Health service cost associated with percutaneous vertebroplasty in patients with spinal metastases.

AIMS: To ascertain prospectively the health service cost of vertebroplasty in a cohort of consecutive patients with spinal metastases. MATERIALS AND METHODS: Percutaneous vertebroplasty was performed under conscious sedation and local anaesthetic in the Interventional Suite with fluoroscopic guidance. Data were collected prospectively on standard forms. Quality of life questionnaires (EQ-5D) were filled out pre-, 6 weeks, and at 6 months post-vertebroplasty. RESULTS: The majority of the procedures were performed on an outpatient basis (8/11). The median duration of the procedure was 60 min (range 40-80 min) with a further 60 min spent in the recovery room (range 10-230 min). Personnel involved included a consultant radiologist, a radiology registrar, four nurses, and two radiographers. The average cost of vertebroplasty per patient, including consumables, capital equipment, hotel/clinic costs, and staffing, was £2213.25 (95% CI £729.95). The mean EQ-5D utility scores increased from 0.421 pre-treatment to 0.5979 post-treatment (p = 0.047). The visual analogue scale (VAS) of perceived health improved from a mean of 41.88 to 63.75 (p = 0.00537). CONCLUSION: Health service costs for percutaneous vertebroplasty in patients with spinal metastases is significantly lower than previously estimated and is in keeping with that of other palliative radiological procedures.

Sorafenib in advanced melanoma: a Phase II randomised discontinuation trial analysis.

The effects of sorafenib--an oral multikinase inhibitor targeting the tumour and tumour vasculature--were evaluated in patients with advanced melanoma enrolled in a large multidisease Phase II randomised discontinuation trial (RDT). Enrolled patients received a 12-week run-in of sorafenib 400 mg twice daily (b.i.d.). Patients with changes in bi-dimensional tumour measurements <25% from baseline were then randomised to sorafenib or placebo for a further 12 weeks (ie to week 24). Patients with > or =25% tumour shrinkage after the run-in continued on open-label sorafenib, whereas those with > or =25% tumour growth discontinued treatment. This analysis focussed on secondary RDT end points: changes in bi-dimensional tumour measurements from baseline after 12 weeks and overall tumour responses (WHO criteria) at week 24, progression-free survival (PFS), safety and biomarkers (BRAF, KRAS and NRAS mutational status). Of 37 melanoma patients treated during the run-in phase, 34 were evaluable for response: one had > or =25% tumour shrinkage and remained on open-label sorafenib; six (16%) had <25% tumour growth and were randomised (placebo, n=3; sorafenib, n=3); and 27 had > or =25% tumour growth and discontinued. All three randomised sorafenib patients progressed by week 24; one remained on sorafenib for symptomatic relief. All three placebo patients progressed by week-24 and were re-started on sorafenib; one experienced disease re-stabilisation. Overall, the confirmed best responses for each of the 37 melanoma patients who received sorafenib were 19% stable disease (SD) (ie n=1 open-label; n=6 randomised), 62% (n=23) progressive disease (PD) and 19% (n=7) unevaluable. The overall median PFS was 11 weeks. The six randomised patients with SD had overall PFS values ranging from 16 to 34 weeks. The most common drug-related adverse events were dermatological (eg rash/desquamation, 51%; hand-foot skin reaction, 35%). There was no relationship between V600E BRAF status and disease stability. DNA was extracted from the biopsies of 17/22 patients. Six had V600E-positive tumours (n=4 had PD; n=1 had SD; n=1 unevaluable for response), and 11 had tumours containing wild-type BRAF (n=9 PD; n=1 SD; n=1 unevaluable for response). In conclusion, sorafenib is well tolerated but has little or no antitumour activity in advanced melanoma patients as a single agent at the dose evaluated (400 mg b.i.d.). Ongoing trials in advanced melanoma are evaluating sorafenib combination therapies.

A phase II study of high-dose bevacizumab in combination with irinotecan, 5-fluorouracil, leucovorin, as initial therapy for advanced colorectal cancer: results from the Eastern Cooperative Oncology Group study E2200.

AIM: Patients with untreated advanced colorectal cancer were enrolled to this single arm phase II multi-center cooperative group trial of bevacizumab combined with IFL. The first 20 patients received irinotecan (125 mg/m(2)), 5-fluorouracil (500 mg/m(2)) and leucovorin (20 mg/m(2)) weekly for four of six weeks and high-dose bevacizumab (10 mg/kg) every other week. Following a toxicity review of other trials using IFL, subsequent patients were enrolled at reduced doses of irinotecan (100 mg/m(2)) and 5-fluorouracil (400 mg/m(2)). RESULTS: Of the 92 patients accrued to the study, toxicity data are available for 87 patients and efficacy data for 81 patients. At a median follow-up of 37.5 months, median overall survival is 26.3 months, median progression free survival is 10.7 months and 1-year survival is 85%. The overall response rate is 49.4% (6.2% complete responses). A reduction in the starting doses of irinotecan and 5-fluorouracil decreased the occurrence of vomiting, diarrhea and neutropenia related complications. Bleeding occurred in 37 patients; all events but two were grade 1 or grade 2. There were nine reports of grade 3 or grade 4 thrombo-embolic events. Hypertension of any grade occurred in 13% of patients and proteinuria was infrequent. CONCLUSION: High-dose bevacizumab added to IFL is a well-tolerated and highly active regimen in patients with previously untreated metastatic colorectal cancer.

Impact of video colonoscopy on stage and outcome of patients with symptomatic colorectal cancer.

BACKGROUND: Double-contrast barium enema still is regarded by many as the investigation of choice for patients with large bowel symptoms. The aim of this study was to compare the stage and outcome of patients with colorectal cancer diagnosed by video colonoscopy (VC) and barium enema (BE) in a single institution. METHODS: Between July 1997 and December 2001, data were gathered prospectively in a series of 489 patients presenting consecutively with symptomatic colorectal cancer. Selection of patients for either VC or BE investigation was made by the clinician who examined the patient in the clinic. Of the 489 patients, 82 were excluded because they presented acutely or other methods were used for the diagnosis. RESULTS: A diagnosis of colorectal cancer was determined by VC for 292 patients and by BE for 115 patients. The patients in both groups were similar in terms of age, gender, and site of disease. Stage 1 disease (T1/2NO) was diagnosed for 87 (29.8%) patients in the VC group, as compared with 10 (8.7%) in the BE group (p < 0.0001). Early colorectal cancer (T1) was diagnosed for 43 patients in the VC group as compared to 1 patient in the BE group (p < 0.0001). During a median follow-up period of 33 months, 8.2% of the patients in the VC group had experienced recurrence after curative resection, as compared with 17.4% of the patients in the BE group p = 0.018). Freedom from disease (p = 0.02) and overall survival (p = 0.03) were significantly increased in the VC group. CONCLUSIONS: Videocolonoscopy used as the investigation of choice for patients with large bowel symptoms detects colorectal cancer at an earlier stage and has a significant impact on the outcome for this condition.

Sensitivity of double contrast barium enema and colonoscopy for the detection of colorectal neoplasms.

BACKGROUND: Double contrast barium enema (DCBE) is the examination carried out most frequently for investigation of patients with large bowel symptoms. The aim of this study was to compare the sensitivity of DCBE and colonoscopy for the detection of colorectal cancer and neoplastic polyps >/= 1 cm. METHODS: All patients undergoing DCBE (1389) or colonoscopy (1081) as the primary investigation for large bowel symptoms or for cancer or polyp surveillance in the first 9 months of 1997 at a large teaching hospital were included in this study. At 1 and 2 years following investigation, a computerized search of appropriate diagnosis and procedure codes to detect any missed cancers or polyps was performed for all patients with a normal investigation. RESULTS: Almost 19% of patients in both groups went on to have an additional large bowel investigation over the 2-year period. In the DCBE group, 47 patients (3.5%) had a cancer diagnosed; eight of them had been missed at the primary investigation (sensitivity 83%). In the colonoscopy group, 37 patients (3.4%) had a cancer; one of them had been missed at the primary investigation (sensitivity 97.5%). Neoplastic polyps >/= 1 cm were diagnosed in 1.6% of the DCBE group and in 7.7% of the colonoscopy group, with sensitivities of 21.7% and 91.4%, respectively. Nine patients (0.6%) had a false positive diagnosis of cancer in the DCBE group; one had an iatrogenic bowel perforation following flexible sigmoidoscopy. CONCLUSIONS: Where adequate facilities and expertise exist, colonoscopy should be the investigation of choice for most patients with large bowel symptoms suggestive of neoplastic disease.

Phase I study of phosphonacetyl-L-aspartate, 5-fluorouracil, and leucovorin in patients with advanced cancer.

Low-dose phosphonacetyl-L-aspartate (PALA) may potentiate both 5-fluorouracil (5-FU) incorporation into RNA and thymidylate synthase inhibition by 5-fluorodeoxyuridylate (5-FdUMP). The gastrointestinal toxicity of 5-FU is not increased by PALA administration. Exogenous leucovorin, on the other hand, which enhances thymidylate synthase inhibition, appears to increase the clinical toxicity of 5-FU in a dose-dependent manner. As a result, the clinical use of high-dose leucovorin requires a marked dose reduction of 5-FU. Extracellular leucovorin levels of 1 microM suffice to maximize the enhancement of thymidylate synthase inhibition in several models. We conducted a trial to add leucovorin to the PALA/5-FU regimen. We chose a leucovorin dose that was predicted to yield end-infusion total reduced folate concentrations of 1 microM. The major endpoint was to determine the maximum tolerated dose of 5-FU in this combination. The regimen consisted of 250 mg/m2 PALA given on day 1 and, 24 h later, escalating 5-FU doses ranging from 1,850 to 2,600 mg/m2 admixed with 50 mg/m2 leucovorin and given by 24-h infusion. Courses were repeated weekly. A total of 24 patients with a median performance status of 1 were entered at three dose levels. Diarrhea was dose-limiting; 6/13 patients had grade II or worse diarrhea at 2,600 mg/m2. Dose modification resulted in a mean dose intensity of 2,300 mg/m2 at both the 2,600- and 2,300-mg/m2 dose levels. The 2,300-mg/m2 dose is suitable for phase II testing of this regimen. Three patients (two with breast cancer and 1 with sarcoma) had a partial remission. We measured steady-state concentrations (Css) of 5-FU in 23 patients. The mean Css increased with dose from 0.738 to 1.03 micrograms/ml. Total body clearance did not vary with dose in this range. Patients with grade II or worse diarrhea had a higher mean Css (1.10 +/- 0.19) than those with grade O or I toxicity (0.835 +/- 0.25, P < 0.02). Total bioactive folates (bound and free) were measured using a biological assay. Pretreatment values ranged from 2 to 52 nM and were not predictive of toxicity. End-infusion (23-h) values were somewhat lower than predicted and ranged from 400 to 950 nM. The risk of diarrhea was positively correlated with end-infusion total folate values. In a logistic regression analysis, total folate values obtained at 23 h were a more powerful predictor of diarrhea than were 5-FU Css values.(ABSTRACT TRUNCATED AT 400 WORDS)

Effect of mechanical bowel preparation on anastomotic integrity following low anterior resection in dogs.

To assess the effect of mechanical bowel preparation on anastomotic integrity after low anterior resection, 36 mongrel dogs were randomized to have low anterior resection with or without mechanical bowel preparation. All dogs received prophylactic antibiotics and anastomotic integrity was assessed on the ninth postoperative day by barium enema, inspection of anastomoses for defects after careful excision at laparotomy, and anastomotic bursting pressures. Bursting pressures were significantly higher (P less than 0.005) in the group with bowel preparation. Anastomotic defects were present in 13 per cent of animals with bowel preparation and 47 per cent without bowel preparation (P = 0.057). Pelvic abscess and death from peritonitis occurred in 6 per cent of the group with bowel preparation and 29 per cent of the unprepared group. Mechanical bowel preparation significantly enhanced anastomotic integrity and reduced complications in this model.

Effect of 13-cis-retinoic acid on tumor prevention, tumor growth, and metastasis in experimental colon cancer.

The effect of 13-cis-retinoic acid (13-cis-RA) on 1,2-dimethylhydrazine (DMH)-induced colon cancer in male, random bred, Sprague-Dawley (S-D) and inbred Wister/Furth (W/Fu) rats and on isograft tumor growth and metastases in a Brown Norwegian (BN) X W/Fu F1 rat was studied. 13-cis-RA (300 mg/kg diet) was administered to S-D rats 1 week before commencing DMH injections and for the duration of the experiment. W/Fu rats received 13-cis-RA (10 mg/kg weight X 5 days) 6 weeks after DMH injection had begun and monthly thereafter. Primary tumors were detected by serial laparotomy under ether anesthesia in both strains. The time to tumor onset was significantly delayed in treated groups, S-D and W/Fu, P = 0.0339 and 0.0322, respectively (Mantel-Haenszel test), compared with placebo-treated controls. 13-cis-RA (15 mg/kg weight) administered 2 days before and for the duration of isograft tumor growth (DMH 2054, a well-differentiated mucin-producing colon adenocarcinoma that spontaneously metastasized to lung) had no effect on tumor growth or metastasis in the BN X W/Fu F1 rat. The findings suggest that the role of 13-cis-RA is in colon cancer prevention and not in its treatment either in an adjuvant or established setting.

Flavone acetic acid (LM 975, NSC 347512). A novel antitumor agent.

Flavone acetic acid (FAA) is a synthetic flavonoid compound which has recently begun clinical trials as an antitumor agent based on its striking activity in solid tumor model systems. The pharmacologic behavior of FAA in animals appears to be predictive of both its cytotoxic efficacy and its toxicity to normal tissues (principally the central nervous system and gastrointestinal tract). The design and conduct of phase I studies in man are based upon these principles, with the goal of maximizing their safety and efficacy.

Trimetrexate: a new antifol entering clinical trials.

Trimetrexate, a 2,4-diaminoquinazoline derivative, is a new antifol recently introduced into clinical trials. It differs from methotrexate principally in its transport (not carrier-mediated), and its intracellular retention (not polyglutamylated). Trimetrexate is active against tumors which are methotrexate-resistant on the basis of impaired transport, and has a broader range of antitumor activity in preclinical models. Animal studies predict toxicity principally to the central nervous system, gastrointestinal tract and bone marrow.

Spiromustine: a new agent entering clinical trials.

Spiromustine is a new alkylating agent, of interest since it was rationally designed as a lipophilic compound capable of penetrating the CNS. This lipophilicity may also enhance alkylating activity against tumors other than brain tumors. Preclinical screening has shown activity against a variety of tumors, including an intracranially implanted ependymoblastoma. Alkylating activity has been demonstrated in an intracerebral glioma in the rat. Spiromustine is a cell cycle non-specific agent. Animal pharmacology studies have shown a biphasic plasma decay curve, with hepatic metabolism and excretion, an enterohepatic circulation of metabolites, and approximately 50% renal excretion of unchanged drug. Toxicology studies in mice, rats and dogs showed that dose-related myelosuppression, and neurotoxicity predominated; other organ toxicities were mild. Spiromustine is currently entering Phase I clinical trials on a variety of schedules.