Japanese Journal of Clinical Oncology 32:255-261 (2002)
© 2002 Foundation for Promotion of Cancer Research
Retrospective Analysis of Postoperative Radiotherapy for Node-negative Cervical Carcinoma with Stage IB–IIB Disease
Departments of 1 Radiation Oncology and 2 Gynecology, Aichi Cancer Center, Nagoya and 3 Department of Radiology, University of Mie School of Medicine, Tsu, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Background: We performed retrospective analysis to evaluate the outcomes of postoperative radiotherapy for patients with cervical carcinoma without lymph node metastasis.
Methods: From 1981 to 1995, 68 stage I–II cervical carcinoma patients without nodal disease who received adjuvant pelvic radiotherapy were entered into the present analysis. Criteria for postoperative radiotherapy were (1) deep stromal invasion (
1/2; n = 63), (2) positive parametrial invasion (n = 38) and (3) close or positive surgical margin (n = 21). The median patient age was 54.0 years (range, 29–69 years). The median dose of 45.3 Gy (range, 43.4–56.4 Gy) was delivered over the whole pelvis median 21.0 days (range 12–68 days) after surgery.
Results: The 5/10-year overall survival, disease-free survival, pelvic control and distant metastasis-free survival rates were 89.7/85.7, 85.3/83.2, 95.5/95.5 and 90.7/90.7%, respectively. Histology of adenocarcinoma (n = 4), large tumor size and prolonged period between operation and radiotherapy were significantly adverse prognostic factors of overall and disease-free survival by univariate analysis. The risk score referred from the GOG report correlated well with disease-free survival (P = 0.018), but showed only a tendency for overall survival as a prognostic factor (P = 0.07). Overall treatment time proved to be a significant variable for overall survival (P = 0.02), but not for disease-free survival (P = 0.056). Both risk score and overall treatment time proved to be significant prognostic factors in the multivariate model. Major adverse effects occurred in three patients (4.4%) without mortality.
Conclusions: In this analysis, clinical outcome from adjuvant postoperative radiotherapy was thought to be feasible with both satisfactory pelvic control and acceptable lower toxicity.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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There are certain treatment strategy variations for patients with cervical cancer of stage I–II disease within institutes and countries. In Japan, younger patients with stage II are usually treated with surgery (1) and elderly patients with radiotherapy. The results from both modalities are thought to be comparable in terms of clinical outcomes (2). Practically, the majority of patients with stage IB disease receive surgery. Some operated patients proved to have several risks, such as bulky disease (3–5), deep stromal invasion (3,4,6,7), lymph-vascular space invasion (4,7–9), lymph node metastasis (1,3,10,11), parametrial invasion (1,3,10), adverse histology (12,13), FIGO stage (3,7), surgical margin (11) and the delay and/or prolongation of radiation (14,15). Lymph node metastasis was one of the major reasons for adjuvant radiotherapy in the present treatment strategy (16). Patients with lymph node metastasis have worse survival estimates and are thought to be at risk of both local and distant failure.
In contrast, patients without lymph node metastasis are reported to have better clinical outcomes and the failure pattern is usually limited within the pelvis (4,17,18). Thus, local adjuvant therapy could be useful for such patients (19). However, careful selection for adaptation is required because of increasing morbidity and/or mortality (20–22), and there is the basic problem of stratification as a function of high risk among these groups (4,23–25). In a large GOG prospective study (4) on stage IB patients without lymph node metastasis, significant prognostic factors of disease-free interval were determined to be depth of tumor penetration, tumor size and capillary/lymphatic space involvement. This model required accurate values for both tumor size and depth and the scoring system is complicated. Hence it is difficult in practice to adopt it easily. In the present analysis, we evaluated clinical outcomes by a modified scoring system using the same prognostic factors of GOG score. We performed retrospective analysis to evaluate the outcome of adjuvant radiotherapy for node-negative patients with early-stage cervical carcinoma.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Patient Eligibility
From 1981 to 1995, 207 patients with cervical cancer were admitted to our department for postoperative radiotherapy. Of these, 11 received a simple hysterectomy (Nx) and nine were confirmed as having paraaortic lymph node metastasis. In addition, there were one, nine, one and one patients with stage Tis, T3, T4 and Tx, respectively. These 32 patients were excluded from the present analysis. The majority group treated with postoperative radiotherapy were 175 patients with stage I–II disease who received radical (class III) or modified radical extended hysterectomy (class II). Between 1981 and 1995, 478 patients with stage IB–IIB received operations. Thus, 36.6% of operated patients with stage I–II disease were prescribed adjuvant pelvic radiation. Sixty-eight of the 175 patients were confirmed as having negative nodes surgically and were entered into the present analysis. One hundred and seven patients with positive nodes were excluded from the analysis, because they were likely to have adverse outcomes compared with those with negative lymph nodes.
Criteria for postoperative radiotherapy among these patients were as follows:
(1) deep stromal invasion (1/2; n = 63);
(2) positive parametrial invasion (n = 38);
(3) positive or close (<5 mm) surgical margin (n = 21).
Patients’ Characteristics
Patient age, disease stage diagnosed by the International Federation of Gynecology and Obstetrics (FIGO), histopathological findings, tumor size, depth of stromal invasion, parametrial extension, vaginal margin status and lymph-vascular space invasion (LVSI) are summarized in Table 1. There were 61 patients with squamous cell carcinoma histology, two with adenosquamous cell carcinomas and four with adenocarcinomas. Only one patient had a carcinosarcoma (malignant mesodermal mixed tumor). The histological grade was not recorded in the majority of these patients (40 of 68), so we did not use it in this analysis. According to the GOG report, the risk score was assessed by large tumor size (40), presence of LVSI and deep stromal invasion (1/2). The patients were divided into groups with 0–1 risk or 2–3 risk as a function of these criteria. The details of the scoring system are shown in Table 2. Sixty-three patients received radical hysterectomy (class III), while the other five patients were treated with modified radical extended hysterectomy (class II).
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Radiotherapy
All patients received external beam radiotherapy (EBRT) using a linear accelerator. In the early period, cobalt was used in a small population. EBRT was given using a 6 MV photon beam with a daily dose of 1.9 Gy, five times per week. Basically, a total dose of 45.6 Gy was delivered over the whole pelvic region. EBRT was given using a unique technique, namely ‘two axial arc therapy using a multileaf collimator’ (26). With this method, the radiation dose to the bladder and rectum were reduced. Two patients received EBRT through antero-posterior parallel opposite portals during the first half of their radiation course. Seven patients with a positive or close margin of surgical proof were added a radiation boost to the surgical stump via a dynamic conformal technique. Five patients who required adjuvant radiation due to only positive or close margin received only small field radiation confined to the surgical stump using a dynamic conformal technique. The median dose of EBRT was 45.3 Gy, ranging from 43.4 to 56.4 Gy. The prescribed dose to the whole pelvis did not exceed 45.6 Gy among this series. The overall treatment time (OTT) of pelvic radiation and duration period (DP) between surgery and pelvic radiation are also given in Table 1. Only one patient received additional intracavitary brachytherapy with a 10 Gy boost using a radium source to the vaginal cuff. Three patients also received prophylactic paraaortic nodal irradiation of 44–45.3 Gy.
Follow-up
Patients were followed at 1–2 month intervals for the first 2 years and at 3–4 month intervals thereafter. Follow-up examinations included physical and pelvic examinations, Pap smears, blood counts and chemistry profiles. Chest X-rays were obtained every year in principle. Radiological and/or laboratory studies were performed if clinically indicated.
The last follow-up was performed on March 1, 2001. At that time, 56 patients were alive without disease and two patients were alive with disease. Eight patients died from disease 10.6 to 210.5 months after the initial treatment (median 24.6 months). Two patients died from intercurrent disease without any evidence of recurrent disease. The follow-up period for the 58 survivors ranged from 46.4 to 208.1 months (median 114.3 months). Late toxicity derived from treatment sessions was described by RTOG/EORTC toxicity criteria (27).
Statistical Analysis
Overall survival (OAS), disease-free survival (DFS), distant metastasis-free survival (DMFS) and pelvic control (PC) rates were calculated from the beginning of the operation according to the Kaplan–Meier method (28). DFS was defined with all deaths and recurrences as the event. PC was defined with pelvic failure as the event. Death and/or recurrence without pelvic failure did not count as an event in this category. DMFS accounted for all distant metastases as an event. Death due to other causes and failure without distant metastasis were not classed as events. For uni- and multivariate analyses, the host and treatment factors described in Table 1 were used. The log-rank test (29) was used to compare survival curves. The Cox proportional-hazards model (30) was used to estimate the relative risk after adjusting for prognostic factors. The final model considered only those variables that were statistically significant at the 10% level in stepwise regression. Proportions and means were compared by the chi-squared test and the Student’s t-test, respectively.
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Results for the Entire Group and Failure Pattern
For all 68 patients, the 5/10-year OAS, DFS, PC and DMFS rates were 89.7/85.7% (95% CI = 82.4–97.0/76.9–94.5%), 85.3/83.2% (95%CI = 76.9–93.7/74.0–92.4%), 95.5/95.5% (95% CI% = 90.6–100/90.6–100%) and 90.7/90.7% (95% CI = 83.6–97.8/83.6–97.8%), respectively.
In this series, we experienced 10 failures, of whom three had developed at pelvic, six at distant and one at both local and distant sites. All pelvic failures developed as peritoneal dissemination and all of them died due to disease 10.6–24.8 months after surgery. A vesico-rectal fistula due to pelvic tumor failure was observed in one patient. Only one patient recurred at the surgical stump accompanied by distant metastasis.
The most frequent sites of distant metastases were the lung (n = 5), followed by the liver (n = 3) and skin (n = 2). Virchow’s node metastasis and adrenal metastasis were each noted in one case. Two patients lived after salvage operations for solitary distant metastasis (lung and liver).
Univariate Analysis
Univariate analysis of predictive factors for each endpoint is shown in Table 3. Patients with a histology of adenocarcinoma had a significantly adverse OAS (5-year OAS: 25.0 vs 95.2%; P < 0.0001) and DFS (5-year DFS: 25.0 vs 90.5%; P < 0.0001) than those with squamous cell and adenosquamous cell carcinomas. Patients with large tumors (40 mm) had a significantly poorer OAS than those with small tumors (5-year OAS: 82.8 vs 96.8%; P = 0.0124). The same results were observed in the analysis of DFS (5-year DFS: 72.4 vs 96.8%; P = 0.0022). Patients scored as 0–1 risk factor had a significantly better DFS than those scored as 2–3 (5-year DFS: 93.9 vs 77.1%, P = 0.0182, Fig. 1), although it only showed a tendency as a prognostic factor of OAS (P = 0.0743). Prolongation of OTT (45 days) showed a significantly unfavorable influence on OAS (5-year OAS: 60 vs 92.1%; P = 0.0227), although it showed only a tendency as a poorer factor of DFS (P = 0.0559). Delay of pelvic radiation (DP 40 days) was a significantly adverse variable for both OAS (5-year OAS: 71.4 vs 91.8%; P = 0.0053) and DFS (5-year DFS: 57.1 vs 88.5%; P = 0.022).
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No patient with a 0–1 risk factor showed recurrence within the pelvic cavity. Patients with 2–3 risk factors had a 5-year PC rate of 91.4%. There was no significant difference between the two groups. Histology of adenocarcinoma was a significantly poorer factor of PC compared with squamous cell and adenosquamous cell carcinomas (5-year PC: 75 vs 100%; P = 0.0092). Prolonged OTT (
45 days) showed a significantly worse impact on PC (5-year PC: 60.0 vs 98.4%; P < 0.0001). Both histology with adenocarcinoma (5-year DMFS: 33.3 vs 93.5%; P < 0.0001) and delay of pelvic radiation (5-year DMFS: 66.7 vs 93.2%; P = 0.0254) were significantly unfavorable factors for DMFS, while tumor size showed only a tendency as a predictive factor of DMFS (P = 0.0614).
Multivariate Analysis
Several prognostic factors justified by univariate analyses were entered into the multivariate model. Tumor size and risk score were not entered into the same model, because the difference between the two factors was small. Histology of adenocarcinoma was excluded in the multivariate analysis due to small patient number (n = 4).
For the DFS model, both prolonged OTT [P = 0.0432; relative risk (RR) = 4.982] and a risk score of 2–3 (P = 0.0268; RR = 5.168) were significantly adverse factors in the model (Table 4). In terms of OAS, both prolonged DP (P = 0.0144; RR = 15.86) and OTT (P = 0.0436; RR = 5.253) were significant prognostic factors in the last model. Prolonged OTT was the only significantly adverse factor for both PC (P = 0.0048; RR = 32.06) and DMFS (P = 0.0192; RR = 8.579) in the multivariate model.
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Toxicity
Toxicity due to adjuvant postoperative radiotherapy is summarized in Table 5. Morbidity of small/large intestine of grades 1, 2, 3 and 4 was observed in one, three, one and one patient, respectively. There was bladder morbidity with grade 1 and bone with grade 2. Ureteral obstruction requiring surgery developed in one patient. This case was scored as grade 4 of NCI-CTC. Seven out of 68 patients developed lower leg edema, but required no antibiotics. Three out of 68 patients (4.4%) developed major adverse effects after treatment sessions.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Treatment results of surgery for early cervical cancer have not improved in the last few decades. During this period, adjuvant radiotherapy was believed to be efficacious in clinical practice, although apparent clinical benefit was shown. There have been many reports about the outcome of operations with or without adjuvant radiotherapy for early cervical carcinoma (3–14,16–19,23–25). Several clinical prognostic factors were reported as meaningful, such as bulky disease (3–5), deep stromal invasion (3,4,6,7) lymph-vascular space invasion (4,7–9) lymph node metastasis (1,3,10,11), parametrial invasion (1,3,10), adverse histology (12,13), FIGO stage (3,7), surgical margin (11) and the delay and/or prolongation of radiation (14,15). One of the most powerful predictors of DFS was reported to be lymph node metastasis (1,3,10,11,24).
Adjuvant radiotherapy for patients with node-positive disease was reported to reduce recurrences within the pelvis, although there is no apparent evidence of its survival benefits (16). Patients with node-positive disease had risk of both pelvic and distant failures (24), so adjuvant pelvic radiation would have only limited advantages in clinical application.
On the other hand, patients without nodal disease had different behaviors compared with those with nodal disease (4,19,25,31). Failures in these patients usually develop chiefly within the pelvis, but rarely at distant sites. Therefore, adjuvant pelvic radiation should have more advantages for these patients (19,31). However, adjuvant radiotherapy was reported to increase major complications (20,21), so its routine use should be avoided because of estimated excellent survival. In addition, efforts to refine the outcome of patients without nodal disease have intensified, because the estimated number of failures in early-stage patients with or without nodal disease is thought to be almost the same (24). In addition, failures in the latter case could be cured, because they are usually limited to the pelvis. The most important issue, therefore, is which patients without nodal disease should be treated with adjuvant radiotherapy.
Delgado et al. (4) reported results of a prospective large-size GOG study in which the significant prognostic factors for patients with stage IB cervical carcinoma without nodal disease proved to be depth of tumor penetration, tumor size and capillary/lymphatic space involvement. Using multivariate analysis, they proposed a model (GOG score) that predicts the disease-free interval. However, this scoring system requires correct values of both depth of stromal invasion (1 mm step) and tumor diameter and it is difficult to adopt it owing to complicated calculations using multiplication of coefficients for each risk factor. Although the patient number was small, Kridelka et al. (19) reported a prospective preliminary result, in which significant benefits in the disease-free interval from adjuvant radiotherapy were included among the high-risk patients decided by GOG score.
Recent completed GOG results (32) from prospective randomized control trials proved the significant benefit in relapse-free survival due to adjuvant radiotherapy for patients with early stage cervical carcinoma without nodal invasion. However, significant improvement in overall survival could not be reported. The patients at intermediate risk determined with the three prognostic factors (not quantitative) were entered into the analysis. This criterion is more practical and applicable than the previous one, but it is still complicated (Table 6). At 2 years, recurrence-free rates were 88 and 79% for the radiation and observation groups, respectively, which means a 47% reduction in the risk of recurrence (P = 0.008, one-tail). Major complications were observed in 6 and 2.1% for the radiation and observation groups, respectively. From the viewpoint of pelvic control and morbidity, the clinical results obtained in our series among the high-risk group are comparable to those in GOG #92 (32). Hence we believe our results from adjuvant postoperative radiotherapy are acceptable and meaningful, especially for lower morbidity.
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In the current study, large tumor size, histology of adenocarcinoma and the delay and/or prolongation of adjuvant radiotherapy showed significant adverse effects on survival by univariate analysis. A histology of adenocarcinoma was reported as a significant prognostic factor for patients without nodal disease (24,25), as in our study. In the multivariate analysis, both risk score and OTT were significant prognostic factors of DFS in this condition. The risk score reflected DFS in the present analysis, which encourages the feasibility of this criterion in terms of recurrence risk. In the present analysis, patients with two or more high-risk factors had a significantly lower survival rate than other patients. The reported GOG score (4) requires accurate values of both the depth of invasion and tumor size, hence we could not adopt it in our present analysis. However, in a recent GOG study (32) the eligible guidelines for adjuvant therapy were more convenient and applicable (Table 6). There are a few reports that mentioned OTT as a prognostic factor of survival among patients treated with adjuvant radiotherapy (14). The majority of these reports were analyzed among patients treated with definitive radiotherapy (15).
Several retrospective reports discussed the clinical outcomes of adjuvant radiotherapy for patients without nodal disease (25,31,33,34). Samlal et al. (25) reported results from multivariate analysis, in which significant prognostic factors were reported to be histology of adenocarcinoma, large fraction of cervical stroma and stromal inflammatory cell infiltration. However, the recurrence rates of patients with or without adjuvant radiotherapy were almost the same. Schorge et al. (31) reported that the prognostic factors of treatment failure were LVSI and histological grade. The rate of isolated pelvic recurrence in an adjuvant radiotherapy group was smaller than that in a no adjuvant group, although the difference between the groups did not reach statistical significance. The majority of these reports concluded that recurrence develops chiefly in the pelvis. In the present study, we experienced three failures at the pelvis, six at distant sites and one at both local and distant sites. The local failure ratio against distant site was in disagreement with reported data. Adjuvant radiotherapy probably reduced locoregional failures in our series.
During the last two decades, the treatment strategy has been consistent in our institutes. We referred to the outcome of adjuvant radiotherapy for node-negative patients in the reported data (Table 7). In some reports (35,36), outcomes from node-positive disease were included. The results obtained were comparable to the reported data. No mortality and three patients (4.4%) with major complications out of 68 were observed in our study. Considering the fact that 2.1% of patients in the control arm of GOG 92 (32) developed major morbidity, it was acceptable in practical use. We usually prescribe a moderately high dose (median 45.3 Gy) with ‘two axial arc therapy using a multileaf collimator’. Using this technique, we believe that severe complications can be avoided by reduction of the radiation dose to the critical organ. In our institutes, we did not usually apply intracavitary brachytherapy as adjuvant treatment, although excellent local control was achieved at 95.5%. We believe that the salvage use of intracavitary brachytherapy and/or surgery are satisfactory for recurrence at the vaginal cuff.
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CONCLUSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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In the current analysis, adjuvant radiotherapy for patients with high-risk node-negative disease was satisfactory with an excellent pelvic control rate and tolerably low morbidity. Application of our original technique of radiotherapy might be meaningful especially for lower toxicity.
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FOOTNOTES |
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+ For reprints and all correspondence: Takeshi Kodaira, Department of Therapeutic Radiology, Aichi Cancer Center. 1–1 Kanokoden Chikusa-ku, 464-8681 Nagoya, Aichi, Japan. E-mail: 109103@aichi-cc.jp
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Received February 21, 2002; accepted April 17, 2002
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