Gemcitabine Taxotere and Xeloda (GTX) for pancreatic cancer – pro

GTX is a promising regimen for pancreatic cancer but still not adequately supported.

Current treatment options for pancreatic cancer include surgery, radiation, and chemotherapy. Although single-agent chemotherapy with gemcitabine has been a standard treatment for pancreatic cancer, research has increasingly focused on the development of combination regimens. Recently, the U.S. Food and Drug Administration approved the combination of the targeted therapy Tarceva ® (erlotinib) and gemcitabine for the treatment of locally advanced, inoperable, or metastatic pancreatic cancer.

Xeloda is an oral chemotherapy drug that belongs to a class of drugs called antimetabolites. According to researchers from Europe, the addition of the drug Xeloda (capecitabine) to Gemzar (gemcitabine) improves the duration of survival in patients with advanced stage pancreatic cancer. These results were presented at the 2005 annual meeting of the American Society of Clinical Oncology. Researchers from Austria evaluated the effects of Gemzar® with or without Xeloda® in 83 patients with metastatic pancreatic cancer. 3 Forty-two patients received bi-weekly Gemzar® (2200 mg per square meter as a 30 min. infusion) and 41 patients received the same GemzarÒ dose and schedule plus oral Xeloda® at a dose of 2500 mg per square meter from days 1 to 7. The PR rate was 14 % for the Gemzar® alone group and 17% for the Gemzar® plus Xeloda® group. Stable disease was observed in 43% of Gemzar® alone patients and 56% of the combined group. Median survival was 4 months for the Gemzar® group and 5.1 months for the Xeloda® group, with overall survivals of 8.2 and 9.5 months, respectively. Using a clinical benefit scale, there was clinical benefit for 33% of patients receiving Gemzar® alone and 48.3% for those receiving Gemzar® and Xeloda®. The toxicities of the two regimens appeared to be equivalent and these investigators were enthusiastic about this drug combination. However, there was no improvement in objective or subjective response. It was speculated that the number of patients studied was too small, possibly the dosage was suboptimal and possibly these agents are not really additive or synergistic.

The Hoosier Oncology Group evaluated a regimen of Gemzar® and Taxotere®. The response rate was 24%, with a median duration of response of 16 weeks. Thirty-five percent of patients had stable disease. The one-year survival was 27.3% and toxicity appeared to be acceptable. German researchers also evaluated the combination of Gemzar® and Taxotere® for the treatment of patients with advanced pancreatic cancer. 6 They observed a 24% response rate, with 3% (one patient) achieving a CR. The median survival was 9 months and toxicity was mild to moderate. The EORTC-GI Group compared a regimen of Taxotere® and Gemzar® to a regimen of Taxetore® and Platinol® for the treatment of advanced or metastatic (80%) pancreatic cancer.  This was a randomized trial, with 49 patients receiving Taxotere® and Gemzar® and 47 receiving Taxotere® and Platinol®. Six cycles of treatment were administered to 44% of patients, with 29% receiving more than 6 cycles. The Gemzar®/Taxotere® arm was associated with low platelets and edema, while the Taxotere®/Platinol® arm had more neutropenia. The response rate was 15.8% for the Gemzar®/Taxotere® arm and 16.1% for the Taxotere®/Platinol® arm. The median survival was 7.4 months for Gemzar®/Taxotere® and 6.3 months for the Taxotere®/Platinol®. There were 11 patients alive in the Gemzar®/Taxotere® arm and 9 in the Taxotere®/Platinol® arm. They concluded that the Gemzar®/Taxotere® arm had more manageable toxicity and possibly better activity. They will be performing a randomized phase III trial to confirm these results.

Although both Xeloda and Gemcitabine/Taxotere have phase II (and for the latter phase III) trial support, putting all three together is investigational. Preliminary work was done and is ongoing at Columbia University by Dr. Fine. Combining Gemzar with Taxotere® (docetaxel) and Xeloda® (capecitabine, the oral drug that metabolizes into 5-FU within tumor cells) shows intriguing signs of efficacy. Xeloda supresses DNA replication needed for tumor growth in a different way than do Gemzar, and Taxotere backs up the cell’s structural proteins. Together, the “GTX” drugs, as they are known, may be synergistic in their antitumor effects.

In a pilot study, GTX combination was administered to 44 patients with advanced pancreatic cancer. A “partial response was observed in the liver metastases of 15 of 32 patients. Liver metastases disappeared on CT and MRI scans in three of the original 15 patients when the GTX regimen was continued for a total of eight to nine cycles. Another 28% of patients had minor response to GTX or stable disease in their liver tumors. Tumors in 12 other subjects were initially inoperable but hadn’t spread to the liver. After drug treatment and radiation, eight of these patients could undergo successful Whipple surgery for cure. For patients who failed GTX and received alternating GX-T chemotherapy, a 30% response rate and 40% stable disease rate was seen. Thus, a triple drug regimen of Xeloda, Gemzar, and Taxotere® (docetaxel) produced a 47% response rate (9% complete response rate) in 32 patients with liver metastases, which may represent an improvement over monotherapy. GTX had been rapidly adopted and a number of phase II studies have been reported, including and especially from Dr. Fine’s group but not recommended by guidelines at this point. For example, it is not mentioned by NCCN. The phase II studies have so far been reported in abstract form and not peer-reviewed except for the one by Katopodis. Partial response was observed in three (9.7%) patients, stable disease in seven (22.6%) (disease control rate: 32.3%, 95% CI: 15.80–48.71%) and disease progression in 21 (67.6%). The median progression-free survival (PFS) was 2.4 months (95% CI: 1.6–3.13) and the median overall survival (OS) was 6.3 months (95% CI: 3.38–9.23); the estimated 1-year survival rate was 14.7%. Grade III/IV neutropenia occurred in 10 (32.2%) patients and febrile neutropenia in one patient. Other severe non-hematologic toxicities were mild and manageable. After 2 chemotherapy cycles, pain control occurred in 20% of patients and stabilization of body weight in 40%.
Katopodis, Ourania (2010) Second-line chemotherapy with Capecitabine (Xeloda) and Docetaxel (Taxotere) in previously treated, unresectable adenocarcinoma of pancreas: the final results of a phase II trial. Cancer Chemotherapy and Pharmacology

Lutz MP, Ducreux M, Wagener T, et al, Docetaxel/gemcitabine or docetaxel/cisplatin in advanced pancreatic carcinoma: a randomized phase II study of the EORTC-GI group. Proceedings of the American Society of Clinical Oncology 2002;21:125a, abstract 498

Scheithauer W, Schüll B, Ulrich-Pur H, et al, Gemcitabine alone or in combination with capecitabine in patients with advanced pancreatic adenocarcinoma. Proceedings of the American Society of Clinical Oncology;21:126a, abstract number 500

Schneider BP, Ganjoo KN, Seitz DE, et al, Phase II study of gemcitabine and docetaxel in combination for advanced pancreatic cancer – a Hoosier Oncology Group study. Proceedings of the American Society of Clinical Oncology 2002; 21:137a, abstract number 546

Schmidt C, Fahlke J, Kettner E, et al, Phase II multicenter study of gemcitabine and docetaxel in patients with inoperable or metastatic pancreatic cancer. Proceedings of the American Society of Clinical Oncology 2002;21:145a, abstract number 5779.

Fine RL, Fogelman DR, Sherman W, et al. The GTX regimen: A biochemically synergistic combination for advanced pancreatic cancer (PC). Proceedings from the 39th Annual Meeting of the American Society of Clinical Oncology. Chicago IL. 2003; Abstract #112 Moore M, Goldstein D, Hamm J, et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a Phase III trial of the National Cancer Institute of Canada Clinical Trials Group. Journal of Clinical Oncology [early online publication]. April 23, 2007.

Fine RL, Fogelman DR, Schreibman SM, Desai M, Sherman W, Strauss J, Guba S, Andrade R, Chabot J. The gemcitabine, docetaxel, and capecitabine (GTX) regimen for metastatic pancreatic cancer: a retrospective analysis.Cancer Chemother Pharmacol. 2008 Jan;61(1):167-75

Fine RL, Fogelman DR, Schreibman SM, Desai M, Sherman W, Strauss J, Guba S, Andrade R, Chabot J. The gemcitabine, docetaxel, and capecitabine (GTX) regimen for metastatic pancreatic cancer: a retrospective analysis.Cancer Chemother Pharmacol. 2008 Jan;61(1):167-75

Fine RL, Fogelman DR, Schreibman SM, Desai M, Sherman W, Strauss J, Guba S, Andrade R, Chabot J. The gemcitabine, docetaxel, and capecitabine (GTX) regimen for metastatic pancreatic cancer: a retrospective analysis. Cancer Chemother Pharmacol. 2008 Jan;61(1):167-75. Epub 2007

R. L. Fine, G. Moorer, W. Sherman, K. Chu, M. Maurer, J. Chabot, I. Postolov, J. Prowda, S. Schreibman, J. Levitz. Phase II trial of GTX chemotherapy in metastatic pancreatic cancer. 2009 ASCO Annual Meeting abstract 4623.

De Jesus-Acosta A, Oliver GR, Blackford A, Kinsman K, Flores EI, Wilfong LS, Zheng L, Donehower RC, Cosgrove D, Laheru D, Le DT, Chung K, Diaz LA Jr. A multicenter analysis of GTX chemotherapy in patients with locally advanced and metastatic pancreatic adenocarcinoma. Cancer Chemother Pharmacol. 2012 Feb;69(2):415-24. Epub 2011 Jul 29. link to original article contains verified protocol–with error as noted above PubMed

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