High-dose-rate afterloading brachytherapy in carcinoma of the uterine cervix

The Brachytron has been used in the University of California at San Diego Medical Center since 1970 as one method of treating gynecological malignancies. This machine contains a high intensity cobalt 60 remote afterloading cycling source used for intracavitary brachytherapy. One hundred twenty-seven patients with epithelial carcinoma of the cervix are available for analysis of 5-year survival, and 176 are analyzed for treatment complications two years following therapy. Five year survival figures for FIGO-staged patients treated with external beam pelvic irradiation and intracavitary Brachytron treatments are as follows: Stage I, 89%; Stage II, 58%; Stage III, 33%, and two of five patients Stage IVa. Rectal complications graded moderate or severe (M, S) were dose-related and gradually decreased over the years as techniques improved. Complications from early results in 1970-1972 (24% M, 10% S) were reduced to lower levels in 1976-1979 (14% M, 4% S). The Brachytron offers the advantage of rapid dose delivery. Thus, patients can be treated in an outpatient setting, avoiding the cost of hospitalization and the risks of anesthesia. The Brachytron also offers virtually complete radiation safety to all attending medical personnel. With survival and complication figures similar to those reported for patients treated with conventional low-dose-rate brachytherapy, the Brachytron represents an effective alternate mode of therapy for uterine carcinoma.     

High-dose-rate intracavitary brachytherapy: results of analyses of late rectal complications

: To examine the incidence of radiation-induced late rectal complications by analyzing the data of measured rectal doses in patients with cancer of the uterine cervix treated with high-dose-rate intracavitary brachytherapy.

: We measured doses to the rectum in 105 patients with cancer of the cervix during high-dose-rate intracavitary brachytherapy with a semiconductor dosimeter that can measure five points in the rectum simultaneously. On the basis of these measurements, equivalent doses, to which the biologically equivalent doses were converted as if given as fractionated irradiation at 2 Gy/fraction, were calculated as components of the cumulative dose at five rectal points in intracavitary brachytherapy combined with the external whole pelvic dose.

: The calculated values of equivalent doses for late effects at the rectum ranged from 15 to 100 Gy (median 60 Gy for patients who did not develop complications and 76 Gy for patients who subsequently developed Grade II or III complications). When converted to a graph of absolute rectal complication probability, the data could be fitted to a sigmoid curve. The data showed a very definite dose-response relationship, with a threshold for complications at approximately 50 Gy and the curve starting to rise more steeply at approximately 60 Gy. The steepest part of the curve had a slope equivalent to approximately 4% incidence/1 Gy increase in equivalent doses.

: The radiation tolerance dose, 5% and 50% complication probability, was about 64 and 79 Gy, respectively. Our data almost agree with the prescribed dose for the rectum for the radiation tolerance doses on the basis of the recorded human and animal data. The probability of rectal complications increased drastically after the maximal rectal dose was >60 Gy.     

High-dose-rate brachytherapy in the treatment of uterine cervix cancer. Analysis of dose effectiveness and late complications

This retrospective analysis aims to report results of patients with cervix cancer treated by external beam radiotherapy (EBR) and high-dose-rate (HDR) brachytherapy.

From September 1992 to December 1996, 138 patients with FIGO Stages II and III and mean age of 56 years were treated. Median EBR to the whole pelvis was 45 Gy in 25 fractions. Parametrial boost was performed in 93% of patients, with a median dose of 14.4 Gy. Brachytherapy with HDR was performed during EBR or following its completion with a dose of 24 Gy in four weekly fractions of 6 Gy to point A. Median overall treatment time was of 60 days. Patient age, tumor stage, and overall treatment time were variables analyzed for survival and local control. Cumulative biologic effective dose (BED) at rectal and bladder reference points were correlated with late complications in these organs and dose of EBR at parametrium was correlated with small bowel complications.

Median follow-up time was 38 months. Overall survival, disease-free survival, and local control at 5 years was 53.7%, 52.7%, and 62%, respectively. By multivariate and univariate analysis, overall treatment time up to 50 days was the only statistically significant adverse variable for overall survival (p = 0.003) and actuarial local control (p = 0.008). The 5-year actuarial incidence of rectal, bladder, and small bowel late complications was 16%, 11%, and 14%, respectively. Patients treated with cumulative BED at rectum points above 110 Gy₃ and at bladder point above 125 Gy₃ had a higher but not statistically significant 5-year actuarial rate of complications at these organs (18% vs. 12%, p = 0.49 and 17% vs. 9%, p = 0.20, respectively). Patients who received parametrial doses larger than 59 Gy had a higher 5-year actuarial rate of complications in the small bowel; however, this was not statistically significant (19% vs. 10%, p = 0.260).

This series suggests that 45 Gy to the whole pelvis combined with four fractions of 6 Gy to point A with HDR brachytherapy is an effective and safe fractionation schedule in the treatment of Stages II and III cervix cancer if realized up to 50 days. To decrease the small bowel complications, we decreased the superior border of the parametrial fields to the S2-S3 level and the total dose to 54 Gy.     

Treatment results of high-dose-rate remote afterloading brachytherapy for cervical cancer and retrospective comparison of two regimens

PURPOSE: To review the treatment results and complications of high-dose-rate (HDR) intracavitary brachytherapy for patients with carcinoma of the cervix in a single institute and to compare them with those of low-dose-rate (LDR) brachytherapy reported in the literature. METHODS AND MATERIALS: Two hundred twenty patients with carcinoma of the cervix were treated by primary radiotherapy between 1991 and 1998. The median age was 63 (range 24-84). The distribution according to Federation of Gynecology and Obstetrics (FIGO) staging system was as follows: Stage IB, 11.4%; IIA, 9.1%; IIB, 50.9%; IIIA, 3.6%; IIIB, 23.2%; and IVA, 1.8%. They were treated with whole pelvic irradiation giving 40 Gy to the midplane in 20 fractions over 4 weeks. This was followed by parametrial irradiation, giving 16-20 Gy in 8-10 fractions. HDR intracavitary brachytherapy was given weekly, with a dose of 7 Gy to point A for three fractions and, starting from 1996, 6 Gy weekly for four fractions. The median overall treatment time was 50 days (range 42-73 days). The median follow-up time was 4.7 years (range 3 months to 11.1 years). Multivariate analysis was performed using the Cox regression proportional hazards model. RESULTS: The complete remission rate after radiotherapy was 93.4% (211/226). The 5-year actuarial failure-free survival (FFS) and cancer-specific survival (CSS) rates for stage IB, IIA, IIB, IIIA, IIIB, and IVA were 87.7% and 86.6%, 85% and 85%, 67.8% and 74%, 46.9% and 54.7%, 44.8% and 50.4%, 0% and 25%, respectively. On multivariate analysis, young age (< 50) (p = 0.0054), adenocarcinoma (p = 0.0384), and stage (p = 0.0005) were found to be independent poor prognostic factors. The 5-year actuarial major complication rates (Grade 3 or above) were as follows: proctitis, 1.0%; cystitis, 0.5%; enteritis, 1.3%; and overall, 2.8%. On multivariate analysis, history of pelvic surgery was a significant prognosticator. The two HDR fractionation schedules were not a significant prognosticator in predicting disease control and complications. CONCLUSION: Our experience in treating cervical cancer with HDR intracavitary brachytherapy is encouraging. Our treatment results and complication rates were compatible with those of the LDR series. Further studies are eagerly awaited to better define the optimal fractionation schedule for HDR brachytherapy and the schedule on how chemotherapy may be combined with it.     

Inter fraction variations in rectum and bladder volumes and dose distributions during high dose rate brachytherapy treatment of the uterine cervix investigated by repetitive CT-examinations

Purpose: To evaluate variation of dose to organs at risk for patients receiving fractionated high dose rate gynaecological brachytherapy by using CT-based 3D treatment planning and dose-volume histograms (DVH).

Materials and methods: Fourteen patients with cancer of the uterine cervix underwent three to six CT examinations (mean 4.9) during their course of high-dose-rate brachytherapy using radiographically compatible applicators. The rectal and bladder walls were delineated and DVHs were calculated.

Results: Inter fraction variation of the bladder volume (CV_mean=44.1%) was significantly larger than the inter fraction variation of the mean dose (CV_mean=19.9%, P=0.005) and the maximum dose (CV_mean=17.5%, P=0.003) of the bladder wall. The same trend was seen for rectum, although the figures were not significantly different. Performing CT examinations at four of seven brachytherapy fractions reduced the uncertainty to 4 and 7% for the bladder and rectal doses, respectively. A linear regression analysis showed a significant, negative relationship between time after treatment start and the whole bladder volume (P=0.018), whereas no correlation was found for the rectum. For both rectum and bladder a linear regression analysis revealed a significant, negative relationship between the whole volume and median dose (P<0.05).

Conclusion: Preferably a CT examination should be provided at every fraction. However, this is logistically unfeasible in most institutions. To obtain reliable DVHs the patients will in the future undergo 3–4 CT examinations during the course of brachytherapy at our institution. Since this study showed an association between large bladder volumes and dose reductions, the patients will be treated with a standardized bladder volume.     

Six fractions per week of external beam radiotherapy and high-dose-rate brachytherapy for carcinoma of the uterine cervix: A phase I/II study

PURPOSE: This study evaluated the treatment results of external beam radiotherapy administered in six fractions per week and high-dose-rate (HDR) brachytherapy for the treatment of cervical cancer. METHODS AND MATERIALS: From July 2000 to July 2003, 43 patients were enrolled in this study. The patients received 45 Gy from a 10-MV photon beam using four-field box or anterior-posterior beams. Parametrial regions and the pelvic side walls were boosted with up to 50.4 Gy using a midline block. The daily fraction dose was 1.8 Gy administered in six-weekly fractions, from Monday to Saturday. HDR brachytherapy was also delivered at doses of 24 Gy to point A in six fractions twice a week. The median follow-up time was 37 months (range, 9-60 months). RESULTS: The median overall treatment time was 51 days for all patients (range, 44-62 days). Thirty-four patients (79.1%) achieved complete remission and 8 (18.6%) achieved partial remission after radiotherapy. Locoregional recurrence occurred in 5 patients (11.6%), and a distant metastasis was encountered in 6 patients (13.9%). The 3-year overall survival, locoregional, and distant metastasis-free survival rates were 74.7%, 87.8%, and 84.7%, respectively. Grade 2 and 3 late rectal complications were encountered in 3 (6.5%) and 1 (2.2%), respectively. There were no Grade 3 late bladder complications. CONCLUSIONS: Six fractions per week of external beam radiotherapy and HDR brachytherapy is an effective treatment for patients with a carcinoma of the uterine cervix and can be used as a possible alternative to concomitant chemoradiotherapy in elderly patients or in patients with co-morbidity.     

Cancer cervix: Establishing an evidence-based strategy,an experience of a tertiary care centre in India

Carcinoma cervix is a common cancer among Indian women. Evidence based management is essential for best practice in treatment of carcinoma cervix for its effective control. The current imaging system like CT, MRI and PET CT scans have contributed in identifying the patients for optimal treatment and delivering treatment accurately. For stages IB2 to IV, concurrent chemoradiation is advocated with improvement in overall survival proven with randomized trials. Brachytherapy is an integral part in the radiation treatment. Imaged-guided brachytherapy using MRI is desirable, however less expensive imaging modalities such as CT and ultrasonography has been evaluated. In special situation such as for HIV positive patients and patients with neuroendocrine tumors have role of radiotherapy. For further improvement in control of cancer, it is required to integrate basic research to answer clinically relevant questions.     

The prediction of late rectal complications in patients treated with high dose-rate brachytherapy for carcinoma of the cervix

: The aim of this work is to invetigate an unusually high rate of late rectal complications in a group of 43 patients treated with concomitant irradiation and chemotherapy for carcinoma of the cervix between December 1988 and April 1991, with a view to identifying predictive factors.

: The biologically effective dose received by each patient to the rectal reference point defined by the International Commission of Radiation Units and Measurements, Report 38, were calculated. Radiotherapy consisted of 46 Gy external beam irradiation plus three dose-rate intracavitary treatments of 10 Gy each prescribed to point A. Cisplatin 30 mg/m² was given weekly throughout the duration of the irradiation. The results have been compared to data from 119 patients treated with irradiation alone to assess the cofounding effect of the cisplatin.

: The relationship between the biologically effective dose delivered to the rectal reference point and the development of late complications shows a strong dose-response with a threshold for complications occurring at aproximately the same biologically effective dose threshold as that found for external beam irradiation in the head and neck region. The date from the group of patients treated wihout cisplatin is comparable to the date from the first group of patients in the lower dose ranges; the higher doses were not used and thus are not available for comparison.

: Using the linear quadratic model applied to our clinical results, we have established a threshold for late rectal complications for patients treated with external beam irradiation and high dose-rate brachytherapy for carcinoma of the cervix. This threshold is consistent with similar data for external irradiation in the head and neck region.     

Clinical experience of fast neutron therapy for carcinoma of the uterine cervix

Fast neutron therapy for locally advanced or radioresistant malignant tumors was started in November 1975 at the National Institute of Radiological Sciences (NIRS), Chiba, Japan. To evaluate the effectiveness of fast neutron therapy, mixed neutron-photon fractionated irradiation, on squamous cell carcinoma of the uterine cervix, 98 patients with Stage IIIb disease were examined to study the correlation between local control rate and histological types. The local control rate after neutron-mixed beam therapy was 73%, which decreased to 66% with photon irradiation. The five year survival rate was 49% for patients receiving neutron therapy and 49% for those receiving photon therapy. There was no statistical significance between neutron and photon therapy; we then attempted to analyze histological types to check for any gain using neutron therapy. This study was a nonrandomized trial. The preliminary results however, gave us useful information for the next of neutron therapy.     

Trans-abdominal ultrasound (US) and magnetic resonance imaging (MRI) correlation for conformal intracavitary brachytherapy in carcinoma of the uterine cervix

Purpose

Trans-abdominal ultrasonography (US) is capable of determining size, shape, thickness, and diameter of uterus, cervix and disease at cervix or parametria. To assess the potential value of US for image-guided cervical cancer brachytherapy, we compared US-findings relevant for brachytherapy to the corresponding findings obtained from MR imaging.

Materials and methods

Twenty patients with biopsy proven cervical cancer undergoing definitive radiotherapy with/without concomitant Cisplatin chemotherapy and suitable for brachytherapy were invited to participate in this study. US and MR were performed in a similar reproducible patient positioning after intracavitary application. US mid-sagittal and axial image at the level of external cervical os was acquired. Reference points D1 to D9 and distances were identified with respect to central tandem and flange, to delineate cervix, central disease, and external surface of the uterus.

Results

Thirty-two applications using CT/MR compatible applicators were evaluable. The D1 and D3 reference distances which represent anterior surface had a strong correlation with R = 0.92 and 0.94 (p < 0.01). The D2 and D4 reference distances in contrast, which represent the posterior surface had a moderate (D2) and a strong (D4) correlation with R = 0.63 and 0.82 (p < 0.01). Of all, D2 reference distance showed the least correlation of MR and US. The D5 reference distance representing the fundal thickness from tandem tip had a correlation of 0.98. The reference distances for D6, D7, D8, and D9 had a correlation of 0.94, 0.82, 0.96, and 0.93, respectively.

Conclusions

Our study evaluating the use of US, suggests a reasonably strong correlation with MR in delineating uterus, cervix, and central disease for 3D conformal intracavitary brachytherapy planning.     

Treatment of carcinoma of the uterine cervix by remotely controlled afterloading intracavitary radiotherapy with high-dose rate: A comparative study with a low-dose rate system

From September, 1974 through December, 1979, a total of 249 patients with carcinoma of the cervix uteri Stage IIb and III were randomly allocated to either remotely controlled high-dose-rate intracavitary radiotherapy or manual afterloading low-dose-rate therapy, with radiotherapy of 20 Gy in 2 weeks to Point A to whole pelvis and 40 Gy in 4 weeks to the parametria. The dose to Point A by intracavitary radiotherapy was 40–60 Gy with one or two fractions in the low-dose-rate group and 30 Gy for the high-dose-rate group by 3 fractions with a once a week schedule. The purpose of this paper is to compare the results between the groups and to clarify the problems in the high-dose-rate group clinically. The local control rate was higher in the high-dose-rate group; however, the complication rate was also higher in this group than in the low-dose-rate group. The dose schedule and the place of rectal dose measurement is discussed. The overall cumulative survival rate was nearly the same in both groups (55 % at 5 years), although some difference was noted in each stage. The most common cause of death was distant metastasis outside the pelvis and the second most common was intercurrent disease in Stage IIb and local failure in Stage III.     

Long-term outcome after radiotherapy for FIGO stage IIIB and IVA carcinoma of the cervix

PURPOSE: To report the long-term outcome after radiotherapy with curative intent for Stage IIIB and IVA carcinoma of the cervix. METHODS AND MATERIALS: We retrospectively reviewed 91 patients treated with radiotherapy with curative intent at the University of Florida between January 1980 and December 2003 for Stage IIIB (84 patients) or IVA (7 patients) carcinoma of the cervix. RESULTS: The median follow-up of the surviving patients was 8.8 years. The 5- and 10-year estimates of local control, regional control, locoregional control, relapse-free survival, and overall survival were 53% and 53%, 55% and 47%, 34% and 29%, 30% and 26%, and 29% and 21%, respectively. Ninety percent of the recurrences occurred within 2 years of treatment. Of these, 60% of all failures were local, 29% were regional, and 11% were distant failures alone. Also, 17% of the failures were in the paraaortic nodes with no evidence of failure in the pelvis. Univariate and multivariate analyses were conducted with the endpoint of relapse-free or overall survival. No factor was statistically significant. Complications from therapy were scored using the Radiation Therapy Oncology Group grading system; the overall severe late complication rate was 13% (Grade 3-5). CONCLUSION: This series is one of the most mature of published reports. With long-term follow-up, approximately one-third of patients with Stage IIIB or IVA carcinoma of the cervix were cured, with a 13% complication rate.     

High-dose-rate intracavitary brachytherapy boost for early T stage nasopharyngeal carcinoma{private}

PURPOSE: To investigate any possible therapeutic gain from dose escalation with brachytherapy for early T stage nasopharyngeal carcinoma (NPC). METHODS AND MATERIALS: One hundred forty-five patients with T1-2b N0-3 NPC were boosted with high-dose-rate intracavitary brachytherapy after completion of two-dimensional external radiotherapy (ERT) during the period from 1999 to 2003. To compare the efficacy of brachytherapy boost, another 142 patients with T1-2b N0-3 disease who were treated with ERT alone during 1994 to 1999 were evaluated. All patients were treated with ERT to a total dose of 66 Gy in 6.5 weeks. The brachytherapy boost group was given 10-12 Gy in 2 weekly fractions. RESULTS: Dose escalation beyond 66 Gy with brachytherapy boost was shown to improve local control and survival. The 5-year actuarial local failure-free survival, regional failure-free survival, distant metastasis-free survival, progression-free survival, cancer-specific survival, and overall survival rates for the brachytherapy group and the control group were 95.8% and 88.3% (p = 0.020), 96% and 94.6% (p = 0.40), 95% and 83.2% (p = 0.0045), 89.2% and 74.8% (p = 0.0021), 94.5% and 83.4% (p = 0.0058), and 91.1% and 79.6% (p = 0.0062), respectively. The 5-year major-complication-free survival rate was 89.5% for the brachytherapy group and 85.6% for the control group (p = 0.23). CONCLUSIONS: For patients who are treated with two-dimensional treatment techniques, dose escalation with brachytherapy boost improves local control and overall survival of patients with T1-T2a and possibly non-bulky T2b disease.     

National audit of the management and outcome of carcinoma of the cervix treated with radiotherapy in 1993

The aim of the study was to investigate the UK prevalence of late, severe side-effects associated with radical radiotherapy for cancer of the cervix and try to identify associated factors. All patients treated for cancer of the cervix with radical radiotherapy in 1993 were identified and retrospective case notes studied to determine mortality and severe complications occurring following treatment. Of the 55 radiotherapy departments in the UK that were treating gynaecological malignancy in 1993, 53 participated in the study. There were 1558 patients with carcinoma of the cervix receiving radical radiotherapy as part of their treatment regimen in 1993, whose patterns of treatment were assessed. The main outcome measures were the development of late severe complications as defined by the Franco-Italian Glossary and mortality. Of the patients receiving surgery and radiotherapy, 58.5% underwent Wertheim's procedure. The crude rate of late severe complications in all patients with cervical cancer treated with radical radiotherapy in 1993 was 6.1% (actuarial rate 8%) at 5 years, and only four of the 91 patients who developed complications died as a result of their morbidity. There was no significant correlation of stage, centre size, surgery or radiotherapeutic approach with late morbidity in univariate analysis. The overall survival at 5 years was 47% and was lower than that of the European data from FIGO's 1990–92 cohort, for all stages. Increasing FIGO stage was the only factor significantly associated with mortality. The absence of variables that were significantly associated with late complications may well be related to the relatively low event rate compared to the sample size. Differences in surgical treatment prior to radiotherapy and radiation technique may be confounding the comparison of outcomes. The relatively poor survival for locally advanced disease and the difficulty with which these data were collated indicates that national prospective data collection is urgently required to monitor performance and hence derive best practice.     

Concurrent mitomycin C, 5-fluorouracil,and radiotherapy in the treatment of locally advanced carcinoma of the cervix: a randomized trial

PURPOSE: This is a prospective, Phase III multicenter randomized trial to assess the effectiveness of concurrent intravenous mitomycin C, oral 5-fluorouracil (5-FU), and radiotherapy (RT) in locally advanced carcinoma of the cervix. METHODS AND MATERIALS: Between January 1988 and November 1994, 926 patients with locally advanced carcinoma of the cervix, FIGO Stage IIB-IVA, were entered into this study. The patients were randomized into four arms, as follows: Arm 1: conventional RT; Arm 2: conventional RT and adjuvant chemotherapy; Arm 3: conventional RT plus concurrent chemotherapy; Arm 4: conventional RT plus concurrent chemotherapy and adjuvant chemotherapy. Concurrent chemotherapy consisting of intravenous mitomycin C at 10 mg/m(2) was given on Days 1 and 29, and oral 5-FU at 300 mg/day was administered on Days 1-14 and 29-42 during RT. Adjuvant chemotherapy of 5-FU orally at 200 mg/day was given for three courses of 4 weeks, with a 2-week rest every 6 weeks. Six centers participated in the trial. RESULTS: The median follow-up time was 89 months. Acute side effects were generally higher in concurrent arms, but most of the patients tolerated the treatment well. Bone marrow toxicity was also higher in concurrent arms. The 5-year actuarial disease-free survival (DFS) was 48.2%, 54.1%, 64.5%, and 59.7% for arms 1, 2, 3, and 4, respectively. The pattern of failure revealed a significant increase in locoregional recurrence in the nonconcurrent chemoradiotherapy arm. The local recurrence was 25.5%, 20.6%, 14.3%, and 17.6% for arms 1, 2, 3, and 4, respectively. The metastatic rates were not significantly different in all four arms. At the time of analysis, there were no increases in late side effects, especially in gastrointestinal and genitourinary systems. CONCLUSIONS: Concurrent chemotherapy, mitomycin C, and 5-FU together with conventional RT showed an improved DFS rate when compared with conventional RT alone in patients with locally advanced carcinoma of the cervix.     

Late urologic morbidity in 177 consecutive patients after radiotherapy for cervical carcinoma: a longitudinal study

: To provide longitudinal data on urologic morbidity after radiotherapy and brachytherapy for cervical carcinoma.

: Five-year longitudinal urologic morbidity data were recorded from 177 consecutive patients of median age 59 years (range: 22–86 years) with cervical carcinoma receiving radiotherapy with curative intent at the Copenhagen University Hospital, Denmark. FIGO stages (%) were as follows: Stage I (15), Stage II (30), Stage III (54), and Stage IV (1). Late morbidity was calculated as cumulative incidence based on actuarial estimates.

: The 5-year cumulative incidence based on actuarial estimates of urologic morbidity Grades 1 + 2 + 3, Grades 2 + 3, and Grade 3 were 62%, 32%, and 5%, respectively. Frequencies of urologic morbidity in the 54 recurrence-free survivors at the end of follow-up indicated some reversibility in the case of Grades 1 and 2 morbidity.

: With the longitudinal design used in the present study, a rate of mild and moderate morbidity higher than that found in most of the previously reported literature was observed, giving cause for concern and underlining the importance of further longitudinal studies on this subject, specifically studies that relate to the background urologic morbidity in the female population, as well as to the fact that urologic morbidity might regress.