Intensified preoperative chemotherapy after (chemo)radiotherapy, (Total Neoadjuvant Therapy–TNT), increases pathological complete response (pCR) rates and local control. In cases of clinically complete response (cCR) and close follow-up, non-operative management (NOM) is feasible. We report early outcomes and toxicities of a long-term TNT regime in a single-center cohort. Fifteen consecutive patients with distal or middle-third locally advanced rectal cancer (UICC stage II–III) were investigated, who received neoadjuvant chemoradiotherapy (total adsorbed dose: 50.4 Gy in 28 fractions and two concomitant courses 5-fluorouracil (250 mg/m²/d)/oxaliplatin (50 mg/m²), followed by consolidating chemotherapy (nine courses of FOLFOX4). NOM was offered if staging revealed cCR 2 months after TNT, with resection performed otherwise. The primary endpoint was complete response (pCR + cCR). Treatment-related side effects were quantified for up two years after TNT. Ten patients achieved cCR, of whom five opted for NOM. Ten patients (five cCR and five non-cCR) underwent surgery, with pCR confirmed in the five patients with cCR. The main toxicities comprised leukocytopenia (13/15), fatigue (12/15) and polyneuropathy (11/15). The most relevant CTC °III + IV events were leukocytopenia (4/15), neutropenia (2/15) and diarrhea (1/15). The long-term TNT regime resulted in promising response rates that are higher than the response rates of short TNT regimes. Overall tolerability and toxicity were comparable with the results of prospective trials.

Total neoadjuvant therapy (TNT) is an evolving treatment schedule for locally advanced rectal cancer (LARC), allowing for organ preservation in a relevant number of patients in the case of complete response. Patients who undergo this so-called “watch and wait” approach are likely to benefit regarding their quality of life (QoL), especially if definitive ostomy could be avoided. In this work, we performed the first cost-effectiveness analysis from the patient perspective to compare costs for TNT with radical resection after neoadjuvant chemoradiation (CRT) in the German health care system. Individual costs for patients insured with a statutory health insurance were calculated with a Markov microsimulation. A subgroup analysis from the prospective “FinTox” trial was used to calibrate the model’s parameters. We found that TNT was less expensive (−1540 EUR) and simultaneously resulted in a better QoL (+0.64 QALYs) during treatment and 5-year follow-up. The average cost for patients under TNT was 4711 EUR per year, which was equivalent to 3.2% of the net household income. CRT followed by resection resulted in higher overall costs for ostomy care, medication and greater loss of earnings. Overall, TNT appeared to be more efficacious and cost-effective from a patient’s point of view in the German health care system.

Total neoadjuvant therapy (TNT) improves local control and complete response (CR) rates in locally advanced rectal cancer (LARC). CR is associated with favorable local tumor control, allowing non-operative management (NOM). However, it remains unclear whether short-course radiotherapy (SCRT) or long-course chemoradiotherapy (LCRT) is preferable within TNT. LARC patients undergoing TNT between 2015 and 2024 were included in this retrospective multicenter analysis (DRKS00033000). The primary endpoint was CR. Secondary endpoints comprised NOM rates, toxicity, and tumor control. Multivariable logistic regression modelling was used to assess the influence of LCRT. Of 295 included patients with a median age at diagnosis of 62 (Q1-Q3: 54-68) years and 210 (71.2 %) men, 172 (58.3 %) underwent LCRT. CR was achieved in 46 (37.4 %) SCRT and 96 (55.8 %) LCRT patients. Acute toxicity grade ≥ 3 occurred in 24 (20.5 %) of 117 SCRT and in 62 (36.3 %) of 171 LCRT patients. Within a median follow-up of 19.4 months (SCRT) and 19.6 months (LCRT), 23 (19.8 %) of 116 and 30 (19.4 %) of 155 patients experienced recurrence, respectively. Regression modelling revealed an increased likelihood for CR (adjusted odds ratio: 3.11; 95 % confidence interval: 1.37-7.07) and NOM (4.40; 1.46-13.21) with LCRT, whereas no significant associations of LCRT with acute toxicity (0.90; 0.40-2.02), chronic toxicity (1.16; 0.48-2.78), postoperative complications (0.89; 0.62-1.28) or recurrence (0.81; 0.31-2.16) were observed. LCRT was associated with higher CR and NOM rates. Whether it might be preferred over SCRT for intended NOM remains a relevant question to be answered by ongoing randomized trials.

Introduction: Conducting neoadjuvant chemoradiotherapy (CRT) and additional preoperative consolidating chemotherapy (CTx), that is, total neoadjuvant therapy (TNT), improves local control and complete response (CR) rates in locally advanced rectal cancer (LARC), putting the focus on organ preservation concepts. Therefore, assessing response before surgery is crucial. Some LARC patients would either not benefit from intensification by TNT or may reach CR, making resection not mandatory. Treatment of LARC should therefore be based on patient individual risk and response to avoid overtreatment. The “PRIMO” pilot study aims to determine early response assessment to form a basis for development and validation of a noninvasive response prediction model by a subsequent prospective multicenter trial, which is highly needed for individual, response-driven therapy adaptions. Methods: PRIMO is a prospective observational cohort study including adult patients with LARC receiving neoadjuvant CRT. At least 4 multiparametric magnetic resonance imaging (MRI) scans (diffusion-weighted imaging [DWI] and hypoxia-sensitive sequences) as well as repeated blood samples in order to analyze circulating tumor cells (CTC) and cell-free tumor DNA (ctDNA) are scheduled. Pelvic radiotherapy (RT, 50.4 Gy) will be performed in combination with a 5-fluorouracil/oxaliplatin regimen in all patients (planned: N = 50), succeeded by consolidation CTx (FOLFOX4) if feasible. Additional (immuno)histochemical markers, such as tumor-infiltrating lymphocytes (TIL) and programmed death ligand 1 (PD-L1) status will be analyzed before and after CRT. Routine resection is scheduled subsequently, nonoperative management is offered alternatively in case of clinical CR (cCR).The primary endpoint is pathological response; secondary endpoints comprise longitudinal changes in MRI as well as in CTCs and TIL. These are evaluated for early response prediction during neoadjuvant therapy, in order to develop a noninvasive response prediction model for subsequent analyses. Discussion: Early response assessment is the key in differentiating “good” and “bad” responders during neoadjuvant CRT, allowing adaption of subsequent therapies (additional consolidating CTx, organ preservation). This study will contribute in this regard, by advancing MR imaging and substantiating new surrogate markers. Adaptive treatment strategies might build on these results in further studies.

Prostate cancer is a leading cause of cancer-related mortality in men, with radiotherapy (RT) playing a pivotal role in treatment. However, reliable biomarkers for assessing relapse risk following RT remain scarce. This study aimed to evaluate circulating epithelial tumor cells (CETC/CTC) as potential biomarkers for assessing relapse risk in prostate cancer patients undergoing RT. Peripheral blood samples were collected from 52 prostate cancer patients, and CETC/CTC were detected using the EpCAM surface marker. Patients received definitive, adjuvant, or salvage RT, and CETC/CTC counts were measured before, at mid-treatment, and at the end of RT. The association between changes in CETC/CTC counts and relapse risk was examined. CETC/CTC were detected in 96% of patients prior to RT. A significant reduction in CETC/CTC counts during RT, particularly in patients who had undergone surgery, was associated with a lower relapse risk. In contrast, an increase in CETC/CTC counts during or after RT was associated with a higher relapse risk (hazard ratio = 8.8; p = 0.002). Furthermore, 36% of patients receiving adjuvant RT and 14% of those receiving definitive RT relapsed, with a higher risk observed in patients showing increasing CETC/CTC counts during RT. Among patients receiving salvage RT, 18% relapsed, though changes in CETC/CTC counts were less significantly associated with relapse. Monitoring CETC/CTC levels during RT offers important prognostic insights into relapse risk in prostate cancer patients. While changes in CETC/CTC counts correlated with relapse, PSA levels measured during the study did not reliably reflect relapse risk in this cohort. CETC/CTC shows promise as a prognostic marker, though further studies are required to validate its clinical superiority over PSA.

Purpose: This study aimed to assess the health-related quality of life (HRQoL) in patients with locally advanced rectal cancer (LARC) undergoing total neoadjuvant therapy (TNT), comparing outcomes with the German general population and colorectal cancer (CRC) patients treated with curative intent. Methods: In a multicenter, cross-sectional study within the “TNTox” study framework (DRKS 00033000), EORTC QLQ-C30 and QLQ-CR29 questionnaires were distributed to LARC patients who had completed TNT. Mean reference values were compared descriptively, and further exploratory comparisons based on clinical features were performed. Results: The study included responses from 72 patients. Compared to the German general population, a reduction in mean HRQoL across most domains was observed; the strongest effect was observed for role functioning (− 28.7 points, Cohen’s d = − 0.95), social functioning (− 25.3 points, d = − 0.89), and for diarrhea (+ 9.9 points, d = 0.80). General HRQoL was similar to that of CRC patients following curative treatment. However, some symptom scores, notably fecal incontinence (+ 13.4 points, d = 0.52), impotence (+ 29.0 points, d = 0.73), and dyspareunia (+ 10.4 points, d = 0.40) appeared to be higher. Significant factors associated with HRQoL included the presence of chronic treatment-related toxicity and duration of TNT; no major differences were observed between patients with or without NOM or stoma. Conclusion: LARC patients undergoing TNT showed comparable HRQoL outcomes to CRC patients treated with curative intent, but with reductions when compared to the general population. The presence of chronic toxicity significantly impacts HRQoL. Survivors may experience HRQoL impairments post-TNT, underscoring the necessity for ongoing management of chronic toxicity tailored to their needs.