ABSTRACT
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.
Subject(s)
Colorectal Neoplasms , Liver Neoplasms , Humans , Colorectal Neoplasms/pathology , Hepatectomy , Retrospective Studies , Chemotherapy, Adjuvant , Liver Neoplasms/surgery , Infusion Pumps, ImplantableABSTRACT
PURPOSE: To evaluate safety and efficacy of radiation segmentectomy (RS) with 90Y glass microspheres in patients with limited metastatic liver disease not amenable to resection or percutaneous ablation. METHODS: Patients with ≤ 3 tumors treated with RS from 6/2015 to 12/2017 were included. Target tumor radiation dose was > 190 Gy based on medical internal radiation dose (MIRD) dosimetry. Tumor response, local tumor progression (LTP), LTP-free survival (LTPFS) and disease progression rate in the treated segment were defined using Choi and RECIST 1.1 criteria. Toxicities were evaluated using modified SIR criteria. RESULTS: Ten patients with 14 tumors underwent 12 RS. Median tumor size was 3 cm (range 1.4-5.6). Median follow-up was 17.8 months (range 1.6-37.3). Response rates per Choi and RECIST 1.1 criteria were 8/8 (100%) and 4/9 (44%), respectively. Overall LTP rate was 3/14 (21%) during the study period. One-, two- and three-year LTPFS was 83%, 83% and 69%, respectively. Median LTPFS was not reached. Disease progression rate in the treated segment was 6/18 (33%). Median overall survival was 41.5 months (IQR 16.7-41.5). Median delivered tumor radiation dose was 293 Gy (range 163-1303). One major complication was recorded in a patient post-Whipple procedure who suffered anaphylactic reaction to prophylactic cefotetan and liver abscess in RS region 6.5 months post-RS. All patients were alive on last follow-up. CONCLUSION: RS of ≤ 3 hepatic segments can safely provide a 2-year local tumor control rate of 83% in selected patients with limited metastatic liver disease and limited treatment options. Optimal dosimetry methodology requires further investigation.
Subject(s)
Liver Neoplasms , Yttrium Radioisotopes , Humans , Liver Neoplasms/diagnostic imaging , Liver Neoplasms/radiotherapy , Microspheres , Pneumonectomy , Retrospective Studies , Treatment Outcome , Yttrium Radioisotopes/therapeutic useABSTRACT
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.
Subject(s)
Antimetabolites, Antineoplastic/administration & dosage , Colorectal Neoplasms/pathology , Floxuridine/administration & dosage , Hepatectomy , Liver Neoplasms/therapy , Neoplasm Recurrence, Local/prevention & control , Adult , Chemotherapy, Adjuvant/instrumentation , Chemotherapy, Adjuvant/methods , Clinical Trials, Phase III as Topic , Colorectal Neoplasms/mortality , Humans , Infusion Pumps, Implantable , Infusions, Intra-Arterial/instrumentation , Infusions, Intra-Arterial/methods , Liver Neoplasms/mortality , Liver Neoplasms/secondary , Multicenter Studies as Topic , Netherlands , Progression-Free Survival , Randomized Controlled Trials as Topic , Retrospective Studies , Young AdultABSTRACT
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.
Subject(s)
Catheter Ablation/methods , Colorectal Neoplasms/surgery , Lung Neoplasms/secondary , Microwaves/therapeutic use , Adult , Aged , Colorectal Neoplasms/diagnostic imaging , Female , Fluorodeoxyglucose F18 , Follow-Up Studies , Humans , Lung Neoplasms/diagnostic imaging , Lung Neoplasms/surgery , Male , Middle Aged , Positron Emission Tomography Computed Tomography , Retrospective Studies , Tomography, X-Ray Computed , Treatment OutcomeABSTRACT
Despite significant improvements in systemic therapy for patients with colorectal liver metastases (crlms), response rates in the first-line setting are not optimal, and response rates in the second-line setting remain disappointing. Hepatic arterial infusion pump (haip) chemotherapy has been extensively studied in patients with crlms, but it remains infrequently used. We convened an expert panel to discuss the role of haip in the contemporary management of patients with crlm. Using a consensus process, we developed these statements: haip chemotherapy should be given in combination with systemic chemotherapy.haip chemotherapy should be offered in the context of a multidisciplinary program that includes expertise in hepatobiliary surgery, medical oncology, interventional radiology, nursing, and nuclear medicine.haip chemotherapy in combination with systemic therapy should be considered in patients with unresectable crlms who have progressed on first-line systemic treatment. In addition, haip chemotherapy is acceptable as first-line treatment in patients with unresectable colorectal liver metastases.haip chemotherapy is not recommended in the setting of extrahepatic disease outside the context of a clinical trial.haip chemotherapy in combination with systemic therapy is an option for select patients with resected colorectal liver metastases. These consensus statements provide a framework that clinicians who treat patients with crlm can use when considering treatment with haip.
ABSTRACT
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.
Subject(s)
Blood Loss, Surgical , Colorectal Neoplasms/pathology , Hemodilution , Hepatectomy/adverse effects , Liver Neoplasms/surgery , Transfusion Reaction , Abdominal Abscess/etiology , Chemotherapy, Adjuvant , Disease-Free Survival , Equipment Failure , Female , Hospital Mortality , Humans , Ileus/etiology , Infusion Pumps, Implantable/adverse effects , Length of Stay , Liver Neoplasms/drug therapy , Liver Neoplasms/secondary , Male , Middle Aged , Multivariate Analysis , Myocardial Ischemia/etiology , Neoplasm, Residual , Recurrence , Risk Assessment , Surgical Wound Infection/etiology , Survival Rate , Tachycardia/etiology , Time Factors , Venous Thrombosis/etiologyABSTRACT
BACKGROUND: This study reports the results of hepatic arterial infusion (HAI) with floxuridine (FUDR) and dexamethasone (dex) in patients with unresectable intrahepatic cholangiocarcinoma (ICC) or hepatocellular carcinoma (HCC) and investigates dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) assessment of tumor vascularity as a biomarker of outcome. PATIENTS AND METHODS: Thirty-four unresectable patients (26 ICC and eight HCC) were treated with HAI FUDR/dex. Radiologic dynamic and pharmacokinetic parameters related to tumor perfusion were analyzed and correlated with response and survival. RESULTS: Partial responses were seen in 16 patients (47.1%); time to progression and response duration were 7.4 and 11.9 months, respectively. Median follow-up and median survival were 35 and 29.5 months, respectively; 2-year survival was 67%. DCE-MRI data showed that patients with pretreatment integrated area under the concentration curve of gadolinium contrast over 180 s (AUC 180) >34.2 mM.s had a longer median survival than those with AUC 180 <34 mM.s (35.1 versus 19.1 months, P = 0.002). Decreased volume transfer exchange between the vascular space and extracellular extravascular space (-DeltaK(trans)) and the corresponding rate constant (-Deltak(ep)) on the first post-treatment scan both predicted survival. CONCLUSIONS: In patients with unresectable primary liver cancer, HAI therapy can be effective and safe. Pretreatment and early post-treatment changes in tumor perfusion characteristics may predict treatment outcome.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Chemotherapy, Cancer, Regional Perfusion , Liver Neoplasms/drug therapy , Liver Neoplasms/mortality , Magnetic Resonance Imaging/methods , Adult , Aged , Aged, 80 and over , Area Under Curve , Bile Duct Neoplasms/drug therapy , Bile Ducts, Intrahepatic/pathology , Carcinoma, Hepatocellular/drug therapy , Cholangiocarcinoma/drug therapy , Dexamethasone/administration & dosage , Disease-Free Survival , Female , Floxuridine/administration & dosage , Humans , Male , Middle Aged , Survival Analysis , Treatment OutcomeABSTRACT
BACKGROUND: The purpose of the study was to determine the maximum tolerated dose of systemic oxaliplatin (oxal), 5-fluorouracil (5-FU) and leucovorin (LV) that could be administered with hepatic arterial infusion (HAI) of floxuridine (FUDR) and dexamethasone (Dex) in the adjuvant setting after hepatic resection. METHODS: Thirty-five patients with resected liver metastases were entered into a phase I trial using HAI FUDR/Dex with escalating doses of oxal and 5-FU. RESULTS: The initial dose of HAI FUDR was fixed at 0.12 mg/kg x pump volume divided by pump flow rate plus Dex infused over the first 2 weeks of a 5-week cycle. Systemic chemotherapy was delivered on days 15 and 29 with the doses of oxal escalated from 85 to 100 mg/m2 and the 5-FU 48-h continuous infusion doses from 1000 to 2000 mg/m2. The LV dose was fixed at 400 mg/m). Dose-limiting toxic effects were diarrhea, 8.5%, and elevated bilirubin, 8.5%. With a median follow-up of 43 months, the 4-year survival and progression-free survival were 88% and 50%, respectively. CONCLUSIONS: Adjuvant therapy after liver resection with HAI FUDR/Dex plus systemic oxal at 85 mg/m2 and 5-FU by continuous infusion at 2000 g/m2 with LV at 400 mg/m2 is feasible and appears effective. Randomized studies comparing this regimen to systemic FOLFOX are suggested.
Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Colorectal Neoplasms/pathology , Liver Neoplasms/drug therapy , Vitamin B Complex/administration & dosage , Adenocarcinoma/secondary , Adenocarcinoma/surgery , Adult , Aged , Chemotherapy, Adjuvant , Cohort Studies , Disease-Free Survival , Female , Floxuridine/administration & dosage , Fluorouracil/administration & dosage , Hepatic Artery , Humans , Infusions, Intra-Arterial , Leucovorin/administration & dosage , Liver Neoplasms/secondary , Liver Neoplasms/surgery , Male , Maximum Tolerated Dose , Middle Aged , Organoplatinum Compounds/administration & dosage , Oxaliplatin , Survival Rate , Treatment OutcomeABSTRACT
BACKGROUND: Response rates to systemic chemotherapy are low after tumor progression on oxaliplatin regimens. Hepatic arterial infusion (HAI) therapy in patients with tumor progression is a viable alternative. PATIENTS AND METHODS: Thirty-nine heavily pre-treated patients (all receiving prior oxaliplatin) with unresectable colorectal hepatic metastases were treated with systemic CPT-11 and concurrent HAI floxuridine (FUDR) and dexamethasone (DEX). RESULTS: Partial responses were seen in 44% of patients. Median time to hepatic progression was 8.6 months, and median time to overall progression was 6.5 months. Median survival from time of initiation of HAI was 20.1 months [95% confidence interval (CI) 16.9-21.4] and from the initiation of treatment of metastatic disease, 32.01 months (95% CI 29.1-34.6). After a median follow-up of 19.1 months, seven patients (18%) proceeded to potentially curative surgery. Grade 3/4 toxic effects included neutropenia (13%), diarrhea (15%), intra-abdominal hemorrhage (2%), and bleeding duodenal ulcer (2%). Elevated liver function tests were seen, including bilirubin concentration >3 mg/dl (7%), alkaline phosphatase 2X baseline (20%), and aspartate aminotransferase >3X baseline (26%). CONCLUSIONS: HAI FUDR/DEX plus systemic CPT-11 achieves a response rate of 44% and a median overall survival of 20 months in heavily pre-treated patients with colorectal hepatic metastases all receiving previous oxaliplatin; 18% of patients proceeded to surgical resection or ablation.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Colorectal Neoplasms/pathology , Liver Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Camptothecin/administration & dosage , Camptothecin/analogs & derivatives , Female , Humans , Irinotecan , Liver Neoplasms/secondary , Male , Middle Aged , Organoplatinum Compounds/administration & dosage , Oxaliplatin , Retrospective StudiesABSTRACT
PURPOSE: Patients who undergo resection of liver metastases from colorectal cancer have an average 2-year survival of 65%. With hepatic arterial infusion (HAI) plus systemic fluorouracil and leucovorin, 2-year survival increased to 86%. For further improvement in both local and systemic control, combinations of new systemic drugs with HAI are being explored. The purpose of this study was to determine the maximum-tolerated dose (MTD) of systemic irinotecan (CPT-11) and HAI floxuridine (FUDR) plus dexamethasone (DEX) as combination adjuvant therapy after liver resection. PATIENTS AND METHODS: Ninety-six patients who underwent complete resection of liver metastases from colorectal cancer were treated with six monthly cycles of HAI FUDR plus DEX for 14 days of each 4-week cycle plus escalating doses of systemic CPT-11. The primary end points of the phase I/II study were the MTD and efficacy of this regimen. RESULTS: The MTD for combined systemic CPT-11 and HAI FUDR was CPT-11 at 200 mg/m2 every other week and FUDR at 0.12 mg/kg x pump volume / pump flow rate. The dose-limiting toxicities were diarrhea and neutropenia. With a median follow-up time of 26 months, the 2-year survival rate is 89%. All of the 27 patients who were treated at the MTD are alive. CONCLUSION: In patients who undergo resection of liver metastases from colorectal cancer, adding systemic CPT-11 to HAI therapy in an adjuvant regimen is feasible. This regimen seems to have comparable activity to fluorouracil and leucovorin, but further studies are needed to assess whether it improves local control or decreases extrahepatic recurrences.
Subject(s)
Adenocarcinoma/drug therapy , Adenocarcinoma/secondary , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Camptothecin/analogs & derivatives , Camptothecin/administration & dosage , Colorectal Neoplasms/pathology , Dexamethasone/administration & dosage , Floxuridine/administration & dosage , Liver Neoplasms/drug therapy , Liver Neoplasms/secondary , Adenocarcinoma/surgery , Adult , Aged , Aged, 80 and over , Disease-Free Survival , Female , Humans , Infusions, Intra-Arterial , Infusions, Intravenous , Irinotecan , Liver Neoplasms/surgery , Male , Middle Aged , Statistics, Nonparametric , Survival Rate , Treatment OutcomeABSTRACT
BACKGROUND: In vitro synergy between Oxal (oxaliplatin) and CPT-11 (irinotecan) has been reported. Oxaliplatin exerts its antineoplastic activity through the formation of platinum-DNA adducts. Resistance to oxaliplatin is through repair of these adducts, which is inhibited by irinotecan. PATIENTS AND METHODS: Oxaliplatin and irinotecan were administered weekly for 4 weeks followed by a 2-week rest period. The dose of oxaliplatin was escalated first, starting at 30 mg/m(2). Once a dose of 60 mg/m(2) was attained, the weekly dose of irinotecan was escalated, from 40 mg/m(2) to 85 mg/m(2). A total of 49 previously treated patients with metastatic colorectal cancer were entered in order to establish the maximum tolerated dose. Pharmacokinetics of oxaliplatin and irinotecan were analyzed. RESULTS: Forty-nine patients were evaluable for toxicity. The recommended phase II doses for this combination are oxaliplatin 60 mg/m(2) and irinotecan 50 mg/m(2), weekly x 4 q 6 weeks. Diarrhea was the most common dose-limiting toxicity. No pharmacological interactions were noted between oxaliplatin and irinotecan. Twelve of the 47 evaluable patients (26%) achieved a partial response. CONCLUSION: Weekly combination of oxaliplatin and irinotecan appears to be a well tolerated and active regimen in patients previously treated for metastatic colorectal cancer. Further investigations of this regimen are warranted.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Camptothecin/analogs & derivatives , Camptothecin/administration & dosage , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/pathology , Organoplatinum Compounds/administration & dosage , Pyridines/administration & dosage , Salvage Therapy , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Colorectal Neoplasms/mortality , Dose-Response Relationship, Drug , Drug Administration Schedule , Female , Humans , Irinotecan , Male , Middle Aged , Neoplasm Metastasis , Neoplasm Staging , Probability , Prognosis , Risk Assessment , Survival Analysis , Treatment OutcomeABSTRACT
BACKGROUND: ras genes encode Ras proteins that are important for signal transduction in cancer cells. Farnesyl protein transferase (FPTase) is an enzyme that is responsible for a critical post-translational modification of Ras. PATIENTS AND METHODS: We report the results of a phase II trial of SCH 66336, an FPTase inhibitor, in patients with metastatic colorectal cancer. This is the first reported experience of an FPTase inhibitor in this disease. All patients were considered refractory to first- and second-line therapy. A total of 21 evaluable patients were treated with a starting dose of 200 mg b.i.d. given continuously. RESULTS: The major side-effects were fatigue (grade 1 in 42%, grade 2 in 42% and grade 3 in 14%), diarrhea (grade 1 in 23% and grade 3 in 42%) and nausea (grade 2 in 16%). Elevations in serum creatinine (grade 2 or 3) were observed in 19% of patients and appeared to be related to dehydration induced by diarrhea. Significant hematological toxicity was not observed (only grade 1 thrombocytopenia in 19% and grade 2 or 3 anemia in 28%). Pharmacological studies revealed adequate mean pre-dose plasma concentrations in this group of patients on day 15 of therapy. No objective responses were observed, although stable disease was seen in three patients for several months. Administration of SCH 66336 was accompanied by gastrointestinal toxicity. CONCLUSIONS: Future development of this compound cannot be recommended as monotherapy in this disease.
Subject(s)
Colorectal Neoplasms/drug therapy , Drug Resistance, Neoplasm , Enzyme Inhibitors/administration & dosage , Fluorouracil/administration & dosage , Piperidines/administration & dosage , Pyridines/administration & dosage , Administration, Oral , Adult , Aged , Aged, 80 and over , Biopsy, Needle , Colorectal Neoplasms/pathology , Dose-Response Relationship, Drug , Drug Administration Schedule , Drug Resistance , Female , Follow-Up Studies , Humans , Liver Neoplasms/secondary , Lung Neoplasms/secondary , Male , Middle Aged , Neoplasm Staging , Survival Analysis , Treatment OutcomeABSTRACT
BACKGROUND: Trimetrexate (TMTX) biochemically modulates 5-fluorouracil (5-FU) and leucovorin (LCV). Two phase II trials demonstrated promising activity for TMTX/5-FU/LCV in patients with untreated advanced colorectal cancer (ACC). This trial was designed to demonstrate the safety and efficacy of TMTX/5-FU/LCV as first-line treatment in ACC. PATIENTS AND METHODS: Eligible patients with ACC were randomized in double-blind fashion to receive placebo or TMTX (110 mg/m2) intravenously (i.v.) followed 24 h later by i.v. LCV 200 mg/m2, and 5-FU 500 mg/m2 plus oral LCV rescue. Both schedules were given weekly for 6 weeks every 8 weeks. Patients were evaluated for progression-free survival (PFS), overall survival (OS), tumor response, quality of life (QoL) and toxicity. RESULTS: A total of 382 eligible patients were randomized. Significant toxicities were noted more frequently with TMTX/5-FU/LCV. Diarrhea was the most common grade 3 or 4 side-effect (41% and 28% on the TMTX and placebo arms, respectively). QoL scores and response rates did not differ between treatment arms. PFS was 5.3 months and 4.4 months in the TMTX and placebo arms, respectively (P = 0.77; Wilcoxon). OS was 15.8 months and 16.8 months, respectively (P = 0.73; Wilcoxon). CONCLUSIONS: The addition of TMTX to a weekly regimen of 5-FU/LCV worsened grade 3 or 4 diarrhea. The inclusion of TMTX did not yield any significant improvements in response rate, PFS or OS.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Colorectal Neoplasms/drug therapy , Fluorouracil/therapeutic use , Leucovorin/therapeutic use , Trimetrexate/therapeutic use , Adolescent , Adult , Aged , Aged, 80 and over , Disease Progression , Double-Blind Method , Female , Humans , Male , Middle Aged , Quality of Life , Survival Rate , Time Factors , Trimetrexate/adverse effectsABSTRACT
Exatecan mesylate (DX-8951f) is a topoisomerase I inhibitor that has increased solubility and antitumor activity compared with other topoisomerase I inhibitors. The purpose of this study was to establish a safe dose of DX-8951f given as a weekly 24-h infusion 3 of every 4 weeks. DX-8951f was administered as a 24-h continuous infusion in escalating doses. Twenty-seven patients were treated with 81 courses of the drug. Dose-limiting toxicities included neutropenia, thrombocytopenia, and inability to administer all three doses in the first cycle. In minimally pretreated patients, a dose of 0.8 mg/m(2) was tolerable. In patients who were heavily pretreated, a slightly lower dose, 0.53 mg/m(2), was tolerated without any severe toxicities. Nonhematological toxicities were mild and consisted of mild diarrhea, asthenia, mild nausea, and constipation. Pharmacokinetic parameters could be well described with a one-compartment model in most patients, although the application of the one-compartment model probably resulted in an underestimated elimination half-life. In conclusion, the recommended Phase II dose for DX-8951f administered as a weekly 24-h infusion on a 3-of-4 week schedule is 0.8 mg/m(2) in minimally pretreated patients and 0.53 mg/m(2) in patients who are heavily pretreated.
Subject(s)
Antineoplastic Agents, Phytogenic/adverse effects , Camptothecin/adverse effects , Enzyme Inhibitors/adverse effects , Neoplasms/drug therapy , Topoisomerase I Inhibitors , Aged , Antineoplastic Agents, Phytogenic/administration & dosage , Antineoplastic Agents, Phytogenic/pharmacokinetics , Camptothecin/administration & dosage , Camptothecin/analogs & derivatives , Camptothecin/pharmacokinetics , Dose-Response Relationship, Drug , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/pharmacokinetics , Female , Humans , Infusions, Intravenous , Leukopenia/chemically induced , Male , Metabolic Clearance Rate , Middle Aged , Neoplasms/blood , Neoplasms/urine , Neutropenia/chemically induced , Thrombocytopenia/chemically inducedABSTRACT
BACKGROUND: Unresectable adenocarcinomas of the biliary tree have a very poor prognosis. No good chemotherapeutic regimen is available. Irinotecan has not yet been fully tested in this disease. We evaluated its activity in unresectable bile duct cancers. PATIENTS AND METHODS: Twenty-five consecutive eligible patients at our two institutions were treated with irinotecan at a starting dose of 125 mg/m2. A cycle consisted of once-a-week treatments for four consecutive weeks, followed by two weeks of rest. All patients were required to have histologically confirmed diagnosis, clinically documented metastatic or unresectable carcinoma and measurable disease. Patients were evaluated for response, toxicity, and survival. RESULTS: A total of 83 cycles of therapy were delivered. Two patients had a partial response (8%; 95% confidence interval (CI): 0%-18%) and ten additional patients had stable disease for at least two months (40%; 95% CI: 20.8%-59.2%). The therapy was well tolerated, with moderate myelosuppression and diarrhea as the main toxicities. The overall median survival was 10 months. CONCLUSIONS: Irinotecan has minimal activity in biliary tree carcinomas, but is well tolerated with appropriate supportive care, and produces occasional objective responses.
Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Agents, Phytogenic/therapeutic use , Camptothecin/therapeutic use , Gallbladder Neoplasms/drug therapy , Adenocarcinoma/chemistry , Adenocarcinoma/mortality , Adult , Aged , Alkaline Phosphatase/analysis , Aspartate Aminotransferases/analysis , CA-19-9 Antigen/analysis , Camptothecin/analogs & derivatives , Female , Gallbladder Neoplasms/chemistry , Gallbladder Neoplasms/mortality , Humans , Irinotecan , L-Lactate Dehydrogenase/analysis , Male , Middle Aged , Survival Rate , Treatment OutcomeABSTRACT
PURPOSE: To determine the maximum-tolerated dose (MTD) and dose-limiting toxicities of concurrent systemic irinotecan and hepatic arterial infusion (HAI) of floxuridine (FUDR) and dexamethasone in patients with unresectable hepatic metastases from colorectal cancer, to determine the safety of this combination in patients who have undergone cryosurgery, and to evaluate the pharmacokinetic effects of HAI FUDR on the metabolism of irinotecan. PATIENTS AND METHODS: Forty-six previously treated patients with unresectable liver metastases and no known extrahepatic disease were treated concurrently with intravenous irinotecan weekly for 3 weeks and with HAI of FUDR and dexamethasone for 14 days (both were recycled in 28 days). Parallel cohorts of patients treated with or without cryosurgery were entered at escalating dose levels. RESULTS: The MTD for patients who did not undergo cryosurgery was 100 mg/m2 of irinotecan weekly for 3 weeks every 4 weeks with concurrent HAI FUDR (0.16 mg/kg/d x pump volume/flow rate) plus dexamethasone for 14 days of a 28-day cycle. The dose-limiting toxicities were diarrhea and neutropenia. The response rate (complete and partial) among all patients who did not undergo cryosurgery was 74%. All patients in the cryosurgery group responded, and seven of the eight cryosurgery patients developed normal positron emission tomography scans after chemotherapy. HAI FUDR had no effect on the metabolism of irinotecan. CONCLUSION: Combination therapy with HAI FUDR and dexamethasone plus systemic irinotecan may be safely administered to patients with unresectable hepatic metastases from colorectal cancer. The MTD has been reached for patients with unresectable disease, and we continue to investigate the MTD for patients who have undergone cryosurgery. Although the main objective of this study was to evaluate the toxicity of the combined regimen, a high response rate (74%) was observed.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Camptothecin/analogs & derivatives , Carcinoma/pathology , Colonic Neoplasms/pathology , Liver Neoplasms/drug therapy , Liver Neoplasms/secondary , Adult , Aged , Aged, 80 and over , Area Under Curve , Camptothecin/administration & dosage , Camptothecin/pharmacokinetics , Cryosurgery , Dexamethasone/administration & dosage , Female , Floxuridine/administration & dosage , Humans , Irinotecan , Liver Neoplasms/metabolism , Male , Middle Aged , Tomography, X-Ray ComputedABSTRACT
OBJECTIVE: To update the 1997 clinical practice guidelines for the use of tumor marker tests in the prevention, screening, treatment, and surveillance of breast and colorectal cancers. These guidelines are intended for use in the care of patients outside of clinical trials. OPTIONS: Six tumor markers for colorectal cancer and eight for breast cancer were considered. They could be recommended or not for routine use or for special circumstances. In addition to carcinoembryonic antigen (CEA) and CA 15-3, CA 27.29 was also considered among the serum tumor markers for breast cancer. OUTCOMES: In general, the significant health outcomes identified for use in making clinical practice guidelines (overall survival, disease-free survival, quality of life, lesser toxicity, and cost-effectiveness) were used. EVIDENCE: A computerized literature search from 1994 to March 1999 was performed. VALUES: The same values for use, utility, and levels of evidence were used by the committee. BENEFITS, HARMS, AND COSTS: The same benefit, harms, and costs were used. RECOMMENDATION: Changes were recommended (see Appendix). VALIDATION: The updated recommendations were validated by external review by the American Society of Clinical Oncology's (ASCO's) Health Services Research Committee and by ASCO's Board of Directors. SPONSOR: American Society of Clinical Oncology.
Subject(s)
Biomarkers, Tumor/analysis , Breast Neoplasms/pathology , Colorectal Neoplasms/pathology , Adult , Aged , Biomarkers, Tumor/economics , Biomarkers, Tumor/standards , Breast Neoplasms/diagnosis , Breast Neoplasms/therapy , Colorectal Neoplasms/diagnosis , Colorectal Neoplasms/therapy , Cost-Benefit Analysis , Disease-Free Survival , Female , Humans , Male , Mass Screening , Middle Aged , Prognosis , Quality of Life , Treatment OutcomeABSTRACT
BACKGROUND: Advanced hepatocellular carcinoma has a poor prognosis. In a Phase II clinical trial, two academic centers assessed irinotecan, a topoisomerase-1 inhibitor with broad spectrum clinical activity, in patients who had advanced hepatocellular cancer. METHODS: Patients who had had up to one prior chemotherapy regimen were eligible. Bidimensionally measurable disease, a good performance status, and adequate major organ function were required. At a starting dose of 125 mg/m2, irinotecan was administered weekly for 4 weeks followed by a 2 week break, which constituted 1 treatment cycle. Patients were restaged radiologically after two cycles of therapy. Dose attenuations were made as indicated for toxicity. RESULTS: Fourteen patients were enrolled over a 10-week period in 1997. There were ten males and four females. The median age was 58 years (range, 38-74 yrs). The Eastern Cooperative Oncology Group median performance status was 1 (range, 0-1). Two patients had prior chemotherapy (14%), and 1 patient (7%) had had radiation. A total of 30 cycles of therapy were delivered (median, 1; range, 1-6). Considerable toxicity was observed, mostly neutropenia, diarrhea, nausea, vomiting, and fatigue. All patients required at least one dose attenuation for toxicity. One partial response (7%; confidence interval, 0-20%) was noted to last 7 months. One patient had transient stable disease, and all others (86%) had progression of disease as their best response. CONCLUSIONS: Irinotecan had modest activity in advanced hepatocellular cancer. Toxicity was substantial, presumably reflecting impaired underlying liver function or poor ability to metabolize and eliminate the drug. The current study indicated that continued new therapy assessment is warranted for this disease.
Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Camptothecin/analogs & derivatives , Camptothecin/pharmacology , Carcinoma, Hepatocellular/drug therapy , Liver Neoplasms/drug therapy , Adult , Aged , Antineoplastic Agents, Phytogenic/administration & dosage , Antineoplastic Agents, Phytogenic/adverse effects , Camptothecin/administration & dosage , Camptothecin/adverse effects , Carcinoma, Hepatocellular/pathology , Diarrhea/chemically induced , Fatigue/chemically induced , Female , Humans , Irinotecan , Liver Neoplasms/pathology , Male , Middle Aged , Nausea/chemically induced , Neutropenia/chemically induced , Prognosis , Treatment Outcome , Vomiting/chemically inducedABSTRACT
BACKGROUND: Aggressive treatment of peritoneal metastases from colon cancer by surgical cytoreduction and infusional intraperitoneal (IP) chemotherapy may benefit selected patients. We reviewed our institutional experience to assess patient selection, complications, and outcome. METHODS: Patients having surgical debulking and IP 5-fluoro-2'-deoxyuridine (FUDR) plus leucovorin (LV) for peritoneal metastases from 1987 to 1999 were evaluated retrospectively. RESULTS: There were 64 patients with a mean age of 50 years. Primary tumor sites were 47 in the colon and 17 in the appendix. Peritoneal metastases were synchronous in 48 patients and metachronous in 16 patients. Patients received IP FUDR (1000 mg/m2 daily for 3 days) and IP leucovorin (240 mg/m2) with a median cycle number of 4 (range, 1-28). The median number of complications was 1 (range, 0-5), with no treatment related mortality. Only six patients (9%) required termination of IP chemotherapy because of complications. The median follow-up was 17 months (range, 0-132 months). The median survival was 34 months (range, 2-132); 5-year survival was 28%. Lymph node status, tumor grade, and interval to peritoneal metastasis were not statistically significant prognostic factors for survival. Complete tumor resection was significant on multivariate analysis (P = .04), with a 5-year survival of 54% for complete (n = 19) and 16% for incomplete (n = 45) resection. CONCLUSIONS: Surgical debulking and IP FUDR for peritoneal metastases from colon cancer can be accomplished safely and has yielded an overall 5-year survival of 28%. Complete resection is associated with improved survival (54% at 5 years) and is the most important prognostic indicator.
Subject(s)
Adenocarcinoma/drug therapy , Adenocarcinoma/surgery , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Appendiceal Neoplasms , Colonic Neoplasms , Peritoneal Neoplasms/drug therapy , Peritoneal Neoplasms/surgery , Adenocarcinoma/secondary , Adolescent , Adult , Aged , Antimetabolites, Antineoplastic/therapeutic use , Combined Modality Therapy , Female , Floxuridine/therapeutic use , Formyltetrahydrofolates/therapeutic use , Humans , Infusions, Parenteral/methods , Leucovorin/therapeutic use , Male , Middle Aged , Peritoneal Neoplasms/secondary , Retrospective Studies , Survival AnalysisABSTRACT
The liver is a common site of metastases from cancers from most sites, but particularly from the gastrointestinal tract, since the portal vein drains into the liver. About half of all patients with colorectal cancer develop liver metastases. The response of liver metastases to systemic combination chemotherapy has improved, but the 2-year survival is only 25-30%. Hepatic-arterial infusion of chemotherapy produces higher response rates, with a 2-year survival of 50-60%. In patients who can undergo liver resection followed by hepatic-arterial infusion, the 2-year survival is 85%. This review summarises the anatomical basis, pharmacokinetic background, and cost-effectiveness of this procedure. We discuss the phase II and phase III studies of hepatic-arterial infusion therapy, with a focus on liver metastases from colorectal cancer.