Phase II study of cisplatin and paclitaxel in advanced carcinoma of the urothelium: an Eastern Cooperative Oncology Group Study.

PURPOSE: Cisplatin and paclitaxel are active agents in advanced urothelial cancer. A phase II trial of this combination was performed to determine the activity and toxicity of these agents in a multi-institutional setting. PATIENTS AND METHODS: Fifty-two patients with advanced urothelial carcinoma were treated on one day with paclitaxel 175 mg/m(2) over 3 hours followed by cisplatin 75 mg/m(2), both intravenously, every 21 days. Cycles were repeated every 21 days until progression or a maximum of six cycles. RESULTS: Twenty-six patients obtained an objective response, for an overall response rate of 50% (95% confidence interval, 36% to 64%). Four patients achieved complete clinical responses. The median overall survival time for the group was 10.6 months. Toxicity was moderate, with granulocytopenia and neurotoxicity being the most common side effects noted. CONCLUSION: The combination of cisplatin and paclitaxel is active in advanced urothelial cancer. Responses in visceral, nodal, and soft tissues sites were observed. Granulocytopenia without fever and grade 2/3 neurotoxicity were common. The confidence interval of the overall response rate in this study overlaps most of the other reported regimens. The optimal therapy for advanced urothelial cancer remains undefined.     

Paclitaxel, cisplatin, and 5-fluorouracil for patients with advanced or recurrent squamous cell carcinoma of the head and neck

BACKGROUND: The combination of cisplatin and 5-fluorouracil (5-FU) is considered standard therapy for patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). Paclitaxel has exhibited single-agent activity in patients with this disease. The authors conducted this study to evaluate the feasibility and efficacy of combining paclitaxel with cisplatin and 5-FU for patients with advanced or recurrent SCCHN. METHODS: Patients with recurrent, metastatic, or locally advanced SCCHN who had measurable or evaluable disease and no prior chemotherapy were eligible. The starting dose level consisted of paclitaxel 135 mg/m(2) on Day 1, cisplatin 75 mg/m(2) on Day 2, and 5-FU 1 gm/m(2)/day on Days 2-6. Due to Grade 4 mucositis, dose level 1 of 5-FU was reduced to 800 mg/m(2)/day on Days 2-6 (for 7 patients), and subsequently the 5-FU dose was adjusted to 1 gm/m(2)/day on Days 2-5 (for 17 patients). RESULTS: Twenty-five patients were enrolled, with a median age of 60 years and a median Southwest Oncology Group performance status of 1. Of the 25 patients, 16 had recurrent disease, 3 had metastatic disease at diagnosis, and 6 had untreated locally advanced SCCHN. Ninety-nine courses of therapy were administered, with a median of 5 courses. Major toxicities were neutropenia and mucositis. Significant neurotoxicity or nephrotoxicity were not observed. There were two treatment-related deaths (one each due to mucositis and neutropenic pneumonia), and these precluded further dose escalation. Fifteen of the 25 patients (60%) achieved a major response. Of significance is the response rate of 58% (11 of 19 patients) in those with recurrent or metastatic disease who had a duration of response ranging from 3 to 19+ months. Two of these 19 patients continue to be in remission of 19+ and 15+ months' duration, respectively. The median survival for patients with recurrent or metastatic disease was 6 months (range, 1-26 months), with a 1-year survival rate of 37%. CONCLUSIONS: The dose and schedule for the combination of paclitaxel, 5-FU, and cisplatin as determined in this study are feasible, with encouraging outcomes and activity in patients with recurrent or metastatic SCCHN. The results of this trial warrant larger-scale evaluation to determine the role of this combination in the management of patients with this disease.     

Chemotherapy with cisplatin and paclitaxel in patients with locally advanced, recurrent or metastatic oesophageal cancer.

Single-agent therapy with paclitaxel is effective against both squamous cell carcinoma and adenocarcinoma of the oesophagus. However, only limited data are available on the combination of paclitaxel with other cytotoxic drugs in this entity. Patients with unresectable stage III, recurrent or metastatic tumours were treated in a multicentre setting with paclitaxel 90 mg m(-2) given over 3 h intravenously, followed by cisplatin 50 mg m(-2). The courses were repeated every 14 days. Twenty patients with squamous cell carcinoma or adenocarcinoma of the oesophagus were evaluable for response. The overall remission rate was 40% (8/20), including 15% (3/20) clinically complete responses. Clinical benefit response, defined as relief of dysphagia and/or significant gain in weight, was achieved in 70% of the patients. Neutropenia of CTC grade 3 occurred only in 10% of the patients; no grade 4 neutropenia and no severe thrombocytopenia was encountered. CTC grade 4 neurotoxicity was seen in 5% of patients. Cisplatin/paclitaxel administered every 14 days, was effective in patients with poor prognosis oesophageal cancer and toxicity was acceptable.     

Phase II trial of low-dose paclitaxel and cisplatin in patients with advanced gastric cancer

BACKGROUND: Paclitaxel has shown promising activity in gastric cancer and has synergism with cisplatin. This study was performed to evaluate the efficacy and toxicity of low-dose paclitaxel (145 mg/m(2)) plus cisplatin chemotherapy in metastatic or relapsed gastric cancer. METHODS: Chemotherapy-na?ve patients with metastatic or relapsed gastric cancer were enrolled. Paclitaxel 145 mg/m(2) was administered intravenously over 3 h, followed by cisplatin 60 mg/m(2) on Day 1 every 3 weeks in the outpatient setting. RESULTS: Of 39 patients enrolled, 17 (44%) had partial responses. Twelve (31%) had stable disease and eight (21%) progressive disease. Two patients (5%) were not evaluable because of early drop-out. The median time to progression was 4.7 months and the median overall survival was 12.1 months. The most common hematologic toxicity was anemia (41%). Grade 3/4 neutropenia and thrombocytopenia developed in 14 and 3%, respectively. The most common non-hematologic toxicities were peripheral neuropathy (43%) and emesis (43%). Grade 3/4 non-hematologic toxicities included emesis (11%), peripheral neuropathy (3%), diarrhea (3%) and hepatotoxicity (3%). CONCLUSIONS: Low-dose paclitaxel and cisplatin chemotherapy was active and well-tolerated in chemotherapy-na?ve gastric cancer patients. This regimen seems to have comparable efficacy to previously reported higher-dose paclitaxel plus cisplatin-containing regimens and fewer toxicities.     

Dose-dense cisplatin/paclitaxel. a well-tolerated and highly effective chemotherapeutic regimen in patients with advanced ovarian cancer

A randomised phase I/II trial with weekly cisplatin 70 mg/m(2) (days 1, 8, 15, 29, 36, 43) in combination with escalating doses of paclitaxel either 4-weekly or weekly was conducted in 49 patients with ovarian cancer; patients were chemotherapy-nai;ve or had a first relapse after platinum-based chemotherapy. Paclitaxel could be safely escalated to 225 mg/m(2) 4-weekly or 100 mg/m(2) weekly, with fatigue as the major adverse event. Myelosuppression, renal toxicity and neurotoxicity were mild to moderate. Pharmacokinetic analysis showed an approximately 2-fold reduction of DNA-adduct formation in leucocytes compared with cisplatin without paclitaxel. No pharmacokinetic interaction was found between paclitaxel and cisplatin. After (re-)induction, additional chemotherapy consisted of conventional paclitaxel/cisplatin, paclitaxel/carboplatin, paclitaxel single agent or carboplatin/cyclophosphamide. The overall response rate was 94% in 17 evaluable chemotherapy-nai;ve patients and 84% in 25 patients with recurrent disease. Median progression-free survival (PFS) was 17 months (chemotherapy-nai;ve: 23 months, recurrent: 11 months) and median overall survival was 41 months (chemotherapy-nai;ve: 48 months, recurrent: 24 months). In conclusion, both cisplatin/paclitaxel regimens showed excellent activity with manageable toxicity in patients with advanced ovarian cancer.     

Ifosfamide, paclitaxel and cisplatin first-line chemotherapy in advanced, suboptimally debulked epithelial ovarian cancer.

BACKGROUND: The combination of paclitaxel with a platinum analogue is the preferred chemotherapy regimen in the treatment of advanced epithelial ovarian carcinoma. The alkylating agent ifosfamide has shown activity in refractory or recurrent ovarian cancer. We conducted a Phase II study with the combination of ifosfamide, paclitaxel, and cisplatin for the treatment of newly diagnosed patients with advanced, suboptimally debulked ovarian carcinoma. METHODS: Thirty-five consecutive patients with advanced ovarian carcinoma (International Federation of Gynecology and Obstetrics [FIGO] Stage III or IV) and residual disease larger than 2 cm after staging laparotomy and cytoreductive surgery were treated with paclitaxel, 175 mg/m(2), as a 3-hour intravenous infusion on Day 1, cisplatin 75 mg/m(2) intravenously over 2 hours on Day 2, and ifosfamide 1500 mg/m(2) intravenously over 1 hour on Days 1-3 (with sodium 2-mercaptoethane sulfonate [MESNA] uroprotection). Courses were administered every 3 weeks on an outpatient basis. Granulocyte-colony stimulating factor was given at a dose of 5 microg/kg/day on Days 7-11. RESULTS: Among 26 patients with measurable disease, 22 (85%) achieved an objective response including 15 complete and 7 partial responses. With a minimum follow-up of 46 months, the median overall survival was 52.8 months (range, 5.3-56.6+ mos), whereas the median time to progression for all patients was 22.2 months. The median remission duration for women with measurable disease who responded to treatment was 12.6 months. The treatment was tolerated relatively well without toxic deaths; the most common toxicity was Grade 3 or 4 neutropenia that occurred in 42% of patients. Significant peripheral neuropathy (Grade 2 or higher) developed in 35% of patients. CONCLUSION: The combination of ifosfamide, paclitaxel, and cisplatin is a well-tolerated outpatient regimen with significant activity in the treatment of newly diagnosed FIGO Stage III or IV epithelial ovarian carcinoma. Further evaluation is justified to clearly define the role of ifosfamide as an additional agent to the current platinum and paclitaxel regimens.     

Paclitaxel by three-hour infusion and carboplatin in advanced carcinoma of nasopharynx and other sites of the head and neck

Background: Paclitaxel has been demonstrated to have significant activityin recurrent or metastatic head and neck cancer (HNC). In addition, thecombination of paclitaxel and cisplatin is active in untreated patients withinoperable HNC. Substitution of carboplatin for cisplatin allows the treatmentto be delivered on an outpatient basis.Purpose of the study: To evaluate the activity and toxicity of thecombination of paclitaxel by three-hour infusion and carboplatin as first-linechemotherapy in patients with recurrent or metastatic HNC.Patients and methods: From March 1994 until August 1996, 49 patients withrecurrent or metastatic HNC were treated with paclitaxel (200mg/m², by three-hour infusion) followed by carboplatin at anAUC of 7 mg·min/ml, every four weeks. G-CSF was administeredprophylactically on days 2 to 12 of each cycle. There were 41 men and 8 womenwith a median age of 57 years (range 23–73). The majority of thepatients were symptomatic and they had recurrent disease locoregionally.Fourteen patients had nasopharyngeal cancer (NPC) and 35 had squamous cellcancers of other areas of the head and neck region (non-NPC).Results: At the completion of treatment, two patients with NPC demonstratedcomplete and six partial responses for an overall response rate of 57%(95% CI 29%–82%). Among patients with non-NPC, theresponse rate was 23% (95% CI 9%–37%). Aftera median follow up period of 15 months, the median time to progression was 4.3months in the non-NPC group and 16.5 months in the NPC group. At the time ofthe analysis, median survival had not been reached in NPC while it was 7.3months in non-NPC patients. Grade 3–4 toxicities included anemia(2%) and leukopenia, thrombocytopenia, stomatitis, nausea/vomiting anddiarrhea (4% each).Conclusions: The combination of paclitaxel and carboplatin appears to bewell tolerated but only moderately active in patients with advanced non-NPCof the head and neck region. However, its activity appears promising in NPCand deserves further investigation.     

Multicenter phase II study of weekly paclitaxel plus cisplatin combination chemotherapy in patients with advanced gastric cancer

Purpose Since a weekly administration of paclitaxel has demonstrated a sustained efficacy and more favorable toxicity profile than a 3-weekly administration for various solid tumors, the present study was conducted to evaluate the efficacy and safety of a combination regimen of weekly paclitaxel plus cisplatin in patients with advanced gastric cancer. Patients and methods Patients with previously untreated metastatic or recurrent, measurable gastric cancer received intravenous paclitaxel 100 mg/m² plus cisplatin 35 mg/m² on days 1 and 8 based on a 3-week cycle. Results Fifty-two patients were enrolled in the current study. Two complete responses and 17 partial responses were confirmed, giving an overall response rate of 36.5%. At a median follow-up of 8.5 months, the median time to progression and median overall survival was 6.0 and 10.8 months, respectively. Grade 3 neutropenia occurred in ten patients, while no grade 4 neutropenia or febrile neutropenia was observed. The most common non-hematologic toxicity was nausea (grade 1/2, 56.9%). There were no treatment-related deaths. Conclusion A weekly paclitaxel and cisplatin combination was found to be well-tolerated and effective in patients with advanced gastric cancer. Accordingly, this regimen can be regarded as an important first-line treatment option for advanced gastric cancer.     

Phase II trial of vinorelbine in patients with advanced and/or recurrent cervical carcinoma: an EORTC Gynaecological Cancer Cooperative Group Study

The objective of this phase II study was to assess the efficacy and toxicity of vinorelbine administered as a single agent in the treatment of chemona?ve cervical cancer patients. 46 patients (41 eligible) with cervical cancer (epidermoid or adenocarcinoma) and measurable metastatic and/or recurrent disease localised outside irradiated areas were treated with weekly intravenous (i.v.) vinorelbine 30 mg/m2 infused over 20 min. No prior chemotherapy was allowed. Median age was 53 years (range: 33-73), and performance status 1 (0-2). 31 patients (76%) had prior radiation therapy. There were 7 partial responders (17, 95% confidence interval (CI) 7-32) and 8 stable diseases (20%). Median duration of response was 5 months (4-11). Granulocytopenia was the major toxicity, with 47% of patients exhibiting grade 3 or 4 toxicity. Dose reduction and/or treatment delay was necessary in 28 patients (78%). Peripheral neuropathy reported in 10 patients was mild (grade 1 in 9 patients and grade 2 in 1 patient). In conclusion, single agent vinorelbine has moderate activity in recurrent or metastatic cervical cancer, but its reduced neurotoxicity warrants further study in combination with cisplatin.     

Paclitaxel and gemcitabine in advanced non-nasopharyngeal head and neck cancer: A phase II study conducted by the Hellenic Cooperative Oncology Group

Background: Paclitaxel as monotherapy or in combination with other drugs has demonstrated significant activity in patients with squamous cell carcinoma of the head and neck region (SCCHN). Preclinical studies have shown gemcitabine to be highly active in SCCHN cell lines.Purpose of the study: To evaluate the activity and toxicity of the combination of paclitaxel by three-hour infusion and gemcitabine as first-line chemotherapy in patients with recurrent and/or metastatic head and neck cancer (HNC).Patients and methods: From September 1996 until May 1998, 44 patients with non-nasopharyngeal recurrent and/or metastatic HNC entered the study. There were 37 men and seven women with a median age of 61 years (range 35–79) and a median performance status of 1 (range 0–2). The location of the primary tumor in the majority of them was either the larynx or the oral cavity. Treatment consisted of six cycles of gemcitabine 1100 mg/m2 over 30 min on days 1 and 8 immediately followed on day 1 by paclitaxel 200 mg/m2 by three-hour infusion. The treatment was repeated every three weeks.Results: Twenty-four (55%) patients completed all six cycles of treatment. A total of 205 cycles were administered, 165 (81%) of them at full dose. The median relative dose intensity (DI) of gemcitabine was 0.93 and of paclitaxel 0.95. Except for alopecia, which was universal, grade 3–4 toxicities included neutropenia (21%), thrombocytopenia (5%), anemia (5%), infection (5%), flu-like syndrome (5%) and peripheral neuropathy (2%). Five (11%) patients achieved complete and 13 (30%) partial responses, for an overall response rate of 41%. After a median follow-up of 13 months, the median time to progression was four months and median survival nine months.Conclusions: The combination of paclitaxel and gemcitabine is active and well tolerated in patients with recurrent and/or metastatic HNC – randomized studies comparing this combination with other regimens are warranted.     

A Phase II trial of cisplatin plus WR-2721 (amifostine) for metastatic breast carcinoma: an Eastern Cooperative Oncology Group Study (E8188).

BACKGROUND: Cisplatin has minimal antitumor activity when used as second- or third-line treatment of metastatic breast carcinoma. Older reports suggest an objective response rate of 8% when 60-120 mg/m2 of cisplatin is administered every 3-4 weeks. Although a dose-response effect has been observed with cisplatin, the dose-limiting toxicities associated with cisplatin (e.g., nephrotoxicity, ototoxicity, and neurotoxicity) have limited its use as a treatment for breast carcinoma. WR-2721 or amifostine initially was developed to protect military personnel in the event of nuclear war. Amifostine subsequently was shown to protect normal tissues from the toxic effects of alkylating agents and cisplatin without decreasing the antitumor effect of the chemotherapy. Early trials of cisplatin and amifostine also suggested that the incidence and severity of cisplatin-induced nephrotoxicity, ototoxicity, and neuropathy were reduced. METHODS: A Phase II study of the combination of cisplatin plus amifostine was conducted in patients with progressive metastatic breast carcinoma who had received one, but not more than one, chemotherapy regimen for metastatic disease. Patients received amifostine, 910 mg/m2 intravenously over 15 minutes. After completion of the amifostine infusion, cisplatin 120 mg/m2 was administered over 30 minutes. Intravenous hydration and mannitol was administered before and after cisplatin. Treatment was administered every 3 weeks until disease progression. RESULTS: Forty-four patients were enrolled in the study of which 7 (16%) were ineligible. A median of 2 cycles of therapy was administered to the 37 eligible patients. Six partial responses were observed for an overall response rate of 16%. Most patients (57%) stopped treatment because of disease progression. Neurologic toxicity was reported in 52% of patients. Seven different life-threatening toxicities were observed in patients while receiving treatment. CONCLUSIONS: The combination of cisplatin and amifostine in this study resulted in an overall response rate of 16%. Neither a tumor-protective effect nor reduced toxicity to normal tissues was observed with the addition of amifostine to cisplatin in this trial.     

Paclitaxel and tamoxifen: An active regimen for patients with metastatic melanoma

BACKGROUND: In early trials of paclitaxel administered as a 24-hour infusion, an overall response rate of 16% was reported for patients with metastatic melanoma. Paclitaxel is a natural product-based agent and is thus subject to the problem of multidrug resistance (MDR). Tamoxifen is an agent that can abrogate MDR and potentially enhance the effect of paclitaxel. A Phase II trial of the combination was undertaken with previously treated patients. METHODS: Patients with metastatic cutaneous or mucosal melanoma who were previously treated with the Dartmouth chemotherapy regimen (dacarbazine, carmustine, cisplatin, and tamoxifen) were evaluated. Paclitaxel was administered at a dose of 225 mg/m(2) intravenously over 3 hours every 3 weeks. All patients also took tamoxifen 40 mg orally daily. Treatment continued until disease progression. RESULTS: Twenty-one patients completed at least two cycles of paclitaxel and were evaluable for response. Five responses were observed, 1 complete response, and 4 partial responses, for an overall response rate of 24%. The combination was well tolerated. The most common nonhematologic side effects were myalgia and paresthesia. Hematologic toxicity was mild. No patients developed neutropenic fever. CONCLUSIONS: This is the first report of a Phase II trial evaluating paclitaxel as a 3-hour infusion in melanoma patients. The 3-hour infusion is well tolerated and results in little myelosuppression and minimal neurotoxicity. The contribution of tamoxifen is difficult to evaluate because plasma levels were not measured. It is possible that a higher response rate might be observed with larger doses of tamoxifen. Further investigation of paclitaxel in the treatment of patients with metastatic melanoma is warranted.     

Phase II trial of carboplatin plus cisplatin in recurrent and advanced squamous cell carcinoma of the head and neck

Cisplatin is one of the most active chemotherapeutic agents for the treatment of squamous carcinoma of the head and neck; however, neurotoxicity and nephrotoxicity are dose-limiting. The analog, carboplatin, is a promising new agent with similar activity but a different spectrum of toxicity. To evaluate if a therapeutic advantage could be achieved with acceptable toxicity, a combination of carboplatin 350 mg/m2 and cisplatin 50 mg/m2 were administered every 28 days to patients with recurrent or metastatic disease who had received no prior chemotherapy. Of 24 patients enrolled in this study, 21 were assessable for response and toxicity. Five partial responses were observed (24%; 95% confidence interval [Cl], 4.9% to 38.6%). No complete response occurred. Two of these patients received definitive radiotherapy and achieved complete responses. The median survival of all patients was 24 weeks. Hematologic toxicity was dose-limiting necessitating a decrease in the starting dose of carboplatin to 300 mg/m2. Nonhematologic toxicity was infrequent and mild. Significant renal impairment occurred in only two patients. Although treatment with the combination of carboplatin and cisplatin is feasible, we found no therapeutic advantage in terms of an increased response or survival.     

Phase II trial of the pegylated liposomal doxorubicin in previously treated metastatic endometrial cancer: a Gynecologic Oncology Group study.

PURPOSE: To determine whether pegylated liposomal doxorubicin (PLD) has antitumor activity in pretreated patients with persistent or recurrent endometrial carcinoma and to define the nature and degree of toxicity of PLD. PATIENTS AND METHODS: Women with histologically documented recurrent or persistent measurable endometrial carcinoma and with failure of one prior treatment regardless of prior anthracycline therapy were enrolled. PLD was administered intravenously over a 1-hour period at a dose of 50 mg/m(2) every 4 weeks; the dosage was modified in accordance with observed toxicity. RESULTS: Of 46 patients entered, 42 were assessable for response, as three were declared ineligible on central pathology review and one was not assessable for response. Forty had received prior chemotherapy, 11 hormonal therapy, and 29 radiation therapy. Doxorubicin had been given to 32 patients, carboplatin with paclitaxel to six, carboplatin to one, and fluorouracil to one. Four patients had partial responses lasting 1.1, 2.1, 3.3, and 5.4 months; the overall response rate was 9.5% (95% confidence interval, 2.7% to 22.6%). Three of these responses (in liver and in lymph node) occurred in patients who had progressed after doxorubicin with either paclitaxel or cisplatin. The median number of courses was 2.5 (range, one to 14). Toxicity was generally mild: only 25 patients experienced leukopenia, with a median WBC count of 2,900 (range, 800 to 3,900) at nadir. The only grade 4 toxicities were one episode each of esophagitis, hematuria, and vomiting. The median overall survival was 8.2 months. CONCLUSION: PLD has only limited activity in pretreated advanced, recurrent endometrial cancer, but further trials in anthracycline-naive patients and in previously untreated patients are ongoing. Its toxicity profile should permit its use in combination with myelosuppressive drugs.     

Randomized study of a short course of weekly cisplatin with or without amifostine in advanced head and neck cancer

Background: Cisplatin is one of the most active cytotoxic agents available for the treatment of patients with head and neck cancer. In a previous phase II study with weekly administration of cisplatin, a response rate of 51% was achieved. However, only in a minority of the patients the planned high dose intensity of 80 mg/m²/week could be reached because of toxicity, mainly thrombocytopenia and ototoxicity. Amifostine is a cytoprotective drug that can diminish the toxicity of alkylating agents and platinum compounds. Therefore the effect of amifostine on toxicity and activity of weekly cisplatin was investigated in a randomized study.Patients and methods: Patients with locally advanced, recurrent or metastatic head and neck cancer were eligible. Patients were randomized to weekly cisplatin 70 mg/m² for six cycles preceded by amifostine 740 mg/m², or cisplatin only. Cisplatin was administered in hypertonic saline (3% NaCl) as a one-hour infusion; amifostine was administered as a 15-minute infusion directly before the administration of cisplatin.Results: Seventy-four patients were entered in the study. The median number of cisplatin administrations was 6 (range 2–6), equal in both arms. In both treatment arms the median dose intensity of cisplatin achieved was the planned 70 mg/m²/week. In the cisplatin only arm 6 out of 206 cycles were complicated by thrombocytopenia grade 3 or 4 versus 1 of 184 cycles in the amifostine arm (P = 0.035). Hypomagnesaemia grade 2 + 3 was significantly less observed in the amifostine arm (P = 0.04). Neurotoxicity analyzed by serial vibration perception thresholds (VPT) showed a diminished incidence of subclinical neurotoxicity in the amifostine arm (P = 0.03). No protective effect on renal and ototoxicity could be shown. Hypotension was the main side effect of amifostine but only of relevance in one patient. The antitumor activity of cisplatin was preserved as 63% of the evaluable patients in the amifostine arm responded compared to 50% of the evaluable patients in the cisplatin alone arm.Conclusion: Our study indicated that in combination with weekly administered cisplatin amifostine reduced the risk of thrombocytopenia, hypomagnesemia as well as subclinical neurotoxicity, but did not result in a higher dose intensity of cisplatin. Addition of amifostine did not compromise the antitumor effect of cisplatin.     

A phase II study of paclitaxel/cisplatin combination in patients with metastatic breast cancer refractory to anthracycline-based chemotherapy

AIMS AND BACKGROUND: To investigate the safety and efficacy of a paclitaxel and cisplatin regimen in a selected group of metastatic breast cancer patients with primary or acquired chemo-resistance to anthracycline-based chemotherapy. PATIENTS AND METHODS: Thirty-eight consecutive women with metastatic breast cancer (PS < or =2) were entered in this phase II trial; all patients had been previously treated for metastatic disease with chemotherapy containing anthracyclines and had shown a progression of the disease during drug administration or after a clinical response lasting less than 6 months. Fifteen patients had received 2 or more chemotherapeutic regimens for advanced disease; 31 patients had > or =2 sites of metastatic disease. Paclitaxel (135 mg/m2) was administered iv by a 3-hr infusion followed by iv infusion of cisplatin (75 mg/m2) on day 1, every 3 weeks for 6 cycles. After the completion of the planned chemotherapy administration, 9 responsive patients continued to receive paclitaxel alone (175 mg/m2) iv, on day 1, every 3 weeks, until disease progression or unacceptable toxicity. RESULTS: A partial clinical response was recorded in 17 cases (45%; 95% CI, 30-64%). The median duration of overall response was 8 months; for the 9 responsive patients who continued treatment with paclitaxel alone, 4 had maintained the partial clinical response at the median follow-up of 24 months from the onset of therapy. The median time to progression was 6 months and median overall survival 8 months. Neurotoxicity was the most frequent adverse effect and caused treatment discontinuation in 5 cases for grade 3-4 paresthesia and/or an arthralgia/myalgia syndrome. Grade 3-4 neutropenia occurred in 16 patients (44%). CONCLUSIONS: Paclitaxel/cisplatin is an active regimen for the treatment of patients with metastatic breast cancer refractory to anthracycline-based chemotherapy. However, the cumulative neurotoxicity should limit the efficacy of prolonged paclitaxel monotherapy in responsive patients.     

Neoadjuvant treatment of locally advanced carcinoma of the uterine cervix with epirubicin, paclitaxel and cisplatin

PURPOSE: The present study was conducted to explore whether neoadjuvant chemotherapy with a combination of epirubicin, paclitaxel and cisplatin could improve the operability and pathological response rate in locally advanced cervical cancer patients. METHODS: Between April 1996 and July 2000, 42 patients with carcinoma of the uterine cervix, FIGO stage Ib(2)-IVa, were treated with two or three 21-day cycles of an epirubicin 100 mg/m(2), paclitaxel 175 mg/m(2), cisplatin 100 mg/m(2) regimen. RESULTS: All patients were eligible for evaluation of toxicity and response. A total of 92 courses of therapy were administered. Three patients had a 20% reduction from the starting dose due to haematological toxicity. Grade 3-4 leukopenia was observed in 15% of cycles, requiring G-CSF support in half of them. Major non-haematological toxicity consisted of grade 3 alopecia (100%), and grade 3 nausea and vomiting (40%). A total of 33 clinical responses (78.5%, 95% CI 63.8-93.2) were recorded, 8 complete responses (CR) and 25 partial responses (PR). Of the 42 patients, 32 (76.2%) underwent radical surgery. At pathological examination 8 complete or microscopic pathological responses, 17 PRs, and 9 patients with stable disease were observed. The median follow-up time was 17 months for the 42 patients enrolled (range 3-62 months). Among the patients submitted to radical surgery, five recurrences were observed, with a median disease-free survival of 47 months. Median overall survival had not been reached at the time of this report. These results appear to be in the range reported for other neoadjuvant cisplatin-based regimens not including paclitaxel. CONCLUSIONS: Neoadjuvant chemotherapy with the epirubicin, paclitaxel and cisplatin combination followed by radical surgery proved to be a safe and effective approach to advanced cervical cancer.     

Phase II trial of gemcitabine plus cisplatin in patients with metastatic urothelial cancer.

PURPOSE: To assess the activity and toxicity of the combination of gemcitabine and cisplatin in the treatment of chemotherapy-naive patients with metastatic urothelial cancer. PATIENTS AND METHODS: Forty-six patients with measurable stage IV carcinoma of the urothelium were enrolled onto this trial. Gemcitabine 1,000 mg/m(2) was administered intravenously for 30 to 60 minutes on days 1, 8, and 15 of each 28-day cycle. Cisplatin was administered after gemcitabine on day 1 of each cycle. The first 11 patients received an initial cisplatin dose of 100 mg/m(2). Due to the hematologic toxicity observed in several of these patients, the dose was reduced to 75 mg/m(2) in the remaining 35 patients. Patients were treated with six cycles, unless disease progression or severe toxicity necessitated earlier discontinuation. RESULTS: Ten of the 46 patients achieved a complete response and nine showed a partial response. The overall response rate was 41%. The median time to treatment failure was 5.5 months. The median survival was 14.3 months, and the 1-year survival probability was 54%. Most of the toxicities were hematologic and, in general, easily manageable. CONCLUSION: Gemcitabine plus cisplatin is active in the treatment of metastatic urothelial cancer in chemotherapy-naive patients and has an acceptable clinical safety profile. Studies are under way to further define the place of gemcitabine in combination with other chemotherapeutic agents in the treatment of metastatic urothelial cancer.     

Retrospective analysis on efficacy and toxicity of paclitaxel-containing treatments in patients with advanced or recurrent breast cancer

Our department recently began using paclitaxel in treating patients with breast cancer. Retrospective analysis was conducted to clarify its clinical usefulness. Forty-one patients with metastatic breast cancer were treated with paclitaxel between November 2000 and September 2002. Hospital records of the patients, except for one unsensored patient, were retrospectively reviewed. Characteristics of the patients were as follows: age, 36-81 Y (median, 56); 8 stage IV and 32 recurrent diseases; most frequent dominant site of metastasis was the liver (22 patients, 55%); number with previous chemotherapy was 0-5 (median, 2); anthracycline-based treatment and docetaxel treatment were previously performed in 21 (53%) and 15 (38%) patients, respectively; weekly dose of paclitaxel was 30-150 mg/body (median, 100); and total dose administered was 600-6, 480+ mg/body (median, 1,820). Objective response and clinical benefit rates were 35% and 80%, respectively. Median duration of response, time-to-progression and overall survival were 27+, 33+ and 41.5 weeks, respectively. Common adverse events were sensory neuropathy (45%) and nausea/vomiting (37.5%). Most were graded as 1 or 2. Various agents, such as hormonal agents and trastuzumab, were administered with paclitaxel in 26 patients (65%). No significant difference was observed in efficacy or toxicity among patients treated with paclitaxel alone or paclitaxel plus other agents. Paclitaxel seems to be a feasible, safe and active agent for patients with metastatic breast cancer.     

Paclitaxel, cisplatin, and epirubicin first-line chemotherapy in stage III and IV ovarian carcinoma: long-term results of a phase II study

BACKGROUND: The combination of paclitaxel with cisplatin or carboplatin has become the preferred chemotherapy regimen in the treatment of epithelial ovarian carcinoma. Anthracyclines also have activity in this disease. We conducted a Phase II study by using the combination of paclitaxel, cisplatin, and epirubicin for the treatment of advanced ovarian carcinoma. METHODS: Forty consecutive patients with optimally (n = 7) or suboptimally (n = 33) debulked advanced ovarian carcinoma (International Federation of Gynecology and Obstetrics (FIGO) Stage III or IV) were treated with paclitaxel, 135 mg/m(2), as a 3-hour intravenous infusion, cisplatin 75 mg/m(2) intravenously (i.v.), and epirubicin 50 mg/m(2) i.v. every 3 weeks on an outpatient basis. Granulocyte-colony stimulating factor was administered at a dose of 5 microg/kg/day on Days 5-9. RESULTS: Among 28 patients with measurable disease, 24 (86%%) achieved an objective response including 19 complete and 5 partial responses. Among 18 patients who underwent reassessment laparotomy, pathologic complete response was confirmed in 9 patients. At a minimum follow-up of 40 months, the median overall survival had not been reached whereas the median time to progression for all patients was 18.7 months. The median remission duration for women with measurable disease who responded to treatment was 14 months. The treatment was well tolerated without toxic deaths; the most common toxicity was Grade 3/4 neutropenia that occurred in 30% of patients. Significant neuropathy (Grade 2 or higher) developed in only 8% of patients. CONCLUSIONS: The combination of paclitaxel, cisplatin, and epirubicin is a well tolerated outpatient regimen with significant activity in the treatment of advanced epithelial ovarian carcinoma.