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Enhancing Therapeutic Decision Making When Options Abound: Toxicities Matter Nicole M. Kuderer, University of Washington School of Medicine, Seattle, WA Antonio C. Wolff, Johns Hopkins Kimmel Cancer Center, Baltimore, MD See accompanying article on page 2010
Medical oncology has come a long way since early chemotherapy studies for advanced-stage cancers. For most malignancies, we now have multiple treatment options to discuss with our patients. Many patients, in particular, the majority of those diagnosed with early-stage breast cancer, have an excellent chance of survival and should go on to live full lives. At the same time, the clinical decision-making process in early-stage breast cancer has become more complicated because clinicians and patients must navigate through various chemotherapy options that might offer similar reductions in cancer recurrence and death. Consequently, considerations beyond treatment efficacy, particularly the possibility of serious and life-threatening shortand long-term toxicities, assume even greater importance in this decision-making process. Older studies revealed that patients were willing to accept greater risks of toxicity in scenarios where chemotherapy offered as little as a 1% absolute survival improvement.1 Our evolving abilities to identify patients who attain only limited benefit from chemotherapy allow us to be more selective about when to recommend more toxic options.2 At the same time, individual patient preferences and quality-of-life considerations can vary considerably. Yet, in a curable setting, intuitively, patients and physicians alike consider iatrogenic death early in the disease course to be particularly tragic; these are also described as situations of high regret because of the many years of life prematurely lost.3 A number of chemotherapy complications can be fatal. Infections in the setting of myelosuppression and thromboembolic events remain common causes of early death as a result of chemotherapy across a range of solid tumors and lymphoma.4 Hospitalizations during or immediately after adjuvant therapy represent an indirect but important surrogate for early, potentially life-threatening complications. In contrast to efficacy results from randomized clinical trials (RCTs) in highly selected patients, effectiveness studies aim to assess how cancer treatments perform in the unselected, frequently sicker, general cancer population. These clinical factors can adversely impact the benefit of therapies observed and deemed safe within the context of healthier patients in RCTs. Surprisingly, there are limited effectiveness data available on the impact of acute and life-threatening toxicities from specific breast cancer therapies. Even when most study participants in RCTs are recruited from community settings, the reported toxicity rates may not necessarily reflect their true incidence in the general patient population.5-8 An important recent example in breast cancer was the discrepancy that 1990
© 2014 by American Society of Clinical Oncology
was observed between the frequency of serious infectious toxicities seen with docetaxel and cyclophosphamide (TC) in the original publication9,10 compared with subsequent cohort studies in unselected patient populations.11,12 Another recent breast cancer study observed unsuspected inappropriate prophylactic antibiotic use in US oncology outpatient practice,13 whereas Hassett et al14 reported higher than expected rates of chemotherapy-associated hospitalizations (12%) and toxicities in younger patients with breast cancer. Likewise, recent randomized trial data suggest that there remains uncertainty about the burden of neuropathy associated with various microtubule inhibitors and drug schedules.15 The traditional reliance on provider clinic notes as source documentation, which are then transcribed by study coordinators into case report forms, further increases the opportunity for recording errors and underreporting of the true burden of toxicities. If the patient fails to mention a particular symptom, the associated adverse effect might well not be recorded, even in high-quality RCTs. Inconsistent data collection together with unknown variations in supportive care use likely explain the remarkable variability of hematologic toxicities reported in numerous, otherwise similar RCTs that use the exact same treatment regimen.16 Such reporting variability would be inconceivable for primary efficacy outcomes assessment. Prospective cohort studies performed in real-world settings and designed specifically to assess toxicities with more consistent data collection of adverse events enhance our knowledge base. Unfortunately, such prospective cohort studies are relatively costly and time consuming and have been provided with limited funding opportunities. It is with these issues in mind that we comment on the article by Barcenas et al17 that accompanies this editorial. The authors undertook an important retrospective study in a general breast cancer population diagnosed between 2003 and 2007. They assessed the frequency of chemotherapy-related hospitalizations among six major adjuvant chemotherapy regimens within 6 months of starting therapy: TC, doxorubicin and cyclophosphamide (AC), TAC, AC plus T (AC⫹T), dose-dense AC plus paclitaxel (ddAC⫹P), or AC plus weekly P (AC⫹wP). They used the SEER/Texas Cancer Registry Medicare (SEER-Medicare) claims database to assess patients older than 65 years of age and the MarketScan administrative data set for those younger than 65 years of age.17a The investigators report that crude hospitalization rates within 6 months of the start of therapy in patients younger than age 65 years Journal of Clinical Oncology, Vol 32, No 19 (July 1), 2014: pp 1990-1993
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Editorial
ranged from a low of 6.2% (ddAC⫹P) and 6.8% (TC) to a high of 10.0% (TAC). Among these patients, those receiving TAC and AC⫹T had significantly higher odds of hospitalization than those receiving TC. Among patients older than age 65 years, hospitalization rates nearly doubled, ranging from 12.7% (TC) to 24.2% (TAC). In this older cohort, the risk of hospitalization increased, compared with TC, for all other chemotherapy regimens except ddAC⫹P. Compared with TC, the three-drug regimens TAC, ddAC⫹P, and AC⫹T had on average a healthier and younger patient distribution with lower rates of comorbidities and higher colony-stimulating factor (CSF) support. Notably, the reported hospitalization rates were not adjusted for these and other potential clinical confounders,18-20 except for the presence of CSF use. The study by Barcenas et al17 provides important data from a large, real-world breast cancer population on hospitalization rates among six of the most common adjuvant breast cancer chemotherapy regimens used in the United States. Interestingly, the authors observed similarly low hospitalization rates for TC and ddAC⫹P. However, there were significantly higher hospitalization rates, especially for TAC, AC⫹T, and AC⫹wP, not only in the elderly but also in the younger cohort, despite the fact that TAC and AC⫹T were more commonly administered to healthier patients in both age cohorts. One might speculate that these crude hospitalization rates for the threedrug regimens would have been even higher, had patient characteristics been similar to those of the generally older and sicker patients receiving TC. The authors appropriately acknowledge the potential limitations of their study, which were largely related to the challenges of using retrospective claims data sets based on billing records instead of the actual clinical data. Although billing data sets help to uncover important issues with regard to describing general practice patterns, they mostly serve as hypothesis-generating data, especially when assessing drug efficacy questions.21,22 Additional major drawbacks of administrative or claims-based data sets include the potential bias that accompanies any retrospective data, associated with the absence of information on crucial clinical confounders such as detailed drug information, severity of comorbidities, specific laboratory abnormalities, performance status, and patient frailty. In addition, toxicities or comorbidities are only captured if they require an intervention that generates a charge. Some adverse events have only recently been introduced or adequately specified in the International Classification of Diseases coding system, and even SEER-Medicare has limited or no data on drug dosing, timing, and actual chemotherapy dose-intensity. The actual recorded timing of drugs is generally based on the billing date, which can differ from the date of actual drug administration. As an example, even a limited discrepancy in these dates could confuse prophylactic CSF use with its secondary (reactive) use after the fact.22 Furthermore, deciding on primary versus secondary reasons for hospitalizations can be influenced by institutional billing preferences rather than reflecting the sequence of the clinical scenario. In the outpatient setting, patients might obtain a specific disease billing code just for undergoing a diagnostic test, even without subsequent confirmation of the suspected diagnosis. Consequently, this lack of clinical granularity of billing data easily explains the inability of this study by Barcenas et al17 to identify previously reported clinical risk factors for chemotherapy-associated toxicities.18-20 The relatively low number of hospitalizations with TC chemotherapy is perhaps surprising, especially given that several rewww.jco.org
cent real-world cohort studies have reported febrile neutropenia rates alone that are higher.11,12 Potentially, this might be in part explained by chemotherapy dose reductions in older patients receiving TC and in part by the relatively high CSF support in the current study (76% in patients older than age 65 years and 48% in younger patients). In addition, patients with febrile neutropenia might be increasingly treated in the outpatient or emergency room setting.23 However, it is perhaps noteworthy that the suggested lack of impact by CSF use in this study conflicts with several previous, well-done randomized industry and nonindustry trials alike and studies including the elderly,24-31 and with SEER-Medicare breast cancer studies that adjusted their findings for available clinical confounders.32-34 At the same time, establishing drug efficacy has also been challenging in other SEER-Medicare studies, which reflects the limited ability to account for all crucial clinical imbalances between treatment arms.22,35,36 Regardless, dose-dense chemotherapy tends to be difficult to administer routinely without CSF support.37,38 As with most good studies, this one raises more questions than it answers. More information is needed on the reasons for, severity, and length of hospitalizations and on the possibly rising associated costs. It is encouraging to see, in this study by Barcenas et al,17 in which relatively extensive supportive care was present, that less than 1% of patients older than age 65 years with breast cancer experienced an early death. For clinical practice, it also would be helpful to know if mortality rates differ for specific chemotherapy regimens, particularly in vulnerable patient groups such as the very elderly, patients with multiple comorbidities, and in hospitalized patients. Previous reports in unselected patients with breast cancer of all stages and acuity indicate that approximately 4% die when hospitalized for neutropenic infections.39 Among older patients with breast cancer, 5% die on average when hospitalized for any chemotherapy-associated adverse effect,40 and the risk of mortality increases incrementally with increasing numbers of major comorbid conditions,39,40 similar to the increases in hospitalizations with comorbidities that were observed by Barcenas et al. To put this in perspective, surgeons consider procedures associated with a 5% or greater fatal complication rate to be high risk. Even less is known about the short- and long-term impact of hospitalization on patient physical and emotional well-being or on independent living in patients who are considered to be predisposed to frailty. In the curative setting of breast cancer, therapeutic decisions must also strike a balance between survival benefits and quality-of-life issues that are associated with delayed and long-term toxicities during survivorship. For instance, in the era of taxane-containing regimens, neuropathy is becoming a relatively common long-term problem to consider, with limited management options to alleviate patient symptoms.41 Despite the opportunities presented by new targeted agents, some may have toxicities that adversely affect survivorship in ways that may match or even exceed those observed with current chemotherapies. The Institute of Medicine report on adverse event reporting has highlighted the limitations encountered in regulatory settings.42,43 Clinical practitioners tend to underestimate the burden of toxicity,5-8,44 and better quality data for toxicity outcomes are needed on all study levels.5-8 In RCTs, we need to establish more reliable methods for collecting toxicity data, with a rigor similar to that devoted to primary efficacy outcomes. Well-designed prospective cohort studies along with biospecimen collections may provide more robust data for postmarketing toxicity assessment. Such prospectively planned cohort © 2014 by American Society of Clinical Oncology
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1991
Editorial
studies are poised to identify clinical as well as potential molecular predictors that also might form the basis for future personalized toxicity prediction and prevention.20,45-47 Patient-reported outcomes strategies may be especially useful for the assessment of subjective end points in RCTs as well as in other comparative effectiveness research.48-50 In toxicity studies, better data on delivered chemotherapy dose-intensity and supportive care are needed, given that they tend to alter the observed toxicity burden.13,31,51 Early deaths, particularly during the active study treatment period, should be a routinely reported study outcome. Additionally, enhanced methodologic strategies are required to overcome inaccuracies of SEER-Medicare and other claims-based data sets before billing data can routinely inform clinical care.21 Not surprisingly, electronic medical records (EMRs) have focused most of their data collection on billing codes, leaving the limitations of these newer data sets less understood than SEER-Medicare. Although newer EMR systems, such as Epic (Epic, Verona, WI), have the capability of collecting discrete clinical data points that could replace at least some billing data, these measures are rarely instituted, given that they incur significant additional operational costs and effort. Unless we go beyond billing codes in our newer EMR databases, we run the risk of missing the true promise of the ongoing, highly expensive EMR revolution.52 Not all evidence is created equal, and that includes evidence on treatment-related toxicities. Toxicity research has provided limited high-quality data because of its secondary role in most trials. Yet one can foresee a time in the not-so-distant future when essentially all patients with early-stage breast cancer will be expected to survive their diagnosis—a time when treatment-related adverse effects become the driving differentiating factor for therapeutic choices. We have come a long way since the days of “the cancer is cured, but the patient is dead,” and, undoubtedly, the search for cures remains paramount in oncology. However, greater funding from government, industry, and private foundations and guidance from policy agencies are needed to enable more quality toxicity research so that we can fully realize the potential of personalized and safe cancer care. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Although all authors completed the disclosure declaration, the following author(s) and/or an author’s immediate family member(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: None Research Funding: Nicole M. Kuderer, Amgen Expert Testimony: None Patents, Royalties, and Licenses: None Other Remuneration: None AUTHOR CONTRIBUTIONS
Manuscript writing: All authors Final approval of manuscript: All authors REFERENCES 1. Ravdin PM, Siminoff IA, Harvey JA: Survey of breast cancer patients concerning their knowledge and expectations of adjuvant therapy. J Clin Oncol 16:515-521, 1998 2. Theriault RL, Carlson RW, Allred C, et al: Breast cancer, version 3.2013: Featured updates to the NCCN guidelines. J Natl Compr Canc Netw 11:753-761, 2013 1992
© 2014 by American Society of Clinical Oncology
3. Djulbegovic B, Hozo I, Schwartz A, et al: Acceptable regret in medical decision making. Med Hypotheses 53:253-259, 1999 4. Khorana AA, Francis CW, Culakova E, et al: Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy. J Thromb Haemost 5:632-634, 2007 5. Sivendran S, Latif A, McBride RB, et al: Adverse event reporting in cancer clinical trial publications. J Clin Oncol 32:83-89, 2014 6. Pakhomov SV, Jacobsen SJ, Chute CG, et al: Agreement between patient-reported symptoms and their documentation in the medical record. Am J Manag Care 14:530-539, 2008 7. Fromme EK, Eilers KM, Mori M, et al: How accurate is clinician reporting of chemotherapy adverse effects? A comparison with patient-reported symptoms from the Quality-of-Life Questionnaire C30. J Clin Oncol 22:3485-3490, 2004 8. Atkinson TM, Li Y, Coffey CW, et al: Reliability of adverse symptom event reporting by clinicians. Qual Life Res 21:1159-1164, 2012 9. Jones S, Holmes FA, O’Shaughnessy J, et al: Docetaxel with cyclophosphamide is associated with an overall survival benefit compared with doxorubicin and cyclophosphamide: 7-year follow-up of US Oncology Research Trial 9735. J Clin Oncol 27:1177-1183, 2009 10. Jones SE, Savin MA, Holmes FA, et al: Phase III trial comparing doxorubicin plus cyclophosphamide with docetaxel plus cyclophosphamide as adjuvant therapy for operable breast cancer. J Clin Oncol 24:5381-5387, 2006 11. Hamilton EP, Topping JM, Marcom PK, et al: Clinical impact of febrile neutropenia (FN) increase among patients receiving adjuvant docetaxel/cyclophosphamide (TC) chemotherapy compared to TC plus pegfilgrastim for breast cancer. J Clin Oncol 31:67s, 2013 (suppl; abstr 1076) 12. Lakhanpal R, Stuart-Harris R, Chan A, et al: A multicenter audit of the incidence of febrile neutropenia and neutropenia associated with docetaxel and cyclophosphamide (TC) chemotherapy for early breast cancer. J Clin Oncol 31:68s, 2013 (suppl; abstr 1079) 13. Culakova E, Thota R, Poniewierski MS: Patterns of chemotherapy-associated toxicity and supportive care in US oncology practice: A nationwide prospective cohort study. Cancer Med 3:434-444, 2014 14. Hassett MJ, O’Malley AJ, Pakes JR, et al: Frequency and cost of chemotherapy-related serious adverse effects in a population sample of women with breast cancer. J Natl Cancer Inst 98:1108-1117, 2006 15. Rugo HS, Barry WT, Moreno-Aspitia A: CALGB 40502/NCCTG N063H: Randomized phase III trial of weekly paclitaxel (P) compared to weekly nanoparticle albumin bound nab-paclitaxel (NP) or ixabepilone (Ix) with or without bevacizumab (B) as first-line therapy for locally recurrent or metastatic breast cancer (MBC). J Clin Oncol 30:49s, 2012 (suppl; abstr CRA1002) 16. Dale DC, McCarter GC, Crawford J, et al: Myelotoxicity and dose intensity of chemotherapy: Reporting practices from randomized clinical trials. J Natl Compr Canc Netw 1:440-454, 2003 17. Barcenas CH, Niu J, Zhang N, et al: Risk of hospitalization according to chemotherapy regimen in early-stage breast cancer. J Clin Oncol 32:2010-2017, 2014 17a. Hansen LG, Chang S: White paper: Health research data for the real world. The Thomson Reuters MarketScan Databases, Thomson Reuters, 2011, p 32 18. Extermann M, Boler I, Reich RR, et al: Predicting the risk of chemotherapy toxicity in older patients: The Chemotherapy Risk Assessment Scale for HighAge Patients (CRASH) score. Cancer 118:3377-3386, 2012 19. Hurria A, Togawa K, Mohile SG, et al: Predicting chemotherapy toxicity in older adults with cancer: A prospective multicenter study. J Clin Oncol 29:34573465, 2011 20. Lyman GH, Kuderer NM, Crawford J, et al: Predicting individual risk of neutropenic complications in patients receiving cancer chemotherapy. Cancer 117:1917-1927, 2011 21. Armstrong K: Methods in comparative effectiveness research. J Clin Oncol 30:4208-4214, 2012 22. Hudis CA, Citron ML, Muss H, et al: Can we really use retrospective subset analyses and surveillance, epidemiology, and end results data to drive clinical practice? J Clin Oncol 30:3148-3149; author reply 3149-3150, 2012 23. Flowers CR, Seidenfeld J, Bow EJ, et al: Antimicrobial prophylaxis and outpatient management of fever and neutropenia in adults treated for malignancy: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol 31:794-810, 2013 24. Chevallier B, Chollet P, Merrouche Y, et al: Lenograstim prevents morbidity from intensive induction chemotherapy in the treatment of inflammatory breast cancer. J Clin Oncol 13:1564-1571, 1995 JOURNAL OF CLINICAL ONCOLOGY
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25. Crawford J, Ozer H, Stoller R, et al: Reduction by granulocyte colonystimulating factor of fever and neutropenia induced by chemotherapy in patients with small-cell lung cancer. N Engl J Med 325:164-170, 1991 26. Osby E, Hagberg H, Kvaløy S, et al: CHOP is superior to CNOP in elderly patients with aggressive lymphoma while outcome is unaffected by filgrastim treatment: Results of a Nordic Lymphoma Group randomized trial. Blood 101: 3840-3848, 2003 27. Timmer-Bonte JN, de Boo TM, Smit HJ, et al: Prevention of chemotherapyinduced febrile neutropenia by prophylactic antibiotics plus or minus granulocyte colony-stimulating factor in small-cell lung cancer: A Dutch randomized phase III study. J Clin Oncol 23:7974-7984, 2005 28. Trillet-Lenoir V, Green J, Manegold C, et al: Recombinant granulocyte colony stimulating factor reduces the infectious complications of cytotoxic chemotherapy. Eur J Cancer 29A:319-324, 1993 29. Vogel CL, Wojtukiewicz MZ, Carroll RR, et al: First and subsequent cycle use of pegfilgrastim prevents febrile neutropenia in patients with breast cancer: A multicenter, double-blind, placebo-controlled phase III study. J Clin Oncol 23:1178-1184, 2005 30. Fosså SD, Kaye SB, Mead GM, et al: Filgrastim during combination chemotherapy of patients with poor-prognosis metastatic germ cell malignancy: European Organization for Research and Treatment of Cancer, Genito-Urinary Group, and the Medical Research Council Testicular Cancer Working Party, Cambridge, United Kingdom. J Clin Oncol 16:716-724, 1998 31. Kuderer NM, Dale DC, Crawford J, et al: Impact of primary prophylaxis with granulocyte colony-stimulating factor on febrile neutropenia and mortality in adult cancer patients receiving chemotherapy: A systematic review. J Clin Oncol 25:3158-3167, 2007 32. Rajan SS, Lyman GH, Carpenter WR, et al: Chemotherapy characteristics are important predictors of primary prophylactic CSF administration in older patients with breast cancer. Breast Cancer Res Treat 127:511-520, 2011 33. Rajan SS, Lyman GH, Stearns SC, et al: Effect of primary prophylactic granulocyte-colony stimulating factor use on incidence of neutropenia hospitalizations for elderly early-stage breast cancer patients receiving chemotherapy. Med Care 49:649-657, 2011 34. Rajan SS, Stearns SC, Lyman GH, et al: Effect of primary prophylactic G-CSF use on systemic therapy administration for elderly breast cancer patients. Breast Cancer Res Treat 130:255-266, 2011 35. Hurwitz HI, Lyman GH: Registries and randomized trials in assessing the effects of bevacizumab in colorectal cancer: Is there a common theme? J Clin Oncol 30:580-581, 2012 36. Meyerhardt JA, Li L, Sanoff HK, et al: Effectiveness of bevacizumab with first-line combination chemotherapy for Medicare patients with stage IV colorectal cancer. J Clin Oncol 30:608-615, 2012 37. Sugarman S, Wasserheit C, Hodgman E, et al: A pilot study of dose-dense adjuvant paclitaxel without growth factor support for women with early breast carcinoma. Breast Cancer Res Treat 115:609-612, 2009 38. Citron ML, Berry DA, Cirrincione C, et al: Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary
breast cancer: First report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol 21:1431-1439, 2003 39. Kuderer NM, Dale DC, Crawford J, et al: Mortality, morbidity, and cost associated with febrile neutropenia in adult cancer patients. Cancer 106:22582266, 2006 40. Du XL, Osborne C, Goodwin JS: Population-based assessment of hospitalizations for toxicity from chemotherapy in older women with breast cancer. J Clin Oncol 20:4636-4642, 2002 41. Hershman DL, Lacchetti C, Dworkin RH, et al: Prevention and management of chemotherapy-induced peripheral neuropathy in survivors of adult cancers: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol [epub ahead of print on April 14, 2014] 42. Benet LZ: Review and critique of the Institute of Medicine report “The Future of Drug Safety”. Clin Pharmacol Ther 81:158-161, 2007 43. Baciu A, Stratton K, Burke SP (eds): The Future of Drug Safety: Promoting and Protecting the Health of the Public. National Academies Press, Washington, DC, 2006. http://www.iom.edu/Reports/2006/The-Future-of-Drug-SafetyPromoting-and-Protecting-the-Health-of-the-Public.aspx 44. Basch E: The missing voice of patients in drug-safety reporting. N Engl J Med 362:865-869, 2010 45. Simonds NI, Khoury MJ, Schully SD, et al: Comparative effectiveness research in cancer genomics and precision medicine: Current landscape and future prospects. J Natl Cancer Inst 105:929-936, 2013 46. Ginsburg GS, Kuderer NM: Comparative effectiveness research, genomics-enabled personalized medicine, and rapid learning health care: A common bond. J Clin Oncol 30:4233-4242, 2012 47. Khorana AA, Kuderer NM, Culakova E, et al: Development and validation of a predictive model for chemotherapy-associated thrombosis. Blood 111:49024907, 2008 48. Wu AW, Kharrazi H, Boulware LE, et al: Measure once, cut twice: Adding patient-reported outcome measures to the electronic health record for comparative effectiveness research. J Clin Epidemiol 66:S12-S20, 2013 49. Pietanza MC, Basch EM, Lash A, et al: Harnessing technology to improve clinical trials: Study of real-time informatics to collect data, toxicities, image response assessments, and patient-reported outcomes in a phase II clinical trial. J Clin Oncol 31:2004-2009, 2013 50. Jensen RE, Snyder CF, Abernethy AP, et al: Review of electronic patientreported outcomes systems used in cancer clinical care. J Oncol Pract [epub ahead of print on December 3, 2013] 51. Hyman DM, Eaton AA, Gounder MM, et al: Nomogram to predict cycle-one serious drug-related toxicity in phase I oncology trials. J Clin Oncol 32:519-526, 2014 52. Fleming NS, Culler SD, McCorkle R, et al: The financial and nonfinancial costs of implementing electronic health records in primary care practices. Health Aff (Millwood) 30:481-489, 2011
DOI: 10.1200/JCO.2014.55.1903; published online ahead of print at www.jco.org on May 27, 2014
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www.jco.org
© 2014 by American Society of Clinical Oncology
Information downloaded from jco.ascopubs.org and provided by at CONS CALIFORNIA DIG LIB on March 6, 2015 from Copyright © 2014 American Society of Clinical Oncology. All rights reserved. 169.230.243.252
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2014
JOURNAL OF CLINICAL ONCOLOGY
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Enhancing Therapeutic Decision Making When Options Abound: Toxicities Matter Nicole M. Kuderer, University of Washington School of Medicine, Seattle, WA Antonio C. Wolff, Johns Hopkins Kimmel Cancer Center, Baltimore, MD See accompanying article on page 2010
Medical oncology has come a long way since early chemotherapy studies for advanced-stage cancers. For most malignancies, we now have multiple treatment options to discuss with our patients. Many patients, in particular, the majority of those diagnosed with early-stage breast cancer, have an excellent chance of survival and should go on to live full lives. At the same time, the clinical decision-making process in early-stage breast cancer has become more complicated because clinicians and patients must navigate through various chemotherapy options that might offer similar reductions in cancer recurrence and death. Consequently, considerations beyond treatment efficacy, particularly the possibility of serious and life-threatening shortand long-term toxicities, assume even greater importance in this decision-making process. Older studies revealed that patients were willing to accept greater risks of toxicity in scenarios where chemotherapy offered as little as a 1% absolute survival improvement.1 Our evolving abilities to identify patients who attain only limited benefit from chemotherapy allow us to be more selective about when to recommend more toxic options.2 At the same time, individual patient preferences and quality-of-life considerations can vary considerably. Yet, in a curable setting, intuitively, patients and physicians alike consider iatrogenic death early in the disease course to be particularly tragic; these are also described as situations of high regret because of the many years of life prematurely lost.3 A number of chemotherapy complications can be fatal. Infections in the setting of myelosuppression and thromboembolic events remain common causes of early death as a result of chemotherapy across a range of solid tumors and lymphoma.4 Hospitalizations during or immediately after adjuvant therapy represent an indirect but important surrogate for early, potentially life-threatening complications. In contrast to efficacy results from randomized clinical trials (RCTs) in highly selected patients, effectiveness studies aim to assess how cancer treatments perform in the unselected, frequently sicker, general cancer population. These clinical factors can adversely impact the benefit of therapies observed and deemed safe within the context of healthier patients in RCTs. Surprisingly, there are limited effectiveness data available on the impact of acute and life-threatening toxicities from specific breast cancer therapies. Even when most study participants in RCTs are recruited from community settings, the reported toxicity rates may not necessarily reflect their true incidence in the general patient population.5-8 An important recent example in breast cancer was the discrepancy that 1990
© 2014 by American Society of Clinical Oncology
was observed between the frequency of serious infectious toxicities seen with docetaxel and cyclophosphamide (TC) in the original publication9,10 compared with subsequent cohort studies in unselected patient populations.11,12 Another recent breast cancer study observed unsuspected inappropriate prophylactic antibiotic use in US oncology outpatient practice,13 whereas Hassett et al14 reported higher than expected rates of chemotherapy-associated hospitalizations (12%) and toxicities in younger patients with breast cancer. Likewise, recent randomized trial data suggest that there remains uncertainty about the burden of neuropathy associated with various microtubule inhibitors and drug schedules.15 The traditional reliance on provider clinic notes as source documentation, which are then transcribed by study coordinators into case report forms, further increases the opportunity for recording errors and underreporting of the true burden of toxicities. If the patient fails to mention a particular symptom, the associated adverse effect might well not be recorded, even in high-quality RCTs. Inconsistent data collection together with unknown variations in supportive care use likely explain the remarkable variability of hematologic toxicities reported in numerous, otherwise similar RCTs that use the exact same treatment regimen.16 Such reporting variability would be inconceivable for primary efficacy outcomes assessment. Prospective cohort studies performed in real-world settings and designed specifically to assess toxicities with more consistent data collection of adverse events enhance our knowledge base. Unfortunately, such prospective cohort studies are relatively costly and time consuming and have been provided with limited funding opportunities. It is with these issues in mind that we comment on the article by Barcenas et al17 that accompanies this editorial. The authors undertook an important retrospective study in a general breast cancer population diagnosed between 2003 and 2007. They assessed the frequency of chemotherapy-related hospitalizations among six major adjuvant chemotherapy regimens within 6 months of starting therapy: TC, doxorubicin and cyclophosphamide (AC), TAC, AC plus T (AC⫹T), dose-dense AC plus paclitaxel (ddAC⫹P), or AC plus weekly P (AC⫹wP). They used the SEER/Texas Cancer Registry Medicare (SEER-Medicare) claims database to assess patients older than 65 years of age and the MarketScan administrative data set for those younger than 65 years of age.17a The investigators report that crude hospitalization rates within 6 months of the start of therapy in patients younger than age 65 years Journal of Clinical Oncology, Vol 32, No 19 (July 1), 2014: pp 1990-1993
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Editorial
ranged from a low of 6.2% (ddAC⫹P) and 6.8% (TC) to a high of 10.0% (TAC). Among these patients, those receiving TAC and AC⫹T had significantly higher odds of hospitalization than those receiving TC. Among patients older than age 65 years, hospitalization rates nearly doubled, ranging from 12.7% (TC) to 24.2% (TAC). In this older cohort, the risk of hospitalization increased, compared with TC, for all other chemotherapy regimens except ddAC⫹P. Compared with TC, the three-drug regimens TAC, ddAC⫹P, and AC⫹T had on average a healthier and younger patient distribution with lower rates of comorbidities and higher colony-stimulating factor (CSF) support. Notably, the reported hospitalization rates were not adjusted for these and other potential clinical confounders,18-20 except for the presence of CSF use. The study by Barcenas et al17 provides important data from a large, real-world breast cancer population on hospitalization rates among six of the most common adjuvant breast cancer chemotherapy regimens used in the United States. Interestingly, the authors observed similarly low hospitalization rates for TC and ddAC⫹P. However, there were significantly higher hospitalization rates, especially for TAC, AC⫹T, and AC⫹wP, not only in the elderly but also in the younger cohort, despite the fact that TAC and AC⫹T were more commonly administered to healthier patients in both age cohorts. One might speculate that these crude hospitalization rates for the threedrug regimens would have been even higher, had patient characteristics been similar to those of the generally older and sicker patients receiving TC. The authors appropriately acknowledge the potential limitations of their study, which were largely related to the challenges of using retrospective claims data sets based on billing records instead of the actual clinical data. Although billing data sets help to uncover important issues with regard to describing general practice patterns, they mostly serve as hypothesis-generating data, especially when assessing drug efficacy questions.21,22 Additional major drawbacks of administrative or claims-based data sets include the potential bias that accompanies any retrospective data, associated with the absence of information on crucial clinical confounders such as detailed drug information, severity of comorbidities, specific laboratory abnormalities, performance status, and patient frailty. In addition, toxicities or comorbidities are only captured if they require an intervention that generates a charge. Some adverse events have only recently been introduced or adequately specified in the International Classification of Diseases coding system, and even SEER-Medicare has limited or no data on drug dosing, timing, and actual chemotherapy dose-intensity. The actual recorded timing of drugs is generally based on the billing date, which can differ from the date of actual drug administration. As an example, even a limited discrepancy in these dates could confuse prophylactic CSF use with its secondary (reactive) use after the fact.22 Furthermore, deciding on primary versus secondary reasons for hospitalizations can be influenced by institutional billing preferences rather than reflecting the sequence of the clinical scenario. In the outpatient setting, patients might obtain a specific disease billing code just for undergoing a diagnostic test, even without subsequent confirmation of the suspected diagnosis. Consequently, this lack of clinical granularity of billing data easily explains the inability of this study by Barcenas et al17 to identify previously reported clinical risk factors for chemotherapy-associated toxicities.18-20 The relatively low number of hospitalizations with TC chemotherapy is perhaps surprising, especially given that several rewww.jco.org
cent real-world cohort studies have reported febrile neutropenia rates alone that are higher.11,12 Potentially, this might be in part explained by chemotherapy dose reductions in older patients receiving TC and in part by the relatively high CSF support in the current study (76% in patients older than age 65 years and 48% in younger patients). In addition, patients with febrile neutropenia might be increasingly treated in the outpatient or emergency room setting.23 However, it is perhaps noteworthy that the suggested lack of impact by CSF use in this study conflicts with several previous, well-done randomized industry and nonindustry trials alike and studies including the elderly,24-31 and with SEER-Medicare breast cancer studies that adjusted their findings for available clinical confounders.32-34 At the same time, establishing drug efficacy has also been challenging in other SEER-Medicare studies, which reflects the limited ability to account for all crucial clinical imbalances between treatment arms.22,35,36 Regardless, dose-dense chemotherapy tends to be difficult to administer routinely without CSF support.37,38 As with most good studies, this one raises more questions than it answers. More information is needed on the reasons for, severity, and length of hospitalizations and on the possibly rising associated costs. It is encouraging to see, in this study by Barcenas et al,17 in which relatively extensive supportive care was present, that less than 1% of patients older than age 65 years with breast cancer experienced an early death. For clinical practice, it also would be helpful to know if mortality rates differ for specific chemotherapy regimens, particularly in vulnerable patient groups such as the very elderly, patients with multiple comorbidities, and in hospitalized patients. Previous reports in unselected patients with breast cancer of all stages and acuity indicate that approximately 4% die when hospitalized for neutropenic infections.39 Among older patients with breast cancer, 5% die on average when hospitalized for any chemotherapy-associated adverse effect,40 and the risk of mortality increases incrementally with increasing numbers of major comorbid conditions,39,40 similar to the increases in hospitalizations with comorbidities that were observed by Barcenas et al. To put this in perspective, surgeons consider procedures associated with a 5% or greater fatal complication rate to be high risk. Even less is known about the short- and long-term impact of hospitalization on patient physical and emotional well-being or on independent living in patients who are considered to be predisposed to frailty. In the curative setting of breast cancer, therapeutic decisions must also strike a balance between survival benefits and quality-of-life issues that are associated with delayed and long-term toxicities during survivorship. For instance, in the era of taxane-containing regimens, neuropathy is becoming a relatively common long-term problem to consider, with limited management options to alleviate patient symptoms.41 Despite the opportunities presented by new targeted agents, some may have toxicities that adversely affect survivorship in ways that may match or even exceed those observed with current chemotherapies. The Institute of Medicine report on adverse event reporting has highlighted the limitations encountered in regulatory settings.42,43 Clinical practitioners tend to underestimate the burden of toxicity,5-8,44 and better quality data for toxicity outcomes are needed on all study levels.5-8 In RCTs, we need to establish more reliable methods for collecting toxicity data, with a rigor similar to that devoted to primary efficacy outcomes. Well-designed prospective cohort studies along with biospecimen collections may provide more robust data for postmarketing toxicity assessment. Such prospectively planned cohort © 2014 by American Society of Clinical Oncology
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Editorial
studies are poised to identify clinical as well as potential molecular predictors that also might form the basis for future personalized toxicity prediction and prevention.20,45-47 Patient-reported outcomes strategies may be especially useful for the assessment of subjective end points in RCTs as well as in other comparative effectiveness research.48-50 In toxicity studies, better data on delivered chemotherapy dose-intensity and supportive care are needed, given that they tend to alter the observed toxicity burden.13,31,51 Early deaths, particularly during the active study treatment period, should be a routinely reported study outcome. Additionally, enhanced methodologic strategies are required to overcome inaccuracies of SEER-Medicare and other claims-based data sets before billing data can routinely inform clinical care.21 Not surprisingly, electronic medical records (EMRs) have focused most of their data collection on billing codes, leaving the limitations of these newer data sets less understood than SEER-Medicare. Although newer EMR systems, such as Epic (Epic, Verona, WI), have the capability of collecting discrete clinical data points that could replace at least some billing data, these measures are rarely instituted, given that they incur significant additional operational costs and effort. Unless we go beyond billing codes in our newer EMR databases, we run the risk of missing the true promise of the ongoing, highly expensive EMR revolution.52 Not all evidence is created equal, and that includes evidence on treatment-related toxicities. Toxicity research has provided limited high-quality data because of its secondary role in most trials. Yet one can foresee a time in the not-so-distant future when essentially all patients with early-stage breast cancer will be expected to survive their diagnosis—a time when treatment-related adverse effects become the driving differentiating factor for therapeutic choices. We have come a long way since the days of “the cancer is cured, but the patient is dead,” and, undoubtedly, the search for cures remains paramount in oncology. However, greater funding from government, industry, and private foundations and guidance from policy agencies are needed to enable more quality toxicity research so that we can fully realize the potential of personalized and safe cancer care. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Although all authors completed the disclosure declaration, the following author(s) and/or an author’s immediate family member(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: None Research Funding: Nicole M. Kuderer, Amgen Expert Testimony: None Patents, Royalties, and Licenses: None Other Remuneration: None AUTHOR CONTRIBUTIONS
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DOI: 10.1200/JCO.2014.55.1903; published online ahead of print at www.jco.org on May 27, 2014
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