Preventing Invasive Fungal Infections in Hematologic Patients No abstract available
Invasive fungal infections (IFIs) are common, preventable infections in those oncology patients who receive hematopoietic stem cell transplantation (HSCT) or therapies for hematologic malignancies. The highest risk periods of neutropenia and graft-versus-host disease (GVHD) treatment, host immune function, prevention strategies, treatment modalities, donor types, and transplant complications can predispose patients to invasive infection with Candida and Aspergillus species (Curr Opin Oncol 2010;22(2):138-142). Both of these infections portend high morbidity and mortality, with attributable mortality at approximately 40 percent, even with new therapeutic drugs (BMC Infect Dis 2013;13;29; Emerg Infect Dis 2014;20(7):1149-1155; Med Mycol 2018;56(2):186-196; Crit Care 2015;19:7).
Decades of translational and clinical study have led to the currently accepted paradigms for preventing fungal infections. Unfortunately, gaps still exist due to difficulties in administering drugs and implementing prevention paradigms, as well as increasing antifungal resistance. The focus here is on the gaps and challenges in current prevention strategies, including drug-drug interactions and toxicities, as well as a discussion on new drugs in development that may have a potential role in preventing IFIs in these vulnerable patients.
Current Prevention Challenges
Currently, there are a handful of drugs that are used to prevent and treat IFIs among oncology patients. The first azole shown to prevent Candida infections in randomized trials (N Engl J Med 1992;326(13): 845-851; J Infect Dis1995;171(6):1545-1552), fluconazole, continues to be frequently used for prevention. While the strengths of this drug include tolerability, flexibility in oral and IV formulations, predictable drug interactions, and generic costs, the largest gap is its spectrum of activity, which misses all molds.
While early randomized trials showed some activity for itraconazole in preventing molds as well as yeasts, this agent is poorly tolerated and in some settings has been associated with poor outcomes (Blood 2004;103(4):1527-1533; Clin Microbiol Infect 2011;17(Suppl 2):1-24; Ann Intern Med 1993;118(7):495-503). The newer azoles, posaconazole and voriconazole, have been shown to have activity in preventing both Candida and Aspergillus in randomized trials. However, when used in this setting, they have variable degrees of limitations associated with bioavailability, toxicities, and drug interactions.
Other antifungal agents that we use occasionally are echinocandins and liposomal amphotericin. Both have good activity profiles against yeasts. However, the currently available echinocandins suffer from inconsistent activity against molds, with increasing reports of breakthrough infection (Clin Microbiol Infect 2010;16(8):1191-1196; J Infect 2012;64(4):424-429). Lack of oral formulations and requirements for daily infusions have limited the enthusiasm and use of these drugs as long-term prophylactic agents. Other toxicities, especially nephrotoxicities, limit the use of long-term amphotericin formulations for prevention. Thus, the current guidelines committees have supported azole drugs (fluconazole, posaconazole, and voriconazole) for prophylaxis against IFIs, with variable strengths given risks for mold infections and tolerability (Ann Hematol 2018;97(2):197-207; Clin Microbiol Infect 2011;17(Suppl 2):1-24).
Our approach to choosing prophylaxis is often iterative, with drugs chosen based on risks and ability to administer agents in a complex therapeutic setting. The azole agents are preferred largely because of their ease of administration—all can be given orally. However, these drugs are often accompanied by toxicities, including hepatotoxicity, visual disturbances, neurotoxicity, prolongation of QT interval, as well as nausea, headaches, dyspepsia, and dysgeusia. Furthermore, when these drugs are combined with chemotherapeutic or immunosuppressive (IS) agents, toxicities can be amplified.
Some chemotherapeutic or IS drugs directly interact with the azoles, adversely impacting the metabolism of one or both drugs. Azole antifungals are not only a substrate for and inhibitors of cytochrome P450 (CYP450) enzymes, but they are also inhibitors of various membrane transporters (an example includes P-glycoprotein). Activation or inhibition of CYP450 enzymes has the potential to modify the pharmacokinetic profile of the drugs involved. This can result in either overdosing with subsequent toxicity or underdosing with subtherapeutic levels and consequent lack of efficacy (Clin Infect Dis 2009;48(10):1441-1458).
The anticipation of drug-drug interactions with azoles and chemotherapeutic or immunosuppressive agents can prevent toxicities while achieving maximal therapeutic effects when treating malignancy and IFIs concurrently. Therapeutic drug monitoring of either the azole or the chemotherapeutic/IS drug(s) (if such assays are available) is a means by which to identify the extent of interactions and help resolve real and/or potential problems by guiding dosing to optimize therapy and prevent subtherapeutic or supratherapeutic levels (Clin Infect Dis 2009;48(10):1441-1458).
The risk of pharmacokinetic interactions between azoles and other drug classes can vary depending on the drugs involved. Thus, not all azoles are created equal in their propensity to induce or inhibit CYP450 enzymes or inhibit membrane transporters. Many of the interactions encountered between azoles and chemotherapeutic or IS agents often render it impossible to use the azoles, requiring alternatives, such as echinocandins.
The echinocandins, however, are administered intravenously daily, thus possibly posing a barrier to outpatient administration. Although echinocandins seem to have a much safer toxicity profile than azoles, and less drug-drug interactions with currently available chemotherapeutic and IS drugs, microbial resistance is growing. This is thought to be due in part to low doses given, poor penetration into various tissue compartments, and ultimately therapeutic failure (Clin Microbiol Rev 2014;27(1):68-88).
New alternative drugs are necessary to prevent both Candida and Aspergillus. Attractive features would include a more convenient dosing schedule with a broad spectrum of activity against both molds and yeasts, and a high barrier to resistance. An ideal agent would also have minimized toxicities and lack interaction with chemotherapeutic or IS agents, especially those with complex interactions with CYP450 enzymes.
Pneumocystis Species
Pneumocystis pneumonia (PCP) is a fungal infection that is routinely treated prophylactically in those undergoing HSCT and, in some instances, amongst those receiving chemotherapy or various IS drugs. Drugs such as trimethroprim/sulfamethoxazole (TMP/SMX), dapsone, atovaquone, or pentamidine (inhaled or IV) are frequently used as prophylaxis. These agents, however, are accompanied by multiple toxicities that often make them difficult to take, including fever, rash (often resembling cutaneous GVHD), neutropenia, pancytopenia, nephrotoxicity, hepatitis, hyperkalemia, methemoglobinemia, rash, bronchospasm (with the use of inhaled pentamidine), hemolytic anemia in those who are glucose-6-phosphate dehydrogenase (G6PD) deficient, and anaphylaxis. Though dapsone, atovaquone, and pentamidine are often used in those intolerant of TMP/SMX (the prophylactic agent of choice), we have seen breakthrough pulmonary and extra-pulmonary PCP develop while patients are on these drugs (J Antimicrob Chemother2016;71(9):2397-2404).
Interestingly, PCP is an infection with a “non-classic,” inferred susceptibility to echinocandins. The echinocandins exhibit in vitro activity against the cyst forms of PCP. This is attributed to these drugs' ability to inhibit the synthesis of beta-1,3-D-glucan, which is in abundance in the cyst form of PCP but not the trophic forms (PLoS One 2010;5(1):e8524).
Emerging Antifungal Approaches
Rezafungin is a novel antifungal echinocandin being investigated in phase III studies to evaluate its role as a treatment for candidemia and invasive candidiasis, as well as its utility as a prophylactic agent against IFIs (J Glob Antimicrob Resist 2018;14;58-64). While current echinocandins are known to be excellent candidal drugs, they have significant limitations, as previously mentioned.
Rezafungin is a once-weekly, IV antifungal with a unique pharmacokinetics profile due to its long half-life (approximately 130 hours), allowing for a more convenient dosing schedule and for use on an outpatient basis. Furthermore, phase I studies have demonstrated that the drug can be given at higher doses than most echinocandins without the toxicities associated with other echinocandins at lower doses (J Glob Antimicrob Resist 2018;14;58-64).
Rezafungin is an analogue of anidulafungin, but with structural differences that lead to increased chemical stability and lack of reactive intermediates that may potentially contribute to toxicity (J Glob Antimicrob Resist 2018;14;58-64). It has a broad spectrum of activity with demonstrated potent in vivo activity against Candida species, Aspergillus species, Pneumocystis, and other less commonly encountered but clinically relevant molds. It is unique in that it has activity against PCP—cyst and trophic forms—making it an effective prophylactic agent against this microbe (Blood2016;128:339).
Because of its spectrum of activity and its unique pharmacokinetics, rezafungin could serve as a once-weekly replacement of azoles and TMP/SMX as prophylaxis, generating improvements in drug compliance, drug interactions, and toxicities. Overall, the drug has the potential to be a promising new approach for IFI prophylaxis amongst those with HSCT and hematologic malignancies.
Conclusion
IFIs carry significant morbidity and mortality amongst HSCT recipients and those with hematologic malignancies. Our current prevention strategies are good, but not excellent. There are gaps that remain, making these patient populations vulnerable to IFIs. Furthermore, with the development of newer chemotherapeutic agents, we are observing numerous drug-drug interactions with the standard-of-care azoles. Additionally, the antifungal agents utilized most often are not benign drugs and are often associated with side effects and toxicities that need to be balanced by the prophylactic benefits that the drugs offer.
While we are familiar with a host of prophylactic drugs, there are newer, novel drugs on the horizon that offer potential advantages to our patients. These drugs, if shown to be effective and tolerable, could displace our current azole and TMP/SMX paradigm for preventing a broad range of fungi that present dangerous health risks in hematologic and transplant patients.
SEEMA ARUN MEHTA, MD, MS, is Clinical Associate Director of Transplant and Oncology Infectious Diseases at Johns Hopkins University School of Medicine, Baltimore.
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Tumor Mutation Burden & Checkpoint Inhibitors in MSI-H Colorectal Cancer No abstract available
Mismatch repair protein deficiency (MMRD) or microsatellite instability-high (MSI-H) occurs in about 5 percent of metastatic colorectal cancers while higher frequencies are described in patients with earlier stages of disease (J Gastrointest Oncol 2018;9(4):610-617, Science 2017;357(6349):409-413). The drop in frequency in MSI-H cancers across increasing stages of colorectal cancer reflects the inherent good prognosis of earlier stage MSI-H, which is attributed to a robust tumor immune response.
MSI-H is characterized by increased tumor mutation, increased frameshift mutations, and insertion-deletion (indel) alterations. This leads to an increased incidence of neoantigen formation, which leads to a robust anti-tumor immune response. The recognition of an immune-overdrive status in MSI-H tumors, characterized by increased intratumor cytotoxic T-cell infiltration (CD8+) and countered by increased intratumor checkpoint expression (PD-L1, CTLA-4, etc.) (Cancer Discov 2015;5(1):43-51) led to the investigation of multiple checkpoint inhibitors in this group of patients.
Research Findings
A pivotal study evaluated pembrolizumab monotherapy in three different patient cohorts: MSI-H metastatic colorectal cancer, microsatellite-stable (MSS) colorectal cancer, and MSI-H non-colorectal cancers (N Engl J Med2015;372(26):2509-2520). Responses were limited to the MSI-H cohorts, with 4/10 and 5/10 of the evaluable MSI-H colorectal cancer patients experiencing a partial response or stable, while only two of 11 MSS patients experienced stable disease (SD) as best response. An updated outcome on the KEYNOTE-016 trial confirmed a 52 percent response rate (RR) and 30 percent SD in MSI-H colorectal cancer compared to 54 percent RR and 18 percent SD in MSI-H non-colorectal cancers (Science 2017;357(6349):409-413).
KEYNOTE-164/158 investigated a similar treatment design and reported 28 percent RR and 23 percent SD in MSI-H colorectal cancers (KEYNOTE-162) and 37 percent RR and 21 percent SD in MSI-H non-colorectal cancers (KEYNOTE-158) (Ann Oncol 2017;28(suppl_5):v122-v141). Nivolumab monotherapy was examined on CheckMate-142 clinical trial and was associated as monotherapy with a RR of 33 percent and a SD rate of 31 percent (Lancet Oncol2017;18(9):1182-1191).
Collectively, these studies suggest that PD-1 blockage is associated with response rates of 28-52 percent and disease control rates of 51-82 percent. Similarly, significant differences in outcome have been reported in terms of progression-free survival across these studies with 43 percent of patients being progression-free at 9 months on KEYNOTE-164 versus 59 percent at 24 months on KEYNOTE-016 versus 50 percent at 12 months on CheckMate-142. Of note, most patients achieving disease control at 1 year maintained protracted subsequent disease control.
While the above results confirm the considerable activity with PD-1 inhibitors in MSI-H colorectal cancer, they also point to the heterogeneity of the MSI-H population in terms of response and the durability of disease control. Indeed, approximately 30 percent of patients with MSI-H tumors will have progressive disease as a best response to PD-1 inhibitors.
Therefore, the identification of additional biomarkers of response may help further refine which MSI-H patients should receive anti-PD1 therapy, especially when considering the integration of checkpoint inhibitors early on in the course of disease treatment. While PD-L1 expression has been shown to predict for response to PD-1 inhibitors in a variety of solid tumors, it has failed to predict for response to PD-1 inhibitors in MSI-H colorectal cancer (Lancet Oncol 2017;18(9):1182-1191; J Clin Oncol 2018;36(8):773-779).
Tumor Mutation Burden
Tumor mutation burden (TMB) has been recently validated as a predictive biomarker of response to checkpoint inhibitors in melanoma, NSCLC, bladder cancer, and a combination of solid tumors treated with PD-1/PD-L1 inhibitors (Ann Oncol2019;30(1):44-56). However, the relevance of TMB as a biomarker of outcome in patients with MSI-H colorectal cancer has not been assessed, especially the fact that most of these patients exhibit a high TMB that exceeds 20.
To test the impact of TMB on checkpoint inhibitor response in MSI-H colorectal cancers, we elected to focus our study on patients' MSI and TMB testing by a CLIA-certified NGS panel (Foundation One) (Ann Oncol 2019; doi:10.1093/annonc/mdz134). Enrolled patients received a PD-1 or PD-L1 inhibitor, either alone or in combination with a CTLA-4 inhibitor. Patients were identified from five cancer centers (City of Hope, The Angeles Clinic, Comprehensive Cancer Centers of Nevada, University of California-Davis, and University of Chicago). A total of 22 patients fit the above eligibility.
Twenty patients were treated with a PD-1 inhibitor (19 pembrolizumab and one nivolumab) and two received combination immunotherapy (nivolumab + ipilimumab and durvalumab + tremelimumab). Similar to prior published data, we did not see a correlation between RAS/BRAF status, primary tumor site, site of metastatic disease, and outcome. However, a significant difference in TMB was noted between responders and non-responders.
Patients with an objective response had a median TMB of 54 mutations/Mb compared with a TMB of 29 mutations/Mb in non-responders (p < 0.001). Similarly, a higher TMB was predictive for a better likelihood of disease control, with an optimal cut-point between 37 and 41 mutations/Mb. The median PFS for patients with a TMB > 41 was not reached at a median follow-up of 18 months. In contrast, the median PFS of patients with a TMB < 37 was only 2 months. Patients with higher TMB experienced a superior overall survival in comparison to the lower TMB group.
Through this study, we showed that TMB is predictive for a benefit from checkpoint inhibitors in patients with MSI-H colorectal (Ann Oncol 2019; doi:10.1093/annonc/mdz134). The cut-point identified in this study lies between 37 and 41 mutations/Mb. It is interesting that 35 percent of patients with MSI-H cancer lie below this cut-point based on a large population database analysis. This is, coincidentally, the same percentage of patients who derive little to no benefit from PD-1 targeting.
We recognize that our study population is limited in number; therefore, there is a need to validate these findings in another, larger data set. However, our results suggest that we should pause on the integration of checkpoint inhibitors in the first- or second-line settings in patients with MSI-H tumors with lower TMB (< 37 mutations/Mb).
It is important to note that, while our findings suggest that lower TMB patients are less likely to respond to PD-1 inhibitors, they do not exclude the possibility of response in this population (2/9 patients who responded had a TMB of < 37 mutations/Mb). Our results add additional confidence to the integration of checkpoint inhibitors in earlier lines of treatment in the patient population with higher TMB (>41 mutations/Mb).
In addition, we note that more than 90 percent of our patients were treated with anti-PD1 monotherapy and, therefore, our results may have limited applications on the combination of nivolumab plus ipilumumab, a combination associated with a disease control rate that exceeds 80 percent and with a 2-year progression-free survival rate of 50 percent (J Clin Oncol 2018;36(8):773-779). Whether a different TMB cut-point would apply in such settings remains to be determined.
MARWAN FAKIH, MD, is Professor in the Department of Medical Oncology and Therapeutics Research, Medical Director in the Judy and Bernard Briskin Center for Clinical Research, and Section Head of GI Medical Oncology at City of Hope, Duarte, Calif. He also holds the Judy and Bernard Briskin Distinguished Directorship in Clinical Research at the cancer center.
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| SIRT1 Plays Key Role in Chronic Myeloid Leukemia No abstract available Patients with chronic myeloid leukemia (CML) can be treated with tyrosine kinase inhibitors. While these effective drugs lead to deep remission and prolonged survival, primitive leukemia stem cells resist elimination during the remission and persist as a major barrier to cure. As a result, the majority of patients with CML require indefinite inhibitor treatment to prevent disease recurrence. They also face risks of noncompliance, toxicity, and financial burden. Development of effective therapeutic strategies to improve patient outcomes for CML and related cancers depends on identifying the key mechanisms that contribute to the persistence of these leukemic stem cells. In a study published in the Journal of Clinical Investigation, Ajay Abraham, PhD, Shaowei Qiu, MD, Ravi Bhatia, MD, and colleagues at the University of Alabama at Birmingham (UAB) show how the stress-responsive protein SIRT1 plays important roles in maintaining the regenerative potential of CML leukemic stem cells and promoting leukemia development in CML (2019; https://doi.org/10.1172/JCI127080). “Our studies provide a conceptual advance and new biological insights regarding the activity of SIRT1 and its role in CML leukemic stem cells,” said senior author Bhatia. At UAB, Bhatia is Professor of Medicine, Director of the Division of Hematology and Oncology, and Interim Director of the O'Neal Comprehensive Cancer Center. In 2012, Bhatia and colleagues reported that SIRT1 was overexpressed in CML leukemic stem cells compared to normal hematopoietic stem cells, and this overexpression contributed to CML leukemic stem cell maintenance and resistance to tyrosine kinase inhibitors. However, the underlying mechanisms were not known. To study those mechanisms, the UAB researchers used a CML mouse model that also has a genetic deletion of SIRT1. This allowed them to compare wild-type leukemic stem cells with SIRT1-deletion leukemic stem cells. Back to Top | Article Outline Study Details Researchers found that SIRT1 plays an important role to enhance oxidative phosphorylation by the mitochondria in leukemic stem cells. Furthermore, the researchers found that this increased mitochondrial metabolism in leukemic stem cells did not depend on activity of the mutated kinase that transforms the normally quiescent hematopoietic stem cells into leukemic stem cells. Mitochondria are the powerhouses of the cell, supplying nearly all the energy a cell normally needs. Oxidative phosphorylation uses oxygen in producing energy; non-leukemic hematopoietic stem cells—the non-cancerous blood-forming cells of the body, from healthy mice or humans—produce energy by an alternative metabolism called glycolysis. Treatment with tyrosine kinase inhibitors is known to suppress leukemic hematopoiesis. When SIRT1-deleted mice were treated with tyrosine kinase inhibitors, the UAB researchers found an even greater suppression of leukemic hematopoiesis. The SIRT1 knock-out also impaired development of CML in the mouse model. Compared with the CML mice without SIRT1 knock-out, the researchers saw significant delays in developing increased numbers of leukocytes and neutrophils, and delayed enlargement of the spleen and time of death. The deletion also reversed redistribution of CML stem cells from the bone marrow to the spleen. SIRT1 is a deacetylase enzyme, known to deacetylate and activate the transcriptional co-activator PGC-1-alpha. This enhances mitochondrial DNA replication and gene expression, and it promotes mitochondrial activity. Bhatia and colleagues showed that PGC-1-alpha inhibitors were able to significantly reduce mitochondrial oxygen consumption, a sign of oxidative phosphorylation. Thus, the inhibitors acted similarly to the SIRT1 deletion. This finding supports an important role for PGC-1-alpha in the regulation of mitochondrial metabolism in CML stem and progenitor cells. The researchers also found that a chemical inhibitor of SIRT1 was able to reduce oxidative phosphorylation in both mouse and human CML leukemic stem cells. Interestingly, the SIRT1 deletion in normal, non-leukemic blood-forming stem cells did not inhibit steady-state normal hematopoiesis in the mouse model. Bhatia noted that development of effective approaches to target the persistent CML leukemic stem cells that resist tyrosine kinase-inhibitor treatment—while not causing toxicity to normal hematopoietic stem cells—has been a challenge. Bhatia noted the impact of this study extends to other hematological malignancies, including acute myeloid leukemia, myelodysplastic syndromes, and myeloproliferative neoplasms. “Our research reveals new knowledge and concepts regarding the role of SIRT1 in metabolic regulation of hematopoietic stem cell and leukemic stem cell maintenance, growth, and resistance,” Bhatia said. “This raises the possibility of developing improved strategies to target kinase-independent metabolic alterations.” |
| Walking Speed & Future Clinical Outcomes for Older Patients With Blood Cancers No abstract available Researchers at Dana-Farber Cancer Institute and the VA Boston Healthcare System have uncovered a new vital sign for gauging survival and likelihood of having an unplanned hospitalization in older patients with blood cancers: the speed at which they can walk. In a new study, researchers report that for every 0.1 meter per second decrease in how fast patients walk 4 meters (about 13 feet), the risk of dying, unexpectedly going to the hospital, or using the emergency room increased by 22 percent, 33 percent, and 34 percent, respectively (Blood 2019; https://doi.org/10.1182/blood.2019000758). The association was strongest in patients with non-Hodgkin lymphoma. “The slower someone walks, the higher their risk of problems,” said the study's senior author, Jane A. Driver, MD, MPH, Co-Director of the Older Adult Hematologic Malignancy (OHM) Program at Dana-Farber and Associate Director of the Geriatric Research Education and Clinical Center at VA Boston Healthcare System. Measuring gait speed not only helps identify individuals who are frail and may have worse long-term outcomes, but it also can indicate those who are in better-than-expected shape based on their age. Researchers say the study results support efforts to integrate gait speed as a routine part of medical assessments for older patients with blood cancer, and that it should be measured over time to guide treatment plans. “There is an unmet need for brief screening tests for frailty that can easily fit into clinic workflow and predict important clinical outcomes. This test can be done in less than a minute and takes no longer than measuring blood pressure or other vital signs,” said Driver. “Based on our findings, it is as good as other commonly used methods which take considerably more time and resources and may not be practical for many oncology clinics.” Back to Top | Article Outline Study Details The new study enrolled 448 adults ages 75 years and older who had hematologic cancers. Participants were 79.7 years old on average and completed several screenings for cognition, frailty, gait, and grip strength. Gait speed was measured using the National Institutes of Health 4-meter gait speed test. Patients were asked to walk at a normal pace for 4 meters and their speed was recorded in meters per second using a stopwatch. The association between slower walking speed and poorer outcomes persisted even after adjusting for cancer type and aggressiveness, patient age and other demographic factors, as well as traditional measures of frailty and functional status. Gait speed remained an independent predictor of death even after accounting for standard measures of physical health. Patients whose performance status—their general well-being and quality of life—was rated as very good or excellent by their physician were stratified into three groups by gait speed—those at risk or frail, pre-frail, or robust. Of the 314 patients in this group, nearly 20 percent had an unplanned hospital stay unrelated to elective or scheduled treatments, and 16.8 percent visited the emergency department. “Our study reveals that the current standard of care for functional assessment in oncology—performance status—is not sufficient for elders with blood cancers. Gait speed appears to be much better at differentiating those patients at highest risk for poor outcomes,” explained Gregory A. Abel, MD, MPH, Director of the OHM clinic. So much a part of everyday life that it's easily taken for granted, walking is a complex activity that involves multiple bodily systems, including the musculoskeletal, cardiovascular, and nervous systems, all of which must function properly together. Gait speed has been widely used as an assessment in rehabilitative and geriatric medicine. Measuring it doesn't require special equipment, is reasonably efficient, and has value even for patients who use a cane or a walker, Driver noted. |
Leadership: What Are We Looking for? No abstract availableMy organizational role has recently expanded. I am now leading our executive physician leadership and development program. It's a nice opportunity to put some of my leadership learnings into practice. One of my first tasks is to see if we can improve the search committee process. Search committees tend to depend on the views of the committee chair. The chair person filters candidates and is frequently heavy-handed about the direction of the committee based on his or her personal beliefs. As a result, there is not a lot of recruiting rigor around the process. We are taking a closer look at our entire search committee process with a goal of standardizing key issues such as: What qualities are we looking for? What type of experience is desirable? How familiar should the candidates be about fundamental leadership qualities? What evaluation tools and interview questions should we use to learn more about the candidate? At first glance, it might seem that this should be a straightforward process. Of course, it is not. An initial step is to identify which leadership jobs require a search committee in the first place. High-level academic appointments require a search committee, yet frequently, hospital physician leadership roles do not. Instead, individuals are simply appointed to those leadership roles. I'm not sure that makes sense. Defining which leadership roles in medicine require a search committee is a pretty important initial step. The next step might be to define the job. What do we expect leaders such as department chairs to actually do? Is their primary role to elevate the scientific presence of the department? To recruit great physicians? To mentor? How much operational responsibility will they have? Will they be responsible for financial results? With these questions in mind, we wonder if we should develop a job description for our physician leaders. Job descriptions are universal in 99 percent of human resource work yet tend to not exist in academic leadership jobs. The entire idea of creating a job description for physician leaders is surprisingly controversial. Many believe that it is unnecessary, largely because we have operated just fine without job descriptions. My personal opinion is that defining the roles and responsibilities of a chairman at any leadership level is a good idea and worthy of the time and effort required to do it. The next step might be to look at desired behavior. Our organization has in fact developed eight desired leadership behaviors: Inspire (earning the followership of others) Drive (achieving results through others) Influence (influencing others) Collaborate (produce stronger outcomes through partnerships) Set direction (provide vision) Account for results (generate value) Transform (drive change and innovation) Build talent (recruiting and talent development) One advantage to this approach is that each pillar can be tailored to the leadership job. For example, tactics to inspire others will vary, as the tools used by a CEO to influence will be broader than those used by a manager. Thematic in these leadership behaviors is the ability to work with others. This should always be examined as you interview candidates for leadership positions. Many will have excellent individual success, but it is important to determine if they can work in a team environment. What about previous job experience? Obviously this is important as you look for a physician leader. The candidate needs to be an expert in their field and be competent clinically, but what else? Increasingly, health care leadership jobs require a working knowledge of financial metrics. Can these be learned by a candidate, or should they bring such knowledge with them? Managing physicians is essential to succeed at health care leadership. How much leadership experience, especially experience managing physicians, is required? And how important is the national reputation of the candidate? For some search committees, this, coupled with federal grant funding, is the primary criteria to evaluate a prospective leadership candidate. But how much weight does a national reputation bare? At the very least, the leader needs to be able to attract top talent, and unquestionably having a big name can help them do so. This is certainly not a black and white issue. In my mind, previous job experience is important, but not as important as trying to define the essence of the potential leader. Assessing character traits is crucial when selecting a physician leader. These include integrity, cultural competency, emotional intelligence, passion, tenacity, motivation, empathy, cognitive ability, inclusion, innovation, teamwork, and many others. I had one person send me a list of character traits and included one entitled “cognitive load management.” I'll leave the definition of that one to each reader to decide. For me, these are all important. But what I am really looking for when I evaluate any prospective recruit is to try to learn about their fundamental core. What are they really like? What do they really care about? Therefore, I generally gravitate to personality traits when I am evaluating potential leaders. While all the traits listed above make sense, I would suggest that the following five are essential. First is emotional intelligence. A leader needs to be able to listen and see things from the perspective of others. Does the candidate create a safe environment for people to speak up and disagree? Are they able to acknowledge when they are wrong, or do not have the answer, or simply messed up? Can they accept honest feedback? Second is grit. Grit is a combination of passion and perseverance. Are they resilient? Do they get back up when they are knocked down and fail? Do they have a true passion for the work? I previously wrote about grit and referenced the work of Angela Duckworth (Oncology Times 2017;39(13):16,39). Third is serving others. Can they work in a team environment? Do they lead with empathy? As I referenced last month, work is about developing relationships. To do so, you not only need to be able to work as a team member (ideally as a giver), but also to support others and have their back (Oncology Times 2018;40(22):24,38). Can they demonstrate loyalty? Fourth is honesty. Do they tell the truth? Are they plain speaking, or are they masters at spin? Can they focus on issues that really matter, or do they avoid difficult topics and focus on the periphery? Do they create an environment of transparency? A corollary to honesty is self-awareness. Importantly, are they aware of unconscious bias and are they able to create and embrace diversity? Finally, and possibly most importantly, is courage. Can they have difficult conversations? Can they clearly state what lines cannot be crossed? Will they be able to be the only person in a room to speak up when necessary? Will the person as a leader consistently do the right thing, even when it's hard to do, and even when it may be challenging to do so politically? Winston Churchill said “Courage is rightly esteemed the first of human qualities... because it is the quality which guarantees all others.” Always try to find a leader who is courageous. As I dive into this work, I am keenly interested in learning more about evaluation tools that can assist one's ability to see if applicants possess these character traits. There is a whole world of talent evaluation that I am just beginning to learn about. I greatly enjoy it, as I enjoy learning about anything to do with leadership. People are complicated and, without question, evaluating candidates for leadership positions is far from easy or straightforward. But if you find somebody with high emotional intelligence who also has a fair amount of courage, you will probably be on the right track. BRIAN J. BOLWELL, MD, FACP, is Chairman of the Taussig Cancer Institute and Professor of Medicine at the Cleveland Clinic Lerner School of Medicine. Cleveland Clinic is a top 10 cancer hospital according to U.S. News & World Report. Brian J. Bolwell, MD, FACP Brian J. Bolwell, MD, FACP |
Forging Therapies for Pediatric Patients for Whom Progress Has Stalled No abstract availableRobbie G. Majzner, MD, is out to prove a point. And it's a potential game-changer. He wants to demonstrate that chimeric antigen receptor (CAR) T-cell therapy can be instrumental in knocking out pediatric solid tumors, just as it does in blood cancers. “We have only seen the beginning of CAR T-cell use. Right now it is reaching only blood cancer patients who are at the end of the therapeutic line and have already been through chemotherapy. When CAR T-cell therapy is pushed up closer to frontline use—in patients who have undergone less chemotherapy and less exposure to toxicities—it will be revolutionary. I firmly believe this will also work for solid tumors,” Majzner told Oncology Times resolutely. Successful use of CAR T cells in solid tumors is something that has been considered unlikely in some medical research circles. But pessimists take note: Majzner, an instructor in pediatric oncology at Stanford University School of Medicine, and colleagues have already had success in engineering immune cells able to attack a variety of solid tumors in mice. They published their optimistic findings in Clinical Cancer Research in January (2019 Apr 15;25(8):2560-2574). The study provided evidence that CAR T cells can target many types of pediatric solid tumors, including brain tumors. It's a hopeful development in light of the imperative need for better treatments for children with these cancers. “The prognosis for children with relapsed or metastatic solid tumors generally is dismal,” said Majzner. “There have been great strides for almost all other classes of patients; survival has increased with the advent of chemotherapy, radiation, and effective surgery. But in pediatric solid tumors and brain tumors, there have been few advancements for decades. Patients with metastatic and relapsed disease have been confronted by 40 years of limited success. We need to use new technologies to change outcomes and give those patients treatment options, and hope.” Majzner, lead author of the referenced study, and his team set about making CAR T cells for pediatric brain tumors and solid tumors, including tumors found in bone and muscle. Because these cancers do not carry the same surface markers as leukemia, the investigators had to look for another marker that the CAR T cells could target. Back to Top | Article Outline Search for a Target “You need very high amounts of the target on the tumor cells, and you may need the target to be on every cell in a tumor,” Majzner said. “We really struggled to identify a good target because, while we needed something that is highly expressed on the tumor, we also needed it to be hardly expressed at all on normal tissue.” Though traditionally it had been thought that the target could not be expressed at all in normal tissue, the investigators now believe CAR T cells may ignore the target when there are only low levels of expression. “We've seen that demonstrated in different clinical trials.” Majzner confirmed. “We think that as long as there is a big difference between tumor and normal tissue, CAR T cells will attack the target on the tumor but may not bother to attack the target on normal tissue. “Even in leukemia, we have disease that comes back. And in a clinical trial targeting CD22—the next-generation target after CD19—in patients who relapsed, their mechanism of relapse was with lower levels of CD22,” he detailed. “So the patient still has CAR T cells and has leukemia cells, but CARs could no longer attack the leukemia cells because they had lowered their amounts of CD22. The therapeutic window requires something that is screaming high on the tumor, and low enough on normal cells that the T cells won't attack it.” Researchers in the published study screened 388 pediatric tumor samples for expression of a surface marker called B7-H3, which prior studies suggested might be a good candidate, according to information provided by Stanford. “B7-H3 was found on 84 percent of the samples, and it was present at high levels in 70 percent of the samples. Many types of pediatric cancer were found to express high levels of B7-H3, including Ewing sarcoma, rhabdomyosarcoma, Wilms tumor, neuroblastoma, and medulloblastoma.” Back to Top | Article Outline Early Success in Mice According to the Stanford report, “The scientists then developed six types of CAR T cells to target B7-H3 and tested them in a dish. The type of B7-H3 CAR T cells that performed best was used for further studies. The researchers tested these B7-H3 CAR T cells against several xenograft models of pediatric cancer, in which human tumors were implanted in mice. In mice with osteosarcoma or Ewing sarcoma, B7-H3 CAR T cells eradicated the tumors. The treated mice lived significantly longer than animals that received a control treatment. “The tumor just goes away,” Majzner said. “It's very consistent. It happened in all the mice, and that's exciting.” Initial tumors were surgically removed from mice with osteosarcoma, and then the mice received B7-H3 CAR T cells to test whether the cells could treat cancer that had spread to their lungs. Again the CAR T cells worked. Additionally, when mice implanted with a pediatric brain tumor called medulloblastoma were treated, the injected B7-H3 CAR T cells crossed the blood-brain barrier and eradicated the tumors. Majzner and colleagues are planning a series of phase I clinical trials for the B7-H3 CAR T cells, starting with adult brain tumor patients. He cautioned that the treatment may leave behind a few rare cancer cells that do not carry B7-H3, opening the door to relapse. “We're already making combination CAR T cells that combine several targets for future clinical trials,” he said. Back to Top | Article Outline A Target for DIPG In another effort, Majzner and team discovered that disialoganglioside GD2, known in many cancers, was “screaming high” on a disease called diffuse intrinsic pontine glioma (DIPG), discussed in a spring paper published in Nature Medicine. “DIPG is basically the worst diagnosis in pediatric oncology. It is a high-grade glioma in the brain stem of children typically between 4 and 10 years old. It is completely unresectable,” said Majzner, noting there has never been a positive clinical trial showing clear clinical benefit, except radiation, which is just a temporizing measure. “We took GD2 CAR T cells and put them in mouse models of that disease and they worked very well. We did not see toxicity in our mice, even though GD2 is expressed on their normal tissue also. We think that it is because the level was lower than the threshold needed to activate the CAR T cells,” reprised Majzner. “So we are going to open a trial,” he said, admitting with caution, “however there are certainly other risks with toxicity when generating a massive immune response in the brain—especially the brain stem. Those risks include cytokine storm, harm to normal tissue, and the chance of pressure caused by inflammation in such a closed space. Too much pressure can cause major damage to the brain, including herniation that can result in death. We call it ‘neuroanatomic toxicity,’ a new type of toxicity that we have to watch for now. This will be done very carefully in the hospital under intensive care monitoring, but because the disease is so lethal we are willing to take these risks.” Back to Top | Article Outline A Look Back & Ahead Majzner, originally from Morris Plains, N.J., is married and father to young two children. Self-described as having been “a normal kid into sports, video games, and TV,” he parlayed an intellectual capacity for science and love of people into training at Harvard Medical School, a pediatric residency at Columbia University (also his undergraduate alma mater), followed by combined fellowships at the NCI/NIH and Johns Hopkins. He followed an esteemed mentor, Crystal Mackall, MD, who had earlier been the head of the pediatric oncology branch at the NIH, to Stanford where she founded a program on cell therapy. From there it has been full steam ahead with research efforts. “My goal is to make things in the laboratory and bring them to young patients with metastatic or relapsed solid tumors or brain tumors. Fortunately, the environment is ripe now to bring therapies rapidly to kids,” said Majzner optimistically. “Through a combination of advocacy by pediatric groups and effective legislation, there has been encouragement in the form of tax benefits for companies to bring therapies—especially for children—to fruition. Companies get a financial boost from it and there are markets for it—even in rare diseases. He added that in the case of the B7-H3 CAR T, “The fact that the same marker exists across so many tumor types increases the chance that it could serve as the basis for a commercially viable therapy.” He explained that, while only a few hundred children in the U.S. are afflicted with each tumor, together they form a larger patient population. “In pediatric oncology, we have stalled in our treatment of patients with metastatic and relapsed disease. I'm hopeful that cellular immunotherapy will be one of those new technologies that will change paradigms of care and improve outcomes,” said Majzner. “One therapy will not be the answer and the cure in itself, but just to start to move the needle for these patients who have had so little progress made on their behalf would be a wonderful thing.” Valerie Neff Newitt is a contributing writer. |
The Potential of Psilocybin Administration in Terminal Cancer Patients No abstract availablePsilocybin is a naturally occurring alkaloid found in more than 200 species of mushrooms. This compound, which was first isolated by the Swiss chemist Albert Hofman in 1959, is the active constituent of psychedelic mushrooms which are thought to have been utilized by humans since prehistoric times. In vivo, psilocybin is converted by the liver to psilocin, which is in fact the active pharmacological agent. Mechanistically, psilocin is thought to function as a partial agonist to several serotonin receptors. In the 1960s, several different groups were performing research using psychedelic agents; however, these studies were drastically affected by the U.S. government's classification of both psilocybin and psilocin as Schedule I drugs in October 1970, though increasingly limited research continued at the Maryland Psychiatric Research Center until 1977 . After a dormant period of 22 years, Roland Griffiths, PhD, and William Richards, PhD, successfully obtained federal and university clearances in 1999 to reinitiate human studies with psilocybin at the Johns Hopkins School of Medicine. In October 2018, the FDA granted Breakthrough Therapy designation to psilocybin for treatment-resistant depression. “I am hopeful that the FDA's designation of psilocybin as a breakthrough therapy for treatment-resistant depression will allow greater exploration of psychedelic therapy in other patient populations,” stated Richards, who is a psychologist in the Psychiatry Department of the Johns Hopkins University School of Medicine, Bayview Medical Center. Back to Top | Article Outline Phase II Study in Cancer Patients Many cancer patients experience psychological stress due to their diagnosis, which can result in clinically significant depression and/or anxiety. In a phase II clinical study (NCT00465595), supported by the Heffter Research Institute and performed at Johns Hopkins, researchers evaluated psilocybin in participants who had received a potentially life-threatening cancer diagnosis who also had anxiety and depressed mood (J Psychopharm 2016;30:1181-1197). In this double-blind study, patients were randomized in a 1:1 ratio to two different psilocybin dosing regimens: high dose (22 or 30 mg/70 kg) first followed by a low dose (1 or 3 mg/70 kg) or low dose first followed by a high dose. Initially, the high dose was 30 mg/70 kg; however, this was reduced to 22 mg/70 kg after two of the first three patients receiving the high dose were discontinued by the study personnel. The low dose of psilocybin was lowered to 1 mg/70 kg from 3 mg/70 kg after dosing 12 participants at the 3 mg level. This dose was altered because data from the same dose-effect study showed significant psilocybin effects at 5 mg/70 kg, and there was concern that 3 mg/70 kg might produce psychedelic effects in some research volunteers and not serve reliably as an inactive placebo. There were two primary therapeutic outcome measures which were utilized: the widely used GRID-HAMD-17 for depression and HAM-A assessed with the SIGH-A for anxiety. These measurements were taken at baseline, 5 weeks after each session, and at 6 months. In clinician-rated measures, clinical significance was noted for those responses with a 50 percent or greater decrease in measure with respect to baseline, while symptom remission was defined as a 50 percent or greater decrease in measure relative to baseline and a score of seven or less on the GRID-HAMD or HAM-A. This study, which included 51 patients (low/high–25; high/low–26), showed that, when administered in a psychologically supportive setting by properly trained personnel, a single dose of psilocybin can produce clinically significant responses, yielding substantial and enduring decreases in both depressed mood and anxiety. In addition, many of these cancer patients also reported increases in quality of life, as well as decreases in death anxiety. Enduring effects at 6 months were noted for the patients in assessments made by the patients, clinicians, and community observers. “At 6 months, the overall rate of clinical response for clinician-rated depression was 78 percent, while the figure for clinician-rated anxiety was 83 percent,” Richards noted. Two similar studies conducted at UCLA and New York University also reported positive findings. Back to Top | Article Outline Pharmacokinetics Study An open-label phase I dose-escalation study (NCT02163707) evaluated the safety and pharmacokinetics of psilocybin in 12 healthy adult participants in sequential doses of 0.3, 0.45, and 0.6 mg/kg (Clin Pharmacokinet 2017;56:1543-1554). In preparation for receiving psilocybin, eligible healthy adults had between 6 and 8 hours of counseling prior to receiving their dosing. Psilocybin administration was performed at monthly intervals in a controlled environment with 24-hour monitoring. In some participants, an extended elimination phase was noted; this was postulated to be due to the hydrolysis of a key psilocin metabolite. An important observation was the fact that variability in psilocin clearance was not predicted by body weight. Importantly, no serious adverse events were noted during the course of this study. Using the pharmacokinetic parameters obtained, a 25 mg oral dose of psilocybin would produce a drug exposure that approximated the 0.3 mg/kg oral dose utilized in this study. Importantly, no serious physical or psychological effects were noted during or up to 30 days after any dose, even at a dose of 0.6 mg/kg, which is roughly double that likely to be used in a clinical setting. Back to Top | Article Outline Future Studies A randomized, double-blind phase II clinical study (NCT03866174), which is being sponsored by the Usona Institute, is planned to include 80 participants from 21 to 65 years old who meet the criteria for major depressive disorder as defined in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). Stratification will be performed according to study site, with participants being randomized in a 1:1 ratio to a single oral dose of either 25 mg psilocybin or placebo (100 mg niacin). “The GMP quality psilocybin that will be used in this study was synthesized in a laboratory and does not come from mushrooms,” Richards noted. The primary outcome in this study is the difference in the centrally rated Montgomery-Asberg Depression Rating Scale (MADRS) total score between baseline and day 8 post-dose. This clinican-rated scale is designed to measure depression severity and to detect changes resulting from antidepressant therapy. The MADRS consists of 10 items, each being scored from 0 (if the item is not present or normal) to 6 (severe or continuous presence of the symptoms); with this scale, a higher score represents a more severe condition. Among the MADRS-derived secondary outcomes in this study were change in a centrally rated MADRS score from baseline to day 43 post-dose; sustained depressive symptom response, which is defined as a 50 percent or greater reduction from baseline in the centrally rated MADRS score at all post-dose assessments (at days 8, 15, 29, and 43 post-dose); and sustained depressive symptom remission, which is defined as a centrally rated MADRS score 10 or less at all post-dose assessments (at days 8, 15, 29, and 43 post-dose). An additional secondary outcome is the difference in the local investigator-assessed Sheehan Disability Scale (SDS) scores between baseline and day 43 post-dose. The SDS, which consists of three self-rated items, is designed to gauge the degree to which a patient's life is affected by psychiatric symptoms, including depression. The study is estimated to start in September 2019 and expected to be completed by February 2021. In another phase IIb clinical study (NCT03775200), the safety and efficacy of psilocybin is being evaluated in patients diagnosed with treatment-resistant depression. This trial, which is being conducted at treatment centers in North America and Europe, is planned to include 216 patients from 18 to 55 years of age. This study, which is quadruple-masked (patient, care provider, investigator, and outcomes assessor), includes three different treatment arms: low-dose psilocybin, medium-dose psilocybin, and high-dose psilocybin. The primary outcome measure in this trial is the MADRS, measured up to 12 weeks after dosing. Back to Top | Article Outline Discussion When asked about his background with psilocybin therapy for cancer patients, Richards replied, “I treated my first cancer patient with psilocybin in 1967. Over the years, the responses that I have noted in cancer patients who have received psilocybin-based psychedelic therapy combined with counseling have been remarkably transformative.” Richards explained the procedure for prospective candidates receiving psychedelic therapy. “First, potential candidates for this therapy are screened to determine if this therapy would be appropriate for them. Next, the patient undergoes a total of 6-8 hours of counseling prior to being dosed with psilocybin. This counseling is extremely important, as it develops a sense of trust with the staff that will be present with the patient when they are under the influence of psilocybin, as well as prepare the participants for what they may experience during the dosing session. “It is essential that the patient establish a significant level of trust with the individuals who will be with them during the action of psilocybin, as that will put them at ease and allow them to be more open to their unfolding inner experiences; the ability to be at ease and open to the alternative states of consciousness is of paramount importance for the patient to derive the most benefit from the agent. Many [bad experiences] are often the result of the patient trying to be in control of the psychedelic experiences instead of allowing them to follow their own course.” Regarding the results he has personally observed, Richards stated, “The outcomes observed in our studies have been significantly transformative, with many patients showing positive effects many months after a single dose of psilocybin. In many instances, not only does the terminal cancer patient lose their fear of death, but they will actually take on the role of a counselor and help those grieving in their families to cope with their impending mortality. “The main thing that I would like to convey to clinicians is that the transformation that psilocybin ushers forth, which is often several months in length, is drawn from the patient's long-term memory, not the result of any lingering compound present in their system or continuing drug administration. When asked why psilocybin was still listed as a Schedule I substance, Richards replied rhetorically, “Now that is a very profound question, isn't it? The University of Wisconsin study showed that, in healthy adults, no serious psychological or physical effects were observed up to 30 days after dosing, even at supratherapeutic levels. “In terms of abuse potential, psilocybin is absolutely not habit-forming, does not result in physical dependence even with repeated use, and in my opinion has much less risk for overuse than the opioids which are routinely prescribed for pain management. That having been said, it is crucial that when someone takes psilocybin that they are in a safe environment in the company of appropriately trained professionals who can ensure their personal safety.” Summarizing, Richards stated, “Now is a very exciting time to be doing psychedelic research using psilocybin; the FDA's granting of Breakthrough Therapy designation for psilocybin for treatment-resistant depression is a noteworthy milestone which may eventually lead to the removal of its Schedule I classification. “I am hopeful that the results that have been obtained for cancer patients with psilocybin therapy and counseling may serve as a springboard to apply this treatment to others in need.” Richard Simoneaux is a contributing writer. Back to Top | Article Outline Read This Article & Earn CME or CNE! Earn continuing education credit by completing a quiz about this article. You may read the article here or on our website, then complete the quiz, answering at least 70 percent of the questions correctly to earn credit. CONTINUING MEDICAL EDUCATION INFORMATION FOR PHYSICIANS Visit http://CME.LWW.com for more information about this educational offering and to complete the CME activity. This enduring material is available to physicians in all specialties. Lippincott Continuing Medical Education Institute, Inc., is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Lippincott Continuing Medical Education Institute, Inc., designates this enduring material for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity expires June 30, 2021. The cost of the exam is $10. The payment covers processing and certificate fees. PROVIDER ACCREDITATION INFORMATION FOR NURSES Lippincott Professional Development (LPD) will award 1.0 contact hour for this continuing nursing education activity. LPD is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's Commission on Accreditation. This activity is also provider approved by the California Board of Registered Nursing, Provider Number CEP 11749 for 1.0 contact hour. LWW is also an approved provider by the District of Columbia, Georgia, and Florida CE Broker #50-1223. Visit www.nursingcenter.com/ce for more information and to complete the CNE activity. Fee: $12.95. Deadline: June 4, 2021 For nurses who wish to take the test for CE contact hours, visit www.nursingcenter.com/ce. Learning Objectives for This Month's CME Activity: After participating in this CME/CNE activity, readers should be better able to: 1. Analyze outcomes observed in various studies that used psilocybin for patients with terminal cancer. 2.Outline the goals of future research that will treat terminal cancer patients with psilocybin. Disclosure: The author(s), faculty, staff, and planners, including spouses/partners (if any), in any position to control the content of this activity have disclosed that they have no financial relationships with, or financial interests in, any commercial companies relevant to this educational activity. |
When Should Women Have a First Breast Screening? Not Everyone Agrees No abstract availableThis spring, during a talk at the 2019 Summit on National & Global Cancer Health Disparities in Seattle, global cancer control expert and surgical oncologist Benjamin O. Anderson, MD, told an audience of colleagues, “If you are under 45, you are on your own.” Anderson, who is Chair and Director of the Breast Health Global Initiative—founded and led by the Fred Hutchinson Cancer Research Center and Susan G. Komen—was referring to patients whose health care providers follow the American Cancer Society's (ACS) breast cancer screening and clinical examination guidelines. ACS recommends annual mammograms for women starting at age 45 and shifting to mammograms every 2 years for women 55 and older. The group does not recommend clinical breast exams as a breast cancer screening tool. Anderson recently told Oncology Times that he is equally concerned about a new “guidance statement” for breast cancer screening by the American College of Physicians (ACP). The ACP's recommendations are based on a review of national and international breast cancer screening guidelines that included breast imaging—mammography, ultrasonography, MRI, or digital breast tomosynthesis—and clinical breast examination in women. Published in the April 16 Annals of Internal Medicine, the statement advises “average-risk women” who have no symptoms of breast cancer to wait until age 50 to get their first breast cancer screening with mammography, and then go every other year after that up until age 74 (2019;170(8):547-560). For women younger than 50, ACP advises that clinicians should discuss their patients' preferences and the potential benefits and harms of breast cancer screening in younger women, including false positives and unnecessary biopsies. “Women screened annually receive more abnormal results that do not represent an actual breast cancer diagnosis than women screened every other year (7.0% vs. 4.8%),” authors wrote. “These false-positive findings result in biopsies and surgeries that would otherwise not have been necessary.” Like ACS, the ACP says clinicians do not need to perform clinical breast examination to screen for breast cancer either. The ACP noted that the recommendations aren't aimed at women who are at a higher risk for breast cancer or those who've had previous abnormal screenings. ACP President and medical oncologist Ana María López, MD, FACP, said in a press statement, “The evidence shows that the best balance of benefits and harms for these women, which represents the great majority of women, is to undergo breast cancer screening with mammography every other year between the ages of 50 and 74.” But Anderson, who is also Professor of Surgery and Global Health Medicine at the University of Washington, noted there are two issues at stake with both the new ACP statement and the ACS guidelines: “One is the question of screening recommendations and the other has to do with clinical management. In particular, the clinical breast examination recommendations are something we need to discuss.” He is concerned that the statement authors only looked at mortality as an endpoint. “When we only look at mortality, we forget about other factors that are equally important to the population, such as breast conservation,” he said. In other words, if early detection efforts in women under 50 picks up cancers at earlier points in their evolution, such that they can be removed before a mastectomy is required, then aren't early detection efforts worth it? If cancers are detected later, such that chemotherapy is going to be required, shouldn't this be considered? Anderson also said removing clinical breast exam from practice is not in the best interest of patients or their physicians and will hinder clinicians from developing the skill set they need to palpate and identify a potential cancer tumor when a patient does present with a suspicious lump. The ACP is “forgetting that their role isn't just about screening, but that it's also about clinical practice,” he said. “I think their recommendation to not do a clinical exam on the basis that they don't feel they have enough evidence to support it is inconsistent with other recommendations for clinical practice. We have never done a randomized trial of using a stethoscope versus not using a stethoscope based on lives saved [mortality]. But the ACP has never come out saying we want everyone to stop using a stethoscope because we have no randomized trials showing it saves lives,” Anderson said. “In highly screened populations, 60 percent of cancers are found on mammography. This means that the remaining 40 percent of breast cancers are detected clinically. Allowing clinicians to become clinically incompetent in physical examination of the breast is unlikely to help women in early breast cancer diagnosis.” Back to Top | Article Outline A Complicated History “When it comes to mammographic screening in average-risk women in their 30s, I think everyone is in agreement that—due to the low number of positives and because false positives are so high—we don't need to recommend screening until age 40,” said Anderson. But after 40, the screening question gets murky. “Do you start at 40, 45, or 50? There are shades of gray to this issue that make it very tricky. I think ACP wanted to weigh in on this challenging and contentious area of screening,” he noted. Numerous other organizations have published breast cancer screening guidelines and recommendations, including the U.S. Preventive Services Task Force, World Health Organization, Canadian Task Force on Preventive Health Care, American College of Obstetricians and Gynecologists, American College of Radiology, International Agency for Research on Cancer, and American Academy of Family Physicians. “Some groups look at the data and err on the side of detection while other groups say, ‘We're going to err on the side of false positives and patient concerns,’” Anderson explained. An editorial by Joann G. Elmore, MD, MPH, and Christoph I. Lee, MD, MS, in the same issue of Annals noted that the ACP guidance statement brings “clarity and simplicity amidst the chaos of diverging guidelines.” The authors wrote: “These ACP guidance statements represent convergence across differing recommendations while highlighting important points for physicians to consider in shared decision-making conversations with their patients about routine breast cancer screening.” Dana Smetherman, MD, MPH, Chair of the American College of Radiology (ACR) Breast Imaging Commission, told Oncology Times that the ACP guidance statement doesn't align with ACR's recommendations. “The American College of Radiology continues to recommend yearly mammography beginning for women at average risk at age 40,” said Smetherman, adding that her sister developed breast cancer at age 45 and they had no family history of the disease. In April, ACR and the Society of Breast Imaging published a joint statement in response to ACP's paper, saying, “Screening only women ages 50-74 every other year, as now recommended by the American College of Physicians and the U.S. Preventive Services Task Force, may result in up to 10,000 additional, and unnecessary, breast cancer deaths in the United States each year.” Back to Top | Article Outline Defining “Average Risk” Tari King, MD, Chief of Breast Cancer Surgery at Dana-Farber/Brigham and Women's Cancer Center in Boston, and founder of the Breast Cancer Personalized Risk Assessment, Education and Prevention (B-PREP) Program, noted, “While guidelines like this are helpful in assimilating available data and highlighting strengths and weaknesses of the available data, the challenge of these statements is that they use words like ‘average-risk women’ and assume women and PCPs understand what ‘average risk’ means. But that's a really hard term to define.” King said “high risk,” according to the Annals article, means a genetic mutation, but the paper does not take into account that there are many other factors involved in determining a woman's “own risk,” such as reproductive health and history, diet, exercise, and weight changes throughout a lifetime. “There are some well-done risk assessments from a population standpoint, but not for individuals, so one-size-fits-all screening guidelines may not be realistic,” she stated. The ACP guidelines won't shift practice at some medical centers. Lauren Cassell, MD, Chief of Breast Surgery at Lenox Hill Hospital in New York City, shared her thoughts. “This gets me so angry, these new guidelines. We see many women in their 40s who have been diagnosed with breast cancer. Why are we going back to the '70s? At my institution, nothing's going to change.” When it comes to breast cancer screening guidelines, she said, “Sometimes they're looking at cost and not at how many lives we are actually saving. And I don't think everything can be put into cost and looked at through the bottom line. I think they're ignoring the fact that, by taking two steps back, you won't see the effect until it's probably too late.” Cassell believes the bottom line is that some patients' cancers won't be discovered early if screening begins at 50. “Truthfully, most breast cancers occur after the age of 50, but that doesn't mean there aren't breast cancers in women in their 40s.” Mary Brophy Marcus is a contributing writer. |
Overtreatment of DCIS: New Meta-Analysis Identifies Prognostic Factors No abstract available
Approximately 1 in 5 new breast cancers is diagnosed as ductal carcinoma in situ (DCIS), an early-stage cancer that is highly treatable. The number of cases of DCIS diagnosed in 2019 is estimated to be 62,930, while the number of new cases of invasive breast cancer is expected to be 268,600 (CA Cancer J Clin 2019;69:7-34). Without clear criteria to predict which women with DCIS will develop invasive breast cancer, it is common for patients with DCIS to receive aggressive treatment. More and more evidence is showing that this may not be appropriate.
“Since most DCIS lesions will never make it to breast cancer, it is urgent that we find out how to distinguish harmless from hazardous DCIS to spare many women the burden of needless treatment,” said Jelle Wesseling, MD, PhD, Professor of Breast Pathology in the Divisions of Oncology and Molecular Pathology at the Netherlands Cancer Institute and Leiden University Medical Center.
Wesseling and colleagues recently published a systemic review and meta-analysis summarizing current knowledge and prognostic factors for invasive disease after a diagnosis of DCIS. It identified six factors that may predict invasive breast cancer recurrence after DCIS (Cancer Epidemiol Biomarkers Prev 2019;28(5)835-845).
Study Background & Design
The natural course of DCIS is not well understood, Wesseling said, mainly because most women with it are treated with mastectomy or lumpectomy that is often complemented by radiotherapy. In addition, hormonal treatment is prescribed for a substantial number of women with DCIS.
“Current guidelines dictate surgical excision of DCIS, yet the majority of cases do not progress nor become life-threatening if left untreated. As a result, many women are overtreated,” Wesseling noted. Through the systemic review and meta-analysis, Wesseling and colleagues sought to examine past data in order to identify prognostic factors that may direct treatment.
The researchers performed a systematic search in Pubmed and identified 1,781 studies that had examined DCIS and the risk of invasive breast cancer recurrence. Forty met the team's inclusion criteria, reflecting the small number of studies that specifically focused on invasive breast cancer recurrence after DCIS. Many studies did not specify recurrence type (in situ or invasive) and were excluded.
The sample size of studies included in the analysis ranged from 52 to 37,692 patients. The mean follow-up time ranged from 3.2 to 15.8 years. Seven studies included patients with DCIS who also had an adjacent invasive component or microinvasion, and seven other studies excluded such patients. Fourteen studies included patients representing all types of treatment modalities (breast-conserving surgery [BCS] alone, BCS + radiotherapy [RT] or hormonal therapy, mastectomy), while 16 other studies included only patients treated with BCS with or without RT. Ten studies included patients who underwent one treatment modality only: BCS with RT or BCS alone.
The data reported by all studies were collected retrospectively and represented patients diagnosed between 1960 and 2010. The studies were published between 1998 and 2018. Hospital registries, national registries, and data from clinical trials were used. Both cohort (80%) and case-control designs (20%) were used. Seventy percent were multicenter studies, and 30 percent involved only a single center.
To assess bias, the researchers used six Quality of Prognosis Studies (QUIPS) domains: study participation, study attrition, endpoint definition, prognostic factor measurement, confounding measurement and handling, and statistical analysis and reporting. In 39 of the 40 studies, they identified a high or moderate risk of bias in at least one domain. Twenty-two studies had a high risk of bias in at least one domain. The domains with the highest risk of bias were study participation and confounding measurement and handling.
Findings: 6 Prognostic Factors
Wesseling and colleagues performed meta-analyses on all data to estimate the average effect of the prognostic factors reported by more than one study, regardless of statistical significance. Most of the factors pointed to a higher relative risk of subsequent invasive breast cancer for patients with DCIS, but the effects were generally small. Six prognostic factors had a statistically significant pooled estimate:
The association between these six prognostic factors and subsequent risk for invasive breast cancer can be biologically explained, the researchers wrote. “When DCIS has involved margins, this indicates that residual tumor cells are left behind at the resection site. These cells can subsequently grow out and form a recurrence, which could be invasive disease. Premenopausal status and African-American race are known independent predictors of worse breast cancer outcome.
“The literature has shown that DCIS detected by palpation would be more aggressive than screening-detected DCIS, as these DCIS lesions are more often ER-negative and HER2-positive. The same holds true for DCIS lesions of high histologic grade. Lastly, p16 mediates cell cycle arrest through the p16/Rb signaling pathway. Disruption of the p16/Rb signaling pathway is an oncogenic event and results in sustained cellular proliferation, which can lead to DCIS progression to invasive breast cancer.”
Wesseling told Oncology Times that the findings of the meta-analyses were at once expected and unexpected. “It was already known to us that many different prognostic factors have been described ... but the findings demonstrated a lack of robust data on validated prognostic factors,” he said, adding that his team is the first to perform bias assessment on prognostic factor studies for DCIS.
“There is a high frequency of biases in previous studies,” he continued. “Some biases are inevitable, as it can be difficult to set up fully annotated cohorts. But other biases can be prevented easily. By mapping these, we aimed to increase awareness among researchers to help the community avoid these biases as much as possible.”
The Future
Wesseling recommends several next steps:
These steps have been incorporated into an international effort, spearheaded by Wesseling, that seeks to prevent unnecessary breast cancer treatment. The project, titled PRECISION (PREvent ductal Carcinoma In Situ Invasive Overtreatment Now) is funded by Cancer Research UK and the KWF Dutch Cancer Society. Experts from the U.S., U.K., the Netherlands, and other countries are involved. Learn more at the following websites: https://www.dcisprecision.org/and https://www.cancerresearchuk.org/funding-for-researchers/how-we-deliver-research/grand-challenge-award/funded-teams-wesseling.
The goal of this research is to reduce overtreatment of DCIS. “I hope that oncologists will support all the efforts to learn how to distinguish harmless from hazardous DCIS,” Wesseling stated. “Together, we can save thousands of women from needless and burdensome treatment every year.”
Michelle Perron is a contributing writer.
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Circulating Tumor DNA in Liquid Biopsies for Classical Hodgkin Lymphoma No abstract availableThe use of circulating tumor DNA (ctDNA) to perform liquid biopsies has been employed previously for a number of solid tumor-bearing malignancies, such as breast, colorectal, and lung cancer. In addition to malignancies with solid tumors, ctDNA analyses have also been performed for a number of hematologic malignancies, including multiple myeloma, diffuse large B-cell lymphoma, and most recently, classical Hodgkin lymphoma (cHL). In a recent publication, research was presented by Davide Rossi, MD, Deputy Head of the Division of Hematology, Oncology Institute of Southern Switzerland, Bellinzona, and colleagues concerning the use of ctDNA obtained from 112 cHL patients (Blood 2018;131:2413-2425). “Longitudinal ctDNA profiling identified treatment-dependent clonal evolution patterns in patients that experienced relapse after chemotherapy and patients maintained in partial remission under immunotherapy. By measuring ctDNA changes during therapy, we propose ctDNA as a radiation-free means of tracking residual disease that may integrate positron emission tomography (PET) imaging for the early identification of patients with chemorefractory cHL,” Rossi noted. Back to Top | Article Outline Advantages of ctDNA Liquid Biopsy The attractiveness of liquid biopsy techniques is a result of their simple, expedient, non-invasive, and cost-effective means of monitoring the patient's disease status or therapeutic response. Liquid biopsy techniques offer several distinct advantages to more conventional tissue sampling. First, liquid biopsy sampling is much less invasive and burdensome than a tissue biopsy, since bodily fluids such as blood, saliva, or urine are much more readily accessible. For many malignancies, taking a tissue biopsy is not clinically feasible, e.g., due to risks for hemorrhage, neurological injury, or further disease metastasis. In addition, tissue biopsies may not adequately reflect the complex genetic makeup of a primary or secondary tumor because of intra- and inter-tumoral heterogeneities. The only way to potentially address this issue with tissue biopsies is by sampling from multiple distinct tumor sites. In contrast, liquid biopsies, which contain DNA shed from tumor sites all over the body, may offer a more thorough cross-section of genetically heterogeneous diseases. In addition, liquid biopsies may also provide genetic evidence of the underlying molecular mechanisms for different primary or secondary tumors, which may be significantly different in the same patient. Since sampling for liquid biopsies often only consists of a blood draw, which can often be combined with blood sampling for other routine analyses, this permits serial sampling of a patient at different stages throughout the treatment cycle. This longitudinal sampling permits surveillance of the disease's clonal evolution, an important benefit for the technique, as tumor cells have a genome that is often highly unstable and vulnerable to selective pressures such as therapy. In general, the liquid biopsy technique is quite complementary with the current approach of individualized treatment, providing a means for identifying ideal candidates for novel targeted therapies while permitting noninvasive disease assessment with important genomic information. When asked to elaborate on why liquid biopsy techniques might be of special relevance to cHL patients, Rossi stated, “The rarity of Hodgkin and Reed-Sternberg tumor cells in cHL lymph nodes, which are usually present at less than 5 percent, and the routine formalin-fixed paraffin-embedded preservation of tissue biopsies imposed major technical limitations upon the identification of cHL genetic features by sequencing of tissue-derived DNA. “Consistently, for other lymphomas as common as cHL, dozen to hundreds of genomes are available. However, for cHL, only 44 cases have been genomically sequenced after cumbersome single cell separation of Hodgkin and Reed-Sternberg tumor cells. Our study establishes ctDNA as a viable source of tumor DNA for cHL mutational profiling. By overcoming the major technical hurdles that have so far limited cHL genotyping, our technical approach, based on ctDNA, has allowed large scale assessment of mutations in different clinical phases of the disease ranging from newly diagnosed to refractory disease, and longitudinally during disease treatment,” Rossi stated. In noting the useful genetic information garnered in their study, Rossi commented, “First, STAT6 was identified as the most frequently mutated gene in cHL, present in approximately 40 percent of our patients, which is in keeping with the known importance of cytokine signaling in the biology of this tumor. It is of interest to note that this fact was not reported in previous exome sequencing studies of cHL cases.” “Second, a few major pathways emerged as recurrently mutated, including NF-κB, PI3K-AKT, cytokine and NOTCH signaling, as well as immune evasion,” Rossi stated. “Of note, these pathways have been previously identified by gene expression profiling and functional genomic studies of cHL, indicating that mutations act as red flags highlighting cellular programs that are relevant for the biology of the disease, and thus potential therapeutic targets.” “The gold standard for lymphoma diagnosis is, and must be, the morphologic, immunophenotyping and molecular analysis performed on tissue samples,” he said. “Though ctDNA cannot substitute tissue biopsy for diagnostic purposes, some advantages of the non-invasive liquid biopsy have been highlighted in recent years. Beyond decreasing procedure-related risks, including hemorrhage, infections, anesthetic risks for an open biopsy, ctDNA can serve an alternative source for tumor DNA for genotyping purposes when the presence of lymphoma cells is insufficient in the tissue sample, as is the case in the cHL subtype.” In the current ctDNA cHL study, a cohort of 24 advanced cHL patients were serially sampled during their treatment with ABVD (adriamycin, bleomycin, vinblastine, dacarbazine). “Those patients that attained a complete response and cure had a larger drop in ctDNA load after 2 courses of ABVD relative to those patients that underwent a relapse. Moreover, the magnitude of the drop was maintained until the end of the therapy, Rossi noted. “A 2-log drop (i.e., 100-fold decrease) in ctDNA after 2 chemotherapy courses, a threshold value which was proposed and validated in diffuse large B-cell lymphoma (J Clin Oncol 2016;34:7511), was confirmed as the best cutoff to predict progression in our cohort and was associated with complete response and cure,” he explained. However, a less than 2-log drop in ctDNA after 2 courses of ABVD had an association with progression and inferior survival. The quantification of ctDNA was complementary to interim PET/CT in assessing residual disease. “Indeed, cured patients who were inconsistently judged as interim PET/CT-positive had a more than 2-log drop in ctDNA, whereas those patients who were inconsistently judged as interim PET/CT-negative had a less than 2-log drop in ctDNA,” Rossi stated. “The lack of correlation between log fold change of maximum standardized uptake value in PET/CT and log fold change of ctDNA between baseline and interim evaluations is consistent with the notion that the maximum standardized uptake value largely reflects the metabolic activity of the inflammatory component of the mass in cHL, whereas ctDNA reflects the tumor load levels.” Back to Top | Article Outline Implications for Treatment Options “PET/CT imaging is the most sensitive tool for residual disease identification in cHL at the clinical grade,” Rossi stated. “Interim PET/CT, which is performed after 2 cycles of treatment, has been tested to preliminarily identify residual disease in chemorefractory patients, as they are prime candidates for treatment intensification in order to maximize the chances of their cure. “In addition, this technique can also identify at an early stage those patients who are already cured, as they are candidates for treatment de-escalation to avoid both short- and long-term complications of chemo-radiotherapy. The ideal analytical tool to be used for such response-adapted therapy needs to be reliable and provide results that carry a strong correlation with the final treatment outcome. Unfortunately, interim PET/CT results are inconsistent with the final patient outcomes, primarily because of false-positive findings which occur in roughly 20-30 percent of patients, who are thus overexposed to their therapy.” “By substituting an invasive tissue biopsy, which is the gold standard for identifying false-positive PET/CT results, the liquid biopsy proved to be a novel precision biomarker for confirming or excluding the presence of residual disease in the case of positive PET/CT findings in various lymphoma types, including cHL. “Quantification of ctDNA, when coupled with PET/CT, improves the accuracy of residual disease assessment at the interim time (i.e., after 2 treatment cycles) compared to PET/CT alone in cHL patients,” Rossi further elaborated. When asked about future directions for research of ctDNA techniques in cHL, Rossi answered, “In order to translate ctDNA monitoring as a routine response assessment tool for cHL, this methodology should be incorporated into cHL-based clinical trials. Doing so would first allow us to precisely assess the accuracy with which ctDNA can anticipate disease course; second, this would also serve as a test to verify if ctDNA can provide predictive and prognostic information for guiding treatment decisions.” Richard Simoneaux is a contributing writer. Back to Top | Article Outline The Value & Future of ctDNA in Non-Hodgkin Lymphoma In a recent interview with Oncology Times, Kieron Dunleavy, MD, Professor of Medicine and Director of the Lymphoma Program at George Washington (GW) University and GW Cancer Center, discussed the use of ctDNA in non-Hodgkin lymphoma (NHL). What are examples of NHLs where ctDNA liquid biopsy has been applied for patient testing? These techniques have been applied for patients with a number of different B-cell lymphomas. In particular, a number of studies have evaluated the use of ctDNA in diffuse large B-cell lymphoma (DLBCL) patients; some studies have also been performed in patients with other lymphomas such as mantle cell lymphoma (MCL) and follicular lymphoma (FL). However, these liquid biopsy methods have not been validated in prospective studies. In a NCI study including 126 DLBCL patients, among the 107 that attained complete remission, those that subsequently showed the presence of ctDNA were more than 200-fold more likely to undergo disease progression than those who did not (Lancet Oncol 2015;16:541-549). Another smaller study utilized ctDNA for 26 patients with MCL, a rare B-cell lymphoma. In that study, lower pre-treatment ctDNA levels were shown to correlate with normalized granulocyte-macrophage colony-stimulating factor response to idiotype vaccine and may be a surrogate marker of ongoing host anti-tumor immunity. Moreover, ctDNA levels did not correlate with traditional tumor proliferation markers. There was also a trend towards improved OS in those achieving minimal residual disease-zero (Blood 2016;128:2943). In another study, ctDNA analyses were utilized to identify genetic predictors of response in DLBCL and FL patients being treated with the selective EZH2 inhibitor tazometostat (Blood 2017;130:4013). What is the benefit for using this technology? One clear area of immediate impact would be the monitoring of patients therapy during treatment to assess how they are responding. Currently, the major means of determining treatment success are PET/CT studies using fludeoxyglucose (18F) FDG as an imager. While the negative predictive value for FDG-PET is good, there are a fair percentage of false positives that can arise; that is, patients who are cancer-free may actually appear to be tumor-bearing. The use of ctDNA might help sort these instances out. In addition, this modality exposes the patient to radiation for monitoring. What are some advantages to applying ctDNA methods to patients with NHLs? The fact that sampling is non-invasive permits easy longitudinal sampling, which could enable following the genomic evolution of a patient's disease over time. Additionally, this access could yield new mutations (e.g., BCl-2, BCL6) for which targeted therapies can be applied. A research group at Stanford University is using CAPP-Seq (CAncer Personalized Profiling by deep Sequencing) methodologies to do just that. Also, as was previously mentioned, genetic predictors of response were identified in DLBCL and FL patients taking tazometostat. What do you see as future research for ctDNA in NHLs? I think we will see prospective studies utilizing ctDNA in interim assessments. Also, another logical topic would be the assessment of ctDNA levels for prognostic and predictive value at the end of therapy and at follow-up or following induction therapy for MCL. All of these studies will take years to complete. |
Δευτέρα 8 Ιουλίου 2019
Oncology Times
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