Epilarynx: pharynx or larynx?

BACKGROUND: As a general rule, epilarynx is studied as a part of supraglottis. On the contrary, in France, due to its particular natural history, it is often studied separately. METHODS: To assess the value of this French classification, we compared from an epidemiologic point of view, in one study, 86 cases of epilarynx squamous cell carcinoma (SCC) with 431 oropharynx, 339 hypopharynx, and 89 vestibule SCC. In another study, we compared, from a clinical point of view, 232 epilarynx SCC with 1351 oropharynx, 652 hypopharynx, and 372 vestibule SCC. RESULTS: Epilarynx patients appeared to be much heavier drinkers than larynx patients and similar to pharynx patients but tobacco consumption did not differ. The patterns of nodal involvement were similar for pharynx and epilarynx SCC. For stages I and II, patterns of failures were similar, but for stages III and IV, there were fewer locoregional failures in vestibule patients; distant metastases were equally frequent for these tumors. From the standpoint of multiple primaries, epilarynx SCC appeared to be more akin to pharynx than to larynx SCC with a much lower incidence of lung cancers. Finally, the outcome after treatment was different for vestibule, epilarynx, and pharynx SCC, with a 5-year survival of 43%, 27%, and 13%, respectively. CONCLUSIONS: These data support the identification of epilarynx as a real entity that should be taken into account for stratification in clinical trials.

Cytarabine and cisplatin as salvage therapy in patients with metastatic colorectal cancer who failed 5-fluorouracil + folinic acid regimen. French Northern Oncology Group.

The combination of CDDP and ARA-C has shown some clinical efficiency as first-line therapy in advanced colorectal cancer. Our study was aimed to evaluate the therapeutic activity of this combination in advanced colorectal cancer who failed 5-fluorouracil (FU) and folinic acid (LV) regimen. Seventeen patients with measureable metastatic colorectal cancer who failed 5FU-LV therapy as first line (n = 14) or second line treatment (n = 3), entered the study. Three patients who recurred during adjuvant treatment with 5FU and levamisol, were also included. Median age was 59.5 (40-69). Performance status was as follows: 0 (n = 5), 1 (n = 11), 2 (n = 3), 3 (n = 1). Site of metastases included liver (n = 16), lung (n = 7), abdomen (n = 2), pelvic recurrences (n = 2), cutaneous (n = 1). Seven patients had 2 metastatic sites and two 3. The treatment was given as follows: ARA-C 75 mg/m2/day, days 1-3, followed 1 hour later by CDDP 30 mg/m2/day, days 1-3, every 28 days. The median number of cycles was 3 (range: 1-6 cycles). All patients but one were evaluable for both response and toxicity. Of these patients, 50% experienced severe hematologic toxicity and nonhematologic toxicity mainly consisted of fatigue and/or vomiting. No objective response was observed, but there were 3 stabilizations and 16 progressive diseases. Median time to progression was 10 weeks. Thus, the CDDP/ARA-C regimen is not of clinical value as salvage therapy in advanced colorectal cancer because of its toxicity and its lack of efficiency.

Type I insulin-like growth factor receptors in human colorectal cancer.

Type I insulin-like growth factor (IGF) receptors have been recently characterised in human colorectal cancers. The aim of this study was to determine whether type I IGF receptor concentration may be related to prognostic variables in colorectal cancers. Saturation experiments with [125I]IGF-I were performed on membrane preparations of 46 frozen specimens (20 tumours, 26 controls) and analysed according to the Scatchard method. In all the studied cases, we found a single class of high affinity binding sites in both normal and malignant colorectal tissues (median 0.17 and 0.15 nmol/l, respectively). Using paired analysis, we found no significant difference in terms of type I IGF receptor concentration between malignant and normal colorectal tissues. There was also no relationship between type I IGF receptors and any of the tumour characteristics studied. This study does not support a critical role of the type I IGF receptors in the clinical management of colorectal cancers.

Vinorelbine (navelbine) as a salvage treatment for advanced breast cancer.

BACKGROUND: Vinorelbine (Navelbine), a new vinca alkaloid, is an effective drug in breast cancer. Our study was undertaken to assess the efficacy and tolerance of Navelbine in refractory advanced and/or metastatic breast cancer (AMBC). PATIENTS AND METHODS: One hundred heavily pretreated patients with AMBC entered the study and were scheduled to receive 30 mg/m2 of Navelbine weekly by a 20 min i.v. infusion with dose adjustments according to tolerance. All patients had previously received at least one chemotherapy regimen including an anthracycline for advanced disease. RESULTS: Sixteen of the 100 assessable patients responded (1 complete response and 15 partial responses), for an overall response rate of 16% (IC 95: 8%-23%). The median duration of response was 5 months (3-18). Responses were seen in lymph nodes (13/27), breast (11/34), soft tissue and skin (13/36), lung (3/14) and liver (2/25), but not in bone metastases. The main toxicities (WHO grade > or = 3) were granulocytopenia and anemia in, respectively, 51% and 9% of all 100 eligible patients. Thrombocytopenia and other non-haematological toxicities consisting of peripheral neuropathy, constipation, nausea/vomiting, alopecia and phlebitis were rare and mild. CONCLUSION: Vinorelbine is an active drug in AMBC, particularly in breast, lymph nodes and skin/soft tissue sites, with an excellent tolerance. Since the mean dose intensity was 19.7 mg/m2/week, a dose of 20 mg/m2/week is recommended for heavily pretreated patients (radiotherapy and chemotherapy).

[Lymphocyte hybridization and cancerology: diagnostic and therapeutic applications. Example of tumor markers]. / Hybridation lymphocytaire et cancérologie: applications diagnostiques et thérapeutiques. Cas particulier des marqueurs tumoraux.

First described in 1975 by Köhler and Milstein, monoclonal antibodies (Mabs) result from the fusion of a B lymphocyte and a myeloma cell. Among the many uses of Mabs, oncology constitute a privileged, but difficult, field of investigation: the antigen heterogeneity and difficulty of access to tumors are major obstacles. In diagnosis, the Mabs allow the identification and the quantification of tumor specific or tumor-associated antigens: the assay of circulating tumor markers is one of the largest applications. In situ localization of tumors is also possible, using radiolabelled Mabs. In therapeutics, Mabs are used alone or linked to radionuclides, toxins, anticancer drugs or enzymes. Ex vivo treatment of bone marrow is used in autologous and allergenic grafts. The use of mono (Fab,Fv) or bivalents (F(ab)'2) antibody fragments, chimeric or human Mabs, cocktails of Mabs, intended to improve sensitivity and specificity of the tests, are the main prospects of this research area.

[A prospective study of alveolar bone resorption after radiotherapy and chemotherapy]. / Etude prospective de la résorption osseuse alvéolaire après radiothérapie et chimiothérapie.

A prospective comparative study of the alveolar bone resorption after teeth extraction was achieved in a series of 79 patients in order to analyze macroscopically the possible consequences of radiotherapy and chemotherapy on the toothless edges. After quarterly coronal and sagittal X-rays for two years, this study enhances quite a similar vertical resorption for the radiation and chemotherapy-treated patients as well as for the witness patients. The alveolar bone resorption progression also appears unaltered by anti cancerous treatments. In both cases, a resorption stabilisation can be clearly seen after 6 months according to dental extractions. The vertical alveolar bone resorption is more important in incisor and canine regions. The anti cancerous treatments may not have significant disastrous consequences as far as available bone amount is concerned, on a post prosthetic restoration.

Plasma insulin-like growth factor-1 (IGF-1) concentrations in human breast cancer.

Insulin-like growth factor-1 (IGF-1) is capable of stimulating breast cancer cell growth in vitro and the presence of IGF-1 receptors has been demonstrated in primary breast cancers. We determined plasma IGF-1 in a primary breast cancer population and in a control population. Radioimmunoassays were performed either directly on plasma, IGF-1 (NE), or after an acid-ethanol extraction of the plasma, IGF-1 (E). We demonstrated an inverse correlation between age and IGF-1: for this reason, only results obtained in females of the same age range (> 35 years) were compared. Median concentrations of IGF-1 were significantly higher in primary breast cancers [IGF-1 (E) = 152 ng/ml, IGF-1 (NE) = 26 ng/ml, n = 44] than in controls [IGF-1 (E) = 115 ng/ml, IGF-1 (NE) = 20 ng/ml, n = 92]. To our knowledge such a growth factor increase has never been described in breast cancer. We conclude that IGF-1 could be an important factor involved in the development of breast cancer and that treatment reducing IGF-1 levels could be beneficial for patients.

Expression of ps2 and cathepsin-d in breast-cancer.

Cytosolic levels of pS2 and Cathepsin D (Cath D) were compared in 145 primary breast cancer patients using the immunoradiometric (IRMA) assays ELSA-pS2-degrees and ELSA-Cath. D-degrees of Cis biointernational. The mean values were 20.04 +/- 41.75 ng pS2/mg of cytosol protein (cp) and 49.94 +/- 33.71 pmol Cath D/mg cp. The pS2 level was significantly associated with Estrogen Receptor (ER), Progesterone Receptor (PgR) and Cath D levels. Significant associations were also found between Log (pS2) or Log (Cath. D) and differentiation grade (SBR), between Log (pS2) and ER (+,-) or PgR (+,-), between Log (Cath. D) and PgR (+,-). No correlations were noted between Log (pS2) or Log (Cath D) and menopausal status, tumor size (T) and lymph node involvement (N), between pS2 and age, between Cath D and age, ER and PgR, between Log (Cath D) and ER (+,-). Contrary to Cath D, pS2 was strongly linked to steroid receptors.

Basic fibroblast growth factor (bFGF): mitogenic activity and binding sites in human breast cancer.

We investigated binding characteristics of basic fibroblast growth factor (bFGF) on membranes prepared from 4 human breast cancer cell lines and 38 primary BC biopsies. Competitive binding experiments were performed and analyzed using the "Ligand" program. Furthermore bFGF mitogenic activity was measured by [3H]thymidine incorporation into DNA from breast cancer cell lines. The presence of high-affinity binding sites was demonstrated in each cell type (MCF-7: Kd = 0.60 nM; T-47D: Kd = 0.55 nM; BT-20: Kd = 0.77 nM; MDA-MB-231: Kd = 0.34 nM). The presence of these high-affinity binding sites was confirmed with saturation experiments. A second class of low-affinity binding sites was detected in the 2 hormone-independent cells (BT-20: Kd = 2.9 nM; MDA-MB-231: Kd = 2.7 nM). bFGF stimulated the proliferation of MCF-7, T-47D, BT-20 but not MDA-MB-231 cell lines. With competition experiments, binding sites were detectable in 36/38 breast cancers; high-affinity binding sites (Kd less than 1 nM) were present in 19/36 cases and low-affinity binding sites (Kd greater than 2 nM) were present in 29/36 cases (the two classes of binding sites were present in 12 breast cancers). No relation between bFGF binding sites and node involvement, histologic type or grading of the tumor was evidenced. There were negative correlations (Spearman test) between total bFGF binding sites and estradiol receptor (P = 0.05) or progesterone receptor (P = 0.009). The demonstration of (1) bFGF specific binding sites in breast cancer membranes, and (2) bFGF growth stimulation of some breast cancer cell lines indicates that this factor may be involved directly in the growth of some breast cancers.

Aminoglutethimide in malignant melanoma. A phase II study.

The role of steroid hormones has been suggested in the growth of malignant melanoma, and since aromatase activity has been found in melanoma tissue, we carried out a phase II study of aminoglutethimide, an aromatase inhibitor in malignant melanoma patients. Fifteen heavily pretreated patients entered the study. No response was observed--the treatment was well tolerated. We concluded that aminoglutethimide is very unlikely to be useful in melanoma patients.

An evaluation of CA 549, a circulating marker of breast cancer using a procedure for comparison with CA 15.3.

A serum assay of CA 549 (Hybri-BREScan CA 549 degrees, Hybritech), a new tumor marker, was performed in 129 patients with breast cancer and 35 healthy women, in parallel with CA 15.3 (ELSA-CA 15.3 degrees, CIS Biointernational). Comparing 95 women with primary breast carcinoma and 35 controls, Relative (or Receiver) Operating Characteristic (ROC) analysis revealed that the Area Under ROC Curve (AUC) of CA 15.3 was significantly higher than that of CA 549, indicating that, for our population, the first marker was more effective. Parallel and series analyses were also performed using ROC AUC and revealed that the combination of these two tests did not give more information than the CA 15.3 test alone; however, they did not in any way constitute diagnostic tools. In our experience, the best field of application for CA 549 seems to be the therapeutic monitoring and early detection of breast cancer recurrences. However, further investigations on a larger scale are necessary to assess more precisely the place of CA 549 in following the clinical course of breast cancer patients.

Drug resistance in oncology: from concepts to applications.

The complex problem of drug resistance is discussed with respect to host toxicity, to tumor characteristics (kinetic resistance, heterogeneity of cell subpopulations, hypoxia, mutation and gene amplification), and to the medication itself (pharmacokinetic and pharmacodynamic resistance: cell membrane, intracellular metabolism, intracellular target). After detailing each type of resistance, the possibilities of fighting against drug resistance are explored (dealing with host toxicity, tumor characteristics and drugs--intensifying therapy, multiple drug therapy, biochemical modulation, particular modalities of drug administration). Finally, perspectives of research and development of new drugs are summarized.

[A study of VMMC protocol (vindesine, mitoxantrone, mitomycin C) as a salvage chemotherapy in advanced breast cancers]. / Etude du protocole VMMC (vindésine, mitoxantrone, mitomycine C) comme chimiothérapie de rattrapage dans les cancers du sein évolués.

One hundred and three patients previously treated with chemotherapy including an anthracycline were entered in a VMMC protocol study: vindesine (Eldisine), mitoxantrone (Novantrone) and mitomycin C (Ametycine). Group A consisted of 41 women who received the protocol published by Belpomme: vindesine (2.5 mg/m2 day 1 and 8) and mitoxantrone (12 mg/m2/day) every 4 weeks, and mitomycin C (8 mg/m2) every 8 weeks. Group B consisted of 62 patients who were treated with a modified protocol: vindesine (2.5 mg/m2) and mitoxantrone (12 mg/m2) every 3 weeks on day 1, and mitomycin C (8 mg/m2) every 6 weeks. Tolerance was acceptable with 79% of patients complaining of weakness. There was a 66% incidence of gastro-intestinal toxicity, a 10.7%-incidence of neurotoxicity (reversible dysethesias), and a 5.8% incidence of cardiotoxicity. There was considerable hematotoxicity of grade 2, 3 and 4: neutropenia 16.6%, thrombocytopenia 7.7%, anemia 21.4%. There was a 19.2% overall objective response rate (CR and PR) (95% confidence interval: 12-30) (CR: 3.2%). The median duration of the response was 39 weeks. There was no significant difference in response rates whether or not the patients (19 cases) were undergoing simultaneous hormonal therapy and no difference according to the protocol used. Similarly, neither menopause nor a previous response to anthracyclines had any effect on the response rate. The 19.2% response in this protocol is similar to other breast cancer salvage chemotherapy protocols for patients who have failed to respond to anthracyclines (< 20%).

Plasma acid and alkaline phosphatase in patients with breast cancer.

Acid and alkaline phosphatase were determined in 107 breast cancer patients to study their potential value in case of bone metastases. The patients were divided into 4 groups: A, patients without metastases (n = 34); B, metastatic patients without bone lesions (n = 37); C, patients with metastases in and outside of bones (n = 24), D, patients with bone-only metastases (n = 12). Tartrate resistant acid phosphatase (TR-ACP), and bone alkaline phosphatase (bone-ALP) were significantly higher in patients with metastases than in patients without. However, no difference in TR-ACP was observed between subgroups of metastatic patients.

[Primary lymphomas of the breast. 9 case reports]. / Les lymphomes primitifs du sein. A propos de 9 observations.

Between the 1st of January 1974 and the 30th of June 1989, we saw 9 cases of primary lymphoma of the breast at the Oscar Lambret Centre, all occurring in women. This comprised 0.27% of the malignant tumours of the breast and 3.2% of all non-Hodgkin lymphomas. 8 occurred on the right side and 1 on the left. There were multiple tumours in 5 cases. The clinical findings were always suggestive of a malignant condition and so were the mammography findings in 6 cases. Two patients had total mastectomy. In the other cases, the diagnosis was made (twice) by biopsy or by lumpectomy (5 cases). Using Kiel-Lennert's classification: 5 were highly malignant and 4 of low grade malignancy (using the Working Formulation, three were moderate and 4 were intermediate; 1 was very high grade and 1 intermediate or high). Treatment changed a lot during the period under consideration. Five patients are still alive without any recurrence. One died of lymphoma and two died of intercurrent causes and one died of unknown causes.

[Breast cancer: can axillary dissection be restricted to Berg stages 1 and 2? Study of 895 cases]. / Cancer du sein: peut-on se limiter aux étages 1 et 2 de Berg, lors du curage axillaire? Etude à propos de 895 cas.

895 axillary clearances were carried out in 3 years between 1986 and 1988 on 878 patients with primary breast cancer. Two procedures were used: either direct total axillary clearance (in stages 1, 2 and 3 of Berg) or inferior axillary clearance (stages 1 and 2 of Berg). This was carried out in association with frozen section diagnosis of the lymph node followed by clearance in Berg stage 3 if the diagnosis on frozen section was positive. The authors found a higher frequency of late complications, particularly of arm lymphoedema in patients who had complete axillary clearance than in patients who only had an inferior axillary clearance. The survival rate actuarilly calculated was not significantly different in the two groups of patients. The carrying out of total axillary clearance was "beneficial" for only 3 patients who had negative inferior axillary clearance and positive sub-clavicular clearance. Finally the frozen section diagnosis of the state of the axillary nodes shown to be correct (specificity -99% and sensitivity -76%) but it was difficult to carry out routinely.

Insulin-like growth factor 1 receptors (IGF1-R) and IGF1 in human breast tumors.

To appreciate the IGF1 sensitivity of breast tumors we detected IGF1-R with a biochemical assay (RRA). We then localized and quantified IGF1-R on frozen tissue sections by histo-autoradiographic analysis (HAA). In some cases, the IGF1 and IGF1-R mRNA expression were studied by Northern blot analysis. We also studied the IGF1 plasma concentration in primary breast cancers compared to controls. IGF1-R (RRA) were found in 87% (n = 297) of the breast cancers. The mean geometric value was 3.87% (specific binding as percentage of total radioactivity); we found a highly significant correlation between IGF1-R and ER on the one hand (P = 0.0001) and PgR on the other (P = 0.0001) (Spearman test). The presence of IGF1-R was associated with a better prognosis, either on relapse-free survival (actuarial analysis: P = 0.004; Cox analysis: P = 0.005) or overall survival (respectively P = 0.003; P = 0.005). The median duration of follow-up was 30 months. By Cox analysis IGF1-R was a better prognostic factor than ER and PgR. In a series of 77 cases of benign breast disease only 47% (36/77) were positive; the mean geometric level was 1.8%. The HAA IGF1-R quantification in 20 breast carcinomas and 12 cases of benign breast disease confirmed the RRA results and demonstrated that the labeling was localized on the epithelial component. In four breast cancers, we did not detect IGF1 mRNA; IGF1-R probe demonstrated two major mRNAs of 11 and 7 kB. Finally we found that IGF1 plasma level was higher in breast cancer patients than in healthy controls of the same age. These results show that IGF1 is implicated in breast cancer growth and suggest that anti-IGF1 treatment might be useful in human breast cancer: for this reason, we and others carried out a phase II clinical trial with somatostatin.

Biological and clinical aspects of prolactin receptors (PRL-R) in human breast cancer.

PRL has a definite activity in the induction and promotion of mouse and in the growth of rat mammary tumors. We and others have found that human PRL or growth hormone (GH) had a growth promoting effect on human mammary cancer cells. It has been shown that prolactin receptors (PRL-R) which are specific for all lactogenic hormones (hPRL, hGH, hPL) are present on mammary cancer cells in long-term tissue culture and also in tumor biopsies. We found that 43% of the tumors had free PRL-R (FPRL-R) and that 72% had total PRL-R (TPRL-R) which have been desaturated in vitro. A significant correlation (Spearman test) was found between PRL-R (especially TPRL-R) on the one hand, estradiol (P less than 0.001) and progesterone receptors (P less than 0.01) on the other. The demonstration of PRL-induced proteins (PIP) might be a better sign of PRL sensitivity than the existence or PRL-R; PIP have been found by Northern blot analysis in 47% of 70 breast cancers. Overall survival (OS) and relapse-free survival (RFS) analysis with a median duration of follow-up of 5.3 yr showed that TPRL-R had a significant prognostic value only in node positive patients (chi 2 = 5.61, P = 0.02). Neither FPRL-R or TPRL-R were a significant prognostic factor when studied by Cox analysis. This confirms our previous results. Since at least some human mammary cancers appear to be PRL-dependent we carried out a multicenter randomized trial comparing as the first hormonal treatment tamoxifen (TAM) (30 mg/day) + bromocriptine (B) (5 mg/day) vs TAM + placebo. 171 patients entered this trial. No difference was observed between the two groups in response rates, duration of response or survival. Recent studies are thus in favor of a role of lactogenic hormones during the course of breast cancer. However no improvement in therapy has been observed yet. The combination of drugs to achieve a total anti-lactogenic treatment, the use of anti-PRL-R antibodies are interesting areas of research; the recent cloning of PRL-R and GH receptors may open new clinical perspectives.