Primary tumour resection may improve survival in functional well-differentiated neuroendocrine tumours metastatic to the liver.

BACKGROUND: Functional well-differentiated neuroendocrine tumours (NET) with liver metastases represent a therapeutic challenge with few alternative options in guidelines. In these patients, the role of surgical resection of the primary tumour is controversial. PATIENTS AND METHODS: From a regional registry collecting somatostatin analogue (SSA)-treated tumours from 1979 to 2005, a series of 139 patients presenting with symptomatic, liver-metastatic, well-differentiated NET (G1-G2, mitoses: ≤20, Ki-67: ≤20%) was prospectively collected and retrospectively analysed. Surgery on either the primary tumour or liver metastases was chosen: 1) when low perioperative risk was predictable; 2) in presence of an impending risk of obstruction, bleeding, or perforation; or 3) if liver metastases were suitable of curative or subtotal (>90%) tumour removal. Impact of the most relevant clinico-pathological parameters on survival was studied. RESULTS: Median follow-up was 127 months and median survival was 94 months, with 138 vs. 37 months in resected vs. non-resected primary NET (p < 0.001), respectively. In the univariate analysis, prolonged survival was significantly associated with primary tumour resection (p < 0.001), resection of liver metastases (p = 0.002), site of primary (carcinoid vs. pancreatic, p = 0.018), basal chromogranin-A (CgA) <200 ng/mL (p = 0.001), and absence of diarrhea (p = 0.012). Multivariate analysis showed that primary tumour resection was an independent positive prognostic factor (HR = 3.17; 95% CI: 1.77-5.69, p < 0.001), whereas diarrhea, basal CgA ≥200 ng/mL, and high tumour load were independent negative prognostic factors. Also, in 103 patients with non-resectable liver metastases, primary tumour resection was significantly associated with prolonged survival (median 137 vs. 32 months, p < 0.0001). CONCLUSIONS: Primary tumour resection may improve survival in functional well-differentiated NET with liver metastases.

Phase I/IIa study evaluating the safety, efficacy, pharmacokinetics, and pharmacodynamics of lucitanib in advanced solid tumors.

BACKGROUND: Lucitanib is a potent, oral inhibitor fibroblast growth factor receptor types 1 and 2 (FGFR), vascular endothelial growth factor receptor types 1, 2, and 3 (VEGFR), platelet-derived growth factor receptor types α and ß (PGFRα/ß), which are essential kinases for tumor growth, survival, migration, and angiogenesis. Several tumor types, including breast carcinoma, demonstrate amplification of fibroblast growth factor (FGF)-related genes. There are no approved drugs for molecularly defined FGF-aberrant (FGFR1- or FGF3/4/19-amplified) tumors. METHODS: This open-label phase I/IIa study involved a dose-escalation phase to determine maximum tolerated dose (MTD), recommended dose (RD), and pharmacokinetics of lucitanib in patients with advanced solid tumors, followed by a dose-expansion phase to obtain preliminary evidence of efficacy in patients who could potentially benefit from treatment (i.e. with tumors harboring FGF-aberrant pathway or considered angiogenesis-sensitive). RESULTS: Doses from 5 to 30 mg were evaluated with dose-limiting toxic effects dominated by vascular endothelial growth factor (VEGF) inhibition-related toxic effects at the 30 mg dose level (one case of grade 4 depressed level of consciousness and two cases of grade 3 thrombotic microangiopathy). The most common adverse events (all grades, all cohorts) were hypertension (91%), asthenia (42%), and proteinuria (57%). Exposure increased with dose and t½ was 31-40 h, suitable for once daily administration. Seventy-six patients were included. All but one had stage IV; 42% had >3 lines of previous chemotherapy. Sixty-four patients were assessable for response; 58 had measurable disease. Clinical activity was observed at all doses tested with durable Response Evaluation Criteria In Solid Tumors (RECIST) partial responses in a variety of tumor types. In the angiogenesis-sensitive group, objective RECIST response rate (complete response + partial response) was 26% (7 of 27) and progression-free survival (PFS) was 25 weeks. In assessable FGF-aberrant breast cancer patients, 50% (6 of 12) achieved RECIST partial response with a median PFS of 40.4 weeks for all treated patients. CONCLUSION: Lucitanib has promising efficacy and a manageable side-effect profile. The spectrum of activity observed demonstrates clinical benefit in both FGF-aberrant and angiogenesis-sensitive populations. A comprehensive phase II program is planned.

Intrapericardial treatment of neoplastic pericardial effusions.

Pericardial effusion and cardiac tamponade are known complications of many advanced malignancies as lung cancer, breast cancer, lymphomas and leukemias. Initial relief can be easily obtained with percutaneous echo-guided pericardiocentesis, without significant mortality and morbidity and well-tolerated even in critically ill patients. Effusion recurrences can be observed, however, in up to 40% of cases if only simple pericardial drainage is performed. Effective management can be obtained by instillation in the pericardial sac of different agents, with sclerosing or cytostatic activity, like tetracyclines, bleomycin, thiotepa or radionuclides. Intrapericardial sclerotherapy is associated to good results in terms of recurrence prevention and survival improvement. Absence of pericardial effusion at 30 days after drainage can be observed in 70 to 90% of all treated patients, without significant variations among different treatments. No significant side effects are observed, with the exclusion of chest pain during tetracyclines instillation. In our opinion pericardiocentesis associated to intrapericardial sclerotherapy with thiotepa is the best compromise in terms of recurrence prevention, tolerability and costs. Real randomized, case-control studies are moreover required to assess the gold standard of malignant pericardial effusions treatment.

Synergistic activity of oxaliplatin and 5-fluorouracil in patients with metastatic colorectal cancer with progressive disease while on or after 5-fluorouracil.

From February 1995 through October 1996, 25 patients with metastatic colorectal cancer showing a clinical resistance to 5-fluorouracil (5-FU) entered this study. Thirteen received oxaliplatin alone and 12 received it in combination with 5-FU. Oxaliplatin was administered at 130 mg/m2 over a 2-hour infusion every 3 weeks, alone or added either to 5-FU as a continuous infusion at 200 mg/m2 to 300 mg/m2 (six patients) or to a 5-FU bolus, 375 mg/m2, plus leucovorin, 100 mg/m2, daily for 5 days every 3 weeks (6 patients). Eighty-six of 98 administered cycles were evaluable for toxicity (47 for oxaliplatin plus 5-FU and 39 for oxaliplatin alone). Hematologic toxicity was mild, occurring as grade 2 leukopenia in 23% of the cycles of 5-FU and oxaliplatin and in 5% of the cycles of oxaliplatin alone. The most common toxicity was neurologic (grade 1 to 2 in 60%-6% of the cycles of the combination, respectively, and 68%-10% of oxaliplatin given alone) as hand-foot paresthesia or hypersensitivity to cold. No grade 4 toxicity was reported and only three patients in the 5-FU group developed grade 3 diarrhea. Grade 2 nausea and vomiting occurred in 33% of the cycles when both drugs were given and in 15% when oxaliplatin was administered alone. The combination of oxaliplatin and 5-FU induced four partial remissions (33%; 95% confidence interval, 6%-60%), whereas eight patients of the whole group had stable disease. No response occurred when oxaliplatin was administered as a single agent. The results of this study confirm the antitumor activity of oxaliplatin when added to 5-FU in patients who have metastatic colorectal cancer previously refractory to 5-FU. The possible therapeutic synergy with 5-FU was not accompanied by increased toxicity.

Chemotherapy of advanced malignant-melanoma (review).

The role of medical treatment in advanced or metastatic malignant melanoma is still controversial, and there is no standard systemic therapy. Dacarbazine has been the most widely used single drug, despite its response rate range of 10-25%. A number of new drugs, polychemo-therapeutic regimens and combined modalities have been explored. Fotemustine, a new chloronitrosourea, is one of the most promising, and is active against disseminated malignant melanoma, in particular against brain metastases. Cisplatin has modest activity as single agent but positive results have been reported when it is combined with dacarbazine. Modulation of the activity of cisplatin and dacarbazine by tamoxifen has recently been postulated. The results of the few clinical trials in malignant melanoma are interesting but controversial. Interleukin-2 and interferon are active in this disease, but no more so than individual chemotherapeutic drugs. However, despite their high cost, combinations of immuno- and chemotherapeutic agents have been extensively investigated in order to evaluate possible synergisms. The above-mentioned efforts have produced contradictory results that are partly related to the difficulty in establishing whether a positive or negative treatment outcome is due to the chosen therapy or patient selection. For these reasons, patients with advanced malignant melanoma should be treated according to research protocols in specialized centers until an effective approach is developed.

Systemic treatment of advanced malignant-melanoma (review).

The medical treatment of advanced or metastatic malignant melanoma is still controversial and no standard systemic therapy can be claimed. The selection of patients is an important factor to evaluate the results from clinical trials. Among the chemotherapeutic agents dacarbazine is still the most widely employed drug, because of the scarce evidence of better survival from multidrugs combinations. Fotoemustine is one of the most promising new drugs showing non cross resistance with dacarbazine and effectiveness on brain metastases. Interleukin-2 and interferon are active, but no more than single chemo-therapeutic agents, despite the higher cost. However, ongoing trials are exploring the combination of immuno- and chemotherapeutic agents with some very good preliminary results. In fact, for the above reported reasons, a patient with advanced malignant melanoma should be treated according to research protocols in specialized centers until an effective standard approach will be developed.

Characterization of the response of human thymocytes and blood lymphocytes to the synergistic mitogenicity of 12-O-tetradecanoylphorbol-13-acetate (TPA)-ionomycin.

The combination of the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) and the calcium ionophore ionomycin is synergistically mitogenic for human fetal and infant thymocytes as well as peripheral blood lymphocytes. Optimal mitogenic stimulation is achieved when TPA and ionomycin are used at doses of 0.5-1 ng/ml and 0.5-1 microgram/ml, respectively. Phenotypic analysis and cell sorting show that the thymocytes responsive to the mitogen have a mature or medullary phenotype (T1+, T3+, T11+, T6-, HLA-A,B++, [TdT]-); similarly in blood the T cell subsets (T11+, T4+ and T11+, T8+) are selectively responsive to TPA-ionomycin. Both activated lymphocytes and thymocytes express HLA-DR antigens as well as activation antigens such as T9, T10 and T cell activation antigen. T cells activated by TPA-ionomycin can be grown for periods of up to 50 days without addition of exogeneous interleukin 2. The observations may have implications for the membrane-associated signals involved in T cell growth and proliferation.