Acta Oncologica
ISSN: 0284-186X (Print) 1651-226X (Online) Journal homepage: http://www.tandfonline.com/loi/ionc20
Unconventional Fractionation for Palliative Radiotherapy of Urinary Bladder Cancer; A retrospective review of 94 patients Eeva Salminen To cite this article: Eeva Salminen (1992) Unconventional Fractionation for Palliative Radiotherapy of Urinary Bladder Cancer; A retrospective review of 94 patients, Acta Oncologica, 31:4, 449-454, DOI: 10.3109/02841869209088288 To link to this article: https://doi.org/10.3109/02841869209088288
Published online: 08 Jul 2009.
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Citing articles: 15 View citing articles
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Acra Oncologica Vol. 31, No. 4, pp. 449-454. 1992
UNCONVENTIONAL FRACTIONATION FOR PALLIATIVE RADIOTHERAPY OF URINARY BLADDER CANCER A retrospective review of 94 patients EEVA SALMINEN
Ninety-four urinary bladder cancer patients with locally advanced, recurrent or metastatic urinary bladder cancer were treated with external radiotherapy with the aim of palliating local disease. Conventional radical radiotherapy was inappropriate because of extensive disease, poor general condition or old age of the patients. The palliative course studied was 30Gy (mid-point dose) in six fractions, two fractions a week. Eighty-two patients (87%) tolerated treatment as planned. Forty patients (43%) had complete palliation of initial symptoms. Thirty-eight patients (40%) had initial local control of the tumour, which was lasting in 25 cases (26%). Median disease-specific survival of the patients was 13.3 months. The estimated five-year survival was 13% and survival from bladder cancer 27%.
Patients with extensive bladder cancer beyond radical local therapy require palliation when the tumour causes symptoms. The aim of palliation is relief of symptoms and local control of cancer without causing serious side-effects. Short-course treatment with unconventional fractionation has been used in pre-operative treatment of urinary bladder tumours ( 1-3). Longer schedules or even radical courses have been recommended for palliative treatment (4, 5 ) . Often, however, the patients d o not tolerate such treatment without deterioration of their quality of life, which negates the initial purpose of palliative treatment. The aim of the present study was to evaluate the effects of an unconventional palliative radiotherapy regimen in the treatment of urinary bladder cancer with respect to local control, palliation of symptoms and adverse effects of the treatment. Material and Methods
The medical records of patients at the Peter MacCallum Cancer Institute, in Melbourne, Australia, who were coded
Submitted 11 September 1990. Accepted 3 January 1992. Correspondence to: Dr Eeva Salminen, Department of Radiotherapy and Oncology, Helsinki University Central Hospital, Haartmaninkatu 4, SF-00290 Helsinki, Finland.
as having urinary bladder cancer and who were planned to receive palliative radiotherapy to the urinary bladder or pelvis between January 1983 and December 1985, were reviewed. Patients who had had prior pelvic radiotherapy were excluded. A questionnaire concerning follow-up and postradiotherapy treatments was sent to doctors of those patients, who had not been followed at the Institute. Pretreatment evaluation included history and physical examination, cystoscopy with biopsy and in most cases transurethral resection, bimanual examination with the patient under anaesthesia, excretory urograms, routine blood tests and chest x-ray. Urine cytology was not routinely performed in all patients. Computed tomography (CT) of pelvis and abdomen and/or bone scan were made if indicated. Tumour category and staging was estimated using the 1978 UICC system of classification (6) revised to accord with the 1987 classification (7). Patients were treated with megavoltage beams from a 4 or 6 MeV linear accelerator. The total mid point dose was 30 Gy given in 6 fractions, 2 fractions per week at least 2 days apart, over 3 weeks. Eighty-one patients (86%)) were treated with two opposed anterior and posterior fields, I 1 patients with three fields and 2 patients with four fields. Field size varied greatly because the treatment was planned according to the extend ot symptom-causing disease. Median field height was 120mm, (range 70 to 190mm). 449
450
E. SALMINEN
Heights of fields were grouped into 129mm (27 patients) to allow statistical comparison of differences in acute and late adverse effects by field height. The patients were reviewed weekly during the radiotherapy and then followed either by referring doctors or at the Peter MacCallum Cancer Institute. Control cystoscopies were performed when the patients’ general condition allowed this. Urine cytology, x-ray and radionuclide scans were performed if indicated. In those patients who could not have cystoscopy a clinical assessment of tumour was made, based on the presence of symptoms or signs indicating local tumour (e.g. haematuria, urine cytology for malignant cells, pain, uremia, lymph oedema or palpable mass). The evaluation of treatment response was based on results of these investigations and clinical assessment within 6 months after the treatment was completed. The requirement for classification as local control was no evidence of malignancy at cystoscopy, urine cytology or autopsy with resolution of tumour-related symptoms. All patients were followed until death or 17 August 1989, giving a minimum follow-up period of 45 months for living patients. BMDP statistical software versions 1988 and 1990 were used in the analysis (8). Survival (all causes), and time to progression (local or distant) were calculated from the date of commencement of radiotherapy. Survival from bladder cancer was measured from the date of commencement of radiotherapy to the date of death or the close-out date. Adverse effects appearing more than 3 months after treatment were regarded as late effects. Duration of response was measured from the date local control was assessed to the date of relapse. Logistic regression analysis was used to study the effects of different variables on local control, the effect of preradiotherapy surgery was also studied using Fisher’s exact test, two tailed. The MantelCox log-rank test was used to test differences and trends in survival (all causes) between subgroups of patients. McNemar’s test of symmetry was used to compare the need for a urethral catheter before and after radiotherapy. The severity of adverse effects was graded according to WHO
criteria (9). Performance status was estimated by the Karnofsky scale (10). Results
Ninety-four patients with invasive or recurrent bladder cancer were planned for palliative radiotherapy. Palliative radiotherapy was required to treat tumour causing symptoms, which could not be relieved o r controlled with surgery or medication. There were 69 men (73%) and 25 women, with a median age of 79 years (range 55-92 years). Eighty-three patients (88%) were aged 70 years or more. Most patients initially had haematuria (85%). Prior to radiotherapy, 82 patients had been treated with transurethral resection, 4 patients with partial and 2 with total cystectomy. Transurethral biopsy was performed in 12 patients. The time between diagnosis and commencement of radiotherapy was less than 6 months for 67 patients (71%)). An analysis of prior treatments for local control was made. The prior treatments had no significant effect on the local control rate. The distribution of patients according to T N M classification is presented in Table 1 . Based on clinical examination and/or investigations with lymphangiogram or CT 15 patients (16%) were estimated to have lymph node involvement and another 15 patients other metastasis. Forty-two patients were coded as NX because there was not sufficient information concerning their nodal status. Survival by T-categories is presented in Fig. I . Patients with TI and T2 tumours had significantly better survival compared to the more advanced T-categories ( p < 0.001). Histologically there were five squamous cell carcinomas, one adenocarcinoma, one carcinosarcoma and two undifferentiated carcinomas. The remaining 85 patients had transitional cell carcinomas (90%), of these 24 had WHO grade 2, and 59 grade 3 while two cases grading was not established. Thirty-three patients (35%) had abnormal pyelography results indicating unilateral hydronephrosis in 27 cases (29%), and bilateral hydronephrosis in 6 cases (6%). Seventeen patients ( I8%) required an indwelling catheter
Table 1 Stuge and T-category prior to radiotherapy
Stage
TI
T2
T3
T4
1
4
I1
0 19 0
IV Unknown
0 0 0 1
0 0 9 6 9
0 0 0 30 0
Total (XI)
5 (5)
111
2 12 33 (35)
24 (26)
30 (32)
TX
Total (YO)
0
4 (4)
0
19 (20)
0 0 2
9 (10) 38 (40) 24 (26)
2 (2)
94 (100)
45 I
PALLIATIVT RADIOTHFRAPY IN BLADDFR CANCTR
100 80 60
1. Survival by T-category after palliative radiotherapy. TI -, T2 I-; T3 . - . -; T4 -
-
-
Table 2
Variable
Hematuria Pain Urgency Incontinence Indwelling catheter
Prior to radiotherapy n
After radiotherapy n
34
12
29 5 17
13
13 --
7 7 9
prior to radiotherapy. The eKects of palliative radiotherapy on main symptoms and need for urethral catether are presented in Table 2. Palliative radiotherapy relieved symptoms in the majority of patients. It was estimated retrospectively, that 43%) of patients had completely. and 29% of patients partially resolved symptoms (Table 3). There was a statistically significant improvement in the need for a urethral catheter after radiotherapy compared to the situation before radiotherapy ( p = 0.02). Eight of the 17 patients who initially had a catheter did not need it
Symptoms
after radiotherapy and one. who did not havc one initially. needed it following radiotherapy. Subjective and objective response rates after palliative radiotherapy are presented in Table 3. Fifty-six patients (60%) had cystoscopies after radiotherapy. for 38 patients (40'%))the cystoscopy result was unknown or cystoscopy was not done. Local control of the bladder disease was achieved in 38 cases giving a local response rate of 40'% (95'% confidence interval: 30-51'%1). Local control after radiotherapy was confirmed with cystoscopy in 33 patients. with negative urine cytology in 2 patients (malignant prcradiotherapy urine cytology) and at autopsy in two patients. Additionally, one patient who was treated with palliative regimen after cystcctomy has remained discascfree for 7 years after treatment. but has developed bowel stricture confirmed by colonoscopy. Of all patients with initial local control 13 patients (34'X)) relapsed during follow-up, 8 patients had local recurrences and 5 patients developed metastases. The patients with local control had significantly longer survival than patients without such control ( p < 0.05). The estimated median survival (all causes) was 9.6 months, 29% of all patients surviving at 2 years and 1 3 ' X ) at 5 years. Patients who had only local disease (NOMO) prior to radiotherapy had a median survival of 17.5 months, 42% surviving at 2 years and 21'% at 5 years. For the whole series, the median disease-specific survival from bladder cancer was 13.3 months, 40 of the patients surviving at 2 years and 27% at 5 years. The estimated median time to progression was 8.3 months. Median duration of remission for 38 patients who achieved local control after radiotherapy was not reached; 54% of these patients were estimated not to have relapsed 5 years after achieving local control. Survival and disease-specific survival for all patients are presented in Fig. 2 . Survival (all causes) was compared to various potential prognostic factors in univariate analysis. The most signifcant factor was the presence of distant metastases ( p < 0.0001. omitting 33 patients whose metastatic status was unknown). There was a highly significant trend towards
Objective response Local control
Persistent disease
Conipletely resolved Partially resolved Unchanged Worse Not evaluable
29 6
8
-7
10
Total ('XI)
38 (40)
I I 1
3
2 0 23 (25)
Progressive disease
Not evaluable
Total ("4)
II 9 9 0
I 0 I 0 0
40 (43) 27 (29) 14 ( 1 5 )
31 ( 3 3 )
2 (3)
94 (100)
12 ( 1 3 ) ](I)
452
F.. SALMINEN
________________...........................
1
.... .............
20 -
07 0
izn
1311
(2n
Ill1
11)
12 24 36 40 60 MONTHS FOLLOWING COMMENCEMENT OF RADIOTHERAPY
IW
72
Fig. -3. Overall survival and disease-specific survival of all patients. Figures in brackets refer to the number of patients at risk in the beginning of each period. All causes -; Bladder cancer only . . . ..
shorter survival with higher T-category ( p < 0.001). Patients with transitional cell carcinomas had better survival than patients with other histological types ( p = 0.02). Within the transitional cell tumours no significant difference in survival was observed between grade 2 and grade 3 tumours ( p = 0.87). Patients with good performance status (Karnofsky performance status 70 or higher) survived significantly longer than patients with poor performance status ( p < 0.01). No significant difference in survival was found when comparing patients by nodal involvement, sex, age, prior abdominal surgery or presence of hydronephrosis. Fifty-eight patients (62%) were recorded to suffer from diarrhoea during the treatment, 15 (16%) with severe diarrhoea (grade 3) which required treatment. Fifteen patients (16%) experienced nausea or vomiting and 19 patients (20%) had urinary frequency or incontinence. The incidence of grade 3 diarrhoea during radiotherapy was not associated with prior abdominal surgery, diabetes, hypertension, gastrointestinal disease or old age (80 years or more compared to 79 years or less). There was no increase in the incidence of grade 3 diarrhoea with fieldheight (Table 4). Radiotherapy was interrupted in 7 cases (7%) due to diarrhoea. The length of treatment break ranged from 9 to 30 days with a median of 17 days. Radiotherapy had to be discontinued early in 5 cases (5%)
because of severe diarrhoea ( n = 3), bowel symptoms ( n = I ) or poor general condition ( n = I ) . Patients requiring interruption or discontinuation of radiotherapy had all been treated with two anterioposterior opposed fields. Late effects occurring more than three months after completion of radiotherapy were noted in 27 patients (29%). These included urethral stricture ( n = lo), proctitis (n = 6), cystitis (n = 6). haematuria ( n = 4), leg oedema ( n = 4), small bowel injury ( n = I ) , subcutaneous fibrosis ( n = I), urinary incontinence ( n = I), and activated diverticulitis ( n = I). Several patients had more than one late effect. There was a statistically significant increase in the incidence of late effects with the increasing field height ( p < 0.05, X*-test for trend, Table 4). In this study the incidence of late effects was not associated with preradiotherapy illnesses or abdominal surgery. No radiotherapyrelated deaths were observed. Discussion
When cure of cancer is impossible or unlikely by conventional means, treatment is essentially palliative. Radiotherapy is the most effective way of relieving local symptoms in radioresponsive tumours. If possible, palliative treatment should not introduce other symptoms except for a brief time. The estimation of effects of palliative radiotherapy in the present study has been done retrospectively which can cause bias due to uncertainty in the estimation. However, the patients had been regularly followed and the effect of radiotherapy estimated with cystoscopy for the majority of patients. In tumours of limited responsiveness, the best palliative treatment may be a radical course of radiation therapy (4, 5). For bladder cancer such a policy would involve 5 to 7 weeks of daily treatment and a high risk of associated proctitis and cystitis. In the elderly, the hazards of sideeffects are greater and for those with demonstrable metastases the treatment is too long. On the other hand, based on the more recent studies of tumour kinetics urinary bladder tumours are suggested to be optimally treated using overall treatment times from 2.5 to 4 weeks ( I I ) . For carcinoma of the bladder short-course treatment with large fractions (20 Gy/5 fractions) has been advo-
Table 4 Field height by incidence of’ .severe diarrhoea and late effects
Field height (mm)
No. of cases
< I09 110-129 >I30
30 ( 100) 31 ( 100) 21 (100)
6 (20) 8 (22) I (4)
Total
94 ( 100)
15 (16)
* Percentage of total
Grade 3 diarrhoea (‘%I)*
number of cases with designated field height.
Late erects
(I%))*
45 3
PALLIATIVE RADIOTHERAPY IN BLADDER CANCER
cated in pre-operative regimens ( I , 3). The reactions to such regimens are submerged in the postoperative period but seem to be tolerable. Schedules for palliation range from single doses of 10 Gy ( 12) to 25 fractions delivering 45 Gy (5) or 50 Gy (13). The programme reported here evolved from the regimen recommended by van den Brenk for use with hyperbaric oxygen and subjected to controlled trial (14). In this trial both arms involved 6 increments of 5 and 5.5Gy with treatment twice weekly. Subcutaneous fibrosis in the suprapubic area in those given 5.5 Gy led to the reduction of the fraction dose to 5 Gy. The main advantage of short courses for palliative indication is obviously the greater acceptance by patients who live at a distance, who are in poor general condition, or who have urgent symptoms requiring rapid relief. Another benefit is the reduction in time spent away from home for those who have to be inpatients. In agreement with results reported by Eberhardt et al. ( 15) the suitability of hypofractionation for palliative treatment was found satisfactory in the present study. Radiobiologically the use of larger doses is inferior to conventional fractionation, but the therapeutic ratio may be reversed when used palliatively in patients with short survival as suggested by Chan et al. (12). With the increase in fraction dose it is necessary to reduce the total dose in order to keep the late effects at an acceptable level. A comparison between six fractions of 5 G y over three weeks and 20 fractions of 2 Gy over four weeks using the alpha/beta model (16) indicated slightly less in the way of acute adverse effects but significantly more late effects of the high-fraction-dose regimen. This was confirmed in the finding of good tolerance to treatment, the observed rate of local control and relatively high incidence of late effects. Complete regression of the tumour during the early follow-up period is known to be of significant prognostic importance for patients with invasive tumours (17, 18). In the present series the patients who achieved local control had relatively good survival, with some of the patients alive more than 5 years after radiotherapy. The rate of local control was slightly inferior to the 42% reported earlier for similar treatment (19). The 5-years survival was in good agreement with the 5- 15%) reported after conventional palliative radiotherapy (20, 21). Age is usually considered to be important in reducing the therapeutic response in both preoperative (22) and full-dose schedules (23). The latter suggests that, with rare exceptions, patients over 79 years of age should not be offered radical radiotherapy as their long-term survival is so poor. Forty per cent of the patients in the present series were over 79 years, but age did not seem to have an influence on the outcome of the palliative treatment. Overall 29% of patients had some late sequelae but none were fatal. Some of the late sequalae, especially bladder problems and leg oedema, might have been partly due to recurrences, but extensive investigation was often contraindicated by patients’ deteriorated general condition.
Urological surgery and medication were used for treatment of strictures, proctitis and other problems. According to earlier studies (24-26) the incidence of adverse effects related to pelvic radiotherapy can be influenced by the irradiated volume, the field arrangement and dose, the number of previous operative procedures, tumour extent and the age of the patient. In the present series an increase in field size was associated with more late morbidity but did not correlate with acute severe diarrhoea. Treatment interruption for diarrhoea was required only for those treated with two opposed fields. A C T planned 3- or 4-field treatment was better tolerated. ACKNOWLEDGEMENTS The author is deeply grateful to Dr Fedora Trinker. Director of Medical Administration at Peter MacCallum Cancer Institute, who gave support to this work and allowed the use of facilities at the department of medical records at PMC to collect the data for the study.
REFERENCES 1. Whitmore WF, Batata MA, Hilaris BS, et al. A comparative
study of two preoperative radiation regimens with cystectomy for bladder cancer. Cancer 1977; 40: 1077-86. 2. Spera JA, Whittington R. Littman P, Solin LJ, Wein AJ. A comparison of preoperative radiotherapy regimens for bladder carcinoma. Cancer 1988; 61: 255-62. 3. FossH SD. Miller A, Ous S, Poppe E, Hsst H, Kaalhus 0. Treatment of muscle infiltrating bladder cancer; The Norwegian Radium Hospital experience 1966- 1982. In: Smith PH, PavoneMacaluso M, eds. Management of advanced cancer of prostate and bladder. New York: Alan R Liss Inc. 1988: 525-44. 4. Silber I, Bowles WT, Cordonnier JJ. Palliative treatment of carcinoma of the urinary bladder. Cancer 1969; 23: 586-8. 5. Rotman M, Macchia R, Silverstein M, et al. Infusion 5-FU and concomitant radiation therapy in the treatment of bladder cancer. Cancer 1987; 59: 710-4. 6. Harmer MH. ed. TNM classification of malignant tumours, 3rd ed Geneva: UICC, 1978: 113-7. 7. Hermanek P, Sobin LH, eds. TNM classification of malignant tumours, 4th ed. Berlin: Springer-Verlag, 1987: 133-5. 8. Dixon WJ, ed. BMDP statistical software manual. Vol. I and 2. Berkeley: University of California Press, 1988 and 1990. 9. Karnofsky DA, Buchenal JH. The clinical evaluation of chemotherapeutic agents against cancer. In: Macleod CM, ed. Evaluation of chemotherapeutic agents. New York: Columbia University Press, 1949: 121 -205. 0. World Health Organization. WHO handbook for reporting results of cancer treatment. Geneva: World Health Organization, 1979. 1. Fowler JF. How worthwhile are short schedules in radiotherapy? A series of exploratory calculations. Radiother Oncol 1990; 18: 165-81. 2. Chan RC, Bracken RB, Johnson DE. Single dose whole pelvis megavoltage irradiation for palliative control of haematuria or ureteral obstruction. J Urol 1979; 132: 750- 1. 13. Shehata WM, Meyer RL, Costandi YT. Curative and palliative radiotherapy of bladder cancer. Radiology 1983; 146: 523-6. 14. Sandeman TF. Malignant disease of the urinary bladder: experience at the Peter MacCallum Clinic Melbourne 196065. Australas Radio1 1969; 13: 193-204.
454
E. SALMINEN
15. Eberhardt HJ, Herrman T, Kohler K. Altered fractionated palliative or curative radiotherapy under radiobiological and clinical aspects. J Cancer Res Clin Oncol 1990; 1 l6( Suppl.): 1040. 16. Fowler JF. Fractionated radiotherapy after Strandqvist. Acta Radio1 Oncol 1984; 23: 209- 16. 17. Blandy JP, England HR, Evans SJW, et al. T3 bladder cancer- the case for salvage cystectomy. Br J Urol 1980; 52: 506- 10. 18. Abratt RP, Tucker RD, Barnes DR. Radical irradiation o f T 2 grade 111 and T3 bladder cancer-tumour response and prognosis. Int J Radiat Oncol Biol Phys 1983; 9: 1213-5. 19. Mameghan H, Sandeman TF. The management of invasive bladder cancer: a review of selected Australasian studies in radiotherapy, chemotherapy and cystectorny. Aust NZ J Surg 1991; 61: 173-8. 20. Mameghan H., Fisher R. Invasive bladder cancer. Prognostic factors and results of radiotherapy with and without cystectomy. Br J Urol 1989; 63: 251-8.
21. Salrninen E. External beam radiation treatment of urinary bladder carcinoma-An analysis of results in 203 patients. Acta Oncol 1990; 29: 909-14. 22. Van der Werf-Messing B. Properative irradiation followed by cystectomy to treat carcinoma of the urinary bladder category T3NX-0-4MO. Int J Radiat Oncol Biol Phys 1979; 5: 394-40 I . 23. Duncan W, Quilty PM. Results of a series of 963 patients with transitional carcinoma of the bladder. primarily managed by rnegavoltage X-ray therapy. J Radiother Oncol 1986; 7: 299-3 10. 24. Goffinet DR. Schneider MJ. Glatstein EJ, et al. Bladder cancer: results of radiation therapy in 384 patients. Radiology 1975; 117: 149-53. 25. Green N. Iba G, Smith WR. Measures to minimize small intestine injury in the irradiated pelvis. Cancer 1975; 35: 1633 -40. 26. Percarpio B. Acute and delayed side-effects of definitive pelvic irradiation for urologic cancer. Conn Med 1984; 48: 497 500.
ISSN: 0284-186X (Print) 1651-226X (Online) Journal homepage: http://www.tandfonline.com/loi/ionc20
Unconventional Fractionation for Palliative Radiotherapy of Urinary Bladder Cancer; A retrospective review of 94 patients Eeva Salminen To cite this article: Eeva Salminen (1992) Unconventional Fractionation for Palliative Radiotherapy of Urinary Bladder Cancer; A retrospective review of 94 patients, Acta Oncologica, 31:4, 449-454, DOI: 10.3109/02841869209088288 To link to this article: https://doi.org/10.3109/02841869209088288
Published online: 08 Jul 2009.
Submit your article to this journal
Article views: 74
View related articles
Citing articles: 15 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ionc20
Acra Oncologica Vol. 31, No. 4, pp. 449-454. 1992
UNCONVENTIONAL FRACTIONATION FOR PALLIATIVE RADIOTHERAPY OF URINARY BLADDER CANCER A retrospective review of 94 patients EEVA SALMINEN
Ninety-four urinary bladder cancer patients with locally advanced, recurrent or metastatic urinary bladder cancer were treated with external radiotherapy with the aim of palliating local disease. Conventional radical radiotherapy was inappropriate because of extensive disease, poor general condition or old age of the patients. The palliative course studied was 30Gy (mid-point dose) in six fractions, two fractions a week. Eighty-two patients (87%) tolerated treatment as planned. Forty patients (43%) had complete palliation of initial symptoms. Thirty-eight patients (40%) had initial local control of the tumour, which was lasting in 25 cases (26%). Median disease-specific survival of the patients was 13.3 months. The estimated five-year survival was 13% and survival from bladder cancer 27%.
Patients with extensive bladder cancer beyond radical local therapy require palliation when the tumour causes symptoms. The aim of palliation is relief of symptoms and local control of cancer without causing serious side-effects. Short-course treatment with unconventional fractionation has been used in pre-operative treatment of urinary bladder tumours ( 1-3). Longer schedules or even radical courses have been recommended for palliative treatment (4, 5 ) . Often, however, the patients d o not tolerate such treatment without deterioration of their quality of life, which negates the initial purpose of palliative treatment. The aim of the present study was to evaluate the effects of an unconventional palliative radiotherapy regimen in the treatment of urinary bladder cancer with respect to local control, palliation of symptoms and adverse effects of the treatment. Material and Methods
The medical records of patients at the Peter MacCallum Cancer Institute, in Melbourne, Australia, who were coded
Submitted 11 September 1990. Accepted 3 January 1992. Correspondence to: Dr Eeva Salminen, Department of Radiotherapy and Oncology, Helsinki University Central Hospital, Haartmaninkatu 4, SF-00290 Helsinki, Finland.
as having urinary bladder cancer and who were planned to receive palliative radiotherapy to the urinary bladder or pelvis between January 1983 and December 1985, were reviewed. Patients who had had prior pelvic radiotherapy were excluded. A questionnaire concerning follow-up and postradiotherapy treatments was sent to doctors of those patients, who had not been followed at the Institute. Pretreatment evaluation included history and physical examination, cystoscopy with biopsy and in most cases transurethral resection, bimanual examination with the patient under anaesthesia, excretory urograms, routine blood tests and chest x-ray. Urine cytology was not routinely performed in all patients. Computed tomography (CT) of pelvis and abdomen and/or bone scan were made if indicated. Tumour category and staging was estimated using the 1978 UICC system of classification (6) revised to accord with the 1987 classification (7). Patients were treated with megavoltage beams from a 4 or 6 MeV linear accelerator. The total mid point dose was 30 Gy given in 6 fractions, 2 fractions per week at least 2 days apart, over 3 weeks. Eighty-one patients (86%)) were treated with two opposed anterior and posterior fields, I 1 patients with three fields and 2 patients with four fields. Field size varied greatly because the treatment was planned according to the extend ot symptom-causing disease. Median field height was 120mm, (range 70 to 190mm). 449
450
E. SALMINEN
Heights of fields were grouped into 129mm (27 patients) to allow statistical comparison of differences in acute and late adverse effects by field height. The patients were reviewed weekly during the radiotherapy and then followed either by referring doctors or at the Peter MacCallum Cancer Institute. Control cystoscopies were performed when the patients’ general condition allowed this. Urine cytology, x-ray and radionuclide scans were performed if indicated. In those patients who could not have cystoscopy a clinical assessment of tumour was made, based on the presence of symptoms or signs indicating local tumour (e.g. haematuria, urine cytology for malignant cells, pain, uremia, lymph oedema or palpable mass). The evaluation of treatment response was based on results of these investigations and clinical assessment within 6 months after the treatment was completed. The requirement for classification as local control was no evidence of malignancy at cystoscopy, urine cytology or autopsy with resolution of tumour-related symptoms. All patients were followed until death or 17 August 1989, giving a minimum follow-up period of 45 months for living patients. BMDP statistical software versions 1988 and 1990 were used in the analysis (8). Survival (all causes), and time to progression (local or distant) were calculated from the date of commencement of radiotherapy. Survival from bladder cancer was measured from the date of commencement of radiotherapy to the date of death or the close-out date. Adverse effects appearing more than 3 months after treatment were regarded as late effects. Duration of response was measured from the date local control was assessed to the date of relapse. Logistic regression analysis was used to study the effects of different variables on local control, the effect of preradiotherapy surgery was also studied using Fisher’s exact test, two tailed. The MantelCox log-rank test was used to test differences and trends in survival (all causes) between subgroups of patients. McNemar’s test of symmetry was used to compare the need for a urethral catheter before and after radiotherapy. The severity of adverse effects was graded according to WHO
criteria (9). Performance status was estimated by the Karnofsky scale (10). Results
Ninety-four patients with invasive or recurrent bladder cancer were planned for palliative radiotherapy. Palliative radiotherapy was required to treat tumour causing symptoms, which could not be relieved o r controlled with surgery or medication. There were 69 men (73%) and 25 women, with a median age of 79 years (range 55-92 years). Eighty-three patients (88%) were aged 70 years or more. Most patients initially had haematuria (85%). Prior to radiotherapy, 82 patients had been treated with transurethral resection, 4 patients with partial and 2 with total cystectomy. Transurethral biopsy was performed in 12 patients. The time between diagnosis and commencement of radiotherapy was less than 6 months for 67 patients (71%)). An analysis of prior treatments for local control was made. The prior treatments had no significant effect on the local control rate. The distribution of patients according to T N M classification is presented in Table 1 . Based on clinical examination and/or investigations with lymphangiogram or CT 15 patients (16%) were estimated to have lymph node involvement and another 15 patients other metastasis. Forty-two patients were coded as NX because there was not sufficient information concerning their nodal status. Survival by T-categories is presented in Fig. I . Patients with TI and T2 tumours had significantly better survival compared to the more advanced T-categories ( p < 0.001). Histologically there were five squamous cell carcinomas, one adenocarcinoma, one carcinosarcoma and two undifferentiated carcinomas. The remaining 85 patients had transitional cell carcinomas (90%), of these 24 had WHO grade 2, and 59 grade 3 while two cases grading was not established. Thirty-three patients (35%) had abnormal pyelography results indicating unilateral hydronephrosis in 27 cases (29%), and bilateral hydronephrosis in 6 cases (6%). Seventeen patients ( I8%) required an indwelling catheter
Table 1 Stuge and T-category prior to radiotherapy
Stage
TI
T2
T3
T4
1
4
I1
0 19 0
IV Unknown
0 0 0 1
0 0 9 6 9
0 0 0 30 0
Total (XI)
5 (5)
111
2 12 33 (35)
24 (26)
30 (32)
TX
Total (YO)
0
4 (4)
0
19 (20)
0 0 2
9 (10) 38 (40) 24 (26)
2 (2)
94 (100)
45 I
PALLIATIVT RADIOTHFRAPY IN BLADDFR CANCTR
100 80 60
1. Survival by T-category after palliative radiotherapy. TI -, T2 I-; T3 . - . -; T4 -
-
-
Table 2
Variable
Hematuria Pain Urgency Incontinence Indwelling catheter
Prior to radiotherapy n
After radiotherapy n
34
12
29 5 17
13
13 --
7 7 9
prior to radiotherapy. The eKects of palliative radiotherapy on main symptoms and need for urethral catether are presented in Table 2. Palliative radiotherapy relieved symptoms in the majority of patients. It was estimated retrospectively, that 43%) of patients had completely. and 29% of patients partially resolved symptoms (Table 3). There was a statistically significant improvement in the need for a urethral catheter after radiotherapy compared to the situation before radiotherapy ( p = 0.02). Eight of the 17 patients who initially had a catheter did not need it
Symptoms
after radiotherapy and one. who did not havc one initially. needed it following radiotherapy. Subjective and objective response rates after palliative radiotherapy are presented in Table 3. Fifty-six patients (60%) had cystoscopies after radiotherapy. for 38 patients (40'%))the cystoscopy result was unknown or cystoscopy was not done. Local control of the bladder disease was achieved in 38 cases giving a local response rate of 40'% (95'% confidence interval: 30-51'%1). Local control after radiotherapy was confirmed with cystoscopy in 33 patients. with negative urine cytology in 2 patients (malignant prcradiotherapy urine cytology) and at autopsy in two patients. Additionally, one patient who was treated with palliative regimen after cystcctomy has remained discascfree for 7 years after treatment. but has developed bowel stricture confirmed by colonoscopy. Of all patients with initial local control 13 patients (34'X)) relapsed during follow-up, 8 patients had local recurrences and 5 patients developed metastases. The patients with local control had significantly longer survival than patients without such control ( p < 0.05). The estimated median survival (all causes) was 9.6 months, 29% of all patients surviving at 2 years and 1 3 ' X ) at 5 years. Patients who had only local disease (NOMO) prior to radiotherapy had a median survival of 17.5 months, 42% surviving at 2 years and 21'% at 5 years. For the whole series, the median disease-specific survival from bladder cancer was 13.3 months, 40 of the patients surviving at 2 years and 27% at 5 years. The estimated median time to progression was 8.3 months. Median duration of remission for 38 patients who achieved local control after radiotherapy was not reached; 54% of these patients were estimated not to have relapsed 5 years after achieving local control. Survival and disease-specific survival for all patients are presented in Fig. 2 . Survival (all causes) was compared to various potential prognostic factors in univariate analysis. The most signifcant factor was the presence of distant metastases ( p < 0.0001. omitting 33 patients whose metastatic status was unknown). There was a highly significant trend towards
Objective response Local control
Persistent disease
Conipletely resolved Partially resolved Unchanged Worse Not evaluable
29 6
8
-7
10
Total ('XI)
38 (40)
I I 1
3
2 0 23 (25)
Progressive disease
Not evaluable
Total ("4)
II 9 9 0
I 0 I 0 0
40 (43) 27 (29) 14 ( 1 5 )
31 ( 3 3 )
2 (3)
94 (100)
12 ( 1 3 ) ](I)
452
F.. SALMINEN
________________...........................
1
.... .............
20 -
07 0
izn
1311
(2n
Ill1
11)
12 24 36 40 60 MONTHS FOLLOWING COMMENCEMENT OF RADIOTHERAPY
IW
72
Fig. -3. Overall survival and disease-specific survival of all patients. Figures in brackets refer to the number of patients at risk in the beginning of each period. All causes -; Bladder cancer only . . . ..
shorter survival with higher T-category ( p < 0.001). Patients with transitional cell carcinomas had better survival than patients with other histological types ( p = 0.02). Within the transitional cell tumours no significant difference in survival was observed between grade 2 and grade 3 tumours ( p = 0.87). Patients with good performance status (Karnofsky performance status 70 or higher) survived significantly longer than patients with poor performance status ( p < 0.01). No significant difference in survival was found when comparing patients by nodal involvement, sex, age, prior abdominal surgery or presence of hydronephrosis. Fifty-eight patients (62%) were recorded to suffer from diarrhoea during the treatment, 15 (16%) with severe diarrhoea (grade 3) which required treatment. Fifteen patients (16%) experienced nausea or vomiting and 19 patients (20%) had urinary frequency or incontinence. The incidence of grade 3 diarrhoea during radiotherapy was not associated with prior abdominal surgery, diabetes, hypertension, gastrointestinal disease or old age (80 years or more compared to 79 years or less). There was no increase in the incidence of grade 3 diarrhoea with fieldheight (Table 4). Radiotherapy was interrupted in 7 cases (7%) due to diarrhoea. The length of treatment break ranged from 9 to 30 days with a median of 17 days. Radiotherapy had to be discontinued early in 5 cases (5%)
because of severe diarrhoea ( n = 3), bowel symptoms ( n = I ) or poor general condition ( n = I ) . Patients requiring interruption or discontinuation of radiotherapy had all been treated with two anterioposterior opposed fields. Late effects occurring more than three months after completion of radiotherapy were noted in 27 patients (29%). These included urethral stricture ( n = lo), proctitis (n = 6), cystitis (n = 6). haematuria ( n = 4), leg oedema ( n = 4), small bowel injury ( n = I ) , subcutaneous fibrosis ( n = I), urinary incontinence ( n = I), and activated diverticulitis ( n = I). Several patients had more than one late effect. There was a statistically significant increase in the incidence of late effects with the increasing field height ( p < 0.05, X*-test for trend, Table 4). In this study the incidence of late effects was not associated with preradiotherapy illnesses or abdominal surgery. No radiotherapyrelated deaths were observed. Discussion
When cure of cancer is impossible or unlikely by conventional means, treatment is essentially palliative. Radiotherapy is the most effective way of relieving local symptoms in radioresponsive tumours. If possible, palliative treatment should not introduce other symptoms except for a brief time. The estimation of effects of palliative radiotherapy in the present study has been done retrospectively which can cause bias due to uncertainty in the estimation. However, the patients had been regularly followed and the effect of radiotherapy estimated with cystoscopy for the majority of patients. In tumours of limited responsiveness, the best palliative treatment may be a radical course of radiation therapy (4, 5). For bladder cancer such a policy would involve 5 to 7 weeks of daily treatment and a high risk of associated proctitis and cystitis. In the elderly, the hazards of sideeffects are greater and for those with demonstrable metastases the treatment is too long. On the other hand, based on the more recent studies of tumour kinetics urinary bladder tumours are suggested to be optimally treated using overall treatment times from 2.5 to 4 weeks ( I I ) . For carcinoma of the bladder short-course treatment with large fractions (20 Gy/5 fractions) has been advo-
Table 4 Field height by incidence of’ .severe diarrhoea and late effects
Field height (mm)
No. of cases
< I09 110-129 >I30
30 ( 100) 31 ( 100) 21 (100)
6 (20) 8 (22) I (4)
Total
94 ( 100)
15 (16)
* Percentage of total
Grade 3 diarrhoea (‘%I)*
number of cases with designated field height.
Late erects
(I%))*
45 3
PALLIATIVE RADIOTHERAPY IN BLADDER CANCER
cated in pre-operative regimens ( I , 3). The reactions to such regimens are submerged in the postoperative period but seem to be tolerable. Schedules for palliation range from single doses of 10 Gy ( 12) to 25 fractions delivering 45 Gy (5) or 50 Gy (13). The programme reported here evolved from the regimen recommended by van den Brenk for use with hyperbaric oxygen and subjected to controlled trial (14). In this trial both arms involved 6 increments of 5 and 5.5Gy with treatment twice weekly. Subcutaneous fibrosis in the suprapubic area in those given 5.5 Gy led to the reduction of the fraction dose to 5 Gy. The main advantage of short courses for palliative indication is obviously the greater acceptance by patients who live at a distance, who are in poor general condition, or who have urgent symptoms requiring rapid relief. Another benefit is the reduction in time spent away from home for those who have to be inpatients. In agreement with results reported by Eberhardt et al. ( 15) the suitability of hypofractionation for palliative treatment was found satisfactory in the present study. Radiobiologically the use of larger doses is inferior to conventional fractionation, but the therapeutic ratio may be reversed when used palliatively in patients with short survival as suggested by Chan et al. (12). With the increase in fraction dose it is necessary to reduce the total dose in order to keep the late effects at an acceptable level. A comparison between six fractions of 5 G y over three weeks and 20 fractions of 2 Gy over four weeks using the alpha/beta model (16) indicated slightly less in the way of acute adverse effects but significantly more late effects of the high-fraction-dose regimen. This was confirmed in the finding of good tolerance to treatment, the observed rate of local control and relatively high incidence of late effects. Complete regression of the tumour during the early follow-up period is known to be of significant prognostic importance for patients with invasive tumours (17, 18). In the present series the patients who achieved local control had relatively good survival, with some of the patients alive more than 5 years after radiotherapy. The rate of local control was slightly inferior to the 42% reported earlier for similar treatment (19). The 5-years survival was in good agreement with the 5- 15%) reported after conventional palliative radiotherapy (20, 21). Age is usually considered to be important in reducing the therapeutic response in both preoperative (22) and full-dose schedules (23). The latter suggests that, with rare exceptions, patients over 79 years of age should not be offered radical radiotherapy as their long-term survival is so poor. Forty per cent of the patients in the present series were over 79 years, but age did not seem to have an influence on the outcome of the palliative treatment. Overall 29% of patients had some late sequelae but none were fatal. Some of the late sequalae, especially bladder problems and leg oedema, might have been partly due to recurrences, but extensive investigation was often contraindicated by patients’ deteriorated general condition.
Urological surgery and medication were used for treatment of strictures, proctitis and other problems. According to earlier studies (24-26) the incidence of adverse effects related to pelvic radiotherapy can be influenced by the irradiated volume, the field arrangement and dose, the number of previous operative procedures, tumour extent and the age of the patient. In the present series an increase in field size was associated with more late morbidity but did not correlate with acute severe diarrhoea. Treatment interruption for diarrhoea was required only for those treated with two opposed fields. A C T planned 3- or 4-field treatment was better tolerated. ACKNOWLEDGEMENTS The author is deeply grateful to Dr Fedora Trinker. Director of Medical Administration at Peter MacCallum Cancer Institute, who gave support to this work and allowed the use of facilities at the department of medical records at PMC to collect the data for the study.
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