Phase II study of estramustine, oral etoposide, and vinorelbine in hormone-refractory prostate cancer.

Hormone-refractory prostate cancer is characterized by a low response rate following second-line therapy. Encouraging results have been reported in Phase II studies with estramustine associated with vinblastine or etoposide. Vinorelbine is a new semisynthetic vinca alkaloid that has demonstrated activity in prostate cancer. We therefore evaluated the activity of the following schedule: estramustine, 400 mg/m2 orally days 1-42; etoposide, 50 mg/m2 orally days 1-14; and 28-42; vinorelbine, 20 mg/m2 days 1, 8, 28, and 35; cycles being repeated every 8 weeks. Twenty-five patients have been included and are assessable for response and side effects. Patient characteristics were as follows: median age, 71 years (range 55-81); ECOG performance status 0-2; nonosseous disease, 3 cases; bone metastases, 23 cases. Sixty-two cycles have been delivered. Two patients with measurable disease and six patients with bone disease had a partial remission for an overall response rate of 32% (95% confidence interval 15-53%). Seven patients had stabilization of disease and 10 had progression of disease. Median duration of response was 3 months (range 2-5). Prostate-specific antigen in 14 patients (56%) decreased from baseline by at least 50%. Toxicity was manageable. Neutropenia was mild, with only three cases of grade III-IV toxicity. Two patients had severe anemia. The results of this study indicate that the schedule is active and well tolerated in hormone-refractory prostate cancer patients.

Activity of combination chemotherapy in brain metastases from breast and lung adenocarcinoma.

Brain metastases represent a common complication of breast and lung cancer, with an overall incidence exceeding 30-40% of cases. Results achieved with radiotherapy are disappointing, with a median survival of a few months, and no clear activity has been observed with chemotherapy. The aims of this study were to assess the activity and feasibility of a new chemotherapeutic approach according to the following schedule: lomustine, 80 mg/m2 day 1; carboplatin, 80 mg/m2 days 1, 8, 15, 22; vinorelbine, 20 mg/m2 days 1, 8, 15, 22; L-leucovorin 250 mg/m2 days 1, 8, 15, 22; and fluorouracil, 500 mg/m2 days 1, 8, 15, 22. Cycles were repeated every 6 weeks. Since January 1994, 28 patients have been enrolled and 26 are evaluable for response and side effects. Major patient characteristics were median age, 55 years (range 31-72); men/women 15/11; lung primary, 20; breast primary, 6; performance status Eastern Cooperative Oncology Group, 0-2. A total of 64 cycles were administered (median/patient, two cycles). Nine partial remissions have been observed (35%, 95% confidence interval 17-56%), 6 disease stabilizations, and 11 disease progressions. Median duration of response was 3 months, and median time to progression for the whole group was 3.7 months (range 1-7). Treatment was well tolerated. Mild or moderate side effects included neutropenia, thrombocytopenia, mucositis, and nausea/vomiting; grade III-IV toxicity included neutropenia and thrombocytopenia. In conclusion, our results indicate that the schedule proposed is feasible and effective in this subset of patients.

Intermittent continuous infusion of fluorouracil and low-dose oral leucovorin in pretreated breast cancer: a pilot study.

AIMS AND BACKGROUND: There is evidence that fluorouracil (FU), when administered by protracted venous infusion, has antitumor activity in pretreated breast cancer. The aims of the study were to assess, in a population of heavily pretreated breast cancer patients (> or = 2 lines of chemotherapy previously administered), the feasibility and activity of a new combination of oral L-leucovorin and continuous FU infusion. METHODS: Patients were treated with the following combination: oral L-leucovorin, 5 mg/m2 days 1 through 14, plus FU, 250 mg/m2 days 1 through 14, with cycles repeated every 21 days. RESULTS: Since November 1994, 22 patients have entered the study and 20 are assessable for response and side effects. Major patient characteristics were: ECOG performance status, 0-2; median age, 56 years (range, 41-70); sites of metastasis, bone 9, lung 8, liver 2, pleura 7; 2 or more metastatic sites, 18. A total of 74 cycles has been administered (median/patient, 3 cycles). Five partial remissions (25%), 4 disease stabilizations and 11 disease progressions have been observed. Median time to progression was 3 months (range 1.6+). Grade I-II mucositis was observed in 8 patients and grade III-IV in 6 patients. Other side effects have included diarrhea and thrombocytopenia. CONCLUSIONS: The schedule has demonstrated moderate activity in heavily pretreated breast cancer, with mucositis as the dose-limiting toxicity.

Intra-arterial chemotherapy followed by chemo-embolisation in unresectable hepatocellular carcinoma.

Unresectable hepatocellular carcinoma is related to a poor prognosis. Encouraging response rates and survival have been reported with intra-arterial (i.a.) chemotherapy and chemo-embolisation, but limited data are available on the association of the two treatment modalities. We therefore started a new programme combining i.a. chemotherapy with chemo-embolisation. The treatment regimen consisted of L-leucovorin (100 mg/m2 i.v.), 5-fluorouracil (800 mg/m2 i.a.), and carboplatin (250 mg/m2 i.a.). Chemo-embolisation with mitoxantrone (10 mg/m2) plus ethiodized oil followed immediately. The same treatment plus gelatin sponge was given after 28 days. 26 patients entered the study and were evaluable for response and side-effects. Main patient characteristics were: males 21, females 5: median age 68 years (range 42-76 years); stage TNM II-III 17, IVA 9; Child's A 12, Child's B 14; elevated baseline alpha-fetoprotein 17; cirrhosis 25. 14 patients had a partial response (54%; 95% confidence interval 33-73%), 3 had stabilisation and 9 had progressive disease. Median survival was 11 months (range 2-20+). 16 patients had grade I-II pain and 15 grade I-II fever. Our results indicate that the regimen is safe, well tolerated and capable of inducing objective remissions in a high percentage of patients with hepatocellular carcinoma.

A randomized phase II trial of cisplatinum plus mitomycin-C plus vinorelbine and carboplatin plus vinorelbine in advanced non-small cell lung cancer.

Vinorelbine represents one of the most active agents in advanced non-small cell lung cancer (NSCLC), with response rates of 14-33%. We therefore evaluated the activity and tolerability of two novel vinorelbine-containing regimens in stage IIIB-IV NSCLC. Fifty-two patients were enrolled in a randomized phase II study of cisplatinum (100 mg/m(2)) day 1, mitomycin-C (8 mg/m(2)) day 1, and vinorelbine (25 mg/m(2)) days 1 and 8 (Arm A); and carboplatin (400 mg/m(2)) day 1, in combination with vinorelbine (25 mg/m(2)) days 1 and 8 (Arm B). Cycles were repeated every 3 weeks. All patients were assessable for reponse and side effects. Patients were well balanced between the two Arms in terms of major characteristics. A total of 98 and 91 cycles were delivered respectively in Arm A and Arm B. Eleven objective responses (42%; 95% confidence interval 26-63%) were observed in Arm A and 7 responses (27%; 95% confidence interval 12-48%) in Arm B. Main toxicity was mild or moderate, nausea and vomiting for Arm A and hematological for Arm B. Other side effects included infections and phlebitis and were similar for the two Arms. In conclusion, both schedules demonstrated activity in advanced NSCLC. The three-drug regimen appeared very promising in terms of activity and manageable toxicity.

Prognostic factors in patients with hepatocellular carcinoma submitted to chemoembolization.

The prognosis of unresectable hepatocellular carcinoma is poor. Encouraging response rates have been reported with chemoembolization, but no survival advantage has been demonstrated. Assessment of the impact of the treatment modality on prognosis is complicated by a poor understanding of the prognostic factors in the disease. We therefore evaluated, through univariate and multivariate analysis, the role on prognosis of 16 variables in 63 patients submitted to chemoembolization. Patients were treated with epirubicin (50 mg) plus ethiodized oil and gelatin sponge (22 cases) or with a new program combining i.a, chemotherapy with chemoembolization (41 cases) as follows: L-leucovorin, 100 mg/m(2) i.v.; fluorouracil, 800 mg/m(2) i.a.; carboplatin, 250 mg/m(2) i.a. Chemoembolization with mitoxantrone, 10 mg/m(2), plus ethiodized oil and gelatine sponge was performed immediately after. Median survival for the whole group of patients was 294 days. A multivariate analysis showed a highly significant influence on survival for Child's status (p=0.002) and for TNM stage (p=0.01). Median survival for patients with Child's A disease was 13.9 months and for patients with TNM stage I-II disease 19 months. In conclusion, our data suggest that patients with limited disease and adequate liver function have a longer survival after chemoembolization.

Mitomycin C and vinorelbine in pretreated breast cancer.

AIMS AND BACKGROUND: Vinorelbine, a new semi-synthetic vinca alkaloid, has demonstrated high activity as a single agent in pretreated metastatic breast cancer. PATIENTS AND METHODS: To evaluate the activity of the combination vinorelbine-mitomycin C and to reduce the incidence of side effects, in particular myelotoxicity, patients with metastatic breast cancer pretreated with 1 or more chemotherapy regimens for metastatic disease were treated according to the following schedule: mitomycin C, 10 mg/m2 day 1, and vinorelbine, 25 mg/m2, days 1, 8 and 15, every 28 days. RESULTS: Twenty-seven patients were enrolled and were evaluable for activity and side effects. A total of 157 cycles were delivered (median 5 cycles per patient). There were 10 partial remissions (37%; 95% confidence interval 20-59%), 5 instances of stable disease and 12 of disease progression. Grade III-IV toxicity was mostly hematological and included thrombocytopenia (4%) and neutropenia (42%). CONCLUSION: Our results indicate that the combination of mitomycin C and vinorelbine has moderate activity in pretreated breast cancer.

Phase II study of oral L-leucovorin, 120-hour fluorouracil infusion and carboplatin in advanced pancreatic cancer.

BACKGROUND: No effective chemotherapy has been developed for patients with metastatic pancreatic cancer. Encouraging results have been reported with the combination of cisplatin and fluorouracil infusion. The aim of the study was to test the activity of oral L-leucovorin, carboplatin and fluorouracil infusion in untreated pancreatic cancer patients. PATIENTS AND METHODS: Patients with advanced pancreatic carcinoma were treated with carboplatin (300 mg/m2 on day 1), L-leucovorin (5 mg/m2 twice a day on days 1-5), and fluorouracil (1,000 mg/m2 as a 120-hr infusion on days 1-5), cycles being repeated every 21 days. RESULTS: Nine patients were included and were assessable for response and side effects. All patients had measurable disease and an ECOG performance status of 0-2. No patient achieved partial remission, 3 had stable disease, and 6 progressive disease. Median time to progression was 2 months (range, 2-8), and median survival was 4 months (range, 3-12). Toxicity consisted of mucositis, diarrhea and neutropenia. CONCLUSIONS: Patients with metastatic pancreatic carcinoma do not benefit from this treatment schedule.

A dose-escalating study of carboplatin combined with vinorelbine in non-small-cell lung cancer.

Platinum compounds and vinorelbine have been demonstrated to be active in non-small-cell lung cancer (NSCLC). The aims of the study were to assess tolerability and feasibility of increasing doses of carboplatin (level 1: 300 mg/ m2 on day 1, level 2: 350 mg/m2 on day 1, level 3: 400 mg/m2 on day 1) in combination with a fixed dose of vinorelbine (25 mg/m2 on days 1 and 8) in advanced NSCLC. Forty-two patients entered the study and were evaluable for toxicity and response. The patients were not treated using systemic chemotherapy, had TNM stage IIIB-IV, performance status ECOG 0-2, and their median age was 62 (range 41-70) years. The number of patients evaluable for each dose level was 14. A total of 138 (median 3) courses was administered. Nonhematologic side effects included grade I-II mucositis (9%), neurotoxicity (6%), and infections (4%). Myelotoxicity was manageable and generally of short duration, with 19% of the patients having grade III-IV neutropenia. No significant difference was observed for the three treatment groups. No drug-related death was observed. An objective remission was observed in 10 patients (24% response rate; 95% confidence interval 12-39%), with 5 responses in 14 patients treated with the 400-mg/m2 dose. In conclusion, the combination of carboplatin at a dose of 400 mg/m2 on day 1 and vinorelbine at a dose of 25 mg/m2 on days 1 and 8 can be safely administered as first-line cytotoxic therapy in advanced NSCLC and warrants further evaluation.

Double modulation with methotrexate and L-leucovorin of weekly 24- hour fluorouracil infusion in fluorouracil-refractory colorectal cancer.

No effective second-line therapy has been developed for patients with metastatic colorectal cancer progressive after than fluorouracil(FU)-containing chemotherapy. Encouraging results have been reported with weekly 24-hour FU infusion. The aim of this study was to test the activity of weekly FU infusion plus modulation with methotrexate and L-leucovorin in pretreated colorectal cancer patients. Seventeen patients with metastatic colorectal carcinoma were treated with methotrexate (40 mg/m2 on day 1), L-leucovorin (100 mg/m2 as a 4-hour infusion on day 2), and FU (2,600 mg/m2 as a 24-hour infusion on day 2). All patients had measurable disease and a performance status of ECOG O-2. Two of the 17 evaluable patients achieved partial remission (12%; 95% confidence interval 2-24%), 9 had stable disease, and 6 progressive disease. Median time to progression was 4 months (range, 2-8) and median survival was 7 months (range, 3-12+). Toxicity was generally mild or moderate and consisted of mucositis, diarrhea and neutropenia. Pretreated patients with metastatic colorectal, carcinoma benefit only marginally from this treatment schedule.

Surgery followed by intracavitary plus systemic chemotherapy in malignant pleural mesothelioma.

AIMS AND BACKGROUND: Malignant mesothelioma is associated with a median survival of 4 to 12 months. Data from the literature indicate that single modality treatment (surgery or intrapleural and/or systemic chemotherapy) does not significantly affect survival. METHODS: We therefore evaluated a combined approach consisting of surgery (pleurectomy + diaphragmatic or pericardial resection), intrapleural chemotherapy with cisplatin (100 mg/m2) and cytarabine (1,000 mg/m2) for 4 h immediately after pleurectomy, and systemic chemotherapy consisting of epirubicin (60 mg/m2) and mitomycin-C (10 mg/m2) day 1 every 4 weeks for 4 cycles. RESULTS: Twenty patients were enrolled in the study and were evaluable. Thirteen cases had residual gross disease after pleurectomy and 7 patients only minimal disease. Median time to disease progression was 7.4 months, and median survival was 11.5 months (range, 2-25+). No treatment-related death have been observed. Side effects after intracavitary chemotherapy included renal toxicity, anaemia and pain. Myelosuppression and alopecia were recorded during systematic chemotherapy. CONCLUSIONS: The results of the study indicate that the schedule is feasible, with encouraging results in terms of survival for patients with minimal residual disease after surgery.

Prognostic value of proliferating cell nuclear antigen (PCNA) expression in unresectable hepatocellular carcinoma.

Recent studies indicate that evaluation of cell proliferation in mallignant tumors may have prognostic value, but limited data are available on its expression in hepatocellular carcinoma. We therefore evaluated the prognostic tool of PCNA antigen expression on paraffin-embedded sections of 54 patients with hepatocellular carcinoma and concomitant cirrhosis. According to the number of positive cells, the PCNA expression ranged between 0.8 and 47%, and was divided into two groups (Group A, PCNA less than or equal to 5.5%; Group B, PCNA >5.5%). The two groups of patients were numerically well balanced. Median survival was 16 months for group A and 12 months for group B. According to the Cox multivariate analysis, PCNA expression (P=0.002),TNM stage (P=0.009) and ECOG performance status (P<0.001) significantly correlated with survival. In conclusion, PCNA antigen expression was found to be a significant prognostic faeature in unresectable hepatocellular carcinoma and may be a useful tool for future trials.

Weekly carboplatin in elderly patients with advanced ovarian cancer.

Ovarian cancer is frequently diagnosed in patients over 65 years old, but limited data are available on tolerance and effectiveness of chemotherapy in this subset of patients. A total of 21 patients with epithelial ovarian cancer were treated with weekly carboplatin following failure of first-line chemotherapy. Median age was 73 years (range, 66-85). Patients received carboplatin at the dose 100 mg/m(2)/week with discontinuation for severe toxicity or documented progression. A total of 228 cycles were administered (median per patients, 10 cycles). Six partial remissions (29%; 95% confidence interval, 11-52%), 6 stabilizations of disease, and 9 disease progressions were observed. Median time to progression was 6 months. No toxic deaths were observed. Side effects consisted mainly of anemia (grade 3 in 3 cases) and neutropenia. Non-hematologic toxicity was minimal. In conclusion, the schedule has moderate activity with good tolerability in elderly patients with advanced epithelial ovarian cancer.

Pleurectomy, intrapleural cisplatin and interferon followed by systemic carboplatin plus interferon in malignant pleural mesothelioma.

Malignant pleural mesothelioma has a dismal prognosis and median survival rarely exceeds 12 months. Since multimodality therapy initially showed promising results, we tested the feasibility of a new approach consisting of pleurectomy, immediately followed by intrapleural chemotherapy with cisplatin (100 mg/m(2) day 1) and alpha-interferon (12x10(6) U/m(2) days 1 and 2), followed by 4 cycles of carboplatin, 350 mg/m(2), repeated every 3 weeks and associated to alpha-interferon (3x10(6) U/x3/week). Fourteen patients have been submitted to the protocol and are evaluable for side effects. All patients had surgery and intrapleural chemotherapy, and 4 patients also had systemic chemotherapy. No treatment-related deaths have been observed. Major postoperative complications included chest tube air leak >7 days (1 pt). Intracavitary chemo-immunotherapy-related toxicity was responsible for 7 cases of grade I nephro-toxicity and 2 cases of grade I fever. Grade I-II toxicity from systemic chemotherapy included asthenia (2 cases), fever (3 cases), anemia (2 cases) and neutropenia (2 cases). Grade III-IV toxicity included asthenia (1 case), anemia (2 cases), neutropenia (2 cases) and fever (1 case). Two cases required interruption of systemic chemotherapy for intolerance. Based on these data, systemic chemotherapy has been stopped. In conclusion, our results indicate that pleurectomy plus intra-cavitary cisplatin and interferon is feasible. Since systemic chemotherapy is correlated with severe side effects, a phase II trial with surgery plus intrapleural treatment alone is ongoing.

Feasibility of intra-arterial chemotherapy followed by chemoembolization, every 28 days, in unresectable hepatocellular carcinoma.

Encouraging response rates and survival have been reported with intra-arterial (i.a.) chemotherapy and chemoembolization, but limited data are available on the association of the two treatment modalities. We therefore started a feasibility study of i.a. chemotherapy plus chemoembolization, performed every 28 days for 3 cycles, according to the following schedule: L-leucovorin (100 mg/m(2) i.v.), fluorouracil (800 mg/m(2) i.a.), and carboplatin (250 mg/m(2) i.a.). Chemoembolization with mitoxantrone (10 mg/m(2)) plus ethiodized oil was performed immediately after this treatment, followed by gelatin powder. Fourteen patients entered the study and were evaluable for side effects. Main patient characteristics were: males 13, females 1; median age 65 yr (range 45-75); stage TNM II-III 10, IVA 4; Childs' A 8, Childs' B 6; elevated baseline alpha-fetoprotein, 11; cirrhosis 14. No drug-related deaths have been observed. Ten patients were able to complete the program. The reasons for discontinuing treatment were worsening of liver functions in 3 cases and grade IV neutropenia in 1 patient. Eight patients had grade I-II pain and 10 patients had grade I-II fever. In conclusion the study demonstrated that chemoembolization plus i.a. chemotherapy is feasible in patients with hepatocellular carcinoma in cirrhosis and deserves further investigation.

Carboplatin and vinorelbine in elderly patients with non-small cell lung cancer.

Many lung cancers are diagnosed in patients over 70 years of age, but there are little published data on chemotherapy in elderly patients. We therefore activated a phase II study in order to assess the tolerance and activity of carboplatin (80 mg/m(2)) and vinorelbine (25 mg/m(2)) administered weekly in patients aged greater than or equal to 70 with advanced non-small cell lung cancer. Twenty-five patients (22 males, 3 females; performance status ECOG, 0-2; median age, 75 years, range 70-85) were included in the study and are assessable for response and side effects. A total of 162 cycles of therapy have been delivered (median/patient, 6 cycles). Seven partial remissions (28%; 95% confidence interval 5-36%), 8 disease stabilizations, and 10 progressions have been observed. Median time to disease progression was 4 months, and median survival was 5 months (range, 2-25+). Grade III/IV toxicity consisted mainly of leukopenia and neutropenia observed respectively in 5 and 7 patients. In conclusion, the schedule demonstrated activity and good tolerability in this subset of patients. Elderly patients with good performance status and adequate organ function can be safely treated with systemic chemotherapy.

Intermittent continuous infusion of fluorouracil, low-dose oral leucovorin and oral etoposide in advanced gastric cancer.

Gastric carcinoma is considered moderately chemosensitive, but a 'standard' chemotherapy regimen has not yet been found. Encouraging results in terms of activity and tolerability have been reported with a combination of i.v. leucovorin, fluorouracil and etoposide. However, etoposide and fluorouracil have demonstrated a schedule-dependency with high activity for the former when administered orally and for the latter when administered as a continuous infusion. In order to improve clinical results, we tested the activity and feasibility of the following combination: oral L-leucovorin, 5 mg/m(2) days 1-14; oral etoposide, 50 mg/m(2) days 1-14; fluorouracil, 200 mg/m(2)/day by continuous infusion days 1-14; cycles repeated every 28 days. A total of 26 patients [male/ female, 17/9; median age, 65 years (range, 42-75); performance status, 0-2] have been enrolled and are evaluable for response and side effects. A total of 78 cycles has been delivered (median/patient, 3 cycles). Two complete remissions (8%), 11 partial remissions (42%), 4 stabilizations of disease, and 9 progressions have been observed, for an overall response rate of 50% (95% confidence interval 30-70%). Median time to disease progression was 4.5 months and median survival 9.5 months. No toxic death or grade III-IV toxicity has been observed. Mild or moderate side effects included mucositis (42%), nausea/vomiting (19%) and leukopenia (8%). In conclusion, our results indicate that the schedule is safe, well tolerated and highly effective in advanced gastric cancer.