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 evaluation of patients submitted to surgery for malignant pleural mesothelioma.

The role of surgical resection remains controversial in malignant pleural mesothelioma. The assessment of its impact 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 24 variables in 57 patients submitted to surgery from 1985 to 1993. Sixteen patients had only exploratory thoracotomy and 12 minimal residual disease after surgery (no nodules >1 cm in diameter). Thirty-four cases had epithelial histotype, 6 sarcomatous and 17 mixed. Median survival for the whole group was 15.7 months. Multivariate analysis showed a highly significant influence on survival for minimal residual disease after surgery (p=0.0006), followed by TNM stage (p=0.01). Median survival for patients with TNM stage I disease was 36.3 months and for patients with minimal residual disease 33 months. In conclusion, these data suggest that patients with limited disease have a longer survival after surgery than those with extensive disease. At the same time, our results indicate that the achievement of significant disease reduction with surgery has a critical impact on the prognosis of pleural mesothelioma.

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.

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.

Feasibility and tolerance of Cisplatin and Fluorouracil infusion in elderly patients with squamous-cell carcinoma.

Many head and neck and esophageal cancers are diagnosed in patients over 65 years old, but limited data are available on the tolerance of elderly patients to chemotherapy protocols designed for adults. We therefore retrospectively evaluated tolerance of cisplatin (100 mg/m(2) day 1) plus fluorouracil (1,000 mg/m(2)/day as a 120 h infusion) in a group of patients over 65 years of age with squamous cell carcinoma (n=20, group A) and compared it with a second group of younger patients (n=20, group B). Baseline patient characteristics were well balanced between the 2 groups. The median age was 69 years (range, 66-76) in group A and 47 years (range, 19-61) in group B. A total of 54 cycles (range, 1-6) and 65 cycles (range, 1-7) were delivered respectively in group A and B. Dose reductions were required in 9% (group A) and in 10% (group B) of the cycles. No toxic death was recorded in either group. No statistical difference in hematological toxicity was observed between the 2 groups of patients. Although the incidence of grade 1-2 renal toxicity was higher in elderly patients (5 vs 1), the difference was not significant (p=0.09). A similar incidence of mucositis (25%), nausea/vomiting (40%) and diarrhea (5%) was observed for each group. In conclusion, selected elderly patients with good performance status and adequate organ function can be safely treated with CDDP and FU without significantly increased 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.

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.

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.

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.

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.

Chemotherapy and bio-chemotherapy in patients with advanced melanoma: combination therapy with a nitrosourea.

The treatment of advanced melanoma is still disappointing. In a multicenter randomized clinical trial to compare a chemotherapy (CT) with or without low doses of IL-2 and IFN (Bio-CT), the participating centers chose whether or not to add a nitrosourea, carmustine (BCNU) to the therapy. The aim of the present paper is to report the clinical results of the patients (pts) treated in both arms with BCNU. One hundred and seventy-six pts with advanced melanoma were enrolled in the study from 27 centers and a total of 18 pts also received BCNU in 3 centers. No further changes to the protocol criteria were allowed. One patient refused the treatment. No complete responses were observed. Irrespectively of the treatment arm, 9/17 pts showed a partial response to therapy (53%) (5/9 in the CT and 4/8 in the BioCT arm). The most important adverse events observed were hematological: 12 pts presented grade 3 (6 pts) or grade 4 (6 pts) leukocytopenia and 9 pts had grade 4 thrombocytopenia, all of which resolved spontaneously. The addition of a nitrosourea to CT or Bio-CT appears to improve response rates compared to the same regimens without nitrosourea. Patient tolerability is acceptable. Further studies using this combination are warranted.

Clinical development of new fluoropyrimidines: a major improvement in colorectal cancer treatment?

AIMS AND BACKGROUND: Colorectal cancer represents an increasing problem and is responsible for about 16,000 deaths per year in Italy. Fluorouracil represents the most widely used agent, but therapeutic responses have remained consistently discouraging. The overall response rates for fluorouracil as a single agent range from 5% to 15%, and the addition of biochemical modulators, although able to improve response rate, has not been shown conclusively to prolong survival. METHODS: In recent years, several new compounds characterized by a high therapeutic index, optimal absorption through the gastrointestinal tract when administered orally and selective hepatic metabolization have been synthesised. In this review we analyzed published data on new fluoropyrimidines in an attempt to better define their role and to evaluate any significant improvement over fluorouracil. RESULTS: Although no sure advantage over fluorouracil has been detected, interesting results have been reported for fluorouracil analogs with alternative routes of administration such as oral or intra-arterial chemotherapy. CONCLUSIONS: Further studies, possibly randomized, should also measure quality of life and treatment-related costs in order to define their real advantage over fluorouracil in the palliation of advanced colorectal cancer.

Megestrol acetate in unresectable hepatocellular carcinoma.

AIMS AND BACKGROUND: No consolidated medical treatment has yet been established for unresectable hepatocellular carcinoma (HCC). A possible interference of hormones in the pathogenesis and cellular growth of HCC has been suggested. METHODS: To evaluate the activity and tolerance of progestins in HCC, patients were treated with megestrol acetate orally at a dose of 160 mg daily until progression of disease or grade III-IV toxicity was observed. RESULTS: Eleven patients entered the study and were assessable for response and side effects. Median duration of treatment was 80 days (range 60-150). No major responses were observed, 4 patients had stabilization of disease for at least 2 months, and 7 had progressive disease. Median time to disease progression was 3 months (range 2-5). Three patients required interruption of treatment because of toxicity (2 patients had worsening of concomitant diabetes and 1 patient had gastric bleeding). CONCLUSIONS: The results of the present study suggest that hormone therapy with megestrol acetate has no significant role in HCC.

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

AIMS AND BACKGROUND: Many lung cancers are diagnosed in patients over 65 years of age, but limited data are available on the tolerance and activity in elderly patients of chemotherapy protocols designed for adults. METHODS: We therefore activated a phase II study in patients aged 65 years or older affected by stage IIIB-IV non-small-cell lung cancer in order to assess the tolerance and activity of vinorelbine administered weekly at a dose of 25 mg/m2. RESULTS: Since June 1992, 25 patients (20 males, 5 females; performance status ECOG, 0-2) have been included in the study and are evaluable for response and side effects. Two-hundred and twenty-eight cycles of therapy have been delivered (median/patient, 9 cycles). Four partial remissions (16%; 95% confidence interval 5-36%), 9 disease stabilizations, and 12 progressions have been observed. Median time to disease progression was 3 months, and median survival was 5 months (range, 2-25+). Mild or moderate side effects included leukopenia (6 cases), neutropenia (4 cases), anemia (4 cases), nausea (4 cases), infection (3 cases) and thoracic pain (2 cases). Grade III/IV toxicity consisted mainly of leukopenia and neutropenia observed respectively in 5 and in 7 patients. No significant difference in terms of tolerability has been observed for patients aged 65 to 70 with respect to patients aged 70 years or older. CONCLUSIONS: The administration of vinorelbine in elderly patients does not seem to differ significantly in terms of response and tolerability from that recorded for adults. Selected elderly patients with good performance status and adequate organ function can be safely treated with systemic chemotherapy.

Apparently nonfunctioning metastases of parathyroid carcinoma.

A 41-year-old woman was operated on for severe hyperparathyroid syndrome. At surgery a parathyroid tumor with the histopathologic pattern of carcinoma was found. After surgery serum calcium settled within normal limits (10.5 mg/dl, N.V. 8.5-10.8), whereas parathormone and calcitonin reached progressively high levels, respectively 400 ng/dl (N.V. up to 250) and 500 pg/ml (N.V. up to 100 ng/ml). Serum ultrafiltration analysis for parathormone and calcitonin showed many peaks of immunoreactivity with high molecular weight of both hormones. One year after surgery, metastases developed in the lymph nodes of the neck and the mediastinal, pleural and pancreatic regions. After death for tumor wasting, immunohistochemical study of the tumoral tissue with the peroxidase-antiperoxidase technique showed a relatively high density of calcitonin-containing cells. The findings in this case suggest that: several cells in this parathyroid cancer could secrete both parathormone and calcitonin; the hormonal secretion was impaired as suggested by the high molecular weight of both hormones found at gel-filtration analysis; the macromolecular profile of parathormone could explain the apparent function of the parathyroid cancer.

[Cardiotoxicity induced by 5-fluorouracil. A case report]. / Cardiotossicità da 5-fluorouracile: descrizione di un caso clinico.

A case of ischemic cardiopathy which was observed after 5-fluorouracil administration for a carcinoma of the small intestine is described.