Staging with PET-CT in Patients with Locally Advanced Non Small Cell Lung Cancer is Superior to Conventional Staging Methods in Terms of Survival

It is widely known that lung cancer is the leading cause of cancer releated deaths in worlwide (Parkin et al., 2005; Demirci et al., 2013). Approximetely 80% of newly diagnosed lung cancers are non small cell lung cancer (NSCLC). At the time of diagnosis approximately 43% of patients who are suffering from NSCLC are locally advanced (Tachfouti et al., 2012). According to the 7th edition of Tumor, Node, Metastasis (TNM) in lung cancer, locally advanced NSCLC consists of stage III A (T1a,b T2 a,b N2M0/T3N1,2M0/T4N0,1M0) and IIIB (T4N2M0/T any N3M0) disease (Marshall et al., 2012). Currently, surgical resection remains the primary strategy for the treatment of patients with NSCLC at stage I, II, and IIIA (Wang et al., 2012). But only 20% of patients with stage III are cured by surgery. Therefore there is a disagreement among the oncologists in terms of whether surgery is necessary for treatment of locally advanced NSCLC or not. In order to improve the outcomes of the locally advanced NSCLC, sequential chemoradiation (Le Chevalier et al., 1992; Sause et al., 1995; Dillman et al., 1996; Brown et


Introduction
It is widely known that lung cancer is the leading cause of cancer releated deaths in worlwide (Parkin et al., 2005;Demirci et al., 2013).Approximetely 80% of newly diagnosed lung cancers are non small cell lung cancer (NSCLC).At the time of diagnosis approximately 43% of patients who are suffering from NSCLC are locally advanced (Tachfouti et al., 2012).According to the 7 th edition of Tumor, Node, Metastasis (TNM) in lung cancer, locally advanced NSCLC consists of stage III A (T1a,b T2 a,b N2M0/T3N1,2M0/T4N0,1M0) and IIIB (T4N2M0/T any N3M0) disease (Marshall et al., 2012).Currently, surgical resection remains the primary strategy for the treatment of patients with NSCLC at stage I, II, and IIIA (Wang et al., 2012).But only 20% of patients with stage III are cured by surgery.Therefore there is a disagreement among the oncologists in terms of whether surgery is necessary for treatment of locally advanced NSCLC or not.In order to improve the outcomes of the locally advanced NSCLC, sequential chemoradiation (Le Chevalier et al., 1992;Sause et al., 1995;Dillman et al., 1996 al., 2013), concurrent chemoradiation (Furuse et al., 1999;Zatloukal et al., 2004;Curran et al., 2011), concurrent chemoradiation with induction or consolidation (Albain et al., 2002;Gandara et al., 2003;Belani et al., 2005;Vokes et al., 2007;Driesen et al., 2013) have been investigated.
Positron emission tomography (PET) with the glucose analogue, 2-[18F]-fluoro-2-deoxy-d-glucose (FDG) has been successfully used in the care of patients with NSCLC such as the staging procedures, radiotherapy planning and the evaluation of response to the treatment (Paesmans et al., 2010).Compared to computerized tomography (CT), PET has been demonstrated to have superior sensitivity and specificity in the detection of mediastinal lymph nodes metastases (Gupta et al., 1999;Birim et al., 2005).Today, PET combined with computerized tomography (PET-CT) is accepted as the most sensitive technique for detecting extracranial metastases from NSCLC (Antoch et al., 2003;Gámez et al., 2006;Li et al., 2013;Silvestri et al., 2013).
In presented study, we aimed to compare the superiority of PET-CT and conventional staging procedure to the decision of curative treatment in locally advanced NSCLC.

Materials and Methods
The patients diagnosed with locally advanced NSCLC from Acıbadem Kayseri Hospital, Acıbadem Adana Hospital and Kayseri Research and Training Hospital were included in this study.Between the years 2006-2011, total of 168 consequitive patients who were diagnosed with locally advanced NSCLC were analysed retrospectively, with the age of using hospital records.The patients were divided into two groups according to staging procedure for baseline staging: PET-CT or conventional methods which include CT and/or brain MR, bone scintigraphy.Staging was made according to the 6 th or 7 th version of TNM lung cancer staging system.PET-CT and conventional groups consisted of 82 and 86 patients, respectively.The patients received one of chemoradiotherapy, induction chemotherapy followed chemoradiotherapy or surgery and chemoradiotherapy followed consolidation chemotherapy for curative treatment regimen.
Age, gender, histological subtypes of cancer, tumor (T) stage, nodal (N) stage, stage, comorbidity and smoking status (current or former smoker) were recorded  to Statistical Package for the Social Sciences 16.0 (SPSS16.0)statistical software for analysis.

PET-CT Protocol
The patients were injected about 10 mCi (370 MBq) of FDG in travenously.After one-hour-relaxing in a silent room, the patient was imaged by using an integrated PET/ CT camera.PET/CT scan was performed by using PET-CT (Siemens Biography 6, LSO, 3D).The CT portion of the study was done without intravenous contrast medium, and used for defining anatomical signs and marks, also for attenuation correction of the PET reconstruction.
Descriptive tests, chi square, independent-samples tests and survival analyses were performed for analysis.Survival time was estimated by the Kaplan-Meier method and the survival difference between groups was assessed by the log-rank test.P<0.05 was considered as a significant statistic.

Results
The characteristics of patients were given in Table 1.Mean age of patients were 62.3±9.3 in PET CT groups and other groups were 63.3±9.9 (p=0.570).The male and female ratio had a significant difference between these groups (p=0.028).However, there was no significant difference regarding histology of cancer (p=0.356),T stage (p=0.162),N stage (p=0.224),stage (p=0.481),comorbidity (p=0.173) and smoking status (p=0.184).
Considering treatment protocols, while Neoadjuvan Chemotherapy" Chemoradiotherapy was mostly offered to the patients in PET-CT groups (38%), Chemoradiotherapy was offered mostly in the other group (54%).Treatment protocols in the groups were given in Table 2 and chemotherapy regimens that were offered as neoadjuvant or concurrent with radiotherapy or consolidation were given in Table 3.
When we evaluated the groups in terms of survival, both of progression free survival (PFS) and overall survival (OS) significantly differed between the groups.While the median PFS were 13.0±1.9(95%CI 9.16-16.8) in PET-CT groups, it was respectively 6.0±0.9 (95%CI 4.07-7.92) in other groups (p<0.001).The median OS was 20. ) in PET-CT groups and 11.5±1.5 (95% CI 8.45-14.55) in the conventional methods group (p<0.001).PFS and OS of groups were depicted in Table 4.In addition to that PFS was shown in Figure 1 and OS was shown in Figure 2.

Discussion
Currently, PET-CT is accepted as the most sensitive technique for detecting the extracranial metastases and it has superior sensitivity and specificity in the detection of mediastinal lymph nodes metastases for baseline staging at the time of diagnosis in NSCLC.In locally advanced NSCLC (potentially curable disease especially stage IIIA), PET-CT is considered as the first line imaging test (Christian, 2010).
In presented study, we did not aim that whether PET-CT is superior to conventional staging procedure or not in terms of staging of patients with locally advanced NSCLC.We evaluated that whether the superiority of PET-CT in terms of staging was leading to the survival advantage in patients who were accepted as locally advanced NSCLC according to baseline staging.And we found that both of PFS and OS were significantly different.The patients who were staged with PET-CT at the time of diagnosis had better PFS and OS.
It has been reported that PET-CT reveals the occult distant metastases in additional 5-29% of patients as CT alone (Schrevens et al., 2004).Our findings maybe related to this result that was mentioned above.Due to occult metastases which were not detected by conventional staging methods, the patients who had distant metastases could be accepted as locally advanced NSCLC; and curative treatment modalities were offered by them.In addition to that it has been reported that the staging with PET-CT had additional value for radiotherapy planning (Grégoire et al., 2007;Ding et al., 2013).This result may save the patients from toxic deaths.
As a result, we found that the staging with PET-CT has better results in terms of survival like staging.The superiority of PET-CT in staging is leading to survival advantage in patients with locally advanced NSCLC.