Phase I Evaluation of Intravenous Ascorbic Acid in Combination with Gemcitabine and Erlotinib in Patients with Metastatic Pancreatic Cancer

Preclinical data support further investigation of ascorbic acid in pancreatic cancer. There are currently insufficient safety data in human subjects, particularly when ascorbic acid is combined with chemotherapy.14 subjects with metastatic stage IV pancreatic cancer were recruited to receive an eight week cycle of intravenous ascorbic acid (three infusions per week), using a dose escalation design, along with standard treatment of gemcitabine and erlotinib. Of 14 recruited subjects enrolled, nine completed the study (three in each dosage tier). There were fifteen non-serious adverse events and eight serious adverse events, all likely related to progression of disease or treatment with gemcitabine or erlotinib. Applying RECIST 1.0 criteria, seven of the nine subjects had stable disease while the other two had progressive disease.These initial safety data do not reveal increased toxicity with the addition of ascorbic acid to gemcitabine and erlotinib in pancreatic cancer patients. This, combined with the observed response to treatment, suggests the need for a phase II study of longer duration.Clinicaltrials.gov NCT00954525

A comparison of the WHO 2004 and 2010 classification systems in pancreatic neuroendocrine tumors (Pancreatic NET)

Pancreatic NETs are rare tumors with multiple classification systems. Previous classification systems included tumor size, histologic grade, mitoses, Ki67, and metastases. The current WHO 2010 system utilizes mitotic rate and Ki67% to assign a grade. We compared the WHO 2004 and 2010 classification systems in predicting mortality and metastasis. Pathologic parameters were used to classify 50 cases of Pancreatic NET according to the WHO 2004 and WHO 2010 systems. The relationship between the WHO 2004 and WHO 2010 grading was investigated using an exact Chi squared test. WHO grade categorization was next explored by vital status, by the exact method, in order to determine if there was a difference in survivorship and metastasis by grading system. Associations between death and categorical variables were tested using exact methods and between death and continuous variables by the Wilcoxon test. Survival was explored using Cox Proportional Hazards regression (Cox). The WHO grades were significantly associated with one another (

Peak plasma ascorbic acid concentrations in millimoles/L after the initial dose and final dose (measurements after the final dose were unavailable for patients 008 and 014).

<p>The green line represents the highest plasma concentration expected with maximally tolerated oral doses of ascorbic acid <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0029794#pone.0029794-Padayatty3" target="_blank">[13]</a>.</p

Patient demographics and disease status.

<p>Bone = bone metastases.</p><p>Liver = liver metastases.</p><p>Locally adv = locally advanced spread of cancer.</p><p>Abdomen = Metastases within the abdomen distant from the pancreas.</p><p>Lung = lung metastases.</p><p>Media = mediastinal metastases.</p><p>Peritoneal = peritoneal metastases.</p><p>Retroper = retroperitoneal nodes or metastases.</p><p>*Patient died during study.</p><p>**Weights were obtained on the first and last day of the ascorbic acid infusions.</p

Adverse Event Chart for all 14 patients (based on standard NCI criteria).

<p>Adverse Event Chart for all 14 patients (based on standard NCI criteria).</p

Study CONSORT flow diagram.

<p>Study CONSORT flow diagram.</p

Response to ascorbic acid plus gemcitabine based on CT findings in patients with scans pre and post the 8 week ascorbic acid treatment cycle plus gemcitabine/erlotinib (these data only include patients that completed both pre and post-treatment CT imaging and not the additional five patients who terminated participation early).

<p>SD = Stable Disease.</p><p>PD = Progressive Disease.</p

Tumor size initially and after 8 weeks of treatment with ascorbic acid, gemcitabine, and erlotinib for each of the patients who completed the study.

<p>Tumor size initially and after 8 weeks of treatment with ascorbic acid, gemcitabine, and erlotinib for each of the patients who completed the study.</p