Rectal cancer irradiation. Long course, short course or something else?

Preoperative radiotherapy has repeatedly been shown to reduce the risk of a local failure in a primary rectal cancer considered to be resectable. In a locally advanced rectal cancer with overgrowth to surrounding non-resectable structures (the more advanced T4s), preoperative radiotherapy, presently together with chemotherapy [1], may allow radical (R0) resection in a substantial proportion of the cases. The ability to decrease local failures in the resectable cases is seen also if surgery is optimized, according to the total mesorectal excision (TME) principles [2]. Postoperative radiotherapy, even if combined with chemotherapy has less effects and is also more toxic than preoperative radiotherapy, as shown in several randomised trials [3 6]. The preoperative hypofractionated, short course 5 /5 Gy radiation schedule and immediate surgery has ever since it was originally explored in the late 1970s, been an attractive alternative to a conventional long course schedule using 1.8 2 Gy per fraction to a dose of about 45 50 Gy. Actually, more patients have probably been included in randomised trials where 5 /5 Gy has been one treatment group than in trials exploring conventionally fractionated schedules. The 5 /5 Gy schedule reduces local failure rates and improves survival with the previous type of surgery (blunt dissection) [7 9] and reduces local failure rates with TME [2]. The incremental gain in local failure reduction together with TME (about 6%-units) is likely too small to show-up as a survival gain even in a trial including 1 800 patients [10]. Recently, preoperative short course 5 /5 Gy was as effective as preoperative long course radiochemotherapy (50 Gy with 5FU) in one trial (local failure rate 11% vs 16%, p /0.23, identical survival) [11] and superior to postoperative radiochemotherapy (45 Gy /5FU) given to patients at high risk for a local failure (local recurrence at 5 years 5% vs 17%, pB/0.0001; disease-free survival 75% vs 67%, p /0.03; overall survival 72% vs 62%, p /0.07) in another trial [5]. Acute toxicity was in both trials much less using 5 /5 Gy, and late toxicity did not differ, however, only with limited follow-up. Hypofractionation, i.e. giving the radiotherapy in fractions above 2 Gy has the advantage of shortening treatment times and reducing the burden to radiotherapy departments. Hypofractionation has, however, also the disadvantage of diminishing the therapeutic index with a particular risk of increased late toxicity. Actually, experience has repeatedly learned that many hypofractionated schedules have resulted in unacceptable late toxicity rates and there is a wide spread, and sound scepticism against any type of hypofractionation. The most recent trends in increased use of hypofractionated radiotherapy in for example breast [12] and prostate cancer [13] have raised genuine concerns of ‘do we have to learn the lesson once more’. These concerns are naturally present also for the rectal cancer 5 /5 Gy schedule not only among those who for theoretical or practical reasons dislike hypofractionation but also among those running the trials. Actually, much more knowledge about late adverse effects are known from the 5 /5 Gy trials than for any of the conventional radio(chemo)therapy schedules. We thus reasonably well know the scale of morbidity that can be seen after 5 /5 Gy with a follow-up to about 15 years [3,14 20]. For most rectal cancer patients, where median age at diagnosis is above 70 years, a 15 year follow-up