2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

CAO/ARO 04 study—which added oxaliplatin to continuous
intravenous infusion 5-FU or capecitabine and 50.4 Gy of
radiotherapy—demonstrated that oxaliplatin did not result
in an overwhelming improvement in pCR rates, although
it was statistically significant (13% v. 17%, p � 0.033) in the
German study. 19,20 The NSABP study showed significantly
more grade 3 and 4 diarrhea with oxaliplatin (15% v. 7%, p �
0.0001), similar to the STAR and ACCORD trials. Interestingly,
the toxicity for the oxaliplatin arm was not higher in
the German study, likely because of a lower cumulative dose
of oxaliplatin and a split course treatment with the 5-FU.
Oxaliplatin did not improve sphincter preservation—one of
the goals of preoperative therapy—in any of the studies.
Clearly, there is no role for oxaliplatin in combination with
neoadjuvant 5-FU-based chemoradiation. It appears to only
increase toxicity without improving pCR rates, sphincter
preservation, or local control.
Individualization of Neoadjuvant Therapy
The neoadjuvant approach is particularly appealing for
assessing the biology of the tumor and identifying active
regimens, which can then be used for the patient in the
postoperative setting. Preoperative therapy also allows us
to identify predictive and prognostic markers for treatment
response. This leads to the potential for individualizing
treatment regimens using information about the tumor and
the patient. Basic prognostic information, such as tumor
stage, histologic grade, and location, are being reinforced by
the use of biomarkers, which may help us identify patients
most likely to benefit from certain drugs. Although there are
many markers that have been evaluated, none have been
validated for clinical use. This is an area of greatly needed
research. Future studies that add new agents may have
the best chance of showing effect if we can use predictive
KEY POINTS
● Preoperative chemoradiation improved local control
rates—even after total mesorectal excision—for patients
with locally advanced rectal cancer.
● Oxaliplatin combined with 5-fluorouracil–based
chemoradiation does not improve pathologic response
rates, sphincter preservation, or disease-free survival
and increases the toxicity of neoadjuvant chemoradiation.
● Pooled analyses of patients who received adjuvant
treatment for rectal cancer have demonstrated intermediate
and high risk disease, potentially identifying
subgroups of patients who may not benefit from
adjuvant radiotherapy.
● Nonoperative approaches for patients with clinical
complete responses to chemoradiation may allow for
a more individualized approach for patients with
distal rectal cancers.
● The PROSPECT trial is investigating the selective
use of chemoradiation in patients treated with neoadjuvant
folinic acid, 5-FU, and oxaliplatin
(FOLFOX) chemotherapy for locally advanced rectal
cancers.
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KARYN A. GOODMAN
biomarkers as eligibility criteria to enrich the population of
patients who will potentially respond.
Until validated biomarkers are available, further refinements
in risk stratification based on clinical factors should
be pursued to allow for better identification of patients
who may or may not benefit from more aggressive multimodality
therapy. In an attempt to stratify patients with locally
advanced rectal cancer, investigators analyzed pooled data
from 2,551 patients enrolled in three North American rectal
trials. Patients with intermediate-risk rectal cancer—defined
as T1 to T2N1 or T3N0—had only approximately 6%
to 8% risk of local recurrence and may not derive any benefit
from adjuvant radiation. 21 In addition, validated nomograms
based on clinical and pathologic features are now
available to assess risks for local or distant recurrence and
neoadjuvant chemoradiation. 22 In Northern Europe, features
on rectal magnetic resonance imaging (MRI) have been
used to stratify patients into low-, intermediate-, and highrisk
groups. Based on MRI findings of extramural extent
of the tumor, the relation to the mesorectal fascia, and the
presence of multiple suspicious lymph nodes, low-risk patients
are treated with surgery alone, patients with
intermediate-risk rectal tumors with “short-course” 5 Gy �
5 preoperative protocol, and patients with high-risk tumors
based on MRI findings with “long-course” preoperative
chemoradiation. 23
Patient-specific risk factors such as age, performance
status, and other medical comorbidities must be considered
when adding chemotherapy or targeted agents to neoadjuvant
therapy. The benefits of bevacizumab are likely to be
outweighed by cardiovascular or thrombotic risks in the
patient with a history of cardiac disease. For young, premenopausal
women who are trying to preserve fertility, the
risks and benefits of pelvic radiation must be addressed. For
these young, female patients, the argument to avoid radiotherapy
could be made.
Selective Use of Therapies for Rectal Cancer
Tailoring therapy can also be achieved by modifying the
pelvic radiotherapy field. With better imaging techniques,
it may not be necessary to treat the whole pelvis for all
patients. There may be patients whose tumors have a lower
risk of lateral pelvic sidewall involvement and, therefore,
can be spared treating internal iliac nodes. Also, after the
use of induction chemotherapy—an area of growing interest—it
may be possible to direct radiation at the postchemotherapy
volume, potentially making the treatment
fields smaller. The use of intensity-modulated radiotherapy
(IMRT) can minimize dose to radiosensitive structures in
the pelvis and potentially minimize toxicity but requires
more in-depth knowledge of pelvic anatomy and nodal drainage
patterns. IMRT may also allow dose escalation to higher
risk areas and to achieve better pCR rates in patients not
receiving surgery.
The option of nonoperative therapy is also emerging as
an option for patients who have clinical complete responses
to neoadjuvant therapy. This approach was initially reported
by investigators from Brazil. They reported on 361
patients with rectal cancer, 99 (27%) of whom demonstrate
a clinical complete response. These patients were observed
without radical resection. The local recurrence rate was
remarkably low (5%), and all five of these patients have been