Abstract
Background
Although incidence and mortality rates of colorectal cancer have progressively decreased during the past decades, early-onset rectal cancer (EORC; <50 years old) is rising alarmingly. EORC is often diagnosed at advanced stages and presents intrinsic molecular alterations. New strategies are necessary to increase early diagnosis and to improve therapeutic management. We present the analysis of our locally advanced EORC patients evaluating their specific response to chemoradiotherapy.
Materials and methods
Patients diagnosed with locally advanced rectal cancer (LARC) and treated with curative surgery after neoadjuvant treatment (NAT) with chemoradiotherapy were retrospectively analysed, comparing differences between EORC and late-onset rectal cancer (LORC). Incidence rates between 2001 and 2020, as well as diagnostic and treatment response variables, were compared.
Results
Up to 1140 patients were diagnosed with rectal cancer and underwent curative surgery. From them, there were 399 patients with LARC who received NAT before surgery, and 9% of them had EORC (36 patients). The incidence of locally advanced EORC increased from 6.6% to 12.7% (2001-2020). No differences were found considering diagnostic variables between the early- and late-onset cohorts, although slightly more deficient mismatch repair tumours were found within the EORC cohort. Mean disease-free survival and mean cancer-specific survival were similar. Notwithstanding, EORC patients achieve higher rates of pathological complete responses (pCRs), compared with LARC (36.3% versus12.4%; P = 0.000).
Conclusions
Our analyses confirm the increase in incidence of EORC from 2001 to 2020 in Navarra. EORC patients achieved a higher pCR rate, thus suggesting that the role of organ preservation strategies should be further investigated in this unique population.
Key words: early-onset rectal cancer, neoadjuvant treatment, pathological complete response, organ preservation strategies, population screening programmes
Highlights
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Incidence of EORC is progressively increasing in Navarra, similar to many countries worldwide.
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This evidence indicates an urgent need to advance the age for starting population screening programmes.
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Disease-free survival and cancer-specific survival were similar between EORC and LORC patients.
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A higher pCR was achieved in patients with EORC.
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Potential organ preservation strategies may be considered for this young population.
Introduction
Colorectal cancer is the second most common cause of cancer-related death and the third most common cancer worldwide.1 Early-onset colorectal cancer (EOCRC), defined as cancer occurring in patients younger than 50 years old, is rising alarmingly. Although this is partially correlated with genetics, it is more often sporadic and thus, partially associated with changes in lifestyle factors and diet.2,3 Actually, EOCRC accounts for ∼10% of all new diagnoses, but it is estimated that 25% of rectal cancers and 10%-12% of colon cancers will be diagnosed in adults younger than 50 years of age in the next 10 years.4,5
EOCRC typically occurs in the distal colon and rectum, while associated precursor adenomatous lesions are less frequent.6 This is relevant due to increasing evidence that right colon cancers differ biologically from left colon and rectal cancers.7 Young patients are often diagnosed with advanced clinical stages (stages III and IV) and have tumours with more frequently aggressive phenotypes, including poor differentiation and signet ring cell histology, as well as presenting higher rates of relapse.8 From a molecular point of view, data are contradictory, although an increase in microsatellite unstable tumours has been described,4 with less mutations in APC, KRAS and BRAFV600E and more alterations in CTNNB1.9 The role of TP53 alterations is unclear.10 Mutations in TP53 and KRAS are associated with an adverse response to neoadjuvant treatment (NAT),11,12 while mismatch microsatellite instability (MSI) is associated with contradictory responses to neoadjuvant chemotherapy and chemoradiotherapy13 but with very impressive positive response to immunotherapy.14,15
However, disease onset in younger patients is not considered in the current therapeutic algorithms for diagnoses and treatment of locally advanced rectal cancer (LARC). Young patients should be treated as a sensitive population due to their stage in life, with other priorities (body image, career development, reproductive functions, family concerns), which should be taken into account when considering acute and long-term sequelae of conventional treatment of rectal cancer. Avoiding surgical interventions with potential harsh consequences would probably improve their quality of life. The current studies considering potential organ preservation strategies after total neoadjuvant therapy16 raise the importance of specifically evaluating the grade of response in young patients. With retrospective data showing no additional oncological risks in young patients, compared with their on-average counterparts,17 watch and wait could potentially be considered in young patients who have a complete clinical response to NAT.
This study analyses the largest cohort of LARC patients treated with neoadjuvant long-course radiotherapy plus chemotherapy in Spain (2001-2020), with a primary focus on evaluating the response rate of patients younger than 50 years of age compared with patients ≥50 years old. Rates of incidence in the following years and clinicopathological characteristics are also described, thus contributing to the knowledge of EOCRC.
Materials and methods
Data from patients diagnosed with LARC were retrospectively extracted from a prospective collected dataset of the Multidisciplinary Colorectal Cancer Unit of our institution. The study cohort was divided into two sub-cohorts: younger than 50 years old (early-onset cohort) and 50 or older (late-onset cohort). The cut-off of 50 years was adopted, as it is widely recognized as the age for the early-onset gastrointestinal cancer3 definition.
After histological confirmation, the diagnosis was established based on a standard rectal cancer work-up with a colonoscopy, a chest and abdominal computed tomography scan, the carcinoembryonic antigen (CEA) level and a pelvic magnetic resonance tomography. Tumours lying at or below 0 and 5 cm were defined as being in the lower third of the rectum, those between 6 and 10 cm in the middle third and those between 11 and 15 cm in the upper third. NAT was the same for all early- and late-onset LARC, and included a long course of radiotherapy (50 Gy; 2 Gy per fraction) with concomitant fluoropyridine chemotherapy (capecitabine 825 mg/m2/12 h twice daily, 7 days per week). Surgery based on a total mesorectal excision was carried out at an interval of 6-10 weeks following NAT. A total mesorectal excision was offered to patients with tumours located in the lower or middle third of the rectum. Instead, the mesorectum was removed up to a distance of 5 cm beyond the malignant lesion in patients with tumours located in the upper third of the rectum. The decision to administer adjuvant chemotherapy was individualized to each patient.
Mismatch repair (MMR) protein immunohistochemistry was carried out in the diagnostic rectal cancer biopsy, using the standard streptavidin–biotin–peroxidase procedure. MMR immunohistochemistry antibodies included MLH1 (Ventana, clone M1), MSH2 (Cell Marque, clone G219.1129), MSH6 (Ventana, clone 44) and PMS2 (BD Biosciences, clone A16.4). Normal expression was defined as nuclear staining within tumour cells, using infiltrating lymphocytes as positive internal control. Negative protein expression was defined as the complete absence of nuclear staining within tumour cells in the face of concurrent positive labelling in internal non-neoplastic tissues. Diagnosis of deficient mismatch repair (dMMR) was defined when at least two of the four proteins’ expression was lost. If tumour growth was found within 1 mm of the circumferential margin, it was reported as involved.
Histopathological examination of the resected specimen was carried out according to a standard protocol. Grade was scored using a four-tiered scheme: grade 1—well differentiated (>95% gland formation), grade 2—moderately differentiated (50%-95% gland formation), grade 3—poorly differentiated (<50% gland formation) and grade 4—undifferentiated (no gland formation or mucin; no squamous or neuroendocrine differentiation). Staging was carried out according to the TNM (tumour–node–metastasis) classification. The evaluation of the pathological tumour response to NAT was carried out based on Mandard’s classification.18 Pathologic complete response (pCR) was defined as no viable tumour cell in the surgical specimen.
Variables
Patient data, including age, sex, body mass index (BMI), pre-treatment CEA level, rectal tumour location, tumour grade in endoscopic biopsy, MMR protein expression, ypT stage, ypN stage19, 20, 21 according to in-time TNM editions (“T” focuses on the invasion depth of the primary tumor, “N” number of lymph nodes affected, “y” indicates staging postneoadjuvant treatment and “p” indicates surgical staging),22, 23, 24 circumferential resection margin status (CRM) and presence or not of pCR were recorded. Pre-treatment CEA level was dichotomized according to its normal (≤5 ng/ml) or elevated value.
Statistical analysis
The categorical variables are described in absolute numbers and in percentages. We assessed whether there was a correlation between the recorded variables and pCR using a univariate and multivariate logistic regression. The log-rank test was used to evaluate means and medians of the variables in relation to disease-free survival and cancer-specific survival. The association between variables and disease-free and cancer-specific survival was evaluated using a univariate and multivariate Cox model regression. Considering the relatively short follow-up of patients diagnosed in the last years of the recruitment (2015-2020), and with the intention of minimizing potential differences in survival secondary to disparate follow-up time of patients, living patients were censored at 120 months. Significant or near-significant variables in the univariate analysis (P < 0.2) and cohorts study based (early-onset versus late-onset) were included in the multivariate analysis. The IBM SPSS Statistics 25 system (IBM, Armonk, NY) for Windows was used for statistical calculations.
This study was approved by the Research Ethics Committee of the Hospital Universitario de Navarra (HUN), Pamplona (PI_2023/66).
Results
Between January 2001 and December 2020, 1140 patients were diagnosed with rectal cancer and underwent surgery with curative purpose at HUN in Pamplona, Spain. Of them, 399 presented with locally advanced tumours (stage II-III) and underwent surgery after NAT (study cohort). Of these, 36 were younger than 50 years (early-onset cohort) and 363 were 50 or older (late-onset cohort).
Diagnosis rates of early-onset rectal cancer (EORC) increased from 2001 to 2020 (Table 1). Considering all patients, regardless of having received NAT or not, EORC rates increased from 3.5% in the first 5-year period (2001-2005) to 7.4% in the last 5-year period (2016-2020). When only considering patients with locally advanced tumours eligible for NAT treatment (the population study cohort), the increase was from 6.6% in the first period to 12.7% in the last period.
Table 1.
Incidence of EORC in consecutive 5-year periods
| 2001-2005 | 2006-2010 | 2011-2015 | 2016-2020 | Total | |
|---|---|---|---|---|---|
| Study cohort, n (%) | |||||
| Late onset | 99 (93.4%) | 75 (91.5%) | 100 (91.7%) | 89 (87.3%) | 363 (91%) |
| Early onset | 7 (6.6%) | 7 (8.5%) | 9 (8.3%) | 13 (12.7%) | 36 (9%) |
| Diagnosed LARCa, n (%) | |||||
| Late onset | 188 (96.5%) | 215 (93.8%) | 319 (94.9%) | 351 (92.6%) | 1073 (93%) |
| Early onset | 7 (3.5%) | 15 (6.2%) | 17 (5.1%) | 28 (7.4%) | 67 (6.2%) |
EORC, early-onset rectal cancer; LARC, locally advanced rectal cancer.
All LARC patients treated with curative surgery, regardless of having received neoadjuvant treatment or not.
Pre-treatment characteristics of both study population cohorts are shown in Table 2. There were no differences regarding sex, tumour location, tumour grade, pre-treatment CEA level or BMI. Patients from the early-onset cohort (n = 3; 8.6%) had a non-significant higher rate of dMMR tumours than patients from the late-onset cohort (n = 5; 2.5%) (P = 0.096). Diagnosis of Lynch syndrome was in two of the three EORC patients, whereas it was only in one of the late-onset rectal cancer patients.
Table 2.
Pre-treatment variables for both the study cohorts
| Early-onset group | Late-onset group | P value | |
|---|---|---|---|
| Gender, n (%) | |||
| Male | 23 (63.9%) | 256 (70.5%) | 0.447 |
| Female | 13 (36.1%) | 107 (29.5%) | |
| Pre-treatment CEA levels, n (%) | |||
| ≤5 | 27 (77.1%) | 254 (73.4%) | 0.693 |
| >5 | 8 (22.9%) | 92 (26.6%) | |
| Tumour location, n (%) | |||
| 11-15 cm | 5 (13.9%) | 52 (14.3%) | 0.315 |
| 6-10 cm | 10 (27.8%) | 144 (39.7%) | |
| 0-5 cm | 21 (58.3%) | 167 (46.0%) | |
| Body mass index, n (%) | |||
| <30 | 29 (80.6%) | 290 (79.9%) | 0.924 |
| ≥30 | 7 (19.4%) | 73 (20.1%) | |
| Tumour grade, n (%) | |||
| Grade 1-2 | 23 (92%) | 240 (87.9%) | 0.751 |
| Grade 3-4 | 2 (8%) | 33 (12.1%) | |
| MMR, n (%) | |||
| dMMR | 3 (8.6%) | 5 (2.5%) | 0.096 |
| pMMR | 32 (91.4%) | 199 (97.5%) |
CEA, carcinoembryonic antigen; dMMR, deficient mismatch repair; pMMR, proficient mismatch repair.
Pathological response
A pCR was evidenced in 59 patients (14.6%). Early-onset tumours [36.3% versus 12.4%, Odds ratio (OR) 0.232, 95% confidence interval (CI) 0.105-0.512, P = 0.000] and normal pre-treatment CEA levels (17.5% versus 7%, OR 3.323, 95% CI 1.377-8.020, P = 0.009) were related to a higher rate of pCR in the multivariate analysis (Table 3). Sustained pCR rates in EORC were found in three 5-year periods (Table 4).
Table 3.
Relation between variables and complete pathological response
| pCR | Non-pCR | Univariate OR(95% CI) P | Multivariate OR (95% CI) P | |
|---|---|---|---|---|
| Age, n (%) | ||||
| Later onset | 45 (12.4%) | 318 (87.6%) | 0.250 (0.118-0.529) | 0.232 (0.105-0.514) 0.000 |
| Early onset | 13 (36.3%) | 23 (63.9%) | ||
| Gender, n (%) | ||||
| Female | 18 (15.0%) | 102 (85.0%) | 1.054 (0.577-1.926) 0.863 | |
| Male | 40 (14.3%) | 239 (85.7%) | ||
| Pre-treatment CEA levels, n (%) | ||||
| ≤5 | 49 (17.4%) | 232 (82.6%) | 3.309 (1.371-7.985) 0.008 | 3.367 (1.365-8.303) 0.008 |
| <5 | 6 (6%) | 94 (94%) | ||
| Tumour location, n (%) | ||||
| 11-15 cm | 31 (16.5%) | 157 (83.5%) | 2.054 (0.759-5.556) 0.156 | |
| 6-10 cm | 22 (14.3%) | 132 (85.7%) | 1.733 (0.623-4.820) 0.292 | |
| 0-5 cm | 5 (8.8%) | 52 (91.2%) | 0.358 | |
| MMR, n (%) | ||||
| dMMR | 2 (25%) | 6 (75%) | 1.931 (0.374-9.968) 0.432 | |
| pMMR | 34 (14.7%) | 197 (85.3%) | ||
| Body mass index, n (%) | ||||
| <30 | 13 (16.3%) | 67 (83.7%) | 1.181 (0.603-2.314) 0.627 | |
| ≥30 | 45 (14.1%) | 274 (85.9%) | ||
| Tumour grade, n (%) | ||||
| Grade 1-2 | 36 (13.7%) | 227 (86.3%) | 1.692 (0.492-5.814) 0.404 | |
| Grade 3-4 | 3 (8.6%) | 32 (91.4%) | ||
| Period, n (%) | ||||
| 2016-2020 | 21 (20.6%) | 81 (79.4%) | 0.103 | 0.232 |
| 2011-2015 | 15 (13.8%) | 94 (86.2%) | 0.686 (0.335-1.404)0.302 | 0.856 (0.392-1.866) |
| 2006-2010 | 6 (7.3%) | 76 (92.7%) | 0.305 (0.117-0.795) 0.015 | 0.340 (0.125-0.926) |
| 2000-2005 | 16 (15.1%) | 90 (84.9%) | 0.616 (0.298-1.272) 0.190 | 0.810 (0.372-1.764) |
CEA, carcinoembryonic antigen; CI, confidence interval; dMMR, deficient mismatch repair; OR, odds ratio; pCR, pathological complete response; pMMR, proficient mismatch repair.
Table 4.
Pathologic complete response in study cohort in consecutive 5-year periods
| 2001-2005 | 2006-2010 | 2011-2015 | 2016-2020 | Total | |
|---|---|---|---|---|---|
| Pathologic complete response, n (%) | |||||
| Late onset | 99 (93.4%) | 75 (91.5%) | 100 (91.7%) | 89 (87.3%) | 363 (91%) |
| Early onset | 7 (6.6%) | 7 (8.5%) | 9 (8.3%) | 13 (12.7%) | 36 (9%) |
Follow-up
After a mean follow-up of 79 months (range 1-197 months), 89 patients from the study cohort population (22.3%) suffered recurrent disease and 74 (18.5%) died from rectal cancer. Thirteen patients (3.3%) had local recurrence, sixty-nine (17.3%) metastases and seven patients had both local and metastatic disease (1.7%). The mean disease-free survival was 96.5 months (95% CI 92.2-100.8 months). Median disease-free survival was not reached. Patients with ypN0 tumours [hazard ratio (HR) 0.373, 95% CI 0.228-0.609, P = 0.000] and normal pre-treatment CEA level (HR 0.459, 95% CI, 0.292-0.0.721, P = 0.001) had a significantly better disease-free survival in the multivariate analysis (Supplementary Table S1, available at https://doi.org/10.1016/j.esmogo.2023.100033).
The mean cancer-specific survival was 104.4 months (95% CI 101.0-107.8 months). Median was not reached. A better cancer-specific survival was significantly related to lower ypT stage (HR 0.446, 95% CI 0.233-0.853, P = 0.015), ypN0 stage (HR 0.487, 95% CI 0.286-0.829, P = 0.008), uninvolved CRM (HR 0.372, 95% CI 0.206-0.670, P = 0.001) and normal pre-treatment CEA level (HR 0.605, 95% CI 0.374-0.0.979, P = 0.041) in the multivariate analysis (Supplementary Table S2, available at https://doi.org/10.1016/j.esmogo.2023.100033).
No differences on disease-free survival or cancer-specific survival were found considering early- versus late-onset cohorts (Figure 1A and B).
Figure 1.
(A) Disease-free survival for patients in early-onset and late-onset cohorts. (B) Cancer-specific survival for patients in early-onset and late-onset cohorts.
Discussion
Although colorectal cancer mortality rates have been dropping throughout the last decades as a result of regular screening detection programmes and improved treatments, the incidence of colorectal cancer among younger adults (EOCRC; patients younger than 50 years) has nearly doubled in recent years2 (https://seer.cancer.gov/statistics-network; accessed May 2023).
EOCRCs are most commonly detected in the left colon and rectum.25 In a study from 20 European countries, rectal cancer incidence rates increased by 1.8% per year from 1990 to 2016, with the greatest annual percentage change among adults aged 20-29 years old.26 A retrospective cohort study using the Surveillance, Epidemiology, and End Results CRC registry shows an increasing incidence rate of rectal cancer in patients aged 35-49 years old. Based on this observed trend, it is estimated that by 2030 the incidence rates for rectal cancers will have increased by 124.2%, for patients 20-34 years old, and by 46.0% for patients 35-49 years old.27 Consistent with these data, our database shows an increase in the diagnosis of patients with post-surgical EORC from 3.5% in the first 5-year period (2000-2005) to 7.4% in the last 5-year period (2016-2020). When considering the study cohort specifically, only LARC patients treated with NAT before surgery, this increase is even worse, ranging from 6.6% to 12.7%. The HUN is the public hospital of reference for local and LARC in the whole province of Navarra. Thus, incidence of rectal cancer in Navarra can be legitimately extrapolated from the HUN comprehensive registry.
Taking into consideration the relatively low proportion of hereditary cases among these cases, a potential key role of environmental and behavioural factors may partially explain its pathogenesis.3 Genetic de novo alterations, environmental factors, lifestyle changes including obesity, a diet high in red or processed meat and lack of physical activity are possible causes. A study from 89 278 women, aged 25-42 years old, showed an adjusted relative risk (RR) of 1.93 (95% CI 1.15-3.25) when BMI was ≥30 kg/m2.28 However, this finding regarding BMI has not been confirmed in our study or by others.29,30 These discrepancies can be partially explained by other confounding factors associated with BMI, such as those related to the Western diet,31 sugar-sweetened beverages32 or sedentary lifestyle.33 Finally, non-alcoholic fatty liver disease has also been correlated with EOCRC.34
When considering the aetiology, a very low percentage of EOCRC is associated with hereditary syndromes. A recent study found that 16% of patients with EOCRC had at least one pathogenic cancer susceptibility gene mutation, half of them with Lynch syndrome.35 MSI-high (MSI-H) status is derived either due to germline mutations in MMR genes or to epigenetic inactivation of the MLH1gene.35,36 MSI-H status has been described in EOCRC with variable rates ranging from 1.5% to 7.8%.37,38 In our study, we found a non-significant higher rate of dMMR tumours within the early-onset cohort, compared to the late-onset (8.6% versus 2.5%, P = 0.097).
Finally, early-onset CRCs have been associated more frequently with adverse histopathological features, which are consequently associated with worse oncological outcomes. Data from over 47 791 patients from the SEER database showed a higher rate of poorly differentiated tumours (27.3% versus 17.2%, P < 0.001) or anaplastic disease (1.6% versus 0.7%, P < 0.001) in younger patients than in their older counterparts.39 In our study, we could neither confirm differences in tumour grade nor in pre-treatment CEA levels.
pCR after NAT has been described as a strong indicator of outcome in rectal cancer. We found a pCR in 14.7% in all our LARC patients treated with NAT, which is similar to what has been previously published.40 Patients from the early-onset cohort presented a significantly higher rate of pCR compared with patients from the late-onset cohort, in the multivariate analysis (36.3% versus 12.4%, OR 0.232, 95% CI 0.105-0.512, P = 0.000). Possible mechanisms underlying this finding are related to intrinsic molecular and clinical features.
Firstly, the improvement on neoadjuvant and surgical treatments over time could have contributed to this higher pCR within the EORC cohort. After the pivotal trial published by Sauer et al., establishing neoadjuvant radiotherapy with concurrent 5-fluorouracil as the standard of care for LARC,41 a better protocol with a more prolonged interval between radiotherapy and surgery or use of capecitabine was implemented. Better pCR within our early cohort could be partially explained because of better treatment adherence and treatment that is administered at a higher intensity than is normally associated with younger patients, as shown by the analyses of the EOCRC patients from the IDEA database.8
Secondly, molecular causes may also have an impact. Tumours in younger patients show different molecular profiles than in older patients. Lieu et al. found that in microsatellite stable tumours, TP53 and CTNNB1 alterations were more common in younger patients while APC, KRAS, BRAF, and FAM123B were more commonly altered in older patients. Although rates of alterations in microsatellite genes were similar between young and old patients, when focusing on MSI-H tumours, alterations in APC and KRAS were more common in younger patients, while BRAF alterations were more common in older patients.9 These differences might partially explain differences in pCR rates. Mutations in TP53 and KRAS are associated with a worse response to NAT,42 while mismatch repair deficiency tumours are associated with a contradictory response as evidenced by a recently published work demonstrating how dMMR tumours correlate with a poor response to the neoadjuvant chemoradiotherapy.13 In the present study, we found a non-significantly higher rate of patients with loss of mismatch repair proteins in the early-onset group, mostly associated with Lynch syndrome. Due to the low number of patients, we were not able to demonstrate any correlation of the MMR status with the response to NAT.
Finally, and considering the age at diagnosis of EOCRC, these patients have an estimated longer life expectancy than older adults do. EOCRC represents a sensitive population, since these patients are still in career development and have sexual and reproductive considerations. Long-term treatment toxicities and survival expectations are especially important. In our study, the disease-free survival and the cancer-specific survival of patients with LARC treated with NAT, followed by surgery, were similar between the early- and late-onset cohorts, in line with what has been previously published.43 Disease-free survival was related to the ypN stage and pre-treatment CEA level. Likewise, cancer-specific survival was related to ypT stage, ypN stage, CRM involvement, pCR and pre-treatment CEA level, independent of the age at diagnosis.
Limitations of our study mainly include the small sample size and the shortcomings inherent to its retrospective nature and the relatively short follow-up period. While the analysed population was homogeneous, considering same schemas of neoadjuvant chemoradiotherapy and surgical procedures, this study lacks data concerning the patients’ treatment compliance. Although some clinical and molecular features are included, a better tumour characterization could have offered more context when interpreting our results.
Conclusions
In conclusion, to our knowledge this is the largest cohort of EORC patients analysed in Spain, with 67 early-onset out of 1140 late-onset diagnosed patients, and 36 early-onset out of 399, when considering only locally advanced stages. We demonstrated how the incidence of EOCRC has progressively increased from 2001 to 2020, in accordance with the literature, which suggests an urgent need for strategies advancing the age of screening programmes. Moreover, higher pCR has been demonstrated within EOCRC, thus revealing an important niche for potential organ preservation strategies in this especially sensitive population, which should be further investigated.
Acknowledgments
Funding
None declared.
Disclosure
MA: consulting fees: BMS and MSD; payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing or educational events: BMS and MSD. RV: payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing or educational events: Merck Sharp and Dohme, AstraZeneca. All the other authors have declared no conflicts of interest.
Supplementary data
References
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