Optimisation of chemotherapy and radiotherapy for untreated Hodgkin lymphoma patients with respect to second malignant neoplasms, overall and progression-free survival: individual participant data analysis.

BACKGROUND: Efficacy and the risk of severe late effects have to be well-balanced in treatment of Hodgkin lymphoma (HL). Late adverse effects include secondary malignancies which often have a poor prognosis. To synthesise evidence on the risk of secondary malignancies after current treatment approaches comprising chemotherapy and/or radiotherapy, we performed a meta-analysis based on individual patient data (IPD) from patients treated for newly diagnosed HL. OBJECTIVES: We investigated several questions concerning possible changes in the risk of secondary malignancies when modifying chemotherapy or radiotherapy (omission of radiotherapy, reduction of the radiation field, reduction of the radiation dose, use of fewer chemotherapy cycles, intensification of chemotherapy). We also analysed whether these modifications affect progression-free survival (PFS) and overall survival (OS). SEARCH METHODS: We searched MEDLINE and Cochrane CENTRAL trials databases comprehensively in June 2010 for all randomised trials in HL since 1984. Key international trials registries were also searched. The search was updated in March 2015 without collecting further IPD (one further eligible study found) and again in July 2017 (no further eligible studies). SELECTION CRITERIA: We included randomised controlled trials (RCTs) for untreated HL patients which enrolled at least 50 patients per arm, completed recruitment by 2007 and performed a treatment comparison relevant to our objectives. DATA COLLECTION AND ANALYSIS: Study groups submitted IPD, including age, sex, stage and the outcomes secondary malignant neoplasm (SMN), OS and PFS as time-to-event data. We meta-analysed these data using Petos method (SMN) and Cox regression with inverse-variance pooling (OS, PFS) for each of the five study questions, and performed subgroup and sensitivity analyses to assess the applicability and robustness of the results. MAIN RESULTS: We identified 21 eligible trials and obtained IPD for 16. For four studies no data were supplied despite repeated efforts, while one study was only identified in 2015 and IPD were not sought. For each study question, between three and six trials with between 1101 and 2996 participants in total and median follow-up between 6.7 and 10.8 years were analysed. All participants were adults and mainly under 60 years. Risk of bias was assessed as low for the majority of studies and outcomes. Chemotherapy alone versus same chemotherapy plus radiotherapy. Omitting additional radiotherapy probably reduces secondary malignancy incidence (Peto odds ratio (OR) 0.43, 95% confidence interval (CI) 0.23 to 0.82, low quality of evidence), corresponding to an estimated reduction of eight-year SMN risk from 8% to 4%. This decrease was particularly true for secondary acute leukemias. However, we had insufficient evidence to determine whether OS rates differ between patients treated with chemotherapy alone versus combined-modality (hazard ratio (HR) 0.71, 95% CI 0.46 to 1.11, moderate quality of evidence). There was a slightly higher rate of PFS with combined modality, but our confidence in the results was limited by high levels of statistical heterogeneity between studies (HR 1.31, 95% CI 0.99 to 1.73, moderate quality of evidence). Chemotherapy plus involved-field radiation versus same chemotherapy plus extended-field radiation (early stages) . There is insufficient evidence to determine whether smaller radiation field reduces SMN risk (Peto OR 0.86, 95% CI 0.64 to 1.16, low quality of evidence), OS (HR 0.89, 95% C: 0.70 to 1.12, high quality of evidence) or PFS (HR 0.99, 95% CI 0.81 to 1.21, high quality of evidence). Chemotherapy plus lower-dose radiation versus same chemotherapy plus higher-dose radiation (early stages). There is insufficient evidence to determine the effect of lower-radiation dose on SMN risk (Peto OR 1.03, 95% CI 0.71 to 1.50, low quality of evidence), OS (HR 0.91, 95% CI 0.65 to 1.28, high quality of evidence) or PFS (HR 1.20, 95% CI 0.97 to 1.48, high quality of evidence). Fewer versus more courses of chemotherapy (each with or without radiotherapy; early stages). Fewer chemotherapy courses probably has little or no effect on SMN risk (Peto OR 1.10, 95% CI 0.74 to 1.62), OS (HR 0.99, 95% CI 0.73 to1.34) or PFS (HR 1.15, 95% CI 0.91 to 1.45).Outcomes had a moderate (SMN) or high (OS, PFS) quality of evidence. Dose-intensified versus ABVD-like chemotherapy (with or without radiotherapy in each case). In the mainly advanced-stage patients who were treated with intensified chemotherapy, the rate of secondary malignancies was low. There was insufficient evidence to determine the effect of chemotherapy intensification (Peto OR 1.37, CI 0.89 to 2.10, low quality of evidence). The rate of secondary acute leukemias (and for younger patients, all secondary malignancies) was probably higher than among those who had treatment with standard-dose ABVD-like protocols. In contrast, the intensified chemotherapy protocols probably improved PFS (eight-year PFS 75% versus 69% for ABVD-like treatment, HR 0.82, 95% CI 0.7 to 0.95, moderate quality of evidence). Evidence suggesting improved survival with intensified chemotherapy was not conclusive (HR: 0.85, CI 0.70 to 1.04), although escalated-dose BEACOPP appeared to lengthen survival compared to ABVD-like chemotherapy (HR 0.58, 95% CI 0.43 to 0.79, moderate quality of evidence).Generally, we could draw valid conclusions only in terms of secondary haematological malignancies, which usually occur less than 10 years after initial treatment, while follow-up within the present analysis was too short to record all solid tumours. AUTHORS' CONCLUSIONS: The risk of secondary acute myeloid leukaemia and myelodysplastic syndrome (AML/MDS) is increased but efficacy is improved among patients treated with intensified chemotherapy protocols. Treatment decisions must be tailored for individual patients. Consolidating radiotherapy is associated with an increased rate of secondary malignancies; therefore it appears important to define which patients can safely be treated without radiotherapy after chemotherapy, both for early and advanced stages. For early stages, treatment optimisation methods such as use of fewer chemotherapy cycles and reduced field or reduced-dose radiotherapy did not appear to markedly affect efficacy or secondary malignancy risk. Due to the limited amount of long-term follow-up in this meta-analysis, further long-term investigations of late events are needed, particularly with respect to secondary solid tumours. Since many older studies have been included, possible improvement of radiotherapy techniques must be considered when interpreting these results.

[Update - health risks induced by ionizing radiation from diagnostic imaging]. / Update - Gesundheitsrisiken durch ionisierende Strahlung in der medizinischen Diagnostik.

Ionizing radiation is the most thoroughly investigated exogenous noxa. Since the early 20th century it is well known that using ionizing radiation in diagnostic procedures causes cancer - physicians themselves frequently being struck by this disease in those early days of radiology. Radiation protection therefore plays an important role. Below doses of 100 Millisievert (mSv) however much research has to be accomplished yet because not only malignant tumors, but cardiovascular diseases, malformations and genetic sequelae attributable to low dose radiation have been described. Unborns, children and adolescents are highly vulnerable. Dose response correlations are subject to continuing discussions because data stem mostly from calculations studying Japanese atomic bomb survivors. Radiation exposure is not exactly known, and it is unknown, if observations of radiation induced diseases in this ethnicity can be generalized. Nowadays the main source of low dose ionizing radiation from medical diagnostics is due to computertomography (CT). Large recent clinical studies from the UK and Australia investigating cancer incidence after exposition to CT in childhood and adolescence confirm that low doses in the range of 5 mSv already significantly increase the risk of malignant diseases during follow up. Imaging techniques as ultrasound and magnetic resonance tomography therefore should be preferred whenever appropriate.

Limited-stage Hodgkin lymphoma: optimal chemotherapy and the role of radiotherapy.

Approximately 90% of patients with early-stage Hodgkin lymphoma (HL) will be cured with first-line therapy. Chemotherapy alone or combined-modality therapy are both acceptable standard treatment options for nonbulky early-stage HL. Combined-modality therapy is associated with more serious late effects and, in at least one study, showed inferior survival rates compared with chemotherapy alone. Modern radiotherapy fields and doses are likely to result in fewer complications, but given the common involvement of the mediastinum in HL, complete avoidance of the heart, lungs, and breasts in the radiotherapy field is unlikely. In patients receiving chemotherapy alone, four to six cycles of doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD), with fewer cycles being given to those with an early complete remission, is recommended. Three cycles of ABVD may be adequate in those with an early negative PET, but these results have been published only in abstract form. Current standards for combined-modality therapy include two cycles of ABVD and 20 Gy of involved field radiotherapy in those with a favorable risk profile and four cycles of ABVD plus 30 Gy for unfavorable HL in early-stage patients. Standard of care for bulky early-stage HL remains combined-modality therapy. Whether an interim PET will allow selection of patients with nonbulky HL who will benefit most from consolidative radiotherapy is still under investigation.

Diagnostic medical imaging radiation exposure and risk of development of solid and hematologic malignancy.

Limiting patients' exposure to ionizing radiation during diagnostic imaging is of concern to patients and clinicians. Large single-dose exposures and cumulative exposures to ionizing radiation have been associated with solid tumors and hematologic malignancy. Although these associations have been a driving force in minimizing patients' exposure, significant risks are found when diagnoses are missed and subsequent treatment is withheld. Therefore, based on epidemiologic data obtained after nuclear and occupational exposures, dose exposure limits have been estimated. A recent collaborative effort between the US Food and Drug Administration and the American College of Radiology has provided information and tools that patients and imaging professionals can use to avoid unnecessary ionizing radiation scans and ensure use of the lowest feasible radiation dose necessary for studies. Further collaboration, research, and development should focus on producing technological advances that minimize individual study exposures and duplicate studies. This article outlines the research used to govern safe radiation doses, defines recent initiatives in decreasing radiation exposure, and provides orthopedic surgeons with techniques that may help decrease radiation exposure in their daily practice.

[Concepts of dosimetry]. / Notions de dosimétrie.

The effects of exposure to ionizing radiation are determined by the absorbed dose D. The equivalent dose H takes into consideration the variation in probability of a stochastic effect (cancer, leukemia, genetic mutation) based on the quality of the exposure. The effective dose E takes into account the sensitivity of tissues (T) to stochastic effects from radiation exposure. Optimization of radiation exposure to patients in diagnostic radiology in based on diagnostic reference levels (DRL): entrance surface dose or dose-area product for conventional radiology; CT dose index and DLP for CT.

[Typical patient radiation doses in diagnostic imaging]. / Ordre de grandeur des doses délivrées en radiodiagnostic.

Radiologists should be able to appreciate the radiation dose delivered to patients for routine diagnostic procedures. The radiology report should include data necessary to calculate the patient dose in Gray. Using the effective dose, it is possible to compare with other source of radiation exposure. Simple formulas, taking into account different anatomical regions, derived from dose-area product (conventional radiography) or dose-length product (CT) are provided to calculate the effective dose in Sievert. For conventional (non-interventional) radiography, the effective dose for a given exam is inferior or equal to the yearly background radiation. For CT, the effective dose corresponds to 1 to 10 years of yearly background radiation.

A precautionary public health protection strategy for the possible risk of childhood leukaemia from exposure to power frequency magnetic fields.

BACKGROUND: Epidemiological evidence showing a consistent association between the risk of childhood leukaemia and exposure to power frequency magnetic fields has been accumulating. This debate considers the additional precautionary intervention needed to manage this risk, when it exceeds the protection afforded by the exposure guidelines as recommended by the International Commission on Non-Ionizing Radiation Protection. METHODS: The Bradford-Hill Criteria are guidelines for evaluating the scientific evidence that low frequency magnetic fields cause childhood leukaemia. The criteria are used for assessing the strength of scientific evidence and here have been applied to considering the strength of evidence that exposures to extremely low frequency magnetic fields may increase the risk of childhood leukaemia. The applicability of precaution is considered using the risk management framework outlined in a European Commission (EC) communication on the Precautionary Principle. That communication advises that measures should be proportionate, non-discriminatory, consistent with similar measures already taken, based on an examination of the benefits and costs of action and inaction, and subject to review in the light of new scientific findings. RESULTS: The main evidence for a risk is an epidemiological association observed in several studies and meta-analyses; however, the number of highly exposed children is small and the association could be due to a combination of selection bias, confounding and chance. Corroborating experimental evidence is limited insofar as there is no clear indication of harm at the field levels implicated; however, the aetiology of childhood leukaemia is poorly understood. Taking a precautionary approach suggests that low-cost intervention to reduce exposure is appropriate. This assumes that if the risk is real, its impact is likely to be small. It also recognises the consequential cost of any major intervention. The recommendation is controversial in that other interpretations of the data are possible, and low-cost intervention may not fully alleviate the risk. CONCLUSIONS: The debate shows how the EC risk management framework can be used to apply the Precautionary Principle to small and uncertain public health risks. However, despite the need for evidence-based policy making, many of the decisions remain value driven and therefore subjective.

[The effects of low doses of low-level gamma-radiation and phenozan injection on structural characteristics of mice spleen DNA].

It is well known that AKR mice with spontaneous leucosis are more sensitive to ionizing irradiation as compared to normal F1 (CBA x C57BL) mice. A study on changes of the structural characteristics of spleen DNA and level of protein p53 in the blood serum under the action of low-level gamma-irradiation in a dose of 1.2 cGy and injections of 10(-14) or 10(-4) mol/kg phenozan was performed. The changes in the structural characteristics of DNA (the adsorption on nitrocellulose filters and number of double-strand breaks) and p53 content were observed for each line of mice under gamma-irradiation and each phenozan concentration. Both factors showed long-time post-effects, and structural changes in AKR DNA were consistent with the life span of these mice. Phenozan in the above doses has abolished the induction of double-strand breaks in case of irradiation of F1 mice in a dose of 1.2 cGy and showed long-time post-irradiation effect. These facts suggest a radioprotection property of phenozan.

Implications from epidemiologic studies on magnetic fields and the risk of childhood leukemia on protection guidelines.

The objective of this review is to discuss the impact of findings in epidemiological studies on magnetic fields and the risk of childhood leukemia on the definition of exposure limits. A large number of epidemiological studies have consistently shown an association between the risk of childhood leukemia and residential extremely low-frequency magnetic field exposures. There is virtually no supportive data from experimental research and, so far, no proposed explanation has reached a level beyond speculation. The contradictory results from epidemiological and experimental research may either be due to methodological limitations creating a spurious association in the epidemiological studies or to a failure of experimental research to examine mechanisms relevant in the complex origin of childhood leukemia. Taking this together, the overall evidence is not strong enough to demand a revision of the current guidelines for public protection. Application of precautionary measures may be an option; however, decision-makers should be advised that these measures are often not straightforward and a careful evaluation of a possible benefit needs to be performed for each individual situation. Undoubtedly there are gaps in research, and no substantial contribution for clarification of the apparent inconsistencies emerges from recent studies. However, there are important lessons to learn, either with respect to the etiology of childhood leukemia or with respect to the need for improving epidemiological methods for the identification of presumably weak associations.

Implications of hemopoietic progenitor cell kinetics and experimental leukemogenesis: Relevance to Gompertzean mortality as possible hematotoxicological endpoint.

OBJECTIVE: The aim of this study is to investigate a possible implication in cell kinetics of the hematopoietic progenitors to the experimental leukemogenesis to elucidate the relevance of various leukemic mode of action to Gompertzean survival curves, a new parameter based on the lifespan. MATERIALS AND METHODS: Mice, C3H/He, and C57BL/6 strain, male and female, with or without genetic modifications, e.g., p53-deficiency or thioredoxin overexpression were used in the present hemopoietic stem/progenitor research, radiation- or benzene-induced leukemogenesis followed by histopathological examination. A lethal dose of radiation for bone marrow transplantation, and a graded increased dose up to 5 Gy of x-rays for induction of hematopoietic malignancies were given. For caloric restriction studies, 77 kcal/week was maintained in accordance to different restriction-timing. For assays of hematopoietic colonization, colony-forming unit spleen and colony-forming unit granulocyte macrophage were evaluated. Hematopoietic progenitor cell-specific kinetics were studied by continuous labeling of bromodeoxyuridine for cycling cells, followed by ultraviolet (UV) exposure and hemopoietic colonization (bromodeoxyuridine UV [BUUV] method). Various experimental survival curves were applied to a mathematical analysis by Gompertz-Makeham law of mortality. RESULTS: Referring current authors' studies on leukemogenesis induced by ionizing radiation and benzene exposure, implications of hematopoietic progenitor cell kinetics to the experimental leukemogenesis were evaluated by means of a novel experimental tool, the BUUV method. Comparative studies to elucidate relevancies of these data, including two prevention studies, one on caloric restriction and the other on antioxidative thioredoxin overexpression, to those Gompertzean survival curves of experimental animals were analyzed. CONCLUSION: The Gompertzean expression may elucidate an appropriate toxicological endpoint for evaluating the effect of radiation and/or benzene-exposure on the lifespan and its modification by various experimental preventive measures.

[Effect of low-level irradiation on incidence rate and development of malignant neoplasms].

Low-level irradiation (1.2-2.4 cGy, dose-rate 0.6 cGy/day) leads to a significant acceleration of the development of spontaneous leukosis in AKR mice: decrease in the average and the maximum life-span of animals leukosis-carriers (by 20 and 120 days, respectively) and an increase in the leukosis incidence rate (%). The introduction of antioxidant phenozan (beta-(4-hydroxy-3,5-ditertbutylphenyl) propionic acid) results in a considerable antileukosis effect: the average life-span increases by more than 40 days and the leukosis incidence rate decreases by 6%.

Caloric restriction prevents radiation-induced myeloid leukemia in C3H/HeMs mice and inversely increases incidence of tumor-free death: implications in changes in number of hemopoietic progenitor cells.

OBJECTIVES: Previously, we found a clear decrease in the incidence of radiation-induced myeloid leukemia in C3H/HeMs mouse caused by caloric restriction (CalR). In this report, CalR before and after irradiation was examined to determine whether they exert different effects on the prevention of radiation-induced myeloid leukemogenesis and the consequent extension of life span by CalR. METHODS: The C3H/HeMS strain, which is prone to radiation-induced myeloid leukemia, was used. Groups subjected to different CalR timings, pre- and postirradiation, were compared with groups not subjected to CalR during their lifetime for the incidences of neoplasms, specifically that of myeloid leukemia, and the incidence of tumor-free death. A single dose of 3Gy X-ray was administered to mice at 10 weeks old. Results of colonization assay before and after CalR were compared with the incidence of leukemogenesis among the groups. RESULTS: Irrespective of the CalR timing in terms of irradiation, there was a significant difference in the prevention of myeloid leukemogenesis, and a consequent difference in longevity (731 approximately 805 days for CalR groups vs. 697 days for the group without CalR; Log rank, P<0.03). During CalR, the number of hemopoietic progenitor cells (HPCs), potential leukemogenic targets, significantly decreased (0.4 x 10(4) vs. 4.2 x 10(4) of granulomacrophage colony forming units per spleen; 1.3 x 10(4) vs. 7.6 x 10(4) of the splenic colony forming units per spleen), but this decreased number of HPCs returned to that of the non-CalR control group, when the CalR group was returned to nonrestricted diet (returned to 1.5 x 10(4) granulomacrophage colony-forming units per spleen; returned to 2.8 x 10(4) splenic colony-forming units per spleen). Although preirradiation CalR followed by a conventional non-CalR diet negates the potential preventive effect, prevention conferred by pre-and postirradiation CalR suggests different underlying mechanisms; preirradiation CalR prevents the initiation of direct genotoxic leukemogenesis, while postirradiation CalR the indirect, epigenetic, leukemogenesis. CONCLUSION: The incidences of tumor-free death significantly increased in all the groups undergoing CalR except for the group subjected to preirradiation CalR, which contributed to the longevity of the groups undergoing CalR.

Research strategies for magnetic fields and cancer.

Widespread concerns about whether electric and magnetic fields (EMF) could adversely affect human health have been raised in epidemiologic studies reported since the 1980s. Possible EMF health effects have been widely publicized in the popular press since that time. We consider here three possible mechanisms of action of EMF on childhood leukemia. We identify the first as "magnetic fields": this hypothesis relates the average level of magnetic field to the incidence of childhood leukemia. We identify a second, recently proposed, mechanism as "contact current": this hypothesis relates the low voltage and consequent current that occurs on the domestic water pipe, due to U.S. grounding practices, as a source for exposure of children. The third hypothesis is that the relationship observed is spurious. Using a modified example taken from the work of Von Winterfeldt and Keeney, we use Decision Analysis to estimate the value of information for distinguishing between the three hypotheses. We believe that this improves on the usual process for deciding on research budgets. Depending on which hypothesis we favor a priori, the value of being informed ranges from US 101 dollars to US 233 dollars per "problem household." Since there could be as many as 2 million such households, the value of information for resolving this issue could approach half a billion dollars! We find that there is no value of information for finding the odds ratio given the contact current hypothesis. In writing this article, we have consciously kept the computations as simple as possible so as to engage the reader's attention and interest. In a penultimate section, we suggest numerous possible extensions for a group interested in discussing and deciding on the value of research on the relationship between magnetic fields and cancer.