DEBATE: What is the Optimal Strategy for Liver Only Metastatic Colon Cancer?

Michael A. Choti, MDDepartment of Surgery

UT Southwestern Medical Center

Great Debates & Updates in GI MalignanciesMarch 28-29, 2014

Chemotherapy Followed By Surgical Resection

Disclosures

• Bayer Healthcare: consultant• Bristol Mayer Squibb: research, consultant

Vigano et al. Ann Surg Onc (Jan 2012)

Overall Survival Recurrence-Free Survival

Trends in Long-Term Outcome of Liver Resection for Metastatic Colorectal Cancer

(1985 -1994)

(1995 -2000)

(2001-2005)

LIVER METASTASES

SURVIVAL BENEFIT~ 60% OS AT 5 YEARS

15% DFS AT 10 YEARS

RESECTABLE~25%

NON RESECTABLE~75%

Integration of chemotherapy

“Neoadjuvant”

“Adjuvant”“Conversion”

Integrating Chemotherapy and Liver Surgery for Metastatic Colorectal Cancer

1. Initially resectable disease by standard approach

2. Initially surgical but requires extended approach

• staged resections • preoperative portal vein embolization • resection plus RFA

3. Initially unresectable but likely convertible with response

4. Initially unresectable and unlikely convertible

Categories of ResectabilityB

OR

DE

RLIN

E

LIVER METASTASES

SURVIVAL BENEFIT~ 60% OS AT 5 YEARS

15% DFS AT 10 YEARS

Downsizing

size

location

number

Liver Metastases in Colorectal Cancer: Outcomes

RESECTABLE~25%

NON RESECTABLE~75%

RESECTABLE10-20%

?

Improving Systemic Chemotherapy for Advanced CRC

1 Saltz LB. NEJM 20002 Tournigand C. J Clin Oncol 20043 Hoff, PM. GI ASCO, 20064 Diaz Rubio E. ASCO, 2005

Response % Median Surv (mo)

BSC 0 75FU/ LV1 21 13Irinotecan1 18 12IFL1 39 15FOLFOX2 or FOLFIRI2 54 – 56 20 - 22With bevacizumab3 ~70 >24

or cetuximab4

IFL = bolus 5FU, folinic acid, and irinotecanFOLFOX = infusion 5FU, folinic acid, and oxaliplatin FOLFIRI = infusion 5FU, folinic acid, and irinotecan

• Initially resectable?

• Initially unresectable but potentially convertible?

• Initially unresectable and unlikely convertible?

• Initially resectable?

• Initially unresectable but potentially convertible?

• Initially unresectable and unlikely convertible?

What is the Role of Preoperative Bevacizumab in the Unresectable But Potentially Convertible Patient?

Chun et al. JAMA (Dec 2009)

Morphologic but not RESCIST response

Chemotherapy Plus Biological Agents For Initially Unresectable Liver Metastases

1. Saltz, L.B., et alJournal of Clinical Oncology, 2008. 26(12): p. 2013-2019. 2. Hurwitz, H., et al., New England Journal of Medicine, 2004. 350(23): p. 2335-2342. 3. Giantonio, B.J., et al.,. Journal of Clinical Oncology, 2007. 25(12): p. 1539-1544. 4. Van Cutsem, E., et al . New England Journal of Medicine, 2009. 360(14): p. 1408-1417. 5. Bokemeyer, C., et al.,. Journal of Clinical Oncology, 2009. 27(5): p. 663-671. 6. Maughan, T.S., et al.,. The Lancet. 377(9783): p. 2103-2114. 7. Douillard JY, et al J Clin Oncol, 2011. 29(Suppl)(:3510).

Which is the best biological agent to use to increase response rate?

Downsizing the Unresectable Patient: Are They All the Same?

1. Should the surgeon operate and resect residual macroscopic sites?

2. Should resection be undertaken only after a waiting period to determine durability of the CR?

3. What is the role of “adjuvant” HAI therapy in such situations of originally liver-only disease?

4. What is the role of a chemotherapy break as a provocative test to determine a durable CR?

How should patients be managed when all original sites could not be resected?

QUESTION

Now What?

Preoperative chemotherapy

Disappearing Colorectal Liver Metastases After Preoperative Chemotherapy

• Disappearing metastases occurred in 24% of patients treated with preoperative chemotherapy.

• Disappearance was associated with high tumor number, longer duration of chemotherapy, and small lesion size.

• 53% of DLM were found during surgery.• When metastases were not found at the time of surgery, only

24% were resected.• Local recurrence occurred in 70% when DLM were left

untreated.• Survival was not significantly impacted if DLM were left

untreated.

Disappearing Colorectal Liver Metastases After Preoperative Chemotherapy

Van Vledder et al. J Gastrointest Surg (Nov 2010)

Disappearing Liver Metastases: Predictors of Complete Pathologic Response

Auer et al. Cancer. 2010 Mar 15;116(6):1502-9.

Disappearing Liver Metastases Left In Situ: Time to Lesion Recurrence

Auer et al. Cancer. 2010 Mar 15;116(6):1502-9.

What is the role of adjuvant therapy or neoadjuvant therapy in initially

resectable patients undergoing hepatic resection?

• Chemotherapy is generally recommended, at least in the chemo-naive patient (based on extrapolation of stage III studies).

• Little evidence to guide recommendations in previously treated patients.

• No RCT has demonstrated efficacy of peri- or postop chemotherapy in resectable stage IV pts.

• Questionable role for biologics in resectable patients, either pre- or postoperatively.

Combining Chemotherapy with Liver Resection in the Initially Resectable Patient

HR= 0.77; CI: 0.60-1.00, p=0.041

Periop CT

28.1%

36.2%

+8.1%At 3 years

(years)

0 1 2 3 4 5 6

0

10

20

30

40

50

60

70

80

90

100

O N Number of patients at risk :125 171 83 57 37 22 8115 171 115 74 43 21 5

EORTC 40983

Progression-Free Survival: Eligible Patients

Surgery only

EORTC 40983: Long Term Follow Up

Nordlinger et al. Lancet Oncol (2013)

Combining Chemotherapy with Liver Resection in the Initially Resectable Patient

Responses occur early… …Toxicity occurs later

Kishi et al. Ann Surg Oncol (Jun 2010)

CHEMOTHERAPY DURATION

No Clear Role of Biologics Combined with Liver Resection in the Initially Resectable Patient

Primrose et al (ASCO 2013, abstr 3504) New EPOC” 272 pts with resectable CRLM, kras wtRandomized to FOLFOX cetuximabFindings: cetuximab group did worse (PFS 14.8 vs 24.2 mo)

de Gramont et al (Lancet Oncol Dec 2012)AVANT Trial stage 3 CRC, FOLFOX bevFindings: detrimental effect of bevacizumab

1. Determine if “borderline” vs “definitely unresectable”

2. Preoperative “conversion” chemotherapy with regimen with high radiologic response (e.g. chemo+cetuximab, FOLFOXIRI)

3. Role of preop bevacizumab is more questionable

4. Monitor every 2 months to evaluate for resectability

5. Limit duration to minimize disappearing lesions and hepatotoxicity

6. Can potentially convertible patient be identified initially or should all fit patients with liver-limited disease be offered aggressive first line therapy?

What is the Optimal Strategy for Liver Only Metastatic Colon Cancer?

The Unresectable Patient

1. Role of any chemotherapy in the low risk patient is controversial (e.g. solitary, long DFI)

2. Consider chemotherapy in the high-risk patient (e.g. synchronous, multiple, short DFI)

3. Optimal sequencing, peri- or postoperative, is dealer’s choice

4. Limited evidence for the use of any biologics, either perioperatively or postoperatively

5. Limit the duration or preoperative chemotherapy to avoid DLM or toxicity (4-6 cycles)

What is the Optimal Strategy for Liver Only Metastatic Colon Cancer?

The Resectable Patient