A novel clinical prognostic score incorporating the number of resected lymph-nodes to predict recurrence and survival in non-small-cell lung cancer

doi:10.1016/j.lungcan.2009.02.024

Lung Cancer

Volume 66, Issue 3, December 2009, Pages 365-371

https://doi.org/10.1016/j.lungcan.2009.02.024 Get rights and content

Abstract

Background

The number of resected lymph-nodes (#RNs) has proven prognostic in breast and colorectal cancer. Here we evaluated its prognostic impact in a series of resected NSCLC patients.

Methods

A panel of established prognostic factors plus (1) #RNs or (2) the ratio between the number of metastatic nodes and #RNs (NR) were correlated to overall- (OS), cancer-specific- (CSS), and disease-free-survival (DFS), using the Cox-model. Risk-classes according to hazard ratios (HR) were generated. Internal and external validation was accomplished.

Results

A dataset of 415 resected NSCLC patients was retrieved. At multivariate analysis, #RNs and NR were independent factor for longer OS, CSS and DFS (p < 0.0001). Patients with a #RNs > 10 (identified optimal cut-off) had a statistically significant OS (p = 0.02) and DFS (p = 0.0005) benefit. In node-positive patients, a NR < 9% significantly correlated with better outcome. Stratification into High-, Medium-, and Low-Risk classes, based on High- (HRFs: stage, N-status, age, #RNs) and Intermediate-Risk Factors (IRFs: sex, grading, histology), efficiently predicted outcomes (p < 0.0001). The risk class model performance was externally validated in and independent dataset of 297 patients.

Conclusions

These results contribute to complete the panel of prognostic factors for resected NSCLC. A prospective larger validation and comparison with molecular prognostic tools is warranted.

Introduction

Lung cancer accounts for 160,000 deaths each year in the United States, and represents the leading cause of cancer death regardless of gender, with an overall 5-year survival rate of 16% [1], [2]; non-small-cell lung cancer (NSCLC) accounts for about 80% of all lung cancers [3]. Approximately 30% of patients present with early-stage disease, a proportion that is expected to increase as newer diagnostic tools and more widespread use of screening techniques gain popularity [3]. Complete surgical removal of both primary tumor (either lobectomy/bilobectomy or pneumonectomy) and loco-regional lymph-nodes represents the standard of care for such group of patients; despite optimal treatment, which today encompasses radical surgery and adjuvant chemotherapy; however, half of early-stage patients will die due to lung cancer.

While the impact on outcome provided by the extent of lympho-adenectomy in patients undergoing surgery for early NSCLC is still controversial, the nodal involvement must be considered as the most important independent prognostic factor for survival [4]. Indeed, whether the extent of nodal dissection is prognostic, therapeutic or both is currently under debate, although several reports have documented a non-significant effect of such procedure on both disease-free and overall-survival [5], [6].

Several clinical parameters taking into account the involvement of loco-regional nodes have been reported [7]; however, none of them has shown to have a better prognostic potential, as compared to the ‘classical’ TNM staging system.

This issue is of particular importance in a rapidly changing landscape, such as that of early NSCLC, where major changes in the current staging system are expected shortly [8] and the routine use of adjuvant chemotherapy is gaining increasingly popularity. With respect to the latter, the predicted benefits are small and need to be weighted against substantial toxicity [9], [10], [11], making the identification of ‘high-risk’ populations that are likely to benefit most from adjuvant approaches of paramount importance.

Recent data obtained in early-stage breast, colo-rectal, and bladder cancer have suggested a prognostic value of the number of resected lymph-nodes, regardless of their metastatic involvement [12], [13], [14]. We have, therefore, investigated the prognostic impact of the number of resected lymph-nodes in context with other established clinical prognostic factors in a series of 415 consecutive NSCLC patients who were surgically treated at the Regina Elena National Cancer Institute.

Section snippets

Materials and methods

A step-by-step protocol was followed according to the methodological approach for building a nomogram for cancer prognosis proposed by Iasonos et al. [15].

Patient characteristics

A retrospective series of 415 patients (median age 67 years, range 28–86) who underwent surgery with curative intent for NSCLC was retrieved from the original files of the Regina Elena National Cancer Institute. Median number of resected nodes was 15 (range 1–85); 136 (32.8%) had involved nodes (Table 1 and Supplementary table S1). Follow-up data were obtained from hospital charts and corresponding with the referring physicians.

Survival analysis

The first and last retrieved patients underwent surgery in May,

Discussion

Here we report for the first time on the prognostic role of the #RNs and NR in the setting of surgically treated early NSCLC. Within our dataset, both #RNs and NR clearly outperformed other parameters taking into account nodal involvement. In addition, risk classes incorporating a dichotomized #RNs parameter were able to discriminate between high, medium, and low risk patients for all considered outcomes (Fig. 2). The performance of the proposed prognostic model in predicting overall survival

Conflict of interest

Supported by a grant of the National Ministry of Health and the Italian Association for Cancer Research (AIRC). There is no conflict of interest.

Acknowledgements

The authors want to thank: Enrico Penitente, MD (Clinical Research Center, Center of Excellence on Aging, University-Foundation, Chieti), Rocco Leggieri, MD (Department of Surgery, University of Chieti), Alessandra Spagnoli, PhD (‘La Sapienza’ University, Rome), Marcella Mottolese, PhD, Barbara Antoniani (Pathology), and the ‘Regina Elena’ Lung Cancer Disease Management Team (DMT); in particular Alessandra Mirri, MD (Radiotherapy) and Mauro Caterino, MD (Radiology), for their support in the

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The survival curves showed clear differences between each pair of N-#number and N-#ratio categories. A significant tendency toward the deterioration of LCSS from N-#number-1 to N-#number-2b was observed in all tumor size categories. However, the differences between each pair of N-#ratio categories were significant only in tumors from 3 to 7 cm. Although all three nodal classifications were independent prognostic indicators, the N-#number classification provided more accurate prognostic stratifications compared with the N-#ratio classification and the current nodal classification.
The N-#number classification followed by the N-#ratio classification might be better prognostic determinants than the current nodal classification in prognostically heterogeneous N1 or N2 NSCLC.
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The minimum number of nodes that should be removed has not yet been clearly defined. There are significant discrepancies between authors in the literature [6,12–17]. According to some, this number will never be determined, which is also associated with individual conditions of patients [20].
The International Association for the Study of Lung Cancer has proposed a new classification of N descriptor based on the number of metastatic lymph nodes (LNs) stations, including skip metastasis. The aim of the study was to determine the effect of removed LNs on the adequacy of this new classification.
The material was collected retrospectively based on the database of the Polish Lung Cancer Group, including information on 8016 patients with non-small cell lung cancer operated in 23 thoracic surgery centers in Poland. The material covered the period from January 2005 to September 2015. We divided patients into two groups: ≤6LNs and >6LNs removed.
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The proposed classification N descriptor is potentially better at differentiating patients into different stages. The accuracy of the classification depends on the number of lymph nodes removed. Therefore, the extent of lymphadenectomy has a significant impact on the staging of surgically-treated lung cancer.
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^☆: Presented as preliminary data at the 44th American Society of Clinical Oncology meeting held in Chicago, IL, May 30th–June 3rd, 2008.

¹: Both authors (E.B. & M.M.) equally contributed to this work.

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A novel clinical prognostic score incorporating the number of resected lymph-nodes to predict recurrence and survival in non-small-cell lung cancer☆

Abstract

Background

Methods

Results

Conclusions

Introduction

Section snippets

Materials and methods

Patient characteristics

Survival analysis

Discussion

Conflict of interest

Acknowledgements

J Thorac Oncol

Chest

Lung Cancer

Lancet Oncol

J Thorac Surg

Surg Clin North Am

Ann Oncol

J Thorac Oncol

J Thorac Oncol

Clinical cancer advances 2007: major research advances in cancer treatment, prevention, and screening—a report from the American Society of Clinical Oncology

J Clin Oncol

Cancer statistics 2007

CA Cancer J Clin

Multidisciplinary management of lung cancer

N Engl J Med

Effect of number of lymph nodes sampled on outcome in patients with stage I non-small-cell lung cancer

J Clin Oncol

New NSCLC staging raises treatment issues

J Natl Cancer Inst

Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer

N Engl J Med

Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer

N Engl J Med