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HPB : The Official Journal of the International Hepato Pancreato Biliary Association logoLink to HPB : The Official Journal of the International Hepato Pancreato Biliary Association
. 2015 May 23;17(7):644–650. doi: 10.1111/hpb.12421

Prospective evaluation of 18F-fluorodeoxyglucose positron emission tomography in patients receiving hepatic arterial and systemic chemotherapy for unresectable colorectal liver metastases

Camilo Correa-Gallego 1, Somali Gavane 2, Ravinder Grewal 2, Andrea Cercek 3, David S Klimstra 4, Alexandra N Gewirtz 3, T Peter Kingham 1, Yuman Fong 1, Ronald P DeMatteo 1, Peter J Allen 1, William R Jarnagin 1, Nancy Kemeny 3, Michael I D'Angelica 1
PMCID: PMC4474513  PMID: 26010778

Abstract

Background

The prognostic and predictive abilities of 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) coupled with conventional computed tomography (CT) have not been studied in patients with unresectable colorectal liver metastases (uCRLM) treated with combined hepatic arterial infusion (HAI) and systemic chemotherapy.

Objectives

The ability of PET-CT metabolic response parameters to predict conversion to resectability and oncologic outcome in this setting was evaluated.

Methods

Thirty-eight patients undergoing serial PET-CT as part of a Phase II trial of HAI and systemic chemotherapy for uCRLM were included. Metabolic response was determined as the percentage change in standard uptake value (SUV) and total lesion glycolysis (TLG). Conversion to resection, overall survival (OS), progression-free survival (PFS) and recurrence-free survival were evaluated using standard statistics.

Results

Volumetric response sufficient to facilitate resection was seen in 53% of patients after a median of 5 months of therapy. Median follow-up was 38 months (range: 32–52 months). Median OS was not reached [95% confidence interval (CI) 32 months–unknown] and 3-year OS was 54% (range: 33–71%). Median PFS was 13 months (95% CI 6–21 months) and 3 year PFS was 10% (range: 3–20%). Neither baseline values nor the percentage change in any of the metabolic parameters evaluated correlated with conversion to resection, survival variables or hepatic recurrence on Cox regression analysis.

Conclusions

Pre- and post-treatment PET-related metabolic parameters do not predict conversion to resection or oncologic outcome in patients with uCRLM treated with HAI and systemic chemotherapy. Metabolic parameters should not be used to monitor response or to determine prognosis in these patients.

Introduction

Approximately 20% of patients with colorectal cancer have synchronous colorectal liver metastases (CRLM). Additionally, 20–30% will develop metachronous liver metastases.1 Hepatic resection is the treatment of choice in the 10–20% of patients in whom complete resection is feasible.1–4 In the remaining patients, chemotherapy constitutes the main therapeutic option. However, a subset of these patients experience significant volumetric response that is sufficient to allow resection with curative intent and thus prolonged survival.5–8 Various combination regimens of intrahepatic arterial and systemic chemotherapy have been shown to achieve conversion to resectability in 30–50% of recipients.7,9,10

Adequate staging is germane to identify patients in whom complete resection is likely. Some advocate the routine use of 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) coupled with conventional computed tomography (CT) in the work-up of patients with CRLM, particularly for the evaluation of extrahepatic disease.11–15 A recent meta-analysis suggested that 18F-FDG PET-CT has higher accuracy than CT alone for the detection of both hepatic and extrahepatic CRLM and that its routine use may lead to a change in therapy in 9–66% of patients.16 A recent trial, however, which randomized patients with resectable CRLM to undergo preoperative PET-CT and evaluated changes in surgical management subsequent to it, found it had no impact on surgical planning compared with CT alone.17

The use of FDG PET-CT for restaging and evaluation of response after chemotherapy in patients with initially unresectable CRLM is less clearly defined. Metabolic response to treatment has been reported to represent a predictive and prognostic biomarker in other malignancies.18–23 However, studies focusing on primary24,25 and metastatic26 colorectal cancer have failed to prove FDG PET-CT an effective biomarker, and its sensitivity to detect metastasis after conversion chemotherapy has been questioned.27,28

Although the role of FDG PET-CT in staging, restaging and patient selection and as a prognostic marker has been an area of study and debate in patients with CRLM receiving systemic chemotherapy, the metabolic response parameters after treatment with hepatic arterial infusion pump (HAIP) in patients with unresectable CRLM have not been studied. Furthermore, the ability of PET metabolic parameters (at baseline and in response to chemotherapy) to predict conversion to resection of initially unresectable CRLM has not been studied to date. The present study specifically aims to define the ability of baseline and post-treatment FDG PET-CT to predict conversion to resectability in the setting of a Phase II clinical trial of HAIP chemotherapy for unresectable CRLM. Secondary aims include an assessment of oncologic outcomes, as related to FDG PET-CT metabolic parameters.

Materials and methods

After approval had been gained from the Memorial Sloan–Kettering Cancer Center Institutional Review Board, 49 patients with unresectable CRLM were enrolled in a prospective Phase II trial (clinicaltrials.gov ID: NCT00492999) evaluating the rate of conversion to complete resection in patients with initially unresectable liver-only metastases from colorectal cancer treated with HAIP with floxuridine (FUDR) and dexamethasone (Dex) in addition to best systemic chemotherapy combined with bevacizumab. Unresectability was prospectively determined by two hepatobiliary surgeons and one radiologist and defined as technical (involvement of three hepatic veins, both portal veins or the retrohepatic vena cava, or resection leaving less than two adequately perfused and drained segments) or biological (more than six metastases in a single lobe, with one lesion of ≥5 cm, or six or more bilobar metastases). Responses that allowed resection with enough functional liver parenchyma (for technically unresectable disease) or radiologically stable disease or response (in biologically unresectable patients) prompted consideration for resection with curative intent. Initial results, including the oncologic outcomes of this trial, have been published previously.9 The present report centres exclusively on the role of FDG PET-CT as a predictive and prognostic tool in this setting.

Chemotherapy regimen

Enrolled patients received systemic chemotherapy with either oxaliplatin and irinotecan (for patients who had received up to two cycles of oxaliplatin and had no persistent neuropathy) or irinotecan plus 5-fluorouracil/leucovorin (5FU/LV) (for those with prior treatment that included over two cycles of oxaliplatin). Both regimens included bevacizumab (5 mg/kg). Therapy was given over a 4-week cycle. HAIP therapy with FUDR was administered on day 1 of each cycle and the pump emptied and filled with heparin and normal saline on day 15. Systemic chemotherapy was administered on days 1 and 15 of each cycle. Treatment recycled on day 29.

As part of the staging protocol, baseline FDG PET-CT and diagnostic CT with angiography of the chest, abdomen and pelvis were obtained. Patients were classified according to the clinical risk score (CRS) as previously reported.29 Resectability was reassessed jointly by two hepatobiliary surgeons and one liver radiologist on CT scans performed every two cycles. Patients considered to be resectable at restaging underwent laparotomy with the intent of complete resection. Examination with FDG PET-CT was repeated after cycles 3 and 6 and/or before patients underwent hepatic resection.

FDG PET-CT

All scans were performed using PET-CT cameras, including the Discovery LS, Discovery ST and Discovery STE (GE Healthcare, Waukesha, WI, USA) or Biograph LSO-16 (Siemens Medical Solutions, Malvern, PA, USA), without preference. Patients fasted for 6 h before undergoing an 18F-FDG PET-CT scan. Approximately 370–555 Mbq (12–15 mCi) of 18F-FDG was injected i.v. Patients received oral contrast during the uptake period. Low-dose CT (120–140 kV, 60–80 mA) and PET emission images were obtained from the base of the skull to the middle of the thigh at 60–90 min after injection. Reconstructed images were loaded onto a PET VCAR (volume computer-assisted reading) workstation (GE Healthcare, Milwaukee, WI, USA). Volumetric regions of interest were placed over five index hepatic lesions with the most abnormal 18F-FDG uptake. Region-of-interest borders were set by manual adjustment in three planes.

A threshold of 42% of the maximum signal intensity was used for segmentation of lesions. Maximum and average standard uptake value (SUVmax and SUVavg), as well as total lesion glycolysis (TLG), a measure of the SUV in relation to the volume of each lesion, were calculated using PET VCAR on baseline and follow-up scans.

Response parameters

Computed tomography response was determined using the World Health Organization (WHO) criteria.30 Thus, a complete response (CR) was indicated by the disappearance of all target lesions. A partial response (PR) was indicated by a reduction of ≥50% from study baseline of all measured defects on CT. Stable disease (SD) was indicated by a reduction of ≤50% and an increase of <25% in summed products of all measured defects on CT, and progressive disease (PD) was indicated by an increase of ≥25% in the sum of the longest diameter of target lesions. Metabolic response was determined as the percentage change in the metabolic parameter (%Δ-MP) between serial FDG PET-CT scans, and was applied to SUVmax and TLG.

Complete metabolic response was defined as a best response of ≥95% in SUVmax. For SUVmax, response was calculated after subtracting the background metabolic activity of the liver (mean ± standard deviation: 2.2 ± 0.25). These responses were calculated after two nuclear radiologists blinded to the clinical outcomes independently reviewed all the available FDG PET-CT scans. Pathologic response was derived from standardized pathology reports of the resected specimens, which included the degree of response to chemotherapy; the cut-off used to determine a clinically relevant response was ≥75%, as determined previously.31

Statistical considerations

All clinical and intervention data were collected prospectively. Descriptive statistics were used to describe demographics and baseline characteristics. Categorical variables are presented as absolute numbers and percentages. Continuous variables are presented as the median and interquartile range (IQR). Logistic regression was used to assess the relationship between conversion to resectability and the metabolic variables obtained at baseline and follow-up FDG PET-CT scans. Correlations between metabolic (PET), volumetric (CT) and pathologic responses were evaluated with Pearson's r. Survival was predicted with the Kaplan–Meier method and reported in months with 95% confidence intervals (CIs). The impact of the metabolic parameters on oncologic outcome (overall and liver progression-free survival) was evaluated with Cox regression. All statistical analyses were performed using stata Version 12.0 (StataCorp LP, College Station, TX, USA).

Results

Between 2007 and 2011, 49 patients were enrolled in the study. Because of prior treatment with oxaliplatin, 59% of patients (29/49) received systemic irinotecan + 5FU/LV in addition to HAIP therapy. The remaining 20 received oxaliplatin-based systemic chemotherapy. Grade 3 or 4 toxicity occurred in 41% (20/49) of patients. The first 24 patients to be treated with bevacizumab showed a 54% toxicity rate, which included significant biliary toxicity. Based on these and additional adverse event data collected at the study institution,32–34 bevacizumab was removed from the protocol; all other therapies remained unchanged. The overall response rate was 76%.9

Metabolic activity on FDG PET and response to therapy

Thirty-nine patients with a baseline FDG PET-CT scan were included in this analysis. General demographics and presentation are detailed in Table1. Thirty-eight patients had at least one follow-up FDG PET-CT scan and 25 had a second follow-up after six cycles of HAIP therapy. Most patients experienced significant metabolic response. The median SUVmax response was 83% (IQR: 75–92%). Complete metabolic response was seen in 11% (n = 4) of patients, a metabolic response of ≥80% in 58% (n = 22), and a metabolic response of ≥70% in 79% (n = 30) of patients. Only three of 38 patients had a metabolic response of <50%. The median TLG response was 92% (IQR: 85–97%). Data for FDG PET metabolic response are summarized in Tables2 and 3. Different degrees of metabolic response are illustrated in Fig.1.

Table 1.

Demographics and baseline characteristics in patients with colorectal liver metastases submitted to 18F-FDG positron emission tomography and computed tomography (PET-CT)

Patients (n) 39
Age, years, median (IQR) 56 (46–63)
Male, n (%) 23 (59%)
Clinical risk score, n (%)
 2 3 (8%)
 3 16 (41%)
 4 13 (33%)
 5 7 (18%)
Prior chemotherapy, n (%) 23 (59%)
Baseline 18F-FDG PET-CT, n (%) 39 (100%)
Lesions on imaging, n, median (IQR) 14 (7–24)
Largest tumour diameter, cm, median (IQR) 4 (3–6)
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18F-FDG, 18F-fluorodeoxyglucose; IQR, interquartile range.

Table 2.

Metabolic parameters at baseline and post-hepatic arterial infusion pump therapy by 18F-FDG positron emission tomography (PET)

Median (interquartile range)
Metabolic variable Baseline (n = 38) First follow-up (n = 38) Second follow-up (n = 25)
SUVmax 10.0 (7.0–13.0) 3.6 (2.8–4.0) 3.2 (2.5–4.0)
SUVavg 6.0 (4.0–8.0) 2.5 (2.2–2.8) 2.5 (2.0–3.0)
TLGmax 91.0 (40.0–213.0) 14.0 (5.0–39.0) 5.5 (2.0–17.0)
Liver background activity 2.3 (2.0–2.4) 2.2 (2.0–2.3) 2.1 (1.9–2.4)
Maximum volume 39 (18–58) 11 (7–18) 6 (2–9)
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18F-FDG, 18F-fluorodeoxyglucose; Maximum volume, maximal metabolically active lesion volume; SUV, standard uptake value; TLG, total lesion glycolysis.

Table 3.

Metabolic response post-hepatic arterial infusion pump therapy by 18F-FDG positron emission tomography (PET)

%Δ, median (interquartile range)
Metabolic response All patients (n = 38) Resection (n = 20) No resection (n = 18) P-valuea
SUVmax 83 (75–92) 83 (72–89) 83 (75–92) 0.4
TLG 92 (85–97) 90 (80–96) 93 (88–97) 0.2
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a

Comparing resected and non-resected patients.

%Δ, percentage change; 18F-FDG, 18-fluorodeoxyglucose; SUV, standard uptake value; TLG, total lesion glycolysis.

Figure 1.

Figure 1

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Different patterns of response to hepatic arterial infusion chemotherapy, showing (a, b) complete resolution of metabolic activity and (c, d) a partial metabolic response.

Conversion to resection and pathologic response

Twenty of 38 (53%) patients had sufficient volumetric response to be deemed resectable and underwent complete resection after a median of 5 months (range: 5–7 months) of therapy. There was no difference in the median percentage Δ-SUV and Δ-TLG between patients who achieved resection and those who did not (Table3). Furthermore, baseline metabolic activity (SUVmax and TLG) and the percentage response after therapy, used as continuous variables in a logistic regression analysis, were unable to predict which patients were more likely to achieve resection (Table5).

Table 5.

Metabolic response in relation to conversion to resection and recurrence-free survival in resected patients (n = 20)

Metabolic variables and conversion to resection OR (P-value)
SUVmax baseline 0.9 (0.2)
TLG baseline 0.9 (0.08)
PET SUVmax % response 0.24 (0.4)
TLG % response 0.04 (0.3)
Metabolic variables and Hep-RFS after resection HR (P-value)
PET SUVmax % response 1.00 (0.93)
PET SUVavg % response 1.01 (0.64)
TLG % response 1.00 (0.87)
SUVmax baseline 1.02 (0.67)
SUVavg baseline 1.01 (0.74)
TLG baseline 0.99 (0.63)
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Hep-RFS, hepatic recurrence-free survival; HR, hazard ratio; OR, odds ratio; PET, positron emission tomography; SUV, standard uptake value; TLG, total lesion glycolysis.

Most patients who underwent resection (18/20) experienced an anatomical PR by WHO criteria on follow-up CT scans. The other two showed minimal responses (SD by WHO criteria) that were sufficient to allow complete resection. The only patient in the entire cohort to experience a radiologic CR did not come to resection and remains disease-free and off all therapy at 57 months of follow-up. Most patients (13/20) had a clinically significant pathologic response defined as a response of <75% (Table4). In two patients, no viable tumour was identified on final pathology.

Table 4.

Radiologic, metabolic and pathologic response in resected patients

Resected patients, n (%) 20 (53%)
WHO response criteria, n
 Partial response 18
 Stable disease 2
Metabolic response, n
 <70% 5
 70–79% 3
 80–94% 11
 ≥95% 1
Pathologic response, n
 <75% 7
 75–99% 11
 100% 2
r-value of metabolic parameters versus PRa
 CT % response 0.41
 PET SUVmax % response 0.25
 PET SUVavg % response − 0.10
 TLG % response 0.13
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a

r-value was estimated using Pearson's correlation.

PET, positron emission tomography; PR, pathologic response; SUV, standard uptake value; TLG, total lesion glycolysis; WHO, World Health Organization.

No linear relationship was identified between the volumetric response on CT, the percentage change in the metabolic variables and the percentage of pathologic response (Table4). Median metabolic response was not greater in the 13 patients with a clinically significant pathologic response [86% (range: 66–91%) versus 81% (range: 79–88%); P = 0.6]. The two patients who achieved CR on pathology had metabolic responses of 93% and 60%, respectively. However, only one of four patients with a complete metabolic response underwent resection and showed a pathologic response of 40%. Furthermore, volumetric CT response did not correlate with Δ-TLG and Δ-SUV on Pearson's correlation (r = 0.1 and r = 0.2, respectively). Moreover, metabolic variables and their percentage change in response to therapy did not predict hepatic RFS after resection (Table5). Findings on FDG PET-CT did not result in a change in therapy or in the detection of unexpected extrahepatic disease in any patient.

Oncologic outcome

At a median follow-up time of 38 months for survivors (range: 32–52 months), median OS in all patients had not been reached (95% CI 32 months–unknown) and the predicted 3-year OS was 54% (range: 33–71%). Median PFS was 13 months (95% CI 6–21 months) and 3-year PFS was 10% (range: 3–20%). On Cox regression, none of the FDG PET metabolic parameters were found to be associated with any of the oncologic outcomes (Table6).

Table 6.

Metabolic variables and oncologic outcomes in all patients (n = 38)

Variable Median (IQR) Hepatic PFS PFS OS
HR P-value HR P-value HR P-value
CT % response 64 (55–80) 0.99 0.3 0.99 0.2 0.99 0.28
PET SUVmax % response 81 (57–93) 0.99 0.5 1.00 0.7 1.01 0.57
PET SUVavg % response 93 (69–100) 1.00 0.4 1.00 0.85 1.01 0.31
TLG % response 84 (68–94) 1.00 0.8 1.00 0.7 1.01 0.47
SUVmax baseline 10 (7–13) 1.10 0.2 1.02 0.6 1.22 0.53
SUVavg baseline 6 (4–8) 0.98 0.6 0.99 0.7 0.76 0.59
TLG baseline 91 (40–203) 0.99 0.6 1.00 0.12 1.00 0.92
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CT, computed tomography; HR, hazard ratio; IQR, interquartile range; OS, overall survival; PET, positron emission tomography; PFS, progression-free survival; SUV, standard uptake value; TLG, total lesion glycolysis.

Discussion

Although many consider FDG PET-CT to be an established tool for the initial staging of patients with CRLM, it does not have a proven role in monitoring disease during or after chemotherapy. Cytotoxic chemotherapy decreases tumoral hexokinase activity, preventing FDG from accumulating in tumours and decreasing the metabolic parameters (SUV and TLG). In a study by Akhurst et al., FDG PET-CT showed sensitivity of 72% in detecting CRLM, which decreased to 63% in patients who received concurrent fluoracil-based chemotherapy.28 These tumours showed a 40% reduction in the activity of hexokinase measured in frozen specimens at the time of resection. In a retrospective study, Tan et al. specifically evaluated CRLM in which a complete metabolic response was achieved after neoadjuvant chemotherapy.26 In that study, 85% of ‘PET-negative’ lesions were found to harbour viable tumour upon histologic examination. Interestingly, patients who showed both metabolic and radiologic response by RECIST (response evaluation criteria in solid tumours) also had a high false-negative rate (86%). A similar false-negative rate (87%) was reported by Glazer et al.35 In the latter study, which evaluated the ability of post-treatment FDG PET-CT to identify liver lesions, only 11% of patients had negative FDG PET-CT after chemotherapy (<90% received oxaliplatin-based therapy). However, most of these (13/15) were false negatives and the negative predictive value was 13%. The authors concluded that FDG PET-CT performed within 4 weeks of chemotherapy for CRLM is not reliable for restaging.35

Recently, a multi-institution, prospective, randomized controlled trial evaluating the effect of preoperative PET-CT on the surgical management of patients with resectable CRLM showed that preoperative PET-CT did not alter surgical plans (proposed after review of CT) in a significant proportion of patients. Furthermore, the impact of PET-CT on survival by way of enhanced patient selection was evaluated. No survival difference was found between patients randomized to PET-CT and controls (CT only).17 Although the patient populations differ (resectable and unresectable CRLM), the conclusions of this study, like those of the present investigation, strongly question the routine use of PET-CT in the staging and follow-up of patients with CRLM.

Until now, FDG PET-CT has not been studied in patients receiving combination HAI and systemic chemotherapy. In the present prospective study of HAI with FUDR and systemic therapy for the treatment of uCRLM, half of the patients experienced enough radiologic response to be considered resectable. The pathologic response among patients undergoing resection varied significantly and only 10% (two of 20) of patients experienced a pathologic CR. Pathologic response did not correlate with the degree of metabolic response. In one patient, who showed a complete metabolic response and underwent resection, pathologic response was only 40%. However, the two patients who achieved a CR had been found to have metabolic responses of only 90% and 60%, which makes these data uninterpretable. Moreover, the percentage change in the metabolic variables (metabolic response) as a continuous variable did not predict conversion to resection or correlate with oncologic outcome.

The results of this study are in line with those reported by Tan et al.26 and Glazer et al.35 regarding the lack of correlation between metabolic and pathologic response. The cited studies, however, did not address the issue of longterm oncologic outcome in relation to metabolic activity before and after treatment. This study evaluates the utility of non-standard metabolic parameters (TLG, SUVmax, SUVavg) and their responses, which have proven useful in other settings18,36,37 in predicting outcomes in this cohort of patients. However, no clinically significant correlation was apparent. Despite being used as a prognostic marker in other malignancies,19–21,23 FDG PET-CT does not seem to be an adequate prognostic or predictive marker in patients with CRLM, particularly in those receiving HAI therapy. No correlation between FDG PET-CT metabolic activity (or metabolic response) and OS, PFS or hepatic RFS was found in patients who underwent resection with curative intent.

The patient population in this study is unique. To the present authors' knowledge, this is the first study to prospectively evaluate the ability of FDG PET-CT to predict conversion to resection of initially unresectable disease based on metabolic response parameters in patients receiving HAI and systemic chemotherapy. Potential limitations include the fact that there was no dedicated review of the available pathology. However, routine pathology reports at the study institution include the degree of response to chemotherapy expressed as a percentage; the cut-off for a clinically relevant response (≥75%) was determined from the present group's prior experience as reported by Poultsides et al.31 Furthermore, FDG PET-CT response was not the primary objective of the trial, but, rather, its investigation was built in as a correlative study and baseline FDG PET-CT data were not available for all patients accrued. However, the fact that FDG PET-CT assessments were part of the protocol allowed for standardization of technique and interpretation in patients for whom FDG PET-CT scans were available.

Conclusions

In this series of patients with unresectable CRLM, responses on FDG PET-CT proved unable to predict conversion to resectability after treatment with a combination of HAI and systemic chemotherapy. Furthermore, no correlation was identified between metabolic response and pathologic response in resected specimens and no prognostic value of the metabolic response assessed with FDG PET-CT was ascertained. Based on these findings, the present authors believe FDG PET-CT should not be used to monitor treatment or in restaging after treatment with HAI chemotherapy, or as a prognostic tool in this group of patients.

Conflicts of interest

None declared.

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