Lung cancer, Lobectomy, Stereotactic body radiation therapy, Thoracic surgery, Quality care, Outcomes, Cancer treatment, Patient selection
Lung cancer remains the leading cause of cancer related death in the United States with mortality rates surpassing breast, prostate, brain, and colorectal cancers combined [1,2]. Recent data shows that susceptibility for both men and women for developing invasive lung and bronchogenic carcinoma peak after the age of 70 years . As the generation of baby boomers age, those older than 65 years will nearly double and the number of elderly population older than 85 years will triple from 2020 to 2050 . These shifting demographics are an early sign of the improvements and advancements in overall care of the elderly population. It therefore remains imperative that lung cancer treatment and selection criteria evolves accordingly in elderly and high-risk population. Some of the challenges facing the elderly and high-risk population relates to comorbidities, limited cardiac and pulmonary function reserve, decreased decision-making capacity, quality of life issues and lack of social support among others [4,5].
Currently, the standard of care for early-stage non-small cell lung cancer (NSCLC) includes an anatomic pulmonary resection with sampling or dissection of mediastinal and hilar lymph nodes amongst appropriate surgical candidates . However, the use of Stereotactic Body Radiotherapy (SBRT), or Stereotactic Ablative Radiotherapy (SAbR), has been increasing over time and has surpassed lobectomy for treatment of Stage I NSCLC in octogenarians . At the same time, researchers in the Netherlands saw a dramatic increase in SBRT in just 9 years from 26% to 42% of patients 75 years or older receiving SBRT for Stage 1 NSCLC .
SBRT greatly impacted the capability of offering definitive ablative treatment for early-stage NSCLC in high-risk patients . With its arrival, patients who refused surgery or were medically inoperable with early-stage NSCLC were given a definitive alternate treatment therapy that had a low toxicity profile and could be conducted in a relatively short amount of time . Given the success of SBRT in early-stage lung cancer amongst populations unfit for surgery, its utility in high-risk populations has been investigated in various trials, but early studies struggled to enroll patients .
In a meta-analysis by Cao et al., when compared to SBRT in patients with early-stage NSCLC, both lobectomy and sublobar resection were associated with better overall survival (OR 1.71 95% CI: 1.52-1.93 p<0.001) . Importantly, periprocedural mortality was 0% in SBRT and as high as 8% in those undergoing surgery . It is important to note that those receiving SBRT disproportionately comprised of patients who were not good surgical candidates or refused surgery, so conclusions regarding differences between lobectomy vs SBRT amongst true surgical candidates cannot be made from this analysis . Of note, patients undergoing surgery frequently reported more severe postoperative morbidities including pneumonia, pulmonary embolism, or myocardial infraction compared to less severe complications such as fatigue and chest pain seen in SBRT patients . Surgery carries a perioperative risk for patients, both in mortality and in major morbidity, that was and is still not seen in SBRT. When compared to the perioperative risks associated with surgery, the relative low toxicity profile and overall better tolerance of SBRT makes this an attractive option for elderly and high-risk populations.
Gulack et al. set out to establish an objective risk classification to aid in determining the appropriate selection of operative technique for resection of earlystage NSCLC . Using the American College of Surgeons National Surgical Quality Improvement Program database, the authors determined that a risk score >5 conferred a statistically higher perioperative mortality rate in patients receiving lobectomy (4.9%) vs segmentectomy (3.6%) or wedge resection (0.8%, p<0.01) . Among patient characteristics used for the calculation of the risk score, patients >80 years of age and patients 65-80 years of age automatically received scores of 5 and 3 respectively . Additionally, dependent functional status was also weighed at a 3 and favored mortality only second to age >80 years . This is critical in understanding the necessity in choosing appropriate surgical candidates, since age alone did not confer an increase in perioperative mortality. For all patients >80 years of age, just one more risk characteristic, such as COPD or smoking within the last year, pushes them over the threshold that raises their perioperative mortality. Additionally, a 65-year-old patient with a dependent functional status would also surpass the threshold leaving patients at an increased risk of perioperative mortality after lobectomy. Further assessments of the Society of Thoracic Surgeons General Thoracic Surgery Database determined Zubrod score, and American Society of Anesthesiologists score to consistently confer the highest likelihoods of major morbidity or mortality after lung cancer resection .
In early 2016, four prospective randomized trials were reported to compare outcomes in operable stage I NSCLC undergoing SBRT vs surgical resection (Table 1) . Of those, a trial in the United Kingdom, SABRTooth, was abandoned after a feasibility study showed difficulty recruiting patients into the surgery group . VALOR, the Veterans Affairs Lung cancer surgery or stereotactic Radiotherapy, was the next referenced listed and is currently in the recruitment phase and most recent updates predict a completion date of September 2027 . The POSTLIV trial is currently active, however it is no longer recruiting patients and lists a total of 44 patients enrolled with a completion date estimated at the beginning of 2026 . Lastly, most recent updates posted for STABLEMATES poses a glimmer of hope with patient recruitment still occurring and an enrollment of 272 patients so far . The ROSEL and STAR trials would go on to combine their study populations for a total of 58 patients. With the authors themselves citing insufficient follow-up and small sample size, this analysis offers the only literature depicting favorable outcomes of SBRT vs surgery in randomized patients deemed surgical candidates with Stage I NSCLC . Overall, 3-year survival was 95% (95% CI 85-100) in the SAbR group and 79% (95% CI 64-97%) in the surgery group proving to be statistically significant (log-rank p=0.037, HR 0.14 95% CI 0.017-1.190) .
|Study (Clinical Trial Number)||Status||Treatment Arms||Description|
|STARS (NCT00840749)||Closed||CyberKnife vs Lobectomy||Abandoned after poor recruitment|
|ROSEL (NCT00687986)||Closed||SBRT vs Lobectomy||Abandoned after poor recruitment|
|ACOSOG Z4099/RTOG 1021 (NCT01336894)||Closed||SAbR vs Sublobar Resection||Abandoned after poor recruitment|
|SABRTooth (NCT02629458)||Closed||SAbR vs Surgery||Abandoned after a feasibility study showed large proportions of those randomized to the surgery arm refused and chose SABR|
|VALOR (NCT02984761)||Open||SBRT vs Surgery||Randomized trial with the primary aim of measuring overall survival up to 10 years. Estimated recruitment is to include 670 participants with an estimated completion by September 2027|
|POSTLIV (NCT01753414)||Open||SBRT vs Surgery||Small phase II trial aimed at measuring efficacy of
local-regional control of T1N0 NSCLC
|STABLE-MATES (NCT02468024)||Open||SAbR vs Sublobar Resection||Randomized trial comparing overall survival in high- risk operable Stage I NSCLC after treatment with either SAbR or Sublobar Resection|
Table 1: Ongoing and previous randomized trials comparing SBRT and surgical resection.
So where have we arrived? There is evidence showing that surgery is inherently risky, and that risk only increases with age and those with poor functional status [11-13,19,20]. Yet, four recent meta-analysis have shown surgical resection for early-stage NSCLC to have superior overall survival than SBRT [11,21-23]. The superior merit of surgery lies in the capability of establishing true pathological staging by virtue of adequate lymph node dissection and negative margins. Consequently, accurate tumor staging affords patients the opportunity for systemic treatment when unsuspected micrometastatic disease is found in the lymph nodes. Additional factors that may continue to improve postoperative outcomes and overall survival after lung cancer surgery includes, but not limiting to, appropriate patient selection after risk stratification, adaptation of minimally invasive techniques, high volume centers and centers of excellence and Enhanced Recovery After Surgery (ERAS) protocols [24-27].
Other trials have come into the fold, providing a glimpse of innovative ways to enhance the potential effectiveness of SBRT. RAXSIA is currently underway in Canada with the primary aim to compare disease free 5-year survival between SBRT and surgery in patients with T1a or T1b NSCLC . Over the last few years, innovations in immunotherapies have shown promise within the realm of cancer therapy. Recently, trials have been developed to combine immunotherapies such as atezolizumab and durvalumab with SBRT for NSCLC [29,30]. If these treatment combinations are proven effective, we could see expansion of these trials to include patients with early-stage NSCLC that might otherwise undergo surgical resection.
In conclusion, surgery remains the standard of care for early-stage lung cancer while SBRT provides a viable treatment alternative for patients who are not suitable candidates for surgery. It therefore remains imperative that thoracic surgeons carefully evaluate and select patients with potentially curable lung cancer, especially when alternate treatment options such as SBRT are being considered.
Conflicts of Interest
The authors have no conflicts of interest to disclose.
This research did not receive any specific grant from funding agencies in the public, commercial, or not-forprofit sectors.
All authors are responsible for the conception of the idea behind this work, writing of this work, and critical review of this work.
2. Siegel RL, Miller KD, Goding Sauer A, Fedewa SA, Butterly LF, Anderson JC, et al. Colorectal cancer statistics, 2020. CA: A Cancer Journal for Clinicians. 2020 May;70(3):145-64.
3. Vincent GK. The next four decades: The older population in the United States: 2010 to 2050. US Department of Commerce, Economics and Statistics Administration, US Census Bureau; 2010;25–1138.
4. Shinde A, Li R, Kim J, Salgia R, Hurria A, Amini A. Stereotactic body radiation therapy (SBRT) for early-stage lung cancer in the elderly. InSeminars in Oncology 2018 Aug 1 (Vol. 45, No. 4, pp. 210-219)
5. Islam KM, Anggondowati T, Deviany PE, Ryan JE, Fetrick A, Bagenda D, et al. Patient preferences of chemotherapy treatment options and tolerance of chemotherapy side effects in advanced stage lung cancer. BMC Cancer. 2019 Dec;19(1):835.
6. Nccn.org [cited 2021 Apr 8]. Available from: https:// www.nccn.org/professionals/physician_gls/pdf/nscl.pdf
7. Razi SS, Kodia K, Alnajar A, Block MI, Tarrazzi F, Nguyen D, et al. Lobectomy Versus Stereotactic Body Radiotherapy in Healthy Octogenarians with Stage I Lung Cancer. The Annals of Thoracic Surgery. 2021 May 1;111(5):1659-65.
8. Palma D, Visser O, Lagerwaard FJ, Belderbos J, Slotman BJ, Senan S. Impact of introducing stereotactic lung radiotherapy for elderly patients with stage I non–smallcell lung cancer: a population-based time-trend analysis. Journal of Clinical Oncology. 2010 Dec 10;28(35):5153-9.
9. Timmerman RD, Herman J, Cho LC. Emergence of stereotactic body radiation therapy and its impact on current and future clinical practice. Journal of Clinical Oncology. 2014 Sep 10;32(26):2847.
10. Maquilan G, Timmerman R. Stereotactic body radiation therapy for early-stage lung cancer. The Cancer Journal. 2016 Jul 1;22(4):274-9.
11. Cao C, Rimner A, Huang J, Jones D. P1. 16-20 A Systematic Review and Meta-Analysis of Stereotactic Body Radiation Therapy Versus Surgery for Patients with Non- Small Cell Lung Cancer. Journal of Thoracic Oncology. 2018 Oct 1;13(10):S634-5.
12. Gulack BC, Yang CF, Speicher PJ, Yerokun BA, Tong BC, Onaitis MW, et al. A risk score to assist selecting lobectomy versus sublobar resection for early-stage nonsmall cell lung cancer. The Annals of Thoracic Surgery. 2016 Dec 1;102(6):1814-20.
13. Kozower BD, Sheng S, O’Brien SM, Liptay MJ, Lau CL, Jones DR, et al. STS database risk models: predictors of mortality and major morbidity for lung cancer resection. The Annals of Thoracic Surgery. 2010 Sep 1;90(3):875-83.
14. Franks KN, McParland L, Webster J, Baldwin DR, Sebag-Montefiore D, Evison M, et al. SABRTooth: a randomised controlled feasibility study of stereotactic ablative radiotherapy (SABR) with surgery in patients with peripheral stage I nonsmall cell lung cancer considered to be at higher risk of complications from surgical resection. European Respiratory Journal. 2020 Nov 1;56(5):2000118.
15. Veterans Affairs Lung Cancer Surgery or Stereotactic Radiotherapy - Full Text View - ClinicalTrials. Gov [Internet]. [cited 2021 Apr 8]. Available from: https:// clinicaltrials.gov/ct2/show/NCT02984761
16. Radical resection vs. Ablative Stereotactic Radiotherapy in Patients With Operable Stage I NSCLC - Full Text View - ClinicalTrials.Gov [Internet]. [cited 2021 Apr 8]. Available from: https://clinicaltrials.gov/ct2/ show/NCT01753414
17. JoLT-Ca Sublobar Resection (SR) Versus Stereotactic Ablative Radiotherapy (SAbR) for Lung Cancer - Full Text View - ClinicalTrials.Gov [Internet]. [cited 2021 Apr 8]. Available from: https://clinicaltrials.gov/ct2/show/ NCT02468024
18. Chang JY, Senan S, Paul MA, Mehran RJ, Louie AV, Balter P, et al. Stereotactic ablative radiotherapy versus lobectomy for operable stage I non-small-cell lung cancer: a pooled analysis of two randomised trials. The Lancet Oncology. 2015 Jun 1;16(6):630-7.
19. Naito T, Mitsunaga S, Miura S, Tatematsu N, Inano T, Mouri T, et al. Feasibility of early multimodal interventions for elderly patients with advanced pancreatic and nonsmall- cell lung cancer. Journal of Cachexia, Sarcopenia and Muscle. 2019 Feb;10(1):73-83.
20. Leduc C, Antoni D, Charloux A, Falcoz PE, Quoix E. Comorbidities in the management of patients with lung cancer. European Respiratory Journal. 2017 Mar 1;49(3):1601721.
21. Wang HH, Zhang CZ, Zhang BL, Chen J, Zeng XL, Deng L, et al. Sublobar resection is associated with improved outcomes over radiotherapy in the management of high-risk elderly patients with Stage I non-small cell lung cancer: a systematic review and meta-analysis. Oncotarget. 2017 Jan 24;8(4):6033-42.
22. Zhang B, Zhu F, Ma X, Tian Y, Cao D, Luo S, et al. Matched-pair comparisons of stereotactic body radiotherapy (SBRT) versus surgery for the treatment of early-stage non-small cell lung cancer: a systematic review and meta-analysis. Radiotherapy and Oncology. 2014 Aug 1;112(2):250-5.
23. Li M, Yang X, Chen Y, Yang X, Dai X, Sun F, et al. Stereotactic body radiotherapy or stereotactic ablative radiotherapy versus surgery for patients with T1-3N0M0 non-small cell lung cancer: a systematic review and metaanalysis. OncoTargets and Therapy. 2017; 10:2885-92.
24. Sarkaria IS, Gorrepati ML, Mehendale S, Oh DS. Lobectomy in octogenarians: real world outcomes for robotic-assisted, video-assisted thoracoscopic, and open approaches. Journal of Thoracic Disease. 2019 Jun;11(6):2420-30.
25. Osarogiagbon RU, Ogbata O, Yu X. Number of lymph nodes associated with maximal reduction of long-term mortality risk in pathologic node-negative non–small cell lung cancer. The Annals of Thoracic Surgery. 2014 Feb 1;97(2):385-93.
26. Jonnalagadda S, Smith C, Mhango G, Wisnivesky JP. The number of lymph node metastases as a prognostic factor in patients with N1 non-small cell lung cancer. Chest. 2011 Aug 1;140(2):433-40.
27. Chi A, Fang W, Sun Y, Wen S. Comparison of Long-term Survival of Patients with Early-Stage Non–Small Cell Lung Cancer After Surgery vs Stereotactic Body Radiotherapy. JAMA network open. 2019 Nov 1;2(11):e1915724.
28. Surgery Versus Stereotactic Body Radiation Therapy for Stage up to IA2 (T1a or T1b) Non-small Cell Lung Cancer - Full Text View - ClinicalTrials.Gov [Internet]. [cited 2021 Apr 11]. Available from: https:// clinicaltrials.gov/ct2/show/NCT03431415?term=SBRT+ Surgery&cond=Lung+Cancer&draw=2
29. Atezolizumab and Stereotactic Body Radiation Therapy in Treating Patients With Non-small Cell Lung Cancer [Internet]. [cited 2021 Apr 12]. Available from: https://clinicaltrials.gov/ct2/show/ NCT02599454?term=SBRT+Surgery&cond=Lung+ Cancer&draw=2&rank=21
30. Treating Early-stage Non-Small Cell Lung Cancer with Durvalumab and Radiation Therapy [Internet]. [cited 2021 Apr 12]. Available from: https://clinicaltrials.gov/ ct2/show/NCT04716946?term=SBRT+Surgery&cond= Lung+Cancer&draw=2&rank=27