EDITORIAL

DON’T SQUEEZE HYPOFRACTIONATED SCHEDULES INTO TOO-SHORT OVERALLTIMES

JACK FOWLER, PH.D., D.SC.,* AND CHRISTOPHER R. KING, PH.D., M.D.y

*Departments of Human Oncology and Medical Physics, University of Wisconsin Medical School, Madison, WI; and yDepartment ofRadiation Oncology, Stanford University School of Medicine, Stanford Medical Center, Stanford, CA

Int. J. Radiation Oncology Biol. Phys., Vol. 75, No. 2, pp. 323–325, 2009Copyright � 2009 Elsevier Inc.

Printed in the USA. All rights reserved0360-3016/09/$–see front matter

doi:10.1016/j.ijrobp.2009.06.022

This editorial uses insights gained from mucosal tolerance

studies in head and neck radiotherapy, together with stan-

dard Linear Quadratic radiotherapy modeling, to predict

whether some hypofractionated prostate schedules could

cause acute rectal mucosal reactions - by using too short

schedules.

With conventional radiotherapy, including hypofractiona-

tion, we restrict total dose to a late normal tissue complica-

tions dose limit, depending on the tissue and volume

irradiated, of 50 to 70–80 Gy equivalent total dose in 2-Gy

fractions (EQD2). These late-effect dose–volume constraints

are well reported in many publications. Some stereotactic

body radiotherapy schedules give high doses and biologi-

cally effective doses (BED), and new information is still

being obtained that might change accepted doses.

But there is also the question of acute reactions; they are

the main factor determining whether any fractionation sched-

ule can be accepted as tolerable. Until recently acute reac-

tions were checked for ‘‘tolerability’’ by irradiating the first

few patients in any new schedule and observing their acute

reactions to ensure healing within a reasonable time. We sug-

gest that radiobiologic modeling (1) can now be used to pre-

dict whether proposed fractionation schemes are in danger of

causing acute mucosal reactions in the treatment of prostate

cancer. An additional potential hazard is the phenomenon

of consequential late damage induced by very high acute

reactions. This has been identified in animal experiments

(2), although it has skeptics in clinical circles.

The important difference between acute and late reactions

is the time factor. Acute reactions are very sensitive to overall

time, unlike late reactions. It means that if acute reactions are

too severe, then a week added to the overall time can avoid

some Grade 3 acute reactions, as shown below.

It was not until 2003 that modeling was proposed to help

predict whether any schedule might cause intolerable acute

complications (1). This was based on the well-known linear-

quadratic formula used for predicting log cell kill in tumors,

32

but with somewhat different parameters for the kinetics of

mucosal cell repopulation (1–3):

BED ¼ ndð1þ d=½a=b�Þ � ðloge2ÞðT� TkÞ=ða:TpÞ (1)

where n fractions of d Gy are given in an overall time of T

days. The ratio a/b is the ratio of nonrepairable radiation

damage (in log_e per gray) to the repairable, dose-

per-fraction-sensitive amount of damage. This ratio is low

for late-responding normal tissues (2 to 3 Gy) but higher (ap-

proximately 10 Gy or above) for rapidly proliferating normal

tissues and tumors. The Loge2 brings in the repopulation rate

at the doubling time assumed to be Tp days during irradia-

tion, starting at the kick-off time of Tk days after starting

irradiation. Note that in this formalism the first day of treatment

is counted Day 0 instead of Day 1. The time available for

repopulation is (T � Tk) days. The precise Tk of 7 days for

human oral mucosa had just been identified (4).

The average mucosal cell doubling time from Tk to the end

of treatment was 2.5 days, determined as described in the re-

view of many schedules (1). This is equivalent to 0.67 Gy

EQD2 and to a BED of 0.8 Gy10 per day, in agreement with

Bentzen et al. (3). Some reports of faster repopulation toward

the end of long schedules are in the literature, but the human

cell-counting biopsies on which the present modeling (1) was

based did not show that, up to 50 days (4), so we maintain the

simple dog-leg shape of Withers’ tumor time–dose curve (5),

together with the usual a = 0.35 Gy per loge and a/b = 10 Gy

for acute reactions.

And yes, in most types of tumor but not in prostate tumors,

some loss of tumor cell kill occurs if acute complications are

reduced by prolongation. However, prostate tumors repopu-

late slowly and have been observed to suffer no detriment in

tumor control until their overall treatment times exceeded 9

or 10 weeks (e.g., Perez et al. [6]).

This mucosal linear-quadratic test has proved reliable for

checking corrections necessary for several head-and-neck

schedules that were too toxic when first used but were

Reprint requests to: Jack F. Fowler, Ph.D., Flat 1, 150 LambethRoad, London SE1 7DF, United Kingdom. Tel: (+44) 207-207-7997; E-mail: jackfowlersbox@gmail.com

3

Conflict of interest: none.Received April 29, 2009, and in revised form June 4, 2009.

Accepted for publication June 5, 2009.

324 I. J. Radiation Oncology d Biology d Physics Volume 75, Number 2, 2009

Table 1. Head-and-neck schedules that were originally too hot and had to be moderated

Schedule*

Treatment given Tumor time, correctedLate complicationsEQD2 (Gy) (aim,

<70 Gy)yAcute mucosal EQD2

(Gy) (aim, < 52.5 Gy)yzTotal

dose (Gy)Overalltime (d)

EQD2(Gy)y

Log10

cell killy

Gortec 1: 2 Gy � 32 fx 64 22 63.6 11.6 64.1 54.1Gortec 2: 1.75 � 36 fx 63 24 60.8 11.1 60.0 51.2Cair 1: 2 Gy � 35 fx 70 34 63.1 11.5 70(+?) 52.2Cair 2: 1.8 Gy � 39 fx 70.2 38 59.8 10.9 67.2 48.6Harde 1: 1.2 + 1.3 + 1.5 + 2 Gy 76 33 65.1 11.9 67.2 54.5Harde 2: 1.2 + 1.5 Gy 73.2 32 60.3 11.0 63.6 49.3Leborgne: 1.6 Gy � 42 fx 67.2 25 62.8 11.5 61.8 53.1in longer Overall Time 67.2 29 60.6 11.1 61.8 50.4Sanguinetti: 1.3 Gy � 60 fx 78 39 63.6 11.6 67.0 52.3in longer Overall Time 78 42 61.9 11.3 67.0 50.3

Abbreviations: EQD2 = equivalent dose in 2-Gy fractions; fx = fractions.Biologically effective doses (BEDS) can be translated to the more familiar EQD2 by dividing any BED by the relative effectiveness (RE) for

2-Gy fractions (when RE = 1 + 2/[a/b]), using the relevant value of a/b. Thus for acute reactions we divide the BED in Gy10 by 1.2, or for latereactions divide the BED in Gy3 by 1.667, to give 49–52.5 Gy EQD2.

* See Bentzen et al. (3) for the original references.y In the fourth, sixth, and seventh columns (from left), the resulting tissue-specific BEDs are converted to EQD2 (in 2-Gy fraction equivalent

doses) by dividing by 1.2, and in the fifth column into nominal log cell kill in tumors using Tk = 21 days and Tp = 3 days.z Acute mucosal grey zone = 49–52.5 Gy EQD2.

subsequently modified (7) to achieve tolerable acute reac-

tions by reduction of dose-per-fraction or increase of overall

time, or both. Table 1 shows those head-and-neck schedules

that were started with the version shown in each top line but

were soon modified by the originators to the second version

of each schedule, without this modeling, and found to be ac-

ceptable. Table 1 shows that in every case it was the acute

mucosal EQD2 that had been altered from above our stated

limit of 52.5 Gy EQD2, not the late complications limit of

70 Gy. This modeling defines a ‘‘grey zone’’ of approxi-

mately 4 Gy of ‘‘probable acute mucosal tolerance total

doses’’ between EQDs of 49 Gy and 52.5 Gy, corresponding

to time-corrected BEDs of 59–63 Gy10, (that is, assuming

a/b = 10 Gy). This ‘‘grey zone’’ covers the range from slight

to almost intolerable acute reactions derived from a large

number of schedules (1). It can apply to any treatment involv-

ing more than a few square centimeters of mucosa.

The reason for this editorial is that similar-tolerance

EQD2s have been found to apply to rectal tolerance DVH

doses, but only when prescribed with due respect to the estab-

lished rectal volume constraints in prostate treatments, such

as those of Huang et al. (8), Vargas et al. (9), and many others

(e.g., Peeters et al. [10]).

Several prostate hypofractionation trials using 20 fractions

� 3.0 Gy in 4 weeks are in progress (11–14). Their predicted

acute mucosal EQD is 53.1 Gy, just above the 52.5-Gy EQD

top of the recommended oral grey zone (1). Do these 5-frac-

tions-per-week treatments (in 25 days) need changing to 4

fractions per week in 5 weeks (32 days)? The resulting

48.5-Gy EQD2 would be much safer, but present clinical re-

ports do not complain about excess acute toxicity. No prefer-

ence is suggested as to which treatment days to leave

unirradiated when such lengthening is done—it is only the

first and the last treatment days that are important for overall

time, although prudently even spacing is advised. A further

point is that this lengthening is only likely to work sensitively

if the schedule is already nearly correct.

In two recent publications in this journal, Arcangeli et al.(13) and Leborgne and Fowler (14) describe the use of the

present algorithm to decide that their 3 Gy � 20 fractions

schedules would use the 4-fractions-per-week option. They

reported, respectively, 0 of 102 and 1 of 22 Radiation Ther-

apy Oncology Group (RTOG) Grade 3 acute rectal reactions

(13, 14), consistent with good safety.

Leborgne and Fowler (14) changed their 20-fraction pros-

tate schedule from 3.0 to 3.15 Gy per fraction because it

seemed so safe, with a predicted rise of acute mucosal

EQD2 from 48.5 Gy (‘‘safe’’) to 52.5 Gy (‘‘upper border’’).

They then observed an increase in RTOG acute Grade 3 rectal

reactions from 1 of 22 (4.5%) to 10 of 34 (29%, p = 0.05)

(see their Table 7 [14]). (Only one of those 10 was at Grade

3 at 49 months.) The more concentrated 5-fractions-per-week

option would have delivered 53.1 (barely tolerable) and

57.2 Gy EQD2 (not tolerable) with the 3.0-Gy and 3.15-Gy

fractions in 4 weeks.

King et al. (15) gave 5� 7.25 Gy = 36.25 Gy prostate ste-

reotactic body radiotherapy and reported that ‘‘a reduced rate

of severe rectal toxicities was observed with every-other-day

vs 5 consecutive days treatment (0% vs 38% p = 0.0035),’’

although none was as high as Grade 3. They predicted that

acute EQDs were 52.1 Gy (near top of the grey zone) for

‘‘daily’’ fractions (5 fractions per week) but only 50.8 Gy

(midrange) for ‘‘every other day.’’

These ‘‘tolerance’’ BEDs and EQDs for rectal mucosa

certainly require further data to be analyzed but already

seem to be useful safety indicators. We ask readers whether

their experiences can confirm or modify the present parame-

ter levels.

Predicting acute rectal tolerance d J. FOWLER AND C. R. KING 325

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