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author:("zaluski, Mark")
1.  Neoadjuvant Stereotactic Body Radiation Therapy (SBRT), Capecitabine, and Liver Transplantation for Unresectable Hilar Cholangiocarcinoma 
Hilar cholangiocarcinoma (CCA) is a difficult malignancy to treat surgically given its anatomical location and its frequent association with primary sclerosing cholangitis (PSC). Neoadjuvant chemoradiotherapy followed by liver transplantation in lymph node negative patients has been advanced by select liver transplant centers for treatment of patients with unresectable disease. This approach has most commonly used external beam radiotherapy combined with biliary brachytherapy and 5-FU based chemotherapy. Our center has recently embarked on a protocol utilizing stereotactic body radiation therapy (SBRT) followed by capecitabine in lymph node negative patients until liver transplantation. We therefore retrospectively determined tolerability and pathologic response in this pilot study. Over a three year period 17 patients with unresectable hilar CCA were evaluated for treatment under this protocol. In all, 12 patients qualified for neoadjuvant therapy and were treated with SBRT (50–60 Gy, 3–5 fractions over two weeks). Following one week of rest, capecitabine was initiated at 1330 mg/m2/day and continued until liver transplantation. During neoadjuvant therapy, there were a total of 35 adverse events with cholangitis and palmar/plantar erythrodysesthesia being the most common. Capecitabine dose reductions were required on 5 occasions. Ultimately, 9 patients were listed for transplant and 6 patients received a liver transplant. Explant pathology of hilar tumors showed at least a partial treatment response in five patients with extensive tumor necrosis and fibrosis noted. Additionally, high apoptotic and low proliferative indices were measured on histological examination. Eleven transplant-related complications occurred, and one-year survival after transplant was 83%. In this pilot study, neoadjuvant therapy with SBRT, capecitabine, and liver transplantation for unresectable CCA demonstrated acceptable tolerability. Further studies will determine the overall future efficacy of this therapy.
PMCID: PMC4185427  PMID: 24115315
Malignancy/liver transplantation; sclerosing cholangitis; bile duct cancer; biliary neoplasms; external beam radiotherapy
2.  Carbohydrate Antigen 19-9 Is a Prognostic and Predictive Biomarker in Patients With Advanced Pancreatic Cancer Who Receive Gemcitabine-Containing Chemotherapy 
Cancer  2012;119(2):285-292.
Carbohydrate antigen 19-9 (CA19-9) is a widely used biomarker in pancreatic cancer. There is no consensus on the interpretation of the change in CA19-9 serum levels and its role in the clinical management of patients with pancreatic cancer.
Individual patient data from 6 prospective trials evaluating gemcitabine-containing regimens from 3 different institutions were pooled. CA19-9 values were obtained at baseline and after successive cycles of treatment. The objective of this study was to correlate a decline in CA19-9 with outcomes while undergoing treatment.
A total of 212 patients with locally advanced (n = 50) or metastatic (n = 162) adenocarcinoma of the pancreas were included. Median baseline CA19-9 level was 1077 ng/mL (range, 15–492,241 ng/mL). Groups were divided into those levels below (low) or above (high) the median. Median overall survival (mOS) was 8.7 versus 5.2 months (P = .0018) and median time to progression (mTTP) was 5.8 versus 3.7 months (P = .082) in the low versus high groups, respectively. After 2 cycles of chemotherapy, up to a 5% increase versus ≥ 5% increase in CA19-9 levels conferred an improved mOS (10.3 vs 5.1 months, P = .0022) and mTTP (7.5 vs 3.5 months, P = 0.0005).
In patients who have advanced pancreatic cancer treated with gemcitabine-containing regimens baseline CA19-9 is prognostic for outcome. A decline in CA19-9 after the second cycle of chemotherapy is not predictive of improved mOS or mTTP; thus, CA19-9 decline is not a useful surrogate endpoint in clinical trials. Clinically, a ≥ 5% rise in CA19-9 after 2 cycles of chemotherapy serves as a negative predictive marker.
PMCID: PMC4261189  PMID: 22786786
pancreatic; gemcitabine; carbohydrate antigen 19-9; outcomes; predictive; prognostic
3.  A Pilot Study of Diffusion-Weighted MRI in Patients Undergoing Neoadjuvant Chemoradiation for Pancreatic Cancer 
Translational Oncology  2014;7(5):644-649.
PURPOSE: In the current study we examined the ability of diffusion MRI (dMRI) to predict pathologic response in pancreatic cancer patients receiving neoadjuvant chemoradiation. METHODS: We performed a prospective pilot study of dMRI in patients with resectable pancreatic cancer. Patients underwent dMRI prior to neoadjuvant chemoradiation. Surgical specimens were graded according to the percent tumor cell destruction. Apparent diffusion coefficient (ADC) maps were used to generate whole-tumor derived ADC histogram distributions and mean ADC values. The primary objective of the study was to correlate ADC parameters with pathologic and CT response. RESULTS: Ten of the 12 patients enrolled on the study completed chemoradiation and had surgery. Three were found to be unresectable at the time of surgery and no specimen was obtained. Out of the 7 patients who underwent pancreaticoduodenectomy, 3 had a grade III histopathologic response (> 90% tumor cell destruction), 2 had a grade IIB response (51% to 90% tumor cell destruction), 1 had a grade IIA response (11% to 50% tumor cell destruction), and 1 had a grade I response (> 90% viable tumor). Median survival for patients with a grade III response, grade I-II response, and unresectable disease were 25.6, 18.7, and 6.1 months, respectively. There was a significant correlation between pre-treatment mean tumor ADC values and the amount of tumor cell destruction after chemoradiation with a Pearson correlation coefficient of 0.94 (P = .001). Mean pre-treatment ADC was 161 × 10− 5 mm2/s (n = 3) in responding patients (> 90% tumor cell destruction) compared to 125 × 10− 5 mm2/s (n = 4) in non-responding patients (> 10% viable tumor). CT imaging showed no significant change in tumor size in responders or non-responders. CONCLUSIONS: dMRI may be useful to predict response to chemoradiation in pancreatic cancer. In our study, tumors with a low ADC mean value at baseline responded poorly to standard chemoradiation and would be candidates for intensified therapy.
PMCID: PMC4225651  PMID: 25389460
4.  A Multi-Institutional Phase II Study of Neoadjuvant Gemcitabine and Oxaliplatin with Radiation Therapy in Patients with Pancreatic Cancer 
Cancer  2013;119(15):2692-2700.
The purpose of this study was to evaluate preoperative treatment with full-dose gemcitabine, oxaliplatin and radiation (RT) in localized pancreatic cancer.
Eligibility included confirmation of adenocarcinoma, resectable or borderline resectable disease, PS≤2, and adequate organ function. Treatment consisted of two, 28 day cycles of gemcitabine (1g/m2 over 30 minutes days 1, 8, 15) and oxaliplatin (85mg/m2 days 1, 15) with RT during cycle 1 (30Gy in 2Gy fractions). Patients were evaluated for surgery following cycle 2. Resected patients received 2 cycles of adjuvant chemotherapy.
Sixty-eight evaluable patients were treated at 4 centers. By central radiology review, 23 patients were resectable, 39 borderline resectable, and 6 unresectable. Sixty-six patients (97%) completed cycle 1/RT and 61 patients (90%) cycle 2. Adverse events ≥ grade 3 during preoperative therapy included neutropenia (32%), thrombocytopenia (25%), and biliary obstruction/cholangitis (14%). Forty-three patients were resected (63%) with R0 resection in 36 (84%). Median overall survival for all patients was 18.2 months (95%CI 13–26.9), those resected 27.1 months (95%CI 21.2–47.1) and those not resected 10.9 months (95%CI 6.1–12.6). A decrease in CA19-9 following neoadjuvant therapy was associated with R0 resection (p=0.02) which resulted in a median survival of 34.6 months (95% CI 20.3–47.1). Fourteen patients (21%) are alive and disease-free at a median follow-up time of 31.4 months (range, 24–47.6).
Preoperative therapy with full dose gemcitabine, oxaliplatin and RT was feasible and resulted in a high percentage of R0 resections. Results are particularly encouraging given a majority of patients with borderline resectable disease.
PMCID: PMC4174603  PMID: 23720019
pancreatic cancer; neoadjuvant; gemcitabine; oxaliplatin
5.  A pilot trial of the anti-angiogenic copper lowering agent tetrathiomolybdate in combination with irinotecan, 5-flurouracil, and leucovorin for metastatic colorectal cancer 
Investigational new drugs  2008;27(2):159-165.
Tetrathiomolybdate (TM) is an oral copper chelator under development as an anti-angiogenic agent. We evaluated TM in combination with irinotecan, 5-fluorouracil, and leucovorin (IFL). Serum vascular endothelial growth factor (VEGF), basic fibroblast growth factor, interleukin 6 (IL-6), and IL-8 were measured to evaluate the anti-angiogenic effect. Twenty-four patients with metastatic colorectal cancer were treated. The combination with IFL was well tolerated and dose intensity of IFL was maintained during combination therapy with TM. By intention to treat analysis, the overall response rate (RR) was 25% (95% CI 9.8–46.7) and the median time to progression (TTP) was 5.6 months (95% CI 2.7–7.7). VEGF levels were correlated with TTP, as were changes in VEGF, IL-8, and IL-6. TM can be safely added to IFL without compromising dose intensity or diminishing the expected RR. Changes in serum VEGF, IL-8, and IL-6 after treatment may directly reflect changes in CRC tissue angiogenesis.
PMCID: PMC4171042  PMID: 18712502
Colorectal cancer; Anti-angiogenesis; Tetrathiomolybdate; Copper chelation; Vascular endothelial growth factor
6.  Prognostic Significance of Carbohydrate Antigen 19-9 in Unresectable Locally Advanced Pancreatic Cancer Treated With Dose-Escalated Intensity Modulated Radiation Therapy and Concurrent Full-Dose Gemcitabine: Analysis of a Prospective Phase 1/2 Dose Escalation Study 
Although established in the postresection setting, the prognostic value of carbohydrate antigen 19-9 (CA19-9) in unresectable locally advanced pancreatic cancer (LAPC) is less clear. We examined the prognostic utility of CA19-9 in patients with unresectable LAPC treated on a prospective trial of intensity modulated radiation therapy (IMRT) dose escalation with concurrent gemcitabine.
Methods and Materials
Forty-six patients with unresectable LAPC were treated at the University of Michigan on a phase 1/2 trial of IMRT dose escalation with concurrent gemcitabine. CA19-9 was obtained at baseline and during routine follow-up. Cox models were used to assess the effect of baseline factors on freedom from local progression (FFLP), distant progression (FFDP), progression-free survival (PFS), and overall survival (OS). Stepwise forward regression was used to build multivariate predictive models for each endpoint.
Thirty-eight patients were eligible for the present analysis. On univariate analysis, baseline CA19-9 and age predicted OS, CA19-9 at baseline and 3 months predicted PFS, gross tumor volume (GTV) and black race predicted FFLP, and CA19-9 at 3 months predicted FFDP. On stepwise multivariate regression modeling, baseline CA19-9, age, and female sex predicted OS; baseline CA19-9 and female sex predicted both PFS and FFDP; and GTV predicted FFLP. Patients with baseline CA19-9 ≤90 U/mL had improved OS (median 23.0 vs 11.1 months, HR 2.88, P<.01) and PFS (14.4 vs 7.0 months, HR 3.61, P = .001). CA19-9 progression over 90 U/mL was prognostic for both OS (HR 3.65, P = .001) and PFS (HR 3.04, P = .001), and it was a stronger predictor of death than either local progression (HR 1.46, P = .42) or distant progression (HR 3.31, P = .004).
In patients with unresectable LAPC undergoing definitive chemoradiation therapy, baseline CA19-9 was independently prognostic even after established prognostic factors were controlled for, whereas CA19-9 progression strongly predicted disease progression and death. Future trials should stratify by baseline CA19-9 and incorporate CA19-9 progression as a criterion for progressive disease.
PMCID: PMC3646633  PMID: 23265573
7.  Randomized Clinical Trial of a Brief and Extensive Dyadic Intervention for Advanced Cancer Patients and Their Family Caregivers 
Psycho-oncology  2012;22(3):555-563.
Few intervention programs assist patients and their family caregivers to manage advanced cancer and maintain their quality of life (QOL). This study examined: 1) whether patient-caregiver dyads (i.e., pairs) randomly assigned to a Brief or Extensive dyadic intervention (the FOCUS Program) had better outcomes than dyads randomly assigned to usual care, and 2) if patients' risk for distress (RFD) and other factors moderated the effect of the Brief or Extensive Program on outcomes.
Advanced cancer patients and their caregivers (N=484 dyads) were stratified by patients' baseline risk for distress (high versus low), cancer type (lung, colorectal, breast, prostate), and research site, and then randomly assigned to a Brief (3-session) or Extensive (6-session) intervention or Control. The interventions offered dyads information and support. Intermediary outcomes were: appraisals (i.e., appraisal of illness/caregiving, uncertainty, hopelessness) and resources (i.e., coping, interpersonal relationships, and self-efficacy). The primary outcome was QOL. Data were collected prior to intervention and post-intervention (3 and 6 months from baseline). The final sample was 302 dyads. Repeated Measures MANOVA was used to evaluate outcomes.
Significant Group by Time interactions showed there was improvement in dyads' coping (p<.05), self-efficacy (p<.05), and social QOL (p<.01), and in caregivers' emotional QOL (p<.05). Effects varied by intervention dose. Most effects were found at 3 months only. Risk for distress accounted for very few moderation effects.
Both Brief and Extensive programs had positive outcomes for patient-caregiver dyads, but few sustained effects. Patient-caregiver dyads benefit when viewed as the “unit of care.”
PMCID: PMC3387514  PMID: 22290823
Oncology; cancer; randomized clinical trial; family caregiver; advanced cancer; quality of life; intervention dose; risk for distress
8.  The Quality-of-Life Effects of Neoadjuvant Chemoradiation in Locally Advanced Rectal Cancer 
Existing studies that examine the effect of neoadjuvant chemoradiation (CRT) for locally advanced rectal cancer on patient quality of life (QOL) are limited. Our goals were to prospectively explore acute changes in patient-reported QOL endpoints during and after treatment and to establish a distribution of scores that could be used for comparison as new treatment modalities emerge.
Methods and Materials
Fifty patients with locally advanced rectal cancer were prospectively enrolled at 2 institutions. Validated cancer-specific European Organization for Research and Treatment of Cancer (EORTC QLQ-CR30) and colorectal cancer-specific (EORTC QLQ-CR38 and EORTC QLQ-CR 29) QOL questionnaires were administered to patients 1 month before they began CRT, at week 4 of CRT, and 1 month after they had finished CRT. The questionnaires included multiple symptom scales, functional domains, and a composite global QOL score. Additionally, a toxicity scale was completed by providers 1 month before the beginning of CRT, weekly during treatment, and 1 month after the end of CRT.
Global QOL showed a statistically significant and borderline clinically significant decrease during CRT (−9.50, P=.0024) but returned to baseline 1 month after the end of treatment (−0.33, P=.9205). Symptoms during treatment were mostly gastrointestinal (nausea/ vomiting +9.94, P<.0001; and diarrhea +16.67, P=.0022), urinary (dysuria +13.33, P<.0001; and frequency +11.82, P=.0006) or fatigue (+16.22, P<.0001). These symptoms returned to baseline after therapy. However, sexual enjoyment (P=.0236) and sexual function (P=.0047) remained persistently diminished after therapy.
Rectal cancer patients undergoing neoadjuvant CRT may experience a reduction in global QOL along with significant gastrointestinal and genitourinary symptoms during treatment. Moreover, provider-rated toxicity scales may not fully capture this decrease in patient-reported QOL. Although most symptoms are transient, impairment in sexual function may persist after the completion of therapy and merits further investigation.
PMCID: PMC3578309  PMID: 23058059
9.  CA19-9 as a predictor of tumor response and survival in patients with advanced pancreatic cancer treated with gemcitabine based chemotherapy 
Asia-Pacific journal of clinical oncology  2010;6(2):10.1111/j.1743-7563.2010.01290.x.
The aim of this study was to determine the predictive role of pretreatment carbohydrate antigen 19-9 (CA19-9) measurement and its change after one cycle of gemcitabine-based therapy for response, time to progression (TTP) and overall survival (OS).
Analyses were derived from three consecutive gemcitabine-containing phase II clinical trials between 1997 and 2004.
A total of 111 patients with pancreas cancer was studied. Baseline CA19-9 concentrations were dichotomized near the median. Lower baseline CA19-9 levels were positively associated with OS (median 9.1 vs 6.1 months, P = 0.0057) and TTP (median 6.4 vs 4.2 months, P = 0.0044). The covariate adjusted hazard ratio (HR) for progression among patients with baseline CA19-9 ≥ 1000 ng/mL was HR = 1.94 (95% CI 1.24–3.02), with P = 0.0035. The covariate adjusted risk of death among patients with baseline CA19-9 ≥ 1000 ng/ml was similarly elevated: HR = 1.90 (95% CI 1.23–2.94), with P = 0.0039. Change in CA19-9 levels from baseline to the end of treatment cycle 1 did not predict objective response (P = 0.75). There was somewhat longer OS (median 8.7 vs 7.1 months) and TTP (median 7.1 vs 5.4 months) in patients with ≥50% reduction in serum CA19-9 concentrations, but this was not statistically significant (P = 0.74 and 0.81, respectively).
Baseline CA19-9 levels may predict survival in patients with advanced pancreas cancer. The change in CA19-9 levels determined within 1 month of the initiation of therapy did not predict treatment outcome.
PMCID: PMC3865855  PMID: 20565421
CA19-9; gemcitabine; pancreatic cancer
10.  Phase-II study of dose attenuated schedule of irinotecan, capecitabine, and celecoxib in advanced colorectal cancer 
Cancer chemotherapy and pharmacology  2007;61(2):10.1007/s00280-007-0472-1.
The cyclooxygenase-2 (COX-2) enzyme plays a major role in tumor progression and resistance to chemotherapy. A Phase-II study was undertaken to determine the activity of a dose attenuated schedule of irinotecan, capecitabine, and the COX-2 inhibitor celecoxib in patients with advanced colorectal cancer.
The eligibility criteria included a pathologically or cytologically confirmed diagnosis of adenocarcinoma of the colon or rectum that was metastatic. Patients received a combination of irinotecan 70 mg/m2 over 30 min I.V. on days 1 and 8, capecitabine 1,000 mg/m2 twice per day orally on days 1–14, and celecoxib at a daily dose of 800 mg continuously. Cycles were repeated every 21 days
Fifty-one patients were enrolled (median age 58 years; M : F 31 : 20). The objective response rate was 21/51=41% [95% confidence intervals (CI), 0.28–0.55]. The median time to progression was 7.7 months (95% CI, 6.2–8.6 months). Median survival time and probability of survival at 1 year were 21.2 months (95% CI, 13.8–n/a), and 75% (95% CI, 0.63–0.88), respectively. The major toxicity was Grade 3 or 4 diarrhea, seen in 24 and 10% of patients, respectively. There were no treatment related deaths.
The lower dose intensity of irinotecan appeared to maintain activity and improve tolerability when combined with capecitabine. The addition of celecoxib to irinotecan and capecitabine did not appear to significantly increase the activity of this doublet based on the RECIST criteria for objective response.
PMCID: PMC3860285  PMID: 17429629
Colorectal cancer; Irinotecan; Celecoxib; Capecitabine
11.  Using 18F Fluorodeoxyglucose Positron Emission Tomography (FDG PET) to Monitor Clinical Outcomes in Patients Treated with Neoadjuvant Chemo-Radiotherapy for Locally Advanced Pancreatic Cancer 
American journal of clinical oncology  2010;33(3):10.1097/COC.0b013e3181a76a0b.
Pancreatic cancer ranks as the fourth leading cause of cancer death in the United States with five year survival ranging from 1-5%. Positron emission tomography (PET) is a metabolic imaging system that is widely used for the initial staging of cancer and detecting residual disease after treatment. There are limited data, however, on the use of this molecular imaging technique to assess early tumor response after treatment in pancreatic cancer.
The objective of the study was to explore the relationship of early treatment response using the 18 F- fluorodeoxyglucose (FDG) PET with surgical outcome and overall survival in patients with locally advanced pancreatic cancer. FDG-PET measurements of maximum standardized uptake value (SUV) and kinetic parameters were compared to the clinical outcome.
Twenty patients were enrolled in the study evaluating neoadjuvant induction chemotherapy followed by concurrent chemoradiotherapy (chemo-RT) for locally advanced pancreatic cancer. All twenty patients had pre-study PET scans and a total of fifty PET scans were performed. Among patients who were PET responders (≥50% decrease in SUV after cycle 1), 100% (2/2) had complete surgical resection. Only 6% (1/16) had surgical resection in the PET non-responders (<50% decrease). Two patients did not have the second PET scan due to clinical progression or treatment toxicity. Mean survival was 23.2 months for PET responders and 11.3 months for non-responders (p=0.234). Similar differences in survival were also noted when response was measured using Patlak analysis.
FDG-PET can aid in monitoring the clinical outcome of patients with locally advanced pancreatic cancer treated with neoadjuvant chemo-RT. FDG-PET may be used to aid patients who could have complete surgical resection as well as prognosticate patients’ survival.
PMCID: PMC3848057  PMID: 19806035
Pancreatic cancer; Combined modality therapy; FDG-PET; treatment response
12.  A phase I/II trial of intensity-modulated radiation (IMRT) dose escalation with concurrent fixed- dose rate gemcitabine (FDR-G) in patients with unresectable pancreatic cancer 
Local failure in unresectable pancreatic cancer may contribute to death. We hypothesized that intensification of local therapy would improve local control and survival. The objectives were to determine the maximum tolerated radiation dose delivered by IMRT with FDR-G, freedom from local progression (FFLP) and overall survival (OS).
Methods and Materials
Eligibility included pathologic confirmation of adenocarcinoma, radiographically unresectable, performance status (PS) of 0–2, ANC of ≥1500/mm3, platelets ≥100,000/mm3, creatinine <2 mg/dl, bilirubin <3 mg/dl and ALT/AST ≤2.5 x ULN. FDR-G (1000 mg/m2/100-minutes I.V.) was given on days −22 and −15, 1, 8, 22, and 29. IMRT started day 1. Dose levels were escalated from 50 to 60 Gy in 25 fractions. DLT was defined as gastrointestinal toxicity ≥Grade (G)3, neutropenic fever, or deterioration in PS to ≥3 between day 1 and 126. Dose level was assigned using TITE-CRM with the target DLT rate set to 0.25.
Fifty patients were accrued. DLTs were observed in 11 patients: G3/4 anorexia, nausea, vomiting, and/or dehydration (7); duodenal bleed (3); duodenal perforation (1). The recommended dose is 55Gy, producing a probability of DLT of 0.24. The 2-year FFLP is 59% (95% CI: 32–79). Median and 2-year overall survival are 14.8 months (95% CI: 12.6–22.2) and 30% (95% CI 17–45). Twelve patients underwent resection (10 R0, 2 R1) and survived a median of 32 months.
High dose radiotherapy with concurrent FDR-G can be delivered safely. The encouraging efficacy data suggest that outcome may be improved in unresectable patients through intensification of local therapy.
PMCID: PMC3421048  PMID: 22543215
pancreatic cancer; chemoradiotherapy; IMRT; gemcitabine; local control
13.  Identification of Targetable FGFR Gene Fusions in Diverse Cancers 
Cancer discovery  2013;3(6):636-647.
Through a prospective clinical sequencing program for advanced cancers, four index cases were identified which harbor gene rearrangements of FGFR2 including patients with cholangiocarcinoma, breast cancer, and prostate cancer. After extending our assessment of FGFR rearrangements across multiple tumor cohorts, we identified additional FGFR gene fusions with intact kinase domains in lung squamous cell cancer, bladder cancer, thyroid cancer, oral cancer, glioblastoma, and head and neck squamous cell cancer. All FGFR fusion partners tested exhibit oligomerization capability, suggesting a shared mode of kinase activation. Overexpression of FGFR fusion proteins induced cell proliferation. Two bladder cancer cell lines that harbor FGFR3 fusion proteins exhibited enhanced susceptibility to pharmacologic inhibition in vitro and in vivo. Due to the combinatorial possibilities of FGFR family fusion to a variety of oligomerization partners, clinical sequencing efforts which incorporate transcriptome analysis for gene fusions are poised to identify rare, targetable FGFR fusions across diverse cancer types.
PMCID: PMC3694764  PMID: 23558953
MI-ONCOSEQ; integrative clinical sequencing; FGFR fusions; driver mutations; therapeutic targets
14.  A Phase 2 Trial of Ixabepilone Plus Cetuximab in First-Line Treatment of Metastatic Pancreatic Cancer 
The aim of this phase 2 study was to evaluate the safety and efficacy of ixabepilone plus cetuximab in patients with advanced pancreatic cancer.
Eligible patients had advanced pancreatic adenocarcinoma that was metastatic or not amenable to resection, a Karnofsky performance status ≥70%, and no prior therapy for advanced disease. Patients received ixabepilone 32 mg/m2 (3-hour IV infusion) every 3 weeks and cetuximab 250 mg/m2 (1-hour IV infusion) weekly. The primary efficacy end point was the 6-month survival rate. Secondary end points included tumor response rate, overall survival, progression-free survival, and tolerability.
A total of 54 patients were enrolled on this study. The 6-month survival rate was 57% (31/54: 95% CI: 43–71%) with a median overall survival of 7.6 months (95% CI: 5.5–12.2 months). Patients who developed acneiform rash (n = 36) had a median survival of 8.8 months, compared with 2.6 months for those without rash (n = 18). Of 31 patients with measurable disease (defined as response-evaluable), 4 had confirmed partial responses and an additional 24 had stable disease. The combination was generally well-tolerated with the most common grade 3/4 hematological toxicities being leucopenia (39%) and neutropenia (33%). The most common grade 3/4 nonhematologic toxicity was fatigue (17%).
The combination of ixabepilone and cetuximab was active and had acceptable toxicity. The efficacy results are similar to single-agent ixabepilone and gemcitabine-based combination therapies in patients with advanced pancreatic cancer. Exploratory analyses suggest a trend toward improved survival for patients who experienced rash.
PMCID: PMC3481147  PMID: 23112883
15.  Screening for Depression, Sleep-Related Disturbances, and Anxiety in Patients with Adenocarcinoma of the Pancreas: A Preliminary Study 
The Scientific World Journal  2012;2012:650707.
Purpose. Screening for depression, sleep-related disturbances, and anxiety in patients with diagnosed adenocarcinoma of the pancreas. Materials and Methods. Patients were evaluated at initial consultation and subsequent visits at the multidisciplinary pancreatic cancer clinic at our University Cancer Center. Cross-sectional and longitudinal psychosocial distress was assessed utilizing Personal Health Questionnaire 9 (PHQ9) to screen for depression and monitor symptoms, the Penn State Worry Questionnaire (PSWQ) for generalized anxiety, and the University of Michigan Sleep Questionnaire to monitor sleep symptoms. Results. Twenty-two patients diagnosed with pancreatic cancer participated during the 6-month pilot study with longitudinal followup for thirteen patients. In this study, mild-to-moderate depressive symptoms, anxiety, and potential sleep problems were common. The main finding of the study was 23% of the patients who were part of this pilot project screened positive for moderately severe major depressive symptoms, likely anxiety disorder or a potential sleep disorder during the study. One patient screened positive for moderately severe depressive symptoms in longitudinal followup. Conclusions. Depression, anxiety, and sleep problems are evident in patients with pancreatic cancer. Prospective, longitudinal studies, with larger groups of patients, are needed to determine if these comorbid symptoms impact outcome and clinical course.
PMCID: PMC3366237  PMID: 22666142
16.  Original Article A phase I study of imexon plus gemcitabine as first-line therapy for advanced pancreatic cancer 
Imexon is an aziridine-derived iminopyrrolidone which has synergy with gemcitabine in pancreatic cancer cell lines. Gemcitabine is a standard therapy for pancreatic cancer. We performed a phase I trial of imexon and gemcitabine to evaluate safety, dose limiting toxicity (DLT), and maximum tolerated dose (MTD) in patients with advanced pancreatic cancer.
Patients with untreated locally advanced or metastatic pancreatic adenocarcinoma received therapy in sequential cohorts on regimen A (n=19; imexon 200 or 280 mg/m2 intravenously (IV) over 30 minutes days 1–5, 15–19 and gemcitabine 800 or 1,000 mg/m2 IV over 30 minutes on days 1,8,15 every 28 days) or regimen B (n=86; imexon 280–1,300 mg/m2 IV over 30–60 minutes days 1, 8, and 15 and gemcitabine 1,000 mg/m2 IV over 30 minutes on days 1, 8, and 15 every 28 days).
One hundred-five patients received 340 treatment cycles (median 2, range 1–16). Patient characteristics: median age 63, 61% male, ECOG PS 0/1 50%/50%, 93% metastatic. DLT was abdominal cramping and pain, often with transient, acute diarrhea. Best response was confirmed partial response (PR) in 11.4%, 8.9% unconfirmed PR, and 48.1% with stable disease. There was a dose proportional increase in imexon AUC across the doses tested with terminal half-life 69 minutes at the MTD and no alteration of gemcitabine pharmacokinetics.
The recommended phase II dose of imexon is 875 mg/m2 with gemcitabine 1,000 mg/m2. DLT was acute abdominal pain and cramping. Encouraging antitumor responses support further evaluation of this combination in advanced pancreatic cancer.
PMCID: PMC2873145  PMID: 19855966
gemcitabine; imexon; pancreatic cancer; phase I clinical trial
17.  Retroperitoneal germ cell tumor diagnosed by endoscopic ultrasound-guided fine needle aspiration 
Isolated extragonadal germ cell tumors can be primary in nature or metastatic from a burned out testicular cancer. Accurate diagnosis is critical as appropriate therapy can be highly curative. We present the case of an isolated extragonadal germ cell tumor in the retroperitoneum diagnosed by endoscopic ultrasound-guided fine needle aspiration. This case underscores the importance of considering germ cell tumors in the differential diagnosis of an unexplained retroperitoneal mass, particularly since immunophenotypic staining may be necessary to establish the diagnosis.
PMCID: PMC3011098  PMID: 21191538
Germ cell tumor; Endoscopic ultrasound; Fine needle aspiration
18.  A Multi-institutional Phase II study of the efficacy and tolerability of Lapatinib in patients with advanced hepatocellular carcinomas 
Hepatocellular carcinoma (HCC) is on the rise worldwide. HCC responds poorly to chemotherapy. Lapatinib is an inhibitor of EGFR and HER2/NEU both implicated in hepatocarcinogenesis. This trial was designed to determine the safety and efficacy of lapatinib in HCC.
A Fleming phase II design with a single stage of 25 patients with a 90% power to exclude a true response rate of < 10% and detect a true response rate of ≥30% was utilized. The dose of lapatinib was 1,500 mg/d administered orally in 28-day cycles. Tumor and blood specimens were analyzed for expression of HER2/NEU/CEP17 and status of downstream signal pathway proteins.
Twenty-six patients with HCC enrolled on this study. 19% had one prior therapy. Most common toxicities were diarrhea (73%), nausea (54%) and rash (42%). No objective responses were observed. Ten (40%) patients had stable disease (SD) as their best response including 6 (23%) with SD lasting > 120 days. Median progression-free-survival was 1.9 months and median overall survival 12.6 months. Patients who developed a rash had a borderline statistically significant longer survival. Tissue and blood specimens were available on >90% of patients. No somatic mutations in EGFR (exons 18–21) were found. In contrast to our previous findings, we did not find evidence of HER2/NEU somatic mutations. PTEN, P-AKT and P70S6K expression did not correlate with survival.
Lapatinib is well-tolerated but appears to benefit only a subgroup of patients for whom predictive molecular or clinical characteristics are not yet fully defined.
PMCID: PMC2774354  PMID: 19737952

Results 1-18 (18)