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 Table of Contents  
ORIGINAL ARTICLE
Year : 2012  |  Volume : 8  |  Issue : 2  |  Page : 247-253

CT findings in non-small-cell lung cancer patients treated with gefitinib or erlotinib


1 Department of Internal Medicine, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, South Korea
2 Department of Radiology, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, South Korea
3 Department of Pathology, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, South Korea
4 Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea

Date of Web Publication26-Jul-2012

Correspondence Address:
Im Il Na
Department of Internal Medicine, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, 215-4, Gongneung-dong, Nowon-gu, Seoul, 139-706
South Korea
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.98979

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 > Abstract 

Purpose: We performed this study to explore the association of computed tomography (CT) findings with outcomes of patients with non-small-cell lung cancer (NSCLC) treated with tyrosin kinase inhibitor (TKI) such as gefitinib or erlotinib.
Materials and Methods: We analyzed outcomes for 240 patients according to primary tumor (T), regional nodal (N) staging and diffuse small pulmonary metastases (DSPM) at the initial presentation. Tests for epidermal growth factor receptor (EGFR) mutation were performed in 92 patients.
Results: On multivariate analysis for tumor response, the N3 stage was predictive of a poor response (P < 0.001), whereas DSPM was a favorable factor (P = 0.007). Multivariate analysis for progression-free survival showed that the T3-4 stage (hazard ratio [HR]: 2.5, P < 0.001), in addition to the N3 stage (HR: 2.1, P < 0.001), was predictive of a poor outcome, whereas DSPM (HR: 0.6, P = 0.006) was a favorable factor. Notably, the multivariate model that included the EGFR mutational status revealed that the T3-4 stage predicted poor progression-free survival (HR: 2.2, P = 0.017) and poor overall survival (HR: 4.1, P < 0.001).
Conclusion: Our data suggest that, in addition to EGFR mutational status, T-stage based on CT is predictive of outcomes of TKI-treated NSCLC patients.

Keywords: Epidermal growth factor receptor, erlotinib, gefitinib, mutation, non-small-cell lung cancer, stage


How to cite this article:
Il Na I, Choe DH, Kim CH, Park SH, Park JH, Lee JC. CT findings in non-small-cell lung cancer patients treated with gefitinib or erlotinib. J Can Res Ther 2012;8:247-53

How to cite this URL:
Il Na I, Choe DH, Kim CH, Park SH, Park JH, Lee JC. CT findings in non-small-cell lung cancer patients treated with gefitinib or erlotinib. J Can Res Ther [serial online] 2012 [cited 2019 Sep 16];8:247-53. Available from: http://www.cancerjournal.net/text.asp?2012/8/2/247/98979


 > Introduction Top


Lung cancer is the leading cause of cancer mortality worldwide and the most common type is non-small-cell lung cancer (NSCLC). [1],[2] Although patients with localized disease can be cured, those with distant metastatic lesions have a dismal prognosis. [3],[4] To improve their poor prognosis, tyrosine kinase inhibitors (TKIs) such as gefitinib or erlotinib have been introduced. Previous studies have shown that Asian ethnicity, an adenocarcinoma histology, and never-smokers are associated with favorable outcomes for TKI-treated patients with NSCLC. [5],[6],[7],[8] Further molecular studies have revealed that mutation in the epidermal growth factor receptor (EGFR) is one of the strongest factors to predict the outcomes of TKI-treated patients. [9],[10]

The phase III IRESS Pan-Asia study (IPASS) has demonstrated that further selection can be useful, based on genetic tests, for patients among a clinically selected population. [9] In that prospective trial, the EGFR mutation testing results were obtained from 35.9% of the study population. [9] However, several limitations of mutational tests, such as a time consuming process and the availability of equipment, still remain. In addition, the data on the EGFR mutational status are often unavailable on account of insufficient tissue. [11] Thus, a further invasive procedure for the molecular test is often needed.

A recent study suggests different outcomes of TKI-treated NSCLC patients according to clinical factors other than molecular data. [12] For example, in that data, prolonged survival in female patients was observed in the population with mutated EGFR. [12] Identifying the independent factors other than EGFR mutation to predict outcomes may be helpful for selecting patients for TKI-treatment, and particularly for those patients who cannot tolerate invasive procedures to obtain tissues for molecular tests.

Computed tomography (CT) scanning is one of the mandatory procedures at initial presentation and a useful tool for clinical information on NSCLC patients. [13] Recent studies suggests that tumor characteristics based on CT findings have been associated with TKI-responsiveness or the presence of EGFR mutation. [14],[15],[16] Investigators have reported the potential impact of diffuse small pulmonary metastases (DSPM) with a military pattern in TKI-treated patients. [14],[15] An association of regional nodal (N) staging with the frequency of EGFR mutation has also been suggested. [16] However, the predictive value of the N stage with respect to TKI therapy has not yet been reported yet. In addition, although some investigators have reported the association of EGFR mutation with the tumor size, [14] the clinical significance of the primary tumor (T) staging in TKI-treated patients has not been defined.

Having a better understanding of the association of the clinical presentation with the outcomes of TKI-treated patients is important for physicians who are dealing with disseminated disease for selecting patients and monitoring their benefits from treatment. In this retrospective study, we attempted to explore the impact of TN staging and DSPM with respect to TKI therapy. In addition, to evaluate potential significance in the context of EGFR mutational status, the outcomes according to TN staging and DSPM were analyzed in patients whose mutational status was tested.


 > Materials and Methods Top


Patients

We identified the consecutive patients with NSCLC and who had received TKI between October 2005 and August 2010 from the database of the Korea Cancer Center Hospital (Seoul, Republic of Korea). We analyzed the patients who were diagnosed as stage IV using a revised staging system. [17] Among these, five patients with a prior history of malignancy (except thyroid cancer) within 5 years were excluded. We also excluded two patients who had received TKI combined with chemotherapeutic agents. Finally, we gathered the data on 240 patients who had received TKI monotherapy (gefitinib [n = 158] or erlotinib [n = 82]). The TN staging at the time of diagnosis was performed based on the CT images. The T staging was determined by the characteristics of the primary tumors without considering the separate nodules [Figure 1]a. Positive regional lymph nodes were determined cytologically or based on the short-axis diameter (>1 cm) on the transaxial CT images. [18] DSPM was defined as pulmonary metastases with numerous discrete small nodules (<1 cm for the diameter) distributed in the whole lung field (the cutoff of ≥ 20 nodules was chosen based on analysis of the tumor response and the number of metastatic nodules using semiquantitative measures [data not shown]) [Figure 1]b. Two thoracic radiologists (DHC and JHP) reviewed the CT images and decisions on the TN staging were reached by consensus.
Figure 1: Representative CT finding of the tumors with an advanced T stage (T4) extending into the mediastinum (a) and diffuse small pulmonary metastases (b)

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In most cases, TKI monotherapy (gefitinib 250 mg or erlotinib 150 mg/day) had been delivered until disease progression. Skin rash, which was manageable in most cases, was observed in 31% of the patients. In seven patients, therapy was discontinued because of intolerable toxicity (interstitial lung disease in three patients and hepatotoxicity in two patients) or refusal (in two patients). CT scans were initially performed at 4 or 8 weeks after TKI treatment and every 8 weeks thereafter. The responses to TKI were classified as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) using the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. [19] The institutional review board of Korea Cancer Center Hospital approved this study.

EGFR genotyping

We gathered the mutational data of 92 patients who had been successfully tested for their EGFR mutational status with their informed consent. DNA extraction using paraffin-embedded tissues or the methanol-fixed cytologic specimens was performed as described elsewhere. [20],[21] Pyrosequencing was performed in 69 patients using a previously described method. [16] In 23 patients, the EGFR mutational status was analyzed by direct sequencing. [20] The presence of EGFR mutations was determined by mutations in exons 18, 19, and 21.

Statistical analysis

Pearson's χ2 -test was used for analysis of the categorical variables. Multivariate logistic regression was used to analyze the clinical factors in terms of TKI responsiveness or the presence of EGFR mutations. The progression-free survival (PFS) and overall survival (OS) were calculated from the time of the initiation of TKI therapy. The survival curves were estimated using the Kaplan-Meier method. Univariate analysis for the survival outcomes was performed using the log-rank test. Multivariate analysis was performed using the Cox proportional hazards model. The odds ratios (ORs), hazard ratios (HRs), and their 95% confidence intervals (CI) were determined. Stata version 9.0 (Stata Corp., College Station, TX) was used for all the statistical analyses. All P values were derived from two-sided tests, and P values <0.05 were considered significant.


 > Results Top


Descriptive data

[Table 1] shows the baseline characteristics of the TKI-treated patients with NSCLC. The median age was 60 years and 56% of the patients were women. More than half of patients were never-smokers and 83% of the patients had adenocarcinomas. The most common sites of extrathoracic metastases at presentation were bone (53%, 121 patients) and brain (32%, 69 patients). Most of the patients received initial chemotherapy with a platinum-based doublet with paclitaxel, docetaxel, or gemcitabine as the initial chemotherpy. Nine patients received gemcitabine (7 patients) or paclitaxel (2 patients) monotherapy. TKI was delivered as a first-line therapy in 26 (11%) patients.
Table 1: Patient characteristics (n = 240)

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Clinical factors and outcomes

The tumor response was evaluable in 223 patients. An antitumor response was observed in 99 patients (2 CR + 97 PR). [Table 2] shows the results for the tumor responsiveness according to the clinical factors, including the TN factors and DSPM. On the univariate analysis, female gender (P < 0.001), adenocarcinoma (P = 0.001), and never-smokers (P < 0.001) were associated with a favorable response. Patients with DSPM showed a better response rate than those patients without it (P < 0.001). T3-4 (P < 0.001), N3 (P < 0.001) and a tumor size ≥ 3.8 cm (P = 0.010) were associated with an unfavorable tumor response. Multivariate analysis showed that a smoking history, the histology, the N factor, and the presence of DSPM maintained statistical significance for a tumor response (P = 0.049, 0.008, and <0.001, respectively). However, the difference of the response rate according to the T stage did not reach statistical significance (P = 0.063).
Table 2: Association of the clinical factors with the tumor response and progression free survival

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Disease progression in 188 patients was observed until November 2010. The median PFS of all the patients was 14.0 weeks (95% CI, 9.0-18.6 weeks). [Table 2] lists the results of the univariate and multivariate analyses of the PFS. On the univariate analysis of PFS, never-smokers (P < 0.001), female gender (P < 0.001), and the presence of DSPM (P = 0.004) were favorable factors for survival. The tendency toward improved survival for adenocarcinomas was observed (P = 0.071). In contrast, T3-4 (P < 0.001), N3 (P < 0.001), and a tumor size ≥ 3.8 cm (P = 0.043) were associated with poor survival. The Cox model, which included age, the histology, a smoking history, the performance status and gender, showed that T3-4 (P < 0.001) and N3 stage (P < 0.001) remained unfavorable factors for survival. In addition, DSPM was associated with favorable outcomes (P = 0.007).

When we analyzed OS, the median survival time was 45.9 weeks (95% CI: 38.0-59.9 weeks) and 175 deaths were observed. Multivariate analysis, as corrected for age, the histology, a smoking history and gender revealed that T2-3 (adjusted HR: 2.71, 95% CI: 1.83-4.03, P < 0.001; [Figure 2]a), N3 (adjusted HR: 1.90, 95% CI: 1.39-2.59, P < 0.001), and a performance status of 2-3 (adjusted HR: 2.01, 95% CI: 1.46-2.77, P < 0.001) were independent factors for poor OS. However, improved survival in the patients with DSPM did not reach a statistical significance (adjusted HR: 0.71, 95% CI: 0.48-1.05, P = 0.089).
Figure 2: Kaplan– Meier plots of overall survival according to the T stage in the whole population (a), and the subpopulation of patients with a mutated EGFR gene (b) and the wild type gene (c)

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Significance of clinical factors with consideration of the EGFR mutational status

EGFR mutations were identified in 42 (46%) patients. These EGFR mutations included in-frame deletions within exon 19 (n = 23), L858R substitutions in exon 21 (n = 15) and a G719X substitution in exon 18 (n = 3). One patient carried two mutations (G719X/L858R). The association between the EGFR mutational status and the clinical factors was analyzed in 92 patients [Table 3]. In addition to a smoking history (P < 0.001) and gender (P < 0.001), the N stage and DSPM were associated with the EGFR mutational status on the univariate analysis (P = 0.001 and 0.016, respectively). On the multivariate analysis, a smoking history and N stage remained significant factors (P = 0.028 and 0.002, respectively). The different frequency of EGFR mutation according to DSPM did not reach a statistical difference (P = 0.118). We next analyzed the clinicomolecular findings with respect to a tumor response [Table 3]. Of the clinicomolecular factors such as a smoking history, gender, histology and the EGFR mutational status, which were significant factors on the univariate analysis, only the molecular status alone maintained an independent statistical value for a tumor response (P < 0.001). On the multivariate analysis for PFS, a mutated EGFR gene (P < 0.001) and the T1-2 stage (P < 0.001) independently predicted favorable survival (P = 0.017). When we analyzed OS according to the T stage and mutational status [Figure 2]b and c, the T3-4 stage was associated with poor OS across the strata of mutated EGFR genes (median OS: 112.3 weeks for T1-2 versus 17.4 weeks for T3-4, P < 0.001) and the wild type gene (median OS: 21.3 weeks for T1-2 versus 9.3 weeks for T3-4, P = 0.049). The multivariate Cox model, corrected for age, histology, the smoking history and gender, also revealed that T3-4 (adjusted HR: 4.1, 95% CI: 2.1-8.1, P < 0.001) and performance status of 2-3 (adjusted HR: 2.5, 95% CI: 1.3-4.7, P = 0.004) were independent factors for poor OS. A mutated EGFR gene was a favorable factor for OS, but the difference did not reach a statistical significance (adjusted HR: 0.5, 95% CI: 0.3-1.0, P = 0.051). The N stage and DSPM did not independently predict OS (data not shown).
Table 3: Predictive factors for EGFR Mutation and the results of the outcome analysis (n = 92)

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 > Discussion Top


In this study, we described the results of analyzing the clinical outcomes of TKI-treated NSCLC patients with respect to the TN factors and the pulmonary metastatic pattern. In addition, the significance of these factors was evaluated according to the EGFR mutational status. In our data, the TN factors were predictive of poor outcomes, whereas DSPM was associated with a favorable outcome. Importantly, an advanced T stage was strongly associated with poor survival even with consideration of the EGFR mutational status, whereas the independent role of DSPM and the N stage was not observed.

Our data indicate that the characteristics of the primary tumor such as the tumor size and the extent of local invasion may be useful to predict the outcome after TKI therapy. It appears that the T stage may be relatively more linked with survival than the tumor response. Of note, the independent value of the T factor was also maintained in the survival model including the EGFR mutational status. Careful interpretation is needed because the T factor in this study was not defined using traditional criteria. [17] In fact, when metastatic pulmonary nodules were considered in the definition of advanced T, it remained predictive of poor survival (data not shown). However, in the survival model including EGFR mutational status, the traditional T stage could not maintain a statistical significance (adjusted HR for PFS: 1.28, 95% CI: 0.69-2.38, P = 0.441), suggesting the more usefulness of the proposed criteria. Further studies need to be followed to define the role of T stage in TKI-treated patients.

The predictive value of the N stage, with respect to tumor response and survival, was not statistically significant when the EGFR mutational status was considered. Similarly, the role of DSPM seems to be weakened on the analysis that included the EGFR mutational status. The inability to maintain the statistical value of the clinical factors, with consideration of the EGFR mutational status, may highlight the results of the IPASS, which documented the impact of the EGFR mutational status even in selected patients based on clinical factors. [9] In addition to the possibility of the limited power from the study's sample size, a plausible explanation is that the impact of N factor along with DSPM, despite their associations with EGFR mutation, did not exceed that of EGFR mutational status. However, this is not the case for the T factor. The association between the T factor and survival in our data suggests that the T factor, in addition to the EGFR mutational status, can improve the predictive accuracy for the outcomes in the TKI-treated patients.

This is the first study to analyze the survival outcomes and mutational status according to the unique pulmonary presentation and the nodal status. Although the retrospective nature of this study has a bias for the patients' selection, the predominance of EGFR mutation in females and never-smokers was consistent with the results of previous observation. [5],[6],[7],[8] The associations of EGFR mutations with DSPM are partly in line with the findings of previous studies. [14],[22] In addition, a previous report suggesting a different nodal presentation according to the mutational status [16] may explain a poor outcome for patients with N3 stage disease. However, there is the uncertainty of the cutoff value for the number of diffuse pulmonary metastases to predict outcomes. The different incidence of EGFR mutations according to N stage also needs to be confirmed in prospective manners.

Our observations indicate improved accuracy to predict outcomes with respect to TKI therapy without an invasive procedure. Despite limited accuracy for N staging, [23] CT has the advantages of wide availability and cost compared with positron emission tomography. It should be considered that CT has relatively easy application in low and moderate-resource areas that have an increasing burden of cancer. [24],[25] In addition, CT findings appear to be relevant in selecting patients who will be beneficial from TKI, if they cannot tolerate an invasive procedure.

It is unclear that TN factors have clinical significance only for TKI-treated patients. Although a recent study suggests that the N stage is associated with survival in patients with an advanced stage, [26] to the best of our knowledge, there is scarce clinical data evaluating impact of the T stage in advanced NSCLC patients. In addition, it should be considered that we have used different criteria of the T stage. Because in the disseminated stage, in contrast to an early stage, separate nodules confined to the ipsilateral lobe seems to be uncommon and they are difficult to pathologically confirm, we did not count separate nodules into the T stage. The prognostic or predictive role of the TN stage needs to be determined through further studies. [27]


 > Conclusion Top


The results of this study indicate that the T stage, in addition to the EGFR mutational status, may be predictive of outcomes in TKI-treated NSCLC patients with advanced stage. Molecular analysis suggests that the N stage and the pulmonary metastatic pattern are associated with the EGFR mutational status. Although we retrospectively collected the data, the result of this study warrant further extensive studies for validation and to increase understanding of the clinical course of TKI-treated patients. In addition, this study may encourage physicians' to pay close attention to the local tumor factors at the time of diagnosis.

 
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    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]


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