A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study.

PURPOSE: A prospective randomized trial was performed to determine if the addition of methotrexate, vinblastine, and doxorubicin to cisplatin (M-VAC) imparted a response rate or a survival advantage over single-agent cisplatin in patients with advanced urothelial carcinoma. PATIENTS AND METHODS: From October 1984 through May 1989, 269 patients with advanced urothelial carcinoma were entered onto this international intergroup trial and randomized to receive intravenous (IV) cisplatin (70 mg/m2) alone or with methotrexate (30 mg/m2 on days 1, 15, 22), vinblastine (3 mg/m2 on days 2, 15, 22) plus doxorubicin (30 mg/m2 on day 2). Cycles were repeated every 28 days until tumor progression or a maximum of six cycles. There were 246 fully assessable patients of whom 126 were randomized to cisplatin alone and 120 were randomized to the M-VAC regimen. RESULTS: As expected, the M-VAC regimen was associated with a greater toxicity, especially leukopenia, mucositis, granulocytopenic fever, and drug-related mortality. Response rates were superior for the M-VAC regimen compared with single-agent cisplatin (39% v 12%; P less than .0001). Similarly, the progression-free survival (10.0 v 4.3 months) and overall survival (12.5 v 8.2 months) were significantly greater for the combined therapy arm. CONCLUSION: Although a more toxic regimen, we found M-VAC to be superior to single-agent cisplatin with respect to response rate, duration of remission, and overall survival in patients with advanced urothelial carcinoma.

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.

Radionuclide measurement of differential glomerular filtration rate in urinary tract obstruction.

In a previous study using dogs whose renal function was rendered asymmetric by unilateral infarction, the efficacy of technetium-99m (99mTc) DTPA and DMSA in measuring differential glomerular filtration rate (GFR) was demonstrated. The present study was undertaken to determine whether the same techniques were applicable to unilateral ureteral obstruction. Five normal dogs and nine dogs with partial unilateral ureteral obstruction had determination of glomerular filtration rate by standard techniques using constant infusions of iothalamate and creatinine after ureteral catheterization. These results were compared with total GFR as measured by single injection of 99mTc DTPA and analysis of the plasma disappearance curve. Calculated differential GFR was obtained by multiplying total GFR from double exponential analysis of this curve (DTPA2) by each of three measures of differential function. These included the percent differential uptake of 99mTc DTPA and 99mTC DMSA in the posterior projection as well as the geometric mean of 99mTc DMSA uptake. There were good correlations between differential GFR determined by iothalamate clearances at ureteral catheterization and all noninvasive methods involving radionuclides and DTPA2 ( r = 0.93-0.99). Single exponential analysis of the 99mTc DTPA plasma disappearance curve was less satisfactory than double exponential analysis. These results and those reported previously support the use of radionuclides in the determination of differential GFR in a variety of clinical situations.

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.

Bilateral emphysematous pyelonephritis.

Emphysematous pyelonephritis is an uncommon and serious infection associated with gas-forming coliform bacteria. Bilateral involvement is rare with only 10 reported cases in the English literature. Prompt and aggressive management is required to salvage these patients. Preservation of renal function using broad-spectrum antibiotics and surgical drainage provide the greatest benefit to these patients. Three new cases are presented with a brief review of the results of management in the reported cases.

Urodynamic evaluation of patients with continent urinary diversion using cecal reservoir and intussuscepted ileocecal valve.

Patients requiring bladder removal for malignant disease have undergone continent urinary diversion employing the ileocecal segment, using the cecum to construct a reservoir and an intussuscepted ileocecal valve as the continence mechanism. Five of these patients have been studied urodynamically and radiographically in the postoperative period. Incontinence was found to be minimal and related only to a prolonged catheterization interval. Passive filling pressure and peristaltic pressure remained low in all patients and was lower than the nipple valve pressure in 4 of 5 patients. A transient increase in reservoir pressure at capacity with peristalsis exceeded the nipple peristaltic pressure in 1 patient and was associated with a small volume of incontinence. This resolved with a shortened catheterization interval. Reflux was not found in any subject studied. These studies indicate that the cecal segment can be used to construct a continent urinary reservoir that provides satisfactory function for the patient while maintaining an acceptable pressure volume relationship.

Prostatic occurrence of transitional cell carcinoma after intravesical chemotherapy.

Thirteen patients with Stage Tis, Ta, or T1 transitional cell carcinoma (TCC) of the bladder treated by transurethral resections and intravesical chemotherapy developed TCC of the prostate. Among the 13 cases, cytology specimens were obtained from 10 at the time prostatic disease was diagnosed; 9 demonstrated TCC. One was treated successfully by transurethral resection of a Ta lesion involving the prostatic urethra only. One of 2 patients declining radical surgery is alive with residual disease at twenty-four months, and the other died of progressive disease at nineteen months. Of the 10 patients who underwent radical cystoprostatectomy, 7 are alive with no evidence of disease eight to forty-two months postoperatively, with 2 of these 7 having received 4 courses of systemic methotrexate, vincristine, Adriamycin, and cisplatinum (MVAC) for metastatic disease. Two of the 10 died of metastatic disease six and thirteen months postoperatively, and one frail patient died of surgical complications. When treating patients with intravesical chemotherapy for superficial TCC, biopsy of the prostate should be done during follow-up examinations, especially in the presence of cytologic or palpable prostatic abnormalities.

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.

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.

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.

Randomized intergroup comparison of bacillus calmette-guerin immunotherapy and mitomycin C chemotherapy prophylaxis in superficial transitional cell carcinoma of the bladder a southwest oncology group study.

To compare the toxicity and efficacy of intravesical bacillus Calmette-Guérin (BCG) immunotherapy and mitomycin C (MMC) chemotherapy in the prophylaxis of recurrent transitional cell carcinoma, 469 patients with completely resected stage Ta or TI transitional cell carcinoma were enrolled in a randomized Southwest Oncology Group Phase III study. All patients were judged to be at increased risk for tumor recurrence due to having had two occurrences of tumor within 56 weeks, stage T I tumor or three or more tumors within 16 weeks, or concurrent carcinoma in situ. Three hundred and seventy-seven evaluable patients received either 50 mg of Tice BCG in 50 cc saline or 20 mg MMC in 20 cc water weekly for 6 weeks and then monthly to one year. Local and systemic grade I and 2 toxicity was seen significantly more frequently following BCG treatment (P = 0.003), but no life threatening toxicity was seen with either treatment. Recurrence-free survival was significantly prolonged (P = 0.017, proportional hazard regression) in patients randomized to the BCG arm compared to the MMC arm, but there were no statistically significant differences at this analysis for worsening-free survival and overall survival, although the number of these events is too low for a definitive analysis of these long-term outcomes. Therefore, when compared to MMC chemotherapy, BCG immunotherapy is associated with a significantly higher frequency of grade 1 and 2 adverse reactions and a significantly lower first recurrence hazard rate.

Prognostic significance of DNA ploidy in Ta/Tl bladder cancer: A southwest oncology group study.

While 80% of transitional cell carcinomas (TCC) present as Ta Tl lesions, they account for only 15% of deaths caused by TCC. We have evaluated the ability of DNA ploidy analysis to predict outcome in 228 patients with Ta Tl TCC. All patients were judged to be at increased risk for tumor recurrence due to having two occurrences of Stage TI tumor within 56 weeks, or three or more tumors presenting simultaneously within 16 weeks of registration. Concurrent carcinoma in situ was acceptable. All patients were treated with either bacillus Calmette Guerin (BCG) immunotherapy or mitomycin-C (MMC) intravesical chemotherapy. Patients with nondiploid tumors had higher hazard rates for both tumor progression and death (p = 0.007 and p = 0.016, respectively); however, the prognostic information of DNA ploidy was not additive to tumor grade.

Surveillance versus nerve-sparing retroperitoneal lymphadenectomy in stage I nonseminomatous germ-cell tumors.

As in any health care situation, treatment for stage I nonseminomatous germ-cell tumor of the testis must be adapted to the needs of the individual patient, and a surveillance protocol may not always provide optimal care. Of concern is the relative paucity of information about relapse rates beyond 4 years, the long-term effects of salvage chemotherapy, and the potential of subclinical disease to become manifest many years after diagnosis. However, for the reliable patient with a stage I tumor demonstrating no histopathologic features indicative of a high risk of relapse, close surveillance may offer the advantages of a high likelihood of survival with less intervention and lower morbidity.

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.

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.

Solitary metastasis of renal adenocarcinoma to the vagina. A case report.

Solitary metastases are not unusual in renal adenocarcinomas. Vaginal metastases occur but rarely and are the cause of presentation in most patients. Because of the tumor's similarity to other primary gynecologic tumors, the patients present difficult diagnostic and management problems, as shown by the case reported here.

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.

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.