| | Prediction for distant failure in patients with stage M0 nasopharyngeal carcinoma: The role of standardized uptake valueReceived 15 February 2008; received in revised form 18 March 2008; accepted 19 March 2008. published online 09 June 2008. Summary Distant failure is an important cause of death in stage M0 primary nasopharyngeal carcinoma (NPC). However, a reliable prognosticator for occurrence of distant failure was lacking. Thus, we conducted this study to investigate prospectively the role of standardized uptake value on 18F-FDG for predicting distant failure in stage M0 NPC. Patients with stage M0 primary NPC diagnosed by both conventional work-up (CWU) and 18F-FDG PET were enrolled. Survival was estimated by the Kaplan–Meier method. Cox proportional hazards models were used to identify independent prognosticators. Between January 2002 and July 2003, 65 NPC patients were investigated. Up to the date of analysis, 12 patients died and 13 patients experienced recurrences, among whom 9 had distant failures. The 5-year overall survival (OS), relapse-free survival (RFS), and distant relapse-free survival (DRFS) were 81.2%, 79.2%, 84.4%, respectively. In multivariate analysis, the following risk factors for poor prognosis were identified: T3–4 (p =0.033) for RFS; and maximal standardized uptake value (SUVmax) of the primary tumor>12.0 (p=0.012), stage IVa–b (p=0.037), and N2–3 disease (p=0.04) for DRFS. The 5-year DRFS in stage IVa–b patients with SUVmax>12.0 was significantly lower than that in stage I–III patients with SUVmax⩽12 (p=0.0001). None of the patients in the latter group developed distant failure. In conclusion, a SUVmax>12.0 of the primary tumor represents a “metabolic phenotype” for occurrence of distant failure in stage M0 NPC patients. And the combined information of SUVmax and tumor staging can guide the use of neoadjuvant/adjuvant therapy and surveillance protocols to improve distant control. Introduction  Nasopharyngeal carcinoma (NPC) differs from other head and neck malignancies terms of its epidemiology, pathology, and treatment outcome.1, 2 NPC has a higher local tumor control rate but a higher incidence of distant metastasis compared with squamous cell carcinomas of other regions of the head and neck.2 Thus, it’s usually considered a distinct study group. In general, patients with stage M0 NPC have a better prognosis than those with other types of cancer in the head and neck area. However, distant failure still remains an important cause of death in these patients.2 Current treatment strategy for NPC is radiotherapy (RT) or concurrent chemoradiotherapy (CCRT). Despite the introduction of modern intensity-modulated radiotherapy in recent years, approximately 20% of stage M0 patients still developed distant failures within 3 years after completion of treatment.3 Attempts had been made to reduce the rates of distant failure such as adding chemotherapy in neoadjuvant or adjuvant settings. Unfortunately, published data indicated no significant benefit of neoadjuvant/adjuvant chemotherapy on the reduction of distant failure in stage M0 NPC patients.4, 5 Negative results of the previous trials may be as a result of improper patient selection. Thus, it seems necessary to find an accurate prognosticator to improve patient selection. Another way to reduce distant failure is through the selection of patients with occult distant metastases in initial staging. Several authors showed that 18F-FDG PET was useful in revealing occult distant metastases6, 7, 8 for NPC. Although PET had the ability to reveal subclinical distant metastases in around 10% of NPC patients at initial staging, 16.4% of distant metastases still remained undetected.7, 8 On the other hand, many studies have indicated FDG uptake, or standardized uptake value (SUV) on FDG, of the tumor represents a valuable prognosticator in many cancers.9, 10, 11, 12, 13, 14 A high SUV of the tumor usually implies a higher chance of metastases. Thus, we conduct this prospective study to examine the prognostic impact of SUV on FDG in predicting distant failure among patients with stage M0 NPC. Patients and methods Patients and study design The local Ethics Committee had approved the protocol and all patients had given their written informed consent. Patients with stage M0 primary NPC diagnosed by conventional work-up (CWU) and 18F-FDG PET were enrolled. To be eligible patients were required to have no evidence of distant metastases. The CWU comprised head and neck MRI, nasopharyngeal fiberoscopy, bone scan, chest X-ray, and abdominal sonography. All scans were performed within 2 weeks. Primary curative therapy was started within one month after diagnosis and consisted of RT or CCRT according to the tumor stage. In general, patients with stage I and IIA disease received RT alone. CCRT was given to stage IIB–IVB patients (2002 AJCC/UICC staging system). Chemotherapy during CCRT consisted of intravenous (IV) cisplatin 50mg/m2 on day 1, and oral tegafur plus uracil 300mg/m2/day plus leucovorin 60mg/day daily for 14 days. All radiotherapy was administered using 6MV photon beams for 2Gy per fraction, every fraction per day and 5 days a week. The radiotherapy area included gross tumor area with at least 1cm margins and whole neck for 46Gy, then cone down boost to the initial gross tumor area with close margins totalling 72Gy (T1–3 tumors) or 76Gy (T4 tumors). Intensity-modulated radiotherapy (IMRT) was used in all patients. Patients were followed every week during treatment, then every 3 months for 2 years, every 4 months for the next 2 years, and every 6 months thereafter. Flexible fiberoptic endoscopy was performed during each visit. A follow-up CWU was performed 3 months after the completion of treatment, and then yearly or when clinically indicated. During each follow-up visit, disease status and treatment-related toxicity were carefully assessed. Some patients received another 18F-FDG PET scan 3 months after the completion of treatment due to enrollment into another prospective study.15 Patients who were reluctant to comply with the follow-up or treatment schedule, who had a simultaneously second primary tumor, or with a serum glucose level>200mg/dL were excluded from this study. Data analysis The following endpoints were evaluated: locoregional relapse-free survival (LRRFS), distant relapse-free survival (DRFS), relapse-free survival (RFS), and overall survival (OS). Overall survival was measured from the date of diagnosis of NPC to the date of death, or censored at last follow-up date. For the other endpoints, the time duration was computed from diagnosis to the date of event occurrence, or censored at last follow-up date. Actuarial survival analysis was done by the Kaplan–Meier method. The log-rank test was used to assess the correlation of these end points with the SUV and with the other clinical parameters. The optimal SUV cutoff SUV for each end point showing the best trade-off between sensitivity and specificity was determined by receiver-operating-characteristic (ROC) analysis following the method of Metz.16 Multivariate analysis using the Cox proportional hazard model was performed for the aforementioned endpoints to define independent predictors among various potential prognostic factors. A p<0.05 was regarded as statistically significant. Results Overall result Between January 2002 and July 2003, a total of 68 patients with stage M0 primary NPC were enrolled into the study. Three patients were excluded due to their reluctance to comply with the follow-up or treatment schedule. Sixty-five patients were available for the final analysis (Table 1). At the time of the last follow-up, 53 patients were alive and 12 had died (8 from the cancer or cancer-related complications, and 4 from intercurrent disease). The median follow-up for surviving patients was 56 months (range: 9–65 months). Thirteen patients experienced recurrences, and sites of failure were as follows: local failure (1 patient), regional nodal failure (1 patient), distant failure (4 patients), concomitant local and regional nodal failure (2 patients), concomitant local and distant failure (2 patients), and concomitant regional nodal and distant failures (3 patients). The 5-year OS, RFS, LRRFS, and DRFS were 81.2%, 79.2%, 84.3%, 84.4%, respectively. The optimal cutoff SUV for each end point showing the best trade-off between sensitivity and specificity was described as followed. The value of 12.0 was chosen as the best primary tumor SUVmax cutoff for OS and DRFS. As for RFS and LRRFS, the best cutoff value for SUVmax at the primary tumor was 11.5. Univariate analysis Univariate analysis was done to identify the relationship of the following risk factors with survival rates: age (⩽or>40), gender, histology (undifferentiated or undifferentiated type), SUVmax (⩽or>best cut-off), T stage, N stage, and overall stage. T, N, or overall TN stages were dichotomized into T1–2 versus T3–4, N0–1 versus N2–3, and stage IIII versus IVa–b, respectively. This division was used since it yielded the highest significance level for survival analysis. Stage IVa–b was found to be the only significant risk factor predicting 5-year OS (p=0.049). As for 5-year RFS, SUVmax>11.5 (p=0.015), T3–4 disease (p=0.009), and stage IVa–b (p=0.02) were significantly associated with a poor prognosis. Patients with a SUVmax value>11.5, T3–4 stage, and stage IVa–b showed a poorer 5-year LRRFS, but these differences failed to reach significance. As for the 5-year DRFS, a SUVmax value>12 (p=0.013), and stage IVa–b (p=0.022) were significant adverse prognosticators at the univariate level. Distant failure in each group Out of the 25 patients in group 2, four (16%) developed distant failures. One occurred at 3 months after treatment whereas the remaining three cases occurred 1–3 years after therapy. Out of the 12 patients in group 3, five (42%) had distant failures. Three cases occurred within 12 months after the completion of treatment (2 cases were undetected by CWU and revealed by 18F-FDG PET). The remaining two cases of distant failures occurred 2 years after therapy. Discussion Distant failure has being a serious issue in NPC and many attempts have been made to lower its incidence. In this study, we show that loss of distant control still remains the main type of treatment failure in stage M0 NPC patients despite of initial evaluation by both CWU and 18F-FDG PET. Nevertheless, we notice that SUVmax of the primary tumor represents an important independent prognostic factor for DRFS. And a combined analysis of SUVmax and tumor stage provides relevant incremental prognostic information and can help in tailoring the adjuvant/neoadjuvant therapy for stage M0 NPC patients. The 3-year and 5-year DRFSs for NPC patients in endemic areas are approximately 65% and 60%, respectively.17, 18 Although CCRT have significantly improved overall survival and disease-free survival rates in NPC patients, distant failure continues to cast a disturbing shadow over these patients.5 After the introduction of modern IMRT, a 3-year DRFS of 78% for stage M0 patients has been reported.3 In our study, the patients also received RT or CCRT with the IMRT technique. The 3-year and 5-year DRFSs were 87.1% and 85.5%, respectively. The improvement in DRFS in our study is likely to be due to the use of 18F-FDG PET in initial staging. Nonetheless, approximately 15% of our patients developed distant failures in the long run. In keeping with the results of Chua et al.19, this study indicates that patients with advanced T and N disease have a higher probability of distant failure compared to those with advanced N disease only. However, we found that SUVmax at the primary tumor was more predictive of distant failure than other prognostic variables. In patient with stage IVa–b disease and a SUVmax value>12, the 5-year DRFS was only 56.25% (group 3). In contrast, none of the patients with stage I–III disease and a SUVmax⩽12 experienced distant recurrence (group 1). The difference in DFRSs between these two patient groups was dramatically significant (p=0.0001). Patients with stage I–III disease and a SUVmax value>12 also had a significantly lower 5-year DRFS than those group 1 patients (p=0.03). It is thus posited that SUVmax>12 may represent a “metabolic phenotype” for occurrence of distant failure in NPC patients, regardless of tumor stage. Results of previous studies investigating the role of neoadjuvant or adjuvant chemotherapy in stage M0 NPC were disappointing.5 The problem may be related to improper patient selection. As mentioned above, investigators of these studies usually recruited patients with advanced TN stage without considering other prognostic factors. In the present study, we noted that not all NPC patients with advanced TN stage would develop distant failure, and identified three patient groups with different risks for distant failure. This prognostic stratification system, based on both tumor stage and SUVmax of the primary tumor, can more efficiently guide the use of neoadjuvant/adjuvant chemotherapy and post-therapy surveillance protocols. We propose a treatment and follow-up schedule (Fig. 4). In group 1, the patients do not need neoadjuvant/adjuvant chemotherapy since they are unlikely to develop distant recurrences. Follow-up for locoregional sites can be considered sufficient in this patient group. On the other hand, the addition of neoadjuvant/adjuvant therapy into routine CCRT or RT is important for patients in group 2 and 3 in order to improve distant control. For patients in group 2, we propose a follow-up schedule with whole body examinations at 3 and 12 months after treatment and on an annual basis thereafter. For patients in group 3, a more intensive whole body surveillance protocol in the first year after treatment is highly recommended, since 60% (3/5) of the distant failures occurred within this period. In conclusion, SUVmax on 18F-FDG represents an important independent prognostic factor for distant recurrence, more predictive than traditional TN stage. A SUVmax>12.0 indicates significantly poorer distant control. And combined analysis of SUVmax and tumor staging can be a useful tool for guiding neoadjuvant/adjuvant chemotherapy and surveillance protocols in this patient group. Conflict of Interest Statement None declared. References 1. 1Marks JE, Phillips JL, Menck HR. The National Cancer Data Base report on the relationship of race and national origin to the histology of nasopharyngeal carcinoma. Cancer. 1998;83(3):582–588. 2. 2Wei WI, Sham JS. Nasopharyngeal carcinoma. Lancet. 2005;365(9476):2041–2054. Abstract | Full Text |
Full-Text PDF (143 KB)
|
CrossRef
3. 3Kam MK, Teo PM, Chau RM, Cheung KY, Choi PH, Kwan WH, et al. Treatment of nasopharyngeal carcinoma with intensity-modulated radiotherapy: the Hong Kong experience. Int J Radiat Oncol Biol Phys. 2004;60(5):1440–1450. Abstract | Full Text |
Full-Text PDF (287 KB)
|
CrossRef
4. 4Ma BB, Chan AT. Recent perspectives in the role of chemotherapy in the management of advanced nasopharyngeal carcinoma. Cancer. 2005;103(1):22–31. 5. 5O’Sullivan B. Nasopharynx cancer: therapeutic value of chemoradiotherapy. Int J Radiat Oncol Biol Phys. 2007;69(2 Suppl):S118–S121. Abstract | Full Text |
Full-Text PDF (70 KB)
|
CrossRef
6. 6Liu FY, Chang JT, Wang HM, Liao CT, Kang CJ, Ng SH, et al. [18F]fluorodeoxyglucose positron emission tomography is more sensitive than skeletal scintigraphy for detecting bone metastasis in endemic nasopharyngeal carcinoma at initial staging. J Clin Oncol. 2006;24(4):599–604.
CrossRef
7. 7Liu FY, Lin CY, Chang JT, Ng SH, Chin SC, Wang HM, et al. 18F-FDG PET can replace conventional work-up in primary M staging of nonkeratinizing nasopharyngeal carcinoma. J Nucl Med. 2007;48(10):1614–1619.
CrossRef
8. 8Yen TC, Chang JT, Ng SH, Chang YC, Chan SC, Lin KJ, et al. The value of 18F-FDG PET in the detection of stage M0 carcinoma of the nasopharynx. J Nucl Med. 2005;46(3):405–410. MEDLINE 9. 9Allal AS, Dulguerov P, Allaoua M, Haenggeli CA, El-Ghazi el A, Lehmann W, et al. Standardized uptake value of 2-[(18)F] fluoro-2-deoxy-d-glucose in predicting outcome in head and neck carcinomas treated by radiotherapy with or without chemotherapy. J Clin Oncol. 2002;20(5):1398–1404.
CrossRef
10. 10Allal AS, Slosman DO, Kebdani T, Allaoua M, Lehmann W, Dulguerov P. Prediction of outcome in head-and-neck cancer patients using the standardized uptake value of 2-[18F]fluoro-2-deoxy-d-glucose. Int J Radiat Oncol Biol Phys. 2004;59(5):1295–1300. Abstract | Full Text |
Full-Text PDF (77 KB)
|
CrossRef
11. 11Downey RJ, Akhurst T, Gonen M, Vincent A, Bains MS, Larson S, et al. Preoperative F-18 fluorodeoxyglucose-positron emission tomography maximal standardized uptake value predicts survival after lung cancer resection. J Clin Oncol. 2004;22(16):3255–3260.
CrossRef
12. 12Kidd EA, Siegel BA, Dehdashti F, Grigsby PW. The standardized uptake value for F-18 fluorodeoxyglucose is a sensitive predictive biomarker for cervical cancer treatment response and survival. Cancer. 2007;110(8):1738–1744. 13. 13Sasaki R, Komaki R, Macapinlac H, Erasmus J, Allen P, Forster K, et al. [18F] fluorodeoxyglucose uptake by positron emission tomography predicts outcome of non-small-cell lung cancer. J Clin Oncol. 2005;23(6):1136–1143.
CrossRef
14. 14Vansteenkiste JF, Stroobants SG, Dupont PJ, De Leyn PR, Verbeken EK, Deneffe GJ, et al. Prognostic importance of the standardized uptake value on (18)F-fluoro-2-deoxy-glucose-positron emission tomography scan in non-small-cell lung cancer: An analysis of 125 cases. Leuven Lung Cancer Group. J Clin Oncol. 1999;17(10):3201–3206. 15. 15Chan SC, Yen TC, Ng SH, Lin CY, Wang HM, Liao CT, et al. Differential roles of 18F-FDG PET in patients with locoregional advanced nasopharyngeal carcinoma after primary curative therapy: response evaluation and impact on management. J Nucl Med. 2006;47(9):1447–1454. MEDLINE 16. 16Metz CE. ROC methodology in radiologic imaging. Invest Radiol. 1986;21(9):720–733. MEDLINE |
CrossRef
17. 17Greene FL PI, Fritz AG, Balch CM, Haller DG, Monica M. AJCC cancer staging maunal. 9th ed.. New York: Springer; 2002;. 18. 18Lee AW, Poon YF, Foo W, Law SC, Cheung FK, Chan DK, et al. Retrospective analysis of 5037 patients with nasopharyngeal carcinoma treated during 1976–1985: overall survival and patterns of failure. Int J Radiat Oncol Biol Phys. 1992;23(2):261–270. MEDLINE |
CrossRef
19. 19Chua DT, Sham JS, Wei WI, Ho WK, Au GK. The predictive value of the 1997 American Joint Committee on Cancer stage classification in determining failure patterns in nasopharyngeal carcinoma. Cancer. 2001;92(11):2845–2855. a Molecular Imaging Center and Department of Nuclear Medicine, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, 333 Taoyuan, Taiwan b Department of Radiation Oncology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, 5 Fu-Shin St, Kueishan, Taoyuan 333, Taiwan c Division of Haematology/Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, 5 Fu-Shin St, Kueishan, Taoyuan 333, Taiwan d Department of Diagnostic Radiology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, 5 Fu-Shin St, Kueishan, Taoyuan 333, Taiwan e Division of Head and Neck Surgery, Department of Otorhinolaryngology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, 5 Fu-Shin St, Kueishan, Taoyuan 333, Taiwan f Department of Head and Neck Oncology Group, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, 5 Fu-Shin St, Kueishan, Taoyuan 333, Taiwan  Corresponding author. Address: Department of Nuclear Medicine, Chang Gung Memorial Hospital, Linkou Medical Center, 5 Fu-Shin St, Kueishan, Taoyuan 333, Taiwan. Tel.: +886 3 3281 200x2673.
PII: S1368-8375(08)00097-3 doi:10.1016/j.oraloncology.2008.03.010 © 2008 Published by Elsevier Inc. | |
|
FULL TEXT
