Globally, breast cancer ranks as the most common malignant neoplasm in the female population (1), significantly impacting their health. Radiotherapy, an effective anti-tumor modality, plays a crucial role in reducing local recurrence following breast cancer surgery and extending patient survival.Radiation dermatitis (RD) is the primary adverse effect of this treatment, affecting 80–95% patients who receive radiotherapy for breast cancer (2). The direct or indirect cytotoxic effects of high-energy radiation cause oxidative stress, DNA damage, the release of inflammatory mediators, and mitochondrial impairment (3), ultimately leading to radiation-induced dermatitis. Clinical manifestations include alterations in skin pigmentation, alopecia, erythema, desquamation, ulceration, hemorrhage, and necrosis (4).To mitigate the occurrence of RD, extensive research has been conducted over the years. This body of research has focused on advancing radiotherapy technology (5, 6), investigating optimal dose-fractionation schedules (7, 8), exploring photobiomodulation therapy (9, 10) and assessing various topical medications. Although these interventions can reduce the occurrence of RD and mitigate symptoms including itching and pain, their overall efficacy remains limited, and the prolonged use of some medications may lead to adverse effects (11).

Polysaccharides, glycoproteins, amino acids, and pectins are active substances found in plant extracts such as Aloe vera (L.) Burm.f. (Aloe vera), Azadirachta indica (Azadirachta indica), and Cucumis sativus L. (Cucumis sativus). These substances can form a hydrating barrier on the skin, thereby providing moisturization and soothing effects that help alleviate skin damage associated with dry desquamation (12, 13).Catechins, flavonolignans, phenolic compounds, follicular acids can scavenge free radicals, especially reactive oxygen species (ROS) and reactive nitrogen species (RNS), increase the activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX), and inhibit the production of inflammatory factors, such as tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6) and interleukin 1β (IL-1β), reducing inflammatory reactions (14–16). Ryan et al. (17), Zhao et al. (18), Karbasforooshan et al. (19), and Xie et al. (20) have demonstrated that active substances contained in plants, including Silybum marianum L.(Milk thistle), Curcuma longa L.(Turmeric), and Camellia sinensis (L.) Kuntze. (Tea plant) can effectively reduce the incidence of acute RD at grade 2 or higher, delay the onset of skin toxicity, and enhance wound healing. In terms of adverse reactions, allergies were more commonly associated with Aloe vera extract, while Turmeric (17) and Tea plant extract (18) scored slightly higher than controls on pain perception, but these differences did not achieve statistical significance. The overall tolerability of these interventions was good, and reports of adverse events leading to discontinuation were rare. Most current studies compare plant-derived interventions with the standard of care (SOC) or best supportive care. However, limited research exists comparing the efficacy of different plant-derived agents. As a result, the selection of interventions is frequently guided by anecdotal evidence from clinical practice rather than empirical clinical data.

This investigation aims to offer valuable insights for clinical decision-making by using a network meta-analysis (NMA) to evaluate the efficacy of various plant-derived substances in reducing RD in breast cancer patients using probability ranking.

This NMA of 18 RCTs, integrating direct and indirect evidence, hierarchically ranks plant-derived interventions for RD prevention in breast-cancer radiotherapy. SUCRA values indicate that Silymarin preparations emerged as the optimal strategy for grade ≥2 RD, and demonstrated superiority over the SOC, whereas Chicory root extract achieved the highest probability for grade ≥3 RD prevention, although without statistically significant superiority over SOC. This analytic framework transcends traditional pairwise meta-analyses by quantifying each intervention’s likelihood of being the best, second-best, or subsequent ranks, thereby supplying clinicians with rank-ordered evidence that directly informs individualized therapeutic choices.

Oxidative stress is recognized as a crucial element in the development and advancement of radiation-induced skin reactions (RISRs) (37, 38). Natural antioxidant compounds extracted from herbs show significant potential in the management of RISRs (39–41). In our NMA, we assessed the efficacy of 17 distinct plant-derived interventions in mitigating RD, and found that Silymarin exhibited the greatest probability of being the optimal intervention for preventing grade ≥2 RD. The primary active component in Silymarin is a flavonoid mixture (42) which has been shown to significantly enhance the levels of cellular antioxidants such as superoxide dismutase (SOD) and catalase (CAT), inhibit lipid peroxidation, and effectively eliminate free radicals and reactive oxygen species (ROS) (43, 44), thereby attenuating oxidative stress and reducing RISRs.These mechanistic pathways have been validated in vitro (45). Our findings collectively substantiate the radioprotective potential of silymarin. A meta-analysis by Suyun et al. (46) published in 2023, supported the efficacy of Silymarin in preventing RD among breast cancer patients. However, this conclusion was based on only two studies involving a total of 141 patients, making it difficult to establish strong clinical validity. Further supporting evidence was provided by Becker-Schiebe et al. (47) and Karbasforooshan et al. (19) who reported that application of 0.25% Silymarin cream or its 1% gel significantly delayed the onset of skin toxicity. During the fifth week of treatment, the incidence of grade ≥2 RD in the Silymarin-treated groups was markedly lower than in the control groups (9.8% vs. 52% and 0% vs. 45%, respectively). These rates were also substantially lower than those reported in previously published studies (31%–50%) (48). Collectively, these findings underscore the promising role of Silymarin in preventing radiation dermatitis in breast cancer patients.

According to our ranking, Chicory root extract was evaluated as the most effective intervention for preventing RD of grade ≥3, even though it was not superior to the SOC. It contains bioactive constituents, including phenolic acids and sesquiterpene lactones, that exert anti-inflammatory and antioxidant effects (49, 50) via ROS scavenging, NF-κB signalling blockade, and Nrf2-mediated up-regulation of HO-1 and NQO1, together with modulation of pro-inflammatory cytokines (e.g., IL-6, TNF-α). Additionally, a naturally occurring hydrogel in Chicory forms a water-absorbing, transparent film that may promote wound healing (51). A study (29) assessing the impact of a 3% Chicory root extract on the incidence and severity of radiation dermatitis reported that participants in the Chicory root group did not develop grade 3 or grade 4 RD. Within our analysis, the efficacy of Chicory root extract was not statistically different from that of other interventions. However, considering that only one study on Chicory root extract was included in our NMA, further large-sample randomized controlled trials are needed to validate its efficacy.

External preparations of Silymarin and Chicory root extract remain limited to institutional compounding or research use. Their absence from the commercial market, poor accessibility, and inadequate safety data preclude routine inclusion in supportive care.In view of cost, availability, and safety, external preparations of Aloe vera, Calendula, and Chamomile are more suitable for primary medical institutions or patients with limited economic conditions, thereby providing references for the selection of interventions in different clinical scenarios.

Compared with grade ≥2 RD, the overall incidence of grade ≥3 RD is relatively lower. Particularly in the era of intensity-modulated radiotherapy (IMRT) and hypofractionated radiotherapy, the incidence rate with routine care ranges from 5% to 15% (27, 52). In our NMA, the overall incidence was 4.69% (69 out of 1, 473 patients). The occurrence of grade ≥3 RD is often associated with more complex, individualized risk factors (38) including BMI, smoking history, and diabetes.Treatments aimed at eliminating oxygen free radicals, supplying antioxidants, and providing moisturization are often insufficient to effectively prevent or reverse such severe skin injury. This may partly explain why none of the evaluated interventions demonstrated statistically significant efficacy in preventing grade ≥3 RD in our study.

This NMA demonstrated that, among the 17 plant-derived interventions evaluated, Silymarin was the most effective in preventing grade ≥2 RD in breast cancer patients, as indicated by probability rankings. In terms of preventing grade ≥3 RD, the efficacy of Chicory root extract was not significantly different from that of the SOC, yet it ranked the highest. However, current evidence on the prevention and management of RD using plant-derived substances remains limited. Further multi-center, high-quality, large-sample RCTs are warranted to validate the therapeutic potential of these interventions in clinical practice.