original articles
Annals of Oncology
Annals of Oncology 23: 1287–1292, 2012 doi:10.1093/annonc/mdr401 Published online 23 September 2011
A phase II study of concurrent cetuximab–cisplatin and intensity-modulated radiotherapy in locoregionally advanced nasopharyngeal carcinoma B. B. Y. Ma1*, M. K. M. Kam1, S. F. Leung1, E. P. Hui1, A. D. King2, S. L. Chan1, F. Mo1, H. Loong1, B. K. H. Yu1, A. Ahuja2 & A. T. C. Chan1 1 State Key Laboratory in Oncology in South China, Sir YK Pao Centre for Cancer, Department of Clinical Oncology, Hong Kong Cancer Institute. The Chinese University of Hong Kong; 2Imaging and Interventional Radiology, Prince of Wales Hospital, Chinese University of Hong Kong, Hong Kong, China
Received 9 November 2010; revised 26 April 2011; revised 3 May 2011; accepted 20 July 2011
Background: Based on our previous work on the clinical activity of cetuximab in recurrent nasopharyngeal carcinoma (NPC), we evaluated the feasibility of adding cetuximab to concurrent cisplatin and intensity-modulated radiotherapy (IMRT) in locoregionally advanced NPC. Patients and methods: Patients with American Joint Committee on Cancer stage III–IVB NPC were given an initial dose of cetuximab (400 mg/m2) 7–10 days before receiving concurrent IMRT, weekly cisplatin (30 mg/m2/week) and cetuximab (250 mg/m2/week). Results: Thirty patients (median age of 45 years) with stage III (67%), IVA (30%) and IVB (3%) nonkeratinizing NPC were enrolled. Grade 3–4 oropharyngeal mucositis occurred in 26 (87%) patients and 10 (33%) patients required short-term nasogastric feeding. Grade 3 radiotherapy-related dermatitis occurred in six patients (20%) and three patients (10%) had grade 3 cetuximab-related acneiform rash. These grade 3–4 skin and mucosal toxic effects were manageable and reversible. At a median follow-up of 31.8 months [95% confidence interval (CI) 26.2–32.1 months], the 2-year progression-free survival was 86.5% (95% CI 74.3% to 98.8%). Conclusions: Concurrent administration of cetuximab, weekly cisplatin and IMRT is a feasible strategy against locoregionally advanced NPC. Preliminary survival data compare favorably with historic data and further follow-up is warranted. Key words: cetuximab, intensity-modulated radiotherapy, nasopharyngeal carcinoma
introduction Nonkeratinizing nasopharyngeal carcinoma (NPC) is endemic to Southern China and Hong Kong where >50% of patients present with locoregionally advanced disease, i.e. stage III–IVB NPC according to the American Joint Committee on Cancer (AJCC; sixth edition) [1]. The current standard of treatment for such patients primarily involves the use of concurrent chemoradiotherapy (chemo-RT), which has been shown to confer survival benefit over radiotherapy (RT) alone in more than eight randomized trials [2]. Some studies have attributed this benefit to an improvement of locoregional control [3–5], while others have attributed this to a lowered rate of distant recurrence [3, 6, 7]. Intensity-modulated radiotherapy (IMRT) is being increasingly adopted as the preferred mode of RT, yielding high local control rates [8]. Despite the availability of modern treatments, up to 30% of patients with locoregionally advanced NPC still die of distant recurrence, while 10%–20% *Correspondence to: Dr B. B. Y. Ma, Department of Clinical Oncology, Basement, LKS Specialist Clinic, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China. Tel: +852-26322118; Fax: +852-26487097; E-mail:
[email protected]
will develop local and regional recurrences [1, 2]; thus newer systemic strategies are needed for the treatment of NPC. Overexpression of the epidermal growth factor receptor (EGFR) can be found in 80% of patients with locoregionally advanced NPC and is associated with shorter survival following RT [9]. Cetuximab is an anti-EGFR antibody that has been shown to improve survival when combined with RT in patients with locoregionally advanced non-NPC head and neck squamous cell carcinoma (HNSCC) [10]. Our previous work has shown that cetuximab can enhance the growth-inhibitory effect of cisplatin in NPC cell lines [11] and has clinical activity when combined with carboplatin in the treatment of recurrent NPC [12]. The primary purpose of this study was to evaluate the feasibility of incorporating cetuximab in the curative treatment of locoregionally advanced NPC with concurrent chemo-RT.
patients and methods patients All patients were 18 years old or above with an Eastern Cooperative Oncology Group performance status of zero or one. Eligible patients had
ª The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email:
[email protected]
original articles previously untreated and histologically confirmed World Health Organization (WHO) type II and III (1991 classification) [13] NPC that belonged to any one of the following AJCC disease stages: T3 or T4 stage and any N stage, M0 or N2 or N3 stage and any T stage, M0. Patients had to have adequate organ function as defined by having an absolute neutrophil count > 1.5 · 109/l, platelet count > 100 · 109/l, hemoglobin level > 8.0 g/dl, bilirubin level £ 1.5 · the upper limit of normal (ULN), alanine aminotransferase level £ 3 · ULN, serum creatinine level £ 1.2 · ULN and a calculated creatinine clearance > 50 ml/min. Patients were excluded from the study if they had a history of another invasive cancer, prior RT to the head and neck area, prior cytotoxic chemotherapy or anti-EGFR therapy or the presence of any serious medical conditions. This study was approved by the Institutional Ethics Committee of the New Territories East Cluster/ Chinese University of Hong Kong, and all patients gave written informed consent before enrollment.
study medications The study design is based on our institutional practice of administering concurrent low-dose cisplatin (40 mg/m2/week) during RT that was previously evaluated in a phase III clinical trial conducted at our hospital [4]. In the current study, an initial dose of cetuximab 400 mg/m2 was given i.v. 1 week before starting IMRT. Starting from the first week of IMRT, cisplatin 30 mg/m2/week was given over 1 h with standard hydration and premedication, followed by cetuximab 250 mg/m2/week over 1 h until the end of IMRT. Patients were intended to receive weekly cetuximab and cisplatin for the entire duration of IMRT, which spanned a period of 6–7 weeks, with a minimum of six cycles of treatment (up to a maximum of seven cycles). The dose of cisplatin in this study was reduced to 30 mg/m2/ week compared with our usual dose of 40 mg/m2/week during RT because the authors were initially concerned about the tolerability of the study treatment. The reason behind this concern is that there had not been any prior published experience in combining cetuximab, cisplatin and IMRT in NPC, where some normal tissues adjacent to the primary tumor could receive up to a relatively high radiation dose of 74 Gy. Cetuximab is also a known radiosensitizer [14] that can also enhance the cytotoxicity of cisplatin in vitro; therefore, it may potentially exacerbate the toxicity of cisplatin and IMRT [11]. Furthermore, in a pilot study of patients with advanced non-NPC HNSCC, the use of concurrent cetuximab, high-dose cisplatin and RT was associated with significant toxic effects that led to premature closure of the study [15].
dose modifications On the first day of each cycle of cisplatin, the blood count and calculated creatinine clearance had to recover within the pretreatment range before cisplatin was continued, while cetuximab could be continued regardless of these test results. If a patient was unable to maintain adequate nutrition orally because of grade 3 or 4 mucositis, cisplatin could be interrupted, while cetuximab could be continued at the discretion of the physician. Cetuximab was withheld if a patient developed grade 3 acneiform rash or dose-reduced in patients who developed intolerable and persistent grade 2 acneiform rash despite the use of adequate supportive measures.
radiotherapy IMRT was given at 66 Gy over 33 daily fractions to the planning target volume (PTV) of the primary tumor and metastatic regional neck nodes, 60 Gy over 33 fractions to the PTV of subclinical disease around the tumor and upper and midneck and 54 Gy to the lower neck in the absence of nodal involvement in the lower neck. The few patients with T1–T2a tumors received high-dose-rate afterloading intracavitary brachytherapy boost at 12 Gy/4 fractions. For patients with T2b–T4 tumors who entered the study before 2007, they were treated with a sequential IMRT boost (8 Gy/4
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fractions) to the nasopharynx after the initial 66-Gy primary course. After 2007, our department adopted the single-phase IMRT simultaneous integrated boost regimen in which a total of 74, 70, 62 and 56 Gy were given to the gross tumor, planning target of primary tumor and enlarged lymph nodes, upper neck lymphatics and lower neck lymphatics, respectively, all completed in 35 daily fractions. For patients with persistent regional nodal disease at the end of IMRT, RT boost was given to the regional lymph nodes. For persistent disease at the nasopharynx up to 12 weeks after IMRT, salvage intracavitary brachytherapy or stereotactic RT was given. Details on RT planning, dose specifications and normal tissue dose–volume constraints were as previously reported [16].
study procedure Pretreatment staging included nasopharyngoscopy and magnetic resonance imaging (MRI) of the nasopharynx and neck, chest X-ray, abdominal ultrasound and bone scan. Patients were assessed for toxicity at 2, 4 and 12 weeks after completion of IMRT. Tumor response was assessed at 12 weeks with an MRI scan of the nasopharynx and neck, clinical examination and nasopharyngoscopy. Patients were followed in the clinics every 3 months during the first 2 years, every 6 months during the next 2 years and then yearly thereafter.
study end points and statistics The primary objective of this pilot study was to determine the safety of adding cetuximab on to concurrent cisplatin and IMRT in NPC. The secondary objectives were response rate, locoregional failure-free rate, distant failure-free rate, progression-free survival (PFS) and overall survival (OS). Treatment response was assessed according to the WHO criteria based on our previous work [17]. Acute toxicity was graded according to the National Cancer Institute—Common Toxicity Criteria for Adverse Events version 3.0; late toxicity was graded according to the Radiation Therapy Oncology Group (RTOG) Late Radiation Morbidity Scoring Criteria. Safety was evaluated in the context of the percentage of patients who experienced grade 3–4 acute and late toxicity and the occurrence of any treatment-related deaths. PFS was determined from the date of enrollment to the date of first occurrence of distant or locoregional recurrence or the date of last follow-up. OS was determined from the date of enrollment to the date of death due to any cause or the date of last follow-up. Locoregional failure was defined as the presence of biopsyproven residual disease at the nasopharynx and/or regional lymph nodes at the scheduled visit at 3 months after RT or the subsequent development of recurrent disease. Distant failure was defined as the presence of distant metastases. Descriptive statistics [with 95% confidence intervals (CIs) where applicable] were used to report the study end points and survival curve was estimated with the Kaplan–Meier method.
results patients and treatment compliance A total of 30 patients were enrolled into the study from June 2006 to June 2008, and their baseline characteristics are outlined in Table 1. All patients completed planned IMRT; 11 patients who entered the study before 2007 received additional IMRT boost to the nasopharynx as part of a two-phase RT treatment protocol as previously mentioned, while the remaining 19 patients who were enrolled since 2007 received single-phase IMRT with simultaneous integrated boost to the nasopharynx. In terms of compliance to cisplatin, 86% and 50% of patients received ‡5 and ‡6 cycles of cisplatin (median 5 cycles, range 3–7 cycles), respectively. The median total dose of cisplatin delivered
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Table 1. Patient baseline characteristics
Table 2. Incidence of acute toxicities attributable to study drugs
Characteristics
No. of patients (%)
Age, median (range), years Sex Male Female ECOG performance status 0 1 Overall stage III IVA IVB AJCC tumor stage 1 2a 2b 3 4 AJCC nodal stage 0 1 2 3
45 (24–46) 26 (87) 4 (13) 24 (80) 6 (20) 20 (67) 9 (30) 1 (3) 1 1 6 16 6
(3) (3) (20) (54) (20)
7 11 8 4
(24) (37) (26) (13)
AJCC, American Joint Committee on Cancer; ECOG, Eastern Cooperative Oncology Group.
per patient was 29.8 mg/m2 per weekly cycle for the entire study, which represents 83% of the minimum planned dose of six cycles. Cisplatin was interrupted in 18 patients (60%) mainly because of grade 3 RT-related mucositis. In terms of compliance to cetuximab, 93% and 73% of patients received ‡5 and ‡6 cycles of cetuximab (median 5 cycles excluding initial dose, range 1–7 cycles), respectively. Excluding the initial dose, the median dose of cetuximab was 250 mg/m2 per patient per cycle. Cetuximab was interrupted in 10 patients (33%) and the most common cause was grade 3 acneiform skin rash.
treatment toxicity Acute toxic effects attributable to the study drugs were generally mild (Table 2). Lymphopenia and leukopenia were the most common grade 3–4 hematological toxic effects that were not complicated by any serious infections. Specific toxic effects that were attributable to cisplatin were uncommon, while the most common grade 3–4 cetuximab-related toxicity was the acneiform rash. Oropharyngeal mucositis was the most common RT-related acute toxicity and was reported as grade 3–4 in severity in 26 (87%) patients. This was associated with grade 3 toxic effects such as dysphagia and oropharyngeal pain in >40% of patients and weight loss in 26% of patients, which necessitated the use of nasogastric feeding in 10 (33%) patients for a median duration of 41 days (range 3–200 days). Oropharyngeal mucositis was completely resolved in all patients within 4 weeks after completion of IMRT. One patient had persistent dysphagia and required prolonged nasogastric feeding for
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Toxicity Hematological toxicities Lymphopenia Leukopenia Non-hematological toxicities Cetuximab-related rash Diarrhea Hypomagnesemia Nausea Hearing impairment Vomiting Hyponatremia Creatinine elevation Fatigue Alanine transferase elevation Infection
No. of patients (%) Grade 1–2 Grade 3
Grade 4
0 12 (40)
8 (26) 0
25 9 5 27 22 22 10 4 27 10 6
(83) (30) (16) (90) (73) (73) (33) (13) (90) (33) (20)
16 (53) 3 (10) 3 1 1 1 2 0 1 0 1 1 0
(10) (3) (3) (3) (6) (3) (3) (3)
0 0 0 0 0 0 0 0 0 0 0
6 months after IMRT. Nasopharyngoscopy carried out in this patient 3 months after IMRT revealed atrophic nasopharyngeal mucosa only, and he recovered completely 6 months after IMRT. Grade 3 dermatitis occurring within the RT field was reported in six (20%) patients (Table 3, Figure 1) and all patients recovered completely within 6 weeks after IMRT. A few patients had persistent hyperpigmentation of the skin within the irradiated field that improved within 3 months after IMRT. Serious adverse events (SAEs) resulting in hospital admissions were reported in 11 patients, with the majority of cases due to oropharyngeal mucositis (grade 3 in 3 patients) and related complications including dysphagia (5 patients) and dehydration (1 patient). IMRT was interrupted for 2 days in one of the three patients who experienced an SAE of grade 3 mucositis. Grade 3–4 late toxic effects (observed 3 months after completion of IMRT) were uncommon (Table 4). Xerostomia was the most common grade 2–3 late toxicity, with 70% of patients (21 patients) reporting grade 2–3 xerostomia. Hearing was not objectively assessed with audiometry in this study; however, two patients reported grade 3 hearing impairment at 3 months after IMRT. One patient had grade 3 s.c. tissue fibrosis, which subsequently improved to grade 2 in severity at 23 months after IMRT. Endocrine toxicity has not been observed to date. One patient developed bilateral cranial nerve (XII) palsy beyond 3 months that did not affect swallowing.
treatment response and survival One patient developed liver metastases soon after completion of IMRT and thus did not undergo response evaluation. Of the 29 patients who underwent MRI assessment, there were 25 complete responses (CRs) and 4 partial responses (PRs) at the primary tumor. Of the 23 patients with regional nodal involvement at diagnosis, there were 22 CRs and 1 PR at the regional nodes. Therefore, the overall response rate was
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96% (29 responses of 30 patients) at both primary tumor and locoregional nodes. All four patients with radiological PR at the primary tumor had biopsy-confirmed persistent local disease confirmed on biopsy at 3 months after IMRT. All four patients were treated with stereotactic RT as salvage treatment, of whom three patients achieved and remained in CR while the last patient failed to respond and subsequently died of distant metastases. At a median follow-up of 31.8 months [95% CI 26.2–32.1 months], three patients had died of recurrent NPC and one died of unknown cause; there were no treatment-related deaths.
Table 3. Incidence of acute toxicities attributable to RT Toxicity Oropharyngeal mucositis Dysphagia Pain, oropharyngeal Weight loss RT-related dermatitis Salivary glands (xerostomia)
No. of patients (%) Grade 1–2 Grade 3
Grade 4
4 16 20 17 24 26
1 (3) 0 0 NA 0 0
(13) (53) (66) (56) (80) (87)
25 14 12 8 6 4
(84) (46) (40) (26) (20) (13)
NA, not applicable; RT, radiotherapy.
Three patients developed locoregional failure and two patients developed distant metastases. The 2-year locoregional failurefree rate was 93% (95% CI 90% to 100%) and the 2-year distant failure-free rate was 92.8% (95% CI 83.5% to 100%). The 2-year PFS was 86.5% (95% CI 74.3% to 98.8%) (Figure 2) and the 2-year OS was 89.9% (95% CI 72.6% to 98.8%); the median OS has not been reached.
discussion This study has shown that cetuximab can be safely combined with concurrent cisplatin and IMRT in the curative treatment of locoregionally advanced NPC. This approach is associated with a relatively high rate of RT-related acute skin and mucosal toxic effects that were manageable and reversible. The tumor response and preliminary survival data of this novel strategy compared favorably with historic data reported by our hospital and other centers. The determination of EGFR expression level in the tumors of study patients was not required as an eligibility criteria, because our previous work has shown that EGFR overexpression is very common in NPC with a detection rate of >80% [9], and has no apparent association with response to cetuximab in a phase II study of patients with recurrent NPC [12]. The incidence of moderate-to-severe acute skin and mucosal toxic effects observed in this study was much higher than our experience with concurrent cisplatin and RT—either IMRT or two-dimensional (2D) RT. Although the incidence of acute RT-related skin toxicity did not significantly increase when cetuximab was added to RT in the original phase III study reported by Bonner et al. [10], subsequent reports from community practice suggested otherwise with an incidence of grade 3–4 skin toxic effects encountered in up to 50% of patients in a questionnaire carried out among the European Organisation for Research and Treatment of Cancer Radiation Oncology Group and Head and Neck Group [18]. As mentioned before, this exacerbation of acute RT-related skin and mucosal toxic effects by the concomitant use of cetuximab, cisplatin and RT has been previously reported by Pfister et al. [15] and more recently by Argiris et al. [19] in the treatment of HNSCC. Pfister et al. used a 3-weekly schedule of high-dose cisplatin during RT, while Argiris et al. [19] employed a weekly
Figure 1. Acute grade 3 RT-related dermatitis of the neck within the RT field. RT, radiotherapy.
Table 4. Incidence of late toxicities at 3 months after completion of IMRT Toxicity Salivary glands (xerostomia) Mucous membrane Esophagus/dysphagia Skin Subcutaneous tissue Hearing
No. of patients (%) Grade 0 Grade 1
Grade 2
Grade 3
3 3 9 3 10 11
18 15 4 8 6 17
3 0 1 0 1 2
(10) (10) (30) (10) (33) (36)
IMRT, intensity-modulated radiotherapy.
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6 12 16 19 13 0
(20) (40) (53) (63) (43)
(60) (50) (13) (27) (20) (56)
(10) (4) (4) (8) Figure 2. Progression-free survival curve.
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schedule of cetuximab and low-dose RT similar to our current study, together with induction chemotherapy and maintenance cetuximab. Both Pfister et al. and Argiris et al. reported high incidence rates of grade 3–4 oral mucositis (38% and 54%, respectively) and RT-related dermatitis (24% and 27%, respectively). This strategy of combining cetuximab with concurrent cisplatin–RT in the treatment of advanced HNSCC is currently being compared with cisplatin–RT in the RTOG 0522 study. Any comparison of the incidence of grade 3–4 mucositis in our current study with other studies of concurrent chemo-RT should be interpreted in light of the differences in RT fields for the treatment of NPC and non-NPC HNSCC. For NPC, the RT field encompasses a larger volume of normal oropharyngeal mucosa than that for hypopharyngeal or laryngeal cancer, therefore rendering patients with NPC more vulnerable to RT-induced mucositis. The use of a circumferential seven- to nine-field IMRT instead of lateral-opposed conventional 2D-RT may also increase the integral dose to normal oral mucosa. In our previous phase III NPC study, patients who received concurrent cisplatin and 2D-RT experienced a grade 3–4 mucositis rate of 48% and grade 3 weight loss of 10.9% [4]. In our early experience with IMRT in 63 patients with stage I–IVB NPC (of whom 16 patients received concurrent weekly cisplatin), 41% of patients had grade 3 mucositis and 7% had grade 3 RT-related dermatitis [16]. In the current study, the incidence rates of grade 3–4 mucositis and grade 3 weight loss were twice as common as the respective rates reported in our phase III study [4], while the rates of grade 3 mucositis and dermatitis were several times more common than those reported with IMRT [16]. These toxic effects contributed in part to the higher rate of nasogastric feeding and dose interruption of cisplatin in this study. With respect to other acute toxic effects, our study did not observe any grade 3–4 infection and renal impairment. The grade 3–4 hypomagnesemia rate is 3% in this study is within the CI reported by a recent meta-analysis of 19 studies of patients treated with cetuximab for different tumor types (5.6%, 95% CI 3.0% to 10.2%) [20] and is much lower than the rate (39%) reported by Argiris et al. [19] where maintenance cetuximab was used following RT. The late toxic effects observed in this study were generally grade 1–2 in severity. The incidence of grade 3 hearing impairment in our cohort is consistent with the rates of 9%–12.3% reported in previous studies of concurrent chemo-RT [3, 21]. The incidence rates of severe skin and s.c. tissue toxic effects and hyperpigmentation were not in excess of the rates reported by others to date [16, 21]. Regarding the incidence of grade 2–3 xerostomia in our study of patients with locoregionally advanced NPC, it is difficult to compare this result with published reports on IMRT because few studies report the rate of late xerostomia. Furthermore, most studies included patients with exclusively or mostly early-stage disease [16, 22–25]. The latter is relevant because parotid-sparing IMRT may not feasible for those cases of NPC that present with bilateral upper and bulky cervical or retropharyngeal nodes, where the tumor target is close to the parotid gland and the mean parotid dose cannot be minimized to 80% of patients (total 64 patients) had stage IIB–IV NPC [23] and 7.8% at 2 years in a Taiwan study of 323 patients with stage II–IV NPC [24]. Of note, in a small Korean study of stage IIB–IV NPC patients treated with IMRT and simultaneous integrated boost, a grade 2 xerostomia rate of 50% at 3 months was observed [25]. Historically, the treatment of locoregionally advanced NPC with concurrent weekly cisplatin and 2D-RT is associated with a 2-year PFS of 76% [4]. Other phase III studies have evaluated different regimens of concurrent chemotherapy with 2D-RT [3, 6, 21]. For instance, Wee et al. [6] reported a distant failure rate of 13% and a 2-year disease-free survival of 75% in the chemo-RT arm of their phase III study. In other randomized studies, although the 2-year survival rates were not reported in the paper, extrapolation from the survival curves published in these papers suggest that the approximate 2-year PFS or the 2-year failure-free survival rates for the chemo-RT arm were within the 70%–80% range [3, 21]. Using similar extrapolations, the respective distant failure-free rates and locoregional failure-free rates at 2 years are approximately between 70% and 80% [7, 21] and 80% and 92% [7, 21]. The RTOG published the result of a phase II study of IMRT in 68 patients with NPC, of whom 58.6% had stage III–IVB NPC and 83.8% had concurrent cisplatin during IMRT [23]; the schedule of cisplatin used was identical to that used in the Intergroup study [3] and other Asian studies [3, 21]. The group reported a 2-year PFS of 68% for those with stage IIB–IVB NPC [23]. Although direct comparison is not feasible, preliminary observation suggests that our 2-year PFS of 86.5% compares favorably with historic data reported by our hospital (2-year PFS of 76%) [4], by the RTOG study (2-year PFS of 68%) and by other centers using non-IMRT (2-year PFS between 70% and 80%) [3, 21]. Our 2-year distant failure-free rate of 92.8% and locoregional failure-free rate of 93% appear promising in comparison with previous data [7, 21]. However, our results should be regarded as preliminary because of the relatively small sample size and differences in patient selection—for instance, 24% of our patients had N0 disease as opposed to 0%–19% in other phase III studies [3, 6, 21]. We recently presented the 6-year update of a series of 231 patients (70% had stage III–IV NPC) who were treated with IMRT at our hospital from the year 2000 to 2005, where the local failure-free rate was 82% and distant metastasis-free rate was 75% [26]. This suggests that both locoregional and distant recurrence remain important contributors to treatment failure in advanced NPC in the era of IMRT. The promising 2-year treatment outcomes reported in the current study warrant longer follow-up and further evaluation in the randomized setting.
acknowledgements This study was presented (poster 6055) in part at the 44th Annual Meeting of the American Society of Clinical Oncology,
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original articles May 30–June 3, 2008, Chicago, IL, USA. Cetuximab was kindly provided by Merck Serono, Singapore.
funding This is an investigator-initiated study, so it is not funded by Merck Serono. Merck Serono only donated the cetuximab for this study.
disclosure BM receives research funding from Merck Sharpe and Dohme. The remaining authors declare no conflict of interest.
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