Table 5.

Areas of Uncertainty on eoCRC and Proposed Research Agenda

Areas of controversy	Issues raised
Topic: diagnosis of eoCRC
Fecal immunochemical test	• FIT vs colonoscopy for alarming signs and symptoms: (1) no cost-effectiveness analysis, (2) higher risk of false negatives with FIT, (3) FIT use may prolong diagnostic delays, (4) FIT may be useful for patients with vague symptoms (ie, not alarming) • Positive FIT follow-up: (1) unknown referral rate to colonoscopy after positive FIT, (2) non-zero risk of non-compliance to follow-up colonoscopy • Screening FIT: (1) unknown diagnostic rate, (2) unknown survival benefit, (3) unknown cost- benefit ratio in many countries • Unclear whether a positive FIT is a sign of eoCRC: lack of data
Sigmoidoscopy versus colonoscopy	• Advantages of sigmoidoscopy: (1) eoCRC often left-sided, (2) sigmoidoscopy marginally faster than colonoscopy, (3) no need for a complete bowel preparation • Advantages of colonoscopy: (1) similar overall costs, (2) similar need for hospital access, (3) lower risk of false negatives
Time to colonoscopy	• Diagnostic delay: (1) 30 days are ideal but difficult to achieve under some circumstances (difficult access to care, incomplete insurance coverage), (2) highlight the need for a timely diagnosis Alarming signs/symptoms + positive FIT: proceed to colonoscopy with the highest priority
Topic: Risk factors of eoCRC
Family history	• Accuracy of family histories: (1) a 2-generation family history is often difficult to obtain under routine circumstances, (2) dedicated hospitals may have more time for such tasks, (3) risk assessment tools may provide a framework for history taking
Risk factors	• Many risk factors identified, but insufficient evidence to recommend earlier access to screening. Further studies necessary on the additional risk factors to include in CRC screening programs (besides age).
Topic: genetics of eoCRC
Ranking the genes by importance	• Costs of germline testing: (1) not all healthcare systems may afford large gene panels, (2) prioritize the most important genes if needed, (3) no cost-benefit analysis on additional genes, (4) further studies necessary before recommending large panels in low resources settings
Risk assessment tools	• Utility: (1) all with eoCRC should receive germline testing
Polygenic risk scores	• Utility: (1) potentially estimate lifetime risk of CRC, (2) further evidence and validation studies in diverse populations are needed before clinical use
Topic: Oncological treatment of eoCRC
Adjuvant therapy	• Aggressive adjuvant therapy: (1) eoCRC often receive more aggressive regimens, (2) increased toxicity, but no evidence of a survival benefit, (3) further randomized clinical trials should include endpoints to evaluate benefits to patients with eoCRC
Neoadjuvant therapy, adding oxaliplatin	• Oxaliplatin addition: (1) post hoc analysis of one large phase II trial suggested that adding oxaliplatin to standard chemoradiotherapy in eoRC improved disease-free survival and overall survival compared with older individuals, (2) no prospectively analyzed randomized clinical trial data, (3) future randomized clinical trials should include endpoints pertaining to eoRC patients specifically.
Rectum, neoadjuvant therapy	• Total neoadjuvant therapy: (1) more and more centers are adopting this strategy as standard management of individuals with rectal cancer, regardless of age, (2) not enough evidence to hypothesize that this should differ for rectal eoCRC, (3) further clinical trials should include endpoints pertaining to eoCRC patients specifically.
Immune checkpoint inhibitors therapy	• Use: (1) not enough evidence to hypothesize a different use for younger patients, (2) higher prevalence of LS among eoCRC, therefore higher likelihood of MSI-H CRC, (3) further clinical trials should include endpoints pertaining to eoCRC patients specifically.
IHC/MMR assessment	• Biopsies vs surgical specimens: (1) ideally, IHC/MMR assessment before treatment, (2) biopsies provide results comparable with staining on surgical specimens, (3) biopsies do not carry a risk of false-negative IHC/MMR results
Targeted therapies	• Use: (1) not enough evidence to hypothesize a different use for younger patients, (2) further clinical trials should include endpoints pertaining to eoCRC patients specifically
Topic: Endoscopy of eoCRC
Clearing colonoscopy	• Ideally, the diagnostic colonoscopy should clear the colon of all synchronous lesions, particularly when multiple polyps are present. It should be emphasized that younger patients do not require an extended surgical resection by default. The scientific panel suggests a clearing colonoscopy to further discourage the use of an extended surgical resection.
Post-treatment follow-up	• Surveillance protocol: (1) insufficient evidence to support an intensified surveillance protocol, (2) insufficient evidence to discharge patients with eoCRC from follow-up, (3) suggestion to continue post-treatment surveillance and not to discharge the patient, (4) significant knowledge gap, (5) further studies necessary on the risk of metachronous CRC and the time of surveillance discharge • Hereditary CRC, family history of CRC, or inflammatory bowel diseases: should receive posttreatment surveillance according to their specific guidelines.
Secondary prevention of CRC	• Aspirin use: (1) insufficient evidence on the secondary prevention of eoCRC, (2) optimal dosage for cancer prevention unclear after CRC • Other medications: (1) insufficient evidence
Topic: Treatment of eoCRC
Standard vs extensive surgical resections	• Extended surgical resections: (1) no evidence to support more extensive resections, unless a distinctly higher risk of CRC is demonstrated, (2) the scientific panel currently discourages further analysis on extensive colorectal surgeries based on early age alone • Factors besides age: (1) can be considered, including (but not limited to) a polyposis phenotype, a colitis-associated CRC, and a genetically higher risk of CRC. Such characteristics do not pertain to these guidelines.
Synchronous gynecologic surgery	• Indications: (1) eoCRC is not an indication for hysterectomy with or without oophorectomy, (2) however, other indications may justify hysterectomy with or without oophorectomy at the time of CRC surgery, (3) consider age of the patient, risk for gynecologic cancers, and reproductive desires when offering a gynecologic prophylactic surgery • Ovarian transposition: (1) patients requiring radiotherapy may benefit from ovarian transposition at the time of colorectal surgery, (2) further evidence is necessary
Fertility preservation	• Information provider: (1) any healthcare professional, if adequately trained, (2) multidisciplinary teams for eoCRC patients may benefit from having a gynecologist • Ovarian damage: (1) CRC-directed chemotherapeutic agents can be gonadotoxic, (2) female patients with eoCRC should receive information on their ovarian health • Menopause: little to no evidence on the menopausal issues on patients with eoCRC receiving treatment. Research necessary • Male reproductive health: scarce evidence on male factors. Further research necessary on the reproductive needs, issues, and desires
Supportive care of eoCRC
Nausea and vomiting	• (1) Higher risk of chemotherapy-induced nausea and vomiting, (2) enough evidence to contemplate the use of enhanced antiemetic prophylaxis with new-generation antiemetic, (3) further evidence may be needed.
Nutritional support and physical therapy	• (1) Higher risk of significant weight loss than patients with CRC at an older age, (2) little to no evidence on the use of nutritional support and physical support programs in patients with eoCRC.