Radiotherapy for painful bone metastases

95
Radiotherapy for painful bone metastases
PR Needham Senior Registrar in Palliative Medicine, Dorothy House Foundation, Bath and PJ Hoskin Consultant Clinical
Oncologist, Mount Vernon Hospital, Middlesex and Senior Lecturer in Oncology, University College London Medical School,
London
Address for correspondence: PJ Hoskin, Consultant Clinical
Oncologist, Mount Vernon Hospital, Northwood, Middlesex
HA6 2RN, UK.
Key words: bone neoplasms; hemibody irradiation (non-MeSH); radiotherapy;
radiotherapy dosage
Bone metastases are a frequent cause of morbidity in patients with malignant
disease. Pain is the commonest symptom; it can be treated successfully in
the majority of patients by local external beam irradiation. Controversy exists
over which regimen should be used, with a single dose necessitating only one
treatment visit to the radiotherapy department, or a fractionated course requiring
several visits. Many radiotherapists continue to use fractionated regimens
despite the current evidence that single fractions are as effective. Many reasons
exist for this, including departmental policy and training, fears of recurrence,
problems with retreatment of previously treated areas, fears of increased early
and late morbidity, and attempts at promoting recalcification. The majority of
these reasons are theoretical and have yet to be substantiated.
In many patients, symptomatic bone metastases are widespread, and
hemibody irradiation, although more toxic, should be considered in order to avoid
the need for repeated courses of local treatment.
Mots-Cles: n6oplasmes osseux; irradiation h6mi-corporelle; radioth6rapie;
dosage radloth6rapeutique
Les metastases osseuses sont une cause fr6quente de mortalit6 chez les
patients atteints de maladies malignes. La douleur en est le sympt6me le plus
frequent. Cette dernibre peut etre tralt6e avec succbs par irradiation par rayon
localls6 chez la plupart des patients. Une controverse existe quant au regime
qui devrait btre utills6, soit une dose unique n6cessitant seulement une seule
visite au service de radioth6raple pour le traitement, ou une s6rie fractionn6e
r6clamant plusieurs visites. Beaucoup de radloth6rapeutes continuent d’utiliser
le traitement fractionn6 en d6pit des donn6es actuelles qui prouvent qu’une dose
unique est aussi efficace. Beaucoup de raisons existent pour cet 6tat de fait, y
compris la politique suivie par les services concern6s, la formation pratiqu6e, la
crainte des rechutes, des problbmes li6s au retraitement de zones
at CARLETON UNIV on June 22, 2015pmj.sagepub.comDownloaded from

96
pr6c6demment traitees, la crainte d’une mortalité accrue 6 court ou long terme
et des tentatives de soutenir la recalcification. La plupart de ces raisons sont
th6oriques et restent a prouver.
Chez un nombre significatif de patients, les metastases osseuses
symptomatiques sont diss6min6es et l’irradiation h6mi-corporelle, quoique plus
toxique, devrait 6tre prise en consideration pour 6viter de devoir recourir à des
traitements locaux repetes.
Introduction
Bone metastases are a frequent cause of mor-
bidity in patients with malignant disease. They
occur most often in patients with breast, lung,
prostate, thyroid and renal cancer, and those
with multiple myeloma. In addition, common
tumours such as carcinomas of the cervix, blad-
der and gastrointestinal tract not infrequently
give rise to bone metastases. Although many
patients remain asymptomatic from their bony
metastases,l a significant proportion have their
quality of life impaired by pain, pathological
fracture, hypercalcaemia, and nerve root or spinal
cord compression.
Pain is the commonest symptom; it is typically
dull, of variable intensity, exacerbated by move-
ment or weight bearing, and associated with local
tenderness. In Twycross and Fairfield’s study2
31 % of patients admitted to Sir Michael Sobell
House, Oxford had this type of pain. In addition,
neuropathic pain from nerve root and spinal cord
compression and muscular pain from secondary
muscle spasm can compound the problem.
The exact mechanism of the pain caused by
bone metastases is uncertain and it is not clear
why some metastases cause pain whilst others do
not. Stretching of the innervated periosteum by
the tumour mass, the presence of microfractures,
and the liberation of prostaglandins and other
cytokines by the tumour cells, with sensitization
and stimulation of the surrounding nociceptors,
have all been postulated.3-6
Bone metastases are usually only treated when
they become symptomatic, or if they are thought
liable to fracture or cause cord compression.
External beam irradiation, used since the begin-
ning of this century, remains the single most
effective form of treatment. In a review from
one radiotherapy department, bone metastases
accounted for 21 % of all patients receiving
radiotherapy; this was 42% of their total pallia-
tive workload.7
Local external beam irradiation
Many papers have been published on the use of
local external beam irradiation.g-23 These studies
were often retrospective, 3,8,9,12-16 based on physi-
cian assessments recorded in the patients’ notes.
Some are prospective, but still rely on physician
assessment of response. 10,11,17,20 Few prospective
studies using validated patient assessment of pain
have been produced.19,21,23 Response rates from
the published prospective studies are shown in
Table 1.
How response is defined, whether changes in
analgesic requirements are taken into account
(and, if they are, whether they in fact indi-
cate other sites of active disease), and whether
other treatment changes are made, all need to
be considered in the interpretation of the data
from the different studies. When the assessment
of response is made is also important. One study’9
found that, although the majority of responses
occurred within the first four weeks (and all by
eight weeks), their complete response rate in the
single fraction group increased from 27% at four
weeks to 45% at six months, possibly reflecting
the early death of many nonresponders.
Optimal regimen
Many treatment regimens have been evaluated
for painful bony metastases, yet optimal dose and
fractionation remains a controversial issue.24-26
One survey of British radiotherapists, referred to
in more detail later, found 40 different dose frac-
tionation regimens recommended for the same
clinical problem. Doses ranged from 8-36 Gy and
number of fractions from 1-15.2~

97
Fractionation .
Radiotherapy is a balancing act between the
amount of damage needed to kill the cancer cells
and the amount of damage which the normal sur-
rounding host tissue can tolerate. By fractionating
a course of treatment, higher total doses can be
given, with more ensuing damage to the tumour
cells relative to that of the normal cells. The
mechanisms by which this can be achieved are
referred to as the ’four Rs’28:
1) Repair of cell damage between fractions is
slower in malignant tissue than normal tissue,
with better recovery of the normal cell lines
between fractions.
2) Repopulation by surviving cells between frac-
tions is normally less in tumour cell lines than
in acutely responding normal tissues. This
does not apply to late responding normal
tissues such as bone and spinal cord, as they
have a very low mitotic rate.
3) Redistribution within the cell cycle is an
important concept. Cells in the radioresistant
phases of the cycle are allowed to progress
to the more radiosensitive phases between
fractions. This is of importance for the late
responding tissues whose cells remain in the
resting phase of the cell cycle, and thus
remain less susceptible to damage by the
next fraction of radiotherapy whilst more of
the tumour cells have entered the susceptible
phase.
4) Reoxygenation of the tumour occurs as the
cells are gradually reduced in number. Oxy-
genated cells are two to three times more
radiosensitive than hypoxic cells. The period
over which the fractionated course is deliv-
ered is therefore important. A single fraction
of 10 Gy is not equivalent to 10 fractions
each of 1 Gy, but is a much higher biological
dose of radiation; the effect of fractionation
and prolonging the duration over which the
treatment is delivered makes the latter far less
efficient in producing biological damage.
Although delivering high total doses is relevant
to radical treatment which attempts to eradicate
all the tumour cells, its relevance in the treatment
of bone metastases is disputed. Pain relief appears
to be independent of reduction in tumour size
and cell kill, as shown by the rapidity of onset of
pain relief after hemibody radiotherapy, absence
of a dose-response effect, and the fact that the
response rate of tumours does not appear to
Table 1 Response rates from the published prospective studies
a
Reanalysis of RTOG trial.

98
be related to their radiosensitivity. The exact
mechanism of action by which radiation relieves
bone pain is unknown.
Single treatments
As with any palliative treatment, the aim of
treating symptomatic bony metastases should be
to control symptoms with a minimum of incon-
venience to the patient with low treatment-related
morbidity and mortality. Single fractions are less
demanding in terms of time and resources, for
the patient and the radiotherapy department,
than the more protracted fractionated regimens.
Most publications suggest that they are equally
effective in terms of pain relief.8,10-12,15,17,19,21-23
Only one prospective study29 has shown any
favourable relationship between multiple frac-
tions and response. This was a reanalysis, taking
into account retreatment and analgesic use, of
an earlier study initially reported as showing no
such link.l~ Pain assessments in this trial were
relatively unreliable physician scores of pain.
One retrospective trial has shown a significant
correlation between total dose and response.16
A complete response rate of 70.2% was found
in those receiving 40 Gy or more, compared with
50.6% in those receiving less.
Single doses of 8 Gy are now generally recom-
mended by most authors. 3--5,30,31 The efficacy of
doses below this is not certain; no correlation
between dose and response was found in one
study 10 comparing single fractions of 3.5-7.0 Gy,
but a more recent study23 found significantly bet-
ter pain relief at four weeks with 8 Gy compared
with 4 Gy. By 12 weeks, however, 8 Gy was only
marginally superior.
The continued use of fractionated regimens
As studies have shown single and fractionated
courses to be of similar efficacy, with a similar
speed of onset of effect,19 why do patients con-
tinue to receive protracted courses? Training and
departmental policy were the commonest reasons
given in the two published surveys.27,32 The first
of these asked a selected sample of 80 British
radiotherapists how they would manage a 64-
year-old lady with painful uncomplicated dorsal
spinal metastases from breast cancer, and the
second asked a similar question of all 227 British
radiotherapists practising at the time (although
the metastases were at L2). The reasons given for
fractionating the treatment are shown in Tables 2
and 3.
In a further study33 of European radiotherapists
given a similar case history, it became apparent
that the radiotherapists’ attitudes to the treat-
ment significantly affected the regimen chosen.
Reasons for giving radiotherapy ranged from pal-
liative intent (99%), symptomatic relief (97%),
prevention of symptom development (35%), and
extension of life (5%), to giving hope to the
patient (12%). Those giving the latter three rea-
sons for treating tended to use higher total doses.
Predicted survival time ranged from less than six
months to over five years. Those predicting a
longer survival gave significantly higher doses of
radiotherapy.
In the two British surveys27,32 a change in
the site of lesion, the age of the patient, or the
presence of neurological problems, changed the
regimen used in the majority of cases. In the
former survey all those proposing a fractionated
course would use only one fraction in certain
circumstances, such as rib metastases (47%), age
over 70 years (71%), long distance from the radio-
therapy centre (70%), and temporary pressure on
Table 2 Reasons given for choosing a fractionated course
of treatment (From Crellin etal.32)
Table 3 Reasons given for choosing a fractionated course
of treatment (From Priestman metal.27)

99
machines (82%). Of those initially proposing to
use one fraction, 73% would use a fractionated
regimen if neurological symptoms were present,
13 % if the patient was aged less than 44 years,
20% if the cervical spine was involved, 33% if it
was the patient’s first metastasis, and 20% if the
metastasis was lytic.
The grounds given in the above studies for the
use of fractionated regimens rather than a single
fraction included the following reasons.
Training and departmentalpolicy
A survey of the difference in national attitudes
to the use of radiotherapy in advanced cancer34
found that palliative therapy tended to be del-
egated to the less experienced therapists, who
may be less confident in the use of large single
doses; it is proposed that this may foster conserva-
tism. It has been suggested that the training and
postgraduate examinations of junior staff should
place more emphasis on the palliative aspect of
their work.
The adoption of a formal policy decision by a
unit as part of an audit procedure has been shown
to alter practice. 7,35,36 The number of patients
receiving five or more fractions of radiotherapy
for metastatic bone pain fell from 80% to 40%
one year later in the first study,~ and from 62%
to 27% in another.35 The third study found that,
following three audits, the number of single frac-
tions used rose from 34% to 68%.36
Relapse rates
There is concern that when a low total dose is
used, as with single doses, there may be a higher
relapse rate. Data to support this are sparse. One
studyl6 has reported that pain recurrence was
less, the closer the total dose was to 40 Gy,
in those who had responded completely. A pros-
pective study,22 comparing 8 Gy with 30 Gy in
10 fractions, reported retreatment rates of 25%
over a six-month follow-up in patients receiving
8 Gy; there were none in the fractionated group.
A larger study using the same treatment arms
found no significant difference in duration of
response between the single and fractionated
groups, 48% and 39% maintaining their response
at 24 weeks.
Retreatment
Late toxicity is known to be related to the size
of fraction given,30 and single doses used for
pain are much larger than those of standard
fractionated regimens, which keep each fraction
at 2-3 Gy in order to try and avoid late damage.
There is uncertainty over the safety of retreatment
following large single doses. Retreatment rates
vary and are often not clearly described in
published trials. One large prospective study23
reported a 71 % retreatment success rate after an
initial single dose of 4 Gy, and 44% after a single
dose of 8 Gy. This included patients who had
failed to respond to the first dose and those who
had responded and then relapsed. There are no
reports of problems in retreating areas previously
treated with a single dose.
Acute toxicity
Acute toxicity includes systemic effects such as
fatigue and nausea, or localized effects such as
mucositis and skin reactions varying from ery-
thema to desquamation. These are seen within
hours to days of treatment, are self-limiting and
are, for palliative doses, generally mild. They are
related to the dose and site treated and certain
sites are especially sensitive, in particular the
abdomen where inclusion of the stomach or liver
results in nausea or vomiting; irradiation of small
bowel causes colic and diarrhoea. The volume of
tissue included in the irradiated area is also impor-
tant, with greatest toxicity for large areas. Acute
toxicity is one factor which limits single doses to
around 8-12 Gy. Wide individual variation is seen
in the reaction to radiation treatment.
Treatment related toxicity is poorly documen-
ted in most of the published literature. In the two
prospective studies comparing 8 Gy with 30 Gy in
10 fractions, the first and larger study’9 found no
difference in the incidence of acute side-effects,
but the second22 reported a higher incidence of
nausea, of brief duration, in those receiving 8 Gy.
Lethargy was similar in both groups in the latter
survey.
Late toxicity
Late damage to normal tissues is irrevers-
ible and tends to be progressive. It does not
become apparent until several months following
therapy. The pathological basis for late damage
is an obliterative endarteritis and fibrosis. It is
dependent upon total dose and fraction size.
Severe acute toxicity does not predict for late

100
radiation damage.
Late morbidity following single fractions, if it
occurs, is only an issue in those patients with a
long survival, usually those with carcinoma of the
breast or prostate. Patients with an expected life
span of only a few weeks or months can receive a
single fraction with no concern for late morbidity.
In fact, to date, no long-term morbidity has so
far been reported for single fractions of up to
8 Gy.
Prevention of pathological fracture
A fractionated regimen may be recommended
for a lytic lesion liable to fracture, as it is felt
that fractionation is more likely to result in
recalcification. A retrospective reviewl4 found
that 78% of treated sites with serial X-ray
examinations available had radiographic signs
of calcification by one to two months, after
receiving 20-25 Gy in eight to 10 fractions.
No such data are available for patients re-
ceiving single fractions but, anecdotally, there
is doubt that recalcification does occur after
single doses of 8 Gy. In the RTOG (Radiation
Therapy Oncology Group) study17 there was an
increase in the incidence of pathological fra itures
in those receiving the higher total dose of 40.5 Gy
compared with those receiving 25 Gy. The rela-
tionship between this and radiographic changes
remains uncertain.
Spinal metastases with a neurological component
Spinal cord compression is often considered
an indication for a fractionated regimen. This
is based on concern about acute oedema during
treatment, thought to be more likely to occur
with high-dose fractions, and also the intention
of reducing tumour mass and stabilizing the bone.
Some centres are however currently successfully
using hypofractionated regimens in the treatment
of spinal cord compression. 37,38
Radioresistant tumours
Some radiotherapists would prefer to use high-
dose fractionated courses in patients with cancers
of poor radiosensitivity (i.e. the well differenti-
ated tumours with slow growth rates, such as
renal cell cancers and melanomas). The majority
of studies reported have however failed to show
any relationship between pain relief and histologi-
cal type of the treated tumour. One retrospective
studyl6 found a lower complete response rate
for adenocarcinoma of the kidney and non-small
cell lung cancer and the RTOG study17 reports
that prostatic and breast metastases were more
responsive than lung metastases or those from
other primary sites. It has also been reported&dquo;
that prostatic bone metastases were slower to
respond, but had a similar response rate to other
tumour types by three months post-treatment.
In summary, the main reservations for the use
of single fractions for metastatic bone pain are
based upon doubts over efficacy and toxicity,
which are not borne out by published data.
However, in some areas, data are sparse and of
poor quality and there is a need for problems
such as bone healing and neurological recovery
to be addressed more fully, to identify the small
proportion of patients who may benefit from more
protracted treatment. This should not detract
from the considerable body of data supporting
the use of one fraction only for simple bone pain
relief.
Hemibody irradiation (HBI)
Hemibody irradiation may often be more appro-
priate than repeated local irradiation, as many
patients with painful bony metastases have
widespread disease requiring several courses of
treatment to sequential sites of pain.
Regimen
Large field irradiation is undoubtedly associ-
ated with greater toxicity than more localized
treatment. The maximum dose tolerated in total
body irradiation is 3 Gy, the bone marrow being
the limiting factor. In HBI (upper, lower or mid)
a higher single dose is tolerated, and sequential
halves may be treated with an interval of four to
six weeks to allow haematological recovery. For
the upper body the lungs are the dose limiting
factor. A single fraction of 6 Gy is the maximum
tolerated dose; 8 Gy can be given to the lower and
mid hemibody. A large prospective dose-finding
study of the RTOG39 found that increasing the
dose above 6 Gy for the upper body, and 8 Gy for
the lower, increased toxicity but did not improve
pain relief.

101
Efficacy
Many studies of HBI have been re-
ported,4°-52 with overall response rates of
73-100%,39,42,44,47-52 and complete response
rates of 5-57%.39,42,45-49,51,52 Pain relief is often
very rapid, with the majority responding within
48 hours,41-54 and is independent of tumour
radiosensitivity.47,52 Relief of pain lasts for the
remainder of the patient’s lifetime in 50-86% of
responders.39.42,4~.a~--s2
Local field irradiation can safely be given fol-
lowing HBI44 for those who require retreatment.
Acute toxicity
HBI is associated with greater toxicity than
local field irradiation. Most units admit patients
overnight for HBI, especially if the upper body
is to be irradiated. Premedication with glucocor-
ticoids and anti-emetics, and adequate hydration
is used to minimize the acute effects which are
mainly gastrointestinal, with nausea and diar-
rhoea occurring 12-24 hours after treatment.
Mild myelosuppression will often occur when a
one-half body field is irradiated, and is more likely
if the pretreatment counts are low or borderline
following previous chemotherapy.39 If the skull is
irradiated, transitory alopecia will also generally
occur.
Acute radiation pneumonitis secondary to
alveolar cell damage is a rare complication seen
from one to six months following treatment. It is
more likely to occur if the lung has been previ-
ously irradiated or if there is concurrent malignant
lung disease.55,56 If the dose of irradiation to the
upper hemibody is limited to 6 Gy, its frequency
is ~-16%.39,45,46,48,52,53,56,57 It is often fatal.
Fractionated HBI
HBI is conventionally given as a single fraction.
Single fraction HBI has been compared with frac-
tionated HBI. 58 This study concluded that, whilst
fractionated HBI was no more effective initially,
fewer retreatments were required than with single
dose HBI and the overall duration of palliation
was longer. However, this was only a small study
of 29 patients who had a surprisingly poor median
duration of palliation (2.8 months) in the single
fraction arm, and further data are required to
confirm this observation.
Combination with local irradiation
One prospective multicentre studys9 has looked
at the combination of single dose HBI with
standard fractionated local field irradiation in
an attempt to delay the onset of metastases
in the treated area. There was a high rate
of noncompliance in the group requiring both
treatments, but by one year fewer patients had
progressed or developed new disease within the
hemibody treated in the combined group than
those who received only local field irradiation.
More severe myelotoxicity was noted in the com-
bined group, but this was transitory.
Other systemic treatment
Other systemic radiation therapies available
include bone-specific radioactive isotopes such
as strontium-89, which is a pure ¡3-emitter, con-
centrated at sites of osteoblastic activity. It is
taken up preferentially in sites of bone metastases
and can deliver a localized dose of radiation along
the short path of ¡3-radiation. It can be given as a
single outpatient intravenous injection with few,
if any, side-effects. Transient falls in blood count,
in particular platelets, are seen, but this is not
usually of clinical relevance. Strontium is cleared
through the kidneys and excreted in urine and
is therefore relatively contraindicated in urinary
incontinence, due to risk of radioactive contamina-
tion, and in renal failure. Response rates ranging
from 37-92% in bone metastases from carcinoma
of the prostate have been reported.60,61 In a
comparison of strontium-89 and HBI, both treat-
ments were found to be equally effective; how-
ever the HBI group required more transfusions
and had a 37% incidence of nausea and vomiting
despite prophylactic anti-emetics.62 Response is
slower with strontium-89, taking two to four
weeks. The principal drawback to its widespread
use is the very high cost, which is approximately
15 times greater than that of single outpatient
external beam radiotherapy treatment.
Other radioisotopes have been investigated in
the past for the treatment of metastatic bone
pain. Iodine-131 is of value in metastases from
carcinoma of the thyroid, although it may be
less effective in this setting than external beam
therapy.63 Phosphorus-32 is also active, but may
be associated with troublesome bone marrow

102
depression, as a result of which it has not achieved
general acceptance.
In addition to the various forms of radiation
therapy discussed above, specific systemic
antitumour treatments such as chemotherapy and
hormone therapy should be considered alongside
the appropriate use of analgesics and coanalgesics
such as nonsteroidal anti-inflammatory agents and
bisphosphonates. Surgical fixation remains opti-
mal therapy for pathological fractures of long
bones and postoperative radiotherapy should
always be considered to prevent further local
tumour progression within the bone.
Careful appraisal and application of radiation
therapy, systemic anticancer therapy, and symp-
tomatic treatments should enable the patient with
bone metastases to have a full and pain-free
course despite the advanced nature of their malig-
nant disease.
Conclusion
Further large scale prospective studies are needed
to look specifically at the issues of late morbidity,
rates of relapse, response rates and morbidity
associated with retreatment, and pathological
fracture following single high-dose treatments. It
is, however, disappointing to find that less than
3% of radiotherapists are apparently influenced
by published literature when deciding on their
management of bone metastases.2~
It may be that the NHS reforms and financial
constraints, in combination with internal audit,
will be more effective in enforcing a change.
Whilst awaiting further studies we would still
agree with Vargha et al. that, ’In view of the high
success rate, low morbidity, rapidity of treatment
as well as the social, psychological and economic
advantages, single session therapy for palliation
warrants wider adoption by radiotherapists.’ This
remains as true today as it was when published in
1969!
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