ESMO Consensus Conference on malignant lymphoma: general perspectives and recommendations for the clinical management of the elderly patient with malignant lymphoma.

The European Society for Medical Oncology (ESMO) consensus conference on mature B cell lymphomas and chronic lymphocytic leukaemia (CLL) was held on 20 June 2015 in Lugano, Switzerland, and included a multidisciplinary panel of 25 leading experts. The aim of the conference was to develop recommendations on critical subjects difficult to consider in detail in the ESMO Clinical Practice Guidelines. The following areas were identified: (1) the elderly patient, (2) prognostic factors suitable for clinical use, and (3) the 'ultra-high-risk' group. Before the conference, the expert panel was divided into three working groups; each group focused on one of these areas in order to address clinically-relevant questions relating to that topic. All relevant scientific literature, as identified by the experts, was reviewed in advance. During the consensus conference, each working group developed recommendations to address each of the four questions assigned to their group. These recommendations were presented to the entire panel and a consensus was reached. This consensus, which was further developed in continuous post-meeting discussions, formed the basis of three manuscripts, each covering one of the three key areas identified. This manuscript presents the consensus recommendations regarding the clinical management of elderly patients diagnosed with malignant lymphoma. Four clinically-relevant topics identified by the panel were: 1) how to define patient fitness, 2) assessing quality of life, 3) diagnostic work-up and 4) clinical management of elderly patients with lymphoma. Each of these key topics is addressed in the context of five different lymphoma entities, namely: CLL, follicular lymphoma, mantle cell lymphoma, peripheral T-cell lymphoma and diffuse large B-cell lymphoma. Results, including a summary of evidence supporting each recommendation, are detailed in this manuscript.

Modeling individual and relative accuracy of screening tools in geriatric oncology.

BACKGROUND: Classification probabilities reflect to what degree a screening test represents the true disease state and include true positive (TPF) and false positive fractions (FPF). With two tests, one can compare TPF and FPF using relative probabilities which offer advantages in terms of interpretation and statistical modeling. Our objective was to highlight how individual and relative TPF and FPF can be easily estimated and compared within a regression modeling framework. This allows the modeling of tests' accuracy while adjusting for multiple covariates, and thus provides valuable information in addition to the crude TPF and FPF. We illustrate our purpose with the G8 and VES-13 screening tests aimed at identifying elderly cancer patients in need for a comprehensive geriatric assessment (CGA). METHODS: Prospective cohort with a paired design. TPF and FPF of each test, as well as relative TPF and FPF were modeled using log-linear models. RESULTS: G8 detected patients in need for CGA better than VES-13 at the expense of misclassifying a large number of normal patients. Both tests had better TPF with older age and poorer performance status (PS), and for all cancer subtypes compared with prostate cancer. Effect of age and PS on TPF was more pronounced with VES-13. Age affected FPF, but not differentially. CONCLUSIONS: Regression modeling helps provide a thorough assessment of the accuracy of diagnostic tests and should be used more frequently. In the context of screening, we encourage the use of G8 as failing to identify patients in need of a CGA might be more problematic than over-detection. Moreover, although we identified variables associated with the sensitivity of these tests, this association was less pronounced for the G8.

Predictive factors of depressive symptoms of elderly patients with cancer receiving first-line chemotherapy.

BACKGROUND: Depression is the most common psychiatric disorder in geriatrics and oncology. For elderly cancer patients, it has a significant impact on quality of life, morbidity, and mortality. Nevertheless, depression is under-diagnosed and under-treated. Cancer management is key in improving the quality of care in this population. We aim to identify sociodemographic, clinical, and treatment-related factors of depression in elderly patients during chemotherapy, thus allowing early detection of patients in need of specific treatment. Further, we investigate whether chemotherapy efficacy and safety are associated with depression. PATIENTS AND METHODS: A prospective multicenter cohort composed of incident cases of cancer diagnosed in patients 70 years and older, receiving first-line chemotherapy. Depressive symptoms were measured by the Geriatric Depression Scale at baseline and after four chemotherapy cycles. Associations between depressive symptoms during chemotherapy and patients' clinical and treatment characteristics were identified by logistic regression. RESULTS: Among 344 patients measured for depression before chemotherapy, 260 had a second assessment at the fourth treatment cycle. At baseline, 45.4% were depressed, and 44.6% were depressed after the fourth cycle. Independent factors of depression were depressive symptoms at baseline (odds ratio (OR) = 6.7, p < 0.001), malnutrition (OR = 5.1, p = 0.014), and risk of malnutrition (OR = 1.6, p = 0.014). After controlling for missing data, effective chemotherapy was associated with a lower risk of depression (OR = 0.4, p = 0.018). CONCLUSION: We highlight the role of depressive symptoms and nutritional status at baseline, on the occurrence of depressive symptoms during chemotherapy. These factors should be taken into account in any pre-treatment consultation and appropriate nutritional and psychiatric preventative measures established. Copyright © 2016 John Wiley & Sons, Ltd.

Approach to therapy of diffuse large B-cell lymphoma in the elderly: the International Society of Geriatric Oncology (SIOG) expert position commentary.

Diffuse large B-cell lymphoma (DLBCL) is a treatable and potentially curable malignancy that is increasing in prevalence in the elderly. Until recently, older patients with this malignancy were under-represented on clinical treatment trials, so optimal therapeutic approaches for these patients were generally extrapolated from the treatment of younger patients with this disorder. Because of heightened toxicity concerns, older patients were sometimes given reduced dose therapy, potentially negatively impacting outcome. Geriatric considerations including functional status and comorbidities often were not accounted for in treatment decisions. Because of these issues as well as the lack of treatment guidelines for the elderly population, the International Society of Geriatric Oncology convened an expert panel to review DLBCL treatment in the elderly and develop consensus guidelines for therapeutic approaches in this patient population. The following treatment guidelines address initial DLBCL therapy, in both limited and advanced stage disease, as well as approaches to the relapsed and refractory patient.

Screening older cancer patients: first evaluation of the G-8 geriatric screening tool.

BACKGROUND: Development of a geriatric screening tool is necessary to identify elderly cancer patients who would benefit from comprehensive geriatric assessment (CGA). We develop and evaluate the G-8 screening tool against various reference tests. PATIENTS AND METHODS: Analyses were based on 364 cancer patients aged>70 years scheduled to receive first-line chemotherapy included in a multicenter prospective study. The G-8 consists of seven items from the Mini Nutritional Assessment (MNA) questionnaire and age. Our primary reference test is based on a set of seven CGA scales: Activities Daily Living (ADL), Instrumental ADL, MNA, Mini-Mental State Exam, Geriatric Depression Scale, Cumulative Illness Rating Scale-Geriatrics, and Timed Get Up and Go. We considered the presence of at least one questionnaire with an impaired score as an abnormal reference exam. Additional reference exams are also discussed. RESULTS: The prevalence of being at risk varied from 60% to 94% according to the various definitions of the reference test. When considering the primary reference test, a cut-off value of 14 for the G-8 tool provided a good sensitivity estimate (85%) without deteriorating the specificity excessively (65%). CONCLUSION: The G-8 shows good screening properties for identifying elderly cancer patients who could benefit from CGA.

Rituximab induction immunotherapy for first-line low-tumor-burden follicular lymphoma: survival analyses with 7-year follow-up.

BACKGROUND: The purpose of this study was to report long-term results of rituximab induction monotherapy in patients with low-tumor-burden follicular lymphoma (LTBFL). PATIENTS AND METHODS: Of 49 first-line LTBFL patients who received weekly doses of rituximab (375 mg/m(2)), 46 have been followed with a long-term analysis of clinical and molecular responses. RESULTS: Best clinical response (at any staging within a year following treatment) was 80%, 24 (52%) patients had complete or unconfirmed complete response, 13 (28%) had partial response and 9 (20%) had stable or progressive disease. Of 31 patients having a positive bcl2-JH rearrangement, 15 (48%) became negative following treatment. After 83.9 months of follow-up (95% confidence interval 6.4-92.8 months), the median progression-free survival is 23.5 months and overall survival (OS) is 91.7%. Five patients died (one progression, one myelodysplasia, one diffuse large B-cell lymphoma and two solid tumors). Seven patients (15%) are progression-free including five who are bcl2 informative. No unexpected long-term adverse event has been observed. CONCLUSION: A significant proportion of patients remain progression-free 7 years after a single 4-dose rituximab treatment in first-line LTBFL. The 7-year overall survivalOS is very high in this selected population of patients.

Anthracycline cardiotoxicity in the elderly cancer patient: a SIOG expert position paper.

BACKGROUND: Comorbidities and risk factors likely to complicate treatment are common in elderly cancer patients. Anthracyclines remain the cornerstone of first-line therapy for non-Hodgkin's lymphoma (NHL) and metastatic and early breast cancer but can cause congestive heart failure. Elderly patients are at increased risk of this event and measures to reduce it should be considered. METHODS: A committee of experts in breast cancer and NHL met under the auspices of the International Society for Geriatric Oncology to review the literature and make recommendations, based on level of evidence, for the assessment, treatment and monitoring of elderly patients requiring anthracyclines. RESULTS AND RECOMMENDATIONS: Use of anthracycline-based chemotherapy illustrates many of the dilemmas facing elderly cancer patients. Age in itself should not prevent access to potentially curative treatment or treatment that prolongs life or improves its quality. The risk of cardiotoxicity with conventional anthracyclines is increased by the following factors: an existing or history of heart failure or cardiac dysfunction; hypertension, diabetes and coronary artery disease; older age (independent of comorbidities and performance status); prior treatment with anthracyclines; higher cumulative dose of anthracyclines and short infusion duration. The fact that cumulative and irreversible cardiotoxicity is likely to be greater in this population than among younger patients calls for effective pretreatment screening for risk factors, rigorous monitoring of cardiac function and early intervention. Use of liposomal anthracycline formulations, prolonging the infusion time for conventional anthracyclines and cardioprotective measures should be considered. However, when treatment is being given with curative intent, care should be taken to ensure reduced cardiotoxicity is not achieved at the expense of efficacy.

Modeling of treatment response to erythropoiesis-stimulating agents as a function of center- and patient-related variables: results from the Anemia Cancer Treatment (ACT) study.

BACKGROUND: In anemic cancer patients treated with erythropoiesis-stimulating agent (ESA), (i) to examine the proportion of variance in hemoglobin (Hb) outcomes attributable to patients versus center, country, and region and (ii) to develop predictive models of treatment response. METHODS: Retrospective study with a minimum of three visits at 1-month intervals. Three hundred and seven centers in 13 European countries contributed 2192 anemic ESA-treated cancer patients. Treatment response criteria included: Hb increase > or =1 g/dl, Hb increase > or =1 g/dl within 8 weeks, hematopoietic response (Hb increase > or =2 g/dl or Hb > or = 12 g/dl), Hb increase > or =2 g/dl, and Hb between 12 and 13 g/dl. RESULTS: Hb increased from 9.54 +/- 0.95 g/dl (baseline) to 10.88 +/- 1.49 g/dl (visit 3). Hb change from visits 1 to 2 (index of relative immediacy of response to ESA) averaged 0.81 +/- 1.17 g/dl. The proportion of variance in Hb outcomes attributable to center was 11.8%-34.3%, country 2.9%-20.7%, and region 0.0%-7.6%. Immediacy of response to ESA was the most prevalent predictor of treatment response, followed by diagnosis of hematological malignancy and age <70 years. CONCLUSIONS: . Hb outcomes are determined significantly by the treating center and less so by country or region. The remaining majority variance was attributable to patient-related factors. Immediacy of response to ESA is the single most important predictor of treatment. When used according to guidelines, ESAs are effective in managing anemia in cancer patients and improving treatment outcomes.

Occupational exposure to pesticides and lymphoid neoplasms among men: results of a French case-control study.

OBJECTIVES: Investigating the relationship between occupational exposure to pesticides and the risk of lymphoid neoplasms (LNs) in men. METHODS: A hospital-based case-control study was conducted in six centres in France between 2000 and 2004. The cases were incident cases with a diagnosis of LN aged 18-75 years. During the same period, controls of the same age and sex as the cases were recruited in the same hospital, mainly in the orthopaedic and rheumatological departments. Exposures to pesticides were evaluated through specific interviews and case-by-case expert reviews. Four hundred and ninety-one cases (244 cases of non-Hodgkin's lymphoma (NHL), 87 of Hodgkin's lymphoma (HL), 104 of lymphoproliferative syndromes (LPSs) and 56 of multiple myeloma (MM) cases) and 456 controls were included in the analyses. The odds ratios (ORs) and 95% CI were estimated using unconditional logistic regressions. RESULTS: Positive associations between HL and occupational exposure to triazole fungicides and urea herbicides were observed (OR = 8.4 (2.2 to 32.4), 10.8 (2.4 to 48.1), respectively). Exposure to insecticides, fungicides and herbicides were linked to a threefold increase in MM risk (OR = 2.8 (1.2 to 6.5), 3.2 (1.4 to 7.2), 2.9 (1.3 to 6.5)). For LPS subtypes, associations restricted to hairy-cell leukaemia (HCL) were evidenced for exposure to organochlorine insecticides, phenoxy herbicides and triazine herbicides (OR = 4.9 (1.1 to 21.2), 4.1 (1.1 to 15.5), 5.1 (1.4 to 19.3)), although based on small numbers. Lastly, despite the increased ORs for organochlorine and organophosphate insecticides, carbamate fungicides and triazine herbicides, no significant associations were evidenced for NHL. CONCLUSIONS: The results, based on case-by-case expert review of occupation-specific questionnaires, support the hypothesis that occupational pesticide exposures may be involved in HL, MM and HCL and do not rule out a role in NHL. The analyses identified specific pesticides that deserve further investigation and the findings were consistent with those of previous studies.

Cigarette smoking, alcohol drinking, and risk of lymphoid neoplasms: results of a French case-control study.

OBJECTIVE: To study potential role of smoking and alcohol in lymphoid neoplasms (LN). METHODS: A case-control study that included 824 cases and 752 hospital controls aged 18-75 years was conducted. Cases were newly diagnosed with non-Hodgkin's or Hodgkin's lymphoma, multiple myeloma, or lymphoproliferative syndrome (LPS). Controls were matched with the cases by gender, age, and center. RESULTS: Overall, smoking was not related to LN. However, average tobacco consumption tended to be inversely related to non-Hodgkin's lymphoma (NHL), LPS, and the hairy cell leukemia (HCL) subtype, with a significant negative trend for the latter (OR of 0.4, 0.2, 0.1 for consumptions of 20 cig/day). An inverse association between 'ever drinking' and Hodgkin's lymphoma (HL: OR = 0.5 [0.3-0.8]) and NHL (OR = 0.7 [0.5-1.0]) was evidenced and restricted to the diffuse large B-cell lymphoma subtype, with significant negative trends. The controls' smoking and drinking habits were similar to those of French population. The results remained unchanged after adjustment for potential confounding factors and when smoking and drinking were both included in the models. CONCLUSION: Results are consistent with those of several previous studies and suggest a direct or indirect protective effect of smoking with respect to HCL although based on small numbers. The negative relationship between alcohol consumption and Hodgkin's and NHL, also previously reported, needs further investigations.

Alterations in comprehensive geriatric assessment decrease survival of elderly patients with cancer.

INTRODUCTION: A comprehensive geriatric assessment (CGA) evaluating several domains of health is recommended for elderly patients with cancer. Effects of altered domains on the risk of death in this population need to be clarified. The aim of this study was to estimate the independent association of each CGA domain to overall survival (OS). METHOD: Patients included in the ONCODAGE cohort completed a CGA at baseline. Cox models (one per domain) estimated the hazard ratio (HR) of death for each CGA domain. Directed Acyclic Graphs (DAGs) selected specific sets of adjustment factors for each model. RESULTS: The analysis included 1264 patients (mean age: 78 years, women: 70%). Median follow-up was 5.2 years, and 446 patients died. Each altered domain had a detrimental effect on survival, sometimes dependent on gender, age, education or time from inclusion. Nutritional status had a time-varying effect, with higher mortality rates if altered only within the first 3 years of follow-up. In case of altered mobility, the risk of death was higher only for the youngest patients and, in case of altered autonomy, only for the youngest women. An altered neurological state led to higher mortality rates; this effect increased with the level of education. Patients with altered psychological status or more than four comorbidities at baseline had also higher mortality rates. CONCLUSIONS: Patients with an altered CGA domain have a higher risk of death than those without any alteration. The effect of some alterations is different in some subgroups or at a given time of the treatments.

Multidisciplinary development of the Geriatric Core Dataset for clinical research in older patients with cancer: A French initiative with international survey.

BACKGROUND: To define a core set of geriatric data to be methodically collected in clinical cancer trials of older adults, enabling comparison across trials. PATIENTS AND METHODS: Following a consensus approach, a panel of 14 geriatricians from oncology clinics identified seven domains of importance in geriatric assessment. Based on the international recommendations, geriatricians selected the mostly commonly used tools/items for geriatric assessment by domain (January-October 2015). The Geriatric Core Dataset (G-CODE) was progressively developed according to RAND appropriateness ratings and feedback during three successive Delphi rounds (July-September 2016). The face validity of the G-CODE was assessed with two large panels of health professionals (55 national and 42 international experts) involved both in clinical practice and cancer trials (March-September 2017). RESULTS AND DISCUSSION: After the last Delphi round, the tools/items proposed for the G-CODE were the following: (1) social assessment: living alone or support requested to stay at home; (2) functional autonomy: Activities of Daily Living (ADL) questionnaire and short instrumental ADL questionnaire; (3) mobility: Timed Up and Go test; (4) nutrition: weight loss during the past 6 months and body mass index; (5) cognition: Mini-Cog test; (6) mood: mini-Geriatric Depression Scale and (7) comorbidity: updated Charlson Comorbidity Index. More than 70% of national experts (42 from 20 cities) and international experts (31 from 13 countries) participated. National and international surveys showed good acceptability of the G-CODE. Specific points discussed included age-year cut-off, threshold of each tool/item and information about social support, but no additional item was proposed. CONCLUSION: We achieved formal consensus on a set of geriatric data to be collected in cancer trials of older patients. The dissemination and prospective use of the G-CODE is needed to assess its utility.

EORTC guidelines for the use of erythropoietic proteins in anaemic patients with cancer: 2006 update.

Anaemia is frequently diagnosed in patients with cancer, and may have a detrimental effect on quality of life (QoL). We previously conducted a systematic literature review (1996-2003) to produce evidence-based guidelines on the use of erythropoietic proteins in anaemic patients with cancer.[Bokemeyer C, Aapro MS, Courdi A, et al. EORTC guidelines for the use of erythropoietic proteins in anaemic patients with cancer. Eur J Cancer 2004;40:2201-2216.] We report here an update to these guidelines, including literature published through to November 2005. The results of this updated systematic literature review have enabled us to refine our guidelines based on the full body of data currently available. Level I evidence exists for a positive impact of erythropoietic proteins on haemoglobin (Hb) levels when administered to patients with chemotherapy-induced anaemia or anaemia of chronic disease, when used to prevent cancer anaemia, and in patients undergoing cancer surgery. The addition of further Level I studies confirms our recommendation that in cancer patients receiving chemotherapy and/or radiotherapy, treatment with erythropoietic proteins should be initiated at a Hb level of 9-11 g/dL based on anaemia-related symptoms rather than a fixed Hb concentration. Early intervention with erythropoietic proteins may be considered in asymptomatic anaemic patients with Hb levels 11.9 g/dL provided that individual factors like intensity and expected duration of chemotherapy are considered. Patients whose Hb level is below 9 g/dL should primarily be evaluated for need of transfusions potentially followed by the application of erythropoietic proteins. We do not recommend the prophylactic use of erythropoietic proteins to prevent anaemia in patients undergoing chemotherapy or radiotherapy who have normal Hb levels at the start of treatment, as the literature has not shown a benefit with this approach. The addition of further supporting studies confirms our recommendation that the target Hb concentration following treatment with erythropoietic proteins should be 12-13 g/dL. Once this level is achieved, maintenance doses should be titrated individually. There is Level I evidence that dosing of erythropoietic proteins less frequently than three times per week is efficacious when used to treat chemotherapy-induced anaemia or prevent cancer anaemia, with studies supporting the use of epoetin alfa and epoetin beta weekly and darbepoetin alfa given every week or every 3 weeks. We do not recommend the use of higher than standard initial doses of erythropoietic proteins with the aim of producing higher haematological responses, due to the limited body of evidence available. There is Level I evidence that, within reasonable limits of body weight, fixed doses of erythropoietic proteins can be used to treat patients with chemotherapy-induced anaemia. This analysis confirms that there are no baseline predictive factors of response to erythropoietic proteins that can be routinely used in clinical practice if functional iron deficiency or vitamin deficiency is ruled out; a low serum erythropoietin (EPO) level (only in haematological malignancies) appears to be the only predictive factor to be verified in Level I studies. Further studies are needed to investigate the value of hepcidin, c-reactive protein, and other measures as predictive factors. In these updated guidelines, we explored a new question of whether oral or intravenous iron supplementation increases the response rate to erythropoietic proteins. We found no evidence of increased response with the addition of oral iron supplementation, but there is Level II evidence of improved response to erythropoietic proteins with the addition of intravenous iron. However, the doses and schedules for intravenous iron supplementation are not yet well defined, and further studies in this area are warranted. The two major goals of erythropoietic protein therapy are prevention or elimination of transfusions and improvement of QoL. The total body of evidence shows that red blood cell (RBC) transfusion requirements are reduced following treatment with erythropoietic proteins. This analysis also confirms that QoL is significantly improved in patients with chemotherapy-induced anaemia and in those with anaemia of chronic disease following erythropoietic protein therapy, with more robust evidence now available that QoL was improved in studies investigating early intervention in cases of chemotherapy- or radiotherapy-induced anaemia. There is only indirect evidence that patients with chemotherapy-induced anaemia or anaemia of chronic disease initially classified as non-responders to standard doses proceed to respond to treatment following a dose increase. None of the studies addressed the question in a prospective, randomised fashion, and so the Taskforce does not recommend dose escalation as a general approach in all patients who are not responding. There is still insufficient data to determine the effect on survival following treatment with erythropoietic proteins in conjunction with chemotherapy or radiotherapy. Our analysis of survival endpoints in studies involving patients receiving radio(chemo)therapy found that most studies were inconclusive, with no clear link between the use of erythropoietic proteins and survival. Likewise, we found no clear link between erythropoietic therapy and other endpoints such as local tumour control, time to progression, and progression-free survival. There is no evidence that pure red cell aplasia occurs in cancer patients following treatment with erythropoietic proteins, and the fear of this condition developing should not lead to erythropoietic proteins being withheld in patients with cancer. There is Level I evidence that the risk of thromboembolic events and hypertension are slightly elevated in patients with chemotherapy-induced anaemia receiving erythropoietic proteins. Additional trials are warranted, especially to define the optimal doses and schedules of intravenous iron supplementation during erythropoietic therapy. While our review did not address cost benefit evaluations in detail, the consensus is that studies taking into account all real determinants of cost and benefit need to be performed prospectively.

[Comprehensive geriatric assessment (CGA) in elderly with cancer: For whom?]. / Évaluation gériatrique en oncologie : pour quels patients ?

Scientific societies recommend the implementation of a comprehensive geriatric assessment (CGA) in cancer patients aged 70 and older. The EGA is an interdisciplinary multidimensional diagnostic process seeking to assess the frail older person in order to develop a coordinated plan of treatment and long-term follow-up. Identification of comorbidities and age-induced physiological changes that may increase the risk of anticancer treatment toxicities is essential to better assess the risk-benefit ratio in elderly cancer patients. The systematic implementation of a CGA for each patient is difficult to perform in daily practice. Therefore, it is recommended to screen vulnerable patients who will benefit from a complete CGA. Our work presents the vulnerability screening tools validated by at least two independent studies in a cancer elderly population setting. Among seven screening tools, the G8 and the VES13 are the most effective, and have been validated specifically in older population with cancer. The G8 is recommended by scientific societies and the French National Cancer Institute (INCa) because of its easy implementation in daily clinical practice, its high sensitivity and fair specificity. Although studies are underway to improve its performance, the G8 is currently the simplest tool to routinely identify older cancer patients who should have a complete assessment in geriatric oncology.

Homeobox gene Cdx1 regulates Ras, Rho and PI3 kinase pathways leading to transformation and tumorigenesis of intestinal epithelial cells.

The Cdx1 homeobox gene encodes for an intestine-specific transcription factor involved in the control of proliferation and differentiation of epithelial cells. Although it has been indicated that Cdx1 may act as a proto-oncogene in cultured fibroblasts, its direct role in the regulation of intestinal tumorigenesis has not been demonstrated. Here we show that expression of Cdx1 in an intestinal epithelial cell line (IEC-6) induces anchorage-independent growth in soft agar and promotes the formation of adenocarcinoma in vivo. The phenotype of Cdx1-induced tumors was exacerbated when IEC-6/Cdx1 cells were injected together with matrigel containing mitogens and extracellular matrix components. These changes were correlated with an increase in the GTP-bound form of Ras, modulation of Cdc42 and Rho-A activities, and accumulation of phosphatidyl inositol 3 (PI3) kinase products. Moreover, combined inhibition of Ras/Rho and PI3 kinase signaling by synthethic inhibitors blocked colony formation of IEC-6/Cdx1 cells in soft agar. Taken together, these results demonstrate a direct involvement of Cdx1, and its collaboration with Ras, Rho and PI3 kinase pathways, in transformation and tumorigenesis of intestinal epithelial cells.

Adjuvant bacillus Calmette-Guérin therapy in non-Hodgkin's malignant lymphomas: long-term results of a randomized trial in a single institution.

Between 1973 and 1977, 48 patients less than 65 years old with non-Hodgkin's malignant lymphoma (NHML) of poor prognosis (+/- high grade malignancy, +/- clinical stages III or IV, +/- first or repeated relapse) were included in a prospective clinical trial. After complete remission (CR), obtained with chemotherapy and radiotherapy, patients were randomized to receive bacillus Calmette-Guérin (BCG) or no further therapy. BCG was administered in weekly scarifications up to 3 years. Forty-three patients are assessable. Twenty-four patients have relapsed: nine out of 21 in the BCG group, and 15 out of 22 in the control group. There is a significant difference in favor of the BCG group in disease-free survival (P = .03). Twenty-one patients have died, 18 from NHML: seven in the BCG group, and 11 in the control group. There is a significant difference in favor of the BCG group for overall survival at 10 years (P = .05). A multivariate analysis points out BCG as a significant prognostic factor. Adjuvant BCG may improve particularly disease-free survival and overall survival for patients with clinical stages I and II or intermediate- and high-grade malignancy. These results suggest that in patients less than 65 years old with NHML of poor prognosis, BCG may significantly increase disease-free survival and overall survival.

Granulocyte-macrophage colony-stimulating factor in patients with neutropenic fever is potent after low-risk but not after high-risk neutropenic chemotherapy regimens: results of a randomized phase III trial.

PURPOSE: A randomized unblinded phase III trial was designed to determine the ability of granulocyte-macrophage colony-stimulating factor (GM-CSF) to accelerate recovery from febrile neutropenia induced by chemotherapy. PATIENTS AND METHODS: A total of 68 patients with febrile neutropenia following chemotherapy defined as axillary temperature greater than 38 degrees C and absolute neutrophil count (ANC) less than 1 x 10(9)/L were included. After stratification for high- and low-risk chemotherapy to induce febrile neutropenia, treatment was randomized between GM-CSF at 5 microg/kg/d or control, both being associated with antibiotics. RESULTS: GM-CSF significantly reduced the median duration of neutropenia from 6 to 3 days for ANC less than 1 x 10(9)/L(P < .001) and from 4 to 3 days for ANC less than 0.5 x 10(9)/L (P=.024), days of hospitalization required for febrile neutropenia, and duration of antibiotics during hospitalization. The greatest benefit with GM-CSF appeared for patients who had received low-risk chemotherapy, for which the median duration of ANC less than 1 x 10(9)/L was reduced from 7 to 2.5 days (P < .001) and from 4 to 2 days for ANC less than 0.5 x 10(9)/L (P=.0011), the duration of hospitalization during the study from 7 to 4 days (P=.003), and the duration on antibiotics during hospitalization from 7 to 3.5 days (P < .001). A multivariate analysis, using Cox regression, showed that variables predictive for recovery from neutropenia were GM-CSF (P=.0010) and time interval between the first day of chemotherapy and randomization (P=.030). There was no benefit for GM-CSF when high-risk chemotherapy was considered. CONCLUSION: GM-CSF significantly shortened duration of neutropenia, duration of neutropenic fever-related hospitalization, and duration on antibiotics during hospitalization when febrile neutropenia occurred after low-risk chemotherapy, but not high-risk chemotherapy.

Chemotherapy alone as initial treatment for primary CNS lymphoma in patients older than 60 years: a multicenter phase II study (26952) of the European Organization for Research and Treatment of Cancer Brain Tumor Group.

PURPOSE: To assess the efficacy and toxicity of chemotherapy alone in patients older than 60 years with primary CNS lymphoma. PATIENTS AND METHODS: Fifty patients with a median age of 72 years and a median Karnofsky performance score (KPS) of 50 were eligible for this multicenter phase II study. The protocol consisted of high-dose methotrexate (MTX), lomustine, procarbazine, methylprednisolone, and intrathecal chemotherapy with MTX and cytarabine. The patients received one induction cycle; if objective response was achieved, five additional maintenance cycles were administered every 6 weeks. The median follow-up of patients was 3 years. RESULTS: Twenty four patients (48%) achieved an objective response (compete response [CR], 42%; partial response, 6%), with a median duration of CR of 27 months (range, 3 to 47+ months). Overall median survival time was 14.3 months, and 1-year progression-free survival was 40% (95% confidence interval [CI], 26% to 53%). Myelosuppression was the most frequent side effect, with grade 3 to 4 neutropenia in 19% of patients. One patient died during chemotherapy, as a result of pulmonary embolism. Most patients improved or preserved their cognitive functions (47% and 45% of the patients, respectively) and KPS (36% and 52% of the patients, respectively) until relapse, whereas cognitive and KPS decline attributed to delayed treatment neurotoxicity occurred in 8% and 12% patients, respectively. CONCLUSION: In the elderly, this chemotherapy regimen compares favorably with radiotherapy (RT) alone and reduces considerably the risk of delayed neurotoxicity associated with combined chemoradiotherapy. Chemotherapy alone is an appropriate strategy in older patients to delay or avoid RT.

[How to identify frailty in older patients with cancer? Available tools]. / Comment identifier les personnes âgées fragiles ? Outils à disposition.

Management of cancer in the elderly needs more attention than in younger patients mainly because of comorbidities and geriatric syndromes. Each frailty encountered will facilitate adverse events and complications which are more frequent and more severe in the elderly and have to be anticipated to control for the risk of organ failure and dependencies. Fortunately, tools which have been developed and validated by geriatricians, are available to the oncologists and their validity has been demonstrated in oncology. Yet, they are quite time-consuming and consequently available for a minority of patients. Furthermore, it appears that some of the older patients can be proposed standard therapy and do not need the intervention of geriatricians. This is the reason why screening tools have been developed and validated among which the G8 questionnaire appears to be one of the best. This approach is beginning to be implemented in the daily routine in France and abroad but their appropriate use according to cancer types and treatment intensity should be further improved for the benefit of our patients.

Cdx1 promotes cellular growth of epithelial intestinal cells through induction of the secretory protein PAP I.

Expression of the Cdx1 homeobox gene in epithelial intestinal cells promotes cellular growth and differentiation. Cdx1and the Pancreatitis Associated Protein I (PAP I) are concomitantly expressed in the epithelial cells of the lower part of the intestinal crypts. Because Cdx1 is a transcription factor and PAP I, in other tissues, is a proliferative factor, we looked for a relationship between these two proteins in the intestinal-derived IEC-6 cells. After stable transfection with a Cdx1 expression vector, they produce high levels of the PAP I transcript and protein indicating a functional link between the two genes. Demonstration of Cdx1 binding to the PAP I promoter region and suppression of PAP I induction after deletion of the corresponding sequence indicated that Cdx1 is a transcription factor controlling PAP I gene expression in intestinal cells. By infecting IEC-6 cells with adenoviruses expressing PAP I, we demonstrated that PAP I induces mitosis in these cells. On the other hand, inhibition of the PAP I expression in the IEC-6 Cdxl-expressing cells using an antisense strategy confirmed the requirement of this protein for the effect of Cdx1 on cell growth. Finally, addition of the immunopurified PAP I to the culture medium promotes cell growth of the IEC-6 cells in a dose-dependent manner. Maximal effect was obtained at 1 ng/ml. Taken together these results demonstrate that PAP I is a target of the Cdx1 homeobox gene in intestinal cells which participates in the regulation of intestinal cell growth via an autocrine and/or paracrine mechanism.