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Clinical Considerations for Automated PET-Based Tumor Localization

Authors: Kevin Dwyer, B.S., Travis Tyson, B.S., Justin Kotrba, B.S., Nishele Lenards, R.T.(R)
(T), M.S., C.M.D., FAAMD, Ashley Hunzeker, M.S., CMD
ABSTRACT
The aim of this study was to evaluate the effectiveness of PET gradient based automated gross
tumor volume (GTV) contouring compared to physicians manually delineated GTV in regard to
maximum diameter, maximum volume, alignment, total number of axial slices and shape.
Fourteen previously treated patients were randomly selected from a pool of patients who
received a diagnostic PET scan for various head and neck (H&N) tumors. Two physicians
contoured GTVs and MIM softwares PET Edge tool was used to generate automated gross
tumor volumes (AGTV) from diagnostic PET scans. The goal was to determine the clinical
feasibility of solely AGTV contouring for clinical treatments in order to increase physician
productivity. Based on the 14 patients 26 volumes, the use of solely AGTV contouring was not
warranted for clinical use. There were frequent errors with misalignment, irregular shapes, low
maximum standardized uptake value (SUV), creating tumor volumes less than 20 cm3, and also
volumes with missing or extra axial slices both inferiorly and superiorly. Though AGTV
contouring alone was not recommended, AGTV contouring paired with user corrections, also
known as semi-automated GTV delineation, was found to be effective in reducing GTV
contouring time. Focusing on common areas of discrepancy with use of semi-automated GTV
contouring is recommended for increasing physician productivity.
Key Words: H&N cancer, GTV contouring, PET, physician productivity.
Introduction
Each year the incidence of cancer increases. In 2012, 14 million cases were diagnosed
worldwide.1 The total number of cases is expected to escalate to 22 million within the next 20
years. The projected increase in incidence is daunting, but the future shows promise due to
progressive treatment techniques. The overall 5-year survival rate of cancer has increased from
around 49% in the late 1970s to nearly 70% in 2011.2 Innovative technology has allowed for

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more benefit and less harm to patients, but it takes more time and consideration to deliver these
complex treatments.
As cancer diagnoses, overall survival rates and treatment complexities have increased, the
time demand on physicians and staff has increased as well. The predicted demand for oncology
services is expected to grow by 40%, while the supply is projected to increase by only 25%;
resulting in a shortage of 2,258 full-time oncologists by 2025.3 Ultimately, this shortage will
hinder a radiation oncologists ability to provide individual, high quality care. Due to this
projection, productivity must be enhanced in order to meet the extreme demand for oncology
services. In order to increase productivity, physicians (and staff) must consider utilizing
automated processes when appropriate.
MIM Software PET Edge is a PET-based auto-contouring tool that automatically
contours a GTV for treatment planning. The supplemental software focuses on improving
workflow and productivity to enrich patient care. The PET Edge tool reduces time spent on
traditional, time consuming, slice-by-slice GTV delineation.4 To define GTV borders, PET Edge
relies on an SUV gradient. An SUV is derived from the amount of fluorodeoxyglucose (FDG)
concentration within the tumor or other highly metabolic cells of the body and is a ratio of
regional radioactivity concentration, measured in mCi/mL, compared to the whole body. The
software was designed to correlate areas of high SUV and contouring automation.
Previous literature has demonstrated the effectiveness of PET imaging for target
delineation in thoracic tumors and automatic contouring. Fogh et al5 evaluated PET based semiautomated GTV delineation based on the overall maximum diameter and volume for tumors
within the thorax. This study demonstrated that the PET Edge AGTV contours maximum
diameter and volume were consistent with what physicians delineated. However, this research
revealed limitations in the AGTV delineation demonstrating that low maximum SUV (2.5-3)
resulted in an overestimation of the GTV contour.5 Similar research, specifically lung and
esophageal cases, revealed that semi-automated GTV generation is effective for increasing
productivity in the clinic.4,5, 6
Another area where PET scans are frequently used is in the H&N region. Physicians
frequently utilize PET scans with FDG for target delineation or metastasis evaluation because
H&N treatment volumes are difficult to delineate from only a CT scan.7 As mentioned, previous

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studies have addressed AGTV delineation in the thoracic region, but there is a gap in the
literature for the H&N region.4,5,6
To narrow the scope of study and fill the literature gap, the focus of this study was on
H&N cases. Over half of newly diagnosed H&N patients have extensive disease involving
regional lymph nodes and 10% have distant metastases.7 A vast majority of physicians utilize
PET scans to aid in localizing a GTV for H&N cases. An axial slice-by-slice analysis, using
Standard Imagings StructSure program, was conducted in this study to examine the accuracy of
AGTV contouring and physician delineated GTV in the H&N region. The purpose of this study
was to evaluate the effectiveness of PET-based AGTV contouring compared to physicians
contoured GTV to determine the clinical feasibility of exclusively using AGTV contouring for
H&N cases.
Methods and Materials
Fourteen patients were randomly selected from a pool of previously treated H&N cancer
patients who received diagnostic PET scans. All patients in this study had disease at various
locations within the H&N, spanning from the inferior aspect of the clivus to a few centimeters
superior of the clavicles. In all, 26 primary and nodal masses were used for comparative analysis.
Two physicians delineated primary and nodal GTV structures on patients simulation CT scan,
using the diagnostic PET-CT (fused using MIM software) in the Eclipse treatment planning
system (TPS). Retrospectively, the PET Edge tool was used to draw the GTV based on the SUV
gradient within the PET-CT scan (Figure 1). To evaluate the effectiveness and accuracy of PET
Edge, the physician delineated GTV was compared to the MIM AGTV contour using Standard
Imagings StructSure software. StructSure analyzes contours; showing areas of congruence in
green, areas that the PET Edge missed in blue and areas that PET Edge drew excessively in red
(Figure 2). Data collected were analyzed quantitatively in Microsoft Excel and qualitatively by
visual, slice-by-slice evaluation of StructSure results.
Tumor volumes were separated into categories for further analysis. The first category
compared volumes greater than 20 cm3 to volumes less than 20 cm3. The second category
separated tumors based upon primary or secondary sites. The third category examined tumors
based on their maximum SUV. The final category examined tumors that had an irregular shape.

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Tumors were classified as irregularly shaped if an axial image contained a GTV contour that was
not close to a rigid circle or oval (Figure 3).
Results
The maximum diameter and volume displayed in MIM was used along with StructSure
software for comparison of the AGTV contour and physician delineated GTV. Maximum volume
and diameter are consistent with previous studies, but StructSure allowed for a more in depth
analysis. Much of the StructSure analysis was quantifiable, but some results were strictly
qualitative because they were based on visual inspection. Quantitative categories included
maximum diameter, maximum volume, primary or nodal volumes, and missing or extra slices.
In terms of evaluation for the volumes greater or less than 20 cm3, physician and MIM
GTV contours were correlated with an R2 value of 0.87 (Figure 4). When broken into tumor
volumes of less than or greater than 20 cm3, it was found that larger volumes were more
consistent with physician contours. Smaller volumes were found to be less reliable (Figure 5).
The accuracy of tumors smaller than 20 cm3 ranged from approximately 0%-100%. After
analysis, it was determined that smaller volumes tended to be nodal volumes.
Nodal volumes were typically smaller than primary volumes. The average percent error
of primary tumors was found to be 51.65% whereas nodal volumes had an average percent error
of 65.53%. When the 4 largest outliers were removed from this data, the average percent error of
primary and nodal volumes had a similar value of about 40%. However, evaluation in terms of
only total volume can sometimes be misleading. Figure 2 shows how similar volumes (in terms
of total size) can be different targets due to misalignment.
No relationship between misalignment and maximum SUV was found, but maximum
SUV was determined to be related to AGTV accuracy. Low maximum SUV (1.5-5) had a
tendency to overdraw the GTV by more than 30% and most often overdrew smaller volumes
(less than 5 cm3). However, for higher maximum SUV, no statistically significant relationship
was found between maximum SUV and AGTV accuracy (p > 0.47). Furthermore, maximum
SUV was found to be unrelated to AGTV size or shape (p >.36).
Of the 8 nodules that were classified as irregularly shaped, 7 of the automated volumes
could not conform to the asymmetrical component. A majority of these tumors were located
around tissue-air borders such as the trachea or larynx (Figure 3). Though the tissue-air interface

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posed difficulties in most cases, a few scans were able to conform to airways or heterogeneous
borders and was not the most frequent dissimilarity between AGTV contours and physician
delineated GTVs.
In addition to the 4 categories, it was noted that the most frequent discrepancy between
physicians and automation was with inferior and superior slices. On average, 5 slices were
missing or drawn extra either inferiorly or superiorly from each volume studied. A t-test based
95% confidence interval found that the true average number of missing or extra slices was
between 3.7 and 6.3 slices. The total number of slices with missing or extra contours ranged from
0 to 14 slices, where slices thickness was 2.5 mm.
Discussion
This study examined the conformity of AGTV contouring to the clinically used physician
delineated GTV. Results demonstrated in Figure 4 show that there is a high correlation between
physician delineated GTV and AGTV contouring in terms of volume. These results are consistent
with previous literature, which supports that AGTV contouring can increase physician
productivity.5,6,8 However, there is reason to believe that this high correlation between volumes
and maximum diameters may be misleading due to observed misalignment and difficulty with
irregular shapes.
Misalignment and irregular shapes can affect the accuracy on the AGTV generation.
Occasionally, the AGTV contour appeared to be shifted in various directions when compared to
the physician delineated GTV, perhaps due to misalignment (Figure 2). Accuracy of maximum
volume and/or diameter does not imply precision in location. Misalignment may be due to errors
with image registration, patient motion or large variations in scan position. Irregular shapes
tended to be around the trachea and larynx. Conformity issues around inhomogeneity borders are
suspected. Automated delineation depends on the amount of FDG uptake in cells and since
airways lack tissue equivalent density, it was reasonable to conclude that these areas were unable
to accumulate FDG and emit a high SUV. Due to this, complete automation is not recommended
in cases near inhomogeneous borders or where misalignment may occur.
In addition to misalignments and GTV irregularity, complete automation was also proven
ineffective by the issues arising with small volumes and a low maximum SUV. The accuracy of
small volumes (less than 20 cm3) ranged from 0%-100% and the average percent error was about

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60%. Tumor volumes with a low maximum SUV (1.5-5) tended to overdraw the GTV by more
than 30%, which was consistent with findings in previous literature.5 These low maximum SUV
tumors were typically smaller volumes (less than 5 cm3), which further supports that smaller
volumes are less accurate for AGTV creation.
The clinical ineffectiveness of complete automation is further demonstrated by the
average total number of either missing or extra slices. A 95% confidence interval found that the
true number of missing or extra contours on axial slices lies between 3.7 and 6.3 slices. Scan and
image registration issues may contribute to the incongruence between AGTV contouring and
physician delineated GTV. Physician expertise and discretion is required in these situations.
Some physicians utilize PET data more exclusively than others when localizing a GTV. Based on
the limitations discovered in research and analysis, AGTV contouring used alone is not
recommended for H&N patients. However, semi-automatic GTV delineation can allow
physicians to use their discretion while still gaining the benefits of increased productivity.4,5,6, 8
Conclusion
Solely PET based GTV automation was deemed insufficient for clinical treatment based
off of this study. However, PET Edge can still be used as a time saving tool, especially for large
spherical tumor volumes and a maximum SUV greater than 5. Utilizing semi-automatic GTV
automation and focusing on areas of discrepancy can increase productivity. It is feasible for
physicians to use PET Edge as a starting point and focus on making corrections 4-6 slices
superior or inferior to the GTV contour, around inhomogeneous borders and give special
attention to volumes less than 20 cm3. Physician experience and discretion is an important
consideration in the use of this technology.
One limitation of this study was the use of only one facility to collect data, specifically,
not enough physician variety was used to determine the effectiveness of gradient based AGTV
contouring. Every physician is considered an expert and every physician contours the GTV
differently from the next. Velazquez et al4 distributed the same PET-CT scan to 5 physicians for
GTV delineation and each GTV contoured by 5 physicians was drawn differently. One potential
benefit of gradient based AGTV delineation is improved consistency between various
physicians GTV contour.4,5,6,8 A prospective study should be conducted due to the known GTV

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variation from physician to physician. Some facilities may find GTV automation more effective
than others.
Further concerns arise from the limitations of PET/CT scan techniques. Simulation CT
and the CT portion of PETs are registered together to create a fusion. However, there is a
significant time difference of about 30-40 minutes to complete the PET portion of the PET-CT
scan. This timeframe contains potential for patient movement and thus misalignment. Other
factors affecting the quality of a PET scan happen within 24 hours of the PET scan and include:
glucose intake, amount of physical excursion, overall weight, and even talking during the scan.
These factors inhibit the quality of scans and may lead to a false positive or negative scan
reading. Differences in patient position during the simulation CT and PET scan can also cause
discrepancies. For these reasons, physicians are often required to exercise their discretion when
delineating GTV volumes. Blind automation could lead to missing targets if all considerations
are not well-thought-out. Although these problems arise with FDG PET scans, there are new
radiopharmaceuticals entering the market with proposed improved accuracy. These improved
methods could overcome the limitations associated with AGTV creation.
New PET radiopharmaceuticals are being used in clinical trials that show promise to
combat some of the limitations with FDG uptake. Currently, FDG and Amyvid are the only
approved radiopharmaceuticals approved for routine use in the United States.9 New
radiopharmaceuticals such as: C-choline (CHO), C-methionine (MET) and fluorothymidine
(FLT), have proven to be superior to FDG for tumor localization.9, C-choline is a biomarker for
measuring the rate of phospholipid synthesis in brain tumors. With CHO, a high activity level is
able to be detected in the brain with a low level of background activity in healthy brain tissue (a
quality FDG does not possess). The final radiopharmaceutical, FLT, is a tracer of tumor
proliferation by identifying areas of DNA synthesis. These improved scanning techniques may
reduce physician discretion and improve the AGTV contouring process.
Although FDG gradient based semi-automatic GTV delineation is effective at increasing
productivity for H&N cases, complete automation still requires development. Utilizing complete
AGTV contouring may become sufficient once new scanning techniques are developed and areas
of discrepancy are addressed. In order to optimize productivity with PET Edge, physicians
should create an AGTV contour and focus on correcting inferior/superior slices, irregular shapes,

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potential misalignment, and give special attention to smaller volumes. Further research should to
be conducted to evaluate the true clinical effectiveness of AGTV delineation.

References

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1. Cancer Statistics. National Cancer Institute website. https://www.cancer.gov/aboutcancer/understanding/statistics. Accessed September 10, 2016.
2. Seigel R, Miller K, Jemal A. Cancer statistics, 2016. J Clin Oncol. 2016;66(1):7-30.
http://dx.doi.org/ 10.3322/caac.21332
3. Yang W, Williams J, Hogan P. Projected supply of and demand for oncologists and radiation
oncologists through 2025: An aging better insured population will result in shortage. J Oncol
Pract. 2014;10(1):39-45. http://dx.doi.org/ 10.1200/JOP.2013.001319
4. Velazquez E, Parmar C, Jermoumi M, et al. Volumetric CT-based segmentation of NSCLC
using 3D-Slicer. Sci Rep. 2013;3(1):3529-3531. http://dx.doi.org/10.1038/srep03529
5. Fogh S, Intenzo C, Farach A, et al. Pathologic correlation of PET-CT based auto contouring
for radiation planning in lung cancer. Int J Radiat Oncol Biol Phys. 2010;78(3):202-203.
http://dx.doi.org/10.1016/j.ijrobp.2010.07.490
6. Zhang G, Han D, Ma C, et al. Gradient-based delineation of the primary GTV on FLT PET in
squamous cell cancer of the thoracic esophagus and impact on radiotherapy planning. Rad
Oncol. 2015;10(1):11-18. http://dx.doi.org/doi: 10.1186/s13014-014-0304-5
7. Head and Neck cancer. American Society of Clinical Oncology web site.
http://www.cancer.net/cancer-types/head-and-neck-cancer/statistics 2015. Accessed
September 12, 2016.
8. Werner-Wasik M, Choi W, Ohri N, et al. Comparison of PET contouring methods in patients
with early stage resected non-small cell lung cancer (NSCLC): A pathologic-imaging
correlation. Int J Radiat Oncol Biol Phys. 2010;3(1):32-33.
http://dx.doi.org/10.1016/j.ijrobp.2013.06.1429
9. DSouza M, Sharma R, Tripath M, et al. Novel positron emission tomography radiotracers in
brain tumor imaging. Indian J Radiol Imaging. 2011;21(3):202-208.
http://dx.doi.org/10.4103/0971-3026.85369
10. Troost E, Busslink J, Hoffmann A et al. 18F-FLT PET/CT for early response monitoring and
dose escalation in oropharyngeal tumors. J Nuc Med. 2010;51(6):866-874.
http://dx.doi.org/10.2967/jnumed.109.069310

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Figures

Figure 1. MIM softwares PET Edge showing SUV uptake in right neck and the crosshairs
used to drag over an area of interest for GTV automation.

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Figure 2. StructSure evaluation report of a physician delineated GTV (primary) and an

AGTV (secondary). Green shows common overlap, red shows extra drawn by
automation, blue shows areas that the physician delineated; where automation failed. Although
total volumes and maximum diameter may be similar in this figure, it can be seen that the AGTV
is shifted anteriorly and to the left.

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Figure 3. Shows PET Edges trouble with irregularly shaped tumors from 3 different patients.

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GTV Comparison (cm3)

120
100
f(x) = 0.77x - 1.21
R = 0.87

80
Physician GTV

Volume Comparison
Linear (Volume Comparison)

60
40
20
0
0

20

40

60

80

100

120

140

MIM GTV

Figure 4. MIM and Physicans GTV volumes (cm3) plotted together. A linear line with a slope of
1 is expected if AGTV and physician contours aligned perfectly. The slope is 0.74 and the R2
value is 0.87.

GTV Comparison < 20 (cm3 )

10
9
8
7
6
Physician GTV

Linear ()

5
4

f(x) = 0.09x + 2.89

R = 0.01

3
2
1
0
0

10

12

MIM GTV

Figure 5. Volumes less than 20 cm3 delineated by MIM and physicians plotted together.
Demonstrating that smaller volumes were less consistent with what physicians contoured.

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