Chemotherapy-induced nausea and vomiting (CINV) in patients with advanced lung cancer during the first-line treatment: assessment by physicians, nurses, and patients from an Italian multicenter survey.

PURPOSE: Chemotherapy-induced nausea and vomiting (CINV) still represents a common side-effect of chemotherapy, and often, its perception differs between patients and healthcare professionals. The aim of this study was to evaluate the agreement on the perception of CINV and other items among clinicians, patients, and nurses. METHODS: This observational prospective study was part of an evaluation program promoted by the Women Against Lung Cancer in Europe (WALCE) Onlus. From August 2015 to February 2016, a survey was administered in 11 oncologic institutions to 188 stage IV lung cancer patients and to their oncologists and nurses during first-line chemotherapy. Our survey investigated 11 aspects: anxiety, mood, weakness, appetite, nausea, vomiting, pain, drowsiness, breath, general condition, and trust in treatments. These items were assessed through Numerical Rating Scale at four consecutive evaluations: at T0 (immediately prior to the first cycle), at T1 (immediately prior to the second cycle), at T2 (immediately prior to the third cycle), and at T3 (immediately prior to the fourth cycle). Clinician versus patient (CvP), nurse versus patient (NvP), and clinician versus nurse (CvN) agreements were estimated applying Weighted Cohen's kappa. A multivariate logistic model and generalized equation estimates were applied to evaluate factors possibly influencing CINV development. RESULTS: The incidence of patients reporting CINV varied from 40% at T0 to 71% at T3. Both CvP and NvP agreement on the investigated items were mainly moderate, slightly increasing over time, and becoming substantial for some items, in particular for NvP. Pre-chemotherapy anxiety in its mild, moderate, and severe manifestations, as well as mild, moderate, and severe anxiety experienced after chemotherapy start, exposed patients to a higher risk of anticipatory and acute/delayed CINV, respectively. CONCLUSIONS: Despite clinical staff awareness of patients' status and perceptions, CINV still represents a clinical problem. This study confirms that particular attention should be paid to anxiety due to its key role in CINV development.

Impact of a supportive care service for cancer outpatients: management and reduction of hospitalizations. Preliminary results of an integrated model of care.

PURPOSE: Supportive care in oncology is a primary need for every oncology department nowadays. In 2012, in our institution, a dedicated supportive care service (SCS) was created in order to deal with any need our on-treatment patients might have (e.g. tumour-related or treatment-related symptoms). We hypothesized that this service had a positive impact on the number of unplanned hospitalizations; to confirm our hypothesis, we decided to review admission data in 2011 and 2012. METHODS: Using our internal software, we compared admission data in 2011 (that is, the year before the dedicated service was created) and 2012 (when such service began, that is April of that year). We also made an evaluation of the costs of these hospitalizations. RESULTS: Despite an increase of the number of patients treated in our day hospital (+6.5 %), the number of unplanned hospital admissions decreased by 3.2 % (from 17.3 to 14.1 %). The number of patients accessing to emergency room went from 66 to 61 % (a reduction of 5 %). The costs of these hospitalizations were reduced by 2.2 %. CONCLUSIONS: The introduction of the dedicated SCS in our oncology department caused a net reduction by 3.2 % of the number of unplanned hospitalizations of on-treatment cancer patients.

Clinical impact of neutropenia and febrile neutropenia in metastatic colorectal cancer patients treated with FOLFOXIRI/bevacizumab: a pooled analysis of TRIBE and TRIBE2 studies by GONO.

BACKGROUND: TRIBE and TRIBE-2 studies demonstrated higher benefit from FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan)/bevacizumab compared with FOLFIRI (fluorouracil, leucovorin, and irinotecan) or FOLFOX/bevacizumab as an upfront option for metastatic colorectal cancer patients, with more toxicities. We focused on the incidence and longitudinal dynamics of neutropenia and febrile neutropenia (FN) in the two studies, to evaluate their clinical relevance, the magnitude of impact of FOLFOXIRI/bevacizumab, and the role of risk factors in predicting their occurrence. METHODS: The overall incidence of grade 3-4 (G3-4) neutropenia and FN, the time to their onset, the use of granulocyte colony-stimulating factor, and the association with risk factors were evaluated in the overall population and according to treatment arm. FN episodes were assessed by Multinational Association for Supportive Care in Cancer (MASCC) score. RESULTS: Among 1155 patients, 568 (49%) received FOLFOXIRI/bevacizumab. Overall, 410 (35%) experienced G3-4 neutropenia and 70 (6%) FN, 21 (2%) at high risk. FOLFOXIRI/bevacizumab was associated with higher incidence of neutropenia (51% versus 21%, P < 0.001), FN (8% versus 4%, P = 0.02), and high-risk FN [18 (3%) versus 3 (1%), P = 0.015]. No related deaths were observed. The first episode of G3-4 neutropenia and FN occurred mainly in the first 2 months in both arms. Longitudinal analysis showed different patterns of evolution over cycles between the arms (P < 0.001) G3-4 neutropenia being more frequent in the first cycles with FOLFOXIRI/bevacizumab. Older patients (P = 0.01) and females (P < 0.001) had a significantly higher risk of G3-4 neutropenia. No significant interaction effect between arm and analysed risk factors in terms of risk of G3-4 neutropenia or FN was observed. The incidence of FN among older females receiving FOLFOXIRI/bevacizumab was 12%. Neither G3-4 neutropenia nor FN impaired efficacy in terms of overall response rate, progression-free survival, and overall survival. CONCLUSIONS: FOLFOXIRI/bevacizumab has a higher risk of G3-4 neutropenia and FN than doublets/bevacizumab. FN occurred in <10% of patients, mostly as low-risk episodes. A closer monitoring during the first 2 months is recommended; prophylactic use of granulocyte colony-stimulating factor may be considered for older females.

A multicenter phase II study of the combination of oxaliplatin, irinotecan and capecitabine in the first-line treatment of metastatic colorectal cancer.

The triple drug combination consisting of irinotecan, oxaliplatin and 5-fluorouracil (FOLFOXIRI) has demonstrated higher activity and efficacy compared to the doublet FOLFIRI. 5-Fluorouracil could be substituted in FOLFOXIRI regimen by capecitabine, an oral fluoropyrimidine with similar efficacy. Recently, a dose-finding trial has demonstrated the feasibility of the combination of irinotecan, oxaliplatin and capecitabine (XELOXIRI) and established their recommended doses. The aim of this study was to evaluate the activity of XELOXIRI. A total of 36 patients with unresectable metastatic colorectal cancer received irinotecan 165 mg m(-2) and oxaliplatin 85 mg m(-2) on day 1 plus capecitabine 2000 mg m(-2) per day orally in two doses from day 1 to day 7, every 2 weeks. Grade 3-4 toxicities were infrequent, expect for neutropenia and diarrhoea, which were each observed in 30% of patients. Two complete and twenty-two partial responses were obtained, corresponding to an overall response rate of 67% (95% CI 51.4-82%). After a median follow-up of 17.7 months, the median progression-free and overall survival were 10.1 and 17.9 months, respectively. The substitution of 5-fluorouracil with capecitabine, in combination with irinotecan and oxaliplatin, is feasible and does not impair the activity of the regimen. However, the XELOXIRI combination is associated with a high incidence of diarrhoea and, therefore, should be considered as a not preferable alternative to FOLFOXIRI.

Azidothymidine in combination with 5-fluorouracil in human colorectal cell lines: in vitro synergistic cytotoxicity and DNA-induced strand-breaks.

The in vitro cytotoxicity of the combination of azidothymidine (AZT) and 5-fluorouracil (5-FU) against the human colorectal cancer cells SW-480, SW-620 and COLO-320DM was evaluated. The cytotoxic effects of 5-FU and AZT were determined by the assay using 2,3-bis(2-methoxy-4-nitro-5-sulfophenil)-2H-tetrazolium-5-carbo xanilide inner salt (XXT), while drug-induced DNA strand-breaks were measured using a fluorometric analysis of DNA unwinding. After an exposure of 72 h, 5-FU and AZT induced a dose-dependent cytotoxicity against each cell line. The addition of 3, 10 and 30 microM AZT to various concentrations of 5-FU, as well as the addition of 0.5, 1 and 3 microns 5-FU to various concentrations of AZT, resulted in an enhanced cytotoxic effect. Isobologram analysis and the combination index (CI) method demonstrated that the interaction between 5-FU and AZT was clearly synergistic in each cell line, except for the 30% level of effect in SW-620, where borderline synergism was observed. The evaluation of DNA strand-breaks after an exposure of 16 h to 5-FU, AZT or 5-FU + AZT demonstrated that the 5-FU + AZT combination produced the greatest DNA damage, and that this interaction was synergistic in each cell line. In conclusion, our study supports the evidence that the potential antitumour activity of AZT can be modulated by combining it with agents which inhibit thymidylate (dTMP) formation, such as 5-FU, and that the increased cytotoxicity is related to enhanced DNA damage. These findings should encourage further experimental and clinical studies of the potential use of AZT in combination with inhibitors of de novo dTMP synthesis.

Phase II study of high-dose paclitaxel and carboplatin in previously untreated, unresectable non-small cell lung cancer.

INTRODUCTION: This phase II study was designed to assess the activity and tolerability of the carboplatin-paclitaxel combination, given without routine growth factor support to previously untreated patients with stage IIIB and IV non-small cell lung cancer. PATIENTS AND METHODS: Sixty patients (15 stage IIIb and 45 stage IV) received paclitaxel 225 mg/ml on day 1, followed by carboplatin AUC 6 mg/ml per minute (Calvert formula) every 3 weeks. Paclitaxel was administered as a 3-h intravenous infusion followed by carboplatin over 30 min, on completion of paclitaxel administration. RESULTS: The combination showed a good safety profile with Grade 4 neutropenia occurring in 31% of patients without any serious infectious episodes requiring hospitalization. Moderate to severe anemia and thrombocytopenia seldom occurred. Sensorimotor peripheral neuropathy (Grade 2-3) and myalgia (Grade 3-4) were documented in 34 and 20% of the patients, respectively. Among 59 evaluable patients, there was one complete response and 26 partial responses for an overall response rate of 46% (95% C.I.: 34-59%). With a minimum follow-up duration of 16.5 months, the median overall survival time is 52 weeks and the 1-year survival rate is 50%. Median duration of response is 20 weeks (range: 4-52) and progression-free survival is 22 weeks (range: 5-77). CONCLUSION: In advanced NSCLC, the combination carboplatin-paclitaxel at doses of AUC 6 mg/ml per minute and 225 mg/ml every 3 weeks, is both active and relatively well-tolerated.

Gemcitabine monotherapy in elderly patients with advanced non-small cell lung cancer: a multicenter phase II study.

BACKGROUND: This trial investigated the activity and toxicity of gemcitabine in previously untreated elderly (> 70 years) patients with advanced (stage IIIB-IV) non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: From January 1997 to July 1998, 46 patients with advanced NSCLC aged over 70 years with a performance status of 0-2 were entered into the study. Gemcitabine 1000 mg/m2 was administered as a 30-min infusion once a week for 3 weeks followed by a week of rest; cycles were repeated every 4 weeks. RESULTS: Forty-four patients were evaluable for response. One complete response and nine partial responses were observed, for an overall response rate of 22.2% (95% C.I.: 11.3-37.5). The median time to disease progression was 5.1 months (95% C.I.: 3.5-6.7), the median duration of response was 6.3 months, and the median overall survival time 6.75 months (95% C.I.: 5.3-8.2). All patients were evaluable for toxicity (184 cycles, median = 3 cycles/patient) and no grade 4 hematologic toxicities were reported. WHO grade 3 leukopenia, neutropenia and anemia occurred in 3.3, 0.5 and 1.1% of cycles, respectively. Grade 3 skin rash occurred in 4.3% of patients. These side effects led to treatment discontinuation in two patients. CONCLUSION: Our data show that gemcitabine is active and well tolerated in patients aged over 70 years with advanced NSCLC.

Protracted continuous infusion of 5-fluorouracil and low-dose leucovorin in patients with metastatic colorectal cancer resistant to 5-fluorouracil bolus-based chemotherapy: a phase II study.

Continuous-infusion (c.i.) 5-fluorouracil (5-FU) can overcome resistance to bolus 5-FU, and leucovorin (LV) enhances the cytotoxic effects of 5-FU, mainly when the duration of exposure to the latter is prolonged. The main objective of this study was therefore to determine the activity of a prolonged infusion schedule of 5-FU + LV in patients with metastatic colorectal cancer resistant to a 5-FU bolus-based chemotherapy. Only patients with metastatic measurable disease in progression during or within 2 months of the end of a 5-FU bolus +/- LV-based chemotherapy were eligible for the study. 5-FU and l-LV were given as a 14-day c.i. every 28 days, the 5-FU dose being 200 mg/m2 per day and the l-LV dose being 5 mg/m2 per day. A total of 59 patients entered the study, of which 48 were resistant to 5-FU + LV and 11, to 5-FU + levamisole. Treatment was well tolerated, and WHO grade 3-4 toxicities were uncommon (11% of patients developed stomatitis and 7%, diarrhea). According to an intent-to-treat analysis, 10 of 59 patients obtained an objective response (1 complete response, 9 partial responses), for an objective response rate of 16% (95% confidence interval 8-25%). The median progression-free survival and overall survival were 4 and 9 months, respectively. The protracted 5-FU + LV c.i. schedule used in the present study is a well-tolerated and moderately active regimen in metastatic colorectal cancer patients resistant to 5-FU bolus +/- LV. Only randomized studies can determine whether this palliative treatment has advantages in comparison with other second-line therapies such as 5-FU c.i. without LV, irinotecan, or oxaliplatin.

Central motor conduction to lower limb after transcranial magnetic stimulation in spinocerebellar ataxia type 2 (SCA2).

OBJECTIVES: To evaluate central motor conduction to lower limbs in spinocerebellar ataxia type 2 (SCA2). METHODS: Transcranial magnetic stimulation was performed to study the corticospinal tracts of 18 patients with SCA2. RESULTS: Central motor conduction time (CMCT) to lower limbs and thresholds were abnormal in 8 patients (44%); CMCT and thresholds were significantly correlated with disease duration and disability. CONCLUSIONS: Corticospinal tract involvement is more frequent than previously reported in SCA2. Prolonged CMCT and increased threshold should not be used to differentiate between various type of autosomal dominant cerebellar ataxia. Similar to that reported in Friedreich's ataxia, we suggest that examining central motor conduction to the lower limbs may assist in evaluating the progressive steps of neurodegeneration in SCA2.

Long-acting depot lanreotide in the treatment of patients with advanced neuroendocrine tumors.

Long-acting depot forms of somatostatin analogs administered by intramuscular injections are now available for the treatment of neuroendocrine tumors (NETs). In the present study, we investigated the efficacy and tolerability of a slow-release form of lanreotide in patients with advanced NETs. From July 1996 to January 1999, 25 patients with advanced NETs (12 carcinoids, 13 endocrine pancreatic tumors) were enrolled in the study. Thirteen patients were pretreated with subcutaneous octreotide, chemotherapy, or hepatic metastasis alcoholization. All the patients had measurable disease. Seventeen patients were symptomatic and 20 patients had elevated serum and/or urine markers. Octreotide scintigraphy was positive in 23 of 25 patients. Lanreotide was administered as intramuscular injections at the dose of 30 mg every 2 weeks until there was objective, biochemical, or symptomatic tumor progression. Objective partial responses (PRs) were documented in 2 patients (8%), whereas 10 patients (40%) had tumor stabilization. The PRs were observed in patients with midgut carcinoids, of whom one was pretreated with subcutaneous octreotide. The response duration was 21+ and 24+ months in responding patients; the median duration of disease stabilization was 8.5 months (range, 4-21+). The overall biochemical response rate was 42%, including 2 complete responses (CRs) (10.5%) and 6 PRs (31.5%); all biochemical responses were observed mostly in patients with carcinoid tumors; the duration of response was 18+ and 30+ months for CRs; the median duration of biochemical response was 7 months (range, 4-18+) for PRs. The overall symptomatic response rate was 70% with a median duration of 7.5, 18, and 18+ months for diarrhea, abdominal pain, and flushing, respectively. Median duration of lanreotide treatment was 10 months (range, 2-30+). No significant side effects were reported. Depot lanreotide 30 mg shows significant efficacy in terms of objective response rate and in biochemical and symptomatic control, in pretreated patients as well as nonpretreated patients with advanced NETs. Tolerability is good, with good patient compliance.

Ambamustine in the second-line treatment of patients with small-cell lung cancer: a phase II Fonicap study.

Despite a high probability of response to first-line chemotherapy, most patients with small-cell lung cancer (SCLC) will eventually have progression of their disease because of the development of resistant disease. Second-line testing of new drugs is an accepted research strategy in SCLC. In this context, the Italian Lung Cancer Task Force (FONICAP) has tested a new synthetic bifunctional alkylating agent, Ambamustine, with preliminary evidence of activity in other solid tumors. Patients with measurable SCLC, progressive after one first-line chemotherapy regimen (either "sensitive" or "refractory"), were eligible for the study. Ambamustine was administered at the dose of 2 mg/kg as a 1-hour intravenous infusion on day 1 every 21 days. The dose was to be increased to 3 mg/kg if no grade IV toxicity and complete hematologic recovery had occurred by day 22. Sample size was calculated according to a two-stage optimal Simon's design. Seventeen patients were entered into the study. Twelve patients were refractory to prior chemotherapy; 12 had extensive disease; the median age was 64 years (range: 46-75 years) and the median performance status was 1. Among 13 patients who received more than one cycle, 9 patients could increase Ambamustine dose from 2 to 3 mg/kg. No objective response was observed: one patient obtained a 50% regression of the primary tumor with contemporary disease progression in the liver and was qualified as having progressive disease. The treatment was well tolerated: grade IV leukopenia occurred in only 1 patient; grade III anemia occurred in 17.6%, grade III leukopenia in 11.8%, and grade III thrombocytopenia in 23.5%. Nonhematologic toxicity was minimal. Ambamustine, at the dose and schedule used in this study, is well tolerated in pretreated patients with SCLC but has no significant antitumor activity in this unfavorable group of patients.

Suramin in combination with 5-fluorouracil (5-FU) and leucovorin (LV) in metastatic colorectal cancer patients resistant to 5-FU+LV-based chemotherapy.

AIMS AND BACKGROUND: Suramin has been shown to be of interest as a potential new anticancer agent because of its capacity to inhibit the binding of several growth factors to their receptors and to inhibit the growth of cancer cells in vitro. Since multi-autocrine loops involving growth factors which are antagonized by suramin have been demonstrated in colorectal cancer, we previously evaluated the activity of suramin in patients with advanced colorectal cancer. Interestingly, in this study three patients who had received 5-FU+LV after suramin, although heavily pretreated with fluoropyrimidines, obtained an objective response. This observation was intriguing as it might have been that suramin had changed the biology of the tumor, making it sensitive to 5-FU+LV. We therefore conducted the present study to investigate the possibility that suramin might overcome the resistance to 5-FU+LV. METHODS AND STUDY DESIGN: Only colorectal cancer patients with metastatic and progressive disease during 5-FU+LV-based chemotherapy were eligible for this study. Suramin was administered for eight weeks at doses determined by means of a computer-assisted dosing algorithm that used Bayesian pharmacokinetics to maintain suramin plasma concentrations of 200-250 microg/ml. 5-FU was administered weekly at a dosis of 450 mg/m2 halfway through a two-hour infusion of I-LV 250 mg/m2 starting one week after the initiation of suramin for a maximum of 26 weeks. RESULTS: Treatment was relatively well tolerated, but no objective responses were observed after the accrual of 13 patients in the first stage of the trial. Consequently, the trial was interrupted according to the initial two-stage sampling design. CONCLUSIONS: The present study does not support the hypothesis that suramin might overcome resistance to 5-FU+LV and its use in colorectal cancer is not recommended.

A dose finding and pharmacokinetic study of capecitabine in combination with oxaliplatin and irinotecan in metastatic colorectal cancer.

PURPOSE: The GONO-FOLFOXIRI regimen demonstrated higher activity and efficacy than FOLFIRI in metastatic colorectal cancer patients. The aim of this study was to determine the maximum tolerated dose of capecitabine, in substitution of 5-fluorouracil, combined with oxaliplatin and irinotecan and to evaluate the pharmacokinetics of the drugs. PATIENTS AND METHODS: We treated 15 patients with escalating doses of capecitabine (from day 1 to 7) and fixed doses of oxaliplatin (85 mg/m(2)) plus irinotecan (165 mg/m(2)) (both administered on day 1), repeated every 2 weeks. Pharmacokinetic analysis was performed on plasma samples collected at the first cycle of treatment. RESULTS: The maximum tolerated dose of capecitabine resulted 2,000 mg/m(2)/day, with diarrhea being the only dose-limiting toxicity. Large interpatient variability in the pharmacokinetic parameters of investigated drugs was observed. Results in terms of activity are promising. CONCLUSIONS: At the maximum tolerated dose of capecitabine of 2,000 mg/m(2)/day the combination is feasible with promising activity and deserves further investigations.

First line chemotherapy with planned sequential administration of gemcitabine followed by docetaxel in elderly advanced non-small-cell lung cancer patients: a multicenter phase II study.

This multicenter phase II study evaluated, in chemonaive patients with stage IIIB-IV NSCLC, age >or=70 and with a performance status 0-2, the activity, efficacy and tolerability of planned sequential administration of gemcitabine 1200 mg m(-2) on days 1 and 8 every 3 weeks for three courses followed by three cycles of docetaxel 37.5 mg m(-2) on days 1 and 8 every 3 weeks, provided there was no evidence of disease progression. A total of 56 patients entered the study. According to intention-to-treat analysis, the objective response rate was 16.0% (95% CI 7.6-28.3%); 23 patients (41.0%) had stable disease and 24 patients (43%) had progressive disease. Five patients who had a stable disease after three courses of gemcitabine obtained a conversion to partial response by docetaxel. Median time to progression was 4.8 months (95% CI 3.6-6.0 months) and median duration of survival was 8.0 months (95% CI 5.6-10.5 months). The 1-year survival rate was 34%. No grade 4 haematological toxicity was observed and grade 3 neutropenia and thrombocytopenia were reported in 5.4 and 3.6% of the patients, respectively. Grade 3/4 mucositis and grade 3 diarrhoea, both occurred in 3.6% of the patients and grade 3 asthenia was observed in 9% of patients. One patient reported a grade 4 skin toxicity. No treatment-related deaths occurred. Sequential gemcitabine and docetaxel is a well-tolerated and effective regimen in elderly advanced NSCLC patients.

Phase II study of sequential chemotherapy with docetaxel-estramustine followed by mitoxantrone-prednisone in patients with advanced hormone-refractory prostate cancer.

Sequential chemotherapy may improve treatment efficacy avoiding the additive toxicity associated with concomitant polichemotherapy in hormone-refractory prostate cancer (HRPC). Forty patients received docetaxel 30 mg m(-2) intravenous (i.v.), weekly, plus estramustine 280 mg twice daily for 12 weeks. After 2 weeks rest, patients with a decline or stable PSA were treated with mitoxantrone 12 mg m(-2) i.v. every 3 weeks plus prednisone 5 mg twice daily for 12 cycles. Forty patients were assessable for toxicity after docetaxel/estramustine. Main toxicities were grade 3-4 AST/ALT or bilirubin increase in seven patients (17.5%) and deep venous thrombosis (DVT) in four patients (10%). Twenty-seven patients received mitoxantrone/prednisone. Main toxicities included DVT in one patient (3.7%) and congestive heart failure in two patients (7%). Thirty-nine patients were assessable for PSA response. Twenty-nine patients (72.5%; 95% CI 63-82%) obtained a >/=50% PSA decline with 15 patients (37.5%; 95% CI 20-50%) that demonstrated a >/=90% decrease. Median progression-free and overall survival were respectively 7.0 (95% CI 5.8-8.2 months) and 19.2 months (95% CI 13.9-24.3 months). In conclusion, although this regimen demonstrated a favourable toxicity profile, sequential administration of mitoxantrone is not able to improve docetaxel activity in patients with HRPC.

Octreotide acetate long-acting release in patients with metastatic neuroendocrine tumors pretreated with lanreotide.

BACKGROUND: In the present study we investigated the efficacy and tolerability of i.m. octreotide acetate (octreotide LAR) in patients with metastatic neuroendocrine tumors (NETs) previously treated and failed on i.m. lanreotide. PATIENTS AND METHODS: Fifteen patients (8 females, 7 males, median age 67 years, range 28-81 years) with metastatic NETs (8 endocrine pancreatic tumors, 7 midgut carcinoids) were enrolled in the study. All patients were in progressive disease (objective: 11 patients, symptomatic: 10 patients, biochemical: 11 patients) after treatment with slow release lanreotide, 30 mg every 14 days for a median time of 8 months (range 3-19 months). All patients had measurable disease; 12 patients had elevated serum and/or urine markers and 11 were symptomatic. Octreotide scintigraphy was positive in 13 of 15 patients. Octreotide LAR was administered as i.m. injection at the dose of 20 mg every four weeks until disease progression. RESULTS: An objective partial response (PR) was documented in one patient (7%), no change (NC) in six (40%), and progressive disease (PD) in eight patients (53%). The PR was observed in one patient with non-functioning endocrine pancreatic tumor with progressive liver and lymph node metastases after 16 months of i.m. lanreotide therapy. The median duration of disease stabilization was 7.5 months (range 6-12+ months). The overall biochemical response rate was 41%, including CRs (33%) and PRs (8%); biochemical responses were observed in carcinoids as well as in endocrine pancreatic tumors; the median duration of response was 5 months for CRs and 7.5 months for PRs. The overall symptomatic response rate was 82%. The median duration of response for diarrhoea, abdominal pain, or both was 6.5 months (range 3-12+ months). Improvement in performance status (PS) was obtained in 5 of 11 patients with PS of 1 at study entry. Median duration of octreotide LAR treatment was seven months (range 3-12+ months). No serious adverse events were reported; mild side effects were reported in 26% of patients. CONCLUSIONS: Octreotide LAR 20 mg shows significant efficacy in terms of objective response rate (PR + SD), biochemical and symptomatic control in patients with metastatic NETs of the GEP system pretreated and progressing on slow release lanreotide.

A randomized study comparing two different schedules of administration of cisplatin in combination with gemcitabine in advanced nonsmall cell lung carcinoma.

BACKGROUND: This randomized trial was designed to investigate the feasibility, toxicity, and activity of two different schedules of gemcitabine plus cisplatin in previously untreated patients with advanced (International Union Against Cancer (UICC) Stage IIIB-IV) nonsmall cell lung carcinoma (NSCLC). METHODS: From February 1997 to September 1998, 82 patients with advanced NSCLC were entered onto the study and were randomized to gemcitabine 1000 mg/m(2) on Days 1, 8, and 15 plus cisplatin 80 mg/m(2) on Day 2 (arm A) or Day 15 (arm B) every 28 days. RESULTS: All the patients were assessable for toxicity (arm A/arm B: 151/177 cycles; median, 4 of 5 cycles per patient), and the following Grade 3-4 toxicities were reported (percentage of cycles in arm A vs. arm B): anemia, 7.9% and 2.3% (P < 0.05); leukopenia, 6.0% and 6.7%; thrombocytopenia, 15.0% and 1.6% (P < 0.01); no World Health Organization (WHO) Grade 3-4 nonhematologic toxicities were observed. These side effects led to gemcitabine dose reductions in 35.1% of courses in arm A and 22.0% of courses in arm B (P < 0.05) and to gemcitabine omissions in 28.5% of courses in arm A versus 7.3% of courses in arm B (P < 0.01). Dose intensities (DIs) of gemcitabine were 607.5 mg/m(2)/week in arm A and 711.6 mg/m(2)/week in arm B (P < 0.01); DIs of cisplatin were 18. 1 mg/m(2)/week in arm A and 18.8 mg/m(2)/week in arm B. The total delivered doses of gemcitabine were 9315.5 mg/m(2) in arm A and 12, 631.0 mg/m(2) in arm B (P < 0.01); the total delivered doses of cisplatin were 277.1 mg/m(2) in arm A and 333.0 mg/m(2) in arm B (P < 0.01). Response rates according to intention to treat were 40.4% (95% confidence interval [CI], 25.5-55.3) in arm A and 45% (95% CI, 29.5-60.5) in arm B. The overall median duration of response was 7.4 months; the median time to disease progression was 6 months (95% CI, 3-9) in arm A and 9 months (95% CI, 4-14) in arm B (P < 0.02); the median overall survival was 10 months (95% CI, 7.0-12.5) in arm A and 17 months (95% CI, 13.0-21.6) in arm B (P < 0.01); the 1-year survival rates were 34% and 63%, respectively. CONCLUSIONS: Our data show that arm B (cisplatin on Day 15) is less toxic than arm A (cisplatin on Day 2) and allows the administration of significantly higher total doses and dose intensities of chemotherapy. No significant differences in response rates were observed between the two schedules; patients on arm B experienced a significantly more prolonged progression free and overall survival; however, the study was not powered to detect differences in these outcomes.

Maximum tolerable doses of intravenous zidovudine in combination with 5-fluorouracil and leucovorin in metastatic colorectal cancer patients. Clinical evidence of significant antitumor activity and enhancement of zidovudine-induced DNA single strand breaks in peripheral nuclear blood cells.

BACKGROUND: Experimental studies have demonstrated that 5-fluorouracil (5-FU) enhances zidovudine (AZT)-induced DNA strand breaks and cytotoxicity. Phase I studies have demonstrated that the maximum tolerable dose (MTD) of AZT is 8000 mg/sqm when administered i.v. over two hours after weekly 5-FU + l-leucovorin (LV), and that this combination has promising antitumor activity. The purpose of this study was therefore to evaluate the antitumor activity of weekly bolus 5-FU + LV + AZT, administered at its MTD, and to determine whether 5-FU enhances AZT-induced DNA strand breaks in blood nuclear cells. PATIENTS AND METHODS: Twenty-nine chemotherapy-naïve metastatic colorectal cancer patients with measurable disease entered the study to evaluate the activity of a weekly 5-FU 500 mg/m2 i.v. bolus + LV 250 mg/m2 i.v. two-hour infusion + AZT 8000 mg/m2 i.v. two-hour infusion. In 10 different patients, who during three different weeks received 5-FU + LV, AZT and 5-FU + LV + AZT, DNA strand breaks in blood nuclear cells were determined by a fluorescent analysis of DNA unwinding. RESULTS: Treatment was generally well tolerated and WHO grades III-IV toxicities, consisting mostly of diarrhea (17%), were uncommon. One patient died of severe diarrhea with consequent hypokalemia and cardiac arrhythmia. All patients were considered evaluable for response, and 3 (10%) complete and 10 (35%) partial responses were observed, for an objective response rate of 45% (95% confidence limit interval 26%-64%). Both 5-FU + LV and AZT decreased the percentage of double stranded DNA in nuclear blood cells. The greatest effect was observed with 5-FU + LV + AZT, which reduced the percentage of double stranded DNA to 50% and 36% after 24 and 48 hours, respectively, and this interaction between 5-FU + LV and AZT was found to be cumulative. CONCLUSIONS: These studies demonstrate that the present dose and schedule of AZT in combination with 5-FU + LV has significant activity in metastatic colorectal cancer and that the combination of 5-FU + LV with AZT increases the amount of DNA damage. Therefore, AZT in combination with 5-FU + LV warrants further study in colorectal cancer.