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Keywords:

  • cervical carcinoma;
  • squamous cell carcinoma;
  • radiotherapy;
  • high-dose rate brachytherapy

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

BACKGROUND

The authors performed a long-term follow-up study to evaluate the efficacy and late toxicity of high-dose rate intracavitary brachytherapy (HDR-ICBT) for cervical carcinoma.

METHODS

From 1968 to 1986, 1148 patients with Stage IB to IVB squamous cell carcinoma of the cervix (staging was performed according to the International Federation of Gynecology and Obstetrics) were treated with a combination of external beam radiotherapy (EBRT) and HDR-ICBT. For patients with early-stage disease, 20 gray (Gy) of EBRT was delivered to the whole pelvis, followed by 24 Gy/4 fractions of HDR-ICBT and 30 Gy of central-shielding EBRT. For patients with advanced-stage disease, 20–40 Gy of whole pelvic EBRT was administered, followed by 24 Gy/4 fractions of ICBT and 30–10 Gy of central-shielding EBRT. The overall treatment time was approximately 6 weeks. Among survivors, the follow-up rate was 98% and the median follow-up duration was 22 years.

RESULTS

The 10-year pelvic tumor control rates were 93% for patients with Stage IB disease, 82% for patients with Stage II disease, and 75% for patients with Stage III disease. The 10-year overall and cause-specific survival rates were 74% and 89% for patients with Stage IB disease, 52% and 74% for patients with Stage II disease, and 42% and 59% for patients with Stage III disease, respectively. The 10-year actuarial rates of major complications were 4.4% in the rectosigmoid colon, 0.9% in the bladder, and 3.3% in the small intestines.

CONCLUSIONS

The results of the current study suggest that the combination of EBRT and HDR-ICBT according to the authors' protocol provided outcomes that were comparable to those of the conventional low-dose rate brachytherapy with acceptable rates of late complications in the treatment of cervical carcinoma. Cancer 2005. © 2004 American Cancer Society.

The combination of external beam radiotherapy (EBRT) and intracavitary brachytherapy (ICBT) is considered to be one of the standard treatments for carcinoma of the uterine cervix. ICBT has the advantage of delivering a very high dose to the central tumor and a lower dose to the surrounding normal structures, such as the bladder and rectum, resulting in high local control while minimizing normal tissue damage. Cervical carcinoma traditionally has been treated with low-dose rate intracavitary brachytherapy (LDR-ICBT). This modality, however, has some drawbacks such as radiation exposure to medical personnel, physical and psychologic stress to patients because of the long treatment time, and difficulty in maintaining good applicator geometry during treatment. High-dose rate intracavitary brachytherapy (HDR-ICBT) was developed by Henschke et al.1 and O'Connell et al.2 in 1964 to overcome these drawbacks.

The greatest concern of HDR-ICBT is its late toxicity. Treatment with large HDR fractions reduces the potential for recovery of sublethal normal tissue injury and may, therefore, narrow the therapeutic ratio between tumor control and late complications. To achieve equivalent disease control to that achieved with LDR treatment without increasing the risk of late complications, various dosages and fractionation schedules of HDR-ICBT have been examined. Several studies, including nonrandomized3–9 and randomized10–12 clinical trials, have demonstrated that HDR-ICBT was comparable to LDR-ICBT in terms of local control, survival, and morbidity rates. However, various fractionation schedules exist, and the optimum dose and fractionation schedule of ICBT and the appropriate combination of EBRT and ICBT remain controversial issues.13

A long-term follow-up study is of great importance in determining the optimum radiotherapy, because late complications continue to occur for many years after irradiation. However, to our knowledge there have been only a very few studies published to date in which disease status and late complications were monitored for > 10 years after treatment, although HDR-ICBT has been used extensively in Asia and Europe for > 3 decades.3–5, 7–12 Therefore, the safety of HDR treatment has not been investigated thoroughly.

Because the HDR remote afterloading system was installed in the National Institute of Radiological Sciences (NIRS) in 1968, we, as one of the pioneers of HDR-ICBT, have attempted to establish the optimum radiotherapy regime for cervical carcinoma. First, a clinical study was performed to demonstrate the correlation between the optimum dose range and the fractionation of HDR-ICBT.14, 15 From the results, a treatment protocol was initiated. Treatment results of this protocol were comparable to those of the conventional LDR-ICBT. Based on these results, guidelines for the radiotherapy protocol were established in Japan in 1987 to standardize the treatment.16 To evaluate the treatment effect and late radiation toxicity, we have carefully followed up patients for > 20 years. The treatment results were reported in 1992.4 The current study updates the previous publication and provides follow-up results covering > 20 years.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Patients

From 1968 to 1986, 1148 patients with histologically confirmed squamous cell carcinoma of the uterine cervix were treated with radiotherapy alone at NIRS. Patients with other histologies were excluded from the study. None of the patients had undergone any surgical procedures including pelvic lymphadenectomy. Pretreatment evaluation was comprised of an assessment of the patient's history, physical and pelvic examinations by gynecologists and radiation oncologists, cervical biopsy, routine blood cell counts, chemistry profile, chest X-ray, and intravenous urography. Lymphangiography, cystoscopy, and proctoscopy were performed only when clinically indicated. Computed tomography (CT) scans of the abdomen and pelvis have been performed since 1976. The mean age of the patients was 60 years (range, 25–95 years). All patients were staged according to the International Federation of Gynecology and Obstetrics (FIGO) staging system. One hundred forty-six patients had Stage IB disease, 44 patients had Stage IIA disease, 261 patients had Stage IIB disease, 9 patients had Stage IIIA disease, 545 patients had Stage IIIB disease, 72 patients had Stage IVA disease, and 71 patients had Stage IVB disease. The cervical tumor size was determined from clinical descriptions and tumor diagrams, and was classified into 3 categories (< 3 cm, 3–5 cm, and > 5 cm; Table 1).

Table 1. Distribution of Patients According to Disease Stage and Tumor Size
Disease stageNo. of patientsTumor size (%)
< 3 cm3–5 cm> 5 cm
IB146 88 (60) 57 (39)  1 (1)
IIA44 94 (31)180 (59) 31 (10)
IIB261
IIIA9 57 (10)374 (68)123 (22)
IIIB545
IVA72 13 (9) 82 (57) 48 (34)
IVB71
Total1148252 (22)693 (60)203 (18)

Radiotherapy

Patients were treated with a combination of EBRT and HDR-ICBT. EBRT was delivered to the pelvis through anterior and posterior parallel-opposed portals using 10-megavolt (MV) X-rays or 60Co γ-rays. The common field borders were at the interspace of the L4–5 vertebrae superiorly, at the inferior border of the obturator foramen inferiorly, and at 1–2 cm lateral to the bony pelvis. When central shields were inserted during EBRT, they usually were 4-cm wide in the lower half of the field and 2-cm wide in the upper half of the field. The total dose to be delivered to the parametrium and pelvic lymph nodes was 45–50 grays (Gy), given at a dose of 1.8–2 Gy per fraction, 5 fractions per week. When patients had bulky parametrial tumors or macroscopic lymph node metastases, an additional 10–15 Gy was applied to boost the external dose to a total of 60–65 Gy.

HDR-ICBT was performed using 60Co sources. The source arrangement, irradiation conditions, and dose distribution were based on the Manchester system. Point A was defined on the X-ray as being 2 cm superior to the external os, and 2 cm lateral from the axis of the intrauterine tandem. HDR-ICBT was performed 1 fraction a week, with a standard prescribed dose to Point A of 5–6 Gy per fraction, for a total dose of 3–5 fractions.

The treatment protocol according to disease stage and tumor size is shown in Table 2. For patients with early-stage diseases, 20 Gy of EBRT was delivered to the whole pelvis, followed by 24 Gy/4 fractions of HDR-ICBT and 30 Gy of central-shielding EBRT. Some small tumors (usually < 3 cm in diameter) were treated with 29 Gy/5 fractions of ICBT and 45–50 Gy of central-shielding EBRT. For patients with advanced-stage diseases, 20–40 Gy of EBRT was delivered to the whole pelvis according to disease stage and tumor volume, followed by 24 Gy/4 fractions of ICBT and 10–30 Gy of central-shielding EBRT, when treated with curative intent. ICBT was performed concurrently with EBRT. The overall treatment time was approximately 5–6 weeks in the majority of patients.

Table 2. Standard Treatment Protocols for Cervical Carcinoma
Disease stage (tumor size)EBRT (Gy)ICBT (Gy/fr)BED Gy10 (tumor)BED Gy3 (late effect)
WPCSPoint A
  1. EBRT: external beam radiotherapy; ICBT: intracavitary brachytherapy; Gy: gray; fr: fraction; WP: whole pelvis; CS: central shielding; BED: biologically effective doses.

IB/II (small)0–2030–5029/5–24/446–6259–83
II (medium to large)/III (small)20–3020–3024/462–7483–100
III (medium to large)30–4015–2515/3–24/471–8695–117
IVA40–5010–2515/3–24/471–9895–133

To compare the different dose fractionation schemes in the literature, the biologically effective dose (BED) was calculated using the linear quadratic model.17, 18 The BED for tumor effect was calculated on the basis that α/β = 10 Gy (BED Gy10). The BED for late tissue effects was calculated on the basis that α/β = 3 Gy (BED Gy3). With adequate packing, the rectum and bladder would usually receive 60–80% of the prescribed dose to Point A at ICBT.13 Therefore, the BED Gy3 to the rectum and bladder was derived by estimating the dose to be 80% of the prescribed dose to Point A. The values of the BED Gy10 and BED Gy3 for each treatment are shown in Table 2.

Follow-Up

After completion of radiotherapy, patients were followed up monthly for 1 year; every 2 months during the second year; every 3 or 4 months in Years 3, 4, and 5; and once or twice a year thereafter. To evaluate the disease status and late complications, > 70% of the patients were admitted to the hospital for 1 or 2 days, at 1 year, 3 years, and 5 years after treatment. The examination consisted of a physical examination, routine blood cell counts, chemistry profile, chest X-ray, intravenous urography, cystoscopy, proctoscopy or barium enema, and CT scan of the abdomen and pelvis. Suspected persistent or recurrent disease was confirmed with a biopsy whenever possible. Treatment failures were classified as pelvic recurrences or distant metastases. Late radiation complications were graded according to the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer (RTOG/EORTC) late radiation morbidity scoring scheme.19 The median follow-up time in surviving patients was 22 years. Information concerning disease status, late complications, and causes of death was available for 98% of the patients either from institutional records, through letter or telephone contact directly with the patients or her relatives, or through communication with the referring physicians.

Statistical Analysis

Survival was measured from the date of initiation of therapy to the date of death or the most recent follow-up. The time to disease recurrence in the pelvis was measured from the date of initiation of therapy to the date of the first disease recurrence in the primary cervical tumor or pelvic lymph nodes. The pelvic tumor control rates (PC) and overall survival rates (OS) were calculated using the actuarial life-table method. Because of the large proportion of older patients and the long follow-up period, many deaths were not caused by cervical carcinoma. Therefore, we also estimated the cause-specific survival rate (CSS) on the basis of available information on the cause of death. For calculation of CSS, deaths owing to cervical carcinoma, deaths resulting directly from treatment-related complications, and deaths occurring from unknown causes > 5 years after treatment were scored as events. Rates of late complications were also calculated using the life table method. In calculating actuarial complication rates, patients who died without complications were censored at the time of death, and surviving patients without complications were also censored at the date of the last follow-up.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Outcomes

Status at the time of last follow-up for all patients is listed in Table 3. For the 902 patients who died before December 2003, 399 patients died of cervical carcinoma, 22 died of late radiation complications, 82 of second primary tumors, 339 of unrelated or other diseases, and 60 of unknown causes.

Table 3. Status at Time of Last Follow-Up
Status and cause of deathNo. of patients (%)
Dead902 (78.6)
 Cervical carcinoma399
 Complications of radiotherapy22
 Second primary tumor82
 Unrelated or other diseases339
 Unknown causes60
Alive223 (19.4)
Lost to follow-up23 (2.0)

Patterns of disease recurrence by stage are shown in Table 4. The overall incidence of pelvic recurrence was 7% for Stage IB disease, 18% for Stage II disease, 24% for Stage III disease, and 39% for Stage IV disease. The overall incidence of distant metastases was 7% for Stage IB disease, 14% for Stage II disease, 25% for Stage III disease, and 58% for Stage IV disease.

Table 4. Patterns of Disease Recurrence by Disease Stage
Disease stageNo. of patientsPelvic recurrence only (%)Pelvic and distant metastases (%)Distant metastasis only (%)Total pelvic recurrence (%)
IB1467 (5)3 (2)7 (5)10 (7)
II30542 (14)11 (4)31 (10)53 (18)
III55493 (17)37 (7)100 (18)130 (24)
IV14329 (20)27 (19)56 (39)56 (39)
Total1148171 (15)78 (7)194 (17)249 (22)

The 5-year and 10-year OS rates were 88% and 74%, respectively, for Stage IB disease, 69% and 52%, respectively, for Stage II disease, 56% and 42%, respectively, for Stage III disease, 21% and 17%, respectively, for Stage IVA disease, and 10% and 4%, respectively, for Stage IVB disease (Fig. 1). The 5-year and 10-year CSS rates were 94% and 89%, respectively, for Stage IB disease, 80% and 74%, respectively, for Stage II disease, 66% and 59%, respectively, for Stage III disease, 32% and 32%, respectively, for Stage IVA disease, and 12% and 5%, respectively, for Stage IVB disease (Fig. 2). The 10-year PC rates were 93% for Stage IB disease, 82% for Stage II disease, and 75% for Stage III disease, respectively.

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Figure 1. Overall survival rates by disease stage.

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Figure 2. Cause-specific survival rates by disease stage.

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Table 5 summarizes the 10-year PC and CSS rates of patients grouped according to stage and cervical tumor size. The 10-year PC rate for different tumor sizes ranged from 71% to 87% for patients with Stage II disease and 62% to 87% for patients with Stage III disease. The 10-year CSS rate ranged from 53% to 79% for patients with Stage II disease and from 46% to 77% for patients with Stage III disease. There was a significant difference between tumor size and treatment outcome for patients with Stage II and III disease.

Table 5. Relation among Stage, Tumor Size, and Treatment Outcomesa
  • a

    Comparison of treatment outcomes between (a) patients with tumors < 3 cm and those with tumors 3–5 cm, (b) patients with tumors 3–5 cm and those with tumors > 5 cm, and (c) patients with tumors < 3 cm and those with tumors > 5 cm. Comparisons were made using generalized Wilcoxan test.

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Late Complications

One hundred eighty-four patients developed late complications of the rectosigmoid colon, 151 of the bladder, and 87 of the small intestines during the 20-year follow-up period. Major (RTOG/EORTC Grade 3–5) complications of the rectosigmoid colon, the bladder, and the small intestines were observed in 35 patients, 8 patients, and 42 patients, respectively.

The actuarial rates of rectosigmoid colon complications at 5 years, 10 years, and 20 years were 21%, 22%, and 23%, respectively. Most of these complications occurred within the first 3 years of follow-up, after which the incidence decreased markedly. In contrast, the incidence of bladder complications was somewhat greater during the first 2–4 years, but continued to occur for ≥ 20 years after irradiation. The corresponding rates of bladder complications were 14%, 18%, and 24%, respectively. The corresponding rates of complications of the small intestines were 6%, 9%, and 16%, respectively. The incidence of complications of the small intestines within the first 5 years was lower compared with those of rectosigmoid colon and bladder complications. Nevertheless, they occurred fairly constantly for ≥ 20 years after irradiation (Fig. 3). With regard to major complications, the 5-year, 10-year, and 20-year actuarial rates of rectosigmoid colon complications were 3.8%, 4.4%, and 5.3%, respectively. The corresponding rates of bladder complications were 0.8%, 0.9%, and 1.3%, respectively. Most occurred within the first 5 years of follow-up. In contrast, the corresponding rates of major complications of the small intestines were 2.6%, 3.3%, and 8.3%, respectively, indicating that the major complications of the small intestines continued to occur for > 20 years after irradiation (Fig. 4).

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Figure 3. Actuarial rates of late complications of the rectosigmoid colon, the bladder, and the small intestines (all grades).

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Figure 4. Actuarial rates of major complications of the rectosigmoid colon, the bladder, and the small intestines.

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DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

We have treated patients with cervical carcinoma with a combination of EBRT and HDR-ICBT according to the standard protocol used for > 30 years. To evaluate the treatment effect and late radiation morbidity, we have carefully followed up the patients. The follow-up rate of 98% with a median follow-up duration of 22 years reported in the current series was considered to be adequate for evaluation of the treatment. To our knowledge, few reports published to date have described the long-term follow-up results of HDR-ICBT for cervical carcinoma, as has the current study.

The optimum dose and fractionation schedule of HDR-ICBT and the appropriate combination of EBRT and ICBT are controversial issues.13 In 2000, the American Brachytherapy Society (ABS) made recommendations for EBRT and HDR-ICBT for cervical carcinoma.20 The recommended doses are as follows. For patients with early disease, 20 Gy or 45 Gy of EBRT is delivered to the whole pelvis, and 45 Gy/6 fractions or 30 Gy/5 fractions of ICBT is given to Point A (BED = 101–102 Gy10). For patients with advanced-stage disease, 45 Gy or 50.4 Gy of EBRT is delivered to the whole pelvis, and 32.5 or 30 Gy/5 fractions of ICBT is given to Point A (BED = 107–108 Gy10). These doses and fractionation schedules are based on the concept that the Point A dose, which is biologically equivalent to the standard LDR treatment21 of 80–85 Gy (BED = 96–102 Gy10), should be delivered to patients with early-stage disease, and 85–90 Gy (BED = 102–108 Gy10) should be delivered to patients with advanced-stage disease. However, to our knowledge, these doses and fractionation schedules have not been thoroughly tested clinically.

The doses delivered to Point A in the current series were much lower than these recommended levels, a finding that has been a cause of criticism.13 In the current series, patients with early-stage diseases received either 29 Gy/5 fractions of ICBT or 20 Gy of whole-pelvic EBRT and 24 Gy/4 fractions of ICBT at Point A (BED = 46–62 Gy10). Patients with advanced-stage diseases received 20–40 Gy of whole-pelvic EBRT and 24 Gy/4 fractions of ICBT at Point A, when treated with curative intent (BED = 62–86 Gy10). These treatment regimens produced a favorable outcome, with the 5-year PC and OS rates of 94% and 88%, respectively, reported for patients with Stage IB disease, 84% and 69%, respectively, reported for patients with Stage II disease, and 76% and 56%, respectively, reported for patients with Stage III disease (Fig. 1). Several other HDR series utilized similar Point A doses (BED = 46–77 Gy10 for early-stage disease, and 67–86 Gy10 for advanced-stage disease), and they also achieved similar results.7, 10, 12 In the large LDR series, the 5-year PC and OS rates were approximately 90% and 80%, respectively, for patients with Stage IB disease, 70–80% and 60–70%, respectively, for patients with Stage II disease, and 50–70% and 30–50%, respectively, for patients with Stage III disease.22–26 The outcomes achieved in the current series therefore were comparable to those of the large LDR series.

The strong correlation between tumor size and treatment outcome is well documented.5, 22–26 The variation of treatment results among the different reports may be due to the wide range of tumor sizes, even for patients with the same stage of disease. The number of bulky tumors in our patient population was relatively small compared with the number of tumors in the American and European series,22, 23 and this might account for the more favorable outcome. In the current series, the 10-year PC and CSS rates for different tumor sizes ranged from 71% to 87% and from 53% to 79%, respectively, for patients with in Stage II disease, and from 62% to 87% and from 46% to 77%, respectively, for patients with Stage III disease (Table 5). When adjusted by stage and tumor size, our results again were comparable to those of the large LDR series.22–26

Petereit and Pearcey13 have pointed out that the Point A doses in the current series were less than tumoricidal. However, the sharp dose gradient of ICBT should be taken into account when evaluating the dose response in cervical carcinoma.7 Because of this gradient, a substantially higher dose is delivered to the central tumor inside Point A rather than to Point A itself after irradiation with ICBT. A tumor outside Point A receives a lower dose with ICBT, but it receives an additional dose of ≥ 50 Gy with EBRT. Therefore, the Point A dose is not always the minimum target dose. In the future, it is important to correlate the three-dimensional dosimetry, especially the isodose line that encompasses the gross tumor volume based on CT or magnetic resonance imaging scan, with the tumor control outcome.20, 21

It is well recognized that overall treatment time is one of the important prognostic factors in patients with cervical carcinoma treated with radiotherapy. Several studies have demonstrated a significant decrease in PC and OS rates when overall treatment time increased beyond 6 weeks.27, 28 In the conventional LDR treatment, the overall treatment time is usually 7–9 weeks.22–26 In some HDR series, the overall treatment time was > 8 weeks, because 4–5 fractions of HDR-ICBT were performed only after delivering 40–45 Gy of EBRT.5, 8 In contrast, most of the patients in the current study were treated for a period within 6 weeks. The first ICBT was initiated as soon as possible to avoid the negative impact of treatment prolongation. Therefore, taking into account the effect of radiation biology on the overall treatment time, our treatment may be more intensive than the other treatments, even though the Point A doses are relatively lower.

In the current series, the 5-year actuarial rates of late complications of the rectosigmoid colon, bladder, and small intestines were 21%, 14%, and 6%, respectively (Fig. 3). Most of these complications were classified as Grade 1–2, and the 5-year rates of major complications were 3.8%, 0.8%, and 2.6%, respectively (Fig. 4). Hareyama et al.10 reported the 5-year major complication rates of 3.5% in the rectum, 4.0% in the bladder, and 2.4% in the small bowel in patients treated with doses similar to those that we used. In the large LDR series, the 5-year overall major complication rates ranged from 10% to 17%, and 50–70% of them were lower gastrointestinal tract complications.24, 25, 29 Hence, compared with these studies, the complication rates of the current study are considered to be acceptable.

It has been asserted that late radiation complications generally occur within the first 2–4 years after treatment.8, 25, 30 In a few studies however, late complications occurring after > 10 years of treatment have been observed. In the current series, rectosigmoid colon complications occurred most frequently during the first 2 years, after which the incidence decreased markedly. In contrast, complications of the bladder and small intestine continued to occur for ≥ 20 years after irradiation (Figs. 3 and 4). Eifel et al.29 reported similar results from their study. These results suggest that a long-term follow-up period is of great importance for the diagnosis and management of late complications and for the proper evaluation of the treatment.

Several investigators have analyzed the relation between the incidence of late complications and the dose to the rectum and bladder. In their LDR series, Perez et al.30 and Pourquier et al.31 demonstrated a positive correlation between a dose to the rectum and bladder of > 80 Gy and severe complications. They reported that the rates of Grade 2 and 3 complications in the urinary tract and rectosigmoid colon were approximately 5% with doses < 75–80 Gy. From these results, the ABS recommended that attempts should be made to keep the total bladder dose at < 80 Gy and the total rectal dose at < 75 Gy21 (BED = 125–134 Gy3). Some investigators also have analyzed in their HDR studies the relation between the incidence of late complications and the dose to the rectum. Clark et al.32 reported that the BED at the rectal reference point was correlated significantly with the incidence of late rectal complications, and they found a threshold of 125 Gy3 at the rectal reference point for severe complication. Ogino et al.33 demonstrated that the calculated incidence of major rectal complications ranged from 5–10% at BED from 119 to 146 Gy3. The BED at the rectum and bladder in our treatment ranged from 59–133 Gy3 (Table 2). Therefore, the low incidence of major complications noted in the current series is considered to be mainly due to the low BED at the rectum and bladder.

The combination of EBRT and HDR-ICBT, as used in the current series, has yielded results comparable to the conventional LDR treatment with acceptable rates of late complications in the treatment of patients with cervical carcinoma. It is worthwhile to investigate the efficacy and toxicity of concurrent cisplatin-based chemotherapy with radiotherapy34–37 using HDR-ICBT according to our treatment schedules for patients with advanced stage cervical carcinoma.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
  • 1
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