Non-pegylated liposomal doxorubicin in older adjuvant early breast cancer patients: cardiac safety analysis and final results of the COLTONE study.

AIMS: To explore the cardiac safety of adjuvant Non-Pegylated Liposomal Doxorubicin (NPL-DOX) plus Cyclophosphamide (CTX) followed by weekly Paclitaxel, in elderly women (≥ 65 years) with high-risk breast cancer. Previously, we described no symptomatic cardiac events within the first 12 months from starting treatment. We now reported the updated results after a median follow-up 76 months. METHODS: The cardiac activity was evaluated with left ventricular ejection fraction (LVEF) echocardiograms assessments, before starting chemotherapy and every 6 months, until 30 months from baseline, then yearly for at least 5 years. RESULTS: Forty-seven women were recruited by two Units of Medical Oncology (Ethics Committee authorization CESM-AOUP, 3203/2011; EudraCT identification number: 2010-024067-41, for Pisa and Pontedera Hospitals). An episode of grade 3 CHF (NCI-CTCAE, version 3.0) occurred after 18 months the beginning of chemotherapy. The echocardiograms assessments were performed comparing the LVEF values of each patient evaluated at fixed period of time, compared to baseline. We observed a slight changed in terms of mean values at 48, 60, 72 and 84 months. At these time points, a statistically significant reduction of - 3.2%, - 4.6%, - 6.4% and - 7.1%, respectively, was observed. However, LVEF remained above 50% without translation in any relevant clinical signs. No other cardiac significant episodes were reported. To this analysis, in 13 patients (28%) occurred disease relapse and,  of them, 11 (23%) died due to metastatic disease. Eight patients died of cancer-unrelated causes. CONCLUSIONS: The combination including NPL-DOX in elderly patients revealed low rate of cardiac toxic effects. Comparative trials are encouraged.

A pharmacogenetic interaction analysis of bevacizumab with paclitaxel in advanced breast cancer patients.

To investigate pharmacogenetic interactions among VEGF-A, VEGFR-2, IL-8, HIF-1α, EPAS-1, and TSP-1 SNPs and their role on progression-free survival (PFS) in metastatic breast cancer (MBC) patients treated with bevacizumab plus first-line paclitaxel or with paclitaxel alone. Analyses were performed on germline DNA, and SNPs were investigated by real-time PCR technique. The multifactor dimensionality reduction (MDR) methodology was applied to investigate the interaction between SNPs. The present study was an explorative, ambidirectional cohort study: 307 patients from 11 Oncology Units were evaluated retrospectively from 2009 to 2016, then followed prospectively (NCT01935102). Two hundred and fifteen patients were treated with paclitaxel and bevacizumab, whereas 92 patients with paclitaxel alone. In the bevacizumab plus paclitaxel group, the MDR software provided two pharmacogenetic interaction profiles consisting of the combination between specific VEGF-A rs833061 and VEGFR-2 rs1870377 genotypes. Median PFS for favorable genetic profile was 16.8 vs. the 10.6 months of unfavorable genetic profile (p = 0.0011). Cox proportional hazards model showed an adjusted hazard ratio of 0.64 (95% CI, 0.5-0.9; p = 0.004). Median OS for the favorable genetic profile was 39.6 vs. 28 months of unfavorable genetic profile (p = 0.0103). Cox proportional hazards model revealed an adjusted hazard ratio of 0.71 (95% CI, 0.5-1.01; p = 0.058). In the 92 patients treated with paclitaxel alone, the results showed no effect of the favorable genetic profile, as compared to the unfavorable genetic profile, either on the PFS (p = 0.509) and on the OS (p = 0.732). The pharmacogenetic statistical interaction between VEGF-A rs833061 and VEGFR-2 rs1870377 genotypes may identify a population of bevacizumab-treated patients with a better PFS.

Effects on quality of life of weekly docetaxel-based chemotherapy in patients with locally advanced or metastatic breast cancer: results of a single-centre randomized phase 3 trial.

BACKGROUND: To evaluate whether weekly schedules of docetaxel-based chemotherapy were superior to 3-weekly ones in terms of quality of life in locally advanced or metastatic breast cancer. METHODS: Patients with locally advanced or metastatic breast cancer, aged ≤ 70 years, performance status 0-2, chemotherapy-naive for metastatic disease, were eligible. They were randomized to weekly or 3-weekly combination of docetaxel and epirubicin, if they were not treated with adjuvant anthracyclines, or docetaxel and capecitabine, if treated with adjuvant anthracyclines. Primary end-point was global quality of life change at 6-weeks, measured by EORTC QLQ-C30. With two-sided alpha 0.05 and 80% power for 35% effect size, 130 patients per arm were needed. RESULTS: From February 2004 to March 2008, 139 patients were randomized, 70 to weekly and 69 to 3-weekly arm; 129 and 89 patients filled baseline and 6-week questionnaires, respectively. Global quality of life was better in the 3-weekly arm (p = 0.03); patients treated with weekly schedules presented a significantly worsening in role functioning and financial scores (p = 0.02 and p < 0.001). Neutropenia and stomatitis were worse in the 3-weekly arm, where two toxic deaths were observed. Overall response rate was 39.1% and 33.3% in 3-weekly and weekly arms; hazard ratio of progression was 1.29 (95% CI: 0.84-1.97) and hazard ratio of death was 1.38 (95% CI: 0.82-2.30) in the weekly arm. CONCLUSIONS: In this trial, the weekly schedules of docetaxel-based chemotherapy appear to be inferior to the 3-weekly one in terms of quality of life in patients with locally advanced or metastatic breast cancer. TRIAL REGISTRATION: ClinicalTrials.gov NCT00540800.

Vandetanib (ZD6474), a dual inhibitor of vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR) tyrosine kinases: current status and future directions.

Vandetanib is a novel, orally available inhibitor of different intracellular signaling pathways involved in tumor growth, progression, and angiogenesis: vascular endothelial growth factor receptor-2, epidermal growth factor receptor, and REarranged during Transfection tyrosine kinase activity. Phase I clinical trials have shown that vandetanib is well tolerated as a single agent at daily doses < or =300 mg. In the phase II setting, negative results were observed with vandetanib in small cell lung cancer, metastatic breast cancer, and multiple myeloma. In contrast, three randomized phase II studies showed that vandetanib prolonged the progression-free survival (PFS) time of patients with non-small cell lung cancer (NSCLC) as a single agent when compared with gefitinib or when added to chemotherapy. Rash, diarrhea, hypertension, fatigue, and asymptomatic QTc prolongation were the most common adverse events. Antitumor activity was also observed in medullary thyroid cancer. Four randomized phase III clinical trials in NSCLC are exploring the efficacy of vandetanib in combination with docetaxel, the Zactima in cOmbination with Docetaxel In non-small cell lung Cancer (ZODIAC) trial, or with pemetrexed, the Zactima Efficacy with Alimta in Lung cancer (ZEAL) trial, or as a single agent, the Zactima Efficacy when Studied versus Tarceva (ZEST) and the Zactima Efficacy trial for NSCLC Patients with History of EGFR-TKI chemo-Resistance (ZEPHYR) trials. Based on a press release by the sponsor of these trials, the PFS time was longer with vandetanib in the ZODIAC and ZEAL trials; the ZEST trial was negative for its primary superiority analysis, but was successful according to a preplanned noninferiority analysis of PFS. Ongoing phase II and III clinical trials will better define the appropriate schedule, the optimal setting of evaluation, and the safety of long-term use of vandetanib.

Adjuvant zoledronic acid and letrozole plus ovarian function suppression in premenopausal breast cancer: HOBOE phase 3 randomised trial.

AIM: The aim of the study is to analyse whether letrozole (L) and zoledronic acid plus L (ZL) are more effective than tamoxifen (T) as adjuvant endocrine treatment of premenopausal patients with breast cancer with hormone receptor-positive (HR+) tumours. PATIENTS AND METHODS: In a phase 3 trial, 1065 premenopausal patients with HR + early breast cancer received triptorelin to suppress ovarian function and were randomly assigned (1:1:1) to adjuvant T, L or ZL for 5 years. Cancer recurrence, second breast or non-breast cancer and death were considered events for the intention-to-treat disease-free survival (DFS) analysis. RESULTS: With a 64-month median follow-up and 134 reported events, the disease-free rate at 5 years was 85.4%, 93.2% and 93.3% with T, L and ZL, respectively (overall P = 0.008). The hazard ratio for a DFS event was 0.52 (95% confidence interval [CI], 0.34 to 0.80; P = 0.003) with ZL vs T, 0.72 (95% CI, 0.48 to 1.07; P = 0.06) with L vs T and 0.70 (95% CI, 0.44 to 1.12; P = 0.22) with ZL vs L. With 36 deaths, there was no significant difference in overall survival (P = 0.14). Treatment was stopped for toxicity or refusal in 7.3%, 7.3% and 16.6% patients, and in the safety population, grade 3-4 side-effects were reported in 4.2%, 6.9% and 9.1% patients treated with T, L or ZL, respectively. CONCLUSION: HOBOE study shows that in premenopausal patients with early breast cancer undergoing ovarian function suppression with triptorelin, ZL significantly improves DFS, while worsening compliance and toxicity, as compared with T. (NCT00412022).

Weekly docetaxel versus CMF as adjuvant chemotherapy for elderly breast cancer patients: safety data from the multicentre phase 3 randomised ELDA trial.

Within an ongoing multicentre phase 3 randomised trial (ELDA, cancertrials.gov ID: NCT00331097), early breast cancer patients, 65-79 years old, with average to high risk of recurrence, are randomly assigned to receive CMF (cyclophosphamide 600 mg/m2, methotrexate 40 mg/m2, fluorouracil 600 mg/m2, days 1-8) or docetaxel (35 mg/m2 days 1-8-15), every 4 weeks. Here we report an unplanned safety analysis prompted by an amendment introducing creatinine clearance as a tool to adjust methotrexate dose. Before such change, 101 patients with a median age of 70 were randomly assigned CMF (53 patients) or docetaxel (48 patients). At least one grades 3-4 toxic event of any type was reported in 40 (75.5%) and 19 (39.6%) patients with CMF and docetaxel, respectively (p=0.0002). Grades 3-4 hematological events were observed in 37 (69.8%) vs. 4 (8.3%) cases (p<0.0001) and grades 3-4 non-hematological toxicity in 12 (22.6%) vs. 15 (31.2%) patients (p=0.11), with CMF and docetaxel, respectively. A higher incidence of anemia, neutropenia, thrombocytopenia and febrile neutropenia was reported with CMF. Constipation, mucositis, nausea and vomiting were more common with CMF; diarrhoea, abdominal pain, dysgeusia, neuropathy and liver toxicity were more frequent with docetaxel. No significant interaction was found between the occurrence of severe toxicity and baseline variables, including creatinine clearance and geriatric activity scales. In conclusion, weekly docetaxel appears to be less toxic than CMF in terms of hematological toxicity.

The MILES-2G phase 2 study of single-agent gemcitabine with prolonged constant infusion in advanced non-small cell lung cancer elderly patients.

BACKGROUND: Gemcitabine has been widely studied in elderly patients affected by advanced non-small cell lung cancer (NSCLC). A prolonged constant infusion (10 mg/m2/min) has been proposed as a way to improve its efficacy. Aim of this study is to describe activity and toxicity of single-agent gemcitabine given as prolonged infusion in the treatment of elderly patients with advanced NSCLC. PATIENTS AND METHODS: Patients aged 70 years or older, with stage IV or IIIB (effusion/supraclavicular nodes) NSCLC, good performance status (0 or 1 according to ECOG classification) who had never received chemotherapy were eligible. Gemcitabine was administered at the dose of 1200 mg/m2 by prolonged infusion (10 mg/m2/min) on days 1 and 8 of each cycle. Courses were repeated every 21 days, for a maximum of 6 cycles, unless disease progression or severe toxicity. A single stage phase 2 design was applied, with 51 patients required to estimate a 25% +/- 10% response rate. Ten responses were required to define the treatment as active. RESULTS: Fifty-one patients were enrolled, with a median age of 76 years (range 70-83). Two complete responses and seven partial responses were observed, for an overall response rate of 17.6% (95% exact C.I.: 8.4-30.9%). The median time to disease progression was 16.1 weeks (95% C.I.: 11.1-20.6) and the median overall survival was 41.3 weeks (95% C.I.: 27.6-50.6). There were 2 toxic deaths, due to bleeding and liver toxicity, and one patient had an ischemic stroke. Other non-haematological toxicities were: fatigue (44% of patients), grade 2-3 pulmonary toxicity (8%), grade 2-3 hepatic toxicity (16%). Nausea and stomatitis were mild and no cases of cardiac toxicity were observed. Haematological toxicity was mild, with no case of febrile neutropenia. CONCLUSION: Gemcitabine at prolonged constant infusion produced a response rate lower than that required by study design and should no longer be of interest for the treatment of elderly patients with advanced NSCLC.

Is human hepatocellular carcinoma a hormone-responsive tumor?

Before the positive results recently obtained with multitarget tyrosine kinase inhibitor sorafenib, there was no standard systemic treatment for patients with advanced hepatocellular carcinoma (HCC). Sex hormones receptors are expressed in a significant proportion of HCC samples. Following preclinical and epidemiological studies supporting a relationship between sex hormones and HCC tumorigenesis, several randomized controlled trials (RCTs) tested the efficacy of the anti-estrogen tamoxifen as systemic treatment. Largest among these trials showed no survival advantage from the administration of tamoxifen, and the recent Cochrane systematic review produced a completely negative result. This questions the relevance of estrogen receptor-mediated pathways in HCC. However, a possible explanation for these disappointing results is the lack of proper patients selection according to sex hormones receptors expression, but unfortunately the interaction between this expression and efficacy of tamoxifen has not been studied adequately. It has been also proposed that negative results might be explained if tamoxifen acts in HCC via an estrogen receptor-independent pathway, that requires higher doses than those usually administered, but an Asian RCT conducted to assess dose-response effect was completely negative. Interesting, preliminary results have been obtained when hormonal treatment (tamoxifen or megestrol) has been selected according to the presence of wild-type or variant estrogen receptors respectively, but no large RCTs are available to support this strategy. Negative results have been obtained also with anti-androgen therapy. In conclusion, there is no robust evidence to consider HCC a hormone-responsive tumor. Hormonal treatments should not be part of the current management of HCC.

Vinorelbine plus 3-weekly trastuzumab in metastatic breast cancer: a single-centre phase 2 trial.

BACKGROUND: After two studies reporting response rates higher than 70% in HER2-positive metastatic breast cancer with weekly trastuzumab and vinorelbine, we planned a phase 2 study to test activity of the same combination, with trastuzumab given every 3 weeks. METHODS: Patients with HER2-positive metastatic breast cancer (3+ at immunohistochemistry or positive at fluorescence in situ hybridization), PS < or =2, normal left-ventricular ejection fraction (LVEF) and no more than one chemotherapy line for metastatic disease were eligible. Vinorelbine (30 mg/m2) was given on days 1 & 8 every 21 and trastuzumab (8 mg/kg day 1, then 6 mg/kg) every 21 days). A single-stage phase 2 design, with p0 = 0.45, p1 = 0.65, type I and II error = 0.10, was applied; 22 objective responses were required in 39 patients. RESULTS: From Nov 2002 to May 2005, 50 patients were enrolled, with a median age of 54 years (range 31-81). Among 40 patients eligible for response assessment, there were 7 complete and 13 partial responses (overall response rate 50%; 95% exact CI 33.8-66.2); 11 patients had disease stabilization, lasting more than 6 months in 10 cases. Response rate did not vary according to patients and tumor characteristics, type and amount of previous chemotherapy. Within the whole series, median progression-free survival was 9.6 months (95% CI 7.3-12.3), median overall survival 22.7 months (95% CI 19.5-NA). Fifteen patients (30%) developed brain metastases at a median time of 12 months (range 1-25). There was one toxic death due to renal failure in a patient receiving concomitant pamidronate. Twenty-three patients (46%) had grade 3-4 neutropenia, 2 (4%) grade 3 anemia, 4 (8%) febrile neutropenia. Two patients stopped treatment because of grade 2 decline of LVEF and one patient because of grade 2 liver toxicity concomitant with a grade 1 decline of LVEF. One patient stopped trastuzumab after 50 cycles because of grade 1 decline of LVEF. CONCLUSION: Although lower than in initial studies, activity of 3-weekly trastuzumab plus vinorelbine fell within the range of results reported with weekly schedules. Toxicity was prevalently manageable. This combination is safe and active for metastatic breast cancer patients who received adjuvant taxanes with anthracyclines.

Pretreatment quality of life and functional status assessment significantly predict survival of elderly patients with advanced non-small-cell lung cancer receiving chemotherapy: a prognostic analysis of the multicenter Italian lung cancer in the elderly study.

PURPOSE: To study the prognostic value for overall survival of baseline assessment of functional status, comorbidity, and quality of life (QoL) in elderly patients with advanced non-small-cell lung cancer treated with chemotherapy. PATIENTS AND METHODS: Data from 566 patients enrolled onto the phase III randomized Multicenter Italian Lung Cancer in the Elderly Study (MILES) study were analyzed. Functional status was measured as activities of daily living (ADL) and instrumental ADL (IADL). The presence of comorbidity was assessed with a checklist of 33 items; items 29 and 30 of the European Organisation for Research and Treatment of Cancer (EORTC) core questionnaire QLQ-C30 (EORTC QLQ-C30) were used to estimate QoL. ADL was dichotomized as none versus one or more dependency. For IADL and QoL, three categories were defined using first and third quartiles as cut points. Comorbidity was summarized using the Charlson scale. Analysis was performed by Cox model, and stratified by treatment arm. RESULTS: Better values of baseline QoL (P = .0003) and IADL (P = .04) were significantly associated with better prognosis, whereas ADL (P = .44) and Charlson score (P = .66) had no prognostic value. Performance status 2 (P = .006) and a higher number of metastatic sites (P = .02) also predicted shorter overall survival. CONCLUSIONS: Pretreatment global QoL and IADL scores, but not ADL and comorbidity, have significant prognostic value for survival of elderly patients with advanced non-small-cell lung cancer who were treated with chemotherapy. Using these scores in clinical practice might improve prognostic prediction for treatment planning.

Characteristics at presentation and outcome of hepatocellular carcinoma (HCC) in the elderly. A study of the Cancer of the Liver Italian Program (CLIP).

PURPOSE: To describe the characteristics at presentation and the outcome of elderly patients (> or =70 years old) with HCC, a retrospective analysis using a CLIP database was performed. PATIENTS AND METHODS: The database included 650 patients. Chi2-test, logistic and Cox model were applied. RESULTS: Baseline characteristics and stage were similarly among elderly (n=158) and non-elderly (n=492) patients. More elderly patients did not receive any local treatment (56% versus 38%, p<0.0001). Age and CLIP score were independently predictive of the odds of locoregional treatment. Prognosis was worse for elderly patients with a hazard ratio of death of 1.49 (95% CI 1.20-1.86) at multivariable analysis. The survival difference disappeared when patients were compared within each treatment group, suggesting a close link between undertreatment and shorter survival. CONCLUSION: Elderly patients with HCC have a worse prognosis compared to non-elderly ones. Such difference seems the consequence of undertreatment.

Tamoxifen is not effective in good prognosis patients with hepatocellular carcinoma.

BACKGROUND: Large randomised clinical trials and systematic reviews substantiate that tamoxifen is ineffective in improving survival of patients with hepatocellular carcinoma (HCC). However, a recent report suggested that the drug might prolong survival among patients with well preserved liver function. The aim of this paper is to validate this hypothesis. METHODS: We used the updated database of the phase 3 randomised CLIP-1 trial that compared tamoxifen with supportive therapy. Primary endpoint was overall survival. Treatment arms were compared within strata defined according to the Okuda stage and the CLIP-score. Survival differences were tested by the Log-rank test. RESULTS: Tamoxifen was not effective in prolonging survival in Okuda I-II subgroup (p = 0.501). Median survival times were equal to 16.8 (95%CI 12.7-18.5) months for tamoxifen and 16.8 (95%CI 13.5-22.4) months for the control arms; 1-year survival probabilities were equal to 58.8% (95%CI 51.7-65.8) and 59.4 (95%CI 52.5-66.2), respectively. Similar results were observed in the better CLIP subgroup (score 0/1), without evidence of difference between the two treatment arms (p = 0.734). Median survival times were equal to 29.2 (95%CI 20.1-36.4) months with tamoxifen and 29.0 (95%CI 23.3-35.2) months without; 1-year survival probabilities were equal to 80.9% (95%CI 72.5-89.3) with tamoxifen and 77.1% (95%CI 68.6-85.7) for the control arm. CONCLUSION: The recent suggestion that tamoxifen might be effective in the subgroup of patients with better prognosis is not supported by a reanalysis of the CLIP-1 trial. Tamoxifen should no longer be considered for the treatment of HCC patients and future trials of medical treatment should concentrate on different drugs.

Hormonal treatment of human hepatocellular carcinoma.

Animal models of experimental liver carcinogenesis and epidemiological studies in humans suggest a relationship between sex hormones and hepatocellular carcinoma (HCC). In 1997, a systematic review of the existing, small randomized trials evaluating the antiestrogen tamoxifen yielded a positive result, but the large randomized CLIP-1 trial showed no survival advantage from the addition of tamoxifen to best supportive care. A possible explanation for the negative results is the lack of patient selection, but the expression of estrogen (ER) and progesterone (PgR) receptors in HCC does not clearly affect the survival outcome of the patients treated with tamoxifen. In the last years, it has been proposed that negative results might be due to the fact that tamoxifen in HCC could act via an ER-independent pathway, which requires much higher doses than those usually administered, but a double-blind Asian randomized trial conducted to assess possible dose-response effect showed no efficacy for tamoxifen, with an inversely negative impact with increasing dose. According to the results of large trials and of the Cochrane systematic review, neither further trials are warranted with tamoxifen in HCC, nor should any use in clinical practice be considered. Interesting results have been obtained when the type of hormonal treatment (tamoxifen or megestrol) has been chosen according to the presence of wild-type or variant ER, but these results should be confirmed in large randomized trials. Negative results have been obtained with antiandrogen therapy. In conclusion, hormonal treatment should not be a part of the current management of HCC patients.

Mechanisms of endocrine resistance and novel therapeutic strategies in breast cancer.

Tamoxifen has been the mainstay of hormonal therapy in both early and advanced breast cancer patients for approximately three decades. The availability of novel compounds such as aromatase inhibitors (AIs) and fulvestrant, with different mechanism of action, is changing the scenario of endocrine treatment of postmenopausal breast cancer patients. In this review article, we have summarized the current knowledge of the mechanisms of resistance to endocrine therapy, in order to derive information that might be useful for therapeutic intervention. We propose that resistance to endocrine therapy is a progressive, step-wise phenomenon induced by the selective pressure of hormonal agents, which leads breast cancer cells from an estrogen-dependent, responsive to endocrine manipulation phenotype to a non-responsive phenotype, and eventually to an estrogen-independent phenotype. In particular, evidence suggests for each 'action' introduced to block estrogen stimulation of breast cancer cells (i.e. treatment with anti-estrogen), there are one or more corresponding 'reactions' that tumor cells can use to escape our attempts to block their growth: estrogen hypersensitivity associated with increased transcriptional activity of estrogen receptor alpha (ERalpha) and/or increased non-genomic activity of ERalpha, estrogen supersensitivity, increased growth factor signaling, suppression of ERalpha expression and finally estrogen independence. Activation of growth factor signaling is involved in each step of this phenomenon, and might ultimately substitute estrogen in sustaining the growth and the survival of breast cancer cells. In this respect, results of pre-clinical and clinical studies with AIs, fulvestrant and signaling inhibitors sustain this hypothesis. More importantly, the knowledge of the mechanisms involved in the resistance of breast cancer cells to endocrine therapy offers potential for novel therapeutic strategies.

Survey of modalities of toxicity assessment and reporting in noncomparative prospective studies of chemotherapy in breast cancer.

PURPOSE: To review how toxicity, a main end point of phase II studies, is assessed and reported in published phase II chemotherapy trials in breast cancer. METHODS: A survey was performed by hand-searching studies published in seven distinguished journals between 1995 and 1999. All selected articles were independently evaluated by two investigators using an ad hoc study report form. Descriptive statistics, contingency tables, and the chi(2) test were applied. RESULTS: Overall, 122 articles were found; 65.6% lacked a statistical study design. Planned modalities for assessment of toxicity were inadequately reported in 20.5% of the studies. The scheduling of assessment of hematologic toxicity varied greatly. Toxicity was predominantly summarized per patient (69.7%). Although overall the World Health Organization scale was adopted more frequently (45.9%), the Common Toxicity Criteria (in different versions) were used more frequently in studies published in journals with a high impact factor (P =.001), in more recently initiated studies (P =.03), in sponsored studies (P =.0006), and in studies with an identifiable statistical design (P =.006). CONCLUSION: The wide diversity in modalities of toxicity assessment and reporting observed in this study suggests that the reliability of the body of published data on the toxicity of chemotherapy in breast cancer may be questionable. Current standards should be revised and harmonized to improve the reliability of such data. A checklist is proposed to help editorial evaluation of assessment and reporting of toxicity in phase II studies.

Compliance and toxicity of adjuvant CMF in elderly breast cancer patients: a single-center experience.

BACKGROUND: Few data are available on compliance and safety of adjuvant chemotherapy when indicated in elderly breast cancer patients; CMF (cyclophosphamide, methotrexate, fluorouracil) can be reasonably considered the most widely accepted standard of treatment. METHODS: We retrospectively reviewed compliance and safety of adjuvant CMF in patients older than 60. The treatment was indicated if patients had no severe comorbidity, a high-risk of recurrence, and were younger than 75. Toxicity was coded by NCI-CTC. Toxicity and compliance were compared between two age subgroups (< 65, > or = 65) by Fisher exact test and exact Wilcoxon rank-sum test. RESULTS: From March 1991 to March 2002, 180 patients were identified, 100 older than 60 and younger than 65, and 80 aged 65 or older. Febrile neutropenia was more frequent among older patients (p = 0.05). Leukopenia, neutropenia, nausea, cardiac toxicity and thrombophlebitis tended to be more frequent or severe among elderlies, while mucositis tended to be more evident among younger patients, all not significantly. Almost one half (47%) of the older patients receiving concomitant radiotherapy experienced grade 3-4 haematological toxicity. Compliance was similar in the two groups, with 6 cycles administered in 86% and 79%, day-8 chemotherapy omitted at least once in 36% and 39%, dose reduction in 27% and 38%, prolonged treatment duration (> or = 29 weeks) in 10% and 11% and need of G-CSF in 9% and 18%, among younger and older patients, respectively. CONCLUSION: Our data show that, in a highly selected population of patients 65 or more years old, CMF is as feasible as in patients older than 60 and younger than 65, but with a relevant burden of toxicity. We suggest that prospective trials in elderly patients testing less toxic treatment schemes are mandatory before indicating adjuvant chemotherapy to all elderly patients with significant risk of breast cancer recurrence.

Transcatheter arterial procedures in the treatment of patients with hepatocellular carcinoma: a review of literature.

BACKGROUND: Transcatheter arterial procedures (TAP) have been widely used to treat hepatocellular carcinoma (HCC) in several clinical settings (advanced and neoadjuvant), and contraindications and secondary effects have been clearly described. However, it is still unclear which patients should be selected for treatment, which procedures should be used, in particular whether or not to add an antiblastic agent to embolization, and if the treatment provides a survival advantage in patient with HCC. METHODS: We conducted a Medline search for all study reports published until May 2002. Data from randomised studies were evaluated in detail. RESULTS: Data on the use of TAP for the treatment of unresectable HCC mainly come from retrospective studies that are difficult to compare because of the lack of standardized procedures. Some prognostic systems have been proposed in order to improve the selection of the patients that can benefit from treatment. While the effects in terms of tumour response are clearly documented, the results in terms of survival are still unclear. CONCLUSIONS: The real impact of TAP on survival remains to be determined in all clinical settings. The very few published prospective randomised trials are underpowered and cannot provide any definitive conclusions. Thus, there is an urgent need for prospective controlled trials in order assess the impact of TAP on survival and to compare different procedures.

Does the sequence of gemcitabine and vinorelbine affect their efficacy in non-small cell lung cancer in vitro?

BACKGROUND: We have recently completed a large phase III trial in advanced non-small cell lung cancer (NSCLC) in the elderly which showed that the combination of gemcitabine (GEM) plus vinorelbine (VNR), with GEM administered first, did not improve any outcome as compared with each single drug. MATERIALS AND METHODS: The anti-tumor efficacy of different sequences of administration of GEM and VNR was investigated in a small panel of NSCLC cell lines, by using an in vitro cytotoxic assay and isobologram analysis. RESULTS: Treatment of lung cancer cells with GEM followed by VNR resulted in moderate synergism in one cell line (A549), and in antagonism in two cell lines (H838 and H1355). However, treatment of NSCLC cells with VNR followed by GEM resulted in antagonism in all cell lines. CONCLUSION: The results of this study show that the GEM/VNR combination is not superior to both single agents against NSCLC cells, independently of the schedule of administration of the drugs.

Phase I-II trial of gemcitabine-based first-line chemotherapies for small cell lung cancer in elderly patients with performance status 0-2: the G-STEP trial.

INTRODUCTION: Treatment of elderly patients with small cell lung cancer (SCLC) is based on scanty evidence. METHODS: Patients with extensive SCLC, age >70 years, and performance status 0-2 were eligible for a study looking for optimal two-drug combination of gemcitabine (Gem) with vinorelbine (Vin), etoposide (Eto), cisplatin (Cis), or carboplatin (Car). Gemcitabine dose was the same (1000 mg/m2, days 1-8) in all combinations. A two-stage minimax flexible design for response was applied to GemVin combination (Vin 25 mg/m2, days 1-8). For GemCar, GemCis, GemEto, a phase I-II Bayesian design was applied, looking for the optimal dose of the partner drugs. Objective response rate ≥ 60% and unacceptable toxicity ≤ 25% were required to define a combination worthy of further studies. RESULTS: Median age of 78 eligible patients was 74 years. GemVin produced a 36.7% objective response rate. GemEto and GemCis arms were found not sufficiently active. GemCar produced 16 responses (14 with area under the curve [AUC] 3.5 and 2 with AUC 4.0) in 26 patients (61.5%) and 6 cases of unacceptable toxicity (3 at each Car dose). CONCLUSIONS: In elderly patients with extensive SCLC, GemVin, GemEto, and GemCis are not enough active and do not merit further studies. Gem plus Car might deserve further attention.

Methodological aspects of lung cancer clinical trials in the era of targeted agents.

Methodology of clinical trials conducted in lung cancer, similarly to other tumours, has been recently challenged by the particular characteristics of new targeted agents. Traditional methodology of phase II trials has been questioned, both for the choice of the endpoint and for the study design itself. Due to the mechanism of action of new drugs, cytostatic more than cytotoxic at least in principle, the usual endpoint of phase II trials, objective response rate, is now often replaced by alternative event-related endpoints, such as progression-free survival or progression-free rate at a fixed time-point. Randomized phase II trials, considered in the past the exception rather than the rule, have been encouraged, as the only design useful to give clear information on the activity of experimental treatments. Conduction of phase III trials remains mandatory to demonstrate treatment efficacy, but their endpoints and design are currently object of discussion. With targeted agents, great efforts have been made to identify predictive factors of treatment efficacy, but this aspect appears to be more complicated than hypothesized in principle. The history of clinical trials with epidermal growth factor receptor inhibitors in advanced NSCLC is a good example of the uncertainty about predictive factors and selection criteria. Moreover, non-inferiority design has been used for several phase III trials comparing targeted agents with chemotherapy. In this review, recent aspects of clinical trials methodology in lung cancer are described, and examples of their application are discussed.