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Academic Year 2015 - 2017 Evaluation of the acute side effects of accelerated radiotherapy in elderly women (>65 years) with breast cancer Dieter NAUDTS Promotor: Liv Veldeman Mentor: Chris Monten Dissertation presented in the 2 nd Master year in the programme of MASTER OF MEDICINE IN MEDICINE

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Academic Year 2015 - 2017

Evaluation of the acute side effects of accelerated

radiotherapy in elderly women (>65 years) with

breast cancer

Dieter NAUDTS

Promotor: Liv Veldeman

Mentor: Chris Monten

Dissertation presented in the 2nd Master year in the programme of

MASTER OF MEDICINE IN MEDICINE

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Acknowledgements

First of all, I would like to thank my promotor, Dr. Liv Veldeman, for giving me the

opportunity to perform this research and to assist me in completing this master’s thesis.

Secondly, many thanks to my mentor, Dr. Monten, for the huge amount of support during the

matching and writing, and for helping me understand several aspects of radiotherapy, which

was definitely necessary to finish this thesis.

Lastly, I would like to thank my girlfriend, my parents and my sister, who kept supporting me

and kept believing in a good outcome, even though sometimes it appeared I was biting off

more than I could chew.

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Table of Contents

Abstract (English) .................................................................................................................................. 1

Abstract (Dutch) ..................................................................................................................................... 2

Introduction ............................................................................................................................................ 3

Breast cancer: prevalence ..................................................................................................................... 3

Risk factors ........................................................................................................................................... 3

Prognosis .............................................................................................................................................. 4

Treatment ............................................................................................................................................. 5

Radiotherapy ........................................................................................................................................ 7

Hypofractionation ................................................................................................................................. 8

Highly Accelerated Irradiation in 5 fractions (HAI-5) ........................................................................ 9

Materials and Methods ........................................................................................................................ 11

Patient selection ..................................................................................................................................... 11

Matching ................................................................................................................................................ 12

Target volumes and doses ...................................................................................................................... 12

Treatment schedule ................................................................................................................................ 14

Planning parameters and treatment techniques ...................................................................................... 14

Assessment of toxicity ........................................................................................................................... 14

Statistics ................................................................................................................................................. 16

Results ................................................................................................................................................... 17

Patient selection ..................................................................................................................................... 17

Paitent and treatment characteristics ...................................................................................................... 18

Acute toxicity ......................................................................................................................................... 21

Treatment schedules ............................................................................................................................... 25

Discussion .............................................................................................................................................. 26

References ............................................................................................................................................. 29

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Abstract (English)

Introduction: Breast cancer is the most prevalent cancer in women. More than 50% of breast

cancers occurs in women aged 65 years or more. Although there are very successful treatment

methods, resulting in an excellent prognosis, many elderly women are under-treated.

Especially the omission of radiotherapy has a negative impact on local control and overall

survival. A possible solution for this under-treatment, often partly due to logistical problems

in the elderly, is an accelerated radiotherapy schedule with higher doses, administered in

fewer fractions. A key condition is that the schedule is associated with acceptable toxicity.

Materials and Methods: A matched case analysis was performed, comparing the acute skin

toxicity (dermatitis) between the accelerated schedule (5 x 5,7 Gy) and the current standard,

hypofractionation (15 x 2,67 Gy). The primary endpoint was the difference of the incidence of

clinically relevant dermatitis (≥ grade 2) between both groups.

Results: Accelerated radiotherapy resulted in significantly less clinically relevant acute skin

toxicity than hypofractionation (16,9% versus 52,5%, P < 0,001). Significant differences were

also found for desquamation (P = 0,001), oedema (P = 0,001) and pruritus (P = 0,042). In the

mastectomy-group, no clinically relevant toxicity was reported.

Discussion: Given the findings, highly accelerated irradiation in 5 fractions seems to be a

feasible alternative for the current standard schedule. However, acceleration should be limited

to clinical research until long-term follow up comes available.

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Abstract (Dutch)

Introduction: Borstkanker is de meest voorkomende kanker bij vrouwen. Meer dan 50% van

de borstkankers komen voor bij vrouwen ouder da 65 jaar. Hoewel er zeer succesvolle

behandelingswijzen bestaan, met een uitstekende prognose tot gevolg, worden veel oudere

vrouwen onderbehandeld. Vooral het weglaten van radiotherapie heeft een negatief effect op

de lokale controle en de overlevingskansen. Een mogelijke oplossing voor deze

onderbehandeling, vaak mede een gevolg van logistieke problemen bij ouderen, is een

versneld bestralingsschema met hogere dosissen, toegediend in minder fracties. Een

belangrijke voorwaarde hiervoor is wel dat het schema gepaard gaat met aanvaardbare

toxiciteit.

Materialen en methoden: Alle patiënten die het versnelde schema (5 x 5,7 Gy) volgden

werden gematcht met een patient die het hypofractionatie-schema (15 x 2,67 Gy) volgde.

Acute huidtoxiciteit werd vergeleken tussen beide groepen. Het primaire eindpunt was het

verschil in voorkomen van klinisch relevante dermatitis (≥ graad 2) tussen beide groepen.

Resultaten: Versnelde bestraling resulteerde in significant minder klinisch relevante acute

huidtoxiciteit dan hypofractionatie (16,9% tegenover 52,5%, P < 0,001). Er werden ook

significante verschillen gevonden op vlak van desquamatie (P = 0,001), oedeem (P = 0,001)

en jeuk (P = 0,042). In de mastectomie-groep werd geen klinisch relevante acute toxiciteit

gerapporteerd.

Discussie: Gezien de bevindingen lijkt verder versnelde bestraling in 5 fracties een haalbaar

alternatief voor het huidige standaardschema. Versnelde bestraling moet echter beperkt

blijven tot klinisch onderzoek tot langdurige follow-up beschikbaar komt.

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Introduction

Breast Cancer: Prevalence

Breast cancer is the most prevalent cancer and the leading cause of cancer mortality in women

worldwide. Specifically for Belgium, there were 10 695 new cases of breast cancer in 2013,

with a clear peak between the ages of 65 and 70 (1). More than 50% of breast cancer occurs in

women aged 65 years or more. In Belgium, 54,6% of all breast cancer patients are aged over

65 (1). Although the International Society of Geriatric Oncology recommends to treat patients

above 70 years according to standard guidelines (except in case of significant co-morbidity or

low functional status) (2), surveys clearly demonstrate lower uptake of radiotherapy,

hormonal therapy and chemotherapy once the age of 70 is reached and even more so above

the age of 80 (3).

Even though advanced age is associated with lower stage and more favorable prognostic

outcomes (due to ER- and PR-receptor status), cancer specific mortality is higher in elderly

patients, indicating a lack of adequate treatment (3,4).

The reasons for this under-treatment in elderly patients with breast cancer are diverse,

including comorbidity, physician and patient bias, views of relatives and caregivers,

psychosocial issues, cost and proximity to the radiotherapy center and limited life expectancy

(5–7).

The use of radiotherapy as well as hormonal therapy and chemotherapy declines with age (3),

but the largest effect on disease-free survival and overall survival is seen by the omission of

radiotherapy (8).

Risk factors

Earlier studies have identified a number of risk factors for breast cancer. These risk factors

can be divided into two categories: inherent and extrinsic factors. Inherent factors are not

modifiable and are in no way dependent of an individual lifestyle. On the contrary, extrinsic

factors may be modified by a person’s way of life, at least to a certain extent (9).

As for the first category, the most important factors are age, race, familial susceptibility to

breast cancer, the time of first menstruation and the occurrence of proliferative lesions of

benign character in the mammary glands (10–12).

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As for the second category, the factor with the largest influence on the occurrence of breast

cancer is obesity, resulting in a twofold increase in the risk of breast cancer in

postmenopausal women, whereas among premenopausal women it is associated with a

reduced incidence (13). Both in premenopausal and in postmenopausal women, physical

activity and the consumption of fruit and vegetables have proven to significantly reduce the

risk of developing breast cancer during one’s lifespan (9). Breastfeeding has also proven to be

inversely associated with risk of breast cancer (14), as well as an early first pregnancy (< 30

years) and multiparity (15, 16).

Other important modifiable risk factors are smoking and excessive drinking of alcohol, both

resulting in a slightly higher risk of breast cancer (17).

Prognosis

The prognosis of every kind of neoplasm depends mainly on disease stage, size of the tumour,

presence of metastasis and the type of treatment. Breast cancer is one of the cancers in women

with the best survival rates. Women with breast cancer have a relatively high chance of

survival, with an average 5-year survival of more than 80%, over all the stadia. The 5-year

survival per stadium ranges from 98% for stage I to 16% for stage IV (18).

Table 1: 5-year breast cancer survival rates per stage

Many breast cancers are detected early, especially since the introduction of mammographic

screening. Treatment, including surgery and adjuvant radiotherapy, chemotherapy, targeted

therapy and hormonal therapy is very successful.

Stadium 0 100%

Stadium I 98%

Stadium IIA 88%

Stadium IIB 76%

Stadium IIIA 56%

Stadium IIIB 49%

Stadium IV 16%

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Treatment

For the treatment of breast cancer, there are several possibilities, including 5 standard

treatments (surgery, radiotherapy, chemotherapy, hormone therapy, targeted therapy). Since

the publication of the Azure trial in 2014 and the ABSCG-12 trials, zoledronic acid in post-

menopauzal patients has been added (19,20).

The first type of standard treatment is breast surgery. Most patients with breast cancer have

their cancer surgically removed. There are 2 possibilities: either mastectomy (ME, the whole

breast, including the tumour, is removed) or breast-conserving surgery (BCS, only the tumour

is removed, along with a part of the surrounding healthy tissue – depending on the volume of

the tissue removed, these interventions are referred to as tumourectomy, lumpectomy,

segmentectomy or quadrantectomy). BCS is less invasive and results in a shorter recovery

period. Multiple studies have shown that BCS is as effective as total ME, with similar

survival rates (21). A slightly higher recurrence rate compared to ME is compensated for by

adding radiotherapy (21–24). When invasive tumour is suspected, the lymph nodes are

removed. Since the introduction of the sentinel procedure, total lymphadenectomy can be

avoided in case clinical staging for lymph nodes is negative. This evolution reduced the risk

for lymphedema, the most important risk of lymphadenectomy. Studies are further exploring

the need for lymphadenectomy or axillary radiotherapy in case of clinically negative staging

for lymph nodes positive sentinel (25).

Chemotherapy is a systemic treatment with cytotoxic agents that stop the growth of cancer

cells, either by killing them or by keeping them from dividing. Chemotoxic agents are usually

administered intravenously.

Treatment with chemotherapy in breast cancer is reserved for selected patients with a high

risk at recurrence. As regards elderly patients, chemotherapy is recommended in patients with

oestrogen-negative tumours (2). In patients with low co-morbidity and good functional

performance score, cytotoxic drugs are relatively well tolerated and they result in a prolonged

survival (26). If advisable, the more aggressive chemotherapy (epirubicine – cyclofosfamide

followed by paclitaxel) can be substituted by less aggressive treatments (docetaxel and

cyclofosfamide) (27).

In case of large tumours, anticipation of involved margins or in case of mastitis

carcinomatosa, chemotherapy can be used in a neo-adjuvant setting, before surgery. In some

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cases, reduction of the tumour volume can be obtained, thus permitting BCS instead of ME.

In case of mastitis carcinomatosa, neo-adjuvant treatment is always followed by ME with

lymphadenectomy. Apart from shrinking the tumour, neo-adjuvant treatment can destroy

potentially circulating tumour cells and decrease the risk of metastatic cells. Another

advantage is the possibility to evaluate the response of the tumour to the chemotherapy (27).

Hormone therapy is used in case of hormone sensitive breast cancer. It stops the cancer from

growing by removing hormones or blocking their action. These products can be subdivided in

two main groups: : tamoxifen and aromatase inhibitors. Whereas tamoxifen is a selective

estrogen receptor modulator, aromatase inhibitors (non-steroidal: letrozole, anastrozole;

steroidal: exemestane) block the aromatase enzyme that converts androgens into estrogens.

Aromatase inhibitors have proven to be superior in postmenopausal women (27–29).

Targeted therapy specifically attacks cancer cells without harming other cells, by targeting

molecules needed for carcinogenesis and tumour growth, like growth factors and their

receptors. The growth of a tumour cell, sensitive for that molecule, is then delayed (30). As

regards the elderly, the use of trastuzumab should be considered as a standard of care in the

adjuvant therapy of elderly patients with HER-2 positive breast cancer (31).

A relatively new kind of treatment is zoledronic acid. It slows down the bone resorption and

was therefore already used in diseases like osteoporosis. It is also used to prevent

complications of bone metastasis in metastatic cancer. Recently, it has been introduced as

adjuvant therapy in the treatment of breast cancer because of its role in reducing bone

metastasis and improving mortality in postmenopausal patients with breast cancer. The

application of Zoledronic acid is considered safe and has several secondary benefits, such as

improving bone mineral density on adjuvant endocrine therapy and reducing fractures (19,20).

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Radiotherapy

Finally, radiotherapy is one of the standard treatments in breast cancer and also the subject of

our study. Radiotherapy uses high-energy X-rays or other types of radiation to kill cancer

cells or to stop them from growing. Multiple studies have shown that, in early breast cancer,

adding radiotherapy to BCS results in a substantial reduction of ipsilateral recurrence (19%),

which translates in a lower risk of breast cancer related mortality (5%) and a better overall

survival (32). It has also been proven to offers clear benefits in terms of local recurrence and

breast cancer mortality in women with positive lymph nodes after ME (33).

However, a slight drawback of this kind of treatment is the acute and long-term radiation

toxicity for nearby organ. In the acute phase, the breast and skin can react with inflammation,

causing erythema, desquamation, oedema and irritation (pain, pruritus). Long-term toxicity of

the breast may consist of volume changes, breast deformation and color changes. Organs at

risk (OAR) for long-term damage are the heart, the lungs, the contralateral breast and the ribs

(34).When the adjacent lymph nodes are being irradiated, the risk of lymphedema increases

and radiation induced brachial plexitis (RIBP) has been described (35). Also, a higher

incidence of second cancers of the thyroid gland and the oesophagus were reported after

radiotherapy in lymph node positive breast cancer patients (36).

Through the years, techniques have improved, thus reducing toxicity.

The first one we would like to discuss is Intensity-Modulated Radiotherapy (IMRT). This is a

kind of external radiation therapy (external means that a machine outside the body sends

radiation towards the body) that improves dosimetry. The radiation beam is divided in smaller

beams that vary in intensity depending on the thickness of the breast. This results in a more

homogenous radiation of the breast and subsequently in lower acute and long-term toxicity.

When using multiple IMRT beams that come in through different angles, OAR are more

easily avoided (37–39).

Another way to reduce toxicity after radiotherapy-treatment is adjustment of the patient’s

position during the treatment. Several studies have shown the advantage of prone position

over supine position concerning toxicity for patients receiving breast-only irradiation after

BCS (40,41). Prone position is not only associated with a reduction of dermatitis, but also

with a reduced ipsilateral lung and heart doses (42). For the heart, the advantage of prone

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positioning on heart dose might be absent for women with small breasts, but this problem can

be tackled with deep inspirational breath-holding, thus combining the best of two worlds (43).

Hypofractionation

For many years, normofractionation was the international standard radiotherapy schedule. It

consisted of a total radiation dose of 45-50 Gy in 25 fractions of 1.8-2 Gy over 5 weeks.

However, hypofractionation (HF) schedules of 15-19 fractions have been shown to be as least

as favourable normofractionation (44–47). HF delivers a higher dose per fraction (> 2 Gy) in

a shorter time span (< 5 weeks) but with a lower total cumulative dose. Over the past decades,

and in fact to solve long waiting lists in the anglo-saxon countries, HF schemes have been

tested. Whereas the Canadian schedule consists of 16 fractions, with promising results

concerning local control and radiation morbidity (44), the UK Standardisation of Breast

Radiotherapy (START) trial A and the START trial B found that a schedule of 15 x 2,67 Gy

gave the best results, as well for local control as for toxicity (45,46). Compared to the former

standard, normofractionation, they even showed at least equivalence to a schedule of 50 Gy in

25 fractions as well for local-regional relapse as for late adverse effects at 10 years follow-up.

The study even reported slightly less permanent damage to normal breast tissues and a

slightly better self-assessed quality of life for the patients treated with the HF schedule (45–

47).

Based on these trials, the sensitivity of normal and malignant tissues to fraction size, the so

called α/β values, were re-evaluated. The results were consistent with the hypothesis that

breast cancer and the dose-limiting normal tissues respond similarly to change in radiotherapy

fraction size. Until then, a high α/β of 10 Gy for breast cancer cells was assumed, which

means that they are very sensitive to radiation and that cell kill cannot improve with higher

dose per fraction. On the other hand, since the normal tissues are assumed to have a low

α/β, HF would only cause more collateral tissue damage. However, in the case of similar

α/β of the tumour compared to the critical surrounding normal tissue, HF with a slight

decrease in total dose may be equally or even more effective with comparable side effects

(48). Since several studies have proven this to be the case in breast cancer, HF seems to be a

feasible alternative (44–47,49,50).

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After the publication of the 10-year results of HF, a schedule in 15 or 16 fractions is now

considered the standard fractionation schedule for breast-only radiotherapy after BCS in most

centers around the world, as it combines better outcome with the obvious advantages in terms

of convenience and cost to patients (51,52).

Highly Accelerated Irradiation in 5 fractions (HAI-5)

However, 15-19 radiotherapy sessions might still be a logistic problem for elderly patients,

compromising radiotherapy accessibility and leading to underutilization.

A solution for this problem might be a further accelerated radiation schedule, reducing the

number of sessions to five. In 2005, Ortholan et al. researched the degree of toxicity as well as

the long-term (10 years) efficacy after radiotherapy given in a once-weekly schedule of 5

fractions of 6.5 Gy, resulting in a total dose of 32.5 Gy. The endpoints all appeared favorable:

excellent long-term control, mild early reactions and acceptable late toxicity. Ortholan et al.

therefore proposed this schedule as an alternative for patients having difficulties sustaining

daily treatment due to old age or disabling co-morbidity (53).

In 2010, Yarnold and Haviland tested the effectiveness of a 5-fraction whole breast irradiation

(WBI) schedule in the FAST-trials. Three year toxicity and local control were promising (54)

and a further acceleration has been tested in the FAST FORWARD trial, comparing 5 x 5,4Gy

and 5 x 5,2Gy over 5 consecutive days to the standard 15-fraction schedule. Recently their

results on acute toxicity were reported, showing very low toxicity (55).

Rovea et al. have performed a comparable study, giving a total dose of 30-32.5 Gy in 5

weekly fractions. After investigating local control, disease-free survival, cancer-specific

survival, overall survival, acute and late toxicity and cosmesis, they concluded this schedule

to be feasible and effective for a selected population of with predominantly low-risk features.

More specifically, they suggested it to be a potential alternative for elderly patients, allowing

fragile patients to receive WBI after BCS, hence increasing radiotherapy accessibility and

consequently improving outcome (56).

The primary goal of our study was to validate these earlier studies and to confirm the

possibility of offering a more accessible yet equally effective alternative for WBI, compared

to our current standard, HF. However, as many women present with locally advanced breast

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cancer, with need for a boost, lymph node irradiation (LNI) or thoracic wall irradiation (TWI)

after ME, the indication was extended to all adjuvant radiotherapy indications. If acceleration

of not only WBI but also thoracic wall and lymph node region could be proven safe and

feasible, the threshold for adjuvant radiotherapy in women above the age of 65 years could be

lowered for all indications, and not only the early stages.

Thus, although our study might seem very similar to the UK trials and Rovea, there are some

substantial differences. Firstly, our patients received a 2-week schedule, in contrast to the

previously tested 5- or 1- week schedules. Secondly, we administered a simultaneously

integrated boost (SIB) in tumours with a high recurrence risk. Thirdly, we also included

patients who received LNI as well as patients wo received TWI. Fourthly, we didn’t only

irradiate patients in supine position, but applied prone position whenever possible, even in

this older population. Also, in contrast to the simple tangential fields used in the other trials,

we applied IMRT or if needed Volumetric Modulated Arc Therapy (VMAT), in order to

improve dose homogeneity and to avoid overlap of treatment fields for the patients with LNI.

This was important, because high doses and overlap accidents might lead to RIBP, a

complication described in early experiments of Scandinavian groups on HF (57).

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Materials and Methods

Patient selection

Female patients of age 65 or older, diagnosed with breast cancer and referred for adjuvant

radiotherapy after BCS or ME, were given the opportunity to participate in an observational

study, the HAI-5 (an acronym for Highly Accelerated Irradiation in 5 fractions), approved by

the ethics committee. In contrast to the studies of Rovea et al. and of the FAST trialists (54–

56), women needing LNI were also included.

Need for bilateral irradiation, doubt for compliance or inability to understand trial

participation (language, cognitive problems) were exclusion criteria. Patients needing a boost

after ME were also excluded, as this would bring very high doses to lungs and ribs.

The age limit was chosen for 2 reasons. Firstly, in this age category, the demand for an

accelerated radiotherapy schedule is high due to the above-mentioned logistic problems. The

second reason is one of caution: so far no evidence exists on long-term local control and

chronic breast toxicity with these highly accelerated schedules. A special concern existed for

the eventuality of RIBP in the lymph node group. For this reason, the trial was subdivided in

two strata (one without and one with LNI) and a stopping rule was included in the second

group, inferring closure of the LNI-group in case an EMG-proven RIBP would occur. All

patients signing the informed consent, were accepted for the accelerated 5-fraction schedule.

The HAI-5 is an observational trial, without randomization between treatments. To compare

acute skin toxicity of the 5 fraction schedule with HF, we performed a matched case analysis.

For each patient in the HAI-5, a comparable match was found in patients who had participated

in former studies evaluating HF.

No matches were possible for the 21 HAI-5-patients who had been treated by ME, because of

lack of usable data: so far no studies have been performed on radiotherapy after ME at Ghent

University Hospital (GUH).

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Matching

In order to obtain two homogenous groups in terms of relevant characteristics, i.e. those with

proven impact on acute toxicity of the breast, we performed a literature search. This pointed

out the following variables to have a significant impact on acute skin toxicity after breast

irradiation: radiation dose, age, breast volume, position during radiation (prone/supine)

smoking habits, concomitant hormonal therapy, BMI, adjuvant chemotherapy and adjuvant

targeted therapy (58,59). Positioning, age, breast volume and smoking habits were withheld

for primary matching. In view of the limited number of patients, inclusion of more variables

would not have been possible.

Continuous variables were transformed into categorical variables, in particular age (65y-75y,

75y-85y, >85y), breast volume (<750 cc, 750-1250 cc, >1250 cc), and BMI (<20,0; 20,0-24,9;

25,0-30,0; >30,0).

Difference of variables between groups is reported, using a Chi Square test, in order to

confirm the homogeneity of both groups for the relevant variables.

For the control group (hypofractionated radiotherapy) all the data of women who had

participated in studies on breast cancer radiotherapy at UZ Ghent in the last 6 years were at

our disposal. This database proved to be insufficient. Especially for the oldest patients and for

the highest breast volume category, perfect matching was not always possible, as older age

groups are often less eligible for studies. Matching of three out of four primary variables was

considered as a second best option. As a result, all of the subjects could be matched for at

least three variables: treatment schedule (LNI-no LNI and boost-no boost), position (prone-

supine) and smoking habits (smoking status at the moment of inclusion).

Target volumes and doses

Target volumes and OARs were defined according to in-hospital guidelines (60).

Details of radiation doses for the accelerated schedule are shown in figure 1. In short, a

median dose of 28,5 Gy/5,4 Gy per fraction was prescribed to the breast or thoracic wall with

a simultaneously integrated boost (SIB) to 32,5 Gy/6.5 Gy per fraction or 34,5 Gy/6.9 Gy per

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fraction if indicated by the hospital’s guidelines. The lymph node regions were limited to 27

Gy/5,4 Gy per fraction because of the proximity of the brachial plexus.

Figure 1: HAI-5 treatment schedules

As for the HF schedule, target doses were prescribed according to current hospital guidelines:

40,05 Gy/2,67 Gy for WBI or TWI as well as LNI. If indicated, an additional boost was

delivered to the tumour bed, with either a sequential boost of 10 Gy/2,5 Gy or a SIB of 46,8

Gy/3,12 Gy. For positive resection margins, doses were respectively 14,88Gy (4 times

2,48Gy) and 49,95Gy/3,33Gy for sequential boost or SIB.

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Treatment schedule

HAI-5 patients received 5 fractions of external beam irradiation over the course of 10 to 11

days, only on week days, with at all times at least one day interval between 2 fractions (e.g.

Monday-Wednesday-Friday-Tuesday-Thursday or Tuesday-Thursday-Monday-Wednesday-

Friday). The start was planned to provide at least 2 fractions in one week.

The matched patients in the HF group received 15 fractions of external beam irradiation over

the course of 3 weeks, on consecutive week days. In case of SIB, the boost was administered

in the same 15 days. In case of a sequential boost, this was given during 4 additional week

days directly following the large field treatment.

Planning parameters and treatment techniques

Step and shoot IMRT plans and VMAT were created and optimized using planning tools

developed at the GUH, which were integrated into the GRATIS treatment planning platform

(61).

Patients were simulated on a large bore Toshiba CT, with, in case of LNI and if not contra-

indicated, injection of contrast (Visipaque, 100cc). They were positioned on a prone breast

board if WBI +/- SIB without LNI was prescribed. TWI or LNI precluded use of the breast

board.

Assessment of toxicity

For each patient involved in the study, acute toxicity (dermatitis) was evaluated during

radiotherapy and 2 to 4 weeks after the last fraction. This timing was based on the FAST-

Forward trial, where the highest prevalence of grade 2-3 toxicity was described during 2 to 4

weeks after treatment.

Desquamation, oedema, pain and pruritus were also registered, as our secondary endpoints.

For each item, the worst score was reported. Desquamation was scored as none (0), dry (1) or

moist (2). Of oedema, pain and pruritus, we reported whether they had occurred during the

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course of our toxicity assessment or not.

To score toxicity (dermatitis), CTCAE version 4.3 was used: 0 for no damage, 1 for mild

dermatitis, 2 for moderate dermatitis, 3 for severe dermatitis, 4 for life-threatening

consequences and 5 for death related to radiation dermatitis.

Radiation Dermatitis (CTCAE v4.3)

Gr 1: Faint erythema or dry desquamation

Gr 2: Moderate to brisk erythema; patchy moist desquamation,

mostly confined to skin folds and creases; moderate oedema

Gr 3: Moist desquamation in areas other than skin folds and creases;

bleeding induced by minor trauma or abrasion

Gr 4: Life-threatening consequences; skin necrosis or ulceration of full thickness

dermis;spontaneous bleeding from involved site; skin graft indicated

Gr 5: Death

Table 2: Assessment of radiation dermatitis

These scores were reclassified according to clinical relevance. Grades 0 and 1 were recoded

as subclinical, as they do not need medical intervention. Grades 2 and 3 were recoded as

clinically relevant, because they do require medical intervention with moisturizing cream or

corticoid containing cream. Grades 4 and 5 did not occur, but would have been retained as

major toxic events.

For every patient, the highest toxicity score during or in the first weeks after treatment is

reported, as well for the experimental as for the control group.

Below, an example of grade 1 dermatitis (figure 2) and an example of grade 3 dermatitis with

moist desquamation (figure 3) are shown.

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Figure 2: Grade 1 dermatitis Figure 3: grade 3 dermatitis with moist desquamation

Statistics

The primary endpoint of our study was difference in acute toxicity (P < 0,05) between HF and

a 5-fraction schedule.

Matching was evaluated with a Chi-square test. This was executed for each variable and

groups were considered homogeneous if significance was not <0,05.

As a null-hypothesis, we assumed that both schedules resulted in similar acute toxicity.

During the sample size calculation, an alpha-error of 0,05 was considered acceptable

(probability of wrongly rejecting the null-hypothesis). The Wilson score confidence interval

test for binomial proportion, a 2-side exact method for power analysis, was applied using

“SAS Power and Sample Size”. The difference in clinically relevant acute toxicity was taken

as endpoint. For the group without LNI, to achieve a conditional probability of 87% with an

alpha-error of 0,1, 35 patients would be needed. For the group with LNI, To achieve a

conditional probability of >95% with an alpha-error of 0,1, a number of 25 patients would be

needed. To compensate for drop-outs, a minimum of 40 and 30 patients was determined for

the group without LNI and the group with LNI, respectively.

Statistical difference in acute toxicity between the two schedules was evaluated with a Chi-

square test, with rejection of the null-hypothesis if a significance of <0,05 was calculated. As

we performed a double sided testing, the experimental treatment was evaluated on being

better or worse than standard HF. In case of retaining of the null-hypothesis, the experimental

arm could be considered non inferior.

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Results

Patient selection

Recruitment of HAI-5-patients started in January 2015 and ended in November 2016. A total

of 95 patients (55 without LNI and 40 with LNI, respectively) signed the informed consent

and underwent the accelerated 5-fraction schedule. For reasons of timing, we report only on

the first 80 patients. Recruitment and treatment were performed in GUH.

Matching was only possible for the breast irradiated patients (WBI). Of the 59 WBI patients

with accelerated radiotherapy, 44 were treated without LNI and 15 with LNI. Two

homogeneous groups were created for patients with and without LNI undergoing either the

28,5 Gy/5F or the standard 40Gy/15F schedule. No matches were possible for the 21 HAI-5-

patients who had been treated by ME, because of lack of usable data: so far, no studies have

been performed on radiotherapy after ME in GUH.

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Patient and treatment characteristics

Patient and treatment features influencing acute toxicity of the breast are represented in table

2 and table 3, respectively. Tumour characteristics are not reported on, as they don’t have an

effect on acute skin toxicity.

The homogeneity of both groups, as could be expected because of the matching of the

variables, was tested using the Chi-square test.

As stated above, all HAI-5 patients were perfectly matched to a corresponding HF patient for

the variables ‘treatment schedule’, ‘position’ and ‘smoking habits’. For the HF group, 3

patients with age less than 65 years were included in our study, given the fact that no better

matches were found older than 65. Of these 3 patients, 2 were aged 63 and were used to

match a HAI-5 patient aged 65 and 68, respectively. The third patient, aged 62, was matched

to a 67-year-old HAI-5 patient.

For the other variables (age, breast volume, concomitant hormonal therapy, BMI, adjuvant

chemotherapy and adjuvant targeted therapy), matching was not perfect.

However, for none of the variables, a significant (P<0,05) P-value was found, meaning that

for all the variables, the groups can be considered homogenous.

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Table 3: Patient Characteristics

CountPercentage

Mean

CountPercentage

Mean

Chi-squareSignificance

Age

73,670,5

5,90,1

<65y0

0,00%3

5,10%

65-75y37

62,70%41

69,50%

75-85y20

33,90%15

25,40%

>85u2

3,40%0

0,00%

Breast volume

879,6851,8

0,40,8

<750 cc26

44,10%25

42,40%

750-1250 cc23

39,00%26

44,10%

>1250 cc10

16,90%8

13,50%

Smoking habits

01

Smoker

11,70%

11,70%

Non-Sm

oker58

98,30%58

98,30%

BMI

27,328,8

5,70,1

<20,00

0,00%1

1,70%

20,0-24,924

40,70%16

27,10%

25,0-30,023

39,00%19

32,20%

>30,012

20,30%22

37,30%

Patient Characteristics

HA

I-5H

FH

omogeneity

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Table 4: Treatment Characteristics

Co

un

tP

erce

nta

ge

Co

un

tP

erce

nta

ge

Ch

i-squ

are

Sig

nifica

nce

Tre

atm

en

t sche

du

le0

1

WB

I7

11

,90

%7

11

,90

%

WB

I_SIB

37

62

,70

%3

76

2,7

0%

WB

I_SIB

_R

01

52

5,4

0%

15

25

,40

%

Po

sition

01

Pro

ne

32

54

,20

%3

25

4,2

0%

Sup

ine

27

45

,80

%2

74

5,8

0%

Co

nco

mita

nt H

orm

on

al T

he

rap

y1

,90

,2

Ye

s4

98

3,1

0%

54

91

,50

%

No

10

16

,90

%5

8,5

0%

Ad

juv

an

t Ch

em

oth

era

py

2,6

0,1

Ye

s1

72

8,8

0%

91

5,3

0%

No

42

71

,20

%5

08

4,7

0%

Ad

juv

an

t Ta

rge

ted

Th

era

py

30

,2

Ye

s7

11

,80

%1

1,7

0%

No

52

88

,20

%5

89

8,3

0%

Tre

atm

en

t Ch

ara

cteristics

HA

I-5H

FH

om

og

en

eity

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Acute toxicity

As regards the primary endpoint of the HAI-5 trial, clinically relevant toxicity (dermatitis)

was significantly less in the accelerated group compared to the HF group (16,9% versus

52,5%, P < 0,001).

Figure 4: Difference in clinically significant skin toxicity between HAI-5 and HF

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Looking at the secondary endpoints, a significant difference (P < 0,05) was found for

desquamation, pruritus and oedema, as shown in table 5 and figure 5. Also, comparing the

grades of dermatitis between HAI-5 and HF, and not just making the distinction between

clinically relevant and not clinically relevant dermatitis, a higher Chi-square value (P < 0,001)

was found.

Table 5: Differences in dermatitis, desquamation, pain, pruritus and oedema between HAI-5 and HF

HAI-5 HF Chi-square Significance

Dermatitis 22,495 < 0,001

Grade 0 14 (23,7%) 2 (3,4%)

Grade I 35 (59,3%) 25 (42,4%)

Grade II 9 (15,3%) 26 (44,1%)

Grade III 1 (1,7%) 6 (10,1%)

Desquamation 15,164 0,001

None 49 (83,1%) 29 (49,2%)

Dry 8 (13,6%) 23 (39,0%)

Moist 2 (3,3%) 7 (11,8%)

Pain 0,148 0,701

No Pain 22 (37,3%) 20 (33,9%)

Pain 37 (62,7%) 39 (66,1%)

Pruritus 4,145 0,042

No Pruritus 38 (64,4%) 27 (45,8%)

Pruritus 21 (35,6%) 32 (54,2%)

Oedema 10,977 0,001

No Oedema 24 (40,6%) 8 (13,6%)

Oedema 35 (59,4%) 51 (86,4%)

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Figure 5: Differences in dermatitis, desquamation, pain, pruritus and oedema between HAI-5 and HF

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In the group of 21 patients who underwent post-ME irradiation, no cases with clinically

significant toxicity were reported.

Reporting on the secondary endpoints in the ME group, we see 14 (66,7%) of ME patients

had grade 1 dermatitis. Only 2 (9,6%) patients had desquamation (1 dry and 1 moist). Pruritus

was only reported in 8 (38,1%) patients, whereas 13 patients (61,9%) suffered from pain.

Oedema was observed, yet not reported on, because it is not certainly induced by

radiotherapy. Often, it is residual seroma after surgery, wrongly scored as ‘oedema’.

Figure 6: Prevalence of dermatitis, desquamation, pain, pruritus and oedema in HAI-5 patients after ME

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Treatment schedules

Looking at the different treatment schedules (BCS without LNI, BCS with LNI and TWI), we

found these to have a significant effect on clinically relevant acute skin toxicity of the breast

(P = 0,001)

BCS - LNI BCS + LNI TWI Chi-square Significance

No clinically relevant toxicity 60 (68,2%) 16 (53,3%) 21 (100,0%) 13,05 0,001

Clinically relevant toxicity 28 (31,8% 14 (46,7%) 0 (0,0%)

Table 6: Difference in clinically significant skin toxicity between BCS without LNI, BCS with LNI and

TWI

Looking at the secondary endpoints, a significant effect of the treatment schedule on oedema

was found (P = 0,002).

Figure 7: Differences in dermatitis, desquamation, pain, pruritus and oedema between BCS with LNI,

BCS without LNI and TWI

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Discussion

Normofractionation has since long been the standard, based on empiric observation rather

than objective data (44). Over the last 20 years, the difference in sensitivity to radiotherapy

between cancers and late reacting normal tissues has been challenged by several studies

providing significant evidence that breast cancer is as sensitive to fraction size as the normal

tissues of the breast (47,49,50,62,63).

This assumption has currently been confirmed by several clinical data. In several studies

exploring HF, efficacy and safety of this schedule has been proven, as well for loco-regional

control as for acute and long-term toxicity (45–47,62,64,65).

Fifteen to nineteen fractions may not represent the lower limits of HF for WBI. Because of the

promising results with moderate HF, highly hypofractionated schedules have been tested

since. Ortholan et al. studied a once-weekly hypofractionated RT schedule, delivering a total

dose of 32,5 Gy in 5 fractions of 6,5 Gy. They reported mild early reactions, acceptable

toxicity and excellent long-term control (53).

Rovea et al. also reported an excellent cosmesis for a 5 fraction schedule with a total dose of

30,0 to 32,5 Gy. However, in contrast to our ‘every other day schedule’, overall treatment

time was long, as fractions were delivered only once weekly and the target was limited to

breast irradiation only, even though 25,40% of patients had been diagnosed with involved

lymph nodes. They concluded that acceleration seemed feasible and effective for a selected

population of elderly breast cancer patients with primarily low-risk features (56).

The FAST trial compared two once-weekly 5-fraction schedules (28,5 Gy and 30 Gy). Three

year follow-up showed good results for the 28,5 Gy/5,7 Gy schedule and worse esthetic

outcome with 30,0 Gy/6,0 Gy (63).

Recently, acute toxicity of the UK FAST-Forward trial was reported, where 2 schedules

(27Gy/5,4Gy and 26Gy/5,2Gy) with daily delivery were compared to a 40 Gy/2,67 Gy

schedule. Erythema was less intense and occurred earlier in the 1-week schedules.

Incidence of clinically significant acute skin toxicity remained low for each schedule (55).

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The primary goal of the HAI-5 feasibility trial was to validate these earlier findings. As breast

cancer in older women is not limited to very early stage breast cancer, in comparison to the

aforementioned trials, inclusion in the HAI-5 was extended to locally advanced breast cancer.

Accelerated radiotherapy including delivery of a SIB and including LNI and of TWI, has so

far not been tested. In this first phase, clinically significant acute dermatitis was chosen as

primary endpoint. To compare toxicity with the current standard of HF, every HAI-5 patient

was matched to a patient who had received HF within other studies. Due to this relatively

small pool of patients, matching proved to be a real challenge, especially for the patients with

LNI. As a consequence, a minority of HAI-5 patients was matched to a HF patient with the

same features for all relevant variables. However, statistical analysis pointed out that for all

these variables, patients were adequately matched.

The findings of our study not only confirmed that the highly accelerated schedule is not

associated with a higher risk of acute skin toxicity, it even suggests a significantly lower

incidence of dermatitis compared to the HF group, with only 10 cases of clinically relevant

acute skin toxicity in the HAI-5 group compared to 31 cases in the HF group. Comparing the

actual grades of dermatitis (0-5) between HAI-5 and HF, and not just making the distinction

between clinically relevant and not clinically relevant dermatitis, this benefit of HAI-5 over

HF became even clearer.

A significant difference between treatment schedules was also found for secondary endpoints

desquamation, pruritus and oedema. For pain, a small yet not significant difference was

found. In the ME group, no cases of clinically relevant dermatitis were observed.

One of the biggest benefits of the HAI-5 trial is that it included elderly patients (> 65 years).

This subgroup, accounting for over 50 percent of the total breast cancer prevalence, remains

undertreated, resulting in worse outcome after breast cancer despite lower stage and more

favourably prognostic outcomes (3). The positive outcomes of our study should encourage

further research on improving access to adequate loco-regional therapy for this group. First,

fewer fractions and shorter total treatment time should result in a better quality of life of

patients, owing significantly less time commitment to undergo RT. This is particularly

important for our study population, the elderly, who are often facing logistic problems,

leading to under-treatment. Second, the reduced number of treatment sessions results in a

lower cost, because of reduced resource use in terms of personnel and machine time

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(51,52,63). In addition to the evident practical advantages, accelerated RT seems to be

clinically beneficial, with comparable loco-regional control and lower toxicity (67).

One of the greatest drawbacks of our study was the small sample size, making perfect

matching impossible. To start with, in an observational study, patients are ideally randomized

among the study groups, like in the FAST and Rovea et al. trials (55,56,63). Since this was

not possible in our study, we tried to compensate this by matching our HAI-5 patients to HF

patients, thus creating two homogenous groups. Even though statistical analysis showed that

for all variables, both groups could be considered homogenous, the fact that several patients

were not perfectly matched for all variables, might still have influenced the outcome of the

study. Also, for the mastectomized patients, matching was not possible due to the lack of a

HF population for matching. Skin toxicity was, however, low, but only 21 patients who

underwent ME were included.

Results are still preliminary, as we only report on acute toxicity. Long-term toxicity, like

breast cosmesis, rib pain, rib fractures, brachial plexopathy, lymphedema, heart diseases and

lung toxicity has to be awaited. The most important difference with earlier studies was the

inclusion of LNI. So far, no symptoms of RIBP have been reported. However, follow-up is

still very short and RIBP might appear years after treatment. Moreover, further studies are

needed to evaluate the effect of acceleration on loco-regional control and survival.

To conclude, based on the findings of the HAI-5 trial, irradiation in 5 fractions appears to be a

feasible alternative for the current standard schedule, being particularly interesting for the

currently undertreated elderly subgroup of breast cancer patients with early breast cancer.

Although promising, acceleration should be limited to clinical research until long-term follow

up comes available.

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