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Concurrent weekly cisplatin versus triweekly cisplatin with radiotherapy for

locally advanced squamous cell carcinoma of the cervix: a retrospective analysis

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from a single institution

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Yoshino Kinjyoa, Yutaka Nagaia, Takafumi Toitab, Wataru Kudakaa, Takuro Arigab,

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Yuko Shimojia, Tadaharu Nakasonea, Yusuke Tairaa, Yoshihisa Arakakia, Tomoko

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Nakamotoa, Akihiko Wakayamaa, Takuma Ooyamaa, Hitoshi Maemotob, Joichi

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Heiannab, Yoichi Aokia. E
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Department of Obstetrics and Gynecology and bDepartment of Radiology, Graduate
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School of Medical Science, University of the Ryukyus, Okinawa, 903-0215, Japan

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Address for correspondence: Yoichi Aoki, Department of Obstetrics and Gynecology,

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Graduate School of Medical Science, University of the Ryukyus. 207 Uehara Nishihara,
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Okinawa 903-0215, Japan. Tel; +81-98-895-1177, Fax; +81-98-895-1426, E-mail;

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yoichi@med.u-ryukyu.ac.jp
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A running title: CCRT weekly vs. triweeky CDDP

Conflict of interest: We have no Conflict of Interest as to this article.

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Financial support: Financial support for this study was not provided.

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4 Abstract
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7 Objectives: To compare patients with cervical cancer who were primarily treated with

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11 concurrent chemoradiotherapy (CCRT) using 20 mg/m2 CCDP for 5 days every 3 weeks

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with weekly regimens of 40 mg/m2.

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18 Methods: We retrospectively analyzed 185 patients with Stage IB to IVA squamous cell

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21 carcinoma of the cervix who were treated with CCRT between 2005 and 2013 at our
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hospital. The CCRT regimen consisted of cisplatin at 20 mg/m2 for 5 days every
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28 3 weeks or 40 mg/m2 weekly, administered concomitantly with RT.
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32 Results: The median age was 50 years (range: 22–70 years) in the triweekly group, and
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35 50.5 years (range: 28–70 years) in the weekly group. The 5-year overall survival (OS)
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39 rate in the triweekly and weekly groups were 82.0% and 83.3%, respectively (p = 0.890
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42 0.851); their disease-free survival (DFS) rate were 79.6% and 78.1%, respectively (p =
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46 0.672). In the triweekly group, 56 patients (50.9%) had grade 3/4 leukopenia, which
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was significantly higher than that of 11 patients (15%) in the weekly group (p <0.0001).
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53 Conclusions: The weekly CDDP regimen for CCRT seems better in patients with FIGO
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Stage IB—IVA squamous cell carcinoma of the cervix.
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Advances in knowledge: The weekly CDDP regimen for CCRT seems better in patients
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7 with FIGO Stage IB–IVA squamous cell carcinoma of the cervix.

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14 Keywords: cervical cancer, CCRT, weekly CDDP, triweekly CDDP, multivariate
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18 analysis.

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Abbreviations: CCRT; concurrent chemoradiotherapy, FIGO; the International
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28 Federation of Gynecology and Obstetrics, CDDP; cisplatin, HDR-ICBT; high-dose-rate
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32 intracavitary brachytherapy , RT; radiotherapy, WP-EBRT; whole-pelvic external beam

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35 radiotherapy, CTCAE; Common Terminology Criteria for Adverse Events, RTOG;
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39 Radiation Therapy Oncology Group, EORTC; European Organization for Research and
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42 Treatment of Cancer, OS; overall survival, DFS; disease-free survival, PFS;
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46 progression-free survival, GI; gastrointestinal.

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4 Introduction
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7 The National Cancer Institute released a clinical alert1 and reported higher

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11 survival rates after concurrent chemoradiotherapy (CCRT) for locally advanced cervical

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14 cancer at different stages from the International Federation of Gynecology and
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18 Obstetrics (FIGO) Stage IB1 with a relatively good prognosis to Stage IVA with poor

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21 prognosis. CCRT has proven effective in the definitive treatment of more
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advanced-stage diseases2–6. E
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28 Regarding a sensitizing agent for CCRT, cisplatin (CDDP) at a dose of
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32 40mg/m2 weekly is used globally as a standard regimen2–6. In Japan, a JGOG 1066

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35 Phase II trial of CCRT using a high-dose-rate intracavitary brachytherapy (HDR-ICBT)
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39 with CDDP at a dose of 40 mg/m2 weekly achieved equivalent outcomes to those by

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42 global radiotherapy (RT) dose schedules (cumulative linear quadratic equivalent dose,
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85 Gy), although with a lower incidence of late toxicity7. Although cisplatin-based
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CCRT for locally advanced cervical cancer is accepted as the standard treatment,
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53 optimal treatment plan is yet to be established.
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In the present study, we retrospectively analyzed data for patients with FIGO
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Stage IB–IVA carcinoma of the uterine cervix who were primarily treated with CCRT
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7 between 2005 and 2013 at our institution. CCRT using 20 mg/m2 CCDP for 5 days

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11 every 3 weeks8, 9
was a routine regimen until 2009. Thereafter, we changed the

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administration schedule of CDDP to weekly regimens of 40 mg/m2 according to the

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18 JGOG1066 protocol7. We analyzed the efficacy of CCRT for squamous cell carcinoma

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21 of the cervix in each of these eras. The present retrospective study with a small series of
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patients might provide useful information for future appropriate treatment strategies.
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32 Materials and Methods

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35 We retrospectively analyzed 185 patients with Stage IB to IVA squamous cell
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39 carcinoma of the cervix who were treated with CCRT between 2005 and 2013 at our
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42 hospital. None of the patients had received prior treatment. All patients provided written
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46 informed consent. Patient charts were reviewed for clinicopathological data. This
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retrospective study was approved by the Institutional Review Board of our university on
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53 September 1, 2016 (#989).
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The RT was performed as described in a previous study10. All patients were
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7 treated with anterior–posterior and posterior–anterior parallel–opposed ports, or with

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11 the four-field technique of whole-pelvic external beam radiotherapy (WP-EBRT). A

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14 50-Gy dose of WP-EBRT was delivered in 25 fractions. A center shield (4-cm wide at
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18 the midline) was used in some patients after delivery of the 40-Gy dose. HDR-ICBT

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21 was delivered once per week at a fractional dose of 6 Gy which was given 1 to 3 times
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at point A for a total dose of 6–18 Gy. Boost EBRT doses of 6–20 Gy in 1 to 4 fractions
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28 were applied to the pelvic walls and/or nodal metastases (≥10 mm in a short-axis
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32 diameter) for patients with nodular parametrial involvement. The CCRT regimen
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35 consisted of cisplatin at 20 mg/m2/day for 5 days triweekly9, 10 or 40 mg/m2 weekly7,
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39 administered concomitantly with RT. The Common Terminology Criteria for Adverse
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42 Events (CTCAE version 4.0) and Radiation Therapy Oncology Group/European
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46 Organization for Research and Treatment of Cancer (RTOG/EORTC) criteria were used
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for grading of acute and late toxicities, respectively. Follow-up examinations were
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53 performed every month for the first year, every other month for the second year, and
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then every 3 to 6 months. The survival curves were estimated by Kaplan–Meier method
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and differences were assessed using the log-rank test; a p-values of less than 0.05 was
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7 considered significant.

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14 Results
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18 Patient characteristics are shown in Table 1. In this retrospective analysis, 185

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21 patients were treated with CCRT in which triweekly CDDP regimen was used for 110
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patients and weekly CDDP regimen for 75 patients. The median follow-up period was
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28 68 months (range: 5–135 months) for the triweekly group and 36 months (range: 2–
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32 88 months) for the weekly group. The median age was 50 years (range: 22–70 years) in
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35 the triweekly group, and 50.5 years (range: 28–70 years) in the weekly group. The
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39 median total CDDP dose was 200 mg/m2 (range: 100–300 mg/m2) in the triweekly
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42 group, and 200 mg/m2 (range: 80–280 mg/m2) in the weekly group (p = 0.129). The
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46 median course of triweekly cisplatin was 2 courses (range, 1–5 courses) and the median
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course of weekly cisplatin was 5 courses (range, 4–6 courses) and the median overall
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53 treatment time, including HDR-ICBT and boost EBRT, was 48 days (range, 37–68
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days) in the triweekly group and 51 days (range, 45–67 days) in the weekly group,
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respectively (p = 0.135). No significant differences were observed in dose intensity of
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7 chemotherapy and the overall treatment time of radiation therapy. No statistically

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11 significant differences were observed in the distribution of FIGO staging classification,

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14 pretreatment Hb level, tumor size, lymph node status, and serum SCC level.
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18 The 5-year overall survival (OS) rate in the triweekly and weekly groups were

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21 82.0% and 83.3%, respectively (p = 0.851) (Figure 1); their disease-free survival (DFS)
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rate were 79.6% and 78.1%, respectively (p = 0.672) (Figure 2). The 5-year local DFS
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28 rates in the triweekly and weekly groups were 88.5% and 87.0%, respectively (p =
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32 0.782), and the distant DFS rates were 83.9% and 84.1% (p = 0.938). Regarding
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35 recurrence, 24 patients (21.8%) in the triweekly group and 16 patients (21.3%) in the
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39 weekly group developed recurrence (Table 2). A total of 15 of the 110 patients in the
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42 triweekly group and 9 of the 75 patients in the weekly group experienced locoregional
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46 recurrence. A total of 19 patients in the triweekly group and 11 patients in the weekly
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group experienced distant recurrence. No significant difference was observed in the

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53 distribution of the site of recurrence between the groups.
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Adverse events of CCRT in each group are described in Table 3. In the
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triweekly group, 56 patients (50.9%) had grade 3/4 leukopenia, which was significantly
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7 higher than that of 11 patients (15%) in the weekly group (p <0.0001). There was no

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11 significant difference in other hematologic adverse effects. In non-hematologic adverse

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14 events, grade 3/4 nausea / vomiting and diarrhea were observed in 13 (11.8%) and 16
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18 (14.5%) patients in the triweekly group, respectively, while only 2 (2.6%) and 3 (4%)

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21 patients in the weekly group, respectively, and those were significant (p = 0.028 and
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0.025, respectively). In terms of late adverse events (Table 4), 1 patient (0.9%) suffered
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28 from grade 4 radiation enterocolitis with required intestinal surgery, and 2 patients
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32 experienced bone fracture (pubic bone, and lumbar vertebra) both in the triweekly group
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35 on the basis of toxicity criteria of RTOG/EORTC. Grade 2 radiation enterocolitis was
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39 observed in 6 patients (the triweekly group) and 3 patients (the weekly group),
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42 respectively. Grade 2 radiation cystitis was appeared in 2 patients only in the triweekly
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46 group. No death due to toxicities occurred during the study period.

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53 Discussion
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Our retrospective study demonstrates that there is no significant survival
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difference, including OS, DFS, local DFS, and distant DFS, among patients treated with
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7 CCRT using 20 mg/m2 CCDP for 5 days every 3 weeks and CCRT using 40 mg/m2

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11 CDDP weekly. Although the CDDP dose intensity and overall treatment time are

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14 important in CCRT for cervical cancer, no significant difference was observed in CDDP
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18 dose intensity and overall treatment time11. However, acute adverse events, namely

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21 grade 3/4 leukopenia, nausea/vomiting, and diarrhea were significantly higher in the
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triweekly group. The weekly CDDP regimen for CCRT seems better in patients with
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28 FIGO Stage IB—IVA squamous cell carcinoma of the cervix in our institutions.
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32 So far, several clinical trials have investigated alternative cisplatin dose and
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35 dosing schedules to weekly cisplatin-based chemoradiation. Einstein et al. reported in
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39 their retrospective study that the weekly group had a 3.43 times higher risk of
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42 developing acute toxicities than the 5-day group in advanced-stage patients with a
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46 significantly shorter 3-year progression-free survival (PFS) . Regarding the acute

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toxicity, they mentioned that the most of early toxicities seen in the weekly patients
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53 were gastrointestinal (GI)-related. Significant GI-related toxicity in the triweekly group
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may have been masked by the use of inpatient intravenous fluids and intravenous
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antiemetic medications.
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7 In an open-label, randomized trial from Korea13, 104 patients with Stage IIB–

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11 IVA cervical cancer were randomly assigned to weekly (weekly cisplatin 40 mg/m 2, six

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cycles) and triweekly (cisplatin 75 mg/m2 every 3 weeks, three cycles) chemotherapy

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18 arms during concurrent radiotherapy. This study postulated that higher peak

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21 concentration of cisplatin is more critical in enhancing the synergy of chemoradiation
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than the weekly cisplatin exposure. Also, the high peak concentration might effectively
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28 eliminates small clumps of micrometastases, which leads to decrease in local failure and
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32 distant metastasis, and thus, to improvement in survival. However, without appropriate

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35 pharmacokinetic (PK) analysis of peak CDDP levels in both CDDP dosings, we cannot
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39 clarify that the observed difference is due to higher peak levels of serum CDDP
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42 concentration in triweekly administration. Furthermore, the advantages of chemotherapy
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46 may not be due to true sensitization but rather by inhibiting tumour repopulation during
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radiotherapy; it is therefore possible that shorter schedules may not require chemotherapy
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53 support14. The Korean group study13 suggested that another explanation for this result is
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that the possible role of cisplatin administration during brachytherapy enhances the
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chemoradiation effect. However, because the third cycle of chemotherapy was delivered
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7 on average 10 days before brachytherapy in that study, there was no way of deducing

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11 what proportion of the cisplatin acted as a radiosensitizer during brachytherapy. Based

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14 on the result of the trial, Tri-weekly Cisplatin Based Chemoradiation in Locally
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18 Advanced Cervical Cancer (TACO) Phase III randomized clinical trial is ongoing by

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21 Korean Gyencologic Onclogy Group (KGOG) 15.
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A randomized Phase 3 trial comparing 2 cisplatin dose schedules (CDDP, 20
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28 mg/m2 per day, on Days 1 to 5 every 21 days, and CDDP, 40 mg/m 2 per day weekly)
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32 concluded that the 21-day CDDP regimen was superior regarding local efficacy and less
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35 toxic compared to the weekly chemotherapy regimen16. Owing to the acute toxicity, the
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39 proposed CDDP dose was delivered only in 79% of the patients from the triweekly
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42 CDDP and in 70% of the patients from the weekly CDDP groups. This underdose in
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46 weekly CDDP can be one of the causes of the better results obtained by the triweekly
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CDDP regimen. However, nodal status was included neither in the randomization
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53 criteria nor in the results evaluation. Another limitation of the study is the inclusion of
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surgery in the therapeutic protocol, deciding optionally on surgery after preoperative
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CCRT. These above mentioned reports recommend triweekly CDDP regimen of CCRT
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7 for cervical cancer.

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11 Meanwhile, a randomized clinical trial comparing 3 monthly cycles of FU

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(1000 mg/m2/day intravenously) plus CDDP (20 mg/m2/day intravenously) for 5 days

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18 with 6 cycles of weekly CDDP (30 mg/m2 intravenously) for CCRT showed that CCRT

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21 by weekly CDDP improves compliance with treatment and reduces acute hematologic
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adverse effects without spoiling response and survival rates17. An analysis of 7 studies
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28 between 1995 and 201118 and a meta-analysis of 5 randomized controlled trials between
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32 1995 and 2015 to compare weekly and triweekly CDDP combined radiotherapy19,
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35 established that weekly CDDP has a lower risk of hematologic toxicity than triweekly
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39 cisplatin with concurrent radiotherapy in the treatment of cervical cancer with no

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42 differences in PFS and OS. Clinicians and patients may choose either weekly cisplatin
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46 or triweekly cisplatin combined radiotherapy for cervical cancer.

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Furthermore, a retrospective analysis comparing CCRT with weekly CDDP

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53 with CCRT with monthly CDDP and 5-FU for two cycles followed by additional
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consolidation chemotherapy for two cycles with the same regimen20 showed that there
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were no statistically significant differences in PFS and OS. They also found that both
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7 regimens seemed to have similar efficacy for patients with locally advanced cervical

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11 cancer, but the weekly cisplatin was better tolerated. Sonoda et al.21, though their

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14 retrospective study, also demonstrated that CCRT with both triweekly and weekly
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18 CDDP appeared to have similar efficacy for cervical cancer patients, but the toxicities

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21 were better tolerated with weekly CCRT. The results from these later four reports are
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consistent with our analysis. E
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28 One of the limitations of our study is that its retrospective nature of the study
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32 is inevitable, which can be affected by recall bias and difficulties with data abstraction
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35 from charts. The other limitation is that only patients with squamous cell carcinoma
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39 were analyzed in our study, which might affect our results, because patients with both
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42 squamous cell carcinoma and adenocarcinoma were investigated in the other reports.
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Actually, the GOG 120 study demonstrates that weekly CDDP at 40 mg/m2 is equally
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effective and less toxic than CDDP and 5-fluorouracil regimen2. However, data from
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53 previous Phase I trials did not lead to the choice of weekly CDDP 40 mg/m 2 for phase
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III CCRT trials, and the maximum tolerated dose of weekly CDDP during CCRT has
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7 not been determined.

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11 Thus, which regimen is better for CCRT in cervical cancer patients remains

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controversial. However, a recent meta-analysis22 showed that for locally advanced

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18 cervical cancer, CCRT with platinum-based doublet regimen contributed to

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21 improvements of prognosis, compared to CCRT with weekly CDDP. Therefore,
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because platinum-based combination therapy should be the preferred treatment over
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28 weekly CDDP during CCRT for Stage IB–IVA cervical cancer, we need to develop
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32 CCRT with new regimens, such as paclitaxel and CDDP23, 24. Furthermore, cisplatin and
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35 radiation therapy with or without carboplatin and paclitaxel in patients with locally
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39 advanced cervical cancer (OUTBACK) trial25 and induction chemotherapy plus

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42 chemoradiation as first line treatment for locally advanced cervical cancer
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(INTERLACE) trial26 are ongoing. We should consider the additional systemic
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chemotherapy to CCRT. We believe that a well-designed prospective, randomized trial

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53 is necessary to develop a novel CCRT strategy for locally advanced cervical cancer.
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4 Acknowledgments: The authors would like to thank Enago (www.enago.jp) for the
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7 English language review.

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11 Conflict of interest: We have no Conflict of Interest as to this article.

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14 Financial support: Financial support for this study was not provided.
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3 References
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5 1. National Cancer Institute. Concurrent chemoradiation for cervical cancer. Clinical
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7

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9 announcement, Washington, D.C., February 22, 1999.
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11

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12 2. Rose PG, Bundy BN, Watkins EB, Thigpen JT, Deppe G, Maiman MA, et al.
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16 Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced

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18

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28 Cervical Cancer (Vulva Cancer) Committee of Japanese Gynecologic Oncology
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35 12. Einstein MH, Novetsky AP, Garg M, Hailpern SM, Huang GS, Glueck A, et al.
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46 13. Ryu SY, Lee WM, Kim K, Park SI, Kim BJ, Kim MH, et al. Randomized clinical
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28 16. Nagy VM, Ordeanu C, Coza O, Alin CR, Traila A, Todor N. Randomized phase 3
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N

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concurrent chemoradiation therapy with weekly cisplatin versus monthly
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35 21. Sonoda K, Yahata H, Ichinoe A, Okugawa K, Kaneki E, Kawano Y, et al.
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42 5-fluorouracil versus weekly cisplatin in cervical cancer. Anticancer Res
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46 2015;35:3447-3454.
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7 Concurrent chemoradiotherapy with paclitaxel and cisplatin for adenocarcinoma of

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11 the cervix. Anticancer Res 2012;32:1475-1479.

O
12
13

O
14 24. Umayahara K, Takekuma M, Hirashima Y, Noda SE, Ohno T, Miyagi E, et al.
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18 Phase II study of concurrent chemoradiotherapy with weekly cisplatin and paclitaxel

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21 in patients with locally advanced uterine cervical cancer: The JACCRO GY-01 trial.
22

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Gynecol Oncol 2016;140:253-258. E
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28 25. Cisplatin and Radiation Therapy With or Without Carboplatin and Paclitaxel in
C

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32 Patients With Locally Advanced Cervical Cancer. In: ClinicalTrials.gov

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35 https://clinicaltrials.gov/ct2/show/NCT01414608 Accessed Feb 2017
R

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39 26. Induction Chemotherapy Plus Chemoradiation as First Line Treatment for Locally
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42 Advanced Cervical Cancer (INTERLACE). In: ClinicalTrials.gov
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N

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46 https://clinicaltrials.gov/ct2/show/NCT01566240?term=interlace&rank=2 Accessed
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Feb 2017
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B

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 1
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3 Figure legends
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5 Figure 1: The 5-year overall survival rate in the triweekly and weekly groups were
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7

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9 82.0% and 83.3%, respectively (p = 0.851).
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11

O
12 Figure 2: The 5-year disease-free survival rate in the triweekly and weekly groups were
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O
14
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16 79.6% and 78.1%, respectively (p = 0.672).

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18

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22

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E
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C

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E

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O

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C

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N

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JR

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B

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 1
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3 Table 1. Patient characteristics
4 Triweekly (n = 110) Weekly (n = 75) p-value
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6 Median age (range) (years) 50 (22—70) 50.5 (28—70) 0.274
7

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8 FIGO stage IB1 5 11 0.550
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10 IB2 22 13
11

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12 IIA 7 7
13
IIB 44 22

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15 III 29 21
16

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17 IVA 3 1
18

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20 Median tumor size (range) (mm) 50 (22—90) 49 (20—113) 0.320
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22 Pelvic lymph node enlargement 0.445

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23 0 64 41
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1 E 23 21
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27 2 16 9
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≥3 2 4
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30 ND 5 0
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33 Median pretreatment Hb (g/dl) 11.9 (4.2—14.8) 11.5 (4.2—15.7) 0.579
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35 Median pretreatment SCC (ng/ml) 4.4 (0.8—283) 5.6 (0.7—51.8) 0.97
R

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37 Median total CDDP dose (mg/m2) 200 (100—300) 200 (80—280) 0.129
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O

39 Median course of chemotherapy (courses) 2 (1–5) 5 (4–6) NA

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Median overall treatment time (days) 48 (37–68) 51 (45–67) 0.135
C

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42 Median follow-up period (months) 68 (5—135) 36 (2—88) < 0.0001
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N

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5 Table 2. Site of recurrence
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7 Triweekly (n = 110) Weekly (n = 75) p-value

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9 Recurrence (total) 24 (21.8%) 16 (21.3%) 0.544
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11 Loco-regional 5 (20.8%) 5 (31.3%)

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Distant 9 (37.5%) 7 (43.8%) 0.482

O
14 Loco-regional+distant 10 (41.7%) 4 (25.0%)
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16

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18

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22

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 1
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3 Table 3. Acute adverse events
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5
Triweekly (n = 110) Weekly (n = 75) p-value
6 Grade 1/2 Grade 3/4 Grade 1/2 Grade 3/4
7

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8 Leukocytepnia 25 56 15 11 <0.0001
9
10 Anemia 50 8 29 6 0.533
11

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12 Thrombocytopenia 29 13 5 3 0.052
13 Nausea/vomiting 57 13 15 2 0.028

O
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15 Diarrhea 51 16 26 3 0.025
16

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17 Radiation dermatitis 3 1 6 1 0.648
18

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22

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 1
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3 Table 4. Late adverse events
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5
Triweekly (n = 110) Weekly (n = 75)
6
7 Grade 3 Grade 4 Grade 3 Grade 4

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9 Small/large intestine 4 1 3 0
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11

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12 Bladder 2 0 0 0
13

O
14 Bone 0 2 0 0
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Figure Click here to download Figure Figure 1.tiff

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Figure Click here to download Figure Figure 2.tiff

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