The Tower of Babel of liver metastases from colorectal cancer: Are we ready for one language?

Critical Reviews in Oncology/Hematology

Case
54 year old male with Stage IV (T2N1cM1b) rectal cancer s/p chemoradiation followed by low anterior resection. Preoperatively he had an anal canal metastasis that clinically completely resolved after his chemoradiation. During LAR, liver and lung nodules were found. F/U CT showed 6 mm RLL nodule. On MRI, 2 superficial liver masses (2 cm x 3 cm) are noted and c/w metastasis with patent hepatic veins and right anterior and posterior portal vein thrombosis. Lung nodule remained unchanged but hepatic metasteses decreased in size and were resected after completing 5 rounds of FOLFOX w/ Bevacizumab.

Primary CRC mass 2.5 x 1.5 cm CEA: 1.5 Metastasis : 1 regional LN, 2 liver metastases V and VII 2.0 x 3.0 cm, RLL nodule 6.0 mm KRAS mutation is negative

Liver Cancer
Most common liver cancer is metastasis usually from the GI tract
Colorectal Cancer

Heraldsdottir et al. 2013

Optimal Treatment Strategies

Strategies for treating CRCLM
Chemotherapy Surgery Locally ablative procedures

Aim
Resectability Reduce recurrences Improving overall survival

Made difficult due to heterogeneity of the patient population

Resectability
Past: defined as how much liver lost Today: defined as how much liver left 5 factor scoring system (Fong et al. 1999)
1. node-positive primary 2. disease free interval < 12 months 3. more than one lesion 4. size >5 cm 5. carcinoembryonic antigen (CEA) >200 ng/ml

5-year survival rate

>1 RF: 14% with a median of 22 months 1 RF: 44% and a median of 51 months 0 RF: 60%

5ySR Stratified by Clinical Risk Score for CRCLM Resections

Low: 0-2 High: 3-5

Tomlinson et al. 2007

CRCLM Patient Groups

Readily resectable
low risk of relapse 10% of the patients few liver metastases (<4) adequate radiological margins no major poor prognostic factors

Unresectable
extensive liver involvement (>70% liver invasion or all three hepatic veins involved) major liver insufficiency extrahepatic unresectable disease unfit for surgery Ultimately resectable
tumor shrinkage with chemotherapy

Unresectable
metastases are never likely to be resectable

CRCLM Patient Groups

Potentially resectable
heterogeneous class of patients high risk of relapse Technically difficult
metastases are close to all hepatic veins or to both portal branches

Biologically challenging
Indicators of short progression-free survival (PFS)
synchronous presentation multiple metastases large (>5 cm) single lesion high CEA

Other factors
age comorbities performance status

EORTC 40983 Phase 3 Trial Study

European Organization for Research and Treatment of Cancer 40983 trial
Randomized 364 patients with resectable liver metastases to two treatment arms
Surgery alone 6 months of perioperative chemotherapy with 5fluorouracil and oxaliplatin
administered 3 months before and 3 months after surgery maximum of four liver metastases not previously treated with oxaliplatin

Primary aim of the study was 3-year PFS

Nordlinger et al. 2013

Chemotherapy Regimens
FOLFOX: Oxaliplatin plus FU and leucovorin
5-fluorouracil: pyrimidine analog antimetabolite that interferes with DNA and RNA synthesi Leucovorin: supplies the necessary cofactor blocked by methotrexate and restores folate for DNA/RNA synthesis, stabilizes the binding of 5-dUMP and thymidylate synthetase, enhancing the activity of fluorouracil

FOLFIRI: Irinotecan plus FU and leucovorin

Irinotecan: bind reversibly to topoisomerase I-DNA complex

XELOX: Oxaliplatin plus capecitabine

Oxaliplatin: platinum compound binds to DNA forming crosslinks which inhibit DNA replication and transcription Capecitabine: undergoes hydrolysis in the liver and tissues to form fluorouracil

Perioperative chemotherapy for resectable colorectal cancer liver metastases results

80% completed the preoperative part of the treatment 52% completed the postoperative six cycles 43% completed full perioperative treatment Toxicity observed during the preoperative chemotherapy was consistent with the previous experiences with FOLFOX Postoperative complications observed in the experimental arm (25% versus 16%; P = 0.04) No impact on postoperative death rate (1% in both arms)
Bittoni et al. 2013

Overall Survival
Follow-up of 8.5 years, and 221 reported deaths (61% of all randomized patients) No statistically significant difference in OS between the patients in the chemotherapy arm and the patients who underwent only surgery 5-year OS rate
51.2% in the chemotherapy arm 47.8% in the surgery arm 52.4% versus 48.3% in all eligible patients

Lack of a benefit in OS for chemotherapy

influence of subsequent treatment lines increase in death unrelated to cancer in the chemotherapy arm

Survival curves of peri-operative and post-operative chemotherapy strategies since intention-to-treat

Average (mos) Peri-op Post-op

Ercolani et al. 2011

1 yr .91 .88

3 yr .62 .59

5 yr .38 .36

54.56 52.62

*Based on model probability parameters from MEDLINE and EMBASE search and excludes bev and cet

WT, KRAS wild-type Bevacizumab: Anti-VEGF Cetuximab: Anti-EGFR

Portal vein embolization

Soreide et al. 2011

References
Bittoni, A., Scartozzi, M., Giampieri, R., Faloppi, L., Maccaroni, E., Del Prete, M., et al. (2013). The tower of babel of liver metastases from colorectal cancer: Are we ready for one language? Critical Reviews in oncology/hematology, 85(3), 332-341. doi:10.1016/j.critrevonc.2012.08.005; 10.1016/j.critrevonc.2012.08.005 Ercolani, G., Cucchetti, A., Cescon, M., Peri, E., Brandi, G., Del Gaudio, M., et al. (2011). Effectiveness and cost-effectiveness of peri-operative versus post-operative chemotherapy for resectable colorectal liver metastases. European Journal of Cancer (Oxford, England : 1990), 47(15), 22912298. doi:10.1016/j.ejca.2011.05.014; 10.1016/j.ejca.2011.05.014 Fong, Y., Fortner, J., Sun, R. L., Brennan, M. F., & Blumgart, L. H. (1999). Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: Analysis of 1001 consecutive cases. Annals of Surgery, 230(3), 309-18; discussion 318-21. Haraldsdottir, S., Wu, C., Bloomston, M., & Goldberg, R. M. (2013). What is the optimal neo-adjuvant treatment for liver metastasis? Therapeutic Advances in Medical Oncology, 5(4), 221-234. doi:10.1177/1758834013485111; 10.1177/1758834013485111 Nordlinger, B., Sorbye, H., Glimelius, B., Poston, G. J., Schlag, P. M., Rougier, P., et al. (2008). Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC intergroup trial 40983): A randomised controlled trial. Lancet, 371(9617), 1007-1016. doi:10.1016/S0140-6736(08)60455-9; 10.1016/S01406736(08)60455-9 Nordlinger, B., Sorbye, H., Glimelius, B., Poston, G. J., Schlag, P. M., Rougier, P., et al. (2013). Perioperative FOLFOX4 chemotherapy and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC 40983): Long-term results of a randomised, controlled, phase 3 trial. The Lancet Oncology, 14(12), 1208-1215. doi:10.1016/S1470-2045(13)70447-9; 10.1016/S1470-2045(13)70447-9 Soreide, K., Berg, M., Skudal, B. S., & Nedreboe, B. S. (2011). Advances in the understanding and treatment of colorectal cancer. Discovery Medicine, 12(66), 393-404. Tomlinson, J. S., Jarnagin, W. R., DeMatteo, R. P., Fong, Y., Kornprat, P., Gonen, M., et al. (2007). Actual 10-year survival after resection of colorectal liver metastases defines cure. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology, 25(29), 4575-4580. doi:10.1200/JCO.2007.11.0833