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

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

Background

In patients who have inoperable stage I non-small cell lung cancer, high dose radiotherapy is a curative treatment option.

There is indirect evidence, derived from the CHART randomised trial, that by improving local control, radiotherapy improves survival in inoperable NSCLC. The CHART trial compared hyperfractionated radiotherapy (three fractions per day to a total of 54 Gy) given over 12 days (CHART) with conventional radiotherapy given daily over six weeks to a total of 60 Gy in patients with inoperable NSCLC who had performance status of WHO 0 or 1.[1] The trial was open to patients with stages I-III; 30% were stage I. The trial demonstrated a survival advantage for patients randomised to CHART; there was no evidence that CHART was more or less effective according to stage. The survival benefit appeared to be in part a result of superior local control.

Other strategies to improve local control, and therefore survival, include concomitant chemotherapy and radiotherapy or dose escalation, either using conventional fractionation, or more recently with hypofractionated SABR. A randomised phase 3 trial of conventional radiotherapy (55 Gy in 20 fractions) with and without concomitant gemcitabine in patients with stage I and II NSCLC was closed early because of slow accrual.[2] There were no differences in survival between arms but significantly more adverse events in patients randomised to gemcitabine.

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Optimal radiotherapy prescription for inoperable stage I NSCLC

In the absence of comparative studies in populations with stage I NSCLC, recommendations for optimal dose and fractionation for this group of patients must rely to some extent on extrapolation of findings from trials conducted in populations with locally advanced disease alone or combined with patients with early stage disease. In this regard, the RTOG 73-01 trial which established 60 Gy in 30 fractions as the standard of care compared with lower doses for stage III disease has not been superseded.[3]

The CHART study compared a shortened 12 day treatment schedule to a total of 54 Gy (CHART) with conventional fractionation over 42 day to a total of 60 Gy.[1] The treatment was accelerated in the CHART arm by giving the radiotherapy three times per day. Patients randomised to CHART had longer survival with a 22% reduction in risk of death (P = 0.008) and three year survival 20% vs 13%. The benefit appeared to be confined to patients with squamous cell carcinoma, but there was no difference in benefit according to stage. The CHARTWEL study compared a modification of CHART (no treatment on weekends) in which 60 Gy was given in 18 days compared with conventional fractionation, 66 Gy given in 6.5 weeks.[4] Ten percent of patients randomised had stage I disease. This study did not show a difference in survival between arms, either in the group as a whole, or within the stage I subset. Although shortening overall treatment time may improve local control and survival, the complexities of delivering treatment three times a day limit the applicability of the CHART findings in the Australian setting. A more convenient method of accelerating radiotherapy by giving larger doses per fraction once a day over three weeks was investigated in a Canadian phase II trial NCIC BR.25.[5] The schedule under investigation (60 Gy in 15 fractions) resulted in a primary tumour control rate of 87% at 2 years without excessive toxicity in patients with peripheral stage I NSCLC. Although promising, direct comparison with more widely used schedules is lacking.

There are no randomised studies directly comparing the effect of increased radiation dose or hypofractionated SABR versus conventional dose/fractionation on survival specifically in stage I NSCLC. SABR is being used increasingly for the treatment of stage I NSCLC, based on a number of phase 2 studies reporting local control rates at two years in excess of 90% (e.g. Timmerman 2006, Timmerman 2010).[6][7] However, fatal toxicity has been reported following SABR, particularly for centrally located and larger tumours.[6] As a result, only peripheral tumours 5 cm or less in diameter were included in the RTOG 0236 phase II trial of SABR for NSCLC.[7]

In a retrospective study using the North American Surveillance, Epidemiology and End Results (SEER) database, the outcomes in 124 propensity-matched pairs of patients having SABR or conventional radiotherapy were compared.[8] Survival favoured the SABR patients, with an HR = 1.97 (95% C. I. 1.31-2.96, P = 0.001). A small retrospective single institution study revealed no differences in primary tumour control and survival between patients treated with conventional fractionation or SABR.[9] It seems reasonable to conclude, based on the limited low level evidence, that SABR is not inferior to conventionally fractionated radiotherapy, but more convenient for the patient and less demanding of resources. A systematic review of SABR concluded that there is a “need for more robust studies to define the optimum technical means of radiation delivery and dose fractionation parameters”.[10]

In the case of SABR, there is little evidence to recommend one dose fraction schedule over another. NRG Oncology’s RTOG 0915 was a randomised phase II trial comparing a single dose of 34 Gy with 48 Gy in 4 fractions in stage I NSCLC.[11] The intent was to determine which regimen resulted in the lower rate of adverse events without a reduction in local primary tumour control. There was no significant difference between treatments in adverse events, and primary control at one year was 97% for the single dose and 93% for the four fractions. The authors concluded that the single dose was worthy of further investigation.

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Evidence summary and recommendations

Evidence summary Level References
In patients with inoperable stage I NSCLC, improved local control following high dose radiotherapy is associated with a survival benefit.

Last reviewed November 2015

II [1]
Evidence-based recommendationQuestion mark transparent.png 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


Evidence summary Level References
A dose of 60 Gy in 30 fractions is associated with improved local control and survival compared with lower doses given by daily 2 Gy fractions.

Last reviewed November 2015

II [3]
Shortening overall radiotherapy treatment time may improve local control and survival.

Last reviewed November 2015

II [1], [4]
Evidence-based recommendationQuestion mark transparent.png Grade
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


Practice pointQuestion mark transparent.png

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

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References

  1. 1.0 1.1 1.2 1.3 Saunders M, Dische S, Barrett A, Harvey A, Griffiths G, Palmar M. Continuous, hyperfractionated, accelerated radiotherapy (CHART) versus conventional radiotherapy in non-small cell lung cancer: mature data from the randomised multicentre trial. CHART Steering committee. Radiother Oncol 1999 Aug;52(2):137-48 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/10577699.
  2. Price A, Yellowlees A, Keerie C, Russell S, Faivre-Finn C, Gilligan D, et al. Radical radiotherapy with or without gemcitabine in patients with early stage medically inoperable non-small cell lung cancer. Lung Cancer 2012 Sep;77(3):532-6 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22672970.
  3. 3.0 3.1 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.
  4. 4.0 4.1 Baumann M, Herrmann T, Koch R, Matthiessen W, Appold S, Wahlers B, et al. Final results of the randomized phase III CHARTWEL-trial (ARO 97-1) comparing hyperfractionated-accelerated versus conventionally fractionated radiotherapy in non-small cell lung cancer (NSCLC). Radiother Oncol 2011 Jul;100(1):76-85 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21757247.
  5. Cheung P, Faria S, Ahmed S, Chabot P, Greenland J, Kurien E, et al. Phase II study of accelerated hypofractionated three-dimensional conformal radiotherapy for stage T1-3 N0 M0 non-small cell lung cancer: NCIC CTG BR.25. J Natl Cancer Inst 2014 Aug;106(8) Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25074417.
  6. 6.0 6.1 Timmerman R, McGarry R, Yiannoutsos C, Papiez L, Tudor K, DeLuca J, et al. Excessive toxicity when treating central tumors in a phase II study of stereotactic body radiation therapy for medically inoperable early-stage lung cancer. J Clin Oncol 2006 Oct 20;24(30):4833-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17050868.
  7. 7.0 7.1 Timmerman R, Paulus R, Galvin J, Michalski J, Straube W, Bradley J, et al. Stereotactic body radiation therapy for inoperable early stage lung cancer. JAMA 2010 Mar 17;303(11):1070-6 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20233825.
  8. Shirvani SM, Jiang J, Chang JY, Welsh JW, Gomez DR, Swisher S, et al. Comparative effectiveness of 5 treatment strategies for early-stage non-small cell lung cancer in the elderly. Int J Radiat Oncol Biol Phys 2012 Dec 1;84(5):1060-70 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22975611.
  9. Safi S, Rauch G, Op den Winkel J, Kunz J, Schneider T, Bischof M, et al. Sublobar Resection, Radiofrequency Ablation or Radiotherapy in Stage I Non-Small Cell Lung Cancer. Respiration 2015;89(6):550-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25968471.
  10. Brock J, Ashley S, Bedford J, Nioutsikou E, Partridge M, Brada M. Review of hypofractionated small volume radiotherapy for early-stage non-small cell lung cancer. Clin Oncol (R Coll Radiol) 2008 Nov;20(9):666-76 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18676130.
  11. Videtic GM, Hu C, Singh AK, Chang JY, Parker W, Olivier KR, et al. A Randomized Phase 2 Study Comparing 2 Stereotactic Body Radiation Therapy Schedules for Medically Inoperable Patients With Stage I Peripheral Non-Small Cell Lung Cancer: NRG Oncology RTOG 0915 (NCCTG N0927). Int J Radiat Oncol Biol Phys 2015 Nov 15;93(4):757-64 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/26530743.

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Appendices

Further resources

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