The Effect of Histopathological Growth Patterns of Colorectal Liver Metastases on the Survival Benefit of Adjuvant Hepatic Arterial Infusion Pump Chemotherapy

Background Histopathological growth patterns (HGPs) are a prognostic biomarker in colorectal liver metastases (CRLM). Desmoplastic HGP (dHGP) is associated with liver-only recurrence and superior overall survival (OS), while non-dHGP is associated with multi-organ recurrence and inferior OS. This study investigated the predictive value of HGPs for adjuvant hepatic arterial infusion pump (HAIP) chemotherapy in CRLM. Methods Patients undergoing resection of CRLM and perioperative systemic chemotherapy in two centers were included. Survival outcomes and the predictive value of HAIP versus no HAIP per HGP group were evaluated through Kaplan–Meier and Cox regression methods, respectively. Results We included 1233 patients. In the dHGP group (n = 291, 24%), HAIP chemotherapy was administered in 75 patients (26%). In the non-dHGP group (n = 942, 76%), HAIP chemotherapy was administered in 247 patients (26%). dHGP was associated with improved overall survival (OS, HR 0.49, 95% CI 0.32–0.73, p < 0.001). HAIP chemotherapy was associated with improved OS (HR 0.61, 95% CI 0.45–0.82, p < 0.001). No interaction could be demonstrated between HGP and HAIP on OS (HR 1.29, 95% CI 0.72–2.32, p = 0.40). Conclusions There is no evidence that HGPs of CRLM modify the survival benefit of adjuvant HAIP chemotherapy in patients with resected CRLM.

The Effect of Histopathological Growth … chemotherapy. 4The potential benefit of HAIP chemotherapy is therefore to be expected in patients who are at risk of developing recurrence confined to the liver.Biomarkers are needed to better identify patients who are most likely to develop recurrence confined to the liver.
Histopathological growth patterns (HGPs) of CRLM are assessed at the tumor-liver interface of resected metastases on routine H&E slides via light microscopy.HGPs can be divided into desmoplastic HGP (dHGP), replacement HGP (rHGP), and pushing HGP (pHGP).dHGP is characterized by a separation between the tumor cells and hepatocytes by a rim of desmoplastic tissue, with no direct contact between the tumor and the liver parenchyma.rHGP shows direct contact between the tumor cells and the hepatocytes.The tumor cells replace the hepatocytes in the liver cell plates and the original architecture of the liver parenchyma is preserved.pHGP is characterized by direct contact between the tumor cells and the hepatocytes.Unlike in rHGP, there is no infiltrative growth.Instead, the surrounding liver cell plates show a compressed aspect. 5Patients can be divided into two clinically relevant groups based on the proportions of the HGPs found at the tumor-liver interface: patients with pure desmoplastic HGP (dHGP) and patients with any amount of non-dHGP, meaning replacement or pushing HGP. 6,7atients with pure dHGP have an associated superior OS and progression-free survival (PFS) compared with patients with any amount of non-dHGP, regardless of the amount of non-dHGP, and independent of other independent clinicopathological prognostic factors such as BRAF and KRAS mutational status. 6,8,9In addition to the prognostic value, pure dHGP has been shown to primarily recur in the liver while non-dHGP has a higher rate of extrahepatic recurrence. 10herefore, HGPs of CRLM may be suitable biomarkers for identifying patients that are predominantly at risk of developing hepatic recurrence after liver metastasectomy. 10his study investigated the predictive value of HGPs for adjuvant HAIP chemotherapy in patients with resectable CRLM.

Study Design and Patients
A retrospective cohort study was performed.Patients who underwent curative intent local therapy (i.e., resection and/ or ablation) and perioperative systemic chemotherapy for CRLM at the Erasmus MC, Rotterdam and Memorial Sloan Kettering Cancer Center, New York between 1990 and 2019 were screened for inclusion.Patients were excluded if there was a history of extrahepatic disease (EHD) at, or prior to, the time of resection.Patients were excluded if HGPs were not assessed (tissue not available for analysis).Patients who underwent preoperative downstaging HAIP chemotherapy were excluded as well.Curative intent was defined as local treatment of all preoperatively identified lesions.Local treatment included surgical resection and local ablation.
HGPs were assessed retrospectively by at least two trained observers following the consensus guidelines. 6All observers were blinded to patient outcomes during HGP assessment.The HGP was scored as a percentage of the tumor-liver interface per H&E slide.The average HGP score of all slides was calculated by lesion and subsequently per patient.Patients were grouped into those with pure dHGP and those with any amount of non-dHGP.
Systemic chemotherapy consisted of a combination of fluorouracil (5-FU) infusion and bolus leucovorin (LV), oxaliplatin (OXA) and/or irinotecan-based chemotherapies.Patients who underwent HAIP chemotherapy underwent surgical pump implantation (combined with resection of CRLM) followed by up to 6 cycles of continuous HAIP floxuridine at 0.12 mg/kg/day, according to MSKCC protocol. 3All patients in the HAIP group received concomitant systemic chemotherapy.
Differences in baseline characteristics were compared using a chi-square exact test for percentages and Kruskal-Wallis test for medians of continuous data.Continuous variables are given as median with the interquartile range (IQR), unless indicated otherwise.OS was defined as the time in months from local treatment of liver metastases to death.PFS was defined as the time in months between local treatment for liver metastases and disease or death.Hepatic PFS (hPFS) was defined as the time in months from local treatment of liver metastases to hepatic progression or death (extrahepatic progression was not considered an event).Median follow-up for survivors was assessed using the reverse Kaplan-Meier method.OS, PFS, and hPFS were assessed via Kaplan-Meier analysis and compared using the log-rank test.Predictors of OS, PFS, and hPFS were assessed using uni-and multivariable Cox regression.Variables included in the initial Cox regression model were selected based on previous literature. 11 p value of < 0.05 was considered statistically significant.All analyses were performed in R version 4.0.2. 12
Table 1 summarizes the baseline characteristics by HGP and HAIP treatment.Patients in the HAIP group were younger, had significantly worse tumor characteristics and a higher ASA score in both HGP groups.All patients undergoing HAIP chemotherapy were treated at MSKCC.

Survival Outcomes of the Whole Cohort
The median follow-up period for survivors of the whole population was 71 months (IQR 38-106).During follow-up, 575 patients died, 810 patients had a recurrence, and 471 patients had a hepatic recurrence with or without the presence of extrahepatic recurrence.

DISCUSSION
No interaction between HGP and adjuvant HAIP chemotherapy was found in patients who underwent resection of CRLM.HAIP was associated with an improved OS, PFS, and hPFS, regardless of HGP.
4][15] In a retrospective series of 2368 patients with resectable CRLM, the median survival was 67 months with, versus 44 months without, HAIP chemotherapy (HR: 0.67 [95% CI 0.59-0.76],p < 0.001). 14Moreover, long-term results of a randomized controlled trial showed a HAIP chemotherapy-associated improvement in 2-year OS and PFS (31.3 vs. 17.2 months, P = 0.02) in patients with resectable CRLM. 13It is likely that not all patients with resected CRLM benefit equally from HAIP chemotherapy.For example, the retrospective study found that patients with extrahepatic disease, whether or not resected, did not appear to benefit from HAIP chemotherapy. 14More biomarkers are needed to select patients who are most likely to benefit from HAIP chemotherapy.
Previous studies have shown that CRLM with a non-dHGP were associated with an increased risk of multiorgan recurrence compared with patients with dHGP. 10 Buisman et al. found that postoperative systemic chemotherapy was associated with a an improved PFS in the non-dHGP group, but not in the dHGP group, albeit only in patients who have not undergone preoperative systemic chemotherapy. 117][18] Previous studies also found that patients with dHGP were more likely to recur in the liver only. 5We therefore hypothesized that HAIPassociated survival benefit would be more pronounced in dHGP patients.However, we could not demonstrate that HGP was predictive of the effectiveness of adjuvant HAIP  for resectable CRLM.What is more, HAIP patients in the dHGP group showed a similar hPFS to the HAIP group in the non-dHGP group, while OS and PFS were lower in the latter group.This further supports our findings that HAIP effectively prevents hepatic recurrence regardless of HGP, while non-dHGP patients are more likely to develop (and succumb to) extrahepatic progression.The lack of interaction between HGP and HAIP chemotherapy in hPFS suggests that the differences in tumor biology do not predict the effectiveness of HAIP chemotherapy.However, the effect of tumor HGPs on HAIP efficacy are unknown and should be considered in future research.
This study has certain limitations.Firstly, the retrospective nature poses a high risk of selection bias between HAIP and no-HAIP treatment.There are some differences in baseline characteristics between HAIP and no-HAIP patients in both HGP groups; HAIP patients were younger, but had overall more unfavorable tumor characteristics in both HGP

TABLE 1
Baseline characteristics in all patients (n = 1233)

TABLE 3
Bold values are statistically significant (p < 0.05)