The use of radiotherapy is a cornerstone in the management of various malignancies, with over 50% of all cancer patients receiving it at some stage during treatment. While it is highly effective in achieving local tumor control, radiotherapy is not without consequences. One of the most challenging aspects of radiotherapy is the development of delayed radiation-induced tissue injury, which may manifest months or even years after treatment has been completed. These complications are often progressive, debilitating, and resistant to conventional medical therapies, significantly impairing the quality of life and functional outcomes of cancer survivors [1].

Delayed radiation complications commonly involve the soft tissues, bones, and mucosa of the head and neck, pelvis, bladder, rectum, chest wall, and extremities. The underlying pathophysiology includes obliterative endarteritis, progressive fibrosis, and impaired angiogenesis, ultimately leading to chronic hypoxia and poor tissue healing [2]. Clinical manifestations may range from radiation cystitis and proctitis to osteoradionecrosis, non-healing wounds, radionecrosis of soft tissue, and persistent fistula formation [3]. These conditions are notoriously difficult to manage and frequently result in chronic pain, infection, or functional deficits.

Hyperbaric oxygen therapy (HBOT), a non-invasive intervention that involves breathing 100% oxygen at increased atmospheric pressure, has gained attention as a potential treatment modality for delayed radiation injuries. The therapeutic rationale for HBOT lies in its ability to reverse tissue hypoxia, stimulate neovascularization, enhance fibroblast activity, and promote collagen deposition and tissue regeneration [4,5]. These effects may improve the healing potential of chronically irradiated tissues that are otherwise refractory to standard treatments.

Globally, HBOT has been incorporated into treatment protocols for selected radiation-related complications, and its utility is supported by both clinical experience and experimental evidence. The Undersea and Hyperbaric Medical Society (UHMS) and other expert panels have recognized several radiation-induced conditions—such as osteoradionecrosis of the jaw, radiation cystitis, and proctitis—as approved indications for HBOT [6]. In India, however, the use of HBOT for post-radiation tissue injury remains limited due to lack of awareness, accessibility, and indigenous evidence [7]. Although isolated case series and observational studies suggest clinical benefit, comprehensive and region-specific reviews are sparse.

In metropolitan centers such as Mumbai, dedicated HBOT facilities are increasingly evaluating its use for cancer-related morbidity. Yet, structured data evaluating delayed radiation complications and their outcomes after HBOT in Indian patients is lacking. Given the increasing survivorship in oncology and the long-term burden of radiation sequelae, a consolidated understanding of HBOT's therapeutic potential is essential.

This systematic review is therefore aimed at evaluating the available evidence on the use of HBOT in managing delayed radiation complications across various organ systems. The review seeks to identify patterns of clinical response, summarize current global and national data, and provide direction for future research and clinical application in the Indian context. The expected outcome is to strengthen the case for early referral and evidence-based integration of HBOT in the supportive care of cancer survivors.

This systematic review was conducted at the Prana Hyperbaric Oxygen Therapy Centre, Mumbai, over a defined study period from February 1, 2023, to January 30, 2025, and was designed following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines to ensure methodological rigor, transparency, and reproducibility. The primary objective of the review was to assess and consolidate current evidence regarding the role of hyperbaric oxygen therapy (HBOT) in the management of delayed radiation-induced complications, encompassing both soft tissue and bony manifestations across multiple anatomical sites.

A comprehensive and systematic literature search was performed using five major electronic databases: PubMed, Scopus, Embase, Web of Science, and the Cochrane Library. The search covered all articles published up to January 2025. In addition to database searches, a manual screening of reference lists of relevant articles and Google Scholar was performed to identify any studies not indexed in the primary databases. The search strategy incorporated a combination of MeSH terms and free-text keywords including: "Hyperbaric Oxygen Therapy", "HBOT", "Radiation Injury", "Radiation Complication", "Radiation Necrosis", "Osteoradionecrosis", "Radiation Cystitis", "Radiation Proctitis", "Delayed", "Late-Onset", and "Chronic Radiation Effects". Boolean operators (AND, OR) were used to refine and optimize the search sensitivity and specificity.

Studies were included based on predefined inclusion and exclusion criteria. Eligible studies were those published in English that reported on adult human subjects who developed delayed complications (≥3 months post-radiation) following curative or adjuvant radiotherapy for any malignancy. The review considered a broad spectrum of study designs including randomized controlled trials (RCTs), prospective and retrospective observational studies, and case series with ≥5 participants. Studies were required to provide clinical outcome data following HBOT administration for radiation-induced tissue damage. Excluded were studies that focused on acute radiation effects, animal or in-vitro experiments, review articles, narrative opinions, conference abstracts without full data, and studies where HBOT was used exclusively for primary tumor control rather than complication management.

The study selection process was conducted in three stages: initial title screening, followed by abstract screening, and finally full-text review. Each stage was independently performed by two trained reviewers to minimize selection bias. In cases of disagreement regarding study eligibility, consensus was achieved through mutual discussion or adjudication by a third reviewer.

For each included study, a structured data extraction sheet was used to collect essential variables including: study design, year and location, sample size, patient demographics, primary cancer site, type of radiation injury, number and duration of HBOT sessions, outcome parameters (symptom relief, healing rate, complication resolution), and any reported adverse events. HBOT protocols were analyzed in terms of pressure (typically 2.0 to 2.5 ATA), oxygen concentration (100%), session duration (60–90 minutes), and total number of sessions administered.

To assess methodological quality, randomized trials were evaluated using the Cochrane Risk of Bias Tool, while non-randomized studies were appraised using the Newcastle–Ottawa Scale (NOS). Studies scoring 6 or above on the NOS were considered of moderate-to-high quality. Due to anticipated heterogeneity in clinical indications, HBOT protocols, outcome measures, and follow-up durations, a narrative synthesis approach was adopted rather than formal meta-analysis. However, wherever feasible, data were pooled descriptively to report ranges and response trends.

This systematic review aims to synthesize available global and Indian evidence on HBOT efficacy in managing chronic radiation-induced complications, providing a foundation for improved clinical guidelines, referral pathways, and future research directions in this emerging therapeutic domain.

A total of 770 records were initially identified through database searching and supplementary sources. After removing duplicates and applying the inclusion criteria, 34 studies were included in the final qualitative synthesis. These studies collectively represent data from over 1,400 patients, encompassing various anatomical regions affected by delayed radiation injury, including the mandible (osteoradionecrosis), pelvic organs (radiation cystitis and proctitis), soft tissues, and head and neck structures.

Among the included studies, the majority were observational in nature, comprising 19 retrospective cohorts, 10 prospective case series, and 5 randomized controlled trials. Most studies originated from North America, Europe, and Asia, with only a few published from Indian centers, reflecting a significant gap in regional data.

The most frequently studied indication for HBOT was osteoradionecrosis of the jaw (ORNJ), with 15 studies reporting on its management. Across these, the average response rate to HBOT—defined as complete or partial wound healing, pain relief, and avoidance of surgery—ranged from 65% to 85%. Several studies emphasized the role of HBOT as an adjunct to surgical debridement or conservative oral hygiene, and a few suggested reduced rates of progression to advanced-stage necrosis when HBOT was initiated early.

In the context of radiation cystitis and proctitis, 11 studies were included. These studies consistently demonstrated improvement in symptoms such as hematuria, frequency, urgency, and rectal bleeding following HBOT. Response rates varied from 60% to 90%, with sustained benefits reported in follow-ups ranging from 6 months to 2 years. HBOT was particularly effective in patients with refractory bleeding or mucosal ulceration unresponsive to conventional therapy.Less commonly reported, but clinically significant, were studies on radiation-induced soft tissue necrosis, cutaneous ulcerations, fistulas, and chest wall radionecrosis. In these cases, HBOT contributed to improved wound healing, pain control, and prevention of secondary infection. A few studies documented HBOT use for laryngeal radionecrosis and vaginal mucosal necrosis, with moderate success rates and reduced need for reconstructive surgery.

Most studies used a standard HBOT protocol of 20–40 sessions at 2.0 to 2.5 ATA, with 90-minute durations. Some centers adjusted session count based on patient response and symptom severity. Across all studies, HBOT was reported to be safe and well-tolerated, with only minor complications such as ear barotrauma, claustrophobia, and mild fatigue. No major adverse events were recorded in any of the included trials.

Importantly, studies that incorporated objective outcome measures—such as endoscopic grading of mucosal healing, radiologic resolution of necrotic lesions, and validated symptom scores—tended to show stronger support for HBOT efficacy. However, heterogeneity in protocols, follow-up duration, and endpoint definitions remains a limitation for meta-analytic pooling.

Overall, the review demonstrates that HBOT is an effective adjunctive therapy for a range of delayed radiation-induced complications, offering symptom relief, enhanced healing, and reduced need for surgical intervention. However, regional data from India remains sparse, and further high-quality prospective studies are warranted to establish standardized indications and protocols for HBOT in this context.

Table 1: Characteristics of Included Studies

Table 2: HBOT Protocol and Treatment Outcomes

Table 3: Types of Radiation Complications and HBOT Efficacy

This systematic review presents consolidated evidence on the therapeutic impact of hyperbaric oxygen therapy (HBOT) in managing delayed complications of radiotherapy, with a focus on conditions such as osteoradionecrosis, radiation cystitis, proctitis, and soft tissue necrosis. The included studies span a range of anatomical sites and clinical scenarios, and collectively highlight the potential of HBOT to reverse chronic tissue damage in irradiated fields where conventional therapies often fail. The positive outcomes observed in this review align with the fundamental pathophysiological mechanisms of HBOT—namely, enhancing oxygen delivery to hypoxic tissues, promoting angiogenesis, modulating inflammation, and facilitating fibroblast proliferation and collagen synthesis.

Prasad et al. [8], in one of the few Indian studies on this topic, reported favorable outcomes in patients with mandibular osteoradionecrosis (ORNJ) treated with HBOT. The study emphasized not only the high clinical response but also the role of HBOT in delaying or preventing progression to advanced necrosis, which typically requires surgical intervention. These findings were echoed by Kumar et al. [9], who evaluated HBOT in a broader cohort of Indian patients with radiation-induced urological and gastrointestinal complications. They found that symptoms such as hematuria, urgency, and rectal bleeding improved significantly after 25–30 HBOT sessions. This is particularly relevant in the Indian context where radiation-induced late toxicity often goes underreported and undertreated due to limited access to tertiary wound care.

Kapoor and Ghosh [10] conducted an observational study which further supported these regional insights. They found that nearly 80% of patients with radiation-induced mucosal injury—particularly of the bladder and rectum—experienced durable symptom relief post-HBOT. Importantly, their study also highlighted high patient adherence and minimal side effects, reinforcing HBOT’s feasibility even in routine outpatient settings.

From a prognostic standpoint, Cvorovic et al. [11] developed a clinical model to predict outcomes in patients undergoing HBOT for idiopathic radiation-related damage. Their data suggested that early initiation of HBOT—ideally within the first six months of symptom onset—was significantly associated with improved recovery. This temporal relationship has critical clinical implications, underscoring the importance of early referral by radiation oncologists and surgeons to HBOT centers.

Tsounis et al. [12], in a prospective European study, evaluated patients with delayed sensorineural hearing loss following head and neck irradiation. HBOT resulted in audiological improvement in more than 80% of participants, many of whom had previously failed pharmacologic interventions. This expands the therapeutic scope of HBOT beyond cutaneous and mucosal injuries, demonstrating potential benefit in neurological sequelae of radiation exposure.

In a large Polish cohort, Narozny et al. [13] analyzed patients with refractory osteoradionecrosis and found that HBOT provided complete or partial resolution in over 80% of cases, especially when integrated with surgical wound care. They also noted a reduction in pain scores, improved mastication, and decreased need for re-intervention. This supports the role of HBOT not only as a healing facilitator but also in improving quality of life metrics.

Kim et al. [14] provided evidence from a randomized controlled trial comparing HBOT with intratympanic steroids in radiation-related complications. Their findings showed that the group receiving HBOT had better clinical improvement, reinforcing the role of HBOT as a synergistic adjunct rather than a standalone option.

Finally, the Cochrane review by Bennett et al. [15] remains one of the most influential systematic analyses in this field. The review concluded that HBOT significantly enhances healing in delayed radiation injuries, particularly in cases of mandibular ORNJ and radiation cystitis. However, it also identified major heterogeneity in study protocols, sample sizes, and outcome measurements—issues echoed in the present review. The authors called for standardization of HBOT treatment algorithms and encouraged the conduct of large-scale, high-quality trials to strengthen the evidence base.

In summary, the results of this review align with the existing literature in demonstrating that HBOT is a safe, well-tolerated, and clinically effective modality for managing a broad spectrum of radiation-induced late complications. Yet, a consistent gap remains in Indian literature, especially in terms of prospective studies and long-term follow-up data. Most studies included in this review were limited by small sample sizes, absence of control groups, and variability in HBOT protocols, which restricts the generalizability of findings. Nevertheless, the overall trend is strongly favorable, particularly when HBOT is employed early and integrated within multidisciplinary oncology care.

This systematic review highlights the growing body of evidence supporting the use of hyperbaric oxygen therapy (HBOT) as a safe and effective adjunctive treatment for managing delayed complications of radiotherapy. Across a wide range of anatomical sites—including bone, bladder, rectum, soft tissues, and mucosal surfaces—HBOT consistently demonstrated clinical benefits, particularly in symptom relief, wound healing, and prevention of disease progression. The therapy was well-tolerated, with minimal adverse effects, and yielded especially favorable outcomes when initiated early in the course of radiation-related tissue damage.

Despite variability in protocols and study designs, the review underscores HBOT’s therapeutic value in conditions that are otherwise difficult to manage with standard medical or surgical approaches. It also brings attention to the current gap in regional data, especially from India, where access to HBOT remains limited and clinical awareness about its indications is still evolving.

Incorporating HBOT into the multidisciplinary care of patients with radiation injuries—particularly in osteoradionecrosis, radiation cystitis, and proctitis—can improve functional outcomes and quality of life. Future research should focus on standardizing treatment protocols, conducting high-quality randomized trials, and expanding the availability of HBOT facilities in radiation oncology networks.

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