Nivolumab in pretreated pleural mesothelioma: Results from an observational real-world study of patients treated within the AIFA 5% Fund.

BACKGROUND: Pleural mesothelioma is a rare cancer with a dismal prognosis and few therapeutic options, especially in the pretreated setting. Immunotherapy with checkpoint inhibitors as single agents yielded interesting results in refractory pleural mesothelioma, achieving a response rate between 10-20%, median progression-free survival of 2-5 months and median overall survival of 7-13 months. PATIENTS AND METHODS: A retrospective, multi-institutional study of pleural mesothelioma patients treated with nivolumab in second and further line was performed. The endpoints of the study are response rate, disease control rate, progression free survival and overall survival. RESULTS: Sixty-five patients with pleural mesothelioma treated with nivolumab in second and further line were enrolled at seven Italian institutions. The response rate was 8%, disease control rate was 37%, median progression free survival was 5.7 months (95% CI: 2.9-9.0) and median overall survival was 11.1 (95% CI 6.2-19.9) months. A higher neutrophils and neutrophils to lymphocytes ratio at baseline were associated with worse prognosis. CONCLUSION: Nivolumab as a single agent is fairly active in a cohort of unselected pretreated pleural mesothelioma patients. Further investigations on clinical and translational factors are needed to define which patient might benefit most from nivolumab treatment in pleural mesothelioma.

Clinical results of randomized trials and 'real-world' data exploring the impact of Bevacizumab for breast cancer: opportunities for clinical practice and perspectives for research.

INTRODUCTION: Angiogenesis plays a fundamental role in breast cancer (BC) growth, progression and metastatic spread. After the promising introduction of bevacizumab for the treatment of advanced BC, the initial enthusiasm decreased when the FDA withdrew its approval in 2011. Nevertheless, several clinical studies exploring the role of bevacizumab have been subsequently published. Areas covered: The aim of this study is to review the available clinical trials exploring the potential effectiveness of bevacizumab in BC, regardless of the disease setting. Expert opinion: Even if the evidence suggests that bevacizumab must be ruled out from the HER2-positive and adjuvant setting, bevacizumab's benefit remains uncertain in the neoadjuvant setting and in the advanced treatment of HER2-negative patients. In the first setting, the addition of bevacizumab to chemotherapy increased the pathological complete response (pCR) rate in most clinical trials. However, the current absence of evidence that pCR is a trial-level surrogate for survival requires waiting for long-term results. In the advanced setting, all trials showed a benefit in progression-free survival, but not in overall survival, highlighting an increase of adverse events. The lack of predictors of response represents the main unmet need in which future clinical research will undoubtedly invest.

Differential Activity of Nivolumab, Pembrolizumab and MPDL3280A according to the Tumor Expression of Programmed Death-Ligand-1 (PD-L1): Sensitivity Analysis of Trials in Melanoma, Lung and Genitourinary Cancers.

BACKGROUND: The potential predictive role of programmed death-ligand-1 (PD-L1) expression on tumor cells in the context of solid tumor treated with checkpoint inhibitors targeting the PD-1 pathway represents an issue for clinical research. METHODS: Overall response rate (ORR) was extracted from phase I-III trials investigating nivolumab, pembrolizumab and MPDL3280A for advanced melanoma, non-small cell lung cancer (NSCLC) and genitourinary cancer, and cumulated by adopting a fixed and random-effect model with 95% confidence interval (CI). Interaction test according to tumor PD-L1 was accomplished. A sensitivity analysis according to adopted drug, tumor type, PD-L1 cut-off and treatment line was performed. RESULTS: Twenty trials (1,475 patients) were identified. A significant interaction (p<0.0001) according to tumor PD-L1 expression was found in the overall sample with an ORR of 34.1% (95% CI 27.6-41.3%) in the PD-L1 positive and 19.9% (95% CI 15.4-25.3%) in the PD-L1 negative population. ORR was significantly higher in PD-L1 positive in comparison to PD-L1 negative patients for nivolumab and pembrolizumab, with an absolute difference of 16.4% and 19.5%, respectively. A significant difference in activity of 22.8% and 8.7% according to PD-L1 was found for melanoma and NSCLC, respectively, with no significant difference for genitourinary cancer. CONCLUSION: Overall, the three antibodies provide a significant differential effect in terms of activity according to PD-L1 expression on tumor cells. The predictive value of PD-L1 on tumor cells seems to be more robust for anti-PD-1 antibody (nivolumab and pembrolizumab), and in the context of advanced melanoma and NSCLC.

Moving towards a customized approach for drug development: lessons from clinical trials with immune checkpoint inhibitors in lung cancer.

Lung cancer has recently been discovered to be an immunological targetable disease, on the basis of the exciting results of the randomized trials with immune checkpoint inhibitors. Nevertheless, the survival benefit appears to not be entirely captured by the usual outcome measures, thus requiring a deep reflection about the appropriateness of the traditional statistical methodologies in this context. The intrinsic biological differences existing both in terms of mechanism of action and kinetic between immunotherapy and chemotherapy or targeted therapy, impact on patients' outcome, requiring a global revolution in the way to design clinical studies with the ideal aim to evolve towards trials carefully 'customized' on the basis of the investigational drug, the specific disease and the biological background. The exciting data recently obtained with immune checkpoint inhibitors, offer an ideal context and background to explore the major questions and future perspectives about the development of immunotherapeutic agents. In this regard, the choice of adequate endpoints, the use of modified statistical methods and the potential introduction of predictive biomarkers for immunotherapy clinical trials, will be discuss in this review in order to provide practical and rationale suggestions aimed to improve the existing model for cancer immunotherapy investigation.

EGFR molecular profiling in advanced NSCLC: a prospective phase II study in molecularly/clinically selected patients pretreated with chemotherapy.

INTRODUCTION: The optimal use of epidermal growth factor receptor (EGFR)-related molecular markers to prospectively identify tyrosine kinase inhibitor (TKI)-sensitive patients, particularly after a previous chemotherapy treatment, is currently under debate. METHODS: We designed a prospective phase II study to evaluate the activity of EGFR-TKI in four different patient groups, according to the combination of molecular (EGFR gene mutations, EGFR gene copy number and protein expression, and phosphorylated AKT expression, pAKT) and clinicopathological (histology and smoking habits) factors. Correlations between molecular alterations and clinical outcome were also explored retrospectively for first-line chemotherapy and EGFR-TKI treatment. RESULTS: Patients who had progressed during or after first-line chemotherapy were prospectively assigned to EGFR-TKI treatment as follows: (G1) EGFR mutation (n = 12); (G2) highly polysomic/amplified EGFR (n = 18); (G3) EGFR and/or pAKT positive (n = 41); (G4) adenocarcinoma/bronchoalveolar carcinoma and no smoking history (n = 15). G1 and G4 had the best and second-best overall response rate (25% and 20%, respectively), whereas the worst outcome was observed in G2 (ORR, 6%; p = 0.05). Disease control was highest in G1 and G4 (>50%) and lowest in G3 (<20%) (p = 0.02). Patients selected by EGFR mutation or clinical parameters (G1 and G4) also had significantly better progression-free survival and overall survival (p = 0.02 and p = 0.01, respectively). Multivariate analysis confirmed the impact of sex, smoking history, EGFR/KRAS mutation, and pAKT on outcomes and allowed us to derive an efficient predictive model. Histology, EGFR mutations, and pAKT were independent predictors of response to first-line chemotherapy at retrospective analysis, whereas pAKT and human epidermal growth factor receptor 2 expression were the only independent predictors of progression-free survival and overall survival. CONCLUSIONS: Selection of patients based on either EGFR mutation or clinical characteristics seems an effective approach to optimize EGFR-TKI treatment in chemotherapy-pretreated non-small-cell lung cancer patients.

Clinical impact of anti-epidermal growth factor receptor monoclonal antibodies in first-line treatment of metastatic colorectal cancer: meta-analytical estimation and implications for therapeutic strategies.

BACKGROUND: Antiepidermal growth factor receptor (anti-EGFR) monoclonal antibodies (MoAbs) are indicated for the treatment of metastatic colorectal cancer patients, but some scientific issues concerning their efficacy are currently unsolved. METHODS: A literature-based meta-analysis was conducted. Hazard ratios (HRs) were extracted from randomized trials for progression-free survival (PFS) and overall survival (OS); the event-based risk ratio was derived for response. Sensitivity analyses to look for interactions according to KRAS status and chemotherapy association regimens were performed. RESULTS: Eight trials (6609 patients) were identified. A significant interaction according to KRAS status was found for PFS (wild type vs mutant, P = .001) and response rate (wild type vs mutant, P < .0001). The addition of an anti-EGFR MoAb to first-line chemotherapy increased PFS in the KRAS wild-type population (HR, 0.91; 95% confidence interval [CI], 0.84-0.99; P = .03), and had a detrimental effect in the KRAS mutant population (HR, 1.13; 95% CI, 1.03-1.25; P = .013). A significant increase in the probability of achieving a response was evident in KRAS wild-type patients (relative risk, 1.17; 95% CI, 1.04-1.33; P = .011). In this population, the interaction in response rate according to adopted chemotherapy favored irinotecan-containing regimens (P = .01), and at meta-regression analysis the relative increase in response rate was significantly related to PFS (P = .00001) and OS (P = .00193) benefit. CONCLUSIONS: The addition of an anti-EGFR MoAb to first-line chemotherapy produces a clear benefit in response rate. This advantage is restricted to KRAS wild-type patients and translates into a small benefit in PFS. At present, irinotecan-based backbone chemotherapy could be a preferable option. The correlation between activity and survival parameters corroborates the hypothesis that anti-EGFR MoAbs might be more suitable for patients needing tumoral shrinkage.

Emerging pathways and future targets for the molecular therapy of pancreatic cancer.

INTRODUCTION: Pancreatic cancer treatment remains a challenge for clinicians and researchers. Despite undisputable advances in the comprehension of the molecular mechanisms underlying cancer development and progression, early disease detection and clinical management of patients has made little, if any, progress in the past 20 years. Clinical development of targeted agents directed against validated pathways, such as the EGF/EGF receptor axis, the mutant KRAS protein, MMPs, and VEGF-mediated angiogenesis, alone or in combination with gemcitabine-based standard chemotherapy, has been disappointing. AREAS COVERED: This review explores the preclinical rationale for clinical approaches aimed at targeting the TGF-ß, IGF, Hedgehog, Notch and NF-κB signaling pathways, to develop innovative therapeutic strategies for pancreatic cancer. EXPERT OPINION: Although some of the already clinically explored approaches (particularly EGFR and KRAS targeting) deserve further clinical consideration, by employing more innovative and creative clinical trial designs than the gemcitabine-targeted agent paradigm that has thus far invariably failed, the targeting of emerging and relatively unexplored signaling pathways holds great promise to increase our understanding of the complex molecular biology and to advance the clinical management of pancreatic cancer.

Magnitude of risks and benefits of the addition of bevacizumab to chemotherapy for advanced breast cancer patients: Meta-regression analysis of randomized trials.

BACKGROUND: Although the addition of bevacizumab significantly improves the efficacy of chemotherapy for advanced breast cancer, regulatory concerns still exist with regard to the magnitude of the benefits and the overall safety profile. METHODS: A literature-based meta-analysis to quantify the magnitude of benefit and safety of adding bevacizumab to chemotherapy for advanced breast cancer patients was conducted. Meta-regression and sensitivity analyses were also performed to identify additional predictors of outcome and to assess the influence of trial design. RESULTS: Five trials (3,841 patients) were gathered. A significant interaction according to treatment line was found for progression-free survival (PFS, p = 0.027); PFS was significantly improved for 1(st) line (Hazard Ratio, HR 0.68, p < 0.0001), with a 1-yr absolute difference (AD) of 8.4% (number needed to treat, NNT 12). A non-significant trend was found in overall survival (OS), and in PFS for 2(nd) line. Responses were improved with the addition of bevacizumab, without interaction between 1(st) line (Relative Risk, RR 1.46, p < 0.0001) and 2(nd) line (RR 1.58, p = 0.05). The most important toxicity was hypertension, accounting for a significant AD of 4.5% against bevacizumab (number needed to harm, NNH 22). Other significant, although less clinically meaningful, adverse events were proteinuria, neurotoxicity, febrile neutropenia, and bleeding. At the meta-regression analysis for 1(st)-line, more than 3 metastatic sites (p = 0.032), no adjuvant chemotherapy (p = 0.00013), negative hormonal receptor status (p = 0.009), and prior anthracyclines-exposure (p = 0.019), did significantly affect PFS. CONCLUSIONS: Although with heterogeneity, the addition of bevacizumab to 1st-line chemotherapy significantly improves PFS, and overall activity. Hypertension should be weighted with the overall benefit on the individual basis.

Impact of hormonal treatment duration in combination with radiotherapy for locally advanced prostate cancer: meta-analysis of randomized trials.

BACKGROUND: Hormone therapy plus radiotherapy significantly decreases recurrences and mortality of patients affected by locally advanced prostate cancer. In order to determine if difference exists according to the hormonal treatment duration, a literature-based meta-analysis was performed. METHODS: Relative risks (RR) were derived through a random-effect model. Differences in primary (biochemical failure, BF; cancer-specific survival, CSS), and secondary outcomes (overall survival, OS; local or distant recurrence, LR/DM) were explored. Absolute differences (AD) and the number needed to treat (NNT) were calculated. Heterogeneity, a meta-regression for clinic-pathological predictors and a correlation test for surrogates were conducted. RESULTS: Five trials (3,424 patients) were included. Patient population ranged from 267 to 1,521 patients. The longer hormonal treatment significantly improves BF (with significant heterogeneity) with an absolute benefit of 10.1%, and a non significant trend in CSS. With regard to secondary end-points, the longer hormonal treatment significantly decrease both the LR and the DM with an absolute difference of 11.7% and 11.5%. Any significant difference in OS was observed. None of the three identified clinico-pathological predictors (median PSA, range 9.5-20.35, Gleason score 7-10, 27-55% patients/trial, and T3-4, 13-77% patients/trial), did significantly affect outcomes. At the meta-regression analysis a significant correlation between the overall treatment benefit in BF, CSS, OS, LR and DM, and the length of the treatment was found (p ≤ 0.03). CONCLUSIONS: Although with significant heterogeneity (reflecting different patient' risk stratifications), a longer hormonal treatment duration significantly decreases biochemical, local and distant recurrences, with a trend for longer cancer specific survival.

Early recurrence risk: aromatase inhibitors versus tamoxifen.

Aromatase inhibitors (AIs) are becoming the hormonal treatment of choice for postmenopausal women with early breast cancer. Large, well-controlled clinical studies have established the efficacy and safety of initial adjuvant therapy with letrozole or anastrozole versus the previous standard of 5 years of adjuvant tamoxifen and support using an AI (exemestane, anastrozole or letrozole) following tamoxifen for 2-3 years (early 'switch' treatment) or 5 years (extended adjuvant treatment). Reducing recurrence risk is a primary goal of adjuvant hormonal therapy. There is an early peak of recurrences 2 years after surgery; most are distant metastases rather than local or regional events. Therefore, treatment strategies such as initial therapy with AIs, which reduce early distant recurrence events, can be expected to improve long-term survival outcomes. Switching to an AI following 2-3 years of initial adjuvant tamoxifen is an effective option for patients unable to begin treatment with an AI.

Magnitude of benefit of the addition of bevacizumab to first-line chemotherapy for metastatic colorectal cancer: meta-analysis of randomized clinical trials.

BACKGROUND: Although the addition of bevacizumab to 1st line chemotherapy provides a significant survival benefit for advanced colorectal cancer, the magnitudes of both advantages and toxicities have not been extensively investigated. METHODS: A literature-based meta-analysis was conducted; Hazard Ratios were extracted from randomized trials for primary end-points (Progression Free Survival, PFS, Overall Survival OS). The log of event-based risk ratio were derived for secondary endpoints (objective/partial response rate, ORR/PR; severe hypertension, bleeding and proteinuria). Absolute differences and the number needed to treat/harm (NNT/NNH) were calculated. A meta-regression analysis with clinical predictors and a sensitivity analysis according to the trial phase-design were conducted as well. RESULTS: Five trials (2,728 pts) were selected. The addition of bevacizumab to 1st line chemotherapy significantly increased both PFS (although with significant heterogeneity) and OS over exclusive chemotherapy by 17.1% and 8.6% (NNT 6 and 12), regardless of the study setting (non significant interaction between phase II and III). The chance to improve PR was significantly increased by 6.5% (NNT 15), with a trend for ORR. The risk of hypertension was significantly increased by 6.2% (NNH 16). According to the meta-regression analysis, female gender and rectal primary site were significant predictors for PFS benefit. CONCLUSIONS: Notwithstanding all the concerns related to costs and the significant HTN risk, the significant outcome improvement provided by bevacizumab in first-line treatment for unselected advanced colorectal cancer patients, should be considered when choosing the appropriate up-front therapy.

Does hormone treatment added to radiotherapy improve outcome in locally advanced prostate cancer?: meta-analysis of randomized trials.

BACKGROUND: To quantify the magnitude of benefit of the addition of hormone treatment (HT) to exclusive radiotherapy for locally advanced prostate cancer, a literature-based meta-analysis was conducted. METHODS: Event-based relative risks (RR) with 95% confidence intervals (CIs) were derived through a random-effect model. Differences in primary (biochemical failure and clinical progression-free survival) and secondary outcomes (cancer-specific survival, overall survival [OS], recurrence patterns, and toxicity) were explored. Absolute differences and numbers of patients needed to treat (NNT) were calculated. A heterogeneity test, a metaregression analysis with clinical predictors of outcome, and a correlation analysis for surrogate endpoints were also performed. RESULTS: Seven trials (4387 patients) were gathered. Hormone suppression significantly decreased both biochemical failure (RR, 0.76; 95% CI, 0.70-0.82; P<.0001) and clinical progression-free survival (RR, 0.81; 95% CI 0.71-0.93; P=.002), with absolute differences of 10% and 7.7%, respectively, which translates into 10 and 13 NNT. cancer-specific survival (RR, 0.76; 95% CI, 0.69-0.83; P<.0001) and OS (RR, 0.86; 95% CI, 0.80-0.93; P<.0001) were also significantly improved by the addition of HT, without significant heterogeneity, with absolute differences of 5.5% and 4.9%, respectively, which translates into 18 and 20 NNT. Local and distant relapse were significantly decreased by HT, by 36% and 28%, respectively, and no significant differences in toxicity were found. Primary and secondary efficacy outcomes were significantly correlated. CONCLUSIONS: Hormone suppression plus radiotherapy significantly decreases recurrence and mortality of patients with localized prostate cancer, without affecting toxicity.

Targeting targeted agents: open issues for clinical trial design.

Molecularly targeted agents for the treatment of solid tumors had entered the market in the last 5 years, with a great impact upon both the scientific community and the society. Many randomized phase III trials conducted in recent years with new targeted agents, despite previous data coming from preclinical research and from phase II trials were often promising, have produced disappointingly negative results. Some other trials have actually met their primary endpoint, demonstrating a statistically significant result favouring the experimental treatment. Unfortunately, with a few relevant exceptions, this advantage is often small, if not negligible, in absolute terms. The difference between statistical significance and clinical relevance should always be considered when translating clinical trials' results in the practice. The reason why this 'revolution' did not significantly impact on cancer treatment to displace chemotherapy from the patient' bedside is in part due to complicated, and in many cases, unknown, mechanisms of action of such drugs; indeed, the traditional way the clinical investigators were used to test the efficacy of 'older' chemotherapeutics, has become 'out of date' from the methodological perspective. As these drugs should be theoretically tailored upon featured bio-markers expressed by the patients, the clinical trial design should follow new rules based upon stronger hypotheses than those developed so far. Indeed, the early phases of basic and clinical drug development are crucial in the correct process which is able to correctly identify the target (when present). Targeted trial designs can result in easier studies, with less, better selected, and supported by stronger proofs of response evidences, patients, in order to not waste time and resources.

A novel clinical prognostic score incorporating the number of resected lymph-nodes to predict recurrence and survival in non-small-cell lung cancer.

BACKGROUND: The number of resected lymph-nodes (#RNs) has proven prognostic in breast and colorectal cancer. Here we evaluated its prognostic impact in a series of resected NSCLC patients. METHODS: A panel of established prognostic factors plus (1) #RNs or (2) the ratio between the number of metastatic nodes and #RNs (NR) were correlated to overall- (OS), cancer-specific- (CSS), and disease-free-survival (DFS), using the Cox-model. Risk-classes according to hazard ratios (HR) were generated. Internal and external validation was accomplished. RESULTS: A dataset of 415 resected NSCLC patients was retrieved. At multivariate analysis, #RNs and NR were independent factor for longer OS, CSS and DFS (p<0.0001). Patients with a #RNs>10 (identified optimal cut-off) had a statistically significant OS (p=0.02) and DFS (p=0.0005) benefit. In node-positive patients, a NR<9% significantly correlated with better outcome. Stratification into High-, Medium-, and Low-Risk classes, based on High- (HRFs: stage, N-status, age, #RNs) and Intermediate-Risk Factors (IRFs: sex, grading, histology), efficiently predicted outcomes (p<0.0001). The risk class model performance was externally validated in and independent dataset of 297 patients. CONCLUSIONS: These results contribute to complete the panel of prognostic factors for resected NSCLC. A prospective larger validation and comparison with molecular prognostic tools is warranted.

Trastuzumab plus weekly epirubicin and paclitaxel for locally advanced and metastatic breast cancer: preliminary results of a feasibility-phase II study aimed at cardiotoxicity.

A feasibility-phase II study was conducted to assess the cardiotoxicity of weekly trastuzumab, epirubicin, and paclitaxel in patients with human epidermal growth factor receptor-2-positive metastatic breast cancer. Untreated patients with human epidermal growth factor receptor-2-positive advanced breast cancer received trastuzumab (day 1), and epirubicin (25 mg/m2) and paclitaxel (80 mg/m2) (day 2) on a weekly basis. The rate of patients with left-ventricular ejection fraction (L-VEF) reduction greater than 10% after 12 weeks was the primary end point. According to a two-stage model, an initial step with 15 patients was required; after 11 patients without toxicity, a second step with 21 patients was planned. After 255 courses in 15 patients (median treatment weeks: 18), the relative dose intensity was 94.7%. At 12 weeks, three patients (20%) displayed a L-VEF reduction greater than 10%, six and six (40%) patients showed a L-VEF reduction < or =10% or no change, respectively. Baseline, -12 weeks, and -24 weeks median L-VEF was 69% (range 61-77), 65% (range 60-76), and 65% (range 55-73), respectively. No EKG/cardiac signs were present. Thirteen patients had grade 3 alopecia and two patients had grade 3 asthenia, in the absence of severe hematological toxicity. Objective responses were observed in 11 patients (73.3%, 95% confidence interval 51.0-95.7), with 10 partial. The weekly administration of trastuzumab-epirubicin-paclitaxel is extremely tolerable, also with regard to L-VEF reduction. These results allowed entrance to the second step of the study.

Magnitude of benefit of adjuvant chemotherapy for non-small cell lung cancer: meta-analysis of randomized clinical trials.

Several randomized trials investigating the benefit of adjuvant chemotherapy after surgery in non-small cell lung cancer (NSCLC) have provided conflicting results. With over 7000 patients included, we analyzed results of 13 reports over the past 10 years in which patients received either platinum-containing chemotherapy or not. The major endpoint was to assess the magnitude of the benefit of adjuvant chemotherapy in terms of the absolute benefit. All phase III randomized trials and meta-analyses published as peer-reviewed papers or as abstracts from 1994 to 2007 were eligible. A literature-based meta-analysis was performed; event-based overall- and disease-free survival (OS/DFS) and Relative Risks (RRs) with 95% confidence intervals (CIs) were derived. Magnitudes of benefit were evaluated with: absolute benefit and the number of patients treated for one patient to benefit. Seven sub-populations were examined. Combined effect estimation was computed with fixed- and random-effect models; a heterogeneity test was also applied. Twelve trials plus an individual patient meta-analysis (7334 patients) were gathered; the trials were designed to determine if cisplatin- or carboplatin-based chemotherapy improves survival over surgery. When data were pooled and plotted, significant differences in favor of chemotherapy were seen in OS in all seven sub-population, with a relative benefit of 7-12% and an absolute benefit ranging from 2.5% to 4.1%. A more significant trend for chemotherapy was found in DFS. No significant heterogeneity was observed for all outcomes and sub-populations. The absolute benefit of adjuvant chemotherapy remains essentially the same regardless of how data are screened. While significant differences are clearly found in this analysis, the small magnitude of benefit seen with this large population, especially when considering the number of patients needed for one to benefit, raises important issues when weighing risks and benefits of treatment for individual patients.

Trastuzumab cardiotoxicity: biological hypotheses and clinical open issues.

BACKGROUND: Trastuzumab has significantly improved the prognosis of breast cancer patients overexpressing the human epidermal growth factor receptor 2 (HER2). This result has been achieved in all disease settings, by increasing overall survival in early stage and advanced disease and by increasing pathological complete responses in neoadjuvant disease. OBJECTIVE: Although the greatest impact of this monoclonal antibody has been seen in the adjuvant setting, by increasing disease-free survival and overall survival rates an increased rate of both symptomatic and non-symptomatic cardiac toxicity has also been observed. METHODS: In the following review, the different mechanisms of trastuzumab cardiac toxicity are described and, in addition, the clinical data coming from both trials and meta-analyses is discussed. RESULTS: While there is strong evidence for the incidence of trastuzumab-related cardiac toxicity, there is still little known on the exact pathogenesis of this toxicity. Interestingly, both experimental and clinical data suggest that trastuzumab may sensitize cardiomyocytes to injuries and stress from administration of anthracyclines. This has led to a proposed novel mechanism of cardiotoxicity that appears to be quite different from the anthracycline-associated cardiotoxicity. Trastuzumab does not seem to cause any overt ultrastructural abnormality; it does, however, lead to myocardial dysfunction. CONCLUSION: Most of the proposed hypotheses seems to be related to the activity of trastuzumab in interfering with the ERBB-2 receptor. Indeed, data from clinical trials in the adjuvant setting report increased cardiac toxicity in those patients who previously received anthracyclines.

Taxanes as primary chemotherapy for early breast cancer: meta-analysis of randomized trials.

BACKGROUND: In patients with locally advanced and operable breast cancer, neoadjuvant chemotherapy has been demonstrated to increase the chance of breast-conserving surgery (BCS) when compared with adjuvant treatment; moreover, patients who achieve a pathologic complete response (pCR) have a better outcome. A literature-based meta-analysis of randomized clinical trials (RCTs) to 'weigh' how much taxanes add to anthracyclines as primary treatment over standard chemotherapy was conducted. METHODS: Event-based relative risk ratios (RR) with 95% confidence intervals (95% CI) were derived through both a fixed-effect and a random-effect model; a heterogeneity test was applied as well. Absolute differences (AD) and the number (of patients) needed to treat (NNT) were calculated. Primary endpoints were: 1) pCR rate and 2) BCS rate. A sensitivity analysis of 3 subgroups according to taxane strategies was conducted. RESULTS: Data for primary endpoints were available for 7 RCTs (2455 patients). The rate of BCS was significantly higher for patients receiving taxanes, with an AD of 3.4% (P = .012), which translates into 29 patients NNT, without significant heterogeneity. The rate of pCR was higher for patients receiving taxanes, although not statistically significant. In the sensitivity analysis, patients receiving taxanes as a sequential schedule had a significant higher probability to achieve pCR, with an AD of 2.4% (P = .013), which translates into 41 patients NNT, without significant heterogeneity. Patients receiving taxanes as a concomitant schedule had a significantly higher probability to achieve BCS, with an AD of 5.3% (P = .027), which translates into 19 patients NNT, without significant heterogeneity. The complete response rate was significantly higher in the taxane arms, regardless of the adopted strategy, with an AD ranging from 6.7% to 15.5%. CONCLUSIONS: The combination of taxanes and anthracyclines as neoadjuvant chemotherapy for early breast cancer improves the chance of achieving both higher BCS and pCR rates.

Cardiotoxicity and incidence of brain metastases after adjuvant trastuzumab for early breast cancer: the dark side of the moon? A meta-analysis of the randomized trials.

BACKGROUND: In five randomized clinical trials (RCTs), adjuvant trastuzumab (T) for early stage breast cancer with human epidermal growth-factor receptor-2 over-expression/gene-amplification has shown to decrease the risk of both recurrence and death. The issue regarding the long-term safety profile of such drug is still open; in particular, questions remain about long-term cardiotoxicity, and specific patterns of relapse such as brain metastases (BM). In order to quantify the magnitude of these two risks, and then balance those with the survival outcome, a literature-based meta-analysis was performed. METHODS: All phase III trials were considered eligible. A literature-based meta-analysis was accomplished, and event-based relative risk ratios with 95% confidence interval were derived. A fixed- and a random-effect model according to the inverse variance and the Mantel-Haenzel method were applied. Heterogeneity test was applied as well. Absolute differences (AD) and the Number of patients Needed to Treat or to Harm (NNT/NNH) were calculated. Safety end-points were: (1) Chronic Heart Failure (CHF) grade III-IV rate, (2) Significant reduction of left-ventricular-ejection-fraction (L-FEV) rate and (3) BM rate. In order to quantify the magnitude of the significant benefit already found in the original RCTs, Efficacy end-points were: (1) disease-free survival (DFS) and (2) overall survival (OS). RESULTS: Five RCTs were gathered (11,187 patients); at an average 2-years follow-up, all data was available for the safety and efficacy end-points, while three RCTs reported results for BM analysis (6,738 patients). When considering RCTs with trastuzumab administered for 1 year, a significant increased risk of grade III-IV Congestive Heart Failure (CHF) was found in the T-arm, with an AD of 1.61% (p < 0.00001), which translates into 62 treated patients required to harm one (NNH). When considering the asymptomatic L-FEV reduction, a significant increased risk of grade significant L-FEV reduction was found in the T-arm, although significantly heterogeneous, with an AD of 7.20% (p < 0.00001), which translates into 14 NNH. The incidence of BM was significantly higher in the T-arm, without significant heterogeneity, with an AD of 0.62 (p = 0.033), which translates into 161 NNH. The DFS, DDFS, and OS were significantly better in the T-arm, with an AD of 6.00, 4.80 and 1.96%, which translates into 16, 21 and 51 NNT, respectively. CONCLUSIONS: The overall outcome results show that trastuzumab is one of the most important discoveries in oncology. Nevertheless, the biological activity of trastuzumab needs to be investigated more extensively to explore both long-term safety and specific relapse patterns.