Chemoradiation Protocols Research Articles

Survival analysis using neoadjuvant rectal score in patients with locally advanced rectal cancer who underwent surgery after neoadjuvant chemoradiotherapy: An ambispective study.

172 Background: Colorectal cancer, the third most common malignancy and a major cause of cancer deaths, is treated using a standard protocol of neoadjuvant chemoradiotherapy (NACTRT) or short-course radiotherapy (SCRT) followed by total mesorectal excision (TME) for locally advanced rectal cancers (LARC). Long-term follow-up is essential to determine study endpoints, necessitating surrogate markers for short-term outcomes. This study aims to stratify patients into risk groups based on their Neoadjuvant Rectal Cancer (NAR) score and evaluate its predictive value for oncological outcomes, including overall survival, disease-free survival (DFS), locoregional relapse-free interval (LRFI), and distant metastasis-free interval (DMFI), while also correlating clinicopathological characteristics with these outcomes. Methods: This ambispective observational study at the Regional Cancer Centre, Thiruvananthapuram, involved 459 patients with biopsy-proven, locally advanced rectal adenocarcinoma (T3/T4 and/or node positive) who underwent long-course neoadjuvant chemoradiotherapy (NACTRT) followed by curative surgery (Anterior Resection or Abdomino-Perineal Resection) between 2010 and 2015, with a minimum follow-up of three years. Exclusion criteria included previous malignancies, synchronous colorectal cancers, oligometastatic disease, and loss to follow-up. The study aimed to determine the predictive value of the Neoadjuvant Rectal Cancer (NAR) score for oncological outcomes. Clinicopathological details were collected from case records, imaging, and operative notes, and postoperative histopathological records were used to calculate the NAR score. Patients were categorized into three groups based on their NAR scores and followed prospectively for recurrence or death. Data were analyzed using frequency, percentages, mean, standard deviation, Chi-square test, Kaplan-Meier method, log-rank test, and Cox regression analysis, with a significance level set at p < 0.05. Results: 459 patients were included in the study, with 41.4% females, and 44% being less than 60 years. Most of the patients had lesion 5-10 cm from anal verge (46%). 77% of patients had T3 disease prior to the start of NATCTRT. 51.9% had underwent APR, and 80.4% had open surgery. 11.1% had PCR attained. 27% had disease recurrence of which most were distant metastasis. NAR was a significant predictor of overall survival, disease free survival, distant metastasis free interval and locoregional failure free interval. Other significant predictors of overall survival were pre-NACTRT T stage, pN stage, PLNR, CRM status and PCR, but only NAR was found to be significant on multivariate analysis. Conclusions: NAR score is a significant predictor of OS, DFS,LRFI and DMFI and can be used as a short term surrogate for survival data in anticipated trials.

Concurrent preoperative eribulin and radiation for resectable retroperitoneal liposarcoma: a phase 1B study.

Management of retroperitoneal liposarcoma (RPLPS) is challenging and recurrence rates remain high despite aggressive surgical resections. Preoperative radiation alone lacks definitive benefit, thus we sought to evaluate combined chemoradiotherapy with the potential to enhance local efficacy of radiation as well as control micrometastatic disease. We assessed the safety and tolerability of preoperative eribulin, a cytotoxic microtubule inhibitor approved for the treatment of advanced liposarcoma, in combination with radiation in patients with RPLPS. In this open-label dose-finding study, patients with primary or recurrent resectable RPLPS received preoperative intensity-modulated radiation therapy (IMRT) with escalating doses of eribulin. Eribulin was administered for three 21-day cycles at a starting dose of 1.1 mg/m2. Concurrent radiation to 50.4 Gy began during cycle 1. Surgical resection occurred 3-10 weeks after completion of chemoradiation. The primary endpoint was determination of the recommended phase 2 doses (RP2D) of concurrent eribulin and radiation. Between 2018-2023, fifteen patients were enrolled. Thirteen patients were evaluable for dose-determination. Four patients treated at starting dose level had no dose-limiting toxicities (DLTs). Two of nine patients treated with escalated eribulin dose had DLTs. The RP2D was established as eribulin 1.4 mg/m2 and IMRT 50.4 Gy. Eleven patients were evaluable for secondary efficacy endpoints. The median recurrence-free survival was 30.4 months (95% CI 12.0-NR) and the median overall survival was 54.1 months (95% CI 9.5-NR). Patient reported outcome data did not show any significant changes over the study period. A preoperative chemoradiation protocol of eribulin in combination with IMRT showed a manageable safety profile and warrants additional prospective evaluation for treatment of resectable RPLPS.

TMIC-14. RAPID EARLY PROGRESSION IN GLIOBLASTOMA: A COMPREHENSIVE REVIEW OF CLINICAL, IMAGING AND HISTOPATHOLOGICAL FEATURES

Abstract BACKGROUND In glioblastoma patients, Rapid Early Progression (REP) refers to tumour growth between the time of surgery and postoperative chemoradiotherapy. Despite its high incidence relatively little is known about it. The aim of this study was to characterise REP using a combination of clinical, imaging and histopathology data. METHODS Ethical approval was obtained. Supratentorial IDH-wildtype glioblastomas undergoing gross-total resection (GTR) between 2015-2021 were included. REP was defined as a nodular increase in enhancement located within or around the surgical cavity, occurring within 6 weeks of surgery, that was not accounted for by initial areas of diffusion-restriction. REP cases were propensity-score matched to controls on baseline characteristics. Imaging was compared using mean apparent diffusion coefficient (ADC) and T1-postcontrast radiomics. Tissue analyses included DNA methylation subtyping and immunohistochemistry for markers of T-cells (CD3), microglia (P2RY12) and proliferation (PHH3). RESULTS REP occurred in 8/60 GTR cases (13%) and these patients were matched to 16 controls. REP cases had a worse preoperative performance status (median Eastern Cooperative Oncology Group [ECOG] 2 vs. 1), overall-survival (p=0.038) and progression-free survival (p = 0.029). REP was more common in patients over 65 years (27%) and significantly fewer REP patients received radical postoperative chemoradiotherapy (p=0.023). REP and control cases were well matched with respect to preoperative T1-postcontrast radiomics and mean ADC in enhancing (p=0.99) and non-enhancing regions (p=0.67). There was no relative excess of any one DNA methylation subtype in REP cases. The two groups had a similar proportion of T-cells (p=0.81), but REP cases had a trend towards a higher proportion of microglia (31% vs. 17%; p=0.22), and a lower proliferation rate (3% vs. 9%; p=0.19). CONCLUSION REP cases had a worse performance status from diagnosis and received less radical postoperative chemoradiotherapy protocols compared to controls, yielding a significantly shorter median OS/PFS. Differences in immune landscape and proliferation rate should be further investigated.

Single institution analysis of glioblastoma multiforme (GBM) outcomes based on year of diagnosis: A 17 year review.

e14023 Background: GBM is the most common brain tumour in adults. The latest WHO classification excludes IDH mutated tumours, acknowledging their favourable prognosis. MGMT methylation is a prognostic biomarker and predicts level of benefit from Temozolomide. The standard of care management includes maximal surgical resection followed by radiotherapy with concurrent and adjuvant Temozolomide. This has remained largely unchanged for nearly 20 years. We analysed 17 years of newly diagnosed GBM cases attending Medical Oncology at our institution to assess outcome advancements. Methods: Demographic information, clinicopathological characteristics, surgery, radiotherapy and systemic anti-cancer treatment data were collected from the charts of patients diagnosed with GBM and seen by the Medical Oncology department at Cork University Hospital between 2005-2021. The study population was divided into 2 time periods: 2005-2016 and 2017-2021. Overall survival was recorded. Baseline characteristics was compared across time periods using the Chi-Square test. Univariate and multivariate analysis was performed to assess impact of different variables on overall survival. Results: The analysis comprised 306 patients, with 142 and 164 diagnosed between 2005-2016 and 2017-2021 respectively. Median age was 62 years (range 17-86) and patients were predominantly male (65%). Patients in the earlier time period were more likely to have ECOG performance status 0-1 (80% vs 65% p = 0.011) and were more likely to commence treatment on Stupp protocol (99% vs 80% p = <0.001). IDH and MGMT testing were less prevalent in the earlier time period. Median overall survival (mOS) for the entire cohort was 11.6 months. Univariate analysis revealed correlations between overall survival and time period of diagnosis, age >65, MGMT status, ECOG performance status, steroid use, surgery, re-resection, and completion of adjuvant chemoradiation protocols. The mOS was 12.3 months in the earlier time period and 10.4 months in the later time period (HR = 1.35 p = 0.012). Time period of diagnosis remained an independent prognostic factor for poor outcome on multivariate analysis. Notably, mOS during the COVID-19 pandemic (2020-2021) was 10.6 months, showing no difference from other time periods. Conclusions: Despite advances in our knowledge regarding the molecular biology of GBM, prognosis remains poor. Our institution’s 17 year survival data indicates no improvement over time emphasising the urgent need for new treatment strategies. Notably, the more recent time period had an increased number of frailer patients who were too unwell to commence any adjuvant treatment, possibly indicating a lower referral threshold which may have negatively impacted mOS in that cohort. Additionally, the absence of IDH status assessment in the earlier era means some IDH mutant patients were likely included, thereby inflating the mOS for that cohort.

Impact of frailty on survival glioblastoma, IDH-wildtype patients.

Frailty increases the risk of mortality among patients. We studied the prognostic significance of frailty using the modified 5-item frailty index (5-mFI) in patients harboring a newly diagnosed supratentorial glioblastoma, IDH-wildtype. We retrospectively reviewed records of patients surgical treated at a single neurosurgical institution at the standard radiochemotherapy era (January 2006 - December 2021). Inclusion criteria were: age ≥ 18, newly diagnosed glioblastoma, IDH-wildtype, supratentorial location, available data to assess the 5-mFI index. A total of 694 adult patients were included. The median overall survival was longer in the non-frail subgroup (5-mFI < 2, n = 538 patients; 14.3 months, 95%CI 12.5-16.0) than in the frail subgroup (5-mFI ≥ 2, n = 156 patients; 4.7 months, 95%CI 4.0-6.5 months; p < 0.001). 5-mFI ≥ 2 (adjusted Hazard Ratio (aHR) 1.31; 95%CI 1.07-1.61; p = 0.009) was an independent predictor of a shorter overall survival while age ≤ 60 years (aHR 0.78; 95%CI 0.66-0.93; p = 0.007), KPS score ≥ 70 (aHR 0.71; 95%CI 0.58-0.87; p = 0.001), unilateral location (aHR 0.67; 95%CI 0.52-0.87; p = 0.002), total removal (aHR 0.54; 95%CI 0.44-0.64; p < 0.0001), and standard radiochemotherapy protocol (aHR 0.32; 95%CI 0.26-0.38; p < 0.0001) were independent predictors of a longer overall survival. Frailty remained an independent predictor of overall survival within the subgroup of patients undergoing a first-line oncological treatment after surgery (n = 549) and within the subgroup of patients who benefited from a total removal plus adjuvant standard radiochemotherapy (n = 209). In newly diagnosed supratentorial glioblastoma, IDH-wildtype patients treated at the standard combined radiochemotherapy era, frailty, defined using a 5-mFI score ≥ 2 was an independent predictor of overall survival.

Hypofractionated re-irradiation with bevacizumab for relapsed chemorefractory glioblastoma after prior high dose radiotherapy: a feasible option for patients with large-volume relapse.

There remains no standard of care for patients with recurrent and chemorefractory glioblastoma. Re-irradiation (reRT) provides an additional management option. However, published series predominantly focus on small reRT volumes utilizing stereotactic hypofractionated regimens. Concerns regarding toxicity have limited utilisation of reRT for larger recurrences, however this may be mitigated with use of bevacizumab (BEV). A prospective database of patients managed with the EORTC-NCIC (Stupp) protocol 60Gy chemoradiotherapy protocol for glioblastoma between 2007 and 2021 was reviewed for those patients receiving reRT for chemorefractory relapse. Serial MRI and PET were used to establish true progression and exclude patients with pseudoprogression or radionecrosis from reRT. The primary endpoint was overall survival (OS) from date of reRT. Prognostic factors were also assessed. 447 patients managed for glioblastoma under the Stupp protocol were identified, of which 372 had relapsed and were thus eligible for reRT. 71 patients underwent reRT. Median relapse-free survival from diagnosis for the reRT and overall cohorts were similar at 11.6 months (95%CI:9.4-14.2) and 11.8 months (95%CI:9.4-14.2) respectively. 60/71 (85%) reRT patients had received BEV prior to reRT and continued concurrent BEV during reRT. Of the 11 patients not managed with BEV during reRT, 10 required subsequent salvage BEV. ReRT patients were younger (median 53 vs. 59 years, p < 0.001), had better performance status (86% vs. 69% ECOG 0-1, p = 0.002) and more commonly had MGMT promoter-methylated tumours (54% vs. 40%, p = 0.083) compared to non-reRT patients. Median reRT PTV volume was 135cm3 (IQR: 69-207cm3). Median OS from reRT to death was 7.1 months (95%CI:6.3-7.9). Patients aged < 50, 50-70 and > 70 years had post-reRT median OS of 7.7, 6.4 and 6.0 months respectively (p = 0.021). Median post-reRT survival was longer for patients with ECOG performance status 0-1 compared to 2-3 (8.1 vs. 6.3 months, p = 0.039). PTV volume, site of relapse, MGMT promoter-methylation status and extent of initial surgical resection were not associated with post-reRT survival. ReRT was well-tolerated. Out of the 6 patients (8%) admitted to hospital after reRT, only one was for reRT toxicity. This was a CTCAE grade 3 radiation necrosis event in a patient managed without prior BEV. Patients with recurrent glioblastoma who have been previously treated with 60Gy radiotherapy have a meaningful survival benefit from large volume re-irradiation which is well tolerated. ReRT should not be ignored as a salvage treatment option in patients with chemorefractory progressive disease.

An Evaluation of Treatment Outcomes and Associated Factors in Nasopharyngeal Cancer Patients at a Tertiary Cancer Center in the United Arab Emirates.

Background and objective Nasopharyngeal carcinoma (NPC) presents a complex epidemiological pattern influenced by demographic characteristics, risk factors such as Epstein-Barr virus (EBV) infection, and smoking. Understanding the clinical profile and optimizing treatment strategies for NPC requires comprehensive analyses of these factors. In light of this, this study aimed to analyze the epidemiological patterns, histological characteristics, and treatment outcomes of NPCpatients diagnosed and treated at a single center from 2016 to 2023. Materials and methods This retrospective study was conducted at Tawam Hospital in the United Arab Emirates (UAE), focusing on patients diagnosed with NPC.It involved the analysis of patient age distribution to identify epidemiological patterns, histological examination to classify NPC types according to WHO guidelines, and evaluation of treatment outcomes based on induction chemotherapy regimens and concurrent chemoradiotherapy protocols. The effectiveness of various chemotherapy combinations, particularly cisplatin and 5-fluorouracil (Cis+5FU), was assessed alongside the integration of advanced radiotherapy techniques like intensity-modulated radiotherapy (IMRT). Results In this study of 41 NPC patients, the age distribution varied widely, ranging from 10 to 74 years, with a mean age of >40 years. There was a significantmale predominance (82.93%). Most patients were non-smokers (68.29%) and did not consume alcohol (92.68%), and there was a high prevalence of EBV positivity (100%). At diagnosis, 80.49% had no metastases. The primary treatment was chemotherapy induction, with a 73.17% uptake and a 92.68% completion rate, leading to a 65.85% complete response (CR) rate. No significant association was found between smoking status and treatment response (p=0.7657). Pathologically, non-keratinizing undifferentiated squamous carcinoma was the most common variant (75.61%). The Cis+5FUregimen was the most frequently employed method (56.67%), associated with a 76.47% CR rate. Concurrent chemotherapy was administered to 87.80% of patients, with the weekly Cis regimen being the most used one (56.09%), resulting in a significant CR rate. Combining radiation therapy with concurrent and induction chemotherapy yielded high CR rates (RT+cCT: 66.66%, RT+cCT+iCT: 80%). Survival analysis revealed the highest 36-month survival rate (46.43%) in the RT+cCT+iCT group, suggesting a potential benefit from incorporating induction chemotherapy into the treatment regimen. Conclusions This study illustrates the impact of demographic variables, EBV infection, and smoking on the development and treatment outcomes of NPC. It points to the success of customized chemotherapy and advanced radiotherapy strategies. Yet, it is limited by its retrospective nature and single-center focus, and hence we recommend multicentric studies to broaden the applicability of the results and improve NPC treatment approaches for varied patient groups.

Efficacy and Safety of Carmustine Wafer Implantation After Ventricular Opening in Glioblastomas, Isocitrate Dehydrogenase-Wildtype, in Adults.

We assessed the impact of ventricular opening on postoperative complications and survival of carmustine wafer implantation during surgery of newly diagnosed supratentorial glioblastomas, isocitrate dehydrogenase (IDH)-wildtype in adults. We performed an observational, retrospective, single-center cohort study at a tertiary surgical neuro-oncological center between January 2006 and December 2021. One hundred ninety-four patients who benefited from a first-line surgical resection with carmustine wafer implantation were included. Seventy patients (36.1%) had a ventricular opening. We showed that ventricular opening (1) did not increase overall postoperative complication rates (P = .201); (2) did not worsen the early postoperative Karnofsky Performance Status score (P = .068); (3) did not increase the time interval from surgery to adjuvant oncological treatment (P = .458); (4) did not affect the completion of the standard radiochemotherapy protocol (P = .164); (5) did not affect progression-free survival (P = .059); and (6) did not affect overall survival (P = .142). In this study, ventricular opening during first-line surgical resection did not affect the survival and postoperative complications after use of carmustine wafer implantation in adult patients with a newly diagnosed supratentorial glioblastoma, IDH-wildtype. This warrants a prospective and multicentric study to clearly assess the impact of the ventricular opening after carmustine wafer implantation in glioblastoma, IDH-wildtype.

Effects of Levetiracetam and Lacosamide on survival and seizure control in IDH-wild type glioblastoma during temozolomide plus radiation adjuvant therapy

IntroductionThere are no clear indications for the best choice of anti-seizure medications to control brain tumor related epilepsy. In vitro studies have shown an antitumoral effect of Levetiracetam and Lacosamide on glioblastoma IDH-wild type. Research questionThis study investigates whether the use of levetiracetam and/or lacosamide impacts survival rates. The secondary aim was to evaluate the efficacy of both ASMs in controlling seizures. Materials and methodsIn this observational retrospective single-cohort study, patients underwent chemoradiation protocol after GBM surgery. They were grouped as follows: (1) use of levetiracetam, (2) use of lacosamide, (3) simultaneous use of levetiracetam and lacosamide, (4) no ASM usage. Survival curves were plotted using the Kaplan-Meier method coupled with a log-rank test for difference assesments. To evaluate the pharmacological efficacy of post-operative seizure control, a negative binomial regression was conducted. ResultsThe study included 272 patients, 174 of which underwent adjuvant chemoradiation treatment. Patients without ASM therapy had a non-significant longer median OS (compared to the other groups (log-rank = 0.37). The IRR of seizure relapse was 2.57 (p = 0.007) times higher in lacosamide users, and MGMT promoter methylation demonstrated a protective effect against postoperative seizure onset (p = 0.05), regardless of the aforementioned confounding factors. Discussion and conclusionsIn patients diagnosed with GBM IDH-WT undergoing chemoradiation therapy, the use of levetiracetam or lacosamide for controlling BTRE does not seem to modify survival. Lacosamide users exhibited a higher IRR of postoperative seizures compared to levetiracetam users, and MGMT promoter methylation appears to be a protective factor.

Chemotherapy in pediatric brain tumor and the challenge of the blood-brain barrier.

Pediatric brain tumors (PBT) stand as the leading cause of cancer-related deaths in children. Chemoradiation protocols have improved survival rates, even for non-resectable tumors. Nonetheless, radiation therapy carries the risk of numerous adverse effects that can have long-lasting, detrimental effects on the quality of life for survivors. The pursuit of chemotherapeutics that could obviate the need for radiotherapy remains ongoing. Several anti-tumor agents, including sunitinib, valproic acid, carboplatin, and panobinostat, have shown effectiveness in various malignancies but have not proven effective in treating PBT. The presence of the blood-brain barrier (BBB) plays a pivotal role in maintaining suboptimal concentrations of anti-cancer drugs in the central nervous system (CNS). Ongoing research aims to modulate the integrity of the BBB to attain clinically effective drug concentrations in the CNS. However, current findings on the interaction of exogenous chemical agents with the BBB remain limited and do not provide a comprehensive explanation for the ineffectiveness of established anti-cancer drugs in PBT. We conducted our search for chemotherapeutic agents associated with the blood-brain barrier (BBB) using the following keywords: Chemotherapy in Cancer, Chemotherapy in Brain Cancer, Chemotherapy in PBT, BBB Inhibition of Drugs into CNS, Suboptimal Concentration of CNS Drugs, PBT Drugs and BBB, and Potential PBT Drugs. We reviewed each relevant article before compiling the information in our manuscript. For the generation of figures, we utilized BioRender software. We focused our article search on chemical agents for PBT and subsequently investigated the role of the BBB in this context. Our search criteria included clinical trials, both randomized and non-randomized studies, preclinical research, review articles, and research papers. Our research suggests that, despite the availability of potent chemotherapeutic agents for several types of cancer, the effectiveness of these chemical agents in treating PBT has not been comprehensively explored. Additionally, there is a scarcity of studies examining the role of the BBB in the suboptimal outcomes of PBT treatment, despite the effectiveness of these drugs for other types of tumors.

Neoadjuvant radiochemotherapy with cisplatin/5-flourouracil or carboplatin/paclitaxel in patients with resectable cancer of the esophagus and the gastroesophageal junction — comparison of postoperative mortality and complications, toxicity, and pathological tumor response

PurposeIn 2012, the CROSS trial implemented a new neoadjuvant radiochemotherapy protocol for patients with locally advanced, resectable cancer of the esophagus prior to scheduled surgery. There are only limited studies comparing the CROSS protocol with a PF-based (cisplatin/5-fluorouracil) nRCT protocol.MethodsIn this retrospective, monocentric analysis, 134 patients suffering from esophageal cancer were included. Those patients received either PF-based nRCT (PF group) or nRCT according to the CROSS protocol (CROSS group) prior to elective en bloc esophagectomy. Perioperative mortality and morbidity, nRCT-related toxicity, and complete pathological regression were compared between both groups. Logistic regression analysis was performed in order to identify independent factors for pathological complete response (pCR).ResultsThirty-day/hospital mortality showed no significant differences between both groups. Postoperative complications ≥ grade 3 according to Clavien-Dindo classification were experienced in 58.8% (PF group) and 47.6% (CROSS group) (p = 0.2) respectively. nRCT-associated toxicity ≥ grade 3 was 30.8% (PF group) and 37.2% (CROSS group) (p = 0.6). There was no significant difference regarding the pCR rate between both groups (23.5% vs. 30.5%; p = 0.6). In multivariate analysis, SCC (OR 7.7; p < 0.01) and an initial grading of G1/G2 (OR 2.8; p = 0.03) were shown to be independent risk factors for higher rates of pCR.ConclusionWe conclude that both nRCT protocols are effective and safe. There were no significant differences regarding toxicity, pathological tumor response, and postoperative morbidity and mortality between both groups. Squamous cell carcinoma (SCC) and favorable preoperative tumor grading (G1 and G2) are independent predictors for higher pCR rate in multivariate analysis.

Photodynamic therapy induced cell cycle arrest and cancer cell synchronization: review.

Cell cycle arrest (CCA) is seen as a prime candidate for effective cancer therapy. This mechanism can help researchers to create new treatments to target cancer cells at particular stages of the cell cycle (CC). The CCA is a characteristic of various therapeutic modalities, including radiation (RT) and chemotherapy (CT), which synchronizes the cells and facilitates the standardization of radio-chemotherapy protocols. Although it was discovered that photodynamic treatment (PDT) had a biological effect on CCA in cancer cells, the mechanism remains unclear. Furthermore, besides conventional forms of cell death such as apoptosis, autophagy, and necrosis, various unconventional types of cell death including pyroptosis, mitotic catastrophe, paraptosis, ferroptosis, necroptosis, and parthanatos after PDT have been reported. Thus, a variety of elements, such as oxygen, the tumor's microenvironment, the characteristics of light, and photosensitizer (PS), influence the effectiveness of the PDT treatment, which have not yet been studied clearly. This review focuses on CCA induced by PDT for a variety of PSs agents on various cell lines. The CCA by PDT can be viewed as a remarkable effect and instructive for the management of the PDT protocol. Regarding the relationship between the quantity of reactive oxygen species (ROS) and its biological consequences, we have proposed two mathematical models in PDT. Finally, we have gathered recent in vitro and in vivo studies about CCA post-PDT at various stages and made suggestions about how it can standardize, potentiate, and customize the PDT methodology.

Bladder-sparing strategies in patients with clinically localized muscle-invasive bladder cancer.

Radical cystectomy is the standard of care for patients with localized muscle-invasive bladder cancer (MIBC). In this context, bladder-sparing strategies (BSS) have been investigated as viable alternatives for patients who are unfit for radical cystectomy or aim to preserve their bladder without compromising oncological outcomes. This review aims to provide the most up-to-date evidence on BSSs as an alternative treatment for patients with MIBC. Different studies have highlighted the long-term efficacy of trimodal therapy or chemoradiation protocols. However, due to the lack of randomized controlled trials, there is still a lack of high-level evidence on BSS efficacy as compared to radical cystectomy. Consequently, the adoption of these approaches is still limited. A possible turning point could be represented by the introduction of immunotherapy, as several studies are investigating the potential combination with chemoradiotherapy or radiotherapy alone. Patient selection, together with the implementation of new predictive biomarkers and imaging tools, may improve the efficacy of BSS in the near future. Radical cystectomy with perioperative chemotherapy remains the gold standard treatment for MIBC patients. Nevertheless, BSS can be considered a viable option in selected patients who desire to preserve their bladder. Further evidence is needed to clearly state the role of BSS in MIBC.

Chemoradiotherapy with concurrent durvalumab for the palliative treatment of oligometastatic esophageal and gastroesophageal carcinoma with dysphagia: A single arm phase 2 clinical trial, PALEO.

TPS4172 Background: Many patients diagnosed with esophageal cancer have dysphagia from their primary tumor and de novo metastatic disease. While multiple therapies are available, there is no accepted standard or sequence of therapies to both relieve dysphagia and control distant disease. Our preceding Phase I clinical trial showed that a 2 week hypofractionated chemoradiotherapy (CRT) protocol (30Gy/10# with concurrent weekly carboplatin and paclitaxel) is well tolerated and provides rapid dysphagia relief. Immune checkpoint inhibition has activity in esophageal and gastroesophageal (GEJ) cancer and concurrent radiotherapy may improve T cell priming through tumor antigen release. In PALEO, patients begin durvalumab concurrent with primary tumor CRT, and receive stereotactic body radiotherapy (SBRT) (24Gy/3#) to a single metastasis to maximize the breadth of tumor antigen exposure. Tissue and blood-based studies are planned to identify biomarkers for response, including immunosequencing to test for post-radiotherapy expansion in T cell receptor diversity. Methods: Eligible patients have biopsy-proven esophageal or GEJ cancer, either squamous cell or adenocarcinoma histology, with oligometastatic (1-5 metastases on FDG-PET scan outside the primary tumor radiotherapy field) or locoregionally advanced disease unsuitable for surgery, dysphagia (Mellow score &gt;0), and ECOG PS 0-2. Key exclusion criteria are prior treatment, tumor HER2 positivity, prior thoracic radiotherapy, tracheo-esophageal fistula, esophageal stent in situ and contraindications to immunotherapy. Patients begin durvalumab 1500mg q4w with CRT to the primary tumour (30Gy/10# with weekly carboplatin AUC2 and paclitaxel 50mg/m2), and continuing to disease progression, unacceptable toxicity or 2 years. SBRT to one metastasis (24Gy/3#) is delivered in week 7. Trial primary endpoint is progression free survival rate at 6 months (PFS6) with the aim to rule out a PFS6 rate of 50% in favor of 67.5%, with 80% power and a one-sided 0.05 significance level. Secondary endpoints include dysphagia relief, nutritional status change (patient weight, removal of enteral feeding tubes, PG-SGA score), quality of life, response rate, toxicity, overall survival and exploratory translational endpoints. PALEO is sponsored by the Australasian Gastro-Intestinal Trials Group (AGITG) for conduct at 8 sites in Australia and New Zealand. 6 of planned 54 patients have been enrolled. ACTRN12619001371189. Clinical trial information: Clinical trial information: ACTRN12619001371189 .

Anti-Cancer and Radio-Sensitizing Properties of New Bimetallic (N-Heterocyclic Carbene)-Amine-Pt(II) Complexes.

Bioactive NHC-transition metal complexes have shown promise as anti-cancer agents, but their potential use as radiosensitizers has been neglected so far. We disclose here a new series of bimetallic platinum(II) complexes displaying NHC-type bridging ligands, (bis-NHC)[trans-Pt(RNH2)I2]2, that have been synthesized via a simple, two-step procedure. They display cytotoxicity in the micromolar range on cancerous cell lines, accumulate in cells, and bind to genomic DNA, by inducing DNA damages. Notably, these bimetallic complexes demonstrate significant radiosensitizing effects on both ovarian cells A2780 and nonsmall lung carcinoma cells H1299. Further investigations revealed that bimetallic species make irradiation-induced DNA damages more persistent by inhibiting repair mechanisms. Indeed, a higher and persistent accumulation of both γ-H2AX and 53BP1 foci post-irradiation was detected, in the presence of the NHC-Pt complexes. Overall, we provide the first in vitro evidence for the radiosensitizing properties of NHC-platinum complexes, which suggests their potential use in combined chemo-radio therapy protocols.

Overall survival in patients with metastatic or locally advanced pancreatic cancer following chemoradiation with novel combination of aldoxorubicin, N-803 IL-15 superagonist, and PDL1- NK cell therapy.

720 Background: Pancreatic cancer claimed an estimated 47,050 lives in the USA in 2020, with an expected median overall survival (OS) of 3 months in 3rd line. (Manax ASCO GI 2019), with no evidence of disease control in these late stage patients. We hypothesize that effective response against pancreatic cancer requires orchestration of both the innate and adaptive immune system to accomplish immunogenic cell death with survival benefit. Herein we report updated results of the fully enrolled cohort of a novel combination immunotherapy protocol of low-dose chemoradiation, cytokine-induced NK and T cell activation via N-803 (an IL-15 cytokine superagonist ), and allogeneic off-the-shelf PDL1-targeted high-affinity NK cell (PDL1 t-haNK) infusion. Methods: We report data from a multi-center study, on 83 3rd line or greater, subjects treated with low dose, chemo radiation Nab-paclitaxel (100 mg/ m2 IV), Gemcitabine (600 mg/m2 IV); Cyclophosphamide (50 mg PO BID) and low dose SBRT. This induction immuno-modulation therapy to induce DAMPs was followed with investigational agents activating the innate and adaptive systems: Aldoxorubicin (150 mg/m2 IV), N-803, an IL-15 superagonist (15 μg/kg SC) and PD-L1 t-haNK (~2 × 109cells/dose IV). Prophylactic G-CSF or EPO was not allowed. All treatments were administered on an outpatient basis. Results: As of submission, median follow-up is 4.9 months. Median age 62, M:F ratio 46:36. ECOG 0-1,97%. 74/83 (89%) reported at least 1 investigational product related AE (TRAE) with 63/83 (76%) reporting at least 1 TRA grade 3 or higher. The most common were anemia 41%, neutropenia 20%, thrombocytopenia 10%, all others &lt;10%. SAEs attributed to investigational agents were reported in 8/83 (10%) patients. Treatment is ongoing for 6 subjects (7%), with 17.1 months as the longest duration on therapy to date. Median OS is 5.7 months (95% CI: 4.9, 6.4) with 26/83 alive to date. Median PFS is 2.3 months (95% CI: 2.0, 3.6) and 37% of subjects achieving stable disease &gt;=8 weeks. Median OS in 3rd line (N=38) is 6.3 months, Median OS in 4th line or greater (N=40) is 5.0 months. Conclusions: Historical 3 month median OS in 3rd line metastatic pancreatic cancer patients has been exceeded. A doubling of survival in 3rd line is seen in QUILT 88 investigating a novel combination immunotherapy protocol of low-dose chemoradiation, N-803 and PDL1 t-haNK therapy. Updated data will be presented. Clinical trial information: NCT03563144 .

Photodynamic therapy in glioblastoma: Detection of intraoperative inadvertent 5-ALA mediated photodynamic therapeutical effect after gross total resection.

Glioblastoma (GBM) remains the most frequent and lethal primary brain tumor in adults, despite advancements in surgical resection techniques and adjuvant chemo- and radiotherapy. The most frequent recurrence pattern (75-90%) occurs in the form of continuous growth from the border of the surgical cavity, thus emphasizing the need for locoregional tumor control. Fluorescence-guided surgical resection using 5-ALA has been widely implemented in surgical protocols for such tumors. Recent literature also highlights the applicability of 5-ALA-mediated photodynamic therapy to obtain locoregional tumor control further. This study aims to identify if 5-ALA mediated photodynamic therapeutic effect after gross total glioblastoma resection has inadvertently occurred due to the exposition of protoporphyrin IX charged peripheral tumoral cells to operative room light sources. Of 146 patients who were intervened from glioblastoma between 2015 and 2020, 33 were included in the present study. Strict gross total resection (without supralocal resection) had been accomplished, and adjuvant chemoradiotherapy protocol was administered. Two comparison groups were created regarding the location of the recurrence (group A: up to 1 centimeter from the surgical cavity, and group B: beyond 1 centimeter from the surgical cavity). The cutoff point was determined to be 1 centimeter because of the visible light penetrance to the normal brain tissue. In univariate analysis, both groups only differed regarding 5-ALA administration, which was significantly related to a minor relative risk of presenting the recurrence within the first centimeter from the surgical cavity (Relative Risk = 0,655 (95% CI 0,442-0,970), p-value=0,046). Results obtained in univariate analysis were corroborated posteriorly in multivariate analysis (RR=0,730 (95% CI 0,340-0,980), p=0,017). In the present study, a probable inadvertent 5-ALA photodynamic therapeutical effect has been detected in vivo. This finding widely opens the door for further research on this promising theragnostic tool.

Outcomes of organ preservation treatment in advanced laryngeal carcinoma: A retrospective analysis from a single institution.

Chemoradiation is the standard treatment for patients with locally advanced laryngeal carcinoma with intact cartilage and functional larynx. The aim of this retrospective study was to assess overall survival (OS) and disease-free survival (DFS) of patients with locally advanced (stage III and stage IV) squamous cell carcinoma of the larynx who have been treated with definitive radical radiotherapy (RT) with or without chemotherapy in a tertiary cancer center in India between January 1, 2006 and December 31, 2015. Data were collected using structured proforma. The patients were treated with RT alone, induction chemotherapy (IC) followed by RT, concurrent chemoradiation therapy (CCRT) or IC followed by CCRT. Response assessment was conducted at 3-4 months post-treatment. Patient-, tumor- and treatment-related factors were documented and were associated with DFS and OS. Survival curves were generated using the Kaplan-Meier method and the statistical significance of survival curves was assessed using the log-rank test. Prognostic factors were assessed using the Cox proportional hazards regression model. A total of 630 patients were included in the present study. The most common age group at presentation was 50-70 years (n=477; 75.7%) and 95.4% (n=601) patients were male. The most common stage at presentation was stage III (n=367, 58.1%). The median follow-up period for the entire group of was 59 months (range, 2-175 months). A complete response after treatment was seen in 549 patients (87.1%). Salvage surgery was performed for 11 patients with residual disease. A total of 134 patients (21.3%) had developed locoregional and distant relapses, and salvage surgery was performed for 31 out of 102 patients with locoregional relapse. The 5-year OS was 48.7% and the 5-year DFS was 45.7%. The stage-wise OS rates were 58.9, 34.9 and 30.4% (P=0.001) and the stage-wise DFS rates were 56.3, 32.0 and 21.7 (P=0.001) for stage III, IVa and IVb, respectively. Results from the present study demonstrated the feasibility of delivery of chemoradiation protocols with good results in a developing country.

Quality of life among cervical cancer patients following completion of chemoradiotherapy at Ocean Road Cancer Institute (ORCI) in Tanzania

ObjectiveEffective cancer treatment involves aggressive chemo-radiotherapy protocols that alter survivors’ quality of life (QOL). This has recently aroused the attention not only to focus on clinical care but rather to be holistic and client-centered, looking beyond morbidity and mortality. The study assessed the QOL and associated factors among patients with cervical cancer (CC) after the completion of chemoradiotherapy.MethodsA cross-sectional analytical study was conducted at Ocean Road Cancer Institute (ORCI) from September to November 2020. A total of 323 CC patients were interviewed with a structured questionnaire of QOL, the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), and its cervical cancer module (EORTC QLQ-CX24). The QOL domains, socio-demographic and clinical variables were analyzed with Mann–Whitney and Kruskal–Wallis on SPSS version 23, and a P < 0.05 was considered significant.ResultsMore than half (54.8%) of the CC patients had a good overall QOL. Overall, QOL was affected by education (P = 0.019), smoking (0.044), sexual partner (P = 0.000), treatment modality (P = 0.018), and time since completion of treatment (P = 0.021). Patients who underwent external beam radiation suffered from significant side effect symptoms (P < 0.05) while those who underwent combined external beam radiation and brachytherapy had higher functioning in most domains (P < 0.05).ConclusionsA significant improvement in QOL was observed after chemoradiotherapy and was affected by socio-demographic and clinical variables. Thus, calls for individualized care in addressing these distressing symptoms.

The Significance of Increased Dose in the Outcome of Definitive Chemoradiotherapy at Doses above 60Gy for cT3-4 Cervical Esophageal Cancer: A Report of 83 Cases from a Single Institution

<h3>Purpose/Objective(s)</h3> We investigated whether increasing the RT dose from 60 Gy to 67-68 Gy, which is comparable to the dose for squamous cell carcinoma of the head and neck, would improve the treatment outcome in cT3-4NxM0 patients enrolled for definitive chemoradiotherapy (CRT) for locally advanced cervical esophageal cancer based on late adverse events and recurrence patterns. <h3>Materials/Methods</h3> From 2004 to 2020, 83 patients with cT3-4bNxM0 squamous cell carcinoma of the cervical esophagus (including 22 cases of Ce, 8 cases of CePh, and 53 cases of CeUt, but not UtCe) were enrolled in a radical CRT (1.8-2.1 Gy/F, total dose >60 Gy, and concurrent CDDP80mg/m²x1 and 5-fluorouracil 800 mg/m²x5, 2 courses) protocol at our institution. Pretreatment imaging, including MRI and ultrasound tracheal endoscopy, showed that 71% of 59 patients were cT4 (89% tracheal invasion) and the rest were cT3. cN1 or higher was found in 73 patients (88%) and cN0 in 10 patients (12%). Thirty-six patients were in the cohort group for VMAT of 67-68 Gy/33 F/7 wks with D50 indication for PTV, and the rest were in the non-cohort group. In the remaining 47 patients in the non-cohort (3DCRT) group, 30 patients were completed at 60 Gy (or less than 60 Gy for surgery), and only 14 patients underwent 3DCRT of 62 Gy or more, which was presumably added due to poor response. A total of four patients were judged to be candidates for salvage surgery at 50 Gy intermediate assessment: one in the cohort group and three in the non-cohort group. The median observation period for survivors was 87.4 months (95% CI: 65.0-109.7). <h3>Results</h3> OS was 30.3% (SE 5.4%) at 5 years in all cT3-4NxM083 patients. cT3/T4, cN0/N1, age, gender ratio, and tumor occupying subsite CePh/CeUt types in cohort vs. non-cohort were not significantly skewed. There was no significant difference in OS between the cohort group and the non-cohort group in the ITT comparison of all patients, including the 4 patients who were converted to surgery (Breslow, p=0.84). Multivariate analysis showed that the two factors significant for OS were cT3 vs. cT4 (p=0.035, HR=2.12) and tumor occupation site Ce/CePh vs. CeUt (p=0.047, HR=1.91). There was no significant difference in local recurrence and regional recurrence, 41.5% and 12.2% in the cohort group and 39.5% and 7.9% in the non-cohort group, respectively. The main late adverse events Grade 3 or higher were esophageal stenosis in 6 cases and bilateral recurrent nerve palsy in 1 case, but there was no significant difference between the cohort group (3 cases) and the non-cohort group (4 cases), and it could not be said to occur at doses higher than 60 Gy by dose. <h3>Conclusion</h3> It has long been pointed out that cervical esophageal cancer may require higher doses than thoracic esophageal cancer. However, in advanced cancers of cT3 or higher, treatment planning to obtain an appropriate dose distribution of 60 Gy or higher in VMAT did not directly lead to improved OS.