The goals of intravesical chemo- and immunotherapy for bladder cancer are to eradicate existing disease, prevent or delay recurrence, and to prevent or delay progression to a more advanced stage with attendant increased risk of development of metastases. It is recognized that all patients found to have superficial carcinoma of the bladder are at risk for disease recurrence and progression and could theoretically benefit from adjunctive intravesical chemo- or immunotherapy. It is also recognized that in many patients, the immediate risk of recurrence and disease progression is low, and that for such patients, the benefits of intravesical therapy may not justify the costs and potential complications involved.
A number of factors are well established as being useful in predicting the likelihood of tumour recurrence and progression in patients with superficial bladder cancer. The following characteristics would be considered adverse in terms of increased likelihood of recurrence and progression:
ˇ Multiple tumours
ˇ High stage of tumour (T1)
ˇ High grade of tumour (Grade 2,3)
ˇ Size of tumour >3 cm (>5cm or>l0g also quoted)
ˇ Presence of dysplasia or carcinoma-in-situ
ˇ Positive cytology
ˇ Positive prostatic urethra biopsy
ˇ Recurrence at 3 months post resection
It is well recognized that there are newer markers which may be helpful in predicting disease recurrence and progression, and work is in progress to detect those tumours which are most likely to respond to intravesical therapy. Until such time as these tests are universally or widely available, they will not be incorporated into these guidelines, but may be incorporated into future revisions.
A decision regarding the need for intravesical chemo- or immunotherapy will be based on the following investigations:
ˇ History (if the patient has disease recurrence)
ˇ Number of tumours at cystoscopy (single vs. multiple)
ˇ Grade of tumour (low vs. high)
ˇ Size of tumours (< 3cm or >3cm)
ˇ Stage of tumour (Ta, T 1)
ˇ Associated dysplasia or carcinoma-in-situ
ˇ Tumour or carcinoma-in-situ in the Prostatic urethra
ˇ Tumour recurrence at follow-up cystoscopy
Patients will therefore have undergone cystoscopy, evaluation and resection of identified tumours and random biopsies of the bladder mucosa and prostatic urethra. It should be noted that intravesical chemo- or immunotherapy is not considered appropriate in the treatment of patients with muscle-invasive disease, or significant residual superficial tumour after initial attempts at tumour resection. These factors will be reviewed individually.
Tumour recurrence rates are higher in patients presenting with multiple as opposed to single tumours. Fitzpatrick et al (J.Urol. 135:920, 1986) reported 69% recurrence rate in 65 patients with multiple tumours compared to a recurrence rate of 46% in his study population. In another study, 51% of 122 patients with single tumours had recurrences, compared with 91% of 56 patients who presented with multiple tumours (Heney N. Urol. Clin. N. Amer. 19(3):429, 1992). In that report, it was noted that the recurrence rate declined through the years in the patients with single tumours but remained constant in patients with multiple tumours. Lutzeyer et al (J.Urol: 127:250, 1982) reported a 29% recurrence rate in patients with a solitary Ta grade 1 bladder tumour compared with a 94% recurrence rate in patients presenting with multiple tumours. Lerman et al reported a 31 % recurrence in patients with a single papilloma, compared with a 66% recurrence rate in patients with multiple lesions (Cancer 25:335, 1970). Intravesical chemo- or immunotherapy has been recommended for patients with multiple tumours (Fitzpatrick, Bassi, P. et al in Superficial Bladder Cancer, p. 75, 1997). Fradet recommends follow-up cystoscopy at 3 months for patients with multiple tumours and no other risk factors for recurrence reserving adjuvant therapy for those patients demonstrating recurrence at follow-up.
Multiple reports have consistently documented higher recurrence rates, progression rates, and death due to metastatic disease in patients with more poorly differentiated tumours. Lutzeyer et al noted a 29% recurrence rate for patients with solitary Ta, Grade 1 tumours, and a 50% recurrence rate for patients with solitary Ta, Grade 2 tumours. Gilbert et al (J.Urol. 119:488, 1978) showed a 94% 5-year survival for patients with grade 1 tumours and a 40% 5-year survival for patients with grade 3 tumours. Heney reported that the National Bladder Cancer Group found that 2% of patients with Grade 1 tumours (Stage Ta or T1) progressed to muscle invasion or metastatic disease, compared with 11% and 45% of patients with Grade 2 and 3 disease respectively. In a 3 year follow-up study, the same group reported a 50% recurrence rate for Grade 1 tumours, 50% for Grade 2, and 80% for Grade 3. (Heney N. Urol. Clin. N. Amer. 19(3): 429, 1992). Fitzpatrick recommends intravesical chemo- or immunotherapy for patients with high-grade superficial bladder tumours, as does Bassi et al. in Superficial Bladder Cancer, p. 75, 1997. Fradet includes high grade as an adverse factor to be considered as a possible indication for intravesical chemo- or immunotherapy in patients with 2 or more associated adverse risk factors. (Fradet Y. in Superficial Bladder Cancer, p. 63, 1997.
Although several authors recommend intravesical chemo- or immunotherapy for patients with large tumours at initial assessment (Fitzpatrick 1992, Brassi 1997), the data supporting such recommendations appears limited. Heney et al reported that 35% of patients with tumours estimated to be >5cm at cystoscopy demonstrated disease progression compared with 9% of patients with smaller tumours.
They also identified a higher recurrence rate for patients with tumours larger that 5cm but no difference was observed between patient groups with tumours smaller than 5 cm. (J. Urol. 130:1083, 1983). Fitzpatrick et al noted an 82% recurrence rate in patients with tumours weighing more than l0g compared with a 46% recurrence rate for his study group overall. Fradet (in Superficial Bladder Cancer, p. 75, 1997) identifies tumours greater than 3cm as representing a risk factor for recurrence.
Heney et al (J.Urol. 130:1083, 1983) reported a 4% disease progression rate for patients with stage Ta disease compared with a 30% progression rate for patients with T1 disease. The tumour recurrence rate was significantly higher for patients with T1 disease. Fitzpatrick (AUA Update Series, Lesson 11, volume V111, 1989) recommends that stage T1 tumours should be considered invasive as opposed to superficial tumours. Bassi et al recommend intravesical chemo- or immunotherapy for patients with stage T1 disease, (in Superficial Bladder Cancer, p. 75, 1997), while Fradet identifies stage T1 disease as an adverse risk factor to be taken into account in considering intravesical chemo- or immunotherapy.
Fitzpatrick et al reported that 79% of patients who had no recurrence at the follow-up cystoscopy at 3 months did not have a further recurrence. Conversely, only 10% of patients who did have a recurrence at 3 months did not have a recurrence during further follow-up. Lutzeyer et al noted recurrences after a primary tumour in 45% of patients, compared with a recurrence rate of 84% in patients who had recurrent tumours. Bassi et al (Superficial Bladder Cancer, p. 75, 1997.) recommend intravesical chemotherapy for patients with recurrent tumours at follow-up.
Based on available evidence, intravesical chemo- or immunotherapy should be considered for the following patients with Ta bladder tumours:
ˇ Patients with recurrent tumour at 3 month follow-up cystoscopy
ˇ Patients with tumours >5cm in diameter at initial resection (?>3cm)
ˇ Patients with Grade 2 or 3 tumours, stage Ta.
ˇ Patients with multiple tumours at initial resection, irrespective of stage or grade.
ˇ All patients with associated dysplasia or carcinoma-in-situ.