RESUMO
The amount of dose reduction on changing from low dose rate (LDR) brachytherapy to medium dose rate (MDR) or high dose rate (HDR) afterloading has been the subject of much debate. The magnitude of reduction depends, together with other possible factors, on two radiobiological parameters: the alpha/beta ratio and the half-time of repair of the relevant tissues. In an attempt to extract these radiobiological parameters for the late rectal complications observed in our previously published clinical results four different schedules using MDR and one using LDR are analyzed. The percentage incidence of complications was a function of increasing biologically effective dose (BED), but would yield nonsense scattergrams if plotted against raw total dose. In addition, for three other published MDR series, three LDR series, and two HDR series, the incidence of rectal complications is plotted against BED to examine the predictive potential of using BED as the surrogate of total dose. Our own results were published in 1996, consisting of 102 patients treated at the LDR of 0.44 Gy/hr and 88 patients treated by four different schedules using an MDR of 1.6-1.7 Gy/hr. Follow-up is at least 3 years in all schedules. The linear quadratic formula including the "g" dose rate factor was used to analyze them, assuming exponential repair of the repairable beta term. First, multivariate and profile likelihood analyses were carried out to obtain estimates of alpha/beta and T1/2 for rectal late responding tissues. Then graphs of incidence of rectal complications vs. BED were constructed, assuming alpha/beta = 3 Gy and T1/2 = 1.5 hr, values which had not been contradicted by the multivariate analysis. Graphs were drawn both for "all grades including mild reactions" (grades 1 + 2 + 3) and for "serious" complications (grade 3 in our system). In addition, other published cervical brachytherapy series were reviewed, with calculation of their BEDs if not published by the authors. It was necessary to review and compare their grading systems, so that "mild and moderate" (grades 1 and 2) could be contrasted with "serious" (grades 3 and 4 or 5 in various systems). Comparisons were made with other published results, including three LDR, three MDR, and two HDR series spanning from 1982 to 1997. The BEDs at which the incidence of rectal complications rose above the arbitrary level of 10% were compared for all three ranges of dose rate. The multivariate analysis gave estimates of alpha/beta and T1/2 which were not significantly different from 3 Gy and 1.5 hr, respectively, so these values were used to compute the BEDs for the subsequent comparisons. It was found that the graphs of incidence of rectal complications for "all grades including mild" agreed rather better between all series than might have been expected, within a provisional (10%) threshold BED of range 100-123 Gy3 (60-74 Gy given as 2 Gy fractionated external beam or as LDR). The dose-response curves diverged above these values, as expected until common grading systems such as SOMA/ LENT become more widely used. For "serious" complications the 10% incidence occurred at a median BED of 140 Gy3 (84 Gy given as 2 Gy fractionated external beam or as LDR), range 124-155 Gy3. The use of BED (or extrapolated response dose), assuming alpha/beta = 3 Gy and T1/2 = 1.5 hr, instead of total dose, enabled incidence of late rectal complications in cervical brachytherapy with LDR, MDR, and HDR to be plotted in a reasonably consistent way. This does not mean that those parameter values have been definitively determined, but they appear to be provisional values that may be of use in comparing the expected effects of new schedules until better values are obtained from greater use of common grading systems.
Assuntos
Braquiterapia/efeitos adversos , Lesões por Radiação/epidemiologia , Reto/efeitos da radiação , Neoplasias do Colo do Útero/radioterapia , Relação Dose-Resposta à Radiação , Feminino , Seguimentos , Humanos , Incidência , Funções Verossimilhança , Análise Multivariada , Estadiamento de Neoplasias , Prognóstico , Lesões por Radiação/patologia , Dosagem Radioterapêutica , Doenças Retais/epidemiologia , Neoplasias do Colo do Útero/patologiaRESUMO
PURPOSE: To establish an optimum fractionation for medium dose rate (MDR) brachytherapy from retrospective data of patients treated with different MDR schedules in comparison with a low dose rate (LDR) schedule. METHODS AND MATERIALS: The study population consists of consecutive Stage IB-IIA-IIB patients who received radiotherapy alone with full dose brachytherapy plus external beam pelvic and parametrial irradiation from 1986-1993. Patients also receiving surgery or chemotherapy were excluded. The LDR group (n = 102, median follow-up: 80 months) received a median dose to Point A of two 32.5 Gy fractions at 0.44 Gy/h plus 18 Gy of external whole pelvic irradiation. The MDR1 group (n = 30, median follow-up: 45 months) received a mean dose of two 32 Gy fractions at 1.68 Gy/h. An individual dose reduction of 12.5% was planned for this group according to the Manchester experience, but only a 4.8% dose reduction was achieved. The MDR2 group (n = 10, median follow-up: 36 months) received a dose of two 24 Gy fractions at 1.65 Gy/h. The MDR3 group (n = 10, median follow-up 33 months) received a mean dose of three 15.3 Gy fractions at 1.64 Gy/h. And finally, the MDR4 group (n = 38, median follow-up: 24 months) received six 7.7 Gy fractions from two pulses 6 h apart in each of three insertions at 1.61 Gy/h. The median external pelvic dose to MDR schedules was between 12 and 20 Gy. The linear quadratic (LQ) formula was used to calculate the biologically effective dose (BED) to tumor (Gy10) and rectum (Gy3), assuming T1/2 for repair = 1.5 h. RESULTS: The crude central recurrence rate was 6% for LDR (mean BED = 95.4 Gy10) and 10% for MDR4 (mean BED = 77.0 Gy10) (p = NS). The remaining MDR groups had no recurrences. Grade 2 and 3 rectal or bladder complications were 0% for LDR (rectal BED = 109 Gy3) 83% for MDR1 (BED = 206 Gy3), and 30% for MDR3 (BED = 127 Gy3). The MDR2 and MDR4 groups presented no complications (BED, 123 Gy3, and 105 Gy3, respectively). The LQ formula appears to correlate with late complications of the different MDR regimens. A BED above 125 Gy3 was associated with Grade 2 + 3 rectal complications. Adequate central tumor control may be compromised with a tumor BED below 90-95 Gy10. CONCLUSIONS: Medium dose rate brachytherapy at 1.6 Gy/h to Point A has a marked dose rate effect. Increased fractionation is the cost of overcoming the less favorable therapeutic ratio for MDR than for LDR. A larger (25%) reduction of brachytherapy dose than previously reported is also necessary. Our most recently developed schedule for Stage I-II patients is three insertions on three treatment days with six 8.0 Gy brachytherapy fractionations, two on each treatment day, following or preceding an external whole pelvis dose of 18 Gy, and followed by additional external parametrial dose.