III disease?

Recommendation	Grade
For patients with good performance status and inoperable stage III NSCLC, the concurrent administration of chemotherapy and radiotherapy is recommended. Last reviewed December 2015	A

Point(s)
In stage III NSCLC patients deemed inoperable at the time of diagnosis, the recommended treatment approach is concurrent chemoradiotherapy. Evidence suggests that the optimal chemotherapy regimen to give concurrently with radiation therapy is a platinum-based doublet. Last reviewed December 2015
In patients with good performance status and inoperable stage III NSCLC in whom chemotherapy is contra-indicated, treatment with a radical dose of radiation therapy alone is a reasonable option. Last reviewed December 2015

What is the optimal radiation dose and fractionation schedule for good performance status patients with inoperable stage III NSCLC undergoing curative therapy?

Recommendation	Grade
It is recommended that for patients with inoperable stage III NSCLC undergoing curative therapy once daily thoracic radiotherapy to at least 60Gy in 2Gy/f plus chemotherapy is administered. Last reviewed December 2015	B
For patients with stage III NSCLC who are suitable for curative therapy, but where chemotherapy is contra-indicated or refused, CHART may be used as an alternative to radical conventionally fractionated radiotherapy. Last reviewed December 2015	B

What are the principles of radiation therapy in the definitive management of stage III inoperable NSCLC?

Recommendation	Grade
Patients can be simulated in the treatment position using an immobilisation device. Last reviewed December 2015	C
Treatment planning utilising multi-slice CT image acquisition and a 3D planning system is encouraged. Last reviewed December 2015	C
The appropriate window settings may be used when contouring the parenchymal and nodal disease. Last reviewed December 2015	C
Tumour volume delineation may be assisted by the incorporation of FDG-PET information into the CT –based planning system. Last reviewed December 2015	B
Tumour volume delineation may be assisted by the use of intravenous contrast during simulation. Last reviewed December 2015	C
The Clinical Target Volume may encompass the Gross Tumour Volume plus a margin of 6-8mm. Last reviewed December 2015	C
Elective nodal irradiation is not recommended. Last reviewed December 2015	C

Point(s)
Treatment planning may utilise an accepted method of evaluating and accounting for tumour motion. Last reviewed December 2015
Individual characteristics of breathing and variations associated with tumour location and pulmonary and tumour pathology lead to individual patterns of tumour motion. Last reviewed December 2015
-The Gross Tumour Volume may encompass the visible disease (both primary and nodal) on CT and/or CT-PET. -The Clinical Target Volume may encompass the Gross Tumour Volume plus a margin to account for microscopic extension of disease . -The Planning Target Volume may encompass the Clinical Target Volume plus a margin to account for tumour motion (as determined by the individual institution’s method of evaluating and accounting for tumour motion) and a margin to account for set-up error (as determined by the individual institutions’ estimation of the specific errors inherent in their process of radiotherapy planning and delivery). Last reviewed December 2015
Normal Tissue Dose Volume Constraints Limiting the lung V20 ≤ 30-35% and the MLD ≤20-23Gy limits the risk of radiation pneumonitis to ≤20% in definitely treated patients with NSCLC. Lung: V20 ≤ 30 -35% , Mean total lung dose (MLD) ≤ 20-23Gy A total dose of 50Gy in 2Gy/f to the full spinal cord cross-section is associated with a 0.2% risk of myelopathy. Spinal Cord: 50Gy in 1.8-2.0Gy/f Last reviewed December 2015
A single best threshold volumetric parameter for oesophageal irradiation has not been identified. Last reviewed December 2015

What is the optimal treatment approach for patients with stage III inoperable NSCLC who, because of patient or tumour factors, are not suitable for curative treatment with concurrent chemo-radiotherapy and who do not have a mutation for targeted therapy?

Recommendation	Grade
For patients with stage III disease who because of performance status or disease extent are not suitable for treatment with curative intent and who are experiencing symptoms as a result of chest disease, palliative radiotherapy is recommended. Last reviewed December 2015	A
The patient’s performance status should be taken into consideration when choosing the radiation dose and fractionation pattern: - Consider treating patients with good performance status with longer radiotherapy regimens because this will lead to a longer duration of symptom relief and may increase survival. Commonly employed radiotherapy regimens include 20Gy/5f, 30Gy/10f, 36Gy/12f, 40Gy/15f, 50Gy/20f. - Patients with poor performance status should be treated with short courses of treatment. Commonly employed radiotherapy regimens include 10Gy/1f, 16Gy/2f (1f/week). Last reviewed December 2015	A
For patients with stage III disease who because of performance status or disease extent are not suitable for treatment with curative intent and who are not experiencing symptoms specifically related to chest disease, referral for systemic therapy is recommended. Last reviewed December 2015	A
For patients with locally advanced, inoperable Stage III NSCLC not fit for curative therapy, consideration should be given to concurrent administration of palliative chemoradiation. Last reviewed December 2015	B

Point(s)
Given the symptomatology experienced by these patients with stage III disease and their poor survival outcomes, referral to palliative care services should be considered. Last reviewed December 2015

What is the role of prophylactic cranial irradiation (PCI) in patients with stage III NSCLC?

Recommendation	Grade
In patients with stage III NSCLC, the use of prophylactic cranial irradiation is not recommended. Last reviewed December 2015	B

What is the optimal management of Pancoast tumours?

Recommendation	Grade
In patients deemed technically and medically fit for surgical resection, pre-operative concurrent chemoradiation followed by surgery is an acceptable treatment option for patients with Pancoast tumours. Last reviewed December 2015	C
For patients with unresectable Pancoast tumours and good performance status, the concurrent administration of chemotherapy and radiotherapy is recommended. Last reviewed December 2015	A
For patients who have a poor performance status or distant metastatic disease, radiation therapy can be used to palliate symptoms due to Pancoast tumour. Last reviewed December 2015	C

Stage IV operable

Radiotherapy

What is the clinical benefit of adjuvant whole brain radiotherapy following resection or stereotactic radiosurgery to the brain metastasis(es)?

Recommendation	Grade
Routine adjuvant whole brain radiotherapy is not recommended following surgical resection or radiosurgery for brain metastases. Last reviewed September 2015	A

Surgery

What is the clinical benefit of resection of brain metastasis?

Recommendation	Grade
In the absence of impending neurological emergency or the requirement of histological confirmation, patients with brain metastases may be managed with WBRT alone. Last reviewed December 2015	B
In younger patients, with good performance status and solitary brain metastasis or single brain metastasis and control of extra cranial disease, addition of surgery to WBRT is a reasonable approach. Last reviewed December 2015	C

Point(s)
Surgery may control symptoms more quickly than WBRT and is reasonable in cases of impending neurological emergency. Last reviewed December 2015
Surgery provides histological confirmation and is reasonable in cases where the aetiology of the brain lesions is in question or histological information is not available from the primary tumour. Last reviewed December 2015
In cases of multiple metastases, addition of surgery to WBRT may be reasonable for rapid symptom control or for histological confirmation. Last reviewed December 2015
In cases of multiple metastases, addition of surgery to WBRT may be reasonable in highly individualised cases with the goal of improvement in local control, overall survival or FIS. Stereotactic radiosurgery may be an alternative to surgery in these patients. Last reviewed December 2015

What is the clinical benefit of resection of primary disease after complete resection of metastatic disease?

Point(s)
In highly selected patients with T1-3 N0-1 lung cancers with good performance status, adequate pulmonary reserve and solitary site of metastasis, it may be reasonable to consider resection of primary and metastatic sites. Last reviewed December 2015
It is advisable to consider only those patients who would require less than pneumonectomy and with T 1-3, N0-1 NSCLC for resection of primary and metastatic sites. Last reviewed December 2015

Stage IV inoperable

Radiotherapy

What is the clinical benefit of radiotherapy to the brain for patients with inoperable brain metastases from NSCLC?

Recommendation	Grade
Patients with multiple brain metastases from lung cancer who have good prognostic factors, based on prognostic models, should be considered for whole brain radiotherapy. Last reviewed December 2015	A
For patients with multiple metastases a dose of 20Gy in 5 fractions or 30Gy in 10 fractions is adequate for palliation of symptoms and improvement in neurological function. Last reviewed December 2015	B
Patients with multiple brain metastases from lung cancer who have adverse prognostic factors, based on prognostic models, should be considered for best supportive care including steroids. Last reviewed December 2015	B

What is the role of stereotactic radiosurgery in the treatment of brain metastases?

Recommendation	Grade
Patients with one to three unresectable brain metastases and stable systemic disease may be considered for a stereotactic radiosurgery boost in addition to whole brain radiotherapy. Last reviewed December 2015	C
Radiosurgery may be used as an alternative to surgery for patients with one to three brain metastases and stable systemic disease. Last reviewed December 2015	C

Point(s)
The study on which the above recommendation is based prescribed whole brain radiotherapy for all patients. However routine adjuvant whole brain radiotherapy is no longer recommended following surgical resection or radiosurgery for brain metastases. Last reviewed December 2015

What is the clinical benefit of radiotherapy to the bone for metastatic disease from NSCLC?

Recommendation	Grade
Patients who have pain from bony metastases (not at risk of pathological fracture) should be offered palliative radiotherapy. Last reviewed December 2015	A
A single fraction of 8Gy is recommended if the clinical endpoint is pain relief. Last reviewed December 2015	A
Patients who have had orthopaedic fixation of a pathological fracture may be considered for adjuvant radiotherapy. Last reviewed December 2015	C

Point(s)
Patients at risk of pathological fracture should be referred for prophylactic fixation prior to radiotherapy. The Mirel score is a useful tool in assessing this but patient factors should also be taken into account. Last reviewed December 2015

What is the clinical benefit of radiotherapy in metastatic spinal cord compression?

Recommendation	Grade
Patients who have spinal cord compression from metastatic cancer should be considered for radiotherapy, either as primary treatment or following surgery. Last reviewed November 2015	B
Recommended radiotherapy doses for patients treated with radiotherapy alone are 8-20Gy in 1-5 fractions. Last reviewed November 2015	B

Point(s)
Patients with spinal cord compression may be commenced on dexamethasone 4-16mg a day to reduce oedema around the spinal cord. This can be weaned once treatment is complete. Last reviewed November 2015
Spinal stability should be assessed in patients with spinal cord compression. The SINS score is a useful tool to assess this but patient factors should also be taken into account. Last reviewed November 2015

Chemotherapy

What is the optimal systemic therapy for stage IV inoperable NSCLC?

Recommendation	Grade
Platinum-based chemotherapy can be used to palliate disease symptoms and extend survival in newly diagnosed patients with stage IV NSCLC	A
First-line combination chemotherapy should in most cases be stopped at disease progression or after four cycles in patients with advanced NSCLC.	B
High dose bevacizumab (15 mg/kg three-weekly) may be considered in addition to chemotherapy (carboplatin/paclitaxel or cisplatin/gemcitabine) in carefully selected** patients with non-squamous cell carcinoma.	B
The first generation EGFR TKIs gefitinib or erlotinib should not be used in unselected patients in combination with standard chemotherapy.	A
In patients with whose tumours have been shown to express EGFR by immunohistochemistry, cetuximab may be considered in addition to cisplatin/vinorelbine chemotherapy to improve response rate and overall survival.	B
In unselected patients with stable or responsive advanced NSCLC after four cycles of initial platinum doublet chemotherapy, “switch maintenance” therapy to an alternative agent is recommended to delay tumour progression. Options in unselected patients include erlotinib or docetaxel, whilst in patients with non-squamous cell carcinoma histology, pemetrexed.	A
In unselected patients previously treated for advanced NSCLC, chemotherapy with docetaxel or pemetrexed may be used as second-line therapy. Pemetrexed is preferred in non-squamous cell carcinoma histology, and docetaxel is preferred in squamous cell carcinoma.	B
In unselected patients previously treated for advanced NSCLC, gefitinib 250 mg per day orally or erlotinib 150 mg per day orally can be used as second-line therapy, instead of chemotherapy.	B
Doublet therapy is not recommended as second-line treatment of advanced NSCLC .	A
In unselected patients having previously received two lines of treatment for advanced NSCLC, erlotinib 150 mg per day orally can be used as third- line therapy.	B
First-line monotherapy with 3G chemotherapy could be offered to selected patients with PS2 for symptom improvement and possible survival gain, who are willing to accept treatment toxicity.	B
In patients with high tumour burden and symptoms from stage IV NSCLC cisplatin based chemotherapy may be used in preference to carboplatin for the purpose of inducing a response, however, this benefit may be offset by its greater risk of toxicity.	B
Poor performance status patients having received 1 or 2 lines of prior therapy, may be offered erlotinib 150 mg daily.	B
Suitably fit patients over 65 years of age, can be offered first-line mono-chemotherapy with a 3G single agent (vinorelbine (25-30 mg/ m2 Day one, eight Q3 weekly), docetaxel (60 mg/m2 (day one, Q3 weekly) or gemcitabine (1150 mg/m2 days one and eight, Q3 weekly).	B
In elderly patients, first-line gemcitabine doublet chemotherapy is not recommended.	B
In fit elderly patients, first-line carboplatin/weekly paclitaxel may be offered instead of 3G monotherapy but at the expense of greater neutropenia.	B
Due to the therapeutic implications, it is important to classify the histologic subtype of NSCLC on diagnostic specimens as accurately as possible, particularly to enable accurate distinction between the key histologic subtypes: adenocarcinoma and squamous cell carcinoma.	A
Patients with known activating gene mutations (exon-19 deletions or exon-21 point mutations) to EGFR should be treated with an EGFR TKI.	A
Where EGFR mutation status is negative or unknown, patients should be treated with standard chemotherapy.	B
3G platinum-based chemotherapy (with vinorelbine, paclitaxel, docetaxel or gemcitabine) is a standard of care as first-line chemotherapy in fit patients with stage IV NSCLC.	A
In the first-line setting, chemotherapy with cisplatin and pemetrexed is recommended in preference to cisplatin and gemcitabine in patients with non-squamous cell carcinoma histology.	B
In the first-line setting, chemotherapy with cisplatin and gemcitabine is recommended in preference to cisplatin and pemetrexed in patients with squamous cell carcinoma histology.	B
Patients fit for chemotherapy should be offered 3G platinum-based combination chemotherapy (vinorelbine, paclitaxel, docetaxel, irinotecan or gemcitabine) in preference to 3G agent monotherapy, as it is more effective.	A
Patients unfit for combination chemotherapy could be considered for 3G monotherapy with vinorelbine, paclitaxel, docetaxel or gemcitabine.	A
Triplet chemotherapy regimens are not recommended, as benefit in response rate does not outweigh extra toxicity.	A
Non-platinum 3G doublet chemotherapy is an effective alternative option for patients unsuitable for platinum-based therapy.	B

Point(s)
The decision to undertake empirical platinum-based chemotherapy in a given patient should consider factors such as patient performance status (0,1 versus 2 or more) and co-morbidities, their disease extent and symptoms, proposed treatment toxicity and their individual preferences for benefit from specific treatment(s) and toxicities.
The choice of cisplatin versus carboplatin in a given patient may consider the balance between perceived benefit (in tumour response) versus known toxicity, whilst considering patient preferences.
The choice of first-line platinum combination chemotherapy in a given patient may consider patient performance status and co-morbidities, the proposed treatment toxicity, treatment scheduling and individual patient preferences.
The duration of first-line chemotherapy in a given patient in practice may be based on the benefit being obtained in terms of tumour response, the desire to delay tumour progression and improve or maintain quality of life balanced against treatment toxicity. In practice maximum benefit from first-line chemotherapy has usually been obtained by four cycles of treatment.
As overall quality of life does not seem to differ across the different chemotherapy regimens, the choice of chemotherapy in an individual patient may involve discussion regarding expected toxicities and the patient’s preferences.
Decision-making on treatment in poor performance status patients may weigh up benefits against toxicity and patient preferences. Whilst a single agent 3G chemotherapy is an option in unselected patients, patients with known activating EGFR MTs should be considered for first line EGFR TKIs as the magnitude of benefit is greater and toxicity profile more favourable.
Given the importance of accurate histologic diagnosis and the potential need to have sufficient tissue for subsequent molecular testing, it is important to obtain as much tissue as possible at initial diagnosis in patients suspected to have NSCLC. A multidisciplinary team discussion may be required in order to decide on the most appropriate diagnostic method to obtain adequate tissue.
The evidence in support of large treatment benefits with first line EGFR TKIs in RR and PFS argues for consideration of obtaining adequate tumour tissue where possible, to enable molecular testing for the presence of activating EGFR gene mutations. This will enable clinicians to offer patients initial EGFR TKIs versus empirical therapy, bearing in mind that overall survival for EGFT GMT + patients does not appear to be compromised as long they go on to receive EGFR TKIs after chemotherapy.

Small cell lung cancer

Limited stage

Chemotherapy

What is the optimal systemic therapy and duration to be used for the treatment of limited stage small cell lung cancer?

Recommendation	Grade
Platinum-etoposide regimens are considered the standard systemic chemotherapy in the treatment of limited stage small cell lung cancer. Last reviewed November 2015	B
Therapy beyond the standard four cycles of induction chemotherapy cannot be recommended. Last reviewed November 2015	A

Point(s)
It is advisable to use platinum plus etoposide for four cycles in patients with limited stage small cell lung cancer. Last reviewed November 2015

What is the optimal concurrent chemotherapy to be used for the treatment of limited stage small cell lung cancer with radiotherapy?

Recommendation	Grade
Platinum plus etoposide is recommended as the chemotherapy backbone for concurrent chemoradiotherapy in patients with limited stage small cell lung cancer. Last reviewed August 2015	B

Point(s)
It is advisable to use three-weekly platinum and etoposide chemotherapy during concurrent chemoradiotherapy for limited stage small cell lung cancer. Chest irradiation is optimally commenced early during the course of chemotherapy. Last reviewed August 2015

Radiotherapy

Which patients with SCLC benefit from prophylactic cranial irradiation?

Recommendation	Grade
Patients with limited stage and a complete response to initial therapy, and patients with extensive stage andstage who do not receive MRI brain and any response to initial therapy, should be offered prophylactic cranial irradiation. Last reviewed September 2017	A

Point(s)
Although there is no high level data to directly support the practice of prophylactic cranial irradiation in SCLC limited stage patients who achieve a partial response to initial therapy, the benefits of such practice may be inferred from randomised data in SCLC extensive stage patients. Prophylactic cranial irradiation may, therefore, be considered for patients with limited stage SCLC who are partial responders to initial therapy. Last reviewed September 2017
It is appropriate to obtain a brain CT scan before embarking on prophylactic cranial irradiation, to exclude pre-existing brain metastases. If brain metastases are detected then a palliative rather than prophylactic dose of whole brain radiotherapy may be delivered. MRI brain is preferable where available, as PCI may be avoided in those ES patients without brain metastases on MRI. Last reviewed September 2017

What is the optimal dose and fractionation schedule of prophylactic cranial irradiation in patients with limited stage SCLC?

Recommendation	Grade
Patients with limited stage small cell lung cancer achieving a complete response to initial therapy should receive prophylactic cranial irradiation to a dose of 25Gy in 10 daily fractions. Last reviewed September 2017	B

What is the optimal timing of thoracic radiotherapy in patients receiving chemotherapy for limited stage SCLC?

Recommendation	Grade
Fit patients with limited stage small cell lung cancer should receive thoracic radiotherapy concurrently with the first cycle of chemotherapy or as soon as possible thereafter. Last reviewed September 2017	B

Point(s)
It is desirable not only to institute radiotherapy as soon as possible, but also to complete it as soon as possible, ideally within 30 days. Last reviewed September 2017

What is the optimal dose and fractionation schedule of thoracic radiotherapy in patients with limited stage SCLC?

Recommendation	Grade
For patients with good performance status receiving chemotherapy for limited stage small cell lung cancer, the concurrent administration of twice daily radiotherapy to a dose of 45Gy in 30 twice-daily fractions is recommended. Last reviewed August 2017	B

Point(s)
When following the accelerated hyperfractionated regimen of Turrisi et al, normal tissue tolerance limits specific to this protocol should be observed and a minimum interval of six hours between fractions should be ensured. Last reviewed August 2017
If resource or other limitations preclude the delivery of twice-daily thoracic radiotherapy then daily radiotherapy should be delivered to a high dose. Pending the results of ongoing trials, doses in the range of 54Gy-60Gy in 27-30 fractions are reasonable provided acceptable dose constraints can be met. If a hypofractionated regimen is desired, then 40Gy in 15 daily fractions may be chosen as good quality toxicity and survival data have been published for this schedule. Last reviewed August 2017

What is the optimal treatment volume in patients with limited stage SCLC receiving thoracic radiotherapy?

Recommendation	Grade
Where radiotherapy is delivered after chemotherapy has begun, radiotherapy target volumes should be based on the post-chemotherapy volume of disease. Radiotherapy should be delivered to all originally involved nodal regions irrespective of their response to chemotherapy. Last reviewed September 2017	B
Elective nodal irradiation may be omitted to reduce toxicity. Last reviewed September 2017	C

Point(s)
In the setting of SCLC, positron emission tomography (PET) appears useful both for staging as well as for the definition of radiotherapy volumes. Where available, information from PET scans should be incorporated into radiotherapy target definition. Last reviewed September 2017

Extensive stage

Chemotherapy

What is the optimal chemotherapy regimen and duration of therapy in extensive stage small cell lung cancer in the first-line setting?

Recommendation	Grade
The platinum etoposide regimen is recommended as the first-line therapy for patients with extensive stage small cell lung cancer. Irinotecan-platinum may be an alternative in selected patients. Last reviewed December 2015	B

Point(s)
It is advisable to consider the platinum etoposide regimen as first-line therapy in patients with extensive stage small cell lung cancer, treatment should continue for at least four to six cycles. Maintenance therapy provides no aditional benefit. Last reviewed December 2015

What is the optimal second-line therapy in patients with extensive stage small cell lung cancer?

Recommendation	Grade
Topotecan or CAV are recommended as second-line therapy in patients with extensive stage small cell lung cancer who have chemotherapy responsive disease (i.e. relapse > three months post first-line therapy). Last reviewed December 2015	A

Radiotherapy

What is the optimal dose and fractionation schedule of prophylactic cranial irradiation in patients with extensive stage SCLC?

Recommendation	Grade
For patients with extensive stage small cell lung cancer who achieve a response to initial therapy, a range of prophylactic cranial irradiation dose schedules from 20Gy in 5 fractions to 30Gy in 10 fractions is reasonable. Last reviewed November 2015	B

Point(s)
There is insufficient evidence to recommend a particular prophylactic cranial irradiation dose or fractionation schedule over any other. However, since extensive stage small cell lung cancer has a median survival of less than a year, a short fractionation schedule (20Gy in 5 fractions) is recommended for most patients. Last reviewed November 2015

Is there a role for thoracic radiotherapy in patients with extensive stage SCLC?

Recommendation	Grade
Strongly consider administering moderate dose consolidative chest radiotherapy (30 Gy in 10 fractions) to chemotherapy responders, especially those with residual disease in the thorax. Last reviewed December 2015	B

Point(s)

Chest radiotherapy was administered 6-7 weeks after chemotherapy and usually 1 week after completion of prophylactic cranial irradiation. Those patients with the heaviest extrathoracic metastatic burden and poor response to chemotherapy may be expected to benefit the least from thoracic radiotherapy. In addition, patients with no residual disease in the thorax after chemotherapy derived no benefit from consolidative thoracic radiotherapy in a post hoc analysis by Slotman et al. Last reviewed December 2015

Palliative care

What is the role of palliative care in symptom management for patients with lung cancer?

Recommendation	Grade
There is strong evidence from consistent randomised trials to support the use of NSAIDS and opioids for the management of pain in patients with NSCLC. Last reviewed December 2015	B
There is a role for the use of bisphosphonates and radiopharmaceuticals in a select group of patients with pain arising from multiple site of bony metastasis. Last reviewed December 2015	B
The use of opioids are recommended for the relief of dyspnoea in patients with NSCLC. Last reviewed December 2015	B
Following individual patient assessment and a therapeutic trial, oxygen administered intranasally may be administered to patients with advanced lung cancer to palliate the symptom of breathlessness. Last reviewed December 2015	B
Subcutaneous methylnaltrexone should be considered in patients where conventional laxatives have failed. Last reviewed December 2015	B

Point(s)
- It is advised that the use of methadone occurs with involvement of specialist palliative care or pain services, due to its complex pharmacodynamic properties. - The choice of opioids used may consider issues of availability, cost and individual patient factors such as route of administration, metabolism and organ impairment such as renal failure. - Anticonvulsants such as gabapentin and pregabalin may be considered in the management of neuropathic pain, based on substantive body of evidence generated in non-cancer patients. - Non-pharmacological approaches and complementary therapies may be considered as part of a multimodal approach when pain remains poorly controlled. Last reviewed December 2015
The use of non-pharmacological strategies, such as breathing retraining, simple relaxation, activity pacing and psychosocial support from nursing or allied health, can be beneficial for the management of breathlessness. Last reviewed December 2015
Benzodiazepines can be used as a second or third line therapy in the treatment of breathlessness in patients with advanced lung cancer, when opioids and non-pharmacological measures have failed. Last reviewed December 2015
Recommendations for the treatment of constipation in the palliative care population have been made based on expert opinion and currently suggest a combination of stimulant and softening agent. Last reviewed December 2015
-Centrally acting oral opioids may be considered for the suppression of cough in NSCLC -Symptomatic treatment with antimuscuranic agents or antibiotics may be helpful by reducing the volume of secretions or mucopurulant sputum. -Where appropriate and accessible, interventions such as brachytherapy may be beneficial for the management of cough in selected patients. (Refer to Brachytherapy section in Radiotherapy Stage IV) Last reviewed December 2015
Palliative measures for the management of haemoptysis include the use of oral haemostatics e.g. tranexamic acid, or radiotherapy, or laser treatment to the tumour site and the active management of underlying causes, such as infection, or pulmonary infarction. Last reviewed December 2015

What is the role of advance care planning and timing of referral for patients with lung cancer?

Recommendation	Grade
It is recommended to refer patients with stage IV inoperable NSCLC to palliative care at the time of diagnosis of metastatic disease. Last reviewed December 2015	B
Advance care planning discussions should be initiated with patients, as there are multiple benefits. Last reviewed December 2015	B
Clinicians may explore patients’ understanding of their health situation and offer to provide further information about their prognosis and to explore the patients’ goals/priorities/fears and concerns about the future. Last reviewed December 2015	C

Point(s)
Consider referral to palliative care when metastatic disease is diagnosed. Don’t wait until there is definite evidence of medical deterioration. Last reviewed December 2015
It may take some time for patients and their families to comprehend and process advance care planning discussions. Discussing patients understanding of their disease and/ or prognosis along with their hopes and fears may enable important conversations. It is never ‘too early’ to explore these concerns. Last reviewed December 2015

What is the role of psychological support and interventions in the treatment of lung cancer?

Recommendation	Grade
Psycho-educational interventions including: counseling, behaviour therapy, education/information giving, and social support will assist in ameliorating the impact of depression. Last reviewed December 2015	B
There is reasonable evidence from systematic reviews to support the use of Cognitive Behaviour Therapy (CBT) in the management of depression particularly in the short-term (in group or individual format). Further randomised controlled trials involving adequately powered studies and consistent methodology should be conducted. Last reviewed December 2015	B
Cognitive Behaviour Therapy (CBT) is recommended for the treatment of anxiety in NSCLC. Further randomised controlled trials involving adequately powered studies and consistent methodology should be conducted. Last reviewed December 2015	B
Supportive and Meaning based group psychotherapies, may be helpful in reducing anxiety in NSCLC patients. Further randomised controlled trials involving adequately powered studies and consistent methodology should be conducted. Last reviewed December 2015	B
Psychological interventions including Cognitive Behaviour Therapy (CBT), education, self-care strategies, behavioural interventions, activity management, supportive psychotherapy have all been found to ameliorate fatigue. Further randomised controlled trials involving adequately powered studies and consistent methodology can be conducted to ascertain unmet needs in advanced cancer. Last reviewed December 2015	C
Psychological interventions have an important role in the management of cancer related pain. Last reviewed December 2015	B
Quality of life of lung patients may improve with behavioural, cognitive or social cognitive therapies. Last reviewed December 2015	C
Non-invasive nurse-led programs with a focus on managing physical symptoms and treatment related toxicities may be used to optimise quality of life. Last reviewed December 2015	C

Supportive care

What is the role of case management in the treatment of patients with lung cancer?

Recommendation	Grade
Lung cancer nurses should be involved in the follow-up care of patients with lung cancer in centres where there is a significant lung cancer case load. The model of implementation should be flexible. Last reviewed October2015	B

Point(s)
The UK standard of 80% involvement of LCNS at the time of lung cancer diagnosis is not a rational one in Australia where lung cancer diagnosis is more de-centralised. With the above caveat, including a LCNS in the care of patients from early in the diagnosis-decision making stage may be highly valuable. By extension of the universal acceptance of the role of breast care nurses, it seems more than probable that patients with lung cancer would benefit in a similar fashion. Last reviewed October2015
When a clinical problem develops, the threshold for a patient to contact a nurse is lower than that for contacting a doctor whom they often wish not to trouble. As lung cancer nurses are introduced to the Australian setting, careful planning will optimise the benefit in improved patient care. In the rural setting, the lung cancer case load may not be sufficient to justify a lung cancer specific nurse and the optimal plan. may be to increase educational standards of existing nurses with more general roles. Last reviewed October2015
Lung cancer nurses can be integral to the care of patients with lung cancer in centres where there is a significant lung cancer case load. Last reviewed October2015

What is the role of topical creams, skin moisturisers and maintenance antibiotics in the treatment of rash from anti-EGFR therapy in patients with lung cancer?

Recommendation	Grade
A tetracycline can be prescribed in conjunction with anti-EGFR therapy, as it may reduce the severity and frequency of rash. Last reviewed September 2017	C

Point(s)
Rash is a common adverse effect and at the commencement of treatment, patients may be informed of this possibility. Patients can be made aware that the severity of rash may be reduced by prophylactic antibiotic treatment. Last reviewed September 2017
Patients may have reduced severity of skin rash by the addition of prophylactic skin moisturiser, however data suggesting frequency and product selection is lacking. Last reviewed September 2017
Vitamin K cream can not be recommended for the purpose of reducing rash. Last reviewed September 2017
Sunscreen cannot be recommended for the purpose of reducing rash. Barrier methods – clothing, hats and limiting time in the sun can be employed in preference. Last reviewed September 2017
For very severe rash, alone or in combination with other skin adverse effects, treatment can be discontinued or suspended. Last reviewed September 2017
Evidence for treatments supplementary to antibiotics for rash is presently lacking, but a useful effect cannot be disproven. Last reviewed September 2017
Topical formulations of steroids and tacrolimus do not add to the benefit of antibiotic treatment. Last reviewed September 2017
Anecdotal evidence supports the use of skin moisturisers but data for product selection, frequency of use and consequential outcomes are lacking. The routine use of moisturisers can be justified at the outset of EGFR-TKI but this is based on expert opinion and reasonable fear of the consequences of inaction not controlled trials. Severe drying with fissuring can be regarded as a serious complication and the opinion of a Dermatologist, ideally one with an interest in this clinical area, may be sought. Last reviewed September 2017
Patients with clinically significant rash may be commenced on oral antibiotic therapy with tetracycline, minocycline or doxycycline. Last reviewed September 2017
The treatment for paronychia is based on expert opinion as no randomised controlled trials have evaluated the therapies. The consensus of expert opinion suggests where there is no signs of infection, the topical application of a corticosteroid combined with a systemic cycline antibiotic. In severe cases and signs of infection, it is recommended to swab, treat with appropriate systemic antibiotic and refer to dermatologist. Last reviewed September 2017

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Levels of evidence and grades for recommendations

The following table provides a list of the evidence-based recommendations detailed in the content of each topic question. The table below provides details on the highest level of evidence identified to support each recommendation (I-IV). The Summary of Recommendations table includes the grade for each recommendation (A-D). The key references that underpin the recommendation are provided in the last column. Individual levels of evidence can be found in the Evidence Summaries for each recommendation in each question.

Each recommendation was assigned a grade by the expert working group taking into account the volume, consistency, generalisability, applicability and clinical impact of the body of evidence supporting each recommendation. When no Level I or II evidence was available and in some areas, in particular where there was insufficient evidence in the literature to make a specific evidence-based recommendation, but also strong and unanimous expert opinion amongst the working group members about both the advisability of making a clinically relevant statement and its content, recommended best practice points were generated. Thus, the practice points relate to the evidence in each question, but are more expert opinion-based than evidence-based. These can be identified throughout the guidelines with the following: Practice point (PP).

Grade of recommendation	Description
A	Body of evidence can be trusted to guide practice
B	Body of evidence can be trusted to guide practice in most situations
C	Body of evidence provides some support for recommendation(s) but care should be taken in its application
D	Body of evidence is weak and recommendation must be applied with caution
PP (practice point)	Where no good-quality evidence is available but there is consensus among Guideline committee members, consensus-based guidance points are given, these are called "Practice points"

Adapted from: National Health and Medical Research Council. NHMRC levels of evidence and grades for recommendations for developers of guidelines. Canberra: NHMRC; 2009. (https://www.nhmrc.gov.au/_files_nhmrc/file/guidelines/developers/nhmrc_levels_grades_evidence_120423.pdf)

Level of evidence was assigned according to the following criteria from the NHMRC Evidence Hierarchy:

Level	Intervention	Diagnosis	Prognosis	Aetiology	Screening
I	A systematic review of level II studies	A systematic review of level II studies	A systematic review of level II studies	A systematic review of level II studies	A systematic review of level II studies
II	A randomised controlled trial	A study of test accuracy with: an independent, blinded comparison with a valid reference standard, among consecutive patients with a defined clinical presentation	A prospective cohort study	A prospective cohort study	A randomised controlled trial
III-1	A pseudo-randomised controlled trial (i.e. alternate allocation or some other method)	A study of test accuracy with: an independent, blinded comparison with a valid reference standard, among non-consecutive patients with a defined clinical presentation	All or none	All or none	A pseudo-randomised controlled trial (i.e. alternate allocation or some other method)
III-2	A comparative study with concurrent controls: Non-randomised, experimental trial Cohort study Case-control study Interrupted time series with a control group	A comparison with reference standard that does not meet the criteria required for Level II and III-1 evidence	Analysis of prognostic factors amongst untreated control patients in a randomised controlled trial	A retrospective cohort study	A comparative study with concurrent controls: Non-randomised, experimental trial Cohort study Case-control study
III-3	A comparative study without concurrent controls: Historical control study Two or more single arm study Interrupted time series without a parallel control group	Diagnostic case-control study	A retrospective cohort study	A case-control study	A comparative study without concurrent controls: Historical control study Two or more single arm study
IV	Case series with either post-test or pre-test/post-test outcomes	Study of diagnostic yield (no reference standard)	Case series, or cohort study of patients at different stages of disease	A cross-sectional study	Case series

Source: National Health and Medical Research Council. NHMRC levels of evidence and grades for recommendations for developers of guidelines. Canberra: NHMRC; 2009. (https://www.nhmrc.gov.au/_files_nhmrc/file/guidelines/developers/nhmrc_levels_grades_evidence_120423.pdf)

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References

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