NcXHF

PRECISION THERAPY FOR RECTAL CANCER
the endopelvic fascia. Anatomic resection ensures complete
removal of all locoregional lymph nodes, while maintaining
negative CRMs, minimizing blood loss, and preserving the
autonomic pelvic nerves. Although no prospective randomized
trial has compared TME with conventional proctectomy, numerous
retrospective and cohort studies demonstrate excellent
local recurrence-free survival in patients undergoing TME. 8-10
The Dutch trial, published in 2001, was the fırst study to
integrate TME into a control arm and underscored the importance
of quality surgical technique. This trial compared
the combination of preoperative radiation therapy and TME
to TME alone, demonstrating a signifıcant (p 0.001) decrease
in local recurrence in patients receiving preoperative
short-course radiation. Critics have argued that, although the
quality of surgery was controlled, up to one-quarter of patients
had inadequate mesorectal excision on pathologic
analysis, which led to a signifıcantly worse outcome (p
0.02). 11 Long-term follow-up demonstrated that certain patient
sub-groups—those with node involvement, negative
CRMS, and/or low-lying tumors (within 5–10 cm of the anal
verge)—obtained the greatest benefıt from preoperative radiation.
12,13 These fındings suggested that some sub-groups
treated with multimodality therapy may benefıt less from the
addition of chemoradiation. Furthermore, neoadjuvant radiation
did not improve overall survival.
Current data support the use of either single-agent 5-FU or
oral capecitabine with concurrent radiation therapy. A recent
large randomized study comparing infusional 5-FU to
oral capecitabine showed equivalent effıcacy. 14 This trial also
demonstrated that concurrent use of oxaliplatin with radiation
adds to toxicity but does not improve effıcacy; therefore,
this approach is not recommended. 14,15 Extrapolating from
data on colon cancer, postoperative oxaliplatin-containing
regimens such as FOLFOX are typically used in the setting of
rectal cancer. Adjuvant chemotherapy begins 4 to 6 weeks
after surgery and administration of 12 cycles is standard, although
discontinuing oxaliplatin upon early signs of neuropathy
is essential to prevent long-term impairment.
Although use of chemoradiation as initial management is
now standard practice, there has been growing interest in the
use of systemic oxaliplatin-containing chemotherapy fırst,
KEY POINTS
Combined modality therapy—including chemotherapy,
radiation, and surgery—is the standard for locally advanced
rectal cancer.
Pelvic radiation reduces local recurrence but does not
reduce distant relapse or improve overall survival.
A noteworthy portion of patients are unable to complete
the prescribed treatment for rectal cancer.
Total neoadjuvant therapy attempts to deliver all therapy
prior to surgery.
PROSPECT is an international randomized trial attempting
to individualize rectal cancer treatment.
followed by chemoradiation, for locally advanced disease.
Chau et al published data on an initial series of patients with
locally advanced, poor-risk rectal cancer who were treated
with CapeOx for 3 months, followed by capecitabine plus radiation
therapy. 16 The radiologic response rate was 88%, and
86% of patients achieved symptomatic response at a median
of 32 days. A recent single-center retrospective study on the
use of initial induction FOLFOX chemotherapy in patients
with locally advanced rectal cancer demonstrated high response
rates. Notably, this treatment strategy enabled the delivery
of virtually all planned systemic chemotherapy without
limiting the ability to deliver the planned chemoradiotherapy.
17 Patients were routinely re-evaluated by their surgeons
after approximately 8 weeks of chemotherapy to rule out local
progression, and no patient in this series was reported to have
local progression at the time of examination. All patients undergoing
TME surgery achieved an R0 resection.
This concept of “chemotherapy fırst” with 4 months of
FOLFOX or CapeOx, followed immediately by chemoradiotherapy
and then TME, is a logical extrapolation from current
practice. It is clear that there never will be an adequately
powered, randomized phase III trial of “chemo fırst” versus
the current routine of “chemo last”; however, there are several
reasons for delivering all planned therapy before resection
with the expectation that this would be advantageous.
Advantages include introduction of the best systemic therapy
as early as possible, thus maximally addressing concerns over
distant micrometastatic disease and enabling the rapid initiation
of chemotherapy to obtain symptomatic relief. Patients
who are treated with chemotherapy as a fırst-line approach
have a high likelihood of receiving all planned chemotherapy,
which is less often the case when chemotherapy is
planned postoperatively. Furthermore, diverting ostomies
can be closed substantially earlier when no postoperative
chemotherapy is required. This approach is especially attractive
in the setting of bulky tumors and radiographic
evidence of tumor involvement of the radial circumferential
mesorectal margin, adjacent organs (prostate or vagina),
or numerous locoregional lymph nodes.
Although the oncologic results of combined modality therapy
for rectal cancer are impressive, trimodality treatment is
diffıcult to endure. This has led many clinicians to question
whether treatment can be simplifıed. Investigators have approached
this by trying to tailor therapy and selectively omit
one of the three major treatment modalities. For example,
one suggested approach is elimination of systemic chemotherapy
for patients who have favorable pathologic stage after
neoadjuvant treatment. Another approach pioneered by Brazilian
investigators is to selectively omit surgical resection for
individuals with clinical complete response to neoadjuvant
chemoradiation. Finally, in North America, there has been
interest in using pelvic radiation selectively for those patients
at greatest risk of pelvic recurrence.
The rationale for selective use of pelvic radiation stems
from its short- and long-term morbidities. Neoadjuvant
chemoradiation is taxing and time intensive, requiring daily
treatment for 5 weeks, and compliance is frequently poor. 18
asco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
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