PURPOSE Total neoadjuvant therapy is a new paradigm for rectal cancer treatment. Optimal scheduling of preoperative chemoradiotherapy (CRT) and chemotherapy remains to be established. PATIENTS AND METHODS We conducted a multicenter, randomized, phase II trial using a pick-the-winner design on the basis of the hypothesis of an increased pathologic complete response (pCR) of 25% after total neoadjuvant therapy compared with standard 15% after preoperative CRT. Patients with stage II or III rectal cancer were assigned to group A for induction chemotherapy using three cycles of fluorouracil, leucovorin, and oxaliplatin before fluorouracil/oxaliplatin CRT (50.4 Gy) or to group B for consolidation chemotherapy after CRT. Secondary end points included toxicity, compliance, and surgical morbidity. RESULTS Of the 311 patients enrolled, 306 patients were evaluable (156 in group A and 150 in group B). CRT-related grade 3 or 4 toxicity was lower (37% v 27%) and compliance with CRT higher in group B (91%, 78%, and 76% v 97%, 87%, and 93% received full-dose radiotherapy, concomitant fluorouracil, and concomitant oxaliplatin in groups A and B, respectively); 92% versus 85% completed all induction/consolidation chemotherapy cycles, respectively. The longer interval between completion of CRT and surgery in group B (median 90 v 45 days in group A) did not increase surgical morbidity. A pCR in the intention-to-treat population was achieved in 17% in group A and in 25% in group B. Thus, only group B ( P < .001), but not group A ( P = .210), fulfilled the predefined statistical hypothesis. CONCLUSION Up-front CRT followed by chemotherapy resulted in better compliance with CRT but worse compliance with chemotherapy compared with group A. Long-term follow-up will assess whether improved pCR in group B translates to better oncologic outcome.

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for the German Rectal Cancer Study Group IMPORTANCE Total neoadjuvant therapy has been increasingly adopted for multimodal rectal cancer treatment. The optimal sequence of chemoradiotherapy (CRT) and chemotherapy needs to be established. OBJECTIVE To report the long-term results of the secondary end points prespecified in the Randomized Phase 2 Trial of Chemoradiotherapy Plus Induction or Consolidation Chemotherapy as Total Neoadjuvant Therapy (CAO/ARO/AIO-12 trial) for Locally Advanced Rectal Cancer. DESIGN, SETTING, AND PARTICIPANTS This secondary analysis of a randomized clinical trial included 311 patients who were recruited from the accrued CAO/ARO/AIO-12 trial population

These retrospective data suggest that, for some patients, postoperative chemotherapy can be spared. For patients with ypN2 status, an intensification of the postoperative chemotherapy should be considered. Further evaluation in prospective studies is urgently recommended.

BackgroundTo determine safety and efficacy of single cycle induction treatment with cisplatin/docetaxel and durvalumab/tremelimumab in stage III-IVB head and neck cancer.MethodsPatients received a single cycle of cisplatin 30 mg/m² on days 1–3 and docetaxel 75 mg/m² on day 1 combined with durvalumab 1500 mg fix dose on day 5 and tremelimumab 75 mg fix dose on day 5. Patients with pathologic complete response (pCR) in the rebiopsy after induction treatment or at least 20% increase of intratumoral CD8+ cell density in the rebiopsy compared with baseline entered radioimmunotherapy with concomitant durvalumab/tremelimumab. The objective of this interim analysis was to analyze safety and efficacy of the chemoimmunotherapy-induction treatment before radioimmunotherapy.ResultsA total of 57 patients were enrolled, 56 were treated. Median pretreatment intratumoral CD8+ cell density was 342 cells/mm². After induction treatment, 27 patients (48%) had a pCR in the rebiopsy and further 25 patients (45%) had a relevant increase of intratumoral CD8+ cells (median increase by a factor of 3.0). Adverse event (AE) grade 3–4 appeared in 38 patients (68%) and mainly consisted of leukopenia (43%) and infections (29%). Six patients (11%) developed grade 3–4 immune-related AE. Univariate analysis computed p16 positivity, programmed death ligand 1 immune cell area and intratumoral CD8+ cell density as predictors of pCR. On multivariable analysis, intratumoral CD8+ cell density predicted pCR independently (OR 1.0012 per cell/mm², 95% CI 1.0001 to 1.0022, p=0.016). In peripheral blood CD8+ cells, the coexpression of programmed death protein 1 significantly increased especially in patients with pCR.ConclusionsSingle cycle induction treatment with cisplatin/docetaxel and durvalumab/tremelimumab is feasible and achieves a high biopsy-proven pCR rate.