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Ipsilateral irradiation for well lateralized carcinomas of the oral cavity and oropharynx: results on tumor control and xerostomia

Ipsilateral irradiation for well lateralized carcinomas of the oral cavity and oropharynx:... Background: In head and neck cancer, bilateral neck irradiation is the standard approach for many tumor locations and stages. Increasing knowledge on the pattern of nodal invasion leads to more precise targeting and normal tissue sparing. The aim of the present study was to evaluate the morbidity and tumor control for patients with well lateralized squamous cell carcinomas of the oral cavity and oropharynx treated with ipsilateral radiotherapy. Methods: Twenty consecutive patients with lateralized carcinomas of the oral cavity and oropharynx were treated with a prospective management approach using ipsilateral irradiation between 2000 and 2007. This included 8 radical oropharyngeal and 12 postoperative oral cavity carcinomas, with Stage T1-T2, N0-N2b disease. The actuarial freedom from contralateral nodal recurrence was determined. Late xerostomia was evaluated using the European Organization for Research and Treatment of Cancer QLQ-H&N35 questionnaire and the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3. Results: At a median follow-up of 58 months, five-year overall survival and loco-regional control rates were 82.5% and 100%, respectively. No local or contralateral nodal recurrences were observed. Mean dose to the contralateral parotid gland was 4.72 Gy and to the contralateral submandibular gland was 15.30 Gy. Mean score for dry mouth was 28.1 on the 0-100 QLQ-H&N35 scale. According to CTCAE v3 scale, 87.5% of patients had grade 0-1 and 12.5% grade 2 subjective xerostomia. The unstimulated salivary flow was > 0.2 ml/min in 81.2% of patients and 0.1-0.2 ml/ min in 19%. None of the patients showed grade 3 xerostomia. Conclusion: In selected patients with early and moderate stages, well lateralized oral and oropharyngeal carcinomas, ipsilateral irradiation treatment of the primary site and ipsilateral neck spares salivary gland function without compromising loco-regional control. Page 1 of 8 (page number not for citation purposes) Radiation Oncology 2009, 4:33 http://www.ro-journal.com/content/4/1/33 tongue, retromolar trigone, lateral alveolar ridge, cheek Background Radiation therapy is an effective treatment for head and mucosa or lateral border of tongue; tumor stage T1-T2 and neck cancer patients, showing a high success rate in the nodal stage N0, N1, N2a or N2b, according to TNM clas- early stages of disease. However, permanent xerostomia is sification of the UICC-AJCC [14]. Patients with N2 disease a common complication, frequently compromising nutri- up to two ipsilateral nodes, less than 2 cm in diameter, tion and speech, and accelerating dental decay [1]. Xeros- were included in the study, but not those with three or tomia is caused from bilateral irradiation of the major more nodes. serous-producing glands, mainly the parotids, and the minor salivary glands which significantly contribute to Patients were assessed by clinical examination, by both mucinous secretion [2]. There is not yet an effective treat- the head and neck surgeon and the radiation oncologist, ment for this late complication once it has occurred, endoscopy and CT scan of the head and neck region. A thereby, reducing the patient's quality of life. chest X-ray or chest CT and blood test were performed to rule out distant metastases. Patients were treated with pri- Head and neck squamous cell carcinomas (HNSCC) are mary or postoperative RT with curative intent. Postopera- characterized by a relatively orderly spread to regional cer- tive RT was given to patients with oral carcinomas vical lymph nodes. Generally, elective neck irradiation is presenting close (less than 5 mm) or positive margins, or not recommended when the risk of subclinical disease is for cases of extracapsular nodal extension in the patholog- less than 15-20% [3]. There is growing evidence in the lit- ical specimen. Two patients received postoperative chem- erature that patients with early oropharyngeal and oral otherapy, concomitantly with RT. Table 1 shows the cavity cancer have a low incidence of contralateral node demographic, tumor and treatment characteristics of involvement, hence, radiation therapy can be limited to patients. No patient in the present series was treated with the ipsilateral neck, without compromising loco-regional contralateral neck dissection. The study was approved by control [4-7]. However, bilateral neck irradiation contin- the ethical committee of the hospital, and informed con- ues to be the standard approach for most patients, espe- sent was obtained from all patients. cially those with ipsilateral clinical node-positive Table 1: Demographic, tumor and treatment characteristics of presentation. One argument for the continued inclusion the 20 patients of the contralateral neck is that morbidity is low using Intensity Modulated Radiation Therapy (IMRT), because Characteristics Number (%) parotid sparing can be easily achieved with this technique Age, mean (range) 60 (31- 94) 20 (100%) [8,9]. However, IMRT is not yet universally available, and, Sex 12 (60%) certainly, morbidity will be still lower if only one side of M12 (60%) the neck is treated. F8 (40%) Tumor site In our department three-dimensional conformal radia- Oral cavity 12 (60%) tion therapy (3D-CRT) was started a decade ago, and Lateral border of tongue 6 (30%) guidelines for unilateral elective nodal irradiation in Retromolar trigone 2 (10%) Lateral alveolar ridge 3 (15%) patients with HNSCC were implemented soon after [10]. Cheek mucosa 1 (5%) Oropharynx 8 (40%) The purpose of the current study was to report on morbid- Tonsil 5 (25%) ity and tumor control for patients with well lateralized Tonsillar pillar 3 (15%) squamous cell carcinomas of the oral cavity and orophar- T stage ynx treated with the ipsilateral technique. These results T1 6 (30%) will contribute to some previous experiences supporting T2 12 (60%) T4* 2 (10%) this conservative approach. N stage N0 11 (55%) Methods N1 4 (20%) Patients N2a-b 5 (25%) Twenty patients with early stage HNSCC, where the risk of Radiation treatment contralateral neck node involvement was estimated to be Primary 8 (40%) less than 15-20%, [3,11-13] were treated with unilateral Postoperative 12 (60%) Concomitant chemotherapy irradiation between 2000 and 2007. The guidelines for Yes 2 (10%) inclusion in the unilateral protocol were as follows: histo- No 18 (90%) logically confirmed squamous cell carcinoma; location of the lesion in the tonsillar region with less than 1 cm of * Two patients with alveolar ridge and retromolar trigone carcinomas medial extension to the soft palate or to the base of the with bone erosion. Page 2 of 8 (page number not for citation purposes) Radiation Oncology 2009, 4:33 http://www.ro-journal.com/content/4/1/33 Radiotherapy technique dry mouth?) and 42 (Have you had sticky saliva?), directly All patients were treated using 3D-CRT. The high dose vol- related to xerostomia, and item 37 (Have you had prob- ume included the gross tumor or the surgical tumor bed lems swallowing solid food?), related to dysphagia, and with 5 mm set-up margin (PTV1). The elective target indirectly related to xerostomia, were analyzed in the included the elective ipsilateral nodal levels with 5 mm present study. set-up margin (PTV2). The guidelines used for the selec- tion of ipsilateral nodal target volume are described in Xerostomia was also graded according to the Common Table 2. The total dose prescribed to the primary tumor Terminology Criteria for Adverse Events (CTCAE) radia- was 66-70 Gy for patients with gross disease and 54-64 Gy tion morbidity grading scale, version 3.0 [17]. The CTC for patients treated in the adjuvant setting. For elective evaluation of xerostomia included subjective patient rat- radiotherapy, 50 Gy was administered to the ipsilateral ing, and objective measurement of the unstimulated sali- regions at risk of subclinical disease (PTV2), both for rad- vary output, collecting the saliva spit by the patient into a ical and postoperative radiotherapy. All patients were plastic cup for five minutes at least two hours after break- treated with continuous, conventional fractionation of 2 fast. The saliva was weighed on a precision balance and Gy, one fraction per day, five fractions per week. then saliva flow was calculated assuming 1 g saliva was equal to 1 ml saliva [18]. The contralateral parotid and submandibular glands, as well as the spinal cord, were outlined on the planning CT- No salivary stimulating or protective agents such as pilo- scan. The goal of treatment planning was maximal exclu- carpine or amifostine were allowed during the study. sion of the contralateral parotid gland, while providing adequate coverage of the target. The most common Statistical analysis arrangement used was a two- or three-field ipsilateral Survival data and loco-regional control rates were ana- technique (Figures 1 and 2). In some cases, where the PTV lyzed from the initiation of radiation treatment using the was more medial, a contralateral field was used to increase Kaplan-Meier method. A descriptive analysis was used for the dose homogeneity of the deep part of the target, the toxicity data. SPSS 16.0 for Windows was used for the always sparing the parotid gland. The use of wedges in statistical analysis. some fields was common. Results Follow-up Patients Patients were followed every 3-4 months during the first Twenty patients consecutively treated with unilateral radi- two years, every 6 months until 5 years, and once yearly otherapy in 2000-2007 were included in this study. No until 10 years. Radiation oncologists and head and neck patients treated in this period with the unilateral tech- surgeons performed a clinical examination. A head and nique were excluded from the analysis. Eight patients neck CT or MRI, examination under general anesthesia (40%) underwent primary RT while 12 patients (60%) and/or biopsy were performed if recurrence was sus- underwent postoperative RT. All patients had T1-T2 squa- pected. mous cell carcinomas, except two patients with alveolar ridge and retromolar trigone carcinomas, respectively, Assessment of xerostomia and quality of life that were staged pT4 because minimal bone invasion was All patients were contacted by phone and given an found in the surgical specimen. Eleven patients were node appointment to assess their morbidity. They completed negative and 9 patients had N1 or N2 disease. the EORTC QLQ-H&N35 questionnaire [15] where items are rated on a four-point scale and normalized to a Dose distribution number between 0 and 100. Higher scores represent According to dose-volume histograms, the mean dose worse symptoms. The questionnaire was translated for use administered to the contralateral parotid gland was 4.72 among Spanish patients [16]. Items 41 (Have you had a Gy (range, 1-10 Gy) and to the contralateral submandib- Table 2: Ipsilateral nodal target volumes Tumor site Stage Nodal levels included Tonsillar fossa T1-2 N0 II, III T1-2 N1-2 II-IV, RP* Lateral border of tongue T1-2 N0 Ib, II, III T1-2 N1-2 Ia, Ib, II, III, IV Retromolar trigone, lateral alveolar ridge, cheek mucosa T1-2 N0 Ib, II, III T1-2 N1-2 Ia, Ib, II, III,IV RP: retropharyngeal lymph nodes Page 3 of 8 (page number not for citation purposes) Radiation Oncology 2009, 4:33 http://www.ro-journal.com/content/4/1/33 P 70 Gy 50 Gy Oral cavit Figure 2 y cancer Oral cavity cancer. Patient with a pT2N0M0 carcinoma of the left lateral border of tongue treated with postoperative Orophar Figure 1yngeal cancer Oropharyngeal cancer. A representative example of a radiation therapy for close margin and perivascular- CT-based dose plan for a patient with a T2N0M0 tonsillar perineural invasion. Ipsilateral technique using three ports: carcinoma treated with a pair of ipsilateral wedged fields. anterior, left posterior oblique and left lateral. Green line: PTV1, treated to 60 Gy; blue line: PTV2 including ipsilateral Green line: PTV1, treated to 70 Gy; red line: PTV2 including ipsilateral II, III and retropharyngeal lymph node levels, Ib, II and III node levels, treated to 50 Gy; cyan line: contral- treated with 50 Gy. Contralateral parotid and part of the ateral parotid, yellow line: contralateral submandibular; mean oral cavity are preserved from significant radiation. dose to the right parotid 8 Gy, mean dose to the submandib- ular gland 20 Gy. ular gland 15.30 Gy (range, 1-37 Gy). At least 95% of the target volumes received 97%-105% of the prescribed completion of RT. Mean score for dry mouth was 28.1 on dose. Mean dose to the PTV1 was 67.5 Gy (range, 64-71 a scale of 0-100, and 26.5 for sticky saliva; mean score for Gy) for primary RT and 58 Gy (range, 54-64 Gy) for post- dysphagia was 4.6 on the same scale (Table 3). operative RT. The mean dose to the PTV2 (elective ipsilat- eral lymph nodes) was 51 Gy (range, 49-52 Gy). The When evaluating patients according to the CTCAE v3.0 average mean dose to the spinal cord was 8 Gy (range, 1- classification at the same visit, 5 patients (31.2%) had 18 Gy). grade 1 xerostomia and 9 patients (56.2%) had no xeros- tomia symptoms. Two patients (12.5%) showed grade 2 Disease control xerostomia. No grade 3 subjective xerostomia was found With a median follow-up of 58 months, the 5-year overall among these patients (Table 4). survival and loco-regional control rates were 82.5% and 100%, respectively. No loco-regional recurrences were Table 3: Xerostomia scores from the EORTC QLQ H&N35 found in these patients. Six patients developed a second scale primary cancer at a median follow-up of 3 years (range, 2- 6 years), four of whom died. Pulmonary non-small cell Scale item Mean Median Range carcinoma was the most frequent type (3 cases), followed by hepatocellular carcinoma (2 cases) and anal carcinoma Dry mouth (item 41) 28.1 25 (0-50) Sticky saliva (item 42) 26.5 25 (0-50) (1 case). Dysphagia (item 37) 4.6 0 (0-25) Xerostomia Results from 16 patients who were alive at last follow-up. The QLQ Sixteen patients (80%) filled out the EORTC QLQ H&N35 scores were normalized to a number between 0 and 100. Higher questionnaire at the concerted visit, at least 1 year after the numbers, worse symptoms. Page 4 of 8 (page number not for citation purposes) Radiation Oncology 2009, 4:33 http://www.ro-journal.com/content/4/1/33 Unstimulated saliva flow was > 0.2 ml/min (grade 0-1 ivary flow measurements. However, the salivary flow xerostomia) in 13 patients (81.2%), and 0.1-0.2 ml/min values do not always correspond to the level of symptoms (grade 2 xerostomia) in 3 patients (18.7%). No grade 3 reported by patients. For example, one patient with sali- objective xerostomia (< 0.1 ml/min) was found in the vary flow 0.1-0.2 ml/min, corresponding to a grade 2 measurements (Table 4, Figure 3). objective finding, rated her symptoms as only a grade 1 subjective xerostomia and gave a score of 25 for dry Discussion mouth on the H&N35 scale. This finding was further ana- Morbidity resulting from irradiation in the head and neck lyzed by Jensen et al [20] who found little correlation area can be reduced significantly by a comprehensive def- between patient-assessed symptom scores according to inition of the CTV, i.e. excluding the contralateral neck in EORTC questionnaires C30 and H&N35 and objective a selected group of patients. A double objective was findings, including saliva flow measurements. Eisbruch et intended with the ipsilateral technique applied in the al [1] also described a low correlation between symptoms present study: to preserve salivary gland function while and salivary measurements. They concluded that both maintaining loco-regional control. The first was achieved subjective side effects questionnaires and measurement of given no grade 3 xerostomia and only 12.5% grade 2 sub- the saliva should be included in the xerostomia evalua- jective xerostomia were found in our series. The absence tion. As the main objective of minimizing side effects is to of loco-regional recurrences, more specifically, the improve patient quality of life, subjective symptoms are absence of isolated contralateral neck recurrences, dem- more relevant, at least in clinical practice. onstrated the second. As expected, this group of patients fared well in terms of The major benefit of ipsilateral radiation treatment is to loco-regional control and survival, since their tumor bur- provide the opportunity for salivary protection by exclu- den was low. Generally, elective neck irradiation is not sion of the contralateral major salivary glands and part of recommended where the risk of subclinical disease is less the oral cavity mucosa. The mean dose of 4.72 Gy admin- than 20%, because of the morbidity of radiotherapy. The istered to the opposite parotid in our study is well below results of the present study demonstrate that the failure the dose of 26 Gy recommended by most authors to pre- rate in the opposite neck is rare in selected cases with well serve salivary function. Accordingly, the subjective and lateralized tumors of the tonsillar region and oral cavity. objective scores for xerostomia reported in our series were In fact, no contralateral neck recurrences were found in low. Eisbruch et al [1] observed a recovery from xerosto- any of the twenty treated patients. Jackson [4] and O'Sul- mia in unilaterally irradiated patients which was accom- livan [5] found similar results, with 2.2% and 3.5% con- panied with a compensatory overproduction of saliva in tralateral failure rates, respectively, in two large the contralateral parotid and submandibular gland at 12- oropharyngeal cancer series that also included some N+ 24 months. Furthermore, Jellema [19] found that the patients. Other authors reporting on oral cavity and mean dose given to the contralateral parotid gland was the oropharyngeal cancer found a low incidence of contralat- most important prognostic factor for patient-rated xeros- eral nodal failure (0-3%), although studying fewer tomia. patients [6,7,21]. In general, the CTCAE v3.0 proved to be a practical and There are frequent scenarios where unilateral irradiation adequate tool to measure late xerostomia, since it has two can be applied when treating HNSCC. In the oral cavity, components, a subjective one, based on patient com- surgery is the most frequent treatment for T1-T2 tumors, plaints, and an objective part, based on unstimulated sal- however, if margins are positive or close, or if invaded Table 4: Frequency and grade of xerostomia according to CTCAE v3.0 scale Endpoint Grade 0 Grade 1 Grade 2 Grade 3 N (%) N (%) N (%) N (%) Subjective Xerostomia No complains of xerostomia Dry or thick saliva Significant dietary alteration Inability to adequately aliment orally 9 (56.2%) 5 (31.2%) 2 (12.5%) 0 (0%) Objective Salivary flow > 0.2 ml/min > 0.2 ml/min 0.1-0.2 ml/min < 0.1 ml/min * 13 (81.2%) 3 (18.7%) 0 (0%) Results from 16 patients who were alive at the evaluation date; * Unstimulated salivary flow for Grade 1 is equal to Grade 0 Page 5 of 8 (page number not for citation purposes) Radiation Oncology 2009, 4:33 http://www.ro-journal.com/content/4/1/33 broaden in the near future, once experience is gained for the various tumor sites. Two patients treated in the last year of the study received postoperative chemoradiation, based on high risk patho- logical factors: extracapsular nodal invasion in one patient and positive resection margin in the other. The objective of adding concurrent chemotherapy in these patients was to increase the loco-regional control probability. As the recommendations for postoperative chemoradiation are relatively recent [23], we found only one publication on patients with high associated risk factors treated with ipsi- lateral irradiation plus chemotherapy [22]. This should be further investigated in future studies. A key question when considering unilateral irradiation, apart from local tumor extension and nodal status, is how a possible contralateral recurrence will be managed. Advances in radiographic and PET imaging have made staging and subsequent follow-up more accurate, allow- ing for better detection of occult contralateral lymph node metastases. A neck dissection can usually be performed Sa Figure 3 livary flow rates with little morbidity if an isolated contralateral nodal Salivary flow rates. Unstimulated salivary flow rates in ml/ recurrence occurs. However, patients should be involved min in 16 available subjects at least 1 year after treatment. in the decision to use this approach when the risk is mod- Above the horizontal bar are 13 patients with normal salivary erate (e.g. those with established regional nodal disease). flow ≥ 0.2 ml/min. Only three patients are located below A close follow-up program is mandatory in these patients the horizontal bar, with salivary flow < 0.2 ml/min (grade 2 in order to diagnose and rescue a possible recurrence as toxicity). soon as possible. The observed incidence of late grade 2 xerostomia in the lymph nodes are found, postoperative radiotherapy is present series compared favorably with other reports of commonly indicated to reduce the risk of loco-regional patients treated with parotid-sparing bilateral IMRT recurrence. Although some authors [8,9] recommend [7,24]. This was likely related to the combined sparing of bilateral irradiation when nodal invasion is found in the the contralateral parotid and part of the contralateral sub- ipsilateral neck, perhaps a watching policy with close fol- mandibular gland. Certainly, the salivary function can be low-up can be adopted, since the risk for contralateral further preserved using ipsilateral IMRT because the major metastases is still low. The recent report by Rusthoven et salivary glands and some part of the oral cavity can be al on 20 patients with node-positive tonsil cancer treated avoided by the radiation ports. In this regard, Par- with ipsilateral technique and without contralateral neck vathaneni et al [25] have reported on the superiority of recurrence illustrates this approach well [22]. IMRT over the wedge pair technique for unilateral treat- ment of tonsil carcinoma in terms of parotid sparing and Some radiation oncologists are still reluctant to spare the conformality of the dose, although the mean dose to the contralateral neck in head and neck cancer patients. This contralateral submandibular gland was not significantly prejudice can be originated in the former standard tech- different. As the 3D-CRT ipsilateral technique is simpler to niques, because a pair of parallel lateral fields assured perform and gives acceptable good results, it seams rea- good coverage of the target in the bi-dimensional radio- sonable to reserve IMRT for more advanced stages for therapy era. Thus, bilateral elective neck irradiation whom bilateral neck irradiation is deemed necessary. remains the prevailing option for many tumor sites and stages. However, the better knowledge of the pattern of Additional methods reported to improve salivary produc- nodal invasion and the advent of three-dimensional plan- tion and reduce xerostomia include protection of the sali- ning has brought along higher precision in the delinea- vary glands by daily amifostine during RT [26] or tion of targets, including the nodal targets in the neck. stimulation with pilocarpine [27]. These methods could This may allow a progressively conservative tendency in only be complementary to planning efforts aimed at the head and neck radiation treatment. Furthermore, it is reducing the dose given to the major salivary glands and feasible that the indications for unilateral techniques will to the oral cavity. For example, Burlage et al [27] reported Page 6 of 8 (page number not for citation purposes) Radiation Oncology 2009, 4:33 http://www.ro-journal.com/content/4/1/33 5. O'Sullivan B, Warde P, Grice B, Goh C, Payne D, Liu F-F, Waldron J, some benefit of prophylactic pilocarpine when the Bayley A, Irish J, Gullane P, Cummings B: The benefits and pitfalls parotid gland was irradiated with a mean dose above of ipsilateral radiotherapy in carcinoma of the tonsillar 40 Gy. region. Int J Radiat Oncol Biol Phys 2001, 51:332-43. 6. Jensen K, Overgaard M, Grau C: Morbidity after ipsilateral radi- otherapy for oropharyngeal cancer. Radiother Oncol 2007, Other functions like swallowing can be better kept with 85:90-7. 7. Corvò R, Foppiano F, Bacigalupo A, Berretta L, Benasso M, Vitale V: the ipsilateral technique since less healthy tissues, like the Contralateral parotid-sparing radiotherapy in patients with pharyngeal constrictor muscles, are irradiated. In our unilateral squamous cell carcinoma of the head and neck: series only 3 patients had some problem swallowing solid technical methodology and preliminary results. Tumori 2004, 90:66-72. food, while the rest had no complaints. Swallowing func- 8. Chao KS, Wippold FJ, Ozyigit G, Tran BN, Dempsey JF: Determina- tion is closely related with salivation, and the reduced rate tion and delineation of nodal target volumes for head-and- of dysphagia in these patients could have been influenced neck cancer based on patterns of failure inpatients receiving definitive and postoperative IMRT. Int J Radiat Oncol Biol Phys by the normal salivary function in most of them. 2002, 53:1174-84. 9. Lee N, Puri DR, Blanco AI, Chao KS: Intensity-modulated radia- tion therapy in head and neck cancers: An update. Head Neck One could also hypothesize that morbidity of the radia- 2007, 29:387-400. tion treatment may influence overall survival in head and 10. Cerezo L, Pérez L, López M, Cruz A: Ipsilateral irradiation for neck patients, since xerostomia can cause malnutrition, oropharynx and oral cavity cancer: a proposal for case selec- tion and preliminary results. Radiother Oncol 2006, 81(Suppl dental infections and other debilitating conditions. Some 1):S500. authors comparing ipsilateral and bilateral irradiation in 11. Lindberg R: Distribution of cervical lymph node metastases from squamous cell carcinoma of the upper respiratory and larger series have found better overall survival within the digestive tracts. Cancer 1972, 29:1446-49. ipsilateral treatment group [6]. 12. Bataini JP, Bernier J, Brugere J, Jaulerry Ch, Picco Ch, Brunin F: Nat- ural history of neck disease in patients with squamous cell carcinoma of the oropharynx and pharyngolarynx. Radiother Conclusion Oncol 1985, 3:245-55. In summary, using an ipsilateral technique in selected 13. Shah JP: Patterns of cervical lymph node metastases from patients with well lateralized squamous cell carcinoma of squamous carcinomas of the upper aerodigestive tract. Am J Surg 1990, 160:405-9. the oral cavity or oropharynx reports clinical benefits, 14. UICC TNM classification of malignant tumours. 2006:19-39. sparing the salivary gland function without compromis- 15. Bjordal K, Ahlner-Elmqvist M, Tollesson E, Jensen AB, Razavi D, Maher EJ, Kaasa S: Development of a European Organization ing loco-regional control. Although the outcomes with for Research and Treatment of Cancer (EORTC) question- ipsilateral RT in the present series were promising, these naire module to be used in quality of life assessments in head findings require validation in a larger patient cohort, espe- and neck cancer patients. EORTC Quality of Life Study Group. Acta Oncol 1994, 33:879-85. cially for oral cavity cancer. 16. Arraras JI, Arias F, Tejedor M, Vera R, Prujá E, Marcos M, Martínez E, Valerdi JJ: El cuestionario de calidad de vida para tumores de cabeza y cuello de la EORTC QLQ-H&N35. Estudio de vali- Competing interests dación para nuestro país. Oncología 2001, 24(10):482-491. The authors declare that they have no competing interests. 17. Trotti A, Colevas AD, Setser A, Rusch V, Jaques D, Budach V, Langer C, Murphy B, Cumberlin R, Coleman CN, Rubin P: CTCAE v3.0: Development of a comprehensive grading system for the Authors' contributions adverse effects of cancer treatment. Semin Radiat Oncol 2003, LC designed the study and drafted the manuscript. MM 13:176-181. participated in the design of the study and performed the 18. Eisbruch A, Rhodus N, Rosenthal D, Murphy B, Rasch C, Sonis S, Scarantino C, Brizel D: How should we measure and report statistical analysis. ML treated some of the patients radiotherapy-induced xerostomia? Semin Radiat Oncol 2003, included in the study and participated in the critical dis- 13(3):226-34. cussion of the data. AM helped draft the manuscript. AG 19. Jellema AP, Slotman BJ, Doornaert P, Leemans CR, Langendijk JA: Unilateral versus bilateral irradiation in squamous cell head revised the clinical dosimetries. All authors improved the and neck cancer in relation to patient-rated xerostomia and manuscript and approved the final version. sticky saliva. Radiother Oncol 2007, 85:83-9. 20. Jensen K, Lambertsen K, Torkov P, Dahl M, Jensen AB, Grau C: Patient assessed symptoms are poor predictors of objective References findings. Results from a cross sectional study in patients 1. Eisbruch A, Kim HM, Terrell J, Marsh LH, Dawson LA, Ship JA: treated with radiotherapy for pharyngeal cancer. Acta Oncol Xerostomia and its predictors following parotid-sparing irra- 2007, 46:1159-68. diation of head-and-neck cancer. Int J Radiat Oncol Biol Phys 2001, 21. 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Ipsilateral irradiation for well lateralized carcinomas of the oral cavity and oropharynx: results on tumor control and xerostomia

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Springer Journals
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Copyright © 2009 by Cerezo et al; licensee BioMed Central Ltd.
Subject
Medicine & Public Health; Oncology; Radiotherapy
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1748-717X
DOI
10.1186/1748-717X-4-33
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19723329
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Abstract

Background: In head and neck cancer, bilateral neck irradiation is the standard approach for many tumor locations and stages. Increasing knowledge on the pattern of nodal invasion leads to more precise targeting and normal tissue sparing. The aim of the present study was to evaluate the morbidity and tumor control for patients with well lateralized squamous cell carcinomas of the oral cavity and oropharynx treated with ipsilateral radiotherapy. Methods: Twenty consecutive patients with lateralized carcinomas of the oral cavity and oropharynx were treated with a prospective management approach using ipsilateral irradiation between 2000 and 2007. This included 8 radical oropharyngeal and 12 postoperative oral cavity carcinomas, with Stage T1-T2, N0-N2b disease. The actuarial freedom from contralateral nodal recurrence was determined. Late xerostomia was evaluated using the European Organization for Research and Treatment of Cancer QLQ-H&N35 questionnaire and the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3. Results: At a median follow-up of 58 months, five-year overall survival and loco-regional control rates were 82.5% and 100%, respectively. No local or contralateral nodal recurrences were observed. Mean dose to the contralateral parotid gland was 4.72 Gy and to the contralateral submandibular gland was 15.30 Gy. Mean score for dry mouth was 28.1 on the 0-100 QLQ-H&N35 scale. According to CTCAE v3 scale, 87.5% of patients had grade 0-1 and 12.5% grade 2 subjective xerostomia. The unstimulated salivary flow was > 0.2 ml/min in 81.2% of patients and 0.1-0.2 ml/ min in 19%. None of the patients showed grade 3 xerostomia. Conclusion: In selected patients with early and moderate stages, well lateralized oral and oropharyngeal carcinomas, ipsilateral irradiation treatment of the primary site and ipsilateral neck spares salivary gland function without compromising loco-regional control. Page 1 of 8 (page number not for citation purposes) Radiation Oncology 2009, 4:33 http://www.ro-journal.com/content/4/1/33 tongue, retromolar trigone, lateral alveolar ridge, cheek Background Radiation therapy is an effective treatment for head and mucosa or lateral border of tongue; tumor stage T1-T2 and neck cancer patients, showing a high success rate in the nodal stage N0, N1, N2a or N2b, according to TNM clas- early stages of disease. However, permanent xerostomia is sification of the UICC-AJCC [14]. Patients with N2 disease a common complication, frequently compromising nutri- up to two ipsilateral nodes, less than 2 cm in diameter, tion and speech, and accelerating dental decay [1]. Xeros- were included in the study, but not those with three or tomia is caused from bilateral irradiation of the major more nodes. serous-producing glands, mainly the parotids, and the minor salivary glands which significantly contribute to Patients were assessed by clinical examination, by both mucinous secretion [2]. There is not yet an effective treat- the head and neck surgeon and the radiation oncologist, ment for this late complication once it has occurred, endoscopy and CT scan of the head and neck region. A thereby, reducing the patient's quality of life. chest X-ray or chest CT and blood test were performed to rule out distant metastases. Patients were treated with pri- Head and neck squamous cell carcinomas (HNSCC) are mary or postoperative RT with curative intent. Postopera- characterized by a relatively orderly spread to regional cer- tive RT was given to patients with oral carcinomas vical lymph nodes. Generally, elective neck irradiation is presenting close (less than 5 mm) or positive margins, or not recommended when the risk of subclinical disease is for cases of extracapsular nodal extension in the patholog- less than 15-20% [3]. There is growing evidence in the lit- ical specimen. Two patients received postoperative chem- erature that patients with early oropharyngeal and oral otherapy, concomitantly with RT. Table 1 shows the cavity cancer have a low incidence of contralateral node demographic, tumor and treatment characteristics of involvement, hence, radiation therapy can be limited to patients. No patient in the present series was treated with the ipsilateral neck, without compromising loco-regional contralateral neck dissection. The study was approved by control [4-7]. However, bilateral neck irradiation contin- the ethical committee of the hospital, and informed con- ues to be the standard approach for most patients, espe- sent was obtained from all patients. cially those with ipsilateral clinical node-positive Table 1: Demographic, tumor and treatment characteristics of presentation. One argument for the continued inclusion the 20 patients of the contralateral neck is that morbidity is low using Intensity Modulated Radiation Therapy (IMRT), because Characteristics Number (%) parotid sparing can be easily achieved with this technique Age, mean (range) 60 (31- 94) 20 (100%) [8,9]. However, IMRT is not yet universally available, and, Sex 12 (60%) certainly, morbidity will be still lower if only one side of M12 (60%) the neck is treated. F8 (40%) Tumor site In our department three-dimensional conformal radia- Oral cavity 12 (60%) tion therapy (3D-CRT) was started a decade ago, and Lateral border of tongue 6 (30%) guidelines for unilateral elective nodal irradiation in Retromolar trigone 2 (10%) Lateral alveolar ridge 3 (15%) patients with HNSCC were implemented soon after [10]. Cheek mucosa 1 (5%) Oropharynx 8 (40%) The purpose of the current study was to report on morbid- Tonsil 5 (25%) ity and tumor control for patients with well lateralized Tonsillar pillar 3 (15%) squamous cell carcinomas of the oral cavity and orophar- T stage ynx treated with the ipsilateral technique. These results T1 6 (30%) will contribute to some previous experiences supporting T2 12 (60%) T4* 2 (10%) this conservative approach. N stage N0 11 (55%) Methods N1 4 (20%) Patients N2a-b 5 (25%) Twenty patients with early stage HNSCC, where the risk of Radiation treatment contralateral neck node involvement was estimated to be Primary 8 (40%) less than 15-20%, [3,11-13] were treated with unilateral Postoperative 12 (60%) Concomitant chemotherapy irradiation between 2000 and 2007. The guidelines for Yes 2 (10%) inclusion in the unilateral protocol were as follows: histo- No 18 (90%) logically confirmed squamous cell carcinoma; location of the lesion in the tonsillar region with less than 1 cm of * Two patients with alveolar ridge and retromolar trigone carcinomas medial extension to the soft palate or to the base of the with bone erosion. Page 2 of 8 (page number not for citation purposes) Radiation Oncology 2009, 4:33 http://www.ro-journal.com/content/4/1/33 Radiotherapy technique dry mouth?) and 42 (Have you had sticky saliva?), directly All patients were treated using 3D-CRT. The high dose vol- related to xerostomia, and item 37 (Have you had prob- ume included the gross tumor or the surgical tumor bed lems swallowing solid food?), related to dysphagia, and with 5 mm set-up margin (PTV1). The elective target indirectly related to xerostomia, were analyzed in the included the elective ipsilateral nodal levels with 5 mm present study. set-up margin (PTV2). The guidelines used for the selec- tion of ipsilateral nodal target volume are described in Xerostomia was also graded according to the Common Table 2. The total dose prescribed to the primary tumor Terminology Criteria for Adverse Events (CTCAE) radia- was 66-70 Gy for patients with gross disease and 54-64 Gy tion morbidity grading scale, version 3.0 [17]. The CTC for patients treated in the adjuvant setting. For elective evaluation of xerostomia included subjective patient rat- radiotherapy, 50 Gy was administered to the ipsilateral ing, and objective measurement of the unstimulated sali- regions at risk of subclinical disease (PTV2), both for rad- vary output, collecting the saliva spit by the patient into a ical and postoperative radiotherapy. All patients were plastic cup for five minutes at least two hours after break- treated with continuous, conventional fractionation of 2 fast. The saliva was weighed on a precision balance and Gy, one fraction per day, five fractions per week. then saliva flow was calculated assuming 1 g saliva was equal to 1 ml saliva [18]. The contralateral parotid and submandibular glands, as well as the spinal cord, were outlined on the planning CT- No salivary stimulating or protective agents such as pilo- scan. The goal of treatment planning was maximal exclu- carpine or amifostine were allowed during the study. sion of the contralateral parotid gland, while providing adequate coverage of the target. The most common Statistical analysis arrangement used was a two- or three-field ipsilateral Survival data and loco-regional control rates were ana- technique (Figures 1 and 2). In some cases, where the PTV lyzed from the initiation of radiation treatment using the was more medial, a contralateral field was used to increase Kaplan-Meier method. A descriptive analysis was used for the dose homogeneity of the deep part of the target, the toxicity data. SPSS 16.0 for Windows was used for the always sparing the parotid gland. The use of wedges in statistical analysis. some fields was common. Results Follow-up Patients Patients were followed every 3-4 months during the first Twenty patients consecutively treated with unilateral radi- two years, every 6 months until 5 years, and once yearly otherapy in 2000-2007 were included in this study. No until 10 years. Radiation oncologists and head and neck patients treated in this period with the unilateral tech- surgeons performed a clinical examination. A head and nique were excluded from the analysis. Eight patients neck CT or MRI, examination under general anesthesia (40%) underwent primary RT while 12 patients (60%) and/or biopsy were performed if recurrence was sus- underwent postoperative RT. All patients had T1-T2 squa- pected. mous cell carcinomas, except two patients with alveolar ridge and retromolar trigone carcinomas, respectively, Assessment of xerostomia and quality of life that were staged pT4 because minimal bone invasion was All patients were contacted by phone and given an found in the surgical specimen. Eleven patients were node appointment to assess their morbidity. They completed negative and 9 patients had N1 or N2 disease. the EORTC QLQ-H&N35 questionnaire [15] where items are rated on a four-point scale and normalized to a Dose distribution number between 0 and 100. Higher scores represent According to dose-volume histograms, the mean dose worse symptoms. The questionnaire was translated for use administered to the contralateral parotid gland was 4.72 among Spanish patients [16]. Items 41 (Have you had a Gy (range, 1-10 Gy) and to the contralateral submandib- Table 2: Ipsilateral nodal target volumes Tumor site Stage Nodal levels included Tonsillar fossa T1-2 N0 II, III T1-2 N1-2 II-IV, RP* Lateral border of tongue T1-2 N0 Ib, II, III T1-2 N1-2 Ia, Ib, II, III, IV Retromolar trigone, lateral alveolar ridge, cheek mucosa T1-2 N0 Ib, II, III T1-2 N1-2 Ia, Ib, II, III,IV RP: retropharyngeal lymph nodes Page 3 of 8 (page number not for citation purposes) Radiation Oncology 2009, 4:33 http://www.ro-journal.com/content/4/1/33 P 70 Gy 50 Gy Oral cavit Figure 2 y cancer Oral cavity cancer. Patient with a pT2N0M0 carcinoma of the left lateral border of tongue treated with postoperative Orophar Figure 1yngeal cancer Oropharyngeal cancer. A representative example of a radiation therapy for close margin and perivascular- CT-based dose plan for a patient with a T2N0M0 tonsillar perineural invasion. Ipsilateral technique using three ports: carcinoma treated with a pair of ipsilateral wedged fields. anterior, left posterior oblique and left lateral. Green line: PTV1, treated to 60 Gy; blue line: PTV2 including ipsilateral Green line: PTV1, treated to 70 Gy; red line: PTV2 including ipsilateral II, III and retropharyngeal lymph node levels, Ib, II and III node levels, treated to 50 Gy; cyan line: contral- treated with 50 Gy. Contralateral parotid and part of the ateral parotid, yellow line: contralateral submandibular; mean oral cavity are preserved from significant radiation. dose to the right parotid 8 Gy, mean dose to the submandib- ular gland 20 Gy. ular gland 15.30 Gy (range, 1-37 Gy). At least 95% of the target volumes received 97%-105% of the prescribed completion of RT. Mean score for dry mouth was 28.1 on dose. Mean dose to the PTV1 was 67.5 Gy (range, 64-71 a scale of 0-100, and 26.5 for sticky saliva; mean score for Gy) for primary RT and 58 Gy (range, 54-64 Gy) for post- dysphagia was 4.6 on the same scale (Table 3). operative RT. The mean dose to the PTV2 (elective ipsilat- eral lymph nodes) was 51 Gy (range, 49-52 Gy). The When evaluating patients according to the CTCAE v3.0 average mean dose to the spinal cord was 8 Gy (range, 1- classification at the same visit, 5 patients (31.2%) had 18 Gy). grade 1 xerostomia and 9 patients (56.2%) had no xeros- tomia symptoms. Two patients (12.5%) showed grade 2 Disease control xerostomia. No grade 3 subjective xerostomia was found With a median follow-up of 58 months, the 5-year overall among these patients (Table 4). survival and loco-regional control rates were 82.5% and 100%, respectively. No loco-regional recurrences were Table 3: Xerostomia scores from the EORTC QLQ H&N35 found in these patients. Six patients developed a second scale primary cancer at a median follow-up of 3 years (range, 2- 6 years), four of whom died. Pulmonary non-small cell Scale item Mean Median Range carcinoma was the most frequent type (3 cases), followed by hepatocellular carcinoma (2 cases) and anal carcinoma Dry mouth (item 41) 28.1 25 (0-50) Sticky saliva (item 42) 26.5 25 (0-50) (1 case). Dysphagia (item 37) 4.6 0 (0-25) Xerostomia Results from 16 patients who were alive at last follow-up. The QLQ Sixteen patients (80%) filled out the EORTC QLQ H&N35 scores were normalized to a number between 0 and 100. Higher questionnaire at the concerted visit, at least 1 year after the numbers, worse symptoms. Page 4 of 8 (page number not for citation purposes) Radiation Oncology 2009, 4:33 http://www.ro-journal.com/content/4/1/33 Unstimulated saliva flow was > 0.2 ml/min (grade 0-1 ivary flow measurements. However, the salivary flow xerostomia) in 13 patients (81.2%), and 0.1-0.2 ml/min values do not always correspond to the level of symptoms (grade 2 xerostomia) in 3 patients (18.7%). No grade 3 reported by patients. For example, one patient with sali- objective xerostomia (< 0.1 ml/min) was found in the vary flow 0.1-0.2 ml/min, corresponding to a grade 2 measurements (Table 4, Figure 3). objective finding, rated her symptoms as only a grade 1 subjective xerostomia and gave a score of 25 for dry Discussion mouth on the H&N35 scale. This finding was further ana- Morbidity resulting from irradiation in the head and neck lyzed by Jensen et al [20] who found little correlation area can be reduced significantly by a comprehensive def- between patient-assessed symptom scores according to inition of the CTV, i.e. excluding the contralateral neck in EORTC questionnaires C30 and H&N35 and objective a selected group of patients. A double objective was findings, including saliva flow measurements. Eisbruch et intended with the ipsilateral technique applied in the al [1] also described a low correlation between symptoms present study: to preserve salivary gland function while and salivary measurements. They concluded that both maintaining loco-regional control. The first was achieved subjective side effects questionnaires and measurement of given no grade 3 xerostomia and only 12.5% grade 2 sub- the saliva should be included in the xerostomia evalua- jective xerostomia were found in our series. The absence tion. As the main objective of minimizing side effects is to of loco-regional recurrences, more specifically, the improve patient quality of life, subjective symptoms are absence of isolated contralateral neck recurrences, dem- more relevant, at least in clinical practice. onstrated the second. As expected, this group of patients fared well in terms of The major benefit of ipsilateral radiation treatment is to loco-regional control and survival, since their tumor bur- provide the opportunity for salivary protection by exclu- den was low. Generally, elective neck irradiation is not sion of the contralateral major salivary glands and part of recommended where the risk of subclinical disease is less the oral cavity mucosa. The mean dose of 4.72 Gy admin- than 20%, because of the morbidity of radiotherapy. The istered to the opposite parotid in our study is well below results of the present study demonstrate that the failure the dose of 26 Gy recommended by most authors to pre- rate in the opposite neck is rare in selected cases with well serve salivary function. Accordingly, the subjective and lateralized tumors of the tonsillar region and oral cavity. objective scores for xerostomia reported in our series were In fact, no contralateral neck recurrences were found in low. Eisbruch et al [1] observed a recovery from xerosto- any of the twenty treated patients. Jackson [4] and O'Sul- mia in unilaterally irradiated patients which was accom- livan [5] found similar results, with 2.2% and 3.5% con- panied with a compensatory overproduction of saliva in tralateral failure rates, respectively, in two large the contralateral parotid and submandibular gland at 12- oropharyngeal cancer series that also included some N+ 24 months. Furthermore, Jellema [19] found that the patients. Other authors reporting on oral cavity and mean dose given to the contralateral parotid gland was the oropharyngeal cancer found a low incidence of contralat- most important prognostic factor for patient-rated xeros- eral nodal failure (0-3%), although studying fewer tomia. patients [6,7,21]. In general, the CTCAE v3.0 proved to be a practical and There are frequent scenarios where unilateral irradiation adequate tool to measure late xerostomia, since it has two can be applied when treating HNSCC. In the oral cavity, components, a subjective one, based on patient com- surgery is the most frequent treatment for T1-T2 tumors, plaints, and an objective part, based on unstimulated sal- however, if margins are positive or close, or if invaded Table 4: Frequency and grade of xerostomia according to CTCAE v3.0 scale Endpoint Grade 0 Grade 1 Grade 2 Grade 3 N (%) N (%) N (%) N (%) Subjective Xerostomia No complains of xerostomia Dry or thick saliva Significant dietary alteration Inability to adequately aliment orally 9 (56.2%) 5 (31.2%) 2 (12.5%) 0 (0%) Objective Salivary flow > 0.2 ml/min > 0.2 ml/min 0.1-0.2 ml/min < 0.1 ml/min * 13 (81.2%) 3 (18.7%) 0 (0%) Results from 16 patients who were alive at the evaluation date; * Unstimulated salivary flow for Grade 1 is equal to Grade 0 Page 5 of 8 (page number not for citation purposes) Radiation Oncology 2009, 4:33 http://www.ro-journal.com/content/4/1/33 broaden in the near future, once experience is gained for the various tumor sites. Two patients treated in the last year of the study received postoperative chemoradiation, based on high risk patho- logical factors: extracapsular nodal invasion in one patient and positive resection margin in the other. The objective of adding concurrent chemotherapy in these patients was to increase the loco-regional control probability. As the recommendations for postoperative chemoradiation are relatively recent [23], we found only one publication on patients with high associated risk factors treated with ipsi- lateral irradiation plus chemotherapy [22]. This should be further investigated in future studies. A key question when considering unilateral irradiation, apart from local tumor extension and nodal status, is how a possible contralateral recurrence will be managed. Advances in radiographic and PET imaging have made staging and subsequent follow-up more accurate, allow- ing for better detection of occult contralateral lymph node metastases. A neck dissection can usually be performed Sa Figure 3 livary flow rates with little morbidity if an isolated contralateral nodal Salivary flow rates. Unstimulated salivary flow rates in ml/ recurrence occurs. However, patients should be involved min in 16 available subjects at least 1 year after treatment. in the decision to use this approach when the risk is mod- Above the horizontal bar are 13 patients with normal salivary erate (e.g. those with established regional nodal disease). flow ≥ 0.2 ml/min. Only three patients are located below A close follow-up program is mandatory in these patients the horizontal bar, with salivary flow < 0.2 ml/min (grade 2 in order to diagnose and rescue a possible recurrence as toxicity). soon as possible. The observed incidence of late grade 2 xerostomia in the lymph nodes are found, postoperative radiotherapy is present series compared favorably with other reports of commonly indicated to reduce the risk of loco-regional patients treated with parotid-sparing bilateral IMRT recurrence. Although some authors [8,9] recommend [7,24]. This was likely related to the combined sparing of bilateral irradiation when nodal invasion is found in the the contralateral parotid and part of the contralateral sub- ipsilateral neck, perhaps a watching policy with close fol- mandibular gland. Certainly, the salivary function can be low-up can be adopted, since the risk for contralateral further preserved using ipsilateral IMRT because the major metastases is still low. The recent report by Rusthoven et salivary glands and some part of the oral cavity can be al on 20 patients with node-positive tonsil cancer treated avoided by the radiation ports. In this regard, Par- with ipsilateral technique and without contralateral neck vathaneni et al [25] have reported on the superiority of recurrence illustrates this approach well [22]. IMRT over the wedge pair technique for unilateral treat- ment of tonsil carcinoma in terms of parotid sparing and Some radiation oncologists are still reluctant to spare the conformality of the dose, although the mean dose to the contralateral neck in head and neck cancer patients. This contralateral submandibular gland was not significantly prejudice can be originated in the former standard tech- different. As the 3D-CRT ipsilateral technique is simpler to niques, because a pair of parallel lateral fields assured perform and gives acceptable good results, it seams rea- good coverage of the target in the bi-dimensional radio- sonable to reserve IMRT for more advanced stages for therapy era. Thus, bilateral elective neck irradiation whom bilateral neck irradiation is deemed necessary. remains the prevailing option for many tumor sites and stages. However, the better knowledge of the pattern of Additional methods reported to improve salivary produc- nodal invasion and the advent of three-dimensional plan- tion and reduce xerostomia include protection of the sali- ning has brought along higher precision in the delinea- vary glands by daily amifostine during RT [26] or tion of targets, including the nodal targets in the neck. stimulation with pilocarpine [27]. These methods could This may allow a progressively conservative tendency in only be complementary to planning efforts aimed at the head and neck radiation treatment. Furthermore, it is reducing the dose given to the major salivary glands and feasible that the indications for unilateral techniques will to the oral cavity. For example, Burlage et al [27] reported Page 6 of 8 (page number not for citation purposes) Radiation Oncology 2009, 4:33 http://www.ro-journal.com/content/4/1/33 5. O'Sullivan B, Warde P, Grice B, Goh C, Payne D, Liu F-F, Waldron J, some benefit of prophylactic pilocarpine when the Bayley A, Irish J, Gullane P, Cummings B: The benefits and pitfalls parotid gland was irradiated with a mean dose above of ipsilateral radiotherapy in carcinoma of the tonsillar 40 Gy. region. Int J Radiat Oncol Biol Phys 2001, 51:332-43. 6. Jensen K, Overgaard M, Grau C: Morbidity after ipsilateral radi- otherapy for oropharyngeal cancer. Radiother Oncol 2007, Other functions like swallowing can be better kept with 85:90-7. 7. Corvò R, Foppiano F, Bacigalupo A, Berretta L, Benasso M, Vitale V: the ipsilateral technique since less healthy tissues, like the Contralateral parotid-sparing radiotherapy in patients with pharyngeal constrictor muscles, are irradiated. In our unilateral squamous cell carcinoma of the head and neck: series only 3 patients had some problem swallowing solid technical methodology and preliminary results. Tumori 2004, 90:66-72. food, while the rest had no complaints. Swallowing func- 8. Chao KS, Wippold FJ, Ozyigit G, Tran BN, Dempsey JF: Determina- tion is closely related with salivation, and the reduced rate tion and delineation of nodal target volumes for head-and- of dysphagia in these patients could have been influenced neck cancer based on patterns of failure inpatients receiving definitive and postoperative IMRT. Int J Radiat Oncol Biol Phys by the normal salivary function in most of them. 2002, 53:1174-84. 9. Lee N, Puri DR, Blanco AI, Chao KS: Intensity-modulated radia- tion therapy in head and neck cancers: An update. Head Neck One could also hypothesize that morbidity of the radia- 2007, 29:387-400. tion treatment may influence overall survival in head and 10. 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Shah JP: Patterns of cervical lymph node metastases from patients with well lateralized squamous cell carcinoma of squamous carcinomas of the upper aerodigestive tract. Am J Surg 1990, 160:405-9. the oral cavity or oropharynx reports clinical benefits, 14. UICC TNM classification of malignant tumours. 2006:19-39. sparing the salivary gland function without compromis- 15. Bjordal K, Ahlner-Elmqvist M, Tollesson E, Jensen AB, Razavi D, Maher EJ, Kaasa S: Development of a European Organization ing loco-regional control. Although the outcomes with for Research and Treatment of Cancer (EORTC) question- ipsilateral RT in the present series were promising, these naire module to be used in quality of life assessments in head findings require validation in a larger patient cohort, espe- and neck cancer patients. EORTC Quality of Life Study Group. Acta Oncol 1994, 33:879-85. cially for oral cavity cancer. 16. 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Radiation Oncology – Springer Journals

Published: Sep 1, 2009

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