1
Hypofractionation to maximize tumor biological effective dose while maintaining chest wall
tolerance in the treatment of peripherally located non-small cell lung cancer: A Case Study
Authors: Amanda Lisher, B.H.S., R.T.(R)(T), Jonathan Taylor, B.S.,
Peter Hirschi, B.S., R.T.(R)(T), Nishele Lenards, M.S., CMD, R.T.(R)(T), FAAMD, Ashley
Hunzeker, MS, CMD, Anne Marie Vann, MEd, CMD, R.T.(R)(T), FAAMD
Medical Dosimetry Program at the University of Wisconsin - La Crosse, WI
Abstract:
Introduction: The purpose of this case study was to communicate the use of alternative
fractionation schemes to maximize tumor biological effective dose (BED) while maintaining
normal tissue tolerances in the treatment of non-small cell lung cancer (NSCLC).
Case Description: A patient presented with sarcomatoid carcinoma of the left upper lung and
was prescribed stereotactic body radiation therapy (SBRT) of 50 Gy in 5 fractions. Treatment
planning revealed unacceptable dose to the chest wall, therefore the prescription was modified to
70.04 Gy in 17 fractions to maintain equivalent tumor BED while reducing chest wall BED. The
patient successfully completed treatment and reported absence of chest pain or rib fracture at 4month follow up.
Conclusion: The prescription was modified to maintain equivalent tumor BED while reducing
chest wall BED. Dose fractionation was modified to 70.04 Gy in 17 fractions and resulted in a
chest wall BED reduction from 217 Gy to 166 Gy, while the tumor BED had only a slight
decrease from 100 Gy to 99 Gy. This case supports the concept that alternative fractionation
regimens that provide equivalent tumor BED are an effective option for lowering chest wall
toxicity while maintaining similar tumor control for patients with inoperable peripherally located
NSCLC.
Key words: hypofractionation, lung cancer, chest wall constraints
Introduction
Lung cancer is the second most common diagnosed cancer among men and women,
causing an estimated 25% of all cancer-related deaths in 2014.1 Lung cancers are broadly
classified into two groups: small cell lung cancers (SCLC) and non-small cell lung cancers
(NSCLC). Approximately 80% of all lung cancers are NSCLC.2 Etiologic factors of lung cancer
include smoking, alcohol consumption, air pollution and heredity. The preferred treatment for
2
stage I NSCLC is surgical resection, however, some cases of early stage NSCLC are considered
inoperable due to poor performance status of the patient.2
Historically, radiation therapy (RT) has been the standard management therapy for
unresectable NSCLC. However, outcomes have been poor when compared with surgical
management. High rates of local failure have been reported with conventional doses of 1.8-2.0
Gy per fraction.2 Several studies have evaluated the effect of increasing fractional dose in an
effort to improve disease-free survival and results have shown that SBRT is an effective
alternative to surgical resection for early stage NSCLC.2,3 Xia et al4 reported a 95% control rate
at 3 years for inoperable stage I/II NSCLC treated with a SBRT dose of 50 Gy in 5 fractions.
Unfortunately, SBRT is not always possible due to limitations of normal tissue dose
tolerance. For patients with inoperable peripherally located lung cancer, the chest wall is
especially sensitive to dose escalation. Dunlap et al5 studied peripheral lung SBRT and observed
severe pain and/or rib fracture at a volume threshold of 30 cc receiving a dose of 30 Gy. In
addition, Dunlap et al5 found severe chest wall toxicity reported in 30% of patients receiving 30
Gy to a chest wall volume of 35 cc.
A hypofractionated schedule can provide equivalent results with decreased toxicity when
SBRT is not possible due to normal tissue constraints.6 The effects of RT on normal tissue
correlate not only with total dose received, but also with dose per fraction and dose rate. The
concept of BED has been used to equate the effects of different fractionation regimens on both
normal tissue and tumor volumes.2 Various predictive models of BED have been utilized to
determine dose schedules that deliver maximal dose to the tumor while minimizing dose to
normal tissues.3,7 One traditionally accepted method for calculating BED is the equation: BED =
nd{1 + (d / α/β)}, where n = number of fractions, d = dose per fraction, and α/β is a ratio
representing inherent biological characteristics of tissue.2 Guckenberger et al8 retrospectively
studied treatment data and outcomes of 509 lung cancer patients treated with varied SBRT
fractionation schemes and found that BED was the most significant factor in predicting 3-year
freedom from local progression (FFLP) and overall survival (OS). Of the 509 patients in the
Guckenberger et al8 study, patients who received treatment resulting in a tumor BED greater than
106 Gy achieved a 3-year FFLP of 92.5% and a 3-year OS of 62.2%.
Selecting a hypofractionation schedule that allows for a shorter overall treatment time has
been shown to maximize tumor BED while reducing normal tissue complications when SBRT is
3
not an option due to potential harm to normal tissue.3 Bogart et al6 assessed outcomes on various
hypofractionated lung treatment regimens and reported results comparable to SBRT with less
toxicity. The results suggest that when SBRT is not a safe treatment option, the RT course
providing the shortest overall treatment time and a BED similar to SBRT can minimize damage
to normal tissue with acceptable tumor control.
Case Description
Patient Selection and Setup
A 59-year-old man was referred to the radiation oncology department for definitive
management of sarcomatoid carcinoma of the left upper lung. A routine CT of the chest in
November 2014 revealed a 4.2 cm mass in the left upper lobe. A follow-up PET scan in
December 2014 revealed significant metabolic activity in the lung lesion, with a standard uptake
value (SUV) of approximately 30. The patient was not considered at risk for pneumothorax,
therefore, the lung lesion was biopsied in late December 2014. Findings were consistent with
Stage IB, T2aN0M0 sarcomatoid carcinoma. Routine CT staging of the head was negative for
metastatic disease.
Based on the patient’s poor lung function as a result of severe COPD, the radiation
oncologist determined the patient was not a reasonable candidate for surgical resection. Research
demonstrated that SBRT in medically inoperable patients offers equal opportunity for local
control, in the range of 80-88%, with a 10-15% chance of developing regional nodal disease
and/or metastatic disease in distant organs within 3 years.2,3 The radiation oncologist’s major
concern was possible loss of lung function in the treated area. Due to the patient’s history of lung
disease, a 5% decrease in lung function could have had a significant clinical impact. The
physician estimated the risk of developing decreased breathing function following SBRT in the
range of 10-20%. Due to the lateral location of the tumor in the left lung, the physician also
approximated the risk of radiation-induced rib fracture to be in the range of 10-20%. The patient
chose to proceed with SBRT.
A treatment planning simulation was performed on a GE LightSpeed CT scanner. A
custom Medical Intelligence BodyFIX Vac-Lok was constructed for immobilization. The patient
was positioned supine on the CT table with both arms above the head, supported by the Vac-Lok.
A pillow was placed under the head, with an angle sponge under the knees for comfort. After the
4
Vac-Lok was made, a plastic sheet was placed over the patient and secured to the BodyFIX with
double-sided adhesive tape. Using a vacuum, the air was removed from the space between the
Vac-Lok and the plastic overlay to tighten the plastic over the patient in order to limit movement
during the stereotactic treatments (Figure 1). Treatment planning CT images were obtained at 2.5
mm intervals through the thoracic region. Scans were acquired during normal breathing,
inspiratory breath hold and expiratory breath hold to assess the maximum range of tumor
movement.
Target Delineation
Following simulation, the CT data sets were uploaded to the Philips Pinnacle3 v9.8
radiation treatment planning system (TPS). The medical dosimetrist contoured the organs at risk
(OR), including the spinal cord, heart and great vessels, right and left lung, combined lung,
trachea and main bronchus, and the left chest wall. The radiation oncologist contoured the gross
tumor volume (GTV) on the unregulated breathing scan. This scan was then fused with the
inspiratory and expiratory breath hold scans and the physician expanded the GTV contours to
include the full range of tumor movement during respiration. The final GTV was uniformly
expanded by 0.5 cm to create the planning target volume (PTV).
Treatment Planning
The radiation oncologist prescribed a total dose of 50 Gy to be delivered in 5 fractions.
The medical dosimetrist placed the isocenter near the center of the GTV, approximately 2 cm
from the left lateral chest wall. Gantry angles were selected to minimize entry dose to the
contralateral lung. A total of 8 coplanar beams were used for this plan. Treatment angles
included 180, 210, 350, 20, 50, 80, 120, and 150 degrees. No couch rotations or collimator
angles were required. The medical dosimetrist set field sizes for each treatment beam to
encompass the entire PTV plus a 1 cm margin. Heterogeneity correction factors were applied to
account for differences in attenuation in the various tissue densities in the thorax.
Prior to optimization, the medical dosimetrist entered treatment objectives into the
Pinnacle3 inverse planning window. Initial objectives included a minimum GTV dose of 50.5 Gy,
a minimum and uniform PTV dose of 50 Gy, and a maximum dose of 47.50 Gy (95%) to a 4 mm
expanded tuning ring. The direct machine parameter optimization (DMPO) algorithm was
utilized for planning. Following the first optimization, the dose distribution was analyzed to
assess dose to adjacent structures. Due to the lateral location of the tumor and the conformity of
5
the treatment beams, dose to the spinal cord, heart and great vessels, esophagus, and combined
lung was well within tolerance. However, the treatment planning CT revealed interval
progression of the tumor, which was then approaching 5 cm with invasion into the chest wall.
Current recommendations for SBRT are that less than 30 cc of the chest wall receive a total dose
greater than 30 Gy, and a daily dose less than 10 Gy.9 Researchers noted a significant increase in
chest wall toxicity, namely pain, fracture, and fibrosis, with increasing dose.5,10 Given the
tumor’s progression, both the GTV and PTV encompassed a portion of the left ribs (Figure 2),
making it extremely difficult to meet the chest wall constraint without compromising dose to the
PTV.
In radiation oncology, the goal is to provide maximum tumor control while respecting the
limitations of healthy tissues. Historically, a larger daily dose has been associated with increased
long-term normal tissue complications.10 The radiation oncologist determined that SBRT would
be unsafe in this case, due to the risk of chest wall injury and subsequent chronic rib pain.
However, given the aggressive nature of the tumor, the physician felt strongly this patient would
benefit from hypofractionated treatment and larger daily doses.
Research has shown that BED is an accurate predictor of the effects of various treatment
fractionations on both tumor and normal tissue.3,6,7 In a Phase I study of accelerated conformal
radiotherapy for medically inoperable patients, Bogart et al6 evaluated BED for several
hypofractionated schedules in an attempt to determine the maximally accelerated course of
radiotherapy that could be tolerated by patients with a history of lung dysfunction. The shortest
course of RT evaluated by Bogart et al6 was 17 fractions of 4.11 Gy. After an average follow-up
of 53 months, local recurrence was reported in only 7% of patients and treatment was welltolerated in all patients, with no reports of subsequent chest wall pain or late toxicity.6 In order to
maintain tumor control while reducing long-term chest wall toxicity, and based on the data from
the Bogart et al2 study, the radiation oncologist modified the treatment prescription to a dose of
70.04 Gy in 17 fractions.
Treatment planning volumes were kept at the original SBRT margins, which maintained
the ideal rapid dose fall off outside of the PTV. Inverse planning objectives were modified to
reflect the updated prescription. Plan optimization demonstrated an acceptable dose to the local
OR and reduced daily dose to the adjacent chest wall (Figure 3). The plan was normalized to the
97% isodose line, which resulted in an actual PTV mean dose of 72.16 Gy. The final isodose
6
distribution for the modified hypofractionated plan is demonstrated in Figure 4. Treatment was
delivered on a Varian 23iX linear accelerator. Patient position was verified daily with kV image
guidance. A kV cone beam CT (CBCT) was completed once each week to assess tumor volume
within the original contours. No plan adjustments were needed.
Plan Analysis and Evaluation
Current recommendations for SBRT are less than 30 cc of the chest wall to receive a total
dose greater than 30 Gy, and a daily dose less than 10 Gy.9 Exceeding chest wall tolerance dose
has been shown to increase chronic pain and late complications such as fracture and fibrosis.5,10
At the originally prescribed dose of 50 Gy in 5 fractions, 100.5 cc of the left chest wall received
a dose of 30 Gy. The volume of chest wall adjacent to the PTV received a maximum daily dose
of 10.63 Gy, and a mean daily dose of 4 Gy. In this case, the physician determined SBRT to the
tumor would result in unacceptable dose to the left chest wall, and would put the patient at risk
for increased long-term complications. Research has shown a fractionation schedule that allows a
shorter overall treatment time will afford the greatest tumor control while reducing long-term
complications when SBRT is not feasible.3 Fowler7 noted that shortening the duration of
radiotherapy to lung tumors from the traditional 6-7 weeks to 2.5-3 weeks could increase 3-year
survival rates by as much as 50%. Due to the rapid progression of the tumor, the physician felt
strongly that the patient needed a hypofractionated course of radiation therapy that would result
in equal tumor control while sparing the chest wall.
In a study evaluating the shortest course of radiation therapy that provided BED
equivalent to lung SBRT, Bogart et al6 demonstrated that a hypofractionated course of 70.04 Gy
in 17 fractions resulted in equal BED to the target while reducing BED to normal tissues.
Research has demonstrated that survival increases with SBRT fractionations which result in a
BED greater than 100 Gy.2,8 In the current case study, in order to select the fractionation that
afforded tumor control equivalent to SBRT, BED for several treatment schedules could be
compared utilizing the equation BED = nd{1 + (d / α/β)}2 (Table 1). Assuming an α/β ratio of 10
Gy for tumor effects and 3 Gy for normal tissue, the original SBRT prescription of 50 Gy in 5
fractions resulted in a tumor BED of 100 Gy, and a normal tissue BED of 217 Gy. Based on
results of the Bogart et al6 study, the radiation oncologist decided on a modified prescription of
70.04 Gy in 17 fractions, which afforded a tumor BED of 99 Gy and a normal tissue BED of 166
Gy. At the modified prescription, approximately 24.45 cc of the chest wall was located within
7
the PTV, which received a mean daily dose of 1.65 Gy and a maximum daily dose of 4.28 Gy.
These doses were well within the acceptable chest wall constraint of less than 10 Gy per fraction.
The final hypofractionated plan resulted in acceptable dose to the spinal cord, heart, esophagus,
and combined lung, as well as a more favorable daily dose to the adjacent chest wall.
Conclusion
Research has suggested hypofractionated treatments at equivalent BED are a practical
consideration when selecting an alternative to SBRT for lung cancer.3,7,8 Although BED cannot
be the sole determinant of fractionation, BED was a significant factor in determining 3-year
FFLP and overall survival.8 The patient in this case study was unable to receive SBRT due to
recommended chest wall dose constraint limitations. By changing the fractionation scheme from
50 Gy in 5 fractions to 70.04 Gy in 17 fractions the normal tissue BED to the chest wall was
lowered from 217 Gy to 166 Gy, while the tumor BED was slightly decreased from 100 Gy to 99
Gy. The hypofractionated alternative delivered the desired BED to the target while minimizing
fractional dose to the abutting chest wall.
At a 4-month follow-up appointment, a chest CT revealed interval decrease in the size of
the treated lung disease. Although reporting slight worsening of lung function since completing
radiation, the patient denied symptoms of chest pain or rib fracture as a result of the successful
BED fractionation scheme prescribed by the radiation oncologist. The current case study
supports the concept that alternative fractionation regimens that provide a tumor BED equivalent
to SBRT are an effective option for lowering chest wall toxicity while providing optimal tumor
control for patients with inoperable peripherally located NSCLC.
8
References
1. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64(1):9-29.
http://dx.doi.org/10.3322/caac.21208
2. Videtic GMM, Singh AK, Chang JY, et al. A randomized phase II study comparing 2
stereotactic body radiation therapy (SBRT) schedules for medically inoperable patients with
stage I peripheral non-small cell lung cancer. Radiation Therapy Oncology Group (RTOG).
https://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?study=0915. Published
2012. Accessed May 7, 2015.
3. Mehta N, King CR, Agazaryan N, et al. Stereotactic body radiotherapy and 3-dimensional
conformal radiotherapy for stage I non-small cell lung cancer: a pooled analysis of biological
equivalent dose and local control. Pract Radiat Oncol. 2012;2(4):288-295.
http://dx.doi.org/10.1016/j.prro.2011.10.004
4. Xia T, Li H, Sun Q, et al. Promising clinical outcome of stereotactic body radiation therapy
for patients with inoperable stage I/II non-small-cell lung cancer. Int J Radiat Oncol Biol
Phys. 2006;66(1):117-125. http://doi:10.1016/j.ijrobp.2006.04.13
5. Dunlap NE, Cai JC, Biedermann GB, et al. Chest wall volume receiving >30 Gy predicts risk
of severe pain and/or rib fracture after lung stereotactic body radiotherapy. Int J Radiat
Oncol Biol Phys. 2010;76(3):796-801. http://dx.doi.org/10.1016/j.ijrobp.2009.02.027
6. Bogart JA, Hodgson L, Seagren SL, et al. Phase I study of accelerated conformal
radiotherapy for stage I non-small-cell lung cancer in patients with pulmonary dysfunction:
CALGB 39904. J Clin Oncol. 2010;28(2):202-206.
http://dx.doi.org/10.1200/JCO.2009.25.0753
7. Fowler JF. 21 years of biologically effective dose. Br J Radiol. 2010;83(991):554-568.
http://dx.doi.org/10.1259/bjr/31372149
8. Guckenberger M, Allgauer M, Appold S, et al. Safety and efficacy of stereotactic body
radiotherapy for stage I non–small-cell lung cancer in routine clinical practice. J Thorac
Oncol. 2013;8(8):1050-1058. http://dx.doi.org/10.1097/JTO.0b013e318293dc45
9. Benedict SH, Yenice KM, Followill D, et al. TG-101: Stereotactic body radiation therapy.
Med Phys. 2010;37(8):4078-4101. http://dx.doi.org/10.1118/1.3438081
9
10. Woody NM, Videtic GMM, Stephans KL, et al. Predicting chest wall pain from lung
stereotactic body radiotherapy for different fractionation schemes. Int J Radiat Oncol Biol
Phys. 2012;83(1):427-434. http://dx.doi.org/10.1016/j.ijrobp.2011.06.1971
10
Figures
Figure 1. Patient positioned for simulation in the Medical Intelligence BodyFIX Vac-Lok with
plastic overlay to limit respiratory motion.
11
Figure 2. Simulation images showing progression of tumor into the left chest wall. (Red = GTV,
Pink = PTV, Maroon = chest wall).
RTP System 9
Patient Name:
Patient ID:
Plan Name:
Lock Status:
LEE restored, FRED,
L2710
L LUNG
Not Locked
Date/Time:
2015− 11− 05 11:49:03
Comment:
dvh
Physician/Physicist:
DK/
Revision:
Planner:
Institution:
R03.P02.D03
SMB
MANDY
PTV
Page:
Scaling:
12
GTV
Chest Wall
Great Vessels
Spinal Cord
Esophagus
Combined Lung
Heart
Figure 3. Final DVH for hypofractionated plan, 70.04 Gy in 17 fractions. (Red = GTV, Pink =
PTV, Maroon = chest wall, Lime = great vessels, Orange = esophagus, Yellow = spinal cord,
Purple = combined lung, Green = heart).
1 of 1
Fill Page
13
Figure 4. Final hypofractionated plan isodose distribution at isocenter in relation to the GTV
(red), PTV (pink) and left chestwall (maroon). (Green = 70.04 Gy, Red = 66.55 Gy, Blue = 63
Gy, Purple = 42 Gy, Yellow = 35 Gy, Orange = 21 Gy).
14
Tables
Table 1. Comparison of BED for various lung fractionation schedules.
Calculated BED* for Standard and Hypofractionated Treatment Schedules
Total Dose
(Gy)
70
69.92
70
70.04
50
Number of
Fractions (n)
35
23
20
17
5
*BED = nd{1 + (d / α/β)}
Dose per Fraction
(d)(Gy)
2
3.04
3.5
4.12
10
BED Tumor (Gy)
(α/β = 10 Gy)
84
91
94.5
99
100
BED Chest Wall (Gy)
(α/β = 3 Gy)
117
141
152
166
217