DEBATE: What is the Optimal Strategy for Liver Only Metastatic
Colon Cancer? Michael A. Choti, MD Department of Surgery UT
Southwestern Medical Center Great Debates & Updates in GI
Malignancies March 28-29, 2014 Chemotherapy Followed By Surgical
Resection
Vigano et al. Ann Surg Onc (Jan 2012) Overall
SurvivalRecurrence-Free Survival Trends in Long-Term Outcome of
Liver Resection for Metastatic Colorectal Cancer (1985 -1994) (1995
-2000) (2001-2005)
Slide 4
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
Slide 5
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 of Resectability
Categories of Resectability BORDERLINE
Slide 6
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%
RESECTABLE 10-20% ?
Slide 7
Improving Systemic Chemotherapy for Advanced CRC 1 Saltz LB.
NEJM 2000 2 Tournigand C. J Clin Oncol 2004 3 Hoff, PM. GI ASCO,
2006 4 Diaz Rubio E. ASCO, 2005 Response % Median Surv (mo) BSC 0 7
5FU/ LV 1 2113 Irinotecan 1 1812 IFL 1 3915 FOLFOX 2 or FOLFIRI 2
54 56 20 - 22 With bevacizumab 3 ~70 >24 or cetuximab 4 IFL =
bolus 5FU, folinic acid, and irinotecan FOLFOX = infusion 5FU,
folinic acid, and oxaliplatin FOLFIRI = infusion 5FU, folinic acid,
and irinotecan
Slide 8
Initially resectable? Initially unresectable but potentially
convertible? Initially unresectable and unlikely convertible?
Slide 9
Initially resectable? Initially unresectable but potentially
convertible? Initially unresectable and unlikely convertible?
Slide 10
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
Slide 11
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?
Slide 12
Downsizing the Unresectable Patient: Are They All the
Same?
Slide 13
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
Slide 14
Now What? Preoperative chemotherapy Disappearing Colorectal
Liver Metastases After Preoperative Chemotherapy
Slide 15
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)
Slide 16
Disappearing Liver Metastases: Predictors of Complete
Pathologic Response Auer et al. Cancer. 2010 Mar
15;116(6):1502-9.
Slide 17
Disappearing Liver Metastases Left In Situ: Time to Lesion
Recurrence Auer et al. Cancer. 2010 Mar 15;116(6):1502-9.
Slide 18
What is the role of adjuvant therapy or neoadjuvant therapy in
initially resectable patients undergoing hepatic resection?
Slide 19
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
Slide 20
HR= 0.77; CI: 0.60-1.00, p=0.041 Periop CT 28.1% 36.2% +8.1% At
3 years (years) 0123456 0 10 20 30 40 50 60 70 80 90 100 ONNumber
of patients at risk : 125171835737228 1151711157443215 EORTC 40983
Progression-Free Survival: Eligible Patients Surgery only
Slide 21
EORTC 40983: Long Term Follow Up Nordlinger et al. Lancet Oncol
(2013)
Slide 22
Combining Chemotherapy with Liver Resection in the Initially
Resectable Patient Responses occur earlyToxicity occurs later Kishi
et al. Ann Surg Oncol (Jun 2010) CHEMOTHERAPY DURATION
Slide 23
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 wt Randomized to FOLFOX
cetuximab Findings: 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 bev Findings: detrimental effect of bevacizumab
Slide 24
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
Slide 25
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 dealers 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
