Updated June 2008
Ta, T1 Low-Grade Tumour
All T1 bladder tumours require a re-resection to ensure adequate staging, as up to 25% of trans-urethral resections (TUR) specimens have been shown to be understaged. Thus, in general, all T1 bladder tumours require a re-resection, usually within four weeks.
After total transurethral resection of low-grade papillary tumour(s) confined to the basement membrane or superficial connective tissue, selected and random biopsies plus urine cytology may be performed to rule out carcinoma in-situ.
Factors associated with increased risk of recurrence include: tumour grade (low grade vs. high grade, G1 vs. G2-3), stage (Ta versus T1), large size, multi-centricity, and a history of prior recurrence (6). Eighty percent of all patients with Ta low grade tumours who have no recurrence at the time of cystoscopy three months after diagnosis will have no recurrence after three years of follow-up. Conversely, 90% of patients with recurrent disease after three months continued to recur over the same time period.
If further biopsies are positive, superficial low-grade lesions too numerous to resect endoscopically, or recheck cystoscopies reveal recurrent low-grade superficial tumours, intravesical BCG immunotherapy may be administered (see GUBCG protocol).
Many trials of intravesical chemotherapy have demonstrated a decrease in the recurrence rate of superficial disease but the effect on the risk of muscle invasion, metastases, or cancer death remains uncertain (7), and physicians are cautioned that delay in performing cystectomy may be fatal.
Tis and High-Grade Ta, T1
Carcinoma in-situ of the urothelium of the high-grade flat type is distinct from papillary in-situ disease as it tends to behave more aggressively. Involvement of the urothelium ranges from a small focus to extensive disease throughout the bladder. The risk of progression to muscle invasive disease and subsequent metastases ranges from 40 to 80% with Tis depending on extent of disease.
Standard treatment is initial resection with or without peri-operative chemotherapy (Mitomycin C). Post-operatively, patients should receive intravesical BCG after three to four weeks. Some retrospective series suggest that overall survival may be improved with early treatment with cystectomy for T1, Grade 3 cancers. Intravesical chemotherapy with BCG has been shown in a randomized trial to decrease the risk of invasive disease and metastatic disease in patients with high-grade Ta, T1 and highly selected cases of Tis(8). Treatment of recurrent high-grade tumour with additional intravesical chemotherapy is potentially hazardous. One randomized trial of radiotherapy versus intravesical therapy after TUR demonstrated no relapse-free survival advantage with radiotherapy.
If BCG fails, cystectomy (and under some circumstances urethrectomy) with frozen section of the ureter is indicated. Tis does not respond reliably to radiotherapy.
There is one positive trial of maintenance using three week courses at 3, 6, 12, 18, 24, and 30 months(9) (see GUBCG for details). Other trials have been negative using other regimes. There is no question that the toxicity of BCG escalates with repeated dosing in most patients and therefore toxicity should be carefully weighed.
1. Patients with CIS or High grade (G3T1) disease at relapse
Treating such patients with any intravesical therapy is risky as they may lose their window of opportunity for surgical cure. Even 'effective' therapy at this point is likely only to delay the need for cystectomy by at most a year or two rather than prevent it. Some retrospective series suggest that overall survival may be improved with early treatment with cystectomy for T1 Grade 3 cancers.
Occasional patients who are not suitable surgical candidates because of age and/or co-morbid disease may be considered for further intravesical therapy. Low-dose BCG and interferon in a six week cycle followed by maintenance for three weeks at 5, 11, and 17 months is suggested.(10) Combination interferon and BCG can be applied for by submission of an undesignated indication request for patients with refractory CIS or G3T1 disease who are not surgical candidates. It is important to note that powdered Interferon, reconstituted with sterile water be used, as the liquid preparation of interferon contains preservatives which destroys BCG. Those who fail such further measures early on will likely not respond to further intravesical therapy, and alternative measures should be considered urgently. Valrubicin appears less effective(11) and is currently neither available nor approved. Mitomycin C produces few responses and is not approved.(12) If surgery is not possible referral for a Radiation Oncology opinion is a consideration.
2. Patients without CIS or High grade (G3) at relapse
Mitomycin C shows activity in some patients with BCG failure and may be worth a trial, but response rates are low (4 of 21 patients).(13)
3. Patients without CIS or High grade (G3) failing BCG.
Further surgical resection whenever the disease recurs is an option, as is cystectomy, but is troublesome for the patient and the surgeon especially when the disease becomes multifocal or inaccessible. Low-dose BCG and interferon has been reported (14) to have a 55% two year disease free survival in this setting and those whose disease seems to be progressing in stage, grade, or frequency may benefit.
One important exception is the micropapilary variant of TCC. If, after confirmation and review with the pathologist, micropapillary tumor is present, aggressive treatment should be considered even if diagnosed as clinical stage T1. This is an aggressive form of bladder cancer which usually requires aggressive treatment.
All superscript references in this chapter, refer to the list of References for Bladder.