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ADAPTIVE RADIOTHERAPY AND USE OF SIMULTANEOUS INTEGRATED BOOST IN TREATMENT OF LOCALLY ADVANCED ORAL
CAVITY, OROPHARYNGEAL AND NASOPHARYNGEAL CANCERS
A Prospective Study
in partial fulfillment of the requirements for the award The degree of
DOCTOR OF MEDICINE (M.D.) IN RADIOTHERAPY
A dissertation submitted to The Tamilnadu Dr. M.G.R. Medical University, Chennai
May 2020
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DECLARATION BY THE CANDIDATE
I solemnly declare that the dissertation titled “ADAPTIVE RADIOTHERAPY AND USE OF SIMULTANEOUS INTEGRATED BOOST IN TREATMENT OF LOCALLY ADVANCED ORAL CAVITY, OROPHARYNGEAL AND NASOPHARYNGEAL CANCERS” was done by me, in the Division of Radiation Oncology, Cancer Institute (W. I. A.), Chennai during the period from November 2017 – September 2019, under the guidance and supervision of Prof.
Dr.G.SELVALUXMY
The dissertation is submitted to the Tamilnadu Dr. M.G.R. Medical University towards the partial fulfillment of the requirement for the award of DOCTOR OF MEDICINE (M.D.) IN RADIOTHERAPY
Place: Chennai
Date: Dr. VENGADA KRISHNAN P.R
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CERTIFICATE BY THE GUIDE
This is to certify that this dissertation titled, “ADAPTIVE RADIOTHERAPY AND USE OF SIMULTANEOUS INTEGRATED BOOST IN TREATMENT OF LOCALLY ADVANCED ORAL CAVITY, OROPHARYNGEAL AND NASOPHARYNGEAL CANCERS” is a bonafide record of the work done by Dr.VENGADA KRISHNAN P.R. in the Division of Radiation Oncology, Cancer Institute (W. I. A.) Chennai during the period of his postgraduate study for the degree of M.D. (Branch IX – Radiotherapy) from 2017-2020 under my direct guidance and supervision.
Date: Dr.ALEXANDER JOHN Place: Chennai Professor,
Division of Radiation Oncology, Cancer Institute, (WIA), Chennai
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CERTIFICATE BY THE HEAD OF DEPARTMENT
This is to certify that this dissertation titled, “ADAPTIVE RADIOTHERAPY AND USE OF SIMULTANEOUS INTEGRATED BOOST IN TREATMENT OF LOCALLY ADVANCED ORAL CAVITY, OROPHARYNGEAL AND NASOPHARYNGEAL CANCERS” is a bonafide record of the work done by Dr.VENGADA KRISHNAN P.R. in the Division of Radiation Oncology, Cancer Institute (W. I. A.), Chennai, during the period of his postgraduate study for the degree of M.D. (Branch IX – Radiotherapy) from 2017- 2020.
Date: Prof. Dr.G.SELVALUXMY Place: Chennai Director and Head of Department,
Division of Radiation Oncology, Cancer Institute (WIA), Chennai
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CERTIFICATE BY THE DEAN OF THE INSTITUTION
This is to certify that this dissertation titled "ADAPTIVE RADIOTHERAPY AND USE OF SIMULTANEOUS INTEGRATED BOOST IN TREATMENT OF LOCALLY ADVANCED ORAL CAVITY, OROPHARYNGEAL AND NASOPHARYNGEAL CANCERS” is a bonafide record of the work done by Dr.VENGADA KRISHNAN P.R. in the Division of Radiation Oncology, Cancer Institute (W. I. A.) Chennai during the period of his postgraduate study for the degree of M.D. (Branch IX – Radiotherapy) from 2017-2020.
Date: Dr.A.S.RAMAKRISHNAN Place: Chennai Dean,
Cancer Institute, (WIA), Chennai.
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CERTIFICATE OF PLAGIARISM
This is to certify that this dissertation work titled, "ADAPTIVE RADIOTHERAPY AND USE OF SIMULTANEOUS INTEGRATED BOOST IN TREATMENT OF LOCALLY ADVANCED ORAL CAVITY, OROPHARYNGEAL AND NASOPHARYNGEAL CANCERS” of the candidate Dr. Vengada Krishnan P.R., with registration number 201719105 for the award of DOCTOR OF MEDICINE (M.D.) in the branch of RADIOTHERAPY. I personally verified urkund.com website for the purpose of plagiarism Check. I found the uploaded thesis file contains from introduction to conclusion pages and result shows 7 percent of plagiarism in the dissertation.
Guide & Supervisor sign with seal
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ACKNOWLEDGMENT
I would like to acknowledge my gratitude to late Dr.S.Krishnamurthy, advisor and Dr.V.Shantha, Chairman, Cancer Institute (WIA) for providing me the opportunity to carry out this study.
I am grateful to Prof.Dr. Selvaluxmy, Director, Head of the department of Radiation Oncology, Cancer Institute for her continued encouragement and invaluable suggestions during this study. Without her this study would not have been possible.
I also thank Dr.Alexander John, Professor, Division of radiation oncology and guide who gave ideas to improve the study. I thank Dr.Harish Kumar.K, Assistant Professor who enlightened me on the basics. I thank Dr.Ramanaiah, Assistant Professor, who encouraged and helped me in completing this study. I also thank Dr.Vasanth Christoper Jayapaul, Consultant Department of radiation oncology Cancer institute (WIA) for giving valid inputs and moral support to improve my study.
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I thank the physists Mr.Sam Deva Kumar, Mr. Arul Pandiyan whose cooperation helped me in completing my study on time.
I thank my wife, my parents and all my family members for their unending support and encouragement. I thank all my teachers who were always the source of
motivation.
I express my gratitude to all my colleagues and all staffs, radiotherapy
technologists in the department who were unfailing in extending their support.
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TABLE OF CONTENTS
I. Introduction:
1) IMRT in head and neck cancers 2) SIB in Head and Neck cancers 3) Concept of adaptive radiotherapy
4) Anatomy of Oral cavity, Oropharynx, Nasopharynx 5) Review of literature
II. Objectives and methodology 1) Aim of the study
2) Objectives
3) Materials and methods.
III. Results and analysis IV. Discussion
V. Conclusion
VI. Reference
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ABSTRACT
ADAPTIVE RADIOTHERAPY AND USE OF SIMULTANEOUS INTEGRATED BOOST IN TREATMENT OF LOCALLY ADVANCED ORAL
CAVITY, OROPHARYNGEAL AND
NASOPHARYNGEAL CANCERS
Aim: To analyse the efficacy, toxicity and feasibility of adaptive radiotherapy while using simultaneous integrated boost in treated locally advanced head and neck cancers. The dose coverage of different sites whether the required level of tumour coverage will also be analyzed.
Materials and methods: This is the prospective study and clinical data of 15 patients with carcinoma oral cavity, oropharynx and Nasopharynx were analyzed.
The Patients were treated with IMRT technique along with Simultaneous Integrated Boost. Cone beam CT was done weekly once and re planning CT was done at TD:
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40Gy after clinically verifying the response to the treatment. The set up errors, weight loss during the period of treatment, volume of tumor shrinkage were noted.
Results: Patient with large volume of disease either in the primary site or as nodal mass had significant decrease in volume at TD: 40 Gy. The tumor regression rate for individual patients were analyzed which showed that the planned inhomogeneity of dose distribution helps in better local control of the disease due to higher dose per fraction.
Conclusion: Adaptive planning is highly individualized. Clinical and radiological examination during the course of treatment decides the necessity for adaptive planning. For patients who are treated with Simultaneous Integrated Boost technique the need for adaptive planning is warranted due to the radiobiological effect of high dose rate which translates to better tumor control.
Key words: Tumor regression rate, SIB, adaptive radiotherapy.
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INTRODUCTION
Multi-modality treatment i.e. Radiation therapy concurrently with chemotherapy is used as a part of treatment for locally advanced head and neck cancer. Intensity-modulated radiation therapy (IMRT) is employed in the recent past with one can achieve required dose to the target with sparing of desired normal tissues. But one should be careful in patient’s setup accuracy as IMRT causes steep dose gradients. In head and neck cancers correct fitting of the thermoplastic mould, change in body contours, and treatment-induced changes such as cell death and tumor shrinkage, tumor growth resulting from accelerated repopulation, weight loss or gain because of changes in appetite caused by
radiation, concomitant chemotherapy, fibrosis of normal tissue leads to volumetric changes. Causes might be independent or can be interrelated. Insufficient
compensation for these uncertainties leads to target under dosing and overdosing of nearby OARs, whereas overcompensation for uncertainties leads to unnecessary irradiation of normal tissue and constraints in treatment planning. Daily image with cone beam CT guidance helps in correcting these setup uncertainties. But image guidance is not always possible especially in high volume centers. For patients with anatomic changes due to tumor shrinkage or weight loss, adaptive
radiotherapy must be considered. But increased costs, higher staff workload should
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also be considered. The need of suitable indications for adaptive radiotherapy in head and neck cancers must be individualized.
Radiation therapy (RT) is the use of ionizing radiation as a part of cancer treatment to control tumor cells. Etymology: In Latin radiare means to emit rays;
and in Greek therapeia means treatment. Thus Radiation Therapy is the treatment of malignancy by using ionizing radiation to deter the proliferation of malignant cells.
The origin of radiotherapy followed on from three major scientific discoveries late in the 19th century: the discovery first of x-ray by the famous German physicist, Wilhelm Conrad Roentgen in 1895, then radioactivity by Henry Becquerel in 1896 and Radium by Madame Curie in 1898.
Radiation varies in type of delivery and mode of delivery also differs. The various types of ionizing radiation used in radiotherapy are X-radiation, gamma radiation, electrons, protons and neutrons, of which gamma rays and high energy X- rays are in common practice. Ionization is the process by which cancer cells are killed. Direct action of radiation kills cancer cells immediately but indirect action is the predominant one. Even though radiation kills both cancer cells and normal tissues most of the normal tissues will recover from effect of radiation due to intrinsic quality of repair mechanism.
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BASIC PRINCIPLES OF RADIOTHERAPY
The aim of this treatment is to deliver uniform homogeneous dose to the target volume which includes the tumor, nodal disease, sub-clinical spread of tumor cells and margin to account for patient movement, organ movement and day-to-day variations in patient set-up. Hence radiation dose to normal tissues have to be kept as low as possible. Hence more efforts should be done to deliver more accurate dose to target volume.
Conventional External Beam Radiotherapy:
Conventional EBRT is delivered by beams of square or rectangular shape. This technique is well established and is generally quick and reliable. The limitation is the escalation of dose to tumor is limited due to the tolerance limit of the nearby critical organs.
Three Dimensional Conformal Radiation Therapy:
Three dimensional conformal therapy (3D CRT), is based on 3D anatomic information and use dose distribution that conforms dose to the target volume and to keep minimum possible dose to normal tissue. The beams are shaped with Multi Leaf Collimator controlled by computer system. The irregular shaped fields provide better avoidance of normal tissue.
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MLC
The main difference between treatment planning of 3D conformal technique and that of conventional radiation therapy is that the former requires the availability of 3D anatomic information and a treatment planning system. The important milestone which sparked in a revolution in not only radiological diagnosis but also in radiotherapy was the invention of Computed Tomography (CT). CT was introduced to the radiotherapy process at the end of 1970’s and this resulted in 3D treatment planning, now being used as a standard tool in radiotherapy. The anatomic information is obtained in the form of closely spaced transverse images, which is processed to reconstruct anatomy in any plane and in three dimensions. Depending
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on the modality which we image critical structures and visible tumors are outlined slice by slice using planner.
Limitations of 3D CRT:
Traditional radiation techniques including 3D CRT provides a method for sparing critical structures that lies in the target and are partially or fully surrounded by a target. To overcome this problem new treatment methods are introduced in external radiotherapy. The intensity modulated radiotherapy provided more conformality than other techniques.
1. INTENSITY MODULATED RADIATION THERAPY (IMRT):
The first clinical IMRT treatment delivery was in 1994 with serial tomotherapy device and then MLC-based IMRT, which was first implemented into clinical use at Memorial Sloan-Kettering Cancer Center in 1995.
The IMRT technique is most advanced forms of conformal treatment which improves Tumor control probability (TCP) and decreases normal tissue complication morbidity. It is based on inverse treatment planning for determination of the required intensity modulated beams and on 3-D multi-modality imaging to define the target volumes. Using IMRT a higher radiation dose is focused to the tumour while minimizing radiation exposure to surrounding normal tissues. IMRT
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also has the potential to reduce treatment toxicity, even though doses are not escalated.
Most of the advantages of IMRT planning technique is based on its ability to manipulate optimally intensities of individual beam lets within each beam.
It permits increased control over radiation fluence, enabling custom-design of optimal dose distributions. In particular, IMRT provides the ability to spare organs at risk that are surrounded by target volumes with concave surfaces. IMRT is the delivery of radiation to the patient via fields that have non-uniform radiation fluence.
A radiation beam which instead of giving the usual flat dose distribution contains deliberately introduced peaks and troughs is called as an intensity modulated beam (IMB) and radiotherapy delivered with a combination of IMBs is called intensity modulated radiotherapy (IMRT).
IMRT techniques are broadly classified into:
1. Fixed gantry IMRT 2. Arc based IMRT
Fixed gantry IMRT treatment can be either MLC based delivery or Compensator based delivery. MLC based delivery technique has two types of treatment delivery Techniques which are Step and Shoot delivery & Dynamic delivery.
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Arc based IMRT can be either FAN beam IMRT and Cone beam IMRT.
Fan beam therapy encompasses slice by slice delivery and helical
Tomotherapy. CONE beam IMRT can be aperture modulated arc therapy (Single arc) and intensity modulated arc therapy (multiple arcs).
REGISTRATION AND ADAPTATION
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Limits and risks of IMRT:
Efficacy and the applicability of the IMRT are also limited to in terms of dosimetric characteristics of dose delivery such as radiation scattering and also the transmission through the MLC leaves. In addition limited temporal and spatial coverage and overall accuracy of the IMRT dose verification systems will diminish the confidence in the delivered dose.
Fixed gantry IMRT:
It consists of two steps. In the first step a set of intensity profiles one for each incident beam is generated using the dose optimization engine. Depending on the treatment planning, beam profile is modified such that it maybe continuous or discrete in space and intensity. One has to take into consideration that incident beam is already divided into beamlets, and each beamlet has its own intensity levels.
Fixed gantry IMRT can be either MLC based delivery or a compensator based delivery. Most frequently used IMRT is the MLC based computer controlled one.
Once the planning is done an intensity map is generated with a set of apertures using the MLC formed apertures by using an algorithm of leaf sequencing. These are also recorded in the treatment planning systems, based on the movement of the MLC, the treatment is delivered. The treatment delivery
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can be either a step and shoot method or it can be a dynamic mode. In the step and shoot method the MLC remains static and treatment is delivered i.e.
dose only, motion only. In dynamic modes MLC moves as the radiation beam moves i.e. Leaf movement and dose delivery occurs simultaneously.
TERMINOLOGY THAT ARE USED IN IMRT:
Monitor units:
It is the dose which is delivered at the central axis of the treatment beam. In a linear accelerator the machines are calibrated such that their 1MU is equivalent to 1 cGy.
Beamlets:
In view of intensity distribution optimization an IMRT beam is divided into a small intensity element which subdivide the intensity modulated beam. These are called pencil beams. It can be
expressed in terms of energy fluence or particle fluence based on dose calculation algorithm.
Dynamic multi leaf collimator:
In this mode leaves move continuously which in turn shapes the incident beam when the radiation is turned on. In this way the treatment time can be shortened and also ensures high spatial resolution.
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Static multi leaf collimator:
In this mode the leaves move only when the radiation beam is turned off. They remain in their predetermined positions and the radiation dose is delivered. This is step and shoot technique.
Segment:
A basic unit of SMLC delivery which is a shaped aperture with a beam intensity which is uniform.
Objective function:
It is a clinical requirement of a mathematical formalism.
It is of three types a) Dose based
b) Dose volume based c) Dose response based.
A. Dosebased—it is the minimum /maximum dose of a critical structure.
B. Dose-Volume based—it is the fraction of the volume which can receive a certain dose.
C. Dose-response based—it uses a clinical data to a dose requirement Which is limited into a clinical outcome. Normal tissue complication probability, tissue complication probability and equivalent uniform doses which are certain clinical indicators.
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Score:
The key parameter for an IMRT optimization is SCORE. It’s a figure of merit– an objective function of indicating the quality of treatment plan can be expressed in a numeric value.
Forward planning:
This is type of planning which is most commonly used in 3D conformal treatment This planning can be a trial and error process such that the direction of the beams and also the beam weights are modified according to the desired acceptable clinical solution. The forward planning system is also employed in planning the field in field technique. This field in field technique is most commonly employed in breast, prostate, head and neck cancers. But still these approaches are
inferior to inverse planning techniques.
Inverse planning:
In this process the clinical requirements calculated from mathematic formalism is transferred into intensity patterns which are deliverable. Ehrgott et al has reviewed an article based on this mathematic formalism.
Leaf sequencing and deliverable optimization:
This consist of two steps. In the first step, there is generation of ideal fluence pattern which can satisfy the optimum solution for objective function. In the
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second step, fluence patterns which are ideal are delivered into the leaf sequences.
A good optimization takes into account the constraints of the dose delivered and also the leaf characteristics so that it can re optimize the leaf
sequences in such a manner that it fulfills the fluence distributions which are deliverable and also objective function is fulfilled.
Aperture based IMRT:
In this the treatment portals are divided into a subset of predefined
apertures/segments. Then the optimization process becomes a standard beam weight optimization. But this technique is inferior to the inverse planning algorithm.
Multimodality image fusion:
IMRT is very important in terms of target organ delineation, so using two or more imaging techniques and fusing them provides additional information about the treatment targets. In simple terms it can be explained that the two or more image sets of the the same subject are combined or fused into a single data set for better understanding of the structures involved.
Image registration:
The process by which the images are registered in correspondence with other image.
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DICOM:
The most widely used image management and transmission protocol.
DICOM RT:
It is an extension protocol of DICOM. It has RT structure set: Contours of the organs in the image set.
RT image: DRR images- Digitally reconstructed radiographs.
RT plan: Collimator settings, Gantry angle, MU’s, MLC leaf position and other treatment parameters.
IMRT TREATMENT PLANNING:
Delineation of Target volumes:
In ICRU 83 there are have certain guidelines for the treating volumes which forms the treatment plan. The contoured organs can be malignant tumor normal tissue near the tumor, distant structures can be contoured. Based on the above structures the volumes are described below.
Gross tumor volume (GTV):
It is the as clinical and/or radiological extent of tumour.
GTV-T: Primary tumor. GTV-N: Metastatic regional node. GTV-M: Metastatic.
Clinical target volume (CTV):
It is the volume which encompasses the GTV along with microscopic
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Disease around it or subclinical malignant tissues. Usually it is GTV plus 1cm to 2cm margin.
Planning target volume (PTV):
It is the volume in which margin was given to the CTV so that the absorbed dose is delivered to all the CTV parts with acceptable probability inspite of differences in the setup variations and organ motion.
ORGAN AT RISK (OAR):
These are the normal tissues/organs which are at risk of exposure to Radiation while treating the tumor. If they receive a certain
amount of radiation it results in significant morbidity. This emphasis the importance of contouring the CTV and PTV with at most care since the OARs can be exposed to the PTV/CTV doses which lead to morbidity to the patient. There are two types of OARs serial organ and parallel organ.
Serial organ are those in which point dose is calculated beyond which it may lead to unacceptable damage.e.g.,spinalcord.
Parallel organs are those in which the dose is calculated according to the
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volume of tissue exposed- they suffer a loss of portion without loss of function.
Planning organ at risk volume (PRV):
In view of the differences in the organ motion and setup variations a margin has to be given to the organ at risk to avoid significant morbidity.
Remaining volume at risk (RVR):
It is the difference between volume enclosed by CTV’s and OAR’s and external contour of the patient. RVR is very much important with respect to IMRT at least in dose constraints. Without these volumes being contoured the dose optimizations software can produce an excellent dose distribution but with significant morbidity to the patient.
Treated volume (TV):
The absorbed dose for the volume of tissue which comes under the Isodose envelope which is prescribed by the radiation Oncologist. The ICRU 83 proposes that the TV defined as the 98% of the PTV receiving the Prescribed dose. So it can be D NEARMINIMUM and D NEARMAXIMUM.
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It should be taken into consideration that the PTV, GTV, CTV are the volumes which are independent of particular radiation protocol employed.
In IMRT treatment planning supplementary margins are given accordingly such that the variations in the organ motion and setup uncertainities are also to be taken into account. So the number of normal structure to be drawn also increases. The dose is escalated to unprecedented levels in IMRT the dose is at unprecedented levels, distribution of the dose is also highly non-uniform and the plans are generated, evaluated by computer optimization process, basically all the structures to which the dose needs to be constrained has to be contoured.
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IMRT TREATMENT PLANNING AND OPTIMIZATION:
The main part of IMRT is the planning and optimization process. In this process the amount of dose to be administered and also the distribution of dose can be monitored. By changing the direction of the beams and also the fluence- by changing the position of the leaf. By these processes the treatment is delivered according to the specific clinical problem into a machine deliverable beams.
Fractionation and treatment schedule:
IMRT plans are designed in line with conventional fractionation schedules.
The doses can be delivered using 3D conformal method followed by IMRT boost. IMRT plans can be delivered from the initial treatment in which larger fields are treated and also the boost fields are planned initially.
When target volumes in an IMRT plan are treated simultaneously, it is the most conformal form of treatment. It can be denoted as SIB
IMRT (Simultaneous Integrated Boost). SIB IMRT produces superior dose
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distribution, more efficient, less error prone in delivering the treatment because the initial plan will be followed till the end of treatment.
During the course of treatment the problems in matching the fields can arise which can be minimized. In SIB IMRT the nominal dose and also the size of fraction are corrected according to the number of IMRT fractions.
The effect of acute and late toxicity of the organ at risk/ normal tissues should also be considered in case of modified fractionation schedule.
Because of the increased conformality of the IMRT plan the dose received by the organ at risk are also very low when compared with the
conventional plans.
BEAM CONFIGURATION:
Optimisation of a beam angle is important in IMRT planning process so that there is a greater control of beam on dose distributions. However greater
control of beam angles may find pathways which is least obstructed by critical structures. The number of beams used and number of combinations which
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are compared are some of the advances in the mathematical research.
For example for a three beam combination at least 60,000 beam combinations are compared, for a five beam combination nearly 14 million combinations are tested, for seven beam combinations nearly 1.5 billion combinations are tested. In general if there is an increase in the number of beams there is an opportunity to get a desired dose distribution very easily. But in practice, in case of fixed
gantry beam IMRT, it is always advisable to reduce the number of beams to reduce the treatment time and also the effort required to put in the
dosimetric verification, delivery of treatment, Quality assurance, planning.
The most advantage of placing the beams is in thedirections such that they are not opposing each other. Most often beams are constrained to lie in the transverse plane.
In general the beam configurations used for 3D conformal are not optimal for IMRT.
Systems using rotating slit approach:
1. Tomotherapy delivery 2. Peacock system
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PLANNING OBJECTIVES:
Optimization engines help in optimization of ray intensities by several methods with its own strengths and weakness depending on the nature of objective function and individual preference. The basic principle is that each ray of each beam that passes through the target volume is traced from
the source of radiation through the patient. Each patient’s 3D image is
divided into VOXELS. Every voxel has a dose in the patient’s body which is calculated for the initial set of rays. The score of the treatment plan is
calculated from this resulting dose distribution. The ray tracing process identifies the tumor and also traces it down to the normal tissues that along the path of the ray. By changing the weight of the ray, score is calculated. If the weight of the score is increased which leads to favorable consequences for that patient then the weight is increased and vice versa.
With each and every change in the weight of the beam the treatment optimization improves. Only a few changes in ray weight is permitted at
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a time.
Objective functions:
Dose base
It can be explained as sum of the squares of differences in dose and computed dose in each point within an each volume of interest. This is called as quadratic or variance objective function. The main function of the optimization process is to bring down the value of S.
Dose—volume based: Advantages:
Both the normal tissue and the tumor mass responds to the radiation which can be explained by the amount of radiation each of it has received which is most commonly expressed in volume. The dose volume based objective function is most widely used and it also explains the volume of the structure which can receive a particular limit of dose. It is mandatory as explained in ICRU-83 that the doses received by the structures should always be expressed in terms of DVH dose volume histograms and dose
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volume criteria. In his study Bortfeld et al, the objective are laid for dose volume histograms. Two points are taken into consideration D1 & D2. The volume receiving more than D1 has a volume which is less than V1. So it is necessary that this constraint needs to be implemented depending on the another dose value D2. So that in the current DVH data V(D2)= V1.
2. SIMULTANEOUS INTEGRATED BOOST
IMRT is designed and delivered using “Simultaneous Integrated Boost” (SIB) technique in which the highest dose i.e. the boost dose is delivered to the primary Gross Tumor Volume (GTV) and the involved nodal region, an intermediate dose to the subclinical tumor extensions, and a lower dose to electively irradiated nodal volumes are delivered simultaneously. Total nominal dose is adjusted to account for the different fraction sizes
3. CONCEPT OF ADAPTIVE RADIOTHERAPY
Adaptive radiotherapy allows the clinician to reconsider the planned dose to accurately deliver the remaining dose fractions to the tumor while minimizing irradiation of normal healthy tissues or the organs at risk. Re planning is desirable in case of IMRT technique which are characterized by high conformality to tumor volumes and steep dose gradients to spare normal tissues. This technique requires
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accurate clinical target volume and set up for treatment. The accuracy of the treatment may be compromised due to alteration of patient anatomy, change in target volume and shrinkage of tumor volume during the course of treatment.
For a range of clinical radiotherapy cases, the treatment plans optimized based on the initial set of computed tomography (CT) images become suboptimal for subsequent irradiations due to deformations of the relevant structures.
The central idea behind Adaptive Radiotherapy is that adaptation of a treatment plan over the course of treatment can, result in better therapeutic ratios than those that would have resulted from delivery of the original treatment plan. In routine practice, treatment plans are done with single CT image set acquired prior to the treatment course and that plan is usually evaluated using DVHs. DVHs based on a single scan may incorrectly estimate the delivered dose. Typically in response to weight loss or other “significant” morphological changes, plans are adapted for patients.
Adaptive radiotherapy is being practiced around the world in various forms. Re-Plan based on Re-CT after therapeutic dose of at least 40Gy is one of the most common techniques of ART being practiced.
Adaptive radiotherapy and image guided radiotherapy has become interlinked and hence modern radiotherapy delivery machines with advanced
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imaging technologies are widely preferred to deliver a better clinical results in patients.
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ANATOMY ORAL CAVITY:
The oral cavity extends from the skin–vermilion junction of the lips to the junction of the hard palate and soft palate above and to the line of circumvallate papillae below and it is divided into specific sites:
Mucosal Lip: The lip begins at the junction of the vermilion border with the skin and includes only the vermilion surface or that portion of the lip that comes in to contact with the opposing lip. It is well defined into an upper and lower lip joined at the commissures of the mouth.
Buccal Mucosa: It includes all the membranous lining of the inner surface of the cheeks and lips from the line of contact of the opposing lips to the line of attachment of mucosa of the alveolar ridge (both upper and lower) and pterygomandibular raphe.
Lower Alveolar Ridge: It refers to the mucosa overlying the alveolar process of the mandible, which extends from the line of attachment of mucosa in the lower gingivobuccal sulcus to the line of free mucosa of the floor of the mouth. Posteriorly it extends to the ascending ramus of the mandible.
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Upper Alveolar Ridge: This refers to the mucosa overlying the alveolar process of the maxilla, which extends from the line of attachment of mucosa in the upper gingivobuccal sulcus to the junction of the hard palate. Its posterior margin is the upper end of the pterygopalatine arch.
Retro molar Trigone: This is the attached mucosa overlying the ascending
ramus of the mandible from the level of the posterior surface of the last molar tooth to the apex superiorly, adjacent to the tuberosity of the maxilla.
Floor of the Mouth: This is a semilunar space overlying the mylohyoid and hyoglossus muscles, extending from the inner surface of the lower alveolar ridge to the undersurface of the tongue. Its posterior boundary is the base of the anterior pillar of the tonsil. It is divided into two sides by the frenulum of the tongue and contains the ostia of both the submandibular and sublingual salivary glands.
Hard Palate: This is the semilunar area between the upper alveolar ridge and the mucous membrane covering the palatine process of the maxillary palatine bones. It extends from the inner surface of the superior alveolar ridge to the posterior edge of the palatine bone.
Anterior Two-Thirds of the Tongue: This is the freely mobile portion of the tongue that extends anteriorly from the line of circumvallate papillae to the undersurface of
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the tongue at the junction of the floor of the mouth. It is composed of four areas: the tip, the lateral borders, the dorsum, and the undersurface. The undersurface of the tongue is considered a separate category.
PHARYNX:
The pharynx is divided into three regions: The Nasopharynx, oropharynx and Hypopharynx. Each region is further subdivided into specific sites as summarized in the following:
Nasopharynx: The nasopharynx begins anteriorly at the posterior choana and extends along the plane of the airway to the level of the free border of the soft palate.
It includes the vault, the lateral walls (including the fossae of Rosenmuller and the mucosa covering the torus tubaris forming the eustachian tube orifice), and the posterior wall. The floor is the superior surface of the soft palate. The posterior margins of the choanal orifices and of the nasal septum are included in the nasal fossa. Nasopharyngeal tumors extending to the nasal cavity or oropharynx in the absence of parapharyngeal space (PPS) involvement do not have significantly worse outcome compared with tumors restricted to the nasopharynx.
PPS is a triangular space anterior to the styloid process (prestyloid) that extends from the skull base to the level of the angle of the mandible. The PPS is located lateral to the pharynx and medial to the masticator space and parotid spaces. The PPS contains
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primarily deep lobe of parotid gland, fat, vascular structures, and small branches of the mandibular division of the fifth cranial nerve. The vascular components include the internal maxillary artery, ascending pharyngeal artery, and the pharyngeal venous plexus. Other less commonly recognized components of the PPS are lymph nodes and ectopic rests of minor salivary gland tissue.
Poststyloid space or carotid space (CS) is an enclosed fascial space located posterior to the styloid process and lateral to the retropharyngeal space (RPS) and prevertebral space (PVS). A slip of alar fascia contributes to the medial wall of the CS and helps separate the RPS and PVS from the CS. In the suprahyoid neck, the CS is bordered anteriorly by the styloid process and the PPS, laterally by the posterior belly of the digastric muscle and the parotid space, and medially by the lateral margin of the RPS. The CS contains the internal carotid artery, internal jugular vein, cranial nerves IX–XII, and lymph nodes. The CS extends superiorly to the jugular foramen and inferiorly to the aortic arch.
Masticator space primarily consists of the muscles of mastication. Anatomically, the superficial layer of the deep cervical fascia splits to enclose the muscles of mastication to enclose this space. These muscles are the medial and lateral pterygoid, masseter, and temporalis. The contents of the masticator space also include the additional structures encompassed within these facial boundaries,
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which include the ramus of the mandible and the third division of the CN V as it passes through foramen ovale into the suprahyoid neck.
THE OROPHARYNX:
The oropharynx is continuous with anteriorly the oral cavity, postero inferiorly with the larynx and hypopharynx, bounded superiorly by nasopharynx. The three main subsites of the oropharynx includes the base of tongue, tonsil and soft palate. Main function of oropharynx is swallowing and speech
Base of tongue composed of the posterior third of tongue. Anteriorly bounded by circumvallate Papillae. Postero- inferiorly its boundaries are the hyoid and epiglottis and lateral boundaries are glossopharyngeal sulci. Lingual tonsil is the collection of lymphatic nodules in mucosa of base of tongue. Vallecula is part of base of tongue, it’s a small mucosal strip of around one cm between base of tongue and epiglottis.
Sensory nerve supply is base of tongue is by Cranial Nerve Nine– Glossopharyngeal nerve, with small area of base of the tongue supplied by internal laryngeal nerve also Tonsillar region includes anterior tonsillar pillar, the posterior tonsillar pillar and palatine tonsil. Palatine Tonsil are lymphoid collections encapsulated incompletely with stratified squamous epithelial mucosa in tonsillar bed, and it lies between palatoglossal (anterior) and palatopahryngeal (posterior) tonsillar pillars
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Soft palate is a fibromuscular structure and their boundaries are hard palate anteriorly, Lateral boundaries are anterior tonsillar pillars and posterior inferior forms a free edge and uvula in midline. Soft palate is made up of five muscles namely Levatorvelipalatini, palatoglossus, Tensor veli Palatini, palatopharyngeus and musculusuvalae. Muscles of soft palate are supplied through pharyngeal plexus (Pharyngeal plexus is composed of pharyngeal branch of cranial nerve nine (glossopharyngeal) and ten (vagus) also from sympathetic branches of superior cervical ganglion, There is one muscle exception in this nerve supply, tensor velipaltini, is supplied by cranial nerve fifth Branch V2. Sensory nerve supply of soft palate is by Glossopharyngeal nerve
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ORAL CAVITY
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BOUNDARIES OF NECK NODE LEVELS:
Level I A (Sub mental)
Superior border is Symphsyis of mandible Inferior border is Body of the hyoid bone
Anterior border is the Anterior belly of the contralateral digastric muscle Posterior border is Anterior belly of ipsilateral digastric muscle
Harbors metastasis from cancer arising from floor of mouth, anterior oral tongue, anterior mandibular ridge, and lower lip.
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Level I B (Sub mandibular)
Superior border is the Body of mandible
Inferior border is the Posterior belly of digastric muscle Anterior border is the anterior belly of digastric muscle Posterior border is the stylohyoid muscle
Harbors metastasis from cancer arising from oral cavity, anterior nasal cavity, skin and soft tissue structures of mid face and submandibular gland
Level II A (Upper jugular)
Superior border is the base of the Skull
Inferior border is the Horizontal plane defined by inferior border of hyoid bone.
Anterior border is the Stylohyoid muscle
Posterior border is the Vertical plane defined by spinal accessory nerve Level II B (Upper jugular)
Superior border is the skull base
Inferior border is the horizontal plane defined by inferior border of hyoid bone
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Anterior border is the Vertical plane defined by spinal accessory nerve Posterior border is the Lateral border of sternocleidomastoid muscle
Upper jugular nodes are at greatest risk for harbouring metastasis from cancers arising from oral cavity, nasal cavity, nasopharynx, oropharynx, hypopharynx, larynx and parotid gland
Level III (Middle jugular):
Superior border is the Horizontal plane defined by inferior body of hyoid
Inferior border is the Horizontal plane defined by inferior body of cricoid cartilage Anterior border is the Lateral border of sternohyoid muscle
Inferior border is the Lateral border of sternocleidomastoid or sensory branches of cervical plexus
Nodes are greatest risk for harboring metastasis from cancers arising from oral cavity, nasal cavity, nasopharynx, oropharynx, hypopharynx, and larynx
Level IV (Lower jugular):
Superior border is the Horizontal plane defined by inferior border of cricoid cartilage
Inferior border is the Clavicle
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Anterior border is the Lateral border of sternohyoid muscle
Posterior border is the Lateral border of sternocleidomastoid or sensory branch of cervical plexus
Nodes are greatest risk for harbouring metastasis from cancer arising from hypopharynx, thyroid, larynx and cervical esophagus
Level V A (Posterior Triangle)
Superior border is the Apex of convergence of sternocleidomastoid and trapezius muscle
Inferior border is the Horizontal plane defined by lower border of cricoid cartilage Anterior border is the Posterior border of sternocleidomastoid muscle or sensory
branches of cervical plexus
Posterior border is the Anterior border of trapezius muscle Level V B (Posterior Triangle)
Superior border is the Horizontal plane defined by lower border of cricoid cartilage Inferior border is the clavicle
Anterior border is the posterior border of sternocleidomastoid muscle Posterior border is the anterior border of trapezius muscle
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Posterior triangle nodes are greatest risk for harbouring metastasis from cancers arising from nasopharynx, oropharynx, cutaneous structure of poaterior scalp and neck
Level VI (Anterior compartment) Nodes in this compartment includes
Pretracheal,
Paratracheal nodes,
Precricoid (Delphian) node
Perithyroidal nodes, including lymph nodes along the recurrent laryngeal nerves.
Superior boundary is hyoid bone,
Inferior boundary is suprasternal notch
Lateral boundaries are common carotid arteries.
Nodes are at risk for harbouring metastasis from cancers arising from thyroid gland, glottis and subglottic larynx, apex of pyriform sinus and cervical esophagus
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Level VII (Superior mediastinal):
Nodes in this group includes pretracheal, paratracheal, and esophageal groove lymph nodes, extending from level of suprasternal notch cephalad and up to innominate artery caudally, nodes are at risk of involvement by thyroid cancer and cancer of esophagus
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LEVELS OF NECK NODES
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NECK NODAL REGIONS ON AXIAL SECTION OF CT SCAN
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TNM classification of carcinomas of the lip and oral cavity
TX: Primary tumour cannot be assessed T0: No evidence of primary tumour Tis: Carcinoma in situ
T1: Tumour 2 cm or less in greatest dimension
T2: Tumour more than 2 cm but not more than 4 cm in greatest dimension T3: Tumour more than 4 cm in greatest dimension
T4a (lip) Tumour invades through cortical bone, inferior alveolar nerve, floor of mouth, or skin (chin or nose)
T4a (oral cavity) Tumour invades through cortical bone, into deep/extrinsic muscle of tongue (genioglossus, hyoglossus, palatoglossus, and styloglossus), maxillary sinus, or skin of face
T4b (lip and oral cavity) Tumour invades masticator space, pterygoid plates, or skull base; or encases internal carotid artery
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Superficial erosion alone of bone/tooth socket by gingival primary is not sufficient to classify a tumour as T4.
N - Regional Lymph Nodes
NX: Regional lymph nodes cannot be assessed N0: No regional lymph node metastasis
N1: Metastasis in a single ipsilateral lymph node, 3 cm or less in greatest dimension
N2: Metastasis as specified in N2a, 2b, 2c
N2a: Metastasis in a single ipsilateral lymph node, more than 3 cm but not more than 6 cm in greatest dimension
N2b: Metastasis in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension
N2c: Metastasis in bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimension
N3: Metastasis in a lymph node more than 6 cm in greatest dimension Midline nodes are considered ipsilateral nodes.
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M - Distant metastasis M0: No distant metastasis M1: Distant metastasis
Hypopharynx
T1: Tumor limited to one sub site of Hypopharynx and/or 2 cm or less in greatest dimension
T2: Tumor invades more than one sub site of Hypopharynx or an adjacent site, or measures more than 2 cm but not more than 4 cm in greatest dimension without fixation of hemi larynx
T3: Tumor more than 4 cm in greatest dimension or with fixation of hemi larynx or extension to esophagus
T4a: Moderately advanced local disease Tumor invades thyroid/cricoid cartilage, hyoid bone, thyroid gland, or central compartment soft tissue
T4b: Very advanced local disease: Tumor invades prevertebral fascia, encases carotid artery, or involves mediastinal structures
NX: Regional lymph nodes cannot be assessed N0: No regional lymph node metastasis
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N1: Unilateral metastasis in cervical lymph node(s), 6 cm or less in greatest dimension, above the supraclavicular fossa, and/or unilateral or bilateral, retropharyngeal lymph nodes, 6 cm or less, in greatest dimension
N2: Bilateral metastasis in cervical lymph node(s), 6 cm or less in greatest dimension, above the supraclavicular fossa
N3: Metastasis in a lymph node(s) more than 6 cm and/or to supraclavicular fossa N3a: Greater than 6 cm in dimension
N3b Extension to the supraclavicular fossa
HPV- Mediated (p 16 +) oropharyngeal cancer:
Definition of Primary Tumour
TX primary tumour cannot be assessed Tis Carcinoma in situ
T1 Tumour 2 cm or small in greater dimension
T2 Tumour larger than 2 cm but not larger than 4 cm in greatest dimension T3 Tumour larger than 4 cm in greatest dimension or extension to lingual surface of epiglottis
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T4 Moderately advanced disease, tumour invades the larynx, extrinsic muscles of tongue, medial pterygoid, hard plate, or mandible or beyond (mucosal extension to lingual surface of epiglottis from primary tumours of the base of tongue nadvallecula does not constitute invasion of larynx)
Defintion of Regional lymph nodes (N) Clinical (cN)
NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis
N1 one or more ipsilateral lymph nodes, none larger than 6 cm N2 contralateral or bilateral lymph node, none larger than 6 cm N3 lymph node (s) larger than 6 cm
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REVIEW OF LITERATURE
1. SIB IMRT in inoperable loco regionally advanced head and neck cancers:
clinical results by M. Dzhugashvili P. Escolar-Perez studied the use of concurrent chemo radiation in inoperable locally advanced head and neck cancer patients using IMRT technique in their institution. Their study included a total of 56 patients from the year 2007 to 2009. According to their protocol they used 69.96Gy to the PTV1 and 59.4 Gy to PTV2 and 54.12 Gy to PTV3. Their mean study period was 12 months. They concluded that SIB IMRT is very effective in non-operable locally advanced head and neck cancers. The disease free survival (DFS) was 67.9% and overall survival (OS) was. 83.6 %. 82% of patients had complete response of primary. All the patients had acute oral mucositis and skin toxicity but were completely reversible in one month post radiation.
2. SIB IMRT of advanced head & neck squamous cell carcinomas using dynamic multi-leaf collimators by Q.Wu, R.Mohan, M.Morris. The objective of their study was to know the feasibility of their SIB IMRT protocol in which the doses were 74 Gy, 71Gy and 68 Gy to low risk, high risk, and intermediate risk areas respectively. The treatment was delivered using multi-leaf collimators. Their study included 14 patients. The predominant disease sites was oropharynx. Brain stem and spinal cord sparing was done and variable degree of parotid sparing was done. The treatment time excluding the setup time was 15 minutes. They concluded that SIB
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IMRT using dynamic MLC is feasible. Planning and delivery processes were efficient. The dose that is predicted can be delivered accurately.
3. SIB in the chemo radiation of patients with locally advanced squamous cell carcinoma of head and neck by A.V. Mikhailov et al. In this study the PI included 102 patients with histologically confirmed HNSCC if stage II-III receiving platinum based chemotherapy. The GTV, CTV (GTV+05-1 cm) and PTV (CTV+0.3cm) were defined. The primary received 70Gy, the upper neck levels received 60Gy, and the lower neck levels received 50Gy. The irradiation was once a day for 5 days a week with a total of 30 fractions. The tolerance doses of eye, lens, optic nerve, optic chaisma, brain stem, spinal cord, parotid gland, mucosa of mouth and pharynx were not exceeded. Position of the patient was controlled by weekly cone beam CT by using kV images. Radiation toxicity were grade II mucositis and grade II skin reaction. After one month post RT the mucositis healed completely. During follow up they noticed that there was no incidence of xerostomia. Hence they concluded that use of SIB with IMRT can increase the effectiveness of treatment by reducing the duration of radiation therapy while maintaining satisfactory tolerability.
4. Dosimetric parameters of SIB IMRT with sequential boost for head and neck cancer by M.Miyazaki observed that 2 phase methods are an approach for resolving the fraction size problem posed by SIB.
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5. Radiobiological basis and clinical results of the simultaneous integrated boost (SIB) in intensity modulated radiotherapy (IMRT) for head and neck cancer: A review by Ester orland, Mauro pallazi, Emaneuele Pignoli where there is an extensive discussion about the dosimetry and the efficacy of SIB-IMRT technique in head and neck cancers.
6. Impact of head and neck cancer adaptive radiotherapy to spare the parotid glands and decrease the risk of xerostomia: by Joel castelli et al who concluded that adaptive planning the dose to parotids decreased by 11 % and the mean dose decreased by 5Gy.
7. Adaptive radiotherapy for head and neck cancer—Dosimetric results from a prospective clinical trial by David L Schwartz et al. They compared four planning scenarios (1) original IMRT plan aligned daily to marked isocenter (BB) (2) original plan aligned daily to bone(IGRT); (3) IGRT with one adaptive replan (ART1) and (4) actual treatment received by each study patient (IGRT with one or two adaptive replans, ART2). 22 patients were include in this study and all the 22 patients underwent one replan (ART1); 8 patients had two replans (ART2). ART1 reduced mean dose to contralateral parotid by 0.6 Gy or 2.8% (p = 0.003) and ipsilateral parotid by 1.3 Gy (3.9%) (p = 0.002) over the IGRT alone. ART2 further reduced the mean contralateral parotid dose by 0.8 Gy or 3.8% (p = 0.026) and ipsilateral parotid by 4.1 Gy or 9% (p = 0.001). ART significantly reduced integral body dose.
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Hence they concluded that head and neck adaptive radiotherapy dosimetrically outperforms IMRT and one properly timed re-plan delivers the majority of achievable dosimetric improvement. The clinical impact of ART must be confirmed by future trials.
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II. Objectives and methodology RATIONALE
Patients receiving fractionated radiotherapy for head-and-neck cancer have marked anatomic changes during their course of treatment, including shrinking of the primary tumor or nodal masses, resolving postoperative changes such as edema, and changes in overall body habitus such as weight loss.
Measurable anatomic changes can occur throughout the treatment period of RT for head-and-neck cancers. These changes in the external contour, shape, location of the target and critical structures appears to be significant during the second half of treatment (after 3 weeks of treatment). It could have potential dosimetric impact when highly conformal treatment techniques are used. Such a planning would maximize the therapeutic ratio of RT.
The simultaneous integrated boost (SIB)-IMRT technique allows the simultaneous delivery of different dose levels to different target volumes within a single treatment fraction. The most important aspect associated with SIB-IMRT is related to the fractionation strategy the shortening of the overall treatment time and the increase of fraction size to the boost volume. The SIB-IMRT technique
therefore represents, a new way to investigate the accelerated fractionation in definitive treatment of head and neck cancers.
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Simultaneous integrated boost delivers differential doses at the same to high risk, intermediate risk and low risk areas. When combined with adaptive radiotherapy it can decrease the doses received by organs at risk which may occur due to loss of weight, response to the therapy.
For this study I would like to utilize the advantage of both SIB IMRT and adaptive radiotherapy which aims at decreasing the tumour volume
simultaneously without crossing the tolerance dose of organs at risk by
simultaneously giving the boost to the high risk and intermediate risk areas so that it may be considered as the standard treatment.
AIM OF THE STUDY:
To evaluate the efficacy, toxicity and feasibility of adaptive radiotherapy and simultaneous integrated boost in locally advanced oral cavity, oropharyngeal and nasopharyngeal cancers.
METHODOLOGY
Study design- Prospective Study.
Study period- Jan 2018 to Aug-2019 Number of patients- 15
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INCLUSION CRITERIA
1. Sites- Gingiva, Buccal mucosa, Tongue, Floor of mouth, Hard palate, Soft palate, Base of tongue, Vallecula, Tonsil- Stage-III/IV
2. Patients receiving definitive chemo radiation with 3 weekly cisplatin or weekly carboplatin
3. ECOG performance scale-0/1 EXCLUSION CRITERIA
1. Re-radiation
2. Patients with ECOG performance status of >2 3. Treatment with palliative intent
4. Recurrent disease.
5. Metastatic disease 6. Unfit for chemotherapy 7. Upfront surgery.
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ORGANS AT RISK
Parotid gland
Submandibular gland
Spinal cord
Brain stem
Pharyngeal constrictors
Mandible
Lens, retina, optic nerve, optic chiasma,
Cochlea, pituitary gland, hippocampus.
PLANNING METHODS
1. Patients are immobilized using perforated thermoplastic head and neck mask.
2. The mask is attached to the couch using indexed patient positioning systems. This ensures maximum patient setup reproducibility.
3. Markers with lead are placed on bony landmark.
4. CT scan is done in RT planning position.
5. The tolerance doses of eye, lens, brain stem, spinal cord, parotids were not exceeded.
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6. Initial investigations include Haemogram,
Renal function test, Liver function test, Serum electrolytes, Coagulation profile,
Fasting blood sugar, post prandial blood sugar, Blood group, viral markers,
Chest x ray, Echocardiogram, Direct laryngoscopy direct pharyngoscopy, Biopsy from the lesion.
7. Weekly blood investigations include haemogram, serum electrolytes, and renal function test.
8. The irradiation regimen is once a day, 5 days a week and course duration is 33 fractions.
9. Patient who are fit for chemotherapy are given 3 weekly cisplatin 10. GTV is defined as clinical and radiological extent of tumour.
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11. CTV is 0.5-1 cm around GTV to account for microscopic disease.
12. PTV is 0.3-0.5cm around CTV to account for organ motion and set up errors.
All the volumes are measured by ICRU 62 guidelines.
13) CT scan is repeated at 40Gy to assess the volumetric changes that have occurred.
14) Cone beam CT is done weekly once.
15) Re- Contouring is done as per the RTOG contouring guidelines. Planning is done using ECLIPSE treatment planning system.
16) The high risk CTV receives TD=66 to 70 Gy (with a daily dose of 2.12 to 2.20 Gy), Intermediate risk CTV which has high chance of disease receives TD=60 Gy (with a daily dose of 2.0 Gy) and low risk CTV receives TD=54 Gy (with a daily dose of 1.8 Gy).
17) Weekly response assessment during treatment is done using RECIST criteria.
18) All patients are evaluated for clinical response to treatment and adverse effects starting at 6 weeks post treatment. Patients are followed up every month during the first year, then every 3 months for 2nd year and then every 6 months thereafter. For this study one year follow up is taken into account. The follow-up visits included a thorough physical examination, oral cavity examination, indirect laryngoscopy and direct laryngoscopy if necessary. Further imaging performed as per the response.
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19) Local control is defined as no evidence of disease at the pretreatment gross tumor site (primary or nodal), whereas local failure was defined either as residual disease (within 6-8 weeks post-CRT) or recurrent disease, verified by biopsy or salvage surgery. When a patient achieved local control, but had evidence of disease in the neck nodes, then this was identified as regional failure. Lastly, distant failure was defined as the development of distant metastasis.
20) Assessment of tumor response is based on the physical examination and/or CT scan of the head and neck. Patient follow-up will be reported to the date last seen in OPD or to the date of death. All events will be measured from the last day of RT.
21) Toxicity is assessed by RTOG grading.
22) Chemotherapy drug administration:
For 3 weekly Cisplatin- Pre medications are capsule aprepitant 125 mg on day 1 and 80 mg on day 2 and day 3, Injection palonosetron 0.25 mg IV bolus, Injection dexamethasone 12 mg IV bolus to be given, prehydration 1000 ml 0.9 % Normal saline over 1 hour on day 1 and day 2, injection cisplatin 50mg metresquare intravenous in 500 ml 0.9 % normal saline over one hour. Post hydration 1000 ml 0.9% normal saline, potassium chloride 20 meq, magnesium sulphate one gram over one hour.
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For weekly carboplatin- premedication are Injection palonosetron 0.25 mg IV bolus followed by Injection carboplatin (AUC 2) in 250 ml 0.9 % normal saline over one hour.
END POINT
To assess the efficacy, toxicity and feasibility. Assessment of dose coverage of different sites will be noted. To assess whether the required level of tumour coverage and sparing of OARs is achieved. The treatment time excluding the setup time will be noted. To assess whether SIB-IMRT with adaptive radiotherapy can be safe and effective and can be followed as a standard of care in all locally advanced head and neck cancer patient in our institute. Toxicities are such as mucositis, xerostomia, dysphagia, dysgeusia are compared with retrospective data of patients treated with only IMRT where simultaneous boost was not included and adaptive technique not used. The toxicity is graded using RTOG toxicity grading.
To assess whether the presented SIB-regimen can offer an effective local control with manageable toxicity. By reducing the total treatment time and limiting the treatment to gross disease, it could be considered for patients who are not able to or not willing to undergo radical treatment. For patients with significant concomitant disease and tumor related risk factors such as pre-cachexia or metastatic disease, even shorter treatments or best supportive care only might be taken into
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consideration. The dose received by the gross tumour, the involved nodes, and the dose received by organs at risk are assessed. The reduction in the GTV at the time of re-planning and clinical response at the end of the treatment gives adequate information about the efficacy of the above treatment plan.
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RTOG Acute Radiation Morbidity Scoring Criteria
0 1 2 3 4
SKIN No
change over baseline
Follicular, Faint or dull erythema/dry desquamation/
decreased sweating
Tender//bright erythema, patchy moist
desquamation/m oderate edema
Confluent moist
desquamtatio n
Ulceration, hemorrhage, necrosis
Mucous membra ne
No change over baseline
Injection/may experience mild pain not requiring analgesia
Patchy mucositis which may produceinfamma tory
serosanguinous discharge/may experience moderate pain requiring analgesia
Confluent fibrinous mucositis/Ma y include severe pain requiring narcotic
Ulceration, hemorrhage, necrosis
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Morbidity criteria are used to Score/Grade toxicity from radiation therapy. The criteria are relevant from day 1, the commencement of therapy to end of therapy.
Lower GI
No change
Increased frequency or change in quality of bowel habits not requiring medication/rect al discomfort not requiring anagesics
Diarrhea requiring
parasympathetic drugs
(eg.Lomotil)/rect al or abdominal pain requiring analgesics.
Diarrhea requiring parenteral support/abdo minal
distension (x- ray
demonstratin g distended bowel loops)
Acute or subacute obstruction,f istula or perforation, GI Bleeding requiring transfusion or tenesmus requiring requiring tube
decmpressio n
WBC =>4000 3000-<4000 2000-<3000 1000-<2000 <1000
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PLATE LETS
>1L 75000-<1L 50000-<75000 25000-
<50000
<25000or spontaneous bleeding Neutrop
hils
=>1900 1500-<1900 1000-<1500 500-<1000 <500 or sepsis Hemogl
obin
>11 11-9.5 <9.5-7.5 <7.5-5 -
Genitou rinary
No change
Frequency of urination or nocturia/dysuri a,urgency not requiring medcation
Frequency of urination or nocturia which is less frequent than every hour,dysuria,urg ency,bladder spasmrequiring local
anaesthetic(pyrid ium)
Frequency of urination or nocturia hourly or more frequently /dysuria,pelvi s pain or bladder spasm requiring regular,frequ
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Any Toxicity Which Caused Death is considered as Grade 5.
ent
narcotic/gros s hematuria with/without clot passage
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RTOG/EORTC Late Radiation morbidity Scoring
Organ Tissue
Grade 1 Grade 2 Grade 3 Grade 4
Skin Slight
Atrophy:pigment ation
changes,some hair loss
Patch
atrophy;moderate telangiectasia;total hair loss
Marked
atrophy;Gross telangiectasia
Ulceratio n
Mucous membrane
Slight atrophy and dryness
Moderate atrophy and telangiectasia
Marked atrophy with complete dryness, severe telangiectasia
ulceration
Intestine Mild
diarrhea,Mild cramping;Bowel movement 5 times daily,slight
Moderate diarrhea and colic;bowel movements>5 times daily;excessive rectal mucus or
Obstruction or bleeding
requiring surgery
Necrosis, perforatio n/fistula
