Japanese Journal of Clinical Oncology 33:221-228 (2003)
© 2003 Foundation for Promotion of Cancer Research
High Dose-rate Brachytherapy for Elderly Patients with Uterine Cervical Cancer
1 Department of Radiation Therapy and Oncology, China Medical College Hospital, Taichung 2 China Medical College, School of Medicine, Taichung and 3 Department of Radiation Therapy and Oncology, Shin Kong Memorial Hospital City, Taichung, Taiwan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Background: The need for radiotherapy (RT) in cancer treatment for the elderly patient is growing. The purpose of this study was to analyze the efficacy and complication rate for radiotherapy, using external-beam irradiation (EBRT) and high dose-rate intracavitary brachytherapy (HDRICB), for patients aged 70 years or older with carcinoma of the uterine cervix.
Methods: From September 1992 to December 1997, 295 patients diagnosed with uterine cervical cancer completed RT at the Shin Kong Memorial Hospital and China Medical College Hospital. Two hundred and fifty-eight patients [International Federation of Gynecology and Obstetrics (FIGO) stage distribution: 35 Ib, 26 IIa, 122 IIb, 10 IIIa, 58 IIIb, 7 IVa] who had undergone at least two courses of HDRICB and a minimum of 3 years of follow-up, were evaluated. A retrospective analysis was conducted to compare the outcome of radiation therapy for the 179 patients under 70 years of age (younger group) and the 79 patients aged 70 years or older (older group). The RT consisted of EBRT followed by HDRICB. After a total EBRT dose of 40–45 Gy/20 in 25 fractions, irradiating the whole pelvis over 4–5 weeks, dosage for patients diagnosed as FIGO stage IIb–IVa bilateral parametrial disease was boosted to 54–58 Gy, with central shielding. HDRICB was administered at 1-week intervals using an Ir-192 remote after-loading technique. Ninety-nine patients (38.4%) received three fractions of HDRICB, while 156 patients (60.5%) had four fractions. Total prescribed Point A dosages (EBRT + HDRICB) ranged from 58 to 71.6 Gy (median, 65.6 Gy) for stage IB–IIA, while for larger lesions (stage IIB–IVA) analogous dosages were 59–75.6 Gy (median, 65.6 Gy). Median follow-up durations for the older and younger groups were 56/55 months, respectively.
Results: The respective 5-year actuarial survivals (AS) for the older and younger groups were 82/85% for stage Ib, 65/65% for IIa, 61/71% for IIb and 35/59% for IIIa–b. The 5-year cause-specific survivals (CSS) for the older and younger groups were 100/95% for stage Ib, 85/75% for IIa, 78/72% for IIb and 42/61% for IIIa–b. The 5-year pelvic relapse-free survivals (PRFS) for the older and younger groups were 100/100% for stage Ib, 91/93% for IIa, 91/90% for IIb and 67/80% for IIIa–b. The 5-year distant metastasis-free survivals (DMFS) for older and younger groups were 100/100% for stage Ib, 92/88% for IIa, 84/73% for IIb and 55/75% for IIIa–b. There was no statistically significant survival difference on comparing the two groups according to stage. The gross tumor-free ratios after EBRT (NRT) for the older and younger groups were 44.3/24.5% (P = 0.001). The 5-year CSS for the 35 NRT patients was 88% for the older group, while for the 44 patients diagnosed with gross residual tumor after EBRT (GRT) it was 64% (P = 0.001). Twelve (15.0%) of the 79 older patients and 14 (7.8%) of the 179 younger patients developed RTOG grade 3–4 rectal complications (P = 0.12), while seven (8.9%) of the 79 older patients and 10 (5.6%) of the 179 younger patients developed RTOG grade 3–4 small bowel complications (P = 0.34).
Conclusion: Radiation therapy, consisting of a combination of EBRT and three or four fractions of HDRICB, proved to be effective for older patients. Further optimization of treatment policy is essential by changing the HDRICB fractionation strategy, shortening the treatment time and designing combination drug regimens that are both effective and tolerable during radiotherapy.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Radiotherapy (RT) plays an important role in the treatment of patients with carcinoma of the uterine cervix. The treatment involves a combination of external beam irradiation (EBRT) followed by intracavitary RT (ICRT). High dose-rate intracavitary brachytherapy (HDRICB) has been widely used in Asia and Europe, despite its questionable radiobiological efficacy (1).
The need for radiotherapy is increasing in cancer therapy for the elderly; however, older patients often have concomitant and chronic medical problems (2).There is some information on the effectiveness of and tolerance to RT for elderly patients with uterine cervix carcinoma (2–5); however, none of the researchers reported the treatment outcome for HDRICB. Since there were only slight modifications in our HDRICB policy for older patients compared with younger patients, it is an interesting issue that elderly patients could expect reasonable survival without undue complications as for those with low dose-rate brachytherapy.
For this study, we analyzed retrospectively the efficacy and complication rate for radiotherapy treatment comparing patients aged 
70 years and <70 years with carcinoma of the uterine cervix treated with EBRT and HDRICB.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Patient Selection
From September 1992 to December 1997, 295 patients with uterine cervical cancer completed RT at Shin Kong Memorial Hospital and China Medical College Hospital. Two hundred and fifty-eight patients [International Federation of Gynecology and Obstetrics (FIGO) stage distribution: 35 Ib, 26 IIa, 122 IIb, 10 IIIa, 58 IIIb, 7 IVa], who had undergone at least two courses of HDRICB with follow-up of at least 3 years, were analyzed. A retrospective analysis was conducted to compare RT outcomes for 179 patients <70 years of age (younger group) and 79 patients aged
70 years (older group). The patient characteristics are summarized in Table 1. Median follow-up for all patients was 55 months (younger group 55, older group 56 months), with a range of 37–108 months.
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Radiotherapy
The RT consisted of EBRT followed by HDRICB (Table 2). Initially, the whole pelvis was treated with 10 MV X-rays via anterior and posterior parallel fields or a box field when the AP diameter was over 20 cm. After an EBRT dose of 40–45 Gy/20 in 25 fractions over 4–5 weeks to the whole pelvis, the radiation dose for patients with FIGO stage IIb–IVa bilateral parametrial disease was boosted to 54–58 Gy, with central shielding.
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After the completion of whole-pelvis RT, HDRICB was performed using an Ir-192 remote after-loading technique at 1-week intervals. Ninety-nine patients (38.4%) received three insertions and 156 patients (60.5%) had four insertions. Three patients (one in the older group and two in the younger group) who had a higher EBRT due to persistent tumor received only two fractions of HDRICB. The overall duration of treatment ranged from 47 to 92 days (median, 68 days).
The standard prescribed dose for each HDRICB was 7.2 Gy to Point A for three insertions (before July 1995) or 6.0 Gy for four insertions (after July 1995), while the Point A dose was decreased to 5.0 Gy for all 79 patients in the older group and 14 in the younger group where the initial calculated International Commission of Radiation Units (ICRU) rectal dose was over 6.0 Gy. To define the ICRU rectal-point and cervical-orifice dosages, orthogonal radiography films were exposed. HDRICB was performed using Henschke applicators and colpostats with diameters of 1.0–2.0 cm, selected on the basis of individual anatomy. During each insertion, the posterior and anterior of the vagina were packed with radio-opaque gauze to reduce rectal and bladder irradiation and to improve visualization of the posterior vaginal septum. The Point A dose was defined as 2 cm ceplalad and 2 cm lateral to the cervical orifice, along the plane of the tandem. The active treatment length for tandem depended on the individual sounding of the uterine cavity. The distance between each source dwell point on tandem was 0.5–1 cm. The standard dose weighting for tandem was three-fourths and that for two colpostats was one-fourth. Therefore, the duration of source dwelling through tandem occupied nearly three-fourths of the total dwell time. Total prescribed Point A doses (EBRT + HDRICB) ranged from 58 to 71.6 Gy (median, 65.6 Gy) for stages IB–IIA, while larger lesions (stages IIB–IVA) received 59–75.6 Gy (median, 65.6 Gy).
Dosimetry
For patients treated with two-field techniques, the EBRT dose was calculated at midplane, while the dosimetry of the box field was calculated using computer-based software. The HDRICB dosimetry was calculated using orthogonal film exposed during each insertion. HDRICB isodose curves were reviewed by physicians to ensure that the residual tumor was fully irradiated within the high-dose area. The rectal reference-dose points were determined according to guidelines set out in Report 38 of the ICRU for rectal doses (ICRU rectal point) (6). The dose at Point A, the rectal reference point, bladder reference dose and isodose distributions were calculated using computer-based software (Nucletron Plato System, Version 2, The Netherlands).
Tumor Response
Pelvic examination was performed for all patients under general anesthesia, with insertion of the applicator before the first brachytherapy session. Tumor response to EBRT was recorded on a subjective basis as follows:
1. NRT response (no gross residual tumor): complete or nearly complete regression of the pelvic tumor, non-specific fibrosis or granulation over the cervix.
2. GRT response (gross residual tumor): gross tumor or palpable nodularity on cervix, and/or palpable induration of the parametrium.
Patient and treatment factors, which probably affect the tumor response to EBRT, such as age, clinical stage, initial hemoglobulin level and interval between EBRT and HDRICB, were analyzed.
Chemotherapy
Although adjuvant chemotherapy was suggested for stage III–IV patients, only 30 of 68 patients (44.1%) with stage III disease and six patients with stage IVa disease completed at least two consecutive courses of adjuvant chemotherapy with ftorafur 1000 mg/m2 on days 1–4 and cisplatin 80 mg/m2 on day 3. Adjuvant chemotherapy was started soon after radiotherapy and the interval between each course was 3–4 weeks. None of the patients in the elderly group received adjuvant chemotherapy.
Follow-up
After completion of radiotherapy, patients received regular follow-up every 1–2 months in the first year, then every 3 months subsequently. A pelvic examination was performed during each follow-up, while tumor markers (squamous cell and carcinoembryonic antigens) were checked every 3–6 months and a radiographic examination (chest X-ray, abdominopelvic CT scan) was conducted yearly. Patients who had bloody stools underwent sigmoidoscopy to identify the site of the bleeding and a blood count every 2–4 weeks for surveillance of the severity of rectal complication.
Analysis of Complications
Rectal and bladder complications and non-rectal gastrointestinal sequelae (small bowel complications) were scored according to the RTOG grading scale.
Cumulative rectal dose (CRD) was simply calculated by adding the EBRT dose and the rectal dose (sum of EBRT and total ICRU rectal dose), while the cumulative rectal biologically equivalent dose (CRBED) was derived using a linear quadratic model by adding the BED of EBRT and HDRICB together. The parametrial boost was not included in either of these calculations because midline blocking shielded the rectum. The CRD (EBRT + total ICRU rectal dose) and the CRBED were calculated for each patient using the linear-quadratic formula as described in Fowler’s review (7).
As the rectum is late-reacting tissue, an 
/ß of 3 is used in the calculations. The CRBED is then calculated using the equation
CRBED = BEDEBRT + BEDICRT= nd[1 + (d/3)] + r1[1 + (r1/3)] + r2[1 + (r2/3)] + r3[1 + (r3/3)] + r4[1 + (r4/3)]
where n = EBRT treatment number, d = EBRT fraction size (Gy) and r = ICRU reference rectal dose for each insertion (Gy).
Statistical Analysis
Patient survival was measured from the date of the initiation of therapy to the date of the last follow-up examination. The survival rate was determined using the Kaplan–Meier method. The statistical significance between the survival curves was calculated by the log-rank test. The two groups were compared for patient characteristics and chronic-complication rates using the chi-squared test, and the logistic regression method was used for analysis of factors affecting EBRT tumor response.
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Survival
The actuarial survival (AS), cause-specific survival (CSS), pelvis relapse-free survival (PRFS) and distant metastasis-free survival (DMFS) are depicted in Figs 1, 2, 3 and 4 and listed in Table 3. The respective 5-year AS for the older and younger groups was 82/85% for stage Ib, 65/65% for IIa, 61/71% for IIb and 35/59% for IIIa–b. Although the AS for the older patients was lower than that for the younger analogs, there was no statistically significant difference between the two groups (P = 0.1). Thirteen of 79 (16.6%) older patients died of concurrent disease, compared with six of 179 (3.6%) of the younger patients. Concurrent medical problems and causes of death other than cancer are listed in Table 4.
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The 5-year CSS for the older and younger groups was 100/95% for stage Ib, 85/75% for IIa, 78/72% for IIb and 42/61% for IIIa–b. There was no statistically significant difference between the two groups according to stage.
The 5-year PRFS for the older and younger groups was 100/100% for stage Ib, 91/93% for IIa, 91/90% for IIb and 67/80% for IIIa–b. The 5-year DMFS for the older and younger groups was 100/100% for stage Ib, 92/88% for IIa, 84/73% for IIb and 55/75% for IIIa–b. No statistically significant difference was demonstrated for PRFS and DMFS between the two groups according to stage.
Tumor response to EBRT was better for the older group (NRT 44.3%) than for the younger group (NRT 24.5%; P = 0.001), and the impact of other parameters, such as clinical stage, initial Hb level and interval between EBRT and HDRICB, are listed in Table 5. The 5-year CSS of the 35 NRT patients in the older group was 88% and that of the 44 GRT patients was 64% (P = 0.001).
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In the older group, the 5-year CSS for the 3 and 4 fraction HDRICB schedule was 76/77% (P = 0.65), while the 5-year PRFS for the same schedule was 86/89% (P = 0.56), respectively. In the younger group with IIIa–b disease, the impact of adjuvant chemotherapy to survival is summarized in Table 6.
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Complications
Only three patients developed acute RTOG grade 3–4 gastrointestinal complications, two in the older group and one in the young group. Table 7 summarizes the radiation-related chronic complications in this study. Nineteen (24.1%) of the 79 older patients and 47 (26.3%) of the 179 younger patients developed RTOG grade 1–4 rectal complications, while 12 (15.0%) of the 79 older patients and 14 (7.8%) of the 179 younger patients developed RTOG grade 3–4 rectal complications. No statistically significant difference was demonstrated between the two groups for incidence of grade 3–4 rectal complications (P = 0.12). The median time for the development of rectal complications was 12 months (range, 8–22 months) after radiotherapy. Seven (8.9%) of the 79 older patients and 10 (5.6%) of the 179 younger patients developed RTOG grade 3–4 small bowel complications (P = 0.34). Two (2.5%) of the 79 older patients and four (2.2%) of the 179 younger patients developed RTOG grade 3–4 bladder complications (P = 0.39). Three (3.8%) of the 79 older patients and 12 (6.7%) of the 179 younger patients developed lower-leg edema. Two patients in the older group had avascular necrosis of the femoral head and underwent total hip replacement.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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HDRICB has been widely used in Asia and Europe, despite its questionable radiobiological efficacy (1). The risk of late complications shortens the therapeutic window for radiation treatment using a combination of EBRT and HDRICB. Although many investigators have assessed the association of age and outcome for RT patients (8–10), there are only a few reports investigating patients >70 years of age (2–5). All these studies, however, investigated the relationship between outcome and low dose-rate brachytherapy, with none exploring the effectiveness or tolerance to HDRICB treatment in for older patients.
Concomitant medical disease is present in many older patients, often resulting in diminished tolerance, slower recovery and reduced life expectancy after RT treatment (2,3). It is necessary, therefore, that older patients should be managed more carefully during treatment to minimize acute and chronic complications, especially when combination EBRT and HDRICB treatment is given. Kennedy et al. reported that 78% of patients aged 75 years have pre-existing medical problems (4). Mitsuhashi et al. reported that 52.4% of their elderly patients were suffering from a concomitant chronic illness (3). In our study, 40 of the 79 older patients (50.6%) had associated medical disease, with all patients completing the allocated treatment schedule.
In our stage I–II patients, AS, CSS, PRFS and DMFS were comparable in the two groups. For patients with stage III disease, however, there was a tendency for inferior survival rates in the older group. The reduced AS in the older group may be a consequence of the higher concurrent deaths (16.6%) compared with the younger group (3.6%). By contrast, although the older stage III patients achieved higher NRT (43.8%) than the younger group (21.2%) during the first HDRICB, CSS in the elderly was still inferior. There are two possible explanations for the failure to demonstrate survival benefit despite the tumor response to EBRT. First, more patients with stage III disease may ultimately develop a distant metastasis (5-year DMFS: older 55%, younger 75%; P = 0.06). Second, a relatively high incidence of grade 3–4 gastrointestinal complications was noted for the older patients.
Our data reveal that, compared with the younger patients, the older patients had a higher proportion of NRT. Hong et al. reported that 83% of patients aged 65 years achieved NRT after EBRT, compared with only 55% of patients <40 years (11). More studies are required to elucidate further the reason why older patients achieve superior rates of NRT response.
Twelve (15%) and seven (8.9%) of the 79 older patients experienced grade 3–4 rectal and small bowel complications in our study, with a tendency towards greater rates of gastrointestinal complications for that group. The Point A dose was modified to 5 Gy for patients >70 years of age in our treatment strategy. However, the median CRD and median CRBED for the younger and older groups were 60.6 Gy/116.3 Gy3 and 60.4 Gy/112.3 Gy3, respectively. The reason why no significant between-group difference in rectal dose was observed may be that older patients had a smaller vagina. Perez et al. reported that age >65 years was not significantly associated with incidence of gastrointestinal or urinary complications (10). They suggested that this might be partially related to the fact that older patients in their study were treated with slightly lower doses of EBRT and ICRT. Mitsuhashi et al. reported that 9.5% of patients aged >70 years had been diagnosed with grade 3–4 rectal complications (3), while Sakurai et al. reported rates for grade 3–4 rectourinary complications of 11.3 and 7.3% for the 70–79 and >80 age groups, respectively (5).
Of the other HDR treatment studies, Akine et al. (12), Chen et al. (13) and Teshima et al. (14) reported that 26.4, 36 and 27% of patients, respectively, developed late rectal complications. In our study, the incidence of late rectal complications for the older patients was 19/79 (24.1%) and 12/79 (15%) for grade 1–4 and grade 3–4, respectively. Since 63.1% (12/19) of the rectal complications were scored as grade 3–4, however, it seems reasonable to suggest that the cumulative rectal dose for this group of patients is lowered once the CRD or CRBED are exceeded. As has been suggested in a previous study (15), if the probability of development of late rectal complication needs to be maintained at <20%, the CRD/CRBED should be kept below 65 Gy/110 Gy.
As recurrence after complete remission of carcinoma of the uterine cervix is difficult to cure, it is imperative that an adequate radiation dose be delivered to achieve maximum tumor control while minimizing complications. First, a once-weekly HDRICB schedule can be modified to twice-weekly with reduction of prescribed dose to Point A. Hama et al. reported that patients treated with a twice-weekly HDRICB regimen (4.5 Gy to Point A twice per week) had a better rate of local recurrence-free survival and a lower incidence of late grade 2–3 complications compared with patients treated with a once-weekly HDRICB schedule (7 Gy to Point A per week) (16). Second, the median treatment duration for the older patients was 69 days, and it is possible that the very prolonged treatment time may have resulted in inferior survival. Girinsky et al. reported a loss of tumor control and survival where the treatment time exceeded 52 days for 386 stage IIb–III patients (17), with a daily 1.1% loss of pelvic control demonstrated. Further, Petereit et al. demonstrated reduced survival and pelvic control where the treatment time exceeded 55 days (18), with respective daily diminutions of 0.67% and 0.76% derived from their analysis. Finally, although we cannot draw conclusions about the role of adjuvant chemotherapy for younger patients with stage III disease from this retrospective analysis, the introduction of randomized study is imperative to elucidate the role of chemotherapy for the both younger and older groups with advanced cervical cancer. As has been suggested in recent studies (19,20), concurrent chemotherapy and radiotherapy may be more effective than radiation alone in terms of distant metastasis and survival rate.
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CONCLUSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Radiation therapy with EBRT combined with 3–4 fractions of HDRICB was well tolerated by elderly patients and proved effective for FIGO stage I–II disease. Although a good response to EBRT was achieved for the older patients independent of stage, treatment policy for older patients should be optimized by changing the HDRICB fractionation strategy, shortening the treatment time and designing combination drug regimens that are both effective and tolerable during radiotherapy.
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FOOTNOTES |
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+ For reprints and all correspondence: Fang-Jen Lin, Department of Radiation Therapy and Oncology, China Medical College Hospital No. 2, Yuh-Der Road, Taichung, Taiwan 404. E-mail: vincent1680616{at}yahoo.com.tw
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REFERENCES |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Received December 13, 2002; accepted March 31, 2003
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