Randomized trial of regional plus systemic fluorinated pyrimidine compared with systemic fluorinated pyrimidine in treatment of colorectal liver metastases.

AIM: We report a prospective randomized study comparing survival, response and toxicity in colorectal liver metastasis (CLM) patients treated by either hepatic arterial floxuridine (HAI) plus continuous systemic fluorouracil/folinic acid or systemic fluorouracil/folinic acid. METHODS: Eighty-four CLM patients received either HAI plus systemic fluorouracil/folinic acid or systemic fluorouracil/ folinic acid. RESULTS: Significantly more HAI plus systemic, compared with systemic only, patients developed WHO grade 3 or 4 diarrhoea (P=0.004), but significant quality of life differences were not detected. Liver metastasis partial response at 4 months after randomization was significantly greater (P=0.003) in HAI plus systemic (13/29, 45%) compared with systemic only (7/30, 23%) patients. There was no significant difference between groups in the proportion of patients who died from extrahepatic disease progression, or in survival. CONCLUSION: Combining regional with systemic fluorinated pyrimidines did not improve survival compared with systemic fluorinated pyrimidine.

Contribution of diet, tumour volume and patient-related factors to weight loss in patients with colorectal liver metastases.

BACKGROUND: One of the difficulties in assessing the contribution of tumour-related factors to cancer cachexia is measurement of the extent of disease where dissemination to multiple organ sites has occurred. METHODS: In this study the extent of tumour (both tumour volume and increase in marker levels), diet and patient-related factors (appetite, metabolic hormones, immune activation, liver function and quality of life) were compared in patients with colorectal liver metastases who had lost at least 1 kg in body-weight (weight loss) and patients who had not lost 1 kg in body weight (stable weight) during the preceding month. RESULTS: Forty patients (22 men; 14 with weight loss) were studied. Liver metastasis volume was significantly greater in patients who lost weight than in those whose weight was stable (median (interquartile range) 1179 (245-1517) versus 119 (23-523) ml; P = 0.003). The prevalence of patients with raised levels of serum immune products was significantly greater in the weight loss group for soluble interleukin (IL) 2 receptor alpha (sIL2ralpha) (P = 0.03) and IL-6 (P = 0.05), but not for soluble tumour necrosis factor receptor 1 (sTNFr1) or neopterin. There were significant correlations between serum C-reactive protein and sIL2ralpha (rs = 0.68, P < 0.0001) and IL-6 (rs = 0.46, P = 0.008) but not sTNFr1 or neopterin levels. Significant differences in appetite, nausea, diet, energy intake, liver function tests and serum levels of metabolic hormones were not detected. CONCLUSION: Weight loss in patients with colorectal liver metastases was not explained by changes in diet, quality of life, or hormones, but activation of the innate and incomplete activation of the acquired immune systems may be involved. Agents that attenuate either the acute-phase inflammatory response or T lymphocyte IL-2 receptor upregulation might reduce weight loss in patients with metastatic disease.

Relation between depression and circulating immune products in patients with advanced colorectal cancer.

We have previously suggested that colorectal liver metastases might produce 'toxins' that reduce both quality of life (QoL) and survival. In this study we assessed whether QoL in patients with such metastases was related to immune activation, as determined by increased serum levels of interleukin 6 (IL6), soluble tumour necrosis factor receptor 1 (sTNFr1), soluble interleukin 2 receptor alpha (sIL2r alpha) or the interferon-gamma marker neopterin. Serum IL6, sTNFr1, sIL2r alpha, neopterin, alkaline phosphatase and carcinoembryonic antigen levels, liver metastasis volume, and QoL (Hospital Anxiety and Depression [HAD] scale, Rotterdam Symptom Checklist [RSC], and Sickness Impact Profile [SIP]) were measured in 43 patients. There were significant positive correlations between serum sIL2r alpha and HAD depression score (r = 0.66, P = 0.0001), RSC physical symptom score (r = 0.46, P < 0.01), and SIP score (r = 0.47, P = 0.009). Multiple regression analysis suggested that serum sIL2r alpha level was a significant independent predictor of HAD depression score. Although survival was shorter (logrank test P < 0.05) where sIL2r alpha, sTNFr1 and IL6 levels were higher, the ability of sIL2r alpha to predict HAD depression score was independent of survival.

Hepatic arterial floxuridine as second-line treatment for systemic fluorouracil-resistant colorectal liver metastases.

Hepatic arterial floxuridine (HAI) in 35 patients with systemic fluorouracil/folinic acid-resistant colorectal liver metastases achieved a 14% partial response and 26% disease stabilization rate, with a median response duration of 7 months from onset of HAI.

Cost-effectiveness of systemic and regional chemotherapy for the treatment of patients with unresectable colorectal liver metastases.

BACKGROUND: Management of unresectable colorectal liver metastases (CLM) can be by regional (hepatic arterial infusion [HAI]) or systemic chemotherapy, or by symptom control alone. In this study the costs of each type of management were related to clinical outcome in 134 patients with CLM. METHODS: The costs (both in terms of health care and to society) and benefits (treatment-added survival and normal quality of life survival) of chemotherapy treatment of 85 patients (HAI with implanted pump: 51 patients; and systemic chemotherapy: 34 patients) were compared with those in 49 patients managed by symptom control only. RESULTS: HAI chemotherapy cost the most (Pound Sterling 18,263 per patient) and symptom control the least (Pound sterling 2136 per patient). When survival was included, HAI was the most cost-effective treatment (health care cost per life year gained with HAI vs. systemic chemotherapy: Pound Sterling 24,604; systemic chemotherapy vs. symptom control: Pound Sterling 32,788), but there was no difference with regard to health care cost per normal quality of life gained. Societal costs incurred by lost work time and welfare payments during illness were higher for HAI (Pound Sterling 12,897) than systemic chemotherapy (Pound Sterling 9143) or symptom control (Pound Sterling 8090) because HAI-treated patients lived longer and, although working longer and contributing more productivity to society, lost more work days than other patients. CONCLUSIONS: The least expensive management for CLM was symptom control, whereas systemic and HAI chemotherapies were equally cost-effective in producing added normal quality survival for health care resources expended. Although overall societal costs were higher for HAI than for either systemic chemotherapy or symptom control, the cost benefit was difficult to interpret because of uncertain attitudes regarding continued work during terminal illness.

Management of symptomatic locoregional recurrence during regional chemotherapy for colorectal liver metastases.

BACKGROUND: The incidence of symptomatic locoregional recurrence is doubled in patients receiving regional chemotherapy with hepatic arterial floxuridine infusion (HAI) compared with that in those with colorectal liver metastases treated by symptom control. This study assessed the management of symptomatic locoregional recurrence in HAI-treated patients with colorectal liver metastases. METHODS: A retrospective review of all patients with colorectal liver metastases treated by HAI in one hospital over a 10-year period was carried out and the management of those who developed symptomatic locoregional recurrence was studied. RESULTS: Twenty-three (14 per cent) of 166 HAI-treated patients with colorectal liver metastases developed symptoms of locoregional recurrence. Liver metastases were responding to HAI at the onset of symptoms in 19 (ten abdominal, nine pelvic recurrence) of the 23 patients. Resection of abdominal recurrence was possible in seven of the ten patients, with a median hospital stay of 14 days; there was one perioperative death. Resected patients survived a median of 15 months after resection of the recurrence, with five of seven remaining free of symptoms of locoregional recurrence. In contrast, six of nine HAI-responding patients with pelvic recurrence treated by external beam radiotherapy died from uncontrolled symptomatic pelvic disease. CONCLUSION: Resection of abdominal recurrence achieved worthwhile palliation in patients with HAI-controlled liver metastases, but palliation of pelvic recurrence by irradiation was unsatisfactory.

Effect of regional and systemic fluorinated pyrimidine chemotherapy on quality of life in colorectal liver metastasis patients.

PURPOSE: Since systemic and regional (HAI) fluorinated pyrimidine chemotherapies offer similar survival benefit in treatment of colorectal liver metastases (CLM), we sought to identify their impact on quality of life (QoL), which might be a useful indicator of treatment preference. METHODS: We compared QoL in 135 CLM patients managed by symptom control (n = 49 patients), systemic fluorouracil (5FU)/folinic acid (n = 35), or hepatic arterial floxuridine (FUDR) (n = 51). Full blood count and liver function tests, World Health Organization (WHO) toxicity criteria, and QoL (Rotterdam Symptom Checklist [RSC], the Sickness Impact Profile [SIP], and the Hospital Anxiety and Depression scale [HAD]) were measured monthly in all patients. RESULTS: The HAD anxiety score was significantly increased in symptom control compared with chemotherapy patients 1 month after randomization. There was a significant increase in RSC physical score (repeated measures, P = .05), and in scores for sore mouth (P < .01), dry mouth (P < .01), and tingling hands and feet (P < .01) in systemic chemotherapy compared with symptom control patients. Significant QoL differences (repeated measures and Mann-Whitney U [MWU]) between HAI and symptom control patients were not detected. Systemic chemotherapy patients lived for significantly longer (log-rank test, P < or = .0001) with abnormal HAD anxiety, RSC psychosocial, or RSC sore mouth scores compared with HAI patients, but there were no overall survival differences. CONCLUSION: Randomization to symptom control only was associated with increased anxiety. QoL with systemic chemotherapy was impaired by side effects. HAI was associated with similar survival to systemic chemotherapy but with better sustained QoL.

Hepatic arterial cannulation for regional chemotherapy is safe in patients with a liver metastasis volume of less than 1 litre.

Hepatic arterial cannulation for regional chemotherapy was achieved in 121/134 (90.2%) of colorectal liver metastasis patients. The perioperative mortality (5.8%) was significantly greater (P = 0.004) in patients with > 1000 ml (5/22, 23%) compared with < 1000 ml (2/83, 2.4%) metastasis volume. Colorectal liver metastasis patients should be considered for regional chemotherapy before metastases become extensive.

Identification of carcinoembryonic antigen-producing cells circulating in the blood of patients with colorectal carcinoma by reverse transcriptase polymerase chain reaction.

BACKGROUND: Application of the reverse transcriptase polymerase chain reaction (RT-PCR) to identification of circulating tumour cells in colorectal cancer. AIMS: To assess whether circulating malignant cells in patients with colorectal liver metastasis could be identified by RT-PCR recognition of mRNA coding for the tumour marker carcinoembryonic antigen (CEA). PATIENTS: A total of 31 with colorectal liver metastases and 22 no-cancer controls. METHODS: Specific cDNA primers for CEA transcripts were used to apply RT-PCR to tissue biopsy specimens, colon carcinoma cell lines, and peripheral blood samples from patients with colorectal liver metastases. A strongly CEA-expressive HT115 colorectal carcinoma cell line was used to spike blood samples from no-cancer control subjects. RESULTS: The limit for detection of CEA cDNA by Southern blotting using HT115 cells was 50 cells per 14 ml of spiked blood. There was a significant difference (p = 0.007) in RT-PCR positive expression between patients with liver metastasis (26/31) compared with controls (5/22). There was no significant relation between the prevalence of CEA cDNA amplification and serum CEA level or metastasis volume in patients with liver metastasis. CONCLUSIONS: This is the first study to suggest that identification of circulating colorectal cancer cells using RT-PCR for detection of CEA cDNA is feasible.

Relation between tumor size, quality of life, and survival in patients with colorectal liver metastases.

PURPOSE AND METHODS: This study assessed the relationship between survival, tumor size, and quality of life (QoL; Rotterdam Symptom Checklist [RSC], Hospital Anxiety and Depression Scale [HAD], and Sickness Impact Profile [SIP]) in 50 patients with colorectal liver metastases (CLM). RESULTS: Physical symptom score (RSC) was a stronger survival predictor than tumor size measured on computed tomographic (CT) scan. The best model for predicting survival included QoL questions about diarrhea, eating, restlessness, and ability to work and sleep. The only clinically measured variable included in this best survival prediction model was serum alkaline phosphatase level. This is the first study to show that QoL indices predict survival in CLM. The findings suggest that differences in tumor products and not just in tumor size could influence patient fitness and survival in CLM. Such differences are more accurately estimated by QoL assessment than measurement of tumor size. CONCLUSION: QoL provides a better survival estimate than measurement of tumor size and could be used as a surrogate end point for survival in treatment trials.

Treatment interruptions and complications with two continuous hepatic artery floxuridine infusion systems in colorectal liver metastases.

Continuous hepatic artery floxuridine infusion benefits patients with colorectal liver metastases. Implanted infusion pumps are more expensive but may result in fewer treatment interruptions than when using an external pump connected to a port. We have assessed device-related complications, treatment interruptions and added nurse interventions in 95 patients undergoing a total of 959 treatment cycles via either implanted pump (64 patients) or port (31 patients). Compared with the implanted pump, the port was associated with a significant increase (P < 0.003) in catheter blockage (24/31 vs 2/64 patients), treatment interruption (15/265 vs 12/694 treatments) and added nurse intervention (80/265 vs 20/694 treatments). Survival in patients with colorectal liver metastases is limited and the complications of treatment should be kept to a minimum. An implanted subcutaneous infusion pump offers the benefit of a 3-fold lower incidence of treatment interruption and a 30-fold lower incidence of catheter blockage than when continuous infusion chemotherapy is given via an external infusion device.

Effect of aberrant hepatic arterial anatomy on tumour response to hepatic artery infusion of floxuridine for colorectal liver metastases.

Regional hepatic artery infusion of colorectal liver metastases produces the highest reported treatment response. The effect of variation in hepatic artery anatomy on tumour response to regional floxuridine (FUdR) was studied. Aberrant hepatic arterial anatomy occurred in 13 of 74 patients (18 per cent) who underwent cannulation of the hepatic artery and infusion of FUdR for colorectal liver metastases. The non-dominant hepatic artery was ligated and the dominant artery cannulated in those with aberrant anatomy. Despite evidence of a collateral circulation to the non-dominant area of the liver in these patients, there was no significant reduction in median tumour volume with treatment (before treatment 214 ml, after treatment 339 ml). By contrast, there was a significant (P < 0.001) decrease in median tumour volume (before treatment 329 ml, after treatment 148 ml) in those with normal anatomy. Delivery of FUdR to metastases via an intrahepatic collateral circulation was not as effective as through a main hepatic artery.

Measurement of response to treatment in colorectal liver metastases.

Assessment of tumour response to chemotherapy is important when assessing efficacy of treatment and comparing differing therapeutic regimens. Percentage hepatic replacement (PHR) is commonly used to assess response to treatment of colorectal hepatic metastases. PHR is dependent not only on tumour volume, but also on hepatic parenchymal volume. The effect of tumour growth on hepatic parenchymal volume is unclear but is of importance owing to its effect on PHR. We assessed tumour and hepatic parenchymal weights in an animal tumour model using dissection, and tumour and hepatic parenchymal volumes in patients with colorectal hepatic metastases using CT scanning, in order to establish how hepatic parenchyma varied with change in metastasis size. There was no significant correlation between tumour and liver parenchyma in either the animal model (r = -0.03, P > 0.05) or the patient study (r = 0.3, P < 0.05). This suggests that hepatic parenchymal volume was preserved in the presence of increasing tumour volume. In a further study of computerised tomographic (CT) scans before and after treatment in patients whose tumours either responded to chemotherapy or continued to grow, change in PHR (median proportion of PHR change = 0.40) significantly (P = 0.04) underestimated the change in tumour volume (median proportion of tumour volume change = 0.56), particularly at higher (> 400 ml) volumes. There was good correlation between change in tumour volume and WHO criteria in assigning patients to tumour growth, stable disease or tumour response categories. This study suggests that, in clinical trials comparing colorectal liver metastasis treatments, metastasis volume and not PHR should be used to assess extent of disease and the effect of treatment.

Importance of hepatic artery node involvement in patients with colorectal liver metastases.

Hepatic artery lymph node (HALN) involvement is an adverse prognostic factor in patients treated for colorectal liver metastases. The prevalence of HALN positivity for mid-gut and hind-gut derived colonic tumours, for differing amounts of liver involvement, and for Dukes' A and B versus Dukes' C primary tumours was compared in 75 patients with colorectal liver metastases. All patients whose primary tumours did not invade lymph nodes (Dukes' A or B) had liver metastases that did not involve local hepatic nodes, regardless of the extent of the disease within the liver. This suggests that factors controlling metastasis are not identical with those which control lymphatic invasion in colorectal cancer. HALN positive patients may benefit less from treatment because they are significantly more likely to have both a greater burden of disease within the liver and a tumour with greater lymph invasive potential than patients with HALN negative liver metastases.

Quality of life and survival with continuous hepatic-artery floxuridine infusion for colorectal liver metastases.

Very few patients with liver metastases from colorectal cancer can be cured. We have investigated whether a treatment to slow the growth of liver metastases, hepatic-artery infusion of floxuridine, improves palliation in this setting. In a randomised study of 100 patients, we compared quality of life and survival in patients who received hepatic-artery infusion of floxuridine and in those who received conventional symptom palliation. 95% of control patient survival time was spent with normal quality-of-life scores, which suggests that the aim of treatment should be to prolong normal-quality survival rather than merely to sustain quality of life. There was a significant prolongation (p = 0.03) in overall survival in floxuridine-treated patients compared with controls (median 405 vs 226 days). There were similar significant prolongations in normal-quality (ie, normal symptom scores) survival for physical symptoms (p = 0.04), anxiety (p = 0.04), and depression (p = 0.04). This survival benefit was associated with significant reductions in metastasis size on computed tomography (p = 0.001) and in serum carcinoembryonic antigen concentration (p = 0.006) in floxuridine-treated patients. There was no evidence of treatment-related hepatotoxicity as assessed by serum aspartate aminotransferase and bilirubin measurements. This is the first demonstration that survival can be prolonged with normal quality of life in patients with colorectal liver metastases. We conclude that hepatic-artery floxuridine infusion can be recommended for suitable patients.