Altered Fractionation

This is probably a good place to quote Withers (from Hall):

"Fraction size is the dominant factor in determining late effects; overall treatment time has little influence. By contrast, fraction size and overall treatment time both determine the response of acutely responding tissues"

Treatment Type Total Dose Overall Time Fraction Size Daily Fractions Weekly Fractions Tumour Control Early Effects Late Effects
Conventional Standard 5 - 7 weeks 1.8 - 2 Gy 1 5 Normal Normal Normal
Hypofractionation Reduced 3 - 5 weeks > 2 Gy 1 5 (or less) Worse Improved Worse (but reduced dose may keep within tolerance)
Hyperfractionation
(EORTC 22791)
Increased 7 weeks 1.15 Gy 2 10 Improved Unchanged Improved
Accelerated Conventional
(eg. DAHANCA 6/7)
Standard 4 - 6 weeks 1.8 - 2 Gy 1 > 5 Improved Worse Unchanged
Accelerated Hyperfractionated
(eg. CHART, EORTC)
Reduced < 5 weeks < 1.8 Gy 2+ 10+ Improved Worse Unchanged (if sufficient time between fractions) or Worse
Concomittant Boost Standard < 5 weeks 1.8 - 2 Gy 1 (initial), 2 (boost) 5 (initial), 10 (boost) Improved Worse Unchanged (if sufficient time between fractions) or Worse
Split Course Standard Conventional + Gap 1.8 - 2 Gy 1 5 Worse Improved Unchanged

'Conventional' Fractionation

What is conventional fractionation?

  • Fraction sizes of 1.8 - 2 Gy
  • 1 fraction per day
  • 5 fractions per week

The total dose varies for different tumours. Lymphoma may require 30 Gy; head and neck cancers typically receive 70 Gy. Conventional fractionation often uses a shrinking field technique, where the site of highest concentration of tumour cells receives additional dose. This is commonly referred to as a boost.
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Hypofractionation

The delivery of total dose in fewer numbers of fractions than conventional fractionation

Hypofractionation involves the use of a smaller number of larger fractions. It is frequently used in palliative treatments as it allows a large dose to be delivered without inconveniencing the patient greatly. Palliative patients are unlikely to live for long enough to experience the increased late tissue toxicity seen with hypofractionated treatment.
Hypofractionation may also have a role to play in slower growing tumours with a low alpha/beta ratio (eg prostate cancer). These tumours are more resistant to small fraction sizes and would benefit from fewer, larger fractions. This is complicated by increased normal tissue toxicity when these schedules are used. Hypofractionation is possible with high dose rate brachytherapy, which limits the normal tissue volume receiving the larger dose.

Advantages

  • Shorter treatment length
  • Increased effect on low alpha/beta ratio tumours such as prostate cancer

Disadvantages

  • Increased rate of late effects in normal tissues
  • Less chance of reoxygenation and redistribution to occur

Hyperfractionation

The delivery of total dose in a larger number of fractions than conventional fractionation

The rationale underlying hyperfractionated radiotherapy is that late responding tissues are generally more sensitive to large fraction sizes (low alpha/beta ratio), but many rapidly growing tumours remain sensitive even at low fraction sizes. This is offset by the increased tumour repopulation that occurs after 3 – 5 weeks. Hyperfractionation treatments are generally delivered as two treatments per day, often with a slightly higher overall dose than conventional fractionation to account for the reduction in cell kill that occurs with smaller fraction sizes.

EORTC 22791

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The EORTC 22791 trial demonstrated the benefits of hyperfractionation. This trial used twice daily treatments of 1.15 Gy, delivered over seven weeks, for a total dose of 80.5 Gy (significantly more than the conventional fractionation scheme of 70 Gy).
This study of hyperfractionation showed:
  • Increased local control and overall survival rates
  • No increase in early or late side effects
  • Advantage for hyperfractionation over standard fractionation in head and neck cancer

There are benefits to be obtained with hyperfractionated treatment, however this needs to be considered with the increased resource use that the treatment entails.
Two important points:

  • When used alone without accelerated treatment, hyperfractionation results in reduced cell kill and poorer outcomes.
  • If multiple doses are given on the same day, caution must be used as some late responding tissues have a slow repair time (particularly the spinal cord) - see the accelerated section below.

Accelerated Fractionation

The delivery of dose over a shorter time than conventional fractionation

Accelerated fractionation attempts to overcome accelerated tumour repopulation by reducing total treatment time. In practice, accelerated treatments involve delivering additional fractions per day; these fractions are usually a bit smaller than conventional fractions. Most accelerated fractionation studies have had a similar overall treatment time due to gaps needed for recovery of severe acute effects; the only exception is the Continuous Hyperfractionated Accelerated RadioTherapy (CHART) schedule which included no gaps and completed a full course over 12 days.

EORTC 22851

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This protocol was an attempt at accelerated treatment. Three fractions were of 1.6 Gy were delivered per day, five days per week. Treatment was given over 7 weeks, including a 2 week gap to allow some recovery from early effects.
This protocol:
  • Improved local control
  • No change in survival
  • Increased rates of early toxicity
  • Increased rates of late toxicity (including death)

Why did this trial do so badly? There are two major factors:

  • There was insufficient time between fractions for late responding tissues to repair damage
  • There was such a high degree of early toxicity that consequential late effects were more prevalent.
  • There was a gap in treatment, negating the benefit of the accelerated treatment

CHART

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CHART stands for Continuous Hyperfractionated Accelerated RadioTherapy, and is a very different schedule. Three fractions of 1.5 Gy were given per day, continuously for 12 days, for a total dose of 54 Gy in 36 fractions. The reduced dose was possible because of the reduced treatment time.
This protocol:

  • Improved local control
  • Increased early toxicity that only reached Grade III toxicity after the completion of radiotherapy (good complicance)
  • Similar or reduced late toxicity, with the exception of spinal cord toxicity which was increased

The major problem with CHART was the time involved to treat patients (at least 12 hours per day required if the patient is treated at 8 am, 2 pm and 8 pm), and the spinal cord toxicity.

Concomitant Boost

The delivery of treatment to a boost volume during the primary treatment

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Concomitant boost is a type of accelerated treatment, as the total dose is delivered in a shorter time. The boost treatment is usually given on the same day, split by 6 - 8 hours from the main treatment to allow some repair to occur. The advantages of utilising concomitant boost are:
  • Improved rate of local control
  • Improved overall survival
  • Increased rate of early toxicity
  • No increased rates of late toxicity (if sufficient time is allowed between main treatment and boost dose)

Similar to standard accelerated treatment, the disadvantage of concomitant boost treatment is an increased rate of early toxicity. However, evidence suggests that late side effects appear to occur with similar frequency to standard fractionation.

Split Course Treatment

A planned gap of at least several days during a course of treatment

Split course treatments are not frequently used except in some palliative settings. For each day added to treatment time, extra dose needs to be given to account for tumour repopulation. In rapidly repopulating tumours this may be up to 0.6 Gy/day. Split course treatments may be better tolerated but also have a significantly poorer outcome in terms of cure.

Advantages

  • Allow time for normal tissue healing to occur to reduce early side effects

Disadvantages

  • Tumour repopulation occurs in the interval between treatments
  • Similar rates of late effects (dependent on total dose)
  • Patient has a longer time between start and finish of treatment

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