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author:("zaluski, Mark")
1.  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 
Purpose
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.
Results
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).
Conclusions
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.
doi:10.1016/j.ijrobp.2012.11.020
PMCID: PMC3646633  PMID: 23265573
2.  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.
Objective
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.
Methods
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.
Results
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.
Conclusions
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.”
doi:10.1002/pon.3036
PMCID: PMC3387514  PMID: 22290823
Oncology; cancer; randomized clinical trial; family caregiver; advanced cancer; quality of life; intervention dose; risk for distress
3.  The Quality-of-Life Effects of Neoadjuvant Chemoradiation in Locally Advanced Rectal Cancer 
Purpose
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.
Results
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.
Conclusions
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.
doi:10.1016/j.ijrobp.2012.09.006
PMCID: PMC3578309  PMID: 23058059
4.  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.
Aims
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).
Methods
Analyses were derived from three consecutive gemcitabine-containing phase II clinical trials between 1997 and 2004.
Results
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).
Conclusion
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.
doi:10.1111/j.1743-7563.2010.01290.x
PMCID: PMC3865855  PMID: 20565421
CA19-9; gemcitabine; pancreatic cancer
5.  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.
Background
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.
Methods
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
Results
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.
Conclusions
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.
doi:10.1007/s00280-007-0472-1
PMCID: PMC3860285  PMID: 17429629
Colorectal cancer; Irinotecan; Celecoxib; Capecitabine
6.  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.
BACKGROUND
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.
METHODS
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.
RESULTS
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.
CONCLUSION
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.
doi:10.1097/COC.0b013e3181a76a0b
PMCID: PMC3848057  PMID: 19806035
Pancreatic cancer; Combined modality therapy; FDG-PET; treatment response
7.  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 
Purpose
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.
Results
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.
Conclusions
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.
doi:10.1016/j.ijrobp.2012.02.051
PMCID: PMC3421048  PMID: 22543215
pancreatic cancer; chemoradiotherapy; IMRT; gemcitabine; local control
8.  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.
doi:10.1158/2159-8290.CD-13-0050
PMCID: PMC3694764  PMID: 23558953
MI-ONCOSEQ; integrative clinical sequencing; FGFR fusions; driver mutations; therapeutic targets
9.  A Phase 2 Trial of Ixabepilone Plus Cetuximab in First-Line Treatment of Metastatic Pancreatic Cancer 
ABSTRACT
BACKGROUND:
The aim of this phase 2 study was to evaluate the safety and efficacy of ixabepilone plus cetuximab in patients with advanced pancreatic cancer.
METHODS:
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.
RESULTS:
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%).
CONCLUSIONS:
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
10.  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.
doi:10.1100/2012/650707
PMCID: PMC3366237  PMID: 22666142
11.  Original Article A phase I study of imexon plus gemcitabine as first-line therapy for advanced pancreatic cancer 
Purpose
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.
Methods
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).
Results
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.
Conclusions
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.
doi:10.1007/s00280-009-1162-y
PMCID: PMC2873145  PMID: 19855966
gemcitabine; imexon; pancreatic cancer; phase I clinical trial
12.  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.
doi:10.4251/wjgo.v2.i12.443
PMCID: PMC3011098  PMID: 21191538
Germ cell tumor; Endoscopic ultrasound; Fine needle aspiration
13.  A Multi-institutional Phase II study of the efficacy and tolerability of Lapatinib in patients with advanced hepatocellular carcinomas 
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1158/1078-0432.CCR-09-0465
PMCID: PMC2774354  PMID: 19737952

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