Breast Cancer Radiotherapy: A Possibility For Fewer Doses

Breast cancer patients can receive radiotherapy in a lower overall dose, given in fewer, larger administrations, while maintaining similar tumor control and creating fewer adverse side effects than current therapy. These conclusions come from the United Kingdom's Standardization of Breast Radiotherapy Trials A and B (START A and B), and were released on March 19, 2008 in Lancet Oncology and The Lancet respectively.

The international standard radiotherapy schedule for early breast cancer administers 50 Grays (Gy) of radiation total, separated into 25 small fractions of 2.0 Gy over five weeks. Cancer specialists have long believed that, when delivered in fewer, larger fractions, a lower total dose could be as safe and effective as this standard.

The START trials collaborative group, including Professor John Yarnold, Institute of Cancer Research and Royal Marsden Hospital, Sutton, Surrey, UK, and Professor Judith Bliss, Clinical Trials and Statistics Unit, Institute of Cancer Research, Sutton, UK, and colleagues from 35 UK cancer centers investigated this option. The study took ten years, and was jointly funded by Cancer Research UK, the UK Medical Research Council, and the UK Department of Health.

START A was comprised of 2,236 women with early breast cancer at 17 different centers in the UK. They were randomly assigned, after primary surgery to one of the following groups:

* 34% (749 women) to receive 50 Gy total in 25 fractions of 2.0 Gy each, the highest total dosage and the international standard;
* 34% (750 women) to receive 41.6 Gy total in 13 fractions of 3.2 Gy each, the intermediate total dosage;
* 33% (737 women) to receive 39 Gy total in 13 fractions of 3.0 Gy each, the lowest total dosage.

Treatment was administered in all groups over a five week period. Women were considered eligible if they were over 18 years of age, did not have immediate surgical reconstruction, and were available for follow up. The endpoints of the trial were: tumor relapse, which was defined as cancer reappearance at the sites which were irradiated; any effects of the treatment on normal or "cancer free" tissues; and effects on the quality of life for the patient.

After a median follow up of 5.1 years, tumor relapse at five years was 3.6% for the highest total dosage group (50 Gy), 3.5% for the intermediate total dosage (41.6 Gy) and 5.2% for the lowest total dosage group (39 Gy.) Late adverse effects and local tumor relapse rates for the highest and intermediate total dosages were similar, which in the lowest dose the absolute difference could range from 1.3% better to 2.6% worse in the lowest dose group. Patient self-assessments as well as photographic surveys indicated that there were lower rates of late adverse effects in the lowest dosage group than in the highest.

In conclusion to the START A study, the authors state that this modification to the international standard regimen could have promise: "A lower total dose (41·6 Gy) in a smaller number of fractions could offer similar rates of tumor control and normal tissue damage as the international standard fractionation schedule of 50 Gy in 25 fractions."

START B tested 2,215 women with early breast cancer at 23 centers in the UK. They were also randomly assigned after primary surgery, but to one of the following groups:

* 50% (1105 women) to receive 50 Gy total in 25 fractions of 2.0 Gy each, over 5 weeks, the international standard;
* 50% (1110 women) to receive 40 Gy total in 15 fractions of 2.67 Gy each, over 3 weeks, a lower total dose and a shorter administration period.

Just as in START A, women were considered eligible if they were over 18 years of age, did not have immediate surgical reconstruction, and were available for follow up. Additionally, the measured endpoints of the trial were: tumor relapse, any effects of the treatment on normal or "cancer free" tissues, and effects on the quality of life for the patient.

In a median follow-up of 6.0 years, the rate of tumor relapse at five years was 2.2% in the shorter and lower total dosage group and 3.3% in the international standard group. Statistically, this represents an absolute difference ranging from 0.9% worse and 1.7% better in this group from the standard. Photographic evidence and patient self-assessments both confirmed that lower rates of adverse events were seen after the lower, shorter dose.

From these results of the START B study, the authors conclude that this lower dose in combination with the shorter total administration time can also yield comparable results to the presently used standard: "After surgery for early breast cancer, a radiotherapy schedule delivering 40 Gy in 15 fractions over three weeks seems to offer local regional tumor control and rates of late normal tissue effects at least as good as the accepted international standard of 50 Gy in 25 fractions over five weeks."

Dr. Harry Bartelink, Netherlands Cancer Institute, Amsterdam, Netherlands, and Dr. Rodrigo Arriagada, Institut Gustave Roussy, Villejuif, France, contributed an accompanying comment in which they note the merits of this new therapy while caution against sudden changes in in the international standard treatment regimen: "We realise that hypofractionation is convenient for patients, because it reduces the number of visits to radiotherapy departments and waiting lists in several cancer centers. Nevertheless we have to wait for data on longer follow-up before final conclusions can be drawn from the START trials."

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