Grazia Lazzari

In post-prostatectomy prostate cancer, combining androgen deprivation therapy (ADT) with salvage radiotherapy (SRT) significantly improves clinical outcomes, though the absolute benefit varies based on baseline PSA, pathological risk, and treatment design. This review synthesizes findings from key randomized trials and contemporary meta-analyses—including RTOG 9601, SPPORT, GETUG-AFU 16, GETUG-AFU 22, and RADICALS-HD—evaluating the integration and duration of ADT with postoperative irradiation. While systemic therapy consistently enhances biochemical and clinical progression-free survival, a universal overall survival benefit remains uncertain or limited to high-risk cohorts with elevated pre-treatment PSA values. Concurrently, data from the prospective phase II OLIGOPELVIS (GETUG P07) and PEACE V-STORM trials are redefining the standard of care for pelvic nodal oligorecurrent disease detected via next-generation imaging (NGI). Transitioning away from exclusive lifelong ADT or isolated focal metastasis-directed therapy, emerging evidence strongly supports a multimodal paradigm: combining prostate bed RT, whole-pelvis elective nodal irradiation, and a high-dose boost to PET-positive nodes, complemented by a short course of systemic therapy. Ultimately, this narrative review provides clinicians with evidence-based guidance on integrating ADT to maximize regional disease control and delay systemic progression, while successfully sparing the majority of patients from the toxicities of continuous ADT.

Breast-conserving surgery followed by adjuvant whole-breast irradiation (WBI) remains the standard of care for patients with early-stage breast cancer. In this setting, irradiation of the tumor bed with an additional boost dose has historically been used to reduce the risk of ipsilateral breast tumor recurrence (IBTR). Major randomized trials established that boost irradiation improved local control, particularly in younger patients, but did not confer a consistent overall survival (OS) benefit and was associated with increased late toxicity, like fibrosis, and poorer cosmetic outcomes as well. More recent evidence, including systematic reviews and contemporary consensus recommendations, suggests that boost irradiation may be safely omitted in selected low-risk patients, especially when the estimated absolute reduction in 10-year local recurrence is less than 3%. At the same time, the routine use of boost irradiation has been challenged by modern systemic therapy treatments questioning if boost could be really omitted in this set. Further advances in radiation techniques are redefining the scheduling and timing of boost administration, shifting from a conventional fractionation to hypofractionation and from the sequential (SEB) to simultaneous delivery with simultaneous integrated boost (SIB). In light of increasingly minimally invasive surgery and a de-escalation RT policy, unresolved clinical issues still remain about the management of positive or close margins and the role of boost irradiation in ductal carcinoma in situ. This narrative review summarizes the biological rationale, historical trial evidence, and recent literature addressing these evolving scenarios. Current evidence supports a more individualized approach to boost prescription based on recurrence risk, patient age, tumor biology, margin status, treatment techniques (surgery and radiotherapy), and patient preference.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by poor clinical outcomes and limited responsiveness to conventional treatments. Beyond delayed diagnosis, its high mortality is linked to limited treatment choices and resistance to chemotherapy. Neoplastic cells characterized by stem-like features and epithelial–mesenchymal transition (EMT) activation are crucial drivers of drug resistance and metastatic progression. Consequently, targeting these cellular programs could represent a promising therapeutic strategy for PDAC. N-acetyl-L-aspartic acid (NAA) is an endogenous metabolite, mainly localized in the central nervous system, where it facilitates acetate storage for lipid metabolism. Previous studies established its antineoplastic effect in neuroblastoma, promoting a more differentiated phenotype of cancer cells. Here we investigated the effects of NAA on BxPC-3 pancreatic cancer cells using both 2D and 3D models. NAA treatment induced a dose-dependent reduction in cell proliferation and led to a significant downregulation of stemness-associated surface markers, with concomitant upregulation of E-cadherin. Furthermore, NAA significantly enhanced cellular radiosensitization with a reduction in caveolin-1 and increased efficacy of gemcitabine in PDAC cells. Collectively, these results confirmed the anticancer activity of NAA and provide a rationale for further investigation of its synergistic effects with radiotherapy to yield better PDAC treatments.

In post-prostatectomy prostate cancer, combining androgen deprivation therapy (ADT) with salvage radiotherapy (SRT) significantly improves clinical outcomes, though the absolute benefit varies based on baseline PSA, pathological risk, and treatment design. This review synthesizes findings from key randomized trials and contemporary meta-analyses including RTOG 9601, SPPORT, GETUG-AFU 16, GETUG-AFU 22, and RADICALS-HD evaluating the integration and duration of ADT with postoperative irradiation. While systemic therapy consistently enhances biochemical and clinical progression-free survival, a universal overall survival benefit remains uncertain or limited to high-risk cohorts with elevated pre-treatment PSA values. Concurrently, data from the prospective phase II trials OLIGOPELVIS (GETUG P07) and PEACE V - STORM are redefining the standard of care for pelvic nodal oligorecurrent disease detected via next-generation imaging (NGI). Transitioning away from exclusive lifelong ADT or isolated focal metastasis-directed therapy, emerging evidence strongly supports a multimodal paradigm: combining prostate bed RT, whole-pelvis elective nodal irradiation, and a high-dose boost to PET-positive nodes, complemented by a short course of systemic therapy. This narrative review provides readers with effective indication to use adjuvant HT according recent literature evidences to maximizes regional disease control and delays systemic progression, while successfully sparing the majority of patients from the toxicities of continuous androgen deprivation.

Breast-conserving surgery followed by adjuvant whole-breast irradiation ( WBI) remains the standard of care for patients with early-stage breast cancer. In this setting, irradiation of the tumor bed with an additional boost dose has historically been used to reduce the risk of ipsilateral breast tumor recurrence (IBTR). The major randomized trials established that boost irradiation improves local control, particularly in younger patients, but does not confer a consistent overall survival (OS) benefit and is associated with increased late toxicity, like fibrosis and poorer cosmetic outcomes as well. More recent evidence, including systematic reviews and contemporary consensus recommendations, suggests that boost irradiation may be safely omitted in selected low-risk patients, especially when the estimated absolute reduction in 10-year local recurrence is is less than 3%. At the same time, the routine use of boost irradiation has been challenged by modern systemic therapy treatments questioning if boost could be really omitted in this set. Further advances in radiation techniques are redefining the scheduling and timing of boost administration, shifting from a conventional fractionation to hypofractionation, and from the sequential (SEB) to the simultaneous delivery with simultaneous integrated boost (SIB). In light of increasingly minimally invasive surgery and de-escalation RT policy, unresolved clinical issues still remains about the management of positive or close margins and the role of boost irradiation in ductal carcinoma in situ. This narrative review summarizes the biological rationale, historical trial evidence, and recent literature addressing these evolving scenarios. Current evidence supports a more individualized approach to boost prescription based on recurrence risk, patient age, tumor biology, margin status, treatment techniques(surgery and radiotherapy), and patient preference.

Phyllodes tumours (PTs) of the breast are rare fibroepithelial neoplasms with potentially aggressive behaviour, characterised by rapid growth, a significant risk of local recurrence, and occasional metastatic spread. Optimal management remains controversial, particularly regarding surgical margins, adjuvant radiotherapy, and the relevance of molecular markers in predicting tumour behaviour. A PRISMA 2020-guided qualitative systematic review was conducted of studies published between January 2000 and December 2024 in PubMed/MEDLINE, Scopus, and Web of Science. Eligible studies included malignant PTs of the breast and addressed at least one of the following domains: molecular pathology, surgical margins and local recurrence, adjuvant radiotherapy, or predictors of recurrence and metastasis. A clinical case of malignant PT treated at our institution is presented as an illustrative study. Thirty-four studies met the inclusion criteria. Evidence suggests that margin status, stromal proliferative activity, and selected molecular markers influence recurrence risk. Several retrospective studies suggest that adjuvant radiotherapy may improve local control in selected high-risk malignant PTs, although the evidence remains heterogeneous, retrospective, and potentially affected by treatment-selection bias, and no consistent survival benefit has been demonstrated. Molecular alterations, including MED12 mutations, TERT promoter mutations, TP53 alterations, and increased Ki-67 expression, have been associated with tumour progression and aggressive behaviour. A 44-year-old woman presented with a 2.4 cm left breast mass on radiological examination. Lumpectomy revealed a malignant PT with stromal hypercellularity, nuclear atypia, and a mitotic index of 20/10 HPF with close margins. Immunohistochemistry showed positivity for CD99, Bcl-2, and CD34 with a Ki-67 proliferation index of 20%. The patient underwent wide local re-excision followed by adjuvant radiotherapy (60 Gy), and at 24-month follow-up, the patient remained disease-free. Evidence synthesis highlights the importance of complete surgical excision, multidisciplinary management, and consideration of adjuvant radiotherapy in selected malignant PTs. Emerging molecular profiling may contribute to improved biological understanding and future risk stratification of malignant PTs, although its routine clinical utility remains to be validated in prospective studies.

Whole breast radiotherapy in adjuvant breast cancer (BC) treatment has been commonly delivered in supine positioning for more than 50 years. Its widespread use is related to the broad availability of simple and common breast board immobilization devices, which exploit the natural recumbent position of the body with arms above the head, the good match with linac tables and well-established set up procedures. However, in scenarios like painful arm discomfort in patients with post-surgery arm or arthritic limitation, unfavorable chest geometry like pectus excavatum (PE), large and pendulous breasts in obese women and cardiac morbidity in left sided BC, supine position seems very uncomfortable for patients and troublesome for radiation oncologists. The question is how to proceed when supine IMRT or DIBH are ineffective strategies? Alternative positions have been analyzed over the past twenty years, starting with a lot of trials testing prone positioning variants with and without DIBH, lateral decubitus or upright standing radiotherapy. A better recognition of new treatment position options in BC adjuvant therapy may provide more opportunities for personalized radiotherapy in this population, to ensure they receive an appropriate, safe and comfortable treatment.

Whole breast radiotherapy in adjuvant breast cancer (BC) treatment is commonly delivered in supine positioning since more than 50 years ago. Its widespread use is related to the broad availability of simply and common breast board immobilization devices which exploit the natural recumbent position of the body with arms above the head, the good match with linac tables and well established set up procedures. However, several criticisms have been raised over time in case of scenarios like painful arm discomfort in patients with post-surgery arm or arthritic limitation, unfavorable chest geometry like pectus excavatum, large and pendulous breasts in obese women, cardiac morbidity in left sided BC. In these scenarios supine position seems very uncomfortable for patients and troublesome for radiation oncologists. Heart dosimetry in pectus excavatum (PE) and left sided breasts, breast size and shape matter when DIBH is not allowed. In fact, not all patients are suitable DIBH candidates because of the limiting factors like obesity or pulmonary morbidities. Thus, adjuvant whole breast radiotherapy in supine positioning could be very critical. Alternative positions have been analyzed in these last twenty years starting from a lot of trials testing prone positioning variants with and without DIBH, lateral decubitus or up-right standing radiotherapy. Customized immobilization devices have been developed to make these alternative positions more comfortable and consistent with beams angles arrangements and modern RT delivery avoiding collisions with the device or the Linac. To standardize the target delineation in these positions, customized guidelines have been also provided and recently several atlas-based segmentation processes have been provided to reduce bias by incorporating an interobserver quality analysis. Researches and a better recognition of new treatment position options in BC adjuvant therapy may provide more opportunities for a personalized radiotherapy mainly in that population not suitable for supine RT, to ensure them an appropriate, safe and comfortable treatment.

Over the past two decades, interest in prone-position whole breast irradiation (WBI) as an effective and practical alternative to supine treatment has been growing a lot. Although solid scientific data has provided evidence of substantial dosimetric benefit with decreased toxicity, there is still conflict in the radiotherapy community over whether to adopt prone-position WBI as a valid alternative to supine radiotherapy (RT) in routine clinical practice. A large number of prone trials have been conducted to assess and address concerns related to prone treatment in large and pendulous breasts and in left and right breast cancer (BC), nodal irradiation, and its reproducibility with deep inspiration breath hold (DIBH) delivery with photons or protons. Appropriate atlases have been defined to improve prone nodal irradiation. Additionally, more comfortable customized immobilization couches have been constructed to permit IMRT beams and VMAT arrangements with modern LINACs. Although our search in literature databases shows a growing body of evidence from the past two decades on this issue, prone WBI is still underused. Given the paradox of the advances and benefits of this positioning and the lack of drive in the radiotherapy community towards its clinical implementation, the purpose of this comprehensive review is to evaluate the true advantages of this position in real life and contextualize it in scenarios like large breasts, left-sided breast cancer, and nodal irradiation to encourage its implementation in clinical practice.

Background: In this study, we retrospectively analyzed clinical and toxicity outcomes of 67 prostate cancer (PCa) patients undergoing moderately hypofractionated radiotherapy (RT) after prostatectomy, with adjuvant or salvage intent. Methods: Irradiation was delivered by volumetric modulated arc therapy. The median follow-up was 48 months. The 3- and 5-year biochemical relapse-free survival rates were 80% and 69%. The RT schedule consisted of a median total dose of 67.5 Gy with a median number of 25 fractions and a median fraction dose of 2.7 Gy to the prostate bed (PB) and 60% of patients simultaneously received whole pelvis irradiation (WP; fraction dose: 1.8 Gy, median total dose of 46.8 Gy). Results: The rate of acute toxicity was 54% for gastrointestinal (GI) and 36% for genitourinary (GU). No grade 3 acute toxicity was observed. Late toxicity was as follows: G1, G2, and G3 GI events in 25.5%, 3.6%, and 1.8% of the cases, respectively; G1, G2, and G3 GU events in 37.1%, 11.1%, and 7.4%, respectively. The toxicity-free survival (TFS) curves showed a different trend for acute and late toxicity. TFS was significantly associated with RT volume, except for acute GI toxicity. Specifically, the concomitant irradiation of PB and WP appeared to be a significant risk factor for late GI and GU toxicity (p = 0.029 and p = 0.012, respectively). Conclusions: At the 48-month median timepoint considered by our study, postoperative hypofractionated RT achieved promising results in terms of clinical outcomes with acceptable toxicity. Only the irradiated volume seems to be an important predictor for toxicity.