Nivolumab plus chemotherapy in first-line metastatic non-small-cell lung cancer: results of the phase III CheckMate 227 Part 2 trial.

BACKGROUND: In CheckMate 227 Part 1, first-line nivolumab plus ipilimumab prolonged overall survival (OS) in patients with metastatic non-small-cell lung cancer (NSCLC) and tumor programmed death-ligand 1 (PD-L1) expression ≥1% versus chemotherapy. We report results from CheckMate 227 Part 2, which evaluated nivolumab plus chemotherapy versus chemotherapy in patients with metastatic NSCLC regardless of tumor PD-L1 expression. PATIENTS AND METHODS: Seven hundred and fifty-five patients with systemic therapy-naive, stage IV/recurrent NSCLC without EGFR mutations or ALK alterations were randomized 1 : 1 to nivolumab 360 mg every 3 weeks plus chemotherapy or chemotherapy. Primary endpoint was OS with nivolumab plus chemotherapy versus chemotherapy in patients with nonsquamous NSCLC. OS in all randomized patients was a hierarchically tested secondary endpoint. RESULTS: At 19.5 months' minimum follow-up, no significant improvement in OS was seen with nivolumab plus chemotherapy versus chemotherapy in patients with nonsquamous NSCLC [median OS 18.8 versus 15.6 months, hazard ratio (HR) 0.86, 95.62% confidence interval (CI) 0.69-1.08, P = 0.1859]. Descriptive analyses showed OS improvement with nivolumab plus chemotherapy versus chemotherapy in all randomized patients (median OS 18.3 versus 14.7 months, HR 0.81, 95.62% CI 0.67-0.97) and in an exploratory analysis in squamous NSCLC (median OS 18.3 versus 12.0 months, HR 0.69, 95% CI 0.50-0.97). A trend toward improved OS was seen with nivolumab plus chemotherapy versus chemotherapy, regardless of the tumor mutation status of STK11 or TP53, regardless of tumor mutational burden, and in patients with intermediate/poor Lung Immune Prognostic Index scores. Safety with nivolumab plus chemotherapy was consistent with previous reports of first-line settings. CONCLUSIONS: CheckMate 227 Part 2 did not meet the primary endpoint of OS with nivolumab plus chemotherapy versus chemotherapy in patients with metastatic nonsquamous NSCLC. Descriptive analyses showed prolonged OS with nivolumab plus chemotherapy in all-randomized and squamous NSCLC populations, suggesting that this combination may benefit patients with untreated metastatic NSCLC.

Long-term survival with first-line nivolumab plus ipilimumab in patients with advanced non-small-cell lung cancer: a pooled analysis.

BACKGROUND: First-line nivolumab plus ipilimumab prolongs survival versus chemotherapy in advanced non-small-cell lung cancer (NSCLC). We further characterized clinical benefit with this regimen in a large pooled patient population and assessed the effect of response on survival. PATIENTS AND METHODS: Data were pooled from four studies of first-line nivolumab plus ipilimumab in advanced NSCLC (CheckMate 227 Part 1, 817 cohort A, 568 Part 1, and 012). Overall survival (OS), progression-free survival (PFS), objective response rate, duration of response, and safety were assessed. Landmark analyses of OS by response status at 6 months and by tumor burden reduction in responders to nivolumab plus ipilimumab were also assessed. RESULTS: In the pooled population (N = 1332) with a minimum follow-up of 29.1-58.9 months, median OS was 18.6 months, with a 3-year OS rate of 35%; median PFS was 5.4 months (3-year PFS rate, 17%). Objective response rate was 36%; median duration of response was 23.7 months, with 38% of responders having an ongoing response at 3 years. In patients with tumor programmed death-ligand 1 (PD-L1) <1%, ≥1%, 1%-49%, or ≥50%, 3-year OS rates were 30%, 38%, 30%, and 48%. Three-year OS rates were 30% and 38% in patients with squamous or non-squamous histology. Efficacy outcomes in patients aged ≥75 years were similar to the overall pooled population (median OS, 20.1 months; 3-year OS rate, 34%). In the pooled population, responders to nivolumab plus ipilimumab at 6 months had longer post-landmark OS than those with stable or progressive disease; 3-year OS rates were 66%, 22%, and 14%, respectively. Greater depth of response was associated with prolonged survival; in patients with tumor burden reduction ≥80%, 50% to <80%, or 30% to <50%, 3-year OS rates were 85%, 72%, and 44%, respectively. No new safety signals were identified in the pooled population. CONCLUSION: Long-term survival benefit and durable response with nivolumab plus ipilimumab in this large patient population further support this first-line treatment option for advanced NSCLC.

First-line nivolumab plus ipilimumab with two cycles of chemotherapy versus chemotherapy alone (four cycles) in advanced non-small-cell lung cancer: CheckMate 9LA 2-year update.

BACKGROUND: To further characterize survival benefit with first-line nivolumab plus ipilimumab with two cycles of chemotherapy versus chemotherapy alone, we report updated data from the phase III CheckMate 9LA trial with a 2-year minimum follow-up. PATIENTS AND METHODS: Adult patients were treatment naïve, with stage IV/recurrent non-small-cell lung cancer, no known sensitizing EGFR/ALK alterations, and an Eastern Cooperative Oncology Group performance status ≤1. Patients were randomized 1 : 1 to nivolumab 360 mg every 3 weeks plus ipilimumab 1 mg/kg every 6 weeks with two cycles of chemotherapy, or four cycles of chemotherapy. Updated efficacy and safety outcomes are reported, along with progression-free survival (PFS) after next line of treatment (PFS2), treatment-related adverse events (TRAEs) by treatment cycle, and efficacy outcomes in patients who discontinued all treatment components in the experimental arm due to TRAEs. RESULTS: With a median follow-up of 30.7 months, nivolumab plus ipilimumab with chemotherapy continued to prolong overall survival (OS) versus chemotherapy. Median OS was 15.8 versus 11.0 months [hazard ratio 0.72 (95% confidence interval 0.61-0.86)]; 2-year OS rate was 38% versus 26%. Two-year PFS rate was 20% versus 8%. ORR was 38% versus 25%, respectively; 34% versus 12% of all responses were ongoing at 2 years. Median PFS2 was 13.9 versus 8.7 months. Improved efficacy outcomes in the experimental versus control arm were observed across most subgroups, including by programmed death-ligand 1 and histology. No new safety signals were observed; onset of grade 3/4 TRAEs was mostly observed during the first two treatment cycles in the experimental arm. In patients who discontinued all components of nivolumab plus ipilimumab with chemotherapy treatment due to TRAEs (n = 61) median OS was 27.5 months; 56% of responders had an ongoing response ≥1 year after discontinuation. CONCLUSIONS: With a 2-year minimum follow-up, nivolumab plus ipilimumab with two cycles of chemotherapy provided durable efficacy benefits over chemotherapy with a manageable safety profile and remains an efficacious first-line treatment of advanced non-small-cell lung cancer.

Second-line nivolumab in relapsed small-cell lung cancer: CheckMate 331☆.

BACKGROUND: Patients with relapsed small-cell lung cancer (SCLC) have few treatment options and dismal survival. Phase I/II data show activity of nivolumab in previously treated SCLC. PATIENTS AND METHODS: CheckMate 331 is a randomized, open-label, phase III trial of nivolumab versus standard chemotherapy in relapsed SCLC. Patients with relapse after first-line, platinum-based chemotherapy were randomized 1 : 1 to nivolumab 240 mg every 2 weeks or chemotherapy (topotecan or amrubicin) until progression or unacceptable toxicity. Primary endpoint was overall survival (OS). RESULTS: Overall, 284 patients were randomized to nivolumab and 285 to chemotherapy. Minimum follow-up was 15.8 months. No significant improvement in OS was seen with nivolumab versus chemotherapy [median OS, 7.5 versus 8.4 months; hazard ratio (HR), 0.86; 95% confidence interval (CI), 0.72-1.04; P = 0.11]. A survival benefit with nivolumab was suggested in patients with baseline lactate dehydrogenase ≤ upper limit of normal and in those without baseline liver metastases. OS (nivolumab versus chemotherapy) was similar in patients with programmed death-ligand 1 combined positive score ≥1% versus <1%. Median progression-free survival was 1.4 versus 3.8 months (HR, 1.41; 95% CI, 1.18-1.69). Objective response rate was 13.7% versus 16.5% (odds ratio, 0.80; 95% CI, 0.50-1.27); median duration of response was 8.3 versus 4.5 months. Rates of grade 3 or 4 treatment-related adverse events were 13.8% versus 73.2%. CONCLUSION: Nivolumab did not improve survival versus chemotherapy in relapsed SCLC. No new safety signals were seen. In exploratory analyses, select baseline characteristics were associated with improved OS for nivolumab.

Metronomic oral vinorelbine in previously untreated advanced non-small-cell lung cancer patients unfit for platinum-based chemotherapy: results of the randomized phase II Tempo Lung trial.

BACKGROUND: To assess the efficacy and safety of a metronomic schedule of oral vinorelbine (mVNR) in advanced non-small-cell lung cancer (NSCLC) in patients unfit for platinum-based combination chemotherapy. PATIENTS AND METHODS: This was a multicenter, prospective, randomized, open-label phase II study in treatment-naive patients with TNM stage IIIB/IV NSCLC. Patients received mVNR at a fixed dose of 50 mg × 3 or standard schedule 60-80 mg/m2 weekly until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS) without grade 4 toxicity (G4PFS; NCI-CTC v4). Main secondary objectives were safety, disease control rate (DCR) without grade 4 toxicity (G4DCR), DCR, PFS, overall survival (OS) and quality of life (QoL). RESULTS: A total of 167 patients were included, 83 and 84 patients in the mVNR and standard arms, respectively. The median G4PFS was 4.0 months [95% confidence interval (CI): 2.6-4.3] and 2.2 months (95% CI: 1.5-2.9), hazard ration (HR) = 0.63 (95% CI: 0.45-0.88), P = 0.0068 in favor of metronomic arm; G4DCR was 45.8% and 26.8% in the mVNR and standard arms, respectively. Grade 3-4 treatment-related adverse events were less frequent in the mVNR arm (25.3% versus 54.4%) mainly owing to a reduction in all grades (15.7% versus 51.9%) and grade 3-4 neutropenia (10.8% versus 42%). PFS was 4.3 (95% CI: 3.3-5.1) and 3.9 months (95% CI: 2.8-5.2) in mVNR and standard arms, respectively. No difference in median OS was observed. QoL was comparable between arms. CONCLUSIONS: Metronomic oral vinorelbine significantly prolonged median G4PFS in advanced NSCLC patients unfit for platinum combinations as first-line treatment. It was associated with a clear reduction in toxicity and may be considered as an important option in this challenging population.

Knowledge, attitudes and practices related to the COVID-19 outbreak among Romanian adults with cancer: a cross-sectional national survey.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic outbreak forced cancer care providers to face different challenges in terms of prevention and treatment management due to specific precautions implemented for oncological patients. We aimed to describe the level of knowledge, attitude and practices (KAP) among cancer patients, with the purpose to provide an image of the impact of COVID-19 and evaluate the effectiveness of pandemic response measures. PATIENTS AND METHODS: We developed a cross-sectional multicentric study that targeted adults with active cancer during the COVID-19 outbreak, aiming to describe KAP related to COVID-19 among Romanian oncological patients. A questionnaire investigating 64 items on KAP related to the novel coronavirus was designed and applied in seven Romanian hospitals. The group of participants consisted of 1585 oncological patients who completed the questionnaire during the outbreak (April-May 2020). RESULTS: Only 172 patients (10.8%) had very good knowledge about severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection symptoms, treatment options and incubation period. Only 44.3% of patients identified diarrhoea as a sign of COVID-19. About one-third of patients (32.6%) declared that they are 'very worried' about getting infected with the novel coronavirus. More than two-thirds of participants (68%) considered that having cancer represents an additional risk for infection with SARS-CoV-2, but 27.8% would rather not vaccinate against SARS-CoV-2 should a vaccine be available. A small percentage (8.8%) believed that the risk of infection justifies delaying/stopping oncological treatment until after the pandemic. Around half of the participants (55.5%) declared being compliant with all the protective measures against coronavirus infection listed in the questionnaire. CONCLUSION: Romanian oncological patients have a less than expected knowledge about SARS-CoV-2, appropriate prevention behaviours, with limited trust in their efficacy, optimistic attitudes towards COVID-19 and low level of trust in information sources. Good COVID-19 knowledge was associated with appropriate practices towards COVID-19 and optimistic attitudes.

Durvalumab with or without tremelimumab in patients with recurrent or metastatic head and neck squamous cell carcinoma: EAGLE, a randomized, open-label phase III study.

BACKGROUND: Targeting the programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) axis has demonstrated clinical benefit in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). Combining immunotherapies targeting PD-L1 and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) has shown evidence of additive activity in several tumor types. This phase III study evaluated the efficacy of durvalumab (an anti-PD-L1 monoclonal antibody) or durvalumab plus tremelimumab (an anti-CTLA-4 monoclonal antibody) versus standard of care (SoC) in R/M HNSCC patients. PATIENTS AND METHODS: Patients were randomly assigned to receive 1 : 1 : 1 durvalumab (10 mg/kg every 2 weeks [q2w]), durvalumab plus tremelimumab (durvalumab 20 mg/kg q4w plus tremelimumab 1 mg/kg q4w × 4, then durvalumab 10 mg/kg q2w), or SoC (cetuximab, a taxane, methotrexate, or a fluoropyrimidine). The primary end points were overall survival (OS) for durvalumab versus SoC, and OS for durvalumab plus tremelimumab versus SoC. Secondary end points included progression-free survival (PFS), objective response rate, and duration of response. RESULTS: Patients were randomly assigned to receive durvalumab (n = 240), durvalumab plus tremelimumab (n = 247), or SoC (n = 249). No statistically significant improvements in OS were observed for durvalumab versus SoC [hazard ratio (HR): 0.88; 95% confidence interval (CI): 0.72-1.08; P = 0.20] or durvalumab plus tremelimumab versus SoC (HR: 1.04; 95% CI: 0.85-1.26; P = 0.76). The 12-month survival rates (95% CI) were 37.0% (30.9-43.1), 30.4% (24.7-36.3), and 30.5% (24.7-36.4) for durvalumab, durvalumab plus tremelimumab, and SoC, respectively. Treatment-related adverse events (trAEs) were consistent with previous reports. The most common trAEs (any grade) were hypothyroidism for durvalumab and durvalumab plus tremelimumab (11.4% and 12.2%, respectively), and anemia (17.5%) for SoC. Grade ≥3 trAE rates were 10.1%, 16.3%, and 24.2% for durvalumab, durvalumab plus tremelimumab, and SoC, respectively. CONCLUSION: There were no statistically significant differences in OS for durvalumab or durvalumab plus tremelimumab versus SoC. However, higher survival rates at 12 to 24 months and response rates demonstrate clinical activity for durvalumab. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02369874.

Analysis of angiogenesis biomarkers for ramucirumab efficacy in patients with metastatic colorectal cancer from RAISE, a global, randomized, double-blind, phase III study.

Background: The phase III RAISE trial (NCT01183780) demonstrated that the vascular endothelial growth factor (VEGF) receptor (VEGFR)-2 binding monoclonal antibody ramucirumab plus 5-fluororuracil, leucovorin, and irinotecan (FOLFIRI) significantly improved overall survival (OS) and progression-free survival (PFS) compared with placebo + FOLFIRI as second-line metastatic colorectal cancer (mCRC) treatment. To identify patients who benefit the most from VEGFR-2 blockade, the RAISE trial design included a prospective and comprehensive biomarker program that assessed the association of biomarkers with ramucirumab efficacy outcomes. Patients and methods: Plasma and tumor tissue collection was mandatory. Overall, 1072 patients were randomized 1 : 1 to the addition of ramucirumab or placebo to FOLFIRI chemotherapy. Patients were then randomized 1 : 2, for the biomarker program, to marker exploratory (ME) and marker confirmatory (MC) groups. Analyses were carried out using exploratory assays to assess the correlations of baseline marker levels [VEGF-C, VEGF-D, sVEGFR-1, sVEGFR-2, sVEGFR-3 (plasma), and VEGFR-2 (tumor tissue)] with clinical outcomes. Cox regression analyses were carried out for each candidate biomarker with stratification factor adjustment. Results: Biomarker results were available from >80% (n = 894) of patients. Analysis of the ME subset determined a VEGF-D level of 115 pg/ml was appropriate for high/low subgroup analyses. Evaluation of the combined ME + MC populations found that the median OS in the ramucirumab + FOLFIRI arm compared with placebo + FOLFIRI showed an improvement of 2.4 months in the high VEGF-D subgroup [13.9 months (95% CI 12.5-15.6) versus 11.5 months (95% CI 10.1-12.4), respectively], and a decrease of 0.5 month in the low VEGF-D subgroup [12.6 months (95% CI 10.7-14.0) versus 13.1 months (95% CI 11.8-17.0), respectively]. PFS results were consistent with OS. No trends were evident with the other antiangiogenic candidate biomarkers. Conclusions: The RAISE biomarker program identified VEGF-D as a potential predictive biomarker for ramucirumab efficacy in second-line mCRC. Development of an assay appropriate for testing in clinical practice is currently ongoing. Clinical trials registration: NCT01183780.

Final results from a randomized phase 3 study of FOLFIRI {+/-} panitumumab for second-line treatment of metastatic colorectal cancer.

BACKGROUND: The study 20050181 demonstrated significant improvements in progression-free survival (PFS), objective response, and a nonsignificant trend toward increased overall survival (OS) with panitumumab-FOLFIRI versus FOLFIRI alone for second-line wild-type (WT) KRAS metastatic colorectal cancer (mCRC). Updated long-term data from a prespecified descriptive analysis are reported. PATIENTS AND METHODS: Patients receiving one prior mCRC treatment were randomly assigned (1:1) to panitumumab (6.0 mg/kg)-FOLFIRI versus FOLFIRI every 2 weeks. Co-primary end points (PFS and OS) were prospectively analyzed by tumor KRAS status. RESULTS: One thousand one hundred and eighty-six patients were randomly assigned. In patients with WT KRAS tumors, panitumumab-FOLFIRI significantly improved PFS versus FOLFIRI [median 6.7 versus 4.9 months; hazard ratio (HR) 0.82 [95% confidence interval (CI) 0.69, 0.97]; P = 0.023]. A trend toward longer OS was observed (median 14.5 versus 12.5 months; HR 0.92 [95% CI 0.78, 1.10]; P = 0.37). Response rates improved from 10% to 36% (P < 0.0001). From post hoc analyses in patients receiving prior oxaliplatin-bevacizumab, panitumumab-FOLFIRI improved PFS (median 6.4 versus 3.7 months; HR 0.58 [95% CI 0.37, 0.90]; P = 0.014). PFS and OS appeared longer for worst-grade skin toxicity of 2-4, versus 0-1 or FOLFIRI. Safety results were as previously reported and consistent with the known toxicities with anti-epidermal growth factor receptor therapy. CONCLUSIONS: These data confirm the primary efficacy and safety findings of this trial and support panitumumab-FOLFIRI as a second-line treatment of WT KRAS mCRC.

Can the epirubicin cardiotoxicity in cancer patients be prevented by angiotensin converting enzyme inhibitors?

PURPOSE: The aim of this study was to assess whether treatment with angiotensin converting enzyme inhibitors (ACEI) can prevent the alteration of left ventricular systolic and diastolic performance in cancer patients treated with different chemotherapy regimens containing epirubicin. METHODS: In this prospective study , 68 patients with different malignant tumors treated with epirubicin and perindopril in different chemotherapy protocols (study group), and a gender- and age-matched group of 68 patients with different malignant tumors treated with epirubicin without perindopril in different chemotherapy protocols (control group), were assessed by Doppler echocardiography. Left ventricular systolic function was assessed by measuring left ventricular ejection fraction (EF). Left ventricular diastolic function was assessed by Doppler ultrasound by evaluating the transmitral flow. We also assessed the QTc on the 12 lead electrocardiograms. RESULTS: At the end of chemotherapy the left ventricular systolic function was less altered in the study group compared to the control group and was superior in the study group (epirubicin+ACEI) compared to the control group (epirubicin alone). We documented a significantly deteriorated left ventricular diastolic function in both groups at the completion of chemotherapy. QTc time in both arms was also significantly prolonged. CONCLUSION: In the present echo-Doppler study we documented a preserved left ventricular systolic performance in patients with various malignancies treated with epirubicin plus perindopril. Although co-treatment with ACEI prevented the alteration of systolic performance, it failed to prevent the deterioration of the left ventricular diastolic performance impairment due to poor left ventricular compliance.

FOLFOX4 plus cetuximab administered weekly or every second week in the first-line treatment of patients with KRAS wild-type metastatic colorectal cancer: a randomized phase II CECOG study.

BACKGROUND: This randomized phase II study investigated first-line chemotherapy plus cetuximab administered every second week in KRAS wild-type metastatic colorectal cancer. PATIENTS AND METHODS: Patients received FOLFOX4 plus either standard weekly cetuximab (arm 1) or cetuximab (500 mg/m(2)) every second week (arm 2), until disease progression or unacceptable toxicity. Primary end point was the objective response rate (ORR). Progression-free survival (PFS), overall survival (OS), disease control rate (DCR) and safety were also investigated. The study was not powered to establish non-inferiority, but aimed at the estimation of treatment differences. RESULTS: Of 152 randomized eligible patients, 75 were treated in arm 1 and 77 in arm 2; ORRs [53% versus 62%, odds ratio 1.40, 95% confidence interval (CI) 0.74-2.66], PFS [median 9.5 versus 9.2 months, hazard ratio (HR) 0.92, 95% CI 0.63-1.34], OS (median 25.8 versus 23.0 months, HR 0.86, 95% CI 0.56-1.30) and DCR (87%) were comparable. HRs adjusted for baseline factors were 1.01 and 0.99 for PFS and OS, respectively. Frequencies of grade 3/4 adverse events in arms 1 versus 2 were similar: most common were neutropenia (28% versus 34%) and rash (15% versus 17%). CONCLUSIONS: Activity and safety of FOLFOX4 plus either cetuximab administered weekly or every second week were similar.

Phase II randomized study of trabectedin given as two different every 3 weeks dose schedules (1.5 mg/m2 24 h or 1.3 mg/m2 3 h) to patients with relapsed, platinum-sensitive, advanced ovarian cancer.

BACKGROUND: This randomized, open-label, phase II clinical trial evaluated the optimal regimen of trabectedin administered every 3 weeks in patients with platinum-sensitive, relapsed, advanced ovarian cancer (AOC). PATIENTS AND METHODS: Patients previously treated with less than two or two previous chemotherapy lines were randomized to receive trabectedin 1.5 mg/m(2) 24 h (arm A, n = 54) or 1.3 mg/m(2) 3 h (arm B, n = 53). Objective response rate (ORR) per RECIST was the primary efficacy end point. Toxic effects were graded according to the National Cancer Institute-Common Toxicity Criteria v. 2.0. RESULTS: ORR was 38.9% [95% confidence interval (CI) 25.9% to 53.1%; arm A] and 35.8% (95% CI 23.1% to 50.2%; arm B) (intention-to-treat primary analysis). Median time to progression was 6.2 months (95% CI 5.3-8.6 months; arm A) and 6.8 months (95% CI 4.6-7.4 months; arm B). Frequent severe adverse events were nausea/vomiting (24%, arm A; 15%, arm B) and fatigue (15%, arm A; 10%, arm B). Common severe laboratory abnormalities were transient, noncumulative neutropenia (55%, arm A; 37%, arm B) and transaminase increases (alanine aminotransferase, 55%, arm A; 59%, arm B). CONCLUSIONS: Both every-3-weeks trabectedin regimes, 1.5 mg/m(2) 24 h and 1.3 mg/m(2) 3 h, were active and reasonably well tolerated in AOC platinum-sensitive patients. Trabectedin every-3-weeks has promising activity and deserves to be further evaluated in relapsed AOC.

Capecitabine as salvage treatment in relapsed nasopharyngeal carcinoma: a phase II study.

PURPOSE: To evaluate the efficacy of capecitabine (Xeloda) as rescue treatment (2nd, 3rd and 4th line) in patients with relapsed nasopharyngeal carcinoma (NPC) in a phase II study. PATIENTS AND METHODS: Between 5/2002-11/2005, 23 relapsed NPC patients (17 locoregional relapse, 3 metastatic, 3 locoregional + metastatic) received capecitabine 2500 mg/m(2)/d, days 1-14 every 3 weeks, until progression or for a maximum of 6 cycles. PATIENT CHARACTERISTICS: 23 patients (14 men, 9 women) with median age 46 years (range 15-59); ECOG performance status 1 n=21, 2 n=2; histology: undifferentiated carcinoma (WHO type III) n=21, non-keratinizing epidermoid carcinoma (WHO type II), n=2. Capecitabine was given as 2nd--(13 patients), 3rd--(7 patients), and 4th--(3 patients) line chemotherapy. Previous chemotherapy regimes were epirubicin + cisplatin, paclitaxel + carboplatin, paclitaxel + 5-fluorouracil and leucovorin (5-FU/LV) or methotrexate. 104 cycles were given (median 5, range 2-6). Two (9%) patients achieved complete response (CR); 9 (39%) partial response (PR); 9 (39%) stable disease (SD) and 3 (13%) progressed (PD). Toxicity was mild without toxic deaths or grade 4 toxicities. The most frequent toxicities (grades 1-3) were anemia (38%), hand-foot syndrome (23%), leukopenia (13%) and diarrhea (7%). Median follow-up was 10 months (range 2-44). Median overall survival was not reached at 18 months and actuarial one-year survival was 62% (95% confidence interval/CI: 41-80). Median progression-free survival was 14 months. CONCLUSION: Capecitabine is active in relapsed NPC patients, achieving 48% objective responses, with mild toxicity. It is an attractive therapy to be administered in an outpatient setting.

Endocrine paraneoplastic syndromes in small cell lung carcinoma. Two case reports.

Paraneoplastic syndromes are frequently detected in many small cell lung cancer (SCLC) patients. In the present paper we report 2 cases of patients diagnosed with SCLC, in whom 2 distinct endocrine paraneoplastic syndromes were identified during diagnosis. In the first patient, severe hyponatremia and renal sodium loss with inappropriate antidiuresis was found during routine laboratory tests. Serum antidiuretic hormone (ADH) level was within normal limits, but the atrial natriuretic peptide (ANP) level was elevated. The second case presented with severe hypercalcemia secondary to an excessive parathormone (PTH) secretion. We discuss the 2 cases and review the literature.

Myocardial function in patients with breast cancer after therapy with anthracyclines and chest irradiation.

PURPOSE: To evaluate and compare the left ventricular performance in female patients with breast cancer treated with chemotherapy (CT) and either left or right thoracic irradiation (RT), using Doppler echocardiography. PATIENTS AND METHODS: Thirty-four patients with cancer of the left breast treated with surgical resection, adjuvant EC CT (epirubicin and cyclophosphamide) and conventionally fractionated left thoracic RT (study group) and a gender-and age-matched group of 34 patients with cancer of the right breast also treated with surgical resection, adjuvant EC CT and right thoracic RT (control group), were studied by echocardiography. Assessed were the left ventricular systolic performance by measuring the global ejection fraction (EF) and the shortening fraction (SF). Left ventricular diastolic performance was assessed by measuring the Doppler transmitral flow: the maximal velocity of the E wave (rapid filling/ Emax) and A wave (atrial filling/Emax) were measured. The ratio of Emax/Amax, the pressure half-time (PHT) of the E wave and the isovolumic relaxation time (IVRT) were also calculated. RESULTS: The left ventricular diastolic performance was altered in the study group which showed a significant decrease (p <0.001) of Emax. A wave was significantly increased in the study group compared with the control group (p <0.001. The mitral E/A ratio was subunitary in both groups but more depressed in the study group. The E wave PHT was more prolonged in the study group compared to the control group (p <0.001). The IVRT was prolonged in the study group compared with the controls (p <0.05). The left ventricular systolic performance was within normal limits in both groups. CONCLUSION: Our Doppler echocardiography study documented an impaired left ventricular diastolic performance in patients with cancer of the left breast treated with fractionated thoracic RT and CT. This impairment is due to poor left ventricular compliance.

Concurrent chemoradiotherapy with vinorelbine and a platinum compound followed by consolidation chemotherapy for unresectable stage III non-small cell lung cancer: preliminary results of a phase II study.

PURPOSE: To determine the efficacy, toxicity and survival of concurrent therapy with vinorelbine and a platinum compound with radiotherapy (RT), followed by consolidation chemotherapy with the same drugs, for locally advanced non small cell lung cancer (NSCLC). PATIENTS AND METHODS: Fifty-seven patients with stage III NSCLC were included in this phase II study: median age 56 years (range 44-71), males / females 49/8, ECOG performance status (PS) 1/2=27/30, stage IIIA/ IIIB 11/46, squamous cell carcinoma 44, adenocarcinoma 7, adenoid cystic carcinoma 1 and large cell carcinoma 5. Treatment consisted of 2 cycles of chemotherapy with vinorelbine and cisplatin or carboplatin, given concurrently with RT, followed by 2-4 more cycles of consolidation chemotherapy with the same drugs. Twenty-two patients received amifostine for radio- and chemoprotection. RESULTS: Grade 3 or 4 toxicities were neutropenia and esophagitis in 19% of the patients each, and gastrointestinal toxicity in 17% of the patients. Of the 55 patients evaluable for response, 23.64% achieved complete response (CR) and 40% partial response (PR) (overall response rate 63.64%). Progression-free survival curves showed 1- and 2-year values of 42% and 21%, respectively, and median time to progression 10.5 months. The 1- and 2- year disease-specific survival was 58% and 29%, and the median overall survival 15 months. CONCLUSION: Preliminary analysis indicates that concurrent vinorelbine and a platinum compound with RT followed by consolidation chemotherapy with the same drugs for advanced stage III NSCLC is well tolerated, has considerable activity and positive impact on survival.

Does epirubicin affect left ventricular systolic performance in oncologic patients?

PURPOSE: In the present study the left ventricular diastolic and systolic functions were evaluated in patients treated with lower total doses of epirubicin using Doppler echocardiography. PATIENTS AND METHODS: Seventeen patients with different malignant tumors treated with epirubicin up to 450 mg/m(2) (study group), and a gender-and age-matched group of 29 patients diagnosed with tumors, who had not started treatment yet (control group), were assessed by echocardiography. Left ventricular diastolic function was assessed by measuring the Doppler transmitral flow. We measured the maximal velocity of the E wave (rapid filling) and A wave (atrial filling). The ratio of Emax/Amax, the pressure half time (PHT) of the E wave and the iso-volumic relaxation time (IVRT) were also calculated. The left ventricular systolic performance was assessed by measuring the global ejection fraction (EF). RESULTS: The left ventricular diastolic performance was altered in the study group. In this group we noticed a significant decrease ( p < 0.001) of Emax. A wave was significantly increased in the study group compared to the control group ( p < 0.001). The mitral E/A ratio was subunitary in the study group. The E wave PHT was prolonged in the epirubicin-treated group in comparison to the controls (p<0.001). The IVRT was prolonged in the study group in comparison to the controls (p<0.05). The left ventricular systolic performance was not significantly altered in the study group compared to the control group. Although the EF was lower in the study group the difference did not reach statistical significance. CONCLUSION: Our Doppler echocardiography study documented an impaired left ventricular diastolic performance in patients with various malignancies treated with lower total doses of epirubicin. This impairment is due to poor left ventricular compliance.

Paclitaxel and carboplatin in relapsed or metastatic nasopharyngeal carcinoma: a multicenter phase II study.

PURPOSE: This multicenter phase II study was conducted to investigate the activity and toxicity of a combination of paclitaxel and carboplatin delivered on an outpatient basis in relapsed/ metastatic nasopharyngeal carcinoma patients. PATIENTS AND METHODS: Patients aged>/= 18 years with histologically proven recurrent or metastatic nasopharyngeal carcinoma, an Eastern Cooperative Oncology Group (ECOG) performance status /= 12 weeks were eligible. Measurable disease outside prior radiotherapy ports was required, unless a subsequent progression of the lesion was documented. An interval of >/= 12 months was required between the previous chemotherapy (neoadjuvant, concurrent chemoradiotherapy or adjuvant) and study entry. Prior radiotherapy or surgery were allowed. All patients had adequate bone marrow (WBC >4000/mL, platelets >100000/mL), hepatic (bilirubin <1,5 mg/dL, SGPT <1.5xN), and renal function (serum creatinine <1.5 mg/dL or creatinine clearance >60 mL/min). Chemotherapy consisted of paclitaxel 175 mg/m(2), given as a 3-hour infusion, followed by carboplatin dosed to an area under the concentration- time curve (AUC) of 6 mg*min/mL, administered every 21 days. RESULTS: 40 patients entered the study. There were 3 complete responders (CR) and 8 partial responders (PR), for an overall response rate (ORR) of 27.5% (95% confidence interval - C.I.: 14.5-44). Median time to progression (TTP) was 3.5 months, and median survival was 11.5 months. Grade 3-4 toxicity included leucopenia (17.5% of the patients), anaemia (17.5%), thrombocytopenia (10%), neutropenia (7.5%), and peripheral neuropathy (2.5%). CONCLUSION: These data indicate that the combination of paclitaxel and carboplatin can be safely administered on an outpatient basis, but it is only moderately active against relapsed/metastatic nasopharyngeal carcinoma patients.

First-line chemotherapy with topotecan and etoposide in advanced small cell lung cancer. A phase II study.

PURPOSE: Topotecan has recently shown activity in small cell lung cancer (SCLC) patients. The aim of the present phase II study was to assess the antitumor activity and toxicity of the combination of topotecan plus etoposide in chemotherapynaive patients with advanced SCLC on an outpatient basis. PATIENTS AND METHODS: From December 1998 to February 2001 24 previously untreated patients with histologically proven advanced (stage IIIB and IV) SCLC received topotecan 1.2 mg/m(2), days 1-5, followed by etoposide 100 mg/m(2), days 8-10, every 3 weeks, up to 6 cycles (less if progressive disease). RESULTS: Twenty-two patients were males and 2 females. Their median age was 54 years (range 37-67 years). World Health Organization (WHO) performance status (PS) was 0-1 in 12 patients and 2 in 12. AJCC stage IIIB was found in 6 patients and IV in 18. TOXICITY: 76 cycles (median 3.5 cycles) were given with no toxic deaths. Grade 4 toxicity was registered in 10 (13%) cycles for neutropenia, 4 (5%) cycles for anaemia, 1 (1.3%) cycle for thrombocytopenia and 1 (1.3%) cycle for diarrhea. Activity: among 23 evaluable patients, 8 had an objective response to chemotherapy (response rate - RR- 34.7%, 95% confidence interval -CI- 14-55%) with 4 (17.4%) complete remissions (CRs) and 4 (17.4%) partial remissions (PRs). Survival: with a median follow-up of 8 months (range 1.5-25 months), one-year actuarial survival was 48% (95% CI 28-69%) and median survival was 47.8 weeks. CONCLUSION: Although the combination of topotecan and etoposide proved easy to administer on an outpatient basis with moderate and manageable toxicity, it showed only moderate activity as first-line chemotherapy in advanced SCLC.