The rationale and radiobiology of altered fractionation in cure and palliation

Michael Joiner

Radiation Oncology Detroit, Michiganjoinerm@wayne.edu

ICARO Vienna 2009

Apr 09 2MCJ

Conventional fractionation

1.8 – 2.0 Gy per fraction, 5 fractions per weekIIIII IIIII IIIII IIIII IIIII IIIII IIIII

<5%

≥

90 (subclinical)~ 85 (Ø 1 cm)~ 70 (Ø 3 cm)~ 30 (Ø 5 cm)

≥

90

Tumor control (%)

≥

60

506070

≤

45

Dose (Gy)

Glioblastoma

SCC, Adeno-Ca

Seminoma, Lymphoma

Example

Resistant

Intermediate

Sensitive

Apr 09 3MCJ

So why not just give more dose in a conventional schedule?

Uncomplicated tumor control is bell-shaped. To increase max, move:•

normal-tissue damage to higher doses (e.g. Hyperfractionation)

•

dose-effect for tumor control to lower doses (e.g. Acceleration)

Apr 09 4MCJ

Key treatment parameters

•

total dose

•

dose per fraction

•

time interval between fractions

•

overall treatment time

Apr 09 5MCJ

Altered fractionation

• Hyperfractionation: – dose per fraction < 1.8 Gy

• Hypofractionation– dose per fraction > 2 Gy

• Accelerated fractionation: – rate of dose accumulation exceeds

10 Gy/week

• Hybrid schedules

Apr 09 6MCJ

Example fractionation schedules

HYPER FX HYPO FX

AC

CEL

ERA

TIO

N

5

10

15

20

25

30

35

1 1.5 2 2.5 3 3.5Dose per fraction (Gy)

Rat

e of

dos

e ac

cum

ulat

ion

(Gy/

wee

k)

CHART

RTOG HF

Manchester

22791Pinto

RTOG SC

22851RTOG CB

DAHANCA 7Gliwice I

GORTEC 9402

Gliwice II

Apr 09 7MCJ

Fractionation response: Early vs Late

Thames et al, Int J Radiat Oncol Biol Phys, 8,

219, 1982

Late

Early

Apr 09 8MCJ

LQ

Apr 09 9MCJ

Low α/β

High α/β

Apr 09 10MCJ

Less effect per gray at low doses/#

n = 1 2 5 10 20

Principle of equal effect per fraction

100 20 30 40 50 60X-ray dose (Gy)

0

Full

Dam

age

= -ln

(SF)

′ E = e−αD−βD2

Low α/β

High α/β Early

Late

D

d

D

d

E´

E´

Apr 09 12MCJ

Values of α/β

for early and late responding normal tissues in animals

Early reactions

Late reactions______________________________________________________________________________________________________________________

α/β

References α/β

References______________________________________________________________________________________________________________________

Skin

Spinal cordDesquamation

9.1 -

12.5

Douglas and Fowler (1976)

Cervical

1.8 -

2.7

van der Kogel (1979)8.6 -

10.6

Joiner et al (1983)

Cervical

1.6 -

1.9

White and Hornsey (1978)9 -

12

Moulder and Fischer (1976)

Cervical

1.5 -

2.0

Ang et al (1983)Jejunum

Cervical

2.2 -

3.0

Thames et al (1988)Clones

6.0 -

8.3

Withers et al (1976)

Lumbar

3.7 -

4.5

van der Kogel (1979)6.6 -

10.7

Thames et al (1981)

Lumbar

4.1 -

4.9

White and Hornsey (1978)Colon

3.8 -

4.1

Leith et al (1981)Clones

8 -

9

Tucker et al (1983)

2.3 -

2.9

Amols, Yuhas (quoted byWeight loss

9 -

13

Terry and Denekamp (1984)

Leith et al, 1981)Testis

ColonClones

12 -

13

Thames and Withers (1980)

Weight loss

3.1 -

5.0

Terry and Denekamp (1984)Mouse lethality

Kidney30d

7 -

10

Kaplan and Brown (1952)

Rabbit

1.7 -

2.0

Caldwell (1975)30d

13 -

17

Mole (1957)

Pig

1.7 -

2.0

Hopewell and Wiernik (1977)30d

11 -

26

Paterson et al (1952)

Rats

0.5 -

3.8

van Rongen et al (1988)Tumour bed

Mouse

1.0 -

3.5

Williams and Denekamp 45d

5.6 -

6.8

Begg and Terry (1984)

Mouse 0.9 -

1.8

Stewart et al (1984 a)Mouse

1.4 -

4.3

Thames et al (1988)Lung

LD50

4.4 -

6.3

Wara et al (1973)LD50

2.8 -

4.8

Field et al (1976)LD50

2.0 -

4.2

Travis et al (1983)Breathing rate

1.9 -

3.1

Parkins and Fowler (1985)Bladder

Frequency,

5 -

10

Stewart et al (1984 b)capacity

______________________________________________________________________________________________________________________

10.6 Gy 3.0 Gy

Table 8.1, Basic Clinical Radiobiology 4th Ed

α /β ratios for human normal tissues and tumorsTissue/organ

Endpoint

α/β(Gy)

95% CL (Gy)

SourceEarly reactionsSkin Erythema 8.8 6.9; 11.6 Turesson and Thames (1989)

Erythema 12.3 1.8; 22.8 Bentzen et al. (1988)Dry desquamation ≈

8 N/A Chogule and Supe (1993)Desquamation 11.2 8.5; 17.6 Turesson and Thames (1989)

Oral mucosa Mucositis 9.3 5.8; 17.9 Denham et al. (1995)Mucositis 15 –15; 45 Rezvani et al. (1991)Mucositis ≈

8 N/A Chogule and Supe (1993)

Late reactionsSkin/vasculature Telangiectasia 2.8 1.7; 3.8 Turesson and Thames (1989)

Telangiectasia 2.6 2.2; 3.3 Bentzen et al. (1990)Telangiectasia 2.8 –0.1; 8.1 Bentzen and Overgaard (1991)

Subcutis Fibrosis 1.7 0.6; 2.6 Bentzen and Overgaard (1991)Breast Cosmetic change in appearance 3.4 2.3; 4.5 START Trialists Group (2008)

Induration (fibrosis) 3.1 1.8; 4.4 Yarnold et al. (2005)Muscle/vasculature/cartilage Impaired shoulder movement 3.5 0.7; 6.2 Bentzen et al. (1989)Nerve Brachial plexopathy < 3.5 N/A Olsen et al. (1990)

Brachial plexopathy 2 N/A Powell et al. (1990)Optic neuropathy 1.6 –7; 10 Jiang et al. (1994)

Spinal cord Myelopathy < 3.3 N/A Dische et al. (1981)Eye Corneal injury 2.9 –4; 10 Jiang et al. (1994)Bowel Stricture/perforation 3.9 2.5; 5.3 Deore et al. (1993)Bowel Various late effects 4.3 2.2; 9.6 Dische et al. (1999)Lung Pneumonitis 4.0 2.2; 5.8 Bentzen et al. (2000)

Lung fibrosis (radiological) 3.1 –0.2; 8.5 Dubray et al. (1995)Head and neck Various late effects 3.5 1.1; 5.9 Rezvani et al. (1991)Head and neck Various late effects 4.0 3.3; 5.0 Stuschke and Thames (1999)Supraglottic larynx Various late effects 3.8 0.8; 14 Maciejewski et al. (1986)Oral cavity + oropharynx Various late effects 0.8 –0.6; 2.5 Maciejewski et al. (1990)

TumoursHead and neck

Various 10.5 6.5; 29 Stuschke and Thames (1999)Larynx 14.5 4.9; 24 Rezvani et al. (1993)Vocal cord ≈

13 ‘wide’ Robertson et al. (1993)Buccal mucosa 6.6 2.9; ∞

Maciejewski et al. (1989)Tonsil 7.2 3.6; ∞

Maciejewski et al. (1989)Nasopharynx 16 –11; 43 Lee et al. (1995)

Skin 8.5 4.5; 11.3 Trott et al. (1984)Prostate 1.1 –3.3; 5.6 Bentzen and Ritter (2005)Breast 4.6 1.1; 8.1 START Trialists Group (2008)Oesophagus 4.9 1.5; 17 Geh et al. (2006)Melanoma 0.6 –1.1; 2.5 Bentzen et al. (1989)Liposarcoma 0.4 –1.4; 5.4 Thames and Suit (1986)

Mean Late 2.9Mean Early 10.6

Tumors usually >10, ? early breast & prostate

TherapeuticLossGain

Early

Late

Tumor

Apr 09 15MCJ

Hyperfractionation (HF)

Exploit the difference between the small effect of dose per fraction on tumor control versus the

larger effect of dose per fraction on the incidence and severity of late normal-tissue damage

Rationale

Apr 09 16MCJ

Hyperfractionation (HF)Reduced dose per fraction (<1.8 Gy)

Expectations (dose-escalated HF):• Increased tumor control

• More severe early reactions

• Unchanged or less late reactions

70 Gy, 2.0 Gy, 7 wCF

HF80.5 Gy, 2 x 1.15 Gy, interval = 6 h, 7 w EORTC 22791

Apr 09 17MCJ

Hyperfractionation: clinical testing

EORTC 22791; Horiot et al, Radiother Oncol 25,

231, 1992

Oropharyngeal Ca T2-3, N0-1, n = 35670 Gy, 35 x 2 Gy, 7 w vs 80.5 Gy, 70 x 1.15 Gy, 4-6 h, 7 w

Log rank p = 0.02 (Overall survival p = 0.08) Log rank p = 0.72

Apr 09 18MCJ

Hyperfractionation: clinical testing

Reduced dose per fraction (<1.8 Gy)

For 15% dose escalation in head & neck cancer:

• Increased tumor control (α/β ≥10 Gy)

• Less sparing of fibrosis than expected from LQ EORTC 22791; Horiot et al, Radiother Oncol 25,

231, 1992

80.5 Gy, 70 x 1.15 Gy, 4-6 h

• Increased late effects compared with CF RTOG 9003; Fu et al, Int J Radiat Oncol Biol Phys 48,

7, 2000

81.6 Gy, 68 x 1.2 Gy, 6 h

Apr 09 19MCJ

Hyperfractionation: summary

•

Gain from hyperfractionation only demonstrated in SCC particularly H&N

•

Sparing of late effects not as great as expected

•

Tumors with low α/β ratios are not

likely to benefit from hyperfractionation e.g. prostate, breast…?

Fractionation in prostate cancer

Mean [3.7, 2.6] = 3.15

Fractionation in breast cancer

Mean = 4.0 [CL 1.0–7.8]

43

Early prostate and breast Ca?

Late tissue α/β ratio

Apr 09 23MCJ

Accelerated fractionation (AF)

In rapidly proliferating tumors, effective dose is “lost” due to compensatory cell proliferation over 7

weeks of conventional treatment. Shortening overall treatment time would gain effective dose

and increase tumor response

Rationale

Apr 09 24MCJ

Overall treatment time: normal tissues

Data from: van der Kogel et al, 1982; Dörr & Kummermehr, 1990

No time factor for late reactions

Apr 09 25MCJ

Head & Neck cancer, Influence of overall time

Dprolif = 0.6 Gy per day Dprolif = 0.48 Gy per day

Withers et al, Acta Oncol 27,

131, 1988 Bentzen & Thames, Radiother Oncol 22,

161, 1991

Apr 09 26MCJ

Head & Neck SCC: Dprolif

Hendry et al, Clin Oncol 8,

297, 1996

00.10.20.30.40.50.60.70.8

Larynx

T2 lary

nxHea

d and nec

kOral

cavit

yOro

pharynx

T2+T3

T2+T3

Head an

d neck

T1-T3

Dpr

olif

(Gy

per d

ay)

Split-course Continuous

Mean: 0.64 Gy per day

Apr 09 27MCJ

Accelerated fractionation (AF)Shortened overall treatment time (>10 Gy per week)

Expectations:• Increased tumor control

• Increased early reactions

• Unchanged late reactions

70 Gy, 1.8-2.0 Gy, 7 wCF AF

72 Gy, 3 x 1.6 Gy, 5 w interval = 4 h, gap 12-14 d EORTC 22851

Apr 09 28MCJ

Accelerated fractionation: clinical testing

EORTC 22851; Horiot et al, Radiother Oncol 44,

111, 1997

Head and Neck SCC T2-4, N0-3, M0, WHO 0-270 Gy, 1.8-2.0 Gy, 7 w vs 72 Gy, 3 x 1.6 Gy, 4 h, 5 w

Log rank p = 0.02 Log rank p < 0.001

(grade 3 and 4)

n = 253

n = 247

Apr 09 29MCJ

Slower recovery in late-reacting tissuesRecovery T1/2 derived from analysis of the outcomes

of Continuous Hyperfractionated Accelerated RadioTherapy (CHART*) in Head and Neck SCC

Bentzen et al, Radiother Oncol 53,

219, 1999

Laryngeal Edema Telangiectasia s.c. Fibrosis

4.9 h (3.2; 6.4) 3.8 h (2.5; 4.6) 4.4 h (3.8; 4.9)

CHART

CF

*

36 x 1.5 Gy to 54 Gy, 3 fractions per day, 6 h interval, 12 days continuous

Apr 09 30MCJ

Limits to altered fractionation

With multiple fractions per day:

•

Sufficient time interval must

be kept between fractions

•

Ideally this should be ≥8 h

Apr 09 31MCJ

Limits to acceleration

Mucositis after altered fractionation in the head and neck

Data from review by Kaanders et al, Radiother Oncol 50,

247, 1999Analysed by Bentzen et al, Radiother Oncol 60,

123, 2001

40

50

60

70

80

90

0 7 14 21 28 35 42 49 56 63 70

Overall treatment time (days)

Tota

l dos

e (G

y)

AcceptableConventionalUnacceptableDividing line

Slope: 0.85 Gy/day

Apr 09 32MCJ

Six versus five fractions per week

Overgaard et al, Lancet 362,

933, 2003

Head and Neck SCC

Tumour control improved 10%

Apr 09 33MCJ

Six versus five fractions per week

Overgaard et al, Lancet 362,

933, 2003

Head and Neck SCC

•

Disease-specific survival improved

•

Acute morbidity more frequent

•

No change in late morbidity

Apr 09 34MCJ

Conclusions

•

Hyperfractionation can improve local tumor control, may be beneficial in more radioresistant cancers

•

Acceleration can improve local tumor control and survival in rapidly proliferating cancer

•

Hyperfractionation and acceleration require careful scheduling to avoid increasing late complications. Interfraction intervals >8 h recommended

•

Hypofractionation, already useful in palliation, may find a role in treating early stage cancers especially in stereotactic and image-guided delivery