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?
The management of Stage III NSCLC has been divided into sections dependent on whether the disease is considered operable or inoperable at the time of diagnosis.
Stage III NSCLC encompasses a broad spectrum of disease extent from tumour involving a single nodal station identified only postoperatively despite extensive pre-operative staging to involvement of multiple contralateral mediastinal nodes and supraclavicular nodes appreciated on clinical examination. In patients with clinically equivocal involvement, pathological confirmation of nodal status should be made if it will influence management options.
The decision as to operability should be made in a multidisciplinary setting.
Patients with Stage III NSCLC may be deemed inoperable because of patient factors (the patient’s respiratory function or co-morbidities may preclude operative intervention or the patient may choose not to proceed with surgery) or tumour factors (the extent or location of gross disease might make surgical resection technically impossible, for example left sided tumours with mediastinal nodes to the right of the aorta, N3 nodal involvement and most T4 tumours).
In the absence of other factors precluding surgery, patients with N1 disease should be considered for surgery. Patients with confirmed N2 disease should not be treated by surgery as the sole modality, but resectable cases may be considered for a multimodality approach. There is no consensus on the distinction between resectable and unresectable N2 disease. Factors influencing assessment of resectability include nodal size, number of stations involved, extracapsular extension and involvement of the recurrent laryngeal nerve.
Patients with inoperable NSCLC can be divided into three groups:
- Patients with good performance status (PS), adequate pulmonary function and localised tumour who should be considered for radical treatment with the accepted “standard of care” being the concurrent administration of chemotherapy and radiotherapy (RT) to doses ≥60Gy
- Patients with poor PS, substantial weight loss (>10%) and advanced disease for whom simple palliative measures are appropriate; and
- An intermediate group of patients who have a good PS but locally advanced disease for whom radical chemo-radiation (≥60Gy) is not feasible either due to tumour extent or patient factors (such as poor respiratory function).
Recommendations in this section apply to patients in groups 2 and 3 who do not have a mutation for targeted therapy. In either group the aim of treatment is to palliate symptoms and maintain quality of life.
The most common symptoms that are considered for palliation include dyspnoea, cough, haemoptysis and pain. A number of randomised controlled trials (RCTs) comparing different palliative RT regimens in locally advanced NSCLC have been performed. The characteristics of these trials and their results are summarised here: Table: Randomised controlled trials comparing different palliative RT regimens in locally advanced NSCLC
Two systematic reviews of these data have been undertaken. A Cochrane review of 14 RCTS involving 3576 evaluable patients found that palliative RT achieves reasonable rates of symptom control (haemoptysis, cough, pain, dyspnoea) but there was no difference in specific symptom control rates between lower dose and higher RT dose schedules. The authors concluded that there was strong evidence, from four studies for an increase in survival in patients with good PS who were given higher dose RT. One large high-quality RCT showed an increase in survival of 5% at one year and 3% at two years. A formal meta-analysis was not attempted due to the apparent heterogeneity of the studies.
An update of this Cochrane review attempted a sub-group analysis by PS. The use of more fractionated palliative regimens to prolong survival in patients with good PS was not supported by strong evidence. The authors warn that as data was only available for 56% of patients and there was significant heterogeneity, this conclusion needed to be treated with caution.
A second systematic review performed a quantitative pooling of the results of 13 RCTS comparing different dose fractionation schedules of palliative thoracic RT in 3473 patients. The authors confirmed the findings of the previous systematic review in terms of the equivalence of specific symptom palliation but reported that, in comparison with lower dose schedules, higher dose schedules ( ≥ 35Gy10 Biologically equivalent dose, BED) resulted in: a greater likelihood of symptom improvement on the total symptom score, a longer duration of symptom relief, an improvement in one year survival (26.5% versus 21.7%, p =0.002) and a higher incidence of toxicity, predominantly oesophagitis.
The following rates of palliation have been reported with higher dose palliative radiotherapy schedules: 79% for haemoptysis, 60% for chest pain, 48% for cough and 36% for dyspnoea.
In advanced NSCLC, systemic chemotherapy improves survival and maintains QOL compared with best supportive care. In a meta-analysis of 16 trials involving 2714 patients, chemotherapy reduced the risk of death (hazard ratio = 0.77; 95% CI 0.71-0.83; p≤ 0.0001), resulting in an absolute improvement in one year survival of 9% (from 20% to 29%). Studies which prospectively evaluate intrathoracic tumour-related symptoms demonstrate an improvement from baseline scores with palliative chemotherapy.
Combined modality therapy
Typically, palliative chemotherapy is delivered before or after palliative RT to avoid the toxicity of concurrent administration in the non-curative setting.
A trial conducted by the Norwegian Lung Cancer Study Group compared the use of palliative concurrent chemoradiation (three weekly carboplatin + oral vinorelbin + 42Gy/15f commencing with the second cycle) with the same chemotherapy alone in the management of patients with locally advanced, inoperable NSCLC not suitable for curative radiotherapy. The trial was closed due to slow accrual with the recruitment of 191 patients. However, the use of chemoradiation was associated with a statistically significant improvement in median overall survival (12.6m versus 9.7m, p<0.01) and in health related quality of life, but with more hospital admissions related to side effects.
Evidence summary and recommendations
|Palliative radiotherapy achieves reasonable rates of symptom control.
|Higher radiation dose schedules result in a greater likelihood of symptom improvement, a longer duration of symptom relief and an improvement in one year survival compared with lower dose radiation schedules.
|As in metastatic disease, in locally advanced Stage III NSCLC, systemic chemotherapy improves survival and maintains QOL compared with best supportive care.
|For patients with locally advanced, inoperable Stage III NSCLC who are not fit for curative radiotherapy, the use of concurrent palliative chemoradiation is superior to chemotherapy alone with respect to survival and HRQOL but is associated with more side effects necessitating admission to hospital.
For patients with locally advanced, inoperable Stage III NSCLC not fit for curative therapy, consideration should be given to concurrent administration of palliative chemoradiation.
Given the symptomatology experienced by these patients with stage III disease and their poor survival outcomes, referral to palliative care services should be considered.
- Hoskin PJ. Palliative radiotherapy for non-small-cell lung cancer: which dose? Clin Oncol (R Coll Radiol) 2005 Feb;17(1):59-60 Available from: http://www.ncbi.nlm.nih.gov/pubmed/15714932.
- Lester JF, Macbeth FR, Toy E, Coles B. Palliative radiotherapy regimens for non-small cell lung cancer. Cochrane Database Syst Rev 2006 Oct 18;(4):CD002143 Available from: http://www.ncbi.nlm.nih.gov/pubmed/17054152.
- Stevens R, Macbeth F, Toy E, Coles B, Lester JF. Palliative radiotherapy regimens for patients with thoracic symptoms from non-small cell lung cancer. Cochrane Database Syst Rev 2015 Jan 1;1:CD002143 Available from: http://www.ncbi.nlm.nih.gov/pubmed/25553505.
- Macbeth FR, Bolger JJ, Hopwood P, Bleehen NM, Cartmell J, Girling DJ, et al. Randomized trial of palliative two-fraction versus more intensive 13-fraction radiotherapy for patients with inoperable non-small cell lung cancer and good performance status. Medical Research Council Lung Cancer Working Party. Clin Oncol (R Coll Radiol) 1996;8(3):167-75 Available from: http://www.ncbi.nlm.nih.gov/pubmed/8814371.
- Reinfuss M, Glinski B, Kowalska T, Kulpa J, Zawila K, Reinfuss K, et al. Radiotherapy for stage III, inoperable, asymptomatic small cell lung cancer. Final results of a prospective randomized study (240 patients). Cancer Radiother 1999;3(6):475-9 Available from: http://www.ncbi.nlm.nih.gov/pubmed/10630160.
- Fairchild A, Harris K, Barnes E, Wong R, Lutz S, Bezjak A, et al. Palliative thoracic radiotherapy for lung cancer: a systematic review. J Clin Oncol 2008 Aug 20;26(24):4001-11 Available from: http://www.ncbi.nlm.nih.gov/pubmed/18711191.
- Langendijk JA, ten Velde GP, Aaronson NK, de Jong JM, Muller MJ, Wouters EF. Quality of life after palliative radiotherapy in non-small cell lung cancer: a prospective study. Int J Radiat Oncol Biol Phys 2000 Apr 1;47(1):149-55 Available from: http://www.ncbi.nlm.nih.gov/pubmed/10758317.
- NSCLC Meta-Analyses Collaborative Group. Chemotherapy in addition to supportive care improves survival in advanced non-small-cell lung cancer: a systematic review and meta-analysis of individual patient data from 16 randomized controlled trials. J Clin Oncol 2008 Oct 1;26(28):4617-25 Available from: http://www.ncbi.nlm.nih.gov/pubmed/18678835.
- Georgoulias V, Ardavanis A, Agelidou A, Agelidou M, Chandrinos V, Tsaroucha E, et al. Docetaxel versus docetaxel plus cisplatin as front-line treatment of patients with advanced non-small-cell lung cancer: a randomized, multicenter phase III trial. J Clin Oncol 2004 Jul 1;22(13):2602-9 Available from: http://www.ncbi.nlm.nih.gov/pubmed/15226327.
- Strøm HH, Bremnes RM, Sundstrøm SH, Helbekkmo N, Fløtten O, Aasebø U. Concurrent palliative chemoradiation leads to survival and quality of life benefits in poor prognosis stage III non-small-cell lung cancer: a randomised trial by the Norwegian Lung Cancer Study Group. Br J Cancer 2013 Sep 17;109(6):1467-75 Available from: http://www.ncbi.nlm.nih.gov/pubmed/23963145.