High coexpression of both insulin-like growth factor receptor-1 (IGFR-1) and epidermal growth factor receptor (EGFR) is associated with shorter disease-free survival in resected non-small-cell lung cancer patients.

BACKGROUND: Insulin-like growth factor receptor-1 (IGFR-1) represents a novel molecular target in non-small-cell lung cancer (NSCLC). IGFR-1 and epidermal growth factor receptor (EGFR) activation is essential to mediate tumor cell survival, proliferation and invasion. We explored the correlation between IGFR-1 and EGFR, their relationship with clinicopathological parameters and their impact on outcome in resected stage I-III NSCLC patients. PATIENTS AND METHODS: Tumors from 125 surgical NSCLC patients were evaluated for IGFR-1 and EGFR expression by immunohistochemistry. Kaplan-Meier estimates of survival and time to recurrence were calculated for clinical variables and biologic markers using the Cox model for multivariate analysis. RESULTS: IGFR-1 protein overexpression was detected in 36.0% of NSCLC patients and was associated with larger tumor size (P = 0.04) but not with other clinical or biological characteristics. EGFR protein overexpression was observed in 55.2% of NSCLC, more frequently in squamous cell carcinoma (SCC) than non-SCC (63.7% versus 36.3%, chi(2) = 9.8, P = 0.001). IGFR-1 protein expression was associated with EGFR protein expression (P = 0.03). At the multivariate analysis, high coexpression of both IGFR-1 and EGFR was a significant prognostic factor of worse disease-free survival (DFS) (hazard ratio 2.51, P = 0.01). CONCLUSION: A statistically significant association was observed between high coexpression of both IGFR-1 and EGFR and worse DFS in early NSCLC patients.

Serum level changes of matrix metalloproteinases 2 and 9, vascular endothelial growth factor and epidermal growth factor receptor during platinum-based chemotherapy in advanced non-small cell lung cancer patients.

PURPOSE: To evaluate serum changes of matrix metalloproteinases (MMPs) 2 and 9, vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) levels in patients with advanced non-small cell lung cancer (NSCLC) and their association with main clinicopathological parameters during chemotherapy with cisplatin and gemcitabine. PATIENTS AND METHODS: In this prospective study, consecutive patients with stage III and IV NSCLC were enrolled. Serum MMP2 and 9, VEGF and EGFR levels were monitored in blood samples taken on day 1 of starting chemotherapy (baseline 1st), and after 3 cycles of chemotherapy (2nd) using commercial sandwich ELISA method. RESULTS: 116 patients were evaluated. Males / females 100 / 6, ECOG performance status (PS) 0/1/2: 47/65/4, stage III / IV: 49/67, squamous /adeno/large cell carcinoma 41/31/19. Forty-two (36%) patients achieved partial response (PR), 32 (28%) stable disease (SD) and 42 (36%) showed progressive disease (PD). Mean serum values -/+ standard deviation (SD) of the analyzed markers at baseline/at response evaluation were: EGFR 86 -/+ 87/96 -/+ 47 fmol/ml; MMP9 236 -/+ 156/162 -/+ 133 ng/ml ; MMP2 525 -/+ 189/569 -/+ 201 ng/ml; VEGF 555 -/+ 476/599 -/+ 611 pg/ml; VEGF adjusted for platelets (PLT) 1.9 -/+ 1.45/2.4 -/+ 2.78 pg/10(6). In logistic regression model for response rate adjusted for stage, the increase in MMP9 levels during chemotherapy (mean = 74 ng/ml -/+ SD 140) was predictive for progression (p=0.041) with 5% increase in the odds of progression for an increase of 10 ng. CONCLUSION: MMP9 level increase was found to be predictive of disease progression. EGFR levels could refl ect extracellular domain (ECD) loss from resistant cells and its shedding into the circulation.

Cost-minimisation analysis comparing gemcitabine/cisplatin, paclitaxel/carboplatin and vinorelbine/cisplatin in the treatment of advanced non-small cell lung cancer in Italy.

A retrospective cost-minimisation analysis was conducted comparing novel chemotherapies for the treatment of chemo-naive patients with locally advanced, recurrent, and/or metastatic non-small cell lung cancer (NSCLC). Resource use information was obtained from a Phase III randomised trial investigating the efficacy and toxicity of gemcitabine/cisplatin (Gem/Cis), paclitaxel/carboplatin (Pac/Carbo) and vinorelbine/cisplatin (Vin/Cis) combination regimens in 612 patients with advanced NSCLC. Since there were no statistically significant differences between the three treatments in terms of progression-free or overall survival in this trial, a cost-minimisation analysis was considered to be the appropriate type of economic evaluation. The perspective was that of the national healthcare provider in Italy. Medical resource use was obtained from the clinical trial database, from which mean cost streams were calculated for each treatment group. The mean total treatment costs per patient were 8094 euros, 11,203 euros and 9320 euros for the Gem/Cis, Pac/Carbo and Vin/Cis regimens, respectively. Based on resource consumption in a clinical trial, Gem/Cis had the lowest overall mean costs of the three chemotherapy regimens. Gem/Cis therefore has the potential to save costs in the treatment of advanced NSCLC in Italy.

Phase II study of weekly paclitaxel and trastuzumab in anthracycline- and taxane-pretreated patients with HER2-overexpressing metastatic breast cancer.

Synergism between anti-HER2 monoclonal antibody (trastuzumab) and paclitaxel has been shown in vitro and in vivo. In previous experiences, weekly administration of trastuzumab and paclitaxel has shown significant activity in metastatic breast cancer. In this phase II study, we evaluated the activity and the toxicity of this weekly regimen in anthracycline- and taxane-pretreated patients with HER2-overexpressing metastatic breast cancer. Between November 1999 and July 2001, 25 patients were treated with trastuzumab (4 mg kg(-1) i.v. loading dose followed by 2 mg kg(-1) i.v. week(-1)) and paclitaxel (60-90 mg m(-2) h(-1) i.v. infusion week(-1)). The treatment was planned to continue until disease progression or prohibitive toxicity; in patients with responsive or stable disease, after 6 months of therapy, the decision to stop paclitaxel while continuing weekly trastuzumab was left to the physicians' judgement. At the median follow-up of 19.6 months (range 9.2-38.1), all patients are evaluable for response and toxicity. We obtained four (16%) complete responses (CR), 10 (40%) partial responses (PR), four (16%) stable diseases and seven (28%) disease progressions. The response rate (CR+PR) was 56% (95% CI, 36.5-75.5%). The median duration of response was 10.4 months (range 4.1-24.2+). Median time to progression was 8.6 months (range 2.5-24.2+). The toxicity was mild; five patients experienced fever and chills during the first infusion of trastuzumab (20%); leukopenia grade 2 was recorded in one patient (4%). Two patients (8%) came off study for grade 3 cardiotoxicity (after 9 and 17 weeks of treatment, respectively): both had already received anthracyclines and taxanes. Onycholysis grade 2 was observed in five patients (20%). These results confirm that weekly administration of trastuzumab and paclitaxel is active in anthracycline- and taxane-pretreated metastatic breast cancer patients HER2-overexpressing. Since cardiac disfunctions grade 3 were observed (8%), we recommend that cardiac function should be monitored in these patients.

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 Cox's 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.

Adjuvant chemotherapy in the treatment of colon cancer: randomized multicenter trial of the Italian National Intergroup of Adjuvant Chemotherapy in Colon Cancer (INTACC).

BACKGROUND: To determine whether the addition of leucovorin to the combination 5-fluorouracil plus levamisole prolongs disease-free survival and overall survival in patients with radically resected colon cancer (Dukes' B(2-3) and C). PATIENTS AND METHODS: Patients (1703) were accrued between March 1992 and February 1995 in a large-scale clinical trial within five Italian cooperative groups. After stratification for center, patients were randomized as follows: arm A, 5-fluorouracil [450 mg/m(2) intravenous (i.v.) bolus on days 1-5] and levamisole (150 mg orally for 3 days, every 14 days for 6 months) versus arm B, 6-S-leucovorin (100 mg/m(2) i.v. bolus on days 1-5) followed by 5-fluorouracil (370 mg/m(2) i.v. bolus on days 1-5), plus levamisole (as arm A), every 4 weeks for six cycles. RESULTS: After a median follow-up of 6.4 years no significant difference was seen for either disease-free survival (58% versus 60%, not significant) or 5-year overall survival (68% versus 71%, not significant), respectively. Gastrointestinal toxicity (World Health Organization grade 3/4) was more frequent in arm B (8% versus 18%, not significant). CONCLUSIONS: In this trial the schedules used showed no statistically significant differences in terms of disease-free survival or overall survival in the treatment of colorectal cancer.

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.

Phase III randomized trial comparing three platinum-based doublets in advanced non-small-cell lung cancer.

PURPOSE: To evaluate whether two commonly used newer platinum-based regimens offer any advantage over vinorelbine-cisplatin (reference regimen) in response rate for patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Chemotherapy-naive patients were randomized to receive gemcitabine 1,250 mg/m(2) days 1 and 8 plus cisplatin 75 mg/m(2) day 2 every 21 days (GC arm), or paclitaxel 225 mg/m(2) (3-hour infusion) then carboplatin (area under the concentration-time curve of 6 mg/mL x min), both on day 1 every 21 days (PCb arm), or vinorelbine 25 mg/m(2)/wk for 12 weeks then every other week plus cisplatin 100 mg/m(2) day 1 every 28 days (VC arm). RESULTS: Six hundred twelve patients were randomized to treatment (205 GC, 204 PCb, and 203 VC). Overall response rates for the GC (30%) and PCb (32%) arms were not significantly different from that of the VC arm (30%). There were no differences in overall survival, time to disease progression, or time to treatment failure. Median survival for the GC, PCb, and VC groups was 9.8, 9.9, and 9.5 months, respectively. Neutropenia was significantly higher on the VC arm (GC 17% or PCb 35% v VC 43% of cycles, P <.001), as was thrombocytopenia on the GC arm (GC 16% v VC 0.1% of cycles, P <.001). Alopecia and peripheral neurotoxicity were most common on the PCb arm, as was nausea/vomiting on the VC arm (P <.05). CONCLUSION: Efficacy end points were not significantly different between experimental and reference arms, although toxicities showed differences. These findings suggest that chemotherapy in NSCLC has reached a therapeutic plateau.

Phase II study of high-dose paclitaxel and carboplatin in previously untreated, unresectable non-small cell lung cancer.

INTRODUCTION: This phase II study was designed to assess the activity and tolerability of the carboplatin-paclitaxel combination, given without routine growth factor support to previously untreated patients with stage IIIB and IV non-small cell lung cancer. PATIENTS AND METHODS: Sixty patients (15 stage IIIb and 45 stage IV) received paclitaxel 225 mg/ml on day 1, followed by carboplatin AUC 6 mg/ml per minute (Calvert formula) every 3 weeks. Paclitaxel was administered as a 3-h intravenous infusion followed by carboplatin over 30 min, on completion of paclitaxel administration. RESULTS: The combination showed a good safety profile with Grade 4 neutropenia occurring in 31% of patients without any serious infectious episodes requiring hospitalization. Moderate to severe anemia and thrombocytopenia seldom occurred. Sensorimotor peripheral neuropathy (Grade 2-3) and myalgia (Grade 3-4) were documented in 34 and 20% of the patients, respectively. Among 59 evaluable patients, there was one complete response and 26 partial responses for an overall response rate of 46% (95% C.I.: 34-59%). With a minimum follow-up duration of 16.5 months, the median overall survival time is 52 weeks and the 1-year survival rate is 50%. Median duration of response is 20 weeks (range: 4-52) and progression-free survival is 22 weeks (range: 5-77). CONCLUSION: In advanced NSCLC, the combination carboplatin-paclitaxel at doses of AUC 6 mg/ml per minute and 225 mg/ml every 3 weeks, is both active and relatively well-tolerated.

Results of a prospective study with high-dose etoposide, thiotepa and carboplatin and peripheral blood stem cell rescue for high-risk stage II-IIIA and selected stage IV breast cancer patients.

AIMS AND BACKGROUND: To investigate the safety and efficacy of a high-dose chemotherapy regimen with etoposide, carboplatin and thiotepa in high-risk stage II-IIIA breast cancer and in responsive metastatic patients. STUDY DESIGN: From April 1992 to December 1998, 24 patients with high-risk stage II-IIIA breast cancer (> or = 9 positive nodes) and 9 responsive metastatic patients were enrolled in the trial. After induction chemotherapy with an anthracycline-based regimen, peripheral blood stem cells were mobilized with cyclophosphamide (7 g/m2) and G-CSF (5-16 microg/kg/s.c./day). The high-dose chemotherapy regimen consisted of etoposide (1000 mg/m2), carboplatin (800 mg/m2) and thiotepa (500 mg/m2). At the end of the high-dose chemotherapy, all stage II-IIIA patients received radiotherapy to the breast or chest wall and draining nodes; stage IV patients were irradiated to sites of disease, if feasible. All ER+ and/or PgR+ patients were treated with hormone therapy. RESULTS: For stage II-IIIA high-risk patients, the median follow-up was 4.36 years (range, 1.93-6.94), and the Kaplan-Meier estimate at 5 years of disease-free survival and overall survival was 54.8 +/- 11% SE and 76.73 +/- 9.4% SE, respectively. For metastatic patients, the median follow-up was 4.93 years (range, 4.15-7.95), and the Kaplan-Meier estimate at 5 years of progression-free survival and overall survival was 22.2 +/- 13.9% SE and 76.2 +/- 14.8% SE, respectively. No treatment-related deaths were observed. CONCLUSIONS: Our results are comparable to those obtained in other high-dose chemotherapy trials but do not seem to be superior to conventional-dose therapy given to similar patients.

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.

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.

Biological prognostic factors for early stage completely resected non-small cell lung cancer.

BACKGROUND AND OBJECTIVES: The different and unpredictable outcomes in early-stage non-small cell lung cancer patients requires urgent research concerning the biological pathway of this neoplasm. Our study investigated the frequency of expression and the clinicopathologic and prognostic significance of a series of biological markers in stage I and II resected non-small cell lung cancer. METHODS: A total of 99 cases of pathologic stage I and II were analyzed. The mean follow-up of surviving patients was 41 months. The expressions of the following biological markers were tested: bcl-2, p53, Ki-67, angiogenesis, and tumor vessel invasion. Kaplan-Meier estimates of survival and time to recurrence were calculated for clinical variables and biological markers using Cox's model for multivariate analysis. RESULTS: Tumoral vessel invasion was present in 22 (22%) pathologic samples, the angiogenesis mean value was 37 +/- 13, and median was 35; 13 (13%) patients showed positive immunostaining for bcl-2 oncoprotein. P53 oncoprotein expression was present in 48 patients (48.5%). All samples presented Ki-67 expression (mean value = 25.3 +/- 19.3, median = 20). The pathologic staging of the tumor was the most important independent prognostic factor for survival (P = 0.037) and for recurrence of disease (P = 0.040). Tumoral vessel invasion was the only marker with an independent predictive factor for survival and recurrence of disease in the group of patients without lymph node involvement (P = 0.02). CONCLUSION: Our data do not support a relevant prognostic role for p53, bcl-2, or Ki-67 immunohistochemical markers in non-small cell cancer. Tumor vessel invasion was an independent predictive factor of poor outcome in the group of patients without lymph node involvement. Pathological stage was confirmed as the most important independent prognostic factor.

Oral estramustine and cyclophosphamide in patients with metastatic hormone refractory prostate carcinoma: a phase II study.

BACKGROUND: Nearly all cases of metastatic prostate carcinoma progress, after hormonal ablation, to a hormone refractory status. To the authors' knowledge no standard chemotherapy for patients with hormone refractory prostate carcinoma (HRPC) exists. In a prospective study, the efficacy and toxicity of an oral combination of estramustine and cyclophosphamide were evaluated. METHODS: Between March 1996 and April 1998, 32 consecutive patients (median age 74 years; range, 53-84 years) with metastatic HRPC were treated with oral estramustine (10 mg/kg/day) and oral cyclophosphamide (2 mg/kg/day) for 14 days every 28 days. Inclusion criteria were previous complete androgen blockade, antiandrogen withdrawal evaluation, and clinical or biochemical disease progression. Response assessment was based on a decrease > or =50% in the prostate specific antigen (PSA) level associated with improvement (or no worsening) in Eastern Cooperative Oncology Group (ECOG) performance status (PS) and relief of bone pain (if present). RESULTS: All patients were evaluable for efficacy and toxicity. PSA levels decreased by at least 50% in 14 patients (43.7%) (95% confidence interval, 26.5-60.9), remained stable in 12 patients (37.5%), and rose in 6 patients (18.8%). ECOG PS was 0 in 5 of 14 patients, improved from 1 to 0 in 7 patients, and remained unchanged in 2 patients. Bone pain, present in 8 of 14 patients, disappeared in 7 and was partially relieved in 1. The median duration of response was 30 weeks (range, 8-88+ weeks). An objective partial response was obtained in two cases. Toxicity was mild and mainly gastrointestinal (World Health Organization [WHO] Grade 1). No cases of WHO Grade 3-4 hematologic toxicity occurred. CONCLUSIONS: The oral combination of estramustine and cyclophosphamide appears to be safe and effective in patients with HRPC. In responding patients its use shows a clinical benefit in terms of improvement of ECOG PS and pain control.

Gemcitabine and cisplatin versus mitomycin, ifosfamide, and cisplatin in advanced non-small-cell lung cancer: A randomized phase III study of the Italian Lung Cancer Project.

PURPOSE: To compare gemcitabine and cisplatin (GC) with mitomycin, ifosfamide, and cisplatin (MIC) chemotherapy in patients with stage IIIB (limited to T4 for pleural effusion and N3 for supraclavicular lymph nodes) or stage IV non-small-cell lung cancer (NSCLC). The end points were the evaluation of quality of life (QoL), response rates, survival, and toxicity. PATIENTS AND METHODS: Three hundred seven patients were randomized to receive either gemcitabine 1,000 mg/m(2) on days 1, 8, and 15 plus cisplatin 100 mg/m(2) on day 2, every 28 days, or mitomycin 6 mg/m(2), ifosfamide 3,000 mg/m(2), and mesna on day 1 plus cisplatin 100 mg/m(2) on day 2, every 28 days. The whole-blood cell count was repeated on day 1 in both arms and weekly in the GC arm before each gemcitabine administration. RESULTS: No major differences in changes in QoL were observed between the two treatment arms. The objective response rate was 38% in the GC arm compared with 26% in the MIC arm (P =.029). The median survival time was 8.6 months in the GC arm and 9.6 months in the MIC arm (P =.877, log-rank test). Grade 3 and 4 thrombocytopenia was significantly worse in the GC arm (64% v 28%, P <.001), whereas grade 3 and 4 alopecia was reported more commonly in the MIC arm (39% v 12%, P <. 001). CONCLUSION: We report an increased response rate without changes in QoL and a similar overall survival, time to progression, and time to treatment failure for the GC when compared with the MIC regimen in the treatment of advanced NSCLC.

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.

Phase I/II dose finding study of paclitaxel and carboplatin in advanced non-small cell lung cancer.

INTRODUCTION: This phase I study was designed to establish the maximum tolerated dose (MTD) of the carboplatin paclitaxel combination, given without routine growth factor support to previously untreated patients with stage IIIB and IV non-small cell lung cancer. PATIENTS AND METHODS: Fifty patients (one stage IIIa, 31 stage IIIb and 18 stage IV) were sequentially assigned to one of 14 treatment groups in which paclitaxel and carboplatin were administered in doses ranging from 130 to 235 mg/m2 and from 230 to 375 mg/m2 , respectively. Paclitaxel was administered as a 3-h intravenous infusion using non-polyvinylchloride tubing and connectors. The carboplatin infusion, over 30 min, was administered at the completion of the paclitaxel infusion. RESULTS: The MTD for the combination has been reached at 235 mg/m2 of paclitaxel and at 375 mg/m2 of carboplatin. The combination shows a good safety profile with very few and brief episodes of neutropenia without any infectious episodes. At the doses tested thrombocytopenia did not occur at all. Among 47 assessable patients there was one complete response and 17 partial responses for an overall response rate of 38%. There has been a tendency to a dose-response relationship for the combination with only six partial responses (27%) reported in 22 patients who received paclitaxel at doses < or = 195 mg/m2 and carboplatin at doses < 350 mg/m2 and 12 partial responses in 25 patients (48%) receiving paclitaxel > 195 mg/m2 and carboplatin > or = 350 mg/m2, respectively. The median event-free survival time is 33 weeks (range, 4-156 +). With a minimum follow up duration of 57 weeks the median overall survival time is 51.81 weeks (range, 7-162 +) and the 1-year survival rate is 49%. CONCLUSION: In advanced NSCLC the carboplatin-paclitaxel combination can be safely administered at the doses of 375 and 225 mg/m2 every 4 weeks, it appears to be active and well tolerated.