Editor's Note: This is the Pro article of a two-part Pro/Con Expert Analysis. Click here for the Con article.

For over a decade, some cardio-oncology experts have used the terms "Type I" and "Type II" to describe patterns of cardiotoxicity that can arise from use of cancer therapies. Unfortunately, despite the growing evidence that this categorization is both incomplete and fundamentally incorrect, the terms continue to be used both in practice and in the literature. The purpose of this article is to critically examine the major flaws in the "Type I versus Type II" characterization scheme.

Flaw 1: The Subtext to the Definition of Type II Toxicity Is Untrue

The terms "Type I" and "Type II" cardiac dysfunction were first proposed in 2005, in an editorial published in Journal of Clinical Oncology.¹ The authors noted that the toxicity of the "relatively new" agent trastuzumab "revealed true clinical and mechanistic differences between the cardiac effects of trastuzumab and those of anthracyclines." As such, the manuscript proposed that anthracycline toxicity be characterized as Type I, whereas toxicity "exemplified by trastuzumab cardiac effects" would be characterized as Type II.¹

The authors then proposed the differences between Type I toxicity ("myocardial damage") and Type II toxicity ("myocardial dysfunction"), emphasizing the purported irreversible nature of the former versus the reversible nature of the latter. Type I toxicity was noted "to be permanent and irreversible... [with a] high likelihood of sequential stress related cardiac dysfunction." Type II toxicity was deemed to have a "high likelihood of recovery to or near baseline cardiac status in 2-4 months... [with a] low likelihood of sequential stress-related cardiac dysfunction."¹

The clear subtext was that anthracycline (Type I) toxicity was bad/irreversible, whereas trastuzumab (Type II) toxicity was not so bad and almost always reversible. The take-home message was that as long as one monitors for trastuzumab (Type II) toxicity and stops the trastuzumab when one sees evidence of its occurrence, nothing bad is likely to happen long-term.

More than a decade since these proposed terms were introduced, this hypothesis has proven to be false. A series of studies have demonstrated that the long-term sequelae of trastuzumab toxicity were originally underestimated, especially in the real-world setting.

A study of over 19,000 patients with breast cancer treated in Canada examined the incidence of heart failure (HF) based on whether patients had received anthracyclines, trastuzumab, or both.² The 5-year cumulative incidence of HF was 3.2% (no anthracycline, no trastuzumab), 2.5% (+ anthracycline, no trastuzumab), 5.1% (no anthracycline, + trastuzumab), and 5.3% (+ anthracycline, + trastuzumab). After adjusting for confounders, adjuvant trastuzumab was independently associated with the development of HF after 18 months, with a hazard ratio (HR) of 5.77 (p < 0.001).² A similar study from the United States examined over 45,000 women age >66 with early-stage breast cancer, examining the incidence of HF based on cancer therapy received. The 1-, 2-, and 3-year cumulative incidence of HF was almost identical regardless of whether patients had received anthracyclines (7.8, 12.4, and 17.0% for no anthracyclines/no trastuzumab vs. 7.7, 11.9, and 15.3% for +anthracyclines/no trastuzumab), whereas it markedly differed based on whether patients had received trastuzumab (15.7, 20.7, and 26.7% for no anthracyclines/+trastuzumab vs. 16.4, 23.8, and 28.2% for +anthracyclines/+trastuzumab) (Figure 1).³ The authors calculated that "adding trastuzumab to anthracycline therapy added 12.1, 17.9, and 21.7 HF or cardiomyopathy events per 100 patients over 1, 2, and 3 years of follow-up, respectively."³ Not only did these data reveal that trastuzumab caused more long-term damage than anthracyclines in real-world patients with breast cancer, but the fact that the incidence continued to increase with time debunked the notion that trastuzumab-treated patients aren't susceptible to "sequential stress-induced cardiomyopathy" in the same fashion that anthracycline-treated patients are.

Figure 1

Yet another study of over 47,000 breast cancer patients age >64 found nearly identical results; the cumulative incidence of HF after 1 year of therapy was 5.5% for patients receiving anthracyclines/trastuzumab vs. 3.2% for those receiving anthracyclines without trastuzumab. The numbers continued to separate with time (15.5% for anthracyclines/trastuzumab vs. 9.1% for anthracyclines/no trastuzumab by year 5).⁴

Further studies revealed similar results. A study of nearly 10,000 patients with breast cancer treated with chemotherapy revealed an increase in the risk of HF from 18.9 to 29.4% when trastuzumab was administered; once again, the stratification among the four groups (+/- anthracyclines, +/- trastuzumab) revealed that trastuzumab administration was the main risk-factor for the subsequent development of HF.⁵

Cardiovascular toxicity from trastuzumab has profound consequences. A study of over 3,000 women who received adjuvant trastuzumab revealed that when trastuzumab was stopped after 1-8 doses due to cardiotoxicity, both the risk of HF/death (HR 4.02) and the risk of clinically significant relapse/death (HR 3.09) were much higher.⁶

In summary, the evidence of the past decade has consistently revealed that trastuzumab toxicity is at least as clinically meaningful as—and probably more meaningful than—anthracycline toxicity for patients with human epidermal growth factor receptor 2 (HER2) positive breast cancer. In addition, trastuzumab cardiotoxicity is not simply transient/reversible but has clinically important long-term sequelae and effects on hard outcomes. As such, much of the theoretical distinction between "Type I" and "Type II" toxicity has proven to be false.

Flaw 2: There Are Far More Than Two Types of Important Cardiotoxicity

The world was a different place in 2005. Flip-phones were state of the art, with the debut of the iPhone a full 2 years away.⁷ Facebook was in its nascent stages, with the ability to open accounts not yet available to the public. The world of "cardio-oncology" was simple, with clinically important toxicity largely limited to two classes: anthracyclines (like doxorubicin) and HER2 inhibitors (trastuzumab). In such a world, classifying cardiotoxicity into only two types made perfect sense. In the modern day, however, it makes no more sense than using a flip-phone to access one's MySpace page.

As specifically stated in the editorial that defined the terms "Type I" and "Type II" toxicity, trastuzumab toxicity was only the second main toxicity type that had been described for cancer therapies.¹ However, the world of cancer therapies and cancer-therapy-associated-cardiotoxicity has markedly changed in the intervening years. Taken conservatively, there are at least 9 classes of current cancer therapy agents causing distinct patterns of cardiotoxicity. If the goal of classifying toxicity into types is to group all agents with similar mechanisms and toxicity characteristics, the following would be an example of how such a scheme could look:

• Type I: Anthracyclines
• Type II: HER2 inhibitors
• Type III: Vascular endothelial growth factor (VEGF) inhibitors⁸
• Type IV: Bcr-Abl inhibitors⁹
• Type V: 5-FU and 5-FU metabolites¹⁰
• Type VI: Checkpoint inhibitors¹¹
• Type VII: Proteosome inhibitors¹²
• Type VIII: Histone deacetylase inhibitors¹³
• Type IX: Bruton's tyrosine kinase inhibitors¹⁴
• Type X... etc.

Clearly, the above system would not simplify the understanding of cardiotoxicity of cancer therapeutic agents for any practitioner. Yet the proposed alternative, lumping all cardiac toxicity into "Type I" (anthracyclines) and "Type II" (everything else) terminology, is simply wrong. As an example, in recent imaging guidelines published in European Heart Journal, the authors defined Type I toxicity to be anthracyclines and Type II toxicity to be HER2 inhibitors and VEGF inhibitors.¹⁵ Given that HER2 inhibitor toxicity (left ventricular systolic dysfunction – common) and VEGF inhibitor toxicity (hypertension/vascular dysfunction – common; severe/idiosyncratic HF – uncommon) share neither mechanistic nor phenotypic similarities, grouping them under the same toxicity term serves to confuse rather than simplify. If we further extend the "Type I" and "Type II" classification scheme to its logical conclusion (Type I being anthracycline cardiotoxicity and Type II being everything else), the classification becomes meaningless.

Conclusion

The past decade has seen an enormous growth in cancer therapeutics for a wide variety of malignancies. Although the new therapies have resulted in markedly improved cancer outcomes, many also have the potential for cardiotoxicity.¹⁶ The toxicities are extremely varied, from left ventricular systolic dysfunction (anthracyclines, trastuzumab), to hypertension (VEGF inhibitors), to thrombosis (Bcr-Abl inhibitors), to vasospasm (5-FU), to myocarditis (checkpoint inhibitors), to atrial fibrillation (Bruton's tyrosine kinase inhibitors). The original characterization lumping cardiotoxicity into two types suffered from two fatal flaws: understating the severity of HER2 inhibitor toxicity and not accounting for the host of toxicities from newer agents that do not fit into either box. The terms "Type I" and "Type II" toxicity should be abolished.

References

1. Ewer MS, Lippman SM. Type II chemotherapy-related cardiac dysfunction: time to recognize a new entity. J Clin Oncol 2005;23:2900-2.
2. Goldhar HA, Yan AT, Ko DT, et al. The Temporal Risk of Heart Failure Associated With Adjuvant Trastuzumab in Breast Cancer Patients: A Population Study. J Natl Cancer Inst 2015;108:djv301.
3. Chen J, Long JB, Hurria A, Owusu C, Steingart RM, Gross CP. Incidence of heart failure or cardiomyopathy after adjuvant trastuzumab therapy for breast cancer. J Am Coll Cardiol 2012;60:2504-12.
4. Du XL, Xia R, Burau K, Liu CC. Cardiac risk associated with the receipt of anthracycline and trastuzumab in a large nationwide cohort of older women with breast cancer, 1998-2005. Med Oncol 2011;28:S80-90.
5. Chaves-MacGregor M, Zhang N, Buchholz TA, et al. Trastuzumab-related cardiotoxicity among older patients with breast cancer. J Clin Oncol 2013;31:4222-8.
6. Wang SY, Long JB, Hurria A, et al. Cardiovascular events, early discontinuation of trastuzumab, and their impact on survival. Breast Cancer Res Treat 2014;146:411-9.
7. Vogelstein F. And then Steve said, 'Let there be an iPhone.' The New York Times Magazine 2013; Oct. 6:MM36.
8. Hall PS, Harshman LC, Srinivas S, Witteles RM. The frequency and severity of cardiovascular toxicity from targeted therapy in advanced renal cell carcinoma patients. JACC Heart Fail 2013;1:72-8.
9. Prasad V, Mailankody S. The accelerated approval of oncologic drugs: lessons from ponatinib. JAMA 2014;311:353-4.
10. Ambrosy AP, Kunz PL, Fisher GA, Witteles RM. Capecitabine-induced chest pain relieved by diltiazem. Am J Cardiol 2012;110:1623-6.
11. Johnson DB, Balko JM, Compton ML, et al. Fulminant Myocarditis with Combination Immune Checkpoint Blockade. N Engl J Med 2016;375:1749-55.
12. Siegel D, Martin T, Nooka A, et al. Integrated safety profile of single-agent carfilzomib: experience from 526 patients enrolled in 4 phase II clinical studies. Haematologica 2013;98:1753-61.
13. Shah MH, Binkley P, Chan K, et al. Cardiotoxicity of histone deacetylase inhibitor depsipeptide in patients with metastatic neuroendocrine tumors. Clin Cancer Res 2006;12:3997-4003.
14. Leong DP, Caron F, Hillis C, et al. The risk of atrial fibrillation with ibrutinib use: a systematic review and meta-analysis. Blood 2016;128:138-40.
15. Plana JC, Galderisi M, Barac A, et al. Expert consensus for multimodality imaging evaluation of adult patients during and after cancer therapy: a report from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging 2014;15:1063-93.
16. Witteles RM, Bosch X. Myocardial Protection During Cardiotoxic Chemotherapy. Circulation 2015;132:1835-45.

Keywords: Anthracyclines, Cardiotoxicity, Cardiotoxins, Troponin I, Consensus, Pharmaceutical Preparations, Heart Failure, Myocardium, Echocardiography, Biopsy, Medical Oncology, Algorithms

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