The outcome of elderly patients with advanced urothelial carcinoma after platinum-based combination chemotherapy.

BACKGROUND: The majority of patients with advanced urothelial cancer are elderly, but data regarding this specific age group are limited. We compared the tolerability and efficacy of first-line platinum (cisplatin or carboplatin)-based chemotherapy in elderly patients (> or =70 years) with those in younger patients. PATIENTS AND METHODS: A total of 381 patients with advanced urothelial carcinoma received CIMV (cisplatin, ifosphamide, methotrexate, vinblastine) (n=32), MVAC (methotrexate, vinblastine, doxorubicin, cisplatin) (n=105), DC (docetaxel, cisplatin) (n=174), CaG (carboplatin, gemcitabine) (n=64) or other regimes (n=6) and were included in this analysis. RESULTS: A total of 116 patients were > or =70 years. Elderly patients experienced more frequent neutropenia grade 3/4 (55% versus 37%, P=0.087) and renal toxicity (28% versus 10%, P=0.033) among patients treated with CIMV/MVAC, and neutropenic infections (4% versus 0%, P=0.019) among patients treated with DC. Median survival did not differ significantly between elderly and younger patients (9.3 versus 10.5 months, P=0.16). Eastern Cooperative Oncology Group performance status (PS) and haemoglobin were independently associated with prognosis. Patients with PS <2 and haemoglobin > or =10 g/dl had a median survival of 14 months as opposed to 5 months for patients with PS > or =2 or haemoglobin <10 g/dl (P <0.001). CONCLUSION: Elderly patients with advanced urothelial cancer tolerate platinum-based chemotherapy well and derive the same benefit as their younger counterparts.     

Randomised Phase III study of biweekly 24-h infusion of high-dose 5FU with folinic acid and oxaliplatin versus monthly plus 5-FU/folinic acid in first-line treatment of advanced colorectal cancer.

BACKGROUND: A phase III study was started to compare oxaliplatin/5FU/LV in the first-line with bolus FU/LV in metastatic colorectal cancer. PATIENTS AND METHODS: 302 patients were randomised and received bolus 5-FU 425 mg/m(2) day 1-5, FA 20 mg/m(2) day 1-5, q 4 wk or oxaliplatin 85 mg/m(2), 2 h-infusion, FA 200 mg/m(2), 1-h infusion. 5-FU 2600 mg/m(2), 24-h infusion day 1, q 2 wk. The primary endpoint was response rate (RR). RESULTS: The median follow-up is 31.8 months, 90.4% of the patients have died. Confirmed RR, progression free survival (PFS; months) and median overall survival (OS; months) in 5FU/LV versus 5FU/LV/oxaliplatin were respectively 18.5% versus (vs) 33.8% (P = 0.004), 5.6 vs 6.7 (P = 0.016) and 13.3 vs 13.8 (P = 0.619). In the 5FU/LV/oxaliplatin arm less grade (3/4) toxicity was measured for diarrhoea, stomatitis, an increase in idiosyncratic side effects and neurosensory events compared with 5FU/LV. The quality of life (QOL) was equal in both arms. Second line treatment was given in 62% of the patients, crossover of 5FU/LV to 5FU/LV/oxaliplatin occurred in 14%. CONCLUSIONS: Oxaliplatin in the first-line resulted in an increased RR and PFS with less grade 3/4 mucositis/diarrhoea compared with 5FU/LV alone. Idiosyncratic side effects deserve attention with oxaliplatin. Despite a low treatment cross over rate, OS in both groups was comparable.     

Treatment-induced anaemia and its potential clinical impact in patients receiving sequential high dose chemotherapy for metastatic testicular cancer

First-line sequential high dose chemotherapy is under investigation in patients with "poor prognosis" metastatic germ cell tumours in order to improve survival. Despite the use of autologous peripheral blood stem cell transplantation and granulocyte colony stimulating factor chemotherapy dose intensification is associated with severe haematotoxicity including anaemia, which may significantly affect quality of life and tolerability of chemotherapy. This study investigates the frequency and degree of anaemia in patients receiving first-line sequential high dose chemotherapy for metastatic testicular cancer and the impact of anaemia on treatment outcome. A total of 101 newly diagnosed patients with "poor prognosis" metastatic nonseminomatous germ cell tumours were treated with one cycle of standard VIP followed by three cycles of HD-VIP-chemotherapy (etoposide, ifosfamide, cisplatin) within a large phase I/II study. Differential blood cell counts were taken prior, during and after every cycle of chemotherapy. Additionally, the numbers of red blood cell and platelet transfusions were recorded. Kaplan-Meier analyses were performed to correlate pre-treatment and post-treatment haemoglobin values to response and overall survival. Forty-eight per cent of the patients were classified anaemic (haemoglobin <12 g dl(-1)) prior to the start of chemotherapy. The application of sequential HD-VIP resulted in median haemoglobin nadirs between 7.8 g dl(-1) (range 5.5-11.1 g dl(-1)) in the first cycle and 7.6 g dl(-1) (range 6.0-11.4 g dl(-1)) in the third cycle despite the frequent use of red blood cell transfusions. Almost all patients (99%) had haemoglobin levels <10 g dl(-1) at some timepoint during first-line sequential high dose chemotherapy. Overall, 97 patients received red blood cell transfusions with a median of 10 units (range 2-25) per patient during the four consecutive cycles of therapy. The time to first transfusion was shortest in patients with the lowest initial haemoglobin values. While there was no prediction of response or outcome by baseline haemoglobin-levels, a significant survival difference in favour of patients with a haemoglobin value >10.5 g dl(-1) after completion of four cycles of therapy (at leukocyte recovery after the last cycle) compared to those with haemoglobin values <10.5 g dl(-1) was found with 3-year overall survival rates of 87% vs 68%, respectively (P<0.05). Severe anaemia is a very frequent side effect of sequential dose intensive therapy in patients with germ cell cancer, with almost all patients becoming transfusion dependent. Despite the frequent use of red blood cell transfusions, median haemoglobin nadirs remained about 7.5-8 g dl(-1) during therapy. A correlation of haemoglobin-values after completion of therapy to overall treatment outcome was found.     

Impact of epoetin beta on quality of life in patients with malignant disease

This open-label, prospective study was conducted to compare the impact of epoetin beta vs standard care on quality of life (QoL) in anaemic patients with lymphoid or solid tumour malignancies. A total of 262 anaemic patients (haemoglobin [Hb]or=2 g dl(-1) increase in Hb level without need of transfusion after the initial 4 weeks of treatment. Baseline to final visit changes in SF-36 PCS, FACT-F and VAS scores were significantly greater with epoetin beta than with standard care (P<0.05); changes in FACT-An subscale score tended to be greater with epoetin beta (P=0.076). Epoetin beta significantly increased Hb concentrations relative to standard care (responders: 47% vs 13%; P<0.001). Levels of endogenous erythropoietin <50 mIU ml(-1) were significantly predictive of response (OR 2.496, 95% CI: 1.21-5.13). Epoetin beta therapy significantly improves QoL compared with standard care in anaemic patients with solid tumours and lymphoid malignancies.     

Erythropoietic agents in anaemic patients with cancer: a retrospective observational survey of epoetin alpha, epoetin beta and darbepoetin alpha use in routine clinical practice

This retrospective observational survey assessed, in a routine clinical practice setting, the modalities of treatment with recombinant erythropoietic agents: alpha erythropoietic agents [epoetin alpha (Eprex) and darbepoetin alpha (Aranesp)] and epoetin beta (NeoRecormon). Evolution of haematological response parameters such as haemoglobin (Hb) during treatment of anaemic patients with cancer were contrasted for the different agents. Records of 125 consecutive adult cancer patients (42 epoetin alpha, 40 epoetin beta, 43 darbepoetin alpha) receiving chemotherapy and erythropoietic treatment for anaemia, and treated between September 2003 and February 2004, were analysed. Mean periods of observation of treatment were 103 days (epoetin alpha), 114 days (epoetin beta) and 95 days (darbepoetin alpha). The mean changes in maximum Hb level during treatment were 2.8 g/dl (epoetin alpha), 3.3 g/dl (epoetin beta) and 2.1 g/dl (darbepoetin alpha) (P=0.02, epoetin beta versus darbepoetin alpha). The proportions of patients achieving > or =1 g/ dl Hb increases were 85.7% (epoetin alpha), 87.5% (epoetin beta) and 79.1% (darbepoetin alpha). The mean cumulative doses administered to achieve these increases were 284, 722 IU; 201, 428 IU; and 208, 823 IU [dose calculated (based on equivalent peptide mass) using 1 microg darbepoetin alpha is equivalent to 200 IU epoetin], respectively. The proportions of patients achieving > or =2 g/dl Hb increases were 66.7% (epoetin alpha), 77.5% (epoetin beta) and 58.1% (darbepoetin alpha). This survey suggests that in real-life clinical conditions the available erythropoietic agents increase Hb effectively in anaemic patients with cancer, and that epoetin beta therapy may have therapeutic advantages over the other agents assessed.     

Anemia is the strongest prognostic factor for outcomes of 5-fluorouracil-based first-line chemotherapy in patients with advanced gastric cancer

Objective: To examine the prevalence of anemia and its impact of hemoglobin (Hgb) levels in predicting outcomes of 5-fluorouracil (FU)-based first-line chemotherapy for patients with advanced gastric cancer (AGC). Methods: We collected data retrospectively from 511 consecutive patients treated with FU-based first-line chemotherapy as a routine clinical practice for AGC and followed up in two centers from 1995 to 2003. FU was given in combination with cisplatin (61%), taxanes (12%), anthracyclines (24%) and/or folinic acid (50%). Results: Hgb values were <10 g/dl in 41%, and patients with baseline Hgb levels <10 g/dl had significantly lower response rates (9%) than patients with Hgb≥10 g/dl (53%; P<0.001). In addition, Hgb<10 g/dl served as a predictor for disease progression (RR, 1.77; 95% CI, 1.42–2.21) and death (RR, 1.85; 95% CI, 1.48–2.32) along with chemotherapy response and performance status. Conclusion: Low baseline Hgb level is a strong and independent prognostic factor for the outcomes of AGC patients receiving FU-based first-line chemotherapy. This results strongly suggest that Hgb level, along with performance status, may be considered as a stratification variable in subsequent studies of AGC.     

Long-term chemotherapy may prolong survival in advanced non-small-cell lung cancer among responders to first-line chemotherapy

Survival in patients with advanced non-small-cell lung cancer (NSCLC) has substantially improved. Long-term chemotherapy with epidermal growth factor tyrosine kinase inhibitors (EGFR-TKIs) and other agents has been associated with long survival. We retrospectively examined the associations between overall survival (OS) and clinical variables in patients with advanced NSCLC who received at least one dose or course of outpatient chemotherapy in our institution. Of 360 patients who received first-line chemotherapy between January 1, 2004 and December 31, 2007, 185 subsequently received additional outpatient chemotherapy and 175 underwent inpatient chemotherapy only. Of the 185 patients, 147 (79.5%), 96 (51.9%), and 60 (32.4%) received second-line, third-line, and fourth-line chemotherapy, respectively. Patients who received outpatient chemotherapy had significantly longer median OS (22.3 months) than did those undergoing inpatient chemotherapy only (7.6 months; P < 0.0001). In univariate analysis of the 185 patients, sex, performance status (PS), smoking status, stage, best response to first-line chemotherapy, use of docetaxel, and EGFR-TKIs were significantly associated with OS (P values: 0.0019, 0.0066, 0.0001, 0.0231, 0.0011, 0.0250, and 0.0023, respectively). In multivariate analysis, PS, stage, best response to first-line chemotherapy, and use of docetaxel were significantly associated with OS (P values: 0.0272, 0.0030, 0.0022, and 0.0376, respectively). Survival was significantly longer among patients who responded to docetaxel and/or EGFR-TKIs. Long-term chemotherapy did not increase cumulative hospitalization. In patients with advanced NSCLC, an effective long-term chemotherapy regimen might prolong survival in responders to first-line chemotherapy.     

Increasing doses of 5-fluorouracil and high-dose folinic acid in the treatment of metastatic colorectal cancer

AIMS AND BACKGROUND: Combined 5-fluorouracil (5FU) and folinic acid (FA) is the first-line treatment of metastatic colorectal cancer. The aims of this study were to individualize the dose of 5FU in a weekly schedule in which the maximum tolerated dose of 5FU is administered to each patient, and to evaluate the impact of increasing 5FU doses on response and survival. METHODS: Thirty-two patients (30 evaluable for response) with metastatic colorectal cancer were treated with weekly intravenous doses of FA 150 mg/m2 and a fast infusion of 5FU, at an initial dose of 600 mg/m2 which was increased by 60 mg/m2 every week until the appearance of a side effect, in order to determine the maximum tolerated dose for the patient. RESULTS: We obtained 11 objective responses (36.7%, median survival 22 months) and 15 disease stabilizations (50%, median survival 15 months); there were four cases of progressive disease (13.3%, median survival 4 months). The overall survival was 15 months. Twenty-eight patients (87.5%) tolerated 5FU doses of 720 mg/m2 or more. CONCLUSIONS: Weekly 5FU with high-dose FA modulation can be individualized by dose escalation. A 5FU dose of 720 mg/m2 per week seems to be critical, as higher doses are no more effective and lead to severe side effects. This schedule gives good results in terms of response, even though the complete response rate remains low.     

Role of BIM Deletion Polymorphism and BIM Expression as Predictive Biomarkers to Maximize the Benefit of EGFR-TKI Treatment in EGFR-Positive NSCLC

Objective: BIM is a modulator of apoptosis that is triggered by EGFR-TKIs. This study evaluated the role of BIM deletion and its expression as predictor of EGFR-TKI treatment outcome. Methods: The medical record of 185 EGFR-positive advanced non-small cell lung cancer (NSCLC) patients with/ without EGFR-TKI treatment between 9/2012 and 12/2014 were retrospectively reviewed. BIM deletion polymorphism and expression were tested by RT-PCR and immunohistochemistry, respectively. Survival outcomes in EGFR-TKI-treated patients were analyzed according to treatment sequence and EGFR mutation. The correlation between BIM deletion polymorphism, expression, response rate (as a function of EGFR-TKI treatment) and schedule was also explored. Result: EGFR-TKIs were administered to 139 (75.1%) of the 185 patients: as the first-line in 52 (37.4%) patients and as later-line treatment in 87 (62.6%) patients. Median overall survival (mOS) was significantly longer in EGFR-TKIs treated patients (28.9 vs. 7.4 months, P<0.001). Among L858R-mutated patients, median progression-free survival (mPFS) was significantly longer in first-line EGFR TKI treatment than a later-line (12.6 vs. 6.3 months, P=0.03). BIM deletion polymorphism and expression was detected in 20.2% and 52.7%, respectively. Patients without BIM deletion polymorphism had a significantly longer mOS when treated with a first-line than with a later-line EGFR-TKI (28.9 vs. 20.7 months, P= 0.04). Patients without BIM expression had a significantly longer mPFS (9.6 vs. 7.3 months, P=0.01) better mOS and response rate (RR). Conclusion: BIM deletion polymorphism and expression may predict an EGFR-TKI response in patients with EGFR-positive during therapy.     

Addition of bevacizumab to bolus fluorouracil and leucovorin in first-line metastatic colorectal cancer: results of a randomized phase II trial.

PURPOSE: Bevacizumab, a monoclonal antibody against vascular endothelial growth factor, increases survival when combined with irinotecan-based chemotherapy in first-line treatment of metastatic colorectal cancer (CRC). This randomized, phase II trial compared bevacizumab plus fluorouracil and leucovorin (FU/LV) versus placebo plus FU/LV as first-line therapy in patients considered nonoptimal candidates for first-line irinotecan. PATIENTS AND METHODS: Patients had metastatic CRC and one of the following characteristics: age > or = 65 years, Eastern Cooperative Oncology Group performance status 1 or 2, serum albumin < or = 3.5 g/dL, or prior abdominal/pelvic radiotherapy. Patients were randomly assigned to FU/LV/placebo (n = 105) or FU/LV/bevacizumab (n = 104). The primary end point was overall survival. Secondary end points were progression-free survival, response rate, response duration, and quality of life. Safety was also assessed. RESULTS: Median survival was 16.6 months for the FU/LV/bevacizumab group and 12.9 months for the FU/LV/placebo group (hazard ratio, 0.79; P = .16). Median progression-free survival was 9.2 months (FU/LV/bevacizumab) and 5.5 months (FU/LV/placebo); hazard ratio was 0.50; P = .0002. Response rates were 26.0% (FU/LV/bevacizumab) and 15.2% (FU/LV/placebo) (P = .055); duration of response was 9.2 months (FU/LV/bevacizumab) and 6.8 months (FU/LV/placebo); hazard ratio was 0.42; P = .088. Grade 3 hypertension was more common with bevacizumab treatment (16% v 3%) but was controlled with oral medication and did not cause study drug discontinuation. CONCLUSION: Addition of bevacizumab to FU/LV as first-line therapy in CRC patients who were not considered optimal candidates for first-line irinotecan treatment provided clinically significant patient benefit, including statistically significant improvement in progression-free survival.     

Evaluation of the nutritional and inflammatory status in cancer patients for the risk assessment of severe haematological toxicity following chemotherapy.

BACKGROUND: The toxicity outcome of cancer patients receiving chemotherapy is difficult to predict. In this study the influence of malnutrition and inflammation on acute haematological toxicity was investigated. PATIENTS AND METHODS: Between January 1999 and January 2000, 48 consecutive cancer patients experienced severe haematological toxicity (SHT), either neutropenic fever or severe thrombocytopenia, following various chemotherapy regimens. Their baseline characteristics were compared with those of 59 control patients. Previous chemotherapy regimens, type of chemotherapy, performance status (PS), calculated creatinine clearance, bilirubin, C-reactive protein (1), alpha-1 acid glycoprotein (2), albumin (3), pre-albumin (4) and the nutritional and inflammatory status (NIS) ratio [NIS = (1 x 2)/(3 x 4)] were studied. Statistical analysis was carried out using either a t-test or a chi-square test. A receiver operating characteristic (ROC) curve determined the cut-off value for NIS. RESULTS: Patients experiencing SHT had a higher PS (P <0.001), inflammatory serum protein levels (P <0.001) and NIS ratio (P <0.0001), but lower haemoglobin (P <0.05) and serum-albumin levels (P <0.0001). Using a cut-off of 0 or 1 for PS and 1 for NIS, sensitivity was 98%, 43% and 89%; specificity was 38%, 90% and 66%, respectively. In 37 patients treated with topotecan as single agent, the determinants for SHT were PS (P <0.0001) and NIS (P <0.0001). CONCLUSIONS: Altered nutritional and inflammatory status correlates with increased risk of severe haematological toxicity following anticancer chemotherapy.     

奈达铂或顺铂联合紫杉醇治疗晚期非小细胞肺癌的随机对照研究

目的观察奈达铂联合紫杉醇(TAX)治疗晚期非小细胞肺癌(NSCLC)的近期疗效、远期生存及毒副反应。方法采用前瞻性随机对照研究方法,以顺铂(DDP)联合TAX为对照,对60例ⅢB和Ⅳ期非小细胞肺癌初治患者进行随机分组。TN组30例,奈达铂30 mg/m2,第1～3天;TAX 175 mg/m2,第1天;每4周重复。TP组27例,DDP 30 mg/m2,第1～3天;TAX 175 mg/m2,第1天;每4周重复。结果TN组与TP组总有效率分别为43.3%和48.1%(P=0.716),疾病控制率分别为86.7%和88.8%(P=0.799)。TN组与TP组患者的中位生存期分别为14.3和13.0个月(P= 0.839),1年生存率分别为62.5%和59.1%,2年生存率分别为0和5.8%。TN组与TP组的中性粒细胞下降和血小板下降相近;TP组比TN组,贫血(38.5%和17.5%,P=0.001)、恶心呕吐(82.6%和35.6%,P=0.000)、乏力反应(35.9%和14.1%,P=0.000)及外周冲经毒性发生率(50.0%和21.9%,P=0.023)更高。结论奈达铂联合TAX是治疗NSCLC的有效方案,可取得与顺铂联合TAX相似的有效率和生存,在某些毒副反应方面显示出一定优势。     

5-Fluorouracil (5FU) with or without folinic acid (LV) in human colorectal cancer? Multivariate meta-analysis of the literature.

This meta-analysis is based on 106 evaluations of response from 77 clinical studies about 5-fluorouracil (5FU) treatment with or without leucovorin (LV) in metastatic colorectal carcinoma. Overall, in naive patients, LV is associated with a median response rate of 31% as compared with a 12% figure with 5FU alone. Using a forward stepwise multilinear regression analysis, it is shown that as much as 44% of the variance in the reported response rates in naive patients can be accounted for by treatment-related variables (P less than 0.001). The significant parameters are LV adjunction (partial R = 0.636), cumulative total 5FU dose (R = 0.344), and 5FU weekly schedule (R = 0.246). In pretreated patients, the latter parameter is the only significant one (R = 0.443). Unexpectedly, LV administration behaves like an all-or-nothing governor, without any obvious dose-effect relationship. Protracted 5FU infusion over weeks allows a mean cumulative drug delivery, 3 times higher than bolus regimens (21.3 vs 7.02 g m-2, P less than 0.001) and may represent the best clinical approach to influence the 5FU-related variables. Accordingly, it is suggested that 5FU protracted infusion, titrated to the highest tolerable doses and potentiated with low doses of leucovorin, could represent the most efficacious way for using 5FU in colorectal disseminated cancer. This hypothesis and its eventual impact on survival should be tested in randomized trials.     

Alpha-interferon does not increase the efficacy of 5-fluorouracil in advanced colorectal cancer

Two meta-analyses were conducted to quantify the benefit of combining alpha-IFN to 5FU in advanced colorectal cancer in terms of tumour response and survival. Analyses were based on a total of 3254 individual patient data provided by principal investigators of each trial. The meta-analysis of 5FU +/- LV vs. 5FU +/- LV + alpha-IFN combined 12 trials and 1766 patients. The meta-analysis failed to show any statistically significant difference between the two treatment groups in terms of tumour response or survival. Overall tumour response rates were 25% for patients receiving no alpha-IFN vs. 24% for patients receiving alpha-IFN (relative risk, RR = 1.02), and median survivals were 11.4 months for patients receiving no alpha-IFN vs. 11.5 months for patients receiving alpha-IFN (hazard ratio, HR = 0.95). The meta-analysis of 5FU + LV vs. 5FU + alpha-IFN combined 7 trials, and 1488 patients. This meta-analysis showed an advantage for 5FU + LV over 5FU + alpha-IFN which was statistically significant in terms of tumour response (23% vs. 18%; RR = 1.26;P = 0.042), and of a borderline significance for overall survival (HR = 1.11;P = 0.066). Metastases confined to the liver and primary rectal tumours were independent favourable prognostic factors for tumour response, whereas good performance status, metastases confined to the liver or confined to the lung, and primary tumour in the rectum were independent favourable prognostic factors for survival. We conclude that alpha-IFN does not increase the efficacy of 5FU or of 5FU + LV, and that 5FU + alpha-IFN is significantly inferior to 5FU + LV, for patients with advanced colorectal cancer.     

Is the therapeutic index better with gemcitabine-based chemoradiation than with 5-fluorouracil-based chemoradiation in locally advanced pancreatic cancer?

PURPOSE: To retrospectively compare the toxicity and efficacy of concurrent gemcitabine-based chemoradiation with that of concurrent 5-fluorouracil (5-FU)-based chemoradiation in patients with unresectable pancreatic cancer. PATIENTS AND METHODS: Between September 1996 and May 2000, 114 patients with localized unresectable adenocarcinoma of the pancreas were treated with concurrent chemoradiation. Locally advanced unresectable disease was defined as low-density tumor in contact with the superior mesenteric artery (SMA) or celiac artery, or occlusion of the superior mesenteric-portal venous confluence. Fifty-three patients were selected to receive gemcitabine in 7 weekly cycles (250-500 mg/m(2)) with concurrent radiotherapy (median dose 30 Gy, range 30-33 Gy in 10-11 fractions). The remaining 61 patients received continuous-infusion 5-FU (200-300 mg/m(2)) with concurrent radiotherapy (30 Gy in 10 fractions). Radiotherapy was delivered to the primary tumor and regional lymphatics. Patients receiving gemcitabine and those receiving 5-FU had a similar mean Karnofsky performance status (KPS, 89% vs. 86%), distribution of tumor grade (43% vs. 33% poorly differentiated), and percent weight loss (all p = NS). However, patients treated with gemcitabine had a significantly larger median maximum cross-sectional tumor area (TA, 8.8 cm(2) vs. 5.7 cm(2), p = 0.046) and were significantly younger (median age 60 vs. 68 years, p <0.001). Severe acute toxicity (ST) was defined as toxicity requiring a hospital stay of more than 5 days, mucosal ulceration with bleeding, more than 3 dose deletions of gemcitabine or discontinuation of 5-FU, or toxicity resulting in surgical intervention or death. Kaplan-Meier analysis was used to calculate the actuarial rate of local progression on imaging (LP), the rate of distant metastasis (DM), and the overall survival (OS) rate. The imaging was reviewed in resected patients. RESULTS: Patients receiving gemcitabine developed significantly more ST during treatment (23% vs. 2%, p < 0.0001) than did those receiving 5-FU. Patients treated with gemcitabine had a similar 10-month LP rate (62% vs. 61%), 10-month DM rate (55% vs. 47%), 1-year OS rate (42% vs. 28%), and median OS duration (11 months vs. 9 months) to patients treated with 5 FU (all p = NS). Five patients who received gemcitabine and 1 patient who received 5-FU underwent margin-negative pancreaticoduodenectomy after chemoradiation. Three patients had a short segment (10 cm(2) (p = 0.03) and poor differentiation (p = 0.07) were associated with a worse survival duration; however, other factors, such as KPS and weight loss >10% and age did not influence OS. CONCLUSION: Despite the selection of healthier patients to receive gemcitabine, there was a significantly higher severe toxicity rate than with 5-FU. The median and 1-year survivals were not significantly different with the use of concurrent gemcitabine; however, the tumors treated were significantly larger. Additionally, a small number of patients with minimal arterial involvement whose disease met our radiographic definition of unresectable disease had margin-negative resections after treatment with gemcitabine-based chemoradiation. These possible benefits and the high rate of severe toxicity define a very narrow therapeutic index for concurrent gemcitabine-based chemoradiation given by this schedule of administration.     

5-Fluorouracil (5FU) with or without folinic acid (LV) in human colorectal cancer? multivariate meta-analysis of the literature

This meta-analysis is based on 106 evaluations of response from 77 clinical studies about 5-fluorouracil (5FU) treatment with or without leucovorin (LV) in metastatic colorectal carcinoma. Overall, in naive patients, LV is associated with a median response rate of 31% as compared with a 12% figure with 5FU alone. Using a forward stepwise multilinear regression analysis, it is shown that as much as 44% of the variance in the reported response rates in naive patients can be accounted for by treatment-related variables(P < 0.001). The significant parameters are LV adjunction (partial R = 0.636), cumulative total 5FU dose (R = 0.344), and 5FU weekly schedule (R = 0.246). In pretreated patients, the latter parameter is the only significant one (R = 0.443). Unexpectedly, LV administration behaves like an all-or-nothing governor, without any obvious dose-effect relationship. Protracted 5FU infusion over weeks allows a mean cumulative drug delivery, 3 times higher than bolus regimens (21.3 vs 7.02 g m^-2,P < 0.001) and may represent the best clinical approach to influence the 5FU-related variables. Accordingly, it is suggested that 5FU protracted infusion, titrated to the highest tolerable doses and potentiated with low doses of leucovorin, could represent the most efficacious way for using 5FU in colorectal disseminated cancer. This hypothesis and its eventual impact on survival should be tested in randomized trials.     

Efficacy and safety of first-line erlotinib in elderly patients with advanced non-small cell lung cancer

TaRceva LUng cancer Survival Treatment (TRUST) was an open-label, phase IV study of advanced non-small cell lung cancer (NSCLC). Patients failing or unsuitable for chemotherapy or radiotherapy received erlotinib 150 mg/day until progression. We examined a subpopulation of elderly patients (≥70 years) receiving first-line erlotinib (n=485) in TRUST. In this subpopulation, disease control rate (n=356 with best response data available) was 79% (vs. 69% for the overall TRUST population; p<0.0001); median progression-free survival (PFS) was 4.57 months [95% confidence interval (CI), 3.68-5.22]; median overall survival (OS) was 7.29 months (95% CI, 6.27-8.67); and one-year survival, was 36.6%. PFS and OS were significantly longer in patients developing rash, compared to those without, and in those with good performance status (PS; 0/1), compared to poor PS (≥2). Eighty-seven subpopulation patients (18%) had an erlotinib-related AE; other than the protocol-defined frequent adverse events (AEs); 4% had a grade ≥3 erlotinib-related AE, 7% had an erlotinib-related serious AE. In the subpopulation, dose reductions were required in 27%, most (97%) were reductions to 100 mg/day; treatment was discontinued in 10%, and one death was associated with treatment-related toxicity (<1%). Erlotinib was effective and well-tolerated and may be considered for elderly patients with advanced NSCLC who are unsuitable for standard first-line chemotherapy or radiotherapy.     

Analysis of salvage treatments for germ cell cancer patients who have relapsed after primary high-dose chemotherapy plus autologous stem cell support

The aim of this study was to identify treatment strategies and therapeutic or clinical factors that predict for response to salvage therapy and survival in patients with metastatic 'Indiana advanced' or International Germ-Cell Cancer Collaborative Group (IGCCCG) poor prognosis' germ cell cancer (GCT) failing first-line sequential high-dose chemotherapy plus autologous stem cell support (HD-CT). A total of 58 'poor prognosis' patients who had relapsed after HD-CT were identified within two large prospective German first-line HD-CT trials (n=286) performed between March 1993 and March 2001. Salvage treatment consisted of the following: cisplatin-based conventional dose CTx+/-resection (19/58; 33%), non-cisplatin based CTx (16/58; 28%) or salvage HD-CT (14/58; 24%)+/-resection; resection (n=3) and/or radiation (n=5) only: 7 patients (12%); no specific therapy: 2 patients. 21 (38%) patients responded favourably (Complete Response (CR)/Partial Response (PR) marker-negative) to salvage therapy. The use of salvage HD-CT (2-year survival 48%; P=0.03, the complete resection of residual masses (2-year survival 42%; P=0.015) as well as a favourable response to salvage therapy (2-year survival: 31%, P=0.014) were the only variables on univariate analysis associated with an improved survival. The estimated 2-year overall survival rate is 32% (95% Confidence Interval CI: 29-45%). Approximately 30% of patients relapsing after first-line HD-CT will survive>2 years, particularly those patients who can be treated with a second HD-CT +and/or surgical resection. If feasible, complete surgical resection of residual tumours appears to be the most efficient treatment.     

Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study

BACKGROUND: Aberrant DNA methylation, which results in leukemogenesis, is frequent in patients with myelodysplastic syndromes (MDS) and is a potential target for pharmacologic therapy. Decitabine indirectly depletes methylcytosine and causes hypomethylation of target gene promoters. METHODS: A total of 170 patients with MDS were randomized to receive either decitabine at a dose of 15 mg/m2 given intravenously over 3 hours every 8 hours for 3 days (at a dose of 135 mg/m2 per course) and repeated every 6 weeks, or best supportive care. Response was assessed using the International Working Group criteria and required that response criteria be met for at least 8 weeks. RESULTS: Patients who were treated with decitabine achieved a significantly higher overall response rate (17%), including 9% complete responses, compared with supportive care (0%) (P < .001). An additional 12 patients who were treated with decitabine (13%) achieved hematologic improvement. Responses were durable (median, 10.3 mos) and were associated with transfusion independence. Patients treated with decitabine had a trend toward a longer median time to acute myelogenous leukemia (AML) progression or death compared with patients who received supportive care alone (all patients, 12.1 mos vs. 7.8 mos [P = 0.16]; those with International Prognostic Scoring System intermediate-2/high-risk disease, 12.0 mos vs. 6.8 mos [P = 0.03]; those with de novo disease, 12.6 mos vs. 9.4 mos [P = 0.04]; and treatment-naive patients, 12.3 mos vs. 7.3 mos [P = 0.08]). CONCLUSIONS: Decitabine was found to be clinically effective in the treatment of patients with MDS, provided durable responses, and improved time to AML transformation or death. The duration of decitabine therapy may improve these results further.     

Phase III study of 5FU, etoposide and leucovorin (FELV) compared to epirubicin, cisplatin and 5FU (ECF) in previously untreated patients with advanced biliary cancer

The purpose of this study was to determine whether epirubicin, cisplatin and infused 5FU (ECF) improves overall survival (OS) compared to 5FU, etoposide and leucovorin (FELV) in patients with previously untreated advanced biliary cancer in a prospective randomised study. Patients were randomly assigned to receive epirubicin, cisplatin and infused 5FU ECF or bolus 5FU etoposide and leucovorin (FELV). The primary end point was OS with secondary end points of objective response rate (ORR), failure-free survival (FFS), quality of life (QOL) and toxicity. In all, 54 patients were recruited with 27 randomly assigned to each arm. The median OS for ECF was 9.02 months (95% confidence interval (CI): 6.46-11.51) and FELV 12.03 months (95% CI: 9.3-14.7), P=0.2059. Objective response rates were similar for both arms: ECF 19.2% (95% CI: 6.55-39.3); FELV 15% (95% CI: 3.2-37.9), P=0.72. There was significantly increased grade 3/4 neutropenia with FELV vs ECF (53.8 vs 29.5%, respectively, P=0.020). Symptom resolution was impressive for both regimens. This is the largest reported randomised study to date in this setting. ECF did not improve OS compared to FELV, but was associated with less acute toxicity. These data suggest that chemotherapy can prolong OS and achieve good symptomatic relief in advanced biliary cancer.