Multicenter non-randomized phase II study of raltitrexed (Tomudex) and oxaliplatin in non-pretreated metastatic colorectal cancer patients.

BACKGROUND: This multicenter, phase II, open-label study evaluated the antitumor efficacy and safety of oxaliplatin and raltitrexed (Tomudex) in non-pretreated advanced colorectal cancer patients. PATIENTS AND METHODS: Seventy-one patients received oxaliplatin 130 mg/m(2) and raltitrexed 3 mg/m(2) intravenously on an outpatient basis every 3 weeks. All patients had histologically proven metastatic colorectal adenocarcinoma, performance status

Carcinomatous meningitis and solid tumours.

This retrospective study concerning patients with a carcinomatous meningitis (CM) associated with solid tumour aimed at identifying risk markers of CM which could be used in the future in order to prevent from this neurological complication. From 1976 to 1996, the patients whose CSF sampling was positive cytologically, were registered recording baseline clinical data, tumour histology with grade, tumour dissemination, treatments and follow-up. Simultaneously to the recruitment of the patients the incidence of CM was derived at each 5-year period. The variables were analysed by uni- and multivariate statistics. Among the 41 cases, the first three sites of the primary were breast, lung, essentially small cell lung cancer, and urinary tumours. At their initial presentation, 22 patients revealed an M1 dissemination and 22 tumours were undifferentiated. Over the 20 years, the incidence of CM has significantly increased for urinary cancers, decreased for breast cancer while the administration of neoadjuvant chemotherapy was increasing, and remained unchanged for lung cancer. M1 and/or undifferentiated tumours shortened the time-to-CM whereas bone metastases, that were the most frequent site for secondary deposits, did not. Breast, lung and urinary cancers produced 80% of the CM in the series. Neoadjuvant chemotherapy possibly could save patients from the meningeal dissemination. M1 and undifferentiated tumours appeared to be independent risk factors, as well as osseous metastases. Other risk factors of CM should be identified in prospective trials.

Phase II trial of oxaliplatin as first-line chemotherapy in metastatic colorectal cancer patients. Digestive Group of French Federation of Cancer Centers.

PURPOSE: To evaluate the objective tumor response rate and safety profile of oxaliplatin when administered to patients with previously untreated metastatic colorectal adenocarcinoma. PATIENTS AND METHODS: A total of 39 patients were entered onto this phase II trial. One patient was excluded for having had a second cancer, so the study was based on 38 patients. Patients were treated with oxaliplatin 130 mg/m2 as a 2-hour infusion on day 1, every 21 days. Patients were assessed for response every three courses. All clinical and radiologic data were reviewed by an external panel of experts, with their assessment being considered definitive. RESULTS: Nine partial responses (PRs) were observed (response rate, 24.3%; 95% confidence interval, 11.8% to 41.2%). The median duration of response was 216+ days. Fifteen patients (40.5%) had stable disease and 13 (35.2%) had progressive disease. The median progression-free survival time for all patients was 126+ days (range, 21 to 447+). The main toxicity was peripheral sensory neuropathy. Grade 3 neurotoxicity (National Cancer Institute common toxicity criteria [NCI-CTC]) was reported in 13%. Hematologic and gastrointestinal toxicities were mild. The incidence of grade 3 neutropenia was 5.2%, while that of grade 3 or 4 thrombopenia was 7.9%. Vomiting (grade 3 or 4) occurred in 7.9% of patients and grade 3 diarrhea in 2.6%. CONCLUSION: This phase II study provides clear evidence of the safety and efficacy of oxaliplatin monotherapy at this dose and schedule in patients with previously untreated metastatic colorectal carcinoma.

Preliminary results of a phase II study of high-dose radiation therapy and neoadjuvant plus concomitant 5-fluorouracil with CDDP chemotherapy for patients with anal canal cancer: a French cooperative study.

BACKGROUND: Chemotherapy (5-fluorouracil-mitomycin C) concomitant with radiotherapy (RT) increases local control and colostomy-free survival in advanced anal canal carcinomas (ACC). The purpose of this prospective trial was to analyse the toxicity of and response to an induction chemotherapy combining 5-fluorouracil (5-FU) and CDDP administered concomitantly with irradiation. PATIENTS AND METHODS: Thirty patients (24 F/6 M, mean age 60, range 38-74) with an advanced ACC > 40 mm and/or with node involvement were prospectively treated (1 T1, 16 T2, 8 T3, 5 T4, 10 N1, 1 N2, 8 N3) from November 1994 to January 1996. Two induction and two concomitant cycles of 5-FU (800 mg/ m2 D1-4 infusion) and CDDP (80 mg/i.v./m2 at D1) were delivered. RT consisted of 45 Gy (1.8 Gy/fr, 5 fr/w) on pelvis +/- inguinal nodes or 30 Gy (3 Gy/fr, 4 fr/w) by direct perineal field. A boost (15-20 Gy) was delivered six weeks later. TOXICITY: one patient died of a pulmonary embolism on D4. The remaining 29 received the entire treatment, with reduced 5-FU doses in 11 patients because of acute toxicity. The RT boost was delayed for one patient (aplasia). In 109 cycles, 3 grade 4 and 17 grade 3 toxicities were observed; there were no toxic deaths. Tumor response: the complete response (CR) and partial response (PR) rates were, respectively, 11% and 61% after induction chemotherapy, 59% and 31% after concomitant radiochemotherapy and 96% and 0% two months after completion of the treatment. No tumor progression was observed. CONCLUSION: the treatment was well tolerated and there was good compliance. After induction chemotherapy, most of the patients were in PR, with some even in CR. After completion of the treatment all but one were in CR. The tumor response and the long term results of 50 patients will be analysed before initiation of a randomised trial is considered.

Early death during initial chemotherapy of squamous cell carcinoma of the oro- or hypopharynx.

Neoadjuvant chemotherapy produces high response rates in squamous cell carcinoma of the head and neck without increasing the survival time. Furthermore authors have observed a death rate of about 5% (up to 10%) during chemotherapy. A series of patients with an oro- or hypo-pharynx cancer, were retrospectively divided into two groups on the basis of a short (< or = 2 months) or long (> or = 2 years) survival time. Clinical, tumoral and usual biological data from either group were compared. By univariate analysis, obesity index, hemoglobin, albumin concentrations and mononuclear cell counts were lower in patients with a short survival time compared with those in the other group. On the contrary, polymorphonuclear cell and platelet counts were higher. Infection appeared to be more frequent for patients with a poor prognosis without being entirely responsible for early death. By multivariate analysis, obesity index and platelet count were both independent variables associated with prognosis. These results call for further investigation of cardiac function, inflammatory, nutritional and immunological status of patients with squamous cell carcinoma of the head and neck who were given initial chemotherapy, particularly Cisplatin and Fluorouracil.

Prognostic significance of routine clinical and laboratory data in advanced head and neck cancers.

Predictive factors for toxicity and response to chemotherapy in patients with advanced head and neck cancer are seldom reported. Therefore, from a short series of patients with a histologically proven cancer, who were treated by a neo-adjuvant protocol with cisplatin and fluorouracil, routine clinical and laboratory data were investigated. ALT (alanine aminotransferase) and Hb (hemoglobin) appeared to be predictive for efficacy. By multivariate analysis (principal component analysis), these laboratory data were involved in two independent axes: one which was considered as "inflammatory" and the other as "hepatic". Initial obesity indices were associated with the former. The predictive variables for toxicity (i.e. age, serum creatinine level, weight loss and plasma cisplatin) were probably biased in this series. Nevertheless cisplatin concentration regularly increased in each cycle. Hence it was dependent on the rank of the course. According to this preliminary study, it would be of interest to conduct future investigations on acquired protein-energy malnutrition, as well as on selected soluble mediators of cellular and humoral immune response.

Microbial contamination of enteral feeding tubes occurring during nutritional treatment.

Enteral nutrition is an effective treatment for catabolic patients with normal intestinal absorption. However, tube-fed patients are at risk from superinfection. Our study is the first to evaluate in vivo the microbial contamination of solutions staying in the nasogastric tube of cancer patients receiving nutritional preparations. After daily feeding, the tube was rinsed with nonsterile tap water. Tap water staying overnight in the tube was considered as tube-rinsing solution. Microbial burden of nutritional preparations was determined on the fifth day of enteral nutrition, from opening the first container and throughout feeding. The next day, a sample of the tube-rinsing solution was cultured. All bacterial species were identified and antibiotic susceptibility pattern was assessed. Thirty-one cancer patients were included, 12 on the hospital's preparations and 19 on commercial feeding. Seven of the hospital--and none of the commercial--preparations were contaminated. Among the 48 samples collected during feeding, 16 were contaminated, including 10 hospital and 6 commercial preparations. All the 31 tube-rinsing solutions were contaminated and 102 strains cultured. Their median concentration was 10(6) colony-forming units/mL (range 10-10(10)). The strains were 48 Enterobacteriaceae, 20 group D streptococci, 9 Candida albicans, 9 Pseudomonas aeruginosa, and 16 others. Multiple antibiotic resistance was present in 12 of the 102 strains. Lower resistance was present in 33. The predominant microorganism of the tube-rinsing solution caused a bacterial colonization for three febrile patients. In conclusion, the feeding tube is an important reservoir for multiple antibiotic-resistant bacteria.

Immunoscintigraphy with indium-111 labeled monoclonal antibodies: the importance of a good display method.

A major drawback of In-111-labeled monoclonal antibodies (MoAb) is the presence of intense liver, renal, and bone marrow nonspecific activity. This makes the display of the images hardly optimal and their visual interpretation difficult. In this study, the "intrinsic color scale" (which consists of selecting the limits of the color scale as the highest and the lowest pixel value of the image) was compared to a new, simple algorithm for the determination of the limits of the color scale. This algorithm was based on the count density in the iliac crest areas. OC-125 or anti-CEA In-111 MoAb F(ab')2 fragments were used in 32 patients with suspected recurrence of ovarian (19 patients) or colorectal cancer (13 patients). Final diagnosis was assessed by surgery (21 patients), biopsy (five patients), or followup (six patients). A 10-minute abdomino-pelvic anterior view was recorded two days after injection. These views are displayed using the two methods and interpreted by two observers. Using their responses in each quadrant of the pelvis, the authors calculated two ROC curves. The comparison of the ROC curves showed better performances for the new method. For example, for the same specificity (73%), the sensitivity of the new method was significantly better (78% versus 68%). This result confirmed the importance of a good methodology for displaying immunoscintigraphic images.

Palliative therapy of inoperable oesophageal carcinoma with radiotherapy and methotrexate: final results of a controlled clinical trial.

Between May 1976 and January 1982, 170 patients were entered in a randomized study comparing a combined treatment consisting of methotrexate followed by irradiation versus radiotherapy alone in patients with non metastatic inoperable oesophageal cancer. Methotrexate was administered subcutaneously in 4 days to a total dose of 24 mg/m2. Radiotherapy was performed, in both groups, at a dose of 56.25 Gy in 25 fractions (5 weeks). The administration of methotrexate did not lead to an increased intolerance to radiotherapy but severe hematological toxicities were observed in 7.8% of the cases. No difference in the duration of survival was detected. Initial performance status of the patients and their weight loss prior to entry on trial were the factors that were most predictive of the patient's prognosis.

Mucin histochemistry of heterotopic gastric mucosa of the upper esophagus in adults: possible pathogenic implications.

The mucin profile of 24 endoscopic biopsies of heterotopic gastric mucosa (HGM) of the upper esophagus in adults and a control group of ten cases of Meckel's diverticula containing heterotopic gastric mucosa were studied with two combined histochemical methods: alcian blue pH 2.5/PAS and high iron diamine/alcian blue pH 2.5. The clinical and light microscopic features of the 24 HGM cases were also reviewed. In addition to overall secretion of neutral mucins by the 24 HGM cases, mucin histochemistry showed prominent secretion of acidic mucins in 19 of 24 HGM cases (79%), with sulphomucins in 11 of 24 HGM cases (45.8%). This mucin profile of HGM was unlike that of either normal gastric mucosa or heterotopic gastric mucosa in Meckel's diverticula. Moreover, a comparison between the mucin profile and clinical features of HGM and Barrett's esophagus showed certain similarities. The data suggest a physiopathologic link between HGM and Barrett's esophagus.

Sequential trial of initial chemotherapy for advanced cancer of the head and neck. DDP versus DDP + 5-fluorouracil.

The study, which compares DDP to DDP + FU, was planned to detect an increase by 60% in efficacy and by 5% in toxicity (2a = B = 5%) for DDP + FU. In a previous trial DDP produced 15% of responders and 5% of high-level toxic manifestations. The eligible patients with an advanced head and neck cancer were paired off successively on the basis of the tumour site and the UICC stage. DDP (100 mg/m2; day 1) was administered with hyperhydration, alone in the first protocol and followed by a 5-day continuous infusion of 5-FU (1 g/m2) in the second one. Courses were repeated every three weeks. Assessment was carried out after three courses or two, in cases of toxic manifestations. Seventy-four patients, who were paired off, entered the trial. The median age was 55 years and the median Karnofsky index was 90. The tumor site was as follows: 28 hypopharynx, 28 oropharynx, 8 oral cavity, and 10 multiple primary cancers. According to the UICC stage, there were 14 T1/T2 N3, 60 T3/T4 with among them 45 N3, and they were all MO. Comparisons were made through sequential closed plans. The combination chemotherapy was more efficacious than DDP with a difference that could be appreciated by the sequential analysis as high as 60% (95% confidence interval, 38% to 82%). The high-level toxicity appeared more significant (+25%) for the association. After radiation therapy 11 of 37 patients (30%) achieved a complete response in the arm with DDP versus 18 of 37 (49%) in that with DDP + FU. The median survival times were 9 and 11.5 months, respectively, and were not statistically different.

A phase III of cisplatinum versus cisplatinum-etoposide for previously untreated squamous cell carcinoma of the head and neck.

136 patients with previously untreated stage III or IV squamous cell carcinoma of the head and neck entered a prospective randomized trial to compare the efficacy and toxicity of DDP vs DDP-VP 16 213 (Etoposide). 69 patients (group A) were given three courses of DDP 100 mg/m2 administered on day 1, while 67 patients (group B) were given three courses of a combination of Etoposide 100 mg/m2 per os administered on days 1 to 5 and DDP 100 mg/m2 on day 4. Objective response rate appeared to be low in both groups: in group A (60 evaluated patients) CR = 1, PR = 9; CR + PR = 14.5%, and in group B (57 evaluated patients) CR = 3, PR = 8; CR + PR = 16.4% (p greater than 0.4). One drug-related death occurred in each group. There was no difference in toxicity between the two treatments with regard to leukopenia, thrombopenia, vomiting and nephrotoxicity. Thus this schedule of oral Etoposide does not seem to increase either the efficacy or the toxicity of DDP.

A new approach to image subtraction in immunoscintigraphy: preliminary results.

Recently proposed image comparison software is applied to immunoscintigraphy. The software performs geometric and gray level registration of two images and generates an image of the statistically significant differences. It permits the comparison of scintigraphic images recorded at different times. It is used to subtract 113mIn and 111Inphytate colloid liver scans and early (blood pool) images from 131I or 111In-monoclonal Ab images and to compare Ab images recorded at different times. Using the procedures made possible by this software, only images recorded using the same radionuclide or using radionuclides of about the same energy are compared. Anti CEA, 19-9 and OC 125 F(ab)2 fragments labeled with 131I or 111In are used in 32 patients with 47 demonstrated recurrences or metastases of colorectal or ovarian cancers. The overall sensitivities of the unprocessed and processed images are 25/47 and 41/47 respectively. The improvement in sensitivity is particularly high in the liver when In labelled Ab are used. This technique improves the contrast of the images, but the interpretation must take into account the components of the non target activity (kidney, bone marrow, colon...) which are not removed by the image subtraction method.