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

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

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.

A high incidence of cerebral failure is observed following radical treatment of locally advanced NSCLC. Between 13-54% of patients can be expected to develop cerebral metastases[1][2][3][4][5][6] with a median time to first brain relapse of between 6-12 months.[5][3][7][6] Brain metastases impair quality of life (QOL) and are associated with a poor prognosis.[8]

The risk of central nervous system (CNS) failure has been related to stage of disease, bulk of disease, histology, female gender, advanced age, age<60, age ≤ 50 years, preoperative chemotherapy, response to neoadjuvant therapy and serum lactate dehydrogenase.[9]

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Prophylactic cranial irradiation (PCI)

The aim of PCI is to eradicate undetectable cerebral micrometastases before they become clinically significant without inducing severe adverse effects.

Six randomised trials of PCI in patients with locally advanced NSCLC have been published.[10][11][12][13][14][15]

A Cochrane review was undertaken after four studies[10][11][12][13] had been published.[16] A meta-analysis could not be performed because of significant heterogeneity in patient selection, thoracic treatment and PCI dose. On systematic review, three studies showed a significant reduction in the cumulative incidence of brain metastases of between 50-90% but no trial reported a survival advantage of PCI over observation. However, these studies were conducted in an era of less aggressive locoregional and systemic therapy compared with current standard practice and thus the applicability of these results to current daily practice is uncertain.

Modern therapy regimens are associated with longer patient survival and an increased incidence of brain metastases.[3][6][17][7][18] The RTOG 0214 study was conducted to determine whether PCI improved overall survival in locally advanced NSCLC treated with modern multimodality therapy.[14] The study was designed to test whether PCI improved the one year overall survival rate at 12 months by 20% and required a sample size of 1058 patients. Patients with stage III NSCLC who completed definitive therapy without progression were randomly assigned to PCI or observation. The study closed early due to poor patient accrual with 356 patients randomised. The one year rates of brain metastases were significantly different (7.7% versus 18.0% for PCI versus observation, p=0.004) with patients in the observation arm 2.52 times more likely to develop brain metastases than those in the PCI arm (unadjusted odds ratio 2.52, 95% CI 1.32 to 4.80). However, there was no statistically significant difference in one year overall survival (75.6% versus 76.9% for PCI versus observation p=0.86) or one year disease free survival (56.4% versus 51.2% for PCI v observation, p=0.11). The study also examined the impact of PCI on neuro-cognitive function (assessed with Mini-mental status examination,MMSE; Activities of Daily Living Scale, ADLS; and Hopkins Verbal Learning Test, HVLT) and quality of life (assessed with the European organisation for Research and treatment of Cancer core tool, EORTC QOL Questionnaire-QLQC30 and brain module QLQBN20). At one year there were no statistically significant differences between the two arms in any component of the QLQC30 or QLQBN20 (p>0.05) or MMSE (p=0.60) and ADLS (p=0.88). However, at one year, patients in the PCI arm showed a greater decline in immediate recall (p=0.03) and delayed recall (p=0.008) as measured by the HVLT.[19]

A Chinese study randomised patients with fully resected Stage IIIA-N2 NSCLC who were deemed to be at high risk of cerebral metastases to receive PCI or observation. The trial was terminated early but the PCI group had a statistically significant improvement in disease free survival (median DFS 28.5m v 21.2m, HR0.67;95% CI 0.46-0.98;p=0.037) and a decreased risk of brain metastases (20.3% v 49.9%; HR0.28; 95%CI 0.14-0.57, p<0.001), with a median follow-up of 68 months. There was no improvement in overall survival.[15]

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Evidence summary and recommendations

Evidence summary Level References
In patients with locally advanced NSCLC, PCI significantly reduces the incidence of brain metastases.

Last reviewed December 2015

I, II [14], [16]
In patients with locally advanced NSCLC, PCI does not improve OS.

Last reviewed December 2015

I, II [14], [16]
PCI was associated with an improvement in DFS, in one study.

Last reviewed December 2015

II [15]
In patients with locally advanced NSCLC, prophylactic cranial irradiation results in a statistically significant reduction in immediate and delayed recall at one year as measured by the HVLT.

Last reviewed December 2015

II [19]
In patients with locally advanced NSCLC, prophylactic cranial irradiation does not cause a statistically significant reduction in QOL (as measured by the EORTC QLQC30 or QLQBN20 modules) or neurocognitive function (as measured by MMSE or ADLS) at one year.

Last reviewed December 2015

II [19]
Evidence-based recommendationQuestion mark transparent.png Grade
In patients with stage III NSCLC, the use of prophylactic cranial irradiation is not recommended.

Last reviewed December 2015

B


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References

  1. Albain KS, Rusch VW, Crowley JJ, Rice TW, Turrisi AT 3rd, Weick JK, et al. Concurrent cisplatin/etoposide plus chest radiotherapy followed by surgery for stages IIIA (N2) and IIIB non-small-cell lung cancer: mature results of Southwest Oncology Group phase II study 8805. J Clin Oncol 1995 Aug;13(8):1880-92 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/7636530.
  2. Stuschke M, Eberhardt W, Pöttgen C, Stamatis G, Wilke H, Stüben G, et al. Prophylactic cranial irradiation in locally advanced non-small-cell lung cancer after multimodality treatment: long-term follow-up and investigations of late neuropsychologic effects. J Clin Oncol 1999 Sep;17(9):2700-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/10561344.
  3. 3.0 3.1 3.2 Law A, Karp DD, Dipetrillo T, Daly BT. Emergence of increased cerebral metastasis after high-dose preoperative radiotherapy with chemotherapy in patients with locally advanced nonsmall cell lung carcinoma. Cancer 2001 Jul 1;92(1):160-4 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/11443622.
  4. Andre F, Grunenwald D, Pujol JL, Girard P, Dujon A, Brouchet L, et al. Patterns of relapse of N2 nonsmall-cell lung carcinoma patients treated with preoperative chemotherapy: should prophylactic cranial irradiation be reconsidered? Cancer 2001 Jun 15;91(12):2394-400 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/11413530.
  5. 5.0 5.1 Robnett TJ, Machtay M, Stevenson JP, Algazy KM, Hahn SM. Factors affecting the risk of brain metastases after definitive chemoradiation for locally advanced non-small-cell lung carcinoma. J Clin Oncol 2001 Mar 1;19(5):1344-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/11230477.
  6. 6.0 6.1 6.2 Carolan H, Sun AY, Bezjak A, Yi QL, Payne D, Kane G, et al. Does the incidence and outcome of brain metastases in locally advanced non-small cell lung cancer justify prophylactic cranial irradiation or early detection? Lung Cancer 2005 Jul;49(1):109-15 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15949596.
  7. 7.0 7.1 Ceresoli GL, Reni M, Chiesa G, Carretta A, Schipani S, Passoni P, et al. Brain metastases in locally advanced nonsmall cell lung carcinoma after multimodality treatment: risk factors analysis. Cancer 2002 Aug 1;95(3):605-12 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/12209754.
  8. Nussbaum ES, Djalilian HR, Cho KH, Hall WA. Brain metastases. Histology, multiplicity, surgery, and survival. Cancer 1996 Oct 15;78(8):1781-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/8859192.
  9. Gore E. Prophylactic cranial irradiation versus observation in stage III non-small-cell lung cancer. Clin Lung Cancer 2006 Jan;7(4):276-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16512983.
  10. 10.0 10.1 Cox JD, Stanley K, Petrovich Z, Paig C, Yesner R. Cranial irradiation in cancer of the lung of all cell types. JAMA 1981 Feb 6;245(5):469-72 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/7452872.
  11. 11.0 11.1 Russell AH, Pajak TE, Selim HM, Paradelo JC, Murray K, Bansal P, et al. Prophylactic cranial irradiation for lung cancer patients at high risk for development of cerebral metastasis: results of a prospective randomized trial conducted by the Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 1991 Aug;21(3):637-43 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/1651304.
  12. 12.0 12.1 Umsawasdi T, Valdivieso M, Chen TT, Barkley HT Jr, Booser DJ, Chiuten DF, et al. Role of elective brain irradiation during combined chemoradiotherapy for limited disease non-small cell lung cancer. J Neurooncol 1984;2(3):253-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/6389779.
  13. 13.0 13.1 Miller T, Crowley J, Mira J, Schwartz J, Hutchins L, Baker L, et al. A randomised trial of chemotherapy and radiotherapy for stage III non-small cell lung cancer. Cancer Therapeutics 1998;1(4):229-236.
  14. 14.0 14.1 14.2 14.3 Gore EM, Bae K, Wong SJ, Sun A, Bonner JA, Schild SE, et al. Phase III comparison of prophylactic cranial irradiation versus observation in patients with locally advanced non-small-cell lung cancer: primary analysis of radiation therapy oncology group study RTOG 0214. J Clin Oncol 2011 Jan 20;29(3):272-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21135270.
  15. 15.0 15.1 15.2 Li N, Zeng ZF, Wang SY, Ou W, Ye X, Li J, et al. Randomized phase III trial of prophylactic cranial irradiation versus observation in patients with fully resected stage IIIA-N2 non-small-cell lung cancer and high risk of cerebral metastases after adjuvant chemotherapy. Ann Oncol 2014 Dec 15 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25515658.
  16. 16.0 16.1 16.2 Patel N, Lester JF, Coles B, Macbeth FR. Prophylactic cranial irradiation for preventing brain metastases in patients undergoing radical treatment for non-small cell lung cancer. Cochrane Database Syst Rev 2005 Apr 18;(2):CD005221 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15846743.
  17. Chen AM, Jahan TM, Jablons DM, Garcia J, Larson DA. Risk of cerebral metastases and neurological death after pathological complete response to neoadjuvant therapy for locally advanced nonsmall-cell lung cancer: clinical implications for the subsequent management of the brain. Cancer 2007 Apr 15;109(8):1668-75 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17342770.
  18. Mamon HJ, Yeap BY, Jänne PA, Reblando J, Shrager S, Jaklitsch MT, et al. High risk of brain metastases in surgically staged IIIA non-small-cell lung cancer patients treated with surgery, chemotherapy, and radiation. J Clin Oncol 2005 Mar 1;23(7):1530-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15735128.
  19. 19.0 19.1 19.2 Sun A, Bae K, Gore EM, Movsas B, Wong SJ, Meyers CA, et al. Phase III trial of prophylactic cranial irradiation compared with observation in patients with locally advanced non-small-cell lung cancer: neurocognitive and quality-of-life analysis. J Clin Oncol 2011 Jan 20;29(3):279-86 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21135267.

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Appendices

Further resources

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