Serial measurement of hepatic lipids during chemotherapy in patients with colorectal cancer: a 1 H MRS study

Abstract

Hepatic steatosis is a hallmark of chemotherapy-induced liver injury. We made serial (1) H MRS measurements of hepatic lipids in patients over the time course of a 24-week chemotherapeutic regimen to determine whether (1) H MRS could be used to monitor the progression of chemotherapy-induced steatosis. Thirty-four patients with stage III or IV colorectal cancer receiving 5-fluorouracil, folinic acid and oxaliplatin (n=21) or hepatic arterial infusion of floxuridine with systemic irinotecan (n=13) were studied prospectively. (1) H MRS studies were performed at baseline and after 6 and 24 weeks of treatment. A (1) H MR spectrum was acquired from the liver during a breath hold and the ratio of fat to fat+water (FFW) was calculated to give a measure of hepatic triglycerides (HTGCs). The methodology was histologically validated in 18 patients and the reproducibility was assessed in 16 normal volunteers. Twenty-seven patients completed baseline, 6-week and 24-week (1) H MRS examinations and one was censored. Thirteen of 26 patients (50%) showed an increase in FFW after completion of treatment. Six patients (23%) developed hepatic steatosis and two patients converted from steatosis to nonsteatotic liver. Patients whose 6-week hepatic lipid levels had increased significantly relative to baseline also had a high probability of lipid elevation relative to baseline at the completion of treatment. Serial (1) H MRS is effective for the monitoring of HTGC changes during chemotherapy and for the detection of chemotherapy-associated steatosis. Six of 26 patients developed steatosis during chemotherapy. Lipid changes were observable at 6 weeks.

Figure 1

Fat-to-(fat+water) ratio (FFW) vs. histologic liver steatosis grade in 18 patients (19 tissue samples). Clinical steatosis was defined as grade 2 or higher. The dashed line indicates a cut-point of FFW = 0.039 for clinically significant steatosis based on the ROC curve generated from our spectroscopy and histology data.

Figure 2

¹H MRS volume-of-interest (a, e) and spectra acquired from patients 15 and 5 who were treated with FOLFOX. Spectra are from baseline (b,f), 3 cycles/6 weeks (c,g) and 12 cycles/24 weeks (d, h). The FFW values for patient 15 were 0.095, 0.150 and 0.260 (b–d). The FFW values for patient 5 were 0.076, 0.061 and 0.049 (f–h). The dimensions of the volume-of-interest were 20 × 20 × 20 mm³. Breath-held spectral acquisition parameters were: repetition time (TR) = 5s, echo time (TE) = 40ms, spectral width (SW) = 2000 Hz, spectral points = 512, acquisitions = 4.

Figure 3

HTGC changes from baseline to post-24 weeks of FOLFOX (a) or FUDR/Iri (b) treatment. Black line = FFW increase greater than 15%; dashed line = FFW decrease greater than 15%, gray line = FFW change less than 15%. *Patient 12 was treated concurrently with anti-HIV HAART therapy.

Figure 3

HTGC changes from baseline to post-24 weeks of FOLFOX (a) or FUDR/Iri (b) treatment. Black line = FFW increase greater than 15%; dashed line = FFW decrease greater than 15%, gray line = FFW change less than 15%. *Patient 12 was treated concurrently with anti-HIV HAART therapy.

Figure 4

A) Baseline, 6-week, and 24-week FFW measurements for 26 patients normalized with respect to their baseline values. Line color indicates change in FFW after 6 weeks of chemotherapy: black solid line = FFW increase greater than 15% at 6 weeks and remained elevated at 24 weeks compared to baseline; black dashed line = FFW increase greater than 15%, but returned to within 15% of baseline at 24 weeks; gray solid line = FFW change less than 15% at 6 weeks but increased > 15% at 24 weeks, gray dashed line < 15% change at both 6 and 24 weeks. *The final ¹H-MRS data point from patient 19 was acquired 3 months after cessation of chemotherapy. B) Diagram of patient FFW changes during chemotherapy with branching determined by increase (+) or no change/decrease (−) in FFW relative to baseline. Primary branching was determined by the FFW change at 6 weeks relative to baseline. For example, 14 patients had increased FFW at 6-weeks relative to baseline, while 12 patients had unchanged or decreased FFW values after 6 weeks. Secondary branching was determined by the FFW change at 24 weeks relative to baseline.

Figure 4

A) Baseline, 6-week, and 24-week FFW measurements for 26 patients normalized with respect to their baseline values. Line color indicates change in FFW after 6 weeks of chemotherapy: black solid line = FFW increase greater than 15% at 6 weeks and remained elevated at 24 weeks compared to baseline; black dashed line = FFW increase greater than 15%, but returned to within 15% of baseline at 24 weeks; gray solid line = FFW change less than 15% at 6 weeks but increased > 15% at 24 weeks, gray dashed line < 15% change at both 6 and 24 weeks. *The final ¹H-MRS data point from patient 19 was acquired 3 months after cessation of chemotherapy. B) Diagram of patient FFW changes during chemotherapy with branching determined by increase (+) or no change/decrease (−) in FFW relative to baseline. Primary branching was determined by the FFW change at 6 weeks relative to baseline. For example, 14 patients had increased FFW at 6-weeks relative to baseline, while 12 patients had unchanged or decreased FFW values after 6 weeks. Secondary branching was determined by the FFW change at 24 weeks relative to baseline.