Interim report of phase II study of new nitrosourea S 10036 in disseminated malignant melanoma.

Thirty-three patients with disseminated malignant melanoma were entered in a phase II study of the new nitrosourea S 10036 using a 100-mg/m2 weekly induction schedule for 3-4 consecutive weeks. Patients who responded to this treatment were followed with a maintenance therapy every 3 weeks. Toxic effects were mainly hematological and consisted of delayed thrombocytopenia and leukopenia. Among 30 patients who could be evaluated, eight partial responses were observed (response rate, 26.67%); among seven patients with cerebral metastasis, two partial responses were observed. This multicentric study is currently being continued to confirm this interim report.

Phase I clinical study of the new amino acid-linked nitrosourea, S 10036, administered on a weekly schedule.

Diethyl-1-[3-(2-chloroethyl)-3-nitrosoureido]ethylphosphonate (S 10036) is a new nitrosourea that has been evaluated in a clinical trial because of its activity in the National Cancer Institute panel screen and its rational chemical approach. A Phase I study was conducted in 22 evaluable patients with advanced cancers. The drug was given as a slow i.v. infusion over a period of 60 min on days 1, 8, 15, and 22 followed by a 4-week rest period. The dose levels ranged from 25 to 200 mg/m2/week for 4 consecutive weeks using a modified Fibonacci scheme. Thrombocytopenia was the only acute dose-limiting toxicity and started at a dose of 100 mg/m2/week and above. Hematological toxicity was delayed, cumulative, and dose related. Nausea and vomiting were moderate to severe and dose related. Three responses (one complete and two partials) have been noted. Phase II studies of S 10036 are planned at a dose of 100 mg/m2/week for 4 consecutive weeks ("induction therapy") for patients without prior therapy and 100 mg/m2/week for 3 consecutive weeks for those with prior chemotherapy or radiotherapy. Because of the cumulative toxicity, the recommended dose for the second cycle of S 10036 chemotherapy ("maintenance therapy") is 100 mg/m2/week every 3 weeks.

Soluble circulating Fc gamma receptors in human serum. A new ELISA assay for specific and quantitative detection.

We have developed a simple, rapid, and sensitive enzyme-linked immunoadsorbent assay (ELISA) to measure soluble cell-free human Fc gamma receptor (Fc gamma R) in serum. This assay is based on the use of two monoclonal antibodies directed against different epitopes expressed on the same low avidity human Fc gamma R (CD16), which is present on polymorphonuclear leukocytes, macrophages and NK cells. This sandwich ELISA, which can measure 2 nM concentration of Fc gamma R, has enabled us to demonstrate the presence and to measure the level of soluble cell-free human Fc gamma R (CfH-Fc gamma R) in normal human serum.

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

The features and prognosis of Hodgkin's 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.

Prognosis and treatment of acute lymphoblastic leukemia. Study of 650 patients.

The complete hematological remission (CHR) rate, duration of remission and survival were studied in relation to age, peripheral blast cell (PBC) count, presence or absence of tumor masses, cytological type, and treatment in 650 patients with acute lymphoblastic leukemia. Prognostic factors were considered separately and divided into prognostic classes. Age and PCB count correlated with both the rate and the duration of CHR. This correlation was still observed for more recent treatment schedules though it appears to be becoming progressively less significant. Meningeal relapses were more common in patients less than 1 year old and in those with a high PCB count. It is suggested that stratification of patients according to such factors as age, PCB count, presence or absence of tumor, and cytological type might be necessary for the design of new treatment protocols and for the evaluation of their results.

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.

Renal effects of S10036 in man.

The renal hemodynamic and tubular effects of S10036 (fotemustine) were evaluated in seven patients with advanced malignancy. Initial evaluation carried out prior to treatment and repeated 1 day after the first fotemustine infusion and 7 days after the second included clinical, haematological parameters, liver-function tests, and determination of the glomerular filtration rate, renal blood flow and enzymuria. The glomerular filtration rate was 108 +/- 3.7 ml/min before treatment and remained stable after the first (117 +/- 5 ml/min) and second (124 +/- 6 ml/min) fotemustine infusions. Renal blood flow and urinary beta 2-microglobulin and N'-acetylglucosaminidase excretion were also not modified by fotemustine administration. We conclude that fotemustine does not acutely alter renal haemodynamics, nor does it have direct tubular toxicity.

Clinical trials of chemotherapy and chemoimmunotherapy in primary malignant melanoma.

We report here two randomized prospective clinical trials of adjuvant treatment in the management of primary malignant melanoma of Clark's level III, IV or V. All patients had curative resection of the primary tumor. In the first trial, 117 patients were randomized between control (surgery alone) systemic chemotherapy and intraarterial chemotherapy. Intraarterial chemotherapy consisted of DTIC 80 mg/m2 + 8 days prior to surgery. Systemic chemotherapy consisted of courses of vinblastine (6 mg/m2), thiotepa (6 mg/m2), rufocromycine (60 microgram/m2), methotrexate (15 mg/m2) on day 1, and procarbazine (30 mg/m12 X 7 days. Courses were repeated every 2 weeks X 6, then every 4 weeks X 15. Twenty-two of 55 patients relapsed in the control group versus 22 of 67 in the chemotherapy group (NS). For male patients, the difference in disease-free survival was significant (P less than 0.005, log rank test), though not in women. In the second trial, 352 patients were entered from July, 1976. Men were randomized between chemotherapy and chemoimmunotherapy. Women were randomized between surgery alone and chemoimmunotherapy. Chemotherapy was identical, except for the addition of DTIC (300 mg/m2) for each course. Immunotherapy consisted of BCG every 4 weeks and C. parvum every week. Immunotherapy seemed to be of no additional benefit.

Long-term cost of combined radiotherapy and chemotherapy.

Complications after treatment of Hodgkin's disease are a good model to evaluate the long-term cost of combined chemo- and radiotherapy. Secondary malignancies and mainly acute myelocytic leukemias are the main complications. The 35 of 1,889 cases reported represent increased risk by factor 129. Often preceded by a leukemic phase, they are of poor prognosis. Solid tumors are increased by factor 2.8. They may occur in patients treated by prolonged chemotherapy with alkylating agent without radiotherapy. In seven of 31 patients, solid tumors appeared in the irradiated area. Sterility in young males was present during the first year, though some recuperation was observed thereafter. Better adjustment of treatment to individual risk, to drug sensitivity, and active combinations devoid of alkylating agents are required to reduce the rate of these complications.

Poor-prognosis acute lymphoblastic leukemias.

Burkitt's-type leukemias have specific cytologic, immunologic, and cytogenetic characteristics. Initial symptomatology frequently includes abdominal tumors and initial CNS involvement. Despite intensive treatment including high-dose cyclophosphamide, prognosis remains poor in most patients because of failures to achieve complete remission (CR) or because of early relapses, especially CNS relapses. Class III acute lymphoblastic leukemia in children is defined by the presence of two or more unfavorable parameters and recent progress has been achieved by intensive therapy. Cox's multifactorial analysis allows improved discrimination. A phase I protocol for increased-risk leukemias, including testis preventive irradiation and monthly reinductions without continuous maintenance for the first 6 months of CR, seems promising.

Experimental and clinical activity of a new anthracycline derivative: detorubicin (14-diethoxyacetoxydaunorubicin).

This report concerns the experimental activity and the preliminary clinical results obtained with detorubicin, an anthracycline. Experimentally, in comparison with doxorubicin, detorubicin is less toxic, less immunodepressive, and less mutagenic, its experimental antitumor activity is equal or superior, and differences are found in pharmacokinetics. Its most interesting activities in clinical cancer therapy are found in non-Hodgkin lymphomas, in carcinomas, and in soft-tissue sarcomas.

[Protocols for the chemotherapy of solid tumors: should we increase or reduce?]. / Protocoles de chimiothérapie des tumeurs solides: faut-il escalader ou réduire?

Contrary to the treatment of leukemia and lymphoma which is clearly defined, for most solid tumors the place, the type and the intensity of treatments remain under discussion. Experimental results are available to prove the benefit of various drug combinations in which doses, routes of treatment, schedule and number of cycles are carefully evaluated. However considering the difficulties in testing all the combinations which are possible and the lack of trust in the predictive value of experimental studies, it is generally according to clinical results that escalation or reduction of chemotherapy are decided, At the present time and for many solid tumors, escalation is predominating due to the low effectiveness of the current drugs we have at our disposal. It is only in the case of curable solid tumors (for example: carcinoma of the testis, choriocarcinoma) that a reduction phase is possible and this behaviour is justified in avoiding the iatrogenic effects of chemotherapy. Many examples of escalation and reduction are given in clinical cancer chemotherapy.

Short-term results of the combination of cis-platinum, 5-fluorouracil and bleomycin in advanced upper aerodigestive tract cancers.

Randomized trials comparing radiotherapy alone with combined radio- and chemotherapy are reviewed. Some 184 patients with advanced upper aerodigestive tract cancers were treated between November 1982 and December 1983 before any loco-regional treatment by three courses of the combination of cis-platinum, 5-fluorouracil and bleomycin, given every three weeks. At the end of three courses 88% of patients (162/184) were evaluable. Among these 162 patients, 102 achieved complete macroscopic remission or over 50% regression. Oropharyngeal cancers were most responsive, whereas results were less satisfactory for oral cancers. Histological sterilization was observed in 30% of patients with complete macroscopic regression. Toxicity was moderate. It is too early to appreciate the the survival benefit.

Neoadjuvant chemotherapy of breast cancer.

About 80% of patients with breast cancer ultimately die of metastatic disease at 20 years. Distant metastases are more important as a cause of death than local or regional relapses. It is for this reason that adjuvant chemotherapy is necessary, especially in young patients and those with extensive disease. Initial chemotherapy preceding any local or regional treatment is justified on the grounds that both surgery and anaesthesia lead to immunodepression. Further, the value of initial chemotherapy has been demonstrated in many experimental and clinical trials by Nissen-Meyer, Bonadonna and Cooper (1-3). In the present study 145 patients, including 67 with inflammatory breast cancer (IBC), were treated with 4-6 weeks of Velbe, thiotepa, methotrexate, fluorouracil and prednisone, with Adriblastin added for patients with IBC, T greater than 7 cm, or N2, N3. Because of tumour regression of greater than 50% observed in 80% of the patients, the majority (123 patients) then received radiotherapy alone (cobalt + iridium), resulting in complete remission in all these cases. Maintenance treatment with the same drugs was prescribed for 6-18 months depending on the initial stage. Tumour regression appears to be an important prognostic factor. Median follow-up is only 17 months, the longest being 42 months. Overall survival at 2 years for IBC is 90%, with a disease-free survival of 80%. Cosmetic results are excellent. While these results are encouraging, longer follow-up is needed to confirm this improvement.

[LAK cells and immunotherapy of cancer]. / Cellules LAK et immunothérapie des cancers.

Cancer immunotherapy still appears very unsatisfactory in humans. However, it has been shown recently that Interleukin 2 (IL2) could be used to generate, in vitro as well as in vivo, a new anti-tumoral activity directed against fresh tumor cells, allogenic as well as autologous, both of leukemic and solid tumor origin. This activity is not connected with the NK activity, but with a lymphocyte sub-population termed 'Lymphokine Activated Killer (LAK) Cells'. The exact nature of these LAK cell precursors is still a matter of controversy: 'nul' lymphocyte, T or NK markers bearing lymphocytes, or different precursors according to the system of activation that has been used. However, after being activation, these LAK cells always express T cell-markers. The activation has a very short lifespan, explaining the need for a prolonged contact of the cells with IL2, and therefore the necessity to continue injecting the lymphokine in vivo. The clinical results that have been reported so far are still very preliminary. The most common treatment protocol consists of 5 days of IL2 injections followed by 5 days of leukapheresis and in vitro activation of the collected cells, and then auto-transfusion of the activated cells and IL2 during the next 5 days. The clinical toxicity encountered is impressive in terms of frequency as well as severity. Clinical activity seems to be relatively weak. Nevertheless, the concept still appears to be very promising.

[Fetal risk of cancer chemotherapy (author's transl)]. / Les risques foeto-embryonnaires des chimiothérapies.

The risks of embryonic, fetal, gondal damage of cancer chemotherapy are reviewed. Contrasting with the numerous malformations seen in laboratory animals, the teratogenic risk is low in man. Methotrexate is really dangerous during the first trimester of pregnancy. In malignant haematological diseases and solid tumours, the prognosis of the disease is the essential target but the use of immuno-suppressive drugs in non-malignant diseases is hazardous before 40 years of age. All the investigations show that alkylating agents injure the gonads. Young women should be avised to use contraceptives. The future of children born after administration of anti cancer drugs is uncertain. Sterility, carcinogenic risk, mutation, teratogenetic effects in future generations cannot be ruled out.

[Acute leukemias and solid tumors in the course of Hodgkin disease]. / Leucémies aiguës et tumeurs solides dans l'évolution de la maladie de Hodgkin.

In a retrospective study of 1 094 patients treated for Hodgkin's disease between 1963 and 1976, we have observed 65 malignant complications including 28 granulosis acute leukemias and 37 solid tumors. The actuarial 10 year risk of developing acute leukemia is 4.7 per cent; and 5.4 per cent for solid tumors. These figures vary according to the medications received. They are more important in the case of polychemotherapy, particularly for acute leukemia, thus confirming the specific role of alkyl agents. While the course of solid tumors does not seem to differ from that of identical primitive tumors; on the other hand, induced leukemia seems to have a more perjorative prognosis than spontaneous leukemia and they are often announced by cytopenia. The overall risk of developing secondary cancer is multiplied by 2.4 compared to the normal population; that of developing acute leukemia is multiplied by 9.3. In order to reduce this risk, active non alkyl agents of limited duration must be advocated. Irradiation fields must also be reduced.

[Combined chemotherapy and radiation therapy in breast cancer: a retrospective study of 406 patients (author's transl)]. / Traitement combiné de radiothérapie et de chimiothérapie dans le cancer du sein. A propos de 406 observations.

This analysis includes 406 patients who entered a controlled and stratified study of adjuvant chemotherapy after total mastectomy preceded (177 pts) or followed (229 pts) by breast radiotherapy. Negative lymph node (NO) patients (stage I or II) were randomized between no treatment or alkeran (600 mg/m2 x 5 days every 6 weeks). Out of 92 patients 2 relapses in each arm were observed. Relapse free survival at 4 years is 91%. For patients with one to three positive lymph nodes, there is not difference between alkeran and the combination of Vinblastine, Thiotepa, Methotrexate and 5 Fu (VTMF). Relapse free survival at 4 years is 78% for alkeran and 70% for VTMF. For patients with more than 3 positive lymph nodes there is no difference between cyclophosphamide, Methotrexate, 5 Fu (CMF) and CMF VP (Vincristine and Prednisone). We observe no difference between menopausal and other patients. Among the 49 relapses, 5 were local recurrences. The sites of distant metastasis were bone (24 pts), liver (10 pts), lung (9 pts). Advantage of adjuvant chemotherapy is not proved for NO patients. In the other categories, the optimal strategy of chemotherapy with or without hormonotherapy is still to be established.

[Multiple chemotherapy (MOPP) followed by either focal or selective radiotherapy in clinical stages IA and II2A of Hodgkin's disease: results after four years of the use of prospective schedule (H 7701) in 79 patients (author's transl)]. / La séquence polychimiothérapie MOPP-radiothérapie sélective ou focale dans la maladie de Hodgkin, stades cliniques IA, II2A: résultats à 4 ans d'un protocole prospectif (H 7701) incluant 79 patients.

Seventy-nine patients with clinical stages IA, or II2A of Hodgkin's disease were treated from January 1977 to April 1980 by a multiple therapy schedule, H 7701. Three courses of MOPP chemotherapy were first given to all patients. They were then randomly allocated to two groups: group 7701 S (38 patients) was treated by mantle irradiation, excluding the mediastinum when this was not initially involved, or inverted Y radiotherapy; group 7701 F (41 patients) was treated by focal irradiation only. After follow-up for 9-48 months (median: 26 months), overall survival was 98,6 p. cent and relapse-free duration 94,9 p cent. No statistical difference exists between the two randomized groups. Four patients relapsed; three are now free of disease after further treatment, while one patient has since died. With this chemotherapy-radiotherapy selective of focal sequence, staging laparotomy is not indicated. Results and side effects of this treatment schedule are compared with those of other treatment strategies.

[Fotemustine: a pilot phase II trial in sarcoma of the soft tissues]. / Fotémustine: essai pilote de phase II dans l'indication sarcomes des parties molles.

Fotemustine has been administered to 10 patients with metastatic or redux soft sarcoma in a phase II pilot study. The main inclusion criteria were: at least one measurable site, Karnofsky index (KI) higher than 60%, no specific treatment within the last 4 weeks, correct haematological status. Induction treatment comprised fotemustine 100 mg/m2 D1-D8-D15 in a 1 h intravenous infusion protected from light, followed by a 5-week rest period. In patients with no progressive disease, maintenance treatment comprised fotemustine 100 mg/m2 D1 q 3 weeks, until progression or toxicity. Patients characteristics were: 9 M/1 F; median age: 51 years [26-66]; median KI 90% [60-100]; median number of previous drugs: 5 [2-8]; 6 patients had two or more metastatic sites and one patient had developed a sarcoma following chest radiotherapy. Evaluation was carried out in weeks 4 and 8, following the first fotemustine injection. One case of minor response and one case of stabilisation were observed, but they were of short duration. The main toxicity was haematological with delayed leucopenia and thrombopenia (nadir: week 6). In patients who have undergone previous chemotherapy, fotemustine is not efficient according to the first step of the Gehan statistical guidelines.