Search

Sixty-six patients with bronchus non resectable squamous cell carcinoma (stage III and 14) entered into a protocol of chemotherapy depending upon their initial immunological status. These patients with (+) skin tests to recall antigens were allocated to a chemotherapy programme; patients with initially (-) skin tests were submitted to a protocol of immunorestauration with B.C.G. After three weeks of B.C.G. applications on scarifications 17 patients out of 31 presented with (+) skin tests and were considered as immunocompetent patients. All the patients then were submitted to chemotherapy protocol. The comparison of different median of survival have demonstrated that immune status appears as the more fundamental prognosis factor; the B.C.G. is able to transitory restore the immunity of the patients without any modification of the tumour progress. The median of survival of patients with initially (+) skin tests was ten months, and only two months for patients with (-) skin tests. The median of survival of patients whom immunity was restored with B.C.G. was nine months. The results of this trial let us to propose new strategy for treatment of these patients.

One thousand and twenty four patients with disseminated breast cancer were submitted to combination chemotherapy. Fifty one patients (group I) were sequentially given VCR, CPM and 5 FU, and seventy three patients (group II) were given ADM, VCR, CPM and 5 FU. The general and haematological tolerance was good and comparable in the both groups of patients: we observed only two severe infectious complications. Bonemarrow hypoplasia, six myocardial ischemia (two of them were lethal) in each group of patients, without any predominance in the group of patients treated with adriamycin. The percentage of objective regression in both groups was respectively: 72% and 71%. The mean duration of response was eight months. The median survival time was 420 days for patients of group I; for patients of group II the median is not obtained at 480 days. This study confirms that responders to chemotherapy significantly increase the mean duration of survival time. However, in this group of responders the presence of the liver metastases is worse prognosis than all other visceral metastases.

Out of 64 patients with non resectable epidermal bronchus carcinoma, 26 patients had before any treatment positive responses of skin tests to recall antigens. In these patients we found a correlation between the reactivity of the skin tests, the presence of seric factor inhibiting the leucocyte migration, the mean count of peripheral lymphocytes and the response to combination chemotherapy protocol. The patients who respond to treatment have a significantly better prognosis than the patients who do not respond. With this correlation it seems to be possible to distinguish between two populations of patients with non resectable bronchus carcinoma : one population with a good risk who can be significantly improved by the treatment : the other population with a very severe prognosis.

Traditional treatments have proved to be of little effect on inflammatory carcinomas of the breast. The later show a tendency to early metastases and the mean survival is less than 19 months. The preliminary results of the therapeutic protocol reported here and whose originality lies in the primary use of non-specific immunotherapy and of high-dosage chemotherapy appear to be very favourable. The protocol was used in 9 patients. "Thermographic cooling" was taken as the criterion of operability. Initial chemotherapy was restarted after surgery up to a total of 10 courses, and followed by maintenance chemotherapy for one year. Immunotherapy using BCG was routinely associated with the antimitotic agents. After 41 months, the results were as follows: -- local recurrence after tumorectomy in 2 patients (18th and 31st months); these recurrences were controlled by cobalt. -- the other 7 patients show no sign of recurrence. These 9 patients are presently in complete remission.

16 patients suffering from primary bronchial tumours which had recurred after surgery and/or radiotherapy and with spread involving at least one visceral or lymphatic metastasis received chemotherapy consisting of the administration of vincristine followed by a combination of CCNU and 5-fluorouracil. Each cycle of treatment lasted 6 days and was restarted only after an interval of 30 days on average, this being necessary for haematological recovery. With the doses of CCNU used, thrombocytopaenia occurred only during the fifth cycle of treatment and made it necessary to increase the interval between subsequent courses to five weeks. All of the patients included in the study have now been followed up for between six and eighteen months. Two patients are presently in complete remission without apparent radiological, clinical or bronchoscopic signs. In seven other patients there was tumour regression greater than 50 p.cent persisting for four to six months. In seven, the therapeutic effect was transient or nil.

New methods helpful in the classification of lymphoid and monocytoid leukaemias and haematosarcomas have recently become available. Among the most valuable procedures have been those detecting immunological markers and the ultrastructural analysis permitted by convention and scanning electron microscopy. The results of these studies, taken together with a meticulous morphologic examination on Giemsa smears allow a more subtle classification on these neoplasias. Among the most interesting points, one can list: a) The observation that all the prognostic parameters in the four types of common acute lymphoid leukaemia (ALL) (prolymphocytic, microlymphoblastic, macrolymphoblastic, prolymphoblastic) such as age, tumour mass (or leucocytosis) are related to the cytological type; T marker may be found in all these types, except in the prolymphoblastic; b) T or B acute lymphoid immunoblastic leukaemias has been described as a fifth type of ALL; c) The lymphosarcomas which can be histologically nodular (composed of B cells) or diffuse (composed of cells presenting B, T or no markers) can be cytologically prolymphocytic or lymphoblastic (or lymphoblastoid) if they are nodular, prolymphocytic, lymphoblastic or immunoblastic if they are diffuse; true (African) Burkitt's lymphosarcomas (BLS) must be distinguished from all the pseudo (non-African) Burkitt's lymphosarcomas which have been described elsewhere and which are either immunoblastic or lymphoblastic (oid) lymphosarcomas with a few macrophages. d) The diagnosis of reticulosarcoma which was in the past abusively carried out (because of confusion with immunoblastic lymphosarcoma) is based on the presence of many reticulins fibers at histological examination and on the cytological aspect of the cells on smears (the distinction of those cells with immunoblasts is easy).

New methods helpful in the classification of lymphoid and monocytoid leukaemias and haematosarcomas have recently become available. Among the most valuable procedures have been those detecting immunological markers and the ultrastructural analysis permitted by convention and scanning electron microscopy. The results of these studies, taken together with a meticulous morphologic examination on Giemsa smears allow a more subtle classification on these neoplasias. Among the most interesting points, one can list: a) The description of macroglobulinemic proplasmocytic leukaemia; b) The observation that all the prognostic parameters in the four types of common acute lymphoid leukaemia (ALL) (prolymphocytic, microlymphocytic, macrolymphocytic, prolymphoblastic) such as age, tumour mass (or leucocytosis are related to the cytological type); T marker may be found in all these types, except for the prolymphoblastic one; c) T or B immunoblastic acute lymphoid leukaemias have been described as a fifth type of ALL; d) The lymphosarcomas which can be histologically nodular (composed of B cells) or diffuse (composed of cells presenting B, T or no markers) can be cytologically prolymphocytic or lymphoblastic (or lymphoblastoid) if they are nodular, prolymphocytic, lymphoblastic, or immunoblastic if they are diffuse; true (African) Burkitt's lymphosarcomas (BLS) must be distinguished from all the pseudo (non-African) Burkitt's lymphosarcomas which have been described elsewhere and which are either immunoblastic or lymphoblastic (oid) lymphosarcomas with a few macrophages; e) The diagnosis of reticulosarcoma which was in the past abusively carried out (because of confusion with immunoblastic lymphosarcoma) is based on the presence of many reticluins fibers at histological examination and on the cytological aspect of the cells on smears (the distinction of those cells with immunoblasts is easy).

Forty-three patients with inoperable and/or recurring malignant gliomas, and 30 patients with multiple recurring brain metastases were treated with a combination of adriamycine (45 mg/m2) and 4-dimethyl-epipodophyllotoxin D-thenylidene (VM 26) (60 mg/m2 for 2 days) with 1-(2-chloroethyl) -3-cyclohexyl-1-nitroso-urea (CCNU) (60 mg/m2 for two days). These cycles of treatment were repeated as soon as the hematological restoration was complete. The treatment was well tolerated and the clinical condition of 31 out of 43 glioblastoma patients improved during the two months after the beginning of the treatment. Six out of eight patients with breast cancer metastases, one out of 13 with bronchial cancer metastases and three out of nine with other types of cancer metastases also benefitted from the treatment. Examination of the results obtained reveals the following characteristics: -A low degree of efficiency of the combination in the treatment of brain metastases, except for breast cancer metastases. -Absence of complete correlation between the clinical results observed and the cinegammagraphic developments. -Similarity of the results independent of the initial localization. -Establishment of a six-months median survival period, with ten patients at present in a state of apparently complete remission, 180 to 506 days after beginning of the treatment.

Sequential administration of VM 26 and CCNU has been used in France for the treatment of glioblastoma since 1973. Results have shown that this association can cause a remission lasting, on average, from seven to eight months after starting chemotherapy. It seems that, adding Adriamycin to this sequential therapy does not increase its efficiency. On the other side, dosage and the interval between cycles of chemotherapy appear to be a determining factor in the activity, but the limits are very narrow. Therapy is either ineffective or has doubtful efficiency in about one third of patients, and even when prolonged clinical remission is obtained, cessation of therapy, usually due to a persistent thrombopenia is followed by progression of the tumour in the following months. The large amount of research being made in the field of cellular kinetics and pharcacology will, hopefully, lead to improvement in results.

This work presents the results obtained on 24 patients with disseminated lymphosarcoma and reticulosarcoma (stage III and IV) with a cyclic combination chemotherapy which combines adriamycin, epipodophyllotoxin (VM 26), cyclophosphamide and prednisone. The complete remission rate is 58 p.cent of the patients who entered the trial, the response rate is 75 p.cent. Tolerance of the regimen is good in general from the hematological point of view.

17 patients suffering from primary tumours of the central nervous system recurring after surgery and/or radiotherapy, received chemotherapy consisting of the administration of VM 26 followed by CCNU. Each cycle of treatment lasted four days and was restarted only after an average interval of 30 days to allow for haematological recovery. All of the patients in the trial have been under treatment for eight months. Five (28 p.cent) are at present in complete remission with no residual clinical, isotopic or radiological signs. In six others there was tumour regression and in four neurological stabilisation. In all those cases where objective tumour regression was obtained functional improvement was noted.

42 patients suffering from terminal leukaemic lymphosarcoma were treated as acute lymphoid leukaemia patients. 26 entered apparently complete remission (CR). They were submitted to complementary cell reducing treatment comprising systemic and intrathecal chemotherapy and radiotherapy on the CNS and on the lymphosarcomatous masses that had been detected at the beginning of leukaemic conversion. Eight relapsed during this treatment and 18 were still in CR at the end of it: nine were submitted to active immunotherapy (BCG + C. granulosum + irradiated allogeneic leukaemic lymphosarcoma cells): five out of the nine have remained free of disease for between 13 to 66 months. Nine served as controls: all except two, who are still at the beginning of the trial, have already died from leukaemic manifestations.

The authors report a ten year study of active immunotherapy using BCG and irradiated allogeneic leukaemic cells in 200 patients. In acute lymphatic leukaemia, 57 out of 168 patients treated in this way remained in primary remission for 18 months to 10 years after active immunotherapy was begun, the relapse rate became low after 18 months and nil after 36 months. The results varied according to prognostic factors: the cytological type, active immunotherapy being above all effective in small cell (microlymphoblastic and prolymphocytic) types with a hope of cure in 50 to 60 p.cent of cases; malignant cellular volume; meningeal deposits. In microlymphoblastic forms the possibility of survival at the 5th year is greater than 90 p.cent. After relapse during active immunotherapy sensitivity to chemotherapy does not seem to be diminished. Trials of active immunotherapy in acute myeloid leukaemia are worthy of further pursuit. The results of active immunotherapy in leukaemic lymphosarcoma show that immunotherapy may be effective in preventing local recurrence, both of tumour as well as in the marrow. Four patients are in apparently complete remission for more than four years. On the basis of these results, trials of active immunotherapy for "residual disease" should be undertaken in the field of cancerology, going beyond the realm of leukaemias.

We have studied 20 cases of haematosarcomas belonging to lymphosarcomas (T or B-cell markers, absence of the reticulosarcoma characters in sections, on smears, with conventional and scanning electron microscopy). Their cells which appear as large pyroninophilic cells on sections, as large very basophilic cells with blastic nuclei and often cytoplasmic vacuoles on smears, as having many polyribosomes and usually no ergastoplasm with conventional electron microscopy, and as large cells of the lymphocytic series with scanning electron microscopy resemble the cells which we described in adenitis in 1955 (9) and in the graft-versus-host-reaction in 1961 (6), which Gowans (15) showed resulted from lymphocyte transformation, and which Dameshek (10) called immunoblasts. Many of these cases of immunoblastic lymphosarcoma (ILS) identified on their cytohistological characteristics [also recognized by Lukes et al. (24, 25) and Lennert et al. (21, 22)], present aetiological, clinical and pronostic characters which let us suppose that it may be not only a cytological entity but also a cytoclinical entity : a) it affects males in 85% or the subjects; eight patients came from mediterranean countries outside France; two patients had a history of chronic rheumatoid manifestations; b) the disease was at stage IV at the first presentation in 10 patients out of 20; it was revealed by profound (mediastinal or abdominal) localizations in 60% of cases (12 out of 20); it presented a hypoglobulinaemia in eight out of 13 patients; in six out of the 15 patients treated before leukaemic conversion, the chemotherapy usually efficient in lymphosarcoma (LS) failed to induce remission. This type of LS has a poorer prognosis than other types of LS (median for all stages : eight months). It led to the death either after its conversion to leukaemia (nine out of 20 cases), or by vital organ (as brain or kidney) infiltrations.

27 patients suffering from disseminated carcinoma of the breast with at least two visceral metastases, and two had become resistant to conventional chemotherpy and hormones, received a combination of, in the present trial, vincristine followed by cyclophosphamide with 5-fluoro-uracil. Chemotherapy was administered intermittently: each cycle of treatment lasted 6 days and was followed by a period without treatment of 25 days. Haematological tolerance was satisfactory. No serious incidents occurred during two years use of the combination. 20 out of 27 patients showed objective tumour regression of more than 50 p.cent lasting for more than 6 months, whilst 9 showed apparent complete regression of the malignant lesions. There was one complete failure. Chemotherapy was continued in all cases after regression of the neoplastic process was obtained.

18 acute myeloid leukemia patients were submitted to a Phase II active immunotherapy trial. The median duration of complete remission (CRD) (60 weeks) and of survival after remission (SAR) (104 weeks) were longer than those for our historical control groups. However, the CRD and SAR curves were not broken to form a "cure expectancy" plateau, as was the case for acute lymphoid leukemia.

The i.v. administration of living BCG to (DBA/2 X C57Bl/6) Fl mice pushd quickly the quiescent stem cells of bone marrow into S phase of the cell cycle. This treatment can be used to shorten the intervals of hemopoietic restoration after administration of combination cytotoxic chemotherapy.

Thirty nine patients with non resectable colonic carcinoma entered into a phase II combination chemotherapy trial. The patients were treated with a sequential cyclic combination of 3 drugs: VM 26 (60 mg/m2), methyl-C.C.N.U. (120 mg/m2) and 5 fluoro-uracile. Seventeen patients out of 39 (43.6%) are considered as good responders. The median survival time of the overall of this group is 12.6 months; it is of 15,6 months for good responders and of 7 months for non responders. The simultaneous application of B.C.G. do not change neither the level of responses nor the median of survival time. The good tolerance of this protocol let us to propose this combination as an adjuvant treatment for patients surgically treated for a Dukes'C colonic cancer.