The Effect of Histopathological Growth Patterns of Colorectal Liver Metastases on the Survival Benefit of Adjuvant Hepatic Arterial Infusion Pump Chemotherapy.

BACKGROUND: Histopathological growth patterns (HGPs) are a prognostic biomarker in colorectal liver metastases (CRLM). Desmoplastic HGP (dHGP) is associated with liver-only recurrence and superior overall survival (OS), while non-dHGP is associated with multi-organ recurrence and inferior OS. This study investigated the predictive value of HGPs for adjuvant hepatic arterial infusion pump (HAIP) chemotherapy in CRLM. METHODS: Patients undergoing resection of CRLM and perioperative systemic chemotherapy in two centers were included. Survival outcomes and the predictive value of HAIP versus no HAIP per HGP group were evaluated through Kaplan-Meier and Cox regression methods, respectively. RESULTS: We included 1233 patients. In the dHGP group (n = 291, 24%), HAIP chemotherapy was administered in 75 patients (26%). In the non-dHGP group (n = 942, 76%), HAIP chemotherapy was administered in 247 patients (26%). dHGP was associated with improved overall survival (OS, HR 0.49, 95% CI 0.32-0.73, p < 0.001). HAIP chemotherapy was associated with improved OS (HR 0.61, 95% CI 0.45-0.82, p < 0.001). No interaction could be demonstrated between HGP and HAIP on OS (HR 1.29, 95% CI 0.72-2.32, p = 0.40). CONCLUSIONS: There is no evidence that HGPs of CRLM modify the survival benefit of adjuvant HAIP chemotherapy in patients with resected CRLM.

Adjuvant hepatic arterial infusion pump chemotherapy and resection versus resection alone in patients with low-risk resectable colorectal liver metastases - the multicenter randomized controlled PUMP trial.

BACKGROUND: Recurrences are reported in 70% of all patients after resection of colorectal liver metastases (CRLM), in which half are confined to the liver. Adjuvant hepatic arterial infusion pump (HAIP) chemotherapy aims to reduce the risk of intrahepatic recurrence. A large retrospective propensity score analysis demonstrated that HAIP chemotherapy is particularly effective in patients with low-risk oncological features. The aim of this randomized controlled trial (RCT) --the PUMP trial-- is to investigate the efficacy of adjuvant HAIP chemotherapy in low-risk patients with resectable CRLM. METHODS: This is an open label multicenter RCT. A total of 230 patients with resectable CRLM without extrahepatic disease will be included. Only patients with a clinical risk score (CRS) of 0 to 2 are eligible, meaning: patients are allowed to have no more than two out of five poor prognostic factors (disease-free interval less than 12 months, node-positive colorectal cancer, more than 1 CRLM, largest CRLM more than 5 cm in diameter, serum Carcinoembryonic Antigen above 200 µg/L). Patients randomized to arm A undergo complete resection of CRLM without any adjuvant treatment, which is the standard of care in the Netherlands. Patients in arm B receive an implantable pump at the time of CRLM resection and start adjuvant HAIP chemotherapy 4-12 weeks after surgery, with 6 cycles of floxuridine scheduled. The primary endpoint is progression-free survival (PFS). Secondary endpoints include overall survival, hepatic PFS, safety, quality of life, and cost-effectiveness. Pharmacokinetics of intra-arterial administration of floxuridine will be investigated as well as predictive biomarkers for the efficacy of HAIP chemotherapy. In a side study, the accuracy of CT angiography will be compared to radionuclide scintigraphy to detect extrahepatic perfusion. We hypothesize that adjuvant HAIP chemotherapy leads to improved survival, improved quality of life, and a reduction of costs, compared to resection alone. DISCUSSION: If this PUMP trial demonstrates that adjuvant HAIP chemotherapy improves survival in low-risk patients, this treatment approach may be implemented in the standard of care of patients with resected CRLM since adjuvant systemic chemotherapy alone has not improved survival. TRIAL REGISTRATION: The PUMP trial is registered in the Netherlands Trial Register (NTR), number: 7493 . Date of registration September 23, 2018.

Perioperative complications influence recurrence and survival after resection of hepatic colorectal metastases.

BACKGROUND: Perioperative outcomes, such as blood loss, transfusions, and morbidity, have been linked to cancer-specific survival, but this is largely unsupported by prospective data. METHODS: Patients from a previous, randomized trial that evaluated acute normovolemic hemodilution during major hepatectomy (≥3 segments) were reevaluated and those with metastatic colorectal cancer (n = 90) were selected for analysis. Survival data were obtained from the medical record. Disease extent was measured using a clinical-risk score (CRS). Log-rank test and Cox proportional hazard model were used to evaluate recurrence-free survival (RFS) and overall survival (OS). RESULTS: Median follow-up was 71 months. The CRS was ≥3 in 45 % of patients; 59 % had extrahepatic procedures. Morbidity and mortality were 33 and 2 %, respectively. Postoperative chemotherapy was given to 87 % of patients (78/90) starting at a median of 6 weeks. RFS and OS were 29 and 60 months, respectively. Postoperative morbidity significantly reduced RFS (23 vs. 69 months; P < 0.001) and OS (28 vs. 74 months; P < 0.001) on uni- and multi-variate analysis; positive resection margins and high CRS also were significant factors. Delayed initiation of postoperative chemotherapy (≥8 weeks) was common in patients with complications (37 vs. 12 %; P = 0.01). CONCLUSIONS: In this selected cohort of patients from a previous RCT, perioperative morbidity was strongly (and independently) associated with cancer-specific outcome. It also was associated with delayed initiation of postoperative chemotherapy, the impact of which on survival is unclear.

Microwave Ablation in the Management of Colorectal Cancer Pulmonary Metastases.

PURPOSE: To review outcomes following microwave ablation (MWA) of colorectal cancer pulmonary metastases and assess predictors of oncologic outcomes. METHODS: Technical success, primary and secondary technique efficacy rates were evaluated for 50 patients with 90 colorectal cancer pulmonary metastases at immediate, 4-8 weeks post-MWA and subsequent follow-up CT and/or 18F-FDG PET/CT. Local tumor progression (LTP) rate, LTP-free survival (LTPFS), cancer-specific and overall survivals were assessed. Complications were recorded according to SIR classification. RESULTS: Median follow-up was 25.6 months. Median tumor size was 1 cm (0.3-3.2 cm). Technical success, primary and secondary technique efficacy rates were 99, 90 and 92%, respectively. LTP rate was 10%. One-, 2- and 3-year LTPFS were: 93, 86 and 86%, respectively, with median LTPFS not reached. Median overall survival was 58.6 months, and median cancer-specific survival (CSS) was not reached. One-, 2- and 3-year overall and CSS were 94% and 98, 82 and 90%, 61 and 70%, respectively. On univariate analysis, minimal ablation margin (p < 0.001) and tumor size (p = 0.001) predicted LTPFS, with no LTP for minimal margin ≥ 5 mm and/or tumor size < 1 cm. Pleural-based metastases were associated with increased LTP risk (p = 0.002, SHR = 7.7). Pre-MWA CEA level > 10 ng/ml (p = 0.046) and ≥ 3 prior chemotherapy lines predicted decreased CSS (p = 0.02). There was no 90-day death. Major complications rate was 13%. CONCLUSIONS: MWA with minimal ablation margin ≥ 5 mm is essential for local control of colorectal cancer pulmonary metastases. Pleural-based metastases and larger tumor size were associated with higher risk of LTP. CEA level and pre-MWA chemotherapy impacted CSS.

Tumor marker utility grading system: a framework to evaluate clinical utility of tumor markers.

Introduction of tumor markers into routine clinical practice has been poorly controlled, with few criteria or guidelines as to how such markers should be used. We propose a Tumor Marker Utility Grading System (TMUGS) to evaluate the clinical utility of tumor markers and to establish an investigational agenda for evaluation of new tumor markers. A Tumor Marker Utility Grading Worksheet has been designed. The initial portion of this worksheet is used to clarify the precise characteristics of the marker in question. These characteristics include the marker designation, the molecule and/or substance and the relevant alteration from normalcy, the assay format and reagents, the specimen type, and the neoplastic disease for which the marker is being evaluated. To determine the clinical utility of each marker, one of several potential uses must be designated, including risk assessment, screening, differential diagnosis, prognosis, and monitoring clinical course. For each of these uses, associations between marker assay results and expected biologic process and end points must be determined. However, knowledge of tumor marker data should contribute to a decision in practice that results in a more favorable clinical outcome for the patient, including increased overall survival, increased disease-free survival, improvement in quality of life, or reduction in cost of care. Semiquantitative utility scales have been developed for each end point. The only markers recommended for use in routine clinical practice are those that are assigned utility scores of "++" or " " on a 6-point scale (ranging from 0 to ) in the categories relative to more favorable clinical outcomes. Each utility score assignment should be supported by documentation of the level of evidence used to evaluate the marker. TMUGS will establish a standardized analytic technique to evaluate clinical utility of known and future tumor markers. It should result in improved patient outcomes and more cost-efficient investigation and application of tumor markers.

Activity of sequential low-dose methotrexate and fluorouracil in advanced colorectal carcinoma: attempt at correlation with tissue and blood levels of phosphoribosylpyrophosphate.

Forty-five patients with metastatic colorectal carcinoma were treated with low-dose methotrexate (MTX) and 5-fluorouracil (5-FU) given sequentially. The dose of MTX was 40 mg/m2 intravenously (IV) on days 1 and 8 followed 24 hours later by 5-FU at 600 mg/m2 IV on days 2 and 9; the drugs were recycled every 28 days. Fourteen (32%) of 43 adequately treated patients had a complete or partial response lasting a median of nine months (range, 6-15 + months). Four patients had a minor response and seven patients had stable disease for a median of nine and 10 months, respectively. Toxicity included mucositis in 28 (65%) patients, diarrhea in 18 (40%), nausea in 11 (24%), and vomiting in seven (16%). Hematologic toxicity was mild: six patients had nadir white blood cell counts less than 3.5 X 10(3) cells/microL, and seven patients had a nadir platelet count less than 100 X 10(3) cells/microL. Serial biopsies and blood samples were obtained in selected patients to evaluate the effect of MTX on tissue and lymphocyte phosphoribosylpyrophosphate (PRPP) and PRPP synthetase levels.

Irinotecan is an active agent in untreated patients with metastatic colorectal cancer.

PURPOSE: To determine the response rate, survival, and toxicity of the new anticancer agent, irinotecan (CPT-11), in the treatment of metastatic colorectal cancer. PATIENTS AND METHODS: Forty-one chemotherapy-naive patients with measurable metastatic colorectal cancer were treated with a 90-minute infusion of irinotecan 125 mg/m2 administered weekly for 4 weeks every 6 weeks. Pretreatment tumor biopsies to assess topoisomerase-I (Topo-I) activity were obtained from 11 patients. The pharmacokinetics for irinotecan and its active metabolite, SN-38, were determined in 18 patients. RESULTS: Thirteen of 41 patients (32%) had a partial response (PR; 95% confidence interval, 18% to 46%). The median response duration was 8.1 months (range, 4.0 to 16.0) and the median survival time was 12.1 months (range, 2.1 to 21.7) for all 41 patients. Grade 3 or 4 toxicities were diarrhea (29% of patients) and neutropenia (22% of patients). Grade 3 or 4 diarrhea was substantially more prevalent in the initial 18 patients on study, with an incidence rate of 56%; a significant reduction in the incidence of severe diarrhea to 9% was noted with strict adherence to an antidiarrheal regimen of loperamide and diphenyldramine. No correlations were seen between pharmacokinetics of irinotecan/SN-38 and the clinical parameters of response, survival, or incidence of diarrhea. CONCLUSIONS: Irinotecan has activity in the treatment of patients with metastatic colorectal cancer. Strict adherence to an antidiarrheal regimen of diphenhydramine/loperamide significantly reduced the incidence of diarrhea; the agent was thereafter well tolerated in the majority of patients.

Phase I clinical and pharmacokinetic study of irinotecan, fluorouracil, and leucovorin in patients with advanced solid tumors.

PURPOSE: To determine the maximum-tolerable dose (MTD) of fluorouracil (5FU) when given with fixed doses of leucovorin and irinotecan (CPT-11), to define the dose-limiting toxicities of this combination, and to evaluate the effect of 5FU on the pharmacokinetics of CPT-11. PATIENTS AND METHODS: CPT-11, leucovorin, and 5FU were administered in repeated 6-week cycles that consisted of weekly treatment with all three drugs for 4 consecutive weeks followed by a 2-week break. On day 1 of treatment, CPT-11 alone was given by 90-minute infusion, and pharmacokinetic sampling was performed over 24 hours. Leucovorin and 5FU were administered by brief intravenous injection on day 2. On days 8, 15, and 22, CPT-11 infusion was immediately followed by leucovorin and then 5FU. A second 24-hour pharmacokinetic sampling was performed on day 8, which permitted comparison of the pharmacokinetics of CPT-11 with and without 5FU. For the second 6-week cycle, leucovorin was administered first, followed by 5FU and then CPT-11, and a third pharmacokinetic sampling was performed. RESULTS: Forty-two patients were entered onto this trial. The CPT-11 dose was initially fixed at 100 mg/m2. Leucovorin was fixed at 20 mg/m2. 5FU doses of 210, 265, 340, 425, and 500 mg/m2 were studied. When the 500-mg/m2 dose of 5FU was found to be tolerable, this was then maintained and CPT-11 was escalated to 125 and then 150 mg/m2. This final CPT-11 dose exceeded the MTD. Neutropenia was the major dose-limiting toxicity. Diarrhea was common, but was rarely dose-limiting. Coadministration of 5FU had no substantial effect on the pharmacokinetics of CPT-11 or SN-38. Among the 38 patients with colorectal cancer, six partial responses (PRs) were seen in this predominantly 5FU-refractory patient population. CONCLUSION: 5FU does not substantially affect the metabolism of CPT-11 to its active metabolite, SN-38. The combination of CPT-11125 mg/m2, 5FU 500 mg/m2, and leucovorin 20 mg/m2 is feasible and tolerable on this schedule.

Phase I/II study of iodine 125-labeled monoclonal antibody A33 in patients with advanced colon cancer.

PURPOSE: A phase I/II study was designed to determine the maximum-tolerated dose (MTD) of iodine 125-labeled monoclonal antibody A33 (125I-mAb A33), its limiting organ toxicity, and the uptake and retention of radioactivity in tumor lesions. PATIENTS AND METHODS: Patients (N = 21) with advanced chemotherapy-resistant colon cancer who had not received prior radiotherapy were treated with a single 125I-mAb A33 dose. 125I doses were escalated from 50 to 350 mCi/m2 in 50-mCi/m2 increments. Radioimmunoscintigrams were performed for up to 6 weeks after 125I-mAb A33 administration. RESULTS: All 20 patients with radiologic evidence of disease showed localization of 125I to sites of disease. Twelve of 14 patients, who underwent imaging studies 4 to 6 weeks after antibody administration, had sufficient isotope retention in tumor lesions to make external imaging possible. No major toxicity was observed, except in one patient with prior exposure to mitomycin who developed transient grade 3 thrombocytopenia. Although the isotope showed variable uptake in the normal bowel, gastrointestinal symptoms were mild or absent, and in no case did stools become guaiac-positive. The MTD was not reached at 125I doses up to 350 mCi/m2. However, cytotoxicity assays demonstrated that patients treated with the highest dose had sufficiently high serum levels of 125I-mAb A33 to lyse colon cancer cells in vitro. Among 21 patients, carcinoembryonic antigen (CEA) levels returned to normal in one patient and decreased by 35% and 23%, respectively, in two patients; one additional patient had a mixed response on computed tomography. Additional, significant responses were observed in those patients treated with chemotherapy [carmustine [BCNU], vincristine, flourouracil, and streptozocin [BOF-Strep]) after completion of the 125I-mAb A33 study. CONCLUSION: Low-energy emission radioimmunotherapy with doses of up to 350 mCi/m2 of 125I-mAb A33 did not cause bowel or bone marrow toxicity. The modest antitumor activity in these heavily pretreated patients is encouraging because of lack of toxicity at the doses studied. The long radioactivity retention in tumors suggests that isotopes with a long half-life may have a therapeutic advantage, based on calculated dose delivery to tumor versus normal tissue. Due to the low bone marrow dose, further 125I trials with humanized mAb A33 are warranted, and controlled studies must be conducted to evaluate the combination of radioimmunotherapy and chemotherapy.

Regional chemotherapy of colorectal cancer.

Hepatic metastases are a major cause of mortality in patients with colorectal carcinoma. The rationale for hepatic arterial chemotherapy has an anatomical and pharmacological basis as presented below. The randomised studies are reviewed and demonstrate a significantly higher response rate with hepatic arterial therapy versus systemic therapy. Survival information is difficult to evaluate because some of the studies are small, and some had a crossover design, but two studies demonstrate a significant improvement in 2-year survival after hepatic arterial therapy compared with systemic therapy. New combinations of 5-fluoro-2-deoxyuridine with dexamethasone and/or leucovorin have produced response rates as high as 72%, median survivals of 22-27 months, and a 2-year survival of 66%. More recent studies on patients who have failed previous systemic chemotherapy have produced response rates around 50%. Hepatic toxicity, especially biliary sclerosis, is the dose limiting toxicity, occurring in 6-25% of patients. To truly define the role of regional therapy, a more accurate randomised study will have to be conducted, to determine if hepatic arterial infusion improves the quality of life and, or survival in patients with hepatic metastases from colorectal cancer.

Is intra-arterial chemotherapy worthwhile in the treatment of patients with unresectable hepatic colorectal cancer metastases?

Regional chemotherapy, from a theoretical and pharmacological stand point, would seem to offer significant advantage over systemic therapy for the treatment of hepatic metastatic colorectal cancer patients. Clinical experience has shown us that the technique itself is fraught with practical problems, but over the years, specialist centres have learned to overcome many of these, making the technique safer and minimising the possibility of complications and toxicity. As a consequence, there is no doubt that high response rates can be achieved with HAI fluoropyrimidines. However, randomised data have only been obtained from small numbers of patients in suboptimally designed trials and, to date, true patient benefit in terms of either survival or quality of life has not been adequately demonstrated. In parallel with the U.S. Intergroup study, the U.K.-based MRC phase III clinical trial of regional versus systemic 5-FU/FA warrants urgent support and we would welcome collaboration with interested European and American centres. The outcome of this trial will fully define the role of HAI chemotherapy in the management of unresectable hepatic metastatic colorectal cancer, in the context of modern, modulated 5-FU.

Overview of N-(phosphonacetyl)-L-aspartate + fluorouracil in clinical trials.

The clearest example of successful biochemical modulation of cancer chemotherapy in the laboratory, followed by initial failure to reproduce successful therapeutic results in the clinic, and then eventually followed by clinical success, is that of the combination of N-(phosphonacetyl)-L-aspartate (PALA) and fluorouracil (5-FU). This review covers the biochemistry involved, the preclinical findings, the many clinical trials, and explains the differences between the initial unsuccessful and the later successful clinical studies. The overall findings demonstrate that, to be successful, the design of modulation-based clinical trials should adhere to the principles determined in preclinical studies.

Modulation of fluorouracil by N-(phosphonacetyl)-L-asparate: a review.

N-(phosphonacetyl)-L-asparate (PALA), a potent inhibitor of de novo pyrimidine synthesis, was demonstrated in preclinical studies to enhance the therapeutic activity of fluorouracil (5-FU). However, the initial clinical trials with the combination failed to conform to these experimental findings. Very recent clinical studies, employing for the first time the principles for the enhanced therapeutic interaction determined in the preclinical studies, have now reported enhanced efficacy with the PALA-FU combination. Reviewing the lessions of the PALA-FU experience, this article explains the potential benefits as well as the need for biochemical modulation in cancer chemotherapy, the need for the appropriate dosage ratio between agents in modulation-based clinical trials, and the necessity to determine in patients, by direct biochemical measurements at the tissue level, the dose and temporal relationship between agents that reproduces the pertinent biochemical changes in human tumors that produced the therapeutic success of that particular drug combination in the preclinical model.

Hepatic arterial chemotherapy in metastatic colorectal patients.

Hepatic metastases are a major cause of morbidity and mortality for patients with colorectal cancer (CRC). The rationale for hepatic arterial chemotherapy has both an anatomical and pharmacological basis. Several randomized clinical studies of fluoropyrimidine showed higher response rates in all trials when the drug was given as an hepatic arterial infusion (HAI) versus systemic administration. However, the studies did not accurately define survival for the following reasons: (1) some allowed a crossover; (2) some were too small; and (3) some used inadequate systemic chemotherapy. Patients who have failed to respond to previous systemic chemotherapy have an approximately 50% response rate with HAI treatment. Hepatic toxicity, especially biliary sclerosis, is the dose-limiting toxicity, occurring in 6% to 25% of patients. Adding dexamethasone to HAI fluoropyrimidine decreases the hepatobiliary toxicity. The therapeutic benefit of HAI in one study was also demonstrated by an increased time with normal quality of life. To truly define the role of regional therapy in patients with CRC confined to the liver, the current Cancer and Leukemia Group B (CALGB) study is randomizing patients to HAI versus systemic therapy without a crossover to demonstrate if HAI improves survival and/or quality of life in addition to response rates.

Increased accumulation of 2-deoxy-2-[18F]Fluoro-D-glucose in liver metastases from colon carcinoma.

Three patients with liver metastases from colon carcinoma were studied with 2-deoxy-2-[F-18]fluoro-d-glucose (F-18-FDG) using positron emission tomography. The radioactivity in the metastatic tumor increased continuously following the injection of F-18-FDG, whereas it decreased in normal liver tissue. This resulted in the tumor to normal-liver ratio of 3.3-4.7 at 50 min after injection. The liver tumor was visualized as an increased accumulation of radioactivity in all patients, with the central area of the tumor showing less activity. These preliminary results suggest that F-18-FDG may be useful as a positive imaging agent for the detection and characterization of liver tumors.

Non-surgical treatment for liver metastases.

The liver is a common site for developing metastatic disease. Although any malignancy can spread to the liver, the direct passage of blood from the gastrointestinal tract to the liver via the portal circulation results in a high rate of liver metastasis from gastrointestinal tract tumours. Various radiographical tests including computed tomography and magnetic resonance imaging can detect the majority of liver metastases. Surgical resection if feasible is the treatment of choice since it produces a 5-year survival rate of about 30%. However, the majority of the patients relapse after hepatic resection, 50% relapsing in the liver. Systemic chemotherapy produces response rates of 15-30% with a median survival of 10-12 months. It is estimated that 30,000 patients each year in the USA are candidates for regional hepatic therapy. Hepatic arterial chemotherapy, hepatic artery embolization, chemoembolization, cryosurgery, ethanol injection of the tumour and radiation therapy are being investigated as potential treatment options for such patients.

A complication of prolonged infusional chemotherapy masquerading as a bone metastasis in a patient with colorectal carcinoma.

A patient with metastatic colorectal carcinoma to the liver, who was being treated with a continuous systemic infusion of floxuridine (FUDR) through a permanent indwelling central venous catheter, developed bone pain. Bone imaging showed abnormal findings, without evidence of metastatic disease progression elsewhere. The patient's complaints and the abnormality seen on the bone scan resolved with removal of the catheter and discontinuation of the systemic infusion. Diagnostic and therapeutic considerations are discussed.

Neutropenic enterocolitis in a patient with colorectal carcinoma: unusual course after treatment with 5-fluorouracil and leucovorin--a case report.

BACKGROUND: Neutropenic enterocolitis is observed in approximately 25% of patients with acute leukemia, but has been reported rarely in patients with solid tumors. If treatment is not initiated promptly, the mortality is high. The incidence of this disease is rising in patients with hematologic malignancies. Increasing numbers of patients with solid tumors are subject to high dose chemotherapy regimens or new drugs known to cause severe neutropenia. Therefore, the frequency of this disease can be expected to increase. METHODS: The authors report a patient with colorectal carcinoma who developed neutropenic enterocolitis after treatment with 5-fluorouracil and leucovorin. RESULTS: The patient developed the typical clinical picture of abdominal pain, diarrhea, and neutropenia. The course was complicated by a recurrence of symptoms after initially successful antibiotic therapy without the patient receiving further chemotherapy. CONCLUSIONS: This case indicates that neutropenic enterocolitis may occur in patients with colorectal carcinoma receiving 5-fluorouracil and leucovorin.