Reporter: R4 李育庭 Supervisor: 鄧豪偉醫師

Pathologic Response to Preoperative Chemotherapy in Colorectal

Liver Metastases: Fibrosis, not Necrosis, Predicts Outcome

Ann Surg Oncol (2012) 19:2797–2804 Aleksey V. George A. Poultsides, Fei Bao, Elliot L. Servais et al.

Reporter: R4 李育庭Supervisor: 鄧豪偉醫師

Introduction Patient and Method Result Discussion Conclusion

Introduction

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Perioperative chemotherapy with FOLFOX4 is compatible with major liver surgery and reduces the risk of events of progression-free survival in eligible and resected patients.

Nordlinger B, Sorbye H, Glimelius B, et al. Lancet. Mar 22 2008;371(9617):1007-1016.

Nordlinger B, Sorbye H, Glimelius B, et al. Lancet. Mar 22 2008;371(9617):1007-1016.

Systemic chemotherapy has been shown to convert initially unresectable tumors to resectable.

Adam R, Delvart V, Pascal G, et al. Annals of surgery 2004;240:644-57.

Pathologic response predicts survival after preoperative chemotherapy and resection of CLM (Colorectal liver metastasis).

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Blazer DG, 3rd, Kishi Y, Maru DM, et al. J Clin Oncol 26:5344-51, 2008

Residual tumor

complete 0%

major 1-49%

minor >50%

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Adam R, Wicherts DA, de Haas RJ, et al. J Clin Oncol 26:1635-41, 2008

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Rubbia-Brandt L, Giostra E, Brezault C, et al. Ann Oncol 18:299-304, 2007

The pathologic response to neoadjuvant therapy in primary colorectal cancer is not homogeneous.FibrosisNecrosisAcellular mucin

Rubbia-Brandt L, Giostra E, Brezault C, et al. Ann Oncol 18:299-304, 2007

Purpose To evaluate the prevalence of the three

components of pathologic response (necrosis, fibrosis, acellular mucin) after resection of CLM, with and without preoperative chemotherapy.

To investigate the association with outcome as well as preoperative factors

Patient and Methods

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A single institution Retrospective review

Patient Preoperative chemotherapy :

Systemic chemotherapy within 6 months before hepatectomy

Hepatic artery infusion Non Preoperative chemotherapy

Chemotherapy-naive patients chemotherapy-free interval of more than 6

months before hepatectomy

Poultsides GA, Bao F, Servais EL, et al. Ann Surg Oncol 19:2797-804, 2012

17Poultsides GA, Bao F, Servais EL, et al. Ann Surg Oncol 19:2797-804, 2012

A median of 3 slides (range, 1–17) were examined for each tumor, typically one section per centimeter of tumor diameter.

All tumors that grossly appeared to show complete or near complete response.

Result

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20Poultsides GA, Bao F, Servais EL, et al. Ann Surg Oncol 19:2797-804, 2012

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Of 21 complete pathologic responders, all but one had received preoperative chemotherapy.

5-year survival probability: 94%N Character

7 >90% Necrosis

6 >90% Fibrosis

3 >90% Mucin

5 Mixed pattern


Preoperative chemotherapy

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Preoperative chemotherapy

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Non Preoperative chemotherapy Only 9 (8 %) and 3 (3 %) of the 117

nonchemotherapy patients had ≥75 % nonviable tumor and fibrosis ≥ 40 %.

Lack of association with disease-specific survival

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Discussion

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Fibrosis is the predominant chemotherapy-induced pathologic change in CLM.

Necrosis in CLM is more related to spontaneous phenomena.

The beneficial effects of chemotherapy appear to be mainly related to the replacement of tumor by fibrosis

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The study is the first to provide a detailed quantitative analysis of the three components of overall pathologic response (fibrosis, necrosis, acellular mucin)

Fibrosis as the main chemotherapy-induced pathologic change independently associated with survival after resection of CLM.

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8 % were found to have a complete absence of viable tumor cells on pathologic review

In the study, patients with complete pathologic response had a 94 % 5-year disease-specific survival probability.

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It is important to identify patient or tumor characteristics that preoperatively predict higher levels of pathologic response.

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Tumor size (after treatment) < 3 cm

High CEA >200ng/ml

Hepatic artery infusion

Bevacizumab + Oxaliplatin based chemotherapy


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Ribero D, Wang H, Donadon M, et al. Cancer 110:2761-7, 2007


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Blazer DG, 3rd, Kishi Y, Maru DM, et al. J Clin Oncol 26:5344-51, 2008


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Klinger M, Tamandl D, Eipeldauer S, et al. Ann Surg Oncol 17:2059-65, 2010

Duration of chemotherapy Longer duration of preoperative

chemotherapy was not associated with pathological response

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Duration of chemotherapy

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Kishi Y, Zorzi D, Contreras CM, et al.Ann Surg Oncol 17:2870-6, 2010

Conclusion

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Approximately 8 % of patients with CLM receiving modern combination chemotherapy can achieve complete pathologic response.

Favorable overall pathologic response is associated with improved long-term survival.

The pathologic finding of necrosis in CLM is a nonspecific finding.

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HAI chemotherapy and bevacizumab may be associated with higher rates of overall pathologic response and fibrosis.

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Reporter: R4 李育庭 Supervisor: 鄧豪偉醫師