tested in larger and more
definitive randomized controlled
trials. The primary endpoint is
a novel pathologic endpoint of
the neoadjuvant rectal (NAR)
score,which measures pathologic
response to TNT and has been
shown to predict long-term
survival endpoints. 7 Such a
pathologic endpoint allows trial
outcomes to be assessed rapidly.
The platform design of the trial
allows for a systematic approach
to study novel radiosensitizers,
such as the poly(ADP-ribose)
polymerase inhibitor veliparib;
personalized treatment selection
using novel targeted systemic
therapeutics; and identification of
patients at exceptionally high risk
for recurrence. Hence, the TNT
protocol will provide a clinical
trial to support the testing of
multiple parallel hypotheses
and help justify more definitive
randomized controlled studies
only after the demonstration
of substantive activity.
Patients must have biopsy-proven clinical stage II/III rectal
adenocarcinoma. The disease
must be clinically determined
as “locally advanced” by any
one of the following criteria:
•Distal location: c T3-4 ≤ 5 cm from
the anal verge, any N
•Bulky: Any c T4 with the majority
of tumor < 12cm from the anal
verge or evidence that the tumor
is adjacent to (defined as within
3 mm of) the mesorectal fascia
•High risk for metastatic disease
with four or more regional lymph
nodes (c N2)
•Not a candidate for sphincter-sparing surgical resection prior to
neoadjuvant therapy (as planned
by the primary surgeon)
Associated translational studies
will correlate clinical outcomes
with molecular, biomarker,
and imaging interrogation.
The study is currently undergoing
the pre-activation phase at
the National Cancer Institute
Cancer Trials Support Unit. It is
expected to be available for all
sites to open in October 2016.
The study is endorsed by all
cooperative groups, including
the Alliance for Clinical Trials in
Oncology. For more information,
1. Sauer R, Becker H, Hohenberger
W, et al. Preoperative versus
for rectal cancer. N Engl J Med.
2. Sauer R, Liersch T, Merkel S, et al.
Preoperative versus postoperative
chemoradiotherapy for locally
advanced rectal cancer: Results of
the German CAO/ARO/AIO- 94
randomized phase III trial after a
median follow-up of 11 years. J Clin
Oncol. 2012; 30( 16):1926-1933.
3. Roh MS, Colangelo LH, O’Connell
MJ, et al. Preoperative multimodality
therapy improves disease-free survival
in patients with carcinoma of the
rectum: NSABP R-03. J Clin Oncol.
2009; 27( 31):5124-5130.
4. NCCN Guidelines. Available at: www.
gls/ f_guidelines.asp. Accessed August
5. Khrizman P, Niland JC, ter Veer A, et al.
Postoperative adjuvant chemotherapy
use in patients with stage II/III rectal
cancer treated with neoadjuvant
therapy: A national comprehensive
cancer network analysis. J Clin Oncol.
2013; 31( 1): 30-38.
6. Fernandez-Martos C, Garcia-Albeniz
X, Pericay C, et al. Chemoradiation,
surgery and adjuvant chemotherapy
versus induction chemotherapy
followed by chemoradiation and
surgery: Long-term results of the
Spanish GCR- 3 phase II randomized
trial. Ann Oncol. 2015; 26( 8):1722-1728.
7. George TJ Jr, Allegra CJ, Yothers G.
Neoadjuvant rectal (NAR) score: A
new surrogate endpoint in rectal
cancer clinical trials. Curr Colorectal
Cancer Rep. 2015; 11( 5):275-280.
FIGURE 1. NRG ONCOLOGY NRG-GI002 SCHEMA
FOLFOX × 8
FOLFOX × 8
FOLFOX + ?
XRT + capecitabine
XRT + capecitabine + veliparib
XRT + capecitabine +
V101 No 10 BULLETIN American College of Surgeons