Whole Body Health Sale

Pancreatic Cancer

Innovative Drug Strategies

Several innovative drug strategies are being explored for the treatment of pancreatic cancer, including FDA approved drugs that were not originally developed for pancreatic cancer treatment but have incidentally been shown to hinder its growth and progression; these include the “Off-label Use” of the anti-diabetic drug metformin and the anti-malarial drug chloroquine. It has been proposed that chloroquine and metformin could eliminate pancreatic cancer cell traits in pre-invasive pre-malignant lesions by inhibiting the genesis and self-renewal of cancer cells (Vazquez-Martin 2011).

  • Chloroquine, Antimalarial: Off-label Use

Chloroquine (Aralen®), which is used to prevent and treat malaria worldwide, selectively stops the growth of pancreatic tumors by inhibiting ‘autophagy’ (Zeilhofer HU 1989). Autophagy is the process whereby cancer cells ‘self-eat,’ or cannibalize, part of their self to survive. Pancreatic cancers have a unique dependence on autophagy and require autophagy for tumor growth (Yang 2011). In pancreatic cancers, K-ras drives autophagy. Chloroquine inactivates this process of autophagy and this causes tumor regression and prolonged survival in pancreatic cancer mouse experiments (Mirzoeva 2011).

These results are immediately translatable to the clinical treatment of pancreatic cancer patients, and provide an urgently needed novel therapeutic strategy. Currently, Hopkins researchers are pushing chloroquine into clinical trials of pancreatic cancer treatment.

Furthermore, chloroquine specifically sensitizes cancer cells to radiation therapy and chemotherapy and could possibly increase the efficacy of conventional cancer therapies (Solomon 2009).

Caution should be exerted by pancreatic cancer patients with hepatic impairment and/or alcoholics.

  • Metformin: Anti-Diabetic Drug, Off-label Use

Metformin has emerged as a novel treatment strategy for pancreatic cancer patients. Metformin is a drug of the biguanide class, approved for the treatment of type 2 diabetes mellitus (i.e., non-insulin dependent diabetes mellitus) worldwide because of its primary anti-hyperglycemic effects (Nathan 2009).

Many studies suggest that diabetes mellitus can cause pancreatic cancer with possible mechanisms involving insulin resistance and high levels of insulin in the blood. Moreover, successful treatment of type 2 diabetes and/or obesity reduces the risk of pancreatic cancer by reducing high insulin levels; insulin is known to stimulate cancer growth and pancreatic cancers overexpress insulin/IGF-1 receptors (Gallagher 2010).

Metformin reduces the risk of pancreatic cancer through antidiabetic and antitumor actions (Magruder 2011). Several studies found that metformin users (including diabetics) had a significantly lower relative risk for developing pancreatic cancer (Lee 2011). Noteworthy, a 62% reduction in the risk of pancreatic cancer in diabetic patients having taken metformin for more than 5 yeas was reported. By contrast, long-term insulin use in patients with long standing diabetes mellitus was associated with an increased risk of pancreatic cancer (Li 2009).

Clinical studies show that metformin reduces insulin resistance and increases complete tumor response rates following neoadjuvant chemotherapy for breast cancer (Jiralerspong 2009). An Italian retrospective cohort study of 3685 type II diabetic patients without cancer found that each 5-year metformin exposure was associated with a significant reduction in cancer death compared to insulin and sulfonylureas (Bo 2011).

A study presented at the 2011 American Society of Clinical Oncology (ASCO) meeting shows that metformin prolongs survival and decreases risk of death in patients with pancreatic malignancy and diabetes (Hsu 2011). The median survival was 16.6 vs. 11.5 months for metformin ever-users vs. never-users, respectively.

Metformin users are cautioned to monitor their vitamin B-12 and homocysteine levels, as its use causes both folate and vitamin B12 deficiency (i.e., serum total B12 level ≤ 150 pmol/L) in up to 30% of diabetic patients (Ting 2006; Lee 2011).

Pancreatic Enzyme Therapy

Pancreatic cancer creates a deficiency of pancreatic enzymes (termed pancreatic insufficiency), bicarbonate, and bile salt, resulting in poor absorption of nutrients from food, profound weight loss, and severe malnutrition. Fortunately pancreatic enzyme supplementation can prevent this occurrence and greatly improve quality of life in these patients (Imrie 2010). To avoid malnutrition-related morbidity and mortality and to improve patients' weight and nutritional status, pancreatic enzyme replacement therapy with oral pancreatic enzymes (enteric-coated minimicrospheres) at meal-times, (aiming at providing the duodenal lumen with a sufficient amount of active lipase at the time of gastric emptying of nutrients) can greatly improve quality of life (Domínguez-Muñoz 2011; Imrie 2010).

Clinical Studies with Pancreatic Enzymes. In a randomized, double-blind trial of twenty-one patients with unresectable cancer of the pancreatic head region (with suspected pancreatic duct obstruction), eight weeks of high dose enteric coated pancreatic enzyme supplementation and dietary counseling prevented weight loss. Patients on pancreatic enzymes gained 1.2% (0.7 kg) body weight whereas patients on placebo lost 3.7% (2.2 kg). Fat absorption and daily total energy intake in patients on pancreatic enzymes improved whereas in placebo patients it worsened (Bruno 1995). Aggressive pancreatic enzyme replacement is important to optimize bowel function and prevent malnutrition in pancreatic cancer patients (Armstrong 2007).

COX-2 (Cyclooxygenase-2) Inhibitors

The COX-2 enzyme is a major angiogenic mediator found to be elevated in pancreatic cancer (Tucker 1999) and indirectly prevents cancer cells from dying (Chu 2003). Therefore, suppressing the COX-2 enzyme may inhibit pancreatic cancer cell propagation. The COX-2 inhibitor apricoxib is now being investigated for enhancing the efficacy of gemcitabine and erlotinib in pancreatic cancer treatment (Strimpakos 2011 Abstract #227).

Selective reduction of COX-2 levels improves response to both chemotherapy and radiotherapy without being toxic to normal healthy tissues (Ferrari 2005).

A well-known COX-2 inhibitor, celebrex has already been combined with gemcitabine and curcumin in an ongoing study in Tel Aviv (ClinicalTrials.gov NCT00486460). Its pre-clinical activity in pancreatic cell lines and other cancer cell lines have been well-documented, it is commercially available, and actively investigated in many cancer studies. In the CALGB 30203 study, celecoxib was shown to confer survival advantage to lung cancer patients who overexpressed COX-2 ( Ferrari 2006; Dragovich 2008).

In addition, the following nutritional supplements which have been shown to reduce COX-2 expression in vitro and in vivo could be employed (Gescher 2004):

  • Gamma-tocotrienol prevents the growth of human pancreatic tumors by reducing COX-2 expression (Kunnumakkara 2010).
  • Omega-3 fatty acids, in particular EPA and DHA, found principally in oily fish, inhibit production of COX-2 significantly. EPA treatment decreases intracellular levels of COX-2 protein in pancreatic tumors (Shirota 2005).
  • Curcumin down-regulates COX-2 expression in pancreatic cancer cells resulting in increased tumor cell death (Lev-Ari 2007).

For a detailed discussion of COX-2 inhibition in cancer treatment, please review the protocol Cancer Treatment: The Critical Factors.

5-LOX (5-Lipoxygenase) Inhibitors

The 5-LOX enzyme is produced in pancreatic cancer (but not in normal pancreatic ducts) and is critical for its growth (Hennig R 2002). Reducing levels of 5-LOX prevents human pancreatic cancer cell lines from multiplying and induces apoptosis (cell death) (Andersen 1998).

Zileuton , a powerful 5-LOX inhibitor, pre-clinical models suggest synergy with various agents in cancer cell lines. Its use in CALGB 30203, an eicosanoid modulation clinical trial in lung cancer was not promising in a factorial designed experiment, however, its role in pancreatic cancer has not been evaluated, and several pre-clinical hamster models suggest it may be active in pancreatic cancer, alone or in combination with Celebrex (Edelman 2008; Gregor 2005; Wenger 2002).

For a detailed discussion of 5-LOX inhibition in cancer treatment, review the protocol Cancer Treatment: The Critical Factors.

Immunotherapy/Vaccine Therapy for Pancreatic Cancer

Vaccines for pancreatic cancer are employed to prevent recurrence and/or metastasis after surgery and to boost immune responses and improve clinical outcome when used in combination with chemotherapy. Several early phase I/II clinical trials have shown that the vaccines studied in pancreatic cancer treatment appear to be safe and well-tolerated. However, their immunogenicity (ability to produce an immune response) has been variable. The survival data indicate that induction of an immune response is correlated with prolonged survival and most clinical trials show increased survival associated with immune responses (see Table 1). Whole tumor cells were initially used to produce vaccines because the proteins expressed by tumor cells that are recognized by the immune system were unknown. However, the identification of proteins expressed by pancreatic tumors enabled the production of specific peptide vaccines such as mutant K-ras, MUC-1, vascular endothelial growth factor receptor 2 (VEGFR2), and telomerase (Koido 2011; Jaffee 1999).

In phase I/II trials, vaccination of advanced pancreatic cancer patients using peptide vaccines of mutant K-ras (Abou-Alfa 2011; Weden 2011), MUC1 (Lepisto 2008; Yamamoto 2005; Ramanathan 2005), VEGFR2 (Miyazawa 2010), or telomerase (Bernhardt 2006) was significantly associated with immune responses and in most cases, prolonged survival.

In clinical trials, patients with advanced or non-resectable pancreatic cancer have been treated by combination therapy of chemotherapy (gemcitabine) with personalized peptide vaccines (Yanagimoto 2007; Yanagimoto 2010) or VEGFR2 (Miyazawa 2010). Combination therapy was shown to be safe and possibly effective in patients with advanced pancreatic cancer refractory to standard treatment (Kimura 2011).

Mutant K-ras Peptide Vaccines: In a recent phase I study using long synthetic mutant ras peptides, 23 patients were vaccinated after surgery for pancreatic cancer. Significantly, 10-year survival was 20% (four patients out of 20 evaluable) versus zero (0/87) in a group of non-vaccinated patients (Weden 2011).

In another recent study of 24 patients with resected pancreatic cancer that were vaccinated with K-ras peptide in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), the median overall survival was 20.3 months. However, although the vaccine was safe and well-tolerated, it did not stimulate an immunogenic response (Abou-Alfa 2011).

In a phase I/II study of 48 patients with pancreatic cancer (38 with advanced disease and 10 post-surgery), vaccination with mutant K-ras peptides in combination with GM-CSF resulted in immune responses and prolonged survival (Gjertsen 2001).

A phase II clinical trial of mutant ras peptide-based vaccine as adjuvant therapy in pancreatic and colorectal cancers was performed with 12 patients (with no evidence of disease). Five pancreatic and seven colorectal cancer patients were vaccinated with mutant ras peptide, corresponding to their tumor's ras mutation. Five out of eleven patients showed a positive immune response. Furthermore, the five patients that responded had a mean disease-free survival of 35.2+ months and a mean overall survival of 44.4+ months. The researchers noted that the vaccine is safe, can induce specific immune responses, and has a positive outcome in overall survival (Toubaji 2008).

MUC1 Peptide Vaccines: MUC1 is a glycoprotein highly overexpressed and mutated in pancreatic tumors, providing a tumor specific antigen and target.

A phase I/II clinical trial evaluated a vaccine consisting of liposomal MUC1 peptide-loaded dendritic cells (DC) (see below for more information on dendritic cell based vaccines). Twelve pancreatic and biliary cancer patients were vaccinated following surgical removal of their primary tumors. MUC1-specific immune responses were observed even in patients with pretreated and advanced disease. Vaccinated patients were followed for over four years and four of the twelve patients were alive at that point, all without evidence of recurrence (Lepisto 2008).

Vaccination of 16 patients with resected or locally advanced pancreatic cancer with MUC1 peptide and SB-AS2 adjuvant (which induces a more portent immune response) resulted in low MUC1-specific immune responses in some patients. Moreover, 2 of 15 vaccinated patients were alive and disease free during follow-up at 32 and 61 months (Ramanathan 2005).

hTERT mRNA Dendritic Cell (DC) Vaccine: hTERT (Human telomerase reverse transcriptase) is an ideal tumor-associated antigen with which to develop a dendritic cell (DC) vaccine (Cui 2011). Immunotherapy targeting the hTERT subunit of telomerase induces powerful immune responses in cancer patients after vaccination with single hTERT peptides. A complete remission was reported in a pancreatic cancer patient associated with the induction of hTERT-specific immune responses against several hTERT epitopes (pieces of the antigen that are recognized by the immune system) (Suso 2011):

A 62-year-old female patient underwent radical surgery for a pancreatic adenocarcinoma. After relapse, she attained stable disease with gemcitabine treatment. Due to severe neutropenia, the chemotherapy was discontinued. The patient was subsequently treated with autologous DCs loaded with hTERT mRNA for 3 years. Immune parameters were monitored regularly after vaccination and clinical outcome was assessed by CT and PET/CT scans. The patient developed an immune response against several hTERT-derived antigens. At the time of writing, she showed no evidence of active disease based on PET/CT scans and continues to receive regular booster injections (Suso 2011).

Telomerase Peptide Vaccines and GM-CSF: A phase I/II study demonstrated the safety, tolerability, and immunogenicity of telomerase peptide (GV1001) vaccination in 48 patients with non-resectable pancreatic cancer. Immune responses were observed in 24 of 38 evaluable patients. One-year survival was 25% for the evaluable patients in the intermediate dose group. Median survival for this group was 8.6 months (Bernhardt 2006).

GV-1001, an injectable telomerase (hTERT) MHC class II peptide vaccine (by GemVax AS), was reported to be undergoing phase III clinical trials for pancreatic cancer in 2007 (Nava-Parada 2007).

HSPPC-96 (gp96, Oncophage): A phase I pilot study of autologous heat shock protein vaccine HSPPC-96 (gp96, Oncophage) in patients with resected pancreatic adenocarcinoma was performed. Ten patients who received neither adjuvant chemotherapy nor radiation were vaccinated with HSPPC-96 weekly with 4 doses. Median overall survival was 2.2 years. Three of 10 treated patients were alive and without disease at 2.6, 2.7, and 5.0 years follow-up (Maki 2007). However, there have been no follow-up studies reported.

Poxvirus Vaccines Targeting CEA and MUC-1: A Phase 1 clinical study of poxviruses targeting carcinoembryonic antigen (CEA) and MUC-1 in 10 patients with advanced pancreatic cancer was conducted. Results showed the poxvirus vaccine to be safe, well tolerated, and capable of generating antigen-specific immune responses in patients with advanced pancreatic cancer. Median overall survival was 6.3 months and a significant increase in overall survival was noted in patients who generated anti CEA- and/or MUC-1-specific immune responses compared with those who did not (15.1 vs. 3.9 months, respectively) (Kaufman 2007).

Personalized Peptide Vaccines: A case of complete remission of liver metastasis of pancreatic cancer, refractory to gemcitabine chemotherapy, under vaccination with a HLA-A2 restricted peptide derived from survivin peptide was reported (Wobser 2006).

Immunotherapy combined with Chemotherapy. Emerging evidence suggests that immunotherapy used in combination with conventional chemotherapy may improve clinical outcome. Noteworthy, gemcitabine has direct antitumor (chemotherapeutic) activity but also mediates immunological effects beneficial for cancer immunotherapy. Gemcitabine treatment is not immunosuppressive and may enhance responses to specific vaccines or immunotherapy and therefore could be combined with vaccines or other immunotherapy (Plate 2005).

Vascular Endothelial Growth Factor Receptor 2 (VEGFR2). VEGFR2 is an essential factor in tumor angiogenesis and in the growth of pancreatic cancer. A phase I clinical trial using a peptide vaccine for VEGFR2 in combination with gemcitabine for patients with advanced pancreatic cancer (metastatic and/or unresectable) was conducted. The median overall survival time of all 18 patients who completed at least one course of treatment was 8.7 months and the disease control rate was 67% (Miyazawa 2010).

A phase II study of personalized peptide vaccination with gemcitabine as the first line therapy in patients with non-resectable pancreatic cancer was performed. The reactive personalized peptides (maximum of 4 types of peptides) were administered with gemcitabine to 21 patients with untreated and nonresectable pancreatic cancer. Median survival time of all 21 patients was 9.0 months with a one-year survival rate of 38%. Immune responses correlated well with overall survival (Yanagimoto 2010).

Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF). GM-CSF is a myeloid growth factor and immune activating protein used clinically. The GM-CSF gene inserted into tumor cells has been used to immunize patients. These genetically modified tumor cells produce GM-CSF in the local environment of the tumor, specifically activating the patient's T cells.

A Phase II trial tested the safety and effectiveness of GM-CSF-based immunotherapy given to 60 patients with resected pancreatic adenocarcinoma. The immunotherapy treatment was given 8 to 10 weeks after surgery followed by 5-fluorouracil (5-FU) based chemoradiation and further immunotherapy. The median survival was 24.8 months and the immunotherapy was well tolerated (Lutz 2011).

Dendritic Cell (DC)-based Vaccines. Dendritic cells (DC) are potent antigen-presenting cells and play a pivotal role in T cell-mediated immunity and thus immunotherapy of cancer. DC-based vaccines are safe and efficient in inducing strong tumor-specific immune responses (i.e., cytotoxic T-cell (CTL) responses) against tumor antigens (in vitro and in vivo) (Dauer 2005). The long-term outcome of dendritic cell (DC) vaccination and immunotherapy for patients with refractory pancreatic cancer has been demonstrated (Nakamura 2009):

Seventeen pancreatic cancer patients underwent immunotherapy in the Kyushu University and the Yakuin CA Clinic. Six patients had postoperative recurrence, 11 were inoperable due to metastasis, 16 developed chemotherapy-resistant cancers, while 1 patient had no prior chemotherapy for recurrent cancer after surgical resection because of leukopenia. Immunotherapy was combined with chemotherapy in 11 patients and without chemotherapy in 6 patients. Immunotherapy was classified into two groups; combined dendritic cell (DC) vaccination and injection of activated lymphocytes (DC vaccine therapy), or injection of lymphokine-activated killer lymphocytes (LAK) alone (LAK therapy). This immunotherapy of refractory pancreatic cancer resulted in a median survival of 9 months. DC vaccine therapy gave a significantly better survival period than LAK therapy alone. Results suggest that immunotherapy utilizing DC vaccination may prolong the survival of patients with refractory pancreatic cancer (Nakamura 2009).

A recent study indicates that DC vaccine-based immunotherapies combined with gemcitabine/S-1 are effective in patients with advanced pancreatic cancer refractory to standard chemotherapy (Kimura 2011). In this report, 38 out of 49 patients had received vaccination with WT1 peptide-pulsed DCs with or without combination of other peptides such as MUC1, CEA, and CA125. Prior to this combination therapy, 46 out of 49 patients had been treated with chemotherapy, radiotherapy, or hyperthermia but without clinical effects. Of 49 patients, 2 patients had complete remission (CR), 5 had partial remission (PR), and 10 had stable disease (SD) and median survival time was 360 days. Survival of patients receiving DC vaccine and chemotherapy plus LAK cell therapy was longer than those receiving DC vaccine in combination with chemotherapy but no LAK cells. “Dendritic cell vaccine-based immunotherapy combined with chemotherapy was shown to be safe and possibly effective in patients with advanced pancreatic cancer refractory to standard treatment” (Kimura 2011).

Another recent pilot study showed that DC-based vaccination can stimulate an antitumor T cell response in patients with advanced or recurrent pancreatic carcinoma receiving concomitant gemcitabine treatment (Bauer 2011). In this study patients were eligible for DC vaccination after recurrence of pancreatic cancer or as palliative care. Twelve patients received DC vaccinations and simultaneous chemotherapy. One patient developed a partial remission, and two patients exhibited stable disease. Median survival was 10.5 months and no severe side effects occurred. DC vaccination increased the frequency of tumor-reactive cells in all patients tested; however, the degree of this increase varied. The patient with the longest overall survival of 56 months had a high frequency of tumor-reactive cells, indicating that the presence of a pre-vaccination antitumor T cell response might be associated with prolonged survival. Five patients survived 1 year or more (Bauer 2011).

Table 1. Vaccines for Pancreatic Cancer

Vaccine

Patients

Response

Reference

Dendritic cell-based with concomitant chemotherapy (gemcitabine)

12 advanced or recurrent pancreatic cancer

1 partial remission (PR), 2 stable disease (SD), median survival 10.5 months

Bauer 2011

GM-CSF post-surgery with 5-FU chemoradiation

60 resected pancreatic adenocarcinoma

Median survival was 24.8 months

Lutz 2011

Dendritic cell-based loaded with WT1, MUC1, CEA, and CA125

Gemcitabine/S-1

49 advanced pancreatic cancer patients refractory to standard chemotherapy

2 complete remissions (CR), 5 PR, and 10 with SD. Median survival 360 days.

Kimura 2011

hTERT mRNA dendritic cell vaccination

1 patient post- chemotherapy

Complete response (i.e., no evidence of active disease based on PET/CT scans).

Suso 2011

Mutant K-ras long peptide

23 resected pancreatic cancer

Ten-year survival was 20% (four patients out of 20 evaluable).

Wedén 2011

MUC1 peptide-loaded dendritic cell

12 pancreatic and biliary cancer patients with resected tumors

4 of the 12 patients followed for over four years were alive.

Lepisto 2008

13-mer mutant ras peptide

12 patients with no evidence of disease; 5 pancreatic and 7 colorectal

Mean DFS of 35.2+ months and a mean overall survival (OS) of 44.4+ months.

Toubaji 2008

Allogeneic GM-CSF-secreting pancreatic cancer cell, alone or in sequence with cyclophosphamide

30 advanced pancreatic cancer

Median survival in gemcitabine-resistant patients was similar to chemotherapy alone.

Laheru 2008

Telomerase peptide with adjuvant GM-CSF

48 advanced pancreatic cancer

One-year survival for the evaluable patients in the intermediate dose group was 25%.

Bernhardt 2006

HLA-A2 restricted peptide derived from Survivin antigen

1 metastatic (liver) pancreatic cancer patient refractory to gemcitabine

Complete remission of liver metastasis with a duration of 8 months.

Wobser 2006

Personalized peptide vaccine

11 advanced pancreatic cancer

The 6- and 12-month survival rates for 10 patients who received >3 vaccinations were 80% and 20%, respectively.

Yamamoto 2005

MUC1 peptide with SB-AS2 adjuvant

16 resected or locally advanced pancreatic cancer

2 of 15 resected pancreatic cancer patients were alive and disease free at follow-up of 32 and 61 months.

Ramanathan 2005

Dendritic cell transfected with MUC1 cDNA

10 patients with advanced pancreatic, breast, or papillary cancer

A vaccine-specific delayed-type hypersensitivity (DTH) reaction occurred in 3 out of 10 patients.

Pecher 2002

Allogeneic GM-CSF-secreting pancreatic cancer cell

14 resected pancreatic cancer

3 patients had DTH responses; 3 patients remained disease-free at least 25 months after diagnosis

Jaffee 2001

Mutant K-ras peptide with adjuvant GM-CSF

10 resected and 38 advanced pancreatic cancer

Prolonged survival of immune -responders compared to nonresponders.

Gjertsen 2001

DFS = Disease Free Survival

Preserving Postoperative Immune Function with Interleukin-2

Pancreatic cancer, more so than many other malignancies, has retained a relatively poor prognosis over recent decades despite dedication of considerable resources and research efforts aimed at improving patient outcomes (Caprotti 2008).

One reason pancreatic cancer remains such a feared disease is that carcinogenic pancreatic tissue appears to directly influence the milieu of cell-signaling molecules that govern immune response within the body, culminating in dramatic suppression of patients’ anti-tumor immunity and allowance of unimpeded growth of malignant cells (Caprotti 2008; Hansel 2003; Elliott 2005; Furukawa 2006).  Exacerbating this problem is that major invasive surgery, which is an important aspect of treatment for individuals with early-stage pancreatic cancer, further weakens the immune system (Caprotti 2008). This dualistic assault on the immune system often heralds poor post-surgery survival for pancreatic cancer patients.

The good news is that scientists at the forefront of cancer immunology research are elucidating strategies for countering immunosuppression associated with pancreatic cancer.

A most promising modality on this front involves administering an immune-boosting cytokine called interleukin-2 to pancreatic cancer patients prior to surgery. Interleukin-2 is naturally produced in the body and one of its chief physiological roles is to promote proliferation of immune cells involved in anti-cancer immunity, namely T-lymphocytes and natural killer (NK) cells (Caprotti 2008).

Evidence from animal and human studies shows that administering interleukin-2 prior to radical surgery for pancreatic cancer, even for just a few days preceding surgery, considerably mitigates the decline in immune function that often compromises outcomes (Wang 2013; Degrate 2009; Uggeri 2009; Caprotti 2008; Nobili 2008).

In a study involving 19 pancreatic cancer patients scheduled for radical surgery, researchers administered interleukin-2 (9 million IU) for 3 days preceding surgery in 9 subjects, and the other 10 underwent the surgery without receiving any preoperative interleukin-2. Both groups were well matched for age, sex, and disease stage. The 2-year survival rate in the group that did not receive interleukin-2 before surgery was 10%, whereas 33% of subjects that received interleukin-2 survived 2 years following surgery. Moreover, postoperative complications occurred more frequently in the group of patients that did not receive interleukin-2 (Angelini 2006).

In a similar but slightly larger study, 30 pancreatic cancer patients were allocated to radical surgery alone (control group) or 3 consecutive days of interleukin-2 (12 million IU) therapy preceding radical surgery. T-lymphocyte counts fell significantly in the control group following surgery (reflecting diminished anti-cancer immunity), whereas they rose significantly in the group that received interleukin-2. After a 3-year follow-up period, both progression-free survival (survival without evidence of disease progression) and overall survival were significantly higher in the interleukin-2 treated patients (Caprotti 2008).

It appears that 12 million IU of interleukin-2 for 3 consecutive days prior to surgery may deliver a more favorable result than 9 million IU. In a trial on 31 pancreatic cancer patients undergoing surgery, researchers allotted 3 treatment variations: surgery alone, 9 million IU of interleukin-2 for 3 days before surgery, or 12 million IU of interleukin-2 for 3 days before surgery. Following surgery, the group allocated to the 12 million IU interleukin-2 dose exhibited more favorable measures of immunological competence than those who received 9 million IU. The scientists concluded “This preliminary result suggests that preoperative subcutaneously IL-2 immunotherapy at 12 million IU for 3 consecutive days before surgery is able to abrogate the effects of the surgical trauma and recover a normal immunofunction in pancreatic cancer patients” (Uggeri 2009).