Rituximab-EPOCH, an effective salvage therapy for relapsed, refractory or transformed B-cell lymphomas: results of a phase II study

Background: Relapsed or refractory diffuse large B-cell and mantle-cell lymphoma have a poor prognosis. The EPOCH regimen and rituximab monotherapy have demonstrated activity as salvage therapies. Because of their non-overlapping toxicity, we evaluated their combination as salvage therapy in a phase II study. Patients and methods: Patients with relapsed or refractory CD20-positive large B-cell and mantle-cell lymphoma were offered treatment with rituximab 375 mg/m2 intravenously (i.v.) on day 1, doxorubicin 15 mg/m2 as a continuous i.v. infusion on days 2-4, etoposide 65 mg/m2 as a continuous i.v. infusion on days 2-4, vincristine 0.5 mg as a continuous i.v. infusion on days 2-4, cyclophosphamide 750 mg/m2 i.v. on day 5 and prednisone 60 mg/m2 orally on days 1-14. Results: Fifty patients, with a median age of 56 years (range 23-72), entered the study. Twenty-five had primary diffuse large B-cell lymphoma, 18 transformed large B-cell lymphoma and seven mantle-cell lymphoma. The median number of prior chemotherapy regimens was 1.7 (range one to four). The median number of treatment cycles was four (range one to six). Possible treatment-related death occurred in two patients. Objective responses were obtained in 68% of patients (28% complete responses, 40% partial responses). Nineteen patients received consolidating high-dose chemotherapy with autologous stem-cell transplantation. The median follow-up was 33 months. Three patients developed a secondary myelodysplastic syndrome. The median overall survival was 17.9 months; the projected overall survival at 1, 2 and 3 years was 66, 42 and 35%, respectively. The median event-free survival was 11.8 months; the projected event-free survival at 1, 2 and 3 years was 50, 30 and 26%, respectively. Conclusion: The rituximab-EPOCH regimen is effective and well tolerated, even in extensively pretreated patients with relapsed or refractory large B-cell lymphoma and mantle-cell lymphom

The bmi-1 oncoprotein is differentially expressed in non-small cell lung cancer and correlates with INK4A-ARF locus expression

Genes of the polycomb group function by silencing homeotic selector genes that regulate embryogenesis. In mice, downregulation of one of the polycomb genes, bmi-1, leads to neurological alterations and severe proliferative defects in lymphoid cells, whilst bmi-1 overexpression, together with upregulation of myc-1, induces lymphoma. An oncogenic function has been further supported in primary fibroblast studies where bmi-1 overexpression induces immortalization due to repression of p16/p19ARF, and where together with H-ras, it readily transforms MEFs. It was the aim of this study to assess the expression of bmi-1 in resectable non-small cell lung cancer (NSCLC) in association with p16 and p14ARF (=human p19ARF). Tumours (48 resectable NSCLC (32 squamous, 9 adeno-, 2 large cell, 4 undifferentiated carcinomas and 1 carcinoid); stage I, 29, II, 7, III, 12; T1, 18, T2, 30; differentiation: G1 12, G2 19, G3 17) were studied by immunohistochemistry for protein expression and by comparative multiplex PCR for gene amplification analysis. In tumour-free, normal lung tissue from patients, weak – moderate bmi-1 staining was seen in some epithelial cells, lymphocytes, glandular cells and in fibroblasts, whereas blood, endothelial, chondrocytes, muscle cells and adipocytes did not exhibit any bmi-1 expression. In tumours, malignant cells were negative/weakly, moderately and strongly positive in 20, 22 and 6 cases, respectively. As assessed by multiplex PCR, bmi-1 gene amplification was not the reason for high-level bmi-1 expression. Tumours with moderate or strong bmi-1 expression were more likely to have low levels of p16 and p14ARF (P = 0.02). Similarly, tumours negative for both, p16 and p14ARF, exhibit moderate–strong bmi-1 staining. 58% of resectable NSCLC exhibit moderate–high levels of bmi-1 protein. The inverse correlation of bmi-1 and the INK4 locus proteins expression (p16/p14ARF) supports a possible role for bmi-1 misregulation in lung carcinogenesis. © 2001 Cancer Research Campaign www.bjcancer.co

Overexpression of aurora B kinase (AURKB) in primary non-small cell lung carcinoma is frequent, generally driven from one allele, and correlates with the level of genetic instability

Aurora kinases are key regulators of chromosome segregation during mitosis. We have previously shown by microarray analysis of primary lung carcinomas and matched normal tissue that AURKB (22 out of 37) and AURKA (15 out of 37) transcripts are frequently over-represented in these tumours. We now confirm these observations in a second series of 44 carcinomas and also show that aurora B kinase protein levels are raised in the tumours compared to normal tissue. Elevated levels of expression in tumours are not a consequence of high-level amplification of the AURKB gene. Using a coding sequence polymorphism we show that in most cases (seven out of nine) tumour expression is predominantly driven from one AURKB allele. Given the function of aurora B kinase, we examined whether there was an association between expression levels and genetic instability. We defined two groups of high and low AURKB expression. Using a panel of 10 microsatellite markers, we found that the group showing the higher level of expression had a higher frequency of allelic imbalance (P=0.0012). Analysis of a number of other genes that are strongly and specifically expressed in tumour over normal lung, including SERPINB5, TERT and PRAME, showed marked allelic expression imbalances in the tumour tissue in the context of balanced or only marginally imbalanced relative allelic copy numbers. Our data support a model of early carcinogenesis wherein defects in the process of inactivation of lung stem-cell associated genes during differentiation, contributes to the development of carcinogenesis

Reduced dose of subcutaneous cladribine induces identical response rates but decreased toxicity in pretreated chronic lymphocytic leukaemia

Purpose To study the efficacy and the safety of cladribine (2-chlorodeoxyadenosine, 2-CDA) administered as 24-hour infusions or as subcutaneous bolus injections at two different doses to patients with relapsing or refractory chronic lymphocytic leukaemia (CLL). Patients and methods In this non randomised 2-cohort study, 20 patients with pretreated CLL received cladribine at a dose of 0.7 mg/kg/cycle as continuous i.v. infusions over seven days (group 1) and 35 patients were treated at a reduced dose of 0.5 mg/kg/cycle given as s.c. bolus injections for five days (group 2). After two cycles of four week duration, response was assessed. In the case of progressive disease, therapy was discontinued, otherwise a maximum of four additional cycles were administered until best response. Results A total of 130 cycles were administered (group 1: 41, group 2: 89). Patient characteristics in both groups were comparable. The median dose intensities were 0.172 mg/kg per week and 0.123 mg/kg per week for groups 1 and 2, respectively (P ≤ 0.0001). The overall response rate for all 55 patients was 38% (95% confidence interval (95% CI): 25%-52%), with 5% CR and 33% PR. Response was similar in both patient groups (35% in group 1, 40% in group 2). No association between cladribine dose intensity and response rate was found, and there was no difference between patients relapsing after or refractory to previous therapies (11 of 24 vs. 10 of 31). Median remission duration was six months in both groups. Toxicity, in particular infections (all WHO grades, 34% in group 1 versus 7% in group 2) and myelosuppression (grade 1-4 neutropenia, 72% versus 41% of cladribine cycles) were statistically significantly more frequent in group 1. Conclusion Cladribine is active in heavily pretreated patients with chronic lymphocytic leukaemias. Dose reduction by 29% led to similar response and remission duration, but to a significant decrease of myelotoxicity and risk of infection. Cladribine administered as s.c. bolus injections at 0.5 mg/kg per cycle is safe and this dose level should not be exceeded in this patient populatio

Patients' experiences with cancer care in Switzerland: Results of a multicentre cross-sectional survey.

The objectives were to describe patients' experiences of cancer care in Switzerland and explore the variation of these experiences by type of cancer. The Swiss Cancer Patient Experiences (SCAPE) study was a cross-sectional, multicentre survey conducted in 2018. Adult patients (n = 7145) with breast, prostate, lung, colorectal, skin or haematological cancer from four large hospitals in French-speaking Switzerland were invited to complete a survey. Logistic regressions were used to assess whether experiences varied according to cancer type, adjusting for confounders. Of the 3121 persons who returned the survey (44% response rate), 2755 reporting an eligible cancer were included in the analyses. Participants' average score for overall care was 8.5 out of a maximum score of 10. Higher rates of positive experiences were found for nurse consultations (94%), diagnostic tests (85%) and inpatient care (82%). Lower positive responses were reported for support for people with cancer (70%), treatment decisions (66%), diagnosis (65%) and home care (55%). We observed non-systematic differences in experiences of care by cancer type. This large study identified that cancer patient experiences can be improved in relation to communication, information and supportive care aspects. Improvement efforts should target these areas of care to enhance responsiveness of cancer care

Multicenter phase II trial of gefitinib first-line therapy followed by chemotherapy in advanced non-small-cell lung cancer (NSCLC): SAKK protocol 19/03

Background: Gefitinib is active in patients with pretreated non-small-cell lung cancer (NSCLC). We evaluated the activity and toxicity of gefitinib first-line treatment in advanced NSCLC followed by chemotherapy at disease progression. Patients and methods: In all, 63 patients with chemotherapy-naive stage IIIB/IV NSCLC received gefitinib 250 mg/day. At disease progression, gefitinib was replaced by cisplatin 80 mg/m2 on day 1 and gemcitabine 1250 mg/m2 on days 1, 8 for up to six 3-week cycles. Primary end point was the disease stabilization rate (DSR) after 12 weeks of gefitinib. Results: After 12 weeks of gefitinib, the DSR was 24% and the response rate (RR) was 8%. Median time to progression (TtP) was 2.5 months and median overall survival (OS) 11.5 months. Never smokers (n = 9) had a DSR of 56% and a median OS of 20.2 months; patients with epidermal growth factor receptor (EGFR) mutation (n = 4) had a DSR of 75% and the median OS was not reached after the follow-up of 21.6 months. In all, 41 patients received chemotherapy with an overall RR of 34%, DSR of 71% and median TtP of 6.7 months. Conclusions: First-line gefitinib monotherapy led to a DSR of 24% at 12 weeks in an unselected patients population. Never smokers and patients with EGFR mutations tend to have a better outcome; hence, further trials in selected patients are warrante

Current status and updated recommendations for diagnosis and treatment of plasma cell myeloma in Switzerland

The availability of drugs such as thalidomide, bortezomib and lenalidomide changed the landscape in myeloma treatment and has extended the median survival up to 10 years with a substantial improvement in quality of life. This development prompted a Swiss expert panel to re-evaluate the current status and formulate updated clinical recommendations for the diagnosis and treatment of plasma cell myeloma. These recommendations should help clinicians in their decision making to achieve the best outcome based on currently available data