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WEISER, ZHANG, AND SCHRAG
Locally Advanced Rectal Cancer: Time for Precision
Therapeutics
Martin R. Weiser, MD, Zhen Zhang, MD, PhD, and Deborah Schrag, MD, MPH
OVERVIEW
The year 2015 marks the 30th anniversary of the publication of NSABP-R01, a landmark trial demonstrating the benefit of adding pelvic
radiation to the treatment regimen for locally advanced rectal cancer with a resultant decrease in local recurrence from 25% to 16%.
These results ushered in the era of multimodal therapy for rectal cancer, heralding modern treatment and changing the standard of
care in the United States. We have seen many advances over the past 3 decades, including optimization of the administration and timing
of radiation, widespread adoption of total mesorectal excision (TME), and the implementation of more effective systemic chemotherapy.
The current standard is neoadjuvant chemoradiation with 5-fluorouracil (5-FU) and a radiosensitizer, TME, and adjuvant chemotherapy
including 5-FU and oxaliplatin. The results of this regimen have been impressive, with a reported local recurrence rate of less than 10%.
However, the rates of distant relapse remain 30% to 40%, indicating room for improvement. In addition, trimodality therapy is arduous
and many patients are unable to complete the full course of treatment. In this article we discuss the current standard of care and
alternative strategies that have evolved in an attempt to individualize therapy according to risk of recurrence.
The current standard of care for patients with stage II (T3/
T4N0) and stage III rectal cancer (TanyN1/N2) is trimodality
therapy including chemotherapy, radiation, and
surgery with complete TME. 1 The primary rationale for systemic
chemotherapy is to reduce the risk of distant recurrence,
whereas the rationale for pelvic radiation is to prevent
local recurrence and, in some cases, convert a patient from
requiring abdominoperineal resection—which requires a
permanent ostomy—to a sphincter-sparing low anterior resection.
The trimodality approach has gained widespread
acceptance, with numerous publications reporting a substantial
reduction in local recurrence rates and prolongation of
disease-free survival. 2-6 Since its inception, progress within
each of the three therapeutic modalities has continued.
The decision to use short-course radiotherapy (25 Gy in 5
fractions) versus long-course therapy (50.4 Gy delivered in
28 fractions with concurrent fluoropyrimidine) has largely
depended on geography. Short-course regimens are generally
favored in Northern Europe and Scandinavia, whereas
long-course chemoradiation is advocated in North America
and Central Europe. A Polish randomized trial compared
long-course and short-course radiochemotherapy in patients
with T3/4 mid- to low-lying rectal tumors, investigating the
effıcacy of each regimen. Higher rates of complete pathologic
response were observed in patients treated with long-course
chemoradiotherapy (16% vs. 1%). Although the rate of positive
circumferential resection margin (CRM) was signifıcantly
higher in patients receiving short-course therapy (13%
vs. 4%; p 0.017), no differences in local recurrence, diseasefree
survival, or overall survival were observed.
The German CAO/ARO/AIO 94 trial, published 11 years
ago, compared preoperative and postoperative long-course
chemoradiotherapy for stage II and III rectal cancer. 7 The
preoperative treatment group demonstrated a signifıcant
(p 0.006) decrease in local recurrence rate after 5 years,
without a difference in rates of distant metastasis or overall
survival. Additional benefıts of preoperative versus postoperative
chemoradiation included a signifıcant decrease in
short-term and long-term toxicity; for example, the incidence
of grade 3 or higher toxicity was reduced from 40% in
the postoperative group to 27% in the preoperative group
(p 0.001). Over the past decade, preoperative chemoradiation
has become the standard of care in the United States.
Although this shift has certainly reduced treatment toxicity
for many patients, many clinicians have questioned whether
it has also resulted in excessive radiation exposure for individuals
with easily resectable tumors (e.g., T3N0) who might
not have required any pelvic radiation at all had they fırst
undergone surgery.
TME involves removal of the rectum together with its cylindrical
mesentery and associated nodal tissue. The development
and dissemination of this technique represented an
incremental advance in oncologic surgery. TME involves
sharp dissection between the visceral and parietal layers of
From the Memorial Sloan Kettering Cancer Center, New York, NY; Shanghai Cancer Center, Fudan University, Shanghai, China; Dana-Farber Cancer Institute, Boston, MA.
Disclosures of potential conflicts of interest are found at the end of this article.
Corresponding author: Martin R. Weiser, MD, Memorial Sloan Kettering Cancer Center, 1275 York Ave., New York, NY 10065; email: weiser1@mskcc.org.
© 2015 by American Society of Clinical Oncology.
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