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

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Introduction

Jutta's info icon.png Defining operable and inoperable disease in stage III

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.

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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 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 some T4 tumours). Patients with N3 nodal involvement are not considered to be surgical candidates.[1]

The recommendations found in this section are applicable to good performance status patients with stage III disease who are inoperable because of patient or tumour factors.

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Surgery in inoperable N2 disease

The European Organization for the Research and Treatment of Cancer (EORTC) conducted a trial in which 579 patients with pathologically proven Stage IIIA-N2 disease deemed unresectable received three cycles of induction platinum-based chemotherapy. Patients demonstrating a radiological response (n=332) were then randomised to surgical resection or radiotherapy.[2] The guidelines for unresectability were: any N2 involvement by a non-squamous carcinoma and for a squamous cell carcinoma, any N2 nodal involvement exceeding level 4R for a right-sided tumour and level 5 and 6 for a left-sided tumour. Of the 154 patients (92% of those randomised) who underwent surgery post induction chemotherapy, 22 patients (14%) had an exploratory thoracotomy, 47% a pneumonectomy and 38% a lobectomy. Fifty percent of patients achieved a complete resection, of which 5% was a pathologically complete response. The operative mortality within 30 days was 4%. Postoperative radiotherapy was administered to 62 (40%) patients. The median and five-year OS survival for patients randomly assigned to resection versus radiotherapy were not significantly different at 16.4m versus 17.5m and 15.7% v 14% respectively (HR=1.06, 95% CI = 0.84-1.35). The authors concluded that surgery did not improve survival after a radiological response to induction chemotherapy in patients with unresectable stage IIIA-N2 NSCLC as compared with radiotherapy. RT was the preferred local treatment modality for these patients because of the lower morbidity and mortality.

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Radiation therapy

Historically, radiation therapy alone was the standard therapy for inoperable stage III disease.

The Veterans Administration Lung Cancer Study Group which included 800 patients with advanced disease (including stage IV) found a small statistically significant survival advantage for radiotherapy compared to placebo.[3] For patient with inoperable stage IIIA/B disease treatment with conventional radiation therapy alone (60Gy in 30f) results in a median survival of 8-10 months and five year survival rates of between 5-8%.[4]

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Chemotherapy and radiation therapy

In an attempt to improve these outcomes and with patterns of relapse data demonstrating a high incidence of extrathoracic relapse, studies evaluating the role of systemic chemotherapy given in combination with RT, either sequentially or concurrently, were initiated.[5][6][7][8][9][10][11]

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Radiation alone versus combination chemoradiotherapy

Several meta-analyses of these studies have been performed. The largest is the Non-small cell Lung Cancer Collaborative Group which analysed updated individual patient data from 22 trials in which 3033 patients were randomised to receive either RT alone or RT and chemotherapy given either sequentially or concurrently.[12] A variety of chemotherapy regimens were used. Eleven trials used cisplatin-containing regimens while the remaining trials used alkylating agents such as cyclphosphamide or nitrosourea in combination with methotrexate; vinca alkaloids or etoposide; or other regimens mainly based on doxorubicin. The results showed a significant overall benefit of chemotherapy with a hazard ratio of 0.90 (p-0.006), corresponding to an absolute survival benefit of 3% at two years and 2% at five years. Cisplatin-based regimens provided the strongest evidence for an effect in favour of chemotherapy with a hazard ration of 0.87 (p=0.005) corresponding to an absolute benefit of 4% at two years and 2% at five years.

The Meta-Analysis of Cisplatin/Carboplatin Based Concomitant Chemotherapy in Non-Small Cell Lung Cancer (MAC3-LC) Group analysed individual patient data from nine trials including 1764 patients randomised to either RT alone or RT alone combined with concurrent cisplatin- or carbopatin-based chemotherapy.[13] The administration of platin-based chemotherapy and radiotherapy was associated with a hazard ratio of death of 0.89 (95% confidence interval, 0.81-0.98, p=0.02) compared to RT alone, corresponding to an absolute benefit of chemotherapy of 4% at two years. However, the authors stated that the results needed to be interpreted cautiously owing to heterogeneity across trials.

The Cochrane Collaboration has recently published an updated review of 19 randomised studies of concurrent chemoradiotherapy versus radiotherapy alone including 2728 patients.[14] Sixteen of the included studies used platinum-based chemotherapy regimens. The addition of chemotherapy to radiotherapy significantly reduced the overall risk of death, with a hazard ratio of 0.71 (95% confidence intervals 0.64-0.80), corresponding to an absolute survival benefit at two years of 8%. This was achieved at the expense of increased toxicity (acute oesophagitis, neutropenia and anaemia).

These meta-analyses demonstrated a survival benefit for the addition of chemotherapy to radiotherapy in the management of locally advanced non-small cell lung cancer.

The question of the optimal sequencing of the two treatment modalities ie sequential or concurrent administration was the subject of further studies.[9][10][11].

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Concurrent versus sequential therapy

The Non-small cell Lung Cancer Collaborative Group has performed a meta-analysis of six randomised trials (including individual patient data from 1205 patients) comparing concurrent versus sequential chemoradiotherapy administration.[15] The concurrent administration of chemoradiotherpay demonstrated a statistically significant survival benefit over sequential administration with a hazard ratio of 0.84 (95% confidence interval 0.74-0.95, p=0.004), corresponding to an absolute benefit of 5.7% at three years and 4.5% at five years. This survival benefit was thought to be due to a significant reduction in locoregional failures with concurrent chemoradiotherapy (hazard ratio 0.77, 95%CI 0.62-0.95; p=.01) corresponding to an absolute decrease of 6.0% at three years and 6.1% at five years. There was no difference between the two arms with respect to distant progression. The concurrent administration of chemoradiotherapy was associated with a significant increase in oesophageal toxicity, but not pulmonary toxicity.

The previously mentioned Cochrane review also performed a meta-analysis of six trials (1024 patients) of concurrent versus sequential chemoradiotherapy. Again, a significant overall survival benefit for concurrent treatment was observed (HR 0.74, 95%CI0.62-0.89), representing a 10% survival benefit at two years.[14]

This data provides strong support for the concurrent administration of chemotherapy and radiation as the standard of care for inoperable stage III disease.

The survival advantage with concurrent administration is at the expense of an increased incidence of grade 3 to 4 oesophageal toxicity.

It is important to note that the majority of patients included in these studies were of good performance status. In many studies patients with weight loss ≥ 5% were excluded and elderly patients were poorly represented.

Elderly patients

A phase 3 trial by the Japan Clinical Oncology Group, randomised 200 patients with unresectable Stage III disease, ECOG performance status 0-2 and a median age of 77 years (range 71-93 years) to chemoradiotherapy (using low-dose carboplatin) or radiotherapy alone. Chemoradiotherapy was associated with a statistically significant improvement in median OS (22.4m v 16.9m, HR 0.68, 95%CI 0.47-0.98, p=0.0179), and a higher incidence of grade 3-4 haematological side effects but not difference in pulmonary toxicity.[16]

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Evidence summary and recommendations

Evidence summary Level References
In good performance status patients with inoperable stage III NSCLC, surgery does not improve survival in patients who have a radiologic response to induction chemotherapy compared with radiotherapy.

Last reviewed December 2015

I [15]
In good performance status patients with inoperable stage III NSCLC, the addition of chemotherapy to radiation therapy is associated with a statistically significant survival benefit compared with radiation therapy alone

Last reviewed December 2015

I [13], [12], [14]
In good performance status patients with inoperable stage III NSCLC, the concurrent administration of chemotherapy and radiation therapy provides a statistically significant survival benefit compared with the sequential administration of chemotherapy then radiation therapy.

Last reviewed December 2015

I [15], [14]
Evidence-based recommendationQuestion mark transparent.png 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


Practice pointQuestion mark transparent.png

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


Practice pointQuestion mark transparent.png

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

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References

  1. Jett JR, Schild SE, Keith RL, Kesler KA, American College of Chest Physicians. Treatment of non-small cell lung cancer, stage IIIB: ACCP evidence-based clinical practice guidelines (2nd edition). Chest 2007 Sep;132(3 Suppl):266S-276S Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17873173.
  2. van Meerbeeck JP, Kramer GW, Van Schil PE, Legrand C, Smit EF, Schramel F, et al. Randomized controlled trial of resection versus radiotherapy after induction chemotherapy in stage IIIA-N2 non-small-cell lung cancer. J Natl Cancer Inst 2007 Mar 21;99(6):442-50 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17374834.
  3. Wolf J, Patno ME, Roswit B, D'Esopo N. Controlled study of survival of patients with clinically inoperable lung cancer treated with radiation therapy. Am J Med 1966 Mar;40(3):360-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/4160252.
  4. Perez CA, Bauer M, Edelstein S, Gillespie BW, Birch R. Impact of tumor control on survival in carcinoma of the lung treated with irradiation. Int J Radiat Oncol Biol Phys 1986 Apr;12(4):539-47 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/3009368.
  5. Dillman RO, Herndon J, Seagren SL, Eaton WL Jr, Green MR. Improved survival in stage III non-small-cell lung cancer: seven-year follow-up of cancer and leukemia group B (CALGB) 8433 trial. J Natl Cancer Inst 1996 Sep 4;88(17):1210-5 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/8780630.
  6. Sause W, Kolesar P, Taylor S IV, Johnson D, Livingston R, Komaki R, et al. Final results of phase III trial in regionally advanced unresectable non-small cell lung cancer: Radiation Therapy Oncology Group, Eastern Cooperative Oncology Group, and Southwest Oncology Group. Chest 2000 Feb;117(2):358-64 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/10669675.
  7. Schaake-Koning C, van den Bogaert W, Dalesio O, Festen J, Hoogenhout J, van Houtte P, et al. Effects of concomitant cisplatin and radiotherapy on inoperable non-small-cell lung cancer. N Engl J Med 1992 Feb 20;326(8):524-30 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/1310160.
  8. Le Chevalier T, Arriagada R, Quoix E, Ruffie P, Martin M, Tarayre M, et al. Radiotherapy alone versus combined chemotherapy and radiotherapy in nonresectable non-small-cell lung cancer: first analysis of a randomized trial in 353 patients. J Natl Cancer Inst 1991 Mar 20;83(6):417-23 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/1847977.
  9. 9.0 9.1 Curran W, Scott C, Langer C et al,. Long-term benefits is observed in a phase III comparison of sequential v concurrent chemo-radiation for patients with unresectable stage III NSCLC. Proc Am Soc clin Oncol 2003;22: 621.
  10. 10.0 10.1 Furuse K, Fukuoka M, Kawahara M, Nishikawa H, Takada Y, Kudoh S, et al. Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine, and cisplatin in unresectable stage III non-small-cell lung cancer. J Clin Oncol 1999 Sep;17(9):2692-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/10561343.
  11. 11.0 11.1 Pierre F, Maurice P, Gilles R et al,. A randomised phase iii trial of sequential chemoradiotherapy versus concurrent chemoradiotherpay in locally advanced non-small cell lung cancer (NSCLC) (GLOT-GFPCNPC95-01. Proc Am Soc Clin Oncol 2001;20:312A.
  12. 12.0 12.1 Non-small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. BMJ 1995;311(7010):899-909 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/7580546.
  13. 13.0 13.1 Aupérin A, Le Péchoux C, Pignon JP, Koning C, Jeremic B, Clamon G, et al. Concomitant radio-chemotherapy based on platin compounds in patients with locally advanced non-small cell lung cancer (NSCLC): a meta-analysis of individual data from 1764 patients. Ann Oncol 2006 Mar;17(3):473-83 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16500915.
  14. 14.0 14.1 14.2 14.3 O'Rourke N, Roqué I Figuls M, Farré Bernadó N, Macbeth F. Concurrent chemoradiotherapy in non-small cell lung cancer. Cochrane Database Syst Rev 2010 Jun 16;(6):CD002140 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20556756.
  15. 15.0 15.1 15.2 Aupérin A, Le Péchoux C, Rolland E, Curran WJ, Furuse K, Fournel P, et al. Meta-analysis of concomitant versus sequential radiochemotherapy in locally advanced non-small-cell lung cancer. J Clin Oncol 2010 May 1;28(13):2181-90 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20351327.
  16. Atagi S, Kawahara M, Yokoyama A, Okamoto H, Yamamoto N, Ohe Y, et al. Thoracic radiotherapy with or without daily low-dose carboplatin in elderly patients with non-small-cell lung cancer: a randomised, controlled, phase 3 trial by the Japan Clinical Oncology Group (JCOG0301). Lancet Oncol 2012 Jul;13(7):671-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22622008.

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Appendices

Further resources

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