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RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES
BANGALORE, KARNATAKA
SYNOPSIS OF DISSERTATION
COMPARATIVE STUDY OF HYPO FRACTIONATED
RADIOTHERAPY V/S CONVENTIONAL
RADIOTHERAPY IN CARCINOMA BREAST
1. / NAME OF THE CANDIDATE / DR.SAJANA K.T2. / ADDRESS FOR CORRESPONDENCE / KIDWAI MEMORIAL INSTITUTE OF ONCOLOGY
M.H MARIGOWDA ROAD
BANGALORE-560029
3. / PERMANENT ADDRESS / DR.SAJANA K.T
MELROSE HOUSE,SOUTH PRABHODINI
KADALUNDI POST
CALICUT(DST)
KERALA
4. / NAME OF THE INSTITUTION / KIDWAI MEMORIAL INSTITUTE OF ONCOLOGY
5. / COURSE OF THE STUDY AND SUBJECT / M.D. RADIOTHERAPY
6. / DATE OF ADMISSION TO THE COURSE / 27th MAY 2013
7. / TITLE OF THE STUDY / COMPARATIVE STUDY OF HYPOFRACTIONATED RADIOTHERAPY V/S CONVENTIONAL RADIOTHERAPY IN CARCINOMA BREAST
8. Brief resume of intended work
8.1 Introduction and need for the study
Radiotherapy (RT) reduces the risk of local relapse and mortality in carcinoma breast and is offered to nearly all patients after conservative surgery and to selected patients after mastectomy(1). The international standard RT regimen after breast conservative surgery for early breast cancer delivers 25 daily fractions of 2 Gy to a total dose of 50 Gy in 25 fraction followed by 10 gy in 5 fractions as a boost to the tumour bed . The increased number of women with breast cancer, receiving postoperative RT, led to thought that a shorter course of irradiation would result in improved quality of life.
These studies seem to offer rates of late adverse effects and local-regional tumour relapse at least as favourable as the standard schedule.
The aim of the present study to assess acute and chronic toxicity of hypofractionated radiotherapy after breast conservative surgery and post mastectomy using a regimen of 40 Gy in 15 fractions of 2•67 Gy in 3 weeks(40 gy/15# at 2.67 gy/1# in 3 wks) with a control group of 50 Gy in 25 fractions of 2•0 Gy over 5 weeks. The problem with five to six and a half weeks of once daily radiotherapy is the burden of cost, emotional distress, and fatigue to patients undergoing prolonged daily treatment. The women undergoing the hypofractionated regimen reported less anxiety, less transient weight change, and less depression compared to the conventional fractionated group. both breast cancer and dose-limiting normal tissue responded similarly to change in radiotherapy fraction size, suggesting a potential benefit for patients receiving larger doses per fraction(10).
Healthy breast tissue is sensitive to radiation fraction size, such that small changes in fraction size can lead to larger changes in radiation effects on these tissues [11]. Conventional breast and/or chest wall irradiation uses 2 Gys daily fractions, for 5-6 weeks. Such a long treatment schedule has major implications on both patient quality of
life and RT departments (12,13)
Obtaining conformed doses around the target has been a double edged sword where in the volume of unintended normal tissue irradiation increases, resulting in increased dose to contralateral breast, heart and lungs. Pneumonitis, cardiac toxicities, arm lymph oedema, neuropathy, skin damage and rib fractures are examples of wide range of complications that have been associated with radiotherapy to the breast(9) .hence the need for the study.
8.2 Review of literature
Five-year tumor control actually improved by as much as 1.7% with a total radiation dose of 40 Gy administered in 15 fractions versus the standard 50 Gy in 25 fractions, John Yarnold, M.D., of the Royal Marsden Hospital, and colleagues in the START trials, reported March 19 in The Lancet and Lancet Oncology.(3)In the another study reported by the trialists, total radiation doses of 41.6 Gy and 39 Gy delivered in 13 fractions resulted in five-year tumor control rates that differed from the conventional regimen by less than 1%.(6)
Photographic and patient self-assessments suggested the 40-Gy dose and the 39-Gy dose reduced late adverse effects compared with 50 Gy.The data are consistent with the hypothesis that breast cancer and the dose-limiting normal tissues respond similarly to changes in radiotherapy fraction size.
The most widely used schedule of adjuvant radiation therapy for localized breast cancer is 50 Gy administered in 25 fractions of 2.0 Gy over five weeks. This schedule evolved from the assumption that delivery of a high total dose of radiation in small fractions minimizes damage to normal tissue and maximizes tumor control, the researchers said.
Initial studies of hypofractionated radiation therapy supported the conventional approach, as rates of damage to normal tissue with fewer but larger fractions were unacceptable. However, they noted, the total radiation dose was not reduced in those early trials.
Healthy breast tissue is sensitive to radiation fraction size, such that small changes in fraction size can lead to disproportionately larger changes in radiation effects on these tissues.Some investigators have hypothesized that breast cancer is as sensitive as normal breast tissue to fraction size.(11)According to the hypothesis, small fraction sizes of 2.0 Gy or less offer no therapeutic advantage, and in fact, a more effective strategy would be to deliver fewer, larger fractions that result in a lower total radiation dose.
Dr. Yarnold and colleagues tested the hypothesis in two large randomized clinical trials, the Standardization of Breast Radiotherapy Trials (START). The first trial involved 2,236 women requiring adjuvant radiation therapy after breast-conserving surgery for early-stage breast cancer.(3)
The patients were randomized to a 50-Gy total dose of radiation in 25 fractions over five weeks or to 41.6 Gy or 39 Gy in 13 fractions of 3.2 Gy or 3.0 Gy, respectively, also administered over five weeks.After a median follow-up of 5.1 years, the five-year rate of locoregional relapse was 3.6% with the conventional radiation regimen, 3.5% with the 41.6-Gy hypofractionated regimen, and 5.2% with 39 Gy in 13 fractions.(6)
The estimated five-year absolute differences were 0.2% for 41.6 Gy and 0.9% for 39 Gy compared with 50 Gy.Similarly, all-cause mortality did not differ among the three groups, ranging from 11.2% with 50 Gy to 11.9% with 41.6 Gy.
In the second trial, investigators randomized 2,215 patients with early breast cancer to conventional radiation therapy or to a total dose of 40 Gy administered in 15 fractions.
After a median follow-up of six years, the five-year rate of locoregional relapse was 2.2% with the 40-Gy regimen versus 3.3% with the 50-Gy regimen.(7).The relapse rates translated into an absolute difference of 0.7% in favor of the 40-Gy regimen. The 95% confidence intervals suggested the advantage could be as much as 1.7% better than the conventional regimen or no more than 0.9% worse.(3)
8.3 Objectives of the study
1.PRIMARY OBJECTIVE- -To assess the acute and chronic toxicity in hypofractionated radiotherapy.
2.SECONDARY OBJECTIVE-Comparing outcome of conventional and hypofractionated radiotherapy in post mastectomy and BCS in carcinoma breast.
9. Materials and Methods
9.1 Source of data
Data will be collected from about 40 patients registered in the Dept of Radiotherapy , Kidwai Memorial Institute of Oncology, Bangalore-560029.
9.2 Method of collection of data
The data will be collected and documented in the following manner-
Source file, case report form, quality of life form tabulated in MS excel sheet.
Sample size
Minimum of 40patients will be registered for the study with 20 patients in each arm.
9.3 Method
Histologically proven carcinoma breast, post mastectomy or conservative breast surgery patients are chosen and enrolled in the study after obtaining an informed consent.
Arm A: (50 Gy/25 fr/5 wk + electron boost 16Gy/8 Fr + interstitial implant) n=20
Arm B: (40 Gy/15 Fr/3 wk + boost 16Gy/8 Fr + interstitial implant) n=20
Patients will be simulated and planned for 2D PLAN.
Patients will undergo baseline cardiac evaluation, pulmonary function tests and CT scan thorax before radiotherapy, end of RT and 3 months after radiotherapy
They will be assessed for acute and subacute toxicities by clinical examination and questionnaire using radiation therapy oncology group (RTOG), common toxicity criteria (CTC) for toxicities and European organization for research and treatment of cancer (EORTC) questionnaire for quality of life (QOL).
9.4 Inclusion criteria
1. Histologically proven carcinoma breast cases.
2. All stages, postoperative
3. Age- 18-75 yrs.
4. Karnofsky performance scale- >70
5. Hemogram- within normal limits.
6. Biochemistry parameters- within normal limits.
7. Hiv/HBsAg- negative
8. Chest x ray- normal
9. Controlled hypertension and diabetes mellitus
9.5 Exclusion criteria
1. Advanced stages of ca breast
2. Palliative radiotherapy
3. Age >75yrs
4. Karnofsky performance scale- <70
5. Uncontrolled hypertension and diabetes mellitus
6. Distant metastasis
7. Coexisting heart disease and chronic pulmonary disorders.
9.6 Investigations
1. Baseline hemogram (haemoglobin, total count, differential count, platelets, erythrocyte sedimentation rate)
2. Biochemistry evaluation- random blood sugar, renal function test, liver function test, electrolytes.
3. Chest x ray
4. Ultrasound abdomen
5. HIV/HBsAg
6. CT scan/ simulation X ray for radiotherapy as indicated.
Special investigations-
For assessment of cardiac toxicities-
1. Electrocardiogram
2. Echocardiography
3. Cardiac troponin T
4. Cardiac enzymes
5. MUGA
For assessment of pulmonary toxicities-
1. Chest x ray
2. Pulmonary function test using spirometry
3. CT scan thorax at 3 months to evaluate pneumonitis.
9.7 METHODOLOGY
After obtaining written informed consent, patients will be randomized to control arm A of conventional radiotherapy (CR),and experimental arm B of hypofractionated radiotherapy.(HF)
In the control arm A, a dose of 50 Gy will be delivered in 25 fractions over 5 weeks to the chest wall (MA) or the whole breast (BCS) by 6 MV photons tangential wedged fields and to the supraclavicular, infraclavicular and axillary nodes in case of pN1 status, using an anterior 6 MV photons half-beam matched to the superior border of the tangential fields. The field borders are set clinically. Breast conserved patients will received an additional electron boost of 16 Gy in 8 fractions to the initial tumor bed using a direct electron field or interstitial implant. No dose constraints for lung and heart are defined in the conventional arm, but the perpendicular distance from the chest wall to the posterior field edge preferably included no more than 2 cm of lung at any point along the length of the tangent. This lung distance is not to exceed 3 cm. For left-sided breast radiotherapy, the maximum heart distance is not to exceed 1.5 cm. The boost volume is given taking into account the preoperative imaging (mammography and CT) and post-operative changes (scar, seroma) seen on the planning-CT. Total dose of 40 Gy in 15 factions over 3 weeks is prescribed to the same target volumes as the conventional arm: chest wall in case of mastectomy or whole breast in case of breast conservative surgery( BCS), and to the supraclavicular, infraclavicular and axillary nodes in case of PN+ status.
Pulmonary and heart function, arm mobility and arm lymphedema will be assessed prior to radiotherapy, 3 and 6 months after completion of radiotherapy. Heart function was assessed by measuring the left ventricular ejection fraction (LVEF) by echocardiography. Pulmonary function tests assessed forced expiratory volume in one second (FEV1). Heart and lung toxicity scoring was based on the common terminology criteria of adverse events (RTOG). Scoring of breast/chest wall skin and subcutaneous toxicity used the Radiation Therapy Oncology Group (RTOG) acute (up to 1 month post radiotherapy) and chronic morbidity scoring schemas .Scoring of arm lymphedema used the SOMA/LENT toxicity scale.
9.8 statistical analysis
The association between categorical variable will be done using chi square test, a p value of <0.05 will be considered as statistically significant.
9.9Does the study require any investigations or interventions to be conducted on patients or other human beings or animals?
YES
9.10Ethical clearance and scientific review board clearance –YES
10.References
1. Letizia Deantonio, Giuseppina Gambaro, Debora Beldi.Hypofraetionated radiotherapy after conservative surgery for breast cancer: analysis of acute and late toxicity.Deantonio et al.radiation oncology 2010,5:112
2. Van parjis, Geertje Miedema , Vincent Vinh-Hung1, Sylvia Verbanck, Nele Adriaenssens^, Dirk Kerkhove , Truus Reynders. Short course radiotherapy with simultaneous integrated boost for stage I-II breast cancer, early toxieities of a randomized clinical trial. Van Parijs et al. Radiation Oncology 2012, 7:80.
3. Joanne S Haviland MSc a c, J Roger Owen FRCR d, Prof John A Dewar FRCR e. The UK Standardisation of Breast Radiotherapy (START) trials of radiotherapy hypofractionation for treatment of early breast cancer: 10-year follow-up results of two randomised controlled trials.. The Lancet Oncology.october 2013;14(11):1086-1094
4. a Daniela Falco,؛no, Mar؛st؛Cr ؛a Barbarino, Sara Cicchetti, Daniela d؛Murro, Rosar ؛Grazia Totorelli.Standard or hypofractionated radiotherapy in the postoperative treatment of breast cancer: a retrospective analysis of acute skin toxicity and dose inhomogeneities. Tortorelli et a).BMC cancer 2013 13:230.
5. Dorn PL, Corbin KS, Al-HAllaq H, Hasan Y, Chmura SJ: Feasibility and acute toxicity of hypofractionated radiation in large-breasted patients. int j
Radiat Oncol Biol Phys 2012 May 1, 83(1):79-83
6. Bentzen SM, Agrawal RK, Aird EG, Barrett JM, Barrett-Lee PJ, Bliss JM, Brown j, Dewar JA, Dobbs HJ, Haviland JS, Hoskin PJ, Hopwood P, Lawton PA, Magee BJ, Mills j, Morgan DA, Owen JR, Simmons S, Sumo G, Sydenham MA, Venables K, Yarnold JR: The UK Standardization of Breast Radiotherapy (START) trial A of radiotherapy hypofractionation for treatment of early breast cancer: A randomised trial. Lancet Oncol 2008;9:331 -341.
7.Bentzen SM, Agrawal RK, Aird EG, Barrett JM, Barrett-Lee PJ, Bliss JM, Brown j, Dewar JA, Dobbs HJ, Haviland JS, Hoskin PJ, Hopwood P, Lawton PA, Magee BJ, Mills J, Morgan DA, Owen JR, Simmons S, Sumo G, Sydenham MA, Venables K, Yarnold JR: The UK Standardisation of Breast Radiotherapy (START) trial B of radiotherapy hypofractionation for treatment of early breast cancer: A randomised trial. Lancet 2008, 371:1098-1107
8.Whelan TJ, Pignol JP, Levine MN, Julian JA, MacKenzie R, Parpia S, Shelley W, Grimard L, Bowen j, Lukka H, Perera F, Fyles A, Schneider K, Gulavita S, Freeman C: Long-term results of hypofractionated radiation therapy for breast cancer. N England j Med 2013;362:513-520.
9. M Koshy, Md, B Zhang, Cmd, S Naqvi, Phd, B Liu, Phd And Mm Moiuddin, Md The problem with five to six and a half weeks of once daily radiotherapy is the burden of cost, emotional distress, and fatigue to patients undergoing prolonged daily treatment. The women undergoing the HF regimen reported less anxiety.. A Novel Technique For Post-Mastectomy Breast Irradiation Utilizing Non-Coplanar Intensity-Modulated Radiation Therapy. The British Journal Of Radiology, Doi:10.1259/Bjr/59469015.