Adjuvant and neoadjuvant treatment of colorectal liver secundarities, tumor downstaging

Dufour P

Centre Paul Strauss Strasbourg Cedex France

Colorectal cancer (CRC) has a high incidence in the world mainly in the western countries. Around half of the patients develops synchronous or metachronous liver metastasis. If early stages have a good prognosis, advanced or metastatic stages have a very poor outcome with less than 10 % of patients alive at 5 years. However, a complete resection of metastasis improves the prognosis with a 20 – 40 % survival rate at 5 years (1). So changing an unresectable stage in a resectable stage is one of the therapeutic goal in a multidisciplinary approach. Some of the patients with a complete resection of their metastasis experienced a very long - term survival. If the metastases are resectable, the standard treatment is a primary resection with subsequent chemotherapy. But in case of non - resecability, we can discuss a neoadjuvant treatment in order to decrease the size of the metastasis and then to offer a secondary resection. S. Giachetti in a phase II study demonstrated that patients with a secondary resection had the same prognosis of pati-ents with a primary resection (2).

Old chemotherapy regimens (5-FU, folinic acid) displays a low response rate (22 %) with only 2 % of complete response (CR). They are not good candidates to observe a significant downstaging. New regimens as FOLFOX (5-FU, folinic acid, oxaliplatin) or FOLFIRI (5-FU, foloinic acid, irinotecan) are more effective with a 55 % response rate and a median survival of 21 months but CR rate is still low (3 – 4 %). In a phase III trial comparing both regimens, Tournigand observed the same efficacy in terms of response rate, progression free survival and overall survival (3). A secondary surgery could be performed in 9 % of patients receiving FOLFIRI and in 22 % of those treated with FOLFOX. More interestingly, the patients with a secondary resection had a better survival than those without resection of metastasis (47 vs. 21.5 months). Molecular targeted therapy has emerged in the treatment of metastatic CRC, Hurwitz studied the value of bevacuzimab (a monoclonal antibody targeting VEGF receptor). In a phase III trial, 813 patients were randomized between IFL (irinotecan, 5-FU, folinic acid) with or without bevacuzimab. A significant improvement of response rate (44.8 % vs 34.8 %), PFS (10.6 vs. 6.2 months) and survival (20.3 vs. 15.6 months) is observed with bevacuzimab(4). In a series of 22 patients with non resectable metastasis treated by Xelox (capecitabine, oxaliplatin) combined with bevacuzimab, B. Gruenberger observed that metastasis became respectable in 92 % of cases, bevacuzimab was stopped 5 weeks before surgery to avoid bleeding (5). These very promising results need to be confirmed in a larger multicentric study.

Several phase III trials evaluating first line oxaliplatin or irinotecan based chemotherapy reported a secondary complete resection in a range of 1 to 21 %. As second line therapies are not so effective with a low response rate (4 – 20 %) and a poor survival (9 - 12 months) (1). The possibility of a secondary resection must be discussed as soon as possible in the course of the disease (at least after 1 or 2 months of chemotherapy).

The number of preoperative chemotherapy cycles is still discussed. S Benoit reported a series of 66 patients with liver metastasis in complete remission on CT scan after neoadjuvant chemotherapy. These patients underwent surgery and a macro-scopic or microscopic residual disease was observed in 32 of the 66 patients and, among the others cases, a recurrence occurred in 23 cases. So the author concluded that in 83 % of patients there was a residual disease although a confirmed CR based on CT scan (6). This observation outlines the absolute necessity to resect the metastatic site even in case of CR. So, it is better to conduct surgery before the complete di-sappearance of metastasis.

Hepatic arterial infusion (HAI) maximizes drug effect with an extraction rate of 94 – 99 % in the liver during the first pass. HAI has demonstrated a very high response rate (40 – 80 %) in previous phase II trials but the secondary complete resection rate does not differ from this observed with new systemic chemotherapies (5 – 40 %) (1). Moreover, this technique is restricted to experienced teams due to the side effects (sclerosing cholangitis, chemical hepatitis).

Conclusion

Neoadjuvant approach can be advised in case of potentially resectable liver metastasis from CRC but a longer follow-up is warranted as a liver toxicity (vascular changes, steatohe-patitis) has been described in pathologic specimens from patients receiving oxaliplatin or irinotecan (7). A secondary resection offers a longer survival for patients with metastatic CRC.

References

1 - Leonard GD, Brenner B, Kemmeny NE: Neoadjuvant chemotherapy before liver resection for patients with unresectable liver metastases from colorectal carcinoma. J Clin Oncol, 2005, 23: 2038 - 48

2 - Giachetti S, Itzhaki M, Gruia G et al: Long-term survi-val of patients with unresectable colorectal cancer liver me-tastases following infusional chemotherapy with 5-fluorou-racil, leucovorin, oxaliplatin and surgery. Ann Oncol, 199, 10: 663 - 669

3 - Tournigand C, Andre T, Achille E et al: FOLFIRI follo-wed by FOLFOX6 or the reverse sequence in advanced co-lorectal cancer: a randomized GERCOR study.

J Clin Oncol, 2004, 22: 229 - 37

4  – Hurwitz H, Fehrenbacher L, Novotny W et al: Bevacuzimab plus irinotecan, fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med, 2004, 350: 2335 - 42

5  – Gruenberger B, Scheithauer W, Tamandl D et al: Neoadjuvant chemotherapy including bevacuzimab in po-tentially curable metastatic colorectal cancer: Proc ASCO 2006, abstract 3548

6 – Benoit S, Brouquet A, Penna C et al: Complete response of colorectal liver metastases after chemotherapy: does it mean cure? J Clin Oncol, 2006, 24 : 3939 -3945

7 – Bilchik AJ, Poston G, Curley SA et al: Neoadjuvant che-motherapy for metastatic colon cancer: a cautionary note. J Clin Oncol, 2005, 23: 9073 - 78.

Address for correspondence:
Prof P Dufour
Centre Paul Strauss
3, rue de la Porte de l’Hôpital
67085 Strasbourg Cedex France