Gemcitabine/Irinotecan/Celecoxib in Pancreatic Cancer
Gemcitabine/Irinotecan/Celecoxib in Pancreatic Cancer
Unresectable pancreatic cancer has few therapeutic options and a dismal prognosis. Cyclooxygenase-2 (COX-2) expression is increased at the RNA and protein levels in most human pancreatic cancers. The purpose of this trial was to determine whether the addition of a COX-2 inhibitor to chemotherapy was beneficial. To date, 11 patients with inoperable pancreatic cancer have been treated with the combination of gemcitabine (Gemzar), irinotecan (Camptosar), and celecoxib (Celebrex) at 400 mg orally twice daily. Encouraging pain relief, improvement in performance status, and decreases in CA 19-9 and carcinoembryonic antigen levels have been observed.
Pancreatic cancer is the fourth leading cause of cancer death in the United States. The 5-year survival rate has increased little from 1% in 1961 to only 3% to 5% in the 1990s. Although in vitro studies have suggested the possible role of tumor suppressor genes (p53, p16) and growth factors (epidermal growth factor [EGF], basic fibroblast growth factor, insulinlike growth factor I) in cancer of the pancreas, the exact pathogenic mechanism remains to be clarified, and at present there is no effective treatment for this disease.[1-5] Mechanisms of Action Cyclooxygenase (COX) enzymes catalyze the rate-limiting step in ara-- chidonate metabolism, resulting in prostaglandin H2 production. This molecule is the precursor of other prostaglandins, prostacyclin, and thromboxanes. Two cyclooxygenase isoforms have been identified: COX-1 and COX-2. COX-1 is expressed constitutively in several cell types in normal mammalian tissues, where it is involved in the maintenance of tissue homeostasis. COX-2 is an inducible enzyme responsible for prostaglandin produc tion at sites of inflammation. Growth factors, tumor promoters, and cytokines have been shown to induce COX- 2 expression.[6,7] For example, EGF is one of the growth factors known to upregulate the expression of the COX- 2 enzyme in many epithelial cells.[8,9] Recent studies have suggested a potential role for COX-2 in pancreatic cancer. Increased levels of COX-2 mRNA were found in four of five human pancreatic cancer cell lines, and only in PANC-1 cells was the low level of transcript comparable to that in the normal pancreatic cell. The level of COX-2/mRNA was positively correlated with the differentiation status of the tumor of origin for each cell line. COX-2 protein expression was upregulated by EGF when the cells were grown in the absence of serum. Using immunohistochemistry, a strong expression of COX-2 protein was present in 23/52 (44%) of pancreatic cancers, a moderate expression in 24/52 (46%), and a weak expression in 5/52(10%). In contrast, benign tumors showed weak or no expression of COX-2, and only islet cells displayed COX-2 expression in normal pancreatic tissues. An important role for the COX-2 enzyme in pancreatic cancer is suggested by the observation that the selective COX-2 inhibitor, NS398, produces a dose-dependent inhibition of cell proliferation in all pancreatic cancer cell lines tested. In the present study we treated newly diagnosed patients with inoperable pancreatic cancer with chemotherapy (gemcitabine [Gemzar] plus irinotecan [Camptosar]) plus the COX-2 inhibitor celecoxib (Celebrex). Materials and Methods Patients with inoperable pancreatic cancer were eligible for this trial. Eligible patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 and had not received prior chemotherapy. All patients were required to have a white blood cell count greater than 3,000, platelets greater than 100,000, and liver function tests no more than three times normal. CA 19-9 and carcinoembryonic antigen (CEA) levels were performed at baseline and every month while on therapy. Pain was evaluated at baseline and each month on a scale of 0 to 3 for intensity and 0 to 3 for frequency. Patients received treatment with gemcitabine at 1,000 mg/m2 IV plus irinotecan at 100 mg/ m2 IV on days 1 and 8 of an every-3-week cycle of therapy. In addition, patients received oral celecoxib at 400 mg twice daily throughout the study. Patients were evaluated by CT scan and other x-rays as indicated prior to therapy and then after every three cycles of treatment. Response Evaluation Criteria in Solid Tumors (RECIST) criteria were used to evaluate disease response. Toxicity was evaluated using ECOG toxicity criteria. Results To date, 11 patients with inoperable pancreatic cancer have been entered on this trial. The median age of patients was 55 years. There were four males and seven females. Six patients had localized inoperable disease and five patients had metastatic pancreatic cancer. Six patients have received more than 3 months of treatment. One patient with partial response (10+ months) and five patients with stable disease (9+, 8+, 6+, 4+ and 4+ months) have been reported. Three patients are too early to evaluate. One patient was inevaluable due to bile duct obstruction from disease that occurred on day 5 of treatment. Finally, one 78- year-old patient expired from diarrhea, neutropenia, and sepsis thought to be related to treatment. No patient has had progression of disease at the time of submission of this manuscript (Table 1). There were other indicators of activity of the combination of gemcitabine/ irinotecan/celecoxib. Of six patients who began treatment with abdominal pain, all six had improvement in their symptoms after two cycles of therapy. Five out of five patients with elevated baseline CA 19-9 (Figure 1) and four out of five with elevated baseline CEA (Figure 2) had a marked decrease in the serum marker (more than 71% and 33%, respectively). Side effects were those that could be expected from treatment with gemcitabine and irinotecan. Adverse events included six patients with diarrhea, four with neutropenia (one grade 3, one grade 4), three with peripheral edema, two with anemia (one grade 3), and one with deep-vein thrombosis. As mentioned above, one elderly female who started treatment with an ECOG performance status of 2 had diarrhea and sepsis and most likely expired as a result of her therapy (Table 2). Discussion Pancreatic cancer is the cause of 5% of all cancer deaths in men and 6% in women. Despite some advanc- es in diagnosis, staging, and treatment, the prognosis for inoperable pancreatic cancer remains poor. A recent randomized phase III trial compared gemcitabine alone with gemcitabine plus irinotecan. The median survival for gemcitabine alone was 6.6 vs 6.3 months for the combination treatment.[ 12] The need for new treatment strategies is urgent. "Targeted therapy" will be effective when the target pathway is responsible for the growth of cancer cells. In human biopsy specimens COX-2 expression is increased at both the RNA and protein levels in most of the pancreatic carcinomas compared with paired normal tissues by reversetranscriptase polymerase chain reaction (RT-PCR) and Western blot analysis[10-12]; RT-PCR analyses indicated that 7 of 13 (54%) pancreatic carcinoma cases displayed an overexpression of COX-2 mRNA. In contrast, the expression of COX-1 mRNA was similar in cancer and normal tissues. That the COX-2 expression in pancreatic cancer cells may be of importance is suggested by in vitro studies that demonstrated that specific inhibition of COX-2 produced a dose-dependent inhibition of cell proliferation in all pancreatic cell lines tested. In the present study we treated 11 inoperable pancreatic cancer patients with chemotherapy (gemcitabine plus irinotecan) plus the COX-2 inhibitor celecoxib administered at a daily dose of 800 mg. All evaluable patients to date have had a response as measured by pain relief, decrease of CA 19-9, and at least stabilization of disease on CT scan. One patient exhibited a partial remission. No patient so far has had progression of disease. Thus, gemcitabine/ irinotecan/celecoxib is a promising therapeutic regimen that deserves further study as treatment for inoperable pancreatic cancer.
The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
1. Caldas C, Hahn SA, da Costa LT, et al: Frequent somatic mutations and homozygous deletions of the p16 (MTS1) gene in pancreatic adenocarcinoma. Nat Genet 8:27-32, 1994.
2. Scarpa A, Capelli P, Mukai K, et al: Pancreatic adenocarcinomas frequently show p53 gene mutations. Am J Pathol 142:1534-1543, 1993.
3. Nakamori S, Yashima K, Mauakami Y, et al: Association of p53 gene mutations with short survival in pancreatic adenocarcinoma. Jpn J Cancer Res 86:174-181, 1995.
4. Hahn SA, Schutte M, Hoque AT, et al: DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1 Science 271:350- 353, 1996.
5. Bergmann U, Funatomi H, Yokoyama M, et al: Insulin-like growth factor I overexpression in human pancreatic cancer: Evidence for autocrine and paracrine roles. Cancer Res 55:2007-2011, 1995.
6. Smith WL, Garavito M, DeWitt DL: Prostaglandin endoperoxide H synthases (cyclooxygenases)-1 and -2. J Biol Chem 271:33157-33160, 1996.
7. Eberhart CE, DuBois RN: Eicosanoids and the gastrointestinal tract. Gastroenterology 109:285-301, 1995.
8. Mestre JR, Subbaramaiah K, Sacks PG, et al: Retinoids suppress epidermal growth factor- induced transcription of cyclooxygenase-2 in human oral squamous carcinoma cells. Cancer Res 57:2890-2895, 1997.
9. Sato T, Nakajima H, Fujio K, et al: Enhancement of prostaglandin E2 production by epidermal growth factor requires the coordinate activation of cytosolic phospholipase A2 and cyclooxygenase-2 in human squamous carcinoma A431 cells. Prostaglandins 53:355- 369, 1997.
10. Molina M, Sitja-Arnau M, Lemoine MG, et al: Increased cyclooxygenase-2 expression in human pancreatic carcinomas and cell lines: Growth inhibition by nonsteroidal anti-inflammatory drugs. Cancer Res 59:4356-4362, 1999.
11. Okami J, Yamamoto H, Fujiwara Y, et al: Overexpression of cyclooxygtenase-2 in carcinoma of the pancreas. Clin Cancer Res 5:2018-2024, 1999.
12. Rocha Lima MS, Rotche R, Jeffery M, for the Gem/I Pancreatic Cancer Study Group: Randomized phase 3 study comparing efficacy and safety of gemcitabine (GEM) and irinotecan (I) to GEM alone in patients (pts) with locally advanced or metastatic pancreatic cancer who have not yet received prior systemic therapy (abstract 1005). Proc Am Soc Clin Oncol 22:251, 2003.