Keywords
overall survival - toxicity - drug metabolism - geriatric patients - ctDNA - MRD
Introduction
Adjuvant chemotherapy (CT) has shown survival benefit in stage 3 and selected stage
2 colon cancers.[1] Initially, fluoropyrimidines were given and later addition of oxaliplatin was found
to be useful (Mayo and Degramont).[2] In the MOSAIC trial, the standard arm of fluorouracil plus leucovorin (LV5FU2) was
compared to the study arm where oxaliplatin was added (FOLFOX4) in the adjuvant setting
for stage II and III colon cancer.[3] Among 2,246 patients, the 6-year overall survival (OS) was 78.5% in the FOLFOX4
arm and 765 in the standard arm of LV5FU2 (p = 0.046). The 5-year disease-free survival (DFS) was also better for the study arm
(73.3% for FOLFOX4 and 67.4% for LV5FU2 group patients; p = 0.003). And the 6-year OS rates were 78.5% with FOLFOX4 and 76.0% with LV5FU2 (p = 0.046). In the FOLFOX4 arm incidence of grade 3 peripheral sensory neuropathy was
1.3% at 12 months after treatment and 0.7% at 4 years. This data cemented the value
of FOLFOX4 in the adjuvant management of stage II or III colon cancer.
However, protocols with more drugs and a longer duration, leads to significant toxicities
affecting quality of life (QoL), the classic example being protocols containing irinotecan
that failed. More recent studies are designed to replace intravenous infusions with
user-friendly oral-based regimens and shorten the duration of adjuvant CT. We present
an updated review for the current management of adjuvant therapy of colon cancer.
Three versus Six Months Adjuvant Therapy
Six months of adjuvant CT has been the standard of care in colon cancer, duration
of which would be either 8 cycles of 3 weekly CAPOX or 12 cycles of 2 weekly FOLFOX.[3]
[4] The toxicities associated with longer duration, especially cumulative neurotoxicity
with oxaliplatin, is troublesome to most patients.[5]
[6] Reducing the duration of adjuvant CT reduces toxicities. It also helps economically
(especially the health care budget) in countries where the funding of treatment is
undertaken by the government. Other than doing dose modifications for dose-limiting
toxicities the scenario remained unchanged—until the International Duration Evaluation
of Adjuvant Chemotherapy (IDEA) study results came in 2017.[7]
[8] The pooled analysis of six randomized controlled trials done concurrently included
data from SCOT (U.K., Denmark, Spain, Sweden, Australia, New Zealand), TOSCA (Italy),
Alliance/SWOG80702 (U.S., Canada), IDEA (France), ACHIEVE (Japan), and HORG (Greece).[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16] This included 12,834 patients with stage 3 colon cancer. A total of 40% of the patients
received CAPOX and the remaining 60% FOLFOX. Three months of CAPOX was noninferior
to 6 months (hazard ratio [HR] = 0.95; 95% confidence interval [CI], 0.85–1.06) but
3 months of FOLFOX was inferior to 6 months (HR = 1.16; 95% CI, 1.06–1.26). Grade
2 to 4 toxicities (especially neurotoxicity and diarrhea) were lesser in the 3 months
arm as expected. Patient compliance and completion of planned therapy was also more
in the 3 months arm. The results allowed us to divide patients into low-risk colon
cancer group (T1 to T3 and N1; 60% of patients) and high-risk colon cancer group (T4
and/or N2).
The TOSCA noninferiority phase 3 randomized clinical study evaluated 3 versus 6 months
of FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine plus
oxaliplatin) in the adjuvant setting for patients with high-risk stage II resected
colorectal cancer (CRC). The 5-year relapse-free survival (RFS) data was in 1,254
evaluable patients. A total of 776 patients (61.9%) received FOLFOX and 478 (38.1%)
received CAPOX. The 5-year RFS was 82.2% for the 3-month arm and 88.2% for the 6-month
arm (p = 0.86 for noninferiority), as confirmed in the pooled analysis.[17] For FOLFOX, the data supported the longer duration of 6 months. This was associated
with neurotoxicity being five times higher in the 6 months arm. The final recommendation
was to use 3 months of CAPOX or 6 months of FOLFOX, when opting for oxaliplatin doublet
adjuvant therapy.
The phase 3 SCOT randomized clinical trial had also compared 3 versus 6 months of
CT in the adjuvant setting. This was also for high-risk stage II or stage III nonmetastatic
CRC patients with potentially curative surgery. The key difference was that patients
were also analyzed for early or late commencement of the adjuvant therapy (with respect
to surgery—less than 6 weeks vs. more than 6 weeks). Of the 5,719 patients, 914 were
in the early-start group and 4,805 were in the late-start group. If adjuvant CT was
commenced more than 6 weeks after surgery, DFS (primary endpoint of the study) was
worse (p = 0.01) ([Table 1]).[18]
Table 1
What should be the duration of adjuvant therapy—evidence from published trials[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
|
Trial
|
Common regimen
|
3 y DFS
3 vs. 6 mo
|
Additional remarks
|
|
SCOT
|
CAPOX
|
76.7% vs. 77.1%
|
Noninferior
CAPOX- noninferior
FOLFOX- not noninferior
Neuropathy more in 6 months
|
|
TOSCA
|
FOLFOX
|
81.1 vs. 83
|
6 months better
|
|
ACHIEVE
|
CAPOX
|
79.5 vs. 77.9%
|
3 months for low risk
6 months for high risk
|
|
IDEA
|
mFOLFOX6
|
72.1 vs. 75.7
|
6 months superior to 3 months
|
|
HORG
|
CAPOX
|
77.2 vs. 77.9
|
6 months better in high risk
|
Abbreviation: DFS, disease-free survival.
The sustained benefit of CAPOX poststoppage could be due to adherence to intended
dose intensity and higher dose of oxaliplatin (130 vs. 85 mg/m2).
The IDEA investigators and the ESMO committee divided patients into “fighters” (only
prepared to accept a 1–2% reduction in efficacy when using 3 months adjuvant therapy)
or “fatalists” (prepared to accept a > 2% reduction in efficacy). Suggested treatment
recommendations (in four scenarios) are shown in [Table 2]. In 2020, updated results of the IDEA data showed 5 year OS rate was 82.4% in the
3 months arm and 82.8% in the 6 months arm (absolute 5-year OS difference of –0.4%
[95% CI –2.1 to 1.3%]). Hence, the recommendations remained unchanged.
Table 2
Management recommendations for fatalists versus fighters
|
High-risk fatalist
3 months CAPOX
|
N2 high-risk fighter
Majority 3 months CAPOX
Minority 6 months CAPOX
|
|
T4 high-risk fighter
6 months CAPOX/FOLFOX
|
Low-risk fighter
3 months CAPOX
|
CAPOX versus FOLFOX
CAPOX and FOLFOX are the two commonly practiced adjuvant CT regimes in colon cancer.
Preference between the two varies on logistics and institutional practice majority
of the times. Despite being only two common regimens there are no good randomized
controlled trials comparing the two, especially using uniform dosing of 5FU, oxaliplatin,
or capecitabine. The advantages of CAPOX regime are oral route, can be given on day
care basis, no continuous infusions, no central lines or port insertions requirement,
reduced risk of thrombophlebitis, or coronary vasospasm. There are differences in
toxicity between the two regimens.[19]
[20] While patients on FOLFOX had increased mucositis and neutropenia, CAPOX was associated
with increased diarrhea and hand–foot syndrome.[21] Aitini et al did a cost analysis study to do an economic comparison between CAPOX
and FOLFOX.[22] They found that central line resulted in 70% cost in infusional regimes and one
cycle of CAPOX was 53% cheaper than FOLFOX. Hence, in resource-limited countries CAPOX
would be more economically feasible. Impact on QoL should also be taken into consideration
based on unique features of individual patients and their preferences.[23]
A recently published systematic review looked at 543 published articles and analyzed
the 29 ones that met their criteria.[24] These collectively included 7,028 patients. In general, the results of the eligible
studies indicated that adjuvant therapy after resection of colorectal liver metastases
led to improved RFS/DFS rates, but this benefit did not contribute to a statistically
significant prolongation of OS.
Patient Selection
As we have seen, about a third of patients with resectable/early CRC relapse in spite
of receiving current standard of care. On the other hand, several potentially cured
cases might be subject to toxicities of unnecessary therapy. Hence, there is a need
to find better means of identifying high-risk patients that require adjuvant CT.
Are Warburg Categories Useful?
The Netherlands Cohort Study involved 1,793 patients.[25] This highlighted the importance of using Warburg categories to identify high-risk
patients. Warburg-low CRC did not benefit from adjuvant CT (HRCRC-specific 1.07; 95% CI 0.76–1.52, HRoverall 0.95; 95% CI 0.70–1.30). On the other hand, Warburg-moderate CRC (HRCRC-specific 0.64; 95% CI 0.47–0.86, HRoverall 0.61; 95% CI 0.47–0.80) and possibly Warburg-high CRC (HRCRC-specific 0.86; 95% CI 0.65–1.14, HRoverall 0.82; 95% CI 0.64–1.05) had survival benefit from adjuvant therapy.
What if the Patient Had Obstructive CRC and Has Already Undergone Stent Placement?
Matsuda et al reported on 129 such patients in a retrospective study.[26] The 3-year RFS between those that did not get adjuvant CT (56.4%) and those that
did (78.5%) was in favor of giving adjuvant CT even in this subgroup (p = 0.003). The data was stronger for patients with high-risk features (high carcinoembryonic
antigen, T4, and lymphovascular invasion).
What about Biomarkers in Identifying High-Risk Patients?
Williams et al reports on the role of CD3 and CD8 in tumor tissue of 868 patients
receiving adjuvant CT in the QUASAR trial.[27] Using artificial intelligence (AI), they showed that risk of recurrence was double
in tumors having all parameters of high risk (CD3-CT: rate ratio, 2.00, p = 0.0008; CD3-IM: 2.38, p < 0.00001; CD8-CT: 2.17, p = 0.0001; CD8-IM: 2.13, p = 0.0001). This was seen in both the training set as well as the validation group.
Similarly, Jiang et al published their data on pathomic signatures in a retrospective
study that indicated benefit of adjuvant CT.[28] A total of 114 pathomic features were identified in hematoxylin and eosin-stained
slides of 785 patients using Cox regression model. Patients with a low pathomic signature
benefited more from CT (DFS p = 0.001; OS p < 0.001).
Other studies looking at analysis of resected tumor tissue focused mainly on mutational
or transcriptomic signatures. No robust prognostic biomarkers could be identified
as yet. However, the application of recent AI-driven tools and refined digital imaging
is expected to make available new algorithms that could stratify patients into clinically
meaningful distinct prognostic groups.[29]
What about Older Patients (Whose Life Expectancy is Limited)?
Okamoto et al published the results of adjuvant CT in 1,138 Japanese patients operated
for high-risk stage II or stage III CRC.[30] Patients were analyzed according to age (cutoff 70 years) and adjuvant chemotherapeutic
regimens. Older patients (N = 507; 45% ≥ 70 years old) were less likely to receive adjuvant CT (p < 0.001). Survival was longer in the younger age group patients (p = 0.006); especially if they received adjuvant CT (p = 0.005). The outcome was not different between the various adjuvant CT used.
Another Surveillance, Epidemiology, and End Results evaluation of 90,347 CRC geriatric
patients (more than 70 years of age) showed that the use of appropriate surgery led
to better OS (significant in the whole group as well as age-stratified analysis of
four age groups [70–74, 75–79, 80–84, ≥ 85; all p < 0.001]).[31] Use of adjuvant therapy was also significant prognostic factor for OS in the elderly
CRC patients (all p < 0.001). Survival advantage with adjuvant CT was maximum for stage III and IV colon
cancer patients. Among rectal cancer patients, the OS benefit was seen with adjuvant
chemoradiotherapy (stage II, III, and IV cases).
Impact of Drug Metabolism
Single-nucleotide polymorphisms (SNPs) in dihydropyrimidine dehydrogenase (DPYD) and
other genes involved in the metabolism and bioavailability of 5FU influence blood
levels, efficacy, and especially toxicity.[32]
[33]
[34]
[35]
[36] Systematic review of published literature (13,929 patients) showed that the incidence
of DPYD variants (heterozygous or homozygous) was in 4.1% of patients.[32] It was associated with treatment-related deaths in 0.1% in patients without identified
DPYD variants and 2.3% of those with known DPYD variants. Another cohort study included
161 patients. It showed that CES1 rs71647871-A phenotype led to severe hand–foot syndrome
(p = 0.030; GG vs. A) and CDA rs1048977-CC (p = 0.030; T vs. CC) was associated with toxicity-related interruption of capecitabine
monotherapy (p = 0.003).[33]
Pooled Indian data from 2,000 patients indicated that V732I, S534N, and rs3918290
variants were associated with 5FU/capecitabine toxicity, whereas C29R, I543V and M166V
variants did not lead to extra toxicity.[34]
Pavitran reported on common variant in Asian population (c.496A > G). In his series,
47 /375 (12.5%) had DPYD mutation (32/47 mutation variant c.496A > G; 15/47 mutation
IVS14 + 1 G > A). A total of 35 out 47 (74.5%) patients had grade II to III toxicity
even after dose reduction during first CT cycle. This included acute myocardial infarct,[1] febrile neutropenia,[4] neutropenia,[25] hand–foot syndrome,[18] diarrhea,[15] and mucositis.[7]
[35]
Minimal Residual Disease (MDR) and Adjuvant CT
A systematic review of adjuvant CT randomized trails found 1,469 publications of which
18 were eligible for analysis.[37] This included 16,682 patients. Among those with stage II to IV CRC, better RFS was
attributed to early divergences during active cytotoxic CT. Adjuvant CT did not seem
to reduce the risk of late recurrences. Hence, there is a need to find better biomarkers
to identify patients likely to benefit most from adjuvant CT.[29]
[38]
The CIRCULATE-Japan GALAXY observational trial involved medial follow-up of 23 months
in 2,240 patients.[38] It showed that circulating tumor deoxyribonucleic acid (ctDNA) positivity correlated
with inferior DFS (p < 0.0001) and OS (p < 0.0001). This was also true for patients who converted to ctDNA positivity while
on follow-up (shorter OS; p < 0.0001). On the other hand, if ctDNA clearance persisted, the 24-month DFS was
better (89.0% vs. 3.3%) and the 24-month OS was also better (100.0% vs. 82.3%).
Chidharla et al reported on a meta-analysis of postsurgical ctDNA among patients with
stage I to IV (oligometastatic) CRC after they had undergone curative resection.[39] This included 23 studies and 3,568 patients. Pooled analysis for RFS in postop ctDNA
positive cases was inferior (p < 0.00001).
Adjuvant Immunotherapy
It is well established that immunotherapy has an important role in metastatic CRC
having mismatch repair deficient or microsatellite instability-high (dMMR/MSI-H) tumors.
What about nonmetastatic CRC? Burley et al reported on dMMR/MSI-H stage III CRC treated
with definitive surgery and adjuvant oxaliplatin-based CT that had early recurrence.[40] This was associated with persistently high plasma ctDNA levels. Change in therapy
to pembrolizumab (immune checkpoint blockade) led to ctDNA clearance.
Conclusion
Adjuvant therapy in CRC is constantly evolving. Accumulation of data over the years
has enabled us to better identify patients that would benefit most from such an approach.
Whether to give treatment for short or long duration is also being refined. Individualizing
patient management allows us to meet their preference with minimal toxicity and better
QoL. Molecular monitoring allows a more precise decision making. Use of AI tools and
algorithms may further improve outcomes in the future.
