Phase I Evaluation of Sequential Doxorubicin Gemcitabine Then Ifosfamide Paclitaxel Cisplatin for Patients With Unresectable or Metastatic Transitional-Cell Carcinoma of the Urothelial Tract
14 Feb 2000-Journal of Clinical Oncology (American Society of Clinical Oncology)-Vol. 18, Iss: 4, pp 840-846
TL;DR: AG was well tolerated at all dose levels, with no grade 3 or 4 myelosuppression, and Sequential chemotherapy with AG-ITP is also well tolerated, and phase II investigation at the highest dose level is ongoing.
Abstract: 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/m2 and gemcitabine 2,000 mg/m2, to determine the MTD of the regimen. The dose and schedule of ITP were constant: ifosfamide 1,500 mg/m2 (days 1 to 3); paclitaxel 200 mg/m2 (day 1); and cisplatin 70 mg/m2 (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 p...
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TL;DR: It is demonstrated that passively tumor-targeted polymeric drug carriers can be used for delivering two different chemotherapeutic agents to tumors simultaneously, and they thereby set the stage for more elaborate analyses on the potential of polymer-based multi-drug targeting.
243 citations
Cites methods from "Phase I Evaluation of Sequential Do..."
...HCl), triethylamine (Et3N), cathepsin B, ethylenediaminetetraacetic acid (EDTA) and reduced glutathione (GSH) were obtained from Fluka....
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...In the second step, this precursor was mixed with doxorubicin (0.045 g; 7.75 10 5 mol) in DMSO (3.5 ml), and Et3N (30 ml) was added in three portions....
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...P-Dox; poly(HPMA-co-MA-GFLGdoxorubicin; also known as PK1)) was synthesized by conjugating doxorubicin to poly(HPMA-co-MA-GFLG-ONp) in DMSO, in the presence of Et3N [18,24,26]....
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...The conjugate carrying only doxorubicin (i.e. P-Dox; poly(HPMA-co-MA-GFLGdoxorubicin; also known as PK1)) was synthesized by conjugating doxorubicin to poly(HPMA-co-MA-GFLG-ONp) in DMSO, in the presence of Et3N [18,24,26]....
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...All agents were applied once weekly for three weeks, rst, the monomers HPMA (1), MA-GFLG-TT (2) and MA-TyrNH2 (3) were copolymerized ecursor (4) in pyridine, yielding a copolymer containing besides gemcitabine several active groups in DMSO, in the presence of Et3N....
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TL;DR: Based on the antitumor activity of doxorubicin and gemcitabine in collecting duct carcinoma of the kidney, the authors used this combination to treat selected patients with sarcomatoid or rapidly progressing RCC.
Abstract: BACKGROUND
Immunotherapy is generally ineffective in patients with sarcomatoid renal cell carcinoma (RCC) and in patients with rapidly progressive metastatic or locally recurrent disease, with a median time to progression of approximately 2 months and a median survival of 4–7 months. Gemcitabine-based regimens have modest antitumor activity, whereas doxorubicin is often used to treat sarcomatoid RCC. Based on the antitumor activity of doxorubicin and gemcitabine in collecting duct carcinoma of the kidney, the authors used this combination to treat selected patients with sarcomatoid or rapidly progressing RCC.
METHODS
Eighteen patients (11 males and 7 females; median age, 53 years; range, 31–81 years) with RCC (56% sarcomatoid; 44% other) were treated at 2 institutions in a collaborative study that was not institutional review board reviewed. Seven patients received previous treatment with interferon or interleukin-2. Sites of metastases included the lung, soft tissue, bone, liver, and brain with 88% of patients having ≥ 3 sites of disease. Treatment consisted of doxorubicin (50 mg/m2) and gemcitabine (1500 or 2000 mg/m2) every 2–3 weeks with granulocyte–colony-stimulating factor support.
RESULTS
A median of 5 courses was administered (range, 2–12 cycles). Therapy was well tolerated with no Grade 4 toxicities. Two patients had a complete response, five had a partial response, three had a mixed response, and one had stable disease. The median duration of response was 5 months (range, 2–21+ months).
CONCLUSIONS
These data suggested that the combination of doxorubicin and gemcitabine has antitumor activity in patients with sarcomatoid RCC or with rapidly progressing RCC. A prospective investigation of this combination in RCC is warranted. Cancer 2004. © 2004 American Cancer Society.
167 citations
Cites methods from "Phase I Evaluation of Sequential Do..."
...The regimen consisted of doxorubicin (50 mg/m(2)) and gemcitabine (2000 mg/m(2)) every 2 weeks with growth factor support and was modeled after a highly effective and well tolerated regimen used to treat patients with advanced bladder carcinoma.(15) Based on this experience, we elected to use this regimen to treat patients with sarcomatoid RCC, and well as patients with rapidly progressive RCC of other histologies who may have progressed after immunotherapy...
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TL;DR: The results in this highly selected cohort suggest that resection of metastatic disease is feasible and may contribute to long-term disease control especially when integrated with chemotherapy.
140 citations
TL;DR: Collecting (Bellini) duct carcinoma of the kidney is associated with an aggressive course and an extremely poor prognosis and neither immunotherapy nor chemotherapy have been found to be effective.
Abstract: BACKGROUND
Collecting (Bellini) duct carcinoma (CDC) of the kidney is associated with an aggressive course and an extremely poor prognosis. To the authors' knowledge, there are no standard treatment regimens and neither immunotherapy nor chemotherapy have been found to be effective.
METHODS
In the current study, the authors report a 49-year-old man who presented with a 7.0 cm × 6.0 cm renal mass with extensive regional, paraaortic, and left supraclavicular lymphadenopathy. Radical nephrectomy revealed a CDC. The patient was treated with doxorubicin, 50 mg/m2 (Day 1), and gemcitabine, 2000 mg/m2 (Day 1), (AG) every 2 weeks with granulocyte–colony-stimulating factor (GCSF) support.
RESULTS
The left supraclavicular lymphadenopathy significantly decreased in size after the first cycle. Computed tomography (CT) scan after the third cycle revealed a significant (68%) reduction in the tumor volume. Toxicity was comprised of only CTC version 2.0, 1998; Grade 1 nausea and fatigue. After Cycle 6, a repeat CT scan demonstrated minimal disease progression. Based on recent Phase II data of an active regimen comprised of AG alternating with ifosfamide, paclitaxel, and cisplatin (ITP) in patients with transitional cell carcinoma, the patient was treated with ifosfamide, 1500 mg/m2 (Days 1–3); paclitaxel, 175 mg/m2 (Day 1); and cisplatin, 35 mg/m2 (Days 1 and 2), every 4 weeks with GCSF support. After two cycles of ITP, the patient developed disease progression in bone and received palliative radiation therapy. Follow-up CT scan demonstrated new liver metastases. The patient received palliative care without further chemotherapy and died approximately 10 months after the initial diagnosis of CDC.
CONCLUSIONS
Immunohistologic and molecular analyses indicate that CDC more closely resembles transitional cell carcinoma than renal cell carcinoma. Chemotherapy regimens used to treat advanced transitional cell carcinoma such as AG should be evaluated as first-line therapy for CDC. Cancer 2002;94:111–6. © 2002 American Cancer Society.
94 citations
Cites background or methods from "Phase I Evaluation of Sequential Do..."
...The patient received a dose-intense regimen of doxorubicin, 50 mg/m(2) (Day 1), and gemcitabine, 2000 mg/m(2) (Day 1), (AG) every other week with granulocyte– colony-stimulating factor (GCSF) support.(6) After the first cycle of chemotherapy, the left supraclaviclular and base of neck lymphadenopathy were found to have significantly decreased in size on physical examination and the patient’s left arm paresthesias resolved....
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...Based on recent data using an active regimen comprised of AG alternating with ifosfamide, paclitaxel, and cisplatin (ITP) in patients with TCC, we elected to treat our patient with ifosfamide, 1500 mg/m(2) (Days 1–3); paclitaxel, 175 mg/m(2) (Day 1); and cisplatin, 35 mg/m(2) (Days 1–2), every 4 weeks with GCSF support.(6) The patient received two cycles of ITP and developed lower back and left hip pain....
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...Phase I data suggest that regimens combining doxorubicin and gemcitabine (AG) and those combining ifosfamide, paclitaxel, and cisplatin (ITP) are well tolerated, active regimens.(6) A recent Phase II trial of 21 patients with TCC who were treated with sequential AG followed by ITP reported that a major response (either complete response or partial response) was achieved in 18 patients (86%)....
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TL;DR: FAP is very likely to be inferior to M-VAC and is certainly no less toxic, and cannot be recommended as part of the standard armamentarium for urothelial cancer.
Abstract: PURPOSE: Previously, we developed a novel biochemotherapy regimen combining interferon alfa-2b with fluorouracil and cisplatin (FAP). We now report the results of a prospective randomized trial comparing FAP with methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC), the standard chemotherapy regimen for locally advanced and metastatic urothelial cancer. The purpose of this study was to compare the response rates and overall survival of patients with metastatic or unresectable urothelial cancer treated with these two chemotherapy regimens. PATIENTS AND METHODS: Between October 1992 and September 1999, 172 previously untreated patients were registered and randomly assigned to treatment with either FAP or M-VAC. Patients were followed until their death. RESULTS: The pretreatment clinical characteristics of the groups were similar except for sex (P < .01). Sex did not affect prognosis or survival. The objective response rate for patients assigned to FAP was 42% (35 of 83 patients), with complete resp...
80 citations
References
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TL;DR: Although a more toxic regimen, M-VAC was found to be superior to single-agent cisplatin with respect to response rate, duration of remission, and overall survival in patients with advanced urothelial carcinoma.
Abstract: PURPOSEA 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 METHODSFrom 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.RESULTSAs expected, the M-VAC regimen was associated with a greater toxicity, especially leukopenia, mucositis, granulocytopenic fever, and drug-related mortality. Respons...
871 citations
TL;DR: Although 68% of CR patients have relapsed, CR median survival will exceed 38 months compared with 11 months for partial (36%) and minor (6%) responders, and 8 months for nonresponders: 2‐year and 3‐year survivals were 68% and 55%, respectively, versus 0% to 7% for the remaining patients.
Abstract: Of 133 patients with advanced urothelial tract cancer given methotrexate (MTX), vinblastine (VBL), Adriamycin (ADR) (doxorubicin; Adria Laboratories, Columbus, OH), and cisplatin (DDP) (M-VAC regimen), significant tumor regression occurred in 72% +/- 8% of 121 with transitional cell carcinoma (TCC) evaluable for response. Complete remission (CR) was achieved in 36% +/- 9% of patients, of whom 11% required the addition of surgical resection of residual disease. Although 68% of CR patients have relapsed, CR median survival will exceed 38 months compared with 11 months for partial (36%) and minor (6%) responders, and 8 months for nonresponders: 2-year and 3-year survivals were 68% and 55%, respectively, versus 0% to 7% for the remaining patients. Sixteen percent of responders developed brain lesions, half of whom had no systemic relapse at the time of progression. Three patients with non-TCC histologies did not respond. In 32 patients who had pathologic restaging, the clinical (T) understaging (T less than pathologic [P] restaging) error was 35%. Although all metastatic sites showed evidence of tumor regression, CR was noted more frequently in lung, in intraabdominal lymph nodes and masses, and in bone (24% to 35%); the rate for hepatic lesions was 15%. There were 52% of 21 N3-4M0 patients who achieved CR versus 33% of 100 with N0-+M+ lesions. Toxicity was significant with 4 (3%) drug-related deaths, 25% incidence of nadir sepsis, 58% greater than or equal to 3+ myelosuppression, and 49% with mucositis. Responsiveness of metastasis in various sites, patterns of relapse, and the usefulness of the new CR response criteria are reported, as is the current status of cisplatin and methotrexate combination regimens.
614 citations
01 Jan 1989
TL;DR: In this article, a study of 133 patients with advanced urothelial tract cancer given methotrexate (MTX), vinblastine (VBL), Adriamycin (ADR) (doxorubicin; Adria Laboratories, Columbus, OH), and cisplatin (DDP) (M•VAC regimen, significant tumor regression occurred in 72% ± 8% of 121 with transitional cell carcinoma (TCC) evaluable for response.
Abstract: Of 133 patients with advanced urothelial tract cancer given methotrexate (MTX), vinblastine (VBL), Adriamycin (ADR) (doxorubicin; Adria Laboratories, Columbus, OH), and cisplatin (DDP) (M‐VAC regimen), significant tumor regression occurred in 72% ± 8% of 121 with transitional cell carcinoma (TCC) evaluable for response. Complete remission (CR) was achieved in 36% ± 9% of patients, of whom 11% required the addition of surgical resection of residual disease. Although 68% of CR patients have relapsed, CR median survival will exceed 38 months compared with 11 months for partial (36%) and minor (6%) responders, and 8 months for nonresponders: 2‐year and 3‐year survivals were 68% and 55%, respectively, versus 0% to 7% for the remaining patients. Sixteen percent of responders developed brain lesions, half of whom had no systemic relapse at the time of progression. Three patients with non‐TCC histologies did not respond. In 32 patients who had pathologic restaging, the clinical (T) understaging (T < pathologic [P] restaging) error was 35%. Although all metastatic sites showed evidence of tumor regression, CR was noted more frequently in lung, in intraabdominal lymph nodes and masses, and in bone (24% to 35%); the rate for hepatic lesions was 15%. There were 52% of 21 N3–4Mo patients who achieved CR versus 33% of 100 with No‐+M+ lesions. Toxicity was significant with 4 (3%) drug‐related deaths, 25% incidence of nadir sepsis, 58% ⩾ 3+ myelosuppression, and 49% with mucositis. Responsiveness of metastasis in various sites, patterns of relapse, and the usefulness of the new CR response criteria are reported, as is the current status of cisplatin and methotrexate combination regimens. Cancer 64:2448–2458, 1989.
604 citations
TL;DR: It is concluded that MVAC chemotherapy is superior to CISCA chemotherapy, achieving a higher response rate and a longer survival for equivalent patients with metastatic urothelial tumors.
Abstract: To evaluate the relative efficacy of cisplatin, cyclophosphamide, and Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH) (CISCA) versus methotrexate, vinblastine, Adriamycin, and cisplatin (MVAC), a prospective randomized trial was performed in patients with advanced metastatic urothelial tumors. Patients were stratified by histologic disease type and degree of tumor dissemination. Equal distribution of the clinical characteristics was achieved. One hundred ten patients with metastatic disease of the urinary tract (86 bladder, 16 renal pelvis, seven ureter, one prostatic urethra) met eligibility criteria and were enrolled on study. These represented 82% of the total patients seen during the study period in the Section of Genitourinary Oncology who met the eligibility criteria. The combined complete and partial response rate was significantly higher for patients treated with MVAC than for those treated with CISCA (65% v 46%; P less than .05). The survival duration of MVAC-treated patients was significantly longer than that of CISCA-treated patients (mean, 62.6 weeks; median, 48.3; range, 5.0+ to 162.3+ v mean, 40.4 weeks; median, 36.1; range, 7+ to 147.1+). We conclude that MVAC chemotherapy is superior to CISCA chemotherapy, achieving a higher response rate and a longer survival for equivalent patients with metastatic urothelial tumors.
572 citations
TL;DR: Long-term follow-up evaluation of the intergroup trial confirms that M-VAC is superior to single-agent cisplatin in patients with advanced urothelial carcinoma; however, durable progression-free survival is rare.
Abstract: PURPOSEA previously reported randomized intergroup trial demonstrated that combination chemotherapy with methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) was superior to single-agent cisplatin in patients with advanced urothelial carcinoma. We conducted a long-term analysis of patients included in the intergroup trial to examine factors associated with long-term survival.PATIENTS AND METHODSTwo-hundred fifty-five assessable patients with urothelial carcinoma were randomized to receive either single-agent cisplatin (70 mg/m2 on day 1) or combination chemotherapy with methotrexate (30 mg/m2 on days 1, 15, and 22), vinblastine (3 mg/m2 on days 2, 15, and 22), doxorubicin (30 mg/m2 on day 2), and cisplatin (70 mg/m2 on day 2). Courses were repeated every 28 days. The association between patient characteristics and survival was assessed using Cox proportional hazards models.RESULTSWith long-term follow-up evaluation, survival in the M-VAC arm continues to be superior to cisplatin (P = .00015, log-...
486 citations