levoleucovorin and Carcinoma--Transitional-Cell

The urachal ligament is an embryologic remnant connecting the dome of the bladder to the umbilicus via the ligamentum commune. Autopsy series suggest that in approximately a third of subjects, the urachal remnant may persist with tubular or cystic structures. However, tumors of this site are extremely rare. Patients usually present with hematuria and upon imaging, have evidence of a cystic or solid structure in the bladder dome or in the bladder midline. If a biopsy confirms adenocarcinoma, these tumors should be considered an urachal cancer until proven otherwise. Although there are no prospective clinical trials reported to date, large single-institution reports suggest surgical resection with a partial cystectomy and en bloc resection of the urachal ligament with umbilicus as the treatment of choice in the setting of localized disease. Although there is currently no definitive role for neoadjuvant or adjuvant chemotherapy in this tumor, risk factors predicting progression may allow for the selection of patients at higher relapse risk for prospective studies. Unfortunately, there are many patients who present with metastatic disease that currently is not likely to be curable. There is no standard chemotherapy regimen for these patients; however, there is new-found hope with a currently accruing clinical trial exploring a 5-fluorouracil-based chemotherapy combination in this patient population.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Transitional Cell; Cisplatin; Clinical Trials as Topic; Clinical Trials, Phase II as Topic; Combined Modality Therapy; Cystectomy; Deoxycytidine; Diagnosis, Differential; Female; Fluorouracil; Gemcitabine; Hematuria; Humans; Leucovorin; Male; Middle Aged; Neoplasm Staging; Prospective Studies; Risk Factors; Umbilicus; Urachal Cyst; Urachus; Urinary Bladder Neoplasms

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.. 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.. 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.. Paclitaxel, cisplatin and high dose 5-fluorouracil/leucovorin is an active regimen against metastatic urothelial carcinoma which has an acceptable toxicity profile.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Transitional Cell; Cisplatin; Drug Administration Schedule; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Paclitaxel; Urinary Bladder Neoplasms; Vitamin B Complex

This prospective, randomized study based on two associated trials was designed to evaluate the effect of neoadjuvant chemotherapy with cisplatin and methotrexate with folinic acid rescue or no chemotherapy prior to local treatment in patients with T2-T4b, NX-3, MO transitional cell carcinoma of the bladder. In the first trial, local treatment consisted of cystectomy (DAVECA 8901) and in the other trial the treatment was radiotherapy (DAVECA 8902); 153 eligible patients were randomized. The majority of the patients (89%) completed the protocol. The overall time to progression for all 153 patients was 12.9 months. Median time to progression was 14.2 months with chemotherapy and 11.4 months without chemotherapy. The actuarial 5-year overall survival rate for all 153 patients was 29%, and 29% for both treatment groups. Multivariate analyses showed that T-stage, tumour size and serum creatinine were independent prognostic factors for survival. The cystectomy trial included 33 patients. Median survival was 78.9 months, 82.5 months with chemotherapy and 45.8 months without chemotherapy (p = 0.76). The radiotherapy trial included 120 patients. The median survival was 17.6 months. Median survival was 19.2 months in the group receiving chemotherapy and 16.3 in the group not receiving chemotherapy. The 5-year survival rate was 19% in the group receiving chemotherapy and 24% in the groups not receiving chemotherapy (p = 0.98). Late toxicity grade 3 or 4 of the bladder was recorded in 25% of the patients (actuarial rate). Neoadjuvant chemotherapy with cisplatin and methotrexate did not significantly improve disease-free or overall survival in 153 randomized patients with invasive bladder cancer.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Carcinoma, Transitional Cell; Chemotherapy, Adjuvant; Cisplatin; Combined Modality Therapy; Creatinine; Cystectomy; Disease-Free Survival; Female; Humans; Leucovorin; Life Tables; Male; Methotrexate; Middle Aged; Muscle, Smooth; Neoadjuvant Therapy; Neoplasm Invasiveness; Prospective Studies; Radiotherapy, High-Energy; Survival Analysis; Survival Rate; Treatment Outcome; Urinary Bladder Neoplasms

To evaluate the feasibility and activity of paclitaxel, carboplatin, and methotrexate in advanced transitional cell carcinoma (TCC) of the urothelium and to relate the activity of this combination to the mutational status of p53.. In the Phase I portion, paclitaxel 200 mg/m(2) (3-hour infusion), carboplatin dosed to an area under the curve (AUC) of 6 mg/mL. min, and methotrexate 10 mg/m(2), increasing in 10-mg/m(2) increments, were administered on day 1 and every 21 days thereafter with granulocyte colony-stimulating factor (G-CSF) and leucovorin support. Subsequently, a Phase II study was initiated in which the carboplatin dose was lowered to an AUC of 5 to allow treatment without G-CSF. p53 expression was evaluated using immunohistochemistry.. Thirty-three patients were accrued. Median age was 66 years. No dose-limiting toxicities were seen in the Phase I portion despite escalation of the methotrexate to 60 mg/m(2). Principal toxicities were myelosuppression and neuropathy. The overall response rate (Phase I and II) was 56% (95% confidence interval 38% to 74%). Median survival was 15.5 months; 88% of patients overexpressed p53 at the primary site.. Paclitaxel, carboplatin, and methotrexate were well tolerated and active in advanced TCC. The high response rate to this regimen despite frequent p53 mutation is consistent with the p53-independent mechanism of paclitaxel. Whether this regimen is superior to methotrexate/vinblastine/doxorubicin/cisplatin, other paclitaxel-based regimens, or to paclitaxel alone will require comparative trials.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Transitional Cell; DNA Mutational Analysis; Dose-Response Relationship, Drug; Drug Administration Schedule; Feasibility Studies; Female; Granulocyte Colony-Stimulating Factor; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Neoplasm Staging; Paclitaxel; Survival Rate; Tumor Suppressor Protein p53; Urinary Bladder Neoplasms

The current treatment of advanced urothelial carcinoma generates high response rates but is associated with poor overall survival. The current study evaluated the efficacy and toxicity of a new combination of active drugs in the treatment of urothelial carcinoma.. Twenty-four patients with muscle invasive or metastatic urothelial carcinoma were enrolled. Fifteen patients (63%) had metastatic disease whereas 9 patients had T2-T4 disease. Three patients were unevaluable for response because of significant toxicity. Patients were treated every 28 days with methotrexate, 60 mg/m(2), intravenously (i.v.) on Day 1; cisplatin, 25 mg/m(2)/day, by continuous i.v. infusion on Days 2-6; 5-flurouracil (5-FU) 800 mg/m(2)/day by continuous i.v. infusion on Days 3-6; and leucovorin, 500 mg/m(2)/day, by continuous i.v. infusion on Days 2-6. Dosage in subsequent cycles was adjusted according to toxicity.. The median follow-up was 81 months (range, 53-97+ months). The overall response rate (complete response + partial response) for all 24 patients was 63% (95% confidence interval, 41-81%). The median survival was 65 months in the patients with muscle invasive disease and 17 months in the patients with metastatic disease. The duration of response in patients with metastatic disease was 6 months (range, 4-19 months). Toxicity was significant, with 82% of patients experiencing Common Toxicity Criteria Grade 3 or 4 neutropenia and 63% experiencing Grade 3 or 4 thrombocytopenia. However, only three patients developed febrile neutropenia and gastrointestinal and neurologic toxicity was moderate.. The combination of methotrexate, cisplatin, 5-fluorouracil, and leucovorin represents an active regimen in the treatment of urothelial carcinoma with a moderate toxicity profile. As new drugs are found to treat urothelial carcinoma, further studies will be needed to evaluate the role of traditional agents such as 5-fluorouracil and methotrexate in new combination chemotherapeutic regimens.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Transitional Cell; Cisplatin; Female; Fluorouracil; Follow-Up Studies; Humans; Kidney Neoplasms; Leucovorin; Male; Methotrexate; Middle Aged; Neoplasm Invasiveness; Neoplasm Metastasis; Survival Rate; Urinary Bladder Neoplasms

Advanced transitional cell carcinoma (TCC) of the urothelial tract is usually fatal despite high response rates to platinum-based chemotherapy regimens. Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) has demonstrated marked single-agent activity in TCC, and combinations of carboplatin and paclitaxel have been well tolerated in other solid tumors. Methotrexate is also active in TCC. Due to unexpectedly severe myelosuppression and mucositis when methotrexate and paclitaxel were combined, we undertook a phase I trial of paclitaxel, carboplatin, and escalating doses of methotrexate with granulocyte colony-stimulating factor and leucovorin support in advanced TCC to determine the feasibility of this combination. Nineteen previously untreated patients with locally advanced or metastatic TCC were eligible. Median age was 62 years. In sequence, paclitaxel 200 mg/m2 (3-hour infusion), carboplatin dosed to an area under the concentration-time curve of 6 mg/mL x min, and methotrexate 10 mg/m2, increasing in 10-mg/m2 increments, were administered on day 1 every 21 days. Granulocyte colony-stimulating factor 300 microg/d or 480 microg/d (in patients <60 kg or >60 kg, respectively) was administered on days 2 through 11 and leucovorin 15 mg orally every 6 hours for 3 days. At this time, the methotrexate dose has been escalated to 50 mg/m2. There were no dose-limiting toxicities in cycle 1. Sixty-eight cycles have been administered (range, one to eight cycles; median, three cycles). Significant hematologic toxicity including neutropenic sepsis (two episodes) occurred in subsequent cycles, but was infrequent. The major nonhematologic toxicity was neuropathy. Sixteen patients are evaluable for response. One patient has achieved a complete response, seven are partial responders, seven have stable disease, and one progressed on therapy. The overall response rate is 50% (95% confidence interval, 25% to 75%). The combination of paclitaxel, carboplatin, and methotrexate holds promise to be well tolerated and active in advanced TCC.

Topics: Administration, Oral; Adult; Aged; Antidotes; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Carboplatin; Carcinoma, Transitional Cell; Confidence Intervals; Disease Progression; Drug Administration Schedule; Feasibility Studies; Female; Granulocyte Colony-Stimulating Factor; Humans; Infusions, Intravenous; Leucovorin; Male; Methotrexate; Middle Aged; Neoplasm Staging; Nervous System Diseases; Neutropenia; Paclitaxel; Remission Induction; Salvage Therapy; Sepsis; Urinary Bladder Neoplasms

Many patients with advanced transitional cell carcinoma are unable to receive cisplatin-based therapy. The efficacy and toxicity of a carboplatin-based regimen in the treatment of patients with advanced transitional cell carcinoma was therefore evaluated.. Twenty-three patients with advanced transitional cell carcinoma were treated. Metastatic disease was present in 19 of 23 patients (83%) whereas 4 patients with T4, and/or N1, disease were treated. Patients were treated every 28 days with methotrexate, 30 mg/m2 intravenously (i.v.) on Days 1 and 15, along with leucovorin, 15 mg/m2 orally every 6 hours, 3 times daily beginning 24 hours after each methotrexate dose; vinblastine, 3 mg/m2 i.v. on Days 1 and 15; mitoxantrone, 15 mg/m2 i.v. on Day 1; and carboplatin, 300 mg/m2 i.v. on Day 1, adjusted for creatinine clearance (MVNCa). Dosage in subsequent cycles was adjusted according to hematologic toxicity.. Median age was 70 years (range, 52-83 years) and median pretreatment creatinine clearance was 50 mL/min (range, 30-106 mL/min). Of 23 patients, 8 (34.8%) obtained a complete response, and 5 (21.7%) obtained a partial response. The overall response proportion was 56.5% (95% confidence interval, 34.5-76.8%). Median survival was 10 months (range, 1-44+ months). Toxicity was moderate. Grade 4 neutropenia occurred in 10 of 107 (9.3%) administered treatment cycles; Grade 4 thrombocytopenia occurred in 11 of 107, (10.3%). There were 4 episodes of febrile neutropenia (3.7% of cycles). Renal, neurologic, or otic toxicity were not observed. Age older than 70 did not appear to impact on response proportion, survival, and toxicity.. The carboplatin-based MVNCa regimen is active in the treatment of patients with advanced transitional cell carcinoma and is well tolerated. Therapy with this regimen may be a less toxic alternative for patients for whom treatment with cisplatin is not an option.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Transitional Cell; Female; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Mitoxantrone; Neoplasm Metastasis; Survival Rate; Urinary Bladder Neoplasms; Vinblastine

There is no known effective salvage chemotherapy for patients with refractory or relapsed urothelial tumors after methotrexate/cisplatin-based regimen. We report the results of a phase II trial with the FIFO regimen that includes from day 1 to 5: fluorouracil 350 mg/m2, folinic acid 20 mg/m2, and ifosfamide 1000 mg/m2, Q4W. Fifteen patients with metastatic measurable urothelial cancer were enrolled in this trial. Previous therapy included M-VAC regimen in 11 patients, CMV regimen in 3 patients, and both regimens in 1 patient. Thirty-one courses were delivered. Toxicity was moderate, including encephalopathy grade 2 in 2 patients and hematological toxicity grade 3 in 2 others. However, an early death occurred on day 1 in a patient who progressed rapidly and died from hepatic insufficiency after initial encephalopathy. No objective response was seen. Twelve patients progressed during FIFO therapy and 3 patients experienced a stable disease. Despite almost encouraging results of fluorouracil and ifosfamide in the literature, their combination according to our schedule is not active in urothelial cancer.

Topics: Adrenal Gland Neoplasms; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Carcinoma, Transitional Cell; Fluorouracil; Hepatic Encephalopathy; Humans; Ifosfamide; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Retroperitoneal Neoplasms; Salvage Therapy; Treatment Failure; Urologic Neoplasms

A phase II study is presented, which encompasses the period June 1987 until July 1993, and includes 53 patients with muscle-invasive bladder cancer T2-4b who, due to age and/or poor health (37 cases) or primarily extensive lesions (18 cases), were considered inoperable and for whom treatment with neoadjuvant chemotherapy (cisplatin/methotrexate/leucovorin rescue) and radical irradiation was planned. The total number of intended chemotherapy courses could be delivered without undue toxicity to 46 patients (83%) and 44 subsequently underwent radiotherapy: this modality was, by and large, well tolerated. The primary transurethral resection and chemotherapy produced an objective response in 62% of the 53 patients and in 75% of the 44 evaluable patients. The combined programme produced an objective response in 83% of the 37 evaluable patients, 71% in the 44 patients who completed the combined programme and in 59% of the total group of 53 patients. The follow-up ranged from 3 to 62 months. Radiotherapy increased the total objective response rate, proving effective in approximately 50% of patients who did not respond to chemotherapy. The results of this study are regarded as promising and pave the way for a phase III trial.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Transitional Cell; Chemotherapy, Adjuvant; Cisplatin; Combined Modality Therapy; Female; Humans; Injections, Intramuscular; Leucovorin; Male; Methotrexate; Middle Aged; Neoplasm Invasiveness; Radiotherapy Dosage; Remission Induction; Treatment Outcome; Urinary Bladder Neoplasms

34 patients with metastatic or recurrent transitional cell carcinoma (TCC) of the urothelium were treated with cisplatin 100 mg/m2 plus methotrexate 250 mg/m2 with folinic acid rescue every 3 weeks. A response rate of 55% was achieved with two complete and 15 partial responses in 31 evaluable patients. The overall median survival was 7 months, 9 months for responding and 4 months for non-responding patients. Toxicity was generally moderate. However, 1 patient with previous infectious problems died of neutropenic sepsis. Overall, 83% of the scheduled doses of cisplatin and 96% of the scheduled doses of methotrexate were given. In conclusion, this schedule of the combination of cisplatin and methotrexate did not improve response rate or survival compared with previous studies of this two-drug combination.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Transitional Cell; Cisplatin; Female; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Urinary Bladder Neoplasms

From 1986 to 1990 the European Organization for Research and Treatment of Cancer--Genitourinary Group conducted a phase 2 trial of neoadjuvant chemotherapy in patients with stage T3-4N0-XM0 transitional cell carcinoma of the bladder. The objectives were to evaluate the clinical response in relation to the pathological response, and to measure the side effects of chemotherapy. Of 171 patients entered 136 were fully evaluable: 18% had clinical complete remissions, 36% had clinical partial remissions, 39% had no clinical remissions and 10% had unknown response. A selected subgroup of 76 patients underwent cystectomy after 2 or 4 courses of chemotherapy: 2 were not evaluable for pathological response because of preoperative radiotherapy after neoadjuvant chemotherapy, 16 had a pathological complete remission, 7 had a pathological partial remission and 51 had no pathological remission. Comparison of the clinical response or T category only after 2 courses of chemotherapy with the pathological response after 2 or 4 courses of chemotherapy showed that in a number of patients the disease status could be downstaged to pathological complete or partial remission by additional courses of chemotherapy. If the discrepancies between clinical and pathological responses, or between T and P categories, induced by further downstaging after additional chemotherapy were left out, it was shown that clinical complete and partial remissions were a heterogeneous group but nonresponders could be delineated with a 100% accuracy by clinical response evaluation and transurethral resection biopsy only. Furthermore it seems important to establish the number of chemotherapy courses to induce a maximal response of the primary tumor.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Carcinoma, Transitional Cell; Chemotherapy, Adjuvant; Cisplatin; Combined Modality Therapy; Female; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Neoplasm Staging; Prospective Studies; Remission Induction; Sensitivity and Specificity; Urinary Bladder Neoplasms

Twenty-three patients with advanced recurrent head and neck carcinoma were randomized to receive either high dose methotrexate with calcium leucovorin rescue (HDMTX) or HDMTX in combination with bacilli Calmette Guerin (HDMTX/BCG). An additional eight patients were treated with escalating doses of HDMTX ranging from 1 to 7 g of methotrexate. Of 12 patients receiving HDMTX, one complete response and two partial responses were noted. Of 11 patients in the HDMTX/BCG group, one complete response and two partial responses were observed. Only one partial response was noted in eight patients receiving escalating doses of the drug. Responses were brief and no significant difference in response duration was seen in any particular group. Toxicities in all groups were tolerable. BCG did not improve response rate, median duration of response, or median survival in these patients. Reported experiences with high dose methotrexate have been reviewed and again, responses to "high dose methotrexate" were found to be of brief duration. Despite acceptable toxicity, the brief duration of response and cost of such therapy raises serious question on the usefulness of chemoimmunotherapy utilizing high dose methotrexate with leucovorin rescue and BCG in the management of advanced recurrent carcinomas of the head and neck region.

Topics: Adult; Aged; BCG Vaccine; Carcinoma, Squamous Cell; Carcinoma, Transitional Cell; Head and Neck Neoplasms; Humans; Leucovorin; Methotrexate; Middle Aged; Stomatitis

We investigated bladder urothelial carcinoma with peritoneal involvement.. Inclusion criteria were: pathology-confirmed urothelial carcinoma; peritoneal spread identified on computed tomographic (CT) scans performed initially or after either cystectomy or concomitant chemoradiotherapy (CCRT), and absence of visceral metastases; and chemotherapy administered after peritoneal spread was diagnosed.. Forty-seven cases included initial modes of therapy with chemotherapy in 24 patients (51%), cystectomy in 17 (36%), and CCRT in six (13%), only given as a result of under-staging. After local therapy, these patients received a continuous maintenance chemotherapy regimen of 5-fluorouracil, leucovorin, cisplatin, and gemcitabine. The overall response rate was 85%, and the side-effects were mild and tolerated. The median survival time was 28 months. The survival time of cases initially treated only with chemotherapy was not statistically different to that of those with local disease.. Bladder urothelial carcinomas with peritoneal involvement can benefit from continuous maintenance chemotherapy.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Transitional Cell; Chemoradiotherapy; Cisplatin; Cystectomy; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Humans; Leucovorin; Maintenance Chemotherapy; Male; Middle Aged; Peritoneal Neoplasms; Retrospective Studies; Survival Analysis; Treatment Outcome; Urinary Bladder Neoplasms

No standard has been established for salvage therapy in gemcitabine refractory advanced urothelial cancer. We report the complete response to FOLFOX4 therapy of a metastatic urothelial cancer patient, for whom adjuvant gemcitabine plus cisplatin combination chemotherapy had failed. A 54-year-old male patient with urothelial cancer (transitional cell carcinoma) in the right kidney underwent three rounds of adjuvant gemcitabine-cisplatin chemotherapy after extensive radical nephrectomy. However, he had new liver, lung metastases and synchronous two separate primary colon cancer. The lung metastasis lesion was confirmed as a metastatic urothelial cancer via percutaneous transthoracic needle biopsy (PTNB). Liver and lung metastasis lesions disappeared after the 4th cycle of FOLFOX4 chemotherapy. In addition, colon cancer also disappeared after the 8th cycle of FOLFOX4 chemotherapy. The patient was still showing a complete response after 4 months. Clinical trials using the FOLFOX regimen as salvage therapy for gemcitabine-refractory advanced urothelial cancer are warranted.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Transitional Cell; Disease Progression; Fluorouracil; Humans; Leucovorin; Lung Neoplasms; Male; Middle Aged; Neoplasm Invasiveness; Organoplatinum Compounds; Remission Induction; Treatment Outcome; Urologic Neoplasms; Urothelium

Despite recent progress in the treatment of advanced urothelial cancer, there continues to be a need to identify new active agents and their toxicity spectra. We conducted a study using FOLFOX-4 (oxaliplatin, fluorouracil, folinic acid) in pre-treated advanced bladder cancer patients.. Sixteen eligible patients with advanced disease were treated with oxaliplatin (85 mg/m(3)) on day 1 followed by fluorouracil and folinic acid (De Gramont schedule) on days 1 and 2 every 14 days until disease progression. All patients received nutritional support to increase their caloric intake. Objective responses and toxicity were evaluated. Biochemical responses (reduction of markers) and nutritional parameters (increase in body weight and albumin, and reduction in ferritin and C-reactive protein) were also considered.. Three patients obtained an objective response (overall response rate 19%). Hematological toxicity and stomatitis were the most commonly noted side effects, but we observed only low (3-4) grade toxicity. In four patients (25%), we observed a reduction in tumoral markers (carcinoembryonic antigen and tissutal polypeptide antigen) and modified nutritional parameters.. Using these doses and schedules of FOLFOX-4 appears to be a promising therapy in patients pre-treated with platinum compounds. More studies are required to assess the possible role of this regimen in the treatment of advanced bladder cancer.

Topics: Aged; Aged, 80 and over; Agranulocytosis; Anemia; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Carcinoembryonic Antigen; Carcinoma, Transitional Cell; Deoxycytidine; Drug Administration Schedule; Energy Intake; Female; Fluorouracil; Gemcitabine; Humans; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Stomatitis; Taxoids; Tissue Polypeptide Antigen; Urinary Bladder Neoplasms

To investigate the tolerance and efficacy of a modified concurrent chemoradiation (CCRT) protocol for patients with invasive bladder cancer "unfit" for radical cystectomy.. Twenty-three muscle-invasive bladder cancer patients who were unfit for or unwilling to receive radical cystectomy were enrolled in this study. All patients had transitional cell carcinoma of bladder, and distribution of stage was 14 (61%), 1 (4%), and 8 (35%) for T3a, T3b, and T4, respectively. This study included a relatively old-age population, with the median age being 75 and 70% of patients over 70 years old. Patients were treated with maximal transurethral resection of the bladder tumor followed by curative CCRT. The chemotherapy (C/T) regimen was comprised of cisplatin, 50 mg/m(2) intravenously (i.v.) on Day 1; 5-fluorouracil (5-FU), 500 mg/m(2)/day by continuous i.v. infusion on Days 1-3; and leucovorin, 50 mg/day by continuous i.v. infusion on Days 1-3. Chemotherapy course was repeated at 21-day intervals. The radiation dose was 44-45 Gy to whole pelvis and 60-61.2 Gy to bladder, with a daily fraction of 1.8-2 Gy. The completeness of the CCRT protocol was defined as patients receiving at least 55 Gy of radiotherapy to the whole bladder and at least three courses C/T.. Seventy-four percent of patients (17/23) completed the CCRT protocol. Radiation Therapy Oncology Group (RTOG) Grade 3 acute toxicities were observed in 4 patients, which included leucopenia, vomiting, genitourinary (GU) tract infection, and diarrhea. No treatment-related deaths occurred during the CCRT period. RTOG Grade 3 or more late complications were observed in 3 patients; one of them died of radiation cystitis superimposed with GU infection. Of the 18 patients whose response to CCRT was evaluated, a complete tumor response was documented in 16 patients (89%). With a median follow-up of 3 years, the 3-year overall survival (OS) and disease-free survival (DFS) for all patients was 69% and 65% respectively. Meanwhile, the 3-year overall and DFS rates for patients who completed CCRT vs. those who did not complete CCRT were 82% vs. 33% and 75% vs. 33%, respectively (p = 0.18 for OS and p = 0.04 for DFS).. Concurrent cisplatin, 5-FU, leucovorin, and radiotherapy for treatment of invasive bladder cancer is a feasible and promising treatment even for relatively old patients. Our results are comparable to those in recent studies by using combined modality treatment or neoadjuvant chemotherapy plus radical cystectomy. Consequently, this novel protocol warrants a prospective clinical trial and may be a safe, effective alternative to radical cystectomy.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Transitional Cell; Cisplatin; Combined Modality Therapy; Drug Administration Schedule; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Staging; Radiotherapy Dosage; Remission Induction; Survival Analysis; Urinary Bladder Neoplasms

Non-invasive magnetic resonance spectroscopy (MRS) can be used in the clinic to monitor the pharmacokinetics of the chemotherapeutic drug 5-fluorouracil (5-FU) and the effects of modifiers. We report two studies of 5-FU toxicity in normal tissue--one with patients and the other an animal study. 1) 19F MRS signals from fluoronucleotides, cytotoxic anabolites of 5-FU metabolism, were observed in the livers of two patients treated with 5-FU for colorectal cancer, shown by computed tomography (CT) and ultrasound (US) to have no liver metastases. This is the first report of non-invasive monitoring of toxic 5-FU metabolites in normal human tissues. 2) In animals, carbogen-breathing enhances tumour uptake and the efficacy of 5-FU, and the method is under trial in patients. This study demonstrates that there were no significant effects of carbogen breathing on the levels of 5-FU and its metabolites in normal rat tissues, or on the histology of the tissues assessed after treatment.

Topics: Adenocarcinoma; Animals; Antimetabolites, Antineoplastic; Biological Availability; Bone Marrow; Carbon Dioxide; Carcinoma, Transitional Cell; Colonic Neoplasms; Colorectal Neoplasms; Combined Modality Therapy; Fatal Outcome; Female; Fluorine Radioisotopes; Fluorodeoxyuridylate; Fluorouracil; Humans; Intestine, Small; Leucovorin; Liver; Liver Neoplasms; Magnetic Resonance Imaging; Middle Aged; Neoplasms, Multiple Primary; Oxygen; Rats; Rats, Inbred WF; Sigmoid Neoplasms; Tomography, X-Ray Computed; Ultrasonography; Urinary Bladder Neoplasms

The patient was a 71-year-old man who had been diagnosed as having a left renal pelvic cancer with liver metastasis. We performed total left nephroureterectomy with lymphnode cleaning and partial resection of the liver. Because abdominal CT 5 months after the operation revealed multiple metastasis of the liver, we performed chemotherapy with a regimen consisting of methotrexate 50 mg (intravenous injection), cisplatin 30 mg and pirarubicin 20 mg (intraarterial infusion), and leucovorin 3 mg (intramuscular injection), three times at intervals of 6 hours. Ten days after chemotherapy, CT revealed the disappearance of most of the liver metastatic lesions, and a partial response was obtained. We are now performing the regimen at an interval of a month to a month and one-half to control the metastatic lesions.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Transitional Cell; Cisplatin; Doxorubicin; Hepatic Artery; Humans; Infusions, Intra-Arterial; Infusions, Intravenous; Injections, Intramuscular; Kidney Neoplasms; Kidney Pelvis; Leucovorin; Liver Neoplasms; Lymph Node Excision; Lymphatic Metastasis; Male; Methotrexate

After radical cystectomy, with or without pelvic radiotherapy, more than 50% of patients affected by infiltrating bladder cancer died of distant metastases. Polychemotherapy yields 25% complete remissions (CR) in patients with invasive transitional cell bladder carcinoma; although many concerns exist about the duration of such CR. This study was undertaken with the aim of evaluating the efficacy and safety of an integrated chemo-radiotherapeutic treatment, in order to broaden indications to a conservative surgical therapy.. Thirty-three consecutive patients with bladder urothelial cancer T2-T4, N0, M0, have been treated. Patients received neoadjuvant chemotherapy (rescue-M-VEC) consisted of methotrexate 30 mg/sqm plus folinic acid 15 mg after 24 h on days 1, 15, 22; vinblastine 3 mg/sqm on days 1, 15 and 22; epidoxorubicin 30 mg/sqm on day 1; cisplatin 70 mg/sqm on day 1. This cycle was repeated on day 29. After 2 cycles of rescue-M-VEC, patients underwent pelvic cobalt teletherapy 40 Gy combined with low dose cisplatin 25 mg/sqm/week. After restaging, responding patients underwent further radiation therapy (24 Gy) as booster consolidation.. After 2 cycles of chemotherapy and pelvic radiotherapy 14/31 evaluable patients (45.2%) achieved CR and 11/31 (35.4%) partial remission, with an overall response rate of 80.6% (25/31). With a median follow up of 21 months the actuarial survival rate at 24 months was equal to 79.8%. Eleven radical cystectomies were performed, 6 of which at restaging in non responding patients and 5 during the follow up due to relapse. Of the 25 patients selected for bladder conservation, 12 (48%) have not yet shown relapses. Three out of 31 (9.7%) patients died of distant metastases. No severe toxicity has been observed: moreover no patient developed stomatitis after chemotherapy.. Our results seem encouraging but longer follow-up and further phase III studies need to be carried out to demonstrate the feasibility of conservative treatment in muscle infiltrating bladder cancer.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Transitional Cell; Cisplatin; Combined Modality Therapy; Doxorubicin; Female; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Neoplasm Staging; Pilot Projects; Radiotherapy Dosage; Remission Induction; Urinary Bladder Neoplasms; Vinblastine

A 56-year-old female underwent treatment with leucovorin and 5-fluorouracil for extensive metastatic moderately differentiated transitional cell carcinoma (TCC) of the renal pelvis. This resulted in a complete response for 20+ months. This combination has not been reported before in TCCs of the urinary tract and requires further exploration.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Transitional Cell; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Kidney Neoplasms; Kidney Pelvis; Leucovorin; Lymphatic Metastasis; Middle Aged; Remission Induction

Methotrexate (MTX) has activity in transitional cell carcinoma (TCC) in man and some have suggested an advantage of high-dose methotrexate versus the standard dose in controlling tumor growth and prolonging survival. MBT-2, a poorly differentiated TCC induced by the carcinogen FANFT, is both grossly and histologically similar to human TCC and has been used as an animal model. One hundred twenty C3H/HE female mice were injected in the hind limb with 7.5 X 10(4) MBT-2 tumor cells. When palpable tumors developed in all animals, therapy was initiated. Animals were randomized into a control group and nine treatment groups as follows: cisplatin (DDP), MTX32 mg, MTX50 mg, MTX80 mg, DDP + MTX32, MTX50 + Leucovorin, MTX80 + Leucovorin, DDP + MTX50 + Leucovorin, DDP + MTX80 + Leucovorin. The combination of MTX50 mg with Leucovorin + DDP and DDP alone were the two most effective regimens in controlling tumor growth and prolonging survival. No statistically significant difference was observed between the group treated by high-dose MTX alone and those treated by low-dose MTX. No toxicity was observed even when high doses of MTX were used.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Transitional Cell; Cisplatin; Dose-Response Relationship, Drug; FANFT; Female; Leucovorin; Methotrexate; Mice; Mice, Inbred C3H; Urinary Bladder Neoplasms

Nineteen patients with recurrent or metastatic transitional cell carcinoma of the urinary tract were treated with a 3-weekly combination of methotrexate 200 mg/m2 as a 24-h infusion with folinic acid rescue and cis-platin 100 mg/m2. An objective response rate of 68% was obtained, with 4 patients (21%) achieving complete remission. Pulmonary disease and lymph node metastases were particularly sensitive to this therapy. The median duration of response was 21 weeks with a median survival of 54 weeks in the responding patients. This regimen warrants further investigation in the treatment of invasive bladder carcinoma.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Transitional Cell; Cisplatin; Humans; Leucovorin; Methotrexate; Middle Aged; Neoplasm Metastasis; Urologic Neoplasms

Forty-nine patients with transitional urothelial tract tumors received methotrexate: 0.5-1.0 mg/kg I.V. Q W (40 patients) or 250 mg/M2 in a 2-hour infusion with citrovorum factor rescue 24 hours later (nine patients). Eleven (26%, 95% confidence limits 13-39%) of 42 patients with bidimensionally measurable metastases achieved partial remission. Most responses occurred within 2-3 weeks and persisted for a median duration of six months (range, 2-20). Response rates were increased to 38% (6/16 patients, 95% confidence limits 18-65%) in patients who had no prior chemotherapy, and a 90-100% performance status (50, 5/10 patients, 95% confidence limits 22-78%) compared with 19% (5/26, 95% confidence limits 8-37%) in patients who had prior chemotherapy and a less than or equal to 80% performance status (19%, 6/32 cases, 95% confidence limits 9-32%). Toxicity included mucositis and myelosuppression. A review of the literature coupled with the present data suggest that methotrexate is as active as cisplatin in the treatment of patients with advanced urinary bladder cancer.

Topics: Adult; Aged; Carcinoma, Transitional Cell; Drug Administration Schedule; Drug Evaluation; Female; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Prognosis; Ureteral Neoplasms; Urinary Bladder Neoplasms

Topics: Carcinoma, Transitional Cell; Drug Therapy, Combination; Humans; Leucovorin; Methotrexate; Neoplasm Invasiveness; Urinary Bladder; Urinary Bladder Neoplasms

Thirty-three patients with category T3 or T4 bladder cancer were treated by partial or total cystectomy followed by 6 to 12 courses of high-dose methotrexate (HDMTX) with folinic acid rescue. Survival at 2 years was 90%. Two patients were treated palliatively with HDMTX alone, one of whom is alive and disease free after 35 months.

Topics: Carcinoma, Transitional Cell; Drug Administration Schedule; Female; Humans; Leucovorin; Male; Methotrexate; Neoplasm Invasiveness; Neoplasm Staging; Prognosis; Urinary Bladder Neoplasms

Topics: Carcinoma; Carcinoma, Squamous Cell; Carcinoma, Transitional Cell; Geriatrics; Head and Neck Neoplasms; Humans; Infusions, Parenteral; Laryngeal Neoplasms; Leucovorin; Maxillary Neoplasms; Methotrexate; Nasopharyngeal Neoplasms; Neoplasm Metastasis; Neoplasms; Orbital Neoplasms; Palatal Neoplasms; Temporal Arteries; Tongue Neoplasms; Toxicology