Polymorphisms of GSTP1 and related genes and prostate cancer risk.

Glutathione S-transferase P1 (GSTP1) is markedly downregulated in prostate cancer and prostatic intraepithelial neoplasia compared to normal prostate tissue. Downregulation of GSTP1 may, therefore, be an early event in prostate carcinogenesis. An A-->G polymorphism at nucleotide 313 results in an amino acid substitution (Ile105Val) in the substrate binding site of GSTP1 and reduces catalytic activity of GSTP1. In a study of 36 prostate cancer patients, Harries et al. reported that the Ile/Ile genotype is associated with a decreased risk of prostate cancer (odds ratio 0.4 (0.17-0.82)). We sought to confirm this finding and to examine the impact of this polymorphism together with several related polymorphisms implicated as risk factors for carcinogen-associated malignancies. One hundred and seventeen patients with prostate adenocarcinoma and 183 population-based controls were recruited to this case-control study. Genotyping of the GSTP1 (Ile105Val), GSTM1 (null), GSTT1 (null) and CYP1A1 (Ile462Val) genes was performed using polymerase chain reaction (PCR) based techniques on DNA prepared from peripheral blood. A questionnaire was used to collect demographic information from each subject. Cases were significantly older (P<0.0001) and had significantly greater family history of prostate cancer (P<0.0001), confirming known risk factors for this disease. By chi(2) analysis, none of the genotype distributions varied among cases and controls. Using a logistic regression model to control for known risk factors we were also unable to demonstrate a significant association with prostate cancer for any of the polymorphisms tested. This population fails to identify a relationship between the above polymorphisms and prostate adenocarcinoma.

Association of codon 72 polymorphism of p53 with lower prostate cancer risk.

BACKGROUND: A common germline polymorphism of p53 produces a protein with an Arg to Pro change at codon 72. This Pro variant has altered biochemical properties suggesting altered cancer susceptibility. METHODS: A case control study with 115 men with prostate cancer and 181 community control male subjects was conducted. Demographics, family history of cancer, and blood were obtained. Codon 72 genotypes were determined using PCR. RESULTS: The Pro/Pro genotype was associated with a markedly lower risk of prostate cancer (OR = 0.23, CI = 0.07-0.79, P = 0.012). Similar reduction in risk was observed when the analysis was limited to Caucasian subjects (86% of total). Reduction in risk remained significant in a logistic regression model after correcting for age and family history of prostate cancer (OR = 0.14, CI = 0.03-0.71, P = 0.017). CONCLUSIONS: Men with the p53 codon 72 Pro/Pro genotype appear to be at reduced risk of prostate cancer.

Phase II study of weekly docetaxel in symptomatic androgen-independent prostate cancer.

BACKGROUND: This study sought to define the activity and toxicity of weekly docetaxel in patients with androgen-independent prostate cancer and cancer-related pain. PATIENTS AND METHODS: Twenty-five patients were treated with docetaxel 36 mg/m2 i.v. administered weekly for six consecutive weeks followed by two weeks without treatment. This eight-week treatment cycle was repeated until progression or unacceptable toxicity. Endpoints included palliative response (a 2-point reduction on the 6-point Present Pain Intensity scale without an increase in analgesic consumption or a 50% decrease in analgesic use without an increase in pain), PSA response (a 50% decrease maintained at least four weeks), measurable disease response, survival, and toxicity. RESULTS: Twelve of 25 patients (48%, 95% confidence interval (95% CI): 28%-68%) had a palliative response. Eleven of the 24 patients who entered with an elevated PSA (46%, 95% CI: 25%-67%) had a PSA response. Two of five patients with measurable disease had a partial response. Toxicity of therapy was modest with no treatment-related mortality. Twenty-five percent of patients experienced a grade 3 or 4 hematologic toxicity and 36% of patients experienced a grade 3 non-hematologic toxicity. CONCLUSIONS: Weekly docetaxel is well tolerated in patients with androgen-independent prostate cancer and has significant activity as measured by relief of pain, reduction in PSA, and reduction in measurable disease.

Weekly high-dose calcitriol and docetaxel in advanced prostate cancer.

Novel treatment regimens for androgen-independent prostate cancer (AIPC) are needed because currently available approaches have not been shown to improve survival. Docetaxel provides a good foundation for new therapeutic combinations because of its promising single-agent activity against prostate cancer and its favorable tolerability profile, particularly when administered weekly. In both tissue culture and animal models of prostate cancer, calcitriol (the biologically active form of vitamin D) enhanced the activity of docetaxel, paclitaxel, and platinum compounds. These effects were particularly notable at supraphysiologic calcitriol concentrations. Weekly calcitriol dosing is associated with minimal toxicity and permits substantial dose escalation over the daily schedule. A weekly calcitriol dose of 0.5 microg/kg produces plasma calcitriol levels 25-fold higher than the physiologic range. In a preclinical study at the Oregon Health Sciences University, calcitriol 5 micromol/L plus docetaxel 0.15 nmol/L was at least additive in inhibiting PC-3 colony formation. A phase II study is evaluating weekly administration of 0.5 microg/kg calcitriol orally on day 1 followed by 36 mg/m(2) docetaxel intravenously on day 2 in patients with AIPC (repeated for 6 consecutive weeks of each 8-week cycle). At the time of a preliminary analysis, 11 patients had been enrolled and were actively being treated. All 5 patients who had completed 8 weeks of calcitriol/docetaxel treatment achieved prostate-specific antigen (PSA) reductions of > or =50%. Two of these patients had confirmatory assessments, both meeting the formal PSA response criteria. Treatment has been well tolerated, with 1 patient experiencing a self-limited grade 3 toxicity and no patients experiencing grade 4 or 5 toxicities.

Phase II trial of bicalutamide in patients with advanced prostate cancer in whom conventional hormonal therapy failed: a Southwest Oncology Group study (SWOG 9235).

OBJECTIVES: To determine the efficacy and tolerability of bicalutamide in patients with advanced prostate cancer with progression after conventional hormonal therapy. METHODS: Fifty-two patients received bicalutamide, 150 mg once daily, as second-line therapy after progressing following treatment with orchiectomy or luteinizing hormone-releasing hormone analogue or diethylstilbestrol, alone or in combination. Patients had measurable (n = 8) or assessable (n = 44) disease, a Southwest Oncology Group performance status of 0 to 2, and no prior antiandrogen therapy or chemotherapy. The objective response to treatment was assessed every 12 weeks; symptoms and pain were assessed monthly with questionnaires for 6 months. RESULTS: There was evidence of palliation with three measures of pain and, to a lesser extent, with a measure of overall symptom status after 3 months of taking bicalutamide. No complete or partial responses occurred. However, 9 (20%) of 44 subjects with adequate prostate-specific antigen data had a 50% or higher decrease in their prostate-specific antigen levels, which did not correlate with symptom improvement. The median survival time was 15 months. The most common side effects were hot flashes (23%) and nausea (21%). CONCLUSIONS: These data suggest that bicalutamide decreases pain and improves symptom status in patients with prostate cancer in whom first-line hormonal therapy failed.

The prognostic significance of S-phase analysis in stage Ta/T1 bladder cancer. A Southwest Oncology Group Study.

OBJECTIVES: An intergroup study (SWOG 8795) comparing two forms of adjunctive therapy (immuno and chemo), bacillus Calmette-Guerin (BCG) and mitomycin C (MMC), furnished preregistration index tumors for 244 patients with superficial, papillary stage Ta/T1 TCC. These were examined by flow cytometry to learn whether DNA ploidy or proliferation (low vs high S-phase fraction (SPF) helped to predict disease recurrence or progression. METHODS: Cell cycle analysis using commercially available (Multicycle) programs was performed on 249 Ta/T1 bladder cancers. Tumor grade, available for 223 cases, was assigned by a single study pathologist. The SWOG statistical office reviewed follow-up information and other data and performed statistical analysis. RESULTS: Disease recurrence occurred in half the cases studied. The most parsimonious model predictive of recurrence included only treatment arm and tumor grade, with the MMC arm and tumor grade greater than I indicating worse prognosis (p = 0. 014). Neither ploidy nor SPF predicted recurrence-free survival or contributed prognostic information that was additive to tumor grade. Within 5 years of follow-up, disease progression or death from bladder cancer occurred for 29/223 (13%) of patients. The most parsimonious model for progression-free survival included only grade greater than I (p<0.001) and high SPF (p = 0.029) (relative risk: tumor grade, 4.3, high SPF, 1.9). CONCLUSIONS: Knowledge of tumor proliferation (low versus high SPF) contributes prognostic information about tumor progression that is additive to tumor grade.

Maintenance bacillus Calmette-Guerin immunotherapy for recurrent TA, T1 and carcinoma in situ transitional cell carcinoma of the bladder: a randomized Southwest Oncology Group Study.

PURPOSE: Bacillus Calmette-Guerin (BCG) immunotherapy has been widely accepted as the optimal treatment for carcinoma in situ and high grade superficial transitional cell carcinoma. However, controversy remains regarding the role of maintenance therapy, and its long-term effect on recurrence and progression. MATERIALS AND METHODS: All patients in the study had transitional cell carcinoma of the bladder with carcinoma in situ or an increased risk of recurrence. The criteria for increased risk were 2 or more episodes of tumor within the most recent year, or 3 or more tumors within 6 months. At least 1 week following biopsy of carcinoma in situ and resection of any stage Ta or T1 transitional cell tumors 660 patients were started on a 6-week induction course of intravesical and percutaneous Connaught BCG. Three months following initiation of BCG induction therapy 550 consenting patients were stratified by purified protein derivative skin test and the presence of carcinoma in situ, and then randomized by central computer to receive BCG maintenance therapy (maintenance arm) or no BCG maintenance therapy (no maintenance arm). Maintenance therapy consisted of intravesical and percutaneous BCG each week for 3 weeks given 3, 6, 12, 18, 24, 30 and 36 months from initiation of induction therapy. The 384 eligible patients who were disease-free at randomization constitute the primary intent to treat analytic group because they could be followed for disease recurrence. All patients were followed for adverse effects of treatment, recurrence, disease worsening and survival. RESULTS: No toxicities above grade 3 were noted in the 243 maintenance arm patients. The policy of withholding maintenance BCG from patients with increased side effects may have diminished the opportunity to observe severe toxicity. Estimated median recurrence-free survival was 35.7 months (95% confidence interval 25.1 to 56.8) in the no maintenance and 76.8 months (64.3 to 93.2) in the maintenance arm (log rank p<0.0001). Estimated median time for worsening-free survival, defined as no evidence of progression including pathological stage T2 disease or greater, or the use of cystectomy, systemic chemotherapy or radiation therapy, was 111.5 months in the no maintenance and not estimable in the maintenance arm (log rank p = 0.04). Overall 5-year survival was 78% in the no maintenance compared to 83% in the maintenance arm. CONCLUSIONS: Compared to standard induction therapy maintenance BCG immunotherapy was beneficial in patients with carcinoma in situ and select patients with Ta, T1 bladder cancer. Median recurrence-free survival time was twice as long in the 3-week maintenance arm compared to the no maintenance arm, and patients had significantly longer worsening-free survival.

Examining the immune response in sentinel lymph nodes of mice and men.

Recently, it was recognized that an immune response develops along one of two major pathways. One leads to a destructive immune response (type 1), while the alternative leads to a nondestructive immune response (type 2). Our studies in animal models suggest that therapeutic vaccines induce a tumor-specific type 1 immune response while ineffective vaccines induce a type 2 response. These results have led us to examine the immune response in sentinel lymph nodes draining tumor vaccines of patients entered onto clinical trials for melanoma, breast and renal cell cancer.

Penile stump advancement as an alternative to perineal urethrostomy after penile amputation.

PURPOSE: We describe a method for avoiding perineal urethrostomy, and maintaining penile cosmesis and function after penile amputation. MATERIALS AND METHODS: Penile reconstruction was performed in 1 patient with traumatic total amputation of the penis and 1 undergoing near total penectomy for carcinoma by advancing the penile stump and covering the resultant phallus with rotational full thickness scrotal flaps. RESULTS: Both patients were able to void while standing, and have intact sensation and erectile capability in the residual neophallus. CONCLUSIONS: Perineal urethrostomy is not necessary after penopubic penile amputation. Advancement of residual cavernosal tissue and skin coverage with scrotal flaps minimize altered body image, and maintain sensation and normal voiding position.

Bilateral orchiectomy with or without flutamide for metastatic prostate cancer.

BACKGROUND: Combined androgen blockade for the treatment of metastatic prostate cancer consists of an antiandrogen drug plus castration. In a previous trial, we found that adding the antiandrogen flutamide to leuprolide acetate (a synthetic gonadotropin-releasing hormone that results in medical ablation of testicular function) significantly improved survival as compared with that achieved with placebo plus leuprolide acetate. In the current trial, we compared flutamide plus bilateral orchiectomy with placebo plus orchiectomy. METHODS: We randomly assigned patients who had never received antiandrogen therapy and who had distant metastases from adenocarcinoma of the prostate to treatment with bilateral orchiectomy and either flutamide or placebo. Patients were stratified according to the extent of disease and according to performance status. RESULTS: Of the 1387 patients who were enrolled in the trial, 700 were randomly assigned to the flutamide group and 687 to the placebo group. Overall, the incidence of toxic effects was minimal; the only notable differences between the groups were the greater rates of diarrhea and anemia with flutamide. There was no significant difference between the two groups in overall survival (P=0.14). The estimated risk of death (hazard ratio) for flutamide as compared with placebo was 0.91 (90 percent confidence interval, 0.81 to 1.01). Flutamide was not associated with enhanced benefit in patients with minimal disease. CONCLUSIONS: The addition of flutamide to bilateral orchiectomy does not result in a clinically meaningful improvement in survival among patients with metastatic prostate cancer.

A rational approach to managing stage I nonseminomatous germ cell cancer.

Regardless of the treatment option selected for management of low-stage germ cell cancer, ultimate survival is nearly identical. Treatment-related morbidity is very low regardless of management modality and the individual patient can expect similar physical limitations owing to therapy. The overall difference in loss of productivity between treatment programs varies by little more than 1 week. The cost of treatment is similar for all methods, although there is a definite financial advantage to surveillance, less so for selective surveillance, when compared with other forms of management. Socioeconomic factors are of importance when managing limited resources for a large population, but are of less concern to an individual, especially when the mean differences in per patient costs vary by only $5000. Because of these close similarities in efficacy, morbidity, and costs treatment decisions should be individualized. A responsible and reliable patient can be managed safely by selective surveillance. Those individuals considered to be less self-motivated to pursue intensive care should be managed by primary therapy. Without more information regarding the long-term outcomes associated with primary adjuvant chemotherapy, primary adjuvant RPLND, where experienced surgical support is available, is the preferred management for low-stage germ cell cancer in patients selected for, or electing, active treatment rather than surveillance. Active investigations examining the role of medical management in this population should be continued. Our preferred choice of initial management is to offer selective surveillance to appropriate patients and modified RPLND to the remainder.

Preservation of the anterior urethral ligamentous attachments in maintaining post-prostatectomy urinary continence: a comparative study.

PURPOSE: The impact was determined on post-prostatectomy urinary incontinence of a technique preserving the anterior attachments of the proximal urethra to the posterior pubis by comparison to the results of other surgical methods. MATERIALS AND METHODS: Urinary continence in 51 patients undergoing preservation of the anterior urethral attachments was compared to that of 70 patients undergoing an anatomical prostatectomy with resection of the bladder neck, 55 patients with preservation of the bladder neck and 14 patients undergoing a dorsal vein gathering procedure. Comparisons were made for rate of total continence, time to return of continence, incidence of extra organ disease and operative blood loss. RESULTS: Total continence at 1 year was 84.3%, 89.1%, 85.7% and 100% respectively. Immediate total continence after catheter removal was seen in 25.5% after preservation of the anterior urethral attachments, 80.4% at 3 months compared to 41.4%, 50.9% and 50% at 3 months for anatomical prostatectomy with bladder neck resection, preservation and dorsal vein gathering. Clinical staging with the incidence of specimen confined disease was similar in all groups. Mean operative blood loss was 1,031 ml. for those patients undergoing anatomical prostatectomy compared to 681 ml. for those with preservation of the anterior urethral attachments. CONCLUSIONS: Preservation of the anterior urethral attachments results in improved urinary continence and lower operative blood loss without an increase in positive surgical margins.

Bleeding ileal conduit stomal varices: diagnosis and management using transjugular transhepatic angiography and embolization.

An uncommon complication of ileal conduit urinary diversion is bleeding varices at the stoma site. Variceal formation is a complication of portal hypertension, which is most commonly due to intrinsic liver disease. Problematic recurrent bleeding is usually managed locally or by portosystemic shunt. We report a case of recurrent, massive ileal conduit variceal hemorrhage in a patient without a significantly elevated portosystemic gradient. Therefore, this patient was not a candidate for a shunt procedure. Using a transjugular transhepatic approach to the portal vein, the varices were embolized to stasis without any complications. The patient has subsequently experienced no further bleeding episodes.

Disease recurrence and progression in untreated pathologic stage T3 prostate cancer: selecting the patient for adjuvant therapy.

PURPOSE: Optimal management of pathologic T3 prostate cancer is poorly defined. We conducted a prospective study of untreated pT3 patients to improve understanding of the natural history of this disease and to identify clinical parameters useful in patient selection for adjuvant therapy. MATERIALS AND METHODS: Of 583 consecutive patients with clinical stage T1 to 2 disease managed by total prostatectomy, 206 had pT3 disease. Excluding patients requesting immediate adjuvant treatment or neoadjuvant therapy, 156 subjects were eligible for the study, including 34 with pT3a, 80 pT3b, 22 pT3c, and 20 pT3N+ disease. Patients were followed for prostate-specific antigen (PSA) recurrence of greater than 0.2 ng./ml. and biopsy proved local or distant tumor progression demonstrated by imaging studies. RESULTS: After a median of 45 months, PSA recurrence was seen in 29.4% of pT3a (10/34), 30% of pT3b (24/80), 27.3% of pT3c (6/22), and 80% of pT3N+ (16/20 cases). Local or distant progression was seen in 2.9% of pT3a (1), 6.2% of pT3b (5), 9.1% of pT3c (2), and 55% of pT3N+ (11 cases). Recurrence and progression correlated with the number of surgical margins involved by tumor, pathological Gleason score and baseline pre-prostatectomy PSA levels. PSA recurrence was seen in 20.8% (10/48) patients with 1 surgical margin involved, 40.9% (9/22) with 2 margins involved and 50% (5/10) with 3 or more margins involved. PSA recurrence was 20.3% (14/69) with Gleason scores of less than 7, 33.9% (19/56) with a score of 7 and 74.2% (23/31) with scores of greater than 7. Pre-prostatectomy PSA levels less than 10 ng./ml. were associated with a PSA recurrence of 17.3% (14/81) and 45.4% (25/55), with levels greater than 10 ng./ml. Selecting patients for high or low risk based upon the results of these parameters allowed accurate prediction of PSA recurrence; 8.5% (4/47) for low risk patients and 44.8% (30/67) for high risk. Tumor progression was seen in no low risk patient and in 9% (6) with high risk. The difference between the 2 risk groups was highly significant (p <0.0001). CONCLUSIONS: The majority of patients with pT3 prostate cancer will not experience recurrent disease for many years if ever. Immediate use of adjuvant treatment should be reserved for those patients with a high risk of recurrent disease.

Endoscopic topical placement of formalin soaked pledgets to control localized hemorrhage due to radiation cystitis.

PURPOSE: A useful technique for treating localized bladder hemorrhage secondary to radiation cystitis is described. MATERIALS AND METHODS: Cotton pledgets soaked in 5% formalin are placed endoscopically onto bleeding foci of the bladder for 15 minutes and then removed. RESULTS: There was immediate cessation of prolonged bleeding refractory to intravesical saline, alum, prostaglandin E1 and estrogen. No subsequent bleeding was noted during 16 months of followup. CONCLUSIONS: Topical application of formalin soaked pledgets is an effective method of controlling localized bleeding secondary to radiation cystitis.

Comparison of bladder neck preservation to bladder neck resection in maintaining postrostatectomy urinary continence.

OBJECTIVES: This study compares the effectiveness of a bladder neck preservation procedure with that of bladder neck resection in maintaining postprostatectomy urinary continence. METHODS: Bladder neck preservation was attempted in 107 men and completed in 91; bladder neck resection was performed in 99 patients. Successful follow-up was performed in 90 and 98 patients, respectively, during a mean interval of 42 months. The two groups were compared for return of urinary continence at monthly intervals to 1 year, the incidence of positive surgical margins, and recurrence, using an unpaired t test and regression curves. RESULTS: Continence at 1 month was 11.2% for patients undergoing a bladder neck resection and 23.3% for those with preservation of the bladder neck. At 3 months, the continence rates were 44.3% and 62.4%, respectively; at 6 months, they were 70.1% and 82.4%, respectively; and at 1 year, they were 86.3% and 89.4%, respectively. There was no significant difference in time to continence at 1 year between the two groups; however, there was a significantly decreased time to continence seen in patients with preservation of the bladder neck. The incidence of positive margins and organ-confined disease was not significantly different between the two groups. Detectable serum prostate-specific antigen levels were seen in 17.3% of patients undergoing bladder neck resection and in 16.7% of those with bladder neck preservation. CONCLUSIONS: Preservation of the bladder neck is technically feasible; in selected patients, it is effective in eradicting disease without an increased recurrence rate. The procedure does not produce an improved rate of postprostatectomy incontinence, although it can be expected to shorten the interval of incontinence.

A phase II trial of interferon-alpha and 5-fluorouracil in patients with advanced renal cell carcinoma. A Southwest Oncology Group study.

BACKGROUND: Renal cell carcinoma is a common neoplasm that is often refractory to treatment. It is occasionally responsive to immunomodulating agents including interferon-alpha, which enhances the effects of 5-fluorouracil upon cells. Combinations of these two drugs have been most frequently tested in patients with gastrointestinal cancers, with some promising results. Because interferon-alpha has activity for renal cell carcinoma, a trial of this combination in patients with this malignancy was undertaken. METHODS: The Southwest Oncology Group performed a Phase II clinical trial of the combination of 5-fluorouracil and interferon-alpha for recurrent or metastatic renal cell carcinoma. Eligibility criteria included no prior treatment with medications for cancer, a performance status of 2 or better, and bidimensionally measurable disease. The regimen studied consisted of 5-fluorouracil, 750 mg/M2/day, by continuous intravenous infusion on Days 1-5, and interferon-alpha-2b (Intron A), 5 x 10(6)U/M2/day, subcutaneously on Days 1, 3, and 5, repeated every 21 days. RESULTS: Forty eligible patients were treated; twenty of the 40 underwent a nephrectomy. The regimen was tolerable: 3 patients had Grade 4, and 17 had Grade 3 toxicity. There were 5 partial responses (13% with 95% confidence limits of 4-27%). Median progression free survival for all 40 patients was 4 months and median overall survival was 15 months from the time of registration. CONCLUSIONS: The combination of 5-fluorouracil and interferon-alpha given by this schedule, although tolerable and occasionally yielding responses, is not an improvement over existing therapies.

Management of stage T1a prostate cancer.

The patient with incidentally discovered prostate cancer by transurethral resection of the prostate (TURP) presents a difficult management problem for the clinician. These tumors are small and generally of low biologic potential. Offering aggressive treatment is not necessary in most patients; though in some patients, the tumor is not organ confined. Selecting that patient who may require tumor eradication to optimize survival requires careful analysis of known histological parameters identified at the time of diagnosis, an estimation of projected individual survival, and extensive counseling regarding options.

Oral bropirimine immunotherapy of carcinoma in situ of the bladder: results of a phase II trial.

OBJECTIVES: Bropirimine is an orally administered immunostimulant that has been shown to have activity against carcinoma in situ (CIS) of the bladder. To further assess this potential activity, bropirimine was administered to 42 patients for bladder CIS in a Phase II trial. METHODS: Patients were treated with bropirimine 3.0 g/day by mouth for 3 consecutive days each week up to 1 year. Cystoscopy with biopsies and bladder wash cytology were performed quarterly. RESULTS: Twenty (61%) of 33 evaluable patients converted malignant biopsies and bladder wash cytology to negative, including 6 (50%) of 12 who failed prior bacillus Calmette-Guérin (BCG) immunotherapy, 14 (67%) of 21 who had not received prior BCG therapy, and 12 (80%) of 15 with primary CIS. Median response duration exceeds 21 months. Four of the 20 responders did have a papillary tumor recurrence at 3 to 15 months, all Stage Ta or T1. Mild toxicity (grade I or II) suggestive to interferon induction or administration occurred in one third of patients. Headache, transient hepatic enzyme elevations, skin rash, and arthralgias each occurred in 5% to 14% of the patients, with nausea or emesis in 21%. Grade 1 tachycardia/palpitations or chest pain each were noted in 5%. CONCLUSIONS: Oral bropirimine can induce remission of bladder CIS with acceptable toxicity at 3.0 g/day. Bropirimine may be a valuable alternative to cystectomy for some failures of BCG therapy and may have the potential to replace BCG as front-line therapy because of its ease of administration.

Combination transurethral resection, systemic chemotherapy, and pelvic radiotherapy for invasive (T2-T4) bladder cancer unsuitable for cystectomy: a phase I/II Southwestern Oncology Group study.

OBJECTIVES: Primarily to evaluate the toxicity and, secondarily, the tumor response and patient survival associated with a three-phase combined modality treatment plan for patients with invasive transitional cell carcinoma (TCC) of the bladder (T2-T4,NX-N2, MO) who are medically unsuitable for or who refuse cystectomy. METHODS: Eligible patients initially underwent extensive transurethral resection (TUR) of the primary tumor with the attempt to resect disease totally. Subsequently, they received systemic combination chemotherapy consisting of two cycles of methotrexate, cisplatin, and vinblastine (MCV), followed by cystoscopic re-evaluation of the bladder tumor. Patients then received 6480 cGy radiotherapy to the bladder with concurrent systemic cisplatin. Toxicity, primary tumor response, and overall survival were evaluated. RESULTS: Of 34 eligible patients, 27 patients completed the treatment series. Twenty-two received 80% to 100% of the prescribed doses of MCV and only 2 patients experienced grade 4 hematologic toxicities. The most common toxicities were gastrointestinal (23), hematologic (21), and renal (8). The complete response (CR) rate after all treatment phases was 56% (19 of 34), 10 patients achieving a complete tumor resection of visible tumor at the initial TUR of the bladder (TURB); 3, a CR after MCV; and 6, after radiotherapy and concomitant cisplatin. The median overall survival was 21 months with 6 of 34 (18%) alive at 57 months (range, 36 to 75). Complete resection of tumor by TURB was associated with prolonged overall survival. The bladder was the initial site of recurrence in 85% of patients who had achieved a CR status. CONCLUSIONS: This older age patient group tolerated this combined modality therapy with acceptable toxicities, but the overall survival rate was not improved compared with those reported with radiotherapy alone.