Presentation

1. NTCP MODELLING OF ACUTE TOXICITY IN
CARCINOMA CERVIX TREATED WITH
CONCURRENT CHEMORADIATION
MODERATOR: DR. S. CHANDER
SPEAKER: DR. RITUPARNA BISWAS

2. • The aim of radiotherapy is to give sufficient dose to the tumor to achieve tumor
control without introducing severe complications in surrounding normal tissue.
• Modern radiation therapy does very well at shaping dose distributions
• For tumor control, tumor localization + sufficiently high dose (understanding tumor
dose-response) are key
• For each normal tissue of interest, we know the planned dose distribution for the
entire organ volume
• What dosimetric features should be restricted to keep normal tissue complication
risk low?
 Grading schemes: 1 is mild → 5 is lethal
 ‘Low’ is usually ≤ Grade 2 in any grading scheme
INTRODUCTION

3. For some of the most critical organs and sites in radiotherapy, the following problems
are addressed:
The identification of the clinically most relevant signs and symptoms of normal tissue
complications in different organs, i.e. those which cause the most significant
impairment of the quality of life of a patient who has been cured by radiotherapy.
The analysis of the probable pathogenic and pathophysiological mechanisms
involved in the development, progression and compensation of the specific
manifestations of those normal tissue complications which would be relevant to
NTCP modelling.
The investigation of the clinical and experimental evidence for dose and dose-
distribution dependence of the severity and incidence of the different functional
(physiological) and structural (anatomical, pathological) normal tissue damage.

6. Emami et al ( Part of NCI funded CWG on 3D planning: IJROBP 21, 109-122, 1991)
• Literature review up to 1991, 26 complications
– Predates 3D-CRT era; even DVHs were new
• Tabulated estimates of TD50/5 and TD5/5
– Doses for 50% & 5% complication probability at 5 years
– Conventional fractionation: 1.8-2 Gy/Fx
• For many complications, the TD’s increase if less of the organ is irradiated
– Partial irradiation of volume fraction v of organ
– Tabulated TD50/5 and TD5/5 for v=1/3, 2/3 and 1.0

8. 1991 to Now
• CT-simulation is routine
– Plus MRI, PET, 4D-CT
• 3D-CRT is the norm, IMRT explodes
– 3D plan evaluation tools
• Complex dose distributions
• Huge amount of published information
– Some listed in handout bibliography
– Noisy data, various grading schemes, different calculation methods and
plans – tough to sort out
• October 2007: QUANTEC
– AAPM/ASTRO funded workshop on NTCP
– Consensus guidance for clinical use of NTCP studies

10. NTCP models
 Mainly based on data from retrospective or prospective clinical studies
 These models are more indicative of average trends rather than outcomes on
individual patients
 The models are not based on radiobiological concepts of the pathogenesis of
normal tissue damage.
 The risk of complications is generally assumed to depend on the mean dose to the
respective organ or the amount of damaged tissue, described as function of local
dose to that tissue.
 They also assume that radiation effects are local effects (i.e. the fate of tissue
depends on the dose to that tissue alone) and that the severity of the effects can
be characterised by a dose-volume histogram (DVH), or parameters derived from
the DVH

11. Empirical models
– Equations with parameters fit to outcomes data sets
– No mechanistic foundation (except LQ if used)
– Examples: Lyman model, gEUD
• Semi-mechanistic models
– Tissue architecture, as well as cellular radiosensitivity,determine NTCP
– Parameters chosen to fit clinical data
– Examples: Serial (critical element) model, Parallel (critical volume) model,
Relative seriality model

12. ACUTE TOXICITIES IN CARCINOMA CERVIX TREATED WITH
CONCURRENT CHEMORADIATION ARE:
1. ACUTE HEMATOLOGICAL TOXICITIES
2. ACUTE GASTROINTESTINAL TOXICITIES
3. ACUTE GENITOURINARY TOXICITIES ( BUT Quantitative
mathematic modeling of bladder toxicity is lacking)

13. NTCP MODELING OF ACUTE HEMATOLOGICAL
TOXICITIES IN CARCINOMA CERVIX TREATED
WITH CONCURRENT CHEMORADIATION

14. • In patients receiving pelvic RT alone, HT is rarely a problem, due to compensatory increased
hematopoiesis in unirradiated BM.
• When chemotherapy is given concurrently, however, additional BM injury and
myelosuppression predispose patients to HT, making effects of pelvic BM irradiation a greater
concern.
• The reduction of CRT-associated HT could improve tolerance to more aggressive
chemotherapy, potentially enhancing disease control in patients with pelvic
malignancies.Though reported rates of acute HT vary in the literature, grade ≥ 3 HT occurs in
approximately 27% of women undergoing CRT.
• HT can also lead to delayed or missed chemotherapy cycles and treatment breaks, potentially
compromising disease control. Reduction of HT is, therefore, an important goal
• Understanding the effects of radiation in active BM subregions, and refining efforts to
selectively spare active BM could help optimize BM-sparing radiation techniques.
INTRODUCTION

15. RADIATION-RELATED PREDICTORS OF HEMATOLOGIC TOXICITY AFTER CONCURRENT
CHEMORADIATION FOR CERVICAL CANCER AND IMPLICATIONS FOR BONE MARROW–
SPARING PELVIC IMRT
KEVIN ALBUQUERQUE, M.D., F.R.C.S., DAVID GIANGRECO, M.D., COURTNEY MORRISON, B.S.,
MOHAMMED SIDDIQUI, C.M.D., JIM SINACORE, PH.D., RONALD POTKUL, M.D., AND JOHN ROESKE, PH.D.
Int. J. Radiation Oncology Biol. Phys., Vol. 79, No. 4, pp.1043–1047, 2011

16. Purpose: To determine factors predictive for hematologic toxicity (HT) associated with concurrent
chemoradiation for Stage II through IV cervical cancer.
Methods and Materials:
Patients and radiation planning
• Number of patients: 40
• Archived treatment planning CT scans for these women were recontoured to estimate BM volume
radiated. Bony contours of the following were used as surrogates for BM volume irradiated: (1)
lumbosacral region (L5 and sacrum), (2) ilium (iliac crests to superior border of femoral heads), (3) lower
pelvis (pubis, ischium, acetabulum, and proximal femurs), (4) pelvis including 2 and 3, and (5) whole
pelvis including 1 and 4
• All patients received 45 Gy in 1.8-Gy daily fractions by use of 23-megavolt photons with concurrent
weekly cisplatin( 40mg/m2) for 5 to 6 cycles .

17. Hematologic toxicity parameters/data recording
• Variables predicting for HT: age, body mass index, transfusions, and bone marrow volumes irradiated were
included.
• Dose–volume histograms corresponding to the delivered dose for each contoured BM region were generated
• The volume of each region receiving doses were designated as follows: lumbosacral BM–V10, BM–V20,
BM–V30, and BM–V45 and similarly for ilium, lower pelvis, pelvis, and whole pelvis.
• Hematologic toxicity was graded according to the Common Terminology Criteria for Adverse Events (version
3.0)
• Hematologic toxicity of Grade 2 or greater (HT2+) was noted as an event, and statistical correlation was
performed with the possible predictors
Statistical considerations
• Descriptive statistics for all variables were obtained.
• In addition,multiple logistic regression analysis was performed to correlate the risk of Grade 2 HT and above
(HT2+) with the predictors (age,stage, BMI, and BM volumes) being studied.
• A data partitioning technique, known as optimal data analysis was used to define the cut points for the
significant predictors of HT

18. Logistic regression analysis of potential
predictors: only V20 whole pelvis was nearing
significance for predicting HT (p = 0.08).
None of the other clinical parameters—was a
significant predictor for this toxicity.
To further test the association between whole-
pelvis BM dose and HT2+ = Pearson
correlation test.
The correlation between V20 whole pelvis and
the proportion of patients exhibiting HT2+ is
0.8 (p < 0.0001).
A partitioning analysis showed if the V20 of
the whole pelvis exceeds 80%, the risk of
HT2+ developing increases by a factor (odds
ratio) of 4.5 (95%, confidence interval, 1.08–
18.69) (p < 0.05).

19. NORMAL TISSUE COMPLICATION PROBABILITY MODELING OF ACUTE
HEMATOLOGIC TOXICITY IN CERVICAL CANCER PATIENTS TREATED WITH
CHEMORADIOTHERAPY
Brent S. Rose, B.S., Bulent Aydogan, Ph.D., Yun Liang, Ph.D., Mete Yeginer, Ph.D.,
Michael D. Hasselle, M.D., Virag Dandekar, B.S., Rounak Bafana, B.S., Catheryn M.
Yashar, M.D., Arno J. Mundt, M.D., John C. Roeske, Ph.D., and Loren K. Mell, M.D
Int J Radiat Oncol Biol Phys. 2011 March 1; 79(3): 800–807. doi:10.1016/j.ijrobp.2009.11.010

20. PURPOSE—
To test the hypothesis that increased pelvic bone marrow (BM) irradiation is associated with increased hematologic
toxicity (HT) in cervical cancer patients undergoing chemoradiotherapy (CRT), and to develop a normal tissue
complication probability (NTCP) model for HT.
METHODS AND MATERIALS
Patients and Study Design
Biopsy-proven clinical stage I-IVA or recurrent cervical carcinoma, and no prior history of chemotherapy
or pelvic irradiation.
Patients treated with extended field (para-aortic) RT (EFRT) were excluded.
The validation cohort consisted of 44 cervical cancer patients treated with concurrent cisplatin and pelvic
radiotherapy.
Pooled with 37 identically treated patients from a prior study, forming a cohort of 81 patients for NTCP analysis.
Chemotherapy Delivery
Chemotherapy consisted of weekly cisplatin(40 mg/m2;maximum:80 mg) delivered concurrently with external
beam RT.

21. Radiation Simulation, Planning and Delivery, Bone Marrow Delineation
• The majority of patients (41 of 44, 94%) received pelvic IMRT.
• Pelvic radiation dose was 39.6-50.4 Gy in 1.8 Gy daily fractions.
• For each patient, the external contour of all bones within the pelvis was delineated on the planning CT using
bone windows
• Bone marrow was not routinely used as an avoidance structure.
• BM volumes receiving ≥10, 20, 30, and 40 Gy (V10, V20, etc.) were quantified.
Hematologic Toxicity
• All patients had complete blood counts (CBC) with differentials weekly during CRT.
• Endpoints of interest
White blood cell count (WBC), absolute neutrophil count (ANC),and hemoglobin (HGB) nadirs
(during or within two weeks of the end of CRT)
• Hematologic toxicity was graded according to the Radiation Therapy Oncology Group acute
radiation toxicity scoring criteria
.

22. Statistical analysis
• For analysis on the validation cohort, hematologic nadirs were associated
with V10 and V20 using least squares regression.
• Univariate analyses on potential confounders: body mass index (BMI),
age(median centered), race,comorbidity, and clinical stage
• Secondary analyses on the association of hematologic nadirs and other
potentially predictive dosimetric parameters including V30, V40, and mean
BM dose.
• Generalized linear modeling was used to test associations between
hematologic nadirs and dosimetric parameters in the combined cohort,
adjusting for body mass index.
• Receiver operating characteristic curves were used to derive optimal
dosimetric planning constraints

23. RESULTS
Patients characteristics

24. RESULTS
Validation Study
In the subgroup of patients treated with IMRT, univariate β estimates for WBC nadir as a function of
V10,V20, V30, V40, and mean BM dose were −0.055 (p=0.019), −0.055 (p=0.012), −0.029
(p=0.10), −0.025 (p=0.20), and −0.11 (p=0.032), respectively.

25. Generalized Linear Modeling on Combined Cohort

27. Receiver Operating Characteristic curves for grade ≥ 3 toxicity as a function of V10 .The
sensitivity and specificity corresponding to the optimal choice of cutoff is indicated by the
intersection of the left-most diagonal line and the ROC curve.
• The optimal V10 cutoff, indicated by
the upper-left-most point of the ROC
curve, was 95%.
• Patients with V10 ≥ 95% were more
Likely to experience grade ≥ 3 toxicity
(68.8% vs. 24.6%,p<0.001).
• Sensitivity - 44.4%
• Specificity-90.7%
• Positive predictive value for V10 ≥ 95%
were 68.8% (95%CI:58.6%,79.0%)
• Negative predictive value-75.4% (95%
CI:66.0%,84.8%),
• Relative risk - 2.79 (95% CI:1.63,4.79).

28. Receiver Operating Characteristic curves for grade ≥ 3 toxicity as a function of V20
.The sensitivity and specificity corresponding to the optimal choice of cutoff is
indicated by the intersection of the left-most diagonal line and the ROC curve.
• The optimal V20cutoff, indicated by
the upper-left-most point of the ROC
curve, was 76%.
• Patients with V20 ≥ 76% were more
Likely to experience grade ≥ 3 toxicity
(57.7% vs. 21.8%, p=0.001)
• Sensitivity - 55.6%
• Specificity-79.6%
• Positive predictive value for V20 ≥
95% 57.7% (95% CI:46.9%,68.5%)
• Negative predictive value-75.4%
(95% CI:66.0%,84.8%),
• Relative risk -2.64 (95% CI:1.45,4.81)

29. Associations between Dosimetric Parameters and Chemotherapy Delivery
• No significant associations between BM dosimetric parameters and them probability of having ≥ 1
cycle of chemotherapy held.
• The number of cycles of chemotherapy held, however, was significantly associated with V20 on
univariate (β=0.018;95% CI:0.005,0.036, p=.047) but not multivariate (β=0.017; 95%CI:−0.001,0.035,
p=0.066) analysis
In summary, this study lends strong support to the hypothesis that V10 and V20 of pelvic
BM are important predictors of HT in cervical cancer patients undergoing CRT. Efforts to
maintain V10 < 95% and V20 < 76% could significantly reduce HT, but further research is
needed to optimize and determine the clinical significance of BM-sparing techniques.

32. Dose Constraint Recommendations and a Predictive Nomogram of Incidence of
Hematological Toxicity for Cervix Cancer Patients Treated with Concurrent Cisplatin
and Intensity Modulated Radiation Therapy(IMRT)
S. Mutyala et al.

33. • Purpose/Objective(s): To report a predictive complication probability nomogram for HT and propose BM dose
constraint recommendations for IMRT planning for the treatment of cervical cancer.
• Materials/Methods:
 Thirty-seven patients with cervical cancer were treated with IMRT and concurrent cisplatin (40mg/m2/wk).
 Of these pts,18 received extended fieldRT to include paraaortic nodes,29 received a parametrial RT boost,and
35 received HDR brachytherapy.
 Toxicities were scored by RTOG criteria.
 For analysis, BM was re-delineated to include the entire marrow of the lumbosacral (to the superior border of
L1), high pelvic, low pelvic and femoral head regions.
 Resulting dose volume histograms were combined with patient HT data to create a cumulative dose-volume HT
nomogram, from which toxicity prediction isoprobability curves can be generated.
 BM volumes receiving 10 - 50 Gy (V10 -V50) and dose received by 5 - 75% of the total marrow volume (D5 -
D75) were statistically analyzed for associations with HT.

34. Results:
 The distribution of HT was: grade 0 - 4 pts; grade 1 - 4 pts; grade 2 - 9 pts; grade 3 -14 pts; and grade 4 - 6pts.
 Total marrow mean dose (p = 0.018), V10 (p = 0.005), V20 (p = 0.002), V30 (p = 0.026) and D75 (p = 0.005)
were all positively correlated with increasingly severe HT.
 From the dose-volume atlas of HT, several significant dose points that were highly predictive of severe (grade
3 or worse) HT were identified.
 These were V10 ≥95% (complication probability [CP] = 87.5%, p = 0.048), V20≥ 80% (CP = 80%, p = 0.018),
V30 ≥64% (relative risk 2.06, CI 1.45 to 2.93), and D75 ≥ 24.5 Gy (CP = 100%, p = 0.020).
 Radiation of extended paraaortic field (CP = 77.8%, p = 0.008) and several lumbosacral marrow dosevolume
parameters (p <0.05) were also predictive of severe HT.
Conclusions:
 The use of marrow sparing IMRT using total bone marrow dose constraints of V10 <95%, V20<80%,
V30<64%, and D75<24.5 Gy to minimize incidence of HT in patients receiving concurrent Cisplatin and RT for
cervical cancer were recommended.
 Furthermore, this nomogram can be used to predict the risk of HT for an IMRT plan, identify high-risk patients,
and prophylactically prevent HT when possible.

35. NTCP MODELING OF ACUTE GASTROINTESTINAL
TOXICITIES IN CARCINOMA CERVIX TREATED WITH
CONCURRENT CHEMORADIATION

36.  Acute gastrointestinal (GI) toxicity is a common problem for cervical patients undergoing concurrent
chemoradiotherapy
 Clinically significant acute GI toxicity occurs in approximately one third of patients adversely
impacting quality of life and potentially posing an important impediment to treatment with concurrent
multiagent chemotherapy
 Validated normal tissue complication probability (NTCP) models of GI toxicity are needed to provide
evidence for dosimetric guidelines in treatment planning and protocols
 However, validated NTCP models of GI toxicity in cervical cancer, particularly in patients undergoing
chemoradiation, are lacking
INTRODUCTION

37. THE DIFFERENT VOLUME EFFECTS OF SMALL-BOWEL TOXICITY DURING
PELVIC IRRADIATION BETWEEN GYNECOLOGIC PATIENTS WITH AND WITHOUT
ABDOMINAL SURGERY: A PROSPECTIVE STUDY WITH COMPUTED
TOMOGRAPHY-BASED DOSIMETRY
ENG-YEN HUANG, M.D., CHIEN-CHENG SUNG, B.S., SHEUNG-FAT KO, M.D.,
CHONG-JONG WANG, M.D.AND KUENDER D. YANG, M.D., PH.D.

38. • Purpose:
To evaluate the effect of abdominal surgery on the volume effects of small-
bowel toxicity during wholepelvic irradiation in patients with gynecologic
malignancies.
• Methods and Materials:
80 gynecologic patients without (Group I) or with (Group II) prior abdominal
surgery were analyzed.
Computed Tomography (CT) planning system was used to measure the small-
bowel volume and dosimetry.(10% (V10) to 100% (V100) of dose, at 10%
intervals)
The onset and grade of diarrhea during whole-pelvic irradiation were recorded
as small-bowel toxicity.

41. A dosimetric analysis of acute gastrointestinal toxicity in women receiving
intensity-modulated whole-pelvic radiation therapy
John C. Roeske, Dacian Bontaa, Loren K. Mella, Anthony E. Lujana, Arno J. Mundta
Radiotherapy and Oncology 69 (2003) 201–207

42. • Purpose: To identify dosimetric factors correlated with acute gastrointestinal (GI) toxicity in gynecology
patients undergoing intensity modulated whole pelvic radiation therapy (IM-WPRT)
• Material and methods:
 50 patients with cervical (29), endometrial (18) or other (3) gynecologic malignancies received IM-
WPRT (45–1.8 Gy/fraction) between 2/00 and 3/02. T
 26 women (all with cervical cancer) received concomitant chemotherapy (cisplatin, 40 mg/m2/weekly).
Grade 2 acute GI toxicity requiring frequent medications and grade 3–5 toxicities were designated as
clinically significant and analyzed as a function of patient and dosimetric variables.
 In addition to the absolute PTV, the SB and rectal volumes receiving 25, 50, 75, 90, 100 and 110% of
the prescription dose were also evaluated.
 Comparison of proportions was performed using the Pearson chi-square test or Fisher exact test
whenever appropriate.
 Logistic regression analysis (multivariate) was performed on all significant factors from the univariate
analysis.
 The most significant volumetric factors were fit to a normal tissue complication probability (NTCP)
function.

44. A multivariate analysis (logistic
regression) was performed
which included the most
significant factors from the
univariate analysis. The sole
factor that reached statistical
significance in terms of acute
GI toxicity was Vol(SB,100)
P=0.012

45. Normal Tissue Complication Probability Analysis of Acute Gastrointestinal Toxicity in Cervical
Cancer Patients Undergoing Intensity Modulated Radiation Therapy and Concurrent Cisplatin
Daniel R. Simpson, M.D.,* William Y. Song, Ph.D.,* Vitali Moiseenko, Ph.D.,Brent S. Rose, M.D.,* Catheryn M. Yashar,
M.D.,* Arno J. Mundt, M.D.,* and Loren K. Mell, M.D.

46. Purpose:
 To test the hypothesis that increased bowel radiation dose is associated with acute gastrointestinal (GI) toxicity in
cervical cancer patients undergoing concurrent chemotherapy and intensity-modulated radiation therapy (IMRT),
using a previously derived normal tissue complication probability (NTCP) model
Methods:
• FIGO Stage IB-IIIB cervical cancer treated with IMRT and concurrent chemotherapy (consisting of weekly
cisplatin [40 mg/m2]) at the UCSD between July 2006 and February 2010.
• IMRT plans consisted of seven to nine coplanar fields using 6-MV photons. The prescription dose ranged
between 45 and 50.4 Gy (median, 45 Gy)
• An external beam boost of 9.0-14.4 Gy was given after pelvic IMRT in patients with gross nodal disease. Only 2
patients received a simultaneous integrated boost.
• The remainder of patients received a sequential boost after the completion of pelvic external beam RT.
• Patients with intact cervical cancer were treated with a high-dose-rate brachytherapy boost of five fractions of
5.5-6.0 Gy prescribed to point A.
• Toxicity during treatment was graded using the Radiation Therapy Oncology Group Acute Radiation Morbidity
Scoring Criteria(weekly for toxicity from the beginning to the end of external beam RT.)
• Only lower GI events (e.g., diarrhea, bleeding, abdominal pain, distension, etc.) were included as events for
analysis

47. Statistical analysis
• The volume of bowel receiving 5, 10, 15, 20, 25, 30, 35, 40, and 45 Gy (V5-V45) were
included separately in the NTCP models as dosimetric predictors (explanatory variables).
• Model covariates included the log of the body mass index (BMI) as a continuous variable,
Stage IIB as a dichotomous variable, treatment intent (definitive vs. postoperative) as a
dichotomous variable, and field volume (pelvic vs. pelvic para-aortic [extended field]) as a
dichotomous variable.
• Correlations between acute GI toxicity and dosimetric predictors and covariates were tested
using univariable and multivariable logistic regression. Toxicity and dosimetric data were
then fit to a logistic NTCP function:
where V is the volume of bowel receiving a given dose level, V50 is the volume corresponding
to 50% incidence of complications, and g is the normalized slope of the volume-response
curve.
• Fisher’s exact test was used as a nonparametric test of the significance of 2x2 tables of
Grade 2 GI toxicity versus varying dose volume cutoffs.
z

48. Results
Patient Characteristics

49. Descriptive statistics of dosimetric predictors

50. Comparison of average dose-volume histograms for patients with and without acute
Grade 2 gastrointestinal toxicity.

51. Univariable analysis of factors associated with acute gastrointestinal toxicity
NTCP modeling

52. Plot of Fisher’s exact p values from 2x2 tables of the probability of
acute gastrointestinal toxicity versus varying dose-volume
cutoffs.
 In the logistic regression model adjusting for age, BMI,
and postoperative status, the associations between
Grade ≥2 GI toxicity and V35, V40, and V45 remained
statistically significant (OR 1.59, 95% CI 1.04-2.43;OR
1.88, 95% CI 1.08-3.30; and OR 2.40, 95% CI 1.10-
5.21,respectively).
 The smallest volume cutoff values for doses 45 and 40
Gy showing statistically significant association with the
incidence of Grade 2 toxicity were 100 and 170 mL,
respectively.
 The incidence of complications was 60% (18/30) in
patients with V45 >100 mL or V40 >170 mL and 25%
(5/20) in patients whose DVHs were below these cutoff
values (p =0.021).

53. • Increased doses of bowel irradiation are associated with acute GI toxicity
in cervical cancer patients undergoing concurrent pelvic IMRT and
cisplatin
• The odds of acute toxicity increased approximately twofold for every 100
mL of small bowel receiving 45 Gy or more.The V45 =100 mL cutoff was
also associated with increased incidence of toxicity (p=0.021).
• In addition, lower dose-volume metrics (e.g., V35 and V40) may also be
useful in NTCP models.
Conclusion

55. TAKE HOME MESSAGE
The volume of pelvic BM receiving low-dose radiation is associated with HT and chemotherapy
delivery in cervical cancer patients undergoing concurrent chemoradiotherapy.
Increased doses of bowel irradiation are associated with acute GI toxicity in cervical cancer
patients undergoing concurrent pelvic IMRT and cisplatin
volume effects are different between patients with and without abdominal surgery. Low-dose
rather than full-dose volume correlates with acute diarrhea in patients without abdominal
surgery. Full-dose volume can predict acute diarrhea in patients with abdominal surgery
Validated normal tissue complication probability (NTCP) models of acute toxicities are needed
in optimizing IMRT dosimetric planning, plan evaluation, and for clinical research protocols.

56. THANK YOU