2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

Radiation in Rectal Cancer: What Are the
Options and If/When Can It Be Avoided?
Overview: Treatment of rectal cancer has improved greatly
over recent decades. This review looks at the pivotal trials in
the development of the current standard of therapy as well
as new directions for more individualized therapy for rectal
cancer. Rates of local recurrence and overall survival (OS) for
surgery alone have improved with the use of (neo)adjuvant
5-fluorouracil (5-FU)-based chemoradiation. New surgical
techniques have improved outcomes, but preoperative radiotherapy
still confers an additional benefit. Despite benefits in
the metastatic setting, the addition of oxaliplatin to 5-FU and
RECTAL CANCER treatment has made great strides
over the last 50 years from the time of surgery alone,
employing a blunt dissection technique that was associated
with local recurrence rates of 30% to 60% for locally advanced
disease. Adjuvant 5-FU-based chemoradiation reduced
local failure rates to 10% to 12% and improved OS
by 10% to 15%. 1-3 These results led to the National Cancer
Institute consensus statement in 1990 recommending adjuvant
chemoradiation for all patients with T3 to T4 or
node-positive rectal cancer. 4 This was the first attempt to
risk stratify patients with rectal cancer.
Subsequently, the introduction of the total mesorectal
excision (TME) and vastly improved surgical techniques
have reduced the risk of positive margins and node disease
left behind. As a result, local recurrence rates have dropped
to 10% to 15% with surgery alone. Despite better surgical
technique, the Dutch TME study (CKVO 95–04) still showed
a benefit in local control for preoperative radiotherapy
compared with surgery alone. 5 These investigators randomly
selected 1,805 eligible patients to receive either
surgery alone or short-course radiation therapy (5 � 5 Gy)
followed by surgery and concluded that the addition of
radiation significantly decreases the rate of local recurrence
at 2 years even with high-quality surgery (p � 0.001). In
addition, the MRC07 trial randomly selected 1,350 patients
with rectal cancer to receive either neoadjuvant short-course
radiation therapy (5 � 5 Gy) or selective postoperative
concurrent chemoradiotherapy for patients with a positive
circumferential resection margin. Preoperative radiotherapy
was associated with improved 3-year local control compared
with selecting patients to receive adjuvant long-course
radiation therapy. 6 Thus, the use of radiotherapy even in
the setting of a high-quality TME appears to improve local
control rates.
To determine the optimal sequence for surgery and chemoradiotherapy,
several randomized trials compared preoperative
with postoperative 5-FU-based chemoradiotherapy.
The German Rectal Study demonstrated an improvement in
local relapse rates and reduced acute and overall toxicity
using preoperative chemoradiation compared with postoperative
chemoradiation. 7 This phase III randomized trial has
established the “standard of care” for T3/4 or node-positive
rectal cancer as neoadjuvant infusional 5-FU with conventionally
fractionated radiotherapy to 5,040 cGy. With this
approach, investigators reported local recurrence rates of
6% and distant recurrence rates of 36%; therefore, bringing
By Karyn A. Goodman, MD
radiotherapy has not shown improved outcomes, although it
increased toxicity. Preoperative therapy also allows for the
identification of predictive and prognostic markers for response
to treatment, which has great potential to individualize
treatment. Currently, the search for validated biomarkers and
the refinement of risk stratification are the focus of ongoing
study. Tailored therapy may include modification of the pelvic
radiotherapy field, nonoperative therapy, or avoidance of
radiotherapy.
rates of local recurrence well below rates of distant recurrence.
The subsequent publications of the EORTC 22921
and FFCD 9203 further confirmed the benefit of combining
5-FU-based chemotherapy with preoperative radiation by
improving the rates of pathologic complete response (pCR)
and local control with acceptable increase in toxicity. 8,9
Intensifying Neoadjuvant Therapy: Is More Better?
The next step in the evolution of therapy for rectal cancer
has been the attempt to improve our current standard of
care with more intensive therapy. Given the multitude of
new chemotherapy combinations and molecularly targeted
systemic therapies being investigated in metastatic colorectal
cancer, it was natural to consider incorporating these
regimens into the adjuvant/neoadjuvant setting. 10
The endpoints for evaluating the benefit of combination
chemotherapy agents for neoadjuvant therapy have been
tailored to allow for earlier assessment of efficacy such as
pCR. For example, pCR following preoperative chemoradiation
is predictive of OS and should therefore be an appropriate
surrogate for evaluating the effect of neoadjuvant
chemoradiation regimens for rectal cancer. 11-16 Other clinically
relevant endpoints may include sphincter preservation
and toxicity.
The wide array of new cytotoxic and targeted agents has
propagated numerous small phase II studies evaluating
pCR rates. Based on promising results of these phase II
studies, there have now been four recently reported phase
III randomized trials that have added oxaliplatin to 5-FUbased
preoperative chemoradiation with the intent of improving
pCR and disease-free survival. Both the ACCORD
trial and the STAR trial found no difference in pCR rate with
the addition of oxaliplatin to standard 5-FU infusional
chemotherapy and 50.4 Gy. 17,18 The toxicity was significantly
greater (ACCORD: 25% v. 11%, p � .001; STAR:
24% v. 8%, p � 0.001) in the oxaliplatin arm as well. The
preliminary reports of the NSABP R-04 and the German
From the Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center,
New York, NY.
Author’s disclosure of potential conflicts of interest are found at the end of this article.
Address reprint requests to Karyn A. Goodman, MD, Department of Radiation Oncology,
Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY, 10065; email:
goodmank@mskcc.org.
© 2012 by American Society of Clinical Oncology.
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