Elsevier

Lung Cancer

Volume 115, January 2018, Pages 89-96
Lung Cancer

Recurrence dynamics after trimodality therapy (Neoadjuvant concurrent chemoradiotherapy and surgery) in patients with stage IIIA (N2) lung cancer

https://doi.org/10.1016/j.lungcan.2017.11.020Get rights and content

Highlights

  • The risk of recurrence after trimodality therapy was evaluated.

  • Hazard rate function revealed a peak at approximately 8 months after surgery.

  • The dynamics of recurrence after trimodality therapy is organ-specific.

  • The risk patterns were dependent on histology, tumor response and nodal status.

Abstract

Introduction

We investigated the timing and patterns of recurrence after the treatment of stage IIIA (N2) non-small cell lung cancer via neoadjuvant concurrent chemoradiotherapy followed by surgery.

Materials and methods

An institutional database was reviewed retrospectively between 1997 and 2013 (N = 570). Eligible patients had pathologically proven N2 disease, and they completed the planned trimodality therapy with curative intent. The hazard rate function and competing risk analysis were used to evaluate the recurrence dynamics.

Results

Among the included patients, 76% had single station N2 involvement and 95% had complete resection. The 5-year overall and recurrence-free survival rates were 47% and 29%, respectively. Of the 290 patients who experienced recurrence, 25 (8.4%) experienced loco-regional recurrence, whereas 238 (80.4%) had distant metastases. The hazard rate function for overall recurrence revealed a peak at approximately 8 months after surgery and a marked decline after 2 years. The peak recurrence frequency of distant metastasis differed at each site, with isolated brain metastases exhibiting the earliest peak (6 months) and a narrow recurrence interval (15 months). A histological comparison revealed a higher recurrence hazard rate for adenocarcinoma than for squamous cell carcinoma but similar pattern of recurrences. Patients with complete responses had a lower cumulative incidence rate of recurrence but a slightly earlier peak of recurrence. Nodal responses to induction therapy demonstrated that patents with ypN0 had the lowest recurrence risk, whereas patients with ypN1 and ypN2 had similar hazard rates and cumulative incidence rates of recurrence.

Conclusions

The dynamics of recurrence after trimodality therapy is organ-specific and varies according to pathologic factors. Our finding provides information on selection patients with risk of recurrence and timing of surveillance study.

Introduction

Recurrence is a major cause of treatment failure in patients with stage IIIA (N2) non-small cell lung cancer (NSCLC) mainly because of its potential risk of occult systemic metastasis [1], and various therapeutic strategies have been developed to improve treatment outcomes. Trimodality therapy (neoadjuvant concurrent chemoradiotherapy [CCRT] followed by surgery) is the most aggressive approach, but it failed to produce a survival benefit over definitive CCRT in previous phase III trials [2], [3], [4]. Recently, we reported encouraging treatment outcomes with a 5-year overall survival (OS) rate of 47%; however, a significant proportion of patients experienced distant failure [5]. Although survival benefits from postoperative surveillance programs have not been demonstrated, [6], [7], [8] careful surveillance may improve outcomes after treatment with curative intent, enabling us to conduct timely management of recurrence. Therefore, a better understanding of the dynamics of recurrence is needed to overcome the dismal prognosis of N2 disease.

The risk of recurrence has been described in the literature according to the interval between the date of surgery and that of a diagnosis of recurrence or recurrence-free survival (RFS) using Kaplan–Meier survival analysis. However, such methods do not provide direct information regarding changes in event probabilities over time (i.e., event dynamics), which can be estimated by calculating event-specific hazard rates over the follow-up interval [9]. Moreover, calculating RFS using the Kaplan–Meier method may lead to biased results because the Kaplan–Meier method was originally developed to describe all-cause mortality and it assumes that all events are independent [10]. Alternatively, competing risk analysis provides cause-specific treatment outcomes and a more accurate comparison of factors associated with outcomes. Hence, competing risk analysis has been recognized as an important methodology for precise patient stratification and prognosis in cancer research [11].

Several studies on the dynamics of recurrence after treatment for early NSCLC demonstrated that the risk of recurrence is not constant over time [12], [13]. Rather, multiple peak patterns exist in hazard rate analysis, and these patterns vary according to clinical or pathological factors such as sex and pathological nodal stage [14]. These findings could be incorporated into future treatment strategies or tailored surveillance protocols. However, at present, no similar study regarding N2 NSCLC has been conducted, and it is unreasonable to apply results previously obtained from early-stage tumors to more advanced stages. Thus, in the present study, we investigated the patterns and timing of recurrence based on clinical and pathological factors in patients who underwent trimodality therapy for N2 NSCLC.

Section snippets

Study population

This study was a retrospective review of a prospectively maintained database for patients who were treated for lung cancer and followed at Samsung Medical Center between January 1997 and December 2013. Individuals with N2 NSCLC who underwent planned neoadjuvant CCRT and complete surgical resection with curative intent were included. Eligible patients had histologically proven NSCLC and mediastinal nodal metastases confirmed by pathological examination. The exclusion criteria were N3 disease,

Patients characteristics and treatment outcomes

From January 1997 to December 2013, 574 patients with N2 NSCLC completed trimodality therapy. Of these, 4 patients who underwent limited resection were excluded. Therefore, the study comprised a total of 570 patients. The median patient age was 60 years (interquartile range [IQR], 53–65), and 441 (77.4%) patients were male. Pretreatment pathologic confirmation of N2 nodal metastasis was performed in 501 (87.7%) patients. Most patients had single nodal station N2 disease (n = 433, 76.0%), whereas

Discussion

In a previous report [5], we provided an encouraging 5-year OS rate of 47% and a 5-year RFS rate of 29% in patients with N2 NSCLC who received trimodality therapy. However, despite the encouraging data, more than 50% of the patients developed recurrence during the study period. The outcomes of treatment for systemic recurrences are disappointing, but a few studies demonstrated that CCRT prolonged survival following postoperative recurrence in select patients. [16], [17] In addition to efforts

Conclusion

The dynamics of recurrence after trimodality therapy is organ-specific and varies according to pathologic factors. The first year after surgery was the most vulnerable period of recurrence, especially regarding brain metastases, which were most frequent in the first 6 months after treatment. Patients with adenocarcinoma, without nodal clearance, and without complete remission were more prone to recurrence. Our finding would provide information on selection patients with risk of recurrence and

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

References (30)

Cited by (23)

  • Postoperative follow-up for gastric cancer needs to be individualized according to age, tumour recurrence pattern, and recurrence time

    2022, European Journal of Surgical Oncology
    Citation Excerpt :

    The recurrence-free time in patients with peritoneal recurrence observed in this study or any other study may fluctuate. This is a common limitation of this and other similar studies [14,33,34]. Third, our cohort did not include data on genetic information, which may underestimate the role of age-specific genetic and molecular subtypes in the prognosis of young gastric cancer patients.

  • Ten-year patient journey of stage III non-small cell lung cancer patients: A single-center, observational, retrospective study in Korea (Realtime autOmatically updated data warehOuse in healTh care; UNIVERSE-ROOT study)

    2020, Lung Cancer
    Citation Excerpt :

    The benefits of trimodal therapy with neoadjuvant CCRT and surgery for stage III-N2 were clear, with a median OS of 63.3 months for patients with pCR, and 78.1 and 45.8 months for N0-1 or N2 disease, respectively. These results are consistent with those reported recently by Lee and colleagues [22], and with American Society for Radiation Oncology (ASTRO) guidelines endorsed by the American Society of Clinical Oncology (ASCO), for the use of CCRT for curative-intent treatment of locally advanced NSCLC [23]. A recent retrospective, observational study of 478 community oncology patients with unresected stage III NSCLC reported that most patients received CCRT as the first therapy, then received chemotherapy without radiation with subsequent disease progression [24].

  • PACIFIC: Time for a surgical IIIA uprising

    2018, Journal of Thoracic and Cardiovascular Surgery
  • High-dose neoadjuvant chemoradiotherapy versus chemotherapy alone followed by surgery in potentially-resectable stage IIIA-N2 NSCLC. A multi-institutional retrospective study by the Oncologic Group for the Study of Lung Cancer (Spanish Radiation Oncology Society)

    2020, Reports of Practical Oncology and Radiotherapy
    Citation Excerpt :

    In our series, the lack of improved survival in the CRT group can probably be attributed to the high incidence of distant metastasis (around 30% in both groups). Several studies have reported similar rates of distant metastasis,3,11,12 with some reporting rates of nearly 80%.20,24 Ultimately, the failure to achieve distant control in this patient population—despite the use of trimodal therapy in these patients counteracts the good locoregional control and may thus explain why there is no improvement in survival outcomes.

View all citing articles on Scopus
1

Present address: Department of Thoracic Surgery, Armed Forces Daejeon Hospital, Daejeon, Republic of Korea.

2

Junghee Lee and Hong Kwan Kim equally contributed to this work as co-first author.

View full text