Radiotherapy and Oncology, 21 (1991) 163-170 © 1991 Elsevier Science Publishers B.V. 0167-8140/91/$03.50
163
RADION 00851
Dose fractionation and tumour repopulation in radiotherapy for bladder cancer B o g u s l a w Maciejewski a n d Stanislaw M a j e w s k i Cancer Center, M. Sktodowska-Curie Memorial Institute branch in Gliwice, 44-101 Poland
(Received 31 January 1990, revision received 19 June 1990, accepted 3 April 1991)
Key words: Bladder cancer; TCP curves; Overall treatment time; Accelerated tumour repopulation
Summary Local control of the 77 transitional cell carcinoma of the bladder was analysed with respect to total dose after normalization for variations in fraction size and to overall treatment time. For the TCDso of 63.3 Gy protraction of overall treatment time from 40 to 55 days average gave the decrease in local control rate from 50 ~o to about 5 }'o. The decrease in local tumour control with extension of overall treatment time likely reflects accelerated tumour repopulation during the treatment. To determine the time onset of the accelerated tumour clonogen repopulation, data taken from the literature were analysed. Results show that on average tumour clonogen repopulation in transitional cell cancer of the bladder accelerates after a lag period of about 5-6 weeks after the start of treatment and that a dose increment of 0.36 Gy per day is required to compensate for this repopulation. Such a dose increment is consistent with about 5-8 day clonogen doubling time. It suggests that overall treatment time is an important factor in the dose fractionation and protraction of time may have a significant impact on treatment outcome. Thus, radiotherapy for bladder cancer should be completed as soon as possible and total dose for high probability of local tumour control should consequently be delivered in more than 5 fractions per week.
Introduction
Material and methods
Recently, a few clinical studies have shown, at least for head and neck cancers, that tumour clonogen repopulation which is time-dependent process, is one of the most important factors influencing tumour control [ 15-17, 23,28,30,31 ]. These studies show a significant decrease in local tumour control rate with protraction of overall treatment time. Review of the literature dealing with external irradiation of the bladder cancer reveals considerable variations both in the total dose, fractionation scheme and in the overall treatment time. However, dose-time relationship for bladder cancer have been analysed infrequently [8,22,24]. The aim of the present study is to analyse the time effect and tumour clonogen repopulation in radiotherapy for bladder cancer.
Present data Among 94 patients with bladder cancer previously analysed by Majewski [17], 77 patients with transitional cell cancer were included in the present study. The remaining 17 patients who had squamous cell carcinoma were excluded. Criteria for inclusion were: (1)age less than 75years; (2)no prior treatment; (3)histologically proven transitional cell carcinoma; (4) no distant metastases; (5) a minimum 3-year followup, There were 40patients with T 2 lesion and 37 patients with T 3 lesion respectively. All cases were treated with 6°Co gamma-rays alone. Total tumour absorbed dose ranged from 60 to 75 Gy, dose per fraction from 1.9 to 2.5 Gy and overall treat-
Address for correspondence: B. Maciejewski, Radiotherapy Clinic, Cancer Center, Institute Ar. Czerwonej Street 15, 44-101 Gliwice, Poland.
164 ment time from 35 to 75 days. In an individual patient, the dose per fraction was constant throughout treatment. Forty-one patients received continuous irradiation and 36 were treated using split-course regimen. The patients presented here are part of the material characterised in more detail elsewhere [17].
TO compare data taken from the literature, in which control rates were usually different from 50%, TCDso values were calculated similarly as for head and neck tumours [31], based on the Poisson assumption that the slope of the dose-response curve reflects and efr~riveD o. Change in dose (AD) to achieve 50% cure probability (Pcur~ = 0.5) was calculated from
Data selected from the literature A D = n X ~frDo
To analyse dose-response relationships and tumour repopulation 13 data sets were taken from the literature [3,4,6-8,11,12,14,19-22,24,28] which permitted a reasonably adequate assessment of local tumour control rate, dose per fraction, total dose and overall treatment time. Transitional cell tumours only were included. Follow-up was usually 5 years, although for the four sets [21,22,24,29] follow-up was shorter. Groupings of data for dose and stage of disease were those of the various authors, although in one case were taken from the figure [24]. Many papers were not taken into consideration because it was impossible to reconstruct treatment parameters. No correction for variations in dosimetry (e.g. calibration, dose specification) was made.
where e~/)o of 5.0 Gy was used and n = In [In 0.5/ln(Pobserv~d)]" The oerDo value of 5.0 Gy was chosen because of heterogeneity of tumours and treatment characteristics affecting the slope of the TCP curves, similarly to the previous analysis of the head and neck tumours [31 ]. Results
Figure 1 shows the actuarial survival according to the T stage. The 5-year actuarial survival was 40.5% for T 2 tumours and 34.8 % for T 3 tumours respectively. At 5 years actuarial local tumour control was 32% and 23.5 % respectively. Since differences in the 5-year survival and local control were not significant, for the present analysis T 2 and W3 tumours were grouped together. Results of treatment were previously presented in details and discussed by Majewski [ 17].
Normalized Total Dose (NTD2 cy)
Total doses for the present data and for those taken from the literature were normalized to the doses which would have been isoeffective if given in 2 Gy fractions, using the linear-quadratic formula [16,32]: NTD2
Gy
=
Dx
+
Latency time of recurrent tumours
Fifty-five of the 77 patients (71%) with transitional cell cancer of the bladder had complete local tumour regression. There were no significant differences in the proportions with complete tumour regression by tumour stage and fractionation schedule. One-third of the
d.
+ 2.0
where D× is a total dose, dx is dose per fraction and ~/fl is a tumour characteristic. An a/flvalue of 15.0 Gy was taken [ 16,30]. Using the a/fl value of 10.0 Gy instead of 15.0 Gy would only slightly increase the adjustment made to the total tumour dose. Calculating TCD so
Present data were subdivided into four groups such that for all cases within each group an overall treatment time was in the narrow range of 35-40, 41-50, 51-60 and 61-75 days. In the last group, only four patients were treated with overall treatment time longer than 70 days. For each of the four time compartments doses to yield from 10 to 90% probability of the 3-year local tumour control (TCDlo-TCD9o) were calculated using the logistic regression analysis, similar to that proposed by Fischer [9] and Porter [25].
100°/o
L.
..J
X rr"
T
163
RADION 00851
Dose fractionation and tumour repopulation in radiotherapy for bladder cancer B o g u s l a w Maciejewski a n d Stanislaw M a j e w s k i Cancer Center, M. Sktodowska-Curie Memorial Institute branch in Gliwice, 44-101 Poland
(Received 31 January 1990, revision received 19 June 1990, accepted 3 April 1991)
Key words: Bladder cancer; TCP curves; Overall treatment time; Accelerated tumour repopulation
Summary Local control of the 77 transitional cell carcinoma of the bladder was analysed with respect to total dose after normalization for variations in fraction size and to overall treatment time. For the TCDso of 63.3 Gy protraction of overall treatment time from 40 to 55 days average gave the decrease in local control rate from 50 ~o to about 5 }'o. The decrease in local tumour control with extension of overall treatment time likely reflects accelerated tumour repopulation during the treatment. To determine the time onset of the accelerated tumour clonogen repopulation, data taken from the literature were analysed. Results show that on average tumour clonogen repopulation in transitional cell cancer of the bladder accelerates after a lag period of about 5-6 weeks after the start of treatment and that a dose increment of 0.36 Gy per day is required to compensate for this repopulation. Such a dose increment is consistent with about 5-8 day clonogen doubling time. It suggests that overall treatment time is an important factor in the dose fractionation and protraction of time may have a significant impact on treatment outcome. Thus, radiotherapy for bladder cancer should be completed as soon as possible and total dose for high probability of local tumour control should consequently be delivered in more than 5 fractions per week.
Introduction
Material and methods
Recently, a few clinical studies have shown, at least for head and neck cancers, that tumour clonogen repopulation which is time-dependent process, is one of the most important factors influencing tumour control [ 15-17, 23,28,30,31 ]. These studies show a significant decrease in local tumour control rate with protraction of overall treatment time. Review of the literature dealing with external irradiation of the bladder cancer reveals considerable variations both in the total dose, fractionation scheme and in the overall treatment time. However, dose-time relationship for bladder cancer have been analysed infrequently [8,22,24]. The aim of the present study is to analyse the time effect and tumour clonogen repopulation in radiotherapy for bladder cancer.
Present data Among 94 patients with bladder cancer previously analysed by Majewski [17], 77 patients with transitional cell cancer were included in the present study. The remaining 17 patients who had squamous cell carcinoma were excluded. Criteria for inclusion were: (1)age less than 75years; (2)no prior treatment; (3)histologically proven transitional cell carcinoma; (4) no distant metastases; (5) a minimum 3-year followup, There were 40patients with T 2 lesion and 37 patients with T 3 lesion respectively. All cases were treated with 6°Co gamma-rays alone. Total tumour absorbed dose ranged from 60 to 75 Gy, dose per fraction from 1.9 to 2.5 Gy and overall treat-
Address for correspondence: B. Maciejewski, Radiotherapy Clinic, Cancer Center, Institute Ar. Czerwonej Street 15, 44-101 Gliwice, Poland.
164 ment time from 35 to 75 days. In an individual patient, the dose per fraction was constant throughout treatment. Forty-one patients received continuous irradiation and 36 were treated using split-course regimen. The patients presented here are part of the material characterised in more detail elsewhere [17].
TO compare data taken from the literature, in which control rates were usually different from 50%, TCDso values were calculated similarly as for head and neck tumours [31], based on the Poisson assumption that the slope of the dose-response curve reflects and efr~riveD o. Change in dose (AD) to achieve 50% cure probability (Pcur~ = 0.5) was calculated from
Data selected from the literature A D = n X ~frDo
To analyse dose-response relationships and tumour repopulation 13 data sets were taken from the literature [3,4,6-8,11,12,14,19-22,24,28] which permitted a reasonably adequate assessment of local tumour control rate, dose per fraction, total dose and overall treatment time. Transitional cell tumours only were included. Follow-up was usually 5 years, although for the four sets [21,22,24,29] follow-up was shorter. Groupings of data for dose and stage of disease were those of the various authors, although in one case were taken from the figure [24]. Many papers were not taken into consideration because it was impossible to reconstruct treatment parameters. No correction for variations in dosimetry (e.g. calibration, dose specification) was made.
where e~/)o of 5.0 Gy was used and n = In [In 0.5/ln(Pobserv~d)]" The oerDo value of 5.0 Gy was chosen because of heterogeneity of tumours and treatment characteristics affecting the slope of the TCP curves, similarly to the previous analysis of the head and neck tumours [31 ]. Results
Figure 1 shows the actuarial survival according to the T stage. The 5-year actuarial survival was 40.5% for T 2 tumours and 34.8 % for T 3 tumours respectively. At 5 years actuarial local tumour control was 32% and 23.5 % respectively. Since differences in the 5-year survival and local control were not significant, for the present analysis T 2 and W3 tumours were grouped together. Results of treatment were previously presented in details and discussed by Majewski [ 17].
Normalized Total Dose (NTD2 cy)
Total doses for the present data and for those taken from the literature were normalized to the doses which would have been isoeffective if given in 2 Gy fractions, using the linear-quadratic formula [16,32]: NTD2
Gy
=
Dx
+
Latency time of recurrent tumours
Fifty-five of the 77 patients (71%) with transitional cell cancer of the bladder had complete local tumour regression. There were no significant differences in the proportions with complete tumour regression by tumour stage and fractionation schedule. One-third of the
d.
+ 2.0
where D× is a total dose, dx is dose per fraction and ~/fl is a tumour characteristic. An a/flvalue of 15.0 Gy was taken [ 16,30]. Using the a/fl value of 10.0 Gy instead of 15.0 Gy would only slightly increase the adjustment made to the total tumour dose. Calculating TCD so
Present data were subdivided into four groups such that for all cases within each group an overall treatment time was in the narrow range of 35-40, 41-50, 51-60 and 61-75 days. In the last group, only four patients were treated with overall treatment time longer than 70 days. For each of the four time compartments doses to yield from 10 to 90% probability of the 3-year local tumour control (TCDlo-TCD9o) were calculated using the logistic regression analysis, similar to that proposed by Fischer [9] and Porter [25].
100°/o
L.
..J
X rr"
T
