Address for
Correspondence: Dr. Durga Prasan, MBBS, MD, DNB (Medical
Oncology), Consultant Medical Oncologist, Department of
Medical Oncology, Baby Memorial Hospital, Kozhikode, Kerala,
India, PIN 673017. Email: durgaprasan@gmail.com
Abstract
Rectal cancer is a common cause of public health burden
worldwide. In India, majority of rectal cancers continue to
present in locoregionally advanced stage, needing
multidisciplinary management in comprehensive cancer centres.
Treatment of locoregionally advanced rectal cancers has
shifted from surgery based management to neoadjuvant
chemoradiation followed by surgery and adjuvant therapy. Newer
approaches in management include integrating neoadjuvant
chemotherapy into the treatment algorithm in order to maximise
long term survival outcomes, and exploring non surgical and
organ conserving approaches in rectal cancer.
Keywords:
rectal cancer, neoadjuvant treatment
Introduction
Colorectal cancer is the third leading cause of cancer and
fourth leading cause of cancer deaths worldwide [1]. In India,
colon and rectal cancer incidence are 4.4 and 4.1 per 100000
population, making it among the leading cause of cancer
related public health burden [2]. Due to various sociocultural
factors, which include lack of awareness, lack of access to
specialist care, popularity of alternative systems of medicine
and lack of community based screening programs, close to 90%
of patients present in locally advanced stage [3].
Management of locally advanced rectal cancer is distinct from
treatment of colon cancer. Multidisciplinary care is essential
in ensuring optimal treatment outcomes for patients with
locally advanced rectal cancer. Treatments involve a
combination of surgery, radiation therapy and systemic therapy
in complex algorithms. Optimization of treatment protocols is
a work in progress.
Initial evaluation of rectal cancers involve locoregional and
distal metastatic staging. Colonoscopy allows for direct
visualization of the tumor, assessment of feasibility of
sphincter preservation, obtaining biopsy, assessment of
potential intestinal obstruction and ruling out synchronous
polyps and colonic cancers. Endoscopic ultrasound is an
accurate mode of evaluation of T and N stage, though high
resolution MRI has supplanted it due to better
characterization of nodal involvement, extramural vascular
involvement, tumor stage and circumferential resection margin
(CRM), information that is crucial in decision making process
in rectal cancer management [4]. Early rectal cancers
include cTis, T1 and T2, without nodal involvement. The
management is surgical, with choice of surgery based on
likelihood of sphincter preservation. Total Mesorectal
Excision (TME), which involves en bloc complete excision of
visceral mesorectal tissue to the levators usually with sharp
dissection, is considered to be the standard of care
[5]. In pioneering work, Dr. Heald and colleagues showed
that rates of locoregional failure can be reduced from 30% [5]
to approximately 8% at 10 years [6]. Clinical stage T3 and
above, and node positive tumors are treated with multimodality
treatment. Addition of radiation and chemotherapy to surgery
has resulted in improvement in disease free survival (DFS) and
overall survival (OS) compared to surgery alone.
Radiation and chemotherapy can either be done after surgery
(adjuvant) or before definitive surgery (neoadjuvant).
Although both the strategies have been equally successful in
terms of improving both DFS and OS, neoadjuvant treatment is
the preferred approach because of significantly lesser short
term and long term morbidity, as well as higher sphincter
preservation [7].
Neoadjuvant chemoradiation
Neoadjuvant chemoradiation involves delivering radiation and
concurrent chemotherapy before Total Mesorectal Excision (TME)
in order to reduce the locoregional recurrence post surgery,
as well as to improve overall survival. This is unique to
rectal cancers unlike other subsites of colon cancer, where
initial surgical management followed by adjuvant chemotherapy
is the standard of care in operable cancers. Apart from the
improvement in locoregional control and distant metastasis,
neoadjuvant chemoradiation allows sphincter preservation in
cases where upfront surgical approach may have not succeeded
in sphincter preservation [7].
The role of neoadjuvant radiation in preventing locoregional
relapses after TME was established by German Rectal Cancer
Study [7]. More than 800 patients with locally advanced rectal
cancer were randomized to receive either long course
preoperative chemoradiation followed by TME or TME followed by
adjuvant chemoradiation. Both arms included adjuvant
chemotherapy. Radiation therapy involved delivering 5040cGy in
28 fractions using 6MV photons, with concurrent infusional 5FU
on week 1 and week 5 for 120 hours. In post op chemoradiation
arm, an additional boost of 540cGy was delivered to the tumour
bed. Although 5 year overall survival remained similar in both
groups, the preoperative group had fewer local relapses (6% vs
13%, p=0.006) and lower acute and chronic Grade 3 and 4
adverse events [7].
The role of chemotherapy in concurrent chemoradiation for
locally advanced rectal cancer was investigated by the EORTC
22921 study. More than 1000 patients were randomized into 4
groups, with one group receiving only preoperative radiation,
second group with preoperative chemoradiation, third group
with preoperative radiation and post operative chemotherapy,
and fourth group with preoperative chemoradiation and post
operative chemotherapy. Chemotherapy regimen was bolus 5FU and
leucovorin for 5 days every 4 weekly. The radiotherapy alone
arm had significantly inferior local recurrence rate compared
to the other three arms containing chemotherapy, thereby
confirming the role of systemic chemotherapy in improving
locoregional control. The lack of overall survival benefit
also shows the lack of effect of chemotherapy on distant
metastasis control [8]. Similar results were obtained in the
French FFCD 9203 trial involving 700 patients comparing
preoperative radiation versus chemoradiation. Addition of
chemotherapy improved local disease control but had no effect
on overall survival [9].
Short course preoperative radiation 1 week prior to planned
surgery has also been effective in improving local disease
free survival rates. The Dutch Colorectal Cancer Group TME
trial randomized 1800 patients to either preoperative short
course radiation in dose of 25Gy in 5 fractions, followed
within 1 week by Total Mesorectal Excision (TME), or to TME
alone. The study did not allow for chemotherapy and hence
provided a clear understanding of the role of preoperative
radiation. This approach is distinct from long course
chemoradiation because the surgery is done within a week of
completing hypofractionated radiation schedule. Unlike long
course chemoradiation, pathological complete response with
short course radiation followed by surgery has been
consistently low compared to long course chemoradiation.
However, the radiation significantly reduced locoregional
recurrence without impacting overall survival [10].
Long versus short debate
Long course chemoradiation and short course radiation have
both proven to be feasible and effective in preventing local
recurrences as preoperative treatment strategies. Randomised
trials comparing long course versus short course preoperative
treatments have not found any significant difference in
locoregional control, overall survival and long term
morbidity. The only significant differences observed has been
a slightly improved local control with long course
chemoradiation in distal tumors (<5cm from anal verge) and
the significantly higher pathological complete response rates
with long course chemoradiation in the surgical specimens
[11,12].
Pathological complete response has been associated with
improved disease free survival [13]. However, despite the fact
that short course preoperative radiation followed by immediate
surgery produces lower pathological complete response than
long course chemoradiation, long term survival data remains
similar. This is perhaps because radiotherapy to surgery
interval (RSI) influences pathological complete response
rates. In a large retrospective cohort of Italian patients
treated with preoperative long course chemoradiation,
pathological complete response rates were assessed based on
radiotherapy surgery interval (RSI) stratified into three
groups: TME within 6 weeks, between 7-12 weeks, and > 13
weeks post radiation [14]. Pathological complete response
rates were significantly higher in patients with RSI of >
13 weeks, and least in RSI of < 6 weeks. Similar
conclusions have been achieved in Stockholm III trial which
compared short course radiation without delay (RSI <1 week)
with short course radiation with delay (RSI 4-8 weeks). The
pathological complete response rates were significantly higher
in the delayed arm compared to immediate surgery arm although
radiation treatment remained the same (15). All the three
modes of preoperative radiation are considered standard of
care.
Chemotherapy in preoperative treatment
Despite achieving significant local control with preoperative
treatment, distant metastasis free survival and overall
survival have not been improved. This could partly be due to
fluorouracil based systemic chemotherapy. Efforts have been
made to improve survival outcomes by intensifying chemotherapy
regimens in preoperative and adjuvant treatment protocols. The
German CAO/ARO/AIO-04 study evaluated addition of oxaliplatin
to both preoperative long course chemoradiation as well as
adjuvant chemotherapy compared to the standard arm of 5FU in
both preoperative and adjuvant treatment. Addition of
oxaliplatin significantly improved disease free survival
[16]. However, the PETACC 6 study, published in abstract form,
failed to show any benefit of adding oxaliplatin to
capecitabine in neoadjuvant and adjuvant regimens [17].
Total Neoadjuvant therapy
The standard of care for locally advanced rectal cancer
management involves preoperative radiation or chemoradiation,
followed by total mesorectal excision, followed by adjuvant
systemic therapy. One of the challenges in adjuvant systemic
treatment is that only about 60% of patients complete 6 months
of adjuvant chemotherapy due to toxicity. Recent studies
suggest that shorter chemotherapy regimens are equally
effective compared to 6 months of adjuvant treatment in
colorectal cancer [18]. With more not necessarily being
better, treatment philosophy is undergoing an evolutionary
churning with interest in using systemic treatment in
neoadjuvant setting either before or after neoadjuvant
concurrent chemoradiation. This approach, also called total
neoadjuvant therapy (TNT), has several theoretical
advantages. It allows optimal utilization of an
effective treatment as chemotherapy in a relatively healthy
patient, allowing more patients to complete their treatment
with less morbidity. It also addresses micrometastasis
early, though it is too early to comment on effect on
survival. Earlier completion of chemotherapy and late surgery
allows earlier closure of stoma, positively influencing
quality of life. Patients who achive clinical complete
response can be kept on "watchful waiting" strategy for non
surgical organ conserving approach to rectal cancer.
Total Neoadjuvant therapy can be delivered in two ways, either
induction chemotherapy followed by chemoradiation followed by
surgery, or chemoradiation followed by chemotherapy followed
by surgery. Initial chemoradiation followed by consolidation
chemotherapy was studied by Garcia-Aguilar et al in a Phase 2
non randomized patient population [19]. Primary end point was
proportion of patients achieving pathological complete
response. Addition of mFOLFOX6 based chemotherapy
significantly improved pCR rates, with higher number of
chemotherapy cycles achieving higher proportional pCR
rates. The Polish II trial [20] studied an interesting
idea. Locally advanced rectal cancer patients were randomized
to two distinct arms. Both arms had oxaliplatin
fluoropyrimidine based chemotherapy, and both arms kept
radiotherapy to surgery interval constant at 12 weeks. While
one arm had long course chemoradiation with concurrent bolus
5FU/Leucovorin/Oxaliplatin based chemotherapy, the other arm
had short course radiation followed by FOLFOX4 based
consolidation chemotherapy. Patients with short course
radiation followed by consolidation chemotherapy surprisingly
had significantly improved disease free and overall survival,
though the locoregional control and distant failure rate was
same in both arms. Clearly, further studies are needed to
validate this schedule of treatment.
In contrast, studies looking at Neoadjuvant chemotherapy
followed by chemoradiation followed by TME schedule have not
been as promising, particularly with respect to pCR rates or
survival outcomes. Hence, this approach is considered
experimental. Larger randomized phase 3 studies are needed to
further refine the role of neoadjuvant chemotherapy in
addition to chemoradiation.
Addition of targeted therapy with chemotherapy has been
studied in Total Neoadjuvant Treatment strategy. EXPERT-C
trial studied role of cetuximab when added to neoadjuvant
chemotherapy and chemoradiation in locally advanced rectal
cancers, 60% of patient population being KRAS/BRAF wild type.
Although the study did not meet it's primary objective of
improved complete response rate, there was a significant
difference in overall survival and response rate [21]. Results
have been similarly disappointing with panitumumab in KRAS
wild type tumors with most studies failing to achieve their
primary objective. Studies involving other targeted agents
such as bevacizumab have been similarly disappointing and have
not added significantly to standard treatment regimens.
Managing rectal cancer without surgery
An interesting outcome of high pathological complete response
rates after neoadjuvant chemoradiation is the advent of
non surgical "watchful waiting" strategy. Patients who achieve
complete clinical response and are endoscopic biopsy negative
for residual disease after neoadjuvant treatment are subjected
to intensive surveillance instead of surgery. Patients who
develop locoregional recurrence are offered TME surgery at the
time of recurrence. In a recent review and meta analysis of 23
studies including more than 800 patients, patients managed
with watchful waiting and salvage treatments during regrowth
had similar survival to patients treated with surgical
approaches [22]. This approach results in almost 85% chance of
sphincter sparing and organ conservation. Although large
randomized data are currently lacking, there is widespread
interest and move towards a conservative approach in patients
attaining clinical complete response. Clearly, there appears
to be a need to optimize neoadjuvant treatment strategies to
improve clinical and pathological complete response rates for
organ conservation in rectal cancer.
Future directions
Rectal cancer management has evolved from surgery based
treatments into combined modality treatments with emphasis on
achieving excellent locoregional control along with organ
conservation. Distant metastasis free survival has become the
most important determinant of overall survival and quality of
life. Systemic therapy in locoregionally advanced rectal
cancer has remained its main Achilles heel, with inconsistent
results with targeted therapy and immune checkpoint inhibitor
therapy. Better characterization of tumor biology with
molecular biology tools such as NextGen Sequencing and other
techniques is likely to help clinicians optimize treatments in
order to improve overall survival significantly from the
plateau we have now reached. Improvement and wider acceptance
of high end radiation techniques such as stereotactic
radiosurgery are further likely to have a significant impact
on treatment outcomes.
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