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Once weekly irradiation for carcinoma of the bladder
Int. 1. Radiation
Oncology
Biol. Phys., Vol. 35, No. 2, pp. 289-292, 1996 Copyright 0 1996 Elsevier Science Inc. Printed in the USA. All rights reserved 0360.3016/96 $15.00 + .OO
PIT: SO360-3016(96)00063-6
l
Clinical Original Contribution ONCE WEEKLY IRRADIATION
FOR CARCINOMA
OF THE BLADDER
A. Y. ROSTOM, F.R.C.R.,’ S. TAHIR, F.R.C.R., A. R. GERSHUNY, M.R.C.P F.R.C.R., A. KANDIL, M.D.,’ A. FOLKES, F.R.C.R. AND W. F. WHITE, F.R.C.R. Regional Centre for Clinical Oncology, St. Lukes Hospital, Surrey, UK Purpose: A dose-searching study was carried out treating selected elderly patients or patients with poor performance with bladder cancer with once weekly fractionation to determine an effective dose per fraction, and to evaluate acute and late effects resulting from this schedule. Methods and Materials: Seventy patients with invasive transitional cell carcinoma of the bladder were entered in the study. The dose used was 36-39 Gy in six fractions over 35 days in 27 patients (Group 1). The remaining 43 patients were treated with 34.5 Gy in six fractions over 39 days (Group 2). Results: Six patients developed Grade l-2 European Organization for Research on Treatment of Cancer (EORTC) bowel reaction. Three patients in Group 1 developed Grade 3 late bowel reaction and a fourth patient developed Grade 4 reaction requiring colostomy. However, only one patient in Group 2 developed Grade 3 reaction. The difference between the two groups was statistically signiftcant (2 = 3.794,~ = 0.05). Conclusions: The acute and late reaction as well as the 5-year free survival for patients in Group 2 compare favorablv with daily treatment. We conclude that 34.5 Gy given over 39 days is a safe and effective treatment for seleckd patients with bladder cancer. Bladder cancer, Radiotherapy, Hypofractionation.
prospective study to assess the efficacy of once weekly limited field irradiation in controlling local disease and to study the effect on normal tissues. A radical radiotherapy dose of 60 Gy given in 30 fractions, on a daily basis should yield a Nominal Standard Dose (NSD) of 1767 ret. To give such a dose in six fractions on a weekly basis, 6.8 Gy fractions should be given. However, on the recommendation of Dr. Frank Ellis (written personal communication, March 1982) a 5% reduction in the total dose was made. The dose per fraction was progressively reduced because of the development of significant late bowel damage from 6.5 to 6.25 to 6.0 Gy. Following Fowlers and Withers et aE. publications (3, 4, 12) on the Linear Quadratic Model in 1983-1984 a further reduction of the weekly dose to 5.75 Gy was made and the overall treatment time was increased to 39 days.
INTRODUCTION Radiotherapy has an established role in the treatment of invasive-transitional cell carcinoma of the bladder. Whereas the cure rate of T2 lesions is about 40-45%, patients with more advanced Stage T3 have a lower cure rate of about 20-30% (2, 5, 6, 7). Significant palliation of local symptoms and occasional cure of some patients with T4 has been reported following radiotherapy (2). The majority of patients with bladder cancer are over 60 years of age and a significant proportion of these will have poor performance status; therefore, short courses of hypofractionated regimens have been advocated for the elderly and patients with poor performance (2, 9, 10). In a previous publication from this center, a selected group of elderly patients with advanced breast cancer were treated on a once weekly regimen. This was well tolerated. The acute and late reactions, as well as local control, were similar to those achieved with daily treatment (8). Between 1983 and 1993, selected elderly patients with advanced bladder cancer were entered in a
METHODS AND MATERIALS Between March 1983 and December 1993,72 patients with histologically proven invasive transitional cell carci-
Reprint requests to: Dr. A. Y. Rostom, Head, Radiation Oncology, MBC 34, King Faisal Specialist Hospital & Research Centre, P.O. Box 3354, Riyadh 11211, Saudi Arabia. Acknowledgements-Our thanks are due to our urological colleagues who referred the patients in this series. In order of referral numbers: Mr. Harvey Hills, Mr. Richard Notley, Mr.
Edward Palfrey, and Mr. Frank Schwitzer. Our thanks also to Ms. Janet Santana for preparing and typing the manuscript. Accepted for publication 5 February 1996. ’ Present address: Section of Radiation Oncology, MBC 34, Department of Oncology, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia. 289
290
1. J. Radiation Oncology l Biology 0 Physics Table 1. Patients criteria
Female Male T-Stage Tl T2 T3 T4 Unknown
No.
9%
1.5 55
21.4 78.6
2 16 41 6 5
2.8 22.8 58.6 8.6 7.2
noma of the bladder were treated with a weekly hypofractionated schedule. Included in this group were elderly patients, those with poor performance status or patients unfit for surgery. The median age was 80 years (Fig. 1) , and 44 patients had T3 tumors (Table 1) . All patients underwent pretreatment cystoscopy, examination under anesthetic (EUA), biopsy and chest x-ray, and computerized tomography (CT) scan of the pelvis in selected cases. The target volume included the bladder with l-2 cm margins after careful radiotherapy planning by cystogram or CT. Two patients who did not complete the planned six fractions were excluded form the final analysis. Sixtyfive patients were treated with the three- to four-field technique using 8 MV x-rays, and the remaining five patients treated with two lateral arc cobalt rotations. The patients in this series can be divided into two groups according to the dose and overall treatment time. Group 1
Twenty-seven patients treated every 7 days (35-day overall time) for a total of six fractions. The first 5 patients received 39 Gy in six fractions (6.5 Gy X 6), a further 6 patients received 37.5 Gy in six fractions (6.25 Gy X 6)) and the remaining 16 patients in this group were given 36 Gy in six fractions (600 Gy X 6). This progressive reduction dose was made because of the development of unexpected Grade 3 and 4 rectal reaction.
Volume 35, Number 2, IYYh
patients received 34.5 Gy (5.75 Gy X 6) and the remaining 8 patients received 34.2 Gy (5.7 Gy x 6). During radiotherapy patients were assessed at weekly intervals and acute reactions recorded. Following radiotherapy, patients were seen after 1 month and every 3 months thereafter. Follow-up of some patients was carried out by the family practitioner who participated by returning a written questionnaire. Only 30 patients had cystoscopic assessment following radiotherapy. This was usually carried out at 6 months or earlier depending on the presence or absence of symptoms. The survival curves were plotted using the life table method. The log rank test was used for statistical analysis. RESULTS Two patients died before the completion of the planned six treatments (one presenting with metastases) ; both patients were from Group 2 and have been excluded from the final analysis. Three patients were lost to follow-up, but these were included in the final survival analysis. Acute reactions
The treatment was well-tolerated by the majority patients. Diarrhea, Grade l-2 European Organization Research and Treatment of Cancer (EORTC) was ported by six patients (8.6% of cases) and settled dietary regulation plus Loperamide or Codeine. Urinary symptom
Completely subsided following the 70 patients (74.3%).
radiotherapy in 52 of
Late bowel reaction Group 1. Three patients developed Grade 3 rectal reac-
tion treated symptomatically and resolved, and a 4th patient developed Grade 4 rectal reaction requiring colostomy (14.8%). She died 10 years later from natural causes at the age of 93.
Group 2
Forty-three patients: this group of patients were treated with a further reduction of the total dose to 34.5 Gy delivered in six fractions in accordance to the linear quadratic model with an increased overall time of 39 days. In the conventional 60 Gy in 6 weeks daily treatment, starting on a Monday, the actual overall time, for instance, the time between the first and the last fraction, was 39 days and not 42 days. Accordingly, it was decided to spread the six fractions over a 39-day period. For example, patients were given the first fraction on a Monday, the next fraction on the Tuesday of the following week, the third fraction on the Wednesday of the week after, the fourth fraction on the Thursday of the fourth week, and the remaining two fractions on the last 2 Fridays, keeping the overall time to 39 days. In this group 37
of for reby
AGE
M YfW?S
Fig. 1. Age distribution.
Once weekly irradiation for carcinoma of the bladder 0 A. Y. ROSTOM ef al. 100
100
90
90
-
T2
80 r-k
80 F7-Y
-
T3
z
6o
2
50
s
5
40 30 : 70-
L
‘I; , , I , , . I , , 0
10
20
30
40
TIME
IN MONTHS
Fig. 2. Overall
50
60
70
10
0
20 TIME
80
Fig. 4. Overall
survival
30 40 IN MONTHS
according
50
60
to T stage.
survival.
Group 2. Only one patient in this group developed Grade 3 reaction (2.3%)) which was treated symptomatically and resolved. The difference between the two groups was statistically significant (x7 = 3.794, p = 0.05). Late bladder reaction Only one patient from Group 1 developed symptomatic contracted bladder of 80 ml capacity. This patient was treated with two lateral arc cobalt rotations and received 6.5 Gy X 6. Patient declined active treatment and is the longest survivor in this series. Survival At the time of reporting, 13 patients were still alive and well. The remaining 57 patients died with a median survival of 47.2 months. The overall crude actuarial survival rate was 28.4% (Fig. 2). There was no statistical difference in survival between patients in Group 1 and Group 2 (p = 0.2) (Fig. 3). Patients with T2 tumor appeared to have fared better than those with T3 tumors, with a 5-year survival rate of
-
(5.7-5.75
Gy/F)
+
(6.0-6.5
Gy/F)
45.8% and 24.9%, respectively. However, this was not statistically significant (p = 0.1) (Fig. 4). The 5-year crude actuarial survival rate of patients over the age of 80 was compared to younger patients and there was no statistical difference between the two groups (p = 0.2) (Fig. 5).
DISCUSSION Conventional fractionation (five fractions per week) is a standard that can be challenged. Two Gy per fraction given daily for 4.5 to 6.5 weeks is the standard treatment for most sites of the body. This schedule has proven safe and effective in controlling cancer. However, a reduced fractionation schedule once, twice, or three times a week has obvious logistical advantages not only for the patient but also for busy oncology departments. Such schedules have been attempted over the years with different results. The overall feeling is that reduced fractionation is associated with reduced or no acute reactions ( 11 ), but the effect on the late reacting tissues is higher than expected from conventional fractionations ( 1). To help solve the fraction size problems, several mathematical formulae
-
a80 YEARS
-
65-79
YEARS
P=O.2 P=O.2
IO ”
1 0
lb
Fig. 3. Overall
2’0 TIME
survival
30 40 IN MONTHS
according
50
to dose/fraction.
60
0
10
20
Fig. 5. Overall
30 TIME
40 50 IN MONTHS
survival
according
60
to age
70
80
32
I. J. Radiation
Oncology
0 Biology
0 Physics
have been proposed and used in practice, for example, NSD, Tumor Dose Fraction (TDF), Cumulative Radiation Effect (CRE), and. more recently, the linear quadratic model. The latter is the most widely accepted in today’s practice. However the original formula (4), when published after the start of this study, did not address the subject of overall time. For this reason, the overall time of 39 days spent in conventional 60 Gy in 6 weeks treatment was adhered to. The only way to spread the six fractions over this period was to allow an &day gap between fractions l-5 and then a 7-day gap before the last fraction. The dose for Group 1 patients proved too high, with three patients developing Grade 3 EORTC rectal reaction and a 4th patient with Grade 4 reaction requiring colostomy. Because of this the dose had to be progressively reduced from 650 to 600 Gy per fraction. Later, with Fowlers and Withers et al. writing on the Linear Quadratic Model assuming an LY//? ratio for late tissue damage of 3 Gy (7.8)) a dose of 3428 Gy in six fractions
Volume
35, Number
2, 1996
would be equivalent to 60 Gy in 30 fractions and, accordingly, the dose of 5.7-5.75 Gy per fraction was used in patients in Group 2 of this study. The acute reaction observed both in Group 1 and Group 2 patients was mild and not excessive. However, 4 out of 27 patients developed Grade 3-4 rectal reaction in Group 1; this was significantly higher than Group 2 patients with 1 out of 43 developing transient Grade 3 reaction. Acute and late reactions in Group 2 patients compare favorably to a daily fractionated regimen (2, 5, 7). In addition. the 5-year survival rate of patients over 80 years of age was 29.4%, for patients with T2 and T3 tumors, this was 45.8% and 24.9%, respectively. These, too, compare favorably with other published data obtained from daily treatment (2. 5. 7). Although the number of patients in Group 2 in this study is small, we feel that 3450 Gy given in six fractions over 39 days is an effective treatment for selected patients with invasive bladder cancer with acceptable acute and late morbidity.
REFERENCES 1.
2.
3.
4. 5.
6.
Cox, J. Large dose fractionation (hypofractionation). Cancer. 95:2105-2111; 1985. Duncan, W.; Quilty, P. M. The results of a series of 963 patients with transitional cell carcinoma of the urinary bladder primarily treated by radical megavoltage x-ray therapy. Radiother. Oncol. 7:299-310; 1986. Fowler, J. F. Fractionated radiation therapy after Strandqvist. Acta Radiol. Oncol. 23:209-216; 1984. Fowler, J. F. What next in fractionated radiotherapy. Br. J. Cancer 49(Suppl. VI):285-300; 1984. Gospodarowicz, M. K.; Rider, W. D.; Keen, C. W.; Connolly. J. G.; Jewett, M. A. S.; Cummings, B. J.; Duncan, W.; Warde, P.; Chua, T. Bladder cancer. Long term followup results of patients treated with radical radiation. Clin. Oncol. 3:155-161; 1991. Hope-Stone, H. F.; Oliver, R. T. D.; England, H. R.; Blandy, J. B. T3 bladder cancer: Salvage rather than elective cystectomy after radiotherapy. Urology 315-320; 1984.
7. Quilty, P. M.; Kerr, G. R.; Duncan, W. Prognostic indices
for bladder cancer: An analysis of patients with transitional cell carcinoma of the bladder primarily treated by radical megavoltage x-ray therapy. Radiother. Oncol. 7:31 l-321; 1986. 8. Rostom, A. Y.; Pradhan, D. G.; White, W. F. Once weekly irradiation in breast cancer. Int. J. Radiat. Oncol. Biol. Phys. 13:551-555; 1987. 9. Salminen, E. Unconventional fractionation for palliative radiotherapy of urinary bladder cancer. Acta Oncol. 3 1:449454; 1992,
IO Srinivasa, V.; Brown, C. H.; Turner, A. G. A comparison of two radiotherapy regimens for the treatment of symptoms from advanced bladder cancer. Clin. Oncol. 6: ll- 13; 1994. 11. Turesson, I.; Netter, G. The influence of fraction size in radiotherapy on the late and normal tissue reactions. Int. J. Radiat. Oncol. Biol. Phys. l&593-598; 1984. 12. Withers, H. R.; Thames, H. D.; Peters,L. J. A new isoeffect curve for change in dose per fraction. Radiother. Oncol. 1:187-191; 1983.
Oncology
Biol. Phys., Vol. 35, No. 2, pp. 289-292, 1996 Copyright 0 1996 Elsevier Science Inc. Printed in the USA. All rights reserved 0360.3016/96 $15.00 + .OO
PIT: SO360-3016(96)00063-6
l
Clinical Original Contribution ONCE WEEKLY IRRADIATION
FOR CARCINOMA
OF THE BLADDER
A. Y. ROSTOM, F.R.C.R.,’ S. TAHIR, F.R.C.R., A. R. GERSHUNY, M.R.C.P F.R.C.R., A. KANDIL, M.D.,’ A. FOLKES, F.R.C.R. AND W. F. WHITE, F.R.C.R. Regional Centre for Clinical Oncology, St. Lukes Hospital, Surrey, UK Purpose: A dose-searching study was carried out treating selected elderly patients or patients with poor performance with bladder cancer with once weekly fractionation to determine an effective dose per fraction, and to evaluate acute and late effects resulting from this schedule. Methods and Materials: Seventy patients with invasive transitional cell carcinoma of the bladder were entered in the study. The dose used was 36-39 Gy in six fractions over 35 days in 27 patients (Group 1). The remaining 43 patients were treated with 34.5 Gy in six fractions over 39 days (Group 2). Results: Six patients developed Grade l-2 European Organization for Research on Treatment of Cancer (EORTC) bowel reaction. Three patients in Group 1 developed Grade 3 late bowel reaction and a fourth patient developed Grade 4 reaction requiring colostomy. However, only one patient in Group 2 developed Grade 3 reaction. The difference between the two groups was statistically signiftcant (2 = 3.794,~ = 0.05). Conclusions: The acute and late reaction as well as the 5-year free survival for patients in Group 2 compare favorablv with daily treatment. We conclude that 34.5 Gy given over 39 days is a safe and effective treatment for seleckd patients with bladder cancer. Bladder cancer, Radiotherapy, Hypofractionation.
prospective study to assess the efficacy of once weekly limited field irradiation in controlling local disease and to study the effect on normal tissues. A radical radiotherapy dose of 60 Gy given in 30 fractions, on a daily basis should yield a Nominal Standard Dose (NSD) of 1767 ret. To give such a dose in six fractions on a weekly basis, 6.8 Gy fractions should be given. However, on the recommendation of Dr. Frank Ellis (written personal communication, March 1982) a 5% reduction in the total dose was made. The dose per fraction was progressively reduced because of the development of significant late bowel damage from 6.5 to 6.25 to 6.0 Gy. Following Fowlers and Withers et aE. publications (3, 4, 12) on the Linear Quadratic Model in 1983-1984 a further reduction of the weekly dose to 5.75 Gy was made and the overall treatment time was increased to 39 days.
INTRODUCTION Radiotherapy has an established role in the treatment of invasive-transitional cell carcinoma of the bladder. Whereas the cure rate of T2 lesions is about 40-45%, patients with more advanced Stage T3 have a lower cure rate of about 20-30% (2, 5, 6, 7). Significant palliation of local symptoms and occasional cure of some patients with T4 has been reported following radiotherapy (2). The majority of patients with bladder cancer are over 60 years of age and a significant proportion of these will have poor performance status; therefore, short courses of hypofractionated regimens have been advocated for the elderly and patients with poor performance (2, 9, 10). In a previous publication from this center, a selected group of elderly patients with advanced breast cancer were treated on a once weekly regimen. This was well tolerated. The acute and late reactions, as well as local control, were similar to those achieved with daily treatment (8). Between 1983 and 1993, selected elderly patients with advanced bladder cancer were entered in a
METHODS AND MATERIALS Between March 1983 and December 1993,72 patients with histologically proven invasive transitional cell carci-
Reprint requests to: Dr. A. Y. Rostom, Head, Radiation Oncology, MBC 34, King Faisal Specialist Hospital & Research Centre, P.O. Box 3354, Riyadh 11211, Saudi Arabia. Acknowledgements-Our thanks are due to our urological colleagues who referred the patients in this series. In order of referral numbers: Mr. Harvey Hills, Mr. Richard Notley, Mr.
Edward Palfrey, and Mr. Frank Schwitzer. Our thanks also to Ms. Janet Santana for preparing and typing the manuscript. Accepted for publication 5 February 1996. ’ Present address: Section of Radiation Oncology, MBC 34, Department of Oncology, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia. 289
290
1. J. Radiation Oncology l Biology 0 Physics Table 1. Patients criteria
Female Male T-Stage Tl T2 T3 T4 Unknown
No.
9%
1.5 55
21.4 78.6
2 16 41 6 5
2.8 22.8 58.6 8.6 7.2
noma of the bladder were treated with a weekly hypofractionated schedule. Included in this group were elderly patients, those with poor performance status or patients unfit for surgery. The median age was 80 years (Fig. 1) , and 44 patients had T3 tumors (Table 1) . All patients underwent pretreatment cystoscopy, examination under anesthetic (EUA), biopsy and chest x-ray, and computerized tomography (CT) scan of the pelvis in selected cases. The target volume included the bladder with l-2 cm margins after careful radiotherapy planning by cystogram or CT. Two patients who did not complete the planned six fractions were excluded form the final analysis. Sixtyfive patients were treated with the three- to four-field technique using 8 MV x-rays, and the remaining five patients treated with two lateral arc cobalt rotations. The patients in this series can be divided into two groups according to the dose and overall treatment time. Group 1
Twenty-seven patients treated every 7 days (35-day overall time) for a total of six fractions. The first 5 patients received 39 Gy in six fractions (6.5 Gy X 6), a further 6 patients received 37.5 Gy in six fractions (6.25 Gy X 6)) and the remaining 16 patients in this group were given 36 Gy in six fractions (600 Gy X 6). This progressive reduction dose was made because of the development of unexpected Grade 3 and 4 rectal reaction.
Volume 35, Number 2, IYYh
patients received 34.5 Gy (5.75 Gy X 6) and the remaining 8 patients received 34.2 Gy (5.7 Gy x 6). During radiotherapy patients were assessed at weekly intervals and acute reactions recorded. Following radiotherapy, patients were seen after 1 month and every 3 months thereafter. Follow-up of some patients was carried out by the family practitioner who participated by returning a written questionnaire. Only 30 patients had cystoscopic assessment following radiotherapy. This was usually carried out at 6 months or earlier depending on the presence or absence of symptoms. The survival curves were plotted using the life table method. The log rank test was used for statistical analysis. RESULTS Two patients died before the completion of the planned six treatments (one presenting with metastases) ; both patients were from Group 2 and have been excluded from the final analysis. Three patients were lost to follow-up, but these were included in the final survival analysis. Acute reactions
The treatment was well-tolerated by the majority patients. Diarrhea, Grade l-2 European Organization Research and Treatment of Cancer (EORTC) was ported by six patients (8.6% of cases) and settled dietary regulation plus Loperamide or Codeine. Urinary symptom
Completely subsided following the 70 patients (74.3%).
radiotherapy in 52 of
Late bowel reaction Group 1. Three patients developed Grade 3 rectal reac-
tion treated symptomatically and resolved, and a 4th patient developed Grade 4 rectal reaction requiring colostomy (14.8%). She died 10 years later from natural causes at the age of 93.
Group 2
Forty-three patients: this group of patients were treated with a further reduction of the total dose to 34.5 Gy delivered in six fractions in accordance to the linear quadratic model with an increased overall time of 39 days. In the conventional 60 Gy in 6 weeks daily treatment, starting on a Monday, the actual overall time, for instance, the time between the first and the last fraction, was 39 days and not 42 days. Accordingly, it was decided to spread the six fractions over a 39-day period. For example, patients were given the first fraction on a Monday, the next fraction on the Tuesday of the following week, the third fraction on the Wednesday of the week after, the fourth fraction on the Thursday of the fourth week, and the remaining two fractions on the last 2 Fridays, keeping the overall time to 39 days. In this group 37
of for reby
AGE
M YfW?S
Fig. 1. Age distribution.
Once weekly irradiation for carcinoma of the bladder 0 A. Y. ROSTOM ef al. 100
100
90
90
-
T2
80 r-k
80 F7-Y
-
T3
z
6o
2
50
s
5
40 30 : 70-
L
‘I; , , I , , . I , , 0
10
20
30
40
TIME
IN MONTHS
Fig. 2. Overall
50
60
70
10
0
20 TIME
80
Fig. 4. Overall
survival
30 40 IN MONTHS
according
50
60
to T stage.
survival.
Group 2. Only one patient in this group developed Grade 3 reaction (2.3%)) which was treated symptomatically and resolved. The difference between the two groups was statistically significant (x7 = 3.794, p = 0.05). Late bladder reaction Only one patient from Group 1 developed symptomatic contracted bladder of 80 ml capacity. This patient was treated with two lateral arc cobalt rotations and received 6.5 Gy X 6. Patient declined active treatment and is the longest survivor in this series. Survival At the time of reporting, 13 patients were still alive and well. The remaining 57 patients died with a median survival of 47.2 months. The overall crude actuarial survival rate was 28.4% (Fig. 2). There was no statistical difference in survival between patients in Group 1 and Group 2 (p = 0.2) (Fig. 3). Patients with T2 tumor appeared to have fared better than those with T3 tumors, with a 5-year survival rate of
-
(5.7-5.75
Gy/F)
+
(6.0-6.5
Gy/F)
45.8% and 24.9%, respectively. However, this was not statistically significant (p = 0.1) (Fig. 4). The 5-year crude actuarial survival rate of patients over the age of 80 was compared to younger patients and there was no statistical difference between the two groups (p = 0.2) (Fig. 5).
DISCUSSION Conventional fractionation (five fractions per week) is a standard that can be challenged. Two Gy per fraction given daily for 4.5 to 6.5 weeks is the standard treatment for most sites of the body. This schedule has proven safe and effective in controlling cancer. However, a reduced fractionation schedule once, twice, or three times a week has obvious logistical advantages not only for the patient but also for busy oncology departments. Such schedules have been attempted over the years with different results. The overall feeling is that reduced fractionation is associated with reduced or no acute reactions ( 11 ), but the effect on the late reacting tissues is higher than expected from conventional fractionations ( 1). To help solve the fraction size problems, several mathematical formulae
-
a80 YEARS
-
65-79
YEARS
P=O.2 P=O.2
IO ”
1 0
lb
Fig. 3. Overall
2’0 TIME
survival
30 40 IN MONTHS
according
50
to dose/fraction.
60
0
10
20
Fig. 5. Overall
30 TIME
40 50 IN MONTHS
survival
according
60
to age
70
80
32
I. J. Radiation
Oncology
0 Biology
0 Physics
have been proposed and used in practice, for example, NSD, Tumor Dose Fraction (TDF), Cumulative Radiation Effect (CRE), and. more recently, the linear quadratic model. The latter is the most widely accepted in today’s practice. However the original formula (4), when published after the start of this study, did not address the subject of overall time. For this reason, the overall time of 39 days spent in conventional 60 Gy in 6 weeks treatment was adhered to. The only way to spread the six fractions over this period was to allow an &day gap between fractions l-5 and then a 7-day gap before the last fraction. The dose for Group 1 patients proved too high, with three patients developing Grade 3 EORTC rectal reaction and a 4th patient with Grade 4 reaction requiring colostomy. Because of this the dose had to be progressively reduced from 650 to 600 Gy per fraction. Later, with Fowlers and Withers et al. writing on the Linear Quadratic Model assuming an LY//? ratio for late tissue damage of 3 Gy (7.8)) a dose of 3428 Gy in six fractions
Volume
35, Number
2, 1996
would be equivalent to 60 Gy in 30 fractions and, accordingly, the dose of 5.7-5.75 Gy per fraction was used in patients in Group 2 of this study. The acute reaction observed both in Group 1 and Group 2 patients was mild and not excessive. However, 4 out of 27 patients developed Grade 3-4 rectal reaction in Group 1; this was significantly higher than Group 2 patients with 1 out of 43 developing transient Grade 3 reaction. Acute and late reactions in Group 2 patients compare favorably to a daily fractionated regimen (2, 5, 7). In addition. the 5-year survival rate of patients over 80 years of age was 29.4%, for patients with T2 and T3 tumors, this was 45.8% and 24.9%, respectively. These, too, compare favorably with other published data obtained from daily treatment (2. 5. 7). Although the number of patients in Group 2 in this study is small, we feel that 3450 Gy given in six fractions over 39 days is an effective treatment for selected patients with invasive bladder cancer with acceptable acute and late morbidity.
REFERENCES 1.
2.
3.
4. 5.
6.
Cox, J. Large dose fractionation (hypofractionation). Cancer. 95:2105-2111; 1985. Duncan, W.; Quilty, P. M. The results of a series of 963 patients with transitional cell carcinoma of the urinary bladder primarily treated by radical megavoltage x-ray therapy. Radiother. Oncol. 7:299-310; 1986. Fowler, J. F. Fractionated radiation therapy after Strandqvist. Acta Radiol. Oncol. 23:209-216; 1984. Fowler, J. F. What next in fractionated radiotherapy. Br. J. Cancer 49(Suppl. VI):285-300; 1984. Gospodarowicz, M. K.; Rider, W. D.; Keen, C. W.; Connolly. J. G.; Jewett, M. A. S.; Cummings, B. J.; Duncan, W.; Warde, P.; Chua, T. Bladder cancer. Long term followup results of patients treated with radical radiation. Clin. Oncol. 3:155-161; 1991. Hope-Stone, H. F.; Oliver, R. T. D.; England, H. R.; Blandy, J. B. T3 bladder cancer: Salvage rather than elective cystectomy after radiotherapy. Urology 315-320; 1984.
7. Quilty, P. M.; Kerr, G. R.; Duncan, W. Prognostic indices
for bladder cancer: An analysis of patients with transitional cell carcinoma of the bladder primarily treated by radical megavoltage x-ray therapy. Radiother. Oncol. 7:31 l-321; 1986. 8. Rostom, A. Y.; Pradhan, D. G.; White, W. F. Once weekly irradiation in breast cancer. Int. J. Radiat. Oncol. Biol. Phys. 13:551-555; 1987. 9. Salminen, E. Unconventional fractionation for palliative radiotherapy of urinary bladder cancer. Acta Oncol. 3 1:449454; 1992,
IO Srinivasa, V.; Brown, C. H.; Turner, A. G. A comparison of two radiotherapy regimens for the treatment of symptoms from advanced bladder cancer. Clin. Oncol. 6: ll- 13; 1994. 11. Turesson, I.; Netter, G. The influence of fraction size in radiotherapy on the late and normal tissue reactions. Int. J. Radiat. Oncol. Biol. Phys. l&593-598; 1984. 12. Withers, H. R.; Thames, H. D.; Peters,L. J. A new isoeffect curve for change in dose per fraction. Radiother. Oncol. 1:187-191; 1983.