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Purpose: To analyze recurrence patterns in patients with cancer of the esophagus or gastroesophageal junction treated with either preoperative chemoradiotherapy (CRT) plus surgery or surgery alone., Patients and Methods: Recurrence pattern was analyzed in patients from the previously published CROSS I and II trials in relation to radiation target volumes. CRT consisted of five weekly courses of paclitaxel and carboplatin combined with a concurrent radiation dose of 41.4 Gy in 1.8-Gy fractions to the tumor and pathologic lymph nodes with margin., Results: Of the 422 patients included from 2001 to 2008, 418 were available for analysis. Histology was mostly adenocarcinoma (75%). Of the 374 patients who underwent resection, 86% were allocated to surgery and 92% to CRT plus surgery. On January 1, 2011, after a minimum follow-up of 24 months (median, 45 months), the overall recurrence rate in the surgery arm was 58% versus 35% in the CRT plus surgery arm. Preoperative CRT reduced locoregional recurrence (LRR) from 34% to 14% (P < .001) and peritoneal carcinomatosis from 14% to 4% (P < .001). There was a small but significant effect on hematogenous dissemination in favor of the CRT group (35% v 29%; P = .025). LRR occurred in 5% within the target volume, in 2% in the margins, and in 6% outside the radiation target volume. In 1%, the exact site in relation to the target volume was unclear. Only 1% had an isolated infield recurrence after CRT plus surgery., Conclusion: Preoperative CRT in patients with esophageal cancer reduced LRR and peritoneal carcinomatosis. Recurrence within the radiation target volume occurred in only 5%, mostly combined with outfield failures.

Purpose: Earlier studies showed that low molecular weight heparin significantly prolongs the survival of a wide variety of patients with cancer without venous thromboembolism. This study was designed to confirm these findings in a more homogeneous group of patients with cancer., Patients and Methods: In this multicenter, randomized, open-label study, patients with non-small-cell lung cancer (stage IIIB), hormone-refractory prostate cancer, or locally advanced pancreatic cancer were randomly assigned to nadroparin or to no nadroparin in addition to their standard anticancer treatment. In the nadroparin arm, subcutaneous nadroparin was administered for 6 weeks (2 weeks at therapeutic dose, and 4 weeks at half therapeutic dose). The patients were eligible to receive additional cycles of nadroparin (2 weeks at therapeutic dose, and 4 weeks of washout period). Outcomes were overall survival, time to progression, and major bleeding. All study outcomes were adjudicated by an independent, blinded committee., Results: A total of 244 patients were allocated to nadroparin, and 259 were allocated to the control group. A median survival of 13.1 months was observed in the nadroparin recipients compared with 11.9 months in the no-treatment arm (hazard ratio, 0.94; 95% CI, 0.75 to 1.18, adjusted for cancer type). No difference in time to progression was observed. The number of major bleedings was comparable at 4.1% in the nadroparin set and 3.5% in the control set., Conclusion: This study did not show a survival benefit of nadroparin in patients with advanced prostate, lung, or pancreatic cancer. Given the ongoing studies in this area and the previous data, the role of low molecular weight heparins in cancer survival remains undefined.

Purpose: The efficacy of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) gefitinib was assessed in a phase II study in patients with advanced esophageal cancer. Several biologic features were investigated as potential markers of gefitinib activity., Patients and Methods: Patients with advanced esophageal cancer, who had failed one line of prior chemotherapy, were administered gefitinib 500 mg/d. Response was evaluated every 8 weeks. Tumor material obtained before gefitinib treatment was investigated for gene mutations in EGFR, k-ras, and PIK3CA; protein expression levels of EGFR, p-Akt, and p-Erk; and EGFR gene amplification., Results: Of the 36 enrolled patients, one (2.8%) achieved a partial response, 10 (27.8%) had stable disease, 17 (47.2%) experienced progression on treatment, and eight (22.2%) were not assessable for response. The progression-free survival time was 59 days, and the median overall survival time was 164 days. Although EGFR or PIK3CA mutations were absent, k-ras mutations were found in two patients with progressive disease. High EGFR gene copy number was identified in two patients experiencing partial response or progressive disease. A higher disease control rate (response plus stable disease) was observed in females (P = .038) and in patients with squamous cell carcinoma (SCC; P = .013) or high EGFR expression (P = .002)., Conclusion: Gefitinib has a modest activity in second-line treatment of advanced esophageal cancer. However, the patient outcome was significantly better in female patients and in patients demonstrating high EGFR expression or SCC histology. The selection of esophageal cancer patients for future studies with EGFR-TKIs based on the level of EGFR expression in their tumors or SCC histology should be considered.

Purpose: Determine whether standard or high-dose chemotherapy leads to changes in fatigue, hemoglobin (Hb), mental health, muscle and joint pain, and menopausal status from pre- to post-treatment and to evaluate whether fatigue is associated with these factors in disease-free breast cancer patients., Patients and Methods: Eight hundred eighty-five patients were randomly assigned between two chemotherapy regimens both followed by radiotherapy and tamoxifen. Fatigue was assessed using vitality scale (score < or = 46 defined as fatigue), poor mental health using mental health scale (score < or = 56 defined as poor mental health) both of Short-Form 36, muscle and joint pain with Rotterdam Symptom Checklist, and Hb levels were assessed before and 1, 2, and 3 years after chemotherapy., Results: Fatigue was reported in 20% of 430 assessable patients (202 standard-dose, 228 high-dose) with at least a 3-year follow-up, without change over time or difference between treatment arms. Mean Hb levels were lower following high-dose chemotherapy. Only 5% of patients experienced fatigue and anemia. Mental health score was the strongest fatigue predictor at all assessment moments. Menopausal status had no effect on fatigue. Linear mixed effect models showed that the higher the Hb level (P = .0006) and mental health score (P < .0001), the less fatigue was experienced. Joint (P < .0001) and muscle pain (P = .0283) were associated with more fatigue., Conclusion: In 3 years after treatment, no significant differences in fatigue were found between standard and high-dose chemotherapy. Fatigue did not change over time. The strongest fatigue predictor was poor mental health.

Purpose: Studies in cancer patients with venous thromboembolism suggested that low molecular weight heparin may prolong survival. In a double-blind study, we evaluated the effect of low molecular weight heparin on survival in patients with advanced malignancy without venous thromboembolism., Methods: Patients with metastasized or locally advanced solid tumors were randomly assigned to receive a 6-week course of subcutaneous nadroparin or placebo. The primary efficacy analysis was based on time from random assignment to death. The primary safety outcome was major bleeding., Results: In total, 148 patients were allocated to nadroparin and 154 patients were allocated to placebo. Mean follow-up was 1 year. In the intention-to-treat analysis the overall hazard ratio of mortality was 0.75 (95% CI, 0.59 to 0.96) with a median survival of 8.0 months in the nadroparin recipients versus 6.6 months in the placebo group. After adjustment for potential confounders, the treatment effect remained statistically significant. Major bleeding occurred in five (3%) of nadroparin-treated patients and in one (1%) of the placebo recipients (P = .12). In the a priori specified subgroup of patients with a life expectancy of 6 months or more at enrollment, the hazard ratio was 0.64 (95% CI, 0.45 to 0.90) with a median survival of 15.4 and 9.4 months, respectively. For patients with a shorter life expectancy, the hazard ratio was 0.88 (95% CI, 0.62 to 1.25)., Conclusion: A brief course of subcutaneous low molecular weight heparin favorably influences the survival in patients with advanced malignancy and deserves additional clinical evaluation.

Purpose: Several preclinical studies suggested a role for 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) in the treatment of cancer. The objective of this study was to compare the risk of incident cancer between users of statins and users of other cardiovascular medication., Methods: Data were used from the PHARMO database, containing drug dispensing records from community pharmacies and linked hospital discharge records for residents of eight Dutch cities. The study base included all patients with one or more prescriptions for cardiovascular drugs in the period between January 1, 1985 and December 31, 1998. Cases were identified as patients in the study base with a diagnosis of incident cancer and matched with four to six controls on sex, year of birth, geographic region, duration of follow-up, and index date. The analysis was adjusted for diabetes mellitus; prior hospitalizations; comorbidity; and use of diuretics, angiotensin-converting enzyme inhibitors, calcium-channel blockers, nonsteroidal anti-inflammatory drugs, sex hormones, and other lipid-lowering drug therapies., Results: In the study base, 3129 patients were identified and matched to 16976 controls. Statin use was associated with a risk reduction of cancer of 20% (adjusted odds ratio [OR], 0.80; 95% CI, 0.66 to 0.96). Our data suggest that statins are protective when used longer than 4 years (adjusted OR, 0.64; 95% CI, 0.44 to 0.93) or when more than 1350 defined daily doses are taken (adjusted OR, 0.60; 95% CI, 0.40 to 0.91)., Conclusion: This observational study suggests that statins may have a protective effect against cancer.

Purpose: Oral bioavailability of docetaxel is very low, which is, at least in part, due to its affinity for the intestinal drug efflux pump P-glycoprotein (P-gp). In addition, metabolism of docetaxel by cytochrome P450 (CYP) 3A4 in gut and liver may also contribute. The purpose of this study was to enhance the systemic exposure to oral docetaxel on coadministration of cyclosporine (CsA), an efficacious inhibitor of P-gp and substrate for CYP 3A4., Patients and Methods: A proof-of-concept study was carried out in 14 patients with solid tumors. Patients received one course of oral docetaxel 75 mg/m(2) with or without a single oral dose of CsA 15 mg/kg. CsA preceded oral docetaxel by 30 minutes. During subsequent courses, patients received intravenous (IV) docetaxel 100 mg/m(2)., Results: The mean (+/- SD) area under the concentration-time curve (AUC) in patients who received oral docetaxel 75 mg/m(2) without CsA was 0.37 +/- 0.33 mg.h/L and 2.71 +/- 1.81 mg.h/L for the same oral docetaxel dose with CsA. The mean AUC of IV docetaxel 100 mg/m(2) was 4.41 +/- 2.10 mg.h/L. The absolute bioavailability of oral docetaxel was 8% +/- 6% without and 90% +/- 44% with CsA. The oral combination of docetaxel and CsA was well tolerated., Conclusion: Coadministration of oral CsA strongly enhanced the oral bioavailability of docetaxel. Interpatient variability in the systemic exposure after oral drug administration was of the same order as after IV administration. These data are promising and form the basis for the further development of a clinically useful oral formulation of docetaxel.

Purpose: This phase III study compared docetaxel with mitomycin plus vinblastine (MV) in patients with metastatic breast cancer (MBC) progressing despite previous anthracycline-containing chemotherapy., Patients and Methods: Patients (n=392) were randomized to receive either docetaxel 100 mg/m2 intravenously (i.v.) every 3 weeks (n=203) or mitomycin 12 mg/m2 i.v. every 6 weeks plus vinblastine 6 mg/m2 i.v. every 3 weeks (n=189), for a maximum of 10 3-week cycles., Results: In an intention-to-treat analysis, docetaxel produced significantly higher response rates than MV overall (30.0% v 11.6%; P < .0001), as well as in patients with visceral involvement (30% v 11%), liver metastases (33% v 7%), or resistance to previous anthracycline agents (30% v 7%). Median time to progression (TTP) and overall survival were significantly longer with docetaxel than MV (19 v 1 weeks, P=.001, and 1 1.4 v 8.7 months, P=.0097, respectively). Neutropenia grade 3/4 was more frequent with docetaxel (93.1 % v62.5%; P < .05); thrombocytopenia grade 3/4 was more frequent with MV (12.0% v 4.1%; P < .05). Severe acute or chronic nonhematologic adverse events were infrequent in both groups. Withdrawal rates because of adverse events (MV, 10.1%; docetaxel, 13.8%) or toxic death (MV, 1.6%; docetaxel, 2.0%) were similar in both groups. Quality-of-life analysis was limited by a number of factors, but results were similar in both groups., Conclusion: Docetaxel is significantly superior to MV in terms of response, TTP, and survival. The safety profiles of both therapies are manageable and tolerable. Docetaxel represents a clear treatment option for patients with MBC progressing despite previous anthracycline-containing chemotherapy.

Purpose: To evaluate the feasibility of administering topotecan in combination with paclitaxel and cisplatin without and with granulocyte colony-stimulating factor (G-CSF) support as first-line chemotherapy in women with incompletely resected stage III and stage IV ovarian carcinoma., Patients and Methods: Starting doses were paclitaxel 110 mg/m2 administered over 24 hours (day 1), followed by cisplatin 50 mg/m2 over 3 hours (day 2) and topotecan 0.3 mg/m2/d over 30 minutes for 5 consecutive days (days 2 to 6). Treatment was repeated every 3 weeks. After encountering dose-limiting toxicities (DLTs) without G-CSF support, the maximum-tolerated dose was defined as 5 microg/kg of G-CSF subcutaneously starting on day 6., Results: Twenty-one patients received a total of 116 courses at four different dose levels. The DLT was neutropenia. At the first dose level, all six patients experienced grade 4 myelosuppression. G-CSF support permitted further dose escalation of cisplatin and topotecan. Nonhematologic toxicities, primarily fatigue, nausea/vomiting, and neurosensory neuropathy, were observed but were generally mild. Of 15 patients assessable for response, nine had a complete response, four achieved a partial response, and two had stable disease., Conclusion: Neutropenia was the DLT of this combination of paclitaxel, cisplatin, and topotecan. The recommended phase II dose is paclitaxel 110 mg/m2 (day 1), followed by cisplatin 75 mg/m2 (day 2) and topotecan 0.3 mg/m2/d (days 2 to 6) with G-CSF support repeated every 3 weeks.