Jerry A. Barbee Jr, PharmD, BCPS, CPh

The National Institutes of Health (NIH) estimates that ovarian cancer (OC) will have accounted for 1.2% of new cases and 2.3% of all cancer deaths in the United States in 2020.

The most recent global statistics from 2018 show that OC is ranked eighth in cancer incidence rates for women, with more than 295,000 or 3.8% cases diagnosed in 2018.

There are no routine screenings for OC, which often results in delayed diagnosis beyond stage I and II, secondary to generalized vague symptoms.

 About 70% of the cases are diagnosed as advanced stage III or IV OC.

 The patients' 5-year survival rate varies greatly, depending on the stage at which they are initially diagnosed (FIGURE

). The CDC reported that new cases are 10.2 of 100,000, with 6.6 of 100,000 women succumbing to death annually.

Ovarian Cancer 5-year Relative Survival vs Diagnosis By Stage

Patients in developed countries have a higher rate of OC, with a peak incidence occurring between 55 and 64 years of age with a higher prevalence in Caucasian women.

 The most common type of OC is epithelial, which accounts for about 90% of all cases, and the remaining 10% are considered to be nonepithelial.

 About 20% of all OCs have been associated with an inherited gene mutation, eg, BRCA1, BRCA2, MLH1, MSH2. This malignancy has been linked to 1 of 3 hereditary patterns: ovarian cancer alone, ovarian cancer plus breast cancer, and ovarian cancer plus colon cancer.

 Women of Ashkenazi Jewish and Eastern European descent are more likely to be carriers of 

 gene mutations and therefore are at an increased risk of developing OC.

The National Comprehensive Cancer Network (NCCN) does not offer screening recommendations for ovarian cancer. Online table 1

 outlines common symptoms that might be produced by OC. If a patient is experiencing any of these signs or symptoms for greater than 2 weeks, diagnostic tests such as a CA-125 blood test, transvaginal ultrasound, or vaginal pelvic exam may be ordered to investigate the presence of OC.

 The staging of OC is determined postsurgically, which should be performed by a gynecologic oncologist and then examined microscopically by a pathologist.

Treatment options for OC include chemotherapy, hormone therapy, immunotherapy, radiation, surgery, and targeted therapy (Table 2

 The NCCN Clinical Practice Guidelines for OC recommend that the primary treatment consist of debulking surgery, plus systemic chemotherapy in most patients.

Clinicians use genetic testing to assess for specific gene mutations, such as 

, homologous-recombination deficiency, which will guide treatment decisions.

 This allows clinicians to prescribe a targeted therapy that includes poly-ADP ribose polymerase (PARP) inhibitors and/or vascular endothelial growth factor inhibitors.

Systemic immunotherapy enhances the activity of the immune system. Immune checkpoint inhibitors target key surface markers, eg, cytotoxic T-lymphocyte-associated protein 4, programmed cell death ligand, and programmed cell death protein 1.

Hormone therapy involves the use of hormones or hormone-blocking agents acting as anti-estrogen agents to suppress OC tumor growth. This type of therapy involves 3 classes of drugs: aromatase inhibitors, luteinizing-hormone-releasing hormone agonists, and tamoxifen. This mode of systemic therapy is rarely employed in epithelial OC but is more commonly used in refractory ovarian stromal tumors.

PARP inhibitors are vital in the treatment and maintenance of OC and may improve outcomes. Some recent clinical trials, ie, PAOLA-1/ENGOT-OV26, PRIMA/ENGOT-OV26, and SOLO-1, (Online table 3

Clinical trials evaluating combination products, eg, cediranib and olaparib, in patients that are considered to platinum-resistant and -sensitive, are showing promise. Cediranib, a VEGF inhibitor with olaparib, a PARP inhibitor, restricts blood supply to the area promoting apoptosis of the cancerous cells. Preliminary reports from the ICON 9 study demonstrate a significant improvement in progression-free survival.

OC negatively affects the lives of many women. It continues to remain one of the most lethal malignancies, despite continuing efforts and constant advances in treatments. The poor clinical outcomes associated with OC are attributable to chemotherapy resistance, its increased heterogeneity, and the ineffective tools for detecting the disease early in its course. New treatments are needed to enhance cure rates and provide long-term disease stability against platinum-resistance OC. Cellular and immune therapies combined with genetic testing and precision assays (biomarkers) are promising strategies that will inevitably lead to more favorable clinical outcomes. Accelerated research and novel approaches will also invariably spawn better therapeutic options to extend the life expectancy and improve the health of patients with OC.

1. United States cancer statistics data visualizations. Centers for Disease Control and Prevention. June 2020. Accessed March 7, 2021. https://www.cdc.gov/cancer/dataviz

2. Worldwide cancer data. World Cancer Research/American Institute for Cancer Research. Accessed February 14, 2021. https://www.wcrf.org/dietandcancer/cancer-trends/worldwide-cancer-data

3. Stages of ovarian cancer. Ovarian Cancer Research Alliance. Accessed February 14, 2021. https://ocrahope.org/patients/about-ovarian-cancer/staging/

4. Gaona-Luviano P, Medina-Gaona LA, Magana-Perez K. Epidemiology of ovarian cancer. 

5. Ovarian germ cell tumors treatment (PDQ)-health professional version. National Cancer Institute. Updated September 3, 2020. Accessed February 14, 2021. https://www.cancer.gov/types/ovarian/hp/ovarian-germ-cell-treatment-pdq

6. Risk factors. Ovarian Cancer Research Alliance. Accessed February 14, 2021. https://ocrahope.org/patients/about-ovarian-cancer/risk-factors/

7. Ovarian germ cell tumors treatment (PDQ)-patient version. National Cancer Institute. Updated January 8, 2021. Accessed February 14, 2021. https://www.cancer.gov/types/ovarian/patient/ovarian-epithelial-treatment-pdq

8. About ovarian cancer. Ovarian Cancer Research Alliance. Accessed February 14, 2021. https://ocrahope.org/patients/about-ovarian-cancer/

9. Treatment. Ovarian Cancer Research Alliance. Accessed February 14, 2021. https://ocrahope.org/patients/about-ovarian-cancer/treatment/

10. Kaplan DA. Overview of the updated NCCN guidelines on ovarian cancer. Journal of Clinical Pathways. June 17, 2020. Accessed February 14, 2021. https://www.journalofclinicalpathways.com/overview-updated-nccn-guidelines-ovarian-cancer

11. Borella F, Ghisoni E, Giannone G, et al. Immune checkpoint inhibitors in epithelial ovarian cancer: an overview on efficacy and future perspectives. 

. 2020;10(3):146. doi:10.3390/diagnostics10030146

12. Gershenson DM, Bodurka DC, Coleman RL, Lu KH, Malpica A, Sun CC. Hormonal maintenance therapy for women with low-grade serous cancer of the ovary or peritoneum. 

. 2017;35(10):1103-1111. doi:10.1200/JCO.2016.71.0632

13. Shylasree TS, Richa B, Lavanya G, Gulia S. Molecular signatures of gynecological cancers: clinicians perspective. 

14. Moore K, Colombo N, Scambia G, et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. 

 2018;379(26):2495-2505. doi:10.1056/NEJMoa1810858

15. Gonazlez-Martin A, Pothuri B, Vergote I, et al. Niraparib in patients with newly diagnosed advanced ovarian cancer. 

. 2019;381(25):2391-2402. doi:10.1056/NEJMoa1910962

16. Ray-Coquard I, Pautier P, Pignata S, et al. Olaparib plus bevacizumab as first-line maintenance in ovarian cancer. 

. 2019;381(25):2416-2428. doi:10.1056/NEJMoa1911361

17. Coleman RL, Fleming GF, Brady MF, et al. Veliparib with first-line chemotherapy and as maintenance therapy in ovarian cancer. 

. 2019;381(25):2403-2415. doi:10.1056/NEJMoa1909707

18. Clovis Oncology announces completion of target enrollment in the ATHENA trial, a phase 3 maintenance treatment study in front-line, newly-diagnosed advanced ovarian cancer. News release. Clovis Oncology. June 10, 2020. Accessed February 10, 2021. https://ir.clovisoncology.com/investors-and-news/news-releases/press-release-details/2020/Clovis-Oncology-Announces-Completion-of-Target-Enrollment-in-the-ATHENA-Trial-a-Phase-3-Maintenance-Treatment-Study-in-Front-line-Newly-Diagnosed-Advanced-Ovarian-Cancer/default.aspx

19. Mirza MR, Coleman RL, Gonzalez-Martin A, et al. The forefront of ovarian cancer therapy: update on PARP inhibitors. 

. 2020;31(9):1148-1159. doi:10.1016/j.annonc.2020.06.004

20. Liu JF, Barry WT, Birrer M, et al. Overall survival and updated progression-free survival outcomes in a randomized phase II study of combination cediranib and olaparib versus olaparib in relapsed platinum-sensitive ovarian cancer. 

. 2019;30(4):551-557. doi:10.1093/annonc/mdz018

21. Chandra A, Pius C, Nabeel M, et al. Ovarian cancer: current status and strategies for improving therapeutic outcomes. 

. 2019;8(16):7018-7031. doi:10.1002/cam4.2560

Articles

Guidelines typically recommend debulking surgery, plus systemic chemotherapy for most patients.

Explore Ovarian Cancer Treatments Through Clinical Trials

Since the onset of COVID-19 cases in January 2020 and the subsequent pandemic, health care has become less accessible, according to the CDC.

 Patients with chronic diseases are reluctant to attend routine appointments and screenings due to concern about COVID-19.

 As a result, screenings, oncology visits, and treatments decreased significantly during the months of March to July 2020 vs the comparable time period in 2019 (Figure 1).

 Enhanced emphasis has been placed on telemedicine or virtual visits to provide follow-up care in this patient population.

Patients’ reluctance to seek care is not unfounded. Those with malignancies are at greater risk of dismal outcomes from infection because of their poor overall health and receiving immunomodulating therapy.

Hematologic malignancies consist of at least 30 tumor types, differing by lineage (ie, myeloid vs lymphoid), genetic alterations, and pathogenesis.

 Lymphomas, multiple myeloma, and most types of leukemia initially affect blood cells used in the immune response.

In contrast to patients with solid tumor cancers, patients with specific hematologic malignancies are confronted with multimodal immunosuppression from their disease and associated treatment.

 Retrospective analyses have suggested 2-fold greater mortality rates in patients who are COVID-19 positive with hematologic malignancies vs those with solid tumors.

According to data from the American Society of Hematology (ASH) Research Collaborative COVID-19 Registry for Hematology, denial of intensive care unit (ICU) care, poor pre–COVID-19 prognosis, and more advanced malignancies were also associated with a higher mortality risk (Figure 2).

Findings from retrospective studies examining this population found higher rates of severe disease as a result of COVID-19 in comparison with patients without cancer, but no significant difference in incidence rates of contracting the virus.

According to a study in the United Kingdom, patients with hematologic malignancies were 57% more likely to experience a severe case of COVID-19 than those with other types of cancer.

 In addition, patients with hematologic malignancies demonstrated prolonged viral shedding (up to a median of 32.7 days) compared with nononcology patients, which affects time for postinfection isolation and time to cancer treatment reinitiation.

Considering that 20% of venous thromboembolisms (VTEs) occur as a result of cancer, the endothelial injury, immobility, and amplified circulation of prothrombotic factors that are present during an acute COVID-19 infection create a potentially lethal combination.

Certain hematologic malignancies are associated with an especially high incidence of VTE. This is particularly concerning because many patients with blood cancers are older and have comorbidities that predispose them to the thrombotic sequela of COVID-19.

 For example, 10% of patients with aggressive lymphomas and 6% with multiple myelomas (MMs) experience VTEs.

Seven retrospective and population-based studies examined outcomes and risk factors due to COVID-19 in patients with hematologic malignancies. The findings demonstrated little consistency among them (Figure 3).

The risk factors identified by investigators of these studies are likely less specific to the cancer itself and more indicative of the patient’s overall health status and advanced age.

During the pandemic, consensus recommendations regarding the treatment of patients with hematological malignancies are focused on strict exposure prevention and the reduction of risk factors; acute treatment is the same as that for the general population.

 This includes strict adherence to social distancing recommendations by the CDC and World Health Organization (WHO) and rigorous COVID-19 screening prior to chemotherapy or procedures.

The use of telemedicine has increased, which balances the potential harm of treatment delay with the risk of disease transmission.20 For example, treatment should not be deferred for cancers that are curable and associated with inferior outcomes when treatment is delayed, such as pediatric acute lymphoblastic leukemia.

Based on a summary of current recommendations, standard treatment for cancer should resume in the absence of active infection with COVID-19, whereas treatment decisions during an active infection should be decided on a case-by-case basis.

 As long as efficacy is not compromised, oral chemotherapy and regimens that minimize infusions are preferred in order to limit exposure of transmission; some experts have switched to oral management exclusively in chronic and small lymphoma leukemia, mantle cell lymphoma, and marginal zone lymphoma.

 Similarly, prompt and prophylactic management of treatment-related adverse events should be provided for patients on chronic, oral chemotherapy to prevent unnecessary hospitalization and subsequent exposure.

A retrospective analysis of patients with a current or past hematologic malignancy from the CCC19 study (NCT04354701) demonstrated a potential benefit of patients receiving convalescent plasma treatment (CPT). Of the 966 patients included, 143 (15%) received CPT.

After adjusting for confounders, 30-day mortality was significantly lower in the CPT cohort from the propensity score-matching analysis (HR, 0.52 [0.29-0.92]). Within this subset of patients, investigators also saw benefit in the 338 patients who were admitted to the ICU (propensity score–matched HR, 0.4 [0.20-0.80]) and in the 227 mechanically ventilated patients (propensity score–matched HR, 0.32 [0.14-0.72]).

 It is worth noting that along with other inherent limitations commonly associated with observational trials, patients were inequitably treated in the interest of expediency with other experimental COVID-19 treatments, such as corticosteroids, hydroxychloroquine, remdesivir, and tocilizumab, even after propensity score matching. Albeit controversial, CPT may play a role in the treatment of patients co-afflicted with COVID-19 plus hematological malignancies and associated B-cell lymphopenia to help restore neutralizing antibodies; however, clinicians must await the results of randomized clinical trials, which remain the gold standard of efficacy.

The Leukemia and Lymphoma Society (LLS) recently launched a substudy (LLS protocol number: BAML-16-001-COV1) as part of its master protocol Beat AML Trial (NCT03013998). The study examines the use of acalabrutinib, a Bruton tyrosine kinase inhibitor, in patients with acute myeloid leukemia, acute lymphoblastic leukemia, aplastic anemia, and myelodysplastic syndromes who are COVID-19 positive.

The theoretical benefit is attributed to acalabrutinib’s ability to diminish the uncontrolled inflammatory response elicited by COVID-19 that often leads to organ failure.

 As we await the results of BAML-16-001-COV1, perhaps the most exciting aspect of Beat AML’s expanding to include COVID-19 patients is that the study’s master protocol design allows for the seamless incorporation of novel treatments as the trial progresses.

With innovations in medication therapy, patient treatment, and video teleconferencing, there is room for cautious optimism regarding patients with hematologic malignancies. Strategies proposed in an attempt to minimize COVID-19-related mortalities in these patients need to be adapted as we navigate through this pandemic. This group will always be at greater risk, with less auspicious outcomes due to their underlying comorbidities and inherent increased propensity for thromboembolic events.

With 3 highly effective COVID-19 vaccines available, improved screening and treatment strategies, and earlier testing, this vulnerable patient population will be able to accrue enhanced outcomes as the pandemic assumes a more favorable trajectory. 

Patt D, Gordan L, Diaz M, et al. Impact of COVID-19 on cancer care: how the pandemic is delaying cancer diagnosis and treatment for American seniors. JCO Clin Cancer Inform. 2020;4:1059-1071. doi:10.1200/CCI.20.00134

Meng Y, Lu W, Guo E, et al. Cancer history is an independent risk factor for mortality in hospitalized COVID-19 patients: a propensity score-matched analysis. J Hematol Oncol. 2020;13(1):75. doi:10.1186/s13045-020-00907-0

Mehta V, Goel S, Kabarriti R, et al. Case fatality rate of cancer patients with COVID-19 in a New York hospital system. Cancer Discov. 2020;10(7):935-941. doi:10.1158/2159-8290. CD-20-0516

Moasser MM, Ai WZ. Neoplasia. In: Hammer GD, McPhee SJ, eds. Pathophysiology of Disease: An Introduction to Clinical Medicine. 8th ed. McGraw-Hill Education; 2019: 89-140. 

Susman E. Blood cancers and COVID-19: ‘a medically vulnerable’ group. MedPage Today. December 6, 2020. Accessed March 6, 2021. https://www.medpagetoday.com/meetingcoverage/ ashhematology/90045?vpass=1

Hus I, Salomon-Perzyński A, Tomasiewicz K, Robak T. The management of hematologic malignancies during the COVID-19 pandemic. Expert Opin Pharmacother. Published online December 21, 2020. doi:10.1080/14656566.2020.1849143

Lee LYW, Cazier JB, Starkey T, et al; UK Coronavirus Cancer Monitoring Project Team. COVID-19 prevalence and mortality in patients with cancer and the effect of primary tumour subtype and patient demographics: a prospective cohort study. Lancet Oncol. 2020;21(10): 1309-1316. doi:10.1016/S1470-2045(20)30442-3

Fernandes CJ, Morinaga LTK, Alves Jr JL, et al. Cancer-associated thrombosis: the when, how and why. Eur Respir Rev. 2019;28(151):180119. doi:10.1183/16000617.0119-2018

Singhania N, Bansal S, Nimmatoori DP, Ejaz AA, McCullough PA, Singhania G. Current overview on hypercoagulability in COVID-19. Am J Cardiovasc Drugs. 2020;20(5):393-403. doi:10.1007/s40256-020-00431-z

Trial to test acalabrutinib for patients with blood cancer, COVID-19. Healio. October 7, 2020. Accessed March 6, 2021. https://www.healio.com/news/hematology-oncology/20201007/ trial-to-test-acalabrutinib-for-patients-with-blood-cancer-covid19

Kekre N, Connors JM. Venous thromboembolism incidence in hematologic malignancies. Blood Rev. 2019;33:24-32. doi:10.1016/j.blre.2018.06.002

Aries JA, Davies JK, Auer RL, et al. Clinical outcome of coronavirus disease 2019 in haemato-oncology patients. Br J Haematol. 2020;190(2):e64-e67. doi:10.1111/bjh.16852

García-Suárez J, de la Cruz J, Cedillo Á, et al; Associación Madrileña de Hematología y Hemoterapia (AMHH). Impact of hematologic malignancy and type of cancer therapy on COVID-19 severity and mortality: lessons from a large population-based registry study. J Hematol Oncol. 2020;13(1):133. doi:10.1186/s13045-020-00970-7

Infante MS, González-Gascón Y Marín I, Muñoz-Novas C, et al. COVID-19 in patients with hematological malignancies: a retrospective case series. Int J Lab Hematol. 2020;42(6):e256-e259. doi:10.1111/ijlh.13301

Martín-Moro F, Marquet J, Piris M, et al. Survival study of hospitalised patients with concurrent COVID-19 and haematological malignancies. Br J Haematol. 2020;190(1):e16-e20. doi:10.1111/bjh.1680

Passamonti F, Cattaneo C, Arcaini L, et al; ITA-HEMA-COV Investigators. Clinical characteristics and risk factors associated with COVID-19 severity in patients with haematological malignancies in Italy: a retrospective, multicentre, cohort study. Lancet Haematol. 2020;7(10):e737-e745. doi:10.1016/S2352-3026(20)30251-9

Piñana JL, Martino R, García-García I, et al; Infectious Complications Subcommittee of the Spanish Hematopoietic Stem Cell Transplantation and Cell Therapy Group (GETH). Risk factors and outcome of COVID-19 in patients with hematological malignancies. Exp Hematol Oncol. 2020;9:21. doi:10.1186/s40164-020-00177-z

Sanchez-Pina JM, Rodríguez Rodriguez M, Castro Quismondo N, et al. Clinical course and risk factors for mortality from COVID-19 in patients with haematological malignancies. Eur J Haematol. 2020;105(5):597-607. doi:10.1111/ejh.13493

Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. National Institutes of Health. Updated March 5, 2021. Accessed March 7, 2021. https://www.covid19treatmentguidelines.nih.gov/ 

Framework for healthcare systems providing non-COVID-19 clinical care during the COVID-19 pandemic. CDC. Updated June 30, 2020. Accessed March 7, 2021. https://www.cdc. gov/coronavirus/2019-ncov/hcp/framework-non-COVID-care.html

Ranjana R, Bartlett N, LaCasce A, et al. COVID-19 and indolent lymphomas: frequently asked questions. American Society of Hematology. Updated February 5, 2021. Accessed March 8, 2021. https://www.hematology.org/covid-19/ covid-19-and-indolent-lymphomas

Thompson MA, Henderson JP, Shah PK, et al. Convalescent plasma and improved survival in patients with hematologic malignancies and COVID-19. medRxiv. February 5, 2021. Accessed March 6, 2021. https://www.medrxiv.org/content/10.1101/2021.02.05.21250953v1

In this high-risk population, strategies for minimizing viral exposure during a pandemic are being considered with oncology treatment options.

Managing Hematologic Cancer Therapies and Reducing COVID-19 Risk

Among the many subtypes of leukemias in the United States, acute myeloid leukemia (AML) is the most commonly diagnosed form in adults and causes the highest number of deaths.

During 2020, the United States had an estimated 20,000 new patient cases of AML, with more than half of these resulting in death.2 Leukemia, a cancer of the blood and bone marrow, affects the function and production of blood cells.

 In AML, immature myeloid cells (myeloblasts) accumulate and are unable to mature into functioning platelets, red blood cells (erythrocytes), or white blood cells (neutrophils).

 Compared with other types of leukemias, AML occurs more frequently in older adults, with a median age at diagnosis of 67.

 Increasing age; exposure to benzene, chemotherapy, or radiation; family history; genetic mutations; male gender; and smoking are risk factors for developing AML.

 Because blood cells are not maturing, AML presents similarly to anemia, neutropenia, and thrombocytopenia (Figure 1

). Symptoms commonly include bleeding, fatigue infection, and pallor.

Evaluation for suspected AML initially involves assessment of medical history and a physical exam.

 Essential laboratory data include a blood sample with a complete blood count with differential, a peripheral blood smear, and a bone marrow biopsy.

 Based on these results, the presence of at least 20% of blast cells in peripheral blood or marrow generally confirms the diagnosis of acute leukemia, as defined by the World Health Organization (WHO) in 2016.

 Immunophenotyping and cytogenetic studies are used to confirm cell lineage, establish risk stratification, and classify subtypes.4 In accordance with the WHO classification system, AML is classified into 1 of 6 groups based on clinical features, genetics, immunophenotype, and morphology. Prognosis and treatment selection are increasingly determined by expression or absence of several key gene mutations (Figure 2.

AML treatment options mainly include chemotherapy, stem cell transplant, and targeted therapy (Figure 3

). AML was considered an oncologic emergency requiring treatment initiation as soon as possible upon diagnosis.

 However, new evidence suggests less of a correlation between time to treatment and prognosis than previously thought.

 As treatment is being targeted to patient-specific gene mutations, there may be benefit to first obtaining genetic and laboratory tests to initiate the most appropriate treatment.

Treatment of AML generally occurs in 2 phases: remission induction therapy and postremission (consolidation) therapy.

 Choice of treatment differs based on age and medical fitness of the patient.

 Healthy patients under age 60 often qualify for “intensive” therapy, whereas older patients who present with a combination of risk factors, such as multiple comorbidities, poor performance status (PS), and unfavorable cytogenetics, may better tolerate a less-intense regimen.

 PS in oncology is often assessed using the ECOG scale, which is the standard for quantifying the functional capacity of a patient and predicting chemotherapy tolerability.

The cornerstone of intensive induction therapy is a regimen of 7 days of continuously infused cytarabine, plus a 3-day course of an anthracycline called “7 + 3 induction therapy,” which results in a complete remission rate of about 65%.

 If remission is achieved, medically fit patients have options for consolidation therapy: an allogeneic (donor) or an autologous (patient’s own) stem cell transplant, or several cycles of chemotherapy with high-dose cytarabine.

 Nonintensive induction therapy includes less-aggressive treatments, such as hypomethylating agents such as azacitidine and decitabine, or low-dose cytarabine (LDAC).

 However, some patients may not receive any antileukemic therapy, depending on their fitness.

 Although less-intensive therapy results in lower rates of treatment-related mortality, median survival time is much lower with these regimens, about 6 to 10 months.

In patients who are too frail to be considered for nonintensive therapy, supportive care is offered.

 This includes management and prophylaxis of hematologic abnormalities and infections with antimicrobial agents, growth factors, hydroxyurea, and transfusions.

For medically fit and unfit patients, targeted therapy may be added to both consolidation and induction therapy based on patient-specific cancer characteristics (Figure 4

Research emphasis is primarily targeted toward improving outcomes, specifically in elderly patients. A high incidence and poor prognosis of AML exists within this population. A 75-year-old patient recently diagnosed with AML has a 20% chance of 1-year survival.

AML in an older adult is associated with poor outcomes because of higher rates of unfavorable cytogenetic abnormalities, cellular mutations that develop resistance to first-line chemotherapy, and a higher prevalence of secondary AML.

 Resistance can manifest as a cellular mutation capable of altering the drug binding site or modifying the apoptotic abilities of the drug.

In August 2020, the American Society of Hematology (ASH) released updated guidelines for the management of AML in older patients.

 Recent literature supports guideline recommendations encouraging antileukemic therapy over supportive treatment and more-intensive therapy over less-intensive treatment whenever possible.

 Overall, the potential benefit of overtreating the elderly population outweighs the risk of toxicities when considering survival rates.

The ASH panel recommends against combination therapy with the following exceptions: LDAC in combination with glasdegib or hypomethylating agents in combination with venetoclax.

 The data supporting these combinations are derived from small and recent phase 2 trials, so the panel states this as a weak recommendation until stronger analyses are published.

 Glasdegib and venetoclax are 2 of 8 agents that the FDA approved between 2017 and 2019 for the treatment of AML.

 The surge in drug development is the result of improved understanding of the chemotherapy resistance mechanisms, as well as apoptotic machinery elucidation.

Venetoclax inhibits an antiapoptotic protein family commonly overexpressed in AML, B-cell lymphoma 2 (BCL2), which has been associated with chemotherapy resistance and poor survival.

 The recently published VIALE-C trial found that the addition of venetoclax to nonintensive azacitidine induction therapy versus azacitidine monotherapy prolonged survival (14.7 months versus 9.6 months) and increased the likelihood of remission in patients with untreated AML.

Glasdegib is a potent and selective oral inhibitor of the Hedgehog signaling pathway, which is often overactive in AML.

 This pathway aids in the development and proliferation of leukemic stem cells, which play a major role in development of resistance to chemotherapy and disease relapse.

 A phase 2 trial (NCT01546038) published in 2018 found that the combination of glasdegib and LDAC significantly improved overall survival and response rates compared with LDAC alone.

 These results were consistent across various combinations of genetic mutations, suggesting the potential for a more universal application of this drug combination.11 A larger phase 3 trial is under way.

The AML genomic landscape plays a vital role in patient prognosis and treatment decisions. Numerous therapeutic options for AML have become available within the past 3 years, but continued research is needed to determine their place in therapy and introduce more-standardized treatment approaches. The risk versus benefit of more-intense treatment options must be heavily weighted in the frail and medically unfit AML population. The rapid rate of chemotherapy resistance and disease relapse in compromised patients makes it imperative to continue research initiatives to develop optimal and safe therapeutic approaches within this population.

GLENN SCHULMAN, PHARMD, MS, BCPS, BCACP, BCGP, BCIDP,

 are clinical pharmacists in Pensacola, Florida. 

 is a PharmD candidate at Belmont University in Nashville, Tennessee.

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Acute myeloid leukemia. Leukemia & Lymphoma Society. Accessed October 28, 2020. http://www.lls.org/leukemia/acute-myeloid-leukemia

Arber DA, Borowitz MJ, Cessna M, et al. Initial diagnostic workup of acute leukemia: guideline from the College of American Pathologists and the American Society of Hematology. 

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Yu J, Li Y, Zhang D, Wan D, Jiang Z, Jiang Z. Clinical implications of recurrent gene mutations in acute myeloid leukemia. 

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Röllig C, Kramer M, Schliemann C, et al. Does time from diagnosis to treatment affect the prognosis of patients with newly diagnosed acute myeloid leukemia? 

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Rao AV. Fitness in the elderly: how to make decisions regarding acute myeloid leukemia induction. 

gram. 2016(1):339-347.doi:10.1182/asheducation-2016.1.339

Sekeres MA, Guyatt G, Abel G, et al. American Society of Hematology 2020 guidelines for treating newly diagnosed acute myeloid leukemia in older adults. 

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Short NJ, Konopleva M, Kadia TM, et al. Advances in the treatment of acute myeloid leukemia: new drugs and new challenges. 

 2020;10:506-25. doi:10.1158/2159-8290.CD-19-1011

DiNardo CD, Jonas BA, Pullarkat V, et al. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. 

. 2020;383:617-629.doi:10.1056/NEJMoa2012971

Cortes JE, HeidelFH, Hellmann A, et al. Randomized comparison of low dose cytarabine with or without glasdegib in patients with newly diagnosed acute myeloid leukemia or high-risk myelodysplastic syndrome. 

. 2019;33(2):379-389. doi:10.1038/s41375-018-0312-9

Numerous therapeutic options are available for acute myeloid leukemia, but more research is needed to determine how best to use them.

AML Genomic Landscape Plays Key Role in Treatment

The National Cancer Institute estimates that by the end of 2020, there will be 73,750 new cases of kidney and renal pelvis cancer, representing 4.1% of all new  cancer diagnoses, with 14,830 new deaths.

The 5-year relative survival rate has slowly increased each year for the past 4 decades. Figure 11 shows the rates for relative 5-year survival by stage at diagnosis.

In addition to the risk factors listed in Figure 21-4, unmodifiable factors, such as age, gender, and race are also associated with an increased risk for renal cancer. African Americans, men, and older individuals have a higher risk.

 Older patients also have a higher rate of death from kidney and renal pelvis cancer.

Renal carcinomas can present in many ways, with the most common form being renal cell carcinoma (RCC), representing about 85% of diagnoses. RCC develops in the epithelium of the proximal renal tubules and can occur in a hereditary or nonhereditary manner. Regardless of the disease’s etiology, a structural alteration in the short arm of chromosome 3 is responsible for the development of cancer.

 Common hereditary syndromes are also summarized in Figure 2.

The National Comprehensive Cancer Network (NCCN) does not offer screening recommendations for RCC. For patients presenting with symptoms or those with a family history of RCC, clinicians can perform an abdominal CT scan, as well as a renal ultrasound, for diagnosis.

 Table 1 outlines common symptoms of RCC.

Patients can  also undergo other tests, such as a bone scan, chest x-ray, cranial MRI, and needle biopsy to aid in tumor staging.

Determining histology subtype is important for choosing an appropriate systemic therapy regimen, as well as for establishing a risk group using a prognostic factor model discussed in the guidelines.

The role of systemic therapy is primarily in stage IV, or metastatic disease, according to the NCCN guidelines. For patients with stage I through III RCC, the preferred treatment is a partial or radical nephrectomy. For patients with stage IV RCC, the recommended algorithm is outlined in Online Figure 3.

The first-line preferred systemic therapies are summarized in Online Table 2.5 For those with clear cell histology, clinicians determine treatment based on the patient’s risk group, either favorable risk or intermediate or poor risk.

Recently, investigators reported significant results in the setting of metastatic or advanced clear-cell RCC in the CheckMate 9ER phase 3 trial (NCT03141177). The trial compared cabozantinib plus nivolumab to sunitinib, an active comparator. The investigators looked at objective response rate (ORR), overall survival (OS), progression-free survival (PFS), and safety, finding that all these measures were statistically significant favoring cabozantinib plus nivolumab versus sunitinib with an acceptable safety profile. The ORR and PFS were both doubled in the intervention group versus sunitinib. The effects on OS and PFS were consistent among each risk group. The follow-up time for this trial was 18 months, which may not be long enough to determine the lasting effects of this regimen, but the results have been promising thus far.

The methodology of treating RCC has evolved rapidly in the past few years, leaning more toward combination therapies and less toward monotherapy, particularly in the setting of metastatic clear-cell RCC.

 A vast number of clinical trials are continuing, some of which are outlined in Online Table 3. Investigators anticipate that results will be released in the next few years, which could greatly affect how clinicians treat metastatic RCC.

In addition to newer drug therapies, there has been an increasing interest surrounding the role of genetic biomarkers in predicting a patient’s response to targeted therapy. A recent study presented at the European Society for Medical Oncology Virtual Congress 2020 analyzed the relationship between the expression of effector T cell and angiogenesis signatures and response to treatment with nivolumab in patients with metastatic RCC. The authors recognized that patients with a high-effector T cell and low angiogenesis expression had a higher response rate and median PFS, whereas patients with low-effector T cell and low angiogenesis expression had a poor response rate. They also recognized that patients with low numbers of stromal cells had a higher response rate and longer median PFS.

RCC can often be cured if it is diagnosed and treated surgically while still confined to the kidney and the immediately surrounding tissue. The probability of a cure is commensurate with the degree or stage of tumor dissemination. Even when regional lymphatics or blood vessels are involved, a high percentage of patients can attain prolonged survival and a probable cure. However, once the tumor has metastasized to stage IV status, surgical cure is improbable and reliance is placed upon pharmacological agents, such as immunological and targeted therapies, but disease-free survival is poor. Because most patients receive their diagnosis when the tumor is still relatively localized and amenable to surgical resection, about three-fourths of all patients with RCC survive for 5 years. As with most solid malignancies, early surgical intervention confers the best benefit.

Early diagnosis, surgery while cancer is confined to kidney are key, but pharmacological agents are used for Stage IV.