The authors report protocols and results observed with various palliative chemotherapy, used successively against epidermoid carcinomas of head and neck area. This study was followed up during the last ten years by a group of physicians working in 8 specialized oncological centers. The poor prognosis and efficiency of antimitotic drugs in head and neck carcinomas require analyse of a great number of patients files. The cooperative work of several teams allows for more rapidly significant results. Each protocol was closed after a two year period. The protocols were dropped one after another, in order to provide a greater efficiency and a lower toxicity. It was possible to confirm the limited efficiency of "heavy" protocols and the most useful association. The members of this group now pursue a randomised study comparing the results obtained with cis-platyl used alone or in addition to three other drugs. The aim of this study is to assess which is more efficient and less toxic.

Peripheral lymphocyte chromosomes were analyzed in 55 consecutive patients with complete remission after treatment for Hodgkin's disease. In 8 patients, observed metaphases were too few in number. The other 47 patients, 29 men and 18 women, had been off all therapy for 53 months (median 41, ext. 1 to 250 months). The mean interval since the diagnosis was 78 months (median: 73 months) and the mean age at the time of chromosome analysis was 38 years (median: 34, ext. 10-78 years). No patient had either a preleukemic syndrome or leukemia. In contrast to karyotypes in normal controls and previously untreated patients, abnormal cells, hypodiploid, hyperdiploid and tetradiploid cells were more frequent. But neither monosomy 5 or 7 nor trisomy 8 were observed. Intrachromosomal rearrangements (gaps, breaks...) were significantly more frequent (12% vs 5% in untreated patients) particularly on chromosomes 1 and 2. Interchromosomal rearrangements were also numerous (1,25%) but no cells showed any specific translocation for malignant hemopathy. Chromosomal aberrations do not seem closely associated with treatments but influenced by the post-diagnosis interval and the factors present at the time of primary treatment.

In past years, health authorities have exempted anti-neoplastic agents from undergoing carcinogenesis tests. However, in view of increasing knowledge of this therapeutic family and of patients' increased life expectancy, toxicologists are having to reconsider the problem from both ethical and scientific points of view. Analysis of data has established a correlation between mutagenic activity of these molecules, carcinogenic activity in the animal and carcinogenic activity in man. For this reason, studies in laboratory animals are of interest at the present time. Assessment of the carcinogenic activity of anti-neoplastic agents in animals must take into account the chemical structure of the drug. The experiments to be carried out are: either in vitro, short term tests aimed to detect genotoxic drugs by mutagenesis tests, or limited in vivo tests, in order to determine the promoting or initiating character of these drugs. However, the obtention of negative results with the latter tests does not exclude the necessity of long term tests. Whatever the results obtained during these experiments, the decision to stop or to continue the development of an anti-neoplastic agent does not belong exclusively to the toxicologist, who can assess the risk, but not the potential benefice.

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.

Sixty patients treated for Hodgkin's disease by radio + chemotherapy and remaining in complete remission with a median follow-up of 26 months answered a questionnaire dealing with their quality of life during and after treatment. Their main request was to be better informed about their disease, treatment and its side effects. Therapeutic toxicity is mainly due to chemotherapy and is digestive in nature (nausea and vomiting) symptoms. The majority of patients complained of disturbances in their personal and professional lives. It is concluded that more complete knowledge of all patients' disorders may help doctors to improve treatment planning in order that the patient's quality of life be less disturbed.

It is reported the first observation of cardiogenic shock without delay, in a leukemic patient during a first injection of Rubidazone (22050 RP) which is recognized so far, as one of the least cardiotoxic anthracyclines. It has been concluded: --anthracyclines, beside the risk of a progressive cardiomyopathy which is related to the dose and very well known, can induce immediate cardiac injuries, which cannot be predicted yet; --the perfect myocardial protector is still to be discovered; --in this case, beta-adrenergic stimulators appeared to be able to control the cardiotoxic effect of Rubidazone; --the last fact could be considered in the decision to maintain the treatment when such an injury occurs during a chemotherapy or when it seems absolutely necessary to use such a drug.

A 62 year old patient with CLL treated by alkylating drugs for more than three years, underwent acute leukaemia (AL). The clinical particularities of the onset and course of this AL, the cytological, cytoenzymological and ultrastructural characteristics of the blasts are discussed in order to find a relation between the two hemopathies. A possible drug-induced etiology of this AL is proposed.

Drugs induced respiratory disorders include bronchospasm, extrinsic alveolitis, and diffuse interstitial pulmonary fibrosis. Bronchospasm may be due to the action of pharmacodynamic agents on autonomic control of bronchial tone (beta-blockers, beta-agonists...) or to a hypersensitivity reaction (penicillins, sulfonamides, anti-inflammatory compounds...). Extrinsic alveolitis usually follows administration of anti-infective medication but other drugs may be implicated. Prolonged use of a wide variety of drugs, particularly cytotoxic agents, is necessary to provoke the onset of a diffuse interstitial pulmonary fibrosis.

Among the neurological side-effects, peripheral neuropathy is a result of therapy with vindesine and above all vincristine. Although in most cases it is responsible only for paresthesias, it may cause extensive paralysis and requires that the drug be discontinued. These drugs may also affect the neurovegetative system. Ototoxicity may be seen with cis-platinum and vigilance disturbances with L-asparaginase. Genetic consequences are mainly due to alkylating agents. These agents almost constantly impair male and female fertility but recovery is possible. Libido is also affected with the attendant psychological consequences. The offspring of patients previously treated by chemotherapeutic agents are normal. Development of secondary carcinoma or leukemia is currently a major concern. Secondary malignant disease may develop after the treatment of any cancer, especially if radiotherapy was associated with alkylating agents. Leukemias are of the acute myeloid type and usually follow a preleukemic phase. A table summarizes the main toxicities of the most usual drugs.

Administered to pregnant Mice of Swiss strain, at stages of 9 to 12 days of gestation and at doses of 15 to 50 mg/kg, 9-hydroxy-ellipticine acts as an acute teratogen; it induces in embryos, cleft palate and limb deformities. Histological examination of embryos from mothers treated by a dose of 30 mg/kg at day 10 or 11 revealed defects in the eyes, spinal cord and a reduction in the number of germinal cells.

Aplastic anemia is the most severe hematologic side-effect. All chemotherapeutic agents, with the exception of bleomycin and L-asparaginase, may induce aplasia, but the degree of hematotoxicity varies according to the drug. With the exception of acute leukemia in which drug-induced aplasia is part of the treatment, aplasia must be prevented through perfect knowledge of the posology and injection schedules for each drug, as well as by adjusting doses to the patient's hematological status. If aplasia develops, intensive hematological care is requisite. The most common cardiac side-effect is toxic cardiomyopathy caused by anthracyclines, which must be diagnosed early by EKG recordings before each injection and repeated ultrasonography or dynamic cardiac scintigraphy. The risk of toxic cardiomyopathy makes it requisite not to exceed the maximal doses set for each drug. Pulmonary side-effects include acute hypersensitivity pneumopathy and chronic diffuse interstitial fibrosis, the latter being more common and mainly caused by bleomycin. The risk of chronic fibrosis demands that patients be closely monitored and that the total dose be kept under 300 mg. Renal toxicity usually results in acute transient renal failure, as with cisplatinum, and requires a thorough biological study before each injection. Vesical hemorrhage, which is threatening in some instances, may occur with cyclophosphamide. VM26 and VP16 may induce anaphylactic shock. Allergic symptoms are possible with L-asparaginase and bleomycin.

Of 91 acute leukaemia patients treated with m-Amsa, 19 received intermittent doses, 23 received daily doses and 49 underwent courses with combined m-Amsa and cytosine arabinoside (Ara-C). Intermittent doses had minimal therapeutic activity and toxicity. Among the 23 patients given daily doses, complete remission was observed in 5/12 relapses of ALL and in 2/11 relapses of AML. When Ara-C (200 mg/m2 x 5 days) was administered concomitantly with m-Amsa (200 mg/m2 x 5 days or 120 mg/m2 x 7 days), 17 out of 37 patients with advanced relapses of ALL (13/25 children and 4/12 adults) went into complete remission. While high doses of m-Amsa alone were well tolerated, the combined treatment with high doses of both drugs resulted in severe gastro-intestinal toxicity. Cardiac disorders were observed in patients who had previously received high doses of anthracyclins; there were 5 cases of dysrhythmia and 1 case each of sudden death, ECG alterations and heart failure. In view of its indisputable activity, m-Amsa should be used at an earlier stage in the treatment of acute leukaemias.

The recent development of chemotherapy in the treatment of cancer and leukemia requires that all practitioners involved have a thorough knowledge of the sometimes life-threatening side-effects of chemotherapeutic agents. All these agents, whether used alone or in a combination, carry a risk because of their lack of specificity which make active on normal cells, especially those with a rapid turn-over such as the hematopoietic cells or the cells of the digestive tract. Prior to the prescription of a chemotherapeutic regimen, the acceptable risk must always be clearly defined, according to the seriousness of the disease and to the patient's age, physical condition and psychological status. During the course continuous monitoring adjusted to the specific toxicity of the agents used is requisite. More or less prominent asthenia and weight loss are common, as the result of various physiopathological mechanisms. Digestive disorders may consist only of nausea and emesis or include mucosal lesions with diarrhea as the main feature. Vincristine and vindesine are responsible for constipation. Hepatic toxicity, which is less common, is usually due to L-asparaginase. Transient hair loss is the most frequent cutaneous side-effect. Hyperpigmentation, photosensitivity, nail lesions, cellulitis and ulcerations may occur, as well as specific lesions with bleomycin. High fever during injection often occurs with this last agent.

The results of three phase II clinical trials with three new analogues belonging to the family of nitrosoureas are reported. One of the studied agents, chlorozotocine (CZT) is American, while the other two, RFCNU and RPCNU, are French. All three drugs have a sugar radical. CZT proved effective mainly in a few cases of leukemia and in one case of blastic transformation of chronic myelocytic leukemia. RFCNU was shown to be effective in 8% of digestive tumors, in 1 out of 7 pancreatic cancers and in 3 out of 10 hepatic and pulmonary metastases from an undiscovered primary adenocarcinoma. As for RPCNU, it's action resembles that of RFCNU: tumor regression lasting for over three years was obtained in a patient with hepatic metastases from a digestive carcinoma; in another patient a regression rate exceeding 50% was seen in pulmonary metastases from a rectal tumor. One of the significant results of our study is the apparent tissular specificity of responses according to the agent given: CZT is more often efficient on the lymphatic localizations of the studied tumors (4/5 responses); RFCNU and RPCNU often proved active on hepatic metastases (17% responses). Digestive tolerance was excellent with CZT and RFCNU and not quite as satisfactory for RPCNU. As predicted by our experimental study, platelet toxicity is both less common and less severe with RFCNU than with CZT and RPCNU.

The effect of antitumor drugs has been considered according to in vivo variations of the polyamine levels. The experimental model of cellular proliferation is not a tumoral process but a hepatic regeneration in partially hepatectomized normal rats. This study consists of the treatment of regenerating animals with antiproliferative, therefore antitumor natural drugs, such as colchicine, vincaleucoblastine, and 9-methoxy-ellipticine. Tissular free polyamines (putrescine, spermidine, spermine) in the livers of the animals are estimated. Important rate fluctuations are observed and are related, first, to regeneration time, thus to cellular cycle, and, second, to the presumed effect of these natural drugs. Such a study would, first show the antiproliferative activity of an unknown drug and, second, indicate its mechanism.

The antiemetic effect of alizapride was evaluated in 50 patients with advanced cancer undergoing chemotherapy with cis-platinum. Our results suggest that alizapride, in a dose of 800 or 900 mg, significantly alleviates nausea and emesis. In a preliminary study, we had established that, without antiemetic therapy, the same patients all suffered from emesis. On the whole, alizapride was well tolerated ; no major side-effects were recorded.