[Value of multiple daily doses in radiotherapy: hyperfractionation].
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Dose-Response Relationship, Radiation↗
Biomedical subjects
J M Cosset
Publications and source records attributed to J M Cosset.
Clinical basis for TBI fractionation.
Most available clinical data strongly suggest a sparing effect of TBI fractionation for the lungs, liver, lens, the growth cartilage and, perhaps the prepubertal ovary; the usual fractionated TBI regimens, delivering from 12 to 15 Gy, appear to be constantly less toxic than the "standard" 10 Gy single dose TBI scheme. However, there is also some clinical suggestion, essentially coming from the T-depleted graft experience, that the largely used 12 Gy fractionated scheme (6 X 2 Gy) might be less effective than the standard 10 Gy single dose TBI for leukemia cell killing and for eradication of the recipient bone marrow. Additional clinical data, ideally coming from well designed randomised trial or from careful large-scale retrospective evaluations, should help to optimize the TBI delivery.
Bone Marrow Transplantation↗
Causes of death after therapy for early stage Hodgkin's disease entered on EORTC protocols. EORTC Lymphoma Cooperative Group.
The risk of dying from different causes after Hodgkin's disease (HD) therapy has been quantified from a series of 1,449 patients with early stages included in four successive clinical trials conducted by the European Organization for Research and Treatment of Cancer (EORTC) Lymphoma Cooperative Group since 1963. Overall, 240 patients died and the 15-year survival rate was 69% whereas the expected rate was 95%. The standardized mortality ratio (SMR) technique was used to quantify excess deaths as a function of time since first therapy. At each interval, SMR was significantly increased, giving: 0-3 year, 8.86 (p less than 0.001); 4-6 year, 9.25 (p less than 0.001); 7-9 year, 7.08 (p less than 0.001); 10-12 year, 9.53 (p less than 0.001); 13-15 year, 4.37 (p less than 0.01); and 16+ years, 3.80 (p less than 0.05). While the proportion of deaths as a consequence of HD progression, treatment side-effect, and intercurrent disease decreased with time, that of second cancer and cardiac failure peaked during the 10-12 year post-treatment interval. After 15 years of follow-up, the risk of dying from causes other than HD continued to increase. These findings indicate that although probably cured from HD, patients are at higher risk for death than expected, a risk that might be a consequence of therapy.
Adult↗
The value of adjunctive radiotherapy when chemotherapy is the major curative method.
Chemotherapy is the main treatment in many human malignancies including non-Hodgkin lymphomas and some solid tumors such as those of embryonal origin and small cell lung carcinomas. The high responsiveness to chemotherapy of these tumors has led some groups to treatment policies limited to chemotherapy alone. A long follow-up has shown a high incidence of recurrence in the sites that were initially macroscopically involved. Some randomized trials evaluating the adjunction of radiotherapy to chemotherapy have shown that a failure in local control can be associated with a decreased overall survival. The survival benefit of combined chemotherapy and radiotherapy is generally moderate and is best evaluated by randomized trials entering a large number of patients. The adjunction of radiotherapy to chemotherapy can lead to an increased rate of acute and late toxicity that may overshadow a therapeutic benefit. Critical points of the combined approach are: types of drugs, radiotherapy parameters, radiotherapy-chemotherapy doses, and timing. In this review, two clinical models, one with a low potential of cure, limited small cell lung cancer, and one with a medium potential of cure, non-Hodgkin lymphoma, are reviewed emphasizing information obtained from randomized trials. The modalities of combining radiotherapy and chemotherapy, particularly the timing, are analyzed to define optimal schedules for a definite therapeutic gain.
Breast Neoplasms↗
Similar effects on murine haemopoietic compartment of low dose rate single dose and high dose rate fractionated total body irradiation. Preliminary results after a unique dose of 750 cGy.
This study was designed to compare two different modalities of TBI which are currently used in clinical practice. The same dose of 750 cGy was given to CBA mice either in a single dose at a low dose rate (4 cGy min-1) (STBI) or in a fractionated regimen (six fractions of 125 cGy three times a day) at a higher dose rate (25 cGy min-1) (FTBI). After TBI completion we simultaneously studied the in vivo radiation response of bone marrow cells, two murine bone marrow clonogenic cells (CFU-S and GM-CFC) and peripheral blood lymphocytes and granulocytes for a period of 1 month. The percentage of spleen erythrocytic and granulocytic colonies was also determined. No significant differences were observed between the two groups in the first 48 hours after irradiation except in bone marrow cell numbers, probably due to differences in the overall treatment time between the two TBI schedules. After the first 48 hours the repopulation patterns of the different cells were very similar in both groups. These findings suggest that the different dose rates and fractionation used in this study caused similar radiation damage to the murine haemopoietic system. Moreover, no significant repopulation occurred during the longer overall treatment time of the fractionated regimen. These preliminary results must be corroborated with a larger range of doses before any firm conclusion can be drawn.
Animals↗
Low-dose (one gray) total-lymphoid irradiation for extensive, drug-resistant chronic graft-versus-host disease.
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Adolescent↗
[Adjuvant treatment of colonic cancer. An important progress?].
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Adjuvants, Immunologic↗
[Primitive digestive localizations of malignant non-Hodgkin's lymphoma. Prognostic factors of locally advanced disease: stage II. Report of 67 cases].
Sixty-seven patients with non-Hodgkin's lymphoma of the digestive tract with locally advanced disease (stage II) were analyzed to determine the main factors influencing survival. There were 19 patients with stage II E1 and 48 with stage II E2 disease (Musshoff classification). According to the Kiel classification, 46 percent were low grade, 46 percent were high grade, and 8 percent were unclassified. The principal sites involved included the stomach: 11 cases, small intestine: 21 cases, colon: 12 cases, and mesentery: 11 cases. Lymphoma was unique in 45 cases (67 percent). Treatment consisted of laparotomy in 61 of 67 cases: partial resection was achieved in 21 cases, complete resection in 27 cases, and exploration only in 13 cases. Chemotherapy, according to histopathological subtypes, was employed in 90 percent of cases. Radiation therapy was applied in 25 patients (37 percent), essentially when there was residual disease after surgery (17 patients). Therapeutic indications were dependent on histological subtype, extension, and the therapy regimen in use at the time of treatment. Five patients were treated by surgery only, 2 by surgery and radiation therapy, 37 by surgery followed by chemotherapy, and 23 by all three treatment modalities. Overall survival was 62 percent at 5 years. Univariate analysis showed that 5-year survival rates were not influenced by sex, age, histopathological subtype (low grade: 69 percent; high grade: 59 percent; NS) or local extension (stage II E1: 76 percent vs stage II E2: 59 percent; NS). In contrast, complete surgical excision (p = 0.06) and radiation therapy in case of local residual disease (p = 0.02) seemed to improve survival. The main prognostic factor was the achievement of a complete therapeutic response (CR) (p = 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
[Malignant non-Hodgkin's lymphoma of the conjunctiva. Apropos of 14 cases treated at the Institut Gustave-Roussy].
Non-Hodgkin lymphomas (NHL) of the conjunctiva are rare. Radiotherapy is usually considered to be the choice of treatment in such situations. Reported here are 14 cases of conjunctival NHL, treated at the Institut Gustave-Roussy from 1981 to 1988. Mean age of the patients was 53 years. The series comprised 7 stages of IE, 4 stages of IIE and 3 stages of III. Histological types were mostly "low-grade" according to the Working Formulation (9 cases out of 14). The irradiation technique took advantage of a customized facial lead mask and of a direct anterior electron beam. A small cylindrical lead block, hanging some millimetres above the eye, shielded the cornea and the lens. Local control was achieved for 17 eyes treated (out of 19 irradiated), with a follow-up ranging from 5 to 90 months. The 2 relapses occurred in the same patient, and could be treated by a second line irradiation of the same type. Immediate tolerance was good. Late sequelae were rare and actually included 4 cases of cataract which clearly could not be entirely attributable to the treatment. In conclusion, this sophisticated technique appears to be efficient and non-toxic, since it was able to achieve an almost 100% local control rate, together with a very low percentage of late complications.
Adult↗
[Biological equivalency of high single doses used in intraoperative irradiation].
UNLABELLED: Intra-operative radiotherapy is being used more and more frequently; this raises the problem of the equivalence of these large doses delivered in a single fraction, especially when a second line, complementary external irradiation is planned afterwards. The linear quadratic (LQ) model is probably the most convenient way to compare 2 irradiation schedules delivered with different doses per fraction. However, in the case of intra-operative radiotherapy, one should question the use of the LQ equation; this model actually predicts a continuous bending of the survival curve, while most experimental curves show a trend towards exponential at high dose levels. As a result, with the very large doses (20-30 Gy) given here, the LQ model would lead to overestimate the efficacy--and the toxicity--of intra-operative irradiation. We thus propose to calculate the equivalent fractionated doses by combining 2 models; the LQ model, considered to be reliable up to 7 Gy, and the 2 components' target model, which tends towards an exponential at high dose level. Moreover, we must take into account the hypoxic component of the tumour, since the single fraction, intra-operative technique cannot benefit from the reoxygenation occurring during conventional fractionated irradiations. Calculations indicate that for a partially hypoxic tumour, the effect of a large dose (20-30 Gy) is very similar to the one which would be achieved by the same dose given in a conventionally fractionated way, increased by the dose necessary to compensate for the proliferation occurring during treatment. For healthy tissues, assuming that all cells are well oxygenated, the equivalent fractionated dose is, in particular, much higher for late responding tissues. IN CONCLUSION: 1) there is little hope for sterilizing any carcinoma with only one fraction of 20-30 Gy; 2) however, intra-operative irradiation, focussing on a small volume, could contribute to the tumour eradication; 3) the intra-operative irradiation technique should, as much as possible, spare the neighbouring normal tissues, regarding the risks of long term complications.
Humans↗
[Predictive tests of radiocurability: towards a custom-made radiotherapy?].
Up to now, radiation oncologists had at their disposal only a number of well-known histological and clinical factors in order to define the optimal dose which should be delivered to a given tumor. Recently, radibiological studies have suggested additional parameters which may play a major role in tumor radiocurability. These parameters are: the number of clonogenic cells, intrinsic radiosensitivity, hypoxia and proliferation kinetics. "Predictive" tests are being developed and evaluated for each of these parameters. The more advanced studies deal with intrinsic radiosensitivity; preliminary data show impressive variations in radiosensitivity within groups of clinically "homogeneous" tumors. Should these tests prove to be reliably predictive of radiocurability, it will be possible, in the near future, to propose to any given patient a "custom-made radiotherapy" adapted to the precise features of his or her tumor.
Animals↗
[Radiosensitizers of hypoxic cells].
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Animals↗
Prognostic factors in primary gastrointestinal non-Hodgkin's lymphoma. A multivariate analysis, report of 106 cases, and review of the literature.
The authors have reviewed 106 cases of primary gastrointestinal non-Hodgkin's lymphoma (GI-NHL) treated at the Institut Gustave-Roussy (IGR), France, between 1975 and 1986. The occurrence was 55 in the stomach, 26 in the small intestine, ten ileocecal, seven in the large intestine, and eight patients had multiple involvement. Patients were clinically staged according to the Ann Arbor staging system using the modification of Musshoff for Stage IIE. All histologic material of the 106 patients were reviewed and graded according to the Working Formulation (WF) and the Kiel classifications. Most patients received combination chemotherapy as part or all of their primary treatment program (95 patients, 90%). Seventy five patients (71%) had a multimodality treatment. The overall 5-year survival rate was 60%. Sixteen variables were tested by univariate analyses for prognostic influence on survival. Of these, only clinical stage (P less than 0.001), the achievement of initial complete remission (CR) (P less than 0.001), erythrocyte sedimentation rate (ESR) (P = 0.01), mesenteric involvement (P = 0.03), and serosal infiltration (P = 0.05) were significant prognostic factors. Important variables were tested by a multivariate analysis using the Cox model taking into account different treatment modalities. Only three variables entered the regression analysis at a significant level: clinical stage (P = 0.02), surgical resection (P = 0.03), and histologic grade (Kiel) (P = 0.04). When the achievement of initial CR was introduced into the model, it was the most significant variable (P less than 0.001) whereas all other variables became nonsignificant except for the histologic grade (Kiel) (P = 0.004). Based on results of the multivariate analyses we propose two prognostic classifications of patients: one at the initial evaluation depending on clinical stage, surgical resectability, and histologic grade (Kiel); the other at the end of primary treatment depending on the achievement or not of CR and the histologic grade.
Adolescent↗
Risk of secondary acute leukemia and preleukemia after Hodgkin's disease: the Institut Gustave-Roussy experience.
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.
Adult↗
Single dose versus hyperfractionated total body irradiation before allogeneic bone marrow transplantation: a non-randomized comparative study of 54 patients at the Institut Gustave-Roussy.
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).
Adult↗
Prognostic value of hemoglobin concentrations and blood transfusions in advanced carcinoma of the cervix treated by radiation therapy: results of a retrospective study of 386 patients.
A retrospective study was carried out on 386 patients with advanced cervical carcinomas treated with radiation therapy between 1973 and 1983. The influence of hemoglobin concentrations and blood transfusions before and/or during treatment on the occurrence of distant and/or local regional failures were examined in a univariate and multivariate analyses. In the multivariate analysis hemoglobin concentrations were prognostic only during treatment and patients with at least one value below the threshold of 10 gm% had a significantly higher risk of local regional failure than the patients with all their values above the threshold. Moreover 70% of these high risk patients had less than half of their values below the threshold. It is possible that blood transfusions might be beneficial when given before treatment. However, although it was not significant, blood transfusions given during treatment tended to be an adverse prognostic factor suggesting that blood transfusions might not have completely offset acute anemia prior to transfusion. Our study suggests that anemia during treatment, even of short duration might be detrimental to patients.
Adenocarcinoma↗
[Blood amylase: a biological marker in irradiation accidents? Preliminary results obtained at the Gustave-Roussy Institut (GRI) and a literature review].
The retrospective evaluation of the dose after an irradiation accident is of paramount importance; it allows an adequate selection of patients and the most appropriate treatment can then be proposed. Classical physical dosimetry often lacks precision for dose assessment in such accidents. Cytogenetics, usually more reliable, is not 100% accurate and cannot be used in some particular instances. At the Institut Gustave-Roussy, we studied amylasemia in 15 patients who received a total body irradiation (TBI) for bone marrow grafting, at various dose levels (10, 2 and 1.35 Gy). Hyperamylasemia was found to be constant and dose-dependent. Ten additional patients given a localized irradiation of 2 Gy in the Waldeyer ring had a similar rise in amylasemia as did TBI patients who had received the same dose. In contrast, 13 patients given a pancreatic irradiation (as part of a localized abdominal irradiation) did not show any increase in amylasemia. This study seems to confirm reported data, which suggested that post-TBI hyperamylasemia is almost only related to salivary gland irradiation. Amylasemia could possibly be used as a "biological dosimeter"; however, the dose-effect relationship should be more precisely defined, as well as individual variations. Moreover, the definition of a "threshold-dose" below which hyperamylasemia can never be detected, would be of interest for radioprotection.
Amylases↗
[Focus on research and results of unusual radiotherapy technics (heavy particles, hyperthermia, radiosensitizers)].
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.
Helium↗