A Randomized Trial Evaluating Rapid Delivery of Dose Escalated Hypofractionated Radiotherapy for Patients Diagnosed With Bone Metastases for Effective Palliation of Symptoms
Phase: PHASE2
Conditions: Bone Metastases
Sponsor: M.D. Anderson Cancer Center

 
 
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A randomized trial evaluating single fraction stereotactic versus standard multi-fraction 
radiotherapy for patients diagnosed with bone metastases for effective palliation of 
symptoms. 
 
 
1. OBJECTIVES:   
a. Primary objective (phase II):  evaluate single fraction stereotactic regimen for 
pain response in terms of time to failure, defined as the first occurrence of any 
of the following events:  
i. worsening in pain score by at least 2 categories by MDASI survey,  
b. Primary objective (phase III): to evaluate the pain response at 3 months in terms 
of pain response by a decrease in 2 categories by MDASI survey and narcotics 
use as defined by international pain consensus criteria. 
c. Secondary objective:  report outcomes  
i. Compare narcotics/opioid use compared to baseline, ≥ 50% increase in 
dose of opioid/narcotic medication,  
ii. re-irradiation, 
iii. radiographic disease progression or development of pathologic fracture 
from disease progression 
iv. 
Prospectively report pain, quality of life, and symptoms using MDASI 
assessment tool to measure pain response 
v. 
Report acute (skin, fatigue, flare reaction) and long term (sclerosis, 
bone ossification, bone fracture rate) toxicity associated with 
treatment. 
vi. 
Report local control and overall survival 
vii. 
Report rate of salvage surgery 
 
2. BACKGROUND: 
a. Radiation therapy is commonly utilized to effectively palliate symptomatic bone 
metastases, 50%-80% of patients experience improvement in the pain and 20%-
50% report complete pain relief (1, 2).  However, the optimal fractionation 
scheme to produce durable pain relief is still being studied.  Historically, clinical 
trials have compared efficacy of varying dose-fractionation in alleviating 
symptoms.  Ratanatharathorn et al. concluded in their analysis that higher dose 
fractionated treatments produced better pain outcomes compared to lower-
dose regimens (3, Ratanatharathorn).  Contrary to this, McQuay et al. in their 
summary determined no difference in efficacy between different fractionation or 
dose response in the total dose delivered for painful bone metastases (4, 
McQuay).  In the meta-analysis performed by Wu et al (5, Wu) the authors 
compared pain relief among various dose-fractionation schedules of localized 
radiotherapy (RT) in the treatment of painful bone metastases.  They concluded 
among the randomized trials, there was no significant difference in overall pain 

 
 
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relief or dose response relationship between single and multi-fraction palliative 
RT for bone metastases.   
 
In the last two decades, multiple randomized trials have compared the  
efficacy of various dose-fractionation in achieving durable pain relief in patients 
diagnosed with bone metastases.  A randomized trial, RTOG 9714 investigated 
whether 8 Gy delivered in a single fraction provided pain and narcotic relief 
equivalent to the standard 30 Gy in 10 fractions.  The study demonstrated both 
regimens were equivalent in terms of pain and narcotic relief, and well tolerated 
with few adverse effects.  The shorter 8 Gy arm had a higher re-treatment rate 
but with less acute toxicity than the longer 30 Gy arm (6, Hartsell).  However, the 
Trans-Tasman Radiation Oncology Group (TROG 96.05) was a randomized trial 
which demonstrated 8 Gy in a single fraction was not as effective as 20 Gy in 5 
fractions; the overall response rate and time to treatment failure were inferior 
(7, Roos).  The re-treatment rate has been reported to be higher in patients 
treated by single fraction radiotherapy; this could be due to the decrease in 
durability of pain response related to the lower dose equivalent (8, Sze). 
 
A single delivery of higher dose of radiation treatment can be advantageous in 
regards to patient convenience and cost effectiveness as long as it can provide 
durable pain control.  The optimal single fraction dose required to achieve pain 
control is still unknown and not determined from current clinical trials.  Gaze et 
al demonstrated and overall pain response rate of 84% and complete pain 
response rate of 34% with delivery of a single fraction of 10 Gy (9, Gaze) for 
patients with osseous metastases.   Higher doses of 12 Gy and 15 Gy have 
demonstrated a dose response of increased overall pain response of 86% and 
complete pain response in 57% of patients (10, Kagei).  Radiosurgery doses of 
>16 Gy has been shown to increase the probability of pain relief for patients with 
spine metastases by multiple institutions such as Henry Ford and University of 
Pittsburgh (11, 12, Ryu, Gerzten).  Researchers at M.D. Anderson have 
demonstrated the use of single fraction SBRT with doses of 16-24 Gy for spinal 
metastases was safe and allowed patients to achieve durable local control (88% 
at 18 months) with few toxicities (13, Garg).   
 
Multiple prospective randomized trials have investigated the efficacy of shorter 
versus longer fractionated radiation therapy courses for the treatment of painful 
bone metastases with conflicting results.  Few studies prospectively address the 
relief of neuropathic pain, re-irradiation rates, fracture rates and prospective 
quality of life endpoints.   In this study, we propose to deliver a dose escalated 
single fraction (12 Gy or 16 Gy) regimen compared to the standard 20 Gy in 5 
fractions to report the safest optimal hypofractionated regimen in providing 
durable symptomatic relief.   
 

 
 
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3. SCIENTIFIC RATIONALE:  
a. This study aims to prospectively evaluate the optimal radiation therapy dose to 
provide durable pain relief, assess patients’ quality of life, narcotics use after 
radiation therapy, outcome, and toxicity.   The goal of this prospective 
randomized trial is to radiate patients with mechanically stable, painful bone 
metastases effectively to provide quick palliation of pain.  The hypothesis is rapid 
delivery of dose escalated hypofractionated radiotherapy for bone metastases 
effectively improves pain and results in durable pain control. 
 
4. PATIENT ELIGIBILITY 
a. INCLUSION: 
i. Patients with a pathologic diagnosis of malignancy 
ii. Patients with any radiographic evidence of bone metastases, including 
plain x-ray, bone scan, CT scan, MRI, or PET scan 
iii. Patients with pain or dysathesia 
iv. Patients with a life expectancy of more than 3 months 
v. Patients able to complete pain assessment and quality of life surveys 
vi. Patients with multiple osseous sites are eligible; however should not 
treat more than 3 separate radiation treatment fields concurrently. 
vii. Patients with surgery for osseous metastases allowed. 
b. EXCLUSION: 
i. Patients with prior radiation therapy to the treatment site 
ii. Patients with a current, untreated spinal cord compression 
iii. Patients with a radiographic or pathologic fracture to the treatment site 
iv. Patients with painful metastases to hands and feet that need to be 
radiated on protocol 
v. Patients previously treated with radioactive isotope (e.g. Sr89) within 30 
days of randomization 
 
5. PRE-TREATMENT EVALUATION: 
a. The workup will include physical examination, radiographic evidence of 
metastases with either x-ray, bone scan, CT scan or MRI, and pathologic 
confirmation of malignancy per MDACC standard of care. 
b. All eligible patients will be enrolled after completion of the eligibility checklist. 
c. Use of pain medications (narcotic/opioids/NSAIDs) will be evaluated. 
 
6. TREATMENT PLAN: 
a. Patients will be randomized to receive radiation therapy to: 
i. Arm 1:  the standard hypofractionated regimen of 3 Gy x 10 fractions  
ii. Arm 2: 12 Gy x 1 fraction or 16 Gy x 1 fractions adaptively depending on 
the size of the metastases or gross tumor volume (GTV).   
b. Patients will undergo CT simulation and either 2-D or 3-D treatment planning for 
radiation therapy. 

 
 
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c. Patients can be treated with 2-D, 3-D, or intensity modulated radiation therapy 
(IMRT) 
d. Patients will be treated with on board imaging (OBI) using KV, MV x-rays, cone 
beam CT or CT on rails per standard of care. 
e. Patients will be treated with 4-20 MV photon beam, 5-20 MeV electron beam, or 
200 MeV-300 MeV proton beam. 
f. More than 1 osseous site may be included into one radiation treatment field. 
 
7. EVALUATION DURING STUDY: 
a. All patients will be evaluated by the radiation oncologist during radiation 
treatment 
b. If surgical intervention is necessary, the patients will be evaluated by the treating 
surgeon 
c. After start of treatment, all patients will be followed by phone calls within 7-14 
days, and at + 1 month (+/- 1 week) and then with clinic visits at months 3, 6, 9, 
12 (+/- 4 weeks for each visit) and every 3 to 6 month intervals thereafter (until 
death) by either the radiation oncology or orthopedic team to evaluate toxicity.   
The validated surveys (MDASI) will be completed at baseline prior to radiation 
and at each follow up interval/appointments.  The patient medical record 
number will be placed on the survey before it is given to the patient for 
completion.  The surveys may be filled out in person or by mail. 
d. Patients will report their symptom measures with validated quality of life 
instrument MDASI index.  The M.D. Anderson Symptom Inventory (MDASI) is a 
multi-symptom patient reported outcome measure evaluating 13 core symptom 
items interfering with patients’ daily life (Appendix B). 
e. We will also prospectively report the narcotics/NSAIDs utilization and outcome 
at each follow-up interval after radiation therapy. 
 
 
8. EVALUATION OF TOXICITY: 
a. During radiotherapy, the patient will be examined weekly and acute reactions 
recorded.   
b. Toxicity occurring after 3 months of radiation therapy; these will be evaluated 
and documented using NCI CTCAE version 4.03 (Appendix A). 
 
9. CRITERIA FOR RESPONSE: 
a. The response to treatment will be determined by both radiographic scans and 
symptoms reported.   
b. Complete pain relief is defined as average pain score of 0 for two consecutive 
analysis periods. 
c. The time to maximal relief of pain is defined from the first day of irradiation until 
the lowest pain score after radiation therapy. 

 
 
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d. Treatment failure is defined as worsening of pain by at least two categories, 
>50% increase in dose of opioid/narcotic medications, re-irradiation for pain or 
disease progression, progression or development of pathologic fracture from 
disease progression.   
e. Any patient with progressive pain in the radiated area will have work up which 
include radiographic scans to evaluate for bone stability and pathologic fracture 
per standard of care. 
 
 
10.   RE-TREATMENT: 
a. Response and pain relief from radiation therapy may take several weeks; 
therefore patients should not be re-irradiated for at least 4 weeks after 
completion of radiation.  Dose and fractionation are left to the discretion of the 
treating radiation oncologist. 
b. Surgical intervention for treatment failures, bone instability, or fractures will be 
reported. 
 
 
11. STATISTICAL CONSIDERATIONS: 
This is a phase II/III non-inferiority trial following the design suggestions of Korn et al. 
(14, Korn). The primary outcome for phase II part is treatment failure at 1 month, where 
treatment failure is as defined in section 1.0. We assume that time to treatment failure 
follows an exponential distribution for each treatment arm (standard radiation, 
hypofractionated radiation). We also assume that the standard radiation arm will have 
25% of patients with treatment failure at 3 months, based on the study by the Bone Pain 
Trial Working Party (15, BPTWP). A hazard ratio of 1.5 implies that the hypofractionated 
radiation arm will have 35% of patients with treatment failure at 3 months. The primary 
outcome for phase III part is pain response rate at 3 months post randomization.  We 
expect to enroll 10 patients per month.  
 
Randomization 
 
Patients will be randomized to standard or single fraction stereotactic radiation therapy 
using CORe. Randomization will be stratified by tumor size (≤ 4 cm vs. > 4 cm) , site of 
bony mets (extremities, pelvis, abdomen, head/neck, chest), and 1 vs >1 site irradiated. 
We expect approximately 40% of patients will have bony mets in the extremities and 
approximately 35% will have bony mets in the pelvis. We expect the distribution of 
patients enrolling will approximately be 40% lung malignancy, 25% genitourinary 
malignancy, 15% breast malignancy, 10% multiple myeloma and 10% other malignancy.  
We will have a total of 14 stratification levels. 
 
Phase II 
 
 We will test the following hypothesis: 

 
 
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H0: ρ = 1.5  
vs.  
H1: ρ = 1.0, 
 
where ρ is the hazard ratio (hypofractionated/standard) for time to treatment failure, as 
defined in section 1.0.   A sample size of 150 patients (75 randomized to each treatment 
arm) will yield 90% power with a 1-sided significance level of 0.20 to reject the null 
hypothesis (H0) and conclude that hypofractionated treatment is not inferior to 
standard treatment in terms of time to treatment failure. We use a 1-sided significance 
level of 0.20 as recommended by Rubinstein et al. (16, Rubinstein) for phase II screening 
trials. This sample size will yield 110 events (i.e., treatment failures). It will take 15 
months to enroll all the patients, and the maximum study duration is expected to be 22 
months to observe the 110 events.  The final analysis for phase II will be performed once 
we’ve observed 110 events, and we will suspend accrual while we wait for these events 
to occur. We will continue to phase III only if we reject H0 at the 0.20 significance level. 
 
Phase III 
 
The patients enrolled in the phase III part of the study will be included in the phase III 
part of the study.  In the Phase II trial, we have already enrolled and randomized 160 
patients, therefore we are requesting to enroll another additional 50 patients to reach a 
total of 210 patients.  We will enroll another 50 patients in total of 210 patients (105 
randomized to each treatment arm), after the rejection of the H0 in the phase II part of 
the trial.  The primary objective is to evaluate the pain response at 3 months by 
international pain consensus criteria after the additional 50 patients have been accrued, 
we will follow all patients for at least 3 months to assess the pain response. Assuming a 
20% of the 3-month pain response rate for patients on MFRT arm, the 210 patients will 
ensure an 80% power to detect a 16% improvement in response rate (36%) with SBRT 
using a 1-sided 5% level test.  
 
Pain response at 3 months is defined as reduction in pain score reported by MDASI at 2 
points below baseline also taking into account narcotics use, as defined by International 
Pain Response Criteria. 
 
This sample size calculation was performed using East 6 (Copyright © 2010, Cytel Inc., 
Cambridge, MA). 
 
Toxicity Monitoring (phase II and phase III) 
 
We will monitor the rate of radiation induced toxicity (skin dermatitis grade ≥ 4, 
gastrointestinal (GI) grade ≥ 3, genitourinary (GU) grade ≥ 3) by 12 months after the 
start of radiation therapy for the hypofractionated radiation therapy arm. We will enroll 
at least 25 patients and at most 105 patients on this treatment arm, and we will use the 
methods of Thall et al. (17, Thall et al.) to monitor the radiation induced toxicity rate. 

 
 
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We will stop enrolling patients on the hypofractionated radiation therapy arm if we 
have reason to believe that the rate of radiation induced toxicity for this arm is more 
than 10%. 
 
We will actually monitor the time to radiation induced toxicity, because these toxicities 
may occur at any time from the start of radiation therapy. We will use the Clinical Trial 
Conduct website (https://biostatistics.mdanderson.org/ClinicalTrialConduct) to monitor 
the toxicity stopping rule. This website is built and maintained by the Department of 
Biostatistics. The research staff will be trained by the study statistician in the use of the 
website to monitor the stopping rules, with an emphasis on the importance of updating 
toxicity outcomes and follow-up dates. 
 
To obtain the operating characteristics for the stopping rule we simulated the trial 1000 
times for various scenarios described in the table below. We assumed that patients are 
enrolled at the rate of 5 per month on the hypofractionated radiation therapy arm, that 
we would follow patients for 12 months, and that we will evaluate the stopping rule 
continually. The table below summarizes the operating characteristics of this stopping 
rule. 
 
Operating Characteristics for the Toxicity Monitoring Rule 
Median time to 
radiation 
induced toxicity 
(months) 
12-Month  
Toxicity Rate 
Pr(Stop 
Early) 
Sample Size 
Avg Trial 
Duration 
(Months) 
P25 
Mean 
P75 
120 
0.07 
< 0.001 
105 
105 
105 
33.2 
60 
0.13 
   0.113 
105 
103 
105 
32.8 
40 
0.19 
   0.667 
77 
89 
105 
30.1 
30 
0.24 
   0.949 
  60 
  73 
85 
26.9 
 
At any point in the trial time to radiation induced toxicity can be calculated for each 
patient, with the time interval regarded as censored at the date of last follow-up if 
toxicity has not been observed for a patient.  We will apply a Bayesian method for 
updating prior information with time to toxicity data observed to that time.  We assume 
that the time to toxicity for each patient is exponentially distributed with a median of λS 
months for the standard treatment and a median of λE for the experimental treatment.  
Given the historical data we assume λS follows an inverse gamma distribution with mean 
78.95 months and a standard deviation of 0.15 months.  The middle 95% of this 
distribution is between 78.66 and 79.24 months. These parameters correspond to a 12-
month toxicity rate between 9.064% and 10.035%.  We assume λE follows an inverse 
gamma distribution with a mean of 78.95 months and a standard deviation of 15.0 
months.  The middle 95% of this distribution is between 54.87 and 113.32 months. 
These parameters correspond to a 12-month toxicity rate between 7.077% and 
14.066%. 

 
 
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Since the goal of the study is to achieve a toxicity rate of less than 10% at 12 months, 
the trial will be stopped early if, based on the available data,  
Pr( λE  <  λS | data from the trial ) >0.90.  This rule was chosen to achieve an 
approximately 0.10 early stopping probability if the true toxicity rate is 10%. 
 
 
Final Analysis 
 
We will use descriptive statistics to summarize the demographic and clinical 
characteristics of patients by treatment arm. 
 
We will use the methods of Gooley et al. (18, Gooley) to estimate the cumulative 
incidence of treatment failure for each treatment arm with death as a competing event, 
and we will estimate the percent of patients without treatment failure at 3, 6, and 12 
months for each treatment arm with a 90% confidence interval. 
 
We will use the methods of Fine and Gray (19, Fine and Gray) to model time to 
treatment failure with death as a competing event and test the hypotheses stated 
above for phase II and for phase III. We will also estimate the hazard ratio for treatment 
with a 90% confidence interval. 
 
For the 3 month pain response rate, the Cochran-Mantel-Haenszel test stratified by 
stratification factors at randomization will used to test the difference between 2 
treatment arms.  Chi-squared test without adjusting for the stratification factors will 
also be performed as a secondary analysis.   
 
We will use descriptive statistics and boxplots to summarize the score from the MDASI 
instrument at each assessment time. We will similarly summarize changes in scores for 
these instruments over time. We will use mixed effects regression methods with 
repeated measures and patient as a random effect to model instrument scores over 
time to test for treatment differences. 
 
We will use the product limit estimator of Kaplan and Meier (20, Kaplan and Meier) to 
estimate overall survival and disease-free survival stratified by treatment arm. We will 
use Cox proportional hazards regression to model OS and DFS as a function of treatment 
arm, and we will estimate the hazard ratio for treatment with a 90 % confidence interval 
(21, Cox). 
 
We will use descriptive statistics to summarize narcotics use and acute and long-term 
adverse events for each treatment arm.  
 

 
 
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We will use Fisher’s exact test to compare treatment arms with respect to the rates of 
re-irradiation and salvage surgery. 
 
12. Database: 
 
Study data will be collected and managed using REDCap 
(Research Electronic Data Capture) electronic data capture tools hosted at MD 
Anderson. [ref 22] REDCap (www.project-redcap.org) is a secure, web-based application 
with controlled access designed to support data capture for research studies, providing: 
1) an intuitive interface for validated data entry; 2) audit trails for tracking data 
manipulation and export procedures; 3) automated export procedures for seamless 
downloads to common statistical packages; and 4) procedures for importing data from 
external sources. REDCap (https://redcap.mdanderson.org) is hosted on a secure server 
by MD Anderson Cancer Center's Department of Research Information Systems & 
Technology Services. REDCap has undergone a Governance Risk & Compliance 
Assessment (05/14/14) by MD Anderson's Information Security Office and found to be 
compliant with HIPAA, Texas Administrative Codes 202-203, University of Texas Policy 
165, federal regulations outlined in 21CFR Part 11, and UTMDACC Institutional Policy 
#ADM0335. 
 
 
13. REFERENCES: 
 
1. Bates T. A review of local radiotherapy in the treatment of bone metastases 
and cord compression. Int J Radiat Oncol Biol Phys 1992; 23:217-221 
2. Maher EJ. The use of palliative radiotherapy in the management of breast 
cancer. Eur J Cancer 1992; 28:706-710. 
3. Ratanatharathorn, Powers, Moss et al.  Bone metastases: review and critical 
analysis of random allocation trials of local field treatment.  Int. J.  Radiat 
Oncol Biol Phys.  1994; 44:1-18. 
4. McQuay, Collins, Carroll et al.  Radiotherapy for the palliation of painful bone 
metastases.  In: The Cochrane Library.  2002, Issue 1.  Oxford: Update 
Software. 
5. Wu, Wong, and Johnston et al.  Meta-analysis of dose-fractionation 
radiotherapy trials for the palliation of painful bone metastases.  Int. J. Radiat. 
Onc. Bio. Phys.  2003: Vol 55(3), pp.594-605, 2003. 
6. Hartsell, Scott, Bruner, et al.  Randomized trial of short versus long-course 
radiotherapy for palliation of painful bone metastases.  JNCI.  2005; 97(11): 
798-804. 
7. Roos, Turner, O’Brien, et al.  Randomized trial of 8 Gy in 1 versus 20 Gy in 5 
fractions of radiotherapy for neuropathic pain due to bone metastases (TROG 
96.05).  Radiotherapy and Oncology.  2005; 75: 54-63. 

 
 
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8. Sze WM, Shelley MD, Wilt TJ, Mason MD.  Palliation of Metastatic Bone Pain:  
Single fraction vs Multifraction Radiotherapy-A systematic Review of 
Randomized trials.  Clinical Oncology.  2003; 15: 345-352. 
9. Gaze MN, Kelly CG, Kerr GY, et al.  Pain relief and quality of life following 
radiotherapy for bone metastases: a randomized trial of two fractionation 
schedules.  Radiother Oncol.  1997; 45: 109-16. 
10. Kagei K, Suzuki K, Shirato H, et al.  A randomized trial of single and 
multifraction radiation therapy for bone metastasis: a preliminary report.  
Japan J Cancer Clin.  1990;36: 2553-8. 
11. Ryu S, Jin R, Jin JJ, et al.  Pain Control by Image-guided Radiosurgery for 
Solitary Spinal Metastases.  J Pain Symp Manage.  2008; 35: 292-298. 
12. Gerzten PC, Burton SA, Ozhasoglu C, et al.  Radisurgery for the treatment of 
renal cell carcinoma.  J Neurosurg Spine.  2005; 3(4): 288-295. 
13. Garg AK, Shiu AS, Yang J.  Phase I/II Trial of Single-session Stereotactic Body 
Radiotherapy for Previously Unirradiated Spinal Metastases.  Cancer. 2012 
Oct 15;118(20):5069-77 
14. Korn EL, Freidlin B, Abrams JS, Halabi S. Design issues in randomized phase 
II/III trials. J Clin Oncol. 2012 Feb 20;30(6):667-71. 
15. Bone Pain Trial Working Party. 8 Gy single fraction radiotherapy for the 
treatment of metastatic skeletal pain: randomized comparison with a 
multifraction schedule over 12 months of patient follow-up. Radiotherapy 
and Oncology. 1999;52:111-121. 
16. Rubinstein LV, Korn EL, Freidlin B, Hunsberger S, Ivy SP, Smith MA. Design 
issues of randomized phase II trials and a proposal for phase II screening 
trials. J Clin Oncol 2005;23:7199-7206. 
17. Thall PF, Simon RM, Estey EH.  Bayesian sequential monitoring designs for 
single-arm clinical trials with multiple outcomes.  Stat Med. 1995 Feb 
28;14(4):357-79. 
18. Gooley TA, Leisenring W, Crowley J, and Storer BE.  Estimation of failure 
probabilities in the presence of competing risks: new representations of old 
estimators.  Statistics in Medicine. 1999; 18:695-706. 
19. Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a 
competing risk. Journal of the American Statistical Association 1999;94:496-
509. 
20. Kaplan EL and Meier P.  Nonparametric estimation from incomplete 
observations.  Journal of the American Statistical Association 1958; 53:457-
481. 
21. Cox DR.  Regression models and life tables (with discussion).  Journal of the 
Royal Statistical Society B 1972; 34:187-220. 
22. Paul A. Harris, Robert Taylor, Robert Thielke, Jonathon Payne, Nathaniel 
Gonzalez, Jose G. Conde. Research electronic data capture (REDCap) - A 
metadata-driven methodology and workflow process for providing 
translational research informatics support. J Biomed Inform, 2009. 
42(2):377-81. 
 

 
 
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14. TABLE A:  PATIENT ASSESSMENT CHECKLIST 
 
Time 
H&P 
CBC 
X-ray, 
CT, 
MRI, 
bone 
scan* 
Path 
Dx 
MDASI 
Survey 
Phone 
call 
follow-
up 
 
Toxicity/AE 
assessment 
Pre-RT 
X 
X 
X 
X 
X 
 
 
X 
Within 7-10 days post 
XRT 
 
 
 
 
X 
X 
 
 
1 month post XRT2 
 
 
 
 
X 
X 
 
 
3 month 
f/u1 
  
  
X 
  
X 
 
 
X 
6 month 
f/u1 
  
  
X 
  
X 
 
 
X 
9 month 
f/u1 
  
  
X 
  
X 
 
 
X 
12 month 
f/u1 
  
  
X 
  
X 
 
 
X 
3-6  month interval 
thereafter (until 
death) 
  
  
X 
  
X 
 
 
X 
 
*Per standard of care 
1 Within +/- 4 weeks 
2 Within +/- 1 week 
 
Time 
H&P 
CBC 
X-ray, 
CT, 
MRI, 
bone 
scan* 
Path 
Dx 
MDASI 
Survey 
Narcotic/ 
Opioid/ 
NSAID 
use 
Toxicity/AE 
assessment 
Pre-RT 
X 
X 
X 
X 
X 
X 
X 
Within 7-14 days post 
start of XRT by phone 
  
  
  
  
X 
X 
X 
1 month post start of 
XRT by phone2 
  
  
  
  
X 
X 
X 
3 month 
f/u1 
  
  
X 
  
X 
X 
X 

 
 
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6 month 
f/u1 
  
  
X 
  
X 
X 
X 
9 month 
f/u1 
  
  
X 
  
X 
X 
X 
12 month 
f/u1 
  
  
X 
  
X 
X 
X 
3-6  month interval 
thereafter (until death) 
  
  
X 
  
X 
X 
X 
 
*Per standard of care 
1 Within +/- 4 weeks 
2 Within +/- 1 week 
 
 
15. APPENDIX A:  NCI CTCAE version 4.03 
16. APPENDIX B:  The M.D. Anderson Symptom Inventory (MDASI) survey