Targeted surgical therapy for lung cancer

Oncologists and precision medicine teams have become the stars of lung cancer treatment. As our understanding of the heterogeneity of the molecular drivers and of the immune landscape of individual patient’s tumors becomes more nuanced, it is now clearer that a one-size-fits-all approach for the treatment of advanced lung cancer makes little sense. Instead, treatment is based upon histology, driver mutations, and immune markers. With that foundation, practice-changing trials of targeted therapies are being reported at a dizzying pace.

Similarly, although not as appreciated, surgical therapy for early-stage lung cancer, has also become more targeted. Expert surgeons now more frequently, utilize minimally invasive techniques, and sublobar resections for lung preservation (1-6). Although the surgical community eagerly awaits the publication of survival results from modern trials evaluating sublobar resection versus lobectomy (JCOG0802 and CALGB 140503), it is safe to assume that those trials may yield just as many questions as answers. Rather than a one-size-fits-all approach of sublobar resection or lobectomy for individual cancers, it seems much more likely that surgeons will continue to evaluate, and carefully select patients for each type of procedure. Our ability to do so has been greatly facilitated by the increased resolution of computed tomography scans that have enabled nodule classification, and pathologic prediction and of positron emission tomography (PET) scans that have enabled identification of gross nodal disease and highly metabolic tumors at risk for micrometastatic nodal disease. Additionally, histological classification, when determined preoperatively, can help predict the outcome of a sublobar resection (7-11). Indeed, such nuances are the basis of surgical targeted therapy.

The thoracic surgery group from the Juntendo University, in Japan, have been leaders in describing the targeted surgical treatment of early-stage lung cancer, publishing numerous manuscripts about their experience in selecting patients for a sublobar resection (7-9,12,13). In their most recent publication in the “Annals of Thoracic Surgery”, they take this concept further, by exploring the role of targeted lymphadenectomy (14). The authors evaluated 462 patients with clinical stage I radiological part-solid adenocarcinomas, who had undergone either a systematic lobe-specific mediastinal lymph node dissection (m-LND) or hilar lymph node only dissection (h-LND). Among these patients, the authors propensity matched 92 pairs of patients for a detailed analysis. Notably, nodal metastases were only present in 4.9% of the solid dominant lesions, and could be predicted by high carcinoembryonic antigen levels (>3.0 ng/mL) and by high SUVmax on PET (>2.8). Only nine patients (1.9%) in the entire cohort, had pathologic N2 disease. Given this low rate of nodal positivity, it is perhaps not surprising that there was no difference in survival between patients who had m-LND or h-LND. Overall survival in the entire cohort at the 5 year mark was 94% for m-LND and 93% for h-LND (P=0.585) and locoregional recurrence was less than 2% for both groups. Survival in propensity matched pairs was essentially identical.

In what context should we put these results? Do the results reported by Hattori et al. indicate we should discourage surgeons from routinely undertaking the laborious task of a mediastinal node dissection? The answer is a resounding “no”, but the reasons why are perhaps subtle. Although it is compelling to pool and compare all of these cases together, it is remarkable how much a priori surgical judgment actually went into the selection of which operative techniques were used in these patients, both regarding the extent of resection, and the extent of lymph node dissection. That judgment, in essence the ability of expert surgeons to perform a targeted surgical resection and lymph node dissection, can never be accounted for in retrospective reviews, even among propensity matched groups which are unable to account for differences in treatment allocation, particularly in the patients with early stage lung cancer with competing risk factors (15).

For example, the surgeons had elected to perform a segmentectomy in 28% of cases, and a hilar node only lymph node dissection in 32% of patients. I would argue, that within these selected groups, the rate of nodal disease and recurrence were so low, and survival was so exceptional, precisely because the surgeons chose the right patients for each procedure, based upon a careful clinical and radiologic assessment of their tumors. Propensity-score matching can account for many factors, but it can never match groups for surgical judgment. It should also be noted that patients in the current study who underwent a “lesser” lymph node dissection (h-LND) still received an excellent oncologic operation with meticulous, anatomic dissection, and a higher number of lymph nodes resected (4.7±4.0 nodes) than in many US and European studies. Additionally, the authors routinely relied upon intraoperative frozen sections for the real-time, pathological assessment of lymph nodes to guide their choices, regarding the extent of the resection and lymphadenectomy. I therefore think that we need to be careful to ensure that the authors’ statement, “extent of lymph nodal dissection was not associated with oncological outcome of clinical-stage I radiological part-solid lung adenocarcinoma” is not applied across the board to all tumors or to all patients.

Certainly, that philosophy should not be the mantra of all surgeons in an era in which too few patients are already undergoing comprehensive lymph node evaluation, particularly during sublobar resection (16). My concern is that surgeons will use this data to infer that lymph node dissection is not important at all for these early stage lung cancers. Clearly, that is not what an in depth look at the approach of the group from Juntendo University shows. Rather, we as thoracic surgeons should perform a detailed lymphadenectomy as part of lobar and sublobar resections, and insist that pathologists carefully examine these nodes. Our ability to optimally stage patients, and to obtain exquisite local and regional control, even with sublobar resection, is what will distinguish surgical from other competing methods of local therapy, such as stereotactic radiation therapy (SABR or SBRT) and radiofrequency ablation (RFA). A large balance of evidence now suggests that a more extensive lymphadenectomy is associated with improvements in survival following NSCLC resection, even for SLR (16-20). It remains undetermined whether this is strictly due to improvements in staging, or whether there is an actual oncological benefit due to the improved locoregional control limiting future recurrences. A provocative paper in Science earlier this year demonstrated that lymph node metastases themselves have the ability to generate systemic metastases, providing some evidence for the latter hypothesis (21).

Ultimately surgeons, just like medical oncologists, must recognize that a one-size-fits-all approach to lung cancer makes little sense. Advances in preoperative radiographic and molecular characterization, now allow experienced surgeons to select patients for targeted sublobar resection, either segmentectomy or wedge resection. This will continue to be the case no matter the results of the randomized trials JCOG0802 and CALGB 140503. Indeed, our ability to treat high risk patients safely, and compete favorably with local ablative techniques depends upon proper patient selection for sublobar resection. Certainly there are also tumors in which the expected rate of lymph node metastases are low, that a lymphadenectomy could probably be skipped. However, it should be pointed out that, more extended lymph node dissection has not been associated with increases in perioperative complications (22,23). Given that fact, surgeons should strongly consider performing at least a lobe-specific sampling of the hilar and mediastinal lymph node stations, even for the low-risk part solid tumors described by Hattori et al. It is of particular interest, that other ablative techniques that do not address the locoregional lymph nodes, such as stereotactic radiation, suffer from high rates of delayed locoregional and systemic recurrences. For example, in two trials of operable patients undergoing stereotactic radiation, despite excellent “in-field” control, 46% of patients recurred in RTOG 0618 at 4 years and 42% of patients recurred in JCOG 0403 at 5 years (24,25). Although this may be the result of under-staging prior to enrollment, one would expect recurrences simply related to inadequate staging to occur earlier in the time course after stereotactic radiation. Rather, it may be that treatment failure at the primary site or that untreated micrometastatic disease in nearby lymph nodes facilitates a later systemic recurrence. Given the previous paper mentioned that demonstrated the ability of lymph node metastases themselves to systemically metastasize, I would argue that lymphadenectomy remains critical, to ensure excellent survival outcomes for patients with presumed early stage lung cancer (21). I am certain that Hattori and colleagues feel the same way. Indeed, their excellent results demonstrate the remarkable survival that can be achieved in patients undergoing a thoughtful, targeted surgical therapy for early stage lung cancer.

Acknowledgements

None.

Footnote

Conflicts of Interest: The author reports personal/spousal financial relationships with AstraZeneca, Merck, Pfizer, and PPD and is a Board member of the Lung Cancer Research Foundation.

References

1. Paul S, Altorki NK, Sheng S, et al. Thoracoscopic lobectomy is associated with lower morbidity than open lobectomy: a propensity-matched analysis from the STS database. J Thorac Cardiovasc Surg 2010;139:366-78. [Crossref] [PubMed]
2. Gulack BC, Yang CJ, Speicher PJ, et al. A risk score to assist selecting lobectomy versus sublobar resection for early stage non-small cell lung cancer. Ann Thorac Surg 2016;102:1814-20. [Crossref] [PubMed]
3. Lee PC, Nasar A, Port JL, et al. Long-term survival after lobectomy for non-small cell lung cancer by video-assisted thoracic surgery versus thoracotomy. Ann Thorac Surg 2013;96:951-60; discussion 960-1. [Crossref] [PubMed]
4. Subramanian M, McMurry T, Meyers BF, et al. Long-Term Results for Clinical Stage IA Lung Cancer: Comparing Lobectomy and Sublobar Resection. Ann Thorac Surg 2018;106:375-81. [Crossref] [PubMed]
5. Speicher PJ, Gu L, Gulack BC, et al. Sublobar resection for clinical stage IA non-small-cell lung cancer in the United States. Clin Lung Cancer 2016;17:47-55. [Crossref] [PubMed]
6. Khullar OV, Liu Y, Gillespie T, et al. Survival after sublobar resection versus lobectomy for clinical stage IA lung cancer: an analysis from the national cancer data base. J Thorac Oncol 2015;10:1625-33. [Crossref] [PubMed]
7. Suzuki K, Koike T, Asakawa T, et al. A prospective radiological study of thin-section computed tomography to predict pathological noninvasiveness in peripheral clinical IA lung cancer (Japan Clinical Oncology Group 0201). J Thorac Oncol 2011;6:751-6. [Crossref] [PubMed]
8. Hattori A, Suzuki K, Matsunaga T, et al. Is limited resection appropriate for radiologically "solid" tumors in small lung cancers? Ann Thorac Surg 2012;94:212-5. [Crossref] [PubMed]
9. Suzuki K, Kusumoto M, Watanabe S, et al. Radiologic classification of small adenocarcinoma of the lung: radiologic-pathologic correlation and its prognostic impact. Ann Thorac Surg 2006;81:413-9. [Crossref] [PubMed]
10. Stiles BM, Nasar A, Mirza F, et al. Ratio of positron emission tomography uptake to tumor size in surgically resected non-small cell lung cancer. Ann Thorac Surg 2013;95:397-403. [Crossref] [PubMed]
11. Nitadori J, Bograd AJ, Kadota K, et al. Impact of micropapillary histologic subtype in selecting limited resection vs lobectomy for lung adenocarcinoma of 2cm or smaller. J Natl Cancer Inst 2013;105:1212-20. [Crossref] [PubMed]
12. Hattori A, Matsunaga T, Takamochi K, et al. Indications for sublobar resection of clinical stage IA radiologic pure-solid lung adenocarcinoma. J Thorac Cardiovasc Surg 2017;154:1100-8. [Crossref] [PubMed]
13. Hattori A, Matsunaga T, Takamochi K, et al. Locoregional recurrence after segmentectomy for clinical-T1aN0M0 radiologically solid non-small-cell lung carcinoma. Eur J Cardiothorac Surg 2017;51:518-25. [PubMed]
14. Hattori A, Matsunaga T, Takamochi K, et al. Significance of Lymphadenectomy in Part-Solid Lung Adenocarcinoma: Propensity Score Matched Analysis. Ann Thorac Surg 2018;106:989-97. [Crossref] [PubMed]
15. Stokes WA, Rusthoven CG. Surgery vs. SBRT in retrospective analyses: confounding by operability is the elephant in the room. J Thorac Dis 2018;10:S2007-10. [Crossref] [PubMed]
16. Stiles BM, Mao J, Harrison S. Extent of Lymphadenctomy is Associated with Oncological Efficacy of Sublobar Resection for Lung Cancer Less than or Equal to 2 cm. J Thorac Cardiovasc Surg. In press.
17. Ludwig MS, Goodman M, Miller DL, et al. Postoperative survival and the number of lymph nodes sampled during resection of node-negative non-small cell lung cancer. Chest 2005;128:1545-50. [Crossref] [PubMed]
18. Samson P, Crabtree T, Broderick S, et al. Quality measures in clinical stage I non-small cell lung cancer: improved performance is associated with improved survival. Ann Thorac Surg 2017;103:303-11. [Crossref] [PubMed]
19. Yendamuri S, Dhillon SS, Groman A, et al. Effect of the number of lymph nodes examined on the survival of patients with stage I non-small cell lung cancer who undergo sublobar resection. J Thorac Cardiovasc Surg 2018;156:394-402. [Crossref] [PubMed]
20. Cao J, Xu J, He Z, et al. Prognostic impact of lymphadenectomy on outcomes of sublobar resection for stage IA non-small cell lung cancer ≤2 cm. J Thorac Cardiovasc Surg 2018;156:796-805.e4. [Crossref] [PubMed]
21. Pereira ER, Kedrin D, Seano G, et al. Lymph node metastases can invade local blood vessels, exit the node, and colonize distant organs in mice. Science 2018;359:1403-7. [Crossref] [PubMed]
22. Allen MS, Darling GE, Pechet TT, et al. ACOSOG Z0030 Study Group. Morbidity and mortality of major pulmonary resections in patients with early-stage lung cancer: initial results of the randomized, prospective ACOSOG Z0030 trial. Ann Thorac Surg 2006;81:1013-9; discussion 1019-20. [Crossref] [PubMed]
23. Stiles BM, Kamel MK, Nasar A, et al. The importance of lymph node dissection accompanying wedge resection for clinical stage IA lung cancer. Eur J Cardiothorac Surg 2017;51:511-7. [PubMed]
24. Timmerman RD, Paulus R, Pass HI, et al. Stereotactic Body Radiation Therapy for Operable Early-Stage Lung Cancer: Findings From the NRG Oncology RTOG 0618 Trial. JAMA Oncol 2018;4:1263-6. [Crossref] [PubMed]
25. Nagata Y, Hiraoka M, Shibata T, et al. A phase II trial of stereotactic body radiation therapy for operable T1N0M0 non-small cell lung cancer: Japan Clinical Oncology Group (JCOG0403)—Long term follow-up results. J Clin Oncol 2018;36:abstr 8512.

(English Language Editor: Jeremy Dean Chapnick, AME Publishing Company)