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Clinical comparison of two linear-quadratic model-based isoeffect fractionation schemes of high-dose-rate intracavitary brachytherapy for cervical cancer
Int. J. Radiation Oncology Biol. Phys., Vol. 59, No. 1, pp. 179 –189, 2004 Copyright © 2004 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/04/$–see front matter
doi:10.1016/j.ijrobp.2003.10.025
CLINICAL INVESTIGATION
Cervix
CLINICAL COMPARISON OF TWO LINEAR-QUADRATIC MODEL-BASED ISOEFFECT FRACTIONATION SCHEMES OF HIGH-DOSE-RATE INTRACAVITARY BRACHYTHERAPY FOR CERVICAL CANCER CHONG-JONG WANG, M.D.,* ENG-YEN HUANG, M.D.,* LI-MIN SUN, M.D.,* HUI-CHUN CHEN, M.D.,* FU-MIN FANG, M.D.,* HSUAN-CHIH HSU, M.D.,* CHAN-CHAO CHANGCHIEN, M.D.,† AND STEPHEN WAN LEUNG, M.S., M.D.‡ Departments of *Radiation Oncology and †Gynecology Oncology, Kaohsiung Chang Gung Memorial Hospital; ‡Department of Radiation Oncology, Yuan’s General Hospital, Kaohsiung, Taiwan Purpose: Two linear-quadratic model– based isoeffect fractionation schemes of high-dose-rate intracavitary brachytherapy (HDR-IC) were used to treat cervical cancer in two consecutive periods. Patient outcomes and complications were analyzed and compared. Methods and Materials: Between November 1987 and December 1996, a total of 541 women diagnosed with cervical cancer were treated with curative-intent radiotherapy. Patients were categorized into two groups according to the two isoeffect schemes used. Group 1 consisted of 254 patients treated with external beam radiotherapy (EBRT) plus 7.2 Gy HDR-IC to Point A for three fractions in the first period. Group 2 consisted of 284 patients treated with EBRT plus 4.8 Gy HDR-IC for five fractions in the second period. The goal of the new scheme for the latter group was to deliver an isoeffect dose that maintained similar tumor control but reduced normal tissue complications. The calculated biologically effective dose (BED10, assuming an ␣/ ratio ⴝ 10) of EBRT plus HDR-IC for tumor and acute responding tissue in Groups 1 and 2 was 90 Gy10 (52.8 ⴙ 37.2 Gy) and 88.6 Gy10 (53.1 ⴙ 35.5 Gy), respectively. The corresponding BED3 for late responding tissue (assuming an ␣/ ratio ⴝ 3) in Groups 1 and 2 was 146.7 Gy3 (73.3 ⴙ 73.4 Gy) and 134.4 Gy3 (72 ⴙ 62.4 Gy), respectively. Patients were followed for 6.1–15.2 years (median, 9.8 years). Results: Overall, 66 patients (12.2%) developed pelvic recurrence. Of these, 53 patients had central recurrence. Of the 53 patients with central recurrence, 24 (9.4%) were in Group 1 and 29 (10.1%) in Group 2 (p ⴝ 0.722). The actuarial pelvic control rate for Groups 1 and 2 was 88.2% and 86.3% at 5 years and 87.3% and 85.5% at 10 years, respectively (p ⴝ 0.504). The actuarial overall survival rate for Groups 1 and 2 was 63.5% and 56.1% at 5 years and 47.8% and 49.3% at 10 years, respectively (p ⴝ 0.734). The actuarial proctitis rate for Groups 1 and 2 was 49.7% and 32.7% at 5 years and 50.5% and 32.7% at 10 years, respectively (p <0.001). Most of the decrease in the rate of proctitis was a result of a decrease in the incidence of low-grade proctitis (38% vs. 22%). The incidence of high-grade complications remained unchanged, 8% vs. 7%. The actuarial cystitis rate for Groups 1 and 2 was 14.3% vs. 11.4% at 5 years and 24.1% vs. 15% at 10 years, respectively (p ⴝ 0.134). Multivariate analysis revealed that the fractionation scheme (three fractions vs. five fractions) was a significant factor influencing the proctitis rate (p ⴝ 0.004, hazard ratio ⴝ 0.807; 95% confidence interval, 0.697– 0.934), but not the local pelvic control rate, overall survival rate, or cystitis rate. Conclusion: The treatment results of the two groups maintained similar outcomes, while the complications decreased. The linear-quadratic model correctly predicted this outcome. Biologically, the manipulation of the fraction size in our study suggested that the sensitivity of the late responding tissue to the fractional change from 7.2 Gy to 4.8 Gy in HDR-IC is high and detectable clinically. The success, however, had its limitations, and the improvement was confined to low-grade complications. © 2004 Elsevier Inc. Cervical carcinoma, Linear-quadratic model, High-dose-rate, Fractionation scheme, Brachytherapy.
change in the fractionation scheme used in this report. Dr. Lo was then a medical physicist at the Memorial Sloan-Kettering Cancer Center in New York, and is now at Mount Sinai Hospital, New York. Received Jul 17, 2003, and in revised form Sep 29, 2003. Accepted for publication Oct 15, 2003.
Reprint requests to: Chong-Jong Wang, M.D., Department of Radiation Oncology, Kaohsiung Chang Gung Memorial Hospital, 123 Ta-Pei Rd., Niao-Sung Hsian, Kaohsiung Hsien, Taiwan. Tel: (⫹886) 7-7317123, ext. 2600; Fax: (⫹886) 7-7322813; E-mail: [email protected] Acknowledgments—We thank Dr. Yeh-Chi Lo, whose visit to our Department in 1993 and help in formulation substantiated the 179
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INTRODUCTION With the data accumulated during the past years, high-doserate intracavitary brachytherapy (HDR-IC) has gained recognition and popularity in the treatment of cervical cancer. The optimal fractionation scheme for this technique, however, remains undetermined. A meta-analysis of the subject conducted by Petereit and Pearcey (1) in 1999 concluded that the optimal schedule was still unknown and could be based only on single institutions with significant experience. Publications on the clinical comparison of different fractionation schemes in HDR-IC were limited. Le Pechoux et al. (2) comparing two different fractionation schemes of 5 Gy twice weekly vs. 6 Gy once weekly, concluded that once-weekly HDR combined with properly adjusted pelvic external beam radiotherapy was safe and effective. Recently, Wong et al. (3) reported a comparison of two fractionation schemes, 7 Gy for three fractions vs. 6 Gy for four fractions, and concluded that the two schemes were not a statistically significant prognosticator in predicting disease control and complications. The biologic basis of these fractionation schemes for HDR-IC and its intercomparison with the low-dose-rate (LDR) setting was derived from a linear-quadratic model, as described by several authors (4 –9). The model largely categorized normal tissues into acute (including tumor) and late responding tissues. Characteristically, late responding tissues exhibited a survival curve of a flat shoulder at a low-dose region and a faster bend at a high-dose region, indicating that the tissues responsible for late complications are more sensitive to fraction size (smaller ␣/ ratio). In theory, if we split larger fraction dose into smaller ones, we can decrease complications without compromising the tumor control rate. Whether the theory works and can translate into the expected outcome in the brachytherapy setting, however, had not been thoroughly tested clinically. In this report, we analyzed 541 HDR-IC patients in two consecutive periods using two isoeffect schemes. Patient outcome and treatment-related complications are reported and compared. The validity of the model on the prediction of normal tissue complications in the HDR-IC setting was examined.
METHODS AND MATERIALS Patient characteristics The analysis included 541 women who were treated with curative-intent radiotherapy (RT) for cervical cancer between November 1987 and December 1996. Patients were categorized into two groups according to the fractionation scheme used in the two consecutive periods. Group 1 consisted of 254 patients treated with external beam RT (EBRT) plus three-fraction HDR-IC between November 1987 and April 1993. Group 2 consisted of 287 patients treated with EBRT plus 5-fraction HDR-IC between May 1993 and December 1996. Patient age ranged from 31 to 86 years (median 61). The Federation Internationale de Gynecologie et d’Obstetrique (FIGO) staging system was used.
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Pretreatment evaluation and staging workup, including complete blood count, chest radiography, intravenous pyelography, CT of the pelvis, cystoscopy, and sigmoidoscopy were done as appropriate. External beam RT The technical details of the EBRT and HDR-IC used in this department have been previously published elsewhere (10, 11). Because the departmental policies and facilities changed during the two treatment periods, the present description focused mainly on the contrast between the two treatment groups. All patients were treated initially with EBRT. In Group 1, whole pelvic EBRT was administered with 10-MV photons through AP parallel-opposing ports (AP–PA). The daily dose was 2 Gy. A four-field “box” technique was not routinely used in these patients. The standardized dose to the central cervix ranged from 40 to 44 Gy in 20 –22 fractions. An additional boost of 0 –14 Gy in zero to seven fractions was given to the bilateral pelvic wall, with a 4-cm midline block to shield the central structures in patients with parametrial or suspected pelvic lymph node involvement, so that total dose to the pelvic wall in Group 1 was maintained at 40 –58 Gy. With the implementation of a multileaf collimator-equipped linear accelerator in early 1995, the daily dose was reduced from 2 Gy to 1.8 Gy, and a four-field box technique was routinely used in all the patients treated thereafter. Thus, in Group 2, the dose to the central cervix was 39.6 – 45 Gy in 22–25 fractions, and the dose to the side wall was maintained at 39.6 –59.6 Gy. High-dose-rate IC The HDR-IC techniques were similar across the two treatment periods. HDR-IC was given after the completion of EBRT in all patients. An interdigitated arrangement of HDR-IC during the EBRT course was not applied in our patients. On a routine basis, the first application was performed under general anesthesia. Tumor regression was evaluated, and the endocervical canal was dilated. The uterine sounding was measured, and the applicator was inserted. The applicator used in all patients was Henschke’s type, consisting of one curved central tandem and two nonshielded ovoids. At the end of the procedure, the vagina was packed tautly with contrasted gauze. A urinary catheter with a urograffin-filled balloon was installed to outline the posterior bladder wall. The International Committee on Radiation Units and Measurements recommended points for rectal/bladder dose evaluation in Report No. 38 were not available until 1991. Before this, orthogonal maximal points were used for rectal/bladder dose evaluation. The HDR-IC facility used in Group 1 was mainly the Ralstron system (Toshiba, Japan) using 60Co sources. The system was replaced by a microSelectron system (Nucletron) using a 192Ir source in early 1993. The patients in Group 2 were all treated with this new system. During the transition of the two systems, brachytherapy in 40 patients were performed at a neighboring institution using the Selectron system. These patients were not included in the
Two isoeffect schemes of HDR-IC
analysis because the method of the source dwell and plan optimization were not consistent with ours. The standard fractionation scheme in Group 1 was 7.2 Gy to Point A for three fractions with each fraction administered 2 weeks apart. On the basis of the linear-quadratic model, the scheme was changed to 4.8 Gy for five fractions given twice weekly in May 1993. The goal was to deliver an isoeffect dose that maintained a similar tumor control rate, while hopefully reducing normal tissue complications. The calculated biologically equivalent dose (BED10) of HDR-IC for tumor and acute responding tissue (assuming ␣/ ratio ⫽ 10) in Groups 1 and 2 was 37.2 Gy10 and 35.5 Gy10, respectively. The corresponding BED3 for late responding tissue (assuming ␣/ ratio ⫽ 3) for the 2 groups was 73.4 Gy3 and 62.4 Gy3. For medical considerations, a reduction of 10 –20% of the total HDR-IC dose was allowed in aged patients with a favorable tumor response after EBRT or in patients with severe chronic disease in both groups. The rules of source dwell and plan optimization have been previously published (10). These rules were consistent across the two treatment periods. The method was partly extended from the Manchester technique. The concept of differential loading in tandem was generally applied to our treatment. This was achieved by modulating the weight of the dwell time in the tandem. The rule was that the highest point of the tandem near the fundus was weighted 1.5 and the lowermost point near the cervical os was weighted 0.8. The rest of tandem points were equally weighted at 1.0. The dose contribution of the central tandem vs. both ovoids was consistently 3:1. For the Ralstron unit, the stepwise distance is adjustable in 0.1-cm intervals; usually 0.9 –1.3 cm (median, 1.1 cm) was used. The stepwise distance of the microSelectron unit is formatted, and 0.5 cm was commonly used. The dwell positions in tandem were adjusted so that the lowermost point (with 0.8 weighting) was generally 0.6 – 0.8 cm above the cervical os. This constraint was set to avoid an excessive dose to the rectovaginal septum. The dose to the point of cervix os was routinely calculated and required to be maintained about twofold of that of Point A. The dose to Point B and the contralateral Point A were calculated in Group 1, but not in Group 2. A newer point of interest, defined as 2 cm directly caudal to the cervix os, was calculated later. The constraint was set to ensure adequate vaginal coverage. The dose required for this vaginal point was about 100% of Point A. Chemotherapy A total of 32 patients received chemotherapy in this study. Its administration was individualized and was largely on a neoadjuvant basis. The selection criteria included locally advanced stage, bulky tumor, positive nodes, and patient preference. Follow-up and statistical analysis Patient, tumor, and treatment characteristics are summarized in Tables 1 and 2. After treatment completion, patients were regularly followed at the Department of Radiation
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Oncology and Gynecology. Living patients were followed for 6.1–15.2 years (median, 9.8 years). Patients without regular visits were interviewed by telephone and/or letter. Patients lost to follow-up were censored and the survival time was counted from the day of treatment completion to the day of the last contact/visit. For a meaningful analysis, the small number of patients with Stage IIA, IIIA, and IVA were included with those with Stage IB, IIB, and IIIB, respectively. Pelvic recurrence was categorized as central or peripheral. Central recurrence was defined as recurrence in the cervix, parametrium, or upper vagina that was encompassed by brachytherapy. Proof of recurrence by pathologic examination in these patients was usually possible. Peripheral recurrence, on the other hand, was defined as recurrence in the side wall, obturator nodes, iliac nodes, lower vagina, or introitus. Any extrapelvic disease was considered distant metastasis. The duration of pelvic control and survival was counted from the day of RT completion. The actuarial pelvic control rate and overall survival rate were estimated with the Kaplan-Meier product-limit method, and their statistical significance tested by log–rank test. The severity of rectal complications was graded according to the Radiation Therapy Oncology Group criteria (12). For analysis and discussion, Grade 1-2 vs. Grade 3-4 rectal complications were considered low-grade vs. high-grade complications, respectively. The International Committee on Radiation Units and Measurements recommended point for evaluation of the rectal/bladder dose was reported, but not analyzed, because this information was not available in patients from the earlier period. Confounding factors that may influence pelvic control, overall survival, and rectal/bladder complications were tested with Cox’s regression model in a stepwise forward manner. Data processing and statistics were carried out on a personal computer using the Statistical Package for Social Sciences (SPSS) Software, version 11, software (SPSS, Chicago, IL) for Windows. RESULTS General data As of March 2003, 263 patients (49%) were alive, and 278 patients (51%) had died; 66 patients (12.2%) had developed tumor recurrence in the pelvis and 110 (20%) had metastasis outside the pelvis. Rectal bleeding developed in 201 patients (37%) to a varying degree. Colostomy was undertaken in 16 patients (3%) because of stenosis or fistula formation in the rectosigmoid area. Hemorrhagic cystitis was observed in 71 patients (13%). Nineteen patients (4%) experienced chronic abdominal cramp pain, possibly because of partial intestinal obstruction. Mild to moderate leg edema occurred in 41 patients (8%). Thirteen patients (2%) developed ureteral obstruction and chronic hydronephrosis related to the treatment. Nineteen patients (4%) developed a second malignancy. The distribution of patient outcome and treatment-related complications by group is summarized in Table 3.
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Table 1. Patients and tumor characteristics Characteristics Treatment period Age (range, 31–86 y; median, 61) ⬍60 ⱖ60 BMI (range, 14.8–44.1 kg/m2; median, 23.6) ⬍24 ⱖ24 Unknown Hemoglobin (range, 4.8–16 g/dL; median, 12) ⬍12 ⱖ12 Unknown Pathologic type SCC Non-SCC Stage IB ⫹ IIA (135 ⫹ 47) IIB ⫹ IIIA (248 ⫹ 12) IIIB ⫹ IVA (96 ⫹ 3) Diabetes mellitus Yes No Hypertension Yes No Follow-up Range median
Overall (n ⫽ 541)
Group 1 (n ⫽ 254)
Group 2 (n ⫽ 287)
1987–1996
1987–1993
1993–1996
247 (46) 294 (54)
120 (47) 134 (53)
127 (44) 160 (56)
285 (53) 252 (46) 4 (1)
136 (54) 117 (45) 1 (1)
149 (52) 135 (47) 3 (1)
235 (43) 292 (54) 14 (3)
111 (44) 138 (54) 5 (2)
124 (43) 154 (54) 9 (3)
517 (96) 24 (4)
244 (96) 10 (4)
273 (95) 14 (5)
182 (34) 260 (48) 99 (18)
70 (27) 124 (49) 60 (24)
112 (39) 136 (47) 39 (14)
74 (14) 467 (86)
38 (15) 216 (85)
36 (13) 251 (87)
104 (19) 437 (81)
41 (16) 213 (84)
63 (22) 224 (78)
6.1–15.2 9.8
9.7–15.2 12.4
6.1–9.6 7.6
Abbreviation: BMI ⫽ body mass index (weight/height in square meters). Data in parentheses are percentages, unless otherwise noted.
Pelvic control Of the 66 patients (12.2%) who developed pelvic recurrence, 30 patients were in Group 1 and 36 in Group 2. The onset of the pelvic recurrence ranged from 3 to 149 months (median, 8 months) for Group 1 and 3– 87.7 months (median, 8.7 months) for Group 2. Of the 30 pelvic recurrences in Group 1, 24 were categorized as central recurrence, 5 as peripheral recurrence, and 1 as both. Of the 36 pelvic recurrences in Group 2, 29 were central and 7 were peripheral. The distribution by group was not statistically significant (p ⫽ 0.722; Table 4). Regardless of treatment group or disease stage, the actuarial pelvic control rate for the entire cohort of 541 patients was 87.2% at 5 years and 86.8% at 10 years. By group, the 5-year actuarial pelvic control rate for Groups 1 and 2 was 88.2% and 86.3%, respectively. The corresponding rate at 10 years for Groups 1 and 2 was 87.3% and 85.5%, respectively. The difference was not statistically significant (p ⫽ 0.504, Fig. 1). By stage, the 5-year actuarial pelvic control rate for Groups 1 and 2 was 96.9% and 88.9% for Stage IB-IIA (p ⫽ 0.037); 91.6% and 88.6% for Stage IIB-IIIA (p ⫽ 0.526); and 68.9% and 69.9% for Stage IIIB-IVA (p ⫽ 0.784), respectively. The 5-year actuarial rate at 10 years for Groups 1 and 2 was 94.4% and 87.2% for IB-IIA (p ⫽
0.037); 91.6% and 88.6% for IIB-IIIA (p ⫽ 0.526); and 62.1% and 69.9% for IIIB-IVA (p ⫽ 0.784). Overall survival rate Regardless of treatment group or stage, the actuarial overall survival rate for the entire cohort of 541 patients was 59.8% at 5 years and 47.9% at 10 years. The 5-year actuarial overall survival rate was 63.5% and 56.1% for Groups 1 and 2, respectively. At 10 years, for Groups 1 and 2, it was 47.8% and 49.3%, respectively (p ⫽ 0.734, Fig. 2). The 5-year actuarial overall survival rate for Groups 1 and 2 was 81.4% and 67.5% for Stage IB-IIA (p ⫽ 0.352); 65.8% and 54.8% for Stage IIB-IIIA (p ⫽ 0.514); and 38.3% and 30.8% for Stage IIIB-IVA (p ⫽ 0.301). The overall survival rate at 10 years for Groups 1 and 2 was 63.8% and 58.3% for IB-IIA (p ⫽ 0.352); 49.4% and 51.3% for IIB-IIIA (p ⫽ 0.514); and 25.7% and 27.7% for IIIBIVA (p ⫽ 0.301). Rectal complications Overall, 201 patients developed rectal complication of varying degree. Of these, 117 (46%) were in Group 1 and 84 (29%) in Group 2. The median onset for Groups 1 and 2 was similar, 11 months (range, 3.1–147 months) and 11.3 months (range, 3.1– 40 months), respectively.
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Table 2. Treatment characteristics Characteristic EBRT Four-field box technique Yes No Daily dose (Gy) 1.8 2 Dose to cervix (Gy) (median, 45) 39.6–43.9 44–45 45.1–59.4 Dose to the parametrium (Gy) (median, 54) 39.6–43.9 44–54 54.1–59.6 BED10 (range, 47–70, median, 53) 47–52 53 54–70 BED3 (range, 63–107, median, 73) 63–71 72–73 74–107 HDR-IC Active length (range, 1–9 cm; median, 4.5) ⬍4.5 ⱖ4.5 Fractionation scheme Standardized ⫹ minor modification (⬍20%) ⱖ20% modification BED10 (range, 12.4–52.2; median, 35.5) ⬍28 28–37.2 ⱖ37.3 EBRT ⫹ HDR-IC Total treatment days (range, 45–228; median, 71) ⬍70 ⱖ70 Total BED10 (range, 70.8–106.8; median, 88.6) 70.8–80.9 81–90 90.1–106.8 Chemotherapy Yes No
Overall (n ⫽ 541)
Group 1 (n ⫽ 254)
Group 2 (n ⫽ 287)
195 (36) 346 (64)
20 (8) 234 (92)
175 (61) 112 (39)
223 (41) 318 (59)
0 (0) 254 (100)
223 (78) 64 (22)
38 (7) 430 (80) 73 (13)
9 (4) 207 (81) 38 (15)
29 (10) 223 (78) 35 (12)
143 (26) 152 (28) 246 (46)
60 (24) 34 (13) 160 (63)
83 (29) 118 (41) 86 (30)
32 (6) 443 (82) 66 (12)
8 (3) 210 (83) 36 (14)
24 (8) 233 (81) 30 (11)
32 (6) 443 (82) 66 (12)
8 (3) 210 (83) 36 (14)
24 (8) 233 (81) 30 (11)
251 (46) 290 (54)
137 (54) 117 (46)
114 (40) 173 (60)
468 (87) 73 (13)
201 (79) 53 (21)
267 (93) 20 (7)
56 (10) 470 (87) 15 (3)
49 (19) 202 (80) 3 (1)
7 (3) 268 (93) 12 (4)
242 (45) 299 (55)
34 (13) 220 (87)
208 (72) 79 (28)
36 (17) 453 (84) 52 (9)
31 (12) 207 (82) 16 (6)
5 (2) 246 (86) 36 (12)
32 (6) 509 (94)
17 (7) 237 (93)
15 (5) 272 (95)
Abbreviations: ERBT ⫽ external beam radiotherapy; BED ⫽ biologically effective dose; HDR-IC ⫽ high-dose-rate intracavitary brachytherapy. Data in parentheses are percentages, unless otherwise noted.
The 5-year actuarial proctitis rate for Groups 1 and 2 was 49.7% and 32.7%, respectively. At 10 years, the rate for Groups 1 and 2 was 50.5% and 32.7%, respectively (p ⬍0.001, Fig. 3). The number of patients with Grade 1, 2, 3 and 4 complication for Groups 1 and 2 was 56 (22%), 40 (16%), 14 (5%), and 7 (3%) and 39 (14%), 24 (8%), 12 (4%), and 9 (3%), respectively. When the complications was categorized as low (Grade 1-2) and high (Grade 3-4) grade, the low-grade complication rate for Groups 1 and 2 was 38% and 22% (p
⬍0.001), and the high-grade complication rate was 8% and 7%, respectively (Table 5). The reduction in rectal complications in Group 2 mainly occurred in low-grade complications, with the incidence of high-grade complications remaining unchanged.
Bladder complications Overall, 71 patients developed radiation cystitis, 45 in Group 1 and 26 in Group 2. The median onset for Groups 1
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Table 3. Distribution of patient outcome and treatment-related complications Outcome/complications
Group 1 (n ⫽ 254)
Group 2 (n ⫽ 287)
p*
Alive Pelvic recurrence Distant metastasis Proctitis Colostomy Cystitis Chronic abdominal cramp Leg edema Ureter obstruction Double cancer
108 (43) 30 (12.2) 54 (21) 117 (46) 7 (3) 45 (18) 12 (5) 33 (13) 7 (3) 9 (4)
155 (54) 36 (13) 56 (20) 84 (29) 9 (3) 26 (9) 7 (2) 8 (3) 6 (2) 10 (4)
0.008 0.795 0.614 ⬍0.001 0.982 0.003 0.150 ⬍0.001 0.614 0.970
Data in parentheses are percentages; percentages determined within group. * Pearson chi-square test.
and 2 was similar, 53 months (range, 10.3–167 months) and 38.9 months (range, 10.9 – 85 months), respectively. The 5-year actuarial cystitis rate for Groups 1 and 2 was 14.3% and 11.4%, respectively. At 10 years, it was 24.1% and 15% for Groups 1 and 2, respectively (p ⫽ 0.134, Fig. 4). The actuarial rates of pelvic control, overall survival, and rectal and bladder complications are summarized in Table 6. Univariate and multivariate analyses To examine the influence of confounding factors, 16 patient-, tumor-, and treatment-related variables were tested with univariate and multivariate analysis (Table 7). These variables included pathologic type (squamous vs. nonsquamous), age (⬍60 vs. ⱖ60 years), body mass index (⬍24 vs. ⱖ24), hemoglobin (⬍12 vs. ⱖ12), stage (FIGO Stage IBIIA vs. IIB-IIIA vs. IIIB-IVA), daily fraction size (1.8 Gy vs. 2 Gy), box technique (yes vs. no), EBRT dose to the cervix (⬍44 vs. 44 – 45 vs. ⬎45.1 Gy), EBRT dose to the parametrium (39.6 – 45 vs. 45.1–54 vs. 54.1–59.6 Gy), diabetes (yes vs. no), hypertension (yes vs. no), HDR-IC fractionation scheme (three fractions vs. five fractions), active length (⬍4.5 vs. ⱖ4.5 cm), total BED10 (⬍ 88.6 vs. ⱖ88.6), and total treatment days (⬍70 vs. ⱖ70). For pelvic control, age (p ⬍0.001, hazard ratio ⫽ 0.367, 95% confidence interval [CI], 0.214 – 0.629), body mass index (p ⫽ 0.020; hazard ratio ⫽ 0.541; 95% CI, 0.322– Table 4. Distribution of pelvic recurrence by group Recurrence
Group 1 (n ⫽ 254)
Group 2 (n ⫽ 287)
None Pelvic recurrence Central Peripheral Both
224 (88.2) 30 (11.8) 24 (9.4) 5 (2) 1 (0.4)
251 (87.5) 36 (12.5) 29 (10.1) 7 (2.4) 0 (0)
Data in parentheses are percentages. p ⫽ 0.722.
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0.909), FIGO stage (p ⫽ 0.001; hazard ratio ⫽ 1.851; 95% CI, 1.306 –2.625), and total BED10 (p ⫽ 0.003; hazard ratio ⫽ 2.234; 95% CI, 1.311–3.808) were statistically significant factors. For overall survival, hemoglobin (p ⬍0.001; hazard ratio ⫽ 0.575; 95% CI, 0.450 – 0.734), FIGO stage (p ⬍0.001; hazard ratio ⫽ 1.649; 95% CI, 1.388 –1.959), and diabetes (p ⫽ 0.025; hazard ratio ⫽ 1.459; 95% CI, 1.049 –2.029) were statistically significant factors. For radiation proctitis, the EBRT dose to the parametrium (p ⫽ 0.007; hazard ratio ⫽ 1.291; 95% CI, 1.074 –1.533), hypertension (p ⫽ 0.020; hazard ratio ⫽ 1.502; 95% CI, 1.065–2.119), and HDR-IC fractionation scheme (p ⫽ 0.004; hazard ratio ⫽ 0.807; 95% CI, 0.697– 0.934) were statistically significant factors. For radiation cystitis, the EBRT dose to the parametrium (p ⫽ 0.045; hazard ratio ⫽ 1.350; 95% CI, 1.006 –1.811) was the only statistically significant factor. DISCUSSION Although the pelvic control rate has been commonly reported and used to compare different treatment modalities in cervical cancer, central recurrence is a more critical indicator to evaluate the tumoricidal effect of HDR-IC. Overall, the central recurrence rate in this series was 10.4% (56 of 541), and its distribution between the two groups was similar, 9.4% vs. 10.1% for Groups 1 and 2, respectively (p ⫽ 0.722). This result showed that the tumoricidal effect of the two schemes was comparable in terms of central control. The patterns of recurrence in the pelvis in the HDR-IC setting have not been well analyzed. Wong et al. (3) reported 34 (16%) local failures in 205 patients achieving a complete remission. Of the 34 cases, 7 (21%) were central failure only, 15 (44%) were pelvic failure only, and 12 (35%) were mixed failure. Takeshi et al. (13), treating 265 Stage III patients with HDR-IC, reported an overall pelvic recurrence rate of 24% (63 of 265). Of the 63 cases, 52 (83%) were central recurrence and 11 (17%) were peripheral recurrence. Similar to the findings of Takeshi et al. (13), most pelvic recurrence in our patients was central, accounting for 80% (53 of 66) of all recurrence in the pelvis. The tumoricidal effect of HDR-IC for advanced cases was a concern. Petereit et al. (14), comparing the Wisconsin experience of HDR vs. LDR, reported significantly poorer pelvic control for Stage IIIB cases in HDR-treated patients (44% vs. 75% for HDR vs. LDR, respectively). In another meta-analysis, Petereit and Pearcey (1) observed several institutions reporting favorable pelvic control in Stage IIIB disease with a tumoricidal dose less than the LDR equivalent of 75 Gy. Barillot et al. (15) also raised the concern of underdosage and/or accurate staging for Stage IIIB cases after analyzing and comparing 642 LDR-treated patients in three periods, 1970 –1978, 1979 –1984, and 1985–1994. The 5-year local control rate in Stage III patients fell from 75% to 55% when the complication rate decreased simultaneously with time. In our study, the 5-year actuarial pelvic
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Fig. 1. Actuarial pelvic control rate by group (p ⫽ 0.504). 3-Fr ⫽ Group 1; 5-Fr ⫽ Group 2.
control rate for Stage IIIB-IVA was 68.9% vs. 69.9% for Groups 1 and 2, respectively (p ⫽ 0.784). This result
appeared slightly more favorable than the findings of Petereit et al. (14) and Barillot et al. (15).
Fig. 2. Actuarial overall survival rate by group (p ⫽ 0.734). 3-Fr ⫽ Group 1; 5-Fr ⫽ Group 2.
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Fig. 3. Actuarial proctitis rate by group (p ⬍0.001). 3-Fr ⫽ Group 1; 5-Fr ⫽ Group 2.
The parametrial dose was a statistically significant factor associated with an increased risk of both rectal and bladder complications in this and one of our previous reports (16). A high parametrial dose has also been reported as a factor of increased small bowel complications by Ferrigno et al. (17), although it was not statistically significant (p ⫽ 0.260). They suggested the boost field should be lower than S2-S3, and the dose ⬍54 Gy. As we pointed out earlier, most cervical cancer recurrences in the pelvis remained central. The value of a high dose to the side wall with EBRT is thus questionable and needs further study. The overall treatment time was not a statistically significant predictor of local control or survival in our study. The overall treatment time has been reported as an independent prognostic factor on pelvic control in cervical carcinoma in Table 5. Distribution of severity of rectal complication by group
None Low grade Grade 1 Grade 2 High grade Grade 3 Grade 4
Group 1 (n ⫽ 254)
Group 2 (n ⫽ 287)
137 (54) 96 (38) 56 (22) 40 (16) 21 (8) 14 (5) 7 (3)
203 (71) 63 (22) 39 (14) 24 (8) 21 (7) 12 (4) 9 (3)
Data in parentheses are percentages. p ⬍ 0.001.
five large series between 1992 and 1995 (18 –22). These authors reported a loss of pelvic control ranging from 0.5% to 1.2% daily if treatment was prolonged. These results were all LDR based. Together with our findings, we noted at least four HDR series that reported the negative influence of treatment prolongation on pelvic control/survival using multivariate analysis (3, 13). The latest detailed analysis of HDR series reported by Chen et al.(23) concluded that treatment prolongation negatively influences cause-specific survival and pelvic control. To the best of our knowledge, only one HDR study by Ferrigno et al. (17) has reported a positive influence from treatment prolongation. We believe the issue remains debatable. Additionally, in practice, shortening the overall treatment time excessively may not be good for advanced cases, because substantial tumor regression may not have been achieved yet for optimal coverage by brachytherapy. This was stressed by Petereit et al. (14) and the report by the American Brachytherapy Society (24). The 5-year actuarial overall survival rate for both groups was similar (p ⫽ 0.734). This result was comparable with most of the recent HDR reports. Ferrigno et al. (17) reported a 5-year overall survival rate of 53.7% in 138 patients treated with HDR-IC. Takeshi et al. (13) reported a 5-year overall survival rate of 50.7% in 265 Stage III patients. Stage for stage, the 5-year actuarial overall survival rate for Groups 1 and 2 was 81.4% vs. 67.5% for Stage IB-IIA (p ⫽ 0.352); 65.8% vs. 54.8% for Stage IIB-IIIA (p ⫽ 0.514); and 38.3% vs. 30.8% for Stage IIIB-IVA, respectively (p ⫽ 0.301). This result is also comparable with existing LDR
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Fig. 4. Actuarial cystitis rate by group (p ⫽ 0.134). 3-Fr ⫽ Group 1; 5-Fr ⫽ Group 2.
reports. Coia et al. (25) reported a 5-year overall survival rate for Stage I-III in the Pattern of Care Study of 33–74%. Fyles et al. (26) reported a 5-year overall survival rate for Stage I-III in the Princess Margaret Hospital study of 41– 78%. Ferrigno et al. (27) reported on the Brazil experience of cobalt teletherapy plus LDR treatment. The 5-year overall survival rate for Stage I-III was 46 – 83% (27). Barillot et al. (28) reported a result of 45– 84% in a French Cooperative study. The proctitis rate in our study was significantly decreased Table 6. Actuarial rate of local control, overall survival, rectal and bladder complications End point Pelvic control (y) 5 10 Overall survival (y) 5 10 Proctitis (y) 5 10 Cystitis (y) 5 10
Overall (%)
Group 1 (%)
Group 2 (%)
87.2 86.8
88.2 87.3
86.3 85.5
0.504
59.8 47.9
63.5 47.8
56.1 49.3
0.734
40.8 41.7
49.7 50.5
32.7 32.7
⬍0.001
12.8 21.5
14.3 24.1
11.4 15.0
0.134
p
in Group 2. We were very pleased to see this result, because it was the main goal of our initial design. This was the first prospectively designed protocol in HDR-IC that successfully demonstrated that a linear-quadratic model– based mathematical calculation can convert into an expected clinical outcome. The success through biologic manipulation of the fraction size in our study suggests that the sensitivity of the late responding tissue to the fraction change from 7.2 Gy to 4.8 Gy in HDR-IC is high and detectable clinically. Wong et al. (3) and Le Pechoux et al. (2) also compared two different schemes in HDR-IC but failed to demonstrate any complication benefit. A possible explanation is that the difference in the fraction size in their studies was too narrow (7 Gy vs. 6 Gy in Wong et al. and 6 Gy vs. 5 Gy in Le Pechoux et al.). The fraction sensitivity may have been too low to be detected. Furthermore, the small fraction difference may need a larger sample size or longer follow-up to detect any differences. Wong et al. (3) reported an overall complication rate for the four-fraction regimen that was lower than that of the three-fraction regimen (44.2% vs. 55.8%), with a p value of marginal significance (p ⫽ 0.0672). Our finding has important implications. The fractionation scheme in HDR-IC has varied widely from 2 to 9 Gy/ fraction in the past. With rare exception (29), we observed that the fractionation schemes used in recent studies have
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Table 7. Univariate and multivariate analysis Pelvic control
Overall survival
Proctitis rate
Cystitis rate
Variable
UVA
MVA
UVA
MVA
UVA
MVA
UVA
MVA
Pathologic finding Age BMI Hemoglobin Stage Daily dose (EBRT) Dose to cervix (EBRT) Dose to parametrium (EBRT) Box field Diabetes Hypertension Active length HDR-IC scheme Total BED10 Total treatment days
0.042 ⬍0.001 0.014 0.003 ⬍0.001 0.296 0.003 0.002 0.823 0.132 0.227 0.453 0.504 0.040 0.432
0.064 ⬍0.001* 0.020* 0.204 0.001* 0.057 0.248 0.806 0.390 0.303 0.699 0.630 0.172 0.003* 0.357
0.029 0.829 0.011 ⬍0.001 ⬍0.001 0.287 0.018 ⬍0.001 0.313 0.143 0.623 0.924 0.743 0.145 0.077
0.066 0.218 0.110 ⬍0.001* ⬍0.001* 0.767 0.807 0.862 0.907 0.025* 0.317 0.906 0.304 0.217 0.747
0.949 0.639 0.174 0.202 0.001 0.008 0.026 0.003 0.040 0.951 0.247 0.327 0.001 0.463 0.011
0.982 0.460 0.153 0.326 0.881 0.318 0.194 0.007* 0.804 0.598 0.020 0.325 0.004* 0.256 0.864
0.283 0.242 0.466 0.566 0.048 0.399 0.060 0.027 0.508 0.806 0.303 0.378 0.134 0.043 0.190
0.356 0.234 0.489 0.446 0.457 0.735 0.325 0.045* 0.475 0.697 0.609 0.603 0.297 0.226 0.891
Abbreviations: UVA ⫽ univariate analysis; MVA ⫽ multivariate analysis; BMI ⫽ body mass index; EBRT ⫽ external beam radiotherapy; BED10 ⫽ biologically equivalent dose, assuming ␣/ ⫽ 10; HDR-IC ⫽ high-dose-rate intracavitary brachytherapy. * Statistically significant in MVA.
mostly converged between 4 and 7 Gy, which agrees with the recent recommendation of the American Brachytherapy Society (24) and the Wisconsin experience (1, 14). Clinically, it is not appropriate to interpolate or extrapolate the results of this study. The fraction sensitivity in the dose range of brachytherapy interest may not be totally linear, so that the clinical results of a dose between 4.8 and 7.2 Gy should not be extrapolated to, for instance, 4.8 Gy and 3 Gy, or 7.2 Gy and 10 Gy. Although the overall proctitis rate decreased, it appeared that the manipulation had its limitations. When the severity of proctitis was compared grade by grade, we found that the decrease was confined to only the low-grade complications (38% vs. 22% for Groups 1 and 2, respectively). The high-grade complication rate remained virtually unchanged (8% vs. 7% for Groups 1 and 2, respectively). Hospitalization or blood transfusion because of severe rectal bleeding or anemia (Grade 3) was needed in 5% (14 cases) and 4% (12 cases) of Groups 1 and 2, respectively. Colostomy (Grade 4) was required in 3% of patients, distributed equally in both groups. Barillot et al. (15) reported the effect of different techniques of radiotherapy in the treatment of 642 patients with cervical cancer in three periods between 1970 and 1994. The rate of Grade 3 rectal/bladder complications decreased over time from 16% to 6%, and no Grade 4 complications was encountered in the last period. They attributed these complications to three factors: a high EBRT dose, a high dose rate at the reference points, and whole vagina brachytherapy with cylinder. The analysis of Barillot et al. (15) highlighted that severe complications in radiotherapy for cervical cancer are more technically or dosimetrically related. It is thus understandable that biologic manipulation of the fraction size in our study may not have been able to change the rate of severe complications. Radi-
ation-induced rectal bleeding is a complicated issue, involving damage of both acute and late responding tissue (30). Although the rate of Grade 3-4 severe rectal complications, 7– 8%, in this study was acceptable, we believe there is still room to improve, particularly in Stage I-II cases. We agree with Petereit and Pearcey’s conclusion in their meta-analysis that the optimal fractionation schedule is still unknown and presently can be based only on single institutions with significant experience (1). The treatment policy in our department will continue to evolve, including decreasing the total EBRT dose to the whole pelvis, restricting the parametrial boost dose/field in Stage I-II cases, and increasing the use of concurrent chemotherapy in selective cases on the basis of recent encouraging results (31–33). Additionally, we noted that the fractionation schemes of HDR-IC have tended to converge further between the dose of 4.5 and 6 Gy, the fraction sensitivity of this range deserves clinical testing. A grant-supported randomized trial is underway in our department. CONCLUSION On the basis of the experiences of treating 541 patients with two isoeffect schemes, we found that the central recurrence, actuarial pelvic control rate, and overall survival rate were similar and the proctitis rate decreased. The linearquadratic model correctly predicted this clinical outcome. This study demonstrated that fraction sensitivity between the dose of 4.8 Gy and 7.2 Gy in HDR-IC is high and detectable clinically. This finding has important implications for the prescription of the fraction dose in HDR-IC. The success through biologic manipulation of the fraction size in this range has limitations, and the improvement was confined to a reduction in low-grade complications.
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REFERENCES 1. Petereit DG, Pearcey R. Literature analysis of high dose rate brachytherapy fractionation schedules in the treatment of cervical cancer: Is there an optimal fractionation schedule? Int J Radiat Oncol Biol Phys 1999;43:359–366. 2. Le Pechoux C, Akine Y, Sumi M, et al. High dose rate brachytherapy for carcinoma of the uterine cervix: Comparison of two different fractionation regimens. Int J Radiat Oncol Biol Phys 1995;31:735–741. 3. Wong FCS, Tung SY, Leung T-W, et al. Treatment results of high-dose-rate remote afterloading brachytherapy for cervical cancer and retrospective comparison of two regimens. Int J Radiat Oncol Biol Phys 2003;55:1254–1264. 4. Ling CC, Sahoo N, Leibel S, et al. High dose rate gynecological applications: Radiobiological considerations based on the ␣/ model. Radiother Oncol 1992;25:103–110. 5. Brenner DJ, Hall EJ. Fractionated high dose rate vs. low dose rate regimens for intracavitary brachytherapy of the cervix. Br J Radiol 1991;64:133–141. 6. Fowler JF. The linear-quadratic formula and progress in fractionated radiotherapy. Br J Radiol 1989;62:679–694. 7. Dale RG. The use of small fraction numbers in high dose rate gynecological afterloading: Some radiobiological considerations. Br J Radiol 1990;63:290–294. 8. Sood B, Garg M, Avadhani J, et al. Predictive value of linear-quadratic model in the treatment of cervical cancer using high dose rate brachytherapy. Int J Radiat Oncol Biol Phys 2002;54:1377–1387. 9. Orton CG. High dose rate vs. low dose rate brachytherapy for gynecological cancer. Semin Radiat Oncol 1993;3:232–239. 10. Wang C-J, Leung SW, Chen H-C, et al. High-dose-rate intracavitary brachytherapy (HDR-IC) in treatment of cervical carcinoma: 5-year results and implication of increased lowgrade rectal complication on initiation an HDR-IC fractionation scheme. Int J Radiat Oncol Biol Phys 1997;38:391–398. 11. Chen M-S, Lin F-J, Hong C-H, et al. High-dose-rate afterloading technique in the radiation treatment of uterine cervical cancer: 399 cases and 9 years experience in Taiwan. Int J Radiat Oncol Biol Phys 1991;20:915–919. 12. Cox JD, Stetz J, Pajak TF. Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). Int J Radiat Oncol Biol Phys 1995;31:1341–1346. 13. Takeshi K, Katsuyuki K, Yoshiaki T, et al. Definitive radiotherapy combined with high dose rate brachytherapy for Stage III carcinoma of the uterine cervix: Retrospective analysis of prognostic factors concerning patients characteristics and treatment parameters. Int J Radiat Oncol Biol Phys 1998;41: 319–327. 14. Petereit DG, Sarkaria JN, Potter DM, et al. High-dose-rate vs. low-dose-rate brachytherapy in the treatment of cervical cancer: Analysis of tumor recurrence—The University of Wisconsin experience. Int J Radiat Oncol Biol Phys 1999;45: 1267–1274. 15. Barillot I, Horiot JC, Maingo P, et al. Impact on treatment outcome and late effects of customized treatment planning in cervix carcinoma: Baseline results to compare new strategies. Int J Radiat Oncol Biol Phys 2000;48:189–200. 16. Huang EY, Lin H, Hsu HC, et al. High external parametrial dose can increase the probability of radiation proctitis in patients with uterine cervix cancer. Gynecol Oncol 2000;79: 406–410. 17. Ferrigno R, Novaes PERDS, Pellizzon ACA, et al. High-dose-
18. 19. 20. 21.
22.
23. 24.
25. 26.
27.
28.
29.
30. 31.
32. 33.
rate brachytherapy in the treatment of uterine cervix cancer: Analysis of dose effectiveness and late complication. Int J Radiat Oncol Biol Phys 2001;50:1123–1135. Fyles A, Keane TJ, Barton M, et al. The effect of treatment duration in the local control of cervix cancer. Radiother Oncol 1992;25:273–279. Petereit DG, Sakaria JN, Chappell R, et al. The adverse effect of treatment prolongation in cervical carcinoma. Int J Radiat Oncol Biol Phys 1995;32:1301–1307. Lanciano RM, Pajak TF, Martz K, et al. The influence of treatment time on outcome for squamous cell cancer of the uterine cervix. Cancer 1992;69:2124–2130. Girinsky T, Rey A, Roche B, et al. Overall treatment time in advanced cervical carcinoma: A critical parameter in treatment outcome. Int J Radiat Oncol Biol Phys 1993;27:1051– 1056. Perez CA, Grigsby PW, Castro-Vita H, et al. Carcinoma of the uterine cervix: Impact of prolongation of treatment time and timing of brachytherapy on outcome of radiation therapy. Int J Radiat Oncol Biol Phys 1995;32:1275–1288. Chen SW, Liang JA, Yang SN, et al. The adverse effect of treatment prolongation in cervical cancer by high-dose-rate intracavitary brachytherapy. Radiother Oncol 2003;67:69–76. Nag S, Erickson B, Thomadsen B, et al. The American Brachytherapy Society recommendations for high dose rate brachytherapy for carcinoma of the cervix. Int J Radiat Oncol Biol Phys 2000;48:201–211. Coia L, Won M, Lanciano R, et al. The patterns of care outcome study for cancer of the uterine cervix: Results of the second National Practice Survey. Cancer 1990;9:431–436. Fyles AW, Pintilie M, Kirkbridge P, et al. Prognostic factors in patients with cervix cancer treated by radiation therapy: Results of a multiple regression analysis. Radiother Oncol 1995;35:107–117. Ferrigno R, Oliveira Faria SLC, Weltman E, et al. Radiotherapy alone in the treatment of uterine cervix cancer with telecobalt and low dose rate brachytherapy: Retrospective analysis of results and variables. Int J Radiat Oncol Biol Phys 2003;55:695–706. Barillot I, Horiot JC, Pigneaux J, et al. Carcinoma of the intact uterine cervix treated with radiotherapy alone: A French cooperative study—Update and multivariate analysis of prognostic factors. Int J Radiat Oncol Biol Phys 1997;38:969–978. Sood BM, Gorla G, Gupta S, et al. Two fractions of highdose-rate brachytherapy in the management of cervix cancer: Clinical experience with and without chemotherapy. Int J Radiat Oncol Biol Phys 2002;53:702–706. Dubray BM, Thames HD. Chronic radiation damage in the rate rectum: An analysis of the influences of fractionation, time, and volume. Radiother Oncol 1994;33:41–47. Morris M, Eifel P, 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. Rose PG, Bundy N, Watkins EB, et al. Concurrent cisplatinbased radiotherapy and chemotherapy for locally advanced cervical cancer. N Engl J Med 1999;340:1144–1153. Green JA, Kirwan JM, Tierney JF, et al. Survival and recurrence after concomitant chemotherapy and radiotherapy for cancer of the uterine cervix: A systematic review and metaanalysis. Lancet 2001;358:781–786.
doi:10.1016/j.ijrobp.2003.10.025
CLINICAL INVESTIGATION
Cervix
CLINICAL COMPARISON OF TWO LINEAR-QUADRATIC MODEL-BASED ISOEFFECT FRACTIONATION SCHEMES OF HIGH-DOSE-RATE INTRACAVITARY BRACHYTHERAPY FOR CERVICAL CANCER CHONG-JONG WANG, M.D.,* ENG-YEN HUANG, M.D.,* LI-MIN SUN, M.D.,* HUI-CHUN CHEN, M.D.,* FU-MIN FANG, M.D.,* HSUAN-CHIH HSU, M.D.,* CHAN-CHAO CHANGCHIEN, M.D.,† AND STEPHEN WAN LEUNG, M.S., M.D.‡ Departments of *Radiation Oncology and †Gynecology Oncology, Kaohsiung Chang Gung Memorial Hospital; ‡Department of Radiation Oncology, Yuan’s General Hospital, Kaohsiung, Taiwan Purpose: Two linear-quadratic model– based isoeffect fractionation schemes of high-dose-rate intracavitary brachytherapy (HDR-IC) were used to treat cervical cancer in two consecutive periods. Patient outcomes and complications were analyzed and compared. Methods and Materials: Between November 1987 and December 1996, a total of 541 women diagnosed with cervical cancer were treated with curative-intent radiotherapy. Patients were categorized into two groups according to the two isoeffect schemes used. Group 1 consisted of 254 patients treated with external beam radiotherapy (EBRT) plus 7.2 Gy HDR-IC to Point A for three fractions in the first period. Group 2 consisted of 284 patients treated with EBRT plus 4.8 Gy HDR-IC for five fractions in the second period. The goal of the new scheme for the latter group was to deliver an isoeffect dose that maintained similar tumor control but reduced normal tissue complications. The calculated biologically effective dose (BED10, assuming an ␣/ ratio ⴝ 10) of EBRT plus HDR-IC for tumor and acute responding tissue in Groups 1 and 2 was 90 Gy10 (52.8 ⴙ 37.2 Gy) and 88.6 Gy10 (53.1 ⴙ 35.5 Gy), respectively. The corresponding BED3 for late responding tissue (assuming an ␣/ ratio ⴝ 3) in Groups 1 and 2 was 146.7 Gy3 (73.3 ⴙ 73.4 Gy) and 134.4 Gy3 (72 ⴙ 62.4 Gy), respectively. Patients were followed for 6.1–15.2 years (median, 9.8 years). Results: Overall, 66 patients (12.2%) developed pelvic recurrence. Of these, 53 patients had central recurrence. Of the 53 patients with central recurrence, 24 (9.4%) were in Group 1 and 29 (10.1%) in Group 2 (p ⴝ 0.722). The actuarial pelvic control rate for Groups 1 and 2 was 88.2% and 86.3% at 5 years and 87.3% and 85.5% at 10 years, respectively (p ⴝ 0.504). The actuarial overall survival rate for Groups 1 and 2 was 63.5% and 56.1% at 5 years and 47.8% and 49.3% at 10 years, respectively (p ⴝ 0.734). The actuarial proctitis rate for Groups 1 and 2 was 49.7% and 32.7% at 5 years and 50.5% and 32.7% at 10 years, respectively (p <0.001). Most of the decrease in the rate of proctitis was a result of a decrease in the incidence of low-grade proctitis (38% vs. 22%). The incidence of high-grade complications remained unchanged, 8% vs. 7%. The actuarial cystitis rate for Groups 1 and 2 was 14.3% vs. 11.4% at 5 years and 24.1% vs. 15% at 10 years, respectively (p ⴝ 0.134). Multivariate analysis revealed that the fractionation scheme (three fractions vs. five fractions) was a significant factor influencing the proctitis rate (p ⴝ 0.004, hazard ratio ⴝ 0.807; 95% confidence interval, 0.697– 0.934), but not the local pelvic control rate, overall survival rate, or cystitis rate. Conclusion: The treatment results of the two groups maintained similar outcomes, while the complications decreased. The linear-quadratic model correctly predicted this outcome. Biologically, the manipulation of the fraction size in our study suggested that the sensitivity of the late responding tissue to the fractional change from 7.2 Gy to 4.8 Gy in HDR-IC is high and detectable clinically. The success, however, had its limitations, and the improvement was confined to low-grade complications. © 2004 Elsevier Inc. Cervical carcinoma, Linear-quadratic model, High-dose-rate, Fractionation scheme, Brachytherapy.
change in the fractionation scheme used in this report. Dr. Lo was then a medical physicist at the Memorial Sloan-Kettering Cancer Center in New York, and is now at Mount Sinai Hospital, New York. Received Jul 17, 2003, and in revised form Sep 29, 2003. Accepted for publication Oct 15, 2003.
Reprint requests to: Chong-Jong Wang, M.D., Department of Radiation Oncology, Kaohsiung Chang Gung Memorial Hospital, 123 Ta-Pei Rd., Niao-Sung Hsian, Kaohsiung Hsien, Taiwan. Tel: (⫹886) 7-7317123, ext. 2600; Fax: (⫹886) 7-7322813; E-mail: [email protected] Acknowledgments—We thank Dr. Yeh-Chi Lo, whose visit to our Department in 1993 and help in formulation substantiated the 179
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INTRODUCTION With the data accumulated during the past years, high-doserate intracavitary brachytherapy (HDR-IC) has gained recognition and popularity in the treatment of cervical cancer. The optimal fractionation scheme for this technique, however, remains undetermined. A meta-analysis of the subject conducted by Petereit and Pearcey (1) in 1999 concluded that the optimal schedule was still unknown and could be based only on single institutions with significant experience. Publications on the clinical comparison of different fractionation schemes in HDR-IC were limited. Le Pechoux et al. (2) comparing two different fractionation schemes of 5 Gy twice weekly vs. 6 Gy once weekly, concluded that once-weekly HDR combined with properly adjusted pelvic external beam radiotherapy was safe and effective. Recently, Wong et al. (3) reported a comparison of two fractionation schemes, 7 Gy for three fractions vs. 6 Gy for four fractions, and concluded that the two schemes were not a statistically significant prognosticator in predicting disease control and complications. The biologic basis of these fractionation schemes for HDR-IC and its intercomparison with the low-dose-rate (LDR) setting was derived from a linear-quadratic model, as described by several authors (4 –9). The model largely categorized normal tissues into acute (including tumor) and late responding tissues. Characteristically, late responding tissues exhibited a survival curve of a flat shoulder at a low-dose region and a faster bend at a high-dose region, indicating that the tissues responsible for late complications are more sensitive to fraction size (smaller ␣/ ratio). In theory, if we split larger fraction dose into smaller ones, we can decrease complications without compromising the tumor control rate. Whether the theory works and can translate into the expected outcome in the brachytherapy setting, however, had not been thoroughly tested clinically. In this report, we analyzed 541 HDR-IC patients in two consecutive periods using two isoeffect schemes. Patient outcome and treatment-related complications are reported and compared. The validity of the model on the prediction of normal tissue complications in the HDR-IC setting was examined.
METHODS AND MATERIALS Patient characteristics The analysis included 541 women who were treated with curative-intent radiotherapy (RT) for cervical cancer between November 1987 and December 1996. Patients were categorized into two groups according to the fractionation scheme used in the two consecutive periods. Group 1 consisted of 254 patients treated with external beam RT (EBRT) plus three-fraction HDR-IC between November 1987 and April 1993. Group 2 consisted of 287 patients treated with EBRT plus 5-fraction HDR-IC between May 1993 and December 1996. Patient age ranged from 31 to 86 years (median 61). The Federation Internationale de Gynecologie et d’Obstetrique (FIGO) staging system was used.
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Pretreatment evaluation and staging workup, including complete blood count, chest radiography, intravenous pyelography, CT of the pelvis, cystoscopy, and sigmoidoscopy were done as appropriate. External beam RT The technical details of the EBRT and HDR-IC used in this department have been previously published elsewhere (10, 11). Because the departmental policies and facilities changed during the two treatment periods, the present description focused mainly on the contrast between the two treatment groups. All patients were treated initially with EBRT. In Group 1, whole pelvic EBRT was administered with 10-MV photons through AP parallel-opposing ports (AP–PA). The daily dose was 2 Gy. A four-field “box” technique was not routinely used in these patients. The standardized dose to the central cervix ranged from 40 to 44 Gy in 20 –22 fractions. An additional boost of 0 –14 Gy in zero to seven fractions was given to the bilateral pelvic wall, with a 4-cm midline block to shield the central structures in patients with parametrial or suspected pelvic lymph node involvement, so that total dose to the pelvic wall in Group 1 was maintained at 40 –58 Gy. With the implementation of a multileaf collimator-equipped linear accelerator in early 1995, the daily dose was reduced from 2 Gy to 1.8 Gy, and a four-field box technique was routinely used in all the patients treated thereafter. Thus, in Group 2, the dose to the central cervix was 39.6 – 45 Gy in 22–25 fractions, and the dose to the side wall was maintained at 39.6 –59.6 Gy. High-dose-rate IC The HDR-IC techniques were similar across the two treatment periods. HDR-IC was given after the completion of EBRT in all patients. An interdigitated arrangement of HDR-IC during the EBRT course was not applied in our patients. On a routine basis, the first application was performed under general anesthesia. Tumor regression was evaluated, and the endocervical canal was dilated. The uterine sounding was measured, and the applicator was inserted. The applicator used in all patients was Henschke’s type, consisting of one curved central tandem and two nonshielded ovoids. At the end of the procedure, the vagina was packed tautly with contrasted gauze. A urinary catheter with a urograffin-filled balloon was installed to outline the posterior bladder wall. The International Committee on Radiation Units and Measurements recommended points for rectal/bladder dose evaluation in Report No. 38 were not available until 1991. Before this, orthogonal maximal points were used for rectal/bladder dose evaluation. The HDR-IC facility used in Group 1 was mainly the Ralstron system (Toshiba, Japan) using 60Co sources. The system was replaced by a microSelectron system (Nucletron) using a 192Ir source in early 1993. The patients in Group 2 were all treated with this new system. During the transition of the two systems, brachytherapy in 40 patients were performed at a neighboring institution using the Selectron system. These patients were not included in the
Two isoeffect schemes of HDR-IC
analysis because the method of the source dwell and plan optimization were not consistent with ours. The standard fractionation scheme in Group 1 was 7.2 Gy to Point A for three fractions with each fraction administered 2 weeks apart. On the basis of the linear-quadratic model, the scheme was changed to 4.8 Gy for five fractions given twice weekly in May 1993. The goal was to deliver an isoeffect dose that maintained a similar tumor control rate, while hopefully reducing normal tissue complications. The calculated biologically equivalent dose (BED10) of HDR-IC for tumor and acute responding tissue (assuming ␣/ ratio ⫽ 10) in Groups 1 and 2 was 37.2 Gy10 and 35.5 Gy10, respectively. The corresponding BED3 for late responding tissue (assuming ␣/ ratio ⫽ 3) for the 2 groups was 73.4 Gy3 and 62.4 Gy3. For medical considerations, a reduction of 10 –20% of the total HDR-IC dose was allowed in aged patients with a favorable tumor response after EBRT or in patients with severe chronic disease in both groups. The rules of source dwell and plan optimization have been previously published (10). These rules were consistent across the two treatment periods. The method was partly extended from the Manchester technique. The concept of differential loading in tandem was generally applied to our treatment. This was achieved by modulating the weight of the dwell time in the tandem. The rule was that the highest point of the tandem near the fundus was weighted 1.5 and the lowermost point near the cervical os was weighted 0.8. The rest of tandem points were equally weighted at 1.0. The dose contribution of the central tandem vs. both ovoids was consistently 3:1. For the Ralstron unit, the stepwise distance is adjustable in 0.1-cm intervals; usually 0.9 –1.3 cm (median, 1.1 cm) was used. The stepwise distance of the microSelectron unit is formatted, and 0.5 cm was commonly used. The dwell positions in tandem were adjusted so that the lowermost point (with 0.8 weighting) was generally 0.6 – 0.8 cm above the cervical os. This constraint was set to avoid an excessive dose to the rectovaginal septum. The dose to the point of cervix os was routinely calculated and required to be maintained about twofold of that of Point A. The dose to Point B and the contralateral Point A were calculated in Group 1, but not in Group 2. A newer point of interest, defined as 2 cm directly caudal to the cervix os, was calculated later. The constraint was set to ensure adequate vaginal coverage. The dose required for this vaginal point was about 100% of Point A. Chemotherapy A total of 32 patients received chemotherapy in this study. Its administration was individualized and was largely on a neoadjuvant basis. The selection criteria included locally advanced stage, bulky tumor, positive nodes, and patient preference. Follow-up and statistical analysis Patient, tumor, and treatment characteristics are summarized in Tables 1 and 2. After treatment completion, patients were regularly followed at the Department of Radiation
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Oncology and Gynecology. Living patients were followed for 6.1–15.2 years (median, 9.8 years). Patients without regular visits were interviewed by telephone and/or letter. Patients lost to follow-up were censored and the survival time was counted from the day of treatment completion to the day of the last contact/visit. For a meaningful analysis, the small number of patients with Stage IIA, IIIA, and IVA were included with those with Stage IB, IIB, and IIIB, respectively. Pelvic recurrence was categorized as central or peripheral. Central recurrence was defined as recurrence in the cervix, parametrium, or upper vagina that was encompassed by brachytherapy. Proof of recurrence by pathologic examination in these patients was usually possible. Peripheral recurrence, on the other hand, was defined as recurrence in the side wall, obturator nodes, iliac nodes, lower vagina, or introitus. Any extrapelvic disease was considered distant metastasis. The duration of pelvic control and survival was counted from the day of RT completion. The actuarial pelvic control rate and overall survival rate were estimated with the Kaplan-Meier product-limit method, and their statistical significance tested by log–rank test. The severity of rectal complications was graded according to the Radiation Therapy Oncology Group criteria (12). For analysis and discussion, Grade 1-2 vs. Grade 3-4 rectal complications were considered low-grade vs. high-grade complications, respectively. The International Committee on Radiation Units and Measurements recommended point for evaluation of the rectal/bladder dose was reported, but not analyzed, because this information was not available in patients from the earlier period. Confounding factors that may influence pelvic control, overall survival, and rectal/bladder complications were tested with Cox’s regression model in a stepwise forward manner. Data processing and statistics were carried out on a personal computer using the Statistical Package for Social Sciences (SPSS) Software, version 11, software (SPSS, Chicago, IL) for Windows. RESULTS General data As of March 2003, 263 patients (49%) were alive, and 278 patients (51%) had died; 66 patients (12.2%) had developed tumor recurrence in the pelvis and 110 (20%) had metastasis outside the pelvis. Rectal bleeding developed in 201 patients (37%) to a varying degree. Colostomy was undertaken in 16 patients (3%) because of stenosis or fistula formation in the rectosigmoid area. Hemorrhagic cystitis was observed in 71 patients (13%). Nineteen patients (4%) experienced chronic abdominal cramp pain, possibly because of partial intestinal obstruction. Mild to moderate leg edema occurred in 41 patients (8%). Thirteen patients (2%) developed ureteral obstruction and chronic hydronephrosis related to the treatment. Nineteen patients (4%) developed a second malignancy. The distribution of patient outcome and treatment-related complications by group is summarized in Table 3.
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Table 1. Patients and tumor characteristics Characteristics Treatment period Age (range, 31–86 y; median, 61) ⬍60 ⱖ60 BMI (range, 14.8–44.1 kg/m2; median, 23.6) ⬍24 ⱖ24 Unknown Hemoglobin (range, 4.8–16 g/dL; median, 12) ⬍12 ⱖ12 Unknown Pathologic type SCC Non-SCC Stage IB ⫹ IIA (135 ⫹ 47) IIB ⫹ IIIA (248 ⫹ 12) IIIB ⫹ IVA (96 ⫹ 3) Diabetes mellitus Yes No Hypertension Yes No Follow-up Range median
Overall (n ⫽ 541)
Group 1 (n ⫽ 254)
Group 2 (n ⫽ 287)
1987–1996
1987–1993
1993–1996
247 (46) 294 (54)
120 (47) 134 (53)
127 (44) 160 (56)
285 (53) 252 (46) 4 (1)
136 (54) 117 (45) 1 (1)
149 (52) 135 (47) 3 (1)
235 (43) 292 (54) 14 (3)
111 (44) 138 (54) 5 (2)
124 (43) 154 (54) 9 (3)
517 (96) 24 (4)
244 (96) 10 (4)
273 (95) 14 (5)
182 (34) 260 (48) 99 (18)
70 (27) 124 (49) 60 (24)
112 (39) 136 (47) 39 (14)
74 (14) 467 (86)
38 (15) 216 (85)
36 (13) 251 (87)
104 (19) 437 (81)
41 (16) 213 (84)
63 (22) 224 (78)
6.1–15.2 9.8
9.7–15.2 12.4
6.1–9.6 7.6
Abbreviation: BMI ⫽ body mass index (weight/height in square meters). Data in parentheses are percentages, unless otherwise noted.
Pelvic control Of the 66 patients (12.2%) who developed pelvic recurrence, 30 patients were in Group 1 and 36 in Group 2. The onset of the pelvic recurrence ranged from 3 to 149 months (median, 8 months) for Group 1 and 3– 87.7 months (median, 8.7 months) for Group 2. Of the 30 pelvic recurrences in Group 1, 24 were categorized as central recurrence, 5 as peripheral recurrence, and 1 as both. Of the 36 pelvic recurrences in Group 2, 29 were central and 7 were peripheral. The distribution by group was not statistically significant (p ⫽ 0.722; Table 4). Regardless of treatment group or disease stage, the actuarial pelvic control rate for the entire cohort of 541 patients was 87.2% at 5 years and 86.8% at 10 years. By group, the 5-year actuarial pelvic control rate for Groups 1 and 2 was 88.2% and 86.3%, respectively. The corresponding rate at 10 years for Groups 1 and 2 was 87.3% and 85.5%, respectively. The difference was not statistically significant (p ⫽ 0.504, Fig. 1). By stage, the 5-year actuarial pelvic control rate for Groups 1 and 2 was 96.9% and 88.9% for Stage IB-IIA (p ⫽ 0.037); 91.6% and 88.6% for Stage IIB-IIIA (p ⫽ 0.526); and 68.9% and 69.9% for Stage IIIB-IVA (p ⫽ 0.784), respectively. The 5-year actuarial rate at 10 years for Groups 1 and 2 was 94.4% and 87.2% for IB-IIA (p ⫽
0.037); 91.6% and 88.6% for IIB-IIIA (p ⫽ 0.526); and 62.1% and 69.9% for IIIB-IVA (p ⫽ 0.784). Overall survival rate Regardless of treatment group or stage, the actuarial overall survival rate for the entire cohort of 541 patients was 59.8% at 5 years and 47.9% at 10 years. The 5-year actuarial overall survival rate was 63.5% and 56.1% for Groups 1 and 2, respectively. At 10 years, for Groups 1 and 2, it was 47.8% and 49.3%, respectively (p ⫽ 0.734, Fig. 2). The 5-year actuarial overall survival rate for Groups 1 and 2 was 81.4% and 67.5% for Stage IB-IIA (p ⫽ 0.352); 65.8% and 54.8% for Stage IIB-IIIA (p ⫽ 0.514); and 38.3% and 30.8% for Stage IIIB-IVA (p ⫽ 0.301). The overall survival rate at 10 years for Groups 1 and 2 was 63.8% and 58.3% for IB-IIA (p ⫽ 0.352); 49.4% and 51.3% for IIB-IIIA (p ⫽ 0.514); and 25.7% and 27.7% for IIIBIVA (p ⫽ 0.301). Rectal complications Overall, 201 patients developed rectal complication of varying degree. Of these, 117 (46%) were in Group 1 and 84 (29%) in Group 2. The median onset for Groups 1 and 2 was similar, 11 months (range, 3.1–147 months) and 11.3 months (range, 3.1– 40 months), respectively.
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Table 2. Treatment characteristics Characteristic EBRT Four-field box technique Yes No Daily dose (Gy) 1.8 2 Dose to cervix (Gy) (median, 45) 39.6–43.9 44–45 45.1–59.4 Dose to the parametrium (Gy) (median, 54) 39.6–43.9 44–54 54.1–59.6 BED10 (range, 47–70, median, 53) 47–52 53 54–70 BED3 (range, 63–107, median, 73) 63–71 72–73 74–107 HDR-IC Active length (range, 1–9 cm; median, 4.5) ⬍4.5 ⱖ4.5 Fractionation scheme Standardized ⫹ minor modification (⬍20%) ⱖ20% modification BED10 (range, 12.4–52.2; median, 35.5) ⬍28 28–37.2 ⱖ37.3 EBRT ⫹ HDR-IC Total treatment days (range, 45–228; median, 71) ⬍70 ⱖ70 Total BED10 (range, 70.8–106.8; median, 88.6) 70.8–80.9 81–90 90.1–106.8 Chemotherapy Yes No
Overall (n ⫽ 541)
Group 1 (n ⫽ 254)
Group 2 (n ⫽ 287)
195 (36) 346 (64)
20 (8) 234 (92)
175 (61) 112 (39)
223 (41) 318 (59)
0 (0) 254 (100)
223 (78) 64 (22)
38 (7) 430 (80) 73 (13)
9 (4) 207 (81) 38 (15)
29 (10) 223 (78) 35 (12)
143 (26) 152 (28) 246 (46)
60 (24) 34 (13) 160 (63)
83 (29) 118 (41) 86 (30)
32 (6) 443 (82) 66 (12)
8 (3) 210 (83) 36 (14)
24 (8) 233 (81) 30 (11)
32 (6) 443 (82) 66 (12)
8 (3) 210 (83) 36 (14)
24 (8) 233 (81) 30 (11)
251 (46) 290 (54)
137 (54) 117 (46)
114 (40) 173 (60)
468 (87) 73 (13)
201 (79) 53 (21)
267 (93) 20 (7)
56 (10) 470 (87) 15 (3)
49 (19) 202 (80) 3 (1)
7 (3) 268 (93) 12 (4)
242 (45) 299 (55)
34 (13) 220 (87)
208 (72) 79 (28)
36 (17) 453 (84) 52 (9)
31 (12) 207 (82) 16 (6)
5 (2) 246 (86) 36 (12)
32 (6) 509 (94)
17 (7) 237 (93)
15 (5) 272 (95)
Abbreviations: ERBT ⫽ external beam radiotherapy; BED ⫽ biologically effective dose; HDR-IC ⫽ high-dose-rate intracavitary brachytherapy. Data in parentheses are percentages, unless otherwise noted.
The 5-year actuarial proctitis rate for Groups 1 and 2 was 49.7% and 32.7%, respectively. At 10 years, the rate for Groups 1 and 2 was 50.5% and 32.7%, respectively (p ⬍0.001, Fig. 3). The number of patients with Grade 1, 2, 3 and 4 complication for Groups 1 and 2 was 56 (22%), 40 (16%), 14 (5%), and 7 (3%) and 39 (14%), 24 (8%), 12 (4%), and 9 (3%), respectively. When the complications was categorized as low (Grade 1-2) and high (Grade 3-4) grade, the low-grade complication rate for Groups 1 and 2 was 38% and 22% (p
⬍0.001), and the high-grade complication rate was 8% and 7%, respectively (Table 5). The reduction in rectal complications in Group 2 mainly occurred in low-grade complications, with the incidence of high-grade complications remaining unchanged.
Bladder complications Overall, 71 patients developed radiation cystitis, 45 in Group 1 and 26 in Group 2. The median onset for Groups 1
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Table 3. Distribution of patient outcome and treatment-related complications Outcome/complications
Group 1 (n ⫽ 254)
Group 2 (n ⫽ 287)
p*
Alive Pelvic recurrence Distant metastasis Proctitis Colostomy Cystitis Chronic abdominal cramp Leg edema Ureter obstruction Double cancer
108 (43) 30 (12.2) 54 (21) 117 (46) 7 (3) 45 (18) 12 (5) 33 (13) 7 (3) 9 (4)
155 (54) 36 (13) 56 (20) 84 (29) 9 (3) 26 (9) 7 (2) 8 (3) 6 (2) 10 (4)
0.008 0.795 0.614 ⬍0.001 0.982 0.003 0.150 ⬍0.001 0.614 0.970
Data in parentheses are percentages; percentages determined within group. * Pearson chi-square test.
and 2 was similar, 53 months (range, 10.3–167 months) and 38.9 months (range, 10.9 – 85 months), respectively. The 5-year actuarial cystitis rate for Groups 1 and 2 was 14.3% and 11.4%, respectively. At 10 years, it was 24.1% and 15% for Groups 1 and 2, respectively (p ⫽ 0.134, Fig. 4). The actuarial rates of pelvic control, overall survival, and rectal and bladder complications are summarized in Table 6. Univariate and multivariate analyses To examine the influence of confounding factors, 16 patient-, tumor-, and treatment-related variables were tested with univariate and multivariate analysis (Table 7). These variables included pathologic type (squamous vs. nonsquamous), age (⬍60 vs. ⱖ60 years), body mass index (⬍24 vs. ⱖ24), hemoglobin (⬍12 vs. ⱖ12), stage (FIGO Stage IBIIA vs. IIB-IIIA vs. IIIB-IVA), daily fraction size (1.8 Gy vs. 2 Gy), box technique (yes vs. no), EBRT dose to the cervix (⬍44 vs. 44 – 45 vs. ⬎45.1 Gy), EBRT dose to the parametrium (39.6 – 45 vs. 45.1–54 vs. 54.1–59.6 Gy), diabetes (yes vs. no), hypertension (yes vs. no), HDR-IC fractionation scheme (three fractions vs. five fractions), active length (⬍4.5 vs. ⱖ4.5 cm), total BED10 (⬍ 88.6 vs. ⱖ88.6), and total treatment days (⬍70 vs. ⱖ70). For pelvic control, age (p ⬍0.001, hazard ratio ⫽ 0.367, 95% confidence interval [CI], 0.214 – 0.629), body mass index (p ⫽ 0.020; hazard ratio ⫽ 0.541; 95% CI, 0.322– Table 4. Distribution of pelvic recurrence by group Recurrence
Group 1 (n ⫽ 254)
Group 2 (n ⫽ 287)
None Pelvic recurrence Central Peripheral Both
224 (88.2) 30 (11.8) 24 (9.4) 5 (2) 1 (0.4)
251 (87.5) 36 (12.5) 29 (10.1) 7 (2.4) 0 (0)
Data in parentheses are percentages. p ⫽ 0.722.
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0.909), FIGO stage (p ⫽ 0.001; hazard ratio ⫽ 1.851; 95% CI, 1.306 –2.625), and total BED10 (p ⫽ 0.003; hazard ratio ⫽ 2.234; 95% CI, 1.311–3.808) were statistically significant factors. For overall survival, hemoglobin (p ⬍0.001; hazard ratio ⫽ 0.575; 95% CI, 0.450 – 0.734), FIGO stage (p ⬍0.001; hazard ratio ⫽ 1.649; 95% CI, 1.388 –1.959), and diabetes (p ⫽ 0.025; hazard ratio ⫽ 1.459; 95% CI, 1.049 –2.029) were statistically significant factors. For radiation proctitis, the EBRT dose to the parametrium (p ⫽ 0.007; hazard ratio ⫽ 1.291; 95% CI, 1.074 –1.533), hypertension (p ⫽ 0.020; hazard ratio ⫽ 1.502; 95% CI, 1.065–2.119), and HDR-IC fractionation scheme (p ⫽ 0.004; hazard ratio ⫽ 0.807; 95% CI, 0.697– 0.934) were statistically significant factors. For radiation cystitis, the EBRT dose to the parametrium (p ⫽ 0.045; hazard ratio ⫽ 1.350; 95% CI, 1.006 –1.811) was the only statistically significant factor. DISCUSSION Although the pelvic control rate has been commonly reported and used to compare different treatment modalities in cervical cancer, central recurrence is a more critical indicator to evaluate the tumoricidal effect of HDR-IC. Overall, the central recurrence rate in this series was 10.4% (56 of 541), and its distribution between the two groups was similar, 9.4% vs. 10.1% for Groups 1 and 2, respectively (p ⫽ 0.722). This result showed that the tumoricidal effect of the two schemes was comparable in terms of central control. The patterns of recurrence in the pelvis in the HDR-IC setting have not been well analyzed. Wong et al. (3) reported 34 (16%) local failures in 205 patients achieving a complete remission. Of the 34 cases, 7 (21%) were central failure only, 15 (44%) were pelvic failure only, and 12 (35%) were mixed failure. Takeshi et al. (13), treating 265 Stage III patients with HDR-IC, reported an overall pelvic recurrence rate of 24% (63 of 265). Of the 63 cases, 52 (83%) were central recurrence and 11 (17%) were peripheral recurrence. Similar to the findings of Takeshi et al. (13), most pelvic recurrence in our patients was central, accounting for 80% (53 of 66) of all recurrence in the pelvis. The tumoricidal effect of HDR-IC for advanced cases was a concern. Petereit et al. (14), comparing the Wisconsin experience of HDR vs. LDR, reported significantly poorer pelvic control for Stage IIIB cases in HDR-treated patients (44% vs. 75% for HDR vs. LDR, respectively). In another meta-analysis, Petereit and Pearcey (1) observed several institutions reporting favorable pelvic control in Stage IIIB disease with a tumoricidal dose less than the LDR equivalent of 75 Gy. Barillot et al. (15) also raised the concern of underdosage and/or accurate staging for Stage IIIB cases after analyzing and comparing 642 LDR-treated patients in three periods, 1970 –1978, 1979 –1984, and 1985–1994. The 5-year local control rate in Stage III patients fell from 75% to 55% when the complication rate decreased simultaneously with time. In our study, the 5-year actuarial pelvic
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Fig. 1. Actuarial pelvic control rate by group (p ⫽ 0.504). 3-Fr ⫽ Group 1; 5-Fr ⫽ Group 2.
control rate for Stage IIIB-IVA was 68.9% vs. 69.9% for Groups 1 and 2, respectively (p ⫽ 0.784). This result
appeared slightly more favorable than the findings of Petereit et al. (14) and Barillot et al. (15).
Fig. 2. Actuarial overall survival rate by group (p ⫽ 0.734). 3-Fr ⫽ Group 1; 5-Fr ⫽ Group 2.
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Fig. 3. Actuarial proctitis rate by group (p ⬍0.001). 3-Fr ⫽ Group 1; 5-Fr ⫽ Group 2.
The parametrial dose was a statistically significant factor associated with an increased risk of both rectal and bladder complications in this and one of our previous reports (16). A high parametrial dose has also been reported as a factor of increased small bowel complications by Ferrigno et al. (17), although it was not statistically significant (p ⫽ 0.260). They suggested the boost field should be lower than S2-S3, and the dose ⬍54 Gy. As we pointed out earlier, most cervical cancer recurrences in the pelvis remained central. The value of a high dose to the side wall with EBRT is thus questionable and needs further study. The overall treatment time was not a statistically significant predictor of local control or survival in our study. The overall treatment time has been reported as an independent prognostic factor on pelvic control in cervical carcinoma in Table 5. Distribution of severity of rectal complication by group
None Low grade Grade 1 Grade 2 High grade Grade 3 Grade 4
Group 1 (n ⫽ 254)
Group 2 (n ⫽ 287)
137 (54) 96 (38) 56 (22) 40 (16) 21 (8) 14 (5) 7 (3)
203 (71) 63 (22) 39 (14) 24 (8) 21 (7) 12 (4) 9 (3)
Data in parentheses are percentages. p ⬍ 0.001.
five large series between 1992 and 1995 (18 –22). These authors reported a loss of pelvic control ranging from 0.5% to 1.2% daily if treatment was prolonged. These results were all LDR based. Together with our findings, we noted at least four HDR series that reported the negative influence of treatment prolongation on pelvic control/survival using multivariate analysis (3, 13). The latest detailed analysis of HDR series reported by Chen et al.(23) concluded that treatment prolongation negatively influences cause-specific survival and pelvic control. To the best of our knowledge, only one HDR study by Ferrigno et al. (17) has reported a positive influence from treatment prolongation. We believe the issue remains debatable. Additionally, in practice, shortening the overall treatment time excessively may not be good for advanced cases, because substantial tumor regression may not have been achieved yet for optimal coverage by brachytherapy. This was stressed by Petereit et al. (14) and the report by the American Brachytherapy Society (24). The 5-year actuarial overall survival rate for both groups was similar (p ⫽ 0.734). This result was comparable with most of the recent HDR reports. Ferrigno et al. (17) reported a 5-year overall survival rate of 53.7% in 138 patients treated with HDR-IC. Takeshi et al. (13) reported a 5-year overall survival rate of 50.7% in 265 Stage III patients. Stage for stage, the 5-year actuarial overall survival rate for Groups 1 and 2 was 81.4% vs. 67.5% for Stage IB-IIA (p ⫽ 0.352); 65.8% vs. 54.8% for Stage IIB-IIIA (p ⫽ 0.514); and 38.3% vs. 30.8% for Stage IIIB-IVA, respectively (p ⫽ 0.301). This result is also comparable with existing LDR
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Fig. 4. Actuarial cystitis rate by group (p ⫽ 0.134). 3-Fr ⫽ Group 1; 5-Fr ⫽ Group 2.
reports. Coia et al. (25) reported a 5-year overall survival rate for Stage I-III in the Pattern of Care Study of 33–74%. Fyles et al. (26) reported a 5-year overall survival rate for Stage I-III in the Princess Margaret Hospital study of 41– 78%. Ferrigno et al. (27) reported on the Brazil experience of cobalt teletherapy plus LDR treatment. The 5-year overall survival rate for Stage I-III was 46 – 83% (27). Barillot et al. (28) reported a result of 45– 84% in a French Cooperative study. The proctitis rate in our study was significantly decreased Table 6. Actuarial rate of local control, overall survival, rectal and bladder complications End point Pelvic control (y) 5 10 Overall survival (y) 5 10 Proctitis (y) 5 10 Cystitis (y) 5 10
Overall (%)
Group 1 (%)
Group 2 (%)
87.2 86.8
88.2 87.3
86.3 85.5
0.504
59.8 47.9
63.5 47.8
56.1 49.3
0.734
40.8 41.7
49.7 50.5
32.7 32.7
⬍0.001
12.8 21.5
14.3 24.1
11.4 15.0
0.134
p
in Group 2. We were very pleased to see this result, because it was the main goal of our initial design. This was the first prospectively designed protocol in HDR-IC that successfully demonstrated that a linear-quadratic model– based mathematical calculation can convert into an expected clinical outcome. The success through biologic manipulation of the fraction size in our study suggests that the sensitivity of the late responding tissue to the fraction change from 7.2 Gy to 4.8 Gy in HDR-IC is high and detectable clinically. Wong et al. (3) and Le Pechoux et al. (2) also compared two different schemes in HDR-IC but failed to demonstrate any complication benefit. A possible explanation is that the difference in the fraction size in their studies was too narrow (7 Gy vs. 6 Gy in Wong et al. and 6 Gy vs. 5 Gy in Le Pechoux et al.). The fraction sensitivity may have been too low to be detected. Furthermore, the small fraction difference may need a larger sample size or longer follow-up to detect any differences. Wong et al. (3) reported an overall complication rate for the four-fraction regimen that was lower than that of the three-fraction regimen (44.2% vs. 55.8%), with a p value of marginal significance (p ⫽ 0.0672). Our finding has important implications. The fractionation scheme in HDR-IC has varied widely from 2 to 9 Gy/ fraction in the past. With rare exception (29), we observed that the fractionation schemes used in recent studies have
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Table 7. Univariate and multivariate analysis Pelvic control
Overall survival
Proctitis rate
Cystitis rate
Variable
UVA
MVA
UVA
MVA
UVA
MVA
UVA
MVA
Pathologic finding Age BMI Hemoglobin Stage Daily dose (EBRT) Dose to cervix (EBRT) Dose to parametrium (EBRT) Box field Diabetes Hypertension Active length HDR-IC scheme Total BED10 Total treatment days
0.042 ⬍0.001 0.014 0.003 ⬍0.001 0.296 0.003 0.002 0.823 0.132 0.227 0.453 0.504 0.040 0.432
0.064 ⬍0.001* 0.020* 0.204 0.001* 0.057 0.248 0.806 0.390 0.303 0.699 0.630 0.172 0.003* 0.357
0.029 0.829 0.011 ⬍0.001 ⬍0.001 0.287 0.018 ⬍0.001 0.313 0.143 0.623 0.924 0.743 0.145 0.077
0.066 0.218 0.110 ⬍0.001* ⬍0.001* 0.767 0.807 0.862 0.907 0.025* 0.317 0.906 0.304 0.217 0.747
0.949 0.639 0.174 0.202 0.001 0.008 0.026 0.003 0.040 0.951 0.247 0.327 0.001 0.463 0.011
0.982 0.460 0.153 0.326 0.881 0.318 0.194 0.007* 0.804 0.598 0.020 0.325 0.004* 0.256 0.864
0.283 0.242 0.466 0.566 0.048 0.399 0.060 0.027 0.508 0.806 0.303 0.378 0.134 0.043 0.190
0.356 0.234 0.489 0.446 0.457 0.735 0.325 0.045* 0.475 0.697 0.609 0.603 0.297 0.226 0.891
Abbreviations: UVA ⫽ univariate analysis; MVA ⫽ multivariate analysis; BMI ⫽ body mass index; EBRT ⫽ external beam radiotherapy; BED10 ⫽ biologically equivalent dose, assuming ␣/ ⫽ 10; HDR-IC ⫽ high-dose-rate intracavitary brachytherapy. * Statistically significant in MVA.
mostly converged between 4 and 7 Gy, which agrees with the recent recommendation of the American Brachytherapy Society (24) and the Wisconsin experience (1, 14). Clinically, it is not appropriate to interpolate or extrapolate the results of this study. The fraction sensitivity in the dose range of brachytherapy interest may not be totally linear, so that the clinical results of a dose between 4.8 and 7.2 Gy should not be extrapolated to, for instance, 4.8 Gy and 3 Gy, or 7.2 Gy and 10 Gy. Although the overall proctitis rate decreased, it appeared that the manipulation had its limitations. When the severity of proctitis was compared grade by grade, we found that the decrease was confined to only the low-grade complications (38% vs. 22% for Groups 1 and 2, respectively). The high-grade complication rate remained virtually unchanged (8% vs. 7% for Groups 1 and 2, respectively). Hospitalization or blood transfusion because of severe rectal bleeding or anemia (Grade 3) was needed in 5% (14 cases) and 4% (12 cases) of Groups 1 and 2, respectively. Colostomy (Grade 4) was required in 3% of patients, distributed equally in both groups. Barillot et al. (15) reported the effect of different techniques of radiotherapy in the treatment of 642 patients with cervical cancer in three periods between 1970 and 1994. The rate of Grade 3 rectal/bladder complications decreased over time from 16% to 6%, and no Grade 4 complications was encountered in the last period. They attributed these complications to three factors: a high EBRT dose, a high dose rate at the reference points, and whole vagina brachytherapy with cylinder. The analysis of Barillot et al. (15) highlighted that severe complications in radiotherapy for cervical cancer are more technically or dosimetrically related. It is thus understandable that biologic manipulation of the fraction size in our study may not have been able to change the rate of severe complications. Radi-
ation-induced rectal bleeding is a complicated issue, involving damage of both acute and late responding tissue (30). Although the rate of Grade 3-4 severe rectal complications, 7– 8%, in this study was acceptable, we believe there is still room to improve, particularly in Stage I-II cases. We agree with Petereit and Pearcey’s conclusion in their meta-analysis that the optimal fractionation schedule is still unknown and presently can be based only on single institutions with significant experience (1). The treatment policy in our department will continue to evolve, including decreasing the total EBRT dose to the whole pelvis, restricting the parametrial boost dose/field in Stage I-II cases, and increasing the use of concurrent chemotherapy in selective cases on the basis of recent encouraging results (31–33). Additionally, we noted that the fractionation schemes of HDR-IC have tended to converge further between the dose of 4.5 and 6 Gy, the fraction sensitivity of this range deserves clinical testing. A grant-supported randomized trial is underway in our department. CONCLUSION On the basis of the experiences of treating 541 patients with two isoeffect schemes, we found that the central recurrence, actuarial pelvic control rate, and overall survival rate were similar and the proctitis rate decreased. The linearquadratic model correctly predicted this clinical outcome. This study demonstrated that fraction sensitivity between the dose of 4.8 Gy and 7.2 Gy in HDR-IC is high and detectable clinically. This finding has important implications for the prescription of the fraction dose in HDR-IC. The success through biologic manipulation of the fraction size in this range has limitations, and the improvement was confined to a reduction in low-grade complications.
Two isoeffect schemes of HDR-IC
● C.-J. WANG et al.
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REFERENCES 1. Petereit DG, Pearcey R. Literature analysis of high dose rate brachytherapy fractionation schedules in the treatment of cervical cancer: Is there an optimal fractionation schedule? Int J Radiat Oncol Biol Phys 1999;43:359–366. 2. Le Pechoux C, Akine Y, Sumi M, et al. High dose rate brachytherapy for carcinoma of the uterine cervix: Comparison of two different fractionation regimens. Int J Radiat Oncol Biol Phys 1995;31:735–741. 3. Wong FCS, Tung SY, Leung T-W, et al. Treatment results of high-dose-rate remote afterloading brachytherapy for cervical cancer and retrospective comparison of two regimens. Int J Radiat Oncol Biol Phys 2003;55:1254–1264. 4. Ling CC, Sahoo N, Leibel S, et al. High dose rate gynecological applications: Radiobiological considerations based on the ␣/ model. Radiother Oncol 1992;25:103–110. 5. Brenner DJ, Hall EJ. Fractionated high dose rate vs. low dose rate regimens for intracavitary brachytherapy of the cervix. Br J Radiol 1991;64:133–141. 6. Fowler JF. The linear-quadratic formula and progress in fractionated radiotherapy. Br J Radiol 1989;62:679–694. 7. Dale RG. The use of small fraction numbers in high dose rate gynecological afterloading: Some radiobiological considerations. Br J Radiol 1990;63:290–294. 8. Sood B, Garg M, Avadhani J, et al. Predictive value of linear-quadratic model in the treatment of cervical cancer using high dose rate brachytherapy. Int J Radiat Oncol Biol Phys 2002;54:1377–1387. 9. Orton CG. High dose rate vs. low dose rate brachytherapy for gynecological cancer. Semin Radiat Oncol 1993;3:232–239. 10. Wang C-J, Leung SW, Chen H-C, et al. High-dose-rate intracavitary brachytherapy (HDR-IC) in treatment of cervical carcinoma: 5-year results and implication of increased lowgrade rectal complication on initiation an HDR-IC fractionation scheme. Int J Radiat Oncol Biol Phys 1997;38:391–398. 11. Chen M-S, Lin F-J, Hong C-H, et al. High-dose-rate afterloading technique in the radiation treatment of uterine cervical cancer: 399 cases and 9 years experience in Taiwan. Int J Radiat Oncol Biol Phys 1991;20:915–919. 12. Cox JD, Stetz J, Pajak TF. Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). Int J Radiat Oncol Biol Phys 1995;31:1341–1346. 13. Takeshi K, Katsuyuki K, Yoshiaki T, et al. Definitive radiotherapy combined with high dose rate brachytherapy for Stage III carcinoma of the uterine cervix: Retrospective analysis of prognostic factors concerning patients characteristics and treatment parameters. Int J Radiat Oncol Biol Phys 1998;41: 319–327. 14. Petereit DG, Sarkaria JN, Potter DM, et al. High-dose-rate vs. low-dose-rate brachytherapy in the treatment of cervical cancer: Analysis of tumor recurrence—The University of Wisconsin experience. Int J Radiat Oncol Biol Phys 1999;45: 1267–1274. 15. Barillot I, Horiot JC, Maingo P, et al. Impact on treatment outcome and late effects of customized treatment planning in cervix carcinoma: Baseline results to compare new strategies. Int J Radiat Oncol Biol Phys 2000;48:189–200. 16. Huang EY, Lin H, Hsu HC, et al. High external parametrial dose can increase the probability of radiation proctitis in patients with uterine cervix cancer. Gynecol Oncol 2000;79: 406–410. 17. Ferrigno R, Novaes PERDS, Pellizzon ACA, et al. High-dose-
18. 19. 20. 21.
22.
23. 24.
25. 26.
27.
28.
29.
30. 31.
32. 33.
rate brachytherapy in the treatment of uterine cervix cancer: Analysis of dose effectiveness and late complication. Int J Radiat Oncol Biol Phys 2001;50:1123–1135. Fyles A, Keane TJ, Barton M, et al. The effect of treatment duration in the local control of cervix cancer. Radiother Oncol 1992;25:273–279. Petereit DG, Sakaria JN, Chappell R, et al. The adverse effect of treatment prolongation in cervical carcinoma. Int J Radiat Oncol Biol Phys 1995;32:1301–1307. Lanciano RM, Pajak TF, Martz K, et al. The influence of treatment time on outcome for squamous cell cancer of the uterine cervix. Cancer 1992;69:2124–2130. Girinsky T, Rey A, Roche B, et al. Overall treatment time in advanced cervical carcinoma: A critical parameter in treatment outcome. Int J Radiat Oncol Biol Phys 1993;27:1051– 1056. Perez CA, Grigsby PW, Castro-Vita H, et al. Carcinoma of the uterine cervix: Impact of prolongation of treatment time and timing of brachytherapy on outcome of radiation therapy. Int J Radiat Oncol Biol Phys 1995;32:1275–1288. Chen SW, Liang JA, Yang SN, et al. The adverse effect of treatment prolongation in cervical cancer by high-dose-rate intracavitary brachytherapy. Radiother Oncol 2003;67:69–76. Nag S, Erickson B, Thomadsen B, et al. The American Brachytherapy Society recommendations for high dose rate brachytherapy for carcinoma of the cervix. Int J Radiat Oncol Biol Phys 2000;48:201–211. Coia L, Won M, Lanciano R, et al. The patterns of care outcome study for cancer of the uterine cervix: Results of the second National Practice Survey. Cancer 1990;9:431–436. Fyles AW, Pintilie M, Kirkbridge P, et al. Prognostic factors in patients with cervix cancer treated by radiation therapy: Results of a multiple regression analysis. Radiother Oncol 1995;35:107–117. Ferrigno R, Oliveira Faria SLC, Weltman E, et al. Radiotherapy alone in the treatment of uterine cervix cancer with telecobalt and low dose rate brachytherapy: Retrospective analysis of results and variables. Int J Radiat Oncol Biol Phys 2003;55:695–706. Barillot I, Horiot JC, Pigneaux J, et al. Carcinoma of the intact uterine cervix treated with radiotherapy alone: A French cooperative study—Update and multivariate analysis of prognostic factors. Int J Radiat Oncol Biol Phys 1997;38:969–978. Sood BM, Gorla G, Gupta S, et al. Two fractions of highdose-rate brachytherapy in the management of cervix cancer: Clinical experience with and without chemotherapy. Int J Radiat Oncol Biol Phys 2002;53:702–706. Dubray BM, Thames HD. Chronic radiation damage in the rate rectum: An analysis of the influences of fractionation, time, and volume. Radiother Oncol 1994;33:41–47. Morris M, Eifel P, 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. Rose PG, Bundy N, Watkins EB, et al. Concurrent cisplatinbased radiotherapy and chemotherapy for locally advanced cervical cancer. N Engl J Med 1999;340:1144–1153. Green JA, Kirwan JM, Tierney JF, et al. Survival and recurrence after concomitant chemotherapy and radiotherapy for cancer of the uterine cervix: A systematic review and metaanalysis. Lancet 2001;358:781–786.