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Prognosticators and Risk Grouping in Patients with Lung Metastasis from Nasopharyngeal Carcinoma: A more accurate and appropriate assessment of prognosis

Prognosticators and Risk Grouping in Patients with Lung Metastasis from Nasopharyngeal Carcinoma:... Background: Lung metastases arising from nasopharyngeal carcinomas (NPC) have a relatively favourable prognosis. The purpose of this study was to identify the prognostic factors and to establish a risk grouping in patients with lung metastases from NPC. Methods: A total of 198 patients who developed lung metastases from NPC after primary therapy were retrospectively recruited from January 1982 to December 2000. Univariate and multivariate analyses of clinical variables were performed using Cox proportional hazards regression models. Actuarial survival rates were plotted against time using the Kaplan-Meier method, and log-rank testing was used to compare the differences between the curves. Results: The median overall survival (OS) period and the lung metastasis survival (LMS) period were 51.5 and 20.9 months, respectively. After univariate and multivariate analyses of the clinical variables, age, T classification, N classification, site of metastases, secondary metastases and disease-free interval (DFI) correlated with OS, whereas age, VCA-IgA titre, number of metastases and secondary metastases were related to LMS. The prognoses of the low- (score 0-1), intermediate- (score 2-3) and high-risk (score 4-8) subsets based on these factors were significantly different. The 3-, 5- and 10-year survival rates of the low-, intermediate- and high-risk subsets, respectively (P < 0.001) were as follows: 77.3%, 60% and 59%; 52.3%, 30% and 27.8%; and 20.5%, 7% and 0%. Conclusions: In this study, clinical variables provided prognostic indicators of survival in NPC patients with lung metastases. Risk subsets would help in a more accurate assessment of a patient’s prognosis in the clinical setting and could facilitate the establishment of patient-tailored medical strategies and supports. Keywords: lung metastasis, nasopharyngeal carcinoma, prognosis, risk subset Background endemic NPCs are type II (non-keratinising carcinoma) Nasopharyngeal carcinoma (NPC) is a common epithe- and type III (undifferentiated carcinoma), with a high lial malignancy in southern China [1-3]. The highest incidence of lymphatic and circulatory metastasis [3,4]. incidence has been reported in Guangdong province, With improvements in the control of local disease due to advanced diagnostic methods, radiotherapeutic tech- where the rate is approximately 20 per 100,000 people per year [1,2]. According to World Health Organisation niques and chemotherapy regimens, distant metastasis (WHO) classification based on histological type, most (DM) is increasingly becoming the major cause of mor- tality in NPCs [5,6]. The survival period after DM is variable, and long-term survival is improved in patients * Correspondence: wenzhsh@sysucc.org.cn who receive aggressive multimodality therapy [7-11]. † Contributed equally Lung metastasis commonly occurs in NPC [9,12,13]. State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat- Sen University, No. 651, Dongfeng Road East, 510060, Guangzhou, China Some studies have reported that patients with lung Full list of author information is available at the end of the article © 2011 Cao et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Cao et al. Radiation Oncology 2011, 6:104 Page 2 of 10 http://www.ro-journal.com/content/6/1/104 metastasis belong to a distinct group with a good prog- Table 1 Patient and disease characteristics of 198 NPC patients with lung metastasis nosis and better survival [8,9,13-15]. Nevertheless, no systematic study has specifically addressed the factors Characteristics No. of Patients % that are associated with lung metastasis in NPC patients. Gender Hence, our retrospective study was designed to examine Male 156 78.8 the relationship between clinical factors and lung metas- Female 42 21.2 tasis survival (LMS) and overall survival (OS), as well as Age (years) to identify low-, intermediate- and high-risk subsets that Median 44.5 may help in the development of patient-tailored medical Range 20-80 support and treatment. ≤45 108 54.5 >45 90 45.5 Methods VCA-IgA Patients ≤1:320 119 60.1 Subjects were recruited at the Sun-Yat-Sun University >1:320 79 39.9 Cancer Centre between January 1982 and December EA-IgA 2000. A total of 198 NPC patients with histologically ≤1:40 128 64.6 confirmed NPC who were previously untreated, had no >1:40 70 35.4 evidence of distant metastases (M0) at the time of diag- Histology (WHO) nosis of NPC, received complete response after primary Type I 3 1.5 treatment and developed only-lung metastasis(es) at the Type II 62 31.3 first failure after primary therapy were eligible for our Type III 133 67.2 study. The cases excluded from the current study ful- AJCC (2002) filled the following criteria: (1) developed extra-pulmon- T classification ary metastasis at the first failure after primary therapy; T1-T2 83 41.9 (2) did not receive any treatment; (3) did not have ade- T3-T4 115 58.1 quate clinical information and/or follow-up data. The N classification pre-treatment evaluation included a complete medical N0-N1 115 58.1 history and physical examination, complete blood cell N2-N3 83 41.9 count, serum biochemistry, Epstein-Barr virus (EBV) Overall stage serology, nasopharyngoscopy, computed tomography I 5 2.5 (CT) or magnetic resonance image (MRI) scans of the II 43 21.7 head and neck, chest X-ray and an ultrasound scan of III 108 54.5 the abdomen. A CT scan of the thorax or the abdomen IV 42 21.3 and a bone scan were performed if the initial examina- Site of metastases tion revealed abnormal findings that were suggestive of Unilateral 94 47.5 metastasis. Forty-five patients had excluded from the Bilateral 104 52.5 present study because the CT chest showed abnormal Number of metastases findings that were suggestive of lung metastasis(es). Solitary 65 32.8 Clinical stages were assigned according to the American Multiple 133 67.2 Joint Cancer Committee staging system (AJCC, 1997). Size of metastases The clinical characteristics of the patients are presented ≤3 cm 142 71.7 in Table 1. >3 cm 56 28.3 Mediastinal nodal metastases Treatment Absent 121 61.1 Radiation therapy was the mainstay of treatment. All Present 77 38.9 patients had planning computerized tomography of the Locoregional recurrence head and neck performed with patient in the treatment Absent 175 88.4 position. Computerized tomography-assisted radiation Present 23 11.6 treatment planning was obtained before the initiation of Secondary metastases radiotherapy. A 4-MV or 6-MV linear accelerator was Absent 149 75.3 used for treatment. The radiation dose ranged from 64 Present 49 24.7 to 70 Gy, according to the tumor stage. Advanced-stage DFI (months) patients (65.2%, n = 129) received 4 to 6 cycles of com- ≤24 108 54.5 bination chemotherapy (cisplatin/5-fluorouracil) before, Cao et al. Radiation Oncology 2011, 6:104 Page 3 of 10 http://www.ro-journal.com/content/6/1/104 Table 1 Patient and disease characteristics of 198 NPC local recurrence received a second course of external patients with lung metastasis (Continued) radiotherapy (n = 23). The survival status was verified using the best avail- >24 90 45.5 able methods, including verifying the clinical attendance Primary treatment records and with direct telecommunication with the Radiotherapy 69 34.8 patient or their family. Chemoradiotherapy 129 65.2 Abbreviation: NPC, nasopharyngeal carcinoma; WHO: World Health Statistical Analysis Organisation; AJCC: American Joint Committee Cancer; DFI: disease-free interval. Disease-free interval (DFI) was defined as the interval A mass in diameter. between the onset of the primary treatment and the Size in the short-axis diameter. time of the first diagnosis of lung metastasis(es). Overall survival (OS) was defined as the time from the date of primary treatment to the date of death or the final clini- during, and/or after radiotherapy. At a clinical examina- cal follow-up. Lung metastatic survival (LMS) was tion six weeks later, all patients were in complete remis- defined as the interval between the date of first diagno- sion (CR), as confirmed by endoscopic examination with sis of lung metastasis(es) and the date of death or final or without biopsy and a CT or MRI scan of the head follow-up. The factor analysis for OS and LMS included and neck. gender, age, VCA-IgA titre, EA-IgA titre, T classifica- tion, N classification, site of metastases (location of pul- Follow-up monary metastasis, unilateral or bilateral), number of After the primary treatment, patients were regularly fol- lowed up until death or the last follow-up (follow-up metastases, size of metastases, mediastinal nodal metas- visits occurred every 4-6 months in the first 3 years and tases, local recurrence, secondary metastases [subse- every 12 months thereafter). The last follow-up was per- quent metastases, any distant organ metastasis(es) just formed in December 2010. To identify local recurrence presented after lung metastasis(es)], and DFI. The or distant metastasis, patients were evaluated with peri- actuarial OS and LMS were estimated using the Kaplan- odic examinations of the nasopharynx. Evaluation of sys- Meier method, and the differences between the survival temic complaints included chest X-rays and abdominal curves were compared using the log-rank test. The Cox ultrasounds. A CT scan of the chest or abdomen and a proportional hazards regression model was used to bone scan were performed if the initial examination assess the prognostic significance of the different factors. showed abnormal findings that were suggestive of Statistical significance was defined as P <0.05. Thesta- tistical analyses were performed using the SPSS 13.0 metastasis. If the results of the CT scan were suspicious, software package (SPSS, Inc., Chicago, IL). lung metastasis was confirmed by biopsy. Pulmonary metastasis was defined by CT imaging and Results clinical characteristics on basis of at least two of the fol- Patients and Disease Characteristics lowing criteria: (1) a soft tissue opacity > 5 mm in the A total of 198 patients (156 male and 42 female) were short-axis diameter; (2) peripheral location; (3) multiple included in this study. The median age was 44.5 years lung lesions; (4) patients with advanced stage of the pri- (range, 20 to 80 years). Increased titres of VCA-IgA and mary NPC; (5) patients with DFI≤ 24 months. These cri- EA-IgA were detected in 39.9% (n = 79) and 35.4% (n = teria and characteristics have been described and used 70) patients, respectively. The histological types of 98.5% by some previous literatures and reports[13,16-22]. of the patients were non-keratinising or undifferentiated When lung metastasis(es) was diagnosed, the patient carcinoma (WHO type II or III). The distribution of was offered cisplatin-based chemotherapy. Fifty-seven cases (chemotherapy group) received palliative resection patients within the T classifications were 83 T1-T2 or radiotherapy in addition to chemotherapy. One hun- patients (41.9%) and 115 T3-T4 patients (58.1%). The dred and forty-one patients (chemoradiotherapy group), distributions in the N classifications were 115 N0-N1 especially the patients with multiple lung metastases (n patients (58.1%) and 83 N2-N3 patients (41.9%). = 133), received only chemotherapy. The treatment dis- Approximately half of the patients had bilateral metas- tribution of patient with solitary lung metastasis were 32 tases (52.5%). DFI≤ 24 months occurred in 108 patients chemotherapy-only patients, 12 chemoradiotherapy (54.5%), compared with DFI > 24 months in 90 patients patients and 21 chemotherapy plus palliative resection (45.5%). Most cases had lung metastasis(es) without patients. The treatment distribution of patients with local recurrence (88.4%) and/or secondary metastases multiple lung metastases were 109 chemotherapy-only (75.3%). In total, 133 patients (67.2%) had multiple lung patients, 17 chemoradiotherapy patients and 7 che- metastases, and 61.1% (n = 121) of those patients did motherapy plus palliative resection. The patients with not have mediastinal node metastases. Metastases ≥3cm Cao et al. Radiation Oncology 2011, 6:104 Page 4 of 10 http://www.ro-journal.com/content/6/1/104 in diameter was present in 56 cases (28.3%). The details significant for the OS and the LMS (P = 0.001, P = are listed in Table 1. 0.002, respectively). Survival Analysis Univariate Analysis of Clinical Variables All the patients were followedupregularly and the last Several factors (age > 45 years, VCA-IgA titre > 1:320, follow-up was carried out in December 2010, 143 cases bilateral lung metastases, multiple lung metastases and developed cancer-related deaths (lung metastasis or sec- secondary metastases) were significantly related to ondary metastasis). shorter LMS in the univariate analysis. Moreover, vari- ThemedianOSand LMSfor theentirecohortwere ables that were statistically significant negative predica- 51.5 months (range, 5.4 to 340.2 months) and 20.9 tors of OS included age > 45 years, AJCC T3-T4 months (range, 0.3 to 157.9 months), respectively (Fig- classification, AJCC N2-N3 classification, bilateral lung ures. 1A and 1B). Median OS was 37.7 months longer metastases, multiple lung metastases, secondary metas- in chemoradiotherapy group (81.8 months) than in the tases, and DFI≤24 months (Table 2). chemotherapy-only group (33.1 months) (P < 0.001) (Figures 1C). Median LMS was also longer in chemora- Multivariate Analysis of Clinical Variables diotherapy group than in the chemotherapy-only group In the multivariate analysis of the clinical variables for (44.1 months vs. 19.1 months, P = 0.001) (Figure 1D). LMS, all of the univariate variables were independently More than half (54.5%, n = 108) of the subjects devel- significant predictors (Figure 2) with the exception of oped lung metastasis(es) within the first 2 years after the site of metastases. Independently negative prognostic primary treatment. After adjustment for clinicopatholo- factors for OS included age > 45 years, AJCC T3-T4 gical characteristics, the modality was still statistically classification, AJCC N2-N3 classification, bilateral lung Figure 1 Kaplan-Meier survival analysis according to different groups. Overall survival (OS) (A) and lung metastasis survival (LMS) (B) for the entire cohort. Comparison of overall survival (C) and lung metastasis survival (D) between patients treated with combined therapy and chemotherapy alone. Cao et al. Radiation Oncology 2011, 6:104 Page 5 of 10 http://www.ro-journal.com/content/6/1/104 Table 2 Univariate analysis of clinical variables for LMS and OS LMS OS Clinical Variable HR 95%CI P value * HR 95%CI P value * Gender 1.084 0.739 to 1.591 0.681 1.645 0.726 to 1.563 0.747 Age 1.579 1.132 to 2.202 0.007 1.731 1.241 to 2.414 0.001 VCA-IgA (≤1:320 vs. >1:320) 1.595 1.067 to 2.383 0.022 1.358 0.909 to 2.028 0.135 EA-IgA (≤1:40 vs. >1:40) 1.038 0.687 to 1.566 0.861 1.153 0.762 to 1.743 0.501 AJCC T classification 1.316 0.939 to 1.845 0.110 1.610 1.139 to 2.276 0.007 AJCC N classification 1.355 0.972 to 1.889 0.073 1.469 1.050 to 2.056 0.024 Site of metastases 1.576 1.127 to 2.205 0.008 2.017 1.433 to 2.840 <0.001 Number of metastases 1.669 1.155 to 2.413 0.006 2.042 1.404 to 2.971 <0.001 3 † Size of metastases 1.034 0.710 to 1.504 0.863 1.428 0.981 to 2.079 0.063 4 ‡ Mediastinal node metastases 1.061 0.753 to 1.496 0.735 1.234 0.875 to 1.740 0.230 Locoregional recurrence 1.277 0.787 to 2.071 0.323 1.058 0.650 to 1.719 0.822 Secondary metastases 3.100 2.116 to 4.541 <0.001 1.830 1.263 to 2.652 0.001 DFI (months, ≤24 vs. >24) 1.330 0.950 to 1.860 0.096 4.209 2.923 to 6.060 <0.001 Abbreviation: LMS: lung metastasis survival; OS: overall survival; AJCC: American Joint Committee Cancer; DFI: disease-free interval; HR: hazard ratio; 95%CI: 95% confidence interval. 1 2 3 4 5 6 Unilateral vs. Bilateral; Solitary vs. Multiple; ≤ 3cm vs. > 3 cm; Absent vs. Present; Absent vs. Present; Absent vs. Present. A mass in diameter. Size in the short-axis diameter. * Cox proportional hazards regression models. Figure 2 Lung metastasis survival curves according to age, VCA-IgA titre, number of metastases and secondary metastases. Comparison of lung metastasis survival (LMS) according to age (A), VCA-IgA titre (B), number of metastases (C), and secondary metastases (D). Cao et al. Radiation Oncology 2011, 6:104 Page 6 of 10 http://www.ro-journal.com/content/6/1/104 metastases, secondary metastases, and DFI≤24 months independently significant, negative prognostic factors (Figure 3). The hazard ratios (HR), the 95% confidence (age, VCA-IgA, T classification, N classification, site of intervals (CI) and the P values are presented in Table 3. metastases, secondary metastases, number of metastases and DFI) for survival. Identification of Low-, Intermediate-, and High-risk A score of 1 was provided if an independently signif- Subsets icant negative prognostic factor was present. A score Based on the univariate and multivariate analyses of the of 0 was assigned if the prognostic factor was absent. clinical variables, we were able to classify the 198 cases Scores were totalled for each patient, and the patients into three subsets according to the presence of were then subdivided into three risk subsets. The low- Figure 3 Overall survival curves according to age, T classification, N classification, site of metastases, secondary metastasis and disease-free interval. Comparison of overall survival (OS) according to age (A), T classification (B), N classification (C), site of metastases (D), secondary metastasis (E), and disease-free interval (DFI) (F). Cao et al. Radiation Oncology 2011, 6:104 Page 7 of 10 http://www.ro-journal.com/content/6/1/104 Table 3 Multivariate analysis of clinical variables for LMS and OS Clinical endpoint Variable HR 95% CI P value * LMS Age 1.659 1.107 to 2.484 0.014 VCA-IgA 1.518 1.012 to 2.277 0.043 Site of metastases 1.033 0.606 to 1.757 0.906 Number of metastases 1.585 1.013 to 2.481 0.044 Secondary metastases 3.132 1.948 to 5.036 <0.001 OS Age 1.906 1.355 to 2.682 <0.001 AJCC T classification 1.530 1.074 to 2.177 0.018 AJCC N classification 1.622 1.149 to 2.289 0.006 Site of metastases 1.464 1.023 to 2.095 0.037 Number of metastases 1.079 0.630 to 1.848 0.782 Secondary metastases 2.343 1.585 to 3.462 <0.001 DFI 5.050 3.356 to 7.576 <0.001 Abbreviation: LMS: lung metastasis survival; OS: overall survival; AJCC: American Joint Committee Cancer; DFI: disease-free interval; HR: hazard ratio; 95% CI: 95% confidence interval. 1 2 3 Unilateral vs. Bilateral; Solitary vs. Multiple; Absent vs. Present Figure 4 Kaplan-Meier survival analysis according to different * Cox proportional hazards regression models. risk subset. Comparison of overall survival (OS) among the low-risk subset, the intermediate-risk subset and the high-risk subset. risk subset included the patients with 0-2 independent prognostic factors (score 0-2), the intermediate-risk Discussion subset included the patients with 3-4 independent Unlike other head and neck squamous cell carcinomas, prognostic factors (score 3-4) and the cases who had NPC is a highly chemo- and radiosensitive tumor [3]. more than 4 independently significant negative factors An intergroup study compared concurrent chemora- were classified into the high-risk subset (score 5-8). diotherapy (CCRT) with radiotherapy alone and found a There were 44, 100 and 54 patients in the low-, inter- significant improvement in survival [23-27]. However, mediate- and high-risk subsets, respectively (Table 4). the cases of long-term survivors were anecdotal. Most The median survival periods for those three subsets patients succumbed to DM [5,6]. Of the patients with were 90.7, 48.2 and 40.2 months, respectively (P < metastases, those with lung metastases comprised a dis- 0.001). The survival curves stratified by risk subset are tinct group with a better prognosis and length of survi- showninFigure4. val [8,9,13-15]. Kwan and associates reported that an 18-year-old patient with NPC and intrathoracic metas- tases survived disease-free for 5 and a half years after Table 4 Identification of low-, intermediate-, high-risk primary therapy [28]. Despite the many reports and the subsets literature on prognostic factors and survival rates in Subset Score No. of patients (%) OS patients with NPC [29-34], the present study is novel (total score) (95% CI) because the cohorts were limited to a specific site of Low-risk 0 3 (1.5) metastasis(es), the lungs. Based on the unique aetiology, (score 0-2) 1 10 (5.1) patient characteristics, uniform therapies and long fol- 2 31 (15.7) low-up after the primary treatment, our study demon- Subtotal 44 (22.2) 90.7 (63.7 to 117.6) strated several clinical factors that are associated not Intermediate-risk 3 45 (22.7) only with LMS but also with OS. Moreover, three risk (score 3-4) 4 55 (27.8) subsets have been defined, based on the prognostic fac- Subtotal 100 (50.5) 48.2 (36.3 to 60.0) tors. These subgroups may aid clinicians in selecting the High-risk 5 36 (18.2) appropriate treatment strategies for patients. (score 5-8) 6 16 (8.1) Compared with previous reports, we examined both 7 1 (0.5) LMS and OS. We believe that the disease has an integral 8 1 (0.5) course that cannot be divided into several parts. Only Subtotal 54 (27.3) 40.2 (35.6 to 44.8) considered LMS was contrasted to the point that DM Abbreviation: OS: overall survival; 95% CI: 95% confidence interval. originated from occult dissemination at the first Cao et al. Radiation Oncology 2011, 6:104 Page 8 of 10 http://www.ro-journal.com/content/6/1/104 diagnosis of NPC and/or at the onset of primary thera- lymph nodes. We have shown that in the current study, pies [35]. In addition, the definition of LMS was influ- for the first time, secondary metastases correlated nega- enced by the time of diagnosis of DM, which was in tively with survival. Future study should focus on ade- turn influenced by the regularity of follow-up. As a con- quate and meticulous collection and analysis of the sequence, we also examined OS, which is a more infor- complaints suggesting micrometastases in the course of mative and appropriate interval. The impact of DFI on managing the NPC patient which may improve the use- fulness of this predictive factor. The impact of the DFI LMS and OS was not ignored in our analysis. We found on survival has been well documented and discussed. that the use of DFI, LMS and OS as the outcome mea- Various investigators chose different cut-off points for sures identified the more comprehensive and credible prognostic factors and minimised potential biases. the DFI[12,13,41]. In this study, we found a statistically Consistent with the findings reported by the previous significant correlation between the DFI (≤24 months vs. studies, we confirmed that the independently significant >24 months) and survival. negative predictive factors for survival included In the design of this study, we hoped to identify prog- advanced increased age, T classification, N classification nostic factors for lung metastatic NPC patients and to and VCA-IgA titre [3,33,36-38]. stratify patients into different risk categories. The survi- Despite some earlier studies that suggested that the val outcomes of the low-, intermediate- and high-risk number of metastasis(es) and the site of metastasis(es) subsets were significantly different. We thought those were not related to survival [13,39,40], we found a sta- subsets would help in a more accurate assessment of a tistically significantly different survival rate between patient’s prognosis in the clinical setting and could facil- patients with solitary and multiple metastases and itate the establishment of patient-tailored medical strate- between unilateral and bilateral pulmonary metastases. gies and supports. The outcome of low-risk patients is The discrepancies between the findings in the literature excellent. The 3-, 5- and 10-year survival rates of the and our study are likely the result of the different meth- low-risk subset were 77.3%, 60%, and 59%, respectively. ods that were used to assess the survival outcome in We should focus on bringing long-term survival and various cohorts of patients. However, this conclusion reducing treatment associated toxicities and complica- merits additional research. However, our study failed to tions. Intermediate-risk patients have a modest outcome. demonstrate the correlations between size of lung The natural history and management of metastatic NPC metastasis(es) and survival by either a univariate or mul- patients has been long an area of controversy. Our results shown that The 3-, 5- and 10-year survival rates tivariate analysis (P>0.05). Furthermore, we investigated of the intermediate-risk subset were 52.3%, 30%, and the impact of mediastinal node metastases on survival. Regardless of the status of mediastinal lymph nodes, 27.8%, respectively. Thus, among those patients, future there was no significant difference in survival. Adenopa- trials should reevaluate the benefit of sequentially thy was defined by CT imaging as a lymph node > 1 cm aggressive treatments, such as concurrent chemora- in size in the short-axis diameter. We postulated that diotherapy and palliative operation. Patients in high-risk the use of node size to predict involvement by the subset have poorer prognosis with 3-, 5- and 10-year tumor had some limitations. For example, some patients survival rates as follow: 20.5%, 7%, and 0%. Future stu- with micrometastases may not be detected, and enlarged dies should focus on relieving clinical symptoms and lymph nodes from other causes may be wrongly diag- improving quality of life. We think that these predictive nosed. Moreover, the various mediastinal node metas- factors and risk groupings could facilitate the establish- tases might lead to various prognoses. For example, ment of patient-tailored medical strategies and supports. metastases in mediastinal and/or subcarinal lymph We acknowledged the limitations of our retrospective nodes may present more extensive spread than peri- analyses. Firstly, not all patients had CT scan of thorax bronchial and/or hilar and intrapulmonary lymph nodes. and/or abdomen at the time of diagnosis of NPC, and it Local recurrence has been widely recognised as an inde- is possible that some patients had micrometastasis at pendent prognostic factor [9,30]. Notably, local recur- the time of diagnosis of NPC which cannot be detected rence did not predict survival in our study. Although by Chest X-ray and/or ultrasound. Secondly, follow-up there was a trend that the patients with lung metastasis CT scan of thorax was not standardized and typically (es) that were concurrent with local recurrence had a only performed in the patients with abnormal chest X- shorter median OS than patients without local recur- ray findings. This would, underestimate the true risk of developing lung metastasis(es). If the CT scan of chest rence (46.7 vs. 52.8 months), a statistical difference was and/or PET/CT were used as the standardized follow- not observed between the two groups. This may be due up, some micrometastasis in lung missed by X-ray to lack of uniform assessment of local recurrence and histological evidence. Additionally, we cannot detect the might be detected. However, the clinical and radio- micro-recurrence of nasopharynx and regional neck graphic picture was consistent with lung metastasis(es) Cao et al. Radiation Oncology 2011, 6:104 Page 9 of 10 http://www.ro-journal.com/content/6/1/104 6. Ng WT, Lee MC, Hung WM, Choi CW, Lee KC, Chan OS, Lee AW: Clinical from NPC. The primary strength of our study was outcomes and patterns of failure after intensity-modulated radiotherapy unique aetiology, patient characteristics, uniform thera- for nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 2011, pies and long follow-up analyzed, which facilitated iden- 79:420-428. 7. Fandi A, Bachouchi M, Azli N, Taamma A, Boussen H, Wibault P, tifying multiple clinicopathological risk parameters in Eschwege F, Armand JP, Simon J, Cvitkovic E: Long-term disease-free lung metastatic NPC patients. survivors in metastatic undifferentiated carcinoma of nasopharyngeal type. J Clin Oncol 2000, 18:1324-1330. 8. Hui EP, Leung SF, Au JS, Zee B, Tung S, Chua D, Sze WM, Law CK, Conclusions Leung TW, Chan AT: Lung metastasis alone in nasopharyngeal Our study is the first to focus on the prognostic factors carcinoma: a relatively favorable prognostic group. A study by the Hong and outcomes in NPC patients with pulmonary metasta- Kong Nasopharyngeal Carcinoma Study Group. Cancer 2004, 101:300-306. 9. Teo PM, Kwan WH, Lee WY, Leung SF, Johnson PJ: Prognosticators sis(es). We illustrated that age > 45 years, advanced T determining survival subsequent to distant metastasis from classification and N classification, elevated VCA-IgA nasopharyngeal carcinoma. Cancer 1996, 77:2423-2431. titre, bilateral lung metastases, multiple lung metastases, 10. Wolff HA, Rodel RM, Gunawan B, Overbeck T, Herrmann MK, Hennies S, Hille A, Vorwerk H, Matthias C, Hess CF, Christiansen H: Nasopharyngeal secondary metastases and a DFI≤24 months were inde- carcinoma in adults: treatment results after long-term follow-up with pendent, significant and negative factors affecting OS or special reference to adjuvant interferon-beta in undifferentiated LMS. The prognosis of the low-, intermediate- and carcinomas. J Cancer Res Clin Oncol 2010, 136:89-97. 11. Khanfir A, Frikha M, Ghorbel A, Karray H, Drira MM, Daoud J: [Metastatic high-risk subsets based on these prognostic factors were nasopharyngeal carcinoma: clinical study and therapeutic results of 95 significantly different. Thus, we would obtain a more cases]. Cancer Radiother 2006, 10:545-549. accurate and appropriate assessment of the prognosis of 12. Ong YK, Heng DM, Chung B, Leong SS, Wee J, Fong KW, Tan T, Tan EH: Design of a prognostic index score for metastatic nasopharyngeal a lung metastatic NPC patient and could facilitate the carcinoma. Eur J Cancer 2003, 39:1535-1541. establishment of patient-tailored medical strategies and 13. Winter H, Meimarakis G, Hoffmann G, Hummel M, Ruttinger D, Zilbauer A, supports. Stelter K, Spelsberg F, Jauch KW, Hatz R, Lohe F: Does surgical resection of pulmonary metastases of head and neck cancer improve survival? Ann Surg Oncol 2008, 15:2915-2926. resection of 14. Cheng LC, Sham JS, Chiu CS, Fu KH, Lee JW, Mok CK: Surgical Acknowledgements pulmonary metastases from nasopharyngeal carcinoma. Aust N Z J Surg This study was supported by grants from the Science and Technology 1996, 66:71-73. Project of Guangzhou, China (2009Y-C011-2). 15. 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Anesthesia, Cancer Center, Sun Yat-Sen University, Guangzhou, China. 18. Askin FB: Something old? Something new? Second primary or pulmonary metastasis in the patient with known extrathoracic Authors’ contributions carcinoma. Am J Clin Pathol 1993, 100:4-5. XC carried out data acquisition, performed the statistical analysis, drafted the 19. Vyas JJ, Desai PB, Rao ND: Exploratory thoracotomy on a patient with manuscript and participated in the sequence alignment. RZL participated in previous malignancy–"metastasis” or “new primary” or “unrelated the design of the study and participated in the sequence alignment. YL, LRH lesion”. J Surg Oncol 1981, 18:281-286. and WQL participated in the sequence alignment. YFC carried out data 20. Adkins PC, Wesselhoeft CW Jr, Newman W, Blades B: Thoracotomy on the acquisition. ZSW conceived of the study, and participated in its design and patient with previous malignancy: metastasis or new primary? J Thorac coordination and helped to draft the manuscript. All authors read and Cardiovasc Surg 1968, 56:351-361. approved the final manuscript. 21. Husband JE, Reznek RH: Imaging in oncology. 2 edition. London: Taylor & Francis; 2004. Competing interests 22. Buthiau D, Khayat D: CT and MRI in oncology Berlin; London: Springer; 1998. The authors declare that they have no competing interests. 23. Lin JC, Jan JS, Hsu CY, Liang WM, Jiang RS, Wang WY: Phase III study of concurrent chemoradiotherapy versus radiotherapy alone for advanced Received: 13 April 2011 Accepted: 26 August 2011 nasopharyngeal carcinoma: positive effect on overall and progression- Published: 26 August 2011 free survival. J Clin Oncol 2003, 21:631-637. 24. Chan AT, Leung SF, Ngan RK, Teo PM, Lau WH, Kwan WH, Hui EP, Yiu HY, References Yeo W, Cheung FY, et al: Overall survival after concurrent cisplatin- 1. 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Am J Otolaryngol 1997, 18:391-395. doi:10.1186/1748-717X-6-104 Cite this article as: Cao et al.: Prognosticators and Risk Grouping in Patients with Lung Metastasis from Nasopharyngeal Carcinoma: A more accurate and appropriate assessment of prognosis. Radiation Oncology 2011 6:104. Submit your next manuscript to BioMed Central and take full advantage of: • Convenient online submission • Thorough peer review • No space constraints or color figure charges • Immediate publication on acceptance • Inclusion in PubMed, CAS, Scopus and Google Scholar • Research which is freely available for redistribution Submit your manuscript at www.biomedcentral.com/submit http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Radiation Oncology Springer Journals

Prognosticators and Risk Grouping in Patients with Lung Metastasis from Nasopharyngeal Carcinoma: A more accurate and appropriate assessment of prognosis

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Copyright © 2011 by Cao et al; licensee BioMed Central Ltd.
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Medicine & Public Health; Oncology; Radiotherapy
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Abstract

Background: Lung metastases arising from nasopharyngeal carcinomas (NPC) have a relatively favourable prognosis. The purpose of this study was to identify the prognostic factors and to establish a risk grouping in patients with lung metastases from NPC. Methods: A total of 198 patients who developed lung metastases from NPC after primary therapy were retrospectively recruited from January 1982 to December 2000. Univariate and multivariate analyses of clinical variables were performed using Cox proportional hazards regression models. Actuarial survival rates were plotted against time using the Kaplan-Meier method, and log-rank testing was used to compare the differences between the curves. Results: The median overall survival (OS) period and the lung metastasis survival (LMS) period were 51.5 and 20.9 months, respectively. After univariate and multivariate analyses of the clinical variables, age, T classification, N classification, site of metastases, secondary metastases and disease-free interval (DFI) correlated with OS, whereas age, VCA-IgA titre, number of metastases and secondary metastases were related to LMS. The prognoses of the low- (score 0-1), intermediate- (score 2-3) and high-risk (score 4-8) subsets based on these factors were significantly different. The 3-, 5- and 10-year survival rates of the low-, intermediate- and high-risk subsets, respectively (P < 0.001) were as follows: 77.3%, 60% and 59%; 52.3%, 30% and 27.8%; and 20.5%, 7% and 0%. Conclusions: In this study, clinical variables provided prognostic indicators of survival in NPC patients with lung metastases. Risk subsets would help in a more accurate assessment of a patient’s prognosis in the clinical setting and could facilitate the establishment of patient-tailored medical strategies and supports. Keywords: lung metastasis, nasopharyngeal carcinoma, prognosis, risk subset Background endemic NPCs are type II (non-keratinising carcinoma) Nasopharyngeal carcinoma (NPC) is a common epithe- and type III (undifferentiated carcinoma), with a high lial malignancy in southern China [1-3]. The highest incidence of lymphatic and circulatory metastasis [3,4]. incidence has been reported in Guangdong province, With improvements in the control of local disease due to advanced diagnostic methods, radiotherapeutic tech- where the rate is approximately 20 per 100,000 people per year [1,2]. According to World Health Organisation niques and chemotherapy regimens, distant metastasis (WHO) classification based on histological type, most (DM) is increasingly becoming the major cause of mor- tality in NPCs [5,6]. The survival period after DM is variable, and long-term survival is improved in patients * Correspondence: wenzhsh@sysucc.org.cn who receive aggressive multimodality therapy [7-11]. † Contributed equally Lung metastasis commonly occurs in NPC [9,12,13]. State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat- Sen University, No. 651, Dongfeng Road East, 510060, Guangzhou, China Some studies have reported that patients with lung Full list of author information is available at the end of the article © 2011 Cao et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Cao et al. Radiation Oncology 2011, 6:104 Page 2 of 10 http://www.ro-journal.com/content/6/1/104 metastasis belong to a distinct group with a good prog- Table 1 Patient and disease characteristics of 198 NPC patients with lung metastasis nosis and better survival [8,9,13-15]. Nevertheless, no systematic study has specifically addressed the factors Characteristics No. of Patients % that are associated with lung metastasis in NPC patients. Gender Hence, our retrospective study was designed to examine Male 156 78.8 the relationship between clinical factors and lung metas- Female 42 21.2 tasis survival (LMS) and overall survival (OS), as well as Age (years) to identify low-, intermediate- and high-risk subsets that Median 44.5 may help in the development of patient-tailored medical Range 20-80 support and treatment. ≤45 108 54.5 >45 90 45.5 Methods VCA-IgA Patients ≤1:320 119 60.1 Subjects were recruited at the Sun-Yat-Sun University >1:320 79 39.9 Cancer Centre between January 1982 and December EA-IgA 2000. A total of 198 NPC patients with histologically ≤1:40 128 64.6 confirmed NPC who were previously untreated, had no >1:40 70 35.4 evidence of distant metastases (M0) at the time of diag- Histology (WHO) nosis of NPC, received complete response after primary Type I 3 1.5 treatment and developed only-lung metastasis(es) at the Type II 62 31.3 first failure after primary therapy were eligible for our Type III 133 67.2 study. The cases excluded from the current study ful- AJCC (2002) filled the following criteria: (1) developed extra-pulmon- T classification ary metastasis at the first failure after primary therapy; T1-T2 83 41.9 (2) did not receive any treatment; (3) did not have ade- T3-T4 115 58.1 quate clinical information and/or follow-up data. The N classification pre-treatment evaluation included a complete medical N0-N1 115 58.1 history and physical examination, complete blood cell N2-N3 83 41.9 count, serum biochemistry, Epstein-Barr virus (EBV) Overall stage serology, nasopharyngoscopy, computed tomography I 5 2.5 (CT) or magnetic resonance image (MRI) scans of the II 43 21.7 head and neck, chest X-ray and an ultrasound scan of III 108 54.5 the abdomen. A CT scan of the thorax or the abdomen IV 42 21.3 and a bone scan were performed if the initial examina- Site of metastases tion revealed abnormal findings that were suggestive of Unilateral 94 47.5 metastasis. Forty-five patients had excluded from the Bilateral 104 52.5 present study because the CT chest showed abnormal Number of metastases findings that were suggestive of lung metastasis(es). Solitary 65 32.8 Clinical stages were assigned according to the American Multiple 133 67.2 Joint Cancer Committee staging system (AJCC, 1997). Size of metastases The clinical characteristics of the patients are presented ≤3 cm 142 71.7 in Table 1. >3 cm 56 28.3 Mediastinal nodal metastases Treatment Absent 121 61.1 Radiation therapy was the mainstay of treatment. All Present 77 38.9 patients had planning computerized tomography of the Locoregional recurrence head and neck performed with patient in the treatment Absent 175 88.4 position. Computerized tomography-assisted radiation Present 23 11.6 treatment planning was obtained before the initiation of Secondary metastases radiotherapy. A 4-MV or 6-MV linear accelerator was Absent 149 75.3 used for treatment. The radiation dose ranged from 64 Present 49 24.7 to 70 Gy, according to the tumor stage. Advanced-stage DFI (months) patients (65.2%, n = 129) received 4 to 6 cycles of com- ≤24 108 54.5 bination chemotherapy (cisplatin/5-fluorouracil) before, Cao et al. Radiation Oncology 2011, 6:104 Page 3 of 10 http://www.ro-journal.com/content/6/1/104 Table 1 Patient and disease characteristics of 198 NPC local recurrence received a second course of external patients with lung metastasis (Continued) radiotherapy (n = 23). The survival status was verified using the best avail- >24 90 45.5 able methods, including verifying the clinical attendance Primary treatment records and with direct telecommunication with the Radiotherapy 69 34.8 patient or their family. Chemoradiotherapy 129 65.2 Abbreviation: NPC, nasopharyngeal carcinoma; WHO: World Health Statistical Analysis Organisation; AJCC: American Joint Committee Cancer; DFI: disease-free interval. Disease-free interval (DFI) was defined as the interval A mass in diameter. between the onset of the primary treatment and the Size in the short-axis diameter. time of the first diagnosis of lung metastasis(es). Overall survival (OS) was defined as the time from the date of primary treatment to the date of death or the final clini- during, and/or after radiotherapy. At a clinical examina- cal follow-up. Lung metastatic survival (LMS) was tion six weeks later, all patients were in complete remis- defined as the interval between the date of first diagno- sion (CR), as confirmed by endoscopic examination with sis of lung metastasis(es) and the date of death or final or without biopsy and a CT or MRI scan of the head follow-up. The factor analysis for OS and LMS included and neck. gender, age, VCA-IgA titre, EA-IgA titre, T classifica- tion, N classification, site of metastases (location of pul- Follow-up monary metastasis, unilateral or bilateral), number of After the primary treatment, patients were regularly fol- lowed up until death or the last follow-up (follow-up metastases, size of metastases, mediastinal nodal metas- visits occurred every 4-6 months in the first 3 years and tases, local recurrence, secondary metastases [subse- every 12 months thereafter). The last follow-up was per- quent metastases, any distant organ metastasis(es) just formed in December 2010. To identify local recurrence presented after lung metastasis(es)], and DFI. The or distant metastasis, patients were evaluated with peri- actuarial OS and LMS were estimated using the Kaplan- odic examinations of the nasopharynx. Evaluation of sys- Meier method, and the differences between the survival temic complaints included chest X-rays and abdominal curves were compared using the log-rank test. The Cox ultrasounds. A CT scan of the chest or abdomen and a proportional hazards regression model was used to bone scan were performed if the initial examination assess the prognostic significance of the different factors. showed abnormal findings that were suggestive of Statistical significance was defined as P <0.05. Thesta- tistical analyses were performed using the SPSS 13.0 metastasis. If the results of the CT scan were suspicious, software package (SPSS, Inc., Chicago, IL). lung metastasis was confirmed by biopsy. Pulmonary metastasis was defined by CT imaging and Results clinical characteristics on basis of at least two of the fol- Patients and Disease Characteristics lowing criteria: (1) a soft tissue opacity > 5 mm in the A total of 198 patients (156 male and 42 female) were short-axis diameter; (2) peripheral location; (3) multiple included in this study. The median age was 44.5 years lung lesions; (4) patients with advanced stage of the pri- (range, 20 to 80 years). Increased titres of VCA-IgA and mary NPC; (5) patients with DFI≤ 24 months. These cri- EA-IgA were detected in 39.9% (n = 79) and 35.4% (n = teria and characteristics have been described and used 70) patients, respectively. The histological types of 98.5% by some previous literatures and reports[13,16-22]. of the patients were non-keratinising or undifferentiated When lung metastasis(es) was diagnosed, the patient carcinoma (WHO type II or III). The distribution of was offered cisplatin-based chemotherapy. Fifty-seven cases (chemotherapy group) received palliative resection patients within the T classifications were 83 T1-T2 or radiotherapy in addition to chemotherapy. One hun- patients (41.9%) and 115 T3-T4 patients (58.1%). The dred and forty-one patients (chemoradiotherapy group), distributions in the N classifications were 115 N0-N1 especially the patients with multiple lung metastases (n patients (58.1%) and 83 N2-N3 patients (41.9%). = 133), received only chemotherapy. The treatment dis- Approximately half of the patients had bilateral metas- tribution of patient with solitary lung metastasis were 32 tases (52.5%). DFI≤ 24 months occurred in 108 patients chemotherapy-only patients, 12 chemoradiotherapy (54.5%), compared with DFI > 24 months in 90 patients patients and 21 chemotherapy plus palliative resection (45.5%). Most cases had lung metastasis(es) without patients. The treatment distribution of patients with local recurrence (88.4%) and/or secondary metastases multiple lung metastases were 109 chemotherapy-only (75.3%). In total, 133 patients (67.2%) had multiple lung patients, 17 chemoradiotherapy patients and 7 che- metastases, and 61.1% (n = 121) of those patients did motherapy plus palliative resection. The patients with not have mediastinal node metastases. Metastases ≥3cm Cao et al. Radiation Oncology 2011, 6:104 Page 4 of 10 http://www.ro-journal.com/content/6/1/104 in diameter was present in 56 cases (28.3%). The details significant for the OS and the LMS (P = 0.001, P = are listed in Table 1. 0.002, respectively). Survival Analysis Univariate Analysis of Clinical Variables All the patients were followedupregularly and the last Several factors (age > 45 years, VCA-IgA titre > 1:320, follow-up was carried out in December 2010, 143 cases bilateral lung metastases, multiple lung metastases and developed cancer-related deaths (lung metastasis or sec- secondary metastases) were significantly related to ondary metastasis). shorter LMS in the univariate analysis. Moreover, vari- ThemedianOSand LMSfor theentirecohortwere ables that were statistically significant negative predica- 51.5 months (range, 5.4 to 340.2 months) and 20.9 tors of OS included age > 45 years, AJCC T3-T4 months (range, 0.3 to 157.9 months), respectively (Fig- classification, AJCC N2-N3 classification, bilateral lung ures. 1A and 1B). Median OS was 37.7 months longer metastases, multiple lung metastases, secondary metas- in chemoradiotherapy group (81.8 months) than in the tases, and DFI≤24 months (Table 2). chemotherapy-only group (33.1 months) (P < 0.001) (Figures 1C). Median LMS was also longer in chemora- Multivariate Analysis of Clinical Variables diotherapy group than in the chemotherapy-only group In the multivariate analysis of the clinical variables for (44.1 months vs. 19.1 months, P = 0.001) (Figure 1D). LMS, all of the univariate variables were independently More than half (54.5%, n = 108) of the subjects devel- significant predictors (Figure 2) with the exception of oped lung metastasis(es) within the first 2 years after the site of metastases. Independently negative prognostic primary treatment. After adjustment for clinicopatholo- factors for OS included age > 45 years, AJCC T3-T4 gical characteristics, the modality was still statistically classification, AJCC N2-N3 classification, bilateral lung Figure 1 Kaplan-Meier survival analysis according to different groups. Overall survival (OS) (A) and lung metastasis survival (LMS) (B) for the entire cohort. Comparison of overall survival (C) and lung metastasis survival (D) between patients treated with combined therapy and chemotherapy alone. Cao et al. Radiation Oncology 2011, 6:104 Page 5 of 10 http://www.ro-journal.com/content/6/1/104 Table 2 Univariate analysis of clinical variables for LMS and OS LMS OS Clinical Variable HR 95%CI P value * HR 95%CI P value * Gender 1.084 0.739 to 1.591 0.681 1.645 0.726 to 1.563 0.747 Age 1.579 1.132 to 2.202 0.007 1.731 1.241 to 2.414 0.001 VCA-IgA (≤1:320 vs. >1:320) 1.595 1.067 to 2.383 0.022 1.358 0.909 to 2.028 0.135 EA-IgA (≤1:40 vs. >1:40) 1.038 0.687 to 1.566 0.861 1.153 0.762 to 1.743 0.501 AJCC T classification 1.316 0.939 to 1.845 0.110 1.610 1.139 to 2.276 0.007 AJCC N classification 1.355 0.972 to 1.889 0.073 1.469 1.050 to 2.056 0.024 Site of metastases 1.576 1.127 to 2.205 0.008 2.017 1.433 to 2.840 <0.001 Number of metastases 1.669 1.155 to 2.413 0.006 2.042 1.404 to 2.971 <0.001 3 † Size of metastases 1.034 0.710 to 1.504 0.863 1.428 0.981 to 2.079 0.063 4 ‡ Mediastinal node metastases 1.061 0.753 to 1.496 0.735 1.234 0.875 to 1.740 0.230 Locoregional recurrence 1.277 0.787 to 2.071 0.323 1.058 0.650 to 1.719 0.822 Secondary metastases 3.100 2.116 to 4.541 <0.001 1.830 1.263 to 2.652 0.001 DFI (months, ≤24 vs. >24) 1.330 0.950 to 1.860 0.096 4.209 2.923 to 6.060 <0.001 Abbreviation: LMS: lung metastasis survival; OS: overall survival; AJCC: American Joint Committee Cancer; DFI: disease-free interval; HR: hazard ratio; 95%CI: 95% confidence interval. 1 2 3 4 5 6 Unilateral vs. Bilateral; Solitary vs. Multiple; ≤ 3cm vs. > 3 cm; Absent vs. Present; Absent vs. Present; Absent vs. Present. A mass in diameter. Size in the short-axis diameter. * Cox proportional hazards regression models. Figure 2 Lung metastasis survival curves according to age, VCA-IgA titre, number of metastases and secondary metastases. Comparison of lung metastasis survival (LMS) according to age (A), VCA-IgA titre (B), number of metastases (C), and secondary metastases (D). Cao et al. Radiation Oncology 2011, 6:104 Page 6 of 10 http://www.ro-journal.com/content/6/1/104 metastases, secondary metastases, and DFI≤24 months independently significant, negative prognostic factors (Figure 3). The hazard ratios (HR), the 95% confidence (age, VCA-IgA, T classification, N classification, site of intervals (CI) and the P values are presented in Table 3. metastases, secondary metastases, number of metastases and DFI) for survival. Identification of Low-, Intermediate-, and High-risk A score of 1 was provided if an independently signif- Subsets icant negative prognostic factor was present. A score Based on the univariate and multivariate analyses of the of 0 was assigned if the prognostic factor was absent. clinical variables, we were able to classify the 198 cases Scores were totalled for each patient, and the patients into three subsets according to the presence of were then subdivided into three risk subsets. The low- Figure 3 Overall survival curves according to age, T classification, N classification, site of metastases, secondary metastasis and disease-free interval. Comparison of overall survival (OS) according to age (A), T classification (B), N classification (C), site of metastases (D), secondary metastasis (E), and disease-free interval (DFI) (F). Cao et al. Radiation Oncology 2011, 6:104 Page 7 of 10 http://www.ro-journal.com/content/6/1/104 Table 3 Multivariate analysis of clinical variables for LMS and OS Clinical endpoint Variable HR 95% CI P value * LMS Age 1.659 1.107 to 2.484 0.014 VCA-IgA 1.518 1.012 to 2.277 0.043 Site of metastases 1.033 0.606 to 1.757 0.906 Number of metastases 1.585 1.013 to 2.481 0.044 Secondary metastases 3.132 1.948 to 5.036 <0.001 OS Age 1.906 1.355 to 2.682 <0.001 AJCC T classification 1.530 1.074 to 2.177 0.018 AJCC N classification 1.622 1.149 to 2.289 0.006 Site of metastases 1.464 1.023 to 2.095 0.037 Number of metastases 1.079 0.630 to 1.848 0.782 Secondary metastases 2.343 1.585 to 3.462 <0.001 DFI 5.050 3.356 to 7.576 <0.001 Abbreviation: LMS: lung metastasis survival; OS: overall survival; AJCC: American Joint Committee Cancer; DFI: disease-free interval; HR: hazard ratio; 95% CI: 95% confidence interval. 1 2 3 Unilateral vs. Bilateral; Solitary vs. Multiple; Absent vs. Present Figure 4 Kaplan-Meier survival analysis according to different * Cox proportional hazards regression models. risk subset. Comparison of overall survival (OS) among the low-risk subset, the intermediate-risk subset and the high-risk subset. risk subset included the patients with 0-2 independent prognostic factors (score 0-2), the intermediate-risk Discussion subset included the patients with 3-4 independent Unlike other head and neck squamous cell carcinomas, prognostic factors (score 3-4) and the cases who had NPC is a highly chemo- and radiosensitive tumor [3]. more than 4 independently significant negative factors An intergroup study compared concurrent chemora- were classified into the high-risk subset (score 5-8). diotherapy (CCRT) with radiotherapy alone and found a There were 44, 100 and 54 patients in the low-, inter- significant improvement in survival [23-27]. However, mediate- and high-risk subsets, respectively (Table 4). the cases of long-term survivors were anecdotal. Most The median survival periods for those three subsets patients succumbed to DM [5,6]. Of the patients with were 90.7, 48.2 and 40.2 months, respectively (P < metastases, those with lung metastases comprised a dis- 0.001). The survival curves stratified by risk subset are tinct group with a better prognosis and length of survi- showninFigure4. val [8,9,13-15]. Kwan and associates reported that an 18-year-old patient with NPC and intrathoracic metas- tases survived disease-free for 5 and a half years after Table 4 Identification of low-, intermediate-, high-risk primary therapy [28]. Despite the many reports and the subsets literature on prognostic factors and survival rates in Subset Score No. of patients (%) OS patients with NPC [29-34], the present study is novel (total score) (95% CI) because the cohorts were limited to a specific site of Low-risk 0 3 (1.5) metastasis(es), the lungs. Based on the unique aetiology, (score 0-2) 1 10 (5.1) patient characteristics, uniform therapies and long fol- 2 31 (15.7) low-up after the primary treatment, our study demon- Subtotal 44 (22.2) 90.7 (63.7 to 117.6) strated several clinical factors that are associated not Intermediate-risk 3 45 (22.7) only with LMS but also with OS. Moreover, three risk (score 3-4) 4 55 (27.8) subsets have been defined, based on the prognostic fac- Subtotal 100 (50.5) 48.2 (36.3 to 60.0) tors. These subgroups may aid clinicians in selecting the High-risk 5 36 (18.2) appropriate treatment strategies for patients. (score 5-8) 6 16 (8.1) Compared with previous reports, we examined both 7 1 (0.5) LMS and OS. We believe that the disease has an integral 8 1 (0.5) course that cannot be divided into several parts. Only Subtotal 54 (27.3) 40.2 (35.6 to 44.8) considered LMS was contrasted to the point that DM Abbreviation: OS: overall survival; 95% CI: 95% confidence interval. originated from occult dissemination at the first Cao et al. Radiation Oncology 2011, 6:104 Page 8 of 10 http://www.ro-journal.com/content/6/1/104 diagnosis of NPC and/or at the onset of primary thera- lymph nodes. We have shown that in the current study, pies [35]. In addition, the definition of LMS was influ- for the first time, secondary metastases correlated nega- enced by the time of diagnosis of DM, which was in tively with survival. Future study should focus on ade- turn influenced by the regularity of follow-up. As a con- quate and meticulous collection and analysis of the sequence, we also examined OS, which is a more infor- complaints suggesting micrometastases in the course of mative and appropriate interval. The impact of DFI on managing the NPC patient which may improve the use- fulness of this predictive factor. The impact of the DFI LMS and OS was not ignored in our analysis. We found on survival has been well documented and discussed. that the use of DFI, LMS and OS as the outcome mea- Various investigators chose different cut-off points for sures identified the more comprehensive and credible prognostic factors and minimised potential biases. the DFI[12,13,41]. In this study, we found a statistically Consistent with the findings reported by the previous significant correlation between the DFI (≤24 months vs. studies, we confirmed that the independently significant >24 months) and survival. negative predictive factors for survival included In the design of this study, we hoped to identify prog- advanced increased age, T classification, N classification nostic factors for lung metastatic NPC patients and to and VCA-IgA titre [3,33,36-38]. stratify patients into different risk categories. The survi- Despite some earlier studies that suggested that the val outcomes of the low-, intermediate- and high-risk number of metastasis(es) and the site of metastasis(es) subsets were significantly different. We thought those were not related to survival [13,39,40], we found a sta- subsets would help in a more accurate assessment of a tistically significantly different survival rate between patient’s prognosis in the clinical setting and could facil- patients with solitary and multiple metastases and itate the establishment of patient-tailored medical strate- between unilateral and bilateral pulmonary metastases. gies and supports. The outcome of low-risk patients is The discrepancies between the findings in the literature excellent. The 3-, 5- and 10-year survival rates of the and our study are likely the result of the different meth- low-risk subset were 77.3%, 60%, and 59%, respectively. ods that were used to assess the survival outcome in We should focus on bringing long-term survival and various cohorts of patients. However, this conclusion reducing treatment associated toxicities and complica- merits additional research. However, our study failed to tions. Intermediate-risk patients have a modest outcome. demonstrate the correlations between size of lung The natural history and management of metastatic NPC metastasis(es) and survival by either a univariate or mul- patients has been long an area of controversy. Our results shown that The 3-, 5- and 10-year survival rates tivariate analysis (P>0.05). Furthermore, we investigated of the intermediate-risk subset were 52.3%, 30%, and the impact of mediastinal node metastases on survival. Regardless of the status of mediastinal lymph nodes, 27.8%, respectively. Thus, among those patients, future there was no significant difference in survival. Adenopa- trials should reevaluate the benefit of sequentially thy was defined by CT imaging as a lymph node > 1 cm aggressive treatments, such as concurrent chemora- in size in the short-axis diameter. We postulated that diotherapy and palliative operation. Patients in high-risk the use of node size to predict involvement by the subset have poorer prognosis with 3-, 5- and 10-year tumor had some limitations. For example, some patients survival rates as follow: 20.5%, 7%, and 0%. Future stu- with micrometastases may not be detected, and enlarged dies should focus on relieving clinical symptoms and lymph nodes from other causes may be wrongly diag- improving quality of life. We think that these predictive nosed. Moreover, the various mediastinal node metas- factors and risk groupings could facilitate the establish- tases might lead to various prognoses. For example, ment of patient-tailored medical strategies and supports. metastases in mediastinal and/or subcarinal lymph We acknowledged the limitations of our retrospective nodes may present more extensive spread than peri- analyses. Firstly, not all patients had CT scan of thorax bronchial and/or hilar and intrapulmonary lymph nodes. and/or abdomen at the time of diagnosis of NPC, and it Local recurrence has been widely recognised as an inde- is possible that some patients had micrometastasis at pendent prognostic factor [9,30]. Notably, local recur- the time of diagnosis of NPC which cannot be detected rence did not predict survival in our study. Although by Chest X-ray and/or ultrasound. Secondly, follow-up there was a trend that the patients with lung metastasis CT scan of thorax was not standardized and typically (es) that were concurrent with local recurrence had a only performed in the patients with abnormal chest X- shorter median OS than patients without local recur- ray findings. This would, underestimate the true risk of developing lung metastasis(es). If the CT scan of chest rence (46.7 vs. 52.8 months), a statistical difference was and/or PET/CT were used as the standardized follow- not observed between the two groups. This may be due up, some micrometastasis in lung missed by X-ray to lack of uniform assessment of local recurrence and histological evidence. Additionally, we cannot detect the might be detected. However, the clinical and radio- micro-recurrence of nasopharynx and regional neck graphic picture was consistent with lung metastasis(es) Cao et al. Radiation Oncology 2011, 6:104 Page 9 of 10 http://www.ro-journal.com/content/6/1/104 6. Ng WT, Lee MC, Hung WM, Choi CW, Lee KC, Chan OS, Lee AW: Clinical from NPC. The primary strength of our study was outcomes and patterns of failure after intensity-modulated radiotherapy unique aetiology, patient characteristics, uniform thera- for nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 2011, pies and long follow-up analyzed, which facilitated iden- 79:420-428. 7. 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Am J Otolaryngol 1997, 18:391-395. doi:10.1186/1748-717X-6-104 Cite this article as: Cao et al.: Prognosticators and Risk Grouping in Patients with Lung Metastasis from Nasopharyngeal Carcinoma: A more accurate and appropriate assessment of prognosis. Radiation Oncology 2011 6:104. Submit your next manuscript to BioMed Central and take full advantage of: • Convenient online submission • Thorough peer review • No space constraints or color figure charges • Immediate publication on acceptance • Inclusion in PubMed, CAS, Scopus and Google Scholar • Research which is freely available for redistribution Submit your manuscript at www.biomedcentral.com/submit

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Radiation OncologySpringer Journals

Published: Aug 26, 2011

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