Feasibility study of external beam radiation therapy followed by high-dose rate endorectal brachytherapy (HDRBT) in inoperable rectal cancer patients

In newly diagnosed rectal cancer patients who are unfit for surgery, there is
no defined radiotherapy schedule. The treatment can vary from wait-and-see, to
schedules ranging from 8 Gy in 1 or 2 fractions to 50 Gy in 25 fractions. The
most applied radiation therapy scheme is 45 Gy in 25 fractions. So far,
radiotherapy alone could only cure rectal cancer if endocavitary irradiation is
used either alone in T1N0 tumors or combined with external beam radiotherapy in
patients with superficial T2-3 tumors. In previous studies, the radiation dose
has been specified on the tumor surface or at 0.5 or 1 cm from the surface.
Therefore, it was only applied in superficial rectal tumors.
Based on the above mentioned literature, the use of high dose rate
brachytherapy (HDRBRT) with the flexible, multichannel applicator is promising.
However, the use of HDRBT has only been studied in neoadjuvant treatment of
rectal cancer patients, and it has not yet been studied in inoperable rectal
cancer patients. The major difference with neoadjuvant treatment is the fact
that resection of the irradiated tissue will not take place. With the use of
this applicator the prescription of the radiation dose will be at the tumor
radial margins instead of more superficial, resulting in potentially high doses
at the normal rectal wall. Therefore, the aim of our study is to investigate
the feasibility and efficacy of HDRBT in rectal cancer patients who will not
undergo surgery. By using HDRBT, we will optimize the dose to the tumor (and
tumorpositive perirectal lymph nodes), while limiting the dose to the adjacent
tissues to reduce toxicity.

-To determine the feasibility and the maximum tolerated radiation dose in HDRBT
of the rectum after EBRT in rectal cancer patients who are unfit for surgery or
refuse surgery
-To determine the incidence and severity of acute and late toxicity of EBRT
followed by HDRBT
-To determine the patient*s sphincter function
-To determine the clinical tumor response of EBRT followed by HDRBT

Feasibility study, phase I design, multicenter study with a planned sample size
of 30 patients
Patients will be treated with external beam raditherapy, followed after 4-6
weeks by brachytherapy in the form of 3 applications with an flexible
multichannel catheter.


Brachytherapy
The following rules will be followed for the dose escalation. A dose limiting
toxicity is defined as proctitis >= grade 3 according to CTCAE version 3.0.

If 0/6 or 1/6 patient exhibit dose limiting toxicity:
- Dose escalation to the next dose level
If 2/6 patients exhibit dose limiting toxicity:
- Expand dose level to a total of 9 patients
- If no further DLT events seen, dose escalation to the next dose level
- If 1 or more further DLT events are seen (i.e. 3 or more of 9
patients), this dose level will be considered the maximum delivered dose
If > 2/6 patients exhibit dose limiting toxicity:
- This dose level will be considered the maximum delivered dose and 3
extra patients will be included one level below the maximum delivered dose-level

The maximum delivered dose is the dose in which >= 3/6 or >= 3/9 patients
experience dose limiting toxicity. One dose level below the maximum delivered
dose will be considered the recommended phase II dose.
Dose level Dose per fraction HDRBT Minimum number of patients
-1 3x4 Gy (12 Gy total) 0
1 (starting) 3x5 Gy (15 Gy total) 6
2 3x6 Gy (18 Gy total) 6
3 3x7 Gy (21 Gy total) 6
4 3x8 Gy (24 Gy total) 6

External beam raditoherapy
39 Gy will be given in 13 fractions of 3 Gy in 21 days
After 6 weeks a MRI will be performed and if the tumor thickness is:
* tumor <= 2 cm, patients will be treated with brachytherapy; dosespecification
at the deepest point of the tumor
* tumor > 2 cm, patients will be treated with brachytherapy, but the dose will
be specified at 2 cm

This will be followed by high dose rate brachytherapy according to the schedule
as given in the study design.

Patients will undergo 3 fractions of high dose rate brachytherapy in addition
to external beam irradiation. This treatment has an increased risk of acute
signs of proctitis, which usually resides in 1-2 months. However, there is a
risk of chronic proctitis, with possible mucus and blood loss per anum.
The benefit for the patients is that a more radical treatment of their rectal
tumor is given, with an considerable greater change of reaching a complete
response of the tumor.