REVIEW URRENT C OPINION
Proton therapy for head and neck cancer J. Nicholas Lukens a, Alexander Lin a, and Stephen M. Hahn b
Purpose of review Proton therapy for head and neck cancer is an area of active research as technological advances are increasingly integrated into clinical practice, and also the subject of heightened scrutiny due to the significant associated cost. This article will highlight recent research into proton dosimetry, studies evaluating its clinical benefit relative to other advanced radiotherapy modalities, and key safety and cost considerations. Recent findings Recent dosimetric analyses have quantified the potential for the most sophisticated form of proton therapy, intensity-modulated proton therapy (IMPT), to reduce dose to key anatomic structures in the head and neck, and highlight the potential for dose uncertainty with IMPT if not implemented in a careful manner. Clinical contributions demonstrate the potential for protons to yield excellent local control and lower than expected morbidity for tumors adjacent to critical neurological structures. There are promising data in the reirradiation setting, and emerging data for IMPT in oropharyngeal cancer. Summary Proton therapy for head and neck cancer holds significant potential, and promising single-institution experiences should be validated, wherever feasible, in prospective randomized clinical trials. In light of the significant associated cost, additional evidence is needed to guide the appropriate allocation of patients to IMPT versus intensity-modulated radiotherapy. Keywords cost-effectiveness research, head and neck cancer, intensity-modulated proton therapy, protons, reirradiation
INTRODUCTION Radiotherapy plays a key role in the treatment of patients with head and neck cancer in the definitive, adjuvant, and recurrent settings. However, the proximity of critical normal structures to tumors in the head and neck can result in severe acute and late toxicity. Technological advancements, such as intensity-modulated radiotherapy (IMRT), have resulted in improvements in some toxicity endpoints such as xerostomia [1]; however, the toxicity remains substantial [2,3]. There has been considerable interest in the use of proton therapy as a means of further reducing the toxicity of head and neck radiotherapy, by taking advantage of the unique physical properties of protons. Protons are charged particles that deliver most of their dose at the distal edge of their range (Bragg peak), and no dose beyond, potentially allowing for better sparing of adjacent organs at risk (OARs). Proton therapy has been in existence for several decades, with dosimetric data suggesting its superiority over conventional IMRT, potentially allowing for decreased toxicity while maintaining equivalent efficacy, or dose escalation for tumors in which the safe delivery of higher
doses is limited by adjacent critical structures such as the brainstem or spinal cord. The bulk of clinical experience to date for head and neck cancer has been limited primarily to the treatment of chordomas and chondrosarcomas, and nasal cavity and paranasal sinus tumors [4 ]. There has been growing interest and controversy regarding proton therapy recently, due to the increasing number of proton centers that are currently operational or in various stages of planning, the significant costs associated with the construction and operation of these centers, and the lack of strong evidence demonstrating its clinical superiority over ‘conventional’ IMRT. In &
a
Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania and bDivision of Radiation Oncology, MD Anderson Cancer Center, Houston, Texas, USA Correspondence to J. Nicholas Lukens, MD, Department of Radiation Oncology, University of Pennsylvania School of Medicine, Perelman Center for Advanced Medicine, 3400 Civic Center Blvd., 4-West, Philadelphia, PA 19104, USA. Tel: +1 215 662 6567; fax: +1 215 349 8975; e-mail: [email protected] Curr Opin Oncol 2015, 27:165–171 DOI:10.1097/CCO.0000000000000181
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this context, over the past year there have been studies addressing the question of whether the apparent dosimetric advantages of proton therapy translate into demonstrable clinical benefit. Simultaneously, there has been considerable research into the optimization of the planning and delivery of proton therapy, to enable the well tolerated treatment of complex target volumes in the head and neck. Intensity-modulated proton therapy (IMPT), analogous to IMRT for photon-based therapy, allows for greater dosimetric optimization and holds the potential to further enhance the therapeutic ratio. However, owing to the greater uncertainty of dose deposition with protons, IMPT for head and neck cancer has been the subject of intense scrutiny, as well as emerging clinical experience. This article will focus on recent studies addressing these emerging trends, specifically recent additions to the dosimetric literature regarding potential advantages of protons (specifically IMPT) over IMRT, and whether this translates into demonstrable clinical benefit relative to what can be achieved with IMRT, and the recent utilization of IMPT for complex head and neck target volumes such as in the definitive treatment of oropharyngeal squamous cell carcinoma (OPSCC).
over photon therapy with regard to the ability to deliver an adequate dose to tumor while decreasing dose to adjacent normal tissues. Initial studies suggested that spot-scanned proton beams, in which a pencil beam is steered by magnets to paint dose, layer by layer into the target, were superior to scattered proton beams with regard to sparing OARs [5,6]. Studies that followed compared the best plans achievable with protons (IMPT) to the best achievable with photons (IMRT), and generally demonstrate that IMPT allows for dose escalation without exceeding the tolerance of critical structures such as the optic chiasm and optic nerves in the treatment of paranasal sinus tumors [7]. Using normal tissue complication probability models (NTCP), several authors have suggested that the apparent dosimetric advantage of IMPT may translate into clinical benefit, such as improving xerostomia by reducing dose to the parotid glands in nasopharyngeal carcinoma [8], and lowering rates of radiation-induced secondary malignancy [9]. Recently, it has been shown that IMPT may reduce dose to the swallowing muscles (pharyngeal constrictor muscles and supraglottic larynx) relative to what can be achieved with IMRT, and that using NTCP models, this would result in an additional 8% reduction in the rate of grades 2–4 swallowing dysfunction [10]. Exploring additional potential advantages of the lower integral dose delivered by proton therapy, it has been hypothesized that IMPT may reduce treatmentrelated fatigue by lowering dose to the posterior fossa for patients with advanced oropharyngeal carcinoma [11]. This hypothesis is based on the finding of increased acute fatigue with the use of IMRT on the randomized phase III Parotid-sparing intensity modulated versus conventional radiotherapy in head and neck cancer (PARSPORT) trial [1], which appeared to correlate at least in part to increased dose to the posterior fossa [12]. The clinical scenario in which protons appear to provide a clear dosimetric advantage, regardless of the method of delivery (passive scattering or spotscanning), is in the treatment of ipsilateral targets, for example, in the treatment of salivary gland malignancies, or well lateralized tonsillar cancer in which only ipsilateral neck treatment is required. Recent studies comparing spot-scanned protons to IMRT in this context quantify the significant sparing of the contralateral salivary glands, oral cavity, and spinal cord in this setting [13].
CURRENT TRENDS IN DOSIMETRIC STUDIES OF HEAD AND NECK PROTON THERAPY
Dose uncertainty of intensity-modulated proton therapy for the treatment of complex target volumes
There is a substantial body of literature demonstrating the dosimetric advantages of proton therapy
The treatment of complex, bilateral target volumes within the head and neck with proton therapy
KEY POINTS There appears to be significant clinical benefit for protons in the setting of full dose reirradiation of tumors at the base of skull, although additional follow-up is required to assess late effects. The integration of IMPT into clinical practice requires strict attention to several variables that contribute to uncertainty of dose deposition; for this reason IMPT is still considered investigational for bulky OPSCC. The results of the currently accruing randomized trial of IMPT versus IMRT for OPSCC will provide valuable insight into the safety and potential for reduced toxicity with IMPT. Pending additional clinical and health economic evidence, the allocation of patients to IMPT versus IMRT is done on a case-by-case basis, weighing the expected costs and benefits for each individual patient. Biological optimization, taking advantage of the variability of biological effectiveness along the path of the proton beam, holds the potential to further enhance the therapeutic ratio with proton therapy.
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Proton therapy for head and neck cancer Lukens et al.
requires spot-scanning proton therapy. Recent efforts have addressed the best method for the optimization of spot-scanned proton plans, to maximize sparing of adjacent OARs, while ensuring delivery of dose in a well tolerated and reliable manner. Although generally two or three fields are used, each field can be optimized separately to cover the entire target (single-field optimization, SFO), or the beams can be optimized simultaneously to cover the target with the sum of the fields, allowing each field to deliver a heterogeneous dose to the target volume (multifield optimization, MFO) (Fig. 1) [14]. MFO planning, which is more commonly referred to as IMPT, allows for greater degrees of freedom to produce optimal dose distributions. However, owing to the high degree of modulation of the spot weights, IMPT is subject to greater uncertainty of delivered dose deposition, resulting from several variables including proton beam range uncertainty, daily setup variability, and anatomic changes over the course of treatment (because of weight loss or tumor shrinkage) [15,16]. Efforts have been made to increase the ‘robustness’ of IMPT planning to account for these uncertainties [17]. For treatment of simpler ipsilateral targets, a form of SFO planning using an integrated boost appears to be optimal [18]. However, for treatment of complex volumes within the head and neck incorporating the primary site and bilateral neck, MFO-IMPT appears to be required Beam 1
to maximize sparing of adjacent normal tissues. A study by Quan et al. [19] compared SFO with MFO, both nominally and in the worst case scenario, the latter accounting for setup and range uncertainty. SFO degraded sparing of the parotids, but improved plan robustness, reducing dose uncertainty in the target by 23% relative to MFO. Nevertheless, the authors concluded that MFO-IMPT had ‘tolerable’ target coverage and recommended MFO as the planning method for cases requiring bilateral treatment. However, their analysis did not take into account anatomic changes over the course of treatment. A separate study that analyzed dose uncertainty with IMPT in light of anatomic changes in addition to setup and range uncertainty found that large dose deviations can occur with the combination of various errors; for example, without adaptive replanning to account for anatomic change, only 69% of 3700 simulations met the prescribed target coverage [20 ]. However, adaptive replanning appeared to significantly improve target coverage, prompting their recommendation of periodic computed tomography scans for recalculation of the dose, and replanning as necessary. Based on these findings, it is imperative that if IMPT is used in the treatment of complex bilateral targets in which there are expected anatomic changes over the course of treatment, such as in the definitive treatment of OPSCC, weekly verification scans and adaptive replanning &&
Beam 2
Total dose
FIGURE 1. Example dose distributions of individual beams (left, center) and the sum of the planned beams (right) for singlefield optimization (SFO) plan (top) and a multifield optimization (MFO) plan (bottom). Reproduced with permission from [14]. 1040-8746 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
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&&
are performed as necessary [20 ,21 ]. Alternatively, another approach for the use of IMPT in oropharyngeal cancer is to limit its use to postoperative cases in which anatomic changes are less pronounced [14].
TRANSLATING PROTON DOSIMETRY INTO THE CLINIC: ATTEMPTS TO QUANTIFY THE CLINICAL BENEFIT The clinical experience with protons has generally been limited to single-institution series, and the majority of experience has been with chordomas and chondrosarcomas near the base of skull [22,23], or nasal cavity and paranasal sinus tumors [24–26], in which delivery of significant radiation dose with photons is limited by adjacent critical neurological tissue (recently reviewed by Holliday and Frank [4 ]). Recent contributions to the literature suggest that now with relatively long follow-up (mean of 46 months), high dose spot-scanning proton therapy appears well tolerated and effective in the treatment of pediatric patients with chordoma and chondrosarcoma [27 ]. This study included 17 children with base of skull tumors, treated after maximal safe resection with high doses [relative biological effectiveness (RBE), 74 Gy(RBE) for chordoma and 66 Gy(RBE) for chondrosarcoma], yielding excellent local control (80%) and a relatively low rate (19%) of late effects attributable to protons, all grade 2 or less. These data lend support to the rationale that proton therapy can be used to safely escalate dose to tumors in close proximity to critical structures, potentially improving clinical outcomes relative to what can be achieved with photons. &
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Does proton therapy improve survival relative to intensity-modulated radiotherapy? Given the relative rarity of the tumor types in the above single-institution series, and the infeasibility of conducting a randomized trial comparing photons and protons for these less common tumors, Patel et al. [28 ] performed a systematic review and meta-analysis to compare outcomes with protons versus photons for paranasal sinus and nasal cavity tumors. Overall, they reported increased overall survival and disease-free survival (DFS) at 5 years for patients treated with charged particle therapy, with no difference in local control at 5 years, but improved local control at longest follow-up. A subgroup analysis was performed to compare proton therapy with IMRT, which found significantly higher DFS at 5 years [relative risk (RR) 1.44, P ¼ 0.045], and locoregional control at longest follow-up (RR 1.26, P ¼ 0.011) for proton patients. &
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However, a greater proportion of photon patients had high-risk histologies relative to proton patients (50 versus 27%, P ¼ 0.06), raising the possibility of confounding. Furthermore, the median radiation dose was equivalent between charged particle and photon patients (60 and 61 Gy, respectively), calling into question the hypothesis that the observed clinical benefit was attributable to dose escalation with protons. The results of this meta-analysis are nevertheless intriguing, and underscore the importance of randomized clinical trials for more common head and neck malignancies to address the question of whether protons yield clinical benefit relative to IMRT [29].
Proton therapy for head and neck reirradiation One of the most compelling clinical scenarios for the use of proton therapy is for reirradiation of patients with recurrent or progressive head and neck cancer. Published experience in this setting is scant, but McDonald et al. [30 ] recently reported a series of 16 patients treated with protons for progressive or recurrent chordoma, 10 of which were in the head and neck region. Despite very high doses of prior radiation (median 75.2 Gy) and reirradiation with protons [median 75.6 Gy(RBE)], toxicities were lower than anticipated with 19% 2-year estimate of grade 3/4 late toxicity, and no myelopathy. Initial 2-year local control of 85% was promising for a population of patients with historically very poor survival. However, with median follow-up of only 26 months, additional follow-up is required to assess true rates of late toxicity for this group of patients treated with full dose reirradiation. &&
Intensity-modulated proton therapy for oropharyngeal squamous cell carcinoma There is considerable interest in the potential for IMPT in the treatment of OPSCC patients, as a means of minimizing long-term morbidity, and reducing the integral dose delivered to a relatively young cohort of patients with an excellent long-term prognosis. However, this is one of the more difficult sites to treat successfully and safely with proton beam therapy given the complex bilateral target volumes, requiring MFO-IMPT, with its attendant dose deposition uncertainties. The clinical outcomes literature has only recently begun to emerge, but appears encouraging. Investigators at MD Anderson have reported in abstract form the acute toxicity among an initial 26 p16þ OPSCC patients treated with IMPT, 16 of whom had minimum 6 month follow-up [31]. They found low rates of grade 3 mucositis (15%) and Volume 27 Number 3 May 2015
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Proton therapy for head and neck cancer Lukens et al.
anterior oral mucositis was rare. Fewer patients required feeding tubes (19%) relative to a historical control group treated with IMRT (48%). The majority of patients (94%) tolerated a regular diet at longest follow-up. These findings are intriguing and suggest the potential for protons to demonstrate their value by reducing healthcare costs associated with the morbidity of head and neck radiotherapy. Now with a median follow-up of 28 months, Frank et al. [21 ] have reported their initial experience with MFO-IMPT, including 10 squamous cell carcinoma (SCC) patients, all of whom obtained a complete clinical response. The majority of patients experienced only grade 1 xerostomia, and no patient developed grade 2 or greater anterior oral mucositis. In light of dose uncertainty with IMPT caused by anatomic changes during the course of therapy, weekly verification scans were obtained to assess the need for replanning; however, it is unclear how many patients required replanning. It is noteworthy that five of 10 SCC patients received induction chemotherapy, which presumably reduces dose uncertainty that would otherwise result from tumor shrinkage, and there was only one patient with at least T3 OPSCC treated with definitive upfront chemoradiotherapy. As such, this study is encouraging but does not provide sufficient clinical evidence to support the routine use of IMPT in the definitive treatment of bulky OPSCC. The efficacy of IMPT and potential differences in toxicity relative to IMRT are being evaluated by the currently accruing phase II/III trial for OPSCC at MD Anderson, which randomizes patients to treatment with IMRT or IMPT [29]. &&
COMPARATIVE AND COSTEFFECTIVENESS OF PROTONS FOR HEAD AND NECK CANCER There is a need for clinical evidence development to guide the appropriate implementation of proton therapy for head and neck cancer. The aboverandomized clinical trial is an important step in the generation of high-quality data [29]. Comparative effectiveness research comparing protons with IMRT should incorporate endpoints such as patientreported quality of life in addition to efficacy and toxicity outcomes [32]. Until such data become available, Dutch investigators have proposed costeffectiveness models incorporating dosimetric comparisons and NTCP models to guide implementation of IMPT [33 ]. Despite the multiple caveats that can be made regarding the assumptions used to build their model (e.g., survival data from studies prior to 2000, and a somewhat arbitrary ‘ceiling ratio’, or acceptable cost per quality-adjusted life year), their recommendations are remarkably &
similar to what is done in routine clinical practice: treatment allocation to IMPT versus IMRT based on a trade-off of expected costs and benefits for each individual patient. In practice, determining which patient is likely to benefit significantly from IMPT requires detailed dosimetric planning, as it can be difficult to determine a priori who is likely to benefit from IMPT. Therefore, until there are additional clinical data for various head and neck subsites, it will be challenging to generate comprehensive guidelines for which patients are appropriate for IMPT. In the current healthcare environment, taking into account the detailed dosimetric studies described above, as well as the significant cost of proton therapy, coverage of protons by insurers will likely be linked to a requirement for evidence development. The American Society for Radiation Oncology has developed model policies to address coverage of protons, and considers head and neck cancer ‘suitable for coverage with evidence development’, with the recommendation for coverage as long as the patient is enrolled in an institutional review board-approved clinical trial, or multiinstitutional patient registry [34]. A similar proposal to hasten evidence development is ‘Reference Pricing With Evidence Development’, in which the reference price for protons would be set at the current rate for IMRT, with a similar requirement that the patient be enrolled on study [35].
FUTURE DIRECTIONS: TAKING ADVANTAGE OF BIOLOGICAL DIFFERENCES OF PROTON DOSE DEPOSITION The potential benefit of protons relative to photons has primarily been evaluated dosimetrically, based on the physical properties of protons, assuming a constant RBE of protons relative to photons of 1.1. However, it is accepted that there are variations in the biological effectiveness of protons, with an increase in the RBE at the distal Bragg peak as the proton loses energy, and there is a corresponding increase in the linear energy transfer (LET), which is assumed to correlate with biological effectiveness. The LET distribution obtained with standard IMPT plans for head and neck cancer has been analyzed by Paganetti et al. [36,37 ], suggesting that current planning algorithms likely place areas of lower LET within the target volume, whereas LET hotspots are located at the periphery of the target, potentially within critical structures such as the brainstem (Fig. 2). There are efforts underway to use LET-based optimization as a form of biological planning, whereby areas of high LET are intentionally situated within target areas (such as areas of tumor hypoxia) and minimized in adjacent normal tissue [37 ].
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Dose
LETd 6 100% 5 4 3 2 1
6 100% 5 4 3 2 1
FIGURE 2. Dose distribution and distribution of dose-averaged linear energy transfer (LETd) for two clinically equivalent intensity-modulated proton therapy (IMPT) treatment plans. The contour for the gross tumor volume is shown in grey. Left: dose in percentage of prescribed dose. Right: LETd distribution in keV/mm. The LET distribution is a potential measure of biological effectiveness. Reproduced with permission from [37 ]. &
CONCLUSION The use of proton therapy for the treatment of head and neck cancer is an area of active research, evolution in practice, and heightened scrutiny due to technological advancements and an increasingly cost-conscious healthcare environment. Dosimetric data demonstrate the potential to reduce dose to critical adjacent normal tissue with protons, and maturing clinical data for base of skull tumors highlight impressive local control and lower than expected toxicity in both the definitive and reirradiation settings. Although there is the suggestion of clinical benefit with protons relative to IMRT from retrospective series and meta-analyses, compelling evidence will be provided by currently accruing randomized trials directly comparing the two treatment modalities. Likewise, although initial data regarding reduction in morbidity (and by extrapolation, potential for reduction in associated healthcare costs) are encouraging [21 ,31], future studies must incorporate health economic endpoints to assess the value of proton therapy. IMPT, the most sophisticated form of proton therapy, is required for the treatment of complex head and neck target volumes. Although it is currently being integrated into clinical practice, its routine use for definitive &&
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treatment of bulky OPSCC remains investigational in light of dose deposition uncertainty. In the future, enhancement of the therapeutic ratio with protons may be possible through biological optimization, whereby areas of potentially higher biological effectiveness at the distal edge of the beam are intentionally situated within hypoxic regions of the tumor. Acknowledgements None. Financial support and sponsorship None. Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Nutting CM, Morden JP, Harrington KJ, et al. Parotid-sparing intensity modulated versus conventional radiotherapy in head and neck cancer (PARSPORT): a phase 3 multicentre randomised controlled trial. Lancet Oncol 2011; 12:127–136.
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Proton therapy for head and neck cancer Lukens et al. 2. Ling DC, Kabolizadeh P, Heron DE, et al. Incidence of hospitalization in patients with head and neck cancer treated with intensity-modulated radiation therapy. Head Neck 2014. [Epub ahead of print] 3. Hunter KU, Lee OE, Lyden TH, et al. Aspiration pneumonia after chemointensity-modulated radiation therapy of oropharyngeal carcinoma and its clinical and dysphagia-related predictors. Head Neck 2014; 36:120–125. 4. Holliday EB, Frank SJ. Proton radiation therapy for head and neck cancer: a & review of the clinical experience to date. Int J Radiat Oncol Biol Phys 2014; 89:292–302. This is a recent comprehensive review of single-institution experiences to date, grouped by anatomic subsite. 5. Cozzi L, Fogliata A, Lomax A, Bolsi A. A treatment planning comparison of 3D conformal therapy, intensity modulated photon therapy and proton therapy for treatment of advanced head and neck tumours. Radiother Oncol 2001; 61:287–297. 6. van de Water TA, Bijl HP, Schilstra C, et al. The potential benefit of radiotherapy with protons in head and neck cancer with respect to normal tissue sparing: a systematic review of literature. Oncologist 2011; 16:366–377. 7. Lomax AJ, Goitein M, Adams J. Intensity modulation in radiotherapy: photons versus protons in the paranasal sinus. Radiother Oncol 2003; 66:11–18. 8. Widesott L, Pierelli A, Fiorino C, et al. Intensity-modulated proton therapy versus helical tomotherapy in nasopharynx cancer: planning comparison and NTCP evaluation. Int J Radiat Oncol Biol Phys 2008; 72:589–596. 9. Steneker M, Lomax A, Schneider U. Intensity modulated photon and proton therapy for the treatment of head and neck tumors. Radiother Oncol 2006; 80:263–267. 10. van der Laan HP, van de Water TA, van Herpt HE, et al. The potential of intensity-modulated proton radiotherapy to reduce swallowing dysfunction in the treatment of head and neck cancer: a planning comparative study. Acta Oncol 2013; 52:561–569. 11. Benghiat H, Cashmore J, Williams T, et al. Can protons or altered fractionation decrease neurotoxicity after chemoradiation in head and neck cancer? Clin Oncol 2014; 26:762–764. 12. Gulliford SL, Miah AB, Brennan S, et al. Dosimetric explanations of fatigue in head and neck radiotherapy: an analysis from the PARSPORT Phase III trial. Radiother Oncol 2012; 104:205–212. 13. Kandula S, Zhu X, Garden AS, et al. Spot-scanning beam proton therapy vs. intensity-modulated radiation therapy for ipsilateral head and neck malignancies: a treatment planning comparison. Med Dosim 2013; 38:390–394. 14. Ahn PH, Lukens JN, Teo BK, et al. The use of proton therapy in the treatment of head and neck cancers. Cancer J 2014; 20:421–426. 15. Lomax AJ. Intensity modulated proton therapy and its sensitivity to treatment uncertainties 2: the potential effects of inter-fraction and inter-field motions. Phys Med Biol 2008; 53:1043–1056. 16. Lomax AJ. Intensity modulated proton therapy and its sensitivity to treatment uncertainties 1: the potential effects of calculational uncertainties. Phys Med Biol 2008; 53:1027–1042. 17. Liu W, Frank SJ, Li X, et al. PTV-based IMPT optimization incorporating planning risk volumes vs. robust optimization. Med Phys 2013; 40:021709. 18. Zhu XR, Poenisch F, Li H, et al. A single-field integrated boost treatment planning technique for spot scanning proton therapy. Radiat Oncol 2014; 9:202. 19. Quan EM, Liu W, Wu R, et al. Preliminary evaluation of multifield and singlefield optimization for the treatment planning of spot-scanning proton therapy of head and neck cancer. Med Phys 2013; 40:081709. 20. Kraan AC, van de Water S, Teguh DN, et al. Dose uncertainties in IMPT for && oropharyngeal cancer in the presence of anatomical, range, and setup errors. Int J Radiat Oncol Biol Phys 2013; 87:888–896. This study evaluates the impact of anatomical changes and realistic simulations of all treatment-related uncertainties on delivered dose with IMPT for oropharyngeal tumors, finding that large deviations can occur. However, adaptive replanning can significantly improve adequate IMPT dose delivery. 21. Frank SJ, Cox JD, Gillin M, et al. Multifield optimization intensity modulated && proton therapy for head and neck tumors: a translation to practice. Int J Radiat Oncol Biol Phys 2014; 89:846–853. This is the first report of oncologic and toxicity outcomes with IMPT for head and neck tumors, including nine patients with OPSCC. Preliminary outcomes are encouraging and support the currently accruing randomized trial between IMPT and IMRT.
22. Noel G, Feuvret L, Calugaru V, et al. Chordomas of the base of the skull and upper cervical spine. One hundred patients irradiated by a 3D conformal technique combining photon and proton beams. Acta Oncol 2005; 44:700– 708. 23. Ares C, Hug EB, Lomax AJ, et al. Effectiveness and safety of spot scanning proton radiation therapy for chordomas and chondrosarcomas of the skull base: first long-term report. Int J Radiat Oncol Biol Phys 2009; 75:1111– 1118. 24. Resto VA, Chan AW, Deschler DG, Lin DT. Extent of surgery in the management of locally advanced sinonasal malignancies. Head Neck 2008; 30:222– 229. 25. Truong MT, Kamat UR, Liebsch NJ, et al. Proton radiation therapy for primary sphenoid sinus malignancies: treatment outcome and prognostic factors. Head Neck 2009; 31:1297–1308. 26. Fukumitsu N, Okumura T, Mizumoto M, et al. Outcome of T4 (International Union Against Cancer Staging System, 7th edition) or recurrent nasal cavity and paranasal sinus carcinoma treated with proton beam. Int J Radiat Oncol Biol Phys 2012; 83:704–711. 27. Rombi B, Ares C, Hug EB, et al. Spot-scanning proton radiation therapy for & pediatric chordoma and chondrosarcoma: clinical outcome of 26 patients treated at Paul Scherrer Institute. Int J Radiat Oncol Biol Phys 2013; 86:578– 584. This study provides long-term outcome data for children treated with high-dose spot-scanned protons for base of skull tumors, supporting its safety and efficacy. 28. Patel SH, Wang Z, Wong WW, et al. Charged particle therapy versus photon & therapy for paranasal sinus and nasal cavity malignant diseases: a systematic review and meta-analysis. Lancet Oncol 2014; 15:1027–1038. This meta-analysis suggests increased locoregional control and DFS with the use of protons relative to IMRT for tumors in this location, with the caveat of the likely presence of confounders. 29. Frank SJ. Phase II/III Randomized Trial of Intensity-Modulated Proton Beam Therapy (IMPT) Versus Intensity-Modulated Photon Therapy (IMRT) for the Treatment of Oropharyngeal Cancer of the Head and Neck. Available from: https://clinicaltrials.gov/show/NCT01893307. [Accessed 12 December 2014]. 30. McDonald MW, Linton OR, Shah MV. Proton therapy for reirradiation of && progressive or recurrent chordoma. Int J Radiat Oncol Biol Phys 2013; 87:1107–1114. One of the few series reporting the use of protons for head and neck reirradiation; patients received high doses initially and at the time of reirradiation, with promising local control and lower than expected toxicity. 31. Hutcheson K, Lewin JS, Garden AS, et al. Early experience with IMPT for the treatment of oropharyngeal tumors: acute toxicities and swallowing-related outcomes. Int J Radiat Oncol Biol Phys 2013; 87:S604. 32. Jagsi R, Bekelman JE, Brawley OW, et al. A research agenda for radiation oncology: results of the radiation oncology institute’s comprehensive research needs assessment. Int J Radiat Oncol Biol Phys 2012; 84:318– 322. 33. Ramaekers BL, Grutters JP, Pijls-Johannesma M, et al. Protons in head-and& neck cancer: bridging the gap of evidence. Int J Radiat Oncol Biol Phys 2013; 85:1282–1288. The authors explore a cost-effectiveness model for head and neck proton therapy and recommend allocating patients to IMPT based on a trade-off of expected costs and benefits for each individual patient. 34. ASTRO Model Policies: Proton Beam Therapy. 2014; Available from: www.astro.org/uploadedFiles/Main_Site/Practice_Management/Reimbursement/ASTRO%20PBT%20Model%20Policy%20FINAL.pdf. [Accessed 18 August 2014]. 35. Bekelman JE, Hahn SM. Reference pricing with evidence development: a way forward for proton therapy. J Clin Oncol 2014; 32:1540–1542. 36. Grassberger C, Trofimov A, Lomax A, Paganetti H. Variations in linear energy transfer within clinical proton therapy fields and the potential for biological treatment planning. Int J Radiat Oncol Biol Phys 2011; 80:1559–1566. 37. Paganetti H, van Luijk P. Biological considerations when comparing proton & therapy with photon therapy. Semin Radiat Oncol 2013; 23:77–87. An excellent discussion of the controversies surrounding potential biological differences between proton and photon radiotherapy, and the implications for future research.
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Proton therapy for head and neck cancer J. Nicholas Lukens a, Alexander Lin a, and Stephen M. Hahn b
Purpose of review Proton therapy for head and neck cancer is an area of active research as technological advances are increasingly integrated into clinical practice, and also the subject of heightened scrutiny due to the significant associated cost. This article will highlight recent research into proton dosimetry, studies evaluating its clinical benefit relative to other advanced radiotherapy modalities, and key safety and cost considerations. Recent findings Recent dosimetric analyses have quantified the potential for the most sophisticated form of proton therapy, intensity-modulated proton therapy (IMPT), to reduce dose to key anatomic structures in the head and neck, and highlight the potential for dose uncertainty with IMPT if not implemented in a careful manner. Clinical contributions demonstrate the potential for protons to yield excellent local control and lower than expected morbidity for tumors adjacent to critical neurological structures. There are promising data in the reirradiation setting, and emerging data for IMPT in oropharyngeal cancer. Summary Proton therapy for head and neck cancer holds significant potential, and promising single-institution experiences should be validated, wherever feasible, in prospective randomized clinical trials. In light of the significant associated cost, additional evidence is needed to guide the appropriate allocation of patients to IMPT versus intensity-modulated radiotherapy. Keywords cost-effectiveness research, head and neck cancer, intensity-modulated proton therapy, protons, reirradiation
INTRODUCTION Radiotherapy plays a key role in the treatment of patients with head and neck cancer in the definitive, adjuvant, and recurrent settings. However, the proximity of critical normal structures to tumors in the head and neck can result in severe acute and late toxicity. Technological advancements, such as intensity-modulated radiotherapy (IMRT), have resulted in improvements in some toxicity endpoints such as xerostomia [1]; however, the toxicity remains substantial [2,3]. There has been considerable interest in the use of proton therapy as a means of further reducing the toxicity of head and neck radiotherapy, by taking advantage of the unique physical properties of protons. Protons are charged particles that deliver most of their dose at the distal edge of their range (Bragg peak), and no dose beyond, potentially allowing for better sparing of adjacent organs at risk (OARs). Proton therapy has been in existence for several decades, with dosimetric data suggesting its superiority over conventional IMRT, potentially allowing for decreased toxicity while maintaining equivalent efficacy, or dose escalation for tumors in which the safe delivery of higher
doses is limited by adjacent critical structures such as the brainstem or spinal cord. The bulk of clinical experience to date for head and neck cancer has been limited primarily to the treatment of chordomas and chondrosarcomas, and nasal cavity and paranasal sinus tumors [4 ]. There has been growing interest and controversy regarding proton therapy recently, due to the increasing number of proton centers that are currently operational or in various stages of planning, the significant costs associated with the construction and operation of these centers, and the lack of strong evidence demonstrating its clinical superiority over ‘conventional’ IMRT. In &
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Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania and bDivision of Radiation Oncology, MD Anderson Cancer Center, Houston, Texas, USA Correspondence to J. Nicholas Lukens, MD, Department of Radiation Oncology, University of Pennsylvania School of Medicine, Perelman Center for Advanced Medicine, 3400 Civic Center Blvd., 4-West, Philadelphia, PA 19104, USA. Tel: +1 215 662 6567; fax: +1 215 349 8975; e-mail: [email protected] Curr Opin Oncol 2015, 27:165–171 DOI:10.1097/CCO.0000000000000181
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this context, over the past year there have been studies addressing the question of whether the apparent dosimetric advantages of proton therapy translate into demonstrable clinical benefit. Simultaneously, there has been considerable research into the optimization of the planning and delivery of proton therapy, to enable the well tolerated treatment of complex target volumes in the head and neck. Intensity-modulated proton therapy (IMPT), analogous to IMRT for photon-based therapy, allows for greater dosimetric optimization and holds the potential to further enhance the therapeutic ratio. However, owing to the greater uncertainty of dose deposition with protons, IMPT for head and neck cancer has been the subject of intense scrutiny, as well as emerging clinical experience. This article will focus on recent studies addressing these emerging trends, specifically recent additions to the dosimetric literature regarding potential advantages of protons (specifically IMPT) over IMRT, and whether this translates into demonstrable clinical benefit relative to what can be achieved with IMRT, and the recent utilization of IMPT for complex head and neck target volumes such as in the definitive treatment of oropharyngeal squamous cell carcinoma (OPSCC).
over photon therapy with regard to the ability to deliver an adequate dose to tumor while decreasing dose to adjacent normal tissues. Initial studies suggested that spot-scanned proton beams, in which a pencil beam is steered by magnets to paint dose, layer by layer into the target, were superior to scattered proton beams with regard to sparing OARs [5,6]. Studies that followed compared the best plans achievable with protons (IMPT) to the best achievable with photons (IMRT), and generally demonstrate that IMPT allows for dose escalation without exceeding the tolerance of critical structures such as the optic chiasm and optic nerves in the treatment of paranasal sinus tumors [7]. Using normal tissue complication probability models (NTCP), several authors have suggested that the apparent dosimetric advantage of IMPT may translate into clinical benefit, such as improving xerostomia by reducing dose to the parotid glands in nasopharyngeal carcinoma [8], and lowering rates of radiation-induced secondary malignancy [9]. Recently, it has been shown that IMPT may reduce dose to the swallowing muscles (pharyngeal constrictor muscles and supraglottic larynx) relative to what can be achieved with IMRT, and that using NTCP models, this would result in an additional 8% reduction in the rate of grades 2–4 swallowing dysfunction [10]. Exploring additional potential advantages of the lower integral dose delivered by proton therapy, it has been hypothesized that IMPT may reduce treatmentrelated fatigue by lowering dose to the posterior fossa for patients with advanced oropharyngeal carcinoma [11]. This hypothesis is based on the finding of increased acute fatigue with the use of IMRT on the randomized phase III Parotid-sparing intensity modulated versus conventional radiotherapy in head and neck cancer (PARSPORT) trial [1], which appeared to correlate at least in part to increased dose to the posterior fossa [12]. The clinical scenario in which protons appear to provide a clear dosimetric advantage, regardless of the method of delivery (passive scattering or spotscanning), is in the treatment of ipsilateral targets, for example, in the treatment of salivary gland malignancies, or well lateralized tonsillar cancer in which only ipsilateral neck treatment is required. Recent studies comparing spot-scanned protons to IMRT in this context quantify the significant sparing of the contralateral salivary glands, oral cavity, and spinal cord in this setting [13].
CURRENT TRENDS IN DOSIMETRIC STUDIES OF HEAD AND NECK PROTON THERAPY
Dose uncertainty of intensity-modulated proton therapy for the treatment of complex target volumes
There is a substantial body of literature demonstrating the dosimetric advantages of proton therapy
The treatment of complex, bilateral target volumes within the head and neck with proton therapy
KEY POINTS There appears to be significant clinical benefit for protons in the setting of full dose reirradiation of tumors at the base of skull, although additional follow-up is required to assess late effects. The integration of IMPT into clinical practice requires strict attention to several variables that contribute to uncertainty of dose deposition; for this reason IMPT is still considered investigational for bulky OPSCC. The results of the currently accruing randomized trial of IMPT versus IMRT for OPSCC will provide valuable insight into the safety and potential for reduced toxicity with IMPT. Pending additional clinical and health economic evidence, the allocation of patients to IMPT versus IMRT is done on a case-by-case basis, weighing the expected costs and benefits for each individual patient. Biological optimization, taking advantage of the variability of biological effectiveness along the path of the proton beam, holds the potential to further enhance the therapeutic ratio with proton therapy.
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Proton therapy for head and neck cancer Lukens et al.
requires spot-scanning proton therapy. Recent efforts have addressed the best method for the optimization of spot-scanned proton plans, to maximize sparing of adjacent OARs, while ensuring delivery of dose in a well tolerated and reliable manner. Although generally two or three fields are used, each field can be optimized separately to cover the entire target (single-field optimization, SFO), or the beams can be optimized simultaneously to cover the target with the sum of the fields, allowing each field to deliver a heterogeneous dose to the target volume (multifield optimization, MFO) (Fig. 1) [14]. MFO planning, which is more commonly referred to as IMPT, allows for greater degrees of freedom to produce optimal dose distributions. However, owing to the high degree of modulation of the spot weights, IMPT is subject to greater uncertainty of delivered dose deposition, resulting from several variables including proton beam range uncertainty, daily setup variability, and anatomic changes over the course of treatment (because of weight loss or tumor shrinkage) [15,16]. Efforts have been made to increase the ‘robustness’ of IMPT planning to account for these uncertainties [17]. For treatment of simpler ipsilateral targets, a form of SFO planning using an integrated boost appears to be optimal [18]. However, for treatment of complex volumes within the head and neck incorporating the primary site and bilateral neck, MFO-IMPT appears to be required Beam 1
to maximize sparing of adjacent normal tissues. A study by Quan et al. [19] compared SFO with MFO, both nominally and in the worst case scenario, the latter accounting for setup and range uncertainty. SFO degraded sparing of the parotids, but improved plan robustness, reducing dose uncertainty in the target by 23% relative to MFO. Nevertheless, the authors concluded that MFO-IMPT had ‘tolerable’ target coverage and recommended MFO as the planning method for cases requiring bilateral treatment. However, their analysis did not take into account anatomic changes over the course of treatment. A separate study that analyzed dose uncertainty with IMPT in light of anatomic changes in addition to setup and range uncertainty found that large dose deviations can occur with the combination of various errors; for example, without adaptive replanning to account for anatomic change, only 69% of 3700 simulations met the prescribed target coverage [20 ]. However, adaptive replanning appeared to significantly improve target coverage, prompting their recommendation of periodic computed tomography scans for recalculation of the dose, and replanning as necessary. Based on these findings, it is imperative that if IMPT is used in the treatment of complex bilateral targets in which there are expected anatomic changes over the course of treatment, such as in the definitive treatment of OPSCC, weekly verification scans and adaptive replanning &&
Beam 2
Total dose
FIGURE 1. Example dose distributions of individual beams (left, center) and the sum of the planned beams (right) for singlefield optimization (SFO) plan (top) and a multifield optimization (MFO) plan (bottom). Reproduced with permission from [14]. 1040-8746 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
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are performed as necessary [20 ,21 ]. Alternatively, another approach for the use of IMPT in oropharyngeal cancer is to limit its use to postoperative cases in which anatomic changes are less pronounced [14].
TRANSLATING PROTON DOSIMETRY INTO THE CLINIC: ATTEMPTS TO QUANTIFY THE CLINICAL BENEFIT The clinical experience with protons has generally been limited to single-institution series, and the majority of experience has been with chordomas and chondrosarcomas near the base of skull [22,23], or nasal cavity and paranasal sinus tumors [24–26], in which delivery of significant radiation dose with photons is limited by adjacent critical neurological tissue (recently reviewed by Holliday and Frank [4 ]). Recent contributions to the literature suggest that now with relatively long follow-up (mean of 46 months), high dose spot-scanning proton therapy appears well tolerated and effective in the treatment of pediatric patients with chordoma and chondrosarcoma [27 ]. This study included 17 children with base of skull tumors, treated after maximal safe resection with high doses [relative biological effectiveness (RBE), 74 Gy(RBE) for chordoma and 66 Gy(RBE) for chondrosarcoma], yielding excellent local control (80%) and a relatively low rate (19%) of late effects attributable to protons, all grade 2 or less. These data lend support to the rationale that proton therapy can be used to safely escalate dose to tumors in close proximity to critical structures, potentially improving clinical outcomes relative to what can be achieved with photons. &
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Does proton therapy improve survival relative to intensity-modulated radiotherapy? Given the relative rarity of the tumor types in the above single-institution series, and the infeasibility of conducting a randomized trial comparing photons and protons for these less common tumors, Patel et al. [28 ] performed a systematic review and meta-analysis to compare outcomes with protons versus photons for paranasal sinus and nasal cavity tumors. Overall, they reported increased overall survival and disease-free survival (DFS) at 5 years for patients treated with charged particle therapy, with no difference in local control at 5 years, but improved local control at longest follow-up. A subgroup analysis was performed to compare proton therapy with IMRT, which found significantly higher DFS at 5 years [relative risk (RR) 1.44, P ¼ 0.045], and locoregional control at longest follow-up (RR 1.26, P ¼ 0.011) for proton patients. &
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However, a greater proportion of photon patients had high-risk histologies relative to proton patients (50 versus 27%, P ¼ 0.06), raising the possibility of confounding. Furthermore, the median radiation dose was equivalent between charged particle and photon patients (60 and 61 Gy, respectively), calling into question the hypothesis that the observed clinical benefit was attributable to dose escalation with protons. The results of this meta-analysis are nevertheless intriguing, and underscore the importance of randomized clinical trials for more common head and neck malignancies to address the question of whether protons yield clinical benefit relative to IMRT [29].
Proton therapy for head and neck reirradiation One of the most compelling clinical scenarios for the use of proton therapy is for reirradiation of patients with recurrent or progressive head and neck cancer. Published experience in this setting is scant, but McDonald et al. [30 ] recently reported a series of 16 patients treated with protons for progressive or recurrent chordoma, 10 of which were in the head and neck region. Despite very high doses of prior radiation (median 75.2 Gy) and reirradiation with protons [median 75.6 Gy(RBE)], toxicities were lower than anticipated with 19% 2-year estimate of grade 3/4 late toxicity, and no myelopathy. Initial 2-year local control of 85% was promising for a population of patients with historically very poor survival. However, with median follow-up of only 26 months, additional follow-up is required to assess true rates of late toxicity for this group of patients treated with full dose reirradiation. &&
Intensity-modulated proton therapy for oropharyngeal squamous cell carcinoma There is considerable interest in the potential for IMPT in the treatment of OPSCC patients, as a means of minimizing long-term morbidity, and reducing the integral dose delivered to a relatively young cohort of patients with an excellent long-term prognosis. However, this is one of the more difficult sites to treat successfully and safely with proton beam therapy given the complex bilateral target volumes, requiring MFO-IMPT, with its attendant dose deposition uncertainties. The clinical outcomes literature has only recently begun to emerge, but appears encouraging. Investigators at MD Anderson have reported in abstract form the acute toxicity among an initial 26 p16þ OPSCC patients treated with IMPT, 16 of whom had minimum 6 month follow-up [31]. They found low rates of grade 3 mucositis (15%) and Volume 27 Number 3 May 2015
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Proton therapy for head and neck cancer Lukens et al.
anterior oral mucositis was rare. Fewer patients required feeding tubes (19%) relative to a historical control group treated with IMRT (48%). The majority of patients (94%) tolerated a regular diet at longest follow-up. These findings are intriguing and suggest the potential for protons to demonstrate their value by reducing healthcare costs associated with the morbidity of head and neck radiotherapy. Now with a median follow-up of 28 months, Frank et al. [21 ] have reported their initial experience with MFO-IMPT, including 10 squamous cell carcinoma (SCC) patients, all of whom obtained a complete clinical response. The majority of patients experienced only grade 1 xerostomia, and no patient developed grade 2 or greater anterior oral mucositis. In light of dose uncertainty with IMPT caused by anatomic changes during the course of therapy, weekly verification scans were obtained to assess the need for replanning; however, it is unclear how many patients required replanning. It is noteworthy that five of 10 SCC patients received induction chemotherapy, which presumably reduces dose uncertainty that would otherwise result from tumor shrinkage, and there was only one patient with at least T3 OPSCC treated with definitive upfront chemoradiotherapy. As such, this study is encouraging but does not provide sufficient clinical evidence to support the routine use of IMPT in the definitive treatment of bulky OPSCC. The efficacy of IMPT and potential differences in toxicity relative to IMRT are being evaluated by the currently accruing phase II/III trial for OPSCC at MD Anderson, which randomizes patients to treatment with IMRT or IMPT [29]. &&
COMPARATIVE AND COSTEFFECTIVENESS OF PROTONS FOR HEAD AND NECK CANCER There is a need for clinical evidence development to guide the appropriate implementation of proton therapy for head and neck cancer. The aboverandomized clinical trial is an important step in the generation of high-quality data [29]. Comparative effectiveness research comparing protons with IMRT should incorporate endpoints such as patientreported quality of life in addition to efficacy and toxicity outcomes [32]. Until such data become available, Dutch investigators have proposed costeffectiveness models incorporating dosimetric comparisons and NTCP models to guide implementation of IMPT [33 ]. Despite the multiple caveats that can be made regarding the assumptions used to build their model (e.g., survival data from studies prior to 2000, and a somewhat arbitrary ‘ceiling ratio’, or acceptable cost per quality-adjusted life year), their recommendations are remarkably &
similar to what is done in routine clinical practice: treatment allocation to IMPT versus IMRT based on a trade-off of expected costs and benefits for each individual patient. In practice, determining which patient is likely to benefit significantly from IMPT requires detailed dosimetric planning, as it can be difficult to determine a priori who is likely to benefit from IMPT. Therefore, until there are additional clinical data for various head and neck subsites, it will be challenging to generate comprehensive guidelines for which patients are appropriate for IMPT. In the current healthcare environment, taking into account the detailed dosimetric studies described above, as well as the significant cost of proton therapy, coverage of protons by insurers will likely be linked to a requirement for evidence development. The American Society for Radiation Oncology has developed model policies to address coverage of protons, and considers head and neck cancer ‘suitable for coverage with evidence development’, with the recommendation for coverage as long as the patient is enrolled in an institutional review board-approved clinical trial, or multiinstitutional patient registry [34]. A similar proposal to hasten evidence development is ‘Reference Pricing With Evidence Development’, in which the reference price for protons would be set at the current rate for IMRT, with a similar requirement that the patient be enrolled on study [35].
FUTURE DIRECTIONS: TAKING ADVANTAGE OF BIOLOGICAL DIFFERENCES OF PROTON DOSE DEPOSITION The potential benefit of protons relative to photons has primarily been evaluated dosimetrically, based on the physical properties of protons, assuming a constant RBE of protons relative to photons of 1.1. However, it is accepted that there are variations in the biological effectiveness of protons, with an increase in the RBE at the distal Bragg peak as the proton loses energy, and there is a corresponding increase in the linear energy transfer (LET), which is assumed to correlate with biological effectiveness. The LET distribution obtained with standard IMPT plans for head and neck cancer has been analyzed by Paganetti et al. [36,37 ], suggesting that current planning algorithms likely place areas of lower LET within the target volume, whereas LET hotspots are located at the periphery of the target, potentially within critical structures such as the brainstem (Fig. 2). There are efforts underway to use LET-based optimization as a form of biological planning, whereby areas of high LET are intentionally situated within target areas (such as areas of tumor hypoxia) and minimized in adjacent normal tissue [37 ].
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Dose
LETd 6 100% 5 4 3 2 1
6 100% 5 4 3 2 1
FIGURE 2. Dose distribution and distribution of dose-averaged linear energy transfer (LETd) for two clinically equivalent intensity-modulated proton therapy (IMPT) treatment plans. The contour for the gross tumor volume is shown in grey. Left: dose in percentage of prescribed dose. Right: LETd distribution in keV/mm. The LET distribution is a potential measure of biological effectiveness. Reproduced with permission from [37 ]. &
CONCLUSION The use of proton therapy for the treatment of head and neck cancer is an area of active research, evolution in practice, and heightened scrutiny due to technological advancements and an increasingly cost-conscious healthcare environment. Dosimetric data demonstrate the potential to reduce dose to critical adjacent normal tissue with protons, and maturing clinical data for base of skull tumors highlight impressive local control and lower than expected toxicity in both the definitive and reirradiation settings. Although there is the suggestion of clinical benefit with protons relative to IMRT from retrospective series and meta-analyses, compelling evidence will be provided by currently accruing randomized trials directly comparing the two treatment modalities. Likewise, although initial data regarding reduction in morbidity (and by extrapolation, potential for reduction in associated healthcare costs) are encouraging [21 ,31], future studies must incorporate health economic endpoints to assess the value of proton therapy. IMPT, the most sophisticated form of proton therapy, is required for the treatment of complex head and neck target volumes. Although it is currently being integrated into clinical practice, its routine use for definitive &&
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treatment of bulky OPSCC remains investigational in light of dose deposition uncertainty. In the future, enhancement of the therapeutic ratio with protons may be possible through biological optimization, whereby areas of potentially higher biological effectiveness at the distal edge of the beam are intentionally situated within hypoxic regions of the tumor. Acknowledgements None. Financial support and sponsorship None. Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Nutting CM, Morden JP, Harrington KJ, et al. Parotid-sparing intensity modulated versus conventional radiotherapy in head and neck cancer (PARSPORT): a phase 3 multicentre randomised controlled trial. Lancet Oncol 2011; 12:127–136.
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Proton therapy for head and neck cancer Lukens et al. 2. Ling DC, Kabolizadeh P, Heron DE, et al. Incidence of hospitalization in patients with head and neck cancer treated with intensity-modulated radiation therapy. Head Neck 2014. [Epub ahead of print] 3. Hunter KU, Lee OE, Lyden TH, et al. Aspiration pneumonia after chemointensity-modulated radiation therapy of oropharyngeal carcinoma and its clinical and dysphagia-related predictors. Head Neck 2014; 36:120–125. 4. Holliday EB, Frank SJ. Proton radiation therapy for head and neck cancer: a & review of the clinical experience to date. Int J Radiat Oncol Biol Phys 2014; 89:292–302. This is a recent comprehensive review of single-institution experiences to date, grouped by anatomic subsite. 5. Cozzi L, Fogliata A, Lomax A, Bolsi A. A treatment planning comparison of 3D conformal therapy, intensity modulated photon therapy and proton therapy for treatment of advanced head and neck tumours. Radiother Oncol 2001; 61:287–297. 6. van de Water TA, Bijl HP, Schilstra C, et al. The potential benefit of radiotherapy with protons in head and neck cancer with respect to normal tissue sparing: a systematic review of literature. Oncologist 2011; 16:366–377. 7. Lomax AJ, Goitein M, Adams J. Intensity modulation in radiotherapy: photons versus protons in the paranasal sinus. Radiother Oncol 2003; 66:11–18. 8. Widesott L, Pierelli A, Fiorino C, et al. Intensity-modulated proton therapy versus helical tomotherapy in nasopharynx cancer: planning comparison and NTCP evaluation. Int J Radiat Oncol Biol Phys 2008; 72:589–596. 9. Steneker M, Lomax A, Schneider U. Intensity modulated photon and proton therapy for the treatment of head and neck tumors. Radiother Oncol 2006; 80:263–267. 10. van der Laan HP, van de Water TA, van Herpt HE, et al. The potential of intensity-modulated proton radiotherapy to reduce swallowing dysfunction in the treatment of head and neck cancer: a planning comparative study. Acta Oncol 2013; 52:561–569. 11. Benghiat H, Cashmore J, Williams T, et al. Can protons or altered fractionation decrease neurotoxicity after chemoradiation in head and neck cancer? Clin Oncol 2014; 26:762–764. 12. Gulliford SL, Miah AB, Brennan S, et al. Dosimetric explanations of fatigue in head and neck radiotherapy: an analysis from the PARSPORT Phase III trial. Radiother Oncol 2012; 104:205–212. 13. Kandula S, Zhu X, Garden AS, et al. Spot-scanning beam proton therapy vs. intensity-modulated radiation therapy for ipsilateral head and neck malignancies: a treatment planning comparison. Med Dosim 2013; 38:390–394. 14. Ahn PH, Lukens JN, Teo BK, et al. The use of proton therapy in the treatment of head and neck cancers. Cancer J 2014; 20:421–426. 15. Lomax AJ. Intensity modulated proton therapy and its sensitivity to treatment uncertainties 2: the potential effects of inter-fraction and inter-field motions. Phys Med Biol 2008; 53:1043–1056. 16. Lomax AJ. Intensity modulated proton therapy and its sensitivity to treatment uncertainties 1: the potential effects of calculational uncertainties. Phys Med Biol 2008; 53:1027–1042. 17. Liu W, Frank SJ, Li X, et al. PTV-based IMPT optimization incorporating planning risk volumes vs. robust optimization. Med Phys 2013; 40:021709. 18. Zhu XR, Poenisch F, Li H, et al. A single-field integrated boost treatment planning technique for spot scanning proton therapy. Radiat Oncol 2014; 9:202. 19. Quan EM, Liu W, Wu R, et al. Preliminary evaluation of multifield and singlefield optimization for the treatment planning of spot-scanning proton therapy of head and neck cancer. Med Phys 2013; 40:081709. 20. Kraan AC, van de Water S, Teguh DN, et al. Dose uncertainties in IMPT for && oropharyngeal cancer in the presence of anatomical, range, and setup errors. Int J Radiat Oncol Biol Phys 2013; 87:888–896. This study evaluates the impact of anatomical changes and realistic simulations of all treatment-related uncertainties on delivered dose with IMPT for oropharyngeal tumors, finding that large deviations can occur. However, adaptive replanning can significantly improve adequate IMPT dose delivery. 21. Frank SJ, Cox JD, Gillin M, et al. Multifield optimization intensity modulated && proton therapy for head and neck tumors: a translation to practice. Int J Radiat Oncol Biol Phys 2014; 89:846–853. This is the first report of oncologic and toxicity outcomes with IMPT for head and neck tumors, including nine patients with OPSCC. Preliminary outcomes are encouraging and support the currently accruing randomized trial between IMPT and IMRT.
22. Noel G, Feuvret L, Calugaru V, et al. Chordomas of the base of the skull and upper cervical spine. One hundred patients irradiated by a 3D conformal technique combining photon and proton beams. Acta Oncol 2005; 44:700– 708. 23. Ares C, Hug EB, Lomax AJ, et al. Effectiveness and safety of spot scanning proton radiation therapy for chordomas and chondrosarcomas of the skull base: first long-term report. Int J Radiat Oncol Biol Phys 2009; 75:1111– 1118. 24. Resto VA, Chan AW, Deschler DG, Lin DT. Extent of surgery in the management of locally advanced sinonasal malignancies. Head Neck 2008; 30:222– 229. 25. Truong MT, Kamat UR, Liebsch NJ, et al. Proton radiation therapy for primary sphenoid sinus malignancies: treatment outcome and prognostic factors. Head Neck 2009; 31:1297–1308. 26. Fukumitsu N, Okumura T, Mizumoto M, et al. Outcome of T4 (International Union Against Cancer Staging System, 7th edition) or recurrent nasal cavity and paranasal sinus carcinoma treated with proton beam. Int J Radiat Oncol Biol Phys 2012; 83:704–711. 27. Rombi B, Ares C, Hug EB, et al. Spot-scanning proton radiation therapy for & pediatric chordoma and chondrosarcoma: clinical outcome of 26 patients treated at Paul Scherrer Institute. Int J Radiat Oncol Biol Phys 2013; 86:578– 584. This study provides long-term outcome data for children treated with high-dose spot-scanned protons for base of skull tumors, supporting its safety and efficacy. 28. Patel SH, Wang Z, Wong WW, et al. Charged particle therapy versus photon & therapy for paranasal sinus and nasal cavity malignant diseases: a systematic review and meta-analysis. Lancet Oncol 2014; 15:1027–1038. This meta-analysis suggests increased locoregional control and DFS with the use of protons relative to IMRT for tumors in this location, with the caveat of the likely presence of confounders. 29. Frank SJ. Phase II/III Randomized Trial of Intensity-Modulated Proton Beam Therapy (IMPT) Versus Intensity-Modulated Photon Therapy (IMRT) for the Treatment of Oropharyngeal Cancer of the Head and Neck. Available from: https://clinicaltrials.gov/show/NCT01893307. [Accessed 12 December 2014]. 30. McDonald MW, Linton OR, Shah MV. Proton therapy for reirradiation of && progressive or recurrent chordoma. Int J Radiat Oncol Biol Phys 2013; 87:1107–1114. One of the few series reporting the use of protons for head and neck reirradiation; patients received high doses initially and at the time of reirradiation, with promising local control and lower than expected toxicity. 31. Hutcheson K, Lewin JS, Garden AS, et al. Early experience with IMPT for the treatment of oropharyngeal tumors: acute toxicities and swallowing-related outcomes. Int J Radiat Oncol Biol Phys 2013; 87:S604. 32. Jagsi R, Bekelman JE, Brawley OW, et al. A research agenda for radiation oncology: results of the radiation oncology institute’s comprehensive research needs assessment. Int J Radiat Oncol Biol Phys 2012; 84:318– 322. 33. Ramaekers BL, Grutters JP, Pijls-Johannesma M, et al. Protons in head-and& neck cancer: bridging the gap of evidence. Int J Radiat Oncol Biol Phys 2013; 85:1282–1288. The authors explore a cost-effectiveness model for head and neck proton therapy and recommend allocating patients to IMPT based on a trade-off of expected costs and benefits for each individual patient. 34. ASTRO Model Policies: Proton Beam Therapy. 2014; Available from: www.astro.org/uploadedFiles/Main_Site/Practice_Management/Reimbursement/ASTRO%20PBT%20Model%20Policy%20FINAL.pdf. [Accessed 18 August 2014]. 35. Bekelman JE, Hahn SM. Reference pricing with evidence development: a way forward for proton therapy. J Clin Oncol 2014; 32:1540–1542. 36. Grassberger C, Trofimov A, Lomax A, Paganetti H. Variations in linear energy transfer within clinical proton therapy fields and the potential for biological treatment planning. Int J Radiat Oncol Biol Phys 2011; 80:1559–1566. 37. Paganetti H, van Luijk P. Biological considerations when comparing proton & therapy with photon therapy. Semin Radiat Oncol 2013; 23:77–87. An excellent discussion of the controversies surrounding potential biological differences between proton and photon radiotherapy, and the implications for future research.
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