Keywords LARC - NACTRT (Cape–RT) - TNT - signet ring adenocarcinoma - mucinous adenocarcinoma
Introduction
Colorectal cancer is the third most common cancer.[1 ] According to the Globocan 2022 data, there are 729,833 cases of rectal cancer worldwide.
Among these cases, Asia accounts for 52.7%. Specifically, India contributes 30,817
cases, constituting 7.4% of the global total.[2 ] For almost the last two decades, neoadjuvant long-course chemoradiotherapy (CRT)
(capecitabine radiotherapy [Cape–RT]) followed by surgery has been the standard of
care for locally advanced rectal cancer (LARC) patients.[3 ] The majority of these patients would need further adjuvant chemotherapy based on
residual high-risk pathological features for significant systemic relapse risk postsurgery.[4 ] However, only 60% of patients can complete the required adjuvant chemotherapy due
to several reasons, making the less-than-desirable impact of therapy.[5 ]
In recent years, the management of LARC has slowly moved toward the use of strategies
such as total neoadjuvant therapy (TNT) to bring an opportunity of complete desired
chemotherapy prior to surgery, thereby decreasing the possibility of relapses, improving
pathological response, and probably improve survival in LARC.[6 ] Several studies have shown noninferior and sometimes better outcomes than Cape–RT.
However, it still needs to be discovered which patient group benefits the most, as
there are concerns of increased toxicity in patients who may not need the TNT approach.[7 ] This is based on data predominantly from North America and some parts of Europe,
where most rectal cancers appear to have favorable baseline characteristics.
Available data from India suggests that a majority of LARCs have unfavorable signs
such as late presentation, signet ring histology, T4 status, and extra mesorectal
nodes.[8 ] The survival rates in such a cohort of patients appear inferior to the outcomes
seen in recently published seminal studies.[9 ] Often, real-world data are different than carefully selected patients in clinical
trials. Local factors of a country or locality play a significant impact in successfully
implementing therapy and achieving outcomes. In this study, we review our outcomes
with Cape–RT in a real-world setting to understand a poor outcome subgroup on which
modern TNT-based therapy can be tested prospectively.
Material and Methods
This is a retrospective study, and patient data was extracted from electronic medical
records after approval from the Institutional Review Board and Ethics Committee (IEC/1116/1799/001)
and was conducted as per the Declaration of Helsinki guidelines. Patients with the
confirmed diagnosis of adenocarcinoma of the rectum, with either T3/T4 and/or node
(N) positive and no evidence of distant metastases from June 2014 to December 2021,
were first identified. So, these patients with LARC (nonmetastatic) who were offered
neoadjuvant CRT (NACTRT), as per the institution protocol decided after multidisciplinary
discussion, were further considered. Patients who were unfit for concurrent capecitabine
or underwent primary surgery, had upfront metastatic disease, received short-course
RT or other forms of neoadjuvant therapy (NAT), and other histologies than adenocarcinoma
were excluded.
Pretreatment Workup
Baseline staging for all patients included a complete physical examination, colonoscopy,
contrast-enhanced computed tomography (CT) (thorax, abdomen) or 18 fluorodeoxyglucose
positron emission tomography-CT, contrast-enhanced-magnetic resonance imaging (MRI)
pelvis, and carcinoembryonic antigen levels. Following this, all patients underwent
multidisciplinary joint clinic discussion and treatment decisions.
Treatment
All patients were decided to receive Cape–RT, followed by an assessment for surgery.
The RT treatment comprised 45 to 50 Gy in 25 daily fractions using 200 cGy per fraction
over 5 weeks. The standard concurrent oral capecitabine at a dosage of 825 mg/m2 , twice daily, throughout the entire RT course was prescribed. Participants who were
concurrently treated with 5-fluorouracil (5-FU) were excluded from the study. Instances
of interruptions in long-course radiation therapy lasting 1 week or more, whether
caused by RT or chemotherapy, were documented. Grade 3 and grade 4 were documented
from medical records and reported as per NCI-CTCAE (National Cancer Institute-Common
Terminology Criteria for Adverse Events) version 4.03.[10 ]
After the completion of Cape–RT, all patients were evaluated using pelvic MRI within
the 6- to 8-week timeframe and were reviewed in a multidisciplinary joint clinic.
The responses were categorized as complete response (CR), partial response (PR), stable
disease (SD), or progressive disease (PD). These categorizations were determined by
assessing changes in signal tumor intensity, regression in tumor and nodal size, regression
in circumferential resection margin (CRM) status, and the presence of fibrosis on
T2-weighted sequences. Patients were considered for surgery after meeting the following
criteria:
CRM negativity
Absence of extension through the greater sciatic notch, encasement of external iliac
vessels, para-aortic lymphadenopathy, or sacral invasion above the S2-S3 junction
Possibility of achieving R0 resection
Patients deemed unresectable were offered consolidation chemotherapy with the aim
of downstaging to a resectable status. NAT options included capecitabine-oxaliplatin
(CAPOX) or modified 5-fluorouracil-leucovorin-irinotecan-oxaliplatin (mFOLFIRINOX)
without bolus 5-FU, for 2 to 3 months based on the medical oncologist's assessment.[11 ] A follow-up MRI was conducted and reviewed as before. Patients still unsuitable
for resection were continued on chemotherapy as suitable with palliative intent.
Patients undergoing surgery were offered CAPOX or single-agent capecitabine as adjuvant
chemotherapy to complete 6 months of perioperative therapy. After the scheduled completion
of the treatment, patients were placed under surveillance in accordance with the institution's
protocol.
Clinical Data Collection and Statistics
For the purposes of this study, demographic information and baseline clinical and
tumor characteristics were gathered from a meticulously maintained electronic database.
The data were entered into IBM SPSS software version 21 for subsequent analysis. Descriptive
statistics, such as median, frequency, and percentage, were employed to depict categorical
variables like age, gender distribution, treatment modalities, and treatment response.
The primary endpoint of the study was event-free survival (EFS) calculated from diagnosis
to the date of recurrence, disease progression, loss to follow-up, or death, whichever
was earlier. Secondary endpoints were overall survival (OS), pathological complete
response (PCR) rate, tolerance to Cape–RT, and local recurrence rate.
Results
A total of 1,189 patients were identified as suitable (Consort; [Fig. 1 ]). The median age of the patients was found to be 49 years, with a predominance of
males, constituting 65% of the study population. Tumor characteristics revealed that
most cases (53%) were located in the lower one-third of the rectum. Additionally,
26% of the tumors were classified as poorly differentiated, with other important characteristics
shown in [Table 1 ]. A significant proportion of patients had high-risk characteristics, such as T3/T4
disease (94%) and node positivity (90%), and they involved CRM (51%) at baseline.
Signet ring and mucinous histology were seen in 13 and 11% of patients.
Fig. 1 Consort figure.
Table 1
Patient characteristics, treatment, and outcomes
Characteristic
Number (percentage where applicable)
Baseline Characteristics
Median age (y)
49 (range: 15–95)
Gender (male:female)
791 (65.5):410 (34.5)
Sites of the disease
Upper: middle: lower
230 (19.3): 329 (27.7): 630 (53)
Histopathology
WDAC
MDAC
PDAC (PDAC/Signet/Mucinous)
Unknown
105 (8.8)
757 (63.7)
311 (26.2)
16 (1.3)
Baseline clinical tumor stage
T3
T4
803 (67)
317 (26.5)
Node positive
1,096 (92.2)
Extra mesorectal LN + ve
347(29.2)
CRM + ve
597(50.2)
Treatment and outcome data
Surgery
945 (79.5)
Anterior resection
136 (14.4)
Abdominoperineal resection
346 (36.6)
Intersphincteric resection
136 (14.4)
Exenteration
89 (9.4)
Low anterior resection
238 (25.2)
Pathological data
ypT category:
0
1
2
3
4
NA
267 (22.5)
46 (3.9)
164 (13.8)
395 (33.2)
58 (4.9)
15 (1.2)
ypN category:
0
1
2
NA
653 (54.9)
185 (15.6)
89 (7.5)
18 (1.5)
LVI + ve
42 (3.5)
PNI + ve
81 (6.8)
EMVI + ve
68 (5.7)
TRG status
1/5
2/5
3/5
4/5
5/5
NA
265 (22.3)
203 (17.1)
267 (22.5)
151 (12.7)
13 (1.1)
46 (3.9)
Pathological CR
252 (21.1)
Lost to follow-up
142 (12)
Recurrence
254 (27)
Isolated local recurrence
34 (14)
Local and distal recurrence
60 (23)
Isolated distal recurrence
160 (63)
Overall survival (5 y)
72%
Resected
78%
Unresected
28%
Abbreviations: CR, complete response; CRM, circumferential resection margin; EMVI,
extramural venous invasion; LN, lymph node; LVI, lymphovascular invasion; MDAC, moderately
differentiated adenocarcinoma; NA, not available; PDAC, poorly differentiated adenocarcinoma;
PNI, perineural invasion; TRG, tumor regression grade; WDAC, well-differentiated adenocarcinoma.
The tolerability of Cape–RT was notably favorable in our study, with less than 10%
of patients experiencing interruptions in chemotherapy and RT administration. Grade
3 or 4 toxicities were reported in 11% of cases, with the most prevalent being diarrhea,
observed in 5 to 8% of patients, followed by hand-foot syndrome and mucositis. Detailed
percentages for these toxicities are mentioned in [Table 2 ]. Significantly increased incidence of diarrhea, infection, and fatigue was noted
in consolidation chemotherapy patients ([Table 2 ]). Encouragingly, the overall response rates, encompassing CR, PR, and SD, approached
90%, with CR observed in 5% of patients (50 individuals) and PR in 68% of patients.
Posttreatment assessment revealed resectability rates of 63%, indicating that 753
patients were deemed suitable candidates for surgical resection.
Table 2
Grade 3 and 4 toxicities across different treatment settings
Toxicity
Cape–RT
Consolidation chemotherapy
Adjuvant chemotherapy
p -Value
Oral mucositis
16 (1.3%)
7 (4%)
23 (2.8%)
0.71
Diarrhea
69 (5.8%)
29 (16.5%)
64 (7.9%)
0.02
Hand-foot syndrome
43 (3.6%)
12 (6.8%)
61 (7.5%)
0.48
Neutropenia
9 (0.8%)
12 (6.8%)
26 (3.2%)
0.07
Anemia
13 (1.1%)
3 (1.7%)
17 (2.1%)
0.81
Infection
21 (1.8%)
16 (9%)
25 (3%)
0.04
Fatigue
21 (1.8%)
18 (10%)
47 (3.9%)
0.02
Peripheral neuropathy
–
7 (4%)
26 (3.2%)
0.7
Abbreviation: RT, radiotherapy.
Bold p -Values are siginificant and <0.05
In cases where surgical resection was deemed unfeasible, a consolidation chemotherapy
strategy was planned in multidisciplinary decision-making, accounting for 23% (276
patients) of the cohort. Persistent radiological margin positivity emerged as the
primary indication for continuing chemotherapy, affecting 17% (198 patients) of the
total cases. The consolidation chemotherapy subgroup included 40% of poorly differentiated
histology (20% were signet ring and 10% mucinous type), 37% had T4 disease, and 46%
had N2 disease. Among the various regimens utilized, CAPOX was the most frequently
administered, representing 58% of cases (160 patients), followed by FOLFIRINOX in
30% (85 patients), and FOLFOX in 8%, and the median number of cycles given was 4 before
surgery as consolidation chemotherapy. Regarding tolerance, diarrhea emerged as the
most common grade 3 or 4 toxicity, affecting 16% of patients, followed by hand-foot
syndrome, neutropenia, and mucositis, which are elaborated in [Table 2 ]. Subsequently, curative surgery with continued margin positivity was successfully
performed in 66% of patients. Detailed radiological response and impact on outcomes
have been reported elsewhere.[12 ]
Among patients who underwent surgery following either Cape–RT or consolidation chemotherapy,
a total of 945 individuals, comprising approximately 80% of the cohort, underwent
surgical intervention. Details regarding surgery, postoperative T staging, N staging,
lymphovascular invasion (LVI), perineural invasion (PNI), extramural venous invasion
(EMVI), and tumor regression grade (TRG) are provided in [Table 1 ]. The most frequently performed surgical procedure was abdominoperineal resection,
conducted in 30% of cases, followed by low anterior resection, accounting for 20%
of surgeries. Notably, PCR to treatment was seen in 21% of cases, highlighting the
efficacy of the therapeutic interventions employed in achieving tumor regression.
Subsequent to surgical intervention, adjuvant chemotherapy was scheduled for 808 patients,
representing 78% of the cohort. However, only 55% of the intended patients were able
to complete the prescribed adjuvant chemotherapy regimen, indicating a notable rate
of intolerance due to treatment-related toxicities. A summary of these toxicities
is provided in [Table 2 ]. Interestingly, our findings suggest a poorer tolerance to chemotherapy in the adjuvant
setting compared with the neoadjuvant setting. The most common toxicities observed
during adjuvant chemotherapy were consistent with those encountered during consolidation
chemotherapy.
Recurrence and Survival
With the median follow-up of 54 months, a total of 379 (31.7) patients had events
(either recurrence/progression). The 3- and 5-year EFS for the whole of the cohort
was 73.2% (95% confidence interval [CI]: 70.6–75.8) and 64.3% (95% CI: 61.1–67.5),
respectively, while the estimated 3- and 5-year OS was 81.3% (95% CI: 78.9–83.7) and
73% (95% CI: 70–76), respectively. The median OS was not reached. Overall, 27% of
the patients experienced recurrences among these, 14% had isolated local recurrences,
23% experienced both local and distant recurrences, and 63% had isolated distant recurrences.
At 54 months, the survival for patients who responded after NACTRT and underwent surgery
was significantly better than those who did not respond and underwent further neoadjuvant
chemotherapy (79.5% vs. 64.7%, respectively, p = 0.001; [Fig. 2A ]). Among the various reasons for which neoadjuvant chemotherapy was offered than
surgery, the patients with continued threatened margins (CRM/peritoneal, prostate,
sphincter, etc.) had significantly better survival (65.7%) than those with poor response
(53.8%) as subjective joint clinic assessment versus PD (40%; p = 0.001) ([Fig. 2B ]).
Fig. 2 (A ) Neoadjuvant chemoradiotherapy (NACTRT) versus NACTRT with consolidation chemotherapy.
(B ) Subgroups of patients who received consolidation chemotherapy.
Prognostic Factors
In assessing prognostic factors, several baseline variables were considered in [Table 3 ]. On univariate analysis, histological types of signet ring (p < 0.001) and mucinous (p = 0.001), as well as clinical T stage (p < 0.001) and interruptions in radiation therapy (p = 0.020), were significant on multivariate analysis, only signet ring histology and
clinical T stage retained their statistical significance ([Table 3 ]). Among post-neoadjuvant Cape–RT pathological factors, ypT3–4 status (p = 0.000), ypN+ status (p = 0.000), LVI (p = 0.000), PNI (p = 0.000), EMVI (p = 0.001), TRG (p = 0.000), and achievement of PCR (p = 0.000), all were associated with reductions in OS. Upon multivariate analysis,
ypT and ypN status remained associated with reduced OS (p = 0.007; 95% CI, 1.073–1.574). Consolidation or adjuvant chemotherapy status was
not associated with survival outcomes.
Table 3
Univariate analysis of selected prognostic factors for overall survival
Characteristic
p -Value (univariate analysis)
p -Value (multivariate analysis)
Hazard ratio (95% CI)
Pretreatment factors
Signet ring histology
0.000
0.004
0.437–0.850
Mucinous histology
0.001
0.379
0.607–1.209
T stage
0.000
0.000
1.251–1.929
N stage
0.269
–
–
Interruption in RT
0.020
0.102
0.459–1.073
Post-Cape–RT factors
ypT status
0.000
0.007
1.073–1.574
ypN0
0.000
0.000
1.622–3.174
LVI
0.000
–
–
PNI
0.000
0.966
0.844–1.194
EMVI
0.001
0.550
0.878–1.277
TRG status
0.000
0.828
0.829–1.161
Pathological CR
0.000
0.89
0.935–2.584
Adjuvant chemotherapy completed
0.224
0.150
0.882–2.269
Abbreviations: Cape–RT, capecitabine radiotherapy; CI, confidence interval; CR, complete
response; EMVI, extramural venous invasion; LVI, lymphovascular invasion; PNI, perineural
invasion; TRG, tumor regression grade.
Discussion
Before the German Rectal Cancer Study Group (GRCSG) trial, adjuvant chemoradiation
therapy was commonly used as the standard treatment for resectable rectal cancer.[13 ]
, This combined approach was based on the rationale that it could improve survival
outcomes significantly compared with surgery alone, which had been the standard curative
therapy for resectable cancers.[14 ]
Based on the GRCSG trial, the NACTRT with conventional fraction RT is associated with
significant downstaging, higher rates of sphincter-sparing surgery, and decreased
pelvic relapse rates with similar disease-free survival (DFS) and OS compared with
postoperative chemotherapy.[15 ] The NSABP R-03 trial showed an increased trend toward better OS.[16 ]
Three randomized trials comparing short-course Swedish-style RT with conventional
fractionation long-course CRT found comparable outcomes in local recurrence, DFS,
distal recurrence, OS, and toxicity.[17 ] The Polish trial (316 patients) showed similar rates of sphincter preservation but
a higher PCR rate and fewer cases of radial margin positivity with long-course CRT.[18 ] The TROG 01.04 trial (326 patients) also demonstrated a higher PCR rate with long-course
CRT but no significant differences in local recurrence, distant recurrence, survival,
or toxicity.[19 ] A subset analysis of distal tumors showed higher local recurrence with short-course
RT. Still, a meta-analysis found no significant difference in low-lying tumors (<
5 cm from the anal verge).
Regarding the choice of chemotherapy regimen during RT in rectal cancer, infusional
5-FU or capecitabine is preferred over bolus FU due to higher rates of PCR.[20 ] Capecitabine, in particular, has shown therapeutic equivalence to infusional FU
with a different toxicity profile.[21 ] Studies, like the phase III German trial, demonstrated similar local recurrence
rates but lower distant metastasis rates with capecitabine.[22 ] Despite increased side effects like hand-foot skin reactions and fatigue, capecitabine
maintains noninferiority in OS compared with FU.[22 ] Its oral administration and comparable efficacy make capecitabine a favorable choice
during CRT in rectal cancer, highlighting its importance as a convenient and effective
treatment option.[22 ]
In this study, we reviewed our institutional data from a less resource setting where
most patients present with advanced disease requiring intense treatments. The toxicity
profile and compliance to CRT were similar to Western data and randomized studies.
The patient cohort in this study presented several unfavorable characteristics, including
a notable prevalence of poorly differentiated histology (26%), baseline CRM positivity
(50%), and extra mesorectal lymph nodes positivity (29%). These high-risk tumors had
a limited response. Poststandard CRT, approximately 23% of all patients still seem
to have a CRM positivity in our cohort.
This emphasizes the unmet need to consolidate response further using neoadjuvant chemotherapy
to improve the resectability rates, which leads to the concept of TNT.
TNT for LARC involves preoperative oxaliplatin-based chemotherapy and RT, followed
by surgical resection. This approach is recommended for patients with specific clinical
features such as T4 or N2 disease, low-lying tumors, or EMVI. TNT aims to improve
resectability, PCR rates, and organ preservation. A randomized trial (PRODIGE 23)
demonstrated that TNT improved DFS and PCR rates compared with neoadjuvant CRT alone.[6 ] Overall, TNT offers promising outcomes for LARC patients, with improved DFS and
PCR rates compared with standard neoadjuvant CRT alone.[23 ]
In our cohort, again, the tolerance, compliance, and toxicity rates for consolidation
chemotherapy as TNT and adjuvant chemotherapy were similar to those published in Western
data from randomized trials. Our cohort did not show OS benefit with the addition
of consolidation chemotherapy, probably because it was added selectively to patients
who did not respond adequately to CRT and a limited sample size.
Real-world data outcomes help determine whether outcomes observed in clinical trials
would happen in real-life clinical practice. The data presents safety and applicability
of consolidation chemotherapy in select cohort of patients. While we show outcomes
in patient who did and who did not receive consolidation chemotherapy based on our
subjective criteria, and use of adjuvant chemotherapy to eligible patients by postoperative
findings, it does not inform us how the outcomes would have been different if consolidation
chemotherapy was offered to all patients irrespective of response like TNT studies,
or if something else (such as surgery) was offered to the poorly responding patients
who received consolidation chemotherapy. We hope, still this practice information
may help patients receive more appropriate treatment that is closer to their needs
and wishes as per available local expertise and resources as offering TNT-based chemotherapy
to all patients may not be always feasible in all settings. There are limited studies
regarding implementing TNT approaches in the real world. Recently, an international
real-world study of TNT was published in abstract form comprising over 1,200 patients
from Europe, Asia, North America, and South America.[24 ] However, the choices of TNT and practice had significant heterogeneity from clinical
trials, which is attuned with possibilities tested in various trials and clinical
judgment at local centers. At a median follow-up of 2 years, consistent tolerance
and impact on outcomes were observed in clinical trials. There is no similar data
available from countries with fewer resources, such as India; hence, this report is
significant.
Several limitations must be acknowledged in this study. First, the data were collected
retrospectively from a single tertiary cancer referral center, which may introduce
biases such as referral bias, recollection bias, limited data availability, lost to
follow-up, and changing practice trends, which may make it difficult to simulate a
true clinical trial situation. Despite these lacunae, this is one of the largest real-world
data for rectal cancer to date and would provide valuable confidence in the safe implementation
of the practice of TNT in resource-constrained settings like ours. Although the impact
of TNT on outcomes was not as impressive as in clinical trials, it needs to be remembered
that we implemented consolidation chemotherapy only in a select group of poor biology
nonresponding patients, unlike clinical trial patient groups.
Conclusion
In this large cohort of approximately 1,200 LARC patients from a single institute,
we present long-term, real-world data from a country with fewer resources where outcomes
match published prospective and Western real-world data. This provides confidence
in implementing consolidation chemotherapy in total neoadjuvant settings in countries
with fewer resources.
