outcomes and prognostic factors of cervical cancer after

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Outcomes and prognostic factors of cervical cancer afterconcurrent chemoradiationjog_1871 1315..1320

Tae-Eung Kim1, Byung-Joon Park4, Hyun-Sung Kwack5, Ji-Young Kwon1,Jang-Heub Kim2 and Sei-Chul Yoon3

1Department of Obstetrics and Gynecology, St. Pauls Hospital, Departments of 2Obstetrics and Gynecology and 3RadiationTherapy, Seoul St. Marys Hospital, College of Medicine, Catholic University of Korea, Seoul, 4Department of Obstetrics andGynecology, Incheon St. Marys Hospital, Incheon, and 5Department of Obstetrics and Gynecology, St. Vincents 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 andObstetrics stage IB1IVA 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 radiotherapywith 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, 596 months). Using multivariate analysis,stage (P =0.014), tumor size (P =0.043), and clinical response (P =0.001) had a significant effect on overallsurvival. 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 IB1IIA, 71.5% (standard error, 7.8%) forstage 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 supportivetherapy.

Conclusions: Cisplatin-based CCRT is well-tolerated. Good clinical response revealed a favorable correlationto 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 havecontinued to decrease the incidence and mortality of

cervical cancer in recent decades. In 1999, after publi-cation of five randomized trials,15 the National CancerInstitute (NCI) issued a clinical announcement thatimproved survival resulted when platinum-based che-

motherapy was added to radiation therapy in patientswith locally advanced cervical cancer.

In South Korea, cervical cancer was ranked as the6th most common gynecologic neoplasm in 2008,with 3888 new cases and a crude incidence rate of

15.8 women per 100 000.6

This study was conductedto evaluate the outcomes and the prognostic factorsfor cervical cancer after concurrent chemoradiation(CCRT).

Received: July 12 2011.Accepted: January 22 2012.Reprint request to: Professor Jang-Heub Kim, Department of Obstetrics & Gynecology, Seoul St. Marys Hospital, College ofMedicine, Catholic University of Korea, 505 Banpo-dong, Seocho-ku, 137-701 Seoul, Korea. Email: [email protected]

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doi:10.1111/j.1447-0756.2012.01871.x J. Obstet. Gynaecol. Res. Vol. 38, No. 11: 13151320, November 2012

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Methods

Patients

A total of 174 patients with untreated stage IB1IVAcervical cancer were entered into this retrospectivestudy. After approval from the Institutional Review

Board of the Catholic University of Korea, all patientswere evaluated for eligibility. The criteria included anEastern Cooperative Oncology Group performancestatus of 02, and normal hematologic, renal, and liverfunction. Patients were excluded if they met any of thefollowing criteria: history of other cancer; prior pelvicradiation or systemic chemotherapy; medical contrain-dications to chemotherapy; and para-aortic lymphad-enopathy (>1 cm in the short axis dimension) above thefirst lumbar vertebra on imaging study.

Treatment

External whole pelvis irradiation using 1015 MVphoton was performed with a dose of 1.8 Gy per frac-tion 5 times per week for a total dose of 50.4 Gy (range;50.456.0 Gy). External whole pelvis irradiation wasfollowed by high-dose rate intracavitary radiation withsix insertions (twice per week) with a fractional dose of5.0 Gy to a total dose of 30.0 Gy at point A. When

brachytherapy could not be done due to closed cervicalos or patient refusal, external-beam boost was added.Those patients were excluded in this study. Centralshielding was added after receiving 45 Gy radio-therapy. Typical field borders (four fields) for the

anteroposteriorposteroanterior (AP-PA) field were asfollows: the superior border (50% isodose line) was atthe L4L5 interspace; inferior border was at the lowerobturator foramen; and lateral borders were 1.5 cmlateral to the bony pelvis. For the lateral fields, thesuperior and inferior borders were the same, the ante-rior field border was at the anterior symphysis pubis,and the posterior border included the anterior sacralsilhouette. In cases of pelvic lymph node involvementon imaging study, external beam irradiation with 3-Dconformal technique to avoid rectum and bladder fromradiation field was performed with a dose up to 56 Gy.In case of para-aortic lymph node enlargement,

extended-field irradiation was administered. Theoverall treatment time was on average 60.4 days (range,5869 days).

Concurrent chemotherapy was given with one of thethree regimens of cisplatin-based chemotherapy: (i)weekly cisplatin (40 mg/m2) in 140 patients; (ii) cispl-atin (60 mg/m2 on day 1) and 5-FU (1000 mg/m2 perday on days 14) every 3 weeks in 13 patients; and (iii)

cisplatin (60 mg/m2) plus paclitaxel (135 mg/m2) every3 weeks in 21 patients.

Follow-up evaluation and statistical analysis

After completion of the whole treatment, the patientswere followed up at 1 month, then every 3 months forthe first 2 years and every 6 months thereafter withphysical examination, tumor marker and pelvicimaging study.

Response to treatment was evaluated based on bothpelvic imaging study and physical examination3 months after the completion of treatment. Completeresponse was defined as the disappearance of grosstumor clinically or radiologically, whereas the partialresponse was defined as a greater than 50% reductionof initial tumor volume.

We conducted immunoradiometric assay for mea-

suring squamous cell carcinoma antigen (SCC-Ag)level using an SCC kit (normal range 4 cm) and 40.2% were lymph-node-negative. Com-plete and partial remissions were achieved in 110patients (63.2%) and 37 patients (22.3%), respectively.

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Among the 116 patients with elevated SCC-Ag beforeCCRT, the level normalized in 77.6% of the patientsafter treatment.

Survival

A total of 151 out of 174 patients (86.8%) completed theplanned treatment. More than three cycles of weekly

cisplatin and more than two cycles of tri-weekly com-bined chemotherapeutic agents were administered tothe remaining 14 patients and nine patients, respec-tively. If there were myelosuppression, we delayedwhole treatment while maintaining supportive care. Incase of hepatic or renal toxicity, we omitted chemo-therapy. We did not reduce the dosage of chemothera-peutic agent due to toxicity. Forty patients (23.0%) hadrecurrences and 41 patients (23.6%) died.

Prognostic factors, such as stage, pelvic or para-aorticlymph node involvement, tumor size, clinical responseand SCC-Ag levels after CCRT were analyzed. Based onunivariate and multivariate analyses of PFS according tothese factors, stage (P =0.004), tumor size (P =0.02),clinical response (P = 0.011), and normalized SCC-Aglevel after CCRT (P =0.007) were statistically significant(Table 2). Based on univariate and multivariate analysison OS, stage (P =0.014), tumor size (P =0.043), and

clinical response (P =0.001) showed a significantoutcome (Table 3).

The estimated 5-year survival rates according topatient subgroups are described in Table 4. The 5-yearsurvival rates were 91.7% (standard error, 5.8%) forstages IB1IIA, 71.5% (standard error, 7.8%) for stageIIB, 44.9% (standard error, 7.8%) for stage III, and 20.9%(standard error, 12.0%) for stage IVA. Tumor size(


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90 days after the 1st day of radiotherapy. The inci-dence of colorectal toxicity was 18.4% (32/174) and theincidence of genitourinary toxicity was 15.5% (29/174),including three fistulas, which required surgical inter-vention. All six cases of lymphedema were grade 2.

Discussion

Despite a few contradictory reports,79

recent reviewsstrongly suggest that CCRT improves OS and PFS ofcervical cancer patients, whether or not platinumis used, with absolute benefits of 10% and 13%,respectively.1012 Like previous studies,15,8,13 we usedcisplatin alone in most patients and administered cis-platin combination regimens in some cases later in thisstudy.

The 5-year survival rates were 91.7% (standard error,5.8%) for stages IB1IIA, 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 ourstudy is retrospective, we have some disadvantages; 23

of 174 patients (14.2%) did not complete the plannedchemotherapy and 34 patients (19.5%) were adminis-tered cisplatin combination regimens; there was varia-tion for dose of external pelvic irradiation according topelvic lymph node status. Despite the obvious limita-tions of comparing our results from other reports,2,9,1416

the 5-year survival rates of stages IBIIB were compa-rable to other results; however, the 5-year survival rates

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 analysisP-value Hazard ratio(95%CI)

P-value Hazard ratio(95%CI)

Stage


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of stages III and IV were lower than other results. Thisdiscrepancy might be due to the fact that patients withpara-aortic lymph node involvement were excluded inother studies. In our study, there were 31 cases withstages IB1IIA. Those patients were older than 65 yearsold or medically unfit for radical surgery. After theexplanation that radiotherapy has almost equal thera-peutic benefit compared to surgery in this stage, weperformed CCRT to those patients.

Anemia, FIGO stage, tumor size, grade, and nodalstatus were reported as prognostic factors of cervicalcancer treated with CCRT.1619 Our study showed thatstage, tumor size and clinical response were prognosticfactors on OS. Lymph node status was not a prognosticfactor because lymph node status was judged accordingto lymph node size on imaging rather than lymph nodesampling.

Pretreatment SCC-Ag level was reported as a prog-

nostic factor on PFS and OS.20,21 In our study, we ana-lyzed normalized level of SCC-Ag after CCRT.Although this factor was shown to be associated withPFS, we failed to demonstrate that this factor pro-longed the OS.

Anemia may decrease tumor sensitivity to chemo-therapy and radiotherapy. Pretreatment hypoxia has

been known to be associated with lower overall anddisease-free survival, greater recurrence and less localcontrol in cervical cancer.22 A retrospective study alsoshowed that the mean hemoglobin level during treat-ment was one of the predictors of disease progres-

sion.23

Considering these outcomes, we tried to correctanemia with frequent transfusions in the presentstudy.

In this study there were three genitourinary fistulas,which required surgical intervention. Other toxicitieswere acceptable with supportive care. There was notreatment-related death.

It was recently reported that surgery after CCRT isfeasible.2426 Pathologic residual cervical tumor is thesingle independent factor which has been shown todecrease the probability of disease-free survival,27 and

best survival was observed for patients with a patho-logic complete response or microscopic residual

disease compared to patients with macroscopic resi-dues.28,29 Hence, maximal efforts to achieve this goal,such as new drug administration, consolidation che-motherapy,30 and surgery after CCRT, might prolongsurvival in patients with cervical cancer.

We conclude that cisplatin-based CCRT is well-tolerated, and additional modality will be needed toprolong survival of patients with poor prognostic factors.

Disclosure

The authors have no potential conflicts of interest todisclose.

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