Hans Wijkström

5-YEAR, FOLLOWUP OF A RANDOMIZED PROSPECTIVE STUDY COMPARING MITOMYCIN C AND BACILLUS CALMETTE-GUERIN IN PATIENTS WITH SUPERFICIAL BLADDER CARCINOMA

PURPOSE We report the 5-year followup of a randomized comparison of mitomycin C and bacillus Calmette-Guerin (BCG) in patients with superficial bladder carcinoma. Recurrence, progression and survival rates, crossover results, prognostic factors and long-term side effects were analyzed. MATERIALS AND METHODS A total of 261 patients were enrolled in the study, and the inclusion criteria were primary Tis, dysplasia G2, T1 G3 and multiple recurrent Ta/T1 G1-2 disease. Intravesical instillations of 40 mg. mitomycin C and 120 mg. Pasteur BCG, Danish strain 1331, were given for 2 years. RESULTS After a median followup of 64 months 101 of the 250 evaluable patients (42%) were disease-free. A significant difference was noted in disease-free survival with BCG (p = 0.04), which was most pronounced for stage Tis disease. No difference in tumor progression, or crude or corrected survival was found between the 2 arms. Crossover treatment was successful in 39% of patients with second line BCG and 19% with second line mitomycin C. Independent risk factors for progression were initial p53 status and stage. Only the completion of treatment was predictive of outcome for patients treated with BCG. Bladder shrinkage occurred in 2.4% of patients. CONCLUSIONS Therapy with BCG was superior to mitomycin C for recurrence prophylaxis but no difference was found for progression and survival.

Distressful symptoms after radical radiotherapy for urinary bladder cancer.

BACKGROUND Radical radiotherapy for muscle-invasive urinary bladder cancer can sterilize the tumour with preserved organ function. Here we studied symptoms, symptom distress and trade-off among long-term survivors and compared figures to those of population controls and patients who had undergone cystectomy. MATERIALS AND METHODS We identified 71 patients who had had urinary bladder cancer treated with radical radiotherapy before 1995. For comparison, 325 patients treated with radical cystectomy and urostomy, continent or non-continent, during the same period and 460 individuals randomly selected from the general population were included. Information was collected by means of an anonymously answered postal questionnaire to avoid investigator-related bias. RESULTS Answers were obtained from 58 (82%) radiated patients, 251 (85%) cystectomized patients and 310 (71%) population controls. Of the radiated patients, 74% reported little or no distress from symptoms from the urinary tract, 38% had had intercourse the previous month and 57% (men) reported they had ejaculated. Among the cystectomized patients, 13% had had intercourse and 0% (men) had ejaculated. Moderate or much distress from symptoms from the gastrointestinal tract was reported by 32% of the radiated patients, 24% of the cystectomized patients and 9% of the population controls. After radical radiotherapy, 46% of the patients were willing to accept some risk of decreased survival to become symptom-free. CONCLUSIONS About 3/4 of these long-term survivors after radical radiotherapy for bladder cancer had a functioning urinary bladder with little or no distress from the urinary tract. The prevalence of sexual dysfunction was lower than after cystectomy and the prevalence of distress from the gastrointestinal tract was comparable.

Distressful Symptoms after Radical Cystectomy with Urinary Diversion for Urinary Bladder Cancer: A Swedish Population–Based Study

Objective: To study the excess prevalence of distressful symptoms after radical surgery for urinary bladder cancer. Methods: We included all patients who underwent cystectomy due to bladder cancer before 1996 in Stockholm County. A control group was randomly selected from the general population. Information was collected by means of an anonymous postal questionnaire. Results: Completed questionnaires were returned by 310 (71%) controls and 251 (85%) cystectomized individuals. A 5–fold (reservoir) and 9–fold (conduit) increase in defecation urgency and a 4–fold (reservoir) and 6–fold (conduit) increase in faecal leakage were reported in individuals operated on. Urinary tract infection was increased 3–fold in cystectomized individuals compared with controls, during the previous year 26% of the patients reported a symptomatic infection. The perception of a reduced physical attractiveness due to disease was more than 5–fold increased in the men operated on compared to the controls. The majority, 135 out of 201 (67%), reported that they would have refused alternative bladder–sparing procedures if they decreased the prospects of survival by even as little as 1%. Conclusions: The patient’s situation after cystectomy is considerably impaired due to changed bowel and sexual function, urinary tract infections and a sense of decreased attractiveness. However, most patients are in spite of this unwilling to compromise survival.

Chromosomal and DNA patterns in transitional cell bladder carcinoma: A comparative cytogenetic and flow-cytofluorometric DNA study

Biopsy tissue from 71 bladder tumors in 57 patients was studied by chromosome analysis and flow cytofluorometry. Chromosome analysis was hampered by preparation difficulties and was successful in only 53% of the analyzed tumors. DNA analysis failed to reveal near‐diploid deviations, while the grossly aneuploid tumors generally had DNA values 10% to 15% above the numerical chromosome counts. Noninvasive tumors were diploid‐near‐diploid with occasional markers. Superficially invasive tumors were both diploid‐near‐diploid and near‐tetraploid, but with a chromosome count of only 80 in the latter cases. Deeply invasive tumors tended to be triploid on DNA analysis, and had chromosome counts in the vicinity of 60. In addition to single chromosome abnormalities, increased malignancy apparently is also associated with an increased total number of chromosomes. A tetraploid DNA level seems to represent a more stable genome, although chromosomes show gross abnormalities including markers.

A population-based study of 538 patients with newly detected urinary bladder neoplasms followed during 5 years.

OBJECTIVE To describe in detail the diagnosis and clinical course of an unselected population-based cohort of patients with newly diagnosed bladder neoplasms. MATERIAL AND METHODS A total of 538 patients registered in the Stockholm region with newly diagnosed primary bladder neoplasms (transitional cell carcinomas) in 1995 and 1996 were followed for at least 5 years. All hospitals and urology units in the region participated in the study. Treatment and follow-up were performed according to a standard-of-care programme. Routine pathological reports were used. Original case records were scrutinized on location in 2001. In addition, a tumour bank of freshly frozen tumour tissue was established. RESULTS The calculated 5-year cancer-specific survival rate for the 538 patients in the cohort was 78%. No patient (0/29) with TaG1 tumours showed progression or died of bladder cancer. Only 2/187 patients (1%) with stage Ta and grade 2A or 2B tumours died of bladder cancer. In contrast, after 5 years of follow-up, patients with TaG3 and T1G2B tumours had disease-specific death rates of 20% and 27%, respectively. The result of the first cystoscopy examination after the initial resection of non-invasive tumours was of prognostic value. Recurrent disease was present in 62% (248/402) of all patients with Ta and T1 tumours at diagnosis and patients with T1 tumours had recurrences earlier than those with Ta tumours. Moreover, 32% (35/110) of the patients who presented with T1 tumours at diagnosis progressed to muscle-invasive disease during the follow-up period. The overall prognosis for patients presenting with muscle-invasive tumours (T2+) was dismal, with 69% (80/116) of the patients dying of the disease. CONCLUSIONS We analysed a population-based cohort of patients with urinary bladder neoplasms in order to establish a clearly defined and unselected clinical series, with the main aims of comparing and evaluating the clinical utility of new molecular biology techniques. In the present series, TaG1 tumours behaved benignly. The disease-specific mortality rate was low for initial TaG2 tumours, intermediate for initial TaG3 and T1 tumours and high for initial T2+ tumours.

Alternating Mitomycin C and BCG Instillations versus BCG Alone in Treatment of Carcinoma in Situ of the Urinary Bladder: A Nordic Study

OBJECTIVES To evaluate whether, in patients with carcinoma in situ (CIS) of the urinary bladder, alternating instillation therapy with mitomycin C (MMC) and bacillus Calmette-Guerin (BCG) was more effective and less toxic than conventional BCG monotherapy. METHODS Patients were stratified prospectively for primary, secondary, and concomitant CIS and randomized to one of two regimens. Patients in the alternating group received six weekly intravesical instillations of MMC 40 mg, followed by alternating monthly instillations of BCG 120 mg and MMC for one year. In the monotherapy group, only BCG was instilled on the same schedule. RESULTS Of 323 enrolled patients, 304 were eligible for analysis. After an overall median follow-up of 56 months, the Kaplan-Meier disease-free estimate for BCG monotherapy was significantly better than that for alternating therapy (p=0.03; log rank test). Risk for progression appeared lower in the BCG monotherapy group (p=0.07), but no differences existed in survival. Besides the regimen, CIS category also predicted outcome to some extent. BCG monotherapy caused significantly more local side-effects and premature cessation of instillation treatment than did the alternating therapy. However, no differences were observed in the number of serious side-effects. CONCLUSION One-year BCG monotherapy was more effective than the alternating therapy for reducing recurrence and compared well with the best regimens reported from substantially smaller series. The alternating therapy was better tolerated.

Loss of heterozygosity in tumour-adjacent normal tissue of breast and bladder cancer

Normal tumour-adjacent breast tissue samples from 12 breast cancer patients forming six monozygotic twin pairs were analysed for loss of heterozygosity (LOH) on chromosomes 1, 13 and 17. 7 patients showed LOH at one or more markers. Each of them had a different LOH pattern. Only one twin pair showed LOH at the same locus, but the twins had lost a different allele. Multiple (n=1-13), histologically normal samples were collected from 6 bladder cancer patients and analysed for LOH on chromosomes 3 and 9. On chromosome 9, all 6 patients analysed showed LOH in at least one sample and one marker. Four of them also showed LOH on chromosome 3. Samples surrounding different tumours of a given patient resembled each other. More heterogeneity was seen between the patients, even though they shared some similarities in LOH clustering. The results demonstrate that tumour-adjacent normal tissues already harbour genetic changes typical for tumours. These alterations can reveal the earliest changes leading to tumorigenesis.

Intravesical Therapy with Adriamycin in Patients with Superficial Bladder Tumors

An 80-mg dose of adriamycin was given intravesically once a month to 58 patients with superficial transitional cell tumor of the bladder. Complete cytological remission was achieved in all 11 patients with previously untreated, flat carcinoma in situ lesions. In 19 carcinoma in situ patients, who were previously treated by other means, cytological remission occurred in 74%. In T1 and T2 papillary tumor remission occurred in 65 and 20%, respectively. Minor local side effects were observed.

Deoxyribonucleic Acid Profile and Tumor Progression in Primary Carcinoma in Situ of the Bladder: A Study of 63 Patients with Grade 3 Lesions

In 63 patients with primary grade 3 carcinoma in situ of the bladder flow cytometric deoxyribonucleic acid (DNA) analysis was performed at diagnosis and during an average followup of 63 months. The results of DNA measurements were related to disease progression, that is invasive tumor and/or metastatic disease. The DNA histograms were classified as diploid (2 patients) or aneuploid (61). A total of 3 categories of aneuploid tumors with different prognostic significance could be defined: 1) carcinoma in situ with 1 aneuploid cell population at diagnosis and with no change to multiple aneuploid cell populations throughout observation, 2) carcinoma in situ with 1 aneuploid cell population at diagnosis but with a later change to multiple aneuploid cell populations and 3) carcinoma in situ with multiple aneuploid cell populations already at diagnosis. At 5 years the progression-free survival for the 3 categories was 94%, 43% and 20%, respectively. Over-all, of the patients with multiple aneuploid cell populations (categories 2 and 3) 76% had progression, in contrast to 19% of those in category 1 (p less than 0.0005). In category 2 development of multiple aneuploid cell populations preceded progression in 8 of 11 progressive cases by an average of 20 months. Therefore, the occurrence of multiple aneuploid cell populations must be considered as a sign of high aggressiveness. We conclude that flow cytometric DNA analysis is a potent predictor of prognosis in cases of primary carcinoma in situ of the bladder.

Relative importance of sources of symptom-induced distress in urinary bladder cancer survivors

OBJECTIVE The influence of specific symptoms on emotions and social activities in the individual patient varies. Little is known about this variation in urinary bladder cancer survivors (in other words, about the relative importance of sources of symptom-induced distress). METHODS We attempted to enroll 404 surgical patients treated with cystectomy and a conduit or reservoir in four Swedish towns (Stockholm, Orebro, Jönköping, Linköping), 101 surgical patients treated with cystectomy and orthotopic neobladder at the Herlev Hospital in Copenhagen, Denmark, and 71 patients treated with radical radiotherapy for bladder cancer, as well as 581 men and women controls in Stockholm and Copenhagen. An anonymous postal questionnaire was used to collect the information. RESULTS A total of 503 out of 576 (87%) treated patients and 422 out of 581 (73%) controls participated but 59 patients were excluded. The primary source of self-assessed distress among cystectomised patients was compromised sexual function; reduced intercourse frequency caused great distress in 19% of the conduit patients, 20% of the reservoir patients and 19% of the bladder substitute patients. The primary source of self-assessed distress in patients treated with radical radiotherapy was symptoms from the bowel; 17% reported great distress due to diarrhoea, 16% due to abdominal pain, 14% due to defecation urgency and 14% due to faecal leakage. The highest proportion of subjects being distressed was 93% (substantial: 43%, moderate: 29% and little: 21%) for treated upper or lower urinary retention (indwelling catheter or nephrostomy). CONCLUSION The distress caused by a specific symptom varies considerably and the prevalence of symptoms causing great distress differs between treatments in bladder cancer survivors. It is possible that patient care and clinical research can be made more effective by focusing on important sources of symptom-induced distress.