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Fourteen patients with stage III aggressive multiple myeloma were treated by high dose chemotherapy (carmustine, etoposide and melphalan) and total body irradiation. This procedure was followed by autografting using blood stem cells previously collected by leukapheresis performed during recovery of cytotoxic drug-induced bone marrow aplasia. One patient died from cerebral bleeding at day 40. All other patients, including 9 whose disease was refractory to conventional treatments, achieved an impressive tumor mass reduction (over 90% in 12 cases). Two patients relapsed and died 12 and 15 months after the graft; another one relapsed but is still alive at 24 months. Two to 23 months (median 12 months) after the autograft, 10 patients are well either in apparent complete remission (2 cases) or with a state of stable minimal residual disease. Autologous blood-derived hematopoietic stem cells induced successful and sustained engraftment in the 13 evaluable patients. The cells collected by leukapheresis were studied for clonal Ig genes rearrangements indicative of circulating tumoral cells (or clonal B precursors) and none were found. Although preliminary, these results appear promising and high dose chemotherapy followed by autologous blood stem cell graft deserves consideration in young patients with multiple myeloma.

Patients with stage I and II non-Hodgkin's lymphoma (NHL) are considered to have a relatively good prognosis. For this reason, they are seldom referred to specialized centers and the accrual of such patients in controlled studies is limited. Therefore, significant studies of homogeneously treated patients are difficult to collect and the management of these patients remains controversial. Some patients do very well after treatments with minimal toxicity while others require a much more aggressive approach. The Radiotherapy-Chemotherapy Group of the EORTC carried out its second controlled trial on patients with stage I and II NHL from 1975 to 1980. Its first aim was to assess the prognostic value of histologic classifications independently of treatment. The second aim was to compare two therapeutic options within each stage. In stage I, 124 patients were randomized to receive extended field radiotherapy (RT) either with or without adjuvant cyclophosphamide, vincristine prednisone (CVP) chemotherapy (CT). Relapse-free survival (RFS) was higher in patients who received adjuvant CVP but the total survival rates were not different. The RFS was lower in patients with diffuse than in those with follicular architectural histologies; in the former, RFS was not influenced by adjuvant CVP. Those patients who underwent a staging laparotomy had a higher 5-year total survival (TS) independent of the histologic type. Fifty-six stage II patients were included and extended field was randomized versus total nodal irradiation. Subsequently, adjuvant CVP was given to all patients. Results are good in follicular histologies but the advantage for total nodal irradiation is not significant. In diffuse histologies, results were unsatisfactory in both arms; a new therapeutic strategy was designed in which RT and CT are alternated and has been successfully tested in a pilot study.

Out of 134 patients irradiated below the diaphragm to a dose of 40 Gy for Hodgkin's disease at the Institut Gustave-Roussy, 19 (14%) were subsequently found to present with radiation injuries of the gastrointestinal tract. Since five patients presented with two different injuries, 24 radiolesions were observed. Most of them (17 out of 24) were gastric or duodenal. Twelve (out of 24) were ulcers. Nine patients required surgery. A complete cure of the radiation injuries was obtained in 15 out of 19 patients. Sex, age, stage, histology or initial chemotherapy were not found to play a role in the occurrence of radiation damage. On the contrary, the role of a previous exploratory laparotomy appeared important; for the patients who underwent laparotomy and irradiation, the complication rate was 23%. For the patients treated by irradiation alone, the complication rate was 7% (p less than 0.01). Fractionation was found to be another important parameter: for 52 patients treated using 3 weekly fractions of 3.3 Gy, the complication rate was 25%, compared to 8% (p less than 0.01) for 76 patients treated using 4 weekly fractions of 2.5 Gy. Combining these two factors, we found a 42% complication rate for the group of patients who underwent laparotomy and who were treated by means of 3 fractions of 3.3 Gy per week, whereas patients irradiated using 4 weekly fractions of 2.5 Gy, without any previous laparotomy, had only a 5% complication risk (p less than 0.001).

The few clinical studies which have utilized irradiation as a treatment modality for chronic lymphocytic leukaemia (CLL) during the last two decades have led to rather conflicting and sometimes disappointing results. Low-dose total body irradiation (TBI) and extracorporeal, or mediastinal, radiotherapy did not appear to be superior to chemotherapy in most trials. Only the fractionated low-dose (600-800 rad) splenic irradiation was found to induce a long-lasting decrease of the lymphocyte count and a decrease in bone marrow infiltration in a significant proportion of cases, without any noticeable haematological toxicity. But new data is recently emerging; stratification of CLL in various subgroups, better understanding of the role of the normal T-cell subsets, better knowledge of the interaction between irradiation and haematopoiesis, and of the radiosensitivity of the various lymphocyte subpopulations. Thus one can now reconsider the possible role radiotherapy, and particularly splenic irradiation, can play as an alternative treatment to chemotherapy for CLL. Haematological toxicity is still limiting the use of TBI. The spleen irradiation avoids this drawback. Recent data suggest that this splenic irradiation could be efficient by means of several mechanisms; the successive destruction, fraction after fraction, of the part of the malignant lymphocyte clone present in the spleen is likely to be the main therapeutic explanation, with the knowledge that the lower the differentiation of the malignant clone, the more efficacious the irradiation. But in parallel, the destruction of the large subset of T-suppressors which is constantly present in the spleen may account for the improvement of the peripheral blood count after splenic irradiation, and possibly for a direct effect towards the malignant clone. With respect to these new data, splenic irradiation clearly needs further clinical evaluation in the treatment of CLL.

From 1960 to 1984, 871 patients were treated for Hodgkin's disease at the Institut Gustave-Roussy. Twenty-six percent of the cohort were treated with radiotherapy (RT) alone, 6% with chemotherapy (CT) alone, and 68% with a combination of RT and CT, either at first line or for salvage treatment. MOPP chemotherapy was given to 42% of the patients. Overall, 19 secondary acute leukemias or preleukemias were observed, 3 of them after extended RT alone, the other 16 after a combination of RT and MOPP. Among the alkylating agents used, only nitrogen mustard (mechloretamine) was shown in a multivariate analysis to be significantly associated (P less than 0.001) with an increased risk of secondary leukemia. A dose response was observed, with the risk relative to general population incidence rates being 45 in patients having been treated with 1-59 mg (total dose) of nitrogen mustard, 211 in those treated with 60-119 mg, and 636 in those treated with greater than or equal to 120 mg. No other factors were found to be associated with leukemia risk. The 10-year cumulative incidence of leukemia was zero in patients treated with limited RT alone, 2.4% in those treated with extended RT alone, 0% in those treated with a combination of RT and CT without nitrogen mustard, and 12.4% in those treated with RT + nitrogen mustard. Whether other alkylating agents give a similar result remains to be determined; these data suggest that the use of nitrogen mustard at a higher total dose than 60 mg is questionable in the treatment of Hodgkin's disease.

One hundred patients with bone metastasis of various histological types have been submitted to a concentrated irradiation: 2 sessions of 850 rads or 650 rads over 3 days. Pain disappeared in 65% of the cases in a 3 to 7 days delay, for a mean duration of two months. The mean survival of this groups of patients is 4.3 months. The concentrated irradiation is well tolerated. Authors emphasize the value of this kind of treatment for patients with plurifocal metastasis and short survival.

Though the majority of procedures involved in curietherapy with Iridium 192 wires cause very few problems concerning radiation protection, this is not true in all cases: in elderly of debilitated patients, young children, or when using special techniques (curietherapy for prostate of bladder cancers for example). In these cases, the need for frequent treatments exposes the therapists to increased doses. The projector of Iridium 192 wires was conceived in order to reduce this irradiation hazard. A simple manipulation places the radioactive wires in a lead container during treatment, and then replaces them in the right position after therapy. This apparatus appears to offer the possibility of: an almost total protection of the therapists, and thus an opportunity for enlarging the indications for curietherapy; an improved quality of treatment to the patient during the application.

The interstitial techniques of hyperthermia allow one to obtain a precise specific absorption rate (S.A.R.) in a well-defined volume. We have available a low-frequency prototype amplifier, that is capable of heating up to 6 needles. This device was able to heat small volumes in animals, and then was used for patients. Five superficial tumoral nodules have been treated: the first results seem positive. The next step will be the combination of the techniques of interstitial hyperthermia with brachytherapy.

Sequential thoracic CT-scanning was performed for 14 patients presenting with residual mediastinal masses on chest X-ray after treatment of stage I and II Hodgkin's disease (HD). Eleven patients initially presented with bulky mediastinal involvement. No mediastinal biopsy was performed. No local recurrence was detected at a 48 month median follow-up. Early evaluation by CT-scanning showed cystic degeneration in three cases. Sequential CT-scans on longer follow-up demonstrated continuous regression of residual masses in six cases and no or limited volume reduction in six other cases. In two patients, part of the residual mass remained stable and the other part showed reduction in size. In addition, late calcifications developed in four cases. The results of sequential CT-scanning suggest that residual mediastinal masses do not generally represent active disease. Hence additional, potentially toxic, therapy can be avoided.

The results obtained with the various types of treatment in non-Hodgkin's lymphoma are reviewed and the data from the recent EORTC trials are summarized. In patients with Stage I follicular histology, regional radiotherapy (RT) alone gives excellent results. The long-term relapse-free survival (RFS) is high and relapsing patients can be rescued by aggressive combination chemotherapy; initial chemotherapy with CVP improves RFS but not total survival (TS). In patients with Stage I diffuse histology, the long-term survival is less satisfactory. CVP chemotherapy does not improve either RFS or TS; therefore if adjuvant chemotherapy is justified, it should be more aggressive than CVP. In patients with Stage II follicular type, regional radiotherapy alone gives good results. The addition of abdominal bath irradiation to regional RT increases RFS but not TS. After relapse, patients can be rescued by combination chemotherapy. In patients with Stage II diffuse histology, extended RT followed by CVP gives poor results and RT should be combined with more aggressive combination CT; the preliminary results of an integrated alternating regimen being excellent. In patients with Stage III and IV follicular type, the 8 year TS of patients treated with combination CT regimen (CHVP) followed by localized irradiation is approximately 55%, however the indications for the various types of treatment are still unclear. In patients with diffuse Stage III and IV, the results obtained with a combination CT regimen (CHVP) are still unsatisfactory, but are better in patients treated by a more aggressive CT regimen (CHVP-Bleo-VCR). Therefore aggressive CT associated with localized irradiation appears to be the best treatment. Further research should aim to identify the optimal combination CT regimen. In patients with high grade lymphomas who have relapsed the use of bone marrow autografts will be investigated. The present data show that besides histological type and age, the main prognostic factor is total tumor body burden as assessed by clinical stage, number of involved lymph node areas, and bulk of the disease. The study of the biological characteristics of the disease may provide more powerful prognostic indicators.

Intracranial localizations of Hodgkin's disease (HD) are uncommon. We report on 2 patients with HD who presented with an intracranial relapse. We discuss 1) the pathogenesis of those rare recurrences; 2) the therapeutic strategy.

The association of radiotherapy (RT) and chemotherapy (CT) constitutes one of the main avenues for research in therapeutic oncology. This association has two aims: (1) increase in control rate of primary tumor (this requires either the potentiation of one of the two modalities by the other or the additivity of their effect on tumor cells without a parallel increase in the toxic effects on critical normal tissues); (2) spatial cooperation (RT being used for the control of the primary tumor or of the sanctuaries, and CT for the control of the disseminated disease). In these two strategies, RT and CT should be given up to full doses in order to be effective. The main risk is an increase in the number and severity of the early and late side effects. To circumvent this problem, two possibilities are being explored: (1) use of drugs without serious toxic effects on those critical tissues which are included in the irradiated volume; and (2) avoidance of concomitant administration and introduction of a sufficiently long-time gap between the completion of one modality and initiation of the other. However, in such sequential treatment, a delay of CT until after the completion of RT, or an interruption of CT cycle during the course of RT, allows the occult metastases to increase in size; a similar delay in initiation of RT is also detrimental, as drugs are often not effective on bulky tumors. Moreover, under CT, the cells which are resistant to the cytotoxic drugs may disseminate and initiate chemoresistant metastases. Taking these disadvantages into account, a treatment protocol was proposed in 1980 in which CT and RT are given alternately, without undue delay. Chemotherapy is started with the usual scheduling of one cycle every month. Radiotherapy courses are interdigitated between CT cycles. Each course is initiated 1 week after interrupting CT and continued until 1 week before beginning the subsequent cycle of chemotherapy, and so on until completion of RT. Such split-course RT should have an effect on a tumor comparable to that of a conventional fractionation. This protocol has been used on 24 patients with non-Hodgkin's lymphoma (NHL) of diffuse histology, and 63 patients with small cell carcinoma of the lung. The 2-year relapse-free survivals are promising (in clinical stage II NHL of diffuse histology, 75%; and in small cell lung carcinomas, 33%).(ABSTRACT TRUNCATED AT 400 WORDS)

In order to study the possible advantages of thoracic CT scanning in the management of mediastinal lymphomas, a retrospective analysis of 16 patients was carried out. In this group, 21 thoracic CT scans were performed. For 10 patients (and 11 CT scans) we found a discrepancy between the results of "classical" radiology and those of CT scan, the latter giving more information about the precise status of the mediastinum. In 10 cases, we had to modify our treatment, either by adding chemotherapy or changing the radiation field size.

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.

Heavy particles have been used in transcutaneous radiotherapy for almost 50 years. If these particles and pi mesons remain the domain of highly specialized centers, neutron therapy and, to a lesser degree, proton therapy can be considered common clinical protocols; their limits, complications, efficacities and costs are sufficiently well known to encourage several centers to acquire the necessary equipment. Their practical advantages involve a limited number of patients however, for the patients implicated, the prognoses are appreciably improved by the application of these therapies. Hyperthermia-associated radiotherapy is limited by the poor technical capabilities of the currently available hyperthermia machines. If biological experimentation was highly promising, clinical results to date have been unfulfilling. Nonetheless, hyperthermia-associated interstitial radiotherapy represents an interesting clinical possibility. Radiosensitizers are being extensively developed. The results of randomized therapeutic trials are still contradictory and the toxicity of these products renders their use difficult. New products are being tested; their lower toxicity and potent radiosensitization capacity are encouraging for the future use of this class of compounds.

Vaginal mouldings were originally introduced as applicators for uterovaginal radium therapy. After 13 years of experience with this method in the Gustave-Roussy Institute we have found that it is also of great value for diagnostic purposes: it enables the site of the uterine cervical and vaginal lesions to be determined in a more precise manner; areas of invasion of the vagina can be detected which would normally not have been found, either because of the difficulty of performing previous investigations, or because of the extremely superficial nature of certain vaginal lesions: the extent of invasion and the subsequent therapeutic approach can then be radically modified; objective records can be kept in the form of photographs which can be compared with any future mouldings. The vaginal moulding can, in fact, be used as a diagnostic tool during supervision of the patients, when there is the least suspicion of an abnormal finding.

At the Institut Gustave-Roussy (IGR), from January 1982 to December 1986, 54 patients received total body irradiation (TBI) as a part of the conditioning regimen before allogeneic bone marrow transplantation. The patients were non-randomly assigned to either single dose TBI (STBI) (31 patients receiving 10 Gy at a 4.5 cGy/min dose rate, 8 Gy to the lungs) or to a hyperfractionated scheme (HTBI) (23 patients receiving 13.2 Gy in 11 fractions, 3 fractions per day, 9 Gy to the lungs). Relapse rate and overall survival were not significantly different in the two STBI and HTBI groups, in spite of a larger number of 2nd and 3rd remission patients in the HTBI subset. The incidence of interstitial pneumonitis (IP) was significantly reduced in the HTBI group (13%, versus 45% after STBI, p = 0.02). Lethality by IP was also lower after HTBI (4%, versus 26% after STBI, p = 0.08). There was no case of veno-occlusive disease of the liver in the HTBI group, whereas three cases were observed after STBI. Based on these results, the IGR activated, in January 1987, a randomized trial comparing the single dose 10 Gy TBI (8 Gy to the lung) to a new hyperfractionated schedule (11 fractions of 1.35 Gy, 3 fractions per day, 9 Gy to the lungs).

Radiosensitivity of lymphocytes is related to the population under study: for B lymphocytes it depends on their degree of differentiation and for each subset of T lymphocyte it depends on their state of activation. Precise knowledge of lymphocyte, radiosensitivity could have interesting therapeutic consequences in all malignant proliferation of B or T lymphocytes. The most typical example seems to be BCLL in which normalisation of lymphocyte subsets could be localized irradiation in volume (the spleen) and in dose (a number of grays) allow the destruction of an important percentage of a malignant clone and the normalisation of the populations of OKT4+, OKT8+ subset which play a part in the pathogenesis of the disease, notably in the mechanism of certain anemias.