HERBERT II: external beam radiation therapy followed by high-dose rate endorectal brachytherapy (HDRBT) in elderly early rectal cancer patients not undergoing surgery: A randomized multicenter phase III study

The incidence of rectal cancer in elderly patients is increasing due to
screening and aging of the population. While TME surgery with or without
pre-operative radio(chemo)therapy is the standard treatment for rectal cancer,
the risk of surgical complications and post-operative mortality rises with
increasing age and comorbidity. Postoperative complications occur in
approximately 50% in patients older than 75 years and one-month postoperative
mortality in patients aged 75-95 with an American Society of Anaesthesiology
classification of II-IV ranges from 5.4%-28.0%. At 6 months, this results in an
overall mortality of 13.4% in patients aged 75-85 increasing and almost 30% in
patients of 85-95 years. Because patients who are unfit for surgery, are
usually also unfit for chemotherapy, they are often offered palliative
radiotherapy to reduce symptoms. There are however indications that patients
might benefit from a more radical approach using radiotherapy alone.
To achieve local control with radiotherapy alone high doses must be delivered.
With standard doses external beam chemoradiotherapy (EBRT, 45-50 Gy) a complete
pathologic response (pCR) is observed in approximately 16%. Dose response
analyses indicate that doses as high as 92 Gy (EQD2) are needed to achieve pCR
in 50% of patients. To further escalate the dose without exceeding normal
tissue tolerance, local boosts on the tumour can be applied with various
techniques. The attraction of intracavitary irradiation, either by contact
therapy or by endoluminal brachytherapy lies in the ability to deliver a
localised high dose with rapid fall-off and sparing of adjacent normal tissues.
Combining EBRT with intracavitary irradiation in such a way that the chances of
local control are increased without causing excessive toxicity, therefore seems
a promising option.
In medically inoperable rectal cancer patients, there is no standard treatment
schedule for radiotherapy. This led to the initiation of a dose escalation
study in this patient group by the LUMC, called the HERBERT trial. The
treatment schedule consisted of 13 fractions of 3 Gy EBRT, followed by high
dose rate endoluminal brachytherapy (HDREBT) 6 weeks later. The brachytherapy
was given in 3 fractions with the starting dose level being 3x5 Gy, prescribed
at the depth of the tumor. Eventually, 38 patients have been included and the
maximum tolerated dose has been reached at a level of 3x7 Gy, with clinical
grade 3 proctitis being the dose limiting factor. In total, clinical response
could be evaluated in 33 patients. Seven patients (21%) had a complete response
after EBRT, whereas an additional 13 achieved a complete response after the
brachytherapy, resulting in 60% complete responders in total. None of the
patients demonstrated progressive disease in the evaluation 6 weeks after the
EBRT. However, of the 5 patients with stable disease (SD), none reached a
complete response. Patient reported bowel symptoms showed a marked increase at
the end of EBRT and two weeks after HDREBT. Acute grade 2 and 3 proctitis
occurred in 68.4% and 13.2% respectively while late grade 2 and >=3 proctitis
occurred in 52% and 36%. Endoscopic evaluation mainly showed erythema and
telangiectasia. In three patients frank haemorrhage or ulceration occurred.
Most severe toxicity was observed 12-18 months after treatment.
Based on this study, it was concluded that for elderly patients with rectal
cancer, definitive radiotherapy can provide good tumour response but has a
substantial risk of toxicity. The potential benefit and risks of a HDREBT boost
above EBRT alone must be further evaluated.

To assess the added value of a brachytherapy boost after external beam
radiotherapy in elderly, frail patients with rectal cancer.

A total of 110 patients will be included and receive EBRT in 13 fractions of 3
Gy to the mesorectum. Patients will then be evaluated and if there is no
progressive disease they will be randomized between no further treatment or a
HDR endorectal brachytherapy boost to the primary tumour in 3 fractions of 7
Gy, given one a week. The first fraction of brachytherapy should take place
within an interval of 11-15 weeks after EBRT.

Control group of EBRT (13 fractions of 3 Gy) alone versus intervention group
EBRT + HDREBT (13 fractions of 3 Gy + 3 fractions of 7 Gy). For patients
randomized to the intervention group, the HDR boost will be given at least 10
weeks after end of EBRT.

Patients included in this study will receive multiple additional examinations.
Prior to the EBRT treatment, all patients will receive a sigmoidoscopy during
which reference markers will be placed to mark the tumor borders. The expected
complication risks of the endoscopy and the marker placement are very limited.
A very low rate of pain, bleeding or infectious complications has been reported
in previous transrectal marker placement or rectal marker placement studies.
Similar results have been found in the recently performed REMARK study with
gold fiducial markers. The endoscopy and fiducial marker placement will last
about 30 minutes.
Patients will undergo the multi-parametric MRI exam 3 additional times in this
study. The repeat of the MRI exam causes a negligible risk for the patient.
Patients in the intervention group will receive endoluminal brachytherapy. The
brachytherapy fractions will be delivered using a endorectal applicator
(Intracavitary Mold Applicator, Elketa, Veenendaal, The Netherlands) with a
diameter of 2 centimeter, consisting of a central flexible tube with 8
catheters arranged around the circumference of a central tube. Patients in both
the control and the intervention groups will fill in questionnaires about their
experiences with the treatment and to evaluate the willingness of patients to
receive endoluminale brachytherapy. Expected complications of endoluminal
brachytherapy are limited. However, the HERBERT study demonstrated 35% late
grade 3 toxicity after the whole treatment. At the same time, increased tumor
control is expected in patients undergoing brachytherapy.