Immunotherapy and radiotherapy for older patients with locally advanced rectal cancer unfit for surgery or decline surgery: a practical proposal by the International Geriatric Radiotherapy Group.

The standard of care for locally advanced rectal cancer is total neoadjuvant therapy followed by surgical resection. Current evidence suggests that selected patients may be able to delay or avoid surgery without affecting survival rates if they achieve a complete clinical response (CCR). However, for older cancer patients who are too frail for surgery or decline the surgical procedure, local recurrence may lead to a deterioration of patient quality of life. Thus, for clinicians, a treatment algorithm which is well tolerated and may improve CCR in older and frail patients with rectal cancer may improve the potential for prolonged remission and potential cure. Recently, immunotherapy with check point inhibitors (CPI) is a promising treatment in selected patients with high expression of program death ligands receptor 1 (PD- L1). Radiotherapy may enhance PD-L1 expression in rectal cancer and may improve response rate to immunotherapy. We propose an algorithm combining immunotherapy and radiotherapy for older patients with locally advanced rectal cancer who are too frail for surgery or who decline surgery.

The Use of Isoflavones as Lung Cancer Chemoprevention Agents and their Implications in Treatment through Radio Sensitization.

Epidemiological trends in cancer research show that lung cancer can affect up to 1 in 15 men and 1 in 17 women. With incidence rates as high as these and significant associated mortality and morbidity, it is no wonder that lung cancer is one of the main areas of research focused on cancer. Advances in targeted treatments and specialized irradiation protocols have allowed the treatment of more advanced cases. However, as the patient numbers grow, so does the need for cancer-preventive strategies. The present narrative review focuses on soy isoflavones' role in the chemoprevention of lung cancer and their possible role in therapeutic adjuncts. Laboratory studies on lung cancer cell lines have shown that isoflavones can induce apoptosis, tamper with the expression of proliferative molecular pathways, and even reduce tumor angiogenesis. Additionally, population-level studies have emerged that correlate the consumption of isoflavonoids with reduced risk for the development of lung cancer. Interestingly enough, the literature also contains small-scale studies with evidence of isoflavones being effective chemotherapeutic adjuncts that are currently understudied. Our literature review underlines such findings and provides a call for the enhancement of research regarding naturally occurring dietary products with possible anticarcinogenic effects.

Metabolic Profiles of Cancer Stem Cells and Normal Stem Cells and Their Therapeutic Significance.

Cancer stem cells (CSCs) are a rare cancer cell population, responsible for the facilitation, progression, and resistance of tumors to therapeutic interventions. This subset of cancer cells with stemness and tumorigenic properties is organized in niches within the tumor microenvironment (TME) and presents altered regulation in a variety of metabolic pathways, including glycolysis, oxidative phosphorylation (OXPHOS), as well as lipid, amino acid, and iron metabolism. CSCs exhibit similarities as well as differences when comparedto normal stem cells, but also possess the ability of metabolic plasticity. In this review, we summarize the metabolic characteristics of normal, non-cancerous stem cells and CSCs. We also highlight the significance and implications of interventions targeting CSC metabolism to potentially achieve more robust clinical responses in the future.

Immunotherapy and Hypofractionated Radiotherapy in Older Patients with Locally Advanced Cutaneous Squamous-Cell Carcinoma of the Head and Neck: A Proposed Paradigm by the International Geriatric Radiotherapy Group.

Cutaneous skin carcinoma is a disease of older patients. The prevalence of cutaneous squamous-cell carcinoma (cSCC) increases with age. The head and neck region is a frequent place of occurrence due to exposure to ultraviolet light. Surgical resection with adjuvant radiotherapy is frequently advocated for locally advanced disease to decrease the risk of loco-regional recurrence. However, older cancer patients may not be candidates for surgery due to frailty and/or increased risk of complications. Radiotherapy is usually advocated for unresectable patients. Compared to basal-cell carcinoma, locally advanced cSCC tends to recur locally and/or can metastasize, especially in patients with high-risk features such as poorly differentiated histology and perineural invasion. Thus, a new algorithm needs to be developed for older patients with locally advanced head and neck cutaneous squamous-cell carcinoma to improve their survival and conserve their quality of life. Recently, immunotherapy with checkpoint inhibitors (CPIs) has attracted much attention due to the high prevalence of program death ligand 1 (PD-L1) in cSCC. A high response rate was observed following CPI administration with acceptable toxicity. Those with residual disease may be treated with hypofractionated radiotherapy to minimize the risk of recurrence, as radiotherapy may enhance the effect of immunotherapy. We propose a protocol combining CPIs and hypofractionated radiotherapy for older patients with locally advanced cutaneous head and neck cancer who are not candidates for surgery. Prospective studies should be performed to verify this hypothesis.

Dose Optimization in Oncology Drug Development: The Emerging Role of Pharmacogenomics, Pharmacokinetics, and Pharmacodynamics.

Drugs' safety and effectiveness are evaluated in randomized, dose-ranging trials in most therapeutic areas. However, this is only sometimes feasible in oncology, and dose-ranging studies are mainly limited to Phase 1 clinical trials. Moreover, although new treatment modalities (e.g., small molecule targeted therapies, biologics, and antibody-drug conjugates) present different characteristics compared to cytotoxic agents (e.g., target saturation limits, wider therapeutic index, fewer off-target side effects), in most cases, the design of Phase 1 studies and the dose selection is still based on the Maximum Tolerated Dose (MTD) approach used for the development of cytotoxic agents. Therefore, the dose was not optimized in some cases and was modified post-marketing (e.g., ceritinib, dasatinib, niraparib, ponatinib, cabazitaxel, and gemtuzumab-ozogamicin). The FDA recognized the drawbacks of this approach and, in 2021, launched Project Optimus, which provides the framework and guidance for dose optimization during the clinical development stages of anticancer agents. Since dose optimization is crucial in clinical development, especially of targeted therapies, it is necessary to identify the role of pharmacological tools such as pharmacogenomics, therapeutic drug monitoring, and pharmacodynamics, which could be integrated into all phases of drug development and support dose optimization, as well as the chances of positive clinical outcomes.

Is immunotherapy at reduced dose and radiotherapy for older patients with locally advanced non-small lung cancer feasible?-a narrative review by the international geriatric radiotherapy group.

Background and Objective: The standard of care for locally advanced non-small cell lung cancer (NSCLC) is either surgery followed by adjuvant chemotherapy with or without radiotherapy or concurrent chemotherapy and radiotherapy. However, older patients (70 years old or above) with multiple co-morbidities may not be able to tolerate the combined treatment due to its toxicity. Since lung cancer prevalence increases significantly with age, a new algorithm needs to be investigated to allow curative treatment for those with locally advanced disease. Methods: A literature search of the literature was conducted through PubMed and Google Scholar using search terms such as locally advanced NSCLC, older cancer patients, immunotherapy with check point inhibitors (CPI), and image-guided radiotherapy (IGRT). Abstracts were screened, full articles fitting the article topic were reviewed, and duplicated and non-English articles were excluded. Key Content and Findings: Recently, CPI has been introduced and proven effective for selected patients with increased program death ligand 1 (PD-L1) expression (50% or above). A reduced dose for CPI (RDCPI) may be as effective as a full dose and may decrease treatment cost. New radiation technique such as IGRT may also minimize radiotherapy complication through normal lung and cardiac sparing. Conclusions: IGRT and RDCPI may be an innovative option for older patients with locally advanced NSCLC and high PD-L1 expression and needs to be investigated in future prospective studies.

The Association Between the Risk of Breast Cancer and Epigallocatechin- 3-Gallate Intake: A Literature Review of a Potential Chemopreventive Agent.

According to the latest epidemiological data, breast cancer has recently been the most frequently diagnosed malignancy. To date, a body of evidence has established the involvement of multiple - and frequently interrelated - genetic and environmental factors in the pathogenesis of the disease. Emerging research on cancer prevention has highlighted the deterrence potential of interventions targeting environmental risk factors, particularly diet. In this aspect, the current review reveals the latest scientific results regarding epigallocatechin-3-gallate (EGCG) - a catechin most commonly found in green tea, as a potential chemopreventive dietary agent against breast cancer. in vitro studies on EGCG have demonstrated its effect on cell cycle progression and its potential to suppress several intracellular signaling pathways involved in breast cancer pathogenesis. In addition, EGCG possesses specific apoptosis-inducing characteristics that seem to enhance its role as a regulator of cell survival. Preclinical data seem to support using EGCG as an effective adjunct to EGFR-targeting treatments. The authors' appraisal of the literature suggests that although preclinical evidence has documented the anticarcinogenic features of EGCG, limited large-scale epidemiological studies are investigating the consumption of EGCG - containing nutrients in the prevention and management of breast cancer risk. This literature review aims to liaise between preclinical and epidemiological research, surveying the existing evidence and unraveling relevant knowledge gaps.

Stereotactic Body Radiotherapy and Immunotherapy for Older Patients with Oligometastases: A Proposed Paradigm by the International Geriatric Radiotherapy Group.

The standard of care for metastatic disease is systemic therapy. A unique subset of patients with limited metastatic disease defined as distant involvement of five anatomic sites or less (oligometastases) have a better chance of remission or improved survival and may benefit from local treatments such as surgery or stereotactic body radiotherapy (SBRT). However, to prevent further spread of disease, systemic treatment such as chemotherapy, targeted therapy, and hormonal therapy may be required. Older patients (70 years old or above) or physiologically frail younger patients with multiple co-morbidities may not be able to tolerate the conventional chemotherapy due to its toxicity. In addition, those with a good performance status may not receive optimal chemotherapy due to concern about toxicity. Recently, immunotherapy with checkpoint inhibitors (CPI) has become a promising approach only in the management of program death ligand 1 (PD-L1)-positive tumors. Thus, a treatment method that elicits induction of PD-L1 production by tumor cells may allow all patients with oligometastases to benefit from immunotherapy. In vitro studies have demonstrated that high dose of radiotherapy may induce formation of PD-L1 in various tumors as a defense mechanism against inflammatory T cells. Clinical studies also corroborated those observations. Thus, SBRT, with its high precision to minimize damage to normal organs, may be a potential treatment of choice for older patients with oligometastases due to its synergy with immunotherapy. We propose a protocol combining SBRT to achieve a minimum radiobiologic equivalent dose around 59.5 Gy to all tumor sites if feasible, followed four to six weeks later by CPI for those cancer patients with oligometastases. All patients will be screened with frailty screening questionnaires to identify individuals at high risk for toxicity. The patients will be managed with an interdisciplinary team which includes oncologists, geriatricians, nurses, nutritionists, patient navigators, and social workers to manage all aspects of geriatric patient care. The use of telemedicine by the team may facilitate patient monitoring during treatment and follow-up. Preliminary data on toxicity, local control, survival, and progression-free survival may be obtained and serve as a template for future prospective studies.