Clinical characteristics and outcome of patients over 60 years with Hodgkin lymphoma treated in Switzerland.

Hodgkin lymphoma (HL) in older patients appears to be a different disease compared with younger patients with historically lower survival rates. This is related to a variety of factors, including increased treatment-related toxicity, the presence of comorbidities, and biologic differences. In order to better assess the clinical characteristics, treatment strategies, and outcome of this particular population, we conducted a population-based, retrospective analysis including 269 patients with HL older than 60 years (median age 71 years, range 60-94), treated between 2000 and 2017 in 15 referral centers across Switzerland. Primary endpoints were overall survival (OS), progression-free survival (PFS), and cause-specific survival (CSS). The vast majority of patients were treated with curative intent, either with a combined modality approach (chemotherapy followed by radiation therapy) or with systemic therapy. At a median follow-up of 6.6 years (95% confidence interval [CI], 6.0-7.6), 5-year PFS was 52.2% (95% CI, 46.0-59.2), 5-year OS was 62.5% (95% CI, 56.4-69.2), and 5-year CSS was 85.1.8% (95% CI, 80.3-90.1) for the entire cohort. A significant difference in terms of CSS was observed for patients older than 71 years in comparison to patients aged 60-70 years (hazard ratio 2.6, 1.3-5.0, p = 0.005). Bleomycin-induced lung toxicity (BLT) was documented in 26 patients (17.7%) out of the 147 patients exposed to this compound and was more frequent in patients older than 71 years (15/60, 25%). Outcome of HL pts older than 71 years appeared to decrease substantially in comparison to the younger counterpart. Treatment-related toxicities appeared to be relevant, in particular, BLT. New, potentially less toxic strategies need to be investigated in prospective clinical trials in this particular frail population.

Rituximab, bendamustine, and lenalidomide in patients with aggressive B cell lymphoma not eligible for high-dose chemotherapy or anthracycline-based therapy: phase I results of the SAKK 38/08 trial.

This phase I trial was designed to develop a new effective and well-tolerated regimen for patients with aggressive B cell lymphoma not eligible for front-line anthracycline-based chemotherapy or aggressive second-line treatment strategies. The combination of rituximab (375 mg/m(2) on day 1), bendamustine (70 mg/m(2) on days 1 and 2), and lenalidomide was tested with a dose escalation of lenalidomide at three dose levels (10, 15, or 20 mg/day) using a 3 + 3 design. Courses were repeated every 4 weeks. The recommended dose was defined as one level below the dose level identifying ≥2/6 patients with a dose-limiting toxicity (DLT) during the first cycle. Thirteen patients were eligible for analysis. Median age was 77 years. WHO performance status was 0 or 1 in 12 patients. The Charlson Comorbidity Index showed relevant comorbidities in all patients. Two DLTs occurred at the second dose level (15 mg/day) within the first cycle: one patient had prolonged grade 3 neutropenia, and one patient experienced grade 4 cardiac adverse event (myocardial infarction). Additional grade 3 and 4 toxicities were as follows: neutropenia (31 %), thrombocytopenia (23 %), cardiac toxicity (31 %), fatigue (15 %), and rash (15 %). The dose of lenalidomide of 10 mg/day was recommended for a subsequent phase II in combination with rituximab 375 mg/m(2) on day 1 and bendamustine 70 mg/m(2) on days 1 and 2.

Management of elderly patients with advanced non-small cell lung cancer: a single-center experience.

BACKGROUND: Optimal management of elderly patients (≥70 years) with non-small cell lung cancer (NSCLC) remains debatable. We compared survival and treatment of advanced NSCLC between elderly and younger patients. METHODS: From the cancer registry, we identified 188 patients treated with chemotherapy for stage IV NSCLC. Patient characteristics, survival, toxicity, chemotherapy regimen and response were compared between age groups (patients 50-69 vs. ≥70 years). RESULTS: There were 96 young and 92 elderly patients. The majority were male (70%) and had adenocarcinoma (53%). More elderly had an ECOG performance status >1 (59 vs. 42%, p = 0.04). Median survival was longer for young patients (11.5 vs. 10.8 months, hazard ratio, HR 1.43, p = 0.04). Patients ≥75 years had a significantly worse outcome compared to the young and patients aged 70-74 years (11.5 vs. 12.8 vs. 7.7 months, HR 1.71, p = 0.01). Hospitalization rate did not differ. Elderly had more hematological toxicities (56 vs. 32%, p = 0.01) and less frequently received first-line platinum combinations (96 vs. 69%, p < 0.001). CONCLUSIONS: Elderly patients had a marginally worse survival compared to young patients. Despite the less frequent use of combination chemotherapy, elderly patients experienced toxicity more often. Survival of those ≥75 years was significantly worse, indicating the urgent need of further research particularly in this age group.

A multicentre phase II trial of gemcitabine for the treatment of patients with newly diagnosed, relapsed or chemotherapy resistant mantle cell lymphoma: SAKK 36/03.

Mantle cell lymphoma (MCL) has a poor prognosis with often short and incomplete remissions. We aimed to test the efficacy and tolerability of gemcitabine in treating MCL. Gemcitabine was given in doses of 1000 mg/m(2) as a 30 min infusion on days 1 and 8 of each 3 week cycle for a maximum of nine cycles. Eighteen patients with a median age of 70 years were recruited. MCL was newly diagnosed in half of patients and relapsed in the remainder. Fifteen patients had Ann Arbor stage IV. The best-recorded responses were 1 CR (complete remission), 4 PRs (partial responses), 8 SDs (stable diseases) and 4 PDs (diseases progression). The response rate (RR) (CR + PR) was 5 (28%; 95% confidence interval: 7.1, 48.5). The patient achieving a CR had stage IV disease. Most haematological adverse events occurred during the first chemotherapy cycle. Three patients developed non-haematological serious adverse events: dyspnea, glomerular microangiopathy with haemolytic uremic syndrome (HUS) and hyperglycaemia. The median time-to-progression and treatment response duration (TRD) was 8.0 (95% confidence interval: 5.5, 9.3) and 10.6 (95% confidence interval: 5.5, 10.9) months, respectively. We conclude that Gemcitabine is well tolerated, moderately active and can induce disease stabilization in patients with MCL.

Nelfinavir and lenalidomide/dexamethasone in patients with lenalidomide-refractory multiple myeloma. A phase I/II Trial (SAKK 39/10).

The antiretroviral agent nelfinavir has antimyeloma activity and can overcome resistance to bortezomib. Our phase I/II trial investigated whether adding nelfinavir to lenalidomide-dexamethasone can overcome lenalidomide resistance in lenalidomide-refractory multiple myeloma (MM). Twenty-nine patients were included (high-risk cytogenetic aberrations 31%; ≥2 prior therapy lines 93%; lenalidomide-bortezomib double-refractory 34%). Twenty-four patients (83%) had prior bortezomib and 10 (34%) were lenalidomide-bortezomib double-refractory. They received four cycles of nelfinavir 2500 mg/day with standard-dose lenalidomide (25 mg days 1-21) and dexamethasone (40/20 mg days 1, 8, 15, 22). Minor response or better was achieved in 16 patients (55%; 95% CI 36-74%), including 40% of those who were lenalidomide-bortezomib double-refractory, and partial response or better in nine patients (31%; 95% CI 15-51%). Median progression-free survival was 3.4 (95% CI 2.0-4.9) months and median overall survival 21.6 (13.0-50.1) months. Lenalidomide-related pneumonitis, pneumonia, and neutropenic fever occurred, but there were no unexpected adverse events. Peripheral blood mononuclear cells showed a 45% (95% CI 40-51%) reduction in total proteasome activity from baseline and significant induction of unfolded protein response and autophagy. Thus, nelfinavir-lenalidomide-dexamethasone is an active oral combination in lenalidomide-refractory MM.

Erlotinib has comparable clinical efficacy to chemotherapy in pretreated patients with advanced non-small cell lung cancer (NSCLC): A propensity-adjusted, outcomes research-based study.

OBJECTIVES: Controversy exists about the integration of erlotinib in patients with EGFR wildtype, advanced NSCLC. MATERIALS AND METHODS: We included patients with advanced NSCLC receiving at least two lines of palliative systemic treatment between January 2005 and December 2014 and not harbouring targetable driver mutations. Primary study endpoint was overall survival (OS), secondary endpoint progression-free survival (PFS). We used Kaplan-Meier statistics, multivariate Cox regression and Propensity score or Inverse Probability Weights (IPW) matching to compare clinical outcome between patients receiving erlotinib in second or further line and those receiving chemotherapy only. The study had a power of 90% to detect a survival superiority of 30%. RESULTS: From a total of 827 patients, we excluded 171 patients with potentially curative treatment, 189 receiving treatment outside of our institute, 206 receiving no or only one line of systemic treatment, 6 with ALK translocations and 28 with EGFR mutations. From 227 patients in the final efficacy analysis, 125 patients received erlotinib in second (89 patients), third (28) or further-line (8), and 102 patients received chemotherapy only. Women and never smokers were significantly overrepresented in the erlotinib group. Both OS (hazard ratio (HR)=1.14, 95% CI 0.80-1.63, P=0.448) and PFS (HR=1.20, 95% CI 0.95-1.52, P=0.119) were similar in the erlotinib compared to the chemotherapy group using IPW-adjusted Cox regression analysis treating the use of erlotinib as a time-dependent covariate starting from second-line treatment and stratified for ECOG performance status and treatment line. ECOG performance status was the most powerful covariate to select patients for erlotinib treatment. CONCLUSION: The present study suggests erlotinib to have similar clinical efficacy compared to chemotherapy in patients with pretreated advanced NSCLC and no known molecular targetable alterations.

[Mabthera for treatment of malignant lymphoma]. / Mabthera zur Behandlung maligner Lymphome.

The incidence of Non-Hodgkin Lymphomas (NHL) is rising in the last decades. The majority of cases are from the B-cell type, characterized by expression of CD-20. Rituximab (Mabthera(r)) is a chimeric monoclonal antibody against CD-20 and has revolutionized the treatment of lymphomas of the B-cell phenotype. This antibody is generally well tolerated and can be given as an outpatient regimen. As monotherapy it has shown good response rates in all CD-20 positive NHL, even in patients with multiple prior treatments. The response rates are even higher by adding Rituximab maintenance therapy. Excellent results have been achieved by combining the antibody with chemotherapy or interferon. In conclusion Rituximab has given us interesting new possibilities in the management of patients with Non-Hodgkin Lymphoma, but the optimal combination, scheduling and duration of this therapy still need to be defined. This review gives an overview of the existing data of Rituximab treatment in different NHL entities.

Pulmonary actinomycosis and Hodgkin's disease: when FDG-PET may be misleading.

We present a patient with advanced Hodgkin's disease treated with escalated BEACOPP chemotherapy. The result from the interim fluorodeoxyglucose positron emission tomography with CT (PET-CT) after two cycles of chemotherapy is crucial for treatment guidance for the clinical trial HD18 from the German Hodgkin Study Group. An increase in size and standard uptake value (SUV) of a pulmonary lesion suggesting refractory Hodgkin's disease was documented. Since all other manifestations of the lymphoma responded well to the treatment, the discordant behaviour was suspicious for another reason for this progressive pulmonary lesion. Bronchoscopy revealed Actinomyces species in cultures from bronchial washings. Specific treatment was initiated and consisted of 2 weeks of intravenous penicillin followed by ceftriaxone intravenous for another 4 weeks and subsequent oral amoxicillin to complete 12 months of antibiotic therapy. For the Hodgkin's lymphoma, complete remission was documented after a total of six cycles of escalated BEACOPP.

Diffuse large B-cell lymphoma in elderly patients: a retrospective analysis.

BACKGROUND: Few data on patterns of care and outcomes are available for elderly patients with diffuse large B-cell lymphoma (DLBCL) outside of clinical trials. METHODS: We identified patients with DLBCL older than 60 years from a regional cancer registry between 2000 and 2010. Based on registry data and chart review, 128 patients from the oncology network of Eastern Switzerland were analysed for patient characteristics, treatment and outcomes of DLBCL. Three age groups were compared: 60-69, 70-79 and over 80 years old. RESULTS: Median age was 73 years (range: 60 to 95 years). 52/121 treated patients received 6 cycles of R-CHOP/CHOP, of those 30 (58%), 18 (35%) and 4 (7%) patients were 60-69 years, 70-79 years or older than 80 years respectively, with a significant difference by age group, p=0.001. Median OS of patients 60-69, 70-79, and 80 years and older receiving 6 cycles of R-CHOP/CHOP were: 54 months, 31 months and 24 months respectively. In comparison, patients receiving other than 6 cycles of R-CHOP/CHOP treatment regimens had a median OS of 22 months, 17 months and 6 months, respectively. In the multivariable analysis other than 6 cycles of R-CHOP/CHOP were significantly associated with poor survival. The risk of dying increased by a mean of 6% for each year of age from age 60 years onwards. CONCLUSION: In conclusion, treatment regimens other than 6 cycles of R-CHOP/CHOP were significant predictors for survival in our oncology network. The possibility of using R-CHOP treatment regimen should be seriously considered in elderly patients with DLBCL.

Safety and pharmacology of gemcitabine and capecitabine in patients with advanced pancreatico-biliary cancer and hepatic dysfunction.

PURPOSE: We assessed the impact of hepatic dysfunction on the safety and pharmacology of gemcitabine/capecitabine in patients with advanced pancreatico-biliary cancer. METHODS: We included 12 patients receiving 3 weekly gemcitabine 1,000 mg/m(2) day 1, 8 and oral capecitabine 650 mg/m(2) b.i.d. over 2 weeks until disease progression or intolerable toxicity. Patients were included into one normal hepatic function cohort [total bilirubin (TB) ≤15 µmol/L] and 3 cohorts with increasing TB (16-39, 40-80, >80 µmol/L). Three patients with a creatinine clearance <60 ml/min were also included. Patients were sampled for gemcitabine, difluoro-deoxy uridine, intracellular gemcitabine triphosphates, capecitabine, 5'-deoxy-5-fluorocytidine, 5'-deoxy-5-fluorouridine and 5-fluorouracil up to 4 h after initiation of chemotherapy on day 1, and up to 90 min on day 8. All compounds were analyzed using validated liquid chromatography-tandem mass spectrometry. Nonlinear mixed-effect modeling was used for population analysis. RESULTS: Hepatic dysfunction was caused by intrahepatic cholestasis in 4 out of 8 patients (50 %) and extrahepatic cholestasis in another 4 patients (50 %). Dose-limiting toxicity was increasing hyperbilirubinemia and severe neutropenia in 2 patients each. Hepatic dysfunction was not associated with dose-limiting toxicity or severe hematological or non-hematological toxicity. However, hepatic dysfunction was associated with low clearance of both gemcitabine (p = 10(-3)) and capecitabine (p = 10(-5)), and low intracellular gemcitabine triphosphate concentrations (p = 10(-3)). CONCLUSIONS: Gemcitabine/capecitabine can be given at the standard dose in patients with severe hyperbilirubinemia, though the present data suggest that gemcitabine's activity may be limited due to poor intracellular activation. In patients with severe hyperbilirubinemia, initial monotherapy with capecitabine should be considered, followed by the addition of gemcitabine with improving hyperbilirubinemia.

[Treatment of metastatic melanoma: are we entering the era of targeted treatment?]. / Update zur Behandlung des metastasierten malignen Melanoms: Beginn einer neuen Ära mit zielgerichteter Therapie?

The treatment of metastatic melanoma has progressed greatly during the last two years. Nowadays melanomas can be divided into molecular subgroups, this being therapeutically relevant. Around 60% of melanomas show a BRAF mutation and can be treated with selected tyrokinase inhibitors. In addition a CTLA-4-antibody was developed which shuts off the natural immune breaking system resulting in a continuous anti-tumor reaction. Angiogenesis inhibitors have shown there importance in different phase II trials. We hope that this represents only the first step of an individualized treatment for metastatic melanoma.

[A rare cause of a cervical lymphadenopathy]. / Eine seltene Differentialdiagnose der zervikalen Lymphadenopathie.

We report on a 15-year-old female patient with a slow-growing, mildly painful swelling on her neck, without any signs of inflammation or any general symptoms. Sonographic findings included two enlarged lymph nodes with hilar markings evident. Based on the histology, Castleman's disease of the hyaline vascular type was ultimately diagnosed. The differential diagnosis of the swelling on the neck is described along with the clinical, diagnostic, pathogenic and therapeutic aspects of Castleman's disease. Castleman's disease is a rare differential diagnosis of non-infectious cervical lymphadenopathy. Unicentric Castleman's is treated by surgical resection. In patients with contraindications, radiotherapy should be discussed as an alternative. Multicentric forms manifest as systemic diseases with poor prognosis and must be managed by an interdisciplinary team.

Effects of an outpatient physical exercise program on hematopoietic stem-cell transplantation recipients: a randomized clinical trial.

Patients who undergo hematopoietic SCT (HSCT) often experience physical and psychological problems, even long after treatment has been completed. This study was performed to evaluate the effects of a 12-week outpatient physical exercise (PE) program, incorporating aerobic and strength exercises, as compared with a usual care control condition on patients' physical performance and psychosocial well-being. Patients who had completed HSCT up to 6 months earlier were randomly assigned to a supervised PE program (n=64) or a usual care control group (n=67). Primary outcomes were quantified physical performance and self-reported physical functioning. Secondary outcomes were body composition measurement, quantified walking activity and patient-reported outcomes (physical activity, fatigue and health-related quality of life). Assessments were at baseline, immediately after program completion and at 3-month follow-up. Significant intervention effects were observed at both posttreatment and follow-up on physical performance measures. No other outcomes yielded statistically significant group differences. PE should be considered in the management of HSCT recipients to improve physical performance after discharge from the hospital. Further research is needed to determine how the program can be enhanced so that improved physical performance also translates into improved physical and psychosocial functioning in daily life.

[Common variable immunodeficiency: a rare humoral immunodeficiency with frequent later change of diagnosis]. / Common variable immunodeficiency: eine seltene humorale Immundefizienz mit meist erst später Diagnosestellung.

Common variable immunodeficiency (CVIS) is a condition associated with a deficiency of humoral immunity. The typical patient is an adolescent or adult with a history of recurrent upper respiratory tract infections over many years. Despite the long history the illness is not readily recognised and diagnosis is usually delayed until the patient is admitted to hospital for a severe respiratory tract infection and is being worked up for causes of immunodeficiency. The diagnosis of CVIS is based on the finding of an immunoglobulin deficiency in immunoelectrophoresis or documentation of reduced IgG subclasses. Typically this leads to upper respiratory tract infections and malabsorption, as illustrated by the case reports. Pathophysiologically this disease is characterised by malfunction of B cells with defective gammaglobulin production or secretion. 7 patients were substituted with IgG, leading to decreased susceptibility to infection and a reduction in hospital admissions due to severe infections.

Acute pericarditis and pleural effusion complicating cytarabine chemotherapy.

BACKGROUND: Pericarditis is a rare but possibly severe complication of treatment of acute leukemia with cytarabine. CASE REPORT: We report a possibly cytarabine-induced acute pericarditis and pleuritis with a rapid onset. A patient with acute myelomonocytic leukemia developed an isolated pericarditis 3 weeks after the first course of chemotherapy with cytarabine and idarubicin. The second course of chemotherapy with cytarabine and amsacrine was started after clinical improvement; 3 days later an acute pericarditis with a large pericardial effusion accompanied by a left pleural effusion developed. A pericardio- and pleuracentesis was performed and the symptoms improved rapidly without reaccumulation of the fluid. The third course of chemotherapy with mitoxantrone and etoposide was completed without further cardiopulmonary complications. CONCLUSION: The differential diagnosis of pericarditis in the setting of chemotherapy with cytarabine should include cytarabine- induced pericarditis. The pathogenesis remains unclear, directly toxic and immunological mechanisms are suggested. Severe progression with massive pericardial effusion necessitating risky pericardiocentesis can occur and therefore a therapy with high-dose corticosteroids should be considered early.