Fluoropyrimidines such as 5-fluorouracil (5-FU) form the foundation of a wide variety of chemotherapy regimens. 5-FU is in fact the third most commonly used chemotherapeutic agent in the treatment of solid malignancies across the world. As with all chemotherapy, balancing the potential benefits of therapy against the risks of drug-related toxicity is crucial when clinicians and patients make shared decisions about treatment. 5-FU is the second most common chemotherapeutic drug associated with cardiotoxicity after anthracyclines, which can manifest as chest pain, acute coronary syndrome/myocardial infarction or death. Nevertheless a widespread appreciation of 5-FU-related cardiotoxicity and its implications is lacking amongst clinicians. In this review, we outline the incidence, possible risk factors, and likely pathophysiological mechanisms that may account for 5-FU-related cardiotoxicity and also highlight potential management strategies for this poorly understood clinical entity.
Colon cancer continues to be one of the leading causes of mortality and morbidity throughout the world despite the availability of reliable screening tools and effective therapies. The majority of patients with colon cancer are diagnosed at an early stage (stages I to III), which provides an opportunity for cure. The current treatment paradigm of early stage colon cancer consists of surgery followed by adjuvant chemotherapy in a select group of patients, which is directed at the eradication of minimal residual disease to achieve a cure. Surgery alone is curative for the vast majority of colon cancer patients. Currently, surgery and adjuvant chemotherapy can achieve long term survival in about two-thirds of colon cancer patients with nodal involvement. Adjuvant chemotherapy is recommended for all patients with stage III colon cancer, while the benefit in stage II patients is not unequivocally established despite several large clinical trials. Contemporary research in early stage colon cancer is focused on minimally invasive surgical techniques, strategies to limit treatment-related toxicities, precise patient selection for adjuvant therapy, utilization of molecular and clinicopathologic information to personalize therapy and exploration of new therapies exploiting the evolving knowledge of tumor biology. In this review, we will discuss the current standard treatment, evolving treatment paradigms, and the emerging biomarkers, that will likely help improve patient selection and personalization of therapy leading to superior outcomes.
Numerous clinical studies link cytomegalovirus (CMV) infection with incomplete posttransplantation T-cell recovery. We hypothesized that the inability of transplant recipients to handle CMV reactivation might correlate with a defective graft-versus-leukemia response and increased posttransplantation morbidity. Between May 1995 and August 2001, 82 patients who were CMV seropositive and survived the first 100 days after transplantation were identified for a day 100 landmark analysis of the effect of CMV reactivation patterns on eventual transplantation outcome. All patients underwent a myeloablative HLA-identical sibling donor T cell-depleted stem cell transplantation with scheduled donor T-cell add-back on day 45. Median follow-up was 1032 days. Forty-two patients who had either no reactivation or only 1 positive test with quick clearance were designated as a CMV immune competent group. Forty patients designated as CMV immune deficient (ID) had at least 2 positive tests. Apart from younger age (33 versus 38 years; P =.05) in the ID group, the 2 groups were balanced for clinical characteristics. In multivariate analysis, ID patients had a significantly higher incidence of leukemia relapse (58% versus 21%; P =.03) and worse disease-free survival (31% versus 66%; P =.04). There was no significant difference in week 1 to 14 posttransplantation lymphocyte counts between the 2 groups. In 67 patients tested 3 to 6 months after transplantation, a proliferative response to CMV antigen (stimulation index > or =2) occurred in 27 of 36 immune competent patients compared with 15 of 31 ID patients (P =.006). These results show that recurrent CMV reactivation in the first 100 days after transplantation predicts for reduced disease-free survival and increased leukemic relapse beyond 100 days and correlates with inferior proliferative responses to CMV. The higher relapse rate may reflect poor immune reconstitution in ID patients or an adverse effect of prolonged antiviral treatment.
Biliary tract cancers (BTCs) are a heterogeneous group of adenocarcinomas that originate from the epithelial lining of the biliary tree. BTCs are characterized by presentation with advanced disease precluding curative surgery, rising global incidence, and a poor prognosis. Chemotherapy is the mainstay of the current treatment, which results in a median overall survival of less than one year, underscoring the need for novel therapeutic agents and strategies. Next-generation sequencing-based molecular profiling has shed light on the underpinnings of the complex pathophysiology of BTC and has uncovered numerous actionable targets, leading to the discovery of new therapies tailored to the molecular targets. Therapies targeting fibroblast growth factor receptor (FGFR) fusion, isocitrate dehydrogenase (IDH) mutations, the human epidermal growth factor receptor (HER) family, DNA damage repair (DDR) pathways, and BRAF mutations have produced early encouraging results in selected patients. Current clinical trials evaluating targeted therapies, as monotherapies and in combination with other agents, are paving the way for novel treatment options. Genomic profiling of cell-free circulating tumor DNA that can assist in the identification of an actionable target is another exciting area of development. In this review, we provide a contemporaneous appraisal of the evolving targeted therapies and the ongoing clinical trials that will likely transform the therapeutic paradigm of BTC.
The current standard treatment for patients with early-stage colon cancer consists of surgical resection, followed by adjuvant therapy in a select group of patients deemed at risk of cancer recurrence. The decision to administer adjuvant therapy, intended to eradicate the clinically inapparent minimal residual disease (MRD) to achieve a cure, is guided by clinicopathologic characteristics of the tumor. However, the risk stratification based on clinicopathologic characteristics is imprecise and results in under or overtreatment in a substantial number of patients. Emerging research indicates that the circulating tumor DNA (ctDNA), a fraction of cell-free DNA (cfDNA) in the bloodstream that originates from the neoplastic cells and carry tumor-specific genomic alterations, is a promising surrogate marker of MRD. Several recent studies suggest that ctDNA-guided risk stratification for adjuvant therapy outperforms existing clinicopathologic prognostic indicators. Preliminary data also indicate that, aside from being a prognostic indicator, ctDNA can inform on the efficacy of adjuvant therapy, which is the underlying scientific rationale for several ongoing clinical trials evaluating ctDNA-guided therapy escalation or de-escalation. Furthermore, serial monitoring of ctDNA after completion of definitive therapy can potentially detect cancer recurrence much earlier than conventional surveillance methods that may provide a critical window of opportunity for additional curative-intent therapeutic interventions. This article presents a critical overview of published studies that evaluated the clinical utility of ctDNA in the management of patients with early-stage colon cancer, and the potential of ctDNA to transform the adjuvant therapy strategies.
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