HepaticArterialTherapywithDrug-ElutingBeadsinthe ...loss of arterial ﬂow to the treated segment or...

Hindawi Publishing CorporationJournal of OncologyVolume 2012, Article ID 292131, 6 pagesdoi:10.1155/2012/292131

Research Article

Hepatic Arterial Therapy with Drug-Eluting Beads in theManagement of Metastatic Bronchogenic Carcinoma to the Liver:A Multi-Institutional Registry

Heba Fouad,1 Tiffany Metzger,2 Cliff Tatum,3 Ken Robbins,4 and Robert C. G. Martin2

1 Radiology Department, Kasr Al-Aini Hospital, Faculty of Medicine, Cairo University, Cairo 11950, Egypt2 Division of Surgical Oncology, Department of Surgery, University of Louisville School of Medicine, Louisville, KY 40202, USA3 Norton Radiology, Louisville, KY 40202, USA4 Baptist Health, Little Rock, AR, USA

Correspondence should be addressed to Robert C. G. Martin, [email protected]

Received 28 September 2011; Revised 14 December 2011; Accepted 15 December 2011

Academic Editor: Bruno Sangro

Copyright © 2012 Heba Fouad et al. This is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Introduction. There has been limited information reported on the use of hepatic arterial therapy in liver dominant hepaticmetastases arising from lung cancer. The aim of this study was to evaluate the safety and efficacy of hepatic arterial therapy inthe treatment of liver dominant hepatic metastases arising from lung cancer. Methods. Thirteen patients underwent a total of 30treatment sessions with Drug-Eluting Beads. Eight of the thirteen received only doxorubicin DEB (17 of the total treatments), andfour patients received Irinotecan DEB (7 of the total treatments). Results. The planned preprocedural dosage was a median of 75 mg(range 19–200), with total hepatic dose exposure being a median of 150 mg (range 0–458), with a technical success rate of 97%in all 29 treatments. There were 4 adverse events related to treatment, but no evidence of hepatic insufficiency. Overall 6-monthand 12-month response rates were 50%. After a median followup of 24 months, the median overall survival in this cohort was 14months (range 7–48 months). Conclusion. Drug-eluting beads loaded with doxorubicin (DEBDOX) or irinotecan (DEBIRI) canbe safely and effectively used in treatment of patients with liver predominant metastatic disease from lung cancer.

1. Introduction

Lung cancer is the leading cause of cancer-related mortalitynot only in the United States but also around the world [1].The four major histological types of lung cancer are squa-mous cell carcinoma (30% to 40% of lung cancers), adeno-carcinoma (25% to 30%), nonsmall cell lung carcinoma (lessthan 10%), and small cell lung carcinoma (15% to 20%).These four types are subdivided into numerous subtypes[2]. Approximately 85% of patients present with squamousor adenocarcinoma defined as nonsmall cell lung cancer(NSCLC) and treatment may consist of surgery, radiationtherapy, chemotherapy, or a combination of these modalitiesdepending on tumor stage and the goals of therapy [3]. Dis-tant metastases speak against treatment with curative intent.The most frequent locations of distant metastases are brain,liver, skeleton, lungs, and adrenals [4].

Since at the time of diagnosis 50% of NSCLC patientspresent with stage IV disease, only palliative treatment canbe offered [5]. The success of chemotherapy depends on ap-propriate selection of the patients. General condition, age,and comorbidities are decisive factors [6]. The combinationof platinum with a modern combination partner, which isthe optimal chemotherapy, leads to survival times of around10 months. The chemotherapy not only lengthens life, but inmost patients also improves symptoms [7].

Transcatheter arterial embolization (TAE) and che-moembolization (TACE) are increasingly used as regionaltherapeutic modalities for the treatment of unresectable he-patic malignancies [8]. In general, TAE and TACE havebeen used when surgical resection and/or systemic therapyhave failed to produce an adequate response or whenconventional therapy has been known to be ineffective[9]. There has been almost no information reported on

2 Journal of Oncology

the use of TACE in hepatic metastases arising from lungcancer.

Drug-eluting bead TACE is a drug delivery system thatcombines the local embolization of vasculature with therelease of chemotherapy into adjacent tissue. Its administra-tion is similar to that of conventional TACE, and it representsa minimally invasive procedure performed by interventionalradiologists [10, 11]. The beads occlude vasculature, causingembolization, and the chemotherapy is delivered locally [12].Early phase 1 and nonrandomized phase 2 studies haveconfirmed the ability of this device to deliver a local, con-trolled, and sustained dose of doxorubicin to the tumors,with minimal systemic doxorubicin exposure [13]. A recentlycompleted randomized Phase 2 study demonstrated thatthese drug-eluting doxorubicin beads had superior responserates when compared to conventional TACE in advancedHCC and significantly less overall adverse events, includingdoxorubicin-related side effects [14].

In this study, the aim was to review our experiencewith drug eluting bead therapy in the multidisciplinarymanagement of patients with liver dominant metastatic lungcancer to the liver.

2. Materials and Methods

An IRB-approved prospective multi-institutional treatmentregistry was reviewed to find patients with lung cancer meta-static to the liver, from which 805 patients undergoing 1358treatments (TACE) for primary or secondary cancers in theliver were evaluated from January 2007 to Jan 2011. Theregistry was designed to satisfy the strict criteria for criticalappraising of the quality of a registry study with (1) a well-described patient population, (2) hypothesis generating andanswering questions, (3) high quality data, with good qualitycontrol, (4) independent assessment of outcomes, (5) goodclinically relevant followup with minimal loss of patients,and (6) comparable patient evaluation across all institutionalparticipating [15]. Thirteen patients presenting with liverdominant metastatic lung cancer to the liver were treatedwith doxorubicin or irinotecan drug-eluting beads.

The inclusion criteria were the following patients wereincluded for therapy if they were 18 years of age, of any raceor sex, histologic and radiologic (defined as a mass lesionin the liver greater than 1 cm in size) proof of metastaticlung cancer to the liver by percutaneous biopsy, whowere able to give informed consent and were eligible fortreatment. Patients must have had an ECOG performancestatus score of less than equal to 2 with a life expectancyof greater than equal to 3 months, nonpregnant with anacceptable contraceptive (defined by the treating physi-cian) in pre-menopausal women. Exclusion to therapywas contraindication to angiographic and selective visceralcatheterization, significant extrahepatic disease, representingan eminent life-threatening outcome, greater than 75% ofhepatic parenchymal involvement, severe liver dysfunction(defined as presence of ascites or bilirubin >2.5 mg/dL),pregnancy, and severe cardiac comorbidities. Only patientswith liver dominant (defined as greater than 50% of theoverall total disease burden as measured on baseline pre-DEB

treating cross-sectional scanning of the Chest-Abdomen-Pelvis.) were considered for treatment.

Patients were followed for any treatment-related adverseexperiences for 30 days after each treatment and monitoredfor survival for two years. Follow-up assessments includeda triphase CT scan of the liver within at least one-to-twomonths from the treatment completion and then everythree months after for the first year and every six monthsafter during the second year, with the evaluation of theenhancement pattern of the target lesion and tumor responserates measured according to modified RECIST criteria [16].

3. Image-Guided Infusion Technique

Defining the amount of liver disease was integral to definingboth the number of treatments and the type of catheterposition and therapy that would be performed. For finitenumbers of lesions defined as less than four lesions, atreatment cycle was planned for a minimum of two dosingschedules of at least 100 mg of drug-eluting beads withdoxorubicin (DEBDOX) to 150 mg of DEBDOX loaded intwo bead vials or 100 mg of drug eluting beads Irinotecan(DEBIRI). Bead sizes of either 100 to 300 microns, 300 to 500microns, or 500 to 700 microns could be utilized (Figure 1).Treatment intervals were planned for every four to eightweeks. The interval can be extended if causing toxicity to theliver. Based on the extent of liver involvement, two-to-threetreatment cycles are planned. A repeat scan is done everythree months from the initial first treatment cycle to evaluateresponse. A treatment cycle is defined as treatment of all liverdisease. A treatment is hepatic arterial therapy to one-singlelobe, which could also be a treatment cycle if a patient hasonly unilobar disease. Finite disease was defined as less than10 total lesions in the liver. The degree of stasis was defined ascomplete-total loss of arterial flow to the treated segment orlobe, near-complete loss of intratumoral vascularity and nearloss of arterial flow to the treated segment or lobe, partial-loss of intratumoral vascularity, and no stasis.

For diffuse disease (bilobar with >25% liver involvement)a plan of a minimum of four-dosing schedule again of 100to 150 mg (depending on the extent of tumor burden andthe extent of hepatic parenchyma reserve) are loaded intotwo bead vials of the similar size as above. The plan includesat least two treatments per lobe with every three-to-fourweek dosing schedule. The toxicity effect is followed, and thetreatment interval is determined accordingly. Repeat CT scanthree months from the first dose to evaluate tumor response.For example, if patients present with bilobar disease, theywould receive first bead treatment to right lobe, then threeweeks after second bead treatment to left lobe, then threeweeks after third bead treatment to right lobe, and then againthree weeks later to left lobe. The decision on bead size wasup to the treating discretion based on their initial experiencewith particle size and the degree of stasis that was planned tobe delivered at the end of the treatment [17–19]. The reasonfor lobar infusion is based on the desire for drug deliveryand less on inducing stasis in patients with multifocallobar disease that is not amenable to superselective delivery[20]. Additional embolic material is not usually followed

Journal of Oncology 3

Patient with liver-predominant metastases from lung cancer

Yes No

Unilobar disease Bilobar disease

Selective and then lobar DEBDOX Lobar DEBDOX in most affected lobe

Contralateral lobe DEBDOX

DEBDOX first lobe

DEBDOX contralateral lobe

Extrahepatic progression?

No Yes

Repeat treatment whenever residual tumour Other treatment options Imaging f-u

DEBDOX algorithm-hepatic lung metastases∗

150 mg doxorubicin in two 100–300 µm vial150 mg doxorubicin in two 100–300 µm vial

150 mg doxorubicin in two 100–300 µm vial

150 mg doxorubicin in two 100–300 µm vial

Selective and then lobar DEBDOX 150 mg doxorubicin in two 100–300 µm vial 150 mg doxorubicin in two 100–300 µm vial

4 wks

2 wks

2 wks

2 wks

3-month tumour response, thenevery 3-4 months for 1 year, then every 6 months for second year

Tumour response


Table 1: Clinical characteristics in 13 lung metastatic patientstreated with LC beads.

Characteristics N = 13Age (years) (median, range) 68 (43–72)

Gender

Male 7 (54%)

Female 6 (46%)

Past medical history

Cardiac 3 (23%)

Vascular 2 (15%)

Pulmonary 7 (54%)

Diabetes 3 (23%)

Insulin 1 (33%)

NonInsulin 2 (67%)

Alcohol 2 (15%)

Tobacco 9 (69%)

Median packs 60 (40–300)

Hypertension 8 (62%)

Prior cholecystectomy 4 (31%)

Karnofsky performance scale 90% (70–100)

Extent of liver lesions

Distinct number 11 (85%)

Numerous 2 (15%)

Liver involvement

3 458

Bead Size Utilized

100–300 24

300–500 5

500–700 1

Complications 14%

Extrahepatic infusion 0

Hematologic changes

WBC −1.9 (−9994.4–9991.8)HGB 0.1 (−9989.1–9987.5)Bilirubin 0 (−9998.7–9998.8)

Table 3: Bead infusion-related morbidity.

Side effect (N = 4) All grades Severe grade∗Confusion 1 —

Dehydration — 1

Angina — 1

Hypotension 1 —∗

Defined as Grade 3 or higher.

7courses (24%), near stasis in 6 courses (21%), and completestasis in 11 courses (38%).

4.2. Patient Tolerance, Morbidity, and Mortality. During the29 treatments, four adverse events occurred (14%), with onepatient developing dehydration and confusion, grades 3 and2 adverse events, respectively, both of which possibly relatedto systemic chemotherapy effect. One patient developedangina, a grade 3 adverse event that revolved. Another patientdeveloped hypotension, a grade 2 adverse event that quicklyresolved (Table 3).

4.3. Follow-Up and Tumor Response. Response rates for allpatients were recorded at 3, 6, 9, 12, and 18 months.Response rate was evaluated using modified RECIST. At threemonths, overall response was 54% with disease control of70%, with one patient (8%) having a complete response, sixpatients (46%) having a partial response, stable disease intwo patients (15%), and progressive disease in four patients(31%). Location of progression was outside the liver inthe lung and bone in separate patients. Two patients diedof disease, and one died of other cause at three months.Progression of disease was seen in two patients at 6 months,and three died of disease at 6 months. Progression of diseasewas seen in the liver in 1 patient with the remaining patients

Journal of Oncology 5

Table 4: Response rates∗ for all 13 patients evaluated.

Response 3 mon N = 13 6 mon N = 10 9 mon N = 8 12 mon N = 6 18 mon N = 6Complete response 1 1 1 2 1

Partial response 6 1 1 1 1

Stable disease 2 3 3 3 3

Progression of disease 4 2 1 0 0

Not Reached time point

DOD 2 3 2 0 1

DOC 1 0 0 0 0

DOD: dead of disease; DOC: dead of complication.∗Response rates measured using modified RECIST criteria.

treated having progression to the bone, lymph nodes, orprimary tumor. At 9-month followup, the response rate was20% with disease control of 50% with 2 patients achievingoverall response (1 patient CR and 1 patient PD). At the finalfollow-up time of 18 months, response rate was 40% withone patient with CR, one patient with PR (Table 4). After amedian followup of 24 months, the median overall survivalin this cohort was 14 months (range 7–48 months).

5. Discussion

Liver metastasis from lung cancer is regarded as stage IVdisease where only palliative treatment can be offered. Chem-otherapy is beneficial for palliation in patients with locallyadvanced and metastatic disease [21]. There is no reporteddata concerning transarterial chemotherapy for liver metas-tasis originating from lung cancer.

Transarterial therapies take advantage of the dual bloodsupply of the liver. Approximately 80% of the blood sup-ply to hepatic metastases arrives via the hepatic artery,whereas three fourths of the blood supply to normal hepaticparenchyma are portal venous. Hence, cytotoxic agents thatare infused selectively into the hepatic artery preferentiallytarget tumor cells over normal hepatic tissue. Transarterialchemoembolization (TACE) is a catheter-based techniquethat combines both regional chemotherapy and emboliza-tion to increase the dwell time of cytotoxic agents and induceischemia in the tumor. The use of drug-eluting microspheresin a new variation of the TACE method is designed toimprove the precision of drug delivery [22]. In our studydrug-eluting beads (DC/LC beads) loaded with doxorubicinor irinotecan were used in treatment of liver metastasesfrom lung cancer. Beads are composed of biocompatiblepolymers such as polyvinyl alcohol (PVA) hydrogel that hasbeen sulphonated to enable the binding of chemotherapy[23]. The beads occlude vasculature, causing embolization,and the chemotherapy is delivered locally [12]. However,drawbacks of this method of treatment include hazards of theprocedure itself and those related to the drug-eluting beadssuch as nausea, vomiting, transient hypertension, pain, liverabscess, and up to mortality.

This treatment so far has been performed in 13 patients,eight of which died of disease progression and one out ofcomplication. The treatment was found to be safe, withoutany significant adverse events during the treatment phase

of the therapy. Systemic progression to lung, bone, andperitoneum was the most common sites where patientsfailed. The remaining is still in the study, and most ofthe target lesions are decreasing in size, showing significantimprovements on the prognosis of the patients, with norelated serious adverse events. These locations of progressiondemonstrate the need for combination therapy of bothsystemic therapy and local hepatic arterial therapy given thepropensity for even liver-dominant metastatic lung cancerto demonstrate significant progression outside the liver.This unpredictability of progression demonstrates that amonotherapy will have limited overall disease control.

The current literature for systemic chemotherapy to treatliver dominant hepatic metastasis to the liver is limited.The main reason for this is that this is a unique subset ofpatients that have not been evaluated or recorded in themedical oncology literature. There is a current unmet needof defining how many patients with stage IV lung cancer haveliver-dominant disease and thus could possibly derive benefitfrom local regional hepatic arterial therapy. One comparativestudy on radiation therapy by Eble et al. evaluated the role ofpalliative irradiation was in 55 patients with liver metastasesfrom colorectal (n = 35), breast (n = 10), and lung cancer(n = 10). A mean dose of 23.8 Gy was delivered, with dailyfractions of 1.5 (n = 30), 1.8 (n = 1), or 2 Gy (n = 16)[24]. Complete and near complete pain relief was obtainedin six (28.6%) and nine (42.9%) patients. Median survivalwas 36.5 days for patients with lung cancer, 70.5 and 73 daysfor patients with breast and colorectal cancer.

Thus in conclusion, this represents the first ever reportof hepatic arterial therapy in the management of liver-dominant metastatic lung cancer. We have demonstrated thatdrug-eluting beads loaded with Doxorubicin or Irinotecancan be safely and effectively used in treatment of patientswith liver-predominant metastatic disease from lung cancer.This should be considered as an alternative or in com-bination with systemic chemotherapy in selected patients,yielding promising tumor response.

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