Cancer-Related Fatigue in Patients With and Survivors of Hodgkin Lymphoma: The Impact on Treatment Outcome and Social Reintegration.

Purpose Cancer-related fatigue occurs frequently in patients with Hodgkin lymphoma (HL) and has a major impact on their quality of life. We hypothesized that severe fatigue (sFA) might have an impact on patients' treatment outcome and social reintegration. Methods Of 5,306 patients enrolled in the German Hodgkin Study Group's fifth generation of clinical trials in HL (HD13, HD14, and HD15; nonqualified and older [> 60 years] patients excluded), 4,529 provided data on health-related quality of life. We describe sFA (defined as a score ≥ 50 on the 0 to 100 scale from the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30) before and up to 9 years after therapy and analyze its impact on treatment outcome and social reintegration. Results The proportion of patients reporting sFA was 37% at baseline and ranged from 20% to 24% during follow-up. Baseline sFA was associated with significantly impaired progression-free survival and a trend to impaired overall survival, which can be overcome in patients receiving highly effective HL therapies as applied in our fifth-generation trials. Our analysis revealed a significant negative association of sFA and employment in survivors: 5 years after therapy, 51% and 63% of female and male survivors, respectively, with sFA were working or in professional education, compared with 78% and 90% without sFA, respectively ( P < .001 adjusted for age, sex, stage, baseline employment status, and treatment outcome). sFA was also associated with financial problems and the number of visits to a general practitioner and medical specialists. Conclusion sFA is an important factor preventing survivors from social reintegration during follow-up. This observation underscores the need to address fatigue as a significant diagnosis when treating patients with and survivors of cancer.

Cancer-related fatigue in patients with and survivors of Hodgkin's lymphoma: a longitudinal study of the German Hodgkin Study Group.

BACKGROUND: Patients with Hodgkin's lymphoma might have persistent fatigue even years after treatment. However, knowledge of the development of fatigue persisting long after completion of treatment is limited. Therefore, we did a detailed analysis of fatigue in our first-line clinical trials for early-stage favourable (HD13 trial), early-stage unfavourable (HD14 trial), and advanced-stage (HD15 trial) Hodgkin's lymphoma. Beyond the description of fatigue from diagnosis up to 5 years after treatment, we aimed to assess any effect of patient characteristics, disease characteristics, or treatment characteristics on persistent fatigue. METHODS: In this longitudinal study, we included patients with early-stage favourable, early-stage unfavourable, and advanced-stage Hodgkin's lymphoma from the HD13, HD14, and HD15 trials, respectively, aged between 18 and 60 years. Eligible patients for these trials had newly diagnosed, histologically proven Hodgkin's lymphoma, an Eastern Cooperative Oncology Group performance status of 2 or lower, HIV negativity, and absence of comorbidity disallowing protocol treatment. We used the fatigue scale of the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire to assess fatigue from diagnosis up to 5 years after the end of treatment. The primary outcomes of interest in this study were fatigue scores in the second and fifth year after end of treatment. We estimated the effect of different disease, patient, and treatment characteristics on fatigue with multiple regression analyses and identified fatigue trajectories with growth mixture models. The regression analyses and growth mixture models used robust and full information maximum likelihood estimates to account for missing data. The HD13, HD14, and HD15 trials are registered as international standard randomised controlled trials, ISRCTN63474366, ISRCTN04761296, and ISRCTN32443041, respectively. FINDINGS: The HD13 trial enrolled patients with early-stage favourable disease from Jan 28, 2003, to Sept 30, 2009; the HD14 trial enrolled patients with early-stage unfavourable disease from Jan 28, 2003, to Dec 23, 2009; and the HD15 trial enrolled patients with advanced-stage disease from Jan 28, 2003, to April 18, 2008. 5306 patients were enrolled in these trials. We analysed 4215 patients with any valid fatigue assessment up to 5 years after the end of treatment. Patients with higher tumour burden at diagnosis had more fatigue at baseline (mean fatigue score in HD13: 30·8 [SD 28·0]; in HD14: 39·8 [29·4], and in HD15: 49·0 [30·2]). Fatigue scores (FA) in the second year after the end of treatment were 28·5 (24·7) in HD13, 28·8 (24·4) in HD14, and 30·7 (24·4) in HD15; in the fifth year after the end of treatment FA was 30·8 (26·0) in HD13, 27·1 (24·8) in HD14, and 28·2 (24·9) in HD15. Predictors of fatigue in the second and fifth year after end of treatment were baseline fatigue (p<0·0001) and age as a continuous variable (p<0·0001). In addition to preceding fatigue and age, patient sex and Hodgkin's lymphoma specific risk factors at baseline did not consistently and significantly improve the prognosis of fatigue in the first, second, and fifth year after end of treatment. There was no significant effect of treatment on fatigue scores in the second and fifth year after treatment. INTERPRETATION: Our findings show a high incidence of severe acute and persistent fatigue in Hodgkin's lymphoma survivors, which is largely independent of tumour stage and treatment. Our results contribute to a better understanding of fatigue in patients with Hodgkin's lymphoma and Hodgkin's lymphoma survivors and could inform development of urgently needed intervention strategies. FUNDING: Deutsche Krebshilfe.

Brentuximab vedotin in relapsed/refractory Hodgkin lymphoma post-autologous transplant: meta-analysis versus historical data.

OBJECTIVE: This meta-analysis evaluated the antitumor activity of brentuximab vedotin versus historical values in patients with relapsed/refractory Hodgkin lymphoma post-autologous stem cell transplantation (ASCT). METHODS: A systematic literature review identified studies (1993-February 2013) reporting complete remission (CR) rates in patients with relapsed/refractory Hodgkin lymphoma post-ASCT. Publications reporting CR rates, identified through interrogation of multiple electronic databases and manual searches (with search terms used to capture 'relapsed', 'refractory', 'HL', and 'ASCT'), were included if they reported: ≥20 relapsed/refractory Hodgkin lymphoma patients, where ≥80% were aged ≥12 years and ≥50% had failed prior ASCT. Overall CR rate was determined using a random-effect model, and compared with that reported for brentuximab vedotin in a pivotal phase 2 trial (SG035-0003). MAIN OUTCOME MEASURES: Across 17 evaluable studies of historical or experimental agents (n = 812), the estimated overall CR rate was 11.1% (95% confidence interval [CI] 7.0, 17.6; range, 0-38.5%) versus 33.3% (95% CI 25.3, 43.9) for brentuximab vedotin (p < 0.0001). In sensitivity analyses, the estimated overall CR rates for historical/experimental agents were 13.6% (95% CI 8.7, 21.4) when only HL trials that reported a CR rate of >0% were included (13 studies; n = 696; p = 0.0009 vs. brentuximab vedotin), and 9.0% (95% CI 4.9, 16.6) when only HL trials were included where CR definition was reported and was measured using the same criteria as in the SG035-0003 study (12 studies; n = 562; p = 0.0001 vs. brentuximab vedotin). CONCLUSIONS: Indirect comparisons against a heterogeneous historical sample population naturally limit our ability to draw comparisons, yet the results from this quantitative meta-analysis suggest that the antitumor activity of brentuximab vedotin may exceed that of other therapies used to treat patients with relapsed/refractory Hodgkin lymphoma post-ASCT.

The epidemiology and targeted therapies for relapsed and refractory CD30+ lymphomas.

BACKGROUND: Hodgkin lymphoma (HL) and systemic anaplastic large cell lymphoma (sALCL) both have consistent expression of CD30, a cytokine receptor that is expressed by activated T and B cells but is largely absent from normal tissue. METHODS: A literature search was conducted via PubMed, Google Scholar, and UpToDate to identify relevant peer-reviewed original research or review articles on HL, sALCL, and CD30 targeted therapies. RESULTS: These lymphomas are both more common among males, young adults and the elderly. Although many patients with HL and sALCL can achieve long-term remission after standard first-line therapy, up to a third of these patients are refractory to or relapse after initial therapy. Among these relapsed/refractory patients, many experience disease progression and/or death despite subsequent treatment, and treatment-related adverse events and mortality are not uncommon. To address the need for safer and more effective therapies for these relapsed/refractory patients, researchers have developed therapies that specifically target CD30-expressing cells. Brentuximab vedotin, an antibody-drug conjugate that selectively delivers a toxic microtubule-disrupting agent to malignant cells with CD30 expression, is the first such therapy to be approved in the US and Europe. In clinical trials, brentuximab vedotin has demonstrated efficacy and safety in patients with HL after failure of autologous stem cell transplantation (ASCT), or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates, and in patients with sALCL after failure of at least one prior multi-agent chemotherapy regimen. CONCLUSION: HL and sALCL are both CD30+ lymphomas, and therapies like brentuximab vedotin that target cells expressing CD30 hold promise for the treatment of these diseases.

Phase I study of pemetrexed and pegylated liposomal doxorubicin in patients with refractory breast, ovarian, primary peritoneal, or fallopian tube cancer.

PURPOSE: Pemetrexed and pegylated liposomal doxorubicin (PLD) are clinically active as single agents and preclinically synergistic. This phase I, open-label trial evaluated the maximum tolerated dose (MTD) and safety of pemetrexed followed by PLD in patients with breast or gynecologic cancers. PATIENTS: Using 3 + 3 dose escalation, cohorts of 3-9 patients received escalating doses of pemetrexed 400-500 mg/m(2) on days 1 and 15 and PLD 30-45 mg/m(2) on day 1 of a 28-day cycle. All patients received folic acid and vitamin B(12) until 21 days after last pemetrexed dose. Patients continued until dose-limiting toxicity (DLT) or progression (PD). RESULTS: From 11/05 to 2/08, 29 patients entered treatment; median age: 60.6 years (range, 47.5-80.1); ECOG PS 0/1: 27.6%/72.4%; primary disease site: ovarian (55.2%), breast (34.5%), peritoneum (10.3%); prior therapies: chemotherapy (100.0%), surgery (72.4%), hormones/biologics (35%), and radiation (20.7%). Pemetrexed/PLD dose levels: L1 = 400/30 (n = 4), L2 = 400/35 (n = 6), L3 = 500/35 (n = 9), L4 = 500/40 (n = 7), and L5 = 500/45 (n = 3). Treatment-related grade 3-4 toxicities: hematologic-neutropenia (86.2%), leukopenia (58.6%), thrombocytopenia (48.3%), anemia (41.4%); nonhematologic-mucosal inflammation (24.1%), febrile neutropenia (24.1%), hand-foot syndrome (13.8%), hypokalaemia (10.3%). Reasons for discontinuation: PD (48.3%), toxicity (27.6%), patient request (13.8%), and investigator request (10.3%). EFFICACY: 5 ovarian patients (20.8%) achieved partial response; median time to progression (TTP) was 6.1 months (range, 1.2-12.5). CONCLUSION: Pemetrexed plus PLD was reasonably tolerated in this heavily-pretreated population. MTD: pemetrexed 500 mg/m(2) and PLD 40 mg/m(2) may be carried forward to phase II studies in specific patient populations. TTP in platinum-refractory ovarian patients was greater than expected.

Results of a phase II study of pemetrexed as first-line chemotherapy in patients with advanced or metastatic breast cancer.

Palliation is the primary goal in metastatic breast cancer (MBC), and safe, efficacious, new single-agent options are needed. Pemetrexed, an antifolate, inhibits several folate-dependent enzymes involved in purine biosynthesis. The primary goal of this study was to determine the objective response rate in patients with advanced or MBC given pemetrexed as a first-line, dose-dense, every 2-week chemotherapy. Women with HER2-negative advanced or MBC, without prior cytotoxic treatment for this stage of disease, were treated with intravenous pemetrexed 600 mg/m² on Day 1 of each 14-day cycle. Standard dexamethasone, folic acid, and vitamin B(12) premedications were given. 37 patients enrolled; 36 received ≥ 1 dose of pemetrexed and 35 were evaluable for response. Median age of patients was 61.4 years, 76% were hormone receptor positive (ER+ and/or PR+). Prior treatment included adjuvant chemotherapy (57%) and/or endocrine (65%). Patients received a median of 6 cycles of pemetrexed (range, 1-21). Based on 35 evaluable patients, the overall response rate (ORR) was 26% (1 CR and 8 PR), and the clinical benefit rate (CR+ PR+ stable disease [SD] ≥ 6 months) was 40%. Median progression-free survival (PFS) was 4.1 months (range, <1-22.4). Median overall survival (OS) was 18.9 months (range, <1-27.7). Grades 3-4 treatment-related toxicities included: neutropenia (36%), leukopenia (17%), fatigue (14%), and anemia (14%). Grade 1/2 alopecia was seen in 8% of patients. This phase II study of dose-dense, single-agent pemetrexed showed moderate activity in the first-line setting with acceptable toxicity and no significant alopecia.

A phase II trial of pemetrexed and gemcitabine in patients with metastatic breast cancer who have received prior taxane therapy.

PURPOSE: This phase II trial assessed efficacy and safety of pemetrexed plus gemcitabine to treat metastatic or locally advanced breast cancer in patients previously treated with taxanes. PATIENTS AND METHODS: Eligible women with advanced breast cancer treated with taxanes in the adjuvant or metastatic setting received pemetrexed 500 mg/m2 on day 1 followed by gemcitabine 1000 mg/m2 on days 1 and 8 of a 21-day cycle. Hematologic toxicities limiting day 8 gemcitabine dosing were observed in the first 20 patients, prompting a protocol amendment to evaluate pemetrexed 500 mg/m2 followed by gemcitabine 1500 mg/m2 on day 1 of a 14-day cycle. Patients received folic acid, vitamin B12, and dexamethasone. The primary endpoint was objective response rate (ORR). RESULTS: Between July 2003 and September 2006, 73 evaluable women (median age, 52.1 years; range, 28-73 years) were enrolled (21-day schedule: 21 patients, 52% estrogen receptor-positive, 24% HER2-positive; 14-day schedule: 52 patients, 58% ER-positive, 15% HER2-positive). For patients on the 21-day and 14-day schedules, median number of cycles was 4 (range, 1-8 cycles) and 5 (range, 1-38 cycles), respectively. The ORRs were 23.8% and 19.2%, respectively; median survival times were 16.2 months and 13.4 months. The most common grade 3/4 hematologic toxicities were neutropenia (71% vs. 33%) and leukopenia (24% vs. 14%); febrile neutropenia occurred in 10% and 6%. The most common grade 3/4 nonhematologic toxicity was fatigue (29% vs. 10%). CONCLUSION: Pemetrexed/gemcitabine given on a 21-day or 14-day schedule is active in patients with advanced breast cancer previously treated with taxanes. A 14-day schedule appears to result in fewer serious toxicities.

A phase II study of oral enzastaurin in patients with metastatic breast cancer previously treated with an anthracycline and a taxane containing regimen.

PURPOSE: Enzastaurin is a potent, serine-threonine kinase inhibitor which selectively targets PKCß and PI3K/AKT signaling pathways to reduce cell proliferation, induce apoptosis, and inhibit angiogenesis. As PKCbeta and PI3K/AKT signaling are both involved in breast cancer pathogenesis, this phase II study evaluated the efficacy and toxicity of enzastaurin in previously treated patients with metastatic breast cancer (MBC). PATIENTS AND METHODS: Eligible patients had histologically confirmed MBC with measurable disease, and must have received prior anthracycline and taxane chemotherapy, but not more than two prior regimens for MBC. Human epidermal growth factor 2 (HER2)-positive patients must have progressed on prior trastuzumab therapy. Enzastaurin, 1,125-mg loading dose on day 1 followed by 500 mg daily, was administered orally in 28-day cycles. Response was assessed every 2 cycles according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. RESULTS: Twenty-one patients enrolled between November 2006 and September 2007. Fourteen (66.7%) patients completed at least two cycles of therapy. No patients developed Grade 3/4 hematologic toxicity. Grade 3 nonhematologic toxicity was rare (<5%) and most commonly attributed to MBC progression. There were no objective responses and no patients with stable disease for >/=6 months. Median progression-free survival was 1.68 months (95%CI: 1.02, 1.74). CONCLUSIONS: Enzastaurin monotherapy was well tolerated, but demonstrated no activity in patients with heavily pretreated MBC.

Neurotrophin-induced melanoma cell migration is mediated through the actin-bundling protein fascin.

Expression of the p75 neurotrophin receptor (p75(NTR)) in primary melanomas is associated with deeply invasive lesions. In turn, there is expression of high levels of neurotrophins at the invasion front of normal tissue adjacent to brain metastases, thus implicating this growth factor-receptor system in melanoma tumorigenesis. The neurotrophins nerve growth factor (NGF) and neurotrophin-3 (NT-3) are potent chemotactic agents for human melanoma cells which express p75(NTR)in vitro. Here we show that the actin-bundling protein fascin specifically interacts with p75(NTR) in an NGF-dependent manner by co-immunoprecipitation and colocalization in melanoma cells that express the two proteins endogenously. In addition, expression of a fascin point mutant at the serine phosphorylation site (serine 39) regulating actin binding abrogates neurotrophin-induced migration. These results suggest a causal role for NGF-mediated dephosphorylation of serine 39 on fascin in mediating actin binding and subsequent melanoma cell migration.