A phase 2 study of a fixed combination of uracil and ftorafur (UFT) and leucovorin given orally in a 3‐times‐daily regimen to treat patients with recurrent metastatic breast cancer

BACKGROUND:

A combination of uracil and ftorafur (UFT) was developed to combine the cytotoxic effects of 5‐fluorouracil (5‐FU) with convenient oral dosing. Leucovorin was combined with UFT to further potentiate the effect of 5‐FU on tumor cells. Orally administered UFT and leucovorin provided higher peak plasma concentrations of 5‐FU and prolonged therapeutic 5‐FU concentrations compared with continuous infusion of 5‐FU.

METHODS:

Ninety‐one patients with metastatic breast cancer who had been previously treated with anthracyclines and/or taxanes were treated with UFT and leucovorin, given orally, for the first 28 days of a 35‐day cycle. The total daily dose of UFT was 300 mg/m², administered in 3 doses of 100 mg/m² each every 8 hours. The primary endpoint was time to disease progression (TTP). Secondary objectives included overall tumor response rate (overall response equals complete response plus partial response) and overall survival.

RESULTS:

Of the 91 patients enrolled, 70 were evaluable for efficacy. Although no complete responses were observed, 7 patients had partial responses, for an overall response rate of 10% in the evaluable population. The median TTP for the evaluable population was 10 weeks, and the proportion of patients who were free of disease progression at 6 months was 23%. The median overall survival was 59.4 weeks for all patients enrolled. Common, drug‐related ≥ grade 3 adverse events (graded according to National Cancer Institute Common Toxicity Criteria, version 2) included diarrhea, vomiting, abdominal pain, and nausea.

CONCLUSIONS:

The combination of UFT and leucovorin administered orally in a 3‐times‐daily regimen was found to have modest activity. Grade 3 toxicities were manageable with appropriate dose adjustments in patients with metastatic breast cancer previously treated with anthracyclines and/or taxanes. Cancer 2010. © 2010 American Cancer Society.     

A phase 2 trial of gemcitabine, 5-fluorouracil, and radiation therapy in locally advanced nonmetastatic pancreatic adenocarcinoma : cancer and Leukemia Group B (CALGB) 80003

BACKGROUND:

The purpose of this study was to assess the efficacy and safety of 5‐fluorouracil (5FU) and gemcitabine administered concurrently with radiation in patients with locally advanced, nonmetastatic pancreatic cancer.

METHODS:

Eligible patients had histologically confirmed pancreatic adenocarcinoma deemed locally unresectable without evidence of metastatic disease. In addition, all patients underwent laparoscopy or laparotomy before study entry to rule out peritoneal carcinomatosis. Patients received radiation therapy (50.4 Gy) with concurrent infusional 5FU (200 mg/m² 5 days/week) and weekly gemcitabine (200 mg/m²). After a 3‐week break, patients received weekly gemcitabine at 1000 mg/m² for 3 of 4 weeks, for 4 cycles. The primary endpoint of the trial was the proportion of patients surviving 9 months from study entry. Secondary endpoints included objective tumor response, CA19‐9 response, overall survival (OS) time to progression (TTP), and toxicity.

RESULTS:

Between November 2001 and October 2004, 81 patients were enrolled, 78 of whom were eligible for analysis. With a median follow‐up of 55.2 months, the median OS was 12.2 months (95% confidence interval [CI], 10.9‐14.9) and the median TTP was 10 months (95% CI, 6.4‐12.0). An objective tumor response was seen in 19 patients (25%), and among 56 patients with an elevated CA19‐9 at baseline, 29 (52%) had a sustained CA19‐9 response. Overall, 41% of patients had grade 3 or greater treatment‐related gastrointestinal adverse events.

CONCLUSIONS:

The combination of 5FU, gemcitabine, and radiation is well tolerated. Survival is comparable with the best results of other recent studies of 5FU and radiation or gemcitabine and radiation. Cancer 2011;. © 2010 American Cancer Society.     

Comparison of doxorubicin and weekly paclitaxel efficacy in metastatic angiosarcomas

BACKGROUND:

Data regarding the role of anthracyclines and taxanes as first‐line treatments of metastatic angiosarcoma are limited.

METHODS:

Records of 117 metastatic angiosarcoma patients who were treated with either doxorubicin or weekly paclitaxel were reviewed.

RESULTS:

Seventy‐five patients (64%) were treated with weekly paclitaxel and 42 (36%) with single‐agent doxorubicin. Patients in the weekly paclitaxel group were older and more frequently had angiosarcomas arising from the skin. In the doxorubicin group, 34 patients were evaluable for response: 2 (6%) had complete response, 8 (23.5%) had partial response, 10 (29.5%) had stable disease, and 14 (41%) had progressive disease. In the weekly paclitaxel group, 68 patients were evaluable for response: 9 (13%) had complete response, 27 (40%) had partial response, 20 (29.5%) had stable disease, and 12 (17.5%) had progressive disease. Objective responses to weekly paclitaxel were more frequent in cutaneous angiosarcomas, whereas tumor location did not impact response to doxorubicin. Median progression‐free survival (PFS) was 4.9 months (95% confidence interval [95% CI], 3.9‐6.0 months). Median overall survival (OS) was 8.5 months (95% CI, 6.4‐10.7 months). On multivariate analysis, ECOG performance status (PS) was the sole independent factor associated with PFS and OS.

CONCLUSIONS:

First‐line single‐agent doxorubicin and weekly paclitaxel seem to have similar efficacy in metastatic angiosarcomas. Cutaneous angiosarcomas respond favorably to weekly paclitaxel. Best supportive care should be considered in patients with poor PS. Cancer 2011. © 2011 American Cancer Society.     

Chemotherapy with 5-fluorouracil and a platinum compound improves outcomes in metastatic small bowel adenocarcinoma

BACKGROUND.

Metastatic small bowel adenocarcinoma (SBA) has a poor prognosis. Because of the rarity of SBA, only a few studies have evaluated the role of chemotherapy in the treatment of metastatic SBA; thus, the benefit, if any, of adding a platinum compound to fluorouracil (5‐FU) is unknown. The objective of this retrospective study was to determine whether the addition of a platinum compound to 5‐FU provided any benefit in the treatment of patients with metastatic SBA.

METHODS.

The authors identified 80 patients with metastatic SBA who were treated with chemotherapy at the University of Texas M. D. Anderson Cancer Center between 1978 and 2005. Response rates, progression‐free survival (PFS), and overall survival (OS) were compared between patients who received 5‐FU and a platinum compound and patients who received other chemotherapy combinations.

RESULTS.

The median patient age was 53 years. The primary tumor site was the jejunum in 35 patients (43%), duodenum in 30 patients (38%), ileum in 6 patients (8%), and nonspecified small bowel in 9 patients (11%). Of all 80 patients, 29 patients (36%) received 5‐FU and a platinum compound, 41 patients (51%) received 5‐FU without a platinum compound, and 10 patients (13%) received non‐5‐FU–based treatment. Compared with other chemotherapy regimens, treatment with 5‐FU and a platinum agent resulted in a higher response rate (46% vs 16% with other regimens; P = .01) and longer median PFS (8.7 months vs 3.9 months; P ≤ .01) but not better OS (14.8 months vs 12 months; P = .1). In multivariate analysis, treatment with 5‐FU and a platinum compound was a significant predictor of response (odds ratio, 4.5; 95% confidence interval [CI], 1.3‐15.8; P = .02) and PFS (hazard ratio. 0.49; 95% CI, 0.29‐0.84; P = .01) but only reached borderline significance for OS (hazard ratio, 0.63; 95% CI, 0.37‐1.07; P = .08).

CONCLUSIONS.

To the authors' knowledge, the current analysis represents the largest number of patients with metastatic SBA treated with chemotherapy in the literature, and the results suggested that the combination of 5‐FU and a platinum compound leads to a higher response rate and PFS compared with other chemotherapy regimes. The authors concluded that prospective investigation of platinum analogues in the treatment of SBA is warranted. Cancer 2008. © 2008 American Cancer Society.     

Phase 2 trial of primary systemic therapy with doxorubicin and docetaxel followed by surgery,radiotherapy, and adjuvant chemotherapy with cyclophosphamide,methotrexate, and 5‐fluorouracil based on clinical and pathologic response in patients with stage IIB to III breast cancer

BACKGROUND:

This study was performed to evaluate the outcomes of patients with locally advanced breast cancer (LABC) who were treated with a multidisciplinary approach including primary systemic chemotherapy and noncross‐resistant adjuvant chemotherapy.

METHODS:

Patients with LABC received 4 or 6 cycles of doxorubicin and docetaxel (DT) as primary systemic chemotherapy (PST) every 21 days. Patients with adequate response underwent surgery followed by adjuvant chemotherapy according to pathologic response: complete (pCR), 2 more cycles of DT; partial (pPR), 2 more cycles of DT followed by 6 cycles of cyclophosphamide, methotrexate, and 5‐fluorouracil (5‐FU) (CMF); and minor (pMR), 6 cycles of CMF. Patients then received radiation and tamoxifen (hormone receptor‐positive patients only).

RESULTS:

Eighty‐eight patients were evaluable. Seventy‐four patients had an adequate response to DT and were considered operable, and 72 underwent surgery. Ten patients (13.9%) achieved a pCR, 22 (30.5%) achieved a pPR, and 40 achieved a pMR (55.5%). Fourteen patients were considered nonoperable after DT and underwent salvage CMF therapy. Five of these patients underwent surgery and 1 had achieved a pCR. The estimated 5‐year recurrence‐free survival (RFS) rates for patients with pCR, pPR, and pMR were 80%, 77%, and 59%, respectively, and the estimated 5‐year overall survival (OS) rates were 90%, 91%, and 74%, respectively. The 5‐year OS rates were 82% for initially operable and 21% for initially inoperable patients (P ≤ .001)

CONCLUSIONS:

Multidisciplinary therapy that includes PST with DT and adjuvant therapy with CMF administered according to the clinical and pathologic response is associated with high long‐term RFS and OS rates in patients with LABC. Clinical or pathologic PR or CR to DT predicts improved RFS and OS. Cancer 2010. Published 2010 by the American Cancer Society.     

Second-line chemotherapy with fluorouracil, leucovorin, and irinotecan (FOLFIRI regimen) in patients with advanced small bowel adenocarcinoma after failure of first-line platinum-based chemotherapy: a multicenter AGEO study

BACKGROUND:

Small bowel adenocarcinoma (SBA) is a rare tumor with poor prognosis. First‐line platinum‐based chemotherapy is active in patients with advanced SBA, but data regarding second‐line chemotherapy are lacking. The aim of this study was to evaluate the efficacy and tolerability of fluorouracil, leucovorin, and irinotecan (FOLFIRI regimen) as second‐line chemotherapy in patients with advanced SBA.

METHODS:

We analyzed all consecutive patients who received second‐line chemotherapy with FOLFIRI among 93 patients with advanced SBA included from 1996 to 2008 in a previous retrospective multicenter study. Progression‐free survival (PFS) and overall survival (OS) were estimated from the start of second‐line chemotherapy using the Kaplan‐Meier method. Cox models were applied for multivariate analyses.

RESULTS:

Among 51 patients who received second‐line chemotherapy, 28 patients (male, 57%; median age, 54 years; metastatic disease, 96%) were treated with FOLFIRI after progression (n = 24) or limiting toxicity (n = 4) to first‐line FOLFOX (n = 19) or LV5FU2‐cisplatin (n = 9). Grade 3‐4 toxicity was observed in 48% of patients (grade 3‐4 neutropenia, 37%). After a median follow‐up of 21.5 months, all patients had tumor progression, and 22 patients died. Objective response rate was 20%, and disease control rate was 52%. Median PFS and OS were 3.2 and 10.5 months, respectively. No clinical, biological, or tumor characteristics were associated with PFS or OS by multivariate analysis.

CONCLUSIONS:

Second‐line chemotherapy with FOLFIRI produced disease control in half of patients with advanced SBA after failure with first‐line platinum‐based chemotherapy. Nevertheless, the short median PFS warrants the evaluation of other treatments including targeted therapies. Cancer 2011. © 2010 American Cancer Society.     

Pegylated liposomal doxorubicin and gemcitabine in patients with advanced hepatocellular carcinoma: results of a phase 2 study

BACKGROUND:

Over the years, doxorubicin and gemcitabine have been among the most widely used drugs for hepatocellular carcinoma (HCC), with relative efficacy. The authors report the results of a phase 2 study of the combination of gemcitabine plus pegylated liposomal doxorubicin.

METHODS:

Patients with advanced HCC received combination chemotherapy with gemcitabine 1000 mg/m² on Days 1 and 8, followed by pegylated liposomal doxorubicin 30 mg/m² on Day 1. Treatment was repeated every 4 weeks to a maximum of 8 cycles. Primary endpoint was overall response rate, and secondary endpoints were time to disease progression (TTP), overall survival (OS), and toxicity.

RESULTS:

Forty‐one patients were enrolled and were evaluable for response, toxicity, and survival. A total of 194 cycles of treatment were administered. Three (7%) patients had a complete response, and 1 of these patients underwent liver transplantation. Seven (17%) patients had a partial response and, among these patients, 1 patient underwent surgical resection. Among the 31 patients who had initial alpha‐fetoprotein levels >400 ng/mL, 20 (64.5%) had a >20% decrease after 2 cycles of treatment. The median TTP and OS were 5.8 and 22.5 months, respectively. Hematologic toxicity was the most common side effect, including neutropenia (17%) and anemia (7%).

CONCLUSIONS:

The combination of gemcitabine plus pegylated liposomal doxorubicin was active and safe in advanced HCC. Moreover, this treatment induced some complete responses and converted some untreatable HCCs into lesions eligible for resection or transplantation. Cancer 2011. © 2010 American Cancer Society.     

Association of fluoropyrimidines, platinum agents, taxanes, and irinotecan in any line of chemotherapy with survival in patients with advanced gastric cancer

Background

Although fluoropyrimidines, platinum agents, taxanes, and irinotecan are used in the treatment of advanced gastric cancer (AGC), it remains unclear whether these agents in any line of chemotherapy are associated with overall survival (OS) in these patients.

Methods

We retrospectively analyzed 704 patients with AGC. To avoid possible lead-time bias, we applied time-varying covariate analysis for chemotherapy with four agents in any line.

Results

Median OS was 12.3?months. The frequency of exposure to each agent class during all lines of treatment was 92.6% for FU (5-fluorouracil or oral fluoropyrimidine), 48.2% for platinum agents, 65.1% for taxanes, and 39.1% for irinotecan. According to a multivariate Cox model with exposure to each agent class as a time-varying covariate, the hazard ratios (HRs) of death were 0.41 (95% confidence interval [CI], 0.27??.57; p?<?0.001) for FU, 0.71 (95% CI, 0.58??.84; p?<?0.001) for platinum agents, 0.51 (95% CI, 0.41??.63; p?<?0.001) for taxanes, and 0.53 (95% CI, 0.43??.65; p?<?0.001) for irinotecan. Although other agents were used in 18.6% of the patients, they did not affect survival.

Conclusions

Each of the four agent classes (FU, platinum agents, taxanes, and irinotecan) appears to be independently associated with improved OS in patients with AGC regardless of timing. This result suggests the importance of developing strategies which make these active agents available to all patients with AGC to prolong OS.     

Effects of a low-fat meal on the oral bioavailability of UFT and leucovorin in patients with colorectal cancer

Background

UFT is composed of tegafur, a prodrug of 5-fluorouracil, and uracil, at a fixed ratio of 1: 4. UFT is widely used with leucovorin as adjuvant chemotherapy in patients with colon cancer. As reported, UFT/leucovorin should not be taken simultaneously with food because a high fat content will reduce the systemic exposure to the active cytotoxic moiety of UFT. In this single-dose, randomized, two-way crossover study, we investigated the effects of a low-fat Japanese meal on the pharmacokinetics and oral bioavailability of UFT (2 × 100-mg capsules; dose in terms of tegafur) and leucovorin (1 × 25-mg tablet).

Methods

Patients (n = 12) were randomly assigned to receive both drugs after an overnight fast or 5 min after eating a standard Japanese breakfast (641 kcal), with a 3-day washout period between treatments. Pharmacokinetics (n = 12) were determined for tegafur, 5-fluorouracil, uracil, leucovorin, and 5-methyltetrahydrofolate (an active metabolite of leucovorin).

Results

For 5-fluorouracil pharmacokinetics, the maximum plasma concentration and the area under the curve were reduced by 73.7% and 47.4%, respectively, when UFT was taken postprandially, and the maximum plasma concentration and the area under the curve for uracil were reduced by 84.1% and 68.9%, respectively, compared with dosing on an empty stomach. These decreases in the systemic exposure to 5-fluorouracil were quite marked and may have an impact on its antitumor effect.

Conclusion

A low-fat meal affects the pharmacokinetics of UFT similarly to a high-fat meal.     

Biweekly vinorelbine and tegafur/uracil in patients with metastatic breast cancer previously treated with anthracyclines and taxanes: GEICAM 2000–02 phase II study

Introduction

To assess the efficacy and safety profile of biweekly vinorelbine and tegafur/uracil (UFT) as treatment in patients with metastatic breast cancer previously treated with anthracyclines and taxanes.

Patients and methods

Patients with histologically confirmed breast cancer, measurable disease, no more than one prior chemotherapy regimen for metastatic disease, an Eastern Cooperative Oncology Group (ECOG) performance status ≤2, and adequate bone marrow, renal and liver function were eligible. Patients received vinorelbine (30 mg/m² on day 1) and UFT (250 mg/m² daily) every two weeks for 12 cycles unless progression or unacceptable toxicity was observed.

Results

Thirty-seven patients were included and received 311 cycles of chemotherapy. Efficacy and toxicity analyses were carried out on an intention-to-treat basis. The overall response rate was 35% (95% CI: 20–53). With a median follow-up of 18.6 months (95% CI: 1.0–74.3), the median time to progression was 7.0 months (96% CI: 5.2–8.9) and the median overall survival was 19.4 months (95% CI: 11.1–27.8). The most common severe toxicities were neutropenia (38% of patients) and asthenia (11% of patients).

Conclusion

The combination of biweekly vinorelbine and UFT in patients with metastatic breast cancer pretreated with anthracyclines and taxanes is a well tolerated and effective regimen. AEMPS Trial Registration No.: 00-0534.     

Prognostic web-based models for stage II and III colon cancer: A population and clinical trials-based validation of numeracy and adjuvant! online

BACKGROUND:

Numeracy and Adjuvant! are 2 web‐based calculators that are used widely to estimate the prognosis and potential benefit of adjuvant 5‐fluorouracil (5‐FU)–based therapy for patients with stage II and III colon cancer. In this study, the authors compared the predicted survival estimates from these models with the actual observed estimates in independent datasets that were derived from a population cohort and from clinical trials.

METHODS:

The population cohort was derived from the British Columbia Colorectal Cancer Outcomes Unit database, which identified referred patients with stage II and III colon cancer from 1995 to 1996 and from 1999 to 2003. Patients who were enrolled in North Central Cancer Trials Group (NCCTG) trials NCCTG 94651 and NCCTG 914653 were included in the trials dataset. Patient and disease data were used to predict 5‐year relapse‐free and overall survival using both tools.

RESULTS:

In the population‐based dataset (N = 2033), Adjuvant! offered more reliable predictions of prognosis for patients who underwent surgery alone, but it had reliability similar to that of Numeracy for predicting the prognosis for patients who received adjuvant 5‐FU. Both models tended to overestimate survival for patients with stage II disease who received 5‐FU. In the trials dataset of patients who underwent and received 5‐FU (N = 1729), Numeracy and Adjuvant! demonstrated similar performance and improved correctness.

CONCLUSIONS:

This independent validation analysis demonstrated that both Numeracy and Adjuvant! had similar predictive performance and acceptable reliability for patients with stage III disease. Survival outcomes of patients with stage II colon cancer who received adjuvant 5‐FU were slightly lower than estimated by either model. Cancer 2011;. © 2011 American Cancer Society.     

Frontline treatment of localized osteosarcoma without methotrexate: results of the St. Jude Children's Research Hospital OS99 trial

BACKGROUND:

The standard treatment of osteosarcoma includes cisplatin and high‐dose methotrexate (HDMTX); both agents exert significant toxicity, and HDMTX requires complex pharmacokinetic monitoring and leucovorin rescue. In the previous OS91 trial, the treatment of localized disease with carboplatin, ifosfamide, doxorubicin, and HDMTX yielded outcomes comparable to those of cisplatin‐based regimens and caused less toxicity. To build on this experience, the authors conducted a multi‐institutional trial (OS99) that evaluated the efficacy of carboplatin, ifosfamide, and doxorubicin without HDMTX in patients with newly diagnosed, localized, resectable osteosarcoma.

METHODS:

Treatment was comprised of 12 cycles of chemotherapy administered over 35 weeks: 3 cycles of carboplatin (dose targeted to area under the concentration‐time curve of 8 mg/mL × min on Day 1) and ifosfamide (at a dose of 2.65 g/m² daily ×3 days) and 1 cycle of doxorubicin (at a dose of 25 mg/m² daily ×3 days) before surgical resection, followed by 2 additional cycles of the combination of carboplatin and ifosfamide and 3 cycles each of doxorubicin (25 mg/m² daily ×2 days) combined with ifosfamide or carboplatin.

RESULTS:

A total of 72 eligible patients (median age, 13.4 years) were enrolled between May 1999 and May 2006. Forty of the 66 (60.6%) evaluable patients had good histologic responses (>90% tumor necrosis) to preoperative chemotherapy. The estimated 5‐year event‐free survival rate was 66.7% ± 7.0% for the OS99 trial compared with 66.0% ± 6.8% for the OS91 trial (P = .98). The estimated 5‐year survival rate was 78.9% ± 6.3% for the OS99 trial and 74.5% ± 6.3% for the OS91 trial (P = .40).

CONCLUSIONS:

The regimen used in the OS99 trial was found to produce outcomes comparable to those of cisplatin‐containing or HDMTX‐containing regimens. This therapy offers a good alternative for patients, particularly those who demonstrate an intolerance of HDMTX, and for institutions that cannot provide pharmacokinetic monitoring for MTX. Cancer 2011. © 2011 American Cancer Society.     

Comparison of adverse events during 5-fluorouracil versus 5-fluorouracil/oxaliplatin adjuvant chemotherapy for stage III colon cancer: a population-based analysis

BACKGROUND:

In clinical trials, combined 5‐fluorouracil (5FU) plus oxaliplatin improves the survival of patients who have resected, stage III colon cancer with manageable toxicity. However, the tolerability of this in the general population of patients with colon cancer is uncertain.

METHODS:

Adverse outcomes were compared in patients with stage III colon cancer who received either 5FU or 5FU/oxaliplatin within 120 days of undergoing resection versus a control group of patients with stage II colon cancer who did not receive chemotherapy in the Surveillance, Epidemiology, and End Results (SEER)‐Medicare database and in data from the New York State Cancer Registry linked to Medicare and Medicaid. Hospitalizations, emergency room (ER) visits, and outpatient adverse events (AEs) were measured in claims from 30 days to 9 months after patients underwent resection. Multiple logistic regression was used to calculate adjusted odds ratios of events by treatment. Propensity score matching was used to minimize selection bias.

RESULTS:

Adverse outcomes were more frequent for chemotherapy recipients. AE rates were higher in patients who received 5FU/oxaliplatin (81%) compared with patients who received 5FU alone (72%), in the SEER‐Medicare data. The effect of oxaliplatin on AEs was greater in older patients: The odds ratio was 2.10 (95% confidence interval, 1.53‐2.87) for patients aged ≥75 years versus 1.75 (95% confidence interval, 1.39‐2.21) for patients aged <75 years. ER use was high in Medicaid patients (83% of those who received chemotherapy), but neither ER use nor hospitalization was increased by oxaliplatin. The 60‐day mortality rate was 1% to 3% for patients who received 5FU alone and 1% to 2% for patients who received combined 5FU/oxaliplatin.

CONCLUSIONS:

The incremental harms of adjuvant chemotherapy with 5FU/oxaliplatin versus 5FU alone were modest in patients with stage III colon cancer who were insured by Medicare and Medicaid. The additional harms in patients aged ≥75 years largely were restricted to outpatient events and did not extend to an increased rate of hospitalization or early death. Cancer 2012. © 2012 American Cancer Society     

Results and patterns of failure in patients treated with adjuvant combined chemoradiation therapy for resected pancreatic adenocarcinoma

BACKGROUND:

Although adjuvant chemoradiation is used commonly in the United States for the treatment of resected pancreatic cancer, there is no consensus on the benefit of this therapy, because the results from randomized trials are conflicting. The authors of this report reviewed their experience in a consecutive, unselected series of patients who received adjuvant 5‐fluorouracil (5‐FU) and radiation therapy (RT) for resected pancreatic adenocarcinoma.

METHODS:

Eighty‐six patients with resected pancreatic adenocarcinoma who received adjuvant therapy from 1998 to 2005 were identified, and their medical records were reviewed. Ninety‐three percent of patients were treated with external beam RT to ≥50.4 grays, and 91% of patients received concurrent 5‐FU by continuous infusion. Forty‐five percent of patients went on to receive adjuvant gemcitabine.

RESULTS:

The median follow‐up was 31 months (range, 21‐62 months) among the 20 patients who remained alive. Less than half of patients had positive (33%) or close (<1 mm; 15%) resection margins, 81% of tumors were classified as T3, and 66% of patients had involved lymph nodes. The median overall survival (OS) for all patients was 22 months. Negative lymph node status (P = .016) was a significant prognostic factor for improved OS, whereas treatment with gemcitabine trended toward improved OS (P = .080). The median disease‐free survival (DFS) for all patients was 10 months: Treatment with gemcitabine (P = .044) and the receipt of any chemotherapy (P = .047) were significant predictors of DFS. Seventy‐five patients (87%) had disease recurrence, and the majority recurred with peritoneal metastases (55%) or liver metastases (53%). Patients who had negative lymph nodes trended toward a lower rate of distant failure (P = .060).

CONCLUSIONS:

The median survival of the current cohort was greater than that of the chemoradiation arms of European Organization for Research and Treatment of Cancer trials and European Study Group for Pancreatic Cancer 1 trials and was comparable to the survival observed on the Gastrointestinal Tumor Study Group chemoradiation arm. Lymph node status and treatment with adjuvant chemotherapy were significant predictors of OS and DFS, respectively. Future survival improvements should be directed at reducing peritoneal and liver metastases. Further randomized trials will be required to define the role of adjuvant therapy for pancreatic adenocarcinoma. Cancer 2009. © 2009 American Cancer Society.     

Characterization of a novel lymph node metastasis model from human colonic cancer and its preclinical use for comparison of anti‐metastatic efficacy between oral S‐1 and UFT/ LV

Although lymph node metastasis (LNM) is the most critical prognostic factor in colorectal cancer patients, the anti‐LNM efficacy of chemotherapeutic agents is largely unknown because of the limitations of reproducible human colorectal cancer LNM models. Here, we developed a new LNM model from a recently established colorectal cancer cell line (COLM‐5) and compared the anti‐LNM efficacy of two oral formulations of 5‐fluorouracil (5‐FU) derivatives, S‐1 and UFT/leucovorin (LV). COLM‐5 cells is a poorly differentiated adenocarcinoma cell line with unique features such as left‐sided, β‐catenin cytoplasmic localization, and microsatellite stable phenotype. COLM‐5 cells expressed vascular endothelial growth factor (VEGF‐C) and exhibited peritumoral lymphangiogenesis. Consequently, they showed high LNM potential at an incidence of approximately 90% when subcutaneously injected into nude mice, allowing use for preclinical study. When chemotherapy with S‐1 or UFT/LV started from the micrometastasis stage, not the advanced macroscopic metastasis stage, anti‐LNM efficacy of S‐1 was significantly higher than that of UFT/LV at the dosage in which antitumor activity of the two drugs against primary subcutaneous tumor was comparable. COLM‐5 cells showed expression pattern of 5‐FU metabolizing enzymes such as high dihydropyrimidine dehydrogenase (DPD) and low thymidylate synthase (TS)/orotate phosphoribosyltransferase (OPRT) both in vitro and in vivo. These results suggest that the preferential anti‐LNM activity of S‐1 compared with UFT/LV against high‐DPD COLM‐5 tumors is due to the higher DPD inhibitory activity of 5‐chloro‐2, 4‐dihydroxypyrimidine (CDHP) present in S‐1 than uracil in UFT. The COLM‐5 model would be an excellent tool for understanding the basic mechanism of LNM and for preclinical study on the anti‐LNM efficacy of the drugs. (Cancer Sci 2010)     

Experience with rituximab immunotherapy as an early intervention in patients with Rai stage 0 to II chronic lymphocytic leukemia

BACKGROUND:

Management of asymptomatic early stage chronic lymphocytic leukemia (CLL) centered on expectant surveillance for active disease warranting chemotherapy. In CLL, elevated serum β‐2 microglobulin (β2M) levels were associated with more rapid disease progression and shorter survival (OS).

METHODS:

An early intervention trial was designed to assess response, time‐to‐progression (TTP), and OS after immunotherapy with standard‐dose rituximab (375 mg/m² intravenously weekly for 8 consecutive weeks) in 34 asymptomatic untreated early stage CLL with β2M level ≥ 2 mg/dL.

RESULTS:

Long‐term follow‐up and results are reported. The overall response rate in 34 patients was 82% (9% complete [CR]), median TTP in the 28 responders was 23 months, the median time to subsequent treatment was 43 months, and the 8‐year OS rate was 74% (median follow‐up, 102 months).

CONCLUSIONS:

Early treatment with rituximab was well tolerated and safe. Further studies are needed to determine if this intervention can decrease CLL‐related morbidity and mortality. Cancer 2011. © 2011 American Cancer Society.     

Phase 2 study of preoperative radiation with concurrent capecitabine,oxaliplatin, and bevacizumab followed by surgery and postoperative 5‐fluorouracil,leucovorin, oxaliplatin (FOLFOX), and bevacizumab in patients with locally advanced rectal cancer: ECOG 3204

BACKGROUND:

Recent studies have demonstrated the feasibility of combining oxaliplatin with 5‐fluorouracil (5‐FU) or capecitibine and radiation therapy. The addition of bevacizumab to chemotherapy improves overall survival for metastatic disease. We initiated a phase 2 trial to evaluate preoperative capecitabine, oxaliplatin, and bevacizumab with radiation therapy followed by surgery and postoperative 5‐FU, leucovorin, oxaliplatin (FOLFOX) and bevacizumab for locally advanced rectal cancer.

METHODS:

Fifty‐seven patients with resectable T3/T4 rectal adenocarcinoma were enrolled. Preoperative treatment was capecitabine (825 mg/m² twice daily from Monday to Friday), oxaliplatin (50 mg/m² weekly), bevacizumab (5 mg/kg on days 1, 15, 29), and radiation therapy (50.4 Gy). Surgery was performed by 6 weeks after neoadjuvant therapy. Beginning 8 to 12 weeks after surgery, patients received FOLFOX plus bevacizumab (5 mg/kg) every 2 weeks for 12 cycles.

RESULTS:

Fifty‐four of 57 enrolled patients were eligible. Forty‐nine (91%) patients completed preoperative therapy and underwent surgery. Nine patients (17%; 90% confidence interval, 9%‐27%) achieved pathologic complete response. Thirty‐two patients (59%) experienced pathologic tumor downstaging, and 53% and 15% of patients experienced worst grade 3 and grade 4 acute toxicity, respectively. Forty‐seven percent of patients who underwent surgery experienced a surgical complication.

CONCLUSIONS:

The primary endpoint of a 30% pathologic complete response rate was not reached; however, the majority of patients experienced pathologic downstaging with this regimen. Increased wound‐healing delays and complications may have been related to the addition of bevacizumab, oxaliplatin, or both. Continued observation of these patients will establish the long‐term morbidity and efficacy of this combined modality approach. Cancer 2013. © 2012 American Cancer Society.     

Q-TWiST analysis of ixabepilone in combination with capecitabine on quality of life in patients with metastatic breast cancer

BACKGROUND:

Combination therapy with ixabepilone and capecitabine (cape) is approved for use in patients with locally advanced/metastatic breast cancer that is resistant to treatment with anthracyclines or taxanes. The current study evaluated the trade‐off between quality and quantity of life using quality‐adjusted time without symptoms or toxicity (Q‐TWiST) outcomes.

METHODS:

Within the trial, 752 women were randomly assigned to receive either the combination of ixabepilone and cape (once every 21 days) or cape alone (on days 1‐14). The area under the survival curve was partitioned into 3 health states: toxicity (TOX), time without symptoms of disease progression or toxicity, and recurrence (relapse [REL]). The mean time in each health state was weighted by a range of utilities and summed to estimate quality‐adjusted survival (QAS). Patient‐reported outcomes were also evaluated using the Functional Assessment of Cancer Therapy (FACT)‐Breast Symptom Index (FBSI).

RESULTS:

A statistically significant difference between groups with regard to change from baseline FBSI scores favoring the cape group was observed (P = .0002), but no differences were observed after adjusting for deaths in the analysis. All combinations of utilities for REL and TOX resulted in an observed difference in QAS favoring combination therapy. Differences were found to be statistically significant for comparisons, with higher tolerance for TOX. QAS was found to be greater for the combination therapy group (42.2 weeks vs 38.4 weeks), assuming the base case scenario of utility equal to 0.5 for both TOX and REL (P = .0227).

CONCLUSIONS:

The Q‐TWiST analysis supports a positive benefit‐risk ratio for the combination of ixabepilone plus cape in patients with advanced/metastatic breast cancer that is refractory to anthracyclines and taxanes versus cape alone, despite the potential for added toxicities with combination therapy. Cancer 2011;. © 2011 American Cancer Society.     

A double-blind, randomized, placebo-controlled, phase 2 study of maintenance enzastaurin with 5-fluorouracil/leucovorin plus bevacizumab after first-line therapy for metastatic colorectal cancer

BACKGROUND:

Enzastaurin and bevacizumab have demonstrated synergistic antitumor effects and, in phase 1 studies, the combination was well tolerated. This phase 2 study assessed enzastaurin with 5‐fluorouracil/leucovorin plus bevacizumab as maintenance therapy for metastatic colorectal cancer (MCRC).

METHODS:

Patients with locally advanced or MCRC and stable or responding disease after completing 6 cycles of first‐line chemotherapy randomly received a loading dose of enzastaurin 1125 mg, followed by 500 mg/d subsequent doses or placebo. Both arms received 5‐fluorouracil/leucovorin (leucovorin 400 mg/m² intravenously [IV], 5‐fluorouracil 400‐mg/m² bolus, 5‐fluorouracil 2400 mg/m² IV) plus bevacizumab 5 mg/kg IV, every 2 weeks. The primary endpoint was progression‐free survival (PFS), from randomization. Overall survival (OS) and PFS were also assessed from start of first‐line therapy. Enrollment was stopped, and the final analysis was conducted after 73 PFS events.

RESULTS:

Fifty‐eight patients were randomized to enzastaurin and 59 to placebo. For the enzastaurin and placebo arms, respectively, the median cycles received were 9 and 10, and the median PFS was 5.8 and 8.1 months (hazard ratio [HR], 1.35; 95% confidence interval [CI], 0.84‐2.16; P = .896). Median OS was not calculable because of high censoring (77.6% enzastaurin; 91.5% placebo). The median PFS from start of first‐line therapy was 8.9 months for enzastaurin and 11.3 months for placebo (HR, 1.39; 95% CI, 0.86‐2.23; P = .913). More enzastaurin patients developed thrombosis or embolism compared with placebo (15.8% and 1.7%; P = .008). One possibly enzastaurin‐related death occurred because of arrhythmia.

CONCLUSIONS:

Enzastaurin combined with bevacizumab‐based therapy is tolerable, but does not improve PFS during maintenance therapy in patients with MCRC compared with bevacizumab‐based therapy alone. Cancer 2012. © 2011 American Cancer Society.     

Costs associated with complications are lower with capecitabine than with 5‐fluorouracil in patients with colorectal cancer

BACKGROUND:

Capecitabine, an oral alternative to 5‐fluorouracil (5‐FU) in patients with colorectal cancer (CRC), has equal clinical efficacy and a favorable safety profile; however, its use may be limited because of unit cost concerns. In this study, the authors measured the cost of chemotherapy‐related complications during treatment with capecitabine‐ and 5‐FU–based regimens.

METHODS:

Patients with CRC who received at least 1 administration of capecitabine or 5‐FU during 2004 and 2005 were identified from the Thomson MarketScan research databases. Monthly frequency and cost for 23 complications were recorded. Logistic regression was used to predict complication probability. General linear models were used to predict monthly complication cost and total monthly expenditure.

RESULTS:

In total, 4973 patients with CRC met the inclusion criteria for this analysis. Although the most frequently observed complications were the same between capecitabine and 5‐FU (nausea and vomiting, infection, anemia, neutropenia, diarrhea), each was observed with greater frequency in 5‐FU–based regimens. The mean predicted monthly complication cost was significantly higher (by 136%) with 5‐FU monotherapy than with capecitabine monotherapy (difference, $601; 95% confidence interval [95% CI], $469‐$737). In addition, the mean predicted monthly complication cost for 5‐FU+oxaliplatin was higher than the cost with capecitabine plus oxaliplatin (difference, $1165; 95% CI, $892‐$1595). When acquisition, administration, and complication costs were taken into consideration, there were no significant differences in the total cost between capecitabine regimens and 5‐FU regimens.

CONCLUSIONS:

Capecitabine compared well with 5‐FU–based therapy in patients with CRC and was associated with lower complication rates and associated costs. Cancer 2009. © 2009 American Cancer Society.