Stereotactic ablative radiotherapy (SABR) versus lobectomy for operable stage I NSCLC Julia Myers

Background Lung cancer has a higher mortality rate than the three most common cancers combined (colon, breast, pancreas)1 5 year survival is only 17.8%2 2 main subtypes: small-cell lung cancer (15%) and non-small-cell lung cancer (85%) NSCLC is further subdivided into adenocarcinoma , squamous cell carcinoma and large cell carcinoma.3

Treatment options Surgery: Preferred treatment for stage I & II NSCLC. Open vs. VATS and lobar vs. sublobar approaches +/- lymph node sampling or resection. Surgery may be combined with adjuvant chemotherapy.4,5

Treatment options Radiotherapy: Patients with localised disease who are not operative candidates Palliative care to improve QOL SABR for early stage disease without metastases – a coordinate system is used to map tumour location and place a tracking device. This allows precise delivery of highly concentrated beams of radiation to the tumour with minimal effect to surrounding tissues.

Methods Stereotactic ablative radiotherapy vs lobectomy for operable stage I NSCLC: a pooled analysis of two randomised trials. JY Chang et al. 2016

Study Design & Funding Published 2016. J Y Chang et al. Pooled analysis of 2 open label, phase 3, randomised trials comparing SABR with surgery for Stage I NSCLC STARS Funded by Accuray – no involvement in data collection/interpretation or report writing but specified use of Cyberknife radiotherapy platform. ROSEL Funded by Netherlands organisation for health research and development – no involvement in data collection/interpretation or report writing.

Eligibility Criteria STARS Histological confirmation of NSCLC Staging studies showing T1-2aN0M0 operable disease ROSEL New or growing pulmonary lesion with radiological features consistent with malignant disease and avidity of 18-F-FDG-PET.

Randomisation STARS Study coordinator and principal investigator made all decisions re. eligibility. 1:1 block randomisation (block sizes of 4) to SABR or surgery using the Merge randomisation system. Stratified by site, location (central/peripheral) and size (T1a,T1b,T2a) ROSEL Enrolled by pulmonologists via local tumour meetings 1:1 randomisation with TENALEA system to SABR or surgery. Stratified by institute, histology and WHO performance status.

Procedures Surgery: Acceptable techniques – lobectomy via open thoracotomy or video-assisted thoracotomy. All accessible hilar lymph nodes had to be dissected from the specimen and mediastinal lymph nodes had to be dissected and sampled.

Procedures Excluded lesions <2cm from hilar structures SABR STARS Used CyberKnife system only (condition specified by Accuray) Peripheral tumours (>2cm from hilar structures e.g.heart) received radiation dose of 54Gy in 3x 18Gy fractions. Central lesions received 50Gy in 4x 12.5Gy fractions. The dose was prescribed to cover 100% of the tumour volume & a 3mm margin Treatment was completed within 5 days ROSEL Used SABR from multiple vendors. Excluded lesions <2cm from hilar structures Doses used - 54Gy in 3x 18Gy fractions or 60 Gy in 5x 12Gy fractions The dose was prescribed to cover 95% of the planning target volume with a 3-5mm margin Treatment was completed over 5-8 days or 10-14 days depending on dosage

Study Endpoints Primary outcome measure = overall survival Secondary outcome measures included recurrence free survival, grade 3 or worse acute or chronic toxicity

Follow-up STARS Every 6 months for 2 years then annually with contrast enhanced CT or PET-CT of the chest and upper abdomen. Enrolment opened on 10/9/2009 and closed on 16/1/13. Last follow-up was on 14/7/14. ROSEL Every 3 months for the first year then every 6 months for the following 60 months with contrast enhanced CT. Enrolment opened on 7/10/08 and closed on 10/12/10. Last follow-up was on 16/04/14.

Statistical Analysis Analysis was based on the intention to treat population.It did not include power, sample size or sensitivity calculation. Overall survival was calculated from date of treatment to last contact date. Time to recurrence was calculated from date of treatment to first recurrence or last assessment date. P values <0.05 were classed as statistically significant Also calculated hazard ratios with 95% CIs with a Cox proportional hazards model.

Results

Treatment variations Surgery: (total 27) Radiotherapy: (total 31) Procedure Number Open lobectomy 19 VATS lobectomy 5 Video-assisted thoracotomy Bx 1 Open wedge resection Aborted resection Radiotherapy: (total 31) STARS ROSEL Peripheral (54Gy in 3 fractions) 16 54Gy in 3 fractions 6 Central (50Gy in 4 fractions) 4 60Gy in 5 fractions 5

Patient Demographics *In the ROSEL study 8 tumours in the SABR group had unknown histology and 6 in the surgical group were unknown but later histologically confirmed as 3 adenocarcinoma, 1 bronchoalveolar carcinoma, 1 squamous cell and 1 benign

Primary Outcome – Overall Survival Median follow-up 40.2 months (IQR 23.0-47.3) for SABR and 35.4 months (IQR18.9-40.7) for surgery

Secondary outcome – recurrence free survival

Secondary outcomes: Recurrence location

Secondary Outcomes: Adverse Events SABR 3 patients (10%) developed grade 3 toxicity: 3 chest wall pain (10%), 2 dyspnoea/cough(6%), fatigue(3%), rib fracture(3%) Surgery 1 patient (4%) died from surgical complications, 1 grade 4 dyspnoea (4 (15%) grade 3 dyspnoea, 2 (7%) grade 3 infection, 4 (15%) grade 3 chest pain. Also 1 case of grade 3 bleeding, fistula, hernia, weight loss, arrhythmia, anaemia, fatigue, nausea

Author’s Conclusion SABR could be an option for treatment of stage 1 operable NSCLC. SABR and lobectomy are at least equally effective as treatment options. SABR appears to be better tolerated and leads to better overall survival than surgery Low study numbers, therefore recommends further trials

Discussion Results suggest a significant improvement in overall survival with SABR vs surgery but no improvement in rates of recurrence Low study numbers Short follow-up period Differences between STARS and ROSEL trials e.g. SABR techniques used, eligibility criteria Further trials with larger study populations are needed to provide further evidence to support these claims

References American Cancer Society. Cancer Facts and Figures 2015. Available online: http://www.cancer.org/acs/groups/ content/@editorial/documents/document/acspc-044552.pdf National Cancer Institute. SEER Cancer Statistics Review, 1975-2011. Available online: http://seer.cancer.gov/ csr/1975_2011/ Kenfield SA, Wei EK, Stampfer MJ, et al. Comparison of aspects of smoking among the four histological types of lung cancer. Tob Control 2008;17:198-204. Howington JA, Blum MG, Chang AC, et al. Treatment of stage I and II non-small cell lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence- based clinical practice guidelines. Chest 2013;143:e278S-313S. Chemotherapy in non-small cell lung cancer: a meta- analysis using updated data on individual patients from 52 randomised clinical trials. Non-small Cell Lung Cancer Collaborative Group. BMJ 1995;311:899-909.