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NATIONAL INSTITUTE FOR HEALTH AND CLINICAL EXCELLENCE INTERVENTIONAL PROCEDURES PROGRAMME Interventional procedures overview of high dose rate (HDR) brachytherapy for carcinoma of the cervix. Introduction This overview has been prepared to assist members of the Interventional Procedures Advisory Committee (IPAC) in making recommendations about the safety and efficacy of an interventional procedure. It is based on a rapid review of the medical literature and specialist opinion. It should not be regarded as a definitive assessment of the procedure.
Date prepared This overview was prepared in August 2005
Procedure name High dose rate brachytherapy HDR afterloading brachytherapy HDR Intracavitary radiation therapy
Specialty societies Royal College of Obstetrics and Gynaecology British Gynaecological Cancer Society Royal College of Radiologists
Description Indications: In the UK as many as 3000 women are diagnosed with cancer of the cervix each year. There are two main types. The most common, squamous cell carcinoma, usually develops from the cells which cover the outer surface of the cervix (ectocervix), within the so-called transformation zone The other, adenocarcinoma, usually develops from the glandular cells which line the cervical canal (endocervix). The stage of a cancer is defined by its size and by the extent of spread beyond the cervix. The initial treatment of cervical cancer is dictated by a number of factors, including the stage of the disease at presentation. The most common symptoms of cervical cancer are abnormal vaginal bleeding or discharge and discomfort during intercourse.
Current treatment and alternatives Cancer of the cervix can be treated with surgery, radiotherapy, chemotherapy or a combination of these treatments. The choice of treatment will depend mainly upon
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305 the stage of the cancer. Surgery is often the main treatment for cancer of the cervix in its early stages (where cancer is found only in the cervix). Chemotherapy is occasionally used before surgery, shrinking the cancer and make the operation simpler. However, it is mainly given in combination with radiotherapy either as a primary therapy or after surgery. Brachytherapy is a form of radiation treatment where radioactive sources are placed on or into cancer tissues. Therapy can be given in low medium or high dose rates. There is no universally accepted definition of these rates, but in principle the higher the dose rate the more radiation is delivered in a shorter time (although total doses may in fact be lowest with high dose rate therapy). Low dose rate brachytherapy was the first internal radiation system developed in which radiation is delivered slowly, or at a low dose rate. In order to administer a radiation dose that will eliminate the cancer, the instruments need to be in place for an extended period of time, with applicators inserted into the vagina for 2 to 3 days. In order to eliminate the radiation hazard to staff, and to reduce the length of inpatient treatment, with requirement for isolation of the patient, and thus improve patient acceptability of treatment, high dose rate (HDR) brachtherapy was developed., Whilst the same treatment may be used for palliation of advanced disease, this overview refers only to HDR brachytherapy used with the intent to cure cervical cancer.
What the procedure involves: In HDR Brachytherapy an implant containing a high dose of radioactivity (microselectron) is inserted into the cervix and this is left in place typically for a few minutes, and then removed. These treatments are often repeated several times, a few days apart, and are usually given as an outpatient. Ultra sound guidance may be used during the planning of the treatment. This intervention gives a high dose of radiation to the cervix and the area close by, but only a low dose to tissues and organs more than a few centimetres away. Practically all high dose rate brachytherapy is given in conjunction with external beam radiation therapy (EBRT).
Efficacy: Across the randomised controlled trials comparing patients treated with HDR and LDR brachytherapy, the overall survival (across all stages of disease) with HDR ranged from 68%1 to 54%2, at three and five years follow up respectively. The corresponding survival following LDR brachytherapy was 71%1 and 55%2 to the same follow up time. Similarly, disease free survival was achieved with HDR brachytherapy in 65%1 to 69%3 of patients with stage II disease at three and five years respectively, while the rate was found to be 76%1 and 87%3 for LDR brachytherapy treated patients respectively. For patients with stage III cancer, disease free survival following HDR brachytherapy was 74%1 and 51%3 at three and five years, while this outcome was achieved in 59%1 and 60%3 of LDR brachytherapy treated patients. None of these differences between groups were significantly different In randomised controlled trial comparing 31 patients receiving HDR brachytherapy to 29 having Medium dose rate (MDR) treatment overall five year survival (across all stages) was 61% Vs 63% (p=0.9839). In the same study local disease free survival achieved in 67% of HDR brachytherapy cases compared to 78% in MDR treated patients (p=0.8603)4 The pattern of treatment failure across HDR treated patients from randomised controlled trials and case series found distant failures occurred in 6% (15/236) 2, 19% (372/1992)5, 22% (43/200)6 and (25/112) 1, 25% (figures not reported) 3 of cases. Where the outcome was reported, local recurrence occurred in 6% (7/112) 1, 18%
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305 3
5
2
(not reported) , 21% (415/1992) , and 22% (51/236) , with follow up ranging from 3 to 10 years.
Safety: Complications have been reported using a range of outcome measures across the studies. Serious complications that required subsequent surgery occurred in between 2%5 and 6% (11/200) 6 of cases from two case series. In a large case series with a median 8 year follow up period the overall complication rate was 35% and radiation therapy oncology group grade 3 or 4 complications occurred in 7% of cases5. In a randomised controlled trial comparing HDR and MDR brachytherapy the grade 2 complication rate among HDR treated patients was 13% (4/31) 4. Where reported separately, rectal complications (all grades) were reported in between 4%3 and 20% (22/112) 1 of cases, and bladder complications between 4% (8/200) 6 and 24%7 of cases.
Literature review Rapid review of literature
The medical literature was searched to identify studies and reviews relevant to high dose rate brachytherapy for all gynaecological malignancies. Searches were conducted via the following databases, covering the period from their commencement to 20/05/2005. MEDLINE, PREMEDLINE, EMBASE, Cochrane Library and Science Citation Index. Trial registries and the Internet were also searched. No language restriction was applied to the searches. The following selection criteria (Table 1) were applied to the abstracts identified by the literature search. Where these criteria could not be determined from the abstracts the full paper was retrieved Table 1 Inclusion criteria for identification of relevant studies Characteristic Publication type
Patient Intervention/test Outcome Language
Criteria Clinical studies included. Emphasis was placed on identifying good quality studies. Abstracts were excluded where no clinical outcomes were reported, or where the paper was a review, editorial, laboratory or animal study. Conference abstracts were also excluded because of the difficulty of appraising methodology. Patients with carcinoma of the cervix High dose rate brachytherapy with curative intent Articles were retrieved if the abstract contained information relevant to the safety and/or efficacy. Non-English-language articles were excluded unless they were thought to add substantively to the English-language evidence base.
List of studies included in the overview This overview is based on four randomised controlled trials 1-4 and three case series57
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305 Existing reviews on this procedure No systematic reviews or evidence based guidelines on ultrasound-guided minimally invasive breast surgery were identified during the literature search.
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305 Table 1 Summary of key efficacy and safety findings on curative high dose rate (HDR) brachytherapy for carcinoma of the cervix. Abbreviations used: Computed tomography – CT, External beam radiation therapy - EBRT, Low Dose Rate - LDR, High dose rate - HDR Study Details
Key efficacy findings
Key safety findings
Comments
El-Baradie M M (1997)(4)
Survival 5 year actuarial survival Overall survival was 61% in the HDR brachytherapy group, and 63% I the MDR group (p=0.9839) Stage HDR MDR I and II 74% 69% III and IV 32% 57% Absolute figures not reported
Complications The five year cumulative complication rate was 14% in the HDR group and 7% in the MDR group (p=0.4466)
Staging using the Union Internationale Contre le Cancer TNM classification (1987)
Randomised controlled trial Japan n=60 (31 HDR brachytherapy) Concurrent EBRT for all cases except stage Ia HDR brachytherapy at 32Gy per four fractions T1 and 2, 30Gy per four fractions T3, and 22.5Gy per 3 fractions in T4.
Overall loco-regional disease free survival was 67% in the HDR brachytherapy group, and 78% in the MDR group (p=0.8603) Stage HDR MDR I and II 85% 83% III and IV 54% 75% Absolute figures not reported
In The HDR arm there were grade 2 complications in 13% (4/31) of cases, three rectal complications and one with paralytic ileus. In the MDR arm there were grade 2 complications in 3% (1/29) of cases (rectal bleeding). There was also grade 3 complications in 3% (1/29) of cases (rectal and bladder fistulae).
MDR brachytherapy at 35.6GY per four fractions, 34Gy per four fractions, and 25.5 Gy per three fractions, respectively Age =61 years, Stage I =12, stage II =22, stage III = 23, stage IV =3. Median follow up = 2 years, (maximum 5 years)
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Allocation to treatment group using random number table No details of concealment of allocation or blinding stated.
305 Abbreviations used: Computed tomography – CT, External beam radiation therapy - EBRT, Low Dose Rate - LDR, High dose rate - HDR Study Details
Key efficacy findings
Key safety findings
Comments
Patel F D (1993)(2)
Survival In group 1, 5 year overall survival was 71.9% in LDR brachytherapy patients and 81.7% with HDR. Stage HDR LDR I 85.0% 81.0% II 71.3% 66.4% Absolute figures not reported.
Complications Complications were classified according to the Radiation Therapy Oncology Group morbidity scoring scheme
No comparison made of baseline demographic or clinical characteristics
Randomised controlled trial India n=482 (236 HDR Brachytherapy) Concurrent EBRT for all cases, identical treatment method and dose (within each group) Previously untreated patients with invasive squamous small cell carcinoma of the uterine cervix Staging according to International Federation of Gynecology and Obstetrics system Patients were randomised using alternative allocation stratified for stage. Two subgroups were established. Group 1: early stage patients, with growths 3cm in diameter where EBRT was the predominant therapy
In group 2, 5 year overall survival was 55.1% in LDR brachytherapy patients and 53.6% with HDR. Stage HDR LDR I 74.6% 69.9% II 62.5% 60.1% III 42.6% 50.0% Absolute figures not reported. Pattern of failure In group 1, of patients treated with HDR brachytherapy 6%(2/34) demonstrated distant failure, 6% (2/34) had loco-regional recurrence, and 6% (2/34) had combined local and distant recurrence. For LDR brachytherapy patients the rates were 11% (4/36), 8% (3/36), and 3% (1/36) respectively.
Site of complication Rectosigmoid – all
Rate HDR Rate LDR group group 6% 20% (15/236) (49/246) P