Causes, treatment and prevention of postradiation xerostomia

1. Causes, treatment and prevention of postradiation xerostomia By • Dr Dimitrios N. Gelis, MD, DDS, ORL • Former President of The Greek Society of Otorhinolaryngology-Head and Neck Surgery (2003-2005) • President of the Greek Association of Otorhinolaryngological Allergy, Immunology and Rhonchopathies • President of the Greek Society of Phoniatrics and Vocal Arts • Scientific Colaborator of the Rinecker Proton Therapy Center, München, Germany

2. Αιτίες, Θεραπεία και Πρόληψη της μετακτινικής Ξηροστομίας • Δρ Δημήτριος Ν. Γκέλης • Ωτορινολαρυγγολόγος, Οδοντίατρος • Επιστημονικός Συνεργάτης του Rinecker Proton Therapy Center, München, Germany

3. Universal prevalence of Head and neck cancers • Each year, worldwide, ∼500,000 individuals are diagnosed with a malignancy in the head and neck region. Adesanya MR, Redman RS, Baum BJ, O'Connell BC. Immediate inflammatory responses to adenovirus-mediated gene transfer in rat salivary glands. Hum Gene Ther. 1996 Jun 10;7(9):1085-93.

4. TREATMENTS OF HEAD AND NECK CANCERS • Most of these patients will receive treatment that includes • surgery ± chemotherapy and • therapeutic irradiation (IR). • While IR is quite effective as adjunctive therapy for the cancer, it can also damage adjacent normal tissues.

5. RADIATION SIDE EFFECTS • In addition to anti-tumor effects, ionizing radiation causes damage in normal tissues located in the radiation portals.

6. Life long threats of Head and Neck radiotherapy There is risk of developing • radiation caries and • osteoradionecrosis is a life-long threat.

7. Direct Side Effects: Mucositis and xerostomia due to radiation therapy Radiation therapy for malignant tumours in the head and neck region are inevitably associated with significant long-term injury to the salivary glands, often resulting in salivary gland hypofunction. The subsequent lack of saliva production leads to many functional and quality-of-life problems for affected patients and there is no effective method to eliminating this problem caused by radiation treatments.

8. ORAL COMPLICATIONS OF RADIOTHERAPY • Oral complications of radiotherapy in the head and neck region are the result of the deleterious effects of radiation on, e.g., salivary glands, oral mucosa, bone, dentition, masticatory musculature, and temporomandibular joints.Vissink et al. 2003

9. Mucositis and xerostomia due to radiation therapy • Although many studies have been done in animal models, the mechanism of this injury in humans is still unclear. Wang SL, Gao RT. Gene transfer-mediated functional restoration for irradiated salivary glands. Chin J Dent Res. 2011;14(1):7-13.

10. CLINICAL CONSEQUENCES OF RADIOTHERAPY • The clinical consequences of radiotherapy include mucositis, hyposalivation, taste loss, osteoradionecrosis, radiation caries, and trismus.

11. Reversible and non reversible consequences of radiotherapy • Mucositis and taste loss are reversible consequences that usually subside early post-irradiation, while hyposalivation is normally irreversible [Bruce J.et al 2009]

12. SALIVARY GLANDS HYPOFUNCTIONS AFTER CONVENTIONAL RADIOTHERAPY • Salivary glands are quite sensitive to IR. Indeed, IR leads to a dramatic loss of the fluid secreting salivary acinar cells, resulting in severe glandular hypofunction (a diminished production of saliva) in most patients (Vissink et al. 2003; Nagler and Baum 2003).

13. Shiboski CH, Hodgson TA, Ship JA, et al. Management of salivary hypofunction during and after radiotherapy. Oral Surg. 2007;103(Suppl):S66.e1–19. • The reason for this damage remains enigmatic, as salivary acinar cells are well differentiated and very slowly dividing, the opposite of the classical target cell for IR sensitivity. • If patients have sufficient functional acinar tissue post-IR, it is possible to treat their salivary hypofunction with cholinergic drugs (Shiboski et al. 2007).

14. Histological changes of the salivary glands • However, most post-IR patients have salivary glands characterized by inadequate acinar cell mass with non-fluid secreting duct cells surviving and predominating

15. Treatment of salivary hypofunction • If patients have sufficient functional acinar tissue post-IR, it is possible to treat their salivary hypofunction with cholinergic drugs (Shiboski et al. 2007). • However, most post-IR patients have salivary glands characterized by inadequate acinar cell mass with non-fluid secreting duct cells surviving and predominating (Vissink et al. 2003; Nagler and Baum 2003).

16. Consequences of hyposalivation • A dry mouth or xerostomia is one of the most common complications during and after radiotherapy for head and neck cancer, because irreparable damage is caused to the salivary glands, which are included in the radiation fields.

17. Consequences of xerostomia due to radiotherapy • Xerostomia not only significantly impairs the quality of life of potentially cured cancer patients, it may also lead to severe and long-term oral disorders.

18. Treatment of xerostomia after radiotherapy • There is no effective conventional therapy for these patients . • If patients have sufficient functional acinar tissue post-IR, it is possible to treat their salivary hypofunction with cholinergic drugs (Shiboski et al. 2007). • Cholinergic drugs have side effects which make the patiens to stop them. • Gene delivery in salivary glands[Samuni Y, Baum BJ.:Biochim Biophys Acta. 2011 Nov;1812(11):1515-21. ]

19. Alternative treatment of postradiation xerostomia • Homeopathy [mouthwash TRAUMEEL S • Acupuncture: • Although preventive accupuncture treatment did not prevent the oral sequelae of RT completely, it significantly minimized the severity of radiation-induced xerostomia. The results suggest that acupuncture focused in a preventive approach can be a useful therapy in the management of patients with head and neck cancer undergoing RT. • Braga Fdo P, Lemos Junior CA, Alves FA, Migliari DA. Acupuncture for the prevention of radiation-induced xerostomia in patients with head and neck cancer. Braz Oral Res. 2011 Apr;25(2):180-5.

20. Strategies for prevention of postradiation xerostomia • Several strategies have been developed to avoid radiation-induced xerostomia without compromising definitive oncologic treatment. • These include salivary gland-sparingradiation techniques, such as 3-dimensional conformal or intensity-modulated radiotherapy, concomitant cytoprotectants, and surgical salivary gland transfer.

21. Safe way of prevention of postradiation xerostomia • The described preventive approaches are not applicable to all patients, and comprehensive scientific research that incorporates new biological insights is warranted to optimize the therapeutic index of radiotherapy for head and neck cancer. • For the moment the safest way of prevention of postradiation radiotherapy is the Proton radiation therapy

22. What is the proton radiation therapy? • Proton therapy • X-ray beams and proton beams can both be targeted with extreme accuracy. However, the range of a proton beam can be precisely controlled, unlike an X-ray beam. This is due to a fundamental difference between the physical properties of electromagnetic waves (x-rays) and accelerated particles (protons).

23. Figure 1 shows the depth dosage profile for radiation coming from the left. For example, the tissue in front of a tumor at a depth of 20 cm receives significantly more radiation than the tumor itself, but the tissue behind the tumor is still exposed to a considerable amount of radiation. Increasing the photon energy by technical means flattens this exponential dose loss. It merely results in a trade-off between tissue damage in front of and tissue damage behind the tumor, but there is no meaningful improvement. Properties of X-rays

24. Tumors often require a higher dose than the surrounding normal tissue in organs like the lungs or GI tract--is able to tolerate (Figure 2). Therefore, tumors require a high local dose of radiation; in practice, one is always limited by the dose administered to the surrounding healthy tissue and the resulting side effects.

25. Figure 3 shows equivalent schematized dose distributions in a cross section of the body. Although the diagram shows the considerable overlap at the tumor site, it is also evident that much of the surrounding tissue is also exposed to a sublethal dose of radiation. Moreover, the physical properties of X-rays mean that some radiation always affects the tissue and organs behind the tumor.

26. A newer procedure, IMRT (Intensity Modulated RadioTherapy) continuously modifies the contour and intensity of the X-ray beam; the X-ray tube rotates while the tumor is being irradiated. • Although a good overlapping effect is achieved, the fundamental problem remains; IMRT cannot overcome the physical limitations of X-ray radiation. • IMRT does not substantially reduce the radiation exposure of healthy tissue, since it merely changes the pattern of the damage. The unfavorable ratio of useful radiation to harmful radiation remains unchanged.

27. Unlike X-rays, proton radiation deposits a lower dose in front of the tumor. The tissue behind the tumor is not exposed to any radiation at all. This physical phenomenon makes it possible to determine the depth of the Bragg peak through modulation of the particle velocity and focus the radiation "three-dimensionally" onto the tumor with absolute precision, greatly improving the ratio of “good radiation” to “bad radiation.” Properties of proton beams

28. Figure 4shows the resulting dose distribution for a large tumor. The reduced upstream dose is maintained while no radiation is deposited downstream of the tumor.

29. Figure 5 provides a direct comparison of the local dose distribution for photon beams versus X-rays as shown in Figure 4.

30. Στο τέλος του διεισδυτικού βάθους στην κορυφή Bragg, τα πρωτόνια διατρυπώντας τον ιστό απελευθερώνουν όμοιες ποσότητες ενέργειας στα μόρια, όπως κάνουν και τα φωτόνια (ακτίνες-Χ) , τουλάχιστον όσον αφορά την παρουσία υδρογόνου στο κυτταρικό νερό. Και στις δύο περιπτώσεις, αυτό προκαλεί τα μόρια να απωλέσουν ηλεκτρόνια. Ο ιστός στη συνέχεια “ξεχνάει” την αιτία απώλειας ηλεκτρονίου (είτε είναι φωτόνια, είτε είναι πρωτόνια) και τον επακόλουθο ιονισμό. Ο ιονισμός, είναι όμοιος και για τους δύο τύπους της ακτινοβολίας, αλλά είναι πιο αποτελεσματικός στην περίπτωση των πρωτονίων, δρώντας ως κυτταρική τοξίνη όπως απεικονίζεται στην εικόνα .

32. Using proton beams instead of X-rays allows medical personnel to increase the therapeutic dose, which is limited due to side effects, while simultaneously reducing the dose deposited in healthy tissue. In clinical practice, this proton beam control, which is three-dimensional rather than two-dimensional thanks to lateral bundling, has reduced the radiation deposited in healthy tissue by roughly 43% to 78%, depending on the tumor geometry.

33. X-rays Protons Figures 7 and 8present comparisons of dose distributions in the same patients. The left-hand image in each figure shows the conventional photon radiation actually received by the patients. The right-hand image shows the exposure that would have been possible with proton therapy. The fine inner line within each image indicates the boundary of the target area (the tumor), while the other colors correspond to the local dose delivered.

34. Left column (X-rays): Two different perspectives of an X-ray treatment plan for a relapsing nasopharyngeal tumor with radiation from several directions are shown. Conventional radiotherapy with X-rays results in an unacceptable exposure of surrounding healthy tissue. In this case, the saliva glands are severely damaged.Figure9 X-rays

39. Clinical benefits of proton therapy • Improves the probability of a cure. • Fewer, less severe side effects. • More treatment options. • Reduced treatment time • Using the scanning method, the beam scans the tumor in a grid-like fashion with the utmost precision, with up to 10,000 target points in the tumor. The beam’s depth of penetration is controlled using variable beam energy. This is the only method that strictly confines the therapy dose, and thus the maximum dose, to the tumor.