Liver-predominant Metastatic Colorectal Cancer Research Articles

Salvage regional therapy using hepatic artery infusion pump in unresectable chemotherapy resistant colorectal liver metastases

BackgroundLittle is known about the influence of hepatic artery infusion pump (HAIP) therapy in the setting of chemotherapy resistant hepatic disease in the era of modern systemic therapies. MethodsPatients who underwent HAIP therapy for chemotherapy resistant and unresectable colorectal liver metastases (CRLM) were reviewed retrospectively. ResultsA total of 25 patients met inclusion criteria. 52% had isolated CRLM and 92% had five or more metastatic lesions. Partial response was noted in 40% of patients. Median hepatic progression-free survival (PFS) was 7 months in those with extrahepatic disease versus 6 months in those with isolated CRLM at the time of HAIP placement (p = 0.75). Median overall survival was 8 months in patients with extrahepatic disease and 14 months in patients with isolated CRLM (p = 0.06). ConclusionsOur findings are comparable to published data and augment the literature which supports HAIP use in chemotherapy-resistant, liver-predominant metastatic colorectal cancer patients.

Phosphorylated transducer and activator of transcription-3 (pSTAT3) immunohistochemical expression in paired primary and metastatic colorectal cancer

BackgroundSignal Transducer and Activator of Transcription-3 (STAT3) mediates cellular functions. We assessed the IHC expression of phosphorylated STAT3 (pSTAT3) in paired primary tumors and liver metastases in patients with advanced stage colorectal cancer (CRC). MethodsWe included patients with tissue blocks available from both the primary CRC and a surgically resected liver metastasis. The IHC pSTAT3 expression agreement was measured using Cohen's kappa statistic. ResultsThe study included 103 patients, 55% male, median age was 64. 43% tumors originated in rectum, and 63% of the primary tumors were synchronous. Expression of pSTAT3 was 76% in liver metastases and 71% in primary tumors. A difference in pSTAT3 staining between the primary tumor and liver metastases was noted in 64%. There was lost expression of pSTAT3 in the liver metastases in 28% and gained expression in 36% of cases compared to the primary. The kappa statistic comparing agreement between staining patterns of the primary tumors and liver metastases was a “less-than-chance”, at -0.02. Median survival was 4.9 years, with no difference in survival outcomes by pSTAT3 expression in the primary tumor or liver metastases. DiscussionSTAT3 is not a prognostic marker in the selective setting of metastatic CRC to liver, but it may remain a potential therapeutic target given most liver metastases expressed pSTAT3. Discordant pSTAT3 expression in between primary tumors and paired liver metastases suggests that use of this class of drug to treat liver predominant metastatic colorectal cancer in a biomarker-driven approach may require confirmatory liver tumor biopsy.

Fat-free muscle area measured by magnetic resonance imaging predicts overall survival of patients undergoing radioembolization of colorectal cancer liver metastases.

To investigate the clinical potential of fat-free muscle area (FFMA) to predict outcome in patients with liver-predominant metastatic colorectal cancer (mCRC) undergoing radioembolization (RE) with 90Yttrium microspheres. Patients with mCRC who underwent RE in our center were included in this retrospective study. All patients received liver magnetic resonance imaging including standard T2-weighted images. The total erector spinae muscle area and the intramuscular adipose tissue area were measured at the level of the origin of the superior mesenteric artery and subtracted to calculate FFMA. Cutoff values for definition of low FFMA were 3644mm2 in men and 2825mm2 in women. The main outcome was overall survival (OS). For survival analysis, the Kaplan-Meier method and Cox regressions comparing various clinic-oncological parameters which potentially may affect OS were performed. Seventy-seven patients (28 female, mean age 60 ± 11years) were analyzed. Mean time between MRI and the following RE was 17 ± 31days. Median OS after RE was 178days. Patients with low FFMA had significantly shortened OS compared to patients with high FFMA (median OS: 128 vs. 273days, p = 0.017). On multivariate Cox regression analysis, OS was best predicted by FFMA (hazard ratio (HR) 2.652; p < 0.001). Baseline bilirubin (HR 1.875; p = 0.030), pattern of tumor manifestation (HR 1.679; p = 0.001), and model of endstage liver disease (MELD) score (HR 1.164; p < 0.001) were also significantly associated with OS. FFMA was associated with OS in patients receiving RE for treatment of mCRC and might be a new prognostic biomarker for survival prognosis. • Fat-free muscle area (FFMA) as a measure of lean muscle area predicts survival in metastatic colorectal liver cancer following radioembolization. • FFMA can easily be assessed from routine pre-interventional liver magnetic resonance imaging. • FFMA might be a new promising biomarker for assessment of sarcopenia.

Salvage use of Y90 coated hepatic arterial beads in the treatment of liver predominant metastatic colorectal cancer: Cancer Treatment Centers of America Southeastern Region experience.

e15554Background: Resin Yttrium-90 hepatic arterial liver directed treatments are commonly used in the treatment of liver predominant metastatic colorectal carcinoma. Although its role in first lin...

Prognostic value of pretreatment diffusion-weighted magnetic resonance imaging for outcome prediction of colorectal cancer liver metastases undergoing 90Y-microsphere radioembolization

To investigate the clinical potential of pretreatment apparent diffusion coefficient (ADC) on diffusion-weighted magnetic resonance imaging (DWI) for therapy response and outcome prediction in patients with liver-predominant metastatic colorectal cancer (CRC) undergoing radioembolization with 90Yttrium-microspheres (90Y-RE). Forty-six consecutive patients with unresectable CRC liver metastases underwent standardized clinical DWI on a 1.5T MR scanner prior to and 4-6 weeks after 90Y-RE. Pretreatment clinical parameters, ADC values derived from region-of-interest analysis, and the corresponding tumor sizes of three treated liver metastases per subject were recorded. Long-term tumor response to radioembolization was categorized into response (partial remission) and nonresponse (stable disease, progressive disease) according to Response Evaluation Criteria in Solid Tumors v1.1 (RECIST) 3 months after treatment. Associations between long-term tumor response and the clinical and imaging parameters were evaluated. The impact of pretreatment clinical and imaging parameters on progression-free survival (PFS) and overall survival (OS) was further assessed by Kaplan-Meier and multivariate Cox-regression analyses. Nonresponders had higher hepatic tumor burden (p = 0.021) and lower ADC values than patients responding to 90Y-RE, both pretreatment (986 ± 215 vs. 1162 ± 178; p = 0.036) and posttreatment (1180 ± 350 vs. 1598 ± 225; p = 0.002). ADC values higher than 935 × 10-6 mm2 (5 vs. 3 months; p = 0.022) and hepatic tumor burden ≤25% (6 vs. 3 months; p = 0.014) were associated with longer median PFS, whereas ADC >935 × 10-6 mm2 (14 vs. 6 months; p = 0.02), hepatic tumor burden ≤25% (14 vs. 6 months; p = 0.048), size of the largest metastasis <4.7cm (18 vs. 7 months; p = 0.024), and Eastern Cooperative Oncology Group (ECOG) score <1 (8 vs. 5 months; p = 0.045) were associated with longer median OS. On multivariate analysis, ADC >935 × 10-6 mm2 and hepatic tumor burden ≤25% remained prognostic factors for PFS, and ADC >935 × 10-6 mm2 and size of the largest metastasis <4.7cm were independent predictors of OS. Pretreatment ADC on DWI represents a valuable prognostic biomarker for predicting both the therapeutic efficacy and survival prognosis in CRC liver metastases treated by 90Y-RE, allowing risk stratification and potentially optimizing further treatment strategies.

Diffusion-weighted magnetic resonance imaging predicts survival in patients with liver-predominant metastatic colorectal cancer shortly after selective internal radiation therapy.

To investigate whether quantifications of apparent diffusion coefficient (ADC) on diffusion-weighted imaging (DWI) can predict overall survival (OS) in patients with liver-predominant metastatic colorectal cancer (CRC) following selective internal radiation therapy with 90Yttrium-microspheres (SIRT). Forty-four patients underwent DWI 19 ± 16days before and 36 ± 10days after SIRT. Tumour-size and intratumoral minimal ADC (minADC) values were measured for 132 liver metastases on baseline and follow-up DWI. Optimal functional imaging response to treatment was determined by receiver operating characteristics and defined as ≥22% increase in post-therapeutic minADC. Survival analysis was performed with the Kaplan-Meier method and Cox-regression comparing various variables with potential impact on OS. Median OS was 8months. The following parameters were significantly associated with median OS: optimal functional imaging response (18 vs. 5months; p < 0.001), hepatic tumour burden <50% (8 vs. 5months; p = 0.018), Eastern Cooperative Oncology Group performance scale <1 (10 vs. 4months; p = 0.012) and progressive disease according to Response and Evaluation Criteria in Solid Tumours (8 vs. 3months; p = 0.001). On multivariate analysis, optimal functional imaging response and hepatic tumour burden remained independent predictors of OS. Functional imaging response assessment using minADC changes on DWI may predict survival in CRC shortly after SIRT. • Relative minADC changes may predict survival in liver-predominant metastatic colorectal cancer following SIRT • Intratumoral minADC changes by ≥22 % were best to predict an improved overall survival • Functional imaging response assessment is feasible before anatomic tumour-size changes occur • minADC changes might guide future therapy management in sequential lobar radioembolization approaches.

Robust evidence for long-term survival with 90Y radioembolization in chemorefractory liver-predominant metastatic colorectal cancer.

Our aim was to provide further evidence for the efficacy/safety of radioembolization using yttrium-90-resin microspheres for unresectable chemorefractory liver metastases from colorectal cancer (mCRC). We followed 104 consecutively treated patients until death. Overall survival (OS) was calculated from the day of the first radioembolization procedure. Response was defined by changes in tumour volume as defined by Response Evaluation Criteria in Solid Tumours (RECIST) v1.0 and/or a ≥30% reduction in serum carcinoembryonic antigen (CEA) at 3months. Survival varied between 23months in patients who had a complete response to prior chemotherapy and 13months in patients with a partial response or stable disease. Median OS also significantly improved (from 5.8months to 17.1months) if response durability to radioembolization extended beyond 6months. Patients with a positive trend in CEA serum levels (≥30% reduction) at 3months post-radioembolization also had a survival advantage compared with those who did not: 15.0 vs 6.7months. Radioembolization was well tolerated. Grade 3 increases in bilirubin were reported in 5.0% of patients at 3months postprocedure. After multiple chemotherapies, many patients still have a good performance status and are eligible for radioembolization. This single procedure can achieve meaningful survivals and is generally well tolerated. • After multiple chemotherapies, many patients are still eligible for radioembolization (RE). • RE can achieve meaningful survival in patients with chemorefractory liver-predominant metastatic colorectal cancer (mCRC). • Tumour responsiveness to prior systemic treatments is a significant determinant of overall survival (OS) after RE. • Radioembolization in patients with a good performance status is generally well tolerated.

Efficacy and safety of chronomodulated hepatic arterial infusion (chronoHAI) of irinotecan (I), oxaliplatin (0) and fluorouracil (F) as salvage treatment for patients (pts) with heavily pretreated liver-predominant metastatic colorectal cancer (MCC).

e14582 Background: Effective treatment options are limited for MCC pts after failure on systemic chemotherapy. The combination of I, O and F as, chronoHAI could revert prior resistance through expl...

Selective Internal Radiation Therapy (SIRT) with yttrium-90 resin microspheres plus standard systemic chemotherapy regimen of FOLFOX versus FOLFOX alone as first-line treatment of non-resectable liver metastases from colorectal cancer: the SIRFLOX study.

BackgroundIn colorectal cancer (CRC), unresectable liver metastases are linked to poor prognosis. Systemic chemotherapy with regimens such as FOLFOX (combination of infusional 5-fluorouracil, leucovorin and oxaliplatin) is the standard first-line treatment. The SIRFLOX trial was designed to assess the efficacy and safety of combining FOLFOX-based chemotherapy with Selective Internal Radiation Therapy (SIRT or radioembolisation) using yttrium-90 resin microspheres (SIR-Spheres®; Sirtex Medical Limited, North Sydney, Australia).Methods/DesignSIRFLOX is a randomised, multicentre trial of mFOLFOX6 chemotherapy ± SIRT as first-line treatment of patients with liver-only or liver-predominant metastatic CRC (mCRC). The trial aims to recruit adult chemotherapy-naïve patients with proven liver metastases with or without limited extra-hepatic disease, a life expectancy of ≥3 months and a WHO performance status of 0–1. Patients will be randomised to receive either mFOLFOX6 or SIRT + mFOLFOX6 (with a reduced dose of oxaliplatin in cycles 1–3 following SIRT). Patients in both arms can receive bevacizumab at investigator discretion. Protocol chemotherapy will continue until there is unacceptable toxicity, evidence of tumour progression, complete surgical resection or ablation of cancerous lesions, or the patient requests an end to treatment. The primary endpoint of the SIRFLOX trial is progression-free survival (PFS). Secondary endpoints include: PFS in the liver; tumour response rate (liver and any site); site of tumour progression; health-related quality of life; toxicity and safety; liver resection rate; and overall survival. Assuming an increase in the median PFS from 9.4 months to 12.5 months with the addition of SIRT to mFOLFOX6, recruiting ≥450 patients will be sufficient for 80% power and 95% confidence.DiscussionThe SIRFLOX trial will establish the potential role of SIRT + standard systemic chemotherapy in the first-line management of mCRC with non-resectable liver metastases.Trial registrationSIRFLOX ClinicalTrials.gov identifier: NCT00724503. Registered 25 July 2008.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2407-14-897) contains supplementary material, which is available to authorized users.

The impact of KRAS mutation on radioembolization in the treatment of unresectable liver predominant metastatic colorectal cancer.

664 Background: Radioembolization with either Yttrium-90 labeled resin or glass microspheres is an FDA approved treatment for hepatic metastases from primary colorectal cancer. Y-90 therapy is used almost exclusively in unresectable liver metastases. However, radioembolization is only an optional part of the treatment process along with first-line, second-line, and salvage chemotherapy. KRAS is a known proto-onco gene that has typically been studied as a negative prognostic factor in the chemotherapeutic treatment of metastatic colorectal cancer (mCRC). KRAS is a known marker for resistance to anti-EGFR antibodies and generally have a poorer prognosis. The aim of this study is to begin to shed light on the impact of KRAS status on the outcome of patients undergoing radioembolization for the treatment of unresectable liver predominant metastatic CRC, regardless of their chemotherapy regimens. Methods: This is a retrospective analysis of 18 subjects treated with radioembolization for liver predominant metastatic CRC. KRAS status and treatment outcomes were followed for each patient up to the study close date of 9/15/13. Statistical analysis was performed using the Mann-Whitney U test. Results: Of the 18 subjects included in the study, 5 were found to have KRAS mutant oncogene. The remaining 13 were found to have the KRAS wildtype. Overall, those subjects with KRAS mutant were found to have a statistically significant difference in median time to progression of intrahepatic metastatic disease burden when compared to KRAS wildtype even when liver-directed therapy was utilized (2.0 vs. 6.4 months). Differences in median time to progression of extrahepatic metastatic disease burden and overall survival were not found to be statistically significant at this time. Conclusions: KRAS mutant patients are exceedingly difficult to treat due to both intrahepatic and extrahepatic disease recurrence/progression.

InSIRT trial: Single-center phase II study of yttrium-90 radioactive resin microspheres in the treatment of liver-predominant metastatic colorectal adenocarcinoma after failure of first-line combination chemotherapy.

685 Background: Liver metastases develop in half of colorectal cancer (CRC) cases and once metastatic ~90% die due to consequences from the hepatic metastases. We are evaluating the aggressive management of liver metastases through the incorporation of selective internal radiation therapy (SIRT) using yttrium-90 radioactive microspheres after evidence of progressive disease following first-line FOLFOX ± bevacizumab. Optimal timing for microsphere treatment relative to chemotherapy is not clearly established. We present preliminary data of a phase II study evaluating tumor response rates to SIRT following FOLFOX ± bevacizumab and prior to FOLFIRI. Methods: Subjects with predominant hepatic metastatic CRC despite first-line FOLFOX based therapy ± bevacizumab are eligible. Interventional radiology and nuclear medicine assess the liver lesions and the subject receives SIRT followed by second-line FOLFIRI (without bevacizumab) 4-6 weeks after the final SIRT. The primary objective is PFS at 6 mos and secondary objectives include: OS, tumor response rates, and toxicity. Results: To date, 8 metastatic CRC subjects have been treated and 9 subjects enrolled (goal 30 subjects). One subject was withdrawn due to progressive lung metastases. 4 of 8 subjects (50%) achieved PFS at 6 mos and average TTP is 6.7 mos (0.7-17.3 mos). Overall treatment has been well tolerated, but one possible study related SAE of liver failure occurred (subject 8). The OS endpoint has not been achieved. Conclusions: Historically, second-line FOLFIRI has achieved a 2.5 mos median PFS. In 8 subjects with liver predominant metastatic CRC, we have observed 50% PFS at 6 mos. These encouraging results demonstrate the utility of an innovative direct approach to metastatic CRC after failure of first-line combination chemotherapy. [Table: see text]

Institutional series of selective internal radiation therapy (SIRT) for liver predominant metastatic colorectal cancer (MCRC)

3665 Background: SIRT using yttrium (Y-90) microspheres infused through hepatic artery circulation was introduced in 1989 and FDA approved for MCRC to the liver in 2002. While used primarily in China and Australia for both hepatocellular and MCRC (Ann Onc 12: 1711–1720, Cancer 83: 1894–1907), few patients have been treated in the US. Methods: Patients with ECOG performance status ≤2 and suitable hepatic vascular anatomy were treated between 2/03 and 12/03. Hospital charts were reviewed for disease status, liver function, toxicity, response, and survival. Results: Twenty patients (16 m, 4 f) with MCRC refractory to standard chemotherapy and extensive hepatic metastases age 47 to 88 yrs (median 63) received treatment. Six patients were treated sequentially to both lobes of the liver, 8 concurrently to both lobes, and 6 to the right lobe only. Most toxicities documented within a two-week post-procedure period were transient and < grade 3, including nausea/vomiting in 5 patients, abdominal pain in 6 patients, fatigue in 6 patients, and fever in 2 patients. One patient had a hypertensive urgency requiring intravenous therapy. Six patients developed hyperbilirubinemia (4 pts grade 2 and 2 pts grade 3). Two of these progressed to hepatic failure (1 attributed to therapy, the other to progression). Grade 3 transaminitis was seen in one other patient. One patient developed a duodenal ulcer with biopsy evidence of Y-90 spheres in the ulcer. Fourteen patients were evaluable by CT scan ≥ 1 month post-SIRT. Three patients had a partial response and 10 had stable disease while 1 patient with initial regression of tumor had progression after 6 months. Five patients with liver control had progression of disease outside the liver. Of the 6 patients not evaluated by CT, 3 declined clinically and died or were discharged to hospice, 3 had recent treatment and have not had a repeat CT. Conclusions: SIRT is an FDA approved novel therapy for liver tumors that has demonstrated promising activity with acceptable toxicity. Monitoring of liver function, blood pressure, and PUD is recommended. Further evaluation of SIRT with chemotherapy and in other settings is warranted. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Sirtex Medical Limited

Institutional series of selective internal radiation therapy (SIRT) for liver predominant metastatic colorectal cancer (MCRC)

Institutional series of selective internal radiation therapy (SIRT) for liver predominant metastatic colorectal cancer (MCRC)