Metabolic tumor volume predicts long-term survival after transplantation for unresectable colorectal liver metastases: 15 years of experience from the SECA study

Patients with CRLM from all regions of Norway that may be candidates for LT are referred to the multidisciplinary hepatobiliary meeting at Oslo University Hospital. This meeting consisting of hepatobiliary surgeon, transplant surgeon, radiologist and oncologist decide on treatment options for these patients.

In total, 40 patients were treated with LT for unresectable CRLM in the SECA-1 (n = 23) and SECA-2 (n = 17) studies in the period November 2006–August 2018. ¹⁸F-FDG PET/CT scan was a part of the preoperative study protocol to exclude extrahepatic disease [8]. The main inclusion criteria were unresectable colorectal liver only metastases, good performance status (ECOG score 0 or 1), previous chemotherapy and completed radical excision of the primary tumor. Patients who fulfilled all inclusion criteria without evidence of extrahepatic malignant disease on ¹⁸F-FDG PET/CT and contrast enhanced CT underwent LT. All liver metastases from these ¹⁸F-FDG PET scans were evaluated in the present study. Chemotherapy was paused the last 4–6 weeks before the ¹⁸F-FDG PET/CT scan.

The SECA studies were approved by the Regional Ethics Committee and registered at clinicaltrials.gov with registration number NCT01311453 for the SECA-1 study and NCT01479608 for the SECA-2 study. All patients signed an informed written consent.

All ¹⁸F-FDG PET/CT procedures were performed on a hybrid PET/CT system (Siemens Biograph 64 or 16), Siemens Medical Systems, Erlangen, Germany. The patients fasted for minimum six hours and serum glucose level was measured before ¹⁸F-FDG was injected intravenously. Median injected dose was 383 MBq (range 252–458). Image acquisition started after about 60 min of rest. A whole-body PET from skull base to the upper thigh with an acquisition time of 3 min per bed position and 30% overlap was performed. The PET was reconstructed with 168 × 168 pixels (pixel size 4.06 mm) using OSEM with four iterations and eight subsets (4i/8s) and Gaussian post-reconstruction filter with full-width at half maximum of 5 mm. A low-dose CT without contrast enhancement was used for anatomical information and attenuation correction. The CT acquisition parameters were: 120 kV, 50mAs, and axial slices of 3 mm.

MTV was obtained from all liver metastases by manually placing a volume of interest (VOI) over each metastasis using a Siemens SyngoVia workstation (version VB10A, Erlangen, Germany) and a fixed threshold of 40%. MTV was only registered if the uptake was higher than the mean liver background uptake × 1.5 + standard deviation of the liver background × 2 [17]. Patients without any metastases with uptake above this value were given an MTV value of zero. Liver background was measured by placing a VOI of 3 cm in the right liver lobe. Total MTV was calculated by adding the values from all metastases for each patient. Maximum standardized uptake value (SUV_max), SUV_mean, SUV_peak, tumor to background (T/B) ratio and total lesion glycolysis (TLG) were also registered. In patients with more than one liver metastasis the highest SUV was registered. SUV_peak was defined as the SUV_mean of the volume of 1 cm³ around the SUV_max. TLG was calculated by multiplying SUV_mean by MTV.

Statistical analyses were performed with SPSS (IBM, version 27, Chicago, Illinois, USA). A receiver operating characteristic (ROC) analysis was used to determine an MTV cut-off value for predicting OS. Cut-off values for SUV_max, SUV_mean, SUV_peak, T/B ratio and TLG were also obtained. OS was defined as time from LT until death or end of follow-up 22nd of December 2021. Disease-free survival (DFS) was defined as time from LT to the detection of suspected metastases or local recurrence on either CT, MRI or PET/CT. Post recurrence survival (PRS) is OS minus DFS. Survival curves were generated using the Kaplan–Meier method and the groups were compared using the log rank test. Synchronous liver metastases were defined as liver metastases occurring less than 12 months and metachronous more than 12 months after the CRC diagnosis. The response evaluation criteria in solid tumors (RECIST) on CT were used to evaluate response to chemotherapy prior to LT. Progression of disease was defined as a 20% or greater increase in the sum of the longest diameter of the target lesions. An increase in carcinoembryonic antigen (CEA) level prior to LT was also interpreted at progression of disease. A nonparametric Mann–Whitney U test was used for comparing continuous data and Fishers exact test was used for comparing categorical data. A 2-tailed probability level less than 0.05 was considered statistically significant.

Patient and baseline characteristics for all patients and a comparison of the MTV low (< 70 cm³) versus MTV high (> 70 cm³) group is given in Table 1. The patients with high MTV had significantly higher CEA levels, number of liver metastases, size of the largest liver metastasis, N-stage, number of chemotherapy lines and frequency of progressive disease at LT compared to the patients with low MTV. A comparison of clinopathological features and PET metrics is given in Table 2.

The ROC analysis determined an MTV cut-off value of 66.09 cm³. Twenty-six patients had low MTV (< 70 cm³) and 14 patients had high MTV (> 70 cm³). Cut-off values based on the ROC analysis were obtained for SUV_max (5.87), SUVmean (3.54), SUV_peak (5.49), T/B-ratio (5.28) and TLG (238.80). The MTV low group had significantly lower SUV_max, SUV_mean, SUV_peak, T/B-ratio and TLG compared to the MTV high group (Table 2).

OS Kaplan–Meier survival curve for patients with low (n = 26) versus high (n = 14) MTV is shown in Fig. 1. OS at 5 and 10 years were 76 and 50% in the MTV low patients compared to 21 and 7% in the patients with high MTV (p < 0.001).

In patients where the ¹⁸F-FDG PET/CT was performed more than 90 days before LT (n = 20), the effect of low MTV was not significant compared to high MTV (p = 0.093, Fig. 2). Twenty patients underwent ¹⁸F-FDG PET/CT less than 90 days before LT. In this subgroup, 71 and 61% were alive at 5 and 10 years when MTV was low (n = 11), and 22% and 0% MTV was high (p < 0.001, Fig. 2).

TLG analysis stratified the exact same patients and gave the same survival results as MTV. SUV_max, SUV_mean, SUV_peak and T/B-ratio showed non-significant differences when comparing OS for patient with low versus high values (p = 0.401, 0.366, 0.355 and 0.056). Figure 3 illustrates one patient with low MTV still alive almost 14 years after LT despite pulmonary relapse. Figure 4 illustrates one patient with high MTV who developed a multiple site recurrence and died only 14 months after LT.

DFS and PRS estimated survival analysis for MTV low versus MTV high is shown in Fig. 2. All 14 patients with high MTV and 19 out of 26 with low MTV had developed recurrence. DFS at 1,3 and 5 years was 53, 31 and 21% in the MTV low group compared to 36, 0 and 0% in the MTV high group (p < 0.001, Fig. 1). Median DFS was 16 months in the MTV low group compared to 4 months in the MTV high group (p < 0.001, Fig. 1). Although the MTV low patients had somewhat higher number of patients with lungs as first site recurrence compared to the MTV high patients, no significant difference in first site recurrence was observed (p = 0.233, Table 2).

PRS was significantly improved in the MTV low compared to the MTV high group with 57 and 37% alive at 5 and 10 years compared to 14 and 7% (p = 0.006, Fig. 1).