Long Term Effects of Radiotherapy
More people are getting cancer but survival rates are increasing meaning more people are living with the long term side effects of radiotherapy.
Radiotherapy – the dose given and the area it is directed at, have all improved hugely over the past two decades. Unfortunately it is often inevitable that some normal body tissue near the cancer, can also receive radiotherapy. Most people are aware of the possible immediate side-effects of radiotherapy such as tiredness and skin changes but the longer term effects, which can occur months or years after radiotherapy are less well known. Over time, oxygen levels in tissue may drop, small blood vessels may reduce in density and the number of cells, the building blocks of the body, may reduce in number. The area of tissue may even die, known as radionecrosis.
Depending on where in the body is affected, this can cause different problems. In general terms the structure and function of that part of the body will be adversely affected, such that the tissue is not able to work normally or to heal if damaged. Bone, skin or body organs such as the bowel or bladder can be affected.
Hyperbaric oxygen (HBO) is used either to
- prevent tissue death , for instance if surgery is planned in an area that has been previously exposed to radiotherapy
- help in treatment of already damaged tissue, for instance bowel damage after radiotherapy for prostate cancer
HBO cannot resurrect dead tissue but can help stimulate small blood vessel growth into tissue damaged by radiotherapy, so improving function of the tissue and improving healing.
HBO and Head & Neck Cancers
Prevention of Osteoradionecrosis (ORN) – bone death caused by radiotherapy
The lower jaw, the mandible, might receive radiotherapy during treatment for cancers such as cancer of the tongue, tonsil, palate or mouth. After radiotherapy, saliva production is often reduced. This has an adverse impact on dental health. Dentists usually refer people needing a tooth removed in an area which has previously received radiotherapy to a Maxillofacial surgeon. This is because dental procedures may precipitate deterioration in the bone to the point that part of the bone may not heal and even die. If this occurs more extensive surgery may be required to remove the dead bone.
Treatment
When bone death has occurred, the bone usually needs to be removed. ORN can even cause bone to spontaneously fracture as it loses its strength. This can involve major surgery if reconstruction is needed.
HBO can help areas of bone not yet dead but affected by the radiotherapy. This not only can help prevent further bone death, but can help make it more obvious during surgery which tissue is likely to survive and which needs removal.
Hyperbaric oxygen (HBO) before and after dental work has been recognised to help prevent this bone death in people who have had radiotherapy.
A common course of treatment in this instance would be 20/30 once daily HBO, 5 days per week before dental work, 10 HBO sessions afterwards.
HBO & Effects of Radiotherapy for Pelvic Cancers
When a person undergoes radiotherapy for a problem such as prostate or cervical cancer, as the other organs in the pelvis are in close proximity – they too can be affected.
Over months and years radiotherapy can affect how well the organs function and cause problems. Examples include radiation proctitis (inflammation of the rectum) or radiation cystitis (inflammation of the bladder).
Radiation proctitis (inflammation of the rectum due to radiotherapy)
- This can cause diarrhoea, pain, bleeding, mucous discharge and incontinence
Radiation cystitis (inflammation of the bladder due to radiotherapy)
- This can also cause pain, incontinence and bleeding
HBO can help improve what are often troublesome and uncomfortable symptoms. Symptoms such as bleeding may be severe enough to need blood transfusions. In some cases, the only other treatment option may be major surgery such as bladder removal.
A common course of treatment would be 40 sessions of HBO, once per day, 5 days per week.
Before, during and after HBO, people undergoing treatment for these conditions are asked to complete questionnaires such as the LENT SOMA scale. This is really useful to help us monitor responses to HBO.
HBO is often used when treating delayed radiation tissue injury. This is usually more than 6 months after a course of radiotherapy but can vary from patient to patient. It is often precipitated by an additional insult such as surgery or some kind of trauma.
The underlying pathology is a degree of obliterative endarteritis and fibrosis that causes hypocellular regions of tissue. As a result these tissues become hypoxic and thus necrotic. The capillary density is often at 20-40% of the normal.
HBO helps by
- Stimulating angiogenesis secondarily improving tissue oxygenation (Marx , 1990)
- Reducing fibrosis (Feldmeier, 1998)
- Mobilising and inducing an increase of stem cells within irradiated tissues (Goldstein, 2006)
Mandibular Osteoradionecrosis
HBO is used in the treatment of ORN and as prophylaxis when dental procedures are planned.
Treatment
Approximately 85% of individuals with osteoradionecrosis have been reported to resolve with conservative measures (Parsons, 1994). However, chronic, progressive or those complicated by soft tissue necrosis will often benefit from HBO. It is used as an adjunct to standard operative intervention following the Marx protocol (Marx, 1999).
Individuals are graded and treated as follows:
Stage 1
Underlying pathology: Exposed bone with no serious manifestations as per stage III
Surgery: Minor bony debridement
HBO: 30 pre-operative and 10 post operative sessions
Stage 2
Underlying pathology: Stage I patients showing limited progress OR more extensive surgery planned
Surgery: Minor bony debridement
HBO: 30 pre-operative and 10 post operative sessions
Stage 3
Underlying pathology: Stage I or II patient showing limited progress OR pathological fracture, orocutaneous fistulae, evidence of lytic involvement extending to the inferior mandibular border
Surgery: Major bony debridement and/or reconstructive surgery
HBO: 30 pre-operative and 10 post operative sessions PLUS additional 10 after further surgery
This protocol and efficacy was further reviewed by Feldmeier and Hampson in 2002 and Annane et al in 2004. Their findings were in favour of HBO for the most part and thus it remains the accepted treatment.
Prophylaxis
Marx has also been key in the development of a treatment protocol for the prevention of ORN in those patients who have been exposed to more than 6800cGy of radiotherapy to the mandibular region. His study shows that those given 20 pre-operative and 10 post operative sessions had better outcomes following the procedure, i.e. less ORN absolute and in those it did occur it was less severe (Marx 1985).
This data was again reviewed by Feldmeier and Hampson (2002) and found to be reproducible.
Research
There are two current multicentre research projects ongoing to further investigate the role of HBO in ORN.
Details of the HOPON trial and participating centres can be found here.
Details of the DAHANCA-21 trial can be found here.
Radiation Cystitis and Proctitis
The use of radiotherapy in the treatment of various pelvic tumours can result in damage to the soft tissues of neighbouring organs. In both radiation cystitis and proctitis the same pathological process occurs resulting in bleeding and frequency of micturition or defaecation. In severe cases this can result in hospital admission with transfusions being required.
Cystitis
The UHMS Hyperbaric Oxygen Therapy Indications text has reviewed the data from multiple case series and the review by Feldmeier and Hampson(2002). They found 18 out of 19 published series applying HBO to radiation cystitis are positive reports. More specifically of the total 257 patients 196(76.3%) had either partial or complete response.
Proctitis
Again, he UHMS Hyperbaric Oxygen Therapy Indications text has reviewed the data from multiple case series and found out of 199 cases of proctitis, colitis and enteritis treated with HBO, 41% had complete resolution while 86% experienced at least a partial response. Only 14% failed to respond at all.
A RCT has been done by Clarke at al(2004) where individuals were given either HBO or sham treatments at 1.1ATA. Their response was measured with SOMA-LENT questionnaires for up to an average of 1 year. A statistically increased improvement in scores was seen with a p-value of 0.0019. The absolute risk reduction was 32% and NNT 3.
The HOT2 trial has now completed and the results are currently awaiting publication.
Other Radiation Tissue Injuries
Given the pathological process and the actions of HBO it is reasonable to assume that HBO will have a similar affect on other soft tissues damaged by radiotherapy.
Case reports have been reported benefits with the following:
- Soft tissues of head and neck
- Chest wall necrosis following breast cancer
- Transverse myelitis
- Optic neuritis
- Radiation Induced Brachial Plexopathy
For information and references regarding these indications please contact us on info@ddrc.org.
Further information regarding the Referral and Funding process can be found here.
References
The Royal College of Surgeons of Edinburgh
Diploma in Remote and Offshore Medicine
Hyperbaric Oxygen Therapy Indications (2014)
Lindell K, Weaver MD Editors
Undersea and Hyperbaric Medical Society
13th Edition
2014 :P113-138
Annane(2004)
Annane D, Depondt J et al
“Hyperbaric oxygen therapy for radionecrosis of the jaw: a randomised, placebo-controlled, double blind trial from the ORN96 study group.”
J Clin Oncol
2004 Dec;22(24):4893-4900
Feldmeier(1998)
Feldmeier JJ, Davolt DA etal
“Histologic morphometry confirms a prophylactic effect for hyperbaric oxygen in the prevention of delayed radiation enteropathy”
Undersea Hyperb Med
1998;25(2):93-97
Feldmeier and Hampson (2002)
Feldmeier JJ, Hampson NB
“A systematic review of the literature reporting the application of hyperbaric oxygen prevention and treatment of delayed radiation injuries: an evidence based approach.”
Undersea Hyperb Med
2002;29:4-30
Goldstein(2006)
Goldstein LJ, Gallacher KA, Bauer SM et al
“Endothelial progenitor cell release into circulation is triggered by hyperoxia-induced increases in bone marrow nitric oxide”
Stem Cells
2006;24:2309-2318
Marx (1985)
Marx RE, Johnson RP, Kline SN
Prevention of osteoradionecrosis: A randomised prospective clinical trial of hyperbaric oxygen versus penicillin
J Am Dent Assoc
1985;11:49-54
Marx (1990)
Marx RE, Ehler WJ, Tayapogsak P, Pierce LW
“Relationship of oxygen dose to angiogenesis induction in irradiated tissue”
Am J Surg
1990;160:519-524
Marx (1999)
Marx RE
“Radiation injury to tissue”
In: Kindwall EP editor
Hyperbaric Medicine Practice 2nd edition
Flagstaff AZ: Best Publishing Company
1999; P 665-723
Parsons (1994)
Parsons JT
“The effect of radiation on normal tissues of the head and neck”
In: Million RR, Cassisi NJ editors
Management of head and neck cancer: A multidisciplinary approach.
Philadephia, PA;
JB Lippincoat
1994: P245-289