Systemic adverse effects and toxicities associated with immunotherapy: A review

Immunotherapy is rapidly evolving secondary to the advent of newer immunotherapeutic agents and increasing approval of the current agents by the United States Food and Drug Administration to treat a wide spectrum of cancers. Immunotherapeutic agents have gained immense popularity due to their tumor-specific action. Immunotherapy is slowly transforming into a separate therapeutic entity, and the fifth pillar of management for cancers alongside surgery, radiotherapy, chemotherapy, and targeted therapy. However, like any therapeutic entity it has its own adverse effects. With the increasing use of immuno-therapeutic agents, it is vital for physicians to acquaint themselves with these adverse effects. The aim of this review is to investigate the common systemic adverse effects and toxicities associated with the use of different classes of immunotherapeutic agents. We provide an overview of potential adverse effects and toxicities associated with different classes of immunotherapeutic agents organized by organ systems, as well as an extensive discussion of the current recommendations for treatment and clinical trial data. As we continue to see increasing usage of these agents in clinical practice, it is vital for physicians to familiarize themselves with these effects.     

Cardiovascular risk management in cancer survivors: Are we doing it right?

Although under-recognized, cancer survivors continue to be at an increased risk of death from cardiovascular complications post-remission or cure. This increased burden of cardiovascular disease results from the interplay of various factors. Adequate cardiovascular risk assessment and timely intervention through a multi-disciplinary approach in these patients plays a pivotal role in the prevention of cardiovascular morbidity and mortality. We discuss the shortcomings of using current risk prediction scores in cancer survivors and provide some insights into cardiovascular risk management relevant for primary care physicians, oncologists, and cardiologists alike.     

Anti-ovarian cancer potential of phytocompound and extract from South African medicinal plants and their role in the development of chemotherapeutic agents

Ovarian cancer (OC) accounts for the highest tumor-related mortality among the gynecologic malignancies. Most of the OC patients diagnosed with advanced-stage (III and IV) this situation creates panic and provokes an emergency to discover a new therapeutic strategy. Plants that possess medicinal properties are gaining attention as they are enriched with various chemical compounds that are potential to treat various diseases. It is a prolonged process to provide innovative and significant leads against a range of pharmacological targets for a human disease management system. Though challenges and difficulties are faced in the development of a new drug, the emergence of combinatorial chemistry is providing a new ray of hope and also, the executed effort in discovering the drug, and a chemical compound has been remarkably successful. This review discussed the role of medicinal plants that are native of South Africa in treating the Ovarian Cancer and in drug discovery.     

A comparison between raltitrexed plus cisplatin and docetaxel plus cisplatin in concurrent chemoradiation for non-surgical esophageal squamous cell carcinoma

PurposeChemoradiotherapy (CRT) is considered as a standard treatment for unresectable and inoperable esophageal cancer (EC) patients. However, no consensus has been reached regarding the optimal synchronous chemotherapy regimen and the best combination of radiotherapy and chemotherapy. The aim of this study was to evaluate the efficacy and toxicity of raltitrexed plus cisplatin and docetaxel plus cisplatin to find a safe and effective concurrent chemotherapy schedule.Patients and methodsOur retrospective study included 151 EC patients treated with raltitrexed and cisplatin (RP) (n = 90) or docetaxel and cisplatin (DP) (n = 61) from 2011 till 2018. Survival outcomes and treatment related toxicity were analyzed between the two groups.ResultsPFS and OS were 18 and 34 months in the RP group, while 13 and 20 months in the DP group (P = 0.118 and P = 0.270). The 1-, 2-, 3-year survival rates of the RP group were 71.1, 55.4 and 46.4%. For the DP group, these were 63.9, 44.3 and 37.6%, respectively. Compared with DP group, RP group received a superior CR rate (68.9% versus 52.5%, P = 0.041). There was a trend that the total number of toxic reactions in RP group was lower than that in DP group (P = 0.058).ConclusionsEven RP and DP groups have the similar survival outcomes and toxicity, raltitrexed/cisplatin get a higher complete response rate. Our study suggests that raltitrexed combined with cisplatin is a safe and effective concurrent chemotherapy regimen and it might be used as an alternative for cisplatin/5-FU and cisplatin/docetaxel in CCRT for EC patients.     

Timing of Palliative Care Referral Before and After Evidence from Trials Supporting Early Palliative Care

BackgroundEvidence from randomized controlled trials has demonstrated benefits in quality of life outcomes from early palliative care concurrent with standard oncology care in patients with advanced cancer. We hypothesized that there would be earlier referral to outpatient palliative care at a comprehensive cancer center following this evidence.Materials and MethodsAdministrative databases were reviewed for two cohorts of patients: the pre‐evidence cohort was seen in outpatient palliative care between June and November 2006, and the post‐evidence cohort was seen between June and November 2015. Timing of referral was categorized, according to time from referral to death, as early (>12 months), intermediate (>6 months to 12 months), and late (≤6 months from referral to death). Univariable and multivariable ordinal logistic regression analyses were used to determine demographic and medical factors associated with timing of referral.ResultsLate referrals decreased from 68.8% pre‐evidence to 44.8% post‐evidence; early referrals increased from 13.4% to 31.1% (p < .0001). The median time from palliative care referral to death increased from 3.5 to 7.0 months (p < .0001); time from diagnosis to referral was also reduced (p < .05). On multivariable regression analysis, earlier referral to palliative care was associated with post‐evidence group (p < .0001), adjusting for shorter time since diagnosis (p < .0001), referral for pain and symptom management (p = .002), and patient sex (p = .04). Late referrals were reduced to <50% in the breast, gynecological, genitourinary, lung, and gastrointestinal tumor sites.ConclusionsFollowing robust evidence from trials supporting early palliative care for patients with advanced cancer, patients were referred substantially earlier to outpatient palliative care.Implications for PracticeFollowing published evidence demonstrating the benefit of early referral to palliative care for patients with advanced cancer, there was a substantial increase in early referrals to outpatient palliative care at a comprehensive cancer center. The increase in early referrals occurred mainly in tumor sites that have been included in trials of early palliative care. These results indicate that oncologists’ referral practices can change if positive consequences of earlier referral are demonstrated. Future research should focus on demonstrating benefits of early palliative care for tumor sites that have tended to be omitted from early palliative care trials.     

Opium Usage and Risk of Head and Neck Cancer: A Systematic Review and Meta-Analysis

Introduction: Opium is among the most used substance of abuse worldwide. More than 50 million opium users are there worldwide, majority of whom are in Asia. Opium usage have been reported to be associated with cancer. This study aimed to find the association between opium use or abuse and head and neck cancer. Methods: A systematic search was conducted in Medline, Scopus, Cochrane, and Google Scholar database for studies published from inception till 1st November 2019. Two authors independently reviewed the studies, did quality assessment, and extracted data in standardized data extraction form. Pooled estimate of OR for risk of head and neck cancer was calculated using random effects model using the method of DerSimonian and Laird, with the estimate of heterogeneity being taken from the inverse-variance model. Subgroup and sensitivity analysis were performed. The protocol was registered in PROSPERO (CRD42020156049). Results: Fourteen studies were included in data synthesis (11 case control studies and 3 cohort studies). Eleven case control studies were included in synthesizing the results for meta-analysis. Pooled odds ratio for risk of cancer among opium users for the 11-case control study was 3.85 (2.18-6.79). Heterogeneity was high (I-squared=92.0%, Tau-squared=0.88). There was no publication bias in the study. Subgroup analysis showed highest OR for pooled estimate for risk of laryngeal cancer (19.98 (11.04-36.15)). Conclusion: There was almost four-fold rise in risk of head and neck cancer among opium users compared to non-users.     

High dose acetaminophen inhibits STAT3 and has free radical independent anti-cancer stem cell activity

High-dose acetaminophen (AAP) with delayed rescue using n-acetylcysteine (NAC), the FDA-approved antidote to AAP overdose, has demonstrated promising antitumor efficacy in early phase clinical trials. However, the mechanism of action (MOA) of AAP''s anticancer effects remains elusive. Using clinically relevant AAP concentrations, we evaluated cancer stem cell (CSC) phenotype in vitro and in vivo in lung cancer and melanoma cells with diverse driver mutations. Associated mechanisms were also studied. Our results demonstrated that AAP inhibited 3D spheroid formation, self-renewal, and expression of CSC markers when human cancer cells were grown in serum-free CSC media. Similarly, anti-CSC activity was demonstrated in vivo in xenograft models - tumor formation following in vitro treatment and ex-vivo spheroid formation following in vivo treatment. Intriguingly, NAC, used to mitigate AAP''s liver toxicity, did not rescue cells from AAP''s anti-CSC effects, and AAP failed to reduce glutathione levels in tumor xenograft in contrast to mice liver tissue suggesting nonglutathione-related MOA. In fact, AAP mediates its anti-CSC effect via inhibition of STAT3. AAP directly binds to STAT3 with an affinity in the low micromolar range and a high degree of specificity for STAT3 relative to STAT1. These findings have high immediate translational significance concerning advancing AAP with NAC rescue to selectively rescue hepatotoxicity while inhibiting CSCs. The novel mechanism of selective STAT3 inhibition has implications for developing rational anticancer combinations and better patient selection (predictive biomarkers) for clinical studies and developing novel selective STAT3 inhibitors using AAP''s molecular scaffold.     

Strength and duration of GIPC-dependent signaling networks as determinants in cancer

GIPC is a PDZ-domain containing adaptor protein that regulates the cell surface expression and endocytic trafficking of numerous transmembrane receptors and signaling complexes. Interactions with over 50 proteins have been reported to date including VEGFR, insulin-like growth factor-1 receptor (IGF-1R), GPCRs, and APPL, many of which have essential roles in neuronal and cardiovascular development. In cancer, a major subset of GIPC-binding receptors and cytoplasmic effectors have been shown to promote tumorigenesis or metastatic progression, while other subsets have demonstrated strong tumor-suppressive effects. Given that these diverse pathways are widespread in normal tissues and human malignancies, precisely how these opposing signals are integrated and regulated within the same tumor setting likely depend on the strength and duration of their interactions with GIPC. This review highlights the major pathways and divergent mechanisms of GIPC signaling in various cancers and provide a rationale for emerging GIPC-targeted cancer therapies.     

Suitability of CD133 as a Marker for Cancer Stem Cells in Melanoma

Objectives: CD133 is considered a cancer stem cell (CSC) marker in various malignancies; however, its role as a biomarker of malignant melanoma remains controversial. The present study was conducted to evaluate the suitability of CD133 surface antigen as a CSC marker in melanoma. Methods: Human melanoma cells were fractionally separated by magnetic cell separation depending on the CD133 phenotype and transplanted into immunodeficient mice to evaluate their tumorigenic capacity. Furthermore, the time until the development of a palpable tumor and the growth rate were measured, and the final tumor volume was assessed after 8 weeks. The immunohistochemical expression of CD133 in the induced neoplasia was then compared using histomorphometry. Results: Notably, neoplasms were induced in all the groups (n = 48), including in the CD133-negative group. Tumors induced by unsorted cells had the largest volume (p = 0.014) but were detected significantly later in this group (p ≤ 0.001). Interestingly, all explanted tumors expressed CD133, with no significant differences among groups. Conclusions: In contrast to the results obtained in prior studies, the suitability of CD133 as a CSC marker could not be demonstrated. The current encouraging progress in targeted therapy for malignant melanoma highlights the need to identify more effective targets.