Differences in the availability of new anti-cancer drugs for Italian patients treated in different regions. Results of analysis conducted by the Italian Society Of Medical Oncology (AIOM).

AIMS AND BACKGROUND: Italy is divided into 20 regions. As a consequence of local autonomy, following marketing authorization by the Italian Medicines Agency, each drug for hospital use is not immediately available, because its approval needs to undergo further steps that can be different among regions. The Italian Society of Medical Oncology conducted the present study to describe the impact of the existence of sub-national pharmaceutical formularies on the disparity of access to new anti-cancer drugs among patients treated in different Italian regions. METHODS: The availability of 8 new anti-cancer drugs at a regional level and the coherence of regional authorizations compared with national authorizations approved by the Italian Medicines Agency were analyzed as of April 2009. RESULTS: Fourteen regions and autonomous province of Trento have a regional pharmaceutical formulary. In most cases, the regional pharmaceutical formularies include the eight analyzed drugs, with therapeutic indications coherent with national marketing authorization indications. Five drugs (bevacizumab, trastuzumab, rituximab, erlotinib, sunitinib) were included in all the existing regional pharmaceutical formularies, without restrictions, whereas three drugs (cetuximab, sorafenib, pemetrexed) were found to have restrictions in some regions. CONCLUSIONS: The presence of multiple hierarchical levels of drug evaluation creates a potential element of disparity in the access to pharmacological therapies for Italian citizens.

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 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.

Peripheral neurotoxicity of weekly paclitaxel chemotherapy: a schedule or a dose issue?

PURPOSE: The rationale for intensification strategies is that more frequent exposure to chemotherapeutics could enhance antitumor activity. Several trials investigated weekly paclitaxel administration, but there are no clear data concerning peripheral neurotoxicity. The aim of this study was to assess the incidence of peripheral neurotoxicity in patients affected by advanced breast cancer treated with weekly paclitaxel. PATIENTS AND METHODS: Neurotoxicity was assessed with neurologic and neurophysiologic evaluation before treatment and after 12 weeks and 24 weeks. A total neurotoxicity score was assigned to each patient on the basis of neurophysiologic and neuropathic signs and symptom changes. Seventeen patients entered the study. RESULTS: After 12 weeks of treatment, 71% showed moderate clinical and/or neurophysiologic signs of neurotoxicity; after 24 weeks, the incidence of neurotoxicity increased to 96%. Sural amplitude at the 24-weeks examination significantly decreased from basal mean value (13.5 microv, standard deviation [SD] 6 microv vs. 7 microv, SD 5.9 microv, respectively; P = 0.01), whereas median sensory amplitude decreased after 24 weeks from 10.3 microv, SD 6.2 microv to 4.9 microv, SD 3.8 microv (P = 0.001). In a subset of 11 patients, we obtained a follow-up examination after 6 months from the end of treatment. In all patients, examined signs and symptoms of neurotoxicity improved with recovery of subjective neuropathic symptoms and neurophysiologic findings. CONCLUSION: Our results demonstrate, in a little population of patients evaluated with a comprehensive neurologic assessment, that weekly paclitaxel is related to a very high incidence of peripheral neurotoxicity. Follow-up data obtained in a subset of patients indicate that peripheral neurotoxicity is reversible.

Impact of five prophylactic filgrastim schedules on hematologic toxicity in early breast cancer patients treated with epirubicin and cyclophosphamide.

PURPOSE: To evaluate the comparative efficacy of varying intensity schedules of recombinant human granulocyte colony-stimulating factor (G-CSF; filgrastim) support in preventing febrile neutropenia in early breast cancer patients treated with relatively high-dose epirubicin plus cyclophosphamide (EC). PATIENTS AND METHODS: From October 1991 to April 1994, 506 stage I and II breast cancer patients were randomly assigned to receive, in a factorial 2 x 2 design, epirubicin 120 mg/m2 and cyclophosphamide 600 mg/m2 intravenously on day 1 every 21 days for 4 cycles +/- lonidamine +/- G-CSF. The following five consecutive G-CSF schedules were tested every 100 randomly assigned patients: (1) 480 microg/d subcutaneously days 8 to 14; (2) 480 microg/d days 8, 10, 12, and 14; (3) 300 microg/d days 8 to 14; (4) 300 microg/d days 8, 10, 12, and 14; and (5) 300 microg/d days 8 and 12. RESULTS: All of the G-CSF schedules covered the neutrophil nadir time. Schedule 5 was equivalent to the daily schedules (schedules 1 and 3) and to the alternate day schedules (schedules 2 and 4) with respect to incidence of grade 3 and 4 neutropenia (P = .79 and P = .89, respectively), rate of fever episodes (P = .84 and P = .77, respectively), incidence of neutropenic fever (P = .74 and P = .56, respectively), need of antibiotics (P = .77 and P = .88, respectively), and percentage of delayed cycles (P = .43 and P = .42, respectively). G-CSF had no significant impact on the delivered dose-intensity compared with the non-G-CSF arms. CONCLUSION: In the adjuvant setting, the frequency of prophylactic G-CSF administration during EC could be curtailed to only two administrations (days 8 and 12) without altering outcome. This nonrandomized trial design provides support for evaluating alternative, less intense G-CSF schedules for women with early breast cancer.

Early switch with aromatase inhibitors as adjuvant hormonal therapy for postmenopausal breast cancer: pooled-analysis of 8794 patients.

BACKGROUND: The magnitude of the survival benefit of aromatase inhibitors (AIs) after 2-3 years of tamoxifen as adjuvant hormonal therapy for early breast cancer is still unclear. We performed a literature-based meta-analysis, to look how much advantages adjuvant the "early switch" strategy add over standard tamoxifen for 5 years. METHODS: A pooled analysis of all phase-III trials was accomplished, and event-based relative risk ratios (RR) with 95% confidence interval (CI) were derived. Significant differences in primary outcome (EFS and RFS, event- and relapse-free survival), and secondary outcomes (OS, overall survival, deaths without progression, other cancers and toxicities), were explored. Magnitude outcome measures were absolute benefits and number of patients needed to treat. Heterogeneity test was applied as well. RESULTS: Five trials (8794 patients) were gathered. The risk of any event is reduced with AIs of 23%, with an absolute benefit of 3.8% (RR 0.67, 95% CI 0.59, 0.76). Again, RFS (RR 0.68, 95% CI 0.59, 0.79) or both LRFS and DFRS, were significantly improved with AIs. OS was significantly prolonged with AIs, with an absolute benefit of 1.2% (RR 0.76, 95% CI 0.62, 0.93), without significant heterogeneity. Bone fractures were significantly higher in patients receiving AIs (RR 1.50, 95% CI 1.12, 2.02), and endometrial cancer in patients who continued to receive tamoxifen (RR 0.32, 95% CI 0.13, 0.77), without significant heterogeneity. CONCLUSIONS: The early switch strategy improves survival over standard tamoxifen for 5 years, with a different toxicity profile. The lack of significant heterogeneity in the analysis underscores the homogenous effect across all trials.

Weekly docetaxel as second line chemotherapy for advanced non-small-cell lung cancer: meta-analysis of randomized trials.

BACKGROUND: Docetaxel has to be considered as the reference control arm for second line chemotherapy for advanced NSCLC. Weekly docetaxel has been compared to standard 3-weekly schedule in a randomized fashion to determine if such schedule improves survival and quality of life. We performed a literature-based meta-analysis of all randomized clinical trials (RCTs) comparing weekly over 3-weekly docetaxel in advanced NSCLC. METHODS: All randomized trials were considered eligible. A literature-based meta-analysis was accomplished, and event-based relative risk ratios (RR) with 95% confidence interval (CI) were derived. A fixed- and a random-effect model according to the inverse variance and the Mantel-Haenszel method were applied. Heterogeneity test was applied as well. RESULTS: We found six RCTs (three phase III, two phase II, 1018 patients), in which data for overall survival (OS), overall response rate (ORR) and grade 3-4 (G3-4) WHO neutropenia were available. When considering only phase III RCTs, OS did not significantly differ between the two arms (RR 1.01, 95% CI 0.76, 1.42, p=0.785) with no significant heterogeneity (p=0.42). Regarding activity, no significant differences in favour of weekly docetaxel were found, although a trend for 3-weekly schedule was observed (RR 0.81, 95% CI 0.47, 1.40, p=0.485), with no significant heterogeneity (p=0.27). No differences were found in the overall population also considering the phase II trials. Regarding G3-4 neutropenia, a significant homogenous advantage in favour of weekly docetaxel was found, with an absolute benefit of 15-19%. CONCLUSIONS: Although considering all drawbacks related to literature-based meta-analyses, weekly docetaxel seems not to improve survival when compared to 3-weekly docetaxel. The significant benefit in grade 3-4 neutropenia seems to suggest this approach in patients with NSCLC pretreated for advanced disease. The quality of life of both schedules needs to be evaluated in an individual patient data meta-analysis.

Randomised phase II study of standard versus chronomodulated CPT-11 plus chronomodulated 5-fluorouracil and folinic acid in advanced colorectal cancer patients.

In this study, a randomised phase II trial explored the effects of 6-h chronomodulated CPT-11 infusion in advanced colorectal cancer patients. Sixty-eight pre-treated patients were randomly assigned to CPT-11 administered at 180 mg/m2 on day 1, by 1-h infusion (Arm A) or 6-h sinusoidal infusion with peak timing at 5:00 a.m. (Arm B). All patients also received chronomodulated folinic acid/5-fluorouracil (FA/5-FU). Patients in Arm B obtained a 25.7% response rate for 7.0 months duration, a progression-free survival for 8.0 months and a median survival of 28 months. The same data in Arm A were 18.2%, 4.5, 6.0 and 18 months, respectively. No differences in drugs dose-intensity or increased toxicity with prolonged chronomodulated infusion were detected. Major grade 3-4 toxicity was diarrhoea: 10 patients in Arm A and 13 in Arm B. In conclusion, this study has shown that chronomodulated infusion of CPT-11 and FA/5-FU is safe, active and can be integrated with oxaliplatin (EORTC 05011) for the treatment of advanced colorectal cancer.

Is recurrent venous thromboembolism after therapy reduced by low-molecular-weight heparin compared with oral anticoagulants?

PURPOSES: To evaluate whether the incidence of recurrent venous thromboembolism (VTE) events after therapy differs for patients treated with long-term low-molecular-weight heparin (LMWH) or oral anticoagulant therapy (OAT). METHODS: All randomized studies were searched through computerized queries of MEDLINE, the Cochrane Controlled Trials Register, the American Society of Hematology abstract database, and the American Society of Clinical Oncology abstract database. RESULTS: Eleven studies including 2,907 patients were identified. Seven studies evaluated a period of 3 to 9 months after cessation of the allocated treatment: 5.4% of patients in the LMWH group vs 4% in the arm allocated to OAT had an episode of recurrent symptomatic VTE. Combined analysis showed a nonsignificant trend in lowering recurrent symptomatic VTE in favor of OAT (relative risk [RR], 1.29; 95% confidence interval [CI], 0.82 to 2.02; p = 0.27). By contrast, during active treatment, a statistically significant reduction of the risk of recurrent symptomatic VTE in favor of LMWH over OAT was registered (RR, 0.63; 95% CI, 0.47 to 0.83; p = 0.001). Regarding cancer patients only, 37 of 569 patients (6.5%) in the LMWH group had recurrent symptomatic VTE vs 69 of 546 patients (12.6%) in the OAT group, with a statistically significant reduction of the risk of recurrent symptomatic VTE in favor of LMWH (RR, 0.52; 95% CI, 0.35 to 0.76; p = 0.001). CONCLUSIONS: Despite the significant reduction of the risk of recurrent symptomatic VTE in favor of LMWH over OAT during treatment, patients treated with long-term LMWH do not seem to have more frequently recurrent VTE events compared with OAT after cessation of therapy. The significant difference favoring LMWH over OAT among all patients receiving treatment comes mostly from studies enrolling cancer patients.

A phase II trial of a biweekly combination of paclitaxel and gemcitabine in metastatic breast cancer.

BACKGROUND: Many emerging new drugs have recently been trialled for treatment of early and advanced breast cancer. Among these new agents paclitaxel and gemcitabine play a crucial role, mostly in patients with relapsed and metastatic disease after failure of chemotherapy with antracyclines. METHODS: A phase II study was started in order to evaluate the activity and toxicity of a combination of paclitaxel and gemcitabine in a biweekly schedule on metastatic breast cancer patients previously treated with antracyclines. RESULTS: Twenty-five patients received paclitaxel (150 mg/mq) by 3-hours infusion, followed by gemcitabine (2000 mg/mq) given as a 60 min i.v. infusion (day 1-14) for a maximum of eight cycles. In all patients treatment was evaluated for toxicity and efficacy; four patients (16%) achieved a complete response, 12 (48%) a partial response giving an overall objective response rate of 64%. Stable disease was documented in 5 patients (20%) and progressive disease occurred in 4 patients (16%). CONCLUSION: The schedule of treatment was safe and tolerable from a haematological and non-haematological point of view. These data confirm that the combination of gemcitabine and paclitaxel on a biweekly basis is an effective and well-tolerated regimen in breast cancer patients with prior therapeutic exposure to antracyclines.

An integrated psychological strategy for advanced colorectal cancer patients.

BACKGROUND: There is evidence regarding the usefulness of psychosocial intervention to improve health related quality of life (HRQOL) in adult cancer patients. The aim of this report is to describe an integrated approach and to evaluate its feasibility in routine clinical practice in 98 advanced colorectal cancer (ACC) patients during chronomodulated chemotherapy. METHODS: A prospective non-randomised design was developed and applied in a cancer out-patient setting. The intervention consisted of an integrated approach, whereby the psycho-oncologist had an active role in the health care team with the physician and routinely included psychological understanding in the medical treatment program. The psychological evaluation assessed: a) adaptation, awareness, psychopathological disorders through a psychodynamic interview; b) anxiety and depression using the HAD scale; c) subjective perception of care quality through a structured interview and d) HRQOL evaluation assessment with the EORTC QLQ C30. Outcomes data were collected before and after 18 weeks of chemotherapy. RESULTS: After 18 weeks of chemotherapy a significant improvement of adaptation and awareness was observed. The HADs results showed a significant decrease in anxiety when compared to pre-treatment. The structured interview showed a significant increase of patients who positively experienced the impact of medical treatment on HRQOL, anxiety, depression, interpersonal relationships, free-time and who positively experienced the care quality. Indeed, a majority of patients positively experienced the team relationship modality during the whole treatment. All scales on the EORTC questionnaire remained unchanged during the entire treatment. CONCLUSION: Our results suggest that it is feasible to carry out an integrated approach during chemotherapy. These results seem to support the integrated approach as a tool in aiding advanced colorectal cancer patients' ability to cope with their diagnosis and treatment although an appropriately designed study is required to confirm this.

Addition of either lonidamine or granulocyte colony-stimulating factor does not improve survival in early breast cancer patients treated with high-dose epirubicin and cyclophosphamide.

PURPOSE: Lonidamine (LND) can enhance the activity of anthracyclines in patients with metastatic breast cancer. A multicenter, prospective, randomized trial was designed to determine whether the association of LND with high-dose epirubicin plus cyclophosphamide (EC) could improve disease-free survival (DFS) in patients with early breast cancer (BC) compared with EC alone. Granulocyte colony-stimulating factor (G-CSF) was added to maintain the EC dose-intensity. PATIENTS AND METHODS: From October 1991 to April 1994, 506 patients with stage I/II BC were randomly assigned to four groups: (A) epirubicin 120 mg/m2 and cyclophosphamide 600 mg/m2 administered intravenously on day 1 every 21 days for four cycles (124 patients); (B) EC plus LND 450 mg/d administered orally (125 patients); (C) EC plus G-CSF administered subcutaneously (129 patients); (D) EC plus LND plus G-CSF (128 patients). RESULTS: Median follow-up was 55 months. Five-year DFS rate was similar for LND (B+D groups; 69.6%) versus non-LND arms (A+C groups; 70.3%) and G-CSF (C+D groups; 67.2%) versus non-G-CSF arms (A+B groups; 72.9%). Five-year overall survival (OS) was comparable in LND (79.1%) versus non-LND arms (81.3%) and in G-CSF (80.6%) versus non-G-CSF arms (79.6%). DFS and OS distributions in LND and G-CSF arms did not change according to tumor size, node, receptor, and menopausal status. G-CSF dramatically reduced hematologic toxicity without having a significant impact on dose-intensity (98.1% v 95.5% for C+D and A+B groups, respectively). CONCLUSION: EC is active and well tolerated in patients with early breast cancer. The addition of LND or G-CSF does not improve DFS or OS.

Primary chemotherapy with epirubicin and vinorelbine in women with locally advanced breast cancer.

BACKGROUND: To assess the activity and toxicity of primary chemotherapy with epirubicin (60 mg/m2 every other week) and vinorelbine (25 mg/m2, weekly) plus granulocyte colony-stimulating factor (G-CSF) for 12 weeks, in patients with locally advanced breast cancer in a multicenter setting. PATIENTS AND METHODS: Patients with stage IIIA or IIIB breast cancer, not older than 70, were eligible. A two-stage phase II design was applied. Response was assessed clinically, instrumentally and pathologically. RESULTS: Out of 48 enrolled patients, 87.5% received all planned cycles, with a median dose-intensity of 30 mg/m2/week for epirubicin and 23.8 mg/m2/week for vinorelbine. A clinical or instrumental objective response was reached in 42 patients (87.5%, exact 95% CI: 74.7-95.3); significant downstaging was reached in all but one patient; 6 cases had a pathological complete response in the breast, and 2 cases in the lymph nodes too (pathological complete response rate 4.2%, exact 95% CI: 0.5-14.2); a further 2 patients had only microscopic cancer foci at pathological examination of the breast. Radiological tests underestimated the treatment effect on the breast. Toxicity was mild, neutropenia being the most frequent (grade 3-4 in 47% of patients), but never complicated with fever or sepsis. Mild constipation (< or =grade 2) occurred in 35% of patients. Moderate to severe asthenia occurred in 12% of 6 patients. No cardiac toxicity was reported. At 3 years, disease-free survival was 68% and overall survival 81%. CONCLUSION: Primary chemotherapy with epirubicin every other week, weekly vinorelbine and G-CSF support is highly active and well tolerated in patients with locally advanced breast cancer.

High-dose chronomodulated infusion of 5-fluorouracil (5-FU) and folinic acid (FA) (FF5-16) in advanced colorectal cancer patients.

PURPOSE: The best way to deliver infusional 5-fluorouracil (5-FU) and folinic acid (FA) has yet to be determined. The aim of this prospective phase II trial was to verify the tolerability, activity and efficacy of chronomodulated 5-FU-FA (FF(5-16)) every 3 weeks in 48 untreated patients (group A), and 28 pretreated and four non-measurable, advanced colorectal cancer (ACC) patients (group B). METHODS: The sinusoidal delivery of both drugs started at 10.00 p.m. and ended at 10.00 a.m., with peak flow at 4.00 a.m. for 5 consecutive days. The initial 5-FU dose was 900 mg/m(2)/day with intra-patient dose increase at 1,000 and 1,100 mg/m(2)/day, at the second and third course, respectively; FA was injected at a fixed dose of 150 mg/m(2)/day (Garufi et al.1997). RESULTS: Neither death from toxicity nor hematological toxicities were encountered. Maximal toxicity consisted of Grade 3 oral mucositis in 41% of patients, in only 8% of 535 courses. It was possible to achieve objective responses in 31% of untreated patients, with a progression free survival (PFS) of 7 months, median survival of 14 months and a 2-year survival rate of 28%. Similar results for PFS and survival were obtained in pretreated patients as well. Univariate analysis and multivariate analysis showed that response was related to the occurrence of mucositis and diarrhea ( p=0.03 and p=0.0007) and to performance status (PS) ( p=0.01). Quality of life, measured with the EORTC QLQ-C30+3 questionnaire, was unaffected by treatment and was better in patients with good PS and responsiveness. CONCLUSIONS: In this chronomodulated FF(5-16) phase II study, the probability of obtaining a relevant tumor reduction was significantly correlated with a patient variable such as PS, and toxicity variables such as mucositis and diarrhea. This observation and the validation of predictive factors for QoL deserve further investigation in ACC patients.

[Anemia induced by solid tumor chemotherapy]. / L'anemia indotta dalla chemioterapia nei tumori solidi.

Cancer patients frequently experience anemia as a complication of chemotherapy. Recent advances in assessing the relationships between anemia, fatigue and quality of life (QOL) in such patients have resulted in a new multidimensional perspective of these parameters. Clinical data suggest that even a mild-to-moderate chemotherapy-induced anemia results in a significant reduction in a patient's energy level and QOL. As recombinant human erythropoetin has recently become available for the treatment of this condition, we performed a review of the incidence and severity of anemia associated with commonly employed chemotherapy regimens in the major non-hematologic malignancies. Although evident flaws in the grading and reporting of treatment-related anemia have limited analysis, the results clearly indicate a relatively high incidence of mild-to-moderate anemia. Research in progress is likely to result in a new classification of chemotherapy-induced anemia that can guide therapeutic interventions on the basis of outcomes and hemoglobin levels. The once widespread belief that lesser degrees of anemia must be endured without treatment may be overcome as greater emphasis is placed on the QOL of the oncology patient. Further insights into the relationships between hemoglobin levels, patient well-being and symptoms may lead to a refinement of current strategies of approaching the treatment of anemia.

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.

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.

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.