Treatment of newly diagnosed symptomatic pure low-grade oligodendrogliomas with PCV chemotherapy.

Based on studies relating to anaplastic oligodendroglioma (OG) chemosensitivity and benefit of time to progression or overall survival, chemotherapy for pure OG has been proposed. Several studies have reported the efficacy of various chemotherapeutic agents in a small number of patients with low-grade gliomas, e.g. pure astrocytomas, OG or mixed histologies. The 5-year survival rate varies from 61% to 89% with a mean time to progression of 5 years. We report the outcome of 33 consecutive patients with pure low-grade OG diagnosed between 1990 and 2006 systematically treated for residual or non-removable tumor with PCV chemotherapy regimen as the front-line treatment after surgery. All the tumors were low grade (grade II) pure OG according to the WHO classification. All patients were symptomatic at presentation and underwent neurosurgical procedure for histological diagnosis. Response was evaluated by clinical assessment and brain magnetic resonance imaging. Twenty-one men and 12 women with a mean age at pathological diagnosis of 46.5 years were studied. The most common first symptom was partial epileptic seizure (73.7%). Six patients (18%) had initial gadolinium enhancement, associated with methoxyisobutyl (MIBI) hypermetabolism (P < 0.001). The resection was partial in seven cases (21%), and 26 patients (79%) had biopsy only. Eleven patients (36%) had a malignant transformation during the follow-up with a median time to progression of 19 months. Favorable prognostic factors were lack of contrast enhancement (P < 0.0001), and age <40 years (P < 0.0003); 90% of patients were progression-free at 1 year. Survival rates at 2, 5 and 10 years were 85%, 75% and 50%, respectively. Up-front chemotherapy with PCV regimen is a good treatment for symptomatic pure low-grade OG, as it increases the number of progression-free patients and time to progression. These results suggest that radiotherapy could be postponed until the malignant transformation occurs to delay cognitive side effects of irradiation.

Expression of epidermal growth factor receptor and survival in upper aerodigestive tract cancer.

PURPOSE: To determine the expression of epidermal growth factor receptor (EGFR) in head and neck squamous cell carcinoma and to evaluate its prognostic value. MATERIALS AND METHODS: EGFR was determined in tumor biopsies obtained from 109 consecutive patients with head and neck cancer (100 men, nine women). Control biopsies were obtained from 94 patients in a symetric nontumoral area of the same anatomic site. EGFR was measured by a binding assay using human recombinant iodine 125-EGF. RESULTS: The presence of detectable EGFR levels was found in all explored tumors with highly marked differences between patients (median, 71 fmol/mg protein; range, 2 to 2,302). In 93 of 94 cases, EGFR levels were higher in tumor samples as compared with healthy control zones. There was no significant difference in EGFR expression according to the various anatomic sites explored or tumoral differentiation status. There was a significant difference of distribution for EGFR levels between stages I and II tumors and stages III and IV tumors. The tumor EGFR levels were not linked to the response to first-line chemotherapy by cisplatin (CDDP) and fluorouracil (5FU). Survival was assessable for 103 patients for overall survival and for 81 patients for recurrence. EGFR overexpression was associated with shorter relapse-free (P = .0125) and overall survival (P = .028) rates. By multivariate analysis, the only significant variable was EGFR for relapse-free survival and tumor staging for overall survival. The association of EGFR to tumor staging markedly improves the significance for overall survival predictability (P = .002). CONCLUSION: EGFR determination deserves particular attention in head and neck cancer, since it independently carries a strong prognostic value.

Relationship between fluorouracil systemic exposure and tumor response and patient survival.

PURPOSE: The aim of this study was to analyze the link between fluorouracil (FU) systemic exposure and tumor response and overall survival. PATIENTS AND METHODS: One hundred eighty-six patients (162 men, 24 women) with head and neck cancer were studied. All received cisplatin plus FU for three cycles as first-line chemotherapy. The treatment consisted of cisplatin (100 mg/m2 intravenously [IV]) followed by a 5-day continuous venous infusion of FU (1 g/m2/d). The median follow-up duration for the 104 patients alive was 24 months. For each cycle, we calculated the area under the curve over the duration of pharmacokinetic follow-up (AUC0-105 h) for plasma FU. For each patient, we analyzed the averaged AUC0-105 h and the averaged total dose for the three cycles. RESULTS: The response rate was 30% complete responses (CRs), 22% partial responses (PRs) more than 75%, 25% PRs less than 75%, and 23% no response (NR). Medians for averaged AUC and dose per cycle were 27,906 ng/mL h (first through third quartile, 25,398 to 31,060) and 7,000 mg (first through third quartile, 6,200 to 7,833), respectively. The tumor response was significantly linked to tumor stage (P < .001) and to averaged AUC (P = .05), but not to averaged dose. Analysis of parameters (continuous variable) expressing FU treatment intensity showed that dose did not influence survival contrary to the AUC (P = .001). The AUC remains significant (P = .025) in a multivariate analysis including tumor stage, demonstrating that the greater the FU systemic exposure, the longer the survival. CONCLUSION: These results strengthen the interest of individual FU dose adaptation based on pharmacokinetics.

CYFRA 21-1, a sensitive and specific new tumour marker for squamous cell lung cancer. Report of the first European multicentre evaluation. CYFRA 21-1 Multicentre Study Group.

The present study was designed to determine whether CYFRA 21-1, measuring cytokeratin 19, could be a specific and sensitive tumour marker for non-small cell lung cancer (NSCLC). Serum measurements were made at diagnosis in 2250 patient samples by an immunoradiometric "sandwich type" assay, using two cytokeratin 19 specific monoclonal antibodies. Among healthy individuals (n = 711) and patients with benign lung disease (n = 546), 95 percentiles were 1.2 and 2.95 ng/ml, respectively. Cumulative distribution analysis curves were established. From these data, 3.3 ng/ml gave 96% specificity. Using this cutoff, the sensitivity for small cell lung cancer was 16% (n = 74) compared to 41% for NSCLC (n = 547). In histological sub-groups, sensitivity was 57% for squamous cell lung cancer, 34% for undifferentiated large cell carcinoma and 27% for adenocarcinoma, the level of CYFRA 21-1 was correlated with tumour size and UICC stage. In squamous cell lung cancer, the sensitivity of the squamous cell carcinoma marker was 30%, 25% for carcinoembryonic antigen and 46% for tissue polypeptide antigen, using the same series of samples and cutoffs defined at 96% specificity. In conclusion, CYFRA 21-1 is a sensitive tumour marker for NSCLC, especially squamous cell lung cancer.

Comparative study of gamma glutamyl transferase, alkaline phosphatase and its alpha 1 isoenzyme as biological indicators of liver metastases.

Biological detection of liver metastases represents an important factor in the surveillance of the course of cancerous affections. The authors present a report on a potential new indicator, the isoenzyme of alkaline phosphatase migrating to the alpha 1 region (alpha 1 ALP). In comparison to those tests considered the most sensitive at present-gamma glutamyl transferase and total alkaline phosphatase-this alpha 1 isoenzyme appears more sensitive and more specific, capable of detecting 97% of liver metastases with a specificity of 90%.

Prognostic value of S-phase fraction in 920 breast cancer patients: focus on T1N0 status.

The aim of this study was to reexamine the prognostic role of tumor cell kinetics measured by S-phase fraction (SPF) and to establish its clinically relevant threshold values. SPF was determined by flow cytometry in a group of 920 consecutive breast cancer patients, all followed at our institute for 10 years (1988 to 1998). Mean age was 60.5 years (27-89 years). Median follow-up was 63 months (3-150 months). All patients had initial surgical treatment. SPF quartiles were: Q1=3.08%, median value = 5.98%, Q3=10.22%. A significant difference in overall specific survival was obtained between two populations divided by a cutoff at Q1 (p < 0.0001). A multifactorial analysis including SPF and known prognostic factors such as tumor size, node status, histological grade, ER and PR status was performed using the Cox model in a population of 719 patients: univariate analysis showed that each of these factors had significant influence on overall survival. Multivariate analysis selected three of them, ranked by decreasing order of hazard ratio (HR) value: SPF (HR: 3.88, p < 0.001), tumor size (HR: 2.49, p < 0.001) and nodal status (HR: 2.28, p < 0.001). In addition, when tumors were stratified according to SPF quartile values, there were statistically different overall survival curves in patients with small tumors (< 2 cm) and in axillary node-negative patients.

Evaluation of prostate-specific antigen in prostate cancer.

Prostate-specific antigen (PSA) was assayed retrospectively in 131 prostate cancer patients. Pretreatment levels at primary tumor diagnosis were above 5 ng/ml in 13/16 (81%) of stage B and C patients and in 28/28 (100%) of stage D (D1 and D2) patients. At the discovery of metastasis in treated patients, they were above this value in 12/17 (71%) of patients. To determine the value of PSA assays when physical exams were negative, 52 patients were reevaluated at a maximum interval of 12 months as a function of their initial PSA concentration. When the initial PSA was negative, there was no clinical evolution during the next 6 months; when PSA was positive, patients had a 55% risk of progression in the next 4 months. All PSA assays were coupled with prostatic acid phosphatase (PAP) measurements. No PAP values were positive when PSA was negative.

[Review of adjuvant breast cancer therapy in non-menopausal women including early results of medical castration with LH-RH analogs]. / Etat actuel du traitement adjuvant des cancers du sein de la femme non ménopausée et premiers résultats préliminaires des castrations médicales par anlaogues de la LH-RH.

Three treatment modalities have successively dominated adjuvant therapy of breast cancer in non-menopausal women, namely, castration, chemotherapy and tamoxifen administration. The benefits afforded by each of these modalities seem similar when the treatments are compared indirectly by meta-analysis. Once the anti-tumour action of LH-RH analogues and their reversible action on ovarian function had been established, these analogues were used instead of surgical castration in direct comparisons of the three treatment modalities. Most of the patients in these trials had estrogen and/or progesterone receptor positive tumours. According to the current state-of-the-art and whilst awaiting the final results of ongoing trials, we can conclude that: The survival of surgically castrated patients is the same as that of patients who have received CMF-type chemotherapy. The survival of patients on tamoxifen is the same as that of patients who have received CMF-type chemotherapy if tamoxifen is administered for 5 years. It is lower if tamoxifen is given for only 2 years. In 2 out of 3 trials, patients receiving the combined treatment castration plus tamoxifen had improved recurrence-free survival rates compared to patients on chemotherapy (regardless of whether an anthracyclin was included or not. It is too early to comment on overall survival. Combining castration and chemotherapy seems to be advantageous in patients less than forty and in those in whom chemotherapy has not induced amenorrhea. Combining tamoxifen and chemotherapy markedly decreases the risks of disease recurrence and of death but the high standard deviations recorded mean that this statement has to be tempered. Finally, an arrest of ovarian function by LH-RH analogues that is only temporary apparently does not adversely impinge upon results. This has, however, to be proved in an ad hoc trial and the optimum duration of analogue administration has to be established.

[Prognostic value of early normalization of CA 125 during chemotherapy in stages III and IV ovarian tumors]. / Valeur pronostique de la normalisation précoce du CA 125 au cours de la chimiothérapie des tumeurs de l'ovaire stades III et IV.

The value of early CA 125 assays and analysis of its diminution kinetics during chemotherapy have been the subject of numerous studies. In contrast, routine utilization of CA 125 assays in clinical practice remains controversial or at best difficult to apply because the definitions and prognostic values associated with CA 125 assays vary greatly from one study to the next. This study was designed to determine whether serial CA 125 assays during induction chemotherapy for ovarian carcinoma, using simple evaluation criteria directly applicable in routine clinical practice such as early normalization (level < 35 UI/ml) are predictive of response to treatment or improved survival. This retrospective longitudinal analysis concerned a historical population of 140 patients with ovarian carcinoma stages III and IV treated at the Antoine-Lacassagne Cancer Center between 1978 and 1993. All the patients were treated by chemotherapy based on platinum salts every 21 days. Serum CA 125 assays were performed both before and after surgery and during each chemotherapy cycle. Eighty-four patients had a pre-operative CA 125 assay. No difference is observed in survival as a function of their preoperative CA 125 concentration (p = 0.4). Sixty-seven patients had a CA 125 assay the 6th week after initiation of chemotherapy, 62 the 9th week and 47 the 18th week. Normalization of CA 125 the 6th week (p = 0.0001), the 9th week (p = 0.0008) and the 18th week (p = 0.03) after the initiation of the chemotherapy cycle are correlated with survival. The median survival in our study is 42 months if the CA 125 is below 35 UI/ml the 6th week versus 13 months if the level of CA 125 remains more than 35 UI/ml. In all, 66 of the 105 FIGO stage III patients underwent second-look surgery. Normalization of CA 125 levels is correlated with the absence of any gross residual tumor at the second-look procedure, the 6th week of chemotherapy (p = 0.0019), the 9th week of chemotherapy (p = 0.0003) and the 18th week of chemotherapy (p = 0.0015). This correlation is not confirmed when the presence of histologic residual tumor in biopsy specimens obtained during second-look surgery is taken into consideration. Overall, 88% of patients whose CA 125 levels failed to normalize during evaluation at the second cycle of chemotherapy have residual tumor at second-look surgery. Outside of clinical trials, repeated early CA 125 assays to determine the chemosensitivity and the prognosis of patients with ovarian carcinoma are of little interest compared to a single CA 125 assay at the 6th week after initiation of chemotherapy. This approach seems to be a good compromise between the information sought and its practical use. However the interest of early modification of chemotherapy regimen after 2 cycles, if the level of CA 125 remains more than 35 UI/ml, will have to be showed.

[EGF receptor, a prognostic factor in epidermoid cancers of the upper aerodigestive tracts]. / Le récepteur d'EGF, facteur de pronostic dans les cancers épidermoïdes des voies aérodigestives supérieures.

EGFR was determined, before treatment; in tumors biopsies obtained from 109 consecutive patients with head and neck cancer (100 men and nine women), using iodine labelled recombinant EGF. The median age of the study population was 60 years. EGFR levels varied from 2 to 2302 fmol/mg membrane protein (median 71). There was a significant difference of distribution for EGFR levels between stages I and II tumors and stages III and IV tumors (P = 0.03). The EGFR cut-off value for overall survival was 120 fmol/mg protein and the median follow-up was 18 months (3-35) EGFR overexpression was associated with shorter relapse-free (P = 0.0125) and overall survival (P = 0.028). By multivariate analysis the only significant variables were EGFR for relapse-free survival and tumor staging and EGFR for overall survival. Analyzed in 60 patients treated by first-line chemotherapy CDDP-5FU, the longest survival was achieved for patients who had a complete response to chemotherapy and the lowest EGFR levels (P = 0.018). EGFR expression in the primary tumor allows survival among first line chemotherapy responder categories to be discriminated.

[Neoadjuvant chemotherapy for symptomatic non operable grade II fibrillary astrocytoma in adults]. / Chimiothérapie néoadjuvante dans les astrocytomes fibrillaires de grade II symptomatiques non opérables de l'adulte.

We collected 6 case-reports of symptomatric non removable low grade fibrillary astrocytoma of adults treated with a procarbazine-CCNU-vincristine chemotherapy regimen. All patients had drug-resistant epilepsy but brain imaging was stable. Total gross resection was rejected because of Volume or tumor location. After 4 to 7 cycles of chemotherapy, 2 patients had partial response and one minor response on brain MRI. All of them were seizure-free. Progression free survival was not reached at 5 Years. Up-front chemotherapy for low-grade astrocytomas may be useful and has to be prospectively evaluated.

[Induction chemotherapy with cisplatin-5 fluorouracil. Current results in cervicofacial carcinology]. / Chimiothérapie d'induction platine-5 fluoro-uracile. Résultats actuels en carcinologie cervico-faciale.

150 patients were treated at the Centre Antoine-Lacassagne by CDDP-5 FU induction chemotherapy. Amongst the 134 cases suitable for evaluation, there were 86.6% of greater than 50% responses including 45.5% complete responses (CR). These clinical findings led to changes in post-chemotherapy protocol, mutilating surgical procedures such as total laryngectomy being replaced in complete responders by radiotherapy only. These changes did not lead to any alteration in the survival of the patients. The degree of tumour control at 1 and 2 years was 91.4% and 81.4% for complete responses, 74.6% and 60.6% for partial responses (PR) with survival rates of 1 and 2 years 94% and 78.3% for CR and 77% and 55.1% for PR. The possibility of conservative treatment with a high level of reliability would alone appear to be justification for the use of induction chemotherapy in cervico-facial oncology.

[Prognostic factors and therapeutic strategy of breast cancer]. / Facteurs pronostiques et stratégie thérapeutique du cancer du sein.

The survival of patients with breast cancer depends on parameters known as prognostic factors. The first generation of prognostic factors are simple, have been validated, and have proved their usefulness. We know the importance of examining axillary lymph nodes. However, because there has been a constant increase in the percentage of patients with no invaded lymph nodes, tumor size has become an important parameter. The 10-year survival rate of patients with tumors less than 1 cm in diameter exceeds 90% suggesting that there might seem to be no need for adjuvant therapy. According to histological grade assessed by the Scarff-Bloom and Richardson method, grade I tumors have a better prognosis than grade II or III tumors. Knowledge of the concentration of estrogen and progesterone receptors in tumors provides not only prognostic information but also indicates whether hormone therapy is justified. All these first generation factors are intimately linked and, taken together, they are the main factors on which the oncologist bases his decision whether or not to prescribe adjuvant therapy. There is still no consensus regarding the assay methods and normal levels of second generation prognostic factors. Amongst these factors, the most promising are those, like S-phase determination by flow cytometry, that evaluate cell proliferation potential and those that investigate tumor invasiveness by assaying urokinase plasminogen activator or its inhibitor.

Different clinical impact of estradiol receptor determination according to the analytical method: A study on 1940 breast cancer patients over a period of 16 consecutive years.

The knowledge of estrogen receptor (ER) status is important in the management of breast cancer patients. More precisely, analytical methods for ER determination have changed over the last two decades from ligand binding assay (LBA) dextran-coated charcoal (DCC) to enzyme immuno-assay (EIA) and more recently immunohistochemistry (IHC). We examined the respective clinical impact of ER determination according to these 3 methods over the period 1983-1999 within a group of 1940 patients, all operated and followed in the single institution Centre Antoine Lacassagne. Validated cut off values were 10 and 15 fmol/mg protein for both LBA-DCC and EIA, respectively and 10% of stained cells for IHC. During the years it was noted that the initial size of the tumor decreased and that the proportion of positive axillary nodes and negative ER tumors was different according to the ER method. ER negativity was 20, 13 and 10% in LBA-DCC, EIA, IHC, respectively. ER was a strong predictor of overall survival in the whole population (Mantel-Cox, p < 0.00001); however when stratifying the analysis on ER method groups, ER was still a prognostic indicator in the EIA, LBA-DCC group but not in the IHC group (the follow-up was too short). It is important to keep these data in mind when conducting large retrospective studies evaluating prognostic markers in breast cancer patients.

Vascular endothelial growth factor-A and Poly(A) binding protein-interacting protein 2 expression in human head and neck carcinomas: correlation and prognostic significance.

Vascular endothelial growth factor-A (VEGF-A) has been demonstrated to play an important role in tumour angiogenesis and to influence prognosis in many cancers. However its prognostic value in head and neck squamous cell carcinomas (HNSCCs) remains controversial. Therefore, we investigated the clinical relevance of VEGF-A expression in HNSCCs and analysed whether its expression was associated with PAIP2 protein levels, a VEGF-A mRNA-binding partner that strongly regulates VEGF-A expression in tissue culture. We determined the correlation of VEGF-A and PAIP2 protein levels, quantitatively evaluated in tumour tissue homogenates from 54 patients with HNSCC, to clinicopathological parameters. We showed that VEGF-A expression in HNSCC is correlated to the stage of tumour differentiation (P=0.050) and is an independent prognostic factor for progression-free survival (P=0.001) and overall survival (P=0.0004). In a pharynx carcinoma cell line, we demonstrated by RNA interference that VEGF-A expression is closely controlled by PAIP2. Moreover, in human HNSCCs, VEGF-A expression is significantly correlated to PAIP2 protein levels (P=0.0018). Nevertheless, PAIP2 expression is associated with neither clinicopathological factors nor patient's survival. Our data suggest that, in contrast to PAIP2 protein levels, which are unrelated to tumour prognosis, VEGF-A expression could serve as a prognostic marker in head and neck cancer and may be helpful for targeted therapies.

[Rheumatoid polyarthritis and life events]. / Polyarthrite rhumatoïde et événements de la vie.

By applying the systematic and quantitative method of life events to 56 patients with rheumatoid arthritis, the activity of which was assessed both clinically and by means of laboratory tests, the authors demonstrated a significantly higher value for the cumulative life event score over the three years prior to the examination (with or without weighting) in patients in an active phase of the disease compared with patients in remission. These results seem to support the concept that the accumulation of life events may increase the incidence of subsequent episodes of the disease and conversely. The non specific nature of the phenomenon seems to be demonstrated by the study of a control group of subjects hospitalised for disease other than rheumatoid arthritis.

Alpha 1 isoenzyme of alkaline phosphatases. Clinical importance and value for the detection of liver metastases.

Measurement of the alpha 1 (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 alpha 1 fraction offers better global value (94%), sensitivity (96%), and specificity (93%) than gamma GT or total alkaline phosphatase determinations for the detection of liver metastases during cancer. Initial data from study of the time of appearance of the alpha 1 fraction reveals that this fraction shows up earlier than rises in the gamma GT or total alkaline phosphatases. Results of a multiparametric study conducted on the alpha 1 fraction and various hepatic enzymatic tests (SGOT, SGPT, GLDH, ALP, gamma GT) indicate that the alpha 1 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 alpha 1 fraction, the majority of the drugs used for anticancer chemotherapy do not seem to affect measurement of the alpha 1 ALP fraction. The alpha 1 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.

Epidermal growth factor receptor expression in 780 breast cancer patients: a reappraisal of the prognostic value based on an eight-year median follow-up.

PURPOSE: Because new therapeutic approaches target tumors expressing epidermal growth factor receptor (EGFR), the aim was to undertake a thorough analysis of the expression profile of EGFR in breast cancer and to reassess its prognostic value. PATIENTS AND METHODS: Tumor EGFR levels were determined by a specific ligand binding assay in 780 consecutive breast cancer patients followed in our institute between 1980 and 1993. Mean age was 61 years (25-85 years). All patients had undergone tumor resection with axillary lymph node dissection: 373 patients (47.8%) underwent mastectomy, 37 (5%) subcutaneous mastectomy and 370 (47.2%) tumorectomy. RESULTS: EGFR levels ranged between non-detectable up to 789 fmol/mg protein. EGFR median value was 9 fmol/mg protein and only a small proportion of patients exhibited a relatively marked EGFR expression. There was no link between tumor size, grade, node status and EGFR tumoral levels. There was a constant and significant decrease in EGFR tumoral levels according to patient age. A significant inverse relationship was found between estradiol receptors (ER) and EGFR. Median follow-up was 97 months with a minimum at 4 months and a maximum at 228 months. From univariate analysis it was found that histological grade, tumor size, node status and ER status were all significant predictors of survival, considering metastasis-free as well as overall survival. Using multivariable analysis, only histological grade, tumor size and node status remained independent predictors of survival. CONCLUSION: EGFR determination is of limited value as a prognostic indicator in breast cancer.