Annamaria Catino

Paclitaxel, cisplatin and lonidamine in advanced ovarian cancer. A phase II study.

A potential way to improve the results obtained with the standard carboplatin/cisplatin (CDDP)-paclitaxel treatment regimen in advanced ovarian cancer is to incorporate a modulating agent such as lonidamine (LND). In fact, LND has been shown to revert the resistance to cisplatin and to potentiate cisplatin activity experimental models and in clinical studies. 35 consecutive patients with advanced ovarian cancer, not previously treated with chemotherapy were treated with paclitaxel at a dose of 135 mg/m(2) intravenously (i.v.) on day 1 (in a 3 h infusion) and cisplatin at a dose of 75 mg/m(2) iv on day 2 plus LND orally (p.o.) at a dose of 450 mg/die for 6 consecutive days starting two days before chemotherapy, every 3 weeks for six cycles. Complete plus partial responses were observed in 8 (80%) out of the 10 women with measurable disease. In the 25 patients with evaluable disease, only four clinical progressions were observed (16%). Median progression-free survival (PFS) and overall survival (OS) were 28.5 (95% confidence interval (CI) 22.2-34.8) and 46.5 (95% CI 32.4-60.00) months respectively. Grade 3-4 neutropenia was observed in 9 (26%) patients. Alopecia, nausea and vomiting (Grade 3) were observed in 33 (94%) and 5 (14%) patients, respectively. In conclusion, the combination of CDDP/paclitaxel plus LND is active and tolerable in the treatment of advanced ovarian cancer.

Radiofrequency thermal ablation of 69 lung neoplasms.

Summary Radiofrequency thermal ablation (RFA) is a new, minimally invasive technique offered in the treatment of various neoplasms. RFA produces ionic agitation within the area to be treated, resulting in the heating of neoplastic tissue using a radiofrequency generator. Well defined areas of coagulative necrosis are formed, thereby destroying the tumor. Percutaneous CT-guided RFA was performed in 34 patients with 69 lung neoplasms. Six patients were affected by primary Non-Small Cell Lung Cancer (NSCLC), and 28 patients presented with metastatic lung nodules originating in various solid tumors. Patients were considered ineligible for surgery for the following reasons: medical comorbidities; technical reasons; severe respiratory insufficiency; refusal of surgery. Adequacy of treatment was assessed by CT-Scan and Nuclear Magnetic Resonance (NMR) with gadolinium. A median follow-up of 9 months (3-25 months) resulted in 30 patients evaluable for response with a total of 63 nodules to be treated, 58 of which achieved complete necrotic response. Relapse occurred in 5/63 treated nodules. In 2 of these patients, relapse occurred exclusively in the treated nodules, whereas in the other 3 patients, relapse occurred in the treated nodules as well as at distant sites. 9 patients are alive and disease free. Pneumothorax requiring pleural drainage was the main complication, observed in 16% of the treatment sessions. Lung RFA has shown itself to be a safe and feasible option in the treatment of lung neoplasms in patients otherwise ineligible for surgery. The high rate of complete responses obtained in our study (92%) suggests that further investigation of lung RFA, combined with chemotherapy and/or radiation therapy is warranted with the objective of improving local disease control and survival rates.

VEGF concentration from plasma-activated platelets rich correlates with microvascular density and grading in canine mast cell tumour spontaneous model.

Canine cutaneous mast cell tumour (CMCT) is a common cutaneous tumour in dog, with a higher incidence than in human. CMCT is classified in three subgroups, well and intermediately differentiated (G1 and G2), corresponding to a benign disease, and poorly differentiated (G3), corresponding to a malignant disease, which metastasize to lymph nodes, liver, spleen and bone marrow. In this study, we have evaluated serum (S), platelet‐poor plasma (P‐PP), plasma‐activated platelet rich (P‐APR) and cytosol vascular endothelial growth factor (VEGF) concentrations, microvascular density (MVD) and mast cell density (MCD) in a series of 86 CMCTs and we have correlated these parameters with each other, by means of ELISA detection of VEGF and immunohistochemistry. Results show that VEGF level from cytosol P‐APR and MVD were significantly higher in G3 CMCTs as compared to G1 or G2 subgroups. Moreover, a significantly strong correlation among VEGF levels from P‐PAR and cytosol, MVD and MCD was found in G3 subgroup. Because VEGF levels from P‐APR well correlated with MVD and malignancy grade in CMCT, we suggest that VEGF might be secreted from MCs and it may be a suitable surrogate inter‐species angiogenetic markers of tumour progression in CMCT. Finally, CMCT seems to be a useful model to study the role of MCs in tumour angiogenesis and inhibition of MCs degranulation or activation might be a new anti‐angiogenic strategy worthy to further investigations.

Carboplatin plus ifosfamide as salvage treatment of epithelial ovarian cancer: a pilot study.

PURPOSE This study aimed to evaluate the activity and toxicity of carboplatin (PPL) and ifosfamide (IFO) in patients with epithelial ovarian cancer previously treated with cisplatin (CDDP)-containing regimens. PATIENTS AND METHODS From July 1989 to December 1991, 35 patients with epithelial ovarian cancer relapsed or refractory to CDDP as first-line chemotherapy were treated. PPL was administered at a dose of 300 mg/m2 intravenously (IV) on day 1 and IFO at a dose of 1,500 mg/m2 IV on days 1 to 3 every 3 to 4 weeks. Criteria for evaluating previous response to CDDP were strictly defined. RESULTS The overall response rate was 43% (complete response [CR], 6%; partial response [PR], 37%) and the median duration of response was 7 months (range, 3 to 16). In potentially platinum-sensitive (PPS; relapsed) patients, the overall response rate was 56%. None of the primary platinum-resistant (PPR) patients obtained a clinical response to PPL plus IFO, whereas one of five secondary platinum-resistant (SPR) patients obtained a PR. The regimen was easily manageable. CONCLUSION PPL plus IFO is useful and well-tolerated combination in salvage treatment of patients with advanced ovarian cancer. However, clear synergism between PPL and IFO that could overcome intrinsic or acquired CDDP resistance was not observed. The advantage of PPL plus IFO as compared with CDDP-containing regimens is represented by the increased tolerability and the reduced neurotoxicity, nephrotoxicity, and ototoxicity as compared with CDDP-containing regimens. It is essential that the patient population be defined according to their previous response to platinum therapy in trials involving second-line therapy of ovarian cancer.

Revertant and potentiating activity of lonidamine in patients with ovarian cancer previously treated with platinum.

PURPOSE Lonidamine (LND) is an energolytic derivative of indazol-carboxylic acid that has been shown to enhance cisplatin (CDDP) activity in both sensitive (A2780) and resistant (A2780/Cp8) ovarian cancer cell lines. The aim of this study was to confirm the potentiating or reverting activity of LND on CDDP activity obtained in experimental models in a phase II study of advanced ovarian cancer patients previously treated with platinum-based regimens. PATIENTS AND METHODS Twenty-seven consecutive women with histologically proven and measurable ovarian cancer previously treated with platinum compounds were treated with CDDP plus LND. CDDP was administered at 1 mg/kg intravenously (IV) once weekly for 6 weeks and every 3 weeks thereafter until disease progression or toxicity. LND was administered at 450 mg daily (1 tablet every 8 hours) for the entire period of therapy starting 3 days before the first CDDP administration. In addition, a higher LND dosage was provided on the day of CDDP administration in an attempt to maximize the synergy of this drug with CDDP. RESULTS Ten patients achieved a complete response (CR) or partial response (PR) for an overall response rate of 37% (95% confidence interval [CI], 19% to 55%). In particular, responses were observed in five of 18 (28%) refractory or early relapsed patients (one CR and four PRs) and in five of nine patients (55%) in the late-relapsed group (two CRs and three PRs). Grade 3 or 4 anemia, leukopenia, and thrombocytopenia were observed in 19%, 15%, and 11% of patients, respectively, whereas seven of 27 patients (26%) showed LND-related myalgia. Grade 3 renal toxicity was observed in two patients (8%). Neurotoxicity, often concealed by LND-related myalgia, was recorded as grade 1 or 2 in six patients (22%) and as grade 3 in one (4%). CONCLUSION The 37% response rate observed in this study (28% in refractory or early-relapsed patients), suggests that the synergism between CDDP and LND observed in vitro against ovarian cancer cell lines can be clinically confirmed. However, larger series and randomized studies are needed to assess definitely the revertant activity of LND on CDDP-refractory patients.

Cisplatin/Pemetrexed Followed by Maintenance Pemetrexed Versus Carboplatin/Paclitaxel/Bevacizumab Followed by Maintenance Bevacizumab in Advanced Nonsquamous Lung Cancer: The GOIM (Gruppo Oncologico Italia Meridionale) ERACLE Phase III Randomized Trial

INTRODUCTION Cisplatin with pemetrexed (CP) and carboplatin with paclitaxel and bevacizumab (CbTB) are standard first-line treatments for patients with advanced nonsquamous (NS) non-small-cell lung cancer (NSCLC). Quality of life (QoL) is a key objective in the management of advanced NSCLC. Thus, effect on QoL could be an additional factor in the choice of treatment. PATIENTS AND METHODS Patients with untreated stage IIIB/IV NS-NSCLC and Eastern Cooperative Oncology Group performance status of 0 or 1 were randomized to receive first-line chemotherapy with cisplatin 75 mg/m(2) and pemetrexed 500 mg/m(2), every 3 weeks, for 6 cycles followed by maintenance pemetrexed; or carboplatin area under the curve 6, paclitaxel 200 mg/m(2), and bevacizumab 15 mg/kg, every 3 weeks, for 6 cycles followed by maintenance bevacizumab. The primary end point was the difference in QoL between the 2 treatment arms after 12 weeks of maintenance, measured using the EuroQoL 5 Dimensions-Index (EQ5D-I) and EQ5D-visual analogue scale (EQ5D-VAS). RESULTS One hundred eighteen patients were randomized to CP (n = 60) or CbTB (n = 58). Baseline characteristics were well balanced. The proportion of patients evaluable for the primary end point was lower than planned. After 12 weeks of maintenance, the difference between mean changes in EQ5D-I was 0.137, favoring CP (95% confidence interval [CI], -0.02 to 0.29, Wilcoxon P = .078), although not statistically significant; and the difference between mean changes in EQ5D-VAS was 0.97 (95% CI, -9.37 to 11.31, Wilcoxon P = .41). CONCLUSION Although the study was underpowered because of a small number of patients evaluable for the primary end point, QoL did not differ between treatment arms. Other factors such as comorbidities and schedule should be used when deciding on first-line treatment.

Activity of the EGFR-HER2 dual inhibitor afatinib in EGFR-mutant lung cancer patients with acquired resistance to reversible EGFR tyrosine kinase inhibitors.

BACKGROUND The purpose of this study was to evaluate the efficacy of afatinib in EGFR-mutant metastatic NSCLC patients with acquired resistance to erlotinib or gefitinib. MATERIALS AND METHODS We retrospectively analyzed the outcome of patients with EGFR-mutant advanced NSCLC treated with afatinib after failure of chemotherapy and EGFR TKIs. RESULTS A total of 96 individuals were included in the study. According to EGFR status, most patients (n = 63; 65.6%) harbored a deletion in exon 19, and de novo T790M mutation was detected in 2 cases (T790M and exon 19). Twenty-four (25%) patients underwent repeated biopsy immediately before starting afatinib and secondary T790M was detected in 8 (33%) samples. Among the 86 patients evaluable for efficacy, response rate was 11.6%, with a median progression free-survival (PFS) and overall survival (OS) of 3.9 and 7.3 months, respectively. No significant difference in PFS and OS was observed according to type of last therapy received before afatinib, type of EGFR mutation or adherence to Jackman criteria, and patients benefiting from afatinib therapy had longer PFS and OS (P < .001). Outcome results for repeated biopsy patients were similar to the whole population, with no evidence of response in T790M-positive patients. All patients were evaluable for toxicity, and 81% experienced an AE of any grade, with grade 3 to 4 AEs, mainly diarrhea and skin toxicity, occurring in 19 (20%) patients. CONCLUSION Our results showed that afatinib has only modest efficacy in a real life population of EGFR mutant NSCLC patients with acquired resistance to erlotinib or gefitinib.

Randomised Clinical Trial of Adjuvant Chemotherapy in Patients with Node-Negative, Fast-Proliferating Breast Cancer

SummaryA prospective randomised clinical trial in patients with node-negative, fast-proliferating breast cancer was initiated in January 1990 to verify the feasibility and reliability of a 3H-thymidine (3H-Tdr) autoradiographic assay in a prospective and consecutive series of node-negative patients and the therapeutic effect of adjuvant chemotherapy in patients with node-negative breast cancer and high tumour proliferative activity. Node-negative patients with a high 3H-Tdr Labelling Index (3H-Tdr-LI) were randomised to receive either no further treatment or combination chemotherapy consisting of fluorouracil, epirubicin plus cyclophosphamide (FEC) for 6 cycles. The autoradiographic assay was performed in 307 of 317 patients (97%) and was evaluable in 291 of 317 patients (92%). A total of 176 patients with a high 3H-Tdr-LI entered the clinical randomised study: 91 in the FEC arm and 85 in the control arm. Patient groups were fairly well balanced regarding the most important clinical and pathological characteristics. In total, 530 FEC cycles have been administered with an actual dose intensity of 90%. Patients receiving FEC demonstrated leucopenia in 35% of cases, alopecia in 70%, and loss of menses in premenopausal patients in an age-dependent manner. Patients are still being entered into the study.

Serum Vascular Endothelial Growth Factor Concentrations in Hepatocellular Cancer Patients Undergoing Percutaneously Radiofrequency Thermal Ablation

Summary Vascular endothelial growth factor (VEGF) is known to play a central role in tumour angiogenesis. However, no data have been published with regard to the clinical-biological significance of serum (S)-VEGF in hepatocellular cancer (HCC) patients undergoing to percutaneously radiofrequency thermal ablation (PRFA). The aim of this study was to assess the modifications of S-VEGF levels in a series of 28 HCC patients in hepatitis C virus-positive cirrhosis before and after PRFA, respectively. Samples of S were taken before, 2 and 5 days after PRFA respectively and VEGF levels were assessed by ELISA. No significant difference was found between pre- and post-VEGF levels (p= n.s.; by Wilcoxon test). We suggest that S-VEGF level is not useful as early predictive marker of response to PRFA.

Phase I/II study of gemcitabine plus mitoxantrone as salvage chemotherapy in metastatic breast cancer

The purpose of this study was to determine the maximum-tolerated dose of gemcitabine plus mitoxantrone in women with metastatic breast cancer (MBC) and to evaluate activity and toxicity of this combination in a phase II trial. Sixty-three patients with MBC, previously treated with chemotherapy including anthracycline and/or taxanes, were treated with mitoxantrone 10 or 12 mg m−2 intravenously on day 1 plus gemcitabine in escalating doses from 600 to 1200 mg m−2 intravenously on days 1 and 8, every 3 weeks. In phase I, on 23 patients entered on study, dose-limiting toxicity occurred at the dosage of 1200 mg m−2 gemcitabine and 10 mg m−2 mitoxantrone, with three out of five patients developing grade 4 neutropenia. In phase II, with gemcitabine administered at 1000 mg m−2 and mitoxantrone at 10 mg m−2, 12 (30%) out of 40 assessable patients responded, even if no complete response was obtained. Moreover, stable disease was observed in eight (20%) patients. The median time to treatment failure was 22 weeks (range, 2–33), and median survival was 42 weeks (range, 2–92). Grade 3 and 4 neutropenia were observed in 12 (30%) and one (2.5%) cases respectively; grade 3 thrombocytopenia was observed in two patients (5%), grade 2 mucositis in two patients (5%), grade 3 anaemia in two patients (5%), grade 3 alopecia in one patient (2.5%) and asymptomatic cardiotoxicity in three patients (8%), respectively. In conclusion, the doses of 10 mg m−2 (day 1) for mitoxantrone and 1000 mg m−2 for gemcitabine (days 1–8) every 3 weeks resulted active and safe in MBC. Further investigations in less heavily pretreated patients are warranted.