A randomized phase III trial of concurrent chemoradiotherapy in locally advanced cervical cancer: Preliminary results

Gynecologic Oncology 104 (2007) 15 – 23 www.elsevier.com/locate/ygyno

A randomized phase III trial of concurrent chemoradiotherapy in locally advanced cervical cancer: Preliminary results Vutisiri Veerasarn a,⁎, Vicharn Lorvidhaya b , Pimkhuan Kamnerdsupaphon b , Nan Suntornpong a , Supatra Sangruchi a , Prasert Lertsanguansinchai c , Chonlakiet Khorprasert c , Lak Sookpreedee d , Suthipol Udompunturak e a

e

Division of Radiation Oncology, Department of Radiology, Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Prannok Rd., Bangkoknoi, Bangkok, 10700, Thailand b Division of Radiation Oncology, Department of Radiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand c Division of Radiation Oncology, Department of Radiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand d Division of Radiation Oncology, Chonburi Cancer Center, Chonburi, Thailand Clinical Epidemiology Unit, Office of Research Promotion, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand Received 5 March 2006 Available online 25 September 2006

Abstract Objective. Concurrent chemoradiation is the standard treatment for locally advanced cervical cancer. This study was a preliminary result of a randomized two arms, prospective, open-label phase III trial comparing the activity and safety of the concurrent chemoradiation of Tegafur-Uracil and carboplatin or carboplatin alone in locally advanced cervical cancer. Materials and methods. The stage IIB–IIIB cervical cancer patients were randomized to have Tegafur-Uracil 225mg/m2/day orally, 5 days a week and carboplatin 100mg/m2 IV over 30–60 min, weekly on day 1 concurrent with standard radiotherapy (Group A) or carboplatin alone concurrent with standard radiotherapy (Group B). Results. Four hundred and sixty-nine patients were randomized to Group A (n = 234) or Group B (n = 235). The tumor response at 3-month follow-up time showed no significant difference. The only prognostic factor to improve the complete response rate was the hemoglobin level. The patients in Group A, who had Hb < 10 gm/dL had the relatively better change to complete response of 1.48 compared to that in Group B (P 0.025, 95% CI 1.07, 2.04). No severe toxicity or adverse event had been reported. The median follow-up time for Group A and Group B was 12.6 and 11.8 months, respectively. There was no statistical difference in PFS and OS. Conclusion. Concurrent chemoradiation by Tegafur-Uracil and carboplatin showed no difference in tumor response rate or treatment toxicity compared to carboplatin alone. The combination drugs might have benefit in poor prognostic patients such as the baseline Hb < 10 gm/dL. © 2006 Elsevier Inc. All rights reserved. Keywords: Cervical cancer; Chemoradiotherapy; Carboplatin

Introduction Cervical cancer is the most common cancer in Thailand. The incidence was 19.5% of all cancer cases [1]. Radiation therapy is the primary treatment for most patients with loco-regional advanced cervical carcinoma. Five-year survival rates of 65% to 75%, 35% to 50 % and 15% to 20% are reported for patients ⁎ Corresponding author. Fax: +662 412 9169. E-mail address: [email protected] (V. Veerasarn). 0090-8258/$ - see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2006.06.045

treated with radiotherapy alone for stages IIB, IIIB and IVA tumors, respectively [2–6]. A large number of investigators have explored the role of chemotherapy in this setting. Concomitant chemoradiation is the most extensively studied of these options. Drugs that are most commonly given concurrently with radiation therapy include hydroxyurea, 5-fluorouracil, mitomycin-C, and cisplatin [7–16]. Recently, five large randomized trials have compared cisplatin-based chemoradiation with radiation alone or with radiation and hydroxyurea in patients with cervical cancer. Collectively, these five randomized trials involving a

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total of 1894 women with cervical cancers of various stages requiring radiation show a significant reduction in the risk of recurrence and death with chemoradiation. The 30% to 50% reductions in the relative risks of relapse or death were remarkably similar for the five studies each of whose details are as follows. The GOG trial reported by Whitney et al. [17] randomized 388 patients with stage IIB–IVA cervical cancer to receive radiation therapy with concurrent cisplatin and 5-FU or with hydroxyurea. Patients on the cisplatin-containing treatment arm had significantly less hematologic toxicity and a better overall survival rate (63% versus 47% at 5 years) than those treated with radiation and hydroxyurea. The Radiation Therapy Oncology Group (RTOG) [18] randomized 401 stage IB–IVA cervical cancer patients to receive chemoradiation with cisplatin and 5-FU or extendedfield radiation. This control arm was based on an earlier RTOG trial that demonstrated an improvement in survival when paraaortic irradiation was added to standard pelvic irradiation for patients with stage IB–IIB cervical cancer [19]. However, the overall survival rate at 5 years was superior for patients who were treated with pelvic radiation and chemotherapy when compared with that of those treated with extended-field radiation (73% versus 58%). In this study, chemoradiation decreased the rate of both local failure and distant metastasis. Acute toxicity was greater with chemoradiation, but with a median follow-up of 43 months, the numbers of late complications were similar. A GOG trial reported by Rose et al. [20] used combined radiation with cisplatin, or cisplatin, 5-FU and hydroxyurea, or hydroxyurea in 575 patients with stage IIB–IVA cervical cancer. The survival rates of both groups that received concurrent cisplatin (66% and 64%, respectively) were superior to that of the group treated with concurrent hydroxyurea alone (39%). The local failure rate was significantly lower in the groups that received cisplatin, which suggests that the chemotherapy was acting as a radiation sensitizer. The toxicity of the single-agent cisplatin regimen was significantly less than that of the three-drug regimen. Keys et al. [21] reported a GOG study that examined whether the regimen of weekly cisplatin during external-beam irradiation improved survival compared with the definitive irradiation alone in patients with stage IB–IIA cervical cancer. Both arms of this study included a completion hysterectomy because the preliminary results of a previous randomized study suggested a lower relapse rate for the patients who had adjuvant hysterectomy. In this trial, pathologic examination demonstrated a significantly less persistent disease in the specimens of patients who received chemoradiation. Significant differences in progression-free survival and overall survival also favored the chemoradiation arm, with estimated survival rates at 48 months of 82% and 68%, respectively. More leukopenia and gastrointestinal toxicity were seen with chemoradiation, but this was transient. Peter et al. [22] reported the results of a cooperative study of the Southwest Oncology Group, GOG, and RTOG in selected patients with FIGO stages IA2, IB, and IIA cervical cancer

simultaneously with high-risk factors (nodal metastasis, parametrial extension, or involved margins of resection) after radical hysterectomy. 268 patients were randomized to receive radiation therapy with cisplatin and 5-FU or radiation alone. This trial differed from the other four trials in that patients received two cycles of chemotherapy after radiation therapy, in addition to the two cycles given concurrent with pelvic irradiation. In this study, the survival rate was also better in the group of patients who received chemoradiation (81% versus 63%). Rationale Carboplatin is a platinum analogue that was introduced in 1981 because of its reduced toxicity, equivalent biochemical selectivity and anti-tumor spectrum relative to cisplatin [23]. In addition, in vivo and in vitro studies also demonstrated a synergistic effect of carboplatin and radiation [24–26]. Three randomized studies examined the role of carboplatin in advanced or recurrent cervical cancer with respect to the desirability of substituting carboplatin for cisplatin [27–30]. Based on existing evidence, carboplatin appears to have comparable activity with that of cisplatin and has a better safety profile [27–29]. Preclinical data suggest that more than one type of interaction between radiation and 5-FU is possible; that the schedule dependency of 5-FU/irradiation varies in different cancer cell lines in both in vitro and in vivo models. The therapeutic index of 5-FU is improved when the drug is given as a continuous intravenous infusion (CIV), with the dose-limiting toxicity being mucositis [31–33]. With regard to our study, we attempted to exploit the use of carboplatin and Tegafur-Uracil by conducting a trial randomizing patients with stage IIB, IIIA or IIIB cervical cancer to radiation concomitant with either carboplatin or the combination of carboplatin plus Tegafur-Uracil. Study objectives The primary goal of this study was to compare overall survival and the time to progression of the combination of Tegafur-Uracil/carboplatin/RT with the carboplatin/RT. A secondary goal of this protocol was to estimate the response rate and toxicities of the two treatment groups. Materials and methods Study design This was a randomized two arms, prospective, open-label phase III trial comparing the activity and safety of the combination of Tegafur-Uracil/ carboplatin/RT (Group A) with the carboplatin/RT (Group B) in locally advanced cervical cancer patients.

Inclusion criteria The patients had locally advanced cervical cancer at stage IIB, IIIA or IIIB with the histology of squamous cell carcinoma or adenosquamous cell carcinoma or adenocarcinoma. The patients had no prior chemotherapy or

V. Veerasarn et al. / Gynecologic Oncology 104 (2007) 15–23 radiotherapy and the ECOG performance status was 0–2. The age of the patients was between 18 and 70 years old. They had adequate bone marrow, liver and renal function defined as follows: hematologic: hemoglobin ≥ 10 g%, granulocytes ≥1500/mm3, WBC ≥4000/mm3, platelet ≥100,000/mm3. The liver functions were bilirubin <2 mg% and SGOT, SGPT, alkaline phosphatase were ≤2 normal value. The renal functions were creatinine ≤1.5mg/mL. The patients were accessible for treatment and follow-up and had given their written informed consent.

Exclusion criteria The exclusion criteria were patients who had evidence of metastatic disease, serious active infection (including HIV positive) or other serious underlying medical conditions or patients who were pregnant or breast feeding that would impair the ability of the patient to receive the treatment.

Randomization Patients were randomized from a central randomization center using computer-generated randomizations and with approximately equal numbers of patients assigned to each treatment group in each center. Patients were not allowed to start protocol treatment prior to randomization.

Treatment administration The concurrent chemoradiotherapy by using weekly carboplatin 100 mg/m2 was conducted by intravenous infusion over 30–60min on days 1 every week for 5–6 weeks according to the radiotherapy duration in both groups. In Group A, Tegafur-Uracil 225mg/m2 was added with weekly carboplatin. The total daily dose of Tegafur-Uracil was determined and rounded to the nearest 100mg. The total daily dose of Tegafur-Uracil was divided into three doses given orally 8h apart. The highest dose was given in the morning and lower doses in the afternoon or evening. The Tegafur-Uracil was taken daily at the same day of radiotherapy, 5 days a week and stopped on the weekend. The total treatment duration was completed within 8 weeks. For radiation treatment, all of the patients had received the standard whole pelvic irradiation 40–50Gy in 20–25 fractions and an additional parametrium boost of 10–16Gy in 5–8 fractions. The treatment machines were linear accelerator 10 MeV or Cobalt units. The intracavitary radiation (ICRT) used the medium dose rate (Cesium-137) machine (MDR) or high dose rate (Iridium192) machine (HDR).

Treatment evaluation During the treatment period, the patients was evaluated weekly by physical examination (PE), CBC and urinalysis. At the end of treatment, we included tumor measurement by per vaginal examination (PV) and the biochemistry test. After the completion of treatment, the PE, PV, CBC and urinalysis were performed at 1-month intervals for the first 3 months. The acute toxicity, from the first date of treatment until 3 months after completion of treatment, was evaluated by using the CTC toxicity criteria (CTC version 2.0 Publish Date: April 30, 1999). When ≥grade 2 toxicity was found, the chemotherapeutic agent(s) were withheld except in cases of nausea, vomiting or diarrhea. When toxicity subsided to grade 0–1, resume treatment was at the same dose level if toxicity was grade 2, or 25% chemotherapy dose reduction if toxicity was ≥ grade 3. When a dose reduction was required, no dose re-escalation was performed subsequently. The patients who experienced ≥grade 3 toxicity, which has not improve within 7 days, had to stop the chemotherapy, and were managed by conservative methods. Radiation was withheld at the discretion of the investigator. Alopecia was not considered as a toxicity factor requiring dose modification. After 3 months follow-up, the patients underwent PE and PV to evaluate their response to the treatment following the WHO criteria while the late toxicity followed the RTOG/EORTC Late Morbidity Scoring Scheme which is used for toxicity occurring more than 90 days after radiation therapy. They were evaluated at 3-month intervals for 1–2 years and 6-month intervals for 3–5 years. The time period of disease progression

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and site of disease progression were recorded. The time period to tumor progression was defined as the time from the first dose of therapy until there was progressive disease. The survival rate of patients was measured from the first day of therapy.

Results Patient characteristics From July 2001 to December 2003, 469 patients were randomized at 4 centers in Thailand, 234 patients in Group A and 235 patients in Group B. There was no significant imbalance in baseline prognostic variables in both groups (Table 1: patient characteristics). Tumor responses At 3 months after complete treatment, there was no significant difference in complete response (CR) rates between Group A and Group B; 170 (73%) and 170 (72%), respectively. The only one independent prognostic factor from various patient characteristics, for improved CR was the hemoglobin level < 10gm/dL, favored in Group A. The relatively better chance to have CR was 1.48 in Group A compared to Group B (P 0.025, 95% CI 1.07–2.04). (Table 2: prognostic factors to improve CR rate in multivariate analysis). There was 1 patient in Group A and 4 patients in Group B who refused treatment and withdrew early during the treatment period. There were 9 patients in Group A and 5 patients in Table 1 Patient characteristics Demographic characteristics

Group A

Group B

P-value

Total cases Age (years): Mean ± SD Body weight (kg): Mean ± SD

234 49.6 ± 10.0 55.9 ± 9.8 n (%)

235 49.7 ± 9.3 54.6 ± 9.7 n (%)

0.905 0.163

WHO performance status 0 1 2

216 (92) 16 (7) 2 (1)

202 (86) 30 (13) 3 (1)

1.0

Histology Squamous cell carcinoma Adenocarcinoma Adenosquamous cell carcinoma

190 (82) 34 (15) 6 (3)

189 (81) 33 (14) 11 (5)

0.479

FIGO staging Stage IIB Stage IIIA Stage IIIB

155 (67) 0 76 (33)

158 (68) 5 (2) 68 (30)

Tumor size ≤4cm >4cm

120 (52) 113 (48)

119 (51) 113 (49)

0.606

Hemoglobin at baseline ≥10gm/dL <10gm/dL

201 (87) 29 (13)

206 (88) 28 (12)

0.945

0.580

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V. Veerasarn et al. / Gynecologic Oncology 104 (2007) 15–23

Table 2 Prognostic factors to improve complete response in multivariate analysis

Toxicity

Prognostic factors

The incidences of grades 2–3 hematologic and nonhematologic toxicity at the end of treatment showed no difference in both groups and most of the patients had recovered to grades 0–1 at 3 months after completion of treatment. Grade 4 toxicity was not found. (Table 4: the hematologic and nonhematologic toxicities).

CR at 3 months

Group A

Group B

P-value

n (%)

n (%)

Histology Squamous cell CA Adenocarcinoma Adenosquamous cell CA

142 (75) 21 (62) 4 (67)

137 (73) 24 (73) 7 (64)

0.703 0.486 1.0

Staging Stage II Stage III

120 (78) 48 (63)

128 (81) 38 (52)

0.519 0.227

85 (71) 84 (74)

94 (79) 74 (66)

0.191 0.191

Hemoglobin at baseline ≥10gm/dL <10gm/dL

143 (71) 26 (90)

152 (74) 17 (61)

0.627 0.025

Intracavitary RT (ICRT) MDR HDR

62 (75) 108 (74)

62 (71) 108 (75)

0.741 0.869

Tumor size T ≤4cm T >4cm

Discussion Cervical cancer is a major health problem in Thailand and worldwide. The cause of death is persistent or recurrent disease after the treatment. Most of the analysis shows that the pattern of failure following radiotherapy in locally advanced disease revealed that more than 70% of patients had some component of pelvic failure as their site of first relapse. Escalation of the

Group B who had disease progression during the first 3 months after completion of treatment. Progression-free survival and overall survival The median follow-up time was 12.6 months in Group A and 11.8 months in Group B. There were no significant differences in progression-free survival (PFS) and overall survival (OS) both of which did not reach the median survival time. The PFS and OS were 76% and 93% in Group A and 75% and 94% in Group B, respectively. The survival curves are shown in Fig. 1A and B. Eight patients in Group A and 13 patients in Group B failed to complete the followup period, but they showed no evidence of disease at their last visit. In a multivariate analysis of the patients' characteristics, the prognostic factor to improve DFS and OS was the CR rate which did not show any significant difference in either group as in Fig. 2A and B. The relative risk of death in the CR group was lower at 0.13 when compared with the non-CR group. Drug interruption and dose modification During the treatment period, there was no difference in chemotherapeutic agent(s) interruption or dose modification. Thirty patients (13%) in Group A and 28 patients (11%) in Group B had drug interruption. There were 2 patients in Group A, but none in Group B who had dose modification. For the radiation treatment, there was no difference in the radiation treatment schedule; the mean total radiation dose and the total treatment time were 55.1 Gy and 49.6 days in Group A and 54.3Gy and 49.5 days in Group B, respectively. (Table 3: treatment interruption and modification).

Fig. 1. (A) Disease free survival curves. (B) Overall survival curves.

V. Veerasarn et al. / Gynecologic Oncology 104 (2007) 15–23

Fig. 2. (A) Disease-free survival curves in complete response (CR) or noncomplete response (non-CR) patients. (B) Overall survival curves in complete response (CR) or non-complete response (non-CR) patients.

radiotherapy dose was needed to achieve local tumor control. However, within the pelvis, escalation of the radiation dose was limited by the increased toxicity factor. Another attempt to improve the efficacy of radiotherapy is to use chemotherapy as the radiosensitizer, which was proved by the results from five multicenter randomized controlled trials. They demonstrate a survival advantage for platinum-based chemotherapy concurrent with radiotherapy in management of locally advanced cervical cancer. From our study, the overall response rate, the tumor control rate and the survival rate were similar using weekly carboplatin with or without Tegafur-Uracil concurrent radiotherapy in the treatment of stages IIB–IIIB cervical cancer patients. TegafurUracil did not increase the efficacy of the treatment in both response rate and tumor control, but did not increase acute toxicity. The only small subgroup in this study that might have

19

benefited from the additional Tegafur-Uracil was those patients who presented the hemoglobin level less than 10g/dL, as we know that anemia is the proven negative prognostic factor for radiotherapy success. The hemoglobin level at presentation was correlated significantly with local control, disease-free survival and overall survival on a univariate analysis, but it did not affect the multivariate analysis [34]. For Thai cancer patients, we usually employ blood transfusions to increase the hemoglobin level to at least 10 g/dL before starting the radiotherapy and maintain this during the whole course of the treatment. There are some studies which recommend the use of recombinant human erythropoietin to increase the hemoglobin level. However, a study from the Southwest Oncology Group, [35] reported that although the recombinant human erythropoietin and oral iron increased the mean hemoglobin level during the chemoradiotherapy, it failed to raise the hemoglobin level to the target of 12.5g/dL in the majority of patients. In addition to its lack of efficacy, they found that recombinant human erythropoietin is associated with a high rate of deep vein thrombosis and recommended not using it routinely in women with cervix cancer during chemoradiotherapy. Blood transfusion before radiotherapy remains the reliable and safe way to maintain the hemoglobin level. However, this can be very difficult in cervical cancer patients. We hope that this additional treatment to standard treatment may compensate for this situation. However, we suggest further investigations are undertaken before reaching any conclusion. Even though this study was a negative trial to improve the treatment results by adding the Tegafur-Uracil, we learnt more about the using a weekly carboplatin-based regimen concurrent with radiotherapy. We had a high overall complete response rate of 72% (79% for stage IIB and 58% for stage III disease) with acceptable toxicity. The only prognostic factor for a complete response rate was the stage of the disease (comparing stage IIB and the stage III disease). The histology types (squamous cell carcinoma, adenocarcinoma, adenosquamous cell carcinoma), tumor size (cut point 4 cm), hemoglobin level at presentation (cut point 10 g/dL), and the mode of intracavitary radiation

Table 3 Treatment interruption and modification Treatment Radiation treatment External radiation Total dose (Gy) Mean ± SD Total treatment time (day) Mean ± SD Intracavitary Radiation (n) MDR (Cesium) HDR (Iridium) Chemotherapy Drug interruption (n) No Yes Dose modification (n) No Yes

Group A

Group B

P-value

55.1 ± 3.0

54.3 ± 5.7

0.801

49.6 ± 14.1 n (%) 83 (36%) 147 (64%)

49.5 ± 11.8 n (%) 87 (38%) 144 (62%)

0.980

n (%)

n (%)

200 (87%) 30 (13%)

207 (89%) 25 (11%)

0.856

227 (99%) 2 (1%)

232 (100%) 0 (0%)

0.162

0.799

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V. Veerasarn et al. / Gynecologic Oncology 104 (2007) 15–23

Table 4 The hematologic and non-hematologic toxicities: maximum toxicity per patient Group A

Group B

P-value

Grade

0

1

2

3

4

0

1

2

3

4

Hematologic

n (%)

n (%)

n (%)

n (%)

n (%)

n (%)

n (%)

n (%)

n (%)

n (%)

1 (1) 8 (4) 0 0

0 0 0 0

137 (63) 128 (59) 183 (86) 212 (99)

47 (22) 58 (27) 16 (7) 0

30 25 10 2

2 (1) 4 (2) 4 (2) 0

0 0 0 0

Maximum acute hematologic toxicity per patient (end of treatment) Anemia 131 (64) 52 (25) 21 (10) Leukopenia 122 (59) 58 (28) 18 (9) Neutropenia 175 (85) 20 (10) 10 (5) Thrombocytopenia 190 (99) 0 2 (1) Group A

(14) (12) (5) (1)

Group B

P-value

Grade

0

1

2

3

4

0

1

2

3

4

Non-hematologic

n (%)

n (%)

n (%)

n (%)

n (%)

n (%)

n (%)

n (%)

n (%)

n (%)

0 0 0 0 0 0 0 0 0 0 0 0

133 (57) 229 (99) 229 (99) 227 (99) 204 (88) 217 (94) 162 (70) 179 (77) 177 (77) 225 (97) 210 (91) 212 (91)

85 2 3 3 26 14 68 47 54 6 22 20

13 (6) 0 0 0 0 0 0 4 (2) 0 1 (1) 0 0

0 0 0 0 1 (1) 0 1 (1) 1 (1) 0 0 0 0

0 0 0 0 0 0 0 0 0 0 0 0

Maximum acute non-hematologic toxicity per patient (end of treatment) Skin dermatitis 136 (59) 84 (37) 9 (4) 0 Photosensitive 226 (98) 4 (2) 0 0 Allergy 229 (99) 1 (1) 0 0 Alopecia 226 (99) 3 (1) 0 0 Nausea 196 (85) 32 (14) 1 (1) 0 Vomiting 214 (93) 13 (6) 2 (1) 0 Anorexia 144 (63) 81 (35) 3 (1) 1 (1) Diarrhea 178 (77) 44 (19) 6 (3) 1 (1) Dysuria 186 (81) 44 (19) 0 0 Urinary incontinence 222 (97) 8 (3) 0 0 Fatigue 204 (89) 24 (10) 2 (1) 0 Myalgia 212 (92) 17 (7) 1 (1) 0 Group A

(37) (1) (1) (1) (11) (6) (29) (20) (23) (2) (9) (9)

Group B

0

1

2

3

4

0

1

2

3

4

Hematologic

n (%)

n (%)

n (%)

n (%)

n (%)

n (%)

n (%)

n (%)

n (%)

n (%)

0 0 0 0

118 (85) 122 (89) 134 (97) 140 (100)

14 (10) 14 (10) 4 (3) 0

6 (4) 2 (1) 0 0

1 (1) 0 0 0

0 0 0 0

Group A

Group B

0

1

2

3

4

0

1

2

3

4

Non-hematologic

n (%)

n (%)

n (%)

n (%)

n (%)

n (%)

n (%)

n (%)

n (%)

n (%)

0 0 0 0 0

172 (91) 189 (99) 187 (98) 168 (98) 189 (99)

18 1 3 21 1

0 0 0 1 (1) 0

0 0 0 0 0

0 0 0 0 0

(high dose rate or low dose rate technique) were not prognostic factors which improved the complete response rate. To improve disease-free survival and overall survival, the complete response rate after the initial treatment was the significant prognostic factor. There are three published studies using concurrent weekly carboplatin and radiation therapy. Corn et al. [36] evaluated seven patients with stages IIA and IIIB cervical cancer using weekly carboplatin administration at a dose of 60mg/m2. The response was evaluated at completion of therapy with complete response in three patients and partial response in four. No patient suffered from severe leukopenia. However, there was no

0.477 0.678 0.804 1.0 P-value

Grade

Maximum late non-hematologic toxicity per patient (3 months after treatment) Skin 179 (93) 13 (7) 0 0 Diarrhea 189 (98) 3 (2) 0 0 Dysuria 184 (95) 7 (4) 1 (1) 0 Urinary frequency 167 (87) 24 (12) 1 (1) 0 Urinary incontinence 190 (99) 2 (1) 0 0

0.521 0.499 0.623 1.0 0.504 0.585 0.075 0.89 0.317 0.987 0.373 0.946 P-value

Grade

Maximum late hematologic toxicity per patient (3 months after treatment) Anemia 117 (81) 19 (13) 9 (6) 0 Leukopenia 127 (87) 17 (12) 1 (1) 0 Neutropenia 140 (97) 3 (2) 1 (1) 0 Thrombocytopenia 144 (100) 0 0 0

0.596 0.849 0.585 1.0

(9) (1) (2) (11) (1)

0.435 0.623 0.108 0.688 1.0

long-term follow-up response data. Duenas-Gonzalez et al. [37] studied 24 stage IIIB cervical cancer patients by using four different weekly carboplatin dosages, 100, 116, 133 and 150mg/m2 concurrent with radiotherapy (six patients in each group). The median number of weekly carboplatin dose was six. After complete treatment, 18 of 24 patients (75%) achieved complete response. The recommended dose was weekly carboplatin 133 mg/m2 for 6 weeks and the dose limiting toxicity was the leukopenia and neutropenia. Higgins et al. [38] evaluated 31 patients with stages IB1–IIIB cervical cancer using an initial dose of carboplatin, AUC of 2, which was administered on the first day of radiation therapy and repeated

V. Veerasarn et al. / Gynecologic Oncology 104 (2007) 15–23

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Table 5 Comparison of current study and other carboplatin used schedules Study

n

Carboplatin/RT

CR n (%)

Med. FU (M)

DFS n (%)

Hemato. Gr 3–4

Corn, 1999 [36] Duenas-Gonzales, 2003 [37] Higgins, 2003 [38] Current Study Muderspach, 1997 [39] Micheletti, 1997 [40] Dubay, 2004 [41]

7 24 31 235 22 12 21

60mg/m2, weekly 100, 116, 133, 150 mg/m2, weekly 60–90mg/m2, weekly 100mg/m2, weekly 30–50mg/m2, twice a week 12mg/m2, daily 300mg/m2, every 3 weeks

3 (43) 18 (75) 28 (90) 170 (72) 19 (86) 9 (75) –

– 8 12 11.8 15 20 33

– – 23 (74) 176 (75) 11 (50) LC 8 (66) LC 16 (76)

– WC Neu <2% WC 2% Neu 2% Hb 13.6% Neu 4.5% WC 8.3% Hb 9.5% Neu 9.5%

RT = radiation treatment, CR = complete response, Med. FU = median follow-up, DFS = disease-free survival, Hemato. = hematologic toxicity, LC = local control, WC = leucopenia, Neu = neutropenia, Hb = hemoglobin.

on a weekly basis for six courses (days 1, 8, 15, 22, 29, 36). An AUC of 2 was chosen to reflect previous dosing of carboplatin using 60–90mg/m2. The dose of carboplatin was recalculated for each treatment cycle. The complete response rate was documented in 28 of 31 patients (90%). Hematologic toxicity was observed in less than 2%. After a mean follow-up time of 12 months, 23 patients (74%) remained disease-free. As in our study, the hematologic toxicity was observed at not more than 2%. There were other treatment schedules of carboplatin concurrent with radiotherapy. They all reported the hematologic toxicity, mainly leukopenia, with a higher incidence than in our weekly regimen. Muderspach et al. [39] reported the use of concurrent carboplatin on a twice weekly dosing schedule with radiation to treat 22 patients with stages IIA–IIIB cervical cancer. The initial carboplatin dose was 30 mg/m2 and the dose was escalated to 40mg/m2 and subsequently 50mg/m2. Nineteen patients were complete responders. Three patients had grade 3 anemia and one patient had grade 3 neutropenia. At 15 months of follow-up, 11 were disease-free and four patients had persistent disease. Micheletti et al. [40] assessed the efficacy and toxicity of continuous infusion of carboplatin during radiation therapy. Twelve patients with stages IIB–IIIB cervical cancer received continuous infusion of carboplatin 12 mg/m2 per day, starting 1 day before the first fraction of radiotherapy. A complete response was seen in 9 of 12 patients (75%). One patient had grade 3 leukopenia. With a median follow-up time of 20 months, the pelvic control rate was 66%. Dubay et al. [41] had reported the outcomes of 21 stages IIB–IVA cervical cancer patients who received carboplatin 300 mg/m2 administered every 3 weeks at the start of radiation. All patients completed at least three courses of chemotherapy during their radiation

therapy. Two patients had grade 3 granulocytopenia, 2 patients had grade 3 anemia and 1 patient had grade 3 gastrointestinal toxicity. Thirteen patients (62%) went on to complete all six intended cycles. The average follow-up time was 51.6 months, the pelvic control rate was 76% and the overall survival rate was 71%. Among the carboplatin used group, the common toxicity of the concurrent carboplatin with the radiotherapy in the treatment of locally advanced cervical cancer was hematologic toxicity, mainly leukopenia, as in our study, which was around 2%. The reason for the low incidence of hematologic toxicity could be that the weekly administration of carboplatin may decrease bone marrow toxicity. For non-hematologic toxicity, there were some reports of grade 3 gastrointestinal toxicity. As would be expected with carboplatin, no nephrotoxicity was seen. Nephrotoxicity is often a problem with cisplatin in this patient population who often present varying degrees of renal obstruction from local tumor extension. (Table 5: comparison of current study and other carboplatin used schedules). Compared to 5 large randomized trials, carboplatin has a more favorable toxicity profile and administration schedule than cisplatin. The bone marrow suppressive effects of carboplatin were mostly limited to grade 1 or 2. In the group that added Tegafur-Uracil, compared to the regimen that included 5 FU, the incidence of grade 3–4 leucopenia and diarrhea was lower. (Table 6: comparison of current study and cisplatin used arm in 5 large randomized trials). In conclusion, the concurrent carboplatin with radiation treatment in the management of locally advanced cervical cancer was effective in tumor control with acceptable toxicity. The survival outcomes were also encouraging. To improved

Table 6 Comparison of current study and cisplatin used arm in 5 large randomized trials Study

n

Treatment

Med. FU (M)

PFS (%)

OS (%)

Hemato. Gr 3–4 (%)

GI Gr 3–4 (%)

Peter, 2000 [22] Key, 1999 [21] Morris, 1999 [18] Rose, 1999 [20]

127 183 193 192 191 177 235 234

RH → Cis/FU/RT Cis/RT Cis/FU/RT Cis/RT Cis/FU/HU/RT Cis/FU/RT Carbo/RT Carbo/TU/RT

42 36 43 35 35 8.7Yr 11.8 12.6

80 – 67 67 64 51 75 76

81 83 73 66 67 55 94 93

WC 33.8 21 38 WC 12 WC 24 WC 3.4 WC 2 WC 4

9.4 14 8.8 6 9 7.3 1 1

Whitney, 1999 [17] Current study

RH = radical hysterectomy, RT = radiation treatment, Cis = cisplatin, FU = 5 fluorouracil, HU = hydroxyurea, Carbo = carboplatin, TU = Tegafur-Uracil, Med FU = median follow-up, PFS = progression-free survival, OS = overall survival, Hemato. = hematologic toxicity, GI = gastrointestinal toxicity, WC = leucopenia.

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