Irinotecan

Pancreatic cancer is the fourth leading cause of cancer death in the United States. It is estimated 31,860 new cases will be diagnosed in the US in 2004.1 At presentation, only 20% of patients with pancreatic cancer have resectable tumors, 40% have locally advanced cancer, and 40% have metastatic cancer.2 The median survival is 5 to 7 months for patients with metastatic pancreatic cancer, and 8 to 11 months for patients with locally advanced disease.3 Pancreatic cancer has a five-year survival rate of 4%.4 This review focuses on chemotherapy for pancreatic cancer, with particular attention to advances in the past few years.

CHEMOTHERAPY FOR METASTATIC PANCREATIC CANCER

Metastatic pancreatic cancer describes patients with disease that has spread from the local-regional area of the pancreas to involve other organs, such as the liver and peritoneum, as shown in Figure 1. Chemotherapy is the primary treatment for patients with metastatic disease.

SINGLE AGENT CHEMOTHERAPY

In advanced pancreatic cancer, the greatest change has been the acceptance of gemcitabine as first line chemotherapy on the basis of the results of a randomized trial comparing gemcitabine with fluorouracil (5-FU).4 This study demonstrated gemcitabine was superior to 5-FU in terms of median survival (5.6 vs 4.4 months), 1-year survival (18% vs 2%), and clinical benefit response (23.8% vs 4.8%). The clinical benefit was defined as an improvement in pain, performance status, and weight gain.

COMBINATION CHEMOTHERAPY

Combinations of gemcitabine with other chemotherapeutic agents such as cisplatin, irinotecan, and oxaliplatin achieved promising preliminary results in phase II trials. At the 2003 meeting of the American Society of Clinical Oncology, phase III trials of these combinations were presented. The combination of gemcitabine and cisplatin was not statistically significant comparing to gemcitabine alone in terms of overall survival (7.6 months vs 6 months).3 Also the combination of gemcitabine and irinotecan was not superior to gemcitabine alone in terms of time to progression (3.5 vs 3 months) and over all survival (6.3 vs 6.6 months).6 However, the combination of gemcitabine and oxaliplatin achieved a statistically significant improvement in response rate and disease free survival as compared to gemcitabine alone. The effect of oxaliplatin on overall survival is not yet known.

MOLECULAR THERAPIES

Intensive research in pancreatic cancer has focused on identifying abnormal genes involved in cancer growth and progression and using these abnormal genes as targets for specific molecular based therapies.

RAS INHIBITORS

Almost 90% of pancreatic cancers harbor a ras gene mutation. Ras proteins are membrane bound proteins that are important in signal transduction stimulating cell growth. To be activated the ras protein requires the addition of a farnesyl group by the enzyme farnesyl transferase. Rl 15777 was the first farnesyl transferase inhibitor to be tested in human trials. In a randomized phase III trial of 680 patients, there was no improvement in survival for patients randomized to RIl 5777 and gemcitabine versus gemcitabine alone with a median survival of 193 days versus 182 days, respectively.

EPIDERMAL GROWTH FACTOR RECEPTOR INHIBITORS

Among the most promising class of new cancer chemotherapeutics are agents that target the HER family of membrane bound receptors, which include HER-1, HER-2, HER-3 and HER-4. HER-1 is the epidermal growth factor receptor (EGFR).7 Inhibitory agents have been designed to either bind to the EGFR or inhibit signal transduction after receptor activation.

Cctuximab (C-225) is a humanized monoclonal antibody that binds the EGFR receptor. Abbruzzese et al have evaluated the anti-EGFR antibody C-225 in combination with gemcitabine in patients with advanced pancreatic cancer.8 Eighty-nine percent of the patients screened for this study tested positive for EGFR expression. Forty-one patients were enrolled into this study. After two courses of therapy, 5 (12%) achieved a partial response and 16 (39%) achieved a minor response or had stable disease. A phase III trial of G-225 and gemcitabine versus gemcitabine alone for patients with metastatic pancreatic cancer will be initiated shortly in the United States.

Tarceva (OSI-774) is a small molecule that selectively inhibits EGFRtyrosine kinase thereby blocking signal transduction. Diarrhea and rash are the most common toxicities.9 OSI-774 has shown promising activity in lung and head and neck cancer. A phase III trial of OSI-774 and gemcitabine versus gemcitabine alone for patients with metastatic pancreatic cancer has been completed by the National Cancer Institute of Canada.

HERCEPTIN

Blocking the HER-2 gene has also been a successful strategy in human cancers. The humanized monoclonal antibody Herceptin has shown substantial activity in metastatic adenocarcinomas of the breast that overcxpress HER-2. The Brown University Oncology Group has tested Herceptin in patients with metastatic pancreatic cancer that overexpress HER-2. Only 16% of patients with pancreatic cancer had tumors that overexpressed HER-2, and most tumors only weakly overexpressed this gene. The median survival for 34 patients was 7 months, and the 1 -year survival was 19%. Low HER-2 expression limits the role of targeting the HER-2 gene in pancreatic cancer.

METASTATIC PANCREATIC CANCER: CONCLUSIONS

Single agent gemcitabine is the standard of care. However, combinations of gemcitabine with the chemotherapeutic agent oxaliplatin and EGFR inhibitors are promising and await the results of phase III trials.

CHEMORADIATION FOR LOCALLY ADVANCED PANCREATIC CANCER

FLUOROURACIL/RADIATION

Locally advanced pancreatic cancer describes patients with cancers that are unresectable due to major blood vessel encasement such as the superior mesenteric or celiac arteries, but who do not have distant organ metastases, as shown in Figure 2. Radiation therapy with the use of radiosensitizing chemotherapy is most commonly used treatment for these patients. A randomized trial by the Gastrointestinal Tumor Study Group (GITSG) showed an improvement in survival with 5-FU and radiation as compared to radiation alone for patients with metastatic pancreatic cancer.10 In a Radiation Therapy Oncology Group (RTOG) phase II trial (RTOG 92-09), the median and 1-year survival for patients with locally advanced pancreatic cancer were 7.4 months and 28.6%, respectively.11

GEMCITABINE/RADIATION

Gemcitabine is a potent radiosensitizer and has been extensively studied with radiation.

The Cancer and Leukemia Group B had completed a phase II trial of gemcitabine and radiation in 38 patients with locally advanced pancreatic carcinoma.12 The median survival was 8 months. More promising results have been reported by the University of Michigan using smaller radiation fields and higher gemcitabine dosages with an 11 month median survival.

PACLITAXEL/RADIATION

The Brown University Oncology Group has evaluated paclitaxel as a radiation sensitizer for patients with locally advanced pancreatic cancer in a series of phase I/II studies.13, 14 This approach was then tested in a national trial by the RTOG.15 Of 122 patients enrolled, median survival and 1-year survival were 11.3 months and 47%, respectively. These results demonstrated doubling of 1-year survival of previous 5-FU based chemoradiation trial.

PACLITAXEL/GEMCITABINE/RADIATION

The Brown University Oncology Group has combined gemcitabine, paclitaxel and radiation in a phase 1 study.16 This trial established the optimal dosages of concurrent gemcitabine, paclitaxel and radiation and demonstrated substantial preliminary activity. Four of 10 assessable patients treated at the MTD responded (40%), including one pathologic complete response. A confirmatory phase II RTOG PA0200 study is under way and has already accrued 150 patients.

MOLECULAR BASED THERAPIES WITH CHEMORADIATION

Systemic progression is the dominant pattern of failure following chemoradiation for locally advanced pancreatic cancer. Molecular based agents may help delay the growth of micrometastasis and improve survival when loco-regional therapy is treated with chemoradiation. The Brown Oncology Group is currently evaluating the EGFR inhibitor Tarceva with gemcitabine, paclitaxel and radiation. The M.D. Anderson Cancer Center in Houston is evaluating anti-angiogenesis agent avastin with 5-FU based chemoradiation.

LOCALLY ADVANCED PANCREATIC CANCER: CONCEUSIONS

5-FU in combination with radiation is the standard of care for patients with locally advanced pancreatic cancer. Phase II trials using gemcitabine and paclitaxel as radiation sensitizers have achieved promising preliminary results. Addition of molecular based therapies to chemoradiation holds promise in delaying the development of systemic metastases.

ADJUVANT CHEMORADIATION

The use of adjuvant chemoradiation following resection of pancreatic cancer was first established by the randomized clinical trial conducted by the GITSG.17 Patients with resected pancreatic cancer were randomized to adjuvant chemoradiation versus no treatment. The study was prematurely terminated due to low rate of accrual and large survival difference between the study arms. The study showed superiority for die adjuvant group in median survival (20 months versus 11 months, P=0.03), 2-year survival (42% versus 15%), and 5-year survival (19% versus 5%). This study has been criticized for small sample size.

The European Organization for Research and Treatment of Cancer (EORTC) also evaluated adjuvant chemoradiation versus observation in patients with curative resection of cancer of the pancreatic head and periampullary region.18 Survival data demonstrated a trend toward improvement in the chemoradiation arm in median survival (24.5 vs 19 months), 2-year survival (51% vs 41%) and 5-year survival (28% vs 22%); however, the improvements were not statistically significant.

In the United Stated, the focus has been to evaluate the addition of gemcitabine before and after 5-FU and radiation. A randomized trial of over 525 patients was completed in 2002 and may define a new standard of care. Future studies will involve the incorporation of molecular based therapies with chemotherapy and radiation.

CONCLUSION

Significant progress is being made in pancreatic cancer. Gemcitabine is the most effective single agent in metastatic pancreatic cancer. Combinations of gemcitabine with oxaliplatin improve response rate and time to progression for patients with metastatic disease, but the effect on overall survival is not yet known. Combinations of gemcitabine with molecular agents such as EGFR inhibitors are particularly promising and results from phase III trials are eagerly anticipated. For patients with locally advanced disease, 5-FU and concurrent radiation is the standard of care, but more potent radiation sensitizers such as gemcitabine and paclitaxel, and incorporation with molecular based agents are new approaches. Patients with resected pancreatic cancer should receive adjuvant therapy. More active systemic therapies and targeted therapy will ultimately improve survival for these patients.

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JAMES Y. TSAI, MD, AHMED NADEEM, MD, AND HOWARD SAFRAN, MD

James Y. Tsai, MD, is a Fellow in Hematology/Medical Oncology, Department of Medicine, Brown Medical School.

Ahmed Nadeem, MD, is Assistant Professor of Medicine, Brown Medical School.

Howard Safran, MD, is Associate Professor of Medicine, Brown Medical School.

CORRESPONDENCE:

Howard Safran, MD

Department of Medicine

The Miriam Hospital

164 Summit Avenue

Providence, RI 02906

Telephone: (401) 793-7151

Fax: (401) 793-7603

Email: hsafran@lifespan.org

Copyright Rhode Island Medical Society May 2004
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