reportClinical evidence for overcoming capecitabine resistance in a woman with breast cancer terminating in radiologically occult micronodular pseudo-cirrhosis with portal hypertension : a case report

Introduction: We report a case of stage IV breast cancer terminating in an unusual picture of radiologically occult micronodular pseudo-cirrhosis. Contrast-enhanced computed tomography showed no evidence of metastatic breast cancer within the liver. Unlike the few previously reported cases of intrasinusoidal spread of breast cancer, our patient was palliated with a transjugular intrahepatic portosystemic shunt along with salvage chemohormonal therapy. In addition, our patient demonstrated proof of the principle of the dependence of capecitabine (Xeloda) efficacy on dose scheduling as predicted by laboratory studies based on Gompertzian tumor growth and the Norton-Simon hypothesis. Case presentation: We report the case of a 52-year-old Caucasian woman who developed radiological signs of portal hypertension without radiological evidence of hepatic metastasis five years after being diagnosed with metastatic breast cancer. She was receiving chemotherapy for stage IV breast cancer initially thought to be metastatic only to the bones. During salvage therapy with high-dose estradiol (Estradiol valerate), vinorelbine (Navelbine) and bevacizumab (Avastin), she suddenly developed signs of portal hypertension confirmed on computed tomography and by portal and systemic venous pressure measurements. Drug toxicity due to bevacizumab (Avastin) was initially and incorrectly entertained as a cause. The patient underwent palliative transjugular intrahepatic portosystemic shunt and transhepatic venous liver biopsy, which revealed the presence of rapidly progressive and uncontrolled metastatic breast cancer. The new discovery of radiologically occult intrasinusodal hepatic metastases with secondary micronodular cirrhosis was found to be the cause of her sudden onset portal hypertension. The patient's resistance to capecitabine (Xeloda) was reversed by changing the schedule of medication to biweekly 7/7 (7 days ingesting drug alternating with 7 days off drug) from the 14/7 (14 days ingesting drug alternating with a 7 day rest period) day schedule approved by the US Food and Drug Administration. Conclusion: This case report demonstrates an unusual presentation of radiographically occult hepatic metastasis from breast cancer palliated with transjugular intrahepatic portosystemic shunt. All patients with advanced breast cancer developing unexpected portal hypertension should be considered candidates for liver biopsy despite normal computed tomography of the liver imaging results. This is the first report of a reversal of clinical resistance to capecitabine (Xeloda) by changing from the schedule of 14/7 day to a biweekly 7/7 day schedule. This suggests that a biweekly schedule may be best for some patients. BioMed Central © 2010 Fournier et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Fournier et al. Journal of Medical Case Reports 2010, 4:112 http://www.jmedicalcasereports. com/content/4/1/112 Page 2 of 6 Introduction We describe a patient who underwent extensive treatment for stage IV breast cancer that had metastasized to her bones and liver. She had unique and medically important clinical features of radiologically occult liver metastases and drug resistance to schedule-dependent chemotherapy. Contrast-enhanced computed tomography (CT) did not demonstrate metastatic liver disease, although it did show advanced portal hypertension. Three similar cases and a review of English literature by Allison et al. confirmed the rarity of such a presentation (21 reported cases) [1]. Most of the patients previously reported were not treated with transjugular intrahepatic portosystemic shunt (TIPS). Our patient underwent a TIPS procedure, which rendered a modest relief of her symptoms. Meanwhile, secondary hepatic encephalopathy did not occur. It was apparent that our patient's drug resistance to capecitabine (Xeloda) was reversed by changing drug scheduling. Such had been previously predicted by laboratory experiments, thus lending support to the validity of chemotherapy schedule modelling based on Gompertzian tumor cell kinetics and the NortonSimon hypothesis [2-5]. Case presentation A 52-year-old Caucasian woman was diagnosed at age 47 with Stage IIB, Grade II T2N3 Mx invasive ductal adenocarcinoma of the breast. She had 14 of 18 tumor positive nodes, wherein one had capsular penetration. Examination showed the following values for our patient: estrogen receptor = 69%, progesterone receptor = 27%, Ki67 = 10% and HER2/neu was not over expressed. She then underwent mastectomy. She was treated within one month with adjuvant chemotherapy. For five months our patient received dose-dense sequential hydroxydaunomycin (Doxorubicin), paclitaxel (Taxol) and cyclophosphamide (Cytoxan). She received four applications of each drug once every 14 days. After completing radiation therapy, she was started on exemestane (Aromasin) and leuprolide (Lupron) for the next nine months. On the eighth month, her CA 27 to 29 increased to 47 U/ml. Bone imaging confirmed osseous metastases. At that time she elected not to receive intravenous chemotherapy. Her relapse after two years was treated with metronomic low-dose oral cyclophosphamide (Cytoxan) and methotrexate (Trexall) plus tamoxifen (Soltamox). She showed no response to this medication. She subsequently began monthly fulvestrant (Faslodex) and weekly albumin-bound paclitaxel nanoparticles (Abraxane). After a 5-month response, which was then followed by resistance, these drugs were discontinued following a total of 17 albumin-bound paclitaxel nanoparticles infusions (Abraxane). She then complained of a new, diffuse and severe bone pain. A bone scan confirmed that diffuse bony metastases had progressed. This was associated with a rise in her CEA from 37.2 to 75.1 ng/ml, CA 15-3 from 88 to 128 U/ml and CA 27-29 from140 U/ml to 285 U/ml. From 16 October 2006 to 15 April 2007, she was treated with daily capecitabine (Xeloda) 1500 mg in the morning and 1000 mg before bedtime two weeks on and one week off as per the US Food and Drug Administration (FDA) approved 14/7 21-day cycle. This was her maximally tolerated dose. She had severe diarrhea limited by gastrointestinal toxicity when trying to increase the dose of her medicaiton by an additional 500 mg/day. She developed a 6-month tumor marker (CEA and CA 15-3) and clinical response with complete relief of disabling diffuse bone pain and tumor marker analysis as outlined in Figure 1. Subsequently, her tumor pain and markers increased and 2 mg diethylstilbestrol compounded (DES) was administered twice daily from 18 April 2007 to 17 June 2007. This treatment was judged to be ineffective. She was rechallenged with capecitabine (Xeloda) and the schedule was changed to the biweekly 7 days on, 7 days off regimen based on experiments by Dr. Larry Norton on the benefits of biweekly capecitabine (Xeloda) [5]. From 26 November 2007 to 03 June 2008, she took capecitabine (Xeloda) 2000 mg orally twice daily one week on and then followed by one week off. This dosing schedule change was associated with a new durable clinical and laboratory remission that lasted approximately six months. Her CA 27-29 decreased from 1025 U/ml to 325 U/ml, while her CA 15-3 decreased from 325 U/ml (<35 U/ml) to 42 U/ml and her CEA from and 410 ng/ml (<5 ng/ml)) to 13.8 ng/ml. A summary of her tumor marker response is presented in Figure 1. Our patient's clinical response was characterized by complete relief from diffuse bone pain which was similar to her first capecitabine (Xeloda) response. However, on 18 June 2008, due to the recurrence of her intense bone pain and increasing tumor markers (CEA from 13.8 to 220 ng/ml) she patient was withdrawn from capecitabine (Xeloda) and given a single dose of ixabepilone (Ixempra). She showed no response to this medicaiton. As a result, bevacizumab (Avastin) was added every 14 days from 19 June 2008 to 10 September 2008 with a total of five doses. On 14 August 2008, she began weekly vinorelbine (Navelbine). She was also started on weekly injections of 60 mg estradiol velestrate on 21 August 2008. During the month of October 2008, our patient complained of abdominal fullness and pressure discomfort of her upper abdomen. She had no history of hepatitis, cir* Correspondence: christa324@gmail.com 1 Glenn Tisman, M.D. Medical Corporation, Bailey Street, Whittier, California,