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Prognostic Stratification of Stage IIIA-N2 Non–Small-Cell Lung Cancer After Induction Chemotherapy: A Model Based on the Combination of Morphometric-Pathologic Response in Mediastinal Nodes and Primary Tumor Response on Serial 18-Fluoro-2-Deoxy-Glucose Positron Emission Tomography

Christophe Dooms, Eric Verbeken, Sigrid Stroobants, Kris Nackaerts, Paul De Leyn, Johan Vansteenkiste

From the Departments of Pulmonology (Respiratory Oncology Unit), Pathology, Nuclear Medicine, and Thoracic Surgery and Leuven Lung Cancer Group, University Hospital Gasthuisberg, Leuven, Belgium

Address reprint requests to Christophe Dooms, MD, Department of Pulmonology, University Hospital Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium; e-mail: christophe.dooms{at}uz.kuleuven.ac.be

	ABSTRACT

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Purpose Surgical resection in patients with stage IIIA-N2 non–small-cell lung cancer (NSCLC) is usually reserved for patients with mediastinal downstaging after induction chemotherapy (IC). However, clinical restaging is often inaccurate, and there are insufficient data to conclude that all patients with persistent mediastinal disease will not benefit from surgery, or that all patients with mediastinal clearance benefit from surgery. We created a data-based restaging strategy combining morphometric tissue analysis of mediastinal lymph nodes (LNs) and 18-fluoro-2-deoxy-glucose positron emission tomography (FDG-PET) response monitoring in the primary tumor.

Patients and Methods Baseline and repeat FDG-PET after IC, as well as complete resection specimens of both mediastinal LNs and primary tumor, were available in 30 patients. Histologic response grading was performed by means of conventional morphometric procedures. Mediastinal response grading combined with the percentage decrease of maximum standardized uptake value (SUV_max) on the primary tumor was correlated with survival.

Results Patients with persistent major mediastinal LN involvement have a 5-year overall survival rate of 0%. The 5-year overall survival rate for patients with cleared or persistent minor mediastinal LN involvement was significantly higher in patients with a more than 60% decrease in SUV_max on the primary tumor as compared with patients with a less than 60% decrease in SUV_max (62% v 13%; log-rank P = .002).

Conclusion These data may suggest that (1) persistent mediastinal disease after IC does not always exclude favorable outcome after surgery; (2) serial FDG-PET may select surgical candidates among patients with mediastinal downstaging or persistent minor disease; (3) persistent major mediastinal disease has a poor prognosis and such patients should not be considered for surgery.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
One approach to patients with resectable stage IIIA-N2 non–small-cell lung cancer (NSCLC) is induction chemotherapy followed by resection.^1-3 Important prognostic factors of 5-year survival (5YS) are (1) the effect of induction chemotherapy on the mediastinal lymph nodes (LNs), (2) its effect on the primary tumor, and (3) the success of surgery.

The clearance of mediastinal lymph nodes (LN downstaging) is the best-studied prognostic factor. First, the 5YS in published series of patients with persistent pN2 disease after induction therapy is poor compared with that of patients with pN0 disease (5YS < 20% v 30% to 40%, respectively^4-8). Second, the pathologic response in the primary tumor is also correlated with outcome.^9,10 Third, patients who have undergone R0 resection do better than those who undergo R1/2 resection.^2,6,7 A problem with these prognostic factors is that they are posthoc analyses, based on pathologic examination of the resection specimen. Moreover, there are insufficient data to exclude all resectable patients with persistent pN2 disease from surgery, as some of these patients can be cured, or to consider surgical resection beneficial for all patients with mediastinal clearance. In patients with persistent pN2 disease, other factors such as the number of LN levels involved^5,11 (single-station better than multistation), baseline subcarinal LN involvement,¹ or pathologic involvement of the upper mediastinal LNs² may play a role.

Ideally, one should have presurgical predictors of good 5YS prospects (prehoc analysis). Unfortunately, the current standard technique for clinical restaging—repeat computer tomography (CT) after induction therapy—is only a raw tool to estimate the degree of (pathologic) response in the LNs and primary tumor and thus prognosis.^12,13 Hence a more quantitative prehoc assessment of the response in mediastinal LNs and primary tumor is warranted.

The morphometric-pathologic regression grade system for NSCLC of Junker et al¹⁴ offers a way to make a quantitative estimate of response in mediastinal LNs. On the other hand, positron emission tomography (PET) using 18-fluoro-2-deoxy-glucose (FDG-PET) can monitor metabolic tumor response after induction therapy for malignant disease, thereby distinguishing between viable tumor and necrosis or fibrosis in indeterminate residual masses often present on conventional imaging.¹⁵ Even in good responders, some residual FDG uptake after induction chemotherapy usually remains in the primary tumor of NSCLC,¹³ so that quantitative comparison of pre- and postinduction PET data (eg, by using standardized uptake value [SUV]) is necessary to have the best estimation of pathologic response, rather than a mere visual assessment post-therapy, as in lymphoma.¹⁶

The purpose of this study was to create a data-driven prehoc prognostic restaging model based on the morphometric-pathologic regression grade in mediastinal LNs in combination with the primary tumor response on FDG-PET after induction chemotherapy for stage IIIA-N2 NSCLC in a cohort of patients with full 5YS data.

	PATIENTS AND METHODS

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Study Population
Between April 1995 and June 2002, 131 patients with potentially operable NSCLC with mediastinoscopy-proven stage IIIA-N2 NSCLC were entered in a prospective institutional protocol with platinum-based induction chemotherapy (IC).¹ A subset of 55 patients also underwent a baseline FDG-PET scan before the start of IC and a repeat FDG-PET scan within 3 to 4 weeks after completion of IC but before the start of locoregional treatment. Thirty of these patients had complete and correct baseline and repeat FDG-PET scan SUV data sets as well as complete surgical resection and were further analyzed in this report (Appendix Fig A1; online only).

Preoperative Assessment
All patients had a baseline spiral CT scan of the thorax and upper abdomen with a slice thickness of 5 mm. A brain scan was requested in all patients with nonsquamous cell lung cancer and in squamous cell lung cancer with neurologic symptoms. Bone scintigraphy was requested only in patients with bone pain, abnormal alkaline phosphatase, or serum calcium. All patients who could potentially undergo resection who had given informed consent underwent baseline FDG-PET followed by cervical mediastinoscopy. In our hospital, a baseline mediastinoscopy was considered standard practice to confirm N2 disease and to rule out N3 disease. During this procedure, the upper right and left paratracheal nodes, the lower right and left paratracheal nodes, and the subcarinal nodes were extensively biopsied and labeled. All patients with proven stage IIIA-N2 NSCLC were consequently treated with IC. Assessment of tumor response was done on a thoracic CT scan 4 weeks after the last dose of cisplatin. After IC, all patients went on to attempted complete resection with systematic mediastinal LN dissection, whereas thoracic radiotherapy was applied only in case of radiologic disease progression on CT, unacceptable surgical risk because of cardiopulmonary limitations, when the disease was considered irresectable after IC by the surgeon, or on patients’ request.¹

Surgical Intervention
Surgical resection was performed with systematic mediastinal LN dissection. Resection was defined complete (R0 resection) if all tumor at the primary site and LNs was removed, with the resection margins negative and the highest mediastinal LNs free of tumor.¹⁷ Adjuvant thoracic radiotherapy (at a total dose of 56 Gy) was given to patients with R1/R2 resection. None of the patients received adjuvant chemotherapy.

Clinical Follow-Up
The follow-up of all patients who are still alive is at least 5 years since histologic diagnosis (median follow-up, 77.3 months; range, 67.2 to 96.7 months). Relapse pattern and cause of death were determined in all cases.

Morphometry of Mediastinal Lymph Nodes and Histologic Response Grading
Two or more hematoxylin-eosin (HE)–stained sections were made of the metastatic LN stations at baseline cervical mediastinoscopy and from the same stations in the postinduction mediastinal LN dissection specimen. The most representative HE-stained slide of the primary tumor and mediastinal LNs have been morphologically analyzed, quantifying the percentage of viable tumor cells on the HE-stained slide after viewing an immunohistochemical prekeratin staining not to miss microfocal disease. According to the fundamentals of stereology of biologic material outlined by Weibel,¹⁸ the tumor was divided in the following compartments of interest: viable tumor cells, fibroblastic connective tissue, necrosis, inflammatory interstitium, foamy macrophages, and cholesterol. The sum of all compartments represents 100% of the tumor volume. The proportion of each compartment has been assessed by a conventional point counting method using a standard light microscope equipped with an eyepiece containing a reticulated counting frame and unbiased counting rule.¹⁹

In line with Junker's regression grading system that separated responders and nonresponders at a cutoff value level of 10% vital tumor tissue,¹⁴ we defined minimal residual microscopic LN disease as the presence of only 10% or less viable tumor cells in the pathologic LN specimen and mediastinal downstaging as clearance of LNs.

Histologic response was predefined in three groups: group 1, downstaging (any percentage of viable tumor cells in the primary tumor and no viable tumor cells in mediastinal LNs); group 2, persistent minor mediastinal involvement (any percentage of viable tumor cells in the primary tumor and 1% to 10% viable tumor cells in mediastinal LNs); group 3, persistent major mediastinal involvement (any percentage of viable tumor cells in the primary tumor and >10% viable tumor cells in mediastinal LNs).

FDG-PET Evaluation of the Primary Tumor Pre- and Postinduction Chemotherapy
All patients who could potentially undergo resection underwent baseline FDG-PET before mediastinoscopy. The methodology of the FDG-PET has been described in detail.²⁰ Interpretation of the FDG-PET was done prospectively and blinded to surgical pathology data. For the determination of the SUV of the primary tumor, regions of interest were manually drawn on the transaxial images around the focal FDG-uptake zones. The maximum SUV within automatically defined three-dimensional regions of interest was used for further calculations. A repeat FDG-PET was performed on the same machine and according to the same acquisition protocol, but the PET result did not influence clinical decision making. Again, the maximum SUV (SUV_max) of the primary tumor was assessed, and the percentage decrease in SUV_max of the primary tumor was calculated.

We chose not to use mediastinal LN assessment on PET in this analysis, as visual interpretation of PET has a suboptimal sensitivity for N-factor restaging,¹² and SUV interpretation is hampered by difficulty in partial volume correction for mediastinal lymph nodes less than 15 mm and by the presence of central location of the primary tumor in some patients. Therefore, pathologic nodal tissue confirmation is needed.

Data Analysis
Spearman rank correlation was used to assess the relationship between decrease in SUV_max and residual viable tumor cells in the primary tumor. The Mann-Whitney U test was applied to assess the association between continuous variables. Survival curves were calculated by the Kaplan-Meier method, and groups were compared with the log-rank test. Survival time was defined as the time between tumor diagnosis by histology and death or last follow-up. All of the statistical analyses were performed with a statistical software package, using GraphPad Prism version 4.00 for Windows (GraphPad Software, San Diego, CA).

	RESULTS

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Patient Characteristics
Thirty patients with stage IIIA-N2 NSCLC underwent complete surgical resection and were analyzed in this report. Patient and tumor characteristics of these 30 patients, as well as response to chemotherapy and surgical characteristics, are listed in Table 1. For these 30 patients, the median survival time (MST) and 5YS were 36.1 months and 29%, respectively.

View larger version (14K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Kaplan-Meier survival curve of single-item prognostic factors according to (A) pathologic mediastinal N stage, and (B) percentage decrease in maximum standardized uptake value (SUVmax) on primary tumor.

Predictive value of prehoc FDG-PET for posthoc pathologic response. We observed a significant correlation between the percentage of residual viable tumor cells in the primary tumor after induction chemotherapy and both SUV_max post (r = 0.55 and P = .0016; Fig 2A), and percentage decrease in SUV_max (r = –0.60 and P = .0005; Fig 2B).

View larger version (15K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Correlation between percentage residual viable tumor cells in the primary tumor and maximum standardized uptake value (SUVmax) post (A) or percentage decrease in SUVmax (B) in the primary tumor.

View larger version (14K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Kaplan-Meier survival curve of combined prognostic factors.

View larger version (9K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 4. Decision flow chart after induction chemotherapy.

	DISCUSSION

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Patients with persistent major mediastinal LN involvement after induction therapy do not benefit from surgery, as they have a poor prognosis. The rationale for considering patients with persistent minor mediastinal LN disease after induction therapy as a distinct subgroup, having major involvement at baseline mediastinoscopy, is generated from the observation that patients with unforeseen minimal pN2 disease after primary surgery for clinical N0 disease have rewarding 5YS rates of 20% to 34% without adjuvant chemotherapy.^5,23 The evaluation after induction therapy of patients with persistent minor mediastinal involvement, as well as the ones with mediastinal clearance after induction therapy, is a challenge, where metabolic response as an additional element may orientate clinical decision making.

Probably the most promising assessment criterion of a repeat PET after induction therapy for stage III NSCLC is the quantitative FDG uptake of the primary tumor, as shown in a pilot study by our group many years ago.²⁰ Since then, prospective studies by other research groups^24,25 confirmed that the magnitude in changes of the FDG uptake in the primary tumor accurately predicts the histopathologic response to induction therapy (Fig 2). Looking at survival outcome rather than pathologic response, literature data for repeat SUV_max are scarce and conflicting. One report with a median patient follow-up of 28 months concluded that residual and median fractional change (set at 48%) of glucose metabolism on the primary tumor provided the best prediction of outcome after IC for stage IIIA-N2 NSCLC.¹² Pottgen et al²⁵ concluded that patients with a better PET response on the primary tumor (defined as a decrease in SUV_max of > 50%) had a similar overall 2-year survival rate as compared with patients with a poor PET response (defined as a decrease of < 50%). A greater than 60% decrease of SUV_max was indicative for a favorable 5YS, whereas a less than 25% decrease could denote a nonresponder and indicated extremely unfavorable outcome in another study.²⁶

Our data suggest that it is promising to combine histologic data on mediastinal LNs (to refine the concept of mediastinal downstaging) with metabolic SUV_max data on the primary tumor (to refine the preoperative information on degree of pathologic response; Fig 4). Dividing patients in good prognosis compared with poor prognosis groups (Fig 3A) according to this combination leads to an HR of 0.18 with a 95% CI of 0.06 to 0.38. The upper limit of the 95% CI is lower than the HR of 0.50 for classical mediastinal downstaging as compared with persistent N2 (Fig 1A). Hence this histologic assessment of mediastinal LNs in combination with the metabolic FDG-PET response on the primary tumor can become important in evaluating which patient is a candidate for surgery after IC for stage IIIA-N2 NSCLC, as it is still unclear whether only or all patients with mediastinal clearance should be offered surgery. The morphometry of mediastinal LNs filters those patients with persistent N2 disease with more than 10% malignant cells having a poor 5YS of 0% in our series. The SUV response filters at some cutoff value of percentage decrease in SUV_max (set at 60% in this study) those patients with mediastinal clearance or persistent minor N2 disease who do not have a favorable prognosis.

The strengths of this study are the long-term follow-up, the meticulous baseline staging, baseline and repeat PET scans on the same machine and prospectively analyzed by the same physician, and complete LN dissection and tumor resection after IC. The weaknesses are the nature of a retrospective data–driven cohort study of a prospective database and the low number of patients.

In the near future, endobronchial ultrasonograhy-controlled transbronchial needle aspiration and esophageal ultrasonography-controlled fine needle aspiration will replace cervical mediastinoscopy for baseline mediastinal LN staging in NSCLC, keeping cervical mediastinoscopy available for postinduction assessment of the mediastinal nodes. Mediastinal restaging using mediastinoscopy after induction therapy and serial FDG-PET of the primary tumor may complement each other as suggested in this analysis. However, this concept needs validation in a large prospective series. Patients having good prognosis in our suggested concept could be considered for radical approaches, whereas this approach may be futile in the others. Furthermore, investigators conducting future clinical trials on the role of surgical multimodality treatment for patients with resectable stage IIIA-N2 NSCLC could consider including this concept within the study design.

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
The author(s) indicated no potential conflicts of interest.

	AUTHOR CONTRIBUTIONS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Conception and design: Christophe Dooms, Johan Vansteenkiste

Provision of study materials or patients: Christophe Dooms, Eric Verbeken, Kris Nackaerts, Johan Vansteenkiste

Collection and assembly of data: Christophe Dooms, Paul De Leyn, Johan Vansteenkiste

Data analysis and interpretation: Christophe Dooms, Eric Verbeken, Sigrid Stroobants, Kris Nackaerts, Paul De Leyn

Manuscript writing: Christophe Dooms, Johan Vansteenkiste

Final approval of manuscript: Christophe Dooms, Eric Verbeken, Sigrid Stroobants, Kris Nackaerts, Paul De Leyn, Johan Vansteenkiste

	Appendix

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View larger version (19K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig A1. Flow chart of patients included in the analysis.

	ACKNOWLEDGMENTS

 
We thank Bea Anrys, RN, for her dedicated assistance in retrieving all clinical follow-up data.

	NOTES

 
Supported by the Fonds voor Wetenschappelijk Onderzoek Grant No. G.0134.04 (C.D.).

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

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Submitted August 19, 2007; accepted November 6, 2007.

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