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Head and neck region consolidation radiotherapy and prophylactic cranial irradiation with hippocampal avoidance delivered with helical tomotherapy after induction chemotherapy for non-sinonasal neuroendocrine carcinoma of the upper airways

Head and neck region consolidation radiotherapy and prophylactic cranial irradiation with... Background: Non-sinonasal neuroendocrine carcinomas (NSNECs) of the head and neck are considered an unfrequent clinico-pathological entity. Combined modality treatment represents an established therapeutic option for undifferentiated forms where distant metastasis is a common pattern of failure. Methods: We report on a case of NSNEC treated with sequential chemo-radiation consisting of 6 cycles of cisplatin and etoposide followed by loco-regional radiation to the head and neck and simultaneous prophylactic cranial irradiation to prevent from intracranial spread, delivered with helical tomotherapy with the ‘hippocampal avoidance’ technique in order to reduce neuro-cognitive late effects. Results: One year after the end of the whole combined modality approach, the patient achieved complete remission, with no treatment-related sub-acute and late effects. Conclusions: The present report highlights the importance of multidisciplinary management for NSNECs of the head and neck, as the possibility to achieve substantial cure rates with mild side effects with modern radiotherapy techniques. Keywords: Radiotherapy, Tomotherapy, Non-sinonasal neuroendocrine carcinoma, Head and neck, Hippocampus avoidance, Prophylactic cranial irradiation Introduction glands [2,3]. Some Authors have proposed a frame distinc- Tumours of neuroendocrine differentiation arising within tion between sinonasal neuroendocrine carcinomas the head and neck region are considered an extremely rare (SNNECs) and non-sinonasal neuroendocrine carcinomas (NSNECs) in terms of pathological classification and ther- clinico-pathological entity [1]. They have been described in several anatomical sites such as upper airways (trachea, apeutic options [1,4]. SNNEC are divided into 4 main his- larynx, nose, paranasal sinuses), ear, tongue and salivary tological categories, namely esthesioneuroblastoma, undifferentiated carcinoma, neuroendocrine carcinoma and small cell undifferentiated carcinoma and might * Correspondence: pfranco@ausl.vda.it deserve a multimodality treatment approach regardless of Radiation Oncology Department, Tomotherapy Unit, Ospedale Regionale ‘U. their differentiation [1,4]. Conversely, NSNECs are Parini’, AUSL Valle d’Aosta, Viale Ginevra n° 3, 11100 Aosta, Italy Full list of author information is available at the end of the article © 2012 Franco et al; BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Franco et al. Radiation Oncology 2012, 7:21 Page 2 of 9 http://www.ro-journal.com/content/7/1/21 represented by undifferentiated (small cell or large cell likely primary tumour sites (nasopharynx, tongue base, subtypes), moderately (atypical carcinoid) and well-differ- tonsils, piriform sinus) with negative findings. Adjunctively entiated (typical carcinoid) carcinomas [1,5]. They mainly a lingual tonsillectomy was performed with the evidence of arise within the larynx (where they represent 0.6-1% of all hyperplastic lingual tonsillitis. At the end of diagnostic epithelial cancers), particularly in the epiglottis and supra- work-up: small cell undifferentiated NSNEC of unknown glottic region (aryepiglottic folds and arytenoids) [6]. They primary site (AJCC-UICC stage cTxN2bM0) was pointed predominantly affect males, smokers and present with out. Multimodality therapeutic approach was chosen con- locally advanced node positive disease [1,7]. Conservative sisting of induction CT followed by consolidation radia- surgery (where possible) might be considered adequate for tion; 6 cycles of the PE regimen were planned (Cisplatin 2 2 well-differentiated subtypes, while combined modality 75 mg/m day1 and Etoposide 100 mg/m days 1,2,3 every treatment (chemotherapy and radiotherapy) is considered 21 days). Intermediate CT and PET restaging was per- a mainstay option for undifferentiated forms where distant formed after 3 PE cycles, with the evidence of the persis- metastasis represent the major pattern of failure [1]. We tent thickening and uptake within the tongue base. The herein report on a case of NSNEC of unknown primary patient underwent a new biopsy of the nasopharynx and site treated with a sequential chemo-radiation approach base of the tongue with no tumour observed. The che- consisting of 6 cycles of cisplatin (DDP) and etoposide motherapy program was completed with mild acute toxi- (VP-16) followed by loco-regional radiation to the head city (grade 2 alopecia ad grade 1 asthenia according to and neck region and simultaneous prophylactic cranial CTCAE v 4.0). A re-evaluation with functional and ana- irradiation (PCI) to prevent from intracranial spread, deliv- tomic imaging (CT-PET scan) was carried out at the end ered with helical tomotherapy (HT) with the ‘hippocampal of the CT program: complete remission (CR) was avoidance’ (HA) technique in order to reduce radiation- achieved. Thirty days after, the patients was planned to induced neuro-cognitive late effects [8]. receive consolidation head and neck region radiation and PCI delivered with the TomoTherapy Hi-Art II system Case report (TomoTherapy Inc,. Madison, WI) with the HA technique, A 53 years old caucasian man was referred to our Institu- as reported by Gondi et al. [10]. In order to evaluate basal tion Hospital due to the sudden appearance of a right neuro-cognitive functions, Mini Mental State Examination latero-cervical enlarged lymphnode with no symptoms (MMSE) test was performed before radiation leading to a complained. He had a previous medical history of child- 30 out of 30 score. After proper immobilization (flat head- hood tonsillectomy, appendectomy, acute bacterial epidi- board and head-shoulders thermoplastic mask) and 2.5 dymitis and asymptomatic hepatitis A infection. He was a mm slice thickness planning CT, target volumes and organs at risk contours were created within the Philips non-smoker and had a low-moderate alcohol intake at meals. Physical examination of the neck region showed a Pinnacle P3 v9.1 treatment planning system (Philips Medi- 3-cm hard and fixed adenopathy close to the posterior cal System, Eindhoven, The Netherlands). The head and belly of the right digastric muscle. He underwent, at first, neck region volumes comprised the whole pharingo-laryn- a pharyngo-laryngoscopy procedure that revealed a macro- geal axis (from the roof of the naso-pharynx to the infra- scopic tongue tonsil hypertrophy. A total body CT-scan glottic larynx) and the bilateral neck (level Ib to V and demonstrated two enlarged lymphnodes (35 and 12 mm retro-pharyngeal nodes according to Robbins classifica- in diameter) in the right upper neck between the sub- tion)with a 5mmexpansion from CTVtoPTV to mandibular group (level Ib) and the upper anterior jugular account for set up errors [9] (Figure 3a and 3c). The PCI group (level IIA) according to Robbins classification with volume comprehended the whole brain from the vertex to an adjunctive level IIA left node (15 mm in diameter) [9]; the occipital foramen (with the same 5 mm CTV to PTV thickening of the base of the tongue could also be expansion) (Figure 3a and 3c). For a correct delineation of observed (Figure 1). He underwent an excisional biopsy of the hippocampal regions, the patient underwent three- the right neck and a punch biopsy of the base of the ton- dimensional spoiled gradient axial magnetic resonance gue; histological findings of the lymphnode specimen imaging (MRI) scans (3D-SPGR), standard axial and fluid documented undifferentiated small cell carcinoma (typical attenuation recovery (FLAIR) scans and T2-weighted oat cells pattern; positive staining for AE1 and AE3 Cyto- acquisitions, as suggested by Gondi et al. [10]. Semi-auto- keratin, Chromogranin A and CD 56) with a Ki67 labelling matic rigid registration was performed between planning index of 80%; base of the tongue was negative for tumour CT scans and MRI scans. The hippocampus was con- cells (Figure 2). For staging purposes a F-deoxyglucose- toured on T1-weighted MRI axial sequences (T1-hypoin- CT-positron emission tomography (CT-PET scan) was tense signal medial to the temporal horn) from the most performed showing focal uptake within the oropharynx caudal extent of the temporal horn to the lateral edges of the quadrageminals cisterns along the anterior-posterior and left neck (Figure 1). Using flexible fiber-optic endo- axis (see Gondi et al. for details, [10]) (Figure 3b and 3d). scopy he underwent directed bilateral biopses of the most Franco et al. Radiation Oncology 2012, 7:21 Page 3 of 9 http://www.ro-journal.com/content/7/1/21 Figure 1 Enlarged level Ib (star) and IIA (arrow) right nodes (Figure 1a-b) and level IIA left node (circle; Figure 1a) with thickening of the base of the tongue (blast; Figure 1a) at diagnostic CT scan; base of the tongue hyperaccumulation at 18-FDG- PET scan (Figure 1c-d). A volumetrically isotropic 5 mm expansion was generated on the Oncentra Masterplan v 3.0 software (Nucletron, around the hippocampus to create the ‘hippocampal Veendhal, The Netherlands), since Tomotherapy does not avoidance volumes’ (HAVs) forappropriatedosefalloff allow for visualization of summed plans. Inverse planning algorithm constraints for head and neck regions organs at between hippocampus and whole brain PTV (whole brain volume minus bilateral HAVs). Taking into account his- risks were as suggested by the Quantitative analysis of nor- tology and complete remission status after induction che- mal tissue effects in the clinic (QUANTEC) [11-14]. Dose motherapy, dose prescription was 60 Gy delivered in 30 constraints for the hippocampus (maximum dose 6 Gy fractions (2 Gy daily) for the head and neck region and and V ≤ 20%) and HAVs (maximum dose 25.2 Gy and 25.2 Gy in 14 fractions (1.8 Gy daily) for the whole brain V ≤ 20%) were adapted from Gondi et al. [10]. Metrics PTV minus HAVs. The prescription dose was defined to employed for tomotherapy planning were field width (FW) the mean PTV and the 95% percentage PTV volume 2.5 cm, pitch 0.287, modulation factor (MF) planned 3.0 should be covered at least by 95% of the prescribed dose. (actual 2.105) for the head and neck region and FW 1 cm, In order to minimize late effects, conventional fractiona- pitch 0.215, MF planned 3.2 (actual 2.7799) for whole tion was employed for the 2 locations. Hence, the substan- brain radiation. Directional blocking was used only for tial difference in the number of fractions (30 vs 14) did lenses. The so obtained dose distribution is shown in Fig- not allow for the use simultaneous integrated boost (SIB) ures 4, 5. Dosimetric parameters are shown in Table 1. that would have lead to hypofractionation for the head Radiation treatment was well tolerated with mild acute and neck region. Therefore 2 different plans were gener- toxicity (grade 1 oral mucositis, skin reaction and xerosto- ated. Isodose visualization was made importing both plans mia according to RTOG toxicity scale). No treatment Franco et al. Radiation Oncology 2012, 7:21 Page 4 of 9 http://www.ro-journal.com/content/7/1/21 Figure 2 Oat cells pattern at hematoxylin-eosin staining (Figure 2a); immunohistochemistry positive staining for AE1 and AE3 Cytokeratin (Figure 2b), Chromogranin A (Figure 2c) and CD 56 (Figure 2d). interruptions occurred. Post-treatment re-evaluation advanced disease at diagnosis) [1]. The cohort underwent showed complete remission at morphological and func- different treatment strategies including surgery, radiation tional imaging with one year follow up. Grade 1 LENT- and chemotherapy (in different combinations). With a SOMA xerostomia could be detected as the only radia- median follow up of 40 months, 2-year and 5-year overall tion-induced sequelae. Finally, MMSE results were survival (OS) rates were 53% and 33%, respectively, while unchanged compared to baseline. corresponding disease free survival (DFS) were 41% and 25%. Interestingly, since NSNEC is highly responsive to Discussion CT, the Authors reported that the inclusion of a DDP NSNECs of the head and neck region are widely uncom- and VP-16 chemotherapeutic regimen in the multimodal- mon and therefore clinical and therapeutic informations ity treatment approach approximately doubled the 2 year are scanty. In addition, the issue is beclouded by the slen- OS and DFS. The most common pattern of failure is dis- derness of the published literature (mainly available tant metastasis (DM) with a 2-year and 5-year rate of throughout anecdotal reports) and by the heterogeneity 54% and 71% respectively. The addition of CT in the of the histological sub-types and anatomical sites of pre- therapeutic strategy reduced by one-half (79% vs 39%; p sentation of the medical cases described. However some = 0.006) the 2-year rate of DM if compared to local ther- informative studies are available. To our knowledge, the apy alone (either in univariate and multivariate analysis) largest case series of NSNECs published is the one by the [1]. Among DMs, intracranial spread often occurs with a MD Anderson Cancer Center: 23 patients were treated 2-year and 5-year rate of 25% and 44% respectively. between 1984 and 2001 (median age 64 years; mainly Moreover, isolated brain metastasis are quite frequent smokers; predominant laryngeal primary tumours; locally (21% and 41% of 2-year and 5-year rates). Local failure Franco et al. Radiation Oncology 2012, 7:21 Page 5 of 9 http://www.ro-journal.com/content/7/1/21 Figure 3 Target volumes including the head and neck region and the whole brain with concomitant sparing of the bilateral hippocampal regions (Figure 3a-c); fusion MRI employed for appropriate delineation of the hippocampus (Figure 3b-d). (LF) is infrequent (2-year and 5 year rate of 23%), specifi- and less toxic approach for NSNECs, since concomitant cally almost half of the frequency of comparably staged CT-RT has not proven to improve early complete squamous cell carcinoma of the head and neck region response rate, local control or survival [1]. However if macroscopic residual disease is present after induction [15].Radiation therapydose(range44-72 Gy)did not correlate with LF (p = 0.23). CT did not prevent from LF CT, thereafter concurrent CT-RT or salvage surgery (p = 0.91); however half of the patients with LF did not should be considered, since local control become the pre- achieve complete remission (CR) after induction CT. dominant clinical issue. The high rate of isolated brain Thereby, some general conclusions might be drawn. Sur- metastasis is consistent with the fact that central nervous gical approaches should be limited to well-differentiated systems might harbour microscopic disease at diagnosis, neuroendocrine carcinoma histological subtypes (typical thus calling for the need of eventual PCI. Generally, PCI carcinoids or carcinoid-like tumours), as it is for other has an established role in preventing the disabling symp- body districts. Combined modality treatment consisting toms due to intracranial metastasis and gives a survival of chemotherapy and local radiotherapy should be benefit for patients affected with SCLC gaining intra- strongly considered for moderately and poorly differen- thoracic CR after combination therapy [16,17]. The tiated NSNECs. The preferable timing of the CT-RT aforementioned evidence might be translated in the clini- combination is the sequential approach. Even if concur- cal setting of NSNECs, considering the high risk of brain rent chemo-radiation has reached satisfactory evidence spread, suggesting the option of PCI for patients achiev- over sequential chemo-radiation in SCLC, induction CT ing CR after induction CT. Hence, the radiation strategy and subsequent consolidation RT for complete or very for this subset of patients might consist in large treat- good partial responders might be considered an efficient ment volumes irradiated at first with a combination of Franco et al. Radiation Oncology 2012, 7:21 Page 6 of 9 http://www.ro-journal.com/content/7/1/21 Figure 4 Planning results in terms of isodoses distribution with organs at risk sparing, namely hippocampus (Figure 4a-d), spinal cord (Figure 4a), parotid glands (Figure 4b), ocular bulbs and lens (Figure 4c). PCI (dose range of 25-30 Gy delivered with conventional radiotherapy in terms of cognitive deterioration and cere- fractionation to reduce late effects) and consolidation RT bellar dysfunction [20]. Moreover and early component to the head and neck region (primary site of tumour and of neurocognitive decline, involving verbal and short- term memory recall, has also been described with 1-4 corresponding draining lymphnodes) and a subsequent prosecution to head and neck only up to 60-70 Gy months from WBRT for brain metastasis, regardless of according to the appropriate clinical context. This response to treatment (diversely than executive and fine approach supposedly avoids concerns regarding field motor functions) [8]. Since the hippocampus has a cru- junctions and isodose overlapping. Helical tomotherapy cial role in supporting memory function, its sparing pos- is particularly well-suited for this type of treatment since sibly allows for a minimization of radiation-induced it is constituted by a continuously rotating, helical fan cognitive late effects, with possibly no detrimental effects beam carved by a binary multileaf collimator mounted on local control given the fact that the vast majority of on a ring gantry that rotates around the treatment couch brain metastasis arise beyond > 5 mm from the hippo- as it slowly progress within the gantry bore, through the campal region [21]. The hypothesis of a possible neuro- beam delivery plane: therefore the length of the target cognitive benefit of hippocampal avoidance in presently volume does not represents a limiting factor since the being tested by the RTOG within a Phase II prospective equipment is able to proceed spirally around the patient trial (namely RTOG 0933) which evaluates the effects on for distances up to 160 cm [18,19]. PCI, as other typolo- onset, frequency and severity of neurocognitive disorders gies of cranial irradiation, might cause some grade of in patients undergoing whole brain radiotherapy with neurocognitive toxicity: late toxicity is described in long- concomitant hippocampus sparing for intracranial metas- term brain metastasis survivors submitted to whole brain tasis [8]. Given all the aforementioned background we Franco et al. Radiation Oncology 2012, 7:21 Page 7 of 9 http://www.ro-journal.com/content/7/1/21 Figure 5 Dose-volume histogram for target volumes and main intracranial organs at risk. Table 1 Dosimetric parameters overview OARs Dosimetric constraints Dosimetric results R hippocampus D < 6 Gy V < 20% D 9,9 Gy D 6,5 Gy max 3Gy max mean Median dose 6,3 Gy L hippocampus D < 6 Gy V < 20% D 10,0 Gy D 6,5 Gy max 3Gy max mean Median dose 6,2 Gy R HAV D <25GyV < 20% D 22,4 Gy V 2,00% max 20 Gy max 20 Gy L HAV D <25GyV < 20% D 23,5 Gy V 3,00% max 20 Gy max 20 Gy R lens D < 6 Gy D 4,8 Gy max max L lens D < 6 Gy D 4,7 Gy max max R ocular bulb D <54GyD <35Gy D 17,8 Gy D 6,8 Gy max mean max mean L ocular bulb D <54GyD <35Gy D 15,6 Gy D 6,3 Gy max mean max mean R optic nerve D <54Gy D 25,9 Gy max max L optic nerve D <54Gy D 25,6 Gy max max Optic chiasm D <54Gy D 28,3 Gy max max Spinal cord D <45Gy D 28,6 Gy max max Brainstem D <54Gy D 39,4 Gy max max Oral cavity D <45Gy D 40,7 Gy mean mean R cochlea D <35Gy D 38,1 Gy mean mean L cochlea D <35Gy D 35,1 Gy mean mean Pituitary gland D <40GyD <35Gy D 29,9 Gy D 28,1 Gy max mean max mean Glottic larynx D <50GyV < 45% D 58,7 Gy V 47,00% mean 60 Gy mean 60 Gy Franco et al. Radiation Oncology 2012, 7:21 Page 8 of 9 http://www.ro-journal.com/content/7/1/21 Table 1 Dosimetric parameters overview (Continued) Mandible D <70GyD <60Gy D 60,5 Gy D 45,6 Gy max mean max mean R parotid D <26GyV < 50% D 28,0 Gy V 35,50% mean 30 Gy mean 30 Gy L parotid D <26GyV < 50% D 25,9 Gy V 28,50% mean 30 Gy mean 30 Gy R brachial plexus D <55Gy D 50,6 Gy max max L brachial plexus D <55Gy D 49,5 Gy max max R lung V < 33% V 1,00% 45 Gy 45 Gy L lung V < 33% V 1,50% 45 Gy 45 Gy Thyroid V < 50% V 67,00% 30 Gy 30 Gy R TMJ D <70GyD <60Gy D 45,6 Gy D 27,0 Gy max mean max mean L TMJ D <70GyD <60Gy D 44,0 Gy D 28,2 Gy max mean max mean OARs organs at risk; R right; L left; TMJ temporo-mandibular joint Viale Ginevra n° 3, 11100 Aosta, Italy. ENT Department, Ospedale Regionale chose to treat our patient (who achieved CR after induc- ‘U.Parini’, AUSL Valle d’Aosta, Viale Ginevra n° 3, 11100 Aosta, Italy. tion CT) with consolidation radiation to the head and Radiotherapy Department, ASL TO4, Ospedale Civile di Ivrea, Ivrea, Italy. neck region and simultaneous PCI with the HA techni- Medical Physics Department, ASL TO4, Ospedale Civile di Ivrea, Ivrea, Italy. Department of Medical and Surgical Sciences, Radiation Oncology Unit, que. The first 14 fraction were delivered both to the University of Torino, Ospedale San Giovanni Battista, Turin, Italy. whole brain and head and neck region (a total of 25.2 Gy and 28 Gy respectively), while the remaining 16 fractions Authors’ contributions PF, GN, FM, DC, PS, PC, MR LP, GG: provided medical assistance to the (2 Gy daily) were only delivered to the head and neck patients and defined the treatment approach; PC, PC, VCB: contributed in that received up to 60 Gy (2 different plans were gener- the treatment planning; PC: provided pathological specimens; PF, GN, DC, ated). Planning and optimization were absolutely challen- VCB, MP: contributed in the acquisition, analysis, interpretation of data; PF, GN: drafted the manuscript; ST, FO, UR: contributed in the critical revision; ging, since dosimetric constraints to the hippocampus UR: gave final revision and approval. All authors read and approved the final revealed hard to be respected due to the dosimetric con- manuscript. tribute given by the head and neck region receiving 60 Competing interests Gy and located only few centimetres below: thus bilateral The authors declare that they have no competing interests. hippocampus received a maximum dose of 7 Gy (instead of the planned 6 Gy), but the fact might be mitigated by Received: 19 December 2011 Accepted: 15 February 2012 Published: 15 February 2012 the conventional fractionation employed. Even though it has been suggested that MMSE might have low sensitiv- References ity and specificity for testing neurocognitive function in 1. Barker JL, Glisson BS, Garden AS, et al: Management of nonsinonasal patients affected with brain metastasis (conversely being neuroendocrine carcinomas of the head and neck. Cancer 2003, 98:2322-2328. well-suited for dementia evaluation) if compared to other 2. Ibrahim NBN, Briggs JC, Corbyshley CM: Extrapulmonary oat cell examinations such as Hopkins Verbal Learning Test carcinoma. Cancer 1984, 54:1645-1661. (HVLT), we chose this text in order to have a simple, 3. Mills SE: Neuroendocrine tumors of the head and neck: a selected review with emphasis on terminology. Endocr Pathol 1996, 7:329-343. agile and generally reliable metric to assess neurocogni- 4. Likhacheva A, Rosenthal DI, Hanna E, Kupferman M, DeMonte F, El- tion [22,23]. At last the whole combined modality Naggar AK: Sinonasal neuroendocrine carcinoma: impact of approach gave excellent short-term results in terms of differentiation status on response and outcome. Head and Neck Oncology 2011, 3:32. tumor control and treatment-related toxicity. 5. Capelli M, Bertino G, Morbini P, Villa C, Zorzi S, Benazzo M: Neuroendocrine carcinomas of the upper airways: a small case series with Consent histopatological considerations. Tumori 2007, 93:499-503. 6. Brisigotti M, Fabretti G, Lanzanova G, Brugnari ER, Presutti L, Artoni S: Written informed consent was obtained from the patient Atypical carcinoid of the larynx: case report. Tumori 1987, 73:417-421. for publication of this case report and any accompany- 7. Procopio G, Ricotta R, Fusi A, et al: Neuroendocrine tumors of the larynx: ing images. A copy of the written consent is available a clinical report and literature review. Tumori 2006, 92:72-75. 8. Gondi V, Tomé W, Metha MP: Why avoid the hippocampus? A Review. for review by the Editor-in-Chief of this journal. Radiother Oncol 2010, 97:370-376. 9. Robbins KT: Integrating radiological criteria into the classification of cervical lymph node disease. Arch Otolaryngol Head Neck Surg 1999, Author details 125:385-387. Radiation Oncology Department, Tomotherapy Unit, Ospedale Regionale ‘U. 10. Gondi V, Tolakanahalli R, Mehta MP, et al: Hippocampal-sparing whole- Parini’, AUSL Valle d’Aosta, Viale Ginevra n° 3, 11100 Aosta, Italy. Medical brain radiotherapy: a ‘How-to’ technique using helical tomotherapy and Oncology Department, Ospedale Regionale ‘U.Parini’, AUSL Valle d’Aosta, linear-accellerator-based intensity-modulated radiotherapy. Int J Radiat Viale Ginevra n° 3, 11100 Aosta, Italy. Medical Physics Department, Ospedale Oncol Bio Phys 2010, 78:1244-1252. Regionale ‘U.Parini’, AUSL Valle d’Aosta, Viale Ginevra n° 3, 11100 Aosta, Italy. 11. Rancati T, Schwarz M, Allen AM, et al: Radiation dose-volume effects in Pathology Department, Ospedale Regionale ‘U.Parini’, AUSL Valle d’Aosta, the larynx and pharynx. Int J Radiat Oncol Biol Phys 2010, 76:S64-S69. Franco et al. Radiation Oncology 2012, 7:21 Page 9 of 9 http://www.ro-journal.com/content/7/1/21 12. Deasey JO, Moiseenko V, Marks L, Chao C, Nam J, Eisbruch A: Radiotherapy dose-volume effects on salivary gland function. Int J Radiat Oncol Biol Phys 2010, 76:S58-S63. 13. Bhandare N, Jackson A, Eisbruch A, et al: Radiation therapy and hearing loss. Int J Radiat Oncol Biol Phys 2010, 76:S50-S57. 14. Mayo C, Martel MK, Marks LB, Flickinger J, Nam J, Kirkpatrick J: Radiation dose-volume effects of optic nerves and chiasm. Int J Radiat Oncol Biol Phys 2010, 76:S28-S35. 15. Corvo’ R: Evidence-based radiation oncology in head and neck squamous cell carcinoma. Radiother Oncol 2007, 85:156-170. 16. Boushey RP, Dackwick AP: Carcinoid tumors. Curr Treat Options Oncol 2002, 3:319-326. 17. Jassem J: The role of radiotherapy in lung cancer: where is the evidence? Radiother Oncol 2007, 83:203-213. 18. Mackie TR, Balog J, Ruchala K, et al: Tomotherapy. Semin Radiat Oncol 1999, 9:108-117. 19. Mackie TR, Holmes T, Swerdloff S, et al: Tomotherapy: a new concept for the delivery of dynamic conformal radiotherapy. Med Phys 1993, 20:1709-1719. 20. Meyers CA, Brown PD: Role and relevance of neurocognitive assessment in clinical trials of patients with CNS tumours. J Clin Oncol 2006, 24:1305-1309. 21. Gondi V, Tome WA, Marsh J, et al: Estimated risk of perihippocampal disease progression after hippocampal avoidance during whole-brain radiotherapy: safety profile for RTOG 0933. Radiother Oncol 2010, 95:327-331. 22. Meyers CA, Wefel JS: The use of the mini-mental status examnation to assess cognitive function in cancer trials: no ifs, ands, buts or sensitivity. J Clin Oncol 2003, 21:3557-3558. 23. Scoccianti S, Ricardi U: Treatment of brain metastasis: review of phase III randomized trials. Radiother Oncol , http://dx.doi.org/10.1016/j. bbr.2011.03.031. doi:10.1186/1748-717X-7-21 Cite this article as: Franco et al.: Head and neck region consolidation radiotherapy and prophylactic cranial irradiation with hippocampal avoidance delivered with helical tomotherapy after induction chemotherapy for non-sinonasal neuroendocrine carcinoma of the upper airways. Radiation Oncology 2012 7:21. 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Head and neck region consolidation radiotherapy and prophylactic cranial irradiation with hippocampal avoidance delivered with helical tomotherapy after induction chemotherapy for non-sinonasal neuroendocrine carcinoma of the upper airways

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Copyright © 2012 by Franco et al; BioMed Central Ltd.
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Medicine & Public Health; Oncology; Radiotherapy
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Abstract

Background: Non-sinonasal neuroendocrine carcinomas (NSNECs) of the head and neck are considered an unfrequent clinico-pathological entity. Combined modality treatment represents an established therapeutic option for undifferentiated forms where distant metastasis is a common pattern of failure. Methods: We report on a case of NSNEC treated with sequential chemo-radiation consisting of 6 cycles of cisplatin and etoposide followed by loco-regional radiation to the head and neck and simultaneous prophylactic cranial irradiation to prevent from intracranial spread, delivered with helical tomotherapy with the ‘hippocampal avoidance’ technique in order to reduce neuro-cognitive late effects. Results: One year after the end of the whole combined modality approach, the patient achieved complete remission, with no treatment-related sub-acute and late effects. Conclusions: The present report highlights the importance of multidisciplinary management for NSNECs of the head and neck, as the possibility to achieve substantial cure rates with mild side effects with modern radiotherapy techniques. Keywords: Radiotherapy, Tomotherapy, Non-sinonasal neuroendocrine carcinoma, Head and neck, Hippocampus avoidance, Prophylactic cranial irradiation Introduction glands [2,3]. Some Authors have proposed a frame distinc- Tumours of neuroendocrine differentiation arising within tion between sinonasal neuroendocrine carcinomas the head and neck region are considered an extremely rare (SNNECs) and non-sinonasal neuroendocrine carcinomas (NSNECs) in terms of pathological classification and ther- clinico-pathological entity [1]. They have been described in several anatomical sites such as upper airways (trachea, apeutic options [1,4]. SNNEC are divided into 4 main his- larynx, nose, paranasal sinuses), ear, tongue and salivary tological categories, namely esthesioneuroblastoma, undifferentiated carcinoma, neuroendocrine carcinoma and small cell undifferentiated carcinoma and might * Correspondence: pfranco@ausl.vda.it deserve a multimodality treatment approach regardless of Radiation Oncology Department, Tomotherapy Unit, Ospedale Regionale ‘U. their differentiation [1,4]. Conversely, NSNECs are Parini’, AUSL Valle d’Aosta, Viale Ginevra n° 3, 11100 Aosta, Italy Full list of author information is available at the end of the article © 2012 Franco et al; BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Franco et al. Radiation Oncology 2012, 7:21 Page 2 of 9 http://www.ro-journal.com/content/7/1/21 represented by undifferentiated (small cell or large cell likely primary tumour sites (nasopharynx, tongue base, subtypes), moderately (atypical carcinoid) and well-differ- tonsils, piriform sinus) with negative findings. Adjunctively entiated (typical carcinoid) carcinomas [1,5]. They mainly a lingual tonsillectomy was performed with the evidence of arise within the larynx (where they represent 0.6-1% of all hyperplastic lingual tonsillitis. At the end of diagnostic epithelial cancers), particularly in the epiglottis and supra- work-up: small cell undifferentiated NSNEC of unknown glottic region (aryepiglottic folds and arytenoids) [6]. They primary site (AJCC-UICC stage cTxN2bM0) was pointed predominantly affect males, smokers and present with out. Multimodality therapeutic approach was chosen con- locally advanced node positive disease [1,7]. Conservative sisting of induction CT followed by consolidation radia- surgery (where possible) might be considered adequate for tion; 6 cycles of the PE regimen were planned (Cisplatin 2 2 well-differentiated subtypes, while combined modality 75 mg/m day1 and Etoposide 100 mg/m days 1,2,3 every treatment (chemotherapy and radiotherapy) is considered 21 days). Intermediate CT and PET restaging was per- a mainstay option for undifferentiated forms where distant formed after 3 PE cycles, with the evidence of the persis- metastasis represent the major pattern of failure [1]. We tent thickening and uptake within the tongue base. The herein report on a case of NSNEC of unknown primary patient underwent a new biopsy of the nasopharynx and site treated with a sequential chemo-radiation approach base of the tongue with no tumour observed. The che- consisting of 6 cycles of cisplatin (DDP) and etoposide motherapy program was completed with mild acute toxi- (VP-16) followed by loco-regional radiation to the head city (grade 2 alopecia ad grade 1 asthenia according to and neck region and simultaneous prophylactic cranial CTCAE v 4.0). A re-evaluation with functional and ana- irradiation (PCI) to prevent from intracranial spread, deliv- tomic imaging (CT-PET scan) was carried out at the end ered with helical tomotherapy (HT) with the ‘hippocampal of the CT program: complete remission (CR) was avoidance’ (HA) technique in order to reduce radiation- achieved. Thirty days after, the patients was planned to induced neuro-cognitive late effects [8]. receive consolidation head and neck region radiation and PCI delivered with the TomoTherapy Hi-Art II system Case report (TomoTherapy Inc,. Madison, WI) with the HA technique, A 53 years old caucasian man was referred to our Institu- as reported by Gondi et al. [10]. In order to evaluate basal tion Hospital due to the sudden appearance of a right neuro-cognitive functions, Mini Mental State Examination latero-cervical enlarged lymphnode with no symptoms (MMSE) test was performed before radiation leading to a complained. He had a previous medical history of child- 30 out of 30 score. After proper immobilization (flat head- hood tonsillectomy, appendectomy, acute bacterial epidi- board and head-shoulders thermoplastic mask) and 2.5 dymitis and asymptomatic hepatitis A infection. He was a mm slice thickness planning CT, target volumes and organs at risk contours were created within the Philips non-smoker and had a low-moderate alcohol intake at meals. Physical examination of the neck region showed a Pinnacle P3 v9.1 treatment planning system (Philips Medi- 3-cm hard and fixed adenopathy close to the posterior cal System, Eindhoven, The Netherlands). The head and belly of the right digastric muscle. He underwent, at first, neck region volumes comprised the whole pharingo-laryn- a pharyngo-laryngoscopy procedure that revealed a macro- geal axis (from the roof of the naso-pharynx to the infra- scopic tongue tonsil hypertrophy. A total body CT-scan glottic larynx) and the bilateral neck (level Ib to V and demonstrated two enlarged lymphnodes (35 and 12 mm retro-pharyngeal nodes according to Robbins classifica- in diameter) in the right upper neck between the sub- tion)with a 5mmexpansion from CTVtoPTV to mandibular group (level Ib) and the upper anterior jugular account for set up errors [9] (Figure 3a and 3c). The PCI group (level IIA) according to Robbins classification with volume comprehended the whole brain from the vertex to an adjunctive level IIA left node (15 mm in diameter) [9]; the occipital foramen (with the same 5 mm CTV to PTV thickening of the base of the tongue could also be expansion) (Figure 3a and 3c). For a correct delineation of observed (Figure 1). He underwent an excisional biopsy of the hippocampal regions, the patient underwent three- the right neck and a punch biopsy of the base of the ton- dimensional spoiled gradient axial magnetic resonance gue; histological findings of the lymphnode specimen imaging (MRI) scans (3D-SPGR), standard axial and fluid documented undifferentiated small cell carcinoma (typical attenuation recovery (FLAIR) scans and T2-weighted oat cells pattern; positive staining for AE1 and AE3 Cyto- acquisitions, as suggested by Gondi et al. [10]. Semi-auto- keratin, Chromogranin A and CD 56) with a Ki67 labelling matic rigid registration was performed between planning index of 80%; base of the tongue was negative for tumour CT scans and MRI scans. The hippocampus was con- cells (Figure 2). For staging purposes a F-deoxyglucose- toured on T1-weighted MRI axial sequences (T1-hypoin- CT-positron emission tomography (CT-PET scan) was tense signal medial to the temporal horn) from the most performed showing focal uptake within the oropharynx caudal extent of the temporal horn to the lateral edges of the quadrageminals cisterns along the anterior-posterior and left neck (Figure 1). Using flexible fiber-optic endo- axis (see Gondi et al. for details, [10]) (Figure 3b and 3d). scopy he underwent directed bilateral biopses of the most Franco et al. Radiation Oncology 2012, 7:21 Page 3 of 9 http://www.ro-journal.com/content/7/1/21 Figure 1 Enlarged level Ib (star) and IIA (arrow) right nodes (Figure 1a-b) and level IIA left node (circle; Figure 1a) with thickening of the base of the tongue (blast; Figure 1a) at diagnostic CT scan; base of the tongue hyperaccumulation at 18-FDG- PET scan (Figure 1c-d). A volumetrically isotropic 5 mm expansion was generated on the Oncentra Masterplan v 3.0 software (Nucletron, around the hippocampus to create the ‘hippocampal Veendhal, The Netherlands), since Tomotherapy does not avoidance volumes’ (HAVs) forappropriatedosefalloff allow for visualization of summed plans. Inverse planning algorithm constraints for head and neck regions organs at between hippocampus and whole brain PTV (whole brain volume minus bilateral HAVs). Taking into account his- risks were as suggested by the Quantitative analysis of nor- tology and complete remission status after induction che- mal tissue effects in the clinic (QUANTEC) [11-14]. Dose motherapy, dose prescription was 60 Gy delivered in 30 constraints for the hippocampus (maximum dose 6 Gy fractions (2 Gy daily) for the head and neck region and and V ≤ 20%) and HAVs (maximum dose 25.2 Gy and 25.2 Gy in 14 fractions (1.8 Gy daily) for the whole brain V ≤ 20%) were adapted from Gondi et al. [10]. Metrics PTV minus HAVs. The prescription dose was defined to employed for tomotherapy planning were field width (FW) the mean PTV and the 95% percentage PTV volume 2.5 cm, pitch 0.287, modulation factor (MF) planned 3.0 should be covered at least by 95% of the prescribed dose. (actual 2.105) for the head and neck region and FW 1 cm, In order to minimize late effects, conventional fractiona- pitch 0.215, MF planned 3.2 (actual 2.7799) for whole tion was employed for the 2 locations. Hence, the substan- brain radiation. Directional blocking was used only for tial difference in the number of fractions (30 vs 14) did lenses. The so obtained dose distribution is shown in Fig- not allow for the use simultaneous integrated boost (SIB) ures 4, 5. Dosimetric parameters are shown in Table 1. that would have lead to hypofractionation for the head Radiation treatment was well tolerated with mild acute and neck region. Therefore 2 different plans were gener- toxicity (grade 1 oral mucositis, skin reaction and xerosto- ated. Isodose visualization was made importing both plans mia according to RTOG toxicity scale). No treatment Franco et al. Radiation Oncology 2012, 7:21 Page 4 of 9 http://www.ro-journal.com/content/7/1/21 Figure 2 Oat cells pattern at hematoxylin-eosin staining (Figure 2a); immunohistochemistry positive staining for AE1 and AE3 Cytokeratin (Figure 2b), Chromogranin A (Figure 2c) and CD 56 (Figure 2d). interruptions occurred. Post-treatment re-evaluation advanced disease at diagnosis) [1]. The cohort underwent showed complete remission at morphological and func- different treatment strategies including surgery, radiation tional imaging with one year follow up. Grade 1 LENT- and chemotherapy (in different combinations). With a SOMA xerostomia could be detected as the only radia- median follow up of 40 months, 2-year and 5-year overall tion-induced sequelae. Finally, MMSE results were survival (OS) rates were 53% and 33%, respectively, while unchanged compared to baseline. corresponding disease free survival (DFS) were 41% and 25%. Interestingly, since NSNEC is highly responsive to Discussion CT, the Authors reported that the inclusion of a DDP NSNECs of the head and neck region are widely uncom- and VP-16 chemotherapeutic regimen in the multimodal- mon and therefore clinical and therapeutic informations ity treatment approach approximately doubled the 2 year are scanty. In addition, the issue is beclouded by the slen- OS and DFS. The most common pattern of failure is dis- derness of the published literature (mainly available tant metastasis (DM) with a 2-year and 5-year rate of throughout anecdotal reports) and by the heterogeneity 54% and 71% respectively. The addition of CT in the of the histological sub-types and anatomical sites of pre- therapeutic strategy reduced by one-half (79% vs 39%; p sentation of the medical cases described. However some = 0.006) the 2-year rate of DM if compared to local ther- informative studies are available. To our knowledge, the apy alone (either in univariate and multivariate analysis) largest case series of NSNECs published is the one by the [1]. Among DMs, intracranial spread often occurs with a MD Anderson Cancer Center: 23 patients were treated 2-year and 5-year rate of 25% and 44% respectively. between 1984 and 2001 (median age 64 years; mainly Moreover, isolated brain metastasis are quite frequent smokers; predominant laryngeal primary tumours; locally (21% and 41% of 2-year and 5-year rates). Local failure Franco et al. Radiation Oncology 2012, 7:21 Page 5 of 9 http://www.ro-journal.com/content/7/1/21 Figure 3 Target volumes including the head and neck region and the whole brain with concomitant sparing of the bilateral hippocampal regions (Figure 3a-c); fusion MRI employed for appropriate delineation of the hippocampus (Figure 3b-d). (LF) is infrequent (2-year and 5 year rate of 23%), specifi- and less toxic approach for NSNECs, since concomitant cally almost half of the frequency of comparably staged CT-RT has not proven to improve early complete squamous cell carcinoma of the head and neck region response rate, local control or survival [1]. However if macroscopic residual disease is present after induction [15].Radiation therapydose(range44-72 Gy)did not correlate with LF (p = 0.23). CT did not prevent from LF CT, thereafter concurrent CT-RT or salvage surgery (p = 0.91); however half of the patients with LF did not should be considered, since local control become the pre- achieve complete remission (CR) after induction CT. dominant clinical issue. The high rate of isolated brain Thereby, some general conclusions might be drawn. Sur- metastasis is consistent with the fact that central nervous gical approaches should be limited to well-differentiated systems might harbour microscopic disease at diagnosis, neuroendocrine carcinoma histological subtypes (typical thus calling for the need of eventual PCI. Generally, PCI carcinoids or carcinoid-like tumours), as it is for other has an established role in preventing the disabling symp- body districts. Combined modality treatment consisting toms due to intracranial metastasis and gives a survival of chemotherapy and local radiotherapy should be benefit for patients affected with SCLC gaining intra- strongly considered for moderately and poorly differen- thoracic CR after combination therapy [16,17]. The tiated NSNECs. The preferable timing of the CT-RT aforementioned evidence might be translated in the clini- combination is the sequential approach. Even if concur- cal setting of NSNECs, considering the high risk of brain rent chemo-radiation has reached satisfactory evidence spread, suggesting the option of PCI for patients achiev- over sequential chemo-radiation in SCLC, induction CT ing CR after induction CT. Hence, the radiation strategy and subsequent consolidation RT for complete or very for this subset of patients might consist in large treat- good partial responders might be considered an efficient ment volumes irradiated at first with a combination of Franco et al. Radiation Oncology 2012, 7:21 Page 6 of 9 http://www.ro-journal.com/content/7/1/21 Figure 4 Planning results in terms of isodoses distribution with organs at risk sparing, namely hippocampus (Figure 4a-d), spinal cord (Figure 4a), parotid glands (Figure 4b), ocular bulbs and lens (Figure 4c). PCI (dose range of 25-30 Gy delivered with conventional radiotherapy in terms of cognitive deterioration and cere- fractionation to reduce late effects) and consolidation RT bellar dysfunction [20]. Moreover and early component to the head and neck region (primary site of tumour and of neurocognitive decline, involving verbal and short- term memory recall, has also been described with 1-4 corresponding draining lymphnodes) and a subsequent prosecution to head and neck only up to 60-70 Gy months from WBRT for brain metastasis, regardless of according to the appropriate clinical context. This response to treatment (diversely than executive and fine approach supposedly avoids concerns regarding field motor functions) [8]. Since the hippocampus has a cru- junctions and isodose overlapping. Helical tomotherapy cial role in supporting memory function, its sparing pos- is particularly well-suited for this type of treatment since sibly allows for a minimization of radiation-induced it is constituted by a continuously rotating, helical fan cognitive late effects, with possibly no detrimental effects beam carved by a binary multileaf collimator mounted on local control given the fact that the vast majority of on a ring gantry that rotates around the treatment couch brain metastasis arise beyond > 5 mm from the hippo- as it slowly progress within the gantry bore, through the campal region [21]. The hypothesis of a possible neuro- beam delivery plane: therefore the length of the target cognitive benefit of hippocampal avoidance in presently volume does not represents a limiting factor since the being tested by the RTOG within a Phase II prospective equipment is able to proceed spirally around the patient trial (namely RTOG 0933) which evaluates the effects on for distances up to 160 cm [18,19]. PCI, as other typolo- onset, frequency and severity of neurocognitive disorders gies of cranial irradiation, might cause some grade of in patients undergoing whole brain radiotherapy with neurocognitive toxicity: late toxicity is described in long- concomitant hippocampus sparing for intracranial metas- term brain metastasis survivors submitted to whole brain tasis [8]. Given all the aforementioned background we Franco et al. Radiation Oncology 2012, 7:21 Page 7 of 9 http://www.ro-journal.com/content/7/1/21 Figure 5 Dose-volume histogram for target volumes and main intracranial organs at risk. Table 1 Dosimetric parameters overview OARs Dosimetric constraints Dosimetric results R hippocampus D < 6 Gy V < 20% D 9,9 Gy D 6,5 Gy max 3Gy max mean Median dose 6,3 Gy L hippocampus D < 6 Gy V < 20% D 10,0 Gy D 6,5 Gy max 3Gy max mean Median dose 6,2 Gy R HAV D <25GyV < 20% D 22,4 Gy V 2,00% max 20 Gy max 20 Gy L HAV D <25GyV < 20% D 23,5 Gy V 3,00% max 20 Gy max 20 Gy R lens D < 6 Gy D 4,8 Gy max max L lens D < 6 Gy D 4,7 Gy max max R ocular bulb D <54GyD <35Gy D 17,8 Gy D 6,8 Gy max mean max mean L ocular bulb D <54GyD <35Gy D 15,6 Gy D 6,3 Gy max mean max mean R optic nerve D <54Gy D 25,9 Gy max max L optic nerve D <54Gy D 25,6 Gy max max Optic chiasm D <54Gy D 28,3 Gy max max Spinal cord D <45Gy D 28,6 Gy max max Brainstem D <54Gy D 39,4 Gy max max Oral cavity D <45Gy D 40,7 Gy mean mean R cochlea D <35Gy D 38,1 Gy mean mean L cochlea D <35Gy D 35,1 Gy mean mean Pituitary gland D <40GyD <35Gy D 29,9 Gy D 28,1 Gy max mean max mean Glottic larynx D <50GyV < 45% D 58,7 Gy V 47,00% mean 60 Gy mean 60 Gy Franco et al. Radiation Oncology 2012, 7:21 Page 8 of 9 http://www.ro-journal.com/content/7/1/21 Table 1 Dosimetric parameters overview (Continued) Mandible D <70GyD <60Gy D 60,5 Gy D 45,6 Gy max mean max mean R parotid D <26GyV < 50% D 28,0 Gy V 35,50% mean 30 Gy mean 30 Gy L parotid D <26GyV < 50% D 25,9 Gy V 28,50% mean 30 Gy mean 30 Gy R brachial plexus D <55Gy D 50,6 Gy max max L brachial plexus D <55Gy D 49,5 Gy max max R lung V < 33% V 1,00% 45 Gy 45 Gy L lung V < 33% V 1,50% 45 Gy 45 Gy Thyroid V < 50% V 67,00% 30 Gy 30 Gy R TMJ D <70GyD <60Gy D 45,6 Gy D 27,0 Gy max mean max mean L TMJ D <70GyD <60Gy D 44,0 Gy D 28,2 Gy max mean max mean OARs organs at risk; R right; L left; TMJ temporo-mandibular joint Viale Ginevra n° 3, 11100 Aosta, Italy. ENT Department, Ospedale Regionale chose to treat our patient (who achieved CR after induc- ‘U.Parini’, AUSL Valle d’Aosta, Viale Ginevra n° 3, 11100 Aosta, Italy. tion CT) with consolidation radiation to the head and Radiotherapy Department, ASL TO4, Ospedale Civile di Ivrea, Ivrea, Italy. neck region and simultaneous PCI with the HA techni- Medical Physics Department, ASL TO4, Ospedale Civile di Ivrea, Ivrea, Italy. Department of Medical and Surgical Sciences, Radiation Oncology Unit, que. The first 14 fraction were delivered both to the University of Torino, Ospedale San Giovanni Battista, Turin, Italy. whole brain and head and neck region (a total of 25.2 Gy and 28 Gy respectively), while the remaining 16 fractions Authors’ contributions PF, GN, FM, DC, PS, PC, MR LP, GG: provided medical assistance to the (2 Gy daily) were only delivered to the head and neck patients and defined the treatment approach; PC, PC, VCB: contributed in that received up to 60 Gy (2 different plans were gener- the treatment planning; PC: provided pathological specimens; PF, GN, DC, ated). Planning and optimization were absolutely challen- VCB, MP: contributed in the acquisition, analysis, interpretation of data; PF, GN: drafted the manuscript; ST, FO, UR: contributed in the critical revision; ging, since dosimetric constraints to the hippocampus UR: gave final revision and approval. All authors read and approved the final revealed hard to be respected due to the dosimetric con- manuscript. tribute given by the head and neck region receiving 60 Competing interests Gy and located only few centimetres below: thus bilateral The authors declare that they have no competing interests. hippocampus received a maximum dose of 7 Gy (instead of the planned 6 Gy), but the fact might be mitigated by Received: 19 December 2011 Accepted: 15 February 2012 Published: 15 February 2012 the conventional fractionation employed. Even though it has been suggested that MMSE might have low sensitiv- References ity and specificity for testing neurocognitive function in 1. Barker JL, Glisson BS, Garden AS, et al: Management of nonsinonasal patients affected with brain metastasis (conversely being neuroendocrine carcinomas of the head and neck. Cancer 2003, 98:2322-2328. well-suited for dementia evaluation) if compared to other 2. 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Gondi V, Tome WA, Marsh J, et al: Estimated risk of perihippocampal disease progression after hippocampal avoidance during whole-brain radiotherapy: safety profile for RTOG 0933. Radiother Oncol 2010, 95:327-331. 22. Meyers CA, Wefel JS: The use of the mini-mental status examnation to assess cognitive function in cancer trials: no ifs, ands, buts or sensitivity. J Clin Oncol 2003, 21:3557-3558. 23. Scoccianti S, Ricardi U: Treatment of brain metastasis: review of phase III randomized trials. Radiother Oncol , http://dx.doi.org/10.1016/j. bbr.2011.03.031. doi:10.1186/1748-717X-7-21 Cite this article as: Franco et al.: Head and neck region consolidation radiotherapy and prophylactic cranial irradiation with hippocampal avoidance delivered with helical tomotherapy after induction chemotherapy for non-sinonasal neuroendocrine carcinoma of the upper airways. Radiation Oncology 2012 7:21. 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Radiation OncologySpringer Journals

Published: Feb 15, 2012

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