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Biomedical subjects

M F Avril

Publications and source records attributed to M F Avril.

At least 91 records · Page 5Linked to original sources

Fotemustine plus dacarbazine for malignant melanoma.

119 patients with metastatic melanoma received fotemustine 100 mg/m2 on days 1 and 8 and dacarbazine 250 mg/m2 on days 15-18. After a 5-week rest, fotemustine 100 mg/m2 on day 1 and dacarbazine 250 mg/m2 on days 2-5 was given every 3-4 weeks. 12 complete responses (11.6%) and 16 partial responses were observed in 103 evaluable patients (response rate 27.2%). The median duration of response was 21.5+ weeks (8+ to 53+). The response rate was 26.3% in CNS, 18.2% in visceral sites and 37.5% in non-visceral sites. The toxicity was mainly haematological: grade III-IV leukopenia in 27.4% and thrombocytopenia in 23.4%. The response rate was lower than that in 63 patients previously reported. The present series had a higher median age (54 vs. 40 years) without any differences in other population variables. However, activity on CNS metastases and on non-visceral sites was confirmed. Haematological toxicity was about 50% lower than that with fotemustine alone. Hence, this is an active outpatient regimen for metastatic melanoma, especially against cerebral and non-visceral metastases.

Adult↗

IL-2 phase II trial in metastatic melanoma: analysis of clinical and immunological parameters.

Twenty-four patients with histologically proven metastatic malignant melanoma were included in a phase II trial of recombinant IL-2 (rIL-2, RU 49637). Twenty million international units (IU)/m2/day were given by continuous intravenous infusion on days 1 to 5, 15 to 18, and 29 to 31, and then monthly for 5 days until disease progression or major intolerance developed. All patients were evaluable for response and toxicity. Toxicity was consistent with one case of myocardial ischemia, 13 cases of grade III and IV hypotension, and 15 cases of proven sepsis. There were 8 objective responses: 4 of them were of short duration as they were observed on day 31 only. An activation of the immune system was detected in all patients. It was demonstrated by an increase in lymphocyte populations, especially in activated NK cells. A tendency for higher numbers of cytotoxic cells was found in patients with objective tumor responses. These results indicate a role for rIL-2 RU 49637 in treating patients with metastatic malignant melanoma. However, further trials are required to determine its optimal dosage and schedule of administration.

Adolescent↗

[Lymph node metastasis of melanoma of unknown primary tumor].

Sixteen patients with clinical stage II melanoma of unknown primary site (regional lymph node metastasis) were followed up between 1978 and 1988. The 5-year survival rate was 47%. These results seem to parallel those for stage II disease with known primary tumor sites, as has been observed in other data from the literature. The hypotheses put forward to explain such lesions are the spontaneous regression of the primary tumor, and the onset of primary malignant melanoma in the lymph nodes.

Adult↗

Fotemustine: an overview of its clinical activity in disseminated malignant melanoma.

Fotemustine is a new chloronitrosourea which is active against disseminated malignant melanoma (DMM), and especially against cerebral metastases (CM). This efficacy has been widely demonstrated through many phase II studies. A multicentre trial of monotherapy was undertaken in 153 evaluable French patients. A response rate (RR) of 24.2% (25.0% RR in CM; 31.8% in non-visceral metastases (NVM) was obtained. Three other phase II studies confirmed these results with respective objective RR of 16.7%, 20.0% and 47.0% and RR in CM of 8.3%, 14.3% and 60.0%. Fotemustine has also been used in combination with dacarbazine (DTIC), in patients with DMM. The RR among 103 patients was 27.2% (26.3% in CM, 37.5% in NVM), confirming the activity of fotemustine. The two drugs have also been administered sequentially, in order to exploit their synergism in interfering with the O6 alkyltransferase. Impressive RR have been achieved, especially in patients with visceral metastases (VM) but at the expense of a pulmonary toxicity that does not arise with other treatment schedules and which precludes its use outside of strictly conducted clinical trials.

Antineoplastic Combined Chemotherapy Protocols↗

[Phase I trial of a recombinant human interleukin 2. Results in patients with disseminated solid tumors].

A phase I trial of Roussel-Uclaf recombinant human interleukin 2 (IL 2) was performed on 31 cancer bearing patients of the Institut Gustave-Roussy, Villejuif, and the Institut Curie, Paris. This study allowed to define a schedule for administration of IL 2 in continuous infusion over 5 day cycles. This schedule is manageable in patients without major visceral failure. It is reproducibly feasible in conventional medical oncology units, without specialized intensive care facilities. Toxicities, although numerous, are acceptable for IL 2 doses below 24,000,000 IU/m2/day. There is a close relationship between secondary effect severity and IL 2 doses received. Main toxicities were: fever with chills, fatigue and general discomfort in 23 patients, nauseas and vomiting in 12, diarrhea in 10 and cutaneous rashes with erythema and dermal vascularitis in 13. One peculiar feature of this study was the minimal occurrence of manifestation related to leaky capillary syndrome prominant in other studies. Oliguria, functional renal failure and edema were observed in only 4 patients with functionally unique kidney. Five patients had severe anemia, 2 grade III thrombocytopenia, 1 grade IV hepatic cytolysis, 4 severe confusion episodes and 2 hypothyroidism with anti-thyroid microsome auto-antibodies. All these toxicities were reversible after withdrawal of IL 2 treatment. During this phase I trial, 3 therapeutic objective responses were observed, all 3 occurring in patients with metastatic melanoma treated with IL 2 doses equal to, or above 16,000,00 IU/m2/d. Recombinant IL 2 Roussel-Uclaf thus can be administered through a simple, manageable and efficient regimen.

Adolescent↗

Primary neuroendocrine carcinoma of the skin. Clinicopathologic study of 18 cases.

The clinical and pathologic features of primary neuroendocrine carcinoma of the skin in 18 elderly patients are reported. The carcinomas arose in the dermis and subcutaneous tissues, particularly on the head and the upper extremities. One tumor occurred in an irradiated area. Using Gould's clinicopathologic classification, we have found four trabecular types, eleven intermediate cell types, and two small cell types. One tumor could not be classified. Other noteworthy pathologic features were association with invasive squamous cell carcinoma, lentiginous melanocytic hyperplasia, and presence of intratumoral melanocytes. Immunoreactivity for cytokeratins (56 kD), neurofilaments, neuron-specific enolase, and epithelial membrane antigen was observed. The paranuclear globular staining pattern of cytokeratins and neurofilaments was conspicuous. The ultrastructural features revealed paranuclear intermediate filament aggregates (fibrous bodies), neurosecretory granules, and cell junctions. In two metastatic tumors, high levels of catecholamines were found. The trabecular types were characterized by localized disease and a good prognosis. The patients with the small cell types died of distant metastases. Postoperative radiotherapy seemed to reduce the rate of local recurrences.

Adenocarcinoma↗

Long-term effects in skin and thyroid after radiotherapy for skin angiomas: a French retrospective cohort study.

To evaluate the long-term effects of skin angioma irradiation, a recall programme was established which included the systematic recalculation of the radiation dose to the skin and the thyroid. 22% of the 6229 patients contacted had a dermatological examination which revealed cutaneous dystrophy in 81% of the 1137 exposed angiomas and in 39% of the 208 unexposed angiomas. The risk of dystrophy (telangiectasia, hypopigmentation, superficial and subcutaneous atrophy) was 12.1 higher (P less than 0.0001) among patients who had received a surface skin dose above 30 Gy than among those who had received a dose of 10 Gy or less. The relative risk for each dystrophy component increased significantly (P less than 0.001) with surface skin dose. Furthermore, 14 basal cell carcinomas (BCC) were observed in 12 patients from the exposed group for all quantities of radiation, with a mean latency period of 22 years. No BCC was observed for a surface skin dose below 10 Gy. Thyroid testing was done on a subgroup of 431 patients whose thyroid gland had been particularly exposed during angioma irradiation. After recalculation, the dose delivered to the gland was below 1 Gy in 98% of patients. Only 13 thyroid nodules were discovered (1 hot and 12 cold). 1 patient with a cold nodule had a malignant thyroid tumour 21 years after irradiation. He belonged to the group of 7 patients who had received a thyroid dose above 1 Gy. Although no morphological abnormality was found in 98% of the tested patients, most (92%) had a thyroid iodine content below 15 mg (the standard French value), while a raised serum thyroglobulin level (greater than 30 ng/ml) was observed in 17%. This might confer a higher risk of subsequently developing thyroid nodules.

Adolescent↗

Chromoblastomycosis with malignant transformation and cutaneous-synovial secondary localization. The potential therapeutic role of itraconazole.

A case of neoplastic transformation of lesions of chromoblastomycosis is reported in a 67-year-old farmer from French Guyana. An interesting aspect of this case was the appearance of new cutaneous lesions of chromoblastomycosis, in a different site from the original lesion, and the presence of an infected synovial cyst. The potential therapeutic role of itraconazole is discussed.

Aged↗

Tumor-infiltrating CD3- NK cells are more effective than CD3+ T cells in killing autologous melanoma cells.

We have studied the phenotype and functional activity of tumor-infiltrating lymphocytes (TIL) derived from eight human melanomas cultured for up to 60 d in the presence of recombinant IL-2. In the early period of the cultures, TIL were predominantly T cells of CD8+ phenotype and contained 10-30% of CD3- cells. Four of the five early TIL cultures tested in a cytotoxicity assay displayed a degree of MHC-unrestricted lysis on a series of autologous and allogenic melanoma cell lines as well as the K562 natural killer-sensitive target. With longer periods of time in culture, all TIL lines showed a decrease in lytic activity that was associated with the loss of CD3- cells. Thus, most of the killing of short-term TIL cultures appeared to be mediated by CD3- natural killer cells, whereas CD3+ T cells were found to be weak anti-tumor effectors. Even though the CD3+ T cells were not cytotoxic on K562 targets, their lytic activity (even weak) against melanoma cells appeared to be non-MHC restricted, and was blocked by anti-CD3 antibodies. In addition, cytotoxicity of the CD3+ TIL cultures was compared to that of a CD3-/NKH1+ cell line purified from peripheral blood. It was found that natural killer cells were much more potent than CD3+ TIL on the melanoma cell lines tested.

Antibodies, Monoclonal↗

[Surgery of pulmonary metastasis from malignant melanoma. Results and criteria of surgical excision].

Lung metastases from malignant melanoma are frequent and they often inaugurate the metastatic stage. Exceptionally, they present as one or a few nodules, and in the absence of any other secondary lesion these cases raise the problem of surgical eradication. A retrospective multicentre study was carried out in a series of 38 patients and its results were compared to the data obtained from a review of 435 published cases in order to assess the value of surgery in terms of survival and to delimit its indications as closely as possible. Our series of 38 patients comprised 20 men and 18 women aged from 22 to 93 years (mean 51 years, median 55 years). The primary tumour was located in the trunk in 47 p. 100 of the cases; it was nodular in 33 p. 100 and superficial but extensive in 37.5 p. 100. The time elapsed before the metastases appeared varied from 0 to 108 months (median 40 months). Surgery had been radical in 70 p. 100 of the patients and usually limited, tumorectomies and segmentectomies accounting for 51 p. 100 of the operations. RESULTS. In this series the duration of survival varied between 2 and 144 months (mean 26 months, median close to 15 months), with a 20 p. 100 probability of survival at 5 years (fig. 1). Disease free survival varied from 0 to 144 months (mean 22.5 months, median 10.5 months) (fig. 2, curve 1). The parameters of response as regards patients, primary tumour, metastases and treatment were analysed. Response was uninfluenced by sex and slightly influenced by age, with a difference of borderline significance between subjects under and over 50. The primary tumour characteristics did not affect survival, and the features of metastases were of extremely varied importance. The number of operable metastases was not determinant. On the other hand, the presence of mediastinal lesions, either isolated or associated with lung lesions, worsened the prognosis of terms of survival and much more significantly so in terms of remission (fig. 3 and 4). The evaluation of evolutive characteristics, such as date of appearance and tumour doubling time, was inconclusive. Survival was of the same duration after wide and limited surgery, so that tumorectomy or segmentectomy should preferably be performed. The results of surgical treatment were determinant, with a highly significant difference in survival between radical and incomplete surgery (fig. 5 and fig. 2, curve 2). DISCUSSION. The median survival of patients operated upon for lung metastases is diversely evaluated in the literature as 8 to 29 months (table V), the mean figure of 16 months being virtually the same as that of our series. In this, as in most of the previously published series, the maximum duration of survival was beyond 8 to 10 years. The mean survival rate at 5 years is very close to the one we have recorded (20 p. 100) (table V). Compared with other treatments of lung metastases, surgery may be considered as capable of prolonging survival by 6 months; this is not much unless we add the possibility of a 5-year survival in 1 out of 5 operated patients and the possibility of a survival exceeding 8 or 10 years in 2 to 5 p. 100 of the cases. Some prognostic factors seem to constitute positive or negative criteria of operability. This is the case with mediastinal lesions which may consist of a metastasis of metastasis or of a lymph node invasion associated or not with the lung lesion, but in any case correspond to the involvement of more than one site. Mediastinal lesions must be systematically looked for and treated as contraindications of surgery, as shown by the differences in survival recorded in our series. Opinions differ as regards the value of evolutive parameters of the metastasis. For some authors, a more than 5 years interval before the metastasis appears is associated with a good chance of prolonged survival, whereas a less than 6 months or 1 year interval reflects a steadily high progressiveness and in practice precludes surgery. The value of the

Adult↗

Final report of the French multicenter phase II study of the nitrosourea fotemustine in 153 evaluable patients with disseminated malignant melanoma including patients with cerebral metastases.

One hundred sixty-nine patients with histologic evidence of disseminated malignant melanoma, including patients with cerebral metastases, were entered into a Phase II study of the nitrosourea fotemustine. The treatment regimen consisted of a 100 mg/m2 1 hour IV infusion every week for 3 consecutive weeks, followed by a 4- to 5-week rest period (induction therapy). In responding or stabilized patients, maintenance therapy consisted of 100 mg/m2 every 3 weeks until the disease progressed. One hundred fifty-three patients were evaluable for response. Three complete responses and 34 partial responses were observed (according to the World Health Organization criteria), leading to an objective response rate of 24.2% (95% confidence interval: 17.4% to 31.0%). Responses were also documented on cerebral (25.0%), visceral (19.2%), or nonvisceral (31.8%) metastatic sites. The median duration of response was 22 weeks (range, 7 to 80 weeks). The objective response rate in previously untreated patients was 30.7% (19 of 62 patients). The main toxicity was hematologic with delayed and reversible leukopenia and/or thrombopenia. The objective response rate observed (especially in untreated patients), the activity on cerebral metastases, and the small amount of extra-hematologic toxicity encountered suggest that fotemustine is an effective drug in disseminated malignant melanoma.

Adult↗

Treatment of advanced squamous cell carcinoma of the skin with cisplatin, 5-fluorouracil, and bleomycin.

The authors treated 14 patients with advanced squamous cell carcinoma (SCC) of the skin or lip with one to four cycles of combination chemotherapy consisting of cisplatin by bolus injection, and 5-fluorouracil (5-FU) and bleomycin by continuous 5-day infusion. Objective responses were seen in 11 of the 13 evaluable patients (84%). Four patients had a complete remission (30%) and seven patients, a partial remission (54%). Local control after definitive complementary radiation and/or surgical treatment was achieved in seven patients. Toxic side effects was acceptable; they consisted of nausea and vomiting in all patients, transient skin changes, hematologic (Grade 3/4) abnormalities in four patients, and pulmonary fibrosis in one elderly patient. These results show that this chemotherapy combination could play a role in reducing the tumor mass and in facilitating definitive treatment to obtain better functional and cosmetic results in advanced SCC of the skin.

Adult↗

Chemotherapy by fotemustine in cerebral metastases of disseminated malignant melanoma.

A total of 42 patients with cerebral metastases of malignant melanoma were included in this study of the nitrosourea fotemustine. The treatment plan consisted of a l-h i.v. infusion of 100 mg/m2 fotemustine every week for 3-4 weeks, followed by a 4- to 5-week rest period. Responding or stabilised patients then received 100 mg/m2 fotemustine every 3 weeks. Among the 39 evaluable patients, 2 complete responses and 9 partial responses were documented, leading to an overall response rate of 28.2%. Most of the responses were obtained in previously untreated patients and/or those presenting with a single cerebral metastasis. Toxicity was mild and mainly hematological, especially in patients previously treated by polychemotherapeutic regimen. Our study confirms the activity of fotemustine in cerebral metastases of disseminated malignant melanoma.

Adult↗

Combination chemotherapy of dacarbazine and fotemustine in disseminated malignant melanoma. Experience of the French Study Group.

A total of 70 patients presenting with a disseminated malignant melanoma were entered into a multicentric study of combination chemotherapy using dacarbazine and fotemustine. In all, 63 patients were evaluable, 31.8% of whom had previously received cytotoxic chemotherapy. The protocol consisted of induction treatment with a weekly infusion of 100 mg/m2 fotemustine on days 1 and 8 and a daily infusion of 250 mg/m2 dacarbazine on days 15/18 followed by a 4- to 5-week rest period. Responding and stabilized patients were given maintenance treatment comprising fotemustine (100 mg/m2, day 1) and dacarbazine (250 mg/m2, days 2/5) every 3 weeks. The response rate was 33.3% (9 complete responses (CRs) and 12 partial responses (PRs)) and was outstanding among pretreated patients (34.9%). Responses were also documented in cerebral (28.6%), visceral (23.1%) and nonvisceral (43.3%) metastatic sites. Toxicity was mainly hematologic (22.2%, grade III/IV leukopenia; 20.3%, grade III/IV thrombocytopenia) and was acceptable. These results are encouraging in terms of the antitumor activity against nonvisceral metastases (43.3%) and the percentage of CRs obtained (23.3%), and they confirm the activity of fotemustine in cerebral metastatic sites.

Adult↗