Phase I evaluation of sequential doxorubicin gemcitabine then ifosfamide paclitaxel cisplatin for patients with unresectable or metastatic transitional-cell carcinoma of the urothelial tract.

PURPOSE: This phase I trial sought to evaluate the toxicity of and determine the maximum-tolerated dose (MTD) for the two-drug regimen doxorubicin and gemcitabine (AG) followed by the three-drug regimen of ifosfamide, paclitaxel, and cisplatin (ITP) in patients with unresectable or metastatic transitional-cell carcinoma. PATIENTS AND METHODS: Patients received AG every other week for six cycles followed by ITP every 3 weeks for four cycles. Five AG dose levels were investigated, up to doxorubicin 50 mg/m(2) and gemcitabine 2, 000 mg/m(2), to determine the MTD of the regimen. The dose and schedule of ITP were constant: ifosfamide 1,500 mg/m(2) (days 1 to 3); paclitaxel 200 mg/m(2) (day 1); and cisplatin 70 mg/m(2) (day 1). Granulocyte colony-stimulating factor was given between all cycles of therapy. RESULTS: Fifteen patients enrolled onto this phase I trial. AG was well tolerated at all dose levels, with no grade 3 or 4 myelosuppression. Toxicity experienced with ITP included grade 3 and 4 granulocytopenia in four patients and grade 3 nausea/vomiting in three patients. No grade 3 and 4 neurotoxicity was observed. Eight of 14 assessable patients experienced a major response to AG, including five of six patients treated at the two highest AG dose levels. After completion of AG-ITP, nine of 14 assessable patients had a major response (three complete responses and six partial responses). CONCLUSION: AG is a well-tolerated and active regimen. Sequential chemotherapy with AG-ITP is also well tolerated, and phase II investigation at the highest dose level is ongoing.

Long-term survival in metastatic transitional-cell carcinoma and prognostic factors predicting outcome of therapy.

PURPOSE: The variation in reported survival of patients with metastatic transitional-cell carcinoma (TCC) treated with systemic chemotherapy may be a consequence of pretreatment patient characteristics. We hypothesized that a prognostic factor-based model of survival among patients treated with methotrexate, vinblastine, doxorubicin, and cisplatin chemotherapy could account for such differences and help guide clinical trial design and interpretation. PATIENTS AND METHODS: A database of 203 patients with unresectable or metastatic TCC was retrospectively subjected to a multivariate regression analysis to determine which patient characteristics had independent prognostic significance for survival. Patients were assigned to three risk categories depending on the number of unfavorable characteristics. Patient selection in phase II studies was addressed by developing a table of expected median survival for patient cohorts that had varying proportions of patients from the three risk categories. RESULTS: Two factors had independent prognosis: Karnofsky performance status (KPS) less than 80% and visceral (lung, liver, or bone) metastasis. Median survival times for patients who had zero, one, or two risk factors were 33, 13.4, and 9.3 months, respectively (P =.0001). The median survival time of patient cohorts could vary from 9 to 26 months simply by altering the proportion of patients from different risk categories. CONCLUSION: The presence of baseline KPS less than 80% or visceral metastasis has an impact on survival. Reporting the proportion of patients with zero, one, and two risk factors will facilitate understanding of the relevance of the median survival in phase II trials. Phase III trials should stratify patients according to the number of risk factors to avoid imbalance in treatment arms.

Outcome of postchemotherapy surgery after treatment with methotrexate, vinblastine, doxorubicin, and cisplatin in patients with unresectable or metastatic transitional cell carcinoma.

PURPOSE: The role of postchemotherapy surgery for patients with metastatic transitional cell carcinoma (TCC) is controversial. We retrospectively analyzed our experience with patients who underwent postchemotherapy surgery after methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) chemotherapy to assess an impact on long-term survival. PATIENTS AND METHODS: This report is based on the retrospective analysis of 203 patients with unresectable primary tumors or metastatic TCC, previously reported in five trials of M-VAC chemotherapy. Fifty patients underwent postchemotherapy surgery for suspected or known residual disease. Characteristics of patients selected for surgery, results of surgery, and the impact of surgery on survival were assessed. RESULTS: In 17 patients, no viable tumor was found at postchemotherapy surgery, pathologically confirming a complete response to chemotherapy. Three patients had unresectable residual TCC. In 30 patients, residual, viable TCC was completely resected, which resulted in a complete response to chemotherapy plus surgery. Ten (33%) of these 30 patients remained alive at 5 years, similar to results observed for patients who attained a complete response to chemotherapy alone (41%). Analysis by baseline extent of disease suggested that patients with unresectable primary tumors or with metastases restricted to lymph node sites were most likely to survive for 5 years. CONCLUSION: Postchemotherapy surgical resection of residual cancer may result in 5-year disease-free survival in some patients who would otherwise succumb to disease. Optimal candidates include patients whose prechemotherapy sites of disease are restricted to the primary or lymph node sites and who have a major response to chemotherapy.

Poor-risk germ cell tumors. Recent developments.

Standard therapy for patients with poor-risk germ cell tumors remains four cycles of bleomycin, etoposide, and cisplatin (BEP) chemotherapy, which cures approximately 50% of this patient population. Randomized trials of conventional-dose chemotherapy have failed to identify a regimen with superior efficacy to BEP. Preliminary data suggesting efficacy for high-dose chemotherapy with stem cell or autologous bone marrow transplantation as initial therapy for poor-risk disease have led to two randomized trials of this approach as initial therapy for poor-risk patients. The recently developed International Germ Cell Consensus Classification provides a standard method for determining poor-risk status and should be uniformly applied for both clinical decision making and risk assignment in clinical trials.

New chemotherapy regimens for metastatic bladder cancer.

M-VAC remains the standard of care for metastatic transitional cell carcinoma (TCC), but its limitations include significant toxicity and infrequent durable disease-free survival. Recent investigation has focused on the identification of novel chemotherapeutics with single-agent activity in metastatic TCC and on their incorporation into more active combination regimens. Paclitaxel, gemcitabine and ifosfamide are among the most active new agents. Numerous phase II trials of novel combinations have yielded promising preliminary results. Longer follow-up and results from randomized trials will be necessary to determine the impact of newer chemotherapy regimens on survival.

Phase II trial of pyrazoloacridine as second-line therapy for patients with unresectable or metastatic transitional cell carcinoma.

PURPOSE: A phase II trial of pyrazoloacridine (PZA) was conducted to assess its activity and toxicity in patients with advanced transitional cell carcinoma (TCC) refractory to or progressing after one prior cisplatin-, carboplatin- or paclitaxel- based regimen. PATIENTS AND METHODS: PZA at a dose of 750 mg/m2 was administered to 14 patients as a three-hour intravenous infusion on day 1 every 21 days. Premedication consisted of lorazepam 0.5-1.0 mg prior to each cycle to alleviate central nervous system toxicity. Reduction of subsequent doses was made for hematologic or central nervous system toxicity. RESULTS: Among fourteen patients evaluable for response, no responses were observed (0% response rate; 95% confidence interval 0% to 23%). The median duration of survival for all patients was 9 months with a median follow-up of 8.5 months. Toxicity to PZA included grade 3 or 4 neutropenia in 8/14 (57%) and grade 3 or 4 thrombocytopenia in 2/14 (14%). Non-hematologic toxicity was mild. CONCLUSIONS: PZA at this dose and schedule does not have significant single-agent activity in patients with TCC who have failed one prior regimen.

Evaluation of drug delivery and survival impact of dose-intense relative to conventional-dose methotrexate, vinblastine, doxorubicin, and cisplatin chemotherapy in urothelial cancer.

The efficacy of dose-intense methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) chemotherapy relative to conventional-dose M-VAC in patients with advanced transitional cell carcinoma is unknown. The outcomes of 33 patients on two successive protocols using dose-intense M-VAC with granulocyte colony-stimulating factor (G-CSF) support were compared with those of 129 patients treated with conventional-dose M-VAC to assess for an impact of dose-intense therapy on long-term survival. The mean relative dose intensity of chemotherapy delivered to the dose-intense cohort was 55% higher than that delivered to the conventional-dose cohort (p = 0.0001). However, no significant differences were observed with regard to response proportion (72% vs. 76%), median survival (13.3 vs. 16.7 months, p = 0.31), or 5-year survival (16% vs. 15%). Growth factor support enabled a statistically significant increase in the delivered dose intensity of M-VAC chemotherapy, but no survival advantage relative to conventional-dose M-VAC was observed.

Ifosfamide, paclitaxel, and cisplatin for patients with advanced transitional cell carcinoma of the urothelial tract: final report of a phase II trial evaluating two dosing schedules.

BACKGROUND: A combination regimen of ifosfamide, paclitaxel, and cisplatin (ITP), recycled every 4 weeks, was reported in the treatment of previously untreated patients with advanced transitional cell carcinoma (TCC). This study sought to examine ITP at 3-week intervals to assess its feasibility and toxicity, compare the results for different schedules, and assess the impact of prognostic factors and postchemotherapy surgery on outcome. METHODS: ITP (ifosfamide 1.5 g/m(2) daily for 3 days, paclitaxel 200 mg/m(2) over 3 hours, and cisplatin 70 mg/m(2) on Day 1) was administered to patients with metastatic or unresectable TCC and was recycled every 4 weeks (for 30 patients) or 3 weeks (for 15 patients). Granulocyte-colony stimulating factor was given during each cycle. RESULTS: Thirty of 44 assessable patients (68%; 95% confidence interval, 52-81%) demonstrated a major response (10 complete responses [23%], 20 partial [45%]), with durations of response ranging from 4 to 36 months. At a median follow-up of 28 months, the median survival was 20 months. Eleven patients (25%) were disease free at last follow-up. Overall toxicity for the 15 patients whose treatment was recycled at 3 weeks was similar to that for patients treated every 4 weeks. Hematologic toxicity included anemia, thrombocytopenia, and febrile neutropenia. Febrile neutropenia was observed in 7 patients (16%) and in 3.3% of cycles of therapy. No Grade 4 nonhematologic toxicity was observed. Grade 3 nonhematologic toxicity included alopecia, renal insufficiency (11%), and neuropathy (9%). CONCLUSIONS: ITP is an active, well-tolerated regimen for previously untreated patients with TCC of the urothelial tract, resulting in a median survival of 20 months. Treatment can be recycled at 3-week intervals without enhanced toxicity.

HHS circulating regulations finalized on June 17.

On June 17, 1986, the US Department of Health and Human Services (HHS) published its final regulations in the Federal Register governing the hospital Conditions of Participation in Medicare and Medicaid programs. The final regulations state that "In accordance with applicable State laws and approved medical staff policies and procedures, ...surgical technologists may assist in circulatory duties under the supervision of a qualified registered nurse who is immediately available to respond to emergencies". Coming after a dozen years of exhaustive research and debate on the conditions, HHS deleted the work "direct" as it applies to the degree of supervision required for circulating surgical technologists because, HHS states, "it will give hospitals maximum flexibility to manage their internal procedures...and will recognize appropriately the special qualifications of surgical technologists". The following article will provide you with the historical background and development of this regulation, scheduled to take effect on September 15.

Phase II trial of intermediate dose methotrexate in combination with vinblastine, doxorubicin, and cisplatin in patients with unresectable or metastatic transitional cell carcinoma.

BACKGROUND: This study was undertaken to determine whether the use of intermediate dose methotrexate in combination with vinblastine, doxorubicin, and cisplatin as first-line therapy increases the proportion of major responders and overall survival in patients with unresectable or metastatic transitional cell carcinoma (TCC) of the urothelial tract. METHODS: Twenty-nine patients with histologically confirmed TCC received methotrexate at a dose of 1000 mg/m2 on Day 1 followed by leucovorin calcium rescue on Day 2 and vinblastine (3 mg/m2), doxorubicin (30 mg/m2), and cisplatin (70 mg/m2) (VAC) on Day 2. Therapy was recycled at 28-day intervals. RESULTS: Fourteen of 28 patients (50%; 95% confidence interval [CI], 31-69%) achieved a major response, including 6 pathologic or clinical complete responses (CR) and 8 partial responses (PR). Nine patients were rendered disease free after postchemotherapy surgical resection of residual disease (surgical CR), including five patients who had PR and four nonresponders to chemotherapy alone. Five of 18 patients with disease limited to lymph nodes attained CR, in contrast to only 1 of 10 patients with visceral metastatic disease. The median survival for the entire population was 13.6 months. CONCLUSIONS: The escalation of methotrexate to 1000 mg/m2 in combination with vinblastine, doxorubicin, and cisplatin did not result in a response proportion or median survival superior to that observed with standard dose M-VAC. As previously observed in a Phase II trial of M-VAC, only the attainment of CR was associated with prolongation of survival.