Preoperative and definitive radiation therapy

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Mary Gospodarowicz

Department of Radiation Oncology, Princess Margaret Hospital, Toronto, Canada

Introduction

The majority ofbladder cancer patients present with superficial disease and are managed with conservative measures. Approximately 20-25% present with muscle-invasive bladder cancer that is potentially life threatening and requires radical treatment. Definitive radiation therapy (RT) has been used for muscle-invasive bladder cancer since the early 1900s and there is evidence that patients can achieve durable local control and maintain a functional bladder without a compromise in the overall survival.1 However, the standard North American approach to the management of muscle-invasive bladder cancer is radical cystectomy.2 In the past few decades, radical radiation therapy has been used infrequently and mostly when patients either refused or were not suitable for radical cystectomy. Therefore there is a limited amount of information on the precise role that radiation therapy plays in the management of bladder cancer.

Radiation therapy has been used in the management of bladder cancer in several distinct situations. The most common therapy is radical RT to eradicate muscle-invasive cancer while preserving normal bladder function. Radical RT may also be used to secure local control following chemotherapy that has been given as definitive treatment for locally advanced bladder cancer. In both situations, salvage cystectomy is used in the event of an incomplete response to RT, local recurrence, or development of a new invasive bladder tumour. Pre-operative RT may be considered in locally advanced bladder cancer to prevent local failure. Post-operative RT is rarely used because of toxicity associated with pelvic RT with fixed loops of small bowel present in the RT volume after cystectomy. Palliative RT is useful in selected cases of locally advanced and metastatic bladder cancer.

Pre-operative radiation therapy

The goal of pre-operative RT is to prevent pelvic recurrence following radical cystectomy. Therefore, only patients who are at high risk of local recurrence in the pelvis are likely to benefit. Patients with bladder cancer without extravesical extension (T2) are at a low risk of pelvic recurrence (<10%), while those with T3 disease are at higher risk of pelvic recurrence (>30%), but they are also at risk of distant failure. In T3 tumours, distant failure will diminish the impact of pre-operative RT on the overall survival. Since pelvic recurrence has a considerable adverse effect on quality of life, improvement in local control is a worthwhile goal of treatment. The Southwest Oncology Group (SWOG) conducted a phase III randomized trial of pre-operative RT followed by cystectomy versus cystectomy alone and found no difference in survival.3 In this trial, a low-dose pre-operative RT (20 Gy in five fractions over one week) was used, most patients had T2 tumours and therefore were at a low risk of pelvic failure. A positive study of pre-operative RT was recently reported by El-Wahidi et al.4 In this trial, patients with schistosomal bladder cancer were randomized to receive pre-operative RT with 44 Gy followed by cystectomy, or cystectomy alone. A significantly higher pelvic failure rate was observed in the surgery alone arm (29%) than in the pre-operative RT arm. This study has been published in abstract form only and no details are available on local control or survival. Huncharek et al. published a meta-analysis of five randomized trials of pre-operative RT and cystectomy versus cystectomy alone (not including the recent El-Wahidi study) and were unable to demonstrate survival advantage for pre-operative RT (odds ratio of 0.71, 95% confidence interval 0.48-1.06), and the impact on local control was not addressed.5 There is little modern data dealing with the toxicity of preoperative RT and cystectomy, but the previously conducted randomized trials suggest that this treatment can be delivered safely. Data from several authors indicate that the use of pre-operative RT does not preclude continent urinary diversion.6,7 The current approach to the management of patients with T3 disease consists of radical cystectomy and pelvic lymph-node dissection followed by adjuvant chemotherapy. The role of preoperative RT in this setting is ill defined. However, it would be reasonable to recommend pre-operative RT to patients with clinical T3 tumours who are not candidates for adjuvant chemotherapy, with the primary aim of reducing pelvic recurrence.

It was recognized in the 1950s and 1960s that radical cystectomy alone or radical radiotherapy alone cured fewer than 50% of patients with muscle-invasive bladder cancer. It was hypothesized, therefore, that combining the two modalities would improve the outcome. To test this hypothesis, a number of trials comparing radical definitive radiation therapy with pre-operative radiation therapy and cystectomy were conducted. The main two include the trial by the Institute of Radiology in the UK and the DAVECA Danish Study Group.8,9 Both trials were negative and established that preoperative RT followed by cystectomy did not result in a significantly better survival than RT alone with the option for later salvage cystectomy. In ensuing years, it was recognized that RT alone did not provide adequate local control in bladder cancer.

Definitive radiation therapy

Definitive radiation therapy in bladder cancer is used to cure cancer and conserve normal bladder function. This treatment modality is not very popular in the United States. Indeed, the very popular textbook of cancer edited by De Vita et al. stated that '. . . in some countries, external beam radiotherapy is considered standard, but not in the United States'.2 With this attitude being prevalent, few clinical trials of definitive radiation therapy are conducted.

To discuss the definitive RT in bladder cancer patients, one should address the issues of patient selection, assessment of disease extent, exact treatment plan, RT prescription technique, delivery, and assessment of outcome and follow-up care.

To address the issue of patient selection, two major factors have to be considered. The first is the adequacy of bladder function. Patients who are incontinent, or who have very irritative bladder symptoms, are not good candidates for bladder conservation. The bladder function has to be adequate to be worthwhile preserving. The second issue is the technical ability to deliver an adequate dose of radiation to the tumour. The factors to consider as contra-indications to radiation treatment include the presence of active inflammatory bowel disease, prior pelvic surgery, prior pelvic infections, and the technical ability to control the disease is the size of radiation field that is required, presence of tumour of diverticulum, etc. The other factors relevant to patient selection are related to the potential for achieving lasting local control and therefore bladder conservation. To define this, we should examine the local control rates and survival data in patients with muscle-invasive bladder cancer treated with radiation therapy. One should remember that the information on the use of RT was gathered in the 1970s and 1980s, when the disease extent was defined clinically. Neither CT scans nor MRIs were available, and RT was planned using simulation with cystogram, and modern planning and treatment techniques including CT plans and conformal radiation therapy were not used.

The largest published series of definitive radiation therapy in bladder cancer is from Edinburgh where Duncan and Quilty reported results in 699 patients with muscle-invasive bladder cancer.10 The five-year survival for patients with T2 cancers was 40%. Patients with T3 and T4 bladder cancers had five-year survival of 25.9% and 11.6% respectively. Similar results are available from the MD Anderson Hospital and the London Hospital.11,12 At the Princess Margaret Hospital, 121 patients with muscle-invasive bladder cancer were treated with external beam radiation therapy between 1981 and 1985.13 The five-year cause-specific survival was 59% of patients with T2 disease and 52% with T3a disease. A much lower survival (30% at five years) was observed in patients with T3b disease. When local control of cancer was examined in the Princess Margaret Hospital series, the local relapse-free was 45% for patients with T2 and T3a disease, but only 28% for patients with T3b cancer. In examining the factors predictive of durable local control in the Princess Margaret Hospital series, the presence of co-existent carcinoma in situ was found to be associated with a lower longterm local control. The patients with no demonstrable carcinoma in situ achieved local control in 55% of patients and in those with co-existent carcinoma in situ, local control was less than 30% at five years. Therefore, the presence of co-existent carcinoma in situ is considered a relative contra-indication to definitive radiation of bladder cancer. However, recent evidence from Pisters et al. suggests that patients who have residual, or recurrent, carcinoma in situ following radical radiation can be treated with intravesical BCG, and response rates are similar to those obtained in patients with primary CIS.14

The low local control rates observed in retrospective series of definitive radiation therapy in bladder cancer have led to research efforts to try to improve the results of radiation therapy in bladder cancer. One of the most common strategies was the use of concurrent chemotherapy and radiation therapy in bladder cancer. Numerous chemotherapeutic agents were combined with radiation therapy. They included 5-FU, 5-FU plus mitomycin-C, and cisplatin. The most common strategy was that of cisplatin, where a number of phase II trials have been conducted.15 The complete response rates in these trials varied between 66% and 93%. A phase II study of concurrent cisplatin and RT conducted in Vancouver by Coppin et al. showed an excellent progression-free survival in patients with T3-T4b cancer, and formed the basis for a prospective randomized trial conducted by the National Cancer Institute of Canada in the late 1980s.16 In this trial, 99 patients were randomized to RT, either high-dose, pre-operative RT or definitive RT, with or without concurrent cisplatin. No difference in the overall survival was observed between the RT alone and RT with concurrent cisplatin arms. However, a statistically significant reduction in pelvic failure rate was observed in patients who received concurrent RT and cisplatin. The actuarial rate of pelvic recurrence at five years was 60% for patients treated with RT alone and 31% for patients who received combined RT and cisplatin. Distant recurrence rate at five years was 43.7% for the RT alone group and 45% for RT and cisplatin. In the early 1990s, the Medical Research Council in the UK and the EORTC GU Group conducted a large multinational study to test the use of CMV neo-adjuvant chemotherapy to improve survival in bladder cancer. The study accrued 975 patients, and with a median follow-up of three years, a 5% survival advantage was demonstrated for the chemotherapy treated group. The study was powered to detect a 10% survival advantage and, therefore, there was no statistically significant improvement for the chemotherapy treated group. It is important to note, however, that the trials that used RT with concurrent cisplatin demonstrated an approximately 40-50% bladder conservation rate. The use of radical external beam RT has not been shown to compromise the overall survival in bladder cancer patients. Therefore, the use of definitive RT with or without concurrent cisplatin should be a recognized treatment option that is offered to patients who wish to preserve normal bladder functions rather than undergo cystectomy.

Conclusions

In summary, the current literature suggests that with appropriate selection of patients for bladder conservation, a complete response can be achieved in approximately 60% of patients with favourable disease. Approximately 30% ofthose patients will develop further recurrence, either with carcinoma in situ or new superficial tumour, or indeed, local recurrence of invasive disease. As in any other series of patients with muscle-invasive bladder cancer, distant metastasis can be expected to develop in approximately 50% of patients, and the overall five-year survival is at best 50%. Longterm bladder conservation can be expected in 40% of patients. The optimal factors for selecting patients for bladder conservation include the presence of T2a and T2b tumours (1997 UICC TNM), bladder cancer without diffuse CIS, and pre-radiation therapy optimal TURBT. A careful assessment of disease extent, preferably with MRI, CT planning and delineation of target volume, the use of conformal techniques, and the use of radiation with concurrent cisplatin, constitute the optimal treatment approach. An aggressive follow-up and early salvage cystectomy for patients who have residual or recurrent invasive disease will further improve the outcomes.

The goals of bladder conservation are often confused with the goals of minimizing treatment toxicity. A large number of patients who are elderly, have very massive disease and are unsuitable candidates for curative surgery, are referred for curative RT. The results of treatment for these patients are very poor. Often they are treated with high-dose per-fraction prescriptions and, instead of assessing the results of treatment in this group of patients in terms of symptom release and palliation, survival is being measured. Clearly, to assess the role of definitive RT in the bladder conservation approaches, reports of patients who are referred for RT by choice rather than by default should be considered.

References

1 Gospodarowicz MK, Quilty PM, Scalliet P et al. (1995) The place of radiation therapy as definitive treatment of bladder cancer. Int J Urol 2: 41-8.

2 Scher H, Shipley W and Herr W (1997) Cancer of the Bladder. In: De Vita JV, Hellman S and Rosenberg S (eds) Cancer, Principle and Practice (5th ed). Lippincott-Raven: Philadelphia, pp. 1300-22.

3 Smith J, Crawford E, Paradelo J et al. (1997) Treatment of advanced bladder cancer with combined pre-operative irradiation and radical cystectomy versus radical cystectomy alone: a phase III intergroup study. J Urol 157: 805-8.

4 El-Wahidi G, Ghoneim M, Saker H et al. (1999) Pre-operative radiotherapy of schistosomal bladder cancer. Prospective randomized study. Eur J Cancer x: xx-xx.

5 Huncharek M, Muscat J and Geschwind JF (1998) Planned pre-operative radiation therapy in muscle-invasive bladder cancer; results of a meta-analysis. Anticancer Res 18: 1931-4.

6 Bochner BH, Figueroa AJ, Skinner EC et al. (1998) Salvage radical cystoprostatectomy and orthotopic urinary diversion following radiation failure. J Urol 160: 29-33.

7 Mannel RS, Manetta A, Buller RE et al. (1995) Use of ileocecal continent urinary reservoir in patients with previous pelvic irradiation. Gynecol Oncol 59: 376-8.

8 Bloom HJ, Hendry WF, Wallace DM et al. (1982) Treatment of T3 bladder cancer: controlled trial of pre-operative radiotherapy and radical cystectomy versus radical radiotherapy. Br J Urol 54: 136-51.

9 Anderstrom C, Johansson S, Nilsson S et al. (1983) A prospective randomized study of pre-operative irradiation with cystectomy or cystectomy alone for invasive bladder carcinoma. Euro Urol 9: 142-7.

10 Duncan W and Quilty PM (1986) The results of a series of 963 patients with transitional cell carcinoma of the urinary bladder primarily treated by radical megavoltage x-ray therapy. Radiother Oncol 7: 299-310.

11 Pollack A and Zagars GZ (1996) Radiotherapy for stage T3b transitional cell carcinoma of the bladder. Semin Urol Oncol 14: 86-95.

12 Blandy JP, Jenkins BJ, Fowler CG et al. (1988) Radical radiotherapy and salvage cystectomy for T2/3 cancer of the bladder. Prog Clin Biol Resear 260: 447-51.

13 Gospodarowicz MK, Hawkins NV, Rawlings GA et al. (1989) Radical radiotherapy for the muscle-invasive transitional cell carcinoma of the bladder: failure analysis. J Urol 142: 1448-54.

14 Pisters LL, Tykochinsky G and Wajsman Z (1991) Intravesical bacillus Calmette-Guerin or mitomycin-C in the treatment of carcinoma in situ of the bladder following prior pelvic radiation therapy. J Urol 146: 1514-7.

15 Gospodarowicz MK (1998) Locally advanced bladder cancer. Radiation therapy and chemotherapy. Eur Urol 33 Suppl 4: 27-31.

16 Coppin C, Gospodarowicz M, James K et al. (1996) The NCI-Canada trial of concurrent cisplatin and radiotherapy for muscle-invasive bladder cancer. J Clin Oncol 14: 2901-7.

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