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Journal of Experimental & Clinical... Oct 2020Inflammation response of epithelial mucosa to chemo- radiotherapy cytotoxic effects leads to mucositis, a painful side effect of antineoplastic treatments. About 40% of... (Review)
Review
Inflammation response of epithelial mucosa to chemo- radiotherapy cytotoxic effects leads to mucositis, a painful side effect of antineoplastic treatments. About 40% of the patients treated with chemotherapy develop mucositis; this percentage rises to about 90% for head and neck cancer patients (HNC) treated with both chemo- and radiotherapy. 19% of the latter will be hospitalized and will experience a delay in antineoplastic treatment for high-grade mucositis management, resulting in a reduction of the quality of life, a worse prognosis and an increase in patient management costs. Currently, several interventions and prevention guidelines are available, but their effectiveness is uncertain. This review comprehensively describes mucositis, debating the impact of standard chemo-radiotherapy and targeted therapy on mucositis development and pointing out the limits and the benefits of current mucositis treatment strategies and assessment guidelines. Moreover, the review critically examines the feasibility of the existing biomarkers to predict patient risk of developing oral mucositis and their role in early diagnosis. Despite the expression levels of some proteins involved in the inflammation response, such as TNF-α or IL-1β, partially correlate with mucositis process, their presence does not exclude others mucositis-independent inflammation events. This strongly suggests the need to discover biomarkers that specifically feature mucositis process development. Non-coding RNAs might hold this potential.
Topics: Chemoradiotherapy; Humans; Neoplasms; Quality of Life; Stomatitis
PubMed: 33028357
DOI: 10.1186/s13046-020-01715-7 -
JAMA Oncology Jan 2022Total neoadjuvant therapy has been increasingly adopted for multimodal rectal cancer treatment. The optimal sequence of chemoradiotherapy (CRT) and chemotherapy needs to... (Randomized Controlled Trial)
Randomized Controlled Trial
Chemoradiotherapy Plus Induction or Consolidation Chemotherapy as Total Neoadjuvant Therapy for Patients With Locally Advanced Rectal Cancer: Long-term Results of the CAO/ARO/AIO-12 Randomized Clinical Trial.
IMPORTANCE
Total neoadjuvant therapy has been increasingly adopted for multimodal rectal cancer treatment. The optimal sequence of chemoradiotherapy (CRT) and chemotherapy needs to be established.
OBJECTIVE
To report the long-term results of the secondary end points prespecified in the Randomized Phase 2 Trial of Chemoradiotherapy Plus Induction or Consolidation Chemotherapy as Total Neoadjuvant Therapy (CAO/ARO/AIO-12 trial) for Locally Advanced Rectal Cancer.
DESIGN, SETTING, AND PARTICIPANTS
This secondary analysis of a randomized clinical trial included 311 patients who were recruited from the accrued CAO/ARO/AIO-12 trial population from June 15, 2015, to January 31, 2018, from 18 centers in Germany. Patients with cT3-4 and/or node-positive rectal adenocarcinoma were included in the analysis. Data were analyzed from June 15, 2015, to January 31, 2018. The follow-up analysis was conducted between January 31, 2018, and November 30, 2020.
INTERVENTIONS
Patients were randomly assigned to group A for 3 cycles of fluorouracil, leucovorin, and oxaliplatin before fluorouracil/oxaliplatin CRT (50.4 Gy), or to group B for CRT before chemotherapy. Total mesorectal excision was scheduled on day 123 after the start of total neoadjuvant therapy in both groups.
MAIN OUTCOMES AND MEASURES
The end points assessed in this secondary analysis included long-term oncologic outcomes, chronic toxicity, patient-reported outcome measures for global health status (GHS) and quality of life (QoL), and the Wexner stool incontinence score.
RESULTS
Of the 311 patients enrolled, 306 were evaluable, including 156 in group A (mean [SD] age, 60 [11] years; 106 men [68%]) and 150 in group B (mean [SD] age, 62 [10] years; 100 men [67%]). After a median follow-up of 43 months (range, 35-60 months), the 3-year disease-free survival was 73% in both groups (hazard ratio, 0.95; 95% CI, 0.63-1.45, P = .82); the 3-year cumulative incidence of locoregional recurrence (6% vs 5%, P = .67) and distant metastases (18% vs 16%, P = .52) were not significantly different. Chronic toxicity grade 3 to 4 occurred in 10 of 85 patients (11.8%) in group A and 8 of 66 patients (9.9%) in group B at 3 years. The GHS/QoL score decreased after total mesorectal excision but returned to pretreatment levels 1 year after randomization with no difference between the groups. Stool incontinence deteriorated 1 year after randomization in both groups and only improved slightly at 3 years, but never reached baseline levels.
CONCLUSIONS AND RELEVANCE
This secondary analysis of a randomized clinical trial showed that CRT followed by chemotherapy resulted in higher pathological complete response without compromising disease-free survival, toxicity, QoL, or stool incontinence and is thus proposed as the preferred total neoadjuvant therapy sequence if organ preservation is a priority.
TRIAL REGISTRATION
ClinicalTrials.gov identifier: NCT02363374.
Topics: Chemoradiotherapy; Consolidation Chemotherapy; Female; Humans; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Neoplasm Staging; Quality of Life; Rectal Neoplasms
PubMed: 34792531
DOI: 10.1001/jamaoncol.2021.5445 -
Annals of Oncology : Official Journal... Sep 2022The standard of care for patients with stage III non-small-cell lung cancer (NSCLC) is concurrent chemoradiotherapy (CCRT) followed by 1 year of adjuvant durvalumab.... (Review)
Review
The standard of care for patients with stage III non-small-cell lung cancer (NSCLC) is concurrent chemoradiotherapy (CCRT) followed by 1 year of adjuvant durvalumab. Despite the survival benefit granted by immunotherapy in this setting, only 1/3 of patients are alive and disease free at 5 years. Novel treatment strategies are under development to improve patient outcomes in this setting: different anti-programmed cell death protein 1/programmed death-ligand 1 [anti-PD-(L)1] antibodies after CCRT, consolidation immunotherapy after sequential chemoradiotherapy, induction immunotherapy before CCRT and immunotherapy concurrent with CCRT and/or sequential chemoradiotherapy. Cross-trial comparison is particularly challenging in this setting due to the different timing of immunotherapy delivery and different patients' inclusion and exclusion criteria. In this review, we present the results of clinical trials investigating immune therapy in unresectable stage III NSCLC and discuss in-depth their biological rationale, their pitfalls and potential benefits. Particular emphasis is placed on the potential mechanisms of synergism between chemotherapy, radiation therapy and different monoclonal antibodies, and how this affects the tumor immune microenvironment. The designs and questions tackled by ongoing clinical trials are also discussed. Last, we address open questions and unmet clinical needs, such as the necessity for predictive biomarkers (e.g. radiomics and circulating tumor DNA). Identifying distinct subsets of patients to tailor anticancer treatment is a priority, especially in a heterogeneous disease such as stage III NSCLC.
Topics: Carcinoma, Non-Small-Cell Lung; Chemoradiotherapy; Humans; Immunologic Factors; Immunotherapy; Lung Neoplasms; Neoplasm Staging; Tumor Microenvironment
PubMed: 35777706
DOI: 10.1016/j.annonc.2022.06.013 -
Radiology Apr 2023The diagnosis and treatment of rectal cancer have evolved dramatically over the past several decades. At the same time, its incidence has increased in younger... (Review)
Review
The diagnosis and treatment of rectal cancer have evolved dramatically over the past several decades. At the same time, its incidence has increased in younger populations. This review will inform the reader of advances in both diagnosis and treatment. These advances have led to the watch-and-wait approach, otherwise known as nonsurgical management. This review briefly outlines changes in medical and surgical treatment, advances in MRI technology and interpretation, and landmark studies or trials that have led to this exciting juncture. Herein, the authors delve into current state-of-the-art methods to assess response to treatment with MRI and endoscopy. Currently, these methods for avoiding surgery can be used to detect a complete clinical response in as many as 50% of patients with rectal cancer. Finally, the limitations of imaging and endoscopy and future challenges will be discussed.
Topics: Humans; Neoadjuvant Therapy; Rectal Neoplasms; Chemoradiotherapy, Adjuvant; Magnetic Resonance Imaging; Watchful Waiting; Neoplasm Recurrence, Local; Chemoradiotherapy; Treatment Outcome
PubMed: 36880951
DOI: 10.1148/radiol.221529 -
Expert Review of Anticancer Therapy Jun 2021: Locally advanced cervical cancer (LACC) (International Federation of Gynecology and Obstetrics (FIGO) 2009/2018 - stages IB2-IVA/IB3-IVA, respectively) is treated... (Review)
Review
: Locally advanced cervical cancer (LACC) (International Federation of Gynecology and Obstetrics (FIGO) 2009/2018 - stages IB2-IVA/IB3-IVA, respectively) is treated using a multimodal approach that includes chemoradiotherapy followed by brachytherapy.: This review provides an overview of the progress made over the past decade in the treatment of LACC. Prognostic factors, FIGO classification and the role of imaging staging will be discussed. Efficacy of external-beam radiotherapy, brachytherapy and chemotherapy will be detailed. Indications for para-aortic staging lymphadenectomy and adjuvant hysterectomy, as well as follow-up and special population, will be covered.: The initial workup is one of the most crucial steps in the optimal care of patients, which should be realized by a multidisciplinary expert team. With the implementation of modern conformal radiotherapy techniques, the local control rate has been optimized. Nevertheless, 40% of patients experience recurrence with distant metastasis and a dismal prognosis. Currently, a clear benefit of neo- and adjuvant chemotherapy has not been established. The future likely involves (1) improved selection of patients for whom treatment intensification is justified, (2) a combination of new drugs with chemoradiation that are currently being tested in trials, and (3) the development of tailored treatment based on molecular characteristics.
Topics: Brachytherapy; Chemoradiotherapy; Female; Humans; Lymph Node Excision; Neoplasm Staging; Retrospective Studies; Treatment Outcome; Uterine Cervical Neoplasms
PubMed: 33472018
DOI: 10.1080/14737140.2021.1879646 -
Clinical and Translational Medicine Jan 2022Chemoradiotherapy-induced PD-L1 upregulation leads to therapeutic resistance and treatment failure. The PD-1/PD-L1 blocking antibodies sensitize cancers to...
BACKGROUND
Chemoradiotherapy-induced PD-L1 upregulation leads to therapeutic resistance and treatment failure. The PD-1/PD-L1 blocking antibodies sensitize cancers to chemoradiotherapy by blocking extracellular PD-1 and PD-L1 binding without affecting the oncogenic function of intracellular PD-L1. Reversing the chemoradiation-induced PD-L1 expression could provide a new strategy to achieve a greater anti-tumour effect of chemoradiotherapy. Here, we aimed to identify candidate small molecular inhibitors that might boost the anti-tumour immunity of chemoradiotherapy by decreasing treatment-induced PD-L1 expression in non-small cell lung cancer (NSCLC).
METHODS
A drug array was used to recognize compounds that can suppress the cisplatin-induced and radiation-induced PD-L1 expression in NSCLC via the flow cytometry-based assay. We examined whether and how targeting bromodomain containing 4 (BRD4) inhibits chemoradiation-induced PD-L1 expression and evaluated the effect of BRD4 inhibition and chemoradiation combination in vivo.
RESULTS
BRD4 inhibitors JQ1 and ARV-771 were identified as the most promising drugs both in the cisplatin and radiation screening projects in two NSCLC cell lines. Targeting BRD4 was supposed to block chemoradiotherapy inducible PD-L1 expression by disrupting the recruitment of BRD4-IRF1 complex to PD-L1 promoter. A positive correlation between BRD4 and PD-L1 expression was observed in human NSCLC tissues. Moreover, BRD4 inhibition synergized with chemoradiotherapy and PD-1 blockade to show a robust anti-tumour immunity dependent on CD8+ T cell through limiting chemoradiation-induced tumour cell surface PD-L1 upregulation in vivo. Notably, the BRD4-targeted combinatory treatments did not show increased toxicities.
CONCLUSION
The data showed that BRD4-targeted therapy synergized with chemoradiotherapy and anti-PD-1 antibody by boosting anti-tumour immunity in NSCLC.
Topics: Animals; Carcinoma, Non-Small-Cell Lung; Cell Cycle Proteins; Chemoradiotherapy; Disease Models, Animal; Gene Expression; Interferon Regulatory Factor-1; Mice; Signal Transduction; Transcription Factors
PubMed: 35083874
DOI: 10.1002/ctm2.718 -
Nature Reviews. Clinical Oncology Dec 2021Multimodal treatment strategies for patients with rectal cancer are increasingly including the possibility of organ preservation, through nonoperative management or... (Review)
Review
Multimodal treatment strategies for patients with rectal cancer are increasingly including the possibility of organ preservation, through nonoperative management or local excision. Organ preservation strategies can enable patients with a complete response or near-complete clinical responses after radiotherapy with or without concomitant chemotherapy to safely avoid the morbidities associated with radical surgery, and thus to maintain anorectal function and quality of life. However, standardization of the key outcome measures of organ preservation strategies is currently lacking; this includes a lack of consensus of the optimal definitions and selection of primary end points according to the trial phase and design; the optimal time points for response assessment; response-based decision-making; follow-up schedules; use of specific anorectal function tests; and quality of life and patient-reported outcomes. Thus, a consensus statement on outcome measures is necessary to ensure consistency and facilitate more accurate comparisons of data from ongoing and future trials. Here, we have convened an international group of experts with extensive experience in the management of patients with rectal cancer, including organ preservation approaches, and used a Delphi process to establish the first international consensus recommendations for key outcome measures of organ preservation, in an attempt to standardize the reporting of data from both trials and routine practice in this emerging area.
Topics: Chemoradiotherapy; Consensus; Delphi Technique; Humans; Organ Preservation; Rectal Neoplasms
PubMed: 34349247
DOI: 10.1038/s41571-021-00538-5 -
Radiotherapy and Oncology : Journal of... Jun 2022The RAPIDO trial demonstrated a decrease in disease-related treatment failure (DrTF) and an increase in pathological complete responses (pCR) in locally advanced rectal... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND AND PURPOSE
The RAPIDO trial demonstrated a decrease in disease-related treatment failure (DrTF) and an increase in pathological complete responses (pCR) in locally advanced rectal cancer (LARC) patients receiving total neoadjuvant treatment (TNT) compared to conventional chemoradiotherapy. This study examines health-related quality of life (HRQL), bowel function, and late toxicity in patients in the trial.
MATERIALS AND METHODS
Patients were randomized between short-course radiotherapy followed by pre-operative chemotherapy (EXP), or chemoradiotherapy and optional post-operative chemotherapy (STD). The STD group was divided into patients who did (STD+) and did not (STD-) receive post-operative chemotherapy. Three years after surgery patients received HRQL (EORTC QLQ-C30, QLQ-CR29 and QLQ-CIPN20) and LARS questionnaires. Patients who experienced a DrTF event before the toxicity assessments (6, 12, 24, or 36 months) were excluded from analyses.
RESULTS
Of 574 eligible patients, 495 questionnaires were returned (86%) and 453 analyzed (79% completed within time limits). No significant differences were observed between the groups regarding QLQ-C30, QLQ-CR29 or LARS scores. Sensory-related symptoms occurred significantly more often in the EXP group compared to all STD patients, but not compared to STD+ patients. Any toxicity of any grade and grade ≥ 3 toxicity was comparable between the EXP and STD groups at all time-points. Neurotoxicity grade 1-2 occurred significantly more often in the EXP and STD+ group at all time-points compared to the STD- group.
CONCLUSION
The results demonstrate that TNT for LARC, yielding improved DrTF and pCRs, does not compromise HRQL, bowel functional or results in more grade ≥3 toxicity compared to standard chemoradiotherapy at three years after surgery in DrTF-free patients.
Topics: Humans; Antineoplastic Combined Chemotherapy Protocols; Chemoradiotherapy; Neoadjuvant Therapy; Neoplasm Staging; Neoplasms, Second Primary; Quality of Life; Rectal Neoplasms
PubMed: 35447283
DOI: 10.1016/j.radonc.2022.04.013 -
Nature Communications Dec 2022Neoadjuvant chemoradiotherapy (nCRT) has become the standard treatment for patients with locally advanced rectal cancer (LARC). Therapeutic efficacy of nCRT is... (Clinical Trial)
Clinical Trial
Neoadjuvant chemoradiotherapy (nCRT) has become the standard treatment for patients with locally advanced rectal cancer (LARC). Therapeutic efficacy of nCRT is significantly affected by treatment-induced diarrhea and hematologic toxicities. Metabolic alternations in cancer therapy are key determinants to therapeutic toxicities and responses, but exploration in large-scale clinical studies remains limited. Here, we analyze 743 serum samples from 165 LARC patients recruited in a phase III clinical study using untargeted metabolomics and identify responsive metabolic traits over the course of nCRT. Pre-therapeutic serum metabolites successfully predict the chances of diarrhea and hematologic toxicities during nCRT. Particularly, levels of acyl carnitines are linked to sex disparity in nCRT-induced diarrhea. Finally, we show that differences in phenylalanine metabolism and essential amino acid metabolism may underlie distinct therapeutic responses of nCRT. This study illustrates the metabolic dynamics over the course of nCRT and provides potential to guide personalized nCRT treatment using responsive metabolic traits.
Topics: Humans; Chemoradiotherapy; Diarrhea; Neoadjuvant Therapy; Rectal Neoplasms; Rectum
PubMed: 36528604
DOI: 10.1038/s41467-022-35511-y -
Dysphagia Aug 2022The diagnosis and treatment of head and neck cancer (HNC) can have substantial impact on swallowing function, nutritional balance, physical function and quality of life... (Randomized Controlled Trial)
Randomized Controlled Trial
The diagnosis and treatment of head and neck cancer (HNC) can have substantial impact on swallowing function, nutritional balance, physical function and quality of life (QoL). Early initiated swallowing exercises are hypothesized to improve swallowing function in HNC patients. The aim was to investigate the effects of swallowing exercises and progressive resistance training (PRT) during radiotherapy on swallowing function, physical function and QoL in patients with pharynx-, larynx-, oral cavity cancer or unknown primary compared to usual care. In a multi-centre RCT participants were assigned to (a) twice-weekly PRT and daily swallowing exercises throughout treatment or (b) usual care. Outcomes were measured at end of treatment and 2, 6 and 12 months after. Primary outcome was penetration aspiration score (PAS). Data were analysed on an "intention-to-treat" basis by GEE logistic regression model, linear mixed effects model and cox regression. Of 371 invited HNC patients, 240 (65%) enrolled. Five participants were excluded. At 12 months follow-up, 59 (25%) participants were lost. Analyses showed significant effect on mouth opening, QoL, depression and anxiety at 12 months when comparing intervention to non-active controls. The trial found no effect on swallowing safety in HNC undergoing radiotherapy, but several positive effects were found on secondary outcomes when comparing to non-active controls. The intervention period may have been too short, and the real difference between groups is too small. Nevertheless, the need to identify long-lasting intervention to slow down or avoid functional deteriorations is ever more crucial as the surviving HNC population is growing.
Topics: Chemoradiotherapy; Deglutition; Deglutition Disorders; Head and Neck Neoplasms; Humans; Quality of Life; Treatment Outcome
PubMed: 34117531
DOI: 10.1007/s00455-021-10320-5