Skip to content

Advertisement

You're viewing the new version of our site. Please leave us feedback.

Learn more

BMC Research Notes

Open Access

Cardiac safety of the adjuvant Trastuzumab in a Moroccan population: observational monocentric study of about 100 patients

  • Meryem Aitelhaj1Email author,
  • Siham LKhouyaali1,
  • Ghizlane Rais1,
  • Amina Mohtaram1,
  • Soundouss Raissouni1,
  • Brahim Ghissassi1,
  • Saber Boutayeb1,
  • Hind Mrabti1,
  • Youssef Bensouda1 and
  • Hassan Errihani1
BMC Research Notes20136:339

https://doi.org/10.1186/1756-0500-6-339

Received: 15 December 2012

Accepted: 21 August 2013

Published: 28 August 2013

Abstract

Background

Trastuzumab is a humanized monoclonal antibody that binds to the extracellular domain of the human epidermal growth factor receptor 2 (HER 2) and inhibits carcinoma cellular proliferation. Its use as an adjuvant for a period of one year is currently an internationally recognised standard for the treatment of localized breast cancer. Its use is generally well tolerated, with the most salient side effect being a particular cardiotoxicity that is typically manifested by an asymptomatic decrease in the left ventricular ejection fraction (LVEF) requiring careful monitoring before and during treatment. To evaluate the cardiac safety of trastuzumab we conducted a retrospective observational study of patients with HER2-positive localized breast cancer treated with trastuzumab between May 2008 and May 2010 in Morocco.

Findings

The study comprised of 100 patients. The average in LVEF before the start of trastuzumab was 70%, and at the end of treatment 66%, a decrease in absolute terms of 4%; this difference was statistically significant. 38% of the patients exhibited cardiotoxicity. 97% of our patients have completed treatment, of whom 23% with a provisional arrest because of a regressive fall in LVEF. A final arrest has been made in 3% of cases due to a non regressive reduction in LVEF. A symptomatic heart failure was found in three patients. Analysis of risk factors toxicity found a baseline LVEF higher in the patients who met cardiotoxicity than the rest of our sample.

Conclusions

The cardiac safety in our study seems comparable with the literature data but located in the upper range of levels of toxicity. Cardiotoxicity is the major complication of Trastuzumab, of which LV dysfunction is the most common. Most instances are transient, asymptomatic and reversible.

Introduction

Breast cancer is the most common malignant disease and among the most frequent causes of cancer mortality in females worldwide [1, 2]. Overexpression of human epidermal growth factor receptor type 2 (HER2) occurs in 20-25% of invasive breast cancers, which is associated with a poor prognosis [3, 4].

Trastuzumab is a humanized monoclonal antibody that binds to the extracellular domain of HER2 receptor and inhibits carcinoma cellular proliferation [5].

Trastuzumab therapy is important in the treatment of early and advanced disease as shown in multiple randomized trials. Its use as an adjuvant treatment for a period of 1 year is currently an international standard of care in HER 2 over expressed localized breast cancer. It is generally well tolerated, with a low incidence of adverse effects [6] of which the most relevant is cardiotoxicity that had not been anticipated on the basis of the results of preclinical or early clinical studies. It is typically manifested by an asymptomatic decrease in left ventricular ejection fraction (LVEF) and less often by clinical heart failure [7].

It requires careful monitoring of the LVEF before and during treatment. Trastuzumab cardiotoxicity was originally described in women with metastatic breast cancer and in several subsequent trials of adjuvant trastuzumab, about 80% of trials show cardiotoxicity [8]. However, the incidence of cardiotoxicity amongst populations of women treated outside of this clinical trial is not well known.

The purpose of this study is to evaluate the cardiotoxicity incidence rate associated with adjuvant trastuzumab treatment in clinical practice in a sample Moroccan population, by describing its characteristics, management and potential associated risk factors.

Patients and methods

This is a retrospective observational institutional study conducted at the Department of Clinical Oncology, in the national institute of oncology of Rabat from May 2008 to May 2010.

Eligibility criteria

Eligible patients had localized breast cancer verified histologically and HER2 positive status assessed by immunohistochemistry (3+) or fluorescent in situ hybridization positivity; adequate cardiac function with normal LVEF ≥ 50% measured on echocardiography and who received adjuvant Tarstuzumab.

Ineligibility criteria included a history of documented congestive heart failure, coronary artery disease with previous Q-wave myocardial infarction, angina pectoris requiring medication, uncontrolled hypertension, clinically significant valvular disease and unstable arrhythmias.

The study respected the ethical rules for medical research involving human subjects as stipulated by the World Medical Association in the Declaration of Helsinki. The local ethical committee of the national institute of oncology of Rabat also approved this study; and patients gave their consent.

Cardiac monitoring included physical examination and an assessment of LVEF by echocardiography: it was evaluated before Trastuzumab administration and every 12 weeks thereafter for the duration of therapy.

Cardiotoxicity was defined as a LVEF decrease below normal values (50%) or an absolute decrease of >10 points below the baseline value or any symptoms or signs of heart failure.

The following cardiovascular risk factors were analysed: age, overweight body mass index (BMI > 25 kg/m2 and < 30 kg/m2), obesity (BMI ≥ 30 kg/m2), hypertension, diabetes, LVEF at baseline, number of anthracycline cycles.

Follow up

Patients were followed up until May, 2012. Any patients who were not reviewed in the last consultation were contacted again by telephone.

Statistical analysis

Data was analysed using an electronic CRF (case report form).

The information was recorded in an Excel database and analysed with the statistics software SPSS, version 12.0. A logistical regression analysis was performed to examine which variables influenced whether or not a patient exhibited cardiotoxicity. A p value less than 0.05 was considered significant.

Findings

A total of 100 patients were enrolled. The median age at diagnosis was 46 years [range: 24-74]. According to TNM staging, 11 patients had T1, 50 patients (50%) had T2 and 39% had T3 or T4. 71 patients (71%) had positive lymph nodes. 67% of our patients were hormone receptor positive.

All patients received surgery, 22% had conservative surgery and 78% received radical mastectomy with axillary lymph nodes dissection. 40 patients (40%) received chemotherapy based on anthracyclines and 60% had sequential chemotherapy with anthracyclines and taxanes. 93 patients had Radiotherapy, of whom 44 on the left breast. All patients received adjuvant Trastuzumab. The baseline characteristics of the patients and the Treatment Delivered are detailed in Table 1. It must be stated that before starting the Trastuzumab treatment, 11% of the patients exhibited arterial hypertension and 7% diabetes.
Table 1

Characteristics of patients and treatment delivered

Characteristic

Age

46 [24-74]

menopausal Status

 postmenopausal

31%

 Premenopausal

69%

Breast

 right

53%

 Left

47%

Tumor size

 T1

11%

 T2

50%

 T3

26%

 T4

13%

Ganglion involvement

 Positive

71%

 Negative

29%

Hormone receptor status

 Positive

67%

 Negative

33%

Surgery

 radical

78%

 conservative

22%

Chemotherapy

 Anthracycline

40%

 Taxanes (sequential)

60%

Radiotherapy

93%

 Right breast

49%

 Left breast

44%

The average in LVEF at baseline was 70% [55%-89%], and it was 66% [42%-87%] at the end of treatment, a decrease in absolute value by 4%. This difference was statistically significant with p < 0, 0001.

38% of the patients presented cardiotoxicity according to the predefined criteria; the details are listed in Table 2.
Table 2

Characteristics of the LVEF decrease in patients with cardiotoxicity (n = 38)

Cardiotoxicity criteria

No. patients

% Patients with cardiotoxicity

% of patient total

LVEF decrease <50%

7

18,42

7

LVEF decrease >10 points below baseline

16

42,10

16

LVEF decrease > 15 points below baseline

22

57,89

22

Of the 38 patients who presented cardiotoxicity, 23 (60.52%) had to discontinue treatment; this number constitutes 23% of the patient total. In 20 patients, treatment was resumed after normalising parameters, the mediane recovery time of LVEF was 21 days in both anthracycline alone and sequential chemotherapy; 9 of these cases received pharmacological treatment with angiotensin converting enzyme inhibitors/angiotensin receptor antagonists.

Treatment was completed in 97% of our patients. Definitive Trastuzumab interruption was necessary in 3 patients due to the non-recovery of the ventricular function. A good clinical improvement was reached under medical treatment. Three cases of grade 2 heart failure (HF) according to the New York Heart Association (NYHA) were noticed.

As shown in Table 3, when we analyse the influence of each separate predictive factor for cardiac dysfunction and the appearance of cardiotoxicity, we find no statistically significant differences for age, arterial hypertension, diabetes, obesity, number of anthracycline cycles or chemotherapy regimen (sequential/ anthracycline alone). Patients who experienced toxicity have a slightly higher mean age than those who did not, and relatively high prevalence of obesity (42.1%); Paradoxically LVFE at the baseline was significantly higher in the group of patients who developed cardiac complications.
Table 3

Risk factors in total population, in group with and without cardiac complications

Risk factor

Total population

Group with cardiac complications

Group with no cardiac complications

Value of p no complications vs complications

 

N = 100

N = 38

N = 62

 

Age (years)

46

47

45

0.96

Overweight

38%

12 (31.57%)

26 (41.93%)

0.61

obesity

35%

16 (42.10%)

19 (30.64%)

0.57

Hypertension

11%

4 (10.52%)

7 (11.29%)

0.88

Diabetes

7%

3 (7.89%)

4 (6.45%)

0.31

LVFE baseline

70%

74%

67%

< 0.001

Chemotherapy with or without anthracycline

100%

Sequential

25 (65.5%)

Sequential

35 (56.5%)

0.3

anthracycline

13 (34.5%)

anthracycline

27 (43.5%)

Nb of anthracycline cycles

4

4

4

0.61

Concomitant radiotherapy with trastuzumab

69

24 (63%)

45 (72%)

0.318

Discussion

The resultant cardiotoxicity of the treatment in oncology often limits its benefits [9]. This is why monitoring and early prevention of aggressive anti-tumour treatment cardiac complications is of clinical interest. Trastuzumab is the standard drug for treating patients with breast cancer that over express HER2 with the most adverse effect being cardiotoxicity. It was initially described in women with metastatic breast cancer, with a higher incidence rate when trastuzumab was administered with anthracyclines [10]. Based on this data, the concomitant use of (anthracyclines and trastuzumab) was discouraged due to the greater risk of causing cardiotoxicity. Subsequently, several adjuvant clinical trials observed cardiotoxicity, which was considered acceptable [811]; Cardiac function was carefully monitored, but difference exists among the trials and how cardiotoxicity was defined. In general these trials demonstrated that the risk of symptomatic congestive heart failure was low; but reveal a much greater asymptomatic decreases in left ventricular ejection fraction [12].

However, the cardiotoxicity incidence rate in the population of women receiving treatment outside of clinical trials is unknown. The current study provides insight into the common experience of trastuzumab use in real life situations common in oncology and cardiology clinics. In a retrospectively evaluated population of 100 HER2 positive, early and locally advanced breast cancer women treated with trastuzumab in the adjuvant setting, 38% of the patients exhibited cardiotoxicity and nearly 23% required discontinuation of the medication due to cardiac complications.

The incidence of left ventricular dysfunction in our study (38%) is consistent with that reported in the combined analysis of National surgical adjuvant breast and bowel project (NSABP) B-31 (34%) [13], less than in Breast Cancer International Research Group (BCIRG) 006 trial (18%) [14] and higher than in the HERceptin Adjuvant (HERA) trial (7.1%) [15]. In our study, 23% of patients had to suspend trastuzumab treatment, whether temporarily or definitively, due to cardiotoxicity. In the McArthur and Chia study [16] the rate of treatment suspension due to cardiac dysfunction was 21.6% which is higher than the number reported in the HERA clinical trial [17] and closer to the rate shown by our patient’s series. However, the same study shows that most of the patients who discontinued treatment were able to restart it after recovering their cardiac function; in our study 20 of the patients who interrupted treatment ended up suspending it definitively.

Symptomatic heart failure events have been observed much less frequently than asymptomatic LV dysfunction. 1.9% in BCIRG 006, 4% in NSABP B-31 and 0.6% in the HERA trial of trastuzumab treated patients reported severe symptoms of HF (NYHA III/IV) [1315]. Tarantini et al. reported 3% symptomatic heart failure incidence in a cohort of 499 women with HER2 positive early breast cancer from 10 Italian institutions treated with trastuzumab observed retrospectively [18]. Such incidence is consistent with that in our study, in which 3% of patients complained of mild heart failure symptoms.

The majority of complications are asymptomatic. The asymptomatic nature of cardiac complications makes monitoring of trastuzumab therapy safety mandatory. This issue has been addressed and regulated by a few guidelines [19, 20]. They suggest that detection of heart damage due to trastuzumab therapy is best accomplished via sequential measurements of LVEF, either by multiple-gated acquisition scans (MUGA) or by echocardiography techniques. In addition to imaging methods, the literature suggests that measurement of plasma markers, such as brain natriuretic peptide (BNP) as a marker of LV stretch and cardiac troponins as markers of myocardium disintegration, may be used to predict and to detect cardiac dysfunction during treatment with trastuzumab [21].

We found no differences in prevalence of cardiovascular risk factors between the group of patients with and without cardiac complications; excepted LVEF at baseline, it was paradoxically higher in the group of patients who developed cardiotoxicity. The association of cardiovascular risk factors with trastuzumab related cardiotoxicity is not apparent and not fully explained. The most well-known independent risk factors are advanced age and previous exposure to anthracyclines [22]. In the NSABP B-31 and NCTTG N9831 trials age ≥ 50 years, requirement for hypertension medications, previous exposure to anthracyclines and LVEF at baseline < 55% were risk factors for heart failure in the course of trastuzumab treatment in univariate analysis [23, 24]. In the HERA trial overweight and obesity were risk factors for cardiac toxicity but age, hypertension, dyslipidaemia and previous heart disease did not increase the risk of trastuzumab-related cardiotoxicity [15]. In a large retrospective cohort study the authors observed that anthracycline and Trastuzumab were associated with increased HF [25].

The mechanisms of trastuzumab related cardiotoxicity remain uncertain. Genetic background has been suggested by some studies [26, 27]. There are two different hypothesis of trastuzumab mechanism of cardiac damage in the literature. Some preclinical data indicate that inhibition of the myocardial HER2 receptor leads to changes in the tertiary structure of the cardiac contractile apparatus, which seems likely to be a reversible effect [28]. Others suggest that trastuzumab induces apoptosis and cardiomyocytes’ death, which is likely a progressive and rather irreversible condition [29]. Both mechanisms may play a role in cardiotoxicity and numerous external factors may decide which predominates and whether heart damage is reversible.

The cardiotoxicity of trastuzumab is always reversible (87% in our study) such as reported in others retrospectives studies in adjuvant and metastatic setting [23, 30].

The limitations of our study are its small sample size and short follow-up. Despite these limitations, the results we obtained coincide with published studies, in that trastuzumab related cardiotoxicity in a clinical care setting is more frequent than is shown by clinical trial estimates.

Conclusion

In conclusion, for trastuzumab, cardiotoxicity is its major complication with LV dysfunction being the most common case. Most incidences are transient, asymptomatic and reversible. Nevertheless, longer follow-up is needed to confirm that cardiotoxicity associated with trastuzumab therapy does not affect it’s long-term outcome. Prior to the institution of trastuzumab therapy, all patients should be evaluated for their cardiovascular status. As the majority of complications are asymptomatic, routine cardiac monitoring must be performed during trastuzumab treatment.

Abbreviations

HER2: 

Human epidermal growth factor receptor 2

LVEF: 

Left ventricular ejection function

HF: 

Heart failure

NCI-CTC: 

National Cancer Institute Common Toxicity Criteria

BMI: 

Body mass index

CRF: 

Case report form.

Declarations

Acknowledgments

I wish to thank the team of epidemiology unit at National Institute of Oncology for its help for the extraction of the data especially Samir Belgazar and Hicham Bahri.

Authors’ Affiliations

(1)
Medical oncology Department, National Institute of Oncology

References

  1. Hortobagyi GN, de la Garza SJ, Pritchard K, et al: The global breast cancer burden: variations in epidemiology and survival. Clin Breast Cancer. 2005, 6: 391-401. 10.3816/CBC.2005.n.043.PubMedView ArticleGoogle Scholar
  2. Albain KS, de la Garza SJ, Pienkowski T, et al: Reducing the global breast cancer burden: the importance of patterns of care research. Clin Breast Cancer. 2005, 6: 412-420. 10.3816/CBC.2005.n.045.PubMedView ArticleGoogle Scholar
  3. Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL: Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987, 235: 177-182. 10.1126/science.3798106.PubMedView ArticleGoogle Scholar
  4. Slamon DJ, Godolphin W, Jones LA, et al: Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science. 1989, 244: 707-712. 10.1126/science.2470152.PubMedView ArticleGoogle Scholar
  5. Force T, Krause DS, Van Etten RA: Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition. Nat Rev Cancer. 2007, 7: 332-344. 10.1038/nrc2106.PubMedView ArticleGoogle Scholar
  6. Hudis CA: Trastuzumab—mechanism of action and use in clinical practice. N Engl J Med. 2007, 357: 39-51. 10.1056/NEJMra043186.PubMedView ArticleGoogle Scholar
  7. Yavas O, Yazici M, Eren O, Oyan B: The acute effect of trastuzumab infusion on ECG parameters in metastatic breast cancer patients. Swiss Med Wkly. 2007, 137: 556-558.PubMedGoogle Scholar
  8. Viani GA, Afonso SL, Stefano EJ, De Fendi LI, Soares FV: Adjuvant trastuzumab in the treatment of her-2-positive early breast cancer: a meta-analysis of published randomized trials. BMC Cancer. 2007, 7: 153-10.1186/1471-2407-7-153.PubMedPubMed CentralView ArticleGoogle Scholar
  9. Wysocki PJ, Hutka M: Cardiotoxicity of 5-fluorouracil in a young colorectal cancer patient – case report and review of literature. Arch Med Sci. 2009, 5: 277-280.Google Scholar
  10. McKeage K, Perry CM: Trastuzumab: a review of its use in the treatment of metastatic breast cancer overexpressing HER2. Drugs. 2002, 62: 209-243. 10.2165/00003495-200262010-00008.PubMedView ArticleGoogle Scholar
  11. Suter TM, Procter M, Van Veldhuisen DJ, Muscholl M, Bergh J, Carlomagno C, et al: Trastuzumab-associated cardiac adverse effects in the Herceptin Adyuvant Trial. J Clin Oncol. 2007, 25: 3859-3865. 10.1200/JCO.2006.09.1611.PubMedView ArticleGoogle Scholar
  12. Telli M, et al: Trastuzumab-related cardiotoxicity: calling into question the concept of reversibility. JCO. 2007, 25 (23): 3525-3533. 10.1200/JCO.2007.11.0106.View ArticleGoogle Scholar
  13. Romond EH, Perez EA, Bryant J: Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005, 353: 1673-1684. 10.1056/NEJMoa052122.PubMedView ArticleGoogle Scholar
  14. Slamon D, Eiermann W, Robert N: 006 oboB BCIRG 006:2nd interim analysis chase III randomised trial comparing doxorubicine and cyclophosphamid followed by docetaxel (AC/T) with doxorubicine and cyclo phosphamid followed by docetaxel and trastuzumab (AC/ETH) with docetaxel, carboplatin and trastuzumab (TCH) in Her2neu positive early breast cancer patients. Proceedings of San Antonio breast cancer symposium (SABCS). 2006, San Antonio: Breast Cancer Research and TreatmentGoogle Scholar
  15. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al: Herceptin Adjuvant (HERA) trial study team: Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005, 353: 1659-1672. 10.1056/NEJMoa052306.PubMedView ArticleGoogle Scholar
  16. McArthur HL, Chia S: Cardiotoxicity of trastuzumab in clinical practice. N Engl J Med. 2007, 357: 94-95. 10.1056/NEJMc070065.PubMedView ArticleGoogle Scholar
  17. Montemurro F, Redana S, Valabrega G, Martinello R, Aglietta M, Almiero R: Trastuzumab-related cardiotoxicity in the herceptin dyuvant trial. J Clin Oncol. 2008, 26: 2052-2053. 10.1200/JCO.2007.15.5044.PubMedView ArticleGoogle Scholar
  18. Wadhwa D, Fallah-Rad N, Grenier D, et al: Trastuzumab mediated cardiotoxicity in the setting of adjuvant chemotherapy for breast cancer: a retrospective study. Breast Cancer Res Treat. 2009, 117: 357-364. 10.1007/s10549-008-0260-6.PubMedView ArticleGoogle Scholar
  19. Mackey JR, Clemons M, Cote MA, et al: Cardiac management adjuvant trastuzumab therapy: recommendation of the Canadian Working Group. Current Oncol. 2008, 15: 24-35. 10.3747/co.2008.199.View ArticleGoogle Scholar
  20. Jones AL, Barlow M, Barrett-Lee PJ, et al: Management of cardiac health in trastuzumab-treated patients with breast cancer: updated United Kingdom National Cancer Research Institute recommendations for monitoring. Br J Cancer. 2009, 100: 684-692. 10.1038/sj.bjc.6604909.PubMedPubMed CentralView ArticleGoogle Scholar
  21. Sparano JA, Brown DL, Wolff AC: Predicting cancer therapyinduced cardiotoxicity: the role of troponins and other markers. Drug Saf. 2002, 25: 301-311. 10.2165/00002018-200225050-00001.PubMedView ArticleGoogle Scholar
  22. Sengupta PP, Northfelt DW, Gentile F, Zamorano JL, Khandheria BK: Trastuzumab-induced cardiotoxicity: heart failure at the crossroads. Mayo Clin Proc. 2008, 83: 197-203.PubMedView ArticleGoogle Scholar
  23. Tan-Chiu E, Yothers G, Romond E, et al: Assessment of cardiac dysfunction in a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel, with or without trastuzumab as adjuvant therapy in nodepositive, human epidermal growth factor receptor 2-over - expressing breast cancer: NSABP B-31. J Clin Oncol. 2005, 23: 7811-7819. 10.1200/JCO.2005.02.4091.PubMedView ArticleGoogle Scholar
  24. Perez EA, Suman VJ, Davidson NE, et al: Cardiac safety analysis of doxorubicin and cyclophosphamide followed by paclitaxel with or without trastuzumab in the NorthCentral Cancer Treatment Group N9831 adjuvant breast cancer trial. J Clin Oncol. 2008, 26: 1231-1238. 10.1200/JCO.2007.13.5467.PubMedPubMed CentralView ArticleGoogle Scholar
  25. Bowles A: Risk of heart failure in breast cancer patients after anthracyclines and Trastuzumab treatment: a retrospective cohort study. J Natl Cancer Inst. 2012, 104: 1293-1305. 10.1093/jnci/djs317.PubMedPubMed CentralView ArticleGoogle Scholar
  26. Hosseini M, Houshmand M, Ebrahimi A: MTHFR polymorphisms and breast cancer risk. Arch Med Sci. 2011, 7: 134-137.PubMedPubMed CentralView ArticleGoogle Scholar
  27. Gluba A, Pietrucha T, Banach M, Piotrowski G, Rysz J: The role of polymorphisms within paraoxonases (192 Gln/Arg in PON1 and 311Ser/Cys in PON2) in the modulation of cardiovascular risk: a pilot study. Angiology. 2010, 61: 157-165. 10.1177/0003319709351258.PubMedView ArticleGoogle Scholar
  28. Pentassuglia L, Graf M, Lane H, et al: Inhibition of ErbB2 by receptor tyrosine kinase inhibitors causes myofibrillar structural damage without cell death in adult rat cardiomyocytes. Exp Cell Res. 2009, 315: 1302-1312. 10.1016/j.yexcr.2009.02.001.PubMedView ArticleGoogle Scholar
  29. Singh KK, Shukla PC, Quan A, et al: Herceptin, a recombinant humanized anti-ERBB2 monoclonal antibody, induces cardiomyocyte death. Biochem Biophys Res Commun. 2011, 411: 421-426. 10.1016/j.bbrc.2011.06.169.PubMedView ArticleGoogle Scholar
  30. Ewer MS, Vooletich MT, Durand JB, et al: Reversibility of trastuzumab related cardiotoxicity: new insights based on clinical course and response to medical treatment. J Clin Oncol. 2005, 23: 7820-7826. 10.1200/JCO.2005.13.300.PubMedView ArticleGoogle Scholar

Copyright

© Aitelhaj et al.; licensee BioMed Central Ltd. 2013

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Advertisement