Dr Chues Article

We are working to publish Dr. Chue's article while he is taking his leave of absence. For beginners we thought we would post it on the blog and also on a website his other patients have created to share cancer information with other patients. I am still researching where the article has already been submitted and working on reformatting it for specific publications. Please feel free to share the information with anyone who might find it useful or be open to publication



There Is Still Hope: A Patient With Metastatic Pancreatic Carcinoma Four Years After Diagnosis

To the Editor:
The article by Kulke et al.l on second-line therapy with capecitabine and erlotinib as well as the letter to the editor by Boeck and Heinemann2 can serve to be an encouragement to those with the devastating disease of advanced stage pancreatic cancer, where median survival for metastatic disease is on the order of three to six months. Here we would like to report a case to give further hope to those suffering from this disease, and hope and encouragement to those physicians who treat such patients. Patient A.B. is a 38-year-old gentleman who presented with abdominal discomfort and complaints of food not going down. A CT scan of the abdomen on 8/26/04 showed a 9 x 8 cm soft tissue mass at the lesser sac and compressing the gastric body and contiguous with the pancreatic body, with a lesion in the left and right lobe of the liver consistent with metastatic disease. The patient underwent an exploratory laparotomy with biopsy of the pancreatic mass, cholecystectomy, and a Roux¬en-Y gastrojejunostomy as a palliative bypass. The pathology showed an adenocarcinoma, metastatic of unknown primary, most likely from a pancreatic carcinoma. The patient was treated with gemcitabine chemotherapy and capecitabine from 10/04 to 11/04, with significant side effects and evidence of disease progression. The patient was then switched to gemcitabine and docetaxel on 12/12/04. A CT scan on 1/10/05 showed further disease progression. Hospice was suggested. The patient then came to our clinic on 1/28/05, greatly debilitated, in a wheelchair with an ECOG score of 4, where he was told that there was no standard treatment after failing a gemcitabine-based regimen. However, he was offered a combination chemotherapy with weekly paclitaxel (60 mg/m2)/oxaliplatin (50 mg/m2)/leucovorin (40 mg)/5-FU (425 mg/m2)(POLF), which he started on 1/31/05. He required transportation by paramedics on a stretcher to go to the clinic for his treatment and back to his nursing home but he continued to insist on being treated despite the grim prognosis. The patient received four weeks of the POLF regimen before his chemotherapy had to be held because of low blood counts, at which time he received a dose of cetuximab, in the hope that this would also contribute to control of his disease. (At this point, it was felt that he would either succumb to his disease quickly, or would be a miracle surviving his disease, and therefore out of desperation it would be reasonable to try any scientifically based treatment.) He continued on the POLF chemotherapy with intermittent cetuximab with a CT scan on 4/26/05 showing a decrease in the patient's tumor in the liver, going from 10 cm to 5 em, and was continued on the chemotherapy with further decrease in the size of his lesion in the liver and continued decrease in the size of the lesion in the pancreas. He also underwent physical therapy, and continued to improve clinically. He went from being transported in a stretcher for the first four months of treatment which also included two hospitalizations, to being transported in a wheelchair, followed by a walker and a cane, and then simply walking by himself. He was continued for 52 weeks of treatment with the chemotherapy and intermittent cetuximab, and his case was presented to the Gastrointestinal Tumor Board at Swedish Hospital in Seattle on 3/28/06, where his pathology and scans were reviewed. Because of his unusually long survival, there was skepticism about his diagnosis of metastatic pancreatic adenocarcinoma but this was confirmed. The patient was originally considered for resection of the remaining lesion in the liver. However, after much deliberation it was felt that the patient was at too high a risk for significant morbidity and mortality given his previous surgery. He was then switched to paclitaxel/CPT¬ll/oxaliplatin given on a weekly basis from 5/9/06 with intermittent cetuximab until 8/28/06, and subsequently was treated with erlotinib and low dose interferon, paclitaxel and gemcitabine, and then again with paclitaxel/oxaliplatin/leucovorin/5-FU (POLF) from 10/15/07 to 2/4/08. His PET/CT scan on 2/5/08 showed only a small lesion in the pancreas and a 1.8 cm lesion in the central part of the liver but without evidence of hypermetabolic activity. However, a more recent PET/CT scan on 8/5/08 showed two hypermetabolic lesions in the tail of the pancreas measuring 2.8 x 1.3 cm and 1.0 x 1.0 cm.. The patient's case was represented to the Gastrointestinal Tumor Board at Swedish Hospital on 8/14/08, where again his pathology was reviewed by another pathologist, who again confirmed the diagnosis of adenocarcinoma of the pancreas but with a few cells staining positive for a neuroendocrine tumor. The recommendation of the Tumor Board was to rebiopsy the lesion to confirm the diagnosis of a metastatic pancreatic adenocarcinoma. The patient therefore underwent endoscopic ultrasound with a trans gastric biopsy of one of the lesions at the tail of the pancreas.
The pathology again revealed an adenocarcinoma with minimal staining for synaptophysin, confirming a diagnosis of a pancreatic adenocarcinoma and excluding a predominantly neuroendocrine differentiated neoplasm. The specimen was also sent for K-ras mutation analysis and was found to have an unmutated K-ras. The patient has restarted further treatment with paclitaxel/cisplatin/CPT -11 and cetuximab. The patient has done extremely well overall, now with an ECOG score of 0, has returned to work, and is over four years out from his diagnosis. He recently completed the Seattle to Portland (STP) bicycle marathon, a distance of 175 miles.
The rationale behind the treatment with a weekly "metronomic" dosing of POLF is that, although there is no standard chemotherapy beyond first-line chemotherapy with a gemcitabine-based regimen, both oxaliplatin and leucovorin/5-FU have shown activity in this disease3,4. A recently reported Phase III trial also supports the use of these agents5. A weekly dosing of pac lit axel may also have some activity6. "Metronomic dosing" of chemotherapy can result in fewer side effects, leading to better tolerability? In addition, this dosing of chemotherapy may have antiangiogenic properties due to its effects on endothelial cells8,9, especially with the drug paclitaxel10,11,12. This may result in better efficacy than "traditional" chemotherapy. Recent results of a weekly "metronomic" dose of paclitaxel have shown this to be more effective than the previous standard doses of this agent given every three weeks in the neoadjuvant13, adjuvant14 and metastatic 15 setting in breast cancer.

Even more recently, there has been shown to be the same benefit ovanan cancer . Improved efficacy of the weekly dosing of-compared to the previous standard doses, appeared to be due to the more steady dosing of treatrnent, the increased dose density, dose intensity and antiangiogenic properties of the metronomic dosing of this agent12. Studies with the antiangiogenic agent bevacizumab indicate that antiangiogenic agents may lower tumor interstitial pressure, which may increase chemotherapy delivery to the tumor bed and thus improve efficac/?,18. Weekly paclitaxel may therefore allow for increased efficacy ofthe other chemotherapy agents such as the oxaliplatin and 5-FU, by allowing for the agents to better reach the tumor and yet cause fewer side effects systemically since lower doses of chemotherapy are used. Some data with this POLF regimen for metastatic pancreatic adenocarcinoma have previously been reportedI9,20,21. A Phase II clinical trial with the POLF regimen is currently underway (clinicaltrials.gov, identifier # NCT00323583). We encourage participation in this clinical trial and would be happy to have anyone consider a Phase III clinical trial using this regimen or this concept.
Of interest is that the patient's pancreatic adenocarcinoma showed no K-ras mutation. Recent work in metastatic colon cancer indicates that colon cancers which have K-ras mutations have a poorer prognosis, and do not respond to cetuximab22,23. A recent trial looking at the addition of cetuximab to gemcitabine showed no survival benefit of cetuximab in the treatment of metastatic pancreatic carcinoma24. However, 90-95 percent of pancreatic adenocarcinomas have a mutated K_rai5,26,27, which may have resulted in these negative findings. It is therefore possible that cetuximab may have efficacy in the remaining 5-10 percent of pancreatic carcinomas that have wild¬type K-ras.
The patient has obviously done well and we hope that he will continue to do well over time. It is hoped that we will be able to make substantial progress in this devastating disease of pancreatic carcinoma with new innovative therapies, and with the help of such unrelenting patients as ours.
REFERENCES:
1. Kulke MH, Blaszkowsky LS, Ryan DR, et al: Capecitabine plus erlotinib in gemcitabine-refractory advanced pancreatic cancer. J CUn OncoI25:4787-4792, 2007.
Continued
There Is Still Hope: A Patient With Metastatic Pancreatic Carcinoma Four Years After Diagnosis
2. Boeck S, Heinemann V: Second-Line Therapy in Gemcitabine-Pretreated Patients With Advanced Pancreatic Cancer, J CUn OncoI26:1178-1179, 2008.
3. DeVita V, Hellman S, Rosenberg S: Cancer: Principles & Practice of Oncology (6th ed). Cancers of the Gastrointestinal Tract, Section 4: Cancer of the Pancreas, pp. 1149-1150.
4. Louvet C, et al. GERCOR; Gemcitabine In Combination With Oxaliplatin Compared With Gemcitabine Alone in Locally Advanced or Metastatic Pancreatic Cancer: Results of a GERCOR and GIS CAD Phase III Trial. J CUn Oncol. 2005; May 20;23(15):3509-16.
5. Pelzer U, Kubica K, Stieler J, et al: A Randomized Trial in Patients with Gemcitabine Refractory Pancreatic Cancer. Final Results of the CONKO 003 Study. J Clin Onco12008; 26(suppl): 215S (abstract 4508).
6. Oettle H, Arnold D, Esser M, et al: Paclitaxel as Weekly Second-Line Therapy in Patients with Advanced Pancreatic Carcinoma. Anticancer Drugs 2000 Sep; 11(8): 635-8.
7. Carmen Philips: "A New "Target" for Chemotherapy?" The National Cancer Institute, June 27, 2006, volume 3, #26.
8. Bertolini F, et al: "Maximum Tolerable Dose and Low Dose Metronomic Chemotherapy Have Opposite Effects on the Mobilization and Viability of Circulating Endothelial Progenitor Cells." Cancer Research, volume 63, August 2003, pp. 4342-4346.
9. Kerbel RS, Kamen B: "The Antiangiogenic Basis of Metronomic Chemotherapy." Nat Rev Cancer 4 (6):423-436,2004.
10. Lau D, et al: Is Inhibition of Cancer Angiogenesis and Growth by Paclitaxel Schedule-Dependent? Anti¬Cancer Drugs 2004 October; 15(9):871-5.
11. Green MC, Buzdar A, et al: Weekly Paclitaxel Improves Pathological Complete Remission in Operable Breast Cancer When Compared with Paclitaxel Once Every Three Weeks. J Clin Oncol, volume 23, #25, September 1,2005, pp. 5983.
12. Seidman A: Will Weekly Work?, Seems to be So ... ", J Clin Oncol, volume 23, #25 (September 1) 2005, pp. 5873-5874.
13. Green M, et al: "Weekly Paclitaxel Improves Pathological Complete Remission in Operable Breast Cancer When Compared with Paclitaxel Once Every Three Weeks", Journal of Clinical Oncology, volume 23, #25, September 1, 2005, pp. 5983-5992.
14. Sparano, J.A. et a1., "Weekly Paclitaxel in the Adjuvant Treatment of Breast Cancer", New England Journal of Medicine, 358:16, April 17, 2008, pp. 1663-1671.
15. Seidman A., Berry D., Cirrincione C., et al: Randomized Phase III Trial of Weekly Compared with Every Three Weeks Paclitaxel for Metastatic Breast Cancer with Trastuzumab for all HER-2 Overexpressors and Random Assignment to Trastuzumab or Not in HER-2 Nonoverexpressors: Final Results of Cancer and Leukemia Group B Protocol 9840. Journal of Clinical Oncology 2008; 26 (10): pp. 1642-1649.
There Is Still Hope: A Patient With Metastatic Pancreatic Carcinoma Four Years After Diagnosis
16. Isonishi S, et al: Randomized Phase III Trial of Conventional Paclitaxel and Carboplatin (c-TC) Versus Dose Dense Weekly Paclitaxel and Carboplatin (dd-TC) in Women with Advanced Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer: Japanese Gynecologic Oncology. J Clin Oncol26: 2008 (May 20 suppl; abstr 5506).
17. Willett CG, et al: Direct Evidence that the VEGF-Specific Antibody Bevacizumab Has Anti-Vascular Effects in Human Rectal Cancer. Nat Med, volume 10, #2, February 2004: pp. 145-147.
18. Jain, R.K., "Taming Vessels to Treat Cancer", Scientific American, January 2008, pp. 56-63.
19. Interim Results of a Weekly, Metronomic Dosing ofPac1itaxel/Oxaliplatin/Leucovorin/5-FU (POLF) in the Treatment of Metastatic Pancreatic Cancer (PC), Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part 1. Vol 25, No. 18S (June 20 Supplement), 2007: Abstract No. 15175.
20. Exciting Results With Weekly "Metronomic Dosing" ofPaclitaxel, Oxaliplatin, Leucovorin, and 5¬Fluorouracil (POLF) in the Treatment of Metastatic Pancreatic Cancer, Ben M. Chue, M.D., PGCR 2007 (Abstract 207),2007 Gastrointestinal Oncology Conference, September 27-29,2007, International Society of Gastrointestinal Oncology.
21. Chue, B., Proof of Concept: Weekly Metronomic Dosing of PaclitaxellGemcitabine (PaG) Followed by Paclitaxel/Oxaliplatin/Leucovorin/5-FU (POLF) for Advanced Stage Pancreatic Adenocarcinoma (PC). Journal of Clinical Oncology 2008 ASCO Annual Meeting Proceedings, Part 1, Volume 26, #15S (May 20 supplement) 2008; abstract 15638.
22. Khambata-Ford S, Garrett CR, Meropol NJ, et al: Expression of Epiregulin and Amphiregulin and K-ras Mutation Status Predict Disease Control in Metastatic Colorectal Cancer Patients Treated with Cetuximab. J Clin Onco12007; 25: pp. 3230-7.
23. Lievre A, Bachet JB, Boige V, et al: K-ras Mutations as an Independent Prognostic Factor in Patients with Advanced Colorectal Cancer Treated with Cetuximab. J Clin Onco12008; 26: pp. 374-379.
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LBA4505 (SWOG S0205).
25. Kahn S, Yamamoto F, Almoguera C, et al: The c-K-ras Gene and Human Cancer (review), Anticancer Res. 1987 Jul-Aug;7(4A): pp. 639-652.
26. Smit VT, Boot AJ, Smits AM, et al: K-ras Codon 12 Mutations Occur Very Frequently in Pancreatic Adenocarcinomas, Nucleic Acids Res. 1988; Vol. 16: pp. 7773-7782.
27. Bos JL: Ras Oncogenes in Human Cancer: A review. Cancer Res. 1989; volume 49: pp. 4682-4689.
Erratum in: Cancer Res. 1990 Feb 15;50(4):1352.
Ben M. Chue, M.D./jeh
Seattle Cancer Treatment and Wellness Center
University of Washington School of Medicine, Seattle, Washington
Cc: Joseph P. Rank, M.D.
Udo P. Schmiedl, M.D., Ph.D.