Brachytherapy for cervix cancer: low-dose rate or high-dose rate brachytherapy – a meta-analysis of clinical trials

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 [1]. HDR is widely used throughout Asia and Europe, and its use is steadily increasing in North and South Americas [2]. The Patterns of Care Studies show that, in the United States, the use of HDR for the treatment of cervical cancer increased from 9% during 1992–1994 to 16% during 1996–1999, although this increase did not reach significance[3].

LDR techniques were developed in an era when remote afterloading technology was unavailable, and remote afterloading techniques were developed due to concerns related to radiation exposure to health care workers. In more recent years, new technology has allowed remote afterloading brachytherapy to be given at LDR. The use of HDR brachytherapy is the result of technological development in the manufacture of high-intensity radioactive sources, sophisticated computerized remote afterloading devices, and treatment planning software [4]. Several advantages of HDR brachytherapy, including rigid immobilization, outpatient treatment, patient convenience, accuracy of source and applicator positioning, individualized treatment with source optimization, and complete radiation protection for personnel have been claimed [5–7].

There are nearly three decades of experience comparing HDR to LDR brachytherapy in the treatment of cervical carcinoma. The literature supporting HDR brachytherapy in the treatment of cervical carcinoma derives primarily from retrospective series [8–14]. However, controversy still persists regarding the efficacy and safety of HDR brachytherapy compared to low-dose rate (LDR) brachytherapy [2–4, 15]. In particular, due to inadequate tumor coverage for stage III patients, whether LDR or HDR brachytherapy produces better results for this patients in terms of survival rate, local control rate and treatment complications remain controversial.

So, the goal of this study was to conduct a meta-analysis to compare the efficacy and safety of HDR and LDR brachytherapy in patients with cervix cancer. In addition to that, we found it appropriate to build the recommendations for the use of HDR based on the GRADE system.

Criteria for considering studies for this review included the following:

Approximately 11,070 women are diagnosed with cervical cancer annually in the US, resulting in 3,870 deaths [27]. This represents 0.13 percent of all cancer deaths in women. Despite this, and the promise of newly developed cervical carcinoma vaccines [28], cervical carcinoma is still the third largest cancer killer of women world-wide, causing 274,000 deaths in 2002 [29]. Cervix cancer is a curable cancer, but achieving the best results depends on well-organized and appropriately resourced cancer services. Brachytherapy is an integral part of the cervical carcinoma treatment armamentarium. It is a technically demanding and highly specialized method of radiotherapy delivery. Depending on the equipment used, the capital expenditures and staff costs may be high. Fractionated HDR brachytherapy in the treatment of uterine cervix cancer has been increasing worldwide, including in the United States [2]. In developing countries such as Brazil, the advantages of outpatient treatment, potential cost savings, radiation protection, patient comfort, reduction of the need for general anesthesia, and less chance of applicators displacement make of this procedure an excellent treatment option [30]. Unfortunately, a well-designed prospective and randomized Phase-III trial with an adequate number of patients that would allow comparison of results between LDR and HDR brachytherapy in the treatment of cervix cancer has not yet been published. Thus, we have performed a meta-analysis to improve the statics precision of the outcomes in the clinical trials that compared these two techniques. Meta-analysis of randomized trials allows a more objective appraisal of the evidence, which may lead to the resolution of uncertainty and disagreement. It works as a valuable tool for studying rare and unintended effects of a treatment, by permitting synthesis of data and providing more stable estimates of effect.

Our results analyzing five RCTs (2,065 patients) really confirm the use of HDR as an alternative to LDR for all stages of cervical carcinoma. The overall survival and local control were similar in both groups for stages I, II and III (Figure 2 and Figure 3).

However, considering the clinical stage III a wide range of results has been found in the literature [31–36]. Vahrson and Romer [14] reported a significantly greater survival rate for stage-III patients using HDR brachytherapy. In the series of Ferrigno et al [37] stage-III patients treated with HDR brachytherapy had a poorer outcome when compared with those treated with LDR brachytherapy. Overall survival and disease-free survival at a 5-year period was statistically superior in the LDR group. These results probably are caused by the different tumor-related prognostic factors in stage-III patients, including tumor volume, extension of parametrial invasion (unilateral or bilateral), presence of hydronephrosis, lymph node metastasis, and extension of vaginal involvement. Consequently, when these patients do not receive radiotherapy combined to chemotherapy, they may still have a large volume of disease at the time of brachytherapy, even if one waits until the end of 5 weeks of daily treatment. With a large tumor volume at brachytherapy, point-A prescription simply does not cover the tumor volume. The current treatment plan and technique for gynecological brachytherapy is still based on the conventional, orthogonal film-based approach developed 40 years ago. The source loading and dose prescription of a conventional point-A plan in cervical cancer is not consistent with the individual tumor extent, resulting in either undercoverage of the tumor extent or unnecessary dosage of the surrounding normal tissue. So, in order to safely treat large volume disease (i.e. stage-IIIB patients), three dimensional (3D) image-based treatment planning is necessary to ensure proper tumor coverage. Several investigators have studied three dimensional (3D) image-based brachytherapy planning using ultrasonography, computed tomography (CT), magnetic resonance imaging (MRI), and positron-emission tomography (PET) in cervical cancer [38–46]. Although the studies had some different findings, the conventional point-A plan, compared with the 3D image-guided plan, generally overestimated the minimal dose delivered to the target volume and underestimated the maximal doses to the rectum and bladder [40, 42–46]. In addition to that, 3D image-guided planning allows the evaluation of individual dose distributions applied to a certain volume, such as the gross tumor volume (GTV), clinical target volume (CTV), and organs at risk. Recently, the GEC-ESTRO working group for gynecologic brachytherapy introduced guidelines for contouring the target volumes and organs at risk (OARs) for 3D image-based treatment planning in cervical cancer [41]. It is therefore imperative with HDR for large volume disease that the practitioners contour the normal tissues and look at the dose volume values to try to minimize normal tissue dose.

Despite these limitations for large tumors (i.e. stage-IIIb and tumors > 4 cm), in recent years, HDR brachytherapy has gained popularity due to the obvious physical advantages of shortened treatment time and better geometric placement. A second major reason for conversion from LDR to HDR is reduced hospitalization. For each LDR patient of around one week of hospitalization is required, whereas, with HDR, this can be reduced to a maximum of one day. In many countries, hospitalization of patients is very expensive and methods to reduce this cost are encouraged. In others, the availability of hospital beds is a problem, especially beds in rooms suitably placed or shielded for LDR brachytherapy. There is also the problem of morbidity due to the long periods of bed-rest associated with LDR treatments. One concern with LDR intracavitary brachytherapy is the stability of positioning of the applicators during the long periods of treatment. Dose calculations are performed soon after the applicators are inserted and before they are loaded. On the few occasions that a second dosimetric study has been performed on treatment completion, this assumption has been shown to be erroneous. For example, a recent study of data from five institutions where dose distributions have been determined both at the beginning and at the end of an intracavitary application with LDR has demonstrated that 'hot-spot' dose rates to bladder and rectum increased during treatment at an average rate of 7% and 19% respectively, with negligible change in the dose rate to Point A [47].

Our results comparing late rectal and bladder complications in patients treated by HDR brachytherapy to LDR brachytherapy show that there is no difference between these two techniques. Similar probability of late complications in rectal, bladder or small intestine was observed in both groups (Table 4).

Theoretically, HDR involves a greater probability of late effects for a given level of tumor control; however, the fractionation of HDR intracavitary brachytherapy appears to offset this difference in tumor and normal tissue effects caused by an increase in dose rate.

Despite its radiobiological disadvantages mentioned by Eifel [48], the possibility of optimizing dose distribution and the lesser chance of applicator displacement seem to outweigh these disadvantages. Furthermore, the variation of dwell time with the single stepping source permits an almost infinite variation on the effective source strength and source positions, which allows for greater control of dose distribution and potentially less morbidity [25]. None of the RCTs in the literature show a higher incidence of late complications in patients with cervix cancer treated with HDR brachytherapy compared to those treated with LDR. In our meta-analysis, incidence of lower 5-year rectal complication in patients from the HDR group was probably the result of the relatively low dose delivered to the rectum with the HDR brachytherapy fractionation used. In LDR brachytherapy, the total rectal dose was commonly limited to 70 Gy. In HDR brachytherapy, this total dose was lower, depending on the fractionation used; however, how much lower remains unclear. Using the linear quadratic formula (total BED = BED EBR + BED HDR = nd [1+(d /3)] +Br [1+(Br/3)], where n = number of EBR fractions, d = dose of EBR fraction in Gy, and Br = total dose of HDR brachytherapy at Point A), the total dose to the rectum of 70 Gy with LDR brachytherapy corresponds to 120 Gy3 with HDR brachytherapy.

But, what is the optimal HDR fractionation schedule for treating cervical cancer? There is not a simple answer for this question. Although universally efficacious, HDR fractionation schedules cannot be ascertained, certain deductions can be made about the literature: No clear consensus of the appropriate number of fractions or the dose per fraction has been reached. Various fractionation schemes have been used "experimentally" in search of the "optimal" technique.

The GRADE system is based on a sequential assessment of the quality of evidence, followed by an assessment of the balance between benefits versus downsides, as well as the subsequent judgment about the strength of recommendations. Because frontline consumers of recommendations will be most interested in the best course of action, the GRADE system places the strength of the recommendation first, followed by the quality of the evidence. Separating the judgments regarding the quality of evidence from judgments about the strength of recommendations is a critical and specific feature of this new grading system. In our meta-analysis, the quality of evidence was moderate for mortality and local recurrence for all clinical stages, except for clinical stage I. Moreover, all included studies were RCTs with moderate percentages of follow-up. This moderate quality of evidence for mortality and local recurrence, and the low likelihood of publication bias, increase the confidence in the internal validity of our findings. Thus, our data are different of a previous and more extensive multi-institutional study including 17,068 patients treated with HDR and 5,666 with LDR at 56 institutions published by Orton et al. [49]. This involved a combination of both published data and information, collected via a questionnaire. A meta-analysis was performed on the combined data sets. The overall 5-year survival rates were similar, being 60.8% for HDR and 59.0% for LDR although, because of the large number of patients, the difference bordered on statistical significance (p < 0.045). However, since no randomization was involved, the use of p-values to demonstrate statistical significance in this context is questionable, especially with such comparable survival rates. For Stage-III patients, however, the difference in five-year survival rates was somewhat more significant, being 47.2% for HDR compared to 42.6% for LDR (p < 0.005).

The comparative results observed in our meta-analysis must be interpreted with caution, since the data comparing HDR to LDR for cancer of the cervix are fraught with bias and may be difficult to compare, due to both a lack of detailed information on the radiation administered and a wide range of external beam and intracavitary dose and fractionation schedules. Moreover, all of 5 selected studies labeled "randomized" are, in fact, not truly randomized studies and all have substantial flaws in their methodology for 'randomization'. Thus, although we have used the GRADE approach to rate the quality of evidence and strength of recommendation, the need for judgment is still required. Indeed, RCTs or meta-analysis could have important methodological differences that may impact on the results.

High-dose rate brachytherapy showed comparable clinical results to LDR brachytherapy. In the subgroup analysis there is no significant difference between HDR or LDR brachytherapy considering the loco-regional recurrence, overall mortality and treatment related to late toxicities for patients with clinical stages I, II and III. Using the GRADE system, we recommend the use of HDR for all clinical stages of cervix cancer. Due to some potential disadvantages of LDR brachytherapy, such as radiation exposure of the professional staff, the need for hospitalization, the risk of anesthesia, bed immobilization that can lead to thromboembolism, discomfort of vaginal packing and applicators during bed immobilization, and displacement of the applicators, HDR brachytherapy should be considered a standard treatment strategy for patients with cervical cancer, especially in developing countries, where this procedure would have greater advantages than LDR brachytherapy. However, although a large number of fractionation schedules are in use for HDR brachytherapy, the optimal schedule has yet to be decided. Further trials are necessaries to investigate 3D brachytherapy, fractionation and dose adjustments of the total dose to reduce the frequency of complications without compromising the treatment results.