Corresponding author: Stefania Giudici, Struttura Complessa Radioterapia, Ospedale Sanremo, Asl 1 Imperiese, Via Giovanni Borea 56, 18038 Sanremo, Italy; Email:
Seventy to 90 percent of patients who have received radiation treatment struggle with radiation skin and mucosal toxicity. The inflicted damage to progenitor cells and local microcirculation makes it more likely that wounds, infections, and fibrosis may occur; lesions of variable severity often co-exist. Acute erythema, hyperpigmentation, and mild desquamation usually wane in weeks and require only minor treatment. Conversely, the management of persistent radiation dermatitis and telangiectasia remains unsatisfactory; chronic lesions may progress to tissue atrophy and disfiguring fibrosis.
Protrophic, natural-origin polynucleotides, formulated as Class III medical devices, have long shown to be a reliable topical option to stop the progression of radiation-related lesions. The present review illustrates the rationale of polynucleotides in skin and mucosal radiodermatitis management. It also illustrates the clinical results in a series of exploratory clinical studies carried out with polynucleotide devices over the last decade. The examined studies open the way to the high-level clinical research program, which will develop over the next years.
More than 50% of cancer patients receive (
Genetics seems to have a role in the individual radiosensitivity and the development of adverse skin reactions. A recent paper described the association between radiation toxicity, ATM, CDKN1A, FDXR, SESN1, XPC, ZMAT3 genes expression, and the BCL2/BAX ratio.[
Administration of high-energy ionizing radiation is usually in small daily doses, delivered with 3D conformal radiotherapy or new techniques such as volumetric modulated arc therapy (
The radiation dose administered is directly related to the radiodermatitis severity with a range of lesions often co-existing within the same radiation field.[
Sustained hyperpigmentation does not occur until 2-4 weeks after
Symptoms and dose-related, first time of onset of acute radiation toxicity
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Erythema and hyperpigmentation | 1 to 2 weeks | 10-40 Gy |
Dry desquamation | 3 to 4 weeks | 20 to 30 Gy |
Moist desquamation | More than four weeks | 30 to 40 Gy |
Gy=gray[5]
Moist desquamation with a breakdown of the skin barrier function occurs at doses above 30 to 40 Gy. It may associate with painful red skin, serous exudation, hemorrhagic crusting, and possibly bullae, contact injury, mainly in flexural areas due to frictional stress, infection, and ulcers. Non-invasive laboratory assessment commonly shows the skin barrier dysfunction to precede clinical symptoms.[
Acute erythema, oedema, and desquamation usually resolve two to four weeks after
Skin atrophy, stiffness and fibrosis are the markers of chronic radiodermatitis after the acute phase; the same is valid for skin hypo- or hyperpigmentation and the loss of sebaceous glands, hair follicles and nails. Dilated neo-vessels form telangiectasia, while tissue hypoxia may cause chronic wounds and ulcerations.[
All radiation-induced chronic lesions are the outcome of aberrant regulation of pro-fibrotic cytokines leading to stromal cell dysfunction, dysregulated re-modeling of the extracellular matrix, and fibrosis
The events in chronic radiation-induced skin and mucosal aberrations are similar to what happens in fibrotic diseases affecting the heart, skin, lungs, kidneys, and other organs.
(
Chronic non-healing ulcerated wound after mediastinal
The hard problem is chronic radiation-induced dermatitis, which can progress to extensive fibrosis.[
Unfortunately, according to the International Society of Dermatology, as late as 2017, none of the many topical agents and specialized wound dressings showed any consistent efficacy to help prevent and manage
Local application of natural-origin polynucleotides has emerged as a promising strategy for treating acute radiodermatitis and preventing chronic sequelae.
Polynucleotides are physiological and ubiquitous molecules in all tissues, including skin and mucosae; damaged or dying cells and local hypoxia physiologically lead to polynucleotide derivatives release in tissues.[
Polynucleotides associate marked lenitive and hydrating properties with a trophic activity on sub-epithelial fibroblasts in skin and mucosae. The highly hydrated tridimensional structure that polynucleotides develop in tissues enhances their moisturizing properties.[
The key of the polynucleotides value is replenishing the tissue reservoirs of metabolic precursors, leading to fibroblast activation after polynucleotides release in the wound bed. Fibroblast activation accelerates skin and mucosal healing, ignited by local hypoxia and damaged or dying cells, by priming fibroblasts to produce new collagen and elastin fibers and new matrix glycosaminoglycans.[
The earliest exploratory studies about the protective potential by polynucleotides against the skin and mucosal
Ten female patients with breast cancers undergoing adjuvant radiotherapy and 14 male patients undergoing radical radiotherapy for prostate cancer participated in the earliest pilot investigation in human subjects.[
There were more experiences after these very first ones over the next few years. Sixty pT1/T2, N0/N+, M0 breast cancer women patients received 46 Gy in four weekly sessions for five weeks with an additional weekly 1.2 Gy-photon boost. They also received the polynucleotide-based cream twice daily until complete disappearance of all skin lesions.[
At the end of the
As regards the prostate cancer patients, only one out of 50 gel-treated subjects showed some modest proctitis (scores: 0.43 out of a maximum of 2 at the end of the
In conclusion, those very early exploratory experiences demonstrated a very low incidence of
The results of a first extensive study in 497 pT1/T2, N0/N+, M0 breast cancer patients appeared in 2010. All participating women received twice-daily treatment (morning and evening) with topical polynucleotides (Leni-Radio® Cream) since the day of the first adjuvant
No Grade-4 toxicity appeared during and after treatment. Leni-Radio® cream was highly successful in the long-term prevention of skin toxicity, with 92% of women showing NCIC Grade 0-1 skin toxicity after six months, 6% showing G2 skin lesions and 2% of women still showing severe G3 skin toxicity. After one year of follow-up, 7% and 3% of women showed chronic G2 and G3 skin toxicity, once again with no difference in incidence or severity in women who had undergone chemotherapy or hormonal therapy.[
The next year, an open study in 36 elderly breast cancer patients (more than 65 years old; mean 74, range 65-87) confirmed the satisfactory cosmetic outcomes and the high safety of Leni-Radio® cream as a preventive treatment of skin radiation toxicity.[
No elderly patient of the polynucleotide-treated cohort showed more than Grade-1 or Grade-2 skin toxicity after one month
In 2013, the results appeared of a study performed in 300 breast cancer patients randomized to post-
Polynucleotide-based Leni-Radio® favorably compared with other agents in women formerly treated with chemotherapy. Grade-1 and Grade-2 toxicity developed in 61% and 3.8% of treated with Leni-Radio®, 73% and 23% of women treated with the ß-glucan, alginates, hyaluronic acid formulation, and in 63% and 17% of women treated with the lenitive and protective galenic formulation. Fourteen per cent of the polynucleotide-treated women had to resort to the triamcinolone cream vs. 15% of the women treated with the commercial formulation and 39% treated with the galenic formulation.[
Incidence and severity of
Incidence and severity of
Percentage of 300 polynucleotide-treated women with evidence of no skin toxicity (G0) at the end of the
Severity of
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Polynucleotide-based Leni-Radio® | 32%*,# | 56% | 11% |
Commercial formulation | 25% | 60% | 15% |
Galenic formulation | 17% | 58% | 25% |
*
The optimal care of
The rationale to leverage the well-known trophic properties exerted by polynucleotides on dermal and mucosal fibroblasts is solid and substantiated by a wealth of preclinical studies. The same is true for the hydrating, moisturizing, and elasticizing properties enjoyed by polynucleotides. The extended program of exploratory and extensive studies herein illustrated supports the rationale; it is also the basis for the vast comparative clinical research program beginning in Europe. Preventing
Summarizing the pieces of evidence accumulated so far, prevention of severe Grade-4 acute toxicity was complete in hundreds of patients treated with topical polynucleotides since the first
Unsurprisingly, Leni-Radio® (TURNOVER®) and topical polynucleotides are useful when the loss of epithelia or stretch marks are the problem or, in specific gel formulations, to treat anal rhagades and, in general, anal and perianal inflammations and proctitis. Of course, the polynucleotide-based cream or gel application should be correct: no more than the needed quantity of gel or abundant amount of cream at least twice daily on
As protection and prevention, once-daily application of Leni-Radio® or TURNOVER® (twice daily with the cream formulation) should begin one or two days before the first
Mastelli S.r.l., Sanremo, Italy, is the producer of the two Leni-Radio® proprietary topical polynucleotide formulations (cream and rectal gel) investigated in the exploratory clinical study program and discussed in this review. TURNOVER® is a second proprietary brand. The author wishes to acknowledge the double contribution, by Mastelli S.r.l. and Mauro Raichi, MD, for editorial support.
The authors have no support to report.
All authors state they have no direct or indirect financial/personal interest that might affect their objectivity and influence their opinions and evaluations, as stated in the manuscript. The only indirect funding they will receive: the producer of the polynucleotide medical devices cited in the document, Mastelli Srl, Sanremo, Italy, will transparently contribute to any article processing charges if requested by Folia Medica if the journal accepts the review manuscript.
Under the general supervision of Prof. Renzo Corvò, Full Professor of Radiotherapy at the University of Genoa Medical School (Corresponding Author), all other authors collaborated to the submitted manuscript by writing the sections that discuss their previous exploratory studies and clinical contributions.
Prof. Renzo Corvò wrote the general introductory chapters, including the rationale for using polynucleotides in preventing and treating radiation-induced skin and mucosal toxicity. Prof. Renzo Corvò is also personally accountable for the accuracy and integrity of the clinical and editorial work leading to the manuscript’s submission to Folia Medica. All authors reviewed the content of the manuscript and consent to publication. The document does not contain data from any person, and specific permissions are “Not applicable”.
Sadly, the author Professor Renzo Corvò, one of the most distinguished academic radiotherapists in Italy and Europe and President of the Italian Society of Radiotherapy, died suddenly on October 3, 2021. This article is dedicated to his cherished memory.