Rubbia-Brandt vs Blazer scores for survival prediction in colorectal liver metastases after chemotherapy

Introduction

Colorectal cancer (CRC) ranks third globally in terms of the most commonly diagnosed cancer and second as the leading cause of cancer-related deaths.¹ CRC progression typically involves metastatic spread, with the liver being the most frequently affected site. Synchronous liver metastases (LM) occur in approximately 20% of patients, while nearly 50% will develop them during the course of their illness.² Surgical resection is considered the most effective treatment option for LM, but only a subset of patients are candidates for resection, depending on factors such as tumor size, number, location, and liver function. Neoadjuvant chemotherapy (CT) significantly improves the prognosis of resectable cases and can make initially unresectable lesions amenable to surgery.³ The pathological response of LM to neoadjuvant therapy is a crucial prognostic factor for recurrence and survival. The Rubbia-Brandt et al. score⁴ was one of the earliest established to evaluate tumor response to therapy, and other scores, such as the one proposed by Blazer et al., have also been suggested.⁵ However, no standardized scoring system currently exists, and studies comparing the performance of different scores are still lacking. This study aims to assess tumor response in liver resection specimens histologically, based on the Rubbia-Brandt and Blazer scores after neoadjuvant treatment, and compare the prognostic performance of these two scoring systems.

Methods

Results

Study analysis of survival and performance of TRG scores

Overall survival for all stages was 85.5% at 12 months, 41.7% at 24 months and 19.3% at 36 months. There was a significant difference in survival between the different grades for Rubbia- Brandt TRG (p=0.03) but not for Blazer TRG (p=0.269). For Rubbia-Brandt TRG, the median survival was better in the case of a major response (TRG 1/TRG 2) assessed at 40.1 and 41.1 months after the initial diagnosis. In the case of partial response (TRG 3), the median survival was 32.1 months. In cases of no response (TRG 4/TRG 5), survival was estimated at 29.9 and 18.5 months. For Blazer, the median survival was greater for complete response, estimated at 41.1 months after initial diagnosis. For the major response group, survival was estimated at 38.2 months. For the minor or no response group, survival was 29.3 months. When discussing homogeneity, the likelihood ratio χ² (LR) for The Rubbia- Brandt TRG had the highest LR+. Rubbia-Brandt has a score of 10.953 and Blazer has a score of 7.246. The RV+ of the Rubbia-Brandt score was greater than 10, so it is a score with very strong diagnostic contribution. The RV+ of the Blazer score was between 5 and 10, so it is a score with strong diagnostic input. When looking at monotonicity with the linear trend χ², of the two scores, the Rubbia-Brandt TRG had the highest linearity value. Rubbia-Brandt has a score of 10.738 and Blazer has a score of 4.446. Looking at the Discriminatory capacity, we can see a sensitivity and specificity of scores for survival prediction. The graphical representation of the predictive capacity of each score for survival is the AUC of the ROC curve is as follows the Figure 1. The Rubbia-Brandt score was a good performing score as its AUC under the ROC curve was 0.8. The Blazer score was a poorly performing score as its AUC under the ROC curve was 0.6. The Rubbia-Brandt TRG score was better at predicting survival than the Blazer score (p=0.003).

Figure 1. ROC Curve for Rubbia Brandt and Blazer scores.

Figure 2. Liver metastasis with tumour regression posing a problem between the two scores: partial/complete.

Predominant fibrosis with scattered residual tumour cells: According to Rubbia-Brandt, partial response (TRG 3) and according to Blazer, this is a major pathological response (presence of 1 to 49% residual tumour cells) (HEx20).

Figure 3. Liver metastasis with major or partial tumour regression, according to the scores.

Abundant fibrosis and rare residual carcinomatous structures (arrow). According to Blazer, this is a major pathological response and TRG2 according to Rubbia-Brandt (HEx25).

Discussion

In this retrospective study of 70 patients with colorectal cancer liver metastases (CRCLM), the average age was 56 years with a male-to-female ratio of 2.2. A total of 57% of patients presented with synchronous liver metastases (LM) at diagnosis. Pathological response was assessed using two scoring systems: the five-tier Rubbia-Brandt Tumor Regression Grade (TRG) and the three-tier Blazer score. According to the Rubbia-Brandt TRG, 11% of metastases were classified as TRG 1, 11% as TRG 2, 24% as TRG 3, 40% as TRG 4, and 10% as TRG 5. Using the Blazer score, 7% of cases had a complete pathological response, 44% showed a major response, and 49% a minor response. Overall survival was 85.5% at 12 months, 41.7% at 24 months, and 19.3% at 36 months. As expected, patients with a major or complete pathological response had longer median survival than those with partial or no response. The Rubbia-Brandt TRG demonstrated superior predictive performance for survival, with an area under the curve (AUC) of 0.8 on ROC analysis, compared to 0.6 for the Blazer score. It also exhibited higher diagnostic contribution (RV+ >10) and better linearity (10.73). These results suggest that the Rubbia-Brandt TRG, through its detailed five-level assessment based on tumor cell regression and fibrosis, may be more accurate in reflecting treatment response and correlating with survival.

Limitations: This study presents several limitations. Its retrospective design, combined with incomplete clinical data and treatment heterogeneity, may have influenced therapeutic responses and survival outcomes. The absence of inter-observer variability assessment for both TRG systems is another important limitation.

Prognostic factors in CRCLM: Multiple prognostic variables are known to impact outcomes in CRCLM. These include the timing of LM occurrence, response to neoadjuvant chemotherapy (CT), number and size of metastases (tumors >10 cm are associated with poor prognosis)⁸, and quality of surgical resection.⁹ Histopathological invasion factors also correlate with reduced overall survival.^10,11 While radiological assessment using RECIST criteria remains standard,¹² studies show it does not always align with survival, particularly after targeted therapy with cytostatic effects.¹³ In contrast, pathological evaluation of the resection specimen more accurately reflects systemic therapy response.^13,14 Additionally, chemotherapy-induced liver injury significantly affects prognosis.³

Rubbia-Brandt TRG system: First proposed in 2006, the Rubbia-Brandt score⁴ was adapted from Mandard’s system¹² for rectal and esophageal cancers. It defines five TRG categories based on the ratio of residual tumor cells to fibrosis: TRG1 (complete fibrosis), TRG2 (predominant fibrosis with rare tumor cells), TRG3 (fibrosis with more tumor cells), TRG4 (predominant tumor cells), and TRG5 (no fibrosis, only tumor). Necrosis is excluded, as it may reflect spontaneous tumor degeneration rather than chemotherapy-induced regression. In the original study,⁴ patients receiving neoadjuvant CT had significantly better pathological regression than those undergoing surgery alone (p < 0.0001). Five-year survival was 41% for TRG 1–2, 38% for TRG 3, and only 9% for TRG 4–5. In our cohort, we observed similar TRG distributions and confirmed the prognostic value of near-complete and partial responses. Importantly, this system aligns with the American Joint Committee on Cancer (AJCC) recommendations for primary tumors, enabling direct comparison between primary CRC and metastases. Nonetheless, TRG2 remains imprecise due to the subjective notion of “rare residual tumor cells.” Introducing defined percentage thresholds could improve reproducibility.¹⁵ Moreover, using two parameters (tumor cells and fibrosis) may complicate routine implementation. Alternative approaches like the PRG (Pathological Response Grade), which relies solely on the percentage of viable tumor cells, have shown prognostic utility¹⁶ but require further validation. Another limitation is the lack of integration of modern targeted therapies in the original Rubbia-Brandt study. Agents like bevacizumab or cetuximab, widely used today, may alter tumor response patterns.¹⁷

Blazer score: In 2008, Blazer et al.⁵ proposed a simplified three-tier regression system based on residual viable tumor cells: complete response (0%), major response (1–49%), and minor response (≥50%). The score averages responses across multiple metastases, which may dilute heterogeneity. In our study, complete response was observed in 7% of patients, major in 44%, and minor in 49%. Blazer et al. reported 5-year survival rates of 75%, 56%, and 33% for complete, major, and minor responders, respectively. While we observed better survival in complete responders, statistical differences between groups were not significant. This score, while simple, has limitations. Its reliance on estimating initial tumor area introduces variability, and its 50% threshold may lack sensitivity. Additionally, fibrosis or necrosis can occur in untreated tumors, complicating interpretation.⁴

Performance of the scores: No prior studies have directly compared the performance of pathological regression scores for CRCLM. Our findings suggest that the Rubbia-Brandt TRG outperforms the Blazer score in prognostic accuracy. With an AUC of 0.8, higher RV+, and greater linearity, it offers more granularity in assessing tumor regression and survival correlation.¹⁸ However, both systems present challenges, especially in interpreting intermediate categories. The “almost complete regression” category is subjective. TRG 3, defined as “residual tumor cells scattered in fibrotic tissue”,⁴ overlaps with the Blazer “major response” (<50% viable tumor),⁵ yet their clinical implications may differ. Importantly, neither score accounts adequately for intra-tumoral heterogeneity. The Rubbia-Brandt system considers only the worst lesion, while the Blazer score averages across all metastases. Evidence suggests that the presence of at least one LM with complete regression is associated with improved prognosis.^19,20 Thus, reporting individual TRG scores for each lesion may enhance prognostic precision.

Perspectives and recommendations: A robust and standardised pathological response system is essential for evaluating resected CRCLM. Future prospective studies with large cohorts should aim to harmonise macroscopic sampling protocols, assess inter-observer reproducibility, and integrate TRG with other histopathological variables in predictive algorithms. Given its superior performance in our study, the Rubbia-Brandt TRG should be incorporated into routine pathology reports for resected CRCLMs following neoadjuvant therapy. Used alongside ypTN staging, it provides valuable prognostic information and could inform clinical decision-making.²¹ Multicentric studies are warranted to validate these findings and further refine pathological assessment strategies.

Conclusion

In conclusion, surgical resection remains the gold standard treatment for CRCLM, and the prognosis is significantly improved with the use of neoadjuvant chemotherapy (CT). Pathological response to neo-adjuvant therapy is a crucial prognostic factor correlated with recurrence and survival. The Rubbia Brandt TRG system can complement the ypTN stage and other pathological criteria to improve the predictivity of survival.