Predictive factor of distant recurrence in locally advanced squamous cell carcinoma of the cervix treated with concurrent chemoradiotherapy

Predictive factor of distant recurrence in locally advanced squamous cell carcinoma of the cervix treated with concurrent chemoradiotherapy

Available online at www.sciencedirect.com Gynecologic Oncology 108 (2008) 126 – 129 www.elsevier.com/locate/ygyno Predictive factor of distant recur...

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Available online at www.sciencedirect.com

Gynecologic Oncology 108 (2008) 126 – 129 www.elsevier.com/locate/ygyno

Predictive factor of distant recurrence in locally advanced squamous cell carcinoma of the cervix treated with concurrent chemoradiotherapy Makoto Hirakawa a,⁎, Yutaka Nagai a , Morihiko Inamine a , Kazuya Kamiyama a , Kazuhiko Ogawa b , Takafumi Toita b , Sadayuki Murayama b , Yoichi Aoki a a

Department of Obstetrics and Gynecology, Faculty of Medicine, University of the Ryukyus, 207 Uehara Nishihara, Okinawa 903-0215, Japan b Department of Radiology, Faculty of Medicine, University of the Ryukyus, Okinawa, Japan Received 22 April 2007 Available online 23 October 2007

Abstract Objective. To identify prognostic factors in patients with locally advanced squamous cell carcinoma of the cervix treated with concurrent chemoradiotherapy (CCRT). Methods. We analyzed 108 patients with FIGO stage Ib2–IVa carcinoma of the cervix treated with CCRT between 1996 and 2003 at the University of the Ryukyus Hospital. Patients with a local tumor size of 4cm or more in diameter or lymph node enlargement were treated with CCRT. Disease-free survival (DFS) was estimated by the Kaplan–Meier method. The log-rank test was used to test differences in survival. Fisher's exact test was used for univariate analysis. The Cox proportional hazard model was used for multivariate analysis. Results. The median age and the median follow-up were 50 years (range: 25–70 years) and 48 months (range: 4–102 months), respectively. The 4-year distant DFS of all patients were 83%. Thirty-two of 108 patients were diagnosed with recurrence. Twenty patients had distant failure, of which 17 had only distant metastasis, three patients both distant and loco-regional recurrence, and the remaining 12 patients recurred locoregionally. Positive serum squamous cell carcinoma antigen (SCC) immediately after CCRT was an independent predictive factor for distant recurrence on multivariate analysis. The 4-year distant DFS of these patients was 62.5%, which was significantly worse than 89.2% in patients with negative serum SCC level ( p = 0.003). It should be noted that the distant metastasis occurred within 6 months in six of the nine patients. Conclusion. Positive serum SCC immediately after the treatment was a predictive factor for distant recurrence. New strategies should be considered to control distant recurrence in this group of patients. © 2007 Elsevier Inc. All rights reserved. Keywords: Squamous cell carcinoma of the cervix; Serum squamous cell carcinoma antigen; Concurrent chemoradiotherapy; Distant recurrence

Introduction Carcinoma of the uterine cervix is a significant cause of death from cancer in women. The US National Cancer Institute released a clinical alert to practicing oncologists based on research showing significant improvement in survival when locally advanced carcinoma of the uterine cervix is treated with concurrent chemoradiotherapy (CCRT) [1]. Five clinical trials have shown a 30–50% improvement in survival and the local control rate was about 90% [2–6]. However, over 50% of the patients with recurrence were found to have distant metastasis after ⁎ Corresponding author. Fax: +81 098 895 1426. E-mail address: [email protected] (M. Hirakawa). 0090-8258/$ - see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2007.08.091

CCRT. It is therefore important to determine predictive factors that can detect early distant recurrence. Various predictive factors for recurrence in advanced carcinoma of the cervix have been reported, such as lymph node metastasis, tumor size, and hemoglobin level. Here, we analyzed retrospectively 108 patients with locally advanced squamous cell carcinoma of the uterine cervix treated with CCRT in our institution and investigated predictive factors for recurrence, especially distant recurrence. Materials and methods We analyzed retrospectively 108 patients with squamous cell carcinoma of the uterine cervix who were treated with CCRT between 1996 and 2003 at the University of the Ryukyus Hospital. Patient charts were reviewed in terms of

M. Hirakawa et al. / Gynecologic Oncology 108 (2008) 126–129 Table 1 Patient characteristics

Table 3 Multivariate analysis of predictive factors for distant disease-free survival No. of patients (n = 108)

Median age (years) Median follow up period (months) FIGO stage

Median serum SCC (ng/ml) Median tumor size (cm) Pre-treatment anemia Pelvic lymph node enlargement Median courses of chemotherapy Recurrence

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50 48 Ib2 II III IVa Pre-treatment immediately after CCRT

2 57 46 3 8.1 1.0 5.6 35 37

≦10.5g/dl

2 Distant Loco-regional Distant + loco-regional

Distant disease-free survival Odds ratio

(25–70) (4–102)

(IIa 2, IIb 55) (IIIa 1, IIIb 45)

Pre-treatment anemia Hb Tumor size Lymph node enlargement Serum SCC pre-treatment Immediately after CCRT

≧ 10.5 g/dl N5.5 cm N1.5 ng/ml N1.5ng/ml

0.373 1.575 0.443 3.392 0.332

95% CI

p

0.128–1.083 0.547–4.536 0.163–1.205 0.669–17.193 0.081–0.662

0.06 0.4 0.1 0.1 0.006

CI, confidence interval. (0.5–192.0) (0.3–38.4) (3.5–8.8)

(1–5)

17 12 3

subsequently every 3–6 months. Receiver-operating characteristic (ROC) curves were used to determine the best cut-off points for serum SCC level, pre-treatment hemoglobin level, and tumor size for predicting disease recurrence. Disease-free survival (DFS) curves were estimated by the Kaplan–Meier method. Differences were tested by the log-rank test. Fisher's exact test and the Cox proportional hazard model were used to analyze recurrence. p-values less than 0.05 were considered significant.

Results

clinicopathological and serological data. CCRT was applied to patients with local tumors of 4 cm or more and/or pelvic lymph node enlargement over a minimum diameter of 1 cm assessed by pretreatment computed tomography (CT) or magnetic resonance imaging (MRI). Patients with para-aortic lymph node enlargement were excluded. All patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 2, age 70 years, and adequate hematological (WBC count, 3000/μl–10,000/μl; hemoglobin, 9.0 g/dl, and platelet count, 100,000/μl), hepatic (bilirubin level, 1.5 mg/dl and aspartate aminotransferase/alanine aminotransferase, 2.5 × the upper limit of normal), renal (creatinine clearance, 60 ml/min), and cardiac functions (normal electrocardiographic findings). All patients gave their written informed consent for the treatment. The patients were treated with anterior–posterior and posteroanterior parallel-opposed ports of external beam radiotherapy (EBRT). The dose of ERBT was 50 Gy delivered in 25 fractions. The center shield (4 cm width at the midline) was set up after the delivering 40 Gy. High-dose rate intracavitary radiation therapy was delivered once per week with a fraction dose of 6 Gy at point A for three or four times. Patients received cisplatin 20 mg/m2 for 5 days every 3 weeks concomitant with radiotherapy [7]. The median course of chemotherapy was 2 courses (range; 1–5 courses). Serum SCC levels were measured before treatment and immediately after the completion of CCRT. All patients completed the planned CCRT. Follow-up examinations were conducted every month for the first year, every other month for the second year, and then Table 2 Univariate analysis of clinicopathological factors for distant and loco-regional recurrence

Patient characteristics are shown in Table 1. The median age was 50 years (range: 25–70 years). The median follow-up period was 48 months (range: 4–102 months). Staging of the disease was determined according to the International Federation of Gynaecology and Obstetrics (FIGO) classification. Stages were distributed as follows: 2 patients in Ib2, 2 patients in IIa, 55 patients in IIb, 1 patient in IIIa, 45 patients in IIIb, and 3 patients in IVa. Complete response was defined as no viable cancer cells clinically or pathologically at 3 months after the completion of CCRT. Complete response was achieved in 103 of 108 patients (95.4%) clinically and pathologically. The 4-year DFS of all patients treated with CCRT was 77%. The 4-year local and distant DFS of all patients were 90% and 83%, respectively. Thirty-two of 108 patients (29.6%) were diagnosed with recurrence. Twenty patients had distant failure, of which 17 had distant metastasis alone, three patients both distant and locoregional recurrence, and the remaining 12 patients recurred locoregionally. Several clinicopathological variables related to the distant and loco-regional recurrence are shown in Table 2. The cut-off levels of serum SCC level, pre-treatment hemoglobin level, and tumor size were determined as 1.5 ng/ml, 10.5 g/dl, and 5.5 cm, respectively, by the ROC curve (data not shown). Serum SCC level immediately after CCRT, pre-treatment

No. of patients No. of p No. of p (n = 108) DRa valueb LRRc valueb Serum SCC (ng/ml) Pre-treatment N1.5 ≦1.5 Immediately after N1.5 CCRTd ≦1.5 Pre-treatment Hb ≦10.5 (g/dl) N10.5 Tumor size (cm) ≦5.5 N5.5 Lymph node Yes enlargement No a

93 15 26 72 33 75 56 52 37 71

17 3 9 8 12 8 7 13 11 9

0.7

14 1 0.009 2 10 0.02 7 8 0.09 5 10 0.03 10 5

0.7 0.5 0.05 0.1 0.005

DR, distant recurrence; bFisher's exact test; cLRR, loco-regional recurrence; defective data (+) .

d

Fig. 1. Distant disease-free survival curve, stratifying the patients into risk group by elevated serum SCC immediately after CCRT.

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hemoglobin, and lymph node enlargement were significantly correlated with distant recurrence, and lymph node enlargement with loco-regional recurrence by univariate analysis (Table 2). When all of these variables were assessed by the Cox proportional regression analysis, elevated serum SCC immediately after CCRT was identified as only factor correlating significantly with distant recurrence (Table 3). Distant DFS curve is shown in Fig. 1, stratifying the patients into risk group by the factor of elevated serum SCC level immediately after CCRT. Nine of the 26 patients with the factor had distant recurrence. The 4-year distant DFS of these patients was 62.5%, which was significantly worse than 89.2% in patients with negative serum SCC level ( p = 0.003). It should be noted that the distant metastasis occurred within 6 months in six of the nine patients.

after CCRT had no discernable therapeutic advantage. Neoadjuvant chemotherapy before CCRT using a cisplatin-containing regimen might reduce distant metastasis. The combination of paclitaxel and cisplatin would be a candidate for this purpose, as this regimen was found to be superior to conventional cisplatin alone in recurrent or advanced squamous cell carcinoma of the cervix [19]. Our study shows that positive serum SCC immediately after CCRT is a significant predictor of distant recurrence in patients with locally advanced squamous cell carcinoma of the cervix treated with CCRT and would be helpful in identifying those patients who are at high risk of distant metastasis.

References Discussion Currently, CCRT is becoming the standard treatment for patients with locally advanced carcinoma of the uterine cervix or with early stage disease with poor prognostic factors [2–6]. When added to radiation, cisplatin reduces the relative risk of death from cervical carcinoma by 30–50% by decreasing local/ pelvic failure and distant metastases. Chemoradiation showed significant benefit for local recurrence and a suggestion of a benefit for distant recurrence. However, over 50% of the patients with recurrence were found to have distant metastasis after CCRT. It is therefore important to identify prognostic factors in patients with locally advanced squamous cell carcinoma of the cervix treated with CCRT and to determine predictive factors that can detect early distant recurrence. Kato and Torigoe [8] first described that serum SCC in squamous cell carcinoma of the uterine cervix was a useful marker for treatment. There are several reports that serum SCC level is useful in evaluating radiotherapy response, chemotherapy response and predicting an early recurrence [9–15]. Ohno et al. [16] demonstrated that among patients treated with radiotherapy alone, serum SCC level predicted response to treatment and was helpful in detecting recurrence. Hong et al. [17] found that the independent risk factor for distant metastasis in patients with squamous cell carcinoma treated by radiotherapy alone was elevated serum SCC level as well as FIGO stage, and lymph node enlargement assessed by CT/MRI. However, few reports have described the usefulness of serum SCC level in patients treated with CCRT. In our study population, serum SCC level immediately after CCRT was found to be an independent predictor of distant recurrence by multivariate analysis. The 4-year distant DFS of patients with positive serum SCC just after CCRT was 62.5%, which was significantly worse than 89.2% in patients with negative serum SCC level ( p = 0.003). It should be noted that the distant metastasis occurred within 6 months in six of the nine patients. We believe that this group of patients had distant micrometastases in their earlier stage of disease that were undetected by CT and MRI, and cisplatin used for CCRT was ineffective in controlling distant metastatic lesions. Therefore, new treatment strategy for distant metastases should be considered. Kim et al. [18] suggested that adjuvant chemotherapy with the same chemotherapeutic regimen given

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