A 3D deep learning model to predict the diagnosis of dementia with Lewy bodies, Alzheimer's disease, and mild cognitive impairment using brain 18F-FDG PET.

PURPOSE: The purpose of this study is to develop and validate a 3D deep learning model that predicts the final clinical diagnosis of Alzheimer's disease (AD), dementia with Lewy bodies (DLB), mild cognitive impairment due to Alzheimer's disease (MCI-AD), and cognitively normal (CN) using fluorine 18 fluorodeoxyglucose PET (18F-FDG PET) and compare model's performance to that of multiple expert nuclear medicine physicians' readers. MATERIALS AND METHODS: Retrospective 18F-FDG PET scans for AD, MCI-AD, and CN were collected from Alzheimer's disease neuroimaging initiative (556 patients from 2005 to 2020), and CN and DLB cases were from European DLB Consortium (201 patients from 2005 to 2018). The introduced 3D convolutional neural network was trained using 90% of the data and externally tested using 10% as well as comparison to human readers on the same independent test set. The model's performance was analyzed with sensitivity, specificity, precision, F1 score, receiver operating characteristic (ROC). The regional metabolic changes driving classification were visualized using uniform manifold approximation and projection (UMAP) and network attention. RESULTS: The proposed model achieved area under the ROC curve of 96.2% (95% confidence interval: 90.6-100) on predicting the final diagnosis of DLB in the independent test set, 96.4% (92.7-100) in AD, 71.4% (51.6-91.2) in MCI-AD, and 94.7% (90-99.5) in CN, which in ROC space outperformed human readers performance. The network attention depicted the posterior cingulate cortex is important for each neurodegenerative disease, and the UMAP visualization of the extracted features by the proposed model demonstrates the reality of development of the given disorders. CONCLUSION: Using only 18F-FDG PET of the brain, a 3D deep learning model could predict the final diagnosis of the most common neurodegenerative disorders which achieved a competitive performance compared to the human readers as well as their consensus.

Adopting transfer learning for neuroimaging: a comparative analysis with a custom 3D convolution neural network model.

BACKGROUND: In recent years, neuroimaging with deep learning (DL) algorithms have made remarkable advances in the diagnosis of neurodegenerative disorders. However, applying DL in different medical domains is usually challenged by lack of labeled data. To address this challenge, transfer learning (TL) has been applied to use state-of-the-art convolution neural networks pre-trained on natural images. Yet, there are differences in characteristics between medical and natural images, also image classification and targeted medical diagnosis tasks. The purpose of this study is to investigate the performance of specialized and TL in the classification of neurodegenerative disorders using 3D volumes of 18F-FDG-PET brain scans. RESULTS: Results show that TL models are suboptimal for classification of neurodegenerative disorders, especially when the objective is to separate more than two disorders. Additionally, specialized CNN model provides better interpretations of predicted diagnosis. CONCLUSIONS: TL can indeed lead to superior performance on binary classification in timely and data efficient manner, yet for detecting more than a single disorder, TL models do not perform well. Additionally, custom 3D model performs comparably to TL models for binary classification, and interestingly perform better for diagnosis of multiple disorders. The results confirm the superiority of the custom 3D-CNN in providing better explainable model compared to TL adopted ones.

Age Prediction Using Resting-State Functional MRI.

The increasing lifespan and large individual differences in cognitive capability highlight the importance of comprehending the aging process of the brain. Contrary to visible signs of bodily ageing, like greying of hair and loss of muscle mass, the internal changes that occur within our brains remain less apparent until they impair function. Brain age, distinct from chronological age, reflects our brain's health status and may deviate from our actual chronological age. Notably, brain age has been associated with mortality and depression. The brain is plastic and can compensate even for severe structural damage by rewiring. Functional characterization offers insights that structural cannot provide. Contrary to the multitude of studies relying on structural magnetic resonance imaging (MRI), we utilize resting-state functional MRI (rsfMRI). We also address the issue of inclusion of subjects with abnormal brain ageing through outlier removal. In this study, we employ the Least Absolute Shrinkage and Selection Operator (LASSO) to identify the 39 most predictive correlations derived from the rsfMRI data. The data is from a cohort of 176 healthy right-handed volunteers, aged 18-78 years (95/81 male/female, mean age 48, SD 17) collected at the Mind Research Imaging Center at the National Cheng Kung University. We establish a normal reference model by excluding 68 outliers, which achieves a leave-one-out mean absolute error of 2.48 years. By asking which additional features that are needed to predict the chronological age of the outliers with a smaller error, we identify correlations predictive of abnormal aging. These are associated with the Default Mode Network (DMN). Our normal reference model has the lowest prediction error among published models evaluated on adult subjects of almost all ages and is thus a candidate for screening for abnormal brain aging that has not yet manifested in cognitive decline. This study advances our ability to predict brain aging and provides insights into potential biomarkers for assessing brain age, suggesting that the role of DMN in brain aging should be studied further.

Interactive microsurgical anatomy education using photogrammetry 3D models and an augmented reality cube.

OBJECTIVE: This study sought to assess the use of an augmented reality (AR) tool for neurosurgical anatomical education. METHODS: Three-dimensional models were created using advanced photogrammetry and registered onto a handheld AR foam cube imprinted with scannable quick response codes. A perspective analysis of the cube anatomical system was performed by loading a 3D photogrammetry model over a motorized turntable to analyze changes in the surgical window area according to the horizontal rotation. The use of the cube as an intraoperative reference guide for surgical trainees was tested during cadaveric dissection exercises. Neurosurgery trainees from international programs located in Ankara, Turkey; San Salvador, El Salvador; and Moshi, Tanzania, interacted with and assessed the 3D models and AR cube system and then completed a 17-item graded user experience survey. RESULTS: Seven photogrammetry 3D models were created and imported to the cube. Horizontal turntable rotation of the cube translated to measurable and realistic perspective changes in the surgical window area. The combined 3D models and cube system were used to engage trainees during cadaveric dissections, with satisfactory user experience. Thirty-five individuals (20 from Turkey, 10 from El Salvador, and 5 from Tanzania) agreed that the cube system could enhance the learning experience for neurosurgical anatomy. CONCLUSIONS: The AR cube combines tactile and visual sensations with high-resolution 3D models of cadaveric dissections. Inexpensive and lightweight, the cube can be effectively implemented to allow independent co-visualization of anatomical dissection and can potentially supplement neurosurgical education.

Endoscopic Endonasal Transtuberculum Approach for Pediatric Tuberoinfundibular Craniopharyngioma: 2-Dimensional Operative Video.

INDICATIONS CORRIDOR AND LIMITS OF EXPOSURE: The endoscopic endonasal transtuberculum approach grants access to suprasellar and retrochiasmatic lesions with hypothalamic involvement. Here, we present a case of a 13-year-old boy with a history of stunted growth, decreased vision, headaches, and low energy with a tuberoinfundibular craniopharyngioma. The patient consented to the procedure. ANATOMIC ESSENTIALS NEED FOR PREOPERATIVE PLANNING AND ASSESSMENT: Evaluation of the sphenoid sinus pneumatization, internal carotid artery disposition, presence of clinoidal rings, variations of the infrachiasmatic corridor (optic chiasm location, height of dorsum sella), and location of the pituitary stalk are crucial for surgical strategy. ESSENTIALS STEPS OF THE PROCEDURE: Harvesting of nasoseptal flap and access to the sphenoid sinus; drilling the sella, tuberculum, and chiasmatic sulcus up to the limbus sphenoidalis and laterally exposing the clinoidal carotid artery segment; wide dural opening to the level of distal rings inferolaterally and falciform ligaments superolaterally; identification and coagulation of superior hypophyseal branches providing tumor supply; intracapsular dissection and debulking and subpial sharp dissection at the hypothalamic tumor interface to achieve complete removal; and reconstruction with inlay collagen, fascia lata, and nasoseptal flap. PITFALLS/AVOIDANCE OF COMPLICATIONS: Preservation of the superior hypophyseal arteries and stalk is essential for preventing pituitary dysfunction. Preoperative reckoning of hypothalamic invasion and identification of adequate interface aids in avoiding complications. To reduce CSF leak risk, multilayer reconstruction was performed and lumbar drain placed postoperatively. VARIANTS AND INDICATIONS FOR THEIR USE: For retroclival extension, intradural pituitary transposition should be considered to expand the corridor; in patients with preoperative hypopituitarism, pituitary sacrifice is most effective to increase retroclival access.

Assessing the Educational and Supportive Care Needs of Canadian Metastatic Melanoma Patients and Survivors Attending an Outpatient Clinic.

The rapid development of metastatic melanoma treatment options has significantly improved overall survival, but paralleled patient educational and supportive care resources have fallen behind. Particularly, the need for grassroots programs targeting environments outside urban centers has grown. Accordingly, an environmental scan of the Durham region in Ontario, Canada, showed the lack of melanoma-specific resources for outpatients. The goal of this study was to identify the needs of metastatic melanoma patients and survivors attending a large outpatient clinic in Durham, and then develop a patient-reviewed intervention plan. Needs were assessed in 5 domains through a melanoma-specific supportive care needs assessment survey. Among 75 surveyed melanoma patients and survivors, high-level needs were identified in 3 domains: psychological, health system information, and melanoma-specific information. Furthermore, domain-specific needs were heightened in specific sociodemographic groups. Based on these survey results, a multifaceted intervention plan was developed to mitigate future needs. The intervention plan was patient-reviewed in focus groups prior to implementation, refining the developed intervention plan.

Results of a phase II study comparing three dosing regimens of fulvestrant in postmenopausal women with advanced breast cancer (FINDER2).

The Faslodex Investigation of Dose evaluation in Estrogen Receptor-positive advanced breast cancer (FINDER)2 study evaluated the efficacy, safety, and pharmacokinetics (PK) of three fulvestrant dosing regimens. FINDER2 enrolled Western postmenopausal women recurring or progressing after prior endocrine therapy. Primary endpoint: objective response rate (ORR); secondary endpoints: time to progression (TTP), clinical benefit rate (CBR), tolerability, and PK parameters. Patients were randomized to receive fulvestrant: 250 mg/month (approved dose [AD]); 250 mg plus loading dose (loading dose [LD]; 500 mg on day 0, 250 mg on days 14, 28, and monthly thereafter); or 500 mg (high dose [HD]; 500 mg/month plus 500 mg on day 14 of Month 1). Treatment continued until disease progression or discontinuation. 144 patients were randomized: fulvestrant AD (n = 47); LD (n = 51); HD (n = 46). ORRs were: 8.5% (95% confidence interval [CI]: 2.4, 20.4%), 5.9% (1.2, 16.2%), and 15.2% (6.3, 28.9%) in the AD, LD, and HD arms, respectively. CBRs were: 31.9% (95% CI: 19.1, 47.1%), 47.1% (32.9, 61.5%), and 47.8% (32.9, 63.1%) for the AD, LD, and HD arms, respectively. Median TTP (months) was numerically longer for HD (6.0) and LD (6.1) versus AD (3.1). Tolerability was similar across dosing regimens. Steady-state plasma fulvestrant concentrations were predictable and achieved earlier with LD and HD. While there appeared to be a trend toward improved efficacy with HD and LD versus AD, no significant differences could be shown. A parallel study (FINDER1) has reported similar findings in Japanese patients.

Weekly epoetin alfa maintains hemoglobin, improves quality of life, and reduces transfusion in breast cancer patients receiving chemotherapy.

PURPOSE: Epoetin alfa administered at 40,000 U once weekly (qw) to anemic cancer patients receiving chemotherapy increases hemoglobin levels, improves quality of life (QOL), and reduces transfusions. The benefit of epoetin alfa in maintaining hemoglobin levels in cancer patients with hemoglobin less than 12 g/dL has not been evaluated. METHODS: Breast cancer patients (N = 354) receiving chemotherapy were randomly assigned in 1:1 ratio to epoetin alfa (40,000 U qw) or standard of care (SOC). QOL was assessed at baseline and week 12. Hemoglobin responses, transfusion requirements, and prognostic factors for responses were measured. RESULTS: At week 12, Functional Assessment of Cancer Therapy-Anemia (FACT-An; mean, 2.16 +/- 12.84 for epoetin alfa v -4.43 +/- 13.42 for SOC) and FACT-An fatigue (mean, 1.85 +/- 10.52 for epoetin alfa v -3.55 +/- 11.14 for SOC) change scores were significantly higher in the epoetin alfa group (P < .0001). Hemoglobin responses defined as mean hemoglobin > or = 12 g/dL or a > or = 2 g/dL increase compared with baseline were significantly higher in the epoetin alfa group versus SOC: 52.0% v 5.1% and 65.7% v 6.3%, respectively (P < .0001 for both comparisons). Percentage transfused was significantly lower in the epoetin alfa group compared with SOC (8.6% v 22.9%). More than 90% of patients did not require a dose increase and 28.7% had a dose reduction. CONCLUSION: Epoetin alfa administered at 40,000 U qw is effective in improving QOL, maintaining hemoglobin level, and reducing transfusion requirements in breast cancer patients. The high effectiveness observed could be attributed in part to early treatment with epoetin alfa.

Safety of Dual Antiplatelet Therapy After Carotid Endarterectomy for Prevention of Restenosis: A Single Center Experience.

INTRODUCTION: The incidence of recurrent carotid stenosis after carotid endarterectomy varies from 1% to 37% with only 0-8% symptomatic restenosis. Safety of short-term (30 days) dual-antiplatelet therapy has not been established in this type of procedure. AIMS: To investigate the safety of dual antiplatelet therapy after carotid endarterectomy to prevent restenosis. METHODS: We retrospectively identified all the patients who underwent carotid endarterectomy (symptomatic or asymptomatic) treated at our center between July 2010 and July 2013 according to local protocols. All patients received a dose of 100 mg of aspirin daily immediately after carotid endarterectomy, with subsequent 100 mg of aspirin daily for the rest of the study period, and some patients received 75 mg of Clopidogrel for 30 days starting immediately after surgical procedure (dual therapy group), assigned according to medical criteria. Duplex carotid ultrasound and clinical assessments were performed at 30 days and 1 year after the procedure. RESULTS: A total of 44 patients (71.2 ± 7.9 years old; 77.2% symptomatic) were analyzed; 35 of them with dual therapy (79.54%). At 30 days, two patients from the mono-therapy group developed restenosis (22.2%), compared to none in dual therapy group (p=0.04). At one year follow-up, only one patient from the dual group showed restenosis (p=0.10). No deaths, major bleeding or new strokes were reported in both groups. CONCLUSIONS: Short-term dual antiplatelet therapy with aspirin and clopidogrel after carotid endarterectomy might be associated with a lower incidence of restenosis. This observation must be validated in a prospective trial.

Del(1)(q23) in a patient with Hutchinson-Gilford progeria.

A 9-year-old patient with the classical clinical picture of Hutchinson-Gilford progeria (HGP) is described. The karyotype shows a 46,XY,del(1)(q23) constitution. Our findings suggest that the interval 1q23 may play a roll in the etiology of HGP. A perturbation in glycosylation in connective tissue has been demonstrated in patients with this condition. This abnormality may be due to a defect in the UDP-galactose:beta-N-acetylglucosamina-beta-1,4-galactosyltransferase 3 (B4GALT3) gene that has been mapped in the interval 1q21-23. The cytogenetical analyses of this patient suggest that the B4GALT3 gene could be involved in the pathogenesis of HGP.

Phase III trial comparing granulocyte colony-stimulating factor to leridistim in the prevention of neutropenic complications in breast cancer patients treated with docetaxel/doxorubicin/cyclophosphamide: results of the BCIRG 004 trial.

This randomized, double-blind, phase III trial compared granulocyte colony-stimulating factor (G-CSF; filgrastim) and leridistim (formerly myelopoietin), a chimeric dual agonist that binds both G-CSF and interleukin-3 receptors, for the prevention of neutropenic complications in patients with breast cancer receiving TAC (docetaxel/doxorubicin/cyclophosphamide) chemotherapy. Patients with metastatic (44%) or localized breast cancer (56%) were randomized to G-CSF 5 microg/kg subcutaneously (s.c.) daily (n = 135), leridistim 5 microg/kg s.c. daily (n = 139), or leridistim 10 microg/kg s.c. every other day alternating with placebo (n = 139). Following administration of TAC (docetaxel 75 mg/m2, doxorubicin 50 mg/m2, cyclophosphamide 500 mg/m2) on day 1, patients received growth factor beginning on day 2 until the postnadir absolute neutrophil count exceeded 1500 cells/ microL. Chemotherapy cycles were repeated every 21 days. The incidence of febrile neutropenia was 7% in the G-CSF arm, 19% in the daily leridistim arm (P = 0.003 for comparison with G-CSF) and 22% in the alternate-day leridistim arm (P < 0.001 for comparison with G-CSF). There was no significant difference between treatment arms in the cumulative percentage of patients experiencing grade 4 neutropenia at some point during therapy (85%-88%). However, grade 4 neutropenia occurred in 53% of cycles in the G-CSF cohort, 61% of cycles in the daily leridistim group (P = 0.063 for comparison with G-CSF), and 63% of cycles in the alternate-day leridistim group (P = 0.015 for comparison with G-CSF). We conclude that G-CSF is superior to leridistim in the prevention of febrile neutropenia in patients with advanced breast cancer receiving TAC chemotherapy. The up-front prophylactic use of G-CSF is a reasonable supportive therapy for patients treated with docetaxel/anthracycline-based combination chemotherapy.

Erythropoiesis-stimulating agents (ESAs): do they still have a role in chemotherapy-induced anemia (CIA)?

PURPOSE: Anemia in cancer patients can be a result of the underlying cancer or related to treatment. Erythropoiesis-stimulating agents (ESAs) are an important option for many patients with chemotherapy-induced anemia, but are immersed in controversy. This article aims to reconcile conflicting opinions and provide expert guidance for appropriate ESA use. METHODS: Teleconference, email, and a face-to-face meeting were used to assess ESA therapy "interpretive" data, which included two current meta-analyses, expert guidelines, and regulatory approved indications from Canada, Europe, and the USA. RESULTS: Risks and benefits are associated with both red blood cell transfusions and ESA therapy, including improvements in hemoglobin levels and quality of life. ESAs have been associated with concerns regarding survival and progression of cancer, particularly when used in patients with cancer-related anemia. CONCLUSION: Although safety concerns do exist, ESA therapy can be considered for use in patients with chemotherapy-induced anemia in accordance with Health Canada labeling.

Metabolic imaging of patients with prostate cancer using hyperpolarized [1-¹³C]pyruvate.

This first-in-man imaging study evaluated the safety and feasibility of hyperpolarized [1-¹³C]pyruvate as an agent for noninvasively characterizing alterations in tumor metabolism for patients with prostate cancer. Imaging living systems with hyperpolarized agents can result in more than 10,000-fold enhancement in signal relative to conventional magnetic resonance (MR) imaging. When combined with the rapid acquisition of in vivo ¹³C MR data, it is possible to evaluate the distribution of agents such as [1-¹³C]pyruvate and its metabolic products lactate, alanine, and bicarbonate in a matter of seconds. Preclinical studies in cancer models have detected elevated levels of hyperpolarized [1-¹³C]lactate in tumor, with the ratio of [1-¹³C]lactate/[1-¹³C]pyruvate being increased in high-grade tumors and decreased after successful treatment. Translation of this technology into humans was achieved by modifying the instrument that generates the hyperpolarized agent, constructing specialized radio frequency coils to detect ¹³C nuclei, and developing new pulse sequences to efficiently capture the signal. The study population comprised patients with biopsy-proven prostate cancer, with 31 subjects being injected with hyperpolarized [1-¹³C]pyruvate. The median time to deliver the agent was 66 s, and uptake was observed about 20 s after injection. No dose-limiting toxicities were observed, and the highest dose (0.43 ml/kg of 230 mM agent) gave the best signal-to-noise ratio for hyperpolarized [1-¹³C]pyruvate. The results were extremely promising in not only confirming the safety of the agent but also showing elevated [1-¹³C]lactate/[1-¹³C]pyruvate in regions of biopsy-proven cancer. These findings will be valuable for noninvasive cancer diagnosis and treatment monitoring in future clinical trials.

Less than ideal: how oncologists practice with limited drug access.

PURPOSE: To evaluate Canadian medical oncologists' perspectives on how barriers to accessing new expensive cancer drugs have affected their practice and their opinions on the drug approval and funding processes. METHODS: Canadian medical oncologists treating colorectal cancer (CRC) were surveyed by means of a self-administered, cross-sectional survey. RESULTS: Of the 164 eligible oncologists, there were 68 respondents (41.4% response rate). Only 29.4% of physicians felt they had been using the ideal first-line chemotherapy regimen for patients with metastatic CRC. Although all considered bevacizumab to be a component of the ideal first-line regimen, only 18% could use bevacizumab routinely, and less than half (44.8%) always discussed its role with their patients. In terms of accessing unfunded drugs, most physicians agreed that private payment should be allowed for drugs to be delivered at their own centers (76.1%) or private infusion clinics (52.2%). Ninety-seven percent of physicians reported major concerns about the drug approval and funding processes, and 85% of physicians supported the establishment of a national drug formulary. CONCLUSIONS: Canadian medical oncologists are struggling to provide optimal cancer care for their patients with metastatic CRC as a result of nonuniform access to preferred therapeutic drugs. In face of these challenges, physicians have had to use clinical trials and private infusion clinics and, at times, may avoid discussing drugs with limited access. Many oncologists are dissatisfied with the existing funding mechanism and approval processes and support private payment for unfunded drugs.

The development of a predictive model to estimate cardiotoxic risk for patients with metastatic breast cancer receiving anthracyclines.

BACKGROUND: Cardiac toxicity from anthracyclines (ACH) can lead to therapy discontinuation, hospitalization or congestive heart failure (CHF). Since such risk may vary by patient, we developed and tested a risk-prediction tool for cardiac toxicity in metastatic breast cancer (MBC) patients receiving chemotherapy with doxorubicin, either in its traditional (DOX) or pegylated liposomal (PLD) formulation. METHODS: Data was obtained (n = 509) from a randomized clinical trial of MBC patients assigned either DOX (60 mg/m(2) every 3 weeks) or PLD (50 mg/m(2) every 4 weeks) (O'Brien Ann Oncol 15, 440-449, 2004). Patient, disease and treatment factors were identified for each cycle of therapy. Factors with a P-value of or=grade 2 cardiac toxicity following a cycle were retained and included in a generalized estimating equations (GEE) regression model A risk scoring algorithm (range 0-62) was then developed from the final model. RESULTS: Factors predictive of cardiac toxicity included an interaction effect between DOX and the number of cumulative cycles, patient age and weight, previous ACH exposure and poor performance status. A ROC analysis had an area under the curve (AUC) of 0.84 (95% CI: 0.79-0.89). A precycle risk score cutoff of >or=30 to <40 was identified to optimally balance sensitivity (58.5%) and specificity (89.0%). Patients with a score in a given cycle, within or above this threshold, would be considered at high risk for cardiac toxicity. CONCLUSION: Our model provides patient specific risk information that could be helpful in assessing the risks and benefits of anthracyclines in the MBC patients.

Identifying patients at high risk for neutropenic complications during chemotherapy for metastatic breast cancer with doxorubicin or pegylated liposomal doxorubicin: the development of a prediction model.

OBJECTIVE: To develop a cycle-based risk prediction model for neutropenic complications (NC) during chemotherapy with doxorubicin (DOX) or a pegylated liposomal formulation (PLD) for patients with metastatic breast cancer (MBC). METHODS: Data analyzed was from a phase III, randomized clinical trial of DOX (60 mg/m(2) every 3 weeks) or PLD (50 mg/m(2) every 4 weeks) for the first line therapy for MBC (n = 509) (O'Brien et al, Ann Oncol. 2004;15:440-449). NC were defined as an absolute neutrophil count < or =1.5 x 10(9) cells/L (ie, > or =grade II) before the next cycle, febrile neutropenia or neutropenia with a documented infection. Patient and hematologic factors potentially associated with NC were evaluated. Factors with a P value of < or =0.25 within a cycle were included in a generalized estimating equations regression model. Using backward elimination, we derived a risk scoring algorithm (range 0-63) from the final reduced model. RESULTS: Risk factors retained in the model included poor performance status, absolute neutrophil count < or =2.0 x 10(9) cells/L in the previous cycle, the first cycle of chemotherapy, DOX versus PLD and advanced age. A precycle risk score from > or =25 to <40 for a given patient was identified as being the optimal threshold for sensitivity (58.0%) and specificity (78.7%). Patients with a score at or beyond this threshold would be considered at high risk for developing NC in later cycles. CONCLUSION: The use of this model may enhance patient care by targeting preventative therapies (eg, granulocyte colony stimulating factor or PLD) to those MBC patients most likely to experience NC during anthracycline-based chemotherapy.

Patients previously transfused or treated with epoetin alfa at low baseline hemoglobin are at higher risk for subsequent transfusion: an integrated analysis of the Canadian experience.

BACKGROUND: The introduction of recombinant human erythropoietin to the management of anemia in cancer patients has resulted in significant reductions in allogeneic blood transfusions, while at the same time contributing to improvements in quality of life. A recent meta-analysis of five randomized, placebo-controlled trials with patient-level data revealed that, while epoetin alfa was very effective in reducing transfusions compared with placebo, patients who were pretransfused were twice as likely to subsequently be transfused during epoetin alfa treatment. METHODS: To further assess the validity of this rather provocative concept, another integrated analysis was conducted with patient-level data from three Canadian trials, with a combined total of 665 patients receiving epoetin alfa treatments for their cancer- and chemotherapy-induced anemia. RESULTS: Once again, pretransfusion was the most significant baseline predictor of transfusion, with patients that were pretransfused having a significantly greater likelihood of being transfused than their transfusion-naive counterparts. Furthermore, and corroborating previous findings, baseline hemoglobin (Hb) level was again found to be a significant predictor of transfusion, with patients who were treated at a baseline Hb level < 10 g/dl having a higher chance of being transfused than patients in whom epoetin alfa was initiated at baseline Hb levels of 10-11 g/dl. In addition, when the total units transfused in patients receiving epoetin alfa at different baseline Hb levels were analyzed, >85% of the units of blood transfused were received by patients with baseline Hb levels < 10 g/dl. CONCLUSION: These data strongly suggest that early treatment with epoetin alfa could significantly optimize clinical benefit in reducing the use of transfusion in cancer patients receiving chemotherapy.

rHuEPO and treatment outcomes: the clinical experience.

Increasingly, anemia is being recognized as a negative prognostic and predictive factor for patients undergoing chemotherapy, radiation therapy, or a combination of these treatment modalities. The results of clinical studies have shown correlations between anemia and shorter survival times in patients with a wide variety of solid tumors and hematologic malignancies, including lung, ovarian, breast, and head/neck cancers, non-Hodgkin's lymphoma, Hodgkin's disease, Waldenstrom's macroglobulinemia, and chronic lymphocytic leukemia. Also, anemia has been shown to predict treatment response in patients with ovarian, cervical, and urothelial cancers, mantle cell lymphoma, and chronic lymphocytic leukemia, as well as refractory/relapsed acute myelogenous leukemia. Based on the presumed causal relationship between anemia and poor patient outcome, several studies have examined the influence of epoetin alfa (a recombinant human erythropoietin) on outcomes in anemic patients undergoing cancer treatment. The results of these studies have been encouraging, with indications of greater locoregional tumor control and higher response rates in epoetin alfa-treated patients. Additionally, epoetin alfa therapy, by correcting anemia, has been shown to improve a patient's energy level, ability to perform daily activities, and overall quality of life (QOL). Such effects not only enhance a patient's general well-being, but may also increase their tolerance of, and willingness to undergo, full courses of their cancer therapy in a timely manner. These findings support the use of epoetin alfa to achieve gains in QOL and cancer treatment outcomes in anemic cancer patients and suggest that additional studies be conducted to further investigate the potential benefits of this agent in regard to improved outcomes.

Weekly administration of epoetin alfa improves cognition and quality of life in patients with breast cancer receiving chemotherapy.

Patients with breast cancer treated with adjuvant chemotherapy experience not only fatigue and menopausal symptoms but also documented cognitive dysfunction and reduced capacity to carry out activities of daily living. The role of epoetin alfa in improving cognition and functional capacity was assessed in a large randomized trial through patient self-reported outcomes. Patients with breast cancer (N = 354, adjuvant and metastatic) undergoing chemotherapy were randomized in a 1:1 ratio to receive epoetin alfa (40,000 IU once weekly) or the standard of care (SOC). Change in patient-reported Health Utilities Index Mark 3 (HUI3) from baseline to week 12 was compared between the epoetin alfa and SOC groups. In addition, correlations between the disease-nonspecific HUI3 utility scale and the cancer-specific quality of life instrument Functional Assessment of Cancer Therapy-Anemia (FACT-An) and Fatigue subscales were assessed. Epoetin alfa treatment significantly improved HUI3 scores compared with patients receiving SOC (P = 0.036). Three subscales within HUI3 were also significantly better for epoetin alfa-treated patients (emotion, P = 0.048; ambulation, P = 0.048; and cognition, P = 0.02). Moreover, a strong correlation (P = 0.0001) exists between the disease-nonspecific utility scale HUI3 and the disease-specific FACT-An and FACT-Fatigue scales in terms of overall scores and score changes. The findings of the study demonstrate for the first time in patients with breast cancer that epoetin alfa significantly enhances functional well-being, which translates into significantly better utility scores. In addition, epoetin alfa also significantly improved cognitive function of women undergoing chemotherapy, and this could have an important impact on their lives from a societal perspective.

Do physicians follow systemic treatment and funding policy guidelines?

BACKGROUND: The use of bisphosphonates for the prevention of skeletal related events in women with bone metastases from breast cancer is well established. We undertook an evaluation of bisphosphonate use in clinical practice in three Canadian cancer centres. In addition we assessed whether or not physicians at these centres are following their local treatment guidelines and funding policies. METHODS: Charts and electronic files of patients who had received either clodronate or pamidronate at any time between January 2000 and December 2001 at three Canadian cancer centres were retrospectively reviewed. RESULTS: There has been a marked improvement in the time between the diagnosis of bone metastases and the commencement of bisphosphonates from a median of 155 days in 1998 to 24 days in 2001. However, despite a local funding policy requiring that oral clodronate be the first bisphosphonate used, this was the case in only 67% of patients. In addition, despite one centre's guidelines recommending that bisphosphonates be stopped once the patient was progressing, 90% of their patients remained on bisphosphonates until they died. CONCLUSIONS: A considerable amount of effort is spent on the creation of "evidence based" treatment guidelines. Funding agencies develop policies based on these treatment guidelines, but often funding is more restrictive than the treatment guideline would suggest. It is clear from this review that physicians still appear to manage a substantial proportion of patients outside of funding policies, but within evidence based recommendations. Therefore, a need exists for either the creation of guidelines and policies that physicians will follow or the implementation of methods to ensure that restrictive policies are actually followed.