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Background: In the attempt to optimize the efficacy of chemotherapy in advanced non-small cell lung cancer (NSCLC) several strategies need to be investigated including the use of non-platinum combinations and the sequential use of different agents., Patients and Methods: In a phase II randomised study 165 patients with stage IIIB or IV NSCLC were assigned to receive docetaxel 40 mg/m(2) days 1 and 8 plus gemcitabine 1200 mg/m(2) days 1 and 8 every 21 days (arm A, N=54) or docetaxel 50 mg/m(2) days 1 and 15 plus gemcitabine 1600 mg/m(2) days 1 and 15 every 28 days (arm B, N=57) or gemcitabine 1200 mg/m(2) days 1 and 8 plus cisplatin 100mg/m(2) day 2 every 21 days for 3 cycles followed by docetaxel 75 mg/m(2) day 1 every 21 days for 3 cycles (arm C, N=54). The primary endpoint of the trial was overall response rate. Secondary end points included safety, progression-free and overall survival., Results: Response rate was 22.2%, 23.2% and 33.3% after 3 cycles, whereas at the end of treatment was 24.1%, 12.5% and 27.8% in arm A-C, respectively. Median time to progression was similar in all the 3 arms: 6.7 months in arm A (95% CI: 4.8-9.7), 5.6 in arm B (5.0-7.9) and 6.6 in arm C (5.7-9.1). The median survival time was 10.7 months in arm A (95% CI: 6.8-15.6), 8.9 in arm B (7.4-12.5) and 14.6 in arm C (8.0-22.4) and 1-year survival rate was 46.3%, 37.9% and 53.9%, respectively. Grade 3-4 haematological toxicities were more frequent in arm C while non-haematological were more common in the gemcitabine and docetaxel arms., Conclusions: The results of this phase II randomised clinical trial do not indicate a clear superior efficacy of one of the tested combinations according to the planned statistical design and none of these regimens is sufficiently active or less toxic to warrant further investigation in a phase III study.

Background and Purpose: During the past decades staging and treatment of rectal cancer are used different in Europe and in North America. To promote a process to integrate the daily practice with the best evidence of the literature an International Conference was organized in Italy. Agreement between Experts, Centres, and specialists who participated in the Conference are reported., Methods: Five aspects were analyzed and a questionnaire was tailored for this purpose. The questionnaire had 159 questions. During the Conference, at the beginning of each Session, the moderators showed the answers from the Experts and the Centres, and, at the end of the session, the audience voted in all controversial issues. Agreements were scored at three levels: minimum, if it was between 51 and 74% of votes for each group; moderate, between 75 and 94%; large, more than 94%., Results: The main results are: staging: endoanal ultrasound was considered as mandatory in T staging, in the evaluation of sphincter infiltration, and in the restaging of T after chemoradiotherapy (chRT). Magnetic Resonance Imaging is mandatory in the evaluation of mesorectal fascia infiltration. Endoscopy had a moderate agreement for the definition of tumour location, and the barium enema as optional. Digital rectal examination is complementary for staging and PET-CT investigational for T, N and yT staging. Preoperative radiotherapy: for T4 stage chRT was always the preferred treatment, often with moderate agreement, for any tumour location and N status. For T3, chRT received the same agreement except for high location and N0-N1. For T2 stage, N2 and positive nodes outside the mesorectum, chRT received minimum agreement for low and middle tumours; for high tumours only positive nodes outside the mesorectum was agreed upon. Preoperative radiotherapy, negative specimen and sphincter preservation: chRT was agreed by many for all T stages and N presentations of lower third tumours, except for T1-2 N0-N1. Postoperative treatments: the selection for these treatments often received moderate agreement according to the infiltration of surrounding organs, positive nodal status and circumferential radial margins. Therapy of metastatic disease: an agreement was found for FOLFOX as first-line therapy and for FOLFIRI as second-line, although comparative studies show similar activity of FOLFOX and FOLFIRI regimens., Conclusions: This process represents an expertise opinion process that may contribute to increased scientific debate and to promote the development of 'guidelines', 'clinical recommendations' and ultimately a Consensus on the evolving approach to rectal cancer treatment.

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.

Background: This randomized, double-blind, placebo-controlled study was designed to assess whether the addition of the matrix metalloproteinase (MMP) inhibitor BMS-275291 to combined paclitaxel and carboplatin chemotherapy had an adverse impact on expected tumor response or had significant toxicity, especially arthrotoxicity, in patients with advanced non-small cell lung cancer (NSCLC)., Patients and Methods: Seventy-five chemotherapy-naive patients with stage IIIB-IV NSCLC were randomly assigned to BMS-275291 or placebo. All patients received paclitaxel 200mg/m(2) as a continuous 3-hour infusion followed by carboplatin calculated using the Calvert formula for a target AUC of 6 mg / (ml min), every 21 days for a maximum of eight cycles. BMS-275291 or placebo was administered on an outpatient basis at a daily oral dosage of 1200 mg., Results: All 75 patients were evaluable for toxicity and 65 (86.7%) for response. Drug-related arthrotoxicity > or =grade 2 occurred in 12 patients (31.6%) in the BMS-275291 group (lower limit of one-sided 95% CI: 19.3) and in 11 patients (29.7%) in the placebo treatment arm. The incidence of rash was higher in patients receiving BMS-275291 (28.9% versus 18.9%). An objective response rate of 21.9% was observed in the BMS-275291 treatment arm and 36.4% in the placebo arm., Conclusion: BMS-275291 plus paclitaxel/carboplatin was well tolerated and active in advanced non-small cell lung cancer. Treatment with BMS-275291 was not limited by drug-related arthrotoxicity and tumor response was as expected. As planned, patient accrual continued to further investigate the effect of BMS-275291 on overall and progression-free survival in a phase III setting.

Vascular endothelial growth factor (VEGF) increases microvascular permeability and stimulates endothelial cell growth. p53 Overexpression has been associated with resistance to cisplatin-based chemotherapy in patients (pts) with NSCLC. The aim of this study was to evaluate the predictive role of VEGF for chemotherapy response, its relationship with p53, Rb, Bcl-2 and hemoglobin levels and its impact on overall survival in pts with advanced NSCLC. Bronchial or fine-needle biopsy specimens from 85 pts with NSCLC obtained before chemotherapy were analyzed using an immunohistochemical method for VEGF, p53, Rb and Bcl-2. There were 73 males and 12 females with a median age of 62.6 years. The majority of pts (48%) had squamous cell histology. Ten pts had stage IIIA, 25 stage IIIB and 50 stage IV. Thirty six (43%) pts had positive immunostaining for VEGF, 37 (44%) had positive p53, 53 (62%) had negative Rb and 4 (5%) had positive Bcl-2. VEGF was negatively correlated with Rb (r(s) = 0.26; P = 0.015), positively with Bcl-2 (r(s) = 0.22; P = 0.42), whereas no statistically significant correlation with p53, age, stage and histological type was found. In a logistic regression model, adjusting for treatment, VEGF expression was not associated with chemotherapy response (odds ratio (OR) = 1.01; P = 0.085 ), unlike p53 positivity and Rb negativity ( OR = 4.0, P = 0.005; OR = 2.6, P = 0.016, respectively). A statistically significant higher VEGF expression was detected in the subgroups defined, using as cut-off value Hb median level (13.3g/dl) (chi-square = 5.00; ; one d.f.; P = 0.025). At a median follow-up time of 8.4 years, 2-year survival was 21%. After adjustment for stage and chemotherapy treatment, VEGF expression was not associated with a better overall survival (OR = 1.06; P = 0.80), unlike Bcl-2 positivity showed a statistically significant effect (OR = 0.28; p = 0.02). Our results suggest that VEGF is weakly correlated with regulators of apoptosis and has not been shown to be an independent predictive factor for resistance to cisplatin-based chemotherapy and prognostic for survival.

Purpose: The aim of this study was to evaluate the impact of Bcl-2, retinoblastoma (Rb) and p53 proteins on overall survival of 102 patients with locally advanced and metastatic NSCLC who underwent cisplatin-based chemotherapy., Materials and Methods: Paraffin-embedded bronchial biopsy and fine-needle biopsy specimens were evaluated by an immunostaining method., Results: Median age of analyzed patients was 61 years. Male/female ratio was 88/14. There were 10 (10%) patients with stage IIIA, 37 (36%) with stage IIIB and 55 (54%) with stage IV NSCLC. Only 15 (15%) tumor specimens had no detectable alterations for analyzed factors. Forty-six samples (45%) had positive immunostaining for p53, 61 (60%) had negative immunostaining for Rb and 8 (8%) had positive immunostaining for Bcl-2. Median and 5-year survival of analyzed population was 12 months and 6%, respectively. In univariate analysis Bcl-2 overexpression, stage (III versus IV) and normal lactate dehydrogenase (LDH) serum levels were associated with better overall survival (P<0.02, 0.001 and 0.03). In multivariate analysis, only stage was identified as an independent predictive factor., Conclusion: High frequency of Rb and Bcl-2 loss was detected in patients with advanced NSCLC. P53, Rb and Bcl-2 have not been shown to be independent predictors of survival even if Bcl-2 might have a particular relevance in patients with advanced NSCLC and should be better explored in this setting.

Purpose: Tumors with p53 overexpression have been associated with enhanced resistance to cisplatin-based chemotherapy in a few and small studies involving non-small cell lung cancer. The relationships and interactions between p53, Rb and bcl-2 immunostaining, clinical parameters and response to cisplatin-based chemotherapy were evaluated in the present study., Experimental Design: Histological specimens obtained by bronchial or fine-needle biopsy from patients who underwent cisplatin-based chemotherapy between 1992 and 1999 were evaluated by immunostaining., Results: There were 102 patients, 88 men. Median age was 63 years; 47 had stage III and 55 stage IV disease. Forty-six tumor samples (45%) had positive immunostaining for p53, 61 (59%) had negative immunostaining for Rb and 8 (8%) had positive immunostaining for bcl-2. The response rate of the group with p53 positive immunostaining was 26% versus 57% of the p53 negative group (P=0.004). In multivariate analyses p53 positive immunostaining was identified as an independent predictive factor for resistance to cisplatin-based chemotherapy (P=0.006)., Conclusions: Our study confirmed an association of p53 immunostaining and response rate of patients treated with cisplatin-based chemotherapy.

The 5-year survival rate for patients with non-small cell lung cancer (NSCLC) who undergo complete surgical resection is only 40-69%, depending on the stage. It is well known that distant metastatic disease is the dominant site of recurrence in such patients and this observation served as the basis for trials of postoperative systemic therapy. The earliest trials of adjuvant chemotherapy, which consisted of single alkylating agents, did not achieve this goal or, even worse, showed a detrimental effect on survival. The introduction of more active drugs, such as cisplatin and vinca alkaloids, made it possible to obtain more promising results in terms of delayed recurrence of the disease. A recent meta-analysis of all randomized trials with accrual from January 1965 to December 1991 showed that the absolute risk of death was reduced by 3% at 2 years and by 5% at 5 years for patients who were treated with postoperative cisplatin-containing regimens compared with patients who were treated with surgery alone. Although the results of this meta-analysis suggest that postoperative cisplatin chemotherapy regimens may result in a slight survival improvement, adjuvant chemotherapy in NSCLC cannot be considered a standard therapy, and it is important that large, carefully conducted, randomized trials are performed in this group of patients. Four such randomized trials are being conducted in Europe. One of them, the ALPI trial, recently completed its accrual with 1200 patients. The IALT, ANITA, and MRC trials are still ongoing. The results of such trials are eagerly awaited and it is hoped that, once the value of postoperative chemotherapy is well ascertained, future developments can further improve results of combined treatment. In such direction, the recently reported results of PORT meta-analysis evaluating the role of radiation therapy are of great contribution in selecting a suitable population for future studies. In fact, only patients with pN2 disease seem to have a beneficial effect in terms of survival, especially if they have a good performance status, while radiotherapy is not justified in N0-1 patients. The optimal integration of chemotherapy and radiation therapy when both therapies are indicated represents another goal for future research., (Copyright 2002 Elsevier Science Ireland Ltd.)

Background: Small cell lung cancer (SCLC) is a chemoresponsive tumor but overall survival remains poor even in limited disease (LD). With the aim of eradicating chemoresistant tumor cells and reducing toxicity, we investigated in this phase II trial the feasibility and outcome of a sequential approach of induction chemotherapy (CT) followed, in responding patients with LD-SCLC, by intensified platinum-based CT and concurrent thoracic irradiation (TI)., Materials and Methods: We treated 55 consecutive LD-SCLC patients with three 21-day cycles of cyclophosphamide, epiadriamycin and vincristine (CEV) as induction CT. In 44 (80%) patients there was an objective response and they received treatment intensification consisting of TI and concomitant CT with carboplatin and etoposide plus recombinant granulocite colony stimulating factor. Twenty-five (57%) patients were submitted to twice-daily thoracic irradiation (TDTI; 1.5 Gy per fraction, to a total dose of 45 Gy) and 19 (43%) to once-daily thoracic irradiation (ODTI; 2 Gy per fraction, to a total dose of 50 Gy)., Results: Median follow up was 75 months (range, 42-102). Of 44 patients submitted to intensification with TI plus CT, 32 (73%) had a complete and 12 (27%) a partial response. Median overall survival of all 55 patients was 17 months with actuarial survival probabilities of 2 and 5 years, 32 and 25%, respectively. Analysis of patient sub-groups showed a 5-month median survival in non-responders, 19 in TDTI and 17 in ODTI patients, respectively. Two and 5 year survival probabilities were 0% in non-responders, 40 and 35% in TDTI and 39 and 21% in ODTI patients, respectively. At present, 13 of 44 responders are still alive, of which nine (20%) have been progression-free from 45 to 93 months (median 60). Treatment failure was registered in 31 (70%) of 44 patients who received both induction and intensification treatment. One-half of patients had intrathoracic recurrence, eight of which only local and the remaining seven local and distant. Fourteen (32%) patients had brain metastases. Grade 3-4 neutropenia occurred in 24 (55%) patients with no differences between treatment groups. Grade 3 esophagitis was registered in four (9%) patients: in 3/25 (12%) and 1/19 (5%) of those who received TDTI and ODTI, respectively (P=not significant). Acute radiation pneumonitis occurred in three (12%) patients submitted to TDTI. No clinically debilitating pulmonary fibrosis, permanent esophageal stricture or toxic death was observed., Conclusions: In LD-SCLC patients late concurrent CT plus TI is feasible and effective. Our long-term results are similar to the best reported in the literature. Despite the high incidence of complete response obtained, however, one-half of the patients had intrathoracic relapse and one-third brain metastases.

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.

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.

Twenty-three patients with brain metastases from non-small cell lung cancer (NSCLC) (median age 62 years, Karnofsky PS 50-100) were treated with cisplatin (100 mg/m2, day 1) and teniposide (80 mg/m2, days 1, 3 and 5) every 3 weeks. Response was evaluated by contrast-enhanced brain CT every two to three cycles of treatment. The objective response rate of brain metastases was 35% (8/23); three patients achieved complete response (CR) and five partial response (PR). The median response duration was 24 weeks for CR patients and 32 weeks for PR patients. The median survival was 21 weeks overall and 45 weeks for responding patients. Grade 3/4 leukocytopenia and thrombocytopenia were seen in 28 and 9%, respectively. Two patients died from infections while in neutropenia. Cisplatin and teniposide seems an active regimen against brain metastases in NSCLC. These data may indicate the need for reconsideration of the role of chemotherapy for brain metastases of NSCLC.