Microsatellite instability and sensitivitiy to FOLFOX treatment in metastatic colorectal cancer.

BACKGROUND: Microsatelite instability (MSI) is the consequence of the inactivation of a mismatch repair gene and is observed in approximately 15% of colon cancer cases. Patients with MSI colon cancer do not benefit from 5-fluorouracil (5-FU)-based chemotherapy. A current treatment of reference for colon cancer is a combination of 5-FU and oxaliplatin (FOLFOX). The aim of this study was to determine the efficiency of the FOLFOX treatment in patients with metastatic MSI colon cancer. PATIENTS AND METHODS: Tumour specimens were collected from patients with metastatic colon cancer treated with FOLFOX 4 modified or FOLFOX 6; these two regimens are based on 85 mg/m2 and 100 mg/m2 oxaliplatin, respectively. The MSI status was assessed by measuring the length of five monomorphic mononucleotide markers. The FOLFOX regimen was evaluated as a first-line treatment according to WHO criteria. RESULTS: Forty patients (22 men, 18 women), median age 63.5 years (27-83 years) were treated with FOLFOX 4 or 6. Nine patients had tumours exhibiting high MSI (MSI group) and 31 patients had tumours exhibiting microsatellite stability (MSS group). In the MSS group, 11 partial responses (36%) were observed, while there were only two in the MSI group (22%) (no significant difference). The two patients who were responders in the MSI group were treated with FOLFOX 6. The overall survival was not significantly different for MSI and MSS patients. CONCLUSION: No significant differences in the overall response rate or overall survival between the two groups of patients were observed. However, these results suggest that patients with MSI colon cancer are more sensitive to a higher dose of FOLFOX.

[Gefitinib treatment for carcinomatous meningitis in non-small cell lung cancer]. / Géfitinib et méningite carcinomateuse d'un carcinome bronchique non à petites cellules (CBNPC).

BACKGROUND: Carcinomatous meningitis is a major complication in Non Small Cell Lung Cancer (NSCLC). Despite treatment with radiotherapy alone or in combination with intrathecal and systemic chemotherapy, its prognosis remains poor. OBSERVATION: We report a case of a female non-smoker with adenocarcinoma with bronchoalveolar features presenting with carcinomatous meningitis three years after the diagnosis of her primary tumour. Gefitinib treatment was proposed because of the persistence of meningitic symptoms despite cranial irradiation. Clinical response was observed within 3 weeks and lasted for 9 months. CONCLUSION: Gefitinib may be effective in treating carcinomatous meningitis complicating NSCLC and should be considered in this situation given the absence of effective alternatives.

Transfer into a mesothelioma cell line of tumor suppressor gene p16 by cholesterol-based cationic lipids.

In this work, the tumor suppressor gene p16 was efficiently transferred into FR cells isolated from a patient with malignant mesothelioma using cationic liposomes prepared from trimethyl aminoethane carbamoyl cholesterol (TMAEC-Chol) and triethyl aminopropane carbamoyl cholesterol (TEAPC-Chol). This transfer was performed after preliminary assays were undertaken to find the optimal transfection conditions. Results showed that an efficient transfer of plasmids containing the reporter gene pCMV-beta galactosidase vectorized by TMAEC-Chol/DOPE and TEAPC-Chol/DOPE liposomes into mesothelioma FR cells was obtained as assessed by luminometric measurements of beta-galactosidase activity. Cytotoxicity studied by MTT test showed that at concentrations used for this study, the cationic liposomes have no effect on cell growth. Transfer into mesothelioma FR cells of a plasmid construct containing the tumor suppressor gene p16 was carried out with these liposomes. Western blotting and immunofluorescence showed the presence of p16 in treated cells. An inhibition of cell growth was observed, indicating that efficient tumor suppressor gene transfer can be performed by using cationic liposomes.

Somatostatin receptor imaging in small cell lung cancer.

To determine its usefulness, we evaluated 111In-DTPA-Octreotide (octreotide scintigraphy) in the initial staging of 19 patients with histologically proven small cell lung cancer (SCLC) and compared the results to those of conventional imaging. Images performed during initial staging demonstrated 21 known pulmonary lesions and two known supraclavicular nodes. We detected a previously unknown mediastinal lesion. The number of metastases was underestimated, with no liver (5), brain (1) or skin metastases detected. Bone lesions were identified in 4 out of 5 patients. There were fewer lesions detected with octreotide scintigraphy than with bone scintigraphy (except for one case). We therefore conclude that octreotide scintigraphy is a highly effective method for detecting SCLC primary tumour and supraclavicular nodes; the procedure is of limited value for distant metastasis. Further studies are needed to establish its ability for detecting residual intrathoracic disease, and confirm the value of octreotide scintigraphy in differentiating residual disease from other benign lesions.

Assessment of malignancy in pulmonary lesions: FDG dual-head coincidence gamma camera imaging in association with serum tumor marker measurement.

UNLABELLED: The purpose of the study was to evaluate the performance of dual-head coincidence gamma camera imaging using FDG in association with serum marker assays in identifying lung carcinoma in patients with abnormal findings on chest radiography. METHODS: A prospective evaluation of FDG imaging with coincidence detection emission tomography (CDET) using a dual-head gamma camera combined with the assessment of 3 sensitive serum markers of lung cancer (carcinoembryonic antigen, neuron specific enolase, and CYFRA 21-1) was performed on the same day on 58 consecutive patients with known or suspected lung malignancy. RESULTS: Fifty-three patients were proven to have lung cancer, and 5 patients had benign lung disease. Coincidence imaging showed significantly increased FDG uptake in 49 of 53 patients with proven malignancy (sensitivity, 92.5%) and in 3 patients with benign disease. FDG imaging had negative findings in 4 patients with proven malignancy and 2 patients with benign disease. Serum tumor marker levels were elevated in 42 of 53 cancer patients (sensitivity, 79.2%) and normal in 11 patients with proven malignancy. Nine patients with proven malignancy had positive findings on FDG images and negative marker assays. Two patients with proven malignancy had negative findings on FDG images and positive marker assays. The positive predictive value for lung cancer was 94.2% for FDG alone and 97.6% for FDG in association with serum markers. CONCLUSION: In this study, FDG CDET imaging was a powerful tool for evaluating patients with lung lesions suggestive of malignancy. Although the determination of serum marker levels was less accurate than FDG imaging, positive FDG results found in association with positive markers significantly increased the likelihood of lung malignancy.

Vinorelbine and ifosfamide for unresectable non-small cell lung cancer.

PURPOSE: The study assessed the efficacy of combination therapy with vinorelbine and ifosfamide in patients with unresectable non-small cell lung cancer. PATIENTS AND METHODS: Forty patients with non-small cell lung cancer whose tumour was unresectable by virtue of the extent of disease or severity of impairment of lung function and who were considered unsuitable for treatment with a cisplatin based treatment were entered onto the study. Thirty-four patients received two cycles of treatment and were considered to be evaluable for response. The treatment schedule consisted of vinorelbine (Navelbine, Pierre Fabre Medicament) 25 mg/m2 on days 1 and 8, and ifosfamide 2 g/m2 per day with mesna 0.5 g/m2 three times daily given on days 1 to 3; cycles were repeated every 21 days and treatment continued in responding patients until progression occurred. RESULTS: Objective responses were observed in 12 patients (30%; CI95, 16-44) with one completed response (CR) and 11 partial response (PR). CONCLUSION: This schedule achieves good levels of response without the use of cisplatin so it is suitable for patients whose performance status or concomitant medical condition precludes the use of platinum based chemotherapy.

Treatment of advanced ovarian cancer with cis-dichlorodiammine platinum in combination with cyclophosphamide. An E.C.O.G. pilot study.

Twenty patients with Stage III and IV carcinoma of the ovary have been treated with a combination of cyclophosphamide and cis-platinum given every 3 weeks. Regarding toxicity, this combination probably included a too-high dose of CTX (1.1 g/m2 every 3 weeks). The response rate was 75% (15/20) but with a significant duration only for those patients who achieved a complete response (7/20). It was seen that, as usual, patients who have undergone extensive reductive surgery are more likely to respond. The regimen described gives results comparable to those of more aggressive combinations but did not achieve significant control of the disease.

Treatment of advanced epithelial ovarian cancer with a cis-dichloro-diammine platinum, cyclophosphamide, and bleomycin combination.

Twenty-five consecutive patients with previously untreated stage III (18) and IV (7) epithelial ovarian carcinoma underwent maximum surgical tumor reduction followed by cyclophosphamide, cisplatinum, and bleomycin chemotherapy, given 5 days every 3 weeks for a total of 6-8 courses. Patients were then submitted to second-look surgery, and complete responders to a 1-year additional chemotherapy with L phenylalanine mustard and hexamethylmelamine. The median survival is 23 months for the whole group, and 31+ months for 13 patients found in microscopically assessed complete remission (CR) at the time of second-look surgery. The possible significance of these results and of the addition of bleomycin to a well-known combination are discussed, together with the limitations of a phase II study.

Bleomycin and cis-platinum with or without mitomycin C in 110 previously untreated patients with head and neck cancer.

Between November 1979 and October 1981, 110 consecutive patients with previously untreated, biopsy-proven squamous cell carcinoma of the head and neck, were treated by chemotherapy prior to scheduled surgery and/or radiotherapy. Two regimens of chemotherapy were used. The first 57 patients received cis-platinum, 20 mg/m2/day for 5 consecutive days and bleomycin 5 mg/m2/day as a continuous infusion over the same 5 days every 3 weeks (Regimen A). The next 53 patients received the same schedule and dose of cis-platinum, bleomycin 2.5 mg/m2 every 12 hours for the same 5 consecutive days and mitomycin C6 mg/m2 on day 1 of each cycle every 3 weeks (Regimen B). The number of courses administered prior to surgery and/or radiotherapy ranged from 1-4 depending on the otorhinolaryngologist's assessment of the optimal time for locoregional treatment. The overall response rate in regimen A was 78% (45/57) compared to 90% for regimen B (48/53). Complete responses were seen in 10/57 (18%) and 13/53 (25%) patients in regimens A and B, respectively. Eight of 57 patients in regimen A and 6/53 in regimen B refused further treatment and follow-up, and 7/53 patients in regimen B chose to pursue chemotherapy (in which methotrexate replaced bleomycin) rather than undergo surgery and/or radiotherapy. Five of these seven patients are surviving disease-free from 7-12 months. In regimen A, 31/57 patients are surviving with a median survival exceeding 15 months. In regimen B, 46/53 patients are surviving up to 14 months. Nausea and vomiting induced by cis-platinum were the major side effects, seen to a variable degree in all patients. No cis-platinum-induced renal toxicity was observed with the 5-day regimen and none of the patients had symptomatic bleomycin-induced pneumonitis. One patient had a bleomycin-induced skin rash which did not require discontinuation of therapy.

Long-term survival of patients given hormonal therapy for metastatic endometrial stromal sarcoma.

Endometrial stromal sarcoma (ESS) is a rare neoplasm, mainly observed in premenopausal women. We describe two women 44 and 34 years old at the time ESS diagnosis, who developed lung metastases 3 and 6 years, respectively, after initial treatment: hysterectomy without (case 1) or with oophorectomy (case 2), followed by hormone replacement therapy (HRT) for the latter. Their estrogen (ER) and progesterone receptors (PR) were analyzed biochemically in metastatic lung tissue, yielding respective concentrations of ER 242 and 184, and PR 910 and 100 fmol/mg of cytosol protein. Both patients started treatment with the aromatase inhibitor aminoglutethimide (500 mg qid) after surgery for the first patient and after stopping HRT for the second. Under aromatase-inhibitor therapy, both patients achieved a complete response, patient 1 remains disease- free with 14+ years of follow-up, and patient 2 with 7+ years. Our data suggest that an aromatase inhibitor may be an effective treatment for ESS. Furthermore, routine ER and PR analyses could be useful to predict the response to hormonal therapy in ESS.

Preoperative chemotherapy in epidermoid bronchogenic carcinoma.

Palliative chemotherapy in cases of epidermoid bronchogenic carcinoma, initially judged to be inoperable, made it possible to perform operative resection in 50 cases. An association of cis-platinum and bleomycin was used, this combination having previously been considered synergistic. In certain cases the tumour seemed to have disappeared on macroscopic examination of the resected specimen, and in some instances no tumoral cells could be found on histological examination. This series brought out several positive features: chemotherapy made it possible to operate on patients previously judged to be inoperable; it ensured maximum local efficiency of drugs because of the absence of abnormal vascularity; and it made it possible to anticipate the cure of occult metastases. However, three negative aspects were also present: modification of postoperative TNM classification making it difficult to establish a prognosis; difficulty in determining therapeutic strategy for pNo; and inadequate long-term follow-up. On the whole the positive points appeared to outweigh the negative aspects, but a randomized study is necessary to confirm this.

[Regression and slowing of the growth of human pulmonary metastases induced by piroxicam, an inhibitor of prostaglandin synthesis]. / Regressions et freinages de croissance de métastases pulmonaires de cancers humains induits par le piroxicam, un inhibiteur de synthèse des prostaglandines.

The action of piroxicam, an inhibitor of prostaglandin synthesis, was evaluated in 31 cases of measurable pulmonary metastases of several primary cancers. In each case, the spontaneous doubling time was measured prior to and after a minimum of 3 months of treatment with piroxicam as a single drug, 20 mg daily po. The doubling time of metastatic lung nodules was significantly increased in 18/31 cases (58%) of which 10 cases had their spontaneous doubling time multiplied by two. Minor regressions were observed in 5/31 cases (16%) and one case of metastatic fibrosarcoma had a complete radiologic response. No effect was observed in 8/31 cases (26%). Prostaglandin synthesis inhibitors may be useful for treating metastatic cancer. Possible mechanisms of action are discussed.

[Brain metastases of malignant melanomas]. / Métastases cérébrales des mélanomes malins.

Cerebral metastases of malignant melanoma are correlated with a very poor prognosis. Surgery of an isolated metastase can lead to a long survival but the brain lesions are frequently numerous and associated with an extracerebral diffusion. Dacarbazine (DTIC) gives a mean response rate of 21% on visceral localisations but doesn't cross the blood brain barrier (BBB). Neither do the biological response modifiers like Interleukin 2 (Il2) that leads to 25% response rate in disseminated melanoma. Nitrosoureas like carmustine (BCNU) and semustine (CCNU) have been investigated in different non randomised studies and the clinical results didn't illustrate their theorical ability to cross the BBB. Radiotherapy is also used as a palliative therapy with 7 to 16 weeks survival. Fotemustine (muphoran), a new amino acid linked nitrosourea, can give a response rate up to 28.2% in patients with cerebral metastases and the increased survival of responding patients is significant. The availability of this new drug may suggest associations with surgery and radiotherapy in the future to improve the survival of such patients.

[Advanced epithelial cancers of the ovary: results of 4 chemotherapy protocols (110 cases)]. / Cancers épithéliaux de l'ovaire avancés: résultats de 4 protocoles de chimiothérapie (110 cas).

Following surgery for epithelial carcinoma of the ovary, FIGO stages IIc, III and IV, 110 patients received chemotherapy in one of four treatment regimens (Melphalan; Cyclophosphamide-Methotrexate-Fluoro uracil; Cyclophosphamide-Cisplatinum; Cyclophosphamide-Cisplatinum-Fluoro-uracil). Melphalan alone was as effective as combination chemotherapy and less toxic. The study confirms that the survival duration is inversely correlated to the stage of the disease and to the amount of residual disease following surgery. It also confirms the role of the "second look" surgery in the evaluation of the response to chemotherapy, and in the overall management of the disease.

[Cancer of the kidney: changes in blood lymphocyte subsets induced by treatment with interferon alpha-2b and interleukin-2r]. / Cancer du rein: variations des populations lymphocytaires sanguines sous traitement par interféron alpha-2b et interleukine-2r.

Twenty patients (6 females and 14 males), age range 36-70 years-old, with metastatic renal cell carcinoma (MRCC), received interferon alpha-2b (IFN-A) 10 x 10(6) units/day IM for 5 days followed by continuous i.v. infusion of interleukin-2 (IL-2) 18 x 10(6) units/day for 5 days. The median follow-up was 10 months. We observed four partial responses (20%), 13 stable (65%) and three progressive diseases (15%). The mean CD4/CD8 ratio, obtained before therapy in patients with MRCC, was compared with CD4/CD8 ratio in 51 patients with different advanced malignancy and in patients with no cancer. The CD4/CD8 ratio was higher in patients with MRCC (2.55) than in other cancers (1.474) and than in populations with no cancer (1.66 x chi 2 = 17,378). The surface phenotypes of peripheral lymphocytes were analysed by cytofluorometry in patients with MRCC during and after treatment with IFN-A and IL-2. Immune modulatory effects of therapy immediately induced a decrease of different sub-populations of lymphocytes except CD25+. Far from the first course, a rise in lymphocyte count was observed. The proliferation effect was as follows: CD4+, CD8+, CD4+ CD45RA- and CD16+ CD8- cells. Far from the second and 3rd course, the sub-populations of lymphocytes decreased, except the CD4+ and CD4- CD45RA+ cells. The CD4/CD8 ratio increased progressively during treatment. Before each course, the CD4/CD8 ratio of patients with response to treatment was higher than the CD4/CD8 ratio of patients with no response. Results were non-significant due to the small number of subjects with responses in this study.

[Malignant melanoma of the uvea]. / Mélanomes malins de l'uvée.

Intraocular melanoma is the most common primary ocular malignancy in Whites. Epidemiologic studies demonstrated the role of sun exposure as a risk for uveal melanoma. Conservative treatment techniques are indicated for localised tumors when feasible. External radiation therapy and radioactive eye plaque brachytherapy seem as effective as surgery in term of survival. High tumor doses can be safely administered with either helium or proton beams. A partial preservation of the vision is possible in most of patients. However, even for locally controlled patients, distant metastases can occur. Liver is the most frequent metastatic site, and also the first involved. Liver metastases are associated with a low response rate, to dacarbazine and nitrosourea. Recent studies using a new nitrosourea, fotemustine, administered locally through an intra-arterial catheter, show that it produces encouraging results with a good hepatic and hematologic tolerance.

[Induction chemotherapy followed by concomitant combined radiotherapy and chemotherapy in stage III non-small cell bronchial carcinoma]. / Chimiothérapie d'induction suivie d'une association concomitante de radiothérapie et de chimiothérapie pour les carcinomes bronchiques non à petites cellules de stade III.

PURPOSE: To determine the efficacy and safety of induction chemotherapy followed by concomitant chemoradiotherapy in the treatment of stage III non-small cell lung cancer and whether the response to induction chemotherapy can predict the response to subsequent chemoradiotherapy and survival. MATERIALS AND METHODS: Between December 1987 and June 1993, 46 patients with previously untreated stage III non-small cell lung cancer received every 21 days induction chemotherapy (ICT) including three cycles of 5-fluorouracil (600 mg/m2/d in short infusion from d1 to d5), cisplatin (15 mg/m2/d from d1 to d5), etoposide (50 mg/m2/d from d1 to d5) and hydroxyurea (1,500 mg/d from d1 to d5). The first 21 patients also received bleomycin (3 mg/m2/d from d1 to d5). All patients received concomitant chemotherapy and had chest radiotherapy (CCRT). Patients received irradiation (65 Gy/33-6 fractions/7 weeks) on d25 after the third cycle of chemotherapy. Concomitant chemotherapy was composed of cisplatin (20 mg/m2) and 5-fluorouracil (500 mg/m2) that were administered each Monday and Thursday during radiotherapy. Maintenance chemotherapy consisted of thiotepa (10 mg/m2) and methotrexate (10 mg/m2) that were administered every 2 weeks for 6 months. RESULTS: Pulmonary toxicity was observed in four out of 21 patients who had received bleomycin and subsequently developed pulmonary fibrosis, leading to death for two of them. ICT alone produced five complete responses (11%) and 13 partial responses (28%). The combination of chemotherapy and radiotherapy led to 19 complete responses (41%) and 14 partial responses (30%). Eighteen of the 18 responders (100%) to ICT responded to subsequent CCRT, of whom 13 (72%) became complete responders. Fifteen of the 28 non-responders to ICT (53%) responded to CCRT, six of them being complete responders (21%) (P < 0.001). The median overall survival rate was 17 months when considering all patients, 25 months in patients responding to ICT and 13 months in non-responders. The 2-year survival rates were 28, 55 and 11%, respectively (P < 0.05). ICT did not influence the rate of subsequent metastatic events. However, locoregional reprogression was lower in responders to ICT. The number of metastatic events was not significantly related to response to ICT. By contrast, the rate of local failure was higher when there was resistance to ICT (75% versus 39%). Out of the 19 complete responders to CCRT (13 responders to ICT and six non-responders to ICT), four developed secondary locoregional reprogression (21%) and six developed metastatic disease (31%). In complete responders to CCRT, the rate of locoregional failure was 15% in responders to ICT (2/13) and 33% (2/6) in non-responders to ICT. Four out of the 13 responders to CCRT after response to ICT (31%) and two out of the six complete responders to CCRT developed metastatic disease after non-response to ICT. CONCLUSION: There is a statistically significant relationship not only between the response to ICT and the response to CCRT, but also between the response to ICT and the local outcome and survival.

[Chronic respiratory insufficiency. Incidence in the results of surgical valvular replacement]. / Insuffisance respiratoire chronique. Incidence sur les résultats de la chirurgie de remplacement valvulaire

Out of 400 files of patients who underwent valvar correction between 1968 and 1974 under extra corporeal circulation by the thoracic route through median sternotomy 180 were kept for this study. All these 180 patients had a complete functional spirometric examination before operation, analysed in correlation with their valve disease. 39 of them had severe ventilatory insufficiency. Nevertheless the post-operative period was usually simple, and respiratory insufficiency was responsible for one death only of this series. These data were confirmed by the study of 45 autopsied patients who died after operation. At distance from operation, 80 patients were studied, 25 of whom had severe ventilatory insufficiency. In more than half the cases, and particularly in the mitral ones, the ventilatory deficiency was improved. Thus it is concluded that, respiratory insufficiency is rarely a contra-indication to valve replacement surgery in habitual conditions of the median sternotomy as a thoracic route.

[Implantable infusion devices. Experience of 360 cases]. / Boîtiers de perfusion implantables. Expérience de 360 cas.

Between january 1, 1983 and december 31, 1986, 360 implantable infusion devices were inserted for systemic chemotherapy. Most of the devices were Port A Cath systems. The main complications observed were thrombosis (18 cases, 5%) and infection (8 cases, 2.2%). Since one year the catheters are being introduced by subcutaneous puncture of the subclavian vein, the chambers being placed in a small lateral subclavicular cavity. Intra-operative radiography is necessary to minimize the risk of malposition and thrombosis. These systems, relayed by external pumps, enable chemotherapeutic regimens to be administered sequentially over a 24-hour period.

[Induction of objective responses by an anticancer chemotherapy based on the prolonged combination of bleomycin and cisplatin. 1062 cases]. / Induction de réponses objectives par une chimiothérapie anticancéreuse fondée sur l'association prolongée de bléomycine et de cis-platine. 1062 cas.

A cis-platin + bleomycin combination, sometimes associated with a third cytostatic drug, was administered for prolonged periods to 1062 cancer patients previously subjected to a wide variety of treatments. The objective response rate was about 70% in localized squamous cell and anaplastic bronchial carcinoma and 40% in bronchial adenocarcinoma and metastatic squamous cell carcinoma. Cancers of the head and neck responded in 70% of the cases before irradiation and in 30% after irradiation. Other epidermoid tumours responded objectively in the proportion of 45%, as did 58% of metastatic and refractory breast cancers. These results were not clearly improved by any of the other cytostatic drugs used concomitantly, and the combination alone was less toxic. The high response rate obtained is attributed to a synergistic effect of cis-platin and bleomycin administered for prolonged periods.