Hepatic Ablation Therapies Hepatic Ablation Therapies Before Systemic TherapyBefore Systemic Therapy

Jordan D. Berlin, M.D.Ingram Professor of Cancer Research

Co-director, GI Oncology

Director, Phase I Research

Vanderbilt-Ingram Cancer Center

DisclosuresDisclosures

• Advisory Boards here and there in last year– Genentech/Roche– Karyopharm– Amgen – Astra Zeneca– BMS– Lilly/Imclone– Symphogen– Celgene– Vertex– Ipsen

• Current Research Support– Amgen, Lilly/Imclone,

Pfizer, Novartis, Abbvie, Immunomedics, Otsuka, Merrimack, Oncomed, Genentech/Roche, Taiho

Presumption by mePresumption by me

Liver dominant or liver only disease with no symptoms from extrahepatic

disease

First, a thank you to the organizersFirst, a thank you to the organizers

• Thanks for recognizing the importance of NE tumors

• Thanks also for finding the debate topic with absolutely no supporting data on either side– This is the most un-winnable and un-losable debate I

have gotten so far

What are the ablative options?What are the ablative options?

• Surgery• Radiofrequency ablation• Cryoablation• Chemoembolization• Bland Embolization• Radioembolization• Stereotactic radiation

– (usually comes with foreign names like cyberknife or gamma knife, terms that loosely translated mean, “we bought these really expensive machines so we’re gonna use ‘em, data or no data”)

Reasons to perform locoregional Reasons to perform locoregional treatment of liver metastasestreatment of liver metastases

• Improve OS (only for complete removal)• Symptom reduction/QOL• Because we can—please don’t use this one

SurgerySurgery

• Limited to patients with a limited number of metastases, or anatmoically resectable disease– Some people perform pluckitouttame removals of some

of the disease• I can’t give you data supporting this and I can’t recommend it

• Surgical resection should be limited to those with “curative intent” although morbidity and mortality are very low for these procedures now

• Data for surgery is retrospective only

SurgerySurgery

Author Reference Total N (N who had resection)

5yr OSResection vs not

10 year OS

Chen, et al J Amer Coll Surg 187: 88-92, 1998

38 (15) 73% vs 29%

Chamberlain, et al

J Amer Coll Surg 190: 432-5, 2000

85 (28) 82% vs

Sarmiento, et al

J Amer Coll Surg 197: 29-37, 2003

(170) 61% 35%

Mayo, et al Ann Surg Oncol 17: 3129-36, 2010

(339) 74% 51%

>90% with symptoms have improvementRecurrences at 5 years reported to be 67-76%

Radiofrequency AblationRadiofrequency Ablation

• One whole decent retrospective study– 89 patients, 39 were symptomatic– Median OS was 6 years

• Women lived 2x longer than men (125 vs 51 months) p, 0.03

– Of 39 symptomatic patients• 97% had symptom improvement or relief• Symptom benefits lasted median of 14 months

– Median DFS was 15 months– Majority add intrahepatic progression, but I could not

figure out if anybody remained disease free

Akyidiz, et al Surgery 148: 1288-93, 2010

EmbolizationEmbolization

• Several modalities, in many ways, but I will separate it into:– Trans-arterial chemoembolization

• Theoretically delivers 10-20 fold concentrations of drug to the tumor

• Traditionally favored in PNET

– Bland embolization• Favored in carcinoid (non-PNET)

EmbolizationEmbolization

• Despite traditions (PNET vs carcinoid), we have little data to tell us which is better– TACE provides symptom relief in 53-95% of patients– Bland embolization provides symptom relief in 65-93% of

patients– Caveat: most studies include both diseases and carcinoid is

more likely to be symptomatic hormonally

• One study looked at 100 patients treated with either of the two methods– 37% of TACE had PNET– 45% of bland had PNET

EmbolizationEmbolization

• TACE vs TAE– Symptom relief in 86% vs 83% for TACE vs bland– OS from diagnosis was 50.1 vs 39.1 months (p, NS) for

TACE vs bland– OS from 1st embolization was 25.5 vs 25.7 months– 5 year survival from 1st embolization was 19% vs 13%

– Not sure we have proven our belief systems but it is clear both modalities improve symptoms

RadioembolizationRadioembolization

• Blood supply is not blocked• Much more expensive Than embolization• Appears there are differences:

– Slower onset to effect for radioembo– Fewer immediate morbidities for radioembo– Not as clear about symptom relief

RadioembolizationRadioembolization

• Largest study was 148 patients– Median survival not reported, but curve looks like ~ 70

months• Caveat is that like most of the reports, there is unclear duration

of follow-up and most of the patients are censored (listed as censured) early

– Long-term toxicity is not reported in most of the studies– Efficacy is mostly reported with RECIST response

• 50-70%

So, what are the systemic agentsSo, what are the systemic agents

• PNET:– Chemo: cape, temozolamide, combination and the oft

maligned (and deservedly so) strepozocin and doxorubicin

– Everolimus – Sunitinib– Octreotide LAR

• Carcinoid– Octreotide LAR– Interferon

Why do hepatic therapies first?Why do hepatic therapies first?

• If surgery is an option, it looks like a small percentage, but a real one, remains disease-free at 5 years, so this is an obvious choice– Especially with carcinoid we don’t produce shrinkages

to make tumors more resectable

• If not, the number one reason would be symptom control– We can’t say we make them live longer than systemic

therapy alone if we can’t remove disease– However, survival may be better, but I can’t prove it.

Why do hepatic therapy first?Why do hepatic therapy first?

• In PNET, systemic therapies have side effects– They prolong PFS, but no data for OS– Not clear they improve symptoms

• In carcinoid, octreotide LAR has limited side effects– But once on octreotide we rarely stop this agent– It is costly and requires regular visits– Local therapy can provide relief, reduce patients’ health

care burdens (ie they don’t actually enjoy seeing us that much)

Other reasonsOther reasons

• Angiogenesis– Sunitinib in PNET and potentially bevacizumab in

carcinoid– After blocking blood supply or reduction of tumor

burden, evaluating these inhibitors to prevent re-growth/delay progression would be reasonable

• Everolimus– Similarly, can delay growth, but does that provide a

survival advantage

ConclusionsConclusions

• In a disease largely treated based on anecdote and retrospective series,– You can pretty much do what you please– However, you need to do what will affect the patient in a

positive way– Symptom relief appears to prolong survival in NE

tumors, so hepatic therapies which are short term and can reduce symptoms for prolonged periods are a nice way to treat them