Hyperbaric, Delayed Radiation Injury


Article Author:
Jeffrey Cooper
Mary Hanley


Article Editor:
Marc Robins


Editors In Chief:
Stephen Leslie
Karim Hamawy


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Trevor Nezwek
Radia Jamil
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Steve Bhimji
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Nazia Sadiq
Hajira Basit
Phillip Hynes
Tehmina Warsi


Updated:
4/3/2019 4:40:37 PM

Introduction

There will be 1.2 million cases of invasive cancer diagnosed in the United States this year. Half of those patients will receive radiation therapy as part of their treatment program. Serious radiation complications will occur in 5% of patients receiving radiation therapy. This represents about 30,000 cases per year.

Radiation is dosed in Rads and Grays:

1 rad = 1 centigray (cGy) = 100 ergs of energy per gm of tissue

Often, delayed effects of radiation are diagnosed when an additional insult to the tissue such as surgery or trauma occurs.

Etiology

The biological effect of radiation on the tissues includes DNA damage, lipid peroxidation, and protein denaturation. The cellular consequences include cell death and dysfunction. In virtually all tissues that demonstrate late effects of radiation, there is a characteristic obliterative endarteritis. Current research into the etiology of delayed radiation injury has shown that the process of radiation injury begins during the time of radiation treatment and involves the elaboration of many bioactive substances, especially fibrogenic cytokines. TGF-beta is the most commonly studied cytokine associated with late effects of radiation as well as several other cytokines.[1][2]

Acute/Subacute radiation patterns usually develop after 5000 centigray (cGy).

Occurs acutely (near immediate) and the result of cellular toxicity by free radical damage to cellular DNA.

Subacute injuries (2 to 3 months post radiation) usually involve the lung.[3]

Delayed injuries occur more than 6 months to years after completion of radiation treatment. These are precipitated by further injuries in the previously irradiated field such as surgery or trauma. Delayed radiation injury often develops after 6500 centigray (cGy).[4]

Epidemiology

Approximately one-third of patients in the United States who received hyperbaric oxygen therapy is being treated for late effects of radiation therapy (LERT). Major advances have been made in the past 50 years in the treatment and prognosis of many cancers. Many cancers which were once considered to be universally terminal, are now routinely survivable. Unfortunately, ionizing radiation when used to treat cancer is a double-edged sword. It is highly effective at killing the malignancy and curing cancer. However, it is indiscriminate, and despite best efforts and intentions, there is no way to protect nonmalignant tissues from being irreparably damaged by the ionizing radiation. Thus the patient is fortunate to be cured of cancer, but may be faced with delayed radiation injury months or even decades after the treatment is complete.[5][3]

Many times, delayed radiation injuries are precipitated by an additional tissue insult such as trauma or surgery.[6]

Pathophysiology

Diffuse injury pattern related to the isodosing concept. The tumor is treated as a spheroidal mass with the most number of target cells at the center. A boost dose is given to the center of the tumor. At incremental distances from the center of the tumor, the mass is less; therefore, the delivered dose is less. However, the patient develops an additional diffuse area of injury from beam divergence. Radiation wounds demonstrate a progressive, proliferative endarteritis. This is an obliterative process that destroys the tissue blood supply. The tissue ends up chronically hypoxic, fibrotic, and with a dearth of blood vessels.[7]

There is no satisfactory treatment of radiation necrosis using conventional therapy.  It is difficult if not impossible to provide adequate nutrients and oxygen to the devascularized tissues. Surgical reconstruction of previously irradiated tissue has a very high failure rate due to poor healing.

The 3 Hs of previously irradiated tissue[8][9]

  • Hypoxia
  • Hypovascularity
  • Hypocellularity

Delayed radiation injury is a problem of impaired and inadequate tissue turnover and wound healing.

Histopathology

Two mechanisms of injury have been proposed and supported by animal and in vitro studies. The first postulates direct damage to small vessel endothelium, being a tissue that exhibits rapid turnover, through interaction with the radiation-induced reactive oxidative species. The resulting debris interrupts the vascular flow, a process known as endarteritis obliterans. The other model describes a delayed process initiated at the time of radiation with the release of bioactive, fibrogenic cytokines inhibiting parenchymal and stem cells and causing the extensive fibrosis seen in several damaged irradiated tissue. This is known as the fibro-atrophic effect.[10][11]

Toxicokinetics

The effects of ionizing radiation on soft tissues are permanent and ever-changing. Patients treated with radiation therapy for prostate cancer can develop post radiation cystitis and hematuria even 20 years after the completion of the radiation therapy. Patients treated for prostate and colon cancers can develop proctitis as well as cystitis due to late effects of ionizing radiation.[12][13][14][15]

History and Physical

Patients who develop delayed effects of radiation present most commonly with radiation cystitis, radiation proctitis, vaginal radionecrosis, soft tissue radionecrosis, or laryngeal radionecrosis.[16][17][16]

Patients who have undergone radiation to the head and neck for soft tissue and palate or bone cancers may develop osteoradionecrosis of the jaw. This can be manifested by exposed bone (usually the maxilla or mandible) in previously irradiated tissue that has failed to close spontaneously or with treatment for at least six months. These patients may also develop chronic draining sinus tracts and fistulae from the bone.[18][8][19]

It is important to document when the radiation treatment was completed and what the total dose was given.

Total doses of more than 6500 cGy are associated with the development of osteoradionecrosis and soft tissue radionecrosis.

Note if the patient has undergone recent bone biopsies, salvage surgery, trauma due to an oral or dental prosthesis, dental or periodontal disease, or extraction.[20][21][7][22]

Often, women who have received radiation for breast cancer develop post-radiation tissue fibrosis and hypovascularity of the chest-wall tissue which can make successful reconstruction and healing difficult, if not impossible.[23][24]

Evaluation

Patients presenting for hyperbaric oxygen treatment for late or delayed effects of radiation should have a formal consultation with the hyperbaric physician and treatment team. Information needed to determine the diagnosis and develop a treatment plan include:

  • Radiation therapy record: Specifically the total dose received and the dates the therapy was given
  • Any history of chemotherapy and agents used
  • Recent imaging results such as PET, CT, or MRI scans to document that the patient is currently cancer-free
  • Reports and records from the referring physician requesting the hyperbaric medicine consultation.[25]

Treatment / Management

Treatment protocols vary depending on the treated tissue.

Robert Marx, DDS did most of the work elucidating the benefit of hyperbaric oxygen for treatment of osteoradionecrosis of the mandible in patients who received head and neck radiation. Osteoradionecrosis of the jaw is the result of an aseptic, avascular necrosis of the bone. Marx showed that for hyperbaric oxygen to be consistently successful, it must be combined with surgery and antibiotic therapy. The major principals elucidated by Marx in the treatment and prevention of ORN include an emphasis on pre-surgical hyperbaric oxygen to improve tolerance to surgical wounding. These patients typically receive 20 pre-extraction treatments followed by ten post-extraction hyperbaric oxygen treatments.[26][27]

Laryngeal necrosis and other soft tissue necrosis of the head and neck due to late effects of radiation therapy have been successfully treated with hyperbaric oxygen to improve tissue quality both preoperatively and postoperatively and to improve survival of surgical flaps in previously irradiated head and neck tissues.[28]

A growing body of literature supports the use of hyperbaric oxygen therapy in the prevention of radiation injury. This is usually in the setting of proposed surgery within a previously irradiated field where the likelihood of complications and difficult wound healing is high.[29]

At present, a reasonable approach is to provide adjunctive hyperbaric oxygen treatments when surgery in heavily irradiated tissue bed is planned.[30][31]

Enhancing Healthcare Team Outcomes

Delayed radiation injuries (soft tissue and bony necrosis) is a CMS-approved diagnosis for hyperbaric oxygen therapy. Depending on the individual patient diagnosis and the proposed surgery, the patient may receive from 20 to 60 hyperbaric oxygen treatments to treat and mitigate the symptoms of LERT. An interprofessional team of specialty trained hyperbaric nurse and clinician should monitor the patient during treatment. [Level V]


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Hyperbaric, Delayed Radiation Injury - Questions

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Delayed, or late effects of radiation therapy is a common diagnosis in patients treated with hyperbaric oxygen therapy. What total radiation dose is associated with symptoms of late effect of radiation therapy (LERT)?



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The Marx Protocol is used for adjunctive hyperbaric oxygen therapy to treat what condition?



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You receive a phone call in your hyperbaric clinic from a local urologist. He has a 56 year old male patient who has been treated for prostate cancer 5 years ago with surgery and radiation therapy. The patient began to experience painless hematuria 6 months ago and has recently required a blood transfusion due to a severe episode last week. The patient mentioned to the Urologist that he read something online about treating this hematuria with hyperbaric oxygen therapy but the Urologist is skeptical. You tell your colleague:



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How does hyperbaric medicine help with healing of late effects of radiation wounds?



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Delayed radiation tissue damage can be treated with hyperbaric oxygen therapy. Which of the following is least likely to characterize the damaged tissue prior to hyperbaric oxygen therapy?



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Hyperbaric, Delayed Radiation Injury - References

References

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Chronic radiation proctitis: issues surrounding delayed bowel dysfunction post-pelvic radiotherapy and an update on medical treatment., Henson C,, Therapeutic advances in gastroenterology, 2010 Nov     [PubMed]
Hyperbaric oxygen therapy for delayed radiation injuries in gynecological cancers., Fink D,Chetty N,Lehm JP,Marsden DE,Hacker NF,, International journal of gynecological cancer : official journal of the International Gynecological Cancer Society, 2006 Mar-Apr     [PubMed]
Hyperbaric oxygen therapy: a meeting place for medicine and dentistry., Adkinson C,Anderson T,Chavez J,Collier R,MacLeod S,Nicholson C,Odland R,Vellis P,, Minnesota medicine, 2005 Aug     [PubMed]
Hyperbaric oxygen and malignancies: a potential role in radiotherapy, chemotherapy, tumor surgery and phototherapy., Al-Waili NS,Butler GJ,Beale J,Hamilton RW,Lee BY,Lucas P,, Medical science monitor : international medical journal of experimental and clinical research, 2005 Sep     [PubMed]
Hyperbaric oxygen for delayed radiation injuries., Feldmeier JJ,, Undersea & hyperbaric medicine : journal of the Undersea and Hyperbaric Medical Society, Inc, 2004 Spring     [PubMed]
A systematic review of the literature reporting the application of hyperbaric oxygen prevention and treatment of delayed radiation injuries: an evidence based approach., Feldmeier JJ,Hampson NB,, Undersea & hyperbaric medicine : journal of the Undersea and Hyperbaric Medical Society, Inc, 2002 Spring     [PubMed]
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Hyperbaric oxygen--an effective tool to treat radiation morbidity in prostate cancer., Mayer R,Klemen H,Quehenberger F,Sankin O,Mayer E,Hackl A,Smolle-Juettner FM,, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology, 2001 Nov     [PubMed]
Hyperbaric oxygen in the treatment of delayed radiation injuries of the extremities., Feldmeier JJ,Heimbach RD,Davolt DA,McDonough MJ,Stegmann BJ,Sheffield PJ,, Undersea & hyperbaric medicine : journal of the Undersea and Hyperbaric Medical Society, Inc, 2000 Spring     [PubMed]
Incidence of complicated healing and osteoradionecrosis following tooth extraction in patients receiving radiotherapy for treatment of nasopharyngeal carcinoma., Tong AC,Leung AC,Cheng JC,Sham J,, Australian dental journal, 1999 Sep     [PubMed]
Hyperbaric oxygen an adjunctive treatment for delayed radiation injuries of the abdomen and pelvis., Feldmeier JJ,Heimbach RD,Davolt DA,Court WS,Stegmann BJ,Sheffield PJ,, Undersea & hyperbaric medicine : journal of the Undersea and Hyperbaric Medical Society, Inc, 1996 Dec     [PubMed]
Hyperbaric oxygen as an adjunctive treatment for delayed radiation injury of the chest wall: a retrospective review of twenty-three cases., Feldmeier JJ,Heimbach RD,Davolt DA,Court WS,Stegmann BJ,Sheffield PJ,, Undersea & hyperbaric medicine : journal of the Undersea and Hyperbaric Medical Society, Inc, 1995 Dec     [PubMed]
Hyperbaric oxygen as a prophylaxis for radiation-induced delayed enteropathy., Feldmeier JJ,Jelen I,Davolt DA,Valente PT,Meltz ML,Alecu R,, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology, 1995 May     [PubMed]
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Hyperbaric oxygen therapy with subtotal extirpation surgery in the management of radionecrosis of the mandible., Guernsey LM,Clark JM,, International journal of oral surgery, 1981     [PubMed]
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