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Pathological complete response after neoadjuvant chemoradiotherapy in locally advanced rectal cancer patients is related to a favorable prognosis. The identification of early biomarkers predictive of pathological complete response would help optimize the multimodality management of the patients. A panel of 11 tumor-related proteins was investigated by immunohistochemistry in the pretreatment biopsy of a group of locally advanced rectal cancer patients to identify early biomarkers of pathological complete response to neoadjuvant chemoradiotherapy. A mono-institutional retrospective cohort of 95 stage II/III locally advanced rectal cancer patients treated with neoadjuvant chemoradiotherapy and surgery was selected based on clinicalpathological characteristics and the availability of a pretreatment tumor biopsy. Eleven selected protein marker expression (MLH1, GLUT1, Ki67, CA-IX, CXCR4, COX2, CXCL12, HIF1, VEGF, CD44, and RAD51) was investigated. The optimal cutoff values were calculated by receiver operating characteristic curve analysis. Classification and regression tree analysis was performed to investigate the biomarker interaction. Patients presenting either Ki-67 or HIF1 or RAD51 below the cutoff value, or CXCR4 or COX2 above the cutoff value, were more likely to get a pathological complete response. Classification and regression tree analysis identified three groups of patients resulting from the combination of Ki-67 and CXCR4 expression. Patients with high expression of Ki-67 had the lowest chance to get a pathological complete response (18%), as compared to patients with low expression of both Ki-67 and CXCR4 (29%), and patients with low Ki-67 and high CXCR4 expression (70%). Pretreatment Ki-67, CXCR4, COX2, HIF1, and RAD51 in tumor biopsies are associated with pathological complete response after neoadjuvant chemoradiotherapy in locally advanced rectal cancer. A combined evaluation of Ki-67 and CXCR4 would increase their predictive potential. If validated, their optimal cutoff could be used to select patients for a tailored multimodality treatment.

Purpose The purpose of study is to investigate the dosimetry of electron intraoperative radiotherapy (IOERT) of the Intraop Mobetron 2000 mobile LINAC in treatments outside of the breast. After commissioning and external validation of dosimetry, we report in vivo results of measurements for treatments outside the breast in a large patient cohort, and investigate if the presence of inhomogeneities can affect in vivo measurements. Methods and materials Applicator factors and profile curves were measured with a stereotactic diode. The applicators factors of the 6 cm flat and beveled applicators were also confirmed with radiochromic films, parallel-plate ion chamber and by an external audit performed with ThermoLuminescent Dosimeters (TLDs). The influence of bone on dose was investigated by using radiochromic films attached to an insert equivalent to cortical bone, immersed in the water phantom. In vivo dosimetry was performed on 126 patients treated with IOERT using metal oxide-silicon semiconductor field effect transistors (MOSFETs) placed on the tumor bed. Results Relatively small differences were found among different detectors for measurements of applicator factors. In the external audit, the agreement with the TLD was mostly within ±0.2%. The largest increase of dose due to the presence of cortical bone insert was +6.0% with energy 12 MeV and 3 cm applicator. On average, in vivo dose was significantly (+3.1%) larger than prescribed dose. Conclusion IOERT in applications outside the breast results in low discrepancies between in vivo and prescribed doses, which can be also explained with the presence of tissue inhomogeneity.

Purpose To apply the German Hodgkin Study Group (GHSG) risk model in patients with recurrent/refractory Hodgkin lymphoma receiving involved-field radiotherapy after autologous stem cell transplantation. Material and methods The study consisted in the retrospective analysis of 30 consecutive patients with recurrent/refractory Hodgkin lymphoma who received involved-field radiotherapy after autologous stem cell transplantation. Our policy was of adding involved-field radiotherapy for patients with positive PET scan before autologous stem cell transplantation (23 out of 30 patients, 77%), and/or irradiating sites of bulky disease at relapse (11 out of 30 patients, 37%). Patients were stratified into four risk groups according to the presence of the five clinical risk factors identified by the GHSG; (1) stage IV disease; (2) time to relapse ≤ 3 months; (3) ECOG-PS ≥ 1; (4) bulk ≥ 5 cm; and (5) inadequate response to salvage chemotherapy. Results The median interval from autologous stem cell transplantation to involved-field radiotherapy was 3 months (range, 1–7 months), and the median involved-field radiotherapy dose was 35 Gy (range, 12–40 Gy). At a median follow-up of 35 months (range, 1–132 months), the 2-year progression-free survival in the entire series was 60%. When examining the four different GHSG risk groups, the progression-free survival rate at 2 years was 86%, 83%, 50%, and 36% for patients with score = 0, score = 1, score = 2, and score = 3 to 5, respectively (P = 0,01). Among the 12 patients having at least three risk factors who underwent thoracic involved-field radiotherapy, three (25%) developed pneumonitis. Conclusion The adoption of the GHSG risk model at the time of recurrence/progression is a useful prognostic tool to select patients with Hodgkin lymphoma for consolidative involved-field radiotherapy after autologous stem cell transplantation.

Simple Summary Concurrent chemo-radiotherapy is the standard treatment in anal cancer. Intensity-modulated radiotherapy (IMRT) was proved to reduce severe, acute and late toxicities. Moreover, IMRT techniques allow for the planning and delivery of a simultaneous integrated boost (SIB), with a differential dose per fraction given to selected sub-regions during the same treatment session. This boost modality provides the chance to employ a dose-painted approach with a reduction in overall treatment time that could result in a potential clinical advantage. Since a large variability in dose prescription to the primary tumor and elective or involved lymph nodes can be found in available guidelines and clinical practice, a multicenter analysis was conducted to evaluate the pattern of care and the impact of radiotherapy parameters on clinical outcomes for anal cancer patients treated with IMRT techniques within a national cohort. Abstract A multi-institutional retrospective study was conducted to evaluate the pattern of care and clinical outcomes of anal cancer patients treated with intensity-modulated radiotherapy (IMRT) techniques. In a cohort of 987 patients, the clinical complete response (CR) rate (beyond 6 months) was 90.6%. The 3-year local control (LC) rate was 85.8% (95% CI: 84.4–87.2), and the 3-year colostomy-free survival (CFS) rate was 77.9% (95% CI: 76.1–79.8). Three-year progression-free survival (PFS) and overall survival (OS) rates were 80.2% and 88.1% (95% CI: 78.8–89.4) (95% CI: 78.5–81.9), respectively. Histological grade 3 and nodal involvement were associated with lower CR (p = 0.030 and p = 0.004, respectively). A statistically significant association was found between advanced stage and nodal involvement, and LC, CFS, PFS, OS and event-free survival (EFS). Overall treatment time (OTT) ≥45 days showed a trend for a lower PFS (p = 0.050) and was significantly associated with lower EFS (p = 0.030) and histological grade 3 with a lower LC (p = 0.025). No statistically significant association was found between total dose, dose/fraction and/or boost modality and clinical outcomes. This analysis reports excellent clinical results and a mild toxicity profile, confirming IMRT techniques as standard of care for the curative treatment of anal cancer patients. Lymph node involvement and histological grade have been confirmed as the most important negative prognostic factors.

PurposeTo explore the feasibility and efficacy of a dose intensification with Intensity Modulated Radiation Therapy and Simultaneous Integrated Boost (IMRT-SIB) in locally advanced esophageal and gastroesophageal cancer (GEJ).Methods and MaterialsWe retrospectively analyzed a series of 69 patients with esophageal or GEJ cancer treated at our Institute, between 2016 and 2019, with preoperative IMRT and SIB up to 52.5–54 Gy in 25 fractions in 5 weeks and concurrent carboplatin (AUC2) and paclitaxel (50 mg/m2), as in the CROSS regimen.ResultsAll patients completed the planned IMRT–SIB program with a median of four (range 1–5) cycles of concurrent paclitaxel/carboplatin. Compliance to IMRT–SIB was 93%, whereas 54% of patients received four to five cycles and 87% at least three cycles of concurrent carboplatin/paclitaxel. Grade 3 toxicity was reported in 19% of patients. Complete clinical response (cCR) was achieved in 48%, and 13% had disease progression after chemoradiation (CRT). Overall, 49% of patients underwent surgery; reasons for non-operation included cCR in cervical tumor location (10%) or cCR and patient decision (13%). A pathologic complete response (pCR) was achieved in 44% of resected patients. Postoperative complications and mortality rates were 21 and 6%, respectively. At a median follow-up of 12 months (6–25), 2-year overall and progression-free (PFS) survival rates were 81 and 54%, respectively. No difference in PFS by histologic type in operated patients was reported. Non-operated cCR patients had higher PFS, including cervical locations and selected cCR patients who decided for non-operation (75 vs 30%, p < 0.01).ConclusionThe study reported favorable results in safety and feasibility of the IMRT–SIB dose intensification in our preoperative CRT program. The toxicity was acceptable, allowing a high compliance to intensified radiation doses with dose reduction of concurrent paclitaxel/carboplatin in some patients. The high rate of cCR and pCR suggested this intensified program is effective in the preoperative CRT and, for selected responsive patients, in the non-operative approach to esophageal and GEJ cancer. The 2-year survival rates were promising. A prospective study is being planned to confirm these observations.

To assess safety, feasibility and efficacy of an intensified preoperative IMRT and concomitant carboplatin and paclitaxel-based chemotherapy (Carbo/Tax CT) in patients (pts) with locally advanced esophageal cancer (LAEC) treated at our Institution. Methods a retrospective analysis of toxicity (CTCAE 4.03), progression free survival (PFS) and overall survival (OS) of pts affected by LAEC, treated with preoperative intensified radiotherapy (IMRT) and weekly concurrent carboplatin and paclitaxel-based chemotherapy (CT) according to the CROSS trial, between February 2016 and October 2019, at the Centro di Riferimento Oncologico, Aviano (CRO). Results Sixty-nine consecutive pts, 57(82.6%) males, were treated. The median age was 69 yrs (38–85), the ECOG PS 0–2. All pts underwent concurrent chemoradiotherapy, IMRT technique, 45 Gy/25 to PTV1 (primary tumor volume + regional nodes), a simultaneous boost from 52.5Gy to 54Gy to PTV2 (gross tumor volume) and weekly concurrent carboplatin (AUC2) and paclitaxel (50 mg/m2). Induction CT was administered to 17 pts. All pts completed RT with median 4 (1–5) CT cycles. Median follow-up was 8 months (4–17); 2-yr PFS and OS were 49.0% and 80.3%, respectively. At 2 yrs, local recurrence rate was 8.4% (CI 95%: 2.6%–18.8%). Conclusion Preoperative intensified IMRT with concomitant Carbo/Tax CT in pts with LAEC appears safe and feasible with promising oncological outcome and needs to be confirmed in a larger series of pts.

Purpose: The aim of this study is to evaluate the long term survival of the addition of gefitinib to chemoradiotherapy (CRT) in locally advanced rectal cancer (LARC). Methods and materials: This previously published multicentre, open-label, phase I-II study, enrolled patients (pts) with LARC to receive CRT with concurrent 5-fluorouracil continuous intravenous infusion and a dose escalation of orally administered gefitinib, followed 6–8 weeks later by surgery. An intra-operative radiotherapy boost of 10 Gy was planned. Adjuvant chemotherapy was administrated in ypN1-2 pts. After a median f/u of >10 years, we analyzed Local Control (LC), Metastasis Free Survival (MFS), Disease Free Survival (DFS), Disease Specific Survival (DSS) and Overall Survival (OS). Predictive endpoints of clinical outcomes were tested by univariate and multivariate analysis. Variables analyzed included: age, gefitinib dose and interruptions, adjuvant CT, surgery type, ypT, ypN, and TRG grade. We have also analyzed late toxicity according to CTCAEv4. Results: Of the 41 initially enrolled pts, 39 were evaluable (27M, 12F). With a median f/u of 133 months, LC, MFS, DFS, OS and DSS at 5 years were 84%; 71%; 64%; 87% and 92%, respectively. The OS and DSS at 10 years were 61,5% and 76%, respectively. Grade 3-4 late toxicity occurred in 38% of pts: sexual (28,2%) and gastrointestinal toxicities (10,2%). Conclusion: Long term outcomes and late toxicity were similar to previously reported series. The addition of gefitinib did not improve outcomes in LARC. Gefitinib is not recommended for rectal cancer patients who received 5-FU based preoperative CRT. Further studies may identify if gefitinib is beneficial in selected group of patients. Keywords: Rectal cancer, Gefitinib, Log term follow-up, Chemoradiotherapy

Background and purpose: The role of the immune system in tumor response to chemo-radiotherapy (CRT) is an emerging issue. This work aimed at identifying predictive and prognostic immunogenetic variants in LARC patients after preoperative (po)-CRT and surgery. Materials and methods: A set of 192 polymorphisms in 34 candidate genes involved in the regulation of the immune response signalling network, was selected and analyzed in 370 LARC patients treated with po-CRT and surgery, split into a Test Set (n = 233) and a Validation Set (n = 137). Immunogenetic markers were selected based on a concordant significant effect on 2-year relapse-free survival (2-yrRFS) (bootstrapped P < 0.05) in both patients Sets. The effect of the selected immunogenetic variants on 5-year metastases-free (5yrMFS), 5-year disease-free (5yrDFS), and 10-year overall (10yrOS) survival was tested in the entire Set of 370 patients. Results: Two immunogenetic IL17F (IL17F-rs641701 and IL17F-rs9463772) markers predictive of 2yrRFS, 5yrDFS, 5yrMFS, and 10yrOS were identified. The combination of tumor regression grade (TRG) and patients genotype for IL17F-rs641701 and IL17F-rs9463772 allowed the identification of subgroups of patients with differential prognosis in term of both 5yrDFS (HR 11.29, P-value

Persistent infection with high-risk Human Papilloma Virus (HPV) leads to the development of several tumors, including cervical, oropharyngeal, and anogenital squamous cell carcinoma. In the last years, the use of high-throughput sequencing technologies has revealed a number of non-coding RNA (ncRNAs), distinct from micro RNAs (miRNAs), that are deregulated in HPV-driven cancers, thus suggesting that HPV infection may affect their expression. However, since the knowledge of ncRNAs is still limited, a better understanding of ncRNAs biology, biogenesis, and function may be challenging for improving the diagnosis of HPV infection or progression, and for monitoring the response to therapy of patients affected by HPV-driven tumors. In addition, to establish a ncRNAs expression profile may be instrumental for developing more effective therapeutic strategies for the treatment of HPV-associated lesions and cancers. Therefore, this review will address novel classes of ncRNAs that have recently started to draw increasing attention in HPV-driven tumors, with a particular focus on ncRNAs that have been identified as a direct target of HPV oncoproteins.

Background Primary cardiac sarcomas (PCS) have a dismal prognosis (a reported median survival of 17 months). Complete surgical resection is the mainstay of treatment, but the resection may be incomplete or impossible because of the local extension. Multimodal treatment (MMT) with chemotherapy and radiotherapy (RT) is widely used in soft tissue sarcomas of the extremities, improving survival, and could be considered for PCS. A consequence of the inclusion of the heart in a radiation field, is acute and chronic radiation-induced heart disease (RIHD). New RT techniques, as Intensity Modulated Radiotherapy (IMRT) reduce the risk, focusing the radiation burden to the target neoplasm and limiting the involvement of the cardiac structures. Nevertheless, RT is rarely used in PCS, because the target lesion is inside the heart, and the heart's movement make difficult to avoid the irradiation of the surrounding structures. Purpose Our aim was to report the short and long term clinical and echocardiographic changes in patients (pts) with cardiac sarcomas treated with IMRT. Methods Amongst a group of 33 with PCS seen in our hospitals, we reviewed the data of 20 pts (12 males, 8 females) with PCS treated with local RT. The tumors were left-sided in 10 pts, right-sided in 8 and involved both right and left chambers in 2; fifteen patients had received also anthracyclines chemotherapy (CT). For every patient, we reviewed the clinical data and the echocardiograms performed (as for protocol) before and after CT, before starting RT, weekly during RT and at follow-up (FU), performed every 3 months for 2 years, every 6 months for 3 more years, then yearly. The mean age at diagnosis was 48 years (range 22–72). The FU lasted 2 to 131 months (mean 31, median 14). Five pts are alive 29–85 months (mean 57), after ending therapies, the others died of non-cardiac causes. Results At the end of RT 3 pts had atrial fibrillation (AF), which was cardioverted with Amiodarone, and one had acute pericarditis, treated with non-steroidal anti-inflammatory drugs for one week. Long-term therapy was not needed. The left ventricular ejection fraction (LVEF) was 52% to 70%, decreased by −1% to −10% in 10 pts. At last FU, LVEF ranged from 52 to 75%; it decreased (compared to baseline) by >11% in 1 pt only; global longitudinal LV strain (GLS), available in 8 pts only, was −17%. Amongst the pts with IMRT on the right heart, right ventricular function (evaluated by tricuspid annulus excursion, and right ventricular area shortening fraction) was within normal limits in all both at short and long term FU. There were no cases of constrictive pericarditis or of valvular disease. Conclusion In our experience IMRT for heart sarcomas seems to be relatively safe using modern RT techniques, without evident RIHD at long term follow-up. Larger studies are necessary to further evaluate the safety of RT in the multimodal treatment of cardiac sarcomas.

Background: Gastric cancer (GC) is the third leading cause of cancer mortality and the fifth most commonly diagnosed malignant disease. While continued efforts have been focused on GC treatment, the introduction of trastuzumab marked the beginning of a new era of target-specific treatments. Considering the diversity of mutations in GC, satisfactory results obtained from various target-specific therapies were expected, yet most of them were unsuccessful in controlled clinical trials. There are several possible reasons underlying the failures, including the absence of patient selection depending on validated predictive biomarkers, the inappropriate combination of drugs, and tumor heterogeneity.

Since benefits have been demonstrated in trials with perioperative chemotherapy, postoperative chemoradiotherapy, and preoperative chemoradiotherapy for patients with locally advanced gastric cancer, a second generation of randomized clinical trials evaluated some refinements of these treatment strategies. These trials included innovative combined modality programs with new drug-radiation combinations and advanced radiation therapy techniques followed by standardized gastric radical surgery to answer the several questions that emerged from the original landmark trials. The results of these trials have been recently reported and will be analyzed. Questions about patient selection and the optimal sequence and timing of treatments in the integrated approach still remain. As tumor location and histologic subtypes are associated to different aggressiveness, treatment response, and prognosis, future studies need to give more focus on gastroesophageal junction and stomach cancer as separate diseases to provide more solid data in these established tumor types. Furthermore, the new insights into histological patterns and molecular characterization of individual tumor subtype could address new and more individualized generation of combined modality treatment programs.

Improvements in prognosis of head-and-neck squamous cell carcinoma (HNSCC) have paralleled with an increase in health-care costs, so that an economic evaluation is of growing importance. Presently, most of the evidence is from insurance-based studies in the USA. Between 2007 and 2010, 879 HNSCC patients were identified through the population-based cancer registry of the Friuli Venezia Giulia region, including 266 oral, 187 oropharyngeal, 136 hypopharyngeal, and 290 laryngeal cancers. Health-care costs from diagnosis to treatment initiation and in the following 2 years were retrieved through a record linkage with the regional health data warehouse. This database collected comprehensive health information on all resident citizens. Generalized linear models with a gamma distribution and log-link function were applied to model costs. The average health-care cost from diagnosis up to 2 years after treatment initiation was €20,184 (95% confidence interval: €19,634 − 20,733). Heterogeneity emerged according to cancer site, elective treatment, and retreatment for cancer persistence/recurrence (no: €13,896; yes: €24,599; p

Lack of information on the clinical utility of preemptive DPYD screening before fluoropyrimidine treatment is a major barrier preventing its use in clinical practice. This study aimed to define the association between DPYD variants and fluoropyrimidine-related toxicity management costs. A cost analysis was conducted on the toxicities experienced by 550 patients with colorectal cancer treated with fluoropyrimidine-based chemotherapy. Genotyping for DPYD*2A, DPYD*13, DPYDc. 2846A>T, DPYD-HapB3, and UGT1A1*28 was done retrospectively and did not affect patients' treatments. Carriers of at least one DPYD variant experienced higher toxicity management costs (€2,972; 95% confidence interval (CI), €2,456-€3,505) than noncarriers (€825; 95% CI, €785-€864) (P

Background: Preoperative chemoradiotherapy (CRT) followed by surgery is the standard care for locally advanced rectal cancer, but tumour response to CRT and disease outcome are variable. The current study aimed to investigate the effectiveness of plasma telomerase reverse transcriptase (TERT) levels in predicting tumour response and clinical outcome. Methods: 176 rectal cancer patients were included. Plasma samples were collected at baseline (before CRT=T0), 2 weeks after CRT was initiated (T1), post-CRT and before surgery (T2), and 4–8 months after surgery (T3) time points. Plasma TERT mRNA levels and total cell-free RNA were determined using real-time PCR. Results: Plasma levels of TERT were significantly lower at T2 (P

Purpose The study of the change of radiomic features extracted from cone-beam CT acquired before each fraction for IGRT opens a new, promising scenario for assessing tumor response to radiotherapy during the treatment [1] . In this preliminary study, we investigated if radiomic features of rectal cancer treated with VMAT extracted from CBCT change significantly in the course of the radiotherapy treatment. Methods and materials 8 patients underwent VMAT for rectal cancer with 54 Gy in 25 fractions. For each patient, the GTV was manually contoured on three CBCT images acquired for IGRT at the first fraction, middle (12th) and last fraction of RT. All the CBCT images were acquired with 125 kVp and 80 mA with a Varian Clinac Trilogy, and the intensity levels of CBCT images were equalized using the mean intensity level of a ROI in the bladder as reference. Radiomic features were extracted after image denoising and smoothing from 3D tumor regions, and can be classified into: shape-based, histogram-intensity and higher-order texture features. The feature changes were evaluated between last and mid-fraction (Delta1), and between last and first fraction (Delta2). Wilcoxon signed-rank test was used to test for significant changes of features. Results 18 features had significant Delta1 and 23 had Delta2, while 12 had both changes of statistical relevance (p Conclusions The results exhibit significant changes of radiomic features extracted from daily CBCT images at different treatment times, showing the possibility for studying early response of tumor during therapy and develop a radiomics-adapted radiotherapy approach. The correlation of feature changes with tumor response at the end of therapy will be subject of ongoing investigation.

4066 Background: This study evaluates the feasibility, safety and efficacy of a trimodality treatment, with surgery postponed after neoadjuvant chemotherapy (CT) and chemoradiotherapy (CRT), in LAGC. Methods: Patients (pts) with cT3-4 and/or N+ LAGC were eligible. Staging included endoscopic ultrasound, PET-CT and laparoscopy. Three cycles of EOX (Epirubicyn 50mg/m2,q21 days, Oxaliplatin 130mg/m2,q21 days, and Capecitabine 625mg/m2 bid, by continuous oral administration (c.a.), followed by IMRT with 45Gy/25 frs, concurrent Capecitabine 625mg/m2 bid c.a. and weekly Oxaliplatin 30mg/m2 for 5 wks, was planned. Early PET-CT was performed after the 2nd EOX cycle to assess response or disease progression. Restaging was repeated after CT and CRT. Surgery was planned 4-6 wks after CRT, 22 wks from the start of NEOX-RT. Pathologic complete response (pCR) was the primary endpoint. Results: From November 2008 to March 2016, 51 pts (5 G-E Junction, 17 Cardia, 15 Corpus, 14 Antrum) entered the study. The NEOX-RT program was completed in 46 pts (90%) who proceeded to surgery and are assessable. Grade 3-4 toxicity (NCI-CTC criteria v.3) occurred in 13/51 pts (25%) during EOX, including 1 toxic death, and 9.5% CT cycles required dose modification, resulting in a CT compliance of 90%. No pts had progression during CT. Persistent G2-G3 toxicity occurred in 32/46 pts (69%) during CRT. However, 41/46 pts (89%) received the planned 45Gy with Capecitabine at dose ≥75% and 4-5 cycles of weekly Oxaliplatin in 52% pts. Curative resection (R0) rate was 89%; 4 pts (8.7%) had peritoneal carcinomatosis at surgery done after a median of 23 wks. pCR was reported in 9/46 pts (19.6%). Major postop complications occurred in 5 pts (11%). At median f-up of 62 mos (23-109), 5-yr OS and DFS in all and pCR pts were 58%, 100% and 51%, 75%, respectively. Conclusions: This trimodality program was feasible and safe. Most pts completed the planned treatment. The pCR rate of 19.6% was remarkable and met the hypothesis of pCR = 20%. A high R0 rate was also reported and delayed surgery didn’t increase complications. The notable survival rates are available to be compared with ongoing phase III trials. Clinical trial information: 2008-002715-40.

Highlights • A large population based analysis to evaluate pathologic response according to time of surgery. • LARC patients were treated with modern techniques of radiotherapy and surgery. • The rate of pCR increased according to time interval from 12.6% to 31.1%. • The pCR increasing was 1.5% (about 0.2%/die) per each week of waiting. • Lengthening the interval (>13 weeks) significantly improved the pathological response., Background To retrospectively evaluate the difference in terms of pathologic complete response (pCR) according to time elapsed between chemoradiation (CRT) and total mesorectal excision (TME) on a large unselected real-life dataset of locally advanced rectal cancer (LARC) patients. Methods A multicentre retrospective cohort study of LARC patients from 21 Italian Radiotherapy Institutions was performed. Patients were stratified into 3 different time intervals from CRT. The 1st group included 300 patients who underwent TME within 6 weeks, the 2nd 1598 patients (TME within 7–12 weeks) and the 3rd 196 patients (TME within 13 or more weeks after CRT), respectively. Results Data on 2094 LARC patients treated between 1997 and 2016 were considered suitable for analysis. Overall, 578 patients had stage II while 1516 had stage III histological proven invasive rectal adenocarcinoma. A CRT schedule of one agent (N = 1585) or 2-drugs (N = 509) was administered. Overall, pCR was 22.3% (N = 468 patients). The proportion of patients achieving pCR with respect to time interval was, as follows: 12.6% (1st group), 23% (2nd group) and 31.1% (3rd group) (p 5040 cGy (p = 0.002) and longer interval (p 13 weeks) from CRT to surgery improves the pathological response (pCR and pathologic partial response; pPR) in comparison to historic data. Furthermore, radiotherapy dose >5040 cGy and two drugs chemotherapy correlated with pPR rate.

Background Preoperative radiotherapy (RT) in combination with fluoropyrimidine-based chemotherapy (CT) is the standard of care in patients with locally advanced, T3-T4 N0–2, rectal cancer (LARC). Given the correlation between RT dose-tumor response and the prognostic role of the tumor regression grade (TRG), treatment intensification represents an area of active investigation. The aim of the study was to analyze the role of RT dose-intensification in the preoperative treatment of LARC in terms of feasibility, efficacy and toxicity. Methods We retrospectively analyzed patients with LARC treated with intensity-modulated radiotherapy (IMRT) and simultaneous integrated boost (SIB) at five Italian radiation oncology centers. Concurrent Capecitabine was administered. Treatment response was evaluated in terms of disease down-staging and TRG. Acute toxicity was evaluated according to the CTC-AE 4.0 scale. Results A total of 76 patients were identified for this analysis. A dose of 45 Gy was prescribed to the entire mesorectum and pelvic lymph nodes with a median SIB dose of 54 Gy (range 52.5–57.5) to the tumor and corresponding mesorectum. Overall, 74/76 (97.4%) patients completed the planned RT, whereas 64/76 (84.2%) patients completed the prescribed CT. Eight (10.5%) patients developed grade 3–4 acute toxicity. Overall, 72/76 patients underwent surgery. The tumor and nodal down-staging was documented in 51 (70.8%) and 43 (67%) patients, respectively. Twenty (27.8%) patients obtained a pathologic complete response. Surgical morbidity was reported in 13/72 patients (18.1%). Conclusions Although retrospective in design, this study indicates that IMRT-SIB with a dose range of 52.5–57.5 Gy (median 54 Gy) and concomitant Capecitabine appears feasible, well tolerated and effective in terms of disease down-staging and pathological complete response. Long-term toxicity and the impact on disease control and patient survival will be evaluated with a longer follow-up time. Trial registration NA

Purpose We sought to determine whether the total body irradiation (TBI) schedule affected outcome in patients with acute leukemia in complete remission who received T cell–depleted allogeneic hematopoietic stem cell transplantation from HLA identical siblings. Methods and Materials The study recruited 55 patients (median age, 48 years; age range, 20-66 years; 30 men and 25 women; 34 with acute myeloid leukemia and 21 with acute lymphoid leukemia). Hyperfractionated TBI (HTBI) (1.2 Gy thrice daily for 4 days [for a total dose of 14.4 Gy] from day −12 to day −9) was administered to 29 patients. Single-dose TBI (STBI) (8 Gy, at a median dose rate of 10.7 cGy/min on day −9) was given to 26 patients. Results All patients achieved primary, sustained engraftment with full donor-type chimerism. At 10 years, the overall cumulative incidence of transplant-related mortality was 11% (SE, ±0.1%). It was 7% (SE, ±0.2%) after HTBI and 15% (SE, ±0.5%) after STBI ( P =.3). The overall cumulative incidence of relapse was 33% (SE, ±0.5). It was 13% (SE, ±0.5%) after HTBI and 46% (SE, ±1%) after STBI ( P =.02). The overall probability of disease-free survival (DFS) was 59% (SE, ±7%). It was 67% (SE, ±0.84%) after HTBI and 37% (SE, ±1.4%) after STBI ( P =.01). Multivariate analyses showed the TBI schedule was the only risk factor that significantly affected relapse and DFS ( P =.01 and P =.03, respectively). Conclusions In patients with acute leukemia, HTBI is more efficacious than STBI in eradicating minimal residual disease after HLA-matched T cell–depleted hematopoietic stem cell transplantation, thus affecting DFS.

Neoadjuvant chemoradiotherapy (nCRT) followed by radical surgery is the standard of care for patients with Locally Advanced Rectal Cancer (LARC). Current selection for nCRT is based on clinical criteria regardless of any molecular marker. Pharmacogenomics may be a useful strategy to personalize and optimize nCRT in LARC. This review aims to summarize the most recent and relevant findings about the role of germline and somatic pharmacogenomics in the prediction of nCRT outcome in patients with LARC, discussing the state of the art of their application in the clinical practice. A systematic literature search of the PubMed database was completed to identify relevant English-language papers published up to January 2020. The chemotherapeutic backbone of nCRT is represented by fluoropyrimidines, mainly metabolized by DPD (Dihydro-Pyrimidine Dehydrogenase, DPYD). The clinical impact of testing DPYD*2A, DPYD*13, c.2846A > T and c.1236G > A-HapB3 before a fluoropyrimidines administration to increase treatment safety is widely acknowledged. Other relevant target genes are TYMS (Thymidylate Synthase) and MTHFR (Methylene-Tetrahydro-Folate Reductase), whose polymorphisms were mainly studied as potential markers of treatment efficacy in LARC. A pivotal role of a TYMS polymorphism in the gene promoter region (rs34743033) was reported and was pioneeringly used to guide nCRT treatment in a phase II study. The pharmacogenomic analysis of other pathways mostly involved in the cellular response to radiation damage, as the DNA repair and the activation of the inflammatory cascade, provided less consistent results. A high rate of somatic mutation in genes belonging to PI3K (Phosphatidyl-Inositol 3-Kinase) and MAPK (Mitogen-Activated Protein Kinase) pathways, as BRAF (V-raf murine sarcoma viral oncogene homolog B1), KRAS (Kirsten Rat Sarcoma viral oncogene homolog), NRAS (Neuroblastoma RAS viral (v-ras) oncogene homolog), PIK3CA (Phosphatidyl-Inositol-4,5-bisphosphate 3-Kinase, Catalytic Subunit Alpha), as well as TP53 (Tumor Protein 53) was reported in LARC. Their pharmacogenomic role, already defined in colorectal cancer, is under investigation in LARC with promising results concerning specific somatic mutations in KRAS and TP53, as predictors of tumor response and prognosis. The availability of circulating tumor DNA in plasma may also represent an opportunity to monitor somatic mutations in course of therapy.