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

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

Introduction

An ECOG-led intergroup trial established 45Gy in 30 twice-daily fractions over three weeks as superior to the same dose administered in 25 daily fractions over five weeks.[1] This trial has been criticised for employing too low a dose in the standard arm and thus two ongoing intergroup trials are comparing 66-70Gy of daily radiotherapy to the 45Gy hyperfractionated schedule (CALGB 30610/RTOG 0538 and CONVERT). A further Norwegian Lung Cancer Group phase II trial is comparing 45Gy/30Fr to 60Gy/40fr both using twice daily radiotherapy.

The North Central Cancer Treatment Group (NCCTG) compared a higher dose of daily radiotherapy (54Gy) to a hyperfractionated regimen.[2] Mature results demonstrated no survival difference between the two regimens.[3] However, the hyperfractionated regimen incorporated a two-week break which may have reduced its efficacy.

Meta-analyses have confirmed a benefit to the prompt completion of thoracic radiotherapy.[4][5] A short overall treatment time is thus important for SCLC. Accelerated hyperfractionation is a proven strategy to achieve this.[1] Hypofractionation may be an alternative approach but high-level evidence comparing this strategy to others is presently lacking. High quality survival and toxicity data for this approach do exist however.[6][7][8] A phase two trial comparing 45Gy/30Fr twice-daily radiotherapy to 42Gy/15Fr once-daily radiotherapy showed significantly higher complete response rates for the hyperfractionated regimen while toxicity was not significantly different.[8] Although survival was 6.3 months longer in the hyperfractionated arm, the trial was not powered to show a survival difference. Total radiation dose also appears to be important with higher doses associated with improved survival.[9][10]

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Evidence summary and recommendations

Evidence summary Level References
Accelerated, hyperfractionated radiotherapy to 45Gy in 30 twice-daily fractions over three weeks is a current standard.

Last reviewed December 2015

II [1]
The accelerated hyperfractionated approach has not yet been compared to a maximally tolerated dose of daily radiotherapy.

Last reviewed December 2015

II [1], [3]
The prompt completion of thoracic radiotherapy is associated with improved survival.

Last reviewed December 2015

I [4], [5]
Evidence-based recommendationQuestion mark transparent.png 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 December 2015

B



Practice pointQuestion mark transparent.png

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 December 2015


Practice pointQuestion mark transparent.png

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 December 2015

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References

  1. 1.0 1.1 1.2 1.3 Turrisi AT 3rd, Kim K, Blum R, Sause WT, Livingston RB, Komaki R, et al. Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med 1999 Jan 28;340(4):265-71 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/9920950.
  2. Bonner JA, Sloan JA, Shanahan TG, Brooks BJ, Marks RS, Krook JE, et al. Phase III comparison of twice-daily split-course irradiation versus once-daily irradiation for patients with limited stage small-cell lung carcinoma. J Clin Oncol 1999 Sep;17(9):2681-91 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/10561342.
  3. 3.0 3.1 Schild SE, Bonner JA, Shanahan TG, Brooks BJ, Marks RS, Geyer SM, et al. Long-term results of a phase III trial comparing once-daily radiotherapy with twice-daily radiotherapy in limited-stage small-cell lung cancer. Int J Radiat Oncol Biol Phys 2004 Jul 15;59(4):943-51 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15234027.
  4. 4.0 4.1 Pijls-Johannesma M, De Ruysscher D, Vansteenkiste J, Kester A, Rutten I, Lambin P. Timing of chest radiotherapy in patients with limited stage small cell lung cancer: a systematic review and meta-analysis of randomised controlled trials. Cancer Treat Rev 2007 Aug;33(5):461-73 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17513057.
  5. 5.0 5.1 De Ruysscher D, Pijls-Johannesma M, Bentzen SM, Minken A, Wanders R, Lutgens L, et al. Time between the first day of chemotherapy and the last day of chest radiation is the most important predictor of survival in limited-disease small-cell lung cancer. J Clin Oncol 2006 Mar 1;24(7):1057-63 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16505424.
  6. Murray N, Coy P, Pater JL, Hodson I, Arnold A, Zee BC, et al. Importance of timing for thoracic irradiation in the combined modality treatment of limited-stage small-cell lung cancer. The National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 1993 Feb;11(2):336-44 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/8381164.
  7. Spiro SG, James LE, Rudd RM, Trask CW, Tobias JS, Snee M, et al. Early compared with late radiotherapy in combined modality treatment for limited disease small-cell lung cancer: a London Lung Cancer Group multicenter randomized clinical trial and meta-analysis. J Clin Oncol 2006 Aug 20;24(24):3823-30 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16921033.
  8. 8.0 8.1 Grønberg BH, Halvorsen TO, Fløtten Ø, Brustugun OT, Brunsvig PF, Aasebø U, et al. Randomized phase II trial comparing twice daily hyperfractionated with once daily hypofractionated thoracic radiotherapy in limited disease small cell lung cancer. Acta Oncol 2015 Oct 23;:1-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/26494411.
  9. Schild SE, Bonner JA, Hillman S, Kozelsky TF, Vigliotti AP, Marks RS, et al. Results of a phase II study of high-dose thoracic radiation therapy with concurrent cisplatin and etoposide in limited-stage small-cell lung cancer (NCCTG 95-20-53). J Clin Oncol 2007 Jul 20;25(21):3124-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17634491.
  10. Tomita N, Kodaira T, Hida T, Tachibana H, Nakamura T, Nakahara R, et al. The impact of radiation dose and fractionation on outcomes for limited-stage small-cell lung cancer. Int J Radiat Oncol Biol Phys 2010 Mar 15;76(4):1121-6 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19665321.

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Appendices

Further resources

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