كلية العلوم الطبية

Faculty of Medical Sciences

Faculty of medicine

كلية طب بشرى

كلية علاج طبيعى

Faculty of Physical Therapy

Includes Bibliographic Referances,p 64:72.

SUMMARY
Worldwide, breast cancer is the most frequently diagnosed life-threatening cancer in women. In less-developed countries, it is the leading cause of cancer death in women; in more-developed countries, however, it has been surpassed by lung cancer as a cause of cancer death in women.
Breast cancer incidence varies widely within regions and countries, likely due to differences in racial and ethnic make-up, health resources, and lifestyle patterns. The median age at diagnosis in Egypt is one decade younger than in countries of Europe and North America, tumors are relatively advanced at presentation and most patients are premenopausal.
A positive family history of breast cancer is the most widely recognized risk factor for breast cancer. Reproductive factors that increase breast cancer risk include a long menstrual history, nulliparity, having one's first child after age 30, never breastfeeding, being overweight after menopause, use of postmenopausal hormone therapy, physical inactivity, and alcohol consumption.
The higher overall mortality rates in high resource countries reflect the high incidence of the disease in many of those countries. However, the burden of deaths due to breast cancer in lower resource countries is disproportionately high due to late-stage disease presentation and inadequate health care systems.
The size, stage, rate of growth and other characteristics of breast cancer determine the methods of treatment. Treatment may include surgery, drugs (hormonal therapy and chemotherapy), radiation and/or immunotherapy. Surgery, the primary treatment for breast cancer, may consist of lumpectomy (breast-conserving surgery) or total mastectomy. Different variants of total mastectomy are performed but the most widely applied one is modified radical mastectomy (total mastectomy with axillary lymph node dissection).
To increase the likelihood of cure, several chemotherapy regimens are commonly given in addition to surgery. Agents used in adjuvant breast cancer chemotherapy include taxanes, anthracyclines, tamoxifen and aromatase inhibitors. Currently, there is a growing interest in combining anticancer drugs aiming at maximizing efficacy while minimizing systemic toxicity through the delivery of lower drug doses.
Radiotherapy is a common modality for cancer treatment in which a therapeutic dose of ionizing radiation is delivered to a tumor with the desired result being cell death or an impairment to cellular division. Radiotherapy can reduce the risk of recurrence by 50-66%. External beam radiotherapy with photon beams is carried out with three types of treatment machines: superficial and orthovoltage x-ray units, isotope teletherapy units (mainly 60Co units) and linear accelerators.
Radiotherapy is given to the breast after conservation surgery or to the chest wall after mastectomy to complete local treatment. The most common schedule for irradiation used in clinical practice is 50 Gy in 25 fractions to the whole breast or chest wall. A shorter fractionation schedule (42.5 Gy in 16 fractions over 22 days) proved to be just as safe and effective. Other schedules delivering 40 Gy in 15 or 16 fractions have also been described in cohort studies.

Breast-conserving surgery followed by adjuvant radiotherapy in early-stage breast cancer is currently considered standard treatment. Not many centers in Egypt have adopted this approach and continue to perform modified radical mastectomy. Also, most of these patients receive post-mastectomy radiotherapy though in some cases it might not be indicated.
Several studies suggested that some previous breast cancer radiotherapy regimens involved some unwanted cardiac irradiation which increased the subsequent risk of heart disease. The risks of both incident and fatal radiation-induced heart disease were usually higher in women irradiated for left-sided breast cancer than in women irradiated for right-sided cancer, suggesting that the risk of cardiac toxicity is related to the radiation dose received by the heart. The main risk was found to occur at least 10 years after radiotherapy, nevertheless, the initiation of damage must have taken place at the time of the radiotherapy and so additional information may be gained by studying vascular abnormalities and cardiac function in asymptomatic patients during the first few years after radiotherapy.
One of the most common manifestations of cardiac toxicity associated with exposure to chemo and radiotherapy is the development of left ventricular dysfunction which presents on echocardiography in the form of asymptomatic decrease in left ventricular ejection fraction (LVEF). Several studies have shown that early damage to the heart can be detected using myocardial perfusion imaging within 6 months to a few years after irradiation. A perfusion defect may result from the blockage of a coronary artery or from microvascular damage to an area of myocardium.
Biomarkers, most prominently cardiac troponins, have been evaluated for their ability to describe the risk of potential cardiac dysfunction in clinically asymptomatic patients. Troponins are released in response to myocardial injury regardless of cause. Troponin levels are now considered to be the criterion standard for defining and diagnosing myocardial infarction (MI). Prior to the introduction of cardiac troponins, the biochemical marker of choice for the diagnosis of acute MI was creatine kinase (CK). As CK is found in the inner mitochondrial membrane and cytoplasm, it can be released into the blood through cell membrane disruption and death. Lactate dehydrogenase (LDH) is a cytoplasmic enzyme present in essentially all major organ systems. The extracellular appearance of LDH is used to detect cardiac cell damage or cell death.
The current study aims to estimate the dose delivered to the heart during breast cancer radiotherapy, evaluate the damage to the heart due to the delivered dose and correlate the dose and location of radiotherapy to the cardiac damage that could have happened due to the late effects of radiation.
This study included fourteen healthy females with no history of heart disease as controls, thirty female patients with right-sided breast cancer and thirty female patients with left-sided breast cancer. For all patients, after receiving radiotherapy, the dose delivered to the heart was estimated depending on the radiotherapy treatment plan, dose and laterality using computerized tomography (CT)-based dose-volume histograms (DVH). Baseline cardiac function was assessed for all patients using echocardiography before the beginning of the radiotherapy course in order to document normal LVEF. LVEF was measured again 12 months after completion of radiotherapy to identify and monitor cardiac toxicity. Troponin I (TnI), CK and LDH were also measured 12 months after radiotherapy and compared to those of the normal females to assess the possible onset of radiation-induced cardiotoxicity. Myocardial perfusion imaging was done to four patients to compare its results to those of biomarkers and echocardiography as markers of early onset of cardiac toxicity.
The mean radiation dose delivered to the heart appeared to be significantly higher in left-sided than in right-sided breast cancer patients. A highly significant correlation was also noted between the total dose of radiotherapy given to left-sided breast cancer patients and the mean dose delivered to the heart, however, that correlation was missing for right-sided patients.
LVEF significantly decreased from baseline in left-sided breast cancer patients after one year of completing radiotherapy. However, that decrease in LVEF was not significant in right-sided patients. There was also a statistically significant difference between right and left-sided patients regarding LVEF dropping 20% or more from baseline.
This study showed that TnI and LDH values were significantly higher in patients (right and left-sided); in which the biomarkers were measured one year after the completion of radiotherapy, than they were in the control group. Despite the CK values were within the normal range in the control group, the mean was significantly higher than it was in the patients’ groups. Tumor multiplicity, size, grade, lymph node involvement and vascular invasion didn’t show a significant correlation with any of the measured biomarkers in either right or left-sided patients. The only exception, however, was a significant difference found in LDH values between right and left-sided patients with tumors larger than 3 cm.
Overall, the current study, comparing cardiac toxicity between women irradiated for left-sided and women irradiated for right-sided breast cancer, provided an indication of the extent to which radiotherapy has increased cardiac risk. The follow-up period of 12 months in this study is still too short. Considering the very long latent period of radiotherapy-induced cardiac toxicity, patients should be followed-up regularly for as long as possible, so that the clinical impact of early LVEF decrease will be further validated.

Includes CD copy for The Thesis

Includes Abstract in Arabic