This study reports the results of a phase II clinical trial using a novel biotherapy, OGF, for the treatment of advanced pancreatic cancer. The design of a phase II clinical trial typically includes naïve subjects, such that tumor resistance is not an issue and an untreated group receives placebo. Since OGF had not previously been examined for efficacy in cancer therapy (ie, phase II clinical trials), and the FDA did not allow naïve subjects to be treated with this medication, therefore, only individuals who had already failed chemotherapy were eligible for study. For ethical reasons, a placebo control group is not employed when treating cancer patients and an IRB does not typically grant permission for this type of study design. Thus, a large control population of patients in this investigation was established from subjects meeting the same inclusion criteria but who desired no further care after failing chemotherapy. One limitation of this study was that it was not a randomized controlled study; therefore, a risk of selection bias may have occurred in that those selecting hospice care may have had a poorer performance status. Unfortunately, the dismal prognosis of pancreatic cancer is only counted in months rather than years and survival with standard chemotherapy using gemcitabine is only reported only for 5.6 months.30
Treatment with any agent at this end-stage of a disease may seem fruitless, whereas others would support that any agent showing improvement with advanced cancer may have potential if used earlier or shortly after diagnosis.
Since chemotherapy has not been very beneficial for survival in the treatment of pancreatic cancer, investigators are studying alternative benefits of treating subjects with advanced disease.4,10,30
The current investigation demonstrated a clinical benefit for improvement in pain, functional status, and weight. Additionally, survival was also improved in those subjects treated with OGF even at this late stage. The historical controls to which we compared our OGF-treated patients in this study were treatment-naïve upon initiation of the trial rather than treatment failures as in our current study. Even though our patient population had much more advanced disease, the clinical benefit we observed was greater. One reason for this difference may be related to OGF being a natural endogenous peptide so off-target toxicity was not as pronounced as that with chemotherapy.
In comparison to subjects electing no further treatment, OGF-treated patients survived three times longer. In fact, more than half of the cancer patients treated with OGF had either regression of tumor size or stabilization of disease. These results extend the findings in a prior study where OGF was used in an acute dose finding protocol.21
In the same study, when subjects were treated with extended therapy, a mean survival of 8.7 months (261 days) in the intravenous-treated group and 9.5 months (291 days) in OGF-treated group via a subcutaneous route was reported.21
Survival in this previous study was 2.4 times greater than that in the current study, and 60% greater than for historical controls treated with gemcitabine.30
The possible rationale for the extended survival advantage in the prior study may be because 56% of the subjects were treatment-naïve. This finding provokes the need to study OGF in previously untreated pancreatic cancer patients.
Three quality of life surveys were conducted during the course of this study. Although none of the surveys showed significant improvements with OGF, they also did not show that the quality of life deteriorated. Crippa and colleagues31
recently published results of a quality of life analysis in different stages of pancreatic cancer. Using the Functional Assessment of Cancer Therapy survey, in contrast to the three quality of life surveys employed in the current study, Crippa and colleagues concluded that the quality of life significantly decreased in subjects with metastatic pancreatic cancer. These investigators thought that the decreased quality of life was either due to the chemotherapy or the progression of the disease. Since biotherapy with OGF did not cause the same toxic side effects as chemotherapy, this may account for the fact that patients in the present study did not show a decrease in their quality of life. Another reason that OGF treatment did not diminish quality of life may be related to the fact that the progression of disease was slowed and survival increased.
The well-known toxicities reported with standard chemotherapeutic agents used in the treatment of pancreatic cancer, such as hematologic toxicities from bone marrow suppression32
and gastrointestinal mucosynovitis,33
was not observed with OGF. Other toxicities like hand-and-foot syndrome (palmar-plantar erythrodysesthesia or chemotherapy-induced acral erythema)34
seen with capecitabine therapy for pancreatic cancer, were similarly not observed in our study. Hypotension has been reported previously in pancreatic cancer patients treated with OGF in a phase I clinical trial21
with an occurrence of 43%. However, the incidence of hypotension in individuals enrolled this current study was less at 8%. This decreased incidence of hypotension was most likely due to the prolongation of the infusion time from 30 to 45 minutes utilized in the present study. Two subjects died prematurely from pulmonary embolism in this phase II trial. It is known that many patients with pancreatic cancer are in a hypercoagulable state (Trousseau’s syndrome), increasing the potential and incidence of thromboembolic events (both venous and arterial), particularly in the setting of advanced disease.35
Therefore, the occurrence of thrombophlebitis and pulmonary embolism in our two subjects may have been due to the pancreatic cancer rather than the treatment with OGF. However, Stein and colleagues36
found only 0.16% of deaths in pancreatic cancer subjects were related to pulmonary emboli; hence, further investigation is needed to determine whether this complication is a coincidence or potential side effect.
Plasma enkephalin levels increased over the course of this study which may have been attributed to the administration of intravenous [Met5
]-enkephalin (OGF) and its accumulation in tissues. We previously reported that plasma enkephalin values were increased in human subjects with advanced pancreatic cancer without OGF treatment.37
The reason for the increase in the current study may be due to several possibilities including: tissue accumulation, a compromising of the OGF-OGFr pathway, or the body’s natural response to fighting off a malignancy.
Since clinical benefit and survival in our patients with advanced pancreatic cancer who had previously failed other treatments was markedly improved, these data support the rationale for testing this biological agent in the treatment of naïve patients where the tumor burden is less and perhaps not yet drug resistant. Additionally, further studies whereby OGF is combined with standard therapy such as gemcitabine to potentiate the cytotoxic effects of chemotherapy drugs should also be considered. Indeed, we have shown in vitro
and in an animal model that the combination of gemcitabine with OGF significantly decreases pancreatic cancer tumor growth compared to either agent alone, and OGF treatment also reduced the toxic effects of gemcitabine.38
Given the aggressive nature of pancreatic cancer and its resistance to standard chemotherapeutic regimens, it may be that OGF in combination with gemcitabine given at the time of diagnosis may be a powerful therapeutic modality for treatment of this deadly disease.