The roles of adoptive and active forms of immunotherapy in the cure of children suffering from acute lymphoid leukemia: a) underestimation of active immunotherapy benefit, b) its immunogenetic indications to select sensitive patients, hence prevent chemotherapy's late effects.

Children's acute lymphoid leukemia (ALL) chemotherapy started in 1948 with antimetabolites combined with steroids. It was enriched in 1959 with vincristine and cyclophosphamide and, in 1970, with daunomycin. It induced more and more apparently what were called complete remissions, and prolonged more and more the survivals without reducing however, until 1973, the (100%) mortality. It started to reduce it at the fifth year, to 20 and even 40% between 1973 and 1976, due to progressive and maximal intensification and duration of chemotherapy. It is in the same period that we proposed to apply in ALL remissions after relapses and in the first remissions of the most malignant type, allogeneic bone marrow grafts; we published the first success in human ALL in 1963, and clinically observed the same actions as those described experimentally: cytoablation of both leukemia and hematopoiesis, the latter being restored by the graft, whose reaction versus the residual neoplastic cells (called graft versus leukemia or GvL) appeared to be able to often eradicate them, at the cost however of a graft-versus-host reaction (both reactions sharing the same mechanism). One of us became a member of the Committee of the International Bone Marrow Transplant Registry, whose results showed the improvement in the prognosis of the aggressive form of ALL. The intensity and length established for chemotherapy for the most severe form of children's ALL have often been applied to the intermediary and to the least aggressive ones. The global 5-year survival increased to 60% between 1976 and 1984, and is around 80% today. But the registration of late debilitating or malignant effects of chemotherapy toxicities makes us wonder if some patients have not received an excessively intense and long application of cytostatics (often combined with ionizing radiations on CNS). In fact, the patients belonging to some HLA phenotypes (A33 and B17) have appeared to be especially often cured with active immunotherapy (killed leukemic cells and/or BCG), whose action was shown by specific cytotoxicity amplification, which was applied after short adjuvant chemotherapy, and hence is able to reduce the long chemotherapy incidence of debilitating or malignant late effects. Sakurai's group confirmed our absence of late relapses after ALL active immunotherapy, which contrasts with their risk after maintenance chemotherapy, whose minimal residual disease is a worrisome stumbling block to the cure.

Screening of human bladder carcinomas for the presence of Ha-ras codon 12 mutation.

Contradictory results were obtained from previous studies aiming at defining the frequency of Ha-ras codon 12 mutations in bladder tumors. Differences in the sensitivities of the methods used could account for this discrepancy. In this study, we reevaluated the frequency of Ha-ras codon 12 mutations in a series of 87 human bladder tumors using a combination of two different methods. The first was derived from the protocol of Ooi et al and consisted in a one-step allele-specific polymerase chain reaction using mismatched primers in two separate PCR. This method is very rapid and highly sensitive, detecting the presence of minor populations (less than 10%) of mutant alleles. The second strategy consisted in screening all tumors using natural restriction fragment length polymorphism (RFLP) analysis. The two methods were in complete concordance and enabled us to show that only one out of 87 primary bladder carcinomas (1%) exhibited the mutation, in accordance with previous studies. These results strongly suggest that, even if minor cell populations overexpress codon 12 Ha-ras mutation, the analysis of this mutation cannot be used to screen potentially invasive transitional cell tumors of the bladder.

Treatment of high-risk gestational trophoblastic disease with chemotherapy combinations containing cisplatin and etoposide.

The authors have treated 22 patients with high-risk gestational trophoblastic disease (GTD) by cisplatin-etoposide-containing combinations. Sixteen patients were treated with dactinomycin, platinum, and etoposide combination (APE regimen) and six patients had platinum and etoposide combination (PE regimen). Fourteen patients were treated for resistant or relapsing GTD after first-line therapy, and eight patients initially. All 22 patients were high risk according to the World Health Organization prognostic score values. Sustained complete remission was achieved in 19 patients (86%). All eight patients who received treatment as initial therapy were cured (100%) whereas only 11 patients were cured among the 14 patients who failed prior chemotherapy (78%). Hematologic and renal toxicities were limited and no treatment-related deaths occurred in this group of patients. Cisplatin and etoposide could be more widely used in chemotherapeutic combinations for high-risk gestational trophoblastic disease.

Cisplatin, vinblastine, and bleomycin combination in the treatment of resistant high-risk gestational trophoblastic tumors.

Eight patients with high-risk gestational trophoblastic tumors (GTT) resistant to multiagent chemotherapy were treated with the combination of cisplatin, vinblastine, and bleomycin (PVB). All patients had a metastatic disease including three patients with two metastatic sites and two patients with brain metastases. Four patients achieved complete remission (CR) with the PVB regimen (50%). Three additional patients had partial remission (PR) of whom two were converted into CR by surgery of resistant residual lesions. One patient relapsed and the remaining five patients in CR were cured (62%). A multimodal approach was necessary in most patients as five of them had hysterectomy and two patients had a whole-brain irradiation. Toxicity was mild with no treatment related deaths.

Prognostic factors in gestational trophoblastic tumors. A multivariate analysis.

One hundred sixty-two gestational trophoblastic tumors (GTT) were treated at the Institute Gustave-Roussy, Villejuif, France, from 1975 to 1985. Sustained complete remission (CR) was obtained in 146 patients (90%). All 97 patients with no histologic diagnosis of choriocarcinoma were cured, including 19 patients considered at high risk initially. Among 65 histologic chariocarcinoma patients, 16 died (CR, 75.5%) including seven initially nonmetastatic patients. Using a univariate analysis, all factors tested in the whole group of patients were more or less significant except for age and parity. However, when the same variables were tested in patients considered at high risk initially, only three factors were statistically significant. Those three factors were the only ones associated with a statistically significant higher relative death risk (RR) on multivariate analysis and are as follows: an antecedent nonmolar pregnancy (RR = 4.3; P less than 0.01); initial presentation with more than one metastatic organ (RR = 7.4; P less than 0.01); and primary resistance to single agent (RR = 18.8; P less than 0.0001) or multi-agent chemotherapy (RR = 26.1; P less than 0.0001). It seems that those three factors, together with a histologic diagnosis of choriocarcinoma, are the prognostic factors that discriminate patients with unfavorable outcomes among the high-risk group.

Twelve-year experience with chemotherapy in adult metastatic renal cell carcinoma at the Institut Gustave-Roussy.

One hundred fifty-three adult patients with metastatic renal carcinoma were treated over a 12-year period. Five successive chemotherapeutic protocols were used: vincristine or teniposide plus CCNU, elliptinium weekly or monthly, ifosfamide, and lastly, a multidrug regimen with adriamycin, vindesine, cyclophosphamide, cisplatinum, and dacarbazine. Results obtained with these different consecutive protocols were very disappointing with only ten (7%) objective responses encountered.

Phase II trial with high-dose elliptinium acetate in metastatic renal cell carcinoma.

Sixteen patients with adult metastatic renal cell carcinoma were treated with elliptinium acetate, 80 mg/m2.day, for 3 consecutive days every 3 weeks. Among the 14 patients evaluable, no objective effects were observed. The toxicity was mild and no patients experienced intravascular hemolysis.

[Initial chemotherapy in the treatment of inflammatory breast cancers. 230 cases]. / Chimiothérapie première dans le traitement des cancers du sein inflammatoires. 230 observations.

The results of 2 chemotherapeutic regimens used in 170 cases of inflammatory breast cancer were compared with those obtained in 60 historical controls treated with radiotherapy and hormonal therapy. Inflammatory breast cancers could be divided into evolutive phase 2 with limited signs of inflammation and evolutive phase 3 where inflammation involved the whole breast. The 60 controls had been treated between 1967 and 1974 with radiotherapy (45 Gy plus an extra dose of 20 or 30 Gy); premenopausal patients underwent ovarian irradiation. The 91 patients treated with regimen A between 1976 and 1980 received a DVM-type induction chemotherapy (doxorubicin 40 mg/m2 on day 1, vincristin 1 mg/m2 on day 2, and methotrexate 6 mg/m2 on days 3, 4, 5) every 3 or 4 weeks, and a VCF-type maintenance chemotherapy (vincristin 1 mg/m2 on day 1, cyclophosphamide 200 mg/m2 on days 2, 3, 4 and 5-fluorouracil 300 mg/m2 on days 2, 3, 4) every 4 weeks. Premenopausal patients had their ovaries irradiated; postmenopausal patients received tamoxifen. The therapeutic sequence was: 3 DVM - 45 Gy - DVM - 15 Gy - 4 DVM - 4-12 VCF. The 79 patients treated between 1980 and 1982 with regimen B received a DVCMF-type induction therapy (doxorubicin 50 mg/m2 on day 1, vincristin 0.6 mg/m2 on day 2, 5-fluorouracil 300 mg/m2 on days 3, 4, 5, cyclophosphamide 200 mg/m2 on days 3, 4, 5 and methotrexate 10 mg/m2 on days 3, 4, 5) every 4 weeks. Hormonal therapy was the same as with regimen A. The sequence was 3 DVCMF - 45 Gy - DVM - 20-25 Gy - 4 DVM - 4-12 VCF. The survival rate at 3 years was 42% in controls, 53% in regimen A patients and 74% in regimen B patients (P less than 0.05). The relapse-free survival rates in these three groups at 3 years were 15%, 32% and 54% respectively (P less than 0.0008). These results suggest that a multidisciplinary approach and initial chemotherapy are useful in this type of breast cancer. The value of prolonged maintenance treatment is discussed.

[Non-Hodgkin's malignant lymphomas of the nasopharynx. Apropos of 24 cases treated at the Institut Gustave-Roussy]. / Les lymphomes malins non hodgkiniens du cavum. A propos de 24 cas traités à l'Institut Gustave-Roussy.

Twenty-four patients with non Hodgkin's lymphoma of nasopharynx were treated in the Institut Gustave-Roussy, France, between 1976 and 1983. Mean age of patients was 53 years and the male/female sex ratio was 2. Symptomatology was immediately suggestive of a lesion in the nasopharynx in 21 of the 24 patients, and histology gave an unfavorable prognosis (diffuse large cell tumors) in 71% of cases. Complete investigations showed the lymphoma to be relatively limited in extent in the majority of cases (68% of stages I and II). These findings are in agreement with published reports. The 4 patient with stage I disease were treated by irradiation alone and are all alive without recurrence after 43 months. The 11 patients with stage II lesions received combined chemo-radiotherapy, and at 42-month follow up 8 were alive without recurrence (1 patient died of intercurrent illness). Results of conventional chemotherapy (CHVmP) in patients with stages III and IV were disappointing, however: only one patient survived for 60 months (after a cerebral recurrence treated by irradiation). Although current therapy is effective for stage I and II lesions, patients with stages III and IV require more aggressive therapy recently developed: heavy multiple chemotherapy, and even intensive chemotherapy-total body irradiation and bone marrow graft.

Preliminary phase I clinical study and pharmacokinetics of (1,2-diaminocyclohexane) (isocitrato) platinum (II) or PHIC.

PHIC [NSC-350602; (1,2-diaminocyclohexane) (isocitrato) platinum (II)] is a new highly water-soluble platinum derivative. Preclinical studies showed antitumor activity on a wide range of tumors, no cross-resistance with cisplatin and little or no nephrotoxicity in mice and baboons. A phase I clinical trial was then initiated at doses of 300 mg/m2 infused intravenously over one hour without induced diuresis or hydration. Dosages were escalated up to 1500 mg/m2. A total of 29 patients received 52 courses of treatment. The most important side-effect is thrombocytopenia which is rapidly reversible. Nausea and/or vomiting were mild or moderate with onset 1 hr after the end of the infusion and seldom persisted beyond 24 hrs. Measurements of biological parameters did not reveal significant evidence of nephrotoxicity except in one patient who developed urinary tract infection and for whom hemodialysis became necessary. No change in the audiogram could be demonstrated. Peripheral neuropathy was documented in one patient, and in two other patients to whom morphine was given confusional episodes were observed. Although no antitumor effect was observed, there was apparent stabilization of disease. Pharmacokinetic parameters were calculated in twelve out of these 29 patients. Based upon total platinum plasma concentrations, the elimination half-life is 58.3 hrs and the plasma clearance is 21.2 ml/min with an apparent volume of distribution of 7.6 liters. However, considering both plasma concentrations and urinary excretion, we could estimate the half-life of free filterable species (60 min), the plasma clearance (125 ml/min) and the renal clearance (86 ml/min). Mean urinary excretion is 64.4% of the dose after 6 days and 53.1% at 24 hrs. Other administration protocols are suggested, based upon these pharmacokinetic parameters.

[Isolated hepatic metastases. Treatment by intra-arterial chemotherapy using a subcutaneous access chamber]. / Métastases hépatiques isolées. Traitement par chimiothérapie intra-artérielle par l'intermédiaire d'une chambre d'accès sous-cutanée.

Twenty eight patients with isolated liver metastases of colorectal origin have been treated with discontinuous intra-arterial chemotherapy. This treatment was performed weekly with a surgically implanted subcutaneous access chamber. In all the patients the metastases were non-resectable and involved less than 75% of the liver. The first six patients were investigated in a phase I study which demonstrated that the method was well tolerated and provided a normal life at a lower price than the totally implanted pump. A subsequent phase II study included 22 patients. After implantation, they received an 8-hour infusion of 5 Fu 1 g/m2 each day for 8 consecutive days and after discharge, a weekly 8-hour infusion of 5 Fu 1 g/m2 and mitomycin C 1.5 mg/m2 as out-patients. Twenty-one patients have now been followed up for more than 3 months and are assessable in terms of response: we observed 4/21 complete responses, 6/21 partial responses, 3/21 minor responses, 7/21 stable disease and 1/21 progression. The objective response rate was 48%. The complication rate was low (2 leukopenias and 2 duodenal ulcerations) and comfort excellent with normal life between courses. In conclusion, with discontinuous intra-arterial chemotherapy we obtained the same response rate as with the totally implanted pump, with good tolerance and quality of life and perhaps a lower rate of complication. The two methods should now be compared in a randomized trial.

The contribution of clinical trials to the treatment of patients with early stages of Hodgkin's disease.

An analysis of the results that have been obtained in several recent controlled clinical trials showed that the inclusion of combination chemotherapy in the initial treatment of Hodgkin's disease significantly improved relapse-free survival but did not improve survival. This is due to the high efficacy of salvage chemotherapy. Paradoxically, the advent of powerful combination chemotherapy makes initial treatment by radiotherapy alone possible in a large proportion of patients with early stages of Hodgkin's disease. Prognostic factors have been identified by a multivariate analysis of the results obtained in the three controlled clinical trials carried out by the EORTC. These factors can help to delineate the subsets of patients who can be treated initially by radiotherapy alone with an acceptable relapse rate and to adjust the size of the radiation fields. The two prominent prognostic factors are: a combination of systemic symptoms and erythrocyte sedimentation rate the number of lymphatic areas involved.

Phase II trial of elliptinium in advanced renal cell carcinoma.

Forty patients with advanced renal cell carcinoma were treated with elliptinium by a weekly infusion of 100 mg/m2. Of 38 evaluable patients, five had an objective response (13.2%). Average response duration was 8 months (range, 5-11). The major dose-limiting toxic effect was induction of antielliptinium antibodies, with the risk of intravascular hemolysis. Elliptinium has modest activity in advanced renal cell cancer and does not produce myelosuppression.

Phase II study of elliptinium in advanced breast cancer.

A group of 74 patients with advanced breast cancer received elliptinium as second- or third-line treatment (100 mg/m2/week). The objective response rate was 19% (30% in soft tissue metastases), lasting from 3 to 12 months. This drug appears to have no marrow toxicity. Mild to moderate nausea and mouth dryness were the most frequently encountered side effects. Hemolysis occurred in five patients who had an IgM antibody and represents the dose-limiting toxicity. Cumulative renal toxicity (World Health Organization, grade 2) was observed in one of ten patients who had received greater than 2000 mg of elliptinium.

A phase I clinical tolerance study of polyadenylic-polyuridylic acid in cancer patients.

Polyadenylic-polyuridylic acid [poly(A) X poly(U)], an immunomodulator, has been shown to have antitumor effects in rodents and in a randomized clinical trial as an adjuvant to surgery in patients with operable breast cancer. The purpose of the present study was to determine the following: (a) clinical tolerance and safety of poly(A) X poly(U) in 13 patients with advanced cancer receiving a single dose of this duplex, using increasing amounts per intravenous injection of 90, 180, 300, and 450 mg; (b) if such high doses increased the level of interferon-mediated protein kinase and enhanced natural killer (NK) cell activity as observed previously with lower doses; and (c) if circulating interferon could be detected. No toxicity was observed in the 13 patients by close observation of clinical parameters, hemogram, and renal and liver functions. Increases of interferon-mediated protein kinase and of NK cell activity were observed, but there was no correlation between the magnitude of the responses and the dose of poly(A) X poly(U). No circulating interferon was detected. We conclude that poly(A) X poly(U) is not toxic in humans, at least up to a dose of 450 mg.

[Treatment of hepatic metastases with unknown primary cancer]. / Traitement des métastases hépatiques sans cancer primitif connu.

A series of 15 cases of hepatic metastases of unknown etiology is reported. All patients had a needle biopsy of the liver. The search for primary tumor was restricted to only those tumors requiring specific therapeutic protocols. Patients received intravenous chemotherapy in accordance with histopathological classification. This chemotherapy induced objective improvement in 46 percent of cases. The average survival of responding patients is about 16 months. Three patients had complete remissions and underwent a second laparotomy with excision of necrotic lesions in one case and installation of a catheter for endarterial hepatic chemotherapy in another. The investigators propose a diagnostic and therapeutic protocol for such patients.

An alternating chemotherapy and radiotherapy combination for non-Hodgkin's lymphomas of unfavourable histologies: feasibility and preliminary results.

In 1980, on the basis of fundamental and clinical data, a protocol was developed at the Institut Gustave-Roussy, alternating eight monthly courses of chemotherapy (CHVP) and two or three radiotherapy sequences (15 Gy in 6 fractions of 10 days, each), to treat non-Hodgkin's lymphomas of unfavourable histologies, mainly stage II, presenting bulky tumours. Systemic, haematological and digestive tolerances were satisfactory. For 19 previously untreated stage II patients, overall survival and relapse-free survival after 30 months were 85 and 65%, respectively. Three of the relapses were observed in patients who did not receive the alternating schedule in an optimal way; this suggests that these results can be further improved.

[Cancers of the bladder: new therapeutic orientations]. / Les cancers de la vessie: nouvelles orientations thérapeutiques.

Based on data obtained from a general review of treatment of infiltrating cancer of bladder, new therapeutic orientations are proposed in which chemotherapy occupies a privileged position as adjuvant treatment of surgical excision. Emphasis is placed on the frequency of bladder cancer and invasive tumors, as well as the high incidence of unsuccessful results due not to local recurrence but to metastases that do not respond to local and regional radiosurgical treatment. Objective results are obtained in approximately 50% of measurable metastases after combined Adriamycin and Cisplatin treatment. The efficacy of this chemotherapy suggests its prophylactic use to eradicate microscopic metastatic lesions remaining after local and regional therapy. If indications are well chosen, and not too heavy chemotherapy administered, then it is probable that as complementary treatment to surgical excision should improve efficacy of treatment of infiltrating cancer of bladder. The observation of necrosis of pulmonary metastases during chemotherapy provides justification for therapeutic orientation of this type.