ShorTrip Trial: A Prospective, Multicentric Phase II Single-Arm Trial of Short-Course Radiotherapy Followed by Intensified Consolidation Chemotherapy With the Triplet FOLFOXIRI as Total Neoadjuvant Therapy in Locally Advanced Rectal Cancer.

BACKGROUND: In patients with locally advanced rectal cancer (LARC) treated with preoperative (chemo) radiotherapy and surgery, adjuvant chemotherapy is poorly feasible and its benefit is questionable. In the last years, several total neoadjuvant treatment (TNT) strategies, moving the adjuvant chemotherapy to the neoadjuvant setting, have been investigated with the aim of improving compliance to systemic chemotherapy, treating micrometastases earlier and then reducing distant recurrence. PATIENTS AND METHODS: ShorTrip (NTC05253846) is a prospective, multicentre, single-arm phase II trial where 63 patients with LARC will be treated with short-course radiotherapy followed by intensified consolidation chemotherapy with FOLFOXIRI regimen and surgery. Primary endpoint is pCR. Among the first 11 patients who started consolidation chemotherapy, a preliminary safety analysis showed a high rate of grade 3 to 4 neutropenia (N = 7, 64%) during the first cycle of FOLFOXIRI. Therefore, the protocol has been emended with the recommendation to omit irinotecan during the first cycle of consolidation chemotherapy. After amendment, in a subsequent safety analysis focused on the first 9 patients treated with FOLFOX as first cycle and then with FOLFOXIRI, grade 3 to 4 neutropenia was reported in only one case during the second cycle. AIM OF THE STUDY: The aim of this study is to assess the safety and activity of a TNT strategy including SCRT, intensified consolidation treatment with FOLFOXIRI and delayed surgery. After protocol amendment, the treatment seems feasible without safety concern. Results are expected at the end of 2024.

Total neoadjuvant treatment and organ preservation strategies in the management of localized rectal cancer: A narrative review and evidence-based algorithm.

The multimodal approach with total mesorectal excision preceded by neoadjuvant (chemo)radiotherapy represented the mainstay treatment for locally advanced rectal cancer (LARC) for a long time. However, the benefit of adjuvant chemotherapy in terms of distant relapse reduction is limited. Recently, chemotherapy regimens administered before surgery and incorporated with (chemo)radiotherapy in total neoadjuvant treatment protocols have been established as new options in the management of LARC. Meanwhile, patients with clinical complete response to neoadjuvant treatment can benefit from organ preservation strategies, aimed at sparing surgery and long-term post-operative morbidities, while preserving an adequate disease control. However, the introduction of a non-operative management in clinical practice is a matter of debate with some concerns regarding the risk of local recurrence and long-term outcomes. In this review, we discuss how these recent advances are reshaping the multimodal management of localized rectal cancer and propose an algorithm to place them in the clinical practice.

Lymph-vascular Space Involvement and/or p53 Overexpression Correlated With the Clinical Outcome of Early-stage Endometrial Cancer Patients Treated With Adjuvant Vaginal Brachytherapy.

BACKGROUND/AIM: The majority of patients with endometrial cancer (EC) are diagnosed at an early stage and undergo primary surgery, followed by observation or adjuvant therapy according to risk factors on surgical samples. The objective of this study was to assess the correlation between a risk profile represented by the presence of substantial lymph-vascular space involvement (LVSI) and/or p53 overexpression and the clinical outcome of patients with early-stage endometrial cancer (EC) who received adjuvant vaginal brachytherapy (BT). PATIENTS AND METHODS: This investigation assessed 79 patients who underwent hysterectomy, bilateral salpingo-oophorectomy, and pelvic and/o aortic lymphadenectomy or sentinel lymph node biopsy followed by hypofractionated (HDR)-vaginal BT, using 192Ir source, for stage I-II endometrioid (n=70) or non-endometrioid (n=9) EC. Thirty-four patients (43.0%) were considered to have an unfavorable risk profile defined by the presence of substantial LVSI and /or p53 overexpression. RESULTS: Five-year disease-free survival (DFS) and five-year overall survival (OS) were 93.7% and 95%, respectively. There was a significant correlation between unfavorable risk-profile and pelvic recurrence rate (p=0.002) and distant recurrence rate (p=0.017). Patients with abnormal p53 had a higher risk of local relapse (p=0.041). Substantial LVSI was strongly associated with pelvic recurrence (p=0.001) and distant metastasis (p<0.001). CONCLUSION: The presence of substantial LVSI and/or p53 overexpression strictly correlated with poor outcome of patients with early-stage EC and should be taken into consideration for better planning adjuvant treatment in this clinical setting.

Impact of temporalis muscle thickness in elderly patients with newly diagnosed glioblastoma treated with radio or radio-chemotherapy.

BACKGROUND: There is an unmet need for new biomarkers able to predict both the outcomes of up-front therapy and the compliance of elderly patients diagnosed with glioblastoma. For this purpose, temporal muscle thickness is a promising tool to be investigated. METHODS: Data from 52 glioblastoma patients older than 65 years, treated with post-operative radio or radio-chemotherapy and referred to Pisa University Hospital, were retrieved. The thickness of temporal muscle (TMT) was divided into quartiles and correlated with overall survival (Our primary endpoint). Survival curves were calculated using Kaplan-Meier method, and log-rank test was used to evaluate the differences between curves. RESULTS: Patients in the lower quartile of TMT, with TMT thinner than 7 mm, have survived longer; both univariate and multivariate analyses showed a statistically significant correlation between TMT and overall survival (P = 0.012 and P = 0.003, respectively). CONCLUSION: Future prospective and more extensive studies focused on elderly glioblastoma patients are needed to confirm the role of TMT as prognostic value on OS and to help explaining this association.

Photon-based High-dose Single-fraction Radiosurgery, an Effective Treatment Modality for Large and Posterior Uveal Melanoma.

BACKGROUND/AIM: Uveal melanoma (UM) is the most common primary intraocular malignant tumor. This malignancy is frequently treated using brachytherapy, stereotactic radiotherapy, or proton therapy. The objective of this study was to assess the role of stereotactic radiosurgery in the treatment of large and posterior UM. PATIENTS AND METHODS: From January 2014 to July 2021, we treated 65 patients (median age=71 years; range=31-89 years) affected by UM. Inclusion criteria were Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤2, life expectancy >6 months, tumor thickness >10 mm, diameter >16 mm or posterior UM. The treatment was delivered with a True Beam™ LINAC with arc modulation technique. All patients received 27 Gy in one fraction (biological effective dose ≈100 Gy, assuming an α/ß of 10). RESULTS: The median follow-up was 36 (range=3-90) months. Acute toxicities were reported in 14 patients, whereas late toxicity occurred in 45 (69.2%). Fifteen patients (23.0%) underwent enucleation: eight (12.3%) for failure of local control and seven (10.7%) for late treatment co-morbidities. The 5-year local control, and progression-free, metastasis-free, enucleation-free, and overall survival rates were 80%, 43%, 62%, 65% and 56%, respectively. In multivariate analysis, tumor dimensions significantly influenced survival [larger basal diameter: progression-free [hazard ratio (HR)=2.42] and overall (HR=2.61) survival; greater thickness: overall survival (HR=2.36)]. In multivariate analysis, patients without local control had a higher risk of distant metastasis (HR=3.25). CONCLUSION: Stereotactic radiosurgery offers an effective and safe approach for selected cases of UM due to the satisfactory results in terms of local control, eye conservation and survival.

MRI-based radiomics: promise for locally advanced cervical cancer treated with a tailored integrated therapeutic approach.

OBJECTIVE: To assess prognostic factors by analyzing clinical and radiomic data of patients with locally advanced cervical cancer (LACC) treated with definitive concurrent cisplatin-based chemoradiotherapy (CCRT) using magnetic resonance imaging (MRI). METHODS: We analyzed radiomic features from MRI in 60 women with FIGO (International Federation of Gynecology and Obstetrics) stage IB2-IVA cervical cancer who underwent definitive CCRT 45-50.4 Gy (in 25-28 fractions). Thirty-nine (65.0%) received EBRT sequential boost (4-20 Gy) on primary tumor site and 56 (93.3%) received high-dose-rate brachytherapy boost (6-28 Gy) (daily fractions of 5-7 Gy). Moreover, 71.7% of patients received dose-dense neoadjuvant chemotherapy for 6 cycles. The gross tumor volume was defined on T2-weighted sequences and 29 features were extracted from each MRI performed before and after CCRT, using dedicated software, and their prognostic value was correlated with clinical information. RESULTS: In univariate analysis, age ⩾60 years and FIGO stage IB2-IIB had significantly better progression-free survival (PFS) (p = 0.022 and p = 0.009, respectively). There was a trend for significance for worse overall survival (OS) in patients with positive nodes (p = 0.062). In multivariate analysis, only age ⩾60 years and FIGO stage IB2-IIB reached significantly better PFS (p = 0.020 and p = 0.053, respectively). In radiomic dataset, in multivariate analysis, pregray level p75 was significantly associated with PFS (p = 0.047), pre-D3D value with OS (p = 0.049), and preinformation measure of correlation value with local control (p = 0.031). CONCLUSION: The combination of clinical and radiomics features can provide information to predict behavior and prognosis of LACC and to make more accurate treatment decisions.

High-dose-rate brachytherapy for non-melanoma skin cancer using tailored custom moulds - a single-centre experience.

AIM OF THE STUDY: The aim of this retrospective study was to analyse tumour control, toxicity, and aesthetic outcome of patients affected by non-melanoma skin cancer (NMSC) treated with 192 Ir high-dose-rate (HDR)-brachytherapy (BT) at the Division of Radiotherapy, University of Pisa. MATERIAL AND METHODS: From January 2014 to December 2019 we treated 37 patients (median age 79 years; range 31-91 years) affected by NMSC, with the following histological subtypes: 62.2% basal cell carcinoma and 37.8% squamous cell carcinoma. We analysed 40 lesions with a depth ≤ 5 mm, located in 40.0% scalp, 17.5% nose, 25.0% face, and 17.5% ear, all treated with 192 Ir-based HDR-BT, using tailored custom moulds, with a median of 5 catheters (range, 1-9) spaced 1 cm apart. The most common fractionation scheme was 40 Gy in 8 daily fractions; the biological effective dose was 60 Gy. RESULTS: The median follow-up was 25 months (range, 3-70 months). The 2-year local control rate was 90%. Common terminology criteria for adverse event (CTCAE vs. 5.0) G1 toxicities were dermatitis (52%), pain (25%), and ulceration (22%). The only G2 acute toxicities were dermatitis and ulceration. The most common G1 late toxicities were fibrosis (17%), atrophy (15%), and hypopigmentation (12%). No G3 or higher acute or late toxicity was reported. Excellent cosmetic results were observed in 65.0% of the lesions; only 1 case (2.5%) reported a poor cosmetic result. CONCLUSIONS: Surface mould HDR-BT is a safe, effective, and well tolerated treatment modality for NMSC and can be considered a good alternative, especially for elderly patients who are often unfit for surgery.

Association of XRCC3 rs1799794 polymorphism with survival of glioblastoma multiforme patients treated with combined radio-chemotherapy.

This study reports the results of a monocentric prospective analysis conducted with the aim of evaluating the impact of XRCC1 rs25487, XRCC3 rs861539, XRCC3 rs1799794, RAD51 rs1801320 and GSTP-1 rs1695 single nucleotide polymorphisms (SNP) on patients with high-grade glioma treated with concomitant radio-chemotherapy. From October 2010 to August 2019, a total of 75 patients aged ≥18 years, with histological diagnosis of high-grade glioma, isocitrate dehydrogenase (IDH) 1/2 wild type and treated with radio-chemotherapy and sequential chemotherapy with temozolomide (TMZ) were prospectively recruited. The local ethic committee approved this study (Comitato Etico di Area Vasta Nord Ovest [CEAVNO]; protocol 3304/2011). After a median follow up of 25 months (range: 7-98 months), median progression-free survival (PFS) and overall survival (OS) were 11 months (CI95%: 8-14 months) and 18 months (CI95%: 15-21 months), respectively. In univariate and multivariate Cox regression analysis, a statistically significant association with PFS and OS was found with XRCC3 rs1799794 SNP. The study suggests that XRCC3 rs1799794 SNP can be associated with different PFS and OS in glioblastoma patients treated with radio-chemotherapy.

Radiotherapy in the COVID-19 Pandemic Era.

BACKGROUND/AIM: In 2020, because of coronavirus pandemic, medical activities changed. The aim of this report is to compare the volumes of Pisa radiotherapy activities from March 9th to May 31st, 2020, with the same period in 2019. PATIENTS AND METHODS: We analyzed the activity of our Unit to evaluate how logistics changes, related to the COVID-19 epidemic, impacted on volumes of radiotherapy (RT) activity and on the number of cases of COVID-19 infections observed in healthcare professionals and patients. RESULTS: The total number of first-time visits between March-May 2020 was reduced by 18%, probably due to delays in diagnosis and histological tests as well as the temporary closure of the operating rooms. None of the healthcare professionals and only two patients contracted the infection. CONCLUSION: We were able to treat all patients referred to our hospital and we were able to reduce risk of infection for both our patients and healthcare staff, guaranteeing continuum of care for our oncological patients.

Different Timing to Use Bevacizumab in Patients with Recurrent Glioblastoma: Early Versus Delayed Administration.

BACKGROUND/AIM: In patients with recurrent glioblastoma, the best timing to administer bevacizumab is not well addressed yet. In this study, we reported the results of a monocentric experience comparing the early use of bevacizumab (following the first GBM recurrence) with the delayed administration (following the second or even further GBM recurrences). MATERIALS AND METHODS: This analysis included 129 glioblastoma patients with a median follow-up of 22.4 months (range=5.26-192 months). RESULTS: The median time lapse from diagnosis of glioblastoma to disease recurrence was 11.6 months; 13.1 for patients treated with deferred administration of bevacizumab and 9.9 for patients with early administration (p=0.047). Bevacizumab progression-free survival with early and delayed use was 3.45 and 2.92 months, respectively (p=0.504). Survival time from the start of bevacizumab was 6.18 months in patients with early administration, and 6.47 in the delayed administration one (p=0.318). CONCLUSION: Delayed administration of bevacizumab can be considered in selected patients with less aggressive recurrent glioblastoma.

Prognostic role of hyponatremia in 564 small cell lung cancer patients treated with topotecan.

OBJECTIVES: Hyponatremia is reported in about 15% of small cell lung cancer (SCLC). Variable results of the prognostic significance of low plasmatic sodium (Napl) have been reported. Our study was performed to investigate the prognostic role of hyponatremia in SCLC patients treated in second-line with topotecan chemotherapy. MATERIALS AND METHODS: Data were retrospectively collected from a database including clinical data from 631 patients enrolled in 6 prospective topotecan iv studies. Final data were obtained from 564 patients in which data on baseline Napl were available. Univariate and multivariate analysis were carried out to study the possible correlation between Napl and second-line clinical outcomes. RESULTS: Hyponatremia (Napl<135mequiv./l) was present in 101 cases (17.9%). Napl was <125mequiv./l in 16 patients (2.8%), 126-130mequiv./l in 11 (2%), 130-134mequiv./l in 74 (13.1%), while 463 patients (82.1%) showed normal values. The median survival was 28.7 weeks in patients with normal Napl, and 21.1 weeks in patients with hyponatremia (p<0.0001, HR=1.67, 95%CI=1.32-2.10). By Cox multivariate analysis, hyponatremia was associated with poorer prognosis (p=0.0024, HR=1.44, 95%CI=1.13-1.82). A not statistically significant trend of correlation between hyponatremia and progression-free survival (p=0.085, HR=1.23, 95%CI 0.97-1.55) and response rate (p=0.5037, OR=0.81, 95%CI 0.44-1.49) was observed. CONCLUSION: Hyponatremia is an independent prognostic factor for patients with SCLC treated with topotecan in second-line setting. Further studies are needed to prospectically confirm these results and to develop an optimal therapy for hyponatremic patients.