Preoperative versus postoperative docetaxel-cisplatin-fluorouracil (TCF) chemotherapy in locally advanced resectable gastric carcinoma: 10-year follow-up of the SAKK 43/99 phase III trial.

BACKGROUND: Fluorouracil-based adjuvant chemotherapy in gastric cancer has been reported to be effective by several meta-analyses. Perioperative chemotherapy in locally advanced resectable gastric cancer (RGC) has been reported improving survival by two large randomized trials and recent meta-analyses but the role of neoadjuvant chemotherapy and optimal regimen remains to be determined. We compared a neoadjuvant with adjuvant docetaxel-based regimen in a prospective randomized phase III trial, of which we present the 10-year follow-up data. PATIENTS AND METHODS: Patients with cT3-4 anyN M0 or anyT cN1-3 M0 gastric carcinoma, staged with endoscopic ultrasound, computed tomography, bone scan, and laparoscopy, were assigned to receive four 21-day/cycles of docetaxel 75 mg/m(2) day 1, cisplatin 75 mg/m(2) day 1, and fluorouracil 300 mg/m(2)/day over days 1-14, either before (arm A) or after (arm B) gastrectomy. Event-free survival was the primary end point, whereas secondary end points included overall survival, toxicity, down-staging, pathological response, quality of life, and feasibility of adjuvant chemotherapy. RESULTS: This trial was activated in November 1999 and closed in November 2005 due to insufficient accrual. Of the 70 enrolled patients, 69 were randomized, 34 to arm A and 35 to arm B. No difference in EFS (2.5 years in both arms) or OS (4.3 versus 3.7 years, in arms A and B, respectively) was found. A higher dose intensity of chemotherapy was observed in arm A and more frequent chemotherapy-related serious adverse events occurred in arm B. Surgery was safe after preoperative chemotherapy. A 12% pathological complete response was observed in arm A. CONCLUSION: Docetaxel/cisplatin/fluorouracil chemotherapy is promising in preoperative setting of locally advanced RGC. The early stopping could mask the real effectiveness of neoadjuvant treatment. However, the complete pathological tumour responses, feasibility, and safe surgery warrant further investigation of a taxane-based regimen in the preoperative setting.

Comparison of oral polyethylene glycol plus a large volume glycerine enema with a large volume glycerine enema alone in patients undergoing colorectal surgery for malignancy: a randomized clinical trial.

AIM: Recent meta-analyses and randomized clinical trials have concluded that mechanical bowel preparation (MBP) before elective colorectal surgery is not associated with a reduction of surgical site infection (SSI). The aim of this randomized clinical trial was to evaluate the impact of preoperative MBP for colon and rectal cancer surgery in comparison with a single glycerine enema. METHOD: Patients scheduled for radical colorectal resection for malignancy with primary anastomosis were randomized to preoperative MBP (4 l of polyethylene glycol) (group 1, 114 patients) plus a glycerine 5% enema (2 l) or a single glycerine 5% enema (2 l) (group 2, 115 patients). The postoperative incidence of SSI was recorded prospectively. Patients undergoing minimally invasive surgery (laparoscopy or robotic) accounted for 55 and 51 in groups 1 and 2 respectively. RESULTS: In all, 229 patients were included in the study, 114 in group 1 and 115 in group 2. At least one SSI was reported in 16 (14.0%) group 1 and in 20 (17.8%) group 2 patients (P=0.475). Perioperative mortality was nil. The incidence of SSI was comparable also in the 73 patients who had a low anterior resection (seven of 33 vs eight of 40, P=1.000), and for the 106 patients who underwent a minimally invasive procedure (nine of 55 vs four of 51, P=0.241). CONCLUSION: A single large-volume glycerine enema is effective bowel preparation before colorectal resection whether performed by an open or minimally invasive technique.

Best choice of central venous insertion site for the prevention of catheter-related complications in adult patients who need cancer therapy: a randomized trial.

BACKGROUND: Central venous access is extensively used in oncology, though practical information from randomized trials on the most convenient insertion modality and site is unavailable. METHODS: Four hundred and three patients eligible for receiving i.v. chemotherapy for solid tumors were randomly assigned to implantation of a single type of port (Bard Port, Bard Inc., Salt Lake City, UT), through a percutaneous landmark access to the internal jugular, a ultrasound (US)-guided access to the subclavian or a surgical cut-down access through the cephalic vein at the deltoid-pectoralis groove. Early and late complications were prospectively recorded until removal of the device, patient's death or ending of the study. RESULTS: Four hundred and one patients (99.9%) were assessable: 132 with the internal jugular, 136 with the subclavian and 133 with the cephalic vein access. The median follow-up was 356.5 days (range 0-1087). No differences were found for early complication rate in the three groups {internal jugular: 0% [95% confidence interval (CI) 0.0% to 2.7%], subclavian: 0% (95% CI 0.0% to 2.7%), cephalic: 1.5% (95% CI 0.1% to 5.3%)}. US-guided subclavian insertion site had significantly lower failures (e.g. failed attempts to place the catheter in agreement with the original arm of randomization, P = 0.001). Infections occurred in one, three and one patients (internal jugular, subclavian and cephalic access, respectively, P = 0.464), whereas venous thrombosis was observed in 15, 8 and 11 patients (P = 0.272). CONCLUSIONS: Central venous insertion modality and sites had no impact on either early or late complication rates, but US-guided subclavian insertion showed the lowest proportion of failures.

Early oral versus "traditional" postoperative feeding in gynecologic oncology patients undergoing intestinal resection: a randomized controlled trial.

BACKGROUND: A randomized controlled trial was performed to assess the outcome of early oral postoperative feeding (EOF) compared with traditional oral feeding (TOF) in gynecologic oncology patients undergoing laparotomy with associated intestinal resection. METHODS: Patients aged 18-75 years, undergoing elective laparotomy, and with preoperative diagnosis of gynecologic malignancy, were eligible. Exclusion criteria included infectious conditions, intestinal obstruction, severe malnutrition, American Society of Anesthesiologists (ASA) score > or =4, and postoperative stay in the intensive care unit lasting >24 h. Patients allocated to EOF received liquid diet in the first postoperative day and then regular diet. Patients received traditional feeding scheme until resolution of postoperative ileus to start liquid diet. The primary end-point of the trial was length of hospital stay. RESULTS: Between January 1st, 2007 and March 15th, 2008, 40 patients were randomized to receive either EOF or TOF. Hospital stay in patients who received EOF (n = 18) was 6.9 days versus 9.1 days in the TOF group (n = 22) (P = 0.022). Requirements for analgesic and antiemetic drugs, intensity of pain, intestinal function recovery, mean levels of postoperative satisfaction, postoperative complications, and quality-of-life scores did not differ between the two groups. CONCLUSION: Early resumption of oral intake is feasible and safe in gynecologic oncology patients undergoing intestinal resection as part of a planned surgical procedure. Moreover, significant reduction in length of hospital stay was demonstrated.

Genital marginal failures after intensity-modulated radiation therapy (IMRT) in squamous cell anal cancer: no higher risk with IMRT when compared to 3DCRT.

Intensity-modulated radiotherapy (IMRT) is considered the preferred option in squamous cell canal cancer (SCAC), delivering high doses to tumor volumes while minimizing dose to surrounding normal tissues. IMRT has steep dose gradients, but the technique is more demanding as deep understanding of target structures is required. To evaluate genital marginal failure in a cohort of patients with non-metastatic SCAC treated either with IMRT or 3DCRT and concurrent chemotherapy, 117 patients with SCAC were evaluated: 64 and 53 patients were treated with IMRT and 3DCRT techniques, respectively. All patients underwent clinical and radiological examination during their follow-up. Tumor response was evaluated with response evaluation criteria in solid tumors v1.1 guideline on regular basis. All patients' data were analyzed, and patients with marginal failure were identified. Concomitant chemotherapy was administered in 97 and 77.4% of patients in the IMRT and 3DCRT groups, respectively. In the IMRT group, the median follow-up was 25 months (range 6-78). Progressive disease was registered in 15.6% of patients; infield recurrence, distant recurrence and both infield recurrence and distant recurrence were identified in 5, 4 and 1 patient, respectively. Two out of 64 patients (3.1%) had marginal failures, localized at vagina/recto-vaginal septum and left perineal region. In the 3DCRT group, the median follow-up was 71.3 months (range 6-194 months). Two out of 53 patients (3.8%) had marginal failures, localized at recto-vaginal septum and perigenital structures. The rate of marginal failures was comparable in IMRT and 3DCRT groups (χ2 test p = 0.85). In this series, the use of IMRT for the treatment of SCAC did not increase the rate of marginal failures offering improved dose conformity to the target. Dose constraints should be applied with caution-particularly in females with involvement of the vagina or the vaginal septum.

Assessing the role of primary tumour resection in patients with synchronous unresectable liver metastases from pancreatic neuroendocrine tumour of the body and tail. A propensity score survival evaluation.

BACKGROUND: The role of primary tumour surgery in pancreatic neuroendocrine tumours (PNETs) with unresectable liver metastases is controversial and international guidelines do not recommend surgery in such cases. Resectability of the primary tumour has never been considered in outcome comparisons between operated and non-operated patients. METHODS: From two institutional prospective databases of patients affected by PNET and unresectable liver metastases, 63 patients who underwent a left-pancreatectomy at diagnosis were identified and compared with a group of 30 patients with a potentially resectable but not-resected primary tumour located in the body or tail. The endpoint was overall survival (OS). RESULTS: The two groups significantly differed at baseline with regard to liver tumour burden Ki-67 labelling index, site of pancreas, results of the 18FDG PET-CT and age. In the operated patients, surgical morbidity comprised 7 cases of pancreatic fistula. Postoperative mortality was nil. Median OS for patients undergoing left-pancreatectomy was 111 months vs 52 for the non operated patients (p = 0.003). At multivariate analysis after propensity score adjustment, no surgery as well as liver tumour burden>25% and higher Ki-67 index were associated with an increased risk of death during follow-up. In patients with unresectable primary tumour, OS was similar in comparison to that in the resectable but non-resected patients, and significantly worse than that in the resected patients (p = 0.032). CONCLUSION: In PNETs located in the body or tail and diffuse liver metastases distal pancreatectomy may be justified in selected patients. Randomized studies may be safely proposed in future on this topic.

Oxaliplatin combined with 5-fluorouracil and methotrexate in advanced colorectal cancer.

BACKGROUND: A promising regimen including 5-Fluorouracil, methotrexate and oxaliplatin is reported. PATIENTS AND METHODS: Patients with untreated measurable metastatic disease received bolus 5-Fluorouracil (600 mg/m2) on days 2 and 16, modulated by methotrexate (200 mg/m2) 24 h earlier, alternated with 4 weeks of continuous infusion of 5-Fluorouracil (200 mg/m2/daily) plus oxaliplatin (130 mg/m2) on days 29 and 56, followed by 2 weeks of rest. Serum vascular endothelial growth factor (VEGF) was analyzed at baseline and before every cycle. RESULTS: Fifty-eight patients were enrolled. Objective remissions were reported in 45.6% (95% CI=34.3%, 57.3%). The median progression-free survival was 7.8 months and the median overall survival was 19.4 months. No grade 4 toxicity was reported, except for one case of diarrhea. The serum VEGF evaluated in 23 patients showed a decreasing trend during therapy. CONCLUSION: The regimen was active, well tolerated and may be a possible option in patients not suitable for radical surgery.

Metal stent placement in acute malignant colorectal obstruction.

BACKGROUND: Obstruction is a common complication of advanced colorectal cancer. Stent insertion can reduce the need for emergency surgery and allows chemotherapy to begin immediately. AIMS: To evaluate the technical and clinical success and long-term outcome of stent placement in the management of acute malignant colorectal obstruction. METHODS: From July 2002 to April 2005, 29 self-expanding metal stents were placed in 24 patients (13 men, mean age 67 years, range 36-83). Stents were inserted under endoscopic and fluoroscopic control. Patients were clinically and endoscopically followed up. RESULTS: Twenty-eight out of 29 stents were successfully placed (96.5%) in 23 out of 24 patients with 25 strictures. The clinical success rate was 95.8% (23/24). Two early stent migrations were observed in two patients (8.3%). Late complications developed in eight patients (33.3%) after a median of 3.8 months (range <1-8.6): two migrations and six occlusions. The median survival was 9.8 months (range <1-27). Eleven patients (45.8%) died from progressive disease without any clinical evidence of recurrent obstruction. CONCLUSION: Stent placement is safe and effective. Stent complications are frequent but not life-threatening, and are easy to manage. An improvement in stent design and well-scheduled follow-up are needed in order to prevent such complications.

[Recent prevention strategies and occupational risk analysis: Control Banding and Sobane]. / Recenti strategie per la prevenzione e l'analisi dei rischi in ambito occupazionale: Control banding e Sobane.

Employers are responsible for the prevention of risks and must provide for the safety and health of their workers. They are obliged to apply the general principles of prevention: to avoid, where possible, any risk; to characterize and hence to estimate residual risks; to eliminate risks at the source; to adjust jobs to the needs of workers and not workers to the jobs. When we pass to the practical performance of these shared principles we introduce many problems: problems concerning terminology; problems in estimating the nature of the risks that are faced; coordination problems between the subjects that preside over prevention; problems arising from the different typology of the companies investigated In order to answer these questions the "Industrial Hygienists" have long since created various strategies for the prevention and control of risks. Among different models the methods Control Banding and Sobane-Deparis are undoubtedly the most promising. Control Banding is designed to assist especially Small and Medium Enterprises in complying with the chemical safety regulations, the scheme uses the R phrases that in Europe must be assigned to potentially harmful chemicals by the manufacturer of the chemical. R phrases describe the most important harmful effects of a chemical and have been adopted in many non European countries also. The combination of the hazard classification of the chemical and assessment of the exposure potential will allow understanding of the level of risk thus leading the person carrying out the assessment to an appropriate control method. Occupational hygienists with experience of assessing occupational exposure to chemicals agreed parameters that could be used to give reasonable indications of exposure potential. One of them is quantity being used and three categories--small, medium and large--are defined. The likelihood of the chemical becoming airborne has been addressed by defining solids according to levels of dustiness and liquids according to volatility. A simple graph that uses the boiling point of the chemical and the process operating temperature assigns the chemical a high, medium or low volatility rating. The user now has enough information to identify the control approach required to adequately reduce exposures to the chemical Occupational hygienists agreed on three broad control approaches: General Ventilation; Engineering Control; Containment. However it is recognised that in some cases specialist advice will be needed. The user takes the hazard group, quantity and level of dustiness/volatility and matches them to a control approach using a simple table. The controls are described in control guidance sheets, which comprise both general information and, for commonly performed tasks, more specific advice. The second section of the document describes a risk-prevention strategy, called SOBANE, in four levels. These four levels are: screening, where the risk factors are detected by the workers and their management, and obvious solutions are implemented; observation, where the remaining problems are studied in more detail, one by one, and the reasons and the solutions are discussed in detail; analysis, where, when necessary, an occupational health (OH) practitioner is called upon to carry out appropriate measurements to develop specific solutions; expertise, where, in very sophisticated and rare cases, the assistance of an expert is called upon to solve a particular problem. The method for the participatory screening of the risks, Deparis, is proposed for the first level screening of the SOBANE strategy. The aim of Sobane strategy is to make risk prevention faster, more cost effective, and more effective in coordinating the contributions of the workers themselves, their management, the internal and external OH practitioners and the experts.

Functional results of robotic total intersphincteric resection with hand-sewn coloanal anastomosis.

BACKGROUND: In recent decades there has been an increasing trend toward sphincter-preserving procedures for the treatment of low rectal cancer. Robotic surgery is considered to be particularly beneficial when operating in the deep pelvis, where laparoscopy presents technical limitations. The aim of this study was to prospectively evaluate the functional outcomes in patients affected by rectal cancer after robotic total intersphincteric resection (ISR) with hand-sewn coloanal anastomosis. METHODS AND PROCEDURES: From March 2008 to October 2012, 23 consecutive patients affected by distal rectal adenocarcinoma underwent robotic ISR. Operative, clinical, pathological and functional data regarding continence or presence of a low anterior resection syndrome (LARS) were prospectively collected in a database. RESULTS: Twenty-three consecutive patients were included in the study: 8 men and 15 women. The mean age was 60.2 years (range 28-73). Eighteen (78.3%) had neoadjuvant radiochemotherapy. Conversion rate was nil. The mean operative time was 296.01 min and the mean postoperative hospital stay was 7.43 ± 1.73 days. According to Kirwan's incontinence score, good fecal continence was shown in 85.7% of patients (Grade 1 and 2) and none required a colostomy (Grade 4). Concerning LARS score, the results were as follows: 57.1% patients had no LARS; 19% minor LARS and 23.8% major LARS. CONCLUSIONS: Robotic total ISR for low rectal cancer is an acceptable alternative to traditional procedures. Extensive discussion with the patient about the risk of poor functional outcomes or LARS syndrome is mandatory when considering an ISR for treatment of low rectal cancer.

Long-term, totally implantable central venous access ports connected to a Groshong catheter for chemotherapy of solid tumours: experience from 178 cases using a single type of device.

The aim of this study was to examine the early and late complications rate of central venous access ports connected to the Groshong catheter for long-term chemotherapy delivering. All patients suffering from a neoplastic disease, who required long-term chemotherapy and underwent insertion of implantable ports during a 21-month period (1 October 1994-30 June 1996) were prospectively studied. A single type of port was used, constructed of titanium and silicone rubber (Dome Port, Bard Inc., Salt Lake City, U.S.A), connected to an 8 F silastic Groshong catheter tubing (Bard Inc.). A team of different operators (two general surgeons, one interventional radiologist and four anaesthesiologists) was involved in inserting the port. All devices were placed in the operating room under fluoroscopic control. A central venous access form was filled in by the operator after the procedure and all ports were followed prospectively for device-related and overall complications. Data from the follow-up of these patients were entered in the form and collected in a database. Follow-up continued until the device was removed, the patient died or the study was closed. 178 devices, comprising a total of 32,089 days in situ, were placed in 175 patients. Three patients received a second device after removal of the first. Adequate follow-up was obtained in all cases (median 180 days, range 4-559). 138 devices (77.5%) were still in situ when the study was closed. Early complications included six pneumothoraxes, three arterial punctures and two revisions for port and/or catheter malfunction (overall early complications in 8 patients). Late complications included 3 cases (1.68% of devices) of catheter rupture and embolisation (0.093 episodes/1000 days of use), 2 cases (1.12% of devices) of venous thrombosis (0.062 episodes/1000 days of use), 1 case (0.56% of devices) of pocket infection (0.031 episodes/1000 days of use), and 4 cases (2.24% of devices) of port-related bacteraemias (0.124 episodes/1000 days of use). Infections were caused by coagulase-negative Staphylococcus aureus (4 cases) and Bacillus subtilis (1 case); they required port removal in 3 out of 5 cases. This study represents the largest published series of patients with totally implantable access ports connected to Groshong catheters; this device is a good option for long-term access to central veins and delivery of chemotherapeutic regimens, including continuous intravenous infusions. The low incidence of major complications related to implantation and management of these devices support increased use in oncology patients.

NK activity during graft-versus-host disease and graft rejection in rats following intestinal semiallogenic and allogenic transplantation with or without mesenteric lymphadenectomy.

Graft-versus-host disease (GVHD) and graft rejection are major problems following intestinal transplantation (IT). Natural killer (NK) cells may be important effector cells in both conditions. In this study, Sprague-Dawley (SD) or SD-Brown Norway (BN) F1 rat intestine was transplanted into BN recipients with and without associated graft mesenteric lymphadenectomy (GML). Cyclosporine (15 mg/kg day) was administered to all animals. Pieces of the intestinal graft were examined 4 days posttransplant and again at death. NK activity calculated using intestinal intraepithelial lymphocytes (IL) was determined utilizing an 18-hr cytotoxic assay assessing 51Cr release and the results are reported as lytic units. YAC-1 cells were used as the target. NK activity was reduced 4 days after IT both in native (8.02 +/- 0.64) and in grafted bowel (3.14 +/- 1.51), with histological evidence of rejection as compared with that of control bowel in ungrafted rats (21.1 +/- 2.14). Survival was increased, on mean, a total of 6 days with the addition of GML in both semiallogenic and allogenic transplanted rats. At the time of death, the NK activity in the native bowel had increased (17.1 +/- 3.02) and histologic evidence of GVHD was present. These data suggest that: (1) NK cells are important in GVHD and (2) both semiallogenic and allogenic transplants survive longer if they are combined with GML (P < or = 0.05 and P < or = 0.01, respectively).

Totally implantable central venous access ports for high-dose chemotherapy administration and autologous stem cell transplantation: analysis of overall and septic complications in 68 cases using a single type of device.

Sixty-eight patients suffering from breast cancer, ovarian cancer, lymphoma or multiple myeloma were treated with high-dose chemotherapy and autologous stem cell transplantation. They underwent placement of a central venous port via the subclavian vein for delivery of chemotherapy and reinfusion of stem cells. All patients were followed prospectively for device-related and overall complications, comprising a total of 18,213 days in situ (median: 267 days, range: 90-480). One patient experienced a pneumothorax (1.4%) spontaneously resolved, as an acute toxicity. Two patients (2.8%, 0.1 episodes/1000 days of use) were forced to have the port removed due to infection, caused by Streptococcus mitis in one case, while the causative agent was not identified by laboratory tests in the second. The other 66 patients completed the therapeutic programme, including peripheral stem cell reinfusions and supportive care, such as i.v. antibiotics, antiemetics or fluid administration and blood sample collection, without additional complications. In conclusion, the use of totally implantable central venous access ports has resulted in good long-term access to central veins, in spite of the severe neutropenia and increased septic risk of this category of oncology patients.

Single turnover mechanism of a trypsin-reactor with high enzyme concentration.

A small column containing 2 mM CH-Sepharose 4B-immobilized trypsin was connected to a flow injection device equipped for potentiometric measurements (0.01-2 mM protons) and for post-column analysis by spectrophotometry and capillary electrophoresis (CE). The device was engaged with N alpha-benzoyl-L-arginine pNO2-anilide (BAPNA), beta-lactoglobulin (beta-Lac) and peptides of V8-protease predigested beta-Lac. At a given flow rate, the reaction with BAPNA or beta-Lac (below 2 mM) produced about 1 proton per substrate molecule in each sample (linear relation to substrate amount); with peptides (below 22 mM), the reaction did not exceed 0.17 acid equivalents per substrate molecule (hyperbolic dependence). Final experiments demonstrated that the reactor gave a correct estimate of available lysine in peptides of beta-Lac modified with 5-nitrosalicylaldehyde. The data could be predicted by a kinetic model describing the reactor performance in 'single turnover' conditions. The interplay between resident time and the non-catalytic amount of trypsin prevented each enzyme molecule from recycling as well as each substrate molecule (containing one or more cleavage sites) from encountering the enzyme more than once. In conclusion, both from the experimental and the theoretical point of view, this work permitted the analysis of trypsin behaviour in some extreme working conditions and indicates how to modulate the performance of an endoprotease-based reactor. A brief discussion on potential applications in protein mapping and tagging and in the quantitative analysis of protein bioavailability by means of a biosensorial strategy is also described.

Complications and long-term outcome of 80 oncology patients undergoing needle catheter jejunostomy placement for early postoperative enteral feeding.

Some findings suggest that needle catheter jejunostomy (NCJ) is associated with a significant rate of potentially dangerous complications. The purpose of this study was to prospectively evaluate the rate and type of early and late complications associated with NCJ in patients with surgical treatment of upper gastrointestinal malignancy. Eighty patients underwent NCJ implant at the end of their scheduled surgical procedure. Enteral nutrition programme was started on postoperative day 1 in the surgical ICU. NCJ was always removed in the outpatient clinic after hospital discharge. One case of tube blockage has been observed as single short-term complication in this series. No long-term complications have been detected after a mean follow-up of 12 months. Routine use of NCJ in malnourished patients undergoing major surgical procedures on upper gastrointestinal tract is safe and effective.

Role of hepatic histologic findings in the prognosis and treatment of bleeding esophageal varices.

In the period from 1976 to 1986, we performed 329 hepatic needle biopsies using a posterior extraperitoneal approach in patients with bleeding esophageal varices. The histologic findings subdivided according to a four-stage classification were correlated significantly with immediate survival. Specifically, 21 of 23 stage IV patients with severe degenerative and necrotic parenchymal lesions died after immediate emergency surgery, whereas 26 of 48 stage IV patients who did not undergo emergency surgery survived. Stage IV patients appeared unable to withstand major surgery. According to our data, histologic stage and Child's class are independent parameters, especially in emergency situations, since they quantify different aspects of functional liver failure. Therapeutic implications are presented based on cumulative analysis of histologic stages and Child's classes.

Synergistic activity of oxaliplatin and 5-fluorouracil in patients with metastatic colorectal cancer with progressive disease while on or after 5-fluorouracil.

From February 1995 through October 1996, 25 patients with metastatic colorectal cancer showing a clinical resistance to 5-fluorouracil (5-FU) entered this study. Thirteen received oxaliplatin alone and 12 received it in combination with 5-FU. Oxaliplatin was administered at 130 mg/m2 over a 2-hour infusion every 3 weeks, alone or added either to 5-FU as a continuous infusion at 200 mg/m2 to 300 mg/m2 (six patients) or to a 5-FU bolus, 375 mg/m2, plus leucovorin, 100 mg/m2, daily for 5 days every 3 weeks (6 patients). Eighty-six of 98 administered cycles were evaluable for toxicity (47 for oxaliplatin plus 5-FU and 39 for oxaliplatin alone). Hematologic toxicity was mild, occurring as grade 2 leukopenia in 23% of the cycles of 5-FU and oxaliplatin and in 5% of the cycles of oxaliplatin alone. The most common toxicity was neurologic (grade 1 to 2 in 60%-6% of the cycles of the combination, respectively, and 68%-10% of oxaliplatin given alone) as hand-foot paresthesia or hypersensitivity to cold. No grade 4 toxicity was reported and only three patients in the 5-FU group developed grade 3 diarrhea. Grade 2 nausea and vomiting occurred in 33% of the cycles when both drugs were given and in 15% when oxaliplatin was administered alone. The combination of oxaliplatin and 5-FU induced four partial remissions (33%; 95% confidence interval, 6%-60%), whereas eight patients of the whole group had stable disease. No response occurred when oxaliplatin was administered as a single agent. The results of this study confirm the antitumor activity of oxaliplatin when added to 5-FU in patients who have metastatic colorectal cancer previously refractory to 5-FU. The possible therapeutic synergy with 5-FU was not accompanied by increased toxicity.