Introduction of the Maastro applicator for endoluminal boosting in rectal cancer: a pilot study

A radiation boost to rectal tumors before or after neoadjuvant
(chemo)radiotherapy is likely to increase the chance of a complete response
(CR) and thereby enable omission of surgery. This radiation boost dose can be
given either by external beam irradiation (EBRT) or by an endoluminal
technique. Important advantages of endoluminal techniques, such as high dose
rate (HDR) brachytherapy and contact X-ray radiotherapy (CXRT), include the
possibility to apply a more selective / localised boost than when using EBRT.
In the recently published international randomised phase III OPERA trial, CXRT
was shown to increase the CR and organ preservation rate significantly compared
to an EBRT boost (organ preservation at 3 years 81 v 60%) (1).

Currently, the wide spread introduction of endoluminal boosting is hampered by
the high costs and low availability of CXRT equipment and, in case of the
existing HDR brachytherapy applicators, relatively unfavorable dose profiles
and complex treatment procedures. In order to overcome the disadvantages of the
currently available rectal endoluminal radiation devices, we have developed a
novel high dose rate (HDR) brachytherapy applicator that allows irradiation
with the same dose profile as in CXRT (2, 3). This applicator has several
advantages over the CXRT X-ray tubes. First of all, it can be used in
conjunction with standard equipment that is already available at most of the
radiotherapy centres, like an HDR afterloader. This will increase the ease of
use, reduces costs, and could catalyse the introduction of endoluminal boosting
in rectal cancer worldwide. Additionally as the tip of the Maastro applicator
has a slanted edge, rectal tumors that are out of reach for perpendicular
irradiation by the right angled CXRT tube can be accurately treated with the
Maastro applicator. Moreover, as opposed to CXRT, the design of the Maastro
applicator allows individualised treatment planning and irradiation. In
contrast to the currently available HDR brachytherapy applicators, the Maastro
applicator has a more favorable dose depth profile and a less complex, i.e.
less error prone, treatment procedure.

We aim to confirm that Maastro endoluminal HDR contact brachytherapy boosting
is feasible and may increase the chance of functional organ sparing of the
rectum in patients with rectal cancer.

We aim to confirm that Maastro endoluminal HDR contact brachytherapy boosting
is feasible and may increase the chance of functional organ sparing of the
rectum in patients with rectal cancer.

A single arm prospective interventional pilot trial in 10 patients with
feasibility and safety checks and early stopping/intermission rules. Interim
analyses regarding feasibility and safely with early stopping/intermission
rules: after 3 and 6 patients. The study treatment will be provided at Maastro
and MUMC+.

The study intervention will be similar to the study treatment of arm B of the
OPERA trial (1). Opposed to the treatment in arm B of the OPERA trial, the
endoluminal boost will be given using HDR brachytherapy with the Maastro
applicator instead of a CXRT device. The dose profile of the Maastro applicator
is similar to the dose profile of CXRT device.
As in the OPERA trial patients will be stratified based on tumor size. As the
diameter of the treatment field of the largest Maastro applicator (there are
two sizes) equals 2.5 cm we will stratify for tumor diameter < 2.5 cm v >= 2.5
cm. In the OPERA trial patients were stratified for a tumor diameter of < 3.0
cm v >= 3.0 cm as currently the largest applicator diameter for the CXRT device
is 3.0 cm (currently available applicators: 2.0, 2.5 and 3.0 cm).
The endoluminal boost will consist of 3 fractions with a dose equivalent to 30
Gy per fraction prescribed at the surface of the applicator. The 3 boost
fractions will be delivered over a 4-week time period (week 1-2-4). Conform
OPERA protocol, patients with a tumor size < 2.5 cm will receive an upfront
endoluminal HDR contact boost followed by concurrent chemoradio-therapy
(25x1.8 Gy combined with capecitabine 825 mg/m2 bd on radiotherapy days).
Patients with a tumor size >= 2.5 cm will first undergo concurrent
chemoradiotherapy (25x1.8 Gy com-bined with capecitabine 825 mg/m2 bd on
radiotherapy days) to first shrink the tumor and will receive the endoluminal
HDR contact boost afterwards in order to eventually fit the tumor sur-face in
the surface of the Maastro applicator.

The standard treatment for patients with cT2-3abN0 rectal cancer would be
upfront TME (total mesorectal excision) surgery and for patients with cT2-3abN1
rectal cancer short-course radiotherapy (5x5 Gy) followed by TME surgery.
Alternatively, in case a patient prefers to have chance of organ preservation
and omission of surgery, chemoradiotherapy is commonly applied. Patients
participating in our study will undergo an endoluminal radiation boost in 3
fractions as well as neo-adjuvant chemoradiotherapy.
We expect that with the experimental treatment, as in de OPERA trial, the
patients chances of being able to avoid surgery and its associated toxicity can
be greatly increased (up to 80% success rate) (1). If the experimental
treatment does not result in a complete response or results in unacceptable
rectal toxicity not responding to conservative treatment, patients will still
be able to undergo the standard surgical treatment.

The toxicity profile of Maastro brachytherapy is expected to be similar as has
been reported for CXRT. Hence, up to 15% reversible G2 rectal bleeding
(moderate symptoms; medical intervention or minor cauterization indicated) and
2.9% G3 rectal bleeding (transfusion, radiologic, endoscopic, or elective
operative intervention indicated) is expected (4). In general, G2 and G3 rectal
bleeding can be treated adequately, in the minority of cases complaints may
persist (5).
Pelvic chemoradiotherapy may cause morbidity. Potential side effects of pelvic
radiotherapy include: proctitis, cystitis and diarrhoea. The most frequent
toxicities of capecitabine include: hand-foot syndrome, asymptomatic
hyperbilirubinaemia, diarrhoea, nausea/vomiting (not requiring anti-emetic
prophylaxis), abdominal pain, stomatitis, anorexia and bone marrow suppression.
The current treatment strategy was also used in the OPERA trial. In the OPERA
trial the risk of G2 toxicity was 37%. The reported risk of G3 toxicity was 5%.
No G4-5 toxicity was observed in the OPERA trial (1).