Ermelinda De Maio

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.

Endocrine Effects of Adjuvant Letrozole Compared With Tamoxifen in Hormone-Responsive Postmenopausal Patients With Early Breast Cancer: The HOBOE Trial

PURPOSE We compared the endocrine effects of 6 and 12 months of adjuvant letrozole versus tamoxifen in postmenopausal patients with hormone-responsive early breast cancer within an ongoing phase III trial. PATIENTS AND METHODS Patients were randomly assigned to receive tamoxifen, letrozole, or letrozole plus zoledronic acid. Serum values of estradiol, follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone, dehydroepiandrosterone-sulphate (DHEA-S), progesterone, and cortisol were measured at baseline and after 6 and 12 months of treatment. For each hormone, changes from baseline at 6 and 12 months were compared between treatment groups, and differences over time for each group were analyzed. Results Hormonal data were available for 139 postmenopausal patients with a median age of 62 years, with 43 patients assigned to tamoxifen and 96 patients assigned to letrozole alone or combined with zoledronic acid. Baseline values were similar between the two groups for all hormones. Many significant changes were observed between drugs and for each drug over time. Namely, three hormones seemed significantly affected by one drug only: estradiol that decreased and progesterone that increased with letrozole and cortisol that increased with tamoxifen. Both drugs affected FSH (decreasing with tamoxifen and slightly increasing with letrozole), LH (decreasing more with tamoxifen than with letrozole), testosterone (slightly increasing with letrozole but not enough to differ from tamoxifen), and DHEA-S (increasing with both drugs but not differently between them). Zoledronic acid did not have significant impact on hormonal levels. CONCLUSION Adjuvant letrozole and tamoxifen result in significantly distinct endocrine effects. Such differences can explain the higher efficacy of letrozole as compared with tamoxifen.

Hepatocellular carcinoma: Systemic treatments

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, with increasing incidence in Western countries. Many pharmacologic treatments have been tested against HCC; most of them belong to three categories: chemotherapy, hormone therapy, and immunotherapy. Neither single agent nor combination chemotherapy have demonstrated a clear reproducible advantage in terms of overall survival; therefore, systemic or intraarterial chemotherapy should not be considered as standard strategies for patients with HCC. Tamoxifen and antiandrogen therapy were not effective in prolonging survival when tested in randomized, controlled trials. Promising results have been obtained with octreotide in a small randomized trial, but confirmation studies are needed. Although adoptive immunotherapy was effective in the adjuvant setting, interferon should be further investigated in this setting or investigated as a preventive strategy in cirrhotic patients. On the contrary, interferon does not seem to have a role in advanced disease, where it is tolerated poorly. In the future, innovative and promising therapeutic strategies will be tested in HCC, including new biologic target-based drugs, cyclooxygenase inhibitors, and gene therapy.

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

BackgroundFew 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.MethodsWe 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, ≥ 65) by Fisher exact test and exact Wilcoxon rank-sum test.ResultsFrom 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 (≥ 29 weeks) in 10% and 11% and need of G-CSF in 9% and 18%, among younger and older patients, respectively.ConclusionOur 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.

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.

First-line chemotherapy with fluorouracil and folinic acid for advanced Colorectal cancer in elderly patients: A phase II study

Background Colorectal cancer is one of the most common cancers in the elderly. Information on tolerability and efficacy of 5-Fluorouracil-based chemotherapy in such patients is limited. Primary aim of the study was to describe tolerability and activity of chemotherapy with the “de Gramont” schedule (FU bolus [400 mg/m2] + FU continuous infusion [600 mg/m2] + folinic acid [100 mg/m2] on days 1 and 2, every 2 weeks), in patients with advanced colorectal cancer aged 70 or older. Patients and methods Patients aged 70 or more, with stage IV colorectal cancer, ECOG performance status not worse than 2. Results Thirty-four patients were treated at two participating centers. Seven (20.6%, 95% exact CI = 8.7–37.9) had an objective response, complete in 3 and partial in 4 patients. Five cases of unacceptable toxicity were registered (2 cardiac, 1 each for liver, anemia and diarrhea). Fitting the statistical model to the observed data indicated that the treatment was sufficiently active and tolerated. Conclusions The de Gramont scheme is active and tolerated in elderly patients with advanced colorectal cancer.

Hormonal Treatment of Human Hepatocellular Carcinoma

Abstract:  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.

Statistical design in phase II clinical trials and its application in breast cancer

Several statistical designs for phase II studies have been proposed, but they are frequently misunderstood or not applied at all. In this review we describe the major characteristics of the available designs. To investigate the extent to which statistical designs were used in some recent phase II studies, and which designs were the most common, we did a survey of 145 trials involving treatment of breast cancer. Studies selected for the survey were published between 1995 and 1999 in one of seven specific oncology journals (all with impact factor consistently higher than 2). 94 of the studies (64.8%) did not have an identifiable statistical design. However, among the 51 studies with statistical design there was a notable heterogeneity in the type of design applied. We put together a list of factors associated with use of statistical design at univariate analysis. These factors included: referral to a previous phase I study, recent trial start date, private sponsorship, single-agent treatment, and multicentre organisation. Single-agent treatment (OR 2.35; 95% CI 1.01-5.51) and multicentre organisation (OR 3.24; 95% CI 1.47-7.15) were independently predictive of the presence of statistical design. Publication in journals with high impact factors and short intervals between the start of the study and publication were also correlated with statistical design.

Tamoxifen is not effective in good prognosis patients with hepatocellular carcinoma

BackgroundLarge 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.MethodsWe 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.ResultsTamoxifen 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.ConclusionThe 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.

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.