Trial Information

A Phase I/II Feasibility/Efficacy Study of HIFU in Otherwise Untreatable Pelvic Rectal Cancer

Background information on the project:

Colorectal cancer is the third most common cause of cancer and cancer death (35000 and 16000
respectively in UK) in both men and women. There are about 1million cases and a 500 000
deaths annually world wide.

Primary treatment is usually surgical with, in appropriate cases, adjuvant or neo−adjuvant
therapy including radiotherapy, cytotoxic chemotherapy or a combination. Unfortunately, the
overall 5 year survival of locally advanced disease is at best 50%. Many patients who have
residual, refractory or recurrent rectal cancer experience serious morbidity from local
tumour invading and destroying adjacent tissues including bone, nerves (sacral), bladder and
skin. This causes severe interference with normal activities of daily living especially with
bowel function and causes great distress in terms of pain, tenesmus and rectal blood and
mucous loss with many patients requiring permanent palliative colostomies.

High Intensity Focused Ultrasound (HIFU) is a method of accurately delivering ablative
energy at high temperature non−invasively or endo−luminally focused to specific areas in the
body using imaging (ultrasound or MR) guidance.

Intracavitary or endo−luminal (also called transrectal) HIFU has been appraised by NICE in
the treatment of prostate cancer. It is currently used in the main for primary prostate
cancer and there is early evidence that it may be effective in treating prostate cancer that
has recurred after radiotherapy. Short and medium term data demonstrate that HIFU may be
equivalent to some current prostate cancer therapies but with much reduced morbidity and
length of stay. Also, as it becomes increasingly possible to accurately determine the
focality and site(s) of primary prostate cancer, research into the use of HIFU to deliver
hemiablation and/or focal ablation (thus preserving otherwise normal areas and decreasing
morbidity even further) is underway. As the prostate and rectum are adjacent we now propose
a natural evolution to translate the success in prostate to the adjacent rectum.

There is a large unmet clinical need for new treatments for patients with residual or
progressing local pelvic cancer (such as rectal in origin but including other pelvic
malignancies) in whom all current therapies are exhausted. Intracavitary (transrectal) HIFU
offers such a therapy. There are 2 distributors of transrectal HIFU devices in the UK.
Sonoblate (UKHIFU) have agreed to loan a device currently CE marked and approved for use in
prostate cancer to be assessed in rectal cancer (current retail cost approx. £280K). They
have agreed to charge only for associated costs e.g. transportation and disposables.

HIFU has the potential to offer a genuine non−invasive alternative to current therapies in a
wide number of clinical conditions, especially cancers, saving substantial patient morbidity
and healthcare costs. Assessing this potential is timely. We propose to test for 1. safety
and 2. efficacy of an intracavitary HIFU device in patients with otherwise untreatable
pelvic rectal cancer (which can subsequently be applied to other pelvic cancers as
appropriate and as experience grows).

Ethical approval from the National Research Ethics Committee has been granted (details). For
the initial study, up to 20 patients with rectal cancer will be offered intracavitary HIFU
(at increasing energy doses) under general anaesthesia and monitored for toxicity and
ablative efficacy using ultrasound & MRI scans pre and post-treatment. None of the
intracavitary devices have been used for rectal tumours; therefore is important that the
energy intensity and resultant rectal cancer tissue destruction from a range of different
treatment energies, starting initially with 50% of that used for prostate cancer. In this
manner, the first phase of this trial is equivalent to the 'dose escalation' phase of a drug
trial.

Once the optimum energy levels, safety and treatment protocol are known, a further 30
patients will be treated. Patients will undergo MRI and ultrasound pre− and 4 weeks
post−treatment to objectively assess tumour changes (ablation should result in a necrotic
area). They will complete QoL questionnaires, pain scores and functional questionnaires.
Survival data will be documented.

Design, hypothesis and measurable aims of project:

Hypothesis: HIFU is safe and will improve patient symptoms and QoL where no alternative
contemporary therapies are available.

Design: In two stages:

Phase I (Up to 20 patients) will assess safety, feasibility and toxicity of HIFU.

Cohorts of 3 patients will be assessed at escalating energy levels starting at 50% of a
standard prostate cancer protocol. If no grade 4 toxicity is observed within 3 weeks, and no
more than one patient has a grade three toxicity, then the next dose escalation will occur
to 75% and thereafter, subject to toxicity, in 25% increments until necrosis of the targeted
cancer areas are achieved. If there is doubt or grade 3 toxicity occurs in more than 2 out
of 3 patients, a further 3 patients will be treated at the same energy level. The optimum
level is where the grade three toxicity is less than or equal to 33% of the expanded cohort,
otherwise we would reduce down one level until this is achieved.

If safety is acceptable by an (already constituted) Data Monitoring Committee we will
proceed to the efficacy part / phase II.

Phase II will extend the Phase I cohort to up to a total of 50 patients and assess efficacy,
symptom and QOL outcomes.

Primary and secondary objectives will be measured using tumour size (RECIST) criteria as
well as tumour marker changes (CEA and CA19.9), pain relief (visual analogue scales,
analgesia consumption), symptom control, rectal function and quality of life scores (EORTC
QLQ−C30 and EORTC QLQ−CR38). Post treatment imaging will involve pelvic MRI at 4 week post
treatment. Patients in this rectal cancer category usually progress rapidly, so that
survival end−points will be calculated at 30, 60 and 90 days post procedure.