Upstaging, not just a non-small matter

We thank Saji et al. and appreciate their thoughtful commentary on our work including its place in the context of the existing small cell lung cancer (SCLC) literature (1). Historically, the management of SCLC has relied heavily upon chemotherapy or chemoradiotherapy without surgery, including patients with early-stage disease (2-5). These recommendations are based, in large part, on randomized clinical trials that demonstrated no improvement in survival for patients who underwent surgery compared with those who received nonoperative treatments (6,7). However, a limitation of these influential trials may have been that they were conducted in an era prior to important advances in the preoperative staging, surgical resection, and adjuvant treatments of SCLC utilized commonly in the current era (8,9).

Many of the previously discussed studies describe data ranging from 1988–2005, while the current study describes a more modern era of treatment from 2004–2013. Our data demonstrates an important update to the literature of the surgical treatment of SCLC, as these data represent 5-year overall survival of patients treated in the modern era of adjuvant treatments, including contemporary radiation therapy techniques (10).

The average 5-year overall survival reported in the current study aligns with prior national database analyses evaluating surgically treated SCLC patients, which are described in Table 1 of the commentary by Saji et al. (10-14). Similarly, the occurrence of pathologic upstaging at the time of surgical resection described in the current study falls in line with the data from these prior studies, ranging from 19% to 25% (10,11,14).

The most exciting finding from our study was the 35% absolute difference in 5-year overall survival in pathologically upstaged patients treated with chemotherapy and radiation therapy compared to chemotherapy alone (10). Additionally, the multivariable analysis identified the addition of adjuvant radiation therapy as significantly lowering the likelihood of overall mortality in patients with pN1 and pN2 disease. Unfortunately, there is limited data to benchmark our findings.

Currently, the National Comprehensive Cancer Network and the American College of Chest Physicians guidelines recommend curative-intent surgery as the initial treatment only for patients with early stage, node negative disease (2,5). As the current commentary notes, there is a growing body of evidence demonstrating favorable outcomes for patients who undergo surgical resection as their index treatment (15,16). This progress has led to a reevaluation of the role of surgery in the treatment of SCLC and an accompanying reevaluation of adjuvant therapies, as surgical resection is considered for an increasing number of SCLC patients. Furthermore, as surgical resections for SCLC increase, the potential for pathologic upstaging (pN+) may also increase accordingly. This clinical dilemma has been demonstrated to be a persistent occurrence despite advances in preoperative staging methods (17-19).

The indications for adjuvant radiation therapy following surgery in the setting of SCLC are not well defined. Current consensus guidelines concerning adjuvant therapy of patients pathologically upstaged at the time of surgical resection either do not address the use of chemotherapy or radiation therapy specifically or simply recommend the use of both (2-5). The discrepancy among recommendations stems from the lack of available data on this clinical quandary. As Saji et al. aptly note, the current guidelines are formed partially from the demonstrated efficacy of concomitant chemoradiation therapy for limited-stage disease (1,20).

Two of the four national database analyses highlighted by Saji et al. (Table 1) discuss the occurrence of pathologic upstaging, and only one was able to assess the impact of adjuvant treatment in upstaged patients (11,14). Of these studies, the study by Takei et al. most closely resembled the current study in its ability to determine the impact of adjuvant treatment on pathologic upstaging in SCLC, by evaluating the impact of adjuvant chemotherapy (14). However, the specific treatment of those pathologically upstaged was not reported and no patients were treated with adjuvant radiation therapy (14). Other comparable studies include those analyzing the National Cancer Database (NCDB) and the Surveillance, Epidemiology, and End Results (SEER) database, which report conflicting results with regard to the survival advantage of adjuvant radiation therapy. These studies report a range of outcomes, from a survival benefit for patients with pN2 disease, to no difference in survival for patients with nodal disease (21-23).

Similar to SCLC, the role of adjuvant radiation therapy in the non-small cell lung cancer (NSCLC) literature has long been debated due to the conflicting results of retrospective studies and nonrandomized trials on the survival benefit of adjuvant radiation therapy after surgical resection (24-26). Recently, there has been a reevaluation of its role in patients both with and without nodal disease, as much of the data suggesting no survival benefit to adjuvant radiation therapy was based on historical studies (27). Indeed, a meta-analysis of patients with stage III NSCLC demonstrated that modern adjuvant radiation therapy may improve local control and overall survival (28). A similar reevaluation also has occurred in SCLC due to concerns that knowledge on this topic emerged from a prior era of radiation therapy that utilized older technology. These outdated approaches frequently utilized two-dimensional radiotherapy, cobalt-based radiotherapy, and unacceptably large doses per fraction (29). Improvements in radiation therapy planning and delivery decrease treatment morbidity by better targeting treatments to spare surrounding tissue while delivering adequate doses to the target margins and nodal basins (30).

Our data highlights the changing landscape of SCLC and the challenges that remain. Upstaging after surgical resection of SCLC remains a very real occurrence and the presence of nodal disease after surgery is associated with an inferior 5-year overall survival. These data add to the growing base of evidence that support the role of surgery as part of a multimodal treatment algorithm for patients with early-stage SCLC. Furthermore, the addition of adjuvant radiation therapy may significantly improve 5-year overall survival when given in addition to adjuvant chemotherapy in patients with nodal disease identified at surgery. These data suggest that SCLC patients may benefit to pursuing aggressive local control with both surgical resection and adjuvant radiation therapy. Further studies should continue to evaluate the role of surgery and adjuvant therapies in the treatment of SCLC, including randomized trials to evaluate the efficacy of adjuvant radiation therapy in the setting of nodal disease after surgery.

Acknowledgements

None.

Footnote

Conflicts of Interest: The authors have no conflicts of interest to declare.

References

1. Saji H, Miyazawa T, Marushima H, et al. Pathological upstaging and treatment strategy of clinical stage I small cell lung cancer following surgery. J Thorac Dis 2017;9:E285-9. [Crossref] [PubMed]
2. Jett JR, Schild SE, Kesler KA, et al. Treatment of 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:e400S-19S.
3. Rudin CM, Ismaila N, Hann CL, et al. Treatment of Small-Cell Lung Cancer: American Society of Clinical Oncology Endorsement of the American College of Chest Physicians Guideline. J Clin Oncol 2015;33:4106-11. [Crossref] [PubMed]
4. Früh M, De Ruysscher D, Popat S, et al. Small-cell lung cancer (SCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013;24 Suppl 6:vi99-105. [Crossref] [PubMed]
5. Kalemkerian GP, Akerley W, Bogner P, et al. Small cell lung cancer. J Natl Compr Canc Netw 2013;11:78-98. [Crossref] [PubMed]
6. Fox W, Scadding JG. Medical Research Council comparative trial of surgery and radiotherapy for primary treatment of small-celled or oat-celled carcinoma of bronchus. Ten-year follow-up. Lancet 1973;2:63-5. [Crossref] [PubMed]
7. Lad T, Piantadosi S, Thomas P, et al. A prospective randomized trial to determine the benefit of surgical resection of residual disease following response of small cell lung cancer to combination chemotherapy. Chest 1994;106:320S-3S. [Crossref] [PubMed]
8. Brock MV, Hooker CM, Syphard JE, et al. Surgical resection of limited disease small cell lung cancer in the new era of platinum chemotherapy: Its time has come. J Thorac Cardiovasc Surg 2005;129:64-72. [Crossref] [PubMed]
9. Bradley JD, Dehdashti F, Mintun MA, et al. Positron emission tomography in limited-stage small-cell lung cancer: a prospective study. J Clin Oncol 2004;22:3248-54. [Crossref] [PubMed]
10. Thomas DC, Arnold BN, Rosen JE, et al. Defining outcomes of patients with clinical stage I small cell lung cancer upstaged at surgery. Lung Cancer 2017;103:75-81. [Crossref] [PubMed]
11. Vallières E, Shepherd FA, Crowley J, et al. The IASLC Lung Cancer Staging Project: proposals regarding the relevance of TNM in the pathologic staging of small cell lung cancer in the forthcoming (seventh) edition of the TNM classification for lung cancer. J Thorac Oncol 2009;4:1049-59. [Crossref] [PubMed]
12. Yu JB, Decker RH, Detterbeck FC, et al. Surveillance epidemiology and end results evaluation of the role of surgery for stage I small cell lung cancer. J Thorac Oncol 2010;5:215-9. [Crossref] [PubMed]
13. Weksler B, Nason KS, Shende M, et al. Surgical resection should be considered for stage I and II small cell carcinoma of the lung. Ann Thorac Surg 2012;94:889-93. [Crossref] [PubMed]
14. Takei H, Kondo H, Miyaoka E, et al. Surgery for small cell lung cancer: a retrospective analysis of 243 patients from Japanese Lung Cancer Registry in 2004. J Thorac Oncol 2014;9:1140-5. [Crossref] [PubMed]
15. Combs SE, Hancock JG, Boffa DJ, et al. Bolstering the case for lobectomy in stages I, II, and IIIA small-cell lung cancer using the National Cancer Data Base. J Thorac Oncol 2015;10:316-23. [Crossref] [PubMed]
16. Lim E, Belcher E, Yap YK, et al. The role of surgery in the treatment of limited disease small cell lung cancer: time to reevaluate. J Thorac Oncol 2008;3:1267-71. [Crossref] [PubMed]
17. Licht PB, Jørgensen OD, Ladegaard L, et al. A national study of nodal upstaging after thoracoscopic versus open lobectomy for clinical stage I lung cancer. Ann Thorac Surg 2013;96:943-9; discussion 949-50. [Crossref] [PubMed]
18. Silvestri GA, Gonzalez AV, Jantz MA, et al. Methods for staging 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:e211S-50S.
19. Bott MJ, Patel AP, Crabtree TD, et al. Pathologic Upstaging in Patients Undergoing Resection for Stage I Non-Small Cell Lung Cancer: Are There Modifiable Predictors? Ann Thorac Surg 2015;100:2048-53. [Crossref] [PubMed]
20. Pignon JP, Arriagada R, Ihde DC, et al. A meta-analysis of thoracic radiotherapy for small-cell lung cancer. N Engl J Med 1992;327:1618-24. [Crossref] [PubMed]
21. Wong AT, Rineer J, Schwartz D, et al. Assessing the Impact of Postoperative Radiation Therapy for Completely Resected Limited-Stage Small Cell Lung Cancer Using the National Cancer Database. J Thorac Oncol 2016;11:242-8. [Crossref] [PubMed]
22. Schreiber D, Rineer J, Weedon J, et al. Survival outcomes with the use of surgery in limited-stage small cell lung cancer: should its role be re-evaluated? Cancer 2010;116:1350-7. [Crossref] [PubMed]
23. Varlotto JM, Recht A, Flickinger JC, et al. Lobectomy leads to optimal survival in early-stage small cell lung cancer: a retrospective analysis. J Thorac Cardiovasc Surg 2011;142:538-46. [Crossref] [PubMed]
24. Douillard JY, Rosell R, De Lena M, et al. Impact of postoperative radiation therapy on survival in patients with complete resection and stage I, II, or IIIA non-small-cell lung cancer treated with adjuvant chemotherapy: the adjuvant Navelbine International Trialist Association (ANITA) Randomized Trial. Int J Radiat Oncol Biol Phys 2008;72:695-701. [Crossref] [PubMed]
25. Lally BE, Zelterman D, Colasanto JM, et al. Postoperative radiotherapy for stage II or III non-small-cell lung cancer using the surveillance, epidemiology, and end results database. J Clin Oncol 2006;24:2998-3006. [Crossref] [PubMed]
26. Wakelee HA, Stephenson P, Keller SM, et al. Post-operative radiotherapy (PORT) or chemoradiotherapy (CPORT) following resection of stages II and IIIA non-small cell lung cancer (NSCLC) does not increase the expected risk of death from intercurrent disease (DID) in Eastern Cooperative Oncology Group (ECOG) trial E3590. Lung Cancer 2005;48:389-97. [Crossref] [PubMed]
27. Corso CD, Rutter CE, Wilson LD, et al. Re-evaluation of the role of postoperative radiotherapy and the impact of radiation dose for non-small-cell lung cancer using the National Cancer Database. J Thorac Oncol 2015;10:148-55. [Crossref] [PubMed]
28. Billiet C, Decaluwé H, Peeters S, et al. Modern post-operative radiotherapy for stage III non-small cell lung cancer may improve local control and survival: a meta-analysis. Radiother Oncol 2014;110:3-8. [Crossref] [PubMed]
29. Benveniste MF, Welsh J, Godoy MC, et al. New era of radiotherapy: an update in radiation-induced lung disease. Clin Radiol 2013;68:e275-90. [Crossref] [PubMed]
30. Chang JY, Cox JD. Improving radiation conformality in the treatment of non-small cell lung cancer. Semin Radiat Oncol 2010;20:171-7. [Crossref] [PubMed]