Introduction
Prostate only versus whole pelvis RT has long been a debate
in management of prostate cancer,[-] especially
for patients with clinically high-risk or locally advanced
who have been diagnosed with localized extensive disease
with the presence of invasion of adjacent structures/
extracapsular extension/ seminal vesicle involvement or
a serum PSA >20 ng/mL or a Gleason score of 8-10 without
lymph node involvement or distant metastases. Until
the results of phase III RTOG 0924 trial (NCT01368588)
will highlight the pathway for a standard of care, most
centers continue to offer pelvic radiotherapy for these
patients. As a clinic that does not recommend pelvic radiotherapy
regardless of the extent of their primary tumor
when there is no documented lymph node involvement,
we would like to evaluate whether the cutting edge
technology effect in BM sparing in case of volumetric
arc radiotherapy (VMAT) or intensity modulated radiotherapy
(IMRT) used for standard pelvic fields.
Radiotherapy causes myelosuppresion because of
apoptosis of bone marrow (BM) stem cells and stromal
damage.[] Considering that approximately 40% of the
total body BM is located in the pelvic bones involving
femur, iliac, and sacrum, BM sparing becomes a raising
question to increase treatment tolerability, especially
for patients with pelvic malignancies receiving pelvic
radiotherapy with concurrent chemotherapy. Therefore,
BM sparing was first evaluated in patients with
cervical cancer receiving concurrent radiochemotherapy
as a standard treatment.[,] Compared to conventional
techniques, IMRT was found to be superior in
terms of BM sparing. As grade 2 or more hematological
toxicities were noted to be related with V20 dose of
whole pelvic bone that requires further clinical evaluation,[] a newer study by Liang et al pointed out a functional
BM sparing pelvic IMRT technique based on
18F-FDG-PET and quantitative MRI for gynecological
and anal canal cancers.[] Sini et al.[] prospectively
evaluated 121 patients with prostate cancer who underwent
adjuvant or salvage WPRT and reported that
higher BM V40 was associated with higher acute grade
3 or late grade 2 lymphopenia. In all dosimetric and
clinical studies, IMRT was the only treatment planning
technique that was used to compare conventional techniques
and applied in the clinical routine approach.
Despite ongoing discussions upon prostate only
versus whole pelvis RT approach in patients with
prostate cancer, these patients with pelvic lymph node
metastasis risk greater than 15% were found to be rationale
to be recommended whole pelvic radiotherapy with hormonal treatment.[] IMRT for pelvic nodal
radiotherapy was also noted to promise safer dose delivery
and fewer side effects.[] VMAT has also been
shown to provide equal or superior dosimetric dose
delivery for critical structures such as rectum, femoral
heads, and bladder with an advantage of less treatment
time.[,] Davidson et al reported a VMAT delivery
efficacy with an average 75% reduction of treatment
time and 15%?38% fewer monitor units.[]
A cone-down technique for a patient with highrisk
prostate cancer with a first phase of 46 Gy whole
pelvic and then second phase of 30-32 Gy prostate
and seminal vesicles irradiation could represent one
of the highest prescribed external doses in the pelvic
malignancies. In our study, we intended to evaluate
and compare the ssIMRT and VMAT techniques for
pelvic radiotherapy in terms of pelvic BM doses based
on the plans created for the same patients with highrisk
prostate cancer and to seek any difference in BM
sparing between these two techniques.
Methods
The planned computerized tomography (CT) scans of
10 consecutive patients with prostate cancer treated
by definitive intent to 78 Gy in 39 fractions to prostate
and seminal vesicles at our institution were retrieved
for this institutional review board approved study. The
details of simulation, volume definition, planning, and
comparison are given below.
Simulation
All patients were simulated in the supine position in a
customized vac loc bed in addition to knee-foot stopper
immobilization (CIVCO, Kalona, Iowa). The CT
images with 3-mm slice thickness from above the L4
vertebra down to the trochanter minor were obtained
with full bladder (200?250 cc) and rectal balloon (Radiadyne,
LLC) by the Philips Brilliance Big Bore 16
slice CT (Phillips, Inc.). Bladder scan (Verathon Bladder
Scan BVI 6400) was routinely used to ensure full
bladder before each treatment.
For this study, CTVlymphatic was delineated according
to the Radiation Therapy Oncology Group (RTOG)
consensus guidelines.[15] First phase radiotherapy of
46 Gy was prescribed to whole pelvis; then second phase
of 32 Gy was prescribed to prostate and the proximal
seminal vesicles that was described as CTV2. According
to this study protocol, CTV1 consists of CTVlymphatic
and CTV2. PTV margin was given as 4 mm posterior
and 6 mm in other (including PTVlymphatic) directions. Normal tissues included bowel, bladder, rectum, and
BM reserve that comprised the sacral BM (SBM), iliac
BM (IBM), and ischium, pubis, and proximal femora
(lower pelvis) as femoral BM (FBM). The external contour
of the pelvic bones was delineated on CT scan to
define the BM, as described previously by Mell et al in
the BM sparing of cervix cancer study (Fig. 1).[] The
prescribed total dose was 78 Gy delivered in two phases
of 23 and 16 fractions, respectively.
Fig 1: Anteroposterior and lateral DRRs showing the delineation of sacrum BM (red), iliac BM (light green), and ischium,
pubis, and proximal femora (lower pelvis) as femoral BM (dark green).
To generate VMAT and IMRT plans for each patient,
we used the Pinnacle3 v9.0 treatment planning
system (Philips Medical Systems Inc. Cleveland, OH) that uses Collapse Cone [cc] Convolution algorithm.
The planning objective was to cover the PTV by at least
95% of the prescribed isodose and CTV by 98% of the
prescribed isodose line. Identical objectives were set
for IMRT and VMAT plans. The treatment plans were
generated utilizing the 6 MV Photon beam from the
Varian Triology 120 leaf millennium multileaf collimator
(MLC) (Varian Medical Systems, Palo Alto, CA).
We delivered the plans with a maximum dose rate of
600 MU/min. All calculations utilized a calculation
grid size of 0.3×0.3×0.3 cm. Figure 2 displays the field
arrangements for IMRT and VMAT plans. The rectum planning goals criteria were V80<5%, V75-76<15%, 70
Gy covering less than 20% of the volume, V60<40%,
V30<80%. For the bladder, the goal was V70 Gy<20%.
The femoral heads were limited to receive 50 Gy in less
than 10% of the volume. The small bowel and sigmoid
doses were set <50 Gy and <60 Gy, respectively.
Fig 2: Field design for (a) VMAT using two 360° arcs with the same isocenter rotating clockwise and counter-clockwise
starting from 182° and 178° with a 10° collimator angle and (b) ssIMRT using eight non-coplanar or coplanar
beams (225°, 260°, 295°, 330°, 30°, 65°, 100°, 135°).
ssIMRT
Step-and-shoot IMRT plans were generated according
to our clinical practice using eight non-coplanar or
coplanar beams (225°, 260°, 295°, 330°, 30°, 65°, 100°,
135°). Multiple segments (80?120) were created using
the direct machine parameter optimization (DMPO)
algorithm of Pinnacle3.
VMAT
The VMAT plans were generated using two 360° arcs
with the same isocenter rotating clockwise and counter-
clockwise starting from 182° and 178° with a 10°
collimator angle. Collimator angle was fixed to 10° to
minimize the effects of interleaf leakage and tongueand
groove effect. For both the ssIMRT and VMAT
plans, the same dose objectives and weightings were
used.
The comparison between plans based on analysis of
dose volume histograms was performed for V5, V10,
V20, V30, V40 of SBM, IBM, and FBM, V20, V30, V40,
V70 for bladder, and V30, V40, V76, V80 for the rectum,
homogeneity index (homogeneity MDPD=MD/
PD; MD: Max Dose; PD: prescribed dose), and the
monitor units (MU). The two different techniques were
statistically compared using a two-tailed pair-wise Wilcoxon
signed-ranked test. A value of p<0.05 was considered
statistically significant.
Results
Table 1 displays a comparison of average DVH parameters
to SBM, IBM, and FBM receiving 5%, 10%, 20%,
30%, and 40% receiving of the prescription dose. The
average doses, which were achieved by ssIMRT and
VMAT, were comparable. V20 values for SBM and
FBM were 92.1% and 74.5% for ssIMRT, 92.4% and
74.5% for VMAT. The V10 and V20 values for IBM
is higher with VMAT without statistical significance
(77.8% vs. 80.6%, p=0.05 and 62.3% vs. 67.2%, p=0.23,
respectively).
Table 1: Comparison of average DVH parameters for
ssIMRT and VMAT
The average organs at risk DVHs of bladder and rectum
were similar except V80 for rectum, where VMAT
was found to be statistically superior to IMRT for V80
that was reduced by 43% (1.6% vs. 0.9%, p=0.01).
Figure 3 delineates dose distributions of a representative
patient for axial, coronal, and sagittal views. The
homogeneity index was 1.07 and 1.05 for IMRT and
VMAT planning, respectively (Table 1). VMAT provided
lower MUs (1591 vs. 1048, p=0.01) in comparison
to ssIMRT.
Fig 3: (a, b) Two different level axial views of pelvis for a representative patient showing isodose lines for VMAT (1) and
IMRT (2) plans, (c) coronal and sagittal views of pelvis for the same patient showing isodose lines for VMAT (1)
and IMRT (2) plans.
Discussion
We have evaluated the difference of BM sparing in our
cohort of patients with high-risk prostate cancer between
pelvic VMAT and IMRT plans, and we revealed
that VMAT plans without a specific constraint for BM
are not found to be superior to ssIMRT in terms of BM
reserve irradiation.
Comparison of VMAT and IMRT in prostate cancer
treatment has been ongoing since the last decade.
In many studies, five to nine beams IMRT and one
or two arc VMAT were in charge.[-] VMAT was
mostly found to provide similar, slightly better normal
organ sparing or superior when compared to IMRT.
[-] The time period of planning process, the quality
parameters specific to planning control steps, and
the effort while generating the plan could be significant
divergence parameters in these studies. In our cohort,
we found VMAT very similar to IMRT for pelvic plus prostate and seminal vesicles irradiation based on the
organ at risk parameter limitations except decrement
of very high dose volume percentages on rectum (80
Gy). These results are also consistent with the recent
meta-analysis reported by Ren et al.[] In this metaanalysis,
V40, V60, and V70 of rectum was significantly
decreased by VMAT. On the other hand, no statistical
differences were found in V50 of rectum and V40, V50,
V60, V70 of bladder. Moreover, VMAT has the edge
over IMRT in regards to MUs and treatment time as
our study.
The clinical significance of BM sparing for patients
with prostate cancer is yet not known. However, when
considering elderly population in prostate cancer, sparing
any of the organs at risk would possibly increase
the quality of life in long run. Pelvic IMRT or VMAT
has been often used for most pelvic malignancies, and
despite the ongoing debates, patients with high-risk
prostate cancer have been treated with pelvic IMRT or
VMAT with one of the highest external radiation doses
delivered.[-] These VMAT and IMRT novel techniques
have been compared in many pelvic tumors as
well as for prostate cancer for the ability to reduce the
acute and long-term side effects. A great majority of previous
dosimetric and clinical studies for prostate cancer
focused on the gastrointestinal and genitourinary side
effects related with effect on quality of life, but not on
BM reserve. Considering the prolonging overall survival
rates, patients with high-risk prostate cancer would have
an increased possibly to need chemotherapy at relapse
that requires normal hematological parameters; while
almost 40% of the whole body BM reserve located in the
pelvic bone is partly in the radiation field during pelvic
radiation. In this cohort, we compare routine ssIMRT
technique with VMAT to see if there was any improvement
in homogeneity, better sparing of BM and other
organs at risk. This study was on patients with high-risk
prostate cancer, but these results could easily be extrapolated
for anal canal cancer, rectum, gynecological cancers,
and lymphomas that require pelvic radiotherapy.
Histopathological changes of BM related with radiation
can be detected with as low doses as 4 Gy; doses
above 10 Gy can lead to progressive changes such as
dilated sinusoids, acute hemorrhage, and reduction of
precursor cell; and regeneration is lost with 50 Gy or
more.[] Initial efforts evaluating the BM focused on
iliac crest sparing that shifted the dose to other pelvic
bones shading the BM sparing effect; and Mell et al
demonstrated that lowering the V10 and V20 of pelvic
BM was associated with lower grade 2 or more hematological
toxicity.[,] Lujan et al noted in their cohort
that the BM of lumbosacral spine and lower pelvis
with femur were strongly associated with hematological
toxicity.[] All previous studies only worked on
the prescribed pelvic dose of 45 Gy; and in that range,
V20 of BM exceeding the 80% of the prescribed dose
was pointed out to increase the risk of grade 2 or more
hematological toxicity by a factor of 4.5.[] Though we
prescribed higher doses with a second phase of cone
down to prostate and seminal vesicles up to 78 Gy, both
the iliac and lumbosacral doses in our cohort were
found to be comparable to the study by Mell et al.
Another aspect could be the dose response relation
for secondary cancer,[] and the risk of leukemia
being dose dependent in long-term survivors.[]
Estimated relative risk of leukemia for radiotherapy
doses ≥15 Gy is shown to be 7.8 (95% CI, 1.1-79).
[] Although there is no direct clinical modeling, reduction
in BM doses could also translate into risk reduction
of leukemia for any pelvic malignancies after
pelvic radiotherapy.
Not all parts of the pelvic bone participate in active
hematopoiesis, and the percentages in hematopoiesis
change based on age. One of the two components of
bone is "red" marrow for active hematopoiesis and
other is "yellow" BM including predominantly fat.
[] To visualize red marrow, newer techniques such
as magnetic resonance spectroscopy or functional
single positron emission CT, 18F-Flurodeoxyglucose-
positron emission tomography/CT simulation, and
MRI by use of quantitative IDEAL IQ were defined
in the literature; however, we chose to delineate pelvic
bony structures as a simple and classic way to estimate
the BM that could be a limitation to define the exact
loss in marrow.[,] Instead, we tried to use dose cutoff
points defined previously to extrapolate the loss.
Conclusion
In summary, routine VMAT planning without specific
dose constraint to BM seems not offering additional
benefit to spare BM in comparison to ssIMRT for
pelvic plus prostate and seminal vesicles irradiation.
This finding could easily be extrapolated to other pelvic
malignancies requiring ssIMRT or VMAT in planning,
while VMAT sounds safer on rectum based on reduction
in high-dose volumes in comparison to IMRT
even though both dose volume parameters remain in
acceptable clinical limits.
Peer-review: Externally peer-reviewed.
Conflict of Interest: No conflict of interest.
Financial Support: No financial support.
Authorship contributions: Concept - Y.B.; Design - D.S.;
Supervision - U.S.; Materials - V.A.; Data collection &/or
processing - D.S.; Analysis and/or interpretation - Y.B.; Literature
search - Y.S.; Writing - V.A.; Critical review - U.S.
References
Roach M 3rd, DeSilvio M, Lawton C, Uhl V, Machtay
M, Seider MJ, et al. Phase III trial comparing whole-pelvic versus prostate-only radiotherapy and neoadjuvant
versus adjuvant combined androgen suppression:
RadiationTherapy Oncology Group 9413. J Clin Oncol
2003;21(10):1904-11.
Lawton CA, DeSilvio M, Roach M 3rd, Uhl V, Kirsch
R, Seider M, et al. An update of the phase III trial comparing
whole pelvic to prostate onlyradiotherapy and
neoadjuvant to adjuvant total androgen suppression:
updatedanalysis of RTOG 94-13, with emphasis on
unexpected hormone/radiationinteractions. Int J Radiat
Oncol Biol Phys 2007;69(3):646-55.
Millar J, Boyd R, Sutherland J. An update of the phase
III trial comparing whole pelvic to prostate only radiotherapy
and neoadjuvant to adjuvant total androgen
suppression: updated analysis of RTOG 94-13, with
emphasis on unexpected hormone/radiation interactions:
in regard to Lawton et al. (Int J Radiat Oncol
Biol Phys 2007;69:646-655.). Int J Radiat Oncol Biol
Phys 2008;71(1):316; author reply 316.
Pommier P, Chabaud S, Lagrange JL, Richaud P, Lesaunier
F, Le Prise E, et al. Is there a role for pelvic
irradiation in localized prostate adenocarcinoma?
Preliminary results of GETUG-01. J Clin Oncol
2007;25(34):5366-73.
Mauch P, Constine L, Greenberger J, Knospe W, Sullivan
J, Liesveld JL, et al. Hematopoietic stem cell
compartment: acute and late effects of radiation therapy
and chemotherapy. Int J Radiat Oncol Biol Phys
1995;31(5):1319-39.
Mundt AJ, Lujan AE, Rotmensch J, Waggoner SE,
Yamada SD, Fleming G, et al. Intensity-modulated
whole pelvic radiotherapy in women with gynecologic
malignancies. Int J Radiat Oncol Biol Phys
2002;52(5):1330-7.
Mell LK, Tiryaki H, Ahn KH, Mundt AJ, Roeske JC,
Aydogan B. Dosimetric comparison of bone marrowsparing
intensity-modulated radiotherapy versus conventional
techniques for treatment of cervical cancer.
Int J Radiat Oncol Biol Phys 2008;71(5):1504-10.
Albuquerque K, Giangreco D, Morrison C, Siddiqui
M, Sinacore J, Potkul R, et al. Radiation-related predictors
of hematologic toxicity after concurrent chemoradiation
for cervical cancer and implications for bone
marrow-sparing pelvic IMRT. Int J Radiat Oncol Biol
Phys 2011;79(4):1043-7.
Liang Y, Bydder M, Yashar CM, Rose BS, Cornell
M, Hoh CK, et al. Prospective study of functional
bone marrow-sparing intensity modulated radiation
therapy with concurrent chemotherapy for
pelvic malignancies. Int J Radiat Oncol Biol Phys
2013;85(2):406-14.
Sini C, Fiorino C, Perna L, Noris Chiorda B, Deantoni
CL, Bianchi M, et al. Dose-volume effects for pelvic
bone marrow in predicting hematological toxicity in
prostate cancer radiotherapy with pelvic node irradiation.
Radiother Oncol 2016;118(1):79-84.
Morikawa LK, Roach M 3rd. Pelvic nodal radiotherapy
in patients with unfavorable intermediate and highrisk
prostate cancer: evidence, rationale, and future directions.
Int J Radiat Oncol Biol Phys 2011;80(1):6-16.
Myrehaug S, Chan G, Craig T, Weinberg V, Cheng C,
Roach M 3rd, et al. A treatment planning and acute
toxicity comparison of two pelvic nodal volume delineation
techniques and delivery comparison of intensity-
modulated radiotherapy versus volumetric
modulated arc therapy for hypofractionated high-risk
prostate cancer radiotherapy. Int J Radiat Oncol Biol
Phys 2012;82(4):e657-62.
Kopp RW, Duff M, Catalfamo F, Shah D, Rajecki M,
Ahmad K. VMAT vs. 7-field-IMRT: assessing the dosimetric
parameters of prostate cancer treatment with a
292-patient sample. Med Dosim 2011;36(4):365-72.
Davidson MT, Blake SJ, Batchelar DL, Cheung P, Mah
K. Assessing the role of volumetric modulated arc therapy
(VMAT) relative to IMRT and helical tomotherapy
in the management of localized, locally advanced,
and post-operative prostate cancer. Int J Radiat Oncol
Biol Phys 2011;80(5):1550-8.
Lawton CA, Michalski J, El-Naqa I, Buyyounouski
MK, Lee WR, Menard C, et al. RTOG GU Radiation
oncology specialists reach consensus on pelvic lymph
node volumes for high-risk prostate cancer. Int J Radiat
Oncol Biol Phys 2009;74(2):383-7.
Quan EM, Li X, Li Y, Wang X, Kudchadker RJ, Johnson
JL, et al. A comprehensive comparison of IMRT
and VMAT plan quality for prostate cancer treatment.
Int J Radiat Oncol Biol Phys 2012;83(4):1169-78.
Wolff D, Stieler F, Welzel G, Lorenz F, Abo-Madyan
Y, Mai S, et al. Volumetric modulated arc therapy
(VMAT) vs. serial tomotherapy, step-and-shoot IMRT
and 3D-conformal RT for treatment of prostate cancer.
Radiother Oncol 2009;93(2):226-33.
Bedford JL. Treatment planning for volumetric modulated
arc therapy. Med Phys 2009;36(11):5128-38.
Boylan CJ, Golby C, Rowbottom CG. A VMAT
planning solution for prostate patients using a commercial
treatment planning system. Phys Med Biol
2010;55(14):N395-404.
Kinhikar RA, Pawar AB, Mahantshetty U, Murthy V,
Dheshpande DD, Shrivastava SK. Rapid Arc, helical
tomotherapy, sliding window intensity modulated
radiotherapy and three dimensional conformal radiation
for localized prostate cancer: a dosimetric comparison.
J Cancer Res Ther 2014;10(3):575-82.
Yoo S, Wu QJ, Lee WR, Yin FF. Radiotherapy treatment
plans with RapidArc for prostate cancer involving
seminal vesicles and lymph nodes. Int J Radiat Oncol
Biol Phys 2010;76(3):935-42.
Khan MI, Jiang R, Kiciak A, Ur Rehman J, Afzal M,
Chow JC. Dosimetric and radiobiological characterizations
of prostate intensity-modulated radiotherapy
and volumetric-modulated arc therapy: A
single-institution review of ninety cases. J Med Phys
2016;41(3):162-8.
Ren W, Sun C, Lu N, Xu Y, Han F, Liu YP, et al. Dosimetric
comparison of intensity-modulated radiotherapy
and volumetric-modulated arc radiotherapy in
patients with prostate cancer: a meta-analysis. J Appl
Clin Med Phys 2016;17(6):254-62.
Lujan AE, Mundt AJ, Yamada SD, Rotmensch J, Roeske
JC. Intensity-modulated radiotherapy as a means of
reducing dose to bone marrow in gynecologic patients
receiving whole pelvic radiotherapy. Int J Radiat Oncol
Biol Phys 2003;57(2):516-21.
Mell LK, Schomas DA, Salama JK, Devisetty K,
Aydogan B, Miller RC, et al. Association between
bone marrow dosimetric parameters and acute
hematologic toxicity in anal cancer patients treated
with concurrent chemotherapy and intensity-modulated
radiotherapy. Int J Radiat Oncol Biol Phys
2008;70(5):1431-7.
Schneider U, Sumila M, Robotka J, Gruber G, Mack
A, Besserer J. Dose-response relationship for breast
cancer induction at radiotherapy dose. Radiat Oncol
2011;6:67.
Travis LB, Andersson M, Gospodarowicz M, van
Leeuwen FE, Bergfeldt K, Lynch CF, Treatment-associated
leukemia following testicular cancer. J Natl
Cancer Inst 2000;92(14):1165-71.
Vande Berg BC, Malghem J, Lecouvet FE, Maldague B.
Magnetic resonance imaging of the normal bone marrow.
Skeletal Radiol 1998;27(9):471-83.
Ai J, Xie T, Sun W, Liu Q. Red bone marrow dose calculations
in radiotherapy of prostate cancer based on
the updated VCH adult male phantom. Phys Med Biol
2014;59(7):1815-30.
