Troponins for predicting cardiotoxicity from cancer therapy

COMMENTARY

controlled patients.20,21 Thus the key finding of Spyer et al is that these can also occur in well-controlled type 2 patients, which clearly differentiates such patients from those with type 1 and which should provide added protection against severe hypoglycaemia. At least two questions come to mind: is this protective alteration in threshold maintained with type 2 diabetes of longer duration, and is it modified by use of insulin to achieve good glycaemic control? Hepburn et al22 have reported that the frequency of severe hypoglycaemia is not significantly different in insulintreated type 2 patients (mean known duration 12 years) and in type 1 patients matched for duration of insulin treatment and having similar HbA1C levels. John E Gerich General Clinical Research Center, University of Rochester School of Medicine, Rochester, NY 14642 USA 1

2

3

4

5 6

7

8

9 10

11

12

13

14

15 16

17

18

19

DCCT Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin dependent diabetes mellitus. N Engl J Med 1993; 329: 977–86. Ohkubo Y, Kishikawa H, Araki E, et al. Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin- dependent diabetes mellitus: a randomized prospective 6-year study. Diabetes Res Clin Pract 1995; 28: 103–17. UK Prospective Diabetes Study (UKPDS) Group. Intensive bloodglucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352: 837–53. Reichard P, Pihl M, Rosenqvist U, Sule J. Complications in IDDM are caused by elevated blood glucose level: the Stockholm Diabetes Intervention Study (SDIS) at 10-year follow up. Diabetologia 1996; 39: 1483–88. Cryer P. Banting Lecture: Hypoglycemia, the limiting factor in the management of IDDM. Diabetes 1994; 43: 1378–89. Reichard P, Pihl M. Mortality and treatment side-effects during longterm intensified conventional insulin treatment in the Stockholm Diabetes Intervention Study. Diabetes 1994; 43: 313–17. Abraira C, Colwell J, Nuttall F, et al, VA CSDM Group. Veterans Affairs cooperative study on glycemic control and complications in type II diabetes (VA CSDM): results of the feasibility trial. Diabetes Care 1995; 18: 1113–23. Saudek C, Duckworth W, Giobbie-Hurder A, et al. Implantable insulin pump vs multiple-dose insulin for non-insulin-dependent diabetes mellitus: a randomized clinical trial. JAMA 1996; 276: 1322–27. van Staa T, Abenhaim L, Monette J. Rates of hypoglycemia in users of sulfonylureas. J Clin Epidemiol 1997; 50: 735–41. Mitrakou A, Ryan C, Veneman T, et al. Hierarchy of glycemic thresholds for counterregulatory hormone secretion, symptoms, and cerebral dysfunction. Am J Physiol 1991; 260: E67–E74. Gerich J, Bolli G. Counterregulatory failure. In: Frier BM, Fisher M, eds. Hypoglycaemia and diabetes. London: Edward Arnold, 1993: 253–67. White N, Skor D, Cryer P, Bier D, Levandoski L, Santiago J. Identification of type I diabetic patients at increased risk for hypoglycemia during intensive therapy. N Engl J Med 1983; 308: 485–91. Veneman T, Mitrakou A, Mokan M, Cryer P, Gerich J. Induction of hypoglycemia unawareness by asymptomatic nocturnal hypoglycemia. Diabetes 1993; 42: 1233–37. Fritsche A, Stumvoll M, Grüb M, et al. Effect of hypoglycemia on badrenergic sensitivity in normal and type 1 diabetic subjects. Diabetes Care 1998; 21: 1505–10. Gerich J, Mokan M, Veneman T, Korytkowski M, Mitrakou A. Hypoglycemia unawareness. Endocrine Rev 1991; 12: 356–71. Bolli G, Tsalikian E, Haymond M, Cryer P, Gerich J. Defective glucose counterregulation after subcutaneous insulin in noninsulin-dependent diabetes mellitus. J Clin Invest 1984; 73: 1532–41. Shamoon H, Friedman S, Canton C, Zacharowicz L, Hu M, Rossetti L. Increased epinephrine and skeletal muscle responses to hypoglycemia in non-insulin-dependent diabetes mellitus. J Clin Invest 1994; 93: 2562–71. Levy C, Kinsley B, Bajaj M, Simonson D. Effect of glycemic control on glucose counterregulation during hypoglycemia in NIDDM. Diabetes Care 1998; 21: 1330–38. Meneilly G, Cheung E, Tuokko H. Counterregulatory hormone responses to hypoglycemia in the elderly patient with diabetes. Diabetes 1994; 43: 403–10.

THE LANCET • Vol 356 • December 9, 2000

20 Korzon-Burakowska A, Hopkins D, Matyka K, et al. Effects of glycemic control on protective responses against hypoglycemia in type 2 diabetes. Diabetes Care 1998; 21: 283–90. 21 Boyle P, Schwartz N, Shah S, Clutter W, Cryer P. Plasma glucose concentrations at the onset of hypoglycemic symptoms in patients with poorly controlled diabetes and in nondiabetics. N Engl J Med 1988; 318: 1487–92. 22 Hepburn D, MacLeod K, Pell A, Scougal I, Frier B. Frequency and Symptoms of hypoglycemia experienced by patients with type 2 diabetes treated with insulin. Diab Med 1993; 10: 231–37.

Troponins for predicting cardiotoxicity from cancer therapy Cardiac toxicity is an uncommon but potentially serious complication of cancer therapy, especially with the anthracyclines and the monoclonal antibody trastuzumab (Herceptin). These agents drugs can cause decreased leftventricular function, which in some cases may result in clinical manifestations of congestive heart failure. Other agents rarely associated with this complication are highdose cyclophosphamide, mitomycin-C, 5-fluorouracil, and the interferons. Anthracyclines such as doxorubicin and epirubicin are commonly used for the treatment of early-stage breast cancer, and they do increase cure rates. Trastuzumab has proved to be a useful palliative treatment for metastatic breast cancers that overexpress HER2/neu protein (about 30% of all breast cancers), and it is the first new agent to improve survival for patients with metastatic breast cancer in the past 25 years.1 The conundrum facing clinical investigators is how to best integrate trastuzumab with doxorubicin and other cytotoxic agents in early-stage breast cancer, maximising the chance for cure while minimising the risk of cardiac toxicity. The formation of oxygen free-radicals that are generated by iron-catalysed pathways is important in the pathogenesis of anthracycline-induced cardiomyopathy.2,3 Iron-chelating agents that prevent generation of oxygen free-radicals, such as dexrazoxane, are protective, which confirms the involvement of iron-catalysed pathways in the pathogenesis of the toxic effect on the heart.4 The mechanism of trastuzumab-associated cardiac dysfunction, on the other hand, is unknown. Reassuringly, this toxic effect seems to respond better to medical therapy for congestive heart failure than does anthracycline-induced dysfunction. Indeed some affected patients who were responding to trastuzumab were able to continue therapy without further deterioration of ventricular function. The frequency of cardiac dysfunction was greatest (28%) for those who received trastuzumab plus doxorubicin, intermediate for those who had a previous history of doxorubicin administration (7–11%), and least for those who had no or very little prior exposure to doxorubicin (1–2%).5 There is no evidence for a pharmacokinetic interaction, however. Furthermore, although the family of human epidermal growth factors (of which HER2/neu is a member) has an important role in cardiac embryogenesis,6 there is little evidence for localisation of anti-HER2/neu to cardiac tissue. Immunohistochemical studies, which are not very sensitive, have not demonstrated HER2 protein expression in human myocardial tissue. In-situ hybridisation for HER2 mRNA has detected low-level expression in myocardial tissue in some trastuzumabtreated patients, but also in patients with ischaemic, nonischaemic, or doxorubicin-associated cardiomyopathy. Finally, animal studies have demonstrated no localisation of trastuzumab to the heart, and monkeys treated with 1947

For personal use only. Not to be reproduced without permission of The Lancet.

COMMENTARY

ten-fold higher doses than used in man exhibited no cardiac toxicity. The timing of trastuzumab administration relative to anthracyclines is critical in the pathogenesis of trastuzumab-associated cardiac dysfunction, and new methods are needed to identify those at greatest risk. Measurement of plasma or serum cardiac troponin may be useful in predicting anthracycline-induced cardiac injury. The troponins are actin-associated regulatory proteins not normally present in serum. An increase in serum cardiac troponin-T (cTnT) is a specific marker for ischaemic myocardial damage, is more sensitive than the creatine phosphokinase MB isoenzyme, and predicts both short-term and long-term prognosis after cardiac ischaemia.7 Herman and colleagues8 have reported that cTnT measurement provides a sensitive means of assessing early doxorubicin-associated cardiotoxicity in rats. Lipshultz and colleagues9 found that that cTnT was raised in about 30% of children treated with doxorubicin, that concentrations were positively correlated with dose, and that raised concentrations of cTnT sometimes persisted for months, suggesting long-term myocardial injury. Finally, Cardinale and colleagues10 have recorded a raised serum cTnI in about one-third of adults 12–72 h after high-dose chemotherapy (usually containing anthracyclines). Moreover, a raised cTnI indicated a significantly greater decrease in left-ventricular ejection fraction (by an absolute 16% on average compared with only 5% when the cTnI was not raised). These preliminary studies may have important implications for the safe administration of trastuzumab in patients with early-stage breast cancers overexpressing HER2/neu. Studies are in progress that will evaluate the value of cTnT and other markers in predicting cardiac dysfunction in patients treated with anthracyclines and/or trastuzumab. The preliminary data are encouraging but it is too soon to recommend that cardiac troponins be routinely monitored in patients treated with anthracyclines and/or trastuzumab. *Joseph A Sparano, Antonio C Wolff, David Brown Albert Einstein Comprehensive Cancer Center, Montefiore Medical Center, Bronx, NY 10461, USA; Johns Hopkins Oncology Center, Baltimore, MD;and Albert Einstein College of Medicine, Bronx, NY 1

2 3

4

5

6

7

8

Norton L, Slamon D, Leyland-Jones B, et al. Overall survival advantage to simultaneous chemotherapy plus the humanized antiHER2 monoclonal antibody Herceptin in HER-2-overexpressing metastatic breast cancer. Proc Amr Soc Clin Oncol 1999; 18: 127a (abstr 483). Myers C. the role of iron in doxorubicin-induced cardiomyopathy. Semin Oncol 1998; 25 (4 suppl 10): 10–14. Billingham ME, Mason JW, Bristow MR, Daniels JR. Anthracycline cardiomyopathy monitored by morphologic changes. Cancer Treatment Reports 1978; 62: 865–72. Sparano JA. Use of dexrazoxane and other strategies to prevent cardiomyopathy associated with doxorubicin-taxane combinations. Sem Oncol 1998; 25(4 suppl 10): 66–71. Hudis C, Seidman A, Paton V, Bednarski D, Ashby M, Keefe D. Characterization of cardiac dysfunction in the Herceptin clinical trials. Breast Cancer Res Treatment 1998 (abstr 24). Erickson SL, O'Shea KS, Ghaboosi N, et al. ErbB3 is required for normal cerebellar and cardiac development: a comparison with ErbB2- and heregulin-deficient mice. Development 1997; 124: 4999–5011. Lindahl B, Toss H, Siegbahn A, Venge P, Wallentin L, for the FRISC Study Group. Markers of myocardial damage and inflammation in relation to long-term mortality in unstable coronary artery disease: Fragmin during Instability in Coronary Artery Disease N Eng J Med 2000; 343: 1139–47. Herman EH, Zhang J, Lipshultz SE, et al. Correlation between serum levels of cardiac troponin-T and the severity of the chronic cardiomyopathy induced by doxorubicin. J Clin Oncol 1999; 17:2237–43.

1948

9

Lipshultz S, Sallan S, Dalton V, et al. Elevated serum cardiac troponin-T as a marker for active cardiac injury during therapy for childhood acute lymphoblastic leukemia. Proc Am Soc Clin Oncol 1999; 8: 568a (abstr 2191). 10 Cardinale D, Sandri MT, Martinoni et al. Left ventricular dysfunction predicted by early troponin I release after high dose chemotherapy. J Am Coll Cardiol 2000; 36: 517–22.

Pies flying low in a blue sky Innovators and problem-solvers from outside oncology intermingled last weekend with cancer experts. The latter had invited scrutiny by fresh eyes. The premise, at least for the oncologists, was that progress in the therapy of the solid tumours in older age-groups has stalled and that the future holds little more than less-overt poisoning of patients. The theme for the weekend was “Rethinking cancer research: blue-skying the future”. Blue-skying is a business method for finding innovative solutions to new or seemingly insoluble problems. The idea of applying the technique to cancer research came from Andrew Hilton (Centre for the Study of Financial Innovation, London) and Michael Baum (University College, London), cancer surgeon and keen challenger of the cancer-research establishment. By the end of the weekend, the non-experts reached a clearer understanding of why advance in clinical cancer research and treatment is so difficult. The cancer specialists became intrigued by the possibilities of using business and economic theories to open new channels for invigorating research. Commerce was seen as more than new sources of finance to carry on as before. The most vaunted innovation was to view the “problem” of the aberrant gene, the abnormal cell, the developing primary tumour, and the disseminating metastases as amenable to mathematical modelling as used in complex organisational, economic, and behavioural systems. Modelling to open fresh lines of research was a deliberate aim, as reflected by the presence of many modellers and even by the choice of venue (Isaac Newton Institute for Mathematical Sciences, University of Cambridge, UK). The non-experts were outraged at the lack of “bangs for the bucks” spent on cancer research, and hinted that more open accountability to the funding public would not go amiss. The non-experts would put the money into areas of rapidly falling cost, such as computational and informational sciences. The non-experts were also shocked because the cancer experts played down the impact of the Human Genome Project. Marketing hype, the oncologists retorted. Scientists were seen as good sharers of academic papers rather than their data. A major financial institution has put its data online for others to use as a model, yet commercial ruin did not ensue. And why, the non-experts asked, did ethics committees and research funders seemingly stifle the truly creative? But human research is not market or industrial research. The cancer experts were delighted that the economic models produced in response to the 1997 Black Monday stock-market crash had failed and that the market response was to increase self-regulation. Some voices that would have made useful contributions (eg, medical ethics, research funding, molecular oncology, cancer nursing) were missing. Undisputed facts about cancer was neglected at times, and the oncologists held the floor for too long. But new links between two worlds that would not otherwise have collided were forged. Any pies flying in the blue sky were low-level and innocuous. David McNamee The Lancet, London WC1X 8RR, UK

THE LANCET • Vol 356 • December 9, 2000

For personal use only. Not to be reproduced without permission of The Lancet.