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RAGE and the “Complete Healing” of radiation late effects.

The term “Complete Healing” was first used in relation to radiotherapy late effects [RTLE] injuries, by Delanian et al., in their 2002 paper.

This section - Towards Complete Healing - examines the progress that has been made in Europe and America to achieve “Complete Healing” for radiation late effects [RTLE] injuries.

Leptospermum Honey to Manage Wounds Impaired by Radiotherapy: A Case Series

Volume 55 - Issue 1 - January, 2009

From Val Robson, BSc, RGN, Aintree Hospital NHS Foundation Trust, Longmoor Lane, Liverpool L9 7AL

And Dr. Rose Cooper, Professor of Microbiology, Department of Applied Life Sciences, University of Wales Institute, Cardiff.

https://www.hmpgloballearningnetwork.com/site/wmp/content/using-leptospermum-honey-manage-wounds-impaired-radiotherapy-a-case-series

Radiation-induced tissue injury and wounds with radiation-impaired healing are traumatic for patients and challenging for their caregivers. Standardized management approaches do not exist. The effect of Leptospermum honey as a primary dressing for managing these wounds was assessed in four patients (age range 63 to 93 years) who had previously undergone radiotherapy that left them with fragile friable areas of damaged skin that did not respond to conventional treatment.

No adverse events were reported. Honey as an adjunct to conventional wound/skin care post radiation therapy shows promise for less painful healing in these chronic wounds. Prospective, randomized, controlled clinical studies are needed to confirm these observations.

What are Late Effects in Normal Tissue [LENT] injuries?

Effects of radiation on normal tissue: consequences and mechanisms

http://www.researchgate.net/publication/10575447_Effects_of_radiation_on_normal_tissue_consequences_and_mechanisms

The use of radiation therapy to treat cancer inevitably involves exposure of normal tissues. As a result, patients may experience symptoms associated with damage to normal tissue during the course of radiotherapy for a few weeks after radiotherapy or months or years later.

Radiation injury is commonly classified as acute, consequential, or late effects, according to the time elapsed before the appearance of symptoms.

• Acute (early) effects are those that are observed during the course of treatment or within a few weeks after treatment.

• Consequential effects (sometimes called consequential late effects) appear later, and are caused by persistent acute damage.

• Late effects emerge months to years after radiation exposure.

Common clinical manifestations of radiation injury:

Radiation injury varies from organ to organ, and tissue to tissue. For each area - the thorax (lung and breast tumours), head and neck, and pelvis (prostate and cervical tumours) – the authors of this Lancet review describe symptoms, the histopathology underlying the symptoms, the medical management of the symptoms, and the future prospects for preventing or treating radiation toxicity:-

http://www.researchgate.net/publication/10575447_Effects_of_radiation_on_normal_tissue_consequences_and_mechanisms

The concept of Anti-Oxidant treatments……

The concept of Anti-Oxidant treatments is that radiation damages cells and tissues in such a way that excess amounts of reactive oxygen species [ROS] are created in the normal healthy cells and tissues in the treatment area.

If reactive oxygen species [ROS] are not purged - using anti-oxidants – then ROS will proliferate [multiply] causing the radiation damage to be perpetuated and to continue to develop.

The proliferative damage of ROS within one cell will eventually impinge on the integrity and molecular stability of adjacent and adjoining cells. In this way a large volume of an entire tissue can become critically compromised due to the chemical instability caused by reactive oxygen species.

Anti-oxidant treatments intervene in these very complex and sophisticated chemical processes by combining with and purging ROS from the cells and tissues. These interventions may be used to prevent permanent and continuing damage to the normal biochemistry of the treated tissues.

First-principles simulations of the interaction of ionic projectiles with water and ice - Jorge Kohanoff - PowerPoint Presentation

Examples of Anti-Oxidant Treatments include:

• Hyperbaric Oxygen Treatment [HBOT] using breathed carbogen (an anti-oxidant)

• Vitamin E (an anti-oxidant)

• Vitamin E (an anti-oxidant) combined with Pentoxyfilline [a vasodilator]

• Vitamin E (an anti-oxidant) combined with Pentoxyfilline, combined with Clodronate (a “non-nitrogenous” bisphosphonate)

• Vitamin C (an anti-oxidant)

• Vitamin D (an anti-oxidant)
  

RAGE and the Repair of Radiation Injuries

[This section and the links are still being developed]…..

One of the four aims of RAGE is to obtain treatment to repair radiotherapy late-effects in normal tissue [LENT] injuries for its members and for the wider patient community.

RAGE first learned of the possibility of repairing radiation induced fibrosis (RIF) and osteoradionecrosis (ORN) in 1995 from the Maher Report [1]. which asked, at section 4.8 on page 10 :-

4.8 Is there treatment for RIBP?

‘Medication

• Thyroxine and salicylates, e.g. phentoxyphylene (sic) have been proposed to inhibit development of radiation fibrosis in selected cases.

• Recently, the antioxidant agent Cu/Zn superoxide dismutase (Lipsod) has been successfully used to reduce fibrosis, in a French study (Delanian et al 1994)[3].

• Again more research is required before recommendations can be made’.

Cu/Zn superoxide dismutase (Lipsod) has fallen out of use following the incidence of BSE/CjD related to bovine products.

Phentoxyphylene is what we now refer to as Pentoxyfilline (PTX).

For RAGE, Delanian et al 1994 became a significant turning point in achieving the possibility of repair for Radiation damage.

By 2007 it was becoming increasingly obvious that RAGE members required some form of treatment to repair their radiation injuries without delay. RAGE members injuries were generally getting worse rather than better. This possibility is discussed in Swedish Research....

Dose Response and Latency for Radiation Induced Fibrosis, Edema and Neuropathy in Breast Cancer Patients [2].
‘ "We have demonstrated that a progression of all the most serious damages occurred beyond 10 years and even beyond 20 years for paralysis. The most intriguing feature about peripheral neuropathy is that what happens to the peripheral nerves during such a long latency period as 30 years is still not understood’".

A series of major breakthroughs in the treatment of radiation induced injuries occurred in the aftermath of the Chernobyl nuclear reactor meltdown, in 1986, and from other nuclear accidents. Clinicians from all over Europe attended the Ukraine to deliver a range of treatments to the grossly injured victims of Chernobyl.

Reporting on the treatments and research from this period Gottlober et al[4] from Ulm in East Germany. stated......

‘"Accidental exposure to ionizing radiation may occur during such catastrophic events as the Chernobyl accident in 1986 or over days to weeks as in Goiania in 1987 and in the military camp during the training of soldiers in Lilo/Georgia in 1997, as well as in medical institutions".

"Based on the results of experimental and clinical research, today treatment may include topical or systemic corticosteroids, gamma-interferon, pentoxifylline, vitamin E and superoxide dismutase’".

Fischer et al.[5] and Hille et al.[6] also report on the use of pentoxifylline and vitamin E. to repair radiation induced injuries.

From 1993 to 2005 Delanian et al.[7]. based in Paris continued to produce an extended series of medical citations concerning what they call "“The Antioxidant Pathway”" for the repair of Radiation Induced Fibrosis [RIF]. and the very important prospect of repairing Osteoradionecrosis (ORN).

Unfortunately two reports emerged from the Royal Marsden Hospital in 2004 and 2005 [8],[9], which indicated failure with these treatment modalities (relative to the claimed successes from Paris and elsewhere).

RAGE members took part in these two studies in addition to three other "anti-oxidant" trials [10] [11] [12].

In 2004 there was an incident at the Cookridge Hospital in Leeds in which a Breast Cancer Patient received a serious overdose (2.5 times greater than the prescribed dose throughout a 14 session cycle of treatment cycle.

In 2005 at the Beatson Institute Lisa Norris received an even more devastating overdose targeting a brain tumour.

Reporting on the Cookridge Incident Prof. Brian Toft [13] stated as follows :-

"Treatment [of the patient at Cookridge Hospital] was based on a similar incident in Poland".

The incident Toft refers to in Poland was "The Accidental Overexposure of Radiotherapy Patients in Bialystok" [14], in February 2001.

Damage inflicted by an electrical storm on a very small diode within the linear accelerator at Bialystok resulted in very serious overexposures involving patients who were undergoing post-operative radiotherapy occurred at the Białystok Oncology Centre (BOC) in Poland.

"On 27 February 2001, a radiological accident occurred in the Białystok Oncology Centre (BOC) in Poland that affected five patients who were undergoing radiotherapy. The patients were given significantly higher doses than intended and, as a result, developed radiation induced injuries.

"The accident resulted from a transitory loss of electrical power that caused an automatic shutdown of the Polish built linear accelerator, an accelerator of the NEPTUN 10P® type". "The power cut occurred during the radiation treatment of a patient”.

“Following the restoration of electrical power, the machine was restarted after its controls had been checked. The treatments were resumed and the patient receiving radiotherapy at the time of the power cut and four additional patients were treated".

"Two patients experienced itching and burning sensations during their irradiation. This prompted the staff to halt the treatment. Subsequent dosimetry measurements revealed that the machine’s output was significantly higher than expected”.

“Further checks revealed that the dose monitoring system of the accelerator was not functioning properly, and that one of the electronic components [a diode] of the safety interlock system was damaged”.

"Subsequently, all five patients developed local radiation injuries of varying severity”.

"In 2002, three of the patients underwent surgery in the Oncological Surgery Ward of the Holy Cross Cancer Centre in Kielce, Poland. With the assistance of the IAEA, the two remaining patients were transferred to the Institut Curie in Paris, France for surgical treatment”.

"All five patients involved in the accident developed local radiation injuries in the form of burns of differing severity".

"In early August 2001, all five patients were administered systemic Pentoxifylline (a vasodilator) and Tocopherol (vitamin E).

"Topical treatment was continued using the enzymatic ointments Iruxol Mono and Fibrolan Salbe (collagenase with proteases, and plasmin deoxyribonuclease ointments)”.

"The IAEA acknowledges:-

Department of Radiology, School of Medicine of the University of New Mexico, Albuquerque, USA;
Department of Radiotherapy of the Institut Curie, Paris, France;
Department of Dermatology, University of Ulm, Ulm, Germany;
Radiation Physics Department, Sahlgren Hospital, Göteborgs Sjukvård, Sweden".

At a conservative annual estimate many thousands of UK cancer patients treated with Radiotherapy (External Beam and Brachytherapy) would benefit from some form of treatment to allieviate, ameliorate, regress, repair or eliminate the severe fibrosis and osteonecrosis they sustain as a result of their treatments.

This is why RAGE believes it is so important to progress this combined treatment, using pentoxifylline and vitamin E, within the UK. We are therefore pleased to report that three eminent Maxillo-facial Surgeons have now reported [15] [16] [17], observing some benefits in the treatment of Osteoradionecrosis [ORN] injuries to the mandible [jawbone].

In the UK it is neccessary to validate any treatment through rigourous trials before it can be generally prescribed or indeed receive government support through NHS funding.

In the absence of this validation patients are left with little alternative other than to seek treatment in France or Germany. Alternatively they may obtain the support of their GP on an individual basis.

These treatments appear to have the potential to prevent developing injuries requiring extensive surgery (triple heart bypass) or to prevent death as a result of Ischemic Heart disease. Delanian already reports consultations with many UK patients in Paris - her "English Days".

Why won't our doctors face up to the dangers of radiotherapy? - Daily Mail

RAGE has had contact with a number of these patients who are impressed with their own experience in Paris.

Anti-Oxidant treatment is now used for the treatment of fibrosis resulting from certain surgical procedures, including Failed Back Surgery Syndrome (FBSS) and Herniated Discs. It's application in France is now quite extensive.

The results from the Royal Marsden trials [8],[9],[10],[11],[12], were all inconclusive and progress became decidedly desultory within the UK. Requests, emanating from the RAGE Committee, for RHM to re-examine some of the potential for the Delanian protocols were not met.

The limited funding then available at RMH has mainly been used to pursue hypobaric oxygen treatment [HBOT] as the treatment of choice.

It is the view of RAGE that, given the substantial and increasing numbers of radiation damaged patients requiring treatment, there remains insufficient HBOT treatment capacity within the UK.

A number of UK based Maxillo-Facial Surgeons are developing anti-oxidant treatments, for radiation induced injuries to the tongue, salivary glands and jawbone.

These treatments are considered to be beneficial as a complement for surgery, or as an alternative to surgery.

Particularly attention is being paid to the PENTOCLO protocol developed by Delanian et al., in Paris.

Elsewhere in Europe, Fischer et al., Gottlober et al., Hille et al., the International Atomic Energy Authority [IAEA], and others, have utilised some parts of these anti-oxidant treatments , either individually or in combination, to treat serious radiation late effects [RTLE] injuries.

References:

[1] Ref No : BFCO(95)2 - Maher Committee. Management of Adverse Effects following Breast Radiotherapy -
https://www.rcr.ac.uk/sites/default/files/publication/maher.pdf

[2] Int. J. Radiation Oncology Biol. Phys., Vol. 52, No. 5, pp. 1207–1219, 2002
Dose Response and Latency for Radiation Induced Fibrosis, Edema and Neuropathy in Breast Cancer Patients.
Department of Radiation Sciences, Translational Research Group, Umeå, Sweden

[3] Radiother Oncol. 1994 Jul;32(1):12-20.
Successful treatment of radiation-induced fibrosis using liposomal Cu/Zn superoxide dismutase: clinical trial.
Delanian S, Baillet F, Huart J, Lefaix JL, Maulard C, Housset M.
Department of Radiation Therapy, Necker Hospital, Universite Paris V, France.

[4] Cutaneous radiation syndrome: clinical features, diagnosis and therapy. Gottlober P, Krahn G, Peter RU.
Abteilung fur Dermatologie (BWK), Universitatsklinikum Ulm. Germany

[5] Crux medicorum ulcerated radiation-induced fibrosis - successful therapy with pentoxifylline and vitamin E.
Fischer M, Wohlrab J, Marsch W. Department of Dermatology and Venerology, Martin-Luther-University
Halle- Wittenberg, Germany.

[6] Strahlenther Onkol. 2005 Sep;181(9):606-614.
Effect of Pentoxifylline and Tocopherol on Radiation Proctitis/Enteritis.
Hille A, Christiansen H, Pradier O, Hermann RM, Siekmeyer B, Weiss E, Hilgers R, Hess CF, Schmidberger H.
Department of Radiotherapy and Radiation Oncology, University of Goettingen, Germany.

[7] (Br J Radiol. 2002 May;75(893):467-9.)
Complete healing of severe osteoradionecrosis with treatment combining pentoxifylline, tocopherol and clodronate.
Delanian S, Lefaix JL. Service d'Oncologie-Radiotherapie, Hopital Saint-Louis Paris, France.

[8] Radiother Oncol. 2004 Nov;73(2):133-9.
Double-blind placebo-controlled randomised trial of vitamin E and pentoxifylline in patients with chronic arm lymphoedema and fibrosis after surgery and radiotherapy for breast cancer.
Gothard L, Cornes P, Earl J, Hall E, MacLaren J, Mortimer P, Peacock J, Peckitt C, Woods M, Yarnold J.
PMID:15542159

[9] Radiother Oncol. 2005 Jun;75(3):334-41. Epub 2005 Mar 16.
Phase II study of vitamin E and pentoxifylline in patients with late side effects of pelvic radiotherapy.
Gothard L, Cornes P, Brooker S, Earl J, Glees J, Hall E, Peckitt C, Tait D, Yarnold J.
PMID:16086914

[10] Radiother Oncol. 2001 Mar;58(3):279-86.
Double-blind randomized phase II study of hyperbaric oxygen in patients with radiation-induced brachial plexopathy.
Pritchard J, Anand P, Broome J, Davis C, Gothard L, Hall E, Maher J, McKinna F, Millington J, Misra VP, Pitkin A, Yarnold JR.
PMID:11230889

[11] Radiother Oncol. 2004 Mar;70(3):217-24.
Non-randomised phase II trial of hyperbaric oxygen therapy in patients with chronic arm lymphoedema and tissue fibrosis after radiotherapy for early breast cancer.
Gothard L, Stanton A, MacLaren J, Lawrence D, Hall E, Mortimer P, Parkin E, Pritchard J, Risdall J, Sawyer R, Woods M, Yarnold J.
PMID:15064005[12] Radiother Oncol. 2006 Apr;79(1):45-51. Epub 2006 Mar 20.
Double-blind, placebo-controlled, randomised phase II trial of IH636 grape seed proanthocyanidin extract (GSPE) in patients with radiation-induced breast induration.
Brooker S, Martin S, Pearson A, Bagchi D, Earl J, Gothard L, Hall E, Porter L, Yarnold J.
PMID:16546280

[13] Toft Report 2005 – The Cookridge Incident.

[14] The Accidental Overexposure of Radiotherapy Patients in Bialystok, Poland.

[15] Pentoxifylline and tocopherol in the management of patients with osteoradionecrosis, the Portsmouth experience.
Dr N M H McLeod - Department of Oral & Maxillofacial Surgery, Queen Alexandra Hospital, Portsmouth and St Rishards Hospital, Chichester
http://www.bjoms.com/article/S0266-4356(10)00382-7/pdf
http://www.bjoms.com/article/S0266-4356(10)00382-7/fulltext

[16] Pharmacologic Modalities in the Treatment of Osteoradionecrosis of the Jaw.
Professor J A McCaul - Department of Oral & Maxillofacial Surgery, Royal Marsden NHS Foundation Trust, London
http://www.researchgate.net/publication/262054341_Pharmacologic_Modalities_in_the_Treatment_of_Osteoradionecrosis_of_the_Jaw

[17] Department of Radiation Medicine, Armed Forces Radiobiology Research Institute, 8901 Wisconsin Avenue, Besthesda, MD 20889-5603, USA.

Further Notes for Reference

The Bialystok Report - was published by the IAEA in conjunction with clinicians from Europe and America (see Report)
The use of Pentoxifylline and vitamin E. would appear to by recognised by IAEA for its efficacy and safety.

[18] Nutritional approaches to radioprotection in the Nuclear Battlefield: Vitamin E.

Kumar KS, Srinivasan V, Toles R, Jobe L, Seed TM.

Radiation Casualty Management Research Team, Department of Radiation Medicine, Armed Forces Radiobiology Research Institute, 8901 Wisconsin Avenue, Besthesda, MD 20889-5603, USA.

"Low-level radiation injury is dependent on the radiation dose and dose rate.

“The major military use of any potential radioprotectant is to prevent the short-term effects of lethality and the long-term effects of cancer and other pathologies from radiation exposure that may occur in a nuclear battlefield or in a nuclear material contaminated field of operation.

“Therefore, a radioprotectant should not affect the ability of military personnel to perform tasks. Because exposure to ionizing radiation induces free radical species, effective antioxidants, either alone or in combination with other agents, can be used as potential radioprotectors.

“To test this hypothesis, we studied vitamin E for its radioprotective efficacy. Using CD2F1 male mice as the model system.

“We observed that vitamin E at a dose of 400 IU/kg acts as a good radioprotectant against lethal doses of cobalt-60 radiation. “Vitamin E was more efficacious when given subcutaneously than when given orally".

[19] Indian J Med Res. 2002 Jul;116:29-34.

Immediate treatment of frostbite using rapid rewarming in tea decoction followed by combined therapy of pentoxifylline, aspirin & vitamin C.
Purkayastha SS, Bhaumik G, Chauhan SK, Banerjee PK,
Selvamurthy W.
Cold Physiology Department,
Defence Institute of Physiology & Allied Sciences,
Defence Research & Development Organization,
Lucknow Road, Timarpur, Delhi 110054, India.

[This section and the embedded links are still being developed]…..

The links below provide some idea of the scale of the Delanian/Lefaix research undertaken in developing the complete repair of radiation injuries - 60 papers published to date:-
http://www.jco.org/cgi/external_ref?access_num=Delanian+S&link_type=AUTHORSEARCH

The most significant of these papers are:-

• http://bjr.birjournals.org/cgi/content/full/75/893/467

• http://www.jco.org/cgi/content/full/21/13/2545

• http://bjr.birjournals.org/cgi/content/full/77/922/885

Medical treatment of osteoradionecrosis of the mandible

http://www.ncbi.nlm.nih.gov/pubmed/24993781

• Osteoradionecrosis (ORN) is a severe, generally irreversible complication of radiotherapy due to failure of healing.

• The pentoxifylline-tocopherol combination decreases the superficial fibrosis induced by radiotherapy.

• Potentiation by Clodronate (PENTOCLO) appears to be effective in ORN of the mandible (jawbone).

[This section and the embedded links are still being developed]…..

Anti-oxidant therapies in Europe and America

Listed below are some of the European and American efforts to develop anti-oxidant therapies during the last 25 years. These references concern the use of Pentoxifylline and vitamin E. either individually or in combination.

[This section and the links are still being developed]…..

Int J Radiat Oncol Biol Phys 19:401-407, 1990
Preliminary study of pentoxifylline in the treatment of late radiation soft tissue necrosis.
Dion M, Hussey D, Doornbos J, et al.

Radiother Oncol 32:12-20, 1994
Successful treatment of radiation induced fibrosis using liposomal Cu/Zn superoxide dismutase: Clinical trial.
Delanian S, Baillet F, Huart J, et al.

Int J Radiat Oncol Biol Phys 35:305-312, 1996
Successful treatment of radiation-induced fibrosis using Cu/Zn-SOD and Mn-SOD: An experimental study.
Lefaix J-L, Delanian S, Leplat J-J, et al.

Laryngoscope 107:391-395, 1997
Pentoxifylline in the treatment of radiation-related soft tissue injury: Preliminary observations
Futran N, Trotti A, Gwede C.

Int J Radiat Oncol Biol Phys 45:147-152,1999
Interferon gamma in survivors of the Chernobyl power plant accident: new therapeutic option for radiation-induced fibrosis.
Peter R, Gottlober P, Nadeshina N, et al.

Int J Radiat Oncol Biol Phys 50:159-166, 2001
Interferon gamma in 5 patients with cutaneous radiation syndrome after radiation therapy.
Gottlober P, Steinert M, Bahren W, et al.

Eur J Dermatol 11:38-40, 2001
Crux medicorum ulcerated radiation-induced fibrosis successful therapy with pentoxifylline and vitamin E (case report).
Fischer M, Wohlrab J, Marsch W.

Br J Radiol 75:467-469, 2002
Complete healing of severe osteoradionecrosis by treatment combining pentoxifylline, tocopherol and Clodronate
(case report). Delanian S, Lefaix J-L.

Radiother Oncol 77:324-326, 2005
Pentoxifylline and Vitamin E combination for superficial radiation-induced fibrosis: A phase II clinical trial.
Haddad P, Kalaghchi B, Amouzegar-Hashemi F.

Strahlenther Onkol 181: 606-614, 2005
Effect of pentoxifylline and tocopherol on radiation proctitis/ enteritis.
Hille A, Christiansen H, Pradier O, et al.

Head Neck 27:114-123, 2005
Major healing of refractory mandible osteoradionecrosis after treatment combining pentoxifylline and tocopherol: a phase II trial.
Delanian S, Depondt J, Lefaix J-L.

Semin Radiat Oncol 17:99-107 © 2007 Elsevier Inc.
Current Management for Late Normal Tissue Injury: Radiation-Induced Fibrosis and Necrosis
Sylvie Delanian, MD, PhD,* and Jean-Louis Lefaix, PhD†

Free Radical Biol Med 2001; 30: 30–42.
Antifibrotic action of Cu/Zn SOD is mediated by TGF-beta 1 repression and phenotypic reversion of myofibroblasts.
Vozenin-Brotons M-C, Sivan V, Gault N, et al.

Radiat Res 2002; 157: 204–23.
Modifying normal tissue damage postirradiation.
Report of a workshop sponsored by the Radiation Research Program, National Cancer Institute, Bethesda, Maryland, September 6–8, 2000.
Stone HB, McBride WH, Coleman CN.

Radiat Res 2002; 158: 118–24.
Report on an interagency workshop on the radiobiology of nuclear terrorism.
Moulder JE.