Proton beam therapy head and neck cancer Recent advances head and neck cancer

1. Proton beam therapy in
head and neck cancers
Dr Ankit Vishwani
Mch head and neck oncology
Rcc trivandrum

2. Background
Radiotherapy -application of radiation for the purpose of therapeutic gain.
Recent decades progress in technology
● effective means of immobilizing patients
● defining treatment volume
● limiting dose to normal tissues.
The balance between delivering treatment of sufficient intensity to cure and
minimizing the risk of serious sequelae remains a challenge for oncologists.

3. Types Of Radiation

4. Therapeutic ratio
● Probability of tumor control and
risk of normal tissue damage
● Primary barrier to dose
escalation -is risk of damaging
normal tissues
● improved by reducing dose to
non-targeted tissues, which both
reduces toxicity and facilitates
dose escalation for increased
tumour control.
● Herein lies the rationale for
proton therapy.

5. Rationale for proton therapy
● Unlike photons, which deposit their
radiation doses close to their entrance
into the body,
● Protons deposit most of their energy at
the end of their paths, in a phenomenon
known as the Bragg peak, the point at
which the majority of energy deposition
occurs.
● Before the Bragg peak, the deposited
dose is about 30% of maximum dose
.
● Thereafter, the deposited dose falls to
zero, nearly nonexistent exit dose.

6. ● The integral dose with proton therapy is approximately 60% lower than
any photon-beam technique.
● But the dose to the tumor remains the same or higher.
● decreasing radiation dose to normal tissues and avoiding collateral
damage.

7. Proton dose distribution
Proton dose distribution- Depends on the concept of Linear
energy transfer (LET) .
The rate of energy loss due to ionisation and excitation
caused by a charged particle travelling in a medium
● proportional to the square of the particle charge
● inversely proportional to the square of its velocity.
As the particle velocity approaches zero near the end of its
range, the rate of energy loss becomes maximum.
The sharp increase or peak in dose deposition at the end of
particle range is called the Bragg peak.

8. Photon vs Proton
Low entrance dose(plateau
Maximum dose at depth( brag
peak)
Rapid distal dose fall off.
Significant entry and exit dose

9. SPREAD OUT BRAG PEAK
● The Bragg peak of a monoenergetic
proton beam is too narrow
● It cannot cover the extent of most target
volumes.
● In order to provide wider depth
coverage,Bragg peak can be spread by
superimposition of several beams of
different energies
● Called as spread-out Bragg peak (SOBP).

10. Conception of proton therapy
● 1946 ,Harvard physicist Robert Wilson
● Protons can be used clinically
● Maximum radiation dose can be placed into
the tumor
● Proton therapy provides sparing of healthy
tissues
● 1990: First hospital based proton therapy
facility was opened at the Loma Linda
University Medical Center (LLUMC) in
California

11. Proton Therapy : An Emerging Modality
● 110 centers in operation
worldwide.
● Apollo proton cancer centre
Chennai Tamil Nadu since 2019 ( c
230, 2 gantries ,1 fixed beam)
● Under construction in India TMC
Mumbai ,Health care global.

12. Components of proton beam therapy
● Proton
accelerator
● Beam
transport
system
● Gantry
● Treatment
delivery
system

13. GENERATION OF PROTON
.
Protons are produced from hydrogen gas
1. Obtained from electrolysis of deionized water or
2. commercially available high-purity hydrogen gas.
Application of a high-voltage electric current to the hydrogen gas strips the
electrons off the hydrogen atoms, leaving positively charged protons.

14. Proton Accelerators
Once protons have been generated, they must be accelerated such that the
proton energy is sufficient to reach the distal edge of a tumor
● Cyclotron
● Synchrotron

15. CYCLOTRON
Cyclotrons are composed of two large
semi-circles with a space between them.
These two semi-circles are known as 'D's'
or 'Dees'.
a magnetic field is perpendicular to the
plane of the dees that is kept constant.
Protons are injected at the center on the
two dees.
By alternating the voltage supplied to the
dees, the protons are gradually
accelerated.

16. SYNCHROTON
Cyclotrons are only able to produce protons of a fixed
energy.
Synchrotrons can produce protons of various energies
by varying the magnetic and electrical fields.
Each complete circuit of the proton pulse through the
accelerator increases the proton energy.
When the desired energy is reached, the proton pulse
is extracted from the applicator.

17. Beam line/ transport system
● Once the protons have been accelerated, they
must be guided to the gantry for delivery to the
patient.
● They are series of magnets that guide the
protons towards gantry .

18. GANTRY
● The gantry is a large
structure to enable protons
with therapeutic energies
bent.
● It can rotate 360 around the
patient to position the
nozzle.

20. Treatment planning
● It is important to take advantage of the physical properties
of the proton beam (Bragg peak) and the lack of exit dose.
● The challenge is to choose the shortest and most reliable
path for the beams to reach the target.
● Treatment plans can be complicated by fluctuations in a
patient’s anatomy, such as changes in tumor size, patient
weight, and daily patient position.
● Intensive quality assurance as well as reimaging during the
treatment is essential to account for all of these technical
uncertainties and ensure the integrity .

21. IPMT
● Intensity-modulated proton therapy
(IMPT)
● advanced proton technology that can result
in treatment plans with remarkable
conformality
● sparing of normal tissue irradiation via the
use of pencil beam scanning.

22. PENCIL BEAM SCANNING
Pencil beam scanning uses a tumor’s location,
shape and size to create a customized pattern of
protons to precisely treat the tumor while avoiding
nearby healthy tissue.
Pencil beam scanning uses two pairs of scanning
magnets that guide beams laterally to a specified spot
and precisely paint the target volume.
Most of the newly built proton therapy centers have
this technique, with many centers only performing
PBS .

23. Passive scattering
In principle, the energy modulator, scatterer, collimator, and the compensator work
together to ensure that the radiation dose to distal and lateral side of the target is
highly conformal, although its proximal side may be conformal, meaning normal
tissue in target’s proximal side may receive excess radiation dose.

25. Oropharyngeal cancers
Traditionally, IMRT has been a successful option for oropharyngeal carcinoma with
reduced toxicities (such as xerostomia).
With an increasing proportion of young, HPV-positive patients,
Treatment related toxicities must be further reduced to ensure optimal quality of life.
Proton therapy offers the benefit of treatment deintensification
Sparing irradiation of contralateral oropharyngeal and nasopharyngeal tissue.
Provide a dosimetric advantage , virtually eliminates irradiation to critical structures

26. Carcinoma oropharynx
When IMRT is used to treat
unilateral targets, incidental
and unnecessary dose to the
uninvolved contralateral
oropharyngeal and
nasopharyngeal mucosa
remains high, often in the
range of 30–45 Gy.
Highly lateralised treatment
with IPMT ,sparing of midline
structures.

28. 25 patients with OPC were treated with IMPT between 2011 and 2012.
Vs
IMRT-treated controls extracted from a database of patients with OPC treated
between 2000 and 2009
Results showed that the mean doses to the anterior and posterior oral cavity,
hard palate, larynx, mandible, and esophagus were significantly lower with IMPT
than with IMRT comparison plans generated for the same cohort.

30. A potential advantage of intensity-modulated proton therapy (IMPT) over intensity-modulated (photon) radiation therapy (IMRT) in
the treatment of oropharyngeal carcinoma (OPC) is lower radiation dose to several critical structures involved in the development of
nausea and vomiting, mucositis, and dysphagia. The purpose of this study was to quantify doses to critical structures for patients
with OPC treated with IMPT and compare those with doses on IMRT plans generated for the same patients and with a matched
cohort of patients actually treated with IMRT. In this study, 25 patients newly diagnosed with OPC were treated with IMPT between
2011 and 2012. Comparison IMRT plans were generated for these patients and for additional IMRT-treated controls extracted from a
database of patients with OPC treated between 2000 and 2009. Cases were matched based on the following criteria, in order:
unilateral vs bilateral therapy, tonsil vs base of tongue primary, T-category, N-category, concurrent chemotherapy, induction
chemotherapy, smoking status, sex, and age. Results showed that the mean doses to the anterior and posterior oral cavity, hard
palate, larynx, mandible, and esophagus were significantly lower with IMPT than with IMRT comparison plans generated for the
same cohort, as were doses to several central nervous system structures involved in the nausea and vomiting response. Similar
differences were found when comparing dose to organs at risks (OARs) between the IMPT cohort and the case-matched IMRT
cohort. In conclusion, these findings suggest that patients with OPC treated with IMPT may experience fewer and less severe side
effects during therapy. This may be the result of decreased beam path toxicities with IMPT due to lower doses to several dysphagia,
odynophagia, and nausea and vomiting– associated OARs. Further study is needed to evaluate differences in long-term disease
control and chronic toxicity between patients with OPC treated with IMPT in comparison to those treated with IMRT

31. From 2012 to 2014, 50 OPC patients IMPT (prospective)
From 2010 to 2012 100 OPC patient IMRT (from institutional
data)(retrospective)
The median follow-up time was 32 months.

34. Sino nasal cancers
The standard treatment for nasal and paranasal tumors is surgical resection
+/-adjuvant radiation, with or without chemotherapy.
In patients with unresectable tumors, treatment with definitive radiation results in
discouraging outcomes -limiting dose constraints of the surrounding critical
structures, optic pathways and brainstem.
Several studies have demonstrated better tumor coverage when using proton
beam therapy in comparison to IMRT or 3D-CRT .

35. Salivary gland tumors

37. Background: As proton beam radiation therapy (PBRT) may allow greater normal tissue sparing when compared with
intensity-modulated radiation therapy (IMRT), we compared the dosimetry and treatment-related toxicities between patients treated
to the ipsilateral head and neck with either PBRT or IMRT.
Methods: Between 01/2011 and 03/2014, 41 consecutive patients underwent ipsilateral irradiation for major salivary gland cancer or
cutaneous squamous cell carcinoma. Acute toxicities were assessed using the National Cancer Institute Common Terminology
Criteria for Adverse Events version 4.0.
Results: Twenty-three (56.1%) patients were treated with IMRT and 18 (43.9%) with PBRT. The groups were balanced in terms of
baseline, treatment, and target volume characteristics. IMRT plans had a greater median maximum brainstem (29.7Gy vs. 0.62Gy
(RBE), P<0.001), maximum spinal cord (36.3 Gy vs. 1.88 Gy (RBE), P < 0.001), mean oral cavity (20.6 Gy vs. 0.94 Gy (RBE), P <
0.001), mean con- tralateral parotid (1.4 Gy vs. 0.0 Gy (RBE), P < 0.001), and mean contralateral submandibular (4.1 Gy vs. 0.0 Gy
(RBE), P < 0.001) dose when compared to PBRT plans. PBRT had significantly lower rates of grade 2 or greater acute dysgeusia
(5.6% vs. 65.2%, P < 0.001), mucositis (16.7% vs. 52.2%, P = 0.019), and nausea (11.1% vs. 56.5%, P = 0.003).
Conclusions: The unique properties of PBRT allow greater normal tissue sparing without sacrificing target coverage when irradiating
the ipsilateral head and neck. This dosimetric advantage seemingly translates into lower rates of acute treatment-related toxicity.

38. Study period 2011 to 2014
41 patients underwent ipsilateral irradiation for major salivary
gland cancer.The availability of PBRT, during this period,
resulted in an immediate shift in practice from IMRT to PBRT.
IMRT plans had a greater
median maximum brainstem (29.7Gy vs. 0.62Gy (RBE),
P<0.001),
maximum spinal cord (36.3 Gy vs. 1.88 Gy (RBE), P < 0.001),
mean oral cavity (20.6 Gy vs. 0.94 Gy (RBE), P < 0.001),
mean contralateral parotid (1.4 Gy vs. 0.0 Gy (RBE), P < 0.001),
mean contralateral submandibular (4.1 Gy vs. 0.0 Gy (RBE), P <
0.001) dose when compared to PBRT plans.

39. PBRT had significantly lower rates of grade 2 or greater acute dysgeusia (5.6%
vs. 65.2%, P < 0.001), mucositis (16.7% vs. 52.2%, P = 0.019), and nausea
(11.1% vs. 56.5%, P = 0.003).
Conclusions:
The unique properties of PBRT allow greater normal tissue sparing without
sacrificing target coverage when irradiating the ipsilateral head and neck

40. The relative biological effectiveness (RBE) is defined as the ratio of the doses
required by two radiations to cause the same level of effect

42. Nasopharyngeal cancer
● Radiation with or without chemotherapy is the treatment of choice for nasopharyngeal
carcinoma (NPC).
● The complex anatomy with close proximity to critical structures, presents several
challenges.
● IMRT -increased dose delivered to nontarget structures along the beam path .
● Some subsets such as EBV-negative or previously irradiated, locally recurrent disease, are
particularly challenging
.
● In such cases, proton beam therapy might allow for dose escalation while minimising dose
to adjacent structures.

43. IMPT versus IMRT treatment plans for 29 organs at risk (OAR),
Lewis and colleagues reported
13 OAR received lower mean dose with proton-based plans.

44. Dosimetric data showed IMPT plans were able
to achieve significantly lower mean doses to
several OARs,
the bilateral cochlea,
the esophagus,
the larynx
the mandible,
the oral cavity, and
the tongue.
result in lower incidence of hearing loss,
dysphagia, osteonecrosis, mucositis, and
dysgeusia.

45. Proton beam therapy offers an alternative radiotherapy approach for treating NPC
Excellent treatment outcomes and possible reduction in overall toxicity.
Future prospective clinical studies are needed to evaluate for neurological toxicity
and treatment outcomes in patients with recurrent and T4 disease, locally
advanced disease.

46. Re-irradiation for recurrent head and neck cancer
● Several patients who were definitively treated for head and neck cancer will
develop recurrence of disease
● May require treatment with high-dose reirradiation in order to achieve
effective disease control.

47. In a cohort of 206 patients, traditional IMRT re-irradiation for recurrent
head and neck disease resulted in suboptimal locoregional control and
survival rates at 2 years of 59 and 51%, respectively, with significant
grade 3+ toxicity (32% at 2 years, 48% at 5 years)

48. (15 passive scattering proton therapy, 35 IMPT).
Locoregional failure-free survival, distant metastasis-free survival (DMFS), progression-free
survival, and overall survival rates at 1 year were 68.4, 74.9, 60.1, and 83.8%, respectively.
Acute grade 3 toxicity was reported in 18 patients (30%), and feeding tubes were placed in
13 patients (22%) .

49. ● Retreating recurrent head and neck disease remains a challenging task
● Larger retreatment volumes have also been strongly associated with
treatment toxicity and death
● Proton beam therapy seems to have a relatively safe toxicity profile in
comparison to traditional photon re-irradiation .
● Treatment planning in the recurrent setting is highly individualized for each
patient

50. Skull base tumors
● Proton beam therapy has been used for many decades
● Skull base tumours including chordomas and chondrosarcomas.
● Require high doses of radiation to obtain local control where dose escalation is
limited by the adjacent brain.
● Results achieved with spotscanning proton beam therapy have been impressive,
with local control achieved in 70–100% of patients.
● Standard of care in NCCN guidelines.

51. 64 patients with skull-base chordomas (n = 42) and chondrosarcomas (n = 22)
5-year LC rates -81% chordomas ,94% chondrosarcomas
Five years rates of DSS and OS were 81% and 62% for chordomas and 100% and 91% for
chondrosarcomas.
High-grade late toxicity ,1 patient -Grade 3 ,1 patient - Grade 4 unilateral optic neuropathy, 2
patients with Grade 3 central nervous system necrosis.
No patient experienced brainstem toxicity. 5-year freedom from high-grade toxicity was 94%.

52. Abstract
Purpose: To evaluate effectiveness and safety of spot-scanning-based proton radiotherapy (PT) in skull-base chordomas and chondrosarcomas.
Methods and materials: Between October 1998 and November 2005, 64 patients with skull-base chordomas (n = 42) and chondrosarcomas (n = 22) were
treated at Paul Scherrer Institute with PT using spot-scanning technique. Median total dose for chordomas was 73.5 Gy(RBE) and 68.4 Gy(RBE) for
chondrosarcomas at 1.8-2.0 Gy(RBE) dose per fraction. Local control (LC), disease specific survival (DSS), and overall survival (OS) rates were calculated.
Toxicity was assessed according to CTCAE, v. 3.0.
Results: Mean follow-up period was 38 months (range, 14-92 months). Five patients with chordoma and one patient with chondrosarcoma experienced local
recurrence. Actuarial 5-year LC rates were 81% for chordomas and 94% for chondrosarcomas. Brainstem compression at the time of PT (p = 0.007) and
gross tumor volume >25 mL (p = 0.03) were associated with lower LC rates. Five years rates of DSS and OS were 81% and 62% for chordomas and 100%
and 91% for chondrosarcomas, respectively. High-grade late toxicity consisted of one patient with Grade 3 and one patient with Grade 4 unilateral optic
neuropathy, and two patients with Grade 3 central nervous system necrosis. No patient experienced brainstem toxicity. Actuarial 5-year freedom from
high-grade toxicity was 94%.
Conclusions: Our data indicate safety and efficacy of spot-scanning based PT for skull-base chordomas and chondrosarcomas. With target definition, dose
prescription and normal organ tolerance levels similar to passive-scattering based PT series, complication-free, tumor control and survival rates are at
present comparable.

53. Local control of less than 50% -observed
with photons when prescription dose was
limited to less than 60 Gy.
Stereotactic radiosurgery-, resulting in
65–85% of patients achieving local control.
Results achieved with spotscanning proton
beam therapy (73 gy)have been
impressive, with local control achieved in
70–100% of patients.

54. Periorbital tumors
● Orbital preservation is a challenge for patients with these rare tumors.
● A multidisciplinary orbit-sparing approach has been described with the aim of
achieving the goals of function (vision), cure, and cosmesis.
● 20 patients were treated according to this protocol orbit-sparing surgery followed by
proton therapy for newly diagnosed malignant epithelial tumors of the lacrimal gland
(n ¼ 7), lacrimal sac or nasolacrimal duct (n ¼ 10), or eyelid (n ¼ 3).

55. ● At a median follow-up time of 27.1 months, no patient had local recurrence; 1
had regional recurrence and 1 developed distant metastases.
● Major toxicity -chronic grade 3 epiphora (3 patients) and grade 3 exposure
keratopathy (3 patients).
● 4 patients experienced a decrease in visual acuity from baseline.
● Proton therapy is now added as an option in the updated National
Comprehensive Cancer Network guidelines for periorbital tumors.

58. Limitations and potential concerns
Toxicities with proton beam therapy including dermatitis (100% grade 2 or worse in
unilateral radiation cases),
Protons have relatively low entrance (skin) doses when monoenergetic beams are used.
However with spread out brag peaks result in significant, entrance dose with loss of the
skin sparing effects —especially for targets ,in close proximity to the skin

61. Limitations and potential concerns
● Neurological toxicity ( 20% in treatment of paranasal sinus and nasal cavity
tumours),
● Temporal lobe necrosis (20% in a small cohort of nasopharyngeal carcinoma
cases).
● Concerns surrounding brainstem necrosis have been raised about paediatric
patients with primary brain tumours.
● To what degree the benefits achieved in acute toxicity ,will translate to real
improvements in chronic toxicity remains to be seen.

62. ● The conformality comes with range uncertainties and concerns regarding
plan robustness .
● Technical research and development to optimise inroom imaging, treatment
planning, and motion management have lagged behind progress achieved
in IMRT
● Proton beam therapy is especially sensitive to fluctuations in patient
positioning and anatomical changes .
● Technological advances and excellent quality assurance are required to
ensure a safe and effective delivery.

63. Cost effectiveness
Most of these studies currently convey that the cost 2-3 times higher than
for delivering IMRT.
($20,257 and $36,659 as the upfront cost of 33 fractions of IMRT and
IMPT, respectively.)
The cost difference is reduced when costs are considered over the entire
cycle of care.
Later cost reductions in use of other resources because of reduced toxicity.

64. Future directions
Multiple efforts are underway to improve the technical delivery of proton beam
therapy, including the development of
● improved quality assurance,
● onboard imaging
● automated methods of adaptive treatment planning.
to precisely deliver the radiation dose to the desired target volumes.

65. ● Proton beam therapy for head and neck cancer -not currently supported by
level one evidence
● Prospective randomised trials comparing IMRT vs proton beam therapy are
currently
● Oropharynx cancer (NCT01893307) (multicenter randomized trial conducted
by MD Anderson Cancer Center for patients with locally advanced OPC)
● Unilateral salivary and skin cancers (NCT02923570).(Memorial Sloan
Kettering Cancer Center)

66. Future direction to focus on the long-term sequelae -secondary malignancy.
In an analysis of the Surveillance, Epidemiology, and End Results (SEER)
database, Chung and colleagues -no significant difference in risk for the
development of secondary malignancies between proton or photon therapy .

67. Conclusion
Based on existing evidence, coming years, proton
beam therapy will almost certainly become
● ubiquitous
● affordable
● more effective.
The clinical benefits for patients with head and
neck cancer are becoming increasingly apparent
Can no longer be ignored in the contemporary
management of head and neck cancer and clinical
trial design.

68. Thank you