Failure to recruit.

This is a single centre pilot trial to establish the feasibility and role of endoluminal HIFU in patients with locally advanced cancer within the pelvis that is either primary or recurrent and with all available current therapy inappropriate and/or exhausted.

The aim is to make a preliminary assessment of efficacy & dosage for evaluation in a randomised controlled trial. Whilst efficacy data are limited in a small feasibility study; radiological, biochemical and histopathological analysis of the patient and patient specimens, along with quality of life questionnaires (QoL), will be used to provide preliminary measures of efficacy in this patient cohort.

These analyses will allow examination of the biochemical, metabolomic and histological changes associated with HIFU treatment in cancer within the pelvis.

CURRENT TREATMENT OF LOCALLY ADVANCED PELVIC CANCER Colorectal cancer This is a common condition with about 40,000 new cases a year in the United Kingdom. The optimal multimodality management of stage III & IV rectal cancer remains an increasing challenge. There is a high risk of local recurrence and poor survival has been reported for patients treated by surgery alone. About 20% of patients may present with locally advanced tumours, which are partially or totally fixed (T3/T4). Until recently there have been no widely accepted and validated methods of defining preoperatively either locally advanced rectal cancer or unresectable disease. The use of pre-operative pelvic magnetic resonance imaging (MRI) to predict the likelihood of achieving an R0 resection (Beets-Tan et al 2001, Brown et al 2003) has resulted in improved selection. Pre-operative chemoradiotherapy can downstage locally advanced tumours, and result in higher resection rates being achieved with reduced risk of local recurrence (Bosset et al 1993, Rich et al 1995).

Gynaecological cancers Treating other advanced pelvic malignancies including vaginal, ovarian, endometrial and cervical cancers is similarly challenging. Disease recurrence at the site of surgical resection or adjacent lymph nodes can also preclude further curative options, due to chemotherapy resistance, reaching maximum safe radiotherapy limits or unsuitable surgical options.

It is proposed that High Intensity Focused Ultrasound (HIFU) may become another modality of treatment in locally advanced or unresectable pelvic disease.

RATIONALE FOR PERFORMING THE STUDY Colorectal cancer This is the third most common cause of cancer and cancer death in both men and women (40,000 cases and just under 16 000 deaths per year in the UK). Worldwide, there are approximately 1 million cases and 500 000 deaths per annum. Primary treatment is usually surgical with, in appropriate cases, adjuvant or neo-adjuvant therapy currently including radiotherapy, cytotoxic chemotherapy or a combination. Unfortunately, the overall 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 (sacrum), bladder and the skin. These interfere severely with normal daily activities, especially bowel function and cause great distress in terms of pain, with many patients requiring permanent palliative colostomies.

Gynaecological cancers Other advanced pelvic malignancies can be equally problematic to manage successfully. Annually in the UK, approximately 250 vaginal cancer, 7000 ovarian cancer, 8000 endometrial cancer and 3000 cervical cancer diagnoses are made, with some being incurable at the time of presentation. Treatment options include surgery, hormonal therapy, chemotherapy, radiotherapy or a combination, although palliative patients can often be left with debilitating symptoms including severe pain and fistula formation, compromising their quality of life.

High Intensity Focused Ultrasound (HIFU) is a method of accurately delivering ablative ultrasound (US) generated high temperatures 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 the National Institute for Clinical Excellence (NICE) in the treatment of prostate cancer. It is currently used for primary prostate cancer; there is also evidence it may be effective in treating post-radiotherapy prostate cancer recurrence. Short and medium term data demonstrate that HIFU may be equivalent to some current prostate cancer therapies but with reduced morbidity and length of stay. As the prostate and rectum are adjacent there is now a natural evolution to translate the success in prostate to the adjacent rectum/other pelvic structures.

There is a large unmet clinical need for new treatments for patients with residual or progressing local pelvic cancer (such as rectal in origin as well as other pelvic malignancies) in whom all current therapies are exhausted. Intracavitary HIFU offers such a therapy.

An initial cohort of 20 patients will be offered intracavitary HIFU using the Sonablate 500 (Sonacare Medical, Charlotte, NC, USA) intra-luminal device (at different, escalating energy doses) under general anaesthetic with monitoring for toxicity and ablative efficacy using pre and post-treatment Imaging.

As none of the intracavitary devices have yet been used in rectal, vaginal, ovarian, endometrial, cervical or pelvic lymph node tumours directly (but have been used in the rectum to treat prostate cancer), it is important that to gauge the levels of energy and resultant cancer tissue destruction from a variety of different treatment energies. 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 in Phase II. Patients will undergo MR Imaging pre- and post-treatment to objectively assess the tumour and will complete quality of life questionnaires, pain scores, and functional questionnaires. Survival data will be documented. Post-treatment imaging will be performed at between 3-4 weeks, as within this time frame the ablative effect (a necrotic area) as seen in prostate cancer treated by HIFU, will become clearer providing useful data for the Phase I element.

The trial will run in two stages: the end of the first phase (for regulatory requirements) is defined as 30 days from the date that the last patient has completed trial therapy. The non-interventional follow-up stage will then commence in which patients are followed up for a minimum of 6 months or death.

Inclusion Criteria:

• Biopsy proven rectal, vaginal, ovarian, endometrial or cervical cancer (tumour <15cm from anal/vaginal verge)
• Lymph node(s) accessible by HIFU for which the primary clinical team advise intervention
• Partially fixed/unresectable disease and locally advanced disease (T3/T4)
• Patient considered to be unsuitable for or have exhausted all currently available therapies
• WHO Performance Status 0-2
• Fit for general anaesthetic and HIFU
• Not pregnant
• No other serious uncontrolled concomitant illness likely to interfere with treatment or assessment
• Written informed consent for treatment

Exclusion Criteria:

• WHO performance status of 3 or more
• Uncontrolled cardiac, respiratory or other disease, or any serious medical or psychiatric disorder that would preclude anaesthetic or informed consent
• Pelvic sepsis
• Currently enrolled in any other treatment trial