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3 Questions on…

Answers straight from the experts on the latest news and topics in oncology

Thursday, June 20, 2019

​With Amita Sehgal, PhD, Professor of Neuroscience and Director of the Chronobiology Program at Penn Medicine

Previous observational studies have linked chronic disruptions of circadian rhythms to increased risk of certain cancers. Now, a new study published online ahead of print in PLOS Biology has shown how circadian disruption may trigger cell proliferation, and that delivering anti-cancer treatment timed to circadian rhythm may inhibit tumor growth more effectively than untimed treatment (2019;

“We suggest that chronic disruption of the normal circadian rhythm tips the balance between tumor-suppressive and tumor-progressive gene expression to favor tumor growth,” senior study author Amita Sehgal, PhD, Professor of Neuroscience and Director of the Chronobiology Program at Penn Medicine, said in a statement.

Additional research will need to be done to better understand the findings and replicate them in humans. (This study was done in cultured human cells and in mice.) The researchers used a hormone to replicate frequent jet lag in cultured human cancer cell models. This change accelerated cell divisions and proliferation, suggesting that frequent circadian disruptions (like those experienced when people experience frequent jet lag or frequently shift their sleeping patterns) do promote cancer growth.

In the second part of the study, the researchers used mouse models to evaluate how administering anti-cancer therapy timed to circadian rhythm affected cancer growth. The results suggest that the timing of treatment could help improve outcomes, when it comes to stopping that tumor growth.

Again, these findings are early—and much more research will need to be done before such a strategy can be used in patients with cancer. But the research suggests that better understanding the relationship between cancer growth and circadian rhythms is important, according to Sehgal.

“Better understanding the molecular effects of jet lag, shift work, and other sources of chronic disruption may lead to strategies to minimize the increased cancer risk associated with these behaviors, as well as to better treatment strategies, including timing delivery of cancer therapy for maximum benefit,” Sehgal noted.

In an interview with Oncology Times, here's what else the study author said about the research.

1. What led you to conduct this research that looks at the mechanism behind circadian rhythm and tumor growth now?

“With all the progress made in basic mechanisms of circadian rhythms (for instance, the 2017 Nobel prize was awarded for these studies), we have been thinking more and more of how these findings apply to the clinic. It is clear that circadian disruption promotes disease, but mechanistic analysis is limited. So we sought to determine, using initially a cell culture model, how basic cellular physiology is affected by circadian disruption.

“[This research approach] was unbiased because we did not set out to look at the link between circadian disruption and cancer. We asked how circadian disruption affects a whole range of cellular functions and found that the major effect was on cell proliferation, which then led to the relevance to cancer.

“The key findings are: 1) A major consequence of circadian disruption is an increase in proliferation of cancer cells. Importantly, we took an unbiased approach towards this problem, so we assayed a wide range of cellular functions and found that the major change was in proliferation rate. 2) Treatment timed to the host's circadian rhythm is more beneficial, but this benefit is lost if the host's rhythms are disrupted.

“This study actually provides a specific circadian-regulated pathway that mediates the effect on the tumor growth and the effect of the anti-cancer drug.”

2. Why do you suspect that treatment timed to the host's circadian rhythm (what you refer to as “chronotherapy” in the paper) boosts the benefit of that treatment?

“In this case, it's because the pathway targeted is rhythmic, so its activity is different at different times of day. This is also true for several other drug targets. However, chronotherapy may also work because other things in the body are cycling—for instance, your response to a drug may be different when cortisol is high versus when it's low (cortisol also cycles).

“In addition, we showed recently that permeability of drugs into the brain can be different at different times of day, so drugs targeting the central nervous system are subject to this additional level of control.

“Sleep cycles can be off for several reasons (for instance dictated by a person's job) and these may not always affect the internal circadian clock. Melatonin, which cycles over the course of the day, is a good marker for determining a person's circadian timing. New assays have also been developed based on expression of clock genes, but these are in their infancy.”

3. What would you say is most important for practicing oncologists, cancer care providers, and cancer researchers to know about this research and your findings?

“They should be aware of the effects of circadian disruption, and they (and all researchers and health care providers) should take time of day into account.

“[This] organismal work was done in mice. However, we also did experiments with cultured human cancerous cells. The drug we used is used to treat cancer and the pathway it targets is conserved in humans, so there is good reason to believe we'd see similar results in people. We need to convince cancer researchers to factor time of day into trials.”

Wednesday, June 5, 2019

With Kirti Malhotra, MD, of University of California, Davis
By Sarah DiGiulio

Talking about life expectancy and prognosis with patients with advanced cancer and their caregivers is difficult. But communicating accurate prognoses is essential to ensuring patients are choosing clinically appropriate treatments and making the decisions they ultimately want at end of life. New research suggests there's work to be done to accomplish that. A recent study analyzed data from 38 oncologists, 263 patients with advanced nonhematologic cancers, and 193 of those patients' caregivers. When it came to predictions about 2-year survival prognoses, the study found that 62 percent of oncologists had realistic views on those prognoses, compared with 38 percent of patients and 42 percent of caregivers (Cancer 2019; doi:10.1002/cncr.32127). Just 12 percent of oncologists' forecasts turned out to be unduly optimistic, compared with 50 percent of patients' forecasts and 46 percent of caregivers' forecasts.

Study co-author Kirti Malhotra, MD, a third-year internal medicine resident at University of California, Davis, said the good news is that these results suggest oncologists themselves are more realistic than has otherwise been reported in terms of their predictions of optimism towards patients' prognoses. But, she noted there's work to be done in terms of better communicating with patients and their caregivers so expectations are more realistic. Here's what Malhotra told Oncology Times.

1. Why look at these questions about prognostic accuracy now and how are the findings different from what has previously been studied?
“Good communication seems essential, especially now when biotechnology and medical treatments are growing at an ever faster rate. Clinical decisions regarding the appropriateness of disease-directed, life-extending, and comfort-oriented approaches to care in advanced cancer often rely on shared decision-making among the oncologists, patients, and caregivers. We wanted to study the understanding of prognosis by the oncologist, patient, and caregivers to further the efforts at improving end-of-life communication.

“We observed relatively poor prognostic estimation by patients, and a large difference between predictions by oncologists and those of caregivers and patients.

“Our study found that, while oncologists may be less certain, they have good discriminatory ability in their 2-year survival predictions and their predictions are well-calibrated. In contrast, patients and caregivers expressed greater certainty; however, their predictions had inferior discriminatory ability and poor calibration. Moreover, among patients and caregivers, optimistic predictions were common. More research is needed to elucidate the causes of errors in judgments about survival prognosis among patients, caregivers, and oncologists to further improve end-of-life communication.

“Their results agree with findings of prior studies regarding accurate estimation of survival probabilities by physicians. However, unlike our study, several prior studies have shown that when prognosticating about cancer, physicians tend towards optimism. Also, few studies have compared prognostic estimates (by patients, caregivers, and oncologists) with actual survival in patients with advanced cancer.”

2. Is overoptimism on the part of patients and caregivers necessarily problematic?
“Undue prognostic optimism can have short-lived psychological benefits; however, it may be harmful in the long run. When patients overestimate their own prognosis, they may pursue aggressive or invasive treatments that detract from quality of life. Accurate perception of prognosis is essential for patient-centered end-of-life care planning and avoiding unnecessary suffering at the end of life. Our research and prior similar studies highlight the need for patients to understand their prognosis and prepare for the most likely outcome while still maintaining hope.

“Our findings highlight the importance of considering how contemplating the prognosis of a patient differs from predicting one's own prognosis or prognosis of a loved one. Optimistically certain predictions by patients and caregivers could be based more on emotion while the pessimistically certain predictions of oncologists could be based more on reason. Oncologists, as experts, have a greater appreciation for unexpected events affecting survival, so they are less likely to be optimistically certain.

“Prior studies have also noted other potential explanations for the optimistically certain predictions seen among patients and caregivers, including poor understanding and recall of a patient's prognosis, poor patient-oncologist communication, and cognitive rigidity or cultural beliefs that are based on avoiding predictions of death.”

3. What is the bottom line that practice oncologists and cancer care providers should know about this research?
“Our findings imply that oncologists were capable of formulating relatively accurate 2-year survival probabilities, both in an absolute sense and in comparison with patients and caregivers. Our analysis suggests that future efforts to enhance patients' prognostic understanding should focus more on communicating oncologists' estimates rather than recalibrating them.

“While oncologists may be less certain, they have good discriminatory ability in their 2-year survival predictions and their predictions are well-calibrated. In contrast, patients and caregivers express greater certainty. However, they have somewhat inferior discriminatory ability, their predictions are poorly calibrated, and they tend toward over-optimism. More research is needed to elucidate the causes of errors in judgments about survival prognosis among patients, caregivers, and oncologists to further improve end-of-life communication.”

Tuesday, May 21, 2019

With Ralph Salloum, MD, of Cincinnati Children's Hospital Medical Center

By Sarah DiGiulio

New cancer treatments and therapies pose exciting opportunities when it comes to improving care overall. But understanding the side effects, as well as the long-term late effects of those new and improved therapies, takes time.

A new study that analyzed long-term health outcomes in a group of 1,311 survivors of childhood medulloblastoma, who were diagnosed before turning 21, is an example. The data, published online ahead of print in the Journal of Clinical Oncology, follows patients diagnosed from 1970 to 1999 with a median follow-up of 21 years, ranging from 5 to 44 years (2019; The researchers found that, while changes in medulloblastoma treatment over those 3 decades have improved survival rates, the rates of subsequent neoplasms and other severe health conditions have increased in modern survivors.

The researchers noted that survivors of medulloblastoma need to be closely monitored for these debilitating late effects and that more survivorship research and follow-up data are needed to better understand the longer-term effects of the newer modalities of medulloblastoma treatments used.

In an interview with Oncology Times, lead author Ralph Salloum, MD, Program Leader of the Young Adult Neuro-Oncology Program and Director of the Brain Tumor Survivorship Program at Cincinnati Children's Hospital Medical Center, stated: "Because of the inherently shorter follow-up of survivors from the 1990s, most comparisons in this study were limited to 15 years of follow-up. So, one question that remains unanswered is: what happens later as this survivor population ages?"

Salloum explains more about this study and why studying long-term and late effects of cancer treatment even decades later is important.

1. Your research analyzed patient data going back to the 1970s, which seems to speak to the value of tracking patients' outcomes over the long-term (via registries and cohorts). Is your research illustrative of this point?

"High-quality data regarding diagnosis, cancer treatment, and longitudinal follow-up of cancer survivors are essential in survivorship research. In this context, the Childhood Cancer Survivor Study with its expansion to include survivors across 3 decades (1970-1999) not only allowed us to evaluate long-term health outcomes of medulloblastoma survivors, but also offered a unique opportunity to explore the impact of temporal changes in therapy on major late effects among more than 1,000 survivors of medulloblastoma in a period when pivotal changes in treatment were made.

"A previous Childhood Cancer Survivor Study had shown an overall temporal reduction in late mortality attributable to late effects in survivors of childhood malignancies across 3 decades (1970-1979, 1980-1989, 1990-1999). Given that central nervous system tumor survivors are at the highest risk for late morbidity and mortality among pediatric cancer survivors, we aimed to focus this analysis on medulloblastoma survivors specifically in order to better understand these temporal trends and their association with treatment evolution during that era."

2. The data you analyzed revealed some underappreciated risks that patients with medulloblastoma face over the long term. Why is this finding important?

"The evolution of medulloblastoma therapy from the 1970s to the 1990s (to include adjuvant chemotherapy and incorporate risk stratification) aimed to improve survival and minimize the risk for late effects of treatment. The key finding from this study is that, while survival of medulloblastoma has improved across these decades, historical changes in medulloblastoma therapy failed to minimize the risk for late effects.

"In fact, we found that more modern survivors have significantly increased risk for severe and life-threatening chronic health conditions and subsequent neoplasms. Fortunately, special education needs were lower for a subgroup of patients treated with reduced doses of craniospinal radiation.

"Currently, most children with medulloblastoma are cured as a result of the tremendous improvements in therapy that the pediatric oncology field has witnessed over the last 50 years. Unfortunately, we show that this cure comes at the cost of a spectrum of adverse outcomes that are experienced by survivors beyond 5 years from diagnosis.

"These late effects are rarely reported by pediatric cooperative groups and consortia whose primary goals are often cure rates, as they don't have the ability to follow their patients past 5 years from diagnosis. It is therefore our responsibility to report more consistently the delayed sequelae of treatment, including quality-of-life outcomes through studies like the Childhood Cancer Survivor Study. This is particularly important considering the longevity of pediatric cancer survivors and the potential implications that long-term follow-up research can have on frontline clinical trials and treatments."

3. What's the bottom line practicing oncologists and cancer care providers should know about this research—particularly for those treating patients with medulloblastoma?

"Our research shows that medulloblastoma survivors remain at a high risk for late effects of treatment. We therefore need to focus modern therapy efforts on reducing risks for late effects for future generations. For example, this could be accomplished by reducing therapy in patients with favorable molecular and clinical features, introducing otoprotective agents in treatment regimens and using advanced radiation modalities such as proton beam therapy.

"Given that the risk for chronic health conditions from late effects of therapy remains very high even in modern survivors of medulloblastoma, we hope that this study also serves as a siren call to closely monitor these survivors and improve rates of screening and guideline-based follow-up."

Friday, May 3, 2019

With Robert J. Hayashi, MD, of Washington University School of Medicine

By Sarah DiGiulio

Compared to the general population, people who have survived cancer at any point in their lives tend to be at higher risk of certain complications and overall early mortality. A recent study published online ahead of print in Cancer finds that individuals diagnosed with cancer when they were adolescents or young adults (between the ages of 15 and 39)—a population historically less studied than those diagnosed as young children or older adults—were at a significantly higher risk of death from something other than cancer decades after their diagnosis (2019;

The research is significant because it's one of the first studies to investigate this question of mortality risk from non-cancer causes in the adolescent and young adult population, according to the study authors.

In an editorial accompanying the research, Robert J. Hayashi, MD, Professor of Pediatrics in the Division of Pediatric Hematology/Oncology at Washington University School of Medicine, argues that the new data illustrate why more research is needed to better understand the late effect of anti-cancer treatment in this population of survivors, and the particular long-term risks they have (2019;

"To date, there's relatively little published data about the complications that may be unique to this particular [adolescent and young adult] age group," Hayashi told Oncology Times.

The data shows that this population is not only at increased risk of early death, but likely for other long-term side effects because of having cancer. "We should not be presumptuous that the scope of problems that young children experience or the scope of problems that older adults experience are readily transferrable to this age group," Hayashi said. "I think there's something unique about their problems."

Here's what else Hayashi said about what research he thinks is needed in this cancer survivor population, what steps are needed to change outcomes for these individuals, and why he calls this gap in research "a new frontier."

1. What are some of the key questions that future research needs to answer?

"First of all, there would be utility in forming more structured, long-term continuity clinics for this population. So-called 'late effects clinics' have been well-established in pediatrics for many years. They're beginning to take hold in adult oncology. And I think there needs to be a culture for oncologists to both support and transition patients to survivorship clinics where there is expertise on potential complications so that we can start to assemble larger populations that would be readily available for further investigation.

"These clinics serve multiple purposes. They provide a service to the patient in terms of giving them education and in terms of maintaining their own wellness and [managing] their risks for subsequent complications. They also give clinicians insights in terms of potentially the unique features of a population that has been relatively understudied.

"If we're successful at the national level assembling these patients into specialized clinics, I think we'll see insights into what are going to be the most obvious and pertinent questions for this group.

"And then we need to start to develop research groups that specifically focus on this age population. The two kind of go hand-in-hand because you can't really do research unless you have a critical number of patients, and it's difficult to assemble these types of populations [to study] if you don't have some mechanism to assemble them and study them systematically."

2. What are the challenges of pursuing this research and moving the needle to actually answer these types of questions?

"Funding is an issue. I think developing infrastructure and networks of survivorship clinics to assemble these populations [is an issue]. I think there needs to be an assemblage of investigators who have an interest and can commit time to start to network together and develop standardized workflows. I think they're going to be very important because the more fragmented the evaluations of the patients, the more difficult it is to try to discern what is the true prevalence of complications of this population.

"To the extent that clinicians who serve this population can learn from the past experiences from how both pediatric oncologists and some of the adult and older populations are beginning to advance, they can hopefully leapfrog on those experiences and establish the momentum, so they can then move their investigation forward.

"And I think what is going to be very important is that we're not presumptuous about what to expect. There are many features of this population that makes them very unique.

"One of the aspects of labeling this as a new frontier is not just the population, but also the rapidly evolving anticancer therapy that's developing with newer targeted therapies. We have whole classes of agents that literally have not been used long enough to know what the long-term toxicities are. So there's going to be a great need to further investigate that, not just for the adolescent and young adult population, but for all populations."

3. What's the bottom-line takeaway message about this new frontier in adolescent and young adult cancer survivorship care?

"We are obviously moving to an age in which winning the battle of cancer is now becoming a much more realistic and prevalent success story, and we can't lose sight of the fact that our obligations to the patient extend beyond achieving a cure for their primary malignancy. As clinicians who are responsible for administering these therapies, we need to at least facilitate access to care, so that [patients] not only remain cancer-free but that they are able to have a long and also functional life."

Friday, April 19, 2019

With Norman Sharpless, MD, former Director of the NCI

By Sarah DiGiulio

Cancer therapies and cancer care are more advanced today than ever before. And cancer researchers are continuously learning how to grow what we know. But to do that effectively, two thought leaders in cancer research say the clinical trial process that validates new treatments and delivery of care needs a revamp.

Norman Sharpless, MD, and James H. Doroshow, MD, coauthored a Viewpoint editorial that was published earlier this year in JAMA highlighting the different ways they suggest cancer clinical trials need to be modernized (2019;321:447-448). At that time, Sharpless was Director of the NCI; in April, he became acting Commissioner of the FDA. Doroshow is NCI's Director of the Division of Cancer Treatment and Diagnosis.

"The approaches we laid out are designed to reduce the financial pressure of clinical trials, conduct trials that complement those of industry, facilitate access to investigational agents, base trials on molecular alterations, and improve accrual rates," Sharpless told Oncology Times.

"Rethinking clinical trials is also about finding ways to overcome barriers that can get in the way of executing the most efficient trials," he noted. Here's what else Sharpless shared about the potential future of cancer clinical trials.

1. What prompted you and Dr. Doroshow to write this JAMA Viewpoint article now?

"With so many new and promising cancer treatments being developed, the importance of clinical trials to test them has never been more important. The past 10 years, in particular, have seen a transformational reworking of the NCI's clinical trials infrastructure.

"Clinical trials are the fundamental means for making progress in cancer treatment and prevention, but we need a shift in how we think about and design clinical trials to make them work better for researchers, clinicians, and patients.

"These changes must address such challenges as cancer heterogeneity, poor accrual rates, the difficulty patients have in finding trials, unnecessary exclusion criteria, and onerous costs. In short, we need to modernize clinical trials, moving towards smaller, more focused, more rapid trials that can often be deployed in a community setting."

2. The editorial talks about "right-sizing" trials as a way to drive down costs. What does it mean to "right-size" a clinical trial?

"'Right-sizing' clinical trials involves looking at the efficiency of trials, including decreasing the number of patients required to test the treatment under investigation. For example, as we say in the article, with some trials of highly active agents, it may be possible to forgo traditional control group interventions in favor of well-annotated 'synthetic' control arms that are created with data from previous trials.

"NCI is also exploring the use of novel endpoints that reflect the mechanism of action of the drug under study through pragmatic trials that are conducted in clinical practice settings, and through augmented annotation and aggregation of new and existing trials data. Such approaches would make it possible to answer relevant clinical questions without additional enrollment.

"Having said that, I am certain the NCI will need to continue to support large randomized trials of certain types of clinical questions. Such trials are sometimes the only appropriate way to answer certain key questions related to oncologic clinical practice. A recent NCI-sponsored example of such a trial is the TAILORx trial, which evaluated therapeutic de-escalation in women with estrogen receptor-positive breast cancer. The key for the NCI is to figure out the smallest appropriate trial design needed to address the clinical question being addressed."

3. You also talk about improving clinical trial accrual rates. What efforts are currently being made at NCI to do this? What will actually push the needle on changing this issue?

"One of our most promising efforts to improve accrual rates among our underserved populations is the NCI Community Oncology Research Program (NCORP) that brings cancer clinical trials to community settings. NCORP also allows us to reach more minority and underserved persons in the communities where they live. NCORP gives patients access to trials they might not otherwise have access to.

"The program not only increases the generalizability of study findings, but also illuminates potential disparities in outcomes. The NCI-MATCH trial, for example, is available at 1,100 sites across the country through NCI's National Clinical Trials Network and NCORP, leading to enrollment that better reflects the overall patient population.

"Maximizing accrual rates to clinical trials while still ensuring patient safety is a priority for NCI. For more than a decade, NCI has been committed to expanding the eligibility criteria for NCI-funded clinical trials, including decreasing the use of upper age limits in adult trials and making it possible for cancer patients who are also HIV-positive to participate in more trials.

"We've also revised our clinical trial protocol template to ensure participation by certain patients with brain metastasis and patients with altered organ function. The goal is to ensure that the results of clinical trials are broadly generalizable, so that as many patients as possible can benefit from new targeted cancer treatments and immunotherapies."