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Radiation Therapy for Cervix Carcinoma: Benefits of Individualized Dosimetry
Clinical Oncology (2002) 14: 43–49 doi:10.1053/clon.2001.0024, available online at http://www.idealibrary.com on
Gynaecology Radiation Therapy for Cervix Carcinoma: Benefits of Individualized Dosimetry F. FOROUDI*, C. A. BULL*, V. GEBSKI*† *Department of Radiation Oncology, Westmead Hospital, Westmead, NSW, †NHMRC Clinical Trials Center, University of Sydney, Australia Received: 15 January 2001
Accepted: 24 September 2001
ABSTRACT: This study is a presentation of the prospective collection of data on patients treated by radical radiotherapy at Westmead Hospital between December 1989 and December 1998. The impact of the routine use of individualized dosimetry and lower brachytherapy dose on patients was examined, by comparing the historical series of patients treated between 1989 to 1991 to the later patients treated with inividualised dosimetry. There were 163 patients treated with external beam and intracavitary radiotherapy during this period. Histology was squamous carcinoma in 80% (132 patients), adenocarcinoma in 13% (22 patients), and adenosquamous carcinoma in 6% (9 patients). Patients were generally treated with 50 Gy in 25 fractions to the pelvis followed by 1 low dose rate caesium intracavitary brachytherapy insertion. Patients who had dosimetry generally received 20 Gy to point A via the insertion compared to 30 Gy in the non-dosimetry group. Median follow-up was 62 months. Only 22% (18) of patients failed with disease outside the pelvis. Pelvic control was similar in the patients who had dosimetry as opposed to no dosimetry (P=0.8). In the dosimetry group there were less grade III or higher bowel toxicity (P=0.01) and less vaginal fistulae (P=0.03). The actuarial two-year survival was 56.2% in the no dosimetry group and 68.6% in the dosimetry group. When controlled for stage and performance status patients who had dosimetry had a statistically significant greater overall survival (P=0.02). Thus we found that the routine use of dosimetry was associated with a lower brachytherapy dose, decreased complications, without any decrease in local control or survival. Foroudi, F. et al. (2002). Clinical Oncology 14, 43–49. 2002 The Royal College of Radiologists Key words: Cervical carcinoma, radiation therapy, dosimetry, rectal toxicity, bladder toxicity
INTRODUCTION
Radiation therapy is the major modality of treatment for carcinoma of the uterine cervix. The impact of multiple patient factors on the risk of late rectal and other complications have been investigated including age [1], stage [2–4], prior surgery, diabetes [5], diverticulitis and pelvic inflammatory disease [6]. The dose of intracavitary radiation based on bladder and rectal dose and not set dosage tables has been proposed to allow higher doses and hence improve control rates without increasing normal tissue complications [7]. However some major centres [8] still do not base prescriptions on point A or bladder or rectum Author for correspondence: C. A. Bull, Department of Radiation Oncology, Westmead Hospital, Westmead, NSW 2145, Australia. E-mail: [email protected] 0936–6555/02/010043+07 $35.00/0
doses. In contrast Perez [9] suggests that dosimetric analysis is paramount to optimize tumour control while maintaining an acceptable incidence of major sequalae. While Lee et al. [10] argued that dose-rate is the most important factor in determining serious normal tissue complications it is likely to be a mixture of total dose, dose rate, normal tissue sensitivity and geometry. The risk of rectal and urinary tract complications developing is greatest within the first 3 years of treatment but there remains an actuarial risk even at 25 years follow up [8]. A recent United Kingdom national audit [30] found that while large bowel and bladder toxicities mainly occurred during the first 3 years, small bowel, vascular and soft tissue events occur at longer observation periods. Patients who had an adjuvant extrafascial hysterectomy and those who had a pretreatment laparotomy were at greater risk of developing 2002 The Royal College of Radiologists
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bowel complications [8]. In addition to stage, large tumour size has also been suggested as a risk factor for complications [8]. Differences in grading systems and methods of reporting make it difficult to compare results of various series, however the range of major complications has varied from 8 to 14.8% [1,8,11]. Large retrospective analyses of the relationship between point dose calculations and complications have yielded only rough correlations [1]. Perez [1] found patients who received greater than 60 Gy and less than or equal to 70 Gy or greater than 70 Gy and less than or equal to 80 Gy to bladder reference points had a similar crude rate of developing major urinary tract complications. The incidence increased for those given higher doses, but was still only 11% when the reference dose was greater than 80 Gy and was 8% in those who received greater than 100 Gy to bladder reference point. A more recent retrospective review from Mallincrodt [12] demonstrated using multivariate analysis that total dose to the rectal point and total dose to the bladder point were the only factors influencing rectal and bladder complications, respectively. Thus it is controversial whether the total dose should be compromised (which could increase the rate of disease recurrence in the pelvis) based on bladder and rectal doses. Using the prospective data collected on patients having cervical cancer treated at Westmead hospital the effect of individual dosimetry on complications, local control and survival were examined.
METHODS
Data on all patients with cervical carcinoma treated by radical radiotherapy at Westmead hospital between December 1989 and December 1998 were prospectively collected. All patients were staged with an examination under anaesthesia, a chest radiograph and either an intravenous pyelogram or a computerized tomogram of the abdomen and pelvis. FIGO staging [13] was prospectively recorded on all patients. When there was a disagreement of staging, patients were assigned the less-advanced stage. Radiation Therapy and Oncology Group (RTOG) toxicity grades were recorded at every clinic visit for bowel and bladder toxicity. Patients were followed up periodically at the radiation oncology department for at least 5 years or until lost to follow-up or death. If there was no information on outcome, then attempts were made to collect the information by contacting the patients’ general practitioners or the referring gynaecologists. External beam radiation was delivered by megavoltage linear accelerators. The majority of patients were treated using an isocentric 4 field technique with a belly board. No central shielding block was used. The external beam dose was usually 50 Gy in 25 daily fractions over 6 weeks. Patients were treated with high-energy photons
with 25 MV and 18 MV from linear accelerators; a small number of patients were treated with 6 MV photons either due to equipment availability or geometry showing minimal benefit for a higher energy arrangement. All fields were treated each day, and the general AP borders were superiorly L5-S1 interspace, inferiorly below the obturator foramina or at least 3 cm below the tumour as marked with gold seeds and laterally 2 cm margin to the pelvic brim, the average field size being 1515 cm. Intracavitary brachytherapy was given using a lowdose rate caesium automatic afterloader, with one insertion generally given 2 weeks after completion of the external beam radiation treatment. The point A is defined as 2 cm cephalad and 2 cm lateral to the cervical os, along the plane of the tandem. Between 1989 and 1991 no routine individualized dosimetry was carried out, in 1991 individualized brachytherapy dosimetry was commenced. At this time the dose at point A was also reduced as was the dose rate of the caesium source. Orthogonal simulation films were obtained with dummy sources in place. Bladder and rectal doses were defined as per ICRU 38 [14]. Where the normal tissue dose particularly the rectal or bladder doses were excessive, the active source geometry was changed and if the dose to normal tissues was still excessive the total prescribed dose was reduced. The biological effective dose (BED) was determined using a / ratio of 3 and a g factor of 0.1475 [31]. The use of individualized dosimetry was based on the availability of physicist resources in our department. Between 1978 and 1989 a single line technique was used, however due to high rates of normal tissue complications a Manchester applicator was purchased in 1989. Until 1991 standard loadings were used and treatment time was read from tables assuming perfect geometry. Only in 1991 with the appointment of further physics staff was individualized dosimetry carried out in each case. While all the data were collected prospectively, the controls or patients treated without individualized brachytherapy were historical as they were treated between 1989 and 1991 and the patients with individualized dosimetry between 1991 and 1998. Survival outcomes were compared using the logrank test of Peto [15] and survival curves were constructed using the method of Kaplan–Meier [16]. Multivariate analysis comparing prognostic factors was performed using proportional hazards (Cox) regression [17]. Analysis of proportions was carried out using the conditional binomial exact test [18].
RESULTS
In the study time period there were 163 women with cervix carcinoma, with a median age of 61 years (range 30–85 years). Histology was squamous cell carcinoma in 80%, adenocarcinoma in 13%, and adenosquamous carcinoma in 6%. Performance status was ECOG 0 in
Table 1 – FIGO stage distribution of patients FIGO Stage IB IIA IIB IIIA IIIB IVB
45
Table 3 – Brachytherapy dosimetry details
No of Patients
%
21 14 63 1 62 2
12.9 8.6 38.6 0.6 38 1.2
Brachytherapy Point A dose Point A dose rate BED Point A* Point B dose Rectal dose Bladder dose
N
Min
Mean
Max
163 163 163 127 105 105
0 0 0 0 6.7 4.6
23.3 1.1 50 6.8 14 17.4
35 2 95.2 74 28.3 42.5
*BED=Biological Effective Dose.
Table 2 – Patient characteristics in dosimetry and non-dosimetry groups Dosimetry Age (yr): Mean (median) Weight (kg): Mean (median) Stage I Stage II Stage III Stage IV ECOG 0 ECOG 1 ECOG 2 ECOG 3 ECOG 4
Non-Dosimetry
58.6(61)
55.4(54)
62 (59) 7 6 30 21 28 31 5 0 1
63.5(63) 12 6 19 21 38 13 6 0 1
Unknown
Table 4 – Dose at Point A – Dosimetry vs no individualised dosimetry (Gy) Dosimetry
0 0 5 9 5 3 5 1
71 patients and ECOG 1 in 47 patients with only 3 patients (2%) being ECOG 3 or 4. Table 1 shows the FIGO stage distribution of the patients. Median follow-up was 62 months, Table 2 shows the patient characteristics in the dosimetry and non dosimetry groups. One hundred and fifty-six patients were treated with radiotherapy alone, 7 patients had concurrent 5-fluoruracil chemotherapy as per a COSA (Clinical Oncology Society of Australia) trial. In addition to the 163 patients, there were 17 patients treated with radical intent for cervical carcinoma who did not have brachytherapy for reasons including dementia, and being medically unfit for a general anaesthetic. One hundred and sixty patients were treated using a Manchester style applicator, with 3 patients treated using an Edinburgh applicator. Table 3 describes the brachytherapy details. At the time of the insertion, there was no pelvic disease present in 85 patients (52%). In 77 patients (47%) there was disease present, and in 1 patient findings at the examination under anaesthesia were equivocal. Table 4 shows the differing dose between the dosimetry and non dosimetry groups. At brachytherapy in the majority of cases a biopsy was not done; when biopsy was done 18 out of the 22 were positive. Table 5 outlines the acute radiation toxicity using RTOG scoring system, defined as
Yes No
N
Median (dose rates)
Mean (dose rates)
SD (dose rates)
105 58
20 (0.8*) 30 (1.4)
20.7 (0.9) 28 (1.4)
6 (0.2) 2.6 (0.13)
*Dose rates in brackets are in Gy/hr while doses are in Gy.
occurring within 6 months of commencement of radiation therapy. At the time of analysis (October 2000) 62 patients (38%) were still alive. In 72 patients the cause of death was tumour related, it was treatment related in 3 patients and due to other causes in 26 patients. The three patients who died of treatment related causes were all in the no dosimetry group. Of the patients relapsing, there were 28% (23 patients) who presented with disease only outside the pelvis. Failure with both pelvic disease and disease outside the pelvis occurred in 35%. In contrast 16% had isolated pelvic failure, but also a proportion of patients did not have a pelvic examination at the time of presenting with distant metastasis. Pelvic control was similar in the patients who had dosimetry and those who did not, despite a lower dose and dose-rate in the former group. Pelvic control was maintained in 30 of 58 (52%) of patients who had no dosimetry and 56 of 105 (53%) patients who had dosimetry (P=0.8). Twenty two patients had a colostomy, 6 patients an ileostomy, and 1 patient had both a colostomy and ileostomy. Table 6 shows the breakdown of fistula aetiology and type. Generally histological diagnosis was obtained to determine if the fistula was due to malignancy or treatment. In 10 cases (52%) it was due to cancer and in 9 cases (48%) it was due to radiation therapy. The mean time to fistula was 15 months in cases due to malignancy and 23 months in cases due to radiation therapy. Seven patients who had no dosimetry had a fistula due to radiation therapy compared to two who had dosimetry carried out (P=0.03). Two patients out of the 156 having radiotherapy alone developed a bone fracture.
46 Table 5 – Acute toxicity of radiation therapy
Nausea & vomiting
Grade 0
Grade 0
Grade 1
Grade 2
Grade 3
P-value*
No Dosimetry Dosimetry
44 78
8 16
2 8
4 2
0.98
122 (74.9)
24 (14)
10 (6.1)
6 (5)
22 53
5 8
31 40
0 3
75 (46)
13 (8)
71 (43.6)
3 (1.8)
39 84
9 9
10 7
0 4
123 (75.5)
18 (11)
17 (10.4)
4 (2.5)
50 64
3 18
5 21
0 1
114 (69.9)
21 (12.9)
26 (16)
1 (0.6)
Total (%) Bowel
No Dosimetry Dosimetry Total
Bladder
No Dosimetry Dosimetry Total
Skin
No Dosimetry Dosimetry Total
0.16
0.05
0.001
*Wilcoxon rank sum test.
Fourteen of 56 patients of the no dosimetry group who had post-treatment bowel complications had grade III or higher toxicity, compared to 9 of the 96 patients in the dosimetry group who had this data recorded (P=0.01). The actuarial survival at 2 years was 56.2% in the non-dosimetry group and 68.6% ib the dosimetry group, as outlined in Fig. 1. Figure 2 shows survival by stage. In a multivariate analysis, adjusting for stage and ECOG status there is a survival advantage for patients receiving dosimetry (Hazard ratio 0.58, 95%CI 0.37–0.91, P-value 0.02). The Cox regression analysis adjusting for age, stage and performance status is shown in Fig. 3.
DISCUSSION
Radiation therapy is a very effective treatment for patients with carcinoma of the uterine cervix. It is also an alternative to surgery in Stages I and IIA, comparable survival and tumour control with either modality have been reported [19]. The recent national audit of cervical carcinoma radiotherapy in the United Kingdom [30] found that overall survival was lower than that for equivalent stage patients treated in the rest of Europe. The crude rate of late severe complications was 6.1% (actuarial rate 8%) at 5 years. Table 6 – Diversional surgery – aetiology Diversional surgery Permanent Temporary Total
Due to cancer
Due to radiation therapy
11 — 11
14 3 17
A number of grading systems have been used to rate the severity of complications in patients with cervical carcinoma, of these the Franco-Italian glossary [20] is the most detailed and specific coding system for cervical carcinoma. We have used the Franco-Italian Glossary in other studies [21,22], but as this study commenced in 1989 we used the more widely accepted RTOG (Radiation Therapy and Oncology Group) scoring system. Comparison of reported treatment sequelae may be very difficult because, as shown by Sismondi et al. [23] in a critical analysis of 97 articles published, 59 made no use of classification of sequelae of any kind, 34 authors used classifications according to different criteria, and 4 classified sequelae according to the treatment period. An accepted quantitative scale was used in only 30 papers. Perez et al. [1] did not find a correlation between grade 2–3 rectal sequelae and external beam radiation dose. However the treatment policy at the Mallinckrodt Institute involves the use of low-dose external beam radiation therapy. Patients with stage IB–IIA disease receive 10–20 Gy external beam radiation therapy before placement of a midline block. The external beam radiation dose is increased to 20–40 Gy in stage IIB–III and 40 Gy in stage IVA. Thus it is possible that the correlation between external beam radiation therapy dose and rectal sequelae may not have been evident. Unlike some centres we did not use a central midline shielding block to allow higher doses to be given by the intracavitary brachytherapy, as we were concerned about geometry and overlap. There have been reports of more urological complications when a midline block is used possibly because the ureters are in a particularly vulnerable position 2–3 cm from the midline, where overlaps between the external-beam fields and high-dose regions of the intracavitary system may occur [8]. Since the commencement of the current study we used a
47
Proportion surviving
1
No dosimetry Dosimetry
0.8
0.6
0.4
0.2 p-value: 0.18 12
0
24
36
48
60
26(6) 35(10)
18(8) 19(5)
15(2) 15(1)
Months Number at risk No dosimetry Dosimetry
58 102
46(11) 74(13)
32(14) 53(14)
numbers in brackets represent the number of events
Fig. 1 – Survival by Individual Dosimetry.
Proportion surviving
1
FIGO IB/IIA FIGO IIB FIGO III/IV
0.8
0.6
0.4
0.2
12
0
24
36
48
60
18 27 14
13 19 4
9 16 3
Months Number at risk FIGO IB/IIA FIGO IIB FIGO III/IV
35 63 65
29 50 41
23 40 19
Fig. 2 – Survival by Stage.
Manchester applicator initially without individualized dosimetry then after 1991 with individualized dosimetry. The Manchester applicator replaced a single line technique used previously with a high rate of complications, however in some centers acceptable results have been reported with such techniques [32,33]. Our calculation of rectal and bladder doses was based on standard reference points though this may be an underestimate of the highest dose received and does
not take into account the volume exposed to a given dose. Using three dimensional (3-D) computerized tomography based dose distributions Schoeppel [24] demonstrated that maximum doses to the rectum and bladder were sometimes two to three times higher than doses calculated from standard reference points. Barillot [25] performed careful dosimetric measurements in 58 patients, 38 of whom had carcinoma of the uterine cervix and 28 had endometrial carcinoma, treated with
48
Proportion surviving
1
No dosimetry Dosimetry
0.8
0.6
0.4
0.2
0
12
24
36
48
60
Months
Fig. 3 – Cox regression: survival by dosimetry adjusted for Age, Stage and ECOG.
external beam radiation therapy and brachytherapy. These data were compared with dose calculations from orthogonal implant films. They found a lack of correlation between the ICRU values calculated from orthogonal films and the ultrasound determined dose values. Maximum and mean doses were on average 2.71 and 2.25 times higher, retrospectively than the ICRU reference dose. Also, the average mean bladder dose was 30% lower than the maximum dose. The ICRU reference dose was representative of the maximum bladder dose in less than 25% of cases. Concurrent chemo-irradiation has become the standard of care based on several randomised control trials both in the definitive [26–28] and adjuvant [29] management of cervical carcinoma. However this study was conducted in the period prior to the evidence of a survival benefit of concurrent chemotherapy being available. The trials have shown a potentiation of acute effects but little increase in late effects of radiation therapy, and it is likely that the same factors of dose, dose-rate, volume are important in patients treated with chemo-irradiation as in patients treated with radiation alone. Possible explanations for the equivalent local control and survival in patients receiving a lower dose are: non-randomised nature of the study, stage migration; and changes in disease over time. Investigations have remained relatively uniform over the study period so stage migration seems unlikely to be a cause. While the study data was collected prospectively it is a comparison of two consecutive groups of patients thus the length of follow-up in the initial non individualized dosimetry group is longer. However this is unlikely to confound the results given that the statistical analysis takes into account differences in follow-up and that the majority of cervix carcinoma recurrences occur within 5 years of treatment. Prior to 1991 no routine individual dosimetry was carried out mainly due to manpower restrictions, such
dosimetry is now our standard technique with modifications as outlined. Given the increasing evidence that cancer survival outcomes are poorer in health systems with less resources, it is not unexpected that complications may also be higher. We feel that there is no role for cervix brachytherapy without individualized dosimetry in the modern management of cervix carcinoma. REFERENCES 1 Perez CA, Breaux S, Bedwinek JM, et al. Radiation therapy alone in the treatment of carcinoma of the uterine cervix. II. Analysis of complications. Cancer 1984;54:235–246. 2 Esche BA, Crook JM, Horiot JM. Dosimetric methods in the optimization of radiotherapy for carcinoma of the uterine cervix. Int J Radiat Oncol Biol Phys 1987;13:1183–1192. 3 Kottmeier HL, Gray MJ. Rectal and bladder injuries in relation to radiation dosage in carcinoma of the cervix. A five year followup. Am J Obstet Gynecol 1961;82:74–81. 4 Monatana GS, Fowler WC. Carcinoma of the cervix: Analysis of bladder and rectal radiation dose and complications. Int J Radiat Oncol Biol Phys 1989;16:95–100. 5 Roeske JC, Mundt AJ, Halpern H, et al. Late rectal sequelae following definitive radiation therapy for carcinoma of the uterine cervix: a dosimetric analysis. Int J Radiat Oncol Biol Phys 1997;37:351–358. 6 Unal A, Hamberger AD, Seski JC, Fletcher GH. An analysis of the severe complications of irradiation of carcinoma of the uterine cervix: Treatment with intracavitary and radium and parametrial irradiation. Int J Radiat Oncol Biol Phys 1981;7:999–1004. 7 Peckham BM, Kline JC, Schultz AE, Cameron JR, Vermund H. Radiation dosage and complications in cervical cancer therapy. Am J Obstet Gynae 1969;104:485–494. 8 Eifel PJ, Levenback C, Wharton JT, Oswald MJ. Time course and incidence of late complications in patients treated with radiation therapy for FIGO Stage IB carcinoma of the uterine cervix. Int J Radiat Oncol Biol Phys 1995;32:1289–1300. 9 Perez CA, Fox S, Lockett MA, et al. Impact of dose in outcome of irradiation alone in carcinoma of the uterine cervix: analysis of two different methods. Int J Radiat Oncol Biol Phys 1991;21:885–898. 10 Lee KH, Kagan AR, Nussabaum H, Wollin MS, Winkley JH, Norman A. Analysis of dose, dose-rate and treatment time in the production of injuries by radium treatment for cancer of the uterine cervix. Br J Radiol 1976;49:430–440.
11 Lanciano RM, Martz D, Montana GS, Hanks GE. Influence of age, prior abdominal surgery, fraction size, and dose on complications after radiation therapy for squamous cell cancer of the uterine cervix treated by radiation: A Patterns of Care Study. Cancer 1992;69:2124–2130. 12 Perez CA, Grisby PW, Lockett MA, Chao CKS, Williamson J. Radiation therapy morbidity in carcinoma of the uterine cervix: dosimetric and clinical correlation. Int J Radiat Oncol Biol Phys 1999;44:855–866. 13 International Federation of Gynecology and Obstetrics. Classification and staging of malignant tumours of the female pelvis. Acta Obstet Gynecol Scand 1971;50:1–7. 14 ICRU. Dose and volume specification for reporting intracavitary therapy in gynecology. ICRU report no. 38. Bethesda MD, International commission on Radiation Units and Measures, 1985. 15 Peto R, Pike M, et al. Design and analysis of randomized clinical trials requiring prolonged observation of each patient. Br J Can 1977;35:1–35. 16 Kaplan E, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Ass 1958;53:457–481. 17 Kalbfeisch J, Prentice R. Analysis of failure time data. New York: John Wiley and Sons, 1980. 18 Rice WR. A new probability model for determining exact P-values for 22 tables when comparing binomial proportions. Biometrics 1988;44:1–22. 19 Landoni F, Maneo A, Colombo A, et al. Randomised study of radical surgery versus radiotherapy for stage IB-IIA cervical cancer. Lancet 1997;350:535–540. 20 Chassagne D, Sismondi P, Horiot JC, et al. A glossary for reporting complications of treatment in gynaecological caners. Radiother Oncol 1993;26:195–202. 21 Foroudi F, Bull CA, Gebski V. Primary vaginal carcinoma: outcome and complications of therapy. Australasian Radiology 1999;43:472–475. 22 Christie D, Bull CA, Gabski V, Langlands AO. Concurrent 5FU, Mitomycin-C, and irradiation in locally advanced cervical cancers. Radiother. Oncol 1995;37:181–189. 23 Sismondi P, Sinistero G, Zola P, et al. Complications of uterine cervix carcinoma treatments: the problem of uniform classification. Radiother Oncol 1989;14:9–17.
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24 Schoeppel SL, Fraass BA, Hopkins MP, et al. A CT-compatible version of the Fletcher system intracavitary applicator: Clinical application and 3-dimensional treatment planning. Int J Radiat Oncol Biol Phys 1989;17:1103–1109. 25 Barillot I, Horiot JC, Maingon P, et al. Maximum and mean bladder dose defined from ultrasonography: Comparison with the ICRU reference in gynaecological brachytherapy. Radiother Oncol 1994;30:231–238. 26 Keys HM, Bundy BN, Stehman FB, et al. Cisplatin, radiation, and adjuvant hysterectomy for bulky stage IB cervical carcinoma. N Engl J Med 1999;340:1154–1161. 27 Morris M, Eifel PJ, Lu J, et al. Pelvic radiation with concurrent chemotherapy compared with pelvic and paraaortic radiation for high risk cervix cancer. N Engl J Med 1999;340:1137– 1143. 28 Rose PG, Bundy BN, Watkins J, et al. Concurrent cisplatin-based chemotherapy and radiotherapy for locally advanced cervical cancer. N Engl J Med 1999;340:1144–1153. 29 Peters WA III, Liu PY, Barrett RJ, et al. Concurrent chemotherapy and pelvic radiation therapy compared with pelvic radiation therapy alone as adjuvant therapy after radical surgery in high-risk early-stage cancer of the cervix. J Clin Oncol 2000; 18:1606–1613. 30 Denton AS, Bond SJ, Matthews S, et al. National Audit of the Management and Outcome of Carcinoma of the Cervix treated with Radiotherapy in 1993. Clin Oncol 2000;12:347–353. 31 van der Kogel AJ, Ruifrok AC. Calculation of isoeffect relationships. In: Steel GG, ed. Basic Clinical Radiobiology. London; Edward Arnold, 1993. 32 Tan LT, Jones B, Gee A, Kingston RE. An audit of the treatment of carcinoma of the uterine cervix using external beam radiotherapy and a single line source brachytherapy technique. Br J Radiol 1997;1259–1269. 33 Tan LT, Jones B, Shaw JE. Radical radiotherapy for carcinoma of the uterine cervix using external beam radiotherapy and a single line source brachytherapy technique: the clatterbridge technique. Br J Radiol 1997; 1252–1258.
Gynaecology Radiation Therapy for Cervix Carcinoma: Benefits of Individualized Dosimetry F. FOROUDI*, C. A. BULL*, V. GEBSKI*† *Department of Radiation Oncology, Westmead Hospital, Westmead, NSW, †NHMRC Clinical Trials Center, University of Sydney, Australia Received: 15 January 2001
Accepted: 24 September 2001
ABSTRACT: This study is a presentation of the prospective collection of data on patients treated by radical radiotherapy at Westmead Hospital between December 1989 and December 1998. The impact of the routine use of individualized dosimetry and lower brachytherapy dose on patients was examined, by comparing the historical series of patients treated between 1989 to 1991 to the later patients treated with inividualised dosimetry. There were 163 patients treated with external beam and intracavitary radiotherapy during this period. Histology was squamous carcinoma in 80% (132 patients), adenocarcinoma in 13% (22 patients), and adenosquamous carcinoma in 6% (9 patients). Patients were generally treated with 50 Gy in 25 fractions to the pelvis followed by 1 low dose rate caesium intracavitary brachytherapy insertion. Patients who had dosimetry generally received 20 Gy to point A via the insertion compared to 30 Gy in the non-dosimetry group. Median follow-up was 62 months. Only 22% (18) of patients failed with disease outside the pelvis. Pelvic control was similar in the patients who had dosimetry as opposed to no dosimetry (P=0.8). In the dosimetry group there were less grade III or higher bowel toxicity (P=0.01) and less vaginal fistulae (P=0.03). The actuarial two-year survival was 56.2% in the no dosimetry group and 68.6% in the dosimetry group. When controlled for stage and performance status patients who had dosimetry had a statistically significant greater overall survival (P=0.02). Thus we found that the routine use of dosimetry was associated with a lower brachytherapy dose, decreased complications, without any decrease in local control or survival. Foroudi, F. et al. (2002). Clinical Oncology 14, 43–49. 2002 The Royal College of Radiologists Key words: Cervical carcinoma, radiation therapy, dosimetry, rectal toxicity, bladder toxicity
INTRODUCTION
Radiation therapy is the major modality of treatment for carcinoma of the uterine cervix. The impact of multiple patient factors on the risk of late rectal and other complications have been investigated including age [1], stage [2–4], prior surgery, diabetes [5], diverticulitis and pelvic inflammatory disease [6]. The dose of intracavitary radiation based on bladder and rectal dose and not set dosage tables has been proposed to allow higher doses and hence improve control rates without increasing normal tissue complications [7]. However some major centres [8] still do not base prescriptions on point A or bladder or rectum Author for correspondence: C. A. Bull, Department of Radiation Oncology, Westmead Hospital, Westmead, NSW 2145, Australia. E-mail: [email protected] 0936–6555/02/010043+07 $35.00/0
doses. In contrast Perez [9] suggests that dosimetric analysis is paramount to optimize tumour control while maintaining an acceptable incidence of major sequalae. While Lee et al. [10] argued that dose-rate is the most important factor in determining serious normal tissue complications it is likely to be a mixture of total dose, dose rate, normal tissue sensitivity and geometry. The risk of rectal and urinary tract complications developing is greatest within the first 3 years of treatment but there remains an actuarial risk even at 25 years follow up [8]. A recent United Kingdom national audit [30] found that while large bowel and bladder toxicities mainly occurred during the first 3 years, small bowel, vascular and soft tissue events occur at longer observation periods. Patients who had an adjuvant extrafascial hysterectomy and those who had a pretreatment laparotomy were at greater risk of developing 2002 The Royal College of Radiologists
44
bowel complications [8]. In addition to stage, large tumour size has also been suggested as a risk factor for complications [8]. Differences in grading systems and methods of reporting make it difficult to compare results of various series, however the range of major complications has varied from 8 to 14.8% [1,8,11]. Large retrospective analyses of the relationship between point dose calculations and complications have yielded only rough correlations [1]. Perez [1] found patients who received greater than 60 Gy and less than or equal to 70 Gy or greater than 70 Gy and less than or equal to 80 Gy to bladder reference points had a similar crude rate of developing major urinary tract complications. The incidence increased for those given higher doses, but was still only 11% when the reference dose was greater than 80 Gy and was 8% in those who received greater than 100 Gy to bladder reference point. A more recent retrospective review from Mallincrodt [12] demonstrated using multivariate analysis that total dose to the rectal point and total dose to the bladder point were the only factors influencing rectal and bladder complications, respectively. Thus it is controversial whether the total dose should be compromised (which could increase the rate of disease recurrence in the pelvis) based on bladder and rectal doses. Using the prospective data collected on patients having cervical cancer treated at Westmead hospital the effect of individual dosimetry on complications, local control and survival were examined.
METHODS
Data on all patients with cervical carcinoma treated by radical radiotherapy at Westmead hospital between December 1989 and December 1998 were prospectively collected. All patients were staged with an examination under anaesthesia, a chest radiograph and either an intravenous pyelogram or a computerized tomogram of the abdomen and pelvis. FIGO staging [13] was prospectively recorded on all patients. When there was a disagreement of staging, patients were assigned the less-advanced stage. Radiation Therapy and Oncology Group (RTOG) toxicity grades were recorded at every clinic visit for bowel and bladder toxicity. Patients were followed up periodically at the radiation oncology department for at least 5 years or until lost to follow-up or death. If there was no information on outcome, then attempts were made to collect the information by contacting the patients’ general practitioners or the referring gynaecologists. External beam radiation was delivered by megavoltage linear accelerators. The majority of patients were treated using an isocentric 4 field technique with a belly board. No central shielding block was used. The external beam dose was usually 50 Gy in 25 daily fractions over 6 weeks. Patients were treated with high-energy photons
with 25 MV and 18 MV from linear accelerators; a small number of patients were treated with 6 MV photons either due to equipment availability or geometry showing minimal benefit for a higher energy arrangement. All fields were treated each day, and the general AP borders were superiorly L5-S1 interspace, inferiorly below the obturator foramina or at least 3 cm below the tumour as marked with gold seeds and laterally 2 cm margin to the pelvic brim, the average field size being 1515 cm. Intracavitary brachytherapy was given using a lowdose rate caesium automatic afterloader, with one insertion generally given 2 weeks after completion of the external beam radiation treatment. The point A is defined as 2 cm cephalad and 2 cm lateral to the cervical os, along the plane of the tandem. Between 1989 and 1991 no routine individualized dosimetry was carried out, in 1991 individualized brachytherapy dosimetry was commenced. At this time the dose at point A was also reduced as was the dose rate of the caesium source. Orthogonal simulation films were obtained with dummy sources in place. Bladder and rectal doses were defined as per ICRU 38 [14]. Where the normal tissue dose particularly the rectal or bladder doses were excessive, the active source geometry was changed and if the dose to normal tissues was still excessive the total prescribed dose was reduced. The biological effective dose (BED) was determined using a / ratio of 3 and a g factor of 0.1475 [31]. The use of individualized dosimetry was based on the availability of physicist resources in our department. Between 1978 and 1989 a single line technique was used, however due to high rates of normal tissue complications a Manchester applicator was purchased in 1989. Until 1991 standard loadings were used and treatment time was read from tables assuming perfect geometry. Only in 1991 with the appointment of further physics staff was individualized dosimetry carried out in each case. While all the data were collected prospectively, the controls or patients treated without individualized brachytherapy were historical as they were treated between 1989 and 1991 and the patients with individualized dosimetry between 1991 and 1998. Survival outcomes were compared using the logrank test of Peto [15] and survival curves were constructed using the method of Kaplan–Meier [16]. Multivariate analysis comparing prognostic factors was performed using proportional hazards (Cox) regression [17]. Analysis of proportions was carried out using the conditional binomial exact test [18].
RESULTS
In the study time period there were 163 women with cervix carcinoma, with a median age of 61 years (range 30–85 years). Histology was squamous cell carcinoma in 80%, adenocarcinoma in 13%, and adenosquamous carcinoma in 6%. Performance status was ECOG 0 in
Table 1 – FIGO stage distribution of patients FIGO Stage IB IIA IIB IIIA IIIB IVB
45
Table 3 – Brachytherapy dosimetry details
No of Patients
%
21 14 63 1 62 2
12.9 8.6 38.6 0.6 38 1.2
Brachytherapy Point A dose Point A dose rate BED Point A* Point B dose Rectal dose Bladder dose
N
Min
Mean
Max
163 163 163 127 105 105
0 0 0 0 6.7 4.6
23.3 1.1 50 6.8 14 17.4
35 2 95.2 74 28.3 42.5
*BED=Biological Effective Dose.
Table 2 – Patient characteristics in dosimetry and non-dosimetry groups Dosimetry Age (yr): Mean (median) Weight (kg): Mean (median) Stage I Stage II Stage III Stage IV ECOG 0 ECOG 1 ECOG 2 ECOG 3 ECOG 4
Non-Dosimetry
58.6(61)
55.4(54)
62 (59) 7 6 30 21 28 31 5 0 1
63.5(63) 12 6 19 21 38 13 6 0 1
Unknown
Table 4 – Dose at Point A – Dosimetry vs no individualised dosimetry (Gy) Dosimetry
0 0 5 9 5 3 5 1
71 patients and ECOG 1 in 47 patients with only 3 patients (2%) being ECOG 3 or 4. Table 1 shows the FIGO stage distribution of the patients. Median follow-up was 62 months, Table 2 shows the patient characteristics in the dosimetry and non dosimetry groups. One hundred and fifty-six patients were treated with radiotherapy alone, 7 patients had concurrent 5-fluoruracil chemotherapy as per a COSA (Clinical Oncology Society of Australia) trial. In addition to the 163 patients, there were 17 patients treated with radical intent for cervical carcinoma who did not have brachytherapy for reasons including dementia, and being medically unfit for a general anaesthetic. One hundred and sixty patients were treated using a Manchester style applicator, with 3 patients treated using an Edinburgh applicator. Table 3 describes the brachytherapy details. At the time of the insertion, there was no pelvic disease present in 85 patients (52%). In 77 patients (47%) there was disease present, and in 1 patient findings at the examination under anaesthesia were equivocal. Table 4 shows the differing dose between the dosimetry and non dosimetry groups. At brachytherapy in the majority of cases a biopsy was not done; when biopsy was done 18 out of the 22 were positive. Table 5 outlines the acute radiation toxicity using RTOG scoring system, defined as
Yes No
N
Median (dose rates)
Mean (dose rates)
SD (dose rates)
105 58
20 (0.8*) 30 (1.4)
20.7 (0.9) 28 (1.4)
6 (0.2) 2.6 (0.13)
*Dose rates in brackets are in Gy/hr while doses are in Gy.
occurring within 6 months of commencement of radiation therapy. At the time of analysis (October 2000) 62 patients (38%) were still alive. In 72 patients the cause of death was tumour related, it was treatment related in 3 patients and due to other causes in 26 patients. The three patients who died of treatment related causes were all in the no dosimetry group. Of the patients relapsing, there were 28% (23 patients) who presented with disease only outside the pelvis. Failure with both pelvic disease and disease outside the pelvis occurred in 35%. In contrast 16% had isolated pelvic failure, but also a proportion of patients did not have a pelvic examination at the time of presenting with distant metastasis. Pelvic control was similar in the patients who had dosimetry and those who did not, despite a lower dose and dose-rate in the former group. Pelvic control was maintained in 30 of 58 (52%) of patients who had no dosimetry and 56 of 105 (53%) patients who had dosimetry (P=0.8). Twenty two patients had a colostomy, 6 patients an ileostomy, and 1 patient had both a colostomy and ileostomy. Table 6 shows the breakdown of fistula aetiology and type. Generally histological diagnosis was obtained to determine if the fistula was due to malignancy or treatment. In 10 cases (52%) it was due to cancer and in 9 cases (48%) it was due to radiation therapy. The mean time to fistula was 15 months in cases due to malignancy and 23 months in cases due to radiation therapy. Seven patients who had no dosimetry had a fistula due to radiation therapy compared to two who had dosimetry carried out (P=0.03). Two patients out of the 156 having radiotherapy alone developed a bone fracture.
46 Table 5 – Acute toxicity of radiation therapy
Nausea & vomiting
Grade 0
Grade 0
Grade 1
Grade 2
Grade 3
P-value*
No Dosimetry Dosimetry
44 78
8 16
2 8
4 2
0.98
122 (74.9)
24 (14)
10 (6.1)
6 (5)
22 53
5 8
31 40
0 3
75 (46)
13 (8)
71 (43.6)
3 (1.8)
39 84
9 9
10 7
0 4
123 (75.5)
18 (11)
17 (10.4)
4 (2.5)
50 64
3 18
5 21
0 1
114 (69.9)
21 (12.9)
26 (16)
1 (0.6)
Total (%) Bowel
No Dosimetry Dosimetry Total
Bladder
No Dosimetry Dosimetry Total
Skin
No Dosimetry Dosimetry Total
0.16
0.05
0.001
*Wilcoxon rank sum test.
Fourteen of 56 patients of the no dosimetry group who had post-treatment bowel complications had grade III or higher toxicity, compared to 9 of the 96 patients in the dosimetry group who had this data recorded (P=0.01). The actuarial survival at 2 years was 56.2% in the non-dosimetry group and 68.6% ib the dosimetry group, as outlined in Fig. 1. Figure 2 shows survival by stage. In a multivariate analysis, adjusting for stage and ECOG status there is a survival advantage for patients receiving dosimetry (Hazard ratio 0.58, 95%CI 0.37–0.91, P-value 0.02). The Cox regression analysis adjusting for age, stage and performance status is shown in Fig. 3.
DISCUSSION
Radiation therapy is a very effective treatment for patients with carcinoma of the uterine cervix. It is also an alternative to surgery in Stages I and IIA, comparable survival and tumour control with either modality have been reported [19]. The recent national audit of cervical carcinoma radiotherapy in the United Kingdom [30] found that overall survival was lower than that for equivalent stage patients treated in the rest of Europe. The crude rate of late severe complications was 6.1% (actuarial rate 8%) at 5 years. Table 6 – Diversional surgery – aetiology Diversional surgery Permanent Temporary Total
Due to cancer
Due to radiation therapy
11 — 11
14 3 17
A number of grading systems have been used to rate the severity of complications in patients with cervical carcinoma, of these the Franco-Italian glossary [20] is the most detailed and specific coding system for cervical carcinoma. We have used the Franco-Italian Glossary in other studies [21,22], but as this study commenced in 1989 we used the more widely accepted RTOG (Radiation Therapy and Oncology Group) scoring system. Comparison of reported treatment sequelae may be very difficult because, as shown by Sismondi et al. [23] in a critical analysis of 97 articles published, 59 made no use of classification of sequelae of any kind, 34 authors used classifications according to different criteria, and 4 classified sequelae according to the treatment period. An accepted quantitative scale was used in only 30 papers. Perez et al. [1] did not find a correlation between grade 2–3 rectal sequelae and external beam radiation dose. However the treatment policy at the Mallinckrodt Institute involves the use of low-dose external beam radiation therapy. Patients with stage IB–IIA disease receive 10–20 Gy external beam radiation therapy before placement of a midline block. The external beam radiation dose is increased to 20–40 Gy in stage IIB–III and 40 Gy in stage IVA. Thus it is possible that the correlation between external beam radiation therapy dose and rectal sequelae may not have been evident. Unlike some centres we did not use a central midline shielding block to allow higher doses to be given by the intracavitary brachytherapy, as we were concerned about geometry and overlap. There have been reports of more urological complications when a midline block is used possibly because the ureters are in a particularly vulnerable position 2–3 cm from the midline, where overlaps between the external-beam fields and high-dose regions of the intracavitary system may occur [8]. Since the commencement of the current study we used a
47
Proportion surviving
1
No dosimetry Dosimetry
0.8
0.6
0.4
0.2 p-value: 0.18 12
0
24
36
48
60
26(6) 35(10)
18(8) 19(5)
15(2) 15(1)
Months Number at risk No dosimetry Dosimetry
58 102
46(11) 74(13)
32(14) 53(14)
numbers in brackets represent the number of events
Fig. 1 – Survival by Individual Dosimetry.
Proportion surviving
1
FIGO IB/IIA FIGO IIB FIGO III/IV
0.8
0.6
0.4
0.2
12
0
24
36
48
60
18 27 14
13 19 4
9 16 3
Months Number at risk FIGO IB/IIA FIGO IIB FIGO III/IV
35 63 65
29 50 41
23 40 19
Fig. 2 – Survival by Stage.
Manchester applicator initially without individualized dosimetry then after 1991 with individualized dosimetry. The Manchester applicator replaced a single line technique used previously with a high rate of complications, however in some centers acceptable results have been reported with such techniques [32,33]. Our calculation of rectal and bladder doses was based on standard reference points though this may be an underestimate of the highest dose received and does
not take into account the volume exposed to a given dose. Using three dimensional (3-D) computerized tomography based dose distributions Schoeppel [24] demonstrated that maximum doses to the rectum and bladder were sometimes two to three times higher than doses calculated from standard reference points. Barillot [25] performed careful dosimetric measurements in 58 patients, 38 of whom had carcinoma of the uterine cervix and 28 had endometrial carcinoma, treated with
48
Proportion surviving
1
No dosimetry Dosimetry
0.8
0.6
0.4
0.2
0
12
24
36
48
60
Months
Fig. 3 – Cox regression: survival by dosimetry adjusted for Age, Stage and ECOG.
external beam radiation therapy and brachytherapy. These data were compared with dose calculations from orthogonal implant films. They found a lack of correlation between the ICRU values calculated from orthogonal films and the ultrasound determined dose values. Maximum and mean doses were on average 2.71 and 2.25 times higher, retrospectively than the ICRU reference dose. Also, the average mean bladder dose was 30% lower than the maximum dose. The ICRU reference dose was representative of the maximum bladder dose in less than 25% of cases. Concurrent chemo-irradiation has become the standard of care based on several randomised control trials both in the definitive [26–28] and adjuvant [29] management of cervical carcinoma. However this study was conducted in the period prior to the evidence of a survival benefit of concurrent chemotherapy being available. The trials have shown a potentiation of acute effects but little increase in late effects of radiation therapy, and it is likely that the same factors of dose, dose-rate, volume are important in patients treated with chemo-irradiation as in patients treated with radiation alone. Possible explanations for the equivalent local control and survival in patients receiving a lower dose are: non-randomised nature of the study, stage migration; and changes in disease over time. Investigations have remained relatively uniform over the study period so stage migration seems unlikely to be a cause. While the study data was collected prospectively it is a comparison of two consecutive groups of patients thus the length of follow-up in the initial non individualized dosimetry group is longer. However this is unlikely to confound the results given that the statistical analysis takes into account differences in follow-up and that the majority of cervix carcinoma recurrences occur within 5 years of treatment. Prior to 1991 no routine individual dosimetry was carried out mainly due to manpower restrictions, such
dosimetry is now our standard technique with modifications as outlined. Given the increasing evidence that cancer survival outcomes are poorer in health systems with less resources, it is not unexpected that complications may also be higher. We feel that there is no role for cervix brachytherapy without individualized dosimetry in the modern management of cervix carcinoma. REFERENCES 1 Perez CA, Breaux S, Bedwinek JM, et al. Radiation therapy alone in the treatment of carcinoma of the uterine cervix. II. Analysis of complications. Cancer 1984;54:235–246. 2 Esche BA, Crook JM, Horiot JM. Dosimetric methods in the optimization of radiotherapy for carcinoma of the uterine cervix. Int J Radiat Oncol Biol Phys 1987;13:1183–1192. 3 Kottmeier HL, Gray MJ. Rectal and bladder injuries in relation to radiation dosage in carcinoma of the cervix. A five year followup. Am J Obstet Gynecol 1961;82:74–81. 4 Monatana GS, Fowler WC. Carcinoma of the cervix: Analysis of bladder and rectal radiation dose and complications. Int J Radiat Oncol Biol Phys 1989;16:95–100. 5 Roeske JC, Mundt AJ, Halpern H, et al. Late rectal sequelae following definitive radiation therapy for carcinoma of the uterine cervix: a dosimetric analysis. Int J Radiat Oncol Biol Phys 1997;37:351–358. 6 Unal A, Hamberger AD, Seski JC, Fletcher GH. An analysis of the severe complications of irradiation of carcinoma of the uterine cervix: Treatment with intracavitary and radium and parametrial irradiation. Int J Radiat Oncol Biol Phys 1981;7:999–1004. 7 Peckham BM, Kline JC, Schultz AE, Cameron JR, Vermund H. Radiation dosage and complications in cervical cancer therapy. Am J Obstet Gynae 1969;104:485–494. 8 Eifel PJ, Levenback C, Wharton JT, Oswald MJ. Time course and incidence of late complications in patients treated with radiation therapy for FIGO Stage IB carcinoma of the uterine cervix. Int J Radiat Oncol Biol Phys 1995;32:1289–1300. 9 Perez CA, Fox S, Lockett MA, et al. Impact of dose in outcome of irradiation alone in carcinoma of the uterine cervix: analysis of two different methods. Int J Radiat Oncol Biol Phys 1991;21:885–898. 10 Lee KH, Kagan AR, Nussabaum H, Wollin MS, Winkley JH, Norman A. Analysis of dose, dose-rate and treatment time in the production of injuries by radium treatment for cancer of the uterine cervix. Br J Radiol 1976;49:430–440.
11 Lanciano RM, Martz D, Montana GS, Hanks GE. Influence of age, prior abdominal surgery, fraction size, and dose on complications after radiation therapy for squamous cell cancer of the uterine cervix treated by radiation: A Patterns of Care Study. Cancer 1992;69:2124–2130. 12 Perez CA, Grisby PW, Lockett MA, Chao CKS, Williamson J. Radiation therapy morbidity in carcinoma of the uterine cervix: dosimetric and clinical correlation. Int J Radiat Oncol Biol Phys 1999;44:855–866. 13 International Federation of Gynecology and Obstetrics. Classification and staging of malignant tumours of the female pelvis. Acta Obstet Gynecol Scand 1971;50:1–7. 14 ICRU. Dose and volume specification for reporting intracavitary therapy in gynecology. ICRU report no. 38. Bethesda MD, International commission on Radiation Units and Measures, 1985. 15 Peto R, Pike M, et al. Design and analysis of randomized clinical trials requiring prolonged observation of each patient. Br J Can 1977;35:1–35. 16 Kaplan E, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Ass 1958;53:457–481. 17 Kalbfeisch J, Prentice R. Analysis of failure time data. New York: John Wiley and Sons, 1980. 18 Rice WR. A new probability model for determining exact P-values for 22 tables when comparing binomial proportions. Biometrics 1988;44:1–22. 19 Landoni F, Maneo A, Colombo A, et al. Randomised study of radical surgery versus radiotherapy for stage IB-IIA cervical cancer. Lancet 1997;350:535–540. 20 Chassagne D, Sismondi P, Horiot JC, et al. A glossary for reporting complications of treatment in gynaecological caners. Radiother Oncol 1993;26:195–202. 21 Foroudi F, Bull CA, Gebski V. Primary vaginal carcinoma: outcome and complications of therapy. Australasian Radiology 1999;43:472–475. 22 Christie D, Bull CA, Gabski V, Langlands AO. Concurrent 5FU, Mitomycin-C, and irradiation in locally advanced cervical cancers. Radiother. Oncol 1995;37:181–189. 23 Sismondi P, Sinistero G, Zola P, et al. Complications of uterine cervix carcinoma treatments: the problem of uniform classification. Radiother Oncol 1989;14:9–17.
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24 Schoeppel SL, Fraass BA, Hopkins MP, et al. A CT-compatible version of the Fletcher system intracavitary applicator: Clinical application and 3-dimensional treatment planning. Int J Radiat Oncol Biol Phys 1989;17:1103–1109. 25 Barillot I, Horiot JC, Maingon P, et al. Maximum and mean bladder dose defined from ultrasonography: Comparison with the ICRU reference in gynaecological brachytherapy. Radiother Oncol 1994;30:231–238. 26 Keys HM, Bundy BN, Stehman FB, et al. Cisplatin, radiation, and adjuvant hysterectomy for bulky stage IB cervical carcinoma. N Engl J Med 1999;340:1154–1161. 27 Morris M, Eifel PJ, Lu J, et al. Pelvic radiation with concurrent chemotherapy compared with pelvic and paraaortic radiation for high risk cervix cancer. N Engl J Med 1999;340:1137– 1143. 28 Rose PG, Bundy BN, Watkins J, et al. Concurrent cisplatin-based chemotherapy and radiotherapy for locally advanced cervical cancer. N Engl J Med 1999;340:1144–1153. 29 Peters WA III, Liu PY, Barrett RJ, et al. Concurrent chemotherapy and pelvic radiation therapy compared with pelvic radiation therapy alone as adjuvant therapy after radical surgery in high-risk early-stage cancer of the cervix. J Clin Oncol 2000; 18:1606–1613. 30 Denton AS, Bond SJ, Matthews S, et al. National Audit of the Management and Outcome of Carcinoma of the Cervix treated with Radiotherapy in 1993. Clin Oncol 2000;12:347–353. 31 van der Kogel AJ, Ruifrok AC. Calculation of isoeffect relationships. In: Steel GG, ed. Basic Clinical Radiobiology. London; Edward Arnold, 1993. 32 Tan LT, Jones B, Gee A, Kingston RE. An audit of the treatment of carcinoma of the uterine cervix using external beam radiotherapy and a single line source brachytherapy technique. Br J Radiol 1997;1259–1269. 33 Tan LT, Jones B, Shaw JE. Radical radiotherapy for carcinoma of the uterine cervix using external beam radiotherapy and a single line source brachytherapy technique: the clatterbridge technique. Br J Radiol 1997; 1252–1258.