The therapeutic landscape in locally advanced rectal cancer (LARC) has undergone a significant paradigm shift in recent years with the rising adoption of total neoadjuvant treatment (TNT). This comprehensive approach entails administering chemotherapy and radiation therapy before surgery, followed by optional adjuvant chemotherapy. To establish and deliver the optimal tailored treatment regimen to the patient, it is crucial to foster collaboration among a multidisciplinary team comprising healthcare professionals from various specialties, including medical oncology, radiation oncology, surgical oncology, radiology, and pathology. This review aims to provide insights into the current state of TNT for LARC and new emerging strategies to identify potential directions for future research and clinical practice, such as circulating tumor-DNA, immunotherapy in mismatch-repair-deficient tumors, and nonoperative management.

Background: CNS involvement in acute lymphoblastic leukemia/AUL is a well-recognized event and CNS prophylaxis is considered mandatory. In NHL, meningeal relapse occurs more rarely, ranging from 4–14% depending on histology, anatomical location and biological parameters. Flow cytometric analysis of cerebrospinal fluid (CSF), however, detected occult lymphomatous meningitis in 22% of NHL cases at risk at diagnosis (Hegde et al. Blood2005;105:496). CNS prophylaxis is currently recommended only in high-risk disease (stage IV/high IPI score) and in patients with extranodal NHL. Sustained-release liposomal cytarabine (DepoCyte®), which is licensed for meningeal relapse in NHL, has proved effective in treating lymphomatous and leukemic meningitis (Glantz et al. J Clin Oncol1999;17:3110; Sancho et al. Haematologica2006;91:ECR02). Intrathecal (IT) liposomal cytarabine is distributed throughout the CSF and has an extended half-life, allowing administration once every 2–4 weeks (Chamberlain et al. Arch Neurol1995;52:912). We therefore tested the efficacy of liposomal cytarabine in CNS prophylaxis for elderly patients with aggressive NHL or AUL, with the aim of testing the safety of IT treatment in elderly patients and the efficacy of liposomal cytarabine in preventing lymphoma/leukemia CNS relapse. Methods: From June to November 2005, 4 patients > 70 years of age entered the study. Diagnoses were: 2 stage IV, IPI 3, diffuse large B-cell lymphoma (DLBCL); 1 mantle cell lymphoma (MCL), and 1 AUL; 2 patients had extranodal bulky disease (1 psoas muscle, 1 retro-orbital plus paranasal sinus involvement). As first-line treatment, the 3 NHL cases were given R-CHOP every 21 days for 6 cycles. The patient with AUL received conventional 3-drug induction (vincristine/idarubicine/prednisone) every week for 3 weeks, followed by 3 courses of L-VAMP (vincristine/cytarabine/intermediate-dose methotrexate/leucovorin rescue) and then conventional maintenance (6-mercaptopurine/methotrexate and monthly re-induction with vincristine/prednisone). All patients received CNS prophylaxis with IT liposomal cytarabine 50 mg followed by systemic steroid injection. In NHL cases, IT therapy was given the day before systemic chemotherapy for a total of 4 administrations; in AUL, prophylaxis was given every 4 weeks during induction and maintenance for a total of 6 doses. Results: Three (2 NHL and 1 AUL) patients achieved a complete response (CR) and 1 (NHL) achieved a partial response, with response durations of 4, 5, 6+ and 8+ months, respectively. As of July 2006, after a median follow-up of 10 months (range 9–12), all patients were alive; 2 (1 DLBCL, 1 AUL) were in continuous CR, and 2 (1 DLBCL, 1 MCL) had progressive disease and were receiving second-line treatment. Isolated relapse of leukemia/lymphoma in the CNS was not seen. Liposomal cytarabine was well tolerated; no drug-related side effects or hematological toxicities were recorded. Conclusions: As occult CNS involvement has been shown to occur in >20% of newly diagnosed patients with high-risk NHL, flow cytometry and cytospin analysis of CSF at diagnosis should be implemented in order to adequately target CNS prophylaxis. Liposomal cytarabine should be the drug of choice for CNS prophylaxis, particularly in elderly patients.

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In patients undergoing ASCT, RBC transfusions are depending on donor availability and correlated with early and late side effects such as immune reactions and infections. Three weeks long acting Darbepoietin is currently available, but its role in ASCT in terms of efficacy, safety and cost has not yet been established. Aim: This pilot study was activated in ASCT patients to test the impact of Darbepoietin on the haemoglobin level; RBC transfusion requirement; the total cost of Darbepoietin therapy during the first 30 days after ASCT. Material and methods. From September 2006 to June 2007, 10 patients - 5 males, median age 57 years (range 20–71) - with Multiple Myeloma (MM n=7) in 1st response, Non-Hodgkin (NHL n=2) and Hodgkin (HL n=1) Lymphoma in 2nd complete remission entered the study. As conditioning regimens, the patients received Mel 200 (n=8) or BEAM (n=2). Baseline Hb and Epo median values were: 12,1g/L (range 10.3 – 16.2 g/L), and 28.7mU/mL (range, 4.1–220 mU/L), respectively. The median value of CD34+ cells infused was 4.99 x109/L (range 3.04 – 5.07) and the median time to engraftment was 10 days (range 8–11). To prevent anaemia, patients were given i.c. single dose 500 U Darbepoietin on day +1, associated with iron therapy and B12 vitamin /weekly, plus folinic acid and B6 vitamin/daily. RBC transfusion was mandatory for Hb level ≤ 8g/L. Results: At day +30, in 9/10 patients (7 MM, 1 NHL and 1HL) the median Hb value was 13.2 g/L (range 10.2 – 15.1g/L), and none of them were transfused. Only 1 NHL received 1 RBC unit on day +7 because of Hb was 8g/L; in this case, the baseline dosage of Epo was high (220 mU/L). On the follow-up (median time 4 months, range 1–11), no thromboembolic events or other side effects occurred. Finally, in our Country the price of 1 vial Darbepoietin and 1 RBC transfusion (packed, filtered and irradiated) is 744.60 and 340 euro, respectively. Therefore,, the cost of the entire supportive therapy in our 10 patients has been 7.786 euro. Comments Despite the small number of patients, from this pilot study we can drawn the conclusion that Darbepoietin seems an effective and safe therapy and could represent an appropriate support in ASCT patients with baseline low/normal Epo level. Only a prospective, randomized study on a large number of patients will be able to answer the question on the Darbepoietin cost-efficacy in ASCT.