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Treatment of Fanconi Anemia-Associated Head and Neck Cancer: Opportunities to Improve Outcomes
Lee RH, Kang H, Yom SS, Smogorzewska A, Johnson DE, Grandis JR
Clinical cancer research : an official journal of the American Association for Cancer Research. 2021
Abstract
Fanconi anemia, the most frequent genetic cause of bone marrow failure, is characterized by an extreme predilection towards multiple malignancies, including a greater than 500-fold incidence of head and neck squamous cell carcinoma (HNSCC) relative to the general population. Fanconi anemia-associated HNSCC and esophageal SCC (FA-HNSCC) often present at advanced stages with poor survival. Surgical resection remains the primary treatment for FA-HNSCC, and there is often great reluctance to administer systemic agents and/or radiation therapy (RT) to these patients given their susceptibility to DNA damage. The paucity of FA-HNSCC case reports limits evidence-based management, and such cases have not been analyzed collectively in detail. We present a systematic review of FA-HNSCC treatments reported from 1966 to 2020, defining a cohort of 119 FA-HNSCC patients including 16 esophageal SCCs (131 total primary tumors), who were treated with surgery, RT, systemic therapy (including cytotoxic agents, EGFR inhibitors, or immune checkpoint inhibitors), or a combination of modalities. We summarize the clinical responses and regimen-associated toxicities by treatment modality. The collective evidence suggests that when possible, surgical resection with curative intent should remain the primary treatment modality for FA-HNSCC. Radiation can be administered with acceptable toxicity in the majority of cases, including patients who have undergone stem cell transplantation (SCT). While there is little justification for cytotoxic chemotherapy, EGFR inhibitors and tyrosine kinase inhibitors (TKIs) may be both safe and effective. Immunotherapy may also be considered. Most oncologists have little personal experience with FA-HNSCC. This review is intended as a comprehensive resource for clinicians.
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Intravenous iron is non-inferior to oral iron regarding cell growth and iron metabolism in colorectal cancer associated with iron-deficiency anaemia
Al-Hassi HO, Ng O, Evstatiev R, Mangalika M, Worton N, Jambrich M, Khare V, Phipps O, Keeler B, Gasche C, et al
Scientific reports. 2021;11(1):13699
Abstract
Oral iron promotes intestinal tumourigenesis in animal models. In humans, expression of iron transport proteins are altered in colorectal cancer. This study examined whether the route of iron therapy alters iron transport and tumour growth. Colorectal adenocarcinoma patients with pre-operative iron deficiency anaemia received oral ferrous sulphate (n = 15), or intravenous ferric carboxymaltose (n = 15). Paired (normal and tumour tissues) samples were compared for expression of iron loading, iron transporters, proliferation, apoptosis and Wnt signalling using immunohistochemistry and RT-PCR. Iron loading was increased in tumour and distributed to the stroma in intravenous treatment and to the epithelium in oral treatment. Protein and mRNA expression of proliferation and iron transporters were increased in tumours compared to normal tissues but there were no significant differences between the treatment groups. However, intravenous iron treatment reduced ferritin mRNA levels in tumours and replenished body iron stores. Iron distribution to non-epithelial cells in intravenous iron suggests that iron is less bioavailable to tumour cells. Therefore, intravenous iron may be a better option in the treatment of colorectal cancer patients with iron deficiency anaemia due to its efficiency in replenishing iron levels while its effect on proliferation and iron metabolism is similar to that of oral iron treatment.
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Efficacy and Safety of Ferric Carboxymaltose Infusion in Reducing Anemia in Patients Receiving Chemotherapy for Nonmyeloid Malignancies: a Randomized, Placebo-Controlled Study (IRON CLAD)
Makharadze T, Boccia R, Krupa A, Blackman N, Henry DH, Gilreath JA
American journal of hematology. 2021
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Editor's Choice
Abstract
PURPOSE Erythropoiesis-stimulating agents (ESA) are effective for chemotherapy-induced anemia (CIA) but associated with serious adverse events. Safer alternatives would be beneficial in this population. The efficacy and safety of ferric carboxymaltose (FCM) as monotherapy for CIA was evaluated. METHODS This Phase 3, 18-week, double-blind, placebo-controlled study randomized adults with ≥4 weeks of chemotherapy remaining for treatment of nonmyeloid malignancies with CIA to FCM (two 15 mg/kg infusions 7 days apart; maximum dose, 750 mg single/1500 mg total) or placebo. The primary efficacy endpoint was percentage of patients with decreases in hemoglobin (Hb) ≥0.5 g/dL from weeks 3 to 18; the key secondary efficacy endpoint was change in Hb from baseline to week 18. Inclusion criteria included: (Hb) 8-11 g/dL, ferritin 100-800 ng/mL, and transferrin saturation (TSAT) ≤35%. RESULTS In 244 patients (n=122, both groups), the percent who maintained Hb within 0.5 g/dL of baseline from weeks 3 to 18 was significantly higher with FCM versus placebo (50.8% vs 35.3%; P=0.01). Mean change in Hb from baseline to week 18 was similar between FCM and placebo (1.04 vs 0.87 g/dL) but significantly greater with FCM with baseline Hb ≤9.9 g/dL (1.08 vs 0.42 g/dL; P=0.01). The percent with ≥1 g/dL increase from baseline was significantly higher with FCM versus placebo (71% vs 54%; P=0.01), occurring in a median 43 versus 85 days (P=0.001). Common adverse events in the FCM arm included neutropenia (17%), hypophosphatemia (16%), and fatigue (15%). CONCLUSION FCM monotherapy effectively maintained Hb and was well tolerated in CIA. This article is protected by copyright. All rights reserved.
PICO Summary
Population
Patients receiving chemotherapy for non-myeloid malignancies with chemotherapy-induced anaemia (CIA), enrolled in the IRON-CLAD study conducted at 58 sites in the United States, Bulgaria, Georgia, Hungary, and Poland (n= 244).
Intervention
Ferric carboxymaltose (FCM) infusions (n= 122).
Comparison
Placebo (n= 122).
Outcome
The percentage of patients who maintained Hb within 0.5 g/dL of baseline from weeks 3 to 18 was significantly higher with FCM versus placebo (50.8% vs. 35.3%). Mean change in Hb from baseline to week 18 was similar between FCM and placebo (1.04 vs. 0.87 g/dL) but significantly greater with FCM with baseline Hb <= 9.9 g/dL (1.08 vs. 0.42 g/dL). The percent with >= 1 g/dL increase from baseline was significantly higher with FCM versus placebo (71% vs. 54%), occurring in a median 43 versus 85 days. Common adverse events in the FCM arm included neutropenia (17%), hypophosphatemia (16%), and fatigue (15%). FCM monotherapy effectively maintained Hb and was well tolerated in CIA.
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Preoperative Intravenous Iron Therapy and Survival after Colorectal Cancer Surgery: Long Term Results from the IVICA Randomised Controlled Trial
Dickson EA, Keeler BD, Ng O, Kumar A, Brookes MJ, Acheson AG
Colorectal disease : the official journal of the Association of Coloproctology of Great Britain and Ireland. 2020
Abstract
AIM: Preoperative iron is frequently used for the correction of anaemia in colorectal cancer surgery. However, enteral iron intake may promote tumour growth and progression which could influence cancer recurrence and patient survival. We explore the long term outcomes of patients receiving either oral or intravenous iron replacement therapy as part of a previous randomised controlled trial. METHODS The IVICA trial randomised anaemic colorectal cancer patients to receive either oral (OI, control) or intravenous (IVI, treatment) iron prior to their elective operation. Follow up analysis of all patients recruited to this multicentre trial who underwent surgical resection with curative intent was performed. Kaplan-Meier survival estimates, and Cox proportional hazard models were used to compare groups. A pooled group multivariable analysis comparing patients who achieved resolution of anaemia preoperatively to those who did not was also undertaken. RESULTS 110 of the 116 patients previously enrolled were eligible for analysis (OI n=56, IVI n=54). Median overall follow up duration was 61 months (IQR 46-67). No significant difference in 5-year overall survival (HR 1.22, 95% CI 0.65-2.28 P=0.522) or disease free survival (HR 1.08, 95% CI 0.61-1.92 P=0.79) was observed between OI and IVI. Pooled analysis of treatment groups found that preoperative resolution of anaemia led to improved 5 year overall survival on multivariable analysis (HR 3.38 [1.07-11.56, P=0.044). CONCLUSION We recommend IVI for the preoperative correction of anaemia. Route of iron therapy did not significantly influence survival. Preoperative anaemia correction may lead to an overall survival advantage following elective colorectal cancer surgery.
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Effect of Erythropoiesis Stimulating Agents on Clinical Outcomes in Breast Cancer Patients: A Systematic Review of Randomised Controlled Trials
Sabir S, Khan YH, Khatoon M, Noreen R, Mallhi TH, Jabeen N
J Coll Physicians Surg Pak. 2020;30(3):292-298
Abstract
The impact of erythropoiesis stimulating agents (ESAs) on clinical outcomes among breast cancer patients is debatable. Current review is aimed to ascertain the efficacy of ESAs among breast cancer patients. Randomised controlled trials (RCTs) were electronically searched. Primary outcomes were mortality, blood transfusion requirements and thromboembolic events (TEEs); whereas, secondary outcomes were safety, tumor progression, anemia treatment, hemoglobin levels and quality of life (QOL). Out of 11 RCTs including 6,849 participants, 9 RCTs reported 2,312 deaths with overall mortality of 33.7%. Mortality reported for epoetin alfa (EA), epoetin beta (EB) and darbepoetin alfa (DA) was 41.24%, 73.1% and 8.99% respectively. TEEs reported for EA, EB and DA were 5.88%, 9.28% and 2.85%, respectively. Serious adverse events were 39.04%, 36.29%, 1.53% for EA, EB and DA, respectively. Tumor progression for EA and EB was 37.53% and 95.46%, respectively. No tumor progression was reported with DA. Erythropoietin reported no mortality, TEEs, serious ADRs and tumor progression. About 9% patients required transfusions during ESA therapy. Current evidence suggests that use of ESA reduces transfusion need but increases mortality and risks of TEEs.
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Impact and Outcomes of Postoperative Anaemia in Colorectal Cancer Patients: A Systematic Review
Moncur A, Chowdhary M, Chu Y, Francis N
Colorectal disease : the official journal of the Association of Coloproctology of Great Britain and Ireland. 2020
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Editor's Choice
Abstract
OBJECTIVES Preoperative anaemia is common in colorectal cancer patients. Little attention has been given to the prevalence and consequences of postoperative anaemia. The aim of this study was to systematically review the published literature and determine the knowledge of prevalence and impact of postoperative anaemia in colorectal cancer patients. METHODS Databases, CINAHL and Medline, via EBSCO Host, were systematically searched to identify suitable articles published between 2004-2020. After an initial search, articles were screened and all eligible articles reported on prevalence of postoperative anaemia, clinical and long-term outcomes data in colorectal cancer patients undergoing surgery were included. The Risk of Bias 2.0 tool for the assessment of Randomised Controlled Trials and Risk of Bias in Non-randomised studies 1.0 tool were used for the assessment of bias in the studies selected in our review. RESULTS Six studies, one randomised control trial and five cohort studies were included with a total population size of 1714. The prevalence of anaemia at discharge of 76.6% was reported as the primary endpoint in only one study. The rate of Red Blood Cell Transfusion and length of hospital stay were found to be significantly increased in anaemic patients, while postoperative infection rate results were variable. Quality of life scores and overall survival at 5 years were significantly affected among anaemic patients as reported in two papers. CONCLUSION The available limited evidence on postoperative anaemia indicates its high prevalence with negative impact on clinical and long-term outcomes. Further research is required to standardise the measurement and address the true impact of correcting postoperative anaemia on functional and oncological outcomes.
PICO Summary
Population
Colorectal cancer patients undergoing surgery (6 studies, n= 1,714).
Intervention
Systematic review to determine the prevalence and consequences of postoperative anaemia.
Comparison
Outcome
The prevalence of anaemia at discharge of 76.6% was reported as the primary endpoint in only one study. The rate of red blood cell transfusion and length of hospital stay were found to be significantly increased in anaemic patients, while postoperative infection rate results were variable. Quality of life scores and overall survival at 5 years were significantly affected among anaemic patients as reported in two papers.
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Intravenous iron versus oral iron or observation for gastrointestinal malignancies: a systematic review
Tang GH, Dhir V, Scheer AS, Tricco AC, Sholzberg M, Brezden-Masley C
European journal of gastroenterology & hepatology. 2019
Abstract
BACKGROUND Anemia is a common condition in patients with gastrointestinal cancer. Current evidence for the use of intravenous compared with oral iron in this clinical setting is inconclusive. A systematic review was performed to assess evidence on the efficacy of intravenous iron versus oral/observation in gastrointestinal cancer patients in the preoperative and postoperative setting. MATERIALS AND METHODS We searched Medline and Embase from inception until December 2017 with no language restrictions. Outcomes included hemoglobin response, red blood cell transfusion, and adverse events. Screening, data abstraction, and risk of bias appraisal were performed by two independent reviewers. The risk of bias was assessed using the Cochrane tools for randomized and nonrandomized studies. RESULTS A total of 10 studies (three randomized-controlled trials and seven nonrandomized studies) were included. Of the six preoperative studies, five reported that hemoglobin was significantly higher in the intravenous group compared with oral iron/observation. Among the four postoperative studies, three studies suggested that hemoglobin was significantly higher in the intravenous group compared with oral iron/observation. The overall risk of bias for all randomized-controlled trials was low. Quality assessments for nonrandomized studies found the risk of bias to be moderate for four studies and critical for three studies. CONCLUSION Despite the limitations of the current body of evidence, there is a likely benefit to the use of intravenous iron in this patient population. Further confirmatory research is needed to draw empirical conclusions.
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A Randomized, Double-Blind, Placebo-Controlled, Phase III Noninferiority Study of the Long-Term Safety and Efficacy of Darbepoetin alfa for Chemotherapy-Induced Anemia in Patients With Advanced Non-Small Cell Lung Cancer
Gascon P, Nagarkar R, Smakal M, Syrigos KN, Barrios CH, Sanchez JC, Zhang L, Henry DH, Gordon D, Hirsh V, et al
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2019
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Abstract
INTRODUCTION This study evaluated noninferiority of darbepoetin alfa versus placebo for overall survival (OS) and progression-free survival (PFS) in anemic patients with non-small cell lung cancer (NSCLC) treated to a 12.0-g/dL hemoglobin (Hb) ceiling. METHODS Adults with stage IV NSCLC expected to receive ≥2 cycles of myelosuppressive chemotherapy and Hb≤11.0 g/dL were randomized 2:1 to blinded 500 mug darbepoetin alfa or placebo Q3W. The primary endpoint was OS; a stratified Cox proportional hazards model was used to evaluate noninferiority (upper confidence limit for hazard ratio [HR] <1.15). Secondary endpoints were PFS and incidence of transfusions or Hb≤8.0 g/dL from week 5 to end of the efficacy treatment period (EOETP). RESULTS The primary analysis set included 2516 patients: 1680 randomized to darbepoetin alfa; 836 to placebo. The study was stopped early per independent Data Monitoring Committee recommendation after the primary endpoint was met with no new safety concerns. Darbepoetin alfa was noninferior to placebo for OS (stratified HR=0.92; 95%CI, 0.831.01) and PFS (stratified HR=0.95; 95%CI, 0.871.04). Darbepoetin alfa was superior to placebo for transfusion or Hb ≤8.0 g/dL from week 5 to EOETP (stratified OR=0.70; 95%CI, 0.570.86; P<.001). Objective tumor response was similar between the arms (darbepoetin alfa, 36.4%; placebo, 32.6%). Incidence of serious adverse events (AEs) was 31.1% in both arms. No unexpected AEs were observed. CONCLUSIONS Darbepoetin alfa dosed to a 12.0-g/dL Hb ceiling was noninferior to placebo for OS and PFS and significantly reduced odds of transfusion or Hb≤8.0 g/dL in anemic patients with NSCLC receiving myelosuppressive chemotherapy.
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Comparative effectiveness and safety of traditional Chinese medicine supporting Qi and enriching blood for cancer related anemia in patients not receiving chemoradiotherapy: a meta-analysis and systematic review
Dang Z, Liu X, Wang X, Li M, Jiang Y, Wang X, Yang Z
Drug design, development and therapy. 2019;13:221-230
Abstract
A systematic review and meta-analysis of previous randomized controlled trials of traditional Chinese medicine (TCM) supporting Qi and enriching blood in the treatment of cancer related anemia (CRA) in patients not receiving chemoradiotherapy were conducted. A total of 13 randomized controlled trials were included. Compared with the control group, better improvement was found for the level of hemoglobin (mean difference=4.57, 95% CI [1.38, 7.76], P=0.005) and overall therapeutic effect (risk ratio [RR]=1.31, 95% CI [1.18, 1.46], P<0.000) in the TCM groups. The incidence of related adverse events was not increased in the TCM groups (RR=0.54, 95% CI [0.29, 0.99], P=0.05). However, due to the relatively low quality and the small sample sizes of the included studies, the results should be interpreted with a degree of caution. Nevertheless, TCM with the role of supporting Qi and enriching blood may be a safe and effective treatment for CRA in patients not receiving chemoradiotherapy and might be considered as an alternative treatment to conventional western medicine including iron supplements and erythropoietin.
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Management of Cancer-Associated Anemia With Erythropoiesis-Stimulating Agents: ASCO/ASH Clinical Practice Guideline Update
Bohlius J, Bohlke K, Lazo-Langner A
Journal of oncology practice. 2019;:Jop1900111
