Optimal sequencing of postoperative radiotherapy and chemotherapy in IIIA-N2 non-small cell lung cancer

Lee et al. questioned the optimal sequencing of postoperative radiotherapy (PORT) and postoperative chemotherapy (POCT) after surgery for patients with IIIA-N2 non-small cell lung cancer (NSCLC) which was left untested in a prospective randomized setting (1); and performed the PORT-first strategy with an institutional multidisciplinary consensus, based on their hypothesis that the PORT-first strategy possibly being more effective in locoregional control than the PORT after POCT without compromising proven overall survival benefit of POCT. Their study is a documentation of retrospective experience revealing a PORT-first strategy with POCT in eligible (43/105) and without POCT in medically (30/105) or protocolly (23/105) ineligible and refusing (8/105) patients. Lee et al. pointed out that their overall survival results of 40.2% was comparable with the literature (2,3) and their survival results of 61.3% in the patients with POCT was superior than previous series (2-5). Lee et al. deserves appreciation for drawing attention to the sequencing of adjuvant treatment in IIIA-N2 NSCLC to claim the possible benefit of PORT-first strategy.

Even after a radical resection, a high locoregional recurrence almost up to 40% was reported after adjuvant chemotherapy (4,6-9), and the common decision such as The American College of Radiology in their multidisciplinary Appropriateness Criteria was to encourage PORT for N2 NSCLC patients to improve locoregional control (10). One of the concerns in retrospective series presenting PORT such as in this manuscript is the variability of PORT target volume definition, especially in a wide range of years treated by different physicians, such as documented by different cohorts (11,12). The objective evaluation of PORT reveals a significant survival benefit for N2 disease independent from chemotherapy, while a local regional control assistance in patients with N1 disease who do not receive chemotherapy (4,13-17). It would not be wrong to note the major problem in all older trials with deaths due to radiotherapy technical weaknesses which avoided local regional control effect turning out into a survival benefit (15). The phase 3 trial of “The Lung Adjuvant Radiotherapy (Lung ART)” enrolling N2 disease into PORT with modern and standardized techniques is expected to shed light on the gray zone in a prospective manner (12,18,19).

The role of PORT seems to traverse a long way from Lung Cancer Study Group trial in 1980 revealing important decrease in local recurrence from 41% to 3% without survival benefit in 5 years (13); to a warning to withhold PORT by Groupe d’Etude et de Traitement des Cancers Bronchiques based on high numbers of death following PORT (31% vs. 8%) (15). Trodella et al. on the other side randomized stage I NSCLC patients to receive PORT or not and concluded a significant disease free benefit with a trend for survival benefit (17). The subgroup analysis of ANITA, trial investigating the benefit of adjuvant vinorelbine by Douillard et al., highlighted the significant survival benefit of PORT for N2 disease independent from chemotherapy in addition to survival benefit for N1 who did not receive chemotherapy (4). Besides, SEER data outlined a major survival gain for N2 patients with PORT (20). A recent meta-analysis, in stage IIIA-N2 NSCLC patients, acknowledged that modern PORT could improve the 5-year OS by 13% (21). A 2015 analysis of the National Cancer Data Base documented that PORT increased survival in pN2 patients (5). It is also evident that modern PORT claims additional survival advantage despite adjuvant chemotherapy (22).

PORT has also been discussed regarding the cohort who is gaining the benefit most; Matsuguma et al. claimed PORT to serve more in case of more than single station mediastinal nodal involvement (23), Saji et al. pointed out the poor prognostic group with less than ten nodes dissected and four or more nodes positive (24). SEER data could also documented the major improvement of survival in N2 group in addition to more than 50% involvement of nodes dissected (25). Lopez Guerra et al. analyzed retrospective MD Anderson Cancer Center series of 1,402 stage I−III (N0−N1) NSCLC patients who did not receive PORT to define local regional risk factors and documented 9% local regional recurrence which provoked decrement in survival (26); where multivariate analysis pointed out the surgical procedure (single/multiple wedge + segmentectomy × lobectomy + bilobectomy + pneumonectomy), tumor size larger than 2.7 cm and visceral pleura invasion to be independent risk factors for local recurrence; N1, visceral pleura invasion, and lymphovascular invasion (LVI) to be independent risk factors for regional recurrence (26). As there is a common consensus for PORT in treating close/positive surgical margins or N2 nodal involvement, multidisciplinary individualized decision for PORT is required based on number and station of N1 involvement, LVI, visceral pleura invasion and extracapsular invasion (26,27). Hui et al. recently emphasized a subgroup of proper candidates among resected IIIA-N2 NSCLC population in whom PORT significantly improved the OS as the ones having three or more of the five factors of SI (smoking index: number of cigarettes smoked per day × number of cigarette-years) ≤400, cN2, pT3, SCC, and ≥4 positive nodes (28). Details of the cohort by Lee et al. needs to be analyzed for the percent of the patients who were expected to get benefit most.

There are points to be extracted from their cohort to enlighten the comparison. The ratio of patients staged with PET-CT before surgery would be helpful hint to understand the cohort treated; besides the follow up of the patients treated in this cohort seems a little loose to be able to capture locoregional and systemic failure with simple chest radiography or chest CT or optional annual PET-CT. As the types of surgical resection were detailed as lobectomy & bilobectomy or pneumonectomy in their patients, quantification of regional lymph node involvement have not been detailed in this paper to reveal the patients’ risk load. As the authors mentioned that no routine preoperative pathological evaluation for mediastinal disease performed and surgical resection decision was based on clinically N0–1 or single station minimal N2 disease, surgical data whether the dissection was formal or selective and postoperative data for the number of dissected nodes, positive N1 nodes/station and positive N2 nodes/stations were lacking in the manuscript. Besides, it would be great to know the related pathological details of the cohort to reveal the accurate R0 complete resection rates in both treatments (29), not only microscopically confirmed free resection margins, but also a systematic nodal dissection and the ratio of extracapsular tumor extension in nodes removed. All the patients except two were defined as clear surgical margins and though there was an enormous difference (2 patients with positive margins, one on each arm; and 101 negative margin patients, 42 on PORT-first plus POCT and 61 PORT alone), the authors analyzed the resection status both univariately and multivariately, instead of exclusing these two patients.

As duration between the surgery and initiation date of POCT seemed to impact survival in colorectal and breast cancer patients, one of the most important questions about timing of PORT is whether postponing POCT might affect survival. In other tumor sites such as head and neck or breast cancer, the delay to initiate PORT has been presented to have a negative impact on outcome (30-33), while the data for lung cancer for this correlation is not reported much (34,35). A recent Canadian data documented 1,032 cases treated with POCT with a median time to adjuvant chemotherapy (TTAC) of 8 weeks where 35% of the cohort received POCT more than 10 weeks after surgery. Booth et al. have appreciated no association between TTAC and overall survival (OR =1.00, 95% CI =0.99−1.00) (36). In the lack of prospective data to clarify the TTAC, data by Lee et al. could also be defined as another cohort, though there is not a direct comparison, to point out the mild delay for POCT might not cause any sacrifice in overall survival.

The histology might have an influence on locoregional failure as adenocarcinoma and squamous cell carcinoma, due to the fact that squamous cell was pointed out to be a poor prognostic factor for survival (37); however the prognostic significance of the histology is yet to be defined in fully resected pN2 NSCLC (2). As the histology seemed to be evenly distributed here for both PORT & POCT and POCT alone groups, histology might not affect the outcome in this cohort.

As a summary, optimal sequencing of PORT and POCT after surgery for patients with IIIA-N2 NSCLC is a candidate topic to be discussed and studied prospectively, however for now, PORT-first strategy sounds to be feasible and triggering related research where Lee et al. provided a first-hand retrospective valuable information to initiate the discussion.

Acknowledgements

None.

Footnote

Provenance: This is an invited Editorial commissioned by the Section Editor Wenyong Tan (Department of Oncology, Shenzhen People’s Hospital, Shenzhen, China).

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

Comment on: Lee HW, Noh OK, Oh YT, et al. Radiation Therapy-First Strategy After Surgery With or Without Adjuvant Chemotherapy in Stage IIIA-N2 Non-Small Cell Lung Cancer. Int J Radiat Oncol Biol Phys 2016;94:621-7.

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