evaluation of the acute side effects of accelerated...
TRANSCRIPT
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
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.
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
1
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.
2
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.
3
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).
4
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%
5
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
6
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).
7
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
8
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).
9
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
10
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).
11
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).
12
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
13
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.
14
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
15
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.
16
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.
17
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.
19
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
20
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
21
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
22
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%)
23
Figure 5: Differences in dermatitis, desquamation, pain, pruritus and oedema between HAI-5 and HF
24
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
25
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
26
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).
27
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
28
(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.
29
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