Clinical features and prognostic factors in patients with nasopharyngeal carcinoma relapse after primary treatment

Page 1 of 7 Clinical features and prognostic factors in patients with nasopharyngeal carcinoma relapse after primary treatment X Peng 1, SF Chen 2, C Du 2 *, P Yang 2, SX Liang 2, G Zhang 3, X Dong 4 *, M Kwan 5 Abstract Nasopharyngeal carcinoma (NPC) relapse after primary treatment is a major cause of cancer-related deaths. There is little comprehensive information on long-term outcomes particularly pertaining to the site of relapse. Therefore, the aim of this study was to determine the clinicopathological features of NPC relapse after primary treatment of 1424 patients referred to our institution from 2000 to 2006. After initial treatment, patients were reviewed at 3 6 month intervals. Information was collected on demographics, pre- and post-management and patient outcomes. The median age was 48 years (range 3 77), with complete data for 82% patients. In total, 152 patients (13%) had a local relapse and 193 patients (16.5%) had a distant relapse. Among patients with distant metastasis, the most common site of first relapse was the bone (in 56 patients), followed by multiple organ involvement (50), lung (37) and liver (30). The median interval from primary treatment until recurrence was 28 months, and diseasefree intervals correlated to survival (P < 0.0001). If a relapse occurred, the 3-year survival was 51% for local * Corresponding authors Emails: ducaiwen@21cn.com; xiaoqun_dong@mail.uri.edu 1 Department of Radiation Oncology, Cancer Hospital of Shantou University Medical College, Shantou, People s Republic of China 2 Department of Medical Oncology, Cancer Hospital of Shantou University Medical College, Shantou, People s Republic of China 3 Tumor Research Laboratory, Cancer Hospital of Shantou University Medical College, Shantou, People s Republic of China 4 Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, The University of Rhode Island, USA 5 Department of Surgery, The University of Hong Kong, Hong Kong, People s Republic of China recurrence and 29.2% for distant recurrence (P < 0.0001). There were four dominant prognostic variables that predicted the patient s clinical course: (1) stage of cancer (P = 0.008), (2) remission duration ( 24 months vs. >24 months, P = 0.043), (3) location of metastases (local recurrence vs. distant recurrence, P = 0.043) and (4) nodal status (P = 0.048). Factors that were not significant in the univariate analysis included the patients age and sex, tumour size and histology. This data provided information on treatment outcomes in NPC patients along with statistical information to inform NPC patients about their expectations after the diagnosis of a relapse. Introduction Nasopharyngeal carcinoma (NPC) is the most common malignancy in the head and neck and has unique histological features, epidemiology, progression behaviours and management approaches. It also has a high prevalence in Southeast Asia and southern China 1. With the introduction of new treatment modalities and earlier detection, survival has steadily improved over recent decades 2. However, cancer relapse is still the leading cause of cancer-related deaths in patients with NPC. The most common cause of death after radiotherapy is distant metastasis, followed by nasopharyngeal and cervical recurrence 3. Although much is known on the treatment and prognostic factors for this cancer, there has not been a systematic study on patterns of relapse and long-term outcomes after relapse occurs. Data from other cancers suggest that patients with bone metastasis have a better prognosis than those with visceral metastasis 4. Whether the same is applicable for NPC remains to be investigated. Additionally, we attempted to find any factors that best predict the clinical course of metastatic NPC. In this paper, we describe the occurrence, survival time and prognosis of relapsed NPC. Patients after initial treatment were followed prospectively for up to 12 years. This information is especially important for NPC because the high propensity for spreading to more sites has a more variable clinical course than most other head and neck cancers. Knowledge about the dominant prognostic variables is also important in designing optimal patient treatment. Methods and materials Patients Between January 1999 and July 2006, a total of 1424 patients (1015 men, 409 women) with NPC were diagnosed and treated with radiotherapy (RT) alone or concurrent chemoradiotherapy at Cancer Hospital of Shantou University Medical College, China. Of these 1424 patients, complete followup information was available for 82% patients. The median age was 48 years (range 3 78). Patient backgrounds are summarized in Table 1. TNM distribution was classified by the Union for International Cancer Control 1997 staging system. Pathology classification is based on the World Health Organization (WHO) with Grade I representing squamous cell carcinoma, Grade II representing non-keratinizing carcinoma and Grade III representing undifferentiated carcinoma. Initial treatment methods for NPC Initial treatment for patients with NPC included primary RT using a two-dimensional (2D) technique, with two lateral opposing faciocervical fields

Page 2 of 7 Table 1 Patient and disease characteristics (total) Characteristics Patients No. % Age, year Median 48 Range 3 77 <40 years 231 20 40 years 937 80 Sex Male 797 68 Female 371 32 AJCC T category T1 2 656 56 T3 4 512 44 AJCC N category N0 1 577 49 N2 3 591 51 AJCC stage I II 310 26 III IV 858 74 WHO histology Grades I II 915 78 Grade III 253 22 Metastasis Yes 345 30 No 823 70 for the first phase. The second phase consisted of two lateral opposing fields to cover the nasopharynx matched with a single anterior cervical field to cover the neck. The dose delivered to the nasopharynx was 64 88 Gy. The radiation doses to the lymph nodepositive and -negative areas were 60 80 Gy and 50 54 Gy, respectively. Concurrent chemotherapy, mostly cisplatin-based, was given to patients with locally advanced disease. Follow-up procedures and evaluation method After initial treatment, patients were seen at 3-month intervals for the first two years, 6-month intervals for up to five years and annually thereafter, unless a recurrence was detected or the patient died. Chest radiography, abdominal ultrasonography, bone scan and contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) of the nasopharynx and cervical region were routine elements of each assessment. Followup data was completed in 82% patients. Recurrence sites were classified as local, bone, liver, lung and multiple organ metastases. Local recurrence was defined as recurrence in the nasopharynx or regional neck nodes according to the first or most significant site of relapse. Multiple metastases were defined as either relapse with local recurrence and one organ recurrence or more than two organs involved simultaneously. Statistics Data analysis was performed using the SPSS software package (version 11.0; SPSS, Chicago, IL). The survival time was defined as the time between the diagnosis of first relapse and death or the last follow-up. Univariate and multivariate analyses were performed using SPSS 17.0 software (IBM, Armonk, NY, USA). The Kaplan Meier method with a log-rank test was used for survival rate calculations and to reveal the cumulative incidence of metastasis. Cox proportional hazard models were used to analyse risk factors for survival time calculated from the time of recurrence. In the analysis for risk factors, univariate analysis was performed for the following factors: age at the time of NPC diagnosis ( 40 years vs. >40 years), sex (male vs. female), T factor (T1 2 vs. T3 4), N factor (N0 1 vs. N2 3), stage factor (stage I II vs. stage III IV), location of metastasis (local recurrence vs. bone vs. liver vs. lung vs. multiple organ vs. others), remission duration ( 2 years vs. >2 years) and pathological type (G1 2 vs. G3). All tests were two-sided, and P < 0.05 was considered statistically significant. Results Frequency and characteristics of recurrence after initial treatment for NPC At the end of the study, there were 256 patients (18%) with incomplete follow-ups, but complete follow-up information was available for 1168 patients with a median follow-up time of 45 months (range 1 103). Of the 1168 patients, the median age was 48 years (range 3 78) at the time of treatment. At the end of the study, 776 patients were alive and 392 were dead. The overall survival rate after 5 years was 67% (median survival: 66 months) (Figure 1). The anatomic

Page 3 of 7 Figure 1: Overall survival rate after initial treatment for NPC. sites of the relapses were combined into two groups: distant (lung, liver, bone and others) versus local sites (nasopharynx or regional neck nodes). In this series, local recurrence was found in 152 patients. Metastases to the distant organ after initial treatment were found in 193 patients. Figure 2 shows that patients with local recurrence had a significantly better prognosis than those who developed distant recurrence. The 3-year-survival time for local relapse was 51% compared with 29.2% for distant metastasis (P = 0.000). Knowing the most frequent sites of distant metastases is important in the follow-up examinations of NPC patients. In our study, single bone was the most common first site of relapses, occurring in 29% (56/193) patients with distant metastasis. Further patient percentages for the first site of relapse included 19.2% (37/193) for single lung, 15.5% (30/193) for single liver, 25.9% (50/193) in multi-organ sites (including concurrent recurrence in both local and distant metastases) and 10% (20/193) in others. The median survival duration for this patient group was 12 months. For patients with any distant metastasis site, the survival rate did not show a statistical difference (Figure 2b). Remission duration We further studied if remission duration for NPC can be a factor in predicting the clinical course of the disease. Survival was calculated from the onset of relapse and the duration from the end of the primary treatment to the diagnosis of first recurrence ranged from 2 to 88 months. The median recurrent interval time was 28 months, in which recurrent interval time less than or equal to the first year accounted for 19.42% (67/345) and the second year accounted for 25.2% (87/345). The 2-year cumulative recurrence cases accounted for 44.6% (154/345). Recurrence from 25 to 60 months accounted for 45.5% (157/345) and more than 60 months accounted for 9.9% (34/345). Our study indicated that patients with remission duration greater than 24 months have a better survival than those with a shorter remission; this factor was significantly different using an analysis of the curves by single factor analysis (P = 0.043, Figure 3). We then compared the two groups (group A: remission duration 24 months, group B: remission duration >24 months) to identify if the survival differences between them were related with clinical characteristics. As shown in Table 2, the median age at the time of confirmed NPC was similar for both groups. Group A presented a higher male-to-female ratio than group B (P = 0.000). A significantly higher proportion of long-latent relapses originated from well-differentiated histology. The percentage of patients with G1 and G2 was 72% in group A and 90% in group B. Likewise, the percentage of patients diagnosed with an earlier stage was lower in group A. T1 2 was 48% in group A vs. 60% in group B (P = 0.001), N0 1 was 37% in group A vs. 48% in group B (P = 0.027) and stage I/II was 48% in group A vs. 60% in group B (P = 0.025). Multifactorial analysis Our final analysis examined the prognostic factors for the predictive value of survival rate. Table 3 presents the relative importance of each single factor, unadjusted for other factors by Cox regression analysis. Using univariate analysis, we found that sex, age (<40 years vs. 40 years) and histology (grade 1 2 vs. grade 3) were not associated with survival rates when metastasis occurred in patients with NPC (P > 0.05). The dominant factors that correlated with survival rates were: (1) nodal status (N0 1 vs. N2 3, P = 0.048), (2) metastatic sites (distant recurrence vs. local recurrence, P = 0.043), (3) stage (T1 2 vs. T3 4, P = 0.008) and (4) remission

Page 4 of 7 Figure 2: Survival curves from the onset of recurrence for NPC patients. Patients were grouped by metastatic location. (a) Patients with local recurrence showed a better prognosis than those with distant metastasis. (b) Patients with single organ metastasis had similar survival time regardless of visceral or bone metastasis. There was a trend for patients with multiorgan involvement to have a worse survival than those with single organ metastasis, but without a statistical significance. Figure 3: Overall survival after diagnosis of recurrent NPC. Patients were grouped by survival time from primary treatment to relapse. Patients with remission duration greater than 24 months had a better survival than those with shorter remission duration. duration (less than or greater than 24 months, P = 0.043). When these factors were analysed in multivariate analysis, we found that only metastatic sites (distant recurrence vs. local recurrence) were associated with survival times in metastatic NPC. Discussion Local recurrences and distant metastases are the main causes of treatment failures in NPC. With advances in imaging technology and the advent of modern radiation techniques, local control has substantially improved, and distant metastases has become the predominant pattern of treatment failure. In this study, majority (90.1%) of the relapses occurred within the first five years of primary treatment. Thus, if patients have no recurrence within 5 years, they are much less likely to have a recurrence at all. The frequency of death due to NPC in late follow-up was low, reflecting a reduced hazard risk for recurrence over time. This finding is consistent with previous studies 5. Our local recurrence rate of 13% (152/1168) after a median follow-up of 45 months is comparable to other studies 5,6. This indicates that local recurrences remain the greatest challenge for NPC treatment. The nasopharynx is surrounded by radiosensitive structures that consequently allow an NPC cell to easily infiltrate and spread towards surrounding normal organs. The results in NPC irradiation target volumes are very irregular, and conventional RT adopted lateral opposing fields for NPC rarely achieve the prerequisite dose and precision to tumour targets. Therefore, local relapse in the nasopharyx is common after primary treatment in an NPC patient. The treatment results in patients with locally recurrent NPC are unsatisfactory, with a 5-year

Page 5 of 7 Table 2 Patient and disease characteristics (relapse) grouped by remission duration Characteristics Remission duration 24 months (%) >24 months (%) χ 2 P Age (years) 40 29 (19%) 41 (21%) 0.303 0.582 >40 124 (81%) 151 (79%) Gender Male 136 (89%) 138 (72%) 15.08 0.000 Female 17 (11%) 54 (28%) Histology G1 2 110 (72%) 173 (90%) 19.151 0.000 G3 43 (28%) 19 (10%) Tumour size T1 2 74 (48%) 116 (60%) 10.34 0.001 T3 4 79 (52%) 76 (40%) Nodal status N0 1 56 (37%) 93 (48%) 4.862 0.027 N2 3 97 (63%) 99 (52%) Stage at first diagnosis I/II 74 (48%) 116 (60%) 4.997 0.025 III/IV 79 (52%) 76 (40%) Table 3 Cox regression analysis of factors influencing overall survival Covariate Univariate analysis Multivariate analysis HR P 95% CI HR P 95% CI Sex 0.925 0.580 0.703;1.218 0.949 0.716 0.716;1.257 Age 1.022 0.885 0.758;1.378 0.943 0.704 0.697;1.277 Tumour size 1.251 0.070 0.982;1.593 1.196 0.283 0.863;1.657 Node status 1.277 0.048 1.002;1.626 1.223 0.267 0.857;1.746 Sites 1.113 0.043 1.003;1.234 1.134 0.018 1.022;1.259 Stage 1.502 0.008 1.111;2.030 1.219 0.433 0.742;2.002 Histology 1.023 0.701 0.882;1.593 1.196 0.293 0.773;1.387 Remission duration 1.343 0.043 1.002;1.626 1.223 0.237 0.887;1.736 actuarial local control rate ranging from 15% to 37.8% 6 9. Additionally, patients with locoregional failure have an increased risk of distant metastasis. Our data indicates that the 1-, 2- and 3-year survival rates in patients with local recurrence were 84.7%, 65% and 51%, respectively. Therefore, more aggressive primary treatment is required to secure a higher level of local control with a decrease in toxicity. Currently, intensity-modulated RT (IMRT) represents a technical innovation for NPC treatment because it can overcome the limitation of conventional 2D RT. It enables the delivery of high radiation dose to targets without jeopardizing the radiosensitive organs, and it has been proven to enhance the local control of NPC 10. IMRT, with or without chemotherapy, in NPC treatment has achieved benefits in reducing local progression and increasing overall survival 11. All patients in this study received conventional 2D RT, and the limited number of patients who received IMRT were excluded from the analysis because their follow-up time was not long enough. NPC comprises a heterogeneous group of tumours as defined by their morphologic appearances and molecular genetic characteristics. The development of distant metastases represents the most important prognostic indicator in patients diagnosed with NPC. In this series, the rate of distant metastases was 16.5% (193/1168), with 1-, 2- and 3-year survival rates being 59.9%, 29.1% and 29.2%, respectively. Compared with patients with local recurrence, our finding supports previous observations that patients with a distant recurrence have a significantly poorer prognosis than patients with a local recurrence. The remission duration was also an important prognostic variable. We made a comparison between the two groups (intervals of relapse-free 24 months and >24 months). The differences in the survival curves were significant between the two groups, which is consistent with Li s observation. Similarly, in a study by Lee, recurrence in patients with long latency had a significantly better survival than patients with short latency 12. The reason for the relatively better prognosis for a patient with long relapse-free intervals after primary treatment is unclear. To explain the favourable outcomes of female NPC patients, we first analysed the clinical characteristics of both groups in our study. We found a higher maleto-female ratio in the group with shorter remission durations. Our result

Page 6 of 7 supports a previous study that female patients have a better survival than males 13. Gonadal hormones and their related receptors may play an important part in regulating the biological behaviour of NPC. Evidence suggests that testosterone negatively affects the immune function of male patients, whereas female sex steroids show a protective immune role 14. Additionally, we found that a higher proportion of long-latent relapse occurred in patients with T1 2, N0 1 status and stages I II at initial diagnosis. Therefore, it is not surprising that relapse with short latency showed a worse prognosis. The proportion of patients who develop metastases after primary treatment is reported to vary from 15% to 25% 6 9. In this study, the rate of distant metastases was 16.5%, with bone being the first and most frequent distant metastatic site occurring in 29% the patients. We further examined whether specific organ metastasis at the time of presentation had a prognostic significance for NPC patients. Our results revealed that there was a significant difference in survival among patients with local metastasis compared with those with distant metastasis. However, among patients with distant metastases, the site of involvement did not appear to have an impact on survival. The presence of bone, liver and lung metastasis, as well as multi-organ metastases, did not demonstrate a statistically significant correlation with survival time. The median survival time in these patients was 12 months. This result is not consistent with studies of other cancer types, which have identified that specific organ metastasis is related to a poor prognosis. For example, the distant organ that breast cancer preferentially metastasizes is also the bone. However, breast cancer patients with bone metastasis remain relatively indolent. These patients often have prolonged survival and usually benefit from palliative systemic therapy 15. In this study, factors that correlated with survival rates included nodal status, metastatic sites, stage and the remission duration. When these factors were analysed in multivariate analysis, we found that only metastatic sites (distant vs. local recurrence) were associated with survival time in metastatic NPC. Although data from literature indicates that tumour size, pathology, sex and age are prognostic variables 16 for NPC patients, our study indicated that once NPC patients have progressed to metastases, these factors are not correlated with survival time. This is an interesting clinical phenomenon and has not previously been studied. Why these well-recognized prognostic factors lose their predictive value in metastatic NPC is unknown and remains unclear. Perhaps, a breakthrough at the gene and protein level comparing NPC patients before and after metastasis will reveal this phenomenon. More research is needed to improve the knowledge of recurrent NPC to discover a prevention or radical cure for the disease. In conclusion, this report reviews NPC recurrence data after primary treatment. Rates of local and distant relapse were comparable with those previously reported, and the majority of recurrences occurred within the first five years. The prognosis after relapse varied with nodal status, stage at the first diagnosis as well as the remission duration after treatment. Local recurrences had a better prognosis than distant recurrences, while distant metastases to the bone had a similar prognosis with those to liver and multi-organ involvement. Sex, age, tumour size and pathology did not seem to impact the survival time in patients with recurrence. Despite these significant findings, there were some limitations because a retrospective design consists of complications such as lead-time and length time biases. Regardless of these limitations, this study showed patterns of metastases in NPC patients after primary treatment. This has a clinical utility, such as determining the duration of follow-up, frequency of followup and sites of first metastases. Acknowledgements This work was supported by funds from the Major State Basic Research Development Program (No. 2011CB707705), National Natural Science Foundation of China (No. 30973377 and No. 31271068), Key Laboratory of Breast Cancer Prevention and Treatment of Guangdong Province, People s Republic of China. References 1. Cao SM, Simons MJ, Qian CN. The prevalence and prevention of nasopharyngeal carcinoma in China. Chin J Cancer. 2011 Feb;30(2):114 9. 2. Liu Q, Chen JO, Huang QH, Li YH. 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