Abstract
Aim
The incidence of early‐onset (age <50 years) rectal cancer (EORC) is rising globally, often presenting at an advanced stage. Total neoadjuvant therapy (TNT) is increasingly utilised in the management of advanced rectal cancers due to improved response and survival rates. However, it remains unclear whether EORC in an unscreened population responds similarly to TNT compared to average or late‐onset (age ≥50 years) rectal cancer (AORC).
Method
This study included consecutive patients treated with curative intent with TNT for rectal cancer at three South Australian hospitals between 2019 and 2024. Patients were divided into EORC and AORC cohorts. The primary outcome was overall complete response (oCR) rate, defined as the proportion of patients who achieved a clinical complete response (cCR) and/or pathological complete response (pCR). Secondary outcomes included compliance and treatment‐related toxicity.
Results
Of 202 eligible patients, 48 (23.8%) were in the EORC cohort and 154 (76.2%) in the AORC cohort. No significant difference in oCR rate was observed between EORC and AORC patients (43.8% vs. 37.9%, P = 0.470). cCR, pCR and complete M1 response rates were also similar between the two groups. EORC patients experienced significantly less Grade 3–4 chemotherapy‐induced toxicity compared to AORC patients (2.1% vs. 25.3%, P < 0.001), but reported higher rates of patient‐reported Grade 3–4 radiotherapy‐induced toxicity than AORC patients (31.3% vs. 12.3%, P = 0.004).
Conclusion
EORC patients exhibit comparable overall tumour response rates to AORC patients treated with TNT. However, toxicity profiles differ, with EORC patients experiencing less chemotherapy‐induced toxicity but more patient‐reported radiation‐induced toxicity.
Keywords: average‐onset, clinical complete response, early‐onset, pathological complete response, rectal cancer, total neoadjuvant therapy
What does this paper add to the literature?
Despite the rising incidence of early‐onset rectal cancer (EORC) and the increased use of total neoadjuvant therapy (TNT), data on EORC patients' responses to TNT are limited. This study demonstrates that EORC patients respond similarly to older patients but exhibit distinct toxicity profiles, including lower chemotherapy‐ and higher radiation‐induced toxicity.
INTRODUCTION
While the overall incidence of advanced colorectal cancer is declining in high‐income countries due to widespread adoption of organised population‐based screening [1, 2], the incidence of early‐onset rectal cancer (EORC) (defined as cancer in patients younger than 50 years) has been rising [3, 4]. By 2030, nearly one in four rectal cancers is expected to be EORC [5]. Although some cases in this unscreened population are linked to hereditary cancer syndromes and germline mutations, most are sporadic and may be influenced by environmental or lifestyle factors [6]. EORC patients often present with more advanced disease and worse histopathological features due to symptom‐driven diagnosis, compared to screening‐driven diagnosis in average‐onset rectal cancer (AORC) patients (aged 50 years and older) [7, 8].
There is conflicting evidence regarding pathological complete response (pCR) rates following neoadjuvant chemoradiotherapy (nCRT) in early‐onset patients with locally advanced rectal cancer (LARC) [9, 10, 11, 12]. Traditionally, LARC has been treated with nCRT followed by total mesorectal excision (TME) surgery and adjuvant chemotherapy. Recently, however, American guidelines have endorsed total neoadjuvant therapy (TNT) as the new standard of care, while European guidelines recommend TNT as the preferred treatment approach for high‐risk LARC patients [13, 14]. TNT encompasses a range of treatment strategies that differ based on the type of radiotherapy (long‐course vs. short‐course) and the sequencing of chemotherapy (induction vs. consolidation). TNT has shown improved clinical complete response (cCR) rates, allowing patients the option of organ preservation through non‐operative management (NOM). However, comparative data on responses to TNT by age group in patients with advanced rectal cancer are limited, and currently recommendations are generalised independently of age as a prognostic feature [15, 16]. Given that response rates and toxicity profiles may be quite different, it is unclear whether a one size fits all approach is valid.
This study aims to compare overall complete response (oCR), defined as the combined pCR and cCR rates, between EORC and AORC patients treated with TNT.
METHOD
Study design and patient selection
This multicentre prospective observational cohort study analysed adult patients (age ≥18 years) with histologically confirmed rectal cancer treated with curative‐intent TNT at three South Australian hospitals from 1 January 2019 to 24 September 2024. Clinical staging utilised pelvic MRI and chest, abdomen and pelvis CT according to American Joint Committee on Cancer guidelines [17]. Data on patient demographics, clinical characteristics, treatment delivery, compliance, toxicity and treatment response were prospectively collected by a consultant colorectal surgeon and a research officer. Patients were stratified based on their age at diagnosis: EORC (<50 years) and AORC (≥50 years), reflecting the age criteria for most international screening programmes [18]. Ethical approval was obtained from the Central Adelaide Local Health Network Human Research Ethics Committee (HREC reference number 11938) and St Andrew's Hospital Research and Ethics Committee (#117) and conducted in accordance with the principles of the Declaration of Helsinki. A waiver of consent was granted, and reporting followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement [19].
Treatment protocol
Patients were recommended for TNT following a multidisciplinary team (MDT) discussion at individual institutions. Two institutions used a personalised TNT protocol based on the patient's risk of local and distant failure at initial staging, while the third institution offered a predominantly consolidation TNT (cTNT) protocol [20].
High‐risk patients for distant failure (i.e., curative distant metastasis, extramural vascular invasion, abnormal mesorectal or lateral pelvic lymph node involvement) received induction TNT (iTNT). This included either eight cycles of mFOLFOX6 (infusional 5‐fluorouracil [5‐FU], leucovorin and oxaliplatin) over 16 weeks, five to six cycles of CAPOX (capecitabine and oxaliplatin) over 18 weeks, or nine cycles of pembrolizumab over 6 months for metastatic mismatch repair deficient (dMMR)/microsatellite‐instability‐high (MSI‐H) patient cases. Following this, patients received long‐course chemoradiotherapy (LC‐CRT), comprising 50 Gy of external beam radiation in 25 fractions over 6 weeks, with concurrent 5‐FU‐based chemotherapy, followed by a 10‐week wait period.
Patients at high risk for local failure (i.e., bulky local disease, T4 extension or low tumours) received cTNT. This consisted of LC‐CRT over 6 weeks, followed by six to eight cycles of mFOLFOX6 or four to six cycles of CAPOX over 12–18 weeks. Patients with dMMR/MSI‐H received iTNT with pembrolizumab for 6 months and were reassessed for LC‐CRT and potential TME surgery if there was an incomplete clinical response.
Restaging via CT, flexible sigmoidoscopy and pelvic MRI occurred within 8 weeks post‐LC‐CRT for the iTNT cohort to evaluate cCR and M1 response, and within 4 weeks post‐chemotherapy in the cTNT cohort to assess cCR. Patients achieving a cCR were offered NOM through a strict ‘watch and wait’ policy, while those with an incomplete clinical response were recommended for TME surgery. Under these circumstances, NOM was only considered if the patient declined surgery.
Outcomes
The primary outcome was oCR rate defined as the proportion of patients with either a cCR and/or pCR. A cCR was defined as the absence of a palpable tumour on digital rectal examination, no visible tumour and the presence of a white scar via flexible sigmoidoscopy, and an MRI tumour regression Grade 1 or 2, with no evidence of abnormal lymph nodes or extramural vascular invasion. pCR was defined as the absence of residual tumour cells in the surgical histopathological specimen.
Secondary outcomes included distant disease (M1) response, categorised as progressive disease, partial response or complete response based on CT restaging by the institutional MDT. Additional outcomes of interest were treatment compliance and toxicity. Chemotherapy‐related toxicity was graded according to the Common Terminology Criteria for Adverse Events (version 5) [21]. Skin toxicity from radiotherapy was assessed by physicians using the Skin Toxicity Assessment Tool (STAT, scale 0–5) and by patients using the Patient Symptom Scale according to the Radiation Induced Skin Reaction Assessment Scale [22, 23].
Statistical analysis
Analysis was performed in an intent‐to‐treat population. Data normality was assessed using the Kolmogorov–Smirnov test. Continuous variables are presented as mean (standard deviation) or median (interquartile range) and compared using the Student's t test or Mann–Whitney U test, as appropriate. Categorical variables are reported as frequencies with percentages and analysed using the χ 2 test or Fisher's exact test. All tests were two‐sided with a P value of <0.05 considered statistically significant. Data were analysed using SPSS for Windows, version 29.0.2.0 (Armonk, NY, IBM Corp.).
RESULTS
Between 2019 and 2024, 492 patients were diagnosed with rectal cancer, of whom 248 were eligible for curative‐intent TNT after MDT discussion. Seventeen patients refused chemotherapy, four died before treatment commencement and the oncologist chose not to administer the MDT‐suggested treatment in one case, resulting in 226 patients who underwent TNT. Among the 202 patients who completed treatment and restaging, there were 48 (23.8%) EORC and 154 (76.2%) AORC patients (Figure 1).
FIGURE 1.
Study flow chart.
Patient demographics and clinical characteristics are displayed in Table 1. Women comprised 31.3% of EORC and 35.1% of AORC patients. A significantly higher proportion of AORC patients were sarcopenic compared to EORC patients (28.6% vs. 10.4%, P = 0.011), while lateral pelvic lymph node involvement was significantly higher in EORC patients (31.3% vs. 17.5%, P = 0.041). Other demographics and clinical characteristics showed no statistically significant differences.
TABLE 1.
Patient demographics and clinical characteristics.
| Variables | EORC (n = 48) | AORC (n = 154) | P value |
|---|---|---|---|
| Sex | |||
| Male | 33 (68.8) | 100 (64.9) | 0.627 |
| Female | 15 (31.3) | 54 (35.1) | |
| BMI (median, IQR), kg/m2 | 26.0 (23.6–30.8) | 26.8 (23.5–30.4) | 0.976 |
| ECOG Performance Status score | |||
| 0–1 | 42 (87.5) | 122 (79.2) | 0.200 |
| ≥2 | 6 (12.5) | 32 (20.8) | |
| Sarcopenia | 5 (10.4) | 44 (28.6) | 0.011 |
| Primary/recurrent | |||
| Primary | 45 (93.8) | 149 (96.8) | 0.398 |
| Locally recurrent | 3 (6.3) | 5 (3.2) | |
| Tumour subtype | |||
| Adenocarcinoma | 46 (95.8) | 139 (90.3) | 0.308 |
| Mucinous adenocarcinoma | 1 (2.1) | 13 (8.4) | |
| Signet‐ring cell carcinoma | 1 (2.1) | 2 (1.3) | |
| Tumour differentiation | |||
| Well to moderate | 35 (72.9) | 107 (69.5) | 0.492 |
| Poor | 5 (10.4) | 22 (14.3) | |
| Missing | 8 (16.7) | 25 (16.2) | |
| MMR | |||
| dMMR | 2 (4.2) | 2 (1.3) | 0.231 |
| pMMR | 46 (95.8) | 146 (94.8) | |
| Missing | 0 (0.0) | 6 (3.9) | |
| RAS status | |||
| Mutation | 9 (18.8) | 50 (32.5) | 0.056 |
| Wild‐type | 15 (31.3) | 34 (22.1) | |
| Missing | 24 (50.0) | 70 (45.5) | |
| cT stage | |||
| T1–2 | 4 (8.3) | 16 (10.4) | 0.969 |
| T3 | 29 (60.4) | 90 (58.4) | |
| T4 | 15 (31.3) | 48 (31.2) | |
| cN stage | |||
| N0 | 10 (20.8) | 40 (26.0) | 0.471 |
| N1–2 | 38 (79.2) | 114 (74.0) | |
| cM stage | |||
| M0 | 33 (68.8) | 110 (71.4) | 0.722 |
| M1 | 15 (31.3) | 44 (28.6) | |
| Clinical AJCC stage | |||
| I | 1 (2.1) | 10 (6.5) | 0.641 |
| II | 6 (12.5) | 25 (16.2) | |
| IIII | 26 (54.2) | 75 (48.7) | |
| IV | 15 (31.3) | 44 (28.6) | |
| Distance from the anal verge (median, IQR), cm | 6.0 (3.8–8.2) | 6.6 (3.8–9.7) | 0.520 |
| EMVI +ve | 28 (58.3) | 81 (52.6) | 0.486 |
| LPLN +ve | 15 (31.3) | 27 (17.5) | 0.041 |
Note: P‐values marked with bold indicate statistically significant differences between the groups.
Abbreviations: AJCC, American Joint Committee on Cancer; AORC, average‐onset rectal cancer; BMI, body mass index; dMRR, deficient mismatch repair; ECOG, Eastern Cooperative Oncology Group; EMVI, extramural vascular invasion; EORC, early‐onset rectal cancer; IQR, interquartile range; LPLN, lateral pelvic lymph node; MMR, mismatch repair; pMMR, proficient mismatch repair.
TNT delivery, compliance and toxicity are summarised in Table 2. Of the patients, 77 (38.1%) received iTNT and 125 (61.9%) received cTNT, with 190 (94.1%) completing LC‐CRT. Compliance with chemotherapy and chemoradiotherapy was similar between the groups. EORC patients experienced significantly less Grade 3–4 chemotherapy‐induced toxicity than AORC patients (2.1% vs. 25.3%, P < 0.001), but had higher rates of patient‐reported Grade 3–4 radiation‐induced toxicity (31.3% vs. 12.3%, P = 0.004). No significant difference was observed in physician‐reported Grade 3–5 radiation‐induced toxicity. Dihydropyrimidine dehydrogenase (DPYD) testing was performed on five patients (2.5%), two of whom had a mutation in the DPYD gene. Toxicity profiles within the age groups for iTNT and cTNT regimens are shown in Table 3. EORC patients experienced significantly less Grade 3–4 chemotherapy‐induced toxicity than AORC patients for both induction (0% vs. 23.2%, P = 0.016) and consolidation regimens (3.7% vs. 26.5%, P = 0.008). However, for the cTNT regimen, EORC patients had significantly higher rates of patient‐reported Grade 3–4 radiation‐induced toxicity than AORC patients (33.3% vs. 11.2%, P = 0.009).
TABLE 2.
TNT delivery, compliance and toxicity.
| EORC (n = 48) | AORC (n = 154) | P value | |
|---|---|---|---|
| TNT | |||
| Induction | 21 (43.8) | 56 (36.4) | 0.358 |
| Consolidation | 27 (56.3) | 98 (63.6) | |
| Chemoradiotherapy | |||
| Long‐course | 46 (95.8) | 144 (93.5) | 1.00 |
| Short‐course | 1 (2.1) | 4 (2.6) | |
| No chemoradiotherapy | 1 (2.1) | 6 (3.9) | |
| Systemic chemotherapy | |||
| mFOLFOX6 | 11 (22.9) | 43 (27.9) | 0.514 |
| CAPOX | 31 (64.6) | 93 (60.4) | |
| Other | 6 (12.5) | 13 (8.4) | |
| No chemotherapy | 0 (0.0) | 5 (3.2) | |
| Compliance with chemotherapy | |||
| Completed planned cycles | 38 (79.2) | 115 (74.7) | 0.526 |
| ≥4 cycles | 46 (95.8) | 137 (89.0) | 0.154 |
| <4 cycles | 2 (4.2) | 17 (11.0) | |
| Compliance with radiotherapy | |||
| Received total dose of radiotherapy | 47 (97.9) | 144 (93.5) | 0.728 |
| Radiotherapy discontinuation (total dose <50 Gy) | 0 (0.0) | 4 (2.6) | |
| No radiotherapy | 1 (2.1) | 6 (3.9) | |
| Median radiation dose, (median, IQR), Gy | 50 (50–50) | 50 (50–50) | 0.135 |
| Worst chemotherapy toxicity grade | |||
| No adverse events | 3 (6.3) | 9 (5.8) | <0.001 |
| Grade 1–2 | 41 (85.4) | 91 (59.1) | |
| Grade 3–4 | 1 (2.1) | 39 (25.3) | |
| Missing | 3 (6.3) | 15 (9.7) | |
| Worst radiotherapy skin toxicity grade | |||
| Physician reported | |||
| No adverse events | 24 (50.0) | 82 (53.2) | 0.725 |
| Grade 1–2 | 8 (16.7) | 24 (15.6) | |
| Grade 3–5 | 8 (16.7) | 19 (12.3) | |
| Missing | 8 (16.7) | 29 (18.8) | |
| Patient reported | |||
| Grade 1–2 | 29 (60.4) | 113 (73.4) | 0.004 |
| Grade 3–4 | 15 (31.3) | 19 (12.3) | |
| Missing | 4 (8.3) | 22 (14.3) | |
Note: P‐values marked with bold indicate statistically significant differences between the groups.
Abbreviations: AORC, average‐onset rectal cancer; CAPOX, capecitabine and oxaliplatin; EORC, early‐onset rectal cancer; IQR, interquartile range; mFOLFOX6, infusional 5‐fluorouracil, leucovorin and oxaliplatin; TNT, total neoadjuvant therapy.
TABLE 3.
Toxicity profiles within the age groups for induction and consolidation TNT regimens.
| Variables | Induction TNT | Consolidation TNT | ||||
|---|---|---|---|---|---|---|
| EORC (n = 21) | AORC (n = 56) | P value | EORC (n = 27) | AORC (n = 98) | P value | |
| Worst chemotherapy toxicity grade | ||||||
| No adverse events | 3 (14.3) | 4 (7.1) | 0.016 | 0 (0.0) | 5 (5.1) | 0.008 |
| Grade 1–2 | 16 (76.2) | 30 (53.6) | 25 (92.6) | 61 (62.2) | ||
| Grade 3–4 | 0 (0.0) | 13 (23.2) | 1 (3.7) | 26 (26.5) | ||
| Missing | 2 (9.5) | 9 (16.1) | 1 (3.7) | 6 (6.1) | ||
| Worst radiotherapy skin toxicity grade | ||||||
| Physician reported | ||||||
| No adverse events | 13 (61.9) | 32 (57.1) | 0.652 | 11 (40.7) | 50 (51.0) | 0.599 |
| Grade 1–2 | 1 (4.8) | 5 (8.9) | 7 (25.9) | 19 (19.4) | ||
| Grade 3–5 | 4 (19.0) | 6 (10.7) | 4 (14.8) | 13 (13.3) | ||
| Missing | 3 (14.3) | 13 (23.2) | 5 (18.5) | 16 (16.3) | ||
| Patient reported | ||||||
| Grade 1–2 | 13 (61.9) | 39 (69.6) | 0.190 | 16 (59.3) | 74 (75.5) | 0.009 |
| Grade 3–4 | 6 (28.6) | 8 (14.3) | 9 (33.3) | 11 (11.2) | ||
| Missing | 2 (9.5) | 9 (16.1) | 2 (7.4) | 13 (13.3) | ||
Note: P‐values marked with bold indicate statistically significant differences between the groups.
Abbreviations: AORC, average‐onset rectal cancer; EORC, early‐onset rectal cancer; TNT, total neoadjuvant therapy.
Responses to TNT are shown in Table 4. The oCR rate did not differ significantly between EORC and AORC patients (43.8% vs. 37.9% P = 0.470). Similarly, cCR and pCR rates were comparable (39.6% vs. 34.4%, P = 0.514; 10.3% vs. 7.0%, P = 0.690, respectively). There was no significant difference in complete M1 response rates between the two groups (40.0% vs. 38.6%, P = 0.740). Both cohorts displayed similar rates of NOM and NOM regrowth (45.8% vs. 44.8%, 13.6% vs. 24.6%, respectively). Of the two patients who received pembrolizumab as part of their TNT regimen, one AORC patient achieved a cCR while the other EORC patient had an incomplete response and subsequently underwent surgery.
TABLE 4.
Responses to TNT.
| EORC (n = 48) | AORC (n = 154) | P value | |
|---|---|---|---|
| oCR (pCR and/or cCR) | |||
| Yes | 21 (43.8) | 58 (37.9) | 0.470 |
| No | 27 (56.3) | 95 (62.1) | |
| cCR | |||
| Yes | 19 (39.6) | 53 (34.4) | 0.514 |
| No | 29 (60.4) | 101 (65.6) | |
| pCR a | |||
| Yes | 3 (10.3) | 6 (7.0) | 0.690 |
| No | 26 (89.7) | 80 (93.0) | |
| M1 response b | |||
| Complete | 6 (40.0) | 17 (38.6) | 0.740 |
| Partial | 6 (40.0) | 14 (31.8) | |
| Progressed | 3 (20.0) | 13 (29.5) | |
| NOM | |||
| Yes | 22 (45.8) | 69 (44.8) | 0.901 |
| No | 26 (54.2) | 85 (55.2) | |
| Regrowth during NOM | |||
| Yes | 3 (13.6) | 17 (24.6) | 0.278 |
| No | 19 (86.4) | 52 (75.4) | |
Abbreviations: AORC, average‐onset rectal cancer; cCR, clinical complete response; EORC, early‐onset rectal cancer; NOM, non‐operative management; oCR, overall complete response; pCR, pathological complete response.
pCR was calculated including only patients who underwent surgery in the denominator.
M1 response was calculated including only patients with distant metastasis in the denominator.
DISCUSSION
This study offers valuable insight into the response rate of EORC and AORC patients treated with TNT. Adding to a growing body of literature, our findings show that EORC patients have similar oCR, cCR and pCR to TNT compared to their AORC counterparts. Notably, toxicity data indicated that early‐onset patients experienced lower rates of severe chemotherapy‐induced toxicity but are more likely to report severe radiation‐induced toxicity.
Prior literature reported that younger patients were more likely to achieve a complete response to TNT [24, 25]; however, few studies have directly compared EORC to AORC patients. Foppa et al. compared responses to both TNT and nCRT between EORC and late‐onset rectal cancer (LORC) patients using the same age stratification as our study [11], but only 16 patients underwent TNT (12 EORC and four LORC). The limited number of EORC and LORC patients who received TNT and the lack of complete response rates stratified by treatment type restricts the applicability of their findings. Lumish et al. found no significant differences in oCR rates between EO‐LARC and AO‐LARC patients treated with TNT (25% vs. 33%, P = 0.16) at Memorial Sloan Kettering Cancer Center between 2009 and 2015 [16], consistent with our findings. Interestingly, they noted a trend towards lower cCR in the EO‐LARC cohort, suggesting clinician hesitance to observe younger patients in the early era of NOM. In contrast, our study found a trend towards higher rates of cCR in EORC patients (39.6% vs. 34.4%, P = 0.514), probably reflecting increased clinician comfort with NOM in contemporary practice.
Another retrospective US study found no significant differences in the oCR rates (15% vs. 30%) and pCR rates (12% vs. 22%) between EO‐LARC and AO‐LARC patients treated with TNT [15]. Directly comparing our results to other studies is difficult due to many being single‐centre experiences, having small sample sizes, and limited publication with details of tumour characteristics and treatment response. Furthermore, many prior studies focused solely on LARC patients, whereas nearly one‐third of patients in our series had Stage IV disease (treated with curative intent). Despite the inclusion, oCR and pCR rates after TNT remained similar between cohorts and consistent with previously published findings [15, 16].
Previous studies have suggested that EORC patients often present with more advanced disease and worse histopathological features, which may contribute to poorer responses to neoadjuvant therapy [9, 12]. In our cohort, clinical stages were comparable between EORC and AORC patients. This homogeneity strengthens our findings by indicating that neither high‐risk tumour features nor advanced disease stage at presentation significantly influenced treatment response in our population. Notably, EORC patients in our study had a significantly higher incidence of lateral pelvic lymph node metastasis. This aligns with a recent meta‐analysis identifying age under 60 as a significant risk factor for lateral pelvic lymph node involvement [26]. Moreover, the prevalence of sarcopenia was significantly higher in AORC patients, presumably due to age‐related physiological and morphological changes in skeletal muscle [27]. Emerging evidence suggests that sarcopenia measured via pre‐treatment CT scans negatively impacts oCR to TNT in advanced rectal cancer, highlighting the potential for prehabilitation regimens to address this issue [28, 29]. Given the high prevalence of sarcopenia in the AORC patient population and its significant negative association with tumour response, prehabilitation has garnered increasing attention as a possible solution [30].
There is a significant paucity of literature investigating TNT toxicity in EORC and AORC patients. A conference proceedings abstract by Conces et al. indicated that EORC patients experienced significantly higher rates of nausea compared to AORC patients, with no differences in other toxicities [31]. On the other hand, our study found that EORC patients experienced lower rates of Grade 3–4 chemotherapy‐induced toxicity. A secondary analysis of the Organ Preservation in Patients with Rectal Adenocarcinoma trial revealed that patients who experienced Grade 3 or higher TNT‐related toxicity were significantly older (62 vs. 56 years, P = 0.002) [32]. However, in the OPRA trial toxicity was reported for the entire TNT regimen rather than being separated by nCRT and systemic chemotherapy regimens, making direct comparisons challenging. Despite these limitations, the collective findings suggest that many AORC patients experience significant TNT toxicity, highlighting the importance of clear communication about TNT‐related toxicities when counselling patients. Furthermore, studies have shown that 31%–69% of severe toxicities can be explained by germline variants in the DPYD genes encoding the enzymes responsible for the catabolism and detoxification of 5‐FU and capecitabine [33, 34]. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines recommend upfront DPYD genetic testing and tailoring fluoropyrimidine administration based on the results [35]. Despite recommendations by the CPIC, Australia is yet to adopt upfront DPYD screening for patients with rectal cancer receiving fluoropyrimidine‐based therapy. In the current study, DPYD testing was performed selectively, often determined only after chemotherapy was initiated and severe toxicity developed. The GeneScreen 5‐FU study will confirm the evidence needed to successfully implement upfront DPYD screening in Australia [36].
Patient‐reported outcome measures, such as radiation‐induced toxicity, are essential to understanding the adverse impacts of radiotherapy. Although there was no difference in physician‐reported radiation‐induced toxicity between the EORC and AORC cohorts, a significant proportion of EORC patients reported Grade 3–4 radiation‐induced toxicity. Recent literature focusing on the patient's perspective of radiotherapy for LARC found that, while nearly half of the responders had heard alarming stories, the majority (83%) reported that their overall experience was less frightening than anticipated [37]. Additionally, physicians frequently and substantially under‐report both the prevalence and severity of treatment‐related toxicities compared to patient reports [38]. Our study further underscores the importance of collecting patient‐reported outcomes to accurately assess TNT‐related toxicities.
Although the rates of NOM were similar between EORC and AORC patients, the efficacy of NOM in EORC patients warrants further investigation. The International Watch & Wait Database found no significant differences in local regrowth or distant metastasis rates between EORC and AORC patients undergoing NOM after cCR over 3 years [39]. Nevertheless, given the longer life expectancy of EORC patients, extended follow‐up is essential to allow for accurately assessing the long‐term incidence of local regrowth and distant metastasis, as well as the local effects of radiotherapy on pelvic fibrosis and function [39].
This study's limitations include a small sample size and inherent biases from its observational design. While the multicentre nature allows for diverse population coverage and provides generalisability of effect across institutions, it does introduce variability due to differing TNT protocols. Additionally, potential selection bias may arise from unequal distribution of patients between study cohorts. Owing to the small number of EORC patients, further subgrouping (<45 years, <40 years) was not possible in this analysis. Changes to recommended screening ages in organised colorectal screening programmes in the future may reduce the generalisability of our findings. It is important to report the potential for underpowered comparisons due to the sample size. While significant trends and differences were observed, some findings did not reach statistical significance, potentially due to limited group sizes. For example, the detection of differences in key outcomes, such as oCR rates and regrowth during NOM, would require substantially larger cohorts to achieve adequate power. This limitation highlights the need for caution when interpreting the results and underscores the importance of larger, multicentre studies to validate these findings. Lastly, as we rely on clinical teams to report the outcomes of interest, we acknowledge the potential for reporting bias. An unconscious bias towards more aggressive treatment in EORC patients may be present and Grade 3–4 toxicities may be under‐reported in the clinical notes in these young patients as toxicities are usually managed through dose reductions. Despite these limitations, this study contributes valuable data on the complete response of EORC patients undergoing TNT, addressing a gap in the existing literature.
CONCLUSION
EORC patients exhibit comparable overall tumour response rates to AORC patients treated with TNT. However, toxicity profiles differ, with EORC patients experiencing less chemotherapy‐induced toxicity but more patient‐reported radiation‐induced toxicity. In the era of personalised treatment, an EORC diagnosis necessitates a tailored TNT strategy based on individual disease risk both to optimise tumour response and to minimise adverse treatment effects.
AUTHOR CONTRIBUTIONS
Sergei Bedrikovetski: Conceptualization; methodology; data curation; formal analysis; writing – original draft. Ishraq Murshed: Conceptualization; methodology; visualization; writing – review and editing. Tracy Fitzsimmons: Investigation; data curation; writing – review and editing. Luke Traeger: Conceptualization; methodology; writing – review and editing. Timothy J. Price: Conceptualization; visualization; writing – review and editing. Michael Penniment: Conceptualization; writing – review and editing. Sudarshan Selva‐Nayagam: Conceptualization; writing – review and editing. Ryash Vather: Supervision; writing – review and editing. Tarik Sammour: Supervision; project administration; resources; writing – review and editing.
FUNDING INFORMATION
No funding was received for this research.
CONFLICT OF INTEREST STATEMENT
The author(s) have no affiliations or financial involvement with any organisation or entity with financial interest. This manuscript was accepted as a poster presentation at the 93rd RACS 2025 Annual Scientific Congress, 3‐6 May 2025 in Sydney, Australia.
ETHICS STATEMENT
Approval was obtained from the Central Adelaide Local Health Network Human Research Ethics Committee (HREC reference number 11938) and St Andrew's Hospital Research and Ethics Committee (#117).
ACKNOWLEDGEMENT
Open access publishing facilitated by The University of Adelaide, as part of the Wiley ‐ The University of Adelaide agreement via the Council of Australian University Librarians.
Bedrikovetski S, Murshed I, Fitzsimmons T, Traeger L, Price TJ, Penniment M, et al. Total neoadjuvant therapy in early‐onset rectal cancer: A multicentre prospective cohort study. Colorectal Dis. 2025;27:e70059. 10.1111/codi.70059
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available upon reasonable request from the corresponding author.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available upon reasonable request from the corresponding author.