Radiotherapy dose escalation using endorectal brachytherapy in elderly and frail patients with rectal cancer unsuitable for surgery: Lessons from studies in fit patients and future perspectives.

Epidemiological data indicate that more than 50 % of patients with newly-diagnosed rectal cancer are older than 70 years, with rising numbers expected over the next decades. Treatment decision-making is challenging in elderly and frail patients with rectal cancer, whereas standardized treatment guidelines for this patient cohort are lacking. Elderly and frail rectal cancer patients are often considered by surgeons as unfit to undergo radical surgery as the risk of surgical complications and postoperative mortality rises with increasing age and comorbidity. Furthermore, these patients often receive no treatment at all, resulting in local and/or systemic disease progression with associated symptoms and impaired quality of life (QoL). Recent data from randomized trials in young fit patients with early stage rectal cancer indicate that RT dose escalation can be safely delivered using external beam (chemo)radiotherapy (EBRT) followed by endoluminal radiotherapeutic modalities, such as contact X-ray brachytherapy (CXB) or high-dose rate endorectal brachytherapy (HDR-BT). However, prospective studies testing this therapeutic concept in elderly and frail patients remain limited. Here, we review the current evidence in the epidemiology and the management of elderly and frail patients with rectal cancer. We summarize the potential of RT dose escalation to achieve long-term local control of the primary tumour, prevent disease-related morbidity, improve QoL and even organ preservation. Future perspectives and open questions will be discussed as well.

Clinical outcome after total neoadjuvant treatment (CAO/ARO/AIO-12) versus intensified neoadjuvant and adjuvant treatment (CAO/ARO/AIO-04) a comparison between two multicenter randomized phase II/III trials.

BACKGROUND: Total neoadjuvant therapy (TNT) can enhance local tumor regression, but its survival benefits compared to intensified chemoradiotherapy (CRT) followed by adjuvant chemotherapy (CT) remain unclear. METHODS: This is a secondary comparison between 607 patients treated with intensified 5-FU/Oxaliplatin neoadjuvant CRT and adjuvant CT within the experimental arm of the CAO/ARO/AIO-04 phase III trial, and 306 patients treated with TNT within the CAO/ARO/AIO-12 phase II trial. Comparison between clinical-pathological characteristics, surgical quality, and post-surgical complications were analyzed using the Pearson's Chi-squared or Mann-Whitney U test. Oncological outcome was examined with log-rank, Gray's test, and multivariate cox regression. In addition, further subgroup analyses and propensity score matching were performed to optimize the balance of baseline covariates. FINDINGS: Patients treated with CRT followed by consolidation CT had a significantly higher rate of pathological complete remission (pCR) compared to patients treated within the experimental arm of the CAO/ARO/AIO-04 trial (25.3 % vs 17.3 %, P = 0.04). Post-surgical complications were less common in the CAO/ARO/AIO-12 trial. After a median follow-up of 46 months, clinical outcome did not differ significantly in the overall cohort, in any subgroup or after propensity score matching. In multivariate analysis, disease-free survival (DFS) was similar between the experimental arm of the CAO/ARO/AIO-04 trial and treatments arms of the CAO/ARO/AIO-12 trial (vs arm A: HR 0.92 [95 % CI 0.62-1.37], P = 0.69; vs arm B: HR 1.06 [95 % CI 0.72-1.58], P = 0.76). INTERPRETATION: Notwithstanding the limitations of intertrial comparison, TNT did not improve long term oncological outcome in our study compared to the intensified neoadjuvant CRT and adjuvant CT treatment in the CAO/ARO/AIO-04 trial. Improved response rates after TNT offers an attractive option to explore organ preservation in selective patients with locally advanced rectal cancer.

Advances in nanotechnology-based platforms for survivin-targeted drug discovery.

INTRODUCTION: Due to its unique functional impact on multiple cancer cell circuits including proliferation, apoptosis, tumor dissemination, DNA damage repair, and immune response, the inhibitor of apoptosis protein (IAP) survivin has gained high interest as a molecular target and a multitude of therapeutics were developed to interfere with survivin expression and functionality. First clinical evaluations of these therapeutics, however, were disappointing highlighting the need to develop advanced delivery systems of survivin-targeting therapeutics. AREAS COVERED: This review focuses on advancements in nanocarriers to molecularly target survivin in human malignancies. A plethora of nanoparticle platforms, including liposomes, polymeric systems, dendrimers, inorganic nanocarriers, RNA/DNA nanotechnology and exosomes, are discussed in the background of survivin-tailored RNA interference, small molecule inhibitors, dominant negative mutants or survivin vaccination or combined modality treatment with chemotherapeutic drugs and photo-dynamic/photothermal strategies. EXPERT OPINION: Novel therapeutic approaches include the use of biocompatible nanoformulations carrying gene silencing or drug molecules to directly or indirectly target proteins, allow for a more precise and controlled delivery of survivin therapeutics. Moreover, surface modification of these nanocarriers may result in a tumor entity-specific delivery. Therefore, nanomedicine exploiting survivin-tailored strategies in a multimodal background is considered the way forward to enhance the development of future personalized medicine.