Liver Metastases From Colorectal Cancer
Recently, interest has been growing regarding the evaluation of histopathological response to chemotherapy as a surrogate marker of patient outcome after liver resection. Recent studies associated the histopathological response to treatment with an improvement in prognosis for patients with CLM. According to the most commonly used scores, responses are graded from 0 (when no tumor regression occurred) to 4 (when total regression or response is achieved) or from tumor regression grade (TRG) 1 (when tumor cell formations are absent) to TRG 5 (when abundance of tumor cells without fibrosis is present). Rubbia-Brandt et al. reported that the histological tumor regression in CLM is mainly related to fibrosis overgrowth and not to an increase of necrosis, and that TRG was an independent prognostic factor for both DFS and OS at multivariate analysis. More recently, the importance of the pathological response in predicting survival after preoperative chemotherapy and the correlation of histopathological response with prognosis have been largely investigated and confirmed in other series. Interestingly, the use of oxaliplatin seemed to improve pathological response compared with irinotecan regimens; even though this finding appears to be in line with the previously discussed data regarding chemotherapy in patients with CLM, it requires further confirmation.
Since the combination of chemotherapy with biologics represents the standard of care for most of mCRC patients nowadays, investigation regarding the impact of targeted agents on histopathological response of CLM represents an area of extensive research, particularly for antiangiogenetic agents. A total of two retrospective analyses seem to suggest that bevacizumab significantly improves tumor regression and this could result in better PFS and OS results. We have recently analyzed histopathological response among 42 patients treated with chemotherapy triplet (either FOLFOXIRI or XELOXIRI) or FOLFOXIRI plus bevacizumab treatment, who underwent secondary resection of CLM. In our series, 15 (63%) of 24 patients treated with FOLFOXIRI plus bevacizumab demonstrated a histopathological response (graded as TRG 1, 2 or 3), compared with five (28%) of 18 patients treated with chemotherapy alone (p = 0.03), despite no difference in the rate of pathological complete responses being detected (17 vs 11%, respectively; p = 0.69). In line with previously cited reports, patients achieving better pathological response (TRG 1, 2 or 3) had a better outcome in terms of median PFS (39.5 vs 15.7 months; HR = 0.50; 95% CI: 0.23–1.10; p = 0.08) when compared with patients with minimal or no tumor regression (TRG 4 or 5), and in the bevacizumab-treated subgroup this difference achieve a statistical significance (37.5 vs 14.1 months; HR = 0.29; 95% CI: 0.06–0.82; p = 0.02).
As far as the relevance of pathological response to treatment is concerned, new indicators and scoring systems are proposed to further refine prognostic indications of surgical specimen evaluation. An interesting approach is represented by the more accurate evaluation of the tumor–normal interface (TNI), where a majority of residual tumor cells seems to be located after treatment. In a study among 103 patients with CLM who were resected after preoperative chemotherapy with or without bevacizumab, Maru et al. reported that tumor thickness at TNI correlated with pathological response and, even more importantly, greater malignant thickness at TNI predicted shorter recurrence-free survival. Again, adding bevacizumab to chemotherapy seems to be an interesting tool for reducing tumor thickness at this level. In the future, we could expect that a more tight integration among pathologists, surgeons and oncologists will be necessary to define the response to medical treatment more precisely and, thus, establish patient prognosis after resection more accurately.
Measuring Histopathological Response to Preoperative Treatment: Many Sides of the Same Dice
Recently, interest has been growing regarding the evaluation of histopathological response to chemotherapy as a surrogate marker of patient outcome after liver resection. Recent studies associated the histopathological response to treatment with an improvement in prognosis for patients with CLM. According to the most commonly used scores, responses are graded from 0 (when no tumor regression occurred) to 4 (when total regression or response is achieved) or from tumor regression grade (TRG) 1 (when tumor cell formations are absent) to TRG 5 (when abundance of tumor cells without fibrosis is present). Rubbia-Brandt et al. reported that the histological tumor regression in CLM is mainly related to fibrosis overgrowth and not to an increase of necrosis, and that TRG was an independent prognostic factor for both DFS and OS at multivariate analysis. More recently, the importance of the pathological response in predicting survival after preoperative chemotherapy and the correlation of histopathological response with prognosis have been largely investigated and confirmed in other series. Interestingly, the use of oxaliplatin seemed to improve pathological response compared with irinotecan regimens; even though this finding appears to be in line with the previously discussed data regarding chemotherapy in patients with CLM, it requires further confirmation.
Since the combination of chemotherapy with biologics represents the standard of care for most of mCRC patients nowadays, investigation regarding the impact of targeted agents on histopathological response of CLM represents an area of extensive research, particularly for antiangiogenetic agents. A total of two retrospective analyses seem to suggest that bevacizumab significantly improves tumor regression and this could result in better PFS and OS results. We have recently analyzed histopathological response among 42 patients treated with chemotherapy triplet (either FOLFOXIRI or XELOXIRI) or FOLFOXIRI plus bevacizumab treatment, who underwent secondary resection of CLM. In our series, 15 (63%) of 24 patients treated with FOLFOXIRI plus bevacizumab demonstrated a histopathological response (graded as TRG 1, 2 or 3), compared with five (28%) of 18 patients treated with chemotherapy alone (p = 0.03), despite no difference in the rate of pathological complete responses being detected (17 vs 11%, respectively; p = 0.69). In line with previously cited reports, patients achieving better pathological response (TRG 1, 2 or 3) had a better outcome in terms of median PFS (39.5 vs 15.7 months; HR = 0.50; 95% CI: 0.23–1.10; p = 0.08) when compared with patients with minimal or no tumor regression (TRG 4 or 5), and in the bevacizumab-treated subgroup this difference achieve a statistical significance (37.5 vs 14.1 months; HR = 0.29; 95% CI: 0.06–0.82; p = 0.02).
As far as the relevance of pathological response to treatment is concerned, new indicators and scoring systems are proposed to further refine prognostic indications of surgical specimen evaluation. An interesting approach is represented by the more accurate evaluation of the tumor–normal interface (TNI), where a majority of residual tumor cells seems to be located after treatment. In a study among 103 patients with CLM who were resected after preoperative chemotherapy with or without bevacizumab, Maru et al. reported that tumor thickness at TNI correlated with pathological response and, even more importantly, greater malignant thickness at TNI predicted shorter recurrence-free survival. Again, adding bevacizumab to chemotherapy seems to be an interesting tool for reducing tumor thickness at this level. In the future, we could expect that a more tight integration among pathologists, surgeons and oncologists will be necessary to define the response to medical treatment more precisely and, thus, establish patient prognosis after resection more accurately.
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