Originally published as JCO Early Release 10.1200/JCO.2008.18.1545 on December 8 2008

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Hui, E. P. Articles by Chan, A. T. Search for Related Content PubMed PubMed Citation Articles by Hui, E. P. Articles by Chan, A. T. Social Bookmarking                            What's this?

Randomized Phase II Trial of Concurrent Cisplatin-Radiotherapy With or Without Neoadjuvant Docetaxel and Cisplatin in Advanced Nasopharyngeal Carcinoma

Edwin P. Hui, Brigette B. Ma, Sing F. Leung, Ann D. King, Frankie Mo, Michael K. Kam, Brian K. Yu, Samuel K. Chiu, Wing H. Kwan, Rosalie Ho, Iris Chan, Anil T. Ahuja, Benny C. Zee, Anthony T. Chan

From the Department of Clinical Oncology; Department of Diagnostic Radiology and Organ Imaging, Prince of Wales Hospital; State Key Laboratory in Oncology in South China, Sir Y.K. Pao Centre for Cancer, Hong Kong Cancer Institute; Center for Clinical Trials, School of Public Health, The Chinese University of Hong Kong; and Sanofi-aventis Hong Kong, Hong Kong SAR, China

Corresponding author: Anthony T. Chan, MD, FRCP, Department of Clinical Oncology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China; e-mail: anthonytcchan{at}cuhk.edu.hk

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Purpose To compare the toxicities, tumor control, survival, and quality of life of nasopharyngeal cancer (NPC) patients treated with sequential neoadjuvant chemotherapy followed by concurrent cisplatin-radiotherapy (CRT) or CRT alone.

Patients and Methods Previously untreated stage III to IVB NPC were randomly assigned to (1) neoadjuvant docetaxel 75 mg/m² and cisplatin 75 mg/m² every 3 weeks for two cycles, followed by cisplatin 40 mg/m²/wk concurrent with radiotherapy, or (2) CRT alone. Planned accrual was 30 patients per arm to detect 20% difference of toxicities based on 95% CIs.

Results From November 2002 to November 2004, 65 eligible patients were randomly assigned to neoadjuvant chemotherapy followed by CRT (n = 34) or CRT alone (n = 31). There was a high rate of grade 3/4 neutropenia (97%) but not neutropenic fever (12%) during neoadjuvant chemotherapy. No significant differences in rates of acute toxicities were observed between the two arms during CRT. Dose intensities of concurrent cisplatin, late RT toxicities and quality of life scores were comparable in both arms. The 3-year progression-free survival for neoadjuvant versus control arm was 88.2% and 59.5% (hazard ratio = 0.49; 95% CI, 0.20 to 1.19; P = .12). The 3-year overall survival for neoadjuvant versus control arm was 94.1% and 67.7% (hazard ratio = 0.24; 95% CI, 0.078 to 0.73; P = .012).

Conclusion Neoadjuvant docetaxel-cisplatin followed by CRT was well tolerated with a manageable toxicity profile that allowed subsequent delivery of full-dose CRT. Preliminary results suggested a positive impact on survival. A phase III study to definitively test this neoadjuvant-concurrent strategy is warranted.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
The current standard treatment for advanced nasopharyngeal cancer (NPC) is concurrent chemoradiotherapy with or without adjuvant chemotherapy.^1,2 Randomized trials of neoadjuvant chemotherapy followed by RT alone have resulted in encouraging response rates and improvement in disease-free survival, but not overall survival.^3-8 Because the use of chemotherapy in the neoadjuvant setting, or as concurrent therapy to RT, has been consistently shown to improve progression-free survival (PFS) and/or overall survival (OS) in advanced NPC, the development of a sequential schedule of neoadjuvant chemotherapy followed by chemoradiotherapy would seem a logical strategy to maximize the benefit from both approaches. In fact, this "neoadjuvant-concurrent" strategy has been pursued by several groups in uncontrolled phase II studies, with favorable outcome reported.^9-11

The taxanes have demonstrated considerable single-agent activity in head and neck cancers and NPC.^12-16 The combination of paclitaxel and carboplatin has yielded high response rates in the range of 59% to 75% in metastatic NPC,^17,18 and has demonstrated encouraging activity and safety profile in the neoadjuvant setting of NPC.¹¹ Docetaxel is associated with less neurotoxicity than paclitaxel and can therefore be more tolerably combined with cisplatin. Docetaxel and cisplatin in combination is highly active in head and neck cancer.^19-21 Therefore, this combination was investigated in NPC and was expected to be highly active in the neoadjuvant setting.

With the experience of a weekly cisplatin schedule from a completed phase III study of chemoradiotherapy in NPC^22,23 and the evidence from other cancers that this may be the best tolerated schedule of chemoradiotherapy,²⁴ the schedule of weekly cisplatin 40 mg/m² for up to 8 weeks concurrently with RT was used in the present protocol.

The primary objective of this study was to compare the toxicities of patients with advanced NPC treated with chemoradiotherapy with or without neoadjuvant docetaxel and cisplatin. Secondary objectives were to compare the tumor response, PFS, OS, and the quality of life of patients between the two treatment arms.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Patient Eligibility and Random Assignment
Patients were eligible if they had biopsy-proven, previously untreated, locoregionally advanced NPC of International Union Against Cancer 1997 stages III to IVB. Other eligibility criteria included assessable disease, Eastern Cooperative Oncology Group performance status grade 0 or 1, age of at least 18 years, adequate bone marrow reserve (WBC count and platelet count of at least the lower limit of normal) and renal function (serum creatinine < 1.5x the upper limit of normal or creatinine clearance 50 mL/min), and absence of hypercalcemia or second malignancy.

Patients were required to provide written informed consent before study entry. The study protocol was approved by the institutional review board and was conducted in accordance with the principles of the Declaration of Helsinki.

The registration and randomization procedure were carried out by telephone from the central office of the Comprehensive Cancer Trials Unit of The Chinese University of Hong Kong (Hong Kong SAR, China) A computer program was used to generate the allocation list. Patients were stratified for stage (stage III v IV) and randomized with equal probability to one of the two treatment arms (Appendix Fig A1, online only): (1) neoadjuvant chemotherapy followed by CRT or (2) CRT alone.

Chemotherapy
In the investigational arm, the neoadjuvant chemotherapy schedule was docetaxel 75 mg/m² as intravenous (IV) infusion over 1 hour on day 1 and cisplatin 75 mg/m² IV over 1 hour with hydration on day 1. Docetaxel was preceded by premedication with oral dexamethasone 8 mg twice daily for 3 days starting 1 day before the infusion. Cycles were repeated every 3 weeks for two cycles. This was followed by RT delivered concurrently with cisplatin 40 mg/m² IV over 2 hours weeks 7 through14 (Appendix Fig A2, online only). In the control arm, RT concurrent with cisplatin 40 mg/m² was administered from week 1 to week 8 without the neoadjuvant chemotherapy.^22,23

Chemotherapy was delayed by 1 week if the absolute neutrophil count (ANC) was less than 1.5 x 10⁹/L or platelet count was less than 75 x 10⁹/L. Both cisplatin and docetaxel were reduced to 65 mg/m² if the nadir ANC was less than 0.5 x 10⁹/L or platelet count was less than 50 x 10⁹/L. No growth factor support was used. During CRT, cisplatin was delayed by 1 week if ANC was less than 1.5 x 10⁹/L or platelet count was less than 75 x 10⁹/L until the counts recovered. Cisplatin was stopped if there were any grade 4 toxicities. RT delays were strongly discouraged. Enteral tube feeding was used as required at the investigators’ discretion.

RT
RT was planned and delivered by the Ho's technique.^11,22 The same RT technique was used for both arms. From March 1, 2004, the protocol was amended to adopt intensity-modulated radiation therapy (IMRT) technique to treat all T3/T4 disease in both arms²⁵ (a detailed description of the RT treatment appears in the Appendix, online only).

Assessment and Follow-Up
All patients completed pretreatment screening procedures within 28 days before the day of random assignment. Staging investigations included computed tomography (CT) scan and magnetic resonance imaging (MRI) of nasopharynx and neck, chest x-ray, ultrasound scan of abdomen, and radionuclide bone scan.

CBC, serum biochemistry, and adverse events were evaluated on days 1 and 10 of neoadjuvant chemotherapy and weekly during CRT, and were graded according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 2.0. Tumor response to neoadjuvant therapy was evaluated before commencement of CRT by nasopharyngoscopy, physical examination, and CT scan. Tumor response after CRT was evaluated by nasopharyngoscopy and biopsy, physical examination, and CT scan at 6 weeks after completion of CRT. Tumor response was classified according to WHO response criteria.²⁶

Patients were followed up every 3 months in the first 2 years, then every 6 months in the third and fourth year, and yearly thereafter. The following assessments were performed at each follow-up visit: (1) history and physical examination, (2) nasopharyngoscopy, and (3) late RT toxicity of the skin, subcutaneous tissue, and salivary gland using the Radiation Therapy Oncology Group and European Organisation for Research and Treatment of Cancer (EORTC) late radiation morbidity scoring schema.²⁷

Quality-of-Life Assessment
The EORTC QLQ-C30 core questionnaire²⁸ together with the head and neck cancer (H&N35) module²⁹ were administered at baseline, on day 1 of each cycle of neoadjuvant chemotherapy, weekly during CRT, and at each follow-up visits.

Statistical Analysis
The incidence of toxicity was the primary end point. We calculated in this study the 95% CIs for the incidence of toxicities with an adjustment of the type I error for multiple comparisons of approximately 10 commonly encountered hematologic and nonhematologic toxicities. Using 30 patients in each arm, we would be able to exclude at least 20% difference using the lower bound of the 95% CI in a reasonable range of toxicities commonly found in most NPC trials (ie, approximately 0% to 25%). Therefore, approximately 30 patients in each of the two arms would allow us to exclude a difference of 20% on one side of 95% CI with 80% power. Secondary end points include tumor response, PFS, OS, and quality of life. The accrual goal was 60 patients.

OS was defined as the duration from the date of random assignment to the date of death resulting from any cause or censored at the date of last follow-up. PFS was defined as the duration from the date of random assignment to the date of disease progression or censored at the date of last follow-up. The survival analysis was based on intention-to-treat (ITT) principle and included all randomly assigned patients (ITT cohort, n = 65). Analysis of toxicities and responses was based on per-protocol treatment cohort (n = 60). The ² test was used to compare the adverse events and other categoric variables between the two treatment arms. The PFS and OS curves were computed by Kaplan-Meier method and compared by log-rank test. The hazard ratios and the corresponding 95% CIs were calculated by Cox proportional hazards model. For quality-of-life scores, a difference or change of 10 units or more on a 0 to 100 scale was regarded as clinically important. Test of differences between the two arms were performed by Wilcoxon test.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Patients
From November 2002 to November 2004, 68 patients were assessed and 65 were randomly assigned to one of the two study arms. Thirty-four patients were randomly assigned to the neoadjuvant chemotherapy arm and 31 patients to the control arm (Fig 1). The two treatment arms were well balanced in the baseline characteristics (Table 1). All patients in the neoadjuvant arm received the allocated treatment, but five patients in the control arm did not receive the allocated treatment. Of these five patients, two withdrew consent before treatment commencement, one was diagnosed to have dermatomyositis, one mandated IMRT mode of RT, and one required further investigation for lung lesion (which was later confirmed to be related to old tuberculosis on CT scan of thorax). Of the two patients who withdrew study consent after random assignment, one sought herbal medicine for 1 month and then received CRT. The other patient sought herbal medicine for 1 year before development of distant metastases and subsequently received palliative chemotherapy. All other three patients received CRT. All together, four of the five patients who withdrew from study received CRT as per standard institutional protocol, which was the same as the control arm to which they were originally allocated. All five patients were followed and included in the ITT analysis.

View larger version (40K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Flow of trial participants. IMRT, intensity modulated radiation therapy.

View larger version (20K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Mean relative dose intensities of cisplatin and docetaxel during two cycles of neoadjuvant chemotherapy and eight weeks of cisplatin-radiotherapy (C = cisplatin 75 mg/m2, D = docetaxel 75 mg/m2, P = cisplatin 40 mg/m2).

Acute Toxicity
No grade 5 toxicity (death) occurred during treatment. The main grade 3 to 4 (G3/G4) adverse events during neoadjuvant chemotherapy were hematological (Table 2). Although G3/G4 neutropenia occurred in 97% of patients during neoadjuvant docetaxel-cisplatin chemotherapy, the rate of febrile neutropenia was only 12%, which were all uncomplicated. During the CRT phase, no significant differences were observed in the rates of G3/G4 neutropenia, other hematologic or nonhematologic toxicities between the two study arms. The mean time to first onset of G3/G4 neutropenia during CRT was also similar in both arms (33 ± 2.8 days in the neoadjuvant arm and 33 ± 14.7 days in the control arm).

View larger version (10K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Kaplan-Meier estimates of survival curves for the two treatment arms. (A) Progression-free survival. There was a trend for improvement of progression free survival in favor of neoadjuvant chemotherapy arm (log-rank P = .11). (B) Overall survival. There was a significant improvement of overall survival in favor of neoadjuvant arm (log-rank P = .0066).

Late Toxicity
There were no significant differences in the cumulative incidence of grade 3 or above late radiation morbidity or adverse events during follow-up between the two study arms (Table 4).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Recently, there has been a renewed interest in the re-exploration of neoadjuvant chemotherapy in advanced NPC. This has resulted from two observations. First, there is the recognition that more effective neoadjuvant chemotherapy regimens may well exist. The second has been the observation that with the use of high-precision RT delivery such as with IMRT, coupled with the wide adoption of concurrent CRT, the local control rate in NPC has improved, and distant metastases has emerged as the predominant mode of treatment failures.^25,30

Although no significant improvement in OS was seen in all the published neoadjuvant chemotherapy trials, the body of available clinical data strongly supports neoadjuvant chemotherapy in terms of improvement in PFS.^3-8 Benefit has been seen in reduction of both local and distant failures.⁷ However, the selection and dosage of drugs may be crucial because an overly toxic schedule has been shown to impair the delivery of subsequent RT, and any possible benefit on survival may be offset by increased treatment-related mortality.⁴

A number of uncontrolled phase II studies,^9,10,31,32 including our own report,¹¹ have explored this sequential schedule of neoadjuvant chemotherapy followed by CRT approach in NPC. The results have been encouraging, and toxicity has been acceptable. Except for the feasibility of this approach, it is difficult to draw further conclusion from these uncontrolled phase II data. There is also concern about the additional toxicity, cost, prolonged treatment duration, compliance, and impact on late physical function and quality of life that could result from this approach.

The results of the present randomized phase II study suggest that neoadjuvant docetaxel and cisplatin chemotherapy followed by CRT is a highly feasible sequential strategy for advanced NPC. The increased acute toxicity during the neoadjuvant chemotherapy was mainly hematologic (neutropenia and neutropenia fever) which was uncomplicated and manageable. Most importantly, this did not compromise the delivery of subsequent CRT. The hematologic toxicity could be further ameliorated with the use of growth factor support and prophylactic antibiotics. The comparable late toxicities and quality-of-life scores in both arms are encouraging. The preliminary results on pattern of failures suggest that the potential benefit of neoadjuvant chemotherapy is in the reduction of distant metastases (11.8% in the neoadjuvant arm v 23.1% to 29.0% in the control arm; Appendix Table A1). There is a suggestion of a positive impact on PFS and OS, although this needs to be confirmed in a definitive phase III trial.

Recently, [¹⁸F]fluorodeoxyglucose positron emission tomography (PET) was compared with conventional staging procedures (ie, chest x-ray, abdominal ultrasound and bone scan) in the staging of advanced NPC, and it was suggested that PET may be more sensitive in detecting distant metastases.^33,34 Sixty-three of the 65 patients enrolled in this trial also participated in a parallel study of PET-CT scan and tumor marker study.³⁵ No distant metastases were detected on PET-CT after conventional staging procedures at study entry. Therefore, it would be unlikely that there was significant imbalance of occult distant metastases between the two treatment arms.

Unlike the traditional cisplatin and fluorouracil combination, docetaxel and cisplatin combination can be conveniently administered as outpatient without the need for a central venous catheter device. A recent phase II study from The University of Texas M. D. Anderson Cancer Center (Houston, TX) has tested docetaxel and carboplatin combination as neoadjuvant therapy in NPC. Their result also confirmed that this regimen could be more conveniently administered in the outpatient setting and was devoid of serious nonhematologic toxicity.³⁶

The triple combination of docetaxel, cisplatin, and fluorouracil (TPF) was compared with cisplatin and fluorouracil (PF) as induction chemotherapy in advanced head and neck cancer in the EORTC/TAX323 and TAX324 studies, and demonstrated superior PFS and OS.^37,38 It was worth noting that in the TAX323 study, TPF induced more neutropenia (76.9%) than PF (52.5%), but did not lead to more frequent infectious complications when patients received prophylactic antibiotics. In the TAX324 study, patients in the TPF group had more G3/G4 neutropenia (83% in TPF v 56% in PF) and more febrile neutropenia (12% in TPF v 7% in PF), but there were fewer treatment delays in the TPF group. Similarly, no significant differences in the rate of adverse events during RT were observed in both studies. It should also be noted that in the aforementioned two neoadjuvant trials, neoadjuvant chemotherapy was administered in both arms, followed by RT alone in the EORTC/TAX323 study by Vermorken,³⁷ or by concurrent carboplatin-RT in the TAX324 study by Posner.³⁸ Our study adopted a pure concurrent CRT as control arm. We used weekly cisplatin during the CRT. However, any conclusion on tolerability of this schedule may not necessarily be extrapolated to the high-dose cisplatin regimen (100 mg/m² every 3 weeks), another commonly used schedule in previous trials. It remains to be proven in head and neck cancer and in NPC whether the addition of any neoadjuvant chemotherapy regimen to concurrent CRT improves OS compared with concurrent CRT alone in a phase III setting.^39,40 To answer the latter question, several phase III studies comparing a sequential approach of neoadjuvant chemotherapy followed by CRT versus CRT alone are ongoing in head and neck cancer.^41,42 In NPC, a Radiotherapy Oncology Group for Head and Neck (GORTEC) multicenter phase III trial of neoadjuvant chemotherapy (TPF) followed by concurrent weekly cisplatin-RT versus weekly cisplatin-RT alone has been started.

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: Iris Chan, Sanofi-aventis (C) Consultant or Advisory Role: None Stock Ownership: None Honoraria: None Research Funding: None Expert Testimony: None Other Remuneration: None

	AUTHOR CONTRIBUTIONS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Conception and design: Edwin P. Hui, Benny C. Zee, Anthony T. Chan

Financial support: Iris Chan, Anthony T. Chan

Administrative support: Frankie Mo, Rosalie Ho, Iris Chan, Benny C. Zee, Anthony T. Chan

Provision of study materials or patients: Edwin P. Hui, Brigette B. Ma, Sing F. Leung, Ann D. King, Michael K. Kam, Brian K. Yu, Samuel K. Chiu, Wing H. Kwan, Rosalie Ho, Anil T. Ahuja, Anthony T. Chan

Collection and assembly of data: Edwin P. Hui, Brigette B. Ma, Sing F. Leung, Ann D. King, Frankie Mo, Michael K. Kam, Brian K. Yu, Samuel K.Chiu, Wing H. Kwan, Rosalie Ho, Anil T. Ahuja

Data analysis and interpretation: Edwin P. Hui, Brigette B. Ma, Sing F. Leung, Frankie Mo, Benny C. Zee, Anthony T. Chan

Manuscript writing: Edwin P. Hui, Brigette B. Ma, Sing F. Leung, Benny C. Zee, Anthony T. Chan

Final approval of manuscript: Edwin P. Hui, Brigette B. Ma, Sing F. Leung, Ann D. King, Frankie Mo, Michael K. Kam, Brian K. Yu, Samuel K. Chiu, Wing H. Kwan, Rosalie Ho, Iris Chan, Anil T. Ahuja, Benny C. Zee, Anthony T. Chan

	Appendix

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Patients and Methods: Radiotherapy
RT was planned and delivered by the Ho's technique. (Chan AT, Ma BB, Lo YM, et al: J Clin Oncol 22:3053-3060, 2004; Chan AT, Teo PM, Ngan RK, et al: J Clin Oncol 20:2038-2044, 2002). The same RT technique was used for both arms. The nasopharynx and adjacent region were treated to 66 Gy in 33 fractions over 6.6 weeks by a shrinking-field technique (two lateral facial-cervical ports to 40 Gy in 20 fractions over 4 weeks, followed by a three-port plan to another 26 Gy in 13 fractions over 2.6 weeks, with 6-MV photons). The cervical lymphatics were treated by a separate anterior photon port. For patients with parapharyngeal disease; a boost dose to the nasopharyngeal and parapharyngeal region was delivered by an ipsilateral posterolateral port, administering 20 Gy in 10 fractions over 2 weeks. Palpable residual nodes at completion of RT were boosted to 7.5 Gy in two fractions with an electron field. Patients with persistent NP disease at 6 weeks after completion of CRT received intracavitary brachytherapy using paired iridium-192 sources, delivering a dose of 18 Gy in four fractions in 15 days. Those with cytologically proven residual neck nodes were referred for radical neck dissection.

From March 1, 2004, the protocol was amended to adopt IMRT to treat all T3/T4 disease in both arms. The prescribed dose was 66 Gy in 33 fractions in 6.6 weeks to the gross tumor volume with margins. Details of the IMRT technique used have been described previously. (Kam MK, Teo PM, Chau RM, et al: Int J Radiat Oncol Biol Phys 60:1440-1450, 2004).

Results: Quality of Life
Compliance with quality of life questionnaire was 100% in both arms (34 patients in neoadjuvant arm and 26 patients in control arm) at baseline and 4 weeks post-treatment, 94.1% at 12 months (n = 32) and 88.2% at 24 months (n = 30) in the neoadjuvant arm and 76.9% at 12 months (n = 20), and 65.4% at 24 months (n = 17) in the control arm. The decrease was the result of patient death or disease progression. The frequency of missing response per each item was low, ranging from none to two of 24 (8%) for items on sexuality. Most items have no missing value.

No significant difference was observed in the global quality-of-life scores in the two treatment arms (mean change in score was –8.59 at 4 weeks, 3.89 at 12 months, and 1.79 at 24 months in the neoadjuvant arm; and –4.00 at 4 weeks, 1.75 at 12 months, and 5.73 at 24 months in the control arm). Regarding physical functioning, patients in the neoadjuvant arm had slightly more deterioration at 4 weeks post-CRT (mean change score, –42.9 v –27.7; P = .0499), with increase in symptom score of appetite (mean change score, 18.6 v –5.3; P = .023) and constipation (mean change score, 24.5 v –3.8; P = .0075) compared with control arm. However, the differences in these items were no longer significant by 12 and 24 months post-treatment. No significant difference was observed in other QLQ-C30 function domains or symptom subscales between the two arms. In the H&N35 module, the only significant difference was an increase of nutritional supplements in neoadjuvant arm compared with control arm (mean change score, 10.0 v –23.5; P = .025) at 24 months post-treatment.

View larger version (17K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Figure A1. Randomization schema. NPC, nasopharyngeal cancer; UICC, International Union Against Cancer, DC, docetaxel-cisplatin; RT, radiotherapy.

View larger version (7K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Figure A2. Treatment plan. D, docetaxel 75 mg/m2; C, cisplatin 75 mg/m2; P, cisplatin 40 mg/m2; RT, radiotherapy.

	NOTES

 
published online ahead of print at www.jco.org on December 8, 2008

Supported in part by a research grant from Sanofi-aventis Hong Kong Limited.

Presented in part at the 41st Annual Meeting of the American Society of Clinical Oncology, May 13-17, 2005, Orlando, FL; the 13th European Cancer Conference, October 30-November 3, 2006, Paris, France; and the 43rd Annual Meeting of the American Society of Clinical Oncology, June 2-5, 2007, Chicago, IL.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
1. Baujat B, Audry H, Bourhis J, et al: Chemotherapy as an adjunct to radiotherapy in locally advanced nasopharyngeal carcinoma. Cochrane Database Syst Rev:CD004329, 2006

2. Ma BB, Chan AT: Systemic treatment strategies and therapeutic monitoring for advanced nasopharyngeal carcinoma. Expert Rev Anticancer Ther 6:383-394, 2006[CrossRef][Medline]

3. Chan AT, Teo PM, Leung TW, et al: A prospective randomized study of chemotherapy adjunctive to definitive radiotherapy in advanced nasopha ryngeal carcinoma. Int J Radiat Oncol Biol Phys 33:569-577, 1995[CrossRef][Medline]

4. Preliminary results of a randomized trial comparing neoadjuvant chemotherapy (cisplatin, epirubicin, bleomycin) plus radiotherapy vs. radiotherapy alone in stage IV(> or = N2, M0) undifferentiated nasopharyngeal carcinoma: A positive effect on progression-free survival. International Nasopharynx Cancer Study Group. VUMCA I trial. Int J Radiat Oncol Biol Phys 35:463-469, 1996[CrossRef][Medline]

5. Chua DT, Sham JS, Choy D, et al: Preliminary report of the Asian-Oceanian Clinical Oncology Association randomized trial comparing cisplatin and epirubicin followed by radiotherapy versus radiotherapy alone in the treatment of patients with locoregionally advanced nasopharyngeal carcinoma. Asian-Oceanian Clinical Oncology Association Nasopharynx Cancer Study Group. Cancer 83:2270-2283, 1998[CrossRef][Medline]

6. Ma J, Mai HQ, Hong MH, et al: Results of a prospective randomized trial comparing neoadjuvant chemotherapy plus radiotherapy with radiotherapy alone in patients with locoregionally advanced nasopharyngeal carcinoma. J Clin Oncol 19:1350-1357, 2001[Abstract/Free Full Text]

7. Chua DT, Ma J, Sham JS, et al: Long-term survival after cisplatin-based induction chemotherapy and radiotherapy for nasopharyngeal carcinoma: A pooled data analysis of two phase III trials. J Clin Oncol 23:1118-1124, 2005[Abstract/Free Full Text]

8. Hareyama M, Sakata K, Shirato H, et al: A prospective, randomized trial comparing neoadjuvant chemotherapy with radiotherapy alone in patients with advanced nasopharyngeal carcinoma. Cancer 94:2217-2223, 2002[CrossRef][Medline]

9. Rischin D, Corry J, Smith J, et al: Excellent disease control and survival in patients with advanced nasopharyngeal cancer treated with chemoradiation. J Clin Oncol 20:1845-1852, 2002[Abstract/Free Full Text]

10. Oh JL, Vokes EE, Kies MS, et al: Induction chemotherapy followed by concomitant chemoradiotherapy in the treatment of locoregionally advanced nasopharyngeal cancer. Ann Oncol 14:564-569, 2003[Abstract/Free Full Text]

11. Chan AT, Ma BB, Lo YM, et al: Phase II study of neoadjuvant carboplatin and paclitaxel followed by radiotherapy and concurrent cisplatin in patients with locoregionally advanced nasopharyngeal carcinoma: Therapeutic monitoring with plasma Epstein-Barr virus DNA. J Clin Oncol 22:3053-3060, 2004[Abstract/Free Full Text]

12. Catimel G, Verweij J, Mattijssen V, et al: Docetaxel (Taxotere): an active drug for the treatment of patients with advanced squamous cell carcinoma of the head and neck. EORTC Early Clinical Trials Group. Ann Oncol 5:533-537, 1994[Abstract/Free Full Text]

13. Dreyfuss AI, Clark JR, Norris CM, et al: Docetaxel: An active drug for squamous cell carcinoma of the head and neck. J Clin Oncol 14:1672-1678, 1996[Abstract/Free Full Text]

14. Forastiere AA, Shank D, Neuberg D, et al: Final report of a phase II evaluation of paclitaxel in patients with advanced squamous cell carcinoma of the head and neck: An Eastern Cooperative Oncology Group trial (PA390). Cancer 82:2270-2274, 1998[CrossRef][Medline]

15. Posner MR: Docetaxel in squamous cell cancer of the head and neck. Anticancer Drugs 12:S21-S4, 2001 (suppl 1)[CrossRef]

16. Au E, Tan EH, Ang PT: Activity of paclitaxel by three-hour infusion in Asian patients with metastatic undifferentiated nasopharyngeal cancer. Ann Oncol 9:327-329, 1998[Abstract/Free Full Text]

17. Yeo W, Leung TW, Chan AT, et al: A phase II study of combination paclitaxel and carboplatin in advanced nasopharyngeal carcinoma. Eur J Cancer 34:2027-2031, 1998[CrossRef][Medline]

18. 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 10:235-237, 1999[Abstract/Free Full Text]

19. Schöffski P, Catimel G, Planting AS, et al: Docetaxel and cisplatin: An active regimen in patients with locally advanced, recurrent or metastatic squamous cell carcinoma of the head and neck. Results of a phase II study of the EORTC Early Clinical Studies Group. Ann Oncol 10:119-122, 1999[Abstract/Free Full Text]

20. Specht L, Larsen SK, Hansen HS: Phase II study of docetaxel and cisplatin in patients with recurrent or disseminated squamous-cell carcinoma of the head and neck. Ann Oncol 11:845-849, 2000[Abstract/Free Full Text]

21. Caponigro F, Massa E, Manzione L, et al: Docetaxel and cisplatin in locally advanced or metastatic squamous-cell carcinoma of the head and neck: A phase II study of the Southern Italy Cooperative Oncology Group (SICOG). Ann Oncol 12:199-202, 2001[Abstract/Free Full Text]

22. Chan AT, Teo PM, Ngan RK, et al: Concurrent chemotherapy-radiotherapy compared with radiotherapy alone in locoregionally advanced nasopharyngeal carcinoma: Progression-free survival analysis of a phase III randomized trial. J Clin Oncol 20:2038-2044, 2002[Abstract/Free Full Text]

23. Chan AT, Leung SF, Ngan RK, et al: Overall survival after concurrent cisplatin-radiotherapy compared with radiotherapy alone in locoregionally advanced nasopharyngeal carcinoma. J Natl Cancer Inst 97:536-539, 2005[Abstract/Free Full Text]

24. Morris M, Eifel PJ, Lu J, et al: Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer. N Engl J Med 340:1137-1143, 1999[Abstract/Free Full Text]

25. Kam MK, Teo PM, Chau RM, et al: Treatment of nasopharyngeal carcinoma with intensity-modulated radiotherapy: The Hong Kong experience. Int J Radiat Oncol Biol Phys 60:1440-1450, 2004[CrossRef][Medline]

26. Miller AB, Hoogstraten B, Staquet M, et al: Reporting results of cancer treatment. Cancer 47:207-214, 1981[CrossRef][Medline]

27. Cox JD, Stetz J, Pajak TF: Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). Int J Radiat Oncol Biol Phys 31:1341-1346, 1995[CrossRef][Medline]

28. Aaronson NK, Ahmedzai S, Bergman B, et al: The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 85:365-376, 1993[Abstract/Free Full Text]

29. Bjordal K, Hammerlid E, Ahlner-Elmqvist M, et al: Quality of life in head and neck cancer patients: Validation of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-H&N35. J Clin Oncol 17:1008-1019, 1999[Abstract/Free Full Text]

30. 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 101:300-306, 2004[CrossRef][Medline]

31. Ozturk B, Buyukberber S, Akmansu M, et al: The results of three different treatment modalities in patients with locally advanced nasopharyngeal carcinoma. Med Oncol [Epub ahead of print December 15, 2007]

32. Xie FY, Qi SN, Hu WH, et al: [Comparison of efficacy of docetaxel combined cisplatin (TP regimen) and cisplatin combined 5-fluorouracil (PF regimen) on locally advanced nasopharyngeal carcinoma]. Ai Zheng 26:880-884, 2007[Medline]

33. Liu FY, Chang JT, Wang HM, et al: [18F]fluorodeoxyglucose positron emission tomography is more sensitive than skeletal scintigraphy for detecting bone metastasis in endemic nasopharyngeal carcinoma at initial staging. J Clin Oncol 24:599-604, 2006[Abstract/Free Full Text]

34. Liu FY, Lin CY, Chang JT, et al: 18F-FDG PET can replace conventional work-up in primary M staging of nonkeratinizing nasopharyngeal carcinoma. J Nucl Med 48:1614-1619, 2007[Abstract/Free Full Text]

35. Ma BB, King A, Lo YM, et al: Relationship between pretreatment level of plasma Epstein-Barr virus DNA, tumor burden, and metabolic activity in advanced nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 66:714-720, 2006[Medline]

36. Johnson FM, Garden A, Palmer JL, et al: A Phase II study of docetaxel and carboplatin as neoadjuvant therapy for nasopharyngeal carcinoma with early T status and advanced N status. Cancer 100:991-998, 2004[CrossRef][Medline]

37. Vermorken JB, Remenar E, van Herpen C, et al: Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer. N Engl J Med 357:1695-1704, 2007[Abstract/Free Full Text]

38. Posner MR, Hershock DM, Blajman CR, et al: Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. N Engl J Med 357:1705-1715, 2007[Abstract/Free Full Text]

39. Adelstein DJ, Leblanc M: Does induction chemotherapy have a role in the management of locoregionally advanced squamous cell head and neck cancer? J Clin Oncol 24:2624-2628, 2006[Abstract/Free Full Text]

40. Glynne-Jones R, Hoskin P: Neoadjuvant cisplatin chemotherapy before chemoradiation: A flawed paradigm? J Clin Oncol 25:5281-5286, 2007[Abstract/Free Full Text]

41. Specenier PM, Vermorken JB: Neoadjuvant chemotherapy in head and neck cancer: Should it be revisited? Cancer Lett 256:166-177, 2007[CrossRef][Medline]

42. Cruz JJ, Ocana A, Navarro M, et al: New options in the treatment of locally advanced head and neck cancer: Role for induction chemotherapy. Cancer Treat Rev 34:268-274, 2008[CrossRef][Medline]

Submitted May 16, 2008; accepted August 18, 2008.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Hui, E. P. Articles by Chan, A. T. Search for Related Content PubMed PubMed Citation Articles by Hui, E. P. Articles by Chan, A. T. Social Bookmarking                            What's this?