Causes, treatment and Causes, treatment and prevention of postradiation prevention of postradiation

xerostomiaxerostomiaByBy

Dr Dimitrios N. Gelis, MD, DDS, ORLDr Dimitrios N. Gelis, MD, DDS, ORL

Former President of The Greek Society of Former President of The Greek Society of Otorhinolaryngology-Head and Neck Surgery (2003-2005)Otorhinolaryngology-Head and Neck Surgery (2003-2005)

President of the Greek Association of Otorhinolaryngological President of the Greek Association of Otorhinolaryngological Allergy, Immunology and RhonchopathiesAllergy, Immunology and Rhonchopathies

President of the Greek Society of Phoniatrics and Vocal ArtsPresident of the Greek Society of Phoniatrics and Vocal Arts Scientific Colaborator of the Scientific Colaborator of the Rinecker Proton Therapy

Center, M Müünchen, Germany nchen, Germany

Αιτίες, Θεραπεία και Αιτίες, Θεραπεία και Πρόληψη της Πρόληψη της μετακτινικής μετακτινικής ΞηροστομίαςΞηροστομίας Δρ Δημήτριος Ν. ΓκέληςΔρ Δημήτριος Ν. Γκέλης

Ωτορινολαρυγγολόγος, ΟδοντίατροςΩτορινολαρυγγολόγος, Οδοντίατρος Επιστημονικός Συνεργάτης του Επιστημονικός Συνεργάτης του

Rinecker Proton Therapy Center, Rinecker Proton Therapy Center, MMüünchen, Germanynchen, Germany

Universal prevalence of Universal prevalence of Head and neck cancersHead and neck cancers

Each year, worldwide, 500,000 ∼Each year, worldwide, 500,000 ∼individuals are diagnosed with a individuals are diagnosed with a malignancy in the head and neck region.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.

TREATMENTS OF HEAD TREATMENTS OF HEAD AND NECK CANCERSAND NECK CANCERS

Most of these patients will receive Most of these patients will receive treatment that includes treatment that includes

surgery ± chemotherapy and surgery ± chemotherapy and therapeutic irradiation (IR). therapeutic irradiation (IR). While IR is quite effective as adjunctive While IR is quite effective as adjunctive

therapy for the cancer, it can also therapy for the cancer, it can also damage adjacent normal tissues. damage adjacent normal tissues.

RADIATION SIDE EFFECTSRADIATION SIDE EFFECTS

In addition to anti-tumor effects, ionizing In addition to anti-tumor effects, ionizing radiation causes damage in normal radiation causes damage in normal tissues located in the radiation portals. tissues located in the radiation portals.

Life long threats of Head Life long threats of Head and Neck radiotherapyand Neck radiotherapy

There is There is risk of developing risk of developing radiation caries and radiation caries and osteoradionecrosis is a life-osteoradionecrosis is a life-

long threat.long threat.

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

ORAL COMPLICATIONS OF ORAL COMPLICATIONS OF RADIOTHERAPYRADIOTHERAPY

Oral complications of radiotherapy in the Oral complications of radiotherapy in the head and neck region are the result of head and neck region are the result of the deleterious effects of radiation on, the deleterious effects of radiation on, e.g., salivary glands, oral mucosa, bone, e.g., salivary glands, oral mucosa, bone, dentition, masticatory musculature, and dentition, masticatory musculature, and temporomandibular joints.temporomandibular joints. VissinkVissink etet alal. 2003. 2003

Mucositis and xerostomia due Mucositis and xerostomia due to radiation therapyto radiation therapy

Although many studies have Although many studies have been done in animal models, been done in animal models, the mechanism of this injury the mechanism of this injury in humans is still unclear. 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.

CLINICAL CONSEQUENCES OF RADIOTHERAPYCLINICAL CONSEQUENCES OF RADIOTHERAPY

The clinical consequences of The clinical consequences of radiotherapy include mucositis, radiotherapy include mucositis, hyposalivation, taste loss, hyposalivation, taste loss, osteoradionecrosis, radiation osteoradionecrosis, radiation caries, and trismus. caries, and trismus.

Reversible and non Reversible and non reversible consequences of reversible consequences of radiotherapyradiotherapy Mucositis and taste loss are Mucositis and taste loss are

reversible consequences that reversible consequences that usually subside early post-usually subside early post-irradiation, while irradiation, while hyposalivation is normally hyposalivation is normally irreversible irreversible [[Bruce J.Bruce J. et al 2009]et al 2009]

SALIVARY GLANDS HYPOFUNCTIONS SALIVARY GLANDS HYPOFUNCTIONS AFTER CONVENTIONAL RADIOTHERAPYAFTER CONVENTIONAL RADIOTHERAPY

Salivary glands are quite sensitive to IR. Salivary glands are quite sensitive to IR. Indeed, IR leads to a dramatic loss of the Indeed, IR leads to a dramatic loss of the fluid secreting salivary acinar cells, fluid secreting salivary acinar cells, resulting in severe glandular resulting in severe glandular hypofunction (a diminished production of hypofunction (a diminished production of saliva) in most patients (saliva) in most patients (VissinkVissink etet alal. 2003. 2003; ; NaglerNagler and and BaumBaum 2003 2003). ).

Shiboski CH, Hodgson TA, Ship JA, et al. Management of Shiboski CH, Hodgson TA, Ship JA, et al. Management of salivary hypofunction during and after radiotherapy. salivary hypofunction during and after radiotherapy.

Oral Surg. 2007;103(Suppl):S66.e1–19.Oral Surg. 2007;103(Suppl):S66.e1–19.

The reason for this damage remains The reason for this damage remains enigmatic, as salivary acinar cells are enigmatic, as salivary acinar cells are well differentiated and very slowly well differentiated and very slowly dividing, the opposite of the classical dividing, the opposite of the classical target cell for IR sensitivity. target cell for IR sensitivity.

If patients have sufficient functional If patients have sufficient functional acinar tissue post-IR, it is possible to acinar tissue post-IR, it is possible to treat their salivary hypofunction with treat their salivary hypofunction with cholinergic drugs (cholinergic drugs (ShiboskiShiboski etet alal. 2007. 2007). ).

Histological changes of Histological changes of the salivary glandsthe salivary glands

However, most post-IR patients have However, most post-IR patients have salivary glands characterized by salivary glands characterized by inadequate acinar cell mass with non-inadequate acinar cell mass with non-fluid secreting duct cells surviving and fluid secreting duct cells surviving and predominatingpredominating

Treatment of salivary Treatment of salivary hypofunctionhypofunction

If patients have sufficient functional acinar If patients have sufficient functional acinar tissue post-IR, it is possible to treat their tissue post-IR, it is possible to treat their salivary hypofunction with cholinergic drugs salivary hypofunction with cholinergic drugs (Shiboski et al. 2007). (Shiboski et al. 2007).

However, most post-IR patients have salivary However, most post-IR patients have salivary glands characterized by inadequate acinar cell glands characterized by inadequate acinar cell mass with non-fluid secreting duct cells mass with non-fluid secreting duct cells surviving and predominating (Vissink et al. surviving and predominating (Vissink et al. 2003; Nagler and Baum 2003). 2003; Nagler and Baum 2003).

ConsequencesConsequences of of hyposalivationhyposalivation

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

Consequences of Consequences of xerostomia due to xerostomia due to radiotherapyradiotherapy Xerostomia not only Xerostomia not only

significantly impairs the significantly impairs the quality of life of potentially quality of life of potentially cured cancer patients, it may cured cancer patients, it may also lead to severe and long-also lead to severe and long-term oral disorders. term oral disorders.

Treatment of xerostomia Treatment of xerostomia after radiotherapyafter radiotherapy

There is no effective conventional therapy for There is no effective conventional therapy for these patients these patients ..

If patients have sufficient functional acinar If patients have sufficient functional acinar tissue post-IR, it is possible to treat their tissue post-IR, it is possible to treat their salivary hypofunction with cholinergic drugs (salivary hypofunction with cholinergic drugs (ShiboskiShiboski etet alal. 2007. 2007). ).

Cholinergic drugs have side effects which Cholinergic drugs have side effects which make the patiens to stop them.make the patiens to stop them.

Gene delivery in salivary glandsGene delivery in salivary glands [[Samuni Samuni Y, Baum BJ.:Y, Baum BJ.: Biochim Biophys Acta. 2011 Biochim Biophys Acta. 2011 Nov;1812(11):1515-21. Nov;1812(11):1515-21. ]]

Alternative treatment of Alternative treatment of postradiation xerostomiapostradiation xerostomia

Homeopathy [mouthwash Homeopathy [mouthwash TRAUMEEL STRAUMEEL S    Acupuncture:Acupuncture: Although Although preventive accupuncture preventive accupuncture treatment did not treatment did not

prevent the oral sequelae of RT completely, it prevent the oral sequelae of RT completely, it significantly minimized the severity of radiation-induced significantly minimized the severity of radiation-induced xerostomia. The results suggest that acupuncture xerostomia. The results suggest that acupuncture focused in a preventive approach can be a useful focused in a preventive approach can be a useful therapy in the management of patients with head and therapy in the management of patients with head and neck cancer undergoing RT.neck cancer undergoing RT.

Braga Fdo P, Lemos Junior CA, Alves FA, Migliari DA. Braga Fdo P, Lemos Junior CA, Alves FA, Migliari DA. Acupuncture for the prevention of radiation-Acupuncture for the prevention of radiation-induced xerostomia in patients with head and neck induced xerostomia in patients with head and neck cancer. cancer. Braz Oral Res. 2011 Apr;25(2):180-5.Braz Oral Res. 2011 Apr;25(2):180-5.

Strategies for prevention of Strategies for prevention of postradiation xerostomiapostradiation xerostomia

Several strategies have been developed to Several strategies have been developed to avoid radiation-induced xerostomia without avoid radiation-induced xerostomia without compromising definitive oncologic treatment. compromising definitive oncologic treatment.

These include These include salivary gland-sparingsalivary gland-sparing radiation techniquesradiation techniques, such as , such as 3-3-dimensional conformaldimensional conformal or or intensity-intensity-modulated radiotherapymodulated radiotherapy, concomitant , concomitant cytoprotectantscytoprotectants, and , and surgical salivary gland surgical salivary gland transfer. transfer.

Safe way of prevention of Safe way of prevention of postradiation xerostomiapostradiation xerostomia

The described preventive approaches are not The described preventive approaches are not applicable to all patients, and comprehensive applicable to all patients, and comprehensive scientific research that incorporates new scientific research that incorporates new biological insights is warranted to optimize the biological insights is warranted to optimize the therapeutic index of radiotherapy for head and therapeutic index of radiotherapy for head and neck cancer. neck cancer.

For the moment the safest way of prevention of For the moment the safest way of prevention of postradiation radiotherapy is the postradiation radiotherapy is the Proton Proton radiation therapyradiation therapy

What is the proton What is the proton radiation therapy?radiation therapy?

Proton therapyProton therapy X-ray beams and proton beams can both be X-ray beams and proton beams can both be

targeted with extreme accuracy. However, the targeted with extreme accuracy. However, the rangerange of a proton beam can be precisely of a proton beam can be precisely controlled, unlike an X-ray beam. This is due to controlled, unlike an X-ray beam. This is due to a fundamental difference between the physical a fundamental difference between the physical properties of electromagnetic waves (x-rays) properties of electromagnetic waves (x-rays) and accelerated particles (protons). and accelerated particles (protons).

Properties of X-raysProperties of X-rays Figure 1Figure 1 shows the depth dosage shows the depth dosage

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

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

resulting side effects.resulting side effects.

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

A newer procedure, IMRT (Intensity Modulated A newer procedure, IMRT (Intensity Modulated RadioTherapy) continuously modifies the contour and RadioTherapy) continuously modifies the contour and intensity of the X-ray beam; the X-ray tube rotates while intensity of the X-ray beam; the X-ray tube rotates while the tumor is being irradiated.the tumor is being irradiated.

Although a good overlapping effect is Although a good overlapping effect is achieved, the fundamental problem remains; achieved, the fundamental problem remains; IMRT cannot overcome the physical limitations IMRT cannot overcome the physical limitations of X-ray radiation. of X-ray radiation.

IMRT does not substantially reduce the IMRT does not substantially reduce the radiation exposure of healthy tissue, since it radiation exposure of healthy tissue, since it merely changes the pattern of the damage. merely changes the pattern of the damage. The unfavorable ratio of useful radiation to The unfavorable ratio of useful radiation to harmful radiation remains unchanged. harmful radiation remains unchanged.

Properties of proton beamsProperties of proton beams Unlike X-rays, proton Unlike X-rays, proton

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

Figure Figure 44  shows the shows the resulting dose resulting dose distribution for a distribution for a large tumor. The large tumor. The reduced upstream reduced upstream dose is maintained dose is maintained while no radiation is while no radiation is deposited deposited downstream of the downstream of the tumor. tumor.

Figure Figure 55 provides a direct comparison of the  provides a direct comparison of the local dose distribution for photon beams local dose distribution for photon beams

versus X-rays as shown in Figure 4.versus X-rays as shown in Figure 4.

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

κυτταρική τοξίνη όπως απεικονίζεται στην εικόνα .κυτταρική τοξίνη όπως απεικονίζεται στην εικόνα .

Using proton beams instead of X-rays Using proton beams instead of X-rays allows medical personnel to increase allows medical personnel to increase the therapeutic dose, which is limited the therapeutic dose, which is limited due to side effects, while due to side effects, while simultaneously reducing the dose simultaneously reducing the dose deposited in healthy tissue. deposited in healthy tissue.

In clinical practice, this proton beam In clinical practice, this proton beam control, which is three-dimensional control, which is three-dimensional rather than two-dimensional thanks to rather than two-dimensional thanks to lateral bundling, has reduced the lateral bundling, has reduced the radiation deposited in healthy tissue by radiation deposited in healthy tissue by roughly 43% to 78%, depending on the roughly 43% to 78%, depending on the

tumor geometry.tumor geometry.

X-rays X-rays ProtonsProtons

Figures 7 and 8 present 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.

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

damaged.damaged. Figure9Figure9

ProtonsX-rays

Clinical benefits of proton Clinical benefits of proton therapytherapy

Improves the probability of a cure.Improves the probability of a cure. Fewer, less severe side effects.Fewer, less severe side effects. More treatment options.More treatment options. Reduced treatment timeReduced treatment time Using the scanning method, the beam scans the tumor Using the scanning method, the beam scans the tumor

in a grid-like fashion with the utmost precision, with up in a grid-like fashion with the utmost precision, with up to 10,000 target points in the tumor. The beam’s depth to 10,000 target points in the tumor. The beam’s depth of penetration is controlled using variable beam of penetration is controlled using variable beam energy. This is the only method that strictly confines energy. This is the only method that strictly confines the therapy dose, and thus the maximum dose, to the the therapy dose, and thus the maximum dose, to the tumor. tumor.