Opioid growth factor improves clinical benefit and survival in patients with advanced pancreatic cancer

Abstract

BACKGROUND: Advanced pancreatic cancer carries the poorest prognosis of all gastrointestinal malignancies. Once the tumor has spread beyond the margins of the pancreas, chemotherapy is the major treatment modality offered to patients; however, chemotherapy does not significantly improve survival. OBJECTIVE: Opioid growth factor (OGF; [Met(5)]-enkephalin) is a natural peptide that has been shown to inhibit growth of pancreatic cancer in cell culture and in nude mice. The purpose of this study was to evaluate the effects of OGF biotherapy on subjects with advanced pancreatic cancer who failed chemotherapy. METHODS: In a prospective phase II open-labeled clinical trial, 24 subjects who failed standard chemotherapy for advanced pancreatic cancer were treated weekly with OGF 250 µg/kg intravenously. Outcomes measured included clinical benefit, tumor response by radiographic imaging, quality of life, and survival. RESULTS: Clinical benefit response was experienced by 53% of OGF-treated patients compared to historical controls of 23.8% and 4.8% for gemcitabine and 5-fluorouracil (5-FU), respectively. Of the subjects surviving more than eight weeks, 62% showed either a decrease or stabilization in tumor size by computed tomography. The median survival time for OGF-treated patients was three times that of untreated patients (65.5 versus 21 days, p < 0.001). No adverse effects on hematologic or chemistry parameters were noted, and quality of life surveys suggested improvement with OGF. LIMITATIONS: Measurements other than survival were not allowed in control patients, and clinical benefit comparisons were made to historical controls. CONCLUSION: OGF biotherapy improves the clinical benefit and prolongs survival in patients with pancreatic cancer by stabilizing disease or slowing progression. The effects of OGF did not adversely alter patient quality of life. The use of OGF biotherapy at earlier stages of disease or in combination with other chemotherapeutic agents may further improve the outcome of this malignancy.

Figures

Figure 1

Clinical benefit of opioid growth factor (OGF) in advanced pancreatic cancer. Clinical benefit as determined by improvement or stability in three cancer-related signs and symptoms (pain, functional status, and weight loss) were determined in OGF-treated subjects. A) Pain measures of clinical benefit based upon pain intensity and narcotic analgesic consumption B) Primary measures of clinical benefit based on Karnofsky performance status and pain. C) Forty-seven percent had a positive clinical benefit that was sustained a minimum of eight weeks with OGF treatment for pain and performance status but the overall clinical benefit was 53% utilizing both the primary outcomes (pain and performance status) and the secondary outcomes (weight gain). The Total positive was determined by the sum of the three shaded boxes in each group.

Figure 2

Opioid growth factor (OGF) decreases and/or stabilizes growth of pancreatic cancer. Radiographic images by computerized tomography are shown demonstrating the sections through the primary pancreatic tumor in the head of the pancreas. The pancreatic tumor (marked with a white +) is shown at baseline and every eight weeks during OGF therapy. The primary tumor size decreased during the study, but at week 24 the patient was noted to have ascites in the peritoneal cavity (arrow) and an 11 mm nodule in the liver (*) suggestive of progression of disease.

Figure 3

Survival of advanced pancreatic cancer is improved compared to untreated controls. A) Opioid growth factor (OGF)-treated patients survived for 209% longer than untreated controls. B) Survival of OGF-treated subjects over time compared to control subjects using the Kaplan–Meier curve. The OGF-treated group differed significantly from controls at p < 0.001. Notes: Data represent means ± standard error of mean. ***Significantly different from hospice controls, p < 0.001.

Figure 4

Plasma [Met5]-enkephalin levels in opioid growth factor (OGF)-treated patients over time. The antibody used for this assay was highly specific for [Met5]-enkephalin with little or no cross reactivity with B-endorphin, dynorphin A, ACTH and endothelin-1. The assay range was 10–1280 pg/mL. Between run precision at concentrations of 21 and 636 pg/mL averaged 16% and 11% CV, respectively, and the lower limit of quantitation was 8 pg/mL. Notes: Data are presented as means ± standard error of mean for baseline, week 4, and week 8 for subjects treated with OGF. Significantly different from baseline are represented by *p < 0.01, and **p < 0.001.