- Email: [email protected]
The effect of hyperbaric oxygen therapy on quality of life in oral and oropharyngeal cancer patients treated with radiotherapy
Int. J. Oral Maxillofac. Surg. 2008; 37: 255–259 doi:10.1016/j.ijom.2007.11.013, available online at http://www.sciencedirect.com
Clinical Paper Head and Neck Oncology
The effect of hyperbaric oxygen therapy on quality of life in oral and oropharyngeal cancer patients treated with radiotherapy
N. L. Gerlach1, R. Barkhuysen1, J. H. A. M. Kaanders2, G. O. R. J. Janssens2, W. Sterk3, M. A. W. Merkx1 1 Department of Oral and Maxillofacial Surgery, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands; 2 Department of Radiotherapy, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands; 3Institute for Hyperbaric Medicine, Hoogeveen, the Netherlands
N. L. Gerlach, R. Barkhuysen, J. H. A. M. Kaanders, G. O. R. J. Janssens, W. Sterk: The effect of hyperbaric oxygen therapy on quality of life in oral and oropharyngeal cancer patients treated with radiotherapy. Int. J. Oral Maxillofac. Surg. 2008; 37: 255–259. # 2007 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved. Abstract. Radiotherapy is used in the setting of curative treatment for head and neck cancer. Xerostomia and related problems occur when major salivary glands are included in the irradiation fields. This reduces quality of life (QOL). Hyperbaric oxygen therapy (HBOT) is a well accepted treatment or prevention modality for osteoradionecrosis of the jawbones and soft-tissue necrosis. It is unknown if and to what extent HBOT influences xerostomia and xerostomia-related QOL. To address this, a prospective study was conducted. Twenty-one patients who underwent radiotherapy for an oral or oropharyngeal carcinoma completed a European Organization for Research and Treatment of Cancer QOL questionnaire before HBOT, as part of the treatment/prevention of osteoradionecrosis, and 1 and 2 years after HBOT. Swallowing-related problems significantly decreased in time, and there was a reported subjective increase in saliva quantity and an improvement in sense of taste. The results suggest that HBOT may positively influence these longterm radiotherapy sequelae.
In the Netherlands the incidence of oral and oropharyngeal carcinomas is 3.5 and 2.4 for males and 1.8 and 0.8 for females per 100,000, respectively12. Surgery, radiotherapy and the combination of both are the main treatment modalities20,22,28. Side effects of radiotherapy include muco0901-5027/030255 + 05 $30.00/0
sitis and skin reaction in the acute phase, and late sequelae such as fibrosis, xerostomia and sometimes necrosis of bone and soft tissues37. Despite the fact that cells from salivary gland tissue have a slow turnover rate, a contradictory high early radiosensitivity is
Keywords: hyperbaric oxygenation; radiotherapy; quality of life; head and neck neoplasms; maxillofacial surgery. Accepted for publication 28 November 2007 Available online 11 February 2008
observed. When major salivary glands such as the parotid and submandibular glands are included in the radiation treatment volume, xerostomia occurs due to a reduction in salivary flow4,24. Although the pathophysiologic mechanism leading to this condition is largely unknown, a
# 2007 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.
256
Gerlach et al.
massive apoptosis, resulting in loss of salivary gland tissue, has been suggested as a possible cause13,34. KONINGS et al.16 suggest that the most probable mechanism of early high radiosensitivity is selective radiation damage to the plasma membrane of the secretory cells, which disturbs muscarinic receptor-stimulated watery secretion. They state that, next to damage to the extracellular environment (thus preventing proper cell functioning), damage in a later stage can be attributed to mitotic cell death of progenitor cells, which has a negative impact on the replacement capacity of secretory cells. In addition to a reduction in flow, radiotherapy alters the biochemical properties of saliva, causing for example a decrease in pH, bicarbonate concentration, immunoglobulins, lysozymes, peroxidases and, as a result of this, a reduced buffer capacity24. There is also a rise in concentration of potassium, chloride, calcium and magnesium ions1,5. These, for the most part irreversible, qualitative and quantitative alterations of saliva mean that patients are prone to oral infections and dental decay14,37. They also result in functional problems such as impairment of oral masticatory function, problems with prosthetic rehabilitation, difficulties with speech and loss of taste. From this it is clear that radiotherapyinduced salivary gland dysfunction significantly impairs quality of life (QOL)5,10. Hyperbaric oxygen therapy (HBOT) is a well accepted treatment for wound-healing problems, although the literature is not always consistent2,18,26,29,36. In the head and neck area HBOT is frequently used to treat osteoradionecrosis (ORN) in a sandwich therapy with surgery conforming to the Marx protocol, or to prevent ORN of the mandible when a surgical intervention is indicated such as dental extractions or dental implant placement3,23. During a HBOT session 100% oxygen is breathed at an elevated ambient pressure up to 2.5 Bar during 90 min. This increases plasma and tissue oxygen concentrations, which is believed to improve wound healing by initiating and accelerating angiogenesis and revascularization3,18,26. THOM et al.35 have recently demonstrated that stem cells are mobilized significantly by hyperbaric oxygen. Possibly, through these mechanisms, HBOT might also ameliorate salivary gland tissue dysfunction with normalization of the qualitative and/or quantitative aspects of saliva to a certain degree and positive effects on QOL. This potential benefit of HBOT has thus far not been explored in a systematic fashion, and no scientific litera-
ture is available on this issue. It is not known if and to what extent HBOT affects salivary gland tissue at a cellular level, and there are no data on its effect on xerostomia and related QOL problems. The aim of this prospective study was to investigate the long-term effects of HBOT on xerostomia and QOL in patients who received radiotherapy for an oral or oropharyngeal carcinoma. Material and methods
In this study 21 consecutive patients were included who received HBOT to treat or prevent ORN of the mandible or softtissue necrosis in the period 2001-2003. All of these patients received radiotherapy in the period 1996-2001, given either as primary treatment or postoperatively, for a T2-4N0-2 (Stage II-IV) squamous cell carcinoma of the oral cavity or oropharynx. The radiation dose was 50–70 Gy given in 2-Gy fractions within 5.5–7 weeks in a conventional or accelerated fractionation schedule. In all patients ipsilateral parotid or submandibular glands were exposed within the high-dose radiation field. All patients were treated with curative intent and they were without residual tumour or recurrent disease when enrolled in the study. HBOT was given in a multi-place hyperbaric chamber pressurized with air to 2.5 Bar, with oxygen by mask or head hood. Duration at pressure was 95 min with oxygen in 4 blocks of 20 min, interrupted by 5-min air breaks to prevent acute oxygen toxicity6. The patients received
HBOT once a day for 5 days per week, 4–6 weeks before operation (20–30 sessions) and 2 weeks after operation (10 sessions), conforming to the Marx protocol, depending on the indication23. Xerostomia-related questions were selected from the European Organization for Research and Treatment of Cancer (EORTC) QLQ-H&N35 survey and from other studies, discussing and recommending questions for assessing salivary disorders and xerostomia27,33 (Table 1). Each patient received this questionnaire before HBOT (preHBOT), 1 year after HBOT (postHBOT1) and 2 years after HBOT (postHBOT2). For each question, depending on the experienced severity of the described issue, the patients had to score one to four points (1 ‘‘not at all’’, 2 ‘‘slight’’, 3 ‘‘moderate’’, 4 ‘‘a lot’’). The scores of the questions based on a common topic (swallowing problems and dry-mouth sensation) were averaged to create a composite score. The other questions were evaluated separately. The average scores of all patients for each topic were calculated and a paired t-test was applied using statistical analysis software (SPPS 12.0.1, LEAD Technologies) in order to appreciate time-related changes and statistical significance levels. All of the patients signed an informed consent form. Results
At the start of this study, questionnaires were given to 21 patients who completed
Table 1. Questionnaire for assessment of salivary gland function and QOL-related topics Topic Swallowing problems
Dry-mouth sensation
Dental problems Viscosity saliva Smell Taste Conversation Saliva quantity Thirst HBO experience
Question Do you have difficulties with swallowing when drinking? Do you have difficulties with swallowing when eating mashed food? Do you have difficulties with swallowing when eating solid food? Do you ever aspirate? Do you have difficulties with eating? Do you frequently use drinks to help swallow your food? Do you find it difficult swallowing because of a dry mouth? Do you have a dry mouth? Does your mouth feel dry when eating? How dry is your mouth? How dry is your throat? How dry are your lips? How dry is your tongue? Do you have problems with your dentition? How viscous is your saliva? Do you have problems with your sense of smell? Do you have problems with your sense of taste? Do you find it difficult speaking because of a dry mouth? How much saliva is present in your mouth? How thirsty are you? Has hyperbaric oxygen therapy in general had a positive influence on the above-mentioned problems?
The effect of hyperbaric oxygen therapy on quality of life in oral and oropharyngeal cancer patients Table 2. Overview of estimated delivered radiation dose (Gy) to the salivary glands and time interval (months) between start of HBOT and radiotherapy Patient 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
PARL 56 41 48 31 32 49 37 36 26 23 70 36 37 43 34 50 13 41 30 25 40
PARR 56 41 40 29 32 37 30 36 32 23 70 38 37 43 34 50 13 35 30 29 40
SUBML 68 51 64 68 68 66 64 64 44 15 14 64 68 58 64 50 64 57 53 50 64
SUBMR 68 51 50 68 49 46 50 64 64 15 14 64 68 58 64 50 64 50 53 64 64
ORAL CAVITY 68 20 48 41 28 40 36 38 34 50 13 38 37 38 38 30 38 46 37 27 51
TIME INTERVAL 61 7 4 19 15 11 4 14 17 82 31 9 35 9 36 25 23 24 8 37 11
PARL = left parotid gland, PARR = right parotid gland, SUBML = left submandibular gland, SUBMR = right submandibular gland, ORAL CAVITY = total dose oral cavity, TIME INTERVAL = months between HBOT and radiotherapy.
them preHBOT and postHBOT1. Twelve patients completed the 2-year follow-up period (57%). The mean age of the 21 patients was 64 years (range 51–80 years) and the male-to-female ratio was 1:0.9. Indications for HBOT were: as a part of treatment for ORN (n = 12) and soft-tissue necrosis (n = 2), and the prevention of ORN (n = 7). Initial tumour stage was stage II in 3, stage III in 5 and stage IV in 13 patients. On average, 27 sessions of HBOT were given when there was a therapeutic indication. When HBOT was used for prevention of ORN 20 sessions were given before and 10 sessions after a possible noxious event (e.g. extractions or dental implantation in an irradiated part of the mandible). The mean time between application of HBOT and the end of radiotherapy was 23 months (range 4–82 months). Thirteen patients received HBOT more than 12 months after radiotherapy (group A) while in 8 patients HBOT was applied less than 12 months after radiotherapy (group B) (Table 2). There were no differences between group A and B at the start of HBOT. At postHBOT1, in group A, a lower score on swallowing problems was reported. At 2 years this difference had disappeared. Also dry-mouth problems were reported to be lower at postHBOT2 in group A. An overview of the estimated radiation dose per salivary gland is also given in Table 2. Tables 3 and 4 provide an overview of the results of preHBOT versus postHBOT1 and preHBOT versus postHBOT2, respectively. There were no statistically significant
differences between mean values at postHBOT1 and postHBOT2. At postHBOT2, 84% of the patients reported a positive influence of HBOT on their dry-mouth and related QOL problems; 17% reported no improvement, and 33% a slight, 17% a moderate, and 17% a lot of improvement. Discussion
Radiotherapy is used as curative treatment for head and neck cancer20,22,28. As a side
257
effect xerostomia often occurs because of radiation damage to salivary glands, altering both the quantity and the quality of saliva, and leading to an increase in viscosity1,4,5,24,37. Studies in which xerostomia was assessed using the toxicity criteria of the Radiation Therapy Oncology Group and sialometrical analysis, and studies that scintigraphically assessed parotid gland function, after radiotherapy, show that there is a dose- and volume-dependent decrease in salivary gland function and spontaneous recovery to a certain degree within 1–2 years7,9,15,19,32. In this study, HBOT was applied on average 23 months after radiotherapy, the time at which the effect of spontaneous recovery of gland function would no longer play a major role. At the start of HBOT, there were no differences between the group of patients who received HBOT within 1 year of radiotherapy (group A) and the group who received HBOT 1 year or more after radiotherapy (group B). Dry-mouth problems were reported to be lower at postHBOT2 in group A. An explanation for this might be that early HBOT partly inhibits the progressive nature of radiation damage. The results of this study show that patients experience a statistically significant subjective increase in salivary fluid quantity 1 and 2 years after HBOT. It is remarkable that an improvement is experienced more than 23 months after radiotherapy, suggesting an effect of HBOT. The lack of a control group means that this improvement cannot be fully attributed to HBOT. There is no scientific
Table 3. Mean scores for preHBOT and postHBOT1, differences and statistical significance levels (n = 21) Swallowing problems Dry-mouth sensation Dental problems Viscosity saliva Smell Taste Conversation Saliva quantity Thirst
preHBOT
postHBOT1
Difference
p-value
17.58 15.82 2.19 2.45 1.90 2.29 2.67 1.86 2.52
14.21 13.47 2.00 2.20 1.71 2.00 2.29 2.24 2.19
19% 15% 8% 10% 10% 13% 14% +20% 13%
0.003 0.049 0.407 0.234 0.214 0.300 0.104 0.008 0.090
Table 4. Mean scores for preHBOT and postHBOT2, differences and statistical significance levels (n = 12) Swallowing problems Dry-mouth sensation Dental problems Viscosity saliva Smell Taste Conversation Saliva quantity Thirst
preHBOT
postHBOT2
Difference
p-value
18.36 16.00 1.92 2.33 1.92 2.58 2.75 1.75 2.58
14.18 13.88 2.00 2.25 1.83 2.00 2.25 2.33 2.17
23% 13% +4% 3% 5% 22% 18% +33% 16%
0.001 0.345 0.830 0.777 0.723 0.027 0.166 0.002 0.137
258
Gerlach et al.
literature available that objectively quantifies, through for example sialometric analysis or other functional measurement methods, if saliva quantity increases in response to HBOT. It is also unknown if, how and to what extend HBOT affects salivary gland tissue on a cellular level. In contrast to these unknown facts it has been demonstrated that HBOT improves wound healing by initiating and accelerating capillary angiogenesis and fibroplasia, especially in soft tissues, due to increased oxygen gradients3,18,23,26. Possibly stemcell mobilization may add to this35. These mechanisms might explain an improvement in salivary gland function. In this study swallowing problems significantly diminished at 1 and 2 years after HBOT. A number of explanations can be given. First of all, most of the patients underwent a combination of radiotherapy and surgery. Surgery dramatically alters oral anatomy and as a consequence affects oral functions such as mastication, swallowing and speech. It is likely that patients adapted to their limitations over the years in the way they handled their food products, and therefore report an improvement in swallowing problems. Only two patients received swallowing therapy following their oncological treatment. Secondly, the reported increase in saliva quantity might be a (additional) beneficial factor by which the reported positive influence on swallowing problems can be explained. It seems rather contradictory that patients report an increase in saliva quantity and that this is only reflected in a significant improvement in their drymouth complaints the first year after HBOT. As viscosity of saliva did not improve (decrease), a possible explanation might be that the cognitive perception of dry mouth relates more to the qualitative state of saliva (e.g. viscosity) and less to the quantitative level. Also, the fact that at postHBOT2 only 12 patients were available for statistical analysis could have negatively affected these results. Due to qualitative and quantitative alterations in saliva after radiotherapy, the inherent antibacterial activity of immunoglobulin-A and lysozymes no longer functions at an optimal level. In addition, there is a shift of the intraoral environment to a more carcinogenic bacterial flora, and there is a greater likelihood of retention of food products. These factors can initiate and accelerate tooth decay at an alarming rate14,37. In this study, patients did not report an improvement in dental problems after HBOT. Tooth decay (breakdown of enamel and dentin) is an irreversible process and in
light of this it is not unexpected that no improvement was observed. What might be possible is the occurrence of stagnation in the rate of tooth decay following HBOT, but long-term follow up is needed to evaluate this hypothesis. Direct radiation damage to the taste buds and/or their innervating nerve fibres is the main reason for taste loss. A reduction in saliva production contributes to a decrease in the number of taste buds and probably changes the morphology and function. In addition, alteration of saliva quantity and quality impairs taste because of a reduced solubility of the food components31,37. In this study, patients reported a statistically significant improvement in taste 2 years after HBOT. Without any treatment, taste sensation recovers to normal or near-normal levels within a year of radiotherapy in most instances, although it can take much longer. The degree of recovery of taste and the time it takes are radiation dose dependent37. To what extent HBOT influences the recovery of taste is unknown. It can be speculated that the rate of taste recovery, by stimulating repair of taste buds and nerves, is accelerated by HBOT. Maybe an increase in food solubility, through an increase in saliva quantity, exerts a positive influence. Although the literature is not always consistent, in general, HBOT is a well accepted modality for the prevention or treatment of radiation-induced woundhealing problems. In a prospective, multicenter, randomized, double-blind and placebo-controlled trial ANNANE et al. tested the efficacy and safety of HBOT for mandibular ORN2. Patients were assigned to receive either HBO (100% O2 at 2.4 ATA) or a placebo (mixture of 9% O2 and 91% N) in combination with a conservative treatment or surgical intervention. Unfortunately, the inclusion of patients was prematurely closed at the second interim analysis because of potentially worse outcomes in the HBO arm, but this trial was criticized, especially with regard to the applied treatment protocol11,17,25,36. The study design was not consistent with what is currently considered standard care of patients with ORN: this is a multimodality approach combining prophylactic HBO, surgery and follow-up HBO. Although the study failed to detect a positive effect of HBOT on ORN, the effect on salivary gland tissue still has to be answered. DELANIAN et al. adopted a different treatment strategy for ORN of the mandible based on the hypothesis that a bone fibroatrophic mechanism is the underlying etiology. By administering a combination of pentoxifylline and tocopherol (vitamin E) to patients with severe ORN, a reduc-
tion of exposed bone and mucosal healing at 6 months was observed in the majority of the patients.8 Pentoxifylline is a methylxanthine derivative that inhibits human dermal fibroblast proliferation and extracellular matrix production and increases collagenase activity. Tocopherol partly inhibits transforming growth factorß1 and procollagen gene expression. These drugs are thus excellent antifibrotic synergic agents. Animal studies show that irradiated salivary gland tissue demonstrates significant interstitial fibrosis and acinar atrophy21,30. The effect of pentoxifylline and tocopherol on salivary gland tissue and on xerostomia-related problems is as yet unknown. In this study patients received a questionnaire with questions relating to different (functional) problems arising from xerostomia. Although this gives a subjective reflection of a patient’s problem, the EORTC QOL is a well validated tool for assessment of QOL in head and neck and surgery. Without a control group, it is not possible to draw a definite conclusion from this study. A placebo effect, disturbing the observed results, cannot be excluded definitively. A future randomized study addressing objective parameters derived from, for example, sialochemical and sialometrical analysis is needed. This, in combination with histological studies and a functional scintigraphic assessment like SPECT (single photon emission computed tomography), should help to gain a better insight into the effects of HBOT on salivary gland tissue and function. The results of the present study certainly warrant future investigation in this direction. In conclusion, the results of this study suggest that there is a positive influence of HBOT on xerostomia and QOL in head and neck cancer patients treated by radiotherapy. Patients indicated significant improvements in saliva quantity, taste and swallowing problems after HBOT. Due to the small number of patients, the subjective assessment methodology and the lack of a control group only a trend can be observed and no definite conclusion can be drawn. Further research into this aspect of HBOT is needed with objective parameters such as sialochemical and sialometrical analysis, histological examination, and functional scintigraphic assessments. References 1. Almstahl A, Wikstrom M. Electrolytes in stimulated whole saliva in individuals with hyposalivation of different origins. Arch Oral Biol 2003: 48: 337–344.
The effect of hyperbaric oxygen therapy on quality of life in oral and oropharyngeal cancer patients 2. Annane D, Depondt J, Aubert P, Villart M, Gehanno P, Gajdos P, Chevert S. Hyperbaric oxygen therapy for radionecrosis of the jaw: a randomized, placebo-controlled, double-blind trial for the ORN96 study group. J Clin Oncol 2004: 22: 4893–4900. 3. Bennett MH, Feldmeier J, Hampson N, Smee R, Milross C. Hyperbaric oxygen therapy for late radiation tissue injury. Cochrane Database Syst Rev 2005: 4. Burlage FR, Coppes RP, Meertens H, Stokman MA, Vissink A. Parotid and submandibular/sublingual salivary flow during high dose radiotherapy. Radiother Oncol 2001: 61: 271–274. 5. Chambers MS, Garden AS, Kies MS, Martin JW. Radiation-induced xerostomia in patients with head and neck cancer: pathogenesis, impact on quality of life, and management. Head Neck 2004: 26: 796–807. 6. Clark JM, Thom SR. Oxygen under pressure. In: Brubakk AO, Neuman TS, eds: Bennett and Elliott’s Physiology and Medicine of Diving. Edinburgh: Saunders 2003: 358–418. 7. Cox JD, Stetz J, Pajak TF. Toxicity criteria of the radiation therapy oncology group (RTOG) and the European organization for research and treatment of cancer (EORTC). Int J Radiat Oncol Biol Phys 1995: 31: 1341–1346. 8. Delanian S, Depondt J, Lefaix JL. Major healing of refractory mandible osteoradionecrosis after treatment combining pentoxifylline and tocopherol: a phase II trial. Head Neck 2005: 27: 114–123. 9. Eisbruch A, ten Haken RK, Kim HM, Marsh LH, Ship JA. Dose, volume, and function relationships in parotid salivary glands following conformal and intensity-modulated irradiation of head and neck cancer. Int J Radiat Oncol Biol Phys 1999: 45: 577–587. 10. Epstein JB, Robertson M, Emerton S, Philips N, Stevenson-Moore P. Quality of life and oral function in patients treated with radiation therapy for head and neck cancer. Head Neck 2001: 23: 389–398. 11. Feldmeier JJ, Hampson NB, Bennett M. In response to the negative randomized controlled hyperbaric trial by Annane et al in the treatment of mandibular ORN. Undersea Hyperb Med 2005: 32: 141–143. 12. Franceschi S, Bidoli E, Herrero R, Munoz N. Comparison of cancers of the oral cavity and pharynx worldwide: etiological clues. Oral Oncol 2000: 36: 106– 115. 13. Guchelaar HJ, Vermes A, Meerwaldt JH. Radiation-induced xerostomia: pathophysiology, clinical course and supportive treatment. Support Care Cancer 1997: 5: 281–288.
14. Hancock PJ, Epstein JB, Sadler GR. Oral and dental management related to radiation therapy for head and neck cancer. J Can Dent Assoc 2003: 69: 585– 590. 15. Kam MKM, Teo PML, Chau RMC, Cheung KY, Choi PHK, Kwan WH, Leung SF, Zee B, Chan ATC. Treatment of nasopharyngeal carcinoma with intensity-modulated radiotherapy: the Hong Kong experience. Int J Radiat Oncol Biol Phys 2004: 60: 1440–1450. 16. Konings AW, Coppes RP, Vissink A. On the mechanism of salivary gland radiosensitivity. Int J Radiat Oncol Biol Phys 2005: 62: 1187–1194. 17. Laden G. Hyperbaric oxygen therapy for radionecrosis: clear advice from confusing data. J Clin Oncol 2005: 23: 4465. 18. Leach RM, Rees PJ, Wilmshurst P. Hyperbaric oxygen therapy. BMJ 1998: 317: 1140–1143. 19. Lee N, Xia P, Quivey JM, Sultanem K, Poon I, Akazawa C, Akazawa P, Weinberg V, Fu KK. Intensity-modulated radiotherapy in the treatment of nasopharyngeal carcinoma: an update of the UCSF experience. Int J Radiat Oncol Biol Phys 2002: 53: 12–22. 20. Lefebvre JL. Current clinical outcomes demand new treatment options for SCCHN. Ann Oncol 2005: 16: 7–12. 21. Li J, Shan Z, Ou G, Liu X, Zhang C, Baum BJ, Wang S. Structural and functional characteristics of irradiation damage to parotid glands in the miniature pig. Int J Radiat Oncol Biol Phys 2005: 62: 1510–1516. 22. Licitra L, Bernier J, Grandi C, Merlano M, Bruzzi P, Lefebvre JL. Cancer of the oropharynx. Crit Rev Oncol Hematol 2002: 41: 107–122. 23. Marx RE, Ehler WJ, Tayapongsak P, Pierce LW. Relationship of oxygen dose to angiogenesis induction in irradiated tissue. Am J Sur 1990: 160: 519–524. 24. Moller P, Perrier M, Ozsahin M, Monnier P. A prospective study of salivary gland function in patients undergoing radiotherapy for squamous cell carcinoma of the oropharynx. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2004: 97: 173–189. 25. Moon RE, McGraw TA, Blakey 3rd G. Hyperbaric oxygen therapy for radiation necrosis of the jaw: comments on a randomized study. Undersea Hyperb Med 2005: 32: 145–147. 26. Neovius EB, Lind MG, Lind FG. Hyperbaric oxygen therapy for wound complications after surgery in the irradiated head and neck: a review of the literature and a report of 15 consecutive patients. Head Neck 1997: 19: 315–322. 27. Pai S, Ghezzi EM, Ship JA. Development of a Visual Analogue Scale questionnaire for subjective assessment of salivary dysfunction. Oral Surg Oral
28.
29.
30.
31. 32.
33. 34.
35.
36.
37.
259
Med Oral Pathol Oral Radiol Endod 2001: 91: 311–316. Palme CE, Gullane PJ, Gilbert RW. Current treatment options in squamous cell carcinoma of the oral cavity. Surg Oncol Clin N Am 2004: 13: 47–70. Pasquier D, Hoelscher T, Schmutz J, Dische S, Mathieu D, Baumann M, Lartigau E. Hyperbaric oxygenation therapy in the treatment of radio-induced lesions in normal tissues: a literature review. Radiother Oncol 2004: 72: 1–13. Radfar L, Sirois DA. Structural and functional injury in minipig salivary glands following fractionated exposure to 70 Gy of ionizing radiation: an animal model for human radiation-induced salivary gland injury. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2003: 96: 267–274. Ravasco P. Aspects of taste and compliance in patients with cancer. Eur J Oncol Nurs 2005: 9: 84–91. Roesink JM, Moerland MA, Hoekstra A, van Rijk PP, Terhaard CHJ. Scintigraphic assessment of early and late parotid gland function after radiotherapy for head-and-neck cancer: a prospective study of dose-volume response relationships. Int J Radiat Oncol Biol Phys 2004: 58: 1451–1460. Ship JA. Diagnosing, managing, and preventing salivary gland disorders. Oral Dis 2002: 8: 77–89. Stephens LC, Schultheiss TE, Price RE, Ang KK, Peters LJ. Radiation apoptosis of serous acinar cells of salivary and lacrimal glands. Cancer 1991: 67: 1539– 1543. Thom SR, Bhopale VM, Velazquez OC, Goldstein LJ, Thom LH, Buerk DG. Stem cell mobilization by hyperbaric oxygen. Am J Physiol Heart Circ Physiol 2006: 290: 1378–1386. van Merkesteyn R, Bakker DJ. Comment on ‘‘hyperbaric oxygen therapy for radionecrosis of the jaw: a randomized, placebo-controlled, double-blind trial from the ORN96 study group’’. J Clin Oncol 2005: 23: 4465–4466. Vissink A, Jansma J, Spijkervet FK, Burlage FR, Coppes RP. Oral sequelae of head and neck radiotherapy. Crit Rev Oral Biol Med 2003: 14: 199–212.
Address: Prof. Dr. M.A.W. Merkx PhD MD DMD Department of Oral and Maxillofacial Surgery 590 Radboud University Nijmegen Medical Centre P.O. Box 9101 6500 HB Nijmegen The Netherlands Tel.: +31 24 3614561 Fax: +31 24 3541165 E-mail: [email protected]
Clinical Paper Head and Neck Oncology
The effect of hyperbaric oxygen therapy on quality of life in oral and oropharyngeal cancer patients treated with radiotherapy
N. L. Gerlach1, R. Barkhuysen1, J. H. A. M. Kaanders2, G. O. R. J. Janssens2, W. Sterk3, M. A. W. Merkx1 1 Department of Oral and Maxillofacial Surgery, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands; 2 Department of Radiotherapy, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands; 3Institute for Hyperbaric Medicine, Hoogeveen, the Netherlands
N. L. Gerlach, R. Barkhuysen, J. H. A. M. Kaanders, G. O. R. J. Janssens, W. Sterk: The effect of hyperbaric oxygen therapy on quality of life in oral and oropharyngeal cancer patients treated with radiotherapy. Int. J. Oral Maxillofac. Surg. 2008; 37: 255–259. # 2007 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved. Abstract. Radiotherapy is used in the setting of curative treatment for head and neck cancer. Xerostomia and related problems occur when major salivary glands are included in the irradiation fields. This reduces quality of life (QOL). Hyperbaric oxygen therapy (HBOT) is a well accepted treatment or prevention modality for osteoradionecrosis of the jawbones and soft-tissue necrosis. It is unknown if and to what extent HBOT influences xerostomia and xerostomia-related QOL. To address this, a prospective study was conducted. Twenty-one patients who underwent radiotherapy for an oral or oropharyngeal carcinoma completed a European Organization for Research and Treatment of Cancer QOL questionnaire before HBOT, as part of the treatment/prevention of osteoradionecrosis, and 1 and 2 years after HBOT. Swallowing-related problems significantly decreased in time, and there was a reported subjective increase in saliva quantity and an improvement in sense of taste. The results suggest that HBOT may positively influence these longterm radiotherapy sequelae.
In the Netherlands the incidence of oral and oropharyngeal carcinomas is 3.5 and 2.4 for males and 1.8 and 0.8 for females per 100,000, respectively12. Surgery, radiotherapy and the combination of both are the main treatment modalities20,22,28. Side effects of radiotherapy include muco0901-5027/030255 + 05 $30.00/0
sitis and skin reaction in the acute phase, and late sequelae such as fibrosis, xerostomia and sometimes necrosis of bone and soft tissues37. Despite the fact that cells from salivary gland tissue have a slow turnover rate, a contradictory high early radiosensitivity is
Keywords: hyperbaric oxygenation; radiotherapy; quality of life; head and neck neoplasms; maxillofacial surgery. Accepted for publication 28 November 2007 Available online 11 February 2008
observed. When major salivary glands such as the parotid and submandibular glands are included in the radiation treatment volume, xerostomia occurs due to a reduction in salivary flow4,24. Although the pathophysiologic mechanism leading to this condition is largely unknown, a
# 2007 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.
256
Gerlach et al.
massive apoptosis, resulting in loss of salivary gland tissue, has been suggested as a possible cause13,34. KONINGS et al.16 suggest that the most probable mechanism of early high radiosensitivity is selective radiation damage to the plasma membrane of the secretory cells, which disturbs muscarinic receptor-stimulated watery secretion. They state that, next to damage to the extracellular environment (thus preventing proper cell functioning), damage in a later stage can be attributed to mitotic cell death of progenitor cells, which has a negative impact on the replacement capacity of secretory cells. In addition to a reduction in flow, radiotherapy alters the biochemical properties of saliva, causing for example a decrease in pH, bicarbonate concentration, immunoglobulins, lysozymes, peroxidases and, as a result of this, a reduced buffer capacity24. There is also a rise in concentration of potassium, chloride, calcium and magnesium ions1,5. These, for the most part irreversible, qualitative and quantitative alterations of saliva mean that patients are prone to oral infections and dental decay14,37. They also result in functional problems such as impairment of oral masticatory function, problems with prosthetic rehabilitation, difficulties with speech and loss of taste. From this it is clear that radiotherapyinduced salivary gland dysfunction significantly impairs quality of life (QOL)5,10. Hyperbaric oxygen therapy (HBOT) is a well accepted treatment for wound-healing problems, although the literature is not always consistent2,18,26,29,36. In the head and neck area HBOT is frequently used to treat osteoradionecrosis (ORN) in a sandwich therapy with surgery conforming to the Marx protocol, or to prevent ORN of the mandible when a surgical intervention is indicated such as dental extractions or dental implant placement3,23. During a HBOT session 100% oxygen is breathed at an elevated ambient pressure up to 2.5 Bar during 90 min. This increases plasma and tissue oxygen concentrations, which is believed to improve wound healing by initiating and accelerating angiogenesis and revascularization3,18,26. THOM et al.35 have recently demonstrated that stem cells are mobilized significantly by hyperbaric oxygen. Possibly, through these mechanisms, HBOT might also ameliorate salivary gland tissue dysfunction with normalization of the qualitative and/or quantitative aspects of saliva to a certain degree and positive effects on QOL. This potential benefit of HBOT has thus far not been explored in a systematic fashion, and no scientific litera-
ture is available on this issue. It is not known if and to what extent HBOT affects salivary gland tissue at a cellular level, and there are no data on its effect on xerostomia and related QOL problems. The aim of this prospective study was to investigate the long-term effects of HBOT on xerostomia and QOL in patients who received radiotherapy for an oral or oropharyngeal carcinoma. Material and methods
In this study 21 consecutive patients were included who received HBOT to treat or prevent ORN of the mandible or softtissue necrosis in the period 2001-2003. All of these patients received radiotherapy in the period 1996-2001, given either as primary treatment or postoperatively, for a T2-4N0-2 (Stage II-IV) squamous cell carcinoma of the oral cavity or oropharynx. The radiation dose was 50–70 Gy given in 2-Gy fractions within 5.5–7 weeks in a conventional or accelerated fractionation schedule. In all patients ipsilateral parotid or submandibular glands were exposed within the high-dose radiation field. All patients were treated with curative intent and they were without residual tumour or recurrent disease when enrolled in the study. HBOT was given in a multi-place hyperbaric chamber pressurized with air to 2.5 Bar, with oxygen by mask or head hood. Duration at pressure was 95 min with oxygen in 4 blocks of 20 min, interrupted by 5-min air breaks to prevent acute oxygen toxicity6. The patients received
HBOT once a day for 5 days per week, 4–6 weeks before operation (20–30 sessions) and 2 weeks after operation (10 sessions), conforming to the Marx protocol, depending on the indication23. Xerostomia-related questions were selected from the European Organization for Research and Treatment of Cancer (EORTC) QLQ-H&N35 survey and from other studies, discussing and recommending questions for assessing salivary disorders and xerostomia27,33 (Table 1). Each patient received this questionnaire before HBOT (preHBOT), 1 year after HBOT (postHBOT1) and 2 years after HBOT (postHBOT2). For each question, depending on the experienced severity of the described issue, the patients had to score one to four points (1 ‘‘not at all’’, 2 ‘‘slight’’, 3 ‘‘moderate’’, 4 ‘‘a lot’’). The scores of the questions based on a common topic (swallowing problems and dry-mouth sensation) were averaged to create a composite score. The other questions were evaluated separately. The average scores of all patients for each topic were calculated and a paired t-test was applied using statistical analysis software (SPPS 12.0.1, LEAD Technologies) in order to appreciate time-related changes and statistical significance levels. All of the patients signed an informed consent form. Results
At the start of this study, questionnaires were given to 21 patients who completed
Table 1. Questionnaire for assessment of salivary gland function and QOL-related topics Topic Swallowing problems
Dry-mouth sensation
Dental problems Viscosity saliva Smell Taste Conversation Saliva quantity Thirst HBO experience
Question Do you have difficulties with swallowing when drinking? Do you have difficulties with swallowing when eating mashed food? Do you have difficulties with swallowing when eating solid food? Do you ever aspirate? Do you have difficulties with eating? Do you frequently use drinks to help swallow your food? Do you find it difficult swallowing because of a dry mouth? Do you have a dry mouth? Does your mouth feel dry when eating? How dry is your mouth? How dry is your throat? How dry are your lips? How dry is your tongue? Do you have problems with your dentition? How viscous is your saliva? Do you have problems with your sense of smell? Do you have problems with your sense of taste? Do you find it difficult speaking because of a dry mouth? How much saliva is present in your mouth? How thirsty are you? Has hyperbaric oxygen therapy in general had a positive influence on the above-mentioned problems?
The effect of hyperbaric oxygen therapy on quality of life in oral and oropharyngeal cancer patients Table 2. Overview of estimated delivered radiation dose (Gy) to the salivary glands and time interval (months) between start of HBOT and radiotherapy Patient 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
PARL 56 41 48 31 32 49 37 36 26 23 70 36 37 43 34 50 13 41 30 25 40
PARR 56 41 40 29 32 37 30 36 32 23 70 38 37 43 34 50 13 35 30 29 40
SUBML 68 51 64 68 68 66 64 64 44 15 14 64 68 58 64 50 64 57 53 50 64
SUBMR 68 51 50 68 49 46 50 64 64 15 14 64 68 58 64 50 64 50 53 64 64
ORAL CAVITY 68 20 48 41 28 40 36 38 34 50 13 38 37 38 38 30 38 46 37 27 51
TIME INTERVAL 61 7 4 19 15 11 4 14 17 82 31 9 35 9 36 25 23 24 8 37 11
PARL = left parotid gland, PARR = right parotid gland, SUBML = left submandibular gland, SUBMR = right submandibular gland, ORAL CAVITY = total dose oral cavity, TIME INTERVAL = months between HBOT and radiotherapy.
them preHBOT and postHBOT1. Twelve patients completed the 2-year follow-up period (57%). The mean age of the 21 patients was 64 years (range 51–80 years) and the male-to-female ratio was 1:0.9. Indications for HBOT were: as a part of treatment for ORN (n = 12) and soft-tissue necrosis (n = 2), and the prevention of ORN (n = 7). Initial tumour stage was stage II in 3, stage III in 5 and stage IV in 13 patients. On average, 27 sessions of HBOT were given when there was a therapeutic indication. When HBOT was used for prevention of ORN 20 sessions were given before and 10 sessions after a possible noxious event (e.g. extractions or dental implantation in an irradiated part of the mandible). The mean time between application of HBOT and the end of radiotherapy was 23 months (range 4–82 months). Thirteen patients received HBOT more than 12 months after radiotherapy (group A) while in 8 patients HBOT was applied less than 12 months after radiotherapy (group B) (Table 2). There were no differences between group A and B at the start of HBOT. At postHBOT1, in group A, a lower score on swallowing problems was reported. At 2 years this difference had disappeared. Also dry-mouth problems were reported to be lower at postHBOT2 in group A. An overview of the estimated radiation dose per salivary gland is also given in Table 2. Tables 3 and 4 provide an overview of the results of preHBOT versus postHBOT1 and preHBOT versus postHBOT2, respectively. There were no statistically significant
differences between mean values at postHBOT1 and postHBOT2. At postHBOT2, 84% of the patients reported a positive influence of HBOT on their dry-mouth and related QOL problems; 17% reported no improvement, and 33% a slight, 17% a moderate, and 17% a lot of improvement. Discussion
Radiotherapy is used as curative treatment for head and neck cancer20,22,28. As a side
257
effect xerostomia often occurs because of radiation damage to salivary glands, altering both the quantity and the quality of saliva, and leading to an increase in viscosity1,4,5,24,37. Studies in which xerostomia was assessed using the toxicity criteria of the Radiation Therapy Oncology Group and sialometrical analysis, and studies that scintigraphically assessed parotid gland function, after radiotherapy, show that there is a dose- and volume-dependent decrease in salivary gland function and spontaneous recovery to a certain degree within 1–2 years7,9,15,19,32. In this study, HBOT was applied on average 23 months after radiotherapy, the time at which the effect of spontaneous recovery of gland function would no longer play a major role. At the start of HBOT, there were no differences between the group of patients who received HBOT within 1 year of radiotherapy (group A) and the group who received HBOT 1 year or more after radiotherapy (group B). Dry-mouth problems were reported to be lower at postHBOT2 in group A. An explanation for this might be that early HBOT partly inhibits the progressive nature of radiation damage. The results of this study show that patients experience a statistically significant subjective increase in salivary fluid quantity 1 and 2 years after HBOT. It is remarkable that an improvement is experienced more than 23 months after radiotherapy, suggesting an effect of HBOT. The lack of a control group means that this improvement cannot be fully attributed to HBOT. There is no scientific
Table 3. Mean scores for preHBOT and postHBOT1, differences and statistical significance levels (n = 21) Swallowing problems Dry-mouth sensation Dental problems Viscosity saliva Smell Taste Conversation Saliva quantity Thirst
preHBOT
postHBOT1
Difference
p-value
17.58 15.82 2.19 2.45 1.90 2.29 2.67 1.86 2.52
14.21 13.47 2.00 2.20 1.71 2.00 2.29 2.24 2.19
19% 15% 8% 10% 10% 13% 14% +20% 13%
0.003 0.049 0.407 0.234 0.214 0.300 0.104 0.008 0.090
Table 4. Mean scores for preHBOT and postHBOT2, differences and statistical significance levels (n = 12) Swallowing problems Dry-mouth sensation Dental problems Viscosity saliva Smell Taste Conversation Saliva quantity Thirst
preHBOT
postHBOT2
Difference
p-value
18.36 16.00 1.92 2.33 1.92 2.58 2.75 1.75 2.58
14.18 13.88 2.00 2.25 1.83 2.00 2.25 2.33 2.17
23% 13% +4% 3% 5% 22% 18% +33% 16%
0.001 0.345 0.830 0.777 0.723 0.027 0.166 0.002 0.137
258
Gerlach et al.
literature available that objectively quantifies, through for example sialometric analysis or other functional measurement methods, if saliva quantity increases in response to HBOT. It is also unknown if, how and to what extend HBOT affects salivary gland tissue on a cellular level. In contrast to these unknown facts it has been demonstrated that HBOT improves wound healing by initiating and accelerating capillary angiogenesis and fibroplasia, especially in soft tissues, due to increased oxygen gradients3,18,23,26. Possibly stemcell mobilization may add to this35. These mechanisms might explain an improvement in salivary gland function. In this study swallowing problems significantly diminished at 1 and 2 years after HBOT. A number of explanations can be given. First of all, most of the patients underwent a combination of radiotherapy and surgery. Surgery dramatically alters oral anatomy and as a consequence affects oral functions such as mastication, swallowing and speech. It is likely that patients adapted to their limitations over the years in the way they handled their food products, and therefore report an improvement in swallowing problems. Only two patients received swallowing therapy following their oncological treatment. Secondly, the reported increase in saliva quantity might be a (additional) beneficial factor by which the reported positive influence on swallowing problems can be explained. It seems rather contradictory that patients report an increase in saliva quantity and that this is only reflected in a significant improvement in their drymouth complaints the first year after HBOT. As viscosity of saliva did not improve (decrease), a possible explanation might be that the cognitive perception of dry mouth relates more to the qualitative state of saliva (e.g. viscosity) and less to the quantitative level. Also, the fact that at postHBOT2 only 12 patients were available for statistical analysis could have negatively affected these results. Due to qualitative and quantitative alterations in saliva after radiotherapy, the inherent antibacterial activity of immunoglobulin-A and lysozymes no longer functions at an optimal level. In addition, there is a shift of the intraoral environment to a more carcinogenic bacterial flora, and there is a greater likelihood of retention of food products. These factors can initiate and accelerate tooth decay at an alarming rate14,37. In this study, patients did not report an improvement in dental problems after HBOT. Tooth decay (breakdown of enamel and dentin) is an irreversible process and in
light of this it is not unexpected that no improvement was observed. What might be possible is the occurrence of stagnation in the rate of tooth decay following HBOT, but long-term follow up is needed to evaluate this hypothesis. Direct radiation damage to the taste buds and/or their innervating nerve fibres is the main reason for taste loss. A reduction in saliva production contributes to a decrease in the number of taste buds and probably changes the morphology and function. In addition, alteration of saliva quantity and quality impairs taste because of a reduced solubility of the food components31,37. In this study, patients reported a statistically significant improvement in taste 2 years after HBOT. Without any treatment, taste sensation recovers to normal or near-normal levels within a year of radiotherapy in most instances, although it can take much longer. The degree of recovery of taste and the time it takes are radiation dose dependent37. To what extent HBOT influences the recovery of taste is unknown. It can be speculated that the rate of taste recovery, by stimulating repair of taste buds and nerves, is accelerated by HBOT. Maybe an increase in food solubility, through an increase in saliva quantity, exerts a positive influence. Although the literature is not always consistent, in general, HBOT is a well accepted modality for the prevention or treatment of radiation-induced woundhealing problems. In a prospective, multicenter, randomized, double-blind and placebo-controlled trial ANNANE et al. tested the efficacy and safety of HBOT for mandibular ORN2. Patients were assigned to receive either HBO (100% O2 at 2.4 ATA) or a placebo (mixture of 9% O2 and 91% N) in combination with a conservative treatment or surgical intervention. Unfortunately, the inclusion of patients was prematurely closed at the second interim analysis because of potentially worse outcomes in the HBO arm, but this trial was criticized, especially with regard to the applied treatment protocol11,17,25,36. The study design was not consistent with what is currently considered standard care of patients with ORN: this is a multimodality approach combining prophylactic HBO, surgery and follow-up HBO. Although the study failed to detect a positive effect of HBOT on ORN, the effect on salivary gland tissue still has to be answered. DELANIAN et al. adopted a different treatment strategy for ORN of the mandible based on the hypothesis that a bone fibroatrophic mechanism is the underlying etiology. By administering a combination of pentoxifylline and tocopherol (vitamin E) to patients with severe ORN, a reduc-
tion of exposed bone and mucosal healing at 6 months was observed in the majority of the patients.8 Pentoxifylline is a methylxanthine derivative that inhibits human dermal fibroblast proliferation and extracellular matrix production and increases collagenase activity. Tocopherol partly inhibits transforming growth factorß1 and procollagen gene expression. These drugs are thus excellent antifibrotic synergic agents. Animal studies show that irradiated salivary gland tissue demonstrates significant interstitial fibrosis and acinar atrophy21,30. The effect of pentoxifylline and tocopherol on salivary gland tissue and on xerostomia-related problems is as yet unknown. In this study patients received a questionnaire with questions relating to different (functional) problems arising from xerostomia. Although this gives a subjective reflection of a patient’s problem, the EORTC QOL is a well validated tool for assessment of QOL in head and neck and surgery. Without a control group, it is not possible to draw a definite conclusion from this study. A placebo effect, disturbing the observed results, cannot be excluded definitively. A future randomized study addressing objective parameters derived from, for example, sialochemical and sialometrical analysis is needed. This, in combination with histological studies and a functional scintigraphic assessment like SPECT (single photon emission computed tomography), should help to gain a better insight into the effects of HBOT on salivary gland tissue and function. The results of the present study certainly warrant future investigation in this direction. In conclusion, the results of this study suggest that there is a positive influence of HBOT on xerostomia and QOL in head and neck cancer patients treated by radiotherapy. Patients indicated significant improvements in saliva quantity, taste and swallowing problems after HBOT. Due to the small number of patients, the subjective assessment methodology and the lack of a control group only a trend can be observed and no definite conclusion can be drawn. Further research into this aspect of HBOT is needed with objective parameters such as sialochemical and sialometrical analysis, histological examination, and functional scintigraphic assessments. References 1. Almstahl A, Wikstrom M. Electrolytes in stimulated whole saliva in individuals with hyposalivation of different origins. Arch Oral Biol 2003: 48: 337–344.
The effect of hyperbaric oxygen therapy on quality of life in oral and oropharyngeal cancer patients 2. Annane D, Depondt J, Aubert P, Villart M, Gehanno P, Gajdos P, Chevert S. Hyperbaric oxygen therapy for radionecrosis of the jaw: a randomized, placebo-controlled, double-blind trial for the ORN96 study group. J Clin Oncol 2004: 22: 4893–4900. 3. Bennett MH, Feldmeier J, Hampson N, Smee R, Milross C. Hyperbaric oxygen therapy for late radiation tissue injury. Cochrane Database Syst Rev 2005: 4. Burlage FR, Coppes RP, Meertens H, Stokman MA, Vissink A. Parotid and submandibular/sublingual salivary flow during high dose radiotherapy. Radiother Oncol 2001: 61: 271–274. 5. Chambers MS, Garden AS, Kies MS, Martin JW. Radiation-induced xerostomia in patients with head and neck cancer: pathogenesis, impact on quality of life, and management. Head Neck 2004: 26: 796–807. 6. Clark JM, Thom SR. Oxygen under pressure. In: Brubakk AO, Neuman TS, eds: Bennett and Elliott’s Physiology and Medicine of Diving. Edinburgh: Saunders 2003: 358–418. 7. Cox JD, Stetz J, Pajak TF. Toxicity criteria of the radiation therapy oncology group (RTOG) and the European organization for research and treatment of cancer (EORTC). Int J Radiat Oncol Biol Phys 1995: 31: 1341–1346. 8. Delanian S, Depondt J, Lefaix JL. Major healing of refractory mandible osteoradionecrosis after treatment combining pentoxifylline and tocopherol: a phase II trial. Head Neck 2005: 27: 114–123. 9. Eisbruch A, ten Haken RK, Kim HM, Marsh LH, Ship JA. Dose, volume, and function relationships in parotid salivary glands following conformal and intensity-modulated irradiation of head and neck cancer. Int J Radiat Oncol Biol Phys 1999: 45: 577–587. 10. Epstein JB, Robertson M, Emerton S, Philips N, Stevenson-Moore P. Quality of life and oral function in patients treated with radiation therapy for head and neck cancer. Head Neck 2001: 23: 389–398. 11. Feldmeier JJ, Hampson NB, Bennett M. In response to the negative randomized controlled hyperbaric trial by Annane et al in the treatment of mandibular ORN. Undersea Hyperb Med 2005: 32: 141–143. 12. Franceschi S, Bidoli E, Herrero R, Munoz N. Comparison of cancers of the oral cavity and pharynx worldwide: etiological clues. Oral Oncol 2000: 36: 106– 115. 13. Guchelaar HJ, Vermes A, Meerwaldt JH. Radiation-induced xerostomia: pathophysiology, clinical course and supportive treatment. Support Care Cancer 1997: 5: 281–288.
14. Hancock PJ, Epstein JB, Sadler GR. Oral and dental management related to radiation therapy for head and neck cancer. J Can Dent Assoc 2003: 69: 585– 590. 15. Kam MKM, Teo PML, Chau RMC, Cheung KY, Choi PHK, Kwan WH, Leung SF, Zee B, Chan ATC. Treatment of nasopharyngeal carcinoma with intensity-modulated radiotherapy: the Hong Kong experience. Int J Radiat Oncol Biol Phys 2004: 60: 1440–1450. 16. Konings AW, Coppes RP, Vissink A. On the mechanism of salivary gland radiosensitivity. Int J Radiat Oncol Biol Phys 2005: 62: 1187–1194. 17. Laden G. Hyperbaric oxygen therapy for radionecrosis: clear advice from confusing data. J Clin Oncol 2005: 23: 4465. 18. Leach RM, Rees PJ, Wilmshurst P. Hyperbaric oxygen therapy. BMJ 1998: 317: 1140–1143. 19. Lee N, Xia P, Quivey JM, Sultanem K, Poon I, Akazawa C, Akazawa P, Weinberg V, Fu KK. Intensity-modulated radiotherapy in the treatment of nasopharyngeal carcinoma: an update of the UCSF experience. Int J Radiat Oncol Biol Phys 2002: 53: 12–22. 20. Lefebvre JL. Current clinical outcomes demand new treatment options for SCCHN. Ann Oncol 2005: 16: 7–12. 21. Li J, Shan Z, Ou G, Liu X, Zhang C, Baum BJ, Wang S. Structural and functional characteristics of irradiation damage to parotid glands in the miniature pig. Int J Radiat Oncol Biol Phys 2005: 62: 1510–1516. 22. Licitra L, Bernier J, Grandi C, Merlano M, Bruzzi P, Lefebvre JL. Cancer of the oropharynx. Crit Rev Oncol Hematol 2002: 41: 107–122. 23. Marx RE, Ehler WJ, Tayapongsak P, Pierce LW. Relationship of oxygen dose to angiogenesis induction in irradiated tissue. Am J Sur 1990: 160: 519–524. 24. Moller P, Perrier M, Ozsahin M, Monnier P. A prospective study of salivary gland function in patients undergoing radiotherapy for squamous cell carcinoma of the oropharynx. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2004: 97: 173–189. 25. Moon RE, McGraw TA, Blakey 3rd G. Hyperbaric oxygen therapy for radiation necrosis of the jaw: comments on a randomized study. Undersea Hyperb Med 2005: 32: 145–147. 26. Neovius EB, Lind MG, Lind FG. Hyperbaric oxygen therapy for wound complications after surgery in the irradiated head and neck: a review of the literature and a report of 15 consecutive patients. Head Neck 1997: 19: 315–322. 27. Pai S, Ghezzi EM, Ship JA. Development of a Visual Analogue Scale questionnaire for subjective assessment of salivary dysfunction. Oral Surg Oral
28.
29.
30.
31. 32.
33. 34.
35.
36.
37.
259
Med Oral Pathol Oral Radiol Endod 2001: 91: 311–316. Palme CE, Gullane PJ, Gilbert RW. Current treatment options in squamous cell carcinoma of the oral cavity. Surg Oncol Clin N Am 2004: 13: 47–70. Pasquier D, Hoelscher T, Schmutz J, Dische S, Mathieu D, Baumann M, Lartigau E. Hyperbaric oxygenation therapy in the treatment of radio-induced lesions in normal tissues: a literature review. Radiother Oncol 2004: 72: 1–13. Radfar L, Sirois DA. Structural and functional injury in minipig salivary glands following fractionated exposure to 70 Gy of ionizing radiation: an animal model for human radiation-induced salivary gland injury. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2003: 96: 267–274. Ravasco P. Aspects of taste and compliance in patients with cancer. Eur J Oncol Nurs 2005: 9: 84–91. Roesink JM, Moerland MA, Hoekstra A, van Rijk PP, Terhaard CHJ. Scintigraphic assessment of early and late parotid gland function after radiotherapy for head-and-neck cancer: a prospective study of dose-volume response relationships. Int J Radiat Oncol Biol Phys 2004: 58: 1451–1460. Ship JA. Diagnosing, managing, and preventing salivary gland disorders. Oral Dis 2002: 8: 77–89. Stephens LC, Schultheiss TE, Price RE, Ang KK, Peters LJ. Radiation apoptosis of serous acinar cells of salivary and lacrimal glands. Cancer 1991: 67: 1539– 1543. Thom SR, Bhopale VM, Velazquez OC, Goldstein LJ, Thom LH, Buerk DG. Stem cell mobilization by hyperbaric oxygen. Am J Physiol Heart Circ Physiol 2006: 290: 1378–1386. van Merkesteyn R, Bakker DJ. Comment on ‘‘hyperbaric oxygen therapy for radionecrosis of the jaw: a randomized, placebo-controlled, double-blind trial from the ORN96 study group’’. J Clin Oncol 2005: 23: 4465–4466. Vissink A, Jansma J, Spijkervet FK, Burlage FR, Coppes RP. Oral sequelae of head and neck radiotherapy. Crit Rev Oral Biol Med 2003: 14: 199–212.
Address: Prof. Dr. M.A.W. Merkx PhD MD DMD Department of Oral and Maxillofacial Surgery 590 Radboud University Nijmegen Medical Centre P.O. Box 9101 6500 HB Nijmegen The Netherlands Tel.: +31 24 3614561 Fax: +31 24 3541165 E-mail: [email protected]