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The future of radiation therapy

A 68-year-old man presented in 2011 with a raised PSA of 5. He had minor obstructive symptoms and his prostate felt enlarged, but benign. Biopsy confirmed a Gleason grade 6 tumour in low volume in both right and left lobes while MRI was normal. He was placed on active surveillance. His follow up was unsatisfactory as he defaulted from follow up. In February 2014 he re-presented with a PSA of 8.4. Repeat biopsy confirmed Gleason grade 7 in high volume. MRI remained clear. He was referred for radiotherapy as a preference as two of his brothers had had radiotherapy for prostate cancer.

Dr Fraser had a full discussion about the options and he elected to have Cyberknife treatment. Four fiducials were inserted into his prostate. He was allowed to rest for two weeks to allow the oedema to settle. He then had both a CT scan and an MRI of his pelvis. Both scans were performed by therapy radiographers in the treatment position with skin marking. The images were transferred to the Cyberknife planning system. The prostate was outlined. The organs at risk, the bladder rectum femoral heads and urethra, were outlined. A margin of 3mm around the prostate was defined. The rectum and bladder were empty.

A plan was drawn up by the physics planners. This was confirmed with the radio-oncologist and signed off. A patient specific quality assurance for the plan was done to verify that the patient would receive the planned dose. The radiotherapists then placed the patient on the treatment couch in the same position as for the scans. The robot only locked on as programmed when the patient was in the treatment position. He received 170 beams. These beams are non coplanar, which means they are centered on the target but come in at multiple angles as defined by the physics plan. The iso doses are tight around the target. Accuracy is confirmed by checking X-rays which are taken every 30 seconds as the robot follows the movement of the prostate.

The radiotherapists constantly monitor the accuracy of the treatment.  The movement is about 7mm in the AP dimension and 3.2mm in the SI dimension (Rosewall PMH). The total treatment time was 38 minutes/fraction. A total of five fractions were delivered from Monday to Friday. The total dose was 35Gy.

Minimal movement of the patient during treatment is not of concern as the robot tracks the fiducials. The patient in fact did not feel any sensation at all during the treatment. His PSA dropped to 5.4 only two months post-treatment and has subsequently continued to drop to 1.1 in May 2016. He is due back shortly for further follow up but has had neither urinary nor bowel side effects and remains in excellent health today. His PSA is static at 1.1.

The use of Cyberknife technology can reduce the radiation margins around the target area and reduce the exposure of normal tissue. It is conventional technology used in a revolutionary way. The technology involves a 6 mega volt (Mv) linear accelerator on a robotic arm, producing a single high energy X-beam. It has been in use in Italy since 2003.

Many thousands of patients have been treated with Cyberknife, including patients attending the Department of Radiology at the Hermitage Medical Clinic, Dublin. The radiation delivery system is mounted on the robot that is guided by a tracking system so that if the patient or target moves the beam follows that movement.

This means that the margins around the target can be reduced when planning the volumes for treatment, and this can reduce the volume of normal tissue being exposed. This technology reduces normal tissue toxicity, something of particular importance when dealing with cancers that are moving such as lung cancer very close to risk organs such as in head and neck cancer.

There is also significant movement of the prostate gland and the robot can track this.

Intracranial

It is only necessary to fix the body when treating intracranial sites. Extracranially we use spinal tracking, fiducial tracking or lung tracking. Fiducials are inert gold grains 5mm x 1mm placed in a geometric pattern within the target. The seeds should be a minimum of 2cm apart up to a maximum 5cm and ideally about 4cm inserted into the target.

This has been the rule applied when monitoring the position of a target during conventional radiotherapy. Though recently the use of on board imaging on linear accelerators means this is not required. The advantage of this approach is accuracy of 0.2mm in treatment delivery, which means that treatment can be delivered in a very short period of time.

A prostate cancer normally given seven to eight weeks exposure can now be treated with Cyberknife technology in one week, and this is obviously attractive to patients. Dr Anand Mahadevan, Assistant Professor, Radiation Oncology, based at Harvard Medical School, recently advised colleagues at the Hermitage that the brachytherapy programme at Harvard has been abandoned in favour of Cyberknife at the request of patients.

The doses used are familiar to radiation oncologists as they are the same doses as those used in skin cancer. The doses delivered are planned in advance and homogeneously spread across the target. This is a combined effort between radiation oncology and physics. Other specialties are also involved such as neurosurgery in brain and spinal lesions.

Neurosurgeon Mr Danny Rawluk saw the need for the adoption of Cyberknife technology here in Ireland. He had been sending patients to the UK, but founded the unit in the Hermitage to treat patients at home. The first cohort was people with trigeminal neuralgia who receive a single dose of 60Gy. This dose can only be given with confidence if you are extremely accurate.

The collimator on Cyberknife can go down to 0.5mm. We have in fact treated then retreated patients though generally only one fraction is required. Other lesions treated are meningiomas schwannomas a/v malformations and secondary brain tumours of all types.

Benign

Treatment of benign disease with radiation is not a familiar route in Ireland at present. Dr Patrick Maguire, CEO of Cyberheart, talked about Cyberheart at a recent symposium in the Hermitage Medical Clinic. He outlined how the accuracy of Cyberknife could be adapted to induce a scar on the heart to interrupt aberrant electrical impulses in atrial fibrillation. This condition he studied in animal models (pigs). Electrophysiological studies were performed pre- and post-therapy, then the animals were euthanised and the heart analysed histologically.

The scar was precisely where it should be, as predicted clinically. Again the planning was performed by specialist physics planners and cardiology specialists who understand the pathophysiology involved. This modality would avoid the current treatment by intra cardiac catheterisation with electrocoagulation. In fact the patient would not even need to take off their shirt and it would be over in about 90 minutes as an outpatient.

‘This technology reduces normal tissue toxicity, something of particular importance when dealing with cancers that are moving…

Dr Maguire has recently published on the treatment of one of the first patients treated in the International Journal of Radiation Oncology and Physics. This treatment was successful. The Cyberheart software has been purchased by the national cancer service of Japan in Tokyo to treat atrial fibrillation, and it will be interesting to see how this project continues. There is no reason why we in Ireland cannot be at the forefront of cardiology as well as oncology.

At the same meeting Dr Maguire mentioned the possibility of irradiation of the renal nervous plexus in order to treat hypertension and perhaps diabetes by reducing noradrenaline production.

Discussion

(With reference to case report above)

Conventional radiotherapy is delivered by planar beams. Treatment is 1.8-2Gy per day for 37-40 fractions in a carcinoma of prostate. The acceleration to a higher dose per fraction is supported by the radiobiology. Prostate tissue has a low alpha/beta ratio. This refers to the radio sensitivity, and it suggests that a large dose per fraction is preferable as regards potential cure with acceptable toxicity.

Arcangeli compared 62Gy in 20 fractions at four fractions per week to 80Gy in 40 fractions over eight weeks. The results suggested that the shorter course gave a superior biochemical disease free survival. The toxicity was the same.

Dearnley in The Institute of Cancer Research, London, compared three groups. 74Gy in 37 fractions with 60Gy in 20 fractions with 57Gy in 19 fractions. There were about 150 men in each group. The 20 fraction regimen was non inferior in terms of efficacy and side effects at two years. This trial may well change practice in the NHS in favour of hypofractionation.

Dr Shafak Aluwini, Radiation Oncologist from the Erasmus centre in Rotterdam, has compared 78Gy in 39 fractions with 64Gy in 34 fractions at three fractions per week. There did seem to be more rectal toxicity in the accelerated arm of 34 fractions and Dr Aluwini has drawn a note of caution, but further follow up is ongoing.

Katz has performed analysis over seven years on 515 patients treated on Cyberknife from 2006-2009 and 72 patients received hormone therapy. Treatment was 35Gy to 36.5Gy in five fractions. Toxicity was assessed using the expanded prostate cancer index composite (EPIC). There was a median follow up of 72 months. The stage of the tumour was up to stage T2c. He had 324 low risk cases, 153 intermediate risk cases and 38 high risk cases. Biochemical disease free survival was excellent. There was no difference in the two doses, however , toxicity may be higher in the 36.5 cohort.

King also analysed pooled data of 1,100 patients in multiple institutions and the excellent results again confirmed the value of Cyberknife. We in the Hermitage have treated a small number of patients with no failures and no real toxicity. One patient did have some dysuria, but this settled on conservative management.

The conclusion is that robotic therapy is highly accurate treatment. It is non invasive apart from the insertion of the inert fiducials. It is given over a short period of time. It is convenient for the patient. It is curative. It does not have an unfriendly toxicity profile. This is the future of radiotherapy. It is only suitable for disease within the capsule. Here the accuracy works against the machine as the position of the target has to be certain. There is no margin for error as with conventional machines. However, as imaging improves, it is certain that we will be able to target our treatments more accurately.

Dr Ian Fraser, Clinical Director of Radiotherapy (primary author); Ms Gillian Moore, Acting Head of Radiotherapy; and Dr Mohamed Galal Ibrahim, Head of Radiotherapy Physics; all based at Hermitage Medical Clinic, Dublin.

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