A dosimetric skin study on postmastectomy breast cancer patients undergoing radiation therapy

A DOSIMETRIC SKIN STUDY ON POSTMASTECTOMY BREAST CANCER PATIENTS UNDERGOING RADIATION THERAPY SHARON WONG MEI MEI THE NATIONAL UNIVERSITY OF SINGAPORE 2011 A DOSIMETRIC SKIN STUDY ON POSTMASTECTOMY BREAST CANCER PATIENTS UNDERGOING RADIATION THERAPY SHARON WONG MEI MEI (MSc (Biomedical Science), BSc(Medical Radiation Science) A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF MEDICINE FACULTY OF MEDICINE THE NATIONAL UNIVERSITY OF SINGAPORE 2011 DECLARATION I hereby declare that the thesis is my original work and it has been written by me in its entirety I have duly acknowledged all the sources of information which have been used in the thesis This thesis has also not been submitted for any degree in any university previously Sharon Wong Mei Mei 25 April 2012 Page | II ACKNOWLEDGEMENTS I would like to express my sincere thanks to my supervisor Professor Jiade Jay Lu, for without his support, his wide range of resources, his splendid vision and keen mind; this work would not have been possible Professor Phan Toan Thang, my cosupervisor for supervising me in my translational research work For helping me get through the well-guarded door into the department of Surgery and patiently guiding me in the planning and execution of experiments My sincere gratitude to the staff at the Department of Radiation Oncology (NUCIS), Department of Medicine (NUH), Department of Surgery (NUH) and the numerous lecturers at Faculty of Medicine (NUS) who provided me with their continuous and encouraging support through the years of my study Of special mention are my collaborators and mentors who provided valuable advice and critique, Prof Bay Boon Huat, Prof Ho Khek Yu, Dr Elaine Lim Hsuen, Dr Lee Khai Mun, Dr Michael Back, Dr Fong Kum Weng and Dr Susan Loong Special thanks to my beloved friends and colleagues especially Alvin Chua, Han Hwan Chour, Ong Chee Tian, Bala Rajaratnam, Dr Sathiyamoorthy Selvarajan and Amarjit Sardul And most importantly, I dedicate this thesis to my husband Royston, my two daughters Nicole and Kylie and my son Cayden who sacrificed their days and nights without me at home as I complete this course of study I share with them this thesis as an expression of my deepest love and happiness for their endless support Page | III TABLE OF CONTENTS Declaration II Acknowledgements III Table of Contents III Publications derived from this thesis X Summary XI List of Tables XIV List of Figures XVI Chapter 1.1 Chapter Introduction Aims and objectives of this thesis Overview of Breast Cancer 11 11 2.1.2 Lymphatic Drainage 11 2.1.3 Local Involvements 12 2.1.4 Recurrence in the skin 2.2 10 2.1.1 Anatomy of the breast 2.1 Background 12 Role of Radiation Therapy 13 2.2.1 Postmastectomy Radiation Therapy 14 2.2.2 15 Use of postmastectomy radiation therapy with systemic therapy 2.2.3 Radiation Therapy Techniques after mastectomy 17 Page | IV 2.2.4 Definition of Clinical target volume 2.2.5 2.3 18 20 Complications of Radiation Therapy 20 2.3.1 Acute skin reactions 21 2.3.2 Chronic skin reactions 22 2.3.3 Dose Distribution in skin 23 Radiation Physics on Production of X-rays 24 2.4.1 Characteristic Radiation 25 2.4.2 Bremsstrahlung 26 2.4.3 Dose computation using 3D Monte Carlo Radiotherapy 2.4 Response of the skin to radiation dose 27 Treatment Planning System Algorithms Chapter A dosimetric study on the use of radiation therapy 28 treatment planning system to predict for surface doses in postmastectomy radiation therapy patients 3.1 Introduction 29 3.2 Materials and method 31 3.2.1 Construction of mastectomy phantom 31 3.2.2 Thermoluminescence dosimeter placements and invivo 33 dosimetry 3.2.3 Thermoluminescence dosimeters (TLD) 36 3.2.4 Treatment Planning System 36 3.2.5 Statistical analysis 37 Page | V 3.3 Results 37 3.3.1 Surface doses between absorbed doses (TLD) and calculated doses (TPS) 38 3.3.2 Entrance dose at the build-up region between absorbed 41 Doses (TLD) and calculated doses (TPS) 3.4 Discussion 44 3.5 Conclusion and future direction 48 3.6 References 50 An ultrasonographic evaluation of skin thickness in 54 Chapter breast cancer patients after postmastectomy radiation therapy 4.1 Introduction 55 4.2 Methods and Materials 58 4.2.1 Patients selection 58 4.2.2 Postmastectomy breast radiation therapy 59 4.2.3 Ultrasound measurements 60 4.2.4 Statistical analysis 64 Results 65 4.3 4.3.1 Skin thickness on the mastectomy side with radiation in comparison to the non-irradiated breast 4.3.2 65 Correlations of acute skin scoring (RTOG) and 66 FibroticThickness 4.4 Discussion 67 Page | VI 4.4.1 Correlations of Acute skin scoring (RTOG) and fibrotic skin thickness 4.5 71 76 4.5.2 Authors’ contributions 76 4.5.3 Acknowledgement 76 4.5.4 Patient’s consent Chapter 75 4.5.1 Competing interest 4.6 Conclusion 76 References 77 Epidermal keratinocytes death and expression of marker proteins of apoptosis in human skin after ionizing radiation exposure 81 5.1 Introduction 82 5.2 Materials and Methods 83 5.2.1 Biopsies and Irradiation 83 5.2.2 Measurement of Radiation Induced Apoptotic 85 Keratinocytes 5.2.2.1 Hematoxylin and Eosin (H&E) staining 5.2.3 TUNEL assay 85 85 5.2.3 Immunohistochemistry (IHC) Analysis of Apoptotic Biomarkers 85 5.2.3.1 Histological Procedures 85 5.2.3.2 Histolopathological Evaluation 87 5.2.5 Western Blot Analysis of Apoptotic Biomarkers 88 Page | VII 5.2.5.1 Protein extraction from tissue culture cells 88 5.2.5.2 Determination of protein concentrations 89 5.2.5.3 SDS-polyacrylamide gel electrophoresis 90 5.2.5.4 Protein electroblotting 91 5.2.5.5 Blocking, antibody incubation, washing and stripping 92 5.2.6 Computerized gel densitometry 5.2.7 Statistical Analysis 5.3 93 93 Results 94 5.3.1 Radiation induced apoptotic keratinocyte cell death is dose and fraction size dependent 94 5.3.1.1 Increased Apoptotic Keratinocyte cell count 94 5.3.1.2 Morphological changes of radiation induced apoptotic keratinocytes 95 5.3.2 Expression of apoptosis related protein markers with increasing radiation dose 5.3.2.1 97 Accumulation of PCNA, p21 and p53 Proteins with increasing dose 97 5.3.3 Morphological changes of PCNA, p21 and p53 with increasing dose 101 5.3.4 Accumulation of, PCNA, p21and p53 proteins with increasing fraction size 102 Page | VIII 5.3.5 Western Blot Analysis revealed elevated levels of PCNA and p21 proteins in irradiated keratinocytes and this is dose and fraction size dependent 107 5.4 Discussion 109 5.5 Conclusion 116 5.6 References 118 Bibliography 122 Appendices 130 Page | IX Chapter Five - Human epidermal keratinocytes death and expression of protein markers of apoptosis after ionizing radiation exposure p53 and p21 in skin exposed to different types of radiation Results show an early onset of increased p53 levels and a correlation between p53 and p21 was evident In other studies, p53, PCNA and p21 were induced in hairless mouse epidermis following UVB radiation [Mallikarjuna 2005], human skin response to x-ray treatment with release of p53 [Mab 2003] and induced expression of p21 and PCNA proteins in UVB irradiated human epidermis [Nazim et al 1999] However, drawbacks of these studies were the use of mice epidermis and UVB radiation and included a range of radiation dose In our study, these factors were closely controlled Results from our studies show predictable patterns of cytokine expression PCNA and P21 levels elevated gradually from 2Gy to 10Gy, followed with a sharp increase at 50Gy On the other hand, p53 was elevated at 2Gy and persisted until 10Gy, and then returned to baseline values This pattern was also consistent with increasing fraction size Not only did this study demonstrate the early and persistent elevation of cytokine production following irradiation, but it also determined consistent patterns of cytokines expression A similar pattern of cytokine expression was observed in murine studies Rubin 1995 and colleagues studied cytokine induction in mice receiving thoracic irradiation They found several cytokines were longitudinally elevated with consistent patterns between mice One question arising from our results is why p53 did not exhibit similar pattern with PCNA and p21 given that all are apoptotic inducing cytokines P53 plays a crucial role in the protection against DNA damage allowing cell cycle arrest, DNA repair or apoptosis by transcriptional activation of p53 related genes such as p21 and Bax [Murphy 2002] Ionizing radiation produces double and single strand DNA breaks Cells respond to DNA photoproducts and DNA breaks by accumulation of functionally active p53 proteins Page | 113 Chapter Five - Human epidermal keratinocytes death and expression of protein markers of apoptosis after ionizing radiation exposure Upon exposure to radiation, p53 is known to sense DNA damage and to subsequently halt the cell cycle in the G1 phase, providing time for DNA repair If the damage to the genome is too serious and repair likely to fail, p53 acts as an inducer of apoptosis [Ponten F 2001] Consistent with this report, we observed that these proteins are upregulated in response to irradiation-caused DNA damage leading to cell cycle arrest to allow enough time for DNA repair This observation is consistent with similar study in animal model showing stimulatory effect of UV radiation on the protein levels of p53 and downstream effector p21 [Kovacs 2003] In a separate time-dose study by Peter Mab et al 2003 human skin was exposed to UVB radiation and p53 expression was detected P53 expression started to increase 3h after irradiation and reached a maximum at 12 h after UVB exposure However, epidermal sections at 36 h appeared to be p53 negative or only faintly stained This seem to suggest p53 has a short half life of less than 24h and is time -dose dependent However, more studies are needed in the future to further support this anticipation, Further in this study, the radiation induced p21 protein was detected much sooner than PCNA, correlating well with the expression of p53 It seems likely that up regulation of p21 could have been mediated via p53 pathway by irradiation The different time course of the expression also supports this hypothesis PCNA is implicated in DNA replication and repair by forming a sliding platform that could mediate the interaction of numerous proteins with DNA [Warbrick 2000] It is known that p21 binds to PCNA and inhibits PCNA function in DNA replication [Fotedar et al 2004] Therefore PCNA is regarded as an important target for p21 as well as reliable biomarker for cell proliferation It has been observed that p53/p21 signal transduction pathway plays a significant role in the regulation of the PCNA response to ionizing radiation [Wenz 1998] Page | 114 Chapter Five - Human epidermal keratinocytes death and expression of protein markers of apoptosis after ionizing radiation exposure In view of the high affinity of PCNA to DNA strand breaks due to the ionizing radiation [Moggs et al 2000], it is logical to expect the rapid recruitment of PCNA to ionizing radiation induced strand breaks In this study, we have demonstrated the induction of PCNA after radiation in human skin cells and this induction is dose and fraction size dependent The evidence from our study and clinical literature demonstrate a significant dose and fraction size response during RT They also support the molecular rationale that increased cytokines expression may serve as indicators of increased normal tissue toxicity The clinical research environment presents a number of unique challenges to prospective proteomics studies from sample collection to processing, storage and analysis There are many sources of error (delays in sample collection or processing, misinterpretation of standard operating procedures (SOP) and so on) that can introduce a myriad of confounding variables, which in turn will render the resulting proteomic data inconclusive We have considered these issues in details and study designs were carefully drawn out to minimize the influence of extraneous environmental factors that may affect our conclusions from these data In addition our principal data were derived from a single volunteer, thus avoided interindividual variations in the responses to DNA damage Another limitation of our work is the small sample size and limited apoptotic markers identified in skin relating to postmastectomy radiotherapy Future studies with bigger sample sizes are warranted to determine the cytokine changes after radiation exposure and how these relate to normal tissue radiation toxicity with greater certainty Page | 115 Chapter Five - Human epidermal keratinocytes death and expression of protein markers of apoptosis after ionizing radiation exposure 5.5 CONCLUSION In summary, our results demonstrate the specific up-regulation of a number of apoptotic related marker proteins after irradiation and suggest that premature keratinocyte elimination occurs via apoptosis Results also demonstrated that their increased expression or activation occurs in relation to radiation dose and fraction size While total dose is critical in determining the severity of skin toxicity, skin effects are more severe following fractionations schedules that employ daily dose fractions of 5Gy or higher than follow dose schedules using 2-2.5Gy daily More importantly, based on our findings, there is a potential for the use of anti-apoptotic strategies which could be targeted at various regions of the apoptotic pathway to prevent radiation induced skin toxicity Access of anti apoptotic factors to the skin could possibly be delivered topically The use of such a target-specific approach would minimize the systemic side effects of anti-apoptotic treatments However, the mechanisms regulating the increase in cytokines in vivo in response to cellular damage and their role need additional study Taken together, all of the experiments discussed in this study lay the groundwork for future larger scale clinical trials within our institution and in collaboration with other clinical centres Protein markers have potential as proxy indicators of radiation sensitivity and exposure It is hoped that the preliminary work presented here will contribute to the identification of protein biomarkers that contributes not only to the advancement of radiation biology in the long-term, but allows us to make a difference in the lives of cancer patients The very high incidence of breast cancer partially attributable to the ageing of population and the increasing use of surgery and postoperative radiotherapy for its treatment make the above type of study of special interest, with the side effects of radiotherapy an increasingly important issue Page | 116 Chapter Five - Human epidermal keratinocytes death and expression of protein markers of apoptosis after ionizing radiation exposure 5.6 REFERENCES Overgaard MJM, Overgaard J, Postoperative radiotherapy in high-risk postmenopausal breast-cancer patients given adjuvant tamoxifen Danish Breast Cancer Cooperative Group DBCG 82c randomised trial Lancet 1999; 353: 1641-1648 Ragaz J, JS, Le N, Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer." N Engl J Med 1997; 337: 956-962 Turesson, I Individual variation and dose dependency in the progression rate of skin telangiectasia Int J of Radiat Oncol Biol Phys.1990; 19: 1569-1574 Turesson I, Nyman J, Holmberg E Prognostic factors for acute and late skin reactions in radiotherapy patients Int J Radiat Oncol Biol Phys 1996; 36; 1065-1075 Tucker SL, Thames HD Evidence for individual differences in the radiosensitivity of human skin European Journal of Cancer 1992; 28A: 1783-1791 Bernier J, Thames HD, Smith CD Tumour response, mucosal reactions and late effects after conventional and hyperfractionated radiotherapy Radiotherapy & Oncology; 1998; 47; 137-143 Rojas A and Joiner MC The influence of dose per fraction on repair kinetics Radiotherapy & Oncology; 1989; 14; 329-336 Vicini FA, Baglan KL, Kestin LL, Mitchell C, Chen PY, Frazier RC, Edmundson G, Goldstein NS, Benitez P, Huang RR, Martinez A: Accelerated treatment of breast cancer J.Clin Onco 2001, 19: 1993-2001 Jager JJ, RL & Jager JJ Clinical relevance of apoptotic markers in breast cancer not yet clear Apoptosis;2002, 7:361-365 Page | 117 Chapter Five - Human epidermal keratinocytes death and expression of protein markers of apoptosis after ionizing radiation exposure 10 Menard CJ Discovering clinical biomarkers of ionizing radiation exposure with serum proteomic analysis Cancer Research 2006; 66;1844-1850 11 Bentzen MS Preventing or reducing late side effects of radiation therapy: radiobiology meets molecular pathology Nature Reviews Cancer 2006; 6; 702-713 12 Faulhaber OA Basis of cell kill folowing clinical radiotherapy In M Sluyser(ed), Application of Apoptosis to Cancer Treatment 2005; 293-320 Springer 13 Hagan MY Ionizing radiation causes a dose-dependent release of transforming growth factor alpha in vitro from irradiated xenografts and during palliative treatment of hormone-refractory prostate carcinoma Clinical Cancer Research 2004; 10;6724- 5731 14 Archambeau JO, Pezner R, Wasserman T Pathophysiology of irradiated skin and breast Int J of Radiat Oncol Biol Phys 1995, 31;1171-1185 15 Wong KL, Tan MGK, Li S, Chua AWC, Goh LK, Wang DY Dose-dependent radiation induced apoptosis in a cochlear cell-line Apoptosis 2006 11: 2127-2136 16 Ponten Fredrik HL Induction of p53 expression in skin by radiotherapy and UV radiation: a randomized study Journal of the National Cancer Insitute 2001, 93, 128133 17 Gorodetsky Raphael, CL Late effects of dose fractionation on the mechanical properties of breast skin following post-lumpectomy radiotherapy Int J of Radiat Oncol Biol Phys 1999; 45:4: 893-9000 18 Rubin P, JC A perpetual cascade of cytokines postirradiation leads to pulmonary fibrosis Int J of Radiat Oncol Biol Phys 1995; 33;99-109 Page | 118 Chapter Five - Human epidermal keratinocytes death and expression of protein markers of apoptosis after ionizing radiation exposure 19 Okunieff PC Molecular markers of radiation related normal tissue toxicity Cancer and Metastasis Reviews 2008; 20 Kovacs CD Cytokine profiles in patients receiving wide-field +prostate boost radiotherapy for adenocarcinoma of the prostate Cytokine 2003; 23;151-163 21 Mallikarjuna Gu SD Dietary Feeding of Silibinin Prevents Early Biomarkers of UVB radiation-induced Carcinogenesis in SKH-1 Hairless Mouse Epidermis Cancer Epidemiology, Biomarkers & Prevention 2005; 1344-1349 22 Mab Peter KH Premature keratinocyte death and expression of marker proteins of apoptosis in human skin after UVB exposure Arch Dermatol Res 2003; 295;71-79 23 Nazim U Ahmed MU Induced expression of p16 and p21 proteins in UVB irradiated human epidermis and cultures keratinocytes Journal of Dermatological Science 1999; 19;175-181 24 Murphy MM The expression of p53, p21, Bax and induction of apoptosis in normal volunteers in response to different doses of ultraviolet radiation Br J Dermatol 2002; 145;110-117 25 Warbrick The puzzle of PCNA's many partners BioEssays 2000; 22;997-1006 26 Fotedar RBM Role of p21 WAF1 in the cellular response to UV Cell Cycle, 2004; 3;134-137 27 Wenz FAE The response of proliferative cell nuclear antigen to ionizing radiation in human lymphoblastiod cell lines is dependent on p53 Radiat Res 1998; 149;32-40 28 Moggs JG, GP A CAF-I-PCNA mediated chromatin assembly pathway triggered by sensing DNA damage Mol Cell Biol 2000; 20;1206-1218 Page | 119 Bibliography BIBLIOGRAPHY Ang K.K., W R in K K James D Cox (2003) The skin Radaition Oncology 127-141 Houston, Texas: Mosby Archanbeau J.R., P R (1995) Pathophysiology of irradiated skin and breast Int J of Radiat Oncol Biol Phys , 1171- 1185 Baker M.R., B D (1989) The effects of single doses of xrays on the mechanical properties of pig skin in vivo Br J Radiol , 830-837 Bentzen S.M, O J (1993) Clinical manifestation of normal tissue damage In O J Bentzen S M, Basic Clinical Radiobiology 1st ed Londong: Arnold Bentzen S.M, O M (1991) Relationship between early and late normal tissue injury after postmastectomy radiotherapy Radiotherapy & Oncology 159-165 Bomford C.K., K I Radiation physics therapy and oncology In Walter and Miller's Textbook of Radiotherapy: 6th Edition 2003; 298-299; Churchill livingstone Buchholz T.A., A.S M (1993) Effect of delay in radiation in the combined modality treatment of breast cancer Int J Radiat Oncol Biol Phys, 23-35 Buchanan C.L., Dorn P.L., Fey J, Giron G, Naik A, Mendez J, Murphy C, Sclafani L.K (2006) Locoregional recurrence after mastectomy: Incidence and Outcomes Journal of the American College of Surgeons 203, 4: 469-474 Calkins, A J (1988) The sonographic appearance of the irradiated breast J Clin Ultrasound 16-409-415 10 Chia K.S., Lee J.J.M., Wong J.L.L., Gao W, Lee H.P., Shanmugaratnam K (2002) Cancer Incidence in Singapore, 1998 to 1999 Ann Acad Med Singapore 31: 745-50 11 Chia K.S., Seow A., Lee H.P., Shanmugaratnam K (2000) Cancer Incidence in Singapore 1993-1997.Singapore Cancer Registry, Report No Page | 122 Bibliography 12 Cozzi Luca, A F.C (1998) Quality assurance in radiation oncology A study of feasibility and impact on action levels of an in vivo dosimetry program during breast cancer irradaition Radiotherapy & Oncology.; 29-36 13 Delaney, G., Beckham, W., Veness, M., Ahern, V., Back, M., Boyages J., Fox C., Graham, P (2000) “Three Dimensional dose distribution of tangential breast irradiation; results of a multicentre phantom dosimetry study.” Radiotherapy & Oncology, 61-68 14 Delaney, G B (2000) Three Dimensional dose distribution of tangential breast irradiation; results of a multicentre phantom dosimetry study Radiotherapy & Oncology 61-68 15 Dische S, W M (1989) The recording of morbidity related to radiotherapy Radiotherapy & Oncology ,16 , 103-108 16 Donegan W.L., Perez M.C (1966) A biostatistical study of locally recurrent breast carcinoma Surg Gynecol Obstet 529-540 17 Donegan W.L., Perez M.C., Watson F.R (1966) A biostatistical study of locally recurrent breast carcinoma Surg Gynecol Obstet.122:529-540, 18 Emami B, L J (1991) Tolerance of normal tissue to therapeutic irradiation Int J Radiat Oncol Biol Phys, 109-122 19 Essers M, M B (1999) In vivo dosimetry during external photon beam radiotherapy Int J Radiat Oncol Biol Phys 245-59 20 Fajardo L.G., B M (2001) Skin Radiation Pathology 411-420 21 Fernando I N, F H (1996) Factors affecting acute skin toxicity in patients having breast irradiation after conservative surgery: A prospective study of treatment practice at the Royal Marsden Hospital Clinical Oncology 226-233 22 Fornage B.D., M M (1993) Imaging of the skin with 20 MHz Ultrasound Radiology 69-76 Page | 123 Bibliography 23 Fraass B A, McShan D (1987) The Use of Computers in Radiation Theray Amsterdam: Elsevier 24 Fraass B A, McShan D.L, Ten Haken R K and Hutchins K M (1987) The Use of Computers in Radiation Theray Amsterdam: Elsevier, 25 Fuller S A, H J (1992) Cardiac doses in post-operative breast irradiation Radiotherapy & Oncology ; 19–24 26 Gorodetsky R, M X (1990) Radiation effect in mouse skin: Dose fractionation and would healing Int J Radiat Oncol Biol Phys 1077-1081 27 Gorodetsky, R (1999) Late effects of dose fractionation on the mechanical properties of breast skin following post-lumpectomy radiotherapy Int J Radiat Oncol Biol Phys, 893-900 28 Group, E B (1999) Effects of radiotherapy and surgery in early breast cancer: An overview of the randomized trials N Eng J Med 333:1444-1455 29 Haagensen, C D (1986) Anatomy of the mammary glands In H C D, Diseases of the breast (3rd Edition) Philadelphia: Saunders W E 30 Harper J.L, F L (2004) Skin toxicity during breast irradiation: pathophysiology and management Sout Med 989-93 31 Harris J.R, H.-M P (1999) Consensus statement on postmastectomy radiation therapy Int J Radiat Oncol Biol Phys 989-990 32 Herbert C.E, E M (2003) Feasible measurement errors when undertaking in vivo dosimetry during external beam radiotherapy of the breast Medical Dosimetry 45-48 33 Higgins P.D, H E (2007) Evaluation of surface and superficial dose for head and neck treatments using conventional or intensity-modulated techniques Int J Radiat Oncol Biol Phys 52 , 1135-46 34 Hopewell, J.W (1990) The skin: its structure and response to ionizing radiation Int J Radiat Oncol Biol Phys 751-773 Page | 124 Bibliography 35 J Tey, S B (2008) Cancer Care in Singapore Biomedical Imaging and Intervention Journal; 4(3):e38 36 Jara Lazaro A.R., Thilagaratnam S, Tan PH (2010) Breast cancer in Singapore: some perspectives Breast Cancer, 17: 1: 23-28 37 Klein, E A (1993) Entrance and exit dose regions for a Clinac 2100C Int J Radiat Oncol Biol Phys 429-435 38 Kols, A (2009) Breast Cancer: Increasing Incidence, Limited Options Retrieved September 20, , from Outlook, 19: http://www.path.org/files/eol19_4rev.pdf 39 Kron, T E (1996) TLD extrapolation for skin dose determination in vivo Radiotherapy and Oncology 119-123 40 Kron, T (1994) Thermoluminescence dosimetry and its applications in medicine Part 1: PHysics 199, materials and equipments, Australasian Physical and Engineering Sciences in Medicine 175-182 41 Krueger Editha A (2001) Complications and patient satisfaction following expander/implant breast reconstruction with and without radiotherapy Int J Radiat Oncol Biol Phys 49 , 713-721 42 Kurtz J M, A R (1991) How important is adequate radiotherapy for the long term results of breast conserving treatment? Radiotherapy Oncology 84-90 43 Lee, P., J, S., G, G (1994) Patient dosimetry quality assurance programe with a commercial diode system Int J Radiat Oncol Biol Phys 1175-82 44 Leunens G, V D (1990) Quality assurance in radiotherapy by vivo dosimetry Entrance dose measurements, a reliable procedure Radiother Oncol 1175-82 45 Magno L, Bignardi M, Micheletti E, Bardelli D, Plebani F (1987) Analysis of prognostic factors in patients with isolated chest wall recurrence of breast cancer Cancer 60: 2; 240-244 Page | 125 Bibliography 46 Margolin S.G, B J (1990) Management of radiation induced moist skin desquamation using hydrocolloid dressing Cancer Nursing, 71-80 47 McShan, F (1993) Use of an octree-like geometry for 3D dose calculations Med Phys 1219-1227 48 Mijnheer B J, S H (1991) In vivo dosimetry during tangential breast treatment Radiotherapy & Oncology Vol 22 Issue , 269-279 49 Narod S.A, D M (2002) Oral contraceptives and the risk of breast cancer N Engl J Med 2025-2032 50 National Comprehensive Cancer Network (2003) Clinical practice guidelines in oncology: Retrieved from http://www.nccn.org/physician_glslf_guidelines.html 51 Nias (1963) Some comparisons of fractionation effects by erythema measurements on human skin Br J Radiol 183-187 52 Nuutinen J, L T (1998) A dielectric method for measuring early and late reactions in irradiated human skin Radiotherapy & Oncology 249-254 53 Overgaard M, J M (1999) Postoperative radiotherapy in high -risk postmenopausal breast cancer patients given adjuvant tamoxifen: Danish Breast Cancer Cooperative Group DBCG 82c randomised trial Lancet 1641-1648 54 Overgaard, M (1999) Overview of randomized trials in high risk breast cancer patients treated with adjuvant systemic therapy with or without postmastectomy irradiation Seminar Radiation Oncology 9;292-299 55 Overgaard M., Nielsen H.M., Overgaard J (2007) Is the benefit of postmastectomy irradiation limited to patients with four or more positive nodes, as recommended in international consensus reports? A subgroup analysis of the DBCG 82 b&c randomized trials Radiotherapy and Oncology, 82: 3:247-253 56 Parthasaradhi, K P (1989) Investigation on the reduction of electron contamination with a 6MV x-ray beam Med Phys 123-125 Page | 126 Bibliography 57 Paszat L.F, M W (1999) Mortality from myocardial infarction following postlumpectomy radiotherapy for breast cancer: a population-based study in Ontario, Canada Int J Radiat Oncol Biol Phys 75 58 Pires A.M.T, S.R (2008) RTOG critieria to evaluate acute skin reaction and its risk factors in patients with breast cancer submitted to radiotherapy Enfermagem 844-9 59 Pisansky T.M, I J (1993) Patterns of tumor relapses following mastectomy and adjuvant systemic therapy in patients with axillary lymph node-positive breast cancer Impact of clinical, histopathologic and flow cytometric factors Cancer, 1247-1260 60 Ragaz, J., Jackson, S., Le, N (1997) Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer N Engl J Med , 337 956-62 61 Rajan, S (2007) The race against breast cancer Retrieved from http://www.nccs.com.sg/epub/CU/vol2_03/main.htm 62 Ramsey C.R., C D (1998) Improved dose homogeneity to the intact breast using three-dimensional treatment planning Medical Dosimetry 25: 1-6 63 Recht A, E S (2001) Postmastectomy radiotherapy: clinical practice guidelines of the American Society of Clinical Oncology J Clin ONcol 1539-1569 64 Redpath A.T, T D (1991) A dimensional scatter correction algorithm for photon beams Physics Med Biol 779-798 65 Redpath, A T (1992) A multidisciplinary approach to improving the quality of tangential chest wall and breast irradiation for carcinoma of the breast Radiotherapy & Oncology , 118-126 66 Russel N.S, K (1994) Quantification of patient to patient variation of skin erythema developing as a response to radiotherapy Radiotherapy & Oncology , 213-221 Page | 127 Bibliography 67 Russell, M H (2004) Dual frequency Ultrasound Examination of skin and subcutis thickness in breast cancer related lymphedema The Breast Journal , 496-503 68 Seow A, Koh W.P., Chia K.S., Shi L.M., Lee H.P., Shanmugaratnam K (2010) Trends in Cancer Incidence in Singapore 1968-2009 Singapore Cancer Registry, Report No 69 Shanmugaratnam K., Lee H.P., Day N.E (1983) Cancer Incidence in Singapore 1968-1977 70 Shu-Hui Hsu, P L (2008) Assessment of skin dose for breast chest wall radiotherapy as a function of bolus material Phys Med Biol , 2593-2606 71 Small W.J.R, W G (2006) Radiation Toxicity: A Practical Guide Springer Science , 66-75 72 Spenzi E, G L (2008) An overview of monte carlo treatment planning for radiotherapy Radiation Protection Dosimetry , 123-129 73 Knoos Tommy, L A (1986) Comparison of measured and calculated absorbed doses from tangential irradiation of the breast Radiotherapy & Oncology , 7, 81-88 74 Troetschel M A (1991) Radiation induced inframammary moist desquamation Oncol Nurs Forum 786 75 Turesson (1976) Skin reaction as a biologic parameter for control of different dose schedules and gap corection Acta Radiol Ther Phys Biol , 162-176 76 Vogel, G V (2006) Epidemiology of Breast Cancer In W DJ, Breast Cancer (2nd Edition) (pp 47-60) New York: Hamilton 77 Wang, C.C (2002) Cancer of the Breast In W C.C, Clinical Radiation Oncology: Indications, Techniques and Results (2nd Ed) 189-261 Wiley-Liss, Inc Page | 128 Bibliography 78 Warszawski A, R E (1998) 20 MHz ultrasonic imaging for quantitative assessment and documentation of early and late posradiation skin reactions in breast cancer patients Radiotherapy & Oncology , 241-247 79 Westermann, C M (1984) Determination of the accuracy of different computer planning systems for treatment with external photon beams Radiotherapy & Oncology , 339-347 80 Winchester D.J, W D (2006) Radiation therapy in early and advanced breast cancer In S E Motwani S B, Breast Cancer 353-379 New York: Hamilton 81 Wolfgang, J R (1988) Sonographic findings following conservative surgery and irradiation for breast carcinoma Ultrasound in Med Biol , 14,27-41 82 Wong J S, H J (2004) Postmastectomy Radiation Therapy In L M Harris J R, Diseases of the Breast 785-799 Boston: Lippincott Williams & Wilkins 83 Wong C.S, Chow K.Y., Lim G.H., Bhalla V., Lee H.P., Chia K.S.(2008) Cancer Survival in Singapore 1968-2002 Singapore Cancer Registry Page | 129 ... S Wong, A Kaur, M Back, K.M Lee, S Baggarley, J.J Lu An Ultrasonographic evaluation of skin thickness in breast cancer patients after undergoing postmastectomy radiation therapy Radiation Oncology.. .A DOSIMETRIC SKIN STUDY ON POSTMASTECTOMY BREAST CANCER PATIENTS UNDERGOING RADIATION THERAPY SHARON WONG MEI MEI (MSc (Biomedical Science), BSc(Medical Radiation Science) A THESIS SUBMITTED... by Jara-Lazaro et al 2010, demonstrated that about 1,100 new cases are diagnosed annually and approximately 270 women die in Singapore each year from breast cancer, translating to breast cancer