G. Lelli

Prospective phase II study of single-agent gemcitabine in untreated elderly patients with stage IIIB/IV non-small-cell lung cancer.

The purpose of this study was to evaluate the efficacy and tolerability of single-agent gemcitabine in untreated elderly patients with stage IIIb/IV non–small-cell lung cancer (NSCLC). Since April 1997, 46 consecutive patients have been enrolled in this multicenter study. Gemcitabine 1,000 mg/m2 was administered as a 30-minute intravenous infusion on days 1, 8, and 15 every 28 days. Primary patient characteristics were: male/female 38/8; median age 73 years (range: 70–82 years); median Karnofsky performance status (PS) 90 (range: 70–100); stage IIIb 61% and stage IV 39%; histotype: epidermoid 48%, adenocarcinoma 43%, and large cell carcinoma 9%. No complete response was observed, but 10 (21.7%) patients achieved partial response (PR) (95% confidence limits: 11–36%), 27 (58.7%) had stable disease (SD), and 7 (15%) progressed early (at the first evaluation). The median duration of PR and SD was 8 months (range: 4–23+ months) and 4 months (range: 2–9 months), respectively. Subjective response evaluating PS and symptoms such as dyspnea, pain, and cough was evaluated in 40 patients; 11 (27.5%) improved, 15 (37.5%) remained stable, and 14 (35%) worsened. The median time to progression was 4 months, the median survival was 9 months, and 1-year survival was 44%. After a median follow-up of 10.5 months, 14 patients are still alive. There were no grade 4 toxicities. Grade 3 neutropenia and thrombocytopenia occurred in 19% and 2% of patients, respectively. Nonhematologic toxicities were mild. Grade I/II side effects of nausea/vomiting, transient fever, increase of hepatic transaminases, transient peripheral edema at lower extremity (not related to cardiac or renal disease or phlebothrombosis) were reported. This phase II study confirms the activity and favorable toxicity profile of single-agent gemcitabine in the treatment of elderly patients with advanced NSCLC.

Multicenter randomized clinical trial on high-dose epirubicin plus cis-platinum versus vinorelbine plus cis-platinum in advanced non small cell lung cancer

BACKGROUND High dose Epirubicin (HD-EPI) (>90 mg/m2) and Vinorelbine (VNR) demonstrated antitumor activity as single agent (about 20%) in the treatment of advanced NSCLC. This trial compares these two agents combined with cisplatin (CP). PATIENTS AND METHODS From August 1992 to February 1996, 228 patients with locally advanced or metastatic NSCLC were randomized to receive either EPI 120 mg/m2 as i.v. bolus plus Cisplatin (CP) 60 mg/m2 on day 1 (regimen A) or VNR 25 mg/m2 as i.v. bolus on day 1 and 8 plus CP 60 mg/m2 on day 1 (regimen B). Both treatments were recycled every 21 days up to a maximum cumulative dose of EPI of 840 mg/m2 or 12 cycles. Eligible patients were 212 and 198 patients were evaluable for objective response (95 in arm A and 103 in arm B). The main characteristics of eligible patients were: male/female 179/33; median age 61 (42-72); median Karnofsky PS 80 (70-100); stage IIIA 12%, stage IIIB 40%, stage IV 41%, recurrence 7%; histotype: epidermoid 48%, adenoca 36%, others 16%. RESULTS The following response rates were observed in regimens A and B, respectively; CR, 1 and 2%, PR, 32 and 25% (P = 0.4567). Median CR + PR duration was 9 and 8 months, respectively. Median survival was 10.5 and 9.6 months, respectively. Grade III-IV leucopenia occurred in 38 and 21% in arm A and arm B, respectively(P = 0.01), thrombocytopenia in 6 and 0% (P = 0.02), anemia in 8 and 7% (n.s.). Non-hematological toxicity was moderate and the only difference between the treatments was alopecia (88 vs. 33% in arm A and B, respectively). Supraventricular arrhythmia occurred in three patients on regimen A; a >15% LVEF absolute decrease was observed in 9 (22.5%) and three (14%) patients on arm A and arm B, respectively (n.s.). No congestive heart failure was observed. CONCLUSION HD-EPI+CP and VNR+CP are both active combinations in advanced NSCLC with a similar response rate, response duration and survival but regimen A was significantly more toxic (myelosuppression and alopecia).

Randomized, Controlled, Multicenter Phase III Trial of Standard-Dose Fluorouracil-Epirubicin- Cyclophosphamide (FEC), Compared with Time-Intensive FEC (FEC-G) and Mitoxantrone-Methotrexate-Mitomycin C (MMM-G) in Metastatic Breast Carcinoma

Abstract The purpose of this multicenter phase III trial was to assess the impact of a time-intensification of FEC (fluorouracil, epirubicin, cyclophosphamide) and MMM (mitoxantrone, methotrexate, mitomycin C) regimens, supported by lenograstim (G-CSF) on the objective response rate, time to progression and survival of patients with chemotherapy-naive metastatic breast cancer (mbc). Women with mbc were randomized to receive as first-line chemotherapy either standard-dose FEC (all doses in μg/m2): arm A (500, 75, 500 every 21 days), or time-intensified FEC-G: arm B (500, 75, 500 every 14 days), or time-intensified MMM-G: arm C (mitoxantrone 10, methotrexate 35 every 14 days and mitomycin C 10 every 28 days), both with support of lenograstim (G-CSF 150 μg/m2/day sc for 10 days). All study treatments were administered for six cycles. Eligible female patients were in the 31-70 year range with histologically proven mbc, and measurable or evaluable disease. An intent-to-treat analysis was performed. The overall response rate (CR + PR, intent-to-treat analysis) was significantly improved in the time-intensified FEC-G regimen (69%) in comparison with standard-dose FEC (41%), p=0.002. Time-intensified MMM-G (51%) did not lead to a significant improvement in the response rate. The percentage of complete responses was significantly higher in the FEC-G arm as compared to standard-dose FEC (17% vs. 4.7%; p=0.002). The median duration was longer in the intensified-dose arms without, however, achieving a statistically significant improvement. The median time to progression (TTP), and the median survival time did not differ between the three treatment arms. Grade 3-4 leukope-nia was significantly higher (p<0.001) in the standard FEC regimen-treated patients. Thrombocytopenia was significantly higher (p<0.001) in both intensified regimens. Alopecia and mucositis were significantly more frequent in both anthracy-cline-containing regimens (p=0.003). Other hematological and non hematological toxicities were similar in the 3 treatment arms. The increase of dose-intensity of both FEC and MMM regimens improved activity, but not efficacy as compared to standard FEC regimen in our group of chemotherapy-naive, metastatic breast cancer patients.

The antiemetic efficacy and the cost-benefit ratio of ondansetron calculated with a new approach to health technology assessment (real cost-benefit index)

In a phase II study including 80 patients treated with highly emetic drugs such as cisplatin, carboplatin or cyclophosphamide > 600 mg/day) we confirmed the potential of ondansetron to prevent cancer chemotherapy- related acute nausea and vomiting. With a total dose of 19.0-37.3 mg ondansetron we achieved 82%-100% acute (0-24 hours) vomiting free patients. Using ondansetron for the prevention of acute nausea and vomiting increases the total chemotherapy costs by 6%. The real cost-benefit ratio for the treatment of acute nausea and vomiting shows better values for ondansetron than for all other recommended regimens.

Differences in the availability of new anti-cancer drugs for Italian patients treated in different regions. Results of analysis conducted by the Italian Society of Medical Oncology (AIOM)

Aims and background Italy is divided into 20 regions. As a consequence of local autonomy, following marketing authorization by the Italian Medicines Agency, each drug for hospital use is not immediately available, because its approval needs to undergo further steps that can be different among regions. The Italian Society of Medical Oncology conducted the present study to describe the impact of the existence of sub-national pharmaceutical formularies on the disparity of access to new anti-cancer drugs among patients treated in different Italian regions. Methods The availability of 8 new anti-cancer drugs at a regional level and the coherence of regional authorizations compared with national authorizations approved by the Italian Medicines Agency were analyzed as of April 2009. Results Fifteen regions and autonomous province of Trento have a regional pharmaceutical formulary. In most cases, the regional pharmaceutical formularies include the eight analyzed drugs, with therapeutic indications coherent with national marketing authorization indications. Five drugs (bevacizumab, trastuzumab, rituximab, erlotinib, sunitinib) were included in all the existing regional pharmaceutical formularies, without restrictions, whereas three drugs (cetuximab, sorafenib, pemetrexed) were found to have restrictions in some regions. Conclusions The presence of multiple hierarchical levels of drug evaluation creates a potential element of disparity in the access to pharmacological therapies for Italian citizens. Free full text available at www.tumorionline.it

The Role of Cetuximab in Pre-Treated Refractory Patients with Metastatic Colorectal Cancer: Outcome Study in Clinical Practice

Abstract We carried out a multicentric retrospective study on cetuximab + chemotherapy in pre-treated refractory patients outside clinical protocols, by registering the main clinical and pathological parameters. We evaluated 144 pre-treated patients. Cetuximab was administered usually in combination with irinotecan (93.8%). A 45% disease control rate (complete plus partial responses plus stable disease) was obtained in 55 patients and was related to absence of weight loss (p<0.0001) and high grade (≥2) skin toxicity (p<0.0001). Median time to progression (TTP) was 4 months (95%CI 2.7-5.3) and median overall survival (OS) was 11.8 months (95%CI 8.5-15.1). Performance status ≤1, no weight loss and high grade (≥2) skin toxicity were related both to a longer TTP (p=0.035, p=0.035, p=0.0017) and OS (p<0.0001, p<0.0001, p=0.006). According to multivariate analysis, the absence of weight loss was related to longer TTP (HR 0.331, p=0.004) and OS (HR 0.176, p<0.0001), and EGFR over-expression (3+) to longer TTP (HR 0.402, p=0.020).

Combined chemo-immuno-hormonotherapy of advanced renal cell carcinoma

Thirty-five patients (pts.) with advanced renal cell carcinoma were treated with a combination of vinblastine (5 mg/m2/IV) plus epirubicin (50 mg/m2/IV) every 3-4 weeks, alpha-2-A-interferon (9 x 10(6) U/IM 3 times in the 1st week, then 18 x 10(6) U/IM 3 times weekly), and medroxyprogesterone acetate (2,000 mg/os/day plus 500 mg IM/week). Thirty-one patients were males and 4 were females with a median age of 63 years (range 35-75) and median performance status of 70% (range 50-90%). We observed nine partial remissions (26%) with median duration of 40 weeks (range 20-232+). Fifteen pts. had no change (43%) while 11 pts. progressed (31%). The main side-effects were: leukopenia (29/35, 83%) with median nadir of 3,100 WBC/mm3 (range 510-3,990) and fever (32/35, 91%). Thrombocytopenia occurred in 4 pts. (11%), anemia in 5 (14%), asthenia in 12 (34%), nausea/vomiting in 12 (34%), alopecia in 8 (23%) and stomatitis in 3 (8.5%). Two patients stopped the therapy with medroxyprogesterone acetate because of muscular cramps. Median survival was 65 weeks (range 6-327+). We conclude that the combination of recombinant alpha 2A-interferon-vinblastine-epirubicin and medroxyprogesterone acetate has modest but definitive activity in patients with advanced renal cell carcinoma.

Salvage treatment with epirubicin and/or paclitaxel in metastatic breast cancer patients relapsed after high-dose chemotherapy with peripheral blood progenitor cells.

Aims and Background To evaluate feasibility and efficacy of paclitaxel as a single agent or in combination with epirubicin in breast cancer taxane-naive patients who have failed previous high-dose chemotherapy. Methods Since February 1995, we have treated 32 patients in first relapse or progression after high-dose chemotherapy. Nineteen patients had metastatic breast cancer, 12 more than 3 involved axillary lymph nodes, and 1 inflammatory breast cancer at inclusion to the program. The median time to relapse after high-dose chemotherapy was 12 months (range, 2-43). At relapse, 12 patients were treated with epirubicin (90 mg/m2) plus paclitaxel (175 mg/m2) administered on day 1 every 21 days. In 20 patients who had previously received more than 350 mg/m2 of a cumulative dose of epirubicin and in one patient pretreated with chemotherapy containing mitoxantrone, we employed paclitaxel (175 mg/m2) alone. A median number of five courses was administered (range, 2-10). Results The overall response rate after 3 courses (29 of 32 patients were assessable) was 55% and after 6 courses (21 of 32 patients were assessable) was 57%. The median time to progression was 7 months (95% CI, 5.7-9.2), and median survival was 27.5 months (95% CI, 17.8-37.0). Toxicity was recorded for 180 cycles (epirubicin + paclitaxel for 62 cycles and paclitaxel alone for 118 cycles). The main toxicity in both regimens was hematologic. We observed WHO grade 3-4 neutropenia (in 8 patients, 25%), for which G-CSF (5 μg/kg/day sc) was employed. WHO grade 3-4 thrombocytopenia occurred in 2 patients (6%) and WHO grade 3 anemia in 1 patient (3%). Conclusions Our study showed that paclitaxel (alone or in combination with epirubicin) is feasible as salvage treatment in heavily pretreated patients.

A new regimen of cisplatin, epirubicin and methotrexate (PEM-3) as primary chemotherapy for locally advanced bladder cancer.

In this phase II study, 41 patients with locally advanced urothelial bladder cancer (T2-4, NO, MO) were treated with primary chemotherapy (cisplatin, epirubicin, methotrexate: PEM-3). All the patients were assessable for response and toxicity. Clinical monitoring was performed with computerized tomography and cystoscopy. Nineteen clinical complete remissions (46%) and 10 partial remissions (24.5%) were obtained (CR + PR, 70.5%; 95% confidence interval, 57%-85%). Ten patients were considered to have clinically stable disease (24.5%), and 2 patients progressed (5%). Surgery after chemotherapy was performed in 22 cases: in 6 patients (27%) a pathologic complete response was achieved. The pathologic stage was lower than the initial clinical stage in 13 patients (59%). After a median follow-up of 3 years (range, 1-4), the median time to progression was 104 weeks. At this writing, 20 patients, 12 of which were submitted to surgery and 8 were not operated, are disease-free. The 3-year survival rate is 52%. No one had to interrupt the treatment because of toxicity. In conclusion, the PEM-3 regimen is a very active and well-tolerated regimen in locally advanced bladder cancer.

Cisplatinum plus epirubicin alternated with cyclophosphamide plus 5-fluorouracil in ovarian cancer.

Fifty-two patients with ovarian cancer (post surgical residual tumor) were treated with the combination of platinum + epirubicin (PE) (P 50mg/m2, E 60 mg/m2) alternated with cyclophosphamide + 5-fluorouracil (CF) (C 800 mg/m2, F 600 mg/m2). The treatment was repeated every 28 days for a maximum of 10 cycles. Forty-three patients were evaluable for response. Complete remission (CR) was achieved in 13 (30%) patients (evaluated by second-look), while partial remission (PR) was achieved in 6 (14%) patients for a mean duration of 27 and 14 months, respectively. Eleven out of 13 patients with CR and 5 out of the nonevaluable patients are alive and do not show signs of disease after a mean follow-up of 29 + months (range 19-36). The main factors that conditioned complete remission were the tumor residue and performance status of the patient.