Hall Book Ch 23 (Time, Dose, and Fractionation in Radiotherapy)

Question 1

The “four Rs” of radiobiology are the following:

Answer 1

Repair of sublethal damage
Reassortment of cells within the cell cycle
Repopulation
Reoxygenation

Question 2

Some have added a fifth R, namely ( ).

Answer 2

Resistance (intrinsic)

Question 3

The basis of conventional fractionation may be explained as follows: Dividing
a dose into several fractions spares normal tissues because of the repair of
sublethal damage between dose fractions and cellular repopulation. At the
same time, fractionation increases tumor damage because of reoxygenation
and reassortment.
The Strandquist plot is the relation between total dose and overall treatment
time. In this context, “time” includes the number of fractions. On a double
log plot, the slope of the line for skin is often close to 0.33.
The Ellis NSD system made the important contribution of separating the
effects of number of fractions and overall time. The time correction was a
power function (T
0.11
) that is far from accurate. The system is seldom used
now.
The extra dose required to counteract proliferation in a normal tissue irradiated
in a fractionated regimen is a sigmoidal function of time. No extra dose is
required until some weeks into a fractionated schedule.
The delay before an extra dose is required to counteract the effects of
proliferation is much longer for late-responding tissues and is beyond the
overall time for conventional radiotherapy schedules.
Prolonging overall time within the normal radiotherapy range has little sparing
effect on late reactions but a large sparing effect on early reactions.
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The dose–response relationship for late effects is more curved than for early
effects. The α/β ratio is about 10 Gy for early effects and about 3 Gy for lateresponding tissues. Consequently, late-responding tissues are more sensitive
to changes in fractionation pattern.
Fraction size is the dominant factor in determining late effects; overall
treatment time has little influence. By contrast, fraction size and overall
treatment time both determine the response of acutely responding tissues.
Accelerated repopulation refers to the triggering of surviving cells (clonogens)
to divide more rapidly as a tumor shrinks after irradiation or treatment with a
cytotoxic drug.
Accelerated repopulation starts in head and neck cancer in humans about 4
weeks after initiation of fractionated radiotherapy. About 0.6 Gy per day is
needed to compensate for this repopulation.
This phenomenon mandates that treatment be completed as soon as practical
once it has started; it may be better to delay the start than to introduce
interruptions during treatment.
Overall treatment time is a very important factor for fast-growing tumors. In
head and neck cancer, local tumor control is decreased by about 1.4% (range
of 0.4% to 2.5%) for each day that the overall treatment time is prolonged.
The corresponding figure for carcinoma of the cervix is about 0.5% (range of
0.3% to 1.1%) per day. Such rapid proliferation is not seen in breast or
prostate cancer.
Multiple fractions per day: In the 1980s and 1990s, thousands of patients were
enrolled in clinical trials to investigate treatment protocols that involved more
than one treatment fraction per day. Hyperfractionation sought to improve
treatment outcome by doubling the number of fractions in the same overall
time by giving two fractions per day. Clinical trials showed a distinct
advantage. Accelerated treatment sought to shorten overall treatment time by
giving two doses per day on the premise that overall time would not affect
late effects. Clinical trials showed an improvement in tumor response but an
unexpected increase in late effects, some of which proved to be lethal.
CHART involved 36 small dose fractions over 12 consecutive days in three
treatment fractions per day. Good local control was seen with most late
effects at an acceptable level except for the spinal cord, where several
myelopathies were observed because the 6-hour period between fractions was
not sufficient to allow repair of sublethal damage in this tissue.
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Multiple fractions per day have never become mainstream in radiotherapy
practice because of the logistical problems.
There is renewed interest in hypofractionation—that is, a smaller number of
high dose fractions. There are several circumstances where this may be
exploited: (1) for prostate cancer for which the α/β ratio is closer to that for
late-responding tissues, which removes the benefit of fractionation; (2) for
SRS and SBRT where technologic advances allow a high tumor dose with
less dose to a smaller volume of normal tissue; and (3) for carbon ion beams,
where the dose distribution is improved and, in addition, the radiation has a
relatively high LET.
The linear-quadratic concept may be used to calculate the biologic
effectiveness of various radiotherapy protocols involving different numbers
of dose fractions. The useful formula is
An approximate allowance can be made for tumor cell proliferation when
comparing protocols involving different overall treatment times. There are
two approaches considered:
1. Fowler has suggested corrections based on the Tpot value for different
tumors.
2. Peters and colleagues have suggested a pragmatic approach in the case
of fast-growing squamous cell carcinomas of the head and neck, where
corrections for overall time may be more important than number of
fractions. They assume that between 5 and 7 weeks after the start of a
fractionated regimen, the dose equivalent of regeneration with
protraction of treatment is about 0.5 Gy per day, rounded down to 3 Gy
per week. The correction will be different for other tumors and probably
negligible for prostate cancer.