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Neoadjuvant Combined-Modality Therapy for Locally Advanced
Rectal Cancer and Its Future Direction
Review Article [1] | June 15, 2016 | Oncology Journal [2], Colorectal Cancer [3], Gastrointestinal
Cancer [4]
By Mohamed E. Salem, MD [5], Marion Hartley, PhD [6], Keith Unger, MD [7], and John L. Marshall,
MD [8]
Here we discuss the evolution of standard therapy for rectal cancer patients and the use of
preoperative CRT for the treatment of locally advanced disease. Treatment schemes that have
attempted to broaden the horizons of standard therapy include the use of induction chemotherapy
and “watch-and-wait” approaches.
Introduction
Colorectal cancer is the second leading cause of cancer-related death in the United States and the
fourth leading cause worldwide.[1] Globally, it is estimated that approximately 1.57 million patients
are diagnosed with, and more than 771,000 are expected to die from, colorectal cancer each year.
Thirty percent of these cancers have been reported to arise in the rectum.[1,2]
Given the challenging nature of rectal cancer, ideally treatment should occur in a multidisciplinary
setting and involve collaborative input from surgical, radiation, and medical oncologists. The choice
of therapeutic approach for rectal cancer is based on several factors; whether trimodality therapy
(surgery, radiotherapy [RT], and chemotherapy) is used depends greatly on tumor stage and the
location of the tumor in the rectum. For patients with locally advanced rectal cancer, preoperative
chemoradiotherapy (CRT) has been established as the standard of care. Thus, accurate preoperative
staging of rectal cancer is, perhaps, the most critical step in the management of this disease.
Staging of rectal cancer is generally carried out using either endoscopic ultrasound (EUS) or
magnetic resonance imaging (MRI). EUS has high sensitivity and specificity in the staging of early (T1
and T2) rectal tumors. However, MRI (thin-section, high-resolution, phased-array coil MRI of the
pelvis) is preferred for T3 or T4 tumors, since it provides excellent soft-tissue spatial and contrast
resolution, is better at predicting mesorectal nodal involvement, and more accurately assesses the
status of the circumferential resection margin.[3]
The Current Standard of Care for Locally Advanced Rectal Cancer
Currently, the only definitive indication for the use of preoperative CRT is the presence of a T3, T4, or
node-positive tumor. This treatment paradigm consists of around 6 weeks of neoadjuvant CRT
(infusional fluorouracil [5-FU] or oral capecitabine concurrent with RT), followed by 6 or more weeks
of recovery prior to surgery (usually with total mesorectal excision [TME]), which in turn is frequently
followed by adjuvant chemotherapy.[4,5]
Preoperative CRT is most often used if a patient has a distal rectal tumor for which an
abdominoperineal resection (APR) is believed to be necessary. The use of CRT prior to surgery could
convert an APR to a sphincter-preserving operation, such as a low anterior resection with coloanal
anastomosis, which has the potential to profoundly improve a patient’s quality of life.
Evolution of the current standard of care
Surgery. Surgical resection, particularly the use of TME, remains the cornerstone of standard
therapy for rectal cancer. TME involves complete removal of the primary tumor and the associated
perirectal lymph nodes, without disruption of the mesorectum.
Surgery plus RT. Advances in surgical resection techniques afford curative potential for rectal
cancer; however, local and distant tumor recurrence following surgical resection continues to be a
problem, and this necessitates further efforts to improve initial local control.[6-8] Additionally, a
permanent colostomy has a major negative impact on patient quality of life. Treatment options that
improve outcome while avoiding the use of colostomy, especially in patients with low-lying tumors,
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are highly desirable.
The combination of surgery with other anticancer therapeutic modalities has been explored in the
hope of improving outcomes. For example, RT was introduced and then quickly integrated into the
treatment paradigm for rectal cancer. This approach was evaluated in several randomized trials, first
in the postoperative and then in the preoperative setting,[9-17] resulting in reduced local recurrence
rates, but with little impact on disease-free survival (DFS) or overall survival (OS). The Swedish
Rectal Cancer Trial randomly assigned 1,168 patients with resectable rectal cancer either to surgery
alone or to short-course preoperative RT (25 Gy delivered in 5 fractions in 1 week) followed by
surgery.[18] The addition of short-course RT resulted in improved survival, although there was a
higher incidence of late gastrointestinal toxicities. The Swedish Rectal Cancer Trial was the only
study to demonstrate a significant improvement in survival following the use of short-course
preoperative RT, even though local recurrence rates were high in this study.[18,19] The Dutch
Colorectal Cancer Group study repeated the trial design used in the Swedish trial, except that TME
was the only surgical technique allowed, and only patients eligible for this procedure were
enrolled.[20,21] As with all other studies,[9-17] improvement in local control was observed but there
was no difference in OS.
Surgery plus CRT. It became evident that the combination of RT and surgery led to an
improvement in the rate of local control; however, no study findings to date have confirmed the
RT-induced improvement in patient survival seen in the Swedish Trial.[18,19] Thus, in continued
efforts to improve outcome, the next rational step was to attempt augmentation of RT with
chemotherapy. Several phase III trials were conducted to examine whether the addition of
5-FU–based chemotherapy to RT resulted in a better pathologic response and better outcome.
In 1993, the European Organisation for Research and Treatment of Cancer (EORTC) Radiotherapy
Group initiated the EORTC 22921 trial, which randomized more than 1,000 patients with T3/4
resectable rectal cancer, using a 2 × 2 factorial design, to one of the following four treatment
regimens (along with surgery): 1) preoperative RT (the control arm), 2) preoperative CRT, 3)
preoperative RT and postoperative chemotherapy, or 4) preoperative CRT and postoperative
chemotherapy. RT consisted of 45 Gy delivered to the posterior pelvis in 25 fractions of 1.8 Gy over a
period of 5 weeks. Preoperative and postoperative chemotherapy regimens involved 5-FU plus
leucovorin. Preoperative chemotherapy was delivered in two 5-day courses during the first and fifth
weeks of RT. 5-FU was given at a dose of 350 mg/m2 per day, and leucovorin at a dose of 20 mg/m2
per day. Surgery was scheduled to take place 3 to 10 weeks after treatment. In addition to effects on
local tumor control, the ability of the four treatment approaches to improve OS and progression-free
survival (PFS) was analyzed.[22]
CRT resulted in downsizing and downstaging of tumors and increased local control rates. Local
failure rates were significantly lower in all three groups that received chemotherapy, compared with
the control arm (preoperative RT alone), regardless of whether chemotherapy was given prior to or
following surgery.
Patients undergoing preoperative CRT had a significantly higher rate of pathologic complete
response (pCR; 14% vs 5%). However, the addition of chemotherapy, either concurrently with
preoperative RT (neoadjuvant chemotherapy), or postoperatively (adjuvant chemotherapy) was not
associated with any improvement in PFS or OS.
Updated long-term results of this study were published in Lancet Oncology in 2014.[23] The reported
cumulative incidence of local relapse at 10 years was 22.4% in patients who received RT alone,
compared with 11% to 15% in the three groups that received chemotherapy.[23] Ten-year DFS was
similar in patients who received preoperative CRT vs RT alone (46% vs 44%), as was OS (51% vs
49%). Moreover, adjuvant 5-FU–based chemotherapy after preoperative RT (with or without
chemotherapy) still did not affect DFS or OS.
Other studies, such as the Fédération Francophone de Cancérologie Digestive (FFCD) trial 9203,[24]
yielded similar results and showed that the addition of 5-FU to RT significantly increased the pCR and
local disease control rate. In a meta-analysis that included EORTC 22921,[23] FFCD 9203,[24] and
four other trials,[25-28] the addition of chemotherapy to preoperative RT for the treatment of locally
advanced (T3/4 or node-positive) rectal cancer was associated with less local recurrence (odds ratio
[OR] for local recurrence, 0.56 [95% CI, 0.42–0.75]).[29]
Thus, the addition of chemotherapy to conventional fractionation RT became a standard approach in
the treatment of locally advanced rectal cancer, likely because of the reduction in local recurrence
and improvement in pCR rates observed with CRT.
Neoadjuvant vs adjuvant CRT
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Adjuvant CRT following resection was considered the standard treatment for stage II/III operable
rectal cancer, primarily on the basis of evidence from colon cancer trials. However, with growing
evidence for the benefits of CRT in the neoadjuvant setting in terms of pCR and local disease control
(in comparison with RT alone), questions were raised regarding: 1) the best sequence of CRT to use
in relation to surgery; 2) the optimal chemotherapy regimen to use; 3) whether the delivery of more
efficient systemic therapy earlier in the course of treatment results in better outcomes, perhaps with
the potential to eradicate subclinical metastatic disease; and 4) whether the lack of compliance
observed for postoperative chemotherapy can be improved.
Several studies investigated pre- and postoperative CRT in patients with locally advanced rectal
cancer, with the aim of determining the best sequence of CRT administration with surgery.[30-33]
Despite researchers’ best earlier efforts, the optimal sequence did not become clear until results
from the German Rectal Cancer Study Group trial became available in 2004.[30] This seminal trial
firmly established the role of neoadjuvant CRT by directly comparing preoperative with postoperative
CRT for locally advanced rectal cancer.[30]
The German Rectal Cancer Study Group trial was initiated in February 1995, and enrollment was
extended through September 2002. The study enrolled 823 patients with clinical stage T3 or T4 or
node-positive disease. Patients were then randomly assigned to receive either preoperative (n =
421) or postoperative (n = 402) CRT. The preoperative treatment consisted of 5,040 cGy delivered in
fractions of 180 cGy per day, 5 days per week, concurrently with infusional 5-FU (1,000 mg/m2 daily
for 5 days during the first and fifth weeks of RT). All patients underwent TME 6 weeks after the
completion of CRT. One month after this surgery, 4 additional cycles of adjuvant 5-FU (500 mg/m2
bolus daily for 5 days, every 4 weeks) were administered. CRT was identical in the postoperative
treatment group, except for the delivery of a boost of 540 cGy in the latter group. The primary
endpoint was OS.
Results from a 46-month median follow-up analysis showed that preoperative CRT was associated
with a significantly lower cumulative incidence of local relapse than postoperative CRT (6% vs 13%;
P = .006). After 11 years of follow-up, the difference was smaller but persisted (7% vs 10% for prevs postsurgical CRT, respectively).[31] The 5-year DFS rates were 68% and 65%, respectively, and
the 5-year OS rates were 76% and 74%, respectively (P = .80). Ten-year survival rates were also
similar for pre- and postsurgical CRT (DFS was approximately 68% and OS was approximately 60%
[taking the average of both pre- and postsurgical groups]). The rate of long-term toxic effects in the
preoperative vs postoperative patients was 14% vs 24%, respectively (P = .01).
Following preoperative CRT, there was a significant shift toward earlier TNM staging, suggestive of
significant preoperative CRT downstaging effects (P < .001). Furthermore, 8% of the patients in the
preoperative CRT group had a complete response, and only 25% had positive lymph nodes
(compared with 40% in the postoperative group).
In patients with tumors that had been predicted preoperatively by a surgeon to require an APR, the
rate of sphincter-preserving surgery was more than twice as high after preoperative CRT compared
with postoperative CRT (39% vs 19%, respectively; P = .004).
Importantly, 18% of patients in the postoperative treatment group (no CRT prior to surgery) who
were determined preoperatively to have T3 or T4 disease or lymph node metastasis were found to
actually have T1 or T2 or node-negative tumors on pathologic examination of the resected specimen.
This important observation clearly highlights the limitations of preoperative staging at the time the
study was performed, and perhaps the potential for overtreatment of some patients. The finding
underscores the need for accurate staging so as to avoid unnecessary treatment of patients with
early-stage tumors.
It is noteworthy that the German study clearly highlighted the postoperative compliance issue: 92%
of patients in the preoperative arm received a full dose of RT, compared with only 54% in the
postoperative arm (P < .001), and 89% compared with 50% received a full dose of chemotherapy (P
< .001). Thus, the administration of CRT prior to major surgery (as opposed to postoperatively) may
enhance the rate of curative surgery and permit sphincter preservation in patients with low-lying
tumors—due to increased compliance, if for no other reason.[30,31]
By 2004, following dissemination of the German study results,[30,31] preoperative CRT was
established as the new standard of care (Figure 1), and the use of postoperative CRT rapidly
declined.
In addition to the German study, two other prospective randomized trials aimed to compare the
efficacy of preoperative CRT with postoperative CRT for rectal cancer; these studies were initiated in
the United States by the Radiation Therapy Oncology Group (RTOG; trial 94-01) and the National
Surgical Adjuvant Breast and Bowel Project (NSABP; protocol R-03). Unfortunately, both studies were
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closed prematurely due to poor accrual.
TO PUT THAT INTO CONTEXT
Bruce D. Minsky, MD
University of Texas MD Anderson Cancer Center, Houston, Texas
In What Direction Is Neoadjuvant Therapy for Rectal Cancer Headed?
Dr. Salem and colleagues provide an excellent overview of the evolution of neoadjuvant therapy for
rectal cancer, from its genesis in the 1980s up through the present. The rationale, successes and
failures, and new controversies are nicely discussed. As the authors mention in the last paragraph,
neoadjuvant therapy is truly moving from one-size-fits-all to the more contemporary approach of
individualized therapy.
What Innovations Are Being Tried in Radiotherapy for Rectal Cancer—and What Are the
Implications for the Other Components of Multimodality Therapy?
Controversies still exist, and the authors have discussed many of the major ones. One that warrants
additional focus is the movement towards short-course radiotherapy (RT). Given the results of the
Polish I[1] and Polish II[2] trials, as well as the Trans-Tasman Radiation Oncology Group trial,[3]
which showed equivalence of short-course RT to long-course chemoradiotherapy (CRT) in selected
patients with rectal cancer, there is increasing interest in sequential chemotherapy, either before
and/or after short-course RT. This approach serves as the experimental arm of the Dutch RAPIDO
phase III trial. Patients are randomized between short-course 5 × 5 Gy RT followed by 6 cycles of
CAPOX (capecitabine and oxaliplatin) chemotherapy and surgery vs long-course CRT followed by
surgery and 8 cycles of postoperative CAPOX. The primary endpoint is 3-year disease-free survival.
Data are pending.
While randomized trials comparing short-course RT with CRT are encouraging, longer follow-up is
needed. The addition of sequential chemotherapy following short-course RT is feasible and is being
tested prospectively. The impact on outcome, acute and chronic toxicity, and sphincter preservation
needs to be determined.
REFERENCES
1. Bujko K, Nowacki MP, Nasierowska-Guttmejer A, et al. Long term results of a randomized trial
comparing preoperative short-course radiotherapy with preoperative conventionally fractionated
chemoradiation for rectal cancer. Br J Surg. 2006;93:1215-23.
2. Bujko K. Neoadjuvant chemoradiation for fixed cT3 or cT4 rectal cancer: results of a Polish II
multicenter phase III study. J Clin Oncol. 2016;34(suppl 4S):abstr 489.
3. Ngan SY, Burmeister B, Fisher RJ, et al. Randomized trial of short course radiotherapy versus long
course chemoradiation comparing rates of local recurrence in patients with T3 rectal cancer:
Trans-Tasman Radiation Oncology Group (TROG 01.04). J Clin Oncol. 2012;30:3827-33.
Although preoperative CRT is widely accepted as the standard of care, an alternative approach using
short-course neoadjuvant RT has been adopted as another standard approach for the treatment of
patients with operable rectal cancer, particularly in Europe. This practice is largely based on the
previously mentioned Swedish and Dutch studies,[18-21] which demonstrated that short-course
neoadjuvant RT is associated with long-term outcomes that are comparable to those achieved using
long-course CRT.
A Polish study compared short-course preoperative RT (25 Gy in 5 fractions of 5 Gy and surgery
within 7 days) vs long-course RT (50.4 Gy) plus chemotherapy (5-FU) followed by surgery 4 to 6
weeks later.[26] There were no differences in sphincter preservation rates (primary endpoint), local
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recurrences, OS, or late toxicity between the two arms. However, long-course RT plus chemotherapy
did result in higher pCR and negative circumferential margin rates. A similarly designed Australian
study that compared short-course with long-course RT demonstrated no statistically significant
difference in 3-year local control rates.[28] However, the authors concluded that long-course RT may
be more effective for distal tumors because of the higher recurrence rates seen with short-course
RT. The Polish and Australian studies have been criticized for their sample sizes, imbalances between
the arms, and overall trial designs.[29]
Although short-course neoadjuvant RT has been adopted by some, particularly in Europe, as a
standard approach for the treatment of patients with operable rectal cancer, the majority of US
oncologists follow the standard of care for rectal cancer established by the German trial, as
described previously and following.
Risk stratification of rectal cancer
The German trial not only established a new standard treatment paradigm for rectal cancer, it also
shed light on some very important aspects of rectal cancer management—specifically, the risk
stratification of rectal cancer patients undergoing neoadjuvant CRT, and the best way to predict DFS
after preoperative therapy.
In a subsequent exploratory analysis of the German rectal cancer study,[34] the pathologic T stage
and the nodal status after CRT were found to be the most important independent prognostic factors
for DFS. The 5-year DFS was 85% for ypN0, 65% for ypN1, and 18% for ypN2 (the “y” added to a
pathologic stage indicates a TNM stage that is determined following CRT). The poor outcomes seen
in patients with ypN2 disease in this report suggest that positive lymph nodes after neoadjuvant CRT
may indicate a more aggressive disease. It is thus reasonable to argue that such patients should
undergo prolonged postoperative chemotherapy.
In addition to the nodal status after CRT, prognosis following neoadjuvant CRT was also associated
with tumor regression grading (TRG). TRG incorporates the degree of fibrosis as well as the
percentage of viable tumor cells.[34] In an updated report of long-term results after a median
follow-up of 132 months, the 10-year DFS rates for patients with TRG 4 were 90%, for those with TRG
2 to 3 they were 74%, and for those with TRG 0 to 1 they were 63%.[35]
Whether the pathologic T stage, nodal status, and TRG can or should be used to modify
postoperative treatment strategies remains unclear, as do questions of whether to use adjuvant
chemotherapy in patients with a favorable or poor prognosis. Determination of the most effective
postoperative treatment strategy is an active area of research and has the potential to offer a unique
opportunity to improve the current treatment paradigm and provide guidance for selection of the
optimal therapy.
Further risk stratification has been proposed in order to more effectively individualize therapy for
stage II/III rectal cancer. In a pooled analysis of survival and relapse rates in five North American
phase III trials, patients were separated into four risk groups by TN stage: low-risk (T1/2N0),
intermediate-risk (T1/2N1, T3N0), moderately high-risk (T1/2N2, T3N1, T4N0), and high-risk (T3N2,
T4N1/2).[36] Appropriateness criteria were recently developed that incorporated this risk
stratification along with the distance from the distal tumor edge to the anal verge and the distance
from the radial tumor edge to the edge of the mesorectal fascia, based on MRI.[37] An expert panel
rated conventionally fractionated CRT as appropriate for neoadjuvant therapy for all stage II/III rectal
cancers. Neoadjuvant short-course RT was rated appropriate for intermediate-risk disease ≤ 10 cm
from the anal verge and ≥ 2 mm from the edge of the mesorectal fascia, and for moderate-risk
disease < 5 cm from the anal verge or ≥ 5 cm from the anal verge and ≥ 2 mm from mesorectal
fascia. The expert panel rated short-course RT as possibly being appropriate for other stage II/III
rectal cancers.
Following the development of orally active fluoropyrimidines (ie, capecitabine), the natural question
was whether capecitabine could replace infusional 5-FU in the CRT setting. Several studies in colon
cancer demonstrated noninferiority and perhaps superiority of capecitabine compared with 5-FU.
Whether such findings hold true for rectal cancer, and whether capecitabine can replace infusional
5-FU during RT in the neoadjuvant treatment of stage II and III rectal cancer were examined. Two
clinical trials studied the effect of using capecitabine in place of infusional 5-FU, combined with RT,
on pCR, sphincter-sparing surgery, and surgical downstaging.
The first such trial, carried out by German investigators,[38] was a neoadjuvant, open-label,
multicenter, noninferiority, randomized phase III study that began in March 2002. The study explored
the substitution of capecitabine for infusional 5-FU.[38] Specifically, the trial directly compared CRT
(50.4 Gy) using capecitabine (825 mg/m2 twice daily, on days 1 to 38) with CRT (50.4 Gy) using 5-FU
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(1,000 mg/m2 by continuous infusion on days 1 to 5 and 29 to 33). A total of 401 patients with locally
advanced rectal cancer were enrolled and randomly assigned to either the oral or IV fluoropyrimidine
group. Five-year OS in the capecitabine group was noninferior to that in the 5-FU group (76% vs
67%; P = .0004), and 3-year DFS was higher in the capecitabine group than in the 5-FU group (75%
[95% CI, 68%–81%] vs 67% [95% CI, 59%–73%]; P = .07; Table 3). Better 3-year DFS with
capecitabine than with 5-FU was noted in both the adjuvant (78% [95% CI, 69%–85%] vs 69% [95%
CI, 59%–77%]) and neoadjuvant cohorts (71% [95% CI, 60%–80%] vs 63% [95% CI, 51%–73%]). The
local recurrence rate was similar for capecitabine and IV 5-FU (6% vs 7%; P = .67), but fewer
patients developed distant metastases in the capecitabine group (19% vs 28% for capecitabine and
IV 5-FU, respectively; P = .04). Patients who received capecitabine had significantly more hand-foot
syndrome, fatigue, and proctitis, but less neutropenia.
The second phase III trial, which was conducted by the NSABP,[39] employed a 2 × 2 factorial
noninferiority design to compare four regimens administered concomitantly with RT (45 Gy in 25
fractions over 5 weeks, followed by a boost). The aim of this study was to determine the optimal
neoadjuvant chemotherapy regimen for stage II/III rectal cancer, including the best sequence of
administration of preoperative CRT. The trial evaluated the substitution of capecitabine for IV 5-FU,
as well as the intensification of chemotherapy via the addition of oxaliplatin.
Between September 2004 and August 2010, a total of 1,608 patients with clinical stage II or III rectal
cancer were enrolled in the trial and randomized to undergo preoperative CRT consisting of one of
the following four regimens: 1) RT plus 5-FU as a continuous infusion (225 mg/m2 daily, 5 days per
week) with oxaliplatin (50 mg/m2 weekly); 2) RT plus 5-FU without oxaliplatin; 3) RT plus
capecitabine (825 mg/m2 twice daily, 5 days per week) with oxaliplatin (50 mg/m2 weekly); or 4) RT
plus capecitabine without oxaliplatin. There were no significant differences between the capecitabine
and infusional 5-FU regimens (regardless of oxaliplatin treatment) for the rates of pCR (21% vs 18%
for the capecitabine and infusional 5-FU regimens, respectively), sphincter-sparing surgery, or
surgical downstaging. Patients who received capecitabine had rates of locoregional control (the
primary endpoint) comparable to those in patients who received IV 5-FU (regardless of oxaliplatin
treatment), with a 3-year incidence of any locoregional events of 12% vs 11%, respectively. OS rates
were also comparable (81% vs 80%). Thus, data support the equivalence of daily oral capecitabine
and IV 5-FU during RT for neoadjuvant therapy; however, different toxicity profiles are evident
(patients who received capecitabine had significantly more hand-foot syndrome, fatigue, and
proctitis, but less neutropenia).
Chemotherapy intensification
Although preoperative CRT combined-modality treatment has been established as the standard of
care for patients with locally advanced rectal cancer, it remains unknown whether the intensification
of chemotherapy will enhance rectal cancer outcomes. This concept is still under investigation, as is
the optimal chemotherapy regimen to be administered concurrently with preoperative RT and
postoperatively.
Preclinical study results show that oxaliplatin is a potent radiosensitizing agent.[40] Additionally, it
has been shown that the addition of oxaliplatin to a 5-FU regimen in both the adjuvant and palliative
treatment of colon cancer improves DFS and OS.[41] Thus, the addition of oxaliplatin to a standard
CRT regimen using 5-FU for the preoperative treatment of patients with rectal cancer appears to be
a logical step in the pursuit of improved local disease control and patient survival. In fact, several
studies have examined the effect of adding oxaliplatin to neoadjuvant 5-FU–based CRT, as well as to
postoperative chemotherapy, in patients with locally advanced rectal cancer (Table 1)[42-47]; most
of these demonstrated greater toxicity from an oxaliplatin-containing regimen, but efficacy data
have been conflicting. Overall, a role for neoadjuvant oxaliplatin in the treatment of locally advanced
rectal cancer remains highly controversial (see Table 1).
In the recently published German CAO/ARO/AIO-04 trial, investigators evaluated two separate
combinations of preoperative CRT, surgery, and adjuvant chemotherapy.[47] This multicenter,
open-label, randomized phase III study included 1,265 patients who had cT3/4 or cN1/2 rectal tumors
that were within 12 cm of the anal verge. Patients were randomly assigned to receive preoperative
CRT (50.4 Gy with infusional 5-FU [1,000 mg/m2 per day on days 1 to 5 and 29 to 33]), followed by
surgery, then adjuvant chemotherapy (IV bolus 5-FU of 500 mg/m2 daily for 5 days, every 29 days for
4 courses) or preoperative CRT with infusional 5-FU plus oxaliplatin, followed by surgery and 4
months of adjuvant therapy with modified FOLFOX6 (leucovorin [400 mg/m2 IV over 2 hrs on day 1]
before 5-FU [400 mg/m2 IV bolus on day 1, followed by 2,400 mg/m2 IV infusion over 46 hrs] plus
oxaliplatin [85 mg/m2 IV on day 1] on a 2-week schedule). The primary endpoint was DFS.
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DFS at 3 years in the oxaliplatin-treated patients was 75.9%, compared with 71.2% in the
non–oxaliplatin-treated group (hazard ratio [HR], 0.79 [95% CI, 0.64–0.98]; P = .03). There was no
difference in the rate of complete (R0) resection, but the addition of preoperative oxaliplatin did
appear to increase pCR rates (17% with oxaliplatin vs 13% without oxaliplatin; OR, 1.40 [95% CI,
1.02–1.92]; P = .038).
In corroboration of other trials, preoperative grade 3/4 adverse events occurred in a greater number
of patients who received oxaliplatin with their preoperative 5-FU–based CRT (24% with oxaliplatin vs
20% without oxaliplatin). However, of the patients who received adjuvant FOLFOX6, 36% had grade
3/4 toxicity, which was identical to the rate in those whose adjuvant regimen did not include
oxaliplatin.
The authors concluded that adding oxaliplatin to 5-FU–based neoadjuvant CRT and adjuvant
chemotherapy significantly improved DFS in patients with cT3/4 or cN1/2 rectal cancer, compared
with oxaliplatin-free regimens. They also concluded that the oxaliplatin-containing regimen could be
deemed a new treatment option for patients with locally advanced rectal cancer. However, in an
editorial that accompanied the publication of the study (entitled “Is the Benefit of Oxaliplatin in
Rectal Cancer Clinically Relevant?”), Bengt Glimelius argued that adding oxaliplatin to both pre- and
postoperative treatment of locally advanced rectal cancer could result in pronounced overtreatment,
thereby risking the development of long-lasting neuropathy in many patients. Glimelius also
questioned whether the observed improvement in 3-year DFS was meaningful. Certainly in patients
with colon cancer, 3-year DFS was shown to be a good surrogate for OS; however, whether the same
will prove to be the case for patients with rectal cancer remains to be seen.
Overall, the role of neoadjuvant oxaliplatin in the treatment of locally advanced rectal cancer
remains controversial.
Future Directions
Neoadjuvant chemotherapy alone
As outlined previously, the present treatment model uses neoadjuvant CRT followed by surgery,
frequently followed by adjuvant chemotherapy, for all patients with stage II or III rectal cancer.
Although preoperative CRT results in less toxicity than postoperative treatment,[30] there is no
doubt that CRT is associated with significant side effects. Since current surgical techniques achieve
very good results and yield excellent local control rates—and given that the majority of disease
recurrence seen in patients consists of distant metastatic disease—why is trimodality therapy
necessary for all patients if the purpose of RT is only to decrease local recurrence rates? This
question has led to significant debate as to whether all patients with stage II or III rectal cancer
require such an intensive treatment approach, especially if they are confirmed TME candidates (a
procedure associated with low rates of local recurrence). Some experts have argued that RT could be
eliminated in certain patient populations, particularly those diagnosed as T3N0/T3N1 or those who
do not require an APR.
Several studies[48-51] have explored the possibility of omitting RT from rectal cancer therapy.
Although data from some of these trials support the use of neoadjuvant chemotherapy alone
followed by tumor resection, the ability to reach any definitive conclusions has been hindered by the
small number of patients in these trials (Table 2).
The potentially practice-changing PROSPECT trial (ClinicalTrials.gov identifier: NCT01515787) is
currently ongoing and aims to yield a new treatment strategy that will enable us to better select
patients and deliver more precise therapy (Figure 2). This prospective, randomized, phase II/III trial
was conceived to challenge the existing treatment paradigm for patients with proximal rectal cancer
not requiring an APR. The goal of the trial is to avoid overtreatment by administering the most
appropriate therapy to all patients, and by tailoring treatment based on tolerance and response to
induction chemotherapy. Patients with stage II/III (T3N0, T3N1, or T2N1) rectal cancer are initially
randomly assigned either to preoperative FOLFOX or to standard preoperative CRT. In the
preoperative FOLFOX arm, initial chemotherapy is followed by comprehensive restaging using MRI.
Only those patients experiencing a less than 20% reduction in their rectal tumor size following initial
FOLFOX will receive preoperative CRT. Following their respective preoperative treatment(s), all
patients undergo TME followed by postoperative chemotherapy (see Figure 2). The primary endpoint
of the study is DFS.
Two other phase II trials (ClinicalTrials.gov identifiers: NCT01211210 and NCT01650428 [BACCHUS
trial]) challenge the standard of care by investigating the use of neoadjuvant chemotherapy alone.
Primary endpoints are 3-year DFS and pCR rate, respectively.
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Once complete, all these trials will play a key role in defining the ideal rectal cancer treatment
regimen and sequence. However, until study endpoints are reached and results are available,
neoadjuvant chemotherapy alone remains only an investigational approach.
Induction chemotherapy followed by chemoradiation
For patients with stage II/III rectal cancer, the current standard treatment sequence is as follows: 5 to
6 weeks of CRT, followed by 4 to 6 weeks of recovery time, followed by surgery (TME), followed by 4
to 6 weeks of postoperative recovery time, followed by initiation of adjuvant chemotherapy (see
Figure 1). This timeline means that full systemic chemotherapy is not delivered until about 4 months
after neoadjuvant CRT is initiated, and such a delay could theoretically allow for the development
and dissemination of metastatic disease.
Thus, one could hypothesize that administering chemotherapy at an earlier point might treat
micrometastases, thereby reducing the incidence of distant recurrence. This is the rationale for
moving full systemic chemotherapy treatment forward to an earlier point in the rectal cancer
treatment algorithm. Such a rationale makes the strategy of induction chemotherapy followed by
CRT—sometimes called the “total neoadjuvant approach”—appear very attractive. Several trials with
various designs and sample sizes have been conducted to examine the strategy of induction
chemotherapy followed by CRT; Table 3 provides a summary of these. Four of the studies were
single-arm trials: the CONTRE study[52]; the EXPERT trial[53]; the Danish study, by Schou et al[54];
and the Swiss study, by Koeberle et al.[55] All four trials treated patients with rectal cancer (T2–4)
with induction chemotherapy (consisting of CAPOX [capecitabine plus oxaliplatin][53-55] or
FOLFOX[52]), followed by neoadjuvant CRT (consisting of concomitant RT and capecitabine[52-54] or
CAPOX[55]), followed by surgery. The EXPERT trial[53] in addition treated patients with
postoperative adjuvant capecitabine. The pCR rates ranged from 20%[53-55] to 33%.[52] Also, the
Danish study[54] reported a 5-year DFS and OS of 63% and 67%, respectively, while the EXPERT
trial[53] reported a 3-year PFS, OS, and relapse-free survival (for patients who had complete
resection) of 68%, 83%, and 74%, respectively. The Swiss Group,[55] who used oxaliplatin both in
their induction therapy and their neoadjuvant CRT regimens, reported R0 resection and sphincter
preservation rates of 98% and 84%, respectively.
The Spanish GCR-3 randomized study[56] aimed to compare the current conventional treatment
paradigm (preoperative CRT, followed by surgery, followed by postoperative adjuvant therapy) with
a similarly planned regimen of induction chemotherapy followed by CRT, then surgery. Of 108 rectal
cancer patients (T3/4 and/or node-positive disease), 52 received preoperative CRT followed by
surgery and then 4 cycles of postoperative adjuvant CAPOX (standard arm), while 56 received 4
cycles of CAPOX followed by CRT and then surgery (experimental arm). There were no significant
differences between the two arms in pCR and DFS rates, 5-year cumulative incidence of local
relapse, incidence of distant metastases, or OS. Thus, the implementation of induction
chemotherapy prior to CRT did not improve outcomes in this study.[56]
Maréchal et al[57] also compared standard therapy (preoperative 5-FU–based CRT followed by
surgery) with induction FOLFOX, followed by CRT, followed by surgery. The primary endpoint was the
rate of achievement of local tumor excision (stage ypT0/1N0). On interim analysis, the ypT0/1N0
rates were 34.5% and 32.1%, respectively, and the study was deemed futile and prematurely closed.
Despite the studies conducted, induction chemotherapy followed by neoadjuvant treatment remains
investigational and the benefits are still unclear. This is largely due to the use of single-arm studies
and small sample sizes. The only randomized studies comparing induction chemotherapy strategies
with CRT alone show no difference in long-term outcomes.
There is clearly a need for well-designed randomized controlled studies in rectal cancer. Currently
there is an ongoing randomized phase III trial (the French PRODIGE 23 trial) that is randomly
assigning 460 patients with locally advanced rectal cancer to either receive induction chemotherapy
with FOLFIRINOX (5-FU, leucovorin, irinotecan, and oxaliplatin), followed by preoperative CRT (arm
1), or to receive preoperative CRT alone (arm 2). All patients will then undergo TME. The results from
this trial should help us better understand the role of induction therapy in rectal cancer and help
shape the treatment paradigm accordingly. The use of induction chemotherapy prior to neoadjuvant
CRT in patients with rectal cancer should remain confined to the research setting until definitive data
on the use of induction strategies become available.
The ‘watch-and-wait’ approach
Another controversial and potentially paradigm-changing approach is that of “watch-and-wait.” This
approach takes as its premise that patients who achieve complete clinical response with CRT do not
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necessarily need to undergo surgical resection. Very recently, a group of oncologists in the United
Kingdom questioned the currently accepted standard approach of tumor resection for all patients
with localized rectal tumors.[58] The OnCoRe project, conducted by Renehan et al, attempted to
provide evidence for the safety of a completely new watch-and-wait approach. In this approach,
patients with rectal cancer and no evidence of metastases were treated with potentially preoperative
CRT, and those who had a clinical complete response were given the option of
“watching-and-waiting” and not going straight to surgery (those patients who did not have a clinical
complete response were offered surgical resection following their CRT). In an analysis involving 218
patients matched for T stage, age, and performance status (among other criteria), 109 patients
underwent the watch-and-wait approach post-CRT, while the other 109 patients underwent CRT
followed by surgery. No difference in 3-year no-regrowth DFS was observed between groups (88% in
the watch-and-wait group vs 78% in the group who underwent surgical resection; P = .02). However,
patients in the watch-and-wait arm had significantly better 3-year colostomy-free survival than those
who underwent surgical resection (74% vs 47%; P < .0001). These findings, which support the
renouncing of surgical resection as the automatic standard treatment, exemplify an approach to
decision making post-CRT that may potentially greatly benefit a large number of patients.
This approach is now being evaluated in a study led by Memorial Sloan Kettering Cancer Center
(ClinicalTrials.gov identifier: NCT02008656), which is examining whether patients with locally
advanced rectal cancer treated with neoadjuvant CRT followed by nonoperative management will
have an improved 3-year DFS compared with patients with similar tumors treated with the same
neoadjuvant therapy, but followed by TME and adjuvant chemotherapy.
Conclusion
Rectal cancer is a complex disease to treat, and its optimal management requires a multidisciplinary
approach, with involvement of surgical, medical, and radiation oncologists. Whereas in decades past
we assumed that rectal cancer was different from colon cancer only in that it had a different
anatomic location, we are beginning to increasingly recognize that it is also quite a different disease
biologically. We cannot simply extend the results of colon cancer trials to rectal cancer patients. We
also cannot treat all rectal cancer patients as if they were cut from the same cloth. We must develop
a personalized treatment plan for each individual patient based on stage, location, gene expression,
and the patient’s priorities—including his or her quality-of-life priorities. We anticipate that molecular
profiling will allow for more precise treatments and predictions of outcomes. Interestingly, we find
ourselves at a treatment turning point: we are beginning to look for ways to minimize treatment and
are asking ourselves whether all that chemotherapy and surgery is really necessary, and whether we
can shorten or even remove RT from the mix.
Financial Disclosure: The authors have no significant financial interest in or other relationship with
the manufacturer of any product or provider of any service mentioned in this article.
Oncology (Williston Park). 30(6):546–562.
Figure 1. The Current Standard of Care for Rectal
Cancer (Established ...
Table 2. Studies of Neoadjuvant Chemotherapy
Alone in Rectal Cancer
Table 1. Oxaliplatin as a Component of
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Neoadjuvant Therapy
Figure 2. The PROSPECT Trial Design
Table 3. Studies of Neoadjuvant (Induction)
Chemotherapy Followed by C...
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Source URL:
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vanced-rectal-cancer-and-its-future-direction
Links:
[1] http://www.cancernetwork.com/review-article
[2] http://www.cancernetwork.com/oncology-journal
[3] http://www.cancernetwork.com/colorectal-cancer
[4] http://www.cancernetwork.com/gastrointestinal-cancer
[5] http://www.cancernetwork.com/authors/mohamed-e-salem-md
[6] http://www.cancernetwork.com/authors/marion-hartley-phd
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[7] http://www.cancernetwork.com/authors/keith-unger-md
[8] http://www.cancernetwork.com/authors/john-l-marshall-md
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