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<p>Seminars in Oncology 46 (2019) 233–245</p><p>Contents lists available at ScienceDirect</p><p>Seminars in Oncology</p><p>journal homepage: www.elsevier.com/locate/seminoncol</p><p>Modern radiotherapy for head and neck cancer</p><p>Daniela Alterio</p><p>a , Giulia Marvaso</p><p>a , ∗, Annamaria Ferrari a , Stefania Volpe</p><p>b , Roberto Orecchia</p><p>c ,</p><p>Barbara Alicja Jereczek-Fossa</p><p>a , b</p><p>a Division of Radiotherapy, IEO European Institute of Oncology, IRCCS, Milan, Italy</p><p>b Department of Oncology and Hemato-oncology, University of Milan, Milan, Italy</p><p>c European Institute of Oncology, IRCSS, Milan Italy</p><p>a r t i c l e i n f o</p><p>Article history:</p><p>Received 28 May 2019</p><p>Accepted 15 July 2019</p><p>Keywords:</p><p>Head and neck cancer</p><p>Modern radiotherapy</p><p>IMRT</p><p>Proton therapy</p><p>a b s t r a c t</p><p>Radiation therapy (RT) plays a key role in curative-intent treatments for head and neck cancers. Its</p><p>use is indicated as a sole therapy in early stage tumors or in combination with surgery or concurrent</p><p>chemotherapy in advanced stages. Recent technologic advances have resulted in both improved oncologic</p><p>results and expansion of the indications for RT in clinical practice. Despite this, RT administered to the</p><p>head and neck region is still burdened by a high rate of acute and late side effects. Moreover, about 50%</p><p>of patients with high-risk disease experience loco-regional recurrence within 3 years of follow-up. There-</p><p>fore, in recent decades, efforts have been dedicated to optimize the cost/benefit ratio of RT in this subset</p><p>of patients. The aim of the present review was to highlight modern concepts of RT for head and neck</p><p>cancers considering both the technological advances that have been achieved and recent knowledge that</p><p>has informed the biological interaction between radiation and both tumor and healthy tissues.</p><p>© 2019 Elsevier Inc. All rights reserved.</p><p>I</p><p>s</p><p>b</p><p>m</p><p>l</p><p>a</p><p>r</p><p>m</p><p>s</p><p>s</p><p>f</p><p>o</p><p>s</p><p>p</p><p>w</p><p>h</p><p>l</p><p>2</p><p>r</p><p>c</p><p>a</p><p>t</p><p>d</p><p>a</p><p>p</p><p>e</p><p>t</p><p>o</p><p>d</p><p>t</p><p>a</p><p>p</p><p>T</p><p>d</p><p>h</p><p>0</p><p>ntroduction</p><p>Squamous cell carcinoma of the head and the neck (HN) is the</p><p>eventh most common malignancy [1] . The main risk factors, to-</p><p>acco smoking and alcohol consumption, are responsible for the</p><p>ajority of HN tumors occurring in the oral cavity, pharynx, and</p><p>arynx. Human papillomavirus (HPV) is increasingly appreciated as</p><p>risk factor that is both important and frequently found in oropha-</p><p>yngeal cancer.</p><p>Along with surgery, radiation therapy (RT) represents one of the</p><p>ain curative-intent treatment options both in early and advanced</p><p>tages with doses ranging from 54 to 70 Gy, administered with a</p><p>tandard fractionation schedule of 2 Gy/fraction, one fraction/day, 5</p><p>ractions/week [2] . Moreover, in high-risk settings the combination</p><p>f RT with concurrent cisplatin (100 mg/m</p><p>2 every 3 weeks) is the</p><p>tandard nonsurgical approach.</p><p>Despite the multimodality approach, treatment of HN cancer</p><p>atients is still burdened by a not yet satisfactory clinical outcome</p><p>ith approximately 50% local recurrence at 3 years and a relatively</p><p>igh rate of severe RT-related toxicity. In order to increase the</p><p>ocal tumor control without worsening the toxicity profile, the</p><p>∗ Corresponding author: European Institute of Oncology, Via Ripamonti 435,</p><p>0141, Milan, Italy. Tel.: + 390257489037; Fax: + 390294379229.</p><p>E-mail address: giulia.marvaso@ieo.it (G. Marvaso).</p><p>t</p><p>b</p><p>s</p><p>R</p><p>m</p><p>ttps://doi.org/10.1053/j.seminoncol.2019.07.002</p><p>093-7754/© 2019 Elsevier Inc. All rights reserved.</p><p>adiation approach is profoundly changing and moving from the</p><p>oncept that “one size fits all” toward a personalized treatment</p><p>pproach. Indeed, not only have technologically-driven advances in</p><p>he field of photons significantly improved the conformity of dose</p><p>istribution, but the introduction of heavy particle RT (hadronther-</p><p>py) together with greater insight into the interaction between</p><p>hotons and tumor/host immune response have opened up new</p><p>xciting scenarios and fields of ongoing investigation. Moreover,</p><p>he increasing incidence of human papillomavirus (HPV)-related</p><p>ropharyngeal cancers has offered the possibility to test new</p><p>eintensified treatment strategies.</p><p>Thus, RT remains a crucial and cost-effective treatment for pa-</p><p>ients with a diagnosis of HN cancers [3] . The present review</p><p>imed to point out the modern approach of RT in this subset of</p><p>atients highlighting the new fields of interest and searches.</p><p>echnological advances in photon-based RT</p><p>Curative RT for HN tumors requires the administration of high</p><p>oses of radiation to a small area containing or located very close</p><p>o a large number of critical structures including the spinal cord,</p><p>rainstem, brain optic pathways, brachial plexus, salivary glands,</p><p>wallowing-related structures, and larynx. Modern curative-intent</p><p>T uses both 3-dimensional (3D) conformal RT and intensity -</p><p>odulated RT (IMRT). In particular, when compared with 3D</p><p>https://doi.org/10.1053/j.seminoncol.2019.07.002</p><p>http://www.ScienceDirect.com/science/journal/00937754</p><p>http://www.elsevier.com/locate/seminoncol</p><p>http://crossmark.crossref.org/dialog/?doi=10.1053/j.seminoncol.2019.07.002&domain=pdf</p><p>mailto:giulia.marvaso@ieo.it</p><p>https://doi.org/10.1053/j.seminoncol.2019.07.002</p><p>234 D. Alterio, G. Marvaso and A. Ferrari et al. / Seminars in Oncology 46 (2019) 233–245</p><p>c</p><p>f</p><p>t</p><p>r</p><p>i</p><p>o</p><p>(</p><p>I</p><p>g</p><p>o</p><p>c</p><p>a</p><p>t</p><p>l</p><p>I</p><p>n</p><p>o</p><p>w</p><p>[</p><p>i</p><p>t</p><p>i</p><p>l</p><p>t</p><p>t</p><p>R</p><p>q</p><p>h</p><p>t</p><p>d</p><p>T</p><p>t</p><p>I</p><p>a</p><p>±</p><p>M</p><p>o</p><p>r</p><p>m</p><p>e</p><p>w</p><p>i</p><p>r</p><p>m</p><p>h</p><p>t</p><p>c</p><p>R</p><p>t</p><p>r</p><p>i</p><p>d</p><p>S</p><p>[</p><p>w</p><p>d</p><p>c</p><p>a</p><p>p</p><p>t</p><p>n</p><p>r</p><p>r</p><p>m</p><p>E</p><p>r</p><p>u</p><p>m</p><p>o</p><p>d</p><p>a</p><p>r</p><p>v</p><p>m</p><p>t</p><p>m</p><p>p</p><p>3</p><p>–</p><p>c</p><p>b</p><p>t</p><p>b</p><p>i</p><p>h</p><p>S</p><p>s</p><p>t</p><p>t</p><p>a</p><p>i</p><p>a</p><p>g</p><p>6</p><p>(</p><p>w</p><p>t</p><p>c</p><p>o</p><p>d</p><p>o</p><p>a</p><p>t</p><p>a</p><p>2</p><p>s</p><p>s</p><p>T</p><p>t</p><p>t</p><p>c</p><p>3</p><p>o</p><p>a</p><p>s</p><p>a</p><p>onformal RT, the IMRT technique enables the RT doses to con-</p><p>orm the dose more precisely to target volumes, thereby allowing</p><p>he radiation oncologist to reduce unintentional irradiation of sur-</p><p>ounding healthy tissues. The extensive use of curative-intent IMRT</p><p>n clinical practice allows the radiation oncologists to: (1) improve</p><p>ncologic outcomes; (2) reduce the radiation-related toxicity; and</p><p>3) expand indications for RT.</p><p>mprove oncologic outcomes</p><p>For tumors located near critical structures, the deep step</p><p>radient dose of IMRT allows a higher rate of tumor control to be</p><p>btained as compared to 2D and 3D RT techniques, without in-</p><p>reasing the toxicity profile. IMRT has therefore been successfully</p><p>pplied for the treatment of locally advanced nasopharyngeal</p><p>umors as well as sinonasal and base of skull cancers, which are</p><p>ocated in close proximity to central nervous system structures.</p><p>n a meta-analysis of 8 studies, that enrolled 3,570 patients with</p><p>asopharyngeal tumors, Zhang et al demonstrated that both 5-year</p><p>verall survival and local control were better in patients treated</p><p>ith IMRT compared to those treated with 2D or 3D Conformal RT</p><p>4] . These results were confirmed by a more recent meta-analysis</p><p>n which, with the limitation of small sample size and low sta-</p><p>istical power, nasopharyngeal tumors were the only HN subsite</p><p>n which IMRT allowed a better response in overall survival and</p><p>ocoregional control [5] . Therefore, IMRT is the recommended</p><p>echnique for locally advanced nasopharyngeal and sinonasal</p><p>umors [2] .</p><p>educe the radiation-related toxicity</p><p>Xerostomia is the most frequent and disabling long-term se-</p><p>uela of curative RT in the HN region. The introduction of IMRT</p><p>as allowed the absorbed dose to the parotid glands to be reduced,</p><p>ranslating into a clinically significant reduction in both the inci-</p><p>ence and severity of physician- and patient-reported xerostomia.</p><p>he benefit of IMRT was observed in a multicentric randomized</p><p>rial and confirmed in 2 recent meta-analyses [5-7] . The use of</p><p>MRT was associated with a 36% relative risk reduction in grade 2</p><p>cute xerostomia (relative risk = 0.64, 95% conformity index = 0.49</p><p>0.84; P = 0.001) [7] . 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Radi-</p><p>ology 1999;213:489–94. doi: 10.1148/radiology.213.2.r99nv29489 .</p><p>https://doi.org/10.1002/cncr.26084</p><p>http://refhub.elsevier.com/S0093-7754(19)30090-9/sbref0140</p><p>http://refhub.elsevier.com/S0093-7754(19)30090-9/sbref0140</p><p>http://refhub.elsevier.com/S0093-7754(19)30090-9/sbref0140</p><p>http://refhub.elsevier.com/S0093-7754(19)30090-9/sbref0140</p><p>http://refhub.elsevier.com/S0093-7754(19)30090-9/sbref0141</p><p>http://refhub.elsevier.com/S0093-7754(19)30090-9/sbref0141</p><p>http://refhub.elsevier.com/S0093-7754(19)30090-9/sbref0141</p><p>http://refhub.elsevier.com/S0093-7754(19)30090-9/sbref0141</p><p>http://refhub.elsevier.com/S0093-7754(19)30090-9/sbref0141</p><p>http://refhub.elsevier.com/S0093-7754(19)30090-9/sbref0142</p><p>http://refhub.elsevier.com/S0093-7754(19)30090-9/sbref0142</p><p>http://refhub.elsevier.com/S0093-7754(19)30090-9/sbref0142</p><p>http://refhub.elsevier.com/S0093-7754(19)30090-9/sbref0142</p><p>https://doi.org/10.1016/j.ijrobp.2007.04.057</p><p>https://doi.org/10.1186/s13014-016-0630-x</p><p>https://doi.org/10.1016/j.radonc.2014.04.018</p><p>https://doi.org/10.1016/j.ijrobp.2005.07.005</p><p>https://doi.org/10.1016/j.ijrobp.2011.01.004</p><p>https://doi.org/10.1016/j.ijrobp.2004.08.029</p><p>https://doi.org/10.1002/hed.23763</p><p>http://refhub.elsevier.com/S0093-7754(19)30090-9/sbref0150</p><p>http://refhub.elsevier.com/S0093-7754(19)30090-9/sbref0150</p><p>http://refhub.elsevier.com/S0093-7754(19)30090-9/sbref0150</p><p>http://refhub.elsevier.com/S0093-7754(19)30090-9/sbref0150</p><p>http://refhub.elsevier.com/S0093-7754(19)30090-9/sbref0150</p><p>https://doi.org/10.1007/s00066-010-2139-9</p><p>http://refhub.elsevier.com/S0093-7754(19)30090-9/sbref0152</p><p>http://refhub.elsevier.com/S0093-7754(19)30090-9/sbref0152</p><p>http://refhub.elsevier.com/S0093-7754(19)30090-9/sbref0152</p><p>http://refhub.elsevier.com/S0093-7754(19)30090-9/sbref0152</p><p>https://doi.org/10.1148/radiology.213.2.r99nv29489</p><p>Modern radiotherapy for head and neck cancer</p><p>Introduction</p><p>Technological advances in photon-based RT</p><p>Improve oncologic outcomes</p><p>Reduce the radiation-related toxicity</p><p>Expand indications for RT</p><p>Image-guided RT (IGRT) and adaptive RT (ART)</p><p>Deintensified RT in HPV-related oropharyngeal tumors</p><p>Hadrontherapy</p><p>Machine learning techniques and radiomics</p><p>RT and the immune system</p><p>Conclusions</p><p>Declaration of Competing Interest</p><p>Acknowledgments</p><p>References</p><p>was seen at every time point.</p><p>oreover, the better dose conformity of IMRT has also allowed for</p><p>ptimization of the absorbed dose administered to other organs at</p><p>isk, such as dysphagia/aspiration-related structures (ie, constrictor</p><p>uscles, supraglottic, and laryngeal glottis), submandibular glands,</p><p>sophagus, and the mandible. Despite the better dose distribution,</p><p>hether these dosimetric advantages translate into clinical benefit</p><p>s yet to be fully established [8] . This lack of evidence could de-</p><p>ive from nonuniform definitions of the target volumes for treat-</p><p>ent planning or nonoptimized IMRT treatment plans for sparing</p><p>ealthy tissues other than the salivary glands. Recent guidelines for</p><p>he contouring of target volumes, standardization of organs at risk</p><p>ontouring and constraints as well as the use of “high precision</p><p>T” in daily clinical practice will help to better clarify the poten-</p><p>ial clinical advantage of IMRT for late side effects other than xe-</p><p>ostomia [8-13] . Moreover, an ongoing randomized phase III trial</p><p>s comparing IMRT treatment plans, which are optimized to spare</p><p>ysphagia-related structures, against standard IMRT (International</p><p>tandard Randomised Controlled Trial register- ISRCTN25458988)</p><p>14] .</p><p>On the other hand, IMRT is also characterized by a “bath dose”</p><p>here a larger volume of normal tissues receive a low-radiation</p><p>ose. This has produced new toxicities such as anterior oral mu-</p><p>ositis, occipital scalp hair loss, headache, nausea, and vomiting</p><p>nd irradiation of a small part of the brainstem (dorsal vagal com-</p><p>lex) [15] . Moreover, irradiation of the posterior fossa is postulated</p><p>o be one cause of fatigue in patients treated with IMRT [16] .</p><p>In conclusion, IMRT has a clear advantage over 2D/3D tech-</p><p>iques in reducing the incidence and severity of xerostomia. Cur-</p><p>ent studies will elucidate its potential role in reducing other</p><p>adiation-related toxicities. Careful plan optimization should mini-</p><p>ize the “bath dose” to which distant healthy tissues are exposed.</p><p>xpand indications for RT</p><p>The use of curative-intent IMRT in clinical practice has allowed</p><p>adiation oncologists to expand the indications for RT in partic-</p><p>lar in 2 clinical situations: (a) reirradiation for locoregional tu-</p><p>or recurrence; and (b) stereotactic ablative RT in patients with</p><p>ligometastases.</p><p>(a) Reirradiation for locoregional tumor recurrence</p><p>Despite advances in the treatment of HN cancer, locoregional</p><p>isease recurrence still occurs in approximately 50% of patients</p><p>nd represents the most common cause of death. In addition, the</p><p>isk of a secondary primary cancer in the HN region among sur-</p><p>ivors can reach up to 40%. Surgical excision represents the treat-</p><p>ent of choice for recurrent/second primary tumors but many pa-</p><p>ients are ineligible for radical surgery due to tumor extension, co-</p><p>orbidity or patient preference. Reirradiation has therefore been</p><p>roposed as an alternative treatment. However, the use of 2D or</p><p>D techniques resulted in unacceptably high rates of severe toxicity</p><p>with 7%–11% treatment-related deaths in Radiation Therapy On-</p><p>ology Group (RTOG) trials) [17-19] . Due to technological advances</p><p>oth in cancer imaging and RT delivery, there is now renewed in-</p><p>erest in curative-intent HN reirradiation. Indeed, IMRT stereotactic</p><p>ody RT (SBRT) and hadrontherapy have shown slight reductions</p><p>n the toxicity profile. Recently published reviews of the literature</p><p>ave summarized the data on reirradiation performed with IMRT,</p><p>BRT, and hadrontherapy [20-22] . When one considers that most</p><p>tudies enrolled a limited number of patients and were retrospec-</p><p>ive, monocentric analyses, the overall clinical outcome of patients</p><p>reated with reirradiation using modern RT techniques seems to be</p><p>lmost similar or even better compared to the 2D-3D era. Overall,</p><p>ncluding patients treated with surgery and concurrent chemoradi-</p><p>tion, oncologic results in terms of median (range) 2-year locore-</p><p>ional control for IMRT, SBRT and proton therapy were 62% (52%–</p><p>7%), 52% (28%–64%), and 73% (50%–80%), respectively. Median</p><p>range) 2-year overall survival for IMRT, SBRT, and proton therapy</p><p>ere: 49% (32%–59%), 29% (28%–58%), and 50% (33%–70%), respec-</p><p>ively [20] . While valuable, these results cannot be considered con-</p><p>lusive due to the differences among the analyzed studies in terms</p><p>f patient selection, tumor volumes, concurrent treatments, total</p><p>oses, fractionations, and inhomogeneity in the reported data. An</p><p>ngoing randomized phase II trial is currently open to enrollment</p><p>t the MD Anderson Cancer Center, comparing conventionally frac-</p><p>ionated reirradiation using modern conformal RT, including IMRT</p><p>nd proton therapy, versus SBRT delivered in 3 to 5 fractions under</p><p>weeks, for small inoperable HN tumors (NCT03164460).</p><p>Due to the lack of guidelines, when selecting a candidate for a</p><p>econd course of RT, the treating oncologist must take into con-</p><p>ideration patient, tumor and previous treatment characteristics.</p><p>able 1 summarizes the main prognostic and predictive parame-</p><p>ers for clinical outcome and toxicity. Moreover, in order to es-</p><p>imate the expected oncologic outcome (in terms of locoregional</p><p>ontrol and 24-month survival probability) and severe toxicity rate,</p><p>nomograms have been published. These offer useful tools not</p><p>nly to define a patient’s risk but also for pretreatment consent</p><p>nd post-treatment survivorship [24-26] .</p><p>Reirradiation can be offered either as a single modality or after</p><p>alvage surgery (adjuvant RT). In the postoperative setting, reirradi-</p><p>tion can be considered in the presence of high-risk factors such as</p><p>D. Alterio, G. Marvaso and A. Ferrari et al. / Seminars in Oncology 46 (2019) 233–245 235</p><p>Table 1</p><p>Overall prognostic and predictive factors (for both clinical outcome and toxicity) to be considered when selecting patients as candidates for curative intent reirradiation.</p><p>Predictive and prognostic factors Reference</p><p>Factors related to patients</p><p>Performance status (PS) Good PS > than poor PS [24,27,134]</p><p>Age Young patients > old patients (60 yr) [29]</p><p>Gender Men > women [29]</p><p>Comorbidity Few/None > a lot of comorbidities [24]</p><p>Organ dysfunction Absence < presence [18,19,24,26,44,49,134]</p><p>Factors related to the tumors</p><p>Tumor site Nasopharynx and larynx > other subsites</p><p>Other subsites > hypopharynx</p><p>Lateral tumors > tumors on median</p><p>[23,27,30,37,46,135-138]</p><p>Histology Salivary gland > squamous carcinoma [40]</p><p>Tumor stage at recurrence rT1-rT2 > rT3-rT4 [23,24,37,139]</p><p>Volume Small volume > extended [24,28,35,46,4 8,4 9,86,134,135,137]</p><p>Second tumor v recurrent disease Second primary > local recurrence [19,38,140,141]</p><p>Number of local recurrence before reirradiation More than one > first recurrence [40]</p><p>Factors related to the treatment</p><p>Treatment of the primary tumor Surgery plus RT > RT alone</p><p>No chemoradiation > chemoradiation</p><p>[51,140,142,143]</p><p>Total dose of first radiation course Less than 50 Gy > more than 50 Gy [32]</p><p>Combined therapy Systemic treatments > RT alone [27,30,144-147]</p><p>Feasibility of surgery before reirradiation Yes > No [26,40,136,144,146-149]</p><p>Time interval between the two treatment</p><p>courses</p><p>Long (minimum 6 months) interval > shorter interval [19,24,29,37,49,137,140,150]</p><p>Total dose of the reirradiation course High dose ( > 46-50-58 Gy) > Lower dose [17,24,28,29,40,134,147,151-153]</p><p>Reirradiation technique IMRT > no IMRT [37,40,144]</p><p>Reirradiation overall duration Equal or shorter than 14 days > than longer than 14 days [137]</p><p>Reirradiation treatment plan better DVH coverage > worse DVH coverage [154]</p><p>Response to treatment Complete > Partial [144]</p><p>> more favorable factor; DVH = dose volume histogram.</p><p>p</p><p>t</p><p>t</p><p>w</p><p>t</p><p>t</p><p>o</p><p>a</p><p>c</p><p>c</p><p>i</p><p>i</p><p>f</p><p>i</p><p>d</p><p>d</p><p>s</p><p>i</p><p>t</p><p>a</p><p>c</p><p>l</p><p>h</p><p>s</p><p>r</p><p>a</p><p>(</p><p>c</p><p>5</p><p>p</p><p>t</p><p>o</p><p>a</p><p>t</p><p>t</p><p>s</p><p>y</p><p>c</p><p>s</p><p>[</p><p>t</p><p>v</p><p>e</p><p>a</p><p>a</p><p>c</p><p>s</p><p>g</p><p>(</p><p>d</p><p>b</p><p>a</p><p>T</p><p>h</p><p>t</p><p>o</p><p>n</p><p>h</p><p>t</p><p>f</p><p>m</p><p>i</p><p>n</p><p>c</p><p>v</p><p>f</p><p>t</p><p>d</p><p>p</p><p>l</p><p>ositive surgical margins and/or extracapsular extension. Despite</p><p>he better local control and disease-free survival, reirradiation af-</p><p>er surgery did not demonstrate any impact on patient survival and</p><p>as burdened by severe acute toxicity in about 40% of treated pa-</p><p>ients in a randomized trial [26] .</p><p>To date there are no guidelines regarding RT technique or even-</p><p>ual association with systemic treatments. Despite the fact that</p><p>ptimal total dose and fractionation schedules have not been yet</p><p>ssessed, data from the published literature support an emerging</p><p>onsensus that higher definitive doses can lead to improved tumor</p><p>ontrol that may possibly translate into a survival benefit. Regard-</p><p>ng standard fractionation schedules, a dose of > 60 Gy seems to</p><p>mprove clinical outcome while for SBRT a dose of least 40 Gy (in 5</p><p>ractions) seems to lead to improved local control [27-30] . In clin-</p><p>cal practice, the most common SBRT schedule ranged from a total</p><p>ose of 30–50 Gy administered in 5–6 total fractions on alternate</p><p>ays [31] . Concerning target volumes, irradiation limited to macro-</p><p>copic disease (avoiding prophylactic irradiation of high-risk areas)</p><p>s recommended [29,32] .</p><p>The benefit of concurrent systemic treatments is still a mat-</p><p>er of controversy given that along with a radiosensitizing effect,</p><p>higher rate of late effects has been observed [20] . Induction</p><p>hemotherapy, followed by surgery and/or radiotherapy was uti-</p><p>ized in patients with advanced squamous cell carcinoma of the</p><p>ead and neck. During these trials, the authors observed that re-</p><p>ponse to chemotherapy predicts further response to subsequent</p><p>adiotherapy. This study was comprised of 57 patients with 60 sep-</p><p>rate neoplasms who demonstrated less than a complete response</p><p>partial or no response) to initial treatment with a combination</p><p>hemotherapy containing cisplatin. Subsequent radiotherapy, either</p><p>0 0 0 rad preoperatively or 6600 rad as definitive therapy, was em-</p><p>loyed. Forty-one of the 42 tumors with initial partial response</p><p>o chemotherapy also responded to radiotherapy (97.6%). Only one</p><p>f the 18 tumors that initially failed to respond to chemother-</p><p>py subsequently responded to radiotherapy (5.5%). This observa-</p><p>ion suggests that patients with head and neck cancer sensitive</p><p>o initial chemotherapy share parameters that also confer sen-</p><p>itivity to radiation [33] . Different systemic agents (ie, hydrox-</p><p>urea, 5-fluorouracil, platinum agents, taxanes, biologic drugs like</p><p>etuximab and immunotherapy) have been associated with both</p><p>tandard fractionation schedule IMRT and hypofractionated SBRT</p><p>17-19,27,29,34-43] .</p><p>Although modern RT techniques have significantly reduced</p><p>reatment-related side effects, reirradiation is still burdened by se-</p><p>ere toxicities including osteoradionecrosis, the need for prolonged</p><p>nteral nutrition, soft tissue necrosis or fibrosis, vascular stenosis</p><p>nd thromboembolic events, and neurologic damage. Indeed,</p><p>lthough with apparently lower rates than those observed with</p><p>onventional techniques, late toxicity remains relevant in reported</p><p>tudies for IMRT, SBRT, and proton therapy with median (range)</p><p>rade ≥3 toxicity rates of 39% (16%–56%), 7% (0%–32%), and 22%</p><p>20%–25%), respectively [20] . The median rate of treatment-related</p><p>eath was 5% (1%–15%) [20] . Among reported side effects, carotid</p><p>lowout syndrome remains the most feared side effect because,</p><p>lthough rare (1%–8%), it is a fatal event in most patients [20] .</p><p>he main factors associated with an increased risk of carotid</p><p>emorrhage are: angle of carotid tumor invasion > 180 °, tumor</p><p>hat invades more than 1/3 of the carotid artery, presence of skin</p><p>r mucosal ulceration, large tumor volume, irradiation of lymph</p><p>ode areas, bifractionated schedule using 1.5 Gy/fr or accelerated</p><p>yperfractionated schedules, daily administration (instead of al-</p><p>ernate day schedule), and the tumor being located within the</p><p>oramen lacerum [44-47] . An example of reirradiation aiming to</p><p>inimize the dose to the carotid artery is showed in Fig. 1 .</p><p>In conclusion, reirradiation of HN recurrent tumor is today be-</p><p>ng increasingly used in clinical practice for patients with recurrent</p><p>on operable tumors. Different authors have tried to summarize</p><p>urrent knowledge on reirradiation of HN cancer in order to pro-</p><p>ide suggestions on when and how to propose an such approach</p><p>or recurrent/second primary tumors [44,48-51] . Overall, reirradia-</p><p>ion for HN cancers using high-precision RT techniques can nowa-</p><p>ays be considered an alternative approach within a multidisci-</p><p>linary context of experienced and appropriately equipped onco-</p><p>ogic centers for patients not eligible for radical salvage surgery.</p><p>236 D. Alterio, G. Marvaso and A. Ferrari et al. / Seminars in Oncology 46 (2019) 233–245</p><p>Fig. 1. Example of a 51-year-old male patient with a diagnosis of a solitary lymph node recurrence in the parapharyngeal space occurring 2 years after curative chemoradi-</p><p>ation for nasopharyngeal cancer. Reirradiation was performed using a Cyberknife technique aiming to optimize the reduction of unnecessary irradiation to the carotid artery.</p><p>Prescription dose was 50 Gy (25 fractions, consecutive days) prescribed at 80% isodose. The figure shows different isodose levels (% of the isodose level prescription): orange</p><p>line = 80%, white line = 75%, yellow line = 65%, pink line = 54%, light blue line = 32%. The treatment achieved complete tumor regression that has been maintained with the</p><p>last follow-up 3 years after reirradiation was administered. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of</p><p>this article.)</p><p>i</p><p>i</p><p>t</p><p>[</p><p>a</p><p>e</p><p>t</p><p>i</p><p>h</p><p>d</p><p>w</p><p>a</p><p>l</p><p>t</p><p>s</p><p>l</p><p>f</p><p>a</p><p>m</p><p>h</p><p>t</p><p>n</p><p>t</p><p>l</p><p>t</p><p>a</p><p>t</p><p>f</p><p>d</p><p>s</p><p>t</p><p>f</p><p>t</p><p>o</p><p>[</p><p>i</p><p>t</p><p>c</p><p>(b) Stereotactic ablative RT in patients with oligometastases</p><p>Patients with oligometastases are defined as those with a lim-</p><p>ted number of distant metastases (generally less than 5) aris-</p><p>ng/occurring over a prolonged period, with a controlled primary</p><p>umor and disease amenable to potential curable local treatment</p><p>52] . These patients who have potentially long survivals represent</p><p>new scenario in the setting of HN cancers. Local treatments (gen-</p><p>rally surgery) have been proposed instead of systemic therapy due</p><p>o the patients’ long life expectancy with the potential benefit of</p><p>mproving the patient’s survival or, at least, to allow for a “drug</p><p>oliday” period before starting first line chemotherapy. In recent</p><p>ecades, together with surgery, high-precision RT has been used</p><p>ith increasing frequency in clinical practice. The radiation ther-</p><p>py approach is becoming feasible thanks to the recent techno-</p><p>ogical advances in RT techniques. In particular, SBRT permitted</p><p>he irradiation of small lesions (generally < 6 cm) yielding very</p><p>teep dose gradients. The term “ablative” means that SBRT is de-</p><p>ivered at tumoricidal doses, higher doses than those usually used</p><p>or palliative intent. Ablative SBRT is therefore now considered as</p><p>treatment option for both bone and visceral (ie, lung and liver)</p><p>etastases. Its use for different tumor histologies and body sites</p><p>as shown an overall efficacy exceeding 85% [53-57] . The advan-</p><p>ages of SBRT over surgery include the noninvasive approach, no</p><p>eed for general anesthesia and ambulatory treatment. Moreover,</p><p>hanks to the high conformity of the RT dose, SBRT has a very</p><p>ow acute and late toxicity profile. In addition, by using hypofrac-</p><p>ionated schedules, logistic discomfort has also been limited with</p><p>n increase in patient compliance. The generally used fractiona-</p><p>ion is 1–5 fractions with dose fraction > 2.5 Gy/fraction or, more</p><p>requently, > 5–8 Gy/fraction up to 20 Gy/fraction. With the intro-</p><p>uction of immunotherapy also in the HN cancer setting, different</p><p>tudies have demonstrated</p><p>that hypofractionation schedules seem</p><p>o have a higher immunogenic effect compared to the standard</p><p>raction schedules [58] . Consequently, regimens combining abla-</p><p>ive SBRT and immunotherapy in the patients with HN cancers and</p><p>ligometastases have emerged as a challenging area of research</p><p>59-62] .</p><p>Among patients with HN cancers and oligometases, the major-</p><p>ty of ablative SBRT studies have focused on 2 cohorts of patients,</p><p>hose with oropharyngeal cancer and those with nasopharyngeal</p><p>ancer.</p><p>(1) Oropharyngeal cancer patients. In this cohort, HPV-related</p><p>tumor, limited number of distant metastases (1–2 lesions)</p><p>and good performance status have been found to be positive</p><p>prognostic factors [63-65] .</p><p>(2) Nasopharyngeal cancer patients. In this cohort, both</p><p>metachronous and synchronous oligometastases have been</p><p>studied. In patients with metachronous metastases, single-</p><p>organ involvement, limited number of metastases ( < 5),</p><p>young age ( < 40 years), long disease-free interval ( > 24</p><p>months), and treatment strategy (combined chemotherapy</p><p>D. Alterio, G. Marvaso and A. Ferrari et al. / Seminars in Oncology 46 (2019) 233–245 237</p><p>a</p><p>t</p><p>n</p><p>s</p><p>p</p><p>o</p><p>r</p><p>(</p><p>a</p><p>t</p><p>T</p><p>t</p><p>o</p><p>t</p><p>s</p><p>a</p><p>n</p><p>a</p><p>t</p><p>g</p><p>t</p><p>s</p><p>e</p><p>I</p><p>s</p><p>v</p><p>p</p><p>t</p><p>T</p><p>r</p><p>f</p><p>t</p><p>g</p><p>v</p><p>l</p><p>F</p><p>r</p><p>e</p><p>t</p><p>(</p><p>c</p><p>I</p><p>a</p><p>l</p><p>(</p><p>w</p><p>o</p><p>g</p><p>p</p><p>I</p><p>v</p><p>t</p><p>t</p><p>e</p><p>c</p><p>c</p><p>t</p><p>a</p><p>s</p><p>b</p><p>t</p><p>c</p><p>o</p><p>A</p><p>1</p><p>p</p><p>r</p><p>c</p><p>a</p><p>a</p><p>c</p><p>t</p><p>t</p><p>d</p><p>r</p><p>d</p><p>d</p><p>(</p><p>h</p><p>p</p><p>f</p><p>r</p><p>t</p><p>h</p><p>m</p><p>d</p><p>D</p><p>a</p><p>t</p><p>r</p><p>a</p><p>n</p><p>t</p><p>o</p><p>s</p><p>i</p><p>t</p><p>g</p><p>and local RT) were found to be independent positive prog-</p><p>nostic factors [66-68] . Moreover, clinical staging and hema-</p><p>tological parameters (Epstein Barr Virus IgA, blood count pa-</p><p>rameters, and liver function) have also been demonstrated as</p><p>able to stratify patients into low versus high risk. Similarly,</p><p>in patients with synchronous oligometastases, single organ</p><p>metastases with 1–5 lesions were found to have better prog-</p><p>nosis compared to patients with multiple organ metastases</p><p>and/or more than 5 lesions (overall survival 38.7% v 7.0%, re-</p><p>spectively) [69] .</p><p>The proper selection of patients who could benefit from SBRT</p><p>nd the optimal therapeutic sequence (combination with sequen-</p><p>ial systemic treatments) and strategy (fractionation schedule)</p><p>eeds to be assessed in prospective randomized trials. Retro-</p><p>pective clinical studies have shown better oncologic results in</p><p>atients with small size ( < 3 cm) lesions and a limited number</p><p>f metastatic sites ( < 3) [70,71] . Ordonez et al proposed an algo-</p><p>ithm which includes patient Eastern Cooperative Oncology Group</p><p>ECOG) performance status ( > 3 v < 3), tumor site (oropharyngeal</p><p>nd nasopharyngeal tumors v other sites), and the biological</p><p>umor characteristics (HPV positive v HPV negative tumors) [54] .</p><p>he best candidates for ablative RT were suggested to be those pa-</p><p>ients with a good performance status, affected by nasopharyngeal</p><p>r HPV + oropharyngeal tumors.</p><p>In conclusion, local ablative SBRT for HN oligometastatic pa-</p><p>ients may appear a promising alternative to surgery in anybody</p><p>ite [53] . Currently, patients are identified for local ablative ther-</p><p>pies with curative intent on the basis of risk factors such as the</p><p>umber of metastases, the interval between disease presentation</p><p>nd the occurrence of metastatic disease, histology of the treated</p><p>umor, and efficacy of systemic chemotherapy. Due to the lack of</p><p>uidelines for patient selection and treatment strategies, indica-</p><p>ions to ablative SBRT should be proposed in a multidisciplinary</p><p>etting in order to offer the best personalized treatment to these</p><p>xpected long-surviving patients.</p><p>mage-guided RT (IGRT) and adaptive RT (ART)</p><p>Tumor shrinkage and patient weight loss are frequent clinical</p><p>ituations in patients treated with chemoradiation for locally ad-</p><p>anced HN tumors. Due to the steep IMRT dose gradient and the</p><p>otential anatomic variations occurring during the course of RT,</p><p>he actual dose delivered may not correspond to the planned dose.</p><p>he result can be an increase in the doses delivered to organs at</p><p>isk and/or a decrease in the doses delivered to the tumor. There-</p><p>ore, the use of IMRT calls for implementing high precision RT</p><p>echniques in clinical practice.</p><p>Technological innovations have made possible the direct inte-</p><p>ration of imaging technology into the radiation treatment de-</p><p>ices. This increases the precision and accuracy of radiation de-</p><p>ivery by controlling the placement of the dose within the body.</p><p>or HN tumors, IGRT techniques have been introduced in order to</p><p>educe the uncertainties of systematic and random patient set-up</p><p>rrors, thereby minimizing the interfractional position uncertain-</p><p>ies. Both 2D (Electronic Portal imaging devices – EPID) and 3D</p><p>Cone beam computed tomography – CBCT) are currently used in</p><p>linical practice for HN setup error control. The introduction of</p><p>GRT for HN tumors permits the operator to reduce the margins</p><p>dded to the clinical target volume for setup errors. Moreover, the</p><p>ast generation of linear accelerator integrated MRI functionality</p><p>MRI-Linac) has helped the high-precision localization of tumors</p><p>ithin soft tissues [72] . Thus, IGRT allows for reduction of dose to</p><p>rgans/structures at risk for irradiation while preserving the tar-</p><p>et volume dose coverage [73] . Thus, the use of IGRT in clinical</p><p>ractice is nowadays considered essential to ensure a high-quality</p><p>MRT delivery.</p><p>IGRT also permits changes in shape and position of both target</p><p>olumes and normal tissues to be monitored. RT replanning due</p><p>o patient and/or tumor modifications during the course of RT led</p><p>o the introduction of the concept of ART. ART uses one or sev-</p><p>ral replanning sessions with the aim of correcting these modifi-</p><p>ations and thus optimizing the delivered dose distribution to the</p><p>hanging anatomy. Most studies on ART have focused on its advan-</p><p>age in preserving healthy tissues (parotid gland and spinal cord)</p><p>nd/or maintaining adequate dose coverage on target volumes. Re-</p><p>ults have shown the dosimetric advantages of ART, however, its</p><p>enefit in HN cancer patients still remains controversial both in</p><p>erms of clinical outcomes (possibly improvement of locoregional</p><p>ontrol) and toxicity profile (mainly on the incidence and severity</p><p>f xerostomia) mainly considering its time-consuming costs [74] .</p><p>Along with anatomical modifications, the new concept of</p><p>RT according to tumor metabolic changes evaluated by either</p><p>8 F-fluorodeoxyglucose (FDG)- or 18 F-fluoromisonidazole (FMISO)-</p><p>ositron emission tomography (PET), and/or functional magnetic</p><p>esonance imaging (MRI) is currently under investigation. The prin-</p><p>ipal aim of this approach is to increase the RT dose in tumor</p><p>reas considered to be more radioresistant. The rationale of this</p><p>pproach comes from the clinical observation that most HN lo-</p><p>al recurrences appeared in the parts of the tumor that were ini-</p><p>ially most FDG-avid [75] . Similarly, higher hypoxic volumes iden-</p><p>ified by FMISO-PET or hypoperfused areas outlined by apparent</p><p>iffusion coefficient MRI were associated with lower tumor control</p><p>ates [76,77] . Although preliminary results were very encouraging,</p><p>ata on metabolic ART are not robust enough to permit its intro-</p><p>uction in daily clinical practice. Results of ongoing clinical studies</p><p>such as NCT01341535), are warranted to better clarify when and</p><p>ow information of tumor metabolism could be integrated into RT</p><p>lans.</p><p>In conclusion, there is accumulating evidence that adaptive RT</p><p>or HN cancer based on midtreatment computed tomography can</p><p>educe side effects and possibly improve local control [74] . Never-</p><p>heless, due to the lack of a standardized procedure on when and</p><p>ow to safely perform replanning following modification of the tu-</p><p>or and/or healthy tissues, ART should be cautiously applied</p><p>in</p><p>aily clinical practice.</p><p>eintensified RT in HPV-related oropharyngeal tumors</p><p>HPV-related oropharyngeal squamous cell carcinoma represents</p><p>disease entity that is now recognized as distinct from the his-</p><p>orically alcohol and tobacco-related HN tumors. Its incidence is</p><p>apidly increasing in western countries. HPV-related tumors have</p><p>higher sensitivity to both chemotherapy and RT as compared to</p><p>on–HPV-related carcinomas and therefore have a better prognosis</p><p>hat is independent of the treatment approach. The more favorable</p><p>utcomes of patients with HPV-related oropharyngeal tumors have</p><p>purred the medical community to explore de-escalation strategies</p><p>n order to minimize the toxicity profile for these patients that of-</p><p>en have long survivals. Briefly, four main deintensification strate-</p><p>ies are currently under investigation:</p><p>(1) Deintensification of concurrent chemotherapy by either using</p><p>cetuximab alone instead of platinum-based chemotherapy or by</p><p>removing all concurrent chemotherapy. The rationale for the</p><p>use of cetuximab was based on the results of the Bonner</p><p>study which found that patients with oropharyngeal cancer,</p><p>small primary, significant nodal involvement, good health</p><p>and younger age deriver the greatest benefit from cetuximab</p><p>[78] . Moreover, cetuximab is “supposed to be” less toxic than</p><p>238 D. Alterio, G. Marvaso and A. Ferrari et al. / Seminars in Oncology 46 (2019) 233–245</p><p>f</p><p>t</p><p>v</p><p>e</p><p>i</p><p>n</p><p>t</p><p>c</p><p>t</p><p>o</p><p>s</p><p>[</p><p>c</p><p>t</p><p>v</p><p>l</p><p>t</p><p>t</p><p>v</p><p>p</p><p>h</p><p>(</p><p>b</p><p>e</p><p>s</p><p>T</p><p>Y</p><p>w</p><p>p</p><p>f</p><p>a</p><p>I</p><p>n</p><p>i</p><p>i</p><p>b</p><p>t</p><p>H</p><p>f</p><p>b</p><p>i</p><p>t</p><p>d</p><p>T</p><p>e</p><p>e</p><p>s</p><p>h</p><p>m</p><p>s</p><p>t</p><p>f</p><p>i</p><p>i</p><p>l</p><p>w</p><p>2</p><p>cisplatin although the data for this conclusion is less certain</p><p>[79] .</p><p>(2) Deintensification of RT doses and/or volumes for patients con-</p><p>sidered low-risk and patients who have experienced a response</p><p>after induction chemotherapy. The reduction of dose derived</p><p>support from the known relationship between the RT dose</p><p>received by structures vulnerable to dysphagia and xerosto-</p><p>mia (pharyngeal constrictors, the base of tongue and supra-</p><p>glottic larynx, major salivary glands) and long-term side ef-</p><p>fects (swallowing dysfunction, xerostomia). Patients eligible</p><p>for deintensified RT doses are those with either a good prog-</p><p>nosis (early stage and minimal/remote history of smoking)</p><p>or those who respond to induction chemotherapy [33] .</p><p>Moreover, the possibility to reduce RT volumes derives support</p><p>rom the observation that the majority of locoregional failures af-</p><p>er chemoradiation occur within the radiation field (gross tumor</p><p>olume/highest risk radiation volume) [80,81] . This allows the op-</p><p>rator to omit some lymph node areas treated with prophylactic</p><p>ntent (eg, level IV in clinically negative patients, retropharyngeal</p><p>odes in contralateral retropharyngeal neck) in low-risk patients.</p><p>Another strategy to reduce unnecessary irradiation to healthy</p><p>issues is the use of proton therapy. Preliminary dosimetric and</p><p>linical results have shown a reduction of the absorbed dose to</p><p>he oral cavity and pharyngeal axis with a consequent reduction</p><p>f acute toxicity in terms of mucositis and dysphagia. These re-</p><p>ults provide the rationale for currently-ongoing prospective trials</p><p>82,83] .</p><p>(1) Deintensification of adjuvant RT after surgery. The introduction</p><p>of transoral robotic surgery (TORS) in clinical practice re-</p><p>launched the use of minimally-invasive surgery for oropha-</p><p>ryngeal tumors. The surgical approach has the advantage</p><p>of guiding postoperative treatment according to pathologic</p><p>staging, thus permitting adjuvant RT to be avoided or dein-</p><p>tensified in patients deemed to be low risk [84] .</p><p>(2) Deintensification of RT according to a midtreatment evaluation.</p><p>This strategy was derived from preliminary results published</p><p>by Lee et al in which pretreatment 18 F-fluorodeoxyglucose</p><p>and dynamic 18 F-FMISO PET were performed [85,86] .</p><p>Patients with tumors exhibiting pretreatment hypoxia as de-</p><p>termined by an</p><p>18 F-FMISO PET had a repeat scan performed</p><p>1 week after chemoradiation. Patients whose tumors did</p><p>not exhibit evidence of pretreatment hypoxia or those with</p><p>resolution of tumor hypoxia on repeat scans had an RT re-</p><p>duction of 10 Gy to metastatic lymph nodes. At the median</p><p>follow-up of 32 months, the 2-year locoregional control was</p><p>100%. These preliminary data encouraged this approach to</p><p>be pursued, which selects patients without initial evidence</p><p>of hypoxia and those who experience a good response to</p><p>deintensification of RT dose on tumor volumes [86] .</p><p>Table 2 provides a brief summary of ongoing clinical trials fo-</p><p>used on deintensification strategies. Focusing on the radiation</p><p>reatment, the main deintensification strategies currently under in-</p><p>estigation include: 1) reduction of total dose both in high- and</p><p>ow-risk areas without reduction of irradiated volumes; 2) reduc-</p><p>ion of total dose only in low-risk areas (cN0, in postoperative set-</p><p>ing or in selected nonhypoxic tumors); 3) reduction of irradiated</p><p>olume by omitting irradiation of low-risk areas (in curative and</p><p>ostoperative settings); 4) reduction of unintentional irradiation of</p><p>ealthy tissues by the use of intensity-modulated proton therapy</p><p>IMPT).</p><p>Although the optimal deintensification strategy has not yet</p><p>een determined, some preliminary information can be found in</p><p>arly results reported in recent publications.</p><p>• Results of RTOG 10.16 and De-Escalate trials have shown that</p><p>RT plus cetuximab achieves inferior oncologic outcomes com-</p><p>pared with RT plus cisplatin [87-89] . On the other hand,</p><p>according to the results of the E1308 trial, for patients</p><p>who achieve an initial response after induction chemotherapy,</p><p>reduced-dose IMRT with concurrent cetuximab achieved en-</p><p>couraging results worthy of further investigation [90] .</p><p>• According to Chera et al, deintensified RT in patients deemed to</p><p>be low-risk achieved favorable results. Indeed, selected patients</p><p>with good prognoses (T0 to T3, N0 to N2c, M0; HPV or p16 pos-</p><p>itive; and minimal/remote smoking history) were treated with a</p><p>deintensified concurrent chemoradiation regimen (60 Gy IMRT</p><p>with concurrent weekly intravenous cisplatin at a dose of 30</p><p>mg/m</p><p>2 ) (NCT01530997) [91] . Using this approach, the investi-</p><p>gators reported a pathologic complete response rate of 86% (37</p><p>of 43 enrolled patients). This finding warranted a subsequent</p><p>trial, which is currently ongoing (NCT02281955).</p><p>• Deintensification treatment after tumor selection according to</p><p>response to induction chemotherapy seems to offer good onco-</p><p>logic results (E1308 and Optima trial) [90,92] . Patients achiev-</p><p>ing a good response could be selected for deintensified treat-</p><p>ment using weekly cisplatin and/or cetuximab and/or reduced</p><p>RT dose and volumes.</p><p>In the light of findings reported in the scientific literature,</p><p>ome institutions have modified their institutional guidelines.</p><p>he Memorial Sloan Kettering Cancer Center (MSKCC) in New</p><p>ork recently reported their reduction of RT intensity in patients</p><p>ith HPV positive oropharyngeal cancers treated with concurrent</p><p>latinum-based chemotherapy. Reduction of both total dose (70 Gy</p><p>or macroscopic disease and 30 Gy for elective treatment regions)</p><p>nd volume (gross tumor volume - GTV70 = CTV 70, omitting level</p><p>V in cN0 and contralateral retropharyngeal lymph nodes in the</p><p>ode-negative neck) are currently considered the standard of care</p><p>n at MSKCC [93] . Nevertheless, the best deintensification approach</p><p>s yet to be established. Results of ongoing prospective trials will</p><p>etter clarify when and how low-risk oropharyngeal cancer pa-</p><p>ients might benefit from a deintensified treatment approach.</p><p>adrontherapy</p><p>Together with the standard RT delivered by photons, a new</p><p>orm of radiation therapy (termed “hadrontherapy” or “particle</p><p>eam therapy”) encompassing the use of heavy particles has been</p><p>ntroduced in clinical practice and</p><p>currently represents the latest</p><p>echnical improvement in radiation oncology. Photon-based RT is</p><p>elivered using high energy X-rays produced by linear accelerators.</p><p>his is uncharged electromagnetic radiation (photons), with ‘‘pack-</p><p>ts’’ of energy able to ionize molecules in the tissue that they pen-</p><p>trate. Over the past 20 years, the use of IMRT, has allowed con-</p><p>iderable improvement in treatment conformity and reduction of</p><p>igh doses to neighboring critical structures. Despite this, for tu-</p><p>ors located very close to critical structures or with low radiosen-</p><p>itivity to photons, clinical outcomes of IMRT remain unsatisfac-</p><p>ory. Hadrons are subatomic particles subject to a strong nuclear</p><p>orce. Neutron therapy was the first form of hadrontherapy applied</p><p>n clinical practice. Despite its high radiobiological efficacy, its clin-</p><p>cal use was slowly abandoned due to the high rate of acute and</p><p>ate side effects. Nowadays, protons and carbon ions are the most</p><p>idely-used form of hadrontherapy in clinical practice. They have</p><p>main advantages over photon-based IMRT ( Fig. 2 ):</p><p>(1) Higher spatial selectivity due to:</p><p>(a) A steeper distal fall-off dose for proton and carbon ions</p><p>that spares critical structures located very close to the</p><p>tumor (ie, central nervous system or optic pathways)</p><p>D. Alterio, G. Marvaso and A. Ferrari et al. / Seminars in Oncology 46 (2019) 233–245 239</p><p>Table 2</p><p>Trials evaluating de-escalated strategy for HPV-related oropharyngeal cancers (in bold the experimental arms).</p><p>Trial Identifier number Phase Study design Status</p><p>Deintensification of concurrent chemotherapy</p><p>RTOG 1016 NCT01302834 III Accelerated RT (70 Gy in 6 weeks) + CDDP (100</p><p>mg/m</p><p>2 x 2 cycles) v Cet</p><p>Published</p><p>De-ESCALATE NCT01874171 III Standard RT (70 Gy in 7 weeks) + CDDP (100</p><p>mg/m</p><p>2 x 3 cycles) v Cet</p><p>Published</p><p>TROG 12.01 NCT01855451 III Standard RT (70 Gy in 7 weeks) + weekly CDDP v</p><p>Cet</p><p>Active NR</p><p>Reduced-intensity therapy for advanced</p><p>oropharyngeal cancer HPV16 + OPC</p><p>NCT01663259 NA Standard RT (70 Gy in 7 weeks) + Cet Active NR</p><p>RT + Cet v CT/RT radiotherapy HPV + OPC NCT01302834 III Accelerated RT (70 Gy in 6 weeks) + CDDP v</p><p>Accelerated RT + Cet</p><p>Active NR</p><p>NRG-HN002 NCT02254278 II Standard RT (70 Gy) + CDDP v RT 60 (in 5</p><p>weeks)</p><p>Active NR</p><p>Deintensification of radiation doses</p><p>E1308 NCT01084083 II Induction CT (CDDP + T + Cet) → R = > RT (54 v</p><p>66–70 Gy) with Cet</p><p>Published</p><p>OPTIMA trial NCT02258659 II Induction CT (C + P) → Deintensified RT</p><p>according to tumor response</p><p>Published</p><p>Quarterback 2 NCT02945631 II Induction CT (TPF) → R = > 56 Gy + Carboplatin</p><p>Recruiting</p><p>Deintensification of RT and CT for low-risk</p><p>HPV-related for OPSCC</p><p>NCT01530997 II IMRT (54–60 Gy) with weekly CDDP (30 mg/m</p><p>2 ) Published</p><p>RT dose de-escalation ( + CT) in HPV + OPC</p><p>hypoxia negative (FMISO)</p><p>NCT03323463 II IMRT (30 Gy in 15 fr) + concurrent CT (CDDP, C,</p><p>5FU) Recruiting</p><p>Randomized phase II trial for p16 Positive,</p><p>OPC</p><p>NCT02254278 II RT 60 Gy in 30 fr + weekly CDDP v RT 60 Gy in</p><p>30 fr</p><p>Active NR</p><p>A pilot single arm study IMRT elective</p><p>nodal dose de-escalation for HPV + OPC</p><p>NCT01891695 NA RT 39.6 Gy radiation to clinically cN0</p><p>Completed</p><p>Deintensification of RT and CT for low-risk</p><p>HPV + OPC</p><p>NCT02281955 II IMRT (54–60 Gy) with CDDP Active NR</p><p>Treatment deintensification in favorable</p><p>OPSCC</p><p>NCT01088802 II RT de-escalation (58.1 Gy in 35 fr) + CDDP or</p><p>Carboplatin</p><p>Active NR</p><p>Deintensification by the reduction of irradiated volumes</p><p>EVADER NCT03822897 II Standard RT dose ( + /- CDDP) omitting some of</p><p>the lymph node areas</p><p>NYR</p><p>IMPT v IMRT in OPC NCT01893307 II/III Standard RT dose (70 Gy in 33 fr) v IMPT (70</p><p>GyRBE in 33 fr) Recruiting</p><p>IMPT or TORS for OPC NCT02663583 Obs TORS or IMPT in low risk (Tx-T2 N2b) OPC</p><p>Recruiting</p><p>Deintensification of postoperative treatments</p><p>ECOG 3311 NCT01898494 II MIS → Deintensified RT and CT according to</p><p>pathologic risk categories</p><p>Active NR</p><p>ADEPT NCT01687413 III MIS → in case of ECE: RT (60 Gy) v RT (60</p><p>Gy) + CDDP</p><p>Active NR</p><p>PATHOS NCT02215265 II/III MIS → Deintensified RT and CT according to</p><p>pathologic risk categories Recruiting</p><p>DART NCT02908477 III Surgery → RT (BID up to 30 Gy/1.5 Gy or 36</p><p>Gy) + Docetaxel Recruiting</p><p>ORATOR2 NCT03210103 TOS and neck dissection v deintensified primary</p><p>RT (60 Gy) ±chemotherapy Recruiting</p><p>TORS followed by adjuvant RT to the</p><p>regional nodes alone in HPV + OPC</p><p>NCT02159703 II TORS → Adjuvant RT omit RT on primary</p><p>tumor surgical bed Recruiting</p><p>Adjuvant de-escalated</p><p>radiation + Nivolumab for</p><p>intermediate-high risk P16 +</p><p>NCT03715946 II MIS → 45–50 Gy in 25 fr + Nivolumab</p><p>Recruiting</p><p>Volume and dose deintensification</p><p>following TORS and ND for p16 + OPC</p><p>NCT03729518 II TORS → Adjuvant IMRT or IMPT omit RT on</p><p>primary tumor surgical bed ( 50 Gy when</p><p>RT required and CT omitted in focal or</p><p>microscopic ECE)</p><p>Recruiting</p><p>De-escalation of adjuvant RT (CT) therapy</p><p>for HPV + HN carcinoma</p><p>NCT03396718 I Surgery → Intermediate risk patients adjuvant RT</p><p>Level 1 = 54/59,4 Gy Level 2 = 48/55 Gy Recruiting</p><p>SIRS TRIAL NCT02072148 NA Surgery → De-intensified RT and CT according to</p><p>pathologic risk categories Recruiting</p><p>Deintensified risk-adapted postoperative RT</p><p>for HPC + OPC</p><p>NCT03875716 II Surgery → Deintensified RT and CT according to</p><p>pathologic risk categories</p><p>NYR</p><p>Mucosal sparing proton beam therapy (PBT)</p><p>in resected OPC</p><p>NCT02736786</p><p>cohort</p><p>Surgery → Mucosal sparing proton therapy</p><p>Recruiting</p><p>RT deintensification according to mid-treatment evaluation</p><p>Adaptive de-escalation in favorable risk</p><p>HPV-positive OPSCC</p><p>NCT03215719 II Evaluation at 4th week of RT course → R ( > 40%</p><p>nodal shrinkage) → dose de-escalation Recruiting</p><p>CDDP = cis-diamminodicloroplatinum; RT = radiotherapy; Cet = Cetuximab; MIS = mini invasive surgery, CT = chemotherapy; NR = not recruiting, BID = bifractionated schedule;</p><p>C + P = Carboplatin + Nab-paclitaxel; HFX = hyperfractionated; OPC = oropharyngeal carcinoma; R = responders; NA = not applicable; NYR = Not Yet Recruiting; TOS = transoral</p><p>surgery; TORS = transoral robotic surgery; ECE = extracapsular extension; Obs = observational.</p><p>240 D. Alterio, G. Marvaso and A. Ferrari et al. / Seminars in Oncology 46 (2019) 233–245</p><p>Fig. 2. Example of a 45-year-old patient with diagnosis of adenoid cystic carcinoma of the nasopharynx (cT4cN0M0) not suitable for surgery, treated with hadrontherapy</p><p>(carbon ion). (a) Baseline T1-weighted RM showing a tumor mass extending through the pterygo-palatine fossa into the masticatory space. The tumor also infiltrated the</p><p>base of skull up to the ipsilateral cavernous sinus. Orange and green lines represent the high- and low-risk volume, respectively, contoured on RM images. (b) Carbon ion</p><p>radiation treatment plan. Total dose 68.8 Gy RBE (relative biological effectiveness) and 38.7 Gy RBE (for high- and low-risk volumes, respectively) administered with 4.3</p><p>GyRBE/fraction, 4 fractions/week. (c) T1-weighted RM at 6 months of follow-up demonstrating complete disappearance of the tumor lesion. Local control was maintained at</p><p>4 years follow- up. (Color version of figure is available online.)</p><p>c</p><p>and, as a consequence, permits the operator to increase</p><p>the dose to the tumor volumes.</p><p>(b) Sharper later penumbra for proton and carbon ions that</p><p>restricts the integral dose. The restriction of low doses</p><p>around the target volume enables the reduction of acute</p><p>and late toxicity to healthy tissues located both near and</p><p>far from the tumor.</p><p>(2) Higher radiobiological efficacy for neutron and carbon ions</p><p>that permits a higher response rate in radioresistant tumors</p><p>(ie, salivary gland, sarcoma, and melanoma).</p><p>The principal clinical applications of hadrontherapy in HN can-</p><p>er are:</p><p>• Nasal and sinonasal tumors. Non comparative studies and meta-</p><p>analyses have shown consistent</p><p>outcomes, both in terms of</p><p>overall survival, loco-regional control and toxicity. In favor of</p><p>proton therapy compared to photon-based treatment [94,95] .</p><p>Thus, in this subset of patients, charged-particle therapy should</p><p>be considered a valid treatment option and, according to in-</p><p>ternational guidelines, it can be considered in clinical practice</p><p>when normal tissue constraints cannot be met by photon-based</p><p>therapy [2] .</p><p>• Oropharyngeal tumors. After initial experiences using a mixed</p><p>beam approach (photon and proton therapy) the use of a proton</p><p>therapy-only approach is increasingly being proposed as a cu-</p><p>rative treatment instead of IMRT in order to further ameliorate</p><p>the acute and late treatment-related toxicity profile [96,97] .</p><p>Compared to IMRT, dosimetric studies have shown that IMPT</p><p>can reduce the mean dose to the oral cavity, hard palate, lar-</p><p>ynx, mandible, and esophagus [83] . Subsequent matched paired</p><p>analyses confirmed that patients treated with IMPT had both</p><p>a lower rate of dependence on feeding tubes and less severe</p><p>weight loss at 3 and 12 months [98] . A Phase II-III trial en-</p><p>rolling patients with stage III-IV oropharyngeal cancers compar-</p><p>ing outcomes with IMPT to those with IMRT is currently ongo-</p><p>ing (NCT01893307). Results of this trial will further address the</p><p>clinical indications of hadrontherapy in this subset of patients.</p><p>• Nasopharyngeal tumors. The location of these cancers very close</p><p>to critical neurologic structures has meant that IMRT is often</p><p>burdened by severe late side effects including optic neuropa-</p><p>thy, temporal lobe necrosis or hearing impairment. Moreover,</p><p>for locally advanced tumors (T3-T4) IMRT does not allow for</p><p>an optimal coverage of the target volumes and this suboptimal</p><p>dose distribution is considered the most relevant cause of local o</p><p>failure [99,100] . Given the location of these dose-limiting struc-</p><p>tures near the tumor mass, several studies have demonstrated</p><p>the feasibility of improving tumor coverage and reducing the</p><p>integral dose to organs at risk with IMPT, compared to the IMRT</p><p>technique [101-104] .</p><p>• Unilateral neck irradiation . In cases of well-lateralized primary</p><p>tumor including tumors of the parotid gland, early stage oral</p><p>cavity cancers or oropharyngeal tumors, unilateral neck irradia-</p><p>tion may be indicated. Preliminary clinical results have shown a</p><p>significant reduction of acute toxicity (dysgeusia, mucositis, and</p><p>nausea) in favor of proton therapy due to the limited low doses</p><p>to the contralateral neck [105] .</p><p>• Reirradiation. In patients with locally recurrent tumors, reir-</p><p>radiation performed with both protons and carbon ions has</p><p>been recently investigated. Indeed, hadrontherapy is ideal from</p><p>a dosimetric standpoint for such cases where minimizing dose</p><p>exposure to reirradiated normal tissue is critical to reducing the</p><p>risks of treatment-related toxicities. Preliminary results have</p><p>shown that reirradiation with IMPT could offer both dosimetric</p><p>and clinical advantages over IMRT. However, further prospective</p><p>studies are required to confirm these encouraging but prelimi-</p><p>nary results [105,106] .</p><p>• Radioresistant tumors (ie, salivary gland, mucosal melanoma). Ini-</p><p>tial studies on patients with salivary gland tumors were con-</p><p>ducted with neutrons. Results showed a higher biological effi-</p><p>cacy but a low spatial selectivity which produced a high rate of</p><p>acute and late side effects [107] . Despite the subsequent intro-</p><p>duction of more modern neutron machines and the availability</p><p>of 3D treatment planning systems, the clinical use of neutrons</p><p>has been progressively abandoned. Nevertheless, the clinical ex-</p><p>perience acquired with the use of neutrons was translated into</p><p>carbon ion therapy which has a high spatial selectivity and has</p><p>allowed a consistent improvement of the cost/benefit ratio. Pre-</p><p>liminary data have been published on adenoid cystic carcinoma</p><p>for which carbon-ion RT was used either as a boost after IMRT</p><p>or as a full course of treatment [108-112] . Fig. 1 shows an ex-</p><p>ample of carbon ion treatment for adenoid cystic carcinoma.</p><p>Other HN non squamous cell carcinomas including adenocar-</p><p>cinoma and mucoepidermoid carcinoma have also been investi-</p><p>gated [113,114] . Encouraging preliminary results have also been</p><p>obtained for mucosal melanomas of the HN [115,116] .</p><p>Hadrontherapy can be applied either as a unique course of RT</p><p>r in combination with photons in the so-called “mixed beam”</p><p>D. Alterio, G. Marvaso and A. Ferrari et al. / Seminars in Oncology 46 (2019) 233–245 241</p><p>t</p><p>v</p><p>t</p><p>h</p><p>i</p><p>a</p><p>d</p><p>M</p><p>t</p><p>s</p><p>a</p><p>v</p><p>t</p><p>g</p><p>a</p><p>r</p><p>F</p><p>h</p><p>p</p><p>t</p><p>s</p><p>i</p><p>t</p><p>a</p><p>a</p><p>i</p><p>r</p><p>c</p><p>v</p><p>t</p><p>R</p><p>p</p><p>o</p><p>i</p><p>n</p><p>a</p><p>t</p><p>i</p><p>i</p><p>a</p><p>t</p><p>g</p><p>t</p><p>v</p><p>a</p><p>c</p><p>p</p><p>o</p><p>a</p><p>m</p><p>n</p><p>t</p><p>t</p><p>o</p><p>t</p><p>s</p><p>o</p><p>g</p><p>i</p><p>e</p><p>c</p><p>w</p><p>i</p><p>o</p><p>u</p><p>a</p><p>c</p><p>e</p><p>l</p><p>T</p><p>s</p><p>P</p><p>b</p><p>w</p><p>fi</p><p>i</p><p>r</p><p>i</p><p>o</p><p>h</p><p>s</p><p>C</p><p>c</p><p>n</p><p>b</p><p>echnique. Moreover, IMPT represents the latest technologic ad-</p><p>ance in hadrontherapy which allows for further optimization of</p><p>he dose conformity to the target volume.</p><p>Due to technological and biological advantages, the number of</p><p>adrontherapy facilities is increasing worldwide, thus providing</p><p>ncreasingly larger series of patients to be included in retrospective</p><p>nd prospective trials leading to an increasingly robust published</p><p>ata supporting its use in different HN cancer settings [94,117] .</p><p>achine learning techniques and radiomics</p><p>Machine learning techniques comprise a branch of artificial in-</p><p>elligence in which an algorithm learns by inference from a data</p><p>et. Clinical application of machine learning in HN RT therefore</p><p>ims to:</p><p>(1) Obtain an automated delineation of organs at risk so as to</p><p>reduce a time-consuming contouring process [118] .</p><p>(2) Perform an adaptive RT during the radiation course with a</p><p>view to optimizing the treatment plan according to tumor</p><p>and/or patient volume and shape modification [119] .</p><p>(3) Predict RT-related toxicity, in particular xerostomia, mucosi-</p><p>tis, and dysphagia [120-122] .</p><p>Radiomics is a new branch of the machine learning that in-</p><p>olves a high-throughput extraction of advanced quantitative fea-</p><p>ures in radiological images with the help of mathematical al-</p><p>orithms. Extracted traits describe radiological intensity, shape</p><p>nd texture characteristics of tumors and can be analyzed on</p><p>outinely performed radiologic images including CT, MRI, and</p><p>DG-PET. These features can be linked to clinical, genomic, and</p><p>istopathological data from other sources and can be tested as</p><p>redictive/prognostic parameters for both clinical outcomes and</p><p>reatment-related toxicity parameters.</p><p>For HN cancer patients, different radiologic images have been</p><p>tudied:</p><p>(1) Baseline CT images were found to be correlated with tu-</p><p>mor characteristics including HPV status and extranodal</p><p>extension and clinical outcomes including overall survival,</p><p>progression-free survival, distant metastases, and locore-</p><p>gional recurrences [123-126] . Moreover, radiomic features</p><p>extracted from simulation CT could predict some radiation-</p><p>related toxicity such as neurosensorial hearing loss [127] .</p><p>(2) Baseline MRI images were mainly analyzed in nasopharyn-</p><p>geal cancers and results showed that different features could</p><p>predict tumor progression after chemoradiation [128] .</p><p>(3) Baseline FDG-PET could provide radiomic features correlated</p><p>with progression-free survival in HN cancer patients treated</p><p>with chemoradiation [129] .</p><p>(4) CT acquired during the course of RT (second week of treat-</p><p>ment) was shown to improve the radiomic prognostic model</p><p>for locoregional control [130] .</p><p>Radiation treatment represents the largest source of radiologic</p><p>mages available for radiomics analysis. Indeed, before and during</p><p>he course of radiation treatment, a large number of radiologic im-</p><p>ges are</p><p>acquired in daily clinical practice and are therefore avail-</p><p>ble for each patient.</p><p>Ongoing studies are aiming to standardize the radiomic process</p><p>n order to obtain robust and reproducible parameters. Such pa-</p><p>ameters could be used as prognostic/predictive tools for HN can-</p><p>er patients treated with RT. Therefore, radiologic biomarkers are</p><p>ery promising tools in the era of personalized medicine for pa-</p><p>ient risk stratification. p</p><p>T and the immune system</p><p>The recent understanding of the interaction existing between</p><p>hotons, the host immune system, and immunotherapy has</p><p>pened the doors to a new frontier of radiation oncology. Specif-</p><p>cally, a growing body of evidence suggests that RT may elimi-</p><p>ate tumors not only by the classically-known deoxyribonucleic</p><p>cid (DNA) damage, but also via the activation of local and/or sys-</p><p>emic immune responses. Indeed, RT has the potential to convert</p><p>mmunologically “cold” tumors (not “T cell inflamed” phenotype)</p><p>nto “hot” tumors (“T cell inflamed” phenotype which demonstrate</p><p>higher response rate to immunotherapy) by a combination of dis-</p><p>inct mechanisms. Additionally, an alternative interpretation sug-</p><p>ests that T-cell activation by cancer immunotherapy may sensi-</p><p>ize tumors to RT treatment through the modification of tumor</p><p>asculature and hypoxia [131] . On the other hand, radiation can</p><p>lso create an immunosuppressive environment through the re-</p><p>ruitment of tumor-associated macrophages, myeloid-derived sup-</p><p>ressor cells, and Tregs [132] . Therefore, despite the large amount</p><p>f preclinical data, the immunomodulating role of radiation ther-</p><p>py in head and neck tumors is not yet completely understood.</p><p>As a consequence, the best RT schedule and volumes to opti-</p><p>ize the possible interaction of RT with immunotherapy have also</p><p>ot been defined. Preclinical studies seem to support a hypofrac-</p><p>ionation schedule suggesting that 14–24 Gy delivered in 2–3 frac-</p><p>ions with concurrent immune checkpoint inhibitors may be the</p><p>ptimal dose and fractionation of radiation, and for sequencing of</p><p>herapies to generate robust antitumor cytotoxic T lymphocyte re-</p><p>ponses. Moreover, avoiding both surgical removal and irradiation</p><p>f neck lymph nodes may be necessary to maximize the immuno-</p><p>enic response that can be achieved with combined radiation and</p><p>mmunotherapy. Whether these findings are true in humans how-</p><p>ver remains to be elucidated.</p><p>The combination of immunotherapy with radiation is generally</p><p>onsidered a treatment “intensification” strategy. Thus, patients</p><p>ith poor prognosis including HPV negative or high-risk HPV pos-</p><p>tive oropharyngeal cancer patients or locally advanced stages of</p><p>ther than HN sites are generally enrolled in clinical trials eval-</p><p>ating the association of RT and immunotherapy ± chemother-</p><p>py and/or biologically target therapies. Data on the efficacy of</p><p>ombined therapy in the clinical setting are still lacking. How-</p><p>ver, many trials are underway. A recent review summarizes the</p><p>arge number of phase I-III clinical studies currently ongoing [132] .</p><p>he majority of available clinical data currently focuses on the</p><p>afety of combining immunomediate cell inhibitor and radiation.</p><p>reliminary results suggest that immunomediate cell inhibitor can</p><p>e safely administered concurrently with RT without a significant</p><p>orsening of the toxicity profile.</p><p>Genomics of head and neck cancers also represent a modern</p><p>eld of search and many studies are ongoing to find the applicabil-</p><p>ty of the recent knowledge in this field into clinical practice [133] .</p><p>In conclusion, the role of RT in modulating the host immune</p><p>esponse and in powering the efficacy of immunotherapy is a very</p><p>ntriguing field of research. Preclinical data have driven the design</p><p>f ongoing clinical data. The results of these clinical studies will</p><p>elp the scientific community to provide guidelines on the optimal</p><p>trategy to combine radiation and immunotherapy.</p><p>onclusions</p><p>Radiation therapy for HN cancers is moving forward a new</p><p>oncept of multimodality integration in which not only the tech-</p><p>ologic advances but also the better knowledge of interaction</p><p>etween radiation and healthy/tumor tissues will lead to new</p><p>romising integrated approaches.</p><p>242 D. Alterio, G. Marvaso and A. Ferrari et al. / Seminars in Oncology 46 (2019) 233–245</p><p>D</p><p>s</p><p>a</p><p>(</p><p>r</p><p>s</p><p>s</p><p>A</p><p>M</p><p>v</p><p>H</p><p>c</p><p>R</p><p>eclaration of Competing Interest</p><p>Roberto Orecchia: No conflict of interest.</p><p>Barbara Alicja Jereczek-Fossa: Outside the submitted work. Re-</p><p>earch funding: Accuray (institutional grant), AIRC Italian Associ-</p><p>tion for Cancer Research (institutional grants), FIEO-CCM & FUV</p><p>institutional grants) Travel expenses or speaker fees: Janssen, Fer-</p><p>ing, Bayer, Roche, Astellas, Elekta, Carl Zeiss, Ipsen, Accuray</p><p>Daniela Alterio: Outside the submitted. Travel expenses or</p><p>peaker fees: Merck serono</p><p>Giulia Marvaso: Outside the submitted. Travel expenses or</p><p>peaker fees: Blue Earth, Ipsen.</p><p>Stefania Volpe: No conflict of interest.</p><p>cknowledgments</p><p>William Russel-Edu (Library, European Institute of Oncology,</p><p>ilan, Italy. william.russell-edu@ieo.it) for English language re-</p><p>ision, Barbara Vischioni, MD (National Center of Oncological</p><p>adrontherapy, Fondazione CNAO, Pavia, Italy) for providing the</p><p>linical case showed in Fig. 1 .</p><p>eferences</p><p>[1] Ferlay J, Soerjomataram I, Dikshit R, et al. 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