1 Accurately Measuring (And Reporting) Cardiotoxicity: Pitfalls & Proposed Solutions Ronald Witteles, MD October 6, 2011 Stanford University School of Medicine
2 Four Hypotheses Hypothesis 1: Product labeling is often a mess Hypothesis 2: Cardiotoxicity definitions in CTCAE 4.0 are in desperate need of reform Hypothesis 3: Those who don t learn from history are doomed to repeat it. Hypothesis 4: This matters
3 Hypothesis 1: Product Labeling is Often a Mess
4 Doxorubicin Label (2011) Treatment of doxorubicin-induced congestive heart failure includes the use of digitalis, diuretics, afterload reducers such as ACE-inhibitors, low salt diet, and bed rest. Such intervention may relieve symptoms and improve the functional status of the patient. The probability of developing impaired myocardial function is estimated to be: 300 mg/m 2 : 1-2% 400 mg/m 2 : 3-5% 450 mg/m 2 : 5-8% 500 mg/m 2 : 6-20% Adapted from Doxorubicin Prescribing Information
5 Doxorubicin: Dose-Relationships 1979: Report by Von Hoff et al Retrospectively reviewed records of 4018 patients who received doxorubicin Definition of doxorubicin-induced CHF: Clinical signs/symptoms of CHF believed to be secondary to doxorubicin by the clinician Findings: Overall incidence: 2.2% (n=88). Inflection point at 550 mg/m 2 (7%) Adapted from Von Hoff et al. Ann Int Med. 1979;91:710-7.
6 Doxorubicin: Dose-Relationships 1979: Report by Von Hoff et al Retrospectively reviewed records of 4018 patients who received doxorubicin Definition of doxorubicin-induced CHF: Clinical signs/symptoms of CHF believed to be secondary to doxorubicin by the clinician Findings: Overall incidence: 2.2% (n=88). Inflection point at 550 mg/m 2 (7%) Adapted from Von Hoff et al. Ann Int Med. 1979;91:710-7.
7 A More Recent Look at the Data Analysis of the placebo-arms of three dexrazoxane trials In all trials: Normal LVEF at start MUGA performed at baseline & after every 50 mg/m 2 of doxorubicin Examined rate of significant EF drop or symptomatic HF Supported by recent trials (e.g. B-31 & N-9831) Adapted from Swain et al. Cancer. 2003;97:
8 Why Isn t This Curve Reproduced? x x x x x x x x x x x x x x Adapted from Von Hoff et al. Ann Int Med. 1979;91:710-7 and Swain et al. Cancer. 2003;97:
9 Sutent Label Do You Know What This Means? Sutent Prescribing Information (Pfizer), May 2011 Sutent Prescribing Information.
10 Hypothesis 2: Cardiotoxicity Definitions in CTCAE 4.0 Are in Desperate Need of Reform
11 Deserves praise far ahead of what we have in Cardiology CTCAE CTCAE : Major changes in definitions of cardiac toxicity Goal to improve cardiac monitoring Was the goal realized?
13 All located here
19 Problems With CTCAE 3.0 Troponin inconsistencies Diastolic dysfunction = Muddy water Defines EF 50-59% as Grade 1 LV systolic dysfunction, even though EF above 55% is generally considered normal Picking nits?
20 Good Things About CTCAE 3.0 All cardiac toxicities were located in one section If LVEF dropped, it was clear what it should be called (LV systolic dysfunction) & with clear description of grading Other than Grade 1 definition going to up to 59%, the grades of toxicity were fairly reasonable
21 CTCAE 4.0: A Step Backwards Increased number of cardiac toxicity terms from 15 to 36 (!) Created three different ways of grading the same event Misdefined left ventricular systolic dysfunction as A disorder characterized by failure of the left ventricle to produce adequate output despite an increase in distending pressure and in end-diastolic volume.
22 The World of CTCAE 4.0 Consider the case of a patient with an asymptomatic LVEF drop from 60% to 35% How should the Oncologist grade this according to CTCAE 4.0?
23 Turns to CTCAE 4.0 Table of Contents
24 Grade 0 or Grade 1?
25 But Wait
26 Maybe It s Grade 3?
27 One More Caveat: When Does an Event Count? Answer: When it is reported by the site investigator When might that make sense? Symptom or exam finding in which the subtlety of being the physician taking the history or performing the exam matters When might that not make sense? Objective laboratory or imaging finding Examples: Neutropenia, Drop in LVEF One more caveat: How likely is the event considered to be related to the intervention being studied? (TRAE) Large can of worms if dealing with unexpected side-effect
28 Hypothesis 3: Those Who Don t Learn From History Are Doomed to Repeat It
29 Sunitinib FDA approved in 2007 based on two Phase III clinical trials Currently under investigation for >30 tumor types in over 300 clinical trials! We can learn a lot from this story
30 Sunitinib: The Story Begins Phase 1 data/cardiotoxicity 15 patients with refractory/resistant AML treated with sunitinib Heart failure: 2/15 (without prospective imaging) One heart-failure mediated death, possibly related to the drug Data adapted from Fiedler et al. Blood. 2005;105:
31 Phase II Study More Worries 63 patients with metastatic renal cell CA All patients: Normal LVEF at start Cardiac monitoring: Echo or MUGA at the end of each cycle Ejection fraction decline to below normal (on 2 or more assessments): 11% of patients 6% removed from protocol for decline in EF Data adapted from Motzer et al. J Clin Onc. 2006;24:16-24.
32 Sunitinib First Phase III Trial Phase III study for GIST, Lancet patients given sunitinib or placebo Cardiac monitoring with MUGA performed at screening & the end of each cycle MUGA data not provided in article Time to Tumor Progression Overall Survival
33 Table of Adverse Events Adapted from Demetri et al. Lancet. 2006;368:
34 Sunitinib (Sutent): Data vs. Label Lancet GIST Study A, October 2006 Sutent Prescribing Information, February 2007 Sutent Prescribing Information. & Demetri et al. Lancet. 2006;
35 Sunitinib (Sutent): Data vs. Label Lancet GIST Study A, October 2006 Sutent Prescribing Information, February 2007 Sutent Prescribing Information. & Demetri et al. Lancet. 2006;
36 Sunitinib (Sutent): Data vs. Label Lancet GIST Study A, October 2006 Sutent Prescribing Information, February 2007 Sutent Prescribing Information. & Demetri et al. Lancet. 2006;
37 Sunitinib (Sutent): Data vs. Label Lancet GIST Study A, October 2006 Sutent Prescribing Information, February 2007 Sutent Prescribing Information. & Demetri et al. Lancet. 2006;
38 Sunitinib Second Phase III Study 750 patients with untreated metastatic renal-cell CA randomized to receive: Sunitinib Interferon alfa Normal LVEF at baseline Data adapted from Motzer et al. NEJM. 2007;356:
39 Heart Failure: Phase III Study Data adapted from Motzer et al. NEJM. 2007;356:
40 Study 2: More Confusion NEJM metastatic renal cell CA (MRCC) Study, January, 2007 Sutent Prescribing Information (Pfizer), February 2007 Sutent Prescribing Information. & Motzer et al. NEJM. 2007;356:
41 Study 2: More Confusion NEJM metastatic renal cell CA (MRCC) Study, January, 2007 Sutent Prescribing Information (Pfizer), February 2007 Sutent Prescribing Information. & Motzer et al. NEJM. 2007;356:
42 Study 2: More Confusion NEJM metastatic renal cell CA (MRCC) Study, January, 2007 Sutent Prescribing Information (Pfizer), February 2007 Sutent Prescribing Information. & Motzer et al. NEJM. 2007;356:
43 Study 2: More Confusion NEJM metastatic renal cell CA (MRCC) Study, January, 2007 Sutent Prescribing Information (Pfizer), February 2007 Sutent Prescribing Information. & Motzer et al. NEJM. 2007;356:
44 Which of These is Accurate? NEJM Treatment-Naïve MRCC Study, January 11, 2007 Sutent Prescribing Information (Pfizer), February 2007 Sutent Prescribing Information (Pfizer), May 2011 Sutent Prescribing Information. & Motzer et al. NEJM. 2007;356:
45 2011: Another Trial, Still Confusion 171 patients with PNET randomized to receive: Sunitinib Placebo Normal baseline EF No cardiac imaging built in! Note: First patient randomized in June 2007 Highlights how to this day this is thought to be a non-issue or trivial issue based on original Phase III publications Treatment-related heart failure deaths 2 out of 83 patients! Adapted from Raymond et al, NEJM. 2011;364:
46 Continued Inconsistencies: 2011 NEJM Phase III PNET Trial, Published February 10, 2011 Sutent Prescribing Information (Pfizer), May 2011 Sutent Prescribing Information. & Raymond et al, NEJM. 2011;364:
47 Continued Inconsistencies: 2011 NEJM Phase III PNET Trial, Published February 10, 2011 Sutent Prescribing Information (Pfizer), May 2011 Sutent Prescribing Information. & Raymond et al, NEJM. 2011;364:
48 Continued Inconsistencies: 2011 NEJM Phase III PNET Trial, Published February 10, 2011 Sutent Prescribing Information (Pfizer), May 2011 Sutent Prescribing Information. & Raymond et al, NEJM. 2011;364:
49 How Could This Happen? Adapted from Demetri et al. Lancet. 2006;368:
50 Misleading Reporting Authors explanation for lack of inclusion in table of adverse events in Lancet: The table summarized the TRAEs that occurred with a frequency of >5% on sunitinib compared with placebo. LVEF declines were not reported in this table since the frequency did not meet the criteria (6.4% vs. 2.0%). The product label, on the other hand, reports the frequency (11% for sunitinib versus 3% for placebo) of LVEF declines to below LLN as measured by MUGA scan. Quoted from response to letter to Lancet by Dr. Demetri, Dr. Motzer, and Dr. Baum (Pfizer).
51 How Could This Happen? NEJM Treatment-Naïve MRCC Study, January 11, 2007 Sutent Prescribing Information (Pfizer), February 2007 Sutent Prescribing Information. & Motzer et al. NEJM. 2007;356:
52 Misleading Reporting Authors explanation for difference in data from article vs. label in NEJM publication: In our assessment, TRAEs as reported by the investigators were clinically more informative and relevant for the purpose of journal publication than MUGA data. Quoted from response to letter to Lancet by Dr. Demetri, Dr. Motzer, and Dr. Baum (Pfizer).
53 TRAEs Lancet GIST study, October, 2007 NEJM Renal Cell CA study, January, 2007 Adapted from Motzer et al. NEJM. 2007;356: and Demetri et al. Lancet. 2006;
54 Let s Be Clear About What Is Being Put Forward The argument is not that the MUGA data was incorrect Rather, the argument is that if a site investigator doesn t report an EF drop as an AE (or considers it not to be treatment related ), there is no responsibility of the investigator to report it in the publication even with a clear signal. Note: The investigators had access to all of this data. In fact, this was the data the FDA insisted on Note 2: A statement like no systemic mean decrease in ejection fraction in the publication in hindsight appears clearly intended to mislead.
55 Hypothesis 4: This Matters
56 It Matters When This is Used to Guide Treatment Decisions in 2011 Adapted from Von Hoff et al. Ann Int Med. 1979;91:710-7.
57 It Matters: Subsequent Sunitinib Data Adapted from Chu et al. Lancet. 2007;370:
58 It Matters: Subsequent Stanford Data Reviewed all patients receiving sunitinib at Stanford from 7/04-7/07 1/3 in clinical trials, 2/3 off of clinical trials Asymptomatic EF monitoring not routinely performed for most patients Findings: 48 patients in cohort 7/48 (15%) developed Grades 3-5 heart failure Dramatic LVEF drops in all 7 cases Follow-up: 2 patients died from heart failure Adapted from Telli et al. Ann Oncol. 2008;19:
59 Relative Risk It Matters: RR of HF with Sunitinib (P<0.001) Adapted from Richards et al. J Clin Oncol. 2011;29:
60 Relative Risk of HF in Sunitinib Arm Screening Matters for Asymptomatic and Symptomatic Detection Adapted from Richards et al. J Clin Oncol. 2011;29: Note: Should not have theoretically needed screening
61 Conclusions What is needed: Get labeling up to date Reform of CTCAE Now! Don t rely on site investigators for reporting objective measures Consider all adverse events no hiding behind whether they re called treatment related Routine cardiac imaging built into more trials Honest trial reporting 5.0 We should not stand for reporting as has happened with sunitinib. Not trying to bring down development of cancer therapeutics Trying to make their use safer
62 One Final Thought People can forsee the future only when it coincides with their own wishes, and the most grossly obvious facts can be ignored when they are unwelcome. -George Orwell, 1945
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