24° CORSO RESIDENZIALE DI AGGIORNAMENTO con il patrocinio dell’Associazione Italiana di Radioterapia Oncologica (AIRO) Moderna Radioterapia, Nuove Tecnologie e Ipofrazionamento della Dose La costante tentazione dei trattamenti ipofrazionati: breve cronistoria dei modelli biologici e degli effetti clinici

1. La costante tentazione dei
trattamenti ipofrazionati: breve
cronistoria dei modelli biologici e
degli effetti clinici
Giovedì, 10 ottobre 2013
Prof. A. Morganti, dott.ssa G. Chiloiro, dott. M.
Vernaleone

2. Hypofractionation
Radiotherapy
S. FRIBERG, B. RUDEN, 2007

3. Radiotherapy divided into four periods
1. Gestation period
2. Birth of clinical radiotherapy
3. The coming of a new science: RADIOBIOLOGY
4. Maturation of the new science
S.FRIBERG, B.RUDEN, 2007

4. Gestation period, 1896-1922
• It started only a few years
after Roentgen’s discovery
• Philosophy: remove a
diseased block of tissue by
giving as high radiation
dose as possible in as short
time as possible, similar to
treatment of infections

5. • The first “radiotherapists” were surgeons
• George Perthes
Gestation period, 1896-1922
G. PERTHES, 1904

6. Hypofractionation examples
• 1901, Williams FH
– Treatments of superficial tumors (basal and
squamous skin cancers)
• 1910, Gosta Forssel
– “Stockolm Method” with radium-containing tubes
placed in proximity to the tumor for intensive
radiation for 24 hours

7. Gestation period, 1896-1922
Single-dose and
brutal treatment
Disastrous effects,
both early and late

8. Birth of clinical radiotherapy 1922-
1930s
• Contribution of French pioneers
• Phylosophy: “selective killing of tumour cells”,
sparing normal tissue as much as possible
• Claudius Regaud and his experiments with rams’
testis, 1905-1919:
– Cells undergoing mitosis were more sensitive to
radiation (REDISTRIBUTION, Basis of
fracionationation)
– Birth of the concept of therapeutic ratio

9. Birth of clinical radiotherapy
• Henry Coutard, fractionated low-dose
radiotherapy for H&N tumours, 1919: a
milestone in the history of radiotherapy.
– He reported on the cure rates and survival of his
patients
– He gave a detailed description about acute and
late toxicities
– He showed relationship between reactions in the
skin and mucous membranes, and dose/time

10. 1920s-1930s: Battle on fractionation
Hypofractionation (one
single fraction)
“German school”, Seitz
and Wintz
Fractionated low-dose
RT
“French school”,
Regaud and Coutard

11. • 1918, B. Kronig and W. Friederich, the dose
necessary to produce the same skin reaction
had to be increased when multiple fractions
were used (“cellular RECOVERY”)
• 1914, Schwartz, multiple small doses would be
more effective, because the time of the
highest radiosensitivity of cells was “mitosis”.
• He recommended a method of small “daily
doses” (for REDISTRIBUTION)

12. 3. Radiobiology: birth of a new science
Avoid as musch normal tissue as possible
Emphasis on detailed physical accuracy and
dosimetry
Very close cooperation between radiotherapist
and radiophycisists
Birth of RADIOBIOLOGY (thanks to
contribution of British scientists and clinicians,
1930s)

13. Fall of hypofractionation…
• 1928 – 1930, during two International
meetings, Coutard described his surprising
results about H&N cancer treatments,
attributed to the fractionation
• Hypofractionation was abandoned as a
method for curative treatment

14. …and rise
• Early 1950s, Stockolm
• Lars Leksell, a neurosurgeon, improved a
system for accurately navigating within the
skull -> “stereotaxy”
• Working with a radiation physicist, B Larsson,
they created the 1st “GAMMA KNIFE”

15. Hypofractionation: 1960’s
Introduction megavoltage machine
“Because the greatest part of
the time used to treat a patient is
spent on the set-up, the actual
treatment time being only a
fraction of the total time, it was
logical to use fewer large fractions
to decrease machine time”
Gilbert Fletcher

16. Mathematical formulae in radioterapy
• Nominal Standard Dose (NSD) (Ellis 1969):
D= K1 T 0.22 T 0.11
• Skin experiments by Fowler and Stern shown
that the isoeffect dose is also function of
number of fractions.
NSD= D N -0.24 T -0.11

17. Mathematical formulae in radioterapy
• Cumulative Response Dose (CRE) (Kirk 1971):
CRE= D n-0.24 t -0.11
As a generalized form of the empirical
function of NSD

18. • Time Dose Fractionation Factor (TDF) (Ellis &
Orton 1969:
TDF= d 1.538 nx-0,169 10-3
• The tollerace directly proportional to the
number of fractions and hence to the total
dose
Mathematical formulae in radioterapy

19. • Tumour Significant Dose (TSD) (Ellis & Lanberg
1969-1973):
TSD= D n-0.18 t-0.06
Mathematical formulae in radioterapy

20. Limitations of NSD, CRE, TDF and TSD
• Don’t take account of the complex biological
process during and after radiotherapy;
• NSD don’t take account of the different
tollerance of tissue;
• Time factor T0.11 suggest increase dose in the
first 3 weeks.

21. Breast radiation injury
1960’s to 1980: hundreds of women with
severe injuries:
– Complete paralysis of the arm and hand;
– Chronic pain;
– Multiple fractures in the arm and thoracic
skeleton;
– Necroses of the skin with chronic infections;
– Severe heart disease
– Oedema in the whole extremity

22. • 1962: 3 treatments vs 5 treatments per weeks
in breast cancer
– Same acute skin reactions
Montague E.D Radiology 90 1968 962-966
Fletcher G. Radiotherapy and Oncology 20 1991 10-15
Breast dose 60 Gy/8 wk;
Axilla 50Gy / 5 wk
88 pts 5 days per week
57 pts 3 days per week
% of severe complications 5 fractions7wk 3 fractions/wk
Severe axillary fibrosis and frozen
shoulder
2 11.5
Chest wall necrosis and fibrosis:
multiple rib fractures
3 13

23. • 1975: St. Thomas Hospital in London
experience with hyperbaric tanks
– 30% arm edema;
– Follow-up a 10 years : telangiectasia, skin atrophy,
subcutaneous fibrosis,
limitation shoulder motion
and arm edema
Schedule A Schedule B
53.5Gy /12 fractions /28 days 36Gy/6 fractions/18days
Bates T.D. Clin radiol 26 1975 297-304
Bates T.D. Br. J. Radiol61 1988 625-630

24. Norway hypofractionated case
• 1975- 1986:
– 4.3 Gy x 10 fractions
• 1998:
- Norwegian Government allotted 89.000. 000 Norwegian
Crowns to compensate 130 injured women out of 230 still
living

25. Group I
40Gy WP in 20 fractions
(TDF:66) + intracavitary
gamma-ray
Group II
5 weekly doses of 5.8Gy
(TDF:66) + intracavitary
gamma-ray
No of patients 19 20
No complications 11 0
Proctitis lasting over 6
mounth
8 8
Severe bowel
complications
0 10 (3 dead)
Rectovaginal fistula 0 2
Edema of vulva 0 2
Cervical cancer
Fletcher G. Rad Onc 20 1991 10-15

26. Reawakening of hypofractionation:
1990’s
• Linear Quadratic formula (LQ):
• BASIC ASSUPTIONS:
– Directly effective lesions vs subeffective lesions;
– Half life of repare subeffective lesions 0.5 to 4 hrs;
– Reponse level consequence of a single dose or of
a series of fractions.

27. Single hit, multi-Target
• Poisson dose-response model:
– Damage every potential malignant cell;
– Random nature of cell killing based on probability
– Probability depends on the average number of
clonogens surviving for tumour

28. Multi hit, multi-Target

29. Reawakening of hypofractionation:
1990’s
• Linear Quadratic formula (LQ):
– Relationship between total isoeffective dose and
dose per fraction in fractionated radiotherapy.
– Biological effect of radiation depend on linear
term (αD) and a quadratic term (βD2)
SF= SF linear x SF quadratic

30. Reawakening of hypofractionation:
1990’s
– Withers 1988: definition of acute and late
responders

32. Reawakening of hypofractionation:
1990’s
• New indication:
– Palliative care;
– Soft- tessue metastases;
– Some tumours as melanoma, liposarcoma,
hypernephroma;
– Rectal cancer prior to surgery;
– Cancer of Urinary bladder, breast and prostate.

33. Hypofractionation breast cancer
START A: 50Gy in 25 fractions
vs
41.6Gy or 39Gy in15 fractions
START B 50Gy in 25 fractions
vs
40Gy in15 fractions
ENDPOINTS: local- regional relapse
and late normal tissue effects

34. • START A:
10-years local-regional relapse no
differ between 39 Gy, 41.6Gy and
50Gy (8.8% vs 6,3% vs 7,45)
Breast shrinkage and induration most
frequent late effect at 10 years:
39Gy: 7% breast edema, 21% breast
induration, 3% telangiectasia, than in
50Gy regime group.
No significantly differences between
41.6Gy and 50Gy groups

35. • START B:
10-years local-regional relapse no
differ significantly between 40Gy
and 50Gy (4.3% vs 5.5%)
Breast shrinkage and induration most
frequent late effect at 10 years:
Breast shrinkage, telangiectasia and
brest edema significantly lower in 40Gy
group.

36. Conclusions
• Short course of treatment decrease cellular
proliferation
• Hypofractionated and accelerated schedules
may lead to better tumor control.
• Need of exact target area supported by
imaging, precise treatment machines,
immobilization systems, flexible multileaf
collimators.

37. Paradox
The Erlangen school in the 1920’s supported the
single dose treatment
“Tumor cells are fast-growing; they must be
killed fast”.
The re-introduction of hypofractionation was
based on:
“slow-growing tumour cells must be killed
rapidly to prevent repopulation”

38. “Sometimes to cure, often to
care, but above all, never to
injure” Hippocrates, 400 a.C.