Maurice Schneider

CLINICAL AND PHARMACOKINETIC EVIDENCE OF A LIFE-THREATENING INTERACTION BETWEEN METHOTREXATE AND KETOPROFEN

Co-administration of ketoprofen was found in 4 of 118 cycles of high-dose methotrexate (MTX) analysed retrospectively in thirty-six patients. All 4 cycles were characterised by severe MTX toxicity, which was fatal in three cases. Simultaneous administration of ketoprofen was associated with prolonged and striking enhancement of serum MTX levels. There were no abnormalities in MTX kinetics or evidence of MTX toxicity when ketoprofen was given at least 12 h after completion of high-dose MTX infusion. The kidney may be the site of drug interaction. This high-risk association between MTX toxicity and ketoprofen may also apply to other non-steroidal anti-inflammatory drugs.

Comparison between nasogastric tube feeding and percutaneous fluoroscopic gastrostomy in advanced head and neck cancer patients

Abstract Wasting is a major complication of advanced head and neck cancer and the aim of this study was to compare nasogastric tube feeding (NG) and percutaneous fluoroscopic gastrostomy (PFG) in these patients. The goal of these two methods of nutritional support was to improve or maintain the initial nutritional status during treatment. A total of 90 patients, all stage IV oropharynx or hypopharynx tumor, were reviewed from a prospective databank. All these patients were treated by concomitant chemotherapy and twice-daily continuous radiotherapy with no acceleration. Fifty patients were managed by PFG, and the rest by NG. Mechanical failure, duration of feeding, complications, nutritonal evaluation and quality of life were analysed. Mechanical failure occurred in 32 of the 40 NG patients and in seven of the gastrostomy group. In the PFG group, 80% of patients conserved their nutritional support after the end of the radiotherapy, none patient in the NG group. In the PFG group, two presented a wound infection and six had aspiration pneumonia while in the NG group, 21 had aspiration pneumonia probably due to the NG tube (gastroesophageal reflux). The feeding methods were found to be equally effective at maintaining body weight and body mass index at time 1 (3 weeks) and at time 2 (6 weeks). Advantages were associated with PFG cosmesis, mobility and quality of life. PFG is a safe and effective method of providing enteral nutrition during treatment to patients with advanced head and neck cancer and offers important advantages over NG.

Clinical pharmacokinetic study of 5-FU in continuous 5-day infusions for head and neck cancer.

SummaryTwenty-nine previously untreated patients with head and neck carcinoma received a total of 63 cycles of an initial chemotherapy protocol combining cis-platinum (100 mg/m2 on day 1) and continuous 5-day infusion of 5-FU (1000 mg/m2/24 h) from day 2 to day 6. This protocol was repeated on day 16 and day 31. Two daily blood samples obtained from all patients every day during 5-FU administration were analyzed by HPLC to determine the 5-FU concentrations. In the majority of cases a constant elevation was observed in total 5-FU cycle exposure (CxT) from cycle to cycle. A close relationship was demonstrated between elevated 5-FU CxT values (over 30 000 ng h ml-1) and the frequency of cycles in which signs of toxicity (myelosuppression, mucositis, diarrhea) were observed. By contrast, no obvious association was noted between response to treatment and systemic 5-FU exposure.

Is routine triple endoscopy for head and neck carcinoma patients necessary in light of a negative chest computed tomography scan

The objective of the current study was to analyze the results obtained by triple endoscopy during the initial evaluation of a primary carcinoma of the head and neck.

Response to chemotherapy as justification for modification of the therapeutic strategy for pharyngolaryngeal carcinomas

From September 1983 to September 1987, 238 patients with squamous cell carcinoma of the upper aerodigestive tract were given 3 cycles of chemotherapy [cisplatinum (cis‐DDP), 100 mg/m2 on day 1; 5‐fluorouracil (5‐FU), 1,000 mg/m2 on days 2‐6] before any local treatment. Eighty‐one of these patients had pharyngolaryngeal cancer. Of the 45 of 50 laryngeal cancers and 26 of 31 hypopharyngeal cancers suitable for evaluation, complete responses (CR) were obtained in 51.1% and 53.8%, respectively. These response rates led to changes in the postchemotherapy protocols. For CRs, mutilating surgical protocols were replaced by definitive radiotherapy: one local recurrence has been observed among the 9 laryngeal cancers, and 3 of 10 hypopharyngeal cancer patients, who had an initial indication of total laryngectomy or total pharyngolaryngectomy replaced by radiotherapy. In the group of CR, survival rates at 2 years were 93% and 69%, respectively, for the larynx and hypopharynx vs 65.6% and 40% for non‐CR patients. The possibility of conservative treatment sparing vocal function with a high degree of reliability would in itself appear to be justification for induction chemotherapy in pharyngolaryngeal cancers, even though its long‐term effects remain controversial.

CONCOMITANT B.I.D. RADIOTHERAPY AND CHEMOTHERAPY WITH CISPLATIN AND 5-FLUOROURACIL IN UNRESECTABLE SQUAMOUS-CELL CARCINOMA OF THE PHARYNX: CLINICAL AND PHARMACOLOGICAL DATA OF A FRENCH MULTICENTER PHASE II STUDY

PURPOSE The aim of this phase II study conducted on unresectable squamous cell carcinoma (USCC) of the oro- and hypopharynx was to associate twice-a-day (b.i.d.) continuous nonaccelerated radiotherapy with concomitant cisplatin (CP)-5-fluorouracil (5-FU) chemotherapy, both given at full dose. Feasibility, efficacy, survival, and pharmacokinetic-pharmacodynamic relationships were analyzed. METHODS AND MATERIALS Fifty-four consecutive patients with strictly USCC of oro- and/or hypopharynx received continuous b.i.d. radiotherapy (RT) (2 daily fractions of 1.2 Gy, 5 days a week, with a 6-h minimal interval between fractions). Total RT dose was 80.4 Gy on the oropharynx and 75.6 Gy on the hypopharynx. Three chemotherapy (CT) courses of CP-5-FU were given during RT at 21-day intervals (third not delivered after the end of RT). CP dose was 100 mg/m2 (day 1) and 5-FU was given as 5-day continuous infusion (day 2-day 6: 750 mg/m2/day cycle 1, 750 mg total dose/day cycle 2 and 3). Pharmacokinetics was performed for 5-FU (105 h follow-up) and CP (single sample at 16 h). Special attention was paid to supportive care. RESULTS Good feasibility of RT was observed (85.2% of patients with total dose > 75 Gy). Five patients received 1 CT cycle, 34: 2 cycles, and 15: 3 cycles. The most frequent and severe acute toxicities were mucositis with grade 3-4 occurring in 28% at cycle 1 and 86% at cycle 2, as well as neutropenia (43% at cycle 2). Locoregional control at 6 months was observed in 66.7% of patients. No late toxicity above grade 2 RTOG was noticed. CP dose and 5-FU AUC(0-105h) were significantly linked to grade 3-4 neutropenia (cycle 2). Cumulative total platinum (Pt) concentration and Karnofsky index were the only independent predictors of locoregional control at 6 months. Finally, total RT dose and total Pt concentration were the only independent predictors of specific survival. CONCLUSION This protocol showed good locoregional response with an acceptable toxicity profile. Pharmacokinetic survey is probably an effective approach to further reduce toxicity and improve efficacy. A multicentric randomized phase III study, now underway, should confirm these encouraging results.

Effect of dose and repeat intravenous 24 hr infusions of methotrexate on cerebrospinal fluid availability in children with hematological malignancies

This pharmacokinetic study examined the relationship between methotrexate (MTX) dose and drug concentrations in blood and cerebrospinal fluid (CSF) during repeated 24 hr infusions. Two regimens were used: an intermediate dose (ID) of 0.5 g/m2 (7 patients, 23 cycles) and a high dose (HD) of 2.5 g/m2 (8 patients, 39 cycles). Inter-patient variability in the drug concentration was apparent in serum and CSF for both doses. The dispersion was particularly wide in CSF for HD MTX. Considering median values, serum and CSF MTX were linked to dose escalation. Individual CSF/serum drug ratios were not modified by the dose (1.1% for ID MTX versus 1.4% for HD MTX). A potentially cytotoxic drug level in CSF (10(-6) M) was never obtained for ID MTX cycles, but was achieved in 44% of HD MTX cycles: for HD MTX, this corresponded to 88% of patients (7/8). Total body clearance did not modify the degree of CSF MTX passage. A positive, significant correlation (r = 0.62, P less than 0.05) was observed for ID MTX between individual serum and CSF MTX; no such relationship was seen with HD MTX. Individual cycle-to-cycle variations in the MTX concentration were particularly marked in CSF and for HD MTX, without strict concordance with blood levels.

Combination of cisplatin-doxorubicin-cyclophosphamide in adenocarcinoma of unknown primary site: a phase II trial.

&NA; The purpose of this report is to evaluate toxicity, response, and survival of the cyclophosphamide‐doxorubicin‐cisplatin (CAP) chemotherapy regimen in patients with adenocarcinoma of unknown primary site (ACUP). Twenty‐two patients with ACUP were eligible for this study between June 1992 and April 1999. There were 13 men (59%) and 9 women (41%) with a median age of 53.5 years (range: 29–78 years). Lung (seven), liver (six), vertebral bone site (six), and abdominal nodes (six) were the most common metastatic sites. Treatment consisted of doxorubicin 50 mg/m2, cyclophosphamide 1,000 mg/m2, and cisplatin 100 mg/m2 (CAP), administered every 3 weeks; a total of six courses were planned. Twenty‐two patients were assessable for toxicity and 20 patients were assessable for response. Grade III to IV neutropenia was observed in 14 patients (64%); febrile neutropenia occurred in 6 patients (27%) and in 10 cycles (12.5%). Grade III to IV anemia and thrombocytopenia were found in 12 (54.5%) and 9 patients (41%), respectively. Grade III to IV nausea and vomiting was observed in 9 patients (41%). Ten patients, 50% of the assessable population, obtained an objective response, including 3 complete (15%) and 7 partial (35%) responses. The median response duration was 3.9 months (range: 0.5–13.3 months). One patient (5%) had stable disease and 5 patients (25%) had progressive disease. The median overall survival and the median time to progression were 10.7 months (range: 0.4–56.9 months) and 8.8 months (range: 6.6–16.5 months), respectively. The CAP regimen in patients with ACUP had significant activity. This chemotherapy regimen induced a high level of grade III to IV toxicities and could not be considered as a treatment of reference. However, the emergence of long‐term survivors among responder patients highlighted the need to search for an active treatment for patients with ACUP.

α1 Isoenzyme of alkaline phosphatases clinical importance and value for the detection of liver metastases

Measurement of the α1 (fast liver) fraction of alkaline phosphatases in the serum for 217 cancer patients, 92 patients with nonmalignant hepatic affections and 131 controls, revealed that the α1 fraction offers better global value (94%), sensitivity (96%), and specificity (93%) than γGT or total alkaline phosphatase determinations for the detection of liver metastases during cancer. Initial data from study of the time of appearance of the α1 fraction reveals that this fraction shows up earlier than rises in the γGT or total alkaline phosphatases. Results of a multiparametric study conducted on the α1 fraction and various hepatic enzymatic tests (SGOT, SGPT, GLDH, ALP, γGT) indicate that the α1 fraction used alone is better than any other test or combination of tests for biological detection of liver metastases. As concerns the influence of chemotherapy on the appearance of the α1 fraction, the majority of the drugs used for anticancer chemotherapy do not seem to affect measurement of the α1 ALP fraction. The α1 fast liver fraction of alkaline phosphatases, detected by electrophoresis on cellulose acetate, can be considered one of the best known tests for the detection of liver metastases. Cancer 52:140‐145, 1983.

Salivary passage of 5-fluorouracil during continuous infusion

SummaryPlasmatic and salivary concentrations of 5-FU were investigated in ten patients given 5-day continuous infusions of 5-fluorouracil (5-FU) (1 g/m2/day). Measurable concentrations of salivary 5-FU were scattered ranging from 6 to 100 ng/ml. Between individual 5-FU concentrations in saliva and plasma the coefficient of correlation was low. The theoretically predicted ratios of 5-FU concentrations in saliva over those in plasma, calculated as a function of salivary pH, did not correlate with the observed ratios, the majority of which ranged between 0.1 and 0.5. Noteworthy, 8 of 10 patients exhibited a more or less pronounced increase in 5-FU salivary excretion during 5-day continuous i.v. infusions.