R01.3: Development of Fractionation

This article is heavily based on several journal articles detailing the history of radiotherapy and fractionation, especially an article by Thames in 1992 - "On the Origins of Dose Fractionation Regimens in Radiotherapy". In fact, the entire 1st issue of the 2nd volume of "Seminars in Radiation Oncology" contains multiple articles dealing with fractionation, including CHART and other hyperfractionation studies.

There was significant debate into the 1920's as to the best method of radiotherapy treatment; some advocated for large single doses whereas others found that longer durations of treatment appeared to have better effects. The most pertinent event was the famous ram testis experiment run by Reguad in 1927 and later human trials published in 1932. Assisting the development of fractionation was more robust dosimetry.

Early Fractionation

The first successful treatments for cancer were made with fractionated radiotherapy; not deliberately intentional, but due to the fact that the early x-ray tubes were low output devices and treatment needed to be repeated daily. Due to the lack of effective dosimetry for decades after the discovery of radiotherapy, skin reaction was the only way of determining the dose. As the machines improved, the ability to deliver higher doses over a shorter period of time became available and debate about the best way of delivering radiotherapy intensified.

The Erlangen School

A group in Germany of which the most influential member was Wintz argued that single doses were the most effective, and that fractionated radiotherapy was "weak" and "primitive". This view of radiotherapy remained popular into the 1920s but increasing evidence of superior outcomes (higher cure rates and lower toxicity) gradually eradicated this method - at least until the introduction of stereotactic radiosurgery several decades later.

Regaud and the Ram Testis

Regaud studied spermatogenesis and radiotherapy in multiple animals in the first third of the 20th century. Some of his work assisted with Bergongie and Tribodeau's formulation of their law in 1906. In 1927 Regaud published his data on ram testis radiotherapy. In summary, he found that:

Sterilisation of a ram testis without acute skin reaction was only possible with fracitionated treatment (3 treatments 15 days apart)

Cure with Fractionated Treatment

From 1919 onwards, French doctor Henri Coutard began fractionated treatments at the Curie Institute in Paris for carcinomas of the head and neck - previously thought incurable. In 1932 Coutard published and presented data on cures with fractionated treatment - this included laryngeal, skin and endometrial carcinomas. Treatment was delivered in twice daily fractions using a low dose rate machine. The goal of treatment was to obtain an intense skin reaction (likely moist desquamation).

Of note, when large tumours were treated, the low dose rate was not thought necessary as the total dose was reduced. This was referred to as 'simple fractionation', the delivery of small doses with high dose rate. As Coutard's results led to the abandonment of single dose radiotherapy, many hospitals preferred the small dose/high dose rate method over the less economical low dose rate treatments.

Excessive Treatment Duration

I can not locate much information on early studies into excessive treatment duration. In the 1980s Withers, Overgaard and Fowler published papers linking prolonged treatment time (over 7 weeks) to inferior outcomes; estimates range up to 2.7% decreased local control per extra day.

Evolution of "Standard" Fractionation Schedules

In 1937 Baclesse took over from Coutard in the Curie Institute. He further extended treatment time to avoid the severe reactions seen by Coutard, limiting the daily doses to 2 Gy and protracting treatment over 6-7 weeks. Data from patients treated between 1919 and 1947 suggests that the best outcomes were seen in those receiving treatment over this time frame as opposed to longer or shorter time periods. This technique was exported to the USA around this time.

In contrast to this technique were those developed in Manchester by Paterson. Due to the usual pressures the NHS seems to have with beds and equipment, treatment times were shortened to three weeks with a corresponding drop in the total dose to compensate for larger fraction sizes. This "Manchester" technique was popular in the Commonwealth in contrast to the "Paris" technique popular in continental Europe and the USA.