PROTON THERAPY IN CANCER MANAGEMENT K.S.

REDDY DIRECTOR REGIONAL CANCER CENTRE PUDUCHERRY

CT-Based Mould Brachytherapy in Early Oral Cancers in Patients Unfit for Surgery: an Option worth Exploring Dr. Ashutosh Mukherji, Mr. S Morougan, Mr. K.Saravannan, Dr. S Vivekanandam, Dr. K S Reddy
Department of Radiotherapy, Regional Cancer Centre, JIPMER
Introduction: Brachytherapy in the oral cavity is an important alternative to conventional treatment and provides a high localized dose and short overall treatment time. A rapid fall of dose beyond radioactive source makes it possible for increased tumour control and sparing surrounding tissue while short overall treatment duration reduces risk of tumour repopulation. Moulds are fabricated to hold the catheters in position as closely as possible to tumour surface to provide adequate dose coverage of tumour volume and increase distance to other normal surrounding structures. Image based planning and dose optimisation help in better defining target volume and dose coverage. Materials and Methods: A retrospective analysis of patients of early squamous cell carcinomas of lip and buccal mucosa otherwise not fit for surgery from September 2011 to September 2013 in Department of Radiotherapy, RCC, JIPMER, to study response to curative mould brachytherapy. Double plane moulds were prepared for all cases except two cases. Patients were then followed up till disease recurrence. In this study evaluation was done of the technique used, planning details, response to therapy and reactions encountered. Results: Six patients treated by mould therapy were reviewed; four cases were of lip and two of buccal mucosal cancers. Dose delivered ranged from 12.5-45 Gy in fraction sizes of 250-350 cGy.EQD2 ranged from 18-64 Gy. Maximum dose to OAR was 91% of prescribed dose. Local mucositis was only reaction in all of cases which resolved in 3-6 weeks.is All patients had CR and only Oral cancers account for 5-7% all cancers and brachytherapy an important alternative to patient nodal recurrence at 18 months. radicalhad surgery especially in oral cavity. It provides a high localized dose of radiation, with rapid Conclusions Mould therapy is a safe and fall-off and:short overall treatment time [1]. effective treatment method for selected early and superficial squamous cell carcinomas of the oral cavity, although indications are limited. Mould brachytherapy is technique of delivering brachytherapy by customised applicator to provide a constant and reproducible frame for source positioning.[2] Local control rate more than 90% for T1 and T2N0 tumours with brachytherapy alone [1]. Mould therapy is indicated: in previously untreated carcinomas of lip, floor of mouth, soft palate, or gingiva, and T1/2 tumours with complete response after external beam radiotherapy. Integration of imaging and optimization of dose distribution by improved planning systems: better tumour localization with improved dose distribution to the tumour.[3] A retrospective analysis of patients of early squamous cell carcinomas of lip and buccal mucosa not fit for surgery. Study done from September 2011 to September 2013 in Department of Radiotherapy, RCC, JIPMER. Double plane moulds were prepared for all cases except two. Patients were then followed up till disease recurrence. Evaluation was done of technique used, planning details, response to therapy and reactions encountered.

Abstract

Mould preparation:

The moulds prepared from thermoplastic + dental wax and customised for each patient. Lesion marked by the oncologist, the physicist makes initial cut out for the mould with thermoplastic frame over which dental wax is layered.

Mould matched with lesion surface and local anatomy; edges trimmed and smoothened and required catheter positions marked into the mould.

Materials and Methods

Catheters then fixed to mould, and mould again positioned on the patient to check feasibility of catheter placement and lesion coverage. The lesion was then marked with lead wires and CT-simulation of patient in treatment position done with mould in place.

Introduction

Initial lesion marked out on examination

Lesion marked by ink before mould preparation

Aims and Objectives

But there is paucity of both literature on the use of HDR mould brachytherapy and the optimal time, dose and fractionation guidelines.[4,5] To assess target dose coverage, acute reactions and dose to organs at risk in mould brachytherapy. To assess clinical outcome in patients with early oral cancer treated by mould brachytherapy

MAIN OBJECTIVES

Thermoplastic frame prepared and matched with local anatomy

Thermoplastic frame moulded to patient anatomy then layered with dental wax and catheters positioned

HYPOTHESIS
Mould therapy is a safe and effective treatment method for selected early and superficial squamous cell carcinomas of the oral cavity with results comparable to surgery although indications are limited.

Mould with catheters positioned on patient, edges trimmed, lead wires are put before CT simulation to identify lesion boundaries

CT-Based Mould Brachytherapy in Early Oral Cancers in Patients Unfit for Surgery: an Option worth Dr. Ashutosh Mukherji , Mr. S Morougan, Mr. K.Saravannan, Dr.Exploring S Vivekanandam, Dr. K S Reddy
Department of Radiotherapy, Regional Cancer Centre, JIPMER
Dose delivered ranged from 12504500cGy in fraction sizes of 250-350 cGy delivered twice daily. Two patients who received mould therapy as boost + EBRT for 4-4.5 weeks; two weeks after completion of mould therapy. EQD2 of these two patients were 18 and 30 Gy. The remaining four patients who received mould therapy as the definitive treatment completed their schedules in 11 15 Dose colour-wash showing lesion fractions over six to eight days. EQD2 of coverage by prescribed isodose patients rangedof from 54 Gy for Dose was prescribed to 80-85% isodose line in most these cases to keep volume tissue receiving recurrent cases doses to 64toGy for greater than 200% of prescribed dose to less than 5% and disease further higher within radically treated cases. substance of the mould. In all cases the organ at risk was the mandible. Maximum dose to OAR was 91% of prescribed dose to 2cc of OAR with median dose being 68% (range 48-91%).

CT based 3D image of patient with lead wires marking site of lesion

Results & Conclusions

All patients had complete response and only one patient with an initial lip lesion had nodal recurrence at 18 months. Other cases have maintained their remission. All patients are under follow-up with median duration being 12 months (range 3-23 months). Three patients have completed more than 18 months follow-up and the rest below 6 months.

RESULTS

Observations

Local mucositis (grade 1 in all cases and grade 2 in 2 cases)

was only reaction in all cases which resolved in 3-6 weeks. There were no late sequelae noted like ulcers, necrosis or strictures in any case. CT-based planning helped identify volumes of tissue receiving dose greater than 150% and optimising accordingly.

Lesion characteristics
SITE INVOLVED Site involved Lip Tongue Floor of Mouth Buccal mucosa Number

4 0 0 2 TYPE OF LESION

BED for 3 and 10 Gy doses were less than 100 Gy in all cases for late toxicities.

Plans optimised so as to keep volumes receiving more than 200% within the mould.

Mould therapy is a safe and effective treatment method for selected early and superficial squamous cell carcinomas of the oral cavity, though indications are limited. Author reports no potential source of conflict of interest boosting early cancers of 1) Mazeron JJ, Ardiet JM, It can be a cost effective method of treating radically or accessible regions in oral Haie-Mder C et al. cavity. GEC-ESTRO
recommendations for brachytherapy for head and neck squamous cell

CONCLUSIONS

Primary Recurrent

4 2

References

Radiother Oncol 2009;91:150 6.dose-volume optimisation carcinomas. CT based treatment planning allows 2) Ariji E, Hayashi N, Kimura Y, Uchida Hayashi K, Nakamura T. Customized more accurately and helpsT, in identifying areas at risk of mould brachytherapy for oral carcinomas through use of high-dose-rate treatment sequelae. remote afterloading apparatus. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1999;87:50812. 3) Nag S. High dose rate brachytherapy: its clinical applications and treatment guidelines. Technol Cancer Res Treat. 2004;3:26987. 4) Fietkau R. Brachytherapy for head and neck tumours. Activity Selectron Brachytherapy J. 1993;27:69-72.

Acute skin reactions immediate post brachy

Healed reactions at 4 weeks post brachy

Treatments of Cancer
Surgery, Radiation

therapy and Chemotherapy are the first line treatments.

RT - Past, Present & Future - Perspectives

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The Evolution of Radiation Therapy

1950s 1960s 1970s 1980s 1990s
Computerized 3D CT Treatment Planning

2000s

Functional Imaging

Standard Collimator
The linac reduced complications compared to Co60

Cerrobend Blocking Electron Blocking Blocks were used to reduce the dose to normal tissues

MLC leads to 3D conformal therapy which allows the first dose escalation trials.

Dynamic MLC and IMRT

Computerized IMRT introduced which allowed escalation of dose and reduced compilations

High resolution IMRT

IMRT Evolution evolves to smaller and smaller subfields and high resolution IMRT along with the introduction of new imaging technologies

Particle therapy
Electrons Protons Neutrons Carbon ions Particle therapy works in a similar manner as x-rays; except since they are bigger and more powerful, they can destroy the DNA more than x-rays, which often ruins the ability of the cell to repair itself.

A Man - A Vision

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In 1946 Harvard physicist Robert Rathbun Wilson

(1914-2000) first proposed*:

Protons can be used clinically Accelerators are available Maximum radiation dose can be placed into the tumor Proton therapy provides sparing of normal tissues Modulator wheels can spread narrow Bragg peak
*Wilson, R.R. (1946), Radiological use of fast protons, Radiology 47, 487.

History of Proton Beam Therapy

1946 1954 1958

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R. Wilson suggests use of protons First treatment of pituitary tumors First use of protons as a neurosurgical tool

1967
1974 1990

First large-field proton treatments in Sweden

Large-field fractionated proton treatments

program begins at HCL, Cambridge, MA First hospital-based proton treatment center opens at Loma Linda University Medical Center, California

Why protons ?

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Protons are attractive to radiotherapy because of their physical dose distribution The RBE of protons are indistinguishable from 250 kV X-rays, which means that they are 10-15% more effective than 60Co (RBE=1.1) The OER of proton beams is not distinguishable from X-rays (2.5 3) Protons are sparsely ionizing, except for a region at the end of particles range In the entrance plateau, the average LET is about 0.5 keV/ rising to a max of 100 keV/ This high LET component is restricted to a tiny portion of the terminal track, it does not have any significant effect (this should be kept in mind when planning treatment close to critical structures)

Just Remember!!!
As

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protons traverse matter, their maximum energy is not distributed at first interaction causing them to scatter in a different direction, leaving a void down range. THINK MASS. stay on relatively straight paths. Interactions along that path simply slow down the proton and shorten its distance.

Protons

Maximum

energy is still delivered at the end of the proton beams path.

Benefits from Protons in Treatment Planning

Finite

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depth (No dose beyond given distance) Sharp penumbra Highest dose is delivered at end of beam path. Allows for a lower integral dose

RADIOBIOLOGY
Protons Not RBE

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have a relatively low LET

much difference from photons

= 1.1 and believed to be slightly higher at distal end of peak

Cobalt

Gray Equivalent (CGE) = Gy x 1.1

Neutron

dose from patient and Nozzle (can be reduced with spot scanning)

Range = Depth
Controlled

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by maximum energy of proton beam Represents the initial peak in a SOBP Maximum range for 230 MV proton: - Passive scattering beam = 28 cm - Active scanning beam = 34 cm

Pristine peak and SOBP

Pristine

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peak is a Pure single Bragg peak SOBP is Spread Out Bragg peak SOBP is defined as 90% - 90% on depth dose curve Beam energy is degraded by a modulation wheel Beam current is also modulated for a smooth useful dose plateau Zero to Full modulation is possible

Proton Accelerators
Cyclotron Mono-energetic Continuous beam Smaller footprint

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Synchrotron Poly- energetic Pulse beam Larger footprint

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Production of Clinical Proton Beam

Cyclotron:

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230 MeV proton beams (~33 cm depth in water) Energy degrader: reduce energy to the desired value Beam line: guide the proton beam to the treatment room

Energy Degrader
Made

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of Carbon.

Variable

steps of thickness. energy level to desired maximum.

Decreases

Dirty produces neutron contamination (contained in degrading area by 15 feet thick walls)

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Why protons ?

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An advanced form of targeted radiation therapy reduction in integral dose to normal tissues compared to conventional radiation including IMRT which may translate into reduced toxicities Dose escalation to tumors increased local control Treat tumors close to critical organs eye, spinal cord

More safely & effectively combine with chemotherapy & surgery

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A Simple Comparison with Photons

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Patient Positioning for Charged Particles

High

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precision in patient positioning is even more important for charged particle therapy, because of the sharp Bragg Peaks. Depending on the disease site, extensive immobilisation procedures need to be adopted

Body mould immobilisation for pelvic sites

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Practical Proton Radiotherapy Beams Range modulator

Practical Proton Radiotherapy Beams Collimators and beam shaping

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Irregular apertures are used to conform the beam to the shape of the tumour as projected along the direction of the incident beam they need to be thick enough to expend all the incident energy (thicker than the range)

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Snout: 10 cm, 18 cm, 25 cm

Aperture

Lucite Compensator

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Simulation
CT

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scans of volume of interest, without contrast, 1 mm thick slices CT scans of same volume, with contrast MR scans of volume to include target and adequate for image fusion 4D-CT used to ascertain motion

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Proton Therapy

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Not the silver bullet Protons are another tool and will not totally replace other modalities Can be combined with other modalities Immobilization, some beam arrangements and treatment schemas can be similar to conventional radiation therapy (building onto current knowledge)

Uncertainties in Proton Therapy

Patient related: Patient setup Patient movements Organ motion Body contour Target definition Biology related: Relative biological effectiveness (RBE)

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Physics related: CT number conversion Dose calculation

Machine related: Device tolerances Beam energy

Treatment Planning
Acquisition Conversion

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of imaging data (CT, MRI)

of CT values into stopping

power

Delineation
Selection Design

of regions of interest

of proton beam directions of the plan

of each beam

Optimization

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Areas where (high-energy) physics may contribute to proton radiation therapy:

Development Nuclear In Radiation

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of proton computed tomography

data evaluation and benchmarking transport codes for treatment planning

vivo localization and dosimetry of proton beams of nuclear events on RBE

Influence

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Maxillary Sinus

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IMRT

Protons

Prostate cancer

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Two-field Protons Six-field IMRT plan Planning comparison for Prostate cancer

Non-small cell lung cancer (NSCLC)

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Proton Total lung - PTV Photon Total lung - PTV

Glioma

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Proton IMRT plans Planning comparison of a brain tumour

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Para-spinal tumour

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Proton IMRT Planning comparison of a juxtaspinal tumour

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Medulloblastoma- CSI

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Proton Therapy Worldwide

Estimated 45 centers by 2013

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58 As of August 2013, there were 43 particle therapy facilities in the world, representing a total of 121 treatment rooms available to patients on a regular basis.

They are located in Canada, China, Czech Republic, France, Germany, Italy, Japan, South Korea, Poland, Russia, South Africa, Sweden, Switzerland, the UK and the US. 28% of the proton therapy facilities are located in the US and 23% are located in Japan and More than 96,537 patients had been treated.

Clinical Studies of Proton Therapy With at Least 20 Patients and With a Follow-Up Period of at Least 2 Years (>36 Studies)

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Challenges

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Incidence of second malignancies in patients treated with protons

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558 patients treated with Protons between1973-2001 at Harvard cyclotron, Cambridge, MA were compared with matched surveillance Median duration of follow-up was 6.7 yrs. Second malignancies occurred in 29 proton patients(5.2%)

and in 42 photon patients(7.5%)

Proton therapy was not associated with increased risk of second malignancies (adjusted hazard ratio: 0.52; P: 0.009)

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The emerging technology committee (2007)of the American Society of Radiation Oncology (ASTRO)

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This report reflects evidence collected up to November 2009. Data was reviewed for PBT in central nervous system tumors, gastrointestinal malignancies, lung, head and neck, prostate, and pediatric tumors.
Proton beam therapy (PBT) is a novel method for treating malignant disease with radiotherapy. Current data do not provide sufficient evidence to recommend PBT in lung cancer, head and neck cancer, GI malignancies, and pediatric non-CNS malignancies.
Radiotherapy and Oncology 103 (2012) 811

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In hepatocellular carcinoma and prostate cancer, there is evidence for the efficacy of PBT but no suggestion that it is superior to photon based approaches. In Pediatric CNS malignancies PBT appears superior to photon approaches but more data is needed. In large Ocular melanomas and Chordomas, there is evidence for a benefit of PBT over photon approaches.

Current evidence provides limited indications for PBT. More robust prospective clinical trials are needed to determine the appropriate clinical setting for PBT.
Radiotherapy and Oncology 103 (2012) 811

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www.protonbob.com

Written by former proton therapy patient and BOB founder, Robert Marckini

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