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The Oncologist, Vol. 5, No. 6, 471-476, December 2000
© 2000 AlphaMed Press

The Initial Results in Muscle-Invading Bladder Cancer of RTOG 95-06: Phase I/II Trial of Transurethral Surgery Plus Radiation Therapy with Concurrent Cisplatin and 5-Fluorouracil Followed by Selective Bladder Preservation or Cystectomy Depending on the Initial Response

Donald S. Kaufmana, Kathryn A. Winterb, William U. Shipleya, Niall M. Heneya, Michael P. Chetnerc, Luis Souhamid, Robert A. Zloteckie, William T. Sausef, Lawrence D. Trueg

a Massachusetts General Hospital, Boston, Massachusetts, USA; b RTOG Headquarters, Philadelphia, Pennsylvania, USA; c University of Alberta, Edmonton, Canada; d McGill University, Montreal, Canada; e University of Florida, Gainesville, Florida, USA; f LDS Hospital, Salt Lake City, Utah, USA; g University of Washington Medical School, Seattle, Washington, USA

Correspondence: D.S. Kaufman, M.D., Department of Medical Oncology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. Telephone: 617-726-8689; Fax: 617-726-8685; e-mail: kaufman.Donald{at}mgh.harvard.edu


   ABSTRACT
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Purpose. To assess the safety, tolerance, and efficacy of transurethral surgery plus concomitant cisplatin, 5-fluorouracil (5-FU), and radiation therapy in conjunction with selective bladder preservation in patients with muscle-invading bladder cancer.

Patients and Methods. Thirty-four eligible patients with clinical stage T2-T4a, Nx M0 bladder cancer without hydronephrosis were entered into a protocol aimed at selective bladder preservation. Treatment began with as complete a transurethral resection as possible followed by induction chemoradiation. This consisted of cisplatin 15 mg/m2 i.v. and 5-fluorouracil (5-FU) 400 mg/m2 i.v. in the mornings on d 1, 2, 3, 15, 16, and 17. On d 1, 3, 15, and 17, radiation was given immediately following the chemotherapy using twice-a-day 3 Gy per fraction cores to the pelvis for a total radiation dose of 24 Gy. Response was evaluated by cystoscopy, cytology, and rebiopsy four weeks later. Patients with a complete response received consolidation therapy with the same drugs and doses on d 1, 2, 3, 15, 16, and 17 combined with twice-daily radiation therapy to the bladder and bladder tumor volume of 2.5 Gy per fraction for a total consolidation dose of 20 Gy and a total induction plus consolidation dose to the bladder and bladder tumor of 44 Gy. Patients who did not achieve a complete response were advised to undergo prompt cystectomy, as were those with a subsequent invasive recurrence. The median follow up is 29 months.

Results. Of the 34 eligible patients, 26 had a visibly complete transurethral resection. One patient did not complete induction treatment due to acute hematologic toxicity. After induction treatment, 22 (67%) of the 33 patients had no tumor detectable on urine cytology or rebiopsy. Of the 11 patients who still had detectable tumor, six underwent radical cystectomy and five underwent consolidation chemoradiation (one because of refusal to have the recommended cystectomy and four because the treating institutions erroneously assigned them to receive consolidation chemoradiation rather than cystectomy). No patient has required a cystectomy for radiation toxicity. Six patients have died of bladder cancer. The actuarial overall survival at three years is 83%. The probability of surviving with an intact bladder is 66% at three years. A total of seven patients (21%) developed grade 3 or grade 4 hematologic toxicity in conjunction with this treatment.

Conclusion. This aggressive protocol comprising local surgery plus concurrent 5-FU, cisplatin, and high-dose hypofractionated radiation has been associated with moderately severe hematologic toxicity. Longer follow-up will be necessary to assess efficacy. Both the 67% complete response rate to induction therapy and the 66% three-year survival with an intact bladder are encouraging.

Key Words. Bladder cancer • Invasive • Bladder preservation • Chemotherapy • Radiation therapy • Combined modality therapy


   INTRODUCTION
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 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
The treatment of muscle-invading bladder cancer using combined modality therapy with selective bladder preservation or cystectomy based on initial tumor response has been a successful approach reported by several institutions and cooperative groups over the last 10 years [1-7]. These series report a five-year overall survival for patients treated by bladder preservation or prompt cystectomy ranging from 49% to 63%. For all the patients treated on these protocols, 38% to 43% have a five-year survival with an intact bladder. Thus, the overall five-year survival rates are comparable to other series using immediate cystectomy-based approaches in patients of similar age presenting with tumors of similar clinical stage. Also, the majority of the long-term survivors retain their bladder. However, in a randomized protocol of neoadjuvant chemotherapy in addition to trimodality therapy (transurethral surgery plus concurrent chemotherapy and radiation), the Radiation Therapy Oncology Group (RTOG) reported that only 70% of the patients assigned to the neoadjuvant chemotherapy arm—methotrexate, cisplatin, vinblastine (MCV)—completed the protocol as specified or with only minor deviations. This protocol accrued 126 patients but was terminated prior to its accrual goal of 174 patients because of poor patient tolerance resulting in a low protocol completion rate. In 1993, Housset and colleagues reported encouraging results with regard to bladder preservation and patient compliance with a hypofractionated twice-a-day radiation approach employing concurrent cisplatin and 5-fluorouracil (5-FU) that could be safely given as an outpatient regimen [3]. This treatment regimen (Fig. 1Go) was judged to be more attractive than one using the same agents but requiring, at that time, 12 days of inpatient chemotherapy to be given concurrently with twice-daily radiation, which had been tested as a single institution approach [8]. The protocol was designed to test the safety, tolerance, and efficacy as well as the protocol completion rate of this selective bladder preservation approach. This protocol targeted a completion rate of 90% as clinically feasible for our cooperative group.



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  		Figure 1. The schema of RTOG 95-06 for the treatment of invasive bladder cancer with combined transurethral resection of the bladder tumor (TURBT) and concurrent radiation therapy and chemotherapy (cisplatin and 5-FU).

 

   MATERIALS AND METHODS
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Patient Selection
Between 1995 and 1997, 35 patients with invasive bladder cancer entered into RTOG 95-06. Thirty-four of the 35 patients were determined to be eligible and are included in this analysis. The range of clinical stage was T2 to T4a Nx M0 without hydronephrosis. Initial evaluation included a chest radiograph, i.v. pyelogram, and/or a computed tomographic scan, and as thorough as possible transurethral resection of the bladder tumor (TURBT). Patients were ineligible for this protocol if there were metastases to lymph nodes or distant metastases, a white count <4,000 per ml and an absolute neutrophil count (ANC) <1,800 per ml, a platelet count <100,000 per mm3, a serum creatinine >1.5 mg/ml, a creatinine clearance of <60 ml/min, hydronephrosis, or a refusal to sign a consent form approved by the institutional review board after the nature of the procedures had been fully explained. Some pretreatment patient characteristics are listed in Table 1Go.


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  		Table 1. Pretreatment characteristics
 
Chemotherapy/Radiation Treatment Protocol
A schema of the protocol is based on that of Housset et al. [3] and shown in Figure 1Go, which includes the treatment details. In summary, induction chemotherapy/radiation (CFI), was given over a 17-day interval and was followed by an interval of three to four weeks to allow tumor regression. In week 7 or 8 the bladder was re-evaluated cystoscopically. Patients were considered complete responders only if there was no visible mass, no tumor in a tumor site on repeat biopsy, and a negative urine cytology. Complete responders underwent consolidation chemotherapy/radiation (CFI), beginning in week 9 and again the chemoradiation was completed in 17 days. Incomplete responders were advised to undergo a prompt radical cystectomy.

Radiation Therapy
Patients were treated twice daily with at least a 4-h interfraction interval on d 1, 3, 15, and 17. During the induction phase, external beam radiation therapy was delivered at 3.0 Gy twice daily to the whole bladder, bladder tumor volume, and the pelvic lymph nodes. Thus, at the end of the induction phase these structures received 24 Gy in eight fractions over 16 elapsed days. Complete responders and some incomplete responders [5] underwent consolidation therapy which began 7 to 10 days after the re-evaluation cystoscopy. External beam radiation for the consolidation was delivered at 2.5 Gy twice daily to the whole bladder and bladder tumor volume on d 1, 3, 15, and 17. Thus, at the end of the consolidation phase the whole bladder and bladder tumor volume had received 44 Gy in 16 fractions and the pelvic lymph nodes had received 24 Gy in eight fractions.

Systemic Chemotherapy
For both induction and consolidation therapy, 400 mg/m2 of 5-FU and 15 mg/m2 of cisplatin were administered i.v. before the first radiation treatment on d 1, 2, 3, 15, 16, and 17. Following i.v. hydration at the rate of 500 ml/h, 5-FU was administered by direct i.v. push followed by cisplatin as a 1-h infusion. The first radiation fractionation was between one and two hours following the completion of the chemotherapy. Dose modifications of cisplatin and 5-FU during the consolidation chemotherapy/radiation therapy were made for myelosuppression, for nephrotoxicity, and/or for gastrointestinal toxicity. If a grade III hematologic toxicity developed (platelets <50,000 per mm3 or ANC <1,800 per mm3), then both the chemotherapy and radiation therapy were discontinued for one week and resumed when the ANC returned to >=1,800 per mm3 and the platelet count returned to >=100,000 per mm3. If the blood counts failed to recover in three consecutive weekly measurements, the patient was considered to be off protocol. If the radiation dose fraction size had to be reduced for diarrhea, additional radiation therapy was given on d 21 and 23 without chemotherapy but using the twice-a-day schedule to ensure a total dose of 44 Gy.

Criteria for Response and Follow-up Procedures
Patients underwent cystoscopy, biopsy of the tumor site, bimanual examination under anesthesia, and urine cytology every three months for the first year and then every six months. Response of the primary tumor was considered a clinical complete response if no tumor was visible on cystoscopy, the tumor-site biopsy was negative, and no tumor cells were found in the urine cytology. Additional therapies such as transurethral resection, intravesical chemotherapy, or cystectomy were initiated at the earliest opportunity if relapse occurred. Uro-dynamic studies were not routinely performed. Median follow-up for the entire group is 29 months (range 7-40) and 30 months for all surviving patients.

Statistical Analysis
The study was designed to accrue a sufficient number of patients to distinguish a 90% protocol completion rate from a 70% protocol completion rate using a one-sided 0.05 test of proportions with an 80% statistical power. This will yield the 95% confidence intervals of the probability of a complete response to be approximately ± 20%. Accrual to this trial was completed in 25 months.

The protocol completion rate was compared statistically to arm 1 (with neoadjuvant MCV chemotherapy) and arm 2 (without MCV neoadjuvant chemotherapy) of RTOG 89-03 using the chi-square test. Overall and bladder intact survival probabilities were estimated using the Kaplan-Meier method [9]. Time to distant metastases was estimated using the cumulative incidence method [10].


   RESULTS
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Thirty-three of 34 patients (97%) completed the induction chemotherapy and radiation therapy per protocol. However, only 26 of the 34 initial patients (76%) completed the whole protocol as planned (Fig. 2Go). The completion rate of the whole protocol is compromised by four patients whose treating institutions erroneously assigned these patients with residual tumor after induction to receive consolidation chemoradiotherapy rather than cystectomy. Of the 30 patients in whom the protocol was appropriately understood, 26 (87%) completed this planned protocol therapy. The four patients who were correctly assigned their treatment but did not complete the protocol included two complete responders who refused consolidation chemoradiation, one who refused the recommended cystectomy and underwent nonprotocol chemoradiation, and one who was incompletely evaluated for his initial response. The protocol completion rate of this study (76%) was not statistically better than were the rates for either arm of RTOG 89-03 or the study overall. The percentages of patients sustaining a grade III or greater leukopenia, thrombocytopenia, neutropenic fever, infection, nausea/vomiting, or bladder irritation during the protocol are shown in Table 2Go. One patient suffered grade 4 leukopenia during the induction chemoradiotherapy. During the chemoradiation, the following grade 3 toxicities were reported: in the bladder in two patients, in the rectum in two patients, and the small bowel in one patient. No grade 4 toxicities were recorded.



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  		Figure 2. Schema of patient protocol compliance.

 

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  		Table 2. Grade 3 treatment-related toxicity (n = 34)
 
The percentage of patients sustaining late morbidity reported during the follow-up phase of this study is shown in Table 3Go. Grade 3 toxicities were reported in two patients for bladder reactions, two patients for bowel reactions, and in four patients for hematologic toxicity. There was one late grade 4 event due to hematologic, renal and small bowel toxicity. All but one of the late grade 3 toxicities have resolved with subsequent treatment and follow-up. In one patient, a grade 3 bladder reaction persists.


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  		Table 3. Late toxicity following treatment (n = 34)
 
Table 4Go shows the complete response rates of the primary tumor following induction therapy and following consolidation therapy. Twenty-two of 33 evaluable patients were complete responders (67%) after induction chemoradiation therapy. In the seven patients who had persistent tumor and who were evaluated for response, none exhibited tumor progression. In the six patients who underwent cystectomy for an incomplete response, cancer was found in the cystectomy specimens of all patients. Ileal conduit urinary diversions were performed on all of the patients undergoing radical cystectomy.


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  		Table 4. Clinical complete response rates by urologic re-evaluation
 
The median follow-up was 29 months. Nine of the 20 patients who were clinical complete responders following induction CFI and completed consolidation CFI have developed a bladder recurrence. Three of these nine have had an invasive recurrence and have undergone a cystectomy; the remainder were superficial tumors and have been treated, so far, successfully with conservative methods. Of the five incompletely responding patients who underwent consolidation by chemoradiation (as a protocol violation), three have suffered a local recurrence. Metastases have developed in 9 of 34 patients. Six patients have died with disease. Three of these patients received further cisplatin-based chemotherapy. The overall actuarial survival is 83% at three years, and 66% are alive without a cystectomy at three years (Fig. 3Go).



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  		Figure 3. Estimates of overall survival and bladder intact survival rates for patients entered on RTOG 95-06.

 
The morbidity of this protocol was documented. Six patients required modification of the induction or consolidation chemotherapy doses due to acute toxicity (neutropenia in two). One of the 34 patients experienced urinary frequency during induction therapy but it was not sufficient to interrupt therapy or to discontinue the protocol. There have been four reported cases of hematuria and one patient has reported some incontinence. No patient has required a cystectomy for a bladder complication.


   DISCUSSION
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
This study evaluated only a relatively small number of patients. It did not include those with advanced T4 tumors nor those with hydronephrosis, and so it is difficult to compare these results with other published bladder-sparing results. A completion rate of 97% for the induction phase indicates that this is clinically feasible. The overall three-year survival rate of 83% compares favorably with the prior RTOG protocol 89-03 (59% for the 99 patients without hydronephrosis) [7] and is similar to that reported by one single institution pilot using these three agents but with different radiation fractionation and different dose schedules (83%) [8]. The likelihood of being alive at three years with a functioning treated bladder (66%) is encouraging relative to the 46% for the 99 patients without hydronephrosis entered on RTOG 89-03 at three years [7] and similar to that reported from an institutional pilot at the Massachusetts General Hospital using a different dose schedule (78%) [8].

Of concern is that within 29 months of median follow-up, 9 of the 20 complete responding patients who completed the protocol have had local recurrence (three invasive, six superficial). This is higher than had been reported recently by the Paris group on whose results this protocol was modeled. In an update that includes 120 patients, Housset and colleagues [11] report a bladder recurrence rate of only 17% (12 of 71 complete responding patients). Clearly these comparisons are subject to unknown biases, and the follow-up on these series is too short for any substantive conclusions. However, until longer follow-up for local bladder tumor recurrence of the patients on this protocol is available for comparison to those from early RTOG studies that may be lower, we are evaluating the feasibility and efficacy of more conventional twice-a-day radiation fractionation (1.8 Gy and 1.6 Gy) with concurrent cisplatin followed by three cycles of adjuvant chemotherapy. Also of concern is that 7 of the 34 patients (21%) developed grade 3 or 4 hematologic toxicity in conjunction with this treatment, which may make this combination a less than optimal one to combine with newer adjuvant chemotherapy regimens as are now being tested [8, 12, 13].


   ACKNOWLEDGMENT
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Supported by Public Health Service grants no. CA-21661 and CA-32115 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland.

Presented at the 40th Annual American Society of Therapeutic Radiology and Oncology Meeting, November 3, 1999, San Antonio, Texas.


   REFERENCES
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Kaufman DS, Shipley WU, Griffin PP et al. Selective preservation by combination treatment of invasive bladder cancer. N Engl J Med 1993;329:1377-1382.[Abstract/Free Full Text]
  2. Tester W, Porter A, Asbell S et al. Combined modality program with possible organ preservation for invasive bladder carcinoma: results of RTOG protocol 85-12. Int J Radiat Oncol Biol Phys 1993;25:783-790.[Medline]
  3. Housset M, Maulard C, Chretien YC et al. Combined radiation and chemotherapy for invasive transitional-cell carcinoma of the bladder. A prospective study. J Clin Oncol 1993;11:2150-2157.[Abstract/Free Full Text]
  4. Dunst J, Sauer R, Schrott KM et al. An organ-sparing treatment of advanced bladder cancer. A 10-year experience. Int J Radiat Oncol Biol Phys 1994;30:261-266.[Medline]
  5. Tester W, Porter A, Heaney J et al. Neoadjuvant combined modality therapy with possible organ preservation for invasive bladder cancer. J Clin Oncol 1996;14:119-126.[Abstract]
  6. Kachnic LA, Kaufman DS, Griffin PP et al. Bladder preservation by combined modality therapy for invasive bladder cancer. J Clin Oncol 1997;15:1022-1029.[Abstract/Free Full Text]
  7. Shipley WU, Winter KA, Kaufman DS et al. Phase III trial of neoadjuvant chemotherapy in patients with invasive bladder cancer treated with selective bladder preservation by combined radiation therapy and chemotherapy: initial results of Radiation Therapy Oncology Group 89-03. J Clin Oncol 1998;16:3576-3583.[Abstract]
  8. Zietman AL, Shipley WU, Kaufman DS et al. A phase I/II trial of transurethral surgery combined with concurrent cisplatin, 5-fluorouracil, and twice-a-day radiation followed by selective bladder preservation in operable patients with muscle-invading bladder cancer. J Urol 1998;160:1673-1677.[CrossRef][Medline]
  9. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457-481.[CrossRef]
  10. Gray RJ. A class of K-sample tests comparing the cumulative incidence of a competing risk. J Ann Stat 1988;16:1141-1154.
  11. Housset M, Dufour E, Maulard-Durtux C. Concomitant 5-fluorouracil, cisplatin and bifractionated split course radiation therapy for invasive bladder cancer. Proc Am Soc Clin Oncol 1997;16:319a.
  12. Shipley WU, Kaufman DS, Heney NM et al. An update of combined modality therapy for patients with muscle invading bladder cancer using either selective bladder preservation or cystectomy. J Urol 1999;162:445-451.[CrossRef][Medline]
  13. Kaufman D, Raghavan D, Carducci M et al. Phase II trial of gemcitabine plus cisplatin in patients with metastatic urothelial cancer. J Clin Oncol 2000;18:1921-1927.[Abstract/Free Full Text]
Received July 31, 2000; accepted for publication September 20, 2000.




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