Do patients with reduced or excellent performance status derive the same clinical benefit from novel systemic cancer therapies? A systematic review and meta-analysis.

BACKGROUND: Whether patients with excellent and reduced performance status (PS) derive different net clinical benefit from novel anticancer systemic therapies on clinical trials is unclear. MATERIALS AND METHODS: A systematic review was conducted of randomised controlled trials (RCTs) cited for drug approvals between 2006 and August 2015 by the Food and Drug Administration, the European Medicines Agency and Health Canada. Included studies had overall survival (OS) and/or progression-free survival (PFS) primary endpoints. Meta-analyses of OS/PFS based on PS dichotomised into excellent and reduced subgroups were performed using random effects. RESULTS: The systematic review identified 110 RCTs, with none reporting PS subgroup analyses for toxicity and 66 (60%) for efficacy. For these 66 RCTs involving 44 511 patients, pooled HRs for excellent and reduced groups were 0.65 (95% CI 0.61 to 0.70) and 0.67 (95% CI 0.62 to 0.72), respectively, with no difference between the two groups (p=0.68). Sensitivity analyses based on drug or cancer type and type of endpoints (OS or PFS) demonstrated similar results. CONCLUSIONS: No decrease in relative efficacy from novel systemic therapy was found for patients with reduced PS when compared with patients with excellent PS for the range which were included in modern RCTs. Reporting of PS subgroup analyses of toxicities and more inclusion of patients with borderline low PS in RCTs should be considered for a more comprehensive understanding of the net clinical benefits of contemporary systemic therapies in patients across the spectrum of different PS.

Five hematologic tests and treatments to question.

Choosing Wisely(®) is a medical stewardship initiative led by the American Board of Internal Medicine Foundation in collaboration with professional medical societies in the United States. The American Society of Hematology (ASH) released its first Choosing Wisely(®) list in 2013. Using the same evidence-based methodology as in 2013, ASH has identified 5 additional tests and treatments that should be questioned by clinicians and patients under specific, indicated circumstances. The ASH 2014 Choosing Wisely(®) recommendations include: (1) do not anticoagulate for more than 3 months in patients experiencing a first venous thromboembolic event in the setting of major, transient risk factors for venous thromboembolism; (2) do not routinely transfuse for chronic anemia or uncomplicated pain crises in patients with sickle cell disease; (3) do not perform baseline or surveillance computed tomography scans in patients with asymptomatic, early-stage chronic lymphocytic leukemia; (4) do not test or treat for heparin-induced thrombocytopenia if the clinical pretest probability of heparin-induced thrombocytopenia is low; and (5) do not treat patients with immune thrombocytopenia unless they are bleeding or have very low platelet counts.

Five hematologic tests and treatments to question.

Choosing Wisely® is a medical stewardship initiative led by the American Board of Internal Medicine Foundation in collaboration with professional medical societies in the United States. The American Society of Hematology (ASH) released its first Choosing Wisely® list in 2013. Using the same evidence-based methodology as in 2013, ASH has identified 5 additional tests and treatments that should be questioned by clinicians and patients under specific, indicated circumstances. The ASH 2014 Choosing Wisely® recommendations include: (1) do not anticoagulate for more than 3 months in patients experiencing a first venous thromboembolic event in the setting of major, transient risk factors for venous thromboembolism; (2) do not routinely transfuse for chronic anemia or uncomplicated pain crises in patients with sickle cell disease; (3) do not perform baseline or surveillance computed tomography scans in patients with asymptomatic, early-stage chronic lymphocytic leukemia; (4) do not test or treat for heparin-induced thrombocytopenia if the clinical pretest probability of heparin-induced thrombocytopenia is low; and (5) do not treat patients with immune thrombocytopenia unless they are bleeding or have very low platelet counts.

The ASH Choosing Wisely®campaign: five hematologic tests and treatments to question.

Choosing Wisely® is a medical stewardship and quality improvement initiative led by the American Board of Internal Medicine Foundation in collaboration with leading medical societies in the United States. The ASH is an active participant in the Choosing Wisely® project. Using an iterative process and an evidence-based method, ASH has identified 5 tests and treatments that in some circumstances are not well supported by evidence and which in certain cases involve a risk of adverse events and financial costs with low likelihood of benefit. The ASH Choosing Wisely® recommendations focus on avoiding liberal RBC transfusion, avoiding thrombophilia testing in adults in the setting of transient major thrombosis risk factors, avoiding inferior vena cava filter usage except in specified circumstances, avoiding the use of plasma or prothrombin complex concentrate in the nonemergent reversal of vitamin K antagonists, and limiting routine computed tomography surveillance after curative-intent treatment of non-Hodgkin lymphoma. We recommend that clinicians carefully consider anticipated benefits of the identified tests and treatments before performing them.

The ASH Choosing Wisely® campaign: five hematologic tests and treatments to question.

Choosing Wisely® is a medical stewardship and quality improvement initiative led by the American Board of Internal Medicine Foundation in collaboration with leading medical societies in the United States. The ASH is an active participant in the Choosing Wisely® project. Using an iterative process and an evidence-based method, ASH has identified 5 tests and treatments that in some circumstances are not well supported by evidence and which in certain cases involve a risk of adverse events and financial costs with low likelihood of benefit. The ASH Choosing Wisely® recommendations focus on avoiding liberal RBC transfusion, avoiding thrombophilia testing in adults in the setting of transient major thrombosis risk factors, avoiding inferior vena cava filter usage except in specified circumstances, avoiding the use of plasma or prothrombin complex concentrate in the nonemergent reversal of vitamin K antagonists, and limiting routine computed tomography surveillance after curative-intent treatment of non-Hodgkin lymphoma. We recommend that clinicians carefully consider anticipated benefits of the identified tests and treatments before performing them.

The use of erythropoiesis-stimulating agents in patients with non-myeloid hematological malignancies: a systematic review.

The effectiveness of erythropoiesis-stimulating agents (ESAs) for the treatment of anemia in patients with non-myeloid hematological malignancies needs to be assessed as the response to their administration is not uniform and their cost is high. We conducted a systematic review (SR) of the literature to identify reports of the effect of ESAs on survival, quality of life (QOL), transfusion requirements, and anemia. The entries to MEDLINE, EMBASE, and the Cochrane Library databases, and abstracts published in the proceedings of the annual meetings of the American Society of Clinical Oncology and the American Society of Hematology were searched. Seventeen reports and five abstracts of randomized trials fulfilled prospective criteria for inclusion. Five trials reported on survival; three failed to detect differences between groups and two demonstrated inferior survival in patients allocated to an ESA. Seven trials and three abstracts reported on QOL with four articles and three abstracts describing improvements in patients allocated to erythropoietin. However, important methodologic limitations were identified in these reports. Seven randomized controlled trials reported a reduction in the proportion of patients transfused. The absolute risk reduction in transfusions ranged from 15% to 24%. This is the only SR that assesses the use of erythropoiesis-stimulating agents specifically in patients with hematological malignancies. We conclude that available data evaluating ESAs in patients with hematologic malignancies demonstrate that these agents reduce transfusion requirements. Limitations of these data preclude conclusions that these agents improve QOL. More data are required to confirm the inferior survival associated with ESAs.

A meta-analysis and systematic review of thalidomide for patients with previously untreated multiple myeloma.

A systematic review and meta-analysis was performed to determine the efficacy and toxicity of thalidomide in previously untreated patients with myeloma. Medline, Embase, Cochrane Controlled Trials Register, and abstracts from the American Society of Hematology and the American Society of Clinical Oncology were searched for randomized controlled trials (RCTs) of either induction or maintenance thalidomide in adults with previously untreated myeloma. Nine RCTs of induction thalidomide, three RCTs of maintenance thalidomide, and one RCT of induction and maintenance thalidomide were identified, involving a total of 4144 subjects. When thalidomide was added to standard, non-transplantation myeloma therapy, overall survival (OS) improved (HR 0.67; 95% CI 0.56-0.81). When thalidomide was given as maintenance following autologous transplantation (ASCT), there was a trend to improved OS (HR 0.61, 95% CI 0.37-1.01); when the only trial which combined induction and maintenance thalidomide was excluded from this analysis, a significant survival advantage emerged (HR 0.49, 95% CI 0.32-0.74). The relative risk of venous thromboembolism (VTE) with induction thalidomide was 2.56 (95% CI 1.88-3.49). A meta-analysis of trials/sub-groups administering low molecular weight heparin (LMWH) as VTE prophylaxis, suggested a persistently increased relative risk of VTE with induction thalidomide (RR 1.54, 95% CI 1.07-2.22). The relative risk of VTE was substantially lower, but still elevated, when thalidomide was given as maintenance therapy following ASCT (RR 1.95, 95% CI 1.15-3.30). In summary, thalidomide appears to improve the overall survival of patients with newly diagnosed myeloma both when it is added to standard, non-transplantation therapy, and when it is given as maintenance therapy following ASCT. However, thalidomide is associated with toxicity, particularly a significantly increased risk of VTE.

Meta-analysis of ifosfamide-based combination chemotherapy in advanced soft tissue sarcoma.

BACKGROUND: This meta-analysis examines the role of ifosfamide-based combination chemotherapy in patients with advanced soft tissue sarcoma. Outcomes of interest include overall survival, response rate, adverse effects, and quality of life. METHODS: A systematic review of the literature was searched to identify relevant articles. RESULTS: Three randomized phase III trials were identified comparing combination chemotherapy regimens containing ifosfamide with regimens without ifosfamide. Two randomized trials demonstrated that the addition of ifosfamide to either doxorubicin or to a regimen of doxorubicin and dacarbazine, significantly improved response rates. One randomized trial reported a significant improvement in overall survival for patients receiving doxorubicin and dacarbazine compared to those receiving a combination of doxorubicin, dacarbazine, and ifosfamide (MAID). A meta-analysis of these studies revealed that the addition of ifosfamide to a chemotherapy regimen significantly improves the tumour response rate (RR, 1.52, p=0.009) but does not produce a significant difference in 1-year survival (RR, 0.98, p=0.76). Higher rates of adverse events, particularly grades 3-4 myelosuppression, were observed in patients who received regimens that contained ifosfamide. A higher rate of toxic deaths was reported in two of the three trials, for the ifosfamide containing regimen. Data on quality of life were not reported. CONCLUSION: In patients with metastatic soft tissue sarcoma, the routine addition of ifosfamide to standard first line doxorubicin-containing regimens is not recommended over single agent doxorubicin. However, it may be reasonable to employ such combinations in patients with symptomatic, locally-advanced, or inoperable soft tissue sarcoma where response might render such tumours resectable.

Dose-intensive chemotherapy with growth factor or autologous bone marrow/stem cell transplant support in first-line treatment of advanced or metastatic adult soft tissue sarcoma: a systematic review.

A systematic review was performed to determine whether first-line dose-intensive chemotherapy supported by growth factor or autologous bone marrow/stem cell transplantation improves response rate, time-to-disease progression, or survival compared with standard-dose chemotherapy in patients with inoperable, locally advanced, or metastatic soft tissue sarcoma. The MEDLINE, EMBASE, and Cochrane Library databases were searched. Three randomized trials (2 phase 3, 1 phase 2), 12 phase 2, and 5 phase 1 dose-escalation trials were located. One randomized trial (N=314) did not detect significant differences in response rate (P=.65) or survival (log-rank P=.98) between high-dose doxorubicin plus ifosfamide with granulocyte macrophage colony-stimulating factor and doxorubicin plus ifosfamide at standard doses. Progression-free survival, however, was significantly longer in the high-dose arm (log-rank P=.03). Higher rates of thrombocytopenia, infection, grade 3 of 4 asthenia, and stomatitis were observed with high-dose compared with standard-dose chemotherapy. Preliminary results from a second randomized trial (N=162) indicated no benefit with respect to tumor response for an intensified mesna, doxorubicin (Adriamycin), ifosfamide, and dacarbazine regimen with granulocyte colony-stimulating factor support compared with standard doxorubicin, ifosfamide, and dacarbazine. Grade 4 thrombocytopenia was significantly higher with the high-dose regimen. Four phase 2 trials of high-dose regimens observed tumor response rates greater than 50%. Phase 1 trials reported dose-limiting toxicity for dose-intensive chemotherapy regimens. On the basis of the available evidence, high-dose chemotherapy with growth factor or autologous bone marrow/stem cell transplantation should not be used in the routine treatment of patients with inoperable, locally advanced, or metastatic soft tissue sarcoma.

Single-agent interleukin-2 in the treatment of metastatic melanoma: a systematic review.

BACKGROUND: The aim of this systematic review was to determine the role of single-agent interleukin-2 in the treatment of adults with metastatic melanoma. Outcomes of interest include objective and complete response rates, duration of response, toxicity and quality of life. METHODS: A systematic review of the literature was conducted to locate randomized controlled trials, meta-analyses, and systematic reviews published between 1985 and 2006. RESULTS: Data from three randomized controlled trials demonstrate that single-agent interleukin-2, when given in high-doses, elicited objective response rates of 5-27% with complete responses in 0-4% of patients. High-dose interleukin-2, administered as a single-agent or in combination with lymphokine-activated killer cells, demonstrates complete response rates ranging from 0% to 11% and has shown consistent observations of long-term responses that range from 6 to 66+ months (median 27 months). Non-comparative phase II trials of high-dose single-agent interleukin-2 have consistently reported objective response rates of 10-33% with complete response rates ranging from 0% to 15%. Complete responders in those trials also demonstrate long-term responses ranging from 1.5 to 148 months (median 70 months). No other therapy for metastatic melanoma offers the possibility for a durable complete remission. CONCLUSION: This systematic review suggests that patients with a good performance status (ECOG 0-1), a normal lactate dehydrogenase level, less than three organs involved or cutaneous and/or subcutaneous metastases, have the highest probability of responding and achieving a durable complete response. This carefully selected group of patients should be considered for treatment with high-dose interleukin-2.

Rituximab in lymphoma: a systematic review and consensus practice guideline from Cancer Care Ontario.

Rituximab is the first antibody-based therapy approved in cancer. The role of this treatment for non-Hodgkin's lymphoma has evolved significantly since its introduction. We aimed to systematically review the literature on rituximab in non-Hodgkin's lymphoma and provide consensus guidelines as to the rational use of this agent. Validated methodology from the Cancer Care Ontario Program in Evidence-Based Care was applied. A comprehensive literature search was completed by reviewers from the Hematology Disease Site Group of Cancer Care Ontario. Data were abstracted from randomized controlled trials of rituximab-containing regimens for patients with non-Hodgkin's lymphoma. Twenty-three randomized controlled trials (RCTs) of rituximab-based therapy were analyzed. Consistent and clinically important benefits in progression-free and overall survival and were seen in the following settings: (1) addition of rituximab to combination chemotherapy for initial treatment of diffuse large B-cell lymphoma and other aggressive B-cell lymphomas; (2) addition of rituximab to combination chemotherapy for initial and subsequent treatment of follicular lymphoma and other indolent B-cell lymphomas; and (3) use of rituximab alone as extended maintenance therapy in patients with indolent B-cell lymphomas who have responded to initial treatment. The consensus opinion of the Hematology Disease Site Group is that rituximab is recommended for these indications.

The role of high-dose-rate brachytherapy in the palliation of symptoms in patients with non-small-cell lung cancer: a systematic review.

PURPOSE: This review addresses the role of high-dose-rate endobronchial brachytherapy (HDREB) for symptom palliation in patients with non-small-cell lung cancer. METHODS AND MATERIALS: Relevant trials were identified through a systematic search of the literature. RESULTS: Twenty-nine trials were eligible. Six randomized trials involved HDREB alone or with external beam radiation therapy (EBR) or laser therapy. Median and 1-year survival ranged from 4 to 10 months and from 11% to 38%, respectively. Symptoms controlled by HDREB were dyspnea, cough, chest pain, and hemoptysis. Fatal hemoptysis ranged from 7% to 22%. Better overall symptom palliation and fewer retreatments were required in previously untreated patients using EBR alone or EBR with HDREB. CONCLUSIONS: EBR alone is more effective than HDREB for symptom palliation in previously untreated patients with endobronchial non-small-cell lung cancer. HDREB with EBR seems to provide better symptom relief than EBR alone. HDREB is recommended for symptomatic patients with recurrent endobronchial obstruction previously treated by EBR, providing it is technically feasible.

Yttrium 90 ibritumomab tiuxetan in lymphoma.

Radioimmunoconjugates are radioisotope-bound monoclonal antibodies that target radiation specifically to sites of lymphoma involvement. Initial studies of 90Y-ibritumomab tiuxetan in non-Hodgkin's lymphoma (NHL) have suggested benefit in patients with relapsed or refractory indolent disease. However, the routine adoption of this agent is tempered by concerns of associated toxicities and unclear long-term benefit. A comprehensive search for studies on 90Y-ibritumomab tiuxetan use in lymphoma was completed. The aims of this systematic review were to summarize and evaluate the evidence on: (1) the benefits and risks of this novel therapy; (2) predictors for response and toxicity; and (3) the role of dosimetry and imaging studies prior to treatment. A total of twenty trials investigating the use of 90Y-ibritumomab tiuxetan for the treatment of adult patients with NHL were identified. In trials of patients with relapsed or refractory indolent NHL, overall response rates ranged from 67 - 83%. In patients with follicular NHL refractory to the monoclonal antibody, rituximab, response rates remained high (74%). However, in rituximab-naïve patients with relapsed or refractory indolent or transformed NHL, the higher response rate seen with 90Y-ibritumomab tiuxetan therapy compared to rituximab monotherapy has not translated into clear improvements in time-to-progression or survival. 90Y-ibritumomab tiuxetan is an active agent in relapsed and refractory non-Hodgkin's lymphoma that should be considered in select patients.

The role of radiation therapy in malignant pleural mesothelioma: a systematic review.

INTRODUCTION: Radiation therapy may offer patients presenting with malignant pleural mesothelioma (MPM) symptom palliation and improvements in quality of life. This systematic review will address the role of radiation therapy in the management of MPM. METHODS: A thorough systematic search of the literature was conducted for published articles and conference proceedings for applicable abstracts. Relevant trials were selected and assessed. RESULTS: Three small randomized controlled trials compared prophylactic external beam radiation therapy to no radiation therapy for patients with thoracic tracts caused by drainage tubes or diagnostic procedures. None of those trials reported any serious adverse effects. A pooled analysis found no significant reduction in the frequency of procedure tract metastases. Four non-comparative studies have shown that hemithoracic irradiation alone resulted in significant toxicity, including radiation-induced pulmonary fibrosis, radiation pneumonitis, and bronchopleural fistula, without any survival benefit. Few of the identified studies reported on symptom control, and no studies included formal measures of quality of life. CONCLUSION: There is limited evidence for the role of radiotherapy in the management of patients with MPM. Future studies including radiotherapy for the treatment of such patients should include formal measures of quality of life and symptom control.

The use of chemotherapy in patients with advanced malignant pleural mesothelioma: a systematic review and practice guideline.

BACKGROUND: This clinical practice guideline, based on a systematic review, was developed to determine which chemotherapeutic agents (or combinations of agents) show the highest response rates, improved survival, quality of life, or symptom control in patients with advanced malignant pleural mesothelioma. METHODS: A thorough systematic search of the literature was conducted for published articles and conference proceedings for applicable abstracts. Relevant trials, published as articles and abstracts, were selected and assessed. External feedback was obtained from Ontario clinicians, and the guideline was approved by the provincial Lung Cancer Disease Site Group. RESULTS: One hundred nineteen studies were eligible, including eight randomized trials and 111 phase II trials. The pooled response rates from phase II trials suggest that response rates with combination chemotherapy are higher than with single agents. Data from the largest randomized controlled trial demonstrated that chemotherapy with cisplatin and pemetrexed significantly improves response rates (41% versus 17%, p < 0.001), time to progression (5.7 months versus 3.9 months, p = 0.001), and overall survival (median, 12.1 months versus 9.3 months, hazard ratio = 0.77, p = 0.020) in comparison to single-agent cisplatin. A second trial demonstrated cisplatin and raltitrexed significantly improved median survival compared to single-agent cisplatin (11.4 months versus 8.8 months; hazard ratio = 0.76, p = 0.0483). Overall response rate (24% versus 14%, p = 0.056) was greater in the combination treatment arm, but this difference was not statistically significant. CONCLUSIONS: There is good evidence to recommend chemotherapy with pemetrexed and cisplatin for adult patients with symptomatic advanced malignant pleural mesothelioma. Such treatment should be administered with supplementation of vitamin B12 and folic acid. If pemetrexed is not available, cisplatin plus raltitrexed is a reasonable alternative.

Surgical management of malignant pleural mesothelioma: a systematic review and evidence summary.

UNLABELLED: An evidence summary was developed for the surgical management of adult patients with diffuse or localized malignant pleural mesothelioma. This evidence summary is based on a systematic search and review of the literature published between 1985 and February 2004. Relevant studies were identified, according to pre-determined criteria by the authors and methodologists. No randomized controlled trials comparing pleurectomy (PL) with extrapleural pneumonectomy (EPP) or comparing surgery with an alternative treatment were identified. Four comparative studies, seven non-comparative prospective studies, and 16 retrospective case series were identified that looked at PL, or EPP, or PL and EPP. Trial results were not pooled due to the heterogeneity of the treatments in the trials and the fact that no trials were randomized and none were designed to directly compare different treatments. External feedback was obtained from Ontario clinicians, and the provincial Lung Cancer Disease Site Group approved the review. CONCLUSIONS: The role of surgery in the management of malignant pleural mesothelioma cannot be precisely defined as the lack of randomized controlled clinical trials makes it impossible to determine whether the use of EPP or PL improves survival or effectively palliates the symptoms of the disease. Future studies of the role of surgery in the treatment of mesothelioma should include evaluations of quality of life.