0007-1331/90/00654032/$10.00
British JournaIo/'UroIogy (1990),65, 32-35
01990 British Journalof Urology
Long-term Follow-up of lntravesical Epodyl Therapy for Superficial Bladder Cancer G. R. MUFTI, J. S. VlRDl and M. H. HALL Department of Urology, Whipps Cross Hospital, London
Summary-The records of 11 1 patients with multiple superficial grade 1-2 transitional cell tumours of the bladder treated with intravesical Epodyl and followed up for a mean period of 6.4 years were retrospectivelyanalysed. The study showed that 65% of patients responded completely after 12 weekly instillationsand 46% of these remained continuously free of disease for 5 years. An initial complete response to therapy and lower pathological grade seemed to indicate a long-term successful response to treatment. In patients who failed to respond by 1 year, further therapy was of no benefit. Clearance of bladder disease by 1 year carried a 14% risk of subsequent tumour invasion by 5 years. This risk increased to 75% in those who failed to respond by 1 year.
Many patients with multiple superficial transitional cell tumours of the bladder require intravesical chemotherapy if endoscopic measures fail to control the disease. Of the many chemotherapeutic agents available, Epodyl (triethylene glycol diglyceridyl ether) has been in use for over 2 decades. It is an alkylating agent, poorly absorbed through the bladder mucosa owing to its higher molecular weight, and therefore carries a lesser risk of systemic toxicity (Abbassian and Wallace, 1966; Riddle and Wallace, 1971). Nonetheless, it has not achieved worldwide popularity in the management of superf i d bladder cancer, which is reflected the relatively small number Of long-term studies On this subject. Most ofthe reports on EPodYl and k k e d on the whole subject of intravesical chemotherapy have tumour recurrences as their end point. Radical treatment is then frequently employed. This Prevents One aSCWtainingthe true incidence Of tUmOUr invasion over the longer term. We report a retrospective study on 1 1 1 Patients with mUltiple Superficial transitional Cell tUmOUrS of the bladder who received intraVeSiCa1 chemotherapy with EPodYl and were f o h w e d UP for a n ~ x i m u mof 1 1 Years. It was departmental Policy to embark on radical treatment Only in the event of
tumour invasion. The aims of the study were to assess the usefulness of Epodyl in the management of superficial bladder cancer, to identify factors which might influence the ultimate success or failure of treatment and to analyse the incidence of tumour invasion in the long term.
and Methods
~~~i~~ the period 1975 to 1985, 11 1 patients with recurrent multiple, grade 1-2, stage T,-T, transitional cell tumours of the bladder uncontrolled by conventional endoscopic methods were treated with intravesical Epodyl. The series comprised of 97 males and 32 females (age range 38-78 years, mean 62). The mean follow-up was 6.4 years. Treatment was started 2 to4 weeks after complete clearance of tumours by endoscopic resection and/ or diathermy to allow the bladder to epithelialise, and was administered weekly or monthly on an outpatient basis. Prior to each instillation, the urine was sent for bacteriological examination. The bladder was emptied by catheterisation with an 8 F Jacques catheter and 100 ml of a freshly prepared 1% solution of Epodyl instilled into the bladder. The patients retained the solution for as long as possible, up to a maximum of 2 h. They were Read at the 44th Annual Meeting of the British ambulatoW during this Period. Treatment was Association of Urological Surgeons in Buxton, June 1988 withheld if the previous urine result revealed the 32
33
INTRAVESICAL EPODYL THERAPY FOR SUPERFICIAL BLADDER CANCER
Patients who responded completely after Course 1 or consecutive Courses 1 and 2 were followed up by regular cystoscopies. They received further therapy on a monthly basis if they developed recurrent tumours at any stage during follow-up. The life table method using BMDP Program PIL Regimen (Fig. 1) was used to analyse the incidence of freedom from All patients had 12 weekly instillations (Course 1). disease and the incidence of tumour invasion in The interval between the instillations was increased various subgroups (Dixon et al., 1985). if the patient developed bacterial or chemical cystitis. Patients with no evidence of recurrent Results tumours on the first cystoscopic evaluation after completing Course 1 had no further treatment. Overall response to treatment (Fig.I ) Those showing definite improvement (character- Of the 1 1 1 patients, 72 (65%) showed no recurrences ised by a decrease in the number and size of the at the first endoscopic assessment following comtumours compared with the pre-treatment cystos- pletion of Course 1. The 39 partial or noncopy) and those with no response received a further responders received a second course of 12 monthly course of 12 monthly instillations (Course 11). Those instillations; 36 of these patients completed the who were tumour-free on cystoscopy after the course, by which time 14 (39%) were tumour-free. completion of Course I1 received no more. At the end of 1 year, 81 patients (73%) were tumourPartial or non-responders to Course I1 were given free; 94 patients were available for follow-up at 3 12 more monthly instillations (Course 111). Those years and 54 of these (57%) were free of disease. with persistent recurrences even after 36 successive Of 22 patients who continued to have multiple instillations were classed as non-responders and recurrences after courses I and 11, 20 completed 12 treatment was discontinued. further monthly instillations (Course 111). None responded. The pre-therapy tumour histology was INTRAVESICAL THERAPY (n I 111) grade 1 in 3 patients (15%) and grade 2 in 17 (85%). Of the 54 patients who were free of disease at 3 years, the pre-therapy tumour histology was grade 1 in 32 (59%) and grade 2 in 22 (41%) (Table 1). The 72 ‘(NR) 39iPT) comparison between the 2 groups was statistically “ours; 1 1 1 *3 significant (P
.-C
+d
C
40
-
a,
P
a n 0
3
2
1
4
20 -
5
Years Fig. 2 Actuarial percentage of patients continuously free of disease after 12 weekly instillations.
After Course 11 (12 weekly and 12 monthly instillations). Of the 14 patients who responded to Course I1 after failure to respond to Course I, 16% remained continuously free of disease for 5 years (Fig. 3). Sequelae A total of 2389 catheterisations were performed on 111 patients and 26 urinary tract infections were documented (1%). Symptoms of chemical cystitis were reported only by patients receiving weekly instillations and the overall incidence was 19%. Symptoms were controlled by increasing the interval between the instillations.
-
Disease lree at one year Persisting turnour at one year
0 0
1
3
2
5
4
Years Fig. 4 Freedom from invasion: comparison between patients disease-free at 1 year and those with persistent tumour at I year.
but only 25% in those having persistent tumour at 1 year (n = 22) (Fig. 4).
Discussion
The overall response rate of 73% at 1 year in this study corroborates the results of other studies (Table 2) (Fitzpatrick et al., 1979; Nielson and Thybo, 1979; Colleen et al., 1980; Riddle et al., 1982). With large numbers and a long follow-up period, the results of this study showed that the best Freedom from invasion indicator of success was the initial response to 12 The incidence of freedom from invasion at 5 years weekly instillations of Epodyl; 72 patients rewas 86% in patients disease-free at 1 year (n = 8 1) sponded to Course I, of whom 46% remained free of tumour for 5 years (Fig. 2). In the event of lack of response to 12 weekly instillations, a further 12 monthly instillations were useful but the response was not long-lasting. After failing to respond to Course I, 36 patients completed Course I1 and 14 (39%) responded. However, of these 14 patients only 16% remained tumour-free for 5 years (Fig. 3). Table 2 Intravesical Epodyl Treatment and Early Response No. of
0
0
1
2
3
4
5
Years Fig. 3 Actuarial percentage of patients continuously free of disease after 12 weekly and 12 monthly consecutive instillations.
Author
Patients
Complete response No. (%)
Nielson and Thybo (1979) Fitzpatrick ei al. (1979) Colleen ei al. (1 980) Riddle ei al. (1982) Present series
36 64 29 139 111
23 39 23 70 81
(64) (61) (79) (50)
(73)
INTRAVESICAL EPODYL THERAPY FOR SUPERFICIAL BLADDER CANCER
If the tumours continued to recur after 24 consecutive instillations, further Epodyl therapy was of no benefit. In retrospect, it seems that the treatment was continued for longer than necessary in 20 patients who received 3 consecutive courses. Pre-therapy tumour grade was significantly related to the response, with grade 2 tumours less likely to respond (Table 1). A patient with multiple bladder tumours which have not cleared after 1 year’s treatment with Epodyl has a 75% chance of developing tumour invasion within 5 years (Fig. 4). Elective radical surgery appears to be mandatory in such a case. Clearance of bladder disease by 1 year carries a subsequent risk of invasive disease of only 14% (Fig. 4). A policy of regular reviews, early drug treatment of recurrences and cystectomy only in the event of lack of response can be justified in this group. The reason why Epodyl has not achieved popularity is possibly due to the reported incidence of chemical cystitis, which has ranged from 8 to 25% (Robinson et a[., 1977; Smith er a[., 1978; Nielson and Thybo, 1979; Fitzpatrick et al., 1979; Colleen etal., 1980).In this study, 19xofpatients developed symptoms of chemical cystitis severe enough to interrupt treatment. However, increasing the interval between instillations helped to alleviate the symptoms and allowed the treatment to be continued. This problem was not encountered in patients receiving monthly instillations. In summary, the present study has shown that Epodyl has a definite place in the management of multiple superficial bladder tumours. It is cost effective, suitable for use in out-patient clinics and has no systemic toxicity. An initial complete response to therapy and a lower pathological tumour grade appear to indicate a long-term successful response. In patients who fail to respond by 1 year, further therapy offers no benefit and radical surgery should be given serious consideration. In those who
35
do respond, careful supervision is necessary to achieve the best results over the longer term.
Acknowledgements We thank Dr G . Murray, Senior Lecturer in Medical Statistics, Glasgow University, for statistical advice and Miss Veronica Mulholland for typing the manuscript.
References Abbassian, A. and Wallace, D. M. (1966). Intracavitary chemotherapy of diffuse non-infiltrating papillary carcinoma of the bladder. J . Urol.,96.46 1-465. Colleen, S., Ek, A., HeUsten,S. et al. (1980). Intracavitary Epodyl for multiple non-invasive highly differentiated bladder tumours. Scand. J . Urol. Nephrol., 14,43-45. Dixon, W. J., Brown, M. B., Engleman, L. er al. (1985). E M D P Statistical Software. Berkeley: UCLA Press. Fitzpatrick, J. M., Khan, O., Oliver R. T. D. et al. (1979). Longterm follow-up in patients with superficial bladder tumours treated with intravesical Epodyl. Br. J . Urol.,51, 545-548. Nielson, H. V. and Thybo, E.(1 979). Epodyl treatment of bladder tumours. Scand.J . Urol. Nephrol., 13, 59-63. Riddle, P. R. and Wallace, D. M. (1971). Intracavitary chemotherapy for multiple non-invasive bladder tumours. Br. J . Urol.,43, 181-184. Riddle,P. R.,Khan,O.,Fitzpatrick, J. M. erd.(1982). Prognostic factors influencing survival of patients receiving intravesical Epodyl. J . Urol., 127,430-432. Robinson, M. R. G., Shetty, M. B., Richards, B. er aL (1977). Intravesical Epodyl in the management of bladder tumours: combined experience of the Yorkshire Urological Cancer Research Group. J. Urol., 118,972-973. Smith, J. M., Lane, V. and O’Flynn, J. D. (1978). Epodyl in management of non invasive vesical neoplasms. Urology, 11, 474477.
The Authors G . R. Mufti, MS, MCh, FRCSE, formerly Registrar in Urology. Now Consultant Urologist (Locum), Royal Infirmary, Glasgow . J. S. Virdi, MS, MCh, FRCS, Clinical Assistant in Urology. M. H. Hall, FRCS, formerly Consultant Urologist. Requests for reprints to: G . R. Mufti, Department of Urology, Royal Infirmary, 16 Alexandra Parade, Glasgow G31 2ER.
British JournaIo/'UroIogy (1990),65, 32-35
01990 British Journalof Urology
Long-term Follow-up of lntravesical Epodyl Therapy for Superficial Bladder Cancer G. R. MUFTI, J. S. VlRDl and M. H. HALL Department of Urology, Whipps Cross Hospital, London
Summary-The records of 11 1 patients with multiple superficial grade 1-2 transitional cell tumours of the bladder treated with intravesical Epodyl and followed up for a mean period of 6.4 years were retrospectivelyanalysed. The study showed that 65% of patients responded completely after 12 weekly instillationsand 46% of these remained continuously free of disease for 5 years. An initial complete response to therapy and lower pathological grade seemed to indicate a long-term successful response to treatment. In patients who failed to respond by 1 year, further therapy was of no benefit. Clearance of bladder disease by 1 year carried a 14% risk of subsequent tumour invasion by 5 years. This risk increased to 75% in those who failed to respond by 1 year.
Many patients with multiple superficial transitional cell tumours of the bladder require intravesical chemotherapy if endoscopic measures fail to control the disease. Of the many chemotherapeutic agents available, Epodyl (triethylene glycol diglyceridyl ether) has been in use for over 2 decades. It is an alkylating agent, poorly absorbed through the bladder mucosa owing to its higher molecular weight, and therefore carries a lesser risk of systemic toxicity (Abbassian and Wallace, 1966; Riddle and Wallace, 1971). Nonetheless, it has not achieved worldwide popularity in the management of superf i d bladder cancer, which is reflected the relatively small number Of long-term studies On this subject. Most ofthe reports on EPodYl and k k e d on the whole subject of intravesical chemotherapy have tumour recurrences as their end point. Radical treatment is then frequently employed. This Prevents One aSCWtainingthe true incidence Of tUmOUr invasion over the longer term. We report a retrospective study on 1 1 1 Patients with mUltiple Superficial transitional Cell tUmOUrS of the bladder who received intraVeSiCa1 chemotherapy with EPodYl and were f o h w e d UP for a n ~ x i m u mof 1 1 Years. It was departmental Policy to embark on radical treatment Only in the event of
tumour invasion. The aims of the study were to assess the usefulness of Epodyl in the management of superficial bladder cancer, to identify factors which might influence the ultimate success or failure of treatment and to analyse the incidence of tumour invasion in the long term.
and Methods
~~~i~~ the period 1975 to 1985, 11 1 patients with recurrent multiple, grade 1-2, stage T,-T, transitional cell tumours of the bladder uncontrolled by conventional endoscopic methods were treated with intravesical Epodyl. The series comprised of 97 males and 32 females (age range 38-78 years, mean 62). The mean follow-up was 6.4 years. Treatment was started 2 to4 weeks after complete clearance of tumours by endoscopic resection and/ or diathermy to allow the bladder to epithelialise, and was administered weekly or monthly on an outpatient basis. Prior to each instillation, the urine was sent for bacteriological examination. The bladder was emptied by catheterisation with an 8 F Jacques catheter and 100 ml of a freshly prepared 1% solution of Epodyl instilled into the bladder. The patients retained the solution for as long as possible, up to a maximum of 2 h. They were Read at the 44th Annual Meeting of the British ambulatoW during this Period. Treatment was Association of Urological Surgeons in Buxton, June 1988 withheld if the previous urine result revealed the 32
33
INTRAVESICAL EPODYL THERAPY FOR SUPERFICIAL BLADDER CANCER
Patients who responded completely after Course 1 or consecutive Courses 1 and 2 were followed up by regular cystoscopies. They received further therapy on a monthly basis if they developed recurrent tumours at any stage during follow-up. The life table method using BMDP Program PIL Regimen (Fig. 1) was used to analyse the incidence of freedom from All patients had 12 weekly instillations (Course 1). disease and the incidence of tumour invasion in The interval between the instillations was increased various subgroups (Dixon et al., 1985). if the patient developed bacterial or chemical cystitis. Patients with no evidence of recurrent Results tumours on the first cystoscopic evaluation after completing Course 1 had no further treatment. Overall response to treatment (Fig.I ) Those showing definite improvement (character- Of the 1 1 1 patients, 72 (65%) showed no recurrences ised by a decrease in the number and size of the at the first endoscopic assessment following comtumours compared with the pre-treatment cystos- pletion of Course 1. The 39 partial or noncopy) and those with no response received a further responders received a second course of 12 monthly course of 12 monthly instillations (Course 11). Those instillations; 36 of these patients completed the who were tumour-free on cystoscopy after the course, by which time 14 (39%) were tumour-free. completion of Course I1 received no more. At the end of 1 year, 81 patients (73%) were tumourPartial or non-responders to Course I1 were given free; 94 patients were available for follow-up at 3 12 more monthly instillations (Course 111). Those years and 54 of these (57%) were free of disease. with persistent recurrences even after 36 successive Of 22 patients who continued to have multiple instillations were classed as non-responders and recurrences after courses I and 11, 20 completed 12 treatment was discontinued. further monthly instillations (Course 111). None responded. The pre-therapy tumour histology was INTRAVESICAL THERAPY (n I 111) grade 1 in 3 patients (15%) and grade 2 in 17 (85%). Of the 54 patients who were free of disease at 3 years, the pre-therapy tumour histology was grade 1 in 32 (59%) and grade 2 in 22 (41%) (Table 1). The 72 ‘(NR) 39iPT) comparison between the 2 groups was statistically “ours; 1 1 1 *3 significant (P
.-C
+d
C
40
-
a,
P
a n 0
3
2
1
4
20 -
5
Years Fig. 2 Actuarial percentage of patients continuously free of disease after 12 weekly instillations.
After Course 11 (12 weekly and 12 monthly instillations). Of the 14 patients who responded to Course I1 after failure to respond to Course I, 16% remained continuously free of disease for 5 years (Fig. 3). Sequelae A total of 2389 catheterisations were performed on 111 patients and 26 urinary tract infections were documented (1%). Symptoms of chemical cystitis were reported only by patients receiving weekly instillations and the overall incidence was 19%. Symptoms were controlled by increasing the interval between the instillations.
-
Disease lree at one year Persisting turnour at one year
0 0
1
3
2
5
4
Years Fig. 4 Freedom from invasion: comparison between patients disease-free at 1 year and those with persistent tumour at I year.
but only 25% in those having persistent tumour at 1 year (n = 22) (Fig. 4).
Discussion
The overall response rate of 73% at 1 year in this study corroborates the results of other studies (Table 2) (Fitzpatrick et al., 1979; Nielson and Thybo, 1979; Colleen et al., 1980; Riddle et al., 1982). With large numbers and a long follow-up period, the results of this study showed that the best Freedom from invasion indicator of success was the initial response to 12 The incidence of freedom from invasion at 5 years weekly instillations of Epodyl; 72 patients rewas 86% in patients disease-free at 1 year (n = 8 1) sponded to Course I, of whom 46% remained free of tumour for 5 years (Fig. 2). In the event of lack of response to 12 weekly instillations, a further 12 monthly instillations were useful but the response was not long-lasting. After failing to respond to Course I, 36 patients completed Course I1 and 14 (39%) responded. However, of these 14 patients only 16% remained tumour-free for 5 years (Fig. 3). Table 2 Intravesical Epodyl Treatment and Early Response No. of
0
0
1
2
3
4
5
Years Fig. 3 Actuarial percentage of patients continuously free of disease after 12 weekly and 12 monthly consecutive instillations.
Author
Patients
Complete response No. (%)
Nielson and Thybo (1979) Fitzpatrick ei al. (1979) Colleen ei al. (1 980) Riddle ei al. (1982) Present series
36 64 29 139 111
23 39 23 70 81
(64) (61) (79) (50)
(73)
INTRAVESICAL EPODYL THERAPY FOR SUPERFICIAL BLADDER CANCER
If the tumours continued to recur after 24 consecutive instillations, further Epodyl therapy was of no benefit. In retrospect, it seems that the treatment was continued for longer than necessary in 20 patients who received 3 consecutive courses. Pre-therapy tumour grade was significantly related to the response, with grade 2 tumours less likely to respond (Table 1). A patient with multiple bladder tumours which have not cleared after 1 year’s treatment with Epodyl has a 75% chance of developing tumour invasion within 5 years (Fig. 4). Elective radical surgery appears to be mandatory in such a case. Clearance of bladder disease by 1 year carries a subsequent risk of invasive disease of only 14% (Fig. 4). A policy of regular reviews, early drug treatment of recurrences and cystectomy only in the event of lack of response can be justified in this group. The reason why Epodyl has not achieved popularity is possibly due to the reported incidence of chemical cystitis, which has ranged from 8 to 25% (Robinson et a[., 1977; Smith er a[., 1978; Nielson and Thybo, 1979; Fitzpatrick et al., 1979; Colleen etal., 1980).In this study, 19xofpatients developed symptoms of chemical cystitis severe enough to interrupt treatment. However, increasing the interval between instillations helped to alleviate the symptoms and allowed the treatment to be continued. This problem was not encountered in patients receiving monthly instillations. In summary, the present study has shown that Epodyl has a definite place in the management of multiple superficial bladder tumours. It is cost effective, suitable for use in out-patient clinics and has no systemic toxicity. An initial complete response to therapy and a lower pathological tumour grade appear to indicate a long-term successful response. In patients who fail to respond by 1 year, further therapy offers no benefit and radical surgery should be given serious consideration. In those who
35
do respond, careful supervision is necessary to achieve the best results over the longer term.
Acknowledgements We thank Dr G . Murray, Senior Lecturer in Medical Statistics, Glasgow University, for statistical advice and Miss Veronica Mulholland for typing the manuscript.
References Abbassian, A. and Wallace, D. M. (1966). Intracavitary chemotherapy of diffuse non-infiltrating papillary carcinoma of the bladder. J . Urol.,96.46 1-465. Colleen, S., Ek, A., HeUsten,S. et al. (1980). Intracavitary Epodyl for multiple non-invasive highly differentiated bladder tumours. Scand. J . Urol. Nephrol., 14,43-45. Dixon, W. J., Brown, M. B., Engleman, L. er al. (1985). E M D P Statistical Software. Berkeley: UCLA Press. Fitzpatrick, J. M., Khan, O., Oliver R. T. D. et al. (1979). Longterm follow-up in patients with superficial bladder tumours treated with intravesical Epodyl. Br. J . Urol.,51, 545-548. Nielson, H. V. and Thybo, E.(1 979). Epodyl treatment of bladder tumours. Scand.J . Urol. Nephrol., 13, 59-63. Riddle, P. R. and Wallace, D. M. (1971). Intracavitary chemotherapy for multiple non-invasive bladder tumours. Br. J . Urol.,43, 181-184. Riddle,P. R.,Khan,O.,Fitzpatrick, J. M. erd.(1982). Prognostic factors influencing survival of patients receiving intravesical Epodyl. J . Urol., 127,430-432. Robinson, M. R. G., Shetty, M. B., Richards, B. er aL (1977). Intravesical Epodyl in the management of bladder tumours: combined experience of the Yorkshire Urological Cancer Research Group. J. Urol., 118,972-973. Smith, J. M., Lane, V. and O’Flynn, J. D. (1978). Epodyl in management of non invasive vesical neoplasms. Urology, 11, 474477.
The Authors G . R. Mufti, MS, MCh, FRCSE, formerly Registrar in Urology. Now Consultant Urologist (Locum), Royal Infirmary, Glasgow . J. S. Virdi, MS, MCh, FRCS, Clinical Assistant in Urology. M. H. Hall, FRCS, formerly Consultant Urologist. Requests for reprints to: G . R. Mufti, Department of Urology, Royal Infirmary, 16 Alexandra Parade, Glasgow G31 2ER.
