La costante tentazione dei trattamenti ipofrazionati: breve cronistoria dei modelli biologici e degli effetti clinici

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Health & Medicine

Published on March 16, 2014

Author: GemelliArt



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

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

Hypofractionation Radiotherapy S. FRIBERG, B. RUDEN, 2007

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

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

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

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

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

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

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

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

• 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)

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)

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

…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”

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

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

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

• 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

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

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.

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

• 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

• 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

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

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

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.

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

Multi hit, multi-Target

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

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

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.

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

• 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

• 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.

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.

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”

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

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