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Preliminary results of treatment of invasive bladder carcinoma with radiotherapy and cisplatin
Inf. J. Radrarm OncologyBiol Phys.. Vol. Printed in the U.S.A. All rights reserved.
15, PP. 871-875 Copyright
0360-3016/88 $3.00 + .M) 0 1988 Pergamon Press plc
??Original Contribution
PRELIMINARY RESULTS OF TREATMENT OF INVASIVE BLADDER CARCINOMA WITH RADIOTHERAPY AND CISPLATIN
R.
SAUER,
M.D.,* K. M.
SCHROTT,
P. HERMANEK,
M.D.,? J. DUNST, M.D.,* H.-J. M.D.* AND C. BORNHOF, M.D.?
THIEL,
M.D.,*
University of Erlangen-Niirnberg,Maximiliansplatz,D-8520 Erlangen From October 1985 to February 1988,41 patients with invasive bladder cancers were treated with transurethral resection (TUR) and radiotherapy with simultaneous cisplatin chemotherapy at the University Hospital in Erlangen. Radiotherapy was performed as primary treatment in case of macroscopic residual tumor after TUR (n = 22) or as adjuvant treatment in patients with macroscopically complete transurethral resection (n = 19). Age ranged from 44 to 77 years. Radiotherapy was given in daily fractions of 1.8 Gy. The pelvis was treated with a box up to 41.4 Gy and the bladder was boosted up to 50.4 Gy by a rotation technique. Cisplatin was administered in the first and fifth treatment week on five consecutive days with 25 mg cisplatin/m2 per day as short infusion. Pathohistologic response was examined by control cystoscopy with biopsies from the deep layers 6 weeks after completing radiochemotherapy. Maximum follow-up is 24 months after control cystoscopy. After TUR plus radiochemotherapy, histologically confirmed complete remission rates according to T-stage were: 7/8 T1-, 26/31 T2_3-,and 2/2 T.&umors. In patients with macroscopic tumor prior to radiochemotherapy, histological and cytological complete remission was achieved in 2/3 T I-, 14/18 T2-3-, and l/l T.,-cancers with an overall complete response rate of 77%. In complete responders, 3 isolated local recurrences (2 Tr- and one T3-recurrence) and two local recurrences with distant metastases have occurred until now. Six patients had only partial response. Mild to moderate side effects occurred frequently, but overall treatment tolerance was good even in older patients. Complications did not occur. So far, 7 cystectomies have been performed, 6 were a result of persistent or recurrent tumor and one a result of a contracted bladder after multiple TURs. Thirty-four of forty-one patients (83%!) maintained their bladder and normal bidder function. In conclusion, moderate dose radiation therapy (50 Gy) in combination with simultaneous cisplatin chemotherapy is a well-tolerated treatment and highly effective for controlling local disease and preservation of bladder function in invasive bladder cancers. Bladder cancer, Radiotherapy, Cisplatin. the protocol was restricted to T3_4-cancers, but was later
INTRODUCTION
opened for T2- and poor prognostic Ti-cancers in 1986. The preliminary data are presented here.
In muscle-invading bladder cancers, radical cystectomy is effective for locoregional tumor control but cannot cure more than 50% of the patients due to systemic spread of disease. Disadvantages of radical surgery arise from urinary diversion and sexual problems in men. Although radiotherapy as a single modality is less effective than cystectomy it has been introduced in bladder preserving treatment programs. Recently, Jakse et cd5 as well as the National Bladder Cancer Group7,8 published encouraging results obtained by a combination of radiotherapy and chemotherapy. Therefore, we started a protocol of radiation therapy with simultaneous cisplatin application in 1985. Our aim was to improve local tumor control. In the first year,
METHODS
AND
MATERIALS
Patients From October 1985 to February 1988, 64 patients with bladder cancers have been treated with radiation therapy at the University Hospital in Erlangen. Fortyone patients were treated with simultaneous cisplatin chemotherapy for invasive bladder cancers and had a histological and cytological verification of response; they will be considered in this paper. There were 10 females and 3 1 males. Age ranged from 44 to 77 years (mean: 63 years). Oral presentation at the Annual ASTRO-Meeting, Boston, October 18-24, 1987. Accepted for publication 2 1 April 1988.
* Department of Radiotherapy. t Department of Urology. $ Department of Clinical Pathology. Reprint requests to: Prof. Dr. R. Sauer, Strahlentherapeutische Klinik, Univerdtsstr.27, D-8520 Erlangen. 871
812
I. J. RadiationOncology 0 Biology 0 Physics
October 1988, Volume 15,Number 4
Table 1. Classification of residual tumor after transurethral resection
was examined by computed tomography-scans. Five patients had involved lymph nodes on computed tomography scans. Additional work-up included chest X ray, ultrasound examination of the liver, bone scan, and laboratory work-up for to exclude distant metastases.
RO: no visible tumor after TUR, biopsies from the ground of resection without tumor R,: no visible tumor after TUR, biopsies from the ground of resection with tumor RZ: macroscopic tumor visible after TUR
Radiotherapy After simulator planning with contrast filling of bladder and rectum, patients were treated with a 10 MV-linear accelerator in supine position using a four-field-boxtechnique. The margins of the ap/pa portals were the L4/ LS-interspace, the middle of the obturator foramina and 1 cm outside the true pelvis at each side. On the lateral portals, the contrasted bladder volume was included with a 2 cm-safety margin anteriorly and posteriorly and the portals covered the pelvic nodes posteriorly up to S2. Individual shielding of the rectum and the small intestine was used whenever possible. All portals were treated daily, five times a week by single doses of 1.8 Gy per fraction (maximum dose 2 Gy). The total dose was 4 1.40 Gy in 4.5 weeks (46 Gy maximum dose) to the small pelvis. Then, a boost of five fractions to the bladder only was delivered by a 360”-rotation technique up to 50.40 Gy to the bladder (56 Gy maximum dose). In patients with positive nodes, the boost was administered by a boxtechnique with reduced field size.
Twenty-three patients were excluded from this analysis. Ten of them were treated with different fractionation schemes and other chemotherapeutic regimens including adriamycine; response was examined only by cystoscopy and cytology. Ten patients have started or completed radiochemotherapy, but have not yet been reevaluated after radiochemotherapy. Three patients who would have been considered candidates for radiochemotherapy were treated with radiotherapy alone because of severe renal failure.
Initial cystoscopy and TUR All patients had cystoscopy with complete or incomplete transurethral resection prior to irradiation. Biopsies were taken from the ground and the margins of resection as well as from the surroundings (=3 cm) of the tumor. Suspicious lesions were resected as well. The procedure included a bladder mapping with at least 6 random biopsies from definite bladder areas.
Chemotherapy Staging and clinical evaluation
Cisplatin (25 mg per square meter per day) was administered as a short infusion over 30 to 60 minutes prior to irradiation on five consecutive days in the first and fifth treatment week (days l-5 and 29-33, Fig. 1). Hyperhydration and prophylactic antiemetics were given routinely in all patients. Sodium, potassium, chloride, and magnesium levels as well as creatinine levels were checked three times weekly during chemotherapy and afterwards in weekly intervals. Blood count was measured weekly. Contraindications to cisplatin administration were a creatinine > 1.6 mg/dl or a creatinine clearance ~50 ml/min. In patients with hydronephrosis, percutaneous nephrostomy was used.
The histologic specimen were examined for typing and grading (G,_4) as well as for lymphatic vessel invasion (L+z) and residual tumor (I&_2, Table 1). T-status was classified according to UICC 1987 and muscle invasion was present in all Tz-tumors. Eight patients had been staged according to UICC 1983 and had muscle-invading cancers (Tz_j) but a retrospective differentiation between T2 and T3 was not possible. In all T4-carcinomas, histologically proven invasion of extravesical organs (prostate) was present. Distribution according to stage was:T,:n=8,Tz:n= 11,T2_3:n=8,T3:n= 12,Tq:n = 2. Fifteen patients had multifocal tumors. Nodal status
TREATMENT DAYS
CISPLATIN (25 mglm 2 d)
’
5
10
15
20
25
30
35
11111111111111111111111111111111111
Ill11
lllll
R*D,GTHERIPY%%% (l.aclGy/oo K p.day)-
%%%
%4%%%!4vi%% 4% 41.40 Gy Box
9 Gy
.
Rotation
Fig. 1. Simultaneous radiochemotherapy. The pelvis is treated with a box-technique and daily fractions of 1.80 Gy (calculated on the 90%isodose surrounding the target volume) up to 41.40 Gy and the bladder is boosted with five additional fractions by a 360’-rotation-technique. Cisplatin (25 mg/m2 per day) is administered on five consecutive days in the first and fifth treatment week as short infusion over 30 to 60 minutes prior to irradiation.
Treatment of bladder cancer with radiotherapy and cisplatin 0 R. SAUER
Two patients with T,-cancers and adjuvant radiochemotherapy received only one chemotherapy course in the first treatment week. In two other patients, the second cisplatin course was omitted because of serum creatinine elevation up to 2.4 mg/dl or pulmonary embolization, respectively. Response criteria andfollow-up All patients had cytology and control-TUR with biopsies from the deep layers 4 to 6 weeks after completing radiotherapy. Bladder mapping was repeated. Complete response was defined as the absence of invasive cancer. Follow-up examinations included a cystoscopy and cytology every 3 months with resection of suspicious lesions. Computed tomography scans of the pelvis and abdomen and chest X ray were repeated every 6 months. Salvage cystectomy Salvage cystectomy was performed in operable patients with locally persistent or recurrent tumor without evidence of distant disease. RESULTS
Response The response rates after radio-chemotherapy according to initial T-stage and residual tumor after TUR are presented in Table 2. Five patients received radiochemotherapy as adjuvant treatment after the tumor had been completely resected with tumor-free biopsies from the ground of resection (R,,). On control cystoscopy, these patients had no invasive cancer; one of them had in-situ carcinoma at the time of control cystoscopy and was treated with TUR and intravesical chemotherapy. Fourteen patients were treated with radiochemotherapy after macroscopically complete transurethral resections of the tumor but positive biopsies from the ground of resection. Thirteen of them (93%) were free of invasive cancer at the time of control cystoscopy, although 2 had non-invasive tumors (Tis, T,) that were treated with TUR and intravesical chemotherapy. One patient with a
T3-primary had muscle-invasive cancer after radiochemotherapy. Twenty-two patients had incomplete resection with macroscopic residual tumor prior to radiochemotherapy. Seventeen of them (77%) had a complete response with no evidence of tumor after radiochemotherapy. Five patients had only partial response (2 with microscopic and 3 with macroscopic residual tumor). One patient with partial response had received only one chemotherapy course because of serum creatinine elevation. Thus, the overall complete remission in T2_4-tumors was 79% ( 15/ 19) and in T3_&umors 72% (8/ 1 l), respectively. In summary, complete remission after TUR and radio-chemotherapy according to T-stage was T, : 88%, T2: 90%, T2_s: lOO%, T3: 67%, T,: 100% (Table 2). The results of irradiation and simultaneous cisplatin chemotherapy are superior to radiation therapy alone. In our former series from 1982 to 1985 with irradiation alone in Tz_jNO-tumors, complete response rates and one-year local control rate were 23% lower when using the same irradiation technique and dosage but no cisplatin (Table 3). Treatment ofpartial responders In six patients, only partial response was achieved; two of them had additional distant metastases at the time of control cystoscopy. Three were treated with cystectomy and one with cystectomy and chemotherapy. One patient with a large T3-tumor had only foci of tumor after radiochemotherapy and was treated by TUR only because of good response and advanced age. One patient with a T,-cancer had rapidly progressive distant disease and died within one month without further treatment. Local recurrences So far, five local recurrences in complete responders have been observed, two of them associated with distant metastases. Three recurrences occurred in T2_3-cancers and both patients with T4-cancers developed recurrences. It should be noted that two recurrences were limited to the mucosa (rT,) without evidence of muscle-invasion.
Table 2. TUR and radiotherapy plus cisplatin for invasive bladder cancer Ro TI
212
T2
313
T2-3 7-3
-
T4
-
c
515
RI 313 515 313
R2
112
213 213 515 7/10
l/l
l/l
13/14
I7122
c
718 10/l 1 818 8112 212
35141
Note: Histologically proven complete remission rates (no invasive cancer) according to T-stage and amount of residual tumor prior to radiochemotherapy: University of ErlangenNumberg, X/85-11/88
873
et al.
For example,
one patient
with a T&umor
devel-
Table 3. Comparison of irradiation alone (1982-1985) and irradiation with simultaneous cisplatin (1985-1988) for T2_3R,_2-bladder cancers, University of Erlangen
Irradiation alone (50.4 Gy) Irradiation (50.4 Gy) + Cisplatin
n
Complete response (no invasive cancer)
1-yearlocal control
30
55% (32/58)
46%
28
82% (23/28)
69%*
* Kaplan-Meier-Method Note: RI or R2 means microscopic or macroscopic residual tumor after transurethral resection prior to irradiation.
874
I. J. Radiation Oncology 0 Biology 0 Physics
oped a recurrence (T’ and in situ carcinoma) outside the primary tumor region 6 months after radio-chemotherapy and was treated by cystectomy because of young age; the pathological specimen showed no muscle-invasive tumor and even the primarily involved prostate was free of tumor. Bladder preservation With a relatively short follow-up (medium follow-up one year), 7 cystectomies have been performed, all without complications. Six salvage-cystectomies were due to isolated persistent or recurrent tumor. One patient required cystectomy because of a contracted bladder due to multiple TURs prior to radiation therapy. In this patient, bladder capacity was already severely reduced prior to irradiation and conservative treatment was not successful; the surgical specimen was free of tumor. The bladder was preserved in 34 out of 41 patients (83%!). All patients with preserved bladder had a normal bladder function. Side efects and complications Mild to moderate acute side effects of radiotherapy (dysuria, slight diarrhea) occurred frequently. One patient required hospitalization because of transitory severe dysuria. Chronic sequelae caused by radiation therapy have not been observed until now. Chemotherapy was tolerated quite well even in older patients. With prophylactic antiemetic medication, gastrointestinal toxicity (nausea, vomiting) was tolerable but occurred in all patients. Mild to moderate leucopenia and thrombopenia (WHO grade I-II) was noted in nearly all patients, but severe hematologic toxicity was rare: WHO grade III in 10 out of 41 patients (24%) WHO grade IV in no patient. Transitory elevation of serum creatinine level over 2 mg/dl up to 2.4 mg/dl was noted in 3 patients (7%). In one patient a pulmonary embolization occurred after the fourth treatment week and further therapy was omitted. This complication was not related to radiochemotherapy, and the patient is in complete remission at this time without evidence of bladder cancer. Survival Any conclusions concerning survival cannot be drawn at this moment because of limited follow-up. Up to now, nine patients have died with systemic disease, three of them had also local disease. One patient has liver metastases with no evidence of loco-regional disease. Thirtyone patients are in complete remission and 27 of them maintained their bladders. DISCUSSION
In Tz_j-bladder cancer, 5-year survival rates of about 50% are achieved by radical cystectomy.3.‘2 Disadvan-
October 1988, Volume 15, Number 4
tages of this procedure include urinary diversion and sexual problems in men. Preoperative irradiation may improve survival in patients who achieve downstaging to pT0 .6 Adjuvant chemotherapy is currently under investigation, but the indication has not yet been clearly defined.13 Radical radiotherapy alone is less effective for local tumor control and survival than cystectomy, but offers the chance to preserve bladder function in a subgroup of patients.9.‘5 Data from several studies indicate that salvage cystectomy for failure after primary irradiation can be curative with an acceptable rate of complications. L*.~.“.’‘.I4 The optimal dose to the bladder in primary radiotherapy is questionable. Moderate doses of 50-60 Gy do not impact bladder function, local control rates however do not exceed 50%. Higher doses to the bladder may improve local control, but the incidence of long-term sequelae to the bladder reaches about 20% if irradiation is combined with chemotherapy.5 In our former series from 1982 to 1985 with primary irradiation alone, XRT with 50 Gy yielded in a l-year local recurrence-free rate of less than 50% in T2-3Rl_2tumors. The introduction of cisplatin chemotherapy has increased local control rates markedly as compared to our former series. Histologically confirmed complete remissions of muscle-invading tumors after radio-chemotherapy were about 25% higher than with irradiation alone. Thus, our preliminary data indicate that results of radiotherapy are improved by the addition of simultaneous chemotherapy. Treatment was well tolerated even in older patients. Complications as reported by other authors5 did not occur. We emphasize that no impact of the radiochemotherapy on bladder function was noted. With cystectomy restricted to patients with isolated local persistent or recurrent tumor, more than 80% of our patients preserved their bladders and all of them maintained a normal bladder function. In our view, it is questionable in how far higher radiation doses may improve local control and if there are any criteria for patient selection for higher radiation doses. In summary, high local response rates can be achieved by primary radiation therapy with simultaneous cisplatin chemotherapy. Conclusions concerning survival cannot be drawn at this moment because of limited follow-up. Nevertheless, we consider this management to be the locoregional treatment of choice in Tz_4-bladder cancers and in T’-cancers with large or multifocal extension or poor differentiation, if preservation of bladder function is desired. In our opinion, this concept should be evaluated in further prospective trials and long-term results are to be obtained. Future trials should focus on the question if more aggressive approaches including polychemotherapy regimens could influence relapse rate and complications especially in younger patients.
Treatment of bladder cancer with radiotherapy and cisplatin 0 R. SAUER et al.
875
REFERENCES 1. Blandy, J.P., England, H.R., Evans, S.J.W., Hope-Stone, H.F., Mair, G.M.M., Mantell, B.S., Oliver, R.T.D., Paris, A.M.I., Ridson, R.A.: TS bladder cancer-The case for salvage cystectomy. Brit. J. Ural. 52: 506-5 10, 1980.
8.
2. Crawford, E.D., Skinner, D.G.: Salvage cystectomy for irradiation failures. J. Ural. 123: 32-34, 1980. 3. Cummings, K.B., Shipley, W.U., Einstein, A.B., Cutler, S.J.: Current concepts in the management of patients with deeply invasive bladder carcinoma. Sem. Oncol. 6: 220228,1979. 4. Goodman, G.B., Hislop, T.G., Elwood, J.M., Balfour, J.: Conservation of bladder function in patients with invasive bladder cancer treated by definitive irradiation and selective cystectomy. Int. J. Radiat. Oncol. Biol. Phys. 7: 569573, 1981. 5. Jakse, G., Rauschmeier, H., Fritsch, E., Frommhold, H., Marberger, H.: Die integrierte Radiotherapie und Chemotherapie des lokal fortgeschrittenen Harnblasenkarzinoms. Akt. Ural. 17: 68-73, 1986. 6. Prout, G.R.: The surgical management of bladder carcinoma. Vrol. Clin. N. Am. 3: 149-175, 1976. 7. Shipley, W., Einstein, A., Coombs, J., Prout, G., Wajsman, Z., Solloway, M., Englander, L., Barton, B., Weinstein, R.: Cisplatin and full-dose irradiation for patients with invasive bladder carcinoma: The National Bladder Cancer Group experience. Conference on the Interaction of Radia-
9.
10.
11.
12. 13. 14.
15.
tion Therapy and Chemotherapy, Williamsburg, Virginia, Sept. 28-Oct. 1, 1986. Shipley, W.U., Einstein, A.B., Soloway, M.S., Wajsman, Z., Prout, G.R. and the National Bladder Cancer Collaborative Group A: Cisplatin and full dose irradiation for patients with invasive bladder carcinoma: A preliminary report of tolerance and local response. J. Ural. 132: 899-903, 1984. Shipley, W.U., Rose, M.A.: Bladder cancer. The selection of patients for treatment by full-dose irradiation. Cancer 55: 2278-2284, 1985. Smith, J.A., Whitmore, W.F.: Salvage cystectomy for bladder cancer after failure of definitive irradiation. J. Ural. 125: 643-645, 198 1. Svanson, D.A., Eschenbach, A.C., von Johnson, D.E.: Salvage cystectomy for bladder carcinoma. Cancer 47: 22752279,198l. Whitmore, W.F.: Management of invasive bladder neoplasms. Sem. Ural. 1: 34, 1983. Whitmore, W.F.: Chemotherapy for bladder cancer. J. Ural. 134: 1181-l 182, 1985. Wizenberg, M.J.: Invasive bladder cancer-Definitive irradiation and salvage cystectomy. Sem. Oncol. 6: 229-235, 1979. Yu, W.S., Sagerman, R.H., Chung,C.T., Dalal, P.S., King, G.A.: Bladder carcinoma. Experience with radical and preoperative radiotherapy in 42 1 patients. Cancer 56: 12931299, 1985.
15, PP. 871-875 Copyright
0360-3016/88 $3.00 + .M) 0 1988 Pergamon Press plc
??Original Contribution
PRELIMINARY RESULTS OF TREATMENT OF INVASIVE BLADDER CARCINOMA WITH RADIOTHERAPY AND CISPLATIN
R.
SAUER,
M.D.,* K. M.
SCHROTT,
P. HERMANEK,
M.D.,? J. DUNST, M.D.,* H.-J. M.D.* AND C. BORNHOF, M.D.?
THIEL,
M.D.,*
University of Erlangen-Niirnberg,Maximiliansplatz,D-8520 Erlangen From October 1985 to February 1988,41 patients with invasive bladder cancers were treated with transurethral resection (TUR) and radiotherapy with simultaneous cisplatin chemotherapy at the University Hospital in Erlangen. Radiotherapy was performed as primary treatment in case of macroscopic residual tumor after TUR (n = 22) or as adjuvant treatment in patients with macroscopically complete transurethral resection (n = 19). Age ranged from 44 to 77 years. Radiotherapy was given in daily fractions of 1.8 Gy. The pelvis was treated with a box up to 41.4 Gy and the bladder was boosted up to 50.4 Gy by a rotation technique. Cisplatin was administered in the first and fifth treatment week on five consecutive days with 25 mg cisplatin/m2 per day as short infusion. Pathohistologic response was examined by control cystoscopy with biopsies from the deep layers 6 weeks after completing radiochemotherapy. Maximum follow-up is 24 months after control cystoscopy. After TUR plus radiochemotherapy, histologically confirmed complete remission rates according to T-stage were: 7/8 T1-, 26/31 T2_3-,and 2/2 T.&umors. In patients with macroscopic tumor prior to radiochemotherapy, histological and cytological complete remission was achieved in 2/3 T I-, 14/18 T2-3-, and l/l T.,-cancers with an overall complete response rate of 77%. In complete responders, 3 isolated local recurrences (2 Tr- and one T3-recurrence) and two local recurrences with distant metastases have occurred until now. Six patients had only partial response. Mild to moderate side effects occurred frequently, but overall treatment tolerance was good even in older patients. Complications did not occur. So far, 7 cystectomies have been performed, 6 were a result of persistent or recurrent tumor and one a result of a contracted bladder after multiple TURs. Thirty-four of forty-one patients (83%!) maintained their bladder and normal bidder function. In conclusion, moderate dose radiation therapy (50 Gy) in combination with simultaneous cisplatin chemotherapy is a well-tolerated treatment and highly effective for controlling local disease and preservation of bladder function in invasive bladder cancers. Bladder cancer, Radiotherapy, Cisplatin. the protocol was restricted to T3_4-cancers, but was later
INTRODUCTION
opened for T2- and poor prognostic Ti-cancers in 1986. The preliminary data are presented here.
In muscle-invading bladder cancers, radical cystectomy is effective for locoregional tumor control but cannot cure more than 50% of the patients due to systemic spread of disease. Disadvantages of radical surgery arise from urinary diversion and sexual problems in men. Although radiotherapy as a single modality is less effective than cystectomy it has been introduced in bladder preserving treatment programs. Recently, Jakse et cd5 as well as the National Bladder Cancer Group7,8 published encouraging results obtained by a combination of radiotherapy and chemotherapy. Therefore, we started a protocol of radiation therapy with simultaneous cisplatin application in 1985. Our aim was to improve local tumor control. In the first year,
METHODS
AND
MATERIALS
Patients From October 1985 to February 1988, 64 patients with bladder cancers have been treated with radiation therapy at the University Hospital in Erlangen. Fortyone patients were treated with simultaneous cisplatin chemotherapy for invasive bladder cancers and had a histological and cytological verification of response; they will be considered in this paper. There were 10 females and 3 1 males. Age ranged from 44 to 77 years (mean: 63 years). Oral presentation at the Annual ASTRO-Meeting, Boston, October 18-24, 1987. Accepted for publication 2 1 April 1988.
* Department of Radiotherapy. t Department of Urology. $ Department of Clinical Pathology. Reprint requests to: Prof. Dr. R. Sauer, Strahlentherapeutische Klinik, Univerdtsstr.27, D-8520 Erlangen. 871
812
I. J. RadiationOncology 0 Biology 0 Physics
October 1988, Volume 15,Number 4
Table 1. Classification of residual tumor after transurethral resection
was examined by computed tomography-scans. Five patients had involved lymph nodes on computed tomography scans. Additional work-up included chest X ray, ultrasound examination of the liver, bone scan, and laboratory work-up for to exclude distant metastases.
RO: no visible tumor after TUR, biopsies from the ground of resection without tumor R,: no visible tumor after TUR, biopsies from the ground of resection with tumor RZ: macroscopic tumor visible after TUR
Radiotherapy After simulator planning with contrast filling of bladder and rectum, patients were treated with a 10 MV-linear accelerator in supine position using a four-field-boxtechnique. The margins of the ap/pa portals were the L4/ LS-interspace, the middle of the obturator foramina and 1 cm outside the true pelvis at each side. On the lateral portals, the contrasted bladder volume was included with a 2 cm-safety margin anteriorly and posteriorly and the portals covered the pelvic nodes posteriorly up to S2. Individual shielding of the rectum and the small intestine was used whenever possible. All portals were treated daily, five times a week by single doses of 1.8 Gy per fraction (maximum dose 2 Gy). The total dose was 4 1.40 Gy in 4.5 weeks (46 Gy maximum dose) to the small pelvis. Then, a boost of five fractions to the bladder only was delivered by a 360”-rotation technique up to 50.40 Gy to the bladder (56 Gy maximum dose). In patients with positive nodes, the boost was administered by a boxtechnique with reduced field size.
Twenty-three patients were excluded from this analysis. Ten of them were treated with different fractionation schemes and other chemotherapeutic regimens including adriamycine; response was examined only by cystoscopy and cytology. Ten patients have started or completed radiochemotherapy, but have not yet been reevaluated after radiochemotherapy. Three patients who would have been considered candidates for radiochemotherapy were treated with radiotherapy alone because of severe renal failure.
Initial cystoscopy and TUR All patients had cystoscopy with complete or incomplete transurethral resection prior to irradiation. Biopsies were taken from the ground and the margins of resection as well as from the surroundings (=3 cm) of the tumor. Suspicious lesions were resected as well. The procedure included a bladder mapping with at least 6 random biopsies from definite bladder areas.
Chemotherapy Staging and clinical evaluation
Cisplatin (25 mg per square meter per day) was administered as a short infusion over 30 to 60 minutes prior to irradiation on five consecutive days in the first and fifth treatment week (days l-5 and 29-33, Fig. 1). Hyperhydration and prophylactic antiemetics were given routinely in all patients. Sodium, potassium, chloride, and magnesium levels as well as creatinine levels were checked three times weekly during chemotherapy and afterwards in weekly intervals. Blood count was measured weekly. Contraindications to cisplatin administration were a creatinine > 1.6 mg/dl or a creatinine clearance ~50 ml/min. In patients with hydronephrosis, percutaneous nephrostomy was used.
The histologic specimen were examined for typing and grading (G,_4) as well as for lymphatic vessel invasion (L+z) and residual tumor (I&_2, Table 1). T-status was classified according to UICC 1987 and muscle invasion was present in all Tz-tumors. Eight patients had been staged according to UICC 1983 and had muscle-invading cancers (Tz_j) but a retrospective differentiation between T2 and T3 was not possible. In all T4-carcinomas, histologically proven invasion of extravesical organs (prostate) was present. Distribution according to stage was:T,:n=8,Tz:n= 11,T2_3:n=8,T3:n= 12,Tq:n = 2. Fifteen patients had multifocal tumors. Nodal status
TREATMENT DAYS
CISPLATIN (25 mglm 2 d)
’
5
10
15
20
25
30
35
11111111111111111111111111111111111
Ill11
lllll
R*D,GTHERIPY%%% (l.aclGy/oo K p.day)-
%%%
%4%%%!4vi%% 4% 41.40 Gy Box
9 Gy
.
Rotation
Fig. 1. Simultaneous radiochemotherapy. The pelvis is treated with a box-technique and daily fractions of 1.80 Gy (calculated on the 90%isodose surrounding the target volume) up to 41.40 Gy and the bladder is boosted with five additional fractions by a 360’-rotation-technique. Cisplatin (25 mg/m2 per day) is administered on five consecutive days in the first and fifth treatment week as short infusion over 30 to 60 minutes prior to irradiation.
Treatment of bladder cancer with radiotherapy and cisplatin 0 R. SAUER
Two patients with T,-cancers and adjuvant radiochemotherapy received only one chemotherapy course in the first treatment week. In two other patients, the second cisplatin course was omitted because of serum creatinine elevation up to 2.4 mg/dl or pulmonary embolization, respectively. Response criteria andfollow-up All patients had cytology and control-TUR with biopsies from the deep layers 4 to 6 weeks after completing radiotherapy. Bladder mapping was repeated. Complete response was defined as the absence of invasive cancer. Follow-up examinations included a cystoscopy and cytology every 3 months with resection of suspicious lesions. Computed tomography scans of the pelvis and abdomen and chest X ray were repeated every 6 months. Salvage cystectomy Salvage cystectomy was performed in operable patients with locally persistent or recurrent tumor without evidence of distant disease. RESULTS
Response The response rates after radio-chemotherapy according to initial T-stage and residual tumor after TUR are presented in Table 2. Five patients received radiochemotherapy as adjuvant treatment after the tumor had been completely resected with tumor-free biopsies from the ground of resection (R,,). On control cystoscopy, these patients had no invasive cancer; one of them had in-situ carcinoma at the time of control cystoscopy and was treated with TUR and intravesical chemotherapy. Fourteen patients were treated with radiochemotherapy after macroscopically complete transurethral resections of the tumor but positive biopsies from the ground of resection. Thirteen of them (93%) were free of invasive cancer at the time of control cystoscopy, although 2 had non-invasive tumors (Tis, T,) that were treated with TUR and intravesical chemotherapy. One patient with a
T3-primary had muscle-invasive cancer after radiochemotherapy. Twenty-two patients had incomplete resection with macroscopic residual tumor prior to radiochemotherapy. Seventeen of them (77%) had a complete response with no evidence of tumor after radiochemotherapy. Five patients had only partial response (2 with microscopic and 3 with macroscopic residual tumor). One patient with partial response had received only one chemotherapy course because of serum creatinine elevation. Thus, the overall complete remission in T2_4-tumors was 79% ( 15/ 19) and in T3_&umors 72% (8/ 1 l), respectively. In summary, complete remission after TUR and radio-chemotherapy according to T-stage was T, : 88%, T2: 90%, T2_s: lOO%, T3: 67%, T,: 100% (Table 2). The results of irradiation and simultaneous cisplatin chemotherapy are superior to radiation therapy alone. In our former series from 1982 to 1985 with irradiation alone in Tz_jNO-tumors, complete response rates and one-year local control rate were 23% lower when using the same irradiation technique and dosage but no cisplatin (Table 3). Treatment ofpartial responders In six patients, only partial response was achieved; two of them had additional distant metastases at the time of control cystoscopy. Three were treated with cystectomy and one with cystectomy and chemotherapy. One patient with a large T3-tumor had only foci of tumor after radiochemotherapy and was treated by TUR only because of good response and advanced age. One patient with a T,-cancer had rapidly progressive distant disease and died within one month without further treatment. Local recurrences So far, five local recurrences in complete responders have been observed, two of them associated with distant metastases. Three recurrences occurred in T2_3-cancers and both patients with T4-cancers developed recurrences. It should be noted that two recurrences were limited to the mucosa (rT,) without evidence of muscle-invasion.
Table 2. TUR and radiotherapy plus cisplatin for invasive bladder cancer Ro TI
212
T2
313
T2-3 7-3
-
T4
-
c
515
RI 313 515 313
R2
112
213 213 515 7/10
l/l
l/l
13/14
I7122
c
718 10/l 1 818 8112 212
35141
Note: Histologically proven complete remission rates (no invasive cancer) according to T-stage and amount of residual tumor prior to radiochemotherapy: University of ErlangenNumberg, X/85-11/88
873
et al.
For example,
one patient
with a T&umor
devel-
Table 3. Comparison of irradiation alone (1982-1985) and irradiation with simultaneous cisplatin (1985-1988) for T2_3R,_2-bladder cancers, University of Erlangen
Irradiation alone (50.4 Gy) Irradiation (50.4 Gy) + Cisplatin
n
Complete response (no invasive cancer)
1-yearlocal control
30
55% (32/58)
46%
28
82% (23/28)
69%*
* Kaplan-Meier-Method Note: RI or R2 means microscopic or macroscopic residual tumor after transurethral resection prior to irradiation.
874
I. J. Radiation Oncology 0 Biology 0 Physics
oped a recurrence (T’ and in situ carcinoma) outside the primary tumor region 6 months after radio-chemotherapy and was treated by cystectomy because of young age; the pathological specimen showed no muscle-invasive tumor and even the primarily involved prostate was free of tumor. Bladder preservation With a relatively short follow-up (medium follow-up one year), 7 cystectomies have been performed, all without complications. Six salvage-cystectomies were due to isolated persistent or recurrent tumor. One patient required cystectomy because of a contracted bladder due to multiple TURs prior to radiation therapy. In this patient, bladder capacity was already severely reduced prior to irradiation and conservative treatment was not successful; the surgical specimen was free of tumor. The bladder was preserved in 34 out of 41 patients (83%!). All patients with preserved bladder had a normal bladder function. Side efects and complications Mild to moderate acute side effects of radiotherapy (dysuria, slight diarrhea) occurred frequently. One patient required hospitalization because of transitory severe dysuria. Chronic sequelae caused by radiation therapy have not been observed until now. Chemotherapy was tolerated quite well even in older patients. With prophylactic antiemetic medication, gastrointestinal toxicity (nausea, vomiting) was tolerable but occurred in all patients. Mild to moderate leucopenia and thrombopenia (WHO grade I-II) was noted in nearly all patients, but severe hematologic toxicity was rare: WHO grade III in 10 out of 41 patients (24%) WHO grade IV in no patient. Transitory elevation of serum creatinine level over 2 mg/dl up to 2.4 mg/dl was noted in 3 patients (7%). In one patient a pulmonary embolization occurred after the fourth treatment week and further therapy was omitted. This complication was not related to radiochemotherapy, and the patient is in complete remission at this time without evidence of bladder cancer. Survival Any conclusions concerning survival cannot be drawn at this moment because of limited follow-up. Up to now, nine patients have died with systemic disease, three of them had also local disease. One patient has liver metastases with no evidence of loco-regional disease. Thirtyone patients are in complete remission and 27 of them maintained their bladders. DISCUSSION
In Tz_j-bladder cancer, 5-year survival rates of about 50% are achieved by radical cystectomy.3.‘2 Disadvan-
October 1988, Volume 15, Number 4
tages of this procedure include urinary diversion and sexual problems in men. Preoperative irradiation may improve survival in patients who achieve downstaging to pT0 .6 Adjuvant chemotherapy is currently under investigation, but the indication has not yet been clearly defined.13 Radical radiotherapy alone is less effective for local tumor control and survival than cystectomy, but offers the chance to preserve bladder function in a subgroup of patients.9.‘5 Data from several studies indicate that salvage cystectomy for failure after primary irradiation can be curative with an acceptable rate of complications. L*.~.“.’‘.I4 The optimal dose to the bladder in primary radiotherapy is questionable. Moderate doses of 50-60 Gy do not impact bladder function, local control rates however do not exceed 50%. Higher doses to the bladder may improve local control, but the incidence of long-term sequelae to the bladder reaches about 20% if irradiation is combined with chemotherapy.5 In our former series from 1982 to 1985 with primary irradiation alone, XRT with 50 Gy yielded in a l-year local recurrence-free rate of less than 50% in T2-3Rl_2tumors. The introduction of cisplatin chemotherapy has increased local control rates markedly as compared to our former series. Histologically confirmed complete remissions of muscle-invading tumors after radio-chemotherapy were about 25% higher than with irradiation alone. Thus, our preliminary data indicate that results of radiotherapy are improved by the addition of simultaneous chemotherapy. Treatment was well tolerated even in older patients. Complications as reported by other authors5 did not occur. We emphasize that no impact of the radiochemotherapy on bladder function was noted. With cystectomy restricted to patients with isolated local persistent or recurrent tumor, more than 80% of our patients preserved their bladders and all of them maintained a normal bladder function. In our view, it is questionable in how far higher radiation doses may improve local control and if there are any criteria for patient selection for higher radiation doses. In summary, high local response rates can be achieved by primary radiation therapy with simultaneous cisplatin chemotherapy. Conclusions concerning survival cannot be drawn at this moment because of limited follow-up. Nevertheless, we consider this management to be the locoregional treatment of choice in Tz_4-bladder cancers and in T’-cancers with large or multifocal extension or poor differentiation, if preservation of bladder function is desired. In our opinion, this concept should be evaluated in further prospective trials and long-term results are to be obtained. Future trials should focus on the question if more aggressive approaches including polychemotherapy regimens could influence relapse rate and complications especially in younger patients.
Treatment of bladder cancer with radiotherapy and cisplatin 0 R. SAUER et al.
875
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