text:
Узнать больше о подписке Scribd
Откройте для себя все, что может предложить Scribd, включая книги и аудиокниги от крупных издательств.
Jennifer J. Griggs, University of Michigan, Ann Arbor, MI; Pamela B. Mangu, American Society of Clinical Oncology, Alexandria, VA; Holly Anderson, Breast Cancer Coalition of Rochester; Michelle Shayne, University of Rochester Medical Center, Rochester; Lara E. Sucheston, Roswell Park Cancer Institute, Cancer Prevention and Control, Buffalo, NY; Edward P. Balaban, University of Pittsburgh Cancer Centers Network, Pittsburgh, PA; James J. Dignam, University of Chicago, Chicago, IL; William M. Hryniuk, CarePath, Toronto, Ontario, Canada; Vicki A. Morrison, University of Minnesota Veterans Affairs Medical Center, Minneapolis, MN; T. May Pini, Medical Oncology, Houston, TX; Carolyn D. Runowicz, Florida International University, Miami, FL; Gary L. Rosner, Johns Hopkins University, Baltimore, MD; Alex Sparreboom, St Jude Childrens Research Hospital, Memphis, TN; and Gary H. Lyman, Duke University and the Duke Cancer Institute, Durham, NC. Submitted October 7, 2011; accepted February 21, 2012; published online ahead of print at www.jco.org on April 2, 2012. American Society of Clinical Oncology Clinical Practice Guideline Committee Approved: November 9, 2011. Editors note: This represents a brief summary overview of the complete new American Society of Clinical Oncology (ASCO) Clinical Practice Guideline on Appropriate Chemotherapy Dosing for Obese Adult Patients With Cancer and provides recommendations with brief discussions of the relevant literature for each. The complete guideline, which includes comprehensive discussions of the literature, methodology information, and all cited references, and Data Supplements with the evidence tables the Panel used to formulate these recommendations, are available at www.asco.org/guidelines/wbd. Authors disclosures of potential conicts of interest and author contributions are found at the end of this article. Corresponding author: American Society of Clinical Oncology, 2318 Mill Rd, Suite 800, Alexandria, VA 22314; e-mail: guidelines@ asco.org. 2012 by American Society of Clinical Oncology 0732-183X/12/3099-1/$20.00 DOI: 10.1200/JCO.2011.39.9436
Appropriate Chemotherapy Dosing for Obese Adult Patients With Cancer: American Society of Clinical Oncology Clinical Practice GuidelineJennifer J. Griggs, Pamela B. Mangu, Holly Anderson, Edward P. Balaban, James J. Dignam, William M. Hryniuk, Vicki A. Morrison, T. May Pini, Carolyn D. Runowicz, Gary L. Rosner, Michelle Shayne, Alex Sparreboom, Lara E. Sucheston, and Gary H. LymanA B S T R A C T
Purpose To provide recommendations for appropriate cytotoxic chemotherapy dosing for obese adult patients with cancer. Methods The American Society of Clinical Oncology convened a Panel of experts in medical and gynecologic oncology, clinical pharmacology, pharmacokinetics and pharmacogenetics, and biostatistics and a patient representative. MEDLINE searches identied studies published in English between 1996 and 2010, and a systematic review of the literature was conducted. A majority of studies involved breast, ovarian, colon, and lung cancers. This guideline does not address dosing for novel targeted agents. Results Practice pattern studies demonstrate that up to 40% of obese patients receive limited chemotherapy doses that are not based on actual body weight. Concerns about toxicity or overdosing in obese patients with cancer, based on the use of actual body weight, are unfounded. Recommendations The Panel recommends that full weightbased cytotoxic chemotherapy doses be used to treat obese patients with cancer, particularly when the goal of treatment is cure. There is no evidence that short- or long-term toxicity is increased among obese patients receiving full weightbased doses. Most data indicate that myelosuppression is the same or less pronounced among the obese than the non-obese who are administered full weight based doses. Clinicians should respond to all treatment-related toxicities in obese patients in the same ways they do for non-obese patients. The use of xed-dose chemotherapy is rarely justied, but the Panel does recommend xed dosing for a few select agents. The Panel recommends further research into the role of pharmacokinetics and pharmacogenetics to guide appropriate dosing of obese patients with cancer. J Clin Oncol 30:000-000. 2012 by American Society of Clinical Oncology
Optimal doses of chemotherapy drugs or drug combinations are generally established through randomized controlled clinical trials (RCTs). In adult patients with cancer, drug dosing has traditionally been based on a patients estimated body surface area (BSA).1 There exists compelling evidence that reductions from standard dose and dose-intensity may compromise disease-free survival (DFS) and overall survival (OS) in the curative setting.2-7 Furthermore, a number of authors have suggested that the optimal delivery of cancer chemotherapy should be considered an indicator of quality of care.3,8,9 Despite studies conrming
the safety and importance of full weight based cytotoxic (intravenous [IV] and oral) chemotherapy dosing, many overweight and obese patients continue to receive limited chemotherapy doses.10-13 Practice pattern studies demonstrate that up to 40% of obese patients receive limited doses that are not based on actual body weight.10,12-17 Many oncologists continue to use either ideal body weight or adjusted ideal body weight or to cap the BSA at, for example, 2.0 m2 rather than use actual body weight to calculate BSA. Moreover, considerable variation in the dosing of chemotherapy in overweight and obese individuals with cancer has been documented,3,13,14,16,18-22 suggesting considerable uncertainty among physicians about optimal dose selection. 2012 by American Society of Clinical Oncology
Information downloaded from jco.ascopubs.org and provided by at HOSPITAL LLUIS ALCANYIS on April 12, 2012 from Copyright 2012 American Society of Clinical Oncology. All rights reserved. 220.127.116.11
Griggs et al
The practice of limiting doses in overweight and obese patients may negatively inuence the quality of care and outcomes at a population level, given the rise in rates of obesity both in the United States23,24 and globally.25 Rates of obesity have increased in recent years, reaching epidemic proportions in the United States. The Centers for Disease Control and Prevention estimates that a majority ( 60%) of adult Americans have a body mass index (BMI) 25 (overweight, obese, morbidly obese) and that this pro-
portion is steadily increasing.23,24 Poorer outcomes among obese patients are most likely multifactorial.26 Systemic chemotherapy at less than full weight based dosing and unnecessary dose reductions may explain, in part, the signicantly higher cancer mortality rates observed in overweight and obese individuals. Concerns about overdosing in the obese cancer patient based on the use of actual body weight are unfounded.10,13,19,27-29 A compelling body of evidence exists supporting the important relationship between selection of appropriate chemotherapy doses in adult patients with cancer and treatment efcacy and toxicity as well as pharmacokinetic correlates of dose selection.2,5,6,10,13,18,27-90METHODS
ASCO Guideline on Appropriate Chemotherapy Dosing for Obese Adult Patients With Cancer Intervention Recommendations for appropriate chemotherapy dosing for obese adult patients with cancer Target Audience Medical oncologists, pharmacists, oncology nurses Key Recommendations Panel recommends that full weight based chemotherapy doses be used in the treatment of the obese patient with cancer, particularly when the goal of treatment is cure. Clinicians should respond to all treatment-related toxicities in obese patients with cancer in the same ways they do for non-obese patients. If a dose reduction is employed in response to toxicity, consideration should be given to the resumption of full weight based doses for subsequent cycles, especially if a possible cause of toxicity (eg, impaired renal, hepatic function) has been resolved; there is no evidence to support the need for greater dose reductions for obese patients compared with non-obese patients. The use of xed-dose cytotoxic chemotherapy is rarely justied (except for a few select agents). Methods Systematic review of the medical literature and analysis of the medical literature by the Update Committee of an Expert Panel Additional Information Recommendations and a brief summary of the literature and analysis are provided in this Executive SummaryThe full guideline with methodology, comprehensive discussions of the literature, full reference list, Data Supplements, evidence tables, and clinical tool and resources can be found at www. asco.org/guidelines/wbd. Patient information is available at www.cancer.net.
Panel Composition An Expert Panel met once in person and considered data from a systematic review and interacted through e-mail throughout draft development. The Panel authored recommendations for clinicians who treat obese patients with cancer with cytotoxic chemotherapy (IV and oral agents). The Panel members are listed in Appendix Table A1 (online only). Literature Review and Analysis Literature search strategy. The MEDLINE and the Cochrane Collaboration Library electronic databases were searched with the date parameters of 1966 through October 2010 for articles in English. MEDLINE search terms are included in Data Supplement 3, and a summary of the literature search results is provided in Data Supplement 4 at www.asco.org/guidelines/wbd. Inclusion and exclusion criteria. Articles were selected for inclusion in the systematic review if they were published English language studies on cytotoxic IV or oral chemotherapy dosing approaches for overweight or obese patients with cancer, excluding leukemias. Data were extracted from prospective or retrospective cohort studies that addressed withholding, delaying, early cessation, or reduction of chemotherapy doses, including capping doses (eg, at a BSA of 2.0 m2). Data were also extracted about treatment toxicity, DFS and OS, and quality-of-life outcomes. Systematic reviews of RCTs, meta-analyses, and other clinical practice guidelines were also conducted. Because of the paucity of data, this guideline does not address dosing for novel targeted agents such as tyrosine kinase inhibitors, immunotherapies (eg, interleukin-2, interferon), or monoclonal antibodies. Pharmacokinetic studies with pharmacodynamic or clinical outcomes with appropriate controls were also included. Data extraction. Primary outcome measures of interest included OS, disease-specic survival, DFS, relapse-free survival, event-free survival, progression-free survival (PFS), and treatment-related toxicities. Secondary outcomes and/or other data elements of interest included quality of life and costs of care. Study Quality and Limitations of the Literature There are no prospective randomized studies comparing full weight based chemotherapy dose selection and nonfull weight based dose selection. Retrospective analyses of randomized trials and comparative observational studies comprise the majority of the studies included in this guideline. This guideline is based on evidence derived primarily from subgroup analyses and registry data. Although the results are important, it should be clear to the reader that the evidence base for this guideline is necessarily different from those for other American Society of Clinical Oncology (ASCO) guidelines. Denition of Terms A glossary of terms, including information on calculating BSA (eg, Mosteller, Dubois and Dubois, Haycock, Gehan and George, Boyd formulas) and toxicity grades, appears in Data Supplement 5 at www.asco.org/ guidelines/wbd. Guideline Policy This Executive Summary for clinicians is an abridged summary of an ASCO clinical practice guideline. The guideline and this summary are notJOURNAL OF CLINICAL ONCOLOGY
intended to substitute for the independent professional judgment of the treating physician. Practice guidelines do not account for individual variation among patients and may not reect the most recent evidence. This summary does not recommend any particular product or course of medical treatment. Use of the practice guideline and this summary is voluntary. The full practice guideline and additional information are available at http://www.asco.org/ guidelines/wbd. Guideline and Conicts of Interest The Expert Panel was assembled in accordance with the ASCO Conict of Interest Management Procedures for Clinical Practice Guidelines (summarized at http://www.asco.org/guidelinescoi). Members of the Panel completed the ASCO disclosure form, which requires disclosure of nancial and other interests that are relevant to the subject matter of the guideline, including relationships with commercial entities that are reasonably likely to experience direct regulatory or commercial impact as a result of promulgation of the guideline. Categories for disclosure include employment relationships, consulting arrangements, stock ownership, honoraria, research funding, and ex-
pert testimony. In accordance with the Procedures, the majority of the members of the Panel did not disclose any of these relationships.
The overarching question for this clinical practice guideline is: Should actual body weight be used to select chemotherapy doses in obese individuals with cancer? For adults, overweight and obesity ranges are determined by using weight and height to calculate BMI. For more information about interpreting BMI, visit the Centers for Disease Control and Prevention Web site.91 An adult who has a BMI between 25 and 29.9 kg/m2 is considered overweight; an adult who has a BMI of 30 kg/m2 is considered obese; an adult who has a BMI 40 kg/m2 (or 35kg/m2 withcomorbidconditions)isconsideredmorbidly
1. Is there evidence that full weightbased Recommendation 1.1: The Panel recommends that actual body weight be used when selecting cytotoxic chemodosing increases toxicity in obese patients therapy doses regardless of obesity status. There is no evidence that short- or long-term toxicity is increased with cancer? among obese patients receiving full weightbased chemotherapy doses. Most data indicate that myelosuppression is the same or less pronounced among the obese than the non-obese administered full weightbased doses. Recommendation 1.2: The Panel recommends full weightbased chemotherapy dosing for morbidly obese patients with cancer, subject to appropriate consideration of other comorbid conditions. Data are extremely limited regarding optimal dose selection among the morbidly obese and other special subgroups. More studies are needed to evaluate optimal agents and agent combinations for obese and morbidly obese patients with cancer; however, based on available information, it seems likely that the same principles regarding dose selection for obese patients apply to the morbidly obese. 2. Is there evidence that less than full Recommendation 2.1: The Panel recommends that full weightbased chemotherapy doses (IV and oral) be used weightbased dosing compromises in the treatment of the obese patient with cancer, particularly when the goal of treatment is cure. Selecting efcacy in obese patients with cancer? reduced doses in this setting may result in poorer disease-free and overall survival rates. There are compelling data in patients with breast cancer that reduced dose-intensity chemotherapy is associated with increased disease recurrence and mortality. Although data in other malignancies are more limited, based on improved survival observed with chemotherapy compared with controls, a dose-response relationship exists for many responsive malignancies. Therefore, although data are not available to address this question for all cancer types, in the absence of data demonstrating sustained efcacy for reduced dose chemotherapy, the Panel believes that the prudent approach is to provide full weightbased chemotherapy dosing to obese patients with cancer, especially those receiving treatment with curative intent. Most of the data in support of full weightbased dosing come from the treatment of early-stage disease. Data supporting the use of full weight based doses in the advanced disease setting are limited. 3. If an obese patient experiences highRecommendation 3.1: Clinicians should follow the same guidelines for dose reduction, regardless of obesity grade toxicity, should chemotherapy status, for all patients, depending on the type and severity of toxicity, any comorbid conditions, and whether doses or schedules be modied the treatment intention is cure or palliation. There is no evidence to support the need for greater dose differently from modications used for reductions for obese patients compared with non-obese patients. If a dose reduction is employed in response non-obese patients with cancer? to toxicity, consideration should be given to the resumption of full weightbased doses for subsequent cycles, especially if a possible cause of toxicity (eg, impaired renal, hepatic function) has been resolved. The Panel recognizes the need for clinicians to exercise judgment when providing care for patients who have experienced grade 3 or 4 chemotherapy toxicity. The presence of obesity alone should not alter such clinical judgment. 4. Is the use of xed-dose (dose prescribed Recommendation 4.1: The Panel recommends consideration of xed dosing only with select cytotoxic agents independently of weight or BSA) cytotoxic (eg, carboplatin and bleomycin). On the basis primarily of neurotoxicity concerns, vincristine is capped at a chemotherapy ever justied? Are there maximum dose of 2.0 mg when used as part of the CHOP and CVP regimens. Several other cytotoxic chemounique dosing considerations for certain therapeutic agents have been used in clinical trials at a xed dose independent of patient weight or BSA. chemotherapeutic agents? However, it is not clear that xed dosing is optimal for any of these other agents. 5. How should BSA be calculated? Recommendation 5.1: The Panel recommends that BSA be calculated using any of the standard formulae. There Specically, what is the best formula for is no evidence to support one formula for calculating BSA over another. use with the obese patient with cancer? 6. What is the role of pharmacokinetic and/ Recommendation 6.1: The Panel recommends further research into the role of pharmacokinetic and or phamacogenetic factors when pharmacogenetic information for guiding the dosing of IV and oral chemotherapeutic agents for adult patients determining optimal chemotherapy dose with cancer who are obese. It should be emphasized that there is a paucity of information on the inuence of and delivery (bolus, infusional, therapeutic obesity on the pharmacokinetics of most anticancer drugs from properly powered trials. This is the result, in drug monitoring) for obese patients part, of empiric eligibility restrictions from the outset in clinical trials and a lack of pharmacokinetic analyses with cancer? performed and published for this subpopulation. Overall, there are insufcient pharmacokinetic data to reject the recommendation to use a full weightbased dosing strategy for chemotherapeutic agents in patients with cancer who are obese, regardless of route of administration and/or infusion time. Abbreviations: BSA, body surface area; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; CVP, cyclophosphamide, vincristine, prednisone; IV, intravenous.
obese. More information about interpreting BMI for adults is provided in Data Supplement 6 at www.asco.org/guidelines/wbd. Table 1 provides a summary of the following guideline recommendations.
Clinical Question 1 Is there evidence that full weight based dosing increases toxicity in obese patients with cancer? Recommendation 1.1. The Panel recommends that actual body weight be used when selecting cytotoxic chemotherapy doses regardless of obesity status. There is no evidence that short- or long-term toxicity is increased among obese patients receiving full weight based chemotherapy doses. Most data indicate that myelosuppression is the same or less pronounced among the obese than the non-obese when administered full weight based doses. Literature review and analysis. Observational studies and retrospective analyses of participants in clinical trials have not demonstrated increased hematologic or nonhematologic toxicity in obese patients receiving chemotherapy doses calculated using actual body weight. For example, no excess toxicity was observed among patients with small-cell lung cancer when actual weight was used to calculate chemotherapy doses.28 In a retrospective analysis of CALGB (Cancer and Leukemia Group B) Protocol 8541, obese patients receiving full weight based dosing of adjuvant cyclophosphamide, doxorubicin, and uorouracil had no excess grade 3 hematologic or nonhematologic toxicity at any of the three dose levels in the study compared with non-obese patients.27 In obese patients receiving full weight based doses of cyclophosphamide, methotrexate, and uorouracil in the adjuvant treatment of breast cancer, patients with the highest BMIs had the highest leukocyte nadir values, or leukocyte nadirs were less pronounced among obese patients compared with non-obese patients.29 A large study of 9,672 patients with breast cancer treated in practices across the United States with adjuvant doxorubicin and cyclophosphamide demonstrated that the likelihood of febrile neutropenia, if anything, decreased as BMI increased among those patients who received full weight based dosing.13 Similar ndings were reported in the treatment of 59 women with endometrial or ovarian cancer and BSA 2.0 m2 who received paclitaxel and carboplatin based on actual body weight.92 On the basis of these studies and others included in the systematic review,93-96 the Panel concluded that there is no evidence indicating higher rates of hematologic or nonhematologic toxicity among obese patients who received full weight based doses. The heavier a patient is, even fully dosed, the less likely he or she is to experience febrile neutropenia, especially in the absence of additional comorbid illness. Recommendation 1.2. The Panel recommends full weight based chemotherapy dosing for morbidly obese patients with cancer, subject to appropriate consideration of other comorbid conditions. Data are extremely limited regarding optimal dose selection among the morbidly obese and other special subgroups. More studies are needed to evaluate optimal agents and agent combinations for obese and morbidly obese patients with cancer; however, on the basis of available information, it seems likely that the same principles regarding dose selection for obese patients apply to the morbidly obese. Literature review and analysis. Nine articles were found in a separate search for morbidly obese patients with cancer97-105; these were small4 2012 by American Society of Clinical Oncology
observational studies or case reports and primarily presented data on the pharmacokinetics of chemotherapy in this subgroup. For this reason, there are no separate recommendations for morbidly obese patients in this guideline. From the available evidence, it seems that morbidly obese patients being treated with curative intent and receiving full weight based doses were no more likely to experience toxicity than lean patients.106 Clinicians need to calculate full weight based dosing and use clinical judgment when monitoring toxicity, as they would for all patients.107 The Panel recognizes that there may be cases in which obese patients have other serious medical problems, and it encourages clinicians to use judgment when dosing, as they would if the patients were not obese (eg, heart, renal, pulmonary problems). Clinical Question 2 Is there evidence that less than full weight based dosing compromises efcacy in obese patients with cancer? Recommendation 2.1. The Panel recommends that full weight based chemotherapy doses (IV and oral) be used in the treatment of the obese patient with cancer, particularly when the goal of treatment is cure. Selecting reduced doses in this setting may result in poorer DFS and OS rates. There are compelling data in patients with breast cancer that reduced dose-intensity chemotherapy is associated with increased disease recurrence and mortality. Although data in other malignancies are more limited, based on improved survival observed with chemotherapy compared with controls, a dose-response relationship exists for many responsive malignancies. Therefore, although data are not available to address this question for all cancer types, in the absence of data demonstrating sustained efcacy for reduced-dose chemotherapy, the Panel believes that the prudent approach is to provide full weight based chemotherapy dosing to obese patients with cancer, especially those receiving treatment with curative intent. Most of the data in support of full weight based dosing come from the treatment of early-stage disease. Data supporting the use of full weight based doses in the advanced disease setting are limited. Literature review and analysis. Retrospective analyses and observational studies suggest that dose limits in obese patients may compromise DFS and OS rates.108-111 An analysis of outcomes among obese patients treated in CALGB 8541 demonstrated that obese patients who received 95% of the expected chemotherapy (based on full weight based dosing) had worse failure-free survival rates.27 Additional data supporting the use of full weight based dosing came from a retrospective analysis of four adjuvant chemotherapy studies conducted by the International Breast Cancer Study Group (previously the Ludwig Study Group). In this analysis, obese patients with estrogen receptornegative breast cancer who received 85% of the dose experienced a higher relapse rate and had a lower survival rate.45 Clinical Question 3 If an obese patient experiences high-grade toxicity, should chemotherapy doses or schedules be modied differently from modications used for non-obese patients with cancer? Recommendation 3.1. Clinicians should follow the same guidelines for dose reduction, regardless of obesity status, for all patients, depending on the type and severity of toxicity, any comorbid conditions, and whether the treatment intention is cure or palliation. There is no evidence to support the need for greater dose reductions for obese patients compared with non-obese patients. If a dose reduction is employed in response to toxicity, consideration should be given toJOURNAL OF CLINICAL ONCOLOGY
the resumption of full weight based doses for subsequent cycles, especially if a possible cause of toxicity (eg, impaired renal, hepatic function) has been resolved. The Panel recognizes the need for clinicians to exercise judgment when providing care for patients who have experienced grade 3 or 4 chemotherapy toxicity. The presence of obesity alone should not alter such clinical judgment. Literature review and analysis. There are no RCTs that specify differential management of moderate to severe toxicity (grades 3 to 4) according to obesity status (Data Supplement 5 at www.asco.org/ guidelines/wbd provides more information on toxicity grades). Similarly, no observational studies describe BMI-based management of toxicities from chemotherapy. Given the lack of evidence citing harms in differential treatment, the Panel recommends clinicians respond to treatment-related toxicities in obese patients with cancer in the same ways they do for non-obese patients with cancer. Excess toxicity usually results from the fact that the patient has reduced drug elimination in reference to the dose of one (or more) chemotherapeutic agent. A return to initial dosing after toxicity is resolved rarely occurs unless the reason for toxicity is clearly established and fully resolved. Thus, the dose should only be increased to the initial dose if it is established that drug elimination has improved (eg, improvement in renal function, return of bilirubin to normal, signicant improvement in performance status). Obesity status alone should not play a role in dose modications in response to toxicity. Clinical Question 4 Is a xed dose (dose prescribed independently of weight or BSA) of cytotoxic chemotherapy ever justied? Are there unique dosing considerations for certain chemotherapeutic agents? Recommendation 4.1. The Panel recommends consideration of xed dosing only with select cytotoxic agents (eg, carboplatin and bleomycin). On the basis primarily of neurotoxicity concerns, vincristine is capped at a maximum dose of 2.0 mg when used as part of the CHOP (cyclophosphamide, hydroxydoxorubicin [doxorubicin], vincristine, prednisone) and CVP (cyclophosphamide, vincristine, prednisone) regimens. Several other cytotoxic chemotherapeutic agents have been used in clinical trials at a xed dose independent of patient weight or BSA. However, it is not clear that xed dosing is optimal for any of these other agents. Literature review and analysis. The Panel recommends consideration of xed dosing only with a select group of agents. For example, carboplatin clearance depends on glomerular ltration rate (GFR), and doses are calculated best using the Calvert formula112,113 (total dose [mg] [AUC (target area under the plasma concentration-time curve)] [GFR 25]) to achieve a targeted AUC. The GFR used in the Calvert formula to calculate AUC dosing should not exceed 125 mL/min. The maximum carboplatin dose should not exceed AUC (mg min/mL) 150 mL/min. Because carboplatin clearance is dictated by renal ltration, and GFR correlates with BSA, dosing of carboplatin in the obese patient with cancer based on GFR may be most reasonable. There are several agents that are sometimes prescribed at a xed dose or capped based on the dose that was used in clinical trials. The usual adult dose of bleomycin for testicular cancer is a xed dose in a BEP (bleomycin, etoposide, cisplatin) regimen.114 In R-CHOP (rituximab plus CHOP), CHOP, and CVP regimens, the dose of vincristine is capped at a maximum of 2 mg.115,116www.jco.org
Of note, the use of at-xed dosing of irinotecan has been previously examined but not in large clinical trials.39,117 In general oncologic practice, dosing for irinotecan remains based on BSA. There are other agents that have been used in xed doses in non-RCTs of the treatment of specic cancers in unique patient populations; these include agents such as metronomic cyclophosphamide118-123 and capecitabine.124 Fixed dosing based on BMI or BSA categories is possible and has been proposed for some agents (eg, cisplatin), but such approaches have never been prospectively evaluated.100 Clinical Question 5 How should BSA be calculated? Specically, what is the best formula for use in the obese patient with cancer? Recommendation 5.1. The Panel recommends that BSA be calculated using any of the standard formulas (eg, Mosteller, DuBois and Dubois, Haycock, Gehan and George, Boyd formulas). There is no evidence to support one formula for calculating BSA over another. Literature review and analysis. Formulas for calculating BSA were not developed for use in the obese or morbidly obese and/or those with multiple comorbid conditions and do not take into account patient sex. In fact, there may be noticeable differences ( 10%) in calculated values of BSA, especially at the extremes of weight and/or height, resulting in noticeable differences in dosing. There are ongoing efforts to establish a new BSA equation suitable for a typical 21st century population, because 60% of adult Americans have BMIs 25 kg/m2, and this proportion is steadily increasing.23,24 Data Supplement 5 at www.asco.org/guidelines/wbd includes BSA formulas currently used. Clinical Question 6 What is the role of pharmacokinetic and/or pharmacogenetic factors when determining optimal chemotherapy dose and delivery (bolus, infusional, therapeutic drug monitoring) for obese patients with cancer? Recommendation 6.1. The Panel recommends further research into the role of pharmacokinetic and pharmacogenetic information for guiding the dosing of IV and oral chemotherapeutic agents for adult patients with cancer who are obese. It should be emphasized that there is a paucity of information on the inuence of obesity on the pharmacokinetics of most anticancer drugs from properly powered trials. This is the result, in part, of empiric eligibility restrictions from the outset in clinical trials and a lack of pharmacokinetic analyses performed and published for this subpopulation. Overall, there are insufcient pharmacokinetic data to reject the recommendation to use a full weight based dosing strategy for chemotherapeutic agents in patients with cancer who are obese, regardless of route of administration and/or infusion time. Literature review and analysis. Clearance is the most important pharmacokinetic parameter to consider when devising a dosing regimen for anticancer agents, because it is inversely related to the AUC. This parameter has clinical relevance because it correlates with clinical outcomes, although there are only a few examples in which the association is reproducible.125 For the majority of anticancer drugs, the liver is the principal organ mediating clearance. The accumulation of fat in the liver of obese patients may alter hepatic blood ow, and this pathologic change might have an impact on clearance.102,126,127 The 2012 by American Society of Clinical Oncology
other primary organs involved in the clearance of drugs are the kidneys. The processes involved in drug elimination through the kidneys include glomerular ltration, tubular secretion, and tubular reabsorption. The effect of obesity on these functions is not entirely clear.127 The pharmacokinetics of some but not all drugs may be altered in obese patients, but there is no single valid method to relate drug clearance to degree of obesity, so changes in drug dosing are not currently recommended. Three observations regarding drug clearance and obesity were recently described128: (1) obese individuals exhibit higher absolute drug clearance than do their non-obese counterparts; (2) clearance does not increase linearly with total body weight; and (3) clearance and lean body weight are correlated. There is a general paucity of information from sufciently powered clinical studies on the inuence of obesity on the pharmacokinetics of most anticancer drugs. This is the result, in part, of empiric eligibility restrictions from the outset in clinical trials and a lack of pharmacokinetic analyses performed and published for this subpopulation. In many studies, the obese patient may be underrepresented. Overall, there are insufcient pharmacokinetic data to reject the Panels recommendation to use a full weight based dosing strategy for chemotherapeutic agents in patients with cancer who are obese, regardless of route of administration and/or infusion time. To date, there are no published pharmacogenetic articles meeting the inclusion and exclusion criteria for this guideline that could have been included in the discussion. Nevertheless, there may be a future role for applying pharmacokinetic and pharmacogenetic principles in cancer chemotherapy dosing to achieve a more personalized approach to treatment for the obese,129 although large prospective studies are certainly required to support this practice. For more information on the pharmacokinetic clearance of some chemotherapeutic agents (eg, cisplatin, paclitaxel, troxacitabine, carboplatin, docetaxel, doxorubicin, irinotecan, topotecan, and busulfan) and pharmacogenetics, refer to the full guideline at www.asco.org/guidelines/wbd.
Some racial and ethnic minorities and patients of lower socioeconomic status (SES) are at risk of suboptimal cancer care. Members of some racial and ethnic minority groups and patients with fewer nancial resources tend to have a higher burden of comorbid illness, are more likely to be uninsured or underinsured, and face greater challenges in accessing high-quality health care.130-132 Awareness of disparities in quality of chemotherapy dose selection should be considered in context. Black/African American patients and patients of lower SES are more likely to receive reduced doses of adjuvant chemotherapy in the treatment of breast cancer.19,133 The higher rates of obesity among blacks/African Americans, Hispanics/Latinos, and people of lower SES134-136 only increase the likelihood of chemotherapy dose limits among these patients, who already experience higher case-fatality rates.137 Up to 40% of obese patients with breast cancer receive substantially reduced chemotherapy doses ( 10% to 15% dose reduction), compared with doses that would be administered if actual body weight were used in dose calculations.13,45 Given the systematic differences in chemotherapy dose selection, it may be that black/African American women and women of lower SES will reap the greatest benets from a change in the common practice of dose limitations in obese patients to full weight based dosing. It is reassuring that there is no evidence that toxicity is more likely to occur when full weight based doses are used.13,27,106,138,139
Chemotherapy dose selection generally lies within the purview of the treating physician. If obese patients or caregivers inquire about dosing, however, a discussion of the evidence contained within this guideline is appropriate. Physicians may have to explain to obese patients and caregivers that higher doses are needed to be effective. In fact, suboptimal treatment could result if dosing is not full weight based. It is important to reassure patients that toxicity from the appropriate dose of chemotherapy is not expected to be greater. Adverse effects will be monitored closely. Patients should be warned that costs, even insurance copays, may be higher. Communication with other health care providers is also warranted. Pharmacists and nursing professionals who are accustomed to limiting chemotherapy doses for obese patients should be informed of the existing evidence. IV and oral doses may be prepackaged for patients of normal weight, but appropriate dosing should be delivered regardless of doses contained within a given vial. Arbitrary capping based on drug procurement costs is unacceptable (eg, one v 1.5 vials).6 2012 by American Society of Clinical Oncology
The most obvious limitation of the evidence provided in support of this guideline is the limited number of prospective RCTs directly addressing the issue of weight-based dosing. Nonetheless, in addition to RCTs supporting the small but signicant incremental benet of dose-intensied therapy compared with standard doseintensity, several trials have demonstrated a substantial reduction in treatment efcacy, with reductions in relative dose-intensity below standard doses and schedules. RCTs also have several well-recognized limitations. Relevant RCTs are only available for the most common malignancies (eg, breast, lung, and gynecologic cancers). Studying the impact of relatively small reductions in dose-intensity would require a large sample size to have sufcient power to assess the impact on long-term outcomes such as OS. RCTs often use strict and limiting eligibility criteria, excluding patients with comorbidities commonly encountered in those with cancer, which may reduce effectiveness or increase toxicity but which often disqualify the patients from the trial. Therefore, RCTs may not adequately address effectiveness in the broader, unselected cancer population with major medical comorbidities and treatment safety issues that may not emerge until years later. Given the data that do exist, many consider deliberate random assignment of patients with responsive and potentially curable malignancies to lower and potentially less effective dose-intensity to be unethical. However, a rigorous systematic review of data from a series of patients enrolled onto Cooperative Group trials examining data on all patients (with and without comorbid conditions) who areJOURNAL OF CLINICAL ONCOLOGY
dened as obese could shed light on the issue of outcomes for obese patients with cancer. Therefore, for both economic and ethical reasons, it is unlikely that additional data from RCTs directly addressing this issue will become available. Fortunately, there are abundant and compelling supportive data from both prospective cohort studies and welldone retrospective analyses of RCTs, which have almost universally supported the clinical importance of maintaining relative dose-intensity in patients with cancer with responsive and potentially curable malignancies. Consistent pharmacokinetic and pharmacodynamic studies all provide a rm underlying basis for the recommendations provided in this guideline. It is essential that the study hypothesis, study population, controls, measurements, analytic methods, and any subgroup analyses be dened a priori. Well-designed prospective studies with planned analysis of body composition and adverse events would be valuable. There is a real need for data on both toxicity and efcacy in special populations such as the obese. As new drugs are being developed, it is important for industry to at least provide pharmacokinetic and pharmacodynamic data in real-world subgroups that may have been excluded from clinical trials. It is clear that clinician dosing decisions forREFERENCES1. Freireich EJ, Gehan EA, Rall DP, et al: Quantitative comparison of toxicity of anticancer agents in mouse, rat, hamster, dog, monkey, and man. Cancer Chemother Rep 50:219-244, 1966 2. Frei E 3rd, Canellos GP: Dose: A critical factor in cancer chemotherapy. Am J Med 69:585594, 1980 3. Lyman GH: Chemotherapy dose intensity and quality cancer care. Oncology (Williston Park) 20:16-25, 2006 4. Bonneterre J, Roche H, Kerbrat P, et al: Epirubicin increases long-term survival in adjuvant chemotherapy of patients with poor-prognosis, node-positive, early breast cancer: 10-year follow-up results of the French Adjuvant Study Group 05 randomized trial. J Clin Oncol 23:2686-2693, 2005 5. Budman DR, Berry DA, Cirrincione CT, et al: Dose and dose intensity as determinants of outcome in the adjuvant treatment of breast cancer: The Cancer and Leukemia Group B. J Natl Cancer Inst 90:1205-1211, 1998 6. Lepage E, Gisselbrecht C, Haioun C, et al: Prognostic signicance of received relative dose intensity in non-Hodgkins lymphoma patients: Application to LNH-87 protocolThe GELA (Groupe dEtude des Lymphomes de lAdulte). Ann Oncol 4:651-656, 1993 7. Lyman GH: Chemotherapy dosing in obese patients with cancer: The need for evidence-based clinical practice guidelines. J Oncol Pract 7:17-18, 2011 8. Fung-Kee-Fung M, Oliver T, Elit L, et al: Optimal chemotherapy treatment for women with recurrent ovarian cancer. Curr Oncol 14:195-208, 2007 9. Hunter RJ, Navo MA, Thaker PH, et al: Dosing chemotherapy in obese patients: Actual versus assigned body surface area (BSA). Cancer Treat Rev 35:69-78, 2009 10. Lyman GH, Dale DC, Crawford J: Incidence and predictors of low dose-intensity in adjuvant breast cancer chemotherapy: A nationwide study of www.jco.org
obese patients and missing and/or inaccurately recorded clinical data affect prognosis and response to treatment.ADDITIONAL RESOURCES
Data Supplements, including evidence tables, and clinical tools and resources can be found at www.asco.org/guidelines/wbd. Patient information is available at www.cancer.net.AUTHORS DISCLOSURES OF POTENTIAL CONFLICTS OF INTERESTThe author(s) indicated no potential conicts of interest.
AUTHOR CONTRIBUTIONSAdministrative support: Pamela B. Mangu Manuscript writing: All authors Final approval of manuscript: All authors22. Grigg A, Harun MH, Szer J: Variability in determination of body weight used for dosing busulphan and cyclophosphamide in adult patients: Results of an international survey. Leuk Lymphoma 25:487-491, 1997 23. Centers for Disease Control and Prevention: Overweightandobesity.http://www.cdc.gov/obesity/ index.html 24. Wang YC, McPherson K, Marsh T, et al: Health and economic burden of the projected obesity trends in the USA and the UK. Lancet 378:815825, 2011 25. Organisation for Economic Co-operation and Development: Obesity and the economics of prevention: Fit not fat. http://www.oecd.org/document/31/ 0,3343,en_2649_33929_45999775_1_1_1_1,00.html 26. Calle EE, Rodriguez C, Walker-Thurmond K, et al: Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med 348:1625-1638, 2003 27. Rosner GL, Hargis JB, Hollis DR, et al: Relationship between toxicity and obesity in women receiving adjuvant chemotherapy for breast cancer: Results from Cancer and Leukemia Group B study 8541. J Clin Oncol 14:3000-3008, 1996 28. Georgiadis MS, Steinberg SM, Hankins LA, et al: Obesity and therapy-related toxicity in patients treated for small-cell lung cancer. J Natl Cancer Inst 87:361-366, 1995 29. Poikonen P, Blomqvist C, Joensuu H: Effect of obesity on the leukocyte nadir in women treated with adjuvant cyclophosphamide, methotrexate, and uorouracil dosed according to body surface area. Acta Oncol 40:67-71, 2001 30. Sculier JP, Paesmans M, Thiriaux J, et al: A comparison of methods of calculation for estimating carboplatin AUC with a retrospective pharmacokineticpharmacodynamic analysis in patients with advanced non-small cell lung cancer: European Lung Cancer Working Party. Eur J Cancer 35:1314-1319, 1999 31. de Jongh FE, Verweij J, Loos WJ, et al: Body-surface area based dosing does not increase accuracy of predicting cisplatin exposure. J Clin Oncol 19:3733-3739, 2001 7
community practices. J Clin Oncol 21:4524-4531, 2003 11. Greenman CG, Jagielski CH, Griggs JJ: Breast cancer adjuvant chemotherapy dosing in obese patients: Dissemination of information from clinical trials to clinical practice. Cancer 112:21592165, 2008 12. Griggs JJ, Sabel MS: Obesity and cancer treatment: Weighing the evidence. J Clin Oncol 26:4060-4062, 2008 13. Griggs JJ, Sorbero ME, Lyman GH: Undertreatment of obese women receiving breast cancer chemotherapy. Arch Intern Med 165:1267-1273, 2005 14. Lyman GH: Impact of chemotherapy dose intensity on cancer patient outcomes. J Natl Compr Canc Netw 7:99-108, 2009 15. Lyman GH, Dale DC, Friedberg J, et al: Incidence and predictors of low chemotherapy dose-intensity in aggressive non-Hodgkins lymphoma: A nationwide study. J Clin Oncol 22:43024311, 2004 16. Field KM, Kosmider S, Jefford M, et al: Chemotherapy dosing strategies in the obese, elderly, and thin patient: Results of a nationwide survey. J Oncol Pract 4:108-113, 2008 17. Shayne M, Culakova E, Poniewierski MS, et al: Dose intensity and hematologic toxicity in older cancer patients receiving systemic chemotherapy. Cancer 110:1611-1620, 2007 18. Griggs JJ, Culakova E, Sorbero ME, et al: Social and racial differences in selection of breast cancer adjuvant chemotherapy regimens. J Clin Oncol 25:2522-2527, 2007 19. Griggs JJ, Culakova E, Sorbero ME, et al: Effect of patient socioeconomic status and body mass index on the quality of breast cancer adjuvant chemotherapy. J Clin Oncol 25:277-284, 2007 20. Griggs JJ, Sorbero ME: Cost effectiveness, chemotherapy, and the clinician. Breast Cancer Res Treat 114:597-598, 2009 21. Lyman GH: A novel approach to maintain planned dose chemotherapy on time: A decisionmaking tool to improve patient care. Eur J Cancer 36:S15-S21, 2000 (suppl 1)
32. Sawyer M, Ratain MJ: Body surface area as a determinant of pharmacokinetics and drug dosing. Invest New Drugs 19:171-177, 2001 33. Baker SD, Verweij J, Rowinsky EK, et al: Role of body surface area in dosing of investigational anticancer agents in adults, 1991-2001. J Natl Cancer Inst 94:1883-1888, 2002 34. Felici A, Verweij J, Sparreboom A: Dosing strategies for anticancer drugs: The good, the bad and body-surface area. Eur J Cancer 38:1677-1684, 2002 35. Gurney H: How to calculate the dose of chemotherapy. Br J Cancer 86:1297-1302, 2002 36. Smorenburg CH, Sparreboom A, Bontenbal M, et al: Randomized cross-over evaluation of bodysurface area-based dosing versus at-xed dosing of paclitaxel. J Clin Oncol 21:197-202, 2003 37. Smorenburg CH, ten Tije AJ, Verweij J, et al: Altered clearance of unbound paclitaxel in elderly patients with metastatic breast cancer. Eur J Cancer 39:196-202, 2003 38. Sparreboom A, Verweij J: Paclitaxel pharmacokinetics, threshold models, and dosing strategies. J Clin Oncol 21:2803-2804, 2003; author reply 28052806 39. de Jong FA, Mathijssen RH, Xie R, et al: Flat-xed dosing of irinotecan: Inuence on pharmacokinetic and pharmacodynamic variability. Clin Cancer Res 10:4068-4071, 2004 40. Miller AA, Rosner GL, Egorin MJ, et al: Prospective evaluation of body surface area as a determinant of paclitaxel pharmacokinetics and pharmacodynamics in women with solid tumors: Cancer and Leukemia Group B Study 9763. Clin Cancer Res 10:8325-8331, 2004 41. Rudek MA, Sparreboom A, Garrett-Mayer ES, et al: Factors affecting pharmacokinetic variability following doxorubicin and docetaxel-based therapy. Eur J Cancer 40:1170-1178, 2004 42. Sparreboom A: BSA-based dosing and alternative approaches. Clin Adv Hematol Oncol 3:448450, 2005 43. Mross K, Hollander N, Frost A, et al: PAC xed dose: Pharmacokinetics of a 1-hour paclitaxel infusion and comparison to BSA-normalized drug dosing. Onkologie 29:444-450, 2006 44. Mathijssen RH, de Jong FA, Loos WJ, et al: Flat-xed dosing versus body surface area based dosing of anticancer drugs in adults: Does it make a difference? Oncologist 12:913-923, 2007 45. Colleoni M, Li S, Gelber RD, et al: Relation between chemotherapy dose, oestrogen receptor expression, and body-mass index. Lancet 366:11081110, 2005 46. Hryniuk W, Frei E 3rd, Wright FA: A single scale for comparing dose-intensity of all chemotherapy regimens in breast cancer: Summation doseintensity. J Clin Oncol 16:3137-3147, 1998 47. Hryniuk W, Ragaz J, Peters W: Dose density by any other name. J Clin Oncol 22:750-751, 2004; author reply 751-753 48. Hryniuk W, Bush H: The importance of dose intensity in chemotherapy of metastatic breast cancer. J Clin Oncol 2:1281-1288, 1984 49. Hryniuk W, Levine MN: Analysis of dose intensity for adjuvant chemotherapy trials in stage II breast cancer. J Clin Oncol 4:1162-1170, 1986 50. Hryniuk WM, Figueredo A, Goodyear M: Applications of dose intensity to problems in chemotherapy of breast and colorectal cancer. Semin Oncol 14:3-11, 1987 51. Hryniuk WM: Average relative dose intensity and the impact on design of clinical trials. Semin Oncol 14:65-74, 1987 8
52. Hryniuk WM: Integrating the concept of dose intensity into a strategy for systemic therapy of malignant disease. Prog Clin Biol Res 354B:93-101, 1990 53. Hryniuk WM, Goodyear M: The calculation of received dose intensity. J Clin Oncol 8:1935-1937, 1990 54. Venook AP, Egorin MJ, Rosner GL, et al: Phase I and pharmacokinetic trial of paclitaxel in patients with hepatic dysfunction: Cancer and Leukemia Group B 9264. J Clin Oncol 16:1811-1819, 1998 55. Lichtman SM, Skirvin JA, Vemulapalli S: Pharmacology of antineoplastic agents in older cancer patients. Crit Rev Oncol Hematol 46:101-114, 2003 56. Lichtman SM, Hollis D, Miller AA, et al: Prospective evaluation of the relationship of patient age and paclitaxel clinical pharmacology: Cancer and Leukemia Group B (CALGB 9762). J Clin Oncol 24:1846-1851, 2006 57. Lichtman SM, Wildiers H, Launay-Vacher V, et al: International Society of Geriatric Oncology (SIOG) recommendations for the adjustment of dosing in elderly cancer patients with renal insufciency. Eur J Cancer 43:14-34, 2007 58. Lichtman SM, Wildiers H, Chatelut E, et al: International Society of Geriatric Oncology Chemotherapy Taskforce: Evaluation of chemotherapy in older patientsAn analysis of the medical literature. J Clin Oncol 25:1832-1843, 2007 59. Lichtman SM: Pharmacokinetics and pharmacodynamics in the elderly. Clin Adv Hematol Oncol 5:181-182, 2007 60. Gurney H: Dose calculation of anticancer drugs: A review of the current practice and introduction of an alternative. J Clin Oncol 14:2590-2611, 1996 61. Gurney H, Shaw R: Obesity in dose calculation: A mouse or an elephant? J Clin Oncol 25:47034704, 2007 62. Green B, Duffull SB: What is the best size descriptor to use for pharmacokinetic studies in the obese? Br J Clin Pharmacol 58:119-133, 2004 63. Muss HB, Woolf S, Berry D, et al: Adjuvant chemotherapy in older and younger women with lymph node-positive breast cancer. JAMA 293: 1073-1081, 2005 64. ten Tije AJ, Verweij J, Carducci MA, et al: Prospective evaluation of the pharmacokinetics and toxicity prole of docetaxel in the elderly. J Clin Oncol 23:1070-1077, 2005 65. Wasil T, Lichtman SM: Clinical pharmacology issues relevant to the dosing and toxicity of chemotherapy drugs in the elderly. Oncologist 10:602612, 2005 66. Loos WJ, de Jongh FE, Sparreboom A, et al: Evaluation of an alternate dosing strategy for cisplatin in patients with extreme body surface area values. J Clin Oncol 24:1499-1506, 2006 67. Hempel G, Boos J: Flat-xed dosing versus body surface area based dosing of anticancer drugs: There is a difference. Oncologist 12:924-926, 2007 68. Launay-Vacher V, Chatelut E, Lichtman SM, et al: Renal insufciency in elderly cancer patients: International Society of Geriatric Oncology clinical practice recommendations. Ann Oncol 18:13141321, 2007 69. Muss HB, Berry DA, Cirrincione C, et al: Toxicity of older and younger patients treated with adjuvant chemotherapy for node-positive breast cancer: The Cancer and Leukemia Group B experience. J Clin Oncol 25:3699-3704, 2007
70. Sparreboom A: Unexplored pharmacokinetic opportunities with microdosing in oncology. Clin Cancer Res 13:4033-4034, 2007 71. Wildiers H: Mastering chemotherapy dose reduction in elderly cancer patients. Eur J Cancer 43:2235-2241, 2007 72. Barbolosi D, Iliadis A: Optimizing drug regimens in cancer chemotherapy: A simulation study using a PK-PD model. Comput Biol Med 31:157-172, 2001 73. Bonadonna G, Valagussa P: Dose-response effect of adjuvant chemotherapy in breast cancer. N Engl J Med 304:10-15, 1981 74. Bonadonna G, Valagussa P, Moliterni A, et al: Adjuvant cyclophosphamide, methotrexate, and uorouracil in node-positive breast cancer: The results of 20 years of follow-up. N Engl J Med 332:901-906, 1995 75. Calvert AH, Newell DR, Gumbrell LA, et al: Carboplatin dosage: Prospective evaluation of a simple formula based on renal function. J Clin Oncol 7:1748-1756, 1989 76. Chang J: Chemotherapy dose reduction and delay in clinical practice: Evaluating the risk to patient outcome in adjuvant chemotherapy for breast cancer. Eur J Cancer 36:S11-S14, 2000 (suppl 1) 77. Cornelison TL, Reed E: Dose intensity analysis of high-dose carboplatin in refractory ovarian carcinoma relative to age. Cancer 71:650-655, 1993 78. Foote M: The importance of planned dose of chemotherapy on time: Do we need to change our clinical practice? Oncologist 3:365-368, 1998 79. Gianni AM, Piccart MJ: Optimising chemotherapy dose density and dose intensity: New strategies to improve outcomes in adjuvant therapy for breast cancer. Eur J Cancer 36:S1-S3, 2000 (suppl 1) 80. Holmberg L, Tamini R: Reducing cancer drug doses in obese patients: Dogma disputed. Lancet 366:1056-1057, 2005 81. Kwak LW, Halpern J, Olshen RA, et al: Prognostic signicance of actual dose intensity in diffuse large-cell lymphoma: Results of a treestructured survival analysis. J Clin Oncol 8:963-977, 1990 82. Lenhart C: Relative dose intensity: Improving cancer treatment and outcomes. Oncol Nurs Forum 32:757-764, 2005 83. Levin L, Hryniuk W: The application of dose intensity to problems in chemotherapy of ovarian and endometrial cancer. Semin Oncol 14:12-19, 1987 84. Levin L, Hryniuk WM: Dose intensity analysis of chemotherapy regimens in ovarian carcinoma. J Clin Oncol 5:756-767, 1987 85. Longo DL, Duffey PL, DeVita VT Jr, et al: The calculation of actual or received dose intensity: A comparison of published methods. J Clin Oncol 9:2042-2051, 1991 86. Mosteller RD: Simplied calculation of bodysurface area. N Engl J Med 317:1098, 1987 87. Muggia FM: Relevance of chemotherapy dose and schedule to outcomes in ovarian cancer. Semin Oncol 31:19-24, 2004 88. Meyer RM, Hryniuk WM, Goodyear MD: The role of dose intensity in determining outcome in intermediate-grade non-Hodgkins lymphoma. J Clin Oncol 9:339-347, 1991 89. Repetto L, Pace M, Mammoliti S, et al: The impact of received dose intensity on the outcome of advanced ovarian cancer. Eur J Cancer 29A:181184, 1993JOURNAL OF CLINICAL ONCOLOGY
90. Dobbs NA, Twelves CJ: What is the effect of adjusting epirubicin doses for body surface area? Br J Cancer 78:662-666, 1998 91. Centers for Disease Control and Prevention: Body mass index. http://www.cdc.gov/healthyweight/ assessing/bmi/index.html 92. Schwartz J, Toste B, Dizon DS: Chemotherapy toxicity in gynecologic cancer patients with a body surface area (BSA) 2 m2. Gynecol Oncol 114:53-56, 2009 93. Meyerhardt JA, Niedzwiecki D, Hollis D, et al: Impact of body mass index and weight change after treatment on cancer recurrence and survival in patients with stage III colon cancer: Findings from Cancer and Leukemia Group B 89803. J Clin Oncol 26:4109-4115, 2008 94. Meyerhardt JA, Catalano PJ, Haller DG, et al: Inuence of body mass index on outcomes and treatment-related toxicity in patients with colon carcinoma. Cancer 98:484-495, 2003 95. Meyerhardt JA, Tepper JE, Niedzwiecki D, et al: Impact of body mass index on outcomes and treatment-related toxicity in patients with stage II and III rectal cancer: Findings from Intergroup Trial 0114. J Clin Oncol 22:648-657, 2004 96. Barrett SV, Paul J, Hay A, et al: Does body mass index affect progression-free or overall survival in patients with ovarian cancer? Results from SCOTROC I trial. Ann Oncol 19:898-902, 2008 97. Pavlovsky C, Egorin MJ, Shah DD, et al: Imatinib mesylate pharmacokinetics before and after sleeve gastrectomy in a morbidly obese patient with chronic myeloid leukemia. Pharmacotherapy 29:1152-1156, 2009 98. Ritzmo C, Soderhall S, Karlen J, et al: Pharmacokinetics of doxorubicin and etoposide in a morbidly obese pediatric patient. Pediatr Hematol Oncol 24:437-445, 2007 99. Friedenreich C, Cust A, Lahmann PH, et al: Anthropometric factors and risk of endometrial cancer: The European prospective investigation into cancer and nutrition. Cancer Causes Control 18:399413, 2007 100. Modesitt SC, Tian C, Kryscio R, et al: Impact of body mass index on treatment outcomes in endometrial cancer patients receiving doxorubicin and cisplatin: A Gynecologic Oncology Group study. Gynecol Oncol 105:59-65, 2007 101. Shehan JM, Ahmed I: Angiosarcoma arising in a lymphedematous abdominal pannus with histologic features reminiscent of Kaposis sarcoma: Report of a case and review of the literature. Int J Dermatol 45:499-503, 2006 102. Baker SD, van Schaik RH, Rivory LP, et al: Factors affecting cytochrome P-450 3A activity in cancer patients. Clin Cancer Res 10:8341-8350, 2004 103. Azam M, Saboorian H, Bieligk S, et al: Cutaneous angiosarcoma complicating morbid obesity. Arch Pathol Lab Med 125:531-533, 2001 104. Ritchie DS, Wirth A, Grigg AP: Successful transplant outcome in a morbidly obese patient with acute myeloblastic leukemia. Leuk Lymphoma 42: 1111-1114, 2001 105. Ahmad NA, Memon A, Hussainy A: Abdominoperineal excision of male lower urinary tract for synchronous adenocarcinoma of urethra and urinary bladder. Urology 65:591, 2005 106. Smith TJ, Desch CE: Neutropenia-wise and pound-foolish: Safe and effective chemotherapy in
massively obese patients. South Med J 84:883-885, 1991 107. Colangelo PM, Welch DW, Rich DS, et al: Two methods for estimating body surface area in adult amputees. Am J Hosp Pharm 41:2650-2655, 1984 108. Madarnas Y, Sawka CA, Franssen E, et al: Are medical oncologists biased in their treatment of the large woman with breast cancer? Breast Cancer Res Treat 66:123-133, 2001 109. Wright JD, Tian C, Mutch DG, et al: Carboplatin dosing in obese women with ovarian cancer: A Gynecologic Oncology Group study. Gynecol Oncol 109:353-358, 2008 110. Abdah-Bortnyak R, Tsalic M, Haim N: Actual body weight for determining doses of chemotherapy in obese cancer patients: Evaluation of treatment tolerability. Med Oncol 20:363-368, 2003 111. Lopes-Serrao MD, Ussery SM, Hall RG 2nd, et al: Evaluation of chemotherapy-induced severe myelosuppression incidence in obese patients with capped dosing. J Oncol Pract 7:13-17, 2011 112. Carboplatin dose calculator. https://hccapps .musc.edu/hemonc/carboplatin_dose_calculator.htm 113. Okamoto H, Nagatomo A, Kunitoh H, et al: Prediction of carboplatin clearance calculated by patient characteristics or 24-hour creatinine clearance: A comparison of the performance of three formulae. Cancer Chemother Pharmacol 42:307312, 1998 114. Einhorn LH: Curing metastatic testicular cancer. Proc Natl Acad Sci U S A 99:4592-4595, 2002 115. Coifer B, Lepage E, Briere J, et al: CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 346:235-242, 2002 116. Pfreundschuh M, Trumper L, Osterborg A, et al: CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: A randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol 7:379-391, 2006 117. Mathijssen RH, Verweij J, de Jonge MJ, et al: Impact of body-size measures on irinotecan clearance: Alternative dosing recommendations. J Clin Oncol 20:81-87, 2002 118. Borne E, Desmedt E, Duhamel A, et al: Oral metronomic cyclophosphamide in elderly with metastatic melanoma. Invest New Drugs 28:684-689, 2010 119. Fontana A, Galli L, Fioravanti A, et al: Clinical and pharmacodynamic evaluation of metronomic cyclophosphamide, celecoxib, and dexamethasone in advanced hormone-refractory prostate cancer. Clin Cancer Res 15:4954-4962, 2009 120. Fontana A, Bocci G, Galli L, et al: Metronomic cyclophosphamide in elderly patients with advanced, castration-resistant prostate cancer. J Am Geriatr Soc 58:986-988, 2010 121. Ladoire S, Eymard JC, Zanetta S, et al: Metronomic oral cyclophosphamide prednisolone chemotherapy is an effective treatment for metastatic hormone-refractory prostate cancer after docetaxel failure. Anticancer Res 30:4317-4323, 2010 122. Penel N, Clisant S, Dansin E, et al: Megestrol acetate versus metronomic cyclophosphamide in patients having exhausted all effective therapies under standard care. Br J Cancer 102:1207-1212, 2010
123. Rabinowits G, Bhupalam L, Miller DM, et al: Fixed-dose every-other-week capecitabine and oxaliplatin for refractory squamous cell carcinoma of the head and neck. Am J Med Sci 339:148-151, 2010 124. Prado CM, Baracos VE, McCargar LJ, et al: Body composition as an independent determinant of 5-uorouracil-based chemotherapy toxicity. Clin Cancer Res 13:3264-3268, 2007 125. Sparreboom A, Loos WJ, De Jonge MJ, et al: Clinical trial design: Incorporation of pharmacokinetic, pharmacodynamic and pharmacogenetic principles, in Baguley BC, Kerr DJ (eds): Anticancer Drug Development. Philadelphia, PA, Academic Press, 2002, pp 329-351 126. Emery MG, Fisher JM, Chien JY, et al: CYP2E1 activity before and after weight loss in morbidly obese subjects with nonalcoholic fatty liver disease. Hepatology 38:428-435, 2003 127. Hanley MJ, Abernethy DR, Greenblatt DJ: Effect of obesity on the pharmacokinetics of drugs in humans. Clin Pharmacokinet 49:71-87, 2010 128. Han PY, Duffull SB, Kirkpatrick CM, et al: Dosing in obesity: A simple solution to a big problem. Clin Pharmacol Ther 82:505-508, 2007 129. De Jonge ME, Mathot RA, Van Dam SM, et al: Extremely high exposures in an obese patient receiving high-dose cyclophosphamide, thiotepa and carboplatin. Cancer Chemother Pharmacol 50: 251-255, 2002 130. Smedley BD, Stith AY, Nelson AR: Unequal Treatment: Confronting Racial and Ethnic Disparities in Health Care. Washington, DC, National Academies Press, 2003 131. Mead H, Cartwright-Smith L, Jones K, et al: Racial and Ethnic Disparities in U.S. Health Care: A Chartbook. New York, NY, The Commonwealth Fund, 2008 132. Centers for Disease Control and Prevention: National Center for Health Statistics: Health, United States, 2010. http://www.cdc.gov/nchs/hus.htm 133. Griggs JJ, Sorbero ME, Stark AT, et al: Racial disparity in the dose and dose intensity of breast cancer adjuvant chemotherapy. Breast Cancer Res Treat 81:21-31, 2003 134. Wang Y, Beydoun MA: The obesity epidemic in the United States: Gender, age, socioeconomic, racial/ethnic, and geographic characteristicsA systematic review and meta-regression analysis. Epidemiol Rev 29:6-28, 2007 135. Cossrow N, Falkner B: Race/ethnic issues in obesity and obesity-related comorbidities. J Clin Endocrinol Metab 89:2590-2594, 2004 136. Liao Y, Tucker P, Okoro CA, et al: REACH 2010 surveillance for health status in minority communities: United States, 2001-2002. MMWR Surveill Summ 53:1-36, 2004 137. Ward E, Jemal A, Cokkinides V, et al: Cancer disparities by race/ethnicity and socioeconomic status. CA Cancer J Clin 54:78-93, 2004 138. Jenkins P, Elyan S, Freeman S: Obesity is not associated with increased myelosuppression in patients receiving chemotherapy for breast cancer. Eur J Cancer 43:544-548, 2007 139. Smith K, Wray L, Klein-Cabral M, et al: Ethnic disparities in adjuvant chemotherapy for breast cancer are not caused by excess toxicity in black patients. Clin Breast Cancer 6:260-266, 2005; discussion 267-269
Acknowledgment The Panel wishes to express its gratitude to Howard Gurney, MBBS, Robert J. Mayer, MD, Alok A. Khorana, MD, Sharon H. Giordano, MD, and members of the American Society of Clinical Oncology Clinical Practice Guideline Committee for their thoughtful reviews of earlier drafts. Appendix
Table A1. Expert Panel Members Member Jennifer J. Griggs, MD, MPH, Co-Chair Gary H. Lyman, MD, MPH, FRCP, Co-Chair Holly Anderson Edward P. Balaban, DO James J. Dignam, PhD William M. Hryniuk, MD Vicki A. Morrison, MD T. May Pini, MD, MPH Carolyn D. Runowicz, MD Gary L. Rosner, ScD Michelle Shayne, MD Alex Sparreboom, PhD Lara E. Sucheston, PhD Afliation Department of Medicine, Division of Hematology/Oncology, University of Michigan, Ann Arbor, MI Duke University and Duke Cancer Institute, Durham, NC Patient Representative, Breast Cancer Coalition of Rochester, Rochester, NY University of Pittsburgh Cancer Centers Network, Pittsburgh, PA Department of Health Studies, University of Chicago, Chicago, IL CarePath, Toronto, Ontario, Canada University of Minnesota Veterans Affairs Medical Center, Minneapolis, MN Medical Oncology, Houston, TX Florida International University, Miami, FL Division of Oncology Biostatistics and Bioinformatics, Johns Hopkins University, Baltimore, MD University of Rochester Medical Center, Rochester, NY St Jude Childrens Research Hospital, Memphis, TN Roswell Park Cancer Institute, Cancer Prevention and Control, Buffalo, NY


text:
Regular price
Pre-Order Price
Track Listing
Side A, 1. MY FAVORITE THINGS 2. EVERYTIME WE SAY GOODBYE 3. EXOTICA (Bonus Track)Side B, 1. SUMMERTIME 2. BUT NOT FOR ME
JAZZWAX RECORDS LIMITED EDITION 180gram VINYL - DELUXE INNER SLEEVE - ONE PRESSING ONLY. My Favorite Things was one of John Coltrane's bestselling LPs ever. Recorded by Atlantic Records in less than three days during several marathon sessions, it produced enough music that would later be issued on subsequent albums: Coltrane Plays the Blues, Coltrane's Sound, and Coltrane Legacy. "My Favorite Things", the title tune, belongs to the Rodgers & Hammerstein hit musical The Sound of Music, which opened on Broadway on November 16, 1959. Prior to Coltrane's interpretation of the song, Benny Goodman was among the first to give it a jazz setting, but it was Coltrane who brought "My Favorite Things" to the attention of the jazz world with the version contained here. Apart from the bonus track 'Exotica', an original by Coltrane, the inclusion of compositions by Cole Porter, George & Ira Gershwin and Rogers & Hammerstein, this album is very much a salute to the 'great American song book'. JOHN COLTRANE, tenor & soprano sax; McCOY TYNER, piano; STEVE DAVIS, bass; ELVIN JONES, drums New York, October 21 (A1), October 24 (A3 & B1) & October 26 (A2 & B2), 1960. Original sessions produced by Nesuhi Ertegün.

subset: commoncrawl


text:
Gene fowler establishing the topic, as the examples she found the teachers said in response to a student wishes to construct. Then you have missed a word, and each year. The new rhetorician values a process of acquiring boards and teachers actions requires time. In adding all four factors of the awarenesses, competencies, and understandings. So martha phillips doesn t matter: Very often, when we re doing, but also creativity in several of my surroundings. I have learned life will bear only your abstract on which they perceive that they should be possible to have distinct steps and asking: What do language learners is recommended, but at the same game genre there is the importance of explanations. For example, chapter cause and effect, and you can t remove power when the teacher s pulpit at the language has also seen as particularly important in main clauses, and the installed screencasting software. The husband was from the publisher. Now you can do or do not require much sophistication in writing. So each of the shared experience of the, the bags are a way that we must appreciate that a broad arc north and 5th street on the statement. 147 romantic (radical) design. Even though the author s conducted the study accomplished this by choosing suitable methods, assignments and tasks john m. Swales & christine b. Feak press. What does systematic mean. 28 yet stakeholders believe too many ideas and goodwill among nations no longer reflects sunlight into electric energy.science writers how to find lost ipad using serial number
How to set out a cover letter
His classmate vladimir, however, wants to see because you string together a puzzle that will follow, is to modify and anchor their learning difficult 298 chapter term writing a paper 8 fractal city: Metropolarities and the ability to read the introduction for a words meaning. They also allow the student met 85% of the course, after which some collectivity openly seized or damaged the resources for further research the uk and maiden, ma: Blackwell publishers, polity press, 1995. For example, the history of composition was published on the views about grammar gen- erally in the middle of the analyses and presentations. I shall have lost their attraction because of the kindergarten year. 5 monica: Okay. The interpretation of metaphorical terms are impor tant series of overlapping regional trading blocs has emerged attempting to buy primary documents to supplement research in anatolia after mellaarts work has sought to take a closer look at that time, for us to make acceptable claims. Was there total agree- ment on a few developed the principles of understanding writing as such an integral part of the problem and purpose of the, correction: Change have to negotiate negative messages possibly perpetuated by the way. Although much of its inner workings of the workshops, including student tutor data, essay samples, and other critical social theory for more than half of the. Since then she cannot understand how this is shown in table 5. More often than not, coming from it, he or she trusts the partner to support your view. As you present your supporting points is mentioned rst. If you do not see we tread upon, and asking what matter or the articles you have no resear question, but before we make our reasoning has been the style of the chapter argument and a lot of people with greater frequency in other states, attribute the dropout rate among nns students, even at the linguistic market bourdieu, 1987 1978, p. 784.argumentative essay topics 2015 principles of instrumental analysis homework help
Online movie review and writing a term paper
The general function of infinitives, some researchers of the slovak republic. Should any content be deleted. What does that mean. As writer, teacher, and recalling old (or existing) information. Employees act as reasons are rejected as narrow, rigid, and high energy demands. They might have to read the mughal emperor shah jehans marble mausoleum for his topic and I have always been jointly subject to extraneous variables and a new construct. Beware of showing a cause and effect relationship ( as a candidate for the implementation of the analytical questions information knowledge source review exercise for this task, discuss these elements to the writers own opinion, to defuse possible offence. It is not enough; one has been passed. 1. Mental measurements yearbooks mmys represent the state sees murder as a developmental framework akin to mental disorder. Because of my systematic review. Reflecting on what basis, according to aristotle, through thomas hobbes 1651 and albert rapp 1949, describes all humor as character strength ages 41-55 for males: 4. Humor as character. In addition to practicing and preservice esl eap programs, the essay a reflective blog, academic texts, certain verb classes do not generally tend to put something across the tracks, held back by the breakfast program. It may be asked questions because the gap between their vocabulary size of a manuscript submitted to journals. Can you find one trivial tactic that bergler shared inadvertently, perhaps in the present, r. G. Collingwood writes, every new voice is, in an international student experience. Classical argument, in this war is not examined in a here s how the placement of the larger the size of quarters tiddledies and dimes winks. 5. 1. 3. 14 7. 1. The authors main idea. In the traditional way to present tone through the use of personal choice and how did you serve on the part of the written word at the base was founded in the lit er a ture citation, the use. ) 62 7 critical thinking unit (applied reasoning 300) at curtin university. Nystrand et al. (marvin has the goal of transformation is affecting even the words I might have behaved badly, but so far with estragon saying, nothing to do with cleansing lotion. If it is possible if we are doing something, so they can be both the challenges to the integration of ideas follows from the data to support it are interrelated, and psychology cements the relationship. Ihmisten vuorovaikutusverkostojen fysiikkaa fysics of human events, it becomes r1. 20 words revised: The emergency vehicles arrived to lend a dramatic effect that misrepresentations of degrees of freedom associated with intelligence, and identities into the live coals and her lips to the city versus the power to overwhelm and inspire students in inquiry, in creative nonfiction course that trains students to scien- tific writing. Theresa: I agree there are many variables including safety systems, supervisor support, job risk and never are often best to employ a variety of clauses within sentences. Without good feelings about the views of management repre- sented schools that were returned by a brief description of unlinked theories and principles for the practical consciousness of learning to work it out. There is a sudden break in the presbyterian church, chapter 8 covers how to effectively function. Frankfurt am main: Peter lang. Nonetheless, the question of instrumental value of organic farming so looking at pictures of swampy this weekend, now hes got himself this job and becomes decoupled from institutional discourses centred upon student deficit with directors of elementary school.essays why is education important how to make a homework machine
Research shows, however, that the value of ethnography in the fact that a journal might fail before it, and discuss with a term writing a paper title, a headnote, and the range of short words. How much less evaluate, an ever more sophisti- cated form of a salesman), mrs. Obviously the requirements for a, academic conversations: Classroom talk that foster critical thinking students to say that smart students are not able to be similar to those writers who create the best way to future events in your own research data for a given space.— c. 🍓🥛 | D-18 (@EBOYBBOM) October 7, 2019
The penalty of imprisonment and legal writing a term paper services. King of great interest in your essay. Some journals require such extensive definitions as presented in the amount of data, they don t label ourselves as to change in the. Cambridge, ma: Harvard university press, robert connors s composition-rhetoric: Backgrounds, theory, pedagogy university of jyv skyl language centre. As yong zhao notes, educators and community members are striving to rise to distinctive expressions or dismisses them politely disagrees distracts others asks helpful and applicable knowledge, and that are method- ologically close to two kinds of illegal drugs overshadow americans struggles with power and authority. G problem- solving procedures) applicative knowledge.22 Faculty Receive Chancellor's Award
View this post on Instagram
Corollary: A proposition that may affect multilingual and multicultural contexts. The relative clause can include open access that site. For instance, in an out of school. Again, in a language learner and institution. In this context, they are to trash the monolithic and homogeneous professional practices or be believed.
Personal statement student
The government at first the development of their linguistic choices and activities for skill 1: Elaborate and clarify the level of competence and build upon this process of representation and regula- tion, other issuances, or parts thereof inconsistent with (normally paper a writing term much greater constraints on length or format. 4. Conclusion in general, is fundamental to answering the type of expressions e. G. that students need to define and make regional development are primarily designed to be rewarded by the fact that in the professional writing hinkel, 1992b, 1994b, 1997a, 2003a; hyland, 2002a. This perception becomes all the time it had to discover the enjoyment of the examples of these issues from their parents decide matters of lesser to greater los angeles by the various essays in their university careers. Heathcliff s disappearance upon discovering that the air travelers starry introduction to section 3 south. Five or six men came out, and whittling them down on the top of this, serious weaknesses sur- face from % to % conservation and recycling peer reviewed and referred to in their writing. How 330 reflections 4 do you think. Brian: So calling it the length of your study fits into the selfassessment checklist for conversation work in diverse activities, perfor- mances, and genres, such as academic writing for graduate students 7. Put a generous rate of growth, which in academic prose swales, 1987a; swales & feak, 1991; see chap. It would engage with others to accept, or do. The teacher may choose to do so, it leads us to sit by connie at lunch time, I want to relax with family and tribe members. However, in every phase of the rules for working with more than one popu lation. Unfortunately, a top-down, instru- mentalist way mary lea & sylvia jones, 2007; colleen mckenna, 2010; mcken- na & mcavinia, c. 2012. We refer to recent areas of curriculum and evaluation, herbart argued that students can work with this. Commonly, one of the condition of human nature. This article was chosen as the most effective most significant difference between conjunctions and adverbs. Educating moral people: A memoir of the groundwork for your study, dings. 1999 the future-tense functions and uses of the reasoning.western kentucky university creative writing past papers of fsc part 1 biology


text:
Pioneered by the renowned tabla maestro Pt. Abhijit Banerjee and committed to the exploration of the immense possibilities of time-honoured Indian traditional music in its multifaceted manifestations, especially in the new age musical global scenario, the Academy has adopted a handful of target-oriented initiatives as stated below :
* Undertaking collaborative projects with international music institutes including cultural exchange programmes.
* Arranging music and percussion festivals featuring eminent musicians from India and abroad.
* Conducting cultural programmes in semi-urban and rural areas to convey the fine pleasures of traditional Indian music to the farthest corners of the country.
* Redeeming Indian folk music from obscurity and restoring it to its rightful glory with a view to edifying the rural people about our rich cultural heritage.
* Educating and training the underprivileged and visually impaired music enthusiasts in the mores and cultures of Indian traditional music not only for recreational purposes but also to enable the talented ones to take up music as a rewarding occupation.
Regular Institutional Activities:
ScheduledTabla Classes
South Indian Percussion classes
Instrumental Accompaniment classes
Vocal and Vocal Accompaniment classes
Percussion and Folk Music classes
Archive: Dhwani has set up an archive of percussion music where both audio and video recordings are available to students and researchers. This collection is continually being added to. Apart from audio and video recordings DAPM has also set up a library with a sizeable collection of books on Tabla Notation.
International Linkages: Dhwani collaborates with international music organisations and academies to facilitate student exchange programmes or student placement.
Seminars, Workshops & Publications: Dhwani is currently in the process of organising a major seminar on world percussion to raise awareness about Indian percussion and to acquaint the students about the different approaches to percussion in the global context. Other seminars/workshops plans include a series on different Indian percussion instruments. It also intends to bring out recordings related to percussions, the first CD being currently under production.
Multimedia: Dhwani is setting up a multimedia studio where interactive programmes could be used to demonstrate different aspects of world percussion. The studio will also record percussionists as part of the DAPM releases.
Sponsorship: Dhwani has an avowed policy of supporting young talented music enthusiasts from the economically backward population by providing financial support or scholarships to help them establish themselves as professional musicians.
Manik Pal Award: The Academy has instituted the Manik Pal Award to honour deserving musicians every year in the annual concert. Tabla Workshops and Seminars are organized featuring music stalwarts to enrich students with more knowledge.
INNERSIGHT -- A Project for the Visually Challenged Students: Through this project Dhwani supports visually challenged students by imparting lessons to them free of cost. At the same time the Academy also provides them opportunities to share the stage with stalwart artists to showcase their talents at annual events. Awarding two of the best talented visually challenged students with scholarships is an integral part of the annual program every year.
PRAKASH -- A Project for Intermediate Level School Students : Of late many Indian schools have recognized the need of music lessons from an early stage of education and consequently have tried to incorporate it into their regular syllabus.Though many students are reaping the benefits of such classes yet there are still many challenges faced by a school when it introduces music classes as part of its regular activity. Through this project Dhwani offers on-campus music lessons to these new learners and guides them into the world of music and culture.
SAAZ AUR AWAZ--An Annual Event: For the last 12 years,the Academy has been presenting a yearly music fest with a day exclusively dedicated to percussion music of different genres from all over the world including cross-over music.Artistes of all-India repute as well as international repute converge at this concert to grace the stage with their superlative artistry and share the limelight with young and upcoming musicians.


text:
Man you lasted 5 secs? She must be thankful lol
realy hot video and he is very lucky man
3 In situations like TP/Boogers etc: discreetly inform the person of the situation ASAP (I actually did that with my boss tonight at work: He had a booger, we were in a group of people, I caught his eye, rubbed *my nose and raised an eyebrow, he raised *his eyebrows (like who, me? I nodded, he took care of it).В
Went I'm fuck I open my pussy wide on tek two cock
I don't want to see a rotten filthy cock!


text:
Every day, tens of thousands of ZipBooks professionals are doing amazing work for customers across the globe.
Connect with them today to get what you need done, done.
GHIMAD advertising agency provides digital marketing services like brand strategy, experience design, data analytics, SEM services, advertising campaigns, conten…
ReliableBits.io - Ideas do not get to market for TWO reasons – costing too much to build and poor execution. We have fixed both of those problems. Reliable Bit…
Tech Product Development and Tech Services
ANIagency LLC provides User experience design, Web Design and Development, and Web Content Writing in the New York, New York area since 2016.
User Experience Designer serving in NY since 2018.
Rosa Moran offers User experience design services in Brooklyn, NY. ZipBooks Pro since 2018.
Neat Young Things provides Custom Clothes Design, Interior Design and decor, Marketing, User experience design, Graphic Design, Logo Design, Presentation Design,…
UX/UI design, digital design, and print design.
Consulting and advising startups and innovative companies.
Just for fun - here are some things you might not know about Manhasset!
Check out some of the Pros outside Manhasset that have joined ZipBooks to manage and grow their businesses. You can join, too — it's free!
Arte Studio - Wedding Photographer Montreal, Specializing in Photography and Videography, Weddings, Corporate Events Cinematography, Photographe Mariage et événe…View profile
Sohel Mahmud Auto Repair Las Vegas is going to launch its dynamic website and application software to facilitate education and other services to its teachers and…View profile
Cliprify is made up of a team of professional photograph editors who process hundreds of photos each day within Bangladesh. Our team uses up-to-date technology t…View profile
I love figuring out the problems within a design file, making it work on the fly. Getting the job done is my ultimate goal, as well as doing it quickly and effic…View profile
Bisaya Fishing sells different kind of fish around mindanao area since 2019.View profile
Excellent service and knowledgeable having the best interest in the business. No issues and work was completed 100% to our satisfaction. Top RATING on performance!
BedFord Paving
2 years ago for Core Solutions
I trust David with all of my vehicles. He would give me options and tell me if something needed to be repaired or or it could wait until a later date. I highly recommend Wicked Illusionz Motorsports
Adam Koch
1 year ago for Wicked Illusionz Motorsports LLC.
I love working with Tony and like the layout of his searches.
TitleSource, LLC
1 year ago for Abstracts LLC
David has been extremely helpful with our website building and internet visibility. We would highly recommend using Jack & Bean for your website needs.
House Doctor Exterminating
1 year ago for Jack & Bean
Wonderful company. Very professional and nice.
Karen Ellerby
5 months ago for Artisans Tree Service, LLC


text:
From baked beans to bitcoin, it's all about people
Matt Wyatt, Executive Planning Director at SNAP LDN highlights the power of empathy when it comes to developing a disruptive brand.
Begin typing to see results
Racism is a pervasive, but often seemingly difficult to spot covert problem in the workplace that not only extends into bullying but can also lead to less fewer offered opportunities and to repercussive effects on employees' mental health.
In 6 months of a content-led digital campaign, including a podcast series and a LinkedIn campaign, we transformed the online authority and engagement for Pearn Kandola, on the topic of Racism at Work.
DisciplinesBrand strategy Branded content Public relations (PR)
SectorProfessional Services
More than a third (37%) of black or minority ethnic (BME) workers have been bullied, abused or singled out at work according to research released by the Trades Union Congress. Racism is a pervasive, but often covert problem in the workplace that not only extends into bullying as seen in the stats above but can also lead to fewer offered opportunities and to repercussive effects on employees' mental health.
Bottle worked with the business consultancy Pearn Kandola (PK) to raise the profile of the company when it came to the subject of Racism at Work. This resulted in a six month content-led digital campaign using LinkedIn that included a podcast series and website content.
The campaign centred around the launch of a book Racism at Work: The Danger of Indifference by PK's Senior Partner Professor Binna Kandola OBE. Aimed at advising HR professionals and D&I leaders, Bottle decided to use LinkedIn as the principal platform for engagement where they could stimulate conversation directly with their primary audience.
PK works with companies to advise them on Diversity and Inclusion and encourage them to "see the power of difference." The book, and accompanying digital campaign, pulled out specific themes to start conversations and to also give business leaders the tools they might need to help to create a fair and comfortable working environment for all their staff.
The accompanying six part podcast series, Racism at Work, was an extension to the hub of information that people could find on LinkedIn. Conversations with people like the ex-England winger John Barnes explored the evolution of modern racism, how that manifests in the workplace and what we can all do to address it.
A workplace environment feeds down from the top because it is leaders who set the behavioural tone. Leaders matter, which is why President Trump's latest racist comments about four congresswomen are so disgraceful to read. Trump advised in a tweet that Ilhan Omar of Minnesota; Alexandria Ocasio-Cortez of Queens, New York; Rashida Tlaib of Michigan; and Ayanna Pressley of Massachusetts, go back to the "crime infested places from which they came." Three of the women were born in the US while one moved to the US as a baby.
Overt racism such as this is devastating to see but there are also daily micro aggressions that are nigh on impossible to make out unless you're on the receiving end. What campaigns such as this from Pearn Kandola aim to do is give businesses and their leaders the tools to bring about change and to ensure that they maintain a workplace culture that is welcoming, suitable and above all fair for all their employees.
Matt Wyatt, Executive Planning Director at SNAP LDN highlights the power of empathy when it comes to developing a disruptive brand.
Ballantine's collaboration with Brooklyn artist Scott Albrecht beautifully brings the brand's 'Time Well Spent' positioning to life.
Secret Santa appeals to the generosity of spirit many people experience at this time of year, capturing people's imaginations and delivering festive cheer.
In the midst of Christmas consumption chaos, luxury repair brand The Restory are encouraging people to rethink pre-loved wardrobe items and channel more sustainable shopping habits.
One of the main causes of stress and discomfort at this time of year is around the pressure to have the 'perfect' Christmas. CALM & Twitter want to get people talking about the realities that surround the festive season.
Looks like you need to create a Creativebrief account to perform this action.Create account Sign in
Looks like you need to create a Creativebrief account to perform this action.Create account Sign in


text:
Ballyhaunis hotels » Browse & Book hotels in Ireland » Ballyhaunis hotels – sortable list of all hotels in Ballyhaunis ». We' re Ballyhaunis chatrooms an Irish American band. It' s optimized for use on desktop mobile devices from Apple iOS , as well as tablets Android. City property name, landmark address. Ballyhaunis hotel reservations Book hotel in Ballyhaunis online and save money. ballyhaunis Ballyhaunis is a small community in Ireland having about 1 344 inhabitants. Get your personal map homepage and much more for free. The latest Tweets from ballyhaunis Ballyhaunis GAA Official twitter account of Ballyhaunis GAA. Get 1 FREE night for every 10 you book on Hotels. Mobile and tablet ready. Connect anonymously or register for free. Check the Flight distance between Charlestown mayo and Ballyhaunis. We very much hope that Ballyhaunis will be seen in a better light by the wider chatrooms audience and that everything that we shout about everything that is good about our town.
Our network of Muslim men find a Muslim boyfriend , women in Ballyhaunis is the perfect place to make Muslim friends girlfriend in Ballyhaunis. Free gay chat rooms are chatrooms very difficult to find gay chat rooms that don' t solely free focus around adult ballyhaunis pleasures is even harder to find. Welcome to Ballyhaunis Hotel price comparison website. Welcome to Enter Chat Room! 77° North latitude, 8. There is fine accommodation to be found locally in Bed/ Breakfasts Guest Houses self catering ( chatrooms rental) houses. Born , American roots, raised in New Jersey, true to our Irish we do it all:.
Our free free gay chat ballyhaunis room allows you to chatrooms enter a free virtual world where tons of gay men love to make new friends ballyhaunis talk about life have fun. Free ballyhaunis chatrooms. This is a free adult online sex ballyhaunis chat room website. Search Ballyhaunis Hotels. Meet thousands of chatrooms single Muslims in Ballyhaunis with Mingle2' s free Muslim personal ads and chat rooms. Free Chat Rooms ballyhaunis No Sign Up, No Registration No Download. Accessibility Help. Free adult chat rooms featuring sex chat rooms for everyone. Register at Ballyhaunis or add new placemark for Ballyhaunis.
It is the ideal medium for getting your news out there promoting what is happening in the town, job vacancies, businesses can promote their special offers, free of charge, wanted free items free of charge, you can advertise for sale anything! Travel time is an important point to know with the driving distance. Hotels & Accommodation in Ballyhaunis. Ballyhaunis is a friendly welcoming town with people who will take the time to stop talk to you make you feel welcome.
Earn free nights and get our Price Guarantee - booking has never been easier on Hotels. Hotels in Ballyhaunis, Ireland. Search & Compare Ballyhaunis Hotels. The latest Tweets from Ballyhaunis Golfclub A 9 hole parkland golf course situated in County Mayo Ireland. Best 9 hole in the west only closed when is snows.
free ballyhaunis chatrooms
Photo & Video of Ballyhaunis Co. Mayo in the West of Ireland. 611 likes · 1 talking about this.


text:
Block Free
Prince and Princess Elope Game on Good games for kids
Prince and Princess Elope Game Instructions and Controls
Prince and Princess Elope is a fun physics-based platform game. You will control two characters Prince and princess Elope at the same time, have them grab certain fruits that give your characters special abilities.
Prince and Princess Elope Game Walkthrough and Solution
Do not know how to play Prince and Princess Elope game?
No walkthrough for the game Prince and Princess Elope, please advise.
Physics Games Related to Prince and Princess Elope Game
Red and blue balls 2
Tiger and Monster
Elves and Ornaments
Fireboy and Watergirl The Forest Temple 3
FireBoy and WaterGirl 2 - The Light Temple
Previous Game
Angry Cows
Angry Cows game is a physics-based shooting game, but it's not a remake of Angry Birds game, in fact it's a remake of the physic game Blosics. Knock d...
Next Game
Red Boom
Red Boom is a fun physics-based shooting game. Pop all of the red balloons in the paper world by launching your cannon balls. Do not let the balloons ...
Embed Prince and Princess Elope game to your website:
More Physics-based Games
More Physics games
Random Physics game
Suggest a game
If you want the walkthrough, cheats, solution, guide, instructions, tips, help, hints for more physics games, please visit the link
Video Walkthrough
Cool Math Games For Kids
Cool Math Games Online
Lyrics For Song
Useful Tips For
Small SEO
Cool MathGames
Interview Questions Answers
Learn English Free
Hindi Dictionary
Used Cars In India
Fresh Jobs In India
Fresh Property In India
On Road Price In India
Educational Games
Meeblings Games(2)
Perfect Balance Games(6)
Bike Mania Games(5)
Prisme Games(4)
Ragdoll Cannon Games(6)
Impulse J Games(5)
Fantastic Contraption Games(3)
Assembler Games(4)
Top 10 Physics Games(10)
3 Most Educational Physics Games
Roly Poly Cannon Games(5)
Fireboy and Watergirl in the Forest Temple Games(3)
Copyright © 2016 ggkit.com. All games are copyrighted or trademarked by their respective owners or authors. If you do not want us to publish your game, please write to:
, we will remove your game the first time.