Radiation Necrosis

Several mechanisms have been proposed for the development of brain RN. Release of vascular endothelial growth factor stimulated by endothelial cell damage triggers this pathologic process; these cascading events lead to microvascular permeability, oedema and necrosis.^{Reference Li, Chen, Jain, Reilly and Wong25–Reference Coderre, Morris and Micca27} Other possible mechanisms include astrocyte hyperplasia and hypertrophy, oligodendrocyte damage and demyelination or perturbation of the fibrinolytic pathway.^{Reference Burger, Boyko, Gutin, Leibel and Sheline28–Reference Sawaya30} However, the mechanism of action of HBOT is not fully understood. HBOT has been used as a treatment for other radiation-induced injuries in various tissues.^{Reference Hart and Mainous31} It has been proposed that HBOT produces a positive oxygen gradient and subsequently promotes cellular and vascular repair.^{Reference Marx, Johnson and Kline32,Reference Marx, Ehler, Tayapongsak and Pierce33} In addition, previous animal studies have shown that HBOT decreases anaerobic conditions in the brain.^{Reference Kapp, Phillips, Markov and Smith34} Adverse radiation effect can occur early on which is mainly due to oedema and is frequently relieved by a course of corticosteroids, but those patients with necrosis occurring after 6 months are typically brain RN and more difficult to treat.^{Reference Buboltz and Tadi35}

The incidence of brain RN ranges from 2.5% to 24% of treated patients, depending on diagnostic criteria used.^{Reference Chao, Ahluwalia and Barnett4} The variation may be due to improvement in RN diagnosis, awareness and length of oncologic follow-up.^{Reference Vellayappan, Tan and Yong36} Brain RN classically has a median time of onset of 6–12 months from last brain RT^{Reference Chuba, Aronin and Bhambhani12,Reference Singh, Tsang, Khan and Merchant14–Reference Aghajan, Grover, Gorsi, Tumblin and Crawford18,Reference Ruben, Dally, Bailey, Smith, McLean and Fedele37} , though prolonged expression of injury can occur as long as 4 years after SRS.^{Reference Leber, Eder, Kovac, Anegg and Pendl38} RN is associated with dose–volume parameters, prior radiation treatment, concurrent chemotherapy, location, primary cancer histology, planning treatment volume and intrinsic idiopathic radiosensitivity.^{Reference Vellayappan, Tan and Yong36} Higher rates of RN can be seen in for patients receiving concurrent chemoradiation compared to radiation alone^{Reference Ruben, Dally, Bailey, Smith, McLean and Fedele37}; in our study, two patients received concurrent chemotherapy for NPC. In our cohort of patients, the median time to develop symptoms after brain RT was 6 months. Interestingly, one patient in the present study developed symptoms of brain RN 29 years after radiotherapy, likely due to an exacerbation of chronic tissue damage. Previous studies have shown that those who manifest symptoms early after brain RT have a better prognosis compared to those who become symptomatic late and are considered as a late radiation injury.^{Reference Sheline, Wara and Smith39} Thus, there may be a difference in the pathogenesis of early- and late-onset brain RN.

Diagnosis of brain RN is challenging because the location of the high-dose radiation area is also a frequent site of local disease progression, which is always on the differential diagnosis of symptoms or imaging findings. The time to develop RN with initial RT is usually similar to the time to develop tumour recurrence. Histopathology is the gold standard for diagnosis; however, in our cohort of patients, biopsy was not performed to confirm the diagnosis of brain RN due to the need to start empiric therapy or an inaccessible lesion location. Brain MRI can sometimes differentiate brain RN through the use of diffusion-weighted imaging (DWI) and spectroscopy, but was not consistently available for our study cohort.^{Reference Zhang, Ma, Wang, Zheng, Wu and Xu40–Reference Rock, Scarpace and Hearshen42}

Treating Necrosis

The initial management of brain RN is observation for an asymptomatic patient, while steroids are given in symptomatic patients to allow for rapid symptom relief.^{Reference Giglio and Gilbert9} A previous case report described brain necrosis that symptomatically improved after steroid initiation but took 6 months to taper the dose.^{Reference Tada, Matsumoto, Nakagawa, Tamiya, Furuta and Ohmoto43} Some studies use steroids as a comparator arm which gives insight on the effectiveness of steroids alone in brain RN. In a study investigating the role of edaravone, the control arm (steroids alone) was only able to provide improvement in 38.5% of patients after 3 months on the Late Effects Normal Tissue Task Force-Subjective, Objective, Management, Analytic criteria (LENT-SOMA) scale and on brain MRI.^{Reference Tang, Rong and Hu44} Long-term use of steroids is associated with many complications and doses should be decreased as soon as possible. Bevacizumab can also be given in RN due to its anti-angiogenesis properties. A small randomised control trial showed bevacizumab was able to reduce oedema, post-gadolinium contrast enhancing lesion size, and neurologic and clinical symptoms compared to a control group.^{Reference Levin, Bidaut and Hou45}

In our cohort, a median of 30 HBOT dives were administered (range 20–60); this is consistent with prior reports, where the number of dives varied between 20 and 60 dives.^{Reference Chuba, Aronin and Bhambhani12,Reference Singh, Tsang, Khan and Merchant14–Reference Kohshi, Imada, Nomoto and Yamaguchi17,Reference Leber, Eder, Kovac, Anegg and Pendl38,Reference Alyahya, Mittal and Rowe46} Our cohort showed that 92% of the patients improved: 61.5% responded clinically during the course of HBOT, while 30.5% responded within 1 month of HBOT. This is consistent with previous reports that some patients attain clinical response even during a course of HBOT.^{Reference Kohshi, Imada, Nomoto and Yamaguchi17,Reference Leber, Eder, Kovac, Anegg and Pendl38} Data from the present study support HBOT as a treatment option for radiation necrosis.

Selected studies from the literature are presented in Table 2; similar to our data, the proportion of patients who develop clinical and radiologic improvement or stability is high. Among these, three studies included both paediatric and young adults in their population. Two case reports even reported patients who had symptomatic recurrence after the course of HBOT; in these studies, the patients were given another course of HBOT which afforded relief.^{Reference Cihan, Uzun, Yildiz and Dönmez16,Reference Kohshi, Imada, Nomoto and Yamaguchi17} In our cohort, one patient had received two courses of HBOT, but that patient was not able to complete the second course due to the development of dyspnea.

Table 2: Previous studies, published and unpublished, on use of hyperbaric oxygen for brain necrosis

* Had two courses of HBOT.

# Only 8 out of the 12 patients had evaluable MRI post-HBOT.

^ Total population is seven patients which included brain tumours, the patients who had developed these toxicities were not specified.

+ Included paediatric population.

Our cohort included some patients who were treated initially with steroids and further improvement was seen with the addition of HBOT. We recognise that the effect of steroids may have contributed to the clinical and radiological improvement of this cohort and cannot be definitively isolated from the effect of HBOT. This practice is in concordance with typical clinical practice, wherein multiple modalities of treatments are instituted for brain RN. However, baseline status was determined at the initiation of HBOT; thus, improvements are more likely attributable to hyperbaric oxygen as opposed to steroids. In fact, all of the previous studies except one that evaluated HBOT for brain RN found that their patients were on steroids either before or during HBOT (Table 2).^{Reference Chuba, Aronin and Bhambhani12,Reference Singh, Tsang, Khan and Merchant14–Reference Aghajan, Grover, Gorsi, Tumblin and Crawford18,Reference Leber, Eder, Kovac, Anegg and Pendl38,Reference Alyahya, Mittal and Rowe46} Furthermore, the effect of HBOT may be effective against both the reversible and irreversible components of brain RN, but this retrospective study is not able to determine this difference. One of the limitations of the present study was that the steroid use after HBOT was unavailable for review.

Seven of the patients reported toxicities related to HBOT, although most of them were treatable. The most common was ear barotrauma, which can be prevented or treated with tympanostomy tubes. One patient (patient 5) had treatment-limiting toxicity (dyspnea), which necessitated discontinuation of a second course of HBOT. A study by Chuba et al. reported that HBOT was tolerable and resulted only in mild toxicity including ear pain requiring myringotomy and sinusitis.^{Reference Chuba, Aronin and Bhambhani12} Two studies reported two patients each and neither reports documented any toxicity from HBOT, even after repeated courses of treatment.^{Reference Cihan, Uzun, Yildiz and Dönmez16,Reference Kohshi, Imada, Nomoto and Yamaguchi17}

HBOT costs 350 CAD (260 USD) per dive. A typical course of treatment of 20–30 dives would cost 7000–10,500 CAD. This might be viewed as costly burden to the healthcare system, but if effective, it may translate to healthcare savings because more costly surgical intervention and complications of prolonged steroids will be averted. Moreover, the cost of bevacizumab, another common therapy for RN, is 12,600 CAD per course (7.5 mg/kg intravenous every 4 weeks for four cycles)^{Reference Levin, Bidaut and Hou45,47} ; this amount does not include nursing or chemotherapy administration costs.

As of our knowledge, this retrospective review is the largest published series of patients investigates the use of HBOT in brain RN. This study does have limitations, however. Use of advanced MRI techniques was limited to standard enhanced T1 and FLAIR sequences; DWI was not always available and spectroscopy was not performed. Because histopathologic diagnosis was not obtained, tumour progression cannot be completely ruled out. This study is unable to compare the efficacy of HBOT as compared with bevacizumab. Varying tumour diagnoses and radiation treatments were included, which is a limitation inherent to retrospective outcomes research. The HBOT treatment protocol varied slightly between patients, typically ranging from 20 to 30 dives and 2.0 to 2.4 ATA; however, all treatments were delivered at a single hyperbaric facility, ensuring consistent treatment protocols and reporting. It would be ideal to measure the patient-reported quality of life outcomes after radiation necrosis and treatment with HBOT, ideally in a prospective manner. In such a study, there should be standardised reporting of clinical outcomes and toxicities of HBOT. We recognise the limited evidence on this topic; there is presently a phase 2, single-arm trial named Adverse Radiation Effects After Gamma Knife Radio Surgery and Hyperbaric Oxygen Therapy from Italian investigators which will expect to finish accrual in May 2019 (ClinicalTrials.gov identifier, NCT02714465). Bevacizumab is also emerging as an efficacious treatment for radiation necrosis; however, efforts to study this have been challenging. There is a multi-institutional, cooperative group study that is evaluating bevacizumab for radiation necrosis after SRS (ClinicalTrials.gov identifier, NCT02490878), though this study closed in late 2018 due to poor accrual.