ANNALES ACADEMIAE MEDICAE STETINENSIS
ROCZNIKI POMORSKIEJ AKADEMII MEDYCZNEJ W SZCZECINIE
2012, 58, 1, 45–48
Elwira Szychot, Andrzej Brodkiewicz1, Jarosław Peregud-Pogorzelski 2
The rationale behind hypofractionated high-dose
intensity-modulated radiotherapy in patients
with localized prostate cancer: short review
Zasadność hipofrakcyjnej radioterapii
dużej dawki z modulowaną intensywnością
u pacjentów z rakiem stercza – krótki przegląd
Paediatric Department, Royal Berkshire NHS Foundation Trust.
London Road, Reading RG1 5AN. UK
1
Oddział Kliniczny Pediatrii, Nefrologii ze Stacji Dializ i Leczenia Ostrych Zatruć Pomorskiego Uniwersytetu Medycznego w Szczecinie
ul. Św. Wojciecha 7, 70-410 Szczecin
Kierownik: dr hab. n. med. Andrzej Brodkiewicz
2
Klinika Pediatrii, Hematologii i Onkologii Dziecięcej Pomorskiego Uniwersytetu Medycznego w Szczecinie
ul. Unii Lubelskiej 1, 71-252 Szczecin
Kierownik: dr hab. n. med., prof. PUM Tomasz Urasiński
Streszczenie
radiotherapy in patients with localized prostate cancer.
Zwiększające się możliwości technicze spowodowały
wzrost zaintesowania napromienianiem hipofrakcyjnym K e y w o r d s: radiation – hypofractionation – cancer –
w leczeniu raka prostaty. Radiobiologia komórek nowotwoprostate.
rowych raka prostaty pozwala na znaczną eskalację dawki
użytego promieniowania.
Celem pracy było podkreślenie zwiększonej skuteczHypofractionation *
ności terapii antynowotworowej przy zastosowaniu napromieniania hipofrakcyjnego.
Hypofractionation, the delivery of radiation therapy
with a dose per fraction > 2.0 Gy, was introduced in radioH a s ł a: radioterapia – frakcjonowana radioterapia – nowo- therapy treatment in many oncological centres all over the
twór – prostata.
world in the period between 1939 to the 1970’s. However,
clinical studies conducted in the 70’s and 80’s revealed
that these schedules were often associated with excessive
Summary
late toxicity compared to standard fractionation schedules
and as the result hypofractionation was abandoned in most
The use of improved technology has fostered increasing centres. This negative experience grossly resulted from
interest in hypofractionated radiation therapy for prostate the over­‍‑estimation of tolerance doses in hypofractionated
cancer. There also is convincing evidence that an unusual schedules arising from Ellis NSD formula [1].
aspect of prostate cancer radiobiology allow a different
Based on the improved physical dose distribution achie­
approach to dose escalation that is radiobiological in nature. vable with intensity modulated radiation therapy (IMRT),
The aim of this paper is to explain the rationale
behind hypo­f ractionated high­‍‑dose intensity­‍‑modulated * Translated by / Tłumaczenie Elwira Szychot
46
ELWIRA SZYCHOT, ANDRZEJ BRODKIEWICZ, JAROSŁAW PEREGUD-POGORZELSKI
there now is convincing evidence that biochemical control
is improved with higher cumulative doses of radiation to the
prostate. There is also a biological rationale for hypofractionation due to an unusual prostate tumour radiobiology
that relates to prostate cancer’s high sensitivity to large
fractions of radiation [2, 3].
Conventional fractionation schemes employ fraction
sizes of 1.8–2.0 Gy based on the hypothesis that tumours
typically are less responsive to fraction size (have higher
α/β ratio) than are late­‍‑responding normal tissues (lower α/β
ratio). The α/β ratio is a measure of fractionation response.
A low α/β ratio is compatible with a greater capacity for
repair between fractions, with an associated greater relative sparing with small fraction sizes, than for tumours
with their typically higher α/β ratios. In those cases an
improved therapeutic ratio is obtained with multiple small
fractions for most types of tumours. For acutely responding
tissues that express their damage within a period of days
to weeks after irradiation, the α/β ratio values are in the
range between 7–20 Gy, while for late responding tissues
that express their damage months to years after irradiation,
α/β ratios vary from 0.5 to 6 Gy [4, 5, 6]. Effective cell
cycle time is often associated with fractionation response,
with slowly proliferating normal tissues and some slowly
proliferating tumours that display stronger fraction size
responses (low α/β ratios). The reason for this difference
might be explained by a hypothesis that the net α/β ratio
of a cell population is determined by its age distribution.
Hence, slowly proliferating tissues with a high preponde­
rance of cells in G0 will have a lower overall α/β ratio (and
therefore higher relative sensitivity to large fractional doses)
than proliferating tissues containing a significant proportion of cells in G2/M [7].
Analyses and reviews of clinical tumour response data
revealed that prostate cancers have a higher sensitivity
to fraction size, reflected in a low α/β ratio, than do late
responding organs at risk such as the rectum or bladder [8, 9].
Brenner et al. conducted a study in which patients with
prostate cancer were treated with a standard external beam
course of treatment followed by high dose rate temporary
implant boost doses which were escalated by decreasing
fraction number from 3 to 2 and by increasing fraction size
from 5.5 to 10.5 Gy [8]. Patients were grouped according
to prognostic factors and biochemical control was formed
versus equivalent dose as calculated via a linear quadratic
model. The authors observed higher biochemical control
rates with escalation of hypofractination, consistent with
an α/β ratio of 1.2. The advantage of this study was comparing several high dose rate brachytherapy schedules that
differed only in the radiation fraction size [8].
Favouring the use of hypofractionation in prostate cancers can be illustrated through the linear quadratic equation
that calculates the biologically effective dose (BED) for
a given total dose (D), dose per fraction (d) and α/β ratio:
Fig. 1. The ratio of biologically effective dose for prostate tumor (α/β = 1.5)
to normal tissue late effects (α/β = 3)
Ryc. 1. Stosunek biologicznie skutecznej dawki dla raka stercza (α/β = 1,5)
do późnych skutków w zdrowych tkankach (α/β = 3). Parametr przedstawiono
jako funkcję wielkości frakcji
A low α/β ratio for tumour (less than for late respon­
ding normal tissue) predicts an improved therapeutic ratio
with hypofractionation. If the ratio of biologically effective
dose at an α/β ratio of 3 for late tissue toxicity versus 1.5
for tumour is considered as a form of therapeutic ratio, in
this situation the ratio, readily calculated using the linear
quadratic equation, increases significantly with fraction
size (fig. 1) [10].
While the relationship is mathematically independent
of total dose, the total dose needs to be accordingly limited
to prevent excessive toxicities. Furthermore, if α/β ratios for
prostate cancer and late normal tissue damage were equal,
there would be no advantage or loss in predicted therapeutic gain from hypofractionation.
Hypofractionation in a clinical setting
Dose­‍‑per­‍‑f raction escalation schedules, as calculated
using the linear quadratic equation, predict increase in
tumour control while maintaining a constant, biologically
effective Gy3 dose for late responding normal tissue (fig. 2).
This type of hypofractionation design exploits the hypothesised radiobiological advantages discussed above. Biochemical freedom from disease (bNED) are estimated by
calculating the equivalent doses if delivered in 2 Gy fractions (α/β = 1.5) and determining the corresponding bNED
values from the biochemical control versus dose data derived
from Fowler et al. [11]. Total dose delivered decreases with
increasing hypofractionation in order to maintain constant
late effects [10]. An α/β ratio for prostate cancer lower than
that for normal tissues provides the basis for improving
tumour control without increasing late effect risk. If normal tissue and tumour α/β ratios were equal, tumour control would not improve with hypofractionation. However
THE RATIONALE BEHIND HYPOFRACTIONATED HIGH-DOSE INTENSITY-MODULATED RADIOTHERAPY
47
Time factor
An increase in overall duration of fractionated radiotherapy usually causes greater repopulation of the irradiated tissues, both in the tumour and in early­‍‑reacting
normal tissues. The time factor in radiotherapy is noticed
to be more complex than had previously been assumed.
For example, Denekamp reported in 1973 that the extra
dose needed to counteract proliferation in mouse does not
become meaningful until about 2 weeks after the start of
daily fractionation [13]. In this situation, the time factor in
the old Ellis NSD formula gives a wrong picture as it predicts
a large amount of sparing if the overall time was increased
from 1 to 12 days. The false time factors also underestimate
the dose required to compensate for planned or unplanned
gaps in treatment. The use of the linear quadratic equation
model in clinical practice with no time factor at all seems
Fig. 2. Dose­‍‑per­‍‑fraction escalation regimens predicted to increase tumour
to be ideal strategy for late­‍‑reacting tissues as any extra
control while maintaining constant late normal tissue toxicity
dose needed to counteract proliferation does not become
Ryc. 2. Zwiększenie dawki radioterapii na frakcje skuteczne w leczeniu
meaningful
until beyond the overall time of treatment, even
guza przy jednoczesnym zapewnieniu niezmiennego wpływu toksycznego
up to 6 weeks. However for early reactions (and for tumour
na zdrowe tkanki
response) a correction for overall treatment time should be
the cost and convenience benefit of delivering fewer frac- taken into consideration [4].
tions would remain.
Incomplete repair
The linear quadratic equation concludes that adequate
time is allowed between fractions for complete repair of
sublethal damage to take place after each dose. The full
repair interval is at least 6 hours. The repair of damage
caused by one radiation dose may not be completed before
the next fraction is given if the interfraction interval is
reduced below 6 hours. In these circumstances interaction
between residual unrepaired damage from one fraction and
the damage from the next fraction occurs. The influence of
incomplete repair is determined by the repair halftime (T1/2)
in the tissue. This is the time required between fractions
or during low dose­‍‑rate treatment, for half the maximum
possible repair to take place. Corrections are required for
the consequent loss of tolerance as an incomplete repair
reduce the isoeffective dose. The corrections can be achieved
by the use of the incomplete repair model that was introduced by Thames in 1985 [4, 12]. In this model, the amount
of unrepaired damage is expressed by a function Hm that
depends on the number of equally spaced fractions (m), the
time interval between them and the repair halftime. For the
purpose of calculations the extra Hm term is added to the
basic EQD2 formula:
EQD2 = D [d(1 + Hm) + (α/β)]/2 + (α/β)
D is the total dose, d the dose per fraction, m is the number
of fractions per day if repair from one day to the next is
assumed to be completed [4].
Concluding remarks
Specialized radiation therapy that delivers a high dose
of radiation directly to the tumor may kill more tumor cells
and cause less damage to normal tissue. The outcomes
of several hypofractination trials support the hypothesis
that the α/β ratio for prostate cancer is low and that future
treatment schedules are expected to emerge, based on the
further trials such as randomized phase III trial CHHIP
that is studying the side effects of different schedules of
intensity­‍‑modulated radiation therapy and compares how
well they work in treating patients with localized prostate
cancer.
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