Effect of adjuvant trastuzumab treatment in conventional clinical setting: an observational retrospective multicenter Italian study.

Clinical trials have shown the efficacy of trastuzumab-based adjuvant therapy in HER2-positive breast cancers, but routine clinical use awaits evaluation of compliance, safety, and effectiveness. Adjuvant trastuzumab-based therapy in routine clinical use was evaluated in the retrospective study GHEA, recording 1,002 patients treated according to the HERA protocol between March 2005 and December 2009 in 42 Italian oncology departments; 874 (87.23 %) patients completed 1-year trastuzumab treatment. In 128 patients (12.77 %), trastuzumab was withdrawn due to cardiac or non-cardiac toxicity (28 and 29 patients, respectively), disease progression (5 patients) or the clinician's decision (66 patients). In addition, 156 patients experienced minor non-cardiac toxicities; 10 and 44 patients showed CHF and decreased LVEF, respectively, at the end of treatment. Compliance and safety of adjuvant trastuzumab-based therapy in Italian hospitals were high and close to those reported in the HERA trial. With a median follow-up of 32 months, 107 breast cancer relapses were recorded (overall frequency, 10.67 %), and lymph node involvement, estrogen receptor negativity, lymphoid infiltration, and vascular invasion were identified as independent prognostic factors for tumor recurrence, indicating that relapses were associated with advanced tumor stage. Analysis of site and frequency of distant metastases showed that bone metastases were significantly more frequent during or immediately after trastuzumab (<18 months from the start of treatment) compared to recurrences in bone after the end of treatment and wash-out of the drug (>18 months from the start of treatment) (35.89 vs. 14.28 %, p = 0.0240); no significant differences were observed in recurrences in the other recorded body sites, raising the possibility that the protection exerted by trastuzumab is lower in bone metastases.

The role of antiangiogenic agents in the treatment of head and neck cancer.

Despite progress in the treatment of locally advanced head and neck squamous cell cancer (HNSCC), the prognosis remains dismal and 5-year survival does not exceed 40%. In metastatic and recurrent disease, in spite of the introduction of cetuximab in combination with platinum and fluorouracil, the median overall survival rate remains lower than 11 months. There are many possible reasons for these disappointing results including acquired drug resistance and tumor hypoxia. Angiogenesis plays an important role in HNSCC development and proliferation. Promising preclinical results with antiangiogenic therapies have engendered a number of clinical trials, but so far there have not been any conclusive results on the value of such treatments. This paper aims to review the role of angiogenesis in head and neck cancer and to suggest future perspectives.

Evaluation of COVID-19 impact on DELAYing diagnostic-therapeutic pathways of lung cancer patients in Italy (COVID-DELAY study): fewer cases and higher stages from a real-world scenario.

INTRODUCTION: COVID-19 has disrupted the global health care system since March 2020. Lung cancer (LC) patients (pts) represent a vulnerable population highly affected by the pandemic. This multicenter Italian study aimed to evaluate whether the COVID-19 outbreak had an impact on access to cancer diagnosis and treatment of LC pts compared with pre-pandemic time. METHODS: Consecutive newly diagnosed LC pts referred to 25 Italian Oncology Departments between March and December 2020 were included. Access rate and temporal intervals between date of symptoms onset and diagnostic and therapeutic services were compared with the same period in 2019. Differences between the 2 years were analyzed using the chi-square test for categorical variables and the Mann-Whitney U test for continuous variables. RESULTS: A slight reduction (-6.9%) in newly diagnosed LC cases was observed in 2020 compared with 2019 (1523 versus 1637, P = 0.09). Newly diagnosed LC pts in 2020 were more likely to be diagnosed with stage IV disease (P < 0.01) and to be current smokers (someone who has smoked more than 100 cigarettes, including hand-rolled cigarettes, cigars, cigarillos, in their lifetime and has smoked in the last 28 days) (P < 0.01). The drop in terms of new diagnoses was greater in the lockdown period (percentage drop -12% versus -3.2%) compared with the other months included. More LC pts were referred to a low/medium volume hospital in 2020 compared with 2019 (P = 0.01). No differences emerged in terms of interval between symptoms onset and radiological diagnosis (P = 0.94), symptoms onset and cytohistological diagnosis (P = 0.92), symptoms onset and treatment start (P = 0.40), and treatment start and first radiological revaluation (P = 0.36). CONCLUSIONS: Our study pointed out a reduction of new diagnoses with a shift towards higher stage at diagnosis for LC pts in 2020. Despite this, the measures adopted by Italian Oncology Departments ensured the maintenance of the diagnostic-therapeutic pathways of LC pts.

Role of interleukin-23 circulating levels increase in resected colorectal cancer before and after chemotherapy: preliminary data and future perspectives.

Expression of IL-23, a heterodimeric cytokine involved in the induction of Th17 cells, is increased in human tumors. Although the endogenous IL-23 expression has been reported to promote tumor development and growth, the studies using local and systemic administration of IL-23 have shown that its application at the excessive amount induces antitumor immune responses. IL-23 is, today, considered the key driver of intestinal inflammation and its role in inflammatory responses is tissue-specific. The aim of this study was to investigate the role of circulating levels of IL-23 in patients with resected colorectal cancer (CRC) before and after chemotherapy, respect to healthy controls. Twenty-five patients were enrolled between June 2007 and January 2009, and followed through 2010. All patients underwent chemotherapy, mostly FOLFOX4. Twenty-sex and age-matched healthy donors were recruited as controls. IL-23 serum concentrations, measured by a quantitative enzyme immunoassay technique, were significantly higher in patients with resected CRC (26.02 ± 28.63 pg/ml versus 7.1 ± 6.4 pg/ml, P < 0.001) and after chemotherapy respect to controls (21.74 ± 23.82 pg/ml versus 7.17 ± 6.43 pg/ml, P < 0.001). An increase was documented also before chemotherapy (26.02 ± 28.63 pg/ml versus 21.74 ± 23.82 pg/ml, P = 0.7) but not statistically significant. This work investigated, for the first time, the role of IL-23 in CRC resection and chemotherapy, showing no correlation with the severity of disease, tumor removal, and chemotherapeutic treatment. However, other works are needed to better clarify if IL-23 could be considered a key-molecule in human CRC and a target for tumor treatment.

Disease management of type 2 diabetes: a follow-up analysis in a sanitary district of Sicily.

AIM: The aim of this paper was to analyze the Disease management of type 2 diabetes in a sanitary district of the Sicily Region (Italy). METHODS: In a population of 9 698 subjects, we selected patients with known type 2 diabetes: a cohort of 385 subjects, (206 women and 179 men) following up for one year. Prevalence of type 2 diabetes in the analyzed population was 3.97%. A great lot of cohort was on a diet. RESULTS: After one year, a per cent reduction of obese and overweight subjects was observed. No differences were observed for Body Mass Index (BMI) at the beginning and at the end of the study. After one year, through educational meetings with the doctor, a significant increase of knowledge on the patient's conditions and on the diabetes complications was verified, but our data showed persistent poor attention by doctors. The poor knowledge of patients led to a difficult disease management. After one year, a great lot of cohort used antistroke and cardiovascular disease therapy, reducing significantly the cardiovascular disease risk. However, our study also highlights a gap between the therapeutic guidelines and the actual treatment, with wide variability in the delivery of secondary prevention. CONCLUSION. Our study showed that a persevering warning and a constant adjournment of doctors improves the disease management, reducing complications risk in type 2 diabetes patients.

Promyelocytic leukemia (PML) gene expression is a prognostic factor in ampullary cancer patients.

BACKGROUND: Promyelocytic leukemia (PML) tumor suppressor gene plays a key role in acute PML pathogenesis but its involvement in pathogenesis and prognosis of solid cancers has not been defined yet. PATIENTS AND METHODS: In all, 62 ampullary adenocarcinoma patients who underwent curative surgery between 1996 and 2005 were included. Expression analysis of PML was carried out by immunohistochemical staining and correlated with disease-free survival (DFS) and overall survival (OS). RESULTS: In 24 tumor specimens (38.7%), PML was classified as absent, in 16 (25.8%) as focally expressed and in 22 (35.5%) as diffusely expressed. By univariate analysis, DFS was significantly influenced by pathological T stage (P=0.03), lymph nodal involvement (P=0.002), and PML expression (P=0.001). DFS in patients without PML expression was 28.0 months versus 45.1 and 75.5 for patients with focal and diffuse expression, respectively. OS in the group of patients without PML expression, with focal expression, and with diffuse expression was 40, 48, and 77 months, respectively (P=0.002). By a multivariate analysis, PML expression was the strongest prognostic factor for DFS (P=0.003) and the only statically significant prognostic factor for OS (P=0.009). CONCLUSIONS: Our preliminary data suggest PML as a novel prognostic tool for ampullary cancer patients.

Evaluation of quality of life of patients submitted to cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal carcinosis of gastrointestinal and ovarian origin and identification of factors influencing outcome.

BACKGROUND: The prognosis of patients with peritoneal tumors has been improved by the association of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy, though still with an unclear impact on patients' quality of life. The purpose of our study was to evaluate the quality of life in 18 cases submitted to cytoreductive surgery and hyperthermic intraperitoneal chemotherapy and particularly to identify the factors that influence it. PATIENTS AND METHODS: Quality of life was evaluated using the functional assessment of cancer therapy; the results were correlated with 25 parameters. RESULTS: The study demonstrated that the patients'quality of life was not modified by treatment with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy; the dose of mitomycin C, the site of the primary tumor, gastrointestinal, renal and neurological toxicity, adjuvant chemotherapy, the patients' age and leukopenia were factors that influenced the quality of life. CONCLUSION: Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy allows conservation of preoperative quality of life.

Pegylated liposomal doxorubicin and gemcitabine in the front-line treatment of recurrent/metastatic breast cancer: a multicentre phase II study.

This multicentre phase II study was aimed at investigating the activity and safety of pegylated liposomal doxorubicin (PLD) and gemcitabine (GEM) as front-line therapy in a large series of chemotherapy-naïve recurrent/metastatic breast cancer patients. From June 2003 to December 2006, a total of 71 recurrent/metastatic breast cancer patients were enrolled. Median age was 63 years (range=37-79), and 31 patients (43.7%) were > or =65 years old. Patients received PLD, 25 mg m(-2), day 1, followed by GEM, 800 mg m(-2), days 1 and 8, q21. Response was evaluable in 64 cases. Eight complete (12.5%) and 17 partial responses (26.6%) were registered, with an overall response rate of 39.1%. Thirty patients (46.9%) experienced stable disease, with an overall clinical benefit of 85.9%. Median time to progression (TTP) was 11 months, whereas median overall survival (OS) was not reached. The rate of 1- and 2-year OS was 79 and 61%, respectively. A total of 443 courses were evaluable for toxicity: grade 3 and 4 neutropaenia affected 14 patients (20.3%) and 3 patients (4.3%), respectively. Grade 3 and 4 palmar-plantar erythrodysesthesia syndrome was documented in five cases (7.2%) and one case (1.4%), whereas grade 3 and 4 mucositis occurred in six cases (8.7%) and two cases (2.9%), respectively. Grade 2 cardiac toxicity was observed in only one case. Interestingly enough, there was no difference in the percentage and severity of either haematological or non-haematological toxicity according to the age of the patients (<65 vs > or =65 years). We confirmed in a large, very homogenous study sample of chemotherapy-naïve recurrent/metastatic breast cancer patients the efficacy and safety of PLD/GEM combination, providing response rates, median TTP and OS values comparable with those achieved with more toxic combinations.

The changing scenario of 1st line therapy in non-oncogene addicted NSCLCs in the era of immunotherapy.

During the last two decades front-line treatment of metastatic Non Small Cell Lung Cancer (NSCLC) has profoundly changed moving from the old "one size fits all" concept to a "histology-based" approach and then, for a small subgroup of patients to a "molecularly-selected" one. The development of immune checkpoint inhibitors and the unprecedented results reported in 2nd/3rd line prompted the evaluation of these novel therapeutic agents in chemotherapy-naïve patients either alone or in combination with platinum-based chemotherapy. Several randomized trials are evaluating the impact of immune-checkpoint inhibitors in 1st line and some of them have yet produced preliminary evidence of efficacy. However, still a long way to go and several questions are still unanswered, including proper patients selection, optimal sequential/combinatorial use of these agents, appropriate treatment duration, and finally the identification of predictive biomarkers. The aim of this paper is to provide a comprehensive overview on the growing role of immune checkpoint inhibitors in the upfront treatment of advanced non-oncogene addicted NSCLC either as single agent or in combination with other agents.

Third generation EGFR TKIs in EGFR-mutated NSCLC: Where are we now and where are we going.

The therapeutic landscape of Non Small Lung Cancer (NSCLC) has been profoundly changed over the last decade with the clinical introduction of Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitors (TKIs) and the discovery of EGFR activating mutations as the major predictive factor to these agents. Despite impressive clinical activity against EGFR-mutated NSCLCs, the benefit seen with 1st and 2nd generation EGFR TKIs is usually transient and virtually all patients become resistant. Several different mechanisms of acquired resistance have been reported to date, but the vast majority of patients develop a secondary exon 20 mutation in the ATP-binding site of EGFR, namely T790M. The discovery of mutant-selective EGFR TKIs that selectively inhibit EGFR-mutants, including T790M-harboring NSCLCs, while sparing EGFR wild type, provide the opportunity for overcoming the major mechanism of acquired resistance to 1st and 2nd generation EGFR TKIs, with a relatively favorable toxicity profile. The development of this novel class of EGFR inhibitors poses novel challenges in the rapidly evolving therapeutic paradigm of EGFR-mutated NSCLCs and the next few years will witness the beginning of a new era for EGFR inhibition in lung cancer. The aim of this paper is to provide a comprehensive overview of the increasing body of data emerging from the ongoing clinical trials with this promising novel therapeutic class of EGFR inhibitors.

Novel P53 mutations detected by FAMA in colorectal cancers.

BACKGROUND: The aim of the study was to identify p53 gene mutations by FAMA (fluorescence-assisted mismatch analysis) in colorectal cancers. PATIENTS AND METHODS: Analytical scanning of the p53 gene (exons 5-9) was performed in colon cancer samples from 44 consecutive patients by FAMA. FAMA is a semiautomatic scanning approach based on the chemical cleavage of the mismatch in fluorescently labeled heteroduplex DNA, obtained from the combination of a normal and a mutated allele. FAMA has already shown optimal levels of diagnostic accuracy and sensitivity in detecting gene mutations (nucleotide substitutions, insertions/deletions) both at the germline and somatic level. The peculiar feature of FAMA is its ability to detect and localize mutations, by a redundant pattern of signals due to fluorescent DNA fragments generated by chemical cleavage. Moreover, previous data have demonstrated that normal contaminating DNA from stromal cells in the sample does not affect the sensitivity of the procedure, leading to the identification of the mutation even when the ratio mutant/normal allele is 10%. RESULTS: Eighteen mutations (12 missense, one nonsense, two deletions, three nucleotide substitutions at the level of the splice-junctions) and two polymorphisms were detected by FAMA in 17 patients (39%) and then confirmed by automated sequence analysis. Six of 18 mutations (33%) were not previously reported for colon cancer samples and two of 18 lesions (11%) were identified as novel p53 mutations. CONCLUSIONS: Analytical scanning of the p53 gene by FAMA in DNA from colon cancer samples provides a sensitive, accurate and specific diagnostic procedure for routine clinical application.

Molecular detection of TP53, Ki-Ras and p16INK4A promoter methylation in plasma of patients with colorectal cancer and its association with prognosis. Results of a 3-year GOIM (Gruppo Oncologico dell'Italia Meridionale) prospective study.

BACKGROUND: Despite the improvement in detection and surgical therapy in the last years, the outcome of patients affected by colorectal carcinoma (CRC) remains limited by metastatic relapse. The aim of this study was to investigate the presence of free tumor DNA in the plasma of CRC patients in order to understand its possible prognostic role. PATIENTS AND METHODS: Ki-Ras, TP53 mutations and p16(INK4A) methylation status were prospectively evaluated in tumor tissues and plasma of 66 CRC patients. RESULTS: In 50 of the 66 primitive tumor cases (76%) at least one significant alteration was identified in Ki-Ras and/or TP53 and/or p16(INK4A) genes. Eighteen of the 50 patients presented the same alteration both in the plasma and in the tumor tissue. At univariate analysis, Ki-Ras mutations proved to be significantly related to quicker relapse (P <0.01), whereas only a trend towards statistical significance (P = 0.083) was observed for the TP53 mutations CONCLUSIONS: Detection of Ki-Ras and TP53 mutation in plasma should be significantly related to disease recurrence. These data suggest that patients with a high risk of recurrence can be identified by means of the analysis of tumor-derived plasma DNA with the use of fairly non-invasive techniques.

Significance of P16INK4A hypermethylation gene in primary head/neck and colorectal tumors: it is a specific tissue event? Results of a 3-year GOIM (Gruppo Oncologico dell'Italia Meridionale) prospective study.

BACKGROUND: Methylation of the p16 promoter is one of the most frequent mechanisms of gene inactivation; its incidence is extremely variable according to the type of tumor involved. Our purpose was to analyze the hypermethylation of the p16 promoter in laryngeal squamous cell carcinomas (LSCC), salivary gland (SG) tumors and in colorectal cancer (CRC), to detect any possible association with the clinicopathological features and to determine the prognostic significance of the p16 gene in the tumors analyzed. PATIENTS AND METHODS: The hypermethylation of the p16 promoter was prospectively analyzed, by MSP, in a consecutive series of 64 locally advanced LSCC patients, in a consecutive series of 33 SG tumor patients and in a consecutive series of 66 sporadic CRC patients. RESULTS: Hypermethylation was observed in 9% of the LSCC cases, in all cases of SG cancer and in 21% of the CRC cases. No significant association was observed between p16 hypermethylation and clinicopathological variables in all the tissue samples analyzed. Moreover at univariate analysis p16 mutations were not independently related at disease relapse and death in LSCC and CRC. CONCLUSIONS: The results of this study suggest that the lack of p16 function could happen in advanced stage of SG tumors.

Detection and quantification of mammaglobin in the blood of breast cancer patients: can it be useful as a potential clinical marker? Preliminary results of a GOIM (Gruppo Oncologico dell'Italia Meridionale) prospective study.

BACKGROUND: Mammaglobin is expressed mainly in mammary tissue, overexpressed in breast cancer (BC) and rarely in other tissue. The aim of this study was to assess the sensitivity and specificity of transcript MGB1 detection and to evaluate the role of MGB1 as potential clinical marker for the detection of disseminated cancer cells in the blood of BC patients. PATIENTS AND METHODS: A consecutive series of 23 BC tissues, 36 peripheral blood BC samples and 35 healthy peripheral blood samples was prospectively recruited to investigate MGB1 expression by means of a quantitative Real Time RT-PCR assay. RESULTS: MGB1 overexpression in tissue samples of BC patients is significantly associated only with high level of Ki67 (P <0.05). None of the samples from peripheral blood of 35 healthy female individuals were positive for MGB1 transcript. In contrast MGB1 mRNA expression was detected in three of 36 (8%) peripheral blood of BC patients. CONCLUSIONS: Our preliminary results demonstrate that the detection of MGB1 transcript in peripheral blood of BC patients was specific but with low sensitivity. MGB1 overexpression by itself or in combination with Ki67 might be considered an index of BC progression.

[Clinical guidelines for the management of gastrointestinal stromal tumors]. / Raccomandazioni cliniche per la diagnosi, la terapia ed il follow-up dei tumori stromali gastrointestinali.

Treatment of gastrointestinal stromal tumors (GIST) has been revolutioned by the recently discovered molecular mechanism responsible for the oncogenesis of this disease. In addition, due to the rapid progress at molecular and clinical level observed in the last few years, there is a need to review the current state of the art in order to delineate appropriate guidelines for the optimal management of these tumors. A panel of experts from several specialities, including medical oncology, surgery, pathology, molecular biology and imaging, were invited to participate in a meeting to present and discuss a number of pre-selected questions, and to achieve a consensus according to the categories of the National Comprehensive Cancer Network (NCCN) and the Standard Options Recommandations (SOR) of the French Federation of Cancer Centers. Generally, consensus points were from categories 2A of the NCCN and B2 of the SOR. Conventional histologic examination with immunohistochemistry for CD117, CD34, SMA, S-100 and desmin is considered standard. Molecular analysis for the identification of KIT and PDGFRA mutation may be indicated in CD117-negative GIST. Complete tumor resection with negative margins is the optimal surgical treatment. Adjuvant imatinib should be considered an experimental approach. Neoadjuvant imatinib is also experimental, although its use may be justified in unresectable or marginally resectable GIST. Imatinib should be started in metastatic or recurrent disease, and should be continued until progressive disease or drug intolerance. In these cases, sunitinib can be used. The optimal criteria for the assessment and monitoring of GIST undergoing imatinib therapy are not well known, but they should include reduction in tumor size and disease stabilization, as well as reduction of tumor density on CT scan and metabolic activity on PET scan.

Cisplatin-gemcitabine combination in advanced non-small-cell lung cancer: a phase II study.

PURPOSE: The nucleoside analog, gemcitabine, has shown activity as a single agent in the treatment of metastatic non-small-cell lung cancer (NSCLC). Its combination with cisplatin in preclinical models suggested synergy between the two drugs. The aim of the study was to evaluate the clinical efficacy and toxicity of the cisplatin-gemcitabine combination in advanced NSCLC. PATIENTS AND METHODS: Forty-eight consecutive previously untreated NSCLC patients entered the trial from January to June 1994. The median age was 60 years (range, 37 to 70) and performance status (PS) was 0 or 1; 22 patients had unresectable stage III disease (21 stage IIIB and one stage IIIA) and 26 had stage IV disease. Gemcitabine 1 g/m2 was administered weekly (days 1, 8, and 15) followed by a 1-week rest and cisplatin 100 mg/m2 on day 2 of each 28-day cycle. Survival and response were determined in accordance with the intention-to-treat principle in all enrolled patients. RESULTS: Of 48 assessable patients, one (stage IV) had a complete response (CR) and 25 achieved a partial response (PR). The overall response rate was 54% (95% confidence interval [CI], 40% to 68%). Thrombocytopenia was the main side effect, with 52% of patients experiencing grade III to IV toxicity, which was usually short-lived and responsible for the omission of gemcitabine administration on day 15 in 50% of chemotherapy courses. The median survival time was 61.5 weeks (95% CI, 40 to 71). CONCLUSION: The combination of gemcitabine and cisplatin induced a high response rate in both stage IIIB and IV NSCLC, with modest side effects. The regimen deserves further careful evaluation in a phase III prospective randomized trial.

Gemcitabine and cisplatin versus mitomycin, ifosfamide, and cisplatin in advanced non-small-cell lung cancer: A randomized phase III study of the Italian Lung Cancer Project.

PURPOSE: To compare gemcitabine and cisplatin (GC) with mitomycin, ifosfamide, and cisplatin (MIC) chemotherapy in patients with stage IIIB (limited to T4 for pleural effusion and N3 for supraclavicular lymph nodes) or stage IV non-small-cell lung cancer (NSCLC). The end points were the evaluation of quality of life (QoL), response rates, survival, and toxicity. PATIENTS AND METHODS: Three hundred seven patients were randomized to receive either gemcitabine 1,000 mg/m(2) on days 1, 8, and 15 plus cisplatin 100 mg/m(2) on day 2, every 28 days, or mitomycin 6 mg/m(2), ifosfamide 3,000 mg/m(2), and mesna on day 1 plus cisplatin 100 mg/m(2) on day 2, every 28 days. The whole-blood cell count was repeated on day 1 in both arms and weekly in the GC arm before each gemcitabine administration. RESULTS: No major differences in changes in QoL were observed between the two treatment arms. The objective response rate was 38% in the GC arm compared with 26% in the MIC arm (P =.029). The median survival time was 8.6 months in the GC arm and 9.6 months in the MIC arm (P =.877, log-rank test). Grade 3 and 4 thrombocytopenia was significantly worse in the GC arm (64% v 28%, P <.001), whereas grade 3 and 4 alopecia was reported more commonly in the MIC arm (39% v 12%, P <. 001). CONCLUSION: We report an increased response rate without changes in QoL and a similar overall survival, time to progression, and time to treatment failure for the GC when compared with the MIC regimen in the treatment of advanced NSCLC.

Phase III randomized trial comparing three platinum-based doublets in advanced non-small-cell lung cancer.

PURPOSE: To evaluate whether two commonly used newer platinum-based regimens offer any advantage over vinorelbine-cisplatin (reference regimen) in response rate for patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Chemotherapy-naive patients were randomized to receive gemcitabine 1,250 mg/m(2) days 1 and 8 plus cisplatin 75 mg/m(2) day 2 every 21 days (GC arm), or paclitaxel 225 mg/m(2) (3-hour infusion) then carboplatin (area under the concentration-time curve of 6 mg/mL x min), both on day 1 every 21 days (PCb arm), or vinorelbine 25 mg/m(2)/wk for 12 weeks then every other week plus cisplatin 100 mg/m(2) day 1 every 28 days (VC arm). RESULTS: Six hundred twelve patients were randomized to treatment (205 GC, 204 PCb, and 203 VC). Overall response rates for the GC (30%) and PCb (32%) arms were not significantly different from that of the VC arm (30%). There were no differences in overall survival, time to disease progression, or time to treatment failure. Median survival for the GC, PCb, and VC groups was 9.8, 9.9, and 9.5 months, respectively. Neutropenia was significantly higher on the VC arm (GC 17% or PCb 35% v VC 43% of cycles, P <.001), as was thrombocytopenia on the GC arm (GC 16% v VC 0.1% of cycles, P <.001). Alopecia and peripheral neurotoxicity were most common on the PCb arm, as was nausea/vomiting on the VC arm (P <.05). CONCLUSION: Efficacy end points were not significantly different between experimental and reference arms, although toxicities showed differences. These findings suggest that chemotherapy in NSCLC has reached a therapeutic plateau.

Phase III randomized study of fluorouracil, epirubicin, and cyclophosphamide v fluorouracil, doxorubicin, and cyclophosphamide in advanced breast cancer: an Italian multicentre trial.

From February 1983 to January 1985, 497 patients with advanced breast cancer were randomly allocated to receive either epirubicin or doxorubicin in the following combination chemotherapy regimen: fluorouracil (5-FU) 500 mg/m2 intravenous (IV) on days 1 and 8; epirubicin or doxorubicin 50 mg/m2 IV on day 1; cyclophosphamide 500 mg/m2 IV on day 1 (FEC or FAC). Cycles were repeated every 21 days until progression or to cumulative doses of 700 mg/m2 for epirubicin and 550 mg/m2 for doxorubicin. Dose reductions were applied according to the standard criteria. Activity was evaluated in 443 patients (222 in the FEC arm and 221 in the FAC arm). The two experimental groups were comparable in age, performance status, menopausal status, histology, previous treatments, and site of the disease. The overall response rate (complete response and partial response [CR + PR]) was not significantly different: 53.6% for FEC and 56.5% for FAC. The median time to progression was 273 days for FEC and 314 days for FAC; the median survival time was 591 and 613 days, respectively. Leukopenia, anemia, nausea, and vomiting were significantly lower in patients treated with FEC. As for cardiotoxicity, four cases of congestive heart failure (CHF) were recorded among patients treated with FAC while only one was observed in the FEC group. These results indicate that epirubicin in a combination chemotherapy regimen is as active as doxorubicin and is significantly less toxic.