Anna Maria Mosconi

Cisplatin-gemcitabine combination in advanced non-small-cell lung cancer: a phase II study.

PURPOSE The nucleoside analog, gemcitabine, has shown activity as a single agent in the treatment of metastatic non-small-cell lung cancer (NSCLC). Its combination with cisplatin in preclinical models suggested synergy between the two drugs. The aim of the study was to evaluate the clinical efficacy and toxicity of the cisplatin-gemcitabine combination in advanced NSCLC. PATIENTS AND METHODS Forty-eight consecutive previously untreated NSCLC patients entered the trial from January to June 1994. The median age was 60 years (range, 37 to 70) and performance status (PS) was 0 or 1; 22 patients had unresectable stage III disease (21 stage IIIB and one stage IIIA) and 26 had stage IV disease. Gemcitabine 1 g/m2 was administered weekly (days 1, 8, and 15) followed by a 1-week rest and cisplatin 100 mg/m2 on day 2 of each 28-day cycle. Survival and response were determined in accordance with the intention-to-treat principle in all enrolled patients. RESULTS Of 48 assessable patients, one (stage IV) had a complete response (CR) and 25 achieved a partial response (PR). The overall response rate was 54% (95% confidence interval [CI], 40% to 68%). Thrombocytopenia was the main side effect, with 52% of patients experiencing grade III to IV toxicity, which was usually short-lived and responsible for the omission of gemcitabine administration on day 15 in 50% of chemotherapy courses. The median survival time was 61.5 weeks (95% CI, 40 to 71). CONCLUSION The combination of gemcitabine and cisplatin induced a high response rate in both stage IIIB and IV NSCLC, with modest side effects. The regimen deserves further careful evaluation in a phase III prospective randomized trial.

Gemcitabine as second-line treatment for advanced non-small-cell lung cancer: A phase II trial.

PURPOSE To investigate the activity and toxicity of gemcitabine as a single agent in patients with advanced non-small-cell lung cancer (NSCLC) after recurrence or failure of previous treatment with a platinum-containing regimen. PATIENTS AND METHODS From November 1995 to October 1997, 83 patients with stage IIIB or IV NSCLC received gemcitabine 1,000 mg/m(2) once a week for 3 weeks every 28 days. Responses were assessed every two treatment courses. The median age of the patients was 63 years; Eastern Cooperative Oncology Group performance status was 0 to 1 in 62 patients and 2 in 21 patients. The predominant histology was squamous (39 patients); 49 patients had stage IV disease and 34 patients had stage III disease (33 stage IIIB and one stage IIIA). RESULTS Sixteen patients (19%) achieved a partial response to treatment; the median duration of response was 29 weeks (range, 6 to 50 weeks). Treatment was well tolerated: grade 2 to 3 (World Health Organization standardized response criteria) leukopenia and thrombocytopenia occurred in 23% and 20% of patients, respectively. Mild asthenia was observed in 16% of patients, and peripheral edema in 5% of patients. Nausea and vomiting were present in 16% of patients. CONCLUSION In this experience, gemcitabine showed significant activity without relevant toxicity, mainly in patients who were previously responsive to chemotherapy. This suggests a possible role for gemcitabine as a second-line treatment in patients who had a previous response or achieved stable disease with a platinum-containing regimen.

Evaluation of the prognostic role of vascular endothelial growth factor and microvessel density in stages I and II breast cancer patients.

In this study, we retrospectively evaluated the expression of vascular endothelial growth factor (VEGF) and microvessel density (MVD) in 228 and 213 specimens, respectively, from stages I and II breast cancer patients (pts) enrolled in a randomized phase III adjuvant chemotherapy trial comparing epirubicin to CMF, while tamoxifen was given to all postmenopausal pts. The expression of VEGF and MVD was assessed on tissue sections formalin-fixed and paraffin-embedded by immunohistochemical staining using anti-VEGF antibody of human origin and anti-CD34 monoclonal antibody. Univariate and multivariate analysis were performed using chi squared test, log-rank test and Coxs regression model. Sixty four of 228 pts were classified as VEGF positive (28%) with no significant difference in the two treatment arms. In 213 pts evaluated for CD34, 103 pts (48%) were classified as MVD high. No significant association between VEGF and MVD was found, and neither were they correlated with many known prognostic factors such as age, tumor size, nodal status, and histological grade. The only significant correlations observed were between VEGF and estrogen receptor (ER) status (p = 0.013) and between MVD and HER2 overexpression (p = 0.023). At a median follow up of 96 months VEGF and MVD were not correlated with relapse-free survival (RFS) and overall survival (OS) in all pts and in pts assigned to one of the two treatment arms. In conclusion, VEGF and MVD retrospectively evaluated, cannot be considered prognostic factors in node negative (N−) high risk and node positive (N+) breast cancer pts treated with two different regimens of adjuvant chemotherapy.

Safety profile of gemcitabine.

This paper reviews the toxicity profile of gemcitabine in a large group of patients (up to 790) from pivotal phase II studies, in which the drug was given intravenously as a 30 min infusion, in a schedule once a week for 3 weeks followed by a week of rest. The safety profile of gemcitabine is unusually mild for such an active agent in solid tumours. Haematological toxicity is mild and short-lived with modest WHO grades 3 and 4 for haemoglobin (6.4% and 0.9% of patients), leukocytes (8.1% and 0.5%), neutrophils (18.7% and 5.7%) and platelets (6.4% and 0.9%. The incidence of grade 3 and 4 infection associated with this level of myelosuppression was low (0.9% and 0.2%). Transaminase elevations occurred frequently, but they were usually mild, and rarely dose limiting. Mild proteinuria and haematuria were seen but were rarely clinically significant. There was no evidence of cumulative hepatic or renal toxicity. Nausea and vomiting was mild, rarely dose limiting, and generally well controlled with standard antiemetics. Flu-like symptoms were experienced in a small proportion of patients but were of short duration. Where oedema/peripheral oedema was experienced there was no evidence of any association with cardiac, hepatic or renal failure. Hair loss was rare, with WHO grade 3 alopecia reported in 0.5% of patients. There was no grade 4 alopecia. Furthermore, gemcitabine displayed minimal toxicity in elderly patients, and the side-effect profile does not seem to be affected by patient age. The adverse events typically experienced with cytotoxic agents, namely myelosuppression, nausea and vomiting and alopecia, are not seen to such a degree with gemcitabine, and this nonoverlapping toxicity profile suggests that gemcitabine is a promising agent for incorporation into combination chemotherapy regimens

A three-week schedule of gemcitabine-cisplatin in advanced non-small-cell lung cancer with two different cisplatin dose levels: a phase II randomized trial.

BACKGROUND To explore a new schedule of gemcitabine-cisplatin (GP) combination therapy using two different cisplatin doses in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS From May to December 1997, 92 chemonaive patients entered the study and 88 (28 with locally advanced and 60 with disseminated NSCLC) were evaluable for response and toxicity (45 in arm A and 43 in arm B). Patients were randomly assigned to arm A or arm B. Gemcitabine 1000 mg/m2 was given on days 1-8 plus cisplatin 100 mg/m2 in arm A and cisplatin 70 mg/m2 in arm B on day 2 of every 21-day cycle. RESULTS The overall response rates in arms A and B were 42% (95% confidence interval (CI): 27.8%-56.7%) and 47% (95% CI: 31.6%-61.5%), respectively. Median duration of response was 9.7 months (range 1.8 to 30.9 months; 13.1 and 9.5 months for arm A and B, respectively), and median survival was 12 months (range 0.2 to 31.1 months; 15.4 and 11.5 months for arm A and B, respectively). Major WHO grade 3-4 toxicities in arm A vs. arm B included: thrombocytopenia (23% vs. 17% of courses), leukopenia (15%, vs. 4% of courses), anemia (7% vs. 6% of courses), and nausea-vomiting (20% vs. 7% of patients). Grade 1-2 nephrotoxicity occurred in 20% of patients in arm A and in 7% of patients in arm B, with one grade 4 episode in arm A. Six patients discontinued treatment because of toxicities, 5 in arm A and I in arm B. CONCLUSIONS Results of this trial indicate that both schedules are feasible and active, with a milder toxicity in the arm with the lower cisplatin dose.

Induction chemotherapy with cisplatin, doxorubicin, and cyclophosphamide (CAP) in a combined modality approach for locally advanced and inflammatory breast cancer. Long-term results.

Thirty-one patients with locally advanced and inflammatory breast carcinoma (stage IIIA and IIIB) were treated with a combined modality approach between 1985 and 1989. All patients received as induction chemotherapy a combination of cisplatin, doxorubicin, and cyclophosphamide (CAP). Responsive patients and patients with operable stable disease underwent modified radical mastectomy followed by concurrent radiotherapy and CMF (cyclophosphamide, methotrexate, 5-fluorouracil) adjuvant chemotherapy. Thirty patients were evaluable for response to CAP. The rate of objective response to induction chemotherapy was 76.7% with 2 patients (6.7%) obtaining a complete response and 21 patients (70%) a partial response. Twenty-five patients were rendered disease-free after induction chemotherapy and surgery. Only 2 of these had pathological complete response (8%). The median overall survival was 48.7 months, the median time to progression was 22.4 months and the median disease-free survival was 29.1 months. The patients with noninflammatory breast tumor had a significantly better overall survival, disease-free survival, and time to progression. The overall survival and the time to progression were statistically superior in patients with primary tumor size < or = 8 cm. At a median follow-up of 6 years, 29% (95% CI, 13.05 to 45.01) of patients were alive and 28% (95% CI, 10.4 to 45.6) were disease-free. This combined modality treatment seems feasible with quite acceptable toxicity; the CAP combination is an effective alternative to the other standard chemotherapeutic regimens. Our results, although encouraging, are still poor, and new drugs and strategies are required to improve the long-term outcome.

Gemcitabine in advanced pancreatic cancer: a phase II trial.

: The 5-year survival for pancreatic cancer is usually less than 5%, and no treatment has demonstrated consistent effect on patient survival and disease-related symptoms. Early studies with gemcitabine suggested a modest antitumor activity with significant improvement in disease-related symptoms. This phase II study reports the activity of gemcitabine on 33 consecutive patients with unresectable pancreatic carcinoma. Twenty-three patients had metastatic and 10 locally advanced unresectable disease. Twenty-six patients had not received any previous treatment and seven had received first-line chemotherapy with 5-fluorouracil. Gemcitabine 1,000 mg/m2 was administered intravenously in 30 minutes in the first cycle once weekly for up to 7 weeks followed by 1 week rest; then in subsequent cycles, once weekly for 3 of every 4-week cycle. Four patients obtained partial response (12%). Fifteen patients (45%) had stable disease with a median duration of 32 weeks (range: 16-75 weeks), and 14 patients experienced progressive disease. Median duration of response was 34.5 weeks (range: 19-50 weeks). Median survival was 33 weeks (range: 2-91 weeks). All 4 responding patients and 14 of 15 (93%) patients with stable disease had improvement in performance status and decrease in daily analgesic requirement. Toxicity was mild and mainly consisted of moderate and rapidly reversible myelosuppression. We conclude that gemcitabine chemotherapy was very well tolerated and determined a significant clinical improvement with modest antitumoral activity in patients with advanced pancreatic cancer.

Weekly paclitaxel in metastatic breast cancer patients: a phase II study.

Aims and background Paclitaxel, a microtubule inhibitor, is one of the most active drugs in metastatic breast cancer. A weekly schedule, at a median dose-intensity of 91 mg/m2, is effective and has less side effects than a 3-week schedule. In this phase II study, we evaluated the toxicity and the activity of weekly 1 hr paclitaxel infusions in metastatic breast cancer patients. Study design Between February 1999 and February 2001, 26 patients with metastatic breast cancer were treated with weekly paclitaxel (60–90 mg/m2/1 hour iv infusion/weekly). The treatment was planned to continue until disease progression or prohibitive toxicity; in patients with responsive or stable disease, paclitaxel was stopped after 6 months of therapy. Results At a median follow-up of 18.7 months (range, 6.8–30.8), all patients are assessable for response and toxicity. We obtained 8 partial responses (30.8%), 8 stable disease (30.8%) and 10 disease progression (38.4.%). The overall response was 30.8% (95% CI, 13.1–48.5). The median duration of response was 7.6 months (range, 1.8–12.4); median time to progression was 4.86 months (range, 1.4–12.4); median overall survival was 9.9 months (range, 1.7–29.2+). Treatment was well tolerated. Hematological toxicity was mild and only one patient developed grade 3 anemia. Two patients experienced grade 3 cardiovascular toxicity; both had received anthracycline-based regimens. Conclusions In our experience, weekly administration of paclitaxel shows a substantial degree of activity even in pretreated metastatic breast cancer patients. The toxicity profile is favorable.

Epirubicin versus CMF as adjuvant therapy for stage I and II breast cancer: a prospective randomised study

We compared a relatively short regimen of monochemotherapy with epirubicin versus polychemotherapy with CMF (cyclophosphamide, methotrexate, 5-fluorouracil) as adjuvant treatment for stage I and II breast cancer patients. 348 patients with oestrogen receptor negative (ER-) node negative and ER- or ER+ node-positive with <10 nodes were accrued. CMF was given intravenously (i.v.) on days 1 and 8, every 4 weeks, for six courses; epirubicin was given weekly for 4 months. Postmenopausal patients received tamoxifen for 3 years. The primary endpoints were overall survival (OS), relapse-free survival (RFS) and event-free survival (EFS). Outcome evaluation was performed both in eligible patients and in all randomised patients according to the intention-to-treat principle. 8 randomised patients were considered ineligible. At a median follow-up of 8 years, there was no difference in OS (Hazard Ratio (HR)=1.11, 95% Confidence Interval (CI): 0.77-1.61, P=0.58), EFS (HR=1.14, 95% CI: 0.78-1.64, P=0.48), and RFS (HR=1.14, 95% CI: 0.8-1.64, P=0.48) between the two arms for all of the patients. At 8 years, the RFS percentages (+/-Standard Error (S.E.)) were 65.4% (+/-4%) in the CMF arm and 62.7% (+/-4%) in the epirubicin arm; for EFS these were 64.2% (+/-4%) for CMF and 60.8% (+/-4%) for epirubicin, respectively. A significant difference in RFS (P=0.015) was observed in patients with 4-9 positive nodes in favour of the CMF arm. Toxicity in the two arms was superimposable except for more frequent grade 3 alopecia in the epirubicin-treated patients (P=0.001). Overall, at a median follow-up of 8 years, there were no differences between the two arms in terms of OS, EFS and RFS.

Regional node failure in patients with four or more positive lymph nodes submitted to conservative surgery followed by radiotherapy to the breast.

A retrospective analysis was conducted to evaluate the incidence of nodal failure in a subgroup of patients who had T1-T2 breast cancer and four or more positive nodes. Sixty-four 5 patients ranging in age from 29 to 73 years (median, 51) received conservative surgery followed by radiotherapy to the breast between November 1980 and May 1995. Adjuvant chemotherapy was administered to 56 patients, 27 of whom were also treated with tamoxifen, which was used alone in 5 patients. Three patients received no adjuvant treatment. Sixty-two patients are evaluable for regional node failure. There were 10 nodal failures, 4 in the axillary and 6 in the supraclavicular regions, in 9 patients, at a median of 56.5 and 27 months, respectively. There was no internal mammary node failure. Median follow-up was 72.6 months. The 10-year probability of developing axillary and supraclavicular failure is 13.9 +/- 7.7% and 10.5 +/- 4.1%, respectively. Prognosis was better for patients with axillary and breast recurrence and worse when relapse was in the supraclavicular region. On the basis of our results and data already published in premenopausal patients, we believe that radiotherapy to the supraclavicular region should be considered in patients with four or more positive axillary nodes, after a complete dissection.