Current concepts in the role of intravesical instillations in the therapy and prophylaxis of superficial transitional-cell cancer of the bladder. The Finnbladder Research Group.

A survey on superficial, local urinary bladder cancer, its prognostic factors, and instillation treatments is presented on the basis of experience with approximately 1,000 patients over a period of 20 years, experimental investigations, and the literature. Personal opinions and practical recommendations are presented in 11 conclusive theses.

Immunoreactivity of bcl-2, p53 and EGFr is associated with tumor stage, grade and cell proliferation in superficial bladder cancer. Finnbladder III Group.

Immunoreactivity of bcl-2, p53, the epidermal growth factor (EGFr) and Ki-67 (MIB-1) proteins was assessed by immunohistochemistry in 185 patients with superficial bladder cancer (SBC) in order to evaluate their usefulness as indicators of tumor progression. Forty-one percent of the tumors were bcl-2 positive, 36% of them were positive for p53 (over 20% of nuclei), while 41% were positive for EGFr, and 30% of the tumors were MIB-1 positive (proliferation index > 15%). Immunoreactivity of all analyzed proteins was highly significantly related to tumor grade and stage. Tumors which were bcl-2, p53 or EGFr positive were also rapidly proliferative (MIB-1 score >15%). The obtained results suggest that all analyzed proteins may have prognostic significance in SBC. The prognostic value of the abnormal immunolabeling of the analyzed proteins will be established after an adequate follow-up period of this same cohort of patients.

Alternating mitomycin C and bacillus Calmette-Guerin instillation prophylaxis for recurrent papillary (stages Ta to T1) superficial bladder cancer. Finnbladder Group.

PURPOSE: We attempted to prove if alternating chemoprophylactic and immunoprophylactic instillations improved efficacy and decreased toxicity in patients with recurrent superficial bladder cancer. MATERIALS AND METHODS: A total of 188 patients with rapidly recurring stage Ta or T1 cancer was randomly treated with mitomycin C (group 1) or alternating mitomycin C and Pasteur strain bacillus Calmette-Guerin (BCG) instillations (group 2) for 2 years. Mean followup was 34 months. RESULTS: Median times to initial recurrence were 12 months in group 1 and 7 months in group 2 (p = 0.976), and treatment failed in 21.5% and 18.9%, respectively. Recurrence rates during the instillation period were 1.01 in group 1 and 0.86 in group 2 (p = 0.376). There was no difference in the disease-free interval between the 2 groups (p = 0.976). Instillations were discontinued because of adverse effects in 6 cases (6%) in both groups. CONCLUSIONS: Efficacy of alternating mitomycin C and BCG was equal to mitomycin C monotherapy, and both methods were effective in prophylaxis of recurrent papillary bladder cancer. Less toxicity occurred in the alternating treatment group compared to earlier BCG monotherapy results.

Alternating mitomycin C and bacillus Calmette-Guerin instillation therapy for carcinoma in situ of the bladder. The Finnbladder Group.

PURPOSE: Our aim was to prove if alternating chemotherapeutic and immunotherapeutic instillations improved efficacy and reduced toxicity in patients with carcinoma in situ of the bladder. MATERIALS AND METHODS: Of 68 carcinoma in situ patients randomly treated with instillations 40 received mitomycin C and 28 received mitomycin C and Pasteur bacillus Calmette-Guerin (BCG) in alternating courses. Mean followup was 33 months. RESULTS: The complete response rates with mitomycin C and mitomycin C/BCG were 45% and 71% at 3 months, 59% and 82% at 12 months, and 47% and 74% at 24 months, respectively (p = 0.041). The disease-free interval showed the superiority of alternating therapy (p = 0.043). Recurrence rates during the instillation period were 1.834 with mitomycin C and 0.922 with mitomycin C/BCG (p = 0.013). No remarkable side effects developed in the alternating group. CONCLUSIONS: Therapy of carcinoma in situ with alternating mitomycin C and BCG is more effective than mitomycin C alone. Compared to BCG monotherapy only few side effects occur.

Proliferation indices as independent prognostic factors in papillary Ta-T1 transitional cell bladder tumours.

A cohort of 148 patients with papillary Ta-T1 transitional cell carcinomas (TCCs) was followed up for over 10 years and flow cytometric (DNA ploidy, S phase fraction) and morphometric variables (5 nuclear factors, volume corrected mitotic index) were related to prognosis during this period. Recurrence-free survival was significantly related to DNA ploidy, S phase fraction and M/V index. Progression in T-category was predicted by M/V index, S phase fraction, DNA ploidy and WHO grade. The same variables predicted progression in N- and M-categories. In a multivariate analysis only M/V index and S phase fraction were independent predictors of progression. Univariate analysis showed that M/V index, SPF, DNA ploidy and WHO grade predicted survival. In a multivariate survival analysis only M/V index and SPF were independent predictors. The results showed that proliferation indices had independent prognostic value in papillary Ta-T1 TCCs and the grading of these tumours could be based on the proliferation indices. Papillary Ta-T1 tumours with a M/V index value < or = 10/mm2 or SPF < or = 10% had a favourable prognosis whereas tumours with M/V index > 10/mm2 or SPF > 10% had a high malignant potential.

Clinical prognostic factors in transitional cell cancer of the bladder.

A cohort of 537 patients with transitional cell cancer of the bladder (TCC) were followed up for a mean of 9 years and the clinicopathological data were related to prognosis. The T category (p < 0.0001), N category (p < 0.0001) and M category (p < 0.0001) were the most important clinical prognostic factors, followed by the age of the patient (p < 0.0001). Of the histological variables the WHO grade (p < 0.0001), papillary status (p < 0.0001) and the presence of R3-4 cells in voided urine (p = 0.0061) predicted unfavorable prognosis. In Ta-T1 tumors the WHO grade (p < 0.0001), papillary status (p < 0.0001) and the age of the patient (p < 0.0001) had a prognostic value in univariate analysis. In Cox's analysis independent predictors of survival were the T category (p < 0.0001), WHO grade (p < 0.0001), patient age (p < 0.0001), papillary status (p = 0.012) and the presence of symptoms before diagnosis (p = 0.033). In superficial tumors the WHO grade (p < 0.0001) and patient age (p < 0.0001) were independent predictors of survival.

Spontaneous peripelvic extravasation of urine as a cause of acute abdomen.

In eight patients with sudden onset of flank pain, urography showed extravasation of urine. The cause of peripelvic leakage was verified ureteral stone in four cases, stricture of the ureteropelvic junction in one, and unknown in three cases. Treatment was symptomatic in four cases, drainage in two and surgery in two cases. Seven patients recovered uneventfully, but one required nephrectomy. The prognosis in spontaneous urinary extravasation is usually good without drainage. Open surgery is seldom indicated.

Superficial urinary bladder cancer. Results from the Finnbladder studies and a review on instillation treatments.

At present, about 80% of primary, newly diagnosed urinary bladder cancers are local (NOMO), i.e., potentially curable. Not less than two thirds of all are superficial cancers (TIS, Ta, T1), and thus subjects of conservative, local treatments. Carcinoma in situ (TIS/CIS) has three clinical manifestations: 1) primary TIS is found without a previous history of bladder cancer, 2) secondary TIS is found during the follow-up of an earlier cancer, and 3) concomitant TIS is found simultaneously with a papillary tumour. Otherwise, there are controversial diagnostic and therapeutic attitudes on TIS. Concerning the primary diagnosis and grading, the reliance on cytological possibilities varies in separate centres. "Wait-and-see policy" might be justified in mild dysplasia Grade 1, whereas both the TIS Grade 2, and TIS Grade 3, are real malignancies which need a more effective treatment than transurethral resection (TUR) alone. Under a close control, intravesical chemo- and immunotherapy with doxorubicin (ADM), mitomycin C (MMC) and bacillus Calmette-Guérin (BCG) offer an alternative to cystectomy. However, it remains to be seen in the future whether combined or alternating instillations will give a still better return. By contrast, the principal treatment of visible superficial (Ta and T1) cancer is TUR, which can be easily repeated. Most recommended strategy for Grade 3 T1 cancer seems to be the same. Anyhow, the high frequency of recurring tumours and the tendency to simultaneous progression in specific categories of Ta-T1 cancer have led to adjuvant prophylactic instillation treatments. Currently, both local cytostatics (ADM and MMC in the present series), and immunoagents (BCG) have been proven safe.(ABSTRACT TRUNCATED AT 250 WORDS)

Prognostic factors in nodular transitional cell bladder tumours.

A cohort of 106 nodular transitional cell bladder cancers (TCC) were followed up for a mean of 9 years. Clinical stage, WHO grade, six morphometric nuclear factors and volume corrected mitotic index (M/V index) were correlated to progression and survival during the follow-up period. Nuclear factors were related to WHO grade with a borderline significance (p = 0.01-0.3) whereas the M/V index showed a highly significant relation to WHO grade. Neither nuclear factors nor the M/V index were related significantly to T-, N- or M-categories at the time of diagnosis. Progression in N- and M-categories was related independently to WHO grade whereas progression in T-category could not be predicted significantly by none of the variables included in this analysis. Survival was predicted by T-category (p = 0.0028), N-category (p = 0.0001), M-category (p = 0.0057) and M/V index (p = 0.010). In T1-T2N0M0 tumours survival was predicted by the Dmax (p = 0.015) and by the M/V index (p = 0.039). In multivariate survival analysis T-category (p < 0.001) had independent prognostic value. In T1-T2N0M0 tumours only the M/V index predicted survival independently (p = 0.007). The results show that only the proliferation rate in addition to T-category have prognostic significance in nodular TCC.

Flow cytometry in comparison with mitotic index in predicting disease outcome in transitional-cell bladder cancer.

The DNA content and S-phase fraction were measured by flow cytometry in 448 tumour biopsy specimens from transitional-cell bladder cancer (TCC). The samples were also analyzed for mitotic index, WHO grade and papillary status, and histological and flow cytometric data were then correlated to clinical behaviour of tumours during a mean follow-up period of 9.9 years. TNM classification, WHO grade, papillary status, mitotic index, DNA ploidy and S phase fraction were significantly interrelated. Twenty-four percent of tumours showed heterogeneous DNA indices when measured from multiple samples (measured in 94 cases). Of the histological parameters, independent predictors of progression in superficial tumours were the S-phase fraction and mitotic index. In superficial tumours, S-phase fraction and the mitotic index included all the available independent prognostic information in survival analysis, whereas in muscle-invasive tumours T category was the most important prognostic factor. The results suggest that DNA ploidy has no independent prognostic value in transitional-cell bladder cancer, whereas proliferation indices (SPF, mitotic index) are important prognostic factors. Accordingly, malignancy classification of papillary bladder tumours can be based on proliferation indices alone. Nodular tumours run an unfavourable course and their malignancy grading by flow cytometry or by mitotic index is not relevant.

Grading of superficial bladder cancer by quantitative mitotic frequency analysis.

A cohort of 270 superficial (stages Ta to T1) transitional cell bladder tumors was followed for more than 8 years. World Health Organization (WHO) grade, papillary status and 2 mitotic indexes were related to progression, recurrence-free survival and bladder cancer related survival during followup. Mitotic activity index and volume corrected mitotic index were significantly related to WHO grade and papillary status (p < 0.0001). WHO grade, papillary status and mitotic indexes were related significantly to progression in univariate analysis (p < 0.001) whereas in a multivariate analysis only volume corrected mitotic index included independent prognostic information (p < 0.001). Recurrence-free survival was related to volume corrected mitotic index in the entire cohort (p = 0.03) and in papillary tumors (p = 0.07). Bladder cancer related survival was related to WHO grade, papillary status, mitotic activity index and volume corrected mitotic index (all p < 0.0001). In papillary tumors mitotic activity index (p < 0.0001), volume corrected mitotic index (p < 0.0001) and WHO grade (p = 0.0036) predicted survival. In multivariate analysis mitotic activity index predicted independently recurrence-free survival in the entire cohort (p = 0.043) and in papillary tumors (p = 0.012). Bladder cancer survival in the entire cohort and in papillary tumors was related independently to volume corrected mitotic index (p < 0.001). The results show that superficial transitional cell bladder tumors can be efficiently categorized into prognostic groups by quantitative mitotic frequency analysis and the results provide a new classification system for superficial transitional cell bladder tumors.

Independent clinical, histological and quantitative prognostic factors in transitional-cell bladder tumours, with special reference to mitotic frequency.

A cohort of 537 transitional-cell bladder cancers (TCC) was followed up for a mean of 9 years. Clinical stage, WHO grade, papillary status, 6 nuclear factors and volume-corrected mitotic index (M/V index) were related to progression and survival. Classic and quantitative prognostic factors were significantly interrelated (p less than 0.001). In Ta-Tl tumours M/V index predicted progression independently (p less than 0.001) and in the entire cohort progression was related independently to the M/V index (p = 0.0001) and to the WHO grade (p = 0.0022). In survival analysis, clinical stage (p less than 0.0001), M/V index (p less than 0.0001), WHO grade (p less than 0.0001), papillary status (p less than 0.0001) and nuclear factors (p less than 0.0001) were significant predictors. In papillary tumours, clinical stage (p less than 0.0001), M/V index (p less than 0.0001), WHO grade (p less than 0.0001) and nuclear factors (p = 0.0001-0.0133) were related to survival. In a multivariate analysis T-category (p less than 0.001), WHO grade (p less than 0.001), M/V index (p = 0.002) and papillary status (p = 0.034) predicted survival independently in the entire cohort whereas in papillary tumours T-category (p less than 0.001) and M/V index (p less than 0.001) were independent predictors. If tumours with pelvic lymph-node metastases or distant metastases at diagnosis were excluded from the analysis, T-category (p less than 0.001), M/V index (p less than 0.001) and WHO grade (p less than 0.001) were independent predictors. In papillary tumours T-category (p less than 0.001), M/V index (p less than 0.001) and WHO grade (p = 0.048) predicted survival. The results emphasize the importance of mitotic activity as a most important histological prognostic factor in TCC, second only to clinical stage. In Ta-TI tumours quantitative mitotic frequency analysis includes all the available independent prognostic information. Accordingly, TCC can be graded by mitotic frequency analysis in place of subjective grading systems.

Independent prognostic factors in T2/T3 transitional cell bladder tumours with special reference to histoquantitative methods.

A cohort of 233 T2/T3 transitional cell carcinomas were followed up for over 10 years. Five nuclear factors, two mitotic indices, DNA ploidy and S-phase fraction (SPF) were related to progression and survival of TCCs during that time period. SPF predicted pelvic lymph node involvement at diagnosis (P = 0.064). Progression in T-category was related to T-category (P = 0.035), DNA ploidy (P = 0.0180), papillary status (P = 0.0021), mitotic activity index (MAI) (P = 0.0011), volume corrected mitotic index (M/V index) (P = 0.0017), WHO grade (P = 0.0003) and S-phase fraction (P = 0.0002). Progression in N and M-categories was related to the same variables. Independent predictors of progression in T-category were SPF (P = 0.0161) and WHO grade (P = 0.0236), whereas progression in M-category was independently related to MAI (P = 0.0012) and T-category (P = 0.0004). The SPF (P < 0.0001), M/V index (P < 0.0001), MAI (P < 0.0001), WHO grade (P < 0.0001) and papillary status (P < 0.0001) were the most important predictors of survival in univariate analysis. In a multivariate analysis SPF and M/V index (P < 0.0001) were the best predictors of survival followed by papillary status and T-category. The results show that the proliferation rate of T2/T3 TCCs as determined by flow cytometric SPF or M/V index are equally powerful predictors. They are clearly better than nuclear morphometry, DNA ploidy or WHO grading as prognostic factors.

Prediction of superficial bladder cancer by nuclear image analysis.

A cohort of 270 superficial transitional cell bladder tumours (Ta-T1) was followed-up for over 8 years. WHO grade, papillary status and six nuclear factors were related to progression, recurrence-free survival (RFS) and bladder cancer-related survival (BS) during the follow-up period. Mean nuclear area (NA), standard deviation of nuclear area (SDNA), nuclear perimetry (PE), standard deviation of nuclear perimetry (SDPE), shortest nuclear axis (Dmin) and longest nuclear axis (Dmax) were significantly related to WHO grade and papillary status (P < 0.0001). All the nuclear factors were related significantly to progression in univariate analysis (P < 0.01) whereas in a multivariate analysis WHO grade (P < 0.0001) and papillary status (P = 0.048) included independent prognostic information. RFS was related to PE (P = 0.009), SDPE (P = 0.013), Dmin (P = 0.021), Dmax (P = 0.028) and SDNA (P = 0.029). In papillary tumours SDPE (P = 0.007) and Dmin (P = 0.024) predicted RFS. BS was related to WHO grade, papillary status, NA, SDNA, PE, Dmax, Dmin (all P < 0.0001) and to SDPE (P = 0.003). In papillary tumours PE (P < 0.0001), Dmax (P = 0.0022), Dmin (P = 0.0027), WHO grade (P = 0.0036), NA (P = 0.0005), SDNA (P = 0.0355) and SDPE (P = 0.0718) predicted BS. In multivariate analysis SDPE (P = 0.029) predicted RFS and survival was related to WHO grade (P < 0.001) and PE (P = 0.014) independently. In papillary tumours only Dmax (P = 0.001) predicted survival independently. The results show that superficial papillary transitional cell bladder tumours can be efficiently categorised into prognostic groups by nuclear image analysis and the results provide a new classification system for superficial papillary bladder tumours. Tumours with high nuclear factor values should be considered for radical primary therapy and adjuvant therapy after transurethral resections.

Tumour infiltrating lymphocytes as an independent prognostic factor in transitional cell bladder cancer.

The prognostic value of tumour infiltrating lymphocytes (TIL) was assessed in a cohort of 514 patients with a transitional cell bladder cancer (TCC) during a follow up period of over 9 years. The density of TIL were positively correlated to WHO grade (P < 0.0001), non-papillary growth architecture (P < 0.0001), morphometric nuclear factors (P < 0.007) and volume corrected mitotic index (M/V index) (P < 0.0001). Dense TIL predicted progression in Ta-T1 tumours (P < 0.0006) whereas in a multivariate analysis they had no independent predictive value. Dense TIL were related to short recurrence-free survival in Ta-T1 tumours in a univariate analysis (P = 0.06) as well as in a multivariate analysis (P = 0.005). Dense TIL predicted unfavourable prognosis in the entire cohort (P = 0.0316) and in papillary tumours (P = 0.062) whereas in nodular tumours TIL were a sign of good prognosis (P = 0.0141). Also in T3-T4 tumours TIL were related to less aggressive behaviour of TCC (P = 0.0259). In a multivariate analysis including clinical stage (T-category), WHO grade, papillary status, six morphometric nuclear factors and M/V index dense TIL were a highly significant indicator of a favourable prognosis (P = 0.007). Particularly TIL categorized rapidly proliferating TCC into prognostic groups (P = 0.001). The results show that TIL are a sign of efficient host defence mechanisms in TCC and TIL predict a favourable prognosis in invasive TCC.

Can fine needle aspiration biopsy detect incidental prostatic carcinoma (T1) prior to TUR?

The purpose of this study was to find out whether randomly taken fine needle aspiration biopsy (FNA) can detect incidental prostatic carcinoma prior to transurethral resection (TUR) and what are the effects of local tumor stage and grade on detection rate. Biopsies were taken from 344 patients, who came to hospitals for elective TUR without clinical evidence of prostatic carcinoma. Histologic examination of the TUR material showed prostatic carcinoma in 49 cases (14%). Sufficient material for cytologic examination was found in 343 cases. Of the 16 cases of T1a carcinoma in histologic examination, cytology found only 1, which was a G3 carcinoma. Of 33 T1b carcinoma in histologic examination, cytology found 6 and an additional 7 were suspect findings. Out of 6 G3 tumors in histologic examination, cytology showed 4. In our hands the proportion of false-negative cytologic findings in randomly taken FNA was so large that routine use of random FNA prior to TUR or as a screening procedure cannot be recommended, but positive FNA finding can be regarded as cancer.

Prognostic factors in WHO grade 2 transitional-cell bladder cancer (TCC); a novel two-grade classification system for TCC based on mitotic index.

A retrospective histological analysis has been carried out on 537 cases of transitional-cell bladder carcinoma, followed-up over a period of 9 years. In the first part of the study WHO grade 2 tumours were analysed and a number of independent factors predictive for survival identified. In a multivariate analysis the T category and M/V index (number of mitotic figures/mm2 neoplastic epithelium) were the most important prognostic factors. In a subsequent analysis of the whole series of 537 cases, overall the M/V index was not as important in predicting survival as the stage of the tumour. However, in superficial tumours (Ta-T1) subsequent analysis showed that the M/V index alone could be used to predict survival.

Effect of oral clodronate on bone pain. A controlled study in patients with metastic prostatic cancer.

Although osteosclerotic metastases are characteristic of prostatic carcinoma, bone resorption is also accelerated. Since clodronate inhibits bone resorption and relieves bone pain, we have given it to patients with painful bone disease from prostatic cancer after failure of hormonal therapy. All patients received estramustine phosphate orally. Simultaneously they were randomly allocated to clodronate (36) and placebo (39) groups. Clodronate was given by mouth. The dose was 3.2 g for the first month, thereafter 1.6 g. Pain relief was more distinct in the clodronate group where one third of patients were totally free of bone pain. The use of analgesics stopped in 38% of patients on clodronate and in 18% on placebo which effect probably belongs to estramustine phosphate. Serum calcium concentration decreased more markedly in the clodronate group. Clodronate dose of 3.2 g seemed to be more potent than that of 1.6 g. Side effects were uncommon and occurred equally in both groups. No significant differences were seen in median survival or survival rates between the groups.

Cytostatic effect of different strains of Bacillus Calmette-Guérin on human bladder cancer cells in vitro alone and in combination with mitomycin C and interferon-alpha.

The cytostatic activity of five Bacillus Calmette-Guérin (BCG) strains (Pasteur, Evans, Tice, RIVM and Connaught) on human transitional cell cancer T24 cells was examined. A striking effect was noted even in 2-day cultures, and the effect was more pronounced when the cells were incubated for 5 days with different BCG strains alone. The concentrations needed were about the same as those used in clinical practice (10(9) colony-forming units of Pasteur strain in 100 ml buffered saline solution). Combination with mitomycin C or interferon-alpha-2b potentiated the cytostatic effect. A slight difference in cytostatic activity between different BCG strains was found.

Intravesical chemotherapy (mitomycin C) versus immunotherapy (bacillus Calmette-Guérin) in superficial bladder cancer.

Both intravesical mitomycin C (MMC) and bacillus Calmette-Guérin (BCG; Pasteur strain F) were effective in the present prospective randomized multicenter study consisting of 91 patients with frequently recurrent superficial (Ta-T1) bladder cancer. The result was in favour of BCG, as shown by the measurements with complete response (CR), disease-free interval and recurrence rate. CR of 58% with MMC and 40% with BCG were reached in 22 instillation series on carcinoma in situ of 18 patients. Due to side effects, MMC instillations were discontinued in 8.6%, and BCG instillations in 19.6%, respectively. After the 2-year follow-up also 1 case of pulmonary tuberculosis occurred in the BCG group.