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A comparative study of locoregionally advanced nasopharyngeal carcinoma treated with intensity modulated irradiation and platinum-based chemotherapy
Cancer/Radiothérapie 17 (2013) 297–303
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Original article
A comparative study of locoregionally advanced nasopharyngeal carcinoma treated with intensity modulated irradiation and platinum-based chemotherapy Étude comparative de carcinomes du nasopharynx évolués pris en charge par radiothérapie avec modulation d’intensité et chimiothérapie à base de platine J.H. Xu 1 , W.J. Guo 1 , X.H. Bian , J.F. Wu , X.S. Jiang , Y.S. Guo , X. He ∗ Department of Radiation Oncology, Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, 42# Baiziting, Xuanwu District, Nanjing 210009, People’s Republic of China
a r t i c l e
i n f o
Article history: Received 19 September 2012 Received in revised form 27 March 2013 Accepted 28 March 2013 Keywords: Locoregionally advanced nasopharyngeal carcinoma IMRT Subgroup Chemotherapy
a b s t r a c t Purpose. – To investigate the prognosis of three subgroups of locoregionally advanced nasopharyngeal carcinoma treated with intensity-modulated radiotherapy and platinum-based chemotherapy. Patients and methods. – Hundred and eighty-one consecutive patients with locoregionally advanced untreated nasopharyngeal carcinoma were retrospectively divided into three subgroups: locally advanced group (T3-4N0-1M0), regionally advanced group (T1-2N2-3M0) and the mixed group (T34N2-3M0). They were all treated with definitive intensity-modulated radiotherapy and platinum-based chemotherapy. Their prognosis were investigated and compared. Multivariate analysis was applied to identify the independent risk factors of study endpoints. Results. – The 3-year locoregional control rates for locally advanced group, regionally advanced group, and the mixed group were 91.5%, 90.6% and 84.3% respectively, no significant difference was observed (P = 0.656, P = 0.429). The 3-year distant metastasis-free survival rates were 89.6%, 75.7% and 76.3%, respectively. The distant metastasis-free survival rate of the locally advanced group was significantly higher than the other two subgroups (P = 0.028, P = 0.028). The 3-year progression-free survival rates were 85.5%, 67.9% and 67.1% respectively with significance also favoring the locally advanced group (P = 0.043, P = 0.023). Nodal stage and the performance status were the independent risk factors of distant metastasis in the observed period. Conclusions. – In the context of intensity-modulated radiotherapy and platinum-based chemotherapy, the locally advanced group had a better prognosis compared with the regionally advanced group and the mixed group. Treatment stratification may be based on nodal stage. © 2013 Société française de radiothérapie oncologique (SFRO). Published by Elsevier Masson SAS. All rights reserved.
r é s u m é Mots clés : Carcinome localement évolué du nasopharynx Radiothérapie conformationnelle avec modulation d’intensité Chimiothérapie
Objectif. – Étudier le pronostic de trois sous-groupes de carcinome du nasopharynx localement évolués dont la prise en charge a consisté en une radiothérapie conformationnelle avec modulation d’intensité et une chimiothérapie à base de platine. Patients et méthodes. – Un total de 181 patients consécutifs atteints d’un carcinome du nasopharynx localement évolué non prélablement traité ont été rétrospectivement divisés en trois sous-groupes : tumeur localement évoluée (T3-4N0-1M0), tumeur régionalement évoluée (T12N2-3M0) et tumeur localement et régionalement évoluée (T3-4N2-3M0). Tous les traitements étaient à visée curative. Leurs facteurs pronostiques et d’échec ont été étudiés et comparés. Une analyse multifactorielle a été réalisée pour identifier les facteurs de risque indépendants.
∗ Corresponding author. E-mail address: [email protected] (X. He). 1 W.J. Guo and J.H. Xu contributed equally to this work. 1278-3218/$ – see front matter © 2013 Société française de radiothérapie oncologique (SFRO). Published by Elsevier Masson SAS. All rights reserved. http://dx.doi.org/10.1016/j.canrad.2013.03.006
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Résultats. – Les taux de contrôle locorégional à trois ans étaient respectivement dans les trois groupes de 91,5 %, 90,6 % et 84,3 %, sans différence significative (p = 0,656, p = 0,429). Les taux de survies sans métastase à trois ans étaient respectivement de 89,6 %, 75,7 % et 76,3 % ; ils étaient significativement plus élevés dans le premier groupes que dans les deux autres (p = 0,028, p = 0,028). Les taux de survies sans progression à trois ans étaient respectivement de 85,5 %, 67,9 % et 67,1 %, en faveur du groupe des patients atteints de tumeur localement évoluée (p = 0,043, p = 0,023). L’extension ganglionnaire et l’indice de performance étaient des facteurs de risque indépendants de dissémination métastatique à distance durant la période considérée. Conclusions. – Le pronostic s’est avéré plus favorable en l’absence d’extension ganglionnaire. Le traitement pourrait être stratifié sur la base de la classification ganglionnaire. © 2013 Société française de radiothérapie oncologique (SFRO). Publié par Elsevier Masson SAS. Tous droits réservés.
1. Introduction Nasopharyngeal carcinoma is the most common head-and-neck malignancy in Southeast Asia people, especially in those with Chinese origin [1]. Because of mild symptoms at an early stage, over 70% patients were diagnosed at a locoregionally advanced stage (III, IVa or IVb, AJCC 7th), which had been demonstrated to be associated with high locoregional recurrences and distant metastasis after treatment [2]. Clinically, the locoregionally advanced nasopharyngeal carcinoma could be divided into three subgroups: locally advanced group (T3-4N0-1M0), regionally advanced group (T1-2N2-3M0) and the mixed group (T3-4N2-3M0). Previous studies investigated locoregionally advanced cases as a whole group, but general statistical results might not clearly reflect the clinical characteristics of each subgroup [3–8]. They may differ in prognosis or failure patterns after similar treatment. Comparison of prognosis among the subgroups may help us develop new treatment strategy of stratification if difference really exists. To the best of our knowledge, no comparative studies were conducted among the subgroups of locoregionally advanced nasopharyngeal carcinoma in the context of intensity modulated radiotherapy (IMRT) and platinum-based chemotherapy. 2. Patients and methods 2.1. Patients Between June 2009 and October 2010, 223 consecutive patients with newly pathologically confirmed, untreated and nondisseminated nasopharyngeal carcinoma were registered in our center for therapy. All patients had standardized pretreatment examinations, including a complete history, physical examinations, routine blood examinations, blood biochemistry examinations, a chest X-ray, electrocardiogram (ECG), whole-body computed tomography (CT), abdominal sonography, and standardized magnetic resonance imaging (MRI). According to the 7th edition of American Joint Committee on Cancer (AJCC) staging system, 186 patients were diagnosed as locoregionally advanced cases, including T3-4N0-1M0 (locally advanced group) 67 patients, T1-2N2-3M0 (regionally advanced group) 43 patients and T3-4N23M0 (mixed group) 76 cases. A total of 181 cases were included for analysis. Five (2.7%) patients were excluded because they could not be followed up regularly after initial therapy. Patient characteristics are presented in Table 1. 2.2. Radiotherapy All patients received intensity-modulated radiotherapy. Patients were immobilized in the supine position with a thermoplastic mask fixing the head and shoulders. Contrasted CT simulation was performed with a scanning scale from the top of
the head to the bottom of the inferior head of the clavicle. Target volume contouring was based on the results of standardized MRI, which consisted of T1-weighted fast spin-echo images in the axial, coronal and sagittal planes, T2-weighted fat-suppressed fast spin-echo MR images in the axial, coronal and sagittal planes, and gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA) contrasted T1-weighted fat-suppressed images in axial, coronal, and sagittal planes. Section thickness was 5 mm with a 1-mm interslice gap for the axial plane, coronal and sagittal planes. Skull base involvement, cranial nerve invasion, and lymph node metastasis had to meet their diagnostic criteria [9–11]. The primary tumour with its direct extensions (including metastatic retropharyngeal lymph node, RPN) were defined as gross tumour volume (GTV) 1, and received a median dose of 72.13 Gy/34 fractions (range, 67.6 Gy/31f–78 Gy/35f), Metastatic cervical lymph nodes were defined as GTV2, and received a median dose of 70 Gy/33f (range, 60 Gy/32f–85 Gy/39f). For patients staged T3-4, a boost of 5 to 6 Gy in 2 to 3 fractions was given to the residual lesions if any. Electron beam was used as an alternative boost when a cervical metastatic lymph node received an X-ray dose of more than 75 Gy.The high-risk area was defined as clinical target volume (CTV) 1, which included the entire GTV1, whole nasopharyngeal
Table 1 Locoregionally advanced nasopharyngeal carcinoma clinical characteristics (n = 181). Caractéristiques cliniques. Pa
Locally advanced (n = 66)
Regionally advanced (n = 42)
Mixed type (n = 73)
Patient gender Male Female
46 20
33 9
59 14
Age ≤ 50 years > 50 years
32 34
17 25
38 35
ECOG ≤1 2
56 10
36 6
61 12
Pathology Non-keratinizing Undifferentiated
64 2
42 0
70 3
Radiation dose < 70 Gy ≥ 70 Gy
3 63
0 42
2 71
43/23
9/33
41/32
0.000
15/51
15/27
33/40
0.021
With/without radiation boost To the residual primary tumor To the residual Lymph nodes a
Pearson 2 test.
0.282
0.487
0.950
0.427
0.373
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space, GTV2 with a margin of 5 to 15 mm, and levels II and III cervical lymphatic drainage region. Typically CTV1 received a dose of 56 to 60 Gy in our institution. Low risk area was defined as CTV2 that encompassed CTV1 with a margin of 3 to 5 mm,the lower neck, and the supraclavicular lymphatic drainage region if there were no metastatic lymph nodes. CTV2 received a dose closely around 50 Gy. Final doses to GTV1 and GTV2 were based on the results of mid-term MRI assessment when GTV1 reached a cumulative dose of 56 to 60 Gy. A second CT simulation and treatment plan were performed in those patients whose primary tumor or metastatic lymph nodes decreased greatly in size. Patients were treated 5 times a week with a fraction of 2.05 to 2.28 Gy/day for GTV1/GTV2, and 1.7 to 2.0 Gy/day for CTV1/CTV2. The dose received by each organ at risk should be less than its tolerance limit according to the RTOG 0225 protocol. However, the parotid gland was an exception at our institution, as we required that 50% parotid gland should not receive a mean dose more than 35 Gy in locoregionally advanced cases with an intent to assure better coverage of the post-styloid space. Target volume contouring in typical planes are presented in Fig. 1. 2.3. Chemotherapy According to the U.S. NCCN guidelines, patients with locoregionally advanced nasopharyngeal carcinoma (stage III, IVa or IVb) were advised to receive neoadjuvant and/or concurrent platinum-based chemotherapy besides definitive IMRT. In our center, nedaplatine, a second generation of platinum with less gastrointestinal, renal and neural toxicities but with greater hemotologic toxicitiy were given as an alternative to cisplatin. One or two cycles of inductive chemotherapy were given during radiation planning with an intent to prevent disease progression. Concurrent chemotherapy with the same regimen was continued during the period of radiotherapy if tolerable. Concurrent chemotherapy cycles were limited to two cycles with an interval of 3 to 4 weeks. After combined therapy, cases with obvious residual lesions and with good tolerability were advised to accept adjuvant chemotherapy with the same regimen after about 4 weeks’ restoration. Total chemotherapy cycles during the whole treatment were limited to no more than six cycles. Nedaplatine (80–100 mg/m2 /cycle averagely given on days 1 to 3) with fluoro-uracil (500–600 mg/m2 /day on days 1 to 5, PF regimen)
299
Table 2 Chemotherapy details. Chimiothérapies. Chemotherapy performed
Number of cases
Percentage
Median cycles (range)
ICT ICT + CCRT ICT + CCRT + ACT ICT + ACT CCRT + ACT CCRT IMRT only
41 75 27 10 4 19 5
22.7 41.4 14.9 5.5 2.2 10.5 2.8
1 (1–2) 2 (2–4) 4 (3–6) 3 (2–5) 4 (3–6) 2 (1–3) –
ICT: inductive chemotherapy; CCRT: concomitant chemotherapy; ACT: adjuvant chemotherapy; IMRT: intensity-modulated radiotherapy.
or with paclitaxel (135–175 mg/m2 /cycle on day 1, TP regimen) were used as inductive, concurrent or adjuvant chemotherapy regimen. Chemotherapy was required to be repeated every 3 to 4 weeks according to the performance status of the patient. Dose modification was subject to the attending radiation oncologists according to the toxicity level. Chemotherapy was cancelled when patients refused to go on or had a delay of more than 2 weeks. Granulocyte colony-stimulating factor (G-CSF) and recombinant erythropoietin (EPO) were not used unless the white blood cells count dropped to less than 3.5 × 109 /L and hemoglobin decreased to less than 10 g/L respectively. Antibiotics were used in cases with neutropenic fever. Platelet transfusion with or without administration of interleukin 11 or recombinant thrombopoietin were used when the platelet count was less than 25 × 109 /L. Red blood cells transfusions were used when hemoglobin dropped to less than 70 g/L. 84.5%, 69.1% and 22.7% patients received inductive, concurrent and adjuvant chemotherapy respectively. 2.8% patients received only definitive intensity-modulated radiotherapy for personal reasons. Chemotherapy types and cycles are listed in Table 2. 2.4. Follow-up All patients were required to be followed up by their attending radiation oncologists after completion of the treatment every 3 months in the first 2 years, every 6 months from year 2 through
Fig. 1. Target volume contouring on the typical planes. Red line for GTV1 and GTV2, pink line for CTV1, and yellow line for CTV2. Volumes cibles sur les plans représentatifs. Ligne rouge pour GTV1 et GTV2, ligne rose pour CTV1, et ligne jaune pour CTV2. GTV : volume tumoral macroscopique ; CTV : volume cible anatomoclinique.
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J.H. Xu et al. / Cancer/Radiothérapie 17 (2013) 297–303 Table 3 Failure types (181 patients). Échecs. Failure types
Locally advanced (n = 66)
Regionally advanced (n = 42)
Mixed type (n = 73)
Pa
Locoregional Distant Disease progression Deathb
5 6 9 9
2 10 12 9
8 17 22 13
0.493 0.054 0.052 0.566
a b
Pearson 2 test. Disease-specific death.
year 5, and then annually. A typical follow-up at our institution included questioning about complaints, physical examinations including indirect or direct nasopharyngoscopy, routine blood examination, blood biochemistry examinations, a chest X-ray and abdominal sonography. MRI examinations of the head and neck was required every 3 to 6 months for the first 2 years after treatment completion, and then every 6 to 12 months from year 3 through year 5. Whole-body CT was performed only in patients with complaints of bone pain. Recurrences or metastasis were identified by either biopsy or close consecutive radiological observations. 2.5. Statistics All statistical analysis were performed by using a Statistical Package for the Social Sciences (IBM© SPSS), version 19.0. The Kaplan-Meier method was used to calculate the locoregional control rate, distant metastasis-free survival rate and progression-free survival rates. The duration of time to local/regional failure or distant metastasis was measured from patient registration. Cox proportion hazards model was used to locate the potential independent risk factors of the research endpoints. In all cases, a 2-sided P value of less than 0.05 was considered statistically significant. 3. Results 3.1. Treatment outcomes The survived patients had a median follow-up time of 34 months (range 29–41 months), 35 months (range 29–43 months) and 34 months (range 27–41 months) for the locally advanced group, regionally advanced group and the mixed group, respectively. At the last time of follow-up (Febuary 2013), a total of 10 and 28 (5.5% and 15.5%)patients developed isolated locoregional and distant failure, respectively. Five patients (2.8%) developed locoregional relapse and distant metastais successively. Disease-specific deaths happened in 31 cases (17.1%). Twenty-two patients died of distant metastasis, three patients died of locoregional recurrences, two patients were treatment-related deaths. A comparison
staged N2-3 (T1-2N2-3M0 and T3-4N2-3M0) had a significantly lower progressionfree survival rate compared with locally advanced group (T3-4N0-1M0). Log Rank test: T3-4N0-1M0 vs. T1-2N2-3M0 2 = 4.112, P = 0.043, T3-4N0-1M0 vs. T3-4N23M0 2 = 5.170, P = 0.023.
Fig. 2. Comparison of locoregional control rate, metastasis-free survival, or progress-free survival of the three subgroups. A. No significant difference in the locoregional control rate was found in the observed period. Log Rank test: T3-4N01M0 vs. T1-2N2-3M0 2 = 0.199, P = 0.656, T3-4N0-1M0 vs. T3-4N2-3M0 2 = 0.625, P = 0.499. B. Patients with N2-3 (T1-2N2-3M0 and T3-4N2-3M0) had a significantly higher distant metastasis rate; Log Rank test: T3-4N0-1M0 vs. T1-2N2-3M0 2 = 4.857, P = 0.028, T3-4N0-1M0 vs. T3-4N2-3M0 2 = 4.805, P = 0.028. C. Patients
Comparaison des courbes de contrôle locorégional, de survie sans métastase et de survie sans progression des trois sous-groupes. A. Aucune différence significative de contrôle locorégional n’a été observée durant la période considérée Log Rank : T34N0-1M0 contre T1-2N2-3M0 2 = 0,199, p = 0,656, T3-4N0-1M0 contre T3-4N2-3M0 2 = 0,625, p = 0,499. B. Les patients atteints de tumeurs de stade N2 et N3 (T1-2N23M0 et T3-4N2-3M0) avaient un taux significativement plus élevé de métastases à distance. Log Rank: T3-4N0-1M0 contre T1-2N2-3M0 2 = 4,857, p = 0,028, T3-4N01M0 contre T3-4N2-3M0 2 = 4,805, p = 0,028. C. Les patients atteints de tumeurs de stades N2 et N3 (T1-2N2-3M0 et T3-4N2-3M0) avaient un taux de survie sans progression significativement inférieur par rapport au groupe de patients atteints de tumeur localement évoluée (T3-4N0-1M0). Log Rank : T3-4N0-1M0 contre T1-2N2-3M0 2 = 4,112, p = 0,043, T3-4N0-1M0 contre T3-4N2-3M0 2 = 5,170, p = 0,023.
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of failure distribution of the three subgroups is shown in Table 3. The locally advanced group had higher distant metastasis-free survival and progression-free survival rates than the regionally advanced group and mixed type group with marginal significance (P = 0.054, P = 0.052 respectively). No locoregional failure and disease-specific death difference were observed among the three subgroups (P = 0.493, P = 0.566 respectively). 3.2. Survival analysis The 3-year locoregional control rates for the locally advanced group, regionally advanced group and the mixed group were 91.5%, 90.6% and 84.3% respectively. 3-year distant metastasisfree survival rates, 89.6%, 75.7% and 76.3% respectively. 3-year progression-free survival rates 85.5%, 67.9%, 67.1%, respectively. Survival curves of the three subgroups are shown and compared in Fig. 2. No locoregional control differences were observed between the locally advanced group and the other two groups in the observed period (P = 0.656, P = 0.429). Patients with N23 tumours (including regionally advanced group and the mixed group) had significantly lower distant metastasis-free survival and progression-free survival rates than the locally advanced group. 3.3. Multivariate analysis To locate the risk factors of distant metastasis which dominated the failure pattern and brought survival difference within the subgroups, several potential predictors including age (≤ 50 y vs. > 50 y), gender (male vs. female), performance status (ECOG [Eastern Cooperative Oncology Group] ≤ 1 vs. ECOG = 2), total chemotherapy cycles (≤ 1 cycle vs. ≥ 2 cycles), radiation dose (≤ 70 Gy vs. > 70 Gy), T-stage (T1-2 vs.T3-4) and N-stage (N0-1 vs. N2-3) were incorporated for multivariate analysis with the Cox proportion hazards model. Cell differentiation (non-keratinizing undifferentiated vs. undifferentiated) was not included as covariate because only five patients (2.7%) were undifferentiated cases. Chemotherapy type was also not included as covariate, because this retrospective study involved several chemotherapy types, which may reduce the statistical power due to a high degree of freedom. Nodal stage and performance status were demonstrated to be the independent prognostic factors of distant metastasis. The locally advanced group (N0-1) had a significantly lower distant metastasis hazard (hazard ratio [HR] = 0.357, 95% confidence interval [CI] 0.139–0.922, P = 0.033). Patients with a good performance status (ECOG ≤ 1) also had a lower distant metastasis hazard (HR = 0.358, 95% CI 0.137–0.933, P = 0.036). Age, gender, T stage, total chemotherapy cycles and radiation dose were not independent prognostic factors of distant metastasis (P = 0.669, 0.268, 0.494, 0.658, and 0.706 respectively). The distant metastasis hazard as a function of nodal stage at the mean of covariates is shown in Fig. 3A. Distant metastasis hazard increased significantly with the escalation of nodal stage. The distant metastasis hazard as a function of ECOG score at the mean of covariates is shown in Fig. 3B. Because 83.9% (26/31) disease-specific deaths happened in metastatic cases, it was not investigated as a separate research endpoint. 4. Discussion Intensity-modulated radiotherapy in combination with platinum-based chemotherapy, neoadjuvantly or concurrently, have now become the mainstream strategy in managing locoregionally advanced nasopharyngeal carcinoma, and have achieved encouraging results (Table 4). Previous investigations focused locoregionally advanced cases as a whole group overlooking the possibility of the existence of subgroups which may be quite different in response to the similar treatment regimen. To answer
Fig. 3. Cumulative distant metastasis hazard function by nodal stage or performance status at the mean of covariates. A. Nodal stage was significantly correlated to distant spread hazard. B. A good performance status (ECOG ≤ 1) was associated with lower metastasis hazard. (—): ECOG ≤ 1; (–): ECOG = 2. Analyse du risque métastatique en fonction de la classification ganglionnaire ou de l’indice de performance. A. L’envahissement ganglionnaire est significativement corrélé au risque de métastases. B. Un bon indice de performance a été associé à un risque de métastase plus faible.
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Table 4 Treatment results of locoregionally advanced nasopharyngeal carcinoma. Résultats de la prise en charge des carcinomes du nasopharynx localement et régionalement évolués. Study
Radiotherapy
Chemotherapy
Results
Dechaphunkul et al., 2011 [3]
50
2D-CRT
Platinum-based
Overall survival: 89.7% Progression-free survival: 72.7% (3 years)
Airoldi et al., 2009 [4]
40
3D-CRT
Platinum -based
Disease free survival: 75% (3 years) 65% (5 years)
223
2D-CRT
Platinum-based
Overall survival: 72% (5 years)
Lee et al., 2011 [5]
n
Kong et al., 2010 [6]
59
IMRT/3D-CRT
ICT + weekly cisplatin
Metastasis free survival: 95.7% Local relapse free survival: 97.7% (1 year)
Hu et al., 2009 [7]
54
2D-CRT
Weekly paclitaxol + AC
Locoregional control rate: 86% Metastasis free survival: 81% (3 years)
Lin et al., 2010 [8]
370
IMRT
Platinum-based
Locoregional control rate: 95% Metastasis free survival: 86% (3 years)
This study T3-4N0-1M0
181 66
IMRT
Platinum-based
T1-2N2-3M0
42
T3-4N2-3M0
73
(3 years) Locoregional control rate: 91.5% Metastasis free survival: 89.6% Progression-free survival: 85.5% Locoregional control rate: 90.6% Metastasis free survival: 75.7% Progression-free survival: 67.9% Locoregional control rate: 84.3% Metastasis free survival: 76.3% Progression-free survival: 67.1%
ICT: inductive chemotherapy; AC: adjuvant chemotherapy; IMRT: intensity-modulated radiotherapy; 3D-CRT: 3-dimensional conformal radiotherapy; 2D-CRT: traditional opposing fields with blocks.
the question above, we retrospectively divided 181 patients with locoregionally advanced nasopharyngeal carcinoma into three subgroups: locally advanced group (T3-4N0-1M0), regionally advanced group (T1-2N2-3M0) and mixed type group (T34N2-3M0). These three groups were comparable in clinical characteristics, radiation technique and follow-up frequency. In the observed period, the locally advanced group showed a significantly lower metastasis rate compared with the other two subgroups while no difference in locoregional control were observed. In the era of two-dimensional and mono-radiotherapy, T stage was already proved to be an important prognostic factor of locoregional control and distant metastasis. But in the context of IMRT and platinum-based chemotherapy, the locoregional control difference brought by T stage seemed to be effectively put off or blurred. The authors hypothesized that this may due to the excellent dosimetric characteristics of IMRT, which could provide satisfying coverage of complicated shape of the target volume, counteracting the difference brought by T stage. Shueng et al. and Xiao et al. have reported similar results [12,13]. At our institution, patients with T3-4 usually received a boost of 5 to 6 Gy given in 2 to 3 fractions to the residual lesions to a total dose closely around 75 Gy. This may provide extra locoregional control, because boosts with IMRT or fractionated stereotactic radiotherapy technique have been already proved to be beneficial in locoregional control [3,14,15]. Platinum-based chemotherapy, inductively or concurrently, contributed to locoregional control, which could also blur the difference brought by T stage [16,17]. Similarly, in a 370 cases retrospective study with a median follow-up time of 31 months (range 5–61 months), Lin et al. also found no significant difference in locoregional control in different T stages [8]. Despite these, the authors believe that a larger sample size with an even longer follow-up time will separate the curves of locoregional control. In terms of treatment, this investigation may prompt that treatment stratification should be based on nodal stage. For
patients with locally advanced lesions (T3-4N0-1M0), currently widely practiced IMRT plus neoadjuvant or concurrent platinumbased chemotherapy have proved to be very effective in both locoregional control and distant control. The necessity of more aggressive chemotherapy, especially post-chemoradiation adjuvant chemotherapy should be re-evaluated. A recently published phase III trial revealed that adjuvant cisplatin and fluoro-uracil chemotherapy did not significantly improve failure-free survival after concurrent chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma [18]. While for patients with N2-3 (including T1-2N2-3M0 and T3-4N2-3M0), in the observed period, distant metastasis dominated the pattern of failure, which implied that IMRT and platinum-based chemotherapy regimen were still not effective enough to prevent distant metastasis from regional spread. Optimal multidisciplinary management with the focus on reducing distant metastasis deserves more prospective randomized trials. Recently, a single arm phase II trial conducted by Ou et al revealed that neoadjuvant gemcitabine plus cisplatin followed by IMRT and adjuvant chemotherapy with the same regimen achieved an encouraging 3-year distant metastasis-free survival rate of 91% in 71 locoregionially advanced nasopharyngeal carcinoma cases [19]. However, there were other explanations to the difference of distant metastasis. Metastases may already exist at the time of diagnosis, while traditional radiological examinations could not detect these potential metastases. Chang et al. reported that FDGPET could detect an extra distant metastasis rate of 11% compared with conventional modalities [20]. Remarkably in our study, 51.9% (14/27) distant metastasis happened within 12 months after treatment start in patients with N2-3. Because of economic constraints, these patients did not receive FDG-PET examinations to detect possible distant metastasis at the time of staging. But the fact that a large propotion of distant failure happened so closely after treatment responded well to the hypothesis that potential metastasis
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already exist before treatment. Another reasonable explanation to the difference of distant metastasis was that the biological behaviors may be different due to their special genetic backgrounds. Tse et al. reported that a single nucleotide polymorphism (SNP) at 2518 of the MCP-1 promoter region influences clinical outcomes. Patients carrying AA or AG genotypes are more likely to develop distant metastasis than those with GG genotype (hazard ratio, 2.21; P = 0.017, and hazard ratio, 2.23; P = 0.005, for AA and AG genotype, respectively) after initial radiotherapy [21]. Invasion of Epstein-Barr virus into peripheral blood cells was also demonstrated to be associated with a significantly higher distant metastasis and lower survival rates [22]. These results imply the existence of a biological heterogeneity within the locoregionally advanced group, or even in the whole nasopharyngeal carcinoma population. Genetic background related to metastasis in locoregionally advanced cases may be the focus of future study. A good performance status was also demonstrated to be statistically correlated to a higher distant metastasis-free survival. Presumably, patients with good performance status are more likely to finish planned treatment schema and achieve good outcome. But statistical coincidence could not be excluded. In conclusion, in the context of IMRT and platinum-based chemotherapy, the locally advanced group had a better prognosis compared with the regionally advanced group and the mixed group. Treatment stratification may be based on nodal stage. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
[6]
[7]
[8]
[9] [10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
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Original article
A comparative study of locoregionally advanced nasopharyngeal carcinoma treated with intensity modulated irradiation and platinum-based chemotherapy Étude comparative de carcinomes du nasopharynx évolués pris en charge par radiothérapie avec modulation d’intensité et chimiothérapie à base de platine J.H. Xu 1 , W.J. Guo 1 , X.H. Bian , J.F. Wu , X.S. Jiang , Y.S. Guo , X. He ∗ Department of Radiation Oncology, Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, 42# Baiziting, Xuanwu District, Nanjing 210009, People’s Republic of China
a r t i c l e
i n f o
Article history: Received 19 September 2012 Received in revised form 27 March 2013 Accepted 28 March 2013 Keywords: Locoregionally advanced nasopharyngeal carcinoma IMRT Subgroup Chemotherapy
a b s t r a c t Purpose. – To investigate the prognosis of three subgroups of locoregionally advanced nasopharyngeal carcinoma treated with intensity-modulated radiotherapy and platinum-based chemotherapy. Patients and methods. – Hundred and eighty-one consecutive patients with locoregionally advanced untreated nasopharyngeal carcinoma were retrospectively divided into three subgroups: locally advanced group (T3-4N0-1M0), regionally advanced group (T1-2N2-3M0) and the mixed group (T34N2-3M0). They were all treated with definitive intensity-modulated radiotherapy and platinum-based chemotherapy. Their prognosis were investigated and compared. Multivariate analysis was applied to identify the independent risk factors of study endpoints. Results. – The 3-year locoregional control rates for locally advanced group, regionally advanced group, and the mixed group were 91.5%, 90.6% and 84.3% respectively, no significant difference was observed (P = 0.656, P = 0.429). The 3-year distant metastasis-free survival rates were 89.6%, 75.7% and 76.3%, respectively. The distant metastasis-free survival rate of the locally advanced group was significantly higher than the other two subgroups (P = 0.028, P = 0.028). The 3-year progression-free survival rates were 85.5%, 67.9% and 67.1% respectively with significance also favoring the locally advanced group (P = 0.043, P = 0.023). Nodal stage and the performance status were the independent risk factors of distant metastasis in the observed period. Conclusions. – In the context of intensity-modulated radiotherapy and platinum-based chemotherapy, the locally advanced group had a better prognosis compared with the regionally advanced group and the mixed group. Treatment stratification may be based on nodal stage. © 2013 Société française de radiothérapie oncologique (SFRO). Published by Elsevier Masson SAS. All rights reserved.
r é s u m é Mots clés : Carcinome localement évolué du nasopharynx Radiothérapie conformationnelle avec modulation d’intensité Chimiothérapie
Objectif. – Étudier le pronostic de trois sous-groupes de carcinome du nasopharynx localement évolués dont la prise en charge a consisté en une radiothérapie conformationnelle avec modulation d’intensité et une chimiothérapie à base de platine. Patients et méthodes. – Un total de 181 patients consécutifs atteints d’un carcinome du nasopharynx localement évolué non prélablement traité ont été rétrospectivement divisés en trois sous-groupes : tumeur localement évoluée (T3-4N0-1M0), tumeur régionalement évoluée (T12N2-3M0) et tumeur localement et régionalement évoluée (T3-4N2-3M0). Tous les traitements étaient à visée curative. Leurs facteurs pronostiques et d’échec ont été étudiés et comparés. Une analyse multifactorielle a été réalisée pour identifier les facteurs de risque indépendants.
∗ Corresponding author. E-mail address: [email protected] (X. He). 1 W.J. Guo and J.H. Xu contributed equally to this work. 1278-3218/$ – see front matter © 2013 Société française de radiothérapie oncologique (SFRO). Published by Elsevier Masson SAS. All rights reserved. http://dx.doi.org/10.1016/j.canrad.2013.03.006
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Résultats. – Les taux de contrôle locorégional à trois ans étaient respectivement dans les trois groupes de 91,5 %, 90,6 % et 84,3 %, sans différence significative (p = 0,656, p = 0,429). Les taux de survies sans métastase à trois ans étaient respectivement de 89,6 %, 75,7 % et 76,3 % ; ils étaient significativement plus élevés dans le premier groupes que dans les deux autres (p = 0,028, p = 0,028). Les taux de survies sans progression à trois ans étaient respectivement de 85,5 %, 67,9 % et 67,1 %, en faveur du groupe des patients atteints de tumeur localement évoluée (p = 0,043, p = 0,023). L’extension ganglionnaire et l’indice de performance étaient des facteurs de risque indépendants de dissémination métastatique à distance durant la période considérée. Conclusions. – Le pronostic s’est avéré plus favorable en l’absence d’extension ganglionnaire. Le traitement pourrait être stratifié sur la base de la classification ganglionnaire. © 2013 Société française de radiothérapie oncologique (SFRO). Publié par Elsevier Masson SAS. Tous droits réservés.
1. Introduction Nasopharyngeal carcinoma is the most common head-and-neck malignancy in Southeast Asia people, especially in those with Chinese origin [1]. Because of mild symptoms at an early stage, over 70% patients were diagnosed at a locoregionally advanced stage (III, IVa or IVb, AJCC 7th), which had been demonstrated to be associated with high locoregional recurrences and distant metastasis after treatment [2]. Clinically, the locoregionally advanced nasopharyngeal carcinoma could be divided into three subgroups: locally advanced group (T3-4N0-1M0), regionally advanced group (T1-2N2-3M0) and the mixed group (T3-4N2-3M0). Previous studies investigated locoregionally advanced cases as a whole group, but general statistical results might not clearly reflect the clinical characteristics of each subgroup [3–8]. They may differ in prognosis or failure patterns after similar treatment. Comparison of prognosis among the subgroups may help us develop new treatment strategy of stratification if difference really exists. To the best of our knowledge, no comparative studies were conducted among the subgroups of locoregionally advanced nasopharyngeal carcinoma in the context of intensity modulated radiotherapy (IMRT) and platinum-based chemotherapy. 2. Patients and methods 2.1. Patients Between June 2009 and October 2010, 223 consecutive patients with newly pathologically confirmed, untreated and nondisseminated nasopharyngeal carcinoma were registered in our center for therapy. All patients had standardized pretreatment examinations, including a complete history, physical examinations, routine blood examinations, blood biochemistry examinations, a chest X-ray, electrocardiogram (ECG), whole-body computed tomography (CT), abdominal sonography, and standardized magnetic resonance imaging (MRI). According to the 7th edition of American Joint Committee on Cancer (AJCC) staging system, 186 patients were diagnosed as locoregionally advanced cases, including T3-4N0-1M0 (locally advanced group) 67 patients, T1-2N2-3M0 (regionally advanced group) 43 patients and T3-4N23M0 (mixed group) 76 cases. A total of 181 cases were included for analysis. Five (2.7%) patients were excluded because they could not be followed up regularly after initial therapy. Patient characteristics are presented in Table 1. 2.2. Radiotherapy All patients received intensity-modulated radiotherapy. Patients were immobilized in the supine position with a thermoplastic mask fixing the head and shoulders. Contrasted CT simulation was performed with a scanning scale from the top of
the head to the bottom of the inferior head of the clavicle. Target volume contouring was based on the results of standardized MRI, which consisted of T1-weighted fast spin-echo images in the axial, coronal and sagittal planes, T2-weighted fat-suppressed fast spin-echo MR images in the axial, coronal and sagittal planes, and gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA) contrasted T1-weighted fat-suppressed images in axial, coronal, and sagittal planes. Section thickness was 5 mm with a 1-mm interslice gap for the axial plane, coronal and sagittal planes. Skull base involvement, cranial nerve invasion, and lymph node metastasis had to meet their diagnostic criteria [9–11]. The primary tumour with its direct extensions (including metastatic retropharyngeal lymph node, RPN) were defined as gross tumour volume (GTV) 1, and received a median dose of 72.13 Gy/34 fractions (range, 67.6 Gy/31f–78 Gy/35f), Metastatic cervical lymph nodes were defined as GTV2, and received a median dose of 70 Gy/33f (range, 60 Gy/32f–85 Gy/39f). For patients staged T3-4, a boost of 5 to 6 Gy in 2 to 3 fractions was given to the residual lesions if any. Electron beam was used as an alternative boost when a cervical metastatic lymph node received an X-ray dose of more than 75 Gy.The high-risk area was defined as clinical target volume (CTV) 1, which included the entire GTV1, whole nasopharyngeal
Table 1 Locoregionally advanced nasopharyngeal carcinoma clinical characteristics (n = 181). Caractéristiques cliniques. Pa
Locally advanced (n = 66)
Regionally advanced (n = 42)
Mixed type (n = 73)
Patient gender Male Female
46 20
33 9
59 14
Age ≤ 50 years > 50 years
32 34
17 25
38 35
ECOG ≤1 2
56 10
36 6
61 12
Pathology Non-keratinizing Undifferentiated
64 2
42 0
70 3
Radiation dose < 70 Gy ≥ 70 Gy
3 63
0 42
2 71
43/23
9/33
41/32
0.000
15/51
15/27
33/40
0.021
With/without radiation boost To the residual primary tumor To the residual Lymph nodes a
Pearson 2 test.
0.282
0.487
0.950
0.427
0.373
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space, GTV2 with a margin of 5 to 15 mm, and levels II and III cervical lymphatic drainage region. Typically CTV1 received a dose of 56 to 60 Gy in our institution. Low risk area was defined as CTV2 that encompassed CTV1 with a margin of 3 to 5 mm,the lower neck, and the supraclavicular lymphatic drainage region if there were no metastatic lymph nodes. CTV2 received a dose closely around 50 Gy. Final doses to GTV1 and GTV2 were based on the results of mid-term MRI assessment when GTV1 reached a cumulative dose of 56 to 60 Gy. A second CT simulation and treatment plan were performed in those patients whose primary tumor or metastatic lymph nodes decreased greatly in size. Patients were treated 5 times a week with a fraction of 2.05 to 2.28 Gy/day for GTV1/GTV2, and 1.7 to 2.0 Gy/day for CTV1/CTV2. The dose received by each organ at risk should be less than its tolerance limit according to the RTOG 0225 protocol. However, the parotid gland was an exception at our institution, as we required that 50% parotid gland should not receive a mean dose more than 35 Gy in locoregionally advanced cases with an intent to assure better coverage of the post-styloid space. Target volume contouring in typical planes are presented in Fig. 1. 2.3. Chemotherapy According to the U.S. NCCN guidelines, patients with locoregionally advanced nasopharyngeal carcinoma (stage III, IVa or IVb) were advised to receive neoadjuvant and/or concurrent platinum-based chemotherapy besides definitive IMRT. In our center, nedaplatine, a second generation of platinum with less gastrointestinal, renal and neural toxicities but with greater hemotologic toxicitiy were given as an alternative to cisplatin. One or two cycles of inductive chemotherapy were given during radiation planning with an intent to prevent disease progression. Concurrent chemotherapy with the same regimen was continued during the period of radiotherapy if tolerable. Concurrent chemotherapy cycles were limited to two cycles with an interval of 3 to 4 weeks. After combined therapy, cases with obvious residual lesions and with good tolerability were advised to accept adjuvant chemotherapy with the same regimen after about 4 weeks’ restoration. Total chemotherapy cycles during the whole treatment were limited to no more than six cycles. Nedaplatine (80–100 mg/m2 /cycle averagely given on days 1 to 3) with fluoro-uracil (500–600 mg/m2 /day on days 1 to 5, PF regimen)
299
Table 2 Chemotherapy details. Chimiothérapies. Chemotherapy performed
Number of cases
Percentage
Median cycles (range)
ICT ICT + CCRT ICT + CCRT + ACT ICT + ACT CCRT + ACT CCRT IMRT only
41 75 27 10 4 19 5
22.7 41.4 14.9 5.5 2.2 10.5 2.8
1 (1–2) 2 (2–4) 4 (3–6) 3 (2–5) 4 (3–6) 2 (1–3) –
ICT: inductive chemotherapy; CCRT: concomitant chemotherapy; ACT: adjuvant chemotherapy; IMRT: intensity-modulated radiotherapy.
or with paclitaxel (135–175 mg/m2 /cycle on day 1, TP regimen) were used as inductive, concurrent or adjuvant chemotherapy regimen. Chemotherapy was required to be repeated every 3 to 4 weeks according to the performance status of the patient. Dose modification was subject to the attending radiation oncologists according to the toxicity level. Chemotherapy was cancelled when patients refused to go on or had a delay of more than 2 weeks. Granulocyte colony-stimulating factor (G-CSF) and recombinant erythropoietin (EPO) were not used unless the white blood cells count dropped to less than 3.5 × 109 /L and hemoglobin decreased to less than 10 g/L respectively. Antibiotics were used in cases with neutropenic fever. Platelet transfusion with or without administration of interleukin 11 or recombinant thrombopoietin were used when the platelet count was less than 25 × 109 /L. Red blood cells transfusions were used when hemoglobin dropped to less than 70 g/L. 84.5%, 69.1% and 22.7% patients received inductive, concurrent and adjuvant chemotherapy respectively. 2.8% patients received only definitive intensity-modulated radiotherapy for personal reasons. Chemotherapy types and cycles are listed in Table 2. 2.4. Follow-up All patients were required to be followed up by their attending radiation oncologists after completion of the treatment every 3 months in the first 2 years, every 6 months from year 2 through
Fig. 1. Target volume contouring on the typical planes. Red line for GTV1 and GTV2, pink line for CTV1, and yellow line for CTV2. Volumes cibles sur les plans représentatifs. Ligne rouge pour GTV1 et GTV2, ligne rose pour CTV1, et ligne jaune pour CTV2. GTV : volume tumoral macroscopique ; CTV : volume cible anatomoclinique.
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J.H. Xu et al. / Cancer/Radiothérapie 17 (2013) 297–303 Table 3 Failure types (181 patients). Échecs. Failure types
Locally advanced (n = 66)
Regionally advanced (n = 42)
Mixed type (n = 73)
Pa
Locoregional Distant Disease progression Deathb
5 6 9 9
2 10 12 9
8 17 22 13
0.493 0.054 0.052 0.566
a b
Pearson 2 test. Disease-specific death.
year 5, and then annually. A typical follow-up at our institution included questioning about complaints, physical examinations including indirect or direct nasopharyngoscopy, routine blood examination, blood biochemistry examinations, a chest X-ray and abdominal sonography. MRI examinations of the head and neck was required every 3 to 6 months for the first 2 years after treatment completion, and then every 6 to 12 months from year 3 through year 5. Whole-body CT was performed only in patients with complaints of bone pain. Recurrences or metastasis were identified by either biopsy or close consecutive radiological observations. 2.5. Statistics All statistical analysis were performed by using a Statistical Package for the Social Sciences (IBM© SPSS), version 19.0. The Kaplan-Meier method was used to calculate the locoregional control rate, distant metastasis-free survival rate and progression-free survival rates. The duration of time to local/regional failure or distant metastasis was measured from patient registration. Cox proportion hazards model was used to locate the potential independent risk factors of the research endpoints. In all cases, a 2-sided P value of less than 0.05 was considered statistically significant. 3. Results 3.1. Treatment outcomes The survived patients had a median follow-up time of 34 months (range 29–41 months), 35 months (range 29–43 months) and 34 months (range 27–41 months) for the locally advanced group, regionally advanced group and the mixed group, respectively. At the last time of follow-up (Febuary 2013), a total of 10 and 28 (5.5% and 15.5%)patients developed isolated locoregional and distant failure, respectively. Five patients (2.8%) developed locoregional relapse and distant metastais successively. Disease-specific deaths happened in 31 cases (17.1%). Twenty-two patients died of distant metastasis, three patients died of locoregional recurrences, two patients were treatment-related deaths. A comparison
staged N2-3 (T1-2N2-3M0 and T3-4N2-3M0) had a significantly lower progressionfree survival rate compared with locally advanced group (T3-4N0-1M0). Log Rank test: T3-4N0-1M0 vs. T1-2N2-3M0 2 = 4.112, P = 0.043, T3-4N0-1M0 vs. T3-4N23M0 2 = 5.170, P = 0.023.
Fig. 2. Comparison of locoregional control rate, metastasis-free survival, or progress-free survival of the three subgroups. A. No significant difference in the locoregional control rate was found in the observed period. Log Rank test: T3-4N01M0 vs. T1-2N2-3M0 2 = 0.199, P = 0.656, T3-4N0-1M0 vs. T3-4N2-3M0 2 = 0.625, P = 0.499. B. Patients with N2-3 (T1-2N2-3M0 and T3-4N2-3M0) had a significantly higher distant metastasis rate; Log Rank test: T3-4N0-1M0 vs. T1-2N2-3M0 2 = 4.857, P = 0.028, T3-4N0-1M0 vs. T3-4N2-3M0 2 = 4.805, P = 0.028. C. Patients
Comparaison des courbes de contrôle locorégional, de survie sans métastase et de survie sans progression des trois sous-groupes. A. Aucune différence significative de contrôle locorégional n’a été observée durant la période considérée Log Rank : T34N0-1M0 contre T1-2N2-3M0 2 = 0,199, p = 0,656, T3-4N0-1M0 contre T3-4N2-3M0 2 = 0,625, p = 0,499. B. Les patients atteints de tumeurs de stade N2 et N3 (T1-2N23M0 et T3-4N2-3M0) avaient un taux significativement plus élevé de métastases à distance. Log Rank: T3-4N0-1M0 contre T1-2N2-3M0 2 = 4,857, p = 0,028, T3-4N01M0 contre T3-4N2-3M0 2 = 4,805, p = 0,028. C. Les patients atteints de tumeurs de stades N2 et N3 (T1-2N2-3M0 et T3-4N2-3M0) avaient un taux de survie sans progression significativement inférieur par rapport au groupe de patients atteints de tumeur localement évoluée (T3-4N0-1M0). Log Rank : T3-4N0-1M0 contre T1-2N2-3M0 2 = 4,112, p = 0,043, T3-4N0-1M0 contre T3-4N2-3M0 2 = 5,170, p = 0,023.
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of failure distribution of the three subgroups is shown in Table 3. The locally advanced group had higher distant metastasis-free survival and progression-free survival rates than the regionally advanced group and mixed type group with marginal significance (P = 0.054, P = 0.052 respectively). No locoregional failure and disease-specific death difference were observed among the three subgroups (P = 0.493, P = 0.566 respectively). 3.2. Survival analysis The 3-year locoregional control rates for the locally advanced group, regionally advanced group and the mixed group were 91.5%, 90.6% and 84.3% respectively. 3-year distant metastasisfree survival rates, 89.6%, 75.7% and 76.3% respectively. 3-year progression-free survival rates 85.5%, 67.9%, 67.1%, respectively. Survival curves of the three subgroups are shown and compared in Fig. 2. No locoregional control differences were observed between the locally advanced group and the other two groups in the observed period (P = 0.656, P = 0.429). Patients with N23 tumours (including regionally advanced group and the mixed group) had significantly lower distant metastasis-free survival and progression-free survival rates than the locally advanced group. 3.3. Multivariate analysis To locate the risk factors of distant metastasis which dominated the failure pattern and brought survival difference within the subgroups, several potential predictors including age (≤ 50 y vs. > 50 y), gender (male vs. female), performance status (ECOG [Eastern Cooperative Oncology Group] ≤ 1 vs. ECOG = 2), total chemotherapy cycles (≤ 1 cycle vs. ≥ 2 cycles), radiation dose (≤ 70 Gy vs. > 70 Gy), T-stage (T1-2 vs.T3-4) and N-stage (N0-1 vs. N2-3) were incorporated for multivariate analysis with the Cox proportion hazards model. Cell differentiation (non-keratinizing undifferentiated vs. undifferentiated) was not included as covariate because only five patients (2.7%) were undifferentiated cases. Chemotherapy type was also not included as covariate, because this retrospective study involved several chemotherapy types, which may reduce the statistical power due to a high degree of freedom. Nodal stage and performance status were demonstrated to be the independent prognostic factors of distant metastasis. The locally advanced group (N0-1) had a significantly lower distant metastasis hazard (hazard ratio [HR] = 0.357, 95% confidence interval [CI] 0.139–0.922, P = 0.033). Patients with a good performance status (ECOG ≤ 1) also had a lower distant metastasis hazard (HR = 0.358, 95% CI 0.137–0.933, P = 0.036). Age, gender, T stage, total chemotherapy cycles and radiation dose were not independent prognostic factors of distant metastasis (P = 0.669, 0.268, 0.494, 0.658, and 0.706 respectively). The distant metastasis hazard as a function of nodal stage at the mean of covariates is shown in Fig. 3A. Distant metastasis hazard increased significantly with the escalation of nodal stage. The distant metastasis hazard as a function of ECOG score at the mean of covariates is shown in Fig. 3B. Because 83.9% (26/31) disease-specific deaths happened in metastatic cases, it was not investigated as a separate research endpoint. 4. Discussion Intensity-modulated radiotherapy in combination with platinum-based chemotherapy, neoadjuvantly or concurrently, have now become the mainstream strategy in managing locoregionally advanced nasopharyngeal carcinoma, and have achieved encouraging results (Table 4). Previous investigations focused locoregionally advanced cases as a whole group overlooking the possibility of the existence of subgroups which may be quite different in response to the similar treatment regimen. To answer
Fig. 3. Cumulative distant metastasis hazard function by nodal stage or performance status at the mean of covariates. A. Nodal stage was significantly correlated to distant spread hazard. B. A good performance status (ECOG ≤ 1) was associated with lower metastasis hazard. (—): ECOG ≤ 1; (–): ECOG = 2. Analyse du risque métastatique en fonction de la classification ganglionnaire ou de l’indice de performance. A. L’envahissement ganglionnaire est significativement corrélé au risque de métastases. B. Un bon indice de performance a été associé à un risque de métastase plus faible.
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Table 4 Treatment results of locoregionally advanced nasopharyngeal carcinoma. Résultats de la prise en charge des carcinomes du nasopharynx localement et régionalement évolués. Study
Radiotherapy
Chemotherapy
Results
Dechaphunkul et al., 2011 [3]
50
2D-CRT
Platinum-based
Overall survival: 89.7% Progression-free survival: 72.7% (3 years)
Airoldi et al., 2009 [4]
40
3D-CRT
Platinum -based
Disease free survival: 75% (3 years) 65% (5 years)
223
2D-CRT
Platinum-based
Overall survival: 72% (5 years)
Lee et al., 2011 [5]
n
Kong et al., 2010 [6]
59
IMRT/3D-CRT
ICT + weekly cisplatin
Metastasis free survival: 95.7% Local relapse free survival: 97.7% (1 year)
Hu et al., 2009 [7]
54
2D-CRT
Weekly paclitaxol + AC
Locoregional control rate: 86% Metastasis free survival: 81% (3 years)
Lin et al., 2010 [8]
370
IMRT
Platinum-based
Locoregional control rate: 95% Metastasis free survival: 86% (3 years)
This study T3-4N0-1M0
181 66
IMRT
Platinum-based
T1-2N2-3M0
42
T3-4N2-3M0
73
(3 years) Locoregional control rate: 91.5% Metastasis free survival: 89.6% Progression-free survival: 85.5% Locoregional control rate: 90.6% Metastasis free survival: 75.7% Progression-free survival: 67.9% Locoregional control rate: 84.3% Metastasis free survival: 76.3% Progression-free survival: 67.1%
ICT: inductive chemotherapy; AC: adjuvant chemotherapy; IMRT: intensity-modulated radiotherapy; 3D-CRT: 3-dimensional conformal radiotherapy; 2D-CRT: traditional opposing fields with blocks.
the question above, we retrospectively divided 181 patients with locoregionally advanced nasopharyngeal carcinoma into three subgroups: locally advanced group (T3-4N0-1M0), regionally advanced group (T1-2N2-3M0) and mixed type group (T34N2-3M0). These three groups were comparable in clinical characteristics, radiation technique and follow-up frequency. In the observed period, the locally advanced group showed a significantly lower metastasis rate compared with the other two subgroups while no difference in locoregional control were observed. In the era of two-dimensional and mono-radiotherapy, T stage was already proved to be an important prognostic factor of locoregional control and distant metastasis. But in the context of IMRT and platinum-based chemotherapy, the locoregional control difference brought by T stage seemed to be effectively put off or blurred. The authors hypothesized that this may due to the excellent dosimetric characteristics of IMRT, which could provide satisfying coverage of complicated shape of the target volume, counteracting the difference brought by T stage. Shueng et al. and Xiao et al. have reported similar results [12,13]. At our institution, patients with T3-4 usually received a boost of 5 to 6 Gy given in 2 to 3 fractions to the residual lesions to a total dose closely around 75 Gy. This may provide extra locoregional control, because boosts with IMRT or fractionated stereotactic radiotherapy technique have been already proved to be beneficial in locoregional control [3,14,15]. Platinum-based chemotherapy, inductively or concurrently, contributed to locoregional control, which could also blur the difference brought by T stage [16,17]. Similarly, in a 370 cases retrospective study with a median follow-up time of 31 months (range 5–61 months), Lin et al. also found no significant difference in locoregional control in different T stages [8]. Despite these, the authors believe that a larger sample size with an even longer follow-up time will separate the curves of locoregional control. In terms of treatment, this investigation may prompt that treatment stratification should be based on nodal stage. For
patients with locally advanced lesions (T3-4N0-1M0), currently widely practiced IMRT plus neoadjuvant or concurrent platinumbased chemotherapy have proved to be very effective in both locoregional control and distant control. The necessity of more aggressive chemotherapy, especially post-chemoradiation adjuvant chemotherapy should be re-evaluated. A recently published phase III trial revealed that adjuvant cisplatin and fluoro-uracil chemotherapy did not significantly improve failure-free survival after concurrent chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma [18]. While for patients with N2-3 (including T1-2N2-3M0 and T3-4N2-3M0), in the observed period, distant metastasis dominated the pattern of failure, which implied that IMRT and platinum-based chemotherapy regimen were still not effective enough to prevent distant metastasis from regional spread. Optimal multidisciplinary management with the focus on reducing distant metastasis deserves more prospective randomized trials. Recently, a single arm phase II trial conducted by Ou et al revealed that neoadjuvant gemcitabine plus cisplatin followed by IMRT and adjuvant chemotherapy with the same regimen achieved an encouraging 3-year distant metastasis-free survival rate of 91% in 71 locoregionially advanced nasopharyngeal carcinoma cases [19]. However, there were other explanations to the difference of distant metastasis. Metastases may already exist at the time of diagnosis, while traditional radiological examinations could not detect these potential metastases. Chang et al. reported that FDGPET could detect an extra distant metastasis rate of 11% compared with conventional modalities [20]. Remarkably in our study, 51.9% (14/27) distant metastasis happened within 12 months after treatment start in patients with N2-3. Because of economic constraints, these patients did not receive FDG-PET examinations to detect possible distant metastasis at the time of staging. But the fact that a large propotion of distant failure happened so closely after treatment responded well to the hypothesis that potential metastasis
J.H. Xu et al. / Cancer/Radiothérapie 17 (2013) 297–303
already exist before treatment. Another reasonable explanation to the difference of distant metastasis was that the biological behaviors may be different due to their special genetic backgrounds. Tse et al. reported that a single nucleotide polymorphism (SNP) at 2518 of the MCP-1 promoter region influences clinical outcomes. Patients carrying AA or AG genotypes are more likely to develop distant metastasis than those with GG genotype (hazard ratio, 2.21; P = 0.017, and hazard ratio, 2.23; P = 0.005, for AA and AG genotype, respectively) after initial radiotherapy [21]. Invasion of Epstein-Barr virus into peripheral blood cells was also demonstrated to be associated with a significantly higher distant metastasis and lower survival rates [22]. These results imply the existence of a biological heterogeneity within the locoregionally advanced group, or even in the whole nasopharyngeal carcinoma population. Genetic background related to metastasis in locoregionally advanced cases may be the focus of future study. A good performance status was also demonstrated to be statistically correlated to a higher distant metastasis-free survival. Presumably, patients with good performance status are more likely to finish planned treatment schema and achieve good outcome. But statistical coincidence could not be excluded. In conclusion, in the context of IMRT and platinum-based chemotherapy, the locally advanced group had a better prognosis compared with the regionally advanced group and the mixed group. Treatment stratification may be based on nodal stage. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
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