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Objective: To evaluate the functionality of the auditory system in patients who underwent radiotherapy and chemotherapy treatment with cisplatin to treat head and neck tumors. Study Design: Case series with planned data collection. Setting: From May 2007 to May 2008 by the Department of Otorhinolaryngology and the Department of Oncology/Radiotherapy at Faculdade de Medicina de Marília. Subjects and Methods: Audiological evaluation (Pure Tone Audiometry (air and bone conduction), Speech Audiometry, Tympanometry, Acoustic Reflex testing and Distortion Product Otoacoustic Emissions) was performed in 17 patients diagnosed with head and neck neoplasia and treated with chemotherapy, using cisplatin, and radiotherapy. Results: 12 left ears (70.5%) and 11 right ears (64.7%) presented bilateral decreased hearing soon after the treatment for the frequency 1 kHz (mild auditory damage) and for the frequency 8 kHz (more significant auditory damage). Conclusion: Patients with head and neck cancer submitted to the conventional radiotherapy treatment, combined with the chemotherapy with cisplatin, presented a high incidence of decreased hearing by the end of treatment. Strong evidence was observed linking auditory alteration to the amount of radiotherapy treatment. tumors . Recently, the addition of chemotherapy (CT) Introduction Auditory damage is one of the main complications of with cisplatin to radiotherapy (RT) has been improving oncological therapy in patients with head and neck the survival rate of patients with these neoplasias, becom- Page 1 of 7 (page number not for citation purposes) Radiation Oncology 2009, 4:53 http://www.ro-journal.com/content/4/1/53 ing a standard treatment for tumors locally advanced. Weekly doses of intravenous cisplatin (30 mg/m ) as first However, both treatments, chemotherapy with cisplatin infusion of the drug in the first day of the radiotherapy and radiotherapy, are known for their ototoxic effects. was prescribed to the patients. As the combined treatment became the standard proce- This prescribed radiotherapy dose varied according to the dure in many cases of head and neck tumors, the objective primary site of the disease and the primary tumor staging. of this study is to evaluate the changes in auditory func- Before beginning the radiotherapy sessions, the patients tion in patients submitted to these procedures regarding were submitted to the conventional simulation (X-ray) for their ototoxic effects; to describe the incidence of the pre- delimitation of the radiotherapy site and to make molded cocious auditory damages after the combined treatment; thermoplastic masks, used to immobilize the patient in to establish a link between the findings obtained and the supine position and to mark the area to be treated. factors related to the treatment, including the cumulative dose of chemotherapy, the total dose of radiotherapy, and The treatment limits (radiation area) varied according to the volume irradiated by the radiotherapy (VTRT). the primary site of the pathology. However, due to the advanced nature of the cases, all the patients had the supe- rior border of the radiotherapy site in the base of the cra- Methods and materials Case series with planned data collection performed by the nium, thus including the cochlea in the radiotherapy area. Department of Otorhinolaryngology and the Department of Oncology/Radiotherapy at Faculdade de Medicina de To calculate the volume of radiotherapy treatment (VRT) Marília (FAMEMA), approved by the Research Ethics we used the patient's latero-lateral distance, measured Committee under protocol # 165/06. during the simulation process, multiplied by the resulting area of the simulation area for each patient. The study involved 17 patients (15 males and 2 females, in a total of 34 ears) that were scheduled for chemoradia- Statistical analysis tion treatment for extracranial head and neck tumors, To analyze the differences in the tonal threshold averages from May 2007 to May 2008. All patients agreed to for each frequency, pre and post treatment, we performed undergo hearing tests and all provided written informed the T - Student Test. consent for participation in this study. To determine which values (variables: age, volume and After having the diagnosis of neoplasia confirmed by the dose of RT and total dose of CT) would have some rela- anatomopathological examination, and being indicated tion to the reduction of the tonal thresholds in the post- this combined treatment, the patients were directed to the treatment, the Fisher Exact Test was applied. According to Otorhinolaryngology clinic at FAMEMA's General Hospi- the Contingency table, the Odds Ratio was calculated to tal (Hospital das Clínicas) for otorhinolaryngological and determine the relation between the probability of occur- audiological evaluation, which consisted of two stages: rence to the probability of non-occurrence of an auditory pre- and post-treatment (within 2 weeks after treatment). alteration after chemo- and concomitant radiotherapy In these stages, the following procedures were used: treatment, taking into consideration the variables: age, Anamnesis and Clínical Otorhinolaryngological Evalua- volume and dose of RT, and total dose of CT. tion, Audiological Anamnesis, Pure Tone Audiometry by air and bone conduction, Speech Audiometry, Tympan- We considered as reduction of the auditory acuity, the ometry, Acoustic Reflex testing and Distortion Product decrease of 20 dB in an isolated frequency or of 10 dB in Otoacoustic Emissions (DPOAE). two or more successive frequencies, according to the ASHA criteria . Patients with otitis media with effusion, hearing loss due to a significant noise exposure, trauma, ototoxic medica- For all the statistical tests, a value up to 5% for the signif- tion, neoplasm, and congenital infection or syndrome, icance level (value of p < 0.05) was considered. congenital or pediatric onset, with nasopharyngeal tumors and those who previously received chemo and/or Results radiotherapy were excluded from the study. The patient's characteristics including age, gender, tumor histology, distribution by clinical staging, number of In the Department of Oncology/Radiotherapy, all patients chemotherapy cycles, cumulative dose of cisplatin, frac- underwent a complete physical examination, direct or tioned and total dose of radiotherapy, and the volume of indirect laryngoscopy, head and neck computerized tom- radiotherapy treatment are described on Table 1. ography and thorax X-ray before the treatment. Page 2 of 7 (page number not for citation purposes) Radiation Oncology 2009, 4:53 http://www.ro-journal.com/content/4/1/53 Table 1: Demonstrates data referring to gender, age, tumor localization, distribution by clinical staging, number of chemotherapy cycles, cumulative dose of cisplatin, dose by fraction and total dose of radiotherapy and the volume of radiotherapy treatment (n = 17). Gender Age Localization Staging Clínico Number of Total Dose Fraction Dose Total Dose VRTT cycles QT QT (mg) RT (Gy) RT (Gy) (cm ) M 54 CEC Larynx T4 N2 M0 7 336 1.8 70.2 1,390 M 49 CEC Larynx T3 N3 M0 5 300 1.8 70.2 2,028 M 71 CEC Hypopharynx T4 N2 M0 5 270 1.8 70.2 2,364 M 51 CEC Hypopharynx T2 N2 M0 7 315 1.8 70.2 1,664 M 61 CEC Oropharynx T4 N2 M0 8 400 1.8 70.2 1,480 M 55 CEC Oral Cavity T2 N2 M0 8 336 1.8 72.2 1,550 M 69 CEC Hard Palate T3 N1 M0 6 270 1.8 70.2 1,306 M 51 CEC Unseen Tx N2 M0 8 220 1.8 70.2 739.64 M 75 CEC Base Tongue T3 N3 M0 7 350 1.8 70.2 2,460 M 69 CEC Oropharynx T4 N0 M0 2 96 2 68 1,392 F 40 CEC Larynx T4 N0 M0 7 455 2 72 1,614 M 57 CEC Larynx T4 N0 M0 6 258 1.8 70.2 1,488 M 64 CEC Larynx T3 N3 M0 7 364 2 64 2,258 M 58 CEC Hypopharynx T4 N3 M0 3 144 1.8 70.2 1,754 F 68 CEC Unseen Tx N2 M0 7 378 2 60 3,364 M 70 CEC Oral Cavity T2 N1 M0 7 399 2 64 1,728 M 54 CEC Oropharynx T3 N0 M0 4 192 1.8 70.2 2,925 All the patients received at least 2 chemotherapy cycles, quencies above 1 KHz, 10 ears had hearing loss above 2 and three patients received 8 cycles resulting in an average KHz and 5 ears showed hearing loss at frequencies above 2 2 dose of 299 mg/m and median of 315 mg/m with varia- 3 KHz. tion from 96 to 455 mg/m . The pre treatment hearing loss etiology may have had a The total dose of the radiotherapy varied from 60.0 Gy to clinical diagnosis of presbycusis because of the age of the 72.0 Gy, being the average dose of 68.9 Gy and median of patients. Patients that had known causes of hearing loss the dose of 72.2 Gy, with a variation of the daily dose were excluded as described in Methods. from 1.8 Gy to 2.0 Gy. In the analysis of the data obtained, it was possible to ver- Regarding the VRT, we have found an average volume of ify that the average of the frequencies analyzed from 0.25 3 3 1,853 cm and median of 1,500 cm with variation of 739 kHz to 8 kHz were shown to be significantly overset when 3 3 cm - 3,364 cm . comparing pre- and post-treatment, as shown on figure 1 and Table 2, which also shows data referring to the stand- Out of 17 patients and 34 ears analyzed, we observed dur- ard deviation, confidence interval and p-value for each ing the otorhinolaryngological evaluation that 2 ears pre- frequency bilaterally. sented perforated tympanic membrane and 32 normal membranes. Alterations during the chemo and radiother- According to the ASHA criteria, described above, 70.5% apy treatment were not observed in the otoscopy. (12 left ears) and 64.7% (11 right ears) presented decreased hearing soon after the treatment. Regarding the audiological evaluations performed before the radio and chemotherapy treatments, it was observed The frequencies of 1 kHz and 8 kHz presented smaller and in our sample that only 2 ears presented thresholds within larger auditory alteration (respectively), bilaterally. the normal patterns (lower than 20 dB) and most of the patients analyzed had already presented some type of The cumulative dose of chemotherapy > 300 mg/m , the auditory alteration: 3 ears with mixed hearing loss (one dose by cycle > 50 mg/m and the total dose of radiother- with a mild hearing loss and 2 with a moderate hearing apy > 70.2 Gy did not show association with decreased loss). hearing, according to Fisher exact test statistical analysis. The only factors associated to this decreased hearing, The other 29 ears presented sensorineural hearing loss of according to the ASHA criteria were the age ≤ 60 years (p unknown etiology: 4 ears showed mild sensorineural = 0.046) and VTRT > 1500 cm (p = 0.016) (Table 3). hearing loss, 10 ears exhibited sensorial hearing loss at fre- Page 3 of 7 (page number not for citation purposes) Radiation Oncology 2009, 4:53 http://www.ro-journal.com/content/4/1/53 Demonstrate q Figure 1 uencies ranging from 250 s the average dif HZ to 8 ference KHz, in le s between pre an ft and right ears, for the 17 pa d pos-treatment air conduction hear tients analyzeding thresholds in decibel, for the fre- Demonstrates the average differences between pre and pos-treatment air conduction hearing thresholds in decibel, for the frequencies ranging from 250 HZ to 8 KHz, in left and right ears, for the 17 patients analyzed. Results about EOAE-DP and acoustic reflexes were ana- In spite of not having performed RT by 3-D image, we lyzed but they did not show statistical significance. EOAE- have estimated the VRT for each patient using the techni- DP were absent in most patients before treatment. In oth- cal parameters of simulation and treatment. It was not ers, was not possible to realize this exam due to large noisy possible to estimate the exact amount of radiation dose respiration. received by the cochlea. However it was observed that the patients that received VRT >1,500 cm were the ones that presented more auditory damage. Discussion The Radiotherapy is one of the most effective treatments for head and neck tumors. The probable explanation for this discovery is that the patients that received VRT > 1,500 had the cochlea irradi- For initial lesions T1 and T2, the results of exclusive use of ated with doses above 45 Gy. This fact, possibly, has led RT are comparable to the ones obtained using surgical these patients to receive radiation doses in the cochlea procedures. For lesions in a more advanced degree, as between 50 and 60 Gy, while patients that received VRT < some head and neck anatomical sites, RT associated to CT 1,500, after this dose (45 Gy), had the cochlea or part of has been preferred, due to the possibility of preserving the it out of the RT field. organ. The complications of the radiotherapy are specific sites, in other words, they depend on the area (radiother- Few studies have evaluated the effect of the volume of irra- apy field) in which the radiation is being applied. diated treatment and the relationship of the total dose of RT received by the cochlea with its irradiated volume, as a Specifically for the advanced disease, due to the presence prognostic factor for the reduction of auditory acuity. of voluminous tumors, there is a need to irradiate the pri- mary site and suspicious areas of microscopic disease. A What is known is the relationship between the punctual potential gamma of complications mainly to healthy tis- dose of radiation received by the cochlea when the three- sues close to the tumoral layer may appear as a conse- dimensional conformed equipment of RT is used, as quence. As an example, we can mention ototoxicity in shown by Chen et al., who evaluated 22 patients submit- cases of RT on the head and neck area. ted to chemo-radiation . They observed that in the fre- quencies of 3,000 and 2,000 Hz, the mean dose of Our study observed an important correlation between radiotherapy > 48 Gy and time (12 months) were signifi- VRT and auditory acuity. (Table 3) cant in multivariate and univariate analyses, whereas the total dose of cisplatin was not shown to have a statistically Page 4 of 7 (page number not for citation purposes) Radiation Oncology 2009, 4:53 http://www.ro-journal.com/content/4/1/53 Table 2: Demonstrates the difference between the averages of air conduction tonal thresholds pre and post-treatment by frequency by ear, standard deviation, confidence interval and p-value. Frequence Diference between the pré- Standard Deviation 95% Diference p-Valor and post-treatment average Confidence Interval Inferior Limit Superior Limit LEFT EAR 250 -2.94 4.69 -5.35 -0.52 0.02 500 -2.94 3.97 -4.98 -0.89 0.008 1 KHz -1.17 3.32 -2.88 0.53 0.163 2 KHZ -4.41 7.68 -8.36 -0.46 0.031 3 KHz -6.47 11.42 -12.34 -0.59 0.033 4 KHz -9.11 9.22 -13.86 -4.37 0.001 6 KHZ -5.00 8.47 -9.35 -0.64 0.027 8 KHz -11.47 9.31 -16.25 -6.68 0.00 RIGHT EAR 250 -5.00 5.30 -7.72 -2.27 0.001 500 -1.76 3.03 -3.32 -0.20 0.029 1 KHz -0.88 2.64 -2.24 -0.47 0.188 2 KHZ -1.76 4.30 -3.98 -0.45 0.111 3 KHz -7.64 8.12 -11.82 -3.47 0.001 4 KHz -5.29 4.83 -7.77 -2.8 0.00 6 KHZ -12.05 11.59 -18.02 -6.09 0.001 8 KHz -15.00 14.03 -22.21 -7.78 0.00 significant contribution to the change in hearing thresh- comitant radiotherapy describe higher risk of hearing loss olds. In that study, a statistically significant contribution in the second group [5,6]. Therefore, we cannot rule out from cochlear mean dose (Dmean) was seen, but not cis- the possibility of a cumulative effect and potentiation of platin, suggesting that after more than12 months post- the combined treatment. treatment the radiation dose may supersede cisplatin in affecting long-term sensorineural sequelae. The ototoxic The ototoxicity caused by cisplatin happens acutely, being effect of radiotherapy found in our study, shows the rela- its collateral effects seen in the first days after its use. The tionship between the radiotherapy treatment volume and audiological changes are typically bilateral, irreversible Dmean in cochlea. Patients irradiated with VRT > 1,500 and progressive; they begin in high frequencies with sub- cm probably received total doses of radiotherapy higher sequent extension for medium and low frequencies as the than 48 Gy in cochlea. Data suggest that the total dose of number of cycles increases . radiation may supersede cisplatin in a short follow-up. Some reports show that when the cumulative dose of cis- , a significant loss of the high Regarding the treatment dose of radiotherapy, results of platin reaches 240 mg/m our statistical analysis do not show significance for the frequencies starts to happen, and the ototoxity increases decreased hearing post-treatment in patients that received as the accumulated dose increases. Others show 400 mg/ doses higher than 70.2 Gy of radiation. It is important to m as a damaging dose [7,8]. highlight that this radiation dose is the total area dose of the performed treatment and not the dose received by the Ho et al. reported that the mean dose of 275 mg/m of cis- cochlea. platin was not associated to the increase of hearing thresh- old . That result is in accordance with our data. The A recent study reported that sensorineural hearing loss is dose of cisplatin used in our group of patients was rela- a potential complication after RT due to cochlear damage. tively low (96-455 mg/m2, mean dosage 299 mg). Our Herrman et al observed significant reduced hearing abil- statistical analysis, did not show significant correlations ity, starting with high frequencies at 40 Gy, subsequently between the total CT dose and the increase of the hearing progressing to deeper frequencies at 60 Gy and post-RT thresholds, being the average and the median dose 300 . mg/m (p = 0.393). (Tables 3) Other studies that compared patients treated only with radiotherapy and patients treated with chemo and con- Page 5 of 7 (page number not for citation purposes) Radiation Oncology 2009, 4:53 http://www.ro-journal.com/content/4/1/53 Table 3: Demonstrates the relation between the probability of occurrence to the probability of non-occurrence of an auditory damage after chemoradiotherapy treatment, being taken into consideration the variables age, volume and dose of RT and total and cycle dose of CT. Age Total p-Valor ≤ 60 years > 60 years Auditory damage Yes 9 4 13 0.046 ASHA No 7 14 21 Total 16 18 34 RT Volume Total p-Value ≤ 1500 cm > 1500 cm Auditory alteration Yes 8 5 13 0.016 ASHA No 4 17 21 Total 12 22 34 RT Total Dose Total p-Value ≤ 70.2 Gy > 70.2 Gy Auditory damage Yes 3 10 13 0.182 ASHA No 5 16 21 Total 8 26 34 CT Dose Total Total p-Value ≤ 300 mg > 300 mg Auditory damage Yes 7 6 13 0.393 ASHA No 9 12 21 Total 16 18 34 CT Dose per Cycle Total p-Value ≤ 50 mg > 50 mg Auditory damage Yes 9 4 13 0.272 ASHA No 11 10 21 Total 20 14 34 The age of patients submitted to the treatment has also change equal or higher than 20 dB in a unique frequency been evidenced as a factor in the increase of the auditory (first ASHA criterion for ototoxity); and 14.7% with acuity reduction risk [10,11]. reduction of 10 dB in at least two consecutive frequencies (second ASHA criterion for ototoxity). In our study, all the patients analyzed presented age ≥ 40 years old, (average age of 60 years old). In the statistical These data are in accordance with the results of Pearson et analysis, it was verified that the patients < 60 years old pre- al., who retrospectively evaluated audiological findings in sented 4.54 times higher chance to increase hearing ability 15 patients with head and neck tumors, treated with after the treatment. radio- and concomitant chemotherapy, using the same criteria to define ototoxicity. Their results showed that Regarding the alteration in the hearing thresholds soon 85% of patients presented changes in frequencies from 4 after the end of the chemo- and radiotherapy treatment, to 8 kHz and more than 50% of them presented a change we have found in our sample a larger increase of the hear- equal to or higher than 10 dB . ing thresholds for frequencies from 3 KHz to 8 KHz, for both left and right ears. Other studies illustrate that auditory deficiency happens in 9% to 91% of the patients, usually bilateral and ini- All patients included presented auditory damage: 70.5% tially in the high frequencies (4.000-8.000 Hz), also of them with significant auditory alteration; 55.8% with affecting the medium and low frequencies with extended Page 6 of 7 (page number not for citation purposes) Radiation Oncology 2009, 4:53 http://www.ro-journal.com/content/4/1/53 treatment. The auditory deficiency may present a certain Competing interests degree of reversibility, when the auditory deficiency is not The authors declare that they have no competing interests. deep [12,13]. Authors' contributions In a prospective study, Ho et al. evaluated 526 ears of AHBD carried out the data collection and design of the patients with nasopharyngeal cancer treated exclusively study, MLI carried out of the design and coordination of with radiotherapy . Within a 4.5-year period of follow the study, GVA carried out of the data collection, design up, they observed that the auditory alterations began soon and statistical analysis, MCBNE carried out of the data col- after the end of the radiotherapy. After two years, 40% of lection, ARD carried out of the design and coordination of the patients partially recovered the auditory alteration, the study, JLSJ carried out of the data collection ad English while the other 60% presented worsening auditory defi- review, AFR carried out of the data collection ad English ciency year after year. review. All authors read and approved the final manu- script. Regarding the auditory complaints presented by the patients, many studies have reported appearance of tinni- Acknowledgements The authors thank Maria Elisa Goulart, Audiology Department, Startship tus. Some of them report that the tinnitus is usually tran- Children's Hospital. Auckland. New Zeland, for her assistance with English sitory, disappearing some hours or weeks after the end of translation. the treatment in 2% to 36% of the patients [12,13]. In a recent study performed by Zocoli et al., 46% of the References patients presented tinnitus after the second cisplatin 1. Pearson SE, Meyer AC, Adams GL, Ondrey FG: Decreased hearing application, which remained until the end of the treat- after combined modality therapy for head and neck cancer. Am J Otolaryngol 2006, 27(2):76-80. ment . 2. American Speech-Language-Hearing Association (ASHA): Guide- lines for the audiologic management of individuals receiving In our study, two patients complained about tinnitus dur- cochleotoxic drug therapy. ASHA 1994, 36(suppl 12):11-19. 3. Chen WC, Jackson A, Budnick AS, Pfister DG, Kraus DH, Hunt MA, ing the treatment but it disappeared after the end of it. Stambuk H, Levegrun S, Wolden SL: Sensorineural hearing loss in Two complained about otalgia throughout treatment, and combined modality treatment of nasopharyngeal carci- noma. Cancer 2006, 15;106(4):820-9. one presented descamative otitis externa, also throughout 4. Herrmann F, Dörr W, Müller R, Herrmann T: A prospective study treatment. on radiation-induced changes in hearing function. Int J Radiat Oncol Biol Phys 2006, 5; 65(1):1338-44. 5. Bhandare N, Antonelli PJ, Morris CG, Malayapa RS, Mendenhall WM: Conclusion Ototoxicity after radiotherapy for head and neck tumors. Int Patients with head and neck cancer submitted to conven- J Radiat Oncol Biol Phys 2007, 1;67(2):469-79. tional radiotherapy treatment combined with the chemo- 6. Low WK, Tho ST, Wee J, Fook-Chong SMC, Wang DY: Sen- sorineural hearing loss after radiotherapy and chemoradio- therapy, presented a high incidence of decreased hearing therapy: a single, blinded, randomized study. Clin Oncol 2006, by the end of the treatment. 26;24(12):1904-9. 7. Stöhr W, Langer T, Kremers A, Bielack S, Lamprecht-Dinnesen A, Frey E, Beck JD: Cisplatin-induced ototoxicity in osteosarcoma The main factor associated with this auditory damage was patients: a report from the late effects surveillance system. the volume of radiotherapy treatment. Cancer Invest 2005, 23(3):201-7. 8. Biro K, Noszek L, Prekopp P, Nagyiványi K, Géczi L, Gaudi I, Bodrogi I: Characteristics and Risk Factors of Cisplatin-Induced Oto- Our data highlighted the importance of making the audi- toxicity in Testicular Cancer Patients Detected by Distor- tory evaluation, pre and post-treatment, in all patients sion Product Otoacoustic Emission. Oncology 2006, 70(3):177-84. submitted to conventional radiotherapy treatment com- 9. Ho WK, Wei WI, Kwong DL, Sham JST, Tai PTH, Yuen APW, Au bined with chemotherapy with cisplatin for head and DKK: Long-term sensorineural hearing deficit following radi- otherapy in patients suffering from nasopharyngeal carci- neck tumors. noma: A prospective study. Head Neck 1999, 21(6):547-53. 10. Honoré HB, Bentzen SM, Moller K, Grau C: Sensori-neural hear- Thus, we stress the importance of the side effects conse- ing loss after radiotherapy for nasopharyngeal carcinoma: individualized risk estimation. Radiother Oncol 2002, 65:9-16. quences of the treatment, so that the patients can be early 11. Pan CC, Eisbruch A, Lee JS, Snorrason RM, Haken RK, Kileny PR: inserted in programs of auditory rehabilitation. Prospective study of inner ear radiation dose and hearing loss in head-and-neck cancer patients. Int J Radiat Oncol Biol Phys 2005, 61:1393-1402. Final considerations 12. Blakley BW, Gupta AK, Myres SF, Schwan S: Risk factors for oto- All the patients that presented auditory degradation in fre- toxicity due to cisplatin. Arch Otolaryngol Head Neck Surg 1994, 120:541-6. quencies responsible for speech audibility were led to the 13. Powis GD, Hacker MP: The Toxicity of Anticancer Drugs. New use of hearing aids. The three patients who reported daily York: Pergamon Press; 1991:269-283. auditory difficulties and interest in using hearing aids 14. Zocoli R, Reichow SL, Zocoli AMF: Otoacousti emissions X Cis- platin: precocious detection of ototoxicity in oncologic were directed and enrolled in the Hearing Aid Program of patients. Braz J Otorhinolaryngol 2003, 69:222-5. this Institution. Page 7 of 7 (page number not for citation purposes)
Radiation Oncology – Springer Journals
Published: Nov 15, 2009
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