Amifostine pretreatment for protection against cyclophosphamide-induced and cisplatin-induced toxicities: results of a randomized control trial in patients with advanced ovarian cancer.

PURPOSE: Serious cumulative toxicity is a well-recognized consequence of chemotherapy. Amifostine, an organic thiophosphate, has demonstrated the ability to protect selectively a broad range of normal, but not neoplastic, tissues from the cytotoxic effects of chemotherapy and radiotherapy. This study was designed to determine if amifostine could reduce the serious toxicities associated with cyclophosphamide and cisplatin (CP), without reducing antitumor efficacy in patients with ovarian cancer. PATIENTS AND METHODS: Two hundred forty-two patients with advanced ovarian cancer were randomized to receive six cycles of cyclophosphamide (1,000 mg/m2) and cisplatin (100 mg/m2) with or without amifostine (910 mg/m2) every 3 weeks for six cycles. The occurrence of hematologic, renal, neurologic, and ototoxicity was evaluated. Antitumor efficacy was assessed by pathologic tumor response and survival. RESULTS: Pretreatment with amifostine before each cycle of chemotherapy resulted in a reduction of cumulative toxicities. Hematologic toxicity consisted of grade 4 neutropenia associated with fever and/or infection that required antibiotic therapy (P = .005), days in hospital (P = .019), and days on antibiotics (P = .031). Platinum-specific toxicities consisted of protracted serum creatinine elevations (P = 0.004), > or = 40% reduction from baseline in creatinine clearance (P = .001), and severity of neurologic toxicity (P = .029). Twenty-four percent of CP patients compared with 9% of amifostine plus CP patients discontinued therapy because of protocol-specified toxicity (P = .002). Pathologic tumor response rates were 37% with amifostine and 28% in controls, with comparable median survival times of 31 months. Amifostine was generally well tolerated; the principal side effects were emesis and a transient decrease in blood pressure. CONCLUSION: Pretreatment with amifostine reduces the cumulative hematologic, renal, and neurologic toxicities associated with the CP regimen, with no reduction in antitumor efficacy.

PAF and hematopoiesis. II. Elevated levels of plasma paf acetylhydrolase after rapid infusion of 5-fluorouracil in cancer patients.

Blood platelet-activating factor (PAF) levels are regulated by a plasma PAF acetylhydrolase. We investigated its levels in cancer patients during the course of a 5-day 5-fluorouracil (5-FU) treatment. PAF acetylhydrolase increased in nine patients with daily bolus infusion of 0.4 g 5-FU per m2 of body surface (81.7 +/- 8.7 nmol PAF/min/ml vs. 66.6 +/- 7.0; P < 0.001 for day 5 as compared to day 1). By contrast PAF acetylhydrolase did not change in seven patients with continuous infusion of 5-FU. The meaning of these results is discussed in respect of the immunoregulatory role of PAF.

AcSDKP plasma concentrations in patients with solid tumours: comparison of two chemotherapeutic regimens.

The tetrapeptide AcSer-Asp-Lys-Pro (AcSDKP) is a physiological inhibitor of the proliferation of haematopoietic stem cells and progenitors. In Ara-C-treated mice, its plasmatic concentrations decrease while the CFU-S start cycling. Infusion of synthetic AcSDKP (Goralatide) at this time protects them from haematoxicity by blocking early cycling of CFU-S. Both in vitro and in vivo, this effect seems to be optimal in a narrow range of concentrations. Thus, a better knowledge of the kinetics of endogenous AcSDKP during cancer treatment could help to optimize the treatments with Goralatide. AcSDKP plasma levels have been measured by a specific EIA in 14 cancer patients during the two initial monthly 5 day courses of chemotherapy with 5-FU alone administered either by continuous infusions (six patients) or by 1 h daily infusions (eight patients). AcSDKP concentrations did not vary significantly during the first and the second course. Together with our previous results in AML patients treated with high doses chemotherapy (Ara-C and Anthracyclin), our present data suggest that the variations of endogenous AcSDKP in patients are dependent of the type, doses and schedule of chemotherapy.

Comparison of 2- and 3-compartment models for the Bayesian estimation of methotrexate pharmacokinetics.

Moderate and high-dose methotrexate was given by a 4-h infusion to 10 patients. The pharmacokinetics of methotrexate, determined by fluorescence polarization immuno-assay, was successively described by a 2- and a 3-compartment open model with elimination from the central compartment. Population pharmacokinetic parameters were obtained by non-linear regression from 8 data points for each course and were subsequently used to fit the same data by the Bayesian estimation method. According to Akaike's information criterion, the 3-compartment model was found statistically superior in 7 patients out of 10. Using this model clearance was well predicted (+/- 5%) by the Bayesian method with only 2 points taken at the end of the infusion and 24 h after. The prediction was less good for the steady-state volume of distribution (+/- 18%) and the half-lives (+/- 20-30%). This procedure enables a good estimation of individual pharmacokinetic parameters for methotrexate, specially with clearance, at minimal cost and minimal disturbance for the patient.

[Determination of serum glycosylated proteins in normoglycemic patients with cancer]. / Dosage des protéines sériques glycosylées chez des malades normoglycemiques atteints de cancers.

The nitroblue tetrazolium "fructosamine" test was elaborated by Johnson et al. in 1982. It gives an easy evaluation of the degree of non enzymatic glycosylation of serum proteins. This degree, like the percentage of HbA1C, is a biochemical test of the average level of glycemia and so is useful in diabetic patient management. The authors test "fructosamine" with a Kone-Progress automated analyzer on blood collected without anticoagulant or antiglycolytic substances; if iodoacetate is added to the blood sample, they observed a partial inhibition of chemical reaction. The results of the tests carried on two groups of normoglycemic patients with localized and metastatic cancers don't show significant statistical difference with healthy subjects. The nitroblue tetrazolium test can be used to manage diabetics patients suffering from cancers; however for metastatic and cachectic patients, an accelerated turn-over of proteins might decrease the non enzymatic glycosylation degree.

[Possible value of variations in the serum alkaline DNAse activity in the prognosis of cancers of the upper respiratory-digestive tract treated by chemotherapy]. / Valeur prédictive des variations de l'activité sérique de la DNAse alcaline dans le pronostic des cancers des voies aérodigestives supérieures traités par chimiothérapie.

Variations in serum alkaline DNase activity before and repeatedly after standardized chemotherapy were examined in patients with head and neck carcinomas. The enzyme activity was measured by way of a modified spectrophotometric method. No variations of such activity observed in patients without therapeutic response or with minor response could be considered as a marker of primary or acquired resistance to chemotherapy. Distinct variations in serum alkaline DNase activity (a steep decrease after therapy followed a few weeks later by a regain of values higher than the initial value) correspond to complete or partial positive responses. Such observations of the variations in enzyme activity in relation to individual initial values measured before therapy could be considered as a reliable prognostic test for the therapy of many head and neck carcinomas.

[Study of vinorelbine (V) combined with hexamethylmelamine (H) (combination V-H) in adenocarcinoma of the ovary: results a phase I-IIA trial, NHO-88, of ARTAC "ovarian" group]. / Etude de la vinorelbine (V) associée à l'hexaméthylmélamine (H) (combinaison V-H) dans les adénocarcinomes de l'ovaire: résultats d'un essai phase I-IIA, NHO-88, du groupe "ovaire" de l'ARTAC.

The lack of decisive progress in ovarian cancer chemotherapy in recent years led the ARTAC "Ovary" group to initiate a study based on the hypothesis of collateral sensitivities. In this phase I-II trial, NHO-88, the V-H combination (associating vinorelbine (VNB) and hexamethylmelamine (HMM) was studied in patients with advanced ovarian adenocarcinomas, most of which had become resistant to previous chemotherapy. The aim of the study was to find an active combination without complete cross resistance with first-line platinum salt based combinations, such as CAP, FAP or CACb-300. A pilot feasibility study was first carried out to determine the maximum tolerated weekly dose (MTWD) of VNB (20 mg/m2/week), HMM being administered per os on days 1-14 of every 28-day cycle at a standard dose of 250 mg/m2/day. An open phase II-A study was further carried out according to a 2-step sequential analysis method for phase II clinical trials. We observed: 1), a good tolerance of the V-H combination apart from frequent neutropenia; 2), a response rate of 35% (95% confidence interval: 23-47%); 3), a median response duration of 4 months (range: 1-7 months); 4), in some cases, the absence of a complete cross-resistance between the V-H regimen and the previously administered platinum-based combinations. These results, which are currently being validated (phase II-B ongoing), constitute the first step in the search for active systems of sequential or alternate chemotherapeutic regimens for the treatment of advanced carcinomas.

[Results of preoperative irradiation in the treatment of rectal adenocarcinoma]. / Résultats de l'irradiation pré-opératoire dans le traitement des adénocarcinomes rectaux.

The goal of this retrospective study was to assess the tolerance and the efficacy of preoperative irradiation in the treatment of rectal carcinoma. From 1980 to 1983, 81 patients with potentially operable rectal carcinoma underwent abdominoperineal resection. Fourty-one were treated with surgery alone; 40 had a preoperative pelvic irradiation. They received 30 Gy in 15 fractions during three weeks. Surgery followed within four weeks after the last irradiation. In one third of the irradiated patients, the size of the tumor decreased by at least 50 p. 100. Postoperative morbidity and mortality were not increased following irradiation and there was no delay in perineal healing. Five year survival was improved by irradiation (78 p. 100 versus 28 p. 100) with statistical significance (p less than 0.05). In patients with stage C tumors according to Astler-Coller's modification of Dukes staging, 5 year survival was higher in patients who received preoperative irradiation (68 p. 100 versus 23 p. 100) with a statistically significant difference (p less than 0.05). Pelvic recurrence occurred in 8 p. 100 of the patients irradiated and in 45 p. 100 of the patients treated with surgery alone respectively. This difference was also statistically significant (p less than 0.05). Survival of patients who underwent abdominoperineal resection for rectal carcinoma appeared to be improved with preoperative irradiation.

[Recurrences of supratentorial meningiomas. Apropos of 17 cases]. / Récidives de méningiomes sus tentoriels. A propos de 17 cas.

17 cases of recurrent meningiomas observed during a 10 years period are reviewed. Meningiomas with a second localisation different from the first were excluded from the study. The tumor recurrence occurred mostly during the first five years after the surgical procedure. One case with femoral and pulmonary metastasis is described. Several factors may play a role in the genesis of the recurrence: age, sex, the tumor localisation, CT scan, the importance of the tumor ablation, the histology. In almost all cases a radiotherapy was carried out after the second surgical procedure. This retrospective study suggests the need for multifactorial prospective analysis with clinical, paraclinical and fundamental factors. Such a study would be useful to precise the natural history of meningiomas.

[Adenoid cystic carcinomas invading the skull base. Apropos of 4 cases and review of the literature]. / Carcinomes adénoïdes kystiques envahissant la base du crâne. A propos de 4 observations et revue de la littérature.

Head and neck adenoid cystic carcinomas may invade the adjacent skull base by bone lysis and/or by perinervous and perivascular spread within the skull base foramina. Neurosurgical decision making is not well defined regarding the extent of intracranial tumor component removal, as neurosurgical expertise is limited for this peculiar type of tumors. The issue is to decide whether a radical supposedly locally curative surgery should be attempted, or if a large non disfigurating surgery is mandatory, keeping in mind the frequency of local recurrences and of distant metastases. Over a 13-year period, four adenoid cystic carcinomas invading the skull base were operated on at our institution: two tumors originated in the parotid gland, one in the sphenoid sinus, and one in the ethmoid sinus. Surgical removal was total in one case, subtotal in three cases. Post-operative irradiation was delivered in the four patients (two neutron irradiation, two conventional). One patient with advanced metastatic disease was submitted to chemotherapy. Three patients died from local tumor progression and distant metastases within three years after the intracranial tumor extension has been diagnosed. The patient with an ethmoid tumor is still alive seven years after surgery without any evidence of local tumor progression nor distant metastases. Surgery remains the gold standard treatment for adenoid cystic carcinomas invading the skull base. However, in our opinion a large tumor removal, without or with bone osteotomies, but without sacrifice of cranial nerves, cavernous sinus, internal carotid artery, and of the orbit allows patient survival with an acceptable comfort and absence of psychological distress due to disfigurating surgery nor surgically induced neurological functional deficit. Post-operative irradiation may sometimes stabilize locally the lesions. The place of chemotherapy has, yet, to be determined.

[Giant cell tumor of the temporal bone. Clinical study of a case. Histologic and therapeutic remarks]. / Tumeur a myéloplaxes de l'os temporal. Etude clinique d'une observation commentaires histologiques et thérapeutiques.

A case of giant cell tumor of the temporal bone is reported. The surgical difficulties encountered in this case are presented and therapeutic modalities for this tumor, consisting of radical surgery and post operatoire radiotherapy, one defined and discussed. Comments are made concerning this rare tumor location, its occurrence in young adults, and difficulties in establishing a histologic diagnosis.

[Adenocarcinoma of the ethmoid sinus in woodworkers. Retrospective study of 25 cases]. / Adénocarcinomes de l'ethmoïde chez les travailleurs du bois. Etude rétrospective de 25 cas.

A retrospective oncological study was performed in 25 woodworkers, in whom an adenocarcinoma of the ethmoid sinuses was discovered between March 1985 and December 1993. All patients were males with a mean age of 57 years, and a mean duration of wood dust exposure of 24 years. Signs of nasal obstruction, drainage, and discomfort were present in all cases. Ophthalmological findings were a poor prognosis indicator. It was possible to precisely evaluate treatment and outcome in 23 cases. The majority of tumors were classified as T3 or T4 (72%), with extension beyond the ethmoid sinuses; all were in contact with the roof of the ethmoidal sinuses. Extension was predominantly into the orbital and intracranial cavities as compared with extension posteriorly or into the maxillary sinuses. Treatment was identical in the 25 patients: a) combined surgery including a paranasal and a neurosurgical approach, b) postoperative radiotherapy. Results were expressed in terms of morbidity related to surgery and the oncologic outcome. Operative morbidity and mortality were substantially reduced with reconstruction of the roof of the ethmoidal sinuses. Meticulous excision, in addition to postoperative radiotherapy, resulted in a decreased rate of local recurrence (26%). On the other hand, metastasis were encountered more frequently (30%). Radiotherapy was insufficient when macroscopic excision was incomplete. Chemotherapy was used as palliative treatment in the event of a recurrence and/or metastases. Survival rate was 68% at 3 years, and 48% at 5 years. Most complications and recurrences arose within the first two years. Exophthalmos, intracranial extension, incompleteremoval, and extensive class T4 tumors were associated with a poor prognosis. Optimal therapy for malignant tumors of the ethmoid sinuses requires combined transfacial and neurosurgical approaches that allow precise assessment of tumor extension and adequate excision, yielding an improved oncologic outcome. Followed by radiotherapy, this association can result in a remission. Patient prognosis depends essentially on management of the initial lesion.

A comparative longitudinal quality of life study using the Spitzer quality of life index in a randomized multicenter phase III trial (FFCD 9102): chemoradiation followed by surgery compared with chemoradiation alone in locally advanced squamous resectable thoracic esophageal cancer.

BACKGROUND: The aim of the study was to compare the longitudinal quality of life (QoL) between chemoradiation with or without surgery in patients with locally advanced squamous resectable esophageal cancer included in a randomized multicenter phase III trial (FFCD 9102). MATERIALS AND METHODS: All patients with locally advanced resectable (T3-4 N0-1 M0) epidermoid or glandular esophageal cancer (n = 451) received induction chemoradiation. Responders (n = 259) were randomized between surgery (arm A) and continuation of chemoradiation (arm B). The Spitzer QoL Index was scored (0-10) at inclusion and at each follow-up, every 3 months during 2 years. QoL at baseline and longitudinal changes were respectively compared with univariate ANOVA and mixed-model analysis of variance for repeated measurements. The time interval between the follow-up was assessed and the same analyses were performed among survivors with 2 years of follow-up. RESULTS: The squamous histology was predominant in both arms. The mean QoL score decreased between baseline and the first follow-up and between the first and the second follow-ups. QoL scores at the first follow-up were comparatively worse in arm A than in arm B (7.52 versus 8.45, P < 0.01), whereas the longitudinal QoL study showed no difference between treatments (adjusted P = 0.26). Furthermore, the longitudinal QoL was not different (adjusted P = 0.23) among survivors with 2 years of follow-up. CONCLUSIONS: Among patients responding to induction chemoradiation, surgery and continuation of chemoradiation had the same impact on QoL in patients with locally advanced, resectable esophageal cancer although a significantly greater decrease in the Spitzer Index was observed in the postoperative period.

[The pulmonary aspiration-washing: new treatment of severe bacterial pneumopathies (author's transl)]. / Le lavage pulmonaire: nouveau traitement des pneumopathies bactériennes sévères.

Over the last few years, the apparition of severe broncho-pulmonary suppurations in relation with an often poly-immune bacterial flora presents intricate therapeutic problems. The use of broncho-fibroscopy to enable several focussed cycles of broncho-pulmonary aspiration-washing perfusion, gave us interesting results.

Osteosarcoma with calcified regional lymph nodes.

A case of osteosarcoma of osteoblastic type with inguinal calcified lymphadenopathy is described. The primary lesion of the distal left femur was treated with limb-sparing surgery. Chemotherapy was given before and after the surgical procedure. Metachronous calcified lymph node metastases were seen on plain radiography, computed tomography and bone radionuclide scan. The patient is alive and free of disease more than 40 months after lymphadenectomy and radiotherapy of regional node metastases.