Patient-reported Outcomes from JAVELIN Bladder 100: Avelumab First-line Maintenance Plus Best Supportive Care Versus Best Supportive Care Alone for Advanced Urothelial Carcinoma.

BACKGROUND: In JAVELIN Bladder 100, avelumab first-line maintenance plus best supportive care (BSC) significantly prolonged overall survival (OS; primary endpoint) versus BSC alone in patients with advanced urothelial carcinoma (aUC) without disease progression with first-line platinum-containing chemotherapy. OBJECTIVE: To evaluate patient-reported outcomes (PROs) with avelumab plus BSC versus BSC alone. DESIGN, SETTING, AND PARTICIPANTS: A randomized phase 3 trial (NCT02603432) was conducted in 700 patients with locally advanced or metastatic urothelial carcinoma that had not progressed with first-line gemcitabine plus cisplatin or carboplatin. PROs were a secondary endpoint. INTERVENTION: Avelumab plus BSC (n = 350) or BSC alone (n = 350). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: National Comprehensive Cancer Network/Functional Assessment of Cancer Therapy Bladder Symptom Index-18 (FBlSI-18) and EuroQol five-level EQ-5D (EQ-5D-5L) assessments were analyzed using descriptive statistics and mixed-effect models. Time to deterioration (TTD; prespecified definition: a ≥3-point decrease from baseline in the FBlSI-18 disease-related symptoms-physical subscale for two consecutive assessments) was evaluated via Kaplan-Meier analyses. RESULTS AND LIMITATIONS: Completion rates for scheduled on-treatment PRO assessments were >90% (overall and average per assessment). Results from descriptive analyses and mixed-effect or repeated-measures models of FBlSI-18 and EQ-5D-5L were similar between arms. TTD was also similar, both in the prespecified analysis (hazard ratio 1.26 [95% confidence interval: 0.90, 1.77]) and in the post hoc analyses including off-treatment assessments and different event definitions. Limitations included the open-label design and limited numbers of evaluable patients at later time points. CONCLUSIONS: Addition of avelumab first-line maintenance to BSC in patients with aUC that had not progressed with first-line platinum-containing chemotherapy prolonged OS, with a relatively minimal effect on quality of life. PATIENT SUMMARY: In this trial of people with advanced urothelial carcinoma who had benefited from first-line chemotherapy (ie, had stable disease or reduced tumor size), treatment with avelumab maintenance plus best supportive care (BSC) versus BSC alone improved survival significantly, without compromising quality of life, as reported by the patients themselves.

Longitudinal assessment of B-RAF V595E levels in the peripheral cell-free tumor DNA of a 10-year-old spayed female Korean Jindo dog with unresectable metastatic urethral transitional cell carcinoma for monitoring the treatment response to a RAF inhibitor (sorafenib).

Transitional cell carcinoma (TCC) is the most common malignant tumor of the canine urinary tract. In this case study, a dog with metastatic urethral TCC was treated with sorafenib. The tumor expression levels of receptor tyrosine kinase genes, including VEGFR-1, VEGFR-2, PDGFR-α, PDGFR-ß, ALK, EGFR, ErbB2, and B-RAF, were analyzed. VEGFR was overexpressed in tumor tissues compared to the normal tissues. Considering the high frequency of B-RAF mutation in canine urological tumors, the B-RAF gene was examined, and the B-RAF V595E mutation was detected in the tumor tissue. Therefore, the antitumor effect of sorafenib, a multi-tyrosine kinase inhibitor, on unresectable metastatic urethral TCC characterized by B-RAF V595E was evaluated and circulating cell-free tumor DNA (ctDNA) was assessed for monitoring the treatment response. After the initiation of oral sorafenib therapy (4 mg/kg/day escalated to 10 mg/kg/day), the dysuria was alleviated gradually, and the patient remained stable for 3 months. During that treatment period, the patient showed various levels of changes associated with B-RAF V595E mutation in ctDNA as evident from longitudinal plasma samples after initiation of sorafenib therapy. The findings of this study suggest that ctDNA may serve as a useful non-invasive tool for monitoring the treatment response to anticancer drugs.

Upper tract urothelial carcinoma topical issue 2016: treatment of metastatic cancer.

PURPOSE: To review the management of metastatic upper tract urothelial carcinoma (UTUC) including recent advances in targeted and immune therapies as an update to the 2014 joint international consultation on UTUC, co-sponsored by the Société Internationale d'Urologie and International Consultation on Urological Diseases. METHODS: A PubMed database search was performed between January 2013 and May 2016 related to the treatment of metastatic UTUC, and 54 studies were selected for inclusion. RESULTS: The management of patients with metastatic UTUC is primarily an extrapolation from evidence guiding the management of metastatic urothelial carcinoma of the bladder. The first-line therapy for metastatic UTUC is platinum-based combination chemotherapy. Standard second-line therapies are limited and ineffective. Patients with UTUC who progress following platinum-based chemotherapy are encouraged to participate in clinical trials. Recent advances in genomic profiling present exciting opportunities to guide the use of targeted therapy. Immunotherapy with checkpoint inhibitors has demonstrated extremely promising results. Retrospective studies provide support for post-chemotherapy surgery in appropriately selected patients. CONCLUSIONS: The management of metastatic UTUC requires a multi-disciplinary approach. New insights from genomic profiling using targeted therapies, novel immunotherapies, and surgery represent promising avenues for further therapeutic exploration.

Clinical response to induction chemotherapy predicts improved survival outcome in urothelial carcinoma with clinical lymph nodal metastasis treated by consolidative surgery.

BACKGROUND: To determine the indications for post-chemotherapy consolidative surgery in patients with clinical lymph node (LN) metastatic (cN+) urothelial carcinoma (UC). METHODS: Sixty UC patients with measurable cN+ but without detectable systemic visceral/bone dissemination received induction platinum-based chemotherapy. Consolidative surgery was offered to all patients except for those with progressive disease. We retrospectively analyzed the clinicopathological response to induction chemotherapy and identified prognostic factors for overall survival (OS). RESULTS: The primary cancer site was the urinary bladder in 31 patients (52 %) and upper urinary tract in 29 (48 %). The median number of chemotherapy courses was 4. Forty-five patients (75 %) showed a clinically objective response to the induction chemotherapy. Fifty-one patients (85 %) underwent subsequent consolidative surgery. Histopathological analysis indicated pT0 status in 10 (20 %) and pN0 in 17 (33 %). When all 60 patients were considered, clinical tumor response was found to be significantly correlated with achievement of pathological complete response. At the median follow-up of 22 months, the median progression-free survival and OS periods were excellent: 18.6 and 31.6 months, respectively. In the multivariate analysis, clinical tumor response was found to be an independent pre-surgical prognostic factor for OS, and pathologically negative lymph node, negative resection margin, more LNs removed, and negative lymphovascular invasion were found to be independent post-surgical prognostic parameters for OS. CONCLUSIONS: The median OS in induction chemotherapy followed by consolidative surgery was very encouraging. Our results suggest that achieving a good clinical response to pre-surgical induction chemotherapy is a good indication for subsequent consolidative surgery in UC patients with cN+ to improve OS through a good pathological response.

Lymph node density for patient counselling about prognosis and for designing clinical trials of adjuvant therapies after radical cystectomy.

UNLABELLED: What's known on the subject? and What does the study add? Patients with positive lymph nodes at radical cystectomy have a poor prognosis. The actual outcome of patients varies based on many factors, among which lymph node density has emerged as being more informative than nodal status of TNM staging. We combined clinical data from two major cancer centres in the USA and identified patients with an adequate lymphadenectomy and no perioperative chemotherapy to understand the natural history of the disease. Using this information, we created prognostic tools incorporating lymph node density that can be used for risk stratification, patient counselling and clinical trial design. OBJECTIVE: • To develop a clinical tool based on lymph node density (LND) for patient counselling after radical cystectomy and for design of clinical trials of adjuvant therapies after radical cystectomy. PATIENTS AND METHODS: • Using pooled data from two comprehensive cancer centres, we identified patients with lymph node metastases after radical cystectomy who received an adequate lymph node dissection according to existing literature (resection of eight or more nodes). • Only patients who had not received neoadjuvant or adjuvant chemotherapy were included to ensure that prediction models were based on the natural course of the disease. • Thresholds for LND ranging from 5% to 35%, in 5% increments, were used to dichotomize the study population. Within each set of two groups, the Kaplan-Meier product-limit estimator was used to estimate disease-specific survival (DSS) for each group, and Cox proportional hazards regression was used to test the significance of differences in DSS between the group with higher LND and the group with lower LND. • Tables and graphs showing the relationship between LND categories and 2-year and 5-year estimated DSS were created to aid in clinical decision-making. RESULTS: • LND was valuable as a tool for stratifying node-positive patients into different risk groups based on expected survival. • At each LND threshold from 10% to 35%, patients with higher LND had significantly worse DSS than patients with lower LND (P ≤ 0.001). • As expected, DSS in the higher-LND group worsened with each 5% increase in LND threshold: patients with LND > 35% had a 5-year DSS rate of 4%. • Using our data as a tool, multiple cut-offs can be employed to categorize patients into various risk groups with different risk. For example, patients with LND ≤ 10% have an estimated 5-year DSS rate of 61.9%, whereas patients with LND > 15% have an estimated 5-year DSS rate of 19.2%. CONCLUSIONS: • Patients with node-positive bladder cancer have poor outcomes, and survival varies widely according to LND. • Categorical LND should be used to risk-stratify patients for counselling regarding prognosis. • Furthermore, categorical LND should be used as a tool for designing and reporting on clinical trials of adjuvant therapies.

Results of the phase II EORTC 22971 trial evaluating combined accelerated external radiation and chemotherapy with 5FU and cisplatin in patients with muscle invasive transitional cell carcinoma of the bladder.

INTRODUCTION: We prospectively evaluated concomitant radiotherapy and chemotherapy for advanced bladder cancer in a phase II EORTC trial to test whether it could be further studied as a potential treatment of bladder cancer. PATIENTS AND METHODS: Patients up to 75 years of age with invasive transitional-cell carcinoma of the bladder up to 5 cm, stage pT2 to pT3b, N0M0, without residual macroscopical tumour after transurethral excision were eligible. Radiotherapy consisted of 2 fractions of 1.2 Gy daily up to 60 Gy delivered in a period of 5 weeks. During the first and the last week, cisplatin 20 mg/m(2)/day and 5 FU 375 mg/m(2)/day were given concomitantly. RESULTS: The study was interrupted early due to poor recruitment. Nine patients of the originally 43 planned were treated. Mean age was 63 years. Five patients had tumour stage pT2, 1 stage pT3a and 3 stage pT3b. All patients completed radiotherapy and chemotherapy as scheduled. Only one grade 3 and no grade 4 toxicity was seen. All patients were evaluated 3 months after treatment: eight patients had no detectable tumour and one had para-aortic lymph nodes. During further follow-up, a second patient got lymph node metastases and two patients developed distant metastases (lung in the patient with enlarged lymph nodes at the first evaluation and abdominal in one other). Those three patients died at respectively 19, 14, and 18 months after registration. Late toxicity was limited and often temporary. After 26 to 57 months of follow-up, no local recurrences were seen. Six patients remained alive without disease. DISCUSSION: Despite the small cohort, this combination of concomitant chemotherapy and accelerated hyperfractionated radiotherapy for invasive bladder cancer seemed to be well tolerated and to result in satisfactory local control with limited early and late toxicity. It could therefore be considered for study in further clinical trials.

Phase II trial of pemetrexed as second-line therapy in patients with metastatic urothelial carcinoma.

PURPOSE: The purpose of this single-center phase II study was to determine the activity of pemetrexed administered as second-line therapy in patients with advanced urothelial carcinoma. METHODS: Patients with advanced urothelial carcinoma that had relapsed after receiving perioperative chemotherapy, or progressed on first-line chemotherapy for metastatic disease, were eligible for enrollment. Patients received pemetrexed 500 mg/m(2) every 21 days along with folic acid and vitamin B12 supplementation. RESULTS: A total of 13 patients were enrolled. An objective response was achieved in 1/12 evaluable patients for an overall response rate of 8% (90% upper limit 29%). This level of activity did not meet criteria for expansion based on the pre-defined optimal 2-stage Simon design and the trial was concluded. Treatment was generally well tolerated, however, 2/13 patients developed febrile neutropenia. Non-hematologic grade > or = 3 toxicity was rare. CONCLUSIONS: Pemetrexed as second-line therapy in advanced urothelial carcinoma is associated with modest activity. The role of this novel antifolate in chemotherapy-naïve patients warrants further investigation.

Phase II trial of weekly paclitaxel, cisplatin plus infusional high dose 5-fluorouracil and leucovorin for metastatic urothelial carcinoma.

PURPOSE: Conventional chemotherapy for urothelial carcinoma, such as methotrexate, vinblastine, doxorubicin and cisplatin, is associated with significant toxicity. We have previously reported a low toxicity and yet moderately active regimen containing weekly infusional cisplatin and high dose 5-fluorouracil/leucovorin for advanced urothelial carcinoma. We tested the efficacy and toxicity of adding paclitaxel to that regimen. MATERIALS AND METHODS: Between April 2000 and December 2004, 44 patients with a median age of 66 years with metastatic urothelial carcinoma were enrolled. The paclitaxel, cisplatin and high dose 5-fluorouracil/leucovorin regimen consisted of 70 mg/m2 paclitaxel daily as a 1-hour infusion on days 1 and 8, 35 mg/m2 cisplatin daily as a 24-hour infusion on days 2 and 9, 2,000 mg/m2 5-fluorouracil daily and 300 mg/m2 leucovorin daily as a 24-hour infusion on days 2 and 9. The cycles repeated every 21 days. A total of 25 patients (64%) had a creatinine clearance of 35 to 60 ml per minute. RESULTS: A total of 210 cycles (mean 4.8 per patient) were administered. Of the 40 patients eligible for response evaluation 11 (28%) and 19 (48%) were complete and partial responders with an overall response rate of 75% (95% CI 61 to 89). Median overall and progression-free survival in the whole group was 17.0 (95% CI 13.7 to 20.3) and 8.3 months (95% CI 6.4 to 10.2), respectively. Two-year disease-free survival was 15%. Grade 3 or 4 anemia, leukopenia and thrombocytopenia occurred at 23, 30 and 12 cycles, respectively. Nonhematological toxicity included infection, vomiting and diarrhea, etc. There were 2 treatment related deaths. CONCLUSIONS: Paclitaxel, cisplatin and high dose 5-fluorouracil/leucovorin is an active regimen against metastatic urothelial carcinoma which has an acceptable toxicity profile.

[Abscopal effect on metastatic tumor induced by oncolytic virus of H101 combining with local heating].

BACKGROUND & OBJECTIVE: The abscopal effect on the tumors is a distant antitumor activity induced by local treatments. The study was to observe the induction of abscopal effect by the combination of H101 oncolytic virotherapy with local heating. METHODS: Five patients with histologically confirmed, surgically unresectable metastatic malignant tumors (2 nasopharyngeal carcinomas, 1 pulmonary carcinoma, 1 parosteal sarcoma and 1 bladder carcinoma) that had definitely failed to the conventional chemotherapy and radiotherapy or refused these therapies were enrolled in this experimental therapy. All patients were treated with local intra tumor injection of H101 (5x10(11) - 15x10(11) VP) combined with 60-min heating at 42 degrees C. RESULTS: Two patients were cured with complete regressions of both injected and non-injected tumors and have survived for a long period up to date. Three patients responded to the novel therapy variously and eventually died from the disease, who survived 29, 15 and 13 months, respectively. CONCLUSION: The abscopal antitumor effect could be induced by the combination of H101 local intratumoral injection with heating.

Lymphovascular invasion is independently associated with overall survival, cause-specific survival, and local and distant recurrence in patients with negative lymph nodes at radical cystectomy.

PURPOSE: We hypothesized that bladder cancer patients with associated lymphovascular invasion (LVI) are at increased risk of occult metastases. METHODS: A multi-institutional group (University of Texas Southwestern [Dallas, TX], Baylor College of Medicine [Houston, TX], Johns Hopkins University [Baltimore, MD]) carried out a retrospective study of 958 patients who underwent cystectomy for bladder cancer between 1984 and 2003. Of patients with transitional-cell carcinoma (n = 776), LVI status was available for 750. LVI was defined as the presence of tumor cells within an endothelium-lined space. RESULTS: LVI was present in 36.4% (273 of 750) overall, involving 26% (151 of 581) and 72% (122 of 169) of node-negative and node-positive patients, respectively. Prevalence of LVI increased with higher pathologic stage (9.0%, 23%, 60%, and 78%, for T1, T2, T3, and T4, respectively; P < .001). Using multivariate Cox regression analyses including age, stage, grade, and number of pelvic lymph nodes removed, LVI was an independent predictor of local (HR = 2.03, P = .049), distant (HR = 2.60, P = .0011), and overall (HR = 2.02, P = .0003) recurrence in node-negative patients. LVI was an independent predictor of overall (HR = 1.84, P = .0002) and cause-specific (HR = 2.07, P = .0012) survival in node-negative patients. LVI maintained its independent predictor status in competing risks regression models (P = .013), where other-cause mortality was considered as a competing risk. LVI was not a predictor of recurrence or survival in node-positive patients. CONCLUSION: LVI is an independent predictor of recurrence and decreased cause-specific and overall survival in patients who undergo cystectomy for invasive bladder cancer and are node-negative. These patients represent a high risk group that may benefit from integrated therapy with cystectomy and perioperative systemic chemotherapy.

Synchronous solitary metastasis of transitional cell carcinoma of the bladder to the testis.

Primary tumors known to metastasize to the testis, in order of decreasing frequency, are prostate, lung, gastrointestinal tract, melanoma, and kidney tumors. Metastasis from bladder cancer to the testis is extremely rare, occurs with advanced and metastatic disease, and is usually a finding at autopsy. We report a rare, and probably the first, case of solitary and synchronous metastatic transitional cell carcinoma of the bladder to the testis, discovered on the preoperative workup. An incidentally discovered testicular mass in a man with high-grade, invasive bladder cancer should be considered a metastatic lesion until proven otherwise.

Treatment of urethral recurrence following radical cystectomy and ileal bladder substitution.

PURPOSE: With the introduction of orthotopic bladder substitution after radical cystectomy in patients with invasive bladder cancer urethral recurrences have become a therapeutic challenge. MATERIALS AND METHODS: We retrospectively evaluated our patients with urethral recurrences treated with a urethra sparing approach after orthotopic bladder substitution. Depending on the extension of recurrence and eventual concomitant metastases patients were treated with urethrectomy, no treatment, systemic chemotherapy or intraurethral bacillus Calmette-Guerin (BCG). Three times the common dose of BCG (ImmuCyst, Aventis, Paris, France or OncoTICE, Organon, West Orange, New Jersey) in 150 ml NaCl 0.9% was used for intraurethral BCG perfusion therapy according to an institutional protocol using a modified Foley catheter. This regimen was repeated weekly for 6 weeks and patients were followed prospectively. RESULTS: Between 1985 and 2001, 15 of 371 patients (4%) who received an orthotopic bladder substitute had urethral recurrence. Two patients were treated with systemic chemotherapy (methotrexate, vinblastine, doxorubicin and cisplatin) alone due to metastatic disease and 10 received intraurethral BCG therapy. Five of 6 patients (83%) with carcinoma in situ remained free of recurrence following treatment with BCG, while in 4 with papillary or invasive disease treatment failed. Three patients underwent urethrectomy, including 2 following failed BCG therapy for papillary disease. CONCLUSIONS: Carcinoma in situ urethral recurrence following orthotopic bladder substitution can be treated successfully with intraurethral BCG perfusion therapy in approximately 80% of patients. However, papillary and invasive transitional cell urethral recurrence should be treated with urethrectomy.

Management and prognosis of transitional cell carcinoma superficial recurrence in muscle-invasive bladder cancer after bladder preservation.

PURPOSE: To assess the bladder preservation rate and cancer-specific survival after conservative treatment of superficial relapses in invasive tumors after bladder preservation. MATERIAL AND METHODS: Fifty-one patients with invasive bladder tumor (T2) were treated using transurethral resection (TUR) followed by three cycles of systemic chemotherapy (carboplatin-vinblastine). After three weeks, an endoscopic reappraisal was made including deep TUR of the site of the original tumor and multiple cold cup biopsies. Forty-two patients retained their bladder (33 complete responses and 9 partial responses). RESULTS: With a median follow-up of 63 months, 18 patients recurred as superficial TCC tumor (43%). Fourteen patients with high grade superficial recurrence were treated with TUR and Bacillus Calmette-Guerin (BCG) instillations; two patients (G2-3 T1) with TUR as well as endovesical mytomicine, and two patients with low grade recurrence with only TUR. With a median follow-up of 44 months after TUR of first superficial relapse, there was only one case with progression of the disease without any evidence of bladder tumor. Two cystectomies were made due to carcinoma in situ (Cis) persistence and high grade superficial recurrence. Eighty-three percent of the patients who had superficial recurrence retained their bladders, with 94% cancer-specific survival. CONCLUSIONS: A very strict follow-up is mandatory due to the high rate of superficial relapses (43%). Cis is the most frequent type of superficial recurrence. Superficial recurrences in bladder preservation may be treated with TUR and BCG instillations when they are high grade and and/or associated with Cis. Superficial recurrences do not imply a worse prognosis for bladder preservation or cancer-specific survival.

Immunohistochemical profile of high-grade urothelial bladder carcinoma and prostate adenocarcinoma.

The differential diagnosis between poorly differentiated prostate adenocarcinoma (PAC) involving the bladder and high-grade urothelial bladder cancer (UC) with prostate extension can be very challenging. The aim of this study is to evaluate the use of a panel of antibodies to distinguish the poorly differentiated forms of these two tumors. We evaluated a series of 40 PAC cases (Gleason's grade >/= 8) and 45 (G3) UC cases obtained from transurethral endoscopic resection material. Immunohistochemical analysis was performed using the following antibodies: prostate acid phosphatase (PAP), prostate-specific antigen (PSA), uroplakin III (UP), thrombomodulin (TM), cytokeratin (CK) 7, and CK20. PAC expressed PSA and PAP in 34 and 38 cases, respectively. The sensitivity and specificity of expressing at least 1 marker (PSA+ or PAP+) is 95% and 100%, respectively. All UC cases were negative for both markers. UC expressed UP and TM in 27 and 22 cases, respectively. In addition, 36 of 45 cases stained positively for at least 1 marker (UP + or TM +) with specificity and sensitivity of 80% and 100%, respectively. All cases of PAC were negative for both markers. Twenty-eight UC cases were CK7+/CK20 +, and 4 PAC cases stained positively for both markers. On the other hand, 29 PAC cases and 4 UC cases were CK7-/CK20-. We concluded that PSA, PAP, UP, and TM are very useful markers in differentiating poorly differentiated UC from PAC. Finally, when all 4 markers (PAP, PSA, UP, and TM) were negative, CK7 and CK20 appeared of no major use in making the differential diagnosis.

[Treatment of infiltrating cancer of the bladder with cisplatin, fluorouracil, and concurrent radiotherapy: results of a pilot study]. / Traitement des cancers infiltrants de vessie par cisplatine, fluoro-uracile et radiothérapie concomitante: résultats d'une étude pilote.

PURPOSE: Pilot study to assess treatment feasibility and results of a 2-drug chemotherapy (CT) regimen administered concurrently with radiotherapy (RT) for muscle-invasive bladder cancer. MATERIALS AND METHODS: Fourty-six patients were included into a prospective study from December 1992 to April 1996. The median age was 66 years. Thirty-seven percent of the patients had T3B-T4 tumors, and 46% had benefited from prior macroscopically complete transurethral resection (TUR). Pelvic irradiation consisted of 50.4 Gy in 28 fractions over 39 days. Concurrent CT consisting of cisplatin (80 mg/m2/d1) and 5-fluorouracil (800 mg/m2/d2 to 5) by continuous infusions (5-FU) was delivered during the first and fifth weeks of radiation therapy. Twenty-three patients received two additional courses of adjuvant CT with cisplatin, methotrexate and vinblastin (MCV). RESULTS: The median follow-up was 38 months. The feasibility of concurrent CT-RT was excellent: 96% of the patients completed radiotherapy and 100% of them received the two courses of P-FU. The acute toxicity was mild: no hematological toxicity or renal toxicity over grade II, 4 cases of bowel or rectal reversible grade III toxicity and 2 cases of reversible grade III cystitis. A complete response was achieved in 30 out of the 42 evaluable patients (65.2%). Nine patients received an immediate salvage treatment (3 TUR, 3 additional radiotherapy and 3 cystectomies). Ten patients had local failure. Projected 3-year locoregional control was 49% for the 46 patients. Projected overall 3-year survival was 53%. Functional results were good for disease-free patients with preserved bladder: 1 grade I, 3 grade II, and no grade III cystitis. CONCLUSION: Concurrent 2-drug chemoradiotherapy with cisplatin and 5-fluorouracil is feasible without major toxicity and offers a potentially curative and conservative treatment for patients with localized muscle-invasive bladder cancer.

A comparative study on effects of doxorubicin alone or mixed with lipiodol given through the hepatic artery or portal vein for liver tumors in rats.

Vascular feeding of metastatic liver tumors at early stage is uncertain. It is controversial whether anticancer agents should be given through the hepatic artery or portal vein. In order to clarify this point, a rat model of liver metastases generated by an intraportal injection of syngeneic tumor cells was used to determine the optimal regional chemotherapeutic modality for early hepatic metastases. The rats given the tumor cells through the portal vein were placed into 5 groups: In groups I and II, Adriamycin (ADR) 4 mg/kg alone was given either into the hepatic artery or into the portal vein, respectively, 24 h after the inoculation of tumor cells. In groups III and IV, ADR mixed with lipiodol (lipiodolized ADR) 4 mg/kg was given into the hepatic artery or into the portal vein, respectively, 24 h after inoculation. For the group V rats, no treatment was given after inoculation of the tumor. When a comparison was made with regard to the forms of anticancer drug administered, statistically significant differences in survival rates were recognized between groups I and III (p < 0.001), and groups II and IV (p < 0.05). The anticancer agent not mixed with lipiodol and given through the hepatic artery had a more preventive effect than that given through the portal vein. Thus, we conclude that administration of ADR not mixed with lipiodol and given through the hepatic artery is the preferred modality for treating early metastatic liver tumors.

Intraoperative autotransfusion in radical cystectomy for carcinoma of the bladder.

From 1984 to 1987, 49 patients with transitional cell carcinoma of the bladder underwent radical cystectomy during which intraoperative autotransfusion was used. Thirty-three patients were observed for a minimum of one year postoperatively; the mean and median follow-up periods in this group were 23.8 and 26.0 months. Twenty-nine of these 33 patients were alive at the time of reporting; 25 were alive with no evidence of disease, and seven had postoperative recurrence of disease, and seven had postoperative recurrence of tumor. Diffused metastatic disease compatible with intravascular dissemination of tumor during autotransfusion did not develop in any of the patients. Intraoperative loss of blood ranged from 400 to 4,000 milliliters; the mean was 1,497, and the median, 1,300 milliliters. The mean volume of autotransfused blood was 492 milliliters. Autotransfusion accounted for 40 per cent of the total transfusion requirements of the patients and proved to be cost effective for the entire study group. Fear of dissemination of tumor has limited the use of intraoperative autotransfusion during surgical procedures for carcinoma. Analysis of our data failed to define any evidence for dissemination of tumor caused by autotransfusion in patients who underwent radical cystectomy.

High-dose intensity systemic therapy of metastatic bladder cancer.

Forty-three consecutively diagnosed patients with widely metastatic transitional cell carcinoma of the bladder (TCCB) were treated with a high-dose intensity, chronobiologically timed combination of doxorubicin and cisplatin, followed by Cytoxan (Mead Johnson Pharmaceuticals, Evansville, IN), 5-fluorouracil (5-FU), and cisplatin maintenance for up to 2 years. Fifty-seven percent of the 35 evaluable patients with widespread metastatic cancer responded objectively. Twenty-three percent had complete disappearance of all cancer. Median survival from first treatment for complete responders (CRs) was more than 2 years, and 1 year for partial responders (PRs). Three of the CRs were alive without evidence of cancer more than 2 years after stopping all therapy. High-dose intensity combination chemotherapy can induce durable CRs of widespread bladder cancer.

[Therapeutic experiences of cis-diamminedichloroplatinum, adriamycin and 5-fluorouracil combination chemotherapy in advanced urothelial cancer, with special reference to adjuvant chemotherapy in invasive urothelial cancer].

The combination chemotherapy including cis-diamminedichloroplatinum (CDDP), adriamycin (ADM) and 5-fluorouracil (5-FU) is reported as one of the most effective regimens of urothelial cancer. We experienced one patient who had multiple metastatic urothelial cancer in the lung, liver and brain and who showed complete response, even in short duration, by this regimen. Since then, we have been using this regimen as the adjuvant chemotherapy of the invasive urothelial cancer. This regimen consists of 15 mg/m2 CDDP on days 1 to 5, 30 mg/m2 ADM on day 1 and 300 mg/m2 5-FU on days 1 to 5, and is repeated 3 times for 3 to 4 weeks. If toxicity is intolerable, the dosage of CDDP and ADM was decreased in thirty percent. As the maintenance, tegaful was administrated oral or suppository for 1 to 2 years. Seven cases which were followed for at least 12 months were evaluated. In one patient, local recurrence appeared after 16 months, but the other patients were disease free. General malaise, nausea, vomiting and alopecia were recognized in all patients in various degrees, but severe myelosuppression did not appear. Because of the toxicity, three patients had to have reduced dosage. In the adjuvant chemotherapy the most effective regimen should be used in the first therapy to eradicate the micrometastasis. At present, the combination chemotherapy of CDDP and ADM is the most effective for urothelial cancer as reported by many authors. Although the number of patients and the duration of follow up are inadequate to evaluate this adjuvant chemotherapy, we believe that this regimen is effective since invasive urothelial cancer usually recurs within 2 years.