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Proton Therapy for Head and Neck Cancer: The Future is Now

Michael Chuong, MDRadiation Oncologist

Disclosures

None

Overview

Physical limitations of photons

Dosimetric/clinical proton data for HNC

Proton patient selection

Practical proton considerations

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The physical characteristics of protons provide the rationale for its use – THIS IS NOT NEW!

“The proton proceeds through the tissue in very nearly a straight line, and the tissue is ionized at the expense of energy of the proton until the proton is stopped…these properties make it possible to irradiate intensely a strictly localized region within the body.”

Robert Wilson, 1946

Proton therapy

X-ray ProtonNo mass Large mass

No charge + charge

Apisarnthanarax et al, 2018

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Courtesy of Varian

Passive scattering (OLD)

Pencil beam scanning (NEW)

MCI Exclusively Has Pencil Beam Scanning

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Why protons?

Superior dose-distribution

Lower normal tissue doses Higher tumor doses

Lower toxicities Higher local control andmaybe survival

Rosenthal et al, IJROBP, 2008

PARSPORT – IMRT vs. 3DCRT

Nutting et al. Lancet Oncol, 2011

3D IMRT

Grade 2+ xerostomia12 months: 3D 74% vs. IMRT 38%, p=.00324 months: 3D 83% vs. IMRT 29%, p<.0001

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x-rays

protons

5 yr

LC %

Dose (GyE)Adapted from Hug PTCOG 2012

CHORDOMA/CHONDROSARCOMA

63 Gy/28 fxGrade 3+ toxicity <1%

LC ~95%

High therapeutic ratio

74.4 Gy/62 fx, BIDGrade 3+ toxicity ~15%

LC ~60%

Unfavorable therapeutic ratio

Where can protons improve the therapeutic ratio?

46 year old female

T4N0 spindle cell carcinoma right maxillary sinus Involvement of infraorbital nerve, orbit, infratemporal fossa s/p endoscopic maxillectomy, rhinotomy, orbital

decompression 74.4 Gy in 1.2 Gy fractions BID (optic structures in target

volume)

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Mendenhall et al. Acta Oncol, 2011

Mendenhall et al. Acta Oncol, 2011

Therapeutic ratio w/ protons

Selected sinonasal/paranasal sinus, NPC patients Optic chiasm/nerve, salivary gland, anterior oral cavity sparing Brainstem/spinal cord avoidance Dose intensification

Selected OPC patients Salivary gland, pharyngeal constrictor, anterior oral cavity sparing

Ipsilateral target

Reirradiation

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10 pts w/ N0 OPC

70 Gy, 46-54 Gy

Primary goal to evaluate parotid and submandibular gland

POTENTIAL BENEFITS OF SCANNED INTENSITY-MODULATED PROTON THERAPYVERSUS ADVANCED PHOTON THERAPY WITH REGARD TO SPARING OF THE

SALIVARY GLANDS IN OROPHARYNGEAL CANCER

TARA A. VAN DE WATER, M.SC.,* ANTONY J. LOMAX, PH.D.,y HENDRIK P. BIJL, M.D., PH.D.,*MARIJE E. DE JONG, B.A.,* CORNELIS SCHILSTRA, PH.D.,* EUGEN B. HUG, M.D.,y

AND JOHANNES A. LANGENDIJK, M.D., PH.D.* Int. J. Radiation Oncology Biol. Phys., Vol. 79, No. 4, pp. 1216–1224, 2011Ó

van de Water, IJROBP, 2011

van de Water, IJROBP, 2011

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Patient selection for protons should be done on an individual patient basis through

comparing x-ray vs. proton treatment plans

van de Water, IJROBP, 2011

Distance between target and normal tissue matters

Jakobi et al. IJROBP, 2015

Langendijk et al, Radiother Oncol, 2013

The same reduction in mean dose to salivary glands will not always result in similar toxicity risk reductions Dependent on baseline value obtained w/ reference technique Dependent on the shape of NTCP curve

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Clinical evidence for protons

Early limited data suggest protons can achieve superior dose escalation and/or reduce toxicity Predominantly passive scattering IMPT is expected to further reduce toxicities Largely retrospective data

Several prospective trials currently underway

Sinonasal/Paranasal sinus

Local failure is common (~50-60% LC)

Improved LC w/ dose escalation (≥65 Gy) is limited w/ photons

Close proximity of brainstem, brain, optic structures, oral cavity, larynx, salivary glands

High rate of severe acute/late toxicity (brain necrosis, blindness, mucositis, etc.) Hoppe et al. IJRBOP,72:763-769,2008, Padovani et al. IJROBP,56:169-176,2003

3DCRT IMRT Proton

Saito et al. Oncology Letters, 2015

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MGH experience Resto et al. (Head Neck, 2008)

102 pts. treated 1991-2002 Proton-photon; median 71.6 Gy(RBE) 5 yr LRC ~90%

Pommier et al. (AOHNS, 2006) 23 pts. w/ ACC BOS 87% had gross residual disease, 48% only had biopsy Proton-photon; median 75.9 Gy(RBE) 5 yr LRC 93%, 5 yr OS 77%

Fitzek et al. (Cancer, 2002) 19 pts. w/ neuroblastoma, neuroendocrine tumors Proton-photon; median 69.2 Gy(RBE) 5 yr LC 88%, 5 yr OS 74%

Zenda et al. IJROBP, 2011

5 yr OS and DFS significantly higher for CPT

Why better outcomes for CPT? Higher dose? Higher RBE?

Phase II trial IMRT or proton (NCT01586767)

Nasopharynx

IMRT is standard of care, reduces xerostomia

Target is in challenging anatomic location

Few clinical proton reports

OAR sparing w/ protons suggested by in silico studies

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Reduced oral cavity dose

Holliday et al. Int J Particle Therapy, 2015.

Matched IMPT and IMRT pts

Mean oral cavity dose:17.3 Gy IMPT vs. 40.6 Gy IMRT; p<.001

G tube rates:20% IMPT vs. 65% IMRT; p=.02

No patient with mean oral cavity dose <26 Gy(RBE) required feeding tube

40 patients26 IMRT, 14 proton17 NPC, 23 nasal/paranasal

MGH Phase II Trial (NCT00592501)

Preliminary results from 23 patients Stage III-IVB (T3/4 60%, N2/3 65%) 70 Gy(RBE) + cis q3 wk cis/5FU Photons for low neck, protons for NPX + upper neck

At median FU 28 months, LRC 100% 2 yr DFS 90% (2 patients w/ DM) 2 yr OS 100%

G3 hearing loss (29%), G tube (48%), weight loss (38%) No G3+ xerostomia

Chan et al. IJROBP, 2012.

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• First 9 NPC patients treated at MDACC w/ IMPT• T1-2 66%, N1-2 89%• Induction 78%, concurrent 100%, adjuvant

chemo 22%• Median 70 Gy(RBE) in 33 fx

Mean dose to 29 OARs

IMRT (Gy) IMPT (Gy) pRight cochlea 45.6 35.4 .041Left cochlea 51.3 41.1 .032Mandible 45.1 33.3 .001Larynx 42.8 29.6 .027Esophagus 43.6 28.9 .031Oral cavity 36.9 16.6 <.001Tongue 48.3 34.2 .005Spinal cord 27.2 15.3 <.001Subthalamic nucleus 34.5 23.6 .049Area postrema 37.2 24.5 .012

Favorable early clinical outcomes

Median FU 24.5 mo

2-yr LRC 100% 2-yr DMFS 88.9% 2-yr OS 88.9%

Grade 3 acute toxicity Mucositis 11% Dysphagia 22% Dermatitis 44%

Grade 3 late toxicity None but longer follow up needed

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Oropharynx

Increasing incidence of HPV+ OPC

Dosimetric studies suggest proton therapy can further reduce xerostomia and dysphagia van der Laan et al. Acta Oncol, 2013; van de Water et al. IJROBP, 2011

Limited clinical data

MD Anderson

Initial 50 OPC patients treated w/ IMPT

Stage IV 80%, p16+ 88%, 50% never smoker

Simultaneous integrated boost GTV 66-70 Gy(RBE) CTV 54-63 Gy(RBE)

Bilateral neck 80%

Induction chemo 40%, concurrent chemo 64%

Gunn et al. IJROBP, 2016

2 yr OS 94.5%2 yr PFS 88.6%

Median follow up 29 months

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Acute G3 toxicities 46% dermatitis

24% dysphagia 58% oral mucositis

2% xerostomia

Late G3 toxicities 12% dysphagia

2% xerostomia

2% mucositis

Frank et al, IJROBP, 2014

Unilateral target

For bilateral targets, OAR overlap by TV limits benefit of sharp dose gradients achieved w/ protons

For unilateral targets, larger separation between target and normal tissue Lower mean parotid dose results in better function, even for doses <10 Gy (Rancati et al,

IJROBP, 2010)

Submandibular gland and oral cavity sparing may also reduce xerostomia

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Kandula et al, Medical Dosimetry, 2013

IMRT Proton p

Cord max (Gy) 36.9 20.1 .034

Brainstem max (Gy) 34.1 13.9 .002

Contra parotid mean (Gy) 5.3 0.45 .003

Oral cavity mean (Gy) 17.6 4.6 .003

Treated w/ 7-beam IMRT

Primary + ipsilateral neck

Comparison IMPT plans generated

MD Anderson

“Immediate shift in practice from IMRT to PBRT” once PBRT become

available

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IMRT Proton

Reirradiation

Up to ~1/3 of HNC patients w/ have LRR

Many are not surgical candidates

Chemotherapy outcomes are dismal Median survival 5-10 months

LR progression is the major cause of death Re-RT can cure some, improve QOL Significant toxicity from re-RT, potentially limiting prescription dose

Improved outcomes >58 Gy (Watkins et al, Head Neck, 2009)

Memorial Sloan Kettering

Largest published HNC re-RT experience

Most treated w/ modern RT techniques

LRC: 2 yr 47%, 5 yr 34%

OS: 2 yr 43%, 5 yr 25% 35 patients alive >5 years!

Grade 3+ toxicity 31%

Riaz et al, Radiother & Oncol, 2014

Nomogram to predict 2 yr LRC

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Proton Beam Re-Irradiation for Recurrent Head and Neck Cancer: Multi-

Institutional Report on Feasibility and Early Outcomes

Paul Romesser, Oren Cahlon, Eli Scher, Eugen Hug, Kevin Sine, Carl DeSelm, Jana Fox, Dennis Mah, Madhur Garg, John Han-Chih Chang, Nancy Lee

IJROBP 2016

Methods

Retrospective analysis of prospective registries from 2 hybrid community-academic proton centers

92 patients w/ recurrent HNC s/p prior definitive intent EBRT 85% had OPC primary 83% had 1 prior RT course, median 61.4 Gy 39% salvage surgery

)

MAN

USC

RIP

T

ACC

EPTE

D

Figure 3!A.!

B.!

Coronal!Axial !

Median 34.4 months to re-RT

Median 60.6 Gy(RBE)

~50% concurrent chemo

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MAN

USC

RIP

T

ACC

EPTE

D

Cum

ulat

ive

Inci

denc

e

0 6 12 18 24

Time (months)

0%

20%

40%

60%

80%

100% Locoregional failure

12-month LRF 25.1%MAN

USC

RIP

T

ACC

EPTE

D

0%

20%

40%

60%

80%

100%

Number at risk 92 66 41 22 9

0 6 12 18 24

12-month OS 65.2%

Median follow up 13.3 months

~95% completed proton re-RT

A Phase II Study of Proton Re-Irradiation for Recurrent Head and Neck Cancer

N=40 pts

Primary Endpoint: Incidence of Grade 3 complications at 3 months

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Practical considerations

Proton dose distribution is sensitive to changes in tissue density

Planned and delivered doses can differ significantly

Setup Inadequate immobilization Weight loss

Anatomic changes Tumor regression Change in air cavities Motion

Range uncertainties Calculating CT Hounsfield units Converting HU to stopping power Reconstruction artifacts

Engelsmann/Knopf, PSI Winter School 2014

Conclusions

Proton therapy has undeniable dosimetric advantages (no exit dose) But are they clinically meaningful?

Very likely yes for selected patients!

Mostly retrospective clinical evidence is encouraging

Results of prospective studies are eagerly awaited, need to enroll to these trials

Patient selection should be done on an individual patient basis

Thank you