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 Practical
Radiotherapy
Planning
This page intentionally left blank
 Practical
Radiotherapy
Planning
Fourth Edition

Ann Barrett MD, FRCP, FRCR ■

Professor Emeritus of Oncology,
University of East Anglia, Norwich
Jane Dobbs MA, FRCP, FRCR ■
Consultant Emeritus in Clinical Oncology,
Guy’s and St Thomas’ NHS Foundation Trust
Stephen Morris MRCP, FRCR ■
Consultant Clinical Oncologist,
Guy’s and St Thomas’ NHS Foundation Trust
Tom Roques MRCP, FRCR ■
Consultant Clinical Oncologist,
Norfolk and Norwich University Hospital NHS Foundation Trust

Illustrations editor:
Jonathan Harrowven BSc (Hons),
Radiographer, Norfolk and Norwich University Hospital
NHS Foundation Trust
Hodder Arnold, an imprint of Hodder Education, an Hachette UK Company
338 Euston Road, London NW1 3BH

http://www.hoddereducation.com

© 2009 Ann Barrett, Jane Dobbs, Stephen Morris and Tom Roques

All rights reserved. Apart from any use permitted under UK copyright law, this
publication may only be reproduced, stored or transmitted, in any form, or by any means
with prior permission in writing of the publishers or in the case of reprographic
production in accordance with the terms of licences issued by the Copyright Licensing
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and made from wood grown in sustainable forests. The logging and manufacturing
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Whilst the advice and information in this book are believed to be true and accurate at
the date of going to press, neither the author[s] nor the publisher can accept any legal
responsibility or liability for any errors or omissions that may be made. In particular (but
without limiting the generality of the preceding disclaimer) every effort has been made to
check drug dosages; however it is still possible that errors have been missed. Furthermore,
dosage schedules are constantly being revised and new side-effects recognized. For these
reasons the reader is strongly urged to consult the drug companies' printed instructions
before administering any of the drugs recommended in this book.

British Library Cataloguing in Publication Data

A catalogue record for this book is available from the British Library

Library of Congress Cataloging-in-Publication Data

A catalog record for this book is available from the Library of Congress

ISBN 978 034 0927731

1 2 3 4 5 6 7 8 9 10

Commissioning Editor: Gavin Jamieson

Project Editors: Eva Senior and Joanna Silman
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Contents

Preface vii
1 What you need to know before planning radiotherapy
treatment 1

2 Principles of radiotherapy planning 9

3 Radiobiology and treatment planning 32

4 Organs at risk and tolerance of normal

tissues 44

5 Principles of brachytherapy 54

6 Emergency and palliative radiotherapy 62

7 Skin 71

8 Head and neck: general considerations 88

9 Lip, ear, nose and treatment of the

neck in skin cancer 111

10 Oral cavity 122

11 Oropharynx cancer and unknown

primary tumour 134

12 Hypopharynx 146

13 Nasopharynx 156

14 Larynx 165

15 Salivary glands 177

16 Sinuses: maxilla, ethmoid and

nasal cavity tumours 185

17 Orbit 196

18 Central nervous system 205

19 Thyroid and thymoma 231

20 Lung 241

21 Mesothelioma 258

22 Breast 265

23 Lymphomas 283

24 Oesophagus and stomach 294

v
CONTENTS
25 Pancreas and liver 303

26 Rectum 311

27 Anus 323

28 Prostate 332

29 Bladder 351

30 Testis 359

31 Penis 365

32 Cervix 370

33 Uterus 384

34 Vagina 394

35 Vulva 401

36 Sarcoma 408

37 Paediatric tumours 415

38 Systemic irradiation 426

Appendix: List of abbreviations 433

Index 435

vi
Preface

Since the last edition of Practical Radiotherapy Planning in 1999, the practice of
radiotherapy has changed radically. Advances in imaging have been integrated with
technological developments in radiotherapy delivery so that 3D planning of
volumes has replaced 2D field arrangements. Major developments in tumour
localisation have included the publication of ICRU reports on target definition
(Report 62 in 1999 and Report 71 in 2004) and the possibility of registration of
different imaging modalities including CT, MRI and PET. In treatment delivery,
multi-leaf collimation has enabled treatments to be shaped to tumours and
intensity-modulated dose plans have provided solutions to previous planning
dilemmas. Accuracy of treatment delivery has been ensured by development of
portal imaging and daily image-guided and adaptive radiotherapy techniques.
This is therefore a completely new book, with new introductory chapters and a
changed structure within each tumour site chapter. We have been able to make
much more use of clinical images to illustrate important planning concepts. The
aim of the book, however, remains unchanged: to provide a guide to radiotherapy
treatment planning that is based on sound pathological and anatomical principles.
Complexity of treatment planning has increased greatly but this new edition
continues to emphasise the underlying principles of treatment, which can be
applied to conventional, conformal, and novel treatments, taking into account
advances in imaging and treatment delivery.
Much treatment is now given according to local, national or international
protocols and these should always be consulted and used when appropriate. Details
of drug and of some radiotherapy regimens are not given as they change frequently.
Again we have largely excluded recommendations for treatment of benign disease.
The ICRU report proposed a colour convention for outlining target volumes,
but with regret we have chosen different colours to ensure optimal reproduction
of plans. We have used the following scheme in all illustrations:
GTV dark blue
CTV cyan (light blue)
CTV2 magenta (purple)
PTV red
PTV2 lime green
OAR yellow, light yellow, light green, dark green
Two authors from the first three editions have been joined by two younger
colleagues from our departments to ensure that we continue to reflect the most
up-to-date approach to treatment planning. It would have been impossible to
vii
PREFACE

produce a book like this one, in the age of site-specialised practice and
multidisciplinary team working, without relying very heavily on expert colleagues
within our respective departments. We are most grateful to them for the time and
effort they have put in to ensuring the accuracy and appropriateness of what we
have written. Special thanks are due to Anna Winship, George Mikhaeel, David
Convery and Kim Ball at Guy’s and St Thomas’ Hospital, Mark Gaze at University
College Hospital, Richard Benson at Addenbrooke’s Hospital, and at the Norfolk
and Norwich University Hospital: Dinos Geropantas, Suat Loo, Adrian Harnett,
Max Dahele, Rob Wade, Jenny Tomes, and our radiological colleagues. We would
like to acknowledge our radiographer colleagues in both departments who have
helped us to find illustrations and plans. The work was supported in part by a
sabbatical leave award to Jane Dobbs from the Clinical Oncology Dean’s Fund of
the Royal College of Radiologists, London, whom we thank.
This small textbook cannot describe all the research which has been undertaken
to develop treatment schedules. We aim always to use evidence-based solutions
where they exist and have suggested, in a short list of information sources at the
end of each chapter, where more detailed data may be found. Some fields of research,
such as the use of gating and adaptive therapy, 3D rotational arc therapy, and
stereotactic radiotherapy are still undergoing evaluation and are therefore beyond the
scope of this book. We give a brief introduction to the principles and practice of
brachytherapy but details must be found elsewhere. Commonly used abbreviations
have been spelled out only at first mention in the book but are included in the
appendix for further reference.
Trainees in radiation oncology and radiographers, working within a
multidisciplinary team, will, we hope, continue to use our book to produce safe
and appropriate plans for common tumours.
Ann Barrett; Jane Dobbs; Stephen Morris; Tom Roques
2008

viii
What you need to 1
know before planning
radiotherapy
treatment
Introduction
Radiotherapy treatment can only produce good effects if it is delivered in an
appropriate clinical context. Attempting radical treatment for a patient with
metastatic disease, or one who is likely to die soon from cardiac or lung disease is
inappropriate. These decisions require a fine balance of judgement between therapeutic
optimism and nihilism and must be firmly based in good clinical history taking and
examination. The clinician must then be able to synthesise all the information about
the patient, tumour, investigations and previous treatment to make a decision about
whether radiotherapy should be given and if so, with radical or palliative intent.
Comorbidities, such as diabetes or vascular disease, which would affect the toxicity
of treatment, must also be considered.
Sometimes the decision to offer radiotherapy may be relatively simple if the
disease is common, the treatment effective and standardised, the histological
features well categorised, and imaging easy to interpret. Some breast cancers fit well
into this category. In contrast, decisions may be very difficult if there is no treatment
of proven benefit, the prognosis is uncertain, the patient’s general performance
status is poor, imaging is of limited usefulness or there is histological uncertainty.
Clinical experience and judgement is then critically important. This expertise is
built on the foundation of good history taking which enables us to set the patient’s
disease in the context of their own ideas, concerns and expectations. Have other
family members had radiotherapy with good or bad outcomes? Are they so
claustrophobic that they will not go into a scanner or treatment room? Do they
have other problems which would affect the feasibility of radiotherapy – arthritis
which limits joint movement, shortness of breath which prevents them lying flat,
heart valves or prostheses which may affect dose delivery?
Clinicians may consider that the new era of cross-sectional and functional imaging
has made examination of the patient irrelevant but it remains the essential foundation
of appropriate clinical judgements; for example, detection of a lymph node in the
axilla, otherwise overlooked in imaging, or the progression of tumour since the last
scan, may change a decision taken earlier in a multidisciplinary team meeting.

Classification systems
Many classification systems have been developed to ensure that clinicians throughout
the world share a common language as they describe patients, tumours, and their
1
PLANNING RADIOTHERAPY TREATMENT

treatment. This is essential to allow effective cancer registration and comparisons

of incidence, prognosis and outcome of treatments. Many protocols for treatment
are also based on such classification systems.

Pathological classification
The International Classification of Disease (ICD) version 10 of the World Health
Organization (WHO) has been in use since 1994. It is the international standard
diagnostic classification for epidemiology and health management. It is used in
hospital records and on death certificates, which in turn are the basis for compiling
mortality and morbidity statistics nationally and internationally. There is a
subclassification, the International Classification of Disease for Oncology version 3
(ICD-O-3) which is used in cancer/tumour registries to code site (topography)
and type (morphology) of neoplasms from the histopathology report.
Information about malignancy (malignant, benign, in situ or uncertain) and
differentiation is also coded. In the UK, this information is abstracted from clinical
notes by trained coders. The introduction of computerised systems suggests that
clinicians will be required to develop greater awareness of this classification, at least
in their own areas of expertise, especially if the information becomes essential data
before income is assured. ICD 10 and ICD-O-3 are available online.
The morphological information for ICD-O-3 coding comes from the pathologist
whose expertise is essential to establish a precise diagnosis and choose appropriate
treatment volumes. A pathology report will contain a description of the macroscopic
appearance of the gross tumour specimen, its size, margins and anatomical
relationships. It will describe the microscopic appearance after appropriate staining of
cut sections of the tumour, including features such as areas of necrosis. Recognition
of the tissue of origin and grading of the tumour will then often be possible.
There has been an explosion of new techniques in pathology, such as
immunocytochemical staining, immunophenotyping and fluorescence in situ
hybridisation, which may help to remove uncertainties about diagnoses following
conventional histopathological examination. Oncologists must be in constant
dialogue with their colleagues in pathology to ensure that they understand the
significance of results of these special investigations and know how to assess the
degree of certainty of the report.

Staging
Tumour stage, histological classification and grading determine prognosis and
treatment decisions. An internationally agreed system of staging is essential to
interpret outcomes of treatment and compare results in different treatment centres.
The behaviour of tumours in different sites is determined by the anatomical situation,
blood supply and lymphatic drainage, as well as the histological classification and
grading. Any staging system must take into account this variability. The most
commonly used systems are the UICC (Union Internationale Contre le Cancer)
TNM, AJCC (American Joint Committee on Cancer) and FIGO (Federation
Internationale de Gynecologie et d’Obstetrique) for gynaecological malignancy. The
TNM system describes the tumour extent (T) nodal involvement (N) and distant
metastases (M). This defines a clinical classification (cTNM) or a pathological one
2
 Staging
(pTNM) which incorporates information derived from an excised tumour and any
draining lymph nodes that are also removed or sampled. Details of this system are
given in the TNM atlas which should be available and used wherever patients are
seen or results of investigation are correlated.
T staging includes measurement of the tumour either clinically, by imaging
techniques or by macroscopic examination of an excised specimen. Correct
pathological T staging can only be assured if the pathologist receives a completely
excised tumour with a rim of surrounding tissue. The tumour should not be cut into
or fixed except by the pathologist. Examination of the whole specimen is needed
to determine the highest grade of tumour (as there is frequently inhomogeneity
across the tumour), any vascular or lymphatic invasion or invasion of adjacent
tissues. Spread into a body space such as the pleural or peritoneal cavity affects T
stage as it changes prognosis.
Numbers are added to indicate extent of disease. T0 implies no primary tumour
(as after spontaneous regression of a melanoma). Categories T1–4 indicate tumours
of increasing size and/or involvement of lymphatic vessels or surrounding tissue. If
it is impossible to ascertain size or extent of primary tumour, it is designated Tx.
N classification describes whether there is lymph node involvement and if so,
how many nodes are involved. Pathological staging requires adequate excision of
the relevant lymph node compartment and a minimum number of nodes which
indicates that this has been achieved may be defined for each site. If there are
positive nodes, the ratio of negative to positive is of prognostic significance. For
example, one node positive out of four removed indicates a worse prognosis than
one out of 12. The size of tumour in the nodes must be recorded as well as any
extension through the capsule. Micrometastases are classified differently from
tumour emboli in vessels and this affects the N staging.
Identification and sampling of a sentinel node may give useful prognostic
information about other potential node involvement and help to choose appropriate
treatment strategies. In breast cancer, for example, it appears highly predictive
(90 per cent) for axillary node involvement.
M category indicates presence (M1) or absence (M0) of metastases to distant
sites.
For some sites, other staging systems have proved clinically more useful. These
include the FIGO system for gynaecological malignancy and Dukes’ classification
of colonic tumours. Useful atlases of patterns of lymph node involvement have
been devised for several tumour sites. These are included in subsequent chapters
where relevant. Recommendations for the most appropriate imaging techniques
for staging in different sites have been published.
Residual tumour after surgical excision is an important poor prognostic factor.
Examination of resection margins assigns tumours to categories: R0, no residual
tumour; R1, histologically detectable tumour at margins; and R2, macroscopic
evidence of residual tumour. Where serum markers (S) convey important prognostic
information, as in tumours of the testis, an S category has been introduced to the
TNM system.
TNM categorisation is often used to group tumours subsequently into stages
indicating local and metastatic extent and correlating with likely outcome.
Grading is defined by degree of differentiation as: G1, resemblance to tissue of
origin; G2, moderately well differentiated; G3, poorly differentiated; and G4,
3
PLANNING RADIOTHERAPY TREATMENT

undifferentiated tumours; with Gx used when it is not possible to determine

grading, as for example from a damaged specimen. GB signifies a borderline
malignant tumour (for example in the ovary). Grading systems have been agreed
to reduce the subjective element of these assessments.

Performance status
Performance status measures attempt to quantify cancer patients’ general wellbeing.
They are used to help to decide whether a patient is likely to tolerate a particular
treatment such as chemotherapy, whether doses of treatment need to be adjusted
or whether palliative treatment has been effective. The status of all patients should
be recorded using one of these scores at presentation and with any change in
treatment or the disease. They are also used as a measure of quality of life in clinical
trials.
There are various scoring systems, of which the most commonly used are the
Karnovsky and WHO scales for adults, and the Lansky score for children. The SF-36
is a short form (SF) survey of overall health (originally with 36 questions, now 12)
which gives a profile of mental and physical health. It has produced statistically
reliable and valid results in many reported studies. There are modifications of this
questionnaire for specific tumour sites. Another commonly used scale in quality of
life assessment is the HADS (Hospital Anxiety and Depression Scale) which is used
to measure changes in mental and emotional wellbeing during treatment or with
progression of disease.

Prognostic factors
All possible information which may help in predicting prognosis should be
collected in order to advise the patient and help make the most appropriate
treatment decision.
Screen detected cancers may have a better prognosis than tumours presenting
symptomatically because diagnosis is made earlier (breast and oesophagus).
However, in other situations, screening is as yet of unproven benefit (for example
chest X-ray for detecting early lung cancer).
Histological tumour type, grading and staging are most influential in
determining outcome for an individual patient, and new techniques of tumour
examination are yielding more information on gene function and expression which
may affect prognosis. Other factors which must also be considered include
epidemiological ones such as age, sex, lifestyle factors such as smoking, alcohol and
other drug use, obesity, and family history of disease. Other biological factors such
as performance status, which may reflect comorbidities, must be considered.
Biochemical tumour markers may be specific enough to give prognostic
information by their absolute value, as for example β subunit of human chorionic
gonadotrophin (β-hCG) levels in testicular cancer. However, they may be only
relatively poorly correlated with tumour volume, such as carcinoembryonic
antigen (CEA) in bowel cancer, but still be useful to indicate treatment response
or disease progression by their rise or fall.
One of the most important prognostic factors is whether there is effective
treatment for the condition. Because new treatments are being introduced all the
4
 Influence of other treatments on radiotherapy
time, prognostic predictions must also be constantly reviewed and validated in
prospective controlled clinical trials.
Predictive tools based on population datasets are available for some tumours
such as ‘Adjuvant! On line’ for breast cancer, and Partin tables and the Memorial
Sloane Kettering nomogram for prostate cancer.
Predictive indicators are variables determined before treatment which give
information on the probability of a response to a specific treatment. Predictive
indices based on multiple indicators give an individual score which may help to
make decisions. These tools can only be developed by painstaking retrospective
analysis and careful prospective studies, but it is likely that their use will increase
steadily. They are important in determining strategies for treating different tumour
subsets in guidelines and protocols.
Increasingly, specific genetic profiles are correlated with natural history of
disease or outcome of treatment. Examples are the predictive value of MYCN
amplification in neuroblastoma, oestrogen/HER2 receptor status and response to
hormone therapy or trastuzumab, and predilection of patients with Li–Fraumeni
syndrome to development of second tumours. Microarray technology will provide
more genetically determined prognostic factors which will have to be taken into
account in planning treatment.

Influence of other treatments on radiotherapy

Surgery is most commonly used as a primary treatment for cancer. If performed
before radiotherapy, it removes the gross tumour volume (GTV) so that a clinical
target volume (CTV) must be used for planning (see Chapter 2).
If it is known from the time of diagnosis that both treatments will be needed,
the best sequencing has to be decided. If the tumour is initially inoperable,
radiotherapy first may produce tumour shrinkage which makes complete excision
possible, thereby improving outcome. Radiotherapy may increase surgical
complications if the interval between the two treatments is not optimal. Surgery
before radiotherapy will alter normal anatomy, causing problems for planning
unless pre- and postsurgical image co-registration is used.
Effective chemotherapy may produce complete resolution of the primary tumour
(no residual GTV), and potentially increased acute normal tissue effects. The treatment
the patient receives will be the best possible only if all these potential interactions are
taken into consideration by all members of the team working together.
A true therapeutic gain from chemotherapy and radiotherapy together requires
either more cell kill for the same level of normal tissue damage (which is useful
in radio-resistant tumours) or the same cell kill with reduced normal tissue
effects (useful for tumours cured with low dose radiotherapy). Concurrent
chemoradiotherapy is now used for many tumours. It may improve outcomes by
promoting spatial cooperation in cell killing, where the chemotherapy kills metastatic
cells, and the radiotherapy those cells in the local tumour, or in-field cooperation
where exploitation of differing molecular, cellular or tissue effects produces more
cell kill than when the two agents are given sequentially.
Patients themselves may be using alternative therapies with possible effects on
efficacy and complications of surgery, chemotherapy and radiotherapy. Antioxidants
may interfere with free radical production which effects cell kill. St John’s wort,
5
PLANNING RADIOTHERAPY TREATMENT

used for depression, may affect the metabolism of some drugs. Aspirin and gingko
biloba may increase risk of bleeding, and phyto-oestrogens may affect hormonally
sensitive cancers. Lifestyle factors such as smoking or eating many vegetables
during radiotherapy may influence the severity of acute treatment side effects such
as mucositis or diarrhoea.

Systems for recording outcomes of treatment

In the past, various systems have been used for recording outcomes of treatment,
including the WHO and European Organisation for Research and Treatment of
Cancer (EORTC) criteria. Following advances in imaging techniques and
improvements in treatment, a new set of tumour response criteria have been agreed –
the Response Evaluation Criteria in Solid Tumours (RECIST). Other outcomes are
recorded as the time to a specific event: time to progression for tumours with partial
response (progression-free survival), time to local recurrence where there has been a
complete remission (relapse-free survival), time to distant metastases, time to death
from any cause (overall survival), time to second malignancy. The start and end dates
for these time periods must be clearly defined and stated as, for example, date of first
treatment, date of randomisation, date of imaging of relapse, or date of histological
proof of relapse. There is still no clear convention for defining these dates.
Quality of life measures are also essential for assessing treatment effects.
Standardised scales such as the EORTC, QLQ-C36 and C30 have been validated
and can be used for many cancer sites and in many countries.
Acute side effects can be recorded using the NCI-CTC 3 (Common Toxicity
Criteria version 3). This is a complex and comprehensive system that has only
partially been adopted. Late effects are recorded either using the Radiation Therapy
Oncology Group (RTOG) criteria or the European LENT-SOMA classification or
other simpler schemes for individual body sites such as gynaecological tumours.
Use of the NCI-CTC 3 is recommended until a more concise system gains
international recognition.

Clinical anatomy
Modern radiotherapy planning requires a comprehensive knowledge of cross-
sectional anatomy and the ability to visualise structures in three dimensions.
Formal teaching in anatomy should be part of training, using standard atlases,
various online resources, e.g. the Visible Man, and three-dimensional (3D) images,
which have become more accessible with picture archiving and conservation
systems (PACS). We attempt to give some relevant anatomical details in the
following chapters, but collaboration with a diagnostic radiologist will be essential
for accurate GTV delineation. Oncologists will tend to develop expertise in their
own specialist area, but are unlikely to be familiar with all the possible normal
variants and anomalies which may occur.

Protocols and guidelines

In the UK, there has been a proliferation of guidance, guidelines and protocols for
the management of cancer. Some, such as Improving Outcomes Guidance (IOG)
6
 Information sources
and decisions of the National Institute for Health and Clinical Excellence (NICE)
have a mandatory element which ensures their adoption. The firmest base for
clinical decision-making is evidence of effectiveness of treatment from well-
designed prospective randomised clinical trials (RCTs). Where this is lacking,
careful analysis of outcomes data can be very informative and has the advantage
of wider generalisability. National and international trial protocols offer useful
information for treatment planning, as they represent current consensus on best
practice, as for example, how to scan lung cancer for treatment planning, or what
quality assurance programme to use. Departments will have their own written
protocols for treatment at different sites to ensure consistency and quality and to
avoid errors.
Not all patients’ circumstances will fit within standardised guidelines and
protocols, although these should be followed whenever possible for best outcomes.
However, with the rate of change in treatment in oncology, there should be a
constant cycle of writing guidelines and using, auditing, challenging and rewriting
them.

Information sources
Adjuvant! Online. www.adjuvantonline.com (accessed 26 November 2008).
Clark A, Fallowfield LJ (1986) Quality of life measurement in patients with malignant disease. Royal
Soc Med 79:165–9.
Cochran AJ, Roberts AA, Saida T (2003) The place of lymphatic mapping and sentinel node biopsy
in oncology. Int J Clin Oncol 8: 139–50.
Common Toxicity Criteria for Adverse Events v3.0 (CTCAE) (2006)
http://ctep.cancer.gov/forms/CTCAEv3.pdf (accessed 26 November 2008).
Dukes CE (1949) The surgical pathology of rectal cancer. J Clin Path 2: 95–8 and at
www.emedicine.com.
ECOG/WHO Oken MM, Creech RH, Tormey DC et al. (1982) Toxicity and response criteria of the
Eastern Oncology Cooperative Group. Am J Clin Oncol 5: 649–55.
Ernst E, Cassileth BR (1998) The prevalence of complementary/alternative medicine in cancer.
Cancer 83: 777–82.
Gipponi M, Solari N, Di Somma FC et al. (2004) New fields of application of the sentinel node biopsy
in the pathological staging of solid neoplasms: Review of the literature and surgical
perspectives. J Surg Oncol 85: 171–9.
Imaging for Oncology: Collaboration Between Clinical Radiologists and Clinical Oncologists in
Diagnosis, Staging, and Radiotherapy Planning. (2004) Royal College of Radiologists, London.
Karnovsky DA, Burchenal JH (1949) The clinical evaluation of chemotherapeutic agents in cancer.
In: MacLeod CM (ed) Evaluation of Chemotherapeutic Agents. Columbia University Press,
New York, p. 196 and at http://en.wikipedia.org/wiki/Performance_status.
Kattan MW, Eastham JA, Stapleton AM et al. (1998) A prospective nomogram for disease
recurrence following radical prostatectomy for prostate cancer. J Natl Cancer Inst 90: 766–71.
Lansky SB, List MA, Lansky LL et al. (1987) The measurement of performance in childhood cancer
patients. Cancer 60: 1651–6.
NICE guidance. www.nice.org.uk.
Partin AW, Mangold LA, Lamm DM et al. (2001) Contemporary update of prostate cancer staging
nomograms (Partin tables) for the new millennium. Urology 58: 843–8.

7
PLANNING RADIOTHERAPY TREATMENT
Pecorelli S, Ngan HYS, Hacker NF (2006) Staging Classifications and Clinical Practice Guidelines for
Gynaecological Cancers. Reprinted from Int J Gynae Obstet 2002; 70: 207–312 at
www.figo.org/docs/staging_booklet.pdf (accessed 2 December 2008).
QLC-30. http://groups.eortc.be/qol/questionnaires_qlqc30.htm (accessed 26 November 2008).
Recommendations for Cross-sectional Imaging in Cancer Management (2006). Royal College of
Radiologists, London.
Seiwert TY, Joseph K, Salama JK et al. (2007) The concurrent chemoradiation paradigm – general
principles. Nat Clin Pract Oncol 4: 86–100.
SF36. www.pdmed.bham.ac.uk/trial/Clinicians/SF36%20Questionnaire.pdf (accessed 2 December
2008).
Sobin LH, Wittekind CH (2002) TNM Classification of Malignant Tumours, 6th edn. John Wiley,
Chichester.
Therasse P, Arbuck SG, Eisenhauer EA et al. (2000) New guidelines to evaluate the response to
treatment in solid tumours. J Natl Cancer Inst 92: 205–16 and at
http://ctep.cancer.gov/forms/TherasseRECISTJNCI.pdf (accessed 26 November 2008).
The Visible Human Project, National Library of Medicine 1989–1995.
www.nlm.nih.gov/research/visible/visible_human.html (accessed 2 December 2008).
Radiation Therapy Oncology Group. www.rtog.org/hnatlas/main.html.
Wittekind CH, Hutter R, Greene FL et al. (2005) TNM Atlas: Illustrated Guide to the TNM
Classification of Malignant Tumours, 5th edn. John Wiley, Chichester.
World Health Organization (2007) International Classification of Disease – Version 10, Chapter 2
Neoplasms. www.who.int/classifications/apps/icd/icd10online (accessed 26 November 2008).
Zigmond AS, Snaith RP (1983) Hospital Anxiety and Depression Scale. Acta Pyschiatr Scand 67:
361–70 and at www.sign.ac.uk/guidelines (Guideline 57).

8
Principles of 2
radiotherapy planning

The practice of radiotherapy requires not only excellent clinical skills but also
appropriate technical expertise. Chapter 1 considered some factors contributing to
making good clinical judgements; Chapter 2 outlines the specialist knowledge
required to plan radiotherapy treatment.

Target volume definition

A common international language for describing target volumes is found in
International Commission on Radiation Units (ICRU) published recommendations
Report 50 (1993), 62 (1999) and 71 (2004). These contain clear definitions (Fig. 2.1)
to enable centres to use the same criteria for delineating tumours for radiation so
that their treatment results can be compared.

IrV
TrV PTV

CTV

GTV

Figure 2.1 ICRU target volume definitions showing

GTV, CTV, PTV, treated and irradiated volume.
Reproduced with permission from ICRU (1993)
Prescribing, Recording and Reporting Photon Beam
Therapy. ICRU report 50.

■ Gross tumour volume

Gross tumour volume (GTV) is the primary tumour or other tumour mass shown
by clinical examination, at examination under anaesthetic (EUA) or by imaging.
GTV is classified by staging systems such as TNM (UICC), AJCC or FIGO.
Tumour size, site and shape may appear to vary depending on the imaging technique
used and an optimal imaging method for each particular tumour site must therefore
also be specified. A GTV may consist of primary tumour (GTV-T) and/or metastatic
lymphadenopathy (GTV-N) or distant metastases (GTV-M). GTV always contains
the highest tumour cell density and is absent after complete surgical resection.
9
PRINCIPLES OF RADIOTHERAPY PLANNING

■ Clinical target volume

Clinical target volume (CTV) contains the GTV when present and/or subclinical
microscopic disease that has to be eradicated to cure the tumour. CTV definition is
based on histological examination of post mortem or surgical specimens assessing
extent of tumour cell spread around the gross GTV, as described by Holland et al.
(1985) for breast cancer. The GTV-CTV margin is also derived from biological
characteristics of the tumour, local recurrence patterns and experience of the
radiation oncologist. A CTV containing a primary tumour may lie in continuity with
a nodal GTV/CTV to create a CTV-TN (e.g. tonsillar tumour and ipsilateral cervical
nodes). When a potentially involved adjacent lymph node which may require elective
irradiation lies at a distance from the primary tumour, separate CTV-T and CTV-N
are used (Fig. 2.2), e.g. an anal tumour and the inguinal nodes.
CTV can be denoted by the dose level prescribed, as for example, CTV-T50 for a
particular CTV given 50 Gy. For treatment of breast cancer, three CTVs may be used
for an individual patient: CTV-T50 (50 Gy is prescribed to the whole breast);
CTV-T66 (66 Gy to the tumour bed); and CTV-N50 (50 Gy to regional lymph nodes).
Variation in CTV delineation by the clinician (‘doctor’s delineation error’) is the
greatest geometrical uncertainty in the whole treatment process. Studies comparing
outlining by radiologists and oncologists have shown a significant inter-observer
variability for both the GTV and/or CTV at a variety of tumour sites. This is
greater than any intra-observer variation. Published results for nasopharynx, brain,
lung, prostate, medulloblastoma and breast all show significant discrepancies in the
volumes outlined by different clinicians. Improvements can be made with training
in radiological anatomy which enables clinicians to distinguish blood vessels from
lymph nodes and to identify structures accurately on computed tomography (CT)
and magnetic resonance imaging (MRI). Joint outlining by radiologists and
oncologists can improve consistency and ensure accurate interpretation of imaging
of the GTV. Consensus guidelines such as those for defining CTV for head and
neck nodes (Gregoire et al. 2000) and pelvic nodes (Taylor et al. 2005) have
improved CTV delineation greatly. Protocols for outlining GTV and CTV at all
tumour sites are needed and suggestions are made in each individual chapter.

■ Planning target volume

When the patient moves or internal organs change in size and shape during a
fraction of treatment or between fractions (intra- or inter-fractionally), the
position of the CTV may also move. Therefore, to ensure a homogeneous dose to
the CTV throughout a fractionated course of irradiation, margins must be added
around the CTV. These allow for physiological organ motion (internal margin)
and variations in patient positioning and alignment of treatment beams (set-up
margin), creating a geometric planning target volume. The planning target volume
(PTV) is used in treatment planning to select appropriate beams to ensure that the
prescribed dose is actually delivered to the CTV.

■ Organ motion/internal margin

Variations in organ motion may be small (e.g. brain), larger and predictable (e.g.
respiration or cardiac pulsation), or unpredictable (e.g. rectal and bladder filling).
10
 Target volume definition

Figure 2.2 ICRU illustrations to show (a) GTV-T plus GTV-N in continuity (CTV-TN) and
(b) CTV-T and CTV-N at a distance. Reproduced with permission from ICRU (2004)
Prescribing, Recording and Reporting Electron Beam Therapy. ICRU report 71.

When treating lung tumours, the displacement of the CTV caused by respiration can
be dealt with in several ways: by increasing the CTV-PTV margin eccentrically to
include all CTV positions during a respiratory cycle; by using suspended respiration
with a technique such as the active breathing control (ABC) device; or by delivery
of radiation using gating or respiratory correlated CT scanning and treatment.
Protocols for minimising effects on the CTV of variations in bladder and rectal
filling are described in relevant chapters. Uncertainties from organ motion can also
11
PRINCIPLES OF RADIOTHERAPY PLANNING

be reduced by using fiducial markers, and published results are available for lung,
prostate and breast tumours. Radio-opaque markers are inserted and imaged at
localisation using CT or MRI, and at treatment verification, using portal films,
electronic portal imaging devices (EPIDs) or online cone beam CT image-guided
radiotherapy (IGRT).
The internal margin therefore allows for inter- and intra-fractional variations in
organ position and shape which cannot be eliminated.

■ Set-up variations/set-up margin

During a fractionated course of radiotherapy, variations in patient position and in
alignment of beams will occur both intra- and inter-fractionally, and a margin for
set-up error must be incorporated into the CTV-PTV margin. Errors may be
systematic or random.
Systematic errors may result from incorrect data transfer from planning to dose
delivery, or inaccurate placing of devices such as compensators, shields, etc. Such
systematic errors can be corrected.
Random errors in set-up may be operator dependent, or result from changes
in patient anatomy from day to day which are impossible to correct. Accuracy of
set-up may be improved with better immobilisation, attention to staff training
and/or implanted opaque fiducial markers, such as gold seeds, whose position can
be determined in three dimensions at planning, and checked during treatment
using portal imaging or IGRT. Translational errors can thereby be reduced to
1 mm and rotational errors to 1°.
Each department should measure its own systematic and random errors for each
treatment technique by comparing portal imaging and digitally reconstructed
radiographs (DRRs). These measurements are then incorporated into the CTV-
PTV margin using the formula devised by Van Herk, where the CTV is covered
for 90 per cent of the patients with the 95 per cent isodoses:

PTV margin  2.5Σ  0.74 σ

where Σ  total standard deviation (SD) computed as the square root of the sum of
the squared individual SD values of all systematic errors for organ motion and set-up;
and σ  total SD of all random errors combined quadratically in a similar way.
This provides a population-derived standard CTV-PTV margin for a particular
technique in a given centre and can be non-isotropic in cranio-caudal, transverse
and anteroposterior (AP) directions. Accurate treatment delivery depends on
reducing or eliminating systematic errors and requires a high level of awareness of
all staff throughout the many different work areas from localisation through to
treatment.
Other theories about how to incorporate organ motion and the uncertainty of
the ‘mean’ position of the CTV on a snapshot CT scan used for localisation have
been proposed. Van Herk suggests a volume large enough to contain the mean
position of the CTV in 90 per cent of cases, called the systematic target volume
(STV) (British Institute of Radiology 2003). Collection of data on the precise CT
location of tumour recurrences in relation to the original target volume is
important to improve margin definition.
12
 Immobilisation
■ Treated volume
This is the volume of tissue that is planned to receive a specified dose and is
enclosed by the isodose surface corresponding to that dose level, e.g. 95 per cent.
The shape, size and position of the treated volume in relation to the PTV should
be recorded to evaluate and interpret local recurrences (in field versus marginal)
and complications in normal tissues, which may be outside the PTV but within the
treated volume.

■ Conformity index
This is the ratio of PTV to the treated volume, and indicates how well the PTV is
covered by the treatment while minimising dose to normal tissues.

■ Irradiated volume
This is the volume of tissue that is irradiated to a dose considered significant in
terms of normal tissue tolerance, and is dependent on the treatment technique
used. The size of the irradiated volume relative to the treated volume (and integral
dose) may increase with increasing numbers of beams, but both volumes can be
reduced by beam shaping and conformal therapy.

■ Organs at risk
These are critical normal tissues whose radiation sensitivity may significantly
influence treatment planning and/or prescribed dose. Any movements of the organs
at risk (OAR) or uncertainties of set-up may be accounted for with a margin similar
to the principles for PTV, to create a planning organ at risk volume (PRV). The
size of the margin may vary in different directions. Where a PTV and PRV are close
or overlap, a clinical decision about relative risks of tumour relapse or normal tissue
damage must be made. Shielding of parts of normal organs is possible with the use
of multi-leaf collimation (MLC). Dose–volume histograms (DVHs) are used to
calculate normal tissue dose distributions.

Immobilisation
The patient must be in a position that is comfortable and reproducible (whether
supine or prone), and suitable for acquisition of images for CT scanning and
treatment delivery. Immobilisation systems are widely available for every anatomical
tumour site and are important in reducing systematic set-up errors. Complex
stereotactic or relocatable frames (e.g. Gill–Thomas) are secured to the head by
insertion into the mouth of a dental impression of the upper teeth and an occipital
impression on the head frame, and are used for stereotactic radiotherapy with a
reproducibility of within 1 mm or less. Perspex shells reduce movement in head and
neck treatments to about 2 mm. The technician preparing the shell must have
details of the tumour site to be treated, e.g. position of the patient (prone, supine,
flexion or extension of neck, arm position, etc.). An impression of the relevant area
13
PRINCIPLES OF RADIOTHERAPY PLANNING

(made using quick setting dental alginate or plaster of Paris) is filled with plaster and
this form is used to make a Perspex shell by vacuum moulding. The shell fits over
the patient and fastens to a device on the couch with Perspex straps and pegs in at
least five places. Alternatively, thermoplastic shells can be made by direct moulding
of heat-softened material on the patient and these have a similar degree of accuracy.
Relocatable whole body fixation systems using vacuum moulded bags of
polystyrene beads on a stereotactic table top restrict movement to 3–4 mm and are
used to immobilise the trunk and limbs with markings on the bag instead of on
the patient’s skin. Where the patient has kyphosis, scoliosis or limitation of joint
movement, extra limb pads or immobilisation devices may be required. Metallic
prostheses, abdominal stomata and the batteries of pacemakers must be located
and excluded from the radiation volume where possible. Details of immobilisation
devices are discussed in each tumour site chapter.
Parameters of limb rests, thoracic or belly boards, foot rests and leg restraints,
Perspex shells and skin tattoos should be clearly recorded to avoid transfer errors
between the planning process and subsequent treatment. Gantry and couch top
flexibility should be measured and couch sag avoided by using rigid radiolucent
carbon fibre tables. Table tops must have fixtures for immobilisation devices and
laser light systems are essential in CT, simulator and treatment units (Fig. 2.3).
Protocols for bladder and rectal filling, respiration and other patient parameters
must be documented at localisation, and reproduced daily during treatment to
minimise uncertainties.
CT scans taken for localisation are only a single snapshot, and the CT scan
should be repeated daily on several days to measure variation in organ motion and
systematic set-up errors for an individual patient. These values can then be used to
inform the CTV-PTV margin on an individual basis rather than using population
derived margin values. This is known as adaptive radiotherapy (ART). Kilovoltage
(kV), cone beam CT, and megavoltage (MV) imaging on treatment machines
make it possible to obtain CT images immediately before treatment. While

Figure 2.3 Patient positioned to show immobilisation on the CT scanner with arms up
and laser lights used to prevent rotational set-up errors.

14
 Data acquisition
resolution is not as good as with diagnostic CT, the use of fiducial markers and
image registration protocols enables daily online IGRT. With this technique only
intra-fractional variations and the doctor’s CTV delineation error remain.

Data acquisition
Accurate 3D data about tumour, target volumes and organs at risk are acquired in
relation to external reference points under exactly the same conditions as those used
for subsequent treatment. Optimal diagnostic imaging modalities are chosen for
each tumour site according to protocols developed with diagnostic radiologists.
Multi-slice CT, MR with dynamic scanning, 3D ultrasound, positron emission
tomography (PET) and single photon emission computed tomography (SPECT)
have provided a wealth of anatomical, functional and metabolic information about
the GTV. These MRI and PET images are fused with CT planning scans to optimise
tumour localisation using a CT scanner with virtual simulation. Alternatively, when
these are unavailable, a simulator or simulator CT is used for 2D planning.

■ CT scanning
CT scanning provides detailed cross-sectional anatomy of the normal organs, as well
as 3D tumour information. These images provide density data for radiation dose
calculations by conversion of CT Hounsfield units into relative electron densities
using calibration curves. Compton scattering is the main process of tissue interaction
for megavoltage beams and is directly proportional to electron density. Hence CT
provides ideal density information for dose corrections for tissue inhomogeneity,
such as occurs in lung tissue. Clinical studies have shown that 30–80 per cent of
patients undergoing radiotherapy benefit from the increased accuracy of target
volume delineation with CT scanning compared with conventional simulation. It has
been estimated that the use of CT improves overall 5-year survival rates by around
3.5 per cent, with the greatest impact on small volume treatments.
CT scans taken for radiotherapy treatment planning usually differ from those taken
for diagnostic use. Ideally, planning CT scans are taken on a dedicated radiotherapy
CT scanner by a therapy trained radiographer. The scanner should have the largest
possible aperture to aid positioning of the patient for treatment. The standard
diagnostic CT aperture is 70 cm but 85 cm wide-bore scanners are available, which
are helpful for large patients and those being treated for breast cancer, who lie with
both arms elevated on an inclined plane that can be extended up to around 15°. The
CT couch must be flat topped with accurate couch registration to better than 1 mm.
The patient is positioned using supporting aids and immobilisation devices and
aligned using tattoos and midline and lateral laser lights identical to those used for
subsequent radiotherapy treatment. A tattoo is made on the skin over an immobile
bony landmark nearest to the centre of the target volume (e.g. pubic symphysis). It
is marked with radio-opaque material such as a catheter or barium paste for
visualisation on the CT image. Additional lateral tattoos are used to prevent lateral
rotation of the patient and are aligned using horizontal lasers (see Fig. 2.3).
Oral contrast medium is used in small concentrated dose to outline small bowel
as an organ at risk (e.g. for pelvic intensity-modulated radiotherapy [IMRT]
treatment), but care must be taken to avoid large quantities which may cause
15
PRINCIPLES OF RADIOTHERAPY PLANNING

diuresis and overfill the bladder. Intravenous contrast is given for patients with
lung and mediastinal tumours to differentiate between mediastinal vascular
structures, tumour and lymph nodes, and in the pelvis to enhance blood vessels for
CTV delineation of lymph nodes. Structures such as the vulva, vaginal introitus,
anal margin, stomata and surgical scars may be marked with radio-opaque material.
Patients with locally advanced tumours should be examined in the treatment
position and tumour margins clearly marked. Protocols to reduce organ motion,
for example by emptying the bladder before bladder radiotherapy and the rectum
before prostate treatment, need to be in place. Patients are given information
leaflets to explain the importance of, and rationale for, these procedures.
Multi-slice CT scanners perform a scan of the entire chest or abdomen in a few
seconds with the patient breathing normally. Scanning for lung tumours can
involve ‘slow’ CT scans, respiratory correlated CT scans, gating, or use of the ABC
device to cope with the effect of respiratory movement.
Protocols for CT scanning are developed with the radiologist to optimise tumour
information, to ensure full body contour in the reconstruction circle and scanning of
relevant whole organs for DVHs. DRRs are produced from CT density information
and are compared with electronic portal images (EPIs). Contiguous thin CT slices
are obtained at 2–5 mm intervals for the head and 3–10 mm for the body.

■ Contouring
CT scans are transferred digitally to the target volume localisation console using
an electronic network system which must be compliant with DICOM 3 and
DICOM RT protocols (Fig. 2.4). The GTV, CTV, PTV, body contour and normal
organs are outlined by a team of radiation oncologist, specialist radiologist and
planning technician, with appropriate training. Where MRI is the optimal imaging
modality for tumours such as the prostate, uterus, brain, head and neck and
sarcomas, it is incorporated into target volume definition by image fusion. Treatment
planning based on MR images alone is reported, but more commonly CT and MR
images are co-registered, ideally scanning using a flat MRI couch top to aid
matching. PET or PET-CT images may give additional information for head and
neck tumours, lymphomas, lung and gynaecological tumours, and SPECT for
brain tumours. Multimodality image fusion of all these images in the treatment
planning process is ideal for accurate delineation of the target.
Departmental protocols for target volume delineation are essential for each
tumour site; these should define optimal window settings, how to construct the
CTV, 3D values for CTV-PTV margins, type of 3D expansion software and
method of outlining for each OAR to be used. ‘Doctor’s delineation errors’
resulting from contouring are said to be the most uncertain part of the whole
planning process and training in, and validation of these procedures is essential.
Contouring starts with definition of the GTV on a central slice of the primary
tumour and then on each axial CT image moving superiorly and then inferiorly.
Involved nodes can then be defined in the same way. Viewing the GTV on coronal
and sagittal DRRs ensures consistency of definition between slices so that no artificial
steps in the volume are created. A volume should not be copied or cut and pasted
onto sequential slices for risk of pasting an error: it is more accurate to redraw the
GTV on each slice. If there are slices where the GTV cannot be defined – for example
16
 Data acquisition
Figure 2.4 Network for transferring data between steps in the radiotherapy planning
process.

due to dental artefact – the planning software will usually allow the missing
contours to be interpolated from those either side.

■ CT virtual simulation
Using CT data, software generates images from a beam’s eye perspective, which
are equivalent to conventional simulator images. External landmarks are used to
define an internal isocentre for treatment set-up. The CT simulator provides
maximal tumour information as well as full 3D capabilities (unlike the simulator
CT facility). It is particularly useful for designing palliative treatments such as for
lung and vertebral metastases, as well as for some breast treatments using
tangential beams, which can be virtually simulated and then 3D planned. The
ability to derive CT scans, and provide target volume definition, margin generation,
and simulation all on one workstation, provides a rapid solution.

■ Conventional simulator
For palliative treatments, a simulator may still be used to define field borders following
the 50 per cent isodose line of the beam, rather than a target volume. A simulator is
an isocentrically mounted diagnostic X-ray machine which can reproduce all the
movements of the treatment unit and has an image intensifier for screening. The
patient is prepared in the treatment position exactly as described above for CT
17
PRINCIPLES OF RADIOTHERAPY PLANNING
scanning. The machine rotates around the patient on an axis centred on a fixed point,
the isocentre, which is 100 cm from the focal spot and is placed at the centre of the
target volume. Digital images or radiographs are used to record the field borders
chosen by reference to bony landmarks. The simulator is commonly used either for
palliative single field treatments of bone metastases or to define opposing anterior and
posterior fields for palliative treatment to locally advanced tumour masses.

■ Simulator-CT
A CT mode attached to the simulator gantry can be used to produce images with
a relatively limited resolution during the simulation process. This provides both
external contouring and some normal anatomical data, such as lung and chest wall
thickness, for simple inhomogeneity corrections. Images do not give detailed
tumour information or accurate CT numbers. These scans are time consuming to
obtain, and are therefore usually limited to the central, superior and inferior levels
of the target volume.

Dose solutions
When the PTV and normal organs have been defined in 3D, the optimal dose
distribution for treating the tumour is sought. Consultation with a dosimetrist is vital
to select the best parameters. For example, a treatment machine must be chosen
according to percentage depth dose characteristics and build up depth which will vary
with energy and beam size as shown in Table 2.1. These can be used to calculate doses
for treatment using single fields and to learn the construction of isodose distributions
using computer modelling. Other factors to be considered in the choice of machine
are the effect of penumbra on beam definition, the availability of independent or
multi-leaf collimators, facilities for beam modification and portal imaging.

Table 2.1 Data from treatment machines in common use, showing variation of Dmax and
percentage depth dose (DD) with energy

Machine Energy (MV) FSD (cm) 10 ⴛ 10 cm field*

Dmax depth (cm) % DD at 10 cm

Cobalt-60 1.25 100 0.5 58.7

Linear accelerator 6 100 1.5 67.5
10 100 2.3 73
16 100 2.8 76.8

*Maximum field size at 100 cm is 40  40 cm.

Three levels of dose planning and treatment are described here:

■ Conventional treatment uses single or opposing beams, with or without 2D
dose distributions, with compensators and simple shielding.
■ Conformal treatment involves target volume delineation of tumour and normal
organs according to ICRU principles with 3D dose calculations using MLC to
shape beams.
18
 Dose solutions
■ Complex treatment includes the use of IMRT to shape the fluence of the beam,
dynamic treatments, IGRT and 3D or 4D delivery.
Most dose computation is done using 3D computerised treatment planning
systems which are programmed with beam data from therapy machines. These
systems require careful quality control programmes. Following production of
a satisfactory isodose distribution to a given target volume using 2D or 3D
algorithms, the calculations are checked by a physicist and detailed instructions for
delivery are prepared by radiographers on the therapy unit.

■ Conventional treatment
Single fields may be used with borders defined by the 50 per cent isodose for bone
metastases. Parallel opposing beams are used for speed and ease of set-up for
palliative treatments (e.g. lung), for target volumes of small separation (e.g. larynx)
or tangential volumes (e.g. breast). Isodose distributions show that the 95 per cent
isodose does not conform closely to the target volume, the distribution of dose is
not homogeneous and much normal tissue is irradiated to the same dose as the
tumour. Beam modification with the use of wedges alters the dose distribution to
compensate for missing tissue, obliquity of body contour or a sloping target
volume, and may produce a more homogeneous result.
For many tumours seated at depth, a radical tumour dose can only be achieved
with a combination of several beams if overdose to the skin and other superficial
tissues is to be avoided. When multiple beams are chosen for a plan, variable
wedges can be used to attenuate the beam and thereby avoid a high dose area at
beam intersections. To achieve the same dose at the patient, the number of
monitor units set will have to be increased compared with those for an open field.
Computerised dose planning systems are used to construct an isodose distribution
with beams of appropriate energy, size, weighting, gantry angle and wedge to give
a homogeneous result over the target volume.

■ Inhomogeneity corrections
Attenuation of an X-ray beam is affected by tissue density, being less in lung than
bone. This variation affects both the shape of the dose distribution and the values
of the isodoses. Lung tissue should therefore be localised when planning treatment
for tumours of the thorax (e.g. lung, breast, oesophagus, mediastinum). The
relative electron density of lung compared with water is in the range 0.2–0.3 and
these values are used to correct for inhomogeneity.
When 2D conventional planning is used, correction is only valid at the planned
central slice of the target volume, e.g. breast treatment planned with a simulator
using central lung distance (CLD). Using CT scanning, the whole lung is localised
in 3D and a pixel by pixel correction made for all tissue densities by conversion of
CT numbers into relative electron densities using calibration curves. CT numbers
are affected by contrast agents but dose distributions in the chest and abdomen are
not significantly changed by the quantities used in most CT scanning protocols.
However, large amounts of gas in the rectum can cause organ motion of the
prostate and uterus as well as affecting CT densities.
19
PRINCIPLES OF RADIOTHERAPY PLANNING

■ Beam junctions
When treatment is given to target volumes that lie adjacent to one another,
consideration must be given to the non-uniformity of dose in the potential overlap
regions caused by divergence of the adjacent beams. If the beams abut on the
skin surface, they will overlap with excess dose at depth. If there is a gap between
beams at the skin, there will be a cold area in the superficial tissues. Clinical examples
of this problem include treatment of (a) adjacent vertebrae with single posterior
fields which may be separated in time, where there is a risk of overlap of dose at the
underlying spinal cord, (b) primary breast cancer and adjacent lymph nodes, where
a single isocentric technique centred at the junction can be used (see Chapter 22),
(c) primary head and neck tumours and their regional nodes which can be treated
with IMRT or matched photon and electron fields to avoid overlap over the spinal
cord (see Chapter 8) and (d) primary central nervous system (CNS) tumours such as
medulloblastoma, where beams are matched at the anterior spinal cord and junctions
between beams shifted during the course of treatment (see Chapter 18).
Various techniques have been developed to minimise dose heterogeneity at beam
junctions in these different clinical situations. Half beam blocking using shielding
or independent collimator jaws can be used to eliminate divergence up to the match
line, but accuracy is then dependent on precise immobilisation and reliability of skin
marks to reproduce the match perfectly. Couch rotation can be used to remove
beam divergence when matching breast and lymph node irradiation. However, for
some sites, it is still common to match beams by using a gap between beams so that
the beam edges converge at a planned depth (Fig. 2.5). The dose in the triangular
gap (x) below the skin surface will be lower than at the point P where the beams
converge because it lies outside the geometric margins of both beams. Doses at (y)
are higher because they include contributions from both beams. The positioning of
point P anatomically will vary according to the aim of treatment. If treatment is for
medulloblastoma, a homogeneous dose is required to potential tumour cells within
the spinal cord which is therefore placed at point P, and point P is moved in a
cranio-caudal direction at regular intervals to prevent any risk of overdose at

Figure 2.5 Technique for matching two

beams I and II (length I1 and l2) at a point P
at depth d by allowing a gap on the skin
surface (x, y, s – see text).

20
 Dose solutions
junctions. Where treatment is aimed at metastases in adjacent vertebral bodies, it is
important to avoid overdosage at the spinal cord which is therefore placed in the
superficial cold triangle (x) with point P anterior to it. The gap on the skin is the
sum of the beam divergence of each beam. It is calculated as the distance from
the edge of the beam as defined by the 50 per cent isodose to the point of
convergence P measured perpendicular to the central axis and marked (s) spread
(beam divergence) for each beam. Graphs have been drawn up expressing beam
divergence as a function of the depth below the skin for different field sizes and
focus skin distance (FSD). Once the gap has been calculated, it may be necessary to
increase it slightly to allow for possible movement of patient or skin tattoos, to
ensure that there is no overdosage. Whenever possible, a patient should be treated
in the same position (supine or prone) for matching adjacent fields.
When planning a new treatment for metastatic disease in the spine, previous
treatment fields should be reconstructed from films and records and the patient
placed in the same position to ensure there is no overlap.

■ Electron therapy
Electron therapy may be used to treat superficial tumours overlying cartilage and
bone (for example nose, ear, scalp and dorsum of hand), in preference to superficial
or orthovoltage therapy where there is increased bone absorption due to the
photoelectric effect. There is a sharp fall in dose beyond the 90 per cent isodose
(4–12 MeV) and electron energy is chosen so that the target volume is
encompassed by the 90–95 per cent isodose at the deep margin. Electrons at higher
energies (15–25 MeV) may be used for treating cervical lymph nodes overlying
spinal cord, parotid tumours and in mixed beams with photons.
The effective treatment depth in centimetres is about one-third of the beam energy
in MeV and the total range about half (Fig. 2.6) but this is dependent on field size
(especially at 40 mm). Different tissue densities such as bone and air (as found in
ribs overlying lung and facial bones containing air filled sinuses) cause
inhomogeneous dose distributions. Doses beyond air cavities may be higher than
expected even after density corrections and this limits the usefulness of electrons for
treating in these clinical situations. Electron beam edges do not diverge geometrically
due to lateral scatter, which is greater at low energies with the characteristic shape
shown in Figure 2.7. Wider margins must be added when choosing the beam width
for adequate treatment of tumours at depth. Where there is tumour infiltration of
skin, the skin sparing characteristics of electron beams below 16 MeV should be
removed by adding bolus material, which can also be used to provide tissue equivalent
material for an irregular contour such as the nose or ear. Beam sizes 40 mm should
be avoided because of inadequate depth of penetration and loss of beam flatness.

■ Conformal treatment
3D conformal radiotherapy (CFRT) links 3D CT visualisation of the tumour with
the capability of the linear accelerator to shape the beam both geometrically and
by altering the fluence of the beam (IMRT). This encloses the target volume as
closely as possible while reducing dose to adjacent normal tissues. The radiation
oncologist and dosimetrist agree the final PTV, which has been created using 3D
21
PRINCIPLES OF RADIOTHERAPY PLANNING

Figure 2.6 Percentage depth dose of varying electron energies for 10  10 cm applicator.

Figure 2.7 9 MeV electron

dose distribution.

growth algorithm software and departmental protocols, taking into consideration

OAR. Discussions between oncologist and dosimetrist include an understanding
of the tumour cell density pattern within the PTV, requirements for homogeneity
of dose distribution, dose constraints to adjacent OAR, avoidance of maximum or
minimum dose spots in 3D and review of a preliminary plan of likely beam
arrangements. Basic CFRT may consist of coplanar and static beams with MLC or
conformal blocks shaping the volume. For coplanar non-standard configuration of
beams, DVHs may aid selection of the best plan, but they do not indicate which
part of the organ is receiving a high or low dose; DVHs of the PTV, CTV and all
PRVs are needed to allow subsequent correlation with clinical outcome. Selection
of the final dose plan is made at the treatment-planning terminal by inspecting
22
 Dose solutions
3D physical dose distributions and DVHs. Good communication is important
between radiographers, dosimetrist, physicist and clinician to avoid transfer errors
occurring between CT, treatment planning and treatment machine.
Conformal therapy may involve the use of mixed beams combining photons and
electrons for part of the treatment. Beams can be modified using bolus, wedges,
compensators, MLCs and shielding blocks. Optimisation of skin dose is achieved by
skin sparing using higher megavoltage energies, or by maximising skin dose with
tissue equivalent bolus. Higher beam energies (10–18 MV) are preferred for pelvic
treatments, to increase dose to the centre and reduce dose to skin and subcutaneous
tissues. Lower energies (6–8 MV) are used for breast and head and neck treatments
to avoid excess skin sparing and treat the relatively superficial target volume.
Treatment is delivered using beam shaping with MLCs which have multiple
leaves or shields which can block part of the radiation beam. Typical MLCs have
20–80 leaves arranged in opposing pairs which can be positioned under computer
control to create an irregular beam conforming to the target shape. As well as
eliminating the hazards of production and use of alloy blocks, this system allows
rapid adjustment of shaping to match the beam’s eye view of the PTV.

■ Complex treatment
IMRT
IMRT is created using MLC to define the beam intensity independently in
different regions of each incident beam, to produce the desired uniform distribution
of dose, or a deliberate non-uniform dose distribution, in the target volume. The
position of the leaves of the MLC can be varied in time with a fixed or moving
gantry. IMRT can be delivered using dose compensation, multiple static fields,
step-and-shoot, dynamic MLC or tomotherapy.
A sequence of static MLC fields can be used with the beam being switched off
between changes in position – the step-and-shoot technique. Alternatively, there
may be automatic sequencing of beam segments without stopping treatment –
dynamic MLC. Other methods include tomotherapy and other devices where
there is intensity modulated rotational delivery with a fan beam.
Forward planned or segmental IMRT provides simple tissue compensation with a
beam’s eye view of the PTV and sub-segments which are shaped with different MLC
to create a uniform dose in the PTV. Inverse planning requires specification of dose
prescription to GTV, PTV and PRV in terms of dose–volume constraints, fluence
optimisation and 3D dose planning. Very careful quality assurance must be developed
to assure accuracy of the beam. Verification of an IMRT plan requires either
measurement of the dose distribution in a phantom, or an independent monitor unit
calculation with portal dosimetry. Dose delivery is verified throughout the course of
treatment using radiographic film or adapted EPIDs or transit dosimetry. Accurate
patient positioning, target volume delineation and reduction of organ and patient
motion uncertainties, especially respiration, are critical for safe IMRT.
IMRT techniques modulate the intensity of the beam as well as its geometric
shape, delivering complex dose distributions, using forward or inverse treatment
planning. Plans can be produced with concave shapes, and critical structures at
sites such as head and neck (eye or spinal cord), prostate (rectum) and thyroid
(spinal cord) avoided. Late toxicity can be reduced significantly for tumour sites
23
PRINCIPLES OF RADIOTHERAPY PLANNING

such as prostate, pelvis, breast and head and neck. Dose escalation studies in
prostate cancer show an improvement in biochemical relapse-free survival using
IMRT with reduced late rectal toxicity. There is proof of sparing of salivary gland
function with IMRT for head and neck cancer with no loss of tumour control.
Late fibrotic changes in the breast can be reduced, and IMRT pelvic treatments,
more conformal to the tumour lymph node drainage, have reduced bone marrow
and acute bowel and bladder toxicity. However, integral dose may be greater with
some IMRT solutions, with increased risk of late malignancies. IMRT dose plans
with steep dose gradients may risk underdosage of tumour if margins are close and
organ motion still present.
It is difficult to produce evidence of benefit from new technology until it is widely
enough available to conduct RCTs, preferably on a multicentre basis. Often,
pioneering groups develop and test the technology from the physical viewpoint and
clinical implementation goes from pilot (phase 1 type) studies to routine use without
a rigorous evidence base of efficacy. A further problem of particular relevance for
radiotherapy is that unwanted late effects of treatment cannot be quantified for many
years, so that determination of therapeutic ratio – the true test of efficacy – is delayed.

IGRT
Organ motion during treatment makes it necessary to consider the fourth
dimension of time. IGRT refers to all techniques in which cross-sectional, X-ray or
ultrasound images obtained during treatment are used to check that the actual
treatment delivered matches that which has been planned. Ideally the moving
tumour outline is imaged during treatment using daily EPIs or real time cone
beam CT. Alternatively, EPIs can be taken on the first few days of treatment and
used to adjust treatment volumes where necessary.
Variations in overall positioning of the body during treatment can be monitored
using optical imaging devices, sometimes in association with markers attached to
the skin. To avoid respiratory motion, treatment may be delivered while the
patient holds his or her breath using the ABC device. This demands cooperation
from the patient and may be difficult in those with lung diseases. Treatment may
be gated to a specific phase of the respiratory cycle, usually expiration, using
optical devices or X-ray fluoroscopic measurements. CT scans obtained by imaging
devices on the linear accelerator can be compared with respiration-correlated spiral
CT planning images. Treatment delivery is triggered when the two images match.
These techniques may reduce the PTV and restrict the dose to normal lung but
are time consuming. Some evidence is accumulating that respiratory gating may be
of limited benefit overall since, although it reduces organ movement effects, it
prolongs treatment time. Composite multi-field conformal plans delivered in
multiple fractions may have a similar overall effect in a more cost effective way.
Further randomised trials are needed to assess 4D treatment delivery.
Adaptive radiotherapy (ART) involves regular changes (weekly or daily) to
treatment delivery for an individual patient based on analysis of images taken before
treatment or ideally during treatment. Linear accelerator mounted imaging devices
are essential for this technique. One integrated approach is to use rotational IMRT
or tomotherapy. The MLC is linked to a machine-mounted CT scanner with
images taken during therapy used to gate treatment to the correct body slice.
24
 Dose-fractionation
Special techniques
■ Protons
Some radiation oncologists consider that many of the advantages of IMRT could
be better obtained by using the superior dose distributions of protons. There are
some indications where the benefits seem to be established firmly enough for this
to be the treatment of choice (some paediatric and skull-based tumours, and radio-
resistant tumours in difficult sites, such as vertebral chondrosarcoma). At present
the cost of installing proton facilities precludes widespread use, but guidelines for
referral to specialist centres have been drawn up.

■ Stereotactic radiotherapy
This technique is only available in a limited number of centres but has been used for
many years, mainly for the treatment of small brain tumours and arteriovenous
malformations. Accuracy of patient positioning to approximately 1 mm is maintained
using a stereotactic frame attached to the patient’s skull. Radiotherapy may be delivered
as a single or multiple fractions and may be considered as an alternative to surgery. The
gamma knife device uses multiple cobalt sources arranged around a half circle, which
irradiate a very conformal volume by blocking selected collimator openings with
different collimation helmets for different time intervals. Alternatively, a linear
accelerator with specialised collimators can be used to deliver multiple arc therapy.
This technique requires very careful quality assurance because of steep dose
gradients and problems of electron equilibration with very small beams. It also
requires close collaboration within a team of people with relevant expertise in
imaging, neuroanatomy, tumour management and physics. This approach may
also be beneficial for some small volume lung and liver tumours.

Dose-fractionation
Prescription of radiotherapy treatment is the responsibility of the radiation
oncologist and usually follows agreed guidelines, taking into consideration individual
patient factors, such as the expected risk–benefit ratio of treatment, comorbidities
and consideration of scheduling of other treatment modalities. Radiotherapy
regimens vary internationally. Fractions of 2 Gy or less delivered 5 days a week are
the standard of care in much of North America and Europe. Regimens given in
this book are safe evidence-based schedules but national and international
protocols or trials should be used as appropriate.
Alternative fractionation schedules using fewer larger fractions in a shorter
overall time (hypofractionation) have been developed, especially in the UK and
Canada, driven initially by resource constraints, but now supported by extensive
published clinical data, e.g. for breast and prostate cancer as well as for palliative
treatments. Accelerated fractionation gives the same overall dose in a shorter time,
often using smaller fraction sizes to reduce toxicity, and has been used successfully
in head and neck cancer trials. Hyperfractionation regimens deliver treatment
twice or three times a day using smaller fraction sizes, thereby increasing the total
dose and remaining within tolerance for late toxicity (see Table 3.2, p. 42).
25
PRINCIPLES OF RADIOTHERAPY PLANNING

The linear quadratic (LQ) model of radiation-induced cell killing is currently the
most useful for comparing different fractionation schedules (see Chapter 3), taking
into account the effect of dose per fraction and repopulation on tumour and normal
tissue late effects. Clinical outcome depends on the total dose, dose per fraction,
overall treatment time, volume of tumour and normal tissues irradiated, dose
specification points and quality control procedures. If treatment has to be stopped
unexpectedly for operational or clinical reasons causing an unscheduled gap in
treatment, the dose-fractionation schedule may need to be altered (see Chapter 3).

Dose specification
All dose distributions are inhomogeneous and so the dose throughout the PTV
varies. The biological effect of a given dose is difficult to predict because of
variations in cell density at the centre and periphery of the CTV, heterogeneity of
tumour cell populations and inadequate knowledge of cellular radio-sensitivity.
Nevertheless, one must attempt to specify a dose which is representative of the
absorbed dose in the target volume as a whole, to assess effectiveness of treatment.
To facilitate understanding and exchange of precise and accurate radiotherapy
treatment data, it is important that all centres report their results using the same
volume concepts and prescribing definitions.
The ICRU reports 50 and 62 recommend that the radiation dose should be
reported, and hence is also best prescribed, at or near the centre of the PTV, and
when possible at the intersection of the beam axes (ICRU reference dose). This
ICRU reference point for prescription is selected because it is clinically relevant,
usually situated where there is maximum tumour cell density, easy to define, often
lies on the central axis of the beam where dose can be accurately determined, and is
not in a region of steep dose gradient. It is essential that this dose specification point
is accompanied by a statement of the homogeneity of the irradiation as defined by at
least the maximum and minimum doses to the PTV. The maximum target dose is
the highest dose in the target volume which is clinically significant (to a volume
greater than 15 mm3 unless in a critical tissue where special considerations apply).
The minimum target dose is an important parameter because it correlates with the
probability of tumour control. Additional information, such as average dose and its
standard deviation, DVHs and an accurate description of dose to OAR, is also very
important (Fig. 2.8).
Superficial treatment machines, with energies ranging from 50 kV to 150 kV and
appropriate filtration which defines percentage depth dose characteristics, are used
to treat superficial skin tumours. The dose prescription point is at Dmax, the
maximum dose, which is at the skin surface. An appropriate energy is selected from
tables for different beam sizes for a given FSD to encompass the target volume
both on the skin and at depth with a 90 per cent isodose.
When a single megavoltage beam is used, dose is prescribed to the ICRU point at
the centre of the target volume rather than to Dmax. For example, for bone metastases,
the prescription point may be at the centre of the vertebra e.g. 40–50 mm depth
for a thoracic vertebra. Alternatively, for palliative treatments, the ICRU point may
be chosen at the dose-limiting structure, such as the spinal cord, and a dose
prescribed to maximum tolerance.
26
 (a) (b
)

(c) (d)

Figure 2.8 Dose distribution to treat carcinoma of the prostate showing (a) axial view with isodoses, ICRU point (100 per cent): maximum  101 per
cent; minimum  95 per cent. (b) DVH showing PTV, and doses to bladder, rectum, left (LFH) and right (RFH) femoral head. (c) Coronal view with
dose colourwash. (d) Sagittal view with dose colourwash.
27
PRINCIPLES OF RADIOTHERAPY PLANNING

For co-axial opposing lateral or AP beams, the dose is specified at the midplane
dose (MPD) on the central axis of the beam, as recommended by ICRU. In
subsequent chapters of this book, these ICRU dose specification conventions have
been followed for all dose distributions and prescriptions.

Verification
Verification is needed of the geometrical set-up of the treatment and the dose being
delivered. Electronic portal imaging is available on most linear accelerators and
images can be compared with DRRs obtained from the treatment planning system.
Image evaluation software tools can be used to match predefined bony landmarks on
both images noting displacements of beam borders, to match the edges of beams
measuring the change in position of bony structures or to match fiducial markers.
Errors may be systematic or random. Repeating the portal image daily for the
first few days will identify any systematic errors, which can then be corrected.
Random errors in set-up may be reduced by better patient immobilisation or staff
education, or the CTV-PTV margin may have to be increased if correction is
impossible.
Image matching of EPIs with DRRs is usually carried out by the treating
radiographers after appropriate training. Verification protocols, both online and
off-line, will define the level of action for any deviation. EPIs or portal films should
be signed by the clinician, verifying and recording any actions taken.
Verification of the dose delivered to the patient is essential using semiconductor
silicon diodes with instant readout, or thermo-luminescent dosimetry (TLD) with
delayed readout, and is performed on the first day of each patient’s treatment.
Transit dosimetry uses a transmission portal image to measure the dose delivered
to the patient, which can be compared with the planned dose distribution. Equally
important are the mechanical checks of MLC that are required to ensure safe
delivery of treatments. These must include examination of the stability of leaf speed,
accuracy of leaf position and transmission through and between leaves.

Patient care during treatment

Response to treatment, both in terms of tumour and acute side effects, should be
monitored regularly. Weekly clinics are held, often led by a therapy radiographer or
radiotherapy clinical nurse specialist, to check for early acute side effects, and to
answer patients’ questions and give them and their carers psychological and
emotional support. Information sheets listing common and uncommon side effects
for each tumour site are discussed with individual patients when they give informed
consent. Protocols for scoring acute side effects, such as NCI-CTC-3 or RTOG,
should be used to document acute reactions and guide appropriate investigations.
The radiation oncologist states on the radiotherapy prescription sheet any specific
imaging or blood tests that are required during treatment and is responsible for
supervising the review clinics and seeing the patient at appropriate intervals. Patients
receiving concurrent radiochemotherapy may experience increased side effects and
require special interventions. Specific instructions for dealing with different acute
reactions are dealt with in each individual tumour site chapter.
28
 Quality assurance
Quality assurance
A comprehensive quality assurance programme is needed to ensure that the best possible
care is delivered to the patient by defining and documenting all procedures involved in
radiotherapy treatments. A quality assurance policy must be formulated by a radiotherapy
manager with overall responsibility for implementation, although large parts of this
responsibility may be delegated to other appropriately trained and qualified members of the
radiotherapy team. Internal quality assurance systems are supplemented by external
accreditation visits. Individual treatment techniques may be checked before trials begin, by
requiring participants to submit sample treatment plans and descriptions of methods of
beam matching, techniques used for tissue compensation and beam data for verification
of output and flatness. Phantom measurements are routinely used to give a composite
check of all factors, including dose homogeneity and beam matching. Any internal or
external system must be periodically reviewed with documentation of all activity according
to a defined protocol. Reference values must be specified with tolerances and action to be
taken if these are exceeded. A departmental procedure for investigation of deviations or
errors must be in place for every part of the system.

■ Practical considerations
Routine checks of the following must be included in the quality assurance protocol:

■ machine checks
■ dosimetry protocols
■ planning checks
■ patient documentation.

Machine checks
During installation and acceptance of new equipment, calibration data are obtained
to provide reference against which subsequent checks are made. Inter-comparisons
between different institutions or with national or international standards are useful
for detecting systematic errors. Quality control should then ensure that a unit
performs according to its specification and is safe for both patients and staff.
It should guarantee accuracy of dose delivered, prevent major errors, minimise
downtime for machines and encourage preventative machine maintenance. There
should be a specific quality control protocol for each unit, which outlines the test
to be performed, the methods to be used to ensure consistency in the performance
of each unit, parameters to be tested, frequency of measurement, staff responsibilities,
reference values, tolerances, action to be taken in case of deviation and rules for
documentation. Daily, weekly and extended testing of dosimetry beam alignment
and safety checks are necessary. Regular checks include tests of optical, mechanical
and computer hardware and software systems. Action levels are defined where
correction is needed before treatment can proceed. Similar checks must be carried
out for all imaging equipment and treatment planning systems. The results of daily
checks must be recorded in the control room of the treatment units and
radiographers must also record any problems in machine functioning. All other
checks, actions and maintenance work are recorded in a separate log book. Good
29
PRINCIPLES OF RADIOTHERAPY PLANNING

cooperation is needed between all staff groups. A physicist who coordinates all
quality control activity checks that tests are up to standard and reports any major
deviations to the clinician.

Dosimetry protocols
These include dose monitor calibration checks, checks of beam quality and
symmetry and evaluation of beam flatness. In vivo dosimetry systems such as TLDs
and silicon diodes must also be regularly checked and calibrated.

Planning checks
Treatment prescriptions are now mostly electronic, and recording of treatment delivery
parameters is automatic by computer systems attached to treatment machines. Reports of
activity obtained from these systems can be used for audit, and central collection of these
output data may give very useful information about patterns of radiotherapy delivery.
Individual weekly review of patients’ treatment records should verify that treatment is being
delivered as planned.

Patient documentation
Electronic systems are being used increasingly. Radiation treatment records are usually
kept separately from other hospital documents to ensure reliable rapid access. Records
should identify the patient, give clinical history and examination findings, histological
diagnosis, staging of the tumour and proposed treatment plan. There should be
written treatment policies for specific tumour sites and data should be recorded to
enable subsequent evaluation of the outcome of treatment. Written consent for
treatment is required. At the end of treatment, a summary detailing actual treatment
parameters must be prepared and appropriate continuing care of the patient assured.

Staffing
A quality programme as described above is essential for the safe delivery of treatment.
It can only be achieved if each member of the team understands clearly the
boundaries of responsibility and if there is excellent coordination of all quality
control activity by a highly qualified physicist acting with the person responsible for
overall management of the radiotherapy department. Careful training of all staff
members must therefore be an integral part of any effective quality assurance system.

Information sources
Bel A, Bartelink H, Vijbrief RE et al. (1994) Transfer errors of planning CT to simulator: a possible
source of set up inaccuracies? Radiother Oncol 31: 176–80.
Bel A, van Herk M, Bartelink H et al. (1993) A verification procedure to improve patient set-up
accuracy using portal images. Radiother Oncol 29: 253–60.
BIR Working Party (2003) Geometric Uncertainties in Radiotherapy: Defining the Planning Target
Volume. British Institute of Radiology, London.
Chao KSC, Majhail N, Huang C-J et al. (2001) Intensity-modulated radiation therapy reduces late
salivary toxicity without compromising tumor control in patients with oropharyngeal carcinoma:
a comparison with conventional techniques. Radiother Oncol 61: 275–80.

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 Information sources
Development and Implementation of Conformal Radiotherapy in the United Kingdom (2002) Royal
College of Radiologists, London.
Dobbs HJ, Parker RP, Hodson NJ et al. (1983) The use of CT in radiotherapy treatment planning.
Radiother Oncol 1: 133–41.
Gregoire V, Coche E, Cosnard G et al. (2000) Selection and delineation of lymph node target
volumes in head and neck conformal therapy. Proposal for standardising terminology and
procedure based on the surgical experience. Radiother Oncol 56: 135–50.
Guidelines for the Management of Unscheduled Interruption or Prolongation of a Radical Course of
Radiotherapy, 2nd edn. (2002) Royal College of Radiologists, London.
Holland R, Veling S, Mravunac M et al. (1985) Histologic multifocality of Tis, T1–2 breast
carcinomas. Implications for clinical trials of breast-conserving surgery. Cancer 56: 979–90.
Hurkmans CW, Remeijer P, Lebesque JV et al. (2001) Set-up verification using portal imaging:
review of current clinical practice. Radiother Oncol 58: 105–20.
International Commission on Radiation Units and Measurements (1993) Prescribing, Recording and
Reporting Photon Beam Therapy ICRU: Report 50. ICRU, Bethesda, Maryland, USA.
International Commission on Radiation Units and Measurements (1999) Prescribing, Recording and
Reporting Photon Beam Therapy (supplement to ICRU Report 50): ICRU Report 62. ICRU,
Bethesda, Maryland, USA.
International Commission on Radiation Units and Measurements (2004) Prescribing, Recording and
Reporting Electron Beam Therapy: ICRU Report 71. ICRU, Bethesda, Maryland, USA.
LENT-SOMA Tables (1995). Radiother Oncol 35: 17–60.
McKenzie AL, van Herk M, Mijnheer B (2000) The width of margins in radiotherapy treatment plans.
Phys Med Biol 45: 3331–42.
McKenzie AL, van Herk M, Mijnheer B (2002) Margins for geometric uncertainty around organs at
risk in radiotherapy. Radiother Oncol 63: 299–307.
National Cancer Guidance (2008) Proton Referral-Treatment Abroad. Royal College of Radiologists,
London.
Radiotherapy Dose-Fractionation. (2006) Royal College of Radiologists, London.
Seddon B, Bidmead M, Wilson J et al. (2000) Target volume definition in conformal radiotherapy for
prostate cancer: quality assurance in the MRC RT-01 trial. Radiother Oncol 56: 73–83.
Suter B, Shoulders S, Maclean M et al. (2000) Machine verification radiographs: an opportunity for
role extension. Radiography 6: 245–51.
Taylor A, Rockall AG, Reznek RH et al. (2005) Mapping pelvic lymph nodes: guidelines for
delineation in intensity-modulated radiotherapy. Int J Rad Oncol Biol Phys 63: 1604–12.
van Herk M, Remeijer P, Rasch C et al. (2000) The probability of correct target dosage:
dose-population histograms for deriving treatment margins in radiotherapy. Int J Rad Oncol
Biol Phys 47: 1121–35.
Webb S (2005) Contemporary IMRT: Developing Physics and Clinical Implementation. Institute of
Physics Publishing, London.
Wong JW, Sharpe MB, Jaffray DA et al. (1999) The use of active breathing control (ABC) to reduce
margin for breathing motion. Int J Radiat Oncol Biol Phys 44: 911–19.
World Health Organization (1988) Quality Assurance in Radiotherapy. WHO, Geneva.
Yan D, Ziaja E, Jaffray D et al. (1998) The use of adaptive radiation therapy to reduce setup error: a
prospective clinical study. Int J Radiat Oncol Biol Phy 41: 715–20.
Zelefsky MJ, Fuks Z, Hunt M et al. (2002) High-dose intensity modulated radiation therapy for
prostate cancer: early toxicity and biochemical outcome in 772 patients. Int J Radiat Oncol
Biol Phys 53: B1111–16.

31
 3 Radiobiology and
treatment planning

Radiation and cell kill

Ionising radiation causes wide-ranging molecular damage throughout cells by the
production of ionised atoms, which cause breakage of chemical bonds, production
of free radicals and damage to DNA. Most clinically significant effects of
radiotherapy are due to irreparable DNA lesions which result in sterilisation – a loss
of proliferative cells’ ability for sustained cell division. In tumours, loss of
proliferative ability by all the cells of the tumour is a necessary condition for tumour
cure. Partial sterilisation of the tumour cell population results in tumour stasis or
regression, giving a clinical remission, followed by regrowth of the tumour from
those cells which have retained their proliferative ability. In self-renewing normal
tissues, sterilisation of proliferative cells leaves the tissues unable to provide
replacements for cells that are ordinarily being lost at a constant rate from the
tissue, and initiates a rundown of the mature cells of the tissue. Proliferative
sterilisation is often referred to as cell kill, with those cells that retain long-term
proliferative ability being described as survivors.

Cell survival curves

Cell culture techniques have been very important in allowing the proliferative
sterilisation of cells to be investigated quantitatively. For an irradiated cell population,
the proportion of cells that still retain the ability to proliferate (relative to an
unirradiated control population) is called the surviving fraction, and a plot of log
surviving fraction against single radiation dose gives a survival curve for the cells
concerned. Typically, survival curves are continuously bending, with a slope that
steepens as the dose increases. Mathematically a continuously bending curve is
most simply described by a linear quadratic (LQ) equation of the form:

SF  Exp (αd  βd2) (3.1)

where SF is the surviving fraction, d is the given single dose and α and β are
parameters characteristic of the cells concerned. The ratio α/β gives the relative
importance of the linear dose term and the quadratic dose term for those cells, and
controls the shape of the survival curve (Fig. 3.1). When α/β is large, the linear
term predominates, so a plot of log (SF) against d is relatively straight, while if α/β
is small, the quadratic term is more important, giving a plot with greater curvature.
For cells whose survival curves have a lower α/β ratio, doubling the dose leads to
more than doubling of the effect on log (SF). Such cells will be particularly sensitive
to changes in fraction size when radiation is given as a fractionated schedule.
32
 Effects on tissues
0 Dose (Gy)
0

Small α/β

0.2 Large α/β

Log (SF)

0.4

0.6

0.8

Figure 3.1 Two contrasting survival curves for irradiated cells, with log of the surviving
fraction (SF) plotted against single radiation dose. The more steeply curving survival curve
has the lower α/β ratio when fitted to the linear-quadratic equation.

Acute and late effects on tissues

The dose–response relationship for normal tissue injury depends on the survival
curves of the tissue stem cells. The timing of expression of injury depends on the
rate of turnover of mature cells in the tissue. Epithelial and haemopoietic tissues
have rapid turnover, and so manifest acute effects (with a timescale of days or
weeks). Late effects (with a timescale of months or years) occur in tissues and
organs with slow turnover (e.g. endothelial and neuroglial tissues, and parenchymal
tissues of lung, liver and kidney). The risk of major late effects is usually dose-
limiting in radiotherapy. Stem cells of late-responding tissues have been found to
have much more curved survival curves (low α/β ratio) than cells of acute-
responding tissues (higher α/β ratio, less curved survival curve). Radiobiologically,
this difference may be related to slow cell turnover in late-responding tissues,
allowing many stem cells to remain in resting states where they are highly proficient
in the repair of damage caused by small doses. Consequently, late-responding
tissues are particularly sensitive to changes in fraction size, larger fractions being
more damaging to these tissues, but small fractions being well tolerated. Acute and
late-responding tissues are also affected differentially by changes in the overall
treatment time. Because surviving stem cells of acute-responding tissues initiate
repopulation during the course of radiotherapy, the time over which the radiation
is distributed makes a difference to the final level of damage. Late-responding
tissues do not experience repopulation during the course of radiotherapy and are
relatively unaffected by the overall treatment time. Expression of late effects will also
be influenced by the organisation of functional subunits within the organ. Serially
arranged subunits, such as are found in the bowel, mean that damage to some units
will lead to change in the whole organ, whereas in those organs where subunits are
arranged in parallel, such as the kidney, each subunit acts independently and
continuing function is possible if only some of the subunits are damaged.
33
RADIOBIOLOGY

The linear quadratic model for tissues

Differences between acute- and late-responding tissues and typical tumours are
important when we consider the biological consequences of replacing one treatment
schedule with a different one. From experience, radiation oncologists developed
‘rules of thumb’ for altering a treatment schedule, e.g. a substantial dose reduction
might be necessary if fraction size was increased, increased treatment time improved
skin tolerance, etc. It is now recognised that tissues react differently to changes in
schedule structure and there is better understanding of how changes in scheduling
will affect different tissues. The application of the LQ model is based on the idea
that the severity of tissue damage is inversely proportional to stem cell survival, and
that stem cell survival can be calculated by mathematical development of the LQ
survival curve equation to allow it to be applied to fractionated treatments. In
particular, two different schedules will have equal biological effects on a tissue (i.e.
they will be ‘isoeffective’ for the tissue) if each schedule produces the same level of
stem cell survival.
We shall not attempt to derive the mathematics of the LQ model in detail, but
will state some results which are useful in practice. Consider two treatment
schedules, namely total dose D1 or D2 given as fractions sized d1 or d2. We shall
assume for now that both schedules are given in the same overall time period. For
a tissue whose cells have a survival curve described by the LQ parameters α and β,
it can be shown that the two schedules are isoeffective, for that tissue, when:

D1 (α/β  d1)  D2 (α/β  d2) (3.2)

Notice that the survival curve parameters appear as a ratio in this expression, which
means that only this single number for a tissue need be known in order to apply
the equation. In fact, α/β estimates have been made and tabulated for many
tissues. Late-responding tissues are usually found to have low values of α/β (about
3 Gy), while acute-responding tissues have higher values (about 10 Gy). (This
means that the cells of late-responding tissues have more steeply curving survival
curves.) Tumours are more variable; many are like acute-responding tissues, with
α/β values of 10 Gy or more, but recent estimates for breast tumours suggest
lower values. In practice, Equation 3.2 is often used to compare an unfamiliar
schedule with a standard schedule which would have the same effect. Most
usefully, the unfamiliar schedule can be assessed by asking what total dose, given
as 2 Gy fractions, would have the same effect (on that tissue) as the unfamiliar
schedule. This is helpful for determining whether the unfamiliar schedule is ‘hot’
or ‘cold’. For example, consider a schedule which consists of 10 twice-weekly
fractions of 4 Gy to a total dose of 40 Gy in 5 weeks. In Equation 3.2, let d1 be
4 Gy and D1 be 40 Gy. If we now set d2  2 Gy, and calculate D2 (for a particular
choice of tissue α/β), we shall get the total dose given as 2 Gy fractions which
would have the same effect on that tissue as the schedule D1, d1. Notice, however,
that the calculation depends on the assumed value of α/β. For this example, we
shall repeat the calculation for acute-responding and late-responding tissues. For
acute-responding tissues (α/β  10 Gy) we find that D2  47 Gy, while for late-
responding tissues (α/β  3 Gy), we find that D2  56 Gy. Therefore, the new
schedule is expected to be ‘hotter’ in terms of its effects on late-responding than
34
 Volume effects
on acute-responding tissues, but it is no ‘hotter’ than a conventional radical
regimen (e.g. 60 Gy in 2 Gy fractions).
It should be noted that the simple LQ model does not allow for differences in
total time between the schedules, which are therefore presumed to be given in the
same overall time (5 weeks in this case), despite their different fractionation
patterns. This restriction is not so important for late-responding tissues (for which
the total time is a minor variable), but the results for acute-responding tissues (for
which the time factor can be significant) need to be interpreted cautiously with this
limitation of the model borne in mind.
In recent years, the LQ model has been developed extensively and applied to
more complex schedules, including brachytherapy. The standard schedule with
which an unfamiliar schedule is to be compared is not necessarily one using 2 Gy
fractions. A rather abstract standard schedule, more appealing to mathematicians
than to clinicians, is a hypothetical regimen in which a very large number of small
fractions are given (mathematically, an infinite number of zero-sized fractions are
given, but to a finite total dose). The equivalent total dose calculated for such a
schedule is called the biological effective dose (BED). It is usually quite a large
dose (e.g. 100 Gy for a typical radical regimen) because it represents the limit of
tissue sparing by fractionation, i.e. the total dose that could be given if the
individual fraction size were vanishingly small. Linear quadratic calculations
performed using BED are mathematically equivalent to those performed with the
standard regimen taken to be one using 2 Gy fractions, although the latter has the
advantage of clinical familiarity. An important feature of the LQ model in its
various forms is the recognition that the cells of different tissues differ in their
survival curve shape and therefore respond differently to changes in fraction size.
Since a target volume may contain several tissue types as well as the tumour, a
change of fractionation regimen will affect these components differently. There is
therefore no such thing as a regimen which is ‘generally equivalent’ to some other
regimen – the regimens can only be matched (by choice of total dose) for
equivalent effects on each specific tissue.

Volume effects
Together with the total dose and fractionation schedule, target volume is a major
variable in radiotherapy. For a given fractionation regimen, higher doses can usually
be given when volumes at the same site are small rather than large. Normal tissues
are required to perform orchestrated functions, which can be impaired in various
ways by irradiation. Most normal tissues also cannot regenerate from a single
surviving cell. However, tissue recovery may be assisted by immigration of
unirradiated neighbouring cells, particularly if the treatment volume is small.
Volume is also an important determinant of normal tissue response to a given dose,
first because larger volumes provide less opportunity for tissues to draw on their
‘functional reserve’ and second because larger irradiated volumes make it more
likely that a critical volume element will exceed some upper dose limit. These factors
differ according to tissue structure, and vary from one treatment to another.
In general, the normal tissue complication probability (NTCP) increases with
dose (for a given fractionation regimen) and with the irradiated volume. It is
important to know, at least approximately, how changes in irradiated volume at a
35
RADIOBIOLOGY

particular site will affect the tolerance dose which can safely be given. The
‘tolerance dose’ may arbitrarily be defined as that dose which gives no more than
5 per cent incidence of significant side effects, based on clinical experience. A body
of data has been amassed which provides some simple ‘rules of thumb’ concerning
the trade-off between treatment volume and tolerance dose, but these need to be
used very cautiously. Tolerance is affected not only by volume, but also by
radiation sensitivity and fraction size, and tolerance to the various new schedules
in use must be carefully confirmed by clinical studies. In some cases, radiation
injury may result from an excessively high dose to a small tissue element within the
treatment volume. The possibility of ensuring better homogeneity of dose
distribution with IMRT may help to ameliorate this problem.

Radiation dose and tumour cure probability

In radical radiotherapy, the objective is complete sterilisation of any tumour cells
present, which must be achieved without incurring an unacceptably high risk of
serious injury to normal tissues.
Radiation kills cells randomly, which means that each tumour cell has the same
probability of surviving irradiation, that probability depending on the given dose.
Suppose that SF2 is the probability of any cell surviving a single dose of 2 Gy, the
most commonly used fraction size. For example, SF2 might be 0.5 for a typical
carcinoma. After the first 2 Gy fraction, 50 per cent of the cells survive; after the
second dose, 50 per cent of those survivors still survive (i.e. 25 per cent of the
original population); after the third dose, 50 per cent of those survivors still survive
(i.e. 12.5 per cent of the original population), and so on. Generally, after F
fractions, the final survival probability will be (SF2)F. Therefore, for a conventional
treatment regimen consisting of 30 treatments of 2 Gy, the final survival
probability (in this example) would be 0.530 or 9  10–10.
These relationships have some interesting clinical implications. First, there is no
dose which gives zero probability of cell survival – even after a large dose there will
be some probability, possibly very small, of survival of each cell. However, a visible
tumour will contain a large number of cells, so even if each cell individually only
has a small chance of surviving, there may be a good chance that at least one cell
will survive and could regenerate the tumour. We therefore need to know the
relationship between the given dose and the probability that a whole cell
population will be sterilised with not a single cell surviving – the basic requirement
for tumour cure. This can be computed using the theory of Poisson statistics. We
can then calculate the number of treatments necessary to achieve some value of
cure probability, such as 90 per cent (remember that 100 per cent cure probability
cannot be achieved by any finite dose).
We can repeat the calculation for tumours of different sizes (different cell
population numbers) for our example of SF2  0.5, and also for other values of
SF2 representing more sensitive or less sensitive tumour types. Figure 3.2 shows
these relationships. Although we have used a rather simple model for these
calculations, we can observe some features which also turn up in more complex
and realistic models.
First, note that the relationship between tumour cell number and number of
treatments is logarithmic, i.e. a large change in cell number corresponds to a rather
36
 Radiation dose and tumour cure probability
60
Treatment fractions (2 Gy) for 90% cure

50 SF2  0.6
(resistant)

40
SF2  0.5
(intermediate)

30

SF2  0.4
(sensitive)

7 8 9 10 11 12
Log (cell numb
er)
Figure 3.2 Shows the calculated number of 2 Gy fractions to achieve 90 per cent cure
probability, as a function of tumour cell population number, for differing values of cellular
intrinsic radiosensitivity (expressed as the surviving fraction following a single 2 Gy
treatment, SF2). Moderate variation of SF2, as seen between cells of different tumour
types, leads to large differences in the number of 2 Gy treatment fractions required for
90 per cent cure probability. In some cases, the predicted number of fractions required is
much larger than could be safely given.

modest change in the number of treatments and hence the total dose required. For
example, the number of treatments required for a tumour of 104 cells is just half
the number required for 108 cells. It is because of this logarithmic relationship that
quite high total doses have to be given to regions containing only microscopic
spread (in fact often about half the dose given to the bulk tumour). Within regions
of microscopic spread it is likely that the tumour cell density will gradually
decrease, on average, with increasing distance from the visible edge. This suggests
that the radiotherapy dose should similarly decrease with distance, roughly in
proportion to log cell density. Although the cell density distribution will not be
known in detail, it is possible that a tapering dose distribution, such as occurs in a
conventional plan with a peripheral dose gradient, or achieved with IMRT and
deliberate dose modulation within the volume, could be advantageous. A second
feature of the model is that a small change in SF2 has quite a large effect on the
required total dose (compare the three curves shown in Fig. 3.2). Small variations
in the intrinsic radiosensitivity of tumour cells could result in a tumour being easily
curable, or completely incurable, by a radiotherapy regimen.
Another feature of the dose–cure relationship is the steepness of the increase in
tumour cure probability with total dose, illustrated in Figure 3.3. In this figure,
the solid curves show the dose–cure relationships for a series of tumours with
slightly different parameters, and they can be seen to be increasing steeply with
total dose in all cases. This implies that relatively small differences in total dose
37
RADIOBIOLOGY

Figure 3.3 The solid lines in this figure show the expected relationship between total
radiation dose and cure probability for individual tumours with differing radiosensitivity and
cell number. The curves are sigmoid in shape, located at different positions on the dose
axis, and each is quite steep. The broken line shows the much shallower dose-response
usually seen when proportion cured is plotted against dose for groups of tumours, as in
clinical trial studies. The shallower response is thought to result from the heterogeneity of
the tumours in each dose group.

could make a significant difference to cure probability for each tumour. However,
these steep relationships are not seen in the dose–cure relationships for treatment
of groups of tumours with differing parameters, such as occur in clinical studies
with patient groups. The broken line in Fig. 3.3 shows the much shallower
gradient which is typically observed in such studies. The shallow gradient of the
curve for tumour groups is the resultant of a series of steep curves for individual
tumours with differing radiosensitivities. This has some significance when we
consider the importance of moderate changes in total dose when treating
individual patients. The importance of a dose increment in treating an individual
tumour depends on how close the treatment regimen has come to achieving cure.
For a large or resistant tumour (such as glioblastoma) with cure probability close
to zero, a modest dose increment will make little difference. Conversely, for a small
or highly sensitive tumour (such as seminoma) with cure probability close to unity,
a small dose increment again makes little difference. However, if the treatment
regimen achieves a cure probability close to 50 per cent (such as head and neck
tumours), it is in this situation that the dose–response curve is as steep as that
calculated from the Poisson model. This means that for any individual patient
there is some probability, usually unknown, that a large change in tumour control
probability will result from a small change in delivered dose. Even where the
average dose–response curve for patient groups is known to be shallow, a minority
of patients may benefit substantially from small changes in the given dose. It is
these patients for whom the choice of treatment plan may be especially critical.
38
 Tumour radiobiology
Tumour radiobiology
It is believed that the main factors controlling tumour response to fractionated
radiotherapy are the so-called ‘five Rs’ of radiobiology (Table 3.1). Currently, the
most important of these factors are thought to be the intrinsic radiosensitivity of
cells and the kinetics of repopulation of surviving cells.
Intrinsic radiosensitivity varies between different tumour cell lines in culture,
with cell lines derived from clinically resistant tumour types having a statistical
tendency towards higher SF2 values. SF2 measurements on tumours are technically

Table 3.1 Radiobiological factors controlling response to fractionated radiotherapy (the

‘five Rs’) and their clinical relevance

Radiobiological Mechanism of effect on Clinical relevance

factor response

Radiosensitivity Intrinsic radiosensitivity differs Can account for variable

between cells of tumours and response of tumours
normal tissue types, and strongly Curative dose is proportional to the
determines final surviving fraction log of cell number (so subclinical
disease needs smaller dose)
Repair Cells differ in their capacity to Repair is maximal in late-responding
repair DNA damage, particularly tissues given small fractions.
after small doses of radiation Hyperfractionation may be advantageous
Repair is usually more effective Treatments need to be well separated
in non-proliferating cells. The in order to avoid compromising repair
repair process takes at least
6 h to complete
Repopulation Surviving cells in many tumours Shortened treatment times (accelerated
and in acute-responding (but therapy) may be advantageous for some
not in late-responding) normal tumours. Acute (but not late) effects will
tissues proliferate more rapidly be increased. Gaps should be avoided
once treatment is in progress
Reoxygenation Hypoxic cells, which occur Very short treatment times could lead to
especially in tumours, are relatively resistance due to persistence of hypoxic
resistant to radiation. Hypoxic cells. Treatment of anaemia is essential
surviving cells reoxygenate, to optimise tumour response
becoming radiosensitive, as
treatment proceeds
Redistribution Cells in certain phases of the Closely spaced treatment fractions could
proliferative cycle (e.g. late S) are lead to resistance due to persistence
relatively resistant and survive of cells in less sensitive phases
preferentially. With time between
fractions, cells redistribute
themselves over all phases
of the cycle

39
RADIOBIOLOGY

difficult and time-consuming, and techniques are not yet clinically available to help
predict radiosensitivity of tumour and normal tissues in individual patients.
Although tumours are very diverse, the radiobiological properties of most
tumours are similar to those of acute-responding tissues, i.e. a high α/β ratio,
moderate sensitivity to changes in fraction size, and some dependence on total
treatment time. The role of treatment time has been controversial, but it is now
widely believed that many tumours repopulate rapidly during the latter part of a
course of radiotherapy, and that any factor which prolongs time in treatment could
lead to significantly reduced tumour cure probability. Attempts are currently being
made to identify which tumours are most capable of rapid repopulation by
measuring kinetic parameters. Measurements of tumour kinetics to detect those
most capable of rapid repopulation are possible using thymidine analogues, but
these tests are not yet available to use as predictive tools for individual patients.

Avoidance of gaps during treatment

The occurrence of rapid repopulation in irradiated tumours, sometimes with
doubling times as short as 3–4 days, has important implications for interruptions
of treatment. Unscheduled gaps occur not infrequently in radiotherapy schedules
because of machine breakdown or patient intercurrent illness or non-attendance.
(We shall exclude from consideration patients whose treatment is deliberately
stopped because of unusually severe acute reactions.) Gaps are important because
they may lead to prolongation of the total treatment time, allowing opportunities
for rapid repopulation for surviving tumour cells towards the end of the schedule.
Although prolongation will often spare acute normal tissue reactions, the risk of
late effects is not reduced. It has been shown for squamous carcinomas of the head
and neck that reductions in cure probability of 1–2 per cent may result from each
day of prolongation. If gaps occur, the best management strategy is ‘post-gap
acceleration’, i.e. the use of twice daily treatments (separated by more than 6 h) or
weekend treatments to enable ‘catching up’ so that treatment is nevertheless
completed within the originally intended period. This does not require any
changes to fraction size or total dose. However, this approach is not always feasible
in practice. Now that the deleterious effect of prolongation is recognised,
avoidance of gaps is an important consideration for all radiotherapy departments.

Treatment scheduling
Conventionally, radiotherapy schedules have consisted of multiple fractions of 2 Gy
delivered for 5 days a week over several weeks. The total dose is usually limited by
anticipated risk of injury to late-responding tissues, although there are situations
where acute responses (e.g. mucosal reactions) are the main concern. Treatment
schedules with this structure probably take advantage of differences between the
survival curves of cells in late-responding tissues (low α/β ratio and fraction size
sensitivity) and the survival curves of those in typical tumours (with higher α/β
ratios). This means that late-responding tissues are spared to a greater extent than
most tumours by the use of small fractions, giving a favourable therapeutic ratio.
Late responses are not strongly influenced by overall treatment time, and it would
be desirable to make the latter as short as possible in order to minimise the
40
 Treatment plan and ‘double trouble’
opportunities for tumour repopulation. However, this must be balanced by the
need to allow time for reoxygenation of hypoxic cells during therapy, and there also
may be an adverse effect of reduced treatment time on acute-responding tissues
(which also have reduced opportunities for repopulation).
There is now considerable experience with different schedules of treatment (for
details, see Table 3.2). All these changes in scheduling may bring important gains
in tumour control. However, tumours are known to be extremely heterogeneous
with regard to cell survival parameters and growth kinetics, as well as other
properties. It is unlikely that any one schedule is ideal for treatment of all tumours,
even those of a single pathological type, and it would be highly desirable to select
treatment schedules for individual patients on the basis of the radiobiological and
kinetic parameters for each tumour. Predictive tests are not yet sufficiently reliable
to be used in this way, but individualised scheduling based on biological assay is a
likely development for the future.

Treatment plan, schedules and

‘double trouble’
The design of physical treatment plans usually proceeds without regard to
treatment schedule. However, there may be interplay between dose distributions
and treatment schedules, which gives an altered biological effect sometimes
described as ‘double trouble’. Consider a treatment plan in which the spread of
dose within the target volume is 10 per cent, so if the intended treatment is
30 fractions of 2 Gy to give 60 Gy in total, the spread of dose will be from 57 Gy to
63 Gy. However, the low-point and high-point doses will not have been delivered
as 2 Gy fractions (the dose variation of 10 per cent affects each dose fraction, so the
fraction size will range from 1.9 Gy to 2.1 Gy). A treatment schedule of
30  2.1 Gy  63 Gy is what is ‘seen’ by cells located close to the high-dose point
in this example, and this 63 Gy dose is more damaging, especially to late-responding
tissues with a low α/β ratio, than 63 Gy given as 2 Gy fractions (which is what is
implied when only the physical total dose is cited). Therefore, the spread of
radiobiological damage within a target volume has two components, namely that
due to variation in the total dose, and that due to variation in the fraction size by
which that total dose is given. The ‘double trouble’ effect is most marked for late-
responding tissues, for large treatment volumes with considerable dose variation,
and for intended treatment schedules where the prescribed fraction size is sometimes
large (radiotherapy of breast cancer may be such a situation). Although not yet
routine, radiobiological considerations need to be included in the analysis of the
dose–response relationship in patients who are experiencing side effects.
Two ways of accounting for ‘double trouble’ can be envisaged. First, IMRT
makes it possible to ensure homogeneity of dose distribution across a treatment
volume and this approach is being used clinically after it has been shown, for
example, to reduce late normal tissue effects of fibrosis after treatment for breast
cancer. Second, radiobiological dose plans may be constructed with the physical
dose mathematically replaced by some radiobiological equivalent which includes
the effect of variation in fraction size. For example, the physical dose at each point
in the dose matrix could be replaced by a dose calculated by the LQ model to have
41
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attest the unfailing interest and wholesomeness of these adventures
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These stories are rich in fun and thrills in all branches of sports
and athletics. They are extremely high in moral tone, and cannot fail
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They have the splendid quality of firing a boy’s ambition to
become a good athlete, in order that he may develop into a strong,
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ALL TITLES ALWAYS IN PRINT

1—Frank Merriwell’s School Days By Burt L. Standish
2—Frank Merriwell’s Chums By Burt L. Standish
3—Frank Merriwell’s Foes By Burt L. Standish
4—Frank Merriwell’s Trip West By Burt L. Standish
5—Frank Merriwell Down South By Burt L. Standish
6—Frank Merriwell’s Bravery By Burt L. Standish
7—Frank Merriwell’s Hunting Tour By Burt L. Standish
8—Frank Merriwell in Europe By Burt L. Standish
9—Frank Merriwell at Yale By Burt L. Standish
10—Frank Merriwell’s Sports Afield By Burt L. Standish
11—Frank Merriwell’s Races By Burt L. Standish
12—Frank Merriwell’s Party By Burt L. Standish
13—Frank Merriwell’s Bicycle Tour By Burt L. Standish
14—Frank Merriwell’s Courage By Burt L. Standish
15—Frank Merriwell’s Daring By Burt L. Standish
16—Frank Merriwell’s Alarm By Burt L. Standish
17—Frank Merriwell’s Athletes By Burt L. Standish
18—Frank Merriwell’s Skill By Burt L. Standish
19—Frank Merriwell’s Champions By Burt L. Standish
20—Frank Merriwell’s Return to Yale By Burt L. Standish
21—Frank Merriwell’s Secret By Burt L. Standish
22—Frank Merriwell’s Danger By Burt L. Standish
23—Frank Merriwell’s Loyalty By Burt L. Standish
24—Frank Merriwell in Camp By Burt L. Standish
25—Frank Merriwell’s Vacation By Burt L. Standish
26—Frank Merriwell’s Cruise By Burt L. Standish
27—Frank Merriwell’s Chase By Burt L. Standish
28—Frank Merriwell in Maine By Burt L. Standish
29—Frank Merriwell’s Struggle By Burt L. Standish
30—Frank Merriwell’s First Job By Burt L. Standish
31—Frank Merriwell’s Opportunity By Burt L. Standish
32—Frank Merriwell’s Hard Luck By Burt L. Standish
33—Frank Merriwell’s Protégé By Burt L. Standish
34—Frank Merriwell on the Road By Burt L. Standish
35—Frank Merriwell’s Own Company By Burt L. Standish
36—Frank Merriwell’s Fame By Burt L. Standish
37—Frank Merriwell’s College Chums By Burt L. Standish
38—Frank Merriwell’s Problem By Burt L. Standish
39—Frank Merriwell’s Fortune By Burt L. Standish
40—Frank Merriwell’s New Comedian By Burt L. Standish
41—Frank Merriwell’s Prosperity By Burt L. Standish
42—Frank Merriwell’s Stage Hit By Burt L. Standish
43—Frank Merriwell’s Great Scheme By Burt L. Standish
44—Frank Merriwell in England By Burt L. Standish
45—Frank Merriwell on the Boulevards By Burt L. Standish
46—Frank Merriwell’s Duel By Burt L. Standish
47—Frank Merriwell’s Double Shot By Burt L. Standish
48—Frank Merriwell’s Baseball Victories By Burt L. Standish
49—Frank Merriwell’s Confidence By Burt L. Standish
50—Frank Merriwell’s Auto By Burt L. Standish
51—Frank Merriwell’s Fun By Burt L. Standish
52—Frank Merriwell’s Generosity By Burt L. Standish
53—Frank Merriwell’s Tricks By Burt L. Standish
54—Frank Merriwell’s Temptation By Burt L. Standish
55—Frank Merriwell on Top By Burt L. Standish
56—Frank Merriwell’s Luck By Burt L. Standish
57—Frank Merriwell’s Mascot By Burt L. Standish
58—Frank Merriwell’s Reward By Burt L. Standish
59—Frank Merriwell’s Phantom By Burt L. Standish
60—Frank Merriwell’s Faith By Burt L. Standish
61—Frank Merriwell’s Victories By Burt L. Standish
62—Frank Merriwell’s Iron Nerve By Burt L. Standish
63—Frank Merriwell in Kentucky By Burt L. Standish
64—Frank Merriwell’s Power By Burt L. Standish
65—Frank Merriwell’s Shrewdness By Burt L. Standish
66—Frank Merriwell’s Set Back By Burt L. Standish
67—Frank Merriwell’s Search By Burt L. Standish
68—Frank Merriwell’s Club By Burt L. Standish
69—Frank Merriwell’s Trust By Burt L. Standish
70—Frank Merriwell’s False Friend By Burt L. Standish
71—Frank Merriwell’s Strong Arm By Burt L. Standish
72—Frank Merriwell As Coach By Burt L. Standish
73—Frank Merriwell’s Brother By Burt L. Standish
74—Frank Merriwell’s Marvel By Burt L. Standish
75—Frank Merriwell’s Support By Burt L. Standish
76—Dick Merriwell At Fardale By Burt L. Standish
77—Dick Merriwell’s Glory By Burt L. Standish
78—Dick Merriwell’s Promise By Burt L. Standish
79—Dick Merriwell’s Rescue By Burt L. Standish
80—Dick Merriwell’s Narrow Escape By Burt L. Standish
81—Dick Merriwell’s Racket By Burt L. Standish
82—Dick Merriwell’s Revenge By Burt L. Standish
83—Dick Merriwell’s Ruse By Burt L. Standish
84—Dick Merriwell’s Delivery By Burt L. Standish
85—Dick Merriwell’s Wonders By Burt L. Standish
86—Frank Merriwell’s Honor By Burt L. Standish
87—Dick Merriwell’s Diamond By Burt L. Standish
88—Frank Merriwell’s Winners By Burt L. Standish
89—Dick Merriwell’s Dash By Burt L. Standish
90—Dick Merriwell’s Ability By Burt L. Standish
91—Dick Merriwell’s Trap By Burt L. Standish
92—Dick Merriwell’s Defense By Burt L. Standish
93—Dick Merriwell’s Model By Burt L. Standish
94—Dick Merriwell’s Mystery By Burt L. Standish
95—Frank Merriwell’s Backers By Burt L. Standish
96—Dick Merriwell’s Backstop By Burt L. Standish
97—Dick Merriwell’s Western Mission By Burt L. Standish
98—Frank Merriwell’s Rescue By Burt L. Standish
99—Frank Merriwell’s Encounter By Burt L. Standish
100—Dick Merriwell’s Marked Money By Burt L. Standish
101—Frank Merriwell’s Nomads By Burt L. Standish
102—Dick Merriwell on the Gridiron By Burt L. Standish
103—Dick Merriwell’s Disguise By Burt L. Standish
104—Dick Merriwell’s Test By Burt L. Standish

In order that there may be no confusion, we desire to say that the

books listed below will be issued during the respective months in
New York City and vicinity. They may not reach the readers at a
distance promptly, on account of delays in transportation.

To be published in January, 1925.

105—Frank Merriwell’s Trump Card By Burt L. Standish
106—Frank Merriwell’s Strategy By Burt L. Standish

To be published in February, 1925.

107—Frank Merriwell’s Triumph By Burt L. Standish
108—Dick Merriwell’s Grit By Burt L. Standish

To be published in March, 1925.

109—Dick Merriwell’s Assurance By Burt L. Standish
110—Dick Merriwell’s Long Slide By Burt L. Standish
111—Frank Merriwell’s Rough Deal By Burt L. Standish

To be published in April, 1925.

112—Dick Merriwell’s Threat By Burt L. Standish
113—Dick Merriwell’s Persistence By Burt L. Standish

To be published in May, 1925.

114—Dick Merriwell’s Day By Burt L. Standish
115—Frank Merriwell’s Peril By Burt L. Standish

To be published in June, 1925.

116—Dick Merriwell’s Downfall By Burt L. Standish
117—Frank Merriwell’s Pursuit By Burt L. Standish
 SPORTS
There is a greater appreciation of athletic sports
among Americans than among people of any other
nationality.
We have had definite proof of this in the
correspondence occasioned by our publication of the
adventures of Frank and Dick Merriwell. These two boys
are active athletes. They are proficient in every line of
sport, and they play fair or not at all.
This last feature of the Merriwell stories fills our daily
mail with letters from readers who say that they
appreciate the integrity and fairness of the Merriwells
more than words can tell.
These books, while of greatest interest to the right-
thinking boy are educational and make for the
development of a character which will enable the
average boy to meet his fellows fairly and squarely in
the battle of life.

STREET & SMITH CORPORATION

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 EVERY ONE SHOULD READ

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Every reader, young and old, has heard of Jack Harkaway. His
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Jack is a splendid, manly character, full of life and strength and
curiosity. He has a number of very interesting companions, Professor
Mole, for instance, who is very funny. He also has some very strange
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Get interested in Jack. It will pay you.

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books listed below will be issued during the respective months in
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1—Jack Harkaway’s School Days By Bracebridge Hemyng
2—Jack Harkaway’s Friends By Bracebridge Hemyng

To be published in February, 1925.

3—Jack Harkaway After School Days, By Bracebridge Hemyng
4—Jack Harkaway Afloat and Ashore, By Bracebridge Hemyng

To be published in March, 1925.

5—Jack Harkaway Among the Pirates, By Bracebridge Hemyng
6—Jack Harkaway at Oxford By Bracebridge Hemyng
 Dick Merriwell’s Day

OR,

IRON NERVE

BY
BURT L. STANDISH
Author of the famous Merriwell Stories.

STREET & SMITH CORPORATION

PUBLISHERS
79–89 Seventh Avenue, New York
 Copyright, 1904
By STREET & SMITH

Dick Merriwell’s Day

(Printed in the United States of America)

All rights reserved, including that of translation into foreign

languages, including the Scandinavian.
DICK MERRIWELL’S DAY.
 CHAPTER I

THE GREAT CRISIS.

Fairhaven had fought desperately for the game at Seaslope, and

three extra innings had been necessary to decide the contest; but
the home club had won in the twelfth, the final score being four to
three.
“I told you before the game began that we were going into second
place to-day!” cried Sam Hyde, addressing Dick Merriwell, captain of
the Fairhavens. “Hard luck for you, but we’re out for the pennant.”
“You’re not out of reach yet, are you?” retorted Dick, as he
prepared to pull on his sweater. “We still have a small show, haven’t
we?”
“Perhaps you may finish in third position if you can hold
Maplewood down,” said the Seaslope captain. “We’re going to finish
at the top, and I fancy Rockford will be in second place. It’s now a
fight between you and Maplewood to see which of you escape being
tail-ender.”
“Evidently you have it all settled—in your mind,” smiled Dick.
“These things don’t always pan out the way they are planned.”
“Just look over our record when you get a chance,” invited Hyde.
“When you’ve considered what we’ve done, it ought to satisfy you
that we’re going to swipe the pennant.”
Having drawn on his sweater, Dick observed that Ray Garrett, the
manager of the Fairhaven team, was looking blue and downcast.
Merriwell clapped him on the shoulder and advised him to cheer up.
“It’s tough!” muttered Garrett. “This game pushed us down from
second position and let Seaslope head us. If Seaslope keeps up the
pace it has set, Hyde is right in thinking it will win the pennant.”
“You talk like a funeral!” exclaimed Dick. “Wait till we reach
Rockford. We’ll figure over the standing of the teams after we get
there. I think you will see they are well bunched.”
The recent victories of the Seaslope team had enthused its
spectators, and the game this day had been witnessed by a
wonderfully large crowd. Early in the season, when Seaslope was
losing steadily, it had been difficult to get out a respectable
gathering of spectators. Merriwell could not help thinking of the
change as he watched the well-satisfied throng pouring out at the
open gate of the inclosure. At last Seaslope was making money, and
Jared Whitcomb, the manager of the team, was smiling and well
satisfied.
“We’ve just about time enough to catch the next car for Rockford,”
said Garrett, looking at his watch. “Have you picked up all the stuff,
fellows? Got all the bats? Where’s the body protector? Don’t leave
anything.”
Carrying their bat bags and other necessary luggage, the
Fairhaven team hurried from the ground and cut across a field to
reach the trolley line and intercept a car. In this manner they
reached the car ahead of many who waited for it at a regular
stopping place, and all the boys secured seats. It had been a hot
day, and twelve hard innings had tired them to such an extent that
they were glad to sit down.
“We must have that game to-morrow,” said Garrett, who had
taken pains to secure a seat beside Dick. “For that reason I’m not
going to send you back to the island to-night. I don’t want you to
take that trip. If it should be rough to-morrow you might get shaken
up coming over.”
 “That’s a good idea,” said Dick; “but I thought you intended to run
an excursion to-morrow.”
“I do. I’ll run it just the same. More than that, I’m going to see if I
can’t stir up things on the island to-night. We must have a good big
crowd of rooters with us in Rockford to-morrow. I will telephone the
boys on the island and set them at work getting up a crowd. Dick,
do you realize that the game to-morrow is going to be one of the
hardest of the season?”
“Haven’t a doubt of it,” nodded Merriwell. “If Rockford won to-day
from Maplewood, she’ll be able to hold first place to-morrow
whether she loses or not; but if Maplewood won——”
“It seems likely to me,” interrupted Garrett. “Maplewood has been
walloping almost everybody but us since getting her new team. A
week ago I fancied Rockford might have the strongest team in the
league. To-day I’m inclined to think she has the weakest.”
“Time will tell. We’ll find out how the teams stand as soon as we
learn what happened in Maplewood.”
Finding the boys were inclined to accept Garrett’s rather gloomy
view of the matter, Dick laughed at them and did his best to cheer
them up.
“Don’t you worry about us!” cried Obediah Tubbs. “We’ll git into
the game to-morrow, dern our picters! If Rockford takes a fall out of
us she’ll have to get up and hump herself.”
On arriving in Rockford the boys eagerly looked over the bulletin
of the Trolley League games displayed in front of the Star office.
“Great horn spoon!” cried Buckhart. “Just look at that! Maplewood
lifted Rockford’s scalp to-day! Nine to two! That was doing it some!”
“The standing is what interests me now,” laughed Dick. “There it
is, boys. Talk about teams being bunched! What do you think of
that? Seaslope and Rockford are tied, having won twenty each and
lost nineteen. Fairhaven and Maplewood are tied, having won
nineteen each and lost twenty. That’s the sort of baseball to make
your hair curl. It keeps everybody guessing.”
“Well, I’m bub-bub-bub-blamed glad Maplewood did beat Rockford
to-day,” chuckled Chip Jolliby. “I ain’t gug-gug-gug-got no love for
Maplewood, but it kinder makes things a little more even.”
The boys left the car at the Corndike Hotel, where Garrett
registered for them and secured rooms for the night.
By this time the various members of the Fairhaven team were well
known in Rockford, and a number of persons lingering about the
hotel office hailed them one after another by name.
Whitney, the clerk, shook hands with Dick.
“Too bad you dropped that game to-day, Merriwell,” he said. “If
you had won you would have been tied with us for first place. I keep
a bulletin up, following the progress of the games. It was plain
enough before the game at Maplewood was half finished that
Rockford was going to lose, but you kept us guessing what the result
would be at Seaslope. Seaslope’s recent success led some of the
boys to offer odds that she would take the game to-day. I dropped a
five on it myself. I took the short end, and you fellows had me
dancing after the ninth inning was finished and the report came in
that the score was tied. Then came the whitewash in the tenth, and
another in the eleventh. We heard that you finished your half of the
twelfth without scoring, and I offered up a humble supplication for
you to shut Seaslope out in her half. How did they get their run?”
“Nobody to blame,” said Dick. “They earned it. Happened to have
their best batters up and made a clean-earned run.”
“No fault of the umpiring?”
“If anything,” confessed Dick, “we got the best end of that.”
“Well, that’s good sporting talk!” exclaimed Whitney. “I am sick of
hearing all the blame put on the umpiring. When a team loses, it
generally blames the umpire. There’ll be a hot time in Rockford to-
morrow. We can’t afford to let you have that game. We’re obliged to
hold first position, you know.”
“Of course, you feel that way,” retorted Dick. “We have ambitions,
Mr. Whitney.”
A Rockford man who had been standing near now stepped
forward.
“You can find all the even money you want offered on Rockford,”
he said. “I’d like to bet ten dollars myself. Where are the sports that
back your team? You’re captain of it, and I suppose you’ll bet
something yourself, eh?”
“I don’t make a practice of betting,” said Dick.
The man laughed in an annoying manner.
“That’s a good excuse for a weak heart,” he said. “Here’s your
manager. I understand he made a heavy bet early in the season—
something like five hundred dollars. He won, too. Perhaps he wants
to peddle a little of that coin.”
Garrett shook his head.
“There are reasons why I can’t bet,” he said, thinking of his
promise to his mother.
Again the Rockford man laughed.
“Your judgment is better than your nerve,” he declared. “Evidently
you’re going to hang onto that five hundred.”
Ray flushed.
“I think you’ll find plenty of men ready to accommodate you to-
morrow,” he said. “There will be an excursion from Fairhaven, and
we expect a crowd.”
“Tell your people to bring all the money they are anxious to lose.”
A few moments later Garrett and Dick were alone in the room
assigned to them. Ray made some figures on a piece of paper and
sat frowning over them. Finally his face cleared a little, and he
began to laugh.
“What is it?” questioned Dick.
“I was just thinking of what might happen to-morrow. Fairhaven
plays Rockford, while Maplewood goes against Seaslope. What if
both Fairhaven and Maplewood win? Have you thought about that?”
“Haven’t given it much thought yet,” said Dick. “Let me see, both
Fairhaven and Maplewood are one game behind at present. If they
win to-morrow—why, every team in this league will be tied!”
“That’s exactly what will happen,” nodded Ray. “Wouldn’t that be
remarkable? If the two tail-end teams win to-morrow every team in
this league will have won twenty games and lost twenty games.
With the season so far advanced, I don’t believe such a thing ever
happened before in any league. Jingoes, wouldn’t it kick up some
excitement!”
“It would be the best thing that could happen for the league,” said
Dick. “But let’s do a little more figuring. If we defeat Rockford and
Seaslope wins from Maplewood, Seaslope will take first position,
while we will be tied with Rockford for second.”
“That’s correct,” said Garrett. “But if we lose and Maplewood wins,
we go clean to the bottom. To-day we had a chance to be tied for
first place and lost it. Another defeat may put us into last place.
Dick, I confess I’m worried about that game to-morrow. Win it if you
can.”
“I promise you that every man on the team will do his level best,”
said Dick.
 CHAPTER II

TOM FERNALD’S PROPOSITION.

Tom Fernald, the Rockford manager, returned home in anything

but a pleasant frame of mind. He had counted on victory, and defeat
had cost him some good money. Having heard of the result at
Seaslope, he also figured over the standing of the teams, and his
anxiousness increased as he fully realized the critical nature of the
situation. He knew enough about baseball to understand that
fortune had favored Rockford in many instances, and enabled her to
retain first place. At one time he had encouraged Seaslope and
rejoiced in her victories over Fairhaven and Maplewood, little
dreaming the team was likely to become a dangerous antagonist for
first position at the end of the season.
He had felt satisfied over the success of Maplewood with a new
team, being confident that Rockford would not suffer through this
success. Now the complexion of things had changed greatly. The
loss of two more games might push Rockford down and make an
opportunity for those who had previously criticised him and his
management to say, “I told you so.”
Fernald dropped off the car at the Corndike and came face to face
with Brad Buckhart, of the Fairhavens, as he entered the hotel.
“How do you do, Buckhart?” he nodded. “So you had hard luck
yourself, did you? It must have been a hot game. Twelve innings,
was it?”
“Yes, twelve warm ones,” nodded the Texan.
 “You did well to hold Seaslope down in such a manner. Didn’t think
you could do it. Those fellows have a hard team to beat over there.
How were the hits?”
“They made one more than we did.”
“And the errors?”
“Neither team made an error to-day.”
Fernald whistled.
“By Jove! that was a great game. What are you going to do to-
morrow?”
Brad grinned.
“We’re going to do our level best to make you hump yourself, Mr.
Fernald,” he replied. “We’ll have my pard in the box to-morrow, and
you know what that means.”
“Then Merriwell didn’t pitch to-day?”
“No.”
“I’d like to have a little talk with you, Buckhart,” said the Rockford
manager, taking Brad by the arm. “Let’s sit down over here.”
The Texan wondered why Fernald should wish to talk with him,
but walked over to some chairs in a corner of the office, where they
sat down quite by themselves.
“You’re a pretty good friend to Merriwell, aren’t you?” asked
Fernald.
“Sure thing,” nodded Brad.
“And you’re the only catcher on the Fairhaven team?”
“I opine I am. Some of the others might go under the bat, but
they don’t advertise themselves as catchers.”
“There’s no other man on the team who can hold Merriwell, is
there?”
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