Outcomes and prognostic factors of cervical cancer after concurrent chemoradiationjog_

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1 bs_bs_banner doi: /j x J. Obstet. Gynaecol. Res. Vol. 38, No. 11: , November 2012 Outcomes and prognostic factors of cervical cancer after concurrent chemoradiationjog_ Tae-Eung Kim 1, Byung-Joon Park 4, Hyun-Sung Kwack 5, Ji-Young Kwon 1, Jang-Heub Kim 2 and Sei-Chul Yoon 3 1 Department of Obstetrics and Gynecology, St. Paul s Hospital, Departments of 2 Obstetrics and Gynecology and 3 Radiation Therapy, Seoul St. Mary s Hospital, College of Medicine, Catholic University of Korea, Seoul, 4 Department of Obstetrics and Gynecology, Incheon St. Mary s Hospital, Incheon, and 5 Department of Obstetrics and Gynecology, St. Vincent s Hospital, Suwon, Korea Abstract Aim: Concurrent chemoradiation (CCRT) is the standard treatment for locally advanced cervical cancer. This study was undertaken to evaluate the outcomes and the prognostic factors for cervical cancer after CCRT. Material and Methods: The medical records of 174 patients with International Federation of Gynecology and Obstetrics stage IB1 IVA who were treated at three affiliated hospitals of the Catholic University of Korea between January 1999 and December 2008 were reviewed and analyzed. Patients received pelvic radiotherapy with one of three regimens of cisplatin-based chemotherapy concurrently and high-dose rate brachytherapy. The radiation field was extended to include para-aortic lymph nodes, if necessary. Results: The median follow-up period was 29.5 months (range, 5 96 months). Using multivariate analysis, stage (P = 0.014), tumor size (P = 0.043), and clinical response (P = 0.001) had a significant effect on overall survival. Similarly, progression-free survival (PFS) was influenced by stage (P = 0.004), tumor size (P = 0.02), clinical response (P = 0.011), and normalized squamous cell carcinoma antigen level after CCRT (P = 0.007). The 5-year survival rates were 91.7% (standard error, 5.8%) for stages IB1 IIA, 71.5% (standard error, 7.8%) for stage IIB, 44.9% (standard error, 7.8%) for stage III, and 20.9% (standard error, 12.0%) for stage IVA. A total of 151 out of 174 patients (86.8%) completed the planned treatment. Toxicities were manageable with supportive therapy. Conclusions: Cisplatin-based CCRT is well-tolerated. Good clinical response revealed a favorable correlation to survival. A maximal effort to achieve this goal might prolong survival in patients with cervical cancer. Key words: cervical cancer, concurrent chemoradiation, prognostic factor. Introduction Significant improvements in screening techniques, diagnostic procedures, and treatment modalities have continued to decrease the incidence and mortality of cervical cancer in recent decades. In 1999, after publication of five randomized trials, 1 5 the National Cancer Institute (NCI) issued a clinical announcement that improved survival resulted when platinum-based chemotherapy was added to radiation therapy in patients with locally advanced cervical cancer. In South Korea, cervical cancer was ranked as the 6th most common gynecologic neoplasm in 2008, with 3888 new cases and a crude incidence rate of 15.8 women per This study was conducted to evaluate the outcomes and the prognostic factors for cervical cancer after concurrent chemoradiation (CCRT). Received: July Accepted: January Reprint request to: Professor Jang-Heub Kim, Department of Obstetrics & Gynecology, Seoul St. Mary s Hospital, College of Medicine, Catholic University of Korea, 505 Banpo-dong, Seocho-ku, Seoul, Korea. janghkim@catholic.ac.kr 2012 The Authors 1315

2 T-E. Kim et al. Methods Patients A total of 174 patients with untreated stage IB1 IVA cervical cancer were entered into this retrospective study. After approval from the Institutional Review Board of the Catholic University of Korea, all patients were evaluated for eligibility. The criteria included an Eastern Cooperative Oncology Group performance status of 0 2, and normal hematologic, renal, and liver function. Patients were excluded if they met any of the following criteria: history of other cancer; prior pelvic radiation or systemic chemotherapy; medical contraindications to chemotherapy; and para-aortic lymphadenopathy (>1 cm in the short axis dimension) above the first lumbar vertebra on imaging study. Treatment External whole pelvis irradiation using MV photon was performed with a dose of 1.8 Gy per fraction 5 times per week for a total dose of 50.4 Gy (range; Gy). External whole pelvis irradiation was followed by high-dose rate intracavitary radiation with six insertions (twice per week) with a fractional dose of 5.0 Gy to a total dose of 30.0 Gy at point A. When brachytherapy could not be done due to closed cervical os or patient refusal, external-beam boost was added. Those patients were excluded in this study. Central shielding was added after receiving 45 Gy radiotherapy. Typical field borders (four fields) for the anteroposterior posteroanterior (AP-PA) field were as follows: the superior border (50% isodose line) was at the L4 L5 interspace; inferior border was at the lower obturator foramen; and lateral borders were 1.5 cm lateral to the bony pelvis. For the lateral fields, the superior and inferior borders were the same, the anterior field border was at the anterior symphysis pubis, and the posterior border included the anterior sacral silhouette. In cases of pelvic lymph node involvement on imaging study, external beam irradiation with 3-D conformal technique to avoid rectum and bladder from radiation field was performed with a dose up to 56 Gy. In case of para-aortic lymph node enlargement, extended-field irradiation was administered. The overall treatment time was on average 60.4 days (range, days). Concurrent chemotherapy was given with one of the three regimens of cisplatin-based chemotherapy: (i) weekly cisplatin (40 mg/m 2 ) in 140 patients; (ii) cisplatin (60 mg/m 2 on day 1) and 5-FU (1000 mg/m 2 per day on days 1 4) every 3 weeks in 13 patients; and (iii) cisplatin (60 mg/m 2 ) plus paclitaxel (135 mg/m 2 ) every 3 weeks in 21 patients. Follow-up evaluation and statistical analysis After completion of the whole treatment, the patients were followed up at 1 month, then every 3 months for the first 2 years and every 6 months thereafter with physical examination, tumor marker and pelvic imaging study. Response to treatment was evaluated based on both pelvic imaging study and physical examination 3 months after the completion of treatment. Complete response was defined as the disappearance of gross tumor clinically or radiologically, whereas the partial response was defined as a greater than 50% reduction of initial tumor volume. We conducted immunoradiometric assay for measuring squamous cell carcinoma antigen (SCC-Ag) level using an SCC kit (normal range <2.0 ng/ml). Among the patients with elevated SCC-Ag before receiving CCRT, normalized SCC-Ag levels were judged 3 month after completing treatment. Overall survival (OS) was assessed from the date of CCRT to death from any cause or the date of last contact. Progression-free survival (PFS) was measured from the treatment start to either the date of progression or the date of last contact. The OS and PFS curves were calculated according to the Kaplan Meier method. Differences in survival were compared using a log rank statistical test. Prognostic factor analyses for OS and PFS were performed using a Cox regression method. Hazard ratio is given with 95% confidence intervals. spss 12.0 was used for a statistical analysis. A P-value <0.05 was considered to be statistically significant. Results Patient characteristics The patients and tumor-associated characteristics are summarized in Table 1. Thirty-four patients (19.5%) were >71 years of age. The major histologic subtype of tumor was SCC (93.1%). The International Federation of Gynecology and Obstetrics (FIGO) stages were as follows: IB1 IIA, 17.8%; IIB, 50.5%; IIIB, 19.0%; and IVA, 12.6%. Of the tumors, 63.2% showed bulky tumor (>4 cm) and 40.2% were lymph-node-negative. Complete and partial remissions were achieved in 110 patients (63.2%) and 37 patients (22.3%), respectively The Authors

3 CCRT of cervical cancer Among the 116 patients with elevated SCC-Ag before CCRT, the level normalized in 77.6% of the patients after treatment. Survival A total of 151 out of 174 patients (86.8%) completed the planned treatment. More than three cycles of weekly Table 1 Patients characteristics (n = 174) n (%) Age (years) <30 1 (0.6) (7.4) (14.9) (26.4) (31.0) (17.8) >80 3 (1.7) Histology Squamous 162 (93.1) Adenosquamous 6 (3.4) Other type 6 (3.4) Stage IB1 IIa 31 (17.8) IIB 88 (50.5) III 33 (19.0) IVA 22 (12.6) Tumor size <4 cm 64 (36.8) >4 cm 110 (63.2) Lymph node status Negative 70 (40.2) Pelvic node positive 74 (42.5) Para-aortic node positive 30 (17.2) Clinical response Complete remission 110 (63.2) Partially remission 37 (22.3) Stable or progressive 27 (15.5) Tumor marker (SCC-Ag) Not elevated before CCRT 58 (33.3) Elevated before CCRT 116 (66.7) Normalized after CCRT 90/116 (77.6) Sustained after CCRT 26/116 (22.4) CCRT, concurrent chemoradiation; SCC-Ag, squamous cell carcinoma antigen. cisplatin and more than two cycles of tri-weekly combined chemotherapeutic agents were administered to the remaining 14 patients and nine patients, respectively. If there were myelosuppression, we delayed whole treatment while maintaining supportive care. In case of hepatic or renal toxicity, we omitted chemotherapy. We did not reduce the dosage of chemotherapeutic agent due to toxicity. Forty patients (23.0%) had recurrences and 41 patients (23.6%) died. Prognostic factors, such as stage, pelvic or para-aortic lymph node involvement, tumor size, clinical response and SCC-Ag levels after CCRT were analyzed. Based on univariate and multivariate analyses of PFS according to these factors, stage (P = 0.004), tumor size (P = 0.02), clinical response (P = 0.011), and normalized SCC-Ag level after CCRT (P = 0.007) were statistically significant (Table 2). Based on univariate and multivariate analysis on OS, stage (P = 0.014), tumor size (P = 0.043), and clinical response (P = 0.001) showed a significant outcome (Table 3). The estimated 5-year survival rates according to patient subgroups are described in Table 4. The 5-year survival rates were 91.7% (standard error, 5.8%) for stages IB1 IIA, 71.5% (standard error, 7.8%) for stage IIB, 44.9% (standard error, 7.8%) for stage III, and 20.9% (standard error, 12.0%) for stage IVA. Tumor size (<4 cm) and good clinical response also had significantly favorable outcome rates with respect to the 5-year OS. The OS curves for stage, tumor size, and clinical response are shown in Figure 1. Toxicity Toxicities were assessed weekly during the treatment and at the time of each visit and adjusted based on the NCI Common Terminology Criteria for Adverse Effect v 3.0. The acute common toxicities were hematologic (65/ 174 [37.4%]), gastrointestinal (48/174 [29.9%]), and renal (7/174 [4.0%]). Among these patients, four had grade 4 hematologic toxicity and the other cases were Table 2 Univariate and multivariate analysis of prognostic factor for progression free survival (Cox proportional hazard) Variables Univariate analysis Multivariate analysis Stage < ( ) < ( ) Pelvic or para-aortic lymph node involvement < ( ) ( ) Tumor size (> or <4 cm) < ( ) ( ) Clinical response < ( ) ( ) Tumor maker (normalized or sustained after CCRT) < ( ) ( ) Complete remission or partial remission or stable and progressive. CCRT, concurrent chemoradiation; CI, confidence interval The Authors 1317

4 T-E. Kim et al. Figure 1 Overall survival curves for stage (left, P = 0.01); tumor size (middle, P = 0.04); and clinical response (right, P < 0.01). CR, complete remission; PR, partial remission. Table 3 Univariate and multivariate analysis of prognostic factor for overall survival (Cox proportional hazard) Variables Univariate analysis Multivariate analysis Stage < ( ) ( ) Pelvic or para-aortic lymph node involvement < ( ) ( ) Tumor size (> or <4 cm) < ( ) ( ) Clinical response < ( ) < ( ) Tumor maker (normalized or sustained after CCRT) < ( ) ( ) Complete remission or partial remission or stable and progressive. CCRT, concurrent chemoradiation; CI, confidence interval. Table 4 Five-year OS rate for patients subgroup No. (%) of patients 5-year OS (%) %SE Stage IB1 IIA 31 (17.8) IIB 88 (50.5) III 33 (19.0) IVA 22 (12.6) Tumor size <4 cm 64 (36.8) >4 cm 110 (63.2) Clinical response Complete remission 110 (63.2) Partial remission 37 (22.3) Stable or progressive 27 (15.5) OS, overall survival; SE, standard error. <grade 4. Late toxicity was defined as that occurring >90 days after the 1st day of radiotherapy. The incidence of colorectal toxicity was 18.4% (32/174) and the incidence of genitourinary toxicity was 15.5% (29/174), including three fistulas, which required surgical intervention. All six cases of lymphedema were grade 2. Discussion Despite a few contradictory reports, 7 9 recent reviews strongly suggest that CCRT improves OS and PFS of cervical cancer patients, whether or not platinum is used, with absolute benefits of 10% and 13%, respectively Like previous studies, 1 5,8,13 we used cisplatin alone in most patients and administered cisplatin combination regimens in some cases later in this study. The 5-year survival rates were 91.7% (standard error, 5.8%) for stages IB1 IIA, 71.5% (standard error, 7.8%) for stage IIB, 44.9% (standard error, 7.8%) for stage III, and 20.9% (standard error 12.0%) for stage IVA. As our study is retrospective, we have some disadvantages; 23 of 174 patients (14.2%) did not complete the planned chemotherapy and 34 patients (19.5%) were administered cisplatin combination regimens; there was variation for dose of external pelvic irradiation according to pelvic lymph node status. Despite the obvious limitations of comparing our results from other reports, 2,9,14 16 the 5-year survival rates of stages IB IIB were comparable to other results; however, the 5-year survival rates The Authors

5 CCRT of cervical cancer of stages III and IV were lower than other results. This discrepancy might be due to the fact that patients with para-aortic lymph node involvement were excluded in other studies. In our study, there were 31 cases with stages IB1 IIA. Those patients were older than 65 years old or medically unfit for radical surgery. After the explanation that radiotherapy has almost equal therapeutic benefit compared to surgery in this stage, we performed CCRT to those patients. Anemia, FIGO stage, tumor size, grade, and nodal status were reported as prognostic factors of cervical cancer treated with CCRT Our study showed that stage, tumor size and clinical response were prognostic factors on OS. Lymph node status was not a prognostic factor because lymph node status was judged according to lymph node size on imaging rather than lymph node sampling. Pretreatment SCC-Ag level was reported as a prognostic factor on PFS and OS. 20,21 In our study, we analyzed normalized level of SCC-Ag after CCRT. Although this factor was shown to be associated with PFS, we failed to demonstrate that this factor prolonged the OS. Anemia may decrease tumor sensitivity to chemotherapy and radiotherapy. Pretreatment hypoxia has been known to be associated with lower overall and disease-free survival, greater recurrence and less local control in cervical cancer. 22 A retrospective study also showed that the mean hemoglobin level during treatment was one of the predictors of disease progression. 23 Considering these outcomes, we tried to correct anemia with frequent transfusions in the present study. In this study there were three genitourinary fistulas, which required surgical intervention. Other toxicities were acceptable with supportive care. There was no treatment-related death. It was recently reported that surgery after CCRT is feasible Pathologic residual cervical tumor is the single independent factor which has been shown to decrease the probability of disease-free survival, 27 and best survival was observed for patients with a pathologic complete response or microscopic residual disease compared to patients with macroscopic residues. 28,29 Hence, maximal efforts to achieve this goal, such as new drug administration, consolidation chemotherapy, 30 and surgery after CCRT, might prolong survival in patients with cervical cancer. We conclude that cisplatin-based CCRT is welltolerated, and additional modality will be needed to prolong survival of patients with poor prognostic factors. Disclosure The authors have no potential conflicts of interest to disclose. References 1. Whitney CW, Sause W, Bundy BN et al. 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