publication date: Nov. 6, 2020

Clinical Roundup

Cancer patients, clinicians find value in electronic real-time symptom reporting

Cancer patients and their medical teams found it beneficial when patients shared their symptoms in real time using a web- or telephone-based reporting system, according to a national multi-institutional study, the PRO-TECT trial.

The PRO-TECT trial is evaluating the use of electronic patient-reported outcomes among adults receiving outpatient treatment for advanced and metastatic cancers. The study was published in JCO Clinical Cancer Informatics.

“Our prior research showed that using a web-based system for patients to self-report symptoms to their cancer care team improves patient satisfaction, quality of life, physical function, reduces emergency room visits and lengthens survival,” Ethan Basch, director of UNC Lineberger’s Cancer Outcomes Research Program and the Richard M. Goldberg Distinguished Professor and chief of oncology at the UNC School of Medicine, said in a statement. “However, it has not been clear whether this approach could be widely used in cancer practices across the U.S. or be seen as useful or valuable by patients and providers. It is essential with any strategy for improving care to make sure that people will actually use it and find it valuable.”

In the new study, the researchers conducted a cluster-randomized controlled study at 52 community-based oncology practices across the United States. Half of the practices were assigned to use ePROs as part of the standard of care.

Participants in the study’s intervention arm were prompted every week for a year to report their symptoms and well-being. This involved using a website or an automated telephone program to answer a series of questions about their symptoms, such as pain, nausea and depression, as well as their physical functioning and financial health.

The responses had a pre-assigned value on a five-point scale. When a patient reported worsening or severe symptoms, they were sent an email with information on symptom management and a nurse was alerted in real-time to intervene.

To measure whether the ePRO process and information gathered provided value, as well as to identify challenges, the researchers surveyed the patients and clinicians. Patients provided feedback three months after they started on the study and when they completed it. Nurses and physicians shared their assessment on clinical usefulness after they had worked with the system for six months or more.

The majority of the 496 patients surveyed found the PRO-TECT digital ePRO system was easy to understand (95%) and use (93%), and the questions were relevant to their care (91%). Most of the 57 nurses responded that the information was helpful for clinical documentation (79%) and useful for patient care (75%). Of the 39 oncologists surveyed, most found ePRO information useful (91%).

Though clinicians said the ePRO system was useful overall, some reported the information collected had limited value. Sixteen percent of the nurses surveyed said it rarely or never improved discussions with patients, and 14% said it didn’t improve care quality. Nearly 30% of physicians said they rarely used patient-reported information to shape their discussions with patients. Also, some nurses felt they received too many symptom alerts, yet 93% wanted to receive future alerts for severe symptoms.

“There is clearly a lot of enthusiasm from patients to connect to their care team through electronic real-time approaches, and providers also recognize this value, but we know it isn’t perfect,” Basch said. “Our findings lay a path forward for determining the best ways to integrate patient-reported outcomes in oncology practice.”

Basch said a number of issues need to be addressed to encourage clinics and hospitals to consider using ePRO systems. The technology must be easy for patients and providers to use. Workflows may need to be modified to give nurses more time to respond to symptom alerts.

Basch said it would be helpful to develop standardized ways to teach patients how to use the system and to remind them of the importance of using it. In addition, it is important to continuously monitor and troubleshoot a program while it is being implemented.

“Patient reported outcomes are well accepted and seen as valuable for quality care by patients and providers, and they improve patient engagement and experience,” Basch said. “Models for health systems to successfully implement PRO programs are needed, likely based on quality improvement approaches. For wide implementation to be effective, a financial model will also be helpful for PROs, most likely through direct reimbursement from insurance companies, or as a key component of value-based alternative payment arrangements between health systems and insurance payers.”


Colon cancer surgery performed by highly skilled surgeons improves long-term survival for patients

Researchers found that colon cancer patients achieve better five-year survival rates when the surgeons who treat them are rated as highly skilled.

The study is published online in JAMA Oncology and was virtually presented as part of the American College of Surgeons Commission on Cancer’s Annual Research Paper Competition.

“In the last few years, studies have shown that patients of more highly skilled surgeons have fewer immediate postoperative complications. This study moves to the next level and shows that patients of more highly skilled surgeons not only have fewer complications in the short term, they survive longer,” lead author Brian C. Brajcich, a clinical scholar with the American College of Surgeons, research fellow at Northwestern University School of Medicine, said in a statement.

The study was conducted by the Illinois Surgical Quality Improvement Collaborative, a group of 56 hospitals that perform 80% of the complex surgical operations across the state. The ISQIC is a collaborative partner with the American College of Surgeons National Surgical Quality Improvement Program.

“A previous study done by our group found that lapses in surgical technique can result in a complication within a few days of surgery. This study is striking because no one has looked directly at the relationship between surgical skill and improved survival at the five-year mark, and, yes, surgeons with better skill achieve considerably better survival rates for their patients,” Karl Y. Bilimoria, director of the Surgical Outcomes and Quality Improvement Center at Northwestern Medicine, and an ACS Faculty Scholar, said in a statement.

The type of surgery for colon cancer depends on the extent and location of the cancer and the goal of treatment. During a laparoscopic colectomy, for example, the surgeon removes the cancerous area of the colon, a small segment of normal colon on either side, and nearby lymph nodes.

Study investigators recruited surgeons from the ISQIC in 2016 to participate in a video-based technical skills assessment program. Each surgeon was videotaped while performing a minimally invasive right hemicolectomy (partial surgical removal of the colon). Videos were reviewed by 12 or more surgeons, including two colorectal surgeons experienced in evaluating surgical video tapes.

Each reviewer assigned a skill score to the video he or she reviewed. Skill scores were derived from the American Society of Colon and Rectal Surgeons Video Assessment Tool, which assesses factors such as gentleness of tissue manipulation, efficient and methodical performance of the procedure, and extent of surgical excision. Skill levels for the surgeons in the study reflected the mean skill score from all reviewers.

The study included 609 patients who underwent laparoscopic colectomy by one of the participating surgeons between 2012 and 2017. Five surgeons who achieved the highest technical skill scores also had the highest volume of procedures in the study, as well as the highest average annual number of surgical cases; the totals were more than two times higher than the number of procedures performed by other surgeons. Overall, five-year survival for these surgeons was 79%. Five-year survival rates were 55% for medium-skilled surgeons and 60% for low-skilled surgeons.

“This study demonstrates that surgical technical skill is an important driver of long-term outcomes in cancer surgery. When talking about ways to improve outcomes for patients, we surgeons should not only think about quality measures but ways to improve surgeons’ skills through some form of surgical coaching,” Brajcich said.

The Northwestern Medicine health system is bringing surgeons together in the Technical Excellence Collaborative to review one another’s work, find opportunities for improvement in technique, and follow patients to track their outcomes, Bilimoria said.

“High surgical volumes have been shown to result in lower morbidity and improved outcomes for many types of surgery and this study shows that technical skill also results in improved survival for patients with colon cancer,” Kelly K. Hunt, professor and chair of the Department of Breast Surgical Oncology at MD Anderson Cancer Center, said in a statement.

“The ACS Cancer Research Program has also shown that adherence to the critical elements of an operation [operative standards] also results in improved outcomes and quality of life for cancer patients,” said Hunt, who is also vice-chair of the Cancer Surgery Program.  Therefore, the Cancer Surgery Standards Program was formed to develop synoptic operative reporting templates, electronic documentation tools, and educational content around these operative standards. Ultimately, the program seeks to facilitate adoption and utilization of synoptic operative reporting tools for improved outcomes in all major cancer operations.”

Other study authors include Jonah J. Stulberg, MD, PhD, MPH; Bryan E. Palis, MA; Jeanette W. Chung, PhD; Reiping Huang, PhD; and Heidi Nelson, MD, FACS.


Active surveillance is safe for African Americans with low-risk prostate cancer

Researchers found that active surveillance is safe for African Americans with low-risk prostate cancer.

In the study, published Nov. 3 in JAMA, researchers hypothesized that African American men undergoing active surveillance are at a significantly higher risk of disease progression, metastases and death from prostate cancer compared to non-Hispanic white men.

Results demonstrate that that 59.9% of African American men experienced disease progression compared to 48.3% of white men. In addition, 54.8% of African Americans required treatment, compared to 41.4% of white men.

However, African American men and white men experience comparable rates of metastasis (1.5% vs 1.4%) and prostate cancer-specific death (1.1% vs 1.0%).

“Our research provides evidence that active surveillance is safe for African American men,” senior author Brent Rose, assistant professor in the Department of Radiation Medicine and Applied Sciences at University of California San Diego School of Medicine, said in a statement. “This means more African American men can avoid definitive treatment and the associated side effects of urinary incontinence, erectile dysfunction and bowel problems.”

The retrospective study looked at outcomes for 2,280 African American men and 6,446 non-Hispanic white men with low-risk prostate cancer who underwent active surveillance under the VA health care. The database included access to the health care records of 9 million veterans between 2000 and 2020 who received care at 1,255 health care facilities in the United States.

Previous studies have shown that African American men are 2.4 times as likely to die from prostate cancer compared to non-Hispanic white men. This, plus a concern that African Americans may develop cancers that are more aggressive, has led to fewer Black men being offered active surveillance as a treatment strategy.

One in nine men will receive a prostate cancer diagnosis in their lifetime. Prostate cancer is more likely to develop in older men and in African American men. While the average age for diagnosis is 66, the number of younger men diagnosed with this disease is increasing.

Active surveillance is the preferred treatment option for many men with low-risk prostate cancer in order to avoid or delay the side effects of definitive treatments.

“Physicians and patients should discuss active surveillance for African American men with low-risk prostate cancer,” said Rose, a radiation oncologist at Moores Cancer Center at UC San Diego Health and senior author on the paper. “Overall outcomes are similar among African American men and white men. However, due to the increased risk of progression, African American men need to be carefully followed and promptly treated if their cancer progresses.”

Co-authors are: Rishi Deka, Patrick T. Courtney, J. Kellogg Parsons, Tyler J. Nelson, Vinit Nalawade, Elaine Luterstein, Daniel R. Cherry, Daniel R. Simpson, Arno J. Mundt, James D. Murphy, Christopher J. Kane, Maria E. Martinez, all of UC San Diego; and Anthony V. D’Amico, of Harvard Medical School and Dana-Farber Cancer Institute.

This research was funded, in part, by NIH (TL1-TR001443) and the Department of Defense (W81XWH-17-PCRP-PRA).


Nerves keep pancreatic cancer cells from starving, study finds

Researchers found that pancreatic cancer cells avert starvation by signaling to nerves, which grow deeply into dense tumors and secrete nutrients.

The study, based on experiments in cancer cells, mice, and human tissue samples, was published Nov. 2 in Cell.

The study addresses pancreatic ductal adenocarcinoma, the deadliest cancer of the pancreas with a five-year survival rate below 10%. Such tumors encourage the growth of dense tissue that presses on blood vessels, reducing the supply of blood-borne nutrients like serine. This amino acid is used as a building block for proteins, and is required for cancer cells to multiply. 

Led by researchers from NYU Grossman School of Medicine, the Department of Radiation Oncology at NYU Langone Health, and Perlmutter Cancer Center, the study found that starving pancreatic cancer cells secrete a protein called nerve growth factor, which sends signals to extensions of nerve cells, instructing them to grow deeply into tumors.

The researchers found further that such extensions, called axons, secrete serine, which rescues pancreatic cancer cells from starvation and restores their growth.   

“Our study offers more proof that pancreatic cancers are remarkable metabolic scavengers, which contributes to their deadliness,” corresponding author Alec Kimmelman,the Anita Steckler and Joseph Steckler Chair of the Department of Radiation Oncology at NYU Langone, said in a statement. “The ability of nerves to funnel nutrients from the bloodstream to the more austere pancreatic tumor microenvironment is a fascinating adaptation, and could lead to therapeutic approaches that interfere with this unique flexibility.”

The study found that pancreatic cancer cells starved of serine take advantage of the process by which messenger RNA strands are translated into proteins. Bases of mRNA molecular strands are decoded into amino acids using three-base units called codons.

Ribosomes read each codon as they link amino acids together in the right order, but ribosomes stall if there is a lack of available amino acids.

The researchers found that serine-starved pancreatic cancer cells more significantly slow the rate at which two of the six serine codons (TCC and TCT), but not all six as assumed, are translated into amino acid chains.

Under serine-starved situations, this variability lets cancer cells minimize the production of certain proteins, but continue to build stress-adaptive proteins like nerve growth factor, which happens to be encoded by few TCC and TCT codons.

NGF and other factors are known to encourage nerves to grow into pancreatic tumors, and to increase tumor growth as well. The study is the first to show that axons, extensions of neuronal cells that transmit their signals, provide metabolic support to cancer cells by secreting serine in nutrient-deprived areas.

In a glimpse of potential future applications for the study, mice with PDAC tumors fed serine-free diets saw 50% slower tumor growth. To go beyond what diet alone could achieve, the researchers also blocked the recruitment of axons into PDAC tumors using FDA-approved LOXO-101. The drug blocks the activation of a receptor protein on the surface of neurons that interacts with nerve growth factor (also called TRK-A), thereby inhibiting the ability of neurons to send their axons into tumors.

LOXO-101 alone did not slow PDAC tumor growth in mice, but slowed it by an additional 50% when combined with a serine-free diet, compared with the diet alone. This suggests that nerves were necessary to support PDAC cell growth in serine-deprived tumor regions.

“As TRK inhibitors are approved in the treatment of some cancers, they might have value in combination with a low serine diet following surgery in the perhaps 40% of patients with PDAC tumors that can’t make serine,” lead study author Robert Banh, a post-doctoral scholar in Kimmelman’s lab, said in a statement. “Whether this approach could decrease tumor recurrence by limiting the nutrient supply would need to be confirmed in clinical trials.”


Large-scale cancer proteomics study profiles protein changes in response to drug treatments

Through large-scale profiling of protein changes in response to drug treatments in cancer cell lines, researchers at MD Anderson Cancer Center have generated a resource to aid in predicting drug sensitivity, to understand therapeutic resistance mechanisms and to identify optimal combination treatment strategies.

Their findings, published in Cancer Cell, include expression changes in more than 200 clinically relevant proteins across more than 300 cell lines after treatment with 168 different compounds, making it the largest dataset available on protein responses to drug treatments in cancer cell lines.

“We’ve seen a number of perturbation studies that look at gene expression changes following drug treatments or CRISPR-mediated changes, but there is a significant gap in terms of proteomic profiling,” senior author Han Liang, professor of bioinformatics and computational biology, said in a statement. “We hoped to fill that gap by profiling changes in major therapeutic target proteins, which provides a lot of insight in terms of drug resistance and designing drug combinations.”

Perturbation biology measures how a system, such as cancer cells, responds to various stimuli. These types of experiments have proven useful in modeling cancer behaviors and understanding responses at a system level, Liang said. To profile protein perturbations, the researchers used a technique called reverse-phase protein array (RPPA), which enables the rapid quantitative analyses of a select group of proteins. Protein levels were measured at baseline and after treatment, often at multiple time points.

The study evaluated drugs targeting a variety of signaling pathways and cellular processes across 319 commonly used, well-characterized cell lines from many cancer types, including breast, ovarian, uterine, skin, prostate and hematologic cancers.

Rather than analyzing all possible drug-cell line combinations, the researchers focused on those most likely to be relevant to the field. In total, they generated RPPA profiles of 15,492 samples, including 11,884 drug-treated samples and 3,608 control samples. The data was highly reproducible and verified by multiple independent pathways.

The data obtained from these analyses provides important insight into the mechanisms of drug response or resistance, highlighting signaling pathways that are activated or suppressed following treatment with a given drug. Further, having data on both baseline and post-treatment protein levels is much more useful in modeling to predict sensitivity to additional drugs, Liang said.

The researchers also constructed a comprehensive map of protein-drug connections to visualize responses and to better study relationships between different proteins and signaling pathways. The maps showcase which proteins have significant changes from a given drug, which drugs yield similar responses and which proteins saw similar patterns of change. Studying these complex relationships can reveal unknown connections and can point to potentially effective therapeutic combinations.

“Through this dataset, one can immediately see the consequences of a given drug, including perturbed pathways and adaptive responses, which can help to identify optimal drug combinations,” Liang said. “As we continue working to expand the data, we think this will be a valuable starting place for researchers doing drug mechanism studies.”

The protein response data is publicly available for researchers in a data portal, which provides various methods for visualizing and downloading the data.

Although the study includes only a subset of cancer types, the researchers hope to continue adding to the dataset in the future. In the long-term, the research team anticipates that proteomic profiling at baseline and following treatment may be a useful tool in clinical trials to better follow patient treatment responses and to optimize therapeutic strategies.

This study was supported by the National Institutes of Health (U01CA168394, U24CA143883, U54HG008100, P50CA098258, P50CA217685, U24CA209851, U01CA217842, P50CA221703, U24CA210950, U24CA210949, R50CA221675, UL1TR003167, and P30CA016672), the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, Susan G. Komen, the Ovarian Cancer Research Foundation, the Breast Cancer Research Foundation, the The Lorraine Dell Bioinformatics for Personalization of Cancer Medicine Program, the Department of Defense (W81XWH-16-1-0237), the Cancer Prevention & Research Institute of Texas (RP170593, RP160015 and RP170640), the Ovarian Cancer Research Alliance, the Fund for Innovation in Cancer Informatics, and NCI’s Office of Cancer Genomics Cancer Target Discovery and Development (CTD2) initiative.

Copyright (c) 2020 The Cancer Letter Inc.