- Email: [email protected]
Phase II study of sorafenib in combination with cisplatin and 5-fluorouracil to treat recurrent or metastatic nasopharyngeal carcinoma†
original articles
Annals of Oncology
Annals of Oncology 24: 1055–1061, 2013 doi:10.1093/annonc/mds581 Published online 21 November 2012
Phase II study of sorafenib in combination with cisplatin and 5-fluorouracil to treat recurrent or metastatic nasopharyngeal carcinoma† C. Xue1,2,‡, Y. Huang1,2,‡, P. Y. Huang1,3,‡, Q. T. Yu5, J. J. Pan6, L. Z. Liu1,4, X. Q. Song5, S. J. Lin6, J. X. Wu1,2,§, J. W. Zhang1,2, H. Y. Zhao1,2, F. Xu1,2, J. L. Liu1,2, Z. H. Hu1,2, L. P. Zhao1,2, Y. Y. Zhao1,2, X. Wu1,2, J. Zhang1,2, Y. X. Ma1,2 & L. Zhang1,2* 1
State Key Laboratory of Oncology in South China; Departments of 2Medical Oncology; 3Nasopharyngeal Carcinoma; 4Ultrasound and Electrocardiography, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong; 5Department of Medical Oncology, Tumor Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi; 6Department of Radiation Oncology, Fujian Province Cancer Hospital, Fuzhou, Fujian, People’s Republic of China
Received 13 June 2012; revised 25 August 2012; accepted 20 September 2012
Background: We aimed to investigate the efficacy and tolerability of sorafenib combined with cisplatin and 5-fluorouracil (5-FU) in patients with recurrent or metastatic nasopharyngeal carcinoma (NPC).
Patients and methods: It was a Simon two-stage designed trial. Chemotherapy-naive patients with recurrent or metastatic disease were enrolled. The regimen was sorafenib 400 mg orally b.i.d., cisplatin 80 mg/m2 i.v. day 1, and 5-FU 1000 mg/m2/day CIV for 4 days, repeated every 21 days. After a maximum of six cycles of chemotherapy, patients received maintenance of sorafenib. Results: In total, 54 patients were enrolled. The objective response rate reached 77.8%, including 1 complete response and 41 partial responses. The median progression-free survival was 7.2 months (95% CI 6.8–8.4 months), and the median overall survival was 11.8 months (95% CI 10.6–18.7 months). Major toxic effects included hand–foot skin reaction, myelosuppression, and gastrointestinal (GI) reaction. The incidence of hemorrhage was 22.2%, and one patient with liver metastases died of GI bleeding. Contrast-enhanced ultrasonography was carried out in a subset of patients with liver metastases. Conclusion: Combination of sorafenib, cisplatin (80 mg/m2) and 5-FU (3000 mg/m2) was tolerable and feasible in recurrent or metastatic NPC. Further randomized trials to compare sorafenib plus cisplatin and 5-FU with standard dose of cisplatin plus 5-FU in NPC are warranted. Key words: angiogenesis, chemotherapy, nasopharyngeal carcinoma, sorafenib
introduction Nasopharyngeal carcinoma (NPC) is characterized by its unique geographic distribution [1]. Southern China has one of the highest incidence rates in the world (20–30 per 100 000), and the incidence remained stable in the last 30 years [2]. Intense-modulated radiotherapy (RT)/RT alone or with chemotherapy are the standard of care for nonmetastatic disease [3]. Owing to the advances in tumor imaging and RT *Correspondence to: Prof. L. Zhang, State Key Laboratory of Oncology in South China, Department of Medical Oncology, Sun Yat-Sen University Cancer Center, 651 Dongfeng Road, East, Guangzhou, People’s Republic of China. Tel: +86-20-87343458; Fax: +86-20-87343365; E-mail: [email protected] †
This study was presented in part at the 48th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, 1–5 June 2012 (General Poster Session, permanent abstract ID: 5538). ‡ These authors contributed equally to this work. § Present address: Department of Medical Oncology, The First Affiliated Hospital of Xiamen University, Xiamen, People’s Republic of China.
technique, the 5-year local control rate rose to 94.9%, and the 5-year disease-free survival rate reached 76.7%. Treatment failures are mainly distant metastasis, which develop in ∼20% of patients with locally advanced disease [4]. Many cytotoxic agents are active against metastatic NPC. Cisplatin-containing regimens remain the cornerstone of palliative chemotherapy. The response rates (RRs) achieved of cisplatin and 5-fluorouracil (5-FU) were ∼60% [5, 6], so they represent the treatment of choice for most patients with recurrent or metastatic NPC. Other active agents, including taxanes, gemcitabine, oxaliplatin, vinorelbine, irinotecan, and capecitabine, yield the objective RR (ORR) from 14% to 73% after failure of platinum-based chemotherapy, but their efficacy in first-line therapy still needs to be validated in randomized phase III trials [7–17]. In spite of the relatively high RRs and emerging new drugs, survival in advanced disease is not significantly improved, with the progression-free survival (PFS) ranged from 5.6 to 10.6 months and overall survival (OS) from 7.6 to 19.6 months
© The Author 2012. 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 [11, 12, 14, 15, 17]. Molecularly targeted drugs have been added to cytotoxic chemotherapy regimens in order to improve the survival of patients with other advanced tumors [18, 19]. Therefore, it is imperative to explore novel targeted therapies for patients with advanced NPC. VEGF/VEGFR is a potential target, as angiogenesis constitutes an important pathway for tumor growth and metastases. Overexpression of VEGF was seen in 60%–67% of patients with NPC and the higher expression was related to lower OS [20, 21]. These evidences provided a rationale for investigating anti-angiogenesis agent for this tumor. Sorafenib is a multi-kinase inhibitor [22]. Previous trial revealed that sorafenib monotherapy had modest antitumor activity in patients with relapsed advanced or metastatic squamous cell carcinoma of the head and neck (SCCHN), including NPC [23, 24]. We conducted the current study to determine the efficacy and toxicity profile of sorafenib combined with cisplatin and 5-FU in advanced NPC. Sorafenib was chosen because its combination with single cytotoxic agents and platinum-based doublet chemotherapy did not severely increase side-effects in several cancer models [25–27]. The hypothesis is that sorafenib might increase the ORR and improve PFS without adding substantial toxicity.
patients and methods
Annals of Oncology other day. No dose escalations were allowed after a dose reduction. The chemotherapy dosage modifications were allowed when patients experienced grade 4 hematologic or grade 3 non-hematologic AEs.
study procedures Tumor size was evaluated by carrying out computed tomography or magnetic resonance imaging at baseline (within 21 days before starting treatment). Target lesions were evaluated every two cycles during the chemotherapy phase and every 2 months during the maintenance period. Objective responses were confirmed 4 weeks after documentation. After withdrawal, patients were followed up once every 3 months until death. AEs were defined according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 3.0 (http:// ctep.cancer.gov/reporting/ctc_v30.html).
contrast-enhanced ultrasonography Contrast-enhanced ultrasonography (CEUS) was carried out in consented patients with liver metastasis at baseline and after two cycles by using standard methodology as described previously [31]. The contrast uptake rate of liver metastases was evaluated by a specialized radiologist using specific image processing software (Image-Pro Plus 6.0, Media Cybernetics). Receiver operating characteristic curve (ROC) analysis was done using the nonparametric assumption to compare contrast uptake rates by means of ultrasonography measurements. The optimal cut-offs point was defined by ensuring best sensitivity and specificity.
patients
statistical analysis and sample size calculation
Patients enrolled in this study had histologically confirmed NPC that was metastatic or locally recurrent at diagnosis or after previous curative treatment. Disease was measurable as defined by RECIST [28]. Patients must not have received prior treatments for recurrent or newly diagnosed metastatic disease; however, chemotherapy or radiation as part of the initial curative therapy was permitted. Patients were excluded if they had significant cardiac disease; were pregnant or breast-feeding; or showed evidence of bleeding diathesis and were unable to take oral medications. All patients provided informed consent, and the institutional ethics review board of each participating center approved the study.
Simon’s optimal two-stage design was used for sample size calculation [32]. We used the baseline RR of 60% seen with cisplatin and 5-FU in the first-line setting as our null hypothesis. To detect a 30% improvement in RR (60% versus 78%) with the proposed regimen, at a significance level of 5% and a statistical power of 90%, we estimated accrual to be 53 patients in a two-stage design. It was determined that 19 assessable patients had to be included at the first stage. If at least 12 objective responses were observed, then an additional 34 patients would be recruited to the second stage. Sorafenib would be considered active if at least 37 responses were observed among the 53 patients. The primary end point of this study was ORR, including the percentage of complete response (CR) and partial response (PR). The secondary end points were toxicity ( particularly hand–foot skin reaction, HFSR), disease control rate (DCR, the proportion of CR, PR, and SD), PFS, and OS. The analysis was done on an intention-to-treat (ITT) basis. ORR was evaluated in patients who received at least one cycle of treatment and then was reevaluated (both at baseline and after treatment). Patients who received at least one cycle of treatment were included in the safety analysis. OS was defined as the duration from the date of consent to the date of death from any cause or the date of last follow-up. PFS was defined as the duration from the date of consent to the date of disease progression or the date of last follow-up. PFS and OS were estimated using Kaplan–Meier methods. Analyses were carried out using the statistical software package SPSS 16.0 (SPSS, Chicago, IL). All statistical tests were two-sided, and a P-value <0.05 was considered as statistically significant.
study medications Sorafenib was administered orally 400 mg twice a day for 21 days. Cisplatin (80 mg/m2) was administered intravenously on day 1, and 5-FU (1000 mg/ m2/day) was administered via continuous infusion on day 1 through 4 of a 21-day cycle during the chemotherapy phase. In the cases of tumor stabilization or response after a maximum of six cycles of chemotherapy, patients received maintenance treatment with sorafenib until there was objective evidence of tumor progression or intolerable drug-related toxic effects. We chose this dose of cisplatin and 5-FU because of the following reasons. First, there were a lot of studies using sorafenib plus cisplatin and other cytotoxic agents in malignant cancers, and the dose of cisplatin ranged from 75 to 80 mg/m2 [27, 29, 30]. Second, this study aimed to assess the efficacy and safety of sorafenib combined with cisplatin and 5-FU. We carried out this trial in a two-stage design. In the first stage, 19 patients were enrolled to check the efficacy as well as the tolerability of the initial dose. If the trial moved on to the second stage with feasible and tolerable set dose, we enrolled the rest of patients at this dose. Otherwise, the initial dose should be reduced. Dose reduction levels of sorafenib were based on interval adverse events (AEs): level 1 was 400 mg once daily, and level 2 was 400 mg once every
| Xue et al.
results patients characteristics Fifty-four patients were enrolled from January 2009 to May 2011. All patients were included in the ITT analysis of efficacy and AEs. Their characteristics are listed in Table 1. Most patients were men (79.6%); the median age was 45.6 years.
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original articles
Annals of Oncology Table 1. Patient characteristics Characteristic
Patients Number
Number of patients included Age, years Median Range Sex Male Female ECOG 0 1 2 Histology Undifferentiated non-keratinizing carcinoma Differentiated non-keratinizing carcinoma Poor differentiated squamous cell carcinoma Disease status Local recurrence Metastatic diseasea Both Number of metastatic organs (n = 52) 1 ≥2 Number of metastatic organs (n = 52) Lung Liver Bone Distant lymph node Pleural Primary curative treatment (n = 38) Radiotherapy Chemoradiotherapy Surgeryb Prior chemotherapy agents (n = 33) Cisplatin 5-FU Docetaxel Paclitaxel Nedaplatin Others
54
Percentage
45.6 27.3–71.2 43 11
79.6 20.4
2 51 1
3.7 94.4 1.9
52 1 1
96.2 1.9 1.9
2 50 2
3.7 92.6 3.7
25 27
48.1 51.9
28 25 21 6 5
53.9 48.1 40.4 11.5 9.6
5 33 1
13.2 86.8 2.6
32 25 10 6 5 3
97 75.8 30.3 18.2 15.2 9.1
study, 63.2% patients (12 out of 19) required 5-FU dose reduction because of mucositis (CTCAE grades 2–3); therefore, the protocol was amended so that the initial dose of 5-FU was 3000 mg/m2 in the second stage. 25.7% patients (9 out of 35) required 5-FU dose reduction at the second stage. Totally, 5-FU dose reduction was carried out on 21 patients (38.9%); among them, 6 patients underwent dose reduction twice. No dose reduction of cisplatin was required. The median sorafenib treatment time was 24.4 weeks (range 5.1–91.4 weeks). Dose intensity was 0.64 in sorafenib due to the dose interruption. Dose reduction of sorafenib was required in 22 patients (40.7%) for the following reasons: HFSR (14, 63.6%), mucositis (4, 18.2%), hypertension (2, 9.1%), diarrhea (1, 4.5%), and arrhythmia (1, 4.5%). Two of them underwent further dose reduction to 400 mg once every other day because of HFSR. Fourteen patients (25.9%) required dose interruption (HFSR 11, 78.6%; poor memory 3, 21.4%). Treatment discontinuation was mainly due to disease progression (30 of 46, 65.2%). Other reasons were death [3, 6.5%, 1 serious AE (SAE), 2 due to progression of disease], complication (1, 2.2%), dose interruption of more than 30 days (5, 10.9%), patient request (2, 4.3%), non-adherence (5, 10.9%).
responses and survival In the ITT analysis, the ORR reached 77.8%: 1 patient (1.9%) experienced CR; 41 (75.9%), PR. Seven (13.0%) patients had stable disease, and five (9.2%) patients had progressive disease. DCR was 90.8%. Waterfall plot of the maximum reduction in target tumor lesions on at least one post-treatment measurement is listed in Figure 1. The median PFS was 7.2 months (95% CI 6.8–8.4 months). Of the 54 patients, 8 (14.8%) continued to receive sorafenib after the data cut-off date for this study (14 December 2011). The duration of treatment is listed in supplementary Figure S1, available at Annals of Oncology online. At a median follow-up of 19.0 months, 33 patients were alive. The median OS was 11.8 months (95% CI 10.6–18.7 months). Of those 28 patients with lung metastasis, 9 patients (9 out of 28, 32.1%) experienced tumor cavitation during the course of treatment (Figure 2). There were no tumor cavitations at baseline.
a
Including patients with metastatic disease at diagnosis and after previous curative treatment. b One patient had both surgery and radiochemotherapy. ECOG, Eastern Cooperative Oncology Group.
Most patients had lung metastases (53.9%), followed by liver (48.1%) and bone metastases (40.4%), and 27 patients had multiple sites of metastases (51.9%). Among those with recurrent/metastatic disease after previous therapy (n = 38), five patients received prior curative-intent RT alone, and 33 had also received chemotherapy with RT.
treatments In the ITT population, the median duration of chemotherapy was 12.1 weeks (range 6.0–18.5 weeks). Dose intensity was 0.86 in cisplatin and 0.81 in 5-FU. During the first stage of the
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contrast-enhanced ultrasonography CEUS was carried out in 16 consented patients with liver metastases before and after two cycles of treatment in one center (SYSUCC). In an ROC analysis, the area under the ROC predicting response by tumor contrast uptake rate at baseline was 0.906. Using the optimal cut-off point identified in the ROC analysis, patients with >85.87% of tumor contrast uptake rate have a better response. Actually, eight of the nine patients with higher uptake rate showed PR, versus none of the seven patients with lower uptake rate (88.9% versus 0%, P = 0.00042). The response was specifically related to the lesions in the liver. The median values of the contrast uptake of responders (eight cases) and non-responders (eight cases) are summarized in supplementary Table S1, available at Annals of Oncology online. Pre-treatment tumor contrast uptake rate was significantly higher in responders than in non-responders:
doi:10.1093/annonc/mds581 |
original articles
Annals of Oncology
Figure 1. Waterfall plot of the maximum decrease in the sum of the longest diameters of target lesions observed. Patients are listed in order of increasing percentage response. The dashed line indicates a tumor reduction of 30% from baseline—the lower limit of partial response, according to Response Evaluation Criteria in Solid Tumors.
Figure 2. Baseline and post-treatment computed tomography scans of one patient with nasopharyngeal carcinoma lung metastases.
93.6% (mean percentage of contrast uptake) versus 56.6% (P = 0.005). After two cycles of treatment, the mean percentage of tumor contrast uptake decreased to 38.0% in responders and remained at 46.1% in non-responders. The changes in contrast uptake before and after treatments were statistically significant in responders (93.6% versus 38.0%, P = 0.002) but not in nonresponders (56.6% versus 46.1%, P = 0.211). The CEUS of patients who experienced PR is shown in Figure 3.
adverse events The most common AEs are listed in Table 2. Most of these were consistent with the known toxic effects of the chemotherapy
| Xue et al.
agents and sorafenib. The most commonly reported AEs include HFSR (83.3%), leucopenia (77.8%), anemia (74.1%), anorexia (74.1%) and nausea (64.8%). Most of these events were mild to moderate. The most common grade 3 or worse toxicity was mucositis with 11 patients (20.3%). Other grade 3 and worse toxicity included HFSR (18.5%), thrombocytopenia (13%), neutropenia (13%), and leukopenia (7.4%). Hemorrhagic events (all grades) occurred in 12 patients (22.2%): epistaxis in 8 patients, gingival bleeding in 2 patients, hemoptysis in 1 patient, and fatal hematemesis in 1 patient. One patient with liver metastasis died of gastrointestinal (GI) bleeding during the sorafenib maintenance treatment period.
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Annals of Oncology
Figure 3. Contrast-enhanced ultrasonography of liver metastasis in one patient who experienced partial response. On a selected single two-dimensional image, the percentage of tumor surface taking up contrast agent was visually evaluated at ∼97.21% on day −1. On the same selected image, the lesion has been outlined and the percentage of pixels was quantified as 18.29% after two cycles of sorafenib plus chemotherapy. Table 2. Drug-related adverse events (N = 54) Adverse event
Hand–foot skin reaction Leukopenia Anemia Anorexia Nausea Thrombocytopenia Mucositis Neutropenia Vomiting Hemorrhage Hypertension Hyponatremia Diarrhea Fatigue Hypopotassaemia Rash
Grade Any Number
Percentage
3 or 4 Number
Percentage
45 42 40 40 35 28 27 27 17 12 9 8 7 4 4 3
83.3 77.8 74.1 74.1 64.8 51.9 50.0 50.0 31.5 22.2 16.7 14.8 13.0 7.4 7.4 5.6
10 4 3 – – 7 11 7 1 1a 1 2 0 0 1 0
18.5 7.4 5.6 – – 13.0 20.3 13.0 1.9 1.9 1.9 3.7 – – 1.9 –
a
One patient died of hemorrhage.
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The patient, aged 45 years, was diagnosed with locally advanced NPC and received CCRT in 2009. He was enrolled into this study in April 2010 after multiple liver metastases were found. In the study, the patient received four cycles of chemotherapy and the efficacy was PR. After that, sorafenib was given for maintenance treatment. However, the patient had fatal GI bleeding during light manual labor in the first maintenance phase. Autopsy was refused. Serious AE (SAEs) occurred in five patients (9.3%): electrolyte disturbance including hyponatremia and/or hypopotassaemia (two), vomiting (one), hemorrhage (one), and active pulmonary tuberculosis (one). All were considered to be drug-related except active pulmonary tuberculosis.
discussion As yet, five anti-angiogenesis agents had been investigated in NPC, including sorafenib, sunitinib, pazopanib, axitinib, and bevacizumab [24, 33–36]. Monotherapy of sorafenib, sunitinib, and pazopanib had demonstrated clinical efficacy in advanced NPC. The clinical benefit rates ranged from 28.6% to 54.5%, most of which were SD, revealing that VEGFR inhibitors might
doi:10.1093/annonc/mds581 |
original articles induce better ORR when combined with chemotherapy or radiation rather than monotherapy [24, 33, 35, 37]. Recently, a phase II study of bevacizumab combined with chemoradiation also revealed promising efficacy in treating Locally advanced NPC [34]. In our study, evidence for the efficacy of sorafenib plus cisplatin–5-FU regimen seems favorable in metastatic NPC with an RR of 77.8%, a DCR of 90.8%, and PFS of 7.2 months. OS was not significantly prolonged in this patient population compared with previous studies [5–8, 10–12, 14, 15, 17]. Several reasons may contribute to this finding. First, nearly half of the patients (48.1%) enrolled had liver metastasis, which is a poor survival prognostic factor. In fact, OS of patients with liver metastasis was significantly shorter than those without liver metastasis (11.2 months versus 17.0 months, P = 0.048). We also found that patients with lung metastases lived longer than those with other organ metastases (20.9 months versus 11.7 months, P = 0.050), which was consistent with previous literature [38]. Second, only a limited proportion of patients received salvage therapy when diseases progressed (26 out of 46, 56.5%). In our subgroup analysis, patients with second-line therapy (chemotherapy or radiation) were associated with a significant longer OS compared with those with best supportive care only [median 13.8 months (95% CI 11.2–20.9) versus 7.6 months (95% CI 7.2–11.7), P = 0.0014]. Third, the modification of dosage might compromise the maximal benefit from systemic chemotherapy combined with a targeted agent. To our knowledge, this is the first clinical trial to evaluate VEGFR TKIs combined with active cytotoxic agents in recurrent or metastatic NPC. Previous data had showed the potential of CEUS in monitoring the response of anti-angiogenetic agents, and initial contrast uptake was a predictive factor of the response of imatinib in GI stromal tumors [31, 39]. In current study, we explored the usage of CEUS as a non-invasive assessment tool for predicting tumor response of liver metastasis in NPC. The ROC analysis was able to identify a threshold of contrast uptake rate at baseline. The correlation between contrast uptake rate and response indicated the potential of using this parameter as a predictive biomarker in future. We also found different patterns of contrast uptake rate changing in CEUS between responders and non-responders, similar to what Lassau et al. [31] found previously. The change of contrast uptake rate pre- and post-treatment may be valuable as a sensitive parameter to monitor response. Whether or not sorafenib aggravated the known toxic effects of chemotherapy is unknown [27, 40]. In our study, we did observe higher incidences of hematologic and non-hematologic toxic effects with combination therapy than previously reported with chemotherapy alone [41], but all events were consistent with the known safety profile of sorafenib, cisplatin, and 5-FU. The overall grade 3 or greater toxic effects showed that we should be more careful when carrying out this combined regimen, although most of them were reversible. Regarding our result, we assumed that the combination of sorafenib with 5-FU might have synergetic effect on onset of mucositis, although a recent study revealed no evidence of sorafenib–5-FU interactions [42]. The regimen was feasible when the initial dose of 5-FU reduced to 3000 mg/m2 at the second stage. So, we recommend having 5-FU dosage reduced in further study.
| Xue et al.
Annals of Oncology
Patients with recurrent or metastatic SCCHN/NPC are prone to bleeding events [33, 37, 43]. In a phase II trial of sunitinib and pazopanib, Hui et al. [33] and Lim et al. [35], respectively, reported fatal hemorrhage in previously treated NPC patients. Bleeding events in our study were mostly low grade, and the overall incidence risk (22.2%) was similar to that found in the meta-analysis of patients being treated with sorafenib or sunitinib (16.7%) [44]. However, there was still one death due to hemorrhage in our study; clinicians should monitor for potentially serious bleeding events in future clinical trials with significant caution. There are some limitations in our study. First, as this was a single-arm study, all patients received sorafenib combined with chemotherapy. The true effect of sorafenib in this combination cannot be defined without control group. Second, the small number of patients meant the results should be interpreted with caution. Third, the dose reduction might not reveal the maximal effect of these drugs. These limitations all argue for a randomized study to further investigate the incorporation of sorafenib with commonly used regimens in the first-line treatment of patients with advanced NPC. In conclusion, our study results revealed that the combination of sorafenib, cisplatin (80 mg/m2), and 5-FU (3000 mg/m2) was a tolerable and feasible regimen in recurrent or metastatic NPC. Further randomized trials to compare sorafenib plus cisplatin and FU with standard dose of cisplatin plus FU in NPC are warranted.
acknowledgements Sorafenib was kindly provided by Bayer Pharmaceuticals Corporation. We thank the patients who participated in this study and their families, the medical, nursing, and research staff at the study centers. We thank Professor Sharlene Gill from BC Cancer Agency (now a visiting professor at Sun YatSen University Cancer Center) and Professor Chao-Nan Qian for their helpful advice in manuscript editing.
funding This is an investigator-initiated study, so it is not funded by Bayer. Bayer only donated sorafenib for this study. This study was supported by a grant from the National High Technology Research and Development Program of China (863 Program), No. 2006AA02A404 (Molecular classification, personalized diagnose and therapy of nasopharyngeal carcinoma) and No. 985-II State Key Laboratory of Oncology in South China.
disclosure LZ has received research support from Boehringer Ingelheim, Bayer, Astra Zeneca, Lilly, and Sanofi Aventis. All other authors have declared that they have no conflicts of interest.
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Annals of Oncology 3. Ma BB, Hui EP, Chan AT. Systemic approach to improving treatment outcome in nasopharyngeal carcinoma: current and future directions. Cancer Sci 2008; 99: 1311–1318. 4. Xiao WW, Huang SM, Han F et al.. Local control, survival, and late toxicities of locally advanced nasopharyngeal carcinoma treated by simultaneous modulated accelerated radiotherapy combined with cisplatin concurrent chemotherapy: longterm results of a phase 2 study. Cancer 2011; 117: 1874–1883. 5. Wang TL, Tan YO. Cisplatin and 5-fluorouracil continuous infusion for metastatic nasopharyngeal carcinoma. Ann Acad Med Singapore 1991; 20: 601–603. 6. Au E, Ang PT. A phase II trial of 5-fluorouracil and cisplatinum in recurrent or metastatic nasopharyngeal carcinoma. Ann Oncol 1994; 5: 87–89. 7. Tan EH, Khoo KS, Wee J et al.. Phase II trial of a paclitaxel and carboplatin combination in Asian patients with metastatic nasopharyngeal carcinoma. Ann Oncol 1999; 10: 235–237. 8. Yeo W, Leung TW, Chan AT et al.. A phase II study of combination paclitaxel and carboplatin in advanced nasopharyngeal carcinoma. Eur J Cancer 1998; 34: 2027–2031. 9. Huang HQ, Cai QQ, Lin XB et al.. Preliminary result of multi-center clinical trial on the docetaxel, 5-Fu and DDP in the treatment of advanced, recurrent or metastatic nasopharyngeal carcinoma. Zhonghua Zhong Liu Za Zhi 2008; 30: 314–316. 10. Ma BB, Tannock IF, Pond GR et al.. Chemotherapy with gemcitabine-containing regimens for locally recurrent or metastatic nasopharyngeal carcinoma. Cancer 2002; 95: 2516–2523. 11. Ngan RK, Yiu HH, Lau WH et al.. Combination gemcitabine and cisplatin chemotherapy for metastatic or recurrent nasopharyngeal carcinoma: report of a phase II study. Ann Oncol 2002; 13: 1252–1258. 12. Zhang L, Zhang Y, Huang PY et al.. Phase II clinical study of gemcitabine in the treatment of patients with advanced nasopharyngeal carcinoma after the failure of platinum-based chemotherapy. Cancer Chemother Pharmacol 2008; 61: 33–38. 13. Zhang L, Zhao C, Peng PJ et al.. Phase III study comparing standard radiotherapy with or without weekly oxaliplatin in treatment of locoregionally advanced nasopharyngeal carcinoma: preliminary results. J Clin Oncol 2005; 23: 8461–8468. 14. Ma BB, Hui EP, Wong SC et al.. Multicenter phase II study of gemcitabine and oxaliplatin in advanced nasopharyngeal carcinoma – correlation with excision repair cross-complementing-1 polymorphisms. Ann Oncol 2009; 20: 1854–1859. 15. Wang CC, Chang JY, Liu TW et al.. Phase II study of gemcitabine plus vinorelbine in the treatment of cisplatin-resistant nasopharyngeal carcinoma. Head Neck 2006; 28: 74–80. 16. Poon D, Chowbay B, Cheung YB et al.. Phase II study of irinotecan (CPT-11) as salvage therapy for advanced nasopharyngeal carcinoma. Cancer 2005; 103: 576–581. 17. Chua DT, Sham JS, Au GK. A phase II study of capecitabine in patients with recurrent and metastatic nasopharyngeal carcinoma pretreated with platinumbased chemotherapy. Oral Oncol 2003; 39: 361–366. 18. Reck M, von Pawel J, Zatloukal P et al.. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil. J Clin Oncol 2009; 27: 1227–1234. 19. Tabernero J, Van Cutsem E, Diaz-Rubio E et al.. Phase II trial of cetuximab in combination with fluorouracil, leucovorin, and oxaliplatin in the first-line treatment of metastatic colorectal cancer. J Clin Oncol 2007; 25: 5225–5232. 20. Hui EP, Chan AT, Pezzella F et al.. Coexpression of hypoxia-inducible factors 1alpha and 2alpha, carbonic anhydrase IX, and vascular endothelial growth factor in nasopharyngeal carcinoma and relationship to survival. Clin Cancer Res 2002; 8: 2595–2604. 21. Krishna SM, James S, Balaram P. Expression of VEGF as prognosticator in primary nasopharyngeal cancer and its relation to EBV status. Virus Res 2006; 115: 85–90. 22. Wilhelm S, Carter C, Lynch M et al.. Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nat Rev Drug Discov 2006; 5: 835–844. 23. Williamson SK, Moon J, Huang CH et al.. Phase II evaluation of sorafenib in advanced and metastatic squamous cell carcinoma of the head and neck: Southwest Oncology Group Study S0420. J Clin Oncol 2010; 28: 3330–3335.
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original articles 24. Elser C, Siu LL, Winquist E et al.. Phase II trial of sorafenib in patients with recurrent or metastatic squamous cell carcinoma of the head and neck or nasopharyngeal carcinoma. J Clin Oncol 2007; 25: 3766–3773. 25. Flaherty KT, Schiller J, Schuchter LM et al.. A phase I trial of the oral, multikinase inhibitor sorafenib in combination with carboplatin and paclitaxel. Clin Cancer Res 2008; 14: 4836–4842. 26. Mross K, Steinbild S, Baas F et al.. Results from an in vitro and a clinical/ pharmacological phase I study with the combination irinotecan and sorafenib. Eur J Cancer 2007; 43: 55–63. 27. Sun W, Powell M, O’Dwyer PJ et al.. Phase II study of sorafenib in combination with docetaxel and cisplatin in the treatment of metastatic or advanced gastric and gastroesophageal junction adenocarcinoma: ECOG 5203. J Clin Oncol 2010; 28: 2947–2951. 28. Therasse P, Arbuck SG, Eisenhauer EA et al.. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000; 92: 205–216. 29. Capecitabine and cisplatin (XP)+sorafenib in advanced gastric cancer (AGC). http://clinicaltrials.gov/ct2/show/NCT00565370?term=sorafenib +cisplatin&rank=9 (29 May 2012 date last accessed). 30. Sorafenib, pemetrexed, and cisplatin in treating patients with advanced solid tumors. http://clinicaltrials.gov/ct2/show/NCT00703638?term=sorafenib +cisplatin&rank=5 (30 May 2012 date last accessed). 31. Lassau N, Lamuraglia M, Chami L et al.. Gastrointestinal stromal tumors treated with imatinib: monitoring response with contrast-enhanced sonography. AJR Am J Roentgenol 2006; 187: 1267–1273. 32. Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials 1989; 10: 1–10. 33. Hui EP, Ma BB, King AD et al.. Hemorrhagic complications in a phase II study of sunitinib in patients of nasopharyngeal carcinoma who has previously received high-dose radiation. Ann Oncol 2011; 22: 1280–1287. 34. Lee NY, Zhang Q, Pfister DG et al.. Addition of bevacizumab to standard chemoradiation for locoregionally advanced nasopharyngeal carcinoma (RTOG 0615): a phase 2 multi-institutional trial. Lancet Oncol 2012; 13: 172–180. 35. Lim WT, Ng QS, Ivy P et al.. A phase II study of pazopanib in Asian patients with recurrent/metastatic nasopharyngeal carcinoma. Clin Cancer Res 2011; 17: 5481–5489. 36. Nasopharyngeal carcinoma (NPC) axitinib. http://www.clinicaltrials.gov/ct2/show/ NCT01249547?term=axitinib+NPC&rank=1. (29 May edition). 37. Zips D, Eicheler W, Geyer P et al.. Enhanced susceptibility of irradiated tumor vessels to vascular endothelial growth factor receptor tyrosine kinase inhibition. Cancer Res 2005; 65: 5374–5379. 38. Hui EP, Leung SF, Au JS et al.. Lung metastasis alone in nasopharyngeal carcinoma: a relatively favorable prognostic group. A study by the Hong Kong Nasopharyngeal Carcinoma Study Group. Cancer 2004; 101: 300–306. 39. De Giorgi U, Aliberti C, Benea G et al.. Effect of angiosonography to monitor response during imatinib treatment in patients with metastatic gastrointestinal stromal tumors. Clin Cancer Res 2005; 11: 6171–6176. 40. Scagliotti G, Novello S, von Pawel J et al.. Phase III study of carboplatin and paclitaxel alone or with sorafenib in advanced non-small-cell lung cancer. J Clin Oncol 2010; 28: 1835–1842. 41. Gibson MK, Li Y, Murphy B et al.. Randomized phase III evaluation of cisplatin plus fluorouracil versus cisplatin plus paclitaxel in advanced head and neck cancer (E1395): an intergroup trial of the Eastern Cooperative Oncology Group. J Clin Oncol 2005; 23: 3562–3567. 42. Shacham SE, Gava R, Figer A et al. Phase I trial of sorafenib in combination with 5-fluorouracil/leucovorin in advanced solid tumors. J Clin Pharmacol 2012; 52 (5): 656–659. 43. Cohen EE, Davis DW, Karrison TG et al.. Erlotinib and bevacizumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck: a phase I/II study. Lancet Oncol 2009; 10: 247–257. 44. Je Y, Schutz FA, Choueiri TK. Risk of bleeding with vascular endothelial growth factor receptor tyrosine-kinase inhibitors sunitinib and sorafenib: a systematic review and meta-analysis of clinical trials. Lancet Oncol 2009; 10: 967–974.
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Annals of Oncology
Annals of Oncology 24: 1055–1061, 2013 doi:10.1093/annonc/mds581 Published online 21 November 2012
Phase II study of sorafenib in combination with cisplatin and 5-fluorouracil to treat recurrent or metastatic nasopharyngeal carcinoma† C. Xue1,2,‡, Y. Huang1,2,‡, P. Y. Huang1,3,‡, Q. T. Yu5, J. J. Pan6, L. Z. Liu1,4, X. Q. Song5, S. J. Lin6, J. X. Wu1,2,§, J. W. Zhang1,2, H. Y. Zhao1,2, F. Xu1,2, J. L. Liu1,2, Z. H. Hu1,2, L. P. Zhao1,2, Y. Y. Zhao1,2, X. Wu1,2, J. Zhang1,2, Y. X. Ma1,2 & L. Zhang1,2* 1
State Key Laboratory of Oncology in South China; Departments of 2Medical Oncology; 3Nasopharyngeal Carcinoma; 4Ultrasound and Electrocardiography, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong; 5Department of Medical Oncology, Tumor Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi; 6Department of Radiation Oncology, Fujian Province Cancer Hospital, Fuzhou, Fujian, People’s Republic of China
Received 13 June 2012; revised 25 August 2012; accepted 20 September 2012
Background: We aimed to investigate the efficacy and tolerability of sorafenib combined with cisplatin and 5-fluorouracil (5-FU) in patients with recurrent or metastatic nasopharyngeal carcinoma (NPC).
Patients and methods: It was a Simon two-stage designed trial. Chemotherapy-naive patients with recurrent or metastatic disease were enrolled. The regimen was sorafenib 400 mg orally b.i.d., cisplatin 80 mg/m2 i.v. day 1, and 5-FU 1000 mg/m2/day CIV for 4 days, repeated every 21 days. After a maximum of six cycles of chemotherapy, patients received maintenance of sorafenib. Results: In total, 54 patients were enrolled. The objective response rate reached 77.8%, including 1 complete response and 41 partial responses. The median progression-free survival was 7.2 months (95% CI 6.8–8.4 months), and the median overall survival was 11.8 months (95% CI 10.6–18.7 months). Major toxic effects included hand–foot skin reaction, myelosuppression, and gastrointestinal (GI) reaction. The incidence of hemorrhage was 22.2%, and one patient with liver metastases died of GI bleeding. Contrast-enhanced ultrasonography was carried out in a subset of patients with liver metastases. Conclusion: Combination of sorafenib, cisplatin (80 mg/m2) and 5-FU (3000 mg/m2) was tolerable and feasible in recurrent or metastatic NPC. Further randomized trials to compare sorafenib plus cisplatin and 5-FU with standard dose of cisplatin plus 5-FU in NPC are warranted. Key words: angiogenesis, chemotherapy, nasopharyngeal carcinoma, sorafenib
introduction Nasopharyngeal carcinoma (NPC) is characterized by its unique geographic distribution [1]. Southern China has one of the highest incidence rates in the world (20–30 per 100 000), and the incidence remained stable in the last 30 years [2]. Intense-modulated radiotherapy (RT)/RT alone or with chemotherapy are the standard of care for nonmetastatic disease [3]. Owing to the advances in tumor imaging and RT *Correspondence to: Prof. L. Zhang, State Key Laboratory of Oncology in South China, Department of Medical Oncology, Sun Yat-Sen University Cancer Center, 651 Dongfeng Road, East, Guangzhou, People’s Republic of China. Tel: +86-20-87343458; Fax: +86-20-87343365; E-mail: [email protected] †
This study was presented in part at the 48th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, 1–5 June 2012 (General Poster Session, permanent abstract ID: 5538). ‡ These authors contributed equally to this work. § Present address: Department of Medical Oncology, The First Affiliated Hospital of Xiamen University, Xiamen, People’s Republic of China.
technique, the 5-year local control rate rose to 94.9%, and the 5-year disease-free survival rate reached 76.7%. Treatment failures are mainly distant metastasis, which develop in ∼20% of patients with locally advanced disease [4]. Many cytotoxic agents are active against metastatic NPC. Cisplatin-containing regimens remain the cornerstone of palliative chemotherapy. The response rates (RRs) achieved of cisplatin and 5-fluorouracil (5-FU) were ∼60% [5, 6], so they represent the treatment of choice for most patients with recurrent or metastatic NPC. Other active agents, including taxanes, gemcitabine, oxaliplatin, vinorelbine, irinotecan, and capecitabine, yield the objective RR (ORR) from 14% to 73% after failure of platinum-based chemotherapy, but their efficacy in first-line therapy still needs to be validated in randomized phase III trials [7–17]. In spite of the relatively high RRs and emerging new drugs, survival in advanced disease is not significantly improved, with the progression-free survival (PFS) ranged from 5.6 to 10.6 months and overall survival (OS) from 7.6 to 19.6 months
© The Author 2012. 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 [11, 12, 14, 15, 17]. Molecularly targeted drugs have been added to cytotoxic chemotherapy regimens in order to improve the survival of patients with other advanced tumors [18, 19]. Therefore, it is imperative to explore novel targeted therapies for patients with advanced NPC. VEGF/VEGFR is a potential target, as angiogenesis constitutes an important pathway for tumor growth and metastases. Overexpression of VEGF was seen in 60%–67% of patients with NPC and the higher expression was related to lower OS [20, 21]. These evidences provided a rationale for investigating anti-angiogenesis agent for this tumor. Sorafenib is a multi-kinase inhibitor [22]. Previous trial revealed that sorafenib monotherapy had modest antitumor activity in patients with relapsed advanced or metastatic squamous cell carcinoma of the head and neck (SCCHN), including NPC [23, 24]. We conducted the current study to determine the efficacy and toxicity profile of sorafenib combined with cisplatin and 5-FU in advanced NPC. Sorafenib was chosen because its combination with single cytotoxic agents and platinum-based doublet chemotherapy did not severely increase side-effects in several cancer models [25–27]. The hypothesis is that sorafenib might increase the ORR and improve PFS without adding substantial toxicity.
patients and methods
Annals of Oncology other day. No dose escalations were allowed after a dose reduction. The chemotherapy dosage modifications were allowed when patients experienced grade 4 hematologic or grade 3 non-hematologic AEs.
study procedures Tumor size was evaluated by carrying out computed tomography or magnetic resonance imaging at baseline (within 21 days before starting treatment). Target lesions were evaluated every two cycles during the chemotherapy phase and every 2 months during the maintenance period. Objective responses were confirmed 4 weeks after documentation. After withdrawal, patients were followed up once every 3 months until death. AEs were defined according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 3.0 (http:// ctep.cancer.gov/reporting/ctc_v30.html).
contrast-enhanced ultrasonography Contrast-enhanced ultrasonography (CEUS) was carried out in consented patients with liver metastasis at baseline and after two cycles by using standard methodology as described previously [31]. The contrast uptake rate of liver metastases was evaluated by a specialized radiologist using specific image processing software (Image-Pro Plus 6.0, Media Cybernetics). Receiver operating characteristic curve (ROC) analysis was done using the nonparametric assumption to compare contrast uptake rates by means of ultrasonography measurements. The optimal cut-offs point was defined by ensuring best sensitivity and specificity.
patients
statistical analysis and sample size calculation
Patients enrolled in this study had histologically confirmed NPC that was metastatic or locally recurrent at diagnosis or after previous curative treatment. Disease was measurable as defined by RECIST [28]. Patients must not have received prior treatments for recurrent or newly diagnosed metastatic disease; however, chemotherapy or radiation as part of the initial curative therapy was permitted. Patients were excluded if they had significant cardiac disease; were pregnant or breast-feeding; or showed evidence of bleeding diathesis and were unable to take oral medications. All patients provided informed consent, and the institutional ethics review board of each participating center approved the study.
Simon’s optimal two-stage design was used for sample size calculation [32]. We used the baseline RR of 60% seen with cisplatin and 5-FU in the first-line setting as our null hypothesis. To detect a 30% improvement in RR (60% versus 78%) with the proposed regimen, at a significance level of 5% and a statistical power of 90%, we estimated accrual to be 53 patients in a two-stage design. It was determined that 19 assessable patients had to be included at the first stage. If at least 12 objective responses were observed, then an additional 34 patients would be recruited to the second stage. Sorafenib would be considered active if at least 37 responses were observed among the 53 patients. The primary end point of this study was ORR, including the percentage of complete response (CR) and partial response (PR). The secondary end points were toxicity ( particularly hand–foot skin reaction, HFSR), disease control rate (DCR, the proportion of CR, PR, and SD), PFS, and OS. The analysis was done on an intention-to-treat (ITT) basis. ORR was evaluated in patients who received at least one cycle of treatment and then was reevaluated (both at baseline and after treatment). Patients who received at least one cycle of treatment were included in the safety analysis. OS was defined as the duration from the date of consent to the date of death from any cause or the date of last follow-up. PFS was defined as the duration from the date of consent to the date of disease progression or the date of last follow-up. PFS and OS were estimated using Kaplan–Meier methods. Analyses were carried out using the statistical software package SPSS 16.0 (SPSS, Chicago, IL). All statistical tests were two-sided, and a P-value <0.05 was considered as statistically significant.
study medications Sorafenib was administered orally 400 mg twice a day for 21 days. Cisplatin (80 mg/m2) was administered intravenously on day 1, and 5-FU (1000 mg/ m2/day) was administered via continuous infusion on day 1 through 4 of a 21-day cycle during the chemotherapy phase. In the cases of tumor stabilization or response after a maximum of six cycles of chemotherapy, patients received maintenance treatment with sorafenib until there was objective evidence of tumor progression or intolerable drug-related toxic effects. We chose this dose of cisplatin and 5-FU because of the following reasons. First, there were a lot of studies using sorafenib plus cisplatin and other cytotoxic agents in malignant cancers, and the dose of cisplatin ranged from 75 to 80 mg/m2 [27, 29, 30]. Second, this study aimed to assess the efficacy and safety of sorafenib combined with cisplatin and 5-FU. We carried out this trial in a two-stage design. In the first stage, 19 patients were enrolled to check the efficacy as well as the tolerability of the initial dose. If the trial moved on to the second stage with feasible and tolerable set dose, we enrolled the rest of patients at this dose. Otherwise, the initial dose should be reduced. Dose reduction levels of sorafenib were based on interval adverse events (AEs): level 1 was 400 mg once daily, and level 2 was 400 mg once every
| Xue et al.
results patients characteristics Fifty-four patients were enrolled from January 2009 to May 2011. All patients were included in the ITT analysis of efficacy and AEs. Their characteristics are listed in Table 1. Most patients were men (79.6%); the median age was 45.6 years.
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Annals of Oncology Table 1. Patient characteristics Characteristic
Patients Number
Number of patients included Age, years Median Range Sex Male Female ECOG 0 1 2 Histology Undifferentiated non-keratinizing carcinoma Differentiated non-keratinizing carcinoma Poor differentiated squamous cell carcinoma Disease status Local recurrence Metastatic diseasea Both Number of metastatic organs (n = 52) 1 ≥2 Number of metastatic organs (n = 52) Lung Liver Bone Distant lymph node Pleural Primary curative treatment (n = 38) Radiotherapy Chemoradiotherapy Surgeryb Prior chemotherapy agents (n = 33) Cisplatin 5-FU Docetaxel Paclitaxel Nedaplatin Others
54
Percentage
45.6 27.3–71.2 43 11
79.6 20.4
2 51 1
3.7 94.4 1.9
52 1 1
96.2 1.9 1.9
2 50 2
3.7 92.6 3.7
25 27
48.1 51.9
28 25 21 6 5
53.9 48.1 40.4 11.5 9.6
5 33 1
13.2 86.8 2.6
32 25 10 6 5 3
97 75.8 30.3 18.2 15.2 9.1
study, 63.2% patients (12 out of 19) required 5-FU dose reduction because of mucositis (CTCAE grades 2–3); therefore, the protocol was amended so that the initial dose of 5-FU was 3000 mg/m2 in the second stage. 25.7% patients (9 out of 35) required 5-FU dose reduction at the second stage. Totally, 5-FU dose reduction was carried out on 21 patients (38.9%); among them, 6 patients underwent dose reduction twice. No dose reduction of cisplatin was required. The median sorafenib treatment time was 24.4 weeks (range 5.1–91.4 weeks). Dose intensity was 0.64 in sorafenib due to the dose interruption. Dose reduction of sorafenib was required in 22 patients (40.7%) for the following reasons: HFSR (14, 63.6%), mucositis (4, 18.2%), hypertension (2, 9.1%), diarrhea (1, 4.5%), and arrhythmia (1, 4.5%). Two of them underwent further dose reduction to 400 mg once every other day because of HFSR. Fourteen patients (25.9%) required dose interruption (HFSR 11, 78.6%; poor memory 3, 21.4%). Treatment discontinuation was mainly due to disease progression (30 of 46, 65.2%). Other reasons were death [3, 6.5%, 1 serious AE (SAE), 2 due to progression of disease], complication (1, 2.2%), dose interruption of more than 30 days (5, 10.9%), patient request (2, 4.3%), non-adherence (5, 10.9%).
responses and survival In the ITT analysis, the ORR reached 77.8%: 1 patient (1.9%) experienced CR; 41 (75.9%), PR. Seven (13.0%) patients had stable disease, and five (9.2%) patients had progressive disease. DCR was 90.8%. Waterfall plot of the maximum reduction in target tumor lesions on at least one post-treatment measurement is listed in Figure 1. The median PFS was 7.2 months (95% CI 6.8–8.4 months). Of the 54 patients, 8 (14.8%) continued to receive sorafenib after the data cut-off date for this study (14 December 2011). The duration of treatment is listed in supplementary Figure S1, available at Annals of Oncology online. At a median follow-up of 19.0 months, 33 patients were alive. The median OS was 11.8 months (95% CI 10.6–18.7 months). Of those 28 patients with lung metastasis, 9 patients (9 out of 28, 32.1%) experienced tumor cavitation during the course of treatment (Figure 2). There were no tumor cavitations at baseline.
a
Including patients with metastatic disease at diagnosis and after previous curative treatment. b One patient had both surgery and radiochemotherapy. ECOG, Eastern Cooperative Oncology Group.
Most patients had lung metastases (53.9%), followed by liver (48.1%) and bone metastases (40.4%), and 27 patients had multiple sites of metastases (51.9%). Among those with recurrent/metastatic disease after previous therapy (n = 38), five patients received prior curative-intent RT alone, and 33 had also received chemotherapy with RT.
treatments In the ITT population, the median duration of chemotherapy was 12.1 weeks (range 6.0–18.5 weeks). Dose intensity was 0.86 in cisplatin and 0.81 in 5-FU. During the first stage of the
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contrast-enhanced ultrasonography CEUS was carried out in 16 consented patients with liver metastases before and after two cycles of treatment in one center (SYSUCC). In an ROC analysis, the area under the ROC predicting response by tumor contrast uptake rate at baseline was 0.906. Using the optimal cut-off point identified in the ROC analysis, patients with >85.87% of tumor contrast uptake rate have a better response. Actually, eight of the nine patients with higher uptake rate showed PR, versus none of the seven patients with lower uptake rate (88.9% versus 0%, P = 0.00042). The response was specifically related to the lesions in the liver. The median values of the contrast uptake of responders (eight cases) and non-responders (eight cases) are summarized in supplementary Table S1, available at Annals of Oncology online. Pre-treatment tumor contrast uptake rate was significantly higher in responders than in non-responders:
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Annals of Oncology
Figure 1. Waterfall plot of the maximum decrease in the sum of the longest diameters of target lesions observed. Patients are listed in order of increasing percentage response. The dashed line indicates a tumor reduction of 30% from baseline—the lower limit of partial response, according to Response Evaluation Criteria in Solid Tumors.
Figure 2. Baseline and post-treatment computed tomography scans of one patient with nasopharyngeal carcinoma lung metastases.
93.6% (mean percentage of contrast uptake) versus 56.6% (P = 0.005). After two cycles of treatment, the mean percentage of tumor contrast uptake decreased to 38.0% in responders and remained at 46.1% in non-responders. The changes in contrast uptake before and after treatments were statistically significant in responders (93.6% versus 38.0%, P = 0.002) but not in nonresponders (56.6% versus 46.1%, P = 0.211). The CEUS of patients who experienced PR is shown in Figure 3.
adverse events The most common AEs are listed in Table 2. Most of these were consistent with the known toxic effects of the chemotherapy
| Xue et al.
agents and sorafenib. The most commonly reported AEs include HFSR (83.3%), leucopenia (77.8%), anemia (74.1%), anorexia (74.1%) and nausea (64.8%). Most of these events were mild to moderate. The most common grade 3 or worse toxicity was mucositis with 11 patients (20.3%). Other grade 3 and worse toxicity included HFSR (18.5%), thrombocytopenia (13%), neutropenia (13%), and leukopenia (7.4%). Hemorrhagic events (all grades) occurred in 12 patients (22.2%): epistaxis in 8 patients, gingival bleeding in 2 patients, hemoptysis in 1 patient, and fatal hematemesis in 1 patient. One patient with liver metastasis died of gastrointestinal (GI) bleeding during the sorafenib maintenance treatment period.
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Annals of Oncology
Figure 3. Contrast-enhanced ultrasonography of liver metastasis in one patient who experienced partial response. On a selected single two-dimensional image, the percentage of tumor surface taking up contrast agent was visually evaluated at ∼97.21% on day −1. On the same selected image, the lesion has been outlined and the percentage of pixels was quantified as 18.29% after two cycles of sorafenib plus chemotherapy. Table 2. Drug-related adverse events (N = 54) Adverse event
Hand–foot skin reaction Leukopenia Anemia Anorexia Nausea Thrombocytopenia Mucositis Neutropenia Vomiting Hemorrhage Hypertension Hyponatremia Diarrhea Fatigue Hypopotassaemia Rash
Grade Any Number
Percentage
3 or 4 Number
Percentage
45 42 40 40 35 28 27 27 17 12 9 8 7 4 4 3
83.3 77.8 74.1 74.1 64.8 51.9 50.0 50.0 31.5 22.2 16.7 14.8 13.0 7.4 7.4 5.6
10 4 3 – – 7 11 7 1 1a 1 2 0 0 1 0
18.5 7.4 5.6 – – 13.0 20.3 13.0 1.9 1.9 1.9 3.7 – – 1.9 –
a
One patient died of hemorrhage.
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The patient, aged 45 years, was diagnosed with locally advanced NPC and received CCRT in 2009. He was enrolled into this study in April 2010 after multiple liver metastases were found. In the study, the patient received four cycles of chemotherapy and the efficacy was PR. After that, sorafenib was given for maintenance treatment. However, the patient had fatal GI bleeding during light manual labor in the first maintenance phase. Autopsy was refused. Serious AE (SAEs) occurred in five patients (9.3%): electrolyte disturbance including hyponatremia and/or hypopotassaemia (two), vomiting (one), hemorrhage (one), and active pulmonary tuberculosis (one). All were considered to be drug-related except active pulmonary tuberculosis.
discussion As yet, five anti-angiogenesis agents had been investigated in NPC, including sorafenib, sunitinib, pazopanib, axitinib, and bevacizumab [24, 33–36]. Monotherapy of sorafenib, sunitinib, and pazopanib had demonstrated clinical efficacy in advanced NPC. The clinical benefit rates ranged from 28.6% to 54.5%, most of which were SD, revealing that VEGFR inhibitors might
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original articles induce better ORR when combined with chemotherapy or radiation rather than monotherapy [24, 33, 35, 37]. Recently, a phase II study of bevacizumab combined with chemoradiation also revealed promising efficacy in treating Locally advanced NPC [34]. In our study, evidence for the efficacy of sorafenib plus cisplatin–5-FU regimen seems favorable in metastatic NPC with an RR of 77.8%, a DCR of 90.8%, and PFS of 7.2 months. OS was not significantly prolonged in this patient population compared with previous studies [5–8, 10–12, 14, 15, 17]. Several reasons may contribute to this finding. First, nearly half of the patients (48.1%) enrolled had liver metastasis, which is a poor survival prognostic factor. In fact, OS of patients with liver metastasis was significantly shorter than those without liver metastasis (11.2 months versus 17.0 months, P = 0.048). We also found that patients with lung metastases lived longer than those with other organ metastases (20.9 months versus 11.7 months, P = 0.050), which was consistent with previous literature [38]. Second, only a limited proportion of patients received salvage therapy when diseases progressed (26 out of 46, 56.5%). In our subgroup analysis, patients with second-line therapy (chemotherapy or radiation) were associated with a significant longer OS compared with those with best supportive care only [median 13.8 months (95% CI 11.2–20.9) versus 7.6 months (95% CI 7.2–11.7), P = 0.0014]. Third, the modification of dosage might compromise the maximal benefit from systemic chemotherapy combined with a targeted agent. To our knowledge, this is the first clinical trial to evaluate VEGFR TKIs combined with active cytotoxic agents in recurrent or metastatic NPC. Previous data had showed the potential of CEUS in monitoring the response of anti-angiogenetic agents, and initial contrast uptake was a predictive factor of the response of imatinib in GI stromal tumors [31, 39]. In current study, we explored the usage of CEUS as a non-invasive assessment tool for predicting tumor response of liver metastasis in NPC. The ROC analysis was able to identify a threshold of contrast uptake rate at baseline. The correlation between contrast uptake rate and response indicated the potential of using this parameter as a predictive biomarker in future. We also found different patterns of contrast uptake rate changing in CEUS between responders and non-responders, similar to what Lassau et al. [31] found previously. The change of contrast uptake rate pre- and post-treatment may be valuable as a sensitive parameter to monitor response. Whether or not sorafenib aggravated the known toxic effects of chemotherapy is unknown [27, 40]. In our study, we did observe higher incidences of hematologic and non-hematologic toxic effects with combination therapy than previously reported with chemotherapy alone [41], but all events were consistent with the known safety profile of sorafenib, cisplatin, and 5-FU. The overall grade 3 or greater toxic effects showed that we should be more careful when carrying out this combined regimen, although most of them were reversible. Regarding our result, we assumed that the combination of sorafenib with 5-FU might have synergetic effect on onset of mucositis, although a recent study revealed no evidence of sorafenib–5-FU interactions [42]. The regimen was feasible when the initial dose of 5-FU reduced to 3000 mg/m2 at the second stage. So, we recommend having 5-FU dosage reduced in further study.
| Xue et al.
Annals of Oncology
Patients with recurrent or metastatic SCCHN/NPC are prone to bleeding events [33, 37, 43]. In a phase II trial of sunitinib and pazopanib, Hui et al. [33] and Lim et al. [35], respectively, reported fatal hemorrhage in previously treated NPC patients. Bleeding events in our study were mostly low grade, and the overall incidence risk (22.2%) was similar to that found in the meta-analysis of patients being treated with sorafenib or sunitinib (16.7%) [44]. However, there was still one death due to hemorrhage in our study; clinicians should monitor for potentially serious bleeding events in future clinical trials with significant caution. There are some limitations in our study. First, as this was a single-arm study, all patients received sorafenib combined with chemotherapy. The true effect of sorafenib in this combination cannot be defined without control group. Second, the small number of patients meant the results should be interpreted with caution. Third, the dose reduction might not reveal the maximal effect of these drugs. These limitations all argue for a randomized study to further investigate the incorporation of sorafenib with commonly used regimens in the first-line treatment of patients with advanced NPC. In conclusion, our study results revealed that the combination of sorafenib, cisplatin (80 mg/m2), and 5-FU (3000 mg/m2) was a tolerable and feasible regimen in recurrent or metastatic NPC. Further randomized trials to compare sorafenib plus cisplatin and FU with standard dose of cisplatin plus FU in NPC are warranted.
acknowledgements Sorafenib was kindly provided by Bayer Pharmaceuticals Corporation. We thank the patients who participated in this study and their families, the medical, nursing, and research staff at the study centers. We thank Professor Sharlene Gill from BC Cancer Agency (now a visiting professor at Sun YatSen University Cancer Center) and Professor Chao-Nan Qian for their helpful advice in manuscript editing.
funding This is an investigator-initiated study, so it is not funded by Bayer. Bayer only donated sorafenib for this study. This study was supported by a grant from the National High Technology Research and Development Program of China (863 Program), No. 2006AA02A404 (Molecular classification, personalized diagnose and therapy of nasopharyngeal carcinoma) and No. 985-II State Key Laboratory of Oncology in South China.
disclosure LZ has received research support from Boehringer Ingelheim, Bayer, Astra Zeneca, Lilly, and Sanofi Aventis. All other authors have declared that they have no conflicts of interest.
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