Abstract
OBJECTIVE To investigate the factors that can accurately predict the prognosis for patients with FIGO stage-IB cervical squamous cell carcinoma treated with radical surgery.
METHODS A retrospective analysis of clinical data from 174 cases of FIGO Stage-IB cervical squamous cell carcinoma treated in our institute was conducted.
RESULTS The 5-year overall disease-free survival of the patients was 79.4% and the recurrence rate was 16.7%. Seventy-five percent of the 60 patients with a tumor > 4 cm and 28.1% of the 114 patients with a tumor ≤ 4 cm received preoperative radiotherapy, resuting in a significant difference between the two groups (P < 0.001). The 5-year disease-free survival rate for the groups with a tumor ≤ 4 cm without and with preoperative radiotherapy, and with a tumor > 4 cm without and with preoperative radiation therapy were 80.5%, 85.2%, 69.3% and 77.1%, respectively. There was no significant difference between any of the groups (P > 0.05). A univariate analysis showed that pelvic node metastasis, a positive parametrial surgical margin and postoperative adjuvant therapy were all significantly correlated with the 5-year disease-free survivals (P < 0.05). Multivariate analysis revealed that pelvic node metastasis (P = 0.004) and a positive parametrial surgical margin (P = 0.040) were independent factors that influenced the prognosis. The 5-year disease-free survivals for the cases with a tumor ≤ 4 cm and > 4 cm were 57.4% and 44.7% respectively in the high-risk group (patients with pelvic lymphatic metastasis and/or positive parametrial surgical margin) (P=0.575) and the recurrence ratio was 7/18 and 6/14 for the cases of the two tumor sizes in the same risk group. There was no significant difference between the two groups (P=0.821). The 5-year disease-free survivals for the cases with a tumor ≤ 4 cm and > 4 cm were 86.5% and 82.9% respectively in the low-risk group (patients without pelvic lymph-node metastasis and/or positive parametrial surgical margin), respectively (P > 0.05) and the recurrence ratio was 9/95 and 7/47 for the cases of the two tumor sizes in the same risk group. There was no significant difference between the two groups (P > 0.05).
CONCLUSIONS For FIGO Stage-IB cervical squamous cell carcinoma patients with radical surgery as the major means of treatment, the features of pelvic lymph-node metastasis and a positive parametrial surgical margin are independent factors that influence the prognosis. The tumor size can not be used as a criterion for predicting the prognosis.
keywords
In 1995, the standards for staging uterine cervix cancer were revised by the International Federation of Gynecology and Obstetrics [FIGO]. Stage IB was divided into IB1 (≤ 4 cm) and IB2 (> 4 cm), based on the tumor size. According to records from the literature, the overall survival of Stage-IB patients amounted to 90%, whereas the Stage-B2 patients accounted for 65% to 80% of the Stage-IB patients[1-4]. The curative effects of radiotherapy and surgical treatment for the Stage-IB patients were similar[5]. However, for the patients who received surgical treatment, besides preservation of the ovarian and vaginal functions and rare occurrence of the long-term complications in relation to the treatment, an overall postoperative pathological appraisement supplied sample histological parameters for prognostic evaluation, such as pelvic lymphatic metastasis, mesenchymal infiltration depth of the cervix, interstitial infiltration of lymphatic blood vessels and surgical margins, etc. Traditionally, the surgical treatment of cervical squamous carcinoma in FIGO Stage IB was used in our hospital. In our study, clinical data from 174 Stage-IB patients were retrospectively analyzed to understand the importance of tumor size as a prognostic factor as well as clinicopathologic factors for precisely predicting the end-results of treatment.
MATERIALS AND METHODS
Objective of the study
The inclusion criteria for cases in the study were as follows: a) pathologically confirmed squamous carcinoma of the cervix; b) Stage IB1 to IB2 of FIGO, combined therapy with surgical operation as the major means of treatment, and integrated clinical data; c) a conclusive follow-up result, such as disease-free survival, (follow-up time was not less than 60 months), recurrence and death, etc. After retrieval of the clinical data from the patients with squmaous carcinoma of the cervix, treated in our center during a period from January 1992 to December 2000, 174 patients were enrolled into the study.
Clinical data
The median age of the patients was 41 years old (ranging from 20 to 70). Among the patients 52 were young (≤ 35 years) and 122 older. The records of diagnosis and treatment for all cases were rechecked. For the clinicopathologic factors, such as the age, tumor size (FIGO staging), histodifferentiation, deep muscular invasion of the cervix, parametrial margin and distribution of the pelvic lymph-node metastasis, see Table 1.
Clinicopathologic factor distribution of patients with a tumor of ≤ 4 cm and > 4 cm.
Method of treatment
A total of 77 patients received preoperative radiotherapy (after-loading therapy) because the tumor was excessively big, with a mean dose of 16 Gy (6 to 30 Gy). An extensive whole-uterus excision plus bilateral pelvic lymphadeneotomy was performed for all cases. Postoperative adjuvant therapy was conducted for 85 patients because of pelvic lymph-node metastasis, tumor infiltration of deep muscular layer of the cervix or a positive parametrial margin, etc. among which 45 patients received radiation therapy, 20 received chemotherapy and 20 received both sequential chemotherapy and radiotherapy. Pelvic external irradiation was used for radiotherapy (46 to 50 Gy) and combined medication using cisplatins for chemotherapy, with a median course of two treatments (1 to 4 courses).
Statistical treatment
The chi-square test was employed for comparison of the enumeration data and life-table method for calculating the 5-year disease-free survivals (DFS). The Kaplan-Meier method was used for drawing survival curves and log-rank for the tests. The Cox and Logistic regression analyses were respectively conducted for multifactorial analysis of the survival and recurrence, and the SPSS10.0, a statistical software, was used for completing various statistical analyses. A P-value of < 0.05 was regarded to be a significant difference.
RESULTS
Distribution of the clinicopathologic factors in patients with a tumor of ≤ 4 cm and > 4 cm
As shown in Table 1, there was no significant difference in the age (≤ 35, > 35 years), differentiation of tumors (Stage-I to II and III), infiltration of deep muscular layers (no, yes), parametrial margins (negative, positive) and pelvic lymphatic metastasis (no, yes), as well as postoperative adjuvant therapy (no, radiotherapy, chemotherapy, chemotherapy plus radiotherapy) in patients with a tumor of ≤ 4 cm or > 4 cm (P > 0.05). Seventy-five percent of the patients with a tumor of > 4 cm (45/60) and 28.1% of patients with a tumor of ≤ 4 cm (32/114) received preoperative radiotherapy, resulting in a significant difference in treatment between the two groups (P < 0.001).
Effect of preoperative radiotherapy on Stage–IB squamous carcinoma of the cervix
As shown in Table 2, based on the tumor size and status of the preoperative radiotherapy, the 5-year disease-free survivals for the groups with a tumor ≤ 4 cm without and with preoperative radiotherapy, and with a tumor > 4 cm without and with preoperative radiation therapy were 80.5%, 85.2%, 69.3% and 77.1%, respectively. After the clinical tests, no significant difference was found between the groups (P > 0.05).
Preoperative radiotherapy and prognosis of stage IB cervical squamous cancer patients.
Monofactorial and multifactorial analysis of prognosis
Up to the last follow-up, 29 cases of relapse occurred in all of the groups, accounting for 16.7% (29/174). The 5-year overall disease-free survival was 79.4%. As shown in Table 3, monofactorial analysis indicated that there was a significant correlation between the 5-year disease-free survivals and related factors, such as pelvic lymph-node metastasis (P < 0.001), a positive parametrial margin (P < 0.001) and mode of postoperative adjuvant therapy (P = 0.023). There was no significant correlation between the tumor sizes (≤ 4 cm vs > 4 cm) (82.0% vs 75.0%, P = 0.053).
Monofactorial analysis for prognosis of the74 cases with FIGO stage IB cervical squamous cancer.
Results of the multifactorial analysis demonstrated, after adding the significative yielded from monofactorial analysis in the Cox model, that the independent factors which influenced the prognosis were the pelvic lymph-node metastasis (P = 0.004) and positive parametrial margin (P = 0.040).
The significance of the tumor size in the patients with different prognostic risk
Based on results of the prognostic analysis, the prognostic risk of the cases in the study can be divided into the high-risk (32 cases with pelvic lymph-node metastasis or a positive parametrial margin) and low-risk (142 cases without the aforementioned symptoms) groups. As seen in Table 4, there was no significant difference in the 5-year disease-free survivals (57.4% vs 44.7%, P = 0.575) and recurrence rate (7/18 vs 6/14, P = 0.821) between the 18 patients with a tumor of ≤ 4 cm and 14 patients with a tumor of > 4 cm in the high-risk group. In the low-risk group, there also was no significant difference in the 5-year disease-free survivals (86.5% vs 82.9%, P = 0.079) and recurrence rate (9/95 vs 7/47, P > 0.05) between the 96 patients with a tumor of ≤ 4 cm compared to 46 patients with a tumor of> 4 cm.
Effects of tumor size on survival and relapse in 32 cases of the high-risk and low-risk groups.
DISCUSSION
The factors influencing prognosis of the Stage-IB squamous carcinoma of the cervix and significance of the tumor size
Because preoperative adjuvant radiotherapy can minimize the local lesion and can enhance the excision rate[6], the percentage of the patients with a tumor of > 4 cm, who received preoperative radiotherapy was significantly greater than the patients with a tumor of ≤ 4 cm. Besides, there was no significant difference between the two groups in distribution of the clinicopathologic features, such as the age, tumor differentiation, infiltration of the deep muscular layer, a parametrial margin and pelvic lymph-node metastasis, etc.
To understand whether or not the preoperative radiotherapy and therapeutic measures related to the tumor size exert an influence on the prognosis, the 5-year disease-free survivals of the 4 groups, i.e. the groups with a tumor ≤ 4 cm without and with preoperative radiotherapy, and with a tumor > 4 cm without and with preoperative radiation therapy have been compared in the study. The results showed that preop erative radiotherapy had no significance in improving long-term survivals of the patients with stage IB1 or IB2 cervical squamous cancer. Monofactorial and multifactorial analyses were then conducted for the non-repeated clinicopatholgic parameters, such as the age, tumor size (FIGO staging), histodifferentiation, deep muscular layer infiltration of the cervix, a parametrial margin and pelvic lymph-node metastasis, etc. It was shown that the independent factors which influenced the prognosis of Stage-IB cervical squamous cancer were the pelvic lymphatic metastasis and a positive parametrial margin. The tumor size had little notable effect on the 5-year disease-free survival. Rutledge[7] et al. have reported a prognostic analysis of 197 cases with FIGO Stage IB uterine cervix cancer (of which 144 were squamous cancer) receiving radical surgery. The results showed that independent factors of the predictable disease-free survivals were the interspaceal infiltration of lymphatic blood vessels and two third extra-mesenchymal infiltration of the cervix[7]. Although our results were different from that study, we suggest that for Stage IB cervical cancer with surgery as the major mode of treatment, postoperative pathohistologic parameters might more precisely predict the prognosis of the disease, com-pared to the clinical parameter of tumor size.
Because the weight coefficient, a prognostic factor, was different[8], the tumor size might be used as a secondary factor along with pelvic lymph-node metastasis and a positive parametrial margin that influence the prognosis. In our study, the significance of tumor size in cases of the high-risk group (accompanied by pelvic lymph-node metastasis and / or a positive parametrial margin) and of the low-risk group (without above factors) have been further analyzed. The findings showed that for both cases of the high-risk group and of low-risk group, there was no significant correlation between the tumor size and 5-year disease-free survivals and the relapse rate. The results above suggest that the tumor size can not provide enough and reliable basis for predicting the prognosis of Stage IB squamous carcinoma of the cervix. The reasons might be related to the following factors, i.e. a) there is at present no standardized method for measuring the tumor size of the cervix. Clinical eye-measurement ranks first in diagnosis, with a bias and definite subjectivity of the observers; b) the form of the cervical tumor is varied, so any single diameter line can not exactly demonstrate the size of the tumor[9]; c) in clinical examinations, such as observation or palpation, it is difficult to precisely judge the size of an intracervical tumor.
Therapeutic strategy for Stage IB squamous carcinoma of the cervix
Screening can exactly predict the factors of the prognostic factors and can be helpful to the clinical staff for correct identification and prognosis of the highrisk cases, with a purposively-made rational individual therapeutic regimen. According to the results of our study, it is not rational to classify the clinical prognostic risk of Stage-IB patients based only on the tumor size or choice of the therapeutic modes. Since there was no significant correlation between the tumor size and incidence of operative complications[3,7], we believe that radical surgery should be preferred for Stage IB cancer cases which is suitable to a onestage operation. Then adequate adjuvant therapy, such as synchronous radiochemotherapy[10,11], can be selectively performed for cases with prognostic high risk (lymph node metastasis and a positive parametrial margin, etc.) based on a pathohistologic report. With a prospective enhancement of the long-term survival, this will avoid an increase of treatment-associated complications caused by unnecessary superposition of multiple therapeutic modes (such as new-adjuvant chemotherapy and/or preoperative radiotherapy, postoperative adjuvant radiotherapy and/or chemotherapy)[5,12,13].
In order to increase the opportunity of excision, neoadjuvant chemotherapy can be considered only when a cervical tumor appears inoperable or if it is unsettled as to whether or not the neoadjuvant chemotherapy can enhance long-term survival. Some scholars believe that neoadjuvant chemotherapy in combination with surgery can enhance long-term survival of the Stage IB2 and IIB patients[14,15]. Others have reported that neoadjuvant chemotherapy can markedly reduce the tumor diameter, but has little significant effect on improvement of the overall survivals and disease-free survivals[16,17]. Certainly, the above-mentioned therapeutic approach remains to be validated by prospective clinical trials.
To summarize, the results indicate that for FIGO Stage-IB squamous carcinoma of the cervix with the radical operation as the major therapeutic tool, pelvic node metastasis and a positive parametrial surgical margin are independent factors that influence the prognosis, and that the tumor size can not supply relevant prognostic information. The above findings will be of significant reference for guiding the selection of the mode of treatment for Stage-IB patients.
- Received January 13, 2007.
- Accepted March 4, 2007.
- Copyright © 2007 by Tianjin Medical University Cancer Institute & Hospital and Springer
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