Survival after liver resection and liver transplantation for colorectal liver metastases: a comparative analysis stratified by metabolic tumor volume assessed by 18F-FDG PET/CT.

BACKGROUND: Many patients undergoing resection for colorectal liver metastases (CRLM) recur with poor survival. Overall survival (OS) following liver transplantation (LT) for CRLM is reported to be about 80% at 5 years. In this study, survival following resection versus transplantation for CRLM in patients with moderate (6-70 cm3) metabolic tumor volume (MTV) from the preoperative positron emission tomography (PET) was compared. METHODS: Disease-free survival (DFS), OS and post recurrence survival (PRS) following resection (n = 18) and LT (n = 12) was compared by using the Kaplan Meier method and log rank test for patients with moderate MTV. RESULTS: Patients undergoing LT had unresectable metastases, significantly lower age, higher tumor burden score and number of liver metastases, longer time from diagnosis to surgery, and more patients received neoadjuvant chemotherapy. OS at 5 years was 39% in the resection group and 83% in the LT group (P = 0.012). PRS was significantly improved in patients treated with LT compared to resection with 71% alive at 5 years from recurrence compared to 17% in the resection group (P = 0.017). CONCLUSION: LT for selected patients seems to be superior to resection as treatment for CRLM for patients with moderate MTV.

Intracranial effect of osimertinib in relapsed EGFR-mutated T790M-positive and -negative non-small cell lung cancer patients: results from a phase II study.

INTRODUCTION: Osimertinib is effective for relapsed T790M-positive patients with brain metastases. The high brain permeability suggests that also such patients without T790M could benefit. Therefore, we evaluated the effect of osimertinib on brain metastases in both T790M-positive and -negative patients. METHODS: The TREM-study was an investigator-initiated phase II, single-arm, multi-institutional clinical trial conducted in Northern Europe. Patients with resistance to prior EGFR-TKIs received osimertinib until radiological progression, unacceptable toxicity or death. Baseline brain scans were performed in patients with known or suspected brain metastases and repeated every 8-12 weeks. We assessed intracranial efficacy in patients with baseline brain metastases. RESULTS: Brain metastases were detected in 48/199 patients at baseline. Of these, 63% were T790M-positive, 27% -negative and 10% had unknown T790M-status. The majority (73%) of the patients had received prior whole brain radiotherapy and additionally 8% had received stereotactic radiosurgery (SRS). Brain scans were available for review for 42 patients. The intracranial progression free survival was 39.7 versus 3.5 months for T790M + and T790M- patients, respectively (p < 0.001). The overall intracranial disease control rate (iDCR) was 81%, and for T790M + and T790M- patients the DCR was 89% versus 55%, respectively. The estimated risk of CNS progression was 0.8% at 6 months and 6% at 12 months for T790M-positive patients, and 14% and 17% at 6 and 12 months, respectively, for the T790M-negative. CONCLUSION: This subgroup analysis confirms CNS efficacy of osimertinib in patients with the T790M resistance mutation, while other treatment options should be considered for EGFR-TKI relapsed T790M-negative patients with brain metastases.

Treatment of relapse and survival outcomes after liver transplantation in patients with colorectal liver metastases.

Liver transplantation (LT) in selected colorectal cancer (CRC) patients with nonresectable liver-only metastases may result in 5-year overall survival of up to about 70-100%. However, the majority will have recurrent disease. All patients included in this report were included in prospective studies. Forty-four out of 56 patients had a relapse, and all 44 patients received treatment for recurrent disease. The organ of the first relapse was lung metastases in 23 of the 44 patients. The first treatment modality of the relapse was the treatment with curative intent in 55.8% of the patients, and chemotherapy was the first treatment administered to 25.6% of the patients. Patients receiving surgery of lung metastases had a 5-year overall survival of 66.5% from the time of metastasectomy. Patients receiving treatment with curative intent for metastases to other organs had a 5-year overall survival of 24.8%. Nine of the 44 patients had no evidence of disease (NED) at the end of the follow-up. Median time of NED in these patients was 54.3 months, and median overall survival from the time of LT was 8.4 years. Because of the high incidence of recurrent disease, these patients should have a systematic long-term follow-up since many of the relapses may be treated with curative intent.

Selection criteria related to long-term survival following liver transplantation for colorectal liver metastasis.

Patients with nonresectable colorectal cancer receiving palliative chemotherapy have a 5-year overall survival rate of about 10%. Liver transplant provided a Kaplan-Meier-estimated 5-year overall survival of up to 83%. The objective of the study was to evaluate the ability of different scoring systems to predict long-term overall survival after liver transplant. Patients with colorectal cancer with nonresectable liver-only metastases determined by computed tomography (CT)/magnetic resonance imaging/positron emission tomography (PET)-CT scans from 2 prospective studies (SECA-I and -II) were included. All included patients had previously received chemotherapy. PET-CT was performed within 90 days of the liver transplant. Overall survival, disease-free survival, and survival after relapse based on the Fong Clinical Risk Score, total PET liver uptake (metabolic tumor volume), and Oslo Score were compared. At median follow-up of 85 months for live patients, Kaplan-Meier overall survival rates at 5 years were 100%, 78%, and 67% in patients with Fong Clinical Risk Score 0 to 2, metabolic tumor volume-low group, and Oslo Score 0 to 2, respectively. Median overall survival was 101, 68, and 65 months in patients with Fong Clinical Risk Score 0 to 2, metabolic tumor volume-low, and Oslo Score 0 to 2. These selection criteria may be used to obtain 5-year overall survival rates comparable to other indications for liver transplant.

Survival Following Liver Transplantation for Patients With Nonresectable Liver-only Colorectal Metastases.

OBJECTIVE: To determine overall survival and disease-free survival in selected patients with nonresectable liver-only colorectal cancer receiving liver transplantation. BACKGROUND: Patients with nonresectable colorectal cancer receiving palliative chemotherapy has a 5-year overall survival of about 10%. Liver transplantation provided an overall survival of 60% in a previous study (SECA-I). Risk factors for death were carcinoembryonic antigen (CEA) >80 µg/L, progressive disease on chemotherapy, size of largest lesion>5.5 cm, and less than 2 years from resection of the primary tumor to transplantation. METHODS: In this prospective (SECA-II) study, we included colorectal cancer patients with nonresectable liver-only metastases determined by computed tomography (CT)/magnetic resonance imaging/positron emission tomography scans and at least 10% response to chemotherapy. Time from diagnosis to liver transplant was required to be more than 1 year. RESULTS: At a median follow-up of 36 months, Kaplan-Meier overall survival at 1, 3, and 5 years were 100%, 83%, and 83%, respectively. Disease-free survival at 1, 2, and 3 years were 53%, 44%, and 35%, respectively. Overall survival from time of relapse at 1, 2, and 4 years were 100%, 73%, and 73%, respectively. Recurrence was mainly slow growing pulmonary metastases amenable to curative resection. Fong Clinical Risk Score of 1 to 2 at the time of diagnosis resulted in longer disease-free survival than score 3 to 4 (P = 0.044). Patients included in the present study had significantly better prognostic factors than the previous SECA-I study. CONCLUSION: Liver transplantation provides the longest overall survival reported in colorectal cancer patient with nonresectable liver metastases. Improved selection criteria give patients with nonresectable colorectal liver metastases a 5-year overall survival comparable to other indications for liver transplantation.

The prognostic value of 18F-FDG PET/CT prior to liver transplantation for nonresectable colorectal liver metastases.

PURPOSE: The main objective of this study was to evaluate the prognostic value of volumetric and metabolic information derivied from F-18 fluorodeoxyglucose positron emission tomography (18F-FDG PET) in combination with computed tomography (CT) prior to liver transplantation (LT) in patients with nonresectable colorectal liver metastases (CLM). Due to scarcity of liver grafts, prognostic information enabling selection of candidates who will gain the highest survival after LT is of vital importance. 18F-FDG PET/CT was a part of the preoperative study protocol. Patients without evidence of extrahepatic malignant disease on 18F-FDG PET/CT who also fulfilled all the other inclusion criteria underwent LT. METHODS: The preoperative 18F-FDG PET/CT examinations of all patients included in the SECA (secondary cancer) study were retrospectively assessed. Maximum, mean and peak standardized uptake values (SUVmax, SUVmean and SUVpeak), tumor to background (T/B) ratio, metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were measured and calculated for all liver metastases. Total MTV and TLG were calculated for each patient. Cut-off values were determined for each of these parameters by using receiver operating characteristic (ROC) analysis dividing the patients into two groups. One, three and five-year overall survival (OS) and disease free survival (DFS) for patients over and under the cut-off value were compared by using the Kaplan-Meier method and log rank test. RESULTS: Twenty-three patients underwent LT in the SECA study. Total MTV and TLG under the cut-off values were significantly correlated to improved OS at three and five years (p = 0.027 and 0.026) and DFS (p = 0.01). One, three and five-year OS and DFS were not significantly related to SUVmax, SUVmean, SUVpeak or T/B-ratio. CONCLUSION: Total MTV and TLG from 18F FDG PET/CT prior to LT for nonresectable CLM were significantly correlated to improved three and five-year OS and DFS and can potentially improve the patient selection for LT.

Metabolic Tumor Volume from 18F-FDG PET/CT in Combination with Radiologic Measurements to Predict Long-Term Survival Following Transplantation for Colorectal Liver Metastases.

The aim of the present study is to report on the ability of metabolic tumor volume (MTV) of liver metastases from pre-transplant 18F-FDG PET/CT in combination with conventional radiological measurements from CT scans to predict long-term disease-free survival (DFS), overall survival (OS), and survival after relapse (SAR) after liver transplantation for colorectal liver metastases. The total liver MTV was obtained from the 18F-FDG PET/CT, and the size of the largest metastasis and the total number of metastases were obtained from the CT. DFS, OS, and SAR for patients with a low and high MTV, in combination with a low and high size, number, and tumor burden score, were compared using the Kaplan-Meier method and log-rank test. Patients with a low number of metastases and low MTV had a significantly longer OS than those with a high MTV, with a median survival of 151 vs. 26 months (p = 0.010). Patients with a high number of metastases and low MTV had significantly longer DFS, OS, and SAR than patients with a high MTV (p = 0.034, 0.006, and 0.026). The tumor burden score of group/zone 3, in combination with a low MTV, had a significantly improved DFS, OS, and SAR compared to those with a high MTV (p = 0.034, <0.001, and 0.006). Patients with a low MTV of liver metastases had a long DFS, OS, and SAR despite a high number of liver metastases and a high tumor burden score.

Long-Term Survival, Prognostic Factors, and Selection of Patients With Colorectal Cancer for Liver Transplant: A Nonrandomized Controlled Trial.

Importance: Liver transplant for colorectal cancer with liver metastases was abandoned in the 1990s due to poor overall survival. From 2006, liver transplant for in nonresectable colorectal liver metastases has been reexamined through different prospective trials. Objective: To determine predictive factors for transplant long-term survival and cure after liver transplant. Design, Setting, and Participants: This was a prospective, nonrandomized controlled cohort study derived from different clinical trials on liver transplant for colorectal liver metastases from 2006 to 2020 at Oslo University Hospital. The trials differed in prognostic inclusion criteria, but the design was otherwise identical regarding follow-up scheme to determine disease recurrence, overall survival, and survival after relapse. Final data analysis was performed on December 31, 2021. All patients with colorectal liver metastases from comparable prospective liver transplant studies were included. Exposure: Liver transplant. Main outcomes and measures: Disease-free survival, overall survival, and survival time after recurrence were determined in all participants. Results: A total of 61 patients (median [range] age, 57.8 [28.7-71.1] years; 35 male [57.4%]) underwent liver transplant at Oslo University Hospital. Posttransplant observation time ranged from 16 to 165 months, and no patient was lost to follow-up. Median disease-free period, overall survival, and survival after relapse were 11.8 (95% CI, 9.3-14.2) months, 60.3 (95% CI, 44.3-76.4) months, and 37.1 (95% CI, 4.6-69.5) months, respectively. Negative predictive factors for overall survival included the following: largest tumor size greater than 5.5 cm (median OS, 25.3 months; 95% CI, 15.8-34.8 months; P <.001), progressive disease while receiving chemotherapy (median OS, 39.8 months; 95% CI, 28.8-50.7 months; P = .02), plasma carcinoembryonic antigen values greater than 80 µg/L (median OS, 26.6 months; 95% CI, 22.7-30.6 months; P <.001), liver metabolic tumor volume on positron emission tomography of greater than 70 cm3 (26.6 months; 95% CI, 11.8-41.5 months; P <.001), primary tumor in the ascending colon (17.9 months; 95% CI, 0-37.5 months; P <.001), tumor burden score of 9 or higher (23.3 months; 95% CI, 19.2-27.4 months; P = .02), and 9 or more liver lesions (42.5 months; 95% CI, 17.2-67.8 months; P = .02). An Oslo score of 0 or Fong Clinical Risk Score of 1 yielded 10-year survival of 88.9% and 80.0%, respectively. Conclusions and relevance: Results of this nonrandomized controlled trial suggest that selected patients with liver-only metastases and favorable pretransplant prognostic scoring had long-term survival comparable with conventional indications for liver transplant, thus providing a potential curative treatment option in patients otherwise offered only palliative care.

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

OBJECTIVE: To report 15 years of experience with metabolic tumor volume (MTV) of liver metastases from the preoperative 18F-FDG PET/CT to predict long-term survival after liver transplantation (LT) for unresectable colorectal liver metastases (CRLM). METHODS: The preoperative 18F-FDG PET/CT from all SECA 1 and 2 patients was evaluated. MTV was obtained from all liver metastases. The patients were divided into one group with low MTV (< 70 cm3) and one group with high MTV (> 70 cm3) based on a receiver operating characteristic analysis. Overall survival (OS), disease-free survival (DFS) and post recurrence survival (PRS) for patients with low versus high MTV were compared using the Kaplan-Meier method and log rank test. Clinopathological features between the two groups were compared by a nonparametric Mann-Whitney U test for continuous and Fishers exact test for categorical data. RESULTS: At total of 40 patients were included. Patients with low MTV had significantly longer OS (p < 0.001), DFS (p < 0.001) and PRS (p = 0.006) compared to patients with high values. The patients with high MTV had higher CEA levels, number of liver metastases, size of the largest liver metastasis, N-stage, number of chemotherapy lines and more frequently progression of disease at LT compared to the patients with low MTV. CONCLUSION: MTV of liver metastases is highly predictive of long-term OS, DFS and PRS after LT for unresectable CRLM and should be implemented in risk stratification prior to LT.

PET-Uptake in Liver Metastases as Method to Predict Tumor Biological Behavior in Patients Transplanted for Colorectal Liver Metastases Developing Lung Recurrence.

The objective of the study was to determine the impact of PET uptake on liver metastases on overall survival (OS) after resection of pulmonary metastases in patients who had received liver transplantation (LT) due to unresectable colorectal liver-only metastases. Resection of pulmonary colorectal metastases is controversial. Some hospitals offer this treatment to selected patients, whereas other hospitals do not perform the procedure in colorectal cancer patients who develop pulmonary metastases. All patients included in the LT studies who developed pulmonary metastases as first site of relapse, and had resection of these as first treatment, were included in this report. Metabolic tumor volume (MTV) in liver was derived from the pre-transplant PET examinations. OS from time of resection was calculated by the Kaplan−Meier method. Patients with low MTV (<70 cm3) had significantly longer OS from time of resection of pulmonary metastases compared to patients with high MTV (>70 cm3). Patients with low MTV in the liver had 10-year OS from time of pulmonary resections of 86%. Liver MTV values from pre-transplant PET examinations may predict long OS in colorectal cancer patients with a resection of pulmonary metastases developing after LT. Thus, in selected colorectal cancer patients developing pulmonary metastases resection of these metastases should be the treatment of choice.

Preoperative 18F-FDG PET/computed tomography predicts survival following resection for colorectal liver metastases.

OBJECTIVE: The liver is the most frequent metastatic site from colorectal cancer and about 20% of these patients are treated by surgical resection. However, the 5-year disease-free survival (DFS) following resection is only about 25% and 5-year overall survival (OS) about 38%. The aim of the study was to evaluate the ability of metabolic and volumetric measurements from fluorine-18-fluorodeoxyglucose (F-FDG) PET/computed tomography (CT) prior to resection for colorectal liver metastases (CLM) to predict survival. PATIENTS AND METHODS: Preoperative F-FDG PET/CT examinations were assessed. Metabolic tumor volume (MTV), total lesion glycolysis (TLG), maximum, mean and peak standardized uptake values and tumor to background ratio, were obtained for all CLM. Cutoff values were determined for each of these parameters by using receiver operating characteristic analysis dividing the patients into two groups. DFS, liver recurrence-free survival (LRFS), OS and cancer-specific survival (CSS) for patients over and under the cutoff value were compared by using the Kaplan-Meier method and log-rank test. RESULTS: Twenty-seven patients who underwent F-FDG PET/CT prior to resection for CLM were included. Low values of total MTV and TLG were significantly correlated to improved 5-year LRFS (P = 0.016 and 0.006) and CSS (P = 0.034 and 0.008). Patients who developed liver recurrence had significantly higher total MTV and TLG compared to patients without liver recurrence (P = 0.042 and 0.047). CONCLUSION: Low values of total MTV and TLG were significantly correlated to improved LRFS and CSS and may improve the risk stratification of patients considered for resection for CLM.

Importance of 18F-FDG PET/CT to select patients with nonresectable colorectal liver metastases for liver transplantation.

OBJECTIVE: The aim of this study was to evaluate fluorine-18-fluorodeoxyglucose (F-FDG) PET/CT for the selection of patients with nonresectable colorectal liver metastases (NCLM) for liver transplantation (LT). In the secondary cancer study, we reported an improved 5-year overall survival in patients treated with LT for NCLM (56%) compared with chemotherapy (9%). However, many patients were rejected for LT owing to the detection of extrahepatic disease at preoperative imaging. PATIENTS AND METHODS: F-FDG PET/CT and contrast-enhanced computed tomography (ceCT) examinations before tentative LT for NCLM were assessed, and findings contraindicating LT were registered. Maximum, mean and peak standardized uptake values; tumor-to-background ratio; metabolic tumor volume; and total lesion glycolysis were measured and calculated for all liver metastases. Overall survival was calculated by the Kaplan-Meier method. RESULTS: Thirty-two patients excluded by F-FDG PET/CT and/or ceCT before tentative LT for NCLM were identified. F-FDG PET/CT from 20 of the 32 excluded patients revealed extrahepatic disease. Eight of the other 12 patients had a negative F-FDG PET/CT finding but were excluded by ceCT. Ten patients were excluded by F-FDG PET/CT only. Four patients were excluded owing to detected malignancy from frozen sections at the start of the intended transplant operation. Tumor-to-background ratio of the liver metastases was significantly higher in patients where F-FDG PET/CT detected extrahepatic disease (P=0.03). The median (range) survival after exclusion was 16 (0-52) months. CONCLUSION: The ability of F-FDG PET/CT to detect extrahepatic disease before LT for NCLM is vital to establish LT as a treatment option.