2D versus 3D laparoscopic total mesorectal excision: a developmental multicentre randomised controlled trial.

AIMS: The role of laparoscopy in rectal cancer has been questioned. 3D laparoscopic systems are suggested to aid optimal surgical performance but have not been evaluated in advanced procedures. We hypothesised that stereoscopic imaging could improve the performance of laparoscopic total mesorectal excision (TME). METHODS: A multicentre developmental randomised controlled trial comparing 2D and 3D laparoscopic TME was performed (ISRCTN59485808). Trial surgeons were colorectal consultants that had completed their TME proficiency curve and underwent stereoscopic visual testing. Patients requiring elective laparoscopic TME with curative intent were centrally randomised (1:1) to 2D or 3D using Karl Storz IMAGE1 S D3-Link™ and 10-mm TIPCAM®1S 3D passive polarising laparoscopic systems. Outcomes were enacted adverse events as assessed by the observational clinical human reliability analysis technique, intraoperative data, 30-day patient outcomes, histopathological specimen assessment and surgeon cognitive load. RESULTS: 88 patients were included. There were no differences in patient or tumour demographics, surgeon stereopsis, case difficulty, cognitive load, operative time, blood loss or conversion between the trial arms. 1377 intraoperative adverse events were identified (median 18 per case, IQR 14-21, range 2-49) with no differences seen between the 2D and 3D arms (18 (95% CI 17-21) vs. 17 (95% CI 16-19), p = 0.437). 3D laparoscopy had non-significantly higher mesorectal fascial plane resections (94 vs. 77%, p = 0.059; OR 0.23 (95% CI 0.05-1.16)) but equal lymph node yield and circumferential margin distance and involvement. 30-day morbidity, anastomotic leak, re-operation, length of stay and readmission rates were equal between the 2D and 3D arms. CONCLUSION: Feasibility of performing multicentre 3D laparoscopic multicentre trials of specialist performed complex procedures is shown. 3D imaging did not alter the number of intraoperative adverse events; however, a potential improvement in mesorectal specimen quality was observed and should form the focus of future 3D laparoscopic TME trials.

EAES classification of intraoperative adverse events in laparoscopic surgery.

BACKGROUND: Surgical outcomes are traditionally evaluated by post-operative data such as histopathology and morbidity. Although these outcomes are reported using accepted systems, their ability to influence operative performance is limited by their retrospective application. Interest in direct measurement of intraoperative events is growing but no available systems applicable to routine practice exist. We aimed to develop a structured, practical method to report intraoperative adverse events enacted during minimal access surgical procedures. METHODS: A structured mixed methodology approach was adopted. Current intraoperative adverse event reporting practices and desirable system characteristics were sought through a survey of the EAES executive. The observational clinical human reliability analysis method was applied to a series of laparoscopic total mesorectal excision (TME) case videos to identify intraoperative adverse events. In keeping with survey results, observed events were further categorised into non-consequential and consequential, which were further subdivided into four levels based upon the principle of therapy required to correct the event. A second survey phase explored usability, acceptability, face and content validity of the novel classification. RESULTS: 217 h of TME surgery were analysed to develop and continually refine the five-point hierarchical structure. 34 EAES expert surgeons (69%) responded. The lack of an accepted system was the main barrier to routine reporting. Simplicity, reproducibility and clinical utility were identified as essential requirements. The observed distribution of intraoperative adverse events was 60.1% grade I (non-consequential), 37.1% grade II (minor corrective action), 2.4% grade III (major correction or change in post-operative care) and 0.1% grade IV (life threatening). 84% agreed with the proposed classification (Likert scale 4.04) and 92% felt it was applicable to their practice and incorporated all desirable characteristics. CONCLUSION: A clinically applicable intraoperative adverse event classification, which is acceptable to expert surgeons, is reported and complements the objective assessment of minimal access surgical performance.

Application of objective clinical human reliability analysis (OCHRA) in assessment of technical performance in laparoscopic rectal cancer surgery.

BACKGROUND: Laparoscopic rectal resection is technically challenging, with outcomes dependent upon technical performance. No robust objective assessment tool exists for laparoscopic rectal resection surgery. This study aimed to investigate the application of the objective clinical human reliability analysis (OCHRA) technique for assessing technical performance of laparoscopic rectal surgery and explore the validity and reliability of this technique. METHODS: Laparoscopic rectal cancer resection operations were described in the format of a hierarchical task analysis. Potential technical errors were defined. The OCHRA technique was used to identify technical errors enacted in videos of twenty consecutive laparoscopic rectal cancer resection operations from a single site. The procedural task, spatial location, and circumstances of all identified errors were logged. Clinical validity was assessed through correlation with clinical outcomes; reliability was assessed by test-retest. RESULTS: A total of 335 execution errors identified, with a median 15 per operation. More errors were observed during pelvic tasks compared with abdominal tasks (p < 0.001). Within the pelvis, more errors were observed during dissection on the right side than the left (p = 0.03). Test-retest confirmed reliability (r = 0.97, p < 0.001). A significant correlation was observed between error frequency and mesorectal specimen quality (r s = 0.52, p = 0.02) and with blood loss (r s = 0.609, p = 0.004). CONCLUSIONS: OCHRA offers a valid and reliable method for evaluating technical performance of laparoscopic rectal surgery.

The selective use of splenic flexure mobilization is safe in both laparoscopic and open anterior resections.

AIM: Splenic flexure mobilization (SFM) is standard practice in anterior resections. No previous studies have compared outcomes with and without SFM in laparoscopic and open colorectal cancer surgery. This study aimed to determine whether routine or selective SFM should be advised. METHOD: Data were collected prospectively on all elective anterior resections for cancer in our unit between October 2006 and November 2009. RESULTS: Of 263 resections, SFM data were recorded in 216; 138 were laparoscopic (32% with SFM, 3.6% converted) and 78 open (68% with SFM). Eighty-eight were low anterior resections (LARs) for mid-low rectal cancers, with 54 laparoscopic (50% with SFM) and 34 open (91% with SFM). Comparing laparoscopic with SFM to without, differences were found in the proportion of LARs (61%vs 29%, P<0.001), defunctioning ileostomy rates (75%vs 46%, P=0.001) and operative time (median 255 vs 185 min, P<0.001), with no differences in age, gender, body mass index, American Society of Anesthesiology score, preoperative treatment, length of stay, lymph node yield, conversion rate, mortality, anastomotic leakage, reoperation, readmission and R0 resection. No differences in outcomes were seen between laparoscopic LARs with and without SFM or between open resections with and without SFM. CONCLUSION: Our results show no disadvantage in short-term clinical or oncological outcomes when SFM was avoided. Laparoscopic anterior resections with SFM take longer. A selective approach to SFM is safe during anterior resection (open or laparoscopic), including mid-low rectal cancers.

Hepatic arterial infusion of chemotherapy after resection of hepatic metastases from colorectal cancer.

BACKGROUND: Two years after undergoing resection of liver metastases from colorectal cancer, about 65 percent of patients are alive and 25 percent are free of detectable disease. We tried to improve these outcomes by treating patients with hepatic arterial infusion of floxuridine plus systemic fluorouracil after liver resection. METHODS: We randomly assigned 156 patients at the time of resection of hepatic metastases from colorectal cancer to receive six cycles of hepatic arterial infusion with floxuridine and dexamethasone plus intravenous fluorouracil, with or without leucovorin, or six weeks of similar systemic therapy alone. Patients were stratified according to previous treatment and the number of liver metastases identified at operation. The study end points were overall survival, survival without recurrence of hepatic metastases, and survival without any metastases at two years. RESULTS: The actuarial rate of overall survival at two years was 86 percent in the group treated with local plus systemic chemotherapy and 72 percent in the group given systemic therapy alone (P=0.03). The median survival was 72.2 months in the combined-therapy group and 59.3 months in the monotherapy group, with a median follow-up of 62.7 months. After two years, the rates of survival free of hepatic recurrence were 90 percent in the monotherapy group and 60 percent in the monotherapy group (P<0.001), and the respective rates of progression-free survival were 57 percent and 42 percent (P=0.07). At two years, the risk ratio for death was 2.34 among patients treated with systemic therapy alone, as compared with patients who received combined therapy (95 percent confidence interval, 1.10 to 4.98; P=0.027), after adjustment for important variables. The rates of adverse effects of at least moderate severity were similar in the two groups, except for a higher frequency of diarrhea and hepatic effects in the combined-therapy group. CONCLUSIONS: For patients who undergo resection of liver metastases from colorectal cancer, postoperative treatment with a combination of hepatic arterial infusion of floxuridine and intravenous fluorouracil improves the outcome at two years.

Phase II trial of docetaxel (Taxotere) for untreated advanced colorectal carcinoma.

The antimicrotubule agent docetaxel (Taxotere), a semisynthetic taxoid, has demonstrated antitumor activity against colorectal cancer cell lines in vitro, and in murine tumor models. We sought to characterize its activity in a group of previously untreated patients with colorectal carcinoma. Eighteen previously untreated patients with advanced, measurable colorectal carcinoma were treated with a 60-min intravenous infusion of docetaxel with a dose of 100 mg/m2 administered every 21 days. Routine premedication with diphenhydramine was given. Patients were required to have normal organ function and a Karnofsky performance status (KPS) > or = 60%. No complete response (CR) or partial responses (PR) were observed. Median survival was 13 months, despite a median time to progression of only 1.3 months. Neutropenia was the most common dose-limiting toxicity, resulting in 5 episodes of febrile neutropenia requiring hospitalization and intravenous antibiotics. One patient experienced a grade 4 hypersensitivity reaction (HSR) requiring treatment termination. No toxic deaths occurred. Despite encouraging preclinical data, docetaxel is an inactive drug in advanced colorectal cancer when given in the dose and on the schedule examined in the present study, and has significant, although reversible, toxicities.

A comparison of umbilical cord blood gas values between newborns with and without true knots.

OBJECTIVE: To compare umbilical cord blood gas values in newborns with and without true knots, and to assess the potential impact of true knot formation on cord blood gases. METHODS: Twelve newborn infants with true umbilical cord knots were identified and compared with a random control population of 104 newborn infants without true knots. The two groups were analyzed for 11 maternal-fetal variables to determine if they were comparable. Subsequently, the principal outcome variable of the study was evaluated: a comparison between the umbilical arterial and venous blood gas results of the true knot and control populations. RESULTS: The true knot and control populations were comparable with respect to the maternal-fetal variables analyzed. The umbilical cord blood gas values did not differ between groups, except for a slightly lower umbilical artery bicarbonate value in the control group (22.0 mEq/L) versus the true knot group (24.5 mEq/L), P = .025. There was no significant difference in the incidence of acidemia (umbilical artery pH less than 7.20) between the two groups. CONCLUSION: The presence of true umbilical cord knots does not alter the incidence of umbilical artery acidemia or change umbilical cord blood gas values. Review of the pertinent obstetric literature supports the hypothesis that true umbilical cord knots lack clinical significance.

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.

Cancer chemotherapy in the elderly.

Gastrointestinal malignancies are very common in the elderly of the U.S. There is controversy about the role of chemotherapy in these elderly patients because of the impression that this population experiences greater toxicity while deriving lesser benefit. Though definitive data is lacking regarding many aspects of chemotherapy in the elderly, some general observations can be made: (a) most chemotherapy agents do not have increased toxicity in the elderly; (b) dosing and regimen should be based more on functional parameters rather than chronologic age; (c) chemotherapy for advanced gastrointestinal malignancies is in general of marginal efficacy and can be potentially toxic, regardless of age; and (d) better prospective studies focusing on the efficacy, toxicity, and quality of life effects of chemotherapy in the elderly should be performed. We review the literature regarding chemotherapy pharmacology, efficacy, and organ-specific toxicity of agents used in gastrointestinal malignancies in the context of these principles.

Relationship of acute gastrointestinal toxicity and the volume of irradiated small bowel in patients receiving combined modality therapy for rectal cancer.

PURPOSE: To determine the relationship between acute gastrointestinal (GI) toxicity during the combined modality segment and the volume of small bowel in the pelvic radiation field in patients who receive either preoperative or postoperative therapy for rectal cancer. PATIENTS AND METHODS: The patient population was derived from four consecutive phase I dose-escalation trials. Combined modality therapy included fluorouracil (5-FU), leucovorin ([LV] bolus daily x 5, days 1 and 29), and pelvic radiation. RESULTS: Twenty patients who received postoperative therapy had a larger volume of small bowel in the pelvic radiation field as compared with 60 who received preoperative therapy (462 +/- 129 v 212 +/- 44 cm3, P = .002). The most significant relationship between acute GI toxicity and volume of small bowel was seen in 12 patients who were treated on the preoperative sequential low-dose LV trial, all of whom received the maximum-tolerated dose (MTD) of 5-FU. The volume of small bowel in patients who experienced grade 3+ toxicity was 731 +/- 274 cm3, as compared with 145 +/- 58 in those who experienced grade 0 to 2 toxicity (P = .005). Likewise, logistic regression analysis showed that 26 patients who received the MTD of 5-FU had the most significant association between GI toxicity and volume of small bowel (P = .036). CONCLUSION: Our data suggest that the volume of small bowel in the pelvic radiation field may be dose-limiting in the delivery of high-dose 5-FU when combined with LV and radiation therapy.

Continuous infusion fluorouracil/leucovorin and bolus mitomycin-C as a salvage regimen for patients with advanced colorectal cancer.

BACKGROUND: No effective systemic salvage therapy exists for patients with advanced colorectal cancer who progress after receiving bolus fluorouracil (FU) and leucovorin (LV) chemotherapy. In vitro data suggest that bolus FU resistance can be overcome by continuous infusion (CI) FU, and that the cytotoxic effects of Mitomycin-C (MMC) and FU are synergistic. Based on this data, a Phase II trial of CI FU and LV with bolus MMC in patients with advanced colorectal carcinoma who progressed on only one previous chemotherapy regimen was performed. METHODS: Twenty-eight patients with advanced colorectal carcinoma who had progressed after one previous chemotherapy regimen of bolus FU/LV were treated with bolus MMC 10 mg/m2 every 6 weeks and CI FU 200 mg/m2/day admixed with LV 10 mg/m2/day given 14 days on/7 days off. RESULTS: The partial response rate in 24 evaluable patients was 17% (95% confidence interval, 2-32%) with a median response duration of 9.5 months (range, 4.2-12.0 months). Twelve (50%) additional patients achieved disease stabilization. Median survival was 9.9 months in the whole group (28 patients) and 11.5 months in the 24 evaluable patients. The major toxicities were grade 4 diarrhea occurring in two patients and grade 3 mucositis occurring in five patients. There was minimal myelosuppression (grade 3 thrombocytopenia in one patient) and no occurrences of hand-foot syndrome or cardiotoxicity. CONCLUSIONS: This regimen demonstrates modest activity with acceptable toxicity in colorectal cancer patients who have failed a single-bolus FU/LV regimen. Modifications of this and other infusional FU-based chemotherapy regimens should be explored as potential salvage chemotherapy regimens in advanced colorectal cancer.

A fixed-ratio combination of uracil and Ftorafur (UFT) with low dose leucovorin. An active oral regimen for advanced colorectal cancer.

BACKGROUND: UFT is a fixed-ratio combination of uracil and Ftorafur, a prodrug that is absorbed orally and metabolized in vivo to 5-fluorouracil (5-FU). Uracil potentiates 5-FU through interference with its catabolism. The combination of UFT and leucovorin in patients with advanced incurable colorectal cancer, to evaluate preliminary activity and toxicity in this patient population. METHODS: Twenty-one patients were treated. Twenty patients were evaluable for toxicity and response. Patients received UFT 350 mg/m2/day divided every 8 hours. Patients took a 5 mg tablet of leucovorin every 8 hours, concurrent with each UFT dose. Treatment was continued for 28 consecutive days, followed by a 7-day rest. RESULTS: Five major objective responses (one complete and four partial) were observed. Toxicity was mild, with no dose-limiting myelosuppression. Four patients experienced grade 3 diarrhea or higher, and two patients experienced dose-limiting mucositis. CONCLUSION: UFT and low dose leucovorin is a well tolerated, orally administered regimen with activity in colorectal cancer. A randomized comparison of this regimen with conventional parenteral regimens is warranted.

Phase II study of hepatic arterial floxuridine, leucovorin, and dexamethasone for unresectable liver metastases from colorectal carcinoma.

PURPOSE: To determine the toxicity, response rate, and survival of a regimen of hepatic arterial floxuridine (FUDR) with leucovorin (LV) and dexamethasone (Dec) for the treatment of unresectable hepatic metastases from colorectal carcinoma. PATIENTS AND METHODS: Sixty-two patients with hepatic metastases (33 previously untreated with chemotherapy) were treated with FUDR (0.30 mg/kg/d) and LV (15 mg/m2/d) and Dec (20 mg total dose) as a 14-day hepatic arterial infusion via an implantable pump alternating with 2 weeks of saline. RESULTS: The complete response (CR) plus partial response (PR) rate was 78% in previously untreated patients, with a median survival duration of 24.8 months; 1- and 2-year survival rates were 91% and 57%, respectively. In the previously treated group, the response rate was 52%, with a median survival duration of 13.5 months. Only 3% of patients (two of 62) developed biliary sclerosis; this was significantly lower than the 21% biliary sclerosis rate observed in our previous trial of hepatic arterial FUDR and LV without Dec (P = .002). CONCLUSION: The addition of Dec to hepatic arterial FUDR and LV reduces biliary toxicity while maintaining an excellent response rate and survival. We recommend that this treatment be studied further.

Colon carcinoma metastatic to the trachea. Report of a case and a review of the literature.

Tracheal metastases are rarely seen from colorectal carcinoma. We describe the third reported case of colorectal carcinoma metastatic to the trachea and review of the current pathogenesis, diagnosis, and management of endotracheal metastases.

Trial of sequential trimetrexate, fluorouracil, and high-dose leucovorin in previously treated patients with gastrointestinal carcinoma.

PURPOSE: Trimetrexate (TMTX) is a dihydrofolate reductase inhibitor, which, like methotrexate (MTX), has been shown to potentiate fluorouracil (FU) cytotoxicity by increasing phosphoribosylpyrophosphate (PRPP) levels. We investigated the safety and efficacy of a sequential TMTX/FU/leucovorin (LV) combination. PATIENTS AND METHODS: Forty-one patients with advanced gastrointestinal carcinoma (mostly colorectal) received variable doses of TMTX followed 24 hours later by FU/LV (500 mg/m2 of each drug). Almost all patients had received previous chemotherapy. The initial 19 patients were treated on a 3-week-on/1-week-off schedule without any significant toxicity; the remaining patients were treated for 6 consecutive weeks followed by a 2-week rest period. TMTX was escalated in 30-mg/m2 increments from 20 to 110 mg/m2 in separate patient cohorts. When the 110-mg/m2 dose of TMTX was reached, the FU dose was escalated from 500 mg/m2 to 600 mg/m2. RESULTS: The partial response (PR) rate in assessable patients with colorectal cancer (all previously treated) was 20% (seven of 35; 95% confidence interval, 7% to 33%), and with other gastrointestinal cancers was one of four patients. Median survival has not been reached with a median follow-up of 13.5 months. The maximum-tolerated dose (MTD) was 110 mg/m2 for TMTX, 500 mg/m2 for FU, and 500 mg/m2 for LV on a 6-weeks-on/2-weeks-off cycle. The principal toxicities were grade 3 or 4 diarrhea, which occurred in 17% of patients, and hypersensitivity reactions, which occurred in 26% of patients. CONCLUSION: TMTX can be administered at maximal doses in combination with FU and LV without increasing toxicity. The PR rate of 20% in advanced colorectal carcinoma patients previously treated with chemotherapy is encouraging and merits further study.

Hereditary spherocytosis and hematologic malignancy.

We report the development of myeloproliferative disorders in two patients with hereditary spherocytosis diagnosed in adulthood. Eight previously reported cases of the coexistence of hereditary spherocytosis and hematologic malignancy are reviewed.

Hepatic arterial floxuridine and leucovorin for unresectable liver metastases from colorectal carcinoma. New dose schedules and survival update.

BACKGROUND: We studied three new dose schedules of hepatic arterial infusion of floxuridine (FUDR) and leucovorin and update survival analysis of a previously reported trial using these drugs by hepatic arterial infusion for patients with hepatic metastases from colorectal carcinoma. METHODS: Untreated patients with hepatic metastases from colorectal cancer were treated with three dose schedules: Group D, FUDR (0.3 mg/kg/day) and leucovorin (30 mg/m2/day) as a 14-day continuous infusion through an implantable hepatic arterial pump alternating with a 4-week rest period; Group E, a lower dose of FUDR (0.25 mg/kg/day) and leucovorin (30 mg/m2/day) as a 14-day infusion alternating with 2 weeks of saline; and Group F, FUDR (0.3 mg/kg/day) with a lower leucovorin dose (15 mg/m2/day) for 2 weeks followed by a 2-week rest. RESULTS: In 42 patients with unresectable hepatic metastases, the complete-plus-partial response rate was 56%, with a median survival of 24.2 months. Complete-plus-partial response rates for groups D, E, and F were 30%, 54%, and 75%, respectively. Twelve percent of the 42 patients developed biliary sclerosis; the percentages of patients per group were 17%, 15%, and 6%, respectively. Updated median survival of the original 24 patients treated with FUDR and leucovorin by hepatic arterial infusion and these 42 new patients (66 total) was 28.8 months. One-, two-, three-, four-, and five-year survival rates were 86%, 62%, 31%, 15%, and 7%, respectively. CONCLUSIONS: Hepatic arterial chemotherapy with FUDR and leucovorin for patients with hepatic metastases from colorectal carcinoma yields a high response rate and 1- and 2-year survivals of 86% and 62%, respectively. Although a lower dose of leucovorin (15 mg/m2) with FUDR produces a high response rate with less toxicity, before larger scale trials are initiated, further investigation is needed to reduce toxicity. A study of hepatic arterial dexamethasone with FUDR and leucovorin has been initiated for this purpose.

A pilot study of hepatic artery floxuridine combined with systemic 5-fluorouracil and leucovorin. A potential adjuvant program after resection of colorectal hepatic metastases.

BACKGROUND: Most patients with colorectal carcinoma metastatic to the liver have relapses after surgical resection of hepatic metastases with failures divided equally between hepatic and extrahepatic sites. A pilot study was begun using a regimen combining intrahepatic floxuridine (FUDR) and systemic 5-fluorouracil (5-FU) and leucovorin (LV) to determine its safety and efficacy. METHODS: Because this was a pilot study, 21 patients with unresectable hepatic metastases from colorectal carcinoma were treated to assess the regimen's toxicity. Eight patients had liver metastases that were resected completely; then they received treatment. FUDR was given by hepatic arterial pump through a 14-day continuous infusion at 0.25 mg/kg/day. Systemic therapy consisted of LV 200 mg/m2 and 5-FU 280 mg/m2 using a bolus dose of 5-FU for 5 days with escalation of the 5-FU dose in separate patient cohorts. The maximally tolerated 5-FU dose was 325 mg/m2. RESULTS: The median survival in the 21 unresectable patients was 16 months with a partial response rate of 56% (10 of 18 evaluable patients; 95% confidence interval, 38-79%). The major systemic toxicity was diarrhea, Grade 3 or 4, in 54% of patients being treated in the 4-week regimen and 19%, in the 5-week regimen. The level of hepatic toxicity was similar to that in previous studies using intrahepatic chemotherapy alone, i.e., 48% of patients had a 200% increase in alkaline phosphatase levels and 10% had bilirubin elevations of more than 3.0 mg/dl (one patient had documented biliary sclerosis). All eight patients treated with adjuvant therapy were alive without disease after a median follow-up of 23 months. CONCLUSIONS: Systemic 5-FU and LV can be combined safely with intraarterial FUDR without loss of efficacy or increased biliary toxicity. Eight patients treated with this regimen as adjuvant therapy after liver metastasis resection were alive and disease-free after a median follow-up of 23 months.

Randomized trial of hepatic arterial floxuridine, mitomycin, and carmustine versus floxuridine alone in previously treated patients with liver metastases from colorectal cancer.

PURPOSE: This study was designed to determine if hepatic arterial therapy with floxuridine (F), mitomycin, and carmustine (BCNU) (FMB) is superior to hepatic arterial therapy with F alone in previously treated patients with hepatic metastases from colorectal cancer. PATIENTS AND METHODS: Ninety-five patients were randomized to intrahepatic FMB versus intrahepatic F. All patients had tumor progression after systemic chemotherapy (either therapeutic or adjuvant). RESULTS: There was no significant difference in response rate (47% FMB v 33% F; P = .17). Median survival was similar in the two groups, 19.1 months for the FMB group compared with 14.0 months for the F group (P = .23). The overall median survival was 16.8 months. In patients who received prior adjuvant therapy, there was no difference between the two groups, but response rate was high in both (50% FMB v 62% F). The response rate for all patients who had received only prior adjuvant therapy versus all those who had received prior therapy for metastatic disease was 57% and 35%, respectively (P = .066). In the subset of patients whose disease had progressed with prior systemic chemotherapy, the response rate to FMB was greater than that to F (47% v 23%; P = .035). CONCLUSION: The overall partial response rate of 39% and the overall survival of 16.8 months from initiation of intrahepatitis therapy show that hepatic arterial therapy is a reasonable treatment option for patients whose tumor does not respond to systemic therapy or whose disease progresses after adjuvant therapy for colorectal cancer.