“ BARRIER SKIN FILM VS. STEROID CREAM PROPHYLAXIS FOR PREVENTION OF RADIATION DERMATITIS IN BREAST CANCER WOMEN UNDERGOING ADJUVANT RADIATION

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“ BARRIER SKIN FILM VS. STEROID CREAM PROPHYLAXIS FOR PREVENTION OF RADIATION DERMATITIS IN BREAST CANCER WOMEN UNDERGOING ADJUVANT RADIATION

THERAPY”

DEPARTMENT OF RADIATION ONCOLOGY, CHRISTIAN MEDICAL COLLEGE,

VELLORE, TAMIL NADU 632004

DISSERTATION SUBMITTED IN PARTIAL FULFILLMENT OF MD – RADIATION ONCOLOGY (BRANCH IX)

EXAMINATION MAY 2020

CANDIDATE REGISTRATION NUMBER: 201719053

TAMIL NADU DR. M.G.R MEDICAL UNIVERSITY,

CHENNAI – 600032

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This is to certify that the dissertation entitled ‘BARRIER SKIN FILM VS. STEROID CREAM PROPHYLAXIS FOR PREVENTION OF RADIATION DERMATITIS IN BREAST CANCER WOMEN UNDERGOING ADJUVANT RADIATION

THERAPY’ is a bonafide work done by Dr. Jerryes Pious Wisely, Post Graduate Student in the Department of Radiation Oncology, Christian Medical College, Vellore during the period from April 2017 to April 2020 and is being submitted to The Tamil Nadu Dr. M.

G. R. Medical University in partial fulfilment of the MD Branch Radiation Oncology examination conducted in May 2020.

Guide

Dr. Rajesh Balakrishnan Professor

Department of Radiation Oncology Unit III Christian Medical College

Vellore, India – 632004

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Principal, Dr. Simon P Pavamani Christian Medical College, Professor and Head,

Vellore, Tamil Nadu – 632004 Department of Radiation Oncology, Christian Medical College

Vellore, Tamil Nadu- 632004

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Dr. Jerryes Pious Wisely PG Registrar,

Department of Radiation Oncology, Christian Medical College,

Vellore, Tamil Nadu – 632004

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ANTI-PLAGIARISM CERTIFICATE:

This is to certify that this dissertation work titled “BARRIER SKIN FILM VS. STEROID CREAM PROPHYLAXIS FOR PREVENTION OF RADIATION DERMATITIS IN BREAST CANCER WOMEN UNDERGOING ADJUVANT RADIATION THERAPY” of the candidate Dr. Jerryes Pious Wisely, with registration number 201719053 in the branch of Radiation Oncology is personally verified with the urkund.com

website for the purpose of plagiarism check. I found that the uploaded thesis file contains from introduction to conclusion pages and result shows 1% percentage of plagiarism in the dissertation.

GUIDE Dr. Rajesh Balakrishnan

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List of Figures:

Figure 1: Number of new cases of all cancers, both sexes, all ages – World, GLOBOCAN

2018 ... 15

Figure 2: Number of new cases of all cancers, both sexes, all ages – India, GLOBOCAN 2018 ... 16

Figure 3: Number of new cases of all cancers, females, all ages – India, GLOBOCAN 2018 16 Figure 4: Percentage of total cancer DALYs due to different types of cancers by sex in India, 2016 ... 17

Figure 5: Breast Anatomy ... 21

Figure 6: Lymphatic drainage of the breast ... 23

Figure 7: Lobular Carcinoma In Situ (LCIS) ... 24

Figure 8: Ductal Carcinoma In Situ (DCIS) ... 24

Figure 9: Invasive Ductal Carcinoma (IDC) Grade I. A: Low power B: High power ... 26

Figure 10: Invasive Ductal Carcinoma (IDC) Grade II. A: Low power B: High power ... 26

Figure 11: Invasive Ductal Carcinoma (IDC) Grade III. A: Low power B: High power ... 26

Figure 12: Layers of the skin ... 37

Figure 13: Age Distribution Histogram ... 58

Figure 14: Address ... 59

Figure 15: Diagnosis ... 59

Figure 16: Side of Breast CA ... 60

Figure 17: Grade of CA Breast ... 60

Figure 18: Stage of CA Breast ... 61

Figure 19: Molecular Subtype ... 61

Figure 20: Site of RT ... 62

Figure 21: RT subsites ... 63

Figure 22: RT Technique ... 63

Figure 23: Dose Fractionation ... 64

Figure 24: Intervention Distribution ... 64

Figure 25: Average Pain Scores ... 65

Figure 26: Incidence of pain in both arms ... 66

Figure 27: Pain Score Distribution – Max Pain Score Experienced ... 67

Figure 28: Cumulative week of Onset of Pain ... 69

Figure 29: Average Grade of Radiation Dermatitis ... 70

Figure 30: Incidence of Radiation Dermatitis in both arms ... 71

Figure 31: Distribution of Radiation Dermatitis ... 73

Figure 32: Cumulative Week of Onset of Radiation Dermatitis: ... 74

Figure 33: Incidence of pain according to fractionation ... 85

Figure 34: Incidence of radiation dermatitis according to fractionation ... 85

Figure 35: Time-to-event curve for the development of Grade II Radiation Dermatitis ... 86

Figure 36: Average RISRAS Scores ... 87

Figure 37: Patient reported outcomes of RISRAS ... 89

Figure 38: Patient Reported Sensation Scores of STAT ... 91

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List of Tables:

Table 1: ASTRO Updated Selection Criteria for APBI - 2017 ... 33

Table 2: Acute Skin Changes with Localised Radiation Dose ... 40

Table 3: MMF Maximum Pain Score ... 66

Table 4: BSF Maximum Pain Score ... 67

Table 5: MMF Week of Onset of Pain: ... 68

Table 6: BSF Week of Onset of Pain: ... 68

Table 7: MMF Grade of Radiation Dermatitis ... 72

Table 8: BSF Maximum Grade of Radiation Dermatitis: ... 72

Table 9: MMF Week of Onset of Radiation Dermatitis: ... 73

Table 10: BSF Week of Onset of Radiation Dermatitis: ... 74

Table 11: Association of various risk factors for development of radiation dermatitis in the MMF arm: ... 76

Table 12: Association of various risk factors for development of radiation dermatitis in the BSF arm: ... 78

Table 13. Association between prophylactic agent and the development of Grade II radiation dermatitis: ... 80

Table 14: Association between side of application and the development of Grade II radiation dermatitis in the MMF arm and BSF arm: ... 81

Table 15: Association between axillary radiation dermatitis and overall radiation dermatitis in the MMF arm and BSF arm: ... 82

Table 16: Association between axillary radiation dermatitis and overall Grade II radiation dermatitis in the MMF arm and BSF arm: ... 83

Table 17: Association between prophylactic agent and the development of pain score of 3 or more: ... 84

Table 18: Association between prophylactic agent and the development of any pain score: ... 84

Table 19: RISRAS Scores: ... 88

Table 20: Patient reported outcomes of RISRAS: ... 90

Table 21: Patient Reported Sensation Scores of STAT ... 92

Table 22: SKINDEX 16 Scores ... 93

Table 23: LASA Scores ... 94

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1. ACKNOWLEDGEMENT

Thesis has been a long and hard journey and it would have not been possible alone if not for the help, support, wisdom and guidance provided by many along the way. There is no basis for a thesis without patients in a clinical setting and therefore I would like to acknowledge and thank the patients who were part of this study and their relatives for their co-operation and good faith in bringing this study to completion.

I would like to thank my guide Dr. Rajesh Balakrishnan who has been a constant support and has very patiently and promptly aided me through various stages of data collection, analysis and interpretation and has helped me stay focussed at my work.

I would like to thank my co-guides Dr. Selvamani B, Dr. Patricia S, Dr. Sunitha S V, Dr.

Susanne Pulimood and Dr. Dincy Peter who have shared their technical expertise and offered timely feedback and guidance.

I would also like to acknowledge the immense support extended by Dr. Selvamani and Dr. Simon Pavamani for their time, patience and guidance throughout my study.

I would like to extend my gratitude to my statistician Mrs. Gowri for promptly providing statistical analysis and results for this study.

I extend my sincere gratitude to the OPD staff nurses for their support and aiding me in patient education and follow up of the patients in the study.

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I would like to thank the entire Radiation Oncology department including my colleagues and peers, Radiation technologists for their support and time at various stages of my thesis.

I would like to thank my family and friends who have supported me constantly and continually motivated me to bring this endeavour to completion.

Last but not the least, I would like to thank the Almighty God for giving me the knowledge, strength and wisdom to undertake this thesis and complete it successfully.

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2. INTRODUCTION

Radiation therapy is one of the major components of breast cancer treatment and is often used for the prevention of recurrence of breast cancer after breast-conserving therapy or post-mastectomy. One of the dose-limiting effects of radiotherapy is radiation dermatitis that ionising radiation induces in normal tissue. Radiation therapy treatment may cause mild to severe radiation dermatitis such as erythema, desquamation, bullae/ulcers and skin necrosis which contribute to pain, discomfort, irritation, itching and burning. Severe radiation dermatitis may significantly interfere with the patient’s daily activities and quality of life, thus, affecting patient compliance and thereby reduce radiotherapy effectiveness and rendering it necessary to interrupt treatment leading to compromise of local control. Several studies have examined the use of prophylactic agents in the reduction of acute radiation dermatitis. Of particular interest, in our department, 3M Cavilon No-Sting Barrier Film, has been in use for a couple of years now and has shown to be an excellent measure to prevent radiation dermatitis. Hence, we wanted to evaluate the efficacy of the same by comparing the use of the same against a topical steroid cream – mometasone furoate whose efficacy in the prevention of radiation dermatitis has been demonstrated in multiple existing trials.

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3. AIM

To study the efficacy of Barrier skin film (3M Cavilon) as compared to topical steroid cream (Mometasone Furoate) for the prophylaxis of radiation dermatitis from the start of radiotherapy up to 4 weeks post radiotherapy in women with breast cancer post mastectomy undergoing adjuvant radiotherapy.

4. OBJECTIVES

4.1 Primary Objective

1. Incidence and time to onset of Grade II radiation dermatitis as assessed by the NCI CTCAE criteria v4.0

2. Grade 3 or more pain score as assessed by the visual analogue scale (VAS)

4.2 Secondary Objectives

1. Incidences of severe (Grade 3) radiation dermatitis as measured by the NCI CTCAE v4.0 for the mometasone and skin barrier methods.

2. Skin toxicity as measured by dermatologic quality of life instrument – SKINDEX 16, Skin Toxicity Assessment Tool (STAT) and RISRAS – Radiation Induced Skin Reactions Assessment score.

3. Global Quality of Life as measured by LASA – Linear Analog Self-Assessment Scale.

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5. LITERATURE REVIEW 5.1 Introduction

Breast cancer patients require multi-modality treatment therapies that include chemotherapy, surgery, radiotherapy, hormonal therapy and targeted therapy separately or in combination, depending on the stage of cancer (1). Radiotherapy is one of the major components of breast cancer treatment and is often used to prevent recurrence of breast cancer after breast-conserving surgery or mastectomy (2). Radiation dermatitis is a common side effect of radiation therapy (RT) in patients receiving RT and is dose dependant (3). Severe radiation dermatitis interferes with the patient’s daily activities and quality of life affecting patient compliance. This would also lead to treatment interruption and hence could reduce the effectiveness of radiotherapy. Hence, in order to mitigate the adverse effects of radiation therapy on skin, several prophylactic measures have been explored with varying efficacies.

5.2 Epidemiology of Breast Cancer

Breast cancer is the second most common malignancy just trailing behind lung cancer on the global scale (4)(Fig.1). Breast cancer is the most common malignancy affecting women in both the developing and developed countries. Looking at the global scale, there were approximately 2.1 million newly diagnosed female breast cancer cases in 2018, which accounted for almost 1 in 4 cancer cases among women (4). Over the last

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few decades, the incidence of breast cancer has been increasing in most countries and regions of the world (4). Contrary to historical patterns of breast cancer incidence being high in developed countries, the incidence of breast cancer is increasing rapidly in the developing world due to the changes in lifestyle and westernisation of the developing world (5). In India, breast cancer is the most frequently diagnosed cancer among both sexes and women (Fig.2, Fig.3). and its incidence has been increasing over time (age- standardised incidence rate from 1990 to 2016 increased by 39.1%) (4) (6)(Fig.4).

Figure 1: Number of new cases of all cancers, both sexes, all ages – World, GLOBOCAN 2018 Source: GLOBOCAN 2018

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Figure 2: Number of new cases of all cancers, both sexes, all ages – India, GLOBOCAN 2018

Figure 3: Number of new cases of all cancers, females, all ages – India, GLOBOCAN 2018

Breast cancer is also the leading cause of cancer death among both sexes in India (4).

According to the Global Burden of Disease Study 1990-2016, breast cancer is the second most leading cause of disability-adjusted-life-years (DALYs) lost among all cancers combined (8.2%) (6).

Source: GLOBOCAN 2018

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Figure 4: Percentage of total cancer DALYs due to different types of cancers by sex in India, 2016

5.3 Aetiology and Risk Factors of Breast Cancer:

Epidemiological studies have identified a number of risk factors that are associated with an increased risk of women developing breast cancer.

Age and Gender:

Increasing age and female sex are established risk factors for carcinoma breast. The risk of developing breast cancer is uncommon among women younger than 40 years of age

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and increases significantly thereafter. According to the SEER database, the probability of a woman developing breast cancer in the United States between 2013 and 2015 was (7):

• Birth to age 49 – 2.0 (1 in 51 women)

• Age 50 to 59 – 2.3 (1 in 43 women)

• Age 60 to 69 – 3.5 (1 in 29 women)

• Age 70 and older – 6.7 (1 in 15 women)

• Birth to death – 12.4 (1 in 8 women)

In the US, over 260,000 women are diagnosed to have breast cancer in a year compared to less than 3000 men who are diagnosed the same in a year (7).

Reproductive factors:

Age of menarche:

Many case-control and population cohort studies have demonstrated that younger age at menarche (<15 years) is associated with an increased risk of breast cancer (8) (9).

Age of menopause:

If menopause is attained over 50 years of age, it is associated with an increased risk of breast cancer (8).

Full term pregnancy:

The risk of developing breast cancer decreases with increase in parity/ number of full- term pregnancies that a particular woman has had (10). Also late age at first child birth

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(>30 years) was an important risk factor with relative risk of more than six times (OR, 6.34; 95% CI, 2.04 – 27)(8).

Duration of lactation/breast feeding:

Lactation has a protective effect over development of breast cancer. The relative risk (RR) of breast cancer was found to increase 14.9 (95% confidence interval: 8.69, 25.7) times in women having mean duration of breastfeeding less than 13 months (11).

Weight and body fat:

Obesity (defined as a BMI 30 kg/m²) is associated with a higher risk of morbidity and mortality. This risk in developing breast cancer is further worsened in post-menopausal women (9)(12).

Hormonal factors:

Increased levels of estrogen are linked to have an increase in risk of developing breast cancer. Oral contraceptive use have been associated with an increased risk of developing breast cancer (11). Postmenopausal patients who have taken hormone replacement therapy (HRT) are at an increased risk of developing breast cancer and the risk decreases after discontinuation of HRT after 5 years (13).

History of Breast Cancer:

Personal history of ductal carcinoma in situ (DCIS) or invasive breast cancer increases the risk of developing invasive breast cancer in the contralateral unaffected breast (14).

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Family history of breast cancer is strongly affected by the number of female first-degree relatives with and without cancer and the age at diagnosis. Risk of breast cancer increased almost twofold if a woman had one affected first-degree relative and increased threefold if she had two affected first-degree relatives (15). The age of diagnosis of the first degree relative (<30 years of age) also leads to a threefold increase in the risk of developing breast cancer (15).

Several inherited genetic mutations can be attributed to breast cancer incidence with 40%

of hereditary breast cancer cases occurring due to mutations in BRCA1 and BRCA2 genes inherited through the autosomal dominant method (16). According to a prospective cohort study, the risk of cumulative breast cancer by the age of 80 years was 72% in the carriers of BRCA1 mutation (95% CI, 65%–79%) and 69% in the carriers of BRCA2 mutation(95% CI, 61%–77%) (17).

Lifestyle factors:

Alcohol consumption is associated with an increased risk of developing hormone receptor positive breast cancer(18,19).

Smoking in post-menopausal women and prenatal smoking is associated with an increased risk of developing breast cancer (20). In a Norwegian study among 302,865 women, there was a consistent dose response relationship between the number of years of smoking before the first childbirth and the risk of developing breast cancer (21).

Increased physical activity has been associated with a reduction in the risk of developing breast cancer, particularly in postmenopausal women (22).

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5.4 Breast Cancer Anatomy:

Breasts are paired structures located as a modified skin appendage that lies on the anterior chest wall superficial to the pectoralis major muscle between the 2^nd and 6^th ribs.

It is suspended from the anterior chest wall by the ligaments of Cooper which are attached to skin and fascia of major and minor pectoral muscles. Breast tissue also projects into the axilla as the axillary tail of Spence. The breast is composed of mammary glands (modified sweat glands with series of ducts and secretory lobules) surrounded by connective tissue stroma and fat. (23)(Fig. 5)

Figure 5: Breast Anatomy

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The breast parenchyma is intermixed with connective tissue, which has a rich vascular and lymphatic network. Lymphatic drainage of the breast begins in the interlobular or prelobular spaces, follow the ducts, and end in the subareolar network of lymphatics of the skin. The predominant lymphatic drainage of the breast is to the axillary lymph nodes (75%). Axillary lymph nodes are commonly divided into three main groups based on their relation to the pectoralis minor,

• Level I – Caudal and lateral to the pectoralis minor

• Level II – Beneath the pectoralis minor

• Level III – Medial to the pectoralis minor

Other clinically important lymph nodal groups are the internal thoracic or internal mammary chain of lymph nodes which predominantly drain the medial part of the breast.

Involvement of the supraclavicular group of lymph nodes usually occurs due to the retrograde spread along blocked lymphatic channels when axillary lymph nodes are largely involved. (24)(Fig. 6)

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Figure 6: Lymphatic drainage of the breast

5.5 Breast cancer pathology:

Most breast malignancies arise from epithelial elements and are categorised as carcinomas. The in-situ carcinomas of the breast are either ductal (also known as intraductal carcinoma) or lobular and usually represent non-invasive cancer that originates and is confined in ducts or lobules (25). Ductal carcinoma in situ (DCIS) is a potential precursor of invasive carcinoma and predicts that cancer may become invasive at that site at a later stage (26)(Fig.7). Lobular carcinoma in situ (LCIS) develops in breast lobules and is usually found incidentally and implies an increased risk of developing invasive ductal or lobular carcinoma in either breast (27)(Fig.8). LCIS is known as a risk factor and a non-obligate morphologic precursor of invasive breast

Moore KL, Dalley AF. Clinically Oriented Anatomy, 4th ed. Baltimore, MD: Lippincott Williams & Wilkins, 1999

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carcinoma (28). In the 8^th edition of the American Joint Committee on Cancer (AJCC) staging system, LCIS has been removed from the staging classification system and is no longer included in the pathologic tumor in situ (pTis) category (29).

The invasive breast carcinomas represent the carcinomas which have penetrated the basement membrane of the duct or lobule of the breast and has spread to the surrounding tissues. It consists of several histologic subtypes and based on a contemporary population-based series of 135,157 women with breast cancer as reported to the Surveillance, Epidemiology, and End Results (SEER) database of the National Cancer Institute (NCI) between 1992 and 2001 (30):

• Infiltrating ductal – 76 percent

• Invasive lobular – 8 percent

• Ductal/lobular – 7 percent

• Mucinous (colloid) – 2.4 percent

• Tubular – 1.5 percent

Figure 8: Ductal Carcinoma In Situ (DCIS) Figure 7: Lobular Carcinoma In Situ (LCIS)

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• Medullary – 1.2 percent

• Papillary – 1 percent

Infiltrating ductal carcinomas are divided into three grades based upon a combination of architectural and cytologic features (31):

• Well-differentiated (Grade 1)

• Moderately differentiated (Grade 2)

• Poorly differentiated (Grade 3)

The grade of the tumor serves as an important prognostic factor and helps direct appropriate treatment strategy.

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Figure 9: Invasive Ductal Carcinoma (IDC) Grade I. A: Low power B: High power

Figure 10: Invasive Ductal Carcinoma (IDC) Grade II. A: Low power B: High power

Figure 11: Invasive Ductal Carcinoma (IDC) Grade III. A: Low power B: High power

Courtesy of Stuart Schnitt, MD.

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Molecular classification of breast cancer:

The St Gallen expert panel met at the 12th International Breast Cancer Conference held at St Gallen (Switzerland) in March 2011 and identified four subtypes of breast cancer according to oestrogen and progesterone receptors (ER and PR receptors), overexpression and/or amplification of the human epidermal growth factor receptor 2 (HER2) oncogene and Ki67 as prognostic and predictive factors (32).

The four subtypes were luminal A, luminal B, Erb-B2 (HER-2) overexpression/enriched and basal-like.

Luminal subtypes — The name "luminal" derives from similarity in gene expression between these tumors and the luminal epithelium of the breast. The luminal subtypes are characterized as luminal A and luminal B. Luminal subtypes are the most common subtypes of breast cancer and contribute to the majority of estrogen (ER)-positive breast cancers.

Luminal A: They are ER positive, PR positive, HER2 negative and low expression of proliferation related genes (Ki67). They make up 40% of all breast cancers and carry the best prognosis(33).

Luminal B: They are ER positive, PR positive, variable HER2 expression ang higher expression of proliferation related genes (Ki67). They make up about 20% of all breast cancers and carry a worse prognosis compared to the Luminal A tumors (33,34).

HER2-enriched — The human epidermal growth factor 2 (HER2)-enriched subtype makes up about 10 to 15 percent of breast cancers and is characterized by high expression of HER2 and proliferation gene clusters and low expression of the luminal and basal

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gene clusters. These tumors are often negative for ER and progesterone (PR). Only half of clinical HER2-positive breast cancers are HER2 enriched on molecular profiling; the other half can include any molecular subtype but is mostly made up of HER2-positive luminal subtypes.

Basal subtypes — Most of these tumors fall under the category of triple-negative breast cancers because they are ER, PR, and HER2 negative. This subtype constitutes about 15 to 20 percent of breast cancers (35).

5.6 Breast cancer staging and classification:

Once a diagnosis of breast cancer has been established by histopathology, it is important to accurately define the initial extent and stage of the disease for prognostication and direction of appropriate treatment. Staging of breast cancer is done by the Tumor–Node–

Metastasis (TNM)-based staging of breast cancers by the new, 8th editions of the relevant Union for International Cancer Control (UICC) and American Joint Committee on Cancer (AJCC) publications. American Joint Committee on Cancer - AJCC 8^th edition (staging details in annexe 11.1) which was initiated in 2017 and implemented in 2018.

The new TNM staging incorporates anatomical stages and prognostic stages. These are derived from a combination of the T, N and M categories and additional data from histological grade, estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) statuses. Gene-expression profiles are also incorporated with the Oncotype DX 21-gene assay. These factors lead to potential upstaging or downstaging of the disease, therefore guiding changes in management (36).

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Non metastatic breast cancer is broadly classified into two categories:

• Early stage – This includes patients with stage I, IIA, or a subset of stage IIB disease (T2N1).

• Locally advanced – This includes a subset of patients with stage IIB disease (T3N0) and patients with stage IIIA to IIIC disease.

5.7 Treatment:

The main goals of therapy in non-metastatic breast cancer are to eradicate the tumor from the breast and lymph nodes and to prevent locoregional and distal recurrence. In early stage breast cancer, patients generally undergo primary surgery (lumpectomy or mastectomy) with removal of axillary lymph nodes as required. Mastectomy was performed as a universal treatment for early breast cancer, however with the improvements and advances in understanding the biology of breast cancer and improved treatment modalities, breast conservation therapy was explored (37). Breast conserving therapy (BCT) is comprised of breast conserving surgery (BCS) plus adjuvant radiation therapy. Breast conserving therapy aimed at providing a cosmetically acceptable breast, the survival equivalent of mastectomy, and a low rate of recurrence in the treated breast as proved by the NSABP B-06 trial (38). Patients undergoing BCS will need post- operative adjuvant radiation therapy to the whole breast alone and to the involved axillary lymph node in case of sentinel lymph node sampling node positive disease based on the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) (39,40). The EORTC AMAROS trial (EORTC 10981/22023) further strengthened the role of axillary

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radiation therapy patients with tumor-positive sentinel lymph node biopsy (SLNB) (41).

A mastectomy is indicated in patients who are not candidates for BCT and those who prefer mastectomy. In the setting of women undergoing mastectomy for early breast cancer, post mastectomy radiation therapy (PMRT) is only indicated in high risk patients who are at an increased risk of local recurrence such as in node positive women (42).

Locally advanced carcinoma breast however has a different approach, systemic therapy for breast cancer is used either in a neo-adjuvant or adjuvant setting. Neo-adjuvant chemotherapy (NACT) is given for non-metastatic invasive cancer to reduce the risk of distant recurrence, to downstage the tumor – in order to allow for a less extensive surgery or breast conservation strategy in locally advanced breast cancer (43). Among patients undergoing neo-adjuvant chemotherapy (NACT), in one EBCTCG meta-analysis, reported more than two-thirds of the women had complete or partial clinical response and patients allocated to NACT had a greater frequency of breast conserving therapy(44). In patients who undergo upfront surgery, chemotherapy is given in the adjuvant setting and is responsible for reduction in the cause specific mortality from breast cancer (45). The common chemotherapeutic agents that have been proven beneficial include anthracycline-based regimens such as doxorubicin and cyclophosphamide followed by or preceded by a taxane (docetaxel or paclitaxel) (46).

In patients with HER2 positive breast cancers, HER2 directed therapy in the form of Inj.

Trastuzumab is added to the chemotherapy regimen with or without Inj. Pertuzumab (47,48). These patients go on to have definitive surgical management based on response assessment by clinical examination or imaging studies. They undergo either simple

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mastectomy and sentinel lymph node biopsy (SLNB) with or without Axillary lymph node dissection (ALND), modified radical mastectomy (MRM) or breast conservation surgery (BCS) depending on the primary tumor and axillary nodal status prior to NACT and post NACT.

5.8 Adjuvant Radiation therapy:

The primary goal of adjuvant radiation therapy is to eradicate any tumor deposits that remain following surgery (39,42).

5.8.1 Whole Breast Radiation Therapy:

Whole breast radiation therapy is given for patients undergoing breast conservation therapy as this brings about almost 50% reduction in the 10 year risk of any first recurrence when compared with breast conserving surgery alone (19 versus 35 percent, respectively, relative risk [RR] 0.52, 95% CI 0.48-0.56) (39). Whole breast radiation therapy is coupled with a boost to the tumor bed to reduce the risk of in-breast tumor recurrence(49). Standard conventionally dosed fractionation of 1.8 to 2 Gy daily fractions over 4.5 weeks to 5 weeks to a total dose of 45 to 50 Gy was recommended historically. A shorter hypo-fractionated schedule (40.05 Gy in 15 fractions or 42.60 Gy in 16 fractions) associated with equivalent tumor control and lesser toxicities is now preferred as per the American Society for Radiation Oncology (ASTRO) guidelines (50).

According to a 2016 meta-analysis of nine randomised control trials (n=8228 women), hypo-fractionated radiation therapy when compared with conventionally fractionated

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whole breast radiation therapy was shown to be associated with no difference in breast cancer specific survival and 10 year mortality, equivalent cosmetic outcomes and late radiation toxicity, decreased acute radiation toxicity, and better patient reported quality of life measures for women treated with breast conservation therapy (BCT) (51).

However, there is insufficient evidence for hypo-fractionated radiation therapy for patients undergoing regional lymph node radiation. Tumor bed boost if considered is given at 10 to 14 Gy in either 2 Gy or 2.5 Gy per fraction (49).

5.8.2 Accelerated Partial Breast Irradiation (APBI):

Accelerated Partial Breast Irradiation (APBI) refers to the use of focused and limited RT as a simpler alternative to conventional whole breast radiation therapy for women following breast conserving surgery (BCS). APBI delivers a higher daily dose of RT to a small volume of tissue – the lumpectomy bed with margin over a shorter period of time which translated to lesser breast symptoms and late side effects (52,53). The preliminary results of the RAPID trial showed that APBI regimen used in their trial (38.5 Gy in 10 twice daily fractions) was non-inferior to whole breast irradiation in preventing local recurrence (54). However, a stringent set of rules apply for patients to be properly selected to undergo APBI as laid forward by ASTRO, the American Society of Breast Surgeons (ASBS) and the American Brachytherapy Society (ABS) (55–57). In 2017, ASTRO updated the guidelines and patient selection criteria (58) as shown below.

Commonly accepted schedules for APBI include 34 Gy in 10 fractions for brachytherapy or 38 Gy in 10 fractions as twice daily fractions with external beam radiotherapy (EBRT).

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Table 1: ASTRO Updated Selection Criteria for APBI - 2017

Patient Group Risk Factor Original Update

Suitable Age ≥ 60 years ≥ 50 years

Margins Negative by ≥2 mm No change.

T stage T1 Tis or T1

DCIS Not allowed If all of the below:

• Screen-detected

• Low to intermediate nuclear grade

• Size ≤ 2.5 cm

• Resected with margins negative at ≥ 3 mm Cautionary Age 50 – 59 years • 40-49 years if all other

criteria for

"suitable" are met

• ≥ 50 if patient has at least one of the

pathologic factors below and does not have

any "unsuitable" factors.

Pathologic factors:

• Size 2.1-3.0 cm*

• T2

• Close margins (<2 mm)

• Limited/focal LVSI

• ER Negative

• Clinically unifocal with total size 2.1-

3.0 cm†

• Invasive lobular histology

• Pure DCIS ≤3 cm if criteria for

"suitable" not fully met

• EIC ≤3 cm Margins Close (<2 mm) No change

DCIS ≤3 cm ≤3 cm and does not meet

criteria for

“suitable”

Unsuitable Age <50 years • <40 years

• 40 – 49 years and do not meet the criteria for cautionary

Margins Positive No change

DCIS >3 cm No change

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5.8.3 Post Mastectomy Radiation Therapy (PMRT):

Patients undergoing mastectomy or modified radical mastectomy require post mastectomy radiation therapy (PMRT) in order to reduce the rate of locoregional recurrence and increase the long term breast cancer specific and overall survival (59,60).

The maximum benefit of PMRT is gained in node positive women post mastectomy and axillary surgery as according to the EBCTCG meta-analysis of 8135 women in 22 randomised controlled trials (42). PMRT is usually delivered to the chest wall and the regional lymph nodal basins as indicated. The regional lymph nodal basins include supraclavicular and infraclavicular nodes, axillary lymph nodes and internal mammary chain of lymph nodes. Treatment of the regional lymph nodal basins follows an individualised approach based on clinical stage including nodal status prior to the initiation of any therapy and post-surgical histopathology(61). The conventional dose and fractionation for PMRT is 50-50.4 Gy in 1.8-2.0 Gy per fraction per day in 25 to 28 total fractions. The UK Standardisation of Breast Radiotherapy (START) A and B trials compared conventional fractionated radiation therapy to hypo-fractionated radiation therapy and showed that hypo-fractionated radiation therapy offers favourable rates of loco-regional tumor control and almost similar late adverse effects as the standard schedule of 50 Gy in 25 fractions (62,63). Also in terms of acute toxicity, hypo- fractionated radiotherapy offered decreased incidence of grade 3 acute skin toxicity when compared to conventional fractionated radiation therapy (64). Hypo-fractionated schedules were typically 40.05 Gy in 15 fractions or 42.6 Gy in 16 fractions at 5 fractions per week for about 3 weeks total duration.

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5.9 Radiation Therapy Techniques:

There are numerous techniques available for the delivery of radiation therapy in both the BCS setting and the PMRT setting and the radiation therapy for breast cancer has evolved dramatically over the last century. External Beam Radiation Therapy (EBRT) techniques range from conventional radiation therapy to Three-Dimensional Conformal Radiation Therapy (3DCRT), Intensity Modulated Radiation Therapy (IMRT) with or without simultaneous integrated boost (SIB) and Volumetric Modulated Arc Therapy (VMAT). Image guidance and respiratory motion management have significantly augmented advanced radiation therapy techniques. Convention radiation therapy uses parallel opposed tangential fields for chest wall or intact breast and direct anterior fields for the supraclavicular, internal mammary and axillary lymph nodal regions. Axillary nodal region radiation therapy may have an additional posterior axilla boost to adequately cover the axillary group of lymph nodes (65). In PMRT, a bolus (a material with similar kind of density to tissue that is kept directly on the skin surface) is occasionally used to circumvent the skin sparing effect produced by the megavoltage photon beam and to increase the chest wall skin dose. The use of boluses has been associated with an increase in acute skin radiation dermatitis and erythema when used (66). 3DCRT and IMRT techniques permit the delivery of radiation therapy to a high- dose volume, minimising the dose to the normal tissue mainly significantly reducing the dose to the ipsilateral lung and heart, thereby decreasing potential morbidity and mortality from pulmonary and cardiac toxicity.

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5.10 Radiation therapy toxicity:

Radiation therapy is associated with several side effects and toxicity both in the acute and late settings, which if not given due attention to, can adversely affect the patient’s quality of life. However, current advances in radiation therapy techniques with higher energy photons and field arrangements to reduce exposure to normal tissues have dramatically reduced the incidence of toxicity (67). In particular, acute skin toxicities have been one of the most impacting factor on patient’s quality of life with almost 90%

of patients undergoing adjuvant radiation therapy experiencing some grade of acute radiation dermatitis (68).

5.11 Skin associated toxicity:

Acute radiation dermatitis is a common side effect particularly in patients who have skin folds in the treatment area and where skin is the target of treatment. Radiation induced acute skin reactions increase with a proportional increase in radiation dose. Radiation induced skin reactions is a continuous process; as the radiation dose accumulates, the severity increases. The usual course of typical acute reactions begins with the appearance of erythema during the second and third week followed dry desquamation with shedding of the outer skin layer and that followed by moist desquamation by the end of treatment where the dry desquamated skin begins to slough off. The general symptoms associated with acute skin toxicity include pruritis, increased warmth, dryness, tightness, burning sensation, tenderness, discomfort and pain. In order to understand the pathophysiology

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behind radiation induced skin reactions, it is necessary to understand the normal anatomical and physiological properties of the skin. The skin is comprised of mainly the dermis and epidermis, the epidermis is further sub-divided into five strata: corneum, granulosum, lucidum, spinosum, and basale (69,70).

Figure 12: Layers of the skin

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Keratinocytes form an essential component of these layers and it produces the primary scaffold protein of the epidermis, keratin. The epidermis functions as the primary barrier and biosensor to the outside environment. The maturation process for these cells average around 2 weeks and complete reconstitution of the epidermis occurs over a period of 1- 2 months. The general pathophysiology involves

(1) Following an initial radiation dose to the skin, a certain amount of the basal keratinocytes cell layer is destroyed or incapacitated, leading to disruption of the balance between the normal production of cells at the basal layer and the destruction or death of skin surface cells (71).

(2) There is also a poorly understood but well defined cascading inflammatory response that is triggered by the injured cells, which result in the release of histamines, serotonin and other proinflammatory molecules – cytokines and chemokines – IL-1 alpha, IL-1 beta, TNF-alpha, IL-6, IL-8, CL4, CXCL10 and CCL2 (72,73).

(3) Subsequent vascular response with extra-capillary cell injury and capillary dilatation in response to the inflammatory mediators, thus leading to erythema and edema (74).

All of the above mechanisms finally lead to skin breakdown and desquamation as seen in acute radiation dermatitis.

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Factors contributing to acute skin reactions are divided into (75) a) Patient related:

• Anatomic site

• Sex

• Body mass index (BMI)

• Age

• Ethnicity

• Sun-reactive subtype

• Breast size

• Collagen vascular disorders

• HIV infection and AIDS

• Smoking

• Genetic mutations b) Treatment related:

• Area of treatment

• Beam energy

• Total dose and fractionation

• Use of bolus and its frequency

• Technique of radiation therapy

• Use of radio-sensitizers

• Chemotherapy

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Late skin reactions include telangiectasia, hyper or hypo pigmentation, fibrosis, atrophy, edema and rarely ulceration. These appear after a latent period of months to years or as an extension or progression of the underlying acute process (76).

Significant toxicities (Grade 3 or more) result in the interruption of required treatment which may adversely affect the treatment outcome in the form of loco-regional control as well as overall survival (77). Also the severity of late reactions have been correlated with the severity of acute reactions such as patients who developed moist desquamation demonstrated a statistically significant increased risk of developing telangiectasia after a particular course of post mastectomy radiation therapy (78).

Given below (Table 2) is the acute skin changes and late skin changes that occur as a result of localised radiation dose and the expected onset of these changes (79):

Table 2: Acute Skin Changes with Localised Radiation Dose

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Intervention strategies for acute radiation dermatitis have been divided into prevention/prophylaxis and management of the acute reaction. However, multiple systematic reviews and meta-analyses have failed to identify any single best practice.

For example, the largest systematic review up to date is from 2012 by Chan et al who conducted a systematic review and meta-analysis of randomised control trials for prevention and treatment of acute radiation-induced skin reactions. The review included 47 studies and evaluated six type of interventions. They concluded that despite a large number of trials conducted in this area, there are no definitive results suggesting the effectiveness of any one strategy for reducing acute radiation dermatitis (80).

The Multinational Association of Supportive Care (MASCC) in 2012 published guidelines for the prevention and treatment of radiation dermatitis based on evidence- based recommendations after extensive literature review. They suggested washing with water, with or without mild soap could be adopted for skin care. They recommended the use of topical prophylactic corticosteroids (mometasone to reduce discomfort and itching. They furthermore reiterated that there is no evidence to support the superiority of any specific intervention over the other (81).

Diagnosis of acute radiation skin toxicity is done clinically without the need for histopathological confirmation. Acute radiation dermatitis is rarely biopsied, however if done, the histopathological features would demonstrate keratinocyte necrosis with spongiosis. Subepidermal vesiculation progressing to bullae or epidermal slough may also be present. There is edema in the endothelial cells and dermis. Occasional features include vasodilatation and erythrocyte extravasation. Arterioles would be occasionally

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obstructed by fibrin thrombin. The inflammatory infiltrate including eosinophils, lymphocytes, macrophages, and plasma cells are found in the dermis. Hair follicles may be shifted into the catagen phase which results in synchronized but reversible hair loss.

Dry desquamation is associated with hyperkeratosis (82).

5.12 Skin associated toxicity assessment systems:

There are multiple assessment systems that have been formulated to grade the extent and severity of acute radiation induced dermatitis. The most commonly used acute toxicity scoring system is by The Common Terminology Criteria for Adverse Event (CTCAE), Version 5 published by the National Institutes of Health (USA). The CTCAE gives 5 grades for acute radiation dermatitis under ‘Dermatitis radiation’. (CTCAE v5 Dermatitis radiation can be found in annexe). The Radiation Therapy Oncology Group (RTOG) also have published acute radiation morbidity scoring criteria for rating erythema and general dermatitis under five subcategories. (RTOG scoring found in Annexe). The RTOG system grades both acute and late effects whereas the CTCAE grades only the acute effects. However, these above scoring systems only provide the physician reported scores and the drawback being lack of consideration of the patient’s experience. To incorporate the patient reported outcomes, additional grading scales such as the RISRAS – Radiation Induced Skin Reaction Assessment Scale (83), the Skindex- 16 (84) and the DLQI - Dermatology Life Quality Index (85) were developed. The RISRAS is a tool (developed by a New Zealand group) that comprises a scale for patient reported symptoms and a scale for the health care professionals’ observations. The

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Skindex-16 is a short 16-item patient-completed assessment tool using numerical analogue scales (0=never bothered to 6=always bothered). It is an analogue scale of symptoms and functional endpoints related to skin toxicity that can occur in the treatment area. Other tools developed include the Skin Toxicity Assessment Tool (STAT) which is a skin specific instrument that comprises a provider-assessed objective measure of skin changes and five measures of patient-reported discomfort (86).

5.13 Management of acute skin toxicity:

As mentioned earlier, available evidence of side effect management is limited to a few studies or clinical trials that are focussed on efficacy of new therapeutics. The available interventions can be classified as either preventive or reactive to toxicities developing over the course of radiation therapy and recovery.

Preventive strategies include behavioural practices and topical agents. Among behavioural practices, smoking cessation should be strongly recommended as it has been associated as an independent risk factor for the development of severe acute skin reactions (87). General hygiene practices must be followed, such as washing the treated area with non-perfume soap (88,89).

The role of topical agents for the prevention of radiation related skin toxicity have also been studied. A systemic review by the Cancer Care Ontario’s Supportive Care Guidelines Group (SCGG) after extensive review of the available literature, did not find sufficient evidence for the support or to refute the use of a particular topical agent (90).

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The agents they had looked at included topical steroid creams, washing practices, sucralfate or sucralfate derivatives, biafine cream, oral enzymes, Amifostine, topical acid cream, aloe vera gel, almond ointment, aqueous cream, mild soap and dressings.

The role of topical corticosteroids in the prevention of acute skin toxicity in particular have been investigated. Topical corticosteroids exert their therapeutic effects due to their anti-inflammation, anti-proliferation, immunosuppression and vasoconstriction characteristics (91).

A 2017 systematic review and meta-analysis by Haruna F et al. investigated the efficacy of topical corticosteroids in managing acute radiation dermatitis in female breast cancer patients. This review included ten randomised controlled trials (RCTs) published between 2001 and March 2017 and included 919 patients in total. They were able to demonstrate that the risk of development of wet desquamation is at least 5 times less likely in breast cancer patients treated with topical corticosteroids. The mean radiation dermatitis scores were also significantly better in the topical corticosteroids treated patients. The patient’s subjective score of pain and pruritis was better in the topical corticosteroids treated patients. The over all quality of life was also significantly better in the topical corticosteroid treatment arm (92).

One of the first trials that investigated topical corticosteroids including mometasone furoate as a potential agent for the prevention of acute radiation skin toxicity was done at Uppsala, Sweden, by Åsa Boström et al. The Swedish group showed that mometasone

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furoate (MMF) has shown to result in less acute radiation dermatitis as assessed by the visual skin scoring and spectrophotometry as compared to emollient alone (93).

There are many more randomised control trials that have compared mometasone furoate to other topical agents such as Eucerin cream, Barrier skin film and aqueous cream and have demonstrated a decrease in the RTOG acute radiation morbidity criteria and an increase in the quality of life that were measured (94).

Topical corticosteroids are divided into 7 classes and mometasone furoate is a Class IV medium potency steroid (95). Mometasone furoate (MMF) has many advantages over other topical corticosteroids (96):

1. It has a low risk of overt cutaneous atrophy when compared to other potent corticosteroids.

2. It has a long duration of action – lasting for 24 hours and thus can be given as a convenient once-a-day schedule.

3. It has a strong inhibitory effect on the IL-6 activity which has been implicated in the development of acute skin toxicity.

The drawback of routine use of steroidal creams is the probability of substantial number of side effects associated with their use such as skin atrophy, thinning of the skin and the risk of introducing bacterial infections among other uncommon side effects (97).

Barrier skin films have also been investigated for the prophylaxis of acute radiation induced skin toxicity. It is an alcohol-free film formulated from two polymers - Acrylate terpolymer that provides durability to the film; methylphenyldisiloxane that acts as a

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plasticizing agent to provide flexibility and prevent cracking (98). Barrier skin film when applied to the skin surface, forms a barrier which protects against friction and trauma – reducing abrasions and allowing time for the repopulation of the epidermal stem cells (help prevent moist desquamation) and helps with the skin hydration. The hypothesis of barrier skin film in the prevention of acute radiation skin toxicity is based on the modification of the physical environment of the skin rather than the radiobiology of the radiation injury which leads to the transformation of the phenotypic expression of the radiation injury. Barrier skin film reduces the chance of skin abrasion which contributes to the overall reaction. This leads to the prolongation of the life of the intact keratinized surface which in turn may increase the chance that the underlying stem cell pool would regenerate adequately to reduce the likelihood of moist desquamation. Also the maintenance of the intact skin surface would assist in maintaining both moisture levels and providing a scaffold for the migration/repair of the damaged skin cells and maximize the efficiency of the repair processes (99,100). Barrier skin films have been compared to other prophylactic agents in a few randomised clinical trials and have shown benefit in the reduction of acute radiation induced skin injury compared to standard skin practices (100,101). They have also been compared with other topical agents such as sorbolene cream (99). Therefore, there is a paucity of data for barrier skin films compared to the umpteen number of clinical trials that have investigated the role of corticosteroids in the prevention of acute radiation induced skin reactions. Moreover, there has been limited evidence comparing barrier skin film to topical corticosteroid therapy for the prophylaxis of acute radiation induced skin reactions in breast cancer women undergoing adjuvant

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radiation therapy. Only Shaw et al. has reported outcomes based on a clinical trial comparing 3M Cavilon No-Sting Barrier Film vs topical corticosteroid (mometasone furoate) for the protection of radiation dermatitis. He reported that patients treated with barrier skin film experienced a delayed occurrence of pruritis when compared to the corticosteroid arm although statistically insignificant. Hence, they concluded that 3M barrier skin film may be helpful against dermatitis associated pruritis. In their study, corticosteroids delayed the onset of grade 2 dermatitis and severe radiation dermatitis (102).

In our department, barrier skin film for the prophylaxis of acute radiation skin toxicity in breast cancer women undergoing adjuvant radiation therapy was started in 2015 replacing standard skin care practices at the time. It was observed that the incidence of grade 2 and grade 3 radiation dermatitis had come down significantly as compared to previous practices. There was also a subjective improvement in patient quality of life and compliance with barrier skin film. Points in favour of the barrier skin film were

1. Easy and simple application – can be done by the patient care provider itself 2. Good compliance – twice a week dosing and once per day was sufficient 3. Non-medicated and potentially no side-effects to the treatment

Hence, we decided to uptake a study comparing the efficacy of the barrier skin film (3M Cavilon) to topical corticosteroids (Mometasone furoate) in the prevention of acute radiation induced skin toxicity.

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6. MATERIALS AND METHODS

6.1 Study Design:

This study is a Non-blinded Phase III Intra-Individual Randomised Controlled Clinical Trial aimed to compare the efficacy of Barrier Skin Film (3M Cavilon) vs Steroid Cream (Mometasone furoate). This study was approved by the Institutional Review Board prior to the initiation of recruitment.

6.2 Inclusion Criteria:

1. Ages 18 to 70 years

2. Histologically confirmed diagnosis of invasive breast cancer or DCIS.

3. Receiving radiotherapy to chest wall with conventional or conformal radiotherapy techniques – (treatment of regional nodes permitted)

4. No pre-existing skin breakdown within the planned radiotherapy field at the time of study.

6.3 Exclusion Criteria:

1. Patients not consenting for the study

2. Hypersensitivity to mometasone furoate or skin film 3. Inflammatory carcinoma of the breast

4. Bilateral breast carcinoma

5. Patients receiving leukotriene inhibitors

6. Receiving over the counter steroid preparations

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6.4 Sample size:

A sample of 88 subjects will be required to obtain a difference of 18% between patients treated with mometasone furoate cream and patients treated with barrier film treatments considering the grade 2 dermatitis as outcome. The 18% difference was assumed because the literature reported the same difference among the two groups in grade 3 dermatitis.

(Shaw S-Z, Nien H-H, Wu C-J, Lui LT, Su J-F, Lang C-H. 3M Cavilon No-Sting Barrier Film or topical corticosteroid (mometasone furoate) for protection against radiation dermatitis: A clinical trial. Journal of the Formosan Medical Association. 2015 May;114(5):407–14.), with 80% power and 5% significance level. In view of attrition, it was decided to recruit 90 patients.

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6.5 Patients:

Between April 2018 and June 2019, a total of 138 patients were screened, of which 90 patients were recruited for the study. The last patient was recruited on 4^th of June, 2019.

Of the 90 patients recruited, 2 patients were non-compliant to the trial protocol and hence were excluded, 1 patient withdrew due to personal reasons and 1 patient developed allergy with the steroid cream and hence was removed from the trail. Therefore, there were a total of 86 patients that were available for analysis.

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6.6 CONSORT Diagram:

Enrolment

Allocation

Assessed for eligibility (n=138)

Randomised (n=90)

Excluded (n=48)

• Not meeting inclusion criteria – 30

• Refused to participate – 18

Steroid Cream – MMF (n=90) (Mometasone furoate)

Barrier Skin Film – SF (n =90) (3M Cavilon Spray) Consent

Medial = 44 Lateral = 42

Medial = 42 Lateral = 44 Within-Patient

Randomization

Assessment n=86

CTCAE, SKINDEX, RISRAS, STAT, LASA *

*Assessment at baseline, every week until completion of RT,

At completion of RT and 4 weeks after

completion of RT Withdrew from study = 2

Non-compliance = 1 Allery to MMF = 1

DATA ENTRY

Analysis n = 86 End of Treatment n=86

4 Week Follow up n=86

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6.7 Intervention Details:

Patients diagnosed to have biopsy proven carcinoma of the breast who have completed radical mastectomy were included in this study. These patients underwent adjuvant radiation therapy to the chest wall and supraclavicular fields primarily, however some of them also had the axillary and internal mammary chain treated as per the post- operative histology and surgery. They were all given both treatment modalities steroid cream (MMF - mometasone furoate) or barrier skin film (BSF - 3M Cavilon) to apply to the affected chest wall on either the medial or lateral half starting from the first 1-3 days of treatment (patients were randomized to which side they would receive what intervention - for medial and lateral). Medial and lateral were divided based on the mid clavicular line.

Left Chest Wall Right Chest Wall

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MEDIAL LATERAL

LATERAL MEDIAL

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6.8 Steroid cream (MMF - Mometasone furoate):

Mometasone furoate cream will be applied to the appropriate half of treated chest wall following the FTU (Fingertip Unit) and 4 hours before or after radiation therapy once daily during and until the end of radiation therapy.

Fingertip unit – FTU for cream application for steroids - mometasone furoate - 2 FTU for unilateral chest wall (103)

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6.9 Barrier Skin Film (BSF – 3M Cavilon):

For the barrier skin film, the area of skin to be applied must be clean and dry. The spray should be held at about 10-15cm away from the skin. To spray a smooth, even coating in a sweeping motion over the whole application area. To allow the area to dry for 30 seconds (98).

Barrier skin film will be used once every three days applied to chest wall to cover the appropriate half of treated chest wall until the end of radiation therapy.

6.10 Data Collection:

Assessment was done once at baseline, once every week until completion of radiation therapy, once at completion of radiation therapy and once after 4 weeks from completion of radiation therapy. The data collected were then analysed using the following tools.

6.11 Tools used for Analysis:

1.

Visual Analog Scale - VAS for pain

2.

CTCAE v4.03 Radiation Dermatitis Score – Common Terminology Criteria for Adverse Events

3.

RISRAS – Radiation Induced Skin Reaction Assessment Score

4.

STAT – Skin Toxicity Assessment Tool

5.

SKINDEX 16

6.

LASA – Linear Analog Scale Assessment

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The final RISRAS scores were calculated by totalling the RISRAS score each week up till 4 weeks follow up and divided by the number of assessments. Lesser scores meaning lesser skin toxicity and higher scores meaning higher skin toxicity. The RISRAS score has two domains, one is the patient symptom scale that includes tenderness and discomfort, itching, burning and activities of daily living affected and the healthcare professional assessment scale.

In the STAT Score, only the patient reported discomfort were taken for analysis as the provider assessed objective measure of skin changes were assessed by the CTCAE score.

Here as well, the score in each week was added up and divided by the number of assessments for the final score. Lower scores indicating lesser discomfort compared to higher scores indicating more discomfort.

SKINDEX 16 score is a score used for the measurement of skin related quality of life which has 16 items divided into Symptom score, Emotional score and functional score.

The total scores each week were taken and added up and divided by the total number of assessments for the final score. Lower scores indicate better skin associated quality of life and higher scores indicate poorer skin associated quality of life.

LASA is a global quality of life questionnaire that looks at the overall quality of life of patients undergoing adjuvant radiation therapy for carcinoma breast. The scores for each week were recorded and added up and divided by the number of assessments for the total score. Higher scores indicate a better global quality of life compared to a lower score.

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6.12 Statistical tools:

Data entry was done using EpiData v3.1 and statistical analysis were done using SPSS v23 (IBM, Chicago, IL). Categorical variables were summarised using counts and percentages. Quantitative variables were summarised using mean and standard deviation or median and IQR. Wilcoxon signed rank tests and chi-square tests were used to compare the proportions between the groups as the two treatments were applied on same individual and paired sample t tests were used to compare means between the two treatment arms as the variable is continuous.

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7. RESULTS:

7.1 Demographics:

Of the 90 patients recruited to the trial, 2 patients were non-compliant to the trial protocol and hence were removed, 1 patient withdrew due to personal reasons and 1 patient developed allergy with the steroid cream and hence was removed from the trail.

Therefore, there were a total of 86 patients that were available for analysis (n=86). The median age of the recruited patients were 49 years (Range 26 – 74).

Figure 13: Age Distribution Histogram

n = 86

“ BARRIER SKIN FILM VS. STEROID CREAM PROPHYLAXIS FOR PREVENTION OF RADIATION DERMATITIS IN BREAST CANCER WOMEN UNDERGOING ADJUVANT RADIATION