Standard Chemoradiation Research Articles

Immune Check-Point Inhibitors and Standard Chemoradiotherapy in Definitive Head and Neck Cancer Treatment.

In head and neck cancer management, there is a need for tailored approaches to optimally implement clinical outcomes. Based on the assumption that efficacy and long-term toxicity are not satisfactory for standard concurrent platinum-based chemoradiotherapy, several trials have been designed to test whether induction immunotherapy and/or concomitant immunotherapy and radiotherapy result in improved survival and toxicity outcomes. Here, we present an overview of the most recent concomitant therapeutic strategies for head and neck cancer, focusing on the knowledge available regarding check-point inhibitors. The aim is to present the characteristics of the main check-point inhibitors and to summarize the clinical trials on the combination of immune check-point inhibitors and (chemo)radiotherapy in the definitive HNC setting, in order to provide a useful clinical tool for further research.

Matched pair analysis for comparison of survival outcome of alternative regimens to standard three-weekly cisplatin-based concurrent chemoradiation of head and neck cancer.

BackgroundTo compare head and neck cancer (HNC) patients treated with three-weekly versus weekly cisplatin-based or other chemotherapy-based concurrent chemoradiation (CRT) and CRT with versus without induction chemotherapy (ICT) to investigate differences in overall survival (OS) and cancer-specific survival (CSS).MethodsHNC patients treated with definitive or adjuvant CRT at Roswell Park Comprehensive Cancer Center between 2003 and 2017 were retrospectively reviewed. Propensity score matching was performed to obtain three sets of balanced matched pairs: three-weekly and weekly cisplatin CRT, three weekly and non-cisplatin CRT, CRT with and without ICT. Multivariate Cox regression and Kaplan-Meier analyses were used to estimate and compare survival outcomes.ResultsA total of 623 patients received either definitive (81%) or post-operative (19%) RT. Of these, 283 patients concurrently received three-weekly cisplatin (45%); 189 patients (30%) received weekly cisplatin; 151 patients (24%) received non-cisplatin regimen. Median follow-up was 55.4 months (interquartile range, 38.0–88.7). Patients who received CRT alone and those who received ICT and CRT had no difference in 5-year OS (51.5% and 41.0% respectively, P=0.53) and CSS (64.9% and 49.7% respectively, P=0.21). Compared to patients who received three-weekly cisplatin, patients who received weekly cisplatin had no difference in 5-year OS (59.3% vs. 54.1%, P=0.35) and CSS (70.3% vs. 62.4%, P=0.09); patients who received non-cisplatin CRT also had no difference in 5-year OS (54.5% vs. 58.3%, P=0.51) and CSS (67.5% vs. 64.7%, P=0.45).ConclusionsNo significant difference in OS and CSS was observed in any of the three pairs of CRT regimens. ICT prior to CRT did not improve survival of CRT alone. Non-cisplatin and weekly cisplatin regimens did not prove to be inferior to the standard three-weekly cisplatin.

De-Escalation of Therapy for Patients with Early-Stage Squamous Cell Carcinoma of the Anus

Simple SummaryManagement of early-stage squamous cell carcinoma of the anus (SCCA) remains controversial. The current standard of care treatment of chemotherapy combined with radiation therapy can result in both acute and late toxicity. Alternative therapies, including radiation therapy alone or local excision, may be less toxic, but the role of these therapies in early-stage SCCA remains unclear. Additional options for reducing the intensity of therapy for early-stage SCCA include reduction of radiation dose, altering treatment volumes, modifying chemotherapy type and dosage, and using intensity-modulated radiation therapy to reduce the radiation dose to adjacent normal tissues. Multiple prospective studies are actively investigating the role of de-escalation of therapy in patients with early-stage SCCA.The incidence of squamous cell carcinoma of the anus (SCCA) is increasing, particularly in the elderly, with increased mortality in this age group. While the current standard of care for localized SCCA remains chemoradiation (CRT), completion of this treatment can be challenging with risks for severe acute and late toxicity. It remains unclear if full course CRT is required for the management of early-stage SCCA or if de-escalation of treatment is possible without compromising patient outcomes. Alternative therapies include radiation therapy alone or local excision for appropriate patients. Modifying standard CRT may also reduce toxicity including the routine use of intensity-modulated radiation therapy for treatment delivery, modification of treatment volumes, and selection and dosing of concurrent systemic therapy agents. Finally, we provide an overview of currently accruing prospective trials focused on defining the role of de-escalation of therapy in patients with early-stage SCCA.

Total Neoadjuvant Therapy in Locally Advanced Rectal Cancer: A Systematic Review and Metaanalysis of Oncological and Operative Outcomes.

Total neoadjuvant therapy in rectal cancer refers to the administration of chemoradiotherapy plus chemotherapy before surgery. Recent studies have shown improved pathological complete response and disease-free survival with this approach. However, survival benefits remain unproven. Our objective is to present a metaanalysis of oncological outcomes of total neoadjuvant therapy in locally advanced rectal cancer. A comprehensive search was performed on PubMed, Medline, and Google Scholars. Studies comparing total neoadjuvant therapy with standardneoadjuvant chemoradiotherapy were included. Data extracted from the individual studies were pooled and a metaanalysis performed. The outcomes of interest are the rate of complete pathological response, nodal response, resection margin, anal preservation, anastomotic leak, local recurrence, distant recurrence, disease-free survival, and overall survival. There were 15 comparative studies with 2437 patients in the neoadjuvant chemoradiotherapy group and 2284 in the total neoadjuvant therapy group. The pooled complete pathological response was 22.3% in the total neoadjuvant therapy group, compared with 14.2% in the standard neoadjuvant chemoradiotherapy group (p<0.001). Even though there was no difference in local recurrence rate, there was a significantly lower rate of distant recurrence (OR 0.81, p=0.02), and better 3-year disease-free survival (70.6% vs. 65.3%, respectively, p<0.001) and overall survival (84.9% vs. 82.3%, respectively, p=0.006), favoring the total neoadjuvant therapy group. Due to significant heterogeneity in the study protocols, there remains uncertainty on the ideal chemotherapy/radiotherapy sequence. This study provides supporting evidence on the favorable immediate and intermediate oncological outcomes with the use of total neoadjuvant therapy for locally advanced rectal cancer.

The importance of radiotherapy in rectal cancer-an update from a surgeon's perspective

Neoadjuvant chemoradiotherapy was implemented in the treatment of rectal cancer for UICC stagesII andIII in 2004. Recent studies have provided new insights with respect to the indications and sequence of radiotherapy in the concept of multimodal treatment. The aim of the study was to review the status of radiotherapy in the context of current developments in the treatment of rectal cancer, such as magnetic resonance imaging (MRI)-based surgery, total neoadjuvant therapy and the watch and wait strategy for complete clinical remission. The indications for neoadjuvant radiotherapy based on the clinical T and Nstages are not exact and can lead to overtreatment in 18-27% of cases. Radiotherapy is associated with a worsening of anorectal and urogenital functions. Local recurrence rates of 3% with surgery alone can be achieved in patients with negative circumferential resection margins (low risk cancer) in MRI. For rectal cancer with high-risk features, such as cT4 tumor, positive circumferential resection margins and extramural vascular invasion, an improved disease-free survival and alower rate of distant metastases could be achieved with total neoadjuvant therapy compared to standard neoadjuvant chemoradiotherapy in recent phaseIII randomized trials. Pathological complete remission is achieved in28% of patients after total neoadjuvant therapy. The high rate of complete remission has fired the debate regarding watch and wait after total neoadjuvant therapy; however, no prospective randomized phase III trials comparing total mesorectal resection vs. watch and wait in complete clinical remission have been published. Hence, resection remains the gold standard in this scenario given the excellent long-term oncological results.

Distinguishing Pseudoprogression From True Early Progression in Isocitrate Dehydrogenase Wild-Type Glioblastoma by Interrogating Clinical, Radiological, and Molecular Features.

Background: Pseudoprogression (PsP) mimics true early progression (TeP) in conventional imaging, which poses a diagnostic challenge in glioblastoma (GBM) patients who undergo standard concurrent chemoradiation (CCRT). This study aimed to investigate whether perioperative markers could distinguish and predict PsP from TeP in de novo isocitrate dehydrogenase (IDH) wild-type GBM patients.Methods: New or progressive gadolinium-enhancing lesions that emerged within 12 weeks after CCRT were defined as early progression. Lesions that remained stable or spontaneously regressed were classified as PsP, otherwise persistently enlarged as TeP. Clinical, radiological, and molecular information were collected for further analysis. Patients in the early progression subgroup were divided into derivation and validation sets (7:3, according to operation date).Results: Among 234 consecutive cases enrolled in this retrospective study, the incidences of PsP, TeP, and neither patterns of progression (nP) were 26.1% (61/234), 37.6% (88/234), and 36.3% (85/234), respectively. In the early progression subgroup, univariate analysis demonstrated female (OR: 2.161, P = 0.026), gross total removal (GTR) of the tumor (OR: 6.571, P < 001), located in the frontal lobe (OR: 2.561, P = 0.008), non-subventricular zone (SVZ) infringement (OR: 10.937, P < 0.001), and methylated O-6-methylguanine-DNA methyltransferase (MGMT) promoter (mMGMTp) (OR: 9.737, P < 0.001) were correlated with PsP, while GTR, non-SVZ infringement, and mMGMTp were further validated in multivariate analysis. Integrating quantitative MGMTp methylation levels from pyrosequencing, GTR, and non-SVZ infringement showed the best discriminative ability in the random forest model for derivation and validation set (AUC: 0.937, 0.911, respectively). Furthermore, a nomogram could effectively evaluate the importance of those markers in developing PsP (C-index: 0.916) and had a well-fitted calibration curve.Conclusion: Integrating those clinical, radiological, and molecular features provided a novel and robust method to distinguish PsP from TeP, which was crucial for subsequent clinical decision making, clinical trial enrollment, and prognostic assessment. By in-depth interrogation of perioperative markers, clinicians could distinguish PsP from TeP independent from advanced imaging.

Abstract IA-006: Enhancing the therapeutic ratio for glioblastoma by combining radiation therapy with PARP inhibitors

Abstract PARP inhibitors (PARPi) enhance radiation sensitivity in multiple cancer models, both in vitro and in vivo. Our observation that the radiosensitizing properties of PARPi are most pronounced in rapidly proliferating cells is reflected in early phase clinical trial data showing exacerbation of acute radiation toxicity in rapidly proliferating tissues such as oropharyngeal and esophageal mucosa. Lack of radiosensitization in late responding, slowly proliferating normal tissues indicates that PARPi may be more effectively combined with radiation therapy (RT) in patients with brain tumors. We are therefore evaluating the oral PARPi olaparib in combination with RT and/or temozolomide (TMZ) in the treatment of glioblastoma (GBM), the most prevalent and most aggressive primary brain tumor. Patients with GBM experience very poor outcomes in terms of median survival (c.1 year) and neurocognitive decline caused primarily by RT. Olaparib was initially evaluated in combination with daily low-dose TMZ in patients with recurrent GBM in the OPARATIC trial. Pharmacokinetic studies revealed that olaparib penetrates both core and margin regions of GBM, indicating that the BBB is significantly disrupted throughout these tumors. Olaparib could be safely combined with daily TMZ (75 mg/m2), but intermittent olaparib dosing (150 mg three days per week) was required to avoid dose-limiting hematological toxicity. Early phase testing of the olaparib-radiotherapy combination is now underway in three populations of patients with newly diagnosed GBM. Patients aged &amp;gt;65 with MGMT unmethylated GBM are being recruited to a randomized, placebo-controlled phase II study (PARADIGM) after a phase I dose escalation study showed that olaparib (200 mg twice daily) was extremely well tolerated when combined with brain irradiation (40 Gray in 15#). Good performance status patients aged &amp;lt;70 are being recruited to two parallel phase I dose escalation studies: patients with MGMT unmethylated tumors are receiving daily olaparib with RT (60 Gy in 30#) without TMZ, while patients with MGMT methylated tumors are receiving intermittent olaparib with standard chemoradiation (60 Gy). The impact of PARPi on RT induced neurotoxicity is being investigated in preclinical studies. In vitro data show that PARPi reduce proliferation of neural stem cells and protect them against RT induced apoptosis, while in vivo studies support the emerging concept that RT induced neuroinflammation is important in the pathogenesis of neurotoxicity. Importantly, preliminary PET and immunohistochemical studies have shown robust anti-neuroinflammatory effects of PARPi in this context. Ongoing experiments are defining the roles of microglia, astrocytes and neurogenesis in this phenomenon. These diverse data sets provide support for our hypothesis that combining PARPi with RT has potential to improve outcomes for GBM patients by enhancing tumor control while simultaneously suppressing neuroinflammation and alleviating RT related neurocognitive decline. Citation Format: Anthony J. Chalmers, Rodrigo Gutierrez-Quintana, David J. Walker, Karin Williams, Duncan Forster, Mark R. Jackson, Sarah Derby, Jon Stobo, Lorna Sweeting, Caroline Kelly, Stephen Durant, Kaye J. Williams. Enhancing the therapeutic ratio for glioblastoma by combining radiation therapy with PARP inhibitors [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr IA-006.

Combining radiotherapy with targeted therapies in non-small cell lung cancer: focus on anti-EGFR, anti-ALK and anti-angiogenic agents.

The combination of radiotherapy (RT) with targeted agents in non-small cell lung cancer (NSCLC) has been expected to improve the therapeutic ratio and tumor control. The EGFR blockade enhances the antitumor effect of RT. The ALK inhibition elicits anti-proliferative, pro-apoptotic and antiangiogenic effects in ALK-positive NSCLC cell lines, enhanced by the exposure to RT. The antiangiogenic agents normalize pathological tumor vessels, thus decrease tumor cell hypoxia and improve radiosensitivity. To date, however, none of the targeted agents combined with RT has shown proven clinical benefit over standard chemoradiation (CRT) in locally advanced NSCLC. The risk of potential excessive toxicity related to the therapeutic combination of RT and targeted agents cannot be ignored. Well-designed clinical trials may allow development of more effective combination strategies. Another potential application of combined RT and targeted therapies in oncogene-driven NSCLC is metastatic oligoprogressive or oligopersistent disease. The use of RT in oligoprogressive oncogene-driven NSCLC, while continuing first line targeted therapy, can potentially eradicate resistant cell clones and provide survival benefit. Likewise, the consolidation of oligopersistent foci (molecularly resistant to first line targeted therapy) may potentially interfere with the natural course of the disease by avoiding or delaying progression. We discuss here the molecular and radiobiological mechanisms of combining RT and targeted agents, and summarize current clinical experience.

Glycolysis and Fatty Acid Oxidation Inhibition Improves Survival in Glioblastoma.

Glioblastoma (GBM) is the most aggressive adult glioma with a median survival of 14 months. While standard treatments (safe maximal resection, radiation, and temozolomide chemotherapy) have increased the median survival in favorable O(6)-methylguanine-DNA methyltransferase (MGMT)-methylated GBM (~21 months), a large proportion of patients experience a highly debilitating and rapidly fatal disease. This study examined GBM cellular energetic pathways and blockade using repurposed drugs: the glycolytic inhibitor, namely dicholoroacetate (DCA), and the partial fatty acid oxidation (FAO) inhibitor, namely ranolazine (Rano). Gene expression data show that GBM subtypes have similar glucose and FAO pathways, and GBM tumors have significant upregulation of enzymes in both pathways, compared to normal brain tissue (p < 0.01). DCA and the DCA/Rano combination showed reduced colony-forming activity of GBM and increased oxidative stress, DNA damage, autophagy, and apoptosis in vitro. In the orthotopic Gl261 and CT2A syngeneic murine models of GBM, DCA, Rano, and DCA/Rano increased median survival and induced focal tumor necrosis and hemorrhage. In conclusion, dual targeting of glycolytic and FAO metabolic pathways provides a viable treatment that warrants further investigation concurrently or as an adjuvant to standard chemoradiation for GBM.

A clinical and molecular portrait of non-metastatic anal squamous cell carcinoma

Anal squamous cell carcinoma (ASCC) is a rare gastrointestinal malignancy associated with high-risk Human papillomavirus (HPV) infection. Despite improved outcomes in non-metastatic ASCC, definitive chemoradiotherapy constitutes the standard treatment for localized disease. Evidences for predictive and prognostic biomarkers are limited. Here, we performed a viral, immune, and mutational characterization of 79 non-metastatic ASCC patients with complete definitive chemoradiotherapy. HPV-16 was detected in 91% of positive cases in single infections (78%) or in coinfections with multiple genotypes (22%). Fifty-four percent of non-metastatic ASCC cases displayed mutations affecting cancer driver genes such as PIK3CA (21% of cases), TP53 (15%), FBXW7 (9%), and APC (6%). PD-L1 expression was detected in 57% of non-metastatic ASCC. Increased PD-L1 positive cases (67%) were detected in patients with complete response compared with non-complete response to treatment (37%) (p = 0.021). Furthermore, patients with PD-L1 positive tumors were significantly associated with better disease-free survival (DFS) and overall survival (OS) compared with patients with PD-L1 negative tumors (p = 0.006 and p = 0.002, respectively). PD-L1 expression strongly impacts CR rate and survival of non-metastatic ASCC patients after standard definitive chemoradiotherapy. PD-L1 expression could be used to stratify good versus poor responders avoiding the associated morbidity with abdominal perineal resection.

Prognostic value of C-reactive protein-to-albumin ratio and inflammatory markers in esophageal cancer patients treated with chemoradiotherapy

Background: This retrospective research, it was aimed to evaluate disease-free survival (DFS) using inflammatory markers in esophageal cancer patients who received chemoradiotherapy (CRT). Methods: A total of 67 patients who received standard curative chemoradiotherapy for esophageal cancer were included in the study between 2011-2018. The patient, treatment characteristics, and pretreatment inflammatory markers were obtained from the patient's file. Results : Median follow up time was 18 months (6-72 months). ROC curve analyses showed the C-Reactive Protein-to-Albumin (CAR) cut-off value 0.9 for DFS (AUC:78.8%; sensitivity: 85%; specificity; 67.5%). 2-year disease free survival for CAR ≥0.9 and CAR <0.9 were 45.7% and 78%, respectively ( P=0.035). The radiation doses >50Gy (versus <50Gy, p=0.027) and CAR ratio < 0.9 (versus ≥ 0.9, p=0.005) appeared significant associates of better DFS in univariate analyses, but the age, gender, stage, localization, neutrophil-to-lympocyte ratio (NLR) and platelet-to-lymhocyte ratio (PLR) were no statistically significant (p>0.005).On the multivariate logistic analysis, our results showed that CAR < 0.9 [hazard ratio (HR) 1.29; 95% confidence interval [CI], 1.336-2.946; P = 0.014]; and radiation dose >50 Gy (HR 0.91; 95% CI, 1.229-4.997; P = 0.027) independent prognostic indictors. Conclusion: Our study found that the C-Reactive Protein/Albumin ratio is easy to apply and maybe a promising marker to predict disease-free survival in esophageal cancer patients who received chemoradiotherapy.

Trimodality Therapy With or Without Neoadjuvant Chemotherapy for Muscle-Invasive Bladder Cancer.

Bladder-sparing chemoradiation therapy is a definitive first-line treatment option for muscle-invasive bladder cancer. Randomized trials have demonstrated that the addition of neoadjuvant chemotherapy to radical cystectomy or radiation monotherapy results in a survival benefit. Whether neoadjuvant chemotherapy improves outcomes when used with definitive chemoradiation is unknown. We identified 2566 patients in the National Cancer Data Base with cT2-4N0M0 urothelial cell carcinoma of the bladder treated with definitive intent concurrent chemoradiation from 2004 to 2015. The exposure of interest was receipt of neoadjuvant chemotherapy versus those without neoadjuvant chemotherapy. The primary outcome was overall survival defined from the time of diagnosis. Kaplan-Meier and multivariable Cox proportional hazard analyses were used to compare survival between groups. Sensitivity analyses tested (1) an interaction term for clinical T stage and (2) defining survival from start of radiation (as opposed to time of diagnosis) to address potential leading time bias. We identified 462 patients treated with neoadjuvant chemotherapy followed by chemoradiation and 2104 patients treated with chemoradiation alone. With a median follow-up of 6.2 years, we found no difference in survival between groups: 5-year or 10-year overall survival of 30.6% (95% confidence interval [CI], 28.4%-32.9%) in the neoadjuvant group versus 31.8% (95% CI, 27.0%-36.8%) in the standard chemoradiation therapy group and 13.3% (95% CI, 11.2%-15.5%) in the neoadjuvant group versus 13.0% (95% CI, 8.4%-18.7%) in the standard chemoradiation therapy group, respectively (log-rank P=.19). On multivariable analysis we found no association between receipt of neoadjuvant chemotherapy and overall survival (hazard ratio, 1.01; 95% CI, 0.88-1.15; P=.921). The sensitivity analyses did not identify any differential effect by clinical T stage nor by defining survival from start of radiation. These results do not support the routine addition of neoadjuvant chemotherapy to definitive chemoradiation for bladder cancer, and optimizing the chemotherapy sequencing and regimens for bladder-preserving approaches to muscle invasive bladder cancer should continue to be studied under prospective clinical trials.

P48.02 NRG Oncology/Alliance LU005: Chemoradiation vs. Chemoradiation Plus Atezolizumab in Limited Stage Small Cell Lung Cancer

Limited stage small cell lung cancer (LS-SCLC) is treated with standard of care platinum/etoposide (EP) and thoracic radiation therapy (TRT) with curative intent, however the majority of patients are not cured and median overall survival is approximately 30 months. Addition of atezolizumab to chemotherapy in extensive stage SCLC has improved progression free and overall survival in a non-curative setting leading to hope that addition of an immune checkpoint inhibitor to standard chemoradiotherapy could benefit LS-SCLC patients.

Response assessment during chemoradiation using a hypercellular/hyperperfused imaging phenotype predicts survival in patients with newly diagnosed glioblastoma.

Adversely prognostic hypercellular and hyperperfused regions of glioblastoma (GBM) predict progression-free survival, and are a novel target for dose-intensified chemoradiation (chemoRT) recently implemented in a phase II clinical trial. As a secondary aim, we hypothesized that dose-intensified chemoRT would induce greater mid-treatment response of hypercellular/hyperperfused tumor regions vs standard chemoradiation, and that early response would improve overall survival (OS). Forty-nine patients with newly diagnosed GBM underwent prospective, multiparametric high b value diffusion-weighted MRI (DW-MRI) and perfusion dynamic contrast-enhanced MRI (DCE-MRI) pre-RT and 3-4 weeks into RT. The hypercellular tumor volume (TVHCV, mean contralateral normal brain + 2SD) and hyperperfused tumor volume (TVCBV, contralateral normal frontal gray matter + 1SD) were generated using automated thresholding. Twenty-six patients were enrolled on a dose-escalation trial targeting TVHCV/TVCBV with 75 Gy in 30 fractions, and 23 non-trial patients comprised the control group. OS was estimated using the Kaplan-Meier method and compared using the log-rank test. The effect of TVHCV/TVCBV and Gd-enhanced tumor volume on OS was assessed using multivariable Cox proportional-hazard regression. Most patients had gross total (47%) or subtotal resection (37%), 25% were MGMT-methylated. Patients treated on the dose-escalation trial had significantly greater reduction in TVHCV/TVCBV (41% reduction, IQR 17%-75%) vs non-trial patients (6% reduction, IQR 6%-22%, P = .002). An increase in TVHCV/TVCBV during chemoRT was associated with worse OS (adjusted hazard ratio [aHR] 1.2, 95%CI 1.0-1.4, P = .02), while pre-treatment tumor volumes (P > .5) and changes in Gd-enhanced volume (P = .9) were not. Multiparametric MRI permits identification of therapeutic resistance during chemoRT and supports adaptive strategies in future trials.

New Challenges of Treatment for Locally Advanced Head and Neck Cancers in the Covid-19 Pandemic Era.

Locally advanced head and neck cancer is a unique challenge for cancer management in the Covid-19 situation. The negative consequences of delaying radio-chemotherapy treatment make it necessary to prioritize these patients, the continuation of radiotherapy being indicated even if SARS-CoV-2 infection is confirmed in the case of patients with moderate and mild symptoms. For an early scenario, the standard chemo-radiotherapy using simultaneous integrated boost (SIB) technique is the preferred option, because it reduces the overall treatment time. For a late scenario with limited resources, hypo-fractionated treatment, with possible omission of chemotherapy for elderly patients and for those who have comorbidities, is recommended. Concurrent chemotherapy is controversial for dose values >2.4 Gy per fraction. The implementation of hypo-fractionated regimens should be based on a careful assessment of dose-volume constraints for organs at risks (OARs), using recommendations from clinical trials or dose conversion based on the linear-quadratic (LQ) model. Induction chemotherapy is not considered the optimal solution in this situation because of the risk of immunosuppression even though in selected groups of patients TPF regimen may bring benefits. Although the MACH-NC meta-analysis of chemotherapy in head and neck cancers did not demonstrate the superiority of induction chemotherapy over concurrent chemoradiotherapy, an induction regimen could be considered for cases with an increased risk of metastasis even in the case of a possible Covid-19 pandemic scenario.

A Comparative Study of Two Protocols of Concurrent Chemotherapy with External Beam Radiotherapy in Treatment of Locally Advanced Cervical Cancer: Cisplatin Versus Cisplatin Plus Capecitabine Combination

Cervical carcinoma is one of the commonest cancers affecting women in the low- and middle-income countries. The standard treatment of locally advanced cases by external beam radiotherapy (EBRT) along with single-agent cisplatin-based concurrent chemotherapy is effective, but rates of treatment failure and recurrence remain high. There exists a need to augment the treatment protocol. One modality to do that is by addition of another radiosensitizer/chemotherapeutic agent. In total, 40 women with histologically proven locally advanced cervical cancer were included in the study. The first 20 (Arm 1) were treated with EBRT along with concurrent cisplatin at 40 mg/m2 (maximum 70 mg). The next 20 patients (Arm 2) received the same treatment but also received oral capecitabine 460 mg/m2 during EBRT. Treatment-related toxicity and disease response rates at 6 months were compared in the two arms. Overall survival at 5 years of patients in the two arms was also compared. During treatment, 40% of patients in Arm 1 developed anemia compared to 45% in Arm 2. In total, 5% patients in Arm 1 and 10% in Arm 2 developed grade 2 leucopenia. A higher incidence of proctitis and diarrhea was seen in Arm 2 (30%) than in Arm 1 (15%). The grade of proctitis and diarrhea was also higher in Arm 2 than in Arm 1. None of the patients developed hand-foot syndrome. All the complications were managed symptomatically and did not cause significant treatment break in either treatment arms except in one patient in Arm 2. At 6-month follow-up, four patients (20%) in both arms had residual or progressive disease. At the end of 5 years, the mean overall survival in the two Arms 1 and 2 was 47.9 and 48.4 months, respectively. The addition of capecitabine to standard concurrent chemoradiotherapy with cisplatin for locally advanced cervical cancer is well tolerated even on an OPD basis though there is increased incidence of acute proctitis and diarrhea with this combination. No difference in treatment efficacy or improvement in survival between the two protocols was seen in our study though this may have been influenced by the small sample size and short period of follow-up of our study. We recommend a phase II/III study to further evaluate the efficacy and tolerability of this regimen.

Decreasing treatment burden in HPV-related OPSCC: A systematic review of clinical trials.

Favorable outcomes are observed after treatment with standard chemoradiotherapy (CRT) for Human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) patients. The consistent growing interest on treatment-related toxicity burden, potentially jeopardizing survivors' quality of life, led clinicians to investigate possible de-escalation strategies. A comprehensive systematic literature search of clinical trials was performed through the EMBASE database to provide an overview of the de-escalation strategies spectrum. Additionally, hand searching and clinicaltrials.gov were also used. Herein, we report and discuss different approaches to de-escalation of therapy, with respect to both local and systemic strategies. Several promising de-escalation experiences have been published. However, while further evidence is awaited, no changes in the management nor deviation from the standard of care should be made outside of clinical trials.

Radiotherapy-induced glioblastoma: distinct differences in overall survival, tumor location, pMGMT methylation and primary tumor epidemiology in Hong Kong chinese patients

Introduction Radiotherapy-induced glioblastomas (RIGB) are a well-known late and rare complication of brain irradiation. Yet the clinical, radiological and molecular characteristics of these tumors are not well characterized. Methods This was a retrospective multicentre study that analysed adult patients with newly diagnosed glioblastoma over a 10-year period. Patients with RIGB were identified according to Cahan’s criteria for radiation-induced tumors. A case-control analysis was performed to compare known prognostic factors for overall survival (OS) with an independent cohort of IDH-1 wildtype de novo glioblastomas treated with standard temozolomide chemoradiotherapy. Survival analysis was performed by Cox proportional hazards regression. Results A total of 590 adult patients were diagnosed with glioblastoma. 19 patients (3%) had RIGB. The mean age of patients upon diagnosis was 48 years ± 15. The mean latency duration from radiotherapy to RIGB was 14 years ± 8. The mean total dose was 58Gy ± 10. One-third of patients (37%, 7/19) had nasopharyngeal cancer and a fifth (21%, 4/19) had primary intracranial germinoma. Compared to a cohort of 146 de novo glioblastoma patients, RIGB patients had a shorter median OS of 4.8 months versus 19.2 months (p-value: <.001). Over a third of RIGBs involved the cerebellum (37%, 7/19) and was higher than the control group (4%, 6/146; p-value: <.001). A fifth of RIGBs (21%, 3/19) were pMGMT methylated which was significantly fewer than the control group (49%, 71/146; p-value: .01). For RIGB patients (32%, 6/19) treated with re-irradiation, the one-year survival rate was 67% and only 8% for those without such treatment (p-value: .007). Conclusion The propensity for RIGBs to develop in the cerebellum and to be pMGMT unmethylated may contribute to their poorer prognosis. When possible re-irradiation may offer a survival benefit. Nasopharyngeal cancer and germinomas accounted for the majority of original malignancies reflecting their prevalence among Southern Chinese.

A single-institution experience using total neoadjuvant therapy to treat locally advanced rectal cancer.

64 Background: The management of locally advanced rectal cancer has historically included preoperative chemoradiation followed by surgery and then adjuvant chemotherapy. Recently there has been an increasing utilization of preoperative chemotherapy in addition to standard chemoradiation, a strategy known as total neoadjuvant therapy (TNT). TNT has been offered to patients at the University of Colorado Cancer Center since 2015. Methods: Records of all patients presenting to the University of Colorado colorectal multidisciplinary clinic since 2015 were screened for treatment with TNT. Data collected on these patients included demographic information, diagnosis and initial staging, preoperative treatment received, and surgical outcomes including treatment response and pathological stage. TNT included preoperative chemotherapy with oxaliplatin combined with either 5-FU (FOLFOX) or capecitabine (CAPOX) as well as chemoradiation, generally given with concurrent capecitabine. Patients then underwent surgical resection; if a complete clinical response was achieved with TNT, non-operative management (NOM) was offered. Results: A total of 81 patients thus far have undergone TNT followed by resection or, if complete clinical response and preferred by the patient, NOM. The mean age of patients was 56 years, ranging from 23 to 87, and 60% of patients were male. The majority of patients (67) had stage III disease at presentation while 1 had stage 1 (T2N0) disease, 11 had stage II disease and 2 patients had oligometastatic disease. Ultimately 13 patients (16%) opted for non-operative management after being found to have a complete clinical response following TNT. Of the 68 patients who underwent surgical resection, 21 (31%) had a pathological complete response, with another 14 (21%) with near-complete response. 28 patients (41%) had a partial treatment response and 5 (7%) had no treatment response. In total, the rate of complete clinical or pathologic response was 42%. Treatment was overall well-tolerated with 90% of patients receiving the full planned dose of radiation and 98% of patients completing all planned cycles of chemotherapy, though most of them with typical dose reductions needed. Of the patients who underwent surgery, 49 (72%) had low anterior resection and 19 (28%) had an abdominoperineal resection. Of patients with temporary ileostomies, 85% of them had their ileostomy reversed within 10 weeks of surgery. Conclusions: Treatment of locally advanced rectal cancer by a total neoadjuvant approach is well-tolerated and results in a high rate of clinical and pathological complete response.

A randomized clinical trial evaluating the efficacy and safety of the addition of oral metronomic chemotherapy after completion of standard chemoradiation versus observation in patients with locally advanced esophageal and gastroesophageal junction squamous cell carcinoma.

163 Background: In RTOG 85-01, patients with locally advanced esophageal and gastroesophageal junction (GEJ) cancer treated with concurrent chemoradiotherapy (CRT) had a median overall survival (OS) of 14 months and 5-year OS of 27%. Improving outcomes in these patients is an unmet need. We investigated the addition of oral metronomic chemotherapy (OMC) following definitive CRT. Methods: A randomized integrated phase II/III clinical trial (CTRI/2015/09/006204) in patients with squamous cell carcinoma of the esophagus or the GEJ who had completed definitive radical CRT within the past 12 weeks, had an ECOG PS 0-2 and no clinical or radiologic evidence of progressive disease. Patients were stratified based on whether or not they had received induction chemotherapy followed by CRT, and then randomized 1:1 to receive OMC (celecoxib 200 mg twice daily and methotrexate 15 mg/m2 weekly) for 12 months or observation. The primary efficacy endpoint for the phase II portion was progression free survival (PFS). The secondary endpoints were OS and toxicity. With a power of 70% and an alpha of 10%, we hypothesized a hazard ratio of 1.5, with a median follow-up of 6 months. The planned sample size for the phase II portion was 151 patients. The p-value for stopping the trial after the phase II part of the study was set at 0.2 for the PFS. Results: Between Jan 2016 and Dec 2019, we enrolled 151 patients, 75 to the OMC arm and 76 to observation. The median age was 57 years, 59% were male. The tumor originated in the upper thoracic esophagus in 79% patients, with median tumor length 6 cm. Induction chemotherapy was received by 14% of the patients. Concurrent CRT consisted of median 63 Gy in median 35 fractions; 91% patients received concurrent weekly paclitaxel and carboplatin with radiation. OMC was started at a median of 11 weeks (IQR, 9 to 12) from the start of CRT. Grade 3 or higher toxicities (regardless of relatedness to study intervention) were noted in 27 patients (17.9%), 18 in the OMC arm and 9 in the observation arm; P=0.071. The median time to disease progression or death was 23 months (95% CI, 7.9-38.1) in the OMC arm and not reached in the observation arm; HR, 1.33, 95% CI, 0.83-2.14; P=0.23. The 1-year PFS was 67% in both the arms; the 2-year PFS were 48% and 61% in the OMC and observation arms respectively. The median OS was 36 months (95% CI, 17.9-54) in the OMC arm and not reached in the observation arm; HR, 1.75; 95% CI, 1.02-2.99; P, 0.037. The 1-year OS was 74.7% in the OMC arm and 88% in the observation arm; the 2-year OS was 53.9% in the OMC arm and 75% in the observation arm. Conclusion: Adjuvant oral metronomic chemotherapy after radical CRT does not improve outcomes in patients with locally advanced esophageal or GEJ squamous cell carcinoma. Clinical trial information: CTRI/2015/09/006204.