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Comparison of weekly versus triweekly cisplatin delivered concurrently with radiation therapy in patients with locally advanced nasopharyngeal cancer: A multicenter randomized phase II trial (KCSG-HN10-02)

  • Author Footnotes
    1 These authors contributed equally.
    Ji Yun Lee
    Footnotes
    1 These authors contributed equally.
    Affiliations
    Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
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  • Author Footnotes
    1 These authors contributed equally.
    Jong-Mu Sun
    Footnotes
    1 These authors contributed equally.
    Affiliations
    Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
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  • Dong Ryul Oh
    Affiliations
    Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
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  • Sung Hee Lim
    Affiliations
    Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
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  • Juna Goo
    Affiliations
    Department of Biostatistics and Bioinformatics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
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  • Se-Hoon Lee
    Affiliations
    Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
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  • Sung-Bae Kim
    Affiliations
    Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
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  • Keon Uk Park
    Affiliations
    Division of Hematology-Oncology, Department of Medicine, Dongsan Medical Center, Keimyung University School of Medicine, Daegu, Republic of Korea
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  • Hoon-Kyo Kim
    Affiliations
    Division of Hematology-Oncology, Department of Medicine, St. Vincent’s Hospital, The Catholic University of Korea College of Medicine, Suwon, Republic of Korea
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  • Dae Sik Hong
    Affiliations
    Division of Hematology-Oncology, Department of Medicine, Soonchunhyang University College of Medicine, Bucheon, Republic of Korea
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  • Jun Suk Kim
    Affiliations
    Division of Hematology-Oncology, Department of Medicine, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Republic of Korea
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  • Seong-Geun Kim
    Affiliations
    Division of Hematology-Oncology, Department of Medicine, Pusan National University, Yangsan, Republic of Korea
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  • Seong Yoon Yi
    Affiliations
    Division of Hematology-Oncology, Department of Medicine, Ilsan Paik Hospital, Inje University College of Medicine, Goyaung, Republic of Korea
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  • Hwan Jung Yun
    Affiliations
    Division of Hematology-Oncology, Department of Medicine, Chungnam National University College of Medicine, Daejeon, Republic of Korea
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  • Myung Soo Hyun
    Affiliations
    Division of Hematology-Oncology, Department of Medicine, Yeungnam University College of Medicine, Daegu, Republic of Korea
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  • Hyo Jung Kim
    Affiliations
    Division of Hematology-Oncology, Department of Medicine, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Republic of Korea
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  • Sin-Ho Jung
    Affiliations
    Department of Biostatistics and Bioinformatics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
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  • Keunchil Park
    Affiliations
    Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
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  • Yong Chan Ahn
    Correspondence
    Corresponding authors at: Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 135-710, Republic of Korea (Y.C. Ahn). Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 135-710, Republic of Korea (M.-J. Ahn).
    Affiliations
    Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
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  • Myung-Ju Ahn
    Correspondence
    Corresponding authors at: Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 135-710, Republic of Korea (Y.C. Ahn). Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 135-710, Republic of Korea (M.-J. Ahn).
    Affiliations
    Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
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  • Author Footnotes
    1 These authors contributed equally.
Published:December 16, 2015DOI:https://doi.org/10.1016/j.radonc.2015.11.030

      Abstract

      Purpose

      Triweekly delivery of cisplatin concurrent with a course of radiation therapy (RT) has been the standard regimen for treatment of locally advanced nasopharyngeal carcinoma (NPC) despite a high level of concern regarding treatment-related complications. We conducted a randomized phase II study to compare weekly and triweekly cisplatin delivery during RT with respect to efficacy and toxicity profiles.

      Material and methods

      Patients with locally advanced NPC (stage II–IVb) were randomly assigned to a regimen of either seven doses of cisplatin (40 mg/m2) given once a week or three doses of cisplatin (100 mg/m2) given every 3 weeks concurrently during RT.

      Results

      Of 109 eligible patients, 53 were assigned to the weekly regimen and 56 to the triweekly regimen. The two groups were comparable with respect to demographic and clinical characteristics. There were no significant differences in mean RT dose (68.3 Gy vs. 67.3 Gy, p= 0.559) and mean cisplatin dose (248.9 mg/m2 vs. 256.6 mg/m2, p= 0.433) between the two regimens. The primary endpoint was 3-year progression-free survival, which was not different between the regimens (64.9% vs. 63.8%, p= 0.074). Overall, the occurrence of grade 3–4 toxicities was similar between the two arms (47.2% vs. 39.3%, p= 0.443). Quality of life (QoL) related to functional outcomes 3 weeks after treatment completion was better for the weekly regimen.

      Conclusions

      Although no definitive conclusions can be made, a once-weekly cisplatin regimen appears to be associated with improved QoL and is not inferior to the standard triweekly regimen with respect to efficacy and toxicity profiles.

      Keywords

      Locally advanced nasopharyngeal carcinoma (NPC) has a relatively poor prognosis if treated with radiation therapy (RT) alone, with a 5-year overall survival (OS) rate of 50–60% [
      • Lee A.W.
      • Poon Y.F.
      • Foo W.
      • et al.
      Retrospective analysis of 5037 patients with nasopharyngeal carcinoma treated during 1976–1985: overall survival and patterns of failure.
      ,
      • Geara F.B.
      • Sanguineti G.
      • Tucker S.L.
      • et al.
      Carcinoma of the nasopharynx treated by radiotherapy alone: determinants of distant metastasis and survival.
      ]. The Intergroup-0099 study (INT-0099) substantiated the benefit of concurrent chemoradiotherapy (CCRT) followed by adjuvant chemotherapy, with an improved 3-year OS compared to RT alone (78% vs. 47%, p< 0.01) [
      • Al-Sarraf M.
      • LeBlanc M.
      • Giri P.G.
      • et al.
      Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized Intergroup study 0099.
      ]. However, concerns have been raised over toxicity and compliance when delivering the standard schedule of cisplatin (every 3 weeks) concurrently with RT. In fact, poor compliance with the triweekly cisplatin regimen during CCRT was reported in the INT-0099 trial (63%) [
      • Al-Sarraf M.
      • LeBlanc M.
      • Giri P.G.
      • et al.
      Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized Intergroup study 0099.
      ] and by Bahl et al. (43%) [
      • Bahl M.
      • Siu L.L.
      • Pond G.R.
      • et al.
      Tolerability of the Intergroup 0099 (INT 0099) regimen in locally advanced nasopharyngeal cancer with a focus on patients’ nutritional status.
      ], and resulted in discontinuation of therapy in the majority of patients due to toxicity.
      To date, there are several reports showing benefits in locoregional disease control and/or survival with an alternative schedule of cisplatin with concurrent radiotherapy for head and neck cancer [
      • Gupta T.
      • Agarwal J.P.
      • Ghosh-Laskar S.
      • Parikh P.M.
      • D’Cruz A.K.
      • Dinshaw K.A.
      Radical radiotherapy with concurrent weekly cisplatin in loco-regionally advanced squamous cell carcinoma of the head and neck: a single-institution experience.
      ,
      • Rampino M.
      • Ricardi U.
      • Munoz F.
      • et al.
      Concomitant adjuvant chemoradiotherapy with weekly low-dose cisplatin for high-risk squamous cell carcinoma of the head and neck: a phase II prospective trial.
      ,
      • Traynor A.M.
      • Richards G.M.
      • Hartig G.K.
      • et al.
      Comprehensive IMRT plus weekly cisplatin for advanced head and neck cancer: the University of Wisconsin experience.
      ,
      • Ho K.F.
      • Swindell R.
      • Brammer C.V.
      Dose intensity comparison between weekly and 3-weekly Cisplatin delivered concurrently with radical radiotherapy for head and neck cancer: a retrospective comparison from New Cross Hospital, Wolverhampton, UK.
      ]. These data suggest that smaller cisplatin doses administered more frequently may result in acceptable acute toxicities without compromising efficacy [
      • Gupta T.
      • Agarwal J.P.
      • Ghosh-Laskar S.
      • Parikh P.M.
      • D’Cruz A.K.
      • Dinshaw K.A.
      Radical radiotherapy with concurrent weekly cisplatin in loco-regionally advanced squamous cell carcinoma of the head and neck: a single-institution experience.
      ,
      • Rampino M.
      • Ricardi U.
      • Munoz F.
      • et al.
      Concomitant adjuvant chemoradiotherapy with weekly low-dose cisplatin for high-risk squamous cell carcinoma of the head and neck: a phase II prospective trial.
      ,
      • Traynor A.M.
      • Richards G.M.
      • Hartig G.K.
      • et al.
      Comprehensive IMRT plus weekly cisplatin for advanced head and neck cancer: the University of Wisconsin experience.
      ,
      • Ho K.F.
      • Swindell R.
      • Brammer C.V.
      Dose intensity comparison between weekly and 3-weekly Cisplatin delivered concurrently with radical radiotherapy for head and neck cancer: a retrospective comparison from New Cross Hospital, Wolverhampton, UK.
      ]. With regard to acute cisplatin-induced nephrotoxicity, vigorous pre- and post-chemotherapy hydration is not necessary in the weekly low-dose cisplatin regimen, which makes it easier to apply in an outpatient setting [
      • Ho K.F.
      • Swindell R.
      • Brammer C.V.
      Dose intensity comparison between weekly and 3-weekly Cisplatin delivered concurrently with radical radiotherapy for head and neck cancer: a retrospective comparison from New Cross Hospital, Wolverhampton, UK.
      ,
      • Beckmann G.K.
      • Hoppe F.
      • Pfreundner L.
      • Flentje M.P.
      Hyperfractionated accelerated radiotherapy in combination with weekly cisplatin for locally advanced head and neck cancer.
      ]. In a retrospective study by Ho et al., more than 80% of elderly patients with NPC were able to receive more than seven doses of weekly cisplatin during the RT course with promising survival outcomes [
      • Ho H.C.
      • Su Y.C.
      • Lee M.S.
      • et al.
      A preliminary result of concurrent chemoradiation with weekly cisplatin in elderly nasopharyngeal carcinoma patients.
      ].
      Although several investigations have been undertaken to reduce toxicity while maintaining efficacy [
      • Chan A.T.
      • Teo P.M.
      • Ngan R.K.
      • et al.
      Concurrent chemotherapy-radiotherapy compared with radiotherapy alone in locoregionally advanced nasopharyngeal carcinoma: progression-free survival analysis of a phase III randomized trial.
      ,
      • Lin J.C.
      • Jan J.S.
      • Hsu C.Y.
      • Liang W.M.
      • Jiang R.S.
      • Wang W.Y.
      Phase III study of concurrent chemoradiotherapy versus radiotherapy alone for advanced nasopharyngeal carcinoma: positive effect on overall and progression-free survival.
      ,
      • Wee J.
      • Tan E.H.
      • Tai B.C.
      • et al.
      Randomized trial of radiotherapy versus concurrent chemoradiotherapy followed by adjuvant chemotherapy in patients with American Joint Committee on Cancer/International Union against cancer stage III and IV nasopharyngeal cancer of the endemic variety.
      ,
      • Lee A.W.
      • Lau W.H.
      • Tung S.Y.
      • et al.
      Preliminary results of a randomized study on therapeutic gain by concurrent chemotherapy for regionally-advanced nasopharyngeal carcinoma: NPC-9901 Trial by the Hong Kong Nasopharyngeal Cancer Study Group.
      ,
      • Yi J.L.
      • Gao L.
      • Huang X.D.
      • et al.
      Nasopharyngeal carcinoma treated by radical radiotherapy alone: ten-year experience of a single institution.
      ,
      • Chen Y.
      • Liu M.Z.
      • Liang S.B.
      • et al.
      Preliminary results of a prospective randomized trial comparing concurrent chemoradiotherapy plus adjuvant chemotherapy with radiotherapy alone in patients with locoregionally advanced nasopharyngeal carcinoma in endemic regions of china.
      ], no randomized controlled trial has been conducted to compare the efficacy and toxicity profiles of two different schedules of cisplatin as part of CCRT in the treatment of locally advanced NPC. We therefore conducted a multicenter randomized phase II trial to evaluate the efficacy, toxicity, and tolerability of a weekly versus triweekly cisplatin regimen in the CCRT setting.

      Patients and methods

      Patients

      This was a prospective, multicenter, randomized phase II trial conducted at 19 centers in Korea. Patients with histologically confirmed WHO type I–III NPC that was locally advanced (Stage II–IVb) by AJCC/UICC-5 staging system without evidence of systemic metastasis were eligible to participate. Other inclusion criteria included age 19 years or older, Eastern Cooperative Oncology Group (EGOG) performance status (PS) of 0–2, and adequate organ function. Patients were not eligible if they had received prior chemotherapy and/or radiotherapy.
      The current study was approved by the Institutional Review Board for Human Research at each participating institute. All patients were required to sign a written informed consent form before enrollment to the study. This study was coordinated by an independent central committee, the Korean Cancer Study Group (KCSG), for monitoring and data collection.

      Concurrent and adjuvant chemotherapy

      The patients were randomly assigned in a 1:1 ratio to a weekly cisplatin regimen (cisplatin 40 mg/m2 infusion over 1 h on days 1, 8, 15, 22, 29, 36, and 43) or to a triweekly cisplatin regimen (cisplatin 100 mg/m2 infusion over 1 h on days 1, 22, and 43). Both regimens were to be delivered concurrent with the RT course. Subsequent adjuvant chemotherapy using a combination of cisplatin 80 mg/m2 intravenously and 5-fluorouracil 1000 mg/m2/day by 96-h infusion was given every 3 weeks for a total of three cycles, beginning 3 weeks after completion of CCRT.

      Radiation therapy

      Patients were stratified by RT technique (3-dimensional conformal RT [3D-CRT] vs. intensity-modulated RT [IMRT]). Delineation of gross tumor volume (GTV) and clinical target volume (CTV) was based on all available clinical and diagnostic image information. The GTV was designated to include all clinically evident gross disease and the CTV was designed to cover the clinically uninvolved adjacent soft tissues or lymphatics that were suspected to harbor subclinical micrometastasis. Radiation dose was prescribed to the planning target volume, which extended the CTV by a few millimeters to consider the neighboring structures. The typical radiation dose schedule when using 3D-CRT was to deliver 70 Gy to the GTV over 7 weeks by daily administration of 2 Gy (50–60 Gy to the CTV followed by 10–20 Gy boost to the GTV). When using IMRT, the dose schedule was not strictly unified among the participating institutes and planned to deliver biologically equivalent doses to those used in 3D-CRT: 66–68.4 Gy to the GTV by daily administration of 2.2–2.4 Gy and 50–60 Gy to the CTV by daily administration of 1.8–2.0 Gy over 6–7 weeks. During the RT course, all patients were examined weekly to assess treatment-related toxicities, which were recorded using the Radiation Therapy Oncology (RTOG) acute morbidity scoring criteria.

      Dose modification and discontinuation of chemotherapy

      If the nadir of absolute neutrophil count (ANC) was <1000/μL and/or that of platelets was <100,000/μL, chemotherapy was delayed for up to 2 weeks until the ANC and platelet counts recovered to greater than 1000/μL and 100,000/μL respectively. For renal toxicities, if serum creatinine was between 1.5 and 2.0 times the upper normal limit (UNL) and calculated creatinine clearance rate (Ccr) was <60 mL/min, the cisplatin dosage was reduced to 50% for the next cycle. If serum creatinine was >2.0 × UNL or calculated Ccr was <45 mL/min, no further cisplatin was given.
      Chemotherapy treatment was discontinued for the following reasons: disease progression, serious adverse events requiring other rescue therapies, delay of longer than 2 weeks for blood count recovery or renal toxicity, or at the request of the patient.

      Patient assessment and follow-up

      Clinical assessment following CCRT was scheduled 3 weeks after CCRT completion and included physical examination, blood tests, chest X-ray, and neck computed tomography (CT). Further clinical assessments were scheduled regularly at 3-month intervals for the first year and at 6-month intervals thereafter until disease progression and/or death. Treatment response was assessed according to Response Evaluation Criteria In Solid Tumor 1.1. All patients were asked to complete quality of life (QoL) questionnaires using the European Organization for Research and Treatment of Cancer (EORTC) Core Questionnaire Version 30 (EORTC QLQ-C30) [
      • Aaronson N.K.
      • 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.
      ] and the EORTC Head and Neck Cancer Module (EORTC QLQ-HN35) [
      • 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.
      ] at four time points: before the start of CCRT and at 3 weeks, 3 months, and 1 year after CCRT completion.

      Statistical analysis

      The primary endpoint of the current study was 3-year progression-free survival (PFS), defined as the time from the first date of CCRT until the date of first failure at any site or death from any cause. The secondary endpoints included OS, overall response rate (ORR), toxicity profile, and QoL changes. We compared the weekly regimen with the triweekly regimen by assessing whether the one-sided 80% confidence limit for the hazard ratio (HR) in PFS excluded a predefined margin of 1.5 for the HR [
      • Jung S.H.
      • Kang S.J.
      • McCall L.M.
      • Blumenstein B.
      Sample size computation for two-sample noninferiority log-rank test.
      ]. Predicated on the INT-0099 trial [
      • Al-Sarraf M.
      • LeBlanc M.
      • Giri P.G.
      • et al.
      Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized Intergroup study 0099.
      ], we expected a 3-year PFS of 75% with the triweekly regimen. For 80% power using a one-sided type I error of 20%, the test required at least 98 patients (49 patients per arm). All analyses were performed for the per-protocol population, excluding patients who withdrew before starting treatment. A χ2-test was used to assess the association of two categorical variables. Survival estimates were calculated according to the Kaplan–Meier method. Statistical analysis was performed using SAS 9.4 (SAS Institute Inc., Cary, NC) and R version 3.1.2 (Vienna, Austria; http://www.R-project.org/). A two-sided P-value <0.05 was considered statistically significant.

      Results

      Patient characteristics

      From September 2009 to December 2013, 111 eligible patients were enrolled from 19 Korean institutes. Two patients (one from each regimen) withdrew their consent before starting CCRT, and the remaining 109 patients (53 in the weekly regimen and 56 in the triweekly regimen) formed the per-protocol population (Fig. 1). The baseline characteristics of the patients were comparable between the regimens (Table 1). The median age of all patients was 53.6 years and 78.9% were male. The majority of the patients had stage III–IVb (77.1%) and WHO type 2 histology (71.6%) and 84.4% of the patients received IMRT.
      Table 1Baseline characteristics.
      CharacteristicsWeekly arm (n= 53)Triweekly arm (n=56)Total (n= 109)p
      No.%No.%No.%
      Age, years
       Median (range)53.6 (18.7–73.9)52.7 (19.2–77.7)52.6 (18.7–77.7)0.848
      Sex
       Male3973.64783.98678.90.186
       Female1426.4916.12321.1
      ECOG PS
       0611.347.1109.20.214
       14788.75089.39789.0
       20023.621.8
      T stage (1997 AJCC)
       T1–T22852.82646.45449.50.568
       T3–T42547.23053.65550.5
      N stage (1997 AJCC)
       N0–N12954.72850.05752.30.689
       N2–N32445.32850.05247.7
      Stage (1997 AJCC)
       II1528.31017.92522.90.435
       III2445.33257.15651.4
       IVa–IVb1426.41425.02825.7
      Histology
       WHO type 1713.21017.91715.60.407
       WHO type 23769.84173.27871.6
       WHO type 3917.058.91412.8
      RT parameter
       3D-CRT815.1916.11715.60.888
       IMRT4584.94783.99284.4
      Abbreviations: ECOG PS, Eastern Cooperative Oncology Group performance status; RT, radiotherapy; 3D-CRT, 3-dimensional conformal RT; IMRT, intensity-modulated radiation therapy.

      Treatment and compliance

      Table 2 shows the dose intensity and compliance in each regimen. The mean total dose of cisplatin and RT given were similar between the weekly and triweekly regimens (cisplatin, 248.9 mg/m2 vs. 256.6 mg/m2, p=0.433; RT, 68.3 Gy vs. 67.3 Gy, p=0.559). During CCRT, 31 patients (58.5%) completed the planned seven cycles of chemotherapy in the weekly regimen and 37 patients (66.1%) completed the planned three cycles of cisplatin in the triweekly regimen (p= 0.414). Thirteen patients (11.9%) could not complete CCRT and dropped out of the study due to toxicity and/or patient refusal: seven in the weekly regimen (13.2%) vs. six in the triweekly regimen (10.7%) (Fig. 1).
      Table 2Treatment and response.
      Weekly arm (n= 53)Triweekly arm (n= 56)p
      No.%No.%
      Total dose given during CCRT
       Cisplatin, mg/m2
        Mean (SD)248.9 (46.5)256.6 (56.0)0.433
       Radiotherapy, Gy
        Mean (SD)68.3 (8.1)67.3 (10.0)0.559
      Intended cycles completed during CCRT
       Yes3158.53766.10.414
       No2241.51933.9
      Dosage alterations
       Dose reduction11.935.40.619
       Dose delay1018.91832.10.113
       Dose omission2750.92239.30.221
      Subsequent systemic adjuvant chemotherapy
       Yes2445.31628.60.070
       No2954.74071.4
      Reason skip adjuvant chemotherapy
      Out of 69 patients who did not received adjuvant chemotherapy, 54 patients were able to further analysis.
       Poor performance status730.41651.60.434
       Refusal1252.21548.4
       Other417.400
      Tumor control after completion of CCRT
      Of a total 109 patients, 104 patients were evaluable for tumor response.
       Complete response1126.61120.71.000
       Partial response3976.54075.5
       Stable disease11.923.8
      Abbreviations: CCRT, concurrent chemoradiation; SD, standard deviation.
      low asterisk Out of 69 patients who did not received adjuvant chemotherapy, 54 patients were able to further analysis.
      Of a total 109 patients, 104 patients were evaluable for tumor response.
      Adjuvant chemotherapy following CCRT was not delivered in 69 patients: 29 patients in the weekly regimen and 40 in the triweekly regimen (54.7% vs. 71.4%, p= 0.070). The main reason was poor performance status following CCRT in the triweekly regimen and refusal in the weekly regimen; however, this difference was not statistically significant (p= 0.434).

      Efficacy

      Response to the treatment protocol at 3 weeks after completion of CCRT could not be evaluated for five patients. The ORR was 98.1% with the weekly regimen and 96.2% with the triweekly regimen; complete response rates were 21.6% and 20.7%, respectively. The median follow-up was 30.0 months (range, 0.3–55.5). By February 6 2015, 29 patients (26.6%) had developed relapse (16 [30.2%] in weekly and 13 [23.2%] in triweekly regimen) and 14 patients (12.8%) had died (seven [13.2%] in weekly and seven [12.5%] in triweekly regimen). The 3-year PFS rate, which is the primary endpoint of the current study, was not inferior with the weekly regimen compared to the triweekly regimen (64.9% vs. 63.8%; HR 0.912, 95% CI, 0.68–1.22, p= 0.074) (Fig. 2A). The major failure pattern was local relapse in the triweekly regimen and distant metastasis in the weekly regimen; however, this difference was not statistically significant (Supplementary Table 1). The 3-year OS rates were 90.8% for weekly vs. 91.0% for triweekly regimen (HR 0.935, 95% CI, 0.33–2.67, p=0.900) (Fig. 2B).
      Figure thumbnail gr2
      Fig. 2Kaplan–Meier curves for progression-free survival (A) and overall survival (B) according to treatment regimen.
      Subset analyses for RT technique (IMRT vs. 3D-CRT) showed that a significantly better 3-year PFS rate was achieved with IMRT than with 3D-CRT (69.3% vs. 41.8%, p= 0.027) (Supplementary Table 2). The addition of adjuvant chemotherapy was not a significant determinant with respect to survival outcome (p=0.910 for PFS, p= 0.993 for OS). Subgroup analyses were consistent with those of the overall study population (Supplementary Fig. 1).

      Toxicity

      Toxicities after completion of CCRT that occurred in ⩾10% of patients in either arm are listed in Table 3. There was no incidence of treatment-related mortality, and the most frequent toxicities were anemia, neutropenia, thrombocytopenia, stomatitis, nausea, and vomiting. Grade 3–4 toxic events of any type were observed in 25 patients (47.2%) in the weekly and 22 patients (39.3%) in the triweekly regimen (p=0.443). In terms of grade 3–4 hematologic toxicity, neutropenia and thrombocytopenia were more common with the weekly regimen, whereas anemia was more frequent with the triweekly regimen. Grade 3–4 nephrotoxicity was not observed in either regimen. Two patients (one in each regimen) developed hearing loss following CCRT.
      Table 3Adverse events.
      ToxicityWeekly arm (n= 53)Triweekly arm (n= 56)p
      Hematologic
      Anemia, n (%)
       <G352 (98.1)51 (91.1)0.207
       ⩾G31 (1.9)5 (8.9)
      Neutropenia, n (%)
       <G338 (71.7)47 (83.9)0.124
       ⩾G315 (28.3)9 (16.1)
      Thrombocytopenia, n (%)
       <G349 (82.5)55 (98.2)0.198
       ⩾G34 (7.5)1 (1.8)
      Non-hematologic
      Nausea/vomiting, n (%)
       <G349 (92.5)50 (89.3)0.743
       ⩾G34 (7.5)6 (10.7)
      Stomatitis, n (%)
       <G345 (84.9)49 (87.5)0.694
       ⩾G38 (15.1)7 (12.5)
      Rash, n (%)
       <G353 (100)55 (98.2)1.000
       ⩾G301 (1.8)
      Neuropathy
      There was no grade 2–4 toxicities in two groups.
      , n (%)
       G051 (96.5)52 (92.9)0.679
       G12 (3.8)4 (7.1)
      Abbreviation: G, grade.
      There was no grade 2–4 toxicities in two groups.

      Quality of life

      Baseline symptom score questionnaires were collected from all 109 patients. Overall, compliance of QoL assessment declined over the course of the study in both groups. The compliance rate of QoL assessment between the weekly and triweekly regimens was different at each time point: 83.0% and 67.9% at 3 weeks (p= 0.067); 67.9% and 60.7% at 3 months (p= 0.433); 58.5% and 37.5% at 1 year (p= 0.028). Overall, QoL decreased 3 weeks after completing CCRT and gradually improved thereafter for both regimens. According to the EORTC QLQ-C30 at 3 weeks after CCRT, patients on the weekly regimen showed better physical (p= 0.039), emotional (p= 0.019), and social functioning (p= 0.008) than those on the triweekly regimen (Fig. 3A). Patients on the triweekly regimen reported more appetite loss than those on the weekly regimen (p= 0.006) (Fig. 3A). EORTC-QLQ-HN35 scoring at 3 weeks after CCRT revealed that patients on the triweekly regimen had more problems with speech (p= 0.003), social contact (p= 0.043), and sticky saliva (p= 0.019) than those on the weekly regimen (Fig. 3B). There were no significant differences in QoL parameters compared to the baseline scores at other time points (3 months and 1 year after CCRT) except for dry mouth at 3 months and social functioning at 1 year after CCRT (Supplementary Table 3 and Supplementary Fig. 2).
      Figure thumbnail gr3
      Fig. 3Time trend for responses to EORTC QLQ-C30 (A) and EORTC-QLQ-HN35 (B) questionnaires according to treatment regimen.

      Discussion

      The mainstay of treatment for locally advanced NPC is cisplatin-based CCRT. Although several randomized studies have been conducted in patients with locally advanced NPC, the optimal CCRT regimen with regard to efficacy and safety remains to be determined. To our knowledge, this is the first randomized trial to evaluate the efficacy, toxicity, and tolerability of weekly administration of cisplatin (40 mg/m2) compared with triweekly administration of cisplatin (100 mg/m2) under a CCRT setting in the treatment of locally advanced NPC.
      The current study confirmed that the primary endpoint of 3-year PFS with the weekly cisplatin regimen was not inferior to that with the triweekly cisplatin regimen (HR 0.912). The 3-year PFS rate achieved with the weekly regimen (64.9%) was comparable to that with the triweekly regimen (63.8%), which in turn was comparable to previous reports [
      • Lee A.W.
      • Lau W.H.
      • Tung S.Y.
      • et al.
      Preliminary results of a randomized study on therapeutic gain by concurrent chemotherapy for regionally-advanced nasopharyngeal carcinoma: NPC-9901 Trial by the Hong Kong Nasopharyngeal Cancer Study Group.
      ,
      • Kwong D.L.
      • Sham J.S.
      • Au G.K.
      • et al.
      Concurrent and adjuvant chemotherapy for nasopharyngeal carcinoma: a factorial study.
      ,
      • Lee A.W.
      • Tung S.Y.
      • Chan A.T.
      • et al.
      Preliminary results of a randomized study (NPC-9902 Trial) on therapeutic gain by concurrent chemotherapy and/or accelerated fractionation for locally advanced nasopharyngeal carcinoma.
      ]. At 3 weeks after completion of CCRT, the ORR was similar between the two arms (98.1% vs. 96.2%). As in previous reports [
      • Pow E.H.
      • Kwong D.L.
      • McMillan A.S.
      • et al.
      Xerostomia and quality of life after intensity-modulated radiotherapy vs. conventional radiotherapy for early-stage nasopharyngeal carcinoma: initial report on a randomized controlled clinical trial.
      ,
      • Wolden S.L.
      • Chen W.C.
      • Pfister D.G.
      • Kraus D.H.
      • Berry S.L.
      • Zelefsky M.J.
      Intensity-modulated radiation therapy (IMRT) for nasopharynx cancer: update of the Memorial Sloan-Kettering experience.
      ], the current study showed better PFS with the IMRT technique than with the 3D-CRT technique; however, subset analysis according to RT technique demonstrated no difference between weekly and triweekly regimens.
      In the current study, more than 85% of the planned cisplatin dose was administered during the RT course for both regimens. This high compliance rate in both regimens could in part be explained by the high rate of IMRT adoption (greater than 85%) as CCRT using the IMRT technique is known to be associated with improved toxicity profiles and QoL [
      • Wolden S.L.
      • Chen W.C.
      • Pfister D.G.
      • Kraus D.H.
      • Berry S.L.
      • Zelefsky M.J.
      Intensity-modulated radiation therapy (IMRT) for nasopharynx cancer: update of the Memorial Sloan-Kettering experience.
      ,
      • Wu V.W.
      • Kwong D.L.
      • Sham J.S.
      Target dose conformity in 3-dimensional conformal radiotherapy and intensity modulated radiotherapy.
      ,
      • Lee N.
      • Xia P.
      • Quivey J.M.
      • et al.
      Intensity-modulated radiotherapy in the treatment of nasopharyngeal carcinoma: an update of the UCSF experience.
      ]. When we compared the compliance of CCRT between weekly and triweekly regimens, the mean cisplatin dose was not significantly different between the two groups (248.9 mg/m2 vs. 256.6 mg/m2), consistent with the study by Ho et al. [
      • Ho K.F.
      • Swindell R.
      • Brammer C.V.
      Dose intensity comparison between weekly and 3-weekly Cisplatin delivered concurrently with radical radiotherapy for head and neck cancer: a retrospective comparison from New Cross Hospital, Wolverhampton, UK.
      ]. Almost two-thirds of the patients in the current study did not receive adjuvant chemotherapy following CCRT completion, and this proportion was higher with the triweekly regimen. Whether the addition of adjuvant chemotherapy provides additional survival benefit over CCRT alone in NPC remains controversial [
      • Baujat B.
      • Audry H.
      • Bourhis J.
      • et al.
      Chemotherapy in locally advanced nasopharyngeal carcinoma: an individual patient data meta-analysis of eight randomized trials and 1753 patients.
      ,
      • Langendijk J.A.
      • Leemans C.R.
      • Buter J.
      • Berkhof J.
      • Slotman B.J.
      The additional value of chemotherapy to radiotherapy in locally advanced nasopharyngeal carcinoma: a meta-analysis of the published literature.
      ,
      • Chen L.
      • Hu C.S.
      • Chen X.Z.
      • et al.
      Concurrent chemoradiotherapy plus adjuvant chemotherapy versus concurrent chemoradiotherapy alone in patients with locoregionally advanced nasopharyngeal carcinoma: a phase 3 multicentre randomised controlled trial.
      ]. In the current study, the overall clinical outcome of patients who did not receive adjuvant chemotherapy was comparable to that of those treated with adjuvant chemotherapy, although this may reflect the high prevalence of favorable histologic types in our study population. It is interesting that poor performance status after CCRT was the main reason for omission of adjuvant chemotherapy in patients treated with the triweekly regimen. It appears that cisplatin-based CCRT is less tolerable in a triweekly regimen than in a weekly regimen.
      The concept of a once-weekly regimen is based on the hypothesis that smaller cisplatin doses administered more frequently will produce a better toxicity profile while maintaining efficacy. It is notable that the incidence of grade 3–4 toxic events of any type was not decreased in the patients on the weekly regimen, similar to findings of the study by Ho et al. [
      • Ho K.F.
      • Swindell R.
      • Brammer C.V.
      Dose intensity comparison between weekly and 3-weekly Cisplatin delivered concurrently with radical radiotherapy for head and neck cancer: a retrospective comparison from New Cross Hospital, Wolverhampton, UK.
      ]. Uygun et al. demonstrated that grade 3–4 toxic events were observed more often with a triweekly regimen (53.3%) compared with a weekly regimen (40%), but this difference was not significant [
      • Uygun K.
      • Bilici A.
      • Karagol H.
      • et al.
      The comparison of weekly and three-weekly cisplatin chemotherapy concurrent with radiotherapy in patients with previously untreated inoperable non-metastatic squamous cell carcinoma of the head and neck.
      ]. In contrast, Geeta et al. [
      • Geeta S.N.
      • Padmanabhan T.K.
      • Samuel J.
      • Pavithran K.
      • Iyer S.
      • Kuriakose M.A.
      Comparison of acute toxicities of two chemotherapy schedules for head and neck cancers.
      ] and Tsan et al. [
      • Tsan D.L.
      • Lin C.Y.
      • Kang C.J.
      • et al.
      The comparison between weekly and three-weekly cisplatin delivered concurrently with radiotherapy for patients with postoperative high-risk squamous cell carcinoma of the oral cavity.
      ] found that a once-weekly cisplatin regimen had a higher rate of severe mucositis. In the current study, per protocol toxicity assessment was once a week, but assessment every 3 weeks was allowed according to the investigator’s decision. The proportion of patients who were evaluated four or more times for toxicity assessment was significantly higher among the patients on the weekly regimen compared with the triweekly regimen (56.6% vs. 7.1%, p<0.001). This finding might represent an undefined bias regarding toxicity profiles.
      To the best of our knowledge, this is the first study that evaluates QoL prospectively using EORTC QLQ-C30 and QLQ-H&N35 using a longitudinal design in randomly assigned patients with NPC. All patients completed the baseline QoL measurement, but low compliance was noted with follow-up assessments. It is noteworthy that the compliance rate of the QoL questionnaire was consistently higher in the weekly regimen arm across all time points. The results indicated an inverse relationship between QoL scores and the probability of dropout. At 3 weeks after CCRT completion a majority patients in each regimen reported temporary worsening of QoL; however, most scores returned to near baseline levels over the course of follow-up. Intriguingly, patients on the weekly regimen reported better physical, emotional, and social functioning and less worsening of symptom scales including appetite loss, speech problems, and sticky saliva. Recently, Tsan et al. [
      • Tsan D.L.
      • Lin C.Y.
      • Kang C.J.
      • et al.
      The comparison between weekly and three-weekly cisplatin delivered concurrently with radiotherapy for patients with postoperative high-risk squamous cell carcinoma of the oral cavity.
      ] demonstrated that the triweekly cisplatin regimen resulted in better physical well-being than the weekly regimen. These contradictory results might be attributed to differences in the study populations.
      This study has several limitations. Given the low incidence of locally advanced NPC in Korea, we chose a relatively large alpha value and a large hazard ratio to attain a reasonable sample size for this phase II trial, resulting in low statistical power. Unbalanced assessment of toxicity profiles between the two regimens is a potentially undefined bias regarding safety. Therefore, a large randomized phase III trial is warranted to confirm the safety and efficacy of the weekly regimen. Considering the favorable prognosis of NPC, further follow-up is needed to fully evaluate the long-term survival and late toxicities.
      Although not conclusive, our data indicate that once-weekly cisplatin combined with radiation for the treatment of locally advanced NPC has comparable efficacy and safety with improved QoL compared to a triweekly regimen.

      Conflicts of interest statement

      The authors declare no conflicts of interest.

      Acknowledgment

      This work was supported by the Korean Cancer Study Group ( KCSG-HN10-02 ).

      Appendix A. Supplementary data

      Figure thumbnail fx1
      Supplementary Fig. 1Subgroup analysis of overall survival.
      Figure thumbnail fx2
      Supplementary Fig. 2Time trend for the responses to (A) EORTC QLQ-C30 and (B) EORTC-QLQ-HN35 by treatment.

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