Feasibility Study of Safety, Toxicity, and Compliance of Concomitant Chemoradiotherapy for HIV-Associated Locally-Advanced Cervical Cancer
Phase: PHASE2
Conditions: Cervical Cancer, Acquired Immunodeficiency Syndrome
Sponsor: AIDS Malignancy Consortium

SUMMARY OF CHANGES 
 
Feasibility Study of Safety, Toxicity, and Compliance of Concomitant Chemoradiotherapy 
for HIV-Associated Locally-Advanced Cervical Cancer 
(Version 3.0) 
 
NCI Protocol #: AMC-081 
Local Protocol #: AMC-081 
 
NCI Version Date: 20 February 2015 
Update Date: 20 February 2015 
 
I. 
Changes made in Amendment v3.0 
# 
Section 
Comments 
1. 
Cover page 
Changed from: 
Version 2.0 
28 May 2013 
NCI Version Date: 28 May 2013 
Update Date: 14 April 2014 
 
Changed to: 
Version 3.0 
NCI Version Date: 20 February 2015 
Update Date: 20 February 2015 
2. 
Footer 
Changed from:  
AMC # 081 (Version 2.0) 14 April 2014 
NCI Version Date 28 May 2013 
 
Changed to: 
AMC # 081 (Version 3.0) 20 February 2015 
NCI Version Date 20 February 2015 
3. 
Signature 
page 
Changed from:  
Version 2.0 28 May 2014 
 
Changed to: 
Version 3.0 20 February 2015 
4. 
Abbreviation 
List 
Changed from: 
Text added. 
 
Changed to: 
IROC Houston QA Center - Imaging and Radiation Oncology Core Houston QA Center 
5. 
Abbreviation 
List 
Changed from:  
RPC – Radiology Physics Center 
 
Changed to: 
Text removed. 
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6. 
Protocol 
Roster 
Changed from: 
Email: amcpm@emmes.com 
 
Changed to: 
Email: amipm@emmes.com 
7. 
Protocol 
Roster 
Changed from: 
Radiological Physics Center 
 
Changed to: 
Imaging and Radiation Oncology Core Houston QA Center 
8. 
Study 
Synopsis 
Changed from:  
All participants with CD4 counts > 200/mm3 (0.2 x 109/L) will receive weekly cisplatin at a 
dose of 40 mg/m2 (maximum of 70 mg) concomitant with radiotherapy (external beam and 
brachytherapy). The first 3 participants with CD4 counts < 200/mm3 (0.2 x 109/L) will 
receive weekly cisplatin at a dose of 25 mg/m2 (maximum of 43.75 mg) with radiotherapy 
(external beam and brachytherapy). Based on review of the safety data from the first 3 
participants, all other participants with CD4 counts < 200/mm3 (0.2 x 109/L) will receive 
weekly cisplatin at a dose of 40 mg/m2 (maximum of 70 mg) or no cisplatin with 
radiotherapy (external beam and brachytherapy). All participants will concomitantly receive 
combination antiretroviral therapy (ART) with an acceptable regimen that adheres to 
national guidelines for treatment of HIV infection. 
 
Changed to: 
All participants with CD4 counts > 200/mm3 (0.2 x 109/L) will receive weekly cisplatin at a 
dose of 40 mg/m2 concomitant with radiotherapy (external beam and brachytherapy). The 
first 3 participants with CD4 counts < 200/mm3 (0.2 x 109/L) will receive weekly cisplatin at 
a dose of 25 mg/m2 with radiotherapy (external beam and brachytherapy). Based on review 
of the safety data from the first 3 participants, all other participants with CD4 counts < 
200/mm3 (0.2 x 109/L) will receive weekly cisplatin at a dose of 40 mg/m2 or no cisplatin 
with radiotherapy (external beam and brachytherapy). All participants will concomitantly 
receive combination antiretroviral therapy (ART) with an acceptable regimen that adheres to 
national guidelines for treatment of HIV infection. 
9. 
1.0 
Changed from: 
Radiation Physics Center 
 
Changed to: 
Imaging and Radiation Oncology Core Houston Quality Assurance Center 
10. 
3.1.9 
Changed from: 
At the investigator’s discretion, participants who are suitable for treatment with radical 
intent using concurrent chemotherapy and pelvic radiation. Subjects who undergo 
emergency radiation therapy (Refer to Section 4.2) prior to enrollment may participate. 
 
Changed to: 
In the opinion of the investigator the protocol treatment is appropriate for the participant. 
11. 
3.2.9 
Changed from:  
Text added. 
 
Changed to: 
Participants with enlarged para-aortic lymph node involvement on imaging that is 
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Comments 
suspicious for metastasis 
12. 
3.4 
Changed from: 
This includes weekly cisplatin at 40 mg/m2 (maximum of 70 mg) concomitant with 
radiotherapy (external beam and brachytherapy). 
 
Changed to: 
This includes weekly cisplatin at 40 mg/m2 concomitant with radiotherapy (external beam 
and brachytherapy) 
13. 
3.5.1 
Changed from: 
After an informed consent form has been signed by the participant, the participant must be 
registered for screening (AMC-081, Segment A) on-line via the AMC AdvantageEDC SM 
Internet Data Entry System. 
 
Changed to: 
After an informed consent form has been signed by the participant, the participant must be 
registered for screening (AMC-081, Screening Segment) on-line via the AMC 
AdvantageEDC SM Internet Data Entry System. 
14. 
3.5.2 
Changed from:  
After a the screening evaluations are completed and the participant is determined to be 
eligible the participating site will complete the protocol-specific eligibility checklist and 
enroll the participant into AMC-081 Segment B on-line via the AMC AdvantageEDC
SM 
Internet Data Entry System. The participating site will ensure the participant meets all 
eligibility criteria prior to completing the protocol-specific eligibility checklist. Participants 
will be enrolled on-line via the AMC Internet Data Entry System no more than 1 week prior 
to the initiation of treatment (enrollment 1 day prior to or on the day of treatment is strongly 
encouraged). Once the eligibility checklist is submitted, a system-generated confirmation 
will be sent to the site staff, AMC ODMC, and Protocol Chair upon successful registration. 
 
If the on-line system is inaccessible for Registration (Segment B), the site should notify the 
AMC ODMC via email at 081protocolteam@emmes.com or via phone at 001-301-251-
1161 for further instructions. If the AMC ODMC cannot be reached, please follow the 
manual randomization procedures detailed in the AMC-081 Manual of Procedures. 
 
Changed to: 
After the screening evaluations are completed and the participant is determined to be 
eligible the participating site will complete the protocol-specific eligibility checklist and 
enroll the participant into AMC-081Treatment Segment (Segment B) on-line via the AMC 
AdvantageEDC
SM 
Internet Data Entry System. The participating site will ensure the 
participant meets all eligibility criteria prior to completing the protocol-specific eligibility 
checklist. Participants will be enrolled on-line via the AMC Internet Data Entry System no 
more than 1 week prior to the initiation of treatment (enrollment 1 day prior to or on the day 
of treatment is strongly encouraged). Once the eligibility checklist is submitted, a system-
generated confirmation will be sent to the site staff, AMC ODMC, and Protocol Chair upon 
successful registration. 
 
If the on-line system is inaccessible for Registration (Treatment Segment), the site should 
notify the AMC ODMC via email at 081protocolteam@emmes.com or via phone at 001-
301-251-1161 for further instructions. If the AMC ODMC cannot be reached, please follow 
the manual randomization procedures detailed in the AMC-081 Manual of Procedures. 
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15. 
4.0 
Changed from: 
To be eligible, participants with invasive squamous cell, adenocarcinoma, or 
adenosquamous carcinoma of the cervix must have undergone clinical staging by physicians 
according to FIGO staging criteria (See Appendix VI). 
 
Changed to: 
To be eligible, participants with invasive squamous cell, adenocarcinoma, or 
adenosquamous carcinoma of the cervix must have undergone clinical staging by physicians 
according to FIGO staging criteria see (Appendix VI). 
16. 
4.2.2 
Changed from: 
Cisplatin 40 mg/m2 (max 70 mg) IV over 30-60 minutes given weekly on days 1, 8, 15, 22, 
29 and 36 for a total of 6 weekly cycles. 
 
Changed to: 
Cisplatin 40 mg/m2 IV over 30-60 minutes given weekly on days 1, 8, 15, 22, 29 and 36 for 
a total of 6 weekly cycles. 
17. 
4.4 
Changed from: 
Drug will be shipped through a third party vendor. Instructions for drug ordering are 
available on the AMC website (www.amcoperations.com). 
 
Changed to: 
Drug will be paid for by the AMC. Instructions for drug ordering/drug purchase will be 
provided to each clinical site by the AMC Operations and Data Management Center. All 
investigators prescribing study agent for an AMC study must have an active NCI-
investigator registration. 
18. 
4.6 
 
Changed from: 
Radiation therapy (RT) must be started within 7 days of enrollment into Segment B; CT 
scan of the pelvis is required for external RT field and block definition. 
 
Changed to: 
Radiation therapy (RT) must be started within 7 days of enrollment into the Treatment 
Segment (Segment B); CT scan of the pelvis is required for external RT field and block 
definition. 
19. 
4.6.1.2.1 
Changed from: 
Following the completion of the whole pelvic RT, the participant will receive 35-43.6 Gy to 
Point A (see Appendix VIII Description of points A, B and ICRU Bladder/Rectum) by 
intracavitary implant with a standard medical radiation source listed on the American 
Association of Physicists in Medicine (AAPM) source registry 
(http://rpc.mdanderson.org). The dose table (see Section 4.6) should be utilized to ensure 
adequate dose delivery.  
 
Changed to: 
Following the completion of the whole pelvic RT, the participant will receive 35-43.6 Gy to 
Point A (Refer to Appendix VIII Description of points A, B and ICRU Bladder/Rectum) by 
intracavitary implant with a standard medical radiation source listed on the American 
Association of Physicists in Medicine (AAPM) source registry 
(http://irochouston.mdanderson.org). The dose table (Refer to Section 4.6) should be 
utilized to ensure adequate dose delivery.  
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20. 
4.6.1.2.2 
Changed from: 
See Appendix VII (HDR Brachytherapy) for guidelines of vaginal surface dose, normal 
tissue tolerances, packing and imaging. 
 
Changed to: 
Refer to Appendix VII (HDR Brachytherapy) for guidelines of vaginal surface dose, normal 
tissue tolerances, packing and imaging. 
21. 
4.6.1.2.5 
Changed from: 
Each HDR brachytherapy fraction will give 6-9 Gy/fraction to Point A. (see Appendix VIII 
Description of points A, B and ICRU Bladder/Rectum). Each participant may be treated 
with up to four HDR implants with the HDR total dose ranging from 18-28 Gy (Total HDR 
dose) that is equivalent to an LDR delivered of 35-43.6 Gy depending on the total external 
beam dose given (see Appendix VII HDR Brachytherapy). 
 
Changed to: 
Each HDR brachytherapy fraction will give 6-9 Gy/fraction to Point A. (Refer to Appendix 
VIII Description of points A, B and ICRU Bladder/Rectum). Each participant may be 
treated with up to four HDR implants with the HDR total dose ranging from 18-28 Gy 
(Total HDR dose) that is equivalent to an LDR delivered of 35-43.6 Gy depending on the 
total external beam dose given (Refer to Appendix VII HDR Brachytherapy). 
22. 
4.6.1.2.7 
Changed from: 
(See Appendix VII: HDR Brachytherapy). 
 
Changed to: 
(Refer to Appendix VII: HDR Brachytherapy). 
23. 
4.6.3.2 
Changed from: 
Intracavitary RT may be delivered by cesium-137 or equivalent radiation source for LDR 
brachytherapy or cobalt-60 or iridium-192 for HDR brachytherapy in standard or commonly 
used tandem and ovoid applicators. Only the medical radiation brachytherapy sources listed 
on the AAPM source registry (http://rpc.mdanderson.org) may be used. 
 
Changed to: 
Intracavitary RT may be delivered by cesium-137 or equivalent radiation source for LDR 
brachytherapy or cobalt-60 or iridium-192 for HDR brachytherapy in standard or commonly 
used tandem and ovoid applicators. Only the medical radiation brachytherapy sources listed 
on the AAPM source registry (http://irochouston.mdanderson.org) may be used. 
24. 
4.6.4 
Changed from: 
External Radiation Fields (see Appendix IX Blank Diagram Anterior and Appendix X Blank 
Diagram Lateral) 
 
Changed to: 
External Radiation Fields (Refer to Appendix IX Blank Diagram Anterior and Appendix X 
Blank Diagram Lateral) 
25. 
4.6.4.4 
Changed from: 
The upper border of the true pelvis field is defined as 1 cm above the inferior aspect of the 
sacroiliac joint (see Appendix VIII Description of ICRU Bladder/Rectal Dose Reporting 
Points). Parametrial block should be a minimum of 4-5 cm wide if bilateral parametrial 
boost is used and may be shaped to the point A isodose. Unilateral parametrial boost would 
be used if only unilateral involvement was noted (see Section 4.6.1.3). 
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Changed to: 
The upper border of the true pelvis field is defined as 1 cm above the inferior aspect of the 
sacroiliac joint (Refer to Appendix VIII Description of ICRU Bladder/Rectal Dose 
Reporting Points). Parametrial block should be a minimum of 4-5 cm wide if bilateral 
parametrial boost is used and may be shaped to the point A isodose. Unilateral parametrial 
boost would be used if only unilateral involvement was noted (Refer to Section 4.6.1.3). 
26. 
4.6.6 
Changed from: 
The Radiological Physics Center (RPC), a National Cancer Institute funded organization 
with guidance from the AAPM, will supervise the dosimetry control for this clinical trial. To 
participate in the trial, the institution must demonstrate the ability to achieve an accuracy of 
±5% in measuring calibrated reference beam output of their external beam therapy units on 
an annual basis. Each participant record will be reviewed by the RPC to verify that each 
participant received their radiation therapy dose to within ±5% for delivering the external 
beam prescribed dose and ±15% for the brachytherapy boost. 
 
Changed to: 
The Imaging and Radiation Oncology Core Houston QA Center (IROC Houston QA 
Center), a National Cancer Institute funded organization with guidance from the AAPM, 
will supervise the dosimetry control for this clinical trial. To participate in the trial, the 
institution must demonstrate the ability to achieve an accuracy of ±5% in measuring 
calibrated reference beam output of their external beam therapy units on an annual basis. 
Each participant record will be reviewed by the IROC Houston QA Center to verify that 
each participant received their radiation therapy dose to within ±5% for delivering the 
external beam prescribed dose and ±15% for the brachytherapy boost. 
27. 
5.1.1 
Changed from: 
Physical examination including: weight and height for BSA calculation, performance status 
(see Appendix II), general physical exam, and pelvic exam if judged as necessary by the 
investigator. 
 
Changed to: 
Physical examination including: weight and height for BSA calculation, performance status 
(Refer to Appendix II), general physical exam, and pelvic exam if judged as necessary by 
the investigator. 
28. 
5.1.2 
Changed from: 
SGOT, alkaline phosphatase, bilirubin 
 
Changed to: 
SGOT, SGPT, alkaline phosphatase, bilirubin 
29. 
5.2.1 
Changed from: 
ART adherence assessment will be collected on Day 8, Day 15, Day 22, Day 29, Day 36, 
and on the final day of radiation therapy. 
Physical Examination on Day 22 prior to treatment and at treatment discontinuation. 
Anal and cervical swabs to evaluate the exploratory objectives within 4 weeks of the 
completion of chemo radiation therapy (refer to Appendix XI) 
Serum to evaluate the exploratory study objectives within 4 weeks of the completion of 
chemo radiation therapy (refer to Appendix XI) 
 
Changed to: 
ART adherence assessment will be collected on Day 8, Day 15, Day 22, Day 29, and Day 
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36. 
Physical examination on Day 22 prior to treatment. 
30. 
5.2.2 
Changed from: 
Text added. 
 
Changed to: 
Assessments at the Time of Chemo-Radiation Therapy Completion 
 
The following assessments must be completed within 7 days of chemo-radiation therapy 
completion unless otherwise specified. These assessments are required for all participants 
regardless of the reason for treatment discontinuation (e.g. treatment completion or early 
discontinuation) 
• 
Review of interim medical history including concomitant medications and adverse 
events. 
• 
ART adherence assessment 
• 
Physical examination 
The following assessments must be completed either on the final day of chemo-radiation 
therapy or within 4 weeks after the final dose of chemo-radiation therapy: 
• 
Anal and cervical swabs to evaluate the exploratory study objectives (refer to 
Appendix XI) 
• 
Serum to evaluate the exploratory study objectives (refer to Appendix XI) 
31. 
5.3 
Changed from: 
Text added. 
 
Changed to: 
Participants are to be followed at 3 intervals for 1 year after completing protocol treatment. 
CT imaging will be repeated at the 6-month time point after discontinuing treatment only for 
participants that have not clinically progressed; other imaging modalities can be employed 
off-study, as appropriate and at the discretion of the treating physician, at other time points. 
Participants that progress or relapse during the 12 month study follow-up period will be 
followed for survival only. 
32. 
5.4 
Changed from: 
Text added. 
 
Changed to: 
Participants will only be followed for survival following the diagnosis of disease 
progression or recurrence. Treatment for progressive/recurrent disease will be at the 
discretion of the site investigator and will not be coordinated or paid for as part of the study. 
33. 
5.5 
Changed from: 
5.5 Premature Treatment Discontinuation Evaluations 
 
For participants who withdraw from treatment (discontinuation prior to completing the 
prescribed therapy), the following evaluations should be performed whenever possible: 
• 
Physical examination 
• 
Review of interim medical history including concomitant medications and adverse 
events 
• 
Anal and cervical swabs to evaluate the exploratory study objectives within 4 
weeks of the completion of chemo-radiation therapy (refer to Appendix XI) 
• 
Serum to evaluate the exploratory study objectives within 4 weeks of the 
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completion of chemo-radiation therapy (refer to Appendix XI) 
 
Changed to: 
Text removed 
34. 
5.5 
Changed from:  
SGOT, alkaline phosphatase, bilirubin 
 
Changed to: 
SGOT, SGPT, alkaline phosphatase, bilirubin 
35. 
6.1.1.2 
Changed from: 
This interruption should be limited to ≤ 1 week if possible (see Section 6.1.2). 
 
Changed to: 
This interruption should be limited to ≤ 1 week if possible (Refer to Section 6.1.2). 
36. 
6.1.1.3 
Changed from: 
Topical steroids and treatment interruption may be necessary also (see Section 6.1.2). 
 
Changed to: 
Topical steroids and treatment interruption may be necessary also (Refer to Section 6.1.2). 
37. 
6.1.1.4 
Changed from: 
The Study Chair should be notified of any Grade 4 toxicity (see Section 6.1.2). 
 
Changed to: 
The Study Chair should be notified of any Grade 4 toxicity (Refer to Section 6.1.2. 
38. 
6.2.1 
Changed from: 
The first three subjects who are enrolled who have a CD4 count < 200 mm3 (0.2 x 109/L) 
(inclusive) will be prescribed a dose of 25mg/m2 (Dose Level -2, see 6.2.2). 
 
Changed to: 
The first three subjects who are enrolled who have a CD4 count < 200 mm3 (0.2 x 109/L) 
(inclusive) will be prescribed a dose of 25mg/m2 (Dose Level -2, refer to Section 6.2.2). 
39. 
6.2.3 
Changed from:  
The following levels should be used for cisplatin dose reductions: 
Dose Level 0 
Dose Level -1 
Dose Level -2 
40 mg/m2 (max 70 mg) 
30 mg/m2 (max 70 mg) 
25 mg/m2 (max 70 mg) 
 
There will be no dose reduction below dose level -2 (i.e. cisplatin will be discontinued if 
further toxicity occurs). Maximum doses refer to subjects with BSA >1.75 m2. 
 
Changed to: 
The following levels should be used for cisplatin dose reductions: 
Dose Level 0 
Dose Level -1 
Dose Level -2 
40 mg/m2  
30 mg/m2  
25 mg/m2  
 
There will be no dose reduction below dose level -2 (i.e. cisplatin will be discontinued if 
further toxicity occurs). 
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40. 
Appendix I 
The row under Tests and Observations reading “SGOT, alkaline phosphatase, bilirubin” was 
edited to read “SGOT, SGPT, alkaline phosphatase, bilirubin.” 
 
The column Following Completion of Protocol Therapy was renamed as Chemo-
Radiation Therapy Completion or Premature Treatment Discontinuation. 
 
The column After Diagnosis of Recurrence was renamed as 3, 6, 9, and 12 Month 
Follow-up. 
 
The column Premature Treatment Discontinuation was changed to After Diagnosis of 
Recurrence. 
 
In the column Chemo-Radiation Therapy Completion or Premature Treatment 
Discontinuation, the following indications were removed CT Scan with contrast of pelvis 
and abdomen; CD4+ T-cell count; and HIV Viral load. 
 
In the column 3, 6, 9, and 12 Month Follow-up, the following indications were removed: 
chest X-ray and serum for HPV-serology. 
 
In the column 3, 6, 9 and 12 Month Follow-up, the following indications were added: 
Physical exam and ART adherence. 
 
In the column After Diagnosis of Recurrence, the following indications were removed: 
Physical exam; ART adherence; and Anal and cervical swabs for HPV-associated disease 
research.  
 
In the column After Diagnosis of Recurrence, the following indications were added: Chest 
X-ray; CD4+ T-cell Count; and HIV viral load 
 
In the column Premature Study Discontinuation, the following indications were added: 
anal and cervical swabs for HPV-associated disease research; and serum for HPV-serology 
 
Footnote 6 “CT with contrast of abdomen and pelvis. Scans are only required if more than 3 
months have elapsed since the last CT scan” was removed. 
 
Footnote 9 “Anal and cervical swabs and serum for HPV-associated disease research will be 
collected within 4 weeks following the discontinuation of treatment” has been changed to 
“Anal and cervical swabs and serum for HPV-associated disease research will be collected 
on the final day of chemo-radiation therapy or within 4 weeks following the final 
chemo-radiation therapy.” 
 
Footnote 10 “Assessment must be completed within 7 days of the completion of chemo-
radiation therapy. This visit is required for all participants and refers both to scheduled 
completion of treatment and premature treatment discontinuation” was added. 
41. 
Appendix 
VII 
Changed from: 
These ICRU #38 and institutional bladder and rectal dose points must be calculated but dose 
modifications should not be made solely based upon these calculations (See Appendix IX). 
 
Changed to: 
These ICRU #38 and institutional bladder and rectal dose points must be calculated but dose 
modifications should not be made solely based upon these calculations (Refer to Appendix 
IX). 
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42. 
Appendix 
XII 
Changed from: 
Participation in the annual mailed OSLD/TLD program conducted by the RPC for an 
independent basic check of the machine output. 
 
Changed to: 
Participation in the annual mailed OSLD/TLD program conducted by the IROC Houston 
QA Center for an independent basic check of the machine output. 
43. 
Appendix 
XII 
Changed from: 
Submission of a complete treatment plan (to include treatment plan summary, beam-on 
times, isodose lines, dose volume histograms, beams eye views (BEV), daily treatment 
record), and completed on-line external beam dosimetry form found on the RPC website 
(http://rpc.mdanderson.org) under forms shall be submitted for review by the RPC and 
protocol PI. This review verifies that the dose reported is that required by the protocol, no 
data entry errors have occurred in the calculation, and that there are no transcription and/or 
reporting errors. The RPC’s participant review may require the participating site to submit 
additional dosimetry data, as specified by the RPC, for the therapy machine used to treat the 
participant if a dose delivery discrepancy is determined. 
 
Changed to: 
Submission of a complete treatment plan (to include treatment plan summary, beam-on 
times, isodose lines, dose volume histograms, beams eye views (BEV), daily treatment 
record), and completed on-line external beam dosimetry form found on the IROC Houston 
QA Center website (http://irochouston.mdanderson.org) under forms shall be submitted 
for review by the IROC Houston QA Center and protocol PI. This review verifies that the 
dose reported is that required by the protocol, no data entry errors have occurred in the 
calculation, and that there are no transcription and/or reporting errors. The IROC Houston 
QA Center’s participant review may require the participating site to submit additional 
dosimetry data, as specified by the IROC Houston QA Center, for the therapy machine 
used to treat the participant if a dose delivery discrepancy is determined. 
44. 
Appendix 
XII 
Changed from:  
Submission of a complete treatment plan to include source strength, for LDR: source 
loading and total time, for HDR: dwell positions and dwell times, orthogonal AP and lateral 
films with magnification factors, and completed on-line Gynecological Brachytherapy 
Protocol Compliance form found on the RPC website (http://rpc.mdanderson.org) under 
forms shall be submitted for review by the RPC and protocol PI. This review verifies that 
the dose reported is that required by the protocol, no data entry errors have occurred in the 
calculation, and that there are no transcription and/or reporting errors. If a dose delivery 
discrepancy is determined, the RPC’s participant review may require the participating site 
to submit additional brachytherapy dosimetry data that was used to treat the participant, as 
specified by the RPC. 
 
Changed to: 
Submission of a complete treatment plan to include source strength, for LDR: source 
loading and total time, for HDR: dwell positions and dwell times, orthogonal AP and lateral 
films with magnification factors, and completed on-line Gynecological Brachytherapy 
Protocol Compliance form found on the IROC Houston QA Center website 
(http://irochouston.mdanderson.org) under forms shall be submitted for review by the 
IROC Houston QA Center and protocol PI. This review verifies that the dose reported is 
that required by the protocol, no data entry errors have occurred in the calculation, and that 
there are no transcription and/or reporting errors. If a dose delivery discrepancy is 
determined, the IROC Houston QA Center’s participant review may require the 
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participating site to submit additional brachytherapy dosimetry data that was used to treat 
the participant, as specified by the IROC Houston QA Center. 
 
II. 
Changes made in Editorial and Administrative Amendment Version 2.1 
# 
Section 
Comments 
1. 
Global 
Changed from: 
Adverse Event Expedited Reporting System (AdEERS) 
 
Changed to: 
CTEP Adverse Event Reporting System (CTEP-AERS) 
2. 
7.1 
Changed from: 
An electronic system for expedited submission of AE reports is available at 
https://webapps.ctep.nci.nih.gov/openapps/plsql/gadeers_main$.startup. 
 
Changed to: 
An electronic system for expedited submission of AE reports is available at https://eapps-
ctep.nci.nih.gov/ctepaers/. 
3. 
Appendix V 
Changed from: 
Version 4.0 September 13, 2010 
 
Changed to: 
Version 5.0 January 28, 2014 
4. 
Appendix XI 
Changed from: 
COLLECTION AND SHIPPING INSTRUCTIONS FOR FORMALIN FIXED TISSUE 
SLIDES OF CANCER BIOSPY TISSUES, SERUM CERVICAL AND ANAL SWABS 
FOR EXPLORATORY OBJECTIVE SPECIMENS 
 
Changed to: 
COLLECTION AND SHIPPING INSTRUCTIONS FOR SERUM, AND CERVICAL AND 
ANAL SWABS FOR EXPLORATORY OBJECTIVE SPECIMENS 
5. 
Appendix XI 
Changed from: 
DNA from the cancer portion of the SIL portion of the biopsy will be studied for DNA 
methylation. This will allow us to determine in a descriptive way if the methylation 
patterns are different and might provide some clues regarding the role of HPV methylation 
in progression to cancer. 
 
Changed to: 
DNA from the swab material will be used to allow us to determine in a descriptive way if 
the methylation patterns are different and might provide some clues regarding the role of 
HPV methylation in progression to cancer. 
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AIDS MALIGNANCY 
CLINICAL TRIALS CONSORTIUM 
 
 
 
AMC PROTOCOL #081 
 
Feasibility Study of Safety, Toxicity, and Compliance of 
Concomitant Chemoradiotherapy for HIV-Associated  
Locally-Advanced Cervical Cancer 
 
A Multi-Center Trial of the AIDS Malignancy 
Clinical Trials Consortium 
 
 
Sponsored by: 
National Cancer Institute 
Division of Cancer Treatment and Diagnosis 
 
 Study Drug and 
Therapy: 
 
Cisplatin (NSC #119875),  
Concomitant Radiation Therapy  
 
  Protocol Chair: 
Mark H. Einstein, MD, MS 
 
 
 
 
 Protocol Co-Chairs: 
 
Joel Palefsky, MD (HPV Working Group Chair) 
Madhur Garg, MD (Radiation Oncology Chair) 
Jeffrey Kotzen, MD 
 
Version 3.0 
 
NCI Version Date: 20 February 2015 
Update Date: 20 February 2015 
 
AMC-081 (Version 3.0) 20 February 2015 
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NCI Version Date 20 February 2015 

AMC PROTOCOL SIGNATURE PAGE 
 
 
I,              , Principal Investigator at site       , agree to conduct and follow this protocol: AMC 
Protocol #081 - Feasibility Study of Safety, Toxicity, and Compliance of Concomitant 
Chemoradiotherapy for HIV-Associated Locally-Advanced Cervical Cancer (Version 3.0 
20 February 2015), as written according to AMC, NCI and FDA guidelines. I understand that 
no deviations from the above protocol eligibility criteria or waivers for protocol deviations will 
be permitted. 
 
 
_________________________________ 
_____________________ 
 
Signature 
Date (ddmmmyyyy) 
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TABLE OF CONTENTS 
 
SUMMARY OF CHANGES ........................................................................................................ i 
AMC PROTOCOL SIGNATURE PAGE ................................................................................. 2 
TABLE OF CONTENTS ............................................................................................................ 3 
ABBREVIATIONS LIST ............................................................................................................ 6 
SITES PARTICIPATING IN THE STUDY ............................................................................. 8 
PROTOCOL ROSTER ............................................................................................................... 9 
STUDY SYNOPSIS ................................................................................................................... 12 
1.0 
INTRODUCTION........................................................................................................... 15 
1.1 
Study Rationale ..................................................................................................... 17 
1.2 
Rationale for Exploratory/Translational Testing .................................................. 17 
2.0 
STUDY OBJECTIVES ................................................................................................... 21 
2.1 
Hypotheses ............................................................................................................ 21 
2.2 
Primary Objectives................................................................................................ 21 
2.3 
Exploratory Objectives ......................................................................................... 22 
3.0 
PARTICIPANT SELECTION ...................................................................................... 24 
3.1 
Inclusion Criteria .................................................................................................. 24 
3.2 
Exclusion Criteria ................................................................................................. 25 
3.3 
Number of Participants to be Enrolled.................................................................. 26 
3.4 
Recruitment Procedures ........................................................................................ 27 
3.5 
Enrollment Procedures .......................................................................................... 27 
3.6 
Required Pathology Material and Data ................................................................. 28 
4.0 
STUDY MODALITIES .................................................................................................. 29 
4.1 
Staging .................................................................................................................. 29 
4.2 
Cancer Treatment Therapies ................................................................................. 29 
4.3 
Chemotherapy ....................................................................................................... 30 
4.4 
Drug Orders, Transfers, Returns, and Accountability .......................................... 31 
4.5 
Emergency Radiation Therapy to Stop Bleeding Prior to Treatment ................... 31 
4.6 
Radiation Therapy Procedures .............................................................................. 32 
4.7 
Duration of Study .................................................................................................. 39 
5.0 
CLINICAL AND LABORATORY EVALUATIONS ................................................. 40 
5.1 
Screening Evaluations ........................................................................................... 40 
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5.2 
Evaluations during Chemo-Radiation Treatment ................................................. 40 
5.3 
Evaluations after Completion of Therapy ............................................................. 41 
5.4 
Evaluations after Diagnosis of Recurrence ........................................................... 42 
5.5 
Premature Study Discontinuation Evaluations ..................................................... 42 
6.0 
TREATMENT MODIFICATIONS .............................................................................. 43 
6.1 
Radiation Therapy ................................................................................................. 43 
6.2 
Drug Therapy ........................................................................................................ 45 
7.0 
ADVERSE EVENTS MONITORING AND REPORTING ....................................... 50 
7.1 
Classification of AEs by Severity and Relationship to Study Drug Administration
............................................................................................................................... 50 
7.2 
Expedited AE Reporting Procedures .................................................................... 52 
7.3 
Routine AE Reporting........................................................................................... 54 
8.0 
CRITERIA FOR DISCONTINUATION ..................................................................... 56 
8.1 
Permanent Treatment Discontinuation ................................................................. 56 
8.2 
Premature Study Discontinuation ......................................................................... 56 
9.0 
EVALUATION CRITERIA .......................................................................................... 57 
9.1 
Outcome Measures................................................................................................ 57 
9.2 
Exploratory Outcome Measures ........................................................................... 57 
10.0 DATA MANAGEMENT ................................................................................................ 58 
10.1 
Data Quality .......................................................................................................... 58 
10.2 
CRF Instructions ................................................................................................... 58 
10.3 
Records to Be Kept ............................................................................................... 58 
10.4 
Role of Data Management .................................................................................... 58 
11.0 STATISTICAL CONSIDERATIONS .......................................................................... 59 
11.1 
Statistical Analysis Plan ........................................................................................ 59 
11.2 
Sample Size Considerations .................................................................................. 60 
11.3 
Site(s) of Recurrence............................................................................................. 60 
11.4 
Toxicity Analysis .................................................................................................. 61 
12.0 ETHICAL AND REGULATORY CONSIDERATIONS ........................................... 62 
12.1 
IRB/IEC Review and Informed Consent .............................................................. 62 
12.2 
Changes to the Protocol and Informed Consent Form .......................................... 62 
12.3 
Women and Minorities ......................................................................................... 63 
12.4 
Subject Confidentiality ......................................................................................... 63 
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12.5 
Study Discontinuation ........................................................................................... 63 
13.0 REFERENCES ................................................................................................................ 64 
APPENDIX I: SCHEDULE OF EVENTS .............................................................................. 69 
APPENDIX II: PERFORMANCE STATUS SCALE ............................................................ 71 
APPENDIX III: THE NEW YORK HEART ASSOCIATION (NYHA) FUNCTIONAL 
CLASSIFICATION SCALE ........................................................................ 72 
APPENDIX IV: CENTRAL PATHOLOGY REVIEW AND HANDLING OF TISSUES 73 
APPENDIX V: AMC DATA AND SAFETY MONITORING PLAN .................................. 74 
APPENDIX VI: CLINICAL STAGING - CARCINOMA OF THE CERVIX UTERI FIGO 
CLASSIFICATION 1995 ............................................................................. 78 
APPENDIX VII: HDR BRACHYTHERAPY ......................................................................... 80 
APPENDIX VIII: DESCRIPTION OF POINTS A AND B AND ICRU 
BLADDER/RECTAL DOSE REPORTING POINTS .............................. 82 
APPENDIX IX: BLANK DIAGRAM ANTERIOR ............................................................... 84 
APPENDIX X: BLANK DIAGRAM LATERAL ................................................................... 85 
APPENDIX XI: COLLECTION AND SHIPPING INSTRUCTIONS FOR SERUM AND 
CERVICAL AND ANAL SWABS FOR EXPLORATORY OBJECTIVE 
SPECIMENS ................................................................................................. 86 
APPENDIX XII: RADIATION THERAPY QUALITY ASSURANCE PROCESS ........... 90 
 
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ABBREVIATIONS LIST 
AAPM 
American Association of Physicists in Medicine 
ADCL 
Accredited Dosimetry Calibration Laboratory 
AIDS 
Acquired immunodeficiency syndrome 
AIN 
Anal intraepithelial neoplasia 
AMC 
AIDS Malignancy Consortium 
ANC 
Absolute Neutrophil Count 
AP/PA 
Anterior Posterior/Posterior Anterior 
BED 
Biological Equivalent Dose 
BEV 
Beams Eye View 
CBC 
Complete Blood Count 
CDDP 
Cisplatin, cisplatinum, or cis-diamminedichloroplatinum(II) 
CIN 
Cervical intraepithelial neoplasia 
CT 
Computed tomography 
CT A/P 
Computed tomography of abdomen/pelvis 
EBRT 
External beam radiation therapy 
EORTC 
European Organization for Research and Treatment of Cancer 
FIGO 
International Federation of Gynecology and Obstetrics 
FNA 
Fine needle aspiration biopsy 
GOG 
Gynecologic Oncology Group 
H&E 
Hematoxylin and eosin staining  
HAART 
Highly Active Antiretroviral Therapy 
HDR 
High dose rate 
HIV 
Human Immunodeficiency virus 
HPV 
Human papilloma virus 
HSIL 
High-grade squamous intraepithelial lesion 
IAEA 
International Atomic Energy Agency 
ICRU 
International Commission on Radiation Units 
IMRT 
Intensity-Modulated Radiation Therapy 
IROC Houston QA Center 
Imaging and Radiation Oncology Core Houston QA Center 
ITT 
Intent to treat 
IV 
Intravenous 
IVP 
Intravenous pyelogram 
LACC 
Locally advanced cervical cancer 
LDR 
Low dose rate 
Min 
Minute 
MRI 
Magnetic resonance imaging 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
NNRTI 
Non-Nucleoside Reverse Transcriptase Inhibitor 
NSC 
National Safety Council 
NYHA 
New York Heart Association 
ODMC 
Operations and Data Management Center 
OHRP 
Office for Human Research Protections 
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OSLD 
Optically Stimulated Luminescent Dosimeter 
PFS 
Progression free survival 
PI 
Principal Investigator 
QA 
Quality Assurance 
RCT 
Radiation concomitant therapy 
RT 
Radiation therapy 
RTOG 
Radiation Therapy Oncology Group 
SSD 
Source-skin distance 
SSDL 
Secondary Standards Dosimetry Laboratories 
SWOG 
Southwest Oncology Group 
TLD 
Thermoluminescent dosimeter 
WPRT 
Whole pelvic radiation therapy 
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SITES PARTICIPATING IN THE STUDY 
This protocol will be open for subject enrollment at the AMC core sites in Africa named in the 
protocol roster, as approved by the AMC Executive Committee and the AMC HPV Working 
Group for participation. The approval will be based on the capacity to perform concomitant 
chemoradiotherapy as required by this protocol. 
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PROTOCOL ROSTER 
Protocol Chair: 
Mark H. Einstein, MD, MS 
Albert Einstein Comprehensive Cancer Center 
Division of Gynecologic Oncology  
Department of Obstetrics & Gynecology 
Bronx, NY 10461 
Tel: 718-405-8082 
Fax: 718-405-8087 
Email: meinstei@montefiore.org 
 
Statistician: 
Jeannette Y. Lee, PhD 
University of Arkansas for Medical Sciences 
4301 W. Markham Street, #781 
Little Rock, AR 72205-7199 
Tel: 501-526-6712 
Fax: 501-526-6729 
Email: jylee@uams.edu 
Protocol Co-Chairs: 
Joel M. Palefsky, MD, CM, FRCPC 
University of California at San Francisco 
S-420E, Box 0654 
3rd and Parnassus Avenue 
San Francisco, CA 94143-0001 
Tel: 415- 476-1574 
Fax: 415- 476-9364 
Email: joel.palefsky@ucsf.edu 
 
Madhur Garg, MB, BS 
Montefiore Medical Center 
Department of Radiation Oncology 
Tel: 718-920-4140 
Fax: 718-231-5064 
Email: mgarg@montefiore.org 
 
Jeffrey Kotzen, MD 
Department Radiation Oncology 
Charlotte Maxeke Johannesburg Academic 
Hospital 
7 York Road, Parktown 
Johannesburg, 2193, South Africa  
Email: jkotzen@yahoo.com 
 
Central Gyn Pathologist: 
Kathleen Whitney, MD 
Director, Anatomic Pathology 
Montefiore Medical Center- Weiler Division 
1825 Eastchester Rd. 
Bronx, NY 10461 
Tel: 718-904-2947  
Email: kwhitney@montefiore.org  
AMC Medical Monitor: 
Thad Zajdowicz, MD 
The EMMES Corporation 
401 N. Washington Street, Suite 700 
Rockville, MD 20850 
Tel: 301-251-1161 
Fax: 240-238-2842 
Email: amipm@emmes.com 
 
Operations & Data Management Center: 
The EMMES Corporation 
401 N. Washington Street, Suite 700 
Rockville, MD 20850 
Tel: 301-251-1161 
Fax: 240-238-2842 
Email: 081protocolteam@emmes.com 
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Protocol Team 
North American Investigators: 
(Consulting members only) 
 
Himu Lukka, MD, MRCP, FRCR, FRCPC 
McMaster University 
Division of Radiation Oncology 
Juravinski Cancer Centre, 3rd Floor 
699 Concession St. 
Hamilton, Ontario, L8V 5C2 Canada  
Tel: 905-387-9711 Ext 64702 
Fax: 905-575-6326 
Email: himu.lukka@hrcc.on.ca 
 
L. Stewart Massad, MD 
Washington University School of Medicine 
Division of Gynecologic Oncology 
4911 Barnes-Jewish Hospital Plaza 
St. Louis, MO 63110 
Tel: 314-362-3181 
Fax: 314-362-2893 
Email: massadl@wudosis.wustl.edu  
 
Warner Huh, MD 
University of Alabama at Birmingham 
619 19th Street South 
176F RM 10250 
Birmingham, AL 35249 
Tel: 205-934-4986 
Fax: 205-975-6174 
Email: warner.huh@ccc.uab.edu  
 
Levi Downs, MD 
University of Minnesota 
420 Delaware Street, MMC #395 
Minneapolis, MN 55455 
Tel: 612-626-6499 
Fax: 612-626-0665 
Email: downs008@umn.edu 
 
African Investigators: 
(Treatment centers) 
 
Jackson Orem, MBChB 
Uganda Cancer Institute 
P.O. Box 3935  
Kampala, Uganda 
Tel: +256 414 540605/680467 
Mobile: +256 782 320543 
Fax: +256 414 540410 
Email: jacksonorem@yahoo.co.uk 
 
Martin Origa, M.Med (Obs/Gyn), MOSG 
(Oncology) 
Uganda Cancer Institute 
P.O. Box 3935  
Kampala, Uganda 
Tel: +256 414 540605/680467 
Mobile: +256/782546253 / 711546253 / 
792546253 / 701777679 
Fax: +256 414 540410 
Email: martinoriga@yahoo.co.uk 
 
Ntokozo Ndlovu, MB ChB, MMed 
Radiation Oncologist/Clinical 
Epidemiologist 
Chairperson Department of Radiology/ 
Head of Radiotherapy and Oncology 
University of Zimbabwe College of Health 
Sciences 
Mazowe Street 
P.O. Box A 178 
Avondale, Harare, Zimbabwe 
Email: nndlovu@mweb.co.zw 
 
Elkanah Omenge Orango, MD 
Moi University School of Medicine, 
Department of Reproductive Health 
P.O. Box 4606 
Eldoret 30100, Kenya 
Tel: +254722609132 
Email: bworango2000@yahoo.com 
 
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Site Pathologists: 
 
 
Michael Odida, MD, PhD  
Uganda Cancer Institute 
P.O. Box 3935  
Kampala, Uganda 
Tel: +256 777 071943 
Email: michaelodida@gmail.com 
 
Rudo Makunike-Mutasa, MD, PhD 
University of Zimbabwe College of Health Science
Mazowe Street 
P.O. Box A 178 
Avondale, Harare, Zimbabwe 
Email: rmutasa@hotmail.com 
 
David Chumba, MD, PhD 
Moi University School of Medicine, 
Department of Reproductive Health 
P.O. Box 4606 
Eldoret 30100, Kenya 
Email: dchumba@yahoo.com 
 
Elizabeth Mayne, MD, PhD  
University of the Witwatersrand 
Epidemiology and Biostatistics 
Clinical HIV Research Unit 
Johannesburg, 2092, South Africa  
Email: esm24@mweb.co.za 
Imaging and Radiation Oncology Core 
Houston QA Center: 
 
 
Jessica Lowenstein Leif, MS, DABR  
Department of Radiation Physics 
UT M.D. Anderson Cancer Center 
1515 Holcombe Blvd. 
Houston, TX 77030 
Tel: 713-745-8989 
Fax: 713-794-1364 
Email: jlowenst@mdanderson.org 
 
 
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STUDY SYNOPSIS 
TITLE: 
Feasibility Study of Safety, Toxicity, and Compliance of 
Concomitant Chemoradiotherapy for HIV-Associated Locally-
Advanced Cervical Cancer 
 
DESIGN: 
Open-label, single arm feasibility study 
 
DURATION: 
36 months (24 months of recruitment and 12 months of follow-
up) 
 
SAMPLE SIZE: 
 
45 women will be enrolled with the goal of 38 evaluable 
women for primary analysis 
 
POPULATION: 
HIV-infected women with incident locally-advanced cancer of 
the cervix (LACC), Stages IB2, IIA*, IIB, IIIB, IVA 
(squamous, adenocarcinoma, adenosquamous) 
(*Stage IIA tumor must be > 4 cm) 
 
REGIMEN: 
All participants with CD4 counts > 200/mm3 (0.2 x 109/L) will 
receive weekly cisplatin at a dose of 40 mg/m2 concomitant 
with radiotherapy (external beam and brachytherapy). The first 
3 participants with CD4 counts < 200/mm3 (0.2 x 109/L) will 
receive weekly cisplatin at a dose of 25 mg/m2 with 
radiotherapy (external beam and brachytherapy). Based on 
review of the safety data from the first 3 participants, all other 
participants with CD4 counts < 200/mm3 (0.2 x 109/L) will 
receive weekly cisplatin at a dose of 40 mg/m2 or no cisplatin 
with radiotherapy (external beam and brachytherapy). All 
participants 
will 
concomitantly 
receive 
combination 
antiretroviral therapy (ART) with an acceptable regimen that 
adheres to national guidelines for treatment of HIV infection. 
 
PRIMARY OBJECTIVES: 
 
1) To determine if it is feasible to administer a regimen of 
cisplatin/RT in HIV-infected women with LACC on ART. 
This regimen is considered standard therapy for women 
with LACC who are not HIV infected. Feasibility will be 
assessed based on: 
• Treatment completion proportion: the proportion of 
participants who complete the cisplatin/RT regimen 
• Screening ratio: the number of potential participants 
screened per enrolled participant 
• Availability 
proportion: 
follow-up 
completion 
proportion at 6 and 12 months 
2) To evaluate the safety and tolerability of concomitant 
chemoradiotherapy with cisplatin in HIV-infected women 
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with LACC who are also receiving concomitant ART. 
 
EXPLORATORY AND 
FUTURE RESEARCH 
OBJECTIVES: 
 
1) Determine the 1-year progression-free survival (PFS) of 
HIV-infected women with locally-advanced invasive 
cervical cancer (LACC) Stage IB, II, III, and IVA who 
receive weekly cisplatin concomitant with radiotherapy and 
ART. 
• Determine PFS in all registered participants, regardless 
of completion (intent to treat-ITT) 
• Determine the PFS in the subset of participants who 
complete the prescribed chemotherapy/radiotherapy 
• Compare PFS in these subjects with PFS of HIV-
uninfected subjects as reported in the literature, stage 
for stage 
2) To describe the effects of treatment on participants’ CD4 
counts, HIV viral load and concurrent AIDS-defining 
conditions 
3) To describe cervical cancer recurrence patterns in HIV-
infected participants with LACC defined as loco-regional 
and/or distant recurrences. 
4) Determine 1-year overall survival and causes of death, (i.e., 
cancer-related, HIV-related, or other). 
5) To evaluate the effects of weekly cisplatin concomitant 
with radiotherapy on adherence to ART 
6) Collect serum and cervical and anal swab material for the 
following exploratory analyses: 
 
a. To describe the distribution of HPV DNA types and 
HPV  strain variants in cervical and anal swabs 
collected at  
baseline, prior to initiation of study 
treatment; 
b. To assess the concordance between HPV DNA types 
and HPV strain variants detected in cervical and anal 
swabs collected at baseline, prior to initiation of study 
treatment; 
c. To investigate the effect of study treatment on HPV 
persistence in cervical and anal swabs and its 
relationship 
to 
cervical 
cancer 
persistence 
or 
recurrence; 
d. To describe the gene methylation profiles in cervical 
and anal swabs collected at baseline, prior to initiation 
of study treatment; 
e. To assess the concordance between gene methylation 
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profiles detected in cervical and anal swabs collected at 
baseline, prior to initiation of study treatment; 
f. To investigate the relationship between baseline gene 
methylation profiles and cervical cancer persistence or 
recurrence; 
g. To measure serum antibody titers to HPV 16 and HPV 
18 at baseline and on study, and to determine whether 
baseline titers or changes during therapy correlate with 
cervical cancer persistence or recurrence. 
 
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1.0 
INTRODUCTION 
The standard of care for the treatment of locally-advanced cervical cancer (LACC) is concurrent 
chemoradiotherapy using cisplatin as the chemotherapeutic radiosensitizing agent. This regimen 
is the current standard of care based on multiple randomized, controlled trials (RCT) that showed 
improved efficacy when cisplatin was added to radiation therapy, even in high-risk patients who 
have histologic evidence of metastatic disease to pelvic and/or para-aortic lymph nodes (1-3). 
Evidence from 5 randomized clinical trials (RCTs) (GOG 85, RTOG 9001, GOG 120, SWOG 
8797, GOG 123) prompted an NCI alert in February 1999 that recommended consideration of 
concomitant chemoradiotherapy for all patients with cervical cancer (4). A Cochrane database 
review of 19 RCTs in LACC confirmed improvement in overall survival and progression free 
survival (PFS) (5). The addition of chemotherapy also appears to afford higher objective 
response rates; however, it was noted that the survival increase did come at the cost of significant 
hematologic and gastrointestinal toxicity in subsets of LACC patients. 
 
Like many AIDS-related malignancies, HIV-associated invasive cervical cancer appears to have 
decreased in incidence in the U.S. due to an understanding of the need for aggressive treatment 
of precancerous cervical lesions in the setting of HIV. Nevertheless, LACC in HIV is still a 
major problem worldwide. None of the pivotal RCTs proving the benefits of adding cisplatin to 
radiation therapy included HIV-infected women with LACC, so efficacy data in the setting of 
HIV are limited to retrospective analyses. Acute and long term toxicity data in LACC in the 
setting of modern antiretroviral therapy (ART) do not exist for two main reasons: 1) HIV-
associated cervical cancer is rare in developed countries, and 2) in countries which have a large 
number of HIV-associated cervical cancer patients, modern ART was not regularly used until 
recently due to lack of access or financial means to pay for the medications. 
 
Optimal cisplatin-based treatments have evolved since the early studies in the mid-1980s. Many 
of the early regimens consisting of cisplatin alone or in combination with other chemotherapeutic 
agents, such as 5-FU or hydroxyurea, were inpatient regimens that required intravenous (IV) 
hydration and mannitol continuously for 5 days (2, 3, 6, 7). Because of the ease of weekly dosing 
and the lower cost of outpatient administration, a trend to use outpatient weekly cisplatin (40 
mg/m2) emerged despite no RCT showing efficacy or toxicity equivalency to inpatient 5-day 
regimens (8,9). Other dosing regimens commonly used worldwide include cisplatin 75 mg/m2 
every 3 weeks for 2 cycles during radiotherapy (unpublished data, but used in South Africa and 
many Southeast Asian sites per personal communications at the State of the Science of Cervical 
Cancer Meeting, Manchester, England, 2009). 
 
Unfortunately, little is known about the effects of ART on standard treatments for cervical 
cancer with regards to drug-drug interactions because HIV-infected women with LACC have 
been typically excluded from clinical trials (10). Many antiretroviral agents are notorious for 
causing drug-drug interactions. Co-administration of standard cytotoxic and targeted therapies 
with ART could impair the efficacy or increase the toxicity of these combined therapies. 
Additionally, HIV-infected patients with cervical cancer often have a poor nutritional status 
while they are undergoing high-dose pelvic radiation therapy. While there are no prospective 
studies in cervical cancer, the combination of factors that causes poor marrow reserve in other 
AIDS malignancies can lead to increased toxicity and reduced efficacy in HIV-infected women 
with cervical cancer compared with their non-HIV-infected counterparts (11). Also, while 
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standard dosing for weekly cisplatin is 40 mg/m2 when given concurrently with RT, there are 
some data that suggest that this weekly dose might be too high for some patient populations, 
especially in Africa (21). 
 
As stage increases with LACC, the incidence of local pelvic or para-aortic lymph node 
metastasis increases. Patients who have histologic evidence of metastatic disease to pelvic and/or 
para-aortic lymph nodes have a worse prognosis. Patients with positive para-aortic lymph nodes 
represent about 20% of all women diagnosed with invasive cervical cancer in the United States; 
the percentage of women with para-aortic lymph node involvement is often higher in HIV-
infected women with cervical cancer (12-18). While there is no prospective evaluation of 
outcomes for HIV-infected individuals with LACC with nodal disease, historically, they do 
worse than their non-HIV-infected counterparts do. In HIV-negative women, 6% of early stage 
cervical cancers (i.e., cancer confined to the cervix) and as high as 25% of advanced stage 
cervical cancer patients (i.e., locally advanced or metastatic) will have histologically positive 
para-aortic lymph nodes. Survival for this subset of patients is poor and quoted from 20%-33%. 
The GOG reported a 33% disease-free survival and 39% overall survival at 3 years in patients 
with positive para-aortic lymph nodes treated with 5-FU and cisplatin with radiation therapy 
(19). We will assess whether the nodal status of patients enrolled in this trial is a prognostic 
characteristic of decreased survival, tolerability, and/or response. 
 
The International Atomic Energy Agency (IAEA) has recently sponsored a prospective clinical 
trial in HIV-infected women with LACC (H. Lukka et al, unpublished data). This is an 
international trial to compare relapse-free survival after 3 years between HIV-infected women 
with LACC treated with radiation alone and those treated with concomitant chemoradiotherapy 
with cisplatin. Sites include South Africa (n=73), Tanzania (n=126), Zimbabwe (n=16), Uganda 
(n=47), and India (n=46). Radiation was prescribed as per standard of local care which included 
external beam radiation therapy (EBRT) with both high-dose rate (HDR) and low-dose rate 
(LDR) brachytherapy, depending on capacity and local standards with total doses being similar 
(however, these are still unaudited data). Only 16% of the participants recruited on this trial 
received or had access to HAART. Monitoring for efficacy is still ongoing as of September 
2011. It has been noted that there is a considerable amount of subjects that have not followed up 
for care on this trial. This is one of the reasons to perform this feasibility study. In summary: 
1) Concomitant chemoradiotherapy with cisplatin-containing regimens show superior efficacy 
for LACC when compared with radiotherapy alone in HIV-uninfected women. 
2) This has not been proven in the setting of HIV, where cervical cancer is common particularly 
in regions of the world that do not have robust screening programs. In fact, there are limited 
data regarding HIV-associated LACC in the literature primarily due to the exclusion of these 
women from the majority of clinical trials. Also, cisplatin-containing regimens have not been 
studied in cohorts of women on HAART throughout their treatment. 
3) The optimal dosing for cisplatin when combined with radiation has not been prospectively 
tested in the setting of differing degrees of viremic suppression with HIV infection in patients 
receiving ART. There is evidence to suggest there are differences in efficacy and toxicity 
with lower doses in HIV-uninfected women with LACC (21). 
4) AMC-081 represents the initial clinical trial of cervical cancer in HIV-infected individuals on 
ART to be conducted in a resource-limited environment. 
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5) AMC-081 represents the first AMC cervical cancer trial and one of its first international 
trials. Hence, this is a feasibility study to assess the treatment completion rate, screening rate 
and safety of a regimen that is standard for women with cervical cancer who are not HIV 
infected. 
6) This trial will also integrate the Imaging and Radiation Oncology Core Houston Quality 
Assurance Center and will provide important information for QA/QC for future AMC trials 
requiring RT in Africa. 
7) This trial will provide estimates of treatment completion rates, screening rates, follow-up 
rates and preliminary estimates of response rates that will inform development of planning a 
phase II trial that will evaluate efficacy endpoints. 
8) AMC-081 will provide the first prospectively-collected data on HPV DNA types and strain 
variants, gene methylation patterns, and HPV serology in HIV-infected women with invasive 
cervical cancer in Africa and, in a preliminary way, will provide important information on 
their potential utility as markers for persistence or recurrence in HIV-associated cervical 
cancer. 
 
1.1 
Study Rationale 
To advance the science in HIV-associated cervical cancer in the HAART era, this 
prospective feasibility trial in HIV-infected women with LACC will be performed at 
African AMC sites to determine and establish baseline data important for future 
evaluation of treatment regimens in this patient population using the standard, simple to 
administer, outpatient regimen of cisplatin concomitant with RT. Secondary analyses will 
include overall and progression-free survival. This trial represents the next step in the 
science of HIV-associated cervical cancer treatment for numerous reasons: 
1) For this protocol, all participants will be receiving ART. All participants must be on 
combination antiretroviral therapy with an acceptable regimen that adheres to national 
guidelines for treatment of HIV infection. This trial would provide additional toxicity 
data in subjects with LACC on ART. 
2) Most current trials in LACC in HIV-uninfected women include additional cytotoxic 
chemotherapy 
for 
higher 
risk 
patients 
(e.g. 
ANZOG/GOG/RTOG/NCIC/ 
GEICO/NSGO ‘Outback’ trial), targeted therapies (e.g. bevacizumab), or additional 
maintenance therapy. This trial would represent the baseline of comparison for future 
trials in HIV-associated LACC using cisplatin in combination with other therapies. 
3) While this study will not stratify by stage or nodal involvement, all participating sites 
will be required to perform baseline imaging (CT A/P with contrast) to assess tumor 
size and enlarged nodes. GOG trials in HIV-uninfected women with positive nodes 
who are treated with concomitant chemoradiotherapy with cisplatin alone have poorer 
survival and increased toxicity compared with those with unenlarged nodes (22-26). 
In this trial, we will assess whether the presence of positive nodes by imaging is a 
poor prognostic characteristic among HIV-infected women with LACC. 
 
1.2 
Rationale for Exploratory/Translational Testing 
1.2.1 HPV DNA Testing 
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High-risk HPV types have been implicated in the etiology of cervical cancer (28-
30), and its precursor, high-grade cervical intraepithelial neoplasia (CIN) (29,31); 
and anal cancer (32-33) and its putative precursor, high-grade anal intraepithelial 
neoplasia (AIN) (34-37). More than 100 HPV types have been identified, which 
by definition differ from one another by at least 10% of their DNA sequences 
(38). Of the HPV types conferring the highest risk for high-grade disease and 
invasive cancer, HPV types 16 and 18 are the most common (32,38), with HPV 
16 infection being the single most common HPV type in anogenital cancer (39). 
 
However, it is not known if the distribution of HPV types in cervical cancer 
developing in HIV-infected is different from that developing in HIV-uninfected 
women, where it has clearly been shown that HPV 16 and 18 are present in 
approximately 50% and 20% of cancers, respectively. We will also collect 
cervical and anal swabs at baseline prior to initiation of therapy, and at 
completion or premature discontinuation of therapy. The post-treatment samples 
will allow us to examine in an exploratory analysis, the effect of treatment on 
HPV persistence, and determine whether HPV persistence is related to disease 
recurrence. We also propose to study anal samples for HPV DNA at these time 
points. Studies have shown a relationship between cervical and anal cancer, and 
little is known about anal HPV in women with cervical cancer. We can also 
examine the effect of cervical cancer treatment on anal HPV persistence.  
 
Therapy for cervix cancer has changed over the last decade. Chemotherapy has 
been shown to be beneficial and has been added to our armamentarium of surgery 
and radiation. Nevertheless, in an era of personalized medicine, the potential 
biological differences of cervix cancer associated with different HPV types and 
host variation have not been adequately evaluated as determinants of cervix 
cancer outcome and/or response to therapy. Prior studies were conducted in the 
era of radiation alone, not concomitant chemoradiotherapy, and none address 
HIV-associated cervical cancer (40-42). Moreover, cervix cancer in an advanced 
state and in the setting of HIV has a poor prognosis. Since HPV types associated 
with cancer have divergent risks and associations with tumor types, we expect 
that knowledge of the HPV type will help to identify patients most at risk for 
treatment failure, recurrence, and response to surgery, radiation and/or 
chemotherapy. 
 
Although detection of an oncogenic HPV type is associated with increased risk of 
anogenital cancer, recent studies of cervical lesions suggest that differences in the 
genome sequence within variants of a given HPV type, such as HPV 16, may 
substantially affect the level of risk. Thus, “European” or “prototype” variants of 
HPV 16 were associated with lower risk of CIN 2 or 3 and cervical cancer than 
were “non-European” or “non-prototype” variants (43). This was shown to be the 
case for AIN as well compared to “prototype” HPV 16 variants. MSM with anal 
“non-prototype” HPV 16 variants were more than three times as likely to develop 
AIN 3 (43-44). In a study by Palefsky et al., an elevated risk for AIN 2 or 3 was 
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associated with infection with G131 European variants of the HPV 16 E6 protein 
when compared with the prototype HPV 16 strain (44). 
 
Amino acid differences in the E6 and E7 proteins are likely to be at least partly 
responsible for the differential pathogenicity of the various HPV types. However, 
the amino acid sequences of these proteins vary not only across HPV types, but 
within type as well. More than 25 sequence variants of HPV 16 have been 
reported, and a phylogeny-based classification incorporating the L1, L2, and E6 
genes has been proposed by Yamada et al (45). Differential pathogenicity of HPV 
16 variants has been reported for cervical HSIL (43,46-47), invasive cervical 
cancer (48), and anal HSIL (49). In a study of variants in the L1 region, 
Hildesheim et al (50) reported that detection of non-European variants, as is 
typically found in Africa, was associated with increased risk of cervical cancer. 
Nothing is currently known of the HPV variants in HIV-associated cervical 
cancer, nor is there an understanding of concomitant anal HPV infection in the 
setting of cervical cancer and HIV in Africa or the US. 
 
1.2.2  DNA Methylation in HIV-associated cervical cancer 
DNA methylation is a mechanism used by cells to regulate gene expression (51-
53). It involves the addition of a methyl group to cytosine nucleotides by enzymes 
called DNA methyltransferases (54). Typically, the methylated cytosines are 
clustered in chromosomal regions rich in cytosine and guanine dinucleotides 
(CpG islands) found in the promoter region, which is involved in regulating gene 
expression. In general, methylation of this region results in altered expression of 
the adjacent gene. The mechanism for this is not entirely clear but involves the 
disruption of the association of transcription factors with the DNA. DNA 
methylation is also associated with histone deacetylation, which compacts the 
chromatin and further represses gene expression. 
 
DNA methylation has an important role in tumorigenesis (55). Methylation-
induced alteration of genes that limit cell growth, termed tumor suppressor genes, 
is an important step in tumorigenesis, in addition to point mutations or deletions. 
Many tumor suppressor genes are specifically methylated in tumors but not in 
normal tissues. Methylation of tumor suppressor genes has been detected in 
virtually every type of malignancy, including cervical cancer. The profile of 
methylated genes appears relatively specific for each tumor type. For example, 
p16INK4a gene methylation is noted in many different tumors, such as colorectal, 
lung, breast, and cervical carcinoma. But other genes such as p15INK4b are 
methylated in leukemia and lymphoma, but not in lung, colon, or breast cancers 
(56). In other words, many tumors have gene methylation profiles that are specific 
for the tumor type. 
 
In prior studies of CIMP profiles in women with different grades of CIN and 
cancer, there are differences in the quantity and profile of methylated genes across 
grades of CIN and cervical cancer (57-61). Differential methylation of MGMT, 
for instance, exists across all grades of CIN and cancer appears to be a late event. 
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There is also differential methylation with other genes, such as CDKN2A gene, 
which expresses the p16ink4A protein. In addition to the gene that encodes for 
p16ink4A and MGMT, others include HIC1, APC, RARβ, GSTP1, Fas, MMP-1, 
and TNF-α. Little is known about methylation in cervical cancer tumors of HIV-
infected women. 
 
The predictive nature and timing of gene methylation in identifying cervical 
cancer recurrences have not yet been elucidated. We plan to examine the 
methylation profile in cervical and anal swab samples from participants in this 
trial and will, in a preliminary fashion, examine their relationship to disease 
recurrence in our cohort. 
 
1.2.3 HPV Serology 
Antibodies to conformational epitopes on synthetically produced virus-like 
particles (VLPs), structurally similar to the HPV virion, have been shown to 
develop in response to HPV infection (62-65). Serologic responses directed at 
type-specific epitopes on VLPs are often detectable when there is clinical 
evidence of disease. Serologic titers can be quantified and related to clinical 
disease status (63, 65-66). In fact, it appears that higher titers might correlate with 
worsening grade CIN and cancer (67). Neither seropositivity nor antibody titers 
have been explored as a marker for persistence or recurrence in HIV-associated 
cervical cancer. 
 
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2.0 
STUDY OBJECTIVES 
2.1 
Hypotheses 
2.1.1 Treatment compliance will be comparable to what has been previously reported in 
retrospective studies (27). 
 
2.1.2 The toxicity of weekly cisplatin in HIV-infected women on HAART is worse than 
that reported in HIV-uninfected women but manageable with limited dose 
reductions and dose delays. 
2.1.2.1 Recurrence patterns for HIV-associated LACC will be similar to that in 
HIV-uninfected women with LACC. 
 
2.1.2.2 Patients with poorly-controlled HIV (defined as CD4 count of ≤ 200/µL 
and/or HIV viral load > 400 copies/mL) will have higher likelihood of 
distant recurrences. 
 
2.1.3 The PFS at 1 year in HIV-infected women on ART who complete the prescribed 
cisplatin and RT doses of concomitant chemoradiotherapy with weekly cisplatin 
is similar, stage for stage, to the PFS in HIV-uninfected women stage for stage in 
LACC. 
 
2.1.4 The subset of participants with poorly-controlled HIV as defined by baseline CD4 
T-cell count and viral load will have worse PFS when compared with participants 
with well-controlled HIV infection. 
 
2.1.5 Baseline measures of HPV types and strain variants, gene methylation patterns, 
and HPV serology and/or changes induced by therapy will be associated with the 
risk of subsequent recurrence of HIV-associated LACC. 
 
2.2 
Primary Objectives 
2.2.1 To determine if it is feasible to administer a regimen of cisplatin/RT in HIV-
infected women with LACC on ART. This regimen is considered standard 
therapy for women with LACC who are not HIV infected. Feasibility will be 
assessed based on: 
2.2.1.1 Treatment completion proportion – the proportion of participants who 
complete the cisplatin/RT regimen 
 
2.2.1.2 Screening ratio: the number of potential participants screened per 
enrolled participant 
 
2.2.1.3 Availability proportion: follow-up completion proportion at 6 and 12 
months 
 
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2.2.2 To evaluate the safety and tolerability of concomitant chemoradiotherapy with 
cisplatin in HIV-infected women with LACC who are also receiving concomitant 
ART. 
2.3 
Exploratory Objectives 
2.3.1 To determine the 1-year progression-free survival (PFS) of HIV-infected women 
with locally-advanced invasive cervical cancer (LACC) Stage IB, II, III, and IVA 
who receive weekly cisplatin concomitant with radiotherapy and ART. 
2.3.1.1 Determine PFS in all registered participants, regardless of completion 
(intent to treat-ITT) 
 
2.3.1.2 Determine the PFS in the subset of participants who complete the 
prescribed chemotherapy/ radiotherapy 
 
2.3.1.3 Compare PFS in these subjects with PFS of HIV-uninfected subjects as 
reported in the literature, stage for stage. 
 
2.3.2 To describe the effects of treatment on participants’ CD4 counts, HIV viral load 
and concurrent AIDS-defining conditions. 
 
2.3.3 To describe cervical cancer recurrence patterns in HIV-infected participants with 
LACC defined as loco-regional and/or distant recurrences. 
 
2.3.4 Determine 1-year overall survival and causes of death (i.e., cancer-related, HIV-
related, or other). 
 
2.3.5 To evaluate the effects of weekly cisplatin concomitant with radiotherapy on 
adherence to ART. 
 
2.3.6 Collect serum and cervical and anal swab material for the following exploratory 
analyses: 
2.3.6.1 To describe the distribution of HPV DNA types and HPV strain variants 
in cervical and anal swabs collected at baseline, prior to initiation of 
study treatment; 
 
2.3.6.2 To assess the concordance between HPV DNA types and HPV strain 
variants detected in cervical and anal swabs collected at baseline, prior to 
initiation of study treatment; 
 
2.3.6.3 To investigate the effect of study treatment on HPV persistence in 
cervical and anal swabs and its relationship to cervical cancer persistence 
or recurrence; 
 
2.3.6.4 To describe the gene methylation profiles in cervical and anal swabs 
collected at baseline, prior to initiation of study treatment; 
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2.3.6.5 To investigate the relationship between baseline gene methylation 
profiles and cervical cancer persistence or recurrence; 
 
2.3.6.6 To measure serum antibody titers to HPV 16 and HPV 18 at baseline and 
on study, and to determine whether baseline titers or changes during 
therapy correlate with cervical cancer persistence or recurrence. 
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3.0 
PARTICIPANT SELECTION 
All protocol participants must meet all stated eligibility criteria. Participating sites must have 
documentation that each eligibility requirement is satisfied prior to subject enrollment. In 
compliance with CTEP policy, no exceptions to eligibility criteria will be granted under any 
circumstance. 
 
3.1 
Inclusion Criteria 
3.1.1 Participants (who have been adequately clinically staged by standard clinical 
guidelines) with primary, untreated, histologically-confirmed, documented 
invasive squamous cell carcinoma, adenocarcinoma, or adenosquamous 
carcinoma of the uterine cervix, FIGO stages IB2, IIA, IIB, IIIA, IIIB, and IVA. 
(Stage IIA tumors must be greater than 4 cm.) 
 
3.1.2 HIV-1 infection, documented by any licensed rapid HIV test or HIV enzyme or 
chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry 
and confirmed by a licensed Western blot or a second antibody test by a method 
other than the initial rapid HIV and/or E/CIA, or by HIV-1 antigen, plasma HIV-1 
RNA viral load. 
 
NOTE: The term “licensed” refers to a U.S FDA-approved kit or for sites located 
in countries other than the United States, a kit that has been certified or licensed 
by an oversight body within that country and validated internally.  
 
WHO (World Health Organization) and CDC (Centers for Disease Control and 
Prevention) guidelines mandate that confirmation of the initial test result must use 
a test that is different from the one used for the initial assessment. A reactive 
initial rapid test should be confirmed by either another type of rapid assay or an 
E/CIA that is based on a different antigen preparation and/or different test 
principle (e.g., indirect versus competitive), or a Western blot or a plasma HIV-1 
RNA viral load. 
 
3.1.3 The following laboratory tests within 14 days of study enrollment: 
 Hemoglobin > 10 g/dL (6.2 mmol/L) 
 Platelet count > 100,000/mm3 (100 x 109/L) 
 ANC > 1500/mm3 (1.5 x 109/L) (Participants receiving transfusion, 
erythropoietin, or myeloid growth factor support will be eligible for this 
study) 
 Creatinine clearance > 60 mL/min (1.00 mL/s) calculated by the Cockcroft-
Gault equation for women 
 AST and ALT < 3 X ULN 
 Total bilirubin < 2 X ULN unless related to antiretroviral use (e.g., atazanavir 
and indinavir), then the direct bilirubin must be < 2 X ULN 
 
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3.1.4 Adults, 18 years of age or older. DOB and age should be determined based on 
best possible information or documentation available. 
 
3.1.5 All patients must be prescribed combination antiretroviral therapy with the goal of 
virological suppression using an acceptable regimen that adheres to national 
guidelines for treatment of HIV infection. Further details can be found in Section 
4.2.3. Non-suppressed, treatment experienced patients, defined as patients with a 
viral load > 400 copies/mL who have been on antiretroviral therapy for more than 
4 months can be enrolled if an alternative ART regimen is available that includes 
at least two ART drugs that, in the opinion of the site investigator, are expected to 
have activity based on genotypic testing (if available) and treatment history.  
 
3.1.6 Ability to understand and the willingness to provide informed consent to 
participate. 
 
3.1.7 ECOG performance status of < 2. 
 
3.1.8 Participants of childbearing potential, defined as a sexually mature woman who: 
1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not 
been naturally postmenopausal for at least 24 consecutive months (i.e., has had 
menses at any time in the preceding 24 consecutive months), must have a negative 
urine or serum pregnancy test within 3 weeks prior to enrollment and agree to use 
an effective form of contraception (e.g., barrier contraception, highly effective 
hormonal contraception). 
 
3.1.9 In the opinion of the investigator the protocol treatment is appropriate for the 
participant.  
 
3.1.10 Life expectancy of greater than 12 months. 
 
3.2 
Exclusion Criteria 
3.2.1 Participants who have undergone hysterectomy. 
 
3.2.2 Acute active (such as tuberculosis or malaria), serious, uncontrolled infection. 
Participants with a CD4 count < 50/mm3 (0.05 x 109/L) will be excluded if they 
have had an opportunistic infection within the past 3 months, or if there is 
evidence of resistance to antiretroviral therapy (i.e., HIV viral load > 400 
copies/mL despite combination antiretroviral therapy for at least 4 months). 
 
3.2.3 Prior invasive malignancy other than LACC diagnosed within the past 24 months, 
excluding anal intraepithelial neoplasia, non-melanoma skin carcinoma, or 
Kaposi’s sarcoma that has not required systemic chemotherapy within the past 24 
months. 
 
3.2.4 Pregnancy or breast-feeding. Radiation therapy to the pelvis is contraindicated 
during any stage of pregnancy. 
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3.2.5 A medical or psychiatric illness that precludes ability to give informed consent or 
is likely to interfere with the ability to comply with the protocol stipulations. 
 
3.2.6 Participants with circumstances that will not permit completion of the study or 
required follow-up. For instance, if travel to and from treatment site is an issue. 
 
3.2.7 Participants with carcinoma of the cervical stump. 
 
3.2.8 Participants with history of cardiovascular disease manifested as: 
• History of myocardial infarction 
• Unstable angina 
• Currently taking medication for treatment of angina 
• History of coronary artery bypass surgery 
• New York Heart Association class 3 or 4 heart failure (Appendix III) 
 
3.2.9 Participants with enlarged para-aortic lymph node involvement on imaging that is 
suspicious for metastasis. 
3.3 
Number of Participants to be Enrolled 
This study will enroll 45 participants, of whom we anticipate 38 will be evaluable. Once 
all sites are open for accrual, we anticipate the accrual rate to be 4-6 per month. Accrual 
is expected to take an estimated 24 months. All participants will have a minimum of 12 
months of follow-up. We anticipate that at least 50% of recruited participants will be 
Stage 3 and 4A. 
 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Female 
 
Male 
 
Total 
Hispanic or Latino 
0 
+ 
0 
= 
0 
Not Hispanic or Latino 
45 
+ 
0 
= 
45 
Ethnic Category: Total of all subjects 
45 (A1) 
+ 
0  (B1) 
= 
45  (C1) 
Racial Category 
 
American Indian or Alaskan Native 
0 
+ 
0 
= 
0 
Asian 
0 
+ 
0 
= 
0 
Black or African American 
45 
+ 
0 
= 
45 
Native Hawaiian or other Pacific  Islander 
0 
+ 
0 
= 
0 
White 
0 
+ 
0 
= 
0 
Racial Category: Total of all subjects 
45  (A2) 
+ 
0  (B2) 
= 
45  (C2) 
 
(A1 = A2) 
 
(B1 = B2) 
 
(C1 = C2) 
 
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3.4 
Recruitment Procedures 
This study will be open at AMC African sites that have the capacity to deliver 
concomitant chemoradiotherapy as prescribed in this protocol. This includes weekly 
cisplatin at 40 mg/m2 concomitant with radiotherapy (external beam and brachytherapy). 
Participating sites will need to have ART available for all enrolled participants that 
adheres to national guidelines for treatment of HIV infection. Sites that have this capacity 
will be approved by the leadership of this protocol. Participants will be either from 
primary clinics or from referrals that have HIV infection and incident LACC. Participants 
may originate from different health care settings. 
 
3.5 
Enrollment Procedures  
This study will be available for enrollment at AMC core sites in Africa. Sites must have 
this protocol approved by their Institutional Review Board (IRB) or Independent Ethics 
Committee (IEC) and any relevant national and local authorities. Sites must also receive 
approval by the protocol leadership and register with the AMC Operations and Data 
Management Center (ODMC) before they may enroll participants. Protocol registration 
instructions and forms will be made available on the AMC Operations web site 
(www.amcoperations.com). Participating sites may not order study drug until protocol 
registration with the AMC ODMC is complete. 
 
3.5.1 Registration for Screening 
After an informed consent form has been signed by the participant, the participant 
must be registered for screening (AMC-081, Screening Segment) on-line via the 
AMC AdvantageEDC SM Internet Data Entry System. After successful registration 
into the screening segment, the participant will receive a nine-digit participant ID 
and will then enter the screening process. Participants will be enrolled on-line via 
the AMC Internet Data Entry System no more than 3 weeks prior to the initiation 
of treatment. Once the eligibility checklist is submitted, a system-generated 
confirmation will be sent to the site staff, AMC ODMC, and Protocol Chair upon 
successful registration.  
 
Please reference the AMC-081 MOP for additional details regarding the required 
tests prior to enrollment in the screening segment. 
 
If the on-line system is inaccessible for Screening Registration (Segment A), the 
site should notify the AMC ODMC via email at 081protocolteam@emmes.com or 
via phone at 001-301-251-1161 for further instructions. Please reference the 
AMC-081 MOP for additional instructions. 
 
3.5.2 Enrollment  
After the screening evaluations are completed and the participant is determined to 
be eligible the participating site will complete the protocol-specific eligibility 
checklist and enroll the participant into AMC-081 Treatment Segment (Segment 
B) on-line via the AMC AdvantageEDC
SM Internet Data Entry System. The 
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participating site will ensure the participant meets all eligibility criteria prior to 
completing the protocol-specific eligibility checklist. Participants will be enrolled 
on-line via the AMC Internet Data Entry System no more than 1 week prior to the 
initiation of treatment (enrollment 1 day prior to or on the day of treatment is 
strongly encouraged). Once the eligibility checklist is submitted, a system-
generated confirmation will be sent to the site staff, AMC ODMC, and Protocol 
Chair upon successful registration.  
 
If the on-line system is inaccessible for Registration (Treatment Segment), the site 
should notify the AMC ODMC via email at 081protocolteam@emmes.com or via 
phone at 001-301-251-1161 for further instructions. If the AMC ODMC cannot be 
reached, please follow the manual randomization procedures detailed in the 
AMC-081 Manual of Procedures. 
 
3.6 
Required Pathology Material and Data 
Local pathology must be performed according to local standard procedures to confirm the 
diagnosis of invasive squamous cell carcinoma, adenocarcinoma, or adenosquamous 
carcinoma of the uterine cervix. The local pathology review must be done prior to 
enrollment to confirm participant eligibility. Appropriate pathology reports from the 
participating institution are required to be maintained for source documentation.  
 
A central pathology review will be performed according to Appendix IV. The purpose of 
the central pathology review is to provide a consistent review and confirmation of the 
diagnosis and histology of cervical carcinoma for all study participants. This requirement 
applies to all cases, regardless of the country in which the subject is enrolled. 
 
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4.0 
STUDY MODALITIES 
To be eligible, participants with invasive squamous cell, adenocarcinoma, or adenosquamous 
carcinoma of the cervix must have undergone clinical staging by physicians according to FIGO 
staging criteria see (Appendix VI). 
 
4.1 
Staging 
4.1.1 Clinical Staging 
Participants must have a chest x-ray and a CT of the abdomen and pelvis with 
contrast. Stage should be assigned and documented as permitted under FIGO 
staging criteria. The para-aortic lymph node region must be negative for 
metastasis by CT with contrast. 
 
Additional procedures, such as IVP, ultrasound, cystoscopy, proctoscopy, or 
barium enema may be performed at the discretion of the investigator.  
 
4.1.2 All participants with cancer confined to the pelvis (Stages IB2, IIA, IIB, IIIB, 
IVA) will receive pelvic irradiation and concurrent cisplatin as outlined below. 
 
4.2 
Cancer Treatment Therapies 
4.2.1 Radiation Therapy 
 
See dose table below (Section 4.6) for details and appropriate fractionation 
schemes. 
• 41.4-45.0 Gy/1.8 Gy per fraction/23-25 fractions/five weeks pelvic RT. 
• 35-43.6 Gy intracavitary brachytherapy in one to two implants LDR or 18-28 
Gy intracavitary brachytherapy in 2-4 fractions HDR. 
• 5.40 - 9.00 Gy/1.8 Gy/3-5 fractions/3-5 days parametrial boost to involved 
parametria. 
• Overall treatment time not to exceed eight weeks. 
 
4.2.2 Chemotherapy 
Cisplatin 40 mg/m2 IV over 30-60 minutes given weekly on days 1, 8, 15, 22, 29 
and 36 for a total of 6 weekly cycles. 
 
4.2.3 Antiretroviral Therapy Regimen 
4.2.3.1 All patients must be prescribed combination antiretroviral therapy with the 
goal of virological suppression using an acceptable regimen that adheres 
to national guidelines for treatment of HIV infection. Patients can already 
be on a regimen and remain on that regimen  during 
treatment 
on 
this 
protocol. Subjects can begin ART on the day of enrolling in this study to 
meet eligibility criteria. 
  
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4.2.3.2 Although specific drugs will not be prohibited, when considering ART, 
please note the following:  
 
• Cisplatin-associated 
neuropathy 
may 
be 
worsened 
by 
co-
administration of didanosine (ddI) or stavudine (d4T) 
 
• Anemia and neutropenia associated with cisplatin may be worsened by 
co-administration of Zidovudine (ZDV) 
 
• Cisplatin-associated renal insufficiency may be worsened by co-
administration of tenofovir 
 
Whenever possible, co-administration of these antiretroviral agents 
should be avoided while study subjects are receiving cisplatin as part 
of this study. If co-administration is unavoidable and graded toxicities 
occur that require modification of the cisplatin dose, it is strongly 
recommended that, where available, the use of alternative 
antiretroviral drugs without overlapping toxicities, be considered 
before modifying the cisplatin dose. 
 
4.3 
Chemotherapy 
4.3.1 Cisplatin (Platinol®-AQ –NSC #119875) 
4.3.1.1 Formulation: Cisplatin is supplied as a sterile aqueous solution, each ml 
containing 1 mg cisplatin and 9 mg sodium chloride. Cisplatin is 
supplied in multidose vials containing either 50mg or 100mg of 
cisplatin. 
 
NOTE: Aluminum reacts with cisplatin causing precipitation formation 
and loss of potency; therefore, needles or intravenous sets containing 
aluminum parts that may come in contact with the drug must not be used 
for the preparation or administration of cisplatin. 
 
4.3.1.2 Storage: Store at 15 to 25°C. Do not refrigerate. Protect unopened 
container from light. The cisplatin remaining in the amber vial following 
initial entry is stable for 28 days protected from light or for 7 days under 
fluorescent room light. 
 
4.3.1.3 Adverse effects: Leukopenia, thrombocytopenia, anemia, nausea, 
vomiting, nephrotoxicity, ototoxicity, peripheral neuropathy, electrolyte 
imbalance, 
hypocalcemia, 
hypomagnesemia, 
aminoglycoside 
ototoxicity, ocular toxicity, and allergic reactions. 
 
 
Infrequent: Cardiac abnormalities, anorexia, elevated SGOT, rash, 
alopecia, and acute myeloid leukemia. 
 
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NOTE: Aminoglycoside antibiotics given before, with, or after cisplatin 
may potentiate renal toxicity and should be avoided whenever possible. 
Gentamicin ototoxicity is also potentiated by cisplatin and should be 
avoided whenever possible. 
 
 
Severe renal toxicity can be largely avoided by induction of diuresis 
before, during and after treatment. Mild renal dysfunction is a common 
complication (10%) of chronic therapy and may require discontinuation 
of therapy if BUN ≥ 30 mg/dL (10.7 mmol/L) or creatinine clearance < 
40 mL/min (0.67 mL/s) or creatinine > 2.0 mg/dL (177 µmol/L) 
develop. If serum creatinine is ≥ 1.5 mg/dL (133 µmol/L) on the planned 
treatment date, please see cisplatin dose modifications in Section 6.2. 
 
4.3.1.4 Supplier: Cisplatin will be purchased commercially and provided by the 
AMC. 
 
*Refer to Package Insert for additional information. 
 
4.4 
Drug Orders, Transfers, Returns, and Accountability 
The Investigator, or a responsible party designated by the Investigator, must maintain a 
careful record of the inventory and disposition of all drugs received using the NCI Drug 
Accountability Record Form (DARF) (available on the CTEP home page 
(http://ctep.cancer.gov) or by calling the Pharmaceutical Management Branch at 001-
301-496-5725). The DARFs document the drug delivery date to the site, inventory at the 
site, use by each study participant, and disposal of the drug (if applicable). A site-specific 
accountability record, either manual or electronic, may be used if it includes all the 
information required on the NCI Investigational Drug Accountability Record and if the 
paper printout is identical to the NCI accountability record. A separate DARF is required 
for each protocol using the same agent. The investigator will ensure that the drugs are 
used only in accordance with this protocol. 
 
Drug will be paid for by the AMC. Instructions for drug ordering/drug purchase will be 
provided to each clinical site by the AMC Operations and Data Management Center.  All 
investigators prescribing study agent for an AMC study must have an active NCI-
investigator registration.  
4.5 
Emergency Radiation Therapy to Stop Bleeding Prior to Treatment 
In some cases of locally-advanced cervical cancer, particularly exophytic tumors, 
radiation therapy is required to stop bleeding emergently. Emergency RT is generally 
delivered in 3-5 fractions of 2-3 Gy per fraction. Patients who receive emergency 
radiation therapy to stop tumor bleeding either prior to enrollment or during screening 
will be allowed to proceed or be registered on this protocol as long as the other eligibility 
and ineligibility criteria are met. If a subject who is in either screening or pre-screening 
has received emergency radiation therapy, then definitive radiation therapy should be 
started as soon as possible so the total treatment time does not exceed 56 days. 
 
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4.6 
Radiation Therapy Procedures 
Radiation therapy (RT) must be started within 7 days of enrollment into the Treatment 
Segment (Segment B); CT scan of the pelvis is required for external RT field and block 
definition. If the participating site cannot perform CT simulation and yet has 3D planning 
software, a diagnostic CT scan with contrast should be available for treatment planning 
purposes. 
 
 
Table of Doses 
This protocol allows for external beam doses ranging from 41.4-45 Gy but still requires 
the treating physician to treat primary disease to 80-85 Gy target dose using the 
appropriate brachytherapy boost as outlined in the following two tables. 
 
Table of Acceptable Combined External Beam and LDR Brachytherapy regimens 
Ext. Beam Dose 
(1.8-2 Gy/fraction)* 
LDR 
(1-2 implants) 
41.4 Gy/23 fractions 
38.6-43.6 Gy total 
43.2 Gy/24 fractions 
36.8-41.8 Gy total 
45 Gy/25 fractions 
35-40 Gy total 
 
Table of Acceptable HDR Brachytherapy regimens 
Number of 
Insertions 
HDR Doses 
2 
9 Gy/fraction 
3 
7-8 Gy/fraction 
4 
6-7 Gy/fraction 
*Any combination of EBRT and LDR/HDR dose regimen is acceptable. Higher dose per fraction should be 
considered only for larger, more advanced tumors. If a higher dose is being considered, the local Radiation 
Oncologist needs to consult with one of the Radiation Oncology PIs. 
 
4.6.1 Standardized Radiotherapy 
4.6.1.1 External Irradiation (IMRT will not be allowed on this study.) 
All participants will receive 41.4-45 Gy external beam RT delivered to 
the pelvis in 23-25 fractions of 1.8 Gy. Treatments are to be delivered 
daily, five fractions per week and should be completed within 5 weeks ± 
3 days. Participants should be treated with bladder distention (although 
this is not mandatory), and bowel exclusion devices (e.g. belly boards) 
are allowed. If overall treatment time for external pelvic RT exceeds 38 
days, the reason for the delay must be documented. If intracavitary RT 
cannot be performed, shrinking field technique should be performed to 
bring the gross tumor volume with adequate margins (minimum 1 cm) to 
a minimum total dose of 65 Gy. An attempt should be made to exclude 
all small bowel from treatment field after 50.4 Gy. 
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4.6.1.1.1 Dose Specification 
The dose to the pelvis shall be calculated at the intersection 
of the axes of the 4-field box. The dose to point B shall also 
be calculated using an off-axis calculation (or identified on 
the isodose distribution). In patients not undergoing 
brachytherapy, point B dose will be calculated at the point on 
pelvic side wall (at the level of superior wall of acetabulum). 
Heterogeneity corrected dose calculations are not allowed. 
 
The dose to CENTRAL STRUCTURES shall be the sum of 
the dose at the intersection of the axes of the 4-field box and 
the dose to point A from the intracavitary treatment. The dose 
to SIDE WALL STRUCTURES shall be calculated 
bilaterally (reported separately) and shall be the sum of the 
dose at the intersection of the axes from the 4-field box plus 
the intracavitary dose to point B plus the contribution from 
the parametrial fields. For 2 dimensional planning, the dose 
at the central axis and pelvic side walls shall not differ by 
more than 10%. For 3 dimensional planning, the dose range 
shall be within 95% to 107% of the prescription dose. 
 
Fractionation: Conventional fractionation will consist of one 
fraction per day, total five fractions per week. 
 
Therapy interruptions: If interruption of radiation should 
occur for greater than two weeks, the protocol Radiation 
Oncology Study Chair must be notified. 
 
Dose deviations: A discrepancy in dose (as specified in the 
protocol) of 6-10% and >10% will be considered as minor 
and major deviations from the protocol, respectively 
 
4.6.1.2 Intracavitary Brachytherapy 
For each participant, institutions will select the dose rate to be used for 
brachytherapy—either HDR or LDR. 
4.6.1.2.1 Low-Dose Rate (LDR) Brachytherapy 
Following the completion of whole pelvic RT, the participant 
will receive 35-43.6 Gy to Point A (Refer to Appendix VIII 
Description of points A, B and ICRU Bladder/Rectum) by 
intracavitary implant with a standard medical radiation 
source listed on the American Association of Physicists in 
Medicine 
(AAPM) 
source 
registry 
(http://irochouston.mdanderson.org). The dose table (Refer to 
Section 4.6) should be utilized in order to ensure adequate 
total dose delivery. The participant may receive the LDR 
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dose in one or two implants at the discretion of the radiation 
oncologist. 
 
Ideally, external should finish within 35 days and 
brachytherapy within 3 weeks of completion of whole pelvic 
RT (WPRT). The first implant should be performed promptly 
upon completion of WPRT. If external is delayed up to 38 
days, and two brachytherapy sessions are planned, the second 
session shall be completed within 18 days of the completion 
of WPRT to keep the total RT duration to within 56 days. 
 
4.6.1.2.2 High-Dose Rate (HDR) Brachytherapy 
Refer to Appendix VII (HDR Brachytherapy) for guidelines 
of vaginal surface dose, normal tissue tolerances, packing 
and imaging. 
 
4.6.1.2.3 HDR Schema 
• Dose to Point A with each HDR brachytherapy fraction: 6 
- 9 Gy. 
• Number of weekly HDR brachytherapy procedures: no 
more than four. 
• Total HDR brachytherapy dose to Point A: 18-28 Gy. 
 
4.6.1.2.4 Timing 
HDR brachytherapy should start by week 4. When HDR 
brachytherapy begins, at least one implant will be performed 
per week with no external beam therapy given on the day of 
the insertion. If the majority of the external beam radiation 
has been given (>20 fractions), then two implants per week 
could be done separated by at least 72 hours in order to 
complete all treatment within eight weeks. 
 
4.6.1.2.5 Doses 
Each HDR brachytherapy fraction will give 6-9 Gy/fraction 
to Point A. (Refer to Appendix VIII Description of points A, 
B and ICRU Bladder/Rectum). Each participant may be 
treated with up to four HDR implants with the HDR total 
dose ranging from 18-28 Gy (Total HDR dose) that is 
equivalent to an LDR delivered of 35-43.6 Gy depending on 
the total external beam dose given (Refer to Appendix VII 
HDR Brachytherapy). 
 
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4.6.1.2.6 HDR Instruments 
It is strongly recommended that tandem and ovoids be used 
for HDR brachytherapy. However, tandem and rings are 
considered acceptable. A tandem and cylinder is allowed 
only for participants where tandem and ovoid application is 
not possible due to extent of disease. 
 
4.6.1.2.7 Determination of Normal Tissue Tolerance 
In order to stay below an LDR equivalent of 70 Gy to the 
rectum (Biological Equivalent Dose (BED):120 Gy3) for four 
HDR implants, including the 45 Gy contribution from the 
external beam radiation, the rectum should receive less than 
4.1-6.1 Gy for each HDR fraction of 6-9 Gy (68% of the 
prescribed dose to Point A). The dose to the bladder should 
be less than 4.6-6.9 Gy per each HDR fraction of 6-9 Gy 
(77% of the prescribed dose to Point A). As in LDR 
brachytherapy, every attempt should be made to deliver 
tumoricidal doses, even if the late responding tissues receive 
a slightly higher dose. (Refer to Appendix VII: HDR 
Brachytherapy). 
 
4.6.1.3 Parametrial Boost to Involved Parametrium 
Participants may receive a parametrial boost at the discretion of the 
treating radiation oncologist. The radiation oncologist will choose the 
dose to be used to the involved parametrium based on bulk of 
parametrial disease at presentation.  
 
The parametrial boost shall be 5.4-9.0 Gy in 3-5 fractions of 1.8 Gy per 
fraction given AP/PA daily to midplane if unilateral or bilateral 
parametrial boost is used. The prescription point should be at the center 
of the unblocked portion of the field. The parametrial boost should be 
delivered if possible between implant 1 and 2 or immediately after 
implant 1 if only one implant is used. The total elapsed time for 
completion of external whole pelvis, intracavitary RT, and parametrial 
RT shall not exceed 56 days. If a subject who is either in screening or 
before study entry has received emergency radiation therapy as 
described in Section 4.5, then definitive radiation therapy should be 
started as soon as possible so the total treatment time does not exceed 56 
days. 
 
4.6.2 Dose Distribution for All Regimens 
A four-field box technique with parallel opposed AP/PA and two opposing lateral 
fields should be used. AP/PA only fields are allowed in thin women but are 
strongly discouraged and should only be used with 10 MV or higher energy 
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beams. Dose distribution across clinical target volume shall not vary more than 
10% from the recommended dose. All fields must be treated daily. 
 
4.6.3 Radiation Equipment 
4.6.3.1 Radiation sources must be of megavoltage energy with an SSD of 80 cm 
or greater. The minimum beam energy allowed on a linear accelerator is 
4MV photons. If Cobalt-60 or 4MV is being used, a 4 field box shall be 
used for patients with a separation of >18 cm. The peak infield dose 
should not exceed the dose at the isocenter by more than 10%. All 
participants will undergo simulation for localization and verification of 
external RT treatment portals. CT scan with contrast is required in pre-
treatment planning. If the participating site cannot perform CT 
simulation and yet has 3D treatment planning software, a diagnostic CT 
scan with contrast shall be available for treatment planning purposes. 
Orthogonal films shall be performed for each implant. Intracavitary 
treatment will be delivered with standard applicators. Interstitial 
brachytherapy is not permitted on this trial. If it is felt to be clinically 
imperative to deliver interstitial brachytherapy, it will be considered a 
major treatment deviation. 
 
4.6.3.2 Intracavitary RT may be delivered by cesium-137 or equivalent radiation 
source for LDR brachytherapy or cobalt-60 or iridium-192 for HDR 
brachytherapy in standard or commonly used tandem and ovoid 
applicators. Only the medical radiation brachytherapy sources listed on 
the AAPM source registry (http://irochouston.mdanderson.org) may be 
used. 
 
4.6.4 External Radiation Fields (Refer to Appendix IX Blank Diagram Anterior and 
Appendix X Blank Diagram Lateral) 
4.6.4.1 Whole Pelvis Field 
The external RT target volume shall encompass, with adequate margins, 
the primary cervical tumor and its gross extension and any grossly 
involved pelvic lymph nodes as well as possible microscopic extension 
to pelvic lymph nodes and the uterus. 
 
The use of IMRT will not be allowed on this study. 
 
4.6.4.2 AP/PA pelvic fields 
The superior border will be through the L4-5 interspace unless the target 
volume (e.g. involved iliac lymph nodes or local disease) would not be 
encompassed adequately in a cephalad direction. In the latter case, a 2 
cm margin should be added to the highest level of pathologic 
abnormality, but should not be cephalad to the L-3/L-4 interspace. The 
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lateral border will be 2 cm beyond the lateral margins of the bony pelvis. 
The inferior border will be inferior to the obturator foramen or the 
lowest extension of disease with at least a 3 cm margin. The inferior 
extent of cervical cancer or vaginal extension should be marked so that 
the inferior border of disease can be documented. Uninvolved normal 
tissues may be blocked although the position of the uterus should be 
drawn on at least one anterior and lateral field to ensure adequate 
coverage by transfer of the volume from imaging of the pelvis onto the 
simulation films. Any bulky adenopathy in the pelvis from imaging 
scans should be documented on the simulation films as well. 
 
4.6.4.3 Lateral Pelvis Fields 
The anterior border should be a horizontal line drawn just anterior to the 
symphysis pubis, and the posterior border a horizontal line at the 
posterior border of the sacrum. Superior and inferior borders will be the 
same as for the anterior and posterior fields. If clips are present from the 
lymph node dissection to document the position of the lymph nodes, 
then these should be used as a guide when anterior blocks are designed 
to shield small bowel. At least 3 cm should not be blocked anterior to 
the L-5 vertebral body. Also the anterior two-thirds of the L-5 vertebral 
body should not be blocked. 
 
Posterior blocking should be designed such that gross disease is 
encompassed with at least a 2 cm margin. The outer table of the sacrum 
should be blocked to protect the sacral plexis on lateral fields. 
 
4.6.4.4 Parametrial Boost Fields 
The superior border should be reduced to include only the true pelvis. 
The upper border of the true pelvis field is defined as 1 cm above the 
inferior aspect of the sacroiliac joint (Refer to Appendix VIII Description 
of ICRU Bladder/Rectal Dose Reporting Points). Parametrial block should 
be a minimum of 4-5 cm wide if bilateral parametrial boost is used and 
may be shaped to the point A isodose. Unilateral parametrial boost 
would be used if only unilateral involvement was noted (Refer to 
Section 4.6.1.3). 
 
4.6.5 Simulation and portal films should be available to the AMC for auditing purposes 
along with the participant records for the whole pelvic RT fields and parametrial 
boost. Orthogonal AP and lateral simulation films will be taken following each 
intracavitary insertion. The orthogonal films and calculations of the intracavitary 
insertion shall also be made available for auditing purposes for the AMC along 
with the participant records. Copies of the CT, MRI or other relevant scans, if 
performed, documenting the relevant tumor volume shall be made available as 
well. 
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4.6.6 Radiation Therapy Quality Control and Documentation 
The Imaging and Radiation Oncology Core Houston QA Center (IROC Houston 
QA Center), a National Cancer Institute funded organization with guidance from 
the AAPM, will supervise the dosimetry control for this clinical trial. To 
participate in the trial, the institution must demonstrate the ability to achieve an 
accuracy of ±5% in measuring calibrated reference beam output of their external 
beam therapy units on an annual basis. Each participant record will be reviewed 
by the IROC Houston QA Center to verify that each participant received their 
radiation therapy dose to within ±5% for delivering the external beam prescribed 
dose and ±15% for the brachytherapy boost. 
 
The radiation therapy quality assurance process is described in Appendix XII. 
 
4.6.7 Expected Toxicity 
Gastrointestinal: Nausea and vomiting may occur, especially after the first few 
treatments. It is recommended that participants be pretreated with anti-emetics 
before each daily treatment. The use of antiemetics, like any prescribed 
concomitant medications, will require documentation. Intractable nausea and 
vomiting beyond the first few days should arouse suspicion of recurrent tumor or 
other causes of bowel obstruction, as it is rarely seen as a result of radiation alone. 
Increased bowel activity with diarrhea can be expected fairly routinely after the 
first two weeks of pelvic radiation. It is recommended that instructions be given to 
participants for a low fiber, low fat, and bland diet. Most participants will require 
antidiarrheal medications during therapy. 
 
Should GI toxicity become severe enough to require hospitalization for IV fluid 
replacement, treatment should be discontinued temporarily until the participant’s 
condition improves. Study Chairs must be notified and documentation of 
appropriate use of antiemetics may be requested. 
 
Radiation therapy to the pelvis with the concomitant use of chemotherapy on this 
protocol may enhance the expected toxicity from radiation therapy alone. The 
expected adverse effects and the guidelines for treatment modifications are 
described in Section 6.0. 
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4.6.8 General Radiation Schedule 
Radiation therapy (RT) Schedule (with low-dose or high-dose rate): 
 
Day Number 
 
Day 1 
Start whole pelvic radiation therapy (WPRT) 
Approximately Day 35 
Complete WPRT 
After Day 35 
Start brachytherapy and deliver parametrial boosts, if prescribed* 
Day 50, but no later than 
Day 56 
Complete all radiation therapy* 
*If a subject who is either in screening or in the pre-screening period has received 
emergency radiation therapy, then definitive radiation therapy should be started as soon as 
possible so the total treatment time does not exceed 56 days. 
*Parametrial boost not required in Stage IB2 and IIA participants. Number of fractions left to the 
discretion of physician. 
 
4.7 
Duration of Study 
Each participant should complete the study treatment unless disease progression occurs 
or toxicity prohibits further therapy. Regardless of whether the treatment is completed, 
the participant should be followed at least at month 6 and month 12 after the completion 
of treatment. 
 
Participants should be contacted by clinic staff by appropriate communication 
mechanisms in order to encourage and maintain the participant’s follow-up with their 
study visits. Follow-up mechanisms may be done by phone, text, email or reminder cards. 
If a participant is unable or unwilling to come to the clinic for a follow-up visit, clinic 
staff may obtain information regarding the patient’s general health, adverse events, 
medication changes, or other appropriate changes verbally or via an email or text 
message from the participant. This information must also be documented within the 
participant’s medical record by a note or copy of the email, phone call, or text message. 
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5.0 
CLINICAL AND LABORATORY EVALUATIONS 
5.1 
Screening Evaluations 
The following will be obtained within the time frames specified in Appendix I: 
5.1.1 Within 28 days prior to initiating protocol therapy 
• Medical history for eligibility 
• Physical examination including: weight and height for BSA calculation, 
performance status (Refer to Appendix II), general physical exam, and pelvic 
exam if judged as necessary by the investigator. 
• Tumor measurements and clinical staging 
• CT scan with contrast of pelvis and abdomen 
• Chest X-ray 
• CD4+ T-cell count 
• HIV viral load 
 
5.1.2 Within 14 days prior to initiating protocol therapy 
• CBC and differential 
• Calculated creatinine clearance 
• SGOT, SGPT, alkaline phosphatase, bilirubin 
• Electrolytes (sodium, potassium, chloride, magnesium) 
• Pregnancy test (serum or urine) 
• Review of interim medical history including concomitant medications 
• Slides for central pathology review--formalin-fixed tissue H&E and unstained 
slides from original cancer biopsy tissues (refer to Appendix IV) 
• Optional: Cytoscopy per local standard of care for clinical staging 
• Optional: Intravenous pyelogram (IVP) per local standard of care for clinical 
staging 
• Anal and cervical swabs to evaluate the exploratory study objectives (refer to 
Appendix XI) 
• Serum to evaluate the exploratory study objectives (refer to Appendix XI) 
 
5.2 
Evaluations during Chemo-Radiation Treatment 
5.2.1 Weekly During Chemo-Radiation (Day 1, 8, 15, 22, 29, 36, (- 2 days)) 
The following laboratory results will be obtained on the same day or up to 2 days 
prior to cisplatin administration unless otherwise noted: 
• CBC and differential 
• Calculated creatinine clearance 
• Electrolytes (sodium, potassium, chloride, magnesium) 
• Review of interim medical history including concomitant medications and 
adverse events 
• ART adherence assessment will be collected on Day 8, Day 15, Day 22, Day 
29, and Day 36. 
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• Physical Examination on Day 22 prior to treatment. 
 
5.2.2 Assessments at the Time of Chemo-Radiation Therapy Completion 
The following assessments must be completed within 7 days of chemo-radiation 
therapy completion unless otherwise specified. These assessments are required 
for all participants regardless of the reason for treatment discontinuation (e.g. 
treatment completion or early discontinuation). 
• Review of interim medical history including concomitant medications and 
adverse events. 
• ART adherence assessment. 
• Physical examination. 
 
The following assessments must be completed either on the final day of chemo-
radiation therapy or within 4 weeks after the final dose of chemo-radiation 
therapy: 
• Anal and cervical swabs to evaluate the exploratory study objectives (refer to 
Appendix XI). 
• Serum to evaluate the exploratory study objectives (refer to Appendix XI). 
 
5.3 
Evaluations after Completion of Therapy 
Participants are to be followed at 3 intervals for 1 year after completing protocol 
treatment. CT imaging will be repeated at the 6-month time point after discontinuing 
treatment only for participants that have not clinically progressed; other imaging 
modalities can be employed off-study, as appropriate and at the discretion of the treating 
physician, at other time points. Participants that progress or relapse during the 12 month 
study follow-up period will be followed for survival only. 
 
5.3.1 Month 3 (+/- 4 weeks) 
• Physical examination 
• Review of interim medical history including concomitant medications and 
adverse events 
 
5.3.2 Month 6 (+/- 4 weeks) 
• Physical examination 
• CT scan with contrast of pelvis and abdomen 
• CD4+ T-cell count 
• HIV viral load 
• Review of interim medical history including concomitant medications and 
adverse events 
 
5.3.3 Month 9 (+/- 4 weeks) 
• Physical examination 
• Review of interim medical history including concomitant medications and 
adverse events 
 
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5.3.4 Month 12 (+/- 4 weeks) 
• Physical examination 
• CT scan with contrast of pelvis and abdomen 
• CD4+ T-cell count 
• HIV viral load 
• Review of interim medical history including concomitant medications and 
adverse events 
 
5.4 
Evaluations after Diagnosis of Recurrence 
For participants who experience a recurrence of disease, the following evaluations should 
be performed, preferably at the time of or up to 2 weeks after diagnosis: 
• CT scan with contrast of pelvis and abdomen 
• Chest X-ray 
• CD4+ T-cell count 
• HIV viral load 
• Review of interim medical history including concomitant medications and adverse 
events 
• Serum to evaluate the exploratory study objectives (refer to Appendix XI) 
 
Participants will only be followed for survival following the diagnosis of disease 
progression or recurrence. Treatment for progressive/recurrent disease will be at the 
discretion of the site investigator and will not be coordinated or paid for as part of the 
study. 
 
5.5 
Premature Study Discontinuation Evaluations 
For participants who withdraw from the study prematurely (discontinuation prior to 12 
month follow-up for any reason), the following evaluations should be performed 
whenever possible, preferably at the time of or up to 1 month after withdrawal from the 
study: 
• Physical examination 
• If more than 3 months after last CT scan, CT scan with contrast of pelvis and 
abdomen 
• Review of interim medical history including concomitant medications and adverse 
events 
• If not done within 3 months of withdraw date, the following diagnostic and laboratory 
tests should be done: 
o Chest X-ray 
o CD4+ T-cell count 
o HIV viral load 
o CBC and differential 
o Calculated creatinine clearance 
o SGOT, SGPT, alkaline phosphatase, bilirubin 
o Electrolytes (sodium, potassium, chloride, magnesium) 
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6.0 
TREATMENT MODIFICATIONS 
6.1 
Radiation Therapy 
It is in the participant’s best interest to receive the radiation therapy on time. Every effort 
should be made to encourage the participant to comply with the radiation treatment 
prescribed where possible since time to completion of therapy is correlated with survival. 
The goal is to complete radiation therapy in 56 days. 
 
6.1.1 Expected Toxicity 
All toxicities will be graded according to the Common Toxicity Criteria (CTCAE 
v4.0). 
 
6.1.1.1 Blood/Bone Marrow (Hematologic) 
Hematologic toxicity is seen infrequently unless pelvic radiation is 
accompanied by chemotherapy. A CBC should be obtained weekly, and 
if the ANC falls below 1500/mm3 (1.5 x 109/L) or the platelet count 
drops below 100,000/mm3 (100.0 x 109/L), counts should be obtained 
twice weekly. Treatment may proceed if ANC > 1000/mm3 (1.0 x 
109/L), and platelet count > 50,000/mm3 (50.0 x 109/L). 
 
Every effort should be made to maintain hemoglobin ≥ 10g/dL (6.2 
mmol/L). It is up to the individual investigator’s discretion as to how 
best to achieve this. 
 
6.1.1.2 Gastrointestinal 
Nausea and vomiting is rather unusual after pelvic radiation. If nausea 
occurs, the subsequent use of prophylactic antiemetics is strongly 
encouraged. Antiemetic regimens are at the discretion of the 
investigator. Anti-emetics may be given when symptoms occur if not 
given prophylactically prior to treatment. Intractable nausea or vomiting 
is rarely seen with pelvic radiation alone and is usually the result of 
another process, i.e., bowel obstruction. Increased bowel activity with 
diarrhea usually can be controlled with low fiber, low fat, bland diets 
and antidiarrheal medications. Should GI toxicity become severe, 
hospitalization may be required at which time the treatment may be 
interrupted temporarily until the participant’s condition improves. This 
interruption should be limited to ≤ 1 week if possible (Refer to Section 
6.1.2). 
 
6.1.1.3 Renal/Genitourinary 
Acute toxicity of the urinary tract is manifested by cystitis. Maintaining 
high fluid intake is important. Bladder antispasmodics, analgesics and 
antibiotics are recommended. Hematuria is not usually seen with acute 
cystitis and suggests bladder invasion by tumor. Acute vulvovaginitis is 
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seen when the pelvic fields extend inferiorly to include the vulvoperineal 
area. Treatment of acute vulvoperineal reaction may require warm saline 
soaks, wearing loose clothing and keeping the area dry. Topical steroids 
and treatment interruption may be necessary also (Refer to Section 
6.1.2). 
 
6.1.1.4 Dermatologic/Skin (Cutaneous) 
With the use of megavoltage external beam radiation therapy, skin 
reactions in the treatment field are infrequent. However, cutaneous 
reactions are more likely to develop if sites such as the inguinal area, 
vulva, and the perineum are in the radiation fields. During radiation 
therapy, mild irritation and redness of the skin may occur within the 
radiation fields. Some participants may experience more intense skin 
reaction such as dry or moist desquamation depending upon the energy 
of the megavoltage beam, number of fields used per day, need to cover 
distal vagina and therefore flashing perineum and use of chemotherapy. 
Hair loss in the pubic area may occur which can be permanent. Late 
subcutaneous fibrosis, telangiectasia, and skin atrophy are uncommon 
sequelae. 
 
Almost all participants with vulvar/perineal skin in the treatment fields 
can expect to develop acute moist desquamation during the course of 
external beam radiation therapy. 
 
Acute skin reactions may be treated according to the institutional 
preferences. Aquaphor or steroid creams may be used for CTCAE v4.0 
Grade 1-2 reactions and it is not necessary to interrupt the radiation 
therapy. For CTCAE v4.0 Grade 3-4 skin reactions when generalized 
macular, papular or vesicular eruptions have developed, or there is 
generalized exfoliative or ulcerative dermatitis in the treatment fields, 
radiation therapy should be interrupted until skin reaction improves to 
Grade 2 or better. Treatment may require symptomatic management of 
pain, use of warm saline soaks, coating ointments, wearing loose 
clothing, and keeping the area dry. Radiation therapy should be resumed 
as soon as the skin reactions have improved to no worse than Grade 2. 
 
The Study Chair should be notified of any Grade 4 toxicity (Refer to 
Section 6.1.2). 
 
6.1.2 Radiation Dose Modifications 
6.1.2.1 Blood Bone Marrow (Hematologic) Adverse Effects 
External RT will be delayed for ANC ≤ 1000/mm3 (1.0 x 109/L) or 
platelet count ≤ 50,000/mm3 (50.0 x 109/L). External RT may continue if 
ANC is < 1000/mm3 and platelets are > 50,000/mm3. If external RT is 
delayed, counts will be obtained twice weekly while participant is on 
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break and treatment resumed when counts are ANC > 1000/mm3 and 
platelets > 50,000/mm3. If longer than a two-week break is required, the 
Study Chair should be contacted during this break. 
 
Febrile 
neutropenia 
requiring 
intravenous 
antibiotics 
or 
thrombocytopenia with bleeding requiring platelet transfusion will 
require holding radiation therapy until symptoms resolve (fever or 
bleeding) and the hematologic parameters described above are met. 
 
6.1.2.2 Gastrointestinal Adverse Effects 
Participants will be treated with a low residue diet and anti-peristaltic 
drugs. External RT will be interrupted for CTCAE v4.0 Grade 3 or 4 GI 
toxicity. If longer than a two-week break is required, the Study Chair 
should be contacted during this break. Use of prophylactic antiemetics is 
strongly recommended. 
 
6.1.2.3 Renal/Genitourinary Adverse Effects 
External RT will be delayed for CTCAE v4.0 Grade 3 or 4 bladder 
toxicity. If longer than a two-week break is required, the Study Chair 
should be contacted during this break. 
 
6.1.2.4 Dermatologic/Skin (Cutaneous) Adverse Effects 
RT will not be delayed for moist desquamation, and if a break is felt to 
be clinically indicated, the Study Chair should be contacted prior to this 
break. 
 
6.1.3 Participants with longer than a 3-week break during combined chemotherapy and 
pelvic radiotherapy, or during brachytherapy will be removed from the protocol-
directed therapy. However, they should re-start radiotherapy off study as soon as 
the toxicities have improved to an acceptable level. 
 
6.2 
Drug Therapy 
6.2.1 Safety run-in dosing for enrolled subjects who have CD4 count < 200/mm3 (0.2 x 
109/L) 
The first three subjects who are enrolled who have a CD4 count < 200 mm3 (0.2 x 
109/L) (inclusive) will be prescribed a dose of 25mg/m2 (Dose Level -2, refer to 
Section 6.2.2). This was the recommended MTD achieved in a prior African trial 
in HIV-infected women with LACC (21). Once the first three subjects with low 
CD4 count are enrolled, enrollment will be held for subjects with CD4 counts ≤ 
200/mm3 until toxicity assessment is completed by the protocol team after the 
completion of treatment (or discontinuation from treatment) for all three subjects. 
 
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6.2.2 Definition of Dose-Limiting Toxicity for Cisplatin 
Dose-limiting non-hematologic toxicities for cisplatin are defined as any grade 3 
or worse peripheral neuropathy or ototoxicity OR any grade 4 GI toxicity that are 
at least possibly related to cisplatin. Dose-limiting hematologic toxicities for 
cisplatin are defined as any grade 4 anemia, thrombocytopenia, or neutropenia 
that are at least possibly related to cisplatin. 
 
1) If no patient out of the initial three on this dose level exhibits a DLT, then 
escalate to dose level 0. 
2) If one patient out of the initial three patients on a dose level exhibits a DLT, 
then up to three additional patients will be added. If a second patient develops 
a DLT, even if it is before there are six total patients on that level, then the 
MTD has been exceeded and no additional patients should be added to this or 
any higher doses. Thus, the MTD is defined as the highest dose level at which 
≤ 1/6 patients have a DLT. If ≥ 2 patients on a dose level experience a DLT, 
then the MTD will have been exceeded and no additional patients will be 
added at that dose level or any higher level. 
 
If dose-limiting toxicity occurs at dose level -2, cisplatin will be discontinued for 
the remainder of the treatment with radiation therapy alone. The protocol team 
will review the toxicity and frequency of dose reductions of subjects enrolled in 
this safety run-in. If the protocol team determines that there is unacceptable 
toxicity and frequent dose reductions at the 40 mg/m2 dose in enrolled subjects 
with a CD4 count < 200/mm3 (0.2 x 109/L), the protocol team will consider 
reducing the dose for all enrolled subjects with low CD4 counts to dose level -1 or 
dose level -2 for the remainder of the trial. 
 
6.2.3 Dose Modifications for Cisplatin 
If different dose levels for cisplatin are required because of two different types of 
toxicities, use the dose level requiring the greatest reduction. There will be no 
dose re-escalation once the cisplatin is dose reduced. 
 
The following levels should be used for cisplatin dose reductions: 
Dose Level 0 
Dose Level -1 
Dose Level -2 
40 mg/m2  
30 mg/m2  
25 mg/m2  
 
There will be no dose reduction below dose level -2 (i.e. cisplatin will be 
discontinued if further toxicity occurs). 
 
Chemotherapy should not be administered during a radiation therapy delay. 
 
All chemotherapy-related toxicities will also be graded according to the Common 
Toxicity Criteria (CTCAE v4.0). 
 
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Radiotherapy will not be omitted or delayed for chemotherapy-related toxicities 
unless the investigator considers that the participant is too sick to be treated. 
 
6.2.4 Cisplatin Modifications 
6.2.4.1 Blood/Bone Marrow (Hematologic) Adverse Effects  
 Granulocyte, ANC or Platelet Counts 
Based on counts within 2 days prior to each scheduled cisplatin dose, 
give the following: 
ANC or 
granulocytes/µL 
 
Platelets/µL 
Cisplatin 
≥ 1,500 
and 
≥ 100,000 
No Dose Reduction 
1,499-1,000 
or 
99,999-75,000 
Reduce by one dose level* 
< 1,000 
or 
< 75,000 
Hold* 
 
Treatment should resume as soon as recovery from toxicity allows. If 
treatment is delayed for >2 weeks, notify the Study Chair. External RT 
should continue while drug is withheld. 
 
*If the maximum number of prior dose reductions of cisplatin have been 
made, treatment may be held for up to two weeks for blood count 
recovery. Treatment will resume at the same dose level as there are no 
more dose reductions allowed. 
 
Nadir blood counts or febrile neutropenia 
For nadir neutropenia in the absence of fever or with fever which is 
successfully treated by oral antibiotics, there will be no dose adjustment. 
 
Hold cisplatin during febrile neutropenia. For febrile neutropenia (ANC  
≤ 500/mm3 (0.5 x 109/L) and temperature ≥ 100.5°F or 38°C) requiring 
intravenous antibiotics, the dose of cisplatin should be reduced by 1 dose 
level for the next and subsequent doses of chemotherapy. 
 
For Grade 4 nadir thrombocytopenia (platelets ≤ 10,000 (10.0 x 109/L)), 
the dose of cisplatin should be reduced by 1 dose level for the next dose 
and for all subsequent doses of chemotherapy. 
 
6.2.4.2 Gastrointestinal Toxicity 
Diarrhea is more likely attributable to radiation treatment in this setting. 
The cisplatin dose will not be reduced for diarrhea.  
 
All patients should receive antiemetics to prevent nausea and vomiting. 
Specific antiemetic therapy is left to the discretion of the investigator. If 
vomiting is severe, study subjects may require hospital admission and 
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treatment with any effective antiemetic regimen. Cisplatin doses will 
NOT be modified for nausea or vomiting. 
 
6.2.4.3 Weight Loss 
If a subject has weight loss of more than 10% from their baseline weight 
at enrollment while receiving cisplatin/RT, the BSA for the cisplatin 
dose will be recalculated based on the new weight for the remainder of 
the cisplatin doses. 
 
6.2.5 Nephrotoxicity 
If serum creatinine is ≥ 1.5 mg/dL (133 µmol/L) on the planned treatment date, 
estimate the creatinine clearance (CrCl) by the Cockcroft and Gault Equation for 
women: 
 
CrCl (mL/min) = (140-age in years) x (Weight in kg x 0.85) / (72 x serum 
creatinine) 
 
Denominator for SI units (mL/s) = (48816 x serum creatinine in µmol/L) 
 
Calculated Creatinine Clearance (CrCl) 
Management 
< 60 but ≥ 50 mL/min 
(<1.00 but ≥ 0.84 mL/s) 
Hydrate as clinically indicated. Treatment 
with cisplatin may continue at a one level 
reduction in the cisplatin dose.  
< 50 but ≥ 40 mL/min 
(< 0.84 but ≥ 0.67 mL/s) 
Hold cisplatin for one week and hydrate as 
clinically indicated. 
If repeat CrCl ≥ 50 mL/min(0.84 mL/s) after 
one week, may resume with a one level 
reduction in the cisplatin dose. 
If CrCl does not recover to ≥ 50 mL/min (0.84 
mL/s) within one week, permanently 
discontinue cisplatin. 
< 40 mL/min 
(< 0.67 mL/s) 
Permanently discontinue cisplatin. 
 
6.2.5.1 Hypomagnesemia 
Hypomagnesemia is not an indication for stopping therapy. Oral or 
parenteral magnesium supplementation is indicated for serum 
magnesium levels ≤ 1.5 mEq/L (0.75 mmol/L). 
 
6.2.5.2 Neurological Toxicity 
For Grade 1 neurotoxicity, there will be no modification in the cisplatin 
dose. For patients with ≥ Grade 2 neurotoxicity, hold the cisplatin dose 
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and delay for up to 2 weeks waiting for neurotoxicity to improve to < 
Grade 1. If neurotoxicity recovers to < Grade 1, resume therapy with a 
dose reduction of cisplatin by one dose level. If neurotoxicity does not 
improve to < Grade 1 within 2 weeks, cisplatin will be permanently 
discontinued. If ≥ Grade 2 neurotoxicity recurs after 1 dose level 
reduction, cisplatin will be give at Dose Level -2 upon resolution of 
neurotoxicity to Grade 0-1. If ≥ Grade 2 neurotoxicity recurs at Dose 
Level -2, or if neurotoxicity does not improve to < Grade 1 within 2 
weeks, cisplatin will be permanently discontinued. 
 
6.2.5.3 Ototoxicity 
Discontinue cisplatin for ≥ grade 3 ototoxicity. 
 
6.2.5.4 Allergic Reactions 
Discontinue cisplatin if ≥ grade 3 anaphylaxis occurs. 
 
6.2.5.4.1 Other Grade 3/4 Non-Hematologic Toxicity 
If a patient develops Grade 3 or 4 non-hematologic toxicity 
not detailed above (excluding nausea, vomiting, anorexia, 
fatigue, fever without Grade 3/4 neutropenia or alopecia), hold 
cisplatin therapy. Treatment can be restarted if the toxicity has 
resolved to ≤ Grade 1 by the time of the next treatment. 
Subsequent doses of cisplatin should then be reduced by 1 
dose level. 
 
6.2.6 Completion of Chemotherapy 
If all 6 cycles of chemotherapy cannot be administered during external 
radiotherapy (whole pelvis and parametrial boost), the 6th cycle should be given 
during brachytherapy but not on the same day as brachytherapy. 
 
Chemotherapy may not be given after completion of radiotherapy. 
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7.0 
ADVERSE EVENTS MONITORING AND REPORTING 
This study will utilize the Common Terminology Criteria for Adverse Event (CTCAE) version 
4.0 for adverse event reporting. A copy of the CTCAE version 4.0 can be downloaded from the 
CTEP home page (http://ctep.cancer.gov.). All appropriate treatment areas should have access to 
a copy of the CTCAE version 4.0. The document “NCI Guidelines: Adverse Event Reporting 
Requirements for NCI Investigational Agents” clearly outlines reporting criteria. 
 
This study will be monitored by the Clinical Data Update System (CDUS). Cumulative CDUS 
data will be submitted quarterly to CTEP by electronic means. Reports are due January 31, April 
30, July 31, and October 31. 
 
7.1 
Classification of AEs by Severity and Relationship to Study Drug Administration 
The Common Terminology Criteria for Adverse Events (CTCAE) is designed as an 
instrument to be used to document AEs identified through a combination of clinical and 
laboratory evaluation. CTCAE is NOT a tool to assist with data extraction from source 
documents without the direct participation and supervision of clinical investigators. AE 
grading and assignment of attribution require documentation by medical personnel who 
are directly involved in the clinical care of protocol subjects. 
 
Each CTCAE term in the current version is a unique representation of a specific event 
used for medical documentation and scientific analysis and is a single MedDRA Lowest 
Level Term (LLT). Grade is an essential element of the Guidelines and, in general, 
relates to severity for the purposes of regulatory reporting to NCI as follows: 
 
Grade 
Description 
0 
No AE (or within normal limits) 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention 
not indicated 
2 
Moderate; minimal, local, or noninvasive intervention (e.g., packing, cautery) indicated; 
limiting age-appropriate instrumental activities of daily living (ADL) 
3 
Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADL 
4 
Life-threatening consequences; urgent intervention indicated 
5 
Death related to AE 
 
NOTE: A severe AE, as defined by the above grading scale, is NOT the same as serious AE which is 
defined below (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
Adverse Event 
Any untoward medical occurrence associated with the use of a drug in humans, whether 
or not considered drug related. Therefore, an AE can be ANY unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or 
not considered related to the medicinal (investigational) product (attribution of unrelated, 
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unlikely, possible, probable, or definite). (International Conference of Harmonization 
[ICH] E2A, E6). 
 
Life-Threatening Adverse Event 
Any AE that places the patient or subject, in view of the Investigator, at immediate risk of 
death from the reaction. It does NOT include an AE that, had it occurred in a more severe 
form, might have caused death (FDA 21 CFR 312.32, ICH E2A). 
 
Serious Adverse Event (SAE) 
Any adverse drug event (experience) occurring at any dose that results in ANY of the 
following outcomes: 
1) Death. 
2) A life-threatening adverse drug experience. 
3) Inpatient hospitalization or prolongation of existing hospitalization (for >24 hours). 
4) A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
5) A congenital anomaly/birth defect. 
6) Important Medical Events (IME) that may not result in death, be life-threatening, or 
require hospitalization may be considered a serious adverse drug experience when, 
based upon medical judgment, they may jeopardize the patient or subject and may 
require medical or surgical intervention to prevent one of the outcomes listed in this 
definition (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
Please note for hospitalization – All hospitalizations (or prolongation of existing 
hospitalization) for medical events that result in an inpatient hospital stay equal to or 
greater than 24 hours must be reported regardless of the requirements for Phase of study, 
expected or unexpected, and attribution. Hospitalization is used as an indicator of the 
seriousness of the AE and should ONLY be used for situations where the AE truly fits 
this definition and NOT for hospitalizations associated with less serious events. For 
example, a hospital visit where a patient is admitted for observation or minor treatment 
such as hydration and released in less than 24 hours should not be reported, but do report 
an admission for a myocardial infarction. 
 
Toxicity 
Toxicity is a term NOT clearly defined by regulatory organizations. Toxicity has been 
described as an AE that has an attribution of possibly, probably or definitely related to 
investigational treatment. To minimize confusion the NCI would recommend that the 
term toxicity NOT be utilized for AE reporting purposes. The CTCAE continues to use 
the term ‘toxicity’ because of familiarity. 
 
Expectedness (Unexpected Adverse Event) 
An unexpected AE is any AE, the specificity or severity of which is not consistent with 
the Instructions for Use or other documentation; or, if an IB or equivalent is not required 
or available, the specificity or severity of which is not consistent with the risk 
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information described in the general investigational plan. Additionally the ICH E2A 
defines an unexpected adverse drug reaction as an AE, the nature and severity of which is 
not consistent with the applicable product information (for example, Investigator’s 
Brochure for investigational agent). The investigator shall report all SAEs immediately to 
the sponsor except for those that the protocol identifies as not requiring immediate 
reporting (EC Directive of 2001; Article 16, #1). 
 
CTEP Adverse Event Reporting System (CTEP-AERS) 
An electronic system for expedited submission of AE reports is available at https://eapps-
ctep.nci.nih.gov/ctepaers/. A username and password are not required for this system. 
 
Attribution 
An assessment of the relationship between the AE and the medical intervention. CTCAE 
does not define an AE as necessarily “caused by a therapeutic intervention.” After 
naming and grading the event, the clinical investigator must assign an attribution to the 
AE using the following attribution categories: 
 
Relationship 
Attribution 
Description 
Unrelated to investigational 
agent/intervention1 
 
Unrelated 
The AE is clearly NOT related to the intervention 
Unlikely 
The AE is doubtfully related to the intervention 
Related to investigational 
agent/intervention1 
Possible 
The AE may be related to the intervention 
Probable 
 
The AE is likely related to the intervention 
Definite 
The AE is clearly related to the intervention 
 
1NOTE: AEs listed as “possibly, probably, or definitely” related to the investigational agent/intervention in 
CTEP-AERS are considered to have a suspected “reasonable causal relationship” to the investigational 
agent/intervention (ICH E2A). For routine, CDUS adverse event reporting purposes, “Attribution” defines 
the relationship between the adverse event and the investigational agent(s)/intervention as defined in 
Clinical Data Update System (CDUS) Instructions and Guidelines that can be found at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/cdus_ig_3r4.pdf. 
 
7.2 
Expedited AE Reporting Procedures 
Expedited AE reporting for this study must use CTEP-AERS, accessed via the CTEP 
home page (http://ctep.cancer.gov). The reporting procedures to be followed are 
presented in the CTEP, NCI Guidelines: Adverse Event Reporting Requirements which 
can be downloaded from the CTEP home page (http://ctep.cancer.gov). These 
requirements are briefly outlined in the table below. 
 
CTEP-AERS is programmed for automatic electronic distribution of reports to the 
following individuals: Study Coordinator of the Lead Organization, Principal 
Investigator, and the local treating physician. CTEP-AERS provides a copy feature for 
other e-mail recipients. 
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Expedited Reporting Requirements for AEs that occur within 30 Days of Last Protocol 
Treatment 
 
Commercial Agent Studies: Expedited Reporting Requirements for Adverse Events that Occur in a Non-
IND/IDE trial within 30 Days of the Last Administration of a Commercial Agent 1, 2  
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312)  
NOTE: Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether 
or not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64)  
An adverse event is considered serious if it results in ANY of the following outcomes:  
1) Death  
2) A life-threatening adverse event  
3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or subject and 
may require medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 21 
CFR 312.32; ICH E2A and ICH E6).  
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via 
CTEP-AERS within the timeframes detailed in the table below.  
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization ≥ 24 hrs  
10 Calendar Days 
24-Hour 5 Calendar 
Days 
Not resulting in  
Hospitalization ≥ 24 hrs  
Not required 
10 Calendar Days 
Expedited AE reporting timelines are defined as:  
• “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour 
report.  
• “10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar days of 
learning of the AE.  
Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
 
Expedited 24-hour notification followed by complete report within 5 calendar days for:  
All Grade 4 and Grade 5 AEs  
 
Expedited 10 calendar day reports for:  
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
Grade 3 adverse events  
 
NOTE: Deaths clearly due to progressive disease should NOT be reported via CTEP-AERS but rather should 
be reported via routine reporting methods (e.g., CDUS and/or CTMS).  
Note: A death on study requires both routine and expedited reporting regardless of causality, unless as noted in the 
above table. Attribution to treatment or other cause must be provided. 
 
Expedited AE reporting timelines defined: 
 
“24 hours; 5 calendar days”– The Investigator must initially report the AE via CTEP-AERS, according to the 
procedures outlined in section 6.2, within 24 hours of learning of the event, and followed by a complete AE report 
submitted via CTEP-AERS within 5 calendar days of the initial 24-hour report. Use the NCI protocol number and 
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protocol-specific subject ID assigned during trial registration on all reports. In the rare event when Internet 
connectivity is disrupted, a 24-hour notification is to be made to NCI by telephone at: 301-897-7497, or 301-897-
7402 for CIP studies. An electronic CTEP-AERS report MUST be submitted immediately upon re-establishment of 
internet connection. 
 
“10 calendar days”– A complete CTEP-AERS report on the AE must be submitted within 10 calendar days of the 
Investigator learning of the event. Use the NCI protocol number and protocol-specific subject ID assigned during 
trial registration on all reports. 
 
Any medical event equivalent to CTCAE Grade 3, 4, or 5 that precipitates hospitalization (or prolongation of 
existing hospitalization) must be reported regardless of attribution and designation as expected or unexpected with 
the exception of any events identified as protocol-specific expedited AE reporting exclusions. 
Any event that results in persistent or significant disabilities/incapacities, congenital anomalies, or birth defects 
must be reported via CTEP-AERS according to the guidelines as described above. 
 
7.2.1 National and Local Adverse Event Reporting 
All Grade 4 related and unexpected events and all Grade 5 events are 
communicated to the study chair and regulatory agencies as mandated in this 
protocol. These reports are reviewed by the study chair (or designated co-chair) 
within two working days for considerations of amendments. 
 
7.3 
Routine AE Reporting 
All AEs reported through CTEP-AERS must also be reported in routine study data 
submissions using the Adverse Event electronic case report form (eCRF). All AEs, 
except for expected Grade 1 events listed below, should be reported. All deaths that occur 
on study should be reported in the Adverse Event form and the Death Form, regardless of 
attribution to the protocol agents.  
 
The following grade 1 AEs will not require reporting in the Adverse Event eCRF. 
Grade 1 Expected Adverse Events for Radiation Therapy (listed by CTCAE Category and 
term): 
GASTROINTESTINAL DISORDERS: diarrhea, proctitis, rectal pain  
INJURY, POISONING AND PROCEDURAL COMPLICATIONS: dermatitis radiation 
RENAL AND URINARY DISORDERS: urinary tract pain, cystitis noninfectious 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS: dyspareunia, pelvic pain, 
vaginal pain 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS: skin hyperpigmentation, skin 
hypopigmentation, alopecia 
 
Grade 1 Expected Adverse Events for Cisplatin: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS: anemia 
 
EAR AND LABYRINTH DISORDERS: tinnitus 
GASTROINTESTINAL DISORDERS: nausea, constipation, diarrhea, abdominal pain 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS: fatigue  
INVESTIGATIONS: creatinine increased, weight loss 
METABOLISM AND NUTRITION DISORDERS: anorexia  
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NERVOUS SYSTEM DISORDERS: dysgeusia, paresthesia 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS: alopecia  
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8.0 
CRITERIA FOR DISCONTINUATION 
8.1 
Permanent Treatment Discontinuation 
8.1.1 Treatment breaks longer than 3 weeks during combined chemotherapy and pelvic 
radiotherapy, or during brachytherapy. 
 
 
8.1.2 Requirement for prohibited concomitant medications. 
 
8.1.3 Completion of treatment as defined in the protocol. 
 
8.1.4 Request by participant to terminate treatment. 
 
8.1.5 Clinical reasons believed life threatening or no longer in the best interest of the 
participant by the site investigator, such as pregnancy or breastfeeding, even if not 
addressed in the toxicity section of the protocol. 
 
8.1.6 Request by the investigator if s/he thinks the participant to be at significant risk of 
failing to comply with the provisions of the protocol as to cause harm to self 
 
8.2 
Premature Study Discontinuation 
8.2.1 Request by the participant to withdraw. 
 
8.2.2 Lost to follow-up. Lost to follow-up will be defined for this purposes of this study 
as 6 months of inability to contact or determine the participant’s vital status, in 
spite of at least 3 documented attempts to contact the participant. 
 
8.2.3 Request by the protocol chairs, AMC, IRB, NCI, OHRP, local government 
agencies, or pharmaceutical sponsors. 
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9.0 
EVALUATION CRITERIA 
9.1 
Outcome Measures 
The major parameters of the outcome measures are feasibility. Also, we will determine 
the safety and tolerability of concomitant chemoradiotherapy with cisplatin in HIV-
infected women with LACC who are also receiving concomitant ART. 
9.1.1 Treatment completion proportion is the proportion of subjects who enroll and 
complete the cisplatin/RT regimen. 
 
9.1.2 Screening ratio is the number of potential participants screened per enrolled 
participant 
 
9.1.3 Availability proportion is the follow-up completion proportion at 6 and at 12 
months. 
 
9.1.4 Safety and tolerability will be evaluated through tracking the number of dose 
delays, dose reductions, missing doses, and compliance 
 
9.2 
Exploratory Outcome Measures 
9.2.1 Progression Free Survival is defined as the date from protocol registration to date 
of first documented reappearance (recurrence) or progression of disease or death. 
Since all subjects will be followed for 12 months after treatment, we will 
determine the 1-year PFS rate. 
 
9.2.2 Recurrence is defined as increasing clinical, radiological or histological evidence 
of disease since study entry. 
9.2.2.1 Site of First Recurrence (e.g., para-aortic or supraclavicular lymph 
nodes, lung, liver, bone, etc.) will also be documented. 
 
9.2.3 Overall Survival will be defined as observed length of life from entry to protocol 
to death; or for living participants, the date of last contact. 
 
9.2.4 Local Control is coded as successful if no recurrence or disease progression is 
within the pelvic field. Persistence of tumor three months after completion of 
therapy will be coded as a failure. It is coded as a failure if there is any clinically 
documented evidence of recurrence or disease progression within the pelvic field. 
 
9.2.5 Effects of treatment on the participant’s HIV disease status will be determined by 
tracking the CD4 count, viral load, and concurrent AIDS-defining conditions. 
 
9.2.6  Effects of treatment on the participant’s HPV status, and the association of these 
factors with treatment outcomes, will be determined by measuring HPV DNA 
types and strain variants and gene methylation in cervical and anal swabs, and by 
measuring antibodies to HPV in serum. 
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10.0 
DATA MANAGEMENT 
CRFs will be provided for each subject via the AMC AdvantageEDCSM Internet Data Entry 
System upon enrollment. Data will be recorded on the CRFs using the unique subject 
identification number assigned at registration. Subjects must not be identified by name, initials, 
birth date, or any other personally identifying numbers or codes. Any study documents that are 
transmitted outside of the site must be labeled with the 9-digit subject ID number, protocol 
number, or other study-generated codes. Sample CRFs will be available on the AMC Operations 
and Data Management Center website. 
 
10.1 
Data Quality 
It is the responsibility of the AMC Operations and Data Management Center to assure the 
quality of data for the study. This role extends from protocol development to generation 
of the final study database. 
 
10.2 
CRF Instructions 
Instructions concerning the recording of study data on CRFs will be provided by the 
AMC.  
 
10.3 
Records to Be Kept 
CRFs will be provided for each subject via the AMC AdvantageEDCSM Internet Data 
Entry System upon enrollment. Subjects must not be identified by name on any study 
documents. Data will be recorded on the CRFs using the unique subject identification 
number assigned at registration. Sample CRFs will be available on the AMC ODMC 
website (www.amcoperations.com). 
 
10.4 
Role of Data Management 
Instructions concerning the recording of study data on CRFs will be provided by the 
AMC ODMC. The AMC Internet Data Entry System User’s Guide can be found on the 
AMC ODMC web site (www.amcoperations.com). Each site is responsible for entering 
data and submitting forms according to the target submission dates set forth by the 
AdvantageEDCSM system. 
 
It is the responsibility of the AMC ODMC to assure the quality of electronic data 
reported for each AMC study. This role extends from protocol development to generation 
of the final study databases. 
 
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11.0 
STATISTICAL CONSIDERATIONS 
11.1 
Statistical Analysis Plan 
 
Treatment completion rate will be estimated as proportion of all women who complete 
cisplatin of those who initiate cisplatin treatment. The binomial proportion and its 95% 
confidence interval will be used to estimate the treatment completion rate. 
 
The screening ratio will be estimated as the number of patients screened divided by the 
number of patients enrolled on the study. The Poisson rate and its 95% confidence 
interval will be used to estimate the screening ratio. 
 
The Kaplan-Meier method will be used to describe the progression-free survival (PFS) 
and overall survival (OS). We will generate KM curves for Stage I/II participants as well 
as Stage III/IV participants. The stratified log-rank test will be used to evaluate the 
association of HAART use, node positivity including enlarged pelvic nodes, stratified for 
stage. Those factors that are significantly associated with PFS and OS will be 
incorporated into a proportional hazards model. The one-year PFS and OS will be 
estimated using the cumulative proportion progression free (for PFS) or surviving (for 
OS) and its 95% confidence interval. 
 
Frequency tables will be used to summarize the occurrences of adverse events by severity 
grade. Frequencies of specific adverse events will be tabulated. 
 
Toxicity assessment: All toxicities will be reported on standard case report forms at visits 
and graded by NCI CTC v4.0. There will be standard dose reduction schedules. All dose 
delays, dose reductions, and missing doses will be tracked via CRFs during therapy. 
These will be tabulated and reported as rates. 
 
Adherence assessments are planned weekly during cisplatin therapy and at the end of 
protocol therapy. Participants will be considered inadherent to ARV if they report 
missing doses on more than one adherence assessment. The proportion of participants 
who were inadherent to ARV during protocol therapy will be estimated using the 
binomial proportion and its exact 95% confidence interval.  
 
To determine the HPV DNA types and HPV strain variants present in cervical cancer and 
in the anus of cervical cancer patients, frequency tables of HPV DNA types and HPV 
strain variants will be constructed for cervical and anal samples at baseline, end of 
treatment and at recurrence (if applicable). The binomial proportion and its 95% 
confidence interval will be used to estimate the proportion of each HPV DNA type and 
each HPV strain variant that occurs in at least 5% of patients in cervical or anal 
specimens. Concordance between anal and cervical specimens with respect to detection 
of specific HPV DNA types and HPV strain variants will be assessed using McNemar’s 
chi-square test. 
 
Changes in HPV DNA types and strain variants between baseline and post-treatment 
measurements will be assessed using McNemar’s chi-square test for each DNA type and 
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strain variant. Proportional hazards models and logistic regression models will be used to 
evaluate the association of change in DNA types with progression free survival and local 
control, respectively. 
 
The binomial proportion and its 95% confidence interval will be used to estimate the 
proportion of patients who have abnormally methylated genes for each gene tested. 
 
Gene methylation profiles will be summarized at baseline. 
 
Concordance between gene methylation profiles between cervical and anal swabs will be 
assessed at baseline using the kappa statistic. 
 
The chi-square test will be used to assess the association between baseline gene 
methylation profiles and cervical persistence or recurrence. 
 
The logistic regression model will be used to assess the effects of HPV-16 and HPV-18 
serologic titer levels with disease persistence or recurrence using the logarithmic 
transformation for the titer levels. Similarly, the effects of changes in HPV-16 and HPV-
18 titer levels from baseline to treatment on outcome measures (progression free survival, 
local control) will be assessed using proportional hazards models and logistic regression 
models. 
 
11.2 
Sample Size Considerations 
The primary outcome measure for this trial is treatment completion rate. A treatment 
completion rate of 70% or above would be sufficient to consider this regimen for further 
study. To test the null hypothesis that the treatment completion rate is 0.50 against the 
alternative that it is 0.70 at the one-sided 0.0510 level with 0.90 power will require 38 
evaluable patients. To allow for potential 15% dropout, 45 patients will be enrolled in the 
study. 
 
We will recruit 45 participants from the AMC core sites in Africa over an estimated 2 
year period of time and have a minimum of 1 year of follow-up. We anticipate that at 
least 50% of recruited participants will be Stage 3 and 4. This will be helpful in stratified 
analyses by stage and node positivity. 
 
11.3 
Site(s) of Recurrence 
The site(s) of first disease recurrence will be classified as: pelvic-only, extrapelvic-only 
or pelvic-and-extra-pelvic or no recurrence and tabulated by treatment group. The test of 
the hypotheses that first site of recurrence is independent of randomized treatment will be 
assessed with a logistic model adjusted for FIGO stage, tumor size, lymph node 
involvement and type of brachytherapy. In addition, empirical plots of cumulative 
incidence of recurrence will summarize incidence of recurrence by treatment arm. 
 
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11.4 
Toxicity Analysis 
The toxicity data will be tabulated by treatment. The scale will be the Common Toxicity 
Criteria grading system (i.e., 1-5), but combining Grades 1 and 2. Five toxicity categories 
(CTCAE v4.0) will be tested: gastrointestinal (nausea, vomiting diarrhea), genito-urinary 
(acute toxicity manifested by cystitis, and acute vaginitis), and dermatologic (inguinal 
area, vulva, perineum, acute rash/desquamation, generalized macular, vesicular eruptions, 
and ulcerative dermatitis), blood/bone marrow and neurologic toxicities. Fisher’s exact 
test will be employed to assess observed frequency differences for (incidence of 
maximum grade) specific adverse events by treatment arm. 
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12.0 
ETHICAL AND REGULATORY CONSIDERATIONS 
12.1 
IRB/IEC Review and Informed Consent 
The principles of IRB/IEC review and informed consent described in the Department of 
Health and Human Services (DHHS) regulations for the Protection of Human Subjects 
(45 CFR part 46) must be followed. IRB/IEC approval of the protocol and the informed 
consent form must be given in writing before research may commence at the institution. 
 
The sponsor must receive a copy of the letter of approval from the IRB/IEC, which 
specifically approves the protocol and informed consent, before subject enrollment. The 
IRB/IEC must also approve any significant changes to the protocol and documentation of 
this approval must be sent to the sponsor. The IRB must review the research project at 
least once every 365 days during the duration of the project. Continuing approval of the 
project must also be given in writing and provided to the sponsor. 
 
Records of all study review and approval documents must be kept on file by the 
Investigator and are subject to inspection during or after completion of the study. AEs 
must be reported to the IRB/IEC. The IRB/IEC should receive notification of completion 
of the study and final report within 3 months of study completion and termination. The 
Investigator will maintain an accurate and complete record of all submissions made to the 
IRB/IEC, including a list of all reports and documents submitted. 
 
Written informed consent will be obtained from the subject. The nature, significance and 
risks associated with the study must be explained to the subject. The informed consent 
will describe the purpose of the study, the procedures to be followed and the risks and 
benefits of participation. A copy of the consent form will be given to the subject to keep. 
 
In addition, any institution(s) conducting research according to the guidelines of this 
protocol is required to adhere to local and national laws and regulations governing the 
confidentiality and disclosure of health information. 
 
12.2 
Changes to the Protocol and Informed Consent Form 
Any change or addition to this protocol or the model informed consent requires a written 
protocol amendment that must be approved by CTEP and the Investigator before 
implementation. Amendments significantly affecting the safety of subjects, the scope of 
the investigation or the scientific quality of the study, require additional approval by the 
IRB/IEC and national regulatory body approval depending upon the local regulations. All 
versions of the local informed consent form and any other written patient materials must 
also be approved by the IRB/IEC before presenting any such documents to participants. 
A copy of the written approval of the IRB/IEC and the national regulatory body (if 
applicable) must be sent to the ODMC for every protocol amendment and consent 
modification. 
 
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12.3 
Women and Minorities 
This study is being conducted by the AMC, a NCI-sponsored clinical trials consortium. 
As part of the AMC’s contractual obligations, each participating site within the AMC and 
the AMC as a whole is required to assure that the participation of women and minority 
subjects reflects the percentage representation of these populations in their geographic 
region. As such, it is expected that the representation of subjects on this trial will reflect 
the constitution of the respective populations. 
 
12.4 
Subject Confidentiality 
To maintain confidentiality, all laboratory specimens, evaluation forms, reports and other 
records will be identified by a coded number only and de-identified from the subject. 
Clinical information will not be released without written permission of the subject, except 
as necessary for monitoring by the AMC or the NCI. 
 
12.5 
Study Discontinuation 
This study may be discontinued at any time by the NCI, the AMC, or the Office for 
Human Research Protections (ORHP). 
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13.0 
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24. Goudy G, Stoeckle E, Thomas L, et al. Prognostic impact of tumour volume and lymph node 
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27. Simonds HM, Wright JD, du Toit N, Neugut AI, Jacobson JS. Completion of and early 
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29. Palefsky JM, Holly EA. Molecular virology and epidemiology of human papillomavirus and 
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33. Frisch M, Glimelius B, van den Brule AJ, et al. Sexually transmitted infection as a cause of 
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36. Palefsky JM, Holly EA, Ralston ML, et al. Anal squamous intraepithelial lesions in HIV-
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37. Palefsky JM, Holly EA, Hogeboom CJ, et al. Virologic, immunologic, and clinical 
parameters in the incidence and progression of anal squamous intraepithelial lesions in 
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38. De Villiers EM. Papillomavirus and HPV typing. Clin Dermatol 1997;15:199-206. 
39. Lorincz AT, Reid R, Jenson AB, Greenberg MD, Lancaster W, Kurman RJ. Human 
papillomavirus infection of the cervix: relative risk associations of 15 common anogenital 
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40. Lombard I, Vincent-Salomon A et al. JCO 16:2613-2619 1998 
41. Schwartz SM, Daling JR et al JCO 19(7): 1906-1915 2001 
42. Burger RA, Monk BJ et al JNCI 88(19): 1361-68. 1996 
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and risk for high grade cervical intraepithelial neoplasia. J Natl Cancer Inst 1997;89:796-
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associated with an HPV 16 E6 sequence variant. J Infec Dis 2001;185:1229-37. 
45. Yamada T, Wheeler CM, Halpern AL, et al. Human papillomavirus type 16 variant lineages 
in United States populations characterized by nucleotide sequence analysis of the E6, L2, 
and L1 coding segments. J Virol 1995;69:7743-53. 
46. Londesborough P, Ho L, Terry G, et al. Human papillomavirus genotype as a predictor of 
persistence and development of high-grade lesions in women with minor cervical 
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HPV16 variant in LoSIL smears. Gynecol Oncol 1999;72:56-9. 
48. Zehbe I, Wilander E, Delius H, Tommasino M. Human papillomavirus 16 E6 variants are 
more prevalent in invasive cervical carcinoma than the prototype. Cancer Res 
1998;58:829-33. 
49. Xi LF, Critchlow CW, Wheeler CM, et al. Risk of anal carcinoma in situ in relation to human 
papillomavirus type 16 variants. Cancer Res 1998;58:3839-44. 
50. Hildesheim A, Schiffman M, Bromley C, et al. Human papillomavirus type 16 variants and 
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55. Baylin SB, Belinsky SA, Herman JG. Aberrant methylation of gene promoters in cancer--
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56. Esteller M, Corn PG, Baylin SB, Herman JG. A Gene hypermethylation profile of human 
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57. Virmani AK, Muller C, Rathi A, Zoechbauer-Mueller S, Mathis M, Gazdar AF. Aberrant 
methylation during cervical carcinogenesis. Clin Cancer Res 2001;7(3):584-9. 
58. Dong SM, Kim HS, Rha SH, Sidransky D. Promoter hypermethylation of multiple genes in 
carcinoma of the uterine cervix. Clin Cancer Res 2001;7(7):1982-6. 
59. Narayan G, Arias-Pulido H, Koul S, et al. Frequent promoter methylation of CDH1, DAPK, 
RARB, and HIC1 genes in carcinoma of cervix uteri: its relationship to clinical outcome. 
Mol Cancer 2003;2:24. 
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61. Einstein MH, Belbin TJ, Abadi MA, Nathan LM, Goldberg GL, Strickler HD, Burk RD, 
Schlecht NF. Prospectively Identified Epigenetic Signatures that Predict Clinical 
Outcomes in CIN. Oral Presentation at the International Papillomavirus Meeting 2011 
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Immunol 2004;4:46-54. 
63. Dillner J, Wiklund F, Lenner P, Eklund C, Frederiksson-Shanazarian V, Schiller JT, Hibma 
M, Hallmans G, Stendahl U. Antibodies against linear and conformational epitopes of 
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64. Kirnbauer R, Hubbert NL, Wheeler CM, Becker TM, Lowy DR, Schiller JT. A virus-like 
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65. Ho GY, Studentsov YY, Bierman R, Burk RD. Natural history of human papillomavirus type 
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66. Ho GY, Studentsov Y, Hall CB, Bierman R, Beardsley L, Lempa M, Burk RD. Risk factors 
for subsequent cervicovaginal human papillomavirus (HPV) infection and the protective 
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67. Einstein MH et al IJOC 120: 55-59. 2006 
 
 
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APPENDIX I: SCHEDULE OF EVENTS 
The following observations and tests are to be performed and recorded on the appropriate 
form(s): 
Tests and Observations 
Prior 
to 
Entry 
Weekly 
During 
Chemo-
Radiation 
Chemo-
Radiation 
Therapy 
Completion or 
Premature 
Treatment 
Discontinuation10 
3, 6, 9, and 
12 Month 
Follow-up 
After 
Diagnosis of 
Recurrence 
Premature 
Study 
Discontinuation6 
Medical History 
X1 
 
 
 
 
 
Physical exam 
X1 
X2 
X2 
X2 
 
X 
Tumor measurements and 
clinical staging 
X1 
 
 
 
 
 
CT scan with contrast of pelvis 
and abdomen  
X1 
 
 
X3 
X 
X 
Chest X-ray † 
X1 
 
 
 
X 
X7 
CD4+ T-cell count 
X1 
 
 
X4 
X 
X7 
HIV viral load 
X1 
 
 
X4 
X 
X7 
CBC + differential 
X5 
X 
 
 
 
X7 
Calculated creatinine clearance 
X5 
X 
 
 
 
X7 
SGOT, SGPT, alkaline 
phosphatase, bilirubin 
X5 
 
 
 
 
X7 
Electrolytes (Na, K, Cl, Mg) 
X5 
X 
 
 
 
 
Serum or urine pregnancy  
test * 
X5 
 
 
 
 
X8 
Review of interim medical 
history 
 
X 
X 
X8 
X 
X 
Slides for central pathology 
review 
X5 
 
 
 
 
 
ART Adherence 
 
X 
X 
X 
 
 
Cytoscopy, IVP 
X5,+ 
 
 
 
 
 
Anal and cervical swabs for 
HPV-associated disease 
research 
X5 
 
X9 
 
 
 
 X 
Serum for HPV-serology 
X5 
 
X9 
 
X 
X  
X 1  
Must be obtained within 28 days prior to initiating protocol therapy 
X 2  
At day 22 prior to treatment, at treatment discontinuation, and every 3 months for 1 year. 
X 3  
CT with contrast of abdomen and pelvis to be done prior to study entry, 6 months +/- 4 weeks and 12 months +/- 4 
weeks after concomitant chemoradiotherapy. Can perform CT without contrast only if recent creatinine >1.5 mg/dl 
(within 4 weeks of scan). 
X 4 
Every 6 months while on protocol 
X 5 
Must be obtained within 14 days prior to initiating protocol therapy. If ANC <1,500/mm3 (1.5 x 109/L) or platelets < 
50,000/mm3 (50 x 109/L), repeat twice per week until over these values or subject off trial. 
X 6 
Evaluations should be performed whenever possible, preferably at the time of or up to 1 month after withdrawal from 
study. 
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X7 
Tests are required if not done within the last 3 months. 
X8 
Every 3 months for 1 year. 
X9 
Anal and cervical swabs and serum for HPV-associated disease research will be collected on the final day of chemo-
radiation therapy or within 4 weeks following the final chemo-radiation therapy. 
X10 
Assessments must be completed within 7 days of the completion of chemo-radiation therapy. This visit is required for 
all participants and refers to both to scheduled completion of treatment and premature treatment discontinuation 
 * 
Excludes participants who have had a bilateral tubal ligation prior to study entry or who are postmenopausal. 
 † 
Chest CT scan with contrast may be substituted for chest x-ray  
 + 
Cystoscopy and IVP are not required for eligibility per protocol, but if the enrolling physician feels they are clinically 
indicated for accurate staging, they should be done according to local standard of care. The costs of these procedures 
will not be borne by the study budget. 
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APPENDIX II: PERFORMANCE STATUS SCALE 
 
ECOG Performance Scale 
Grade 
Descriptions 
0 
Normal activity. Fully active, able to carry out all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous activity, 
but ambulatory and able to carry out work of a light or sedentary 
nature (e.g., light house work or office work).  
2 
In bed < 50% of the time. Ambulatory and capable of all self care, but 
unable to carry out work activities. Up and about for more than 50% of 
waking hours. 
3 
In bed >50% of the time. Capable of only limited self care. Confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self care. 
Totally confined to bed or chair. 
5 
Dead 
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APPENDIX III: THE NEW YORK HEART ASSOCIATION (NYHA) FUNCTIONAL 
CLASSIFICATION SCALE 
 
NYHA 
Class 
Symptoms 
I 
No symptoms and no limitation in ordinary physical activity, e.g., shortness of 
breath when walking, climbing stairs, etc. 
II 
Mild symptoms (mild shortness of breath and/or angina) and slight limitation 
during ordinary activity. 
III 
Marked limitation in activity due to symptoms, even during less-than-ordinary 
activity, e.g., walking short distances (20-100 m). 
Comfortable only at rest. 
IV 
Severe limitations. Experiences symptoms even while at rest. Mostly bedbound 
patients. 
 
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APPENDIX IV: CENTRAL PATHOLOGY REVIEW AND HANDLING OF TISSUES 
Handling of Tissues 
The designated pathologist at each site will collect the tissues from each patient enrolled in the 
protocol. One hematoxylin and eosin stained slide plus 3 unstained tissue slides must be made 
available for centralized pathology review. The unstained slides will be used in the event that 
additional stains (e.g., hematoxylin and eosin or immunohistochemical stains) are required to 
confirm the diagnosis (e.g., to differentiate a poorly differentiated adenocarcinoma of the uterus 
from a primary cervical cancer). A de-identified copy of the local pathology report must be 
submitted with the slides for central pathology review. 
 
Slides for centralized pathology review should be batched at each site, and shipped via World 
Courier, every six months to the AMC study laboratory. Specimen storage, shipping and labeling 
requirements are detailed in the AMC-081 Manual of Procedures.  
 
If any of the blank slides are not needed for central pathology review, then the slides will be 
destroyed. 
 
Record of Specimens 
This study will track specimens via GlobalTraceSM, a component of the AMC AdvantageEDCSM 
system. The GlobalTraceSM shipment manifest must accompany all specimen shipments. 
 
Pathology Review 
Specimens received from AMC will undergo histopathologic diagnosis and classification as 
follows: 
1. H&E 
2. Pathologist interpretation. 
3.  Additional stains for pathologic confirmation and subclassification, if needed for atypical and 
unusual cases, from unstained slides. 
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APPENDIX V: AMC DATA AND SAFETY MONITORING PLAN 
Version 5.0  January 28, 2014 
 
Monitoring the Progress of Trials and the Safety of Participants 
 
All AMC protocols that collect safety data follow the National Cancer Institute (NCI), Cancer 
Therapy Evaluation Program (CTEP) Guidelines: Adverse Event Reporting Requirements 
(http://ctep.cancer.gov/guidelines/index.html). All adverse events that meet the NCI’s expedited 
reporting requirements are reported to the Investigational Drug Branch (IDB) of the NCI via the 
CTEP Adverse Event Reporting System (CTEP-AERS) web application. All expedited adverse 
event reports are also required to be submitted to the local Ethics Committee/Institutional 
Review Board (IRB) of the reporting institution. If NCI holds the IND or no IND is required for 
a study, the AMC site reports serious adverse events directly to the AMC Operations and Data 
Management Center (ODMC) via CTEP-AERS. In some instances, the AMC sites may report 
serious adverse events directly to a commercial sponsor holding the IND, who will then report 
the event to the AMC ODMC. Most AMC protocols require sites to report all serious adverse 
events via CTEP-AERS and the AMC ODMC to forward a copy of the report to the sponsor. The 
AMC ODMC also distributes all IND safety reports to all investigators upon receipt, and makes 
these reports available on the password-protected section of the AMC Operations web site. 
Unless an AMC protocol specifies an alternate plan for the review and submission of serious 
adverse events, all serious adverse events received by the AMC ODMC will be reviewed by the 
AMC Medical Monitor at the AMC ODMC prior to submission to NCI and the sponsor. For 
protocols for which the IDB does not have an assigned drug monitor to review serious adverse 
event reports, in the event of disagreement between the reporting physician and the AMC 
Medical Monitor regarding the attribution of the event to the investigational agent(s) (i.e., 
determination of whether the relationship is unrelated, unlikely, possible, probable, or definite), 
the AMC Medical Monitor will provide the final determination of the relationship. 
 
The AMC ODMC provides listings of all reported adverse events and serious adverse events to 
the Protocol Chair and Co-chair(s) for review on a regular basis. The AMC ODMC compiles 
these events in a tabular format and posts them on the password-protected section of the AMC 
web site where these reports are updated nightly. The AMC web site is accessible to all AMC 
investigators, co-investigators, and their staff. Email notification that this information is available 
on the web site will be sent to all site PIs. It is the responsibility of each site to provide this 
information to their respective IRBs, if required by their IRB. For blinded studies, the serious 
adverse events are reviewed and tabulated without treatment assignment. The AMC Medical 
Monitor will review listings of all reported adverse events on a quarterly basis for safety 
concerns. 
 
Accrual summaries for each AMC trial are updated nightly on the password-protected section of 
the AMC web site. The progress of each AMC trial is reviewed regularly by the Protocol Chair 
and also by the appropriate disease-oriented Working Group during scheduled conference calls. 
For Phase I dose escalation trials, dose escalation (or dose de-escalation) is based on the rules in 
the protocol and the Protocol Chair, AMC Medical Monitor, and Group Statistician determine 
whether these criteria have been met. For Phase II trials, stopping the trial for toxicity or 
efficacy, or suspending enrollment pending observation of responses in a multi-stage Phase II 
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trial, is based on meeting criteria stated in the protocol, and the Protocol Chair, AMC Medical 
Monitor, and Group Statistician determine whether these criteria have been met. 
 
For Phase III trials, the AMC has formed an independent Data Safety and Monitoring Board 
(DSMB). Voting members of the DSMB are physicians, a statistician, and a patient advocate. All 
voting members are from outside the AMC. Nonvoting members are the AMC Group 
Statistician, the Statistician listed on the protocol, an AMC Operations Center staff member, two 
representatives (normally a clinician or statistician) from the Office of HIV AIDS Malignancy 
(OHAM) or from the Cancer Therapy Evaluation Program, Division of Cancer Treatment and 
Diagnosis, of the National Cancer Institute (NCI). The AMC Data Safety and Monitoring Board 
reviews AMC Phase III studies in accordance with the National Cancer Institute’s Policy for 
Data Safety and Monitoring. Confidential reports of all Phase III trials are prepared by the AMC 
Group Statistician with support from the AMC ODMC. A written report containing the current 
status of each trial monitored, and when appropriate, any toxicity and outcome data, are sent to 
DSMB members by the AMC ODMC within the timelines specified by the AMC DSMB 
Charter. This report addresses specific toxicity concerns as well as concerns about the conduct of 
the trial. The report may contain recommendations for consideration by the DSMB concerning 
whether to close the trial, report the results, or continue accrual or follow-up. 
 
The results of each DSMB meeting are summarized in a formal report sent by the DSMB Chair 
to the Group Chair and AMC ODMC. The DSMB report contains recommendations on whether 
to close each study reviewed, whether to report the results, and whether to continue accrual or 
follow-up. A primary recommendation (e.g., continue with no change; recommended or required 
modification; stop) must be included in the document. The Group Chair is then responsible for 
notifying the Protocol Chair and relevant Disease-oriented Working Group Chair before the 
recommendations of the DSMB are carried out. In the unlikely event that the Protocol Chair does 
not concur with the DSMB, then the NCI Division Director or designee must be informed of the 
reason for the disagreement. The Study Chair, relevant Disease-oriented Working Group Chair, 
Group Chair, DSMB Chair, and NCI Division Director or designee will be responsible for 
reaching a mutually acceptable decision about the study. CTEP approval of a formal amendment 
will be required prior to any implementation of a change to the study. 
 
Following a DSMB meeting, a summary of the serious adverse events reported to the DSMB is 
posted to the AMC web site. It is each site’s responsibility for conveying this information to its 
IRB. 
 
Plans for Assuring Compliance with Requirements Regarding the Reporting of Adverse 
Events (AE) 
 
For trials monitored by the NCI’s Clinical Data Update System (CDUS), adverse event 
information is transmitted electronically to NCI on a quarterly basis. For trials monitored by 
NCI’s Clinical Trials Monitoring Service (CTMS), adverse event information is transmitted 
electronically to NCI every two weeks. 
 
The Protocol Chair, AMC Group Chair, and the AMC ODMC share responsibility in assuring 
that participating investigators comply with the protocol requirements for adverse event 
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reporting. All AMC investigators certify compliance with NCI and FDA requirements for 
adverse event reporting by signing the AMC Adherence Statement for site membership, the 
protocol signature page for each protocol active at the site, and Form FDA-1572 for CTEP 
investigator registration and IND studies sponsored by AMC investigators. Investigators are 
responsible for identifying and reporting all adverse events to the AMC ODMC, CTEP-AERS, 
and/or sponsors according to the protocol requirements, and assuring compliance with reporting 
to the local IRB. Protocol compliance with adverse event reporting requirements is assessed by 
the AMC ODMC during routine site monitoring visits by reviewing the site’s source 
documentation.  
 
The data entry system used for AMC studies, AdvantageEDCSM (a web-based data entry and 
enrollment system), is programmed to notify the site investigator, protocol chair, and AMC 
ODMC via email in the event that a site reports an adverse event that meets expedited reporting 
criteria to NCI and/or FDA. If the site does not follow with a CTEP-AERS report, the AMC 
ODMC contacts sites to request an expedited report. Additionally, the protocol chair, AMC 
ODMC, and the AMC Medical Monitor review reported adverse events on a routine basis to 
identify adverse events reported by sites that require expedited reporting via CTEP-AERS. The 
Protocol Chair, AMC Group Chair, and IND sponsors have general oversight for assuring that 
routine and expedited adverse reporting requirements are met by the responsible parties. 
 
Plans for Assuring that any Action Resulting in a Temporary or Permanent Suspension of 
an NCI-Funded Clinical Trial is Reported to the NCI Grant Program Director Responsible 
for the Grant 
 
In the event that termination of the trial or major modification to the protocol is under 
consideration, the Protocol Chair will convene the AMC Data Coordinator and Disease-oriented 
Working Group Chair by conference call to discuss the options. For Phase I and II trials, the 
Protocol Chair also has the option of asking the AMC DSMB to review the study. The AMC 
ODMC will inform the CTEP Protocol Information Office (PIO) when studies are temporarily or 
permanently closed. The Cancer Treatment and Evaluation Program (CTEP) of the National 
Cancer Institute (NCI) must approve all protocol amendments prior to distributing to the AMC 
sites. 
 
Plans for Assuring Data Accuracy and Protocol Compliance 
 
All study data for AMC clinical trials are entered directly by AMC site staff into 
AdvantageEDCSM. During data entry, the system performs validation checks on many fields and 
performs consistency checks between select fields. Range checks are placed on each field to 
eliminate entry of out-of-range values. Edit check programs are run on the database on a set 
schedule to identify and resolve inconsistencies between forms or data collected at different 
points in time. AMC ODMC staff routinely interacts with site staff to resolve any data problems. 
 
In accordance with NCI guidelines, the AMC ODMC conducts monitoring visits at the AMC 
sites to evaluate compliance with regulatory issues, and to review data for specific cases by 
checking source documents. These reports are sent to the site Principal Investigator and to the 
NCI. In the event that major violations are identified, sites are asked to provide a plan to correct 
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deficiencies within 30 days. If needed, a repeat site visit is conducted. In the event that a site 
does not correct deficiencies in a pre-determined time frame, the AMC Executive Committee has 
the option of taking action against the site. Possible actions include, but are not limited to, 
suspending enrollment of new patients to AMC trials until deficiencies are corrected; 
recommending a decrease in funding to the site; and requiring specific training for site 
investigators or staff members. 
 
 
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APPENDIX VI: CLINICAL STAGING - CARCINOMA OF THE CERVIX UTERI FIGO 
CLASSIFICATION 1995 
 
PRE-INVASIVE CARCINOMA STAGE 0: Carcinoma in situ, intraepithelial carcinoma. 
(Cases of Stage 0 should not be included in any therapeutic statistics) 
 
INVASIVE CARCINOMA STAGE I: Carcinoma strictly confined to the cervix.  
 
STAGE IA: Invasive cancer identified only microscopically. (All gross lesions, even with 
superficial staging, are Stage IB cancers) Invasion is limited to measured stromal invasion with 
maximum depth of 5.0 mm and no wider than 7.0 mm. 
 
STAGE IA1: Measured invasion of stroma no greater than 3.0 mm in depth and no wider than 
7.0 mm.  
 
STAGE IA2: Measured invasion of stroma greater than 3 mm and no greater than 5 mm and no 
wider than 7 mm.  
 
STAGE IB: Clinical lesions confined to the cervix or pre-clinical lesions greater than Stage IA. 
 
STAGE IB1: Clinical lesions no greater than 4.0 cm in size. 
 
STAGE IB2: Clinical lesions greater than 4 cm in size. 
 
STAGE II: The carcinoma extends beyond the cervix but has not extended on to the pelvic wall. 
The carcinoma involves the vagina, but not the lower third.  
 
STAGE IIA: No obvious parametrial involvement. 
 
STAGE IIB: Obvious parametrial involvement. 
 
STAGE III: The carcinoma has extended on to the pelvic wall. On rectal examination, there is 
no cancer-free space between the tumor and the pelvic wall. The tumor involves the lower third 
of the vagina. All cases with hydro-nephrosis or non-functioning kidney. 
 
STAGE IIIA: No extension on to the pelvic wall. 
 
STAGE IIIB: Extension on to the pelvic wall and/or hydro-nephrosis or non-functioning kidney. 
 
STAGE IV:  The carcinoma has extended beyond the true pelvis or has clinically involved the 
mucosa of the bladder or rectum. A bullous edema as such does not permit a case to be allotted 
to Stage IV. 
 
STAGE IVA: Spread of the growth to adjacent organs. 
 
STAGE IVB: Spread to distant organs. 
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Notes on Staging: 
Stage IA carcinoma should include minimal microscopically evident stromal invasion as well as 
small cancerous tumors of measurable size. Stage IA should be subdivided into those lesions 
with minute foci or invasion visible only microscopically as Stage IA1 and the macroscopically 
measurable microcarcinomas as Stage IA2 in order to gain further knowledge of the clinical 
behavior of these lesions. The term IB occult should be omitted. 
 
The diagnosis of both Stage IA1 and IA2 should be based on microscopic examination of 
removed tissue, preferably a cone, which must include the entire lesion. As noted above, the 
lower limit of Stage IA2 should be that it can be measured macroscopically (even if dots need to 
be placed on the slide before measurement) and the upper limit of Stage IA2 is given by 
measurement of the two largest dimensions in any given section. The depth of invasion should 
not be more than 5 mm taken from the base of the epithelium, either surface or glandular, from 
which it originates. The second dimension, the horizontal spread, must not exceed 7 mm. 
Vascular space involvement, either venous or lymphatic, should not alter the staging but should 
be specifically recorded as it may affect treatment decisions in the future. 
 
Lesions of greater size should be staged as IB. 
 
As a rule, it is impossible to estimate clinically whether a cancer of the cervix has extended to 
the corpus. Extension to the corpus should therefore be disregarded. 
 
A patient with a growth fixed to the pelvic wall by a short and indurated, but not nodular, 
parametrium should be allotted to Stage IIB. It is impossible at clinical examination to decide 
whether a smooth and indurated parametrium is truly cancerous or only inflammatory. Therefore, 
the case should be placed in Stage III even if according to the other findings the case should be 
allotted to Stage I or Stage II. 
 
The presence of the bullous edema as such should not permit a case to be allotted to Stage IV. 
Ridges and furrows into the bladder wall should be interpreted as signs of submucous 
involvement of the bladder if they remain fixed to the growth at palpation (i.e., examination from 
the vagina or the rectum during cystoscopy). A cytological finding of malignant cells in 
washings from the urinary bladder requires further examination and a biopsy from the wall of the 
bladder. 
 
The depth of invasion should be no more than 5 mm taken from the base of the epithelium, either 
surface or glandular, from which it originates. Vascular space involvement, either venous or 
lymphatic, should not alter the staging. 
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APPENDIX VII: HDR BRACHYTHERAPY 
 
I. Vaginal Surface Dose – HDR (03/23/2009) 
 
The vaginal mucosa will receive 138-140% of the prescribed dose to Point A—8.28-12.6 Gy. 
The vaginal mucosa dose is defined on the lateral surface of the ovoids taken through a 
coronal section. Computerized dosimetry is required for each HDR insertion. 
 
In patients with either significant vaginal narrowing due to tumor infiltration or normal 
anatomy, tandem and cylinders may be necessary to encompass the volume of disease. Since 
little or no packing will be possible in these patients, the vaginal mucosa dose should not 
exceed 110-120% of the prescribed dose to Point A, unless the bladder and rectum are 
receiving doses within normal tissue tolerance.  
 
II. Normal Tissue Tolerance 
 
In LDR brachytherapy, most institutions attempt to keep the total bladder dose below 75 Gy 
and the total rectal dose below 70 Gy, unless the tumor is poorly regressing and/or observing 
these normal tissue tolerances would compromise tumoricidal radiation doses. The total 
bladder and rectal dose will be less in HDR brachytherapy because of the dose rate effect. 
There are a number of methods available to calculate these normal tissue doses. The linear 
quadratic model (LQM), total rectal and bladder dose, in addition to the ratio of bladder or 
rectal dose divided by the Point A dose, have been employed to calculate normal tissue 
tolerance. Certainly, if the total bladder and/or rectal dose equals or exceeds the above LDR 
guidelines, or if the ratio of the normal tissue dose to the Point A dose is 80% or greater, then 
the packing will need to be re-evaluated. The LQM is probably the most accurate model at 
present to evaluate normal tissue tolerance to account for the dose rate effect. Using the 
LQM, a dose to the late responding tissues of 70 Gy corresponds to a Gy3 of 120 (Gy3-not 
real dose, but biologically effective one to the late responding tissues). A total dose of 75 Gy 
corresponds to a Gy3 of 130. These Gy3 terms are helpful in calculating the total doses to the 
normal tissues when adjusting for the dose rate effect.  
 
In order to stay below an LDR equivalent of 70 Gy to the rectum (120 Gy3) for five HDR 
insertions, including the 45 Gy contributions from the external beam radiation, the rectum 
should receive less than 4.1-6.1 Gy for each HDR fraction of 6-9 Gy (68% of the prescribed 
dose to Point A). The dose to the bladder should be less than 4.6-6.9 Gy per HDR fraction of 
6-9 Gy (77% of the prescribed dose to Point A). As in LDR brachytherapy, every attempt 
should be made to deliver tumoricidal doses, even if the late responding tissues receive a 
slightly higher dose. (03/23/2009)  
 
III. Packing 
 
For both LDR and HDR brachytherapy, careful attention should be paid to the bladder and 
rectal packing. Radio-opaque gauze is recommended to determine the location of the packing 
for calculation of ICRU #38 bladder and rectal doses. Using the posterior blade of a 
speculum may facilitate rectal packing. Bladder and rectal points will be taken for normal 
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tissue tolerance for both HDR and LDR brachytherapy according to ICRU recommendations 
(ICRU #38) as well as standard institutional bladder and rectal points. These ICRU #38 and 
institutional bladder and rectal dose points must be calculated but dose modifications should 
not be made solely based upon these calculations (Refer to Appendix IX). 
 
IV. Imaging - HDR 
 
A dedicated brachytherapy suite in which an orthogonal x-ray pair can be taken is the ideal 
setting for the HDR insertions. This will allow for patient immobilization and a reduction in 
the overall time spent with applicators in the gynecologic tract. If patients must be moved to 
another room for an orthogonal x-ray pair, every attempt should be made to maintain rigid 
immobilization. Since the HDR tandem diameter is only 2.5 mm, as opposed to a LDR 
tandem diameter of 5.0 mm, sounding the uterus is often easier with a potential increased risk 
for uterine perforations. If a uterine perforation is suspected, it is highly recommended that a 
transabdominal ultrasound be performed to rule out this event. Ultrasound may also facilitate 
uterine sounding with difficult insertions. 
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APPENDIX VIII: DESCRIPTION OF POINTS A AND B AND ICRU 
BLADDER/RECTAL DOSE REPORTING POINTS 
 
 
 
 
Point A is defined as 2 cm along the intrauterine tandem in the superior direction from the 
flange, and 2 cm perpendicular to the tandem in the lateral direction. 
 
Point B is defined as 2 cm along the intrauterine tandem in the superior direction from the flange, 
and 5 cm lateral from the midline of the patient. 
 
 
The bladder reference point is obtained as follows. A Foley catheter is used. The balloon must be 
filled with 7 cm3 of radio-opaque fluid. The catheter is pulled downwards to bring the balloon 
against the urethra. On the lateral radiograph, the reference point is obtained on an anterio-
Description of ICRU 38 Bladder/Rectal Dose Reporting Points 
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posterior line drawn through the center of the balloon. The reference point is taken on this line at 
the posterior surface of the balloon. The frontal radiograph, the reference point is taken at the 
center of the balloon. 
 
The point of reference for the rectal dose is obtained as follows. On the lateral radiograph, an 
anteroposterior line is drawn from the lower end of the intrauterine source (or from the middle of 
the intravaginal sources). The point is located on this line 5 mm behind the posterior vaginal 
wall. The posterior vaginal wall is visualized, depending upon the technique, by means of an 
intravaginal mould or by opacification of the vaginal cavity with a radio-opaque gauze used for 
the packing. On the AP radiograph, this reference point is at the lower end of the intrauterine 
source or at the middle of the intravaginal source(s). 
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APPENDIX IX: BLANK DIAGRAM ANTERIOR 
 
 
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APPENDIX X: BLANK DIAGRAM LATERAL 
 
 
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APPENDIX XI: COLLECTION AND SHIPPING INSTRUCTIONS FOR SERUM AND 
CERVICAL AND ANAL SWABS FOR EXPLORATORY OBJECTIVE SPECIMENS 
 
SPECIMEN COLLECTION 
 
The specimen collection requirements for exploratory objective specimens are detailed in the 
AMC-081 Manual of Procedures.  
 
SAMPLE SHIPPING AND LABELING 
 
Specimens should be batched at each site, and shipped via World Courier, every six months to 
the study laboratory. The shipping and labeling requirements are detailed in the AMC-081 
Manual of Procedures.  
 
RECORD OF SPECIMENS 
 
This study will track specimens via GlobalTraceSM, a component of the AMC AdvantageEDCSM 
system. The GlobalTraceSM shipment manifest must accompany all specimen shipments. 
 
HPV DNA TESTING 
 
To perform HPV DNA testing on cervical and anal swab specimens, the swabs will be obtained 
following the procedures listed in the AMC-081 MOP and inserted into Specimen Transport 
medium (STM). The swab should then be cut with sterile or single-use scissors to allow the swab 
to fit in the vial. The cap should then be replaced securely and sealed with tape or parafilm. The 
specimens must then be stored at -20°C or -80°C prior to shipping every 6 months. The 
specimens should be shipped Monday through Wednesday on dry ice to: 
 
Maria Da Costa 
University of California, San Francisco 
513 Parnassus Ave Room S-420 
San Francisco, CA 94143-0654 
TEL: 001-415-476-8885 
 
Laboratory methods: A crude DNA preparation is made from the STM/swab specimen. First the 
specimen is incubated at 56°C for 1 hour, then proteinase K (Invitrogen Life Technologies) is 
added to a concentration of 250 µg/ml and incubated at 50°C overnight. In the morning the 
proteinase K is heat inactivated, and 200 µl of the specimen is ethanol precipitated and 
suspended in 25 µl Tris-EDTA buffer. Five µl of sample are used for PCR amplification. PCR 
products from positive samples were also typed by dot-blot hybridization using 38 individual 
type-specific probes as well as 2 separate mixtures of types. 
 
The presence or absence of HPV and beta-globin DNA is determined using DNA hybridization. 
Negative controls for each blot consist of amplification of DNA of BJAB cells and tubes 
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containing all reaction components except target DNA. Positive controls consist of amplification 
of DNA from 100 SiHa cells as well as amplified DNA from the individual HPV types being 
sought. Five percent of the samples are amplified in duplicate. Six µL of the PCR amplification 
mixtures are applied to dot blots and the DNA is fixed on the membrane. To detect HPV DNA, 
the membranes are pretreated in 0.1 x sodium chloride-sodium phosphate-EDTA (SSPE), 0.5% 
sodium dodecyl sulfate for 30 min at 65˚C. Probes consisting of amplified biotinylated DNA 
from HPV 16, HPV 18, HPV 11 and HPV 51 are denatured and added in the presence of 2 
mg/mL sheared salmon sperm DNA to the hybridization buffer and hybridized at 55˚C for at 
least 1.5 h. After washing, streptavidin-horse radish peroxidase (SA-HRP) (Vector Laboratories, 
Burlingame, CA) is added to the blots at a concentration of 30 ng/mL in 250 mL of wash 
solution and binding allowed to occur with gentle agitation for 15 min at room temperature. 
After vigorous washing, detection of HPV types is performed using Enhanced 
ChemiLuminescent detection (ECL) (Amersham, Arlington Heights, IL) according to the 
manufacturer’s 
instructions. 
Type-specific 
probing 
is 
performed 
using 
biotinylated 
oligonucleotide probes at a final concentration of 0.5 pmol/mL for the following HPV types 
individually: 6/11, 16, 18, 26/69, 30, 31, 32/42, 33, 34, 35, 39, 45, 51, 52, 53, 54, 56, 57/2/27, 58, 
59, 61, 62, 66, 67, 68, 70, 71, 72, 73, 81, 82, 83, 84, 85, 86/87, 90/106, 97, 102/89, as well as 2 
separate mixtures. Mix1 contains 7, 13, 40, 43, 44, 55, 74, and 91, and Mix2 contains 3, 10, 28, 
29, 77, 78, and 94.A sample is considered HPV positive when it was positive with the consensus 
probes. Specimens positive with the consensus probes but negative with the individual type 
probes are considered to have one or more “other” types. Specimens negative for beta-globin 
gene amplification are excluded from analysis. 
 
DNA Methylation Analysis 
 
DNA from swab material will be used to allow us to determine in a descriptive way if the 
methylation patterns are different and might provide some clues regarding the role of HPV 
methylation in progression to cancer. DNA will be treated with sodium bisulfite using the EZ 
DNA Methylation Kit (Zymo Research, Orange, CA) in preparation for MSP. The methylation-
specific PCR reactions will utilize 10 ng of the sodium bisulfite-treated DNA in 12.5  µl of 2x 
Brilliant SYBR Green QPCR Master Mix (dNTPs, Taq DNA polymerase, 2.5 mM MgCl2) 
(Stratagene), 30 nM ROX reference dye, and 500 nM of forward and reverse primers, in a final 
volume of 25 µl. Real-time methylation-specific PCR will be performed on a Mx3000 
Thermocycler (Stratagene, La Jolla, CA). The methylation-specific primer sequences are listed in 
Table X. The real time methylation-specific PCR reaction utilizes the following conditions: 
Segment one - one cycle - 95°C for 10 minutes; Segment two - 65 cycles - 95°C for 30s, then 
60°C-64°C (depending on primers) for 30s, then 72°C for 30s; Segment three - one cycle - 72°C 
for 30s, then 95°C for 1 minute, then 55°C for 30s. Normal male white blood cell genomic DNA 
(Novagen, Madison, WI) will used as a negative DNA control and CpGenome Universal 
Methylated DNA, Human Male (Chemicon International, Temecula, CA) will be used as a 
positive control. Unmethylated MyoD primer sets will be used to confirm the presence of PCR-
amplifiable DNA in each sample. Each gene will be scored as positive or negative for 
methylation; the assay will not be quantitative. The individual target gene will be considered 
positive for methylation if there is a PCR product detected at the appropriate temperature of the 
dissociation curve, and the gene will considered negative if there is no peak at the appropriate 
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temperature of the dissociation curve. Samples will be considered non-informative if there is no 
PCR product generated from the gene of interest and the unmethylated MyoD control. 
 
Table X. Real-Time Methylation Specific PCR Primers and Probes 
Locus 
5’ to 3’ Forward Primer 
5’ to 3’ Reverse Primer 
MYOD1 
CCAACTCCAAATCCCCTCTCTAT 
TGATTAATTTAGATTGGGTTTAGAGAAGGA 
APC 
TTATATGTCGGTTACGTGCGTTTATAT 
GAACCAAAACGCTCCCCAT 
hMLH1 
CTATCGCCGCCTCATCGT 
CGTTATATATCGTTCGTAGTATTCGTGTTT 
MGMT 
GCGTTTCGACGTTCGTAGGT 
CACTCTTCCGAAAACGAAACG 
GSTP1 
AGTTGCGCGGCGATTTC 
GCCCCAATACTAAATCACGACG 
p16INK4a 
TTATTAGAGGGTGGGGCGGATCGC 
GACCCCGAACCGCGACCGTAA 
CDH1 
AATTTTAGGTTAGAGGGTTATCGCGT 
TCCCCAAAACGAAACTAACGAC 
RARβ 
AAGTAGTAGGAAGTGAGTTGTTTAGA 
CCAAATTCTCCTTCCAAATAA 
HIC1 
GTTAGGCGGTTAGGGCGTC 
CCGAACGCCTCCATCGTAT 
TSLC1 
GTGAGTGACGGAAATTTGTAATGTTTGGTT AATCTAACTTCTTATACACCTTTATTAAAA 
RASSF1A 
GCGTTGAAGTCGGGGTTC 
CCCGTACTTCGCTAACTTTAAACG 
DAPK 
GGATAGTCGGATCGAGTTAACGTC 
CCCTCCCAAACGCCGA 
FHIT 
TTGGGGCGCGGGTTTGGGTTTTTACGC 
CGTAAACGACGCCGACCCCACTA 
PTEN 
GGTTTTTCGAGGCGTTCG 
CGCCTCACAACGACTCAACT 
p14ARF 
GTGTTAAAGGGCGGCGTAGC 
AAAACCCTCACTCGCGACGA 
VHL 
TGGAGGATTTTTTTGCGTACGC 
GAACCGAACGCCGCGAA 
p73 
GGACGTAGCGAAATCGGGGTTC 
ACCCCGAACATCGACGTCCG 
FANCF 
TTTTTGCGTTTGTTGGAGAATCGGGTTTTC ATACACCGCAAACCGCCGACGAACAAAACG 
BRCA1 
TCGTGGTAACGGAAAAGCGC 
AAATCTCAACGAACTCACGCCG 
TNFRSF10C TTACGCGTACGAATTTAGTTAAC 
ATCAACGACCGACCGAAACG 
TNFRSF10D GGGATAAAGCGTTTCGATC 
CGACAACAAAACCGCG 
 
SERUM SPECIMENS 
 
HPV Serology 
 
Serology to measure neutralizing antibodies against HPV 16 and HPV 18 will be performed 
using a pseudovirion (PsV)-based neutralizing assay (PBNA). HPV-16 and HPV-18 PsVs were 
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prepared as described. PsVs will be synthesized using the 293TT cell line transfected with the 
p16sheLL, p18sheLL and pYSEAP plasmids. PsVs will be purified by loading on a 2% agarose 
gel column. The crude stock and column-purified stock will be titrated using 293TT cells. 
Neutralization assays will be performed using established methods. PsVs carrying the SEAP-
encoding plasmid will be incubated with participants’ sera for 1 hour on ice. The mix will be 
added to the 293TT cells and SEAP activity will be measured in the medium after 72 hours. 
SEAP in 25 µl of culture supernatant will be detected using the Great Escape SEAP 2.0 detection 
kit (Clontech, Mountain View, CA) per the manufacturer’s instructions. Chemiluminescence will 
be read on a microplate reader (Dynatech Laboratories, Chantilly, VA). Negative controls consist 
of sera known to lack neutralizing HPV antibodies. Positive controls consist of assays performed 
with addition of heparin (1mg/ml) and sera known to contain neutralizing antibodies from HPV-
16- and HPV-18-vaccinated individuals. The neutralization titer will be defined as the reciprocal 
of the highest dilution of test serum that reduce the SEAP activity by at least 50% in comparison 
with the reactivity in the wells that receive PsV but no antibody. All assays will be done in 
duplicate at four different dilutions-1:100, 1:200, 1:400 and 1:800. Data for each serum sample 
at each dilution represent an average of the duplicate wells. Samples that do not reduce SEAP 
activity by 50% or more at a 1:100 dilution will be considered to be seronegative for analysis. In 
some cases where the titers are higher than 800 the assays will be repeated with higher dilutions 
to obtain accurate titers. 
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APPENDIX XII: RADIATION THERAPY QUALITY ASSURANCE PROCESS 
 
External Beam Therapy 
A. Machine QA: all of the following are required:  
1) Participation in the annual mailed OSLD/TLD program conducted by the IROC Houston 
QA Center for an independent basic check of the machine output. 
2) Submission of machine output calibration as per AAPM TG-51 protocol or IAEA TRS 
277 or 398 protocols. 
3) Provide standards lab (SSDL or ADCL) calibration certificates for the ion chamber and 
electrometer used in the calibration of the reference beam output for the external  beam 
RT. 
 
B.  External Beam Treatment Plan 
Submission of a complete treatment plan (to include treatment plan summary, beam-on 
times, isodose lines, dose volume histograms, beams eye views (BEV), daily treatment 
record), and completed on-line external beam dosimetry form found on the IROC Houston 
QA Center website (http://irochouston.mdanderson.org) under forms shall be submitted for 
review by the IROC Houston QA Center and protocol PI. This review verifies that the dose 
reported is that required by the protocol, no data entry errors have occurred in the calculation, 
and that there are no transcription and/or reporting errors. The IROC Houston QA Center’s 
participant review may require the participating site to submit additional dosimetry data, as 
specified by the IROC Houston QA Center, for the therapy machine used to treat the 
participant if a dose delivery discrepancy is determined. 
 
Brachytherapy 
A. Machine QA: all of the following are required: 
b. Submit sample brachytherapy source assay document plus a copy of manufacturer source 
certificate. 
c. Submit copies of standards lab (SSDL or ADCL) calibration certificates for 
 
brachytherapy chamber and electrometer used in source assay. 
 
B. Brachytherapy Treatment Plan 
Submission of a complete treatment plan to include source strength, for LDR: source loading 
and total time, for HDR: dwell positions and dwell times, orthogonal AP and lateral films 
with magnification factors, and completed on-line Gynecological Brachytherapy Protocol 
Compliance 
form 
found 
on 
the 
IROC 
Houston 
QA 
Center 
website 
(http://irochouston.mdanderson.org) under forms shall be submitted for review by the IROC 
Houston QA Center and protocol PI. This review verifies that the dose reported is that 
required by the protocol, no data entry errors have occurred in the calculation, and that there 
are no transcription and/or reporting errors. If a dose delivery discrepancy is determined, the 
IROC Houston QA Center’s participant review may require the participating site to submit 
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NCI Version Date 20 February 2015 

additional brachytherapy dosimetry data that was used to treat the participant, as specified by 
the IROC Houston QA Center. 
 
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NCI Version Date 20 February 2015