The Evolving Role of Hypofractionated

Radiotherapy in Older Adults with

Gastrointestinal Cancers
Elizabeth Zhang-Velten, MD, PhD, and Nina N. Sanford, MD

While radiotherapy treatment of gastrointestinal (GI) malignancies has historically

involved 5−6 weeks of low dose fractions of radiation, hypofractionated radiation over 1
−4 weeks has emerged as an efficacious alternative in treatment of many cancer types,
including GI cancers. Hypofractionation is of particular relevance in the treatment of older
adult patients, wherein the balance between cancer cure, toxicity, goals of care and con-
venience must be carefully weighed. The role of hypofractionated radiation in the defini-
tive treatment of GI malignancies remains an active area of investigation in sites such as
the esophagus, anus, and pancreas, an efficacious alternative for unresectable cases hepa-
tocellular carcinoma and cholangiocarcinoma and standard of care for locally advanced
rectal cancer. Meanwhile, hypofractionated radiation therapy represents an efficacious
method of palliation for all GI cancers. In this review, we will discuss the application of
hypofractionation in gastrointestinal malignancies by disease subsite, with a focus on car-
ing for older adults.
Semin Radiat Oncol 32:159−167 Ó 2021 Published by Elsevier Inc.

G astrointestinal (GI) malignancies include cancers of the

GI tract (from esophagus to anus), pancreas, and hepa-
tobiliary system. Historically, radiotherapy treatment of GI
malignancies has involved 5−6 weeks of low dose (1.8−2.0
Gy) fractions of radiation,1-3 so-called “conventional frac-
tionation.” In contrast, hypofractionation, the delivery of
radiation therapy in fewer fractions at higher dose per frac-
tion, has emerged as an efficacious alternative in treatment of
many cancer types, including gastrointestinal cancers. Fur-
thermore, with advances in image-guided radiation therapy
(IGRT), the amount of healthy tissue exposed to radiation
can be further reduced, allowing radiation oncologists to uti-
lize stereotactic ablative radiation therapy (SAbR).
Hypofractionation is of particular relevance in the treat-
ment of older adult patients, wherein the balance between
cancer cure, toxicity, goals of care and convenience must be
carefully weighed. For example, in several GI cancers, multi-
modality therapy is considered standard of care.1-3 However,
guidelines are often based upon randomized controlled trials
comprising mostly younger patients and/or those with good
Department of Radiation Oncology, University of Texas Southwestern, Dal-
las, TX, USA
Conflict of interest: None.
Address reprint requests to Nina N. Sanford, Department of Radiation
Oncology, University of Texas Southwestern, 2280 Inwood Road, Dal-
las, TX 75390-9303, USA. E-mail: Nina.Sanford@UTSouthwestern.edu
performance status with few medical comorbidities. In con-
trast, the older adult patient population is more likely to be
frail, with multiple medical comorbidities (although some
older patients have few comorbidities and excellent perfor-
mance status, which must be factored against their chrono-
logic age as well), such that the benefits of multimodality
therapy may be outweighed by associated potential short
and long-term side effects. For example, in patients who are
ineligible for concurrent chemoradiation, hypofractionation
can deliver increased biological equivalent dose (BED) to
compensate for the absence of radiosensitization from con-
current chemotherapy. Additionally, hypofractionation pro-
vides the convenience of a shortened treatment course,
which is relevant in patients who have mobility issues that
may make radiation treatment positions difficult to maintain
over long periods, or transportation issues precluding daily
treatment over months. Meanwhile, the ablative doses
achieved by SAbR make it a suitable alternative to surgery in
patients with early-stage cancers, as well as an efficacious
and less toxic treatment option for oligometastases.
Unique considerations of applying hypofractionation to
the GI system include the motility of the organs due to peri-
stalsis and proximity to the mobile diaphragm, as well as
concern for short and long-term toxicity to gastrointestinal
mucosa. Broadly speaking, this limits the use of SAbR for
tumors originating in the gastrointestinal tract, while

https://doi.org/10.1016/j.semradonc.2021.11.005 159
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160
Figure 1 Hypofractionated radiotherapy regimens for gastrointestinal cancers. (Color version of figure is available
online).
moderate hypofractionation can be safely utilized for most
gastrointestinal sites. In this review, we will discuss the appli-
cation of hypofractionation in gastrointestinal malignancies
by disease subsite (summarized in Fig. 1 and Table 1), with
a focus on caring for older adults.
Esophageal Cancer
The standard of care for locally advanced esophageal cancer
involves neoadjuvant chemoradiation with carboplatin and
paclitaxel followed by esophagectomy per the Chemoradio-
therapy for Oesophageal Cancer followed by Surgery Study
(CROSS) trial,1 in which complete pathologic response rates
of 23% in patients with adenocarcinoma and 49% in patients
with squamous cell carcinoma were observed in the chemo-
radiation arm. The dose used in this trial was 41.4 Gy in 23
fractions, although doses from 41.4 to 50.4 Gy are within
acceptable range.4 However, even prior to this trial, Walsh
et al. reported an overall survival advantage with neoadju-
vant hypofractionated chemoradiation (40 Gy in 15 frac-
tions) given with concurrent 5-fluorouracil and cisplatin vs
surgery alone in patients with esophageal adenocarcinoma.5
Direct comparison between these 2 trials is difficult given
that patients received different chemotherapeutic regimens
and the absence of preoperative stage details in the hypofrac-
tionated study. However, a comparable pathologic complete
response rate of 25% was observed in these patients, similar
to the adenocarcinoma subgroup in the CROSS study. More
recently, a retrospective analysis compared hypofractionated
neoadjuvant chemoradiation via 30 Gy in 10 fractions vs 40
Gy in 20 fractions in patients with stage II or III esophageal
squamous cell carcinoma.6 Between the 2 fractionation
schemes, overall survival, progression free survival, and
pathologic complete response rate were similar. However,
the pathologic complete response rates observed (33.3%
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E. Zhang-Velten and N.N. Sanford
hypofractionated vs 35.3% conventional) were lower than
those observed for patients within the CROSS trial who had
squamous histology (»49%).
Many patients, particularly older adult individuals, may
have medical contraindications to esophagectomy.7 Further-
more, randomized trials of locally advanced esophageal
squamous cell carcinoma patients receiving chemoradiation
demonstrated no survival benefit with surgery, rather than
continuation of chemoradiation to a definitive rather than
neoadjuvant dose.8,9 Therefore, hypofractionation is a mean-
ingful regimen in the definitive management of esophageal
cancer as well. In patients with locally advanced esophageal
cancer, hypofractionation has been trialed with concurrent
chemotherapy in an effort to deliver more biologically potent
dose for definitive treatment. For example, a Chinese pro-
spective study of T2-4N0-1 esophageal squamous cell carci-
noma patients demonstrated significantly improved local
control with hypofractionated radiation (54 − 60 Gy in 18
− 20 fractions) as compared to conventional (60 Gy in 30
fractions), with concurrent paclitaxel followed by consolida-
tive paclitaxel and cisplatin, though overall survival was not
different between the treatment regimens. With hypofractio-
nation for esophageal cancer there is the concern for acute
toxicities such as esophagitis or late toxicities such as fistulas,
pneumonitis, cardiac toxicities, or hematologic toxicities;
however, no statistically significant differences in grade 3 or
higher instances of these toxicities were observed between
the conventionally fractionated and hypofractionated
patients treated in this prospective study of definitive chemo-
radiation10 or in the recent retrospective study of neoadju-
vant chemoradiation.6
Finally, for patients who are not candidates for curative
treatment, palliative radiotherapy alone is a safe and effective
treatment option for malignant dysphagia. The most com-
monly used regimens are 30 Gy in 10 fractions,11 20 Gy in 5
fractions,11-13 or 40 Gy in 15 fractions.
 The Evolving Role of Hypofractionated Radiotherapyin Older Adults
Table 1
Author Year Title Institution Study Design Intent Hypofractionated Primary
RT Regimen Outcome
Esophageal Walsh et al. 1996 A Comparison of Multimodal Trinity College, Randomized Neoadjuvant 40 Gy in 15 frac- Median OS (16
Therapy and Surgery for Dublin, UK phase III tions months neoad-
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Esophageal (concurrently juvant CRT vs

Adenocarcinoma with cisplatin/5- surgery alone)
FU)
Lyu et al. 2019 Comparison of efficacy, University of Elec- Retrospective Neoadjuvant 30 Gy in 10 frac- OS, PFS statisti-
safety, and costs between tronic Science and tions (concur- cally similar
neoadjuvant hypofractio- Technology of rently with 5-FU
nated radiotherapy and China, Chengdu, or taxane)
conventionally fractionated China
radiotherapy for esoph-
ageal carcinoma
between HFRT vs 40 Gy in
20 fractions
Ma et al. 2012 Moderately hypofractionated Qingdao University, Prospective Definitive 54v60 Gy in 18−20 LRF improved
conformal radiation treat- Yantai, China fractions (concur- (27.0% HFRT vs
ment of thoracic esoph- rently with pacli- 47.3% 60 Gy in
ageal carcinoma taxel, followed by 30 fractions)
consolidative OS statistically
paclitaxel and similar
cisplatin)
Walterbos 2019 Effectiveness of several Leiden University Retrospective Palliative 20 Gy in 5 frac- Improvement of
et al. external beam radiotherapy Medical Center, tions, 30 Gy in 10 symptoms (72%
schedules for palliation of Leiden, fractions or 39 Gy all schedules)
esophageal cancer Netherlands in 13 fractions
Murray 2012 Palliative radiotherapy in Weston Park Hospi- Retrospective Palliative 20 Gy in 5 fractions Improvement of
et al. patients with esophageal tal, Sheffield, UK dysphagia (75%)
carcinoma: A retrospective
review

Borg et al. 2020 Palliative short-course hypo- Skane University Phase II Palliative 20 Gy in 5 fractions Improvement of
fractionated radiotherapy Hospital, Lund, (followed by 4 dysphagia (79%)
followed by chemotherapy Sweden cycles FOLFOX)
in esophageal adenocarci-
noma: the phase II PALAES-
TRA trial
Gastric Tey et al. 2019 Palliative radiotherapy in National Cancer Phase II Palliative 36 Gy in 12 Improvement of
symptomatic locally Institute of fractions symptoms (80%
advanced gastric cancer: A Singapore experienced
phase II trial relief from
bleeding)
(continued on next page)

161
 162
Table 1 (Continued)
Author Year Title Institution Study Design Intent Hypofractionated Primary
RT Regimen Outcome
personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2022. Elsevier Inc. Todos los derechos reservados.

Tanaka 2020 Hemostatic radiotherapy for Asahi University Prospective Palliative 20 Gy in 5 fractions Improvement of
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et al. inoperable gastric cancer: a Hospital, Mizuho, (whole stomach) bleeding (80%)
pilot study Japan 15 Gy in 5 frac-
tions (partial
stomach)
Pancreatic Versteijne 2020 Preoperative Chemoradio- Multi-institutional, Randomized Neoadjuvant 36 Gy in 15 frac- OS (17.6 neoadju-
et al. therapy Versus Immediate Netherlands Phase III tions (followed by vant CRT vs.
Surgery for Resectable and gemcitabine) 13.2 months
Borderline Resectable Pan- surgery alone in
creatic Cancer: Results of borderline
the Dutch Randomized resectable)
Phase III PREOPANC Trial.
Koong 2004 Phase I study of stereotactic Stanford University, Phase I Definitive 25 Gy in 1 fraction Acute GI toxicity
et al. radiosurgery in patients Stanford, CA, USA (MTD not
with locally advanced pan- reached)
creatic cancer
HCC/IHC Tse et al. 2008 Phase I study of individualized Princess Margaret Phase I Definitive 24−54 in 6 Toxicity (MTD not
stereotactic body radiother- Hospital, Toronto, fractions reached)
apy for hepatocellular carci- Canada
noma and intrahepatic
cholangiocarcinoma.
Bujold et al. 2013 Sequential phase I and II trials Princess Margaret Phase I, II Definitive 30−54 in 6 Toxicity (MTD not
of stereotactic body radio- Hospital, Toronto, fractions reached)
therapy for locally advanced Canada LC (87% at 1
hepatocellular carcinoma. year)
Scorsetti 2015 The challenge of inoperable Humanitas Clinical Prospective Definitive 48−75 Gy in 3 frac- LC (improved
et al. hepatocellular carcinoma and Research Cen- tions (<3 cm) with BED > 100
(HCC): results of a single- ter, Rozzano, MI, 36−60 Gy in 6 Gy)

E. Zhang-Velten and N.N. Sanford

institutional experience on Italy fraction (3−6 cm)
stereotactic body radiation
therapy (SBRT).
Tao et al. 2016 Ablative Radiotherapy Doses MD Anderson Can- Retrospective Definitive 58.05 Gy in 15 frac- LC (improved
Lead to a Substantial Pro- cer Center, Hous- tions with BED > 80.5
longation of Survival in ton, TX, USA 67.5 Gy in 15 Gy)
Patients With Inoperable fractions
Intrahepatic Cholangiocarci- 75 Gy in 25
noma: A Retrospective fractions
Dose Response Analysis
Yeung et al. 2020 Palliative Liver Radiotherapy Tuen Mun Hospital, Retrospective Palliative 8 Gy in 1 fraction Improvement of
(RT) for Symptomatic Hepa- Tuen Mun, Hong symptoms
tocellular Carcinoma (HCC) Kong (SAR), China. (52%)
(continued on next page)
 The Evolving Role of Hypofractionated Radiotherapyin Older Adults
Table 1 (Continued)
Author Year Title Institution Study Design Intent Hypofractionated Primary
RT Regimen Outcome
Soliman 2013 Phase II Trial of Palliative Princess Margaret Phase II Palliative 8 Gy in 1 fraction Improvement of
et al. Radiotherapy for Hepato- Cancer Centre, symptoms
personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2022. Elsevier Inc. Todos los derechos reservados.
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cellular Carcinoma and Liver Toronto, Ontario, (48%)

Metastases Canada.
Bydder 2003 A prospective trial of short- Sir Charles Gairdner Prospective Palliative 8 Gy in 1 fraction Improvement of
et al. fractionation radiotherapy Hospital, Western symptoms
for the palliation of liver Australia, Australia (54%)
metastases
Rectal Bujko et al. 2016 Long-course oxaliplatin- Polish Colorectal Phase III Neoadjuvant 25 Gy in 5 fractions R0 resection rate
based preoperative chemo- Study Group (77% short-
radiation versus 5£5 Gy and course vs 71%
consolidation chemother- long-course)
apy for cT4 or fixed cT3 rec-
tal cancer: results of a
randomized phase III study
Ngan et al. 2012 Randomized trial of short- Trans-Tasman Radia- Phase III Neoadjuvant 25 Gy in 5 fractions LC at 3 years
course radiotherapy versus tion Oncology (7.5% short-
long-course chemoradiation Group course vs 4.4%
comparing rates of local long-course)
recurrence in patients with
T3 rectal cancer: Trans-Tas-
man Radiation Oncology
Group trial 01.04
Bahadoer 2021 Short-course radiotherapy 54 centres in the Phase III Neoadjuvant 25 Gy in 5 fractions Disease-related
et al. followed by chemotherapy Netherlands, Swe- treatment fail-
before total mesorectal den, Spain, Slov- ure at 3 years
excision (TME) versus pre- enia, Denmark, (23.7% short-
operative chemoradiother- Norway, and the course vs
apy, TME, and optional USA 304% long-
adjuvant chemotherapy in course)
locally advanced rectal can-
cer (RAPIDO): a rando-
mised, open-label, phase 3
trial
Picardi 2016 Palliative Short-Course Radia- Fondazione di Phase II Palliative 25 Gy in 5 fractions Reduction of pain
et al. tion Therapy in Rectal Can- Ricerca e Cura (88%) and
cer: A Phase 2 Study “Giovanni Paolo bleeding (100%)
II,” Campobasso,
Italy

163
164
Gastric Cancer
The role of radiation therapy in the management of non-met-
astatic gastric cancer is controversial. While many trials of
radiotherapy in the post-operative setting have been nega-
tive,14-17 several open studies are assessing neoadjuvant che-
moradiotherapy.18-20 In the current landscape,
hypofractionated radiotherapy in gastric cancer is mainly
used for palliation. Prospectively, 36 Gy in 12 fractions21 or
20 Gy in 5 fractions22 have been shown to be effective and
well-tolerated, and 30 Gy in 10 fractions is also commonly
used. Nausea and vomiting are common toxicities for any of
these hypofractionated palliation regimens; in the previously
mentioned study using 36 Gy in 12 fractions one case of
grade 3 gastritis was observed.21 For older adult patients
who are not eligible for surgical or definitive treatment, these
are reasonable regimens for urgent symptomatic relief of
bleeding, obstruction, or pain.
Pancreatic Cancer
Although the role of radiotherapy in the curative manage-
ment pancreatic cancer also remains controversial, many
believe there to be a subset of patients who do benefit from
radiotherapy, and ongoing trials seek to optimize criteria for
patient selection. Studies have consistently shown that radio-
therapy increases the rate of R0 resection.23 Notably, one of
these, the PREOPANC study used hypofractionated radio-
therapy (36 Gy in 15 fractions with gemcitabine) and com-
pared this to upfront surgery.24 The study found that R0
resection rate, disease-free survival, locoregional-failure-free
interval, and pathologic parameters (lymph node involve-
ment, perineural invasion, and venous invasion) were
improved with neoadjuvant chemoradiation. Although the
primary outcome of overall survival was similar, among a
predefined subgroup of patients with borderline resectable
pancreatic adenocarcinoma, overall survival was improved
with neoadjuvant chemoradiation (17.6 vs 13.2 months),
with no statistically significant differences in acute toxicities.
Of note, the trial’s standard arm of upfront surgery is differ-
ent from the current practice among many cancer centers
across the United States, wherein neoadjuvant high dose
double or triplet therapy is given25; however, the results of
the PREOPANC study suggest that neoadjuvant chemoradia-
tion may be a good option in older adult patients who may
not tolerate combination chemotherapy.
Stereotactic ablative radiotherapy provides the highest
biologic effective dose and can be used in the pre-operative,
post-operative or definitive setting, providing ability to meet
metrics for duodenum, stomach and jejunum. Although a
comprehensive discussion of SAbR in pancreatic cancer is
beyond the scope of this review, the majority of experts agree
that delivering higher BED results in superior tumor control.
Initial studies of SAbR in pancreatic cancer established 25
Gy as the maximum tolerated dose in the definitive setting26
with acceptable toxicities of nausea, abdominal pain, and
diarrhea; however, current trials are consistently pushing the
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E. Zhang-Velten and N.N. Sanford
dose to 50 Gy in 5 fractions, or higher. The most commonly
used regimen off study at our institution is 40 Gy in 5 frac-
tions to the gross tumor and tumor/vessel interface, with an
elective nodal volume receiving 25 Gy in 5 fractions. Proton
pump inhibitors should be prescribed prophylactically to
reduce the risk of toxicities such as gastritis or duodenal
ulceration which can be further complicated by bleeding and
fistula creation, though such toxicities are rare even in
patients who receive gemcitabine chemotherapy only 1 week
before starting stereotactic radiation.27 Stereotactic ablative
radiation therapy represents a convenient and, when per-
formed at an experienced facility, safe option for older adult
patients that can provide durable tumor control and symp-
tomatic relief.28 Ongoing trials assessing novel technologies
(such as MR-guided adaptive radiation therapy29) and radia-
tion-drug combinations (such as with a superoxide dismu-
tase inhibitor as in GALERA30 and GRECO-2
NCT04698915) may further improve the therapeutic ratio of
SAbR in pancreatic cancer.
Hepatocellular Carcinoma/
Cholangiocarcinoma
Historically, the role of radiotherapy for liver tumors has
been limited by the risk of radiation induced liver disease
(RILD), which occurs when large volumes of the liver are
irradiated with high doses.31 In particular, older adult
patients are at greater risk for RILD given higher likelihood
of liver dysfunction32 or limited hepatic reserve33 at older
ages. With advances in image-guided radiation therapy and
respiratory motion management, SAbR can be safely given to
unresectable hepatocellular carcinomas and intrahepatic
cholangiocarcinomas. In a phase I study of 6-fraction SAbR
(24 to 54 Gy) in 41 patients (30 with hepatocellular carci-
noma and 11 with cholangiocarcinoma), no RILD or grade 4
or 5 toxicity was observed and thus no maximum tolerated
dose was determined.34 Next, an expanded phase I/II study
and immediate subsequent phase II trial of 102 combined
patients demonstrated a promising local control rate of 87%
at 1 year.35 A three-fraction (48 − 75 Gy) SAbR trial similarly
observed a local control rate of 86% at 1 year, with the find-
ing that local control was significantly improved for lesions
treated with biological equivalent dose >100 Gy,36 while a
study of 79 patients with inoperable intrahepatic cholangio-
carcinoma37 demonstrated that 3-year local control was sig-
nificantly higher with a biological equivalent dose of at least
80.5 Gy (78%) versus lower doses (45%). Toxicities in these
trials typically included transient biliary obstruction, grade 3
transaminitis, and non-classic radiation induced liver dise-
sase, although the incidence is low. Meanwhile, in a study of
31 patients treated with 5 fraction SAbR (26 of whom
received 40 Gy) and the majority of whom had extrahepatic
cholangiocarcinoma and thus closer proximity to the duode-
num, 5 patients (16%) experienced severe late duodenal
obstruction or duodenal ulcer formation,38 similar to the
proportion of late toxicities observed with pancreatic
SAbR.27 At 1-year, local control was 78% and overall survival
The Evolving Role of Hypofractionated Radiotherapyin Older Adults
was 59%, a marked improvement over historical controls.
SAbR therefore represents a meaningful intervention for
patients with hepatocellular carcinoma or cholangiocarci-
noma who are unresectable or medically inoperable. The
safety and efficacy of single-fraction SAbR at doses of 35 and
40 Gy for patients with liver metastases39 may potentially be
extrapolated in the future for treatment of primary hepatocel-
lular carcinoma and cholangiocarcinoma. Other than SAbR,
a palliative treatment option for symptomatic patients is
whole liver radiation with 8 Gy in 1 fraction40,41 or 10 Gy in
2 fractions.42
Rectal Cancer
Preoperative long-course chemoradiation (50 − 50.4 Gy in
25 − 28 fractions with concurrent capecitabine or 5-fluoro-
uracil) has been a standard of care for locally advanced rectal
cancer since the publication of the German Rectal Trial in
2004.3,43 Multiple trials44,45 have since shown statistically
similar outcomes between long course chemoradiation and
hypofractionated short course radiation therapy (SCRT, 25
Gy in 5 fractions) with the latter offering convenience and
less acute toxicity, both of which are relevant in older adult
patients. Also, SCRT is more cost effective.46 However,
SCRT remained underutilized in the US,47 although this may
be changing due to recent publications and also the COVID-
19 pandemic, which provided a urgent motivation to mini-
mize treatments in order to limit patient contact. In regards
to the former, SCRT in high risk rectal cancer was further
investigated in the Rectal cancer And Preoperative Induction
therapy followed by Dedicated Operation (RAPIDO) trial.48
Here, the experimental arm received total neoadjuvant ther-
apy (TNT; 25 Gy in 5 fractions radiation followed by 18
weeks of systemic chemotherapy consisting of either 6 cycles
of CAPOX [capecitabine and oxaliplatin] or 9 cycles of FOL-
FOX) before total mesorectal excision. This was compared to
the previous neoadjuvant standard of 50.4 Gy in 28 fractions
or 50 Gy in 25 fractions radiation with concurrent capecita-
bine prior to total mesorectal excision; adjuvant chemother-
apy (8 cycles of CAPOX or 12 cycles of FOLFOX) was
optional, based on the hospital policy of enrolling institu-
tions. The RAPIDO trial was designed as a superiority trial,
with the amended hypothesis that 3-year disease-related
treatment failure events would be reduced in the experimen-
tal, short-course treatment arm. A statistically significant
benefit to TNT was observed, with fewer disease-related
treatment failure events at 3 years in the TNT treatment arm
(23.7%) than the standard of care arm (30.4%). This
improvement was attributed to a reduction in distant metas-
tases (20.0% short-course vs 26.8% long-course), which in
turn may have been due to better compliance with preopera-
tive chemotherapy in the short-course experimental arm
(15% of patients stopped chemotherapy prematurely). In
comparison, 187 out of 398 patients in the standard of care
arm who completed surgery had adjuvant therapy, of whom
37% stopped chemotherapy prematurely. The results of the
RAPIDO trial suggest that TNT with SCRT followed by
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165
systemic chemotherapy in the neoadjuvant setting can be a
new standard of care for locally advanced rectal cancer.
Additionally, the rate of pathologic complete response in
the TNT arm of RAPIDO was double that of the standard of
care arm (28% vs 14%),48 and, in the generally less locally
advanced patients in the Stockholm III trial, 10.4% (short-
course) vs 2.2% (long-course).49 These findings are notable,
given ongoing interest in watch-and-wait, non-operative
strategies for rectal preservation, in which most neoadjuvant
treatment has traditionally been long-course chemoradia-
tion50-53. Studies are now exploring the possibility of using
short-course radiation for watch-and-wait management of
rectal cancer.54,55 However, given the limited data at this
time on SCRT for organ preservation, older adults who are
interested in avoiding an operation may be best treated with
long course chemoradiation as part of non-operative man-
agement.
We anticipate that SCRT will be used more frequently in
older adults due to convenience, cost-effectiveness,46 and
now additional studies demonstrating efficacy.48 In patients
who are not candidates for curative treatment, short-course
radiation alone is an effective option for palliation.56.
Anal Cancer
The standard of care for treatment of anal cancer is conven-
tionally fractionated chemoradiation over 5-6 weeks.2,57-59
Whether lower radiation dosage can be the standard of care
in early stage T1-2N0M0 anal cancer is now being investi-
gated in the DECREASE trial (NCT04166318). Findings
from this trial may guide the development of hypofractio-
nated radiation regimens in the definitive management of
anal cancer in the future. For palliation, 25 Gy in 5 fractions
or 20 Gy in 5 fractions can help with pain or bleeding.
Conclusion
The role of hypofractionated radiation in the definitive treat-
ment of GI malignancies remains an active area of investiga-
tion in sites such as the esophagus, anus, and pancreas, an
efficacious alternative for unresectable cases hepatocellular
carcinoma and cholangiocarcinoma and has become a stan-
dard of care for locally advanced rectal cancer. Hypofractio-
nated radiation therapy represents an efficacious method of
palliation for all GI cancers. Across all disease sites and set-
tings, the therapeutic ratio of hypofractionation may be par-
ticularly high among older adult patients. With further
improvements in both image-guided radiation therapy and
systemic therapies, ongoing and future studies will help to
make hypofractionated radiation therapy not only more con-
venient, but also increasingly safe and efficacious.
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