Cardiac blood biomarkers in patients receiving thoracic (chemo)radiation

Lung Cancer (2008) 62, 351—355

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Cardiac blood biomarkers in patients receiving thoracic (chemo)radiation Kevin R. Kozak a,b,∗, Theodore S. Hong b, Patrick M. Sluss c, Elizabeth L. Lewandrowski c, Samir L. Aleryani c, Shannon M. MacDonald b, Noah C. Choi b, Torunn I. Yock b a

Harvard Radiation Oncology Program, Massachusetts General Hospital, Boston, MA, USA Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA c Department of Pathology, Massachusetts General Hospital, Boston, MA, USA b

Received 13 January 2008; received in revised form 21 March 2008; accepted 25 March 2008

KEYWORDS Cardiotoxicity; Troponin; CK-MB; BNP; Radiation; Lung cancer

Summary Cardiotoxicity is a known consequence of thoracic irradiation and there are multiple overlapping risk factors for cardiac disease and thoracic malignancies. In this study, we quantified the impact of thoracic (chemo)radiation on cardiac troponin T (TnT), creatine kinasemyocardial band (CK-MB) and aminoterminal pro-brain natriuretic peptide (NT-proBNP). Thirty patients receiving radiation therapy to the thorax with or without concurrent chemotherapy were evaluated. Serum was collected at baseline, 2 weeks into treatment and at the completion of radiation therapy. TnT, CK-MB and NT-proBNP were quantified using commercially available immunoassays. Cardiac dosimetric parameters and clinical risk factors were examined. In 29 of 30 patients, serum TnT remained undetectable (<0.01 ng/mL) throughout (chemo)radiation. In the one patient with detectable serum TnT, levels did not change significantly with treatment. Similarly, thoracic (chemo)radiation did not cause statistically significant elevations in serum CK-MB and NT-proBNP. Thus, contemporary thoracic (chemo)radiation does not commonly result in elevations of serum TnT, CK-MB or NT-proBNP. Elevations in these markers during treatment merit further evaluation. © 2008 Elsevier Ireland Ltd. All rights reserved.

1. Introduction

∗ Corresponding author at: Department of Radiation Oncology, Massachusetts General Hospital, 100 Blossom Street, Cox-3, Boston, MA 02114, USA. Tel.: +1 617 724 1160; fax: +1 617 726 3603. E-mail address: [email protected] (K.R. Kozak).

Thoracic radiation is associated with significant, dosedependent, cardiac morbidity. The estimated incidence of clinically evident, radiation-induced cardiac disease is between 10% and 30% at 5—10 years post-radiation [1]. Furthermore, with extensive screening, cardiac dysfunction can be identified in the majority of cancer survivors who

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352 received mediastinal radiation during their treatment [2,3]. Although generally regarded as a late consequence of radiation, emerging evidence suggests that cardiac dysfunction can develop within 6 months of radiotherapy [4]. Attempts to reduce the burden of radiation-induced cardiotoxicity, including limiting cardiac doses and the volume of irradiated heart through conformal radiation treatment, are proving helpful [5—7]. However, these efforts are imprecise and do not necessarily permit tailoring of treatment in patients at high risk for subsequent heart disease. Cardiac blood biomarkers, obtained before and during radiation therapy, may help identify patients at risk for clinically significant cardiac toxicity. This information may permit (1) a more accurate assessment of the risks of subsequent toxicity, (2) real-time modification of radiation treatment to limit toxicity and (3) tailored cardiac surveillance following treatment. In addition to these potential benefits, characterization of the effect of thoracic (chemo)radiation on clinically employed cardiac blood biomarkers may clarify the utility of these markers in cancer patients. There is significant overlap among risk factors for both thoracic malignancy and cardiac disease. Consequently, patients treated with thoracic radiation are often at high risk for treatment-independent, acute cardiac events. Furthermore, there is significant overlap in clinical presentations. For example, in a review of 1340 lung cancer patients, chest pain occurred in 66% of patients. Additionally, dyspnea and cough were present in 59% and 81%, respectively [8]. Cardiac troponin T (TnT) and creatine kinase-myocardial band (CK-MB) are cornerstones in the diagnosis, management and prognostication of chest pain and acute myocardial ischemia [9]. Aminoterminal pro-brain natriuretic peptide (NT-proBNP) is valuable in the evaluation of dyspnea, left ventricular dysfunction and acute congestive heart failure [10,11]. The effective use of TnT, CK-MB and NT-proBNP in discerning the etiology of symptoms such as chest pain, cough and dyspnea in patients receiving thoracic (chemo)radiation requires an understanding of the impact of treatment on these biomarkers. To address these issues, we measured TnT, CK-MB and NT-proBNP levels in 30 patients receiving thoracic (chemo)radiation prior to treatment, 2 weeks into treatment and at the end of treatment.

2. Materials and methods Beginning in May 2006, patients older than 18 years of age undergoing three-dimensional conformal or intensity modulated radiation therapy for a thoracic malignancy at Massachusetts General Hospital were approached for enrollment on this study. The intended accrual goal of 30 patients, designed to provide greater than 90% power to detect a mean TnT difference of 0.01 ng/mL (alpha 0.05), was met in May 2007. Patients with prior thoracic radiation therapy, a history of renal failure or a hematocrit less than 25% were ineligible. The study was approved by the Human Research Committee of Partners Healthcare and written informed consent was obtained from all patients. Patient-reported cardiac risk factors were collected prospectively at patient accrual. Blood (10 mL) was obtained by venipuncture and

K.R. Kozak et al. serum was prepared by centrifugation. Serum was stored at −80 ◦ C until analysis. Blood samples were obtained prior to radiation therapy (0—8 days prior to treatment), following 2 weeks of radiation therapy (following 8—10 fractions of radiation) and at the end of radiation therapy. The final blood sample was drawn after the last fraction of radiation in 19 patients, following the penultimate fraction in 5 patients and following the third to last fraction in 3 patients. In one patient, the last blood draw was not obtained. In an additional two patients, the last blood draw was delayed (5 and 7 days following radiation therapy) due to patient request. TnT, CK-MB and NT-proBNP were quantified in duplicate using commercially available immunoassays on an Elecsys 2010 platform (Elecsys Troponin T STAT, CK-MB STAT, and NT-proBNP Immunoassays, Roche Diagnostics, Indianapolis, Indiana) according to established methods. Results were not provided to patients or their treating oncologists.

Table 1 (N = 30)

Patient, disease and chemotherapy characteristics

Characteristic

Median or N

Range or %

Age Male Female

61 17 13

38—83 57% 43%

18

60%

4 5 2

13% 17% 7%

1

3%

Stage I II III IV Limited SCLC Recurrent

1 6 13 5 4 1

3% 20% 43% 17% 13% 3%

Prior resection Yes No

7 23

23% 77%

Induction chemotherapy None Carboplatin/paclitaxel 5-Fluorouracil/leucovorin

23 4 3

77% 13% 10%

Concurrent chemotherapy None Cisplatin/etoposide Carboplatin/paclitaxel 5-Fluorouracil/cisplatin 5-Fluorouracil Cisplatin

6 10 6 4 3 1

20% 33% 20% 13% 10% 3%

Diagnosis Non-small cell lung cancer Small cell lung cancer Esophagus cancer Gastroesophageal junction cancer Thymic carcinoma

Cardiac biomarkers during thoracic (chemo)radiation Table 2

Cardiac characteristics (N = 30)

Characteristic

N

%

Cardiac family history Yes No

5 25

17 83

Smoking history Yes No

24 6

80 20

Diabetes mellitus Yes No

4 26

13 87

Hypertension Yes No

12 18

40 60

Hypercholesterolemia Yes No

13 17

43 57

Congestive heart failure Yes No

2 28

7 93

Prior myocardial infarction Yes No

3 27

10 90

Prior angina Yes No

5 25

17 83

Cardiac family history defined as a first degree relative with a myocardial infarction prior to 50 years of age. Smoking history defined as greater than or equal to a 20 pack-year smoking history.

Radiation therapy and chemotherapy were at the discretion of the treating oncologists. The entire heart, including atria and ventricles, was contoured on radiation planning CT images and cardiac dosimetry was collected from approved treatment plans by a radiation oncologist.

Table 3

353 Table 4

Serum TnT levels (ng/mL)

Patient

Baseline

Week 2

Last day

Patient 18 Others

0.018 <0.01

0.020 <0.01

0.012 <0.01

3. Results Patient diagnoses and treatment details are shown in Table 1. As anticipated, the majority of patients had lung cancer. Cancers tended to be advanced with 60% of patients having Stage III or IV disease. When radiation therapy is employed in lung cancer treatment regimens at our institution, induction chemotherapy is uncommonly employed in favor of upfront concurrent chemoradiotherapy. This tendency is reflected in the studied patients; only 7 of 30 patients received induction chemotherapy whereas 24 of 30 patients received concurrent chemotherapy. Platinumbased regimens predominated. As expected given the overlap in risk factors for the development of heart disease and thoracic malignancies, cardiac risk factors were common among the 30 study patients (Table 2). With lung cancer as the most common diagnosis, the prevalence of tobacco abuse (80%) is unsurprising. Hypertension and hypercholesterolemia were also common. Furthermore, six patients (20%) had a diagnosis of angina, prior myocardial infarction or congestive heart failure prior to treatment (1 with angina, prior myocardial infarction and congestive heart failure, 2 with angina and prior myocardial infarction, 2 with angina alone and 1 with congestive heart failure alone). Cardiac dosimetry is shown in Table 3. Anatomic constraints in treating thoracic malignancies that preclude heart avoidance account for the high cardiac doses and irradiated volumes observed. Serum TnT levels were undetectable at all timepoints in 29 of 30 patients with a threshold of 0.01 ng/mL (Table 4). In the single patient with detectable TnT, no significant elevation was detected at 2 weeks or at the end of treatment. Interestingly, this patient had the lowest mean cardiac dose (0.6 Gy) of all patients and an extensive cardiac his-

Radiation therapy details and cardiac dosimetry (N = 30)

Characteristic

Median (range)

Mean ± S.E.

Prescribed Dose (Gy) Fraction size (Gy) Mean cardiac dose (Gy) Maximum cardiac dose (Gy) V5Gy (%) V10Gy (%) V20Gy (%) V30Gy (%) V40Gy (%) V50Gy (%) V60Gy (%) V70Gy (%)

50.4 (36—75) 1.8 (1.8—2.5) 12.7 (0.6—41.0) 50.3 (1.6—73.4) 63.4 (0—100) 44.8 (0—100) 22.1 (0—100) 11.9 (0—87.3) 4.3 (0—65.0) 0 (0—13) 0 (0—3.2) 0 (0—0.2)

54.5 ± 1.8 ± 13.4 ± 47.0 ± 55.6 ± 42.0 ± 27.2 ± 16.7 ± 9.2 ± 1.8 ± 0.3 ± 0

VXGy (%) represents the percent total cardiac volume receiving XGy.

1.7 0.1 1.8 3.7 6.8 5.8 4.8 3.7 2.7 0.6 0.1

354 Table 5

K.R. Kozak et al. Serum CK-MB and NT-proBNP levels

Biomarker

Baseline (mean ± S.E.)

CK-MB (ng/mL) 3.1 ± 0.4 NT-proBNP (pg/mL) 350 ± 90

Week 2 (mean ± S.E.)

P (vs. baseline)

Last day (mean ± S.E.)

P (vs. baseline)

3.2 ± 0.4 580 ± 290

0.46 0.36

3.1 ± 0.4 520 ± 160

0.74 0.23

P values determined using a two-tailed, paired t-test.

tory including severe coronary artery disease requiring two bypass procedures, aortic valve replacement and atrial fibrillation. Similarly, no change in serum CK-MB levels was evident at 2 weeks or at the end of treatment (Table 5). Finally, although NT-proBNP levels varied markedly, no systematic changes were detected due to radiation (Table 5). At the 2 weeks timepoint, 13 patients had serum NT-proBNP levels higher than baseline values and 17 patients had serum NT-proBNP levels lower than baseline values. At the end of treatment, 17 patients had serum NT-proBNP levels higher than baseline and 12 patients had levels lower than baseline.

4. Discussion Cardiac irradiation increases the risk of cardiovascular disease. Although best documented in breast cancer and lymphoma patients, cardiotoxicity has been documented in both lung cancer and esophageal cancer patients who received chest radiation as a component of their management. In a randomized trial of postoperative thoracic radiation for patients with completely excised non-small cell lung cancer, cardiac mortality was shown to increase threefold with the addition of radiation therapy [12]. Similarly, the PORT (Postoperative Radiation Therapy) Meta-analysis Trialists Group demonstrated an absolute 7% increase in 2-year overall mortality with the addition of thoracic radiation [13]. Mukherjee and colleagues found reductions in cardiac ejection fraction in 12 of 15 evaluated patients following chemoradiation for carcinoma of the mid- and lower-esophagus [14]. These deleterious effects of cardiac irradiation are often overlooked in this patient population due to the poor prognosis of most thoracic malignancies and the frequent presence of extensive comorbidities. However, as newer systemic therapies and higher radiation doses are explored in patients with thoracic malignancies, cancer specific survival is likely to improve. As survival improves, greater attention will need to be paid to the potential toxicities of treatment. Cardiac blood biomarkers, particularly troponins, have been extensively studied as markers of cytotoxic chemotherapy cardiotoxicity, producing variable, and at times contradictory, results [15,16]. Nonetheless, troponin measurements, during or shortly after chemotherapy, have permitted prospective evaluation of cardioprotective agents in the concurrent and adjuvant settings [17,18]. In contrast, very limited data exist regarding the impact of thoracic radiation on cardiac blood biomarkers. Hughes-Davies et al. quantified serum TnT levels in 50 left-sided breast cancer patients being treated with adjuvant radiation at baseline and after a whole breast dose of 45—46 Gy [19]. Serum TnT levels did not exceed the threshold of 0.02 ng/mL in 49 patients either before or after treatment and in the

remaining patient, no significant increase was detected (0.06 ng/mL pretreatment and 0.07 ng/mL posttreatment). Although this study convincingly demonstrated that modern adjuvant breast irradiation does not cause elevations in serum TnT, the patient population and treatment differs markedly from patients receiving chest radiation for thoracic malignancies. A small minority of the breast cancer patients received preradiation or concurrent chemotherapy. In contrast, concurrent chemoradiotherapy is the standard of care for most lung and esophageal cancers. Additionally, although the cardiac history of the breast cancer patients was not reported, the underlying cardiac disease burden among lung and esophageal cancer patients is expected to be higher given the overlap of risk factors. Most importantly, in the treatment of thoracic malignancies, cardiac irradiated volumes, doses and dose per fraction tend to be higher than those seen with modern breast cancer treatment. Although cardiac dosimetric data was not reported by Hughes-Davies, Gyenes and colleagues reported a mean cardiac volume receiving 25 Gy (V25Gy) of 5.7% in 100 leftsided breast cancer patients treated with modern tangential radiation fields [20]. In contrast, as seen in Table 3, the mean V25Gy was 3—5-fold higher in our patient population. Furthermore, the mean cardiac V40Gy in our patient population was nearly double the reported mean V25Gy in breast patients. Despite these marked differences, our results are in agreement with Hughes-Davies and colleagues. Contemporary thoracic (chemo)radiation does not appear to commonly cause elevations of serum TnT. Our data also extend these findings to include CK-MB and NT-proBNP. Our results do not eliminate the possibility that, in rare circumstances, cardiac biomarker elevations may be caused by thoracic (chemo)radiation. However, these observations strongly suggest that if elevations are detected during treatment, further clinical investigation is warranted to discern alternative etiologies for the cardiac insult. Alternative biomarkers will need to be identified to prospectively assess the risks of radiation-induced cardiac toxicity, guide real-time modification of radiation treatment to limit cardiac toxicity and tailor posttreatment cardiovascular surveillance.

5. Conclusion Our study clarifies the value of serum TnT, CK-MB and NT-proBNP in the management of patients receiving thoracic (chemo)radiation. As discussed, chest pain, dyspnea and cough are common in patients with thoracic malignancies and cardiac blood biomarkers may be employed to investigate these symptoms. Our data demonstrate that elevations in TnT, CK-MB and NT-proBNP during thoracic (chemo)radiation should not routinely be attributed to

Cardiac biomarkers during thoracic (chemo)radiation

355

treatment, and, if detected, require further clinical evaluation.

Conflict of interest statement

[10]

No author reports a conflict of interest.

Acknowledgements We thank Dr. Jay Harris, Dr. Andrea Ng and Dr. Abram Recht for thoughtful review of the manuscript.

[11]

[12]

References [1] Carver JR, Shapiro CL, Ng A, Jacobs L, Schwartz C, Virgo KS, et al. Vaughn DJ for the ASCO cancer survivorship expert panel. American society of clinical oncology clinical evidence review on the ongoing care of adult cancer survivors: cardiac and pulmonary late effects. J Clin Oncol 2007;25:3991—4008. [2] Adams MJ, Lipsitz SR, Colan SD, Tarbell NJ, Treves ST, Diller L, et al. Cardiovascular status in long-term survivors of Hodgkin’s disease treated with chest radiotherapy. J Clin Oncol 2004;22:3139—48. [3] Heidenreich PA, Schnittger I, Strauss HW, Vagelos RH, Lee BK, Mariscal CS, et al. Screening for coronary artery disease after mediastinal irradiation for Hodgkin’s disease. J Clin Oncol 2007;25:43—9. [4] Marks LB, Yu X, Prosnitz RG, Zhou S-M, Hardenbergh PH, Blazing M, et al. The incidence and functional consequences of RTassociated cardiac perfusion deficits. Int J Radiat Oncol Biol Phys 2005;63:214—23. [5] Patt DA, Goodwin JS, Kuo Y-F, Freeman JL, Zhang DD, Buchholz TA, et al. Cardiac morbidity of adjuvant radiotherapy for breast cancer. J Clin Oncol 2005;23:7475—82. [6] Giordano SH, Kuo YF, Freeman JL, Buchholz TA, Hortobagyi GN, Goodwin JS. Risk of cardiac death after adjuvant radiotherapy for breast cancer. J Natl Cancer Inst 2005;97:419—24. [7] Darby SC, McGale P, Taylor CW, Peto R. Long-term mortality from heart disease and lung cancer after radiotherapy for early breast cancer: prospective cohort study of about 300, 000 women in US SEER cancer registries. Lancet Oncol 2005;6: 557—65. [8] Ak G, Metintas M, Metintas S, Yildirim H, Erginel S, Alatas F. Lung cancer in individuals less than 50 years of age. Lung 2007;185:279—86. [9] Alpert JS, Thygesen K, Antman E, Bassand JP. Myocardial infarction redefined—–a consensus document of the Joint European

[13]

[14]

[15]

[16]

[17]

[18]

[19]

[20]

Society for Cardiology/American College of Cardiology committee for the redefinition of myocardial infarction. J Am Coll Cardiol 2000;36:959—69. Maisel AS, Krishnaswamy P, Nowak RM, McCord J, Hollander JE, Duc P, et al. McCullough PA for the breathing not properly multinational study investigators. Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure. New Engl J Med 2002;347:161—7. Januzzi JL, Camargo CA, Anwaruddin S, Baggish AL, Chen AA, Krauser DG, et al. The N-terminal pro-BNP investigation of dyspnea in the emergency department (PRIDE) study. Am J Cardiol 2005;95:948—54. Dautzenberg B, Arriagada R, Chammard AB, Jarema A, Mezzetti M, Mattson K, et al. A controlled study of postoperative radiotherapy for patients with completely resected nonsmall cell lung carcinoma. Groupe d’Etude et de Traitement des Cancers Bronchiques. Cancer 1999;86:265—73. PORT Meta-analysis Trialists Group. Postoperative radiotherapy in non-small-cell lung cancer: systematic review and meta-analysis of individual patient data from nine randomised controlled trials. PORT Meta-analysis Trialists Group. Lancet 1998; 352:257—263. Mukherjee S, Aston D, Minett M, Brewster AE, Crosby TD. The significance of cardiac doses received during chemoradiation of oesophageal and gastro-oesophageal junctional cancers. Clin Oncol (R Coll Radiol) 2003;15:115—20. Bryant J, Picot J, Baxter L, Levitt G, Sullivan I, Clegg A. Use of cardiac markers to assess the toxic effects of anthracyclines given to children with cancer: a systematic review. Eur J Cancer 2007;43:1959—66. Urbanova D, Urban L, Carter A, Maasova D, Mladosievicova B. Cardiac troponins—–biochemical markers of cardiac toxicity after cytostatic therapy. Neoplasma 2006;53:183— 90. Lipshultz SE, Rifai N, Dalton VM, Levy DE, Silverman LB, Lipsitz SR, et al. The effect of dexrazoxane on myocardial injury in doxorubicin-treated children with acute lymphoblastic leukemia. New Engl J Med 2004;351:145—53. Cardinale D, Colombo A, Sandri MT, Lamantia G, Colombo N, Civelli M, et al. Prevention of high-dose chemotherapy-induced cardiotoxicity in high-risk patients by angiotensin-converting enzyme inhibition. Circulation 2006;114:2474—81. Hughes-Davies L, Sacks D, Rescigno J, Howard S, Harris J. Serum cardiac troponin T levels during treatment of early-stage breast cancer. J Clin Oncol 1995;13:2582—4. Gyenes G, Gagliardi G, Lax I, Fornander T, Rutqvist LE. Evaluation of irradiated heart volumes in stage I breast cancer patients treated with postoperative adjuvant radiotherapy. J Clin Oncol 1997;15:1348—53.