Michael S Wheatley

DOS – 741
Protocol Summary
The Radiation Oncology Group (RTOG)
RTOG – 0529
Clinical Trials Identifier: NCT00003596
The investigation into the feasibility of treating patients with
anal cancer to higher doses with a multi-modality approach of
using IMRT along with 5 – Fluorouracil
(5-FU) and Mitomycin – C (MMC)
The belief is that by using IMRT, Grade 2+ and Grade 3+
morbidities can be decreased without compromising loco-
regional control
The Radiation Oncology Group (RTOG)
Objectives
Primary – determine if combined rate of grade 2 and higher
GI & GU adverse events decreased by 15% in first days
following start of treatment
Secondary – evaluate adverse events to decrease grade 2 & 3
rates by 15 or 20% compared to RTOG 9811, evaluate
complete response at 8 weeks post tx, estimate the following
endpoints – local-regional failure, disease-free survival, time
to colostomy, colostomy-free survival & overall survival.
Before we discuss RTOG 0529 we need to discuss RTOG 9811
RTOG 9811

Clinical Trials Identifier NCT00003596

Phase III Trial with 682 Randomized Participants in 2 study arms

Arm 1 – Patients received 5 – FU and MMC on days 1 and 29 with

conventional XRT beginning on day 1 of Chemotherapy

Arm 2 – Patients received induction Chemotherapy on days 1, 29, 57 and 85

with conventional XRT starting on day 57.

Trial completed Dec 2016

Study showed Arm 1 provided good locoregional control, but patients

experienced high acute morbidities including
- Grade 2+ hematologic, dermatologic and gastrointestinal

This led to further prospective studies to include RTOG 0529

RTOG 0529

Phase II Trial

Prospective multicenter study

Enrolled 63 participants placed in a single arm

Created a standardized IMRT and contouring Atlas for anal cancer for equal comparison for the XRT
component of treatment
To compare to the RTOG 9811 arm of
5 – FU and MMC on days 1 and 29 with concurrent XRT starting on day 1
The XRT compared the standardized IMRT versus the conventional 3D techniques used in RTOG 9811

RTOG 0529 followed the same schedule of Chemotherapy and XRT

Patient Inclusion Criteria
Histologically-proven invasive primary squamous,
basaloid, or cloacogenic carcinoma of anal canal
T2 – T4 and N0 – N3 staging
H&P within 14 days prior to registration
Groin examination within 42 days prior to registration
Clinically positive nodes
X-ray, CT Scan or PET of chest and abdomen 42 days
prior to registration
Zubrod Performance Status 0-1
Patient Inclusion Criteria contd.
Age 18 and up
Lab panels to show adequate bone marrow, hepatic and
renal function
Participants of childbearing age agree to birth control
methods
AIDS negative test if suspicion 42 days prior to
registration
Signed Study specific informed consent prior to study
entry
 Patient Ineligibility
Prior invasive malignancies
Prior systemic chemotherapy
Prior XRT to pelvis
T1 stage or evidence of Mets
Prior surgery of anal canal
Severe active co-morbidity
Women who are pregnant
Active co-morbidities
Congestive heart failure
Acute bacterial or fungal infections
COPD
Hepatic insufficiency
Uncontrolled diabetes
Heart disease – high blood pressure
AIDS
Other immunocompromised status
Radiation Treatment Planning
IMRT mandatory (does allow the use of Tomotherapy)

Dose Specifications

T2N0 – primary tumor to receive 50.4 Gy 28 fxs 1.8 Gy/fx

nodal PTVs to receive 42 Gy 1.5 Gy/fx
T3N0 or T4N0 – primary tumor 54 Gy 30 fxs 1.8 Gy/fx
nodal PTVs to receive 45 Gy 1.5 Gy/fx

N+ - primary tumor will receive 54 Gy

nodes less than or equal to 3 cm 50.4 Gy
nodes greater than 3 cm 54 Gy
Radiation Treatment Planning contd.
Treatment delivered once daily, 5days week excluding
holiday weeks
Dose specifications
5% or less of PTVs to receive < 90% of prescription
2% or less of PTVs to receive < 80% of prescription
No more than 2% of primary target to get > 115%
Simulation requirements
Proper immobilization
5 mm or less CT slice thickness to include entire anatomy
Radiation Treatment Planning
Required Target Volumes

Gross Tumor Volumes (GTV)

GTVa – primary anal volume, GTVN50 – nodal regions
less than 3 cm, GTVN54 – nodal regions greater than 3 cm

Clinical Target Volumes (CTV)

The GTV plus potential microscopic disease

Planning Target Volumes (PTV)

Minimum 1 cm expansion from CTV trimmed 3-5 mm
from noninvolved skin surfaces, primary and nodal PTV
to not overlap when different doses are prescribed
Radiation Treatment Planning contd.
Critical Normal Structures
Small bowel, femoral heads, iliac crests, external genitalia,
bladder, large bowel
Contoured and considered solid organs
Tissue outside of critical normal structures and PTVs to be
considered unspecified tissue
DVHs generated to evaluate dose constraints for all critical
normal structures
 Dose Constraints
Small Bowel - 200 cc above 30 Gy, 150 cc above 35 Gy
20 cc above 45 Gy, none above 50 Gy
Femoral Heads – 50% above 30 Gy, 35% above 40 Gy, 5% above 44 Gy
Iliac crests – 50% above 30 Gy, 35% above 40 Gy, 5% above 50 Gy
External genitalia – 50% above 20 Gy, 35% above 30 Gy, 5% above 50 Gy
Bladder – 50% above 35 Gy, 35% above 40 Gy, 5% above 50 Gy
Large bowel – 200 cc above 30 Gy, 150 cc above 35 Gy, 20 cc above 45 Gy
Plan Compliance Criteria
PTVs meet required prescription
Minor deviation – 6-10% of PTV receives < 90%, 2-5% receives < 80%, 2% > 115%
Major deviation – 10% or more of PTV receives < 90%, 5% or more < 80%

Small Bowel meets all criteria

Minor deviation – 150-300 cc above 35 Gy, 20-30 cc above 45 Gy
Major deviation – 300 cc above 35 Gy, 30 cc above 45 Gy

Femoral heads meets all criteria

Minor deviation – 5-10% above 44 Gy
Major deviation – 10% above 44 Gy

Treatment interruptions discouraged but allowed for up to 7 days for Grade 4 skin reactions, ANC <
500/mm3 or platelets < 50,000, Grade 3 diarrhea, Grade 4 dermatitis, Grade 3 vomiting, general
infections in areas of moist desquamation

Chemotherapy consisting of 5 – FU and MMC to begin day 1 of XRT and second course to be given
on day 29. If radiation delayed, 2nd course of chemo to also be delayed
Results of RTOG 0529
Clinical Trial showed similar locoregional control as the
RTOG 9811 arm consisting of conventional radiation
combined with 5 FU & MMC concurrently.
Grade 2+ and Grade 3+ toxicities were decreased with the
addition of IMRT planning component
Will be used as the basis for future RTOG anal cancer
trials to allow for higher dose escalation for improved
locoregional control and decreased toxicity
Thank You
For
Watching