COMBINED INTRAARTERIAL CISPLATIN INFUSION AND RADIATION THERAPY FOR INVASIVE BLADDER CANCER

Combined intraarterial cisplatin infusion and radiation therapy were performed as the initial treatment for 23 patients (mean age: 70 years) with invasive bladder cancers (T2 in 17, T3 in 6) who were suitable for total cystectomy. Of these patients, five who had multiple invasive cancers without laterality had their intrapelvic hemodynamics altered by embolizing a contralateral internal iliac artery. Cisplatin (50 mg) was infused into the internal iliac artery through a subcutaneous reservoir twice a week over three weeks while concurrent radiation therapy with 30 Gy, delivered in 15 fractions, was performed. Additional cisplatin infusions were given in six patients. After this combined therapy, total cystectomy and ileal conduit was performed in six patients and transurethral resection of bladder tumor (TURBT) in 17. Two of the patients who underwent total cystectomy were found to exhibit a complete response. Therefore, the overall response rate was 87%, including 13 complete responses and seven partial responses. The complete response rates in patients with clinical stage T2 and T3 disease were 53 and 67%, respectively. The complete response rate was slightly higher in patients with a non-papillary cancer than in those with a papillary one. Toxic reactions included a decrease in bladder capacity in two patients and severe diarrhea due to methicillin-resistant Staphylococcus aureus colitis in one. Other forms of toxicity, including nausea, vomiting, neurotoxicity in the gluteal region, nephrotoxicity and myelosuppression, were tolerable. All but one of the patients are alive. This patient died of distant metastasis and seven other patients had a local recurrence of bladder cancer. One patient who developed invasive bladder cancer reaching the prostatic urethra underwent total cystectomy and ileal conduit. One who had a recurrence at the same site as the previous tumor underwent partial cystectomy. Five patients who had superficial bladder cancer were easily controlled by TURBT. Finally, bladder function was preserved in 65% of all patients in this study at a mean follow-up time of 29 months. We conclude that combined intraarterial cisplatin infusion and radiation therapy is useful for the initial treatment of invasive bladder cancer because this combined therapy provides a favorable quality of life with the preservation of bladder function. Further detailed follow-up is necessary to determine whether this therapy also has a prophylactic effect on the recurrence of bladder cancer.     

RACE AS AN INDEPENDENT PREDICTOR OF OUTCOME AFTER TREATMENT FOR LOCALIZED PROSTATE CANCER

PURPOSE: We analyze the outcome after prostatectomy or radiotherapy for localized prostate cancer with respect to race. MATERIALS AND METHODS: A total of 2,219 consecutive patients with prostate cancer were treated with radiotherapy (1,183) or radical prostatectomy (1,036) between June 1986 and June 1998. Initial prostate specific antigen (PSA) and biopsy Gleason scores were available in all cases. Androgen deprivation was used in 22% of men (492). Of the patients 86% (1,901) were white, including Hispanic and Asian, and 14% (318) were black. The outcomes of interest were biochemical relapse-free survival, clinical relapse-free survival and overall survival. Median followup was 24 months (range 2 to 140). RESULTS: There was no difference in the incidence of familial prostate cancer, patient age at presentation, clinical stage or biopsy Gleason scores between black and white men. However, black men had higher initial PSA levels (median 13.3 versus 8.6 for white men, p<0.001). The 5-year biochemical relapse-free survival rate was 59% for the entire group, 54% (95% confidence interval 44 to 63) for black men and 61% (95% confidence interval 57 to 65) for white men (p = 0.11). Multivariate analysis was performed for the variables of age, race, family history of prostate cancer (brother or father), initial PSA, biopsy Gleason sum, clinical T stage, treatment modality and androgen deprivation. Familial prostate cancer (p = 0.001), higher T stage (p<0.001), higher initial PSA (p<0.001), higher biopsy Gleason score (p<0.001) and use of androgen deprivation (p = 0.001) were independent predictors of biochemical failure and all other factors, including race, were not (p = 0.46). The projected 10-year clinical relapse-free survival rate was 74% for the entire group, and was identical for black and white men (p = 0.77). The projected 10-year overall survival rate for black and white men was 92 and 79%, respectively (p = 0.62). CONCLUSIONS: We have demonstrated a statistically nonsignificant trend for higher biochemical failure rates in black men presenting with localized prostate cancer. This trend could be due to the higher pretreatment PSA levels in black patients. Treatment recommendations should not differ with respect to race.     

BREAST CANCER: THE ROLE OF RADIATION THERAPY AFTER TREATMENT BY CONSERVATIVE SURGERY

The role of conservative surgery (CS) as definitive treatment of invasive breast cancer has not been established. Previous studies have demonstrated high rates of local tumour recurrence if CS is not followed by radiotherapy (RT). At present, it is impossible to identify subsets of patients who may be at acceptably low risk of recurrence after CS. The treatment of breast cancer by CS alone remains an important research question as this may avoid over-treatment by radiation for some patients. In Australia, a trial has been proposed by the ANZ Breast Cancer Trials Group, comparing CS alone to CS + RT. This paper reviews all available data on CS alone in order to stimulate debate as to the appropriateness of the trial and its end-points. Given that all prospective randomized trials have failed to show a survival disadvantage for CS alone it is essential to consider the value of all outcomes after CS or CS + RT. The conventional end-points proposed in the Australian study (mastectomy rate, disease-free survival (DFS) and overall survival (OS)) are selective. Without the addition of quality of life measures, the utilities of the strategies addressed in the trial cannot be evaluated. Data are presented on the desirability (utility) of the alternative approaches of CS or CS + RT based on data obtained from a questionnaire completed by Westmead Hospital staff. This preliminary study indicates that the majority of respondents to the questionnaire perceived that the strategy of CS + RT to have a higher utility than the strategy of CS alone.     

INTRAVESICAL ANTITUMOR THERAPY IMMEDIATELY AFTER TRANSURETHRAL RESECTION OF BLADDER CANCER

Patients with superficial transitional cell cancer of the urinary bladder were entered into a randomized trial to compare the effects of immediate and short-term postoperative instillation of peplomycin sulfate with simple irrigation. Although the recurrence-free rate of the 46 peplomycin-treated patients was lower, the difference was not significant. Repeated washing of the bladder at the end of transurethral resection might partly replace the role of cytotoxic therapy.     

RADIATION THERAPY OF GLOTTIC CARCINOMA: PETER MacCALLUM CANCER INSTITUTE EXPERIENCE

The medical records of patients with T1NO, T2NO and T3NO squamous cell carcinomas of the glottis treated at the Peter MacCallum Cancer Institute between January 1983 and October 1988 were retrospectively reviewed. One hundred and twenty-seven patients were identified. There were 93 T1, 26 T2 and eight T3 tumours. These patients were treated with curative radiotherapy (60–70 Gy). The survival from glottic cancer of patients with T1, T2 and T3 turnours at 5 years was estimated to be 97, 62 and 100% respectively. The local disease free survival for T1 and T2 disease at 5 years was estimated to be 82 and 65% respectively. The local disease free survival for T3 tumours at 2 years was estimated to be 63% with 5 year survival not yet reached. The surgical salvage rates for 24 radiotherapy failures were 77, 25 and 66% for T1, T2 and T3 turnours respectively. Radiotherapy remains the treatment of choice for T1 tumours and a viable alternative to primary laryngectomy in more advanced glottic tumours, with salvage surgery in reserve.     

INTRAVESICAL THERAPY FOR THE TREATMENT OF NEUROGENIC BLADDER IN CHILDREN

Background : Oral pharmacotherapy has been commonly used as an adjunct to clean intermittent catheterization (CIC) in the treatment of neurogenic bladder in order to achieve continence, but may be associated with unacceptable side effects. The authors' experience with sterile intravesical preparations of oxybutynin hydrochloride and ephedrine in children is reported here. Methods : Patients requiring CIC for neurogenic bladder but with incontinence that was unresponsive to standard oral therapy or that was associated with severe systemic side effects were studied over a 1-year period. Clinical, radiological and urodynamic assessments were made prior to commencing treatment with intravesical oxybutynin hydrochloride. Patients who remained incontinent with poor internal sphincter muscle tone had intravesical ephedrine added. Results : Seven patients were involved in the study over a 1-year period. Two patients became continent and one patient had an improvement in upper tract dilatation. One patient had a limited improvement with oxybutynin alone but became continent with the addition of ephedrine. Three patients had no response to treatment. There were few side effects. Conclusion : Intravesical agents have a role in the management of paediatric neurogenic bladder for those children with significant adverse sequelae from oral pharmacotherapy who would otherwise require surgical intervention. Intravesical therapy is a safe technique in children with sterile preparations. Further investigation of this modality should be pursued.     

FAMILIAL BLADDER CANCER IN THE NATIONAL SWEDISH FAMILY CANCER DATABASE

PURPOSE: We analyzed the risk of bladder cancer in offspring according to parental and sibling cancer using the national Swedish Family Cancer Database. MATERIALS AND METHODS: Cancer data were obtained from the Swedish Cancer Registry for 1958 to 1996, including 2,105 cases of bladder cancer in offspring. The standardized incidence ratio was used to measure cancer risk in offspring according to familial cancer status. RESULTS: The incidence ratio of bladder cancer increased in Sweden from 1958 to 1996 and it was 3 to 4-fold higher in males than in females. We identified 65 families in which the parents and offspring had bladder cancer with a familial risk of 1.35 (95% confidence interval [CI] 0.97 to 1.79) in sons and 2.29 (95% CI 1.46 to 3.29) in daughters. Discordant cancer sites associated with bladder cancer in the 2 generations were the kidney and thyroid with a standardized incidence ratio of 1.58 (95% CI 1.18 to 2.05) and 1.89 (95% CI 1.00 to 3.05), respectively. Sibling risk was higher compared with offspring risk with a standardized incidence ratio of 2.96 (95% CI 1.41 to 5.08) and in males there was a statistically significant ratio of sibling-to-offspring risk of 2.66 (95% CI 1.29 to 5.45). Patient age at onset modified the familial risk. The highest familial risk of 7.26 (95% CI 2.61 to 14.24) was observed in the brothers of bladder cancer probands diagnosed before age 45 years. CONCLUSIONS: The relatively high ratio of sibling-to-offspring risk as well as observed gender specific effects in bladder cancer may reflect an X linked susceptibility gene.     

PHOTODYNAMIC THERAPY IN THE TREATMENT OF SUBCUTANEOUSLY IMPLANTED HUMAN BLADDER TUMOUR

Photodynamic therapy (PDT) is an experimental treatment modality for malignant tumours. The effect of PDT with haematoporphyrin derivative (HpD) was studied using a human bladder tumour (BL-17) which was implanted subcutaneously (s.c.) into immunodeficient Balb/c nude mice. This model is only suitable for short-term investigation of PDT because of the high mortality that arises due to the immune deficiency of the animals. In a short-term observation (2 weeks post-treatment), HpD sensitized PDT was effective in the control of tumour growth, with 71 % of tumours cured. The effect of PDT was found to be highly dependent on doses of HpD and/or the activating laser light. The comparison of PDT effects of the gold metal vapour laser (GMVL) and argon ion pumped dye laser (AIPDL) indicated that no significant difference exists between these two different laser sources for PDT. The irradiation with laser light alone and the administration of HpD alone had no significant effect on tumour growth.     

TREATMENT OF ADVANCED BLADDER CANCER USING C/S-PLATINUM

Cis-platinum (120 mg/m²) was given to 14 patients with locally inoperable or metastatic transitional cell carcinoma of the bladder. Five patients (35%) showed a response, two complete (14%), and three partial (21%). Nine patients (65%) had no response. The median duration of survival was 3.5 months for non-responders; 6.5 months for partial responders; and 25 months for complete responders. The side effects and implications of treatment using this agent are discussed.     

OVER-EXPRESSION OF METALLOTHIONEIN AND DRUG-RESISTANCE IN BLADDER CANCER

Metallothionein (MT) in tumor cells has been implicated as one of the factors involved in mechanisms of resistance to anti-cancer drugs, including cis-diaminedichroloplatinum (CDDP) and adriamycin (ADM). The relationship between the expression of MT and chemotherapy with anti-cancer drugs was studied in CDDP- and ADM-resistant human bladder cancer cell lines and tissue samples from clinical cases. In drug-resistant cell lines (T-24/ADM, CI-7/CDDP) established in our laboratory, MT expression was studied by immunohistochemistry using the avidin-biotin peroxidase complex (ABC) method and radioimmunoassay (RIA), using anti-MT antibody. In addition, other potentfal mechanisms of drug resistance, such as P-glycoprotein expression were examined and the levels of reduced glutathione (GSH), oxidized glutathione (GSSG) and glutathione-S-transferase (GST) determined in these cell lines. The results of these investigations demonstrate that the expression of MT in resistant cell lines increased 2.1- and 2.5-fold when compared with parent cell lines (CI-7, T-24). GSH, GSSG and GST levels were unchanged and P-glycoprotein was not over-expressed. A total of 120 tissue samples from 35 clinical cases of bladder cancer, before and after chemotherapy, were stained for MT which was detected in 10 of the 35 cases before chemotherapy. The incidence of MT expression was significantly higher (p less than 0.05) in cases with lower pathological tumor grades. By analyzing the MT staining after chemotherapy in the cases whose MT staining was negative before chemotherapy, it was found that cases receiving continuous administration (intravesical chemotherapy or peroral chemotherapy) showed a higher incidence (9/13) of positive staining for MT, than patients receiving intermittent administration (intravenous chemotherapy) (1/8), (p less than 0.05). These results demonstrate that: 1) a correlation exists between MT expression and tumor differentiation and 2) repetitive and continuous administration of anti-cancer drugs results in increased MT expression in bladder cancer cells. MT expression may therefore be one of the mechanisms by which urothelial tumors acquire resistance to anti-cancer drugs.     

LIMITATIONS OF RADIOTHERAPY IN THE DEFINITIVE TREATMENT OF SQUAMOUS CARCINOMA OF THE TONSILLAR FOSSA

Between 1970 and 1990, 104 patients with squamous cell carcinoma (SCC) of the tonsil were treated. The median age was 58 years and 80% of patients were males. Distribution among clinical stages was: stage I, 19 patients; stage II, 12 patients; stage III, 23 patients; and stage IV, 48 patients. More than 70% of patients had initial radiotherapy as definitive treatment irrespective of stage, reflecting the treatment philosophy over much of this period. The overall survival rate was 26% at 5 years, with survival being significantly affected by T stage, clinical stage and age. Clinical node status did not significantly affect survival rates. Good local control of T₁N₀ cancers was achieved with radiotherapy alone, but patients with more advanced cancers did poorly. We have now moved away from a non-selective policy and use initial surgery combined with postoperative radiotherapy in most patients, reserving radiotherapy alone for mainly early tonsil cancers.     

BACILLUS CALMETTE-GUERIN (BCG) IMMUNOTHERAPY FOR BLADDER CANCER: REVIEW OF COMPLICATIONS AND THEIR TREATMENT

Background: Intravesical bacillus Calmette–Guerin (BCG) is widely used in the management of bladder cancer but because it is a living organism, local and disseminated infection may result. Methods: A prospective assessment of complications of this therapy in 200 patients in Queensland was performed. A review of management of complications of intravesical BCG was also carried out. Results: Major side effects were rare. Cystitis was the most common side effect, being seen to some degree in all patients, although only forcing cessation of BCG therapy in two patients. Two patients developed persistent cystitis necessitating institution of isoniazid and rifampicin. Two patients had culture-proven bladder infection that presented several months after the BCG treatment. These patients also responded to two-drug antituberculous therapy. While low-grade fever is very common with this therapy, seven patients (3.5%) had fevers of > 39°C within 48 h of receiving BCG. Fevers may be an indication of severe disseminated mycobacterial infection, which has a high mortality, so it needs to be treated aggressively. Alternatively bacterial sepsis with Gram-negative bacterial pathogens or a hypersensitivity reaction to BCG may cause this degree of fever, and cannot be rapidly distinguished from fulminant mycobacterial infection. One patient in the present series developed pneumonia attributed to mycobacterial dissemination. Conclusions: The key to appropriate management of complications of BCG therapy is awareness of their possibility, even months or years after the therapy has been given. Appropriate empirical therapy in acute situations and mycobacterial culture in chronic situations can then be performed.