The British Journal of Radiology, 77 (2004), 177182 E 2004 The British Institute of Radiology

DOI: 10.1259/bjr/54028034

Review article
Clinical use of intensity-modulated radiotherapy: part II
M T GUERRERO URBANO, MRCPI, FRCR and C M NUTTING, MRCP, FRCR, MD
Radiotherapy Department and Head and Neck Unit, Institute of Cancer Research and Royal Marsden NHS Trust,
London and Surrey, UK

Abstract. Intensity-modulated radiotherapy (IMRT) is a novel conformal radiotherapy technique which

is gaining increasingly widespread use. This second clinical article aims to summarize the published data
pertaining to prostate cancer, pelvic irradiation, gynaecological and breast cancer. Prostate cancer patients
represent the largest group treated to date. The main indication has been radiation dose escalation within
acceptable normal tissue late toxicity. Phase II data are promising, but no randomized clinical trial data are
available to support its use. Pelvic IMRT aims to deliver radical radiation doses to pelvic lymph nodes while
sparing the bowel and bladder. Indications for breast IMRT data are reviewed, and current data presented.
Further data from randomized trials are required to confirm the anticipated benefits of IMRT in patients.

Intensity-modulated radiotherapy (IMRT) is a novel

conformal radiotherapy (CRT) technique that produces
highly conformal dose distributions. The clinical applica-
tions include conformal avoidance strategies aimed at
reducing the radiation dose to organs at risk (OR) and
hence normal tissue radiation toxicity, or radiation dose
escalation to tumours with the goal of increased tumour
control. This second of two articles [1] presents the
published clinical data on the treatment of prostate cancer,
pelvic lymph node irradiation including gynaecological
tumours and breast cancer.

Urological malignancies
Prostate cancer
Prostate cancer is currently the single most common
tumour site treated with IMRT Worldwide. The treatment
goals are increased tumour control through dose escala-
tion, and reduced late radiation toxicity.
At Memorial Sloane Kettering Cancer Center, a Phase
II dose escalation study has been underway. IMRT was
initially used at this institution to boost prostate cancer
treated with 3DCRT to 72 Gy in 40 fractions. An addi-
tional 9 Gy in 5 fractions were given with 6 inverse-planned
intensity modulated beams using dynamic multileaf colli-
mation (DMLC) [2]. Stein et al [3] evaluated the number
of equispaced co-planar IMRT fields required to obtain an
optimum treatment plan for prostate cancer and showed
an increase in the number of fields with increased pres-
cription dose, ranging from 3 fields for 70 Gy plans to 7 to
9 beams for 81 Gy plans. Burman [4] showed that using a
five-field IMRT plan, good conformal dose distributions
were obtained to deliver 81 Gy to the planning target
volume (PTV), and that the dose to the bladder and
rectum were kept within tolerance (Figure 1). This group
first reported the acute toxicity observed using IMRT [5]
Received 2 October 2003 and accepted 1 December 2003.
Address correspondence to Dr C Nutting, Head and Neck Unit,
Royal Marsden NHS Trust, Fulham Road, London SW3 6JJ, UK.
Figure 1. A dose distribution for the treatment of prostate
cancer using a five-field technique. Colourwash: 95% green,
70% yellow, 50% orange, 20% dark blue.
comparing 61 patients with clinical stage T1cT3 N0 M0
prostate cancer treated with 3DCRT and 171 with IMRT
to a prescribed dose of 81 Gy, between 1992 and 1998.
Acute and late radiation-induced morbidity was evaluated
in all patients and graded according to the Radiation
Therapy Oncology Group (RTOG) toxicity scale. They
reported a 2 year actuarial risk of grade 2 bleeding of 2%
for IMRT and 10% for conventional 3DCRT (p,0.001).
A further report showed a significant reduction in the
incidence of late grade 2 rectal toxicity in the patients
treated to 81 Gy with IMRT compared with 3DCRT (2%
versus 14%) and suggested an improvement in 5 year
actuarial prostate specific antigen (PSA) failure and
positive biopsy rates with increasing dose [6]. The largest
report of IMRT for prostate cancer was published from
the same group in 2002 [7]. A total of 772 patients were
reported (698 treated to 81 Gy and 74 treated to 86 Gy).
The maximum RTOG acute rectal toxicity was grade 2 in
4.5%. Only one patient reported acute bladder toxicity
grade 3 and 28% had grade 2. Late rectal toxicity was

The British Journal of Radiology, March 2004 177

 M T Guerrero Urbano and C M Nutting

grade 2 in 1.5% patients and grade 3 in 0.1%. Late bladder

toxicity was grade 2 in 9% and grade 3 in 0.5% patients.
The 3 year actuarial PSA relapse-free survival rates for
favourable, intermediate and unfavourable risk group
patients were 92%, 86%, and 81%, respectively. This phase
II data appears to show increased PSA control with
increasing radiation dose compared with historical con-
trols. However, during the time period of this study, there
has been an improvement in the prognosis of prostate
cancer patients in the USA [8], and this represents a
potential bias in the interpretation of data based on
historical controls without randomized controlled data.
De Meerler et al [9] used segmented static beams to
escalate the dose to the prostate while keeping the anterior
rectal wall maximum dose at 72 Gy. They showed that a
three-field solution (0, 116 and 244 ) using a biological
objective function based computer optimization provided a
significant increase the ratio of predicted tumour control
probability (TCP) over rectal normal tissue control pro-
bability (NTCP).
The Cleveland Clinic Foundation used the increased
rectal sparing observed with IMRT to deliver a hypo-
fractionated schedule (70 Gy in 28 daily fractions) pre- Figure 2. A dose distribution for the irradiation of pelvic
scribed to an isodose line ranging from 83% to 90%. Tight lymph nodes (pink outline) and bowel (blue outline). 60 Gy
(4 mm posteriorly, 8 mm laterally and 5 mm in all other (yellow colourwash) is delivered as a boost to an enlarged
node thought to be a metastasis, the remainder of the nodes
directions) clinical target volume (CTV) to PTV margins
receive 55 Gy (orange colourwash).
were used and a 7% actuarial rate of rectal bleeding at 18
months was reported [10]. This group reported a stati- boost is now used clinically at the University of California
stically significant improvement in biochemical relapse-free [15]. In a modelling study, a simultaneous integrated boost
survival in 166 patients treated with IMRT (70 Gy in 28 technique was used to dose escalate intraprostatic tumour
fractions) versus 116 patients treated with 3DCRT (78 Gy nodules to 90 Gy by Nutting et al [16]. Improvements in
in 39 fractions) (94% vs 88%, p50.084, non-randomized TCP to NTCP ratio were suggested, although it was noted
comparison). Actuarial late rectal toxicity for the hypo- that this was dependent on the position of the intrapro-
fractionated IMRT group was 5%. static node in relation to the anterior rectal wall. This
Bastash et al [11] reported no increase in erectile technique is now used at this institution to boost positive
dysfunction following post-operative IMRT in 18 patients pelvic nodes in patients with prostate cancer who are at
who remained potent after nerve-sparing prostatectomy, high risk of pelvic node involvement (.30% risk), or
having received a mean dose of 69.6 Gy to the prostate bed. patients with small volume pelvic lymphadenopathy in the
absence of distant metastases utilizes the abovementioned
phase I study.
Pelvic lymph node irradiation for prostate cancer
IMRT was shown in planning studies to reduce the dose
Bladder
to the small bowel during pelvic irradiation. Nutting et al
[12] showed a significant 5075% reduction in the volume Improved PTV dose homogeneity with a reduction in
of bowel irradiated to more than 45 Gy with inverse both the high and low dose areas and reduction in normal
planned 3 to 9 field IMRT. A 57 beam DMLC technique tissue Dmax and rectal dose has been shown, both with
to treat pelvic nodes and prostate has been implemented at DMLC [17] and forward planned partially wedged lateral
the Royal Marsden Hospital to treat patients within a beams [18].
Phase I dose escalation study (Figure 2) [13]. The first
phase of the study involved delivery of 70 Gy to the
Gynaecological malignancies
prostate gland, 64 Gy to the seminal vesicles and 50 Gy to
the pelvic nodes to 20 patients. To date 53 patients have Primary radiotherapy for gynaecological malignancies
been treated and the current dose level is to 60 Gy. No usually requires whole pelvis radiotherapy followed by
Grade 3 late gastrointestinal complications have been brachytherapy, with small bowel, rectum and bladder
recorded so far (Dr DP Dearnaley, personal communication). being the main dose limiting structures. The use of con-
Advances in imaging modalities such as endorectal MRI comitant chemotherapy in locally advanced cancer of the
and MR spectroscopy (MRS) have made it possible to cervix, while improving survival, is also associated with
identify foci of carcinoma within the prostate. Pickett et al increased morbidity. Radiotherapy to the whole pelvis is
[14] used IMRT to boost an intraprostatic lesion, defined also required following surgery if there is a high risk of
by MRI+MRS, to 90 Gy using 2.25 Gy per fraction while lymph node involvement, especially in uterine carcinoma.
the entire prostate was treated to 70 Gy at 1.8 Gy per frac- Low et al [19] postulated that IMRT may replace high
tion and not exceeding normal tissue tolerances. Because dose-rate brachytherapy using an immobilization device
of differences in the dose per fraction the biologic advantages within the vagina. Portelance et al and Roeske et al [20,
of this technique are likely to be even greater. Intraprostatic 21] have shown in planning studies that IMRT reduces the

178 The British Journal of Radiology, March 2004

Review article: Clinical use of IMRT: part II
volume of small bowel irradiated to 45 Gy during whole
pelvis radiotherapy (WPRT) both for cervical and uterine
cancer. Portelance et al [20] studied 10 patients with
cervical cancer, treating the uterus, cervix and pelvic and
para-aortic nodes to 45 Gy in 25 fractions. They compared
4-, 7- and 9-field Corvus plans delivered by DMLC with a
4-field box technique and showed a 5867% reduction in
the volume of small bowel irradiated to more than 45 Gy
with IMRT that increased with the number of fields, but
not beyond 7 fields.
Roeske et al [21] reported similar results in 10 patients
with cervical or uterine carcinoma, treating the proximal
vagina, parametrial tissues, uterus and pelvic nodes to 45 Gy
in 25 fractions. A 50% reduction in the volume of small bowel
irradiated to more than 45 Gy was observed with a 9-field
Corvus plan when compared with 4 field 3DCRT.
Mutic et al [22] used IMRT to escalate the dose to
positive para-aortic lymph nodes identified by PET to
59.4 Gy, and to 50.4 Gy to the para-aortic area while
treating the pelvis with conventional methods. Similar
results were achieved with arc IMRT in Japan [23].
Hong et al [24] developed a technique to treat the
whole abdomen with DMLC IMRT. Five 15 MV intensity
modulated beams were designed to spare the kidneys and
bone marrow resulting in a 60% reduction in the volume
of pelvic bones receiving more than 21 Gy and the same
level of kidney sparing when compared with a conven-
tional anteroposterior (AP)/posteroanterior (PA) 6 MV
treatment.
Early clinical experience in 40 patients with gynaecologi-
cal malignancies who received whole pelvis irradiation
with IMRT, and brachytherapy to the cervix, uterus or
vaginal vault if necessary, showed excellent PTV coverage
(98.1% of the PTV receiving the target dose, with a median
of 9.8% and 0.2% receiving 110% and 115% of the pre-
scription dose, respectively) and reduced acute Grade 2
RTOG gastrointestinal toxicity (60% vs 91%) (p50.002)
and similar acute genitourinary toxicity (p50.22) when
compared with a contemporary cohort of patients receiving
whole pelvis radiotherapy within chemoradiation proto-
cols [25, 26]. A reduction in haematological toxicity was
also observed by this group, in the chemo-IMRT treated
patients, when compared with standard treatment (31% vs
60% grade 2 or greater white blood cell toxicity). This was
attributed to a significant reduction of bone marrow
irradiated, particularly within the iliac crests [27].
Accurate delineation of the pelvic nodes is required for
pelvic radiotherapy in these patients and guidelines for the
target volume definition have been proposed by Chao et al
[28] using lymphangiography to determine the greatest
distance from lymph node to vessel and pelvic side wall as
a guide to CTV definitions on CT.
IMRT has been shown to provide improved dose dis-
tributions (Figure 3) when treating the pelvic nodes in the
setting of both uterine and cervical carcinoma, with a
reduction in the volume of small bowel irradiated beyond
45 Gy. The data currently available does not allow
separate conclusions with regards to uterine and cervical
cancer and primary and post-operative treatments. Another
issue is whether IMRT could be a substitute for brachy-
therapy. In our opinion this is unlikely as brachytherapy
offers the advantage of organ immobilization and very
conformal dose distributions with steep dose gradients,
which, so far, have not been achieved with IMRT.
The British Journal of Radiology, March 2004
Figure 3. A dose distribution for adjuvant pelvic node irradia-
tion for endometrial cancer.
Grade 3/4 bowel toxicity following conventional radio-
therapy is reportedly low, but Grade 1 and 2, with their
potential impact in the patients quality of life is most
likely under-reported. IMRT has an important role to play
in future clinical studies evaluating possible reductions in
bowel toxicity and their impact on quality of life following
whole pelvis radiotherapy.
Upper gastrointestinal tumours
Oesophagus
Nutting at al [29] found that a 9-field Corvus plan had
no advantages over 3DCRT but that a 4-field plan reduced
the mean lung dose from 11 Gy to 9.5 Gy (p50.001).
Pancreas
Forward-planned and inverse-planned IMRT and pro-
ton therapy were evaluated in the treatment of pancreatic
and biliary duct tumours by Zurlo et al [30]. Proton
therapy was superior to both IMRT techniques in both
PTV coverage and normal tissue sparing.
Landry et al [31] predicted a reduction in bowel com-
plication probability for pancreatic tumours using inverse-
planned IMRT designed to deliver 61.2 Gy to the gross
tumour volume (GTV) and 45 Gy to the CTV. An attempt
by Crane et al [32] to escalate both the radiation dose and
gemcitabine dose using IMRT resulted in dose limiting
toxicity in all 5 evaluated patients.
Second malignancy with IMRT
An important issue with IMRT treatment delivery is
that it requires a substantial increase in monitor units
per target dose, therefore possibly increasing the risk of
secondary malignancies outside the treatment area. In
addition, the use of multiple fields in IMRT increases the
volume of tissue receiving a low dose of radiation. Dorr
et al [33] suggested that the majority of secondary
malignancies are seen within 2.5 cm inside to 5 cm outside
the margin of the PTV. Verellen et al [34] calculated the
estimated whole-body equivalent dose for IMRT (1969 mSv)
and conventional (242 mSv) delivery of 70 Gy with 6 MV
photons. Using the nominal probability coefficient for a
179

lifetime risk of excess fatal cancer (recommended by the
ICRP 60) they suggested an increase in the risk of
secondary malignancies by a factor of 8. Hall [35] has
suggested that IMRT will almost double the incidence of
second malignancies, from about 1% with conventional
radiotherapy to 1.75% for patients surviving 10 years.
Long-term follow up of patients currently treated with
IMRT is essential to evaluate accurately the risk of second
malignancies in this group.
Breast cancer
Post-operative radiotherapy in women with breast
cancer has been shown to improve locoregional disease-
free survival [36] and overall survival [3739] in several
series. The Early Breast Cancer Trialists Collaborative
Group (EBCTCG) meta-analysis [36] suggested that
radiation improved breast cancer-specific mortality but
this was offset by an increase in deaths from cardiovas-
cular disease. This was not apparent in the first 9 years
after treatment and this study included trials that used
radiotherapy techniques and equipment considered sub-
optimal by todays standards. Further studies have failed
to show conclusively a difference in cardiac-related mor-
tality [40, 41], and no differences in cardiac mortality
between right and left sided breast irradiation have, so far,
been identified. However long term follow up is necessary
to evaluate fully the risk of cardiac toxicity, as this risk
increases with time, and new radiation techniques such as
IMRT offer the potential to reduce dose delivered not only
to the left ventricle, but also the lung.
Treatment to the whole breast with standard tangential
fields produces rather inhomogeneous dose distributions
due to the variations in thickness across the target volume,
in particular in large breasted patients [42]. The underlying
ribs, lung and apex of the left ventricle are in part included
within the same isodose as the target volume and hot spots
are often found in areas of reduced tissue thickness, such
as the superior and inferior aspects of the chest wall
included in the radiotherapy field. These dose inhomo-
geneities may lead to increased late skin toxicity (poor
cosmesis, fibrosis, pain) and increased cardiac and lung
morbidity.
The dosimetric advantages of IMRT have been eva-
luated in several planning studies. Evans et al [43, 44]
described the use of portal imaging in determining the
relative thickness of breast and lung followed by the design
of an automatic dose calculation algorithm to determine the
optimum beam profile that allowed delivery of intensity
modulated beams, first with custom-made compensators,
and then with static multileaf collimation (SMLC) [45, 46]
(Figure 4). A 25% reduction in the dose encompassing
20% of the coronary artery region in left breast treatments,
and a 42% reduction in the mean dose to the contralateral
breast using DMLC was shown by Hong et al [47]. There
was also a 30% reduction in the ipsilateral lung volume
receiving more than the 46 Gy prescribed dose and
improved homogeneity across the target volume, particu-
larly in the superior and inferior regions of the breast. Li
et al [48] used four intensity modulated photon beams
combined with an electron field to show a reduction in the
dose to the ipsilateral lung and heart. Several planning
studies [4951] have also shown these dosimetric advantages
and Landau et al [52] showed improved cardiac sparing with
180
M T Guerrero Urbano and C M Nutting
Figure 4. Isodose comparisons between standard conventional
radiotherapy and intensity-modulated radiotherapy (IMRT) for
breast cancer. Image provided by the Breast Technology
Group, Royal Marsden Hospital/ Institute of Cancer Research,
Sutton, Surrey, UK.
IMRT. This is of importance when considering treatment
of the internal mammary nodes, which has been shown to
improve disease free survival in high risk patients [53].
Remouchamps et al [54] showed that a significant reduc-
tion in the V30 heart volume to 3.1% is possible, with 2
direct tangential IMRT fields, as well as a mean lung V20
to 15.2% using moderate deep inspiration breath hold
using an active breathing control system when compared
with free breathing. In post-mastectomy patients, Krueger
[55] showed an increased volume of contralateral breast
was treated and increased contralateral lung dose with
IMRT. Hurkmans et al [56] showed a 50% reduction in the
NTCP for late cardiac toxicity.
Vicini et al [57] reported 281 patients with early stage
breast cancer treated with breast conserving surgery,
followed by whole breast radiotherapy using SMLC
IMRT with a median number of 6 SMLC segments required
per patient. Good dose homogeneity was reported with a
median volume of breast receiving .105% of the pre-
scribed dose of 11%. 97% of patients experienced acute
skin toxicity grades 12.
A randomized controlled trial of 300 patients comparing
IMRT with standard wedged tangential fields finished
recruitment in 2000 at The Institute of Cancer Research
and Royal Marsden Hospital [58]. The primary endpoint is
late toxicity, measured with external photographic review
and clinical and patient assessment. An analysis of the
positional distribution of dose showed doses above 105%
of that prescribed in the upper or lower breast regions in
only 4% of patients treated with IMRT versus over 70% of
patients treated with standard techniques [59] (Figure 4).
This analysis will allow effective correlation of dosimetry
and clinical effects.
IMRT has also been shown to reduce the volume of
ipsilateral lung treated beyond 15 Gy in a patient with
pectum excavatum, although this was associated with an
increase in the volume of heart, spinal cord and con-
tralateral breast and lung receiving low-dose irradiation
[60].
The British Journal of Radiology, March 2004
Review article: Clinical use of IMRT: part II
Conclusions
IMRT dose distributions have been shown, for a num-
ber of tumour types, to offer potential improvements in
clinical outcomes. Planning studies have demonstrated
which tumour types have the largest potential gains and
small clinical studies are beginning to report short-term
outcome data from patients. Most of these reports are
small Phase I or II trials where there has been no true
comparison of IMRT with the conventional radiotherapy
technique. There is a tendency in some health care systems
to adopt IMRT as standard of care for some tumour types
without full testing in controlled trials. It is the authors
views that IMRT delivery should remain in the context of
clinical trials until such time as these improved dose
distributions have proven clinical benefits for patients.
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The British Journal of Radiology, March 2004