[Paraneoplastic Leukocytosis and Thrombocytosis as Prognostic Biomarkers in Non-small Cell Lung Cancer].

BACKGROUND: Search for inexpensive laboratory markers have identified associations between blood counts and lung cancer outcomes. In this study, we evaluated the prognostic value of paraneoplastic leukocytosis (p-Leukocytosis) and paraneoplastic thrombocytosis (p-Thrombocytosis) in patients with non-small cell lung cancer (NSCLC). We also studied their relation to the expression of commonly detected molecular markers. METHODS: We conducted a retrospective chart review on 571 consecutive NSCLC patients over a 10 year period. Blood counts were recorded at the time of cancer diagnosis. Kaplan-Meier survival curves were used to compare overall survival (OS) between patients with and without p-Leukocytosis (or) p-Thrombocytosis (p-Leuko/Thrombocytosis). Cox regression was used to determine if leukocytosis/thrombocytosis was a predictor of OS in NSCLC. RESULTS: Patients with p-Leukocytosis and p-Thrombocytosis had a significantly poorer survival compared patients with normal blood counts (P<0.001). In a multivariate survival analysis, both continued to correlate even when adjusted for histology, gender, stage and chemotherapy (P<0.01, 0.03 respectively). Stage I and II NSCLC with p-Leuko/Thrombocytosis did not perform poorly compared to stage I/II NSCLC patients without paraneoplasia. Patients with the combined leukothrombocytosis syndrome did not have worse outcomes compared to those with either paraneoplastic syndrome alone. CONCLUSIONS: p-Leuko/Thrombocytosis is an accessible laboratory parameter of prognostic value in NSCLC. Evidence of p-Leuko/Thrombocytosis portends poor survival. The role of various cytokines in tumor pathobiology provides a rationale for identifying cytokine factors responsible for the paraneoplasia and administering anti-cytokine therapies alongside traditional chemotherapy in an attempt to improve survival outcomes in these subset of patients.

Adjuvant chemotherapy is associated with improved survival in patients with stage II colon cancer.

BACKGROUND: The role of adjuvant chemotherapy in patients with stage II colon cancer remains to be elucidated and its use varies between patients and institutions. Currently, clinical guidelines suggest discussing adjuvant chemotherapy for patients with high-risk stage II disease in the absence of conclusive randomized controlled trial data. To further investigate this relationship, the objective of the current study was to determine whether an association exists between overall survival (OS) and adjuvant chemotherapy in patients stratified by age and pathological risk features. METHODS: Data from the National Cancer Data Base were analyzed for demographics, tumor characteristics, management, and survival of patients with stage II colon cancer who were diagnosed from 1998 to 2006 with survival information through 2011. Pearson Chi-square tests and binary logistic regression were used to analyze disease and demographic data. Survival analysis was performed with the log-rank test and Cox proportional hazards regression modeling. Propensity score weighting was used to match cohorts. RESULTS: Among 153,110 patients with stage II colon cancer, predictors of receiving chemotherapy included age <65 years, male sex, nonwhite race, use of a community treatment facility, non-Medicare insurance, and diagnosis before 2004. Improved and clinically relevant OS was associated with the receipt of adjuvant chemotherapy in all patient subgroups regardless of high-risk tumor pathologic features (poor or undifferentiated histology, <12 lymph nodes evaluated, positive resection margins, or T4 histology), age, or chemotherapy regimen, even after adjustment for covariates and propensity score weighting (hazard ratio, 0.76; P<.001). There was no difference in survival noted between single and multiagent adjuvant chemotherapy regimens. CONCLUSIONS: In what to the authors' knowledge is the largest group of patients with stage II colon cancer evaluated to date, improved OS was found to be associated with adjuvant chemotherapy regardless of treatment regimen, patient age, or high-risk pathologic risk features. Cancer 2016;122:3277-3287. © 2016 American Cancer Society.

A brief yoga intervention implemented during chemotherapy: A randomized controlled pilot study.

OBJECTIVES: Fatigue and other treatment-related symptoms (e.g., sleep disturbance) are critical targets for improving quality of life in patients undergoing chemotherapy. Yoga may reduce the burden of such symptoms. This study investigated the feasibility of conducting a randomized controlled study of a brief yoga intervention during chemotherapy for colorectal cancer. DESIGN: We randomized adults with colorectal cancer to a brief Yoga Skills Training (YST) or an attention control (AC; empathic attention and recorded education). SETTING: The interventions and assessments were implemented individually in the clinic while patients were in the chair receiving chemotherapy. INTERVENTIONS: Both interventions consisted of three sessions and recommended home practice. MAIN OUTCOME MEASURES: The primary outcome was feasibility (accrual, retention, adherence, data collection). Self-reported outcomes (i.e., fatigue, sleep disturbance, quality of life) and inflammatory biomarkers were also described to inform future studies. RESULTS: Of 52 patients initially identified, 28 were approached, and 15 enrolled (age Mean = 57.5 years; 80% White; 60% Male). Reasons for declining participation were: not interested (n = 6), did not perceive a need (n = 2), and other (n = 5). Two participants were lost to follow-up in each group due to treatment changes. Thus, 75% of participants were retained in the YST and 71% in the AC arm. Participants retained in the study adhered to 97% of the in-person intervention sessions and completed all questionnaires. CONCLUSIONS: This study demonstrated the feasibility of conducting a larger randomized controlled trial to assess YST among patients receiving chemotherapy for colorectal cancer. Data collected and challenges encountered will inform future research.

Phase II trial of adjuvant oral thalidomide following cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal surface disease from colorectal/appendiceal cancer.

PURPOSE: This phase II single-institution trial of adjuvant thalidomide after cytoreductive surgery (CS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for patients with appendiceal and colorectal malignancies sought to detect an improvement in progression-free survival (PFS) from 7 to 12 months. METHODS: Eligible patients received CS, HIPEC, and baseline imaging, followed by pretreatment thalidomide counseling. All participants were then started on a 28-day regimen of thalidomide, 100 mg by mouth at bedtime, followed by 200 mg for 4 weeks, followed by 300 mg as the final maintenance dose, as tolerated. RESULTS: Twenty-seven eligible patients (median age 52 years; 52% appendiceal/48% colorectal) were enrolled on this trial and included in the analysis, and 26 were evaluable for response. Eighteen patients demonstrated stable disease on adjuvant thalidomide, while eight showed evidence of progression. Approximately 30% of the patients withdrew due to toxicity. Grade 3/4 toxicities included neurological disorders (16%), nausea (12%), vomiting (8%), and thromboembolism (8%). Median overall survival (OS) and PFS were 43.0 and 9.3 months, respectively, and median follow-up was 40.4 months. Multivariate modeling showed significant improvements in PFS and OS for appendiceal patients and those with R0 or R1 resections. On an intent-to-treat analysis, the PFS of the study group was 9 months. CONCLUSIONS: Based on these findings, thalidomide cannot be recommended as adjuvant therapy after CS and HIPEC for gastrointestinal malignancies. Further research is needed to identify active agents in this population.

A randomized phase II study of immunization with dendritic cells modified with poxvectors encoding CEA and MUC1 compared with the same poxvectors plus GM-CSF for resected metastatic colorectal cancer.

OBJECTIVE: To determine whether 1 of 2 vaccines based on dendritic cells (DCs) and poxvectors encoding CEA (carcinoembryonic antigen) and MUC1 (PANVAC) would lengthen survival in patients with resected metastases of colorectal cancer (CRC). BACKGROUND: Recurrences after complete resections of metastatic CRC remain frequent. Immune responses to CRC are associated with fewer recurrences, suggesting a role for cancer vaccines as adjuvant therapy. Both DCs and poxvectors are potent stimulators of immune responses against cancer antigens. METHODS: Patients, disease-free after CRC metastasectomy and perioperative chemotherapy (n = 74), were randomized to injections of autologous DCs modified with PANVAC (DC/PANVAC) or PANVAC with per injection GM-CSF (granulocyte-macrophage colony-stimulating factor). Endpoints were recurrence-free survival overall survival, and rate of CEA-specific immune responses. Clinical outcome was compared with that of an unvaccinated, contemporary group of patients who had undergone CRC metastasectomy, received similar perioperative therapy, and would have otherwise been eligible for the study. RESULTS: Recurrence-free survival at 2 years was similar (47% and 55% for DC/PANVAC and PANVAC/GM-CSF, respectively) (χ P = 0.48). At a median follow-up of 35.7 months, there were 2 of 37 deaths in the DC/PANVAC arm and 5 of 37 deaths in the PANVAC/GM-CSF arm. The rate and magnitude of T-cell responses against CEA was statistically similar between study arms. As a group, vaccinated patients had superior survival compared with the contemporary unvaccinated group. CONCLUSIONS: Both DC and poxvector vaccines have similar activity. Survival was longer for vaccinated patients than for a contemporary unvaccinated group, suggesting that a randomized trial of poxvector vaccinations compared with standard follow-up after metastasectomy is warranted. (NCT00103142).

Optimal timing of systemic therapy in resectable colorectal liver metastases.

Perioperative chemotherapy has been shown to improve disease-free survival compared with surgery alone for resectable colorectal liver metastases (CLM). We examined our experience with systemic chemotherapy in this clinical setting. A prospectively collected liver surgery database identified 210 patients treated for resectable CLM from 1996 to 2010. Results were correlated to four treatment groups: posthepatectomy adjuvant only, prehepatectomy preoperative only, perioperative (preoperative and adjuvant), and surgery only. Seventy-nine (37.6%) patients received posthepatectomy adjuvant only treatment, 33 (15.7%) received prehepatectomy preoperative only treatment, 46 (21.9%) received perioperative (preoperative and adjuvant) treatment, whereas 52 (24.8%) received surgery alone. Preoperative and adjuvant systemic chemotherapy regimens were as follows: 23 (29.1%) and 18 (14.4%) received a 5-fluorouracil monotherapy regimen, 19 (24.1%) and 31 (24.8%) received an irinotecan-based regimen, and 28 (35.4%) and 37 (29.6%) received an oxaliplatin-based regimen. Nine (11.4%) and 12 (9.6%) received some other unknown combination. Treatment groups showed no difference in gender, mean tumor size, number of tumors, margin status, or postoperative complications with the only difference being a higher incidence of metachronous tumors in the preoperative only and perioperative groups (P = 0.01). Median follow-up and overall survival were 25 and 41 months, respectively. The adjuvant, preoperative, perioperative, and surgery only groups had a median survival time of 48, 35, 39, and 29 months, respectively (log-rank P = 0.04). Independent predictors of overall survival on multivariate analysis included treatment algorithm used and postoperative complication status. Adjuvant only systemic therapy was associated with an improved survival in resectable CLM. Prospective randomized trials are needed to confirm these findings.

A two-cohort phase I study of weekly oxaliplatin and gemcitabine, then oxaliplatin, gemcitabine, and erlotinib during radiotherapy for unresectable pancreatic carcinoma.

OBJECTIVES: Gemcitabine is a potent radiosensitizer. When combined with standard radiotherapy (XRT) the gemcitabine dose must be reduced to about 10% of its conventional dose. Oxaliplatin and erlotinib also have radiosensitizing properties. Oxaliplatin and gemcitabine have demonstrated synergy in vitro. We aimed to determine the maximum tolerated dose of oxaliplatin and gemcitabine with concurrent XRT, then oxaliplatin, gemcitaibine, and erlotinib with XRT in the treatment of locally advanced and low-volume metastatic pancreatic or biliary cancer. METHODS: A modified 3+3 dose-escalation design was used for testing 4 dose levels of oxaliplatin and gemcitabine given once weekly for a maximum of 6 weeks with daily XRT in fractions of 1.8 Gy to a total dose of 50.4 Gy. Dose-limiting toxicity (DLT) was defined as any grade 4 toxicity or grade 3 toxicity resulting in a treatment delay of >1 week. In addition, dose reduction in 2 of the 3 patients in a given cohort was counted as a DLT in dose escalation-deescalation rule in the modified 3+3 design. RESULTS: Eighteen patients were enrolled, all with pancreatic cancer. Grade 4 transaminitis in a patient in cohort 3 resulted in cohort expansion. Cohort 4, the highest planned dose cohort, had no DLTs. The recommended phase II dose is oxaliplatin 50 mg/m(2)/wk with gemcitabine 200 mg/m(2)/wk and 50.4 Gy XRT. The most prevalent grade 3 toxicities were nausea (22%), elevated transaminases (17%), leucopenia (17%), and hyperglycemia (17%). Median progression-free survival was 7.1 months (95% confidence interval, 4.6-11.1 mo) and median overall survival was 10.8 months (95% confidence interval, 7.1-16.7 mo). The addition of erlotinib was poorly tolerated at the first planned dose level, but full study of the combination was hindered by early closure of the study. CONCLUSIONS: Weekly oxaliplatin 50 mg/m/wk combined with gemcitabine 200 mg/m/wk and XRT for pancreatic cancer has acceptable toxicity and interesting activity.

A randomized pilot phase I study of modified carcinoembryonic antigen (CEA) peptide (CAP1-6D)/montanide/GM-CSF-vaccine in patients with pancreatic adenocarcinoma.

BACKGROUND: CEA is expressed in >90% of pancreatic cancers (PC) and may be an appropriate immunotherapy target. CEA is poorly immunogenic due to immune tolerance; CAP1-6D, an altered peptide ligand can help bypass tolerance. We conducted a pilot randomized phase I trial in PC patients to determine the peptide dose required to induce an optimal CD8(+) T cell response. METHODS: Patients with a PS 0-1, HLA-A2+ and CEA-expressing, previously-treated PC were randomized to receive 10 µg (arm A), 100 µg (arm B) or 1000 µg (arm C) of CEA peptide emulsified in Montanide and GM-CSF, given every 2 weeks until disease progression. RESULTS: Sixty-six patients were screened and 19 enrolled of whom 14 received at least 3 doses of the vaccine and thus evaluated for the primary immunologic endpoint. A median of 4 cycles (range 1-81) was delivered. Median and mean peak IFN-γ T cell response by ELISPOT (spots per 10(4) CD8(+) cells, Arm A/B/C) was 11/52/271 (A vs. C, p = 0.028) for medians and 37/148/248 (A vs. C, p = 0.032) for means. T cell responses developed or increased in 20%/60%/100% of pts in Arms A/B/C. Seven of the 19 patients remain alive at a minimum 32 months from trial initiation, including three with unresectable disease. CONCLUSIONS: The T cell response in this randomized phase I trial was dose-dependent with the 1 mg CEA peptide dose eliciting the most robust T cell responses. A signal of clinical benefit was observed and no significant toxicity was noted. Further evaluation of 1 mg CEA peptide with stronger adjuvants, and/or combined with agents to overcome immune inhibitory pathways, may be warranted in PC pts. TRIAL REGISTRATION: ClinicalTrials.gov NCT00203892.

Reverse translation of phase I biomarker findings links the activity of angiotensin-(1-7) to repression of hypoxia inducible factor-1α in vascular sarcomas.

BACKGROUND: In a phase I study of angiotensin-(1-7) [Ang-(1-7)], clinical benefit was associated with reduction in plasma placental growth factor (PlGF) concentrations. The current study examines Ang-(1-7) induced changes in biomarkers according to cancer type and investigates mechanisms of action engaged in vitro. METHODS: Plasma biomarkers were measured prior to Ang-(1-7) administration as well as 1, 2, 3, 4, and 6 hours after treatment. Tests for interaction were performed to determine the impact of cancer type on angiogenic hormone levels. If a positive interaction was detected, treatment-induced biomarker changes for individual cancer types were assessed. To investigate mechanisms of action, in vitro growth assays were performed using a murine endothelioma cell line (EOMA). PCR arrays were performed to identify and statistically validate genes that were altered by Ang-(1-7) treatment in these cells. RESULTS: Tests for interaction controlled for dose cohort and clinical response indicated a significant impact of cancer type on post-treatment VEGF and PlGF levels. Following treatment, PlGF levels decreased over time in patients with sarcoma (P = .007). Treatment of EOMA cells with increasing doses of Ang-(1-7) led to significant growth suppression at doses as low as 100 nM. PCR arrays identified 18 genes that appeared to have altered expression after Ang-(1-7) treatment. Replicate analyses confirmed significant changes in 8 genes including reduction in PlGF (P = .04) and hypoxia inducible factor 1α (HIF-1α) expression (P < .001). CONCLUSIONS: Ang-(1-7) has clinical and pre-clinical activity for vascular sarcomas that is linked to reduced HIF-1α and PlGF expression.

The effect of targeted agents on outcomes in patients with brain metastases from renal cell carcinoma treated with Gamma Knife surgery.

OBJECT: Gamma Knife surgery (GKS) has been reported as an effective modality for treating brain metastases from renal cell carcinoma (RCC). The authors aimed to determine if targeted agents such as tyrosine kinase inhibitors, mammalian target of rapamycin inhibitors, and bevacizumab affect the patterns of failure of RCC after GKS. METHODS: Between 1999 and 2010, 61 patients with brain metastases from RCC were treated with GKS. A median dose of 20 Gy (range 13-24 Gy) was prescribed to the margin of each metastasis. Kaplan-Meier analysis was used to determine local control, distant failure, and overall survival rates. Cox proportional hazard regression was performed to determine the association between disease-related factors and survival. RESULTS: Overall survival at 1, 2, and 3 years was 38%, 17%, and 9%, respectively. Freedom from local failure at 1, 2, and 3 years was 74%, 61%, and 40%, respectively. The distant failure rate at 1, 2, and 3 years was 51%, 79%, and 89%, respectively. Twenty-seven percent of patients died of neurological disease. The median survival for patients receiving targeted agents (n = 24) was 16.6 months compared with 7.2 months (n = 37) for those not receiving targeted therapy (p = 0.04). Freedom from local failure at 1 year was 93% versus 60% for patients receiving and those not receiving targeted agents, respectively (p = 0.01). Multivariate analysis showed that the use of targeted agents (hazard ratio 3.02, p = 0.003) was the only factor that predicted for improved survival. Two patients experienced post-GKS hemorrhage within the treated volume. CONCLUSIONS: Targeted agents appear to improve local control and overall survival in patients treated with GKS for metastastic RCC.

Oncologic management of hereditary colorectal cancer.

Colorectal cancer (CRC) is the second most common cancer in females and the third most common cancer diagnosed in males. Familial CRC comprises ~20 to 30% of all CRC cases. Lynch syndrome (LS), previously called hereditary nonpolyposis CRC (HNPCC), is the most common of the hereditary CRC syndromes. In this review, the oncological management of hereditary colorectal cancer from the medical oncologist perspective is discussed with special emphasis on Lynch syndrome. Lynch syndrome is characterized by the presence of germline mutations in the mismatch repair genes (MMR)-MSH2, MLH1, MSH6, and PMS2. The available data regarding the prognostic role of mismatch repair genes (MMR), the predictive role of MMR genes, and the implications of that in the management of patients with deficient MMR genes (dMMR/MSI-H) tumors including Lynch syndrome patients are also discussed.

The current landscape of locally advanced rectal cancer.

Postoperative adjuvant chemoradiotherapy was recommended as the standard treatment for patients with rectal cancer because it reduces local recurrence. This paradigm shifted with the use of neoadjuvant chemoradiotherapy, which not only reduces local recurrence but also improves sphincter preservation and surgical outcomes. However, the treatment of rectal carcinoma remains complicated. The accuracy of tumor staging can be compromised depending on the imaging modality used. The addition of modern chemotherapeutics and biologics to 5-fluorouracil as radiation sensitizers is questionable. Oxaliplatin as a radiation sensitizer has minimal effects on the pathologic complete response, but improves the radiographical response at the expense of an increased risk of toxicities. The role of biologics in addition to radiation therapy continues to be explored. Attention has focused on improving diagnostic imaging, radiation oncology, and surgical techniques, treatment regimens, and on exploring a role of molecular markers for patients with rectal cancers. We review the pivotal trials that have led to the current treatment paradigm for locally advanced rectal cancer and discuss novel methodologies that are being developed for the treatment of this prevalent malignancy.

A phase II study of capecitabine, oxaliplatin, bevacizumab and cetuximab in the treatment of metastatic colorectal cancer.

AIM: This study was designed to determine the efficacy and tolerability of capecitabine, oxaliplatin and bevacizumab in combination with cetuximab as first-line therapy for advanced colorectal cancer. PATIENTS AND METHODS: Patients with previously untreated advanced colorectal cancer received oxaliplatin 130 mg/m² and bevacizumab 7.5 mg/kg every three weeks, capecitabine 850 mg/m² twice daily on days 1-14, and cetuximab at 400 mg/m² load and 250 mg/m² weekly. KRAS, BRAF and PI3K mutation status from paraffin-embedded tumor samples were assessed using real-time polymerase chain reaction. RESULTS: Thirty patients were evaluable for safety and efficacy. One patient had a complete response and 12 patients had a partial response, giving an overall response rate of 43% (95% confidence interval (CI) 25%-63%). Fifteen patients had stable disease. The median time to progression was 10.3 months (95% CI, 6.8-16.3 months). The median overall survival was 18.8 months (95% CI, 14.2-23.7 months). Common grade ≥ 3 non-hematological toxicities were skin rash (37%), sensory neuropathy (27%) and diarrhea (17%). Grade ≥ 3 hematological toxicities were uncommon. Mutations in KRAS, BRAF and PI3K occurred in 34.5%, 10.3% and 10.3% of patients respectively, but did not correlate with treatment outcome. CONCLUSION: The addition of cetuximab to capecitabine, oxaliplatin and bevacizumab did not improve the three-drug regimen activity compared to published data and was associated with significant toxicities requiring frequent dose modifications. KRAS, BRAF, and PI3K mutation status were consistent with published literature, but did not affect outcome in this small study.

Outcomes of patients with esophageal cancer staged with [¹8F]fluorodeoxyglucose positron emission tomography (FDG-PET): can postchemoradiotherapy FDG-PET predict the utility of resection?

PURPOSE: To determine whether [(18)F]fluorodeoxyglucose positron emission tomography (FDG-PET) can delineate patients with esophageal cancer who may not benefit from esophagectomy after chemoradiotherapy. PATIENTS AND METHODS: We reviewed records of 163 patients with histologically confirmed stage I to IVA esophageal cancer receiving chemoradiotherapy with or without resection with curative intent. All patients received surgical evaluation. Initial and postchemoradiotherapy FDG-PET scans and prognostic/treatment variables were analyzed. FDG-PET complete response (PET-CR) after chemoradiotherapy was defined as standardized uptake value ≤ 3. RESULTS: Eighty-eight patients received trimodality therapy and 75 received chemoradiotherapy. Surgery was deferred primarily due to medical inoperability or unresectable/metastatic disease after chemoradiotherapy. A total of 105 patients were evaluable for postchemoradiotherapy FDG-PET response. Thirty-one percent achieved a PET-CR. PET-CR predicted for improved outcomes for chemoradiotherapy (2-year overall survival, 71% v 11%, P < .01; 2-year freedom from local failure [LFF], 75% v 28%, P < .01), but not trimodality therapy. On multivariate analysis of patients treated with chemoradiotherapy, PET-CR is the strongest independent prognostic variable (survival hazard ratio [HR], 9.82, P < .01; LFF HR, 14.13, P < .01). PET-CR predicted for improved outcomes regardless of histology, although patients with adenocarcinoma achieved a PET-CR less often. CONCLUSION: Patients treated with trimodality therapy found no benefit with PET-CR, likely because FDG-PET residual disease was resected. Definitive chemoradiotherapy patients achieving PET-CR had excellent outcomes equivalent to trimodality therapy despite poorer baseline characteristics. Patients who achieve a PET-CR may not benefit from added resection given their excellent outcomes without resection. These results should be validated in a prospective trial of FDG-PET-directed therapy for esophageal cancer.

Arsenic trioxide in patients with adenocarcinoma of the pancreas refractory to gemcitabine: a phase II trial of the University of Chicago Phase II Consortium.

OBJECTIVES: There is no effective therapy for patients with metastatic pancreatic cancer who fail initial therapy with gemcitabine. Arsenic trioxide has potent antiproliferative and proapoptotic effects in pancreatic cancer cell lines. We conducted a multicenter phase II trial in patients with advanced pancreatic cancer who experienced disease progression on or after a gemcitabine-containing regimen. METHODS: Arsenic trioxide 0.3 mg/kg was administered intravenously over 1 hour daily for 5 consecutive days every 28 days. Restaging computed tomography scans were obtained every 2 cycles. RESULTS: Thirteen patients were enrolled between December 2002 and November 2003. Twenty-four cycles were administered (median 2; range 1-2). There were no grade 3/4 hematologic toxicities; grade 1/2 anemia and leukopenia occurred in 50% and 25% of patients, respectively. Grade 3 toxicities included fatigue and thrombosis in 17% of patients. Only 1 patient developed a prolongation of the QTc interval. There were no objective responses. Median progression-free survival was 1.6 months (95% confidence interval, 1.2-1.9). Median survival was 3.8 months (95% confidence interval, 1.6-6.8). CONCLUSIONS: Despite promising in vitro data, arsenic trioxide has no activity in pancreatic cancer patients who develop progressive disease after gemcitabine. Multicenter phase II trials are feasible in this patient population, and novel agents are clearly needed.

Targeted agents and esophageal cancer--the next step?

Esophageal cancer (EC) is an aggressive cancer and is a leading cause of cancer-related death worldwide. In the United States and Western Europe, there has been a decline in the incidence of squamous cell carcinomas coupled with a rapid rise in incidence of adenocarcinoma of the esophagus and gastroesophageal junction. Although the 5-year survival rates have slowly increased over time from 4% to 14%, the outcomes are still dismal. The lack of adequate preventative strategies, inadequate screening techniques, early lymphatic and hematogenous spread, and lack of truly effective therapeutic agents all contribute to the poor outcome. This review will highlight the current status of targeted therapies in EC. This will include a review of agents targeting the vascular endothelial growth factor and epidermal growth factor receptor pathways and trials planned or ongoing to incorporate these and other agents into therapy for advanced disease and into combined modality therapy for early-stage tumors. Further work is required regarding the rational integration of these targeted agents and the optimal selection of patients who will most likely benefit.