Chemoradiotherapy for localized non-Hodgkin's lymphoma.
Explore the source record for details and available documents.
Antineoplastic Combined Chemotherapy Protocols↗
Biomedical subjects
J M Cosset
Publications and source records attributed to J M Cosset.
[Prognostic factors and treatment of localized Hodgkin's disease].
Cure is warranted in most cases of localized Hodgkin's disease, the more frequent ones. However, after 10 years of follow-up, early and late mortality of iatrogenic origin exceed casualties related to tumor progression. Reductions in irradiation doses and fields, as well as wiser chemotherapy choices attempt to circumvent these complications. Nevertheless, as long as the mechanism of disease propagation and the prognostic factors are not better defined, only pragmatic approaches are being tested. Large cooperative trials are therefore needed to improve the outcome.
Adult↗
Comparative analysis of apoptosis measured by Hoechst and flow cytometry in non-Hodgkin's lymphomas.
Fine-needle samples of 75 non-Hodgkin's lymphomas were investigated for apoptosis immediately and after 24 h of culture after in vitro irradiation (2 Gy, 10 Gy, and nonirradiated controls). Apoptotic cells were simultaneously quantified by fluorescence microscopic enumeration of apoptotic cells using Hoechst 33342 staining, and by flow cytometric detection of sub-G1 peak cells. The nonirradiated controls showed a similar mean percent apoptotic cells using both methods, analyzed immediately (9% by morphology vs. 10% by flow) or after 24 h of culture (40% by morphology vs. 41% by flow). In the irradiated samples, the mean percent apoptotic cells quantified by morphology was higher than by flow cytometry (64% by morphology vs. 55% by flow after 2 Gy irradiation, and 71% vs. 58% after 10 Gy). The results of the two methods were correlated, although large differences were seen between the techniques in individual tumors. In our system, flow cytometric sub-G1 peak analysis appears to underestimate apoptosis. Of these two methods, we find the Hoechst morphology method to be more reliable for quantitation of apoptosis utilizing fresh fine-needle sample material, in that discrimination of apoptotic cells from debris is easier and that both early and late apoptotic cells are detectable.
Apoptosis↗
In vitro radiation-induced apoptosis and early response to low-dose radiotherapy in non-Hodgkin's lymphomas.
PURPOSE: Prospective investigation of spontaneous and in vitro radiation-induced apoptosis to predict early response to palliative radiotherapy in patients with non-Hodgkin's lymphomas. PATIENTS AND METHODS: Fine-needle sampling was performed in 28 tumor sites (26 patients) and yielded adequate cell numbers in 27 cases. Apoptotic cells were counted by fluorescence microscopy immediately after sampling and after 24-h culture (spontaneous apoptosis) and 24 h after 2- and 10-Gy in vitro irradiation (radiation-induced apoptosis). Early response to low-dose in vivo radiotherapy (mostly 4 Gy in two fractions over 3 days) was evaluated 15 days after treatment. RESULTS: The tumor response rates at 15 days were 11 (39%) complete responses, nine (32%) responses of greater than 50% reduction in volume, six (21%) responses of less than 50% reduction in volume and two (7%) cases of no response. Tumors achieving complete or major response after in vivo irradiation had higher percentages of apoptotic cells after in vitro irradiation, while no significant differences in terms of spontaneous apoptosis were observed between responders and non-responders. CONCLUSION: Spontaneous and in vitro radiation-induced apoptosis can be easily and quickly assessed on cells obtained by fine-needle sampling of non-Hodgkin's lymphoma lesions. The present results suggest that in vitro radiation-induced apoptosis could be used as a predictive assay of early response to low-dose in vivo irradiation in patients with non-Hodgkin's lymphomas.
Adult↗
[Chemoradiotherapy: history and state of the art].
The idea of combining radiotherapy and chemotherapy goes back to the very beginning of the antimitotic drugs era. At that time, this association was mainly based on a simple concept: spatial cooperation. The first period was one of so-called "adjuvant" (post-irradiation) chemotherapy, soon followed by the once-fashionable "neo-adjuvant" chemotherapy era. Today, concomitant administration of both therapies, mainly based on radiosensitization, appears promising, although the previous schemes were clearly efficient for some specific indications. In 1998, radiochemotherapy combinations represent an unavoidable part of the anticancer strategy. A number of them have been recognized as the standard treatment for some localizations, and there is little risk to imagine that this number will increase within the next decade.
Chemotherapy, Adjuvant↗
The proteasome inhibitor lactacystin induces apoptosis and sensitizes chemo- and radioresistant human chronic lymphocytic leukaemia lymphocytes to TNF-alpha-initiated apoptosis.
Apoptosis can be triggered by cytotoxic agents and radiation currently used in cancer treatment. However, the apoptotic response appears to vary between cell types (normal or transformed) and between types of malignancy. Thus, irradiation induces apoptosis in normal human lymphocytes but not in lymphocytes derived from a subset of chronic lymphocytic leukaemia (CLL). Moreover, in this subset, spontaneous apoptosis is inhibited by irradiation. Why irradiation does not allow the initiation of the apoptotic death pathway could be explained, at least in part, and in agreement with recent findings on experimental models, by the activation of the transcriptional factor NF-kappaB, which is able to inhibit apoptotic cell response. Low doses (at which no effect is observed with normal human lymphocytes) of the highly specific proteasome inhibitor lactacystin are sufficient to trigger apoptosis in these malignant cells. Proteasome inhibition by lactacystin prevents the nuclear translocation of both p50 and p65 NF-kappaB subunits and sensitizes these cells to apoptosis by tumour necrosis factor (TNF)-alpha treatment. As this subset of CLL is totally resistant to any treatment, proteasome inhibition by lactacystin provides a new therapeutic approach to be explored, considering the sensitivity of malignant CLL-derived lymphocytes to be quite different from that of normal human lymphocytes.
Acetylcysteine↗
VIP (etoposide, ifosfamide and cisplatinum) as a salvage intensification program in relapsed or refractory Hodgkin's disease.
Forty-two patients with refractory (15 patients) or relapsed (27 patients) Hodgkin's disease (HD) were included in a prospective single center study evaluating the efficacy of a regimen VIP combining etoposide 75 mg/m2/day days 1-5, ifosfamide 1.2 g/m2/day days 1-5 and cisplatinum 20 mg/m2/day days 1-5, one course every 4 weeks as salvage therapy in patients with refractory or relapsed Hodgkin's disease, potentially eligible for high-dose chemotherapy with reinjection of hematopoietic stem cells (HSC). If patients were considered chemosensitive after two courses of VIP, high-dose chemotherapy followed by the reinjection of HSC was planned. After two courses of VIP, 67% achieved an objective response including 38% complete responses. Overall, 28 patients went on to high-dose therapy with reinjection of HSC, and 46% of grafted patients are in a sustained complete remission. When the overall patient population is considered, 33% are in complete remission (CR) with a median follow-up of 37 months. A CR of less than 12 months and refractory disease were associated with a poor survival. These results showed that the VIP regimen is effective in relapsed or refractory HD and allows high-dose therapy to be given in the case of most responding patients. However, results in patients with refractory disease or a first complete remission of less than 12 months need to be further improved.
Adolescent↗
Autologous hematopoietic stem cell transplantation as salvage treatment for advanced B cell chronic lymphocytic leukemia.
Given the generally poor outcome of advanced B cell chronic lymphocytic leukemia, experimental approaches are warranted, especially for younger patients in whom classical treatments have failed. We therefore conducted a prospective single-center study, using polychemotherapy (ESHAP) to prepare patients for hematopoietic stem cell collection and autologous stem cell transplantation as consolidation therapy. Twenty patients entered the study. An adequate response to ESHAP was obtained in 13 patients, and sufficient stem cells for grafting were obtained in eight of the 12 patients who underwent the collection procedure. Six of these grafted patients are alive in complete clinical remission a median of 30 months after transplantation. It should be noted that we were only able to graft 40% of the patients enrolled in this study, either because a new remission could not be obtained or because not enough hematopoietic stem cells could be collected. This argues for stem cell collection as soon as a first remission is obtained, even if the autograft is done later in the course of the disease.
Adult↗
The role of radiotherapy for early stage Hodgkin's disease: limitations and perspectives.
For limited stage Hodgkin's disease (HD), the role of radiotherapy has been changing during the last decades, the main point being the (almost) complete disappearance of irradiation used alone. Actually, exclusive radiotherapy yielded satisfactory results in terms of long-term survival, but in 1998, it was becoming impossible not to take into account the late overmortality observed in all large cohorts of HD patients. This overmortality has been shown to be related (1) to cardiac toxicity of irradiation and (2) to secondary radiation-induced solid tumors. So the search for new strategies, as efficient, but less toxic, could not be avoided any more. For surgically staged patients (pathological stages I and II), irradiation alone (i.e., mantle field radiotherapy) can still be proposed to patients without unfavourable prognostic factors after a negative surgical infra-diaphragmatic exploration. For clinically staged patients with limited disease and favourable prognostic indicators, the association of chemotherapy and radiotherapy appears more and more as a standard. In parallel, efforts are being made to alleviate the therapeutic burden. For radiotherapy, previous experience showed that, after a chemotherapy-induced complete remission, irradiation of the initially involved areas only was enough treatment. Ongoing trials are now exploring the possibility of a dose desescalation from the conventional 36 Gy to 20 Gy (as for children HD), and maybe to ... 0 Gy (no radiotherapy at all). Desescalation in the number of chemotherapy cycles is also being investigated. For clinically staged patients with unfavourable prognostic indicators, a higher percentage of cases still appears to be refractory to treatment. So, while chemo-radiotherapy clearly became the standard strategy, efforts are essentially being devoted to identify new--and hopefully more efficient--chemotherapy schemes. In parallel, irradiation dose desescalation is being investigated. Most of these pending questions are addressed in a number of ongoing trials, as well in the US as in Europe, with the aim of offering to patients treatments at least as efficient as the presently used schedules, and less toxic in the long term.
Antineoplastic Combined Chemotherapy Protocols↗
[Localized or metastatic cancer of the prostate: review of new treatment modalities].
Amongst men, prostatic adenocarcinoma is the most common cancer and the second most frequent cause of deaths. Widespread PSA measurement have led to earlier diagnosis. Recent clinical trials have tried to show an improvement in the prognosis. Early stages are mainly treated surgically even if local control results are similar with radiotherapy. Radiotherapy is the main stay of treatment for more locally advanced disease, either conventionally or conformational. Adjuvant hormonotherapy has been shown to improve survived as opposed to neoadjuvant hormonotherapy which only has local effects. The treatment of metastatic disease is palliative with the use of antiandrogens. In case of relapse, a second line of hormonotherapy or a chemotherapy is given. However the problem is the lack of effective drugs. Response rates to the main drug treatment are around 10 to 20%. New therapeutic approaches are now based on antimicrotubules agents but it is difficult to evaluate their efficacity. Further clinical trials will provide more information about improvement in survival rates and in quality of life.
Humans↗
[Hodgkin's disease. Long-term complications of radiotherapy].
Explore the source record for details and available documents.
Hodgkin Disease↗
[Radiotherapy. Radiobiological notions, main side effects].
Explore the source record for details and available documents.
Humans↗
[Pulmonary and cardiac late effects of ionizing radiations alone or combined with chemotherapy].
High doses of ionizing radiation (> 40 Gy) cause severe lung fibrosis in approximately 5% of the cases. There is a twofold increase when chemotherapy is added to ionizing radiation. Lung fibrosis is due to the destruction of lung tissue by ionizing radiation but also to various cytokine effects (PDGF-beta, TGF-beta). Only a minority of patients (approximately 10%) with abnormal X-rays will experience clinical symptoms. The most important radiobiological parameters which accounts for pulmonary tolerance is the fraction size. Irradiation of the heart begets multifarious late sequelae which are often left unrecognized. Chronic pericarditis affects approximately 5% of the patients when the irradiation dose exceeds 40 Gy. Coronary artery disease can be diagnosed in 5 to 10% of the patients. This late complication is more likely to occur if the patient was young at the time of the irradiation or if other risk factors are associated. Valvular defects can be found in 15 to 30% of the patients. However, the mortality rate is very low (0.5%). Finally, conduction defects can also be seen in approximately 5% of the patients. It is very likely that the radiation dose given to the heart should not exceed 30 Gy if late sequelae are to be avoided.
Antineoplastic Combined Chemotherapy Protocols↗
[Radiation-induced cancers: state of the art in 1997].
Scientists now have available a large amount of data dealing with radiation-induced neoplasms. These data went back to anecdotal observations which were made in the very first years of utilization of X-rays and radioactive elements. In fact, it is essentially the strict follow-up of the Japanese populations irradiated by the Hiroshima and Nagasaki bombing which allowed a more precise evaluation of the carcinogenicity of ionizing radiations. Further refinements came from therapeutical irradiations: it is now possible to study large cohorts of patients given well-known doses in well-defined volumes and followed for more than 20 years. Last but not least, a significant increase in the incidence and mortality of thyroid cancer has been detected in children contaminated by iodine radioisotopes after the Tchernobyl accident. Recently, some data suggested the emergence of "clusters" of leukemias close to some nuclear facilities, but this question remains highly polemical, both in France and in the UK. Other questions are still waiting for a precise answer; of course, the extrapolation of our available data to very low doses delivered at very low dose rates, but also the carcinogenic risk at high doses. For these "high" doses (about 30 to 70 Gy), a competition between mutagenesis and cell killing was expected, so that these dose levels were expected to be less carcinogenic than lower (a few sieverts) doses. Actually, recent data suggest that the carcinogenic risk goes on increasing up to relatively important doses. In addition, carcinogenic factors, such as tabacco, anticancer chemotherapy and individual susceptibility, are found more and more to be closely intricated with ionizing radiation in the genesis of a given cancer. Even if a number of questions are still pending, the already available data allow specialists, both in medicine and radioprotection, to edict strict rules which can be reasonably expected to have significantly reduced the risk of radiation-induced neoplasms in most situations.
Electromagnetic Fields↗
[A combined radiochemotherapy trial for non-small cell lung cancers: initial results].
PURPOSE: Analysis of the preliminary results of a phase I study investigating the feasibility of concomitant chemotherapy with daily doses of carboplatin (20 to 25 mg/m2/d over 45 or 10 min) and accelerated chest irradiation (60 to 64 Gy over 4 weeks, 2 Gy per fraction, using the concomitant boost technique). MATERIALS AND METHODS: This combination was given alone or following three cycles of induction chemotherapy (cisplatin, 25 mg/m2 per day from d1 to d5; 5-fluorouracil, 600 mg/m2 per day from d1 to d5 and vinorelbine, 25 mg/m2 per day at d1 and d5 with a 4-week interval) in 15 patients with locally advanced unresectable non-small cell lung cancer. All patients received the planned sequence. RESULTS: The dose-limiting toxicity was esophagitis (5 out of 15 grade 4). No toxic deaths were observed. The tumor response rate was high: six out of 15 complete responses and 14 out of 15 tumor regressions greater than 50%. The median survival was not reached after a mean follow-up of 14 months (range, 6-28 months). CONCLUSION: We are now planning a multicenter phase II study using the following combination: 20 mg/m2 of daily carboplatin over 10 min and a 60-Gy irradiation dose over 4 weeks.
Adult↗
[Biological basis of combined chemo-radiotherapy. Applications to lung cancers].
Radiation therapy has been for years the treatment of choice of locally advanced non small cell lung cancer. Improvement due to the combination of radiation and chemotherapy has been shown recently through several randomized trials and a recent meta-analysis. These results may be explained by biological mechanisms, yet uncompletely explored, which are detailed in this review and applied to lung cancer. The optimal combination scheme is not yet defined, even though the concurrent approach is promising, at the expense of an increased toxicity which is the limiting factor of treatment escalation doses. Biological findings and future results of randomized trials will hopefully open new avenues in the therapeutic strategy of this poor prognosis disease.
Carcinoma, Non-Small-Cell Lung↗
[Predictive tests of response to radiotherapy. Assessment and perspectives in 1997].
The potential tailoring of radiotherapy modalities to the biological characteristics of individual tumours and normal tissues appears to be an exciting way to improve the therapeutic, ratio in radiation therapy patients. Numerous assays have been proposed to provide the clinician with the biological information necessary to predict the outcome after irradiation and to guide the treatment prescription, but none of them has made its way to daily practice. Major difficulties are due to the technical burden of the procedures, the poor characterization of the assayed cells, and, moreover, the high complexity of tumour and normal tissues biology. The present paper reviews the present status of the assessment of tumour cells radiosensitivity, proliferation and oxygenation. Research remains extremely active in the field of biological predictors of response to irradiation. Future steps forwards are expected from progress in the available technologies, (re-)discovery of apoptosis and investigation of normal tissue tolerance.
Apoptosis↗
In vitro radiation-induced apoptosis and tumour response to radiotherapy: a prospective study in patients with non-Hodgkin lymphomas treated by low-dose irradiation.
Explore the source record for details and available documents.
Apoptosis↗