Total neoadjuvant therapy in early-onset versus average-onset locally advanced rectal cancer: patient characteristics and tolerance of therapy☆

Background: Patients with early-onset (EO, age <50 years) compared with average onset (AO, age ≥50 years) colorectal cancer have significantly higher rates of gastrointestinal toxicity with fluoropyrimidine and oxaliplatin therapy in the metastatic and adjuvant settings. Limited data exist regarding tolerance of total neoadjuvant therapy (TNT) when treating younger patients with locally advanced rectal cancer (LARC) despite the rising incidence of EO rectal cancer. Materials and methods: Data were abstracted from a retrospective database of patients with LARC treated with TNT from 1 January 2015 through 28 April 2021. Characteristics compared between EO and AO patients were demographic features, baseline characteristics of tumor, treatment delivery, antiemetic use, and toxicities. Results: Of 115 patients (39 EO, 76 AO), female patients constituted 51% of EO patients and 34% of AO patients (P = 0.077). No differences were found in race, ethnicity, clinical stage, dose of radiation or chemotherapy received, and antiemetic premedications and prescriptions. EO patients (versus AO patients) had more nausea (59% versus 28%, P = 0.001), fatigue (72% versus 47%, P = 0.013), and proctitis (28% versus 13%, P = 0.048) during chemoradiation and more nausea (69% versus 42%, P = 0.006) and stomatitis (21% versus 3.9%, P = 0.007) during chemotherapy. After adjusting for sex, EO patients were still at a greater odds of nausea compared with AO during chemoradiation (odds ratio 3.45, 95% confidence interval 1.51-7.69, P = 0.004) and chemotherapy (odds ratio 2.85, 95% confidence interval 1.28-6.67, P = 0.012). Conclusions: Patients with EO, compared with AO, LARC receiving TNT appear to have higher rates of nausea and should be considered for enhanced antiemetic regimens

CDK4/6 inhibition presents as a therapeutic option for paediatric and adult germ cell tumours and induces cell cycle arrest and apoptosis via canonical and non-canonical mechanisms

Background!#!Germ cell tumours (GCTs) are the most common solid malignancies in young men. Although high cure rates can be achieved, metastases, resistance to cisplatin-based therapy and late toxicities still represent a lethal threat, arguing for the need of new therapeutic options. In this study, we analysed the potential of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors palbociclib and ribociclib (PaRi) as molecular drugs to treat cisplatin-resistant and -sensitive paediatric and adult GCTs.!##!Methods!#!Ten GCT cell lines, including cisplatin-resistant subclones and non-malignant controls, were treated with PaRi and screened for changes in viability (triphenyl tetrazolium chloride (XTT) assay), apoptosis rates (flow cytometry, caspase assay), the cell cycle (flow cytometry), the transcriptome (RNA-sequencing, quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) and on protein level (western blot). Expression profiling was performed on paediatric and adult GCT tissues (expression microarrays, qRT-PCR, immunohistochemistry, 'The Cancer Genome Atlas' database).!##!Results!#!We demonstrate that adult GCTs highly express CDK4, while paediatric GCTs strongly express CDK6 instead. Thus, both GCT types are potentially treatable by PaRi. GCTs presented as highly sensitive towards PaRi, which caused a decrease in viability, cell cycle arrest and apoptosis. Although GCTs mainly arrested in the G1/G0 phase, some embryonal carcinoma cell lines were able to bypass the G1/S checkpoint and progressed to the G2/M phase. We found that upregulation of CDK3 and downregulation of many mitosis regulation factors, like the HAUS genes, might be responsible for bypassing the G1/S checkpoint and termination of mitosis, respectively. We postulate that GCT cells do not tolerate these alterations in the cell cycle and eventually induce apoptosis.!##!Conclusion!#!Our study highlights PaRi as therapeutic options for cisplatin-resistant and -sensitive paediatric and adult GCTs