M. Weil

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.

Chemotherapy by fotemustine in cerebral metastases of disseminated malignant melanoma.

SummaryA 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 1-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.

Non-Hodgkin's lymphoma occurring after hodgkin's disease four new cases and a review of the literature

This article describes four cases of non‐Hodgkins lymphomas occurring after successful treatment of Hodgkins disease (HD). The clinical symptoms consisted of digestive disorders, and the histology confirmed an intestinal involvement in these four patients. In all cases patients had diffuse large cell types (intermediate or high grade). The respective role of HD treatment (combination chemotherapy in 3 of 4 patients with irradiation in 3 of 4 patients) and of other pathogenic hypotheses, are discussed.

Fotemustine, dacarbazine, vindesine combination chemotherapy in advanced malignant melanoma: a phase II study of 43 patients.

Fotemustine and dacarbazine constitute the most active single chemotherapeutic agents in the treatment of melanoma. In this phase II study we evaluated the activity and toxicity of a combination of fotemustine, dacarbazine and vindesine as a means of increasing response rate and survival time. Between September 1989 and November 1993, 43 patients with advanced melanoma were treated with a combination of 100 mg/m2 fotemustine on days 1 and 8, 250 mg/m2 dacarbazine on days 15 and 16 and 2 mg/m2 vindesine on days 15 and 16 as induction treatment. After a 5-week rest period, the patients exhibiting a response or stable disease received the same drugs administered once every 28 days as maintenance therapy until either progression or toxicity was observed. Among 41 evaluable patients, there were six complete responses and eight partial responses. The overall response rate was 32% (95% confidence interval: 18–46%), with 8 months median duration of response. Median survival time was 10 months. This regimen was well tolerated. From this large phase II study, we conclude that such a combination is active against advanced malignant melanoma and seems to be more effective than fotemustine or dacarbazine used alone, especially on visceral metastatic sites.

Fotemustine (S 10036) in the intra-arterial treatment of liver metastasis from malignant melanoma : a phase II study

Fotemustine is a new nitrosourea which has shown some efficacy on disseminated malignant melanoma (DMM) (24.2% response rate (RR) among 153 patients in a Phase II trial) but little activity on hepatic metastasis (8.8% RR). In order to improve those poor results, hepatic intra-arterial infusion (HlAI) of fotemustine was performed. After two years, thirteen patients, all in good general condition, were evaluable. Seven were pretreated and six had extrahepatic metastasis on entry into the study. All patients had a surgically implanted intra-arterial catheter. The induction cycle consisted of 100 mg/m2/week for 3–4 weeks, followed by 5 weeks rest and maintenance therapy of 100 mg/m2 every 3 weeks for stabilized or responding patients. Two complete responses (CR) (72+ and 145+ weeks) and six partial responses (PR) (7–18.5 weeks) were observed. The hepatic RR reached 61.5%. A RR of 42.8% was registered on preexisting EHM (one CR and one PR on cerebral lesions). Nevertheless, this treatment is limited by the high progression rate of 46.1% in extrahepatic disease. Toxicity was mainly hematologic (grade III-IV), comprising 36% neutropenia and 15% thrombopenia. Hepatic intra-arterial infusion of fotemustine is efficient therapy for liver metastases of DMM, but combination schedules (IV + HIA) are warranted.

A phase II study of tamoxifen combined with cisplatin-interleukin 2 and alpha-interferon in metastatic melanoma

Tamoxifen (JAM) has been reported to enhance cisplatin (CDDP) cytotoxicity in experimental and clinical melanoma studies. Based on our previous experience with sequential cisplatin-interleukin-2 (IL2)-interferon (IFN), we performed a phase II study of TAM combined with our original CDDPIL2-IFN regimen in 22 pretreated metastatic melanoma patients. With a 41 % response rate (95% C1, 21 −61) we confirmed the interesting antitumor activity of CDDP-IL2-IFN combination; however, TAM enhanced neither the response rate nor the duration of response, but appeared to induce significantly more myelotoxicity, as compared to our previous results with CDDP-IL2-IFN alone. Whereas mechanisms by which TAM may modulate CDDP cytotoxicity in melanoma tumors remain unknown, the exact place of TAM, if any, and its safety in chemotherapeutic or chemoimmunotherapeutic combinations require further investigations.

Phase I study of Datelliptium chloride, hydrochloride given by 24-h continuous intravenous infusion

SummaryDatelliptium chloride, hydrochloride (SR 95 156B, NSC 626718X, DHE) was studied in a phase I trial of escalating doses given on a single 24-h continuous intravenous infusion schedule. Doses were escalated from 40 to 500 mg/m2 in 19 patients who received a total of 24 courses. Courses were repeated after a minimal interval of 3 weeks. Local venous toxicity occurred at low doses (≤100 mg/m2) and was circumvented by the use of a central venous access for higher doses. Other clinical adverse events occurred (≥330 mg/m2), including moderate nausea and vomiting, mild diarrhea, dry mouth, neuropsychiatric manifestations, and fatigue. All of these side effects were reversible and none was dose-limiting. The dose-limiting toxicity was related to hepatic laboratory-test abnormalities in the form of reversible elevations of levels of serum bilirubin and liver enzymes at doses of ≥330 mg/m2. The maximum tolerated dose for this schedule is 500 mg/m2. Hematologic toxicity was minimal and non-dose-limiting. Neither drug-related deaths nor objective complete or partial responses were observed. However, a minor response and a long-term disease stabilization were obtained.

Features and prognosis of chemotherapy-treated Hodgkin's disease with initial bone marrow involvement

SummaryThe features and prognosis of Hodgkins disease with bone marrow involvement were studied in a series of 53 patients. This form of the disease is characterized by the high incidence of clinical and biological signs reflecting disease activity, common cytopenia (which is rare in other forms), an increased incidence of the lymphocyte depletion histologic type, and extensive lymphoid involvement, often with splenomegaly. In bone marrow biopsy specimens, Sternberg-Reed cells are found in 80% of cases and fibrosis is common, though it always disappears if remission is achieved.Chemotherapy, essentially with the MOPP combination, produced an 82% remission rate with 44% complete remission (CR). Hematologic toxicity was relatively severe in patients with marrow fibrosis. Recurrence occurred in 14 of the 39 remissions and was either localized and successfully treated by complementary radiotherapy, or diffuse and beyond any form of therapy. In nine cases, the first sign of recurrence was observed in the lymph node group initially most affected. Among the 18 patients treated by reinduction chemotherapy, four recurrences were observed. However, there was only one recurrence among the 12 patients who achieved CR and none among those who had received complementary radiotherapy. The long-term prognosis is similar to that of other visceral forms, and if CR is achieved the chance of maintaining the remission is 83% after the first year, with a follow-up exceeding 6 years.

Virtual cystoscopy of the urinary tract

Today it is recommended that all patients with the suspicion of bladder, either because of an episode of hematuria or a previous bladder papilloma, be examined endoscopically. Conventional cystoscopy remains the mainstay for diagnosis, management and follow-up of urothelial tumors, and repeated surveillance cystoscopy examinations are requisites to assess disease control. Particularly in man, this clinical cystoscopy has its own drawbacks, including patient discomfort and relatively high cost. Generally, conventional cystoscopy is planned under general anesthesia, with antibiotic therapy and an overnight hospital stay. In order to avoid these requirements, a less invasive and costly method may be represented by virtual endoscopy or 3D CT endoscopy. 3D CT endoscopy is a new term used to describe computersimulated endoscopy procedures derived from thin section-CT of gas-filled or contrast enhanced hollow viscus of the human body, and has been widely applied to the paranasal sinuses, the upper respiratory tract, the tracheobronchial tree, the gastric and the colonic tubes, the vascular structures and more recently to the urinary tract and especially the bladder, in which carcinoma must be conceived as a focal expression of epithelial abnormalities that may be quite diffuse.

Present Results on Daunorubicine (Rubidomycin, Daunomycin)

We have treated 1299 patients with Daunorubicine between 1966 and 1969 (Table 1). Among those patients 785 were treated at the Hopital Saint Louis with our personal protocols, 514 were treated according to protocols of ALGB. I am glad to have this opportinuty to thank Dr. J. F. Holland for his chairmanship and for his friendship.