Gynecologic Oncology 137 (2015) 462–467

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A randomized trial comparing concurrent chemoradiotherapy with single-agent cisplatin versus cisplatin plus gemcitabine in patients with advanced cervical cancer: An Asian Gynecologic Oncology Group study☆ Chun-Chieh Wang a,f, Hung-Hsueh Chou b,f, Lan-Yan Yang c,d,f, Hao Lin e,f, Wen-Shiung Liou g, Chih-Wen Tseng h, Feng-Yuan Liu i,f, Jui-Der Liou b,f, Kuan-Gen Huang b,f, Huei-Jean Huang b,f, Eng-Yen Huang j, Chien-Hsun Chen k, Ting-Chang Chang b,f, Chee-Jen Chang d,l, Ji-Hong Hong a,f,⁎, Chyong-Huey Lai b,f,⁎⁎ a

Department of Radiation Oncology, Chang Gung Memorial Hospital at Linkou and Chang Gung University College of Medicine, Taoyuan, Taiwan Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital at Linkou and Chang Gung University College of Medicine, Taoyuan, Taiwan c Clinical Trial Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan d Data Management and Biostatistical Core, Asian Gynecologic Oncology Group, Taiwan e Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan f Gynecologic Cancer Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan g Department of Obstetrics and Gynecology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan h Department of Obstetrics and Gynecology, Chiayi Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Chiayi, Taiwan i Department of Nuclear Medicine, Chang Gung Memorial Hospital at Linkou and Chang Gung University College of Medicine, Taoyuan, Taiwan j Department of Radiation Oncology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan k Department of Radiation Oncology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan l Research Center of Clinical Informatics and Medical Statistics, Chang Gung University, Taoyuan, Taiwan b

H I G H L I G H T S • An Asian GOG trial was conducted to determine whether only adding gemcitabine to cisplatin in CCRT can improve outcome. • Only adding gemcitabine at the CCRT phase does not provide substantially superior results, but toxicities could increase. • Further studies are required to determine the role of post-CCRT adjuvant chemotherapy in advanced cervical cancer.

a r t i c l e

i n f o

Article history: Received 30 January 2015 Accepted 22 March 2015 Available online 28 March 2015 Keywords: Cervical cancer Squamous cell carcinoma Chemoradiotherapy Cisplatin Gemcitabine

a b s t r a c t Objective. A recent randomized trial demonstrated that concurrent chemoradiotherapy (CCRT) with weekly cisplatin and gemcitabine, followed by two adjuvant cycles of cisplatin and gemcitabine improved survival for advanced cervical cancer patients. An Asian Gynecologic Oncology Group (AGOG) study was designed to determine whether only adding gemcitabine in the chemoradiation phase without adjuvant chemotherapy could improve survival. Methods. Between March 2009 and March 2013, 74 eligible patients with International Federation of Obstetrics and Gynecology stage III/IVA cervical cancer or stage I/II with positive pelvic/para-aortic nodal metastasis were enrolled. Thirty-seven patients were randomized to arm C (weekly cisplatin 40 mg/m2) and 37 patients were randomized to arm CG (weekly cisplatin 40 mg/m2 and gemcitabine 125 mg/m2), for six cycles. Six eligible patients were excluded before the beginning of treatment. Results. An interim analysis showed superimposable progression-free (PFS) and overall survival (OS), a decision of closing accrual was made. A 3-year PFS was similar in both arms (arm C 65.1% vs. arm CG 71.0%, p = 0.71), and a 3-year OS was 74.1% in arm C vs. 85.9% in arm CG (p = 0.89), but crossed over at 5 years. Grade 2–4 hematological toxicities, including neutropenia (p = 0.028) and thrombocytopenia (p = 0.001), were more frequent in arm CG than arm C.

☆ This trial is registered as NCT00842660 on https://clinicaltrials.gov/ct2/show/NCT00842660. ⁎ Correspondence to: J.-H. Hong, Department of Radiation Oncology, Chang Gung Memorial Hospital, 5 Fu-Shin St. Kueishan, Taoyuan 333, Taiwan. Tel.: +886 3 3282177; fax: +886 3 3280797. ⁎⁎ Correspondence to: C.-H. Lai, Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, 5 Fu-Shin St. Kueishan, Taoyuan 333, Taiwan. Tel.: +886 3 328 1200x8254; fax: +886 3 328 8252. E-mail addresses: [email protected] (J.-H. Hong), [email protected] (C.-H. Lai).

http://dx.doi.org/10.1016/j.ygyno.2015.03.046 0090-8258/© 2015 Elsevier Inc. All rights reserved.

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Conclusions. Despite limitation in power, it suggests that only adding gemcitabine at the CCRT phase does not provide substantially superior results, but treatment toxicities could increase. Further studies are required to determine the role of post-CCRT adjuvant chemotherapy in advanced cervical cancer. © 2015 Elsevier Inc. All rights reserved.

Introduction

Patients and methods

Cervical cancer is the third most common cancer and the fourth leading cause of cancer mortality among women worldwide [1]. Since 1999, several randomized trials have shown that patients with cervical cancer when treated concurrently with cisplatinbased chemotherapy and radiotherapy (CCRT) had a significant survival advantage when compared with those treated with radiotherapy alone [2]. The magnitude of the observed survival benefits quickly made CCRT the standard-of-care in patients with cervical cancer. While these studies differed in regimens (e.g. single cisplatin or cisplatin plus 5-fluorouracil), there was no suggestion that the combination cisplatin-based chemotherapy programs were superior to simpler and less toxic single-agent cisplatin [3]. From the available data, it is reasonable to conclude that single-agent cisplatin in combination with radiation would be the preferred treatment. However, patients with advanced cervical cancer treated with concurrent CCRT still have 20–30% chance of local failure [4,5] and 18–25% of distant failure [5,6]. How to improve the control of both locoregional and distant sites is still an important issue for the treatment of advanced cervical cancer. Gemcitabine (2′,2′-difluorodeoxycytidine) is a nucleoside analog which replaces deoxycytidine during DNA replication and inhibits the activity of ribonucleotide reductase [7]. In addition to its established uses in pancreatic and non-small cell lung cancer, this drug has been shown in clinical trials to be active against a wide variety of solid tumors [8]. As a single agent, gemcitabine has little activity as first- or second-line therapy for cervical cancer [9]. However, when gemcitabine is combined with cisplatin, the combination achieves 75% partial or complete response rates in patients with metastatic cervical cancer [10]. Since gemcitabine is also a potent radiosensitizer [7], several studies have been undertaken to clarify the use of cisplatin and gemcitabine in combination with radiotherapy for patients with cervical cancer. For example, in a phase II trial for 23 patients with stage IIA through IIIB cervical cancer, Umanzor et al. reported a 90% complete response rate and 80% 2-year disease-free survival when using standard radiotherapy with weekly cisplatin 40 mg/m2 and gemcitabine 125 mg/m2 [11]. Toxicity was moderate: only one patient developed grade 3 neutropenia and there were no grade 4 hematological toxicities. A recent randomized phase III trial by Dueñas-González et al. showed improved survival for the treatment of stage IIB–IVA cervical cancer by the addition of weekly concurrent gemcitabine and 2 cycles of adjuvant gemcitabine and cisplatin to standard singleagent CCRT [12]. The 3-year progression-free survival (PFS) rates were significantly improved from 65% in the standard chemoradiotherapy arm to 74.4% in the cisplatin and gemcitabine arm. This is the first phase III trial showing advancement in the treatment of locally advanced cervix cancer in the past decade. However, it remains uncertain to what extent the survival benefit observed is attributable to the addition of gemcitabine in the chemoradiation phase or of an adjuvant chemotherapy phase. An Asian Gynecologic Oncology Group (AGOG) study was designed to determine whether the addition of gemcitabine in the chemoradiation phase, without the adjuvant chemotherapy, can improve survival in locally advanced cervical cancer, two years before the Dueñas-González's trial results were known.

Eligibility criteria The study was approved by the Institutional Review Board of the participating hospitals and abided with the ethical standards of the Helsinki Declaration on good clinical practice. All patients signed informed consent. Eligibility criteria for this AGOG 09-001 trial were as listed on the ClinicalTrials.gov with an Identifier: NCT00842660. Eligible patients were between 35 and 70 years old with a new pathological diagnosis of cervical cancer with squamous cell carcinoma. They were International Federation of Obstetrics and Gynecology (FIGO) stage III–IVA or any stage with 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) defined positive pelvic or para-aortic lymph node (PALN). Eligibility required a ECOG performance status 0 or 1, and documentation of adequate bone marrow function (WBC N 3000/mm3, platelet N 100,000/mm3), liver function (serum transaminases (GOT, GPT) b 60 IU/mL, total bilirubin b 1.5 mg%), and renal function (creatinine b 1.4 mg%, creatinine clearance N 60 mL/min). Exclusion criteria included: other histology types (adenocarcinoma, adenosquamous carcinoma, small cell carcinoma), prior pelvic radiation, prior systemic chemotherapy, or evidence of distant metastasis other than PALN. Study design This study was an open-label phase III randomized clinical trial of radiotherapy with cisplatin and gemcitabine compared with radiotherapy with single-agent cisplatin in patients with advanced cervical squamous carcinoma. The primary outcome measures were the overall survival (OS) and PFS at 3 years. The secondary outcome measures included acute toxicities and sites of recurrence. According to a previous study from our hospital, a 3-year PFS was approximately 50% for stage III/IV squamous carcinoma of the cervix or maximum standardized uptake value (SUVmax) at PALN ≥ 3.3 by FDG-PET scan [13]. Assuming that the 3-year PFS of arm CG and arm C was 70% and 50%, 154 patients were required to achieving an 80% power at 5% significance level for a two-sided test. Allowing for 10% ineligible or lack-of-data cases, the study initially planned to enroll 172 patients when recruitment began in March 2009. Surveillance and treatment schedule The pretreatment workup, including pelvic and abdominal MRI and FDG-PET, and radiation treatment, was similar to our previous report [14]. Positive lymphadenopathy was determined by FDG-PET even if there was a nodal size of ≥1 cm at its maximal dimension in MRI. For radiotherapy, patients were treated with external-beam radiotherapy initially, delivered with a daily fraction 1.8 Gy in five fractions weekly. Large-field radiation doses to the whole pelvis were 45 Gy via a fourfield box technique. When the involvement of common iliac or PALN was suspected from imaging studies, irradiation fields were extended to the abdominal para-aortic region. For patients with lower vaginal tumor extension, bladder or rectal invasion, or persistent bulky tumor after 45 Gy RT, who were not undergoing brachytherapy, the primary tumor was treated with total doses of 68–72 Gy. Intensity-modulated

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radiotherapy was allowed for patients treated with para-aortic irradiation or without brachytherapy. Patients undergoing brachytherapy with six fractions of 4.3 Gy to point A received a parametrial boost dose (5.4–12.6 Gy) by parallel-opposed anterior–posterior fields with a 4-cm-wide midline block. The gross nodal lesions outside the parametrial boost field were treated to a total dose of 54–57.6 Gy. The chemotherapy protocol included six cycles of weekly intravenous infusions, for arm C (cisplatin 40 mg/m2 alone) and for arm CG (cisplatin 40 mg/m2 and gemcitabine 125 mg/m2), during the radiotherapy course. For arm CG, cisplatin was administered over 60 min, immediately followed by gemcitabine infused over 30 min. Chemotherapy was initiated during the first week of radiotherapy and then was given every 7 days thereafter for 6 weeks. Chemotherapy was withheld when the granulocyte count was b1500/mL or the platelet count was b 100,000/mL, and restarted after recovery. During treatment, all patients underwent weekly hematology and blood chemistry testing for safety and dose adjustment purposes. Safety was evaluated by recording clinical adverse events (AEs) using the National Cancer Institute Common Toxicity Criteria (version 3.0). Treatment response was evaluated by WHO criteria with physical examination and MRI at two months. The follow-up protocol was the same as that in our previous study [14,15]: MRI or CT imaging was performed every 6 months for 2 years or whenever relapse was suspected. Survival and disease status were monitored at least every 6 months until death or study end.

test was used to evaluate the associations between categorical variables. Survival curves were estimated using Kaplan–Meier method and comparisons were made using the log-rank test. Cox regression was used to estimate hazard ratios (HRs) and the related comparisons. A two-tailed p b 0.05 was considered statistically significant. All statistical analyses were performed using SAS version 9.2 software (SAS Institute, Inc., Cary, NC, USA). Results Between March 2009 and March 2013, 89 candidates, after MRI examination, were reviewed at a combined conference. Fifteen patients were excluded during screening, mainly because of additional findings by PET or poor renal/liver function. The study CONSORT diagram is presented in Fig. 1. Thirty-seven patients were randomized to arm C and the other 37 patients were randomized to arm CG. Six eligible patients were excluded before the beginning of treatment, five in arm C and one in arm CG. Three withdrew their consent. One foreign patient and one with schizophrenia were removed (physician decision) because they could not cooperate with the regular follow-up in our clinics. One patient who died of an accident before treatment was also excluded. Thirty-two patients in arm C and 36 patients in arm CG were included in the safety analysis. The follow-up phase lasted until December, 2014. Clinical characteristics were well balanced between these two arms (Table 1).

Statistical analysis Early closure of this study An interim safety analysis was performed after 27 evaluable patients on each arm had finished their treatment. Treatment-related significant adverse events were defined in the protocol (Supplementary data). A significant adverse-event rate of 55% or greater (14 of 27) was considered to be excessive. Efficacy analyses were based on intention-totreat population. PFS was calculated from the date of enrollment to the date of disease relapse (or death due to disease progression). OS was calculated from the date of enrollment to death for non-censored observations or censored at the date of last contact. The comparison of clinical characteristics between the two groups was based on a t test for continuous variables, and Pearson's chi-square test or Fisher exact

Accrual was closed early after 68 patients were enrolled, 39.5% of the expected sample size. The power analysis demonstrated that sample size of 32 in arm C and 36 in arm CG could only achieve 39% power to detect a difference between these two groups under the original assumption at a significance level of 0.05. Safety interim analysis when 27 evaluable subjects on each arm had completed treatment did not indicate early stopping (10 significant adverse events for CG arm and 7 for C arm). The original plan was a 4-year enrollment and a 3-year follow-up. The funding source, Chang Gung Memorial Hospital (CGMH), requested a survival analysis at 4 years in order to decide if

Fig. 1. CONSORT diagram of the study design. Arm C treatment consisted of cisplatin single-agent chemotherapy combined with radiotherapy. Arm CG treatment consisted of gemcitabine plus cisplatin chemoradiotherapy. LTFU: lost to follow-up.

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Table 1 Patient demographics and clinical characteristics. Characteristic

Arm Ca

All patients N = 74

Age (years) Median Range ECOG performance status 0 1 Hemoglobin level ≧10 b10 Differentiation Moderate Poor Unknown FIGO stage IB IIA IIB IIIB IVA Pelvic node Yes No Paraaortic node Yes No Largest diameter Mean Range a b

%

N = 37

% 53 38–69 0.790

55 19

74.3 25.7

28 9

75.7 24.3

27 10

73.0 27.0

51 17

75.0 25.0

24 10

70.6 29.4

27 7

79.4 20.6

27 33 1

44.3 54.1 1.6

14 15 1

46.7 50.0 3.3

13 18 0

41.9 58.1 0.0

7 2 31 31 2

9.6 2.7 42.5 42.5 2.7

5 1 17 13 1

13.5 2.7 45.9 35.1 2.7

2 1 14 18 1

5.6 2.8 38.9 50.0 2.8

59 15

79.7 20.3

28 9

75.7 24.3

31 6

83.8 16.2

0.386

16 58

21.6 78.4

9 28

24.3 75.7

7 30

18.9 81.1

0.572

0.401

0.698

0.669

0.440 5.61 1.1–10.6

5.44 1.1–10.6

5.78 3.3–10

Arm C: radiotherapy with cisplatin. Arm CG: radiotherapy with cisplatin and gemcitabine.

With a median follow-up of 46.1 months, 24 (35.3%) patients experienced treatment failure; six had failures confined to locoregional region and seven distant relapse alone, 11 patients had both, and none failed at PALN alone. Patterns of failure are summarized in Table 2. Of them, the median time to progression was 11.1 months (range, 2.8–

Table 2 Failure patterns. Arm Ca (n = 32)

Locoregional Para-aortic region alone Distant alonec Locoregional and distantd Total relapse

Arm CGb (n = 36)

No. of patients

%

No. of patients

%

4 0 2 6 12

12.5 0.0 6.3 18.7 37.5

2 0 5 5 12

5.6 0.0 13.9 13.9 33.3

p-Value

0.41 – 0.43 0.59 0.72

Arm C: radiotherapy with cisplatin. Arm CG: radiotherapy with cisplatin and gemcitabine. Site(s) of metastasis other than para-aortic lymph nodes or para-aortic node metastasis plus other distant site(s). d Locoregional recurrence plus any extrapelvic metastasis including para-aortic lymph nodes. c

p-Value

N = 37

56 39–69

Overall and progression-free survival

b

%

0.366 55.0 38–69

extending enrollment period was feasible. At that time, a 3-year PFS of arm C and arm CG was 60.3% and 62.9%, respectively (Supplementary Fig. 1). Based on our observed results in PFS, to achieve 80% power for detecting the 2.6% difference, the required sample size is over four thousand for each arm at a lower significance level of 0.1. DueñasGonzález's results showed only around 10% survival improvement with adding gemcitabine during CCRT and post-CCRT adjuvant chemotherapy. Slow recruitment, overly optimistic assumption of benefit and the unexpected low difference of this trial made continuing the trial unfavorable. The Research Review Committee of CGMH recommended ending the accrual in March 2013.

a

Arm CGb

62.6 months). There were 16 deaths, and none of them were from intercurrent disease. The 3-year OS estimates and the corresponding PFS estimates for the entire cohort were 79.9% (95% CI, 67.8–87.8%) and 68.3% (95% CI, 55.6–78.1%), respectively. OS at 3 years was 74.1% in arm C vs. 85.9% in arm CG (p = 0.89, Fig. 2A). PFS at 3 years was similar in both arms (arm C 65.1% vs. arm CG 71.0%, p = 0.71, Fig. 2B). Patients of arm CG did not benefit from gemcitabine compared to arm C (OS: HR 0.93, 95% CI = 0.35–2.49, p = 0.89; PFS: HR 0.86, 95% CI = 0.39–1.91, p = 0.71). Notably, both PFS and OS curves crossed over at 5 years, because three relapses (one on C arm, two on CG arm) and three deaths (all on CG arm) occurred after 3 years of enrollment. Metastatic disease, including PALN recurrence, was observed in 8 patients (25.0%) in arm C versus 10 (27.8%) in arm CG. Similarly, there was no significant difference between the two arms in locoregional control (p = 0.41). Treatment compliance and adverse effects During CCRT, the median number of gemcitabine and cisplatin doses in arm CG was five (range, three to six doses); the median number of cisplatin doses in arm C was six (range, one to six doses). Sixty-eight patients completed the planned radiotherapy course. The incidences and categories of the adverse events are listed in Table 3. Overall rates of grade 2–4/3–4 acute adverse events were 100%/66.7% for arm CG and 90.6%/50.0% for arm C, respectively. Grade 4 toxicities, including leukopenia and neutropenia, were infrequent. There was a statistically significant increase in grade 2 to 4 neutropenia (p = 0.028) and thrombocytopenia (p = 0.001) in arm CG. Discussion Despite theoretical advantages of adding gemcitabine to CCRT, this trial did not demonstrate the superiority of multi-agent compared with single-agent CCRT for patients with locallyadvanced cervical cancer. The OS and PFS rates were similar in both arms (OS: HR 0.93, 95% CI = 0.35–2.49, p = 0.89; PFS: HR 0.86,

0 0 0 0 0 0 0 1 0 0 0 0 0 0.0 2.8 5.6 16.7 0.0 47.2 5.6 25.0 0.0 0.0 16.7 2.8 2.8 0 1 2 6 0 17 2 9 0 0 6 1 1 0.0 69.4 2.8 38.9 11.1 47.2 25.0 33.3 0.0 2.8 38.9 25.0 22.2 0 25 1 14 4 17 9 12 0 1 14 9 8 2.8 27.8 50.0 36.1 66.7 5.6 44.4 16.7 27.8 13.9 38.9 36.1 38.9 1 10 18 13 24 2 16 6 10 5 14 13 14 97.2 0.0 41.7 8.3 22.2 0.0 25.0 22.2 72.2 83.3 5.6 36.1 36.1 35 0 15 3 8 0 9 8 26 30 2 13 13 0.0 0.0 0.0 0.0 0.0 3.1 0.0 6.3 0.0 0.0 0.0 0.0 0.0 0 0 0 0 0 1 0 2 0 0 0 0 0 0.0 9.4 0.0 9.4 0.0 31.3 0.0 9.4 3.1 0.0 6.3 0.0 0.0 0 3 0 3 0 10 0 3 1 0 2 0 0 0.0 46.9 6.3 37.5 6.3 43.8 6.3 18.8 3.1 0.0 9.4 15.6 9.4 0 15 2 12 2 14 2 6 1 0 3 5 3 b

a

Arm C: radiotherapy with cisplatin. Arm CG: radiotherapy with cisplatin and gemcitabine.

0.0 34.4 46.9 31.3 62.5 15.6 71.9 28.1 21.9 3.1 62.5 25.0 31.3 0 11 15 10 20 5 23 9 7 1 20 8 10 100.0 9.4 46.9 21.9 31.3 6.3 21.9 37.5 71.9 96.9 21.9 59.4 59.4 32 3 15 7 10 2 7 12 23 31 7 19 19 Alopecia Anemia Anorexia Diarrhea Fatigue Leukopenia Nausea Neutropenia Skin Stomatitis Thrombocytopenia Vomiting Weight loss

No. of patients % No. of patients %

%

No. of patients

%

Grade 3 Grade 2 Toxicity

Table 3 Acute toxicities during treatment.

95% CI = 0.39–1.91, p = 0.71). The combination regimen was tolerable, but the addition of gemcitabine increased grade 2–4 hematological toxicities, including neutropenia and thrombocytopenia. The combination of gemcitabine and cisplatin has shown a synergic interaction in several studies, although the mechanism remains unclear [16]. In a phase I–II study, Zarba et al. recommended a dose of gemcitabine at 125 mg/m2 plus cisplatin 40 mg/m2 weekly and external radiotherapy for locally advanced cervical cancer [17]. For the 36 patients treated with this regimen, the complete response rate was 88.8% and the 3-year PFS and OS were 67% and 72%, respectively. With the same regimen, another phase II trial showed a 90% complete response rate and an 80% 2-year disease-free survival [11]. These formed the basis for the prospective phase III trial comparing standard CCRT and gemcitabine CCRT followed by adjuvant gemcitabine and cisplatin [12]. Dueñas-González's trial was the first to demonstrate a statistically significant survival advantage for combination chemotherapy in patients with advanced cervical cancer the cisplatin/gemcitabine regimen (OS: HR 0.68, 95% CI 0.49 to 0.95, p = 0.0224). The distant failure rate was improved in the study arm (8.1% vs. 16.4%, p = 0.005), while the difference in local failure rate was not significant (11.2% vs. 16.4%, p = 0.097). However, the failure patterns were similar in both arms in our study. This suggests that the reduction of recurrence may be contributed mainly by the adjuvant chemotherapy. A meta-analysis has found significant improvements in PFS (HR 0.61, p b 0.0001) and the absolute benefit in PFS and OS was 16% and 12%, respectively. Besides, both local (odds ratio 0.61, p b 0.0001) and distant relapses (odds ratio 0.57, p b 0.0001) were

No. of patients

Grade 4

%

No. of patients

% No. of patients No. of patients

No. of patients

%

No. of patients

%

No. of patients

%

Grade 4 Grade 3 Grade 2 Grade 0 Grade 1 Grade 0

Grade 1 Arm CGb (n = 36) Arm Ca (n = 32)

Fig. 2. Kaplan–Meier analysis of (A) overall survival and (B) progression-free survival for patients who were randomized to arm C or arm CG. Arm C treatment consisted of cisplatin single-agent chemotherapy combined with radiotherapy. Arm CG treatment consisted of gemcitabine plus cisplatin chemoradiotherapy.

0.0 0.0 0.0 0.0 0.0 0.0 0.0 2.8 0.0 0.0 0.0 0.0 0.0

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%

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benefited when concurrent chemotherapy was added to radiation [18]. The Radiation Therapy Oncology Group (RTOG) 90-01 trial observed an 8-year OS of 67% with CCRT (3-weekly cisplatin and 5-fluorouracil) and two additional cycles after CCRT in patients with stage I/II with pelvic node metastasis or stage III/IV cervical cancer without PALN metastasis, while an 8-year OS rate was 41% with extended-field radiotherapy [6]. A matched-case comparison to compare the efficacy and toxicity of consolidation chemotherapy of 3 additional cycles of cisplatin 60 mg/m2 (D1) and 5-fluorouracil 1000 mg/m2/day (D1–5) significantly improved OS than those without (92.7% versus 69.9%, p = 0.042) [19]. Our study implies that adjuvant chemotherapy could be important to further improving outcome. An ongoing trial phase III trial (OUTBACK), which randomizes patients to receive 4 cycles of 3-weekly adjuvant chemotherapy with carboplatin and paclitaxel or not after cisplatin single-agent CCRT, may answer this important clinical question. Whether a second antitumor agent can enhance the clinical utility of standard CCRT in the management of cervical cancer is still undetermined. A recent phase III trial has revealed that the addition of tirapazamine, a hypoxia-selective antitumor agent, to cisplatin when administered concurrently with radiation failed to improve the 3-year OS and PFS in patients with bulky cervical cancer [20]. While adding other novel agents, such as bevacizumab, cetuximab, or lapatinib, may improve treatment outcome, there is also concern for increased toxicities, especially when administered concurrently with radiation. In our study, adding low dose gemcitabine following cisplatin weekly during CCRT phase resulted in higher rates of acute grade 2–4 complications but tolerable overall. Unacceptable toxicities, as in previous phase I studies where gemcitabine preceded cisplatin during CCRT [21,22], were not seen in our study. Nevertheless, such low-dose gemcitabine (125 mg/m2) contribution to systemic effects may be compromised. The Dueñas-González's study also showed that the cisplatin/ gemcitabine arm had a higher rate of acute grade 3–4 toxicities (86.5% vs. 46.3%) than the cisplatin arm. Most of the toxicities and discontinuations caused by adverse events occurred during the CCRT phase [12], suggesting that other agents to be add-on to cisplatin during CCRT phase could be explored in order to provide better systemic control at a tolerable dose. Limited by the low accrual rate, the power of the study was approximately 40%. An assumption of absolute improvement of a 3-year PFS of 20% seemed to be overly optimistic. However, the two survival curves in arm C and arm CG almost overlap with a relatively high p-value of the log-rank test. We could not envision how a significant difference of survival in two treatment arms could occur even if the enrollment achieved the proposed number. In conclusion, this study suggests that CCRT with cisplatin and gemcitabine does not provide substantially superior results to singleagent cisplatin CCRT in patients with advanced squamous cell carcinoma of the cervix. CCRT is a major step forward in optimizing therapy of locally advanced cervical cancer. Adjuvant treatment following CCRT seems to be the next step. The hope of improvement in outcome for patients with advanced cervical cancer lies in discovery of novel combinations during CCRT phase and adjuvant therapy post-CCRT. Grant supports This study was supported by grants from the Chang Gung Medical Foundation (CMRPG380471, CMRPG380671 and OMRPG3A0011) and the Ministry of Health and Welfare — Taiwan (DOH101-TD-B-111005, DOH102-TD-B-111-005 and DOHW103-TDU-B-212-113003). Role of funding source Chang Gung Medical Foundation, the Ministry of Health and Welfare — Taiwan or Eli Lilly and Company were not involved in the

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design of the study, collection, management, analysis or interpretation of the data, preparation, review or approval of the manuscript. Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.ygyno.2015.03.046. Conflict of interest statement We declared that none of the above will cause conflicts of interest.

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