*10.3.2 Tumour regression grade (TRG)*

*Current Cancer Treatment*

**54**

**Figure 2.**

*chemotherapy.*

*10.3.1 Percentage viable tumour*

Microscopic assessment of the percentage residual viable tumour on haematoxylin & eosin-stained sections of resected tissue has been employed as a predominant parameter in assessing the efficacy of different pre-operative chemotherapy regimens in tumour types such as oesophageal, gastric and rectal adenocarcinomas [113]. Based on this methodology, Ribero and colleagues modified this scoring system for application in CRLMs treated preoperatively, with or without bevacizumab [114]. A semi-quantitative estimation of the percentage area of residual viable tumour cells relative to total tumour surface area within each CRLM metastasis was made with the analysis of four tumour cell viability subsets (<25%, 25–49%,

*Morphological response criteria on contrast-enhanced CT (CECT) scans as a predictor of outcome (i) and (ii) CECT performed in a 43-year old patient before and after 10 cycles of bevacizumab containing chemotherapy demonstrating an optimal response (OR). (i) Before therapy, the liver metastasis presented with profound heterogeneous attenuation, a hyperattenuated peripheral rim and a thick, poorly defined tumour-liver interface ('group 3' metastasis). (ii) After therapy, the same liver metastasis shows complete resolution of these features (i.e. it is homogeneous, of low attenuation, with a thin, sharply defined tumor-liver interface). Change in size of lesion is minimal. (iii) and (iv) CECT of the liver performed in a 67-year old patient before and after 2 cycles of bevacizumab-containing chemotherapy demonstrating a partial response (PR). (iii) Before therapy, the liver metastas is presented with features of a 'group 3' metastasis. (iv) After therapy, the same liver metastasis shows moderate resolution of these features (i.e. it has a moderate degree of heterogeneous attenuation, a moderately defined tumor-liver interface with a slight hyperattenuating peripheralrim ('group 2' metastasis)). (v) and (vi) CECT of the liver performed in a 56-year old patient before and after 2 cycles of bevacizumab-containing chemotherapy demonstrating an absent response (AR). (v) Before therapy, the liver metastasis presented with features of a 'group 3' metastasis. (vi) After therapy, the same liver metastas is shows a decrease in tumour size without change in attenuation or tumour-liver interface ('group 3' metastasis). Changes in tumour morphology on CECT have been shown to correlate more significantly with survival than the use of RECIST citeria in CRLM patients treated with bevacizumab-containing* 

Mandard and colleagues were one of the first to establish a five-point histological scoring system for pathological response. This was based on cytological and stromal changes on haematoxylin & eosin-stained sections of primary oesophageal squamous cell carcinomas treated with chemoradiotherapy prior to resection [115].

#### **Figure 3.**

*Tumour regression grade (TRG) scoring system as a component of measuring pathological response in treated CRLMs. (A–E) TRG as scored on haematoxylin and eosin sections of CRLMs based on the proportion of fibrosis to viable tumour cells. The five TRGs shown in this cartoon roughly illustrate the different proportions of fibrosis (fibrils) to tumour cells (black areas). (A) TRG1. There is an absence of viable tumour cells and large amounts of fibrosis. (B) TRG2. The presence of viable tumour cells is rare and they are scattered throughout the fibrosis. (C) TRG3. There is the presence of more residual tumour cells but fibrosis predominates. (D) TRG4. Residual cancer cells predominate over fibrosis. (E) TRG5. There are no signs of tumour regression. The percentage of the CRLM surface area occupied by necrosis is also incorporated as a parameter for pathological response (grey areas). 3 main pathological response groups: TRG1-2: major response (MjHR), TRG3: partial response (PHR), TRG4-5: no histological response (NHR).*

#### *Current Cancer Treatment*

Tumour response was scored according to five tumour regression grades (TRG1-5) based on the proportion of fibrosis to viable tumour cells. Later, this TRG scoring system was modified for its application in CRLMs receiving different chemotherapy backbones prior to liver resection (**Figure 3A–E**) [116]. Correlation analyses have demonstrated a significant association of major histological responders with increased survival.

Similar retrospective studies using the TRG in CRLMs were undertaken to see whether adding bevacizumab to chemotherapy would further increase pathological response rate, without necessarily increasing radiographic response rate, after liver resection. Indeed, several retrospective analyses demonstrated that a significantly increased percentage of patients treated with bevacizumab achieved a major pathological response and a significantly higher percentage area of tumour necrosis compared to chemotherapy-only treated patients [117]. Furthermore, the extent of pathological response correlated significantly with long-term-outcomes such as 3- and 5-year overall survival.
