Current controversies in high-dose-rate versus low-dose-rate brachytherapy for cervical cancer
The use of brachytherapy in the treatment of cervical cancer has increased worldwide since its initial introduction over 100 years ago. However, certain aspects of the use of high-dose-rate (HDR) versus low-dose-rate (LDR) brachytherapy continue to be controversial, particularly the role of HDR in FIGO Stage III cervical cancer and the use of HDR with concurrent chemotherapy. This study represents a systematic literature review of prospective and retrospective series of patients with cervical carcinoma treated with external-beam radiation (EBRT) followed by either HDR or LDR radiation. The local control rates, survival rates, and treatment-related complications in patients with Stage III cervical cancer treated with HDR or LDR and those treated with concomitant chemotherapy are examined. Patients with Stage III cervical cancer treated with EBRT and brachytherapy have a local control rate of >50% in most series. Randomized prospective and retrospective studies show overall statistically equivalent local control, overall survival, and complication rates between HDR and LDR. However, LDR may be preferable for large, bulky tumors at the time of brachytherapy. Retrospective studies of HDR and concurrent chemotherapy are limited but have demonstrated toxicity rates similar to those with LDR. Selected patients with Stage III cervical carcinoma who have an adequate response to EBRT and concomitant chemotherapy may be treated with HDR brachytherapy. The existing literature shows no significant increase in complications in patients treated with HDR and concurrent chemotherapy; however, sufficient tumor shrinkage prior to HDR and careful monitoring of the dose to the normal tissues are imperative. Cancer 2006. © 2006 American Cancer Society.
Locally advanced carcinoma of the cervix must be treated with a combination of external-beam radiotherapy (EBRT) and intracavitary radiotherapy. Studies show that the use of brachytherapy increases local control and survival in FIGO Stage III cervical cancer.1, 2 Brachytherapy is a form of conformal dose escalation and decreases the risk of residual cancer and pelvic relapse.3, 4 Since 1999, concurrent chemotherapy with radiation has been the standard of care in the treatment of cervical cancer.5
Intracavitary radiation in the form of low-dose-rate (LDR) brachytherapy has been in use for the treatment of cervical cancer for nearly a century, although the method has been greatly refined. High-dose-rate (HDR) brachytherapy for carcinoma of the cervix has been in use for over 30 years. LDR is defined as a dose of 0.4–2 Gray (Gy)/h, and HDR is defined as a dose of >12 Gy/h.6 HDR is widely used throughout Asia and Europe, and its use is steadily increasing in North America.7 The Patterns of Care Studies show that, in the United States, the use of HDR for treatment of cervical cancer increased from 9% during 1992–1994 to 16% during 1996–1999, although this increase did not reach significance (P = .3).8
LDR uses fixed source positions and strengths to calculate the dose at the prescription point. Doses can be varied slightly by using sources of different activities. Tapering of the dose at the tandem tip results in a lower dose to the small bowel and sigmoid and decreases grade 3–5 late complications without affecting local control.9 Source dwell times can be optimized with HDR to customize the dose to the patient's anatomy and tumor volume, thereby decreasing doses to normal tissues of the rectum, bladder, and vaginal mucosa.10 However, standard treatment parameters as derived from LDR must be considered. Specifically, the dose to the surface of the ovoids should be approximately twice the dose to point A, and the standard loading pattern (15-10-10) of LDR should be converted to HDR, with only slight modifications to consider normal tissue tolerance. Most commonly, a high dose to the sigmoid requires decreasing the top dwell times. LDR tolerance limits for the rectum and sigmoid (70 Gy) and vagina (130 Gy) must be maintained. HDR optimization to maintain a rectal biologically equivalent dose (BED) below tolerance is recommended to decrease late complications.19
HDR has several practical advantages over LDR and is therefore increasing in popularity, particularly in the developing world. These will be discussed in greater detail below. However, these benefits must be weighed against any potential risk of decreased tumor control or increased late complications (Table 1).
Table 1. The Advantages and Disadvantages of LDR and HDR Brachytherapy for Cervical Cancer
| @100 years of data||Outpatient treatment|
| Standardized doses||Short administration time|
| Standardized treatment plan||Standard source strength|
| Standardized treatment time||Source easily available|
| Maximum two insertions||IV conscious sedation feasible|
|Reassess tumor size with multiple fractions|
|Dose optimization of normal tissues|
|Minimal staff exposure|
|Applicator stabilized by board during treatment|
| Inpatient treatment||High risk of errors:|
| Radiation exposure to staff|| • Intense quality assurance|
| Limited by source strength|| • Intense maintenance|
| Limited sources available|| • Intense physician/physicist time|
| Spinal or general anesthesia||>Two fractions required|
| Prolonged bedrest:||Treatment required on day of insertion|
| • Need for anticoagulation||Expensive|
| • Constipating medication||Caution with large tumors|
| • Need for inpatient pain control||Caution with normal tissue dose|
In carcinoma of the cervix, the response to radiotherapy is clearly dose-dependent; as the dose increases, so too does the probability of tumor control. However, the risk of damage and late complications in normal tissues also increases with the dose. This applies to both the overall dose from LDR and the dose per fraction for HDR treatment.
The lower the dose rate of radiation a cell is exposed to, the greater the likelihood of repair. Late-reacting normal tissues seem more capable of repair than tumor; at a given therapeutic dose, the tumor is preferentially killed over normal tissue. The time course of LDR treatment (several days) allows for sublethal damage repair. The short treatment time of HDR prohibits this repair during the actual irradiation. However, if an interval of more than 24 hours is maintained, normal tissues can undergo full repair.11 Therefore, LDR may allow recovery of more normal tissues during treatment, but HDR may offer the advantage of increased cytotoxicity to the tumor.
Various studies have shown improved tumor control and increased patient survival in carcinoma of the cervix when radiotherapy is given in the shortest overall time.12, 13 Shorter treatment times decrease the tumor cell repopulation time and shorten the time for accelerated repopulation. The continuous administration of LDR prevents repopulation during treatment. HDR at the end of a radiotherapy regimen may increase overall treatment time, decrease tumor control and disease-free survival, although not morbidity.14
The fractionated nature of HDR allows for the integration of brachytherapy within the EBRT schedule, permitting shorter overall treatment times. The American Brachytherapy Society (ABS) recommends starting HDR for small tumors after 2 weeks of pelvic EBRT at one fraction per week, continuing EBRT on the other 4 days of the week, or after the fourth week for patients with bulkier tumors, with all treatment completed within 56 days.15
The effect of hypoxia on tumor control in carcinoma of the cervix has been documented, with decreased survival in patients with a low initial hemoglobin level.16–18 Because of the duration of administration of LDR, acute hypoxia may correct within the tumor during treatment. With HDR treatment, the tumor shrinks between insertions, allowing reoxygenation of areas of chronic hypoxia. The oxygen enhancement ratio is lower for LDR than for HDR.19
During the overall treatment time of LDR, tumor cells may pass from the relatively radioresistant phases of late S and early G2 to the more radiosensitive phases of G2 and M. This might provide a theoretical advantage over HDR.
Dose and Fractionation
The dose and fractionation of HDR are closely correlated with local control and late complications.20, 21 Lack of standardization of the conversion used complicates dose comparison between studies. The 1999 ABS survey on brachytherapy practice in the United States showed that physicians administering HDR gave an average dose of 48–50 Gy to the pelvis in EBRT with an additional 30 Gy in five fractions of HDR brachytherapy.7 Sixty-seven percent of physician respondents used a midline shield after an average of 40 Gy. The use of a midline shield is controversial, with reports of both increased and decreased bladder and rectal toxicity.22 With HDR the probability of late damage increases as the dose increases and the number of fractions decreases.20, 21 This probability is also related to the percentage of dose received by normal tissue. If the normal tissue received 100% of the dose, 30 fractions would be needed for equivalent late complications with LDR.
Brachytherapy for Stage III Cervical Cancer
The use of HDR as an alternative to LDR for all stages of cervical carcinoma has been reported in a number of retrospective series23–36 and four randomized prospective trials.37–40 However, the data comparing HDR to LDR for cancer of the cervix are fraught with bias and may be difficult to compare because of a lack of detailed information on the radiation administered and a wide range of external-beam and intracavitary dose and fractionation schedules. The prospective trials do not represent blinded clinical trials, and the retrospective series suffer from the potential bias of historic controls, stage migration over time, and improvement in radiotherapy techniques and dosimetry with modern imaging.
The randomized trials of LDR versus HDR have generally comparable results for all stages of cervical cancer. No significant difference in disease-free survival is detected for any stage of cervical cancer; however, Teshima et al.37 demonstrated an increased overall survival for patients with Stage I disease treated with LDR (Table 2). However, the randomization techniques may be questioned. Patel et al.38 did not state their randomization method but stratified 246 LDR patients and 236 HDR patients according to stage. Teshima et al.37 stated that they fully randomized before 1979, after which they ‘selectively randomized,’ with older, more infirm patients being placed in the HDR arm. This gave 171 LDR patients and 258 HDR patients. Hareyama et al.40 randomized 71 patients to LDR and 61 patients to HDR by month of birth. Lertsanguansinchai et al.39 stratified by age and stage and then randomized 109 LDR patients and 112 HDR patients before starting EBRT.
Table 2. Randomized Trial Results of Toxicity, Overall and Disease-Free Survival Comparing HDR and LDR
|Patel et al.38||Stage I <3 cm||100||100||85||81||0.4||2.4|
|Stage II <3 cm||82||82||71||66|
|Stage I >3 cm||87||88||75||70|
|Stage II >3 cm||74||78||63||60|
|Teshima et al.37||Stage I||66||89‡||85||93||9||4|
|Hareyama et al.40||Stage II||89||100||69||87||10||13|
|Lertsanguansinchai et al.39§||Stage IIB||65||74||65||76||9||4|
The role of HDR in Stage III cancer of the cervix is controversial, with two retrospective series23, 32 showing a significant survival advantage for LDR, and one showing an advantage for HDR26 (Table 3). Although other retrospective series do not demonstrate a significant survival difference, none have a sufficient number of patients and resulting power to detect a difference between HDR and LDR if such a difference exists. Ferrigno et al.32 reported all Stage III results together and stated that the BED for the HDR patients was below that for the LDR patients, which may account for the survival advantage with LDR. In contrast, Kucera et al.26 showed a survival advantage with HDR. The authors stated that the improvement in EBRT practice over the time of analysis must be considered in addition to a higher BED for the HDR patients.
Table 3. Stage III Overall Survival, Pelvic Control and Toxicity in Retrospective Series
|Akine et al.30†‡||212||38||61|| ||37||54||64|| |
|Arai et al.31†‡||143||46.5|| || ||508||52.2|| || |
|Falkenberg et al.36§†‖||23||45||72||4.8||6||33||83||3.5|
|Ferrigno et al.32‡||69||46¶||58||3.7¶||56||36¶||50||2.5¶|
|Hsu et al.29‡#||73||50.2|| ||16.8||30||51.1 (6)42.9 (4)|| ||25.6 (6)11.0 (4)|
|Kim et al.24**||8||35.7|| ||0||16||43.8|| ||1.4|
|Kucera et al.26§||212||37.3¶|| || ||78||53.8¶|| ||9.0|
|Okkan et al.28†‡||21||47.3||53||10.4||98||31.6||45||2.4|
|Orton et al.27‡||1464||42.6|| ||9.1||2721||47.2|| ||22.7|
|Petereit et al.23†§||50||58¶||75¶|| ||50||33¶||44¶|| |
|Sarkaria et al.25§||57||46||63||10.0||12||58||50||2.5|
|Lorvidhaya et al.35†‡|| || || || ||675||47.8||68.8||7.0|
|Sakata et al.33‡|| || || || ||48|| ||63|| |
|Souhami et al.41†|| || || || ||77||42|| || |
|Wong et al.34†‡|| || || || ||51||25||63.2||2.8|
Petereit et al.23 showed equivalent 3-year survival and pelvic control rates with HDR or LDR brachytherapy for all stages of cervical cancer except Stage IIIB. Survival and local control rates were 58% and 75% for LDR versus 33% and 44% for HDR, respectively. Possible explanations for the disparity in survival include insufficient tumor shrinkage, higher than expected local control rates in the LDR patients, and significantly higher rates of hydronephrosis in the HDR group. The timing of HDR may have contributed to these results.23 HDR commenced at week one of pelvic EBRT, when tumor shrinkage would not yet have been adequate. This would give a volume advantage to LDR in these advanced cases with bulky tumors. Rates of pelvic control improved with the first brachytherapy insertion after most of the EBRT had been delivered, allowing for better dose distributions around a smaller tumor volume. With HDR, the outer margins may be missed if the implant is optimized to point A without 3D imaging and the tumor has not regressed sufficiently by the time of the implant. Use of CT or MR imaging with the brachytherapy applicator in place and optimization to the tumor volume as well as to the standard prescription points may obviate this discrepancy between HDR and LDR in large-volume cancers.42–44 A metaanalysis of the primary data from 56 centers27 showed an overall survival advantage at 5 years for HDR over LDR for groups with advanced disease (47.2% vs. 42.6% for Stage III, P = .05). However, patients with larger tumors have a significantly shorter disease-free survival than those with smaller tumors, independent of FIGO stage, when HDR brachytherapy is used.45 In Stage IIIB patients, the rate of local failure increases four-fold if HDR brachytherapy is administered before the 25th day of treatment.41 Therefore, individualized treatment is crucial; the amount of disease present at the time of brachytherapy is paramount in choosing between HDR and LDR brachytherapy, with consideration of the location and tolerance of normal tissues.
Low survival rates for patients with Stage III cervical cancer may be due to inadequate radiation delivery. Conventional intracavitary brachytherapy may not be adequate to deliver a sufficient dose of radiation to an extensive and bulky tumor, such as those with lower vaginal involvement or pelvic sidewall involvement. In these situations, the use of interstitial needles may assist with the delivery of radiation dose.
Interstitial implantation has conventionally been used with a template and LDR radiation. Local control rates for Stage III range from 44% to 88%.46–48 With a median follow-up of 51 months, Syed et al. reported a 10% rate of Grade 3 or 4 late gastrointestinal and genitourinary complications for all stages of cervical cancer. Stage III patients had a 5-year disease-free survival of 49%; Stage IIIB patients had a locoregional control rate of 61%.49
For interstitial implantation with HDR, Demanes et al. treated 62 patients with six fractions of HDR over two insertions; with a mean follow-up of 40 months, the 5-year disease-free survival rate for Stage III patients was 39%, but the regional pelvic control rate was 79%.50 A report of a combined tandem and ring with interstitial applicator using HDR on a fractionated basis was published, though long-term survival and toxicity data are not yet available.51
Several randomized trials set the current standard of care for cervical cancer as radiotherapy with concomitant chemotherapy5; one of these studies allowed the use of HDR, MDR (medium-dose-rate), or LDR.52 A total of eight studies have used chemotherapy with HDR and reported toxicity. Three were single-arm retrospective analyses in which all patients received chemo-radiation53–55; 3 retrospectively compared patients treated with and without chemotherapy56–58; 2 present prospectively collected data.52, 59 None of these studies shows a significant difference in Grades 3 and 4 gastrointestinal and genitourinary late complications (Table 4).
Table 4. Fractionation and Toxicity of HDR and Concurrent Chemotherapy
|Tseng et al.59†||4.3||6||6.5 (GI)||10 (GI)||47|
|Pearcey et al.52†‡||8||3||9 (GI)||5 (GI)||82|
|7 (GU)||10 (GU)|
|Sood et al.57§||9||2||5 (GI)||5 (GI)||36|
|Saibishkumar et al.58§||9||2||1.1 (GI)||1.8 (GI)||39|
|1.0 (GI)||0 (GU)|
|Sood et al.56§||9||2||10||6||28|
|Ozsaran et al.55‖||8.5–9||1–2||0||0||20|
|Souhami et al.53‖||10||3|| ||28 (GI)||27|
|Strauss et al.54‖||7||5|| ||3.7 (GI)||19|
The single-arm series all administered weekly cisplatin. The comparative retrospective series administered cisplatin on days to 5 in weeks 1 and 456, 57 or weekly cisplatin.58 One prospective trial administered weekly cisplatin,52 the other cisplatin, vincristine and bleomycin every 3 weeks.59 All trials administered daily external-beam radiation, with a range of doses from 44–50.4 Gy. The HDR fractionation regimens are detailed in Table 4. Souhami et al.53 reported a high rate of rectal toxicity; however, the fraction size was larger than that used in the modern era. The randomized NCIC trial of weekly cisplatin chemotherapy with radiation versus radiation alone allowed HDR (15%), MDR (8%), or LDR (77%). Long-term toxicities were not significantly different between the 2 arms, although the type of brachytherapy in relation to the use of chemotherapy was not presented.52
A metaanalysis of concurrent cisplatin-based chemotherapy and radiotherapy with both HDR and LDR showed rates of grade 3–4 toxicity of 0%–15% for gastrointestinal toxicity and 1%–8% for genitourinary toxicity.60 The Radiation Therapy Oncology Group (RTOG) trial 90-01 required insertion of LDR brachytherapy; with a median follow-up of 6.6 years, the incidence of Grade 3 or higher late complications was 14% in both arms. No review with HDR and chemotherapy has such long follow-up. However, the RTOG 90-01 initially published, and their results with a median follow-up of 43 months, which had a 12% versus 11% rate of grade 3–4 late toxicity for those treated with and without chemotherapy. These are very similar to the follow-up time and toxicity rates presented in the HDR retrospective reviews (Table 4). Current clinical trials allow the use of HDR brachytherapy and require that chemotherapy not be administered on the same day as brachytherapy treatment.
The risk of late normal-tissue complications depends on a number of factors: whole-pelvic EBRT dose, total dose of brachytherapy, number of fractions of brachytherapy, normal-tissue proximity and dose, intercurrent illnesses, and the use of chemotherapy or other radiation sensitization. The rate of late normal-tissue toxicity of brachytherapy ranges between 5% and 35% for all grades of complications.11, 27, 28 The anterior rectal wall adjacent to the posterior often receives the highest dose of radiation. With 3D imaging, the recommended dose limit for HDR to a 2-cc volume of rectum is 70 Gy3 and 90 Gy3 for a 2-cc volume of bladder.43
Most series show comparable rates of Grades 3–5 late complications with LDR and HDR therapy. Toxicity rates in the randomized trials with LDR and HDR are listed in Table 2 and for the Stage III retrospective series in Table 3. Table 4 lists the toxicity with HDR and chemotherapy already described. An analysis of the primary data from 56 centers27 showed a significant decrease in all major complications (grades 1–5) when HDR brachytherapy was used (9% vs. 21% with LDR, P < .001). This corresponded to a significant decrease in the bladder and rectal maximum dose point of 13%.
HDR may be an acceptable alternative to LDR brachytherapy in carefully selected patients with carcinoma of the cervix. To individualize treatment, it is useful to have both HDR and LDR available. Ideal candidates for HDR will have a small volume of disease, a vagina large enough to hold packing, and an inability to complete treatment in less than 56 days, or the ability to tolerate an inpatient stay. Ideal candidates for LDR are patients who cannot tolerate outpatient treatment or who have bulky residual disease at the time of implantation.
In the setting of Stage III carcinoma of the cervix, patients must have sufficient tumor shrinkage to ensure adequate coverage of the target with radiation when an optimized HDR treatment plan is used. Patients with persistent large bulky tumors and/or vaginal disease who do not respond to EBRT may require interstitial therapy. HDR may be used with chemotherapy, although doses to the bladder and rectum must be monitored to prevent increased normal-tissue toxicity. As data mature, additional information regarding late toxicities resulting from HDR and concomitant chemotherapy will become available. Imaging with 3D techniques such as CT and MRI during brachytherapy will allow for optimization of dose away from normal tissues. Future studies comparing LDR and HDR with CT or MR imaging will be necessary to determine if visualization of critical structures will reduce long term morbidity and increase local control for cervical cancer patients.