Radiotherapy is the attractive treatment option for prostate cancer and has a clear role in all stages of the disease. Over the last decade, advances in technology, imaging capabilities, and improved ...radiobiological understanding have deeply transformed radiotherapy for prostate cancer, allowing dose escalation and wide adoption of hypofractionation. Furthermore, the integration of magnetic resonance imaging (MRI) and improved physical precision of dose delivery have given an impetus to additionally target intraprostatic tumor lesions, previously agnostic to conventional radiotherapy target definition concept. The emerging data from randomized clinical trials and observation research show that ultra-hypofractionation is a safe approach while further follow-up is needed to assess its efficacy compared to standard fractionation. There is an ongoing uncertainty surrounding true alpha/beta ratio for prostate cancer since hypofractionation has so far failed to yield theoretically envisioned superior biochemical control outcomes. Finally, recently published randomized trial settled ongoing controversy regarding the role of elective pelvic lymph node radiotherapy in patients with high-risk prostate cancer, showing clear benefit when pelvic nodes were treated to SO Gy. The role of partial gland dose escalation/tumor boosting is evolving, and more data is needed to adopt this approach in routine clinical care. Going forward, molecular imaging will be crucial to assess biology of the disease, predict a response potentially, and optimally personalize radiotherapy treatment decisions. In this narrative review, we critically analyzed the published literature and provided practical summary of recent prostate radiotherapy advances for busy clinicians. Key words:prostate cancer, radiotherapy, hypofractionation, stereotactic body radiotherapy, dose escalation, boost, clinical trials Radioterapija je neizostavan oblik lijecenja ralea prostate i ima ulogu u svim fazama bolesti. Zadnjeg desetljeca napreci u tehnologiji i radiobiologiji su preobrazili radioterapiju ralea prostate te omogucili eskalaciju doze i hipofrakcioniranje. Nadalje, integracija magnetske rezonance i povecana fizikalna preciznost isporuke radioterapije omogucila je ciljanje intraprostatickih tumora. Mnoge studije pokazuju da je ultra hipofrakcioniranje obecavajuci koncept lijecenja, iako postoje mnoge nejasnoce o pravom alfa-beta omjeru raka prostate te posljedicnom stvarnom terapijskom benefitu hipofrakcioniranja. Recentno objavljena studija ukazala je na korist elektivne radioterapije zdjelicnih limfnih evorova u bolesnika sa visokorizicnim rakom prostate. Nadalje, u tijeku su studije koje ce ocijeniti valjanost daljnje intraprostaticke eskalacije doze. Moderno molekularno oslikavanje donosi veliku promjenu u nacinu kako shvacamo i lijecimo rak prostate. U ovom preglednom clanku kriticki smo analizirali literaturu i dali smjernice za svakodnevnu radioterapijsku klinicku praksu. Kljucne rijeci: rak prostate, radioterapija, hipofrakcioniranje, stereotaksijska radioterapija, eskalacija doze, klinicke studije
Despite numerous advances in cancer radiotherapy, tumor radioresistance remain one of the major challenges limiting treatment efficacy of radiotherapy. Conventional strategies to overcome ...radioresistance involve understanding the underpinning molecular mechanisms, and subsequently using combinatorial treatment strategies involving radiation and targeted drug combinations against these radioresistant tumors. These strategies exploit and target the molecular fingerprint and vulnerability of the radioresistant clones to achieve improved efficacy in tumor eradication. However, conventional drug-screening approaches for the discovery of new drug combinations have been proven to be inefficient, limited and laborious. With the increasing availability of computational resources in recent years, novel approaches such as Quadratic Phenotypic Optimization Platform (QPOP), CURATE.AI and Drug Combination and Prediction and Testing (DCPT) platform have emerged to aid in drug combination discovery and the longitudinally optimized modulation of combination therapy dosing. These platforms could overcome the limitations of conventional screening approaches, thereby facilitating the discovery of more optimal drug combinations to improve the therapeutic ratio of combinatorial treatment. The use of better and more accurate models and methods with rapid turnover can thus facilitate a rapid translation in the clinic, hence, resulting in a better patient outcome. Here, we reviewed the clinical observations, molecular mechanisms and proposed treatment strategies for tumor radioresistance and discussed how novel approaches may be applied to enhance drug combination discovery, with the aim to further improve the therapeutic ratio and treatment efficacy of radiotherapy against radioresistant cancers.
•Tumor radioresistance limit radiotherapy efficacy and is due to diverse biological mechanisms.•Drug combinations targeting specific molecular vulnerabilities may have suboptimal efficacy.•Exhaustive screening may discover new drug combinations but are costly and slow.•Artificial intelligence (AI)-based approaches can prioritize drug combinations for testing.•AI approaches can be used to rapidly develop personalized treatment for radioresistant cancers.
Abstract Purpose To assess the prognostic value of neutrophil-to-lymphocyte ratio (NLR) in patients with International Union Against Cancer (UICC)–staged III/IVA,B nasopharyngeal carcinoma (NPC), who ...were enrolled into two randomised controlled trials of concurrent/adjuvant chemotherapy when added to radiotherapy (SQNP01), and induction chemotherapy when added to chemoradiotherapy (NCC0901). Material and methods A post hoc analysis of pooled cohorts from SQNP01 (N = 221) and NCC0901 (N = 172) was performed. We employed a threshold of pre-treatment NLR = 3.0 (median) to stratify patients. Survival outcomes were compared using log-rank test. Multivariable Cox regression analyses were performed to assess association between NLR and overall survival (OS), disease-free survival (DFS), distant metastasis–free survival (DMFS), and locoregional recurrence–free survival (LRFS). Results High NLR (≥3.0) was associated with advanced T-status (p = 0.002), N-status (p = 0.002), overall UICC stage (p = 0.004), and high pre-treatment Epstein–Barr virus DNA titre (p = 0.001). High NLR was not associated with OS (0.94 0.67–1.32, p = 0.7), DFS (0.98 0.73–1.33, p = 0.9), DMFS (1.02 0.66–1.57, p = 0.9), and LRFS (1.37 0.84–2.22, p = 0.2) on univariable and multivariable analyses, while conventional clinical indices (T-status, N-status, and overall UICC stage) were prognostic of clinical outcomes. High NLR also did not predict for a treatment effect with the experimental arms in both trials. Conclusion Our pooled analyses that were confined to a homogenous patient population of locally advanced NPC do not suggest that NLR adds prognostic value to conventional clinical indices in identifying patients with unfavourable disease.
The role of locoregional radiotherapy in patients with de novo metastatic nasopharyngeal carcinoma (mNPC) is unclear.
To investigate the efficacy and safety of locoregional radiotherapy in de novo ...mNPC.
Patients with biopsy-proven mNPC, who demonstrated complete or partial response (RECIST v1.1) following 3 cycles of cisplatin and fluorouracil chemotherapy, were enrolled. Eligible patients were randomly assigned (1:1) to receive either chemotherapy plus radiotherapy or chemotherapy alone. Overall, 126 of 173 patients screened were eligible to the study, and randomized to chemotherapy plus radiotherapy (n = 63) or chemotherapy alone (n = 63). Median (IQR) follow-up duration was 26.7 (17.2-33.5) months.
The chemotherapy regimens were fluorouracil continuous intravenous infusion at 5 g/m2 over 120 hours and 100 mg/m2 intravenous cisplatin on day 1, administered every 3 weeks for 6 cycles. Patients assigned to the chemotherapy plus radiotherapy group received intensity-modulated radiotherapy (IMRT) after chemotherapy.
The primary end point of the study was overall survival (OS). The secondary end point was progression-free survival (PFS) and safety.
Overall, 126 patients were enrolled (105 men 83.3% and 21 women 16.7%; median IQR age, 46 39-52 years). The 24-month OS was 76.4% (95% CI, 64.4%-88.4%) in the chemotherapy plus radiotherapy group, compared with 54.5% (95% CI, 41.0%-68.0%) in the chemotherapy-alone group. The study met its primary end point of improved OS (stratified hazard ratio HR, 0.42; 95% CI, 0.23-0.77; P = .004) in favor of chemotherapy plus radiotherapy. Progression-free survival was also improved in the chemotherapy plus radiotherapy group compared with the chemotherapy-alone group (stratified HR, 0.36; 95% CI, 0.23-0.57). No significant differences in acute hematological or gastrointestinal toxic effects were observed between the treatment arms. The frequency of acute grade 3 or higher dermatitis, mucositis, and xerostomia was 8.1%, 33.9%, and 6.5%, respectively, in the chemotherapy plus radiotherapy group. The frequency of late severe grade 3 or higher hearing loss and trismus was 5.2% and 3.4%, respectively, in the chemotherapy plus radiotherapy group.
In this randomized clinical trial, radiotherapy added to chemotherapy significantly improved OS in chemotherapy-sensitive patients with mNPC.
ClinicalTrials.gov Identifier: NCT02111460.
•Anti-PD1 antibodies demonstrate considerable activity in previously treated RM-NPC.•Response rate increases when combined with Gemcitabine and Cisplatin.•Future studies should investigate potential ...biomarkers and combinational therapies.
Anti-PD1 antibody has emerged as a promising immunotherapeutic option in patients with recurrent and/or metastatic nasopharyngeal cancers (RM-NPC). We aim to summarise existing evidence on the use of anti-PD1 antibodies in the treatment of these patients and compare its effectiveness with standard-of-care palliative chemotherapy. Our secondary aim is to explore potential combination therapies with anti-PD1 antibodies.
PubMed, Embase and Cochrane databases were systematically searched for studies comparing the efficacy of various anti-PD1 antibodies in the treatment of RM-NPC (either as first or second line treatment) from inception to 2 September 2022. Meta-analyses were performed to correlate the various anti-PD1 antibodies with primary endpoints including overall response rate disease control rate (DCR), progression free survival (PFS) and overall survival (OS).
Eighteen studies with 1,887 patients met the inclusion criteria. The use of anti-PD1 antibody monotherapy as second-line treatment of RM-NPC revealed an ORR of 23 % (95 % CI = 19 %-28 %) and DCR of 51 % (95 % CI = 42 %-60 %). The ORRs for first-line as well as a combination of first and second-line treatments were 21 % (95 % CI = 15 % − 30 %) and 22 % (95 % CI = 6 % − 56 %, I2 = 75 %) respectively. The 12-month PFS and 12-month OS was also 27 % (95 % CI = 21 %–33 %) and 63 % (95 % CI = 53 %-72 %) respectively. ORR was much higher at 73 % (95 % CI = 32 %-94 %) when anti-PD1 antibodies were combined with Gemcitabine plus Cisplatin.
Anti-PD1 antibody demonstrate considerable activity in previously treated RM-NPC patients. Combining anti-PD1 antibodies with gemcitabine and cisplatin chemotherapy enhanced the efficacy of treatment.
Abstract
Objective
To assess large language models on their ability to accurately infer cancer disease response from free-text radiology reports.
Materials and Methods
We assembled 10 602 computed ...tomography reports from cancer patients seen at a single institution. All reports were classified into: no evidence of disease, partial response, stable disease, or progressive disease. We applied transformer models, a bidirectional long short-term memory model, a convolutional neural network model, and conventional machine learning methods to this task. Data augmentation using sentence permutation with consistency loss as well as prompt-based fine-tuning were used on the best-performing models. Models were validated on a hold-out test set and an external validation set based on Response Evaluation Criteria in Solid Tumors (RECIST) classifications.
Results
The best-performing model was the GatorTron transformer which achieved an accuracy of 0.8916 on the test set and 0.8919 on the RECIST validation set. Data augmentation further improved the accuracy to 0.8976. Prompt-based fine-tuning did not further improve accuracy but was able to reduce the number of training reports to 500 while still achieving good performance.
Discussion
These models could be used by researchers to derive progression-free survival in large datasets. It may also serve as a decision support tool by providing clinicians an automated second opinion of disease response.
Conclusions
Large clinical language models demonstrate potential to infer cancer disease response from radiology reports at scale. Data augmentation techniques are useful to further improve performance. Prompt-based fine-tuning can significantly reduce the size of the training dataset.
Abstract Purpose To test the association of DNA double-strand break (DSB) repair and chromosomal radiosensitivity in ex vivo irradiated blood lymphocytes with late-onset normal tissue responses ...following breast radiotherapy. Methods Breast cancer patients with minimal (controls) or marked late radiotherapy changes (cases) were retrospectively selected. DSB were quantified by γH2AX/53BP1 immunofluorescence microscopy 0.5 and 24 h after exposure of unstimulated blood lymphocytes to 0.5 and 4 Gy X-rays, respectively. Chromosomal aberrations were scored in blood lymphocyte metaphases after 6 Gy X-rays. Results Despite similar foci levels at 0.5 h in cases ( n = 7) and controls ( n = 7), foci levels 24 h after 4 Gy irradiation differed significantly between them (foci per cell were 12.8 in cases versus 10.2 in controls, p = 0.004). Increased chromosomal radiosensitivity was also observed in cases (aberrations per cell were 5.84 in cases versus 3.79 in controls, p = 0.001) with exchange and deletion type aberrations contributing equally to the difference between cases and controls. Residual foci correlated with formation of deletions (Spearman’s R = 0.589, p = 0.027) but not exchanges ( R = 0.367, p = 0.197) in blood lymphocytes from the same patients. Conclusions Higher levels of exchange type aberrations observed among radiosensitive breast cancer patients suggest a role for DSB misrepair, in addition to residual damage, as determinants of late normal tissue damage. Correlation of residual foci levels with deletion type aberration yields in the same cohort confirms their mechanistic linkage.
Abstract Background Localized prostate cancer is clinically heterogeneous, despite clinical risk groups that represent relative prostate cancer-specific mortality. We previously developed a 100-locus ...DNA classifier capable of substratifying patients at risk of biochemical relapse within clinical risk groups. Objective The 100-locus genomic classifier was refined to 31 functional loci and tested with standard clinical variables for the ability to predict biochemical recurrence (BCR) and metastasis. Design, setting, and participants Four retrospective cohorts of radical prostatectomy specimens from patients with localized disease were pooled, and an additional 102-patient cohort used to measure the 31-locus genomic classifier with the NanoString platform. Outcome measurements and statistical analysis The genomic classifier scores were tested for their ability to predict BCR ( n = 563) and metastasis ( n = 154), and compared with clinical risk stratification schemes. Results and limitations The 31-locus genomic classifier performs similarly to the 100-locus classifier. It identifies patients with elevated BCR rates (hazard ratio = 2.73, p < 0.001) and patients that eventually develop metastasis (hazard ratio = 7.79, p < 0.001). Combining the genomic classifier with standard clinical variables outperforms clinical models. Finally, the 31-locus genomic classifier was implemented using a NanoString assay. The study is limited to retrospective cohorts. Conclusions The 100-locus and 31-locus genomic classifiers reliably identify a cohort of men with localized disease who have an elevated risk of failure. The NanoString assay will be useful for selecting patients for treatment deescalation or escalation in prospective clinical trials based on clinico-genomic scores from pretreatment biopsies. Patient summary It is challenging to determine whether tumors confined to the prostate are aggressive, leading to significant undertreatment and overtreatment. We validated a test based on prostate tumor DNA that improves estimations of relapse risk, and that can help guide treatment planning.
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