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Postoperative low-pelvic irradiation for stage I–IIA cervical cancer patients with risk factors other than pelvic lymph node metastasis
Int. J. Radiation Oncology Biol. Phys., Vol. 53, No. 5, pp. 1284 –1290, 2002 Copyright © 2002 Elsevier Science Inc. Printed in the USA. All rights reserved 0360-3016/02/$–see front matter
PII S0360-3016(02)02831-6
CLINICAL INVESTIGATION
Cervix
POSTOPERATIVE LOW-PELVIC IRRADIATION FOR STAGE I–IIA CERVICAL CANCER PATIENTS WITH RISK FACTORS OTHER THAN PELVIC LYMPH NODE METASTASIS JI-HONG HONG, M.D., PH.D.,*† CHIEN-SHENG TSAI, M.D.,* CHYONG-HUEY LAI, M.D.,‡ TING-CHANG CHANG, M.D.,‡ CHUN-CHIEH WANG, M.D.,* STEVE P. LEE, M.D., PH.D.,§ CHIH-JEN TSENG, M.D.,‡ AND SWEI HSUEH, M.D.㛳 Departments of *Radiation Oncology, ‡Obstetrics and Gynecology, and 㛳Pathology, Chang Gung Memorial Hospital and Chang Gung University; †Department of Medical Technology, Chang Gung University School of Medicine, Taoyuan, Taiwan; §Department of Radiation Oncology, University of California, Los Angeles, School of Medicine, Los Angeles, CA Purpose: To retrospectively investigate whether postoperative low-pelvic radiotherapy (RT) is an appropriate treatment for node-negative, high-risk Stage I–IIA cervical cancer patients. Methods and Materials: A total of 228 Stage I–IIA cervical cancer patients treated by radical surgery and postoperative RT were included in this study. All patients had histopathologically negative pelvic node metastasis, but at least one of the following risk factors: parametrial involvement, positive or close resection margins, invasion depth two-thirds or greater cervical stromal thickness. Seventy-nine patients (35%) received 30 –50 Gy (median 44) to whole pelvis and a boost dose to the low pelvis (whole-pelvic RT group); the other 149 patients (65%) received low-pelvic RT only (low-pelvic RT group). For both groups, the total external RT dose to the low pelvis ranged from 40 to 60 Gy (median 50). The potential factors associated with survival, small bowel (gastrointestinal) complications, and leg lymphedema were analyzed, and patients who had a relapse in the upper pelvis were identified. Results: The 5-year overall and disease-specific survival rate was 84% and 86%, respectively. After multivariate analysis, only bulky tumor (>4 cm) and non–squamous cell carcinoma were significantly associated with survival. Parametrial involvement, lymph-vascular invasion, <50.4 Gy to the low pelvis, positive or close margins, and low-pelvic RT alone did not significantly affect survival. Grade I–V small bowel complications occurred in 33 patients (15%). Whole pelvic RT and >50.4 Gy to the low pelvis, but not old age and treatment technique (AP–PA vs. box), were significantly associated with gastrointestinal complications. Three patients (2%) in the low-pelvic RT group and 6 patients (8%) in the whole-pelvic RT group were found to have Grade III or higher small bowel complications (p ⴝ 0.023). Thirty-one percent of patients developed lymphedema of the leg. A dose to the low pelvis >50.4 Gy and an AP–PA field, but not whole-pelvic RT, old age, or the number of sampled lymph nodes, were associated with lymphedema of the leg. Five patients (3.6%) of the low-pelvic RT group and none of the whole-pelvic RT group developed upper pelvis relapse. Three of these 5 patients had upper pelvic relapse alone. Conclusion: Compared with whole-pelvic RT plus low-pelvic boost, low-pelvic RT alone significantly reduces the small bowel complications in node-negative, high-risk, Stage I–IIA cervical cancer patients. Although low-pelvic RT alone increases the incidence of upper pelvic relapse, its effect on survival is not substantial. Low-pelvic RT alone appears to be an appropriate treatment method for this group of patients. © 2002 Elsevier Science Inc. Early-stage cervical cancer, Postoperative radiotherapy, Low-pelvic irradiation, Gastrointestinal complications, Lymphedema.
INTRODUCTION Radical surgery is an effective treatment for early-stage (Stage IB–IIA) cervical cancer patients. However, risk factors such as pelvic lymph node metastasis, bulky tumor size, deep stromal invasion, positive resection margins, adenocarcinoma, and capillary or lymphatic vascular involvement have been shown to correlate with an increased incidence of treatment failure (1–3). Patients with these risk factors were
usually suggested to receive postoperative adjuvant treatment. Although most studies showed that adjuvant radiotherapy (RT) significantly reduced local relapse (2, 4), its impact on survival improvement was controversial and depended on the selection criteria used in each study (2, 4 – 6). Our prior experiences showed that postoperative chemoradiotherapy significantly increases relapse-free survival and overall survival in patients with pelvic lymph node metas-
Reprint requests to: Ji-Hong Hong, M.D., Ph.D., Department of Radiation Oncology, Chang Gung Memorial Hospital, No. 5 FuShin St., Kwei-Shan, Taoyuan, Taiwan. Tel: 886-3-328-2177; Fax: 886-3-328-0797; E-mail: [email protected] Presented at the ASTRO 43rd annual meeting in San Francisco,
CA, November 4 – 8, 2001. Acknowledgment—The authors thank Shin-Shin Lee, M.P.H. for her assistance in the statistical analysis. Received Nov 15, 2001, and in revised form Mar 13, 2002. Accepted for publication Mar 19, 2002. 1284
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tases but no parametrial extension (2). We also found that for patients with risk factors other than pelvic lymph node metastasis, adjuvant RT significantly improved relapse-free survival and marginally increased overall survival (2). Our data supported the idea that postoperative adjuvant RT is beneficial for certain subsets of patients. Postoperative RT for cervical cancer patients, however, did increase the incidence of complications. Barter et al. (7) reported that as many as 16% of patients developed serious complications requiring surgery after adjuvant RT. In a randomized trial of pelvic RT vs. no further therapy in selected patients after radical hysterectomy, a higher percentage of Grade III/IV urinary and gastrointestinal (GI) complications was found in patients receiving postoperative RT (4). The incidence of lymphedema of the foot could be 42% at 5 years in patients receiving adjuvant RT (8). Because the volume of irradiated normal tissue is a major factor affecting the degree of complications, Kridelka et al. (9) used a small pelvic field instead of whole-pelvic RT as an adjuvant treatment of nodenegative, high-risk cervical cancer patients. Their pilot study demonstrated that only 1 (4%) of 25 patients had pelvic relapse and no major morbidity was found. However, the case number in the study was small, and the authors suggested a need for further verification. We identified the risk factors associated with treatment failure in early-stage cervical cancer patients receiving adjuvant RT (10). For patients without pelvic lymph node metastasis, the 5-year disease-specific survival rate was 87%. Because of the high survival rate of these patients, we tried to reduce the complications by treating patients with a smaller (low-pelvic) field instead of the conventional whole-pelvic field. In both treatment fields, the first echelon-draining nodes of the cervix were included, although the histopathologic findings showed negative nodal metastasis. The “low-pelvic” field excluded the common iliac nodes and consequently reduced the irradiated volume of small bowel and lymphatic channels, which was expected to decrease complications. In the present study, we aimed not only to compare the incidence of small bowel complications and lymphedema after RT with different fields, but also to identify the factors associated with rates of survival and treatment failure. We evaluated whether lowpelvic RT compromises pelvic control and assessed the relapse rate in the upper pelvis covered within the whole-pelvic field but excluded in the low-pelvic field. Our goal was to devise an appropriate method to reduce the complications, but not comprise patients’ survival. Because the sample size in this study was relatively large, our findings may be worthy references for others to select an appropriate postoperative RT method for node-negative, high-risk, early-stage cervical cancer patients. METHODS AND MATERIALS Between January 1990 and December 1997, 228 women with International Federation of Gynecology and Obstetrics Stage IB–IIA cervical cancer were treated in our institute and included in this study. All patients were treated by radical hysterectomy and bilateral pelvic node dissection and postop-
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erative radiotherapy (RT). Para-aortic lymph node sampling was performed only when para-aortic lymph node metastasis was suspected. Patients included in this study had negative pelvic node metastasis by histopathologic examination, but had at least one of the following findings: parametrial involvement, positive or close (⬍3 mm) resection margin, invasion depth two-thirds or greater cervical stromal thickness. Lymph-vascular permeation was considered as a risk factor, but it alone was not an indication for adjuvant RT. More than 80% of surgical samples were examined by a pathologist (S.H.) who specialized in gynecologic oncology. The percentage of patients with different pathologic risk factors are listed in Table 1. An invasion depth of two-thirds or greater cervical stromal thickness was present in 91% patients and was the most common indication for adjuvant RT. Fifty-four percent of patients had more than one pathologic risk factor. The patient clinical characteristics and treatment methods are also listed in Table 1. The median age at diagnosis was 53 years. The median number of sampled lymph nodes shown in the pathologic report was 22 (range 5–57). The number of sampled lymph nodes was not recorded for 2 patients. Of the 228 patients, 77% and 23% had Stage IB and IIA disease, respectively. Forty-six patients (20%) had bulky cervical tumor, defined as tumor diameter ⱖ4 cm by pelvic examination. Squamous cell carcinoma (SCC) was diagnosed in 88% of patients, the rest had adenocarcinoma or adenosquamous cell carcinoma; no patient with small cell carcinoma was included. Before surgery, the usual radiographs, endoscopic examinations, and laboratory analyses were carried out, and all patients underwent pelvic and abdominal CT or MRI to evaluate the primary tumor extension and lymph node status. Preoperative chemotherapy was given to 22 patients with bulky tumor. The chemotherapy regimen and scheme was the same as that previously reported (11). In brief, patients received cisplatin 50 mg/m2 by i.v. drip for 1 h, vincristine 1 mg/m2 by i.v. bolus on Day 1, and bleomycin 25 mg/m2 daily by continuous i.v. infusion for 72 h from Day 2. The regimen was repeated at 10-day intervals for 3 cycles followed by radical hysterectomy. Adjuvant external beam RT (EBRT) was delivered with 10-MV or 15-MV X-rays by a parallel-opposed (AP–PA) or 4-field box technique. The daily fraction size was 1.8 –2 Gy, 5 fractions weekly. The treatment field was categorized as low pelvis and whole pelvis. Typical simulation films for these 2 fields are shown in Fig. 1. The boundaries of the whole-pelvic field were similar to the standards recommended by Perez (12) in which the superior (cephalad) boundary was set at the L4–L5 junction. The low-pelvic field irradiated the primary tumor bed and first echelon lymph nodes and excluded the upper pelvic nodes. The superior boundary of the lowpelvic field was usually set at 1–2 cm above the low end of the sacroiliac joint; the other boundaries resembled those for the whole-pelvic field. The median length of the cephalocaudal direction at the mid-plane was 18 cm (range 15–22) for whole pelvis and 12 cm (range 10–14) for the low pelvis. Of the 228 patients, 149 (65%) received low-pelvic EBRT alone (median dose 50 Gy, range 40 – 60) and were categorized as the lowpelvic RT group. Seventy-nine patients (35%) received 30– 45
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Table 1. Patient characteristics and distribution of clinical and pathologic parameters All patients Patient total (n) Age (y) Median Range Stage (n) IB IIA Preoperative tumor size (n) Bulky tumor (ⱖ4 cm) Nonbulky tumor Uncertain Histologic features (n) Squamous cell carcinoma Non–squamous cell carcinoma Pathologic risk factors† Invasion ⱖ2/3 stroma thickness Parametrial invasion Positive or close vaginal margin Lymphovascular permeation Field direction AP–PA Box Sampled lymph nodes‡ (n) Median Range
228
Low-pelvis group 149
Whole-pelvis group
p*
79
53 25–75
53 25–75
54 32–71
176 (77) 52 (23)
119 (80) 30 (20)
57 (72) 22 (28)
0.2
46 (20) 170 (76) 12 (4)
26 (17) 114 (77) 9 (6)
20 (25) 56 (71) 3 (4)
0.25
200 (88) 28 (12)
128 (86) 21 (14)
72 (91) 7 (9)
0.2
208 (91) 31 (14) 29 (13) 104 (46)
137 (92) 11 (7) 21 (14) 64 (43)
71 (90) 20 (28) 8 (10) 40 (51)
0.6 0.0002 0.39 0.27
97 (43) 131 (57)
69 (46) 80 (54)
28 (35) 51 (65)
0.09
22 5–57
23 5–57
20 8–49
* Numbers in parentheses are percentage. Comparison between low-pelvis group and whole-pelvis group. Patients might have more than one risk factor. Comparisons were made based on each risk factor. ‡ Lymph node number not provided in pathologic report in 2 cases. †
Gy (median 44) whole-pelvic RT and subsequently received a boost to the low pelvis up to a total of 40– 60 Gy (median 50) and were categorized as the whole-pelvic RT group. The selection of treatment field and technique was not randomized, but was determined by the preferences of the responsible attending physician. However, patients with positive resection margins were usually treated with higher low-pelvic doses. The distribution of the clinical and pathologic parameters of
both groups are outlined in Table 1. Significant differences were detected only in the risk factor of parametrial invasion, for which the whole-pelvic RT group had a significantly higher incidence. After EBRT, 198 patients (87%) received additional vaginal cuff RT using high-dose-rate remote after-loading techniques. Intravaginal brachytherapy was usually given in 2 or 3 fractions to a total dose of 4– 6 Gy at 0.5– 0.75 cm below the vaginal mucosa.
Fig. 1. Typical simulation films for the 2 fields. The boundaries of the low-pelvic field were the same as those of the whole-pelvic field except the superior boundary was reduced from the L4 –L5 junction to the level of 1–2 cm above the low end of the sacroiliac joint (shown by the dotted line).
Postoperative low-pelvic RT for node-negative cervical cancer
Patients were followed regularly up to December 2000 (minimal follow-up 3 years). Two patients were lost to followup. The follow-up frequency was every 2–3 months for the first year, 3– 4 months for the second year after treatment, and every 4 – 6 months thereafter. Local recurrence was defined by either pathologic proof of recurrence in the vaginal and/or adjacent tissues or an imaging study showing regrowth of tumor or enlargement of a pelvic lymph node below the L4–L5 junction. Distant metastasis was also defined by pathologic, cytologic, or radiologic evidence; para-aortic node relapse above the L4 –L5 junction was considered distant failure. In this study, we only defined the initial failure site or sites as the site of treatment failure. The definition of synchronous local and distant failure was an interval between the two events of ⬍1 month. The severity of small bowel complications was according to the late radiation morbidity scoring schema defined by the Radiation Therapy Oncology Group and European Organization for Research and Treatment of Cancer (13). Lymphedema was defined as swelling of the leg and thigh as determined by physical examination. Statistical analysis of the data was carried out by the chi-square test. Survival curves were constructed using the Kaplan–Meier method, and comparisons between curves were performed by the log–rank test. Multivariate analysis of the prognostic factors for survival and risk factors for complications was made by the Cox proportional hazard model and logistic regression model, respectively. RESULTS Survival rate, prognostic factors, and relapse pattern The 5-year overall and disease-specific survival rate was 84% and 86%, respectively, for all patients. We assessed the association of clinical and pathologic factors with the survival rate. The 5-year disease-specific survival rate was 91% vs. 64% for nonbulky vs. bulky disease (p ⫽ 0.0001); 88% vs. 74%, for SCC vs. non–SCC (p ⫽ 0.02); 80% vs. 87% for with vs. without parametrial involvement (p ⫽ 0.26); 87% vs. 86% for with vs. without lymph-vascular permeation (p ⫽ 0.74), 75% vs. 88% for with vs. without positive or close resection margins (p ⫽ 0.059); 89% vs. 81% for ⱕ50.4 Gy vs. ⬎50.4 Gy to the low pelvis (p ⫽ 0.22); 87% vs. 84% for the lowpelvic RT group vs. the whole-pelvic RT group (p ⫽ 0.57). As shown in Table 2, only bulky tumor and non–SCC histologic features were significantly associated with poor disease-specific survival by multivariate analysis. The risk ratio for bulky tumor was 5.56 (95% confidence interval [CI] 2.3–13.7, p ⫽ 0.0002) and for non–SCC was 6.9 (95% CI 2.3–20.2, p ⫽ 0.0004), with both factors proven to be independent prognostic factors. These results suggest that a higher radiation dose (⬎50.4 Gy) and larger treatment portal (whole pelvis) did not significantly improve patient survival in general. Even for patients in the low-pelvic RT group, no benefit from the higher radiation dose was found, because the 5-year disease-specific survival rate was 88% vs. 85% for the low-pelvic dose ⱕ50.4 Gy vs. ⬎50.4 Gy (p ⫽ 0.98). Because 54% of patients had more than one pathologic risk factor, we analyzed its impact on
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Table 2. Multivariate analyses of certain factors on diseasespecific survival Factor Tumor size Nonbulky* Bulky Parametrial involvement No* Yes Lymph-vascular permeation No* Yes Radiation dose (Gy) ⱕ50.4* ⬎50.4 Resection margin Negative* Positive or close Histologic type SCC* Non–SCC Treatment field Low-pelvis group* Whole-pelvis group
RR (95% CI)
p
1 5.6 (2.3–13.7)
0.0002
1 1.5 (0.5–4.7)
0.51
1 1.5 (0.6–3.6)
0.41
1 1.1 (0.4–3.1)
0.81
1 2.1 (0.5–7.9)
0.3
1 6.9 (2.3–20.3)
0.0004
1 1.1 (0.4–2.9)
0.87
Abbreviations: RR ⫽ risk ratio; CI ⫽ confidence interval; SCC ⫽ squamous cell carcinoma. * Reference category.
survival. The 5-year disease-specific survival rate was 86% vs. 87% for patients with 1 vs. ⬎1 pathologic risk factor (p ⫽ 0.87), suggesting that patients with more than one pathologic risk factor were not prone to worse survival after adjuvant RT. Thirty-five patients (15%) had local failure or distant metastasis. Of the 35 patients, 11 (31%), 19 (54%), and 5 (14%) had initial relapse at local, distant, or synchronous local and distant sites, respectively. The risk of distant failure was higher than that of local relapse. We also analyzed the effects of the treatment field, because it might have affected the incidence and location of treatment failure. The incidence of local failure, distant relapse, and synchronous local and distant failure for patients in the low-pelvic RT group vs. the whole-pelvic RT group was 6.5% vs. 2.5%, 8% vs. 10%, and 2% vs. 2.5%, respectively; no statistical significance could be detected (p ⫽ 0.396). Relapse in the upper pelvis, which was out of the low-pelvic field, was found in 5 patients (3.4%) in the lowpelvic RT group and in no patients in the whole-pelvic RT group (p ⫽ 0.1). Only 3 of 5 patients had an isolated relapse in the upper pelvis. Of the remaining 2, 1 had synchronous relapses at the upper pelvis and paraaortic region and 1 had other distant failure. These data suggest that whole-pelvic RT effectively prevents upper pelvis failure, but its effect on improving patients’ survival is not substantial and should be ⬍3.4%. Complications and factors associated with complications Because the treatment field will affect the volume of irradiated small bowel and lymphatic tissue, small bowel complications and lymphedema were our primary concern in analyzing
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Table 3. Multivariate analyses by logistic regression to evaluate effects of certain factors on small bowel complications OR (95% CI) RT dose to low pelvis (Gy) ⱕ50.4* ⬎50.4 Treatment field True-pelvis group* Whole-pelvis group Field direction Box* AP–PA Age (y) ⬍60* ⱖ60
1 2 (0.50–7.96) 1 2.29 (1.0–5.35)
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Table 4. Small bowel complications in patients treated with lowpelvic RT alone (low-pelvis group) and whole-pelvic plus lowpelvic RT (whole-pelvis group)
p
0.1026
Grade
Low-pelvis group (n)
Whole-pelvis group (n)
0 1–2 3–5 Total*
130 (89.7) 12 (8.3) 3 (2.1) 145 (100)
57 (76) 12 (16) 6 (8) 75 (100)
0.05
1 1.02 (0.44–2.21)
0.96
1 1.27 (0.52–3.14)
0.60
Abbreviations: OR ⫽ odds ratio; CI ⫽ confidence interval; RT ⫽ radiotherapy. * Reference category.
the complications. Grade I–V small bowel complications occurred in 33 patients (15%). The median time of having bowel complications was 13 months (range 0–101) after RT. We examined the association of GI complications with the radiation dose to the low pelvis (ⱕ50.4 Gy vs. ⬎50.4 Gy), treatment field (low-pelvic RT group vs. whole-pelvic RT group), field directions (AP–PA vs. box), and age (⬍60 years vs. ⱖ60 years). The incidence of small bowel complications was 23% vs.10% for radiation dose to the low pelvis of ⬎50.4 Gy vs. ⱕ50.4 Gy (p ⫽ 0.012); 24% vs.10% for whole-pelvic RT group vs. low-pelvic RT group (p ⫽ 0.007); 16% vs. 13% for AP–PA portal vs. box technique (p ⫽ 0.536); and 17% vs. 14% for age ⱖ60 years vs. ⬍ 60 years (p ⫽ 0.622). As shown in Table 3, only treatment field remained an independent factor for predicting small bowel complications, with an odds ratio (OR) of 2.3 (95% CI 1.0–5.35, p ⫽ 0.05). The OR for RT dose ⬎50.4 Gy was 2, but it did not reach statistical significance (95% CI 0.5–7.96, p ⫽ 0.1). The severity of GI complications in the whole-pelvic and low-pelvic RT group is listed in Table 4. The incidence of Grade 3 or higher complications was significantly less in the low-pelvic RT group (p ⫽ 0.023), and one fatal complication occurred in the whole-pelvic RT group, suggesting low-pelvic RT alone reduces the incidence, as well as the severity, of GI complications. The effects of the radiation dose to the low pelvis, field directions, treatment field, age, and number of sampled lymph node shown in the pathologic report (ⱕ22 vs. ⬎22) on the incidence of leg lymphedema were examined. In total, 31% of patients developed lymphedema, and the median time of occurrence was 17 months (range 0 –97). The incidence of lymphedema was 43% vs. 25% for a radiation dose to the low pelvis of ⬎50.4 Gy vs. ⱕ50.4 Gy (p ⫽ 0.005); 33% vs. 30% for whole-pelvic RT vs. low-pelvic RT (p ⫽ 0.598); 29% vs. 34% for AP–PA portal vs. box technique (p ⫽ 0.387); 41% vs. 28% for age ⱖ60 years vs. ⬍60 years (p ⫽ 0.08); and 30% vs. 33% for number of sampled lymph nodes ⱕ22 vs. ⬎22 (p ⫽ 0.55). As shown
Data in parentheses are percentages. Severity determined according to late radiation morbidity scoring schema defined by the Radiation Therapy Oncology Group and European Organization for Research and Treatment of Cancer. p ⫽ 0.018. * Complications were not evaluated in 8 patients, 4 in each group, because they died within 1 year after irradiation and did not develop complications when alive.
in Table 5, the radiation dose to the low pelvis and field directions were shown to be independent factors associated with lymphedema after logistic regression analysis; OR was 2.79 (95% CI 1.43–5.46, p ⫽ 0.0027) for dose ⬎50.4 Gy and 1.89 (95% CI 1–3.6, p ⫽ 0.05) for AP–AP technique. The treatment field and number of sampled lymph nodes were not associated with lymphedema. The OR for age ⬎60 years was 1.76 (95% CI 0.89 –3.46, p ⫽ 0.1), but similar to what was found by univariate analysis, it did not reach statistical significance. These results suggest that lymphedema is associated with the dose to the low pelvis and field direction, but not associated with upper pelvic RT if the dose to upper pelvis is not ⬎45 Gy, as used in this study. DISCUSSION The benefit of postoperative adjuvant RT on the rates of local control and survival for node-negative, Stage I–IIA cervical cancer patients is controversial. In a retrospective analyTable 5. Multivariate analyses by logistic regression to evaluate effects of certain factors on lymphedema of leg Factor RT dose to low pelvis (Gy) ⱕ 50.4* ⬎ 50.4 Treatment field Low-pelvis group* Whole-pelvis group Field direction Box AP–PA Sampled nodes (n) ⱕ22* ⬎22 Age (y) ⬍60* ⱖ60 Abbreviations as in Table 3. * Reference category.
OR (95% CI)
p
1 2.79 (1.43–5.46)
0.0027
1 1.25 (0.63–2.50)
0.52
1 1.88 (1–3.55)
0.05
1 1.00 (0.98–1.04)
0.95
1 1.755 (0.89–3.46)
0.105
Postoperative low-pelvic RT for node-negative cervical cancer
sis, Schorge et al. (5) reported that postoperative RT did not reduce the relapse rate except in patients with lymph-vascular space invasion, but patient selection was biased because patients receiving adjuvant RT had more risk factors than those treated by surgery alone. van der Velden et al. (14) studied treatment failure in patients whose tumor was confined in the cervix but had risk factors such as large tumor diameter, vascular space invasion, and deep stromal penetration. Of 56 patients, 3 (5.3%) had pelvic relapse and only 1 (2%) had pelvic relapse alone. The authors suggested that postoperative RT is not indicated for this group of patients, because the incidence of pelvic relapse alone is low. On the other hand, a prospective randomized trial conducted by the Gynecologic Oncology Group demonstrated a 44% reduction in relapse and 36% less mortality in patients receiving adjuvant RT (4). Patients in that study had negative pelvic nodal metastasis, but had at least 2 of the risk factors, including stromal invasion greater than one-third, lymph-vascular space involvement, and large clinical tumor diameter. Our prior experience showed that for node-negative patients with risk factors such as deep stromal invasion, parametrial invasion, bulky tumor size, and positive vaginal margins, the 5-year relapse-free and overall survival rate was 63.5% vs. 84.3% (p ⫽ 0.015) and 70.8% vs. 86% (p ⫽ 0.087), respectively, for patients without vs. with adjuvant RT (2). Our experience supported the findings of the Gynecologic Oncology Group study. We also found that patients with recurrent cervical cancer after radical surgery had a very poor outcome, with a 5-year survival rate of only 10% (15). On the basis of our observations, we suggested that postoperative RT should be given to node-negative, high-risk patients. The benefit of postoperative RT, however, was attenuated by the increased risk of complications. Although SnijdersKeilholz et al. (16) detected only a 2% and 11% incidence of severe GI complications and lymphedema, respectively, in patients receiving adjuvant RT, comparable to their surgeryalone group; other studies showed much higher incidences. In a study focusing on GI complications, the incidence of small bowel obstruction was 5% vs. 20% (p ⬍ 0.05) for patients receiving surgery alone vs. surgery plus adjuvant RT (17). Barter et al. (7) reported that 30% of patients treated by adjuvant RT had serious complications and 16% underwent reoperation for complications. Chatani et al. (8) showed lymphedema of the foot occurred in 42% of their patients at 5 years after adjuvant RT. The wide range of incidences of complications among these studies might have been caused by nonuniform case selection and variations in treatment technique and complication definitions, but the increased incidences of complications observed by many studies suggested that more efforts should be made to reduce the side effects of adjuvant RT. Several methods were used to reduce the irradiated volume of normal tissues and thus the likelihood of complications. Burnett et al. (18) inserted a specially designed, removable displacement prosthesis into the pelvis during surgery and enabled the small bowel to be excluded from the radiation field. By using three-dimensional treatment planning, others
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showed that the doses to the small bowel could be significantly reduced (19). Kridelka et al. (9) treated node-negative, highrisk patients with low-pelvic RT and shrunk the treatment field in all directions. They found this method to be very effective in improving the 5-year disease-free survival and to carry low morbidity, with only 1 (4%) of 25 patients experiencing pelvic relapse. However, only 25 patients were studied, and the authors suggested further verification was needed. In this study, our approach to reducing complications was similar to that of Kridelka et al., with some variations. Because we thought that the first echelon-draining lymph nodes were still at risk of metastasis for node-negative patients, we only shrunk the fields to avoid the upper pelvis but not in other directions, to cover the primary tumor bed and adjacent lymphatic tissue adequately. On average, a 6-cm reduction in field length at the upper pelvis resulted. The radiation dose to the low pelvis was around 50 Gy, similar to that in the study by Kridelka et al. We found that 12 (8%) of 149 patients in the low-pelvic RT group had an initial relapse inside the pelvis, with or without synchronous distant failure; the corresponding figure was 4 (5%) of 79 patients in the whole-pelvic RT group. No relapse in the upper pelvis was found in whole-pelvic RT group. If the 5 relapses in the upper pelvis were excluded from the low-pelvic RT group, their low-pelvic relapse rate was also 5%. These data suggest that low-pelvic RT alone did increase, although not significantly, the risk of upper pelvic failure. Because only 25 patients for small-field RT were included in the study by Kridelka et al., it is highly possible they could not observe any upper pelvic relapse. If upper pelvic relapse alone or upper pelvis plus synchronous PA node relapse was considered preventable by whole-pelvic RT, the impact of lowpelvic RT on survival is less than 3%. Omitting upper pelvic RT reduced the incidence and severity of small bowel complications. The total and surgical small bowel complications dropped from 24% to 10% (p ⫽ 0007) and 8% to 2.1% (p ⫽ 0.023), respectively. A 1% rate of fatal GI complications was found in patients in the whole-pelvic RT group, but none in low-pelvic RT group. In consideration of the tradeoff between decreasing survival and reducing surgical and total GI complications, we recommend low-pelvic RT alone as an acceptable or even better method for postoperative adjuvant RT for node-negative cervical cancer patients. The results of this study also showed several other ways to reduce the complication rate further. Doses ⬎50.4 Gy to the low pelvis by EBRT did not improve survival, but significantly increased the incidence of leg edema and had a tendency to increase the incidence of small bowel complications. Doses of EBRT should be not ⬎50.4 Gy. However, in this study, patients with positive resection margins usually received a higher EBRT dose, their local tumor control rate might have been lower if they had received a lower dose to reduce complications. A possible solution for this concern is to use more intravaginal brachytherapy instead of escalating the EBRT dose. Although using box fields did not reduce the small bowel complications in our patients, it was associated with a lower incidence of lymphedema in multivariate analysis. Even after adjuvant RT, adenocarcinoma or adenosquamous
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carcinoma and bulky tumor were predictors for poor prognosis in node-negative cervical cancer patients. This agreed with our previous finding that patients with cervical adenocarcinoma or adenosquamous carcinoma in general had worse local control and survival than those with SCC, whether treated primarily by RT (20), surgery (3), or surgery plus adjuvant RT (10). Although cisplatin-based, concurrent chemoradiotherapy (CCRT) appeared to improve survival in early-stage, high-risk cervical cancer patients (21), its effects on adenocarcinoma or adenosquamous carcinoma need to be verified further. Our recent finding showed that neoadjuvant chemotherapy followed by radical surgery, and adjuvant RT for high-risk patients did not achieve a better outcome than RT alone for bulky Stage I and IIA patients (11). Because several prospective studies have shown that CCRT achieves better local control for
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patients with advanced cervical cancer than RT alone (22, 23), and the combination of radical surgery and adjuvant RT increases the risk of complications, we recommend CCRT as the major treatment for this group of patients, with radical surgery reserved as a salvage procedure. In summary, the results of this retrospective study demonstrate that low-pelvic RT alone is an appropriate method for node-negative, high-risk Stage I–IIA cervical cancer patients. Compared with whole-pelvic RT, low-pelvic RT alone significantly reduces the incidence and severity of small bowel complications and does not compromise patient survival. Because more CCRT protocols are being used in adjuvant treatment of cervical cancer, with associated exacerbation of RT morbidity, our findings have the potential to have a significant impact on the treatment of this group of patients.
REFERENCES 1. Zreik TG, Chambers JT, Chambers SK. Parametrial involvement, regardless of nodal status: A poor prognostic factor for cervical cancer. Obstet Gynecol 1996;87:741–746. 2. Lai CH, Hong JH, Hsueh S, et al. Preoperative prognostic variables and the impact of postoperative adjuvant therapy on the outcomes of Stage IB or II cervical carcinoma patients with or without pelvic lymph node metastases: An analysis of 891 cases. Cancer 1999;85:1537–1546. 3. Lai CH, Hsueh S, Hong JH, et al. Are adenocarcinomas and adenosquamous carcinomas different from squamous carcinomas in stage IB and II cervical cancer patients undergoing primary radical surgery? Int J Gynecol Cancer 1999;9:28 –36. 4. Sedlis A, Bundy BN, Rotman MZ, et al. A randomized trial of pelvic radiation therapy versus no further therapy in selected patients with stage IB carcinoma of the cervix after radical hysterectomy and pelvic lymphadenectomy: A Gynecologic Oncology Group study. Gynecol Oncol 1999;73:177–183. 5. Schorge JO, Molpus KL, Koelliker D, et al. Stage IB and IIA cervical cancer with negative lymph nodes: The role of adjuvant radiotherapy after radical hysterectomy. Gynecol Oncol 1997;66:31–35. 6. Lahousen M, Haas J, Pickel H, et al. Chemotherapy versus radiotherapy versus observation for high-risk cervical carcinoma after radical hysterectomy: A randomized, prospective, multicenter trial. Gynecol Oncol 1999;73:196 –201. 7. Barter JF, Soong SJ, Shingleton HM, et al. Complications of combined radical hysterectomy-postoperative radiation therapy in women with early stage cervical cancer. Gynecol Oncol 1989;32:292–296. 8. Chatani M, Nose T, Masaki N, et al. Adjuvant radiotherapy after radical hysterectomy of the cervical cancer: Prognostic factors and complications. Strahlenther Onkol 1998;174:504 – 509. 9. Kridelka FJ, Berg DO, Neuman M, et al. Adjuvant small field pelvic radiation for patients with high risk, stage IB lymph node negative cervix carcinoma after radical hysterectomy and pelvic lymph node dissection: A pilot study. Cancer 1999;86: 2059 –2065. 10. Tsai CS, Lai CH, Wang CC, et al. The prognostic factors for patients with early cervical cancer treated by radical hysterectomy and postoperative radiotherapy. Gynecol Oncol 1999; 75:328 –333. 11. Chang TC, Lai CH, Hong JH, et al. Randomized trial of neoadjuvant cisplatin, vincristine, bleomycin, and radical hysterectomy versus radiation therapy for bulky stage IB and IIA cervical cancer. J Clin Oncol 2000;18:1740 –1747.
12. Perez CA. Uterine cervix. In: Perez CA, Brady LW, editors. Principles and practice of radiation oncology, 3rd ed. Philadelphia: Lippincott-Raven; 1998. p. 1733–1834. 13. Perez CA, Brady LW. Overview. In: Perez CA, Brady LW, editors. Principles and practice of radiation oncology, 2nd ed. Philadelphia: JB Lippincott; 1992. p. 1– 63. 14. van der Velden J, Samlal R, Schilthuis MS, et al. A limited role for adjuvant radiotherapy after the Wertheim/Okabayashi radical hysterectomy for cervical cancer confined to the cervix. Gynecol Oncol 1999;75:233–237. 15. Wang CJ, Lai CH, Huang HJ, et al. Recurrent cervical carcinoma after primary radical surgery. Am J Obstet Gynecol 1999;181:518 –524. 16. Snijders-Keilholz A, Hellebrekers BW, Zwinderman AH, et al. Adjuvant radiotherapy following radical hysterectomy for patients with early-stage cervical carcinoma (1984 –1996). Radiother Oncol 1999:51:161–167. 17. Montz FJ, Holschneider CH, Solh S, et al. Small bowel obstruction following radical hysterectomy: Risk factors, incidence, and operative findings. Gynecol Oncol 1994;53:114 –120. 18. Burnett AF, Coe FL, Klement V, et al. The use of a pelvic displacement prosthesis to exclude the small intestine from the radiation field following radical hysterectomy. Gynecol Oncol 2000;79:438 – 443. 19. Olofsen-van Acht, MJ, Quint S, Seven M, et al. Three-dimensional treatment planning for postoperative radiotherapy in patients with node-positive cervical cancer: Comparison between a conventional and a conformal technique. Strahlenther Onkol 1999;175:462– 469. 20. Hong JH, Tsai CS, Wang CC, et al. Comparison of clinical behaviors and responses to radiation between squamous cell carcinomas and adenocarcinomas/adenosquamous carcinomas of the cervix. Changgeng Yi Xue Za Zhi 2000;23:396 – 404. 21. Peters WA, Liu PY, Barrett RJ, et al. Concurrent chemotherapy and pelvic radiation therapy compared with pelvic radiation therapy alone as adjuvant therapy after radical surgery in high-risk early-stage cancer of the cervix. J Clin Oncol 2000; 18:1606 –1613. 22. Morris M, Eifel PJ, Lu J, et al. Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer. N Engl J Med 1999;340: 1137–1143. 23. Rose PG, Bundy BN, Watkins EB, et al. Concurrent cisplatinbased radiotherapy and chemotherapy for locally advanced cervical cancer. N Engl J Med 1999;340:1144 –1153.
PII S0360-3016(02)02831-6
CLINICAL INVESTIGATION
Cervix
POSTOPERATIVE LOW-PELVIC IRRADIATION FOR STAGE I–IIA CERVICAL CANCER PATIENTS WITH RISK FACTORS OTHER THAN PELVIC LYMPH NODE METASTASIS JI-HONG HONG, M.D., PH.D.,*† CHIEN-SHENG TSAI, M.D.,* CHYONG-HUEY LAI, M.D.,‡ TING-CHANG CHANG, M.D.,‡ CHUN-CHIEH WANG, M.D.,* STEVE P. LEE, M.D., PH.D.,§ CHIH-JEN TSENG, M.D.,‡ AND SWEI HSUEH, M.D.㛳 Departments of *Radiation Oncology, ‡Obstetrics and Gynecology, and 㛳Pathology, Chang Gung Memorial Hospital and Chang Gung University; †Department of Medical Technology, Chang Gung University School of Medicine, Taoyuan, Taiwan; §Department of Radiation Oncology, University of California, Los Angeles, School of Medicine, Los Angeles, CA Purpose: To retrospectively investigate whether postoperative low-pelvic radiotherapy (RT) is an appropriate treatment for node-negative, high-risk Stage I–IIA cervical cancer patients. Methods and Materials: A total of 228 Stage I–IIA cervical cancer patients treated by radical surgery and postoperative RT were included in this study. All patients had histopathologically negative pelvic node metastasis, but at least one of the following risk factors: parametrial involvement, positive or close resection margins, invasion depth two-thirds or greater cervical stromal thickness. Seventy-nine patients (35%) received 30 –50 Gy (median 44) to whole pelvis and a boost dose to the low pelvis (whole-pelvic RT group); the other 149 patients (65%) received low-pelvic RT only (low-pelvic RT group). For both groups, the total external RT dose to the low pelvis ranged from 40 to 60 Gy (median 50). The potential factors associated with survival, small bowel (gastrointestinal) complications, and leg lymphedema were analyzed, and patients who had a relapse in the upper pelvis were identified. Results: The 5-year overall and disease-specific survival rate was 84% and 86%, respectively. After multivariate analysis, only bulky tumor (>4 cm) and non–squamous cell carcinoma were significantly associated with survival. Parametrial involvement, lymph-vascular invasion, <50.4 Gy to the low pelvis, positive or close margins, and low-pelvic RT alone did not significantly affect survival. Grade I–V small bowel complications occurred in 33 patients (15%). Whole pelvic RT and >50.4 Gy to the low pelvis, but not old age and treatment technique (AP–PA vs. box), were significantly associated with gastrointestinal complications. Three patients (2%) in the low-pelvic RT group and 6 patients (8%) in the whole-pelvic RT group were found to have Grade III or higher small bowel complications (p ⴝ 0.023). Thirty-one percent of patients developed lymphedema of the leg. A dose to the low pelvis >50.4 Gy and an AP–PA field, but not whole-pelvic RT, old age, or the number of sampled lymph nodes, were associated with lymphedema of the leg. Five patients (3.6%) of the low-pelvic RT group and none of the whole-pelvic RT group developed upper pelvis relapse. Three of these 5 patients had upper pelvic relapse alone. Conclusion: Compared with whole-pelvic RT plus low-pelvic boost, low-pelvic RT alone significantly reduces the small bowel complications in node-negative, high-risk, Stage I–IIA cervical cancer patients. Although low-pelvic RT alone increases the incidence of upper pelvic relapse, its effect on survival is not substantial. Low-pelvic RT alone appears to be an appropriate treatment method for this group of patients. © 2002 Elsevier Science Inc. Early-stage cervical cancer, Postoperative radiotherapy, Low-pelvic irradiation, Gastrointestinal complications, Lymphedema.
INTRODUCTION Radical surgery is an effective treatment for early-stage (Stage IB–IIA) cervical cancer patients. However, risk factors such as pelvic lymph node metastasis, bulky tumor size, deep stromal invasion, positive resection margins, adenocarcinoma, and capillary or lymphatic vascular involvement have been shown to correlate with an increased incidence of treatment failure (1–3). Patients with these risk factors were
usually suggested to receive postoperative adjuvant treatment. Although most studies showed that adjuvant radiotherapy (RT) significantly reduced local relapse (2, 4), its impact on survival improvement was controversial and depended on the selection criteria used in each study (2, 4 – 6). Our prior experiences showed that postoperative chemoradiotherapy significantly increases relapse-free survival and overall survival in patients with pelvic lymph node metas-
Reprint requests to: Ji-Hong Hong, M.D., Ph.D., Department of Radiation Oncology, Chang Gung Memorial Hospital, No. 5 FuShin St., Kwei-Shan, Taoyuan, Taiwan. Tel: 886-3-328-2177; Fax: 886-3-328-0797; E-mail: [email protected] Presented at the ASTRO 43rd annual meeting in San Francisco,
CA, November 4 – 8, 2001. Acknowledgment—The authors thank Shin-Shin Lee, M.P.H. for her assistance in the statistical analysis. Received Nov 15, 2001, and in revised form Mar 13, 2002. Accepted for publication Mar 19, 2002. 1284
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tases but no parametrial extension (2). We also found that for patients with risk factors other than pelvic lymph node metastasis, adjuvant RT significantly improved relapse-free survival and marginally increased overall survival (2). Our data supported the idea that postoperative adjuvant RT is beneficial for certain subsets of patients. Postoperative RT for cervical cancer patients, however, did increase the incidence of complications. Barter et al. (7) reported that as many as 16% of patients developed serious complications requiring surgery after adjuvant RT. In a randomized trial of pelvic RT vs. no further therapy in selected patients after radical hysterectomy, a higher percentage of Grade III/IV urinary and gastrointestinal (GI) complications was found in patients receiving postoperative RT (4). The incidence of lymphedema of the foot could be 42% at 5 years in patients receiving adjuvant RT (8). Because the volume of irradiated normal tissue is a major factor affecting the degree of complications, Kridelka et al. (9) used a small pelvic field instead of whole-pelvic RT as an adjuvant treatment of nodenegative, high-risk cervical cancer patients. Their pilot study demonstrated that only 1 (4%) of 25 patients had pelvic relapse and no major morbidity was found. However, the case number in the study was small, and the authors suggested a need for further verification. We identified the risk factors associated with treatment failure in early-stage cervical cancer patients receiving adjuvant RT (10). For patients without pelvic lymph node metastasis, the 5-year disease-specific survival rate was 87%. Because of the high survival rate of these patients, we tried to reduce the complications by treating patients with a smaller (low-pelvic) field instead of the conventional whole-pelvic field. In both treatment fields, the first echelon-draining nodes of the cervix were included, although the histopathologic findings showed negative nodal metastasis. The “low-pelvic” field excluded the common iliac nodes and consequently reduced the irradiated volume of small bowel and lymphatic channels, which was expected to decrease complications. In the present study, we aimed not only to compare the incidence of small bowel complications and lymphedema after RT with different fields, but also to identify the factors associated with rates of survival and treatment failure. We evaluated whether lowpelvic RT compromises pelvic control and assessed the relapse rate in the upper pelvis covered within the whole-pelvic field but excluded in the low-pelvic field. Our goal was to devise an appropriate method to reduce the complications, but not comprise patients’ survival. Because the sample size in this study was relatively large, our findings may be worthy references for others to select an appropriate postoperative RT method for node-negative, high-risk, early-stage cervical cancer patients. METHODS AND MATERIALS Between January 1990 and December 1997, 228 women with International Federation of Gynecology and Obstetrics Stage IB–IIA cervical cancer were treated in our institute and included in this study. All patients were treated by radical hysterectomy and bilateral pelvic node dissection and postop-
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erative radiotherapy (RT). Para-aortic lymph node sampling was performed only when para-aortic lymph node metastasis was suspected. Patients included in this study had negative pelvic node metastasis by histopathologic examination, but had at least one of the following findings: parametrial involvement, positive or close (⬍3 mm) resection margin, invasion depth two-thirds or greater cervical stromal thickness. Lymph-vascular permeation was considered as a risk factor, but it alone was not an indication for adjuvant RT. More than 80% of surgical samples were examined by a pathologist (S.H.) who specialized in gynecologic oncology. The percentage of patients with different pathologic risk factors are listed in Table 1. An invasion depth of two-thirds or greater cervical stromal thickness was present in 91% patients and was the most common indication for adjuvant RT. Fifty-four percent of patients had more than one pathologic risk factor. The patient clinical characteristics and treatment methods are also listed in Table 1. The median age at diagnosis was 53 years. The median number of sampled lymph nodes shown in the pathologic report was 22 (range 5–57). The number of sampled lymph nodes was not recorded for 2 patients. Of the 228 patients, 77% and 23% had Stage IB and IIA disease, respectively. Forty-six patients (20%) had bulky cervical tumor, defined as tumor diameter ⱖ4 cm by pelvic examination. Squamous cell carcinoma (SCC) was diagnosed in 88% of patients, the rest had adenocarcinoma or adenosquamous cell carcinoma; no patient with small cell carcinoma was included. Before surgery, the usual radiographs, endoscopic examinations, and laboratory analyses were carried out, and all patients underwent pelvic and abdominal CT or MRI to evaluate the primary tumor extension and lymph node status. Preoperative chemotherapy was given to 22 patients with bulky tumor. The chemotherapy regimen and scheme was the same as that previously reported (11). In brief, patients received cisplatin 50 mg/m2 by i.v. drip for 1 h, vincristine 1 mg/m2 by i.v. bolus on Day 1, and bleomycin 25 mg/m2 daily by continuous i.v. infusion for 72 h from Day 2. The regimen was repeated at 10-day intervals for 3 cycles followed by radical hysterectomy. Adjuvant external beam RT (EBRT) was delivered with 10-MV or 15-MV X-rays by a parallel-opposed (AP–PA) or 4-field box technique. The daily fraction size was 1.8 –2 Gy, 5 fractions weekly. The treatment field was categorized as low pelvis and whole pelvis. Typical simulation films for these 2 fields are shown in Fig. 1. The boundaries of the whole-pelvic field were similar to the standards recommended by Perez (12) in which the superior (cephalad) boundary was set at the L4–L5 junction. The low-pelvic field irradiated the primary tumor bed and first echelon lymph nodes and excluded the upper pelvic nodes. The superior boundary of the lowpelvic field was usually set at 1–2 cm above the low end of the sacroiliac joint; the other boundaries resembled those for the whole-pelvic field. The median length of the cephalocaudal direction at the mid-plane was 18 cm (range 15–22) for whole pelvis and 12 cm (range 10–14) for the low pelvis. Of the 228 patients, 149 (65%) received low-pelvic EBRT alone (median dose 50 Gy, range 40 – 60) and were categorized as the lowpelvic RT group. Seventy-nine patients (35%) received 30– 45
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Table 1. Patient characteristics and distribution of clinical and pathologic parameters All patients Patient total (n) Age (y) Median Range Stage (n) IB IIA Preoperative tumor size (n) Bulky tumor (ⱖ4 cm) Nonbulky tumor Uncertain Histologic features (n) Squamous cell carcinoma Non–squamous cell carcinoma Pathologic risk factors† Invasion ⱖ2/3 stroma thickness Parametrial invasion Positive or close vaginal margin Lymphovascular permeation Field direction AP–PA Box Sampled lymph nodes‡ (n) Median Range
228
Low-pelvis group 149
Whole-pelvis group
p*
79
53 25–75
53 25–75
54 32–71
176 (77) 52 (23)
119 (80) 30 (20)
57 (72) 22 (28)
0.2
46 (20) 170 (76) 12 (4)
26 (17) 114 (77) 9 (6)
20 (25) 56 (71) 3 (4)
0.25
200 (88) 28 (12)
128 (86) 21 (14)
72 (91) 7 (9)
0.2
208 (91) 31 (14) 29 (13) 104 (46)
137 (92) 11 (7) 21 (14) 64 (43)
71 (90) 20 (28) 8 (10) 40 (51)
0.6 0.0002 0.39 0.27
97 (43) 131 (57)
69 (46) 80 (54)
28 (35) 51 (65)
0.09
22 5–57
23 5–57
20 8–49
* Numbers in parentheses are percentage. Comparison between low-pelvis group and whole-pelvis group. Patients might have more than one risk factor. Comparisons were made based on each risk factor. ‡ Lymph node number not provided in pathologic report in 2 cases. †
Gy (median 44) whole-pelvic RT and subsequently received a boost to the low pelvis up to a total of 40– 60 Gy (median 50) and were categorized as the whole-pelvic RT group. The selection of treatment field and technique was not randomized, but was determined by the preferences of the responsible attending physician. However, patients with positive resection margins were usually treated with higher low-pelvic doses. The distribution of the clinical and pathologic parameters of
both groups are outlined in Table 1. Significant differences were detected only in the risk factor of parametrial invasion, for which the whole-pelvic RT group had a significantly higher incidence. After EBRT, 198 patients (87%) received additional vaginal cuff RT using high-dose-rate remote after-loading techniques. Intravaginal brachytherapy was usually given in 2 or 3 fractions to a total dose of 4– 6 Gy at 0.5– 0.75 cm below the vaginal mucosa.
Fig. 1. Typical simulation films for the 2 fields. The boundaries of the low-pelvic field were the same as those of the whole-pelvic field except the superior boundary was reduced from the L4 –L5 junction to the level of 1–2 cm above the low end of the sacroiliac joint (shown by the dotted line).
Postoperative low-pelvic RT for node-negative cervical cancer
Patients were followed regularly up to December 2000 (minimal follow-up 3 years). Two patients were lost to followup. The follow-up frequency was every 2–3 months for the first year, 3– 4 months for the second year after treatment, and every 4 – 6 months thereafter. Local recurrence was defined by either pathologic proof of recurrence in the vaginal and/or adjacent tissues or an imaging study showing regrowth of tumor or enlargement of a pelvic lymph node below the L4–L5 junction. Distant metastasis was also defined by pathologic, cytologic, or radiologic evidence; para-aortic node relapse above the L4 –L5 junction was considered distant failure. In this study, we only defined the initial failure site or sites as the site of treatment failure. The definition of synchronous local and distant failure was an interval between the two events of ⬍1 month. The severity of small bowel complications was according to the late radiation morbidity scoring schema defined by the Radiation Therapy Oncology Group and European Organization for Research and Treatment of Cancer (13). Lymphedema was defined as swelling of the leg and thigh as determined by physical examination. Statistical analysis of the data was carried out by the chi-square test. Survival curves were constructed using the Kaplan–Meier method, and comparisons between curves were performed by the log–rank test. Multivariate analysis of the prognostic factors for survival and risk factors for complications was made by the Cox proportional hazard model and logistic regression model, respectively. RESULTS Survival rate, prognostic factors, and relapse pattern The 5-year overall and disease-specific survival rate was 84% and 86%, respectively, for all patients. We assessed the association of clinical and pathologic factors with the survival rate. The 5-year disease-specific survival rate was 91% vs. 64% for nonbulky vs. bulky disease (p ⫽ 0.0001); 88% vs. 74%, for SCC vs. non–SCC (p ⫽ 0.02); 80% vs. 87% for with vs. without parametrial involvement (p ⫽ 0.26); 87% vs. 86% for with vs. without lymph-vascular permeation (p ⫽ 0.74), 75% vs. 88% for with vs. without positive or close resection margins (p ⫽ 0.059); 89% vs. 81% for ⱕ50.4 Gy vs. ⬎50.4 Gy to the low pelvis (p ⫽ 0.22); 87% vs. 84% for the lowpelvic RT group vs. the whole-pelvic RT group (p ⫽ 0.57). As shown in Table 2, only bulky tumor and non–SCC histologic features were significantly associated with poor disease-specific survival by multivariate analysis. The risk ratio for bulky tumor was 5.56 (95% confidence interval [CI] 2.3–13.7, p ⫽ 0.0002) and for non–SCC was 6.9 (95% CI 2.3–20.2, p ⫽ 0.0004), with both factors proven to be independent prognostic factors. These results suggest that a higher radiation dose (⬎50.4 Gy) and larger treatment portal (whole pelvis) did not significantly improve patient survival in general. Even for patients in the low-pelvic RT group, no benefit from the higher radiation dose was found, because the 5-year disease-specific survival rate was 88% vs. 85% for the low-pelvic dose ⱕ50.4 Gy vs. ⬎50.4 Gy (p ⫽ 0.98). Because 54% of patients had more than one pathologic risk factor, we analyzed its impact on
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Table 2. Multivariate analyses of certain factors on diseasespecific survival Factor Tumor size Nonbulky* Bulky Parametrial involvement No* Yes Lymph-vascular permeation No* Yes Radiation dose (Gy) ⱕ50.4* ⬎50.4 Resection margin Negative* Positive or close Histologic type SCC* Non–SCC Treatment field Low-pelvis group* Whole-pelvis group
RR (95% CI)
p
1 5.6 (2.3–13.7)
0.0002
1 1.5 (0.5–4.7)
0.51
1 1.5 (0.6–3.6)
0.41
1 1.1 (0.4–3.1)
0.81
1 2.1 (0.5–7.9)
0.3
1 6.9 (2.3–20.3)
0.0004
1 1.1 (0.4–2.9)
0.87
Abbreviations: RR ⫽ risk ratio; CI ⫽ confidence interval; SCC ⫽ squamous cell carcinoma. * Reference category.
survival. The 5-year disease-specific survival rate was 86% vs. 87% for patients with 1 vs. ⬎1 pathologic risk factor (p ⫽ 0.87), suggesting that patients with more than one pathologic risk factor were not prone to worse survival after adjuvant RT. Thirty-five patients (15%) had local failure or distant metastasis. Of the 35 patients, 11 (31%), 19 (54%), and 5 (14%) had initial relapse at local, distant, or synchronous local and distant sites, respectively. The risk of distant failure was higher than that of local relapse. We also analyzed the effects of the treatment field, because it might have affected the incidence and location of treatment failure. The incidence of local failure, distant relapse, and synchronous local and distant failure for patients in the low-pelvic RT group vs. the whole-pelvic RT group was 6.5% vs. 2.5%, 8% vs. 10%, and 2% vs. 2.5%, respectively; no statistical significance could be detected (p ⫽ 0.396). Relapse in the upper pelvis, which was out of the low-pelvic field, was found in 5 patients (3.4%) in the lowpelvic RT group and in no patients in the whole-pelvic RT group (p ⫽ 0.1). Only 3 of 5 patients had an isolated relapse in the upper pelvis. Of the remaining 2, 1 had synchronous relapses at the upper pelvis and paraaortic region and 1 had other distant failure. These data suggest that whole-pelvic RT effectively prevents upper pelvis failure, but its effect on improving patients’ survival is not substantial and should be ⬍3.4%. Complications and factors associated with complications Because the treatment field will affect the volume of irradiated small bowel and lymphatic tissue, small bowel complications and lymphedema were our primary concern in analyzing
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Table 3. Multivariate analyses by logistic regression to evaluate effects of certain factors on small bowel complications OR (95% CI) RT dose to low pelvis (Gy) ⱕ50.4* ⬎50.4 Treatment field True-pelvis group* Whole-pelvis group Field direction Box* AP–PA Age (y) ⬍60* ⱖ60
1 2 (0.50–7.96) 1 2.29 (1.0–5.35)
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Table 4. Small bowel complications in patients treated with lowpelvic RT alone (low-pelvis group) and whole-pelvic plus lowpelvic RT (whole-pelvis group)
p
0.1026
Grade
Low-pelvis group (n)
Whole-pelvis group (n)
0 1–2 3–5 Total*
130 (89.7) 12 (8.3) 3 (2.1) 145 (100)
57 (76) 12 (16) 6 (8) 75 (100)
0.05
1 1.02 (0.44–2.21)
0.96
1 1.27 (0.52–3.14)
0.60
Abbreviations: OR ⫽ odds ratio; CI ⫽ confidence interval; RT ⫽ radiotherapy. * Reference category.
the complications. Grade I–V small bowel complications occurred in 33 patients (15%). The median time of having bowel complications was 13 months (range 0–101) after RT. We examined the association of GI complications with the radiation dose to the low pelvis (ⱕ50.4 Gy vs. ⬎50.4 Gy), treatment field (low-pelvic RT group vs. whole-pelvic RT group), field directions (AP–PA vs. box), and age (⬍60 years vs. ⱖ60 years). The incidence of small bowel complications was 23% vs.10% for radiation dose to the low pelvis of ⬎50.4 Gy vs. ⱕ50.4 Gy (p ⫽ 0.012); 24% vs.10% for whole-pelvic RT group vs. low-pelvic RT group (p ⫽ 0.007); 16% vs. 13% for AP–PA portal vs. box technique (p ⫽ 0.536); and 17% vs. 14% for age ⱖ60 years vs. ⬍ 60 years (p ⫽ 0.622). As shown in Table 3, only treatment field remained an independent factor for predicting small bowel complications, with an odds ratio (OR) of 2.3 (95% CI 1.0–5.35, p ⫽ 0.05). The OR for RT dose ⬎50.4 Gy was 2, but it did not reach statistical significance (95% CI 0.5–7.96, p ⫽ 0.1). The severity of GI complications in the whole-pelvic and low-pelvic RT group is listed in Table 4. The incidence of Grade 3 or higher complications was significantly less in the low-pelvic RT group (p ⫽ 0.023), and one fatal complication occurred in the whole-pelvic RT group, suggesting low-pelvic RT alone reduces the incidence, as well as the severity, of GI complications. The effects of the radiation dose to the low pelvis, field directions, treatment field, age, and number of sampled lymph node shown in the pathologic report (ⱕ22 vs. ⬎22) on the incidence of leg lymphedema were examined. In total, 31% of patients developed lymphedema, and the median time of occurrence was 17 months (range 0 –97). The incidence of lymphedema was 43% vs. 25% for a radiation dose to the low pelvis of ⬎50.4 Gy vs. ⱕ50.4 Gy (p ⫽ 0.005); 33% vs. 30% for whole-pelvic RT vs. low-pelvic RT (p ⫽ 0.598); 29% vs. 34% for AP–PA portal vs. box technique (p ⫽ 0.387); 41% vs. 28% for age ⱖ60 years vs. ⬍60 years (p ⫽ 0.08); and 30% vs. 33% for number of sampled lymph nodes ⱕ22 vs. ⬎22 (p ⫽ 0.55). As shown
Data in parentheses are percentages. Severity determined according to late radiation morbidity scoring schema defined by the Radiation Therapy Oncology Group and European Organization for Research and Treatment of Cancer. p ⫽ 0.018. * Complications were not evaluated in 8 patients, 4 in each group, because they died within 1 year after irradiation and did not develop complications when alive.
in Table 5, the radiation dose to the low pelvis and field directions were shown to be independent factors associated with lymphedema after logistic regression analysis; OR was 2.79 (95% CI 1.43–5.46, p ⫽ 0.0027) for dose ⬎50.4 Gy and 1.89 (95% CI 1–3.6, p ⫽ 0.05) for AP–AP technique. The treatment field and number of sampled lymph nodes were not associated with lymphedema. The OR for age ⬎60 years was 1.76 (95% CI 0.89 –3.46, p ⫽ 0.1), but similar to what was found by univariate analysis, it did not reach statistical significance. These results suggest that lymphedema is associated with the dose to the low pelvis and field direction, but not associated with upper pelvic RT if the dose to upper pelvis is not ⬎45 Gy, as used in this study. DISCUSSION The benefit of postoperative adjuvant RT on the rates of local control and survival for node-negative, Stage I–IIA cervical cancer patients is controversial. In a retrospective analyTable 5. Multivariate analyses by logistic regression to evaluate effects of certain factors on lymphedema of leg Factor RT dose to low pelvis (Gy) ⱕ 50.4* ⬎ 50.4 Treatment field Low-pelvis group* Whole-pelvis group Field direction Box AP–PA Sampled nodes (n) ⱕ22* ⬎22 Age (y) ⬍60* ⱖ60 Abbreviations as in Table 3. * Reference category.
OR (95% CI)
p
1 2.79 (1.43–5.46)
0.0027
1 1.25 (0.63–2.50)
0.52
1 1.88 (1–3.55)
0.05
1 1.00 (0.98–1.04)
0.95
1 1.755 (0.89–3.46)
0.105
Postoperative low-pelvic RT for node-negative cervical cancer
sis, Schorge et al. (5) reported that postoperative RT did not reduce the relapse rate except in patients with lymph-vascular space invasion, but patient selection was biased because patients receiving adjuvant RT had more risk factors than those treated by surgery alone. van der Velden et al. (14) studied treatment failure in patients whose tumor was confined in the cervix but had risk factors such as large tumor diameter, vascular space invasion, and deep stromal penetration. Of 56 patients, 3 (5.3%) had pelvic relapse and only 1 (2%) had pelvic relapse alone. The authors suggested that postoperative RT is not indicated for this group of patients, because the incidence of pelvic relapse alone is low. On the other hand, a prospective randomized trial conducted by the Gynecologic Oncology Group demonstrated a 44% reduction in relapse and 36% less mortality in patients receiving adjuvant RT (4). Patients in that study had negative pelvic nodal metastasis, but had at least 2 of the risk factors, including stromal invasion greater than one-third, lymph-vascular space involvement, and large clinical tumor diameter. Our prior experience showed that for node-negative patients with risk factors such as deep stromal invasion, parametrial invasion, bulky tumor size, and positive vaginal margins, the 5-year relapse-free and overall survival rate was 63.5% vs. 84.3% (p ⫽ 0.015) and 70.8% vs. 86% (p ⫽ 0.087), respectively, for patients without vs. with adjuvant RT (2). Our experience supported the findings of the Gynecologic Oncology Group study. We also found that patients with recurrent cervical cancer after radical surgery had a very poor outcome, with a 5-year survival rate of only 10% (15). On the basis of our observations, we suggested that postoperative RT should be given to node-negative, high-risk patients. The benefit of postoperative RT, however, was attenuated by the increased risk of complications. Although SnijdersKeilholz et al. (16) detected only a 2% and 11% incidence of severe GI complications and lymphedema, respectively, in patients receiving adjuvant RT, comparable to their surgeryalone group; other studies showed much higher incidences. In a study focusing on GI complications, the incidence of small bowel obstruction was 5% vs. 20% (p ⬍ 0.05) for patients receiving surgery alone vs. surgery plus adjuvant RT (17). Barter et al. (7) reported that 30% of patients treated by adjuvant RT had serious complications and 16% underwent reoperation for complications. Chatani et al. (8) showed lymphedema of the foot occurred in 42% of their patients at 5 years after adjuvant RT. The wide range of incidences of complications among these studies might have been caused by nonuniform case selection and variations in treatment technique and complication definitions, but the increased incidences of complications observed by many studies suggested that more efforts should be made to reduce the side effects of adjuvant RT. Several methods were used to reduce the irradiated volume of normal tissues and thus the likelihood of complications. Burnett et al. (18) inserted a specially designed, removable displacement prosthesis into the pelvis during surgery and enabled the small bowel to be excluded from the radiation field. By using three-dimensional treatment planning, others
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showed that the doses to the small bowel could be significantly reduced (19). Kridelka et al. (9) treated node-negative, highrisk patients with low-pelvic RT and shrunk the treatment field in all directions. They found this method to be very effective in improving the 5-year disease-free survival and to carry low morbidity, with only 1 (4%) of 25 patients experiencing pelvic relapse. However, only 25 patients were studied, and the authors suggested further verification was needed. In this study, our approach to reducing complications was similar to that of Kridelka et al., with some variations. Because we thought that the first echelon-draining lymph nodes were still at risk of metastasis for node-negative patients, we only shrunk the fields to avoid the upper pelvis but not in other directions, to cover the primary tumor bed and adjacent lymphatic tissue adequately. On average, a 6-cm reduction in field length at the upper pelvis resulted. The radiation dose to the low pelvis was around 50 Gy, similar to that in the study by Kridelka et al. We found that 12 (8%) of 149 patients in the low-pelvic RT group had an initial relapse inside the pelvis, with or without synchronous distant failure; the corresponding figure was 4 (5%) of 79 patients in the whole-pelvic RT group. No relapse in the upper pelvis was found in whole-pelvic RT group. If the 5 relapses in the upper pelvis were excluded from the low-pelvic RT group, their low-pelvic relapse rate was also 5%. These data suggest that low-pelvic RT alone did increase, although not significantly, the risk of upper pelvic failure. Because only 25 patients for small-field RT were included in the study by Kridelka et al., it is highly possible they could not observe any upper pelvic relapse. If upper pelvic relapse alone or upper pelvis plus synchronous PA node relapse was considered preventable by whole-pelvic RT, the impact of lowpelvic RT on survival is less than 3%. Omitting upper pelvic RT reduced the incidence and severity of small bowel complications. The total and surgical small bowel complications dropped from 24% to 10% (p ⫽ 0007) and 8% to 2.1% (p ⫽ 0.023), respectively. A 1% rate of fatal GI complications was found in patients in the whole-pelvic RT group, but none in low-pelvic RT group. In consideration of the tradeoff between decreasing survival and reducing surgical and total GI complications, we recommend low-pelvic RT alone as an acceptable or even better method for postoperative adjuvant RT for node-negative cervical cancer patients. The results of this study also showed several other ways to reduce the complication rate further. Doses ⬎50.4 Gy to the low pelvis by EBRT did not improve survival, but significantly increased the incidence of leg edema and had a tendency to increase the incidence of small bowel complications. Doses of EBRT should be not ⬎50.4 Gy. However, in this study, patients with positive resection margins usually received a higher EBRT dose, their local tumor control rate might have been lower if they had received a lower dose to reduce complications. A possible solution for this concern is to use more intravaginal brachytherapy instead of escalating the EBRT dose. Although using box fields did not reduce the small bowel complications in our patients, it was associated with a lower incidence of lymphedema in multivariate analysis. Even after adjuvant RT, adenocarcinoma or adenosquamous
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● Biology ● Physics
carcinoma and bulky tumor were predictors for poor prognosis in node-negative cervical cancer patients. This agreed with our previous finding that patients with cervical adenocarcinoma or adenosquamous carcinoma in general had worse local control and survival than those with SCC, whether treated primarily by RT (20), surgery (3), or surgery plus adjuvant RT (10). Although cisplatin-based, concurrent chemoradiotherapy (CCRT) appeared to improve survival in early-stage, high-risk cervical cancer patients (21), its effects on adenocarcinoma or adenosquamous carcinoma need to be verified further. Our recent finding showed that neoadjuvant chemotherapy followed by radical surgery, and adjuvant RT for high-risk patients did not achieve a better outcome than RT alone for bulky Stage I and IIA patients (11). Because several prospective studies have shown that CCRT achieves better local control for
Volume 53, Number 5, 2002
patients with advanced cervical cancer than RT alone (22, 23), and the combination of radical surgery and adjuvant RT increases the risk of complications, we recommend CCRT as the major treatment for this group of patients, with radical surgery reserved as a salvage procedure. In summary, the results of this retrospective study demonstrate that low-pelvic RT alone is an appropriate method for node-negative, high-risk Stage I–IIA cervical cancer patients. Compared with whole-pelvic RT, low-pelvic RT alone significantly reduces the incidence and severity of small bowel complications and does not compromise patient survival. Because more CCRT protocols are being used in adjuvant treatment of cervical cancer, with associated exacerbation of RT morbidity, our findings have the potential to have a significant impact on the treatment of this group of patients.
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