Cisplatin and Full Dose Irradiation for Patients with Invasive Bladder Carcinoma: A Preliminary Report of Tolerance and Local Response

0022-534 7/84/1325-0899:I;02.0/0

Vol. 132: November Printed in U.S.A.

THE JOURNAL OF UROI..OGY

Copyright© 1984 by The Williams & Wilkins Co.

CISPLATIN AND FULL DOSE IRRADIATION FOR PATIENTS WITH INVASIVE BLADDER CARCINOIYIA: A PRELIMINARY REPORT OF TOLERANCE AND LOCAL RESPONSE W. H SHIPLEY,* L. J. COOMBS, A. B. EINSTEIN, JR., M. S. SOLOWAY, Z. WAJSMAN, GEORGE R. PROUT, JR. AND NATIONAL BLADDER CANCER COLLABORATIVE GROUP At

ABSTRACT

Twenty-seven patients with invasive bladder carcinoma (clinical stages T2 to T4) who were not candidates for cystectomy were treated by transurethral resection, cis-diamminedichloroplatinum (cisplatin) and full dose radiotherapy according to protocol 8 of the National Bladder Cancer Collaborative Group A. Nausea and vomiting occurred in 74 per cent of the patients but were mild in 41 per cent. Maximum followup was 27 months and during that time 3 significant toxic reactions occurred: renal failure, systemic sepsis and a transient partial small bowel obstruction. Of 17 evaluable patients complete responses of the primary bladder cancer to the treatment were achieved in 11 of 13 with stages cT2 and cT3 cancer and in 2 of 4 with stage cT4 disease. The members of National Bladder Cancer Collaborative Group A have found transurethral resection, cisplatin and full dose external beam radiotherapy practical clinically. Longer followup will be necessary to determine if the observed high initial complete response rate of the tumor indicates real lasting benefit for these patients. While modern megavoltage radiation therapy may be curative for a minority of patients with muscle-invading primary bladder carcinoma, the survival rates have been disappointingly low (17 to 38 per cent at 5 years). 1- 6 About 50 per cent of the patients with invasive bladder carcinoma treated with external beam radiation therapy sustain a local recurrence of that tumor within the bladder from persistent viable tumor cells. 1• 3 In addition, approximately a third of the patients treated with external beam radiation therapy alone whose disease is controlled locally will die of distant metastases. 3 Thus, improvement in survival rates for patients with locally invasive bladder carcinoma treated with full dose external beam radiation therapy might be enhanced by combining this treatment with adjuvant chemotherapy if this were effective against local tumor and/or in sterilizing subclinical deposits of :metastatic disease. Studies of combined chemotherapy and external beam radiation therapy in patients with locally advanced bladder carcinoma have been few, uncontrolled and inconclusive. 7 - 9 Phase II institutional trials of cisplatin reported 30 to 50 per cent objective response rates when used alone or in combination with other chemotherapeutic agents in patients with measurable metastatic bladder cancer. 10 • 11 However, members of the National Bladder Cancer Collaborative Group A reported re· Accepted for publication June 27, 1984. Read at annual meeting of American Urological Association, Las Vegas, Nevada, April 17-21, 1983. Supported by grants from the National Cance!' Institute, National Institutes of Health and United States Public Health Service to participating institutions of the National Bladder Cancer Collaborative Group A. * Requests for reprints: Radiation Medicine Service, Massachusetts General Hospital, Boston, Massachusetts 02114. t George R. Prout, Jr., Massachusetts General Hospital, Boston (CA23082 and CA15944), and G. H. Friedell, St. Vincent Hospital, Worcester, Massachusetts (CA15490); S. J. Cutler, Georgetown University, Washington D. C. (CA23078); G. Brannen, Virginia Mason Research Center, Seattle, Washington (CA17466); M. S. Soloway, University of Tennessee, Memphis, Tennessee (CA15934); Z. Wajsman, Roswell Park Memorial Institute, Buffalo, New York (CA15937); W. W. Koontz, Jr., Medical College of Virginia, Richmond, Virginia (CA15492); D. Culp and S. Loening, University of Iowa, Iowa City, Iowa (CA15933); H. Pearse, University of Oregon, Portland, Oregon (CA25918); M. J. Flanagan, Rush Presbyterian-St. Luke's Medical Center, Chicago, Illinois (CA16886), and K. Cummings, University of Wisconsin, Madison, Wisconsin (CA31793). 899

cently a 20 per cent objective response rate in a phase II multiinstitutional trial with this agent. Nearly all of these responses were partial and of short duration. 12 Studies with murine tumor models indicated a significant activity of combined cisplatin and external beam radiation therapy against transplantable transitional cell tumors. 13 The major dose-limiting toxicities of cisplatin are nausea, vomiting and nephrotoxicity. Small field, high dose pelvic irradiation, which would include less than half of the blood-forming marrow of the patient, may produce some myelosuppression when given with cisplatin, although this has not been seen in limited clinical experience. 14• 15 Animal studies indicated no increased sensitivity in gastrointestinal epithelium to the combination of cisplatin and external beam radiotherapy, provided that the administration of these 2 modalities is separated by at least 2 hours. 16 Patients with advanced head and neck cancers treated with external beam radiotherapy at the Memorial Sloan-Kettering Cancer Center experienced little increase in morbidity when cisplatin was added. 17 These laboratory and preliminary clinical experiences supported the proposition that the combined regimen of cisplatin and full dose pelvic external beam radiotherapy would not lead to significant early or delayed complications, such as those reported recently with 5-fluorouracil and large field pelvic radiation therapy. 18 Thus, members of the National Bladder Cancer Collaborative Group A have proposed that the 2 agents in combination might yield a significant improvement in local complete response rate and curability without increase in treatment complications. PATIENTS AND MATERIALS

Patient selection. All patients had biopsy-proved bladder cancer that invaded the muscle (clinical stage T2 or greater) and were not candidates for cystectomy because the tumors were judged unresectable or they were not fit for a radical operation. All histological material was reviewed by members of the National Bladder Cancer Collaborative Group A Central Pathology Laboratory. Pre-treatment evaluations included history and physical examination, cystoscopy with bimanual examination under anesthesia, excretory urogram (IVP), hematocrit and hemoglobin, white blood cell and platelet counts, serum creatinine, serum

900

SHIPLEY AND ASSOCIATES

glutamic oxaloacetic transaminase, serum alkaline phosphatase, chest radiograph, audiogram, bone scan, urine and/or saline bladder washing cytology, and lymphangiogram and/or computerized tomography of the abdomen and pelvis. Patients were considered ineligible for the study if 1) they had disease proved to be metastatic to lymph nodes at or above the bifurcation of the common iliac arteries, or to contiguous organs except the prostate, vagina and uterus, or to distant sites, 2) they had a second primary malignancy (except nonmelanoma skin cancer or stage 0, A or B prostatic cancer), 3) they had undergone previous pelvic external beam radiation therapy or systemic chemotherapy, or had platinum allergy, a white blood count <4,000/mm. 3 , platelet count <100,000/mm. 3 or serum creatinine >2.0 mg./100 ml., 4) they were taking nephrotoxic or ototoxic drugs, or had a significant hearing loss, 5) they were incapable of self-care (performance levels >2, Karnofsky scale 50 to 60 per cent) or 6) if consent could not be obtained after the nature of the procedures had been explained fully. While patients were receiving cisplatin the performance status, serum creatinine, hematocrit and hemoglobin, and white blood cell and platelet counts were measured every 3 weeks. During external beam radiation therapy blood counts and treatment tolerance were monitored weekly. Patients were re-evaluated endoscopically under anesthesia 1 to 2 months following completion of the radiation therapy if they had known residual cancer in the bladder at the start of treatment or if no visible tumor remained in the bladder on entry to the study 3 months following completion of external beam radiation therapy. After all therapy was completed patients underwent evaluative cystoscopy studies every 3 months, and an audiogram, bone scan, surveillance cystoscopy and IVP every 6 months. A complete response was defined as complete visual disappearance of tumor on cystoscopy and negative biopsy of the tumor site as well as of any other sampled areas. There were 36 patients entered into the study between June 1980 and December 1982. The distribution by clinical stage according to the American Joint Committee 19 was cT2 in 11 patients (31 per cent), cT3 in 16 (44 per cent) and cT4 in 9 (25 per cent). However, protocol forms of at least the first clinical

and cystoscopic re-evaluation within 3 months after completion of external beam radiation therapy are available in the National Bladder Cancer Collaborative Group A Statistical Center for analysis on the first re-evaluation in 27 patients who form the basis of this report. Of the 27 patients 5 had cytologically (aspiration) or histologically confirmed pelvic lymph node metastases below the bifurcation of the common iliac vessels. Patient age ranged from 46 to 87 years, with a median age of 69 years. Of the patients 78 per cent were men. Cisplatin treatment. The first dose of cisplatin was given within 4 weeks after the initial endoscopic evaluation and transurethral resection, and 1 day before the initiation of external beam radiation therapy (fig. 1). Cisplatin courses 2 and 3 were given during the course of external beam radiation therapy. However, external beam radiation therapy was omitted on the days of the administration of doses 2 and 3 of cisplatin. A total of 8 courses of cisplatin given every 3 weeks was planned. All patients received a 60-minute infusion of 500 cc 5 per cent dextrose in 0.5 normal saline followed by 12.5 gm. mannitol by intravenous push before receiving 70 mg./M. 2 cisplatin intravenously during 15 minutes. An additional 500 cc 5 per cent dextrose in 0.5 normal saline were infused during the next 60 to 90 minutes. Antiemetic therapy was selected at the discretion of the treating oncologists. A cisplatin dose modification scheme was based on the 3-week blood counts. The dosage was decreased to 50 mg./M. 2 for a white blood count between 2,500 and 3,000/mm. 3 or a platelet count between 75,000 and 50,000/mm. 3 • Radiation treatment. Radiation therapy consisted of treatment of a small pelvic field via a 4-field box technique with carefully contoured fields (fig. 2) encompassing the bladder and the perivesical, obturator, and distal internal and external iliac lymph nodes to a dose of 4,500 rad during 5 weeks. Treatment included 180 rad at each of 5 sessions per week. The radiation field then was coned-down with either shaped lateral fields or a rotation to include only the bladder tumor volume to a total tumor dose of 6,480 rad (range 6,120 to 6,660 rad). All patients underwent pre-treatment simulation. No cobalt teletherapy was used. All radiations were with megavoltage beams from linear accelerators or betatrons of 4 to 25 MV. The Radiologic Physics

~7 1/2-!0wks-- - - - ~ t-...3-4wks-

Radiation Therapy 6300-6840 rads

I

reduced volume

I

I I

L3wks-4

'I I

I

I

1--3wks-,

I

Cystoscopy 11 TURB

~

ASSESS EL I GIB IL I TY

Bx only

Cystoscopy

Bx

only

* Does not exclude patients who required pretreatment urinary diversion

Primary bladder carcinoma Muscle invasion **

Stages cT2-4cNX (pN0-3)M~nodal evaluation by LAG +/or CBT with biopsy confirmation to exclude N4 patients

Unsuitable for cystectomy

Eligible for XRT and DDP

Clinical evaluation and surveillance cystoscopy q 15 weeks. Patients are to be followed for 5 years or until death

No (known distant nor juxtaregional l,'lj)Ph node metastases

To allow evaluation of therapeutic response

FIG. 1. Schematic diagram of National Bladder Cancer Collaborative Group A protocol 8

, ~FU***

801 'TABLE

L 1:1atient distribution by atnoun,,t of cis_platin received

No. Cisplatin Courses

No. Pts. (cnmulative %) g 2

8

7

2 (44) (48) 3 (59) 2 (62) 4 (82)

6 5

4 3

2 1

TABLE 2.

5 (100)

Radiation attributable toxicity by degree of toxicity Degree of Toxicity None No.(%)

Urinary frequency Dysuria Hematuria Diarrhea Other

Mild No.(%)

Severe No.(%)

20 (80.0)

4 (16.0)

19 (76.0)

4 (16.0)

1 (4.0) 2 (8.0)

24 (96.0)

1 (4.0)

0 (0.0)

13 (52.0)

10 (40.0) 0 (0.0)

2 (8.0) 1 (4.0)

24 (96.0)

Total No.(%) 25 25 25 25 25

(100.0) (100.0) (100.0) (100.0) (100.0)

An individual is counted once for each type of radiation toxicity.

B

FIG. 2. Radiation treatment fields to bladder tumor volume, and distal external and internal iliac lymph nodes using 4-field box technique. A, anterior and posterior fields. B, paired lateral fields. Volume of cone-down boost to tumor is not shown.

Center monitored each institution for its radiation dose calibration and for the homogeneity of treatment RESULTS

Patient compliance. All but 2 patients completed the planned external beam radiation therapy. One patient received only 360 rad because irreversible renal failure developed associated with an episode of hypotension following the initial course of cisplatin. An 83-year-old man died of pneumonia, which developed after he had received 3,060 rad and 1 course of cisplatin. Only 8 of the 27 patients have completed the planned 8 courses of cisplatin. The median number of cisplatin courses completed was 4. The distribution of the 27 patients by number of cisplatin courses is shown in table 1. Two patients presently are completing the planned 8 courses. The reasons for early discontinuation of chemotherapy in the remaining 17 patients were progression of disease in 3, toxicity in 3, death in 1, patient :r:efusal owing to vomiting in 7 and unclear in 3.

Treatment tolerance. The toxicity attributable to radiation was minimal (table 2). Diarrhea was severe enough to interrupt radiation therapy in only 2 of 25 patients, and urinary frequency and/or dysuria was severe enough to require a break in radiation therapy in the same proportion. With a median followup of 12 months 1 has suffered transient small bowel obstruction that responded to conservative measures. Severe pain developed in 1 patient owing to necrosis of the right femoral head that was corrected by a hip replacement. This patient received 4,400 rad in 8 weeks to the upper femora and 8 courses of 70 mg./M. 2 cisplatin. Two patients had an episode of hematuria 2 and 4 months, respectively, following completion of the external beam radiation therapy, which terminated promptly without intervention. Bladder function and bladder capacity were not decreased significantly. During the cisplatin and external beam radiation therapy 60 per cent of the patients had no white blood counts <3,000/mm. 3 , while 2 per cent had white blood counts <100,000/mm. 3 • Mild thrombocytopenia to 100,000/mm. 3) occurred in 3 of the 27 patients. Chemotherapeutic toxicity was evaluated for the 27 patients receiving ?;1 cournes of cisplatin (table Nausea and vomiting were experienced in ?;7 4 per cent of the patients, although in 41 per cent these symptoms were mild. However, this effect was scored as the n1ain reason why 7 of the 17 patients terminated the ,oh,<>im,oth" :·,irm before receiving the 1-'"'''u"·'°'"' 8 courses. Of 16 patients who '""'''"''"" i:;;4 courses of ~"'''"'~"·u after comof external beam radiation therapy 50 per cent had a 3 but none had counts <2,000/ white blood count mm. 3 • 1 had a platelet count that decreased to the 50,000 to 75,000/mm. 3 range. Serum creatinine increased to >2.0 mg. per cent in 4 of the 27 patients. Two patients were scored as having complications related to the chemotherapy: renal failure was associated with an episode of hypotension following 1 course of cisplatin in 1 patient and systemic sepsis was associated with a white blood count <3,000/ mm. 3 and a serum creatinine of 3.0 mg./100 ml. in l. Tumor response. The local response of the primary tumor by endoscopic evaluation with the patient under anesthesia is shown in table 4. All 17 patients who were fully evaluable for a therapeutic response had known residual disease in the bladder at entry, completed the planned external beam radiation therapy with ~1 courses of cisplatin and underwent cystoscopic reevaluation following completion of radiotherapy. Cystoscopic re-evaluation was done 3 to 4 weeks after external beam radiation therapy in 11 patients and 6 to 10 weeks after radiotherapy in 6. Of the 17 evaluable patients 13 (76 per cent) achieved a 1

902

SHIPLEY AND ASSOCIATES TABLE 3. Patients who experienced chemotherapeutic toxicity by degree of toxicity Severity of Toxicity Totals No. audiologic (%) No. nausea and vomiting(%) No. other(%) White blood count:* Mm. 3 No.(%) Platelets: Mm. 3 No.(%)

None

Mild

Moderate

Severe

Unknown

23 (85.2) 3 (11.1) 21 (77.8)

1 (3.7) 11 (40.8) 0 (0.0)

0 (0.0) 8 (29.6) 2 (7.4)

0 (0.0) 1 (3.7) 1 (3.7)

3 (11.1) 4 (14.8) 3 (11.1)

27 (100.0) 27 (100.0) 27 (100.0)

3,500 5 (31.3)

3,000-3,499 2 (12.5)

2,000-2,999 8 (50.0)

2,000 0 (0.0)

1 (6.2)

16* (100.0)

100,000 12 (75.0)

75,000-99,999 2 (12.5)

50,000-74,999 1 (6.2)

50,000 0 (0.0)

1 (6.2)

16* (100,0)

* The most severe toxicity reported after completion of radiotherapy was among patients receiving ;;:;4 courses of cisplatin.

complete response. The complete response rate was 11 of 13 patients with stages cT2 and cT3 disease, and 2 of 4 with stage cT4 cancer. Although urine cytology was not a criterion for response 1 patient with stage cT4 disease who was scored a complete response had malignant cells in the bladder washings on review by the Central Pathology Laboratory. An additional 4 patients entered into the study with known residual disease in the bladder were not re-evaluated cystoscopically because of progression of distant metastases, cisplatin toxicity or death. The complete local response rates by conservatively scoring these 4 nonevaluated patients as nonresponders also are shown in table 4. The known complete response rate of all treated patients was 13 of 21 (62 per cent). All 6 patients with no visible tumor remaining in the bladder at entry had negative endoscopic re-evaluations following external beam radiation therapy and cisplatin. Of the 27 patients 19 with followup information from 3 to 27 months after entry are alive. The 12 and 24-month survival rates by life-table calculation were 73 per cent (± 19 per cent) and 53 per cent (± 28 per cent). The numbers in parentheses represent 2 standard errors for the cumulative probability of survival. 20 All but 2 of the complete responses have been maintained locally. Distant metastases have developed in 4 patients: 1 among those with a complete response and 3 of those who were never locally free of disease. DISCUSSION

In the dose schedules used in our study we have seen no significant increased toxicity to the pelvic tissues by combining cisplatin and external beam radiation therapy. The low incidence of acute toxicity during external beam radiation therapy (table 2) is only slightly greater than that which we reported in a different group of patients who received less radiotherapy (4,000 rad) without cisplatin before radical cystectomy. 21 The single episodes of late transient small bowel obstruction and aseptic necrosis of the femoral head are of concern but can, of course, be seen following external beam radiation therapy alone. The toxicities attributable to cisplatin were similar to those reported when cisplatin alone was used in patients with bladder cancer at m~tastatic sites. For instance, of 50 patients with metastatic disease receiving 70 mg./M. 2 cisplatin per course 31 per cent had moderate or severe nausea and vomiting, and 22 per cent had elevations of serum creatinine above the pretreatment levels. 12 These effects occurred in 34 and 15 per cent, respectively, of our patients. At this time the local efficacy of our treatment is measured best by the complete response rate in patients who had visible residual disease before cisplatin and external beam radiation therapy; 13 (76 per cent) of these 19 evaluated patients (or 62 per cent of 21 treated patients) achieved a complete local response. All but 2 of the complete responses have been maintained as evaluated by cystoscopic re-evaluation every 3 months. A complete response following full dose external beam radiation therapy in patients with bladder cancer has been

TABLE 4. Complete local response rate No. Complete Local Response/ Total No. Pts. Clinical Stage Totals(%*)

With visible residual disease after transurethral resection Without visible residual disease after transurethral resection Totals With visible residual disease after transurethral resection Without visible residual disease after transurethral resection Totals

cT2

cT3

3/4

8/9

3/3

2/2

1/1

6/7

10/11

3/5

cT4

All evaluabl.e pts. t 2/4 13/17 76 (56-96)

6/6 (100) 19/23 83 (68-98)

3/4§

All treated pts. :j: 8/10§ 2/7 13/21 62 (41-83)

3/3

2/2

1/1

6/7

10/12

3/8

6/6 (100) 19/27 70 (53-87)

* Ninety-five per cent confidence limits. t Patients re-evaluated endoscopically after cisplatin and external beam radiation therapy. :j: One patient with stage cT3 and 3 with stage cT4 disease were not reevaluated endoscopically due to toxicity, progression as distant disease or death. § Patients with stages cT2 and cT3 disease included in table 5.

reported as an important favorable prognostic sign for longterm survival. For instance, in the London Hospital series 43 per cent of 220 patients with clinical stage T3 disease were recorded as having a complete response. The actuarial 5-year survival of those with a complete response was 72 per cent, while it was 17 per cent for those with partial or no response. 4 In the Institute of Urology trial 40 per cent of 85 patients with stage T3 disease had a complete response following 6,000 rad in 6 weeks. The projected 5-year survival for patients with a complete response was 49 per cent, compared to 20 per cent for those with partial or no response. 6 Our results with regard to complete response rates following cisplatin and full dose external beam radiation therapy were compared to other published series using external beam radiotherapy alone or in combination with chemotherapy (table 5). Such a comparison is made with caution because these reported series likely differ from each other and from ours in staging accuracy, amount of tumor debulking by transurethral resection, radiation schedules and patient selection. To minimize some of these differences we have 1) limited the comparison of complete response rates to patients with clinical stage T2 or T3 tumors and 2) used only our patients who had visible residual disease before beginning cisplatin and external beam radiation therapy. Of the 14 patients with clinical stages T2 and T3 disease who had visible disease remaining after transurethral resection complete responses were observed in 11 (79 per cent). Further patient accrual and longer followup will allow evaluation of the importance of the number of cisplatin

CISPLATIN AND FULL DOSE IRRADIATION FOR PATIENTS WITH INVASIVE BLADDER CARCINOMA TABLE 5.

Reported complete local response rates to full-dose external beam radiation therapy

Reference

Bloom and associates• Blandy and associates• Walborn-Jorgensen, S. W.: Scand. J. Urol. Nephrol., suppl. 15, 6: 113, 1972 Lundbeck and Christophersen9

Present study

Rad Treatment Clinical (No. courses X Stage dose/course) 6,000 (30 5,500 (22 6,000 (24

X X X

200) T3 250) T3 250) T2, T3

No. Pts.

85 220 196

% Complete Local Response (95% confidence levels)

6.

7.

40 (30-50) 43 (36-50) 57 (50-64)

8. 6,000 (24 X 250) T2, T3 doxorubicin, 5-fluorouracil andlevamisole 6,480 (36 X 180) T2, T3 cisplatin

15

60 (35-85)

9.

14

79 (59-100)

courses for achieving and for maintaining a complete response. Improved antiemetic therapy and changes in the cisplatin schedule are under consideration to improve tolerance to the chemotherapy. This preliminary analysis suggests that the combined cisplatin and external beam radiation therapy regimen is practical clinically and yields a high complete clearance rate of the primary bladder cancer. We are hopeful but by no means certain that the favorable early complete response rate from cisplatin and full dose external beam radiation therapy (at least for patients with clinical stages T2 and T3 tumors) will predict a favorable long-term survival with preservation of bladder function. Ms_ Gwendolyn McKenzie and Ms. Cynthia J. Kapnis of the Radiation Medicine Service, Massachusetts General Hospital, Boston, Massachusetts, assisted in the preparation of this manuscript. REFERENCES 1. Miller, L. S. and Johnson, D. E.: Megavoltage irradiation for bladder cancer: alone, postoperative, or preoperative? Proc. Nat!. Cancer Conference, 7: 771, 1973. 2. Goffinet, D. R., Schneider, M. J., Glastein, E. J., Ludwig, H., Ray, G. R., Dunnick, N. R. and Bagshaw, M. A.: Bladder cancer: results of radiation therapy in 384 patients. Radiology, 117: 149, 1975. 3. Miller, L. S.: Bladder cancer: superiority of preoperative irradiation therapy and cystectomy in clinical stages B2 and C. Cancer, suppl. 2, 39: 973, 1977. 4. 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. and Risdon, R. A.: T3 bladder cancer-the case for salvage cystectomy. Brit. J. Urol., 52: 506, 1980. 5. Goodman, G. B., Hislop, T. G., Elwood, J. M. and Balfour, J.: Conservation of bladder function in patients with invasive blad-

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