Cetuximab plus FOLFOX-4 in untreated patients with advanced colorectal cancer: a Gruppo Oncologico dell'Italia Meridionale Multicenter phase II study.

OBJECTIVES: FOLFOX-4 and FOLFIRI are considered equivalent in terms of activity and efficacy as first-line chemotherapy in metastatic colorectal cancer (mCRC). The monoclonal antibody (mAb) cetuximab showed intrinsic activity as a single agent in mCRC and was approved in combination with CPT-11 for patients who failed previous CPT-11-based treatment. The purpose of this phase II study was to evaluate the activity and safety of FOLFOX-4 plus cetuximab in untreated mCRC patients. METHODS: Untreated patients with measurable metastatic disease and expressing epidermal growth factor receptor (EGFR) received cetuximab at a loading dose of 400 mg/m(2), followed by weekly doses of 250 mg/m(2), in combination with the FOLFOX-4 regimen every 2 weeks for a maximum of 12 cycles, after which a maintenance program using cetuximab alone was allowed for a maximum of 6 months. RESULTS: Eighty-two unselected patients were screened; 70 were EGFR+ and entered the trial. Of the 67 assessable patients, the objective response rate was 64.2% (95% CI: 52.5-75.5%) and the tumor growth control rate was 94% (95% CI: 88-99%). All the objective responses except 1 were confirmed. In the group of patients with initially unresectable liver disease alone, 7/33 (21%) were resected. The median time to progression (TTP) and overall survival (OS) were 10.0 and 22.0 months, respectively. The treatment was well tolerated, with no treatment-related deaths, while 24.2% of the patients were affected by cutaneous toxicity of grade >2. Mutational analysis of the KRAS and BRAF genes was retrospectively performed on 35 of the 69 patients treated with cetuximab (51%). KRAS was mutated in 13 out of the 35 cases (37%), whereas no mutations were detected in the BRAF gene. A trend toward an association between KRAS mutations and objective response to treatment (p = 0.07) was demonstrated. Analysis of survival showed that patients harboring KRAS mutations had a trend toward worst TTP (p = 0.14) confirmed by age- and sex-adjusted Cox multivariate regression (hazard ratio, HR = 0.62; 95% CI: 0.36-1.06; p = 0.08). Indeed, KRAS mutations were significantly associated with worst OS in both unadjusted analysis (p = 0.047; log rank test) and age- and sex-adjusted Cox multivariate regression (HR = 0.458; 95% CI: 0.248-0.847; p = 0.01). CONCLUSIONS: These results suggest that the combination of FOLFOX-4 plus cetuximab is very active and obtains long TTP with an acceptable toxicity profile. Indeed, our results are in line with recent findings from phase II and phase III randomized studies providing strong evidence that the efficacy of anti-EGFR mAb is confined to patients with wild-type KRAS mCRC. Investigation of other predictive biomarkers may be useful to further define the responder population.

The antiretroviral nucleoside analogue Abacavir reduces cell growth and promotes differentiation of human medulloblastoma cells.

Abacavir is one of the most efficacious nucleoside analogues, with a well-characterized inhibitory activity on reverse transcriptase enzymes of retroviral origin, and has been clinically approved for the treatment of AIDS. Recently, Abacavir has been shown to inhibit also the human telomerase activity. Telomerase activity seems to be required in essentially all tumours for the immortalization of a subset of cells, including cancer stem cells. In fact, many cancer cells are dependent on telomerase for their continued replication and therefore telomerase is an attractive target for cancer therapy. Telomerase expression is upregulated in primary primitive neuroectodermal tumours and in the majority of medulloblastomas suggesting that its activation is associated with the development of these diseases. Therefore, we decided to test Abacavir activity on human medulloblastoma cell lines with high telomerase activity. We report that exposure to Abacavir induces a dose-dependent decrease in the proliferation rate of medulloblastoma cells. This is associated with a cell accumulation in the G(2)/M phase of the cell cycle in the Daoy cell line, and with increased cell death in the D283-MED cell line, and is likely to be dependent on the inhibition of telomerase activity. Interestingly, both cell lines showed features of senescence after Abacavir treatment. Moreover, after Abacavir exposure we detected, by immunofluorescence staining, increased protein expression of the glial marker glial fibrillary acidic protein and the neuronal marker synaptophysin in both medulloblastoma cell lines. In conclusion, our results suggest that Abacavir reduces proliferation and induces differentiation of human medulloblastoma cells through the downregulation of telomerase activity. Thus, using Abacavir, alone or in combination with current therapies, might be an effective therapeutic strategy for the treatment of medulloblastoma.

Multicenter phase II trial of first-line docetaxel/gemcitabine in advanced breast cancer pretreated with adjuvant anthracyclines.

UNLABELLED: The aim of this study was to evaluate activity and tolerability of docetaxel-gemcitabine combination as first-line treatment in patients with metastatic breast cancer previously treated with adjuvant anthracyclines. PATIENTS AND METHODS: Sixty-eight women received gemcitabine 1,000 mg/m(2) as 30-minute infusion on days 1 and 8, and docetaxel 80 mg/m(2) as 1-hour infusion on day 8, with cycles repeated every 3 weeks. RESULTS: Objective responses were observed in 32 out of 68 evaluable patients (45%; 95% confidence interval, 35.2-58.8%). Responses were 44%, 42%, 49% in soft tissue, bone and visceral lesions, respectively, 50% /52% in HER2-positive/-negative tumors, and 50% in both ER- positive/-negative tumors. Median time to progression and overall survival were 6 and 16 months, respectively. Treatment was usually well tolerated, with grade 3-4 neutropenia in 32% - 7% of the patients, and neutropenic fever, grade 3 vomiting, mucositis and peripheral neurotoxicity in 3% of the patients. CONCLUSION: Gemcitabine-docetaxel combination is effective and well tolerated as first-line treatment in advanced breast cancer previously treated with adjuvant anthracyclines.

Laparoscopic resection of sporadic synchronous gastric and jejunal gastrointestinal stromal tumors: report of a case.

Multicentricity of gastrointestinal stromal tumors (GISTs) has been described only in patients with neurofibromatosis type 1 (NF1) or within the small intestine, and different pathogenetic mechanisms are involved. We report a case of synchronous sporadic gastric and jejunal GISTs, which were resected laparoscopically in a 67-year-old man. Immunohistochemical analysis revealed that both lesions were KIT (CD117)-positive, but that the gastric lesion was CD34-positive, whereas the jejunal one was Vimentin-, S-100-, and SMA-positive. Molecular analysis of mutations in KIT exons 9, 11, 13, and 17, and in PDGFRA exons 12 and 18 revealed the presence of a gastric sporadic GIST with a KIT mutation of the exon 11 and a jejunal sporadic GIST without KIT or PDGFRA mutations. To our knowledge, this is the first report of laparoscopically resected synchronous sporadic gastric and jejunal GISTs.

A phase II trial of docetaxel and vinorelbine in patients with advanced breast cancer previously treated with anthracyclines.

BACKGROUND: It was the aim of this study to evaluate the efficacy of docetaxel and vinorelbine combination in well-defined anthracycline-'exposed' or -'resistant' advanced breast cancer patients. PATIENTS AND METHODS: A phase II trial was carried out enrolling 43 advanced breast cancer patients, all previously treated with anthracyclines, both in an adjuvant or advanced setting. Docetaxel 75 mg/m(2) as 1-hour infusion and vinorelbine 25 mg/m(2) as 30-min infusion were administered on day 1, every 3 weeks. RESULTS: According to an intent-to-treat analysis, the response rate was 37.2% (95% CI 22.8-51.6) in 43 patients, whereas responses were observed in 16 (1 complete response, 15 partial response) out of 39 evaluable patients (41%, 95% CI 25.6-56.5); there were 50% with first-line and 33% with second-line therapy, and 50 and 29% of patients were considered anthracycline 'exposed' and 'resistant', respectively; responses by estrogen receptor (ER) status were given in 48% (ER positive) and 25% (ER negative), and by HER2 status, in 21% (HER2 positive) and 52% (HER2 negative). Median time to progression and median overall survival were 7.7 and 28.7 months, respectively. Toxicity was generally acceptable, with grade 3 neutropenia encountered in 15 (35%) patients and grade 4 neutropenia in 1 (2%) patient. Neutropenic fever occurred in 7 patients (16%), usually short-lasting. Grade 3 mucositis was encountered in 2 patients (5%). CONCLUSIONS: The combination of docetaxel and vinorelbine as a 3-weekly schedule is active and manageable in advanced breast cancer patients previously treated with anthracyclines.

Impact of five prophylactic filgrastim schedules on hematologic toxicity in early breast cancer patients treated with epirubicin and cyclophosphamide.

PURPOSE: To evaluate the comparative efficacy of varying intensity schedules of recombinant human granulocyte colony-stimulating factor (G-CSF; filgrastim) support in preventing febrile neutropenia in early breast cancer patients treated with relatively high-dose epirubicin plus cyclophosphamide (EC). PATIENTS AND METHODS: From October 1991 to April 1994, 506 stage I and II breast cancer patients were randomly assigned to receive, in a factorial 2 x 2 design, epirubicin 120 mg/m2 and cyclophosphamide 600 mg/m2 intravenously on day 1 every 21 days for 4 cycles +/- lonidamine +/- G-CSF. The following five consecutive G-CSF schedules were tested every 100 randomly assigned patients: (1) 480 microg/d subcutaneously days 8 to 14; (2) 480 microg/d days 8, 10, 12, and 14; (3) 300 microg/d days 8 to 14; (4) 300 microg/d days 8, 10, 12, and 14; and (5) 300 microg/d days 8 and 12. RESULTS: All of the G-CSF schedules covered the neutrophil nadir time. Schedule 5 was equivalent to the daily schedules (schedules 1 and 3) and to the alternate day schedules (schedules 2 and 4) with respect to incidence of grade 3 and 4 neutropenia (P = .79 and P = .89, respectively), rate of fever episodes (P = .84 and P = .77, respectively), incidence of neutropenic fever (P = .74 and P = .56, respectively), need of antibiotics (P = .77 and P = .88, respectively), and percentage of delayed cycles (P = .43 and P = .42, respectively). G-CSF had no significant impact on the delivered dose-intensity compared with the non-G-CSF arms. CONCLUSION: In the adjuvant setting, the frequency of prophylactic G-CSF administration during EC could be curtailed to only two administrations (days 8 and 12) without altering outcome. This nonrandomized trial design provides support for evaluating alternative, less intense G-CSF schedules for women with early breast cancer.

Phase III randomized trial of FOLFIRI versus FOLFOX4 in the treatment of advanced colorectal cancer: a multicenter study of the Gruppo Oncologico Dell'Italia Meridionale.

PURPOSE: We performed this phase III study to compare the irinotecan, leucovorin (LV), and fluorouracil (FU) regimen (FOLFIRI) versus the oxaliplatin, LV, and FU regimen (FOLFOX4) in previously untreated patients with advanced colorectal cancer. PATIENTS AND METHODS: A total of 360 chemotherapy-naive patients were randomly assigned to receive, every 2 weeks, either arm A (FOLFIRI: irinotecan 180 mg/m(2) on day 1 with LV 100 mg/m(2) administered as a 2-hour infusion before FU 400 mg/m(2) administered as an intravenous bolus injection, and FU 600 mg/m(2) as a 22-hour infusion immediately after FU bolus injection on days 1 and 2 [LV5FU2]) or arm B (FOLFOX4: oxaliplatin 85 mg/m(2) on day 1 with LV5FU2 regimen). RESULTS: One hundred sixty-four and 172 patients were assessable in arm A and B, respectively. Overall response rates (ORR) were 31% in arm A (95% CI, 24.6% to 38.3%) and 34% in arm B (95% CI, 27.2% to 41.5%; P = .60). In both arms A and B, median time to progression (TTP; 7 v 7 months, respectively), duration of response (9 v 10 months, respectively), and overall survival (OS; 14 v 15 months, respectively) were similar, without any statistically significant difference. Toxicity was mild in both groups: alopecia and gastrointestinal disturbances were the most common toxicities in arm A; thrombocytopenia and neurosensorial were the most common toxicities in arm B. Grade 3 to 4 toxicities were uncommon in both arms, and no statistical significant difference was observed. CONCLUSION: There is no difference in ORR, TTP, and OS for patients treated with the FOLFIRI or FOLFOX4 regimen. Both therapies seemed effective as first-line treatment in these patients. The difference between these two combination therapies is mainly in the toxicity profile.

Clinical trials.

A clinical trial is a research study in human patients aimed at answering specific health questions. If a clinical trial is well-conducted, it is the fastest way to find treatments that work in people and ways to improve health. A clinical trial is one of the final stages of a long research process. It determines whether new experimental treatments or new ways of using known therapies are safe and effective, but it must meet ethical and scientific quality requirements. This paper reviews the principal phases of clinical trials and discusses the basic requirements needed to ensure a well-conducted experimental study.

Sequential chemotherapy with cisplatin/gemcitabine (CG) followed by mitoxantrone/methotrexate/mitomycin (MMM) in patients with malignant pleural mesothelioma. A multicenter Italian Phase II Study (SITMP1).

PURPOSE: We performed a multicenter phase II trial to evaluate the impact on the activity, efficacy, symptom control and safety of using two active regimens in a sequential schedule (cisplatin/gemcitabine followed by mitoxantrone/methotrexate/mitomycin) as first-line chemotherapy for unresectable malignant pleural mesothelioma (MPM). PATIENTS AND METHODS: A total of 54 patients received cisplatin 75 mg/m(2) on day 1 and gemcitabine 1,200 mg/m(2) on days 1 and 8, every 3 weeks for four courses (CG regimen) followed by mitoxantrone 10 mg/m(2) on day 1, methotrexate 35 mg/m(2) on day 1 and mitomycin 7 mg/m(2) on day 1, every 3 weeks with mitomycin in alternate cycles for four courses (MMM regimen). RESULTS: We observed 3 complete responses (CRs) (5.6%) and 13 partial responses (PRs) (24.0%), with an overall response rate (ORR) of 29.6% (95% confidence interval, 17-42%), 33 stable disease (SD) (61.1%) and 5 progressive disease (PD) (9.2%). Median time to progression (TTP) was 9.5 months (range, 2-23). Median overall survival (OS) was 13 months (range, 3-33); 1-year survival rate was 63%. The treatment produced a good symptom control, with an improvement during chemotherapy in dyspnea and pain in 52.9 and 48.3% of patients, respectively. The major toxicity observed was hematological. Grades 3-4 NCI-CTC v 2.0 toxicity with the CG regimen included: neutropenia (11.1%), anemia (1.9%), thrombocytopenia (7.4%), vomiting (11.1%) and with the MMM regimen: neutropenia (35.2%), anemia (5.5%), thrombocytopenia (7.4%) and stomatitis (1.9%). CONCLUSION: This phase II study with the sequential approach of two active regimens showed a good disease control in MPM, with symptom improvement and only mild toxicity.

Increasing single epirubicin doses in advanced soft tissue sarcomas.

PURPOSE: To evaluate the maximum-tolerated dose and the clinical efficacy of epirubicin in patients with advanced soft tissue sarcoma. PATIENTS AND METHODS: Sixty-one patients were treated at three different epirubicin dose levels: 140 mg/m(2) (six patients), 160 mg/m(2) (52 patients), and 180 mg/m(2) (three patients). Cycles were repeated every 3 weeks for a maximum of eight cycles. The first two dose levels proved to be feasible and safe without dose-limiting toxicity (DLT). Because the first three patients entering the third dose level experienced DLT, subsequent patients received the next lower dose level. RESULTS: The overall response rate was 44% (95% confidence interval, +/- 12%), with six complete (10%) and 21 partial (34%) responses. Responses seemed related to epirubicin dose level, because the response rate was 17%, 44%, and 100% for the three dose levels (chi(2) test for trend, P =.02). Median response duration, median time to progression, and median overall survival were 10, 8, and 15 months, respectively. Myelosuppression was the most frequent side effect, with grade 3 or 4 neutropenia occurring in 79% of the patients; 31% of patients were febrile. Nonhematologic toxicity was mainly grades 1 and 2. The mean epirubicin dose-intensity was 49 mg/m(2) per week. CONCLUSION: The third epirubicin dose level (180 mg/m(2)) was the maximum-tolerated dose. The recommended drug dose for clinical use is 160 mg/m(2) every 3 weeks with hematopoietic support. Single high-dose epirubicin is effective as first-line treatment and should be preferentially used whenever a high response rate is important to allow the resection of an otherwise unresectable disease or whenever it might result in a significant symptomatic benefit.

First-line treatment with epirubicin and vinorelbine in metastatic breast cancer.

PURPOSE: This phase II multicenter trial was aimed at investigating the activity of epirubicin-vinorelbine combination as first-line chemotherapy in metastatic breast cancer patients. PATIENTS AND METHODS: Ninety-seven patients with metastatic breast cancer and no prior exposure to anthracyclines received the following regimen: epirubicin 100 mg/m(2) by intravenous (IV) bolus infusion on day 1 plus vinorelbine 25 mg/m(2) by 30-minute IV infusion on days 1 and 5, every 3 weeks for up to eight cycles. All patients also received granulocyte colony-stimulating factor (G- CSF) on days 7 to 12 of every cycle. RESULTS: Objective responses, confirmed at least 4 weeks after the first documentation, were observed in 65 out of 92 assessable patients (70.6%; 95% CI, 62% to 80%). Disease remained stable in 17 patients (18.5%). Responses were observed in all disease sites, being 94% in soft tissue, 60% in bone, and 66% in visceral disease. Median time to response, median duration of response, median time to progression, and median overall survival were 2, 9, 10, and 26 months, respectively. The dose-limiting toxicity was neutropenia, which was grade 4 in 36% of the patients, and was accompanied by fever in 26% of the cases. Grade 3 to 4 mucositis was encountered in 28% of the patients. Other toxicities were mild to moderate. No cardiotoxicity was observed. CONCLUSION: The epirubicin-vinorelbine combination with G-CSF support has been shown in this study to be highly active as first-line treatment of metastatic breast cancer patients, with significant although transient toxicity. This justifies further evaluation in the neoadjuvant setting and in early-stage breast cancer.

Addition of either lonidamine or granulocyte colony-stimulating factor does not improve survival in early breast cancer patients treated with high-dose epirubicin and cyclophosphamide.

PURPOSE: Lonidamine (LND) can enhance the activity of anthracyclines in patients with metastatic breast cancer. A multicenter, prospective, randomized trial was designed to determine whether the association of LND with high-dose epirubicin plus cyclophosphamide (EC) could improve disease-free survival (DFS) in patients with early breast cancer (BC) compared with EC alone. Granulocyte colony-stimulating factor (G-CSF) was added to maintain the EC dose-intensity. PATIENTS AND METHODS: From October 1991 to April 1994, 506 patients with stage I/II BC were randomly assigned to four groups: (A) epirubicin 120 mg/m2 and cyclophosphamide 600 mg/m2 administered intravenously on day 1 every 21 days for four cycles (124 patients); (B) EC plus LND 450 mg/d administered orally (125 patients); (C) EC plus G-CSF administered subcutaneously (129 patients); (D) EC plus LND plus G-CSF (128 patients). RESULTS: Median follow-up was 55 months. Five-year DFS rate was similar for LND (B+D groups; 69.6%) versus non-LND arms (A+C groups; 70.3%) and G-CSF (C+D groups; 67.2%) versus non-G-CSF arms (A+B groups; 72.9%). Five-year overall survival (OS) was comparable in LND (79.1%) versus non-LND arms (81.3%) and in G-CSF (80.6%) versus non-G-CSF arms (79.6%). DFS and OS distributions in LND and G-CSF arms did not change according to tumor size, node, receptor, and menopausal status. G-CSF dramatically reduced hematologic toxicity without having a significant impact on dose-intensity (98.1% v 95.5% for C+D and A+B groups, respectively). CONCLUSION: EC is active and well tolerated in patients with early breast cancer. The addition of LND or G-CSF does not improve DFS or OS.

Potentiation of the antitumoral activity of gemcitabine and paclitaxel in combination on human breast cancer cells.

The purpose of this study was to evaluate the antitumoral activity of different gemcitabine-based combination on an experimental model of human breast cancer, in order to identify the most effective treatment and to provide a rationale for clinical investigations. To this end, CG5 breast cancer cells were treated in vitro with gemcitabine followed by epirubicin, doxorubicin, docetaxel or paclitaxel. The reversed sequence was also investigated. Results, analyzed by multiple drug effect/combination index (CI) isobologram, demonstrated that the combination gemcitabine/paclitaxel was the most active showing synergism with a CI of about 0.5 in the two sequences employed. Moreover, the synergistic interaction of gemcitabine and paclitaxel was correlated to a block of the cells in the G0/G1 compartment of cell cycle and to an increase of apoptotic cells compared to each drug. Based on these evidences, the antitumoral efficacy of gemcitabine/paclitaxel combination has been studied in vivo. Mice bearing CG5 human breast xenografts treated with paclitaxel and gemcitabine in combination showed a significant higher inhibition of tumor growth (approximately 70%) compared to that with either agent alone (25%). In conclusion, this study suggests that paclitaxel is the most promising agent for combination protocols with gemcitabine and supports the use of gemcitabine/paclitaxel combination in the clinical management of advanced breast cancer.

Sequential docetaxel followed by epirubicin-vinorelbine as first-line chemotherapy in advanced breast cancer.

BACKGROUND: This phase II study evaluated the efficacy and the tolerability of a sequential regimen of docetaxel followed by epirubicin-vinorelbine combination as first-line chemotherapy in advanced breast cancer. PATIENTS AND METHODS: Twenty-seven patients received docetaxel 100 mg/m2 (4 cycles) followed by 4 cycles of epirubicin 90 mg/m2 (day 1) combined with vinorelbine 25 mg/m2 (days 1 and 5), with cycles repeated every 3 weeks. G-CSF was administered during epirubicin-vinorelbine treatment. RESULTS: There were 1 (3.7%) CR and 14 (51.9%) PR, for an overall response rate of 55.6% (95% CI, 36.9%-74.3%). Median time to response, time to progression and overall survival were 2, 9 and 25 months, respectively. The dose-limiting toxicity was neutropenia (grade 3 to 4 in 85% of the patients). There was one toxic death due to neutropenic fever. Gastrointestinal side-effects were generally mild According to the Simon two-stage design the response rate was considered unsatisfactory and patient accrual was terminated. CONCLUSION: This sequential regimen appears to be moderately effective; possibly, a modulation of the treatment based on objective responses instead of a fixed number of cycles may be more appropriate in order to obtain better results.

Novel association with gemcitabine and docetaxel as salvage chemotherapy in metastatic breast cancer previously treated with anthracyclines: results of a multicenter phase II study.

The goals of this study were to evaluate the efficacy and toxicity of the gemcitabine/docetaxel combination in metastatic breast cancer previously treated with anthracyclines. Fifty-three patients with metastatic breast cancer who had failed or relapsed after anthracycline-based chemotherapy entered the study and were evaluable. Patients received gemcitabine (1,000 mg/m(2) days 1 and 8) and docetaxel (80 mg/m(2) day 8), every 3 weeks. The regimen was generally well tolerated with good feasibility. A complete response occurred in six patients (9.4%) and partial response in 23 (43.4%) for an overall response rate of 53% (95% confidence interval, 38.9% to 66.7%). Median survival rate was 70%; and the duration of response, time to progression, and overall survival were 6, 7.5, and 16.5 months, respectively. We conclude that the gemcitabine/docetaxel combination constitutes a manageable and tolerable combination as salvage chemotherapy in metastatic breast cancer and may represent a valid treatment option in patients previously treated with anthracyclines.

Interleukin-2, interferon-alpha and medroxyprogesterone acetate in metastatic renal cell carcinoma.

BACKGROUND: Interleukin-2 (IL-2) and interferon-alpha (IFN-alpha) are the main immuno-biological agents used in the therapy of metastatic renal cell carcinoma (RCC). Unfortunately the promising results obtained in biological studies have not yet been confirmed in clinical studies. One reason is linked to the immunosuppression of metastatic patients which is caused by macrophage products. IL-6 in particular is considered a growth factor for RCC. Medroxyprogesterone acetate (MPA) may interfere with IL-6 macrophage production, possibly causing a synergistic effect in association with IL-2 and IFN-alpha. Therefore the purpose of our study was to evaluate the toxicity and the efficacy of the association between IL-2, IFN-alpha and MPA. PATIENTS AND METHODS: Forty-two consecutive patients with metastatic RCC were enrolled. IL-2 was administered subcutaneously at doses of 4.5 million UI on days 1-5, 8-12, 15-19 and 22-26; IFN-alpha was administered s.c. at a dose of 3 million t.t.w; MPA was administered orally at a dose of 1000 mg daily. This schedule was repeated after a rest of 2 weeks. RESULTS: Toxicity was mild: the main symptoms observed were fatigue and fever. Six CR (14%), five PR (12%), thirteen SD (31%) and seventeen PD (41%) were observed for an overall response rate of 26%. Patients with good PS and low levels of CRP had a better prognosis. CONCLUSION: Considering both the good activity and the low toxicity of this scheme, we think that it could be carried out in normal clinical practice.

Phase I-II trial of prolonged gemcitabine infusion plus paclitaxel as a biweekly schedule for advanced breast cancer patients pretreated with anthracyclines.

PURPOSE: Paclitaxel (PACL) plus gemcitabine (GEM) is an effective regimen for advanced breast cancer patients pretreated with anthracyclines. A prolonged GEM infusion at a fixed dose rate (FDR) of 10 mg/m²/min produces higher levels of intracellular active metabolites of GEM when compared with a standard 30-min infusion. In the present phase I/II trial, we investigated the association of FDR GEM plus PACL. METHODS: 1,200 mg/m² was the dose of GEM recommended for the phase II study, in which patients received PACL at 150 mg/m², followed by FDR GEM at 1,200 mg/m² (total GEM infusion time = 120 min), both drugs administered biweekly. RESULTS: Forty-two anthracycline-pretreated advanced breast cancer patients with disease recurrence following at least one line of chemotherapy were enrolled. Two (4.8%) and 12 (33.3%) patients experienced a complete and partial response, respectively, for an overall response rate of 38.1% (95% CI 23.4-52.8%). Median progression free survival and overall survival were 5 and 19.9 months, respectively. No statistically significant association was noted between in situ protein expression of RRM1 and BRCA1 (as assessed by immunofluorescence combined with automated quantitative analysis) and response to treatment in 15 patients with tissue available for analysis. Toxicity was mostly mild to moderate, mainly consisting of G3-G4 neutropenia (9.6%) and hypertransaminasemia (9.5%). CONCLUSIONS: Biweekly FDR GEM in combination with PACL is an active and safe regimen for advanced breast cancer patients pretreated with anthracyclines. A prolonged infusion regimen of GEM does not seem to improve the efficacy of a standard 30-min infusion.

Chemotherapy with or without low-dose interleukin-2 in advanced non-small cell lung cancer: results from a phase III randomized multicentric trial.

Non-small cell lung cancer (NSCLC) is associated with IL-2-dependent cell-mediated immunodeficiency. As IL-2 is the main lymphocyte growth factor, a phase III randomized multicenter trial was conducted to evaluate the impact of subcutaneous low-dose IL-2 added to standard chemotherapy (CT) on overall survival (OS) in advanced NSCLC patients. Patients (n=241) with histologically confirmed stage IIIb or IV non-operable NSCLC underwent stratified randomization on the basis of center, ECOG PS, stage of disease and percentage of weight loss. Patients received gemcitabine (1000 mg/m2) on days 1 and 8 + cisplatin (100 mg/m2) on day 2 every 21 days for a maximum of 6 cycles [chemotherapy (CT) arm]. In the CT+IL-2 arm, patients also received low-dose subcutaneous IL-2 3,000,000 IU/die on days 3-5, 9-11, 15-17. The study had 90% power to detect a 20% absolute increase in 1-year OS with 118 patients/arm. An overall response (OR) rate of 12.8% (14% in the CT+IL-2 arm and 11.4% in CT arm) was observed. Stable disease was 70 and 66.7%, and progressive disease 16 and 21.8% in the CT+IL-2 and CT arms, respectively. No differences in response were found in any subgroup analysis. At a median follow-up of 32 months, 1-year OS was 45% for the CT+IL-2 arm vs. 51% for the CT arm (p=0.456 log-rank). Median progression-free survival was 6.6 months in the CT+IL-2 arm vs. 6.9 months in the CT arm (p=0.573, log-rank). A higher number of grade 4 toxicities were reported with CT+IL-2. The most common grade ≥3 adverse events were gastrointestinal toxicity (mainly nausea and diarrhea) and myelosuppression. No relevant differences in clinical outcome were observed from the addition of IL-2 to CT. Future studies investigating the role of T-regulators in chemoimmunotherapeutic regimens could be performed.

A multicenter prospective phase II randomized trial of epirubicin/vinorelbine versus pegylated liposomal doxorubicin/vinorelbine as first-line treatment in advanced breast cancer. A GOIM study.

BACKGROUND: To evaluate activity and tolerability of two anthracycline-containing regimens as first-line treatment for anthracycline-naïve relapsed breast cancer patients. METHODS: Patients with relapsed breast cancer not previously treated with adjuvant anthracyclines were randomly assigned to epirubicin/vinorelbine (arm A: EPI/VNB, EPI 90 mg/m2 on day 1, VNB 25 mg/m2 on days 1,5 plus G-CSF subcutaneously on days 7-12, with cycles repeated every 21 days), or to pegylated liposomal doxorubicin/VNB (arm B: PLD/VNB, PLD 40 mg/m2 on day 1, VNB 30 mg/m2 on days 1, 15, with cycles repeated every 4 weeks). Primary objective was to evaluate the efficacy of the two regimens in terms of response rate, secondarily toxicity, progression free survival and overall survival. RESULTS: One hundred and four patients have been enrolled (arm A 54, arm B 50): characteristics were well balanced between the 2 arms. Responses were as follows: arm A, 3 (5.6%) CR, 20 (37%) PR, (ORR 42.6%, 95%CI 29.3%-55.9%); arm B, 8 (16%) CR, 18 (36%) PR, (ORR 52%, 95%CI 38.2%-65.8%). Median progression free survival was 10.7 months in arm A (95% CI, 8.7-12.6), and 8.8 months in arm B (95% CI, 7.1-10.5). Median overall survival was 34.6 months in arm A (95%CI, 19.5-49.8) and 24.8 months in arm B (95%CI, 15.7-33.9). As toxicity concerns, both treatment regimens were well tolerated; myelosuppression was the dose-limiting toxicity, with G3-4 neutropenia occurring in 18.5% and 22% of the patients of arm A and B, respectively. No relevant differences in main toxic effects have been observed between the two arms, except for alopecia, more common in arm A, and cutaneous toxicity, observed only in arm B. No clinical congestive heart failures have been observed, one case of tachyarrhythmia was reported after the last EPI/VNB cycle, and two reversible ≥ 20% LVEF decreases have been observed in arm A. CONCLUSIONS: Both anthracycline- containing regimens evaluated in the present study seem to be active and with a satisfactory tolerability in anthracycline-naïve relapsed breast cancer patients.