Clinical Experience With Gemcitabine in Pancreatic Carcinoma

For decades, pancreatic cancer has been one of the most difficult and frustrating cancers to treat. Despite the promising response rates achieved with a number of chemotherapeutic regimens evaluated in phase II trials in the 1970s and ’80s, no regimen proved superior to single-agent fluorouracil (5-FU) in terms of overall survival. As a result, some oncologists adopted a position of therapeutic nihilism and criticized what appeared to be futile attempts to identify effective therapy for patients with advanced-stage disease. Instead, they argued that clinical research efforts should focus on the development of adjuvant therapy for patients with earlier-stage disease.[1]

How things have changed! In their insightful review, Michael and Moore describe how the impact of gemcitabine (Gemzar) on tumor-related symptoms was first recognized, and how this observation gave rise to two trials designed to capture “clinical benefit” in a systematic and prospective manner.[2-4] Both trials demonstrated that approximately one-quarter of patients with advanced-stage, symptomatic pancreatic cancer achieve marked and sustained relief of symptoms when treated with gemcitabine. These results, along with data demonstrating that patients treated with gemcitabine have a significant prolongation of survival compared with those treated with 5-FU, resulted in the approval of gemcitabine by the Food and Drug Administration in May 1996.

One factual error in the review by Michael and Moore should be corrected: In both the phase II and III trials, there was an association between clinical benefit response and survival. In the phase III trial, regardless of the treatment received, clinical benefit responders survived a median of 10.7 months, while nonresponders survived a median of 4.8 months.[3] In the phase II trial of gemcitabine as second-line treatment, patients who attained a clinical benefit response lived a median of 7.0 months, as opposed to 3.1 months for those who did not.[4] Although no statistical comparison could be made between clinical benefit responders and nonresponders, it was encouraging to see that, in both studies, survival and clinical benefit response tracked in the same direction.

How to Best Utilize Gemcitabine?

This represents more of a beginning than an end to the story. Over the past few years, there has been a veritable explosion of activity in the development of novel therapies for pancreatic cancer. Some of this activity relates to unanswered questions about how best to utilize gemcitabine:

• Is there any advantage to administering higher doses of the drug on a weekly basis?
• Is the activity of gemcitabine improved by administering it as a 2½-hour infusion rather than a 30-minute infusion?
• Can the potent radiosensitizing effects of gemcitabine be safely harnessed into a combined-modality adjuvant or neoadjuvant approach for patients with localized or locally advanced pancreatic cancer?
• Will combining gemcitabine with other drugs, such as cisplatin (Platinol), 5-FU, or octreotide (Sandostatin), result in greater activity than single-agent therapy?
• What is the role of gemcitabine in asymptomatic patients with advanced-stage pancreatic cancer?

Clinical trials addressing each of these questions are either planned or underway.

Other Promising Therapeutic Agents

A number of other therapeutic agents have generated substantial interest for their potential application in patients with pancreatic cancer.

Dihydropyrimidine Dehydrogenase Inhibitor—One such compound, 776C85, inactivates dihydropyrimidine dehydrogenase (DPD), the first and rate-limiting enzyme involved in the catabolism of 5-FU.[5] Among its many effects, DPD inactivation results in predictable and complete absorption of orally administered 5-FU, prolongation of the plasma half-life of 5-FU, and prevention of the formation of fluoro-beta-alanine, a 5-FU metabolite that may interfere with the drug’s antitumor effect.[6] The combination of 5-FU and 776C85 is currently being evaluated in a Southwest Oncology Group phase II trial (S9629) in patients with advanced-stage pancreatic cancer who have received no or only one prior chemotherapy regimen.

Matrix Metalloproteinase Inhibitor—Cancer cells that are destined to metastasize must have the means to invade through the extracellular matrix in order to gain access to nearby blood vessels. Matrix metalloproteinases (MMPs) are a family of enzymes expressed by both normal tissue (where they may be involved in wound healing) and malignant tissue (where they may be involved in metastasis).[7]

Marimastat (BB-2516) is an orally administered inhibitor of MMP 2 and 9 that has been evaluated in a broad array of solid tumors. Although patients with inoperable pancreatic cancer showed no objective responses to the drug in a preliminary analysis of a phase II trial, 63% had stabilization of disease for varying lengths of time.[8] Based on these results, a phase III trial has been initiated in which patients with advanced-stage disease are being randomized to treatment with marimastat or gemcitabine.

Angiogenesis Inhibitors—It is now understood that new blood vessel formation is essential to the growth and dissemination of solid tumors. This process, known as angiogenesis, has become a new target for anticancer therapy.[9] The fumagillin derivative TNP-470 is a potent inhibitor of angiogenesis that delays the development of distant metastases in animal models.[10-11]

A two-arm, phase II trial of TNP-470 is underway in patients with locally advanced, unresectable pancreatic cancer. Patients are being randomized to receive either TNP-470 administered three times per week or standard therapy with radiation and concurrent 5-FU. This is another situation in which standard end points, such as response rate, may not be appropriate given the drug’s known mechanism of action. This factor has been taken into account in the design of this trial, and the primary end point is time to the development of distant metastases.

Farnesyl Protein Transferase Inhibitors—Mutations in the K-ras gene are found in more than 80% of all human pancreatic cancers. Mutant ras protein is located on the inner surface of the plasma membrane and induces persistent stimulation of cellular growth.[12] Farnesyl protein transferase (FPTase) is an enzyme that converts ras from an inactive protein found within the cell’s cytoplasm to a potentially active, membrane-bound protein.

A number of new compounds have demonstrated preclinical activity against tumor cells expressing mutant forms of ras by inhibiting FPTase. Several FPTase inhibitors have been identified and are expected to enter clinical testing within the next year.

A Period of Extraordinary Opportunity

We are clearly still at the very early stages in our quest to identify effective therapies for patients with advanced-stage pancreatic cancer. However, we are also in the midst of a period of extraordinary opportunity in which an unprecedented number of new therapeutic agents, each with a distinct molecular target and mechanism of action, are available for our patients diagnosed with inoperable pancreatic cancer. In order to evaluate each of these new agents adequately, we will need to break through the therapeutic “depression” that has long been associated with this disease and make sure that our colleagues and patients are aware of these latest developments and the exciting opportunities that lie before us in the development of more effective therapy for advanced pancreatic cancer.

References:

1. Taylor I: Should further studies of chemotherapy be carried out in pancreatic cancer? Eur J Cancer 29A:1078-1081, 1993.

2. Casper ES, Green MR, Kelsen DP, et al: Phase II trial of gemcitabine (2´2´-difluorodeoxycytidine) in patients with adenocarcinoma of the pancreas. Invest New Drugs 12:29-34, 1994.

3. Burris HA III, Moore MJ, Andersen J, et al: Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: A randomized trial J Clin Oncol 15:2403-2413, 1997.

4. Rothenberg ML, Moore MJ, Cripps MC, et al: A phase II trial of gemcitabine in patients with 5-FU-refractory pancreas cancer. Ann Oncol 7:347-353, 1996.

5. Porter DJT, Chestnut WG, Merrill BM, et al: Mechanism-based inactivation of dihydropyrimidine dehydrogenase by 5-ethynyluracil. J Biol Chem 267:5236-5242, 1992.

6. Baker SD, Diasio R, Lucas VS, et al: Phase I and pharmacologic study of oral 5-fluorouracil on a chronic 28-day schedule in combination with the dihydropyrimidine dehydrogenase inactivator 776C85 (abstract). Proc Am Soc Clin Oncol 15:486, 1996.

7. Brown PD, Giavazzi R: Matrix metalloproteinase inhibition: A review of anti-tumor activity. Ann Oncol 6:967-974, 1995.

8. Evans J, Bramhall S, Carmichael J, et al: A phase II study of marimastat (BB-2516) in advanced pancreatic cancer (abstract 239P). Ann Oncol 7(suppl 5):51, 1996.

9. Fidler IJ, Ellis LM: The implications of angiogenesis for the biology and therapy of cancer metastasis. Cell 29:185-188, 1994.

10. Ingber D, Fujita T, Kishimoto S, et al: Synthetic analogues of fumagillin that inhibit angiogenesis and suppress tumor growth. Nature 348:555-557, 1990.

11. Ahmed MH, Konno H, Nahar L, et al: The angiogenesis inhibitor TNP-470 (AGM-1470) improves long-term survival of rats with liver metastasis. J Surg Res 64:35-41, 1996.

12. Gibbs JB, Oliff A: The potential of farnesyltransferase inhibitors as cancer chemotherapeutics. Ann Rev Pharmacol Toxicol 37:143-166, 1997.