How altered fractionation effects the radiation treatment

1. RADIOBIOLOGY OF ALTERED
FRACTIONATION
DR. RUBY GHOSH
1st year PG, DNB Radiation Oncology
HCG Hospital

2. 1. INTRODUCTION
2. HISTORY
3. RADIOBIOLOGIC PRINCIPLES
4. CLASSIFICATION OF ALTERED FRACTIONATION
5. COMPARISON
CONTENTS

3.  Multifraction regimens commonly used in conventional Radiation therapy are
a consequence of Radiobiologic experiments performed in France in the
1920s and in the 1930s.
 It was concluded that fractionation of the radiation dose produces, in most
cases, better tumor control for a given level of normal tissue toxicity than a
single dose.
 Implementation of altered fractionation schedules in clinical practice came as
a need to improve loco-regional control and survival in those cancer patient
groups which did not respond satisfactorily to conventionally fractionated
radiotherapy.
INTRODUCTION

4. HISTORY - RAM EXPERIMENT
• Based on experiments performed in Paris in the
1920s and 1930s, the effect of fractionation on
the sterilization of rams was used to justify the
need to fractionate.
• It was possible to sterilize rams by irradiation of
their testes without excessive damage to the skin
of the scrotum only if the treatments were
fractionated.
• When single doses were given, such sterilization
was possible only with induction of unacceptable
skin damage.
• Regaud postulated that the testes could be
considered a good model to simulate a rapidly
dividing cancer and, therefore, fractionation
ought to allow a cancerocidal dose to be
delivered without exceeding normal tissue
tolerance.

5. HISTORY
• This led to a careful study of fractionated radiotherapy by Henri Coutard at the
Curie Institute in Paris.
• The debate over fractionation was not settled until 1932, when Coutard published
the excellent results obtained using fractionated radiotherapy.
• Fractionation was thereafter established as the standard of practice of
radiotherapy.
• It is only relatively recently that the radiobiologic rationales for fractionated
radiotherapy have been fully understood.

6. RADIOBIOLOGIC PRINCIPLES OF FRACTIONATION
• Basic principle of Radiotherapy : Destruction of all cancer cells without killing so many
normal cells as to exceed tolerance.
• Rationale behind fractionation is explained by the 4 Rs of Radiobiology: Repair of
sublethal damage, Reassortment of cells within cell cycle, Repopulation,
Reoxygenation
• Dividing a dose into several fractions spares normal tissues because of repair of
sublethal damage between dose fractions and repopulation of cells if the overall time
is sufficiently long.
• Dividing a dose into several fractions increases damage to the tumour because of the
reoxygenation and reassortment of cells into radiosensitive phases of the cycle
between dose fractions.

7. CELL SURVIVAL CURVE
It is a plot of the fraction of surviving
cells (log scale) as a function of dose
(linear scale).
Over a larger dose range, the
relationship between cell killing and
dose is more complex and is described
by- initial slope (D1); final slope (Do)

8. LINEAR QUADRATIC MODEL

9. Response of all normal tissues to Radiation is
not the same.
Early responding tissues: Constitute fat
proliferating cells such as skin, mucosa, intestinal
epithelium, colon, testis
Late responding tissues: Have large number of
cells in the resting phase eg. Spinal cord,
Bladder, Lung, Kidney
EARLY AND LATE RESPONDING TISSUES

10. SURVIVAL CURVE IN EARLY & LATE RESPONDING TISSUES

11. CLASSIFICATION OF ALTERED FRACTIONATION
• HYPERFRACTIONATION
• ACCELERATED FRACTIONATION – TYPE A, TYPE B, TYPE C
• HYPOFRACTIONATION

12. • Fraction sizes of 1.8 - 2 Gy
• 1 fraction per day
• 5 fractions per week
• Total dose varies for different tumours
• Convenient - No weekend treatments
• Efficient - Treatment every weekday
• Effective - High doses can be delivered without exceeding either acute or
chronic normal tissue tolerance).
CONVENTIONAL FRACTIONATION

13. • Delivery of Radiation in small-dose fractions (2-3 times / day)
• More than one fraction / day but the overall treatment time remains similar to that for conventional
fractionation.
• Typically- 1.2 to 1.3 Gy/fraction, two fractions a day, with an increase in total dose of the order of 20% to
30% to account for increased repair at the lower dose per fraction.
• Major rationale - to take maximal advantage of the difference in repair capacity of late-reacting normal
tissues compared with tumors.
• Aims to improve therapeutic ratio, reducing the dose in each fraction, so as to reduce late side effects while
also permitting an increased total dose to the tumour.
• With such a low dose per fraction, more than one fraction per day is necessary to keep the course of therapy
short enough to avoid the risk of excessive tumor cell repopulation.
• Furthermore, to treat with higher than 1.3 Gy/fraction at more than one fraction per day may exceed acute
tolerance, and to use <1.2 Gy/fraction will require three fractions per day in order not to increase overall
treatment time.
• Hence hyperfractionation usually is 1.2 to 1.3 Gy/fraction, two fractions a day.
The delivery of total dose in a larger number of fractions than conventional fractionation
HYPERFRACTIONATION

14. • Greatest benefit for the treatment of patients with head and neck,
bladder, lung, brainstem tumors, whole brain radiotherapy for
pediatric acute lymphoblastic leukemia, whole brain radiotherapy for
brain metastases, and rhabdomyosarcoma.
• The most striking results are from trials in head and neck squamous-
cell carcinoma (HNSCC) where hyperfractionation was accompanied
by an increase in dose.
HYPERFRACTIONATION

15. • Alternative to hyperfractionation.
• Rationale: To reduce repopulation in rapidly proliferating tumours by reducing
overall treatment time.
• For rapidly growing tumors with short potential doubling times of the viable
cycling cancer cells .
• Especially important for types of tumors that exhibit accelerated repopulation.
• Ways to achieve reduced overall treatment time:
oModest acceleration - to treat 6 or 7 days a week instead of the normal 5,
keeping the dose per fraction the same as with conventional fractionation..
oDrastic acceleration - Twice a day at 1.4 to 1.6 Gy/fraction, but only at the risk of
exceeding acute normal tissue tolerance. unsuccessful because many patients
had to be given a rest of 1 to 2 weeks during the course of therapy to allow acute
reactions to subside.
The delivery of dose over a shorter time than conventional fractionation
ACCELERATED FRACTIONATION

16. • Another possibility is to increase the dose per fraction to approximately 2.5 Gy
(k/a rapid fractionation), but this risks losing the repair advantage of late-
responding normal tissues.
• Acceleration achieves significantly improved local control for well-differentiated
tumors and advanced primary mucosal site tumors but may be of little benefit to
advanced nodal disease and poorly differentiated tumors. This supports the
existence of the accelerated proliferation phenomenon in mucosa-derived tumor
cells.
ACCELERATED FRACTIONATION

17. • Major problem - cancerocidal doses delivered in such short overall times are
likely to exceed acute tolerance.
• One way around this is to complete the treatments in such a short time that the
acute reactions reach their peak only after the radiotherapy has been completed.
Continuous hyperfractionated accelerated radiotherapy (CHART)
• Treatments 6 hours apart are delivered three times a day, 7 days a week. With a
dose fraction of 1.5 Gy, a total dose of 54 Gy can be delivered in 36 fractions over
12 successive treatment days including weekends.

18. • Characteristics: Low dose, short treatment time, No gap in treatment (3/day at 6
hr interval)
• These patients have had to be hospitalized for several weeks after irradiation to
treat very painful and often life-threatening acute reactions.
• CHART is also difficult for the staff, since delivery of three fractions per day 6
hours apart for 12 successive days, including weekends, is very inconvenient.
• 54 Gy at 1.5 Gy/fraction at three fractions/day is delivered over a total of 16 days
without the weekend treatments).
CHART

19. • Good local tumour control owing to short overall time
• Acute reactions that are brisk but peak after treatment is completed.
• Most late effects acceptable because of small dose per fraction
• Exception: Spinal cord with severe myelopathies occurring at 50 Gy because the
time between fractions was too short.
Continuous hyperfractionated accelerated radiotherapy (CHART)
CHART

20. • Total dose is delivered in two halves with a gap in between with interval of 4
weeks.
• Purpose of gap is: To allow elderly patients to recover from acute reactions of
treatment, further morbidity who have poorly tolerated or disease progressed
despite treatment.
• Applied to elderly patients in radical treatment of Ca Bladder, Prostate and Lung
cancer.
A planned gap of at least several days during a course of treatment
SPLIT-COURSE ACCELERATED FRACTIONATION REGIMEN (TYPE B)

21.  Designed at the M.D. Anderson Cancer Center
 54 Gy of wide-field irradiation in 1.8-Gy fractions over 6 weeks and 18 Gy of boost dose
given in 1.5-Gy fractions as second daily fractions during the last 2.5 weeks, - also
addressed by the RTOG.
 Found to improve the locoregional control rate with a strong trend for a higher disease-
free survival rate, with more severe mucositis but no detectable increase in late
complications.
 Acceleration does not seem worthwhile postoperatively for carcinoma of the head and
neck, although it might be an option for patients who delay starting radiotherapy.
The delivery of treatment to a boost volume during the primary treatment
CONCOMITANT BOOST ACCELERATED FRACTIONATION REGIMEN (TYPE C)

22. COMPARISON OF CONVENTIONAL AND ACCELERATED FRACTIONATED
SCHEDULES

23. High dose is delivered in 2-3 fractions/ week
Rationale: Treatment completed in shorter period of time, higher dose gives
better control for larger tumours, also useful for hypoxic fraction.
Typical hypofractionation schemes range from as many as 10 fractions of 3 Gy to
as few as a single fraction of approximately 10 Gy, with anything from one to five
fractions/week.
Larger doses of radiation per treatment fraction delivering a full course of
treatment over a shorter period of time compared to conventional fractionation
2.25 - >20 Gy per day
Applications: SBRT (lung, liver), pre-op rectal, glottic larynx
The delivery of total dose in fewer numbers of fractions than conventional fractionation
HYPOFRACTIONATION

24. • Increased dose per fraction→ increased tumor kill
• Relative dose to late-responding tissues is higher than to early-responding
tissues (mucosa, tumor) raising concerns about late-tissue toxicity
HYPOFRACTIONATION - RADIOBIOLOGY

25. Reduced cost (fewer fractions)
Increased convenience (1-3 weeks vs 6-7)
Decreased patient travel and lodging
Increased treatment compliance and acceptance of therapy
Improved access to care
Machine time well utilized for busy centres.
HYPOFRACTIONATION - BENEFITS

26. • Late normal tissue toxicity
• Cosmesis
• Loco-regional control
Biologically equivalent dose may actually be less than compared to standard
fractionation
HYPOFRACTIONATION - DISADVANTAGES

27. • Some exceptional instances where hypofractionated treatments are used for
curative radiotherapy: Stereotactic radiosurgery and high dose-rate
brachytherapy.
• Suggested for prostate cancer, for which α/βvalues -1.5 Gy - hypofractionation
for prostate cancer might be the preferred treatment.
HYPOFRACTIONATION

28. COMPARISON OF DIFFERENT FRACTIONATION SCHEDULES

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