Balancing treatment efficacy and complications in early-onset locally advanced rectal cancer

Sporadic colorectal cancer has usually been considered as a malignancy of older persons. As the incidence of cases diagnosed among adults and in young adults is increasing in many high-income countries, greater attention is being given to early-onset colorectal cancer (1).

Early-onset colorectal cancers, defined as diagnosis in patients younger than 50 years of age, are more frequently detected in the rectum; it is estimated that by 2030 around 25% of all rectal cancers will be diagnosed in subjects younger than 50 years of age, compared to less than 10% in the early 2000s (1). The rise in early-onset colorectal cancer is paralleled by a falloff of late adults/elderly-onset cases. This phenomenon is primarily ascribed to screening programs that have modified the median age at diagnosis from 72 years in the early 2000s to 66 years at present (2). The opportunity to anticipate the starting age of screening programs for persons at average risk is thus being debated.

The causes of this rise in colorectal cancer incidence in younger adults are not identified and probably multifactorial (1). Patients with early-onset colorectal cancer tend to present with a more advanced disease-stage with no mutational or hereditary susceptibility. Somatic mutational profiling of early-onset colorectal cancers has not identified specific formerly unknown alterations to apprise our comprehension of the pathogenesis. In a large study including over 750 patients with early-onset sporadic colorectal cancer, no significant dissimilarities in genomic tumor profiles of microsatellite stable tumors were observed between early-onset and later-onset colorectal cancers in three different age groups (≤35, 36–49 and ≥50 years), including driver pathways gene alterations (3). Moreover, reports indicate that there are no substantial discrepancies in the tumor mutation load, the level of genetic alterations, or the loss of heterozygosity.

Cancer risk is influenced by polygenic effects and insulin-related signaling, other than single-gene alterations and gene-environment interactions (4,5). In colorectal cancer a “birth cohort” effect has been described (6) among individuals born after 1960 with higher risk of early colorectal cancer across successive birth cohorts. This suggests that the exposure to various risk factors (i.e., dietary, lifestyle, microbial, environmental, hormonal and genetic factors) (7,8) during childhood and young adulthood has risen over the years, particularly from the mid-20th century onward. Birth cohort colorectal cancers show distinctive characteristics, notably the growing prevalence of rectal tumors. The developing field of integrative molecular pathological epidemiology (MPE) has recognized links between long-term risk factor exposures (7) and early-cancer incidence, suggesting that etiologic factors may promote cancer growth through an ‘etiologic field effect’, creating a tissue microenvironmental milieu of neoplasia susceptibility (8-11).

Alongside, comprehensive treatment planning for early-onset disease requires resources for supportive measures comprising family and genetic counselling, career planning, sexual/reproductive health (1). Also, the potential acute and chronic side-effects of receiving specific therapy in both the adjuvant and advanced setting can have a substantial impact on quality of life. This is particularly relevant for patients with a long-life expectancy, with an active working and family life. This is a key aspect as younger patients are more likely to receive postoperative chemotherapy and more intense treatment approaches (1).

In rectal cancer, radiotherapy-free neoadjuvant treatment regimens are demonstrating results comparable to standard chemoradiotherapy regimens especially in patients with low-risk tumors (12-14). This strategy may be particularly appealing in younger patients as the long-term complications of radiotherapy (i.e., low anterior resection syndrome, urinary and sexual dysfunction) can be particularly troublesome in young socially active people, also relating worse anxiety and body image perception (15).

In the post-hoc analysis of the multicenter phase III FORWARC trial (16), published in the British Journal of Cancer earlier last year, the authors compared local tumor response, risk of complications and long-term outcome of early-onset and late-onset locally advanced rectal cancer (LARC) treated preoperatively with standard chemoradiotherapy or neoadjuvant chemotherapy only. The results appear to show that standard chemoradiotherapy does result in a limited benefit compared to the experimental radiotherapy-free arm in early-onset LARC with more risk of complications and no improvement in survival. These data put in question the value of standard chemoradiotherapy particularly in this group of patients.

Though the FORWARC trial has some limitations as it included only an Asian population and was not formally designed to demonstrate the non-inferiority of neoadjuvant modified infusional fluorouracil, leucovorin and oxaliplatin (mFOLFOX6) in disease-free, overall survival and local relapses compared to fluorouracil or mFOLFOX6 plus radiotherapy and this is a post-hoc analysis, the results lend support to discussion in multidisciplinary team meetings to optimize the cost-benefit ratio of combined modality therapy for young LARC patients. Whether and how these data will be incorporated in upcoming updates guidelines will be crucial at this end. The impact of radiotherapy dose on tumor response has been evaluated in several studies, including the INTERACT trial (17,18). Of note, selective use of preoperative radiotherapy in patients failing to achieve major response to initial fluorouracil, leucovorin and oxaliplatin (FOLOX) or capecitabine and oxaliplatin (XELOX) may optimize this strategy as proposed in the recent published landmark PROSPECT study (12). The results of the PROSPECT trial have further expanded the therapeutic options in T2 node-positive, T3 node-negative, or T3 node-positive rectal cancer candidates for sphincter-sparing surgery by showing the non-inferiority of neoadjuvant FOLFOX with selective use of chemoradiotherapy in patients with low-risk tumors (12). Unfortunately, age-specific analyses of this study are not yet available.

Survival data for early-onset rectal cancer are scarce and controversial. In addition, there is not a universal agreement on cut-off age to define early-onset disease and this complicates the comparison among studies. Current recommendations for therapy are thus based on results from trials where this patient population was underrepresented (around 10%) and therefore largely imprecise. A comprehensive study utilizing a national cancer database analyzed survival trends by categorizing patients based on age and treatment guided by the National Comprehensive Cancer Network (NCCN) recommendations. In patients with stage II and III rectal cancer under 50 years old (21% of the population), neoadjuvant chemoradiotherapy did not provide a survival benefit compared to surgery alone (19). Yet, these data came from a United States cohort, where the younger cohort had a significantly higher proportion of minorities, female and uninsured, which could have biased the results. A possible solution could be to consider age as a continuous variable rather than using predefined age cut-offs (20). However, a routine aggressive surgical and/or adjuvant/neoadjuvant attitude in young patients might not be justified.

Nowadays, the growing range of therapeutic alternatives for LARC allows for personalized therapy according to the specific characteristics of the tumor. Patients with tumors showing microsatellite instability (MSI) (less than 5% of all rectal cancers) can have a long-lasting complete clinical response with immunotherapy only (21). In colorectal cancer, tumors harboring POLE mutations show an increased tumor mutation load (22). This is particularly critical as somatic POLE mutations tend to be more prevalent in early-onset colorectal cancers (22), and detecting POLE mutations may select patients’ candidate to immunocheckpoint inhibitors therapy.

Further improvements are likely to be achieved from several ongoing trials of liquid biopsy in rectal cancer. Preliminary results of the NOCUT study (NCT03565029), a phase 2 clinical trial, showed that circulating tumor DNA (ctDNA) positivity was significantly associated with incomplete response after total neoadjuvant therapy and worse distance relapse free survival (23). Besides, the tumor microenvironment significantly influences the growth, progression, and immune evasion of colorectal tumors. In particular, for rectal cancer, the local immune profile prior to neoadjuvant therapy has been linked to improved responses and extended disease-free survival (24). Findings from a recent study showed a greater percentage of cells that express the immune checkpoint programmed cell death ligand 1 (PD-L1) among younger patients (25). The role for immunotherapy in young patients with microsatellite stable rectal cancer is worth to be explored. An integrative MPE methodology which relates early-life and long-term exposures with early-onset predisposition and tumor phenotype, may also enhance our understanding of tumor etiologies, pathogenesis and eventually treatment strategies.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-24-234/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-234/coif). C.A. has participated in the advisory boards for Steering Committees and served as a speaker for EISAI, Novartis, BMS, Roche, Servier, Merck-Serono, Astella, GSK, and AstraZeneca. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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