Sustained metabolic response in metastatic melanoma after intraperitoneal ozone therapy: a case report

Introduction

Advanced melanoma continues to represent a significant therapeutic challenge. However, in the contemporary era of immunotherapy, long-term survival has substantially improved compared with previous decades, reflecting a meaningful shift in disease prognosis (1). The introduction of immune checkpoint inhibitors has been central to this progress. In particular, the combination of nivolumab and ipilimumab has demonstrated superior overall survival and durable response rates compared with monotherapy, albeit at the cost of a high incidence of immune-related adverse events (2). These combination regimens may also produce transient but clinically relevant impairment in health-related quality of life (3). Although many patients experience subsequent functional recovery, tolerability remains a limiting factor in clinical practice.

Anti-programmed cell death protein 1 (PD-1) monotherapy presents a more favorable safety profile and less impact on quality of life, though with lower rates of deep and sustained responses compared with combination regimens (4). In patients harboring BRAF V600 mutations, combined BRAF and MEK inhibition constitutes another effective therapeutic strategy; however, long-term benefit is limited by acquired resistance and the need for sequential treatments (5). Furthermore, both immunotherapy and targeted therapy impose a considerable economic burden, potentially affecting accessibility and sustainability across healthcare systems (6).

In this context, exploration of complementary approaches with a plausible tolerability profile is of interest. Medical ozone therapy has been used as supportive treatment in various clinical scenarios, including oncologic patients. Case reports have described intraperitoneal ozone administration in advanced cancer patients, with good clinical tolerability and symptomatic improvement (7). We present this article in accordance with the CARE reporting checklist (available at https://acr.amegroups.com/article/view/10.21037/acr-2026-0063/rc).

Case presentation

A 66-year-old woman presented to our clinic in June 2024. She had a history of cutaneous melanoma of the right lower limb diagnosed in 1982, with regional lymph node involvement, treated with surgical resection, inguinal lymphadenectomy, and chemotherapy, subsequently developing chronic lymphedema. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for the publication of this case report. A copy of the written consent is available for review by the editorial office of this journal.

In June 2022, she was diagnosed with nodular malignant melanoma of the right forearm (Clark level IV, Breslow thickness 1.2 mm, no ulceration, 1 mitosis/mm²), with negative surgical margins and pathological staging pT2a N0 M0. The patient declined margin re-excision and sentinel lymph node biopsy. Lymph node ultrasound surveillance remained negative until January 2023.

In July 2023, a progressively enlarging right axillary nodule was identified. Ultrasound examination and biopsy confirmed nodal metastasis. A positron emission tomography-computed tomography (PET-CT) performed on July 27, 2023, demonstrated a hypermetabolic right axillary lymph node measuring 36 mm × 26 mm × 24 mm, without evidence of distant disease. Initial molecular testing for BRAF mutation was negative; however, it was subsequently found to be positive in the post-surgical biopsy specimen. A right axillary lymphadenectomy was performed on August 28, 2023, revealing metastatic involvement in 3 of 16 lymph nodes, one measuring 4 cm with extracapsular extension. Postoperative recovery was uneventful. A PET-CT performed on September 4, 2023, showed no evidence of active disease, with only post-surgical changes observed.

Adjuvant therapy with pembrolizumab was initiated on September 8, 2023, with a planned duration of one year. In November 2023, the patient developed immunotherapy-associated autoimmune hyperthyroidism.

On March 6, 2024, a PET-CT confirmed systemic metastatic progression, with subcutaneous, muscular, pulmonary, pleural, and left adrenal involvement. Targeted therapy with dabrafenib and trametinib was initiated. Following treatment initiation, on April 5, 2024, the patient developed clinically significant systemic toxicity characterized by febrile syndrome and persistent gastrointestinal and respiratory symptoms, resulting in marked deterioration of quality of life. Dose adjustments were implemented; however, tolerability did not improve. The patient ultimately decided to discontinue therapy.

In the context of disease progression, treatment intolerance, and therapy discontinuation, the patient was referred to our clinic. At the time of referral, the patient’s main concerns were progression of metastatic disease, poor tolerance to previous systemic treatment, fatigue, and loss of functional capacity affecting her daily activities.

No relevant family history contributing to the interpretation of the present case was documented. No psychosocial factors considered clinically relevant to therapeutic decision-making or follow-up were identified. At the initial clinical evaluation, the patient presented with deterioration of general condition and reduced functional capacity, with a Karnofsky performance status (KPS) of 60%, without other acute clinically relevant findings requiring urgent intervention.

Intraperitoneal ozone therapy (IPO₃) was initiated. The first cycle began on June 17, 2024, and consisted of four consecutive sessions of IPO₃ using an ozone concentration of 50 µg/mL, with progressive increases in administered volume and total ozone dose, as detailed in Table 1. Subsequent cycles were administered using the same concentration, with adjustments in intraperitoneal volume and total dose according to the planned protocol (Table 1). Treatment adherence was complete for all planned sessions in each cycle. Tolerability was assessed clinically and longitudinally during and after each session, taking into account patient-reported symptoms, general clinical status, and the absence of clinically significant adverse events. Stabilization of leukocyte count was observed during treatment.

Before each session, the patient underwent complete fasting for 6 to 8 hours. The procedure was performed under anesthetic sedation administered and continuously supervised by an anesthesiologist. Intraperitoneal administration was not performed laparoscopically; instead, a specific intraperitoneal catheter was placed for ozone delivery. The oxygen-ozone gas mixture was generated from medical oxygen using a medical ozone generator, and ozone concentration was controlled with an ozone analyzer (BMT964).

During administration, intra-abdominal pressure was strictly monitored to ensure procedural safety and tolerance. The insufflation rate was adjusted individually according to the abdomino-peritoneal resistance perceived during the procedure. The target therapeutic volume was approximately 80 mL/kg body weight, and total administration time depended on the volume delivered according to patient weight. Throughout each session, the patient remained under continuous cardiac and respiratory monitoring, as well as pulse oximetry, with permanent clinical surveillance.

A PET-CT performed on October 22, 2024, demonstrated absence of pathological hypermetabolic uptake in previously documented systemic sites (pulmonary, pleural, muscular, and subcutaneous), with significant reduction of the left adrenal lesion. Due to persistent metabolic activity in the adrenal lesion, additional cycles of IPO₃ were administered in combination with focal radiotherapy directed to that site.

The PET-CT performed on January 23, 2025, demonstrated a mild transient metabolic increase in the treated adrenal area, a finding that could be compatible with post-radiotherapy inflammatory changes, without subsequent clinical or radiological evidence of progression (Table 2).

At follow-up evaluation in March 2025, PET-CT showed no pathological hypermetabolic uptake in previously affected sites and no evidence of metabolically active disease. Laboratory parameters remained within normal ranges. Objective functional improvement was documented, with the KPS increasing from 60% at treatment initiation to 90% at the most recent evaluation (Table 2). The chronological evolution of the disease, treatments, and imaging findings is summarized in Table 3.

Patient perspective

The patient reported that during and after the cycles of IPO₃, she began to feel progressively better. She explained that she regained energy, was able to resume daily activities that had previously been difficult for her, and noticed a clear reduction in the fatigue she had experienced with prior treatments. She particularly emphasized that the therapy was well tolerated and that she did not experience relevant side effects, which allowed her to maintain a more stable and active daily life.

Discussion

The clinical and metabolic evolution observed in this patient displays an unusual pattern within the natural course of advanced metastatic melanoma. Following documented progression under immunotherapy and early discontinuation of targeted therapy due to toxicity, systemic disease reactivation would have been expected. However, from October 2024 onward, sustained disappearance of systemic metastases was documented, with exclusive persistence of the left adrenal lesion and oscillations in maximum standard uptake value (SUVmax) temporally associated with cycles of IPO₃.

This behavior contrasts with the available evidence regarding conventional systemic treatments. Combinations of immune checkpoint inhibitors, such as nivolumab and ipilimumab, have demonstrated significant improvements in overall survival, albeit at the cost of a high incidence of immune-mediated adverse events (2). Anti-PD-1 monotherapy offers better tolerability but is associated with a lower probability of deep and sustained responses (4). In patients harboring BRAF V600 mutations, combined BRAF/MEK inhibition produces rapid responses, although these are frequently limited by acquired resistance (5). Early interruption of these therapies is not typically associated with sustained metabolic remission, but rather with progressive loss of tumor control (1,5). In this clinical context, the prolonged systemic stability observed in the absence of active conventional systemic treatment is striking and requires a biologically coherent interpretation consistent with the available evidence.

Accumulated experience with cellular therapies, such as adoptive tumor-infiltrating lymphocyte (TIL) therapy, confirms that activation of T cell-mediated immunity can translate into sustained tumor control in metastatic melanoma (8). This principle supports the hypothesis that immunomodulatory mechanisms, even when not part of the standard therapeutic armamentarium, may play a role in selected clinical scenarios.

Several experimental studies have demonstrated that medical ozone can modulate redox balance and influence inflammatory cytokine production (9,10). In tumor models involving intraperitoneal administration of ozone/oxygen, increased CD3⁺ lymphocytic infiltration and tumor regression associated with immune activation have been described (11,12). Likewise, in malignant ascites models, intraperitoneal ozone insufflation has been associated with inhibition of neutrophil extracellular traps (NETs) and activation of AMP-activated protein kinase (AMPK), with downstream effects on the tumor inflammatory microenvironment (13). Activation of the AMPK-SIRT1 axis, which is involved in the regulation of energy metabolism and immune function (14), provides a conceptual framework consistent with the possibility of systemic immunometabolic activation.

From this perspective, the temporal correlation between cycles of IPO₃ and the observed metabolic oscillations may reflect dynamic modulation of the systemic immune environment. The sustained functional improvement (KPS 60→90) provides a clinical correlate that reinforces the hypothesis of a global biological effect beyond a purely radiological phenomenon.

The persistence of metabolic activity in the adrenal metastasis introduces an additional element for consideration. The adrenal gland possesses a distinct immunobiological microenvironment (15), characterized by intense glucocorticoid signaling. Endogenous activation of this pathway may induce CD8⁺ T cell dysfunction within the tumor microenvironment (16), and elevated glucocorticoid levels have been associated with reduced response to immunotherapy (17). Furthermore, adrenal metastases from melanoma have demonstrated relative resistance compared with other metastatic sites (18). This organ-specific phenomenon may explain the persistence of localized metabolic activity despite systemic disease control.

Although the observational nature of this report precludes establishing a direct causal relationship between IPO₃ and systemic metabolic remission, the magnitude and duration of tumor control in the absence of active conventional systemic therapy justify prospective exploration of this strategy as a hypothesis-generating approach. Integration of immunological and metabolic biomarkers in future studies would allow more precise elucidation of the mechanisms involved and better delineation of its potential clinical role.

The strengths of this report include longitudinal clinical documentation, serial metabolic imaging by PET-CT, and parallel functional assessment during follow-up. However, several limitations should be acknowledged. First, a single case does not allow the establishment of a causal relationship. Second, concomitant treatment with focal radiotherapy in the persistent adrenal lesion makes it difficult to establish a specific causal interpretation of the metabolic changes observed at that site. Third, the absence of correlative immunological or molecular biomarkers prevents mechanistic confirmation of the hypothesized immunometabolic effects.

Conclusions

In this case, high-dose IPO₃ was well tolerated and was temporally associated with sustained systemic metabolic remission during follow-up, accompanied by objective functional improvement according to the Karnofsky scale. Although a causal relationship cannot be established on the basis of a single observation, these findings justify the conduct of prospective studies to evaluate its potential complementary role in selected clinical contexts.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://acr.amegroups.com/article/view/10.21037/acr-2026-0063/rc

Peer Review File: Available at https://acr.amegroups.com/article/view/10.21037/acr-2026-0063/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://acr.amegroups.com/article/view/10.21037/acr-2026-0063/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for the publication of this case report. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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