PD-1 and PD-L1 expression in molecularly selected non-small-cell lung cancer patients.

BACKGROUND: Agents targeting programmed death-1 receptor (PD-1) and its ligand (PD-L1) are showing promising results in non-small-cell lung cancer (NSCLC). It is unknown whether PD-1/PD-L1 are differently expressed in oncogene-addicted NSCLC. METHODS: We analysed a cohort of 125 NSCLC patients, including 56 EGFR mutated, 29 KRAS mutated, 10 ALK translocated and 30 EGFR/KRAS/ALK wild type. PD-L1 and PD-1 expression were assessed by immunohistochemistry. All cases with moderate or strong staining (2+/3+) in >5% of tumour cells were considered as positive. RESULTS: PD-1 positive (+) was significantly associated with current smoking status (P=0.02) and with the presence of KRAS mutations (P=0.006), whereas PD-L1+ was significantly associated to adenocarcinoma histology (P=0.005) and with presence of EGFR mutations (P=0.001). In patients treated with EGFR tyrosine kinase inhibitors (N=95), sensitivity to gefitinib or erlotinib was higher in PD-L1+ vs PD-L1 negative in terms of the response rate (RR: P=0.01) time to progression (TTP: P<0.0001) and survival (OS: P=0.09), with no difference in PD1+ vs PD-1 negative. In the subset of 54 EGFR mutated patients, TTP was significantly longer in PD-L1+ than in PD-L1 negative (P=0.01). CONCLUSIONS: PD-1 and PD-L1 are differentially expressed in oncogene-addicted NSCLC supporting further investigation of specific checkpoint inhibitors in combination with targeted therapies.

Birth defects in a national cohort of pregnant women with HIV infection in Italy, 2001-2011.

OBJECTIVE: We used data from a national study of pregnant women with HIV to evaluate the prevalence of congenital abnormalities in newborns from women with HIV infection. DESIGN: Observational study. SETTING: University and hospital clinics. POPULATION: Pregnant women with HIV exposed to antiretroviral treatment at any time during pregnancy. METHODS: The total prevalence of birth defects was assessed on live births, stillbirths, and elective terminations for fetal anomaly. The associations between potentially predictive variables and the occurrence of birth defects were expressed as odds ratios (ORs) with 95% confidence intervals (95% CIs) for exposed versus unexposed cases, calculated in univariate and multivariate logistic regression analyses. MAIN OUTCOME MEASURES: Birth defects, defined according to the Antiretroviral Pregnancy Registry criteria. RESULTS: A total of 1257 pregnancies with exposure at any time to antiretroviral therapy were evaluated. Forty-two cases with major defects were observed. The total prevalence was 3.2% (95% CI 1.9-4.5) for exposure to any antiretroviral drug during the first trimester (23 cases with defects) and 3.4% (95% CI 1.9-4.9) for no antiretroviral exposure during the first trimester (19 cases). No associations were found between major birth defects and first-trimester exposure to any antiretroviral treatment (OR 0.94, 95% CI 0.51-1.75), main drug classes (nucleoside reverse transcriptase inhibitors, OR 0.95, 95% CI 0.51-1.76; non-nucleoside reverse transcriptase inhibitors, OR 1.20, 95% CI 0.56-2.55; protease inhibitors, OR 0.92, 95% CI 0.43-1.95), and individual drugs, including efavirenz (prevalence for efavirenz, 2.5%). CONCLUSIONS: This study adds further support to the assumption that first-trimester exposure to antiretroviral treatment does not increase the risk of congenital abnormalities.

Correlation of cytidine deaminase polymorphisms and activity with clinical outcome in gemcitabine-/platinum-treated advanced non-small-cell lung cancer patients.

BACKGROUND: The aim of this study was to evaluate whether cytidine deaminase (CDA) polymorphisms 79A>C and 435C>T and/or CDA enzymatic activity influenced clinical outcome in 126 advanced non-small-cell lung cancer patients treated with gemcitabine-platinum-regimens. PATIENTS AND METHODS: CDA polymorphisms and activity were analysed by PCR and high-performance liquid chromatography, respectively. Univariate and multivariate analyses compared biological/clinical parameters with response, clinical benefit, time to progression (TtP) and overall survival (OS) using Pearson's χ(2) test, log-rank test and Cox proportional hazards model. RESULTS: Patients with CDA A79A/A79C genotypes had significantly longer TtP (6.0 versus 3.0 months; P = 0.001) and OS (11.0 versus 5.0 months; P = 0.001) than patients with C79C genotype. Patients harbouring CDA C435C/C435T genotypes also had a longer OS (P = 0.025), but no correlations were observed with TtP. Conversely, patients with low-CDA activity had a significantly higher response rate (37.7% versus 13.8%; P = 0.006), clinical benefit (91.8% versus 51.7%; P < 0.001), as well as longer TtP (8.0 versus 3.0 months; P < 0.001) and OS (19.0 versus 6.0 months; P < 0.001). Furthermore, enzymatic activity emerged as an independent predictor for death/progression risk at multivariate analysis. CONCLUSIONS: CDA enzymatic activity appears to be the strongest candidate biomarker of activity and efficacy of platinum-gemcitabine-based chemotherapy and should be validated in a prospective study.

Consequences of targeted treatments for second-line therapy.

The paradigm for first-line treatment of relapsed or metastatic non-small cell lung cancer (NSCLC) is changing. Large phase III trials demonstrated that, in 2010, we cannot select a therapy without an accurate definition of tumor histology and epidermal growth factor receptor (EGFR) status. Patients harboring an EGFR-activating mutation have a better prognosis and certainly are extremely sensitive to EGFR-tyrosine kinase inhibitors, while other agents, such as bevacizumab or pemetrexed, are more effective and less toxic in patients with non-squamous histology. Moreover, data from large phase III trials demonstrated that maintenance therapy with pemetrexed, docetaxel or erlotinib is an effective strategy against metastatic NSCLC. Overall, the changing paradigm in first-line treatment of NSCLC inevitably is changing the second-line strategy. In addition, the emerging role of maintenance therapy is leading to early use of all agents potentially active in a second- or third-line setting, with the consequence that very few options are available at disease progression. The aim of this article is to discuss the consequences of targeted treatments for second-line therapy in metastatic NSCLC.

Declining HCV seroprevalence in pregnant women with HIV.

We assessed recent trends in hepatitis C virus (HCV) prevalence in pregnant women with HIV using data from a large national study. Based on 1240 pregnancies, we observed a 3.4-fold decline in HCV seroprevalence in pregnant women with HIV between 2001 (29.3%) and 2008 (8.6%). This decline was the net result of two components: a progressively declining HCV seroprevalence in non-African women (from 35.7% in 2001 to 16.7% in 2008), sustained by a parallel reduction in history of injecting drug use (IDU) in this population, and a significantly growing presence (from 21.2% in 2001 to 48.6% in 2008) of women of African origin, at very low risk of being HCV-infected [average HCV prevalence 1%, adjusted odds ratio (aOR) for HCV 0.09, 95% CI 0.03-0.29]. Previous IDU was the stronger determinant of HCV co-infection in pregnant women with HIV (aOR 30.9, 95% CI 18.8-51.1). The observed trend is expected to translate into a reduced number of cases of vertical HCV transmission.

Chemo-radiotherapy integration in unresectable locally advanced non-small-cell lung cancer: a review.

Approximately one-third of all non-small-cell lung cancer (NSCLC) are locally-advanced at diagnosis, and 15-17% of these tumors are unresectable at presentation. Definitive chemo-radiotherapy (CRT) represents the standard therapeutic approach. However, the literature has shown that only 15% of patients are alive at 5 years and this percentage has remained unchanged despite various attempts of improvement. The recent introduction of immunotherapy has not only strongly changed the clinical scenario but has also drawn attention to a stage of disease apparently forgotten for decades. Stage III NSCLC can represent an interesting setting for the combined use of chemo-radiation and immunotherapy, due to the potential synergistic effect between radiation and immune checkpoint inhibitors. We reviewed the available literature in order to report the state of art of stage III NSCLC, by focusing on trials that evaluate different combinations of CRT and new drugs of PD-1/PD-L1 axis, and anti-CTLA-4. The future goal in the management of unresectable stage III NSCLC will be the optimal patients' selection combined with the use of individualized immuno/chemotherapies that could potentially improve clinical outcomes.

Hepatitis B or hepatitis C coinfection in HIV-infected pregnant women in Europe.

OBJECTIVES: The aim of the study was to investigate the prevalence of and risk factors for hepatitis C or B virus (HCV or HBV) coinfection among HIV-infected pregnant women, and to investigate their immunological and virological characteristics and antiretroviral therapy use. METHODS: Information on HBV surface antigen (HBsAg) positivity and HCV antibody (anti-HCV) was collected retrospectively from the antenatal records of HIV-infected women enrolled in the European Collaborative Study and linked to prospectively collected data. RESULTS: Of 1050 women, 4.9% [95% confidence interval (CI) 3.6-6.3] were HBsAg positive and 12.3% (95% CI 10.4-14.4) had anti-HCV antibody. Women with an injecting drug use(r) (IDU) history had the highest HCV-seropositivity prevalence (28%; 95% CI 22.8-35.7). Risk factors for HCV seropositivity included IDU history [adjusted odds ratio (AOR) 2.92; 95% CI 1.86-4.58], age (for > or =35 years vs. <25 years, AOR 3.45; 95% CI 1.66-7.20) and HBsAg carriage (AOR 5.80; 95% CI 2.78-12.1). HBsAg positivity was associated with African origin (AOR 2.74; 95% CI 1.20-6.26) and HCV seropositivity (AOR 6.44; 95% CI 3.08-13.5). Highly active antiretroviral therapy (HAART) use was less likely in HIV/HCV-seropositive than in HIV-monoinfected women (AOR 0.34; 95% CI 0.20-0.58). HCV seropositivity was associated with a higher adjusted HIV RNA level (+0.28 log(10) HIV-1 RNA copies/mL vs. HIV-monoinfected women; P=0.03). HIV/HCV-seropositive women were twice as likely to have detectable HIV in the third trimester/delivery as HIV-monoinfected women (AOR 1.95; P=0.049). CONCLUSIONS: Although HCV serostatus impacted on HAART use, the association between HCV seropositivity and uncontrolled HIV viraemia in late pregnancy was independent of HAART.

Baseline elevated leukocyte count in peripheral blood is associated with poor survival in patients with advanced non-small cell lung cancer: a prognostic model.

PURPOSE: We aimed to investigate the prognostic significance of several baseline variables in stage IIIB-IV non-small cell lung cancer to create a model based on independent prognostic factors. METHODS/RESULTS: A total of 320 patients were treated with last generation chemotherapy regimens. The majority of patients received treatment with cisplatin + gemcitabine or gemcitabine alone if older than 70 years or with an ECOG performance status (PS) = 2. Performance status of 2, squamous histology, number of metastatic sites >2, presence of bone, brain, liver and contralateral lung metastases and elevated leukocyte count in peripheral blood were all statistically significant prognostic factors in univariate analyses whereas the other tested variables (sex, stage, age, presence of adrenal gland and skin metastases) were not. Subsequently, a multivariate Cox's regression analysis identified PS 2 (P < 0.001, hazard ratio 2.57), elevated leukocyte count (P < 0.001, hazard ratio 1.79), squamous histology (P = 0.005, hazard ratio 1.45) and presence of brain metastases (P = 0.035, hazard ratio 1.5) as independent prognostic factors for poor survival. Patients were assigned to one of three risk groups according to the cumulative risk defined as the sum of simplified risk scores of the four independent prognostic factors. Low-, intermediate- and high-risk patients achieved a median survival of 10.2 months (95% confidence interval (CI) 8.9-11.6), 5.1 months (95% CI 4.0-6.2) and 2.8 months (95% CI 0.5-5.2), respectively. The high-risk group encompassed PS 2 patients with two or three adjunctive unfavourable independent prognostic factors. CONCLUSIONS: Performance status, white blood cells count, histology and brain metastases resulted in our series prognostic factors of survival in NSCLC patients treated with chemotherapy at a multivariate analysis. Leukocyte count resulted the stronger factor after performance status. If prospectly validated, the proposed prognostic model could be useful to stratify performance status 2 patients in specific future trials.

Pregnancy outcomes and antiretroviral treatment in a national cohort of pregnant women with HIV: overall rates and differences according to nationality.

We used data from the main surveillance study of HIV and pregnancy in Italy to evaluate possible differences in pregnancy care and outcomes according to nationality. Among 960 women followed in 2001-06, 33.5% were of foreign nationality, mostly from African countries. Foreign women had lower rates of preconception counselling and planning of pregnancy. They had more frequently HIV diagnosed during pregnancy, with a later start of antiretroviral treatment and lower treatment rates at all trimesters but not when the entire pregnancy, including delivery, was considered. No differences were observed between the two groups in ultrasonography assessments, hospitalisations, AIDS events, intrauterine or neonatal deaths, and mode and complications of delivery. Foreign women had a slightly lower occurrence of preterm delivery and infants with low birthweight. The results indicate good standards of care and low rates of adverse outcomes in pregnant women with HIV in Italy, irrespective of nationality. Specific interventions, however, are needed to increase the rates of counselling and HIV testing before pregnancy in foreign women.

Prolonged gemcitabine infusion in advanced non-small-cell lung cancer with stable disease after gemcitabine 30-min infusion.

BACKGROUND: Although 30-min gemcitabine infusion has become the standard administration, pre-clinical and clinical studies have suggested the possibility that an infusion rate of 10 mg/m(2) per minute may be more effective. The main objective of this study was to investigate whether the pursuance of gemcitabine, administered at a prolonged infusion rate, was able to convert stable disease to objective response after two or three cycle of standard administration. The secondary end-point was the evaluation of the new schedule toxicity. PATIENTS AND METHODS: Thirty-eight patients, with stage IIIA-B and IV NSCLC already treated by two or three cycles of 30-min gemcitabine infusion, alone or in combination with cisplatin, were enrolled: 26 patients (aged <70 years) were treated with cisplatin 80 mg/m(2) on day 1 plus gemcitabine 1200 mg/m(2) over 120 min on day 1 and 8 every three weeks and 12 patients (aged > or =70 years) were treated with gemcitabine alone 1200 mg/m(2) over 120 min on day 1 and 8 every three weeks, for two courses. Simon's two stage minimax design was applied to calculate the sample size. Assuming p(0) (low conversion rate) 5%, p(1) (target conversion rate of interest) 20%, alpha error 0.05, beta error 0.10 a total of 29 evaluable patients had to be accrued during stage 1. In case at least one objective response was observed, a further nine evaluable patients had to be enrolled into the study during stage 2. The regimen was considered promising if > or =4 objective responses out of 38 evaluable patients were observed. RESULTS: Thirty-eight patients were evaluable for response and in five patients (with stable disease after two courses of gemcitabine 30' infusion) a partial response was observed (conversion rate 13.1%, 95% confidence interval 4.4-28%). Toxicities were more frequently observed with cisplatin plus 120-min gemcitabine infusion: grade 3-4 neutropenia, thrombocytopenia and anaemia in 28, 22 and 16% of the courses, respectively. CONCLUSIONS: The prolongation of gemcitabine infusion time is able to convert stable disease to partial response in 13% of the cases. The haematological toxicity seems enhanced with cisplatin plus gemcitabine prolonged infusion.

Lipid profile during pregnancy in HIV-infected women.

PURPOSE: We investigated the evolution of serum lipid levels in HIV-infected pregnant women and the potential effect of antiretroviral treatment during pregnancy using data from a national surveillance study. METHOD: Fasting lipid measurements collected during routine care in pregnancy were used, analyzing longitudinal changes and differences in lipid values at each trimester by protease inhibitors (PIs) and stavudine use. Multivariate analyses were used to control for simultaneous factors potentially leading to hyperlipidemia. Study population included 248 women. RESULTS: Lipid values increased progressively and significantly during pregnancy: mean increases between the first and third trimesters were 141.6 mg/dL for triglycerides (p < .001), 60.8 mg/dL for total cholesterol (p < .001), 13.7 mg/dL for HDL cholesterol (p < .001), and 17.8 mg/dL for LDL cholesterol (p = .001). At all trimesters, women on PIs had significantly higher triglyceride values compared to women not on PIs. The effect of PIs on cholesterol levels was less consistent. Stavudine showed a dyslipidemic effect at first trimester only. Multivariate analyses confirmed these observations and suggested a potential role of other cofactors in the development of hyperlipidemia during pregnancy. CONCLUSION: The changes observed point to the need to further explore the causes and the clinical correlates of hyperlipidemia during pregnancy in women with HIV.

Dose-finding study and pharmacokinetics of epirubicin and paclitaxel over 3 hours: a regimen with high activity and low cardiotoxicity in advanced breast cancer.

PURPOSE: To determine the maximum-tolerated dose (MTD) of paclitaxel over 3 hours with a fixed dose of epirubicin, to investigate the plasma pharmacokinetics of this combination, and to evaluate the toxicity and the activity in previously untreated metastatic breast cancer patients. PATIENTS AND METHODS: Fifty patients with metastatic breast cancer, measurable disease, and normal left ventricular ejection fraction (LVEF) were eligible. Epirubicin was administered as an intravenous (I.V.) bolus at the fixed dose of 90 mg/m2 before the infusion of paclitaxel over 3 hours. The initial dose of paclitaxel was 135 mg/m2 and was increased by 20 mg/m2 in subsequent cohorts of six patients until dose-limiting toxicity (DLT). Plasma pharmacokinetics of paclitaxel and epirubicin was performed at cycle 1 in at least two patients per dose level of paclitaxel (175 up to 225 mg/m2). RESULTS: The DLT of this combination was febrile neutropenia in two of eight patients who received paclitaxel at 225 mg/m2. The mean peak plasma concentration of paclitaxel ranged between 5.1 and 6.2 micromol/L at doses of 175 to 225 mg/m2. The concentration of epirubicinol decreased from 47.3 +/- 9.4 to 37.9 +/- 7.5 ng/mL in patients treated with paclitaxel 175 and 225 mg/m2. The most relevant toxicity was grade 4 neutropenia (61% of all courses). The pharmacokinetic data of paclitaxel, in particular the time above the threshold level of 0.05 micromol/L, were not significantly related to myelosuppression. Cardiac toxicity was mild: three patients (6%) developed mild congestive heart failure that was responsive to therapy. Among 49 assessable patients, 41 responses (84%; 95% confidence interval [CI], 70% to 92%) were observed, and nine (18%) of these were complete. CONCLUSION: Our study demonstrates that (1) the MTD is epirubicin 90 mg/m2 and paclitaxel 200 mg/m2; (2) no clear relationship exists between pharmacokinetic data of paclitaxel and myelosuppression, while the increase in the dose of paclitaxel is associated with a reduction in epirubicinol plasma levels; and (3) the association is feasible, with low cardiotoxicity, and has a high activity in metastatic breast cancer.

Multicenter randomized controlled clinical trial to evaluate cardioprotection of dexrazoxane versus no cardioprotection in women receiving epirubicin chemotherapy for advanced breast cancer.

PURPOSE: Dexrazoxane was found effective in reducing doxorubicin cardiotoxicity when given at a dose ratio (dexrazoxane: doxorubicin) of 20:1. Preclinical studies indicated that dexrazoxane at a dose ratio of 10 to 15:1 also protected against epirubicin-induced cardiotoxicity. The main objective of this study was to investigate the efficacy of dexrazoxane, given at a dose ratio of 10:1 against epirubicin cardiotoxicity. PATIENTS AND METHODS: One hundred sixty-two advanced breast cancer patients were randomized to receive epirubicin-based chemotherapy with or without dexrazoxane. Patients who had previously received adjuvant chemotherapy that contained anthracyclines were treated with cyclophosphamide 600 mg/m2 intravenously (IV), epirubicin 60 mg/m2 IV, and fluorouracil 600 mg/m2 IV, on day 1 every 3 weeks. The other patients were treated with epirubicin 120 mg/m2 IV on day 1 every 3 weeks. Cardiac toxicity was defined as clinical signs of congestive heart failure, a decrease in resting left ventricular ejection fraction (LVEF) to < or = 45%, or a decrease from baseline resting LVEF of > or = 20 EF units. RESULTS: One hundred sixty patients were evaluated. Cardiotoxicity was recorded in 18 of 78 patients (23.1%) in the control arm and in six of 82 (7.3%) in the dexrazoxone arm. The cumulative probability of developing cardiotoxicity was significantly lower in dexrazoxane-treated patients than in control patients (P = .006; odds ratio, 0.29; 95% confidence limit [CL], 0.09 to 0.78). Noncardiac toxicity, objective response, progression-free survival, and overall survival were similar in both arms. CONCLUSION: Dexrazoxane given at a dexrazoxane:epirubicin dose ratio of 10:1 protects against epirubicin-induced cardiotoxicity and does not affect the clinical activity and the noncardiac toxicity of epirubicin. The clinical use of dexrazoxane should be recommended in patients whose risk of developing cardiotoxicity could hamper the eventual use and possible benefit of epirubicin.

Increased dose-intensity of gemcitabine in advanced non small cell lung cancer (NSCLC): a multicenter phase II study in elderly patients from the "polmone toscano group" (POLTO).

Gemcitabine is usually administered at a planned dose-intensity (DI) from 750 to 800 mg/m2/week. Preclinical data have suggested a possible dose-response relationship of gemcitabine. A multicenter phase II study was conducted to evaluate the activity in terms of no progression rate (complete responses+partial responses+stable diseases) of gemcitabine administered at an increased DI (1000 mg/m2/week) in elderly advanced non-small-cell lung cancer (NSCLC) patients. Secondary endpoints were to evaluate tolerability, progression free survival and overall survival. Elderly (age>or=70 years) chemo-naive advanced NSCLC patients, ECOG PS 0-2, were treated with intravenous gemcitabine 1500 mg/m2 intravenous (30 min infusion) on days 1 and 8 every 21 days for four courses. One hundred and twenty-two patients with a median age of 75 years (range 70-84) entered the study. The following grade 3 (NCI-CTC) haematological toxicities were reported (percent of patients): neutropenia 2.4%, thrombocytopenia 1.6%, anaemia 2.4%. No grades 3-4 non-haematological toxicities were observed. Among 111 evaluable patients 52 (46.8%) no progressions, 17 (15.3%) partial responses (WHO criteria), 35 (31.5%) stable diseases and 59 (53.2%) progressions were observed. Median time to progression was 3.2 months and median duration of survival was 5.4 months. The overall 1-year survival rate was 27%. Although increased dose-intensity of gemcitabine in elderly NSCLC patients is feasible without severe toxicities, this does not seem to be associated with an increased activity and efficacy in comparison to standard gemcitabine regimens with lower dose-intensities.

The incidence of complications after caesarean section in 156 HIV-positive women.

OBJECTIVE: To investigate the risks of post-operative complications in HIV-positive mothers who undergo a caesarean section (CS) because the delivery cannot be safely accomplished by the vaginal route or to protect the infant from viral infection. DESIGN: In a multicentre study, we reviewed the incidence and type of post-operative complications in 156 HIV-positive women who underwent a CS. These results were compared with those observed in an equal number of HIV-uninfected women who matched for the indication requiring a caesarean delivery, the stage of labour, the integrity or rupture of membranes, and the use of antibiotic prophylaxis. SETTING: Seven teaching hospitals providing obstetrical care for mothers infected with HIV. RESULTS: We found that six HIV-infected mothers suffered a major complication (two cases of pneumonia, one pleural effusion, two severe anaemia and one sepsis) compared with only one HIV-negative woman who required blood transfusion after surgery. Minor complications like post-operative fever, endometritis, wound and urinary tract infections were significantly more frequent in HIV-positive women than controls. Multivariate analysis revealed that in HIV-infected women the only factor associated with a significant increase in the rate of complications was a CD4 lymphocyte count < 200 x 10(6)/l. CONCLUSIONS: The results of our study indicate that HIV-positive mothers are at an increased risk of post-operative complications when delivered by CS. The risk of post-operative complications is higher in HIV-infected women who are severely immunodepressed.

Sequential chemoradiation therapy with vinorelbine, ifosfamide, and cisplatin in stage IIIB non-small cell lung cancer: a phase II study.

Meta-analysis has demonstrated survival benefit for patients with stage IIIB non-small cell lung cancer treated with sequential chemoradiotherapy versus radiotherapy alone. The introduction of chemotherapy as part of a multimodality approach has improved the outcome in this poor prognostic subset of cancer patients. In the present phase II study we evaluated the safety and activity of a new cisplatin-based three-drug regimen consisting of vinorelbine/ifosfamide/cisplatin (VIP) followed by curative thoracic irradiation in 28 patients with stage IIIB non-small cell lung cancer. Patients received vinorelbine 25 mg/m2 on days 1 and 8, ifosfamide 3 g/m2 on day 1 (with mesna), and cisplatin 80 mg/m2 on day 1 every 3 weeks. After three courses of induction chemotherapy, patients with objective response or stable disease were eligible for thoracic radiotherapy. Twenty-six of the 28 patients received at least three courses of chemotherapy and were evaluable for response. The response rate to induction VIP was 58% (15 of 26 patients; one complete response and 14 partial responses). Seven patients had disease stabilization and four progressed during chemotherapy. Radiation treatment started from 4 to 6 weeks after the end of chemotherapy with standard fractionation (200 cGy/day, 5 fractions/wk/6 wk). Eighteen of 22 patients started thoracic irradiation; 14 completed the treatment plan, reaching the total dose of 60 Gy. The most relevant acute and late toxicities of radiotherapy were grade 3 dysphagia and pneumonitis in two patients and grade 3 lung fibrosis in six patients. By comparing the tumor volumes before and after radiation treatment we observed six clinical remissions, three stable diseases, and five local progressions. The first site of recurrence was local in 10 of 18 patients (56%), distant in seven patients (38.8%), and both local and distant in one patient. Median progression-free survival and overall survival for the patients treated with radiotherapy (18 patients) were 14 months (range, 4 to 36 months) and 26 months (range, 7 to 54+ months), respectively; the 1- and 2-year survival rates were 61% and 52%. Curative thoracic radiotherapy was well tolerated after VIP induction chemotherapy; it reduced residual tumor volume in six patients.

Combination chemotherapy with vinorelbine, ifosfamide, and cisplatin: a phase II study in stage IIIB-IV non-small cell lung cancer.

Forty-five stage IIIB-IV non-small cell lung cancer (NSCLC) patients entered a phase II study designed to evaluate the toxicity and the activity of a combination chemotherapy regimen consisting of vinorelbine (25 mg/m2 days 1 and 8), ifosfamide (3 g/m2 day 1 with uroprotective mesna), and cisplatin (80 mg/m2 day 1). The regimen, VIP, was administered on an outpatient basis every 3 weeks. White blood cell counts were checked weekly, and granulocyte colony-stimulating factor was administered in case of grade 4 neutropenia lasting for more than 48 hours. Leukopenia was the most frequent toxicity, with grades 3 and 4 neutropenia reported in 25% of cycles and 11 episodes of febrile neutropenia recorded in 175 evaluable courses. The combination of vinorelbine and cisplatin did not result in additive neurotoxicity: only five patients experienced grade 2 neurotoxicity after six courses of treatment. Thirty-five patients were evaluable for response. Twenty partial responses (57%) and one complete response (2.8%) were observed, for an overall response rate of 60% (95% confidence interval, 42% to 76%). The median time to progression, measured from the start of treatment, was 7 months (range, 1 to 18+), and median survival for the whole group was 12 months (range, 1 to 18+). VIP is a well-tolerated regimen and shows interesting activity in advanced NSCLC.

A dose-finding study of epirubicin in combination with paclitaxel in the treatment of advanced breast cancer.

We performed a dose escalation study to evaluate the maximum tolerated dose of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) given over 3 hours plus bolus epirubicin 90 mg/m2. The starting dose of paclitaxel, 135 mg/m2, was escalated by 20-mg/m2 increments in cohorts of three to six patients. Courses were repeated every 3 weeks. Filgrastim (5 micrograms/kg/d) was administered to shorten the duration of grade 4 neutropenia lasting longer than 72 hours. Twenty-nine patients have been treated, 86% of whom had failed adjuvant chemotherapy (with anthracyclines in 14 cases). One hundred forty-eight courses have been administered, and the paclitaxel dose has been escalated to 225 mg/m2 without reaching the maximum tolerated dose. The most frequent dose-related toxicity has been grade 4 neutropenia, which occurred in 59% of courses. The median duration of grade 4 neutropenia was 4 days, which was shortened with filgrastim only in patients treated with paclitaxel 225 mg/m2. Eleven episodes of febrile neutropenia (7% of courses) have been observed. Nonhematologic toxicities were mild or moderate: grade 1 or 2 peripheral neuropathy was reported by 41% and 10% of patients, respectively. The cardiac toxicities of this regimen were surprisingly low: median left ventricular ejection fraction was 57% at study entry and 56% after six courses. Only two patients showed a decrease of left ventricular ejection fraction below 50% after six courses, and no signs of anthracycline-induced congestive heart failure were noted. The activity of this novel combination is encouraging: the overall response rate is 80%, with 16% complete responses. We have demonstrated that the combination of epirubicin plus paclitaxel given over 3 hours is feasible with acceptable toxicities, does not appear to be associated with clinically relevant cardiotoxicity, and is active in a population of patients who have failed adjuvant chemotherapy.

Paclitaxel in combination with vinorelbine in pretreated advanced breast cancer patients.

This phase II study combined paclitaxel (Taxol; Bristol Myers Squibb Company, Princeton, NJ) 135 mg/m2 by 3-hour infusion on day 1 and vinorelbine 25 mg/m2 on days 1 and 8 (in the first 14 patients) or on days 1 and 3 (in the subsequent 20 patients). The courses were repeated every 3 weeks. The second vinorelbine dose (on days 3 or 8) was reduced or omitted according to the toxicities encountered. Thirty-four patients have been treated to date; 21 had received one prior regimen of chemotherapy, 11 had two prior regimens, and two had three prior regimens. Only two patients (6%) had not been exposed to anthracyclines. One hundred twenty-six courses have been administered: 52 with vinorelbine given on days 1 and 8, and 74 with vinorelbine administered on days 1 and 3. The most frequent toxicity was grade 4 neutropenia, which occurred in 64% of the courses; 13 episodes of febrile neutropenia have been reported in eight patients. Filgrastim was administered in 43% of the courses because of febrile neutropenia or delayed recovery (> 72 hours) from grade 4 neutropenia. Mucositis was observed in 18% of the courses (12% grade 1, 3% grade 2, and 3% grade 3). The dose of vinorelbine was reduced or omitted in 86% of courses with the days 1 and 8 schedule, and in 48% of courses with the days 1 and 3 schedule. Among 28 evaluable patients, two complete and 10 partial responses have been observed (response rate, 43%, 95% confidence interval, 19% to 51%). Median duration of response is 5+ months (range, 1 to 15 months). In conclusion, this combination is active and has acceptable toxicities in anthracycline-pretreated breast cancer patients. The delivered dose intensity of vinorelbine is higher with the schedule adopted later in the study, with vinorelbine given on days 1 and 3.