[Neoadjuvant chemotherapy FEC-HD in locally advanced breast cancer]. / Chimiothérapie néoadjuvant FEC-HD dans le cancer du sein localement évolué.

The tolerance and the clinical and histological efficacy of a neoadjuvant chemotherapy FEC-HD including hematopoietic growth factors have been studied in 40 patients with stade II or III breast cancer between February 1991 and February 1997. Four courses were given, every 21 days, with 5-fluorouracil (750 mg/m2/day D1 to D4 by continuous infusion), epirubicin (35 mg/m2/day D2 to D4) and cyclophosphamide (400 mg/m2/day D2 to D4) with G-CSF (5 mug/kg/day D6 to D15). The surgery was performed 3 or 4 weeks after the end of the chemotherapy. All patients had radiotherapy. The neoadjuvant chemotherapy induced 37.5% CR, 45% PR, and 15% SD. In 40% of the patients, the surgery was conservative. An histological CR was obtained in 15% with no axillary involvement one time out of two. There was intraductal carcinoma without invasive carcinoma in 7.5%. There was no differences between the response of inflammatory and non inflammatory tumors. One hundred and fifty-eight courses have been delivered. A grade 3 or 4 leuconeutropenia, anemia and thrombopenia have been observed in respectively 34.6%, 6.3% and 8.8% of the courses. A grade 3 or 4 mucositis has been noticed in 2.5% of the courses. A febrile granulocytopenia has occurred in 3.8% of the courses. The median survival without metastatic progression was 48 months and the median overall survival was not achieved. In stade II and III breast cancer, neoadjuvant chemotherapy with FEC-HD obtains an important histological response with an acceptable toxicity. The role of the dose-intensity increase on survival remains to be determined.

Loss of heterozygosity at the TP53 gene: independent occurrence from genetic instability events in node-negative breast cancer.

TP53 abnormalities have been reported as an early event in the process of cellular transformation of human breast cancers, and involved in mammary-tumor evolution, from in situ to invasive disease. In this study, node-negative (N-) tumors were examined for TP53 allelic loss in relation to different genetic instability events, including allelic loss at chromosome 17p13.3 and c-H-ras-1 loci, as well as alteration of the c-myc and c-erbB-2/neu oncogenes. TP53 allelic loss was analyzed to determine whether such an abnormality was the more important, among other genetic events, in the N- tumors, whether it appeared independently of these genetic events, and whether accumulation of genetic events arises in this group of breast tumors. Clinicopathological parameters were also examined. Loss of heterozygosity (LOH) at the TP53 gene appears the most frequent alteration detected (26% vs. 13%, 8%, 9% and 3% for LOH at D17S30 and c-H-ras-1 loci, and amplification of c-myc and c-erbB-2/neu respectively). There was no association between LOH at the TP53 locus and other genetic events. Among clinicopathological parameters, significant associations were observed only with estrogen-receptor-negative tumors (p = 0.05). Our results demonstrate that LOH at TP53 arises more frequently in the N- breast cancer, thus supporting earlier findings suggesting that TP53 abnormality has a role early in the pathogenesis of breast lesions. Moreover, the data indicate that accumulation of many genetic events occurs at a low level in N- breast tumors, and that TP53 abnormality occurs independently of these genetic events.

p53 gene alterations are associated with a decreased responsiveness to neoadjuvant chemotherapy in human breast cancer.

Recent evidence indicates that alterations of the p53 tumor suppressor gene can modulate the response of tumor cells to DNA-damaging agents and increase drug resistance. To evaluate whether p53 alterations affect response to chemotherapy in breast cancer, we examined the p53 status before and after treatment of primary tumors from 44 patients who received neoadjuvant chemotherapy. p53 status was determined by gene mutations and by mRNA expression levels. Eleven patients (25%) showed alterations in the p53 gene. Comparison of the clinical response between subgroups with or without p53 alterations revealed that p53 alterations were strongly associated to clinical resistance to chemotherapy (p<0.001).

[Clinical value of the estimation of growth kinetics of primary ovarian cancer recurrences by CA125 doubling time]. / Intérêt clinique de l'estimation de la vitesse de croissance des récidives ovariennes premières par le temps de doublement du CA125.

The aim of this retrospective work was to study the clinical importance of growth rate determination for ovarian cancer primary recurrence in term of CA125 doubling time (dt). Fifty-one patients with epithelial ovarian carcinoma stage III or IV who developed a recurrence were included. Eighteen spontaneous dt values were calculated in non-treated patients during follow-up and 33 apparent dt values were estimated in patients undergoing treatment during CA125 increase before the clinical and/or radiological diagnosis of recurrence. No early treatment of the recurrence has permitted a drop in CA125 level. We applied exponential regression models to CA125 individual kinetics in order to calculate dt values. Individual dt values vary from 5 to 375 days. Spontaneous and apparent dt medianes (respectively 64 and 39 days) are not significantly different. Among all early clinical, histological, biological and therapeutic parameters, the initial CA125 half-life calculated during the third courses of the first-line chemotherapy is the unique predictive parameter of dt (relative risk (RR) = 78; p < 0.01). The prognostic impact was more important in spontaneous dt values than in apparent ones. Being spontaneous or apparent dt was the major predictive parameter of the delay between the initial CA125 increase and clinical and/or radiological signs of recurrence (RR = 0.3; p < 0.0001). Its prognostic impact is superior to the T1/2 one (RR = 2.9; p = 0.0010). For equivalent treatments, dt (RR = 0.4; p < 0.0001) and T1/2 (RR = 4.0; p < 0.0001) are the only predictive parameters of the survival after CA125 increase. This work shows that dt was an essential predictive parameter of ovarian epithelial tumor recurrences.

[Feasability of the dose adjustment of continuous infusion administration over 120 hours of 5-fluorouracil associated with cisplatin]. / Faisabilité de l'adaptation de la posologie du 5-fluorouracile administré en perfusion continue de 120 heures associé au cisplatine.

Therapeutic monitoring of 120 hours continuous 5-fluorouracil associated with cisplatin. For 31 patients treated by continuous 5-fluorouracil with cisplatin, a therapeutic monitoring of 5-fluorouracil is performed, based on the 48 first hours area under the curve (AUC) and the total AUC. The 5-fluorouracile taylorization allows to reduce some toxicity's while preserving an efficiency (objective responses 42%). Many patients are considered with potentially low 5-fluorouracile clearance. Dose reductions of 5-fluorouracile are frequent, reach 50% during the third cure and allow the achievement of targeted AUC. The role of cisplatin in this necessary reduction of dose is unknown.

[Prognostic value of CA 125 initial half-life measured during first-line chemotherapy in 62 patients with epithelial ovarian cancer stage III or IV]. / Valeur pronostique de la demi-vie initiale du CA 125 mesurée au cours de la chimiothérapie d'induction chez 62 patientes porteuses de tumeur épithéliale ovarienne stade III ou IV.

The prognostic value of CA 125 initial half-life in serum (Tb) during the first cycles of first-line chemotherapy was studied in 62 patients with stage III or IV ovarian cancer. The half-life was strongly correlated; 1) with the rate of biological remission (P < 0.001). This one was respectively equal to 94.7% when Tb was lower than 20 days, 66.6% when Tb was between 20 and 40 days and 7.7% when Tb was higher than 40 days; 2) with the rate of histological remission (P < 0.001) which was equal to 66.6% when Tb was lower than 13 days; 3) with the speed of recurrence growth measured by the doubling time (dT) of CA 125. The median of dT was equal to 182 days when Tb was lower than 13 days, 63 days when Tb was between 13 and 20 days (P < 0.02) and 38 days when Tb was higher than 20 days (P < 0.001); 4) with the duration of disease-free survival (DFS) (P < 0.001): the medians were equal to 23.9 months, 18.0 months, 12.0 months, and 5.5 months, respectively, when Tb was lower than 13 days, between 13 and 20 days; 20 and 40 days, and higher than 40 days; and 5) with the duration of overall survival (OS). The probability of survival at five years was equal to 48% when Tb was lower than 13 days. This probability falled to 13%, 12%, and 8%, when Tb was respectively between 13 and 20 days, 20 and 40 days and higher than 40 days. Multiple regression analysis showed that CA 125 half-life was the most important prognostic factor for DFS and OS. Analysis of correlation allowed to identify a relation between: 1) dT and Tb [dT = Tb/[-0.305 + (0.0388)(Tb)]; P < 10(-4)]; 2) the slope of CA 125 initial regression (P) and DFS [DFS = 201.9e (-16.64*P); P < 10(-8)]; 3) P and OS [OS = 285.0e(-17.00*P); P < 10(-7)]. The initial CA 125 half-life measured during the first cycles of first time chemotherapy seemed to be a critical predictor of response to therapy.

Adjuvant treatment of node-positive breast cancer with cyclophosphamide, doxorubicin, fluorouracil, and vincristine versus cyclophosphamide, methotrexate, and fluorouracil: final report after a 16-year median follow-up duration.

PURPOSE: To determine the long-term impact on disease-free survival (DFS) and overall survival (OS) of adjuvant anthracycline-based chemotherapy, when prospectively compared by random allocation with standard cyclophosphamide, methotrexate, and fluorouracil (CMF) in node-positive (N+) breast cancer patients. PATIENTS AND METHODS: Two hundred forty-nine patients with N+ breast cancer, recruited from eight French cancer centers, were randomized to receive 12 monthly cycles of adjuvant chemotherapy, either CMF (n = 112) or doxorubicin, vincristine, cyclophosphamide, and fluorouracil (AVCF) (n = 136). All had a negative metastatic work-up before inclusion, which was stratified by accrual center, tumor stage (International Union Against Cancer [UICC]), and menopausal status. RESULTS: No severe adverse effect related to grade 4 (World Health Organization [WHO]) toxicity was observed. There was no difference in second primary tumor incidence between the two arms. The treatment given was 88% of planned for AVCF and 75% for CMF in both premenopausal and menopausal patients. With a median follow-up time of 16 years (range, 13 to 17), the OS and DFS rates are significantly longer in the AVCF arm (56% v 41% [P = .01] for OS, and 53% v 36% [P = .006] for DFS). These differences are significant, irrespective of tumor stage (T1 to T2 v T3 to T4), and remain positive in patients with or without postoperative locoregional radiotherapy (55% of cohort). When analyzed according to menopausal status, the differences remain significant only for premenopausal patients. CONCLUSION: This set of mature controlled data confirms the added value of anthracycline-based combination adjuvant therapy for N+ breast cancer patients when compared with CMF, with both regimens given for 1 year.

Benign breast disease: absence of genetic alterations at several loci implicated in breast cancer malignancy.

Benign breast disease (BBD) is a heterogeneous group of benign breast problems that has been associated with breast cancer risk by several investigators. Genetic alterations have been described in breast carcinomas under the headings of loss of heterozygosity (1p, 3p, 7q, 11p, 17p, 17 and 18q), mutations (p53, c-H-ras-1), and/or gene amplifications (c-myc, int-2/FGF3, and c-erbB-2/neu). In an attempt to determine whether these genetic alterations might also be involved in the development of BBD, we have analyzed such alterations in 50 BBD lesions. The histological types of samples studied were: 37 fibroadenomas; 8 benign phyllode tumors; and 5 fibrocytic diseases. Cellular DNA was extracted from tissues and from corresponding blood leukocytes according to standard techniques, digested with appropriate restriction endonucleases, and analyzed by Southern blot. The following are informative cases found in a total number of patients analyzed for each locus: 13 of 26 for L-myc (1p); 9 of 23 for THRB (3p); 11 of 29 for met (7q); 27 of 50 for c-H-ras-1 (11p); 3 of 13 for TP53 (17p); 14 of 50 for D17S30 (17p); 20 of 33 for D17S4 (17q); and 13 of 33 for D18S5 (18q). No loss of heterozygosity was detected at any of the examined loci. Alternatively, none of the 50 BBD cases displayed an amplification of the three genes tested (c-myc, int-2/FGF3, and c-erbB-2/neu). Our results show that molecular alterations, which are more frequently involved in malignant breast carcinomas, do not occur in BBD lesions. These results indicate that these molecular alterations could constitute late events in the pathogenesis of breast carcinomas.

[Amplification of c-myc and c-erbbeta-2(HER-2/neu) in breast cancer without axillary lymph node metastasis: correlation with other prognostic parameters]. / Amplification des protooncogènes c-myc et c-erb beta-2 (HER-2/neu) dans les cancers du sein sans métastase ganglionnaire axillaire: corrélation avec les autres paramètres de pronostic.

Amplification of c-myc and c-erb beta-2 (HER-2/neu) proto-oncogenes were analyzed in breast cancer tissues obtained from 100 patients without lymph node involvement (N-). An amplification of the c-myc gene was detected in four cases and a c-erb beta-2 (HER-2/neu) amplification in eight cases. The frequency of these abnormalities were compared to classical prognostic parameters as well as to new biological prognostic markers (cellular cycle, cathepsin-D and pS2 protein). Most of altered tumors were associated to some classical poor prognostic factors such as: steroid receptor-negative tumors, poorly differentiated tumors, high histoprognostic grade and tumor cell density. In contrast, no relation was found with new biological parameters. The analyses of these data in relation to clinical evolution will be of interest to evaluate their prognostic value.

[Course of blood creatinine during repeated injections of cisplatin. Influence of drug combinations]. / Evolution de la créatininémie lors d'injections répétées de cisplatine. Influence des associations médicamenteuses.

Cisplatin (CDDP) is known to induce nephrotoxicity. In this retrospective study, we have investigated the evolution of plasma creatinine in long term therapy with CDDP. We have studied case history, mode of administration of CDDP and associations with other chemotherapeutic agents or drugs which could potientiate CDDP renal damage (non steroidal anti-inflammatory agents, analgesics, antibiotics, antihypertensive agents, diuretics and contrast media). Mean creatinine concentration versus time rises significantly. This elevation is significantly higher in patients with hypertension, diabete, one functional kidney, or abdominoperineal irradiation. The association with other drugs has not proved a real influence on creatinine evolution.

Influence of hydration on ultrafilterable platinum kinetics and kidney function in patients treated with cis-diamminedichloroplatinum(II).

It has been reported that hypertonic saline provides protection against the renal toxicity of cisplatin (CDDP). We therefore evaluated its influence on the plasma and urinary pharmacokinetics of ultrafilterable platinum and kidney function as estimated by creatinine, inulin and PAH clearance. We undertook a randomized trial including two groups of ten patients receiving 100 mg/m2 CDDP in isotonic (group 1) or hypertonic saline (group 2) by a 20-min infusion. The hydration consisted of dextrose in group 1 and isotonic saline in group 2. Maximal concentration (Cmax), protein binding and cumulative urinary excretion were significantly higher in the dextrose group. Urinary flow decreased in this group but not in the other one. Inulin clearance was higher in the dextrose group than in the saline group and P-aminohippuric acid (PAH) clearance was not significantly different in these groups of patients. Hyponatremia was observed in the dextrose group. These results suggest that hypertonic saline infusion and saline hydration may enhance the diffusion of CDDP into tissues, lowering Cmax and renal excretion of platinum. The reduction of protein binding may indicate a diminution of aquation of CDDP in plasma. Our results suggest that the infusion of CDDP in hypertonic saline with salt hydration could exert a protective effect on the kidney. Moreover, there is a lessening of the risk of cellular hyperhydration. However, the better influence of dextrose hydration on glomerular filtration leads us to recommend a combination of the two methods of hydration for better tolerance and efficacy.

Non-Hodgkin's lymphoma of the urethra: a rare extranodal entity.

We report a rare case of non-Hodgkin's lymphoma of the urethra in a female patient. A review of the literature showed that all such reported cases were described in females, were of varying histologic grade, and presented as a polyp or caruncle. Whether this entity is often localized and has the excellent prognosis of early carcinoma of the urethra will have to be determined by study of more cases.

[Prostatic tumors. Detection by proton nuclear magnetic resonance spectroscopy of plasma lipoproteins]. / Tumeurs prostatiques. Détection par spectroscopie de résonance magnétique nucléaire protonique des lipoprotéines plasmatiques.

Recently, there has been interest over detection of malignant tumors by water-Suppressed Proton Nuclear Magnetic Resonance Spectroscopy (1 HNMR) of plasma lipoproteins (N. Engl. J. Med., 1986, 315, 1369-76). We performed a similar prospective and blinded study comprising 75 subjects; 40 control (C), 15 untreated prostate cancer patients (PC) and 20 patients with benign prostate tumors (BT). We measured the parameter W 1/2, as mean of the full width at half height of the resonances of the methyl and methylene groups of the lipids of the plasma lipoproteins which is inversely related to the spin-spin apparent relaxation time (T2*). W 1/2 values were determined at a fixed baseline of 310 Hz. The W 1/2 mean values were 37.6 +/- 3.7 Hz for C, 37.4 006 5.2Hz for PC and 36.4 +/- 3.9 Hz for BT, essentially identical for all three groups. Furthermore, no difference was seen between any group on scatter pattern that could serve as a basis for a useful detection test. The major difficulty in the determination of W 1/2 was due to interference of metabolite protons (lactate) within the lipoprotein resonance signal. There was no correlation seen between W 1/2 triglyceride, total cholesterol, HDL-cholesterol and (LDL + VLDL)-cholesterol levels. We conclude the Water-Suppressed 1HNMR Spectroscopy of plasma lipoproteins as performed, is not a valid method for detection of prostate cancer.

Evaluation of the effect of furosemide on ultrafilterable platinum kinetics in patients treated with cis-diamminedichloroplatinum.

It has been reported that furosemide can prevent platinum nephrotoxicity by dilution of the toxic drug in the tubule or by another unknown mechanism. To evaluate its influence on ultrafilterable platinum pharmacokinetics, we undertook a randomized prospective trial of cis-diamminedichloroplatinum (CDDP) (80 mg/m2 by a 20-min infusion) administered to 20 patients with hydration-induced diuresis. Ten patients received 20 mg/m2 furosemide 1 h before CDDP administration, and 10 patients received no diuretic drug. Plasma and urinary pharmacokinetics of platinum and creatinine were compared in both groups of patients. Plasma total and ultrafilterable platinum was always higher in the furosemide group. However, protein binding, urinary concentrations, cumulative urinary excretion, renal clearance and creatinine clearance/renal clearance ratio (fractional clearance) were not statistically different. Moreover, the fractional clearance was successively lower, equal and higher than one in both groups. These results suggest that: (1) furosemide probably causes water depletion leading to a rise in plasma concentrations; (2) its protection by a pharmacokinetic interaction is doubtful, since all other parameters (especially urinary parameters) are not significantly modified; (3) renal clearance and fractional clearance suggest a bidirectional transport of platinum in the tubule not influenced by the diuretic drug.

Proton nuclear magnetic resonance spectroscopy of plasma lipoproteins in malignancy.

A recent study (N. Eng. J. Med. 315 (1986), 1369), described a method of detecting malignant tumors by water-suppressed proton nuclear magnetic resonance (1 H NMR) study of plasma. We performed a similar study of the W 1/2, a mean of the full width at half height of the resonances of the methyl and methylene groups of the lipids of plasma lipoproteins which is inversely related to the spin-spin apparent relaxation time (T 2*). W 1/2 values were measured at a fixed baseline width of 310 Hz. The study was prospective and blinded and comprised 182 subjects consisting of 40 controls, 68 patients with untreated malignancies, 45 with malignant tumors undergoing therapy and 29 benign tumor patients. No differences were seen between any groups that could serve as a basis for a useful clinical test. The major difficulty in the determination of W 1/2 was due to interference of metabolite protons (particularly lactate) within the lipoprotein resonance signal. Triglyceride level was seen to correlate inversely with W 1/2 within malignant patient groups. These discrepant results may be related to differing triglyceride-rich very low density lipoprotein (VLDL) levels in the patient populations of each study. We conclude that the water-suppressed 1H NMR of plasma lipoproteins is not a valid measurement for assessing malignancy.

A clinico-pathological and prognostic analysis of non-Hodgkin lymphoma. A study of 203 patients.

In a retrospective analysis of 203 patients with non-Hodgkin lymphoma (NHL) treated between 1975 and 1985, the relationship between pathology, clinical presentation and course, was studied, using the Kiel classification. This classification was a much better predictor of prognosis than clinical stage and within the different pathology groups there was no significant difference between the stages concerning the survival rate. In the group with low grade malignancy this latter was positively associated with nodular architecture, bone marrow involvement and complete or partial response to therapy. In the high grade group, the survival was positively correlated to complete remission, but no plateau was seen in the survival curve. All extranodal sites had poor survival. For both grades, age (greater than 60 years), systemic symptoms and biologic signs (Ann Arbor 'B' and 'b') were unfavorable prognostic factors.

Modification of Kiel and working formulation classifications for improved survival prediction in non-Hodgkin's lymphoma.

The total survival of 203 patients with non-Hodgkin's lymphoma (NHL) was analyzed according to the working formulation (WF) and "expanded" Kiel classifications. The original Kiel classification consisting of low grade (LG) and high grade (HG) forms corresponded well to the LG and HG forms of the WF. When an expanded Kiel containing an intermediate grade (IG) composed of the original LG diffuse group was devised, this gave a much better separation of survival of the three grades as compared with the WF where the survival of IG and HG forms were nonsignificantly different. The main reason for this difference was the inclusion of the so-called centroblastic diffuse form in the HG Kiel, but in the IG according to the WF. In a "modified" WF analysis where this histologic entity was placed in the HG subgroup, the three survival curves then gave excellent separation like the expanded Kiel classification. Since the centroblastic diffuse form (and its analogous forms according to other classifications) has a poor prognosis, it is important that it be so recognized and treated accordingly with aggressive therapy. We propose either our expanded Kiel or modified WF classification of the three grade forms as an excellent predictor of survival.

Influence of frusemide on cis-dichlorodiammineplatinum (II) pharmaco-kinetics.

Cis-dichlorodiammineplatinum (CDDP) pharmacokinetics were evaluated in eighteen patients with cancer who received 80 mg/m2 CDDP as a 20 min infusion. One hour before, 10 of them had 20 mg/m2 frusemide. Fifteen blood samples and fifteen urine samples were collected over the 5 hours following the infusion of CDDP. Platinum was assayed by flameless atomic absorption. The data did not detect any difference between patients with or without frusemide for the following platinum parameters: plasma concentration, urinary concentration, cumulative urinary excretion, renal clearance. These results suggest that frusemide has no influence upon cisplatin (CDDP) pharmacokinetics and if it protects the kidneys, it is not via kinetic modifications.

Urinary beta 2-microglobulin: early indicator of high dose cisdiamminedichloroplatinum nephrotoxicity? Influence of furosemide.

To evaluate the efficacy of beta 2-microglobulin as an indicator of cisplatinum nephrotoxicity, creatinine clearance and urinary beta 2-microglobulin were measured in 19 patients during 5 h after administration of a single dose of 80 mg/m2 cisplatinum. Eleven patients received furosemide as a concomitant therapy. Serum creatinine and beta 2-microglobulin remained unchanged. A decrease of creatinine clearance was observed. Urinary beta 2-microglobulin increased between 1 and 3 h after administration. This suggests transient tubular damage immediately after the treatment course. The concomitant administration of furosemide does not modify these results. However, patients who developed long-term nephrotoxicity had no early rise of urinary beta 2-microglobulin excretion; thus, it is not possible to predict cumulative nephrotoxicity by measuring beta 2-microglobulin immediately after the first course of high-dose cisplatinum.